hospital

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journals.sagepub.com/home/hpx  ISSN: 1545-1569

Volume 57  Number 6  December 2022

Director’s Forum
Review of Medication Error Sources Associated With Inpatient Subcutaneous Insulin: Recommendations 689
for Safe and Cost-Effective Dispensing Practices
Connor McKay, Dan Schenkat, Kristin Murphy, and Elizabeth Hess

FMS
Nasal Glucagon 697
Thomas J. Borden, Terri L. Levien, and Danial E. Baker
Lefamulin 704
Liliya Kozhokar, Terri L. Levien, and Danial E. Baker

Original Articles
Short-Term Readmission Following Community-Acquired Pneumonia: A Cross-Sectional Study 712
Dung Thien Nguyen, Sang Thanh Huynh, and Ho Nhu Nguyen
Opioid Use in Vaso-Occlusive Crisis During Intravenous Opioid Drug Shortage 721
Katherine V. Katsivalis, Jeremy Kosacz, and Jennifer Austin Szwak
Safety and Efficacy Analysis of Apixaban Compared to Heparins in Hospitalized Non-Critically Ill COVID-19 Patients 727
Daniel Appiah, Nicholas J. Quinn, Emily G. Messing, and Keith T. Veltri
Assessment of an In-Sourced Patient Assistance Program at a Health System in West Virginia 734
Calvin Parmiter, David Cecere, Staci Czyzewski, and Michelle Gibson
Heparin Resistance in SARS-CoV-2 Infected Patients with Venous Thromboembolism 737
Terence Chau, Merlyn Joseph, Diana M. Solomon, Bryan Lee, and Lauren A. Igneri
Spontaneous Adverse Event Reporting by COVID-19 Vaccinated Healthcare Professionals Through an 744
Electronic Form Implemented by the Hospital Pharmacy
João Paulo Garcia Lopes da Cruz, Cristina da Conceição Ribeiro de Carvalho, Paula Alexandre da Cruz Silva,
Luis Filipe Campos Guerreiro, Tatiana Vedes Bento, Leila Vanessa Carmo Cardoso Martins Costa,
Raquel Filipa Miguel Margarido Duarte Simões, Rui Pedro Pinheiro Gonçalves Marques, Ana Cristina Castro Fernandes,
Luís Miguel Costa de Mendonça Galaio, Ana Isabel B. Correia, Ema Maria S. Leite Resende, and João Manuel Braz Gonçalves
The Impact of Job Instruction Training Within Pharmacy 752
Faria Munir, Christopher Loucks, and Petal Bartlett
Effect of Paralytic Agents on Post-Intubation Sedation in the Emergency Department 759
Jessica A. Pankey, Scott Christofferson, Ginger Barrick, Brandon A. Knettel, and Christine Knettel

case reports
Omadacycline for a Carbapenem-Resistant Enterobacter cloacae-Associated Wound Infection 767
Dylan C. VanDuyn, Saloni Chadha, Lauren A. Paul, Andrea R. Dressler, Mario V. Beccari, and Rajinder P.S. Bajwa
Mirabegron Associated Angioedema: A Case Report 771
Matthew T. Zuchowski, Jaylan M. Yuksel, and John Novi
Coronavirus Disease 2019-Related Extensive Thrombosis in a Patient Receiving Therapeutic Anticoagulation 774
With Dabigatran
Robert C. Ross, Andrew L. Hendrickson, Miranda P. Boraas, Abbie N. Rosen, and Andrew J. Franck
Calcium and Phosphate Solubility Curve Equation for Determining Precipitation Limits in Compounding 779
Parenteral Nutrition
Collin Anderson, Larry Eggert, Kristie Fitzgerald, Daniel Jackson, and Fred Farr
Carvedilol-Induced Thrombocytopenia: A Case Report 786
Angelina R. Raimonde and Anthony K. Dennis
SAGE
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 Hospital Pharmacy
Editor in Chief
Joyce A. Generali, RPh, MS, FASHP
Clinical Professor, Emeritus

Assistant Editors
Danial E. Baker, PharmD, FASHP, FASCP
Professor of Pharmacy Practice, College of Pharmacy
Michael R. Cohen, RPh, MS, ScD, FASHP
President, Institute for Safe Medication Practices

Consulting Editor
Dennis J. Cada, PharmD, FASHP, FASCP
Executive Editor, The Formulary

Editor Emeritus
Neil M. Davis, MS, PharmD, FASHP
President, Safe Medication Practices Consulting, Inc.

Editorial Advisory Board

Yousef Alomi, BSC, MS, BCPS, BCNSP, DIBA, CDE
Head, National Clinical Pharmacy and Pharmacy Practice Programs
Debra S. Devereaux, MBA, FASHP
Vice President, Pharmacy
Kate Farthing, PharmD, BCPS, FASHP
Pharmacy Clinical Coordinator, Legacy Salmon Creek Medical Center
Harold Godwin, MS, RPh, FASHP
Kansas University Medical Center
Terri L. Levien, PharmD
Washington State University Spokane
Sondra K. May, PharmD
University of Colorado
Barbara Poe, BS, MBA
Norman Regional Hospital
Terry S. Smith, RPh, MS
McKesson Pharmacy Optimization
Jacyntha A. Sterling, PharmD
Saint Francis Hospital, Tulsa, Oklahoma
Burgunda V. Sweet, PharmD
University of Michigan Healthcare System
 Hospital
Volume 57  Number 6  December 2022 Pharmacy

Contents
Director’s Forum

Review of Medication Error Sources Associated With Inpatient Subcutaneous Insulin: Recommendations 689
for Safe and Cost-Effective Dispensing Practices
Connor McKay, Dan Schenkat, Kristin Murphy, and Elizabeth Hess

FMS

Nasal Glucagon 697

Thomas J. Borden, Terri L. Levien, and Danial E. Baker

Lefamulin 704
Liliya Kozhokar, Terri L. Levien, and Danial E. Baker

Original Articles

Short-Term Readmission Following Community-Acquired Pneumonia: A Cross-Sectional Study 712

Dung Thien Nguyen, Sang Thanh Huynh, and Ho Nhu Nguyen

Opioid Use in Vaso-Occlusive Crisis During Intravenous Opioid Drug Shortage 721
Katherine V. Katsivalis, Jeremy Kosacz, and Jennifer Austin Szwak

Safety and Efficacy Analysis of Apixaban Compared to Heparins in Hospitalized Non-Critically Ill COVID-19 Patients 727
Daniel Appiah, Nicholas J. Quinn, Emily G. Messing, and Keith T. Veltri

Assessment of an In-Sourced Patient Assistance Program at a Health System in West Virginia 734
Calvin Parmiter, David Cecere, Staci Czyzewski, and Michelle Gibson

Heparin Resistance in SARS-CoV-2 Infected Patients with Venous Thromboembolism 737

Terence Chau, Merlyn Joseph, Diana M. Solomon, Bryan Lee, and Lauren A. Igneri

Spontaneous Adverse Event Reporting by COVID-19 Vaccinated Healthcare Professionals Through an 744
Electronic Form Implemented by the Hospital Pharmacy
João Paulo Garcia Lopes da Cruz, Cristina da Conceição Ribeiro de Carvalho, Paula Alexandre da Cruz Silva,
Luis Filipe Campos Guerreiro, Tatiana Vedes Bento, Leila Vanessa Carmo Cardoso Martins Costa,
Raquel Filipa Miguel Margarido Duarte Simões, Rui Pedro Pinheiro Gonçalves Marques, Ana Cristina Castro Fernandes,
Luís Miguel Costa de Mendonça Galaio, Ana Isabel B. Correia, Ema Maria S. Leite Resende, and João Manuel Braz Gonçalves

The Impact of Job Instruction Training Within Pharmacy 752

Faria Munir, Christopher Loucks, and Petal Bartlett

Effect of Paralytic Agents on Post-Intubation Sedation in the Emergency Department 759

Jessica A. Pankey, Scott Christofferson, Ginger Barrick, Brandon A. Knettel, and Christine Knettel
Case Reports

Omadacycline for a Carbapenem-Resistant Enterobacter cloacae-Associated Wound Infection 767

Dylan C. VanDuyn, Saloni Chadha, Lauren A. Paul, Andrea R. Dressler, Mario V. Beccari, and Rajinder P.S. Bajwa

Mirabegron Associated Angioedema: A Case Report 771

Matthew T. Zuchowski, Jaylan M. Yuksel, and John Novi

Coronavirus Disease 2019-Related Extensive Thrombosis in a Patient Receiving Therapeutic Anticoagulation 774
With Dabigatran
Robert C. Ross, Andrew L. Hendrickson, Miranda P. Boraas, Abbie N. Rosen, and Andrew J. Franck

Calcium and Phosphate Solubility Curve Equation for Determining Precipitation Limits in Compounding 779
Parenteral Nutrition
Collin Anderson, Larry Eggert, Kristie Fitzgerald, Daniel Jackson, and Fred Farr

Carvedilol-Induced Thrombocytopenia: A Case Report 786

Angelina R. Raimonde and Anthony K. Dennis
Hospital Pharmacy (HPX) is a peer-reviewed journal that is practitioner-focused and dedicated to the promotion of best
practices and medication safety. Turn to Hospital Pharmacy for essential information on medication errors, adverse reaction
reporting, formulary drug reviews, original research, current FDA-related drug information, off-label drug uses, new tech-
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1095771
research-article2022
HPXXXX10.1177/00185787221095771Hospital PharmacyMcKay et al

Director’s Forum

Hospital Pharmacy

Review of Medication Error Sources

2022, Vol. 57(6) 689­–696
© The Author(s) 2022
Article reuse guidelines:
Associated With Inpatient Subcutaneous sagepub.com/journals-permissions
DOI: 10.1177/00185787221095771
https://doi.org/10.1177/00185787221095771

Insulin: Recommendations for Safe and journals.sagepub.com/home/hpx

Cost-Effective Dispensing Practices

Connor McKay1 , Dan Schenkat2, Kristin Murphy1,3,

and Elizabeth Hess4

Abstract

Background: The challenge of addressing variation in practice is underlined by variation in institutional operational and
financial limitations, which ultimately directs institutional insulin dispensing strategy. Insulin therapy is multi-modal, and
inpatient pharmacies may be responsible for simultaneously managing up to 8 formulations. While available as a tool for
glycemic management in the inpatient setting, intravenous (IV) insulin and insulin pumps are out of scope for this review.
Considerations when designing subcutaneous insulin dispensing processes include medication safety, infection control,
pharmacy workflow, nursing workflow, drug cost, hardware cost, and hospital policy. Objective: This review provides
an overview of common inpatient subcutaneous insulin dispensing practices, describes the regulations directing current
practice, and discusses the benefits and risks of each dispensing practice. Finally, the review provides recommendations
for subcutaneous insulin dispensing practices with respect to institutional limitations that minimize patient safety risk and
consider the variable costs that practices incur. Methods: Common formulations will be presented along with medication
safety considerations and potential medication administration errors to preface strategies for management. Conclusion:
Nearing the centennial anniversary of the invention of insulin, the practice of dispensing subcutaneous insulin products has
remained a core responsibility of the hospital pharmacy as a primary treatment option for Diabetes Mellitus. Despite the
continued presence of this product as a universal component of the hospital formulary, subcutaneous insulin dispensing
practices remain varied institution-to-institution.

Keywords
cost, dispensing, insulin, safety

Introduction In 2017, the Institute for Safe Medication Practices

Based on the American Diabetes Association (ADA)1
Standards of Medical Care in Diabetes, insulin therapy
remains the primary method of glycemic management in the
inpatient setting. A combination of basal (ie, long acting)
and bolus (ie, short acting) insulin should be used to manage
hospitalized patients with hyperglycemia. In the United
States in 2020, data from the National Diabetes Statistics
Report estimated that 34.2 million Americans (10.5% of
total Americans) had diabetes, with a total of 7.8 million
admissions possessing a diagnosis of diabetes (21.8% of
total hospital admissions) in 2016.2 Given these 2 factors,
insulin is likely one of the most commonly dispensed prod-
ucts in the hospital setting. Strategies that outline the safest
and most efficient pharmacy dispensing processes for these
agents remain undefined.
(ISMP) released guidance for optimization of safe subcuta-
neous insulin use in adults for safer handling practices
within the medication use process.3 Insulin has been associ-
ated with 11% to 16% of harmful medication errors and is
considered a high-alert medication.4-6 In 2019, a National
Diabetes Inpatient Audit by the National Health Service
within 950-bed, teaching hospital found that 20.2% of
1
UNC Medical Center, Chapel Hill, NC, USA
2
UW Health, Madison, WI, USA
3
UNC Health Care System, Chapel Hill, NC, USA
4
UK Healthcare, Lexington, KY, USA
Corresponding Author:
Connor McKay, UNC Medical Center, 101 Manning Drive, Chapel Hill,
NC 27514-4220, USA.
Email: Connor.McKay@unchealth.unc.edu
690 Hospital Pharmacy 57(6)
inpatient drug charts contained 1 or more insulin errors.4
ISMP defines a high-alert medication as a drug that bears a
heightened risk of causing significant patient harm when
they are used in error.3 Efforts to standardize and mitigate
the risk of patient harm that insulin causes have been a long-
standing focus of inpatient pharmacies. ISMP event analysis
has identified that the patient safety risk with dispensing
subcutaneous insulin increases when intermediate and long
acting insulin doses are not dispensed in the most ready-to-
use format.3 There is an expanding volume of error reports
associated with selecting the wrong vial of insulin from unit
stock and measuring the wrong dose for administration on
the patient care unit.3-6 Periodic evaluation of dispensing
practices and incorporation of best practices is the best solu-
tion to risk minimization.
The Centers for Disease Control and Prevention (CDC)
offers guidance on utilizing multi-dose vials (MDVs) to min-
imize the risk of disease transmission. The CDC defines an
MDV as a vial of liquid medication intended for parenteral
administration that contains more than 1 dose of medica-
tion.7 While MDVs contain preservatives to help prevent the
growth of bacteria, preservatives do not protect against con-
tamination when healthcare personnel fail to follow safe
injection practices. Several insulin formulations may be
obtained as MDVs, which presents considerations to reduce
the risk of vial contamination. The CDC recommends that
MDVs be dedicated to a single patient when possible or kept
in a singular medication preparation area separated from the
direct patient care area.7 If the MDV enters a patient room, it
should be dedicated to single patient use only. Upon vial
access, the insulin vial should be discarded according to a
beyond-use date (BUD) of either 28 or 42 days as instructed
by the manufacturer package insert or upon product expira-
tion, aligning with recommendations provided by The United
States Pharmacopeia (USP).
The Joint Commission provides additional guidance to
pharmacies on dispensing subcutaneous insulin within the
Medication Management Standards for Hospitals found in
“Section MM.05.01.11: The hospital safely dispenses medi-
cations.” According to The Joint Commission, quantities of
medications should be dispensed consistent with patient
need.8 The implications of this standard are relevant to the
dispensing process when considering the intent to minimize
the quantity of unnecessary insulin doses for sliding scale
parameters.
The purpose of this review is to provide an overview of
common inpatient subcutaneous insulin dispensing prac-
tices, describe regulations directing current practice, and dis-
cuss the benefits and risks of each dispensing practice.
Finally, the review will provide recommendations for insulin
dispensing practices with respect to institutional limitations
that minimize patient safety risk and consider the variable
costs that practices incur.
Background
Short Acting Insulin
Short acting insulins possess a relatively short onset of action
and work over a narrow range of time (3-8 hours) to provide
correctional or meal-time coverage that may result in a
requirement for multiple administrations throughout the
day.9-11 Given the similar roles in therapy, rapid acting insu-
lins will be referred to as short acting insulin for the purpose
of this review. Common formulations include insulin aspart
(Novolog®), insulin lispro (Humalog®), insulin glulisine
(Apidra®), and insulin regular (Humulin R® or Novolin R®).
Despite ADA guideline recommendation against use, short
acting insulin in the form of a sliding scale order is routinely
used as first-line therapy in patients on oral agents prior to
admission. The operational challenge of managing short act-
ing insulin is that dosing may be scheduled or held based on
order parameters; thus, batch filling pharmacy-drawn insulin
doses may lead to incremental waste either through lack of
utilization or delays in administration which situationally
incentivizes the allocation of floor stock. Errors with short
acting insulin are usually easily identified and corrected.
However, hypoglycemic events may still occur, causing
patient harm.
Intermediate Acting Insulin
Intermediate acting insulin contains buffers that extend the
onset and duration of action to confer an additional basal rate
of insulin release for when blood glucose remains relatively
stable.12 The only formulation available is insulin NPH
(Humulin N® or Novolin N®). As a twice-daily agent, this
agent is more readily titratable than other basal agents for
patients with external causes of hyperglycemia, such as
enteral nutrition or glucocorticoid administration. Given the
longer duration of action (8-12 hours), insulin NPH is rou-
tinely scheduled. Scheduled medications may be more rou-
tinely prepared by pharmacy for ready-to-use format in
patient-specific doses. Errors with intermediate acting insu-
lin may be more challenging to identify due to the pharmaco-
kinetics of the medication.
Long Acting Insulin
Long acting and ultra long acting insulins possess the most
prolonged onset and duration of actions (24-48 hours) rela-
tive to other formulations due to the design of a pH-depen-
dent release mechanism providing the longest basal rate of
insulin release.13 Long acting formulations include insulin
glargine (Lantus® or Basaglar®), insulin glargine-yfgn
(Semglee®), insulin detemir (Levemir®), insulin degludec
(Tresiba®), and concentrated insulin glargine (Toujeo®).
Dosed once or twice daily, this agent is useful for lowering
McKay et al 691
persistent hyperglycemia. Similar to insulin NPH, long act-
ing insulins may be readily prepared by pharmacy for ready-
to-use format in patient-specific doses. Errors with long
acting insulin may be more challenging to identify due to the
pharmacokinetics of the medication. Errors can lead to
delayed hypoglycemia and harm if not identified and treated
appropriately.
Concentrated Insulin
In patients with severe insulin resistance (ie, requiring more
than 200 units of insulin per day to maintain normoglyce-
mia), concentrated insulins are typically employed for type II
diabetic management.9 While onset is similar to short acting
insulin, duration of action for concentrated insulins is largely
dose-dependent, with larger doses generally providing basal
coverage. The only formulation commonly available is insu-
lin regular U-500 (Humulin R U-500). Concentrated formu-
lations other than U-500 are unlikely to be on formulary in
the inpatient setting and are out of the scope of the recom-
mendations provided below. If concentrated pens are used,
typically, they are utilized as patient home medications.
Concentrated insulins are high-alert medications and should
be managed accordingly as case reports of overdose have
been reported in the literature.14 Given the infrequency of
prescribing, dispensing either patient-specific pens or phar-
macy-drawn, patient-specific doses are preferred to mini-
mize the risk of preparation errors (eg, 1 unit on the U-100
insulin syringe is equivalent to 5 units of U-500 insulin) or
administration error. Stock concentrated insulin should not
be stored on patient care units, and each dose should be pre-
pared or verified by pharmacy given literature suggesting a
higher incidence of hypoglycemic events.15 In the absence of
patient-specific pens, the pharmacy should dispense U-500
doses from vial stock in a patient-specific U-500 syringe.
Errors with concentrated insulin can be devastating since the
insulin is 5 times more concentrated than typical insulins.
Due to the pharmacokinetics, monitoring and treatment of an
error may extend over 12 hours.
Insulin Pens
Insulin pens of various formulations are utilized in the inpa-
tient setting to reduce pharmacy and nursing time to prepare
and administer insulin. All formulations of short acting,
intermediate acting, long acting, and concentrated insulins
are available in pen dosage form. While assumed, there is
evidence to support that insulin vials and pens confer the
same clinical efficacy in achieving glycemic control in the
inpatient setting.16 The advantages and disadvantages of
insulin pens will be discussed further below. Errors with
insulin pens are less common due to the human factored
design of the pen. However, reports with wrong patient errors
have occurred and require blood-borne pathogen monitoring
to confirm no harm to the patient.17
Medication Administration Errors
Wrong Dose
Wrong dose errors may be defined as the intended patient
receiving an intended dose of insulin at an amount differing
from the written order, including errors of omission.18 Given
the varying number of health professionals involved in pre-
paring patient-specific subcutaneous insulin doses, dosing
errors may occur when staff are not familiar with standard
concentrations or routine doses. For example, a U-100 vial
may be mistaken to only contain 100 units of insulin, or a
10 mL vial may be mistaken to contain only 10 units of insu-
lin. There have been numerous reports of adverse drug
events associated with wrong dose errors from U-500 con-
centrated insulin.3 Additional clinical interpretation of slid-
ing scale orders may lead to doses deviating from the
original treatment plan. In any case, lack of product or soft-
ware familiarity may be contributory to knowledge-based
errors. Further dosing errors may be introduced with memory-
based errors from incorrectly drawn doses, interruptions, or
communication between staff.
Wrong Patient
Wrong patient errors occur as an unordered drug error for the
patient receiving the subcutaneous insulin dose and an error
of omission for the intended patient.18 While barcode medi-
cation administration (BCMA) is a commonplace feature in
many hospitals, inadequate compliance or lack of patient-
specific labeling may lead to unintended administration.
Wrong patient errors may also occur in the prescribing and
transcribing process when orders are incorrectly input for the
wrong patient yet are correctly dispensed and administered.
Wrong Drug
Wrong drug errors represent the administration of an incor-
rect insulin product. Wrong drug errors may be introduced in
the prescribing, transcribing, dispensing, or administration
processes.18 Attention to selecting the correct insulin product
when ordering or preparing insulin doses should be taken to
minimize the risk of administering the wrong product. Access
to a variety of floor stock insulin products may amplify the
risk of wrong drug errors in the setting of subcutaneous insu-
lin administration.
Monitoring Error
While inappropriate monitoring may lead to uncontrolled
blood glucose levels resulting in increased morbidity, moni-
toring errors may also lead to improper management of insu-
lin administration. The American Diabetes Association
recommends that blood glucose be monitored in accordance
with meal schedule. While alterations in dietary status, renal
function, acuity, or introduction of drug interactions should
692 Hospital Pharmacy 57(6)
ensure that blood glucose is monitored 4-to-6 times daily.1
Error in monitoring may lead to suboptimal therapy or over-
treatment as exogenous insulin requirements fluctuate.
Wrong Time
Wrong time errors are doses that are administered greater
than 60 minutes from the intended administration time. Not
including instances of documentation omission, wrong time
errors occur in the transcribing, dispensing, administration,
and monitoring process from pharmacy delay, with the pres-
ence of more acute patient needs, or with patient-related fac-
tors (eg, the patient is sleeping, is in a procedure, patient
transfer, or has not yet eaten).18 Orders may also be incor-
rectly timed, leading to wrong time errors.
Wrong Route
Since insulin may be given intravenously or subcutaneously,
there is additional potential for wrong route errors in the pre-
scribing, transcribing, or administration processes.19 A cor-
rectional insulin order may be incorrectly input for an
intravenous route when subcutaneous administration is
intended. Comparatively, the medication may be incorrectly
administered when ordered correctly. Either method of error
may confer suboptimal treatment or overdose requiring cor-
rectional administration of additional insulin or closer moni-
toring for hypoglycemia.
Insulin Dispensing Practices
Variation in inpatient subcutaneous insulin dispensing prac-
tice may be delineated into 2 categories: product selection
and workflow design. Product selection variation originates
from institutional clinical practice and formulary determina-
tion. Product pricing and provider prescribing preference
will primarily dictate bolus and basal insulin therapy choice
to treat hyperglycemia. The impact of product selection may
result in the utilization of vials versus pens. However, the
majority of variation in practice will be driven by the institu-
tion’s workflow design between sterile compounding, auto-
mated dispensing cabinet (ADC) restocking, and nurse
medication administration. The design of the dispensing pro-
cess is done with resource availability (eg, labor, hardware,
software, and supplies) in mind. The following list defines
the key variabilities that must be considered when outlining
any subcutaneous insulin dispensing practices:
1. Source of product: vial or pen
2. Product that is dispensed: vial, pen, or pharmacy-
prepared syringe
3. Location of product dispensed: pharmacy or ADC
4. Personnel labeling the product: pharmacy or nurse
5. Recipient(s) of the dispensed product: multiple
patients or a single patient.
Pharmacy Dispensing
As previously mentioned, the utilization of vials or pens is a
differentiating factor across institutions. Product may be dis-
pensed as patient-specific in the original container with mul-
tiple doses intended for a single patient or as a patient-specific,
drawn-up syringe intended for a single patient. Patient-specific
syringes containing long acting or intermediate acting insulin
and patient-specific insulin pens dispensed by a central phar-
macy are used to reduce the risk of inaccurate dosing, provide
a ready-to-use format, decrease pharmacy and nursing time in
preparation, decrease needle-stick injuries, and prevent cross-
contamination.19-22 Cross-contamination may occur through
direct or indirect contact with potentially contaminated sur-
faces or equipment such as when a multi-dose vial is re-entered
with a contaminated needle or when an insulin pen is used for
multiple patients. For concentrated insulins, the use of pens
may confer an additional safety benefit by removing U-500
syringes from circulation with proper inventory management
processes in place to prevent mix-up with other potential insu-
lin pen products. However, patient-specific pens are more
expensive than stocking vials, are prone to duplicate dispens-
ing, have the potential for premature needle withdrawal lead-
ing to underdosing, and must be primed prior to first
administration, leading to waste.23-27 In a survey of 474 inpa-
tient institutions, 30% (142) reported inadvertently using insu-
lin pens on multiple patients despite CDC recommendation
that insulin pens be patient-specific.28,29 Comparatively, sin-
gle-use, patient-specific syringes are prepared in a sterile envi-
ronment and verified in the pharmacy to ensure product and
dose accuracy.
Floor Stock
MDVs stocked in an ADC throughout the hospital are utilized
to minimize waste at the expense of additional work to ensure
patient safety. Floor stock vials or pens may be labeled and
assigned as patient-specific with multiple doses for a single
patient or remain as non-patient-specific ADC stock invento-
ried per unit with multiple doses for multiple patients. As
MDVs stored in ADCs are prone to human error, operational
processes outlining the proper identification of the vial and
patient must be well-designed with proper procedure to
ensure sterile administration and minimize cross-contamina-
tion. A 2-nurse double-check is only recommended for insulin
intended for intravenous administration and is no longer rec-
ommended for subcutaneous insulin.30 Subcutaneous Insulin
doses prepared by a nurse may be verified in several ways:
1. The prepared dose is labeled with a patient-specific
label that has a barcode generated by the ADC printer.
2. The prepared dose is labeled with a generic barcode
label stocked in or around the ADC.
3. The patient-specific vial is scanned at the patient
bedside.
McKay et al 693

4. The floor stock vial is scanned in the medication Table 1.  Cost Comparison of Available Insulin Products.31
room with a mobile scanner. The mobile scanner is
Insulin Product 3 mL Vial 3 mL Pen 10 mL Vial
then used to scan the patient prior to administration.
5. The product is not scanned or labeled. Regular $49.56 $62.46 $165.20
100 units/mL
When examining workflow for utilization of MDVs for Lispro $98.88 $127.29 $329.60
nurse-drawn preparation, the hospital pharmacy is typically 100 units/mL
Aspart $104.16 $134.13 $347.20
responsible for monitoring expiration dating, removing
100 units/mL
expired vials, and restocking to a unit-specific inventory
Glulisine $102.21 $131.64 $340.70
count. Insulin MDVs have an expiration date of either 28 days, 100 units/mL
42 days, or as instructed by the manufacturer package insert NPH $49.56 $62.46 $165.20
once the protective seal has been punctured or upon storage at 100 units/mL
room temperature.8 Expiration reporting functionality may be Glargine – $102.06 $340.30
automated through the ADC. However, some institutions 100 units/mL
store MDVs in ADC refrigerators with the expectation for Glargine-yfgn – $35.52 $118.40
manual documentation of expiration dating by nursing or 100 units/mL
pharmacy when puncturing the vial. With nursing documen- Detemir – $110.94 $369.80
tation, there is a reduced waste by ensuring the product is 100 units/mL
Degludec – $122.01 $406.70
short-dated upon initial use. Alternatively, pharmacy may
100 units/mL
manually pre-date the vials stored in the ADC refrigerator and
U-500 $267.66 $344.52 $1784.40a
re-label if the refrigerated product remains unused. Both 500 units/mL
manual processes are prone to error of omission.
mL = milliliter.
a
Product available as a 20 mL vial.
Cost
A review of available insulin formulations with associated confident with processes to prevent cross-contamination and
costs is listed below (Table 1). Costs are organized by regulatory noncompliance.
Average Wholesale Price (AWP) pricing for 3 mL vials, 3 mL
pens, and 10 mL vials for comparison.
In 2019, the average length of stay (ALOS) for hospital- Risk Reduction Strategies
ized patients in the United States was 5.5 days.32 For an illus-
Floor Stock
tration of cost difference, total short acting insulin cost across
ALOS for floor stock vials, patient-specific vials, and Storing MDVs as floor stock may be useful with operational
patient-specific pens will be extrapolated for insulin regular and technological limitations. When MDVs are stored as
at a dose of 12 units daily using each formulation. Utilizing floor stock rather than patient-specific pens or patient-spe-
floor stock 10 mL vials or 3 mL vials results in a total AWP cific vials, there are several considerations for establishing
acquisition cost of $10.90, while a patient-specific 3 mL vial safe handling practices. Compared to storage in central phar-
would result in a total AWP acquisition cost of $49.56, macy or medication room refrigerators, MDVs should ide-
assuming vial wasting following discharge. Comparatively, ally be stored in an ADC to prevent delays in care and wrong
short acting, patient-specific pen usage would result in a drug errors. MDVs may be used for multiple patients when
total AWP cost of $62.46, assuming pen wasting following stored under the described conditions using proper aseptic
discharge. While AWP pricing does not reflect pharmacy technique and smaller volume vials (ie, 3 mL vials) to limit
acquisition costs in practice, the relationship in pricing repeated vial access.5 When MDVs are stored in ADCs,
between products holds true for contractual pricing through ISMP states that MDVs should be segregated in locked-lid-
Wholesale Acquisition Cost or Group Purchasing Organi­ ded pockets to prevent the possibility of selecting the wrong
zations. Additionally, the demonstrative analysis performed insulin product for nurse preparation.
aligns with the literature. In prior budget impact analyses, Additionally, barcode scanners and automatic label print-
utilizing short acting 3 mL floor stock vials has considerably ers can be implemented to correctly identify insulin product,
reduced acquisition cost and waste.27,33 When considering prepare patient-specific syringes away from patient care
cost for short acting insulin products, preference should be areas, and correctly identify the patient for medication
shown for 3 mL vial products with larger volume vials and administration. Patient labels are ideally employed in con-
pens reserved for pharmacy dispensed products (ie, interme- junction with BCMA when possible.4 Floor stock should be
diate acting, long acting, and concentrated insulin products). limited to short acting insulin as these products carry a
As described previously, introducing floor stock product greater risk for wrong time errors. Subsequently, minimizing
carries organizational risk, and pharmacy leaders must be the availability of long acting, intermediate acting, and
694 Hospital Pharmacy 57(6)
Table 2.  Advantages and Disadvantages of Common Dispensing Strategies.
Advantages
Pharmacy dispensing of •  Low risk of wrong product error
patient-specific vials •  Lower risk of wrong-patient error
or pens •  Low operational pharmacy support required
Pharmacy dispensing •  Low risk of wrong dose error
of patient-specific •  Low risk of wrong product error
pre-drawn syringes •  Lowest risk of wrong patient error
•  Lowest risk of waste
•  Lowest risk of cross-contamination
•  Lowest technological pharmacy support required
ADC patient-specific •  Low risk of wrong time error
vials or pens •  Low risk of cross contamination
•  Low risk of wrong product error
•  Low risk of wrong patient error
Floor stock vials or pens •  Low risk of wrong time error
•  Lower risk of waste
•  Lowest operational pharmacy support required
ADC = automated dispensing cabinet.
concentrated floor stock insulin reduces excess waste from
vial loss, cross-contamination from multi-patient use, and
risk of wrong drug errors. Advantages and disadvantages for
floor stock dispensing are listed in Table 2.
Patient-Specific Vials
Utilizing patient-specific MDVs is a strategy to minimize the
risk of cross-contamination or to mitigate operational limita-
tions. Per the CDC, MDVs should be stored and punctured in
a location away from patient care areas (eg, operating rooms,
procedure carts, patient bays, and patient rooms). MDVs that
do enter these areas shall be designated for that patient for
continued use.5 In institutions that do not have product bar-
coding or patient-specific labeling capability, designated
vials may be dispensed from the central pharmacy or assigned
from floor stock for patient use. Concerns with this approach
include excess waste when a patient is discharged or when a
vial is lost and the potential for wrong time errors when
patient-specific vials are dispensed from the central phar-
macy. To limit the potential for wrong drug errors, product
availability for patient-specific vials assigned from floor
stock should be limited to short acting insulin segregated in
locked-lidded pockets with BCMA scanning when possible.
Advantages and disadvantages for patient-specific vial dis-
pensing are listed in Table 2.
Patient-Specific Dose
ISMP and TJC state that insulin doses should be provided in
the most ready-to-use format for administration.3,8 Pharmacy
dispensing of patient-specific doses reduces the risk of wrong
Disadvantages
•  Highest risk for wrong time error
•  Highest risk of wrong dose error
•  Highest risk of cross-contamination
•  High risk for wrong time error
•  Highest operational pharmacy support required
•  High technological pharmacy support required
•  Highest risk of waste
•  Moderate risk of wrong dose error
•  Highest technological pharmacy support required
•  Moderate risk of wrong patient error
•  Highest risk of wrong dose error
•  Highest risk of wrong product error
•  Highest risk of cross-contamination
product and wrong dose errors. However, there are opera-
tional concerns to providing short acting insulin as patient-
specific doses that incurs a risk of wrong time errors. Given
that long acting, intermediate acting, and concentrated insu-
lins are routinely scheduled, these doses should be prepared
as patient-specific doses utilizing product barcode scanning
in the pharmacy and dispensed to the floor in a ready-to-use
format rather than as floor stock to limit the potential for
wrong dose, wrong product, or wrong patient error.
Advantages and disadvantages for patient-specific dose dis-
pensing are listed in Table 2.
Recommendations for Safe insulin use
Short acting insulin may be dispensed in several ways, abid-
ing by the proper risk reduction strategies in place. Floor
stock vials are common, reduce departmental costs, and
improve ease of use for sliding scale orders. The authors
preferably recommend that institutions provide patient-spe-
cific, short acting insulin vials to comply with CDC guid-
ance. Alternatively, due to the cost of vials, the authors also
support institutions utilizing floor stock short acting insulin
vials, assuming infection risks, wrong dose, and wrong drug
errors are minimized through the use of technology. If staff
are to use floor stock short acting insulin vials, institutions
must be able to provide appropriately labeled syringes before
entering the patient room.
The authors recommend that long acting and intermedi-
ate acting insulin be prepared in a patient-specific, ready-to-
use format by the pharmacy. Floor stock vials of long acting
and intermediate acting insulin are not recommended given
the potential for product mix-up and wrong drug error.
McKay et al 695
Table 3.  Summary of Recommendations for Subcutaneous Insulin Dispensing.
Pharmacy patient-specific preparation
Short acting
Intermediate acting 
Long acting 
Concentrated a
ADC = automated dispensing cabinet.
a
Insulin pen dispensed from pharmacy.
The pharmacist product verification process and pharmacy
access to technology-assisted workflow (TAWF) confirm
the right drug for the right patient. Administration errors
with long acting and intermediate acting insulin may be
more difficult to recognize and intervene to preclude harm.
While this may mean more workload for the pharmacy, it
avoids calculation errors by nursing, who are tasked with
many other important tasks. The authors recommend that
the pharmacy batch prepare all standing patient-specific
long acting and intermediate acting insulin orders together
for ease of workload and determine a standard administra-
tion time to successfully accomplish this.
At a minimum, the pharmacy must always prepare con-
centrated insulin in patient-specific doses to minimize the
need for manipulation and calculation by nursing. Vials
should never be stored on the patient care unit as floor stock.
Given the risk of morbidity with wrong dose errors and infre-
quency of use, insulin pens for U-500 are preferred. Some
institutions may utilize insulin pens due to the low opera-
tional pharmacy support required, patient and nurse satisfac-
tion associated with administration, and minimal difference
in cost relative to vials.21 The authors preferably recommend
that insulin pens be used only for U-500 concentrated insulin
to reduce the risk of product mix-up. For example, in 2016,
Brown and Hertig,28 reported in a survey of 474 institutions
that approximately 30% of the survey respondents accounted
that insulin pens had been used on more than 1 patient at
least once in their institution. In institutions that do not pos-
sess the operational and technological capabilities to imple-
ment components of the described subcutaneous insulin
dispensing best practices, patient-specific insulin pens may
be an acceptable, provisional alternative for institutional use
with the intent to align with dispensing best practices.
Recommendations are summarized below in Table 3.
Conclusion
Subcutaneous insulin is one of the most commonly ordered
medications in the hospital, yet there remains little consen-
sus on best practices for dispensing insulin products. Waste
and patient safety remain active concerns for this high-
alert medication. While variation in practice is conditional
to institutional resources, processes may be refined to
ensure optimal usage. Institutions may use either MDVs or
pens exclusively or a blend of pens and MDVs depending
ADC patient-specific ADC floor stock
 
 
 
 
on pharmacy capability to absorb additional sterile com-
pounding preparation and ADC inventory management
capabilities. Thus, strategies for insulin dispensing should
be formulated by class. In this review of subcutaneous
insulin dispensing, recommendations are provided to
refine institutional processes and emphasize patient safety
for each class of insulin.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
ORCID iD
Connor McKay https://orcid.org/0000-0002-0313-4878
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3. Institute for Safe Medication Practices (ISMP). ISMP guidelines
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888914
research-article2019
HPXXXX10.1177/0018578719888914Hospital PharmacyBorden et al

FMS

Hospital Pharmacy

Nasal Glucagon
2022, Vol. 57(6) 697­–703
© The Author(s) 2019
Article reuse guidelines:
sagepub.com/journals-permissions
DOI: 10.1177/0018578719888914
https://doi.org/10.1177/0018578719888914
journals.sagepub.com/home/hpx

Thomas J. Borden1, Terri L. Levien1 ,

and Danial E. Baker1

Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well-documented monographs on drugs that are
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Generic Name: GLUCAGON NASAL POWDER
Proprietary Name: Baqsimi (Eli Lilly)
Approval Rating: 3S
Therapeutic Class: Antidotes, Hypoglycemia
Similar Drugs: Glucagon Injection
Sound-/Look-Alike Names: Glimepiride, Glipizide, GlucaGen,
Glucophage, Glucotrol, Glyburide, Glycotrol
Indications
Nasal glucagon is Food and Drug Administration (FDA)-
approved for the treatment of severe hypoglycemia in patients
4 years of age and older with diabetes mellitus.1
Glucagon injection is approved for the treatment of severe
hypoglycemia in patients with diabetes mellitus.2,3
Glucagon injection is also approved as a diagnostic aid in
radiological examination of the stomach, duodenum, small
bowel, and colon to temporarily diminish intestinal motility.2,3
Clinical Pharmacology
Glucagon is a hormone normally synthesized in the alpha
cells in the islets of Langerhans in the pancreas. Glucagon
primarily influences glycogenolysis in hepatocytes, and suf-
ficient hepatic glycogen stores are required for efficacy.
Repeated use of glucagon over a short period of time becomes
less efficacious.1-4
Recombinant glucagon is a polypeptide hormone identi-
cal to endogenous human glucagon that raises blood glucose
levels by glycogenolysis. For the injectable pharmaceutical
product available as a powder for reconstitution, glucagon is
synthesized in a nonpathogenic laboratory strain of
Escherichia coli that has been genetically altered3 or is pro-
duced by expression of recombinant DNA in a Saccharomyces
cerevisiae vector with subsequent purification.2 The gluca-
gon used in the nasal formulation is a synthetic form with the
same 29 amino acids as both recombinant injectable and
endogenous human glucagon.5
Pharmacokinetics
Glucagon is rapidly absorbed after intranasal administration.
Peak plasma levels (Cmax) are reached within 15 minutes in
adults and 15 to 20 minutes in children. The apparent volume
of distribution is approximately 885 L. Median half-life is
approximately 35 minutes in adults and 21 to 31 minutes in
children. Glucagon is degraded in the liver, kidneys, and
plasma.1
In a crossover study comparing intranasal glucagon 3 mg
and intramuscular (IM) glucagon 1 mg in adults with type 1
diabetes, time to maximum change in blood glucose concen-
tration from baseline was approximately 5 minutes slower
with intranasal glucagon; however, pharmacologic levels of
glucagon were detected within 5 minutes of administration
by both routes. Median time to Cmax was 20 minutes after
intranasal administration and 15 minutes after IM adminis-
tration (P < .001). Mean Cmax was lower after intranasal
administration (3155 pg/mL) than after IM administration
(3672 pg/mL; P = .003). In an analysis of administration
when nadir glucose was less than 50 mg/dL, the mean time
required to achieve blood glucose normalization (at least 70
mg/dL, or at least a 20 mg/dL increase from glucose nadir)
was 13 minutes for IM glucagon and 16 minutes for intrana-
sal glucagon (P < .001).6
1
Washington State University, Spokane, USA
Corresponding Author:
Terri L. Levien, Clinical Professor, Pharmacotherapy Department, College
of Pharmacy and Pharmaceutical Sciences, Washington State University,
412 E. Spokane Falls Blvd, Spokane, WA 99202-2131, USA.
Email: levient@wsu.edu
698 Hospital Pharmacy 57(6)
Similar results were observed in a study comparing intra-
nasal glucagon 2 mg and 3 mg with IM glucagon 1 mg in
children and adolescents 4 to 16 years of age with type 1
diabetes. Both routes produced a rise in glucose of at least 25
mg/dL within 20 minutes of dosing. Plasma glucagon levels
rose within 5 minutes of administration by either route,
reaching peak glucagon concentrations in a mean of 15 to 20
minutes with intranasal administration and 17 minutes with
IM administration. Peak glucagon levels ranged from 2952
to 5832 pg/mL following intranasal administration and from
4382 to 6343 pg/mL following IM administration.7
The presence of nasal congestion or concomitant use of a
nasal decongestant had no impact on the pharmacokinetics
of glucagon following nasal administration.1,8
Comparative Efficacy
Indication: Hypoglycemia in Type 1 Diabetes
Mellitus
Guidelines
Guideline: American Diabetes Association: standards of
medical care in diabetes – 2019
Reference: American Diabetes Association9
Comments: Glucagon is used in hypoglycemic emergen-
cies to rapidly raise plasma blood glucose levels in dia-
betic patients. Glucagon should be prescribed in
individuals at increased risk of hypoglycemia (blood glu-
cose less than 54 mg/dL), so it is available if needed.
Glucagon is indicated especially for those unable or
unwilling to consume carbohydrates by mouth. In addi-
tion, supplemental administration of carbohydrates is rec-
ommended after administration of glucagon. Caregivers
and individuals in close contact with the patient should
receive instruction on the use of glucagon and its admin-
istration. The intranasal form of glucagon is not specifi-
cally mentioned in the guidelines.
Studies
Drug: Nasal Glucagon
Reference: Deeb LC, et al, 20185
Study Design: Phase 3, prospective, open-label, multi-
center, nonrandomized study
Study Funding: Eli Lilly & Company
Patients: 26 children or adolescents (4 to younger than
18 years) with type 1 diabetes mellitus of more than 1
year’s duration and experiencing moderate or severe
hypoglycemic events. Patients had to be living with 1 or
more caregivers and in good general health. Exclusion
criteria were pheochromocytoma or insulinoma; cardio-
vascular, gastrointestinal (GI), liver, or kidney disease; or
use of systemic beta-blockers, indomethacin, warfarin, or
anticholinergic medications. Of the 26 patients enrolled,
11 were excluded due to study site noncompliance; of the
remaining 15 patients, 14 experienced 1 or more hypo-
glycemic events and received treatment with nasal gluca-
gon; the 14 patients were included in the efficacy and
safety analyses. Mean patient age was 10.2 years; 64.3%
were male; 100% were white; mean duration of diabetes
was 6.3 years; and 71.4% were using an insulin pump,
with a mean total daily insulin dose of 42.3 units.
Intervention: Patients received nasal glucagon 3 mg
administered as a single dose for the treatment of a mod-
erate to severe hypoglycemic event. Blood glucose was
measured just before or immediately after treatment and
again at 15, 30, and 45 minutes after dosing. If the patient
did not respond within 15 minutes after nasal glucagon
administration, the caregiver was instructed to seek emer-
gency medical assistance. During the study, administra-
tion of nasal glucagon was allowed whenever a patient
experienced a moderate or severe hypoglycemic event,
for up to a maximum of 4 events.
Results: During the study, the 14 patients experienced 33
moderate hypoglycemic events. All patients had neuro-
glycopenic symptoms with a blood glucose level of 70
mg/dL or less (range, 42-70 mg/dL) at the time of nasal
glucagon administration.
Primary End Point(s)
•• Proportion of patients with treatment response
(defined as awakening or returning to normal status,
as judged by caregiver, within 30 minutes following
nasal glucagon administration): All hypoglycemic
events (100%) resolved, with patients returning to
normal status within 30 minutes after nasal adminis-
tration of glucagon. More than half (54.5%) of
hypoglycemic events resolved and patients returned
to normal status within 10 minutes of nasal gluca-
gon administration. Time to return to normal status
after nasal administration was less than 5 minutes in
21.2% of patients, 5 to less than 10 minutes in
33.3%, 10 to less than 15 minutes in 12.1%, 15 to
less than 20 minutes in 15.2%, 20 to less than 25
minutes in 15.2%, and 25 to less than 30 minutes in
3%.
Secondary End Point(s)
•• Blood glucose levels improved over time, from a
baseline mean of 55 mg/dL to greater than 70 mg/dL
at 15 minutes after nasal glucagon administration;
levels continued to increase over 45 minutes.
•• Very few of the caregivers had previous experience
with injectable glucagon. Caregivers reported that the
nasal form was easy to very easy to administer in
93.9% of hypoglycemic events. Overall, caregivers
were relatively satisfied, satisfied, or very satisfied
with the nasal formulation. The glucagon dose was
administered within 30 seconds of the hypoglycemic
Borden et al 699
episode in 60.6% of events and within 2 minutes in
100% of events.
Comments: The study was conducted at 2 medical centers
in the United States. Hypoglycemia awareness at baseline
was evaluated using the Clarke Hypoglycemia Awareness
Questionnaire. Caregivers and patients were trained in nasal
glucagon use. Caregivers were given the User-Friendliness
Assessment Questionnaire to describe nasal glucagon ease
of use. Patients were given a Nasal Score Questionnaire
post episode. Caregiver reports of ease of use of the nasal
glucagon formulation were similar to a smaller study con-
ducted to evaluate the ability of primary caregivers and
acquaintances without medical training to administer nasal
glucagon versus injectable glucagon during simulated
severe hypoglycemic episodes. The study found that instruc-
tion time was faster, retention of information was more
complete, and time to deliver the medication to the patient
and success in delivering the medication were superior in
the nasal glucagon groups compared with the IM groups for
both laypersons and experienced caregivers.10
Limitations: This was a small study that did not use ran-
domization, concealed allocation, blinding, or controls.
The study population was primarily male and all white.
Reference: Seaquist ER, et al, 201811,12
Study Design: Phase 3, prospective, multicenter, single-
arm, nonrandomized, open-label study
Study Funding: Eli Lilly & Company, Locemia Solutions
Patients: 129 adults (18-75 years of age) with type 1 diabe-
tes mellitus of more than 1 year’s duration and body mass
index (BMI) of 18.5 to 35 kg/m2; patients were otherwise
healthy. Exclusion criteria were pheochromocytoma or
insulinoma, or use of systemic beta-blockers, indometha-
cin, warfarin, or anticholinergic medications. Of the 101
patients who completed the study, 69 patients experiencing
1 or more hypoglycemic episode(s) requiring nasal gluca-
gon and with evaluable response data were included in the
efficacy analysis. In the main safety analysis population
(patients who experienced at least 1 hypoglycemic episode
and received at least 1 nasal glucagon dose; n = 74), mean
patient age was 46.2 years, and 52.7% were female.
Intervention: Patients received nasal glucagon 3 mg
administered as a single dose following the onset of a
hypoglycemic episode.
Results
Primary End Point(s)
•• Proportion of patients with treatment response (defined
as awakening or returning to normal status within 30
minutes following nasal glucagon administration): Of
69 patients, 66 (95.7%) awakened or achieved normal
status within 30 minutes of administration of nasal glu-
cagon in at least 1 evaluable hypoglycemic event; 64
(92.8%) awakened or achieved normal status within 30
minutes in all evaluable events. Of the 157 evaluable
hypoglycemic episodes (145 moderate and 12 severe)
treated during the study, 151 (96.2%) resolved within
30 minutes, and all (100%) severe hypoglycemic epi-
sodes resolved within 15 minutes.
Secondary End Point(s)
•• Mean blood glucose level improved progressively,
from 47.9 mg/dL at the time of nasal glucagon admin-
istration to 84.4 mg/dL after 15 minutes; levels con-
tinued to increase further. In 4 of the 6 events that did
not resolve within 30 minutes of nasal glucagon
administration, blood glucose levels were greater than
70 mg/dL within 30 minutes but did not return to nor-
mal status because of headache and/or nasal irritation;
in the other 2 events, patients eventually returned to
normal status within 45 minutes.
•• Caregivers rated the nasal glucagon drug instructions as
easy to understand in 91% of events and rated the drug as
easy to administer in 80.5% of events. Overall, caregivers
were satisfied with nasal glucagon in 94.4% of events.
Comments: Patients were selected from 9 centers in the
United States and Canada. Hypoglycemia awareness at
baseline was evaluated using the Clarke Hypoglycemia
Awareness Questionnaire. Caregivers were trained in
nasal glucagon use. Caregivers were given the User-
Friendliness Assessment Questionnaire to describe nasal
glucagon ease of use. Patients were given a Nasal Score
Questionnaire post episode. The study demonstrated ease
of use and preference for nasal glucagon by caregivers.
Limitations: This was a small, single-arm study with no
comparator group. Participants were predominantly white.
Drug: Nasal Glucagon vs Glucagon for Injection
Reference: Rickels MR, et al, 20166,13
Study Design: Phase 3, randomized, open-label, noninfe-
riority, crossover study
Study Funding: Leona M. and Harry B. Helmsley
Charitable Trust, National Center for Research Resources,
National Center for Advancing Translational Sciences,
National Institutes of Health
Patients: 77 adults (18-64 years of age) with type 1 diabetes
mellitus of at least 2 years’ duration and weighing 50 kg or
more, with BMI between 20 and 35 kg/m2. Exclusion criteria
included severe hypoglycemic episode in the month before
enrollment; pheochromocytoma or insulinoma; history of
seizure disorder; cardiovascular, GI, liver, or kidney disease;
use of systemic beta-blockers; donation of 225 mL or more
of blood within 8 weeks of enrollment; or consumption of 3
or more alcoholic beverages daily. The efficacy analysis
included 75 patients who successfully completed both dos-
ing visits. Baseline characteristics were similar between the
nasal and injection groups.
700 Hospital Pharmacy 57(6)
Intervention: Patients underwent 2 glucagon dosing
visits. Hypoglycemic episodes were induced using an
infusion of insulin after an overnight fast of at least 8
hours. The infusion was stopped once glucose concen-
tration was less than 60 mg/dL; blood samples for glu-
cose and glucagon were obtained 5 minutes later and a
dose of glucagon was administered (time zero). At one
visit, glucagon 1 mg was given IM in the deltoid muscle
of the nondominant arm, and at a separate visit, intrana-
sal glucagon 3 mg was administered into the nostril on
the same side of the body. Dosing visits were scheduled
1 to 4 weeks apart.
Results
Primary End Point(s)
•• Treatment success (defined as an increase in blood glu-
cose to at least 70 mg/dL or an increase of at least 20
mg/dL from glucose nadir within 30 minutes after
receiving study glucagon, without receiving additional
actions to increase blood glucose level): Success crite-
ria were met in 74 of 75 (98.7%) administrations of
nasal glucagon and in 75 of 75 (100%) administrations
of IM glucagon (unadjusted difference, 1.3% [1-sided
97.5% confidence interval (CI), 4%]; adjusted differ-
ence, 1.5% [1-sided 97.5% CI, 4.3%]); prespecified
criteria for noninferiority were met. One patient who
failed to achieve success criteria in the nasal group had
a blood glucose nadir of 47 mg/dL, with a rise to 65
mg/dL in 30 minutes and to 72 mg/dL in 40 minutes
without any other intervention.
Secondary End Point(s)
•• Mean time to success was 13 minutes with IM gluca-
gon and 16 minutes with nasal glucagon (P < .001).
Comments: The study was conducted at 8 clinics within
the Type 1 Diabetes Mellitus Exchange Clinic Network.
Because of the residual activity of circulating insulin, glu-
cose nadir was defined as the minimum glucose measure-
ment at the time of, or within 10 minutes following,
glucagon administration. The rise in blood glucose con-
centration after nasal administration was about 5 minutes
slower than after IM administration.
Contraindications, Warnings, and
Precautions
Contraindications
Intranasal glucagon is contraindicated in patients with hyper-
sensitivity to glucagon nasal powder or any of its inactive
ingredients (ie, betadex, dodecylphosphocholine), patients
with pheochromocytoma, or those with insulinoma.1
Warnings and Precautions
Catecholamine release in patients with pheochromocytoma
is possible due to interactions between nasal glucagon and
the catecholamine-secreting tumor. The resulting elevation
in catecholamine release may cause an increase in blood
pressure. Patients who experience a sudden increase in blood
pressure after the administration of glucagon should be given
phentolamine mesylate 5 to 10 mg intravenously (IV).1
Use of intranasal glucagon is contraindicated in patients
with insulinoma. Administration of glucagon in patients with
insulinoma may produce an initial increase in blood glucose
levels and then stimulate exaggerated insulin release from an
insulinoma and cause hypoglycemia. If a patient develops
hypoglycemia following nasal glucagon, administer oral or
IV glucose.1
Allergic reactions and hypersensitivity, including general-
ized rash, breathing difficulty, hypotension, and anaphylactic
shock, have been reported with glucagon.1
Lack of efficacy in those with reduced hepatic glycogen
(eg, patients in states of starvation, with adrenal insuffi-
ciency, or with chronic hypoglycemia) may occur. Nasal glu-
cagon relies on stored hepatic glycogen to increase blood
sugar. Patients with these conditions should be treated with
oral or IV glucose.1
Reports (eg, case studies, a small number of observational
studies) of the use of glucagon during pregnancy have not
identified a drug-associated risk of major birth defects, mis-
carriage, or adverse maternal or fetal outcomes. In addition,
glucagon may not be able to cross the human placental bar-
rier during early gestation.1
No information is available on the presence of glucagon in
human or animal milk, or its effects on breastfeeding infants
or milk production. Because glucagon is a peptide, it should
be broken down in the infant’s digestive tract to constituent
amino acids and is unlikely to cause harm to the infant.1
The safety and effectiveness of nasal glucagon have not
been established in pediatric patients younger than 4 years of
age.1
Adverse Reactions
Because clinical trials are conducted under widely varying
conditions, adverse reaction rates observed in clinical trials
of nasal glucagon cannot be directly compared with rates in
clinical trials of other similar drugs and may not reflect the
rates observed in practice.1 Common adverse reactions in
adults and children related to nasal administration of gluca-
gon were nausea, vomiting, and upper respiratory irritation
(see Tables 1 and 2). The incidence of other types of adverse
reactions is summarized in Tables 3 and 4.1 Table 5 is a com-
parison of the adverse events reported in the prescribing
information for nasal glucagon and injectable glucagon dos-
age forms.1-3
Borden et al 701

Table 1.  Pooled Adverse Reactions (≥2%) in Adult Patients Table 5.  Comparison of the Adverse Events Reported With
With Type 1 and Type 2 Diabetes Receiving Nasal Glucagon in Nasal Glucagon and Injectable Glucagon Dosage Forms.1-3
Clinical Trials.1
Nasal Injectable
Nasal glucagon 3 mg Adverse reaction glucagon glucagon
Adverse reaction (N = 153)
Headache X X
Nausea 26.1% Nausea X X
Headache 18.3% Vomiting X X
Vomiting 15% Upper respiratory tract irritation X  
Upper respiratory tract irritationa 12.4% Necrolytic migratory erythema X
Injection-site reaction X
a
Rhinorrhea, nasal discomfort, congestion, cough, and epistaxis.

The majority of adverse reactions in the published clinical

Table 2.  Adverse Reactions (≥2%) in Children With Type 1
trials were classified as low to moderate in severity and
Diabetes Receiving Nasal Glucagon in a Clinical Trial.1
resolved within 1 hour.5,12 Other observed adverse reactions
Nasal glucagon 3 mg with nasal glucagon–treated patients across clinical trials
Adverse reaction (N = 36) were dysgeusia, pruritus, tachycardia, hypertension, and
Vomiting 30.6% additional upper respiratory tract irritation events (nasal pru-
Headache 25% ritus, throat irritation, and parosmia).1
Nausea 16.7% Necrolytic migratory erythema (NME), a skin rash asso-
Upper respiratory tract irritationa 16.7% ciated with glucagonomas, can be exacerbated by continuous
glucagon administration. This adverse event has only been
a
Nasal discomfort, nasal congestion, and sneezing. reported postmarketing with use of injectable glucagon fol-
lowing continuous infusion and is characterized by scaly,
pruritic erythematous plaques, bullae, or erosions on the
Table 3.  Pooled Solicited Nasal and Nonnasal Adverse
Reactions in Adult Patients With Type 1 and Type 2 Diabetes face, groin, perineum, and legs. Treatment involves discon-
Receiving Nasal Glucagon in Clinical Trials.1 tinuation of glucagon. The use of corticosteroids may be
ineffective. There have been no reports of NME with the
Adverse reaction Nasal glucagon 3 mg (N = 153) nasal glucagon formulation.1-3
Watery eyes 58.8%
Nasal congestion 42.5% Drug Interactions
Nasal itching 39.2%
Runny nose 34.6% Patients taking beta-blockers may have a transient increase
Redness of the eyes 24.8% in pulse and blood pressure when given glucagon.1-3
Itching of the eyes 21.6% In patients taking indomethacin, nasal glucagon may lose
Sneezing 19.6% its ability to raise blood glucose or may even produce
Itching of the throat 12.4% hypoglycemia.1-3
Itching of the ears 3.3% Glucagon, including the nasal formulation, may increase
in the anticoagulant effect of warfarin.1-3 Drug interactions
reported with nasal and injectable glucagon are compared in
Table 4.  Solicited Nasal and Nonnasal Adverse Reactions Table 6.1-3
in Pediatric Patients With Type 1 Diabetes Receiving Nasal Coadministration with an anticholinergic drug may
Glucagon in a Clinical Trial.1 increase GI adverse effects and is not recommended.2
Adverse reaction Nasal glucagon 3 mg (N = 36)
Watery eyes 47.2% Recommended Monitoring
Nasal congestion 41.7% Monitor for improvements in the signs and symptoms of
Nasal itching 27.8% hypoglycemia; blood glucose measurements can be used to
Runny nose 25% monitor response.1
Sneezing 19.4%
Itchy eyes 16.7%
Redness of eyes 13.9% Dosing
Itching of throat 2.8%
The recommended dose of nasal glucagon is 3 mg adminis-
Itching of ears 2.8%
tered as 1 actuation of the intranasal device into 1 nostril;
702 Hospital Pharmacy 57(6)
Table 6.  Comparison of Nasal Glucagon and Injectable Glucagon
Drug Interactions.1-3
Nasal Injectable
glucagon glucagon
Beta-blockers X X
Anticholinergics X intervene on the patient’s behalf.
Indomethacin X X
Warfarin X X
emergency assistance should be called immediately after
administering the dose. The tip of the device should be
inserted into the nostril and then the plunger pressed in until
the green line is no longer showing. No inhaling is required.
If the patient responds to treatment, they should be given oral
carbohydrates to restore liver glycogen and prevent recur-
rence of hypoglycemia. If there has been no response after 15
minutes, an additional 3 mg dose of nasal glucagon from a
new device may be administered.1
Product Availability and Storage
Glucagon nasal powder was approved on July 24, 2019.14 It is
available as an intranasal device containing one 3 mg dose of
glucagon as a preservative-free, white powder. The product is
available in cartons that contain 1 or 2 intranasal devices.1
Nasal glucagon should be stored at temperatures not
exceeding 30°C (86°F) in the shrink-wrapped tube pro-
vided.1 Removal of the shrink wrapping from the tube prior
to use may expose the product to moisture and cause it to not
work as expected. The shrink wrap should be kept on the
tube until administration of the product is necessary.1
Drug Safety/Risk Evaluation and
Mitigation Strategy (REMS)
No REMS program has been established for nasal glucagon.14
Conclusion
Nasal glucagon is FDA-approved for the treatment of
severe hypoglycemia in patients 4 years of age and older
with diabetes mellitus. The standard of care for moderate or
severe hypoglycemia in patients with diabetes mellitus is
IM or subcutaneous administration of glucagon. Glucagon
emergency kits are carried by many diabetic patients, espe-
cially those treated with insulin. Correct administration of
glucagon by a layperson or otherwise inexperienced
bystander can be crucial in an emergency, and glucagon for
injection kits can be intimidating or difficult to use for the
general public. Instructions and pictures can be insufficient
to guide in reconstituting and administering the drug. A
nasal glucagon dosage form offers an alternative that is
easier for laypersons to use and has similar efficacy and
pharmacokinetic profiles to its injectable counterpart. The
nasal device is associated with fewer steps and only requires
insertion into 1 nostril for delivery. Outcomes and safety in
diabetic patients, especially children, can be greatly
improved by prescription of nasal glucagon rescue kits,
particularly in cases when an inexperienced user must
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
ORCID iDs
Terri L. Levien https://orcid.org/0000-0001-5114-6067
Danial E. Baker https://orcid.org/0000-0002-4605-3357
References
1. Baqsimi (glucagon nasal powder) [prescribing information].
Indianapolis, IN: Lilly USA; 2019.
2. GlucaGen (glucagon for injection) [prescribing information].
Plainsboro, NJ: Novo Nordisk; 2018.
3. Glucagon for injection [prescribing information]. Indianapolis,
IN: Lilly USA; 2018.
4. Oh SH, Darwiche H, Cho JH, Shupe T, Petersen BE.
Characterization of a novel functional protein in the pancreatic
islet: islet homeostasis protein regulation of glucagon synthesis
in α cells. Pancreas. 2012;41(1):22-30.
5. Deeb LC, Dulude H, Guzman CB, et al. A phase 3 multicenter,
open-label, prospective study designed to evaluate the effec-
tiveness and ease of use of nasal glucagon in the treatment of
moderate and severe hypoglycemia in children and adolescents
with type 1 diabetes in the home or school setting. Pediatr
Diabetes. 2018;19(5):1007-1013.
6. Rickels MR, Ruedy KJ, Foster NC, et al. Intranasal glucagon
for treatment of insulin-induced hypoglycemia in adults with
type 1 diabetes: a randomized crossover noninferiority study.
Diabetes Care. 2016;39(2):264-270.
7. Sherr JL, Ruedy KJ, Foster NC, et al. Glucagon nasal pow-
der: a promising alternative to intramuscular glucagon in youth
with type 1 diabetes. Diabetes Care. 2016;39(4):555-562.
8. Guzman CB, Dulude H, Piché C, et al. Effects of common cold
and concomitant administration of nasal decongestant on the
pharmacokinetics and pharmacodynamics of nasal glucagon
in otherwise healthy participants: a randomized clinical trial.
Diabetes Obes Metab. 2018;20(3):646-653.
9. American Diabetes Association. Standards of medical care in
diabetes—2019. Diabetes Care. 2019;42(suppl 1):S1-S204.
http://care.diabetesjournals.org/content/42/Supplement_1.
Accessed April 4, 2019.
10. Yale JF, Dulude H, Egeth M, et al. Faster use and fewer failures
with needle-free nasal glucagon versus injectable glucagon
in severe hypoglycemia rescue: a simulation study. Diabetes
Technol Ther. 2017;19(7):423-432.
Borden et al 703

11. Eli Lilly and Company. Clinical usability of intranasal

13. Eli Lilly and Company. Efficacy and safety of nasal gluca-
glucagon in treatment of hypoglycemia. NLM Identifier: gon for treatment of hypoglycemia in adults. NLM Identifier:
NCT02171130. ClinicalTrials.gov. https://clinicaltrials.gov/ NCT01994746. ClinicalTrials.gov. https://clinicaltrials.gov/
ct2/show/NCT02171130. Accessed April 8, 2019. ct2/show/NCT01994746. Accessed April 8, 2019.
12. Seaquist ER, Dulude H, Zhang XM, et al. Prospective study 14. Yanoff LB. NDA approval letter: Baqsimi (glucagon nasal
evaluating the use of nasal glucagon for the treatment of mod- powder) (NDA 210134). Food and Drug Administration.
erate to severe hypoglycaemia in adults with type 1 diabetes https://www.accessdata.fda.gov/drugsatfda_docs/appletter/20
in a real-world setting. Diabetes Obes Metab. 2018;20(5): 19/210134Orig1s000ltr.pdf. Published July 24, 2019. Accessed
1316-1320. August 7, 2019.
897071
research-article2019
HPXXXX10.1177/0018578719897071Hospital PharmacyKozhokar et al

FMS

Hospital Pharmacy

Lefamulin
2022, Vol. 57(6) 704­–711
© The Author(s) 2019
Article reuse guidelines:
sagepub.com/journals-permissions
DOI: 10.1177/0018578719897071
https://doi.org/10.1177/0018578719897071
journals.sagepub.com/home/hpx

Liliya Kozhokar1, Terri L. Levien1 , and Danial E. Baker1

Abstract

Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well-documented monographs on drugs that
are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees.
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Keywords
anti-infectives, drug information, formulary management/P & T, infectious diseases

Generic Name: Lefamulin
Proprietary Name: Xenleta (Nabriva Therapeutics US, Inc)
Approval Rating: 1P
Therapeutic Class: Antibiotics, Pleuromutilins
Similar Drugs: Retapamulin
Sound- or Look-Alike Names: Leflunomide, Xenical
Indications
Lefamulin is indicated for the treatment of adults with com-
munity-acquired bacterial pneumonia (CABP) caused by the
following susceptible microorganisms: Streptococcus pneu-
moniae, Staphylococcus aureus (methicillin-susceptible
Staphylococcus aureus [MSSA] isolates), Haemophilus
influenzae, Legionella pneumophila, Mycoplasma pneu-
moniae, and Chlamydophila pneumoniae.1
Lefamulin is also undergoing evaluation for use in the
treatment of health care–acquired bacterial pneumonia/ven-
tilator-associated bacterial pneumonia, osteomyelitis, pros-
thetic joint infections, acute bacterial skin and skin structure
infections, and sexually transmitted diseases.2,3
Clinical Pharmacology
Lefamulin, a pleuromutilin derivative, is a semisynthetic
antibacterial agent for oral and intravenous (IV) administra-
tion that inhibits bacterial protein synthesis by selectively
binding to the peptidyl transferase center of the 50S subunit
of the bacterial ribosome, preventing correct positioning of
the 3′ CCA ends of tRNAs (transfer ribonucleic acids) for
peptide transfer.1,4,5
Lefamulin’s in vitro antibacterial profile includes a broad
spectrum of common bacterial pathogens causing respiratory
tract, sexually transmitted, and skin and skin structure infec-
tions. The antibacterial spectrum comprises the gram-positive
bacteria S pneumoniae, S aureus (including methicillin-resis-
tant Staphylococcus aureus [MRSA] and community-acquired
MRSA), Streptococcus agalactiae, Streptococcus pyogenes,
Streptococcus anginosus, Streptococcus mitis, Streptococcus
salivarius, and Enterococcus faecium (including vancomycin-
resistant enterococci); the gram-negative bacteria H influen-
zae, Haemophilus parainfluenzae, Moraxella catarrhalis, and
Neisseria gonorrhoeae; and the atypical pathogens L pneu-
mophila, C pneumoniae, Chlamydia trachomatis, Mycoplasma
genitalium, and M pneumoniae.1,5-12 Lefamulin is bactericidal
in vitro against S pneumoniae, H influenzae, and M pneu-
moniae (including macrolide-resistant strains) and bacterio-
static against S aureus and S pyogenes at clinically relevant
concentrations. It is not active against Enterobacteriaceae and
Pseudomonas aeruginosa.1,12
In cross-resistance studies, lefamulin remained active
against some clinical isolates resistant to macrolides, tetra-
cyclines, beta-lactams, quinolones, sulfamethoxazole/trim-
ethoprim, mupirocin, and glycopeptides.1,11 Resistance due
to spontaneous mutations has been observed infrequently.
Resistance mechanisms affecting lefamulin include specific
protection or modification of the ribosomal target by ABC-F
proteins, Cfr methyltransferase, or mutations of ribosomal
proteins L3 and L4.1,13 Cfr methyltransferase has the
1Washington State University, Spokane, USA
Corresponding Author:
Terri L. Levien, Pharmacotherapy Department, College of Pharmacy and
Pharmaceutical Sciences, Washington State University, 412 E. Spokane
Falls Blvd, Spokane, WA 99202-2131, USA.
Email: levient@wsu.edu
Kozhokar et al 705
Table 1.  Pharmacokinetics of Single or Multiple Dosesa of
Lefamulin in Patients With Community-Acquired Bacterial
Pneumonia.1
Mean value after Mean value at
Parameter Route single dose steady state
Cmax, mcg/mL IV 3.5
Oral 2.24
Cmin, mcg/mL IV 0.398
Oral 0.593
AUC0-24h, mcg h/mL IV 27
Oral 30.7
Note. IV = intravenous; AUC = area under the curve.
a150 mg IV infused over 60 minutes (every 12 hours for multiple dosing);
600 mg orally 1 hour before or 2 hours after a meal (every 12 hours for
multiple dosing).
potential to mediate cross-resistance between lefamulin and
phenicols, lincosamides, oxazolidinones, and streptogramin
A antibacterials.1
In vitro, lefamulin has demonstrated synergy with doxy-
cycline against S aureus. No antagonism was observed
between lefamulin and other antibacterials (eg, amikacin,
azithromycin, aztreonam, ceftriaxone, levofloxacin, line-
zolid, meropenem, penicillin, tigecycline, sulfamethoxazole/
trimethoprim, vancomycin).1,14
Pharmacokinetics
Mean pharmacokinetic parameters observed after lefamulin
single doses of 150 mg IV and 600 mg orally in the fasted
state were comparable.1,15 Mean oral bioavailability of
lefamulin is approximately 25%, and peak plasma concentra-
tion (Cmax) occurred 0.88 to 2 hours after administration to
healthy participants.1 Bioequivalence was not established
between oral lefamulin in the fed state and IV or oral admin-
istration in the fasted state; exposure was reduced and time to
peak concentration was prolonged (median, 4.5 hours) when
administered with food.1,15,16 Coadministration of a single
oral dose of lefamulin 600 mg with a high-fat (approximately
50% of total calories from fat), high-calorie (approximately
800-1000 calories) breakfast slightly reduced bioavailability.
The mean relative reduction for oral lefamulin (fasted vs fed)
was on average 22.9% (90% confidence interval [CI], 12.2%-
32.3%) for Cmax and 18.43% (90% CI, 11.7%-24.7%) for
area under the curve (AUC0-∞). Following a single IV dose,
the AUC of lefamulin increased approximately dose propor-
tionally, whereas Cmax increased less than dose proportion-
ally over a dose range of 25 to 400 mg. Following a single
oral dose, lefamulin AUC increased more than dose propor-
tionally over a dose range of 500 to 750 mg. Mean lefamulin
AUC0-24h and Cmax were 73% and 30% higher, respectively,
in patients with CABP compared with healthy participants.1
The pharmacokinetics of oral and IV lefamulin in patients
with CABP are summarized in Table 1.1
Mean plasma protein binding of lefamulin ranges from
94.8% at 2.35 mcg/mL to 97.1% at 0.25 mcg/mL in healthy
adults.1 The mean steady-state volume of the distribution of
lefamulin is 86.1 L (range, 34.2-153 L) in patients with CABP
after IV administration of lefamulin. Following single IV
administration of lefamulin 150 mg to healthy participants,
3.6
the highest lefamulin epithelial lining fluid (ELF) concentra-
2.24
tions were observed at the end of infusion. Mean ELF and
0.573
plasma AUC0-8 were 3.87 and 5.27 mcg h/mL, respectively.
0.765
28.6
Following a single IV administration, the estimated ratio of
32.7 ELF AUC to unbound plasma AUC is approximately 15.1
Mean total body clearance of lefamulin is 11.9 L/h (range,
2.94-30 L/h) in patients with CABP after IV administration.
Mean elimination half-life of lefamulin is approximately 8
hours (range, 3-20 hours) in patients with CABP.1
Lefamulin is primarily metabolized by CYP3A4. In
healthy adult participants administered radiolabeled lefam-
ulin IV and oral doses, the mean total radioactivity excreted
in feces was 77.3% (4.2%-9.1% unchanged) and 88.5%
(7.8%-24.8% unchanged), respectively, and mean total
radioactivity excreted in urine was 15.5% (9.6%-14.1%
unchanged) and 5.3% (percentage unchanged not deter-
mined), respectively.1
Pharmacokinetics did not differ based on age, sex, race,
weight, or renal impairment, including patients undergoing
hemodialysis.1 Lefamulin pharmacokinetics have been eval-
uated in noninfected participants with normal hepatic func-
tion and with moderate (Child-Pugh class B) or severe
(Child-Pugh class C) hepatic impairment following adminis-
tration of the injection form. Following IV administration,
half-life was prolonged in participants with severe hepatic
impairment compared with participants with normal hepatic
function (17.5 vs 11.5 hours). Protein binding of lefamulin
was also reduced in participants with hepatic impairment,
resulting in unbound active lefamulin concentrations that
increased with the degree of hepatic impairment. Unbound
lefamulin plasma AUC0-∞ was increased 3-fold in partici-
pants with severe hepatic impairment compared with partici-
pants with normal hepatic function. The effects on lefamulin
pharmacokinetics following oral administration in partici-
pants with hepatic impairment have not been assessed; the
oral formulation is not recommended in patients with moder-
ate or severe hepatic impairment.1
Comparative Efficacy
Indication: Community-Acquired Pneumonia
Guidelines
Guideline: Diagnosis and treatment of adults with com-
munity-acquired pneumonia: An official clinical practice
guideline of the American Thoracic Society and Infectious
Diseases Society of America
Reference: American Thoracic Society/Infectious Diseases
Society of America17
706 Hospital Pharmacy 57(6)
Comments: For healthy outpatient adults with commu-
nity-acquired pneumonia without comorbidities (eg,
chronic heart, lung, liver, or renal disease; diabetes mel-
litus; alcoholism; malignancy; asplenia) or risk factors
for antibiotic-resistant pathogens (MRSA, P aerugi-
nosa), treatment with amoxicillin, doxycycline, or a mac-
rolide (azithromycin, clarithromycin, clarithromycin
extended release) is recommended; macrolide therapy
should be considered only in areas with less than 25%
pneumococcal resistance to macrolides. For outpatient
adults with comorbidities, the guidelines recommend
combination therapy with amoxicillin/clavulanate or
cephalosporin plus a macrolide (azithromycin, clarithro-
mycin) or doxycycline, or monotherapy with a respira-
tory fluoroquinolone (levofloxacin, moxifloxacin,
gemifloxacin). Treatment strategies for inpatients with
community-acquired pneumonia are based on severity
and risk for drug resistance. For inpatient adults with
nonsevere community-acquired pneumonia without risk
factors for resistance, combination therapy with a beta-
lactam and macrolide (ampicillin/sulbactam, cefotaxime,
ceftriaxone, or ceftaroline plus azithromycin or clarithro-
mycin) or monotherapy with a respiratory fluoroquino-
lone (levofloxacin, moxifloxacin) is recommended; if
contraindications to both macrolides and fluoroquino-
lones exist, combination therapy with a beta-lactam and
doxycycline is an option. For inpatients with severe com-
munity-acquired pneumonia without risk factors for
resistance, a beta-lactam plus a macrolide or a beta-lac-
tam plus a fluoroquinolone is recommended. The guide-
lines note that further research is needed regarding the
use of newer agents, including lefamulin, for the treat-
ment of community-acquired pneumonia in adults.
Studies
Drug: Lefamulin vs Moxifloxacin
Reference: File TM, et al, 2019 (LEAP 1 trial)1,18,19
Study Design: Phase 3, randomized, double-blind, dou-
ble-dummy, active-controlled, parallel-group, multi-
center, noninferiority study
Study Funding: Nabriva Therapeutics
Patients: 551 patients (at least 18 years of age) with
acute CABP, with radiographic findings suggestive of
pneumonia, Pneumonia Outcomes Research Team
(PORT) risk class of at least III, and at least 3 of 4 symp-
toms consistent with the disease (new or increased cough,
Primary End Point(s)
purulent sputum production, chest pain, dyspnea).
Exclusion criteria were receipt of more than 1 dose of a
short-acting oral or IV antibacterial for CABP within 72
hours before randomization; need for concomitant sys-
temic antibacterial therapy potentially effective against
CABP pathogens; hospitalization for 2 or more days
within 90 days before symptom onset, or residence in a
nursing home or long-term health care facility within 30
days before symptom onset; confirmed or suspected
CABP caused by a pathogen resistant to any of the study
drugs or attributable to etiologies other than community-
acquired bacterial pathogens; noninfectious cause of pul-
monary infiltrates; confirmed or suspected pleural
empyema; or need for mechanical ventilation. Patients
were mostly male (60%) and white (87%). Median
patient age was 62 years (range, 19-91 years); more
patients in the lefamulin group were 65 years or older
(47.8% vs 39.3%) and 75 years or older (21% vs 15.3%).
Approximately 53% of patients had creatinine clearance
(CrCl) less than 90 mL/min. Approximately 72% of
patients were classified as PORT risk class III and 28%
as PORT risk class IV or V. Common comorbid condi-
tions included hypertension (41%), asthma or chronic
obstructive pulmonary disease (COPD; 17%), and diabe-
tes mellitus (13%). The most common pathogens at base-
line were S pneumoniae, H influenzae, M catarrhalis, M
pneumoniae, L pneumophila, and C pneumoniae.
Intervention: Patients were randomized (1:1) to receive
lefamulin 150 mg IV every 12 hours (n = 276) or moxi-
floxacin 400 mg every 24 hours (n = 275). Moxifloxacin-
treated patients received alternating doses of a placebo to
maintain blinding. After 3 days (6 doses), patients could
be switched to oral study drug if prespecified improve-
ment criteria were met (lefamulin 600 mg every 12 hours
or moxifloxacin 400 mg every 24 hours). If MRSA was
suspected at screening, patients in the moxifloxacin group
received adjunctive linezolid and patients in the lefamulin
group received linezolid placebo. Treatment duration
ranged from 5 to 10 days. In the initial protocol, patients
with CABP due to MRSA or L pneumophila and patients
with S pneumoniae with bacteremia received 10 days of
active treatment, whereas all other lefamulin-treated
patients received 5 days of active therapy and all other
moxifloxacin-treated patients received 7 days of active
therapy. After a protocol amendment, therapy duration
changed to 7 days for both lefamulin- and moxifloxacin-
treated patients, except for patients with MRSA who
received 10 days of active therapy. The median duration
of IV treatment was 7 days in the lefamulin group and 6
days in the moxifloxacin group, and the median duration
of oral therapy was 4 days in both groups. A switch from
IV to oral therapy occurred in 38.1% of lefamulin-treated
patients and in 44.3% of moxifloxacin-treated patients.
Results
•• Rate of early clinical response (ECR; defined as an
improvement in 2 or more CABP signs/symptoms, no
worsening in any signs/symptoms, and no use of a con-
comitant, nonstudy antibiotic for CABP) in the inten-
tion-to-treat (ITT) population at 96 (±24) hours after
the first study drug dose (Food and Drug Administration
[FDA]-required end point): 87.3% of patients with
lefamulin compared with 90.2% with moxifloxacin
Kozhokar et al 707
(treatment difference, −2.9% [95% CI, −8.5%-2.8%]);
noninferiority of lefamulin was demonstrated.
•• Rate of investigator assessment of clinical response
(IACR; defined as the resolution or improvement of
CABP such that no additional antibiotic therapy was
administered for CABP) at test of cure (5-10 days
after the last dose of the study drug) in the modified
intention-to-treat (mITT) and clinically evaluable
(CE) populations (European Medicines Agency
[EMA] coprimary end point):
|| mITT population: 81.7% of patients treated
with lefamulin compared with 84.2% treated
with moxifloxacin (treatment difference,
−2.6% [95% CI, −8.9%-3.9%]); noninferiority
of lefamulin was demonstrated.
|| CE population: 86.9% of patients treated with
lefamulin compared with 89.4% treated with
moxifloxacin (treatment difference, −2.5%
[95% CI, −8.4%-3.4%]); noninferiority of
lefamulin was demonstrated.
Secondary End Point(s)
•• Response (ECR) and success (IACR) by baseline
pathogen in the microbiological ITT population did
not differ substantially between the treatment groups,
but comparisons were limited by small numbers of
patients in the subgroups by pathogen. The ECR
ranged from 84.2% (M pneumoniae) to 100% (S
aureus) for lefamulin and from 85.7% (L pneumoph-
ila) to 100% (M catarrhalis) for moxifloxacin. The
IACR ranged from 72.7% (C pneumoniae) to 84.9% (S
pneumoniae) for lefamulin and from 68.4% (C pneu-
moniae) to 100% (M catarrhalis) for moxifloxacin.
Other End Point(s)
•• The most common treatment-emergent adverse events
were hypokalemia, nausea, insomnia, and infusion-
site pain in the lefamulin group (each in 2.9% of
patients) and diarrhea in the moxifloxacin group
(7.7%). Rates of study drug discontinuation due to
treatment-emergent adverse events were 2.9% for
lefamulin and 4.4% for moxifloxacin.
Comments: Most patients were enrolled in Eastern
Europe (79%); less than 1% were enrolled in North
America. Baseline pathogens were similar between the 2
groups. Noninferiority of lefamulin was concluded if the
Primary End Point(s)
lower limit of the 2-sided 95% CI for the treatment differ-
ence in ECR responder rates was greater than −12.5% and
if the lower limit of the 2-sided 95% CI for the treatment
difference in IACR success rates was greater than −10%
for both the mITT and CE populations. The ECR and
IACR rates by PORT risk class did not differ between the
lefamulin and moxifloxacin treatment groups. The sub-
population analysis suggested that moxifloxacin was
more effective than lefamulin in patients younger than 65
years based on rates of both ECR (93.4% with moxifloxa-
cin vs 84.7% with lefamulin) and IACR (88% vs 75.9%),
as well as in patients with minor disease severity accord-
ing to American Thoracic Society criteria (93.8% vs
75.9% for ECR and 89.6% vs 62.3% for IACR); in
patients younger than 65 years, response rates were sig-
nificantly lower with lefamulin than with moxifloxacin in
the presence of minor disease severity compared with
those not meeting criteria for minor disease severity.
Limitations: This study included a small number of
patients with severe disease (PORT risk class V); enroll-
ment from North America, Western Europe, and Latin
America was low, precluding a sensitivity analysis by
geographic region.
Reference: Alexander E, et al, 2019 (LEAP 2 trial)1,20-22
Study Design: Phase 3, randomized, double-blind, dou-
ble-dummy, multicenter, noninferiority study
Study Funding: Nabriva Therapeutics
Patients: 738 patients (at least 18 years of age) with
CABP and at least 3 of 4 symptoms consistent with the
disease (dyspnea, new or increased cough, purulent spu-
tum production, chest pain) and a PORT risk class of II
to IV. Exclusion criteria were receipt of more than 1 dose
of a short-acting oral or IV antibacterial for CABP within
72 hours before randomization; hospitalization for 2 or
more days within the past 90 days; confirmed or sus-
pected MRSA; risk of major cardiac events or dysfunc-
tion; significant hepatic, immunologic, or hematologic
diseases; or severe renal impairment (estimated CrCl
less than 30 mL/min). Patients were mostly white (74%),
and 52% were male. Median patient age was 59 years
(range, 19-97 years); approximately 16% were 75 years
or older. Approximately 50% had CrCl of less than 90
mL/min. Approximately 50% of patients were classified
as PORT risk class II and 49% as PORT risk class III or
IV. Common comorbid conditions included hyperten-
sion (36%), asthma or COPD (16%), and diabetes mel-
litus (13%).
Intervention: Patients were randomized (1:1) to receive
lefamulin 600 mg orally every 12 hours for 5 days (n =
370) or moxifloxacin 400 mg orally every 24 hours for 7
days (n = 368).
Results: The same FDA- and EMA-defined primary end
points from Leap 1 were evaluated.
•• Rate of ECR in the ITT population at 96 (±24) hours
after the first dose of the study drug: 90.8% of patients
with lefamulin compared with 90.8% with moxifloxacin
(treatment difference, 0.1% [95% CI, −4.4%-4.5%]);
noninferiority of lefamulin was demonstrated.
708 Hospital Pharmacy 57(6)
•• Rate of IACR at test of cure (5-10 days after the last
dose) in mITT and CE populations:
|| mITT population: 87.5% of patients with lefamu-
lin and 89.1% with moxifloxacin (treatment dif-
ference, −1.6% [95% CI, −6.3%-3.1%]).
|| CE population: 89.7% of patients with lefamulin
and 93.6% with moxifloxacin (treatment differ-
ence, −3.9% [95% CI, −8.2%-0.5%]); noninferi-
ority of lefamulin was demonstrated.
Secondary End Point(s)
•• Response (ECR) and success (IACR) by baseline
pathogen in the microbiological ITT population did
not differ substantially between the treatment
groups, but comparisons were limited by small
numbers of patients in the subgroups by pathogen.
The ECR ranged from 81.3% (L pneumophila) to
100% (S aureus, M pneumoniae) for lefamulin and
from 91.3% (S pneumoniae) to 100% (S aureus, M
catarrhalis, M pneumoniae, C pneumoniae) for
moxifloxacin. The IACR ranged from 75% (C pneu-
moniae) to 95% (M pneumoniae) for lefamulin and
from 83.3% (S aureus, H influenzae, C pneumoniae)
to 100% (M catarrhalis, M pneumoniae) for
moxifloxacin.
•• The ECR response rates by PORT risk class did not
significantly differ between groups (ITT population):
For PORT risk classes II, III, and IV, the rates were
91.8%, 91%, and 85%, respectively, with lefamulin
and 93.1%, 90.2%, and 85.7%, respectively, with
moxifloxacin.
•• Comments: For ECR and IACR, lefamulin noninferi-
ority vs moxifloxacin was concluded if the lower limit
of the 2-sided 95% CI for the treatment difference
exceeded −10%.
•• Limitations: Results are only available in a meeting
abstract and poster, and in the lefamulin prescribing
information. The study included a small number of
patients with severe disease (PORT risk class V).
Contraindications, Warnings, and
Precautions
Contraindications
Lefamulin is contraindicated in patients with known hyper-
sensitivity to lefamulin, to the pleuromutilin class of drugs,
or to any components of the formulation (tablets: colloidal
silicon dioxide, croscarmellose sodium, FD&C Blue No. 2
aluminum lake, ferrosoferric oxide, magnesium stearate,
mannitol, microcrystalline cellulose, polyethylene glycol,
polyvinyl alcohol, povidone K30, shellac glaze, talc, and
titanium dioxide; injection diluent: citric acid anhydrous,
sodium chloride, and trisodium citrate dihydrate).1
Lefamulin is also contraindicated with the use of sensitive
CYP3A4 substrates that prolong the QT interval (eg, pimo-
zide) because of the potential for increased plasma concen-
tration of these drugs leading to QT prolongation and cases
of torsades de pointes.1
Warnings and Precautions
Lefamulin has the potential to prolong the QT interval on
electrocardiogram (ECG). Lefamulin should be avoided in
patients with known prolongation of the QT interval or ven-
tricular arrhythmias, including torsades de pointes; in
patients receiving class IA (eg, quinidine, procainamide) or
class III (eg, amiodarone, sotalol) antiarrhythmic agents; and
in patients receiving other drugs that prolong the QT interval,
such as antipsychotics, erythromycin, pimozide, moxifloxa-
cin, and tricyclic antidepressants. In patients with renal fail-
ure who require dialysis, metabolic disturbances associated
with renal failure may lead to QT prolongation. In patients
with mild, moderate, or severe hepatic impairment, meta-
bolic disturbances associated with hepatic impairment may
lead to QT prolongation. If use with lefamulin cannot be
avoided in patients predisposed to QT prolongation or in
those receiving another drug that prolongs the QT interval,
ECG monitoring is recommended during treatment. The
magnitude of QT prolongation may increase with increased
concentrations of lefamulin or with an increased infusion
rate of the IV formulation; therefore, the recommended dose
and infusion rate should not be exceeded.1
Clostridioides difficile–associated diarrhea (CDAD) has
been reported with most antibacterial agents, including
lefamulin, and may range in severity from mild diarrhea to
fatal colitis. Clostridioides difficile–associated diarrhea must
be considered in all patients presenting with diarrhea follow-
ing antibacterial use.1
To reduce the risk of development of drug-resistant bacte-
ria, lefamulin should only be used in the treatment of infec-
tion proven or strongly suspected to be caused by susceptible
bacteria.1
Based on findings from animal studies, lefamulin may
cause fetal harm when administered to pregnant women.
Pregnancy status in women of reproductive potential must be
verified prior to initiating lefamulin therapy. Women of
reproductive potential should be advised to use effective
contraception during lefamulin treatment and for 2 days after
the final dose. A pregnancy pharmacovigilance program has
been established (1-855-5NABRIVA); health care profes-
sionals should report lefamulin exposure if the drug is inad-
vertently administered during pregnancy or if a patient
becomes pregnant while receiving lefamulin.1
There are no data regarding the presence of lefamulin in
human milk, or its effects on breastfeeding infants or milk
production. Animal studies showed that lefamulin was con-
centrated in the milk of lactating rats. Because of the poten-
tial for serious adverse reactions in a breastfeeding infant,
Kozhokar et al 709
Table 2.  Adverse Reactions (≥2% Incidence) in Patients Receiving Lefamulin (Lefamulin Evaluation Against Pneumonia 1 Study Safety
Population).1
Adverse reaction
Administration-site reactions (infusion-site pain,
infusion-site phlebitis, injection-site reaction)
Hepatic enzyme elevation (ALT increase, AST
increase, liver function test increase)
Nausea
Hypokalemia
Insomnia
Headache
Note. IV = intravenous; ALT = alanine aminotransferase; AST = aspartate aminotransferase.
Table 3.  Adverse Reactions (≥2% Incidence) in Patients Receiving Lefamulin (Lefamulin Evaluation Against Pneumonia 2 Study Safety
Population).1
Adverse reaction
Diarrhea
Nausea
Vomiting
Hepatic enzyme elevation (ALT increase,
AST increase, liver function test increase)
Note. ALT = alanine aminotransferase; AST = aspartate aminotransferase.
including QT prolongation, a woman should pump and dis-
card her milk for the duration of treatment with lefamulin
and for 2 days after the final dose.1
Safety and efficacy of lefamulin have not been established
in patients younger than 18 years.1 Initial pediatric studies
are expected to be completed in 2024.23
Adverse Reactions
The most common adverse reactions reported with lefamulin
include diarrhea, administration-site reactions, hepatic
enzyme elevation, nausea, hypokalemia, insomnia, and
headache.1 Tables 2 and 3 summarize the frequency of reac-
tions with the injection and oral formulations.
Drug Interactions
Concomitant use of oral or IV lefamulin with strong CYP3A4
inducers or P-gp inducers decreases lefamulin AUC and
Cmax, which may reduce the efficacy of lefamulin.
Concomitant use of lefamulin with strong CYP3A4 inducers
or P-gp inducers should be avoided unless the benefit out-
weighs the risk.1
Concomitant use of oral lefamulin with strong CYP3A
inhibitors or P-gp inhibitors increases lefamulin AUC,
IV with or without a switch to oral dosing
Lefamulin (n = 273), % Moxifloxacin (n = 273), %
7 3
3 3
3 2
3 2
3 2
2 2
Oral dosing
Lefamulin (n = 368), % Moxifloxacin (n = 368), %
12 1
5 2
3 1
2 2
which may increase the risk of adverse reactions.
Concomitant use of oral lefamulin with strong CYP3A4
inhibitors or P-gp inhibitors should be avoided; patients
receiving oral lefamulin with moderate CYP3A inhibitors
or P-gp inhibitors should be monitored for lefamulin
adverse effects.1
Concomitant use of lefamulin tablets with sensitive
CYP3A4 substrates increases AUC and Cmax of the CYP3A4
substrates, which may increase the risk of toxicities associ-
ated with cardiac conduction. Concomitant use of oral
lefamulin with CYP3A substrates known to prolong the QT
interval is contraindicated. Close monitoring for adverse
effects is required when using oral lefamulin concomitantly
with alprazolam, diltiazem, verapamil, simvastatin, or var-
denafil. Concomitant use of injectable lefamulin with
CYP3A substrates does not affect exposure to the CYP3A
substrates.1
The pharmacodynamic interaction potential to prolong
the QT interval between lefamulin and other drugs that effect
cardiac conduction is unknown. Concomitant use of inject-
able or oral lefamulin with drugs known to affect cardiac
conduction (eg, class IA and III antiarrhythmics, antipsy-
chotics, erythromycin, moxifloxacin, tricyclic antidepres-
sants) should be avoided.1
710 Hospital Pharmacy 57(6)
Recommended Monitoring
Hepatic function should be assessed; ECG should be moni-
tored in patients predisposed to or with risk factors for QT
prolongation. Prior to initiating therapy, pregnancy status
must be verified in women of reproductive potential.1
Dosing
The recommended lefamulin dosage is 150 mg every 12
hours by IV infusion over 60 minutes for 5 to 7 days, or 600
mg orally every 12 hours for 5 days. Intravenous dosing can
be switched to oral lefamulin therapy (600 mg every 12
hours) to complete the treatment course.1 The oral dose
should be administered at least 1 hour before or 2 hours after
a meal. The tablets should be swallowed whole with 6 to 8
ounces of water.1
Prior to administration, the injectable lefamulin solution
must be diluted in a 250 mL solution of 10 mM citrate-buff-
ered sodium chloride 0.9% using the aseptic technique. The
diluent IV bag should not be used in series connections, and
no other additives should be added to the bag.1
In patients with severe hepatic impairment (Child-Pugh
class C), the dosage of lefamulin injection should be reduced
to 150 mg administered by IV infusion over 60 minutes
every 24 hours; no adjustment to the injectable dosage is
required for patients with mild (Child-Pugh class A) or mod-
erate (Child-Pugh class B) hepatic impairment. In patients
with mild hepatic impairment, no adjustment to the oral dos-
age is required. Oral lefamulin has not been studied in and is
not recommended in patients with moderate or severe hepatic
impairment.1 No dosage adjustments are required in patients
with renal impairment.1
Product Availability and Storage
Lefamulin tablets and injection received FDA approval on
August 19, 2019.23 The oval, film-coated tablets contain
671 mg of lefamulin acetate (equivalent to 600 mg of
lefamulin) and are supplied in HDPE (high-density poly-
ethylene) bottles containing 30 tablets.1 The injection is
supplied as a clear, colorless, sterile, nonpyrogenic solu-
tion for IV administration containing 168 mg of lefamulin
acetate (equivalent to 150 mg of lefamulin) in 15 mL of
sodium chloride 0.9% in a single-dose vial. The vial must
be diluted using the supplied infusion bags containing 250
mL of 10 mM citrate-buffered (pH 5) sodium chloride
0.9%. The vials are packaged in cartons of 6, and the
citrate-buffered diluent bags are separately packaged in
cartons of 6.1
Lefamulin injection should be stored at 2°C to 8°C
(36°F-46°F). The diluent bags should be stored at 20°C to
25°C (68°F-77°F), with excursions permitted between 15°C
and 30°C (59°F and 86°F). After dilution, the injectable solu-
tion may be stored for up to 24 hours at room temperature or
for up to 48 hours when refrigerated at 2°C to 8°C (36°F-46°F).
Lefamulin tablets should also be stored at 20°C to 25°C
(68°F-77°F), with excursions permitted between 15°C and
30°C (59°F and 86°F).1
Drug Safety/Risk Evaluation and
Mitigation Strategy
No Risk Evaluation and Mitigation Strategy (REMS) is
required for lefamulin.23
Conclusion
Lefamulin, a pleuromutilin, is approved by the FDA for the
treatment of adults with CABP caused by susceptible
microorganisms. Lefamulin is available as an IV or oral
formulation, and efficacy is supported by 2 phase 3 clinical
studies demonstrating noninferiority to moxifloxacin in
the treatment of CABP. Use should be limited to infections
suspected or observed to be resistant to alternative agents.
Adverse event and drug interaction data are limited.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
ORCID iDs
Terri L. Levien https://orcid.org/0000-0001-5114-6067
Danial E. Baker https://orcid.org/0000-0002-4605-3357
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appletter/2019/211672Orig1s000,%20211673Orig1s000ltr.
pdf. Published August 19, 2019. Accessed September 4, 2019.
1078815
research-article2022
HPXXXX10.1177/00185787221078815Hospital PharmacyNguyen et al

Original Article

Hospital Pharmacy

Short-Term Readmission Following

2022, Vol. 57(6) 712­–720
© The Author(s) 2022
Article reuse guidelines:
Community-Acquired Pneumonia: sagepub.com/journals-permissions
DOI: 10.1177/00185787221078815
https://doi.org/10.1177/00185787221078815

A Cross-Sectional Study journals.sagepub.com/home/hpx

Dung Thien Nguyen1,2, Sang Thanh Huynh2,3,

and Ho Nhu Nguyen2,4

Abstract

Background: Community-acquired pneumonia continues to be a major cause of morbidity and mortality. Hospital
readmissions following community-acquired pneumonia are linked to significant cost of care and medical burdens. This
study aimed to determine the incidence and reasons for readmission as well as to assess factors associated with short-term
hospital readmission among community-acquired pneumonia patients. Methods: A retrospective, cross-sectional study
was conducted on 582 medical records of community-acquired pneumonia inpatients from December 2018 to December
2019 at an 800-bed tertiary hospital in Ho Chi Minh City, Vietnam. We collected data on patient characteristics, pneumonia
severity at hospital admission, microbiology and antibiotic resistance, appropriateness of empiric antibiotic therapies, and the
readmissions information. Multivariable logistic regression analyses were performed to identify factors associated with 30-day
hospital readmission. Results: Of the 582 hospitalized community-acquired pneumonia patients, 11.9% were readmitted to
the hospital within 30 days. About half of the cases (43.5%) were due to pneumonia. Multidrug-resistant bacteria accounted
for 43.2% of the pathogen isolates. A high Charlson comorbidity index (aOR, 1.40; CI 95%, 1.08-1.82) and multidrug-resistant
infection (aOR, 2.63; CI 95%, 1.05-6.56) were associated with higher odds of all-cause readmission. Conclusions: Hospital
readmissions within 30 days occurred frequently among community-acquired pneumonia inpatients, and the most common
reason for readmission recorded was pneumonia-related. Monitoring closely patients with multimorbidity or multidrug-
resistant infections may improve treatment outcomes.

Keywords
community-acquired pneumonia, readmission, antibiotic, antibiotic resistance.

Introduction patient characteristics, comorbidities, adherence to guide-

Community-acquired pneumonia (CAP) is one of the world’s
leading causes of morbidity and mortality.1 CAP accounts for
1.2 million hospitalizations per year in the United States and
also is the most significant cause of death among elderly
patients in comparison to other infectious diseases.2 In
Vietnam, CAP accounts for 47% of lower respiratory tract
infections with the annual estimated hospitalized incidence
rate of 81/100 000 person-years.3
Readmission following CAP is one of the clinically rel-
evant outcome parameters of CAP according to the Infec­
tious Diseases Society of America and American Thoracic
Society (IDSA/ATS).4 In the United States, it is estimated
that about 18% of hospitalized patients are readmitted
within 30 days of discharge.2
There are many factors associated with short-term read-
mission following CAP described in prior studies including
lines based antibiotic therapy, and certain social factors.5–9
However, there was a limited number of studies evaluating
1
Department of Pharmacy, University Medical Center Ho Chi Minh City,
Ho Chi Minh City, Vietnam
2
Department of Clinical Pharmacy, School of Pharmacy, University
of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City,
Vietnam
3
Department of Clinical Pharmacy, School of Pharmacy, Ho Chi Minh
City University of Technology (HUTECH University), Ho Chi Minh City,
Vietnam
4
Department of Pharmacy, Nguyen Trai Hospital, Ho Chi Minh City,
Vietnam
Corresponding Author:
Ho Nhu Nguyen, Department of Clinical Pharmacy, School of Pharmacy,
University of Medicine and Pharmacy at Ho Chi Minh City, 41 Dinh Tien
Hoang Street, Ben Nghe District, Ho Chi Minh City 70000, Vietnam.
Email: nhnguyen@ump.edu.vn
Nguyen et al 713
the impacts of multidrug-resistant (MDR) infections on read-
mission outcome among CAP patients. Meanwhile, antimi-
crobial resistance is a major healthcare problem worldwide
and also in Vietnam, given that a high prevalence of resis-
tance to common antimicrobials is seen in both nosocomial
and community-acquired infections.10–12
Because pneumonia hospital readmission is one of the
factors associated with a rise in healthcare expenditure and
medical resources,13,14 identifying patients who are at risk for
readmissions is important to both healthcare professionals
and policy makers.
Therefore, this study aimed to determine the following:
(1) incidence of 30-day hospital readmission, (2) primary
reason for readmission (pneumonia vs non-pneumonia
related) and (3) patient specific risk factors associated with
readmissions among hospitalized CAP patients.
Methods
Ethics approval was obtained from the Institutional Review
Board of Nguyen Trai Hospital (Approval reference number:
1064/QĐ-BVNT; Date of approval: November 20, 2020).
The procedures used in this study adhere to the tenets of the
Declaration of Helsinki.
Study Design and Setting
A retrospective, cross-sectional study was conducted on
adults 18 years of age or older, who were hospitalized with a
CAP diagnosis between December 2018 and December
2019. This study was carried out at an 800-bed tertiary hos-
pital at Ho Chi Minh City, Vietnam. The hospital currently
has 23 wards and provides general healthcare services for
approximately 1000 outpatients, 600 inpatients, and 200
emergency department visits per day.
Participants
All patients hospitalized with a primary diagnosis of CAP
based on International Classification of Diseases, Tenth
Revision (ICD-10) codes were included in the study if they
were at least 18 years of age and hospitalized for a minimum
of 5 days with a diagnosis of CAP (ICD-10 codes J12-J18)
between December 2018 and December 2019.
We excluded patients who (i) were hospitalized ≥ 2 days
during the prior 90 days; (ii) had unresolved or worsening
symptoms of pneumonia at discharge; (iii) were transferred to
another healthcare center; (iii) discharged themselves against
medical advice; (iv) died in the hospital; (v) were known to
have active pulmonary tuberculosis at the time of admission
(ICD-10 codes A15-A16), and (vi) were diagnosed with HIV
infection (ICD-10 codes B20-B24, R75, Z21).
We tracked the 30-day readmission information by screen-
ing medical records as each patient had a unique patient code
for every admission at the hospital. If a patient was admitted
to the hospital more than 1 time within 30 days after dis-
charge, only the first readmission was considered as an index
readmission.
Measurements
Eligible medical records were reviewed to extract data on
patient demographics, microbiology and antibiotic resis-
tance, antibiotic therapies and their appropriateness, and
readmission information.
Clinical status and laboratory test results at the time of
admission were collected to evaluate the severity of pneumo-
nia using the CURB-65 score (score of 0 or 1: mild pneumo-
nia; score of 2: moderate pneumonia; and score of 3 or above:
severe pneumonia).15 Comorbidity burden was assessed
using the Charlson comorbidity index (CCI),16 which assigns
a weighted score to each comorbid condition depending on
the risk associated with one-year mortality.
Information on microbiology and susceptibility tests was
collected using samples from lower respiratory tract (sputum
or bronchoalveolar lavage fluid) or blood samples which
were acquired within 48 hours of hospital admissions. Gram
staining, conventional bacterial culture, and antimicrobial
susceptibility testing for typical bacteria were performed.
Disk diffusion testing was used to determine the antimicro-
bial susceptibility of the isolated pathogens. Tests for the
detection of atypical bacteria and viruses were not available
at the hospital’s laboratory. A pathogen was considered to be
MDR if it was resistant to at least 3 antimicrobial agents
belonging to 3 different antimicrobial classes.17
We assessed the appropriateness of the empiric antibiotic
selection using the 2007 ATS/IDSA consensus guidelines4
and hospital guidelines for CAP. The 2019 IDSA CAP guide-
line recommendations were not applied at the time of the
study, as it takes time for new recommendations to be imple-
mented into clinical practice.
Clinical instability at hospital discharge was defined
using the 2007 IDSA/ATS criteria.4 In brief, a patient with
any of the following criteria within 24 hours before dis-
charge was considered to be unstable: (i) temperature >
37.8°C, (ii) heart rate > 100 beats per min, (iii) systolic
blood pressure < 90 mmHg, (iv) respiratory rate > 24
breaths per min, (v) oxygen saturation <90% or pO2 <
60 mmHg, (vi) abnormal mental status or (vii) inability to
eat. For those whose arterial blood gas results were not
available, oxygenation was considered to be unstable if the
patients experienced dyspnea (at room air), required oxygen
support within 24 hours prior to discharge or had a SpO2
value lower than 90%.18
714 Hospital Pharmacy 57(6)
Figure 1.  Short-term hospital readmission among community-acquired pneumonia inpatients.
The flowchart describes how the final population was selected. CAP: community-acquired pneumonia.
A hospital readmission was considered pneumonia-related
if the patient had a primary diagnosis of pneumonia based on
ICD-10 codes J12-J18. Patients were categorized as having a
pneumonia-unrelated readmission if their primary diagnoses
were different from pneumonia.
Statistical Methods
We compared the characteristics between patients who had
all-cause hospital readmissions and those who did not. For
these analyses, continuous variables were compared using a
t-test (normally distributed data) or Mann–Whitney test
(non-normally distributed data), and categorical variables
were compared using a Chi-square test or Fisher’s exact test.
Multivariable logistic regression analyses were performed to
identify factors associated with all-cause readmissions. We
included the following factors in the analyses (considering
their potential association with hospital readmissions
described in prior studies and based on clinical practice): (i)
age; (ii) sex (male/female); (iii) CURB-65 score; (iv) CCI (v)
MDR infection (yes/no); (vi) duration of antibiotic therapy;
(vii) appropriate empiric antibiotic therapy (yes/no); (viii)
number of clinical instabilities at discharge.
All analyses were performed using SPSS version 20.0
with the significance level of 5%.
Results
Between December 2018 and December 2019, there were
684 hospitalized CAP patients discharged alive. Of those, 49
had unresolved or worsening symptoms of pneumonia at
discharge, 10 were transferred to another healthcare center,
and 43 discharged themselves against medical advice. After
excluding these patients, the final number of index hospital
admissions for CAP was 582 (Figure 1).
Demographic and Clinical Characteristics of the
Study Population
More than 3 quarters of the study population (76.1%) were
over the age of 65 years. Females accounted for more than
half of the study population (54.6%). CURB-65 score calcu-
lation was performed on 579 patients to determine the pneu-
monia severity, with more than half (62.2%) having mild
pneumonia. The median CCI was 1 (1-2), with 74.1% of the
patients having a CCI ≥ 1. Hypertension and coronary heart
disease were the most frequent comorbidities observed in the
study. Median duration of antibiotic therapy and length of
hospital stay were 13 days and 14 days, respectively. There
were 579 out of 582 patients treated with an empiric antibi-
otic therapy, the other 3 patients had delayed antibiotic treat-
ment until the antimicrobial susceptibility testing results
were available. Appropriate use of empiric antibiotic therapy
was observed in 51.6% of the patients. There were 106
patients (18.2%) discharged with at least one clinical insta-
bility factor. Detailed information about characteristics of the
study population is provided in Table 1.
Characteristics of Pathogens Causing CAP
Among 582 patients hospitalized for CAP, bacterial culture
identification was indicated in 301 patients within 48 hours
Nguyen et al 715

Table 1.  Demographic and Clinical Characteristics of the Study Reasons for Hospital Readmission
Population (n = 582).
Sixty-nine out of 582 CAP patients (11.9%) were readmitted
Characteristics Frequency (%) to the hospital within 30 days after discharge. The most sig-
Sex nificant cause of hospital readmission was pneumonia
 Male 264 (45.4) (36.2%), followed by cardiovascular causes (29.0%).
Age Reasons for rehospitalizations were illustrated in Table 3.
  ≥65 years 443 (76.1)
 Median 76 (65-83) Factors Associated With Hospital Readmission
Comorbidities
Within 30 days
 Hypertension 483 (83.0)
  Coronary heart disease 373 (64.1) A higher percentage of patients above the age of 65 years was
  Cerebrovascular disease 96 (16.5) observed in the 30-day readmission group compared to the
  Congestive heart failure 102 (17.5) non-readmisison group (82.6% vs 75.2%, P > .05). Patients
  Diabetes mellitus 195 (33.5) who had readmission within 30 days had higher prevalence
  Chronic kidney disease 42 (7.2) of comorbidities, specifically congestive heart failure (34.8%
  Chronic obstructive pulmonary 81 (13.9) vs 15.2%, P < .001) and chronic kidney disease (18.8% vs
disease 5.7%, P < .001). CCI was also higher in those with readmis-
 Malignancy 25 (4.3)
sions than those without (2 vs 1, P < .001). The percentage of
No. of comorbidities 5 (3-6)
MDR bacteria isolates was significantly higher in the read-
Charlson comorbidities index
mission group (24.3% vs 11.4%, P = .037). Appropriate use
  ≥1 431 (74.1)
of empiric antibiotic therapy was observed with a lower
 Median 1 (0-2)
Severity (CURB-65)a
prevalence in readmitted than non-readmitted patients
 0-1 360 (62.2) (34.8% vs 53.9%, P = .003). Characteristics of patients with
 2 175 (30.1) and without 30-day readmission are shown in Table 4.
  ≥3 44 (7.6) In the multivariable logistic regression analyses shown in
 Median 1 (1-2) Table 5, a high CCI (aOR, 1.40; 95% CI, 1.08-1.82) and
Empiric antibioticsc   MDR infection (aOR, 2.63; 95% CI 1.05-6.56) were associ-
  β-lactam or β-lactam/β-lactamase 500 (85.9) ated with higher odds of all-cause readmissions.
inhibitor
 Fluoroquinolone 310 (53.3) Discussion
 Otherd 17 (2.9)
Duration of antibiotic therapy (days) 13 (9-14) Overall, 582 CAP inpatients were included in this retrospec-
Appropriate use of empiric antibiotic 299 (51.6) tive, cross-sectional study. Of which, 69 patients (11.9%)
therapyb were readmitted within 30 days of discharge. The number of
Length of stay (days) 14 (11-18) readmissions due to pneumonia-related causes were 25
Clinical instabilities   (36.2%). Results from multivariable logistic regression anal-
  ≥1 106 (18.2) yses showed that a high CCI and infection caused by a MDR
 Median 0 (0-0) pathogen were associated with the increased likelihood of
Values are given as frequency (percentage) or median (interquartile
all-cause readmissions within 30 days among CAP patients.
range).
Characteristics of Pathogens Causing CAP
a
n = 579 (3 patients whose CURB-65 score could not be measured).
b
n = 579 (3 patients did not receive empiric antibiotic therapy).
c
Some patients were prescribed with combination therapies, so the totals Among the pathogens isolated, Klebsiella pneumonia (35.8%)
add to more than 100 percent.
d
Other antibiotics included aminoglycoside (8), macrolide (4),
and Staphylococcus aureus (20.0%) were the most common.
glycopeptide (2), lincosamide (2), oxazolidinone (1). Notably, major CAP pathogens such as Streptococcus pneu-
moniae, Haemophilus influenzae, and Moraxella catarrhalis
accounted for a very small percentage (1.1%-2.1%). Some
of admission. There were 95 bacterial isolates, 41 (43.2%) patients might have been exposed to antibiotics, or self-med-
of which were MDR bacteria (Table 2). The majority of bac- icated with antibiotics in the outpatient settings prior to the
teria strains identified in this study were Gram-negative index hospital admissions,19 which decreased the detection
bacteria, with Klebsiella pneumoniae being the most preva- rates of community-acquired bacteria such as Streptococcus
lent (35.8%). Staphylococcus aureus was the most com- pneumoniae and Haemophillus influenzae in culture-based
monly isolated Gram-positive pathogens (20.0%). tests.20–22 Moreover, the sputum culture method had low
716 Hospital Pharmacy 57(6)

Table 2.  Characteristics of Isolated Pathogens Causing CAP.

Strains of isolated bacteria No. of isolates % No. of MDR %

Gram-negative bacteria 74 77.9 24 58.5
  Klebsiella pneumoniae 34 35.8 1 2.4
  Escherichia coli 11 11.6 7 17.1
  Pseudomonas aeruginosa 9 9.5 1 2.4
  Proteus mirabilis 7 7.4 5 12.2
  Haemophilus parainfluenzae 4 4.2 4 9.8
  Acinetobacter spp. 3 3.2 3 7.3
  Pseudomonas spp. 2 2.1 1 2.4
  Moraxella catarrhalis 2 2.1 0 0.0
  Haemophilus influenzae 1 1.1 1 2.4
  Burkholderia spp. 1 1.1 1 2.4
Gram-positive bacteria 21 22.1 17 41.5
  Staphylococcus aureus 19 20.0 15 36.6
  Streptococcus pneumoniae 1 1.1 1 2.4
  β-hemolytic Streptococci 1 1.1 1 2.4
Total 95 100.0 41 100.0

MDR: multidrug-resistant.

Table 3.  Reasons for Readmissions Within 30 days of Discharge (n = 69).

Reasons Number of patients %

Pneumonia-related 25 36.2
Pneumonia-unrelated
  Cardiovascular 20 29.0
 Hypertension 6 8.7
  Congestive heart failure 5 7.2
  Ischemic heart disease 3 4.3
  Hypertensive urgency 3 4.3
 Stroke 1 1.4
  Non-ST-segment elevation myocardial infarction 1 1.4
  Angina pectoris 1 1.4
  Gastrointestinal 8 11.6
  Gastrointestinal bleeding 2 2.9
  Gastro-intestinal reflux disease 2 2.9
 Cirrhosis 2 2.9
 Dyspepsia 1 1.4
  Functional diarrhea 1 1.4
  Pulmonary (unrelated to pneumonia) 6 8.7
  Chronic obstructive pulmonary disease 5 7.2
 Asthma 1 1.4
  Other infection 4 5.8
  Intestinal infection 2 2.9
  Urinary tract infection 1 1.4
  Upper respiratory tract infection 1 1.4
  Other 6 8.7
  Iron deficiency anemia 1 1.4
  Age-related physical debility 1 1.4
  Vestibular function disorder 1 1.4
 Malignancy 1 1.4
  Injury of toe 1 1.4
  Parkinson’s disease 1 1.4
Nguyen et al 717

Table 4.  Characteristics of Patients With and Without 30-day Readmission.

Characteristics 30-day readmission (n = 69) Non-readmission (n = 513) P

Sex
 Male 35 (50.7) 229 (44.6) .340
Age
  ≥65 years 57 (82.6) 386 (75.2) .178
  Median years 77 (66-83) 76 (65-83) .366
Comorbidities
 Hypertension 60 (87.0) 423 (82.5) .350
  Coronary heart disease 48 (69.6) 325 (63.4) .313
  Cerebrovascular disease 13 (18.8) 83 (16.2) .576
  Congestive heart failure 24 (34.8) 78 (15.2) <.001
  Diabetes mellitus 28 (40.6) 167 (32.6) .185
  Chronic kidney disease 13 (18.8) 29 (5.7) <.001
  Chronic obstructive pulmonary disease 13 (18.8) 68 (13.3) .208
 Malignancy 4 (5.8) 21 (4.1) .523
No. of comorbidities 5 (4-7) 5 (3-6) .001
Charlson comorbidities index
  ≥1 59 (85.5) 372 (72.5) .021
 Median 2 (1-3) 1 (0-2) <.001
Severity (CURB-65)a
 0-1 39 (56.5) 321 (62.9) .302
 2 23 (33.3) 152 (29.8) .549
  ≥3 7 (10.1) 37 (7.3) .395
 Median 1 (1-2) 1 (1-2) .203
Microbiologyb
  Multidrug-resistant infection 9 (24.3) 30 (11.4) .037
Duration of antibiotic therapy (days) 12 (9-15) 13 (9-14) .946
Appropriate use of empiric antibiotic therapyc 24 (34.8) 275 (53.9) .003
Length of stay (days) 14 (12-20) 14 (11-17) .171
Clinical instabilities
  ≥1 14 (20.3) 92 (17.9) .634
  Median (IQR) 0 (0-0) 0 (0-0) .715

Note. Values were given as frequency (percentage) or median (interquartile range).

P-value obtained from comparing the characteristics between 2 groups.
a
Readmission: n = 69; Non-readmission: n = 510 (3 patients whose CURB-65 score could not be measured).
b
Readmission: n = 37; Non-readmission: n = 264 (281 patients were not indicated for bacterial culture identification).
c
Readmission: n = 69; Non-readmission: n = 510 (3 patients did not receive empiric antibiotic therapy).

Table 5.  Multivariable logistic regression analysis of factors sensitivity to detect Streptococcus pneumoniae,3,23 while
associated with all-cause hospital readmissions among CAP Staphylococcus aureus and aerobic Gram-negative bacteria
patients. were easier to be detected so their proportions might be con-
siderably larger than the actual results.24
Variable P OR 95 % CI
Age .392 1.02 0.98-1.05
Male sex .109 1.85 0.87-3.90
Reasons for Admissions
CURB-65 score .626 0.86 0.48-1.56 The all-cause readmission rate following hospital treatment
Charlson comorbidity index score .010 1.40 1.08-1.82 for CAP was 11.9%, in comparison to 7.3% to 15.5% in pre-
Multidrug-resistant infection .039 2.63 1.05-6.56 vious studies.6,25–29 The 30-day rehospitalization incidence
Duration of antibiotic therapy .112 1.06 0.99-1.14 from our study was more similar to those conducted on the
Appropriate use of empiric .061 0.46 0.21-1.04 elderly population (12.3%-15.5%)6,29 than those conducted
antibiotic therapy
on adults aged  ≥ 18 years (7.3%-12%).25–28 Pneumonia-
Clinical instabilities at discharge .101 0.47 0.19-1.16
related readmission rate within 30 days of discharge was
718 Hospital Pharmacy 57(6)
higher in our study (36.2%) compared to other studies
(16.9%-35.8%).25,27–29 Most patients in our study had at least
1 underlying condition along with pneumonia, including
chronic lung diseases, congestive heart failure, cerebrovas-
cular diseases, or diabetes. These conditions have long been
known as factors that could increase the risk of
pneumonia.30,31
Factors Associated With Hospital Readmission
Within 30 days
Our study confirmed the finding from prior studies that
comorbidities were associated with readmission in CAP
patients.6,32 In fact, the study population largely consisted of
elderly patients who had at least 1 comorbidity, specifically
cardiopulmonary diseases. People who had underlying
chronic lung conditions such as chronic obstructive pulmo-
nary diseases were also prone to recurrent CAP as they are
usually colonized with Streptococcus pneumoniae and
Haemophilus influenzae in the trachea and main stem bron-
chi. Along with the impaired cough and mucociliary clear-
ance, these bacteria could easily cause pneumonia in the
alveoli.33 In addition, for elderly patients that had several
comorbidities which were not adequately controlled during
the index hospital admission, this could slow the recovery
after a pneumonia or symptoms may continue to worsen after
discharge and lead to unplanned readmissions.
In our study, the percentage of MDR bacteria among the
isolates collected was considerably high (43.2% in total). As
expected, the multivariable regression analysis showed that
infection with a MDR organism was associated with rehospi-
talization within 30 days (aOR, 2.63; 95% CI, 1.05-6.56).
Infection caused by antibiotic resistant bacteria has been
proved to be an independent predictor of readmission fol-
lowing pneumonia in a study conducted by Andruska et al.34
Results from the study by Jang and Ahn27 also showed that
patients who were readmitted to the hospital after the first
treatment of CAP had a higher though not statistically sig-
nificant incidence of infection caused by a MDR organism
than their non-readmitted counterparts.
Adherence to empiric antibiotic regimens recommended
in the treatment guidelines was associated with lower mor-
tality rate, shorter length of stay in CAP patients in prior
studies.5,35,36 In the study conducted by Nour et al.,5 nonad-
herence to guideline-based antibiotic treatment was associ-
ated with a higher risk of all-cause 30-day readmission. In
our study, the overall adherence rate to empiric antibiotic
recommendations was moderate (51.6%), and it was lower
in patients who had 30-day hospital readmissions. Although
we did not find that appropriateness of antibiotic selection
was associated with 30-day readmission in the multivariable
regression analyses, this is still an important consideration
as overprescribing of antibiotics could increase the likeli-
hood of recurrent infections caused by antibiotic resistant
pathogens,37 while antibiotic underprescribing might not
resolve pneumonia and therefore leads to other adverse out-
comes.38,39 Furthermore, most pathogens causing CAP could
not be identified at the time of hospitalization especially in
developing countries, where molecular methods such as
polymerase chain reaction or urinary antigen test are not
always available. With a low culture positivity rate in CAP,
the choice of antibiotic treatment mostly depends on guide-
line-based recommendations. Our finding reassured the
need to adhere to current guidelines to improve outcomes in
CAP patients.
Our study did not find the association of other factors,
namely age, sex, pneumonia severity, duration of antibiotic ther-
apy, and clinical instabilities at discharge with hospital read­
mission, while prior studies showed opposite results.6,26,29,40,41
The most significant differences of these studies from ours were
(i) their outcome of interest was 60-day readmission41; (ii) their
study design was a prospective study,26 and (iii) their study sam-
ples had different baseline characteristics with respect to sex
and age.6,29,40
Strengths and Limitations
There are several limitations of this study that must be
noted. Firstly, this study was conducted at a single center, so
the results may not be generalized to other institutions in
different countries. Secondly, the study design was retro-
spective and data were collected by reviewing medical
records. Therefore, some data would be unavoidably miss-
ing and bias could have occurred. For example, arterial
blood gas results were not usually done on stable patients at
discharge. Lastly, we did not take rehospitalizations at other
hospitals into account so the actual incidence of hospital
readmission could be higher. However, results from this
study could reflect the characteristics of CAP patients and
pathogens as well as the quality of hospital care of this par-
ticular geographic area. Furthermore, patients who were dis-
charged at hospice state or who transferred to another
hospital were excluded from this study. Also, most eligible
patients had healthcare insurance registered at this hospital,
and they should visit this hospital so that their medical
expenses could be covered. In this context, the number of
loss samples was insignificant.
One of the strengths of our study was that we included
every qualified patient in a 1-year period at one of the high-
profile hospitals in the country. Therefore, the results could
represent the general incidence of hospital readmissions fol-
lowing CAP as well as the practice of treating CAP in such a
setting of low-income countries. Another strength of the
study is that we investigated patient and pathogen character-
istics, as well as the appropriateness of antibiotics for the
treatment of CAP, which would help medical professionals
and policy makers improve the practice of treating CAP and
develop future guidelines.
Nguyen et al 719
Conclusions
In conclusion, we identified a significant number of patients
who were readmitted within 30 days after an initial episode
of CAP. The presence of comorbidities and MDR infection
appeared to associate with 30-day all-cause hospital read-
missions. These results suggested that thoroughly obtaining
medical history and providing adequate treatment for under-
lying chronic diseases may reduce the readmission rate
among patients with CAP. Also, a guideline on empiric anti-
biotic therapy should be developed to target the most com-
mon pathogens based on microbiological results, and
improvement should be made to increase adherence rate to
empiric antibiotic practice guidelines.
Author Contributions
All authors have met the ICMJE authorship criteria. The authors’
contributions were as follows: Conceptualization and methodol-
ogy: Dung Thien Nguyen, Sang Thanh Huynh, Ho Nhu Nguyen;
Data acquisition: Dung Thien Nguyen, Sang Thanh Huynh;
Formal analysis and interpretation of data: Dung Thien Nguyen,
Sang Thanh Huynh, Ho Nhu Nguyen; Writing - original draft
preparation: Dung Thien Nguyen; Writing - review and editing:
Dung Thien Nguyen, Sang Thanh Huynh, Ho Nhu Nguyen;
Supervision: Ho Nhu Nguyen. All authors read and approved the
final manuscript.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
ORCID iD
Ho Nhu Nguyen https://orcid.org/0000-0003-1629-9775
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1095894
research-article2022
HPXXXX10.1177/00185787221095894Hospital PharmacyKatsivalis et al

Original Article

Hospital Pharmacy

Opioid Use in Vaso-Occlusive Crisis

2022, Vol. 57(6) 721­–726
© The Author(s) 2022
Article reuse guidelines:
During Intravenous Opioid Drug Shortage sagepub.com/journals-permissions
DOI: 10.1177/00185787221095894
https://doi.org/10.1177/00185787221095894
journals.sagepub.com/home/hpx

Katherine V. Katsivalis1 , Jeremy Kosacz2, and

Jennifer Austin Szwak3

Abstract

Introduction: In October 2017, the Food and Drug Administration announced a shortage of intravenous (IV) opioid
medications. Patients with sickle cell disease (SCD) are particularly vulnerable, as high amounts of IV opioid medications
are standard therapy during vaso-occlusive crises (VOC). Our institution responded to the crises by implementing IV to
oral (PO) conversions of opioid therapies and encouraging multimodal pain management with non-opioid medications.
Objectives: The primary objective was the assessment of IV opioid medication utilization before and during the shortage.
Secondary objectives included total opioid consumption, length of stay, and prescribing of non-opioid analgesics. Methods:
This single-institution retrospective study included patients >18 years of age admitted to adult medicine teams with VOC
during February 2017 or February 2018. The amount of opioid medication administered to patients during both periods
was assessed, and quantities were then converted to PO morphine milligram equivalents and compared between years. The
number of patients receiving scheduled non-opioid medications were also compared. Length of stay and readmissions were
compared between years. Results: Between 2017 and 2018, IV opioid use for VOC decreased by 52% on inpatient services,
and there was a 34% reduction in overall opioid use. Oral opioid use more than doubled during the period (10.2% in 2017 vs
39.1% in 2018, P < .01). LOS between 2017 and 2018 (6 vs 6 days, P = .4774) and total number of ED visits (27 vs 8, P = .276)
were similar. There were significantly fewer 30-day readmissions in 2018 versus 2017 (15 vs 28, P = .025). Conclusion:
The implementation of IV opioid restrictions resulted in a decrease in IV opioid use in treatment of VOC in patients with
SCD without causing increases in length of stay or readmissions. Oral opioids should be considered an option for VOC
management in patients with SCD.

Keywords
analgesics, clinical services, disease management, intravenous therapy, pain management, drug/medical use evaluation

Background Society of Hospital Pharmacists noted that 98.4% of hospi-

Intravenous (IV) opioids are the cornerstone for manage-
ment of vaso-occlusive crises (VOC) in sickle cell diseases.
The 2014 and 2020 NHLBI guidelines recommend rapid
analgesic administration; however, large studies describing
efficacious analgesic therapies are limited.1,2 Pain manage-
ment should be guided by reported pain and prior opioid use.
For patients with severe pain, IV opioids are recommended
either by patient-controlled analgesia (PCA) or frequently
scheduled doses, which can be gradually titrated down as
VOC improves. The use of individualized care plans includ-
ing effective medications and doses are recommended by the
American Society of Hematology, but no specific dosing
strategies are recommended as first-line.
In 2017, the Food and Drug Administration announced a
nation-wide IV opioid shortage, which most notably affected
institutional supplies of IV morphine and hydromorphone.3
In a survey of 343 hospitals across the country, the American
tals were affected by this shortage, and of those hospitals,
96.2% indicated that the shortage at their institution was
either moderate or severe in nature. In order to respond to the
impact this shortage would have on patient care, most insti-
tutions (74.4%) implemented an IV to oral (PO) conversion
process for patients.4 This is an opioid management strategy
that has been advocated for by the Society of Hospital
Medicine (SHM). In a recent consensus statement regarding
the use of opioids for non-cancer pain in adult patients, the
SHM recommends that clinicians use the oral route of
1
University of Illinois at Chicago College of Pharmacy, Chicago, IL, USA
2
University of Wisconsin-Madison School of Pharmacy, Madison, WI, USA
3
University of Chicago Medicine, Chicago, IL, USA
Corresponding Author:
Katherine V. Katsivalis, University of Illinois at Chicago College of
Pharmacy, 10340 Kilpatrick, Oak Lawn, IL 60453, USA.
Email: kvkatsivalis@gmail.com
722 Hospital Pharmacy 57(6)
administration for opioid medications, reserving the IV route
for those who cannot take medications by mouth, have gas-
trointestinal malabsorption, or who require immediate pain
control.5
Although the consensus statement made by the SMH pro-
vides guidance for the preferential use of PO opioids in the
hospital setting, it does not specify management strategies
for the sickle cell population.5 Previous studies have shown
that utilization of a standard care pathway for all sickle cell
patients leads to an increased use of PCAs but also a decrease
in total length of stay.6 Conti and colleagues7 proposed an
oral morphine regimen in an emergency department (ED)
setting where IV meperidine had previously been used. They
reviewed the ED visits of 9 patients prior to the implementa-
tion of the oral morphine protocol and after and noted a sta-
tistically significant decrease in total ED visits, length of
stay, and number of admissions after the implementation of
the oral protocol. Literature evaluating the use of oral opioid
agents for inpatient management of VOC are limited. One
case series of 3 patients reported successful transition of
patients from PCAs to oral opioids during admissions for
VOC pain.8
During the shortage, our Pharmacy and Therapeutics
Committee approved IV opioid limitations on ordering that
was implemented at the time of order verification. All IV
push doses were limited to one-time orders if patients had an
active diet order or were able to take oral medications. For
patients who were not able to take medications by mouth, IV
opioid orders were given a 24-hour limit. After 24 hours,
these orders could be renewed if patients were still not able
to take medications by mouth. All PCA-administered medi-
cations were given a 24-hour limit. For patients with sickle
cell VOC, the primary pharmacist in conjunction with the
acute pain service would determine if the patient needed
additional time on the PCA, could transition to oral medica-
tions, or required an alternative agent such as methadone,
ketamine infusion, or lidocaine infusion. This evaluation
sought to determine the impact of the IV opioid shortage on
adult patients requiring inpatient management of VOC.
Methods
All patients 18 years and older with sickle cell disease dis-
charged from our institution with a primary admission diagno-
sis of VOC in February of 2017 and 2018 were included. All
admissions to the children’s hospital or where VOC was not
the primary reason for admission were excluded. These time
frames were selected to provide similar periods before (2017)
and during (2018) the IV opioid shortage. Patients were identi-
fied by ICD-10 codes, and a retrospective chart review was
performed to determine the amount of opioid medications and
non-opioid analgesia received by each patient.
The medication administration report was reviewed to
calculate the total dose of opioids received during the hospi-
talization and assess prescribing of non-opioid analgesics.
Table 1.  Patient Characteristics.
2017 (n = 47) 2018 (n = 42) P-value
Male sex, n (%) 21 (44.7) 18 (41.9) .0863
Age (years), 23 [16-35] 24 [16-33] .6711
median [IQR]
Service .267
 Non-rounding, 18 (38) 21 (50)  
n (%)
  Rounding, n (%) 29 (62) 21 (50)  
All opioid doses were converted to oral morphine milligram
equivalents (MME).9 Doses administered via PCA were
determined by nursing documentation in the medical record
every 12 hours. The primary endpoint was the utilization of
IV opioid medications before and during the IV opioid
shortage. Secondary endpoints included total opioid con-
sumption, length of stay, and prescribing of scheduled, non-
opioid analgesics. A subgroup analysis was performed to
assess patients admitted to housestaff services with round-
ing pharmacists (rounding service) compared to hospitalist
services where pharmacists review patients but do not attend
formal patient rounds (non-rounding service).
This study received a formal Determination of Quality
Improvement status according to University of Chicago
Medicine’s institutional policy. As such, this was deemed
non-human subjects research and was therefore not reviewed
by the Institutional Review Board. Statistical analysis was
performed using StataCorp. 2013 (College Station, TX:
StataCorp LP). Descriptive statistics were summarized using
median and interquartile range. Chi square test and Fisher’s
exact test were used for categorical data, and Wilcoxon Rank
Sum was used for continuous data.
Results
During the 2 study periods, 89 patients (2017: N = 47; 2018:
N = 42) were admitted for treatment of VOC. Patient charac-
teristics are described in Table 1. After implementing restric-
tions on IV opioid usage during the shortage, there was a 34%
reduction in overall opioid use for treatment of VOC (Table
2). IV opioid use for VOC decreased by 54% and 52% in the
ED and on inpatient services, respectively. Oral opioid use
more than doubled during the period. Total opioid administra-
tion per patient was similar between the 2 years (P = .651);
however, significantly less IV opioid was used (P = 0.023)
and more oral opioids were administered (P = .012) following
the implementation of restrictions on IV opioids (Table 3). Of
total opioid usage, 79% was IV and 13% was oral in 2017
compared to 57% IV and 43% oral in 2018. Transdermal fen-
tanyl was a small portion of total opioid use in each time
period. During the 2017 time period, 2 patients received fen-
tanyl patches consistent with their home regimens which
accounted for 91% of the total fentanyl use during that period.
Katsivalis et al 723

Table 2.  Hospital Opioid Use for Vaso-Occlusive Crisis.

2017 (n = 47) 2018 (n = 42) % Change

Total opioids administered, mg MMEs 209 546 138 877 −34%
IV opioids administered in the ED, mg MMEs 6842 3164 −54%
IV opioids administered inpatient, mg MMEs 158,793 76 227 −52%
Oral opioids administered, mg MMEs 27 728 59 311 +213%
Transdermal fentanyl administered, mg MMEs 16 183 175 −99%

Note. MME = morphine milligrams equivalents; IV = intravenous.

Table 3.  Median MMEs Administered per Patient.

2017 2018
Median [IQR] Median [IQR] % Change P-value
Total opioids, mg 1616 [881-6364] 1650 [733-3775] +2.1% 0.651
IV opioids, mg† 1170 [386-5288]   573 [214-1702] −51% 0.023
Oral opioids, mg† 180 [8-520]   719 [144-1560] +399% 0.012

Note. MME = morphine milligrams equivalents.

†
Excludes ED use.

(27 vs 8, P = .276) were similar. Of note, there were signifi-

Figure 1.  Percent of opioid MMEs per patient administered
orally (10.2% vs 39.1%, P < .01).
Fewer patients received any oral opioids during hospital-
ization in 2017 compared to 2018 (5% vs 23%, P = .016), and
fewer patients received more than half of their total opioids
orally (9% vs 40%, P < .01). The median percentage of opi-
oid MMEs administered orally per patient was significantly
lower in 2017 compared to 2018 (10.2% vs 39.1%, P < .01)
(Figure 1). The use of scheduled non-opioid analgesics is
summarized in Table 4. A similar percentage of patients in
each time period had at least 1 scheduled non-opioid analge-
sic prescribed during the hospitalization (77% vs 88%,
P = .539).
Health care utilization for included patients is descri­
bed in Table 5. Length of stay between 2017 and 2018
(6 days vs 6 days, P = .4774) and total number of ED visits
cantly fewer 30-day readmissions in 2018 compared to
2017 (15 vs 28, P = .025).
When the route of opioid administration during inpatient
stay was assessed by the type of service, non-rounding ser-
vices administered a similar percentage of opioids intrave-
nously in 2017 and 2018 despite restrictions (75.2% vs
77.8%, P = .99) (Figure 2). Rounding services, however,
used IV opioids significantly less frequently in 2018 (80.7%
vs 33.1%, P < .01) and relied more heavily on oral opioids
(18.6% vs 66.9%, P < .01) (Figure 3). During 2017, a similar
percentage of patients received at least half of their opioid
MMEs orally on non-rounding and rounding services (11%
vs 17%, P = .45); however, rounding services had a signifi-
cantly higher portion of patients receiving a majority of opi-
oid MMEs orally in 2018 (14% vs 67%, P < .01).
Discussion
This natural experimental model based on limited availability
of IV opioids allowed for the evaluation of clinical outcomes
based on routes of opioid administration. The focus of the IV
opioid restrictions was to curtail continued use of IV opioids
during hospitalization and was not intended to limit IV use in
the emergency department or during the first 24 hours of inpa-
tient admission; therefore, we did not expect to see a signifi-
cant reduction in IV opioid use in the ED or the absence of IV
opioid use in the inpatient setting. The implementation of
restrictions to IV opioids during a medication shortage
resulted in a more than 50% reduction in IV opioid use with-
out increasing length of stay, readmissions, or ED visits.
During the 2018 period, prescribers relied more heavily on
oral opioids to provide pain relief for VOC admissions.
724 Hospital Pharmacy 57(6)

Figure 2.  Intravenous opioid administration by service type during inpatient stay.

Table 4.  Scheduled Non-Opioid Analgesic Prescribing in Vaso-Occlusive Crisis.

2017 (n = 47) 2018 (n = 42)

Acetaminophen, n (%) 14 (30) 25 (60)
Gabapentin, n (%) 29 (62) 25 (60)
Ketorolac, n (%) 1 (2) 11 (26)
Ibuprofen, n (%) 11 (23) 9 (21)
Naproxen, n (%) 3 (6) 0 (0)
Lidocaine patch, n (%) 9 (19) 22 (52)
Ketamine infusion, n (%) 1 (2) 3 (7)

Table 5.  Healthcare Utilization During and Following Admission for Vaso-Occlusive Crisis.

2017 (n = 47) 2018 (n = 42) P-value

Length of stay (days), median [IQR] 6 [3-8] 6 [4-10] 0.4774
  Non-rounding service 6 [3-7] 7 [4-9] 0.6754
  Rounding service 5 [4-8] 6 [4-10] 0.9477
Patients with readmission within 30 d, n (%) 28 (60) 15 (36) 0.025
Patients with ED visit within 30 d, n (%) 12 (26) 7 (17) 0.308
Patients with readmission or ED visit, n (%) 29 (62) 18 (43) 0.075
Number of readmissions, n 40 19 0.0227
Number of ED visits, n 27 8 0.2706

The decision to transition to oral opioids during a hospi-
talization is often challenging and can be impacted by patient
readiness, provider comfort with pain management, or the
desire to allow for increased patient control of opioid dosing
through PCAs.10 Prior to IV opioid restrictions, almost a
quarter of patients treated for VOC at our institution did not
receive any oral opioids. The IV opioid shortage and subse-
quent restrictions allowed for increased multidisciplinary
efforts to evaluate IV opioid use frequently, discuss early
transition to equianalgesic doses of oral opioids, and opti-
mize non-opioid analgesic use. Our analysis shows that
patients receiving treatment during the time of the opioid
Katsivalis et al 725
Figure 3.  Oral opioid administration by service type during inpatient stay.
shortage and restrictions received slightly higher total opioid
doses; therefore, the use of oral agents did not preclude
patients from getting higher opioid doses. The need for
reduced IV opioid use also likely increased prescriber com-
fort with opioid conversions and use of scheduled and as-
needed short-acting opioids.
The use of oral opioids prior to discharge may have also
allowed for prescribers to identify appropriate opioid dis-
charge regimens, as has been described in previous literature.8
We found a significant reduction in hospital readmissions
within 30 days, which may demonstrate that by identifying
effective oral regimens, patients had better pain control fol-
lowing discharge. Alternatively, patients may have chosen to
seek care at other institutions; however, we expect that most
institutions had similar restrictions on IV opioid use due to
the national shortage.
The restrictions were more successful at reducing IV opi-
oid use when a pharmacist was present during rounds. The
reason for this is likely multifactorial. By being present on
rounds, the pharmacist could verbally reinforce the IV opioid
restrictions and provide recommendations for equianalgesic
oral options as part of the discussion of patient management.
The pharmacist was also available to discuss the restrictions
on IV opioids directly with the patient and explain the pro-
cess of transitioning to an equivalent oral regimen. This is
similar to findings that pharmacist-driven opioid stewardship
can decrease IV opioid use and increase oral opioid use.11
Alternatively, on non-rounding services, pharmacist recom-
mendations may have been conveyed via page or have
occurred after the prescriber already evaluated the patient
and discussed a pain management plan for the day. Not being
physically present for pain management assessments and
discussions can limit the impact of recommendations because
prescribers may not want to change the plan once it has been
established with the patient.
There are several limitations to our study. The 2 study
populations were not randomly assigned; however, we did
select the same month in 2 different years to better match
weather patterns and viral illnesses that may trigger VOCs in
patients with SCD. Additionally, we were not able to deter-
mine if patients sought care at other local EDs or hospitals
for VOC pain. Finally, the IV opioid restrictions limited use
to 24-hours but could be extended based on patient needs.
We did, however, notice that IV opioids were often reordered
after the initial 24-hour time restriction and verified by our
central pharmacy team who were not part of the team dis-
cussing optimization of pain management. While this
decreased the impact of our restrictions on our IV opioid sup-
ply, we did not feel it was safe practice to enforce a hard
24-hour rule on IV opioids.
Conclusion
The implementation of IV opioid restrictions resulted in a
decrease in IV opioid use in treatment of VOC in patients
with SCD without causing increases in length of stay or read-
missions. Oral opioids should be considered as an option for
VOC management in patients with SCD.
726 Hospital Pharmacy 57(6)
Authors’ Note
At the time of the study, Dr. Szwak was a Clinical Pharmacy
Specialist at University of Chicago Medicine, and Drs. Katsivalis
and Kosacz were fourth year student pharmacists completing APPE
rotations at University of Chicago Medicine. Currently, Dr.
Katsivalis is affiliated with Cleveland Clinic Children’s Hospital
Department of Pharmacy, Dr. Kosacz is affiliated with UW Health
SwedishAmerican Hospital Department of Pharmacy, and Dr.
Szwak is affiliated with the Johns Hopkins Hospital Department of
Pharmacy.
Acknowledgments
Amechi Alozie, PharmD contributed to data collection.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
ORCID iD
Katherine V. Katsivalis https://orcid.org/0000-0001-5488-0953
Jennifer Austin Szwak https://orcid.org/0000-0002-9911-5750
References
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1095764
research-article2022
HPXXXX10.1177/00185787221095764Hospital PharmacyAppiah et al

Original Article

Hospital Pharmacy

Safety and Efficacy Analysis of Apixaban

2022, Vol. 57(6) 727­–733
© The Author(s) 2022
Article reuse guidelines:
Compared to Heparins in Hospitalized sagepub.com/journals-permissions
DOI: 10.1177/00185787221095764
https://doi.org/10.1177/00185787221095764

Non-Critically Ill COVID-19 Patients journals.sagepub.com/home/hpx

Daniel Appiah1, Nicholas J. Quinn2 , Emily G. Messing2,

and Keith T. Veltri2,3

Abstract

Purpose: Heparin-based regimens are recommended for anticoagulation in hospitalized patients with COVID-19 though
a study reported similar mortality with apixaban in critically ill hospitalized COVID-19 patients. Our pilot study sought to
determine the differences in all-cause mortality, venous thromboembolism (VTE), and bleeding events between apixaban
and therapeutic heparin-based regimens in hospitalized non-critically ill COVID-19 patients. Methods: We conducted a
retrospective analysis of non-critically ill COVID-19 patients aged ≥ 18 years admitted to 3 campuses of Montefiore Medical
Center during the first (March 2020 to May 2020) and second (January 2021 to February 2021) COVID-19 surges, who
received within 48 hours of admission and continued for ≥72 hours a therapeutic dose of low-molecular-weight heparin
(LMWH), unfractionated heparin (UFH), or any apixaban dose for VTE prophylaxis. Outcomes data analyzed included
mortality, suspected or imaging-confirmed VTE, and bleeding using a defined criteria. Results: Overall, 162 patients met
eligibility for analysis. Baseline characteristics were similar between the 2 groups except liver and renal functions. Mortality
occurred in 10 (13.3%) patients on apixaban and 23 (26.4%) patients on a heparin-based regimen (P = .059). Confirmed VTE
events were not different between the groups (8% vs 13.8%, P = .359), but higher incidence of bleeding occurred in heparin-
based group (4% vs 52.9%, P < .001). Conclusion: There were no differences in mortality or confirmed VTE between
apixaban and heparin-based regimens except for more bleeding events with the heparins. This study highlights the utility of
apixaban in COVID-19.

Keywords
anticoagulants, COVID, disease management, respiratory

Background strategies in COVID-19 patients. Most of these guidelines

Since the onset of the Coronavirus Disease 2019 (COVID-19)
pandemic, coagulation abnormalities have been a common
finding in affected patients, possibly presenting as dissemi-
nated intravascular coagulation (DIC) or other thrombotic
complications such as venous thromboembolism (VTE), both
with an associated increase in mortality,1-4 COVID-19
increases the risk of thrombotic complications in the venous
and arterial vasculature,1 with the incidence of VTE in
COVID-19 patients estimated to be as high as 25% to 27%,2-4
with the intensive care setting estimated to reach 69%.5
Coagulopathies among COVID-19 patients are associated
with elevated levels of fibrinogen, D-dimer, and other acute-
phase reactants,1 and optimal management of anticoagulation
is important to improve overall outcomes. Anticoagulation
in COVID-19 has been addressed in various guidelines6-8
underscoring the importance of appropriate anticoagulation
initially endorsed elevated D-dimer and fibrinogen as key
objective markers for thrombotic risk due to their strong
correlation with thrombosis and mortality.3 However, the
International Society of Thrombosis and Hemostasis (ISTH),9
the National Institutes of Health, and American College of
Chest Physicians guidelines now recommend thrombopro-
phylaxis with either unfractionated heparin (UFH) or low-
molecular-weight heparin (LMWH) in all hospitalized
non-critically ill COVID-19 patients regardless of VTE risk
1
Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
2
Montefiore Medical Center, Bronx, NY, USA
3
Touro College of Pharmacy, New York, NY, USA
Corresponding Author:
Nicholas J. Quinn, Department of Pharmacy, Montefiore Medical Center,
111 E 210th Street, Bronx, NY 10467, USA.
Email: nquinn@montefiore.org
728 Hospital Pharmacy 57(6)
assessment score unless there are absolute contraindica-
tions.3,6-8,10 These guidelines favor the use of heparins against
direct oral anticoagulants (DOACs) due to the increased risk of
drug-drug interactions with DOACs and the potential declining
patient status may worsen bleeding risk.11 Additionally,
DOACs are more difficult to reverse and monitor.
Despite these guideline recommendations, anticoagula-
tion protocols for COVID-19 developed by various institu-
tions also incorporated the use of DOACs in addition to UFH
and LMWH to their thromboprophylaxis management strat-
egy. The addition of DOACs was based primarily on their
safety and efficacy in other hypercoagulable disease states,
the convenience of oral administration as well as lack of
required monitoring and less pharmacokinetic (PK) and
pharmacodynamic (PD) variability .12,13
Billett et al14 observed in their study that the DOAC, apix-
aban, was associated with a reduction in mortality in hospital-
ized COVID-19 patients when compared to no anticoagulation.
Paranjpe et al15 also suggested that systemic anticoagulation
confers a survival benefit in COVID-19 patients regardless of
the anticoagulant used, though this study had significant limi-
tations. This conclusion was similar to Kabir16 who showed
early, high-dose anticoagulation in non-critically ill COVID-
19 patients improved survival, including with apixaban.
Some notable clinical trials on anticoagulation in COVID-19
such as REMAP-CAP,17 ACTIV4,18 and ATTACC19 com-
pared therapeutic heparin-based regimens to the usual care
thromboprophylaxis in hospitalized COVID-19 patients
without including DOACs as a study arm. Combined results
from these trials reported that in non-critically ill patients
therapeutic anticoagulation with heparin increased survival to
discharge.20 This leaves the question of the impact of DOACs
in non-critically ill COVID-19 patients still unanswered. To
build on previous literature and address confounders in previ-
ous studies, we examined the safety and efficacy of apixaban
compared to therapeutic heparin-based regimens on outcomes
in non-critically ill patients hospitalized with COVID-19.
Methods
Study Design
This pilot study was a retrospective cohort study of adult
inpatients admitted to the 3 main campuses of Montefiore
Medical Center, all located in the Bronx, New York. Data
were collected at 2 time periods: the first COVID-19 surge
from March 2020 to May 2020, and the second COVID-19
surge from January 2021 to February 2021. Approval for the
study was obtained through the institutional review board
(IRB #2020-12313).
Patients
Patients ≥18 years of age were included in this study if they
were admitted to a general medical floor, if they tested
positive for COVID-19 within 72 hours of floor admission,
and if they were initiated on either apixaban or a therapeu-
tic heparin-based regimen for at least 72 hours within
48 hours of admission. We excluded patients who within
48 hours of floor admission were either intubated or
transferred to the intensive care unit (ICU), identified as
palliative care, or had a code status of “do-not-resuscitate/
do-not-intubate.” Patients were also excluded if they did
not continue their outpatient anticoagulation regimen upon
admission or presented with confirmed VTE upon admis-
sion. Apixaban was dosed either 5 mg by mouth twice daily
or 2.5 mg twice daily based on renal function (Scr > 2.5 mg/
dL or CrCl < 30 mL/min) per institutional guideline. The
heparin-based regimens were dosed as either low-molecu-
lar-weight heparin (LMWH) enoxaparin 1 mg/kg SQ every
12 hours (daily for CrCl  < 30 mL/min) or enoxaparin
1.5 mg/kg SQ. Any intravenous infusion of unfractionated
heparin (UFH) was administered to a therapeutic aPTT of
46 to 70 following institutional protocol for VTE of 80 units/
kg bolus followed by 18 units/kg/h infusion.
Data Sources
All patients eligible for the study were identified in our elec-
tronic medical record using Business Universe (SAP
BusinessObjects®). Data obtained included index date of
admission as well as the type and duration of anticoagulation
used. Patients’ baseline demographics, pertinent laboratory
markers relevant to coagulopathy, occurrence of bleeding
and/or venous thromboembolic (VTE) event, and mortality
were obtained through our electronic medical record.
Outcomes
The primary outcome of this study was the difference in
all-cause mortality between an apixaban and therapeutic
heparin-based regimens from the index date to event occur-
rence, discharge, or transfer to the ICU. Secondary outcomes
assessed were the incidence of venous thromboembolism
(VTE) and the incidence of major bleeding between apixa-
ban and heparin-based regimens in hospitalized non-criti-
cally ill COVID-19 patients. VTE was determined through
either diagnostic imaging (ultrasound and/or CT scan) or by
a surrogate indicator (D-dimer and/or fibrinogen elevation)
with clinical symptomatology of VTE. Bleeding was deter-
mined if the patient was only initiated on pantoprazole IV
drip or IV push every 12 hours because of signs and symp-
toms of gastrointestinal bleeding after anticoagulant initia-
tion, or bleeding defined by the ISTH21,22 criteria as: Fatal
bleeding, and/or symptomatic bleeding in a critical area or
organ, such as intracranial, intraspinal, intraocular, retro-
peritoneal, intraarticular, or pericardial, or intramuscular
with compartment syndrome, and/or bleeding causing a fall
in hemoglobin level ≥2 g/dL (1.24 mmol/L) or leading to
transfusion of ≥2 units of whole blood or red cells.
Appiah et al 729

Table 1.  Characteristics of Patients at Baseline.

Characteristic Apixaban regimena (n = 75) Heparin-based regimenb (n = 87) P-value

Age, mean (SD), years 68.4 (13.9) 67.5 (13.7) .678
Male, n (%) 31 (41.3) 50 (57.5) .058
Weight (SD), kg 82.7 (21.5) 84 (23.3) .732
Race/ethnicity, n (%)
 White 7 (9.3) 19 (21.8) .114
 Black 29 (38.7) 23 (26.4)
 Hispanic 25 (33.3) 27(31)
 Others 14 (18.7) 18 (20.6)
Comorbidities, n (%)
  History of VTE 5 (6.7) 13 (14.9) .076
  Atrial fibrillation 7 (9.3) 14 (16.1)
 Hypertension 60 (80) 68 (78.2)
 Cancer 15 (20) 8 (9.2)
 T2DM 47 (62.7) 38 (43.7)
 Asthma/COPD 15 (20) 14 (16.1)
 Immunosuppression 9 (12) 5 (5.7)
  AKI, n (%) 21 (28) 40 (46) .028
  AST or ALT >3 ULN, n (%) 2 (2.7) 11 (12.6) .036
D-dimers, μg/mL, n (%)
  ≤3 43 (57.3) 29 (44.8) .174
  >3 29 (38) 45 (51.7)
  Fibrinogen, mean (SD), mg/dL 675 (203.9) 604 (189) .034
  Remdesivir use, n (%) 10 (13.3) 4 (4.6) .090
  Steroid use, n (%) 35 (46.7) 35 (40.2) .506
  Steroid exposure, mean (SD), days 7 (2.9) 6 (4) .068
  Anticoagulant use, median (IQR), days 6 (4,9) 6 (4,10) –

Note. AST = aspartate aminotransferase; ALT = alanine aminotransferase; COPD = chronic obstructive pulmonary disease; IQR = interquartile range;
SD = standard deviation; T2DM = type 2 diabetes mellitus; ULN = upper limit of normal; VTE = venous thromboembolism.
a
Apixaban: Low dose (n = 36), high dose (n = 39).
b
Heparin-based regimen: UFH (n = 42), LMWH (n = 45).

Statistical Analysis patients on apixaban and 87 on heparin-based regimens. The

Collected data were coded and analyzed using OpenEpi®
version 3.01. Baseline data on study participants were
reported as mean with standard deviation and median with
interquartile range for continuous variables, and frequen-
cies and percentages for categorical variables. Differences
in continuous variables were assessed using the student
t-test and for categorical variables chi-square test or fish-
er’s exact test.
The primary and secondary outcomes were analyzed
using the chi-square test or the Fisher exact test where appro-
priate. The results of all statistical tests were reported as
P-values and odds ratios with confidence intervals as appro-
priate. A 2-tailed P-value of less than .05 was considered sta-
tistically significant.
Results
Baseline Characteristics
During the study period, 162 participants met eligibility cri-
teria and were included in the analysis. This comprised 75
mean duration of follow up was 42 days. The mean age of the
population was 67.9 ( ± 13.8) years with half being male.
Rate of acute kidney injury (AKI), AST or ALT> 3 times
upper limit of normal, and fibrinogen levels were signifi-
cantly different among baseline groups. AKI was defined as
an increase in serum creatinine by >0.3 mg/dL within 48
hours or an increase by at least 1.5 times from baseline prior
to the initiation of anticoagulation in patients. Remdesivir
use, steroid use and exposure were not statistically different
between the groups (Table 1).
Primary Outcome
Overall, 33 (20.4%) patients died from the index day of
admission till the end of the study. They were made up of
13.3% in the apixaban group and 26.4% in the heparin-based
group. Though there was a lower incidence of death in the
apixaban group, it was not statistically significant (OR = 0.43,
95% CI: 0.17-1.03, P = .059) (Figure 1). A subgroup analysis
comparing the incidence of death among 2.5 mg apixaban,
5 mg apixaban, UFH, and LMWH found no statistically
730 Hospital Pharmacy 57(6)
Figure 1.  All-cause mortality between apixaban and heparin-based regimen.
significant difference among the subgroups (χ2 = 4.778,
P = .189) (Supplemental Table 2).
Secondary Outcomes
The incidence of confirmed VTE was 8% in the apixaban
group compared to 13.8% in the heparin-based group
(P = .359). Suspected VTE was 8% in the apixaban group
compared to 24.1% in the heparin-based group (P = .001)
(Figure 2).
Bleeding occurred in 4% and 52.9% of apixaban and hep-
arin-based regimens respectively (P < .001). Hemoglobin
drop ≥2 g/dL in 24 hours after anticoagulant initiation was
significantly higher in patients on heparin-based regimen
compared to apixaban (P ≤ .001) (Table 2). Hemoglobin
drop was then major contributor to overall bleeding rates
especially in the heparin-based regimen.
Discussion
Early in the COVID-19 pandemic, DOACs were included as
an anticoagulant option in our institution’s COVID-19 man-
agement protocols. Apixaban was chosen as the agent of
choice in this class because of its better safety profile in
patients with impaired renal function and its availability on
the hospital formulary.
The primary outcome from this study showed that there
was no significant difference in mortality between patients
on apixaban and a heparin-based regimen. These results are
similar to that of Billet et al14 which also demonstrated simi-
lar in mortality between apixaban and enoxaparin anticoagu-
lation . Our data from Table 1 shows baseline characteristics
were similar between the groups except for those admitted
with acute kidney injury or AST/ALT ≥ 3 ULN. Significant
differences in the agents used in these patients with organ
dysfunction reflects their real-world use as the heparins espe-
cially UFH as opposed to apixaban are more likely to be
selected for therapeutic anticoagulation in patients with renal
or hepatic impairment due to risk for excessive anticoagula-
tion with DOACs in these populations and the difficulty of
anticoagulant reversal.
Despite the fact that most patients in the apixaban
group received remdesivir (Table 1), this agent has been
found not to have any impact on overall mortality in
COVID-19 patients23 and as such less likely to affect the
results of our primary outcome. Although steroids have
been found to reduce overall mortality in COVID-19,24
steroid use and their exposure time were similar between
the groups (Table 1). Thus, the impact of steroids on over-
all mortality is expected to be similar in both groups.
Additionally, data collection was performed at 2 different
time periods during the pandemic, during the first COVID
surge when standard of care was still evolving with lots of
experimental agents being used in COVID-19 manage-
ment and during the second COVID-19 surge where
greater evidence was available to guide care. This ensured
that the results of the primary outcome were unduly
impacted by standard of care practices in these eras.
Appiah et al 731

Figure 2.  Confirmed and suspected VTE events between apixaban and heparin-based regimen.

Table 2.  Bleeding Incidence Between Apixaban and Heparin-Based Regimen.

Characteristics Apixabana (N = 75) Heparin-based regimenb (N = 87) P-value

Bleeding, n (%) 3 (4) 46 (52.9) <.001
Hemoglobin drop ≥2 g/dL in 24 h, n (%) 2 (2.7) 39 (44.8) <.001
Blood transfusion ≥2 units, n (%) 0 (0) 3 (3.4) .304
Intravenous pantoprazole, n (%) 1 (1.3) 4 (4.6) >.999
a
Apixaban: Low dose (n = 36), high dose (n = 39).
b
Heparin-based regimen: UFH (n = 42), LMWH (n = 45).

For VTE measurement, we chose to report both diagnos-
tic confirmed VTE and clinically suspected VTE to reflect
clinical practice. Even though the baseline levels of fibrino-
gen, a risk factor for developing blood clots, were signifi-
cantly higher in the apixaban group compared to the
heparin-based group (Table 1), confirmed VTE was lower
in the apixaban group, though not statistically significant.
However, suspected VTE was observed at a significantly
higher rate in the heparin-based group than in the apixaban
group. Though baseline d-dimer levels were not statisti-
cally different between the groups (Table 1), d-dimers
greater than 3 μg/mL were seen more often in the patients
on heparin-based regimen at baseline underscoring a pos-
sible ongoing clotting cascade in the heparin-based group.
Additionally, d-dimers and fibrinogen levels were still high
at the time of suspected VTE in the heparin-based group
(Supplemental Table 3). The aPPT at time of VTE event
showed 4 out of 6 on UFH having therapeutic aPPT with
the remaining 2 subtherapeutic underscoring the unreliabil-
ity of aPPT measurements in COVID-19 for UFH. Despite
DOACs not currently being recommended as a preferred
anticoagulant for the prevention or management of COVID-
19 coagulopathy in hospitalized patients, our results did not
show any increased risk of VTE with the use of apixaban in
non-critically ill hospitalized patients.
Bleeding events were also significantly lower in the apix-
aban group compared to the heparin-based group, with more
significant bleeding in those patients on unfractionated hepa-
rin (Supplemental Table 4). A hemoglobin drop greater than
2 mg/dL within 24 hours was significantly higher in the hep-
arin-based regimen group compared to the apixaban group.
Blood transfusion ≥2 units or the use of pantoprazole for
gastrointestinal bleeding from anticoagulant use were all
higher in the heparin-based group. This implied a higher
732 Hospital Pharmacy 57(6)
incidence of hemorrhage in the heparin-based group could be
due excessive anticoagulation. We also confirmed aPPT at
the time of a bleeding event for unfractionated heparin (1/3
therapeutic aPPT, 2/3 supratherapeutic aPPT).
The randomized control trial ACTION compared therapeu-
tic anticoagulation of rivaroxaban or a heparin transitioned to
rivaroxaban, versus thromboprophylaxis with a heparin. They
found no improvement in clinical outcomes or reduction in
death with the therapeutic strategy (0.86 [95% CI: 0.59-1.22],
P = .40).25 Additionally, because the ACTION trial assessed 2
anticoagulation strategies rather than comparing anticoagu-
lants, a crossover was only considered if a patient changed
from prophylactic to therapeutic dose (or vice versa) and not
between different drugs within the same study group per study
protocol. In our study, no patients receiving heparin thrombo-
prophylaxis were included, based on results of prior litera-
ture.15,17,18 Also in contrast to our study, compared to
rivaroxaban, apixaban has been found to have a lower overall
risk of bleeding26,27 and a more recent single-arm study of
apixaban use in COVID-19 patients admitted to the ICU found
apixaban to be safe and efficacious with no major bleeding
events or thrombotic events.28 As the most preferred antico-
agulation approach during hospitalization is still unclear and
many off-label and non-evidence-based strategies have been
used in institutions to date, our results may provide evidence
for further investigation in this clinical setting.
Most similar to our study, Billett et al used logistic regres-
sion to show a decrease in mortality with prophylactic use of
apixaban (OR = 0.46, P < .001) and enoxaparin (OR = 0.49,
P <  .001) compared to other anticoagulant strategies.
Additionally, therapeutic apixaban was associated with
decreased mortality (OR = 0.57, P < .006), similar to the pro-
phylactic regimens. However, these results were taken from
the entire cohort including both general medicine and inten-
sive care patients.14
Our study has several limitations. First being a retrospec-
tive study, treatment groups were not allocated randomly
creating a selection bias. This bias is seen in the twice as
many patients in the heparin group having AKI. Patients with
transaminitis were also mostly found in the heparin-based
group. Also, as the study took place during 2 different surges
of COVID-19, standard treatments and the variants likely
changed. We did not have an advantage to monitor the hepa-
rin effect with anti-Xa, a more predictable marker of heparin
response in COVID-19 patients as aPPT values may be
altered from the normal baseline in COVID-19. Some of the
patients had comorbidities that required anticoagulation, and
this could have an effect on the outcome. We did not account
for other medications used by the participants which may
have pharmacokinetically or dynamically interacted with the
oral anticoagulant or increased the risk of bleeding. This
could have impacted the bleeding or VTE incidence in our
patients. Additionally, suspected VTE may have been con-
founded by observation bias from providers. Participants
who received various anticoagulants through substitution
throughout the hospital stay were also excluded. Therefore,
the true impact of anticoagulants when extrapolated to this
patient population should be done with caution. Lastly,
patients were only followed for the duration of their inpatient
stay, limiting our ability to assess any outcomes that occurred
post-discharge.
Conclusion
Our study adds to the existing but limited literature in a
racially and ethnically diverse population, evaluating opti-
mal anticoagulation strategies in patients with COVID-19
induced coagulopathy. Mortality and VTE events between
apixaban and therapeutic heparin-based regimens are not
significantly different when used in non-critically ill hospi-
talized patients. Apixaban, however, appears to have a lower
incidence of bleeding compared to heparin-based regimens.
More data are needed to better determine this benefit-to-risk
profile of apixaban with respect to noncritically ill COVID-
19 patients requiring hospitalization.
Authors’ Note
Work by Daniel Appiah was conducted at Montefiore Medical
Center, Bronx, NY.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
ORCID iD
Nicholas J. Quinn https://orcid.org/0000-0002-9703-5845
Supplemental Material
Supplemental material for this article is available online.
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anticoagulant therapy during the COVID-19 pandemic: interim
clinical guidance from the anticoagulation forum. J Thromb
Thrombolysis. 2020;50(1):72-81. doi:10.1007/s11239-020-
02138-z
9. Thachil J, Tang N, Gando S, et al. ISTH interim guidance
on recognition and management of coagulopathy in COVID-
19. J Thromb Haemost. 2020;18(5):1023-1026. doi:10.1111/
jth.14810
10. Moores LK, Tritschler T, Brosnahan S, et al. Prevention,
diagnosis, and treatment of VTE in patients with coronavirus
disease 2019. Chest. 2020;158(3):1143-1163. doi:10.1016/j.
chest.2020.05.559
11. Cuker A, Tseng EK, Nieuwlaat R, et al. American Society of
Hematology 2021 guidelines on the use of anticoagulation for
thromboprophylaxis in patients with COVID-19. Blood Adv.
2021;5(3):872-888. doi:10.1182/bloodadvances.2020003763
12. Carrier M, Abou-Nassar K, Mallick R, et al. Apixaban to prevent
venous thromboembolism in patients with cancer. New Engl J
Med. 2019;380(8):711-719. doi:10.1056/NEJMoa1814468
13. Cohoon KP, De Sanctis Y, Haskell L, McBane RD, Spiro
TE. Rivaroxaban for thromboprophylaxis among patients
recently hospitalized for acute infectious diseases: a sub-
group analysis of the MAGELLAN study. J Thromb Haemost.
2018;16(7):1278-1287. doi:10.1111/jth.14146
14. Billett HH, Reyes-Gil M, Szymanski J, et al. Anticoagulation
in COVID-19: Effect of Enoxaparin, heparin, and apixaban
on mortality. Thromb Haemost. 2020;120(12):1691-1699.
doi:10.1055/s-0040-1720978
15. Paranjpe I, Fuster V, Lala A, et al. Association of treatment dose
anticoagulation with In-hospital survival among hospitalized
patients with COVID-19. J Am Coll Cardiol. 2020;76(1):122-
124. doi:10.1016/j.jacc.2020.05.001
16. Kabir AA. Anticoagulation is the answer in treating noncriti-
cal COVID-19 patients. Open Med. 2021;16(1):1486-1492.
doi:10.1515/med-2021-0354
17. Angus DC, Berry S, Lewis RJ, et al. The REMAP-CAP (ran-
domized, embedded, multifactorial adaptive platform trial for
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2020;17(7):879-891. doi:10.1513/AnnalsATS.202003-192SD
18. Nct. Anti-thrombotics for adults hospitalized with COVID-19
(ACTIV-4). 2020. Accessed February 12, 2021. https://clini-
caltrials.gov/show/NCT04505774
19. Houston BL, Lawler PR, Goligher EC, et al. Anti-thrombotic
therapy to ameliorate complications of COVID-19 (ATTACC):
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tive Bayesian randomized controlled trial. Clin Trials.
2020;17(5):491-500. doi:10.1177/1740774520943846
20. Lawler PR, Goligher EC, Berger JS, et al. Therapeutic antico-
agulation with heparin in noncritically ill patients with COVID-
19. New Engl J Med. 2021;385(9):790-802. doi:10.1056/
NEJMoa2105911
21. Kaatz S, Ahmad D, Spyropoulos AC, Schulman S. Definition
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doi:10.1111/jth.13140
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surgical patients. J Thromb Haemost. 2005;3(4):692-694. doi:
10.1111/j.1538-7836.2005.01204
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24. RECOVERY Collaborative Group, Horby P, Lim WS,
Emberson JR, et al. Dexamethasone in hospitalized patients
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doi:10.1056/NEJMoa2021436
25. Lopes RD, de Barros e Silva PGM, Furtado RHM, et al.;
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Open. 2020;4(4):e376-e382. doi:10.1055/s-0040-1720962
1108718
research-article2022
HPXXXX10.1177/00185787221108718Hospital PharmacyParmiter et al

Original Article

Hospital Pharmacy

Assessment of an In-Sourced Patient

2022, Vol. 57(6) 734­–736
© The Author(s) 2022
Article reuse guidelines:
Assistance Program at a Health System in sagepub.com/journals-permissions
DOI: 10.1177/00185787221108718
https://doi.org/10.1177/00185787221108718

West Virginia journals.sagepub.com/home/hpx

Calvin Parmiter1 , David Cecere1, Staci Czyzewski1, and

Michelle Gibson1

Abstract

Background: Lack of insurance coverage in conjunction with the high cost of prescription drugs plays a large role in
patient’s obtaining and properly taking their medications. Many drug manufacturers provide assistance opportunities for
indigent patients lacking the financial means to obtain the medication. It is hypothesized that providing a dedicated insourced
team to coordinate this process can successfully increase medication access for indigent patient populations. Methods:
Patients with little or no means for payment whom the patient assistance team was contacted to obtain a medication were
included. Information collected included the medication requested, the drug manufacturer, the cost of the medication, the
dose required, the number of doses approved, and whether the request was approved or denied. This data was analyzed for
approval rate, most common medications requested, total cost of medications provided, as well as which system hospitals
are utilizing the program most frequently. Results: In total, 153 patients were assessed to obtain medication assistance
through the program. With an overall approval rate of 59.5%, 91 patients were provided medication through this program.
58% of patients received insurance approval and were therefore denied no-cost drug. The program was able to obtain 283
fills of no-cost medications for patients with a total value of $2 060 633.83. Conclusion: A dedicated patient assistance
program is effective in obtaining financial assistance for patients to obtain high-cost medications for which they otherwise
could not provide payment. With the continued expansion of biologic medication development, the necessity for programs
to aid indigent populations increases exponentially.

Keywords
management, pharmacoeconomics, purchasing, technicians

Background income of under $50 000, patients who do not qualify for

Healthcare costs, especially those associated with brand-
name prescription medications, continue to rise exponen-
tially year over year.1 These costs affect low-income patients
at alarmingly higher rates than those patients of higher
income status.2 Despite expansions to Medicaid access,
large amounts of low-income Americans remain uninsured
and therefore at risk of healthcare being cost-prohibitive.
With more than a quarter-million individuals living in pov-
erty as of 2019, West Virginia has the sixth highest poverty
rate of any state within the United States.3 West Virginians
also hold the second lowest median household income in the
United States.3
Significant costs are associated with many new biologic
and specialty agents utilized to treat malignancies and other
specialized disease states. These medications often come
with price tags upwards of $20 000 per dose and annual costs
exceeding $100 000. In a state with a median household
government-funded insurance and do not have effective pri-
vate insurance, cost substantially prohibits access to these
medications.
Drug manufacturer sponsored patient assistance pro-
grams provide access to medications for uninsured or under-
insured low-income patients. These programs may often be
unknown to patients may also be difficult to navigate with-
out guidance and assistance from a medical provider.
Previously, at West Virginia University Hospitals a third-
party company aided patients and providers in navigating
1
WVU Medicine – WVU Hospitals Department of Pharmacy,
Morgantown, WV, USA
Corresponding Author:
Calvin Parmiter, WVU Medicine – WVU Hospitals Department of
Pharmacy, 1 Medical Center Drive, Morgantown, WV 26506, USA.
Email: calvin.parmiter@gmail.com
Parmiter et al 735

these programs. Outsourcing this program came with an Table 1.  Value of No-Cost Medication Obtained for Patients
administrative fee billed to the institution in addition to a Through the Patient Assistance Program at Each System Hospital
perceived limited scope of services. It was then hypothe- During the First Full Year of the Program.
sized that providing this assistance locally could allow for Hospital Dollars saved
program expansion and improved coordination of care
through greater access within the electronic health record to Camden Clark Medical Center $104 790.86
patient information and provider communication. Reynolds Memorial Hospital $18 247.54
St. Joseph’s Memorial Hospital $56 958.90
United Hospital Center $65 000.00
Methods Wheeling Hospital $65 000.00
West Virginia University Hospitals $1 750 636.53
One clinical pharmacy technician FTE, due to the back-
Grand total $2 060 633.83
ground pharmacy experience and medication knowledge to
allow for educated conversations with patients and providers
during the enrollment process, was designated to launch our
Table 2.  Number of Patients Provided No-Cost Medication
local patient assistance program. Initial training for this tech- Through the Patient Assistance Program and the Number of
nician involved discussions with an external company and Medication Fills Completed for the Patients During the First Full
financial counselors within our local cancer center to deter- Year of the Program.
mine the process for the program within our electronic health
record. The team also met with health-systems familiar with Patients Prescriptions
Hospital assisted filled
the infrastructure necessary for maintaining a program such
as this. Requests for medication assistance are initially routed Camden Clark Medical Center 4 12
through our local patient financial services and prior authori- Reynolds Memorial Hospital 2 5
zation teams who forward these requests along to our clinical St. Joseph’s Memorial Hospital 2 6
pharmacy technician. United Hospital Center 1 2
Patient and medication request information is gathered Wheeling Hospital 1 2
from the provider and patient or his/her representative and West Virginia University Hospitals 81 256
then entered into a third-party software containing the neces- Grand total 91 283
sary documents required to apply for the manufacturer-spon-
sored programs. Much of this work may be completed for the
patient while still admitted to the hospital during his/her ini- obtaining a medication for that patient. Data collected
tial diagnosis. Patient privacy is ensured through a business included medication requested, dose requested, approved/
associate agreement (BAA), requiring maintained security of denied, number of doses approved, and denial reason if
PHI and HIPAA compliance, entered annually with the third- applicable. Requests were then separated by each system
party company. Patient consent is obtained at time of pro- hospital to determine program utilization throughout the
gram application. Once the application is complete the WVU Medicine enterprise.
manufacturer responds with either an approval or denial.
Approval duration varies by manufacturer and medication
Results
but is generally 1 year from the time of initial approval, at
which point the patient must be re-enrolled in the program. Between January 1st, 2020 and December 31st, 2020, 153
Delivery and medication administration is then coordinated patients requested medications through the patient assistance
on a recurring basis for doses delivered to the patient’s home program. Of these 153 patients, 91 (59.5%) were approved
or prior to each appointment for facility-administered medi- and able to obtain a medication through the program. Of the
cations. Further appeals may be conducted for any denials 62 patients who were not approved for medication assistance
that may occur upon initial enrollment or re-enrollment if the through the program, 36 (58.1%) were rejected related to
patient’s situation or manufacturer’s requirements changed insurance coverage of the requested medications. The remain-
after the initial approval. ing 26 (16.9%) patients were not approved for no-cost medi-
The primary aim of this analysis was to assess the rates of cation for other reasons including, but not limited to, loss of
approval of medications requested through our insourced follow up. These unapproved patients were often due to loss
patient assistance program from January 1, 2020 through of follow up. Patients also may have not been approved if the
December 31, 2020. Secondary objectives include deter- medication was prescribed for an unapproved indication for
mining the value of medications provided to patients and which the manufacturer could not supply the medication.
assessing reason for denial. The analysis was a retrospec- For the 91 patients approved for medication through
tive, IRB-approved analysis of patient data collected by our the program, there were 283 unique fills of medication
patient assistance program. Patients were included if the (Table 2) providing a total patient savings of $2 060 633.83
patient assistance program was contacted regarding (Table 1). Patients were referred from 6 different hospitals
736 Hospital Pharmacy 57(6)
Table 3.  The 5 Medications Most Commonly Obtained for
Patients Through the Patient Assistance Program During the First
Full Year of the Program.
Medication N (%)
Ocrelizumab (Ocrevus®) 25 (13.9)
Pembrolizumab (Keytruda®) 17 (9.4)
Immune Globulin (Privigen®) 12 (6.7)
Rituximab (Rituxan®) 11 (6.1)
Bevacizumab (Avastin®) 10 (5.6)
within our, then 18-member, health system. The majority, 81
(89%) patients, were referred from the flagship academic
medical center. The most common (14%) no-cost medica-
tion obtained for patients was ocrelizumab (Ocrevus®) fol-
lowed by other high-cost monoclonal antibodies and
immune globulin (Table 3).
Discussion
Though not specifically targeted by the program, patients
referred to and assisted by this program are commonly
ordered medications for debilitating and life-threatening
diseases such as multiple sclerosis and various malignan-
cies. Many of these patients now have a limited ability to
work as a result of their disease. Concerns regarding their
ability to provide for their family, continue to pay their bills,
and keep a roof over their head are only amplified by the
fear of not being able to afford treatment for their disease.
Our staff feel an overwhelming sense of purpose in assisting
these patients who often express gratitude toward our clini-
cal pharmacy technician who works tirelessly obtaining
medications and financial assistance for them. The reward-
ing nature of assisting patients through this program was
one of the key barriers to overcome when initially transi-
tioning this program from its previous department to live
within the pharmacy department.
With continued expansion of the health system into more
disproportionately low-income, rural areas of West Virginia,
there is a consistent increase in volume of patients with need
for patient assistance programs to access medication therapy.
This patient population represents a vulnerable group who
frequently have high readmission rates.4 By assisting these
patients through provision of medication access, adherence
to therapy may be improved, in turn, potentially reducing
readmission rates.
Through calculation of an estimated per-bed savings
based on data from the hospitals with patients assisted
through the program, an additional estimated $1 M per year
could be saved across the health system with the addition of
new sites. Healthcare costs rising at rates higher than that of
inflation may also lead to more patients requiring financial
assistance to continue to afford their healthcare which may
inflate this number even further. Additionally, through the
continued expansion of biologic and other high-cost medica-
tion development, the necessity for a program such as this
increases exponentially. Through the first half of 2021, 11
new medications with available patient assistance were
added to the health system formulary.
Conclusions
Our in-sourced patient assistance program is effective in
obtaining financial assistance for patients to obtain high-cost
medications. Growth and expansion of the patient assistance
team will be key to its continued. The program’s ability to
provide these services to all patients in need throughout our
health system hinges upon the resources we are able to allo-
cate to handle requests promptly and efficiently. Programs
such as ours have opportunity throughout the entire country
but their greatest impact can be seen in poverty-stricken
areas with large income disparities.
Further research should be done to determine any links
between obtaining no-cost medications and readmission rates
of patients as gathering clinical outcomes are not currently
obtained by our team and determining these may be crucial to
ensuring continued success and support for the program as it
matures. Additionally, further analyzing treatment adherence
rates for patients receiving no-cost medications compared to
those who did not may prove beneficial. Finally, a link to
treatment outcomes should also be researched. Results of
these further studies could allow for additional support for
implementation of programs such as these.
ORCID iD
Calvin Parmiter https://orcid.org/0000-0002-7082-7930
References
1. Parekh N, McClellan M, Shrank WH. Payment reform, medi-
cation use, and costs: can we afford to leave out drugs? J Gen
Intern Med. 2019;34(3):473-476. doi:10.1007/s11606-018-
4794-y.
2. Okunrintemi V, Khera R, Spatz ES, et al. Association of
income disparities with patient-reported healthcare experience.
J Gen Intern Med. 2019;34(6):884-892. doi:10.1007/s11606-
019-04848-4
3. United States Census Bureau. Median household income (in
2020 dollars), 2016–2020.
4. Murray F, Allen M, Clark CM, Daly CJ, Jacobs DM. Socio-
demographic and -economic factors associated with 30-day
readmission for conditions targeted by the hospital readmis-
sions reduction program: a population-based study. BMC Public
Health. 2021;21:1922. doi:10.1186/s12889-021-11987-z
1111743
research-article2022
HPXXXX10.1177/00185787221111743Hospital PharmacyChau et al

Original Article

Hospital Pharmacy

Heparin Resistance in SARS-CoV-2

2022, Vol. 57(6) 737­–743
© The Author(s) 2022
Article reuse guidelines:
Infected Patients with Venous sagepub.com/journals-permissions
DOI: 10.1177/00185787221111743
https://doi.org/10.1177/00185787221111743

Thromboembolism journals.sagepub.com/home/hpx

Terence Chau1 , Merlyn Joseph2 , Diana M. Solomon1,

Bryan Lee3, and Lauren A. Igneri1

Abstract

Introduction: Heparin resistance has been reported in coronavirus disease 2019 (COVID-19) patients receiving intravenous
unfractionated heparin (IV UFH). Anti-Xa monitoring of IV UFH has been suggested over activated partial thromboplastin
times due to laboratory interference from elevated factor VIII and fibrinogen levels in COVID-19 patients. Information on
heparin resistance with anti-Xa monitoring in COVID-19 patients with confirmed venous thromboembolism (VTE) is lacking.
Methods: In this retrospective cohort study of patients with radiographically confirmed VTE, IV UFH dosage requirements
in COVID-19 positive patients were compared with COVID-19 negative patients. The primary endpoint was the IV UFH
dose needed to achieve a therapeutic anti-Xa level. Secondary endpoints included time to therapeutic anti-Xa, number
of dose adjustments to achieve therapeutic anti-Xa, and bleeding. Results: Sixty-four patients with confirmed VTE were
included (20 patients COVID-19 positive, 44 patients COVID-19 negative). Eighty-five percent (17 of 20) of COVID-19
positive patients achieved anti-Xa ≥ 0.3 units/mL with the first anti-Xa level drawn post-IV UFH infusion initiation. The
median UFH dose needed to achieve first therapeutic anti-Xa was similar between COVID-19 positive and COVID-19
negative patients (median [IQR]: 18 units/kg/hour [18-18] vs 18 units/kg/hour [18-18], P = .423). The median number of dose
adjustments and time to achieve therapeutic anti-Xa were also similar between the 2 groups. The frequency of patients
receiving IV UFH of more 35 000 units/day did not differ between the 2 groups. Two cases of clinically significant heparin
resistance in the COVID-19 positive group were identified. Conclusions: During the first wave of COVID-19, heparin
dose and time to therapeutic anticoagulation appeared to be similar between COVID-19 positive and COVID-19 negative
patients monitored by anti-Xa at our institution. More studies are required to evaluate clinically significant heparin resistance
in the context of the wide range of viral variants which developed, and beyond the population observed in this single center
retrospective study.

Keywords
anticoagulants, blood, COVID, critical care

Background method. Heparin binds reversibly to antithrombin leading to

Despite the use of standard venous thromboembolism (VTE)
prophylaxis and therapeutic anticoagulation dosing strate-
gies, anticoagulation failures including heparin resistance
(ie, requiring heparin doses >35 000 units/day to achieve
therapeutic anticoagulation), have been described in corona-
virus disease 2019 (COVID-19) patients.1-3 Potential mecha-
nisms for anticoagulation failures have been proposed
including severe inflammatory process, direct endovascular
injury, elevated risk of thromboembolism in COVID-19,
increased heparin-binding proteins, and altered pharmacoki-
netics (ie, augmented renal clearance, increased heparin
clearance), or lower antithrombin levels.4-6
One concern with heparin resistance in COVID-19
patients may be due to the anticoagulation monitoring
inactivation of factors IIa and Xa. Thus, antithrombin defi-
ciency will result in lower anti-Xa and activated partial
thromboplastin times (aPTT) in patients on intravenous (IV)
unfractionated heparin (UFH). Elevated levels of factor VIII
and fibrinogen will affect aPTT, but not anti-Xa assays.
Small observational, retrospective studies in COVID-19
1
Cooper University Health Care, Camden, NJ, USA
2
Texas A&M University, Irma Lerma Rangel College of Pharmacy,
Houston, TX, USA
3
Kaiser Permanente Oakland Medical Center, Oakland, CA, USA
Corresponding Author:
Terence Chau, Department of Pharmacy, Cooper University Hospital,
One Cooper Plaza, Camden, NJ 08103, USA.
Email: chau-terence@cooperhealth.edu
738 Hospital Pharmacy 57(6)
patients showed these patients had normal antithrombin val-
ues, but elevated levels of factor VIII and fibrinogen.
Therefore, it is suggested anti-Xa activity assays be utilized
over aPTT monitoring in COVID-19 patients.7,8
We conducted a retrospective cohort study to determine if
COVID-19 positive patients required more IV UFH to
achieve therapeutic anticoagulation with anti-Xa monitoring
compared to COVID-19 negative patients. We hypothesized
the heparin dosage needed to achieve therapeutic anti-Xa
levels between COVID-19 positive and COVID-19 negative
patients would not differ significantly when using anti-Xa
monitoring.
Methods
This was an IRB-approved, retrospective medication use
evaluation of IV UFH in adult patients with radiographi-
cally confirmed VTE during the first wave of the COVID-
19 pandemic (March 2020 through June 2020). Exclusion
criteria included: conditions which may alter heparin phar-
macokinetics including pregnancy and targeted tempera-
ture management; acquired conditions which may increase
risk for heparin resistance, including extracorporeal mem-
brane oxygenation; less than 3 anti-Xa levels drawn or
duration of IV UFH infusion of less than 24 hours; or
received a direct oral anticoagulant (DOAC) prior to IV
UFH initiation (to avoid DOAC influence on the heparin
anti-Xa assay). Baseline and peak inflammatory markers,
such as C-reactive protein, ferritin, fibrinogen, D-dimer,
and lactate dehydrogenase were collected in the COVID-19
positive patients.
The primary outcome was to compare the IV UFH dose
needed to achieve an anti-Xa ≥ 0.3 units/mL between
COVID-19 positive and COVID-19 negative patients.
Anti-Xa levels of <0.3, 0.3 to 0.7, and >0.7 units/mL were
considered to be subtherapeutic, therapeutic, and suprathera-
peutic, respectively. Secondary outcomes included: time to
anti-Xa ≥ 0.3 units/mL; number of dose adjustments needed
to achieve anti-Xa ≥ 0.3 units/mL; IV UFH dose needed to
achieve therapeutic anti-Xa (0.3-0.7 units/mL); number of
dose adjustments needed to achieve therapeutic anti-Xa con-
centrations; time to therapeutic anti-Xa concentrations; and
bleeding.
Data was analyzed with the Chi-Square/Fisher’s exact test
and Mann-Whitney U-test where appropriate. All laboratory
analyses were performed using the same analyzer (ACL TOP
750 CTS; Werfen) and reagents (HemosIL Liquid Anti-Xa;
Werfen).
Our institution’s VTE protocol has an optional IV UFH
bolus of 80 units/kg with an initial starting dose of 18 units/
kg/hour. Doses were based upon actual body weight and
dose-capping was at the provider discretion during the study
timeframe. Anti-Xa levels are drawn 6 hours after initiation
of the UFH infusion and every 6 hours thereafter until 2 con-
secutive anti-Xa levels are therapeutic, then anti-Xa levels
are checked daily. For patients unable to achieve anti-Xa
≥ 0.3 units/mL within 24 hours of IV UFH protocol initia-
tion, they were further evaluated for potential clinically sig-
nificant heparin resistance. Heparin resistance was defined
as either: (1) requirement >35 000 units of IV UFH per day
to achieve anti-Xa ≥ 0.3 units/mL; or (2) >35 000 units of IV
UFH per day and unable to achieve anti-Xa ≥ 0.3 units/mL.
Results
A total of 321 patients were screened for eligibility. We
included 64 patients with confirmed VTE in the analysis (20
patients COVID-19 positive, 44 patients COVID-19 nega-
tive). COVID-19 positive patients were more likely to be
admitted or transferred to the intensive care unit (85% vs
52.3%, P = .014), receive mechanical ventilation (65% vs
31.8%, P = .013), and experience acute kidney injury (25%
vs 2.3%, P = .010). There were no significant differences
between age, weight, body mass index, or the use of UFH
loading dose between the 2 groups (Table 1). The median
duration of hospitalization was longer in COVID-19 positive
patients (median [interquartile range (IQR)]: 18.5 days [7.3-
27] vs 7 days [4-17.8], P = .006).
Eighty-five percent (17 of 20) of COVID-19 positive
patients achieved anti-Xa ≥ 0.3 units/mL with the first anti-
Xa level drawn post-IV UFH infusion initiation. In COVID-
19 negative patients, 90.9% (40 of 44) achieved this value
with the first anti-Xa lab draw. For the primary outcome
(Table 2), the median UFH dose needed to achieve first anti-
Xa ≥ 0.3 units/mL was similar between COVID-19 positive
and COVID-19 negative patients (median [IQR]: 18 units/
kg/hour [18-18] vs 18 units/kg/hour [18-18], P = .423). The
median number of dose adjustments and time to achieve anti-
Xa ≥ 0.3 units/mL were also similar between the 2 groups.
All patients achieved anti-Xa ≥ 0.3 units/mL with IV
UFH. A total of 23 patients (7 COVID-19 positive and 16
COVID-19 negative) required more than 35 000 units/day to
achieve or maintain anti-Xa ≥ 0.3 units/mL. There was no
significant difference between the COVID-19 positive and
COVID-19 negative patients in the frequency of IV UFH
requirements greater than 35 000 units/day (35% vs 36.5%,
P = .916). The median weight for these patients were 99.1 kg
(IQR: 84.3-115.2). The median IV UFH dose required for
first anti-Xa ≥ 0.3 units/mL achievement was 18 units/kg/
hour (IQR: 18-18). The median time to anti-Xa ≥ 0.3 units/
mL achievement was 6.7 hours (IQR: 6.2-12.5). There was
no statistically significant difference between median weight,
median IV UFH dose for first anti-Xa ≥ 0.3 units/mL, or
median time to anti-Xa ≥ 0.3 units/mL between the COVID-
19 positive and COVID-19 negative patients.
Three patients (2 COVID-19 positive patients and 1
COVID-19 negative patient) did not achieve anti-Xa
≥ 0.3 units/mL within 24 hours of UFH initiation. Of these 3
patients, we identified 2 cases of potentially clinically sig-
nificant heparin resistance. Both cases were COVID-19
Chau et al 739

Table 1.  Baseline Characteristics.

Variable COVID-19 positive n = 20 COVID-19 negative n = 44 P-value

Patient demographics
  Male, n (%) 13 (65) 24 (54.5) .432
  Age, years 62 (56.0-72.8) 60 (48.0-73.8) .755
  Diabetes mellitus, n (%) 7 (35) 7 (15.9) .087
  Heart failure, n (%) 0 (0) 3 (6.8) .546
  Chronic kidney disease or end-stage renal disease, n (%) 3 (15) 1 (2.3) .087
  Malignancy, n (%) 1 (5) 6 (13.6) .419
  Chronic obstructive pulmonary disease, n (%) 0 (0) 3 (6.8) .546
Hospital course
  Length of stay, days 18.5 (7.3-27.0) 7.0 (4.0-17.8) .006
  ICU, n (%) 17 (85) 23 (52.3) .014
  Mechanical ventilation, n (%) 13 (65) 14 (31.8) .013
  Cardiac arrest, n (%) 0 (0) 4 (9.1) .300
  Infection, other than COVID-19, n (%) 7 (35) 8 (18.2) .141
  Acute kidney injury, n (%) 5 (25) 1 (2.3) .010
Heparin dosing characteristics
  BMI, mg/kg2 29.9 (25.6-36.2) 29.8 (23.5-37.0) .696
  Height, inch 69 (64.5-70.8) 66.5 .300
  Weight, kg 92.1 (75.1-107.5) 84.4 (68.0-104.6) .434
  Deep vein thrombosis, n (%) 14 (70) 22 (50) .453
  Pulmonary embolism, n (%) 5 (25) 18 (40.9)  
  Other thrombus type, n (%) 1 (5) 4 (9.1)  
  UFH loading dose, n (%) 9 (45) 16 (36.4) .512
  UFH loading dose, unit/kg 79.9 (65.8-80.2) 79.6 (79.2-79.7) .760
Laboratory information
Serum creatinine, mg/dL
 Initial 1.3 (1.0-1.7) 1.3 (0.9-1.6) .456
 Peak 2.8 (1.5-4.4) 1.5 (1.0-1.9) .003
Albumin, g/dLa
 Initial 3.1 (2.7-3.6) 3.4 (2.8-3.7) .245
 Nadir 2.5 (2.0-2.8) 2.7 (2.3-3.5) .053
Total bilirubin, mg/dLa
 Initial 0.7 (0.4-1.0) 0.6 (0.2-0.8) .288
 Peak 0.9 (0.6-1.5) 0.7 (0.5-1.1) .131
AST, u/La
 Initial 50 (21-96) 27.5 (15.5-57.5) .239
 Peak 81 (50-271) 36.5 (19-135) .056
ALT, μ/La
 Initial 34 (14-52) 22 (14.3-45.5) .479
 Peak 52 (31-98) 36 (15.5-107.5) .229
Hemoglobin, g/dL
 Initial 12.9 (10.9-14.4) 11.2 (9.0-14.0) .192
 Nadir 8.2 (5.9-9.9) 8.5 (6.7-11.1) .235
INRb
 Initial 1.2 (1.1-1.3) 1.2 (1.1-1.4) .918
 Peak 1.4 (1.2-2.2) 1.4 (1.2-2.1) .934
aPTT, sc
 Initial 31.4 (27.6-47.7) 32.1 (27.5-43.3) .933
 Peak 50.6 (39.9-69.8) 41.7 (30.6-120.0) .516
Platelet, 103/μL
 Initial 243.5 (170.5-305.3) 222 (172.5-360.0) .873
 Nadir 140 (63-228.5) 170 (107-234.5) .281
Triglycerides, mg/dLd
 Initial 249 (183.5-380.8) 112 (91-266) .071
 Peak 355.5 (226.8-571.3) 112 (103-266) .021
(continued)
740 Hospital Pharmacy 57(6)

Table 1.  (continued)

Variable COVID-19 positive n = 20 COVID-19 negative n = 44 P-value

e
Inflammatory markers
  Initial C-reactive protein, mg/dL 14.7 (8.0-24.6) — —
  Peak C-reactive protein, mg/dL 20.75 (10.3-27.2) — —
  Initial ferritin, ng/mL 1320.5 (924.3-1541) — —
  Peak ferritin, ng/mL 1967 (1538.3-2742.8) — —
  Initial d-dimer, μg/mL 3.7 (2-10.7) — —
  Peak d-dimer, μg/mL 7.4 (5.4-21.6) — —
  Initial lactate dehydrogenase, unit/L 517 (400.5-848.8) — —
  Peak lactate dehydrogenase, unit/L 819.5 (499-1016.5) — —

Note. Median (IQR) unless otherwise specified. BMI = body mass index; ICU = intensive care unit; UFH = unfractionated heparin; AST = aspartate
transaminase; ALT = alanine transaminase; PT = prothrombin time; INR = international normalized ratio; aPTT = activated partial thromboplastin time.
a
Data available for 19 COVID-19 positive patients, 36 COVID-19 negative patients.
b
Data available for 18 COVID-19 positive patients, 36 COVID-19 negative patients.
c
Data available for 19 COVID-19 positive patients, 43 COVID-19 negative patients.
d
Data available for 14 COVID-19 positive patients, 11 COVID-19 negative patients.
e
Data available for 18 COVID-19 positive patients.

Table 2. Results.

COVID-19 COVID-19
positive n = 20 negative n = 44 P-value
Primary outcome
  UFH dose for first anti-Xa ≥ 0.3 units/mL, units/kg/h 18 (18-18) 18 (18-18) .423
UFH dose ranges for first anti-Xa ≥ 0.3 units/mL, units/kg/h, n (%)
 18 17 (85) 40 (90.9) .448
  >18-22 1 (5) 3 (6.8)
  >22-26 1 (5) 1 (2.3)
  >26-30 0 (0) 0 (0)
  >30 1 (5) 0 (0)
Other outcomes
  Time to first anti-Xa ≥ 0.3 units/mL, h 6.13 (5.92-9.44) 6.25 (6.03-7.29) .317
  Number of dose adjustments to achieve ≥0.3 units/mL 0 (0-0) 0 (0-0) .430
Frequency of dose adjustments to achieve ≥0.3 units/mL, n (%)
 0 17 (85) 40 (90.9) .173
 1 1 (5) 3 (6.8)
 2 0 (0) 1 (2.3)
  >2 2 (10) 0 (0)
First anti-Xa level post-UFH infusion ≥0.3 units/mL, n (%) 17 (85) 40 (90.9) .483
UFH dose for first therapeutic anti-Xa level range, unit/kg/h 15 (12-18) 15.5 (12.3-18) .865
Number of dose adjustments to achieve first therapeutic anti-Xa level range 1.5 (0.25-3) 1 (0-2) .190
Time to therapeutic target range attainment, h 21.1 (7.8-32.7) 15.8 (9.1-27.9) .690
High dose heparin infusions
 Received >35 000 units/day to achieve or maintain anti-Xa ≥ 0.3 units/mL 7 (35) 16 (36.4) .916
  Clinically significant heparin resistance* 2 (10) 0 (0) .094

Note. Median (IQR) unless otherwise specified. UFH = unfractionated heparin.

*In patients unable to achieve anti-Xa ≥ 0.3 units/mL within 24 hours; heparin resistance definition: (1) requirement >35 000 units of IV UFH per day to
achieve anti-Xa ≥ 0.3 units/mL; or (2) >35 000 units of IV UFH per day and unable to achieve anti-Xa ≥ 0.3 units/mL).

positive, exhibited prolonged time to achieve anti-Xa
≥ 0.3 units/mL, and required over 50 000 units of IV UFH
per day. The third patient was determined not to be heparin
resistant as prolonged time to achieve anti-Xa ≥ 0.3 units/mL
was attributed to IV access issues and required less than
35 000 units/day of UFH per day. Details of these 3 patients
are described in Table 3.
Initial anti-Xa levels were frequently supratherapeutic
(>0.7 units/mL) and occurred in 64.1% of our patients (70%
in COVID-19 positive and 61.4% in COVID-19 negative
Chau et al 741
Table 3.  Characteristics of Patients not Achieving Anti-Xa ≥ 0.3 units/mL at 24 hours.
COVID-19 Indication for ICU
Patient status anticoagulation status
59 year old male Positive Deep vein ICU
thrombosis
41 year old male Positive Pulmonary Floor
embolism
87 year old female Negative Deep vein Floor
thrombosis
*In patients unable to achieve anti-Xa > 0.3 units/mL within 24 hours; heparin resistance definition: (1) requirement >35 000 units of IV UFH per day to
achieve anti-Xa ≥ 0.3 units/mL; or (2) >35 000 units of IV UFH per day and unable to achieve anti-Xa ≥ 0.3 units/mL)
patients, P = .504). There were no differences in the UFH
dose needed to achieve therapeutic anti-Xa range concentra-
tions (0.3-0.7 units/mL) between the COVID-19 positive and
COVID-19 negative patients (median [IQR]: 15 units/kg/
hour [12-18] vs 15.5 units/kg/hour [12.3-18], P = .865). The
median number of dose adjustments needed to achieve thera-
peutic anti-Xa range was also similar (P = .190). Time to
therapeutic target range attainment was longer in the COVID-
19 group, but not statistically significant (median [IQR]:
21.1 hours [7.8-32.7] vs 15.8 hours [9.1-27.9], P = .690).
Hemoglobin decrease ≥2 g/dL from baseline occurred
more frequently in COVID-19 patients (80% vs 47.7%,
P = .028), but there was no difference in number of patients
with hemoglobin <7 g/dL compared to COVID-19 negative
patients (35% vs 29.5%, P = .633). Protamine administration
occurred once in the COVID-19 negative group. No patients
received ≥2 units of packed red blood cells during or imme-
diately after IV UFH infusion. Full International Society of
Thrombosis and Hemostasis Criteria for major bleeding and
clinically relevant non-major bleeding was unable to be col-
lected due to the retrospective nature of the study.
Discussion
Heparin resistance has been traditionally defined as: (1) the
need for IV UFH doses of >35 000 units/day to achieve tar-
get anticoagulation; or (2) the need for more than 500 units/
kg to achieve target activated clotting time in patients under-
going cardiopulmonary bypass.9,10 The mechanisms behind
heparin resistance include: increased heparin-binding pro-
teins; increased heparin clearance; antithrombin deficiency;
and elevated levels of factor VIII and fibrinogen.10
In a patient with increased heparin-binding proteins,
increased clearance, or antithrombin deficiency, the aPTT
and anti-Xa values will be lower than expected while receiv-
ing IV UFH. Management of heparin resistance due to
increased heparin-binding proteins and clearance include
increasing the heparin dosage or consideration of an alterna-
tive anticoagulation (ie, direct thrombin inhibitor). If anti-
thrombin deficiency is identified as the cause of heparin
Estimated Time to anti-
Weight, UFH bolus, UFH dose, Xa ≥ 0.3 units/ Heparin Discharge
kg units/kg units/day mL, h resistance* status
98.4 None 56 696 28.23 Yes Alive
77.6 80 59 577 53.62 Yes Alive
59.2 None 28 393 27.52 No Alive
resistance, the patient may either be transitioned to a direct
thrombin inhibitor or antithrombin may be increased by
supplementation.
For IV UFH patients with elevated levels of factor VIII
and fibrinogen, such as those seen with substantial systemic
inflammation, aPTT values will be falsely low but anti-Xa
values will not be affected. These cases have been referred to
as heparin pseudo-resistance.6,11 Management of these cases
include changing the laboratory monitoring method of IV
UFH from aPTT to anti-Xa. Alternatively, anticoagulation
with low molecular weight heparin would be an acceptable
option. Switching to a direct thrombin inhibitor would not be
ideal as aPTT is typically used to monitor therapy.12
Any COVID-19 patient with suspected heparin resistance
needs to be evaluated in the context of the laboratory test
used to monitor IV UFH and the target anticoagulation goal.
Small observational, retrospective studies in COVID-19
patients with heparin resistance have shown normal anti-
thrombin values, but elevated levels of factor VIII and fibrin-
ogen. Therefore, it is suggested anti-Xa activity assays be
utilized over aPTT monitoring in COVID-19 patients as
aPTT will be falsely low due to elevation of those factors.7,8
In our overall patient cohort, dosage requirements and
time to anti-Xa ≥ 0.3 units/mL with an UFH anti-Xa moni-
toring strategy for VTE treatment were similar between
COVID-19 positive and COVID-19 negative patients.
While the incidence of heparin resistance outside of cardiac
surgery is unknown, small retrospective studies reported
potential heparin resistance in 75% to 80% of examined
COVID-19 patients.8,13 Notably, we identified 10% of our
COVID-19 positive patients with potential clinically sig-
nificant heparin resistance with anti-Xa monitoring. Our
results suggest concerns for apparent heparin resistance in
COVID-19 patients may potentially be mitigated with anti-
Xa monitoring of IV UFH. While the COVID-19 group pre-
sumably had higher inflammatory markers, higher rates of
acute renal failure and hypertriglyceridemia were also pres-
ent. Renal failure and elevated triglycerides (>360 mg/dL)
may impact anti-Xa levels through decreased heparin clear-
ance and assay interference, respectively.14 In this study,
742 Hospital Pharmacy 57(6)
only one patient received IV UFH with hypertriglyceride-
mia concomitantly. The significance of the interaction
between these factors on anti-Xa achievement would need
to be further evaluated in larger studies.
There are several limitations to this retrospective, single-
center study. The small sample size could increase the risk of
a Type II error. One reason for the small number of COVID-
19 positive patients was our strict inclusion criteria of radio-
graphically confirmed VTE with IV UFH treatment. Previous
studies reporting heparin resistance in COVID-19 positive
patients included patients on UFH or low molecular weight
heparin with or without confirmed thrombosis.7,8,13 Second,
we included patients on UFH infusions for at least 24 hours.
We may not have captured all heparin resistant patients as
those with initial low anti-Xa levels may have transitioned to
alternative anticoagulants. Third, inflammatory markers
such as interleukin-6, C-reactive protein, ferritin, and
D-dimer are not routinely obtained in our COVID-19 nega-
tive patients thus we were unable to make comparisons
between the 2 study groups. It is assumed the COVID-19
positive group would have higher levels of inflammation
than COVID-19 negative patients. Fourth, the impact of
COVID-19 variants on heparin resistance and thrombotic
complications is largely unknown. This study reviewed
COVID-19 patients during the first wave in the northeastern
United States (March through June 2020). The results of this
study may not be generalizable to the current variant. Fifth,
although doses and time to anti-Xa ≥ 0.3 units/mL achieve-
ment was evaluated in our study, ongoing IV UFH doses
required to maintain this therapeutic target was not evalu-
ated. Heparin resistance was primarily screened during the
acute phase of IV UFH initiation and there is a possibility of
the development of heparin resistance later in the hospital
stay. One final consideration is the definition of heparin
resistance. While doses of >35 000 units/day of IV UFH has
been suggested,9,10 this definition has not been validated in
clinical trials. Additionally, patient body weight will signifi-
cantly impact heparin resistance rates using this definition.
Patients in our study had median weights of 92.1 and 84.4 kg
in the COVID-19 positive and negative groups, respectively.
Generally accepted doses for initial treatment of VTE
(18 units/kg/hour) could easily exceed 35 000 units/day of IV
UFH with these body weights. With strict application of this
definition alone, 23 patients (median weight of 99.1 kg)
would meet heparin resistance criteria (7 COVID-19 positive
and 16 COVID-19 negative). By applying the definition of
heparin resistance on patients unable to achieve anti-Xa
≥ 0.3 units/mL within 24 hours of IV UFH initiation, we
identified 2 potentially clinically significant cases of heparin
resistance in COVID-19 positive patients with active VTE
where delayed time to therapeutic goal may be detrimental.
Strengths of our study are the use of a control group and
limiting therapeutic anticoagulation to IV UFH only. Any
concerns about variation in heparin potency in the IV UFH
were minimized both treatment groups were on IV UFH
during the same timeframe. Another strength is the inclusion
of patients only with radiographically confirmed VTE. Our
study timeframe spanned the first wave of the COVID-19
pandemic when there was much discussion in both the
public and medical media about thromboembolic events,
whether macrovascular or microvascular, contributing to
the complexity and severity of illness of patients diagnosed
with COVID-19. During this first wave, some institutions
adopted practices for empiric therapeutic-dose and inter-
mediate-dose prophylactic anticoagulation. Our institution
did not adopt these practices due to inadequate supporting
evidence in the literature. Much data has since been pub-
lished on the subject of therapeutic-dose and intermediate-
prophylactic dose anticoagulation in COVID-19 in the
2 years the pandemic has impacted the United States.15-19
While the authors’ note the importance of VTE prophy-
laxis, our study is different as it only included patients with
confirmed VTE and an indication for therapeutic-dose
anticoagulation. At this time, empiric therapeutic antico-
agulation in critically ill COVID-19 patients is not recom-
mended.20,21 The majority of our COVID-19 patients were
critically ill and our results reflect a more realistic clinical
situation where therapeutic anticoagulation would be uti-
lized in the intensive care unit. To date, there is a lack of
large studies examining the use of IV UFH for the treat-
ment of VTE in COVID-19 patients as these studies uti-
lized empiric anticoagulation or primarily low molecular
weight heparins, such as enoxaparin.15-19
Conclusion
Previous studies have suggested anti-Xa over aPTT monitor-
ing of IV UFH may be advantageous in COVID-19 patients.
Our study revealed heparin dosage and time to therapeutic
anticoagulation appear to be similar between COVID-19
positive and COVID-19 negative patients with anti-Xa mon-
itoring. COVID-19 patients may be successfully anticoagu-
lated with IV UFH using an anti-Xa monitoring strategy;
however concern for clinically significant heparin resistance
in COVID-19 patients monitored with anti-Xa levels may
still exist based on our findings. Future studies examining
the use of anti-Xa for IV UFH in COVID-19 patients are
needed to strengthen the recommendation to use an anti-Xa
monitoring strategy over aPTT and to further define heparin
resistance in this population.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
Chau et al 743
ORCID iDs
Terence Chau https://orcid.org/0000-0002-3671-8394
12. Kennedy DM, Alaniz C. Apparent argatroban resistance in a
Merlyn Joseph https://orcid.org/0000-0003-4190-8800
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1111725
research-article2022
HPXXXX10.1177/00185787221111725Hospital PharmacyCruz et al

Original Article

Hospital Pharmacy

Spontaneous Adverse Event Reporting

2022, Vol. 57(6) 744­–751
© The Author(s) 2022
Article reuse guidelines:
by COVID-19 Vaccinated Healthcare sagepub.com/journals-permissions
DOI: 10.1177/00185787221111725
https://doi.org/10.1177/00185787221111725

Professionals Through an Electronic Form journals.sagepub.com/home/hpx

Implemented by the Hospital Pharmacy

João Paulo Garcia Lopes da Cruz1,2 , Cristina da Conceição

Ribeiro de Carvalho1, Paula Alexandre da Cruz Silva3, Luis
Filipe Campos Guerreiro1, Tatiana Vedes Bento1, Leila Vanessa
Carmo Cardoso Martins Costa1, Raquel Filipa Miguel Margarido
Duarte Simões1, Rui Pedro Pinheiro Gonçalves Marques1, Ana
Cristina Castro Fernandes1, Luís Miguel Costa de Mendonça
Galaio4, Ana Isabel B. Correia4, Ema Maria S. Leite Resende4,
and João Manuel Braz Gonçalves2

Abstract

Aim: Implementation of a web-form based pharmacovigilance plan for the spontaneous notification of adverse events to
the Comirnaty® COVID-19 vaccine during its administration to hospital healthcare professionals. Methods: An electronic
pharmacovigilance form was developed containing 8 pre-defined event options, an open answer option for the description
of other events and/or symptoms, and a question about the overall intensity of symptoms. The adverse events reports were
standardized according to physiological and pathological condition. Results: A total of 4119 adverse events notifications were
obtained with a 45% rate of electronic notification. The most clinically relevant events reported were:tachycardia (n = 19),
dyspnea (n = 7), chest pain (n = 6), facial/labial edema (n = 6), lipothymia (n = 5), bronchospasm (n = 2), herpetic infection
(n = 2), vasculitis (n = 2), arrhythmia (n = 1), difficult to control arterial hypertension (n = 1), gastritis (n = 1), and spontaneous
abortion (n = 1). Regarding the intensity of symptoms (n = 2928), 70.0% were reported as mild, 25.8% as moderate, and 4.27%
as severe, with higher intensity in the second dose compared to first dose. The highest frequency of severe events were
reported in the groups from 40 to 59 years in both vaccination periods. During the vaccination process, no hospitalizations
and no deaths were notified and/or recorded. Conclusion: In this real world study, comparing with Comirnaty clinical trials
program, it was observed a higher frequency of adenomegaly and gastrointestinal disorders. Noteworthy, the notification of
a case of miscarriage. The use of hospital pharmacy pharmacovigilance electronic forms, seemed to be relevant to notification
adherence and to obtain a greater and faster knowledge of COVID-19 vaccine safety profile

Keywords
COVID, vaccines, medication safety, adverse drug reactions reporting/monitoring, pharmacists, education

Key Messages
WHAT IS ALREADY KNOWN ON THIS SUBJECT
•• Emergence of the COVID-19 pandemic lead to rap-
idly development of vaccines against SARS-CoV-2.
•• The information related to COVID-19 vaccines safety
are mainly based on clinical trials data and there is a
lack of real world data.
•• Electronic pharmacovigilance forms are important
fast resources for obtaining safety data, but there are
limit data in context of COVID-19 vaccines.
1
Pharmacy Service of Centro Hospitalar Universitário Lisboa Norte,
Hospital de Santa Maria, Lisbon, Portugal
2
iMed.ULisboa – Research Investigation for Medicines, Faculty of
Pharmacy, University of Lisbon, Lisbon, Portugal
3
Information and Safety of Medicines, Pharmacovigilance Unit of Pharmacy
Service of Centro Hospitalar Universitário Lisboa Norte, Hospital de
Santa Maria, Lisbon, Portugal
4
Occupational Health Medical Service of Centro Hospitalar Universitário
Lisboa Norte, Hospital de Santa Maria, Lisbon, Portugal
Corresponding Author:
João Paulo Garcia Lopes da Cruz, Pharmacy Service of Centro Hospitalar
Universitário Lisboa Norte/Hospital de Santa Maria, Av. Egas Moniz, Nº1,
Lisboa 1649-028, Portugal.
Email: jplopescruz@chln.min-saude.pt
Cruz et al 745
WHAT THIS STUDY ADDS
•• Although this real-world study shows an overall
adverse event profile similar to Comirnaty’s clinical
trials, it also reveals an increase in the frequency of
adenomegaly, gastrointestinal disturbances, and one
case of miscarriage.
•• The hospital pharmacy activity, namely through the
development of electronic pharmacovigilance tools,
could contribute to fast obtain real data on safety of
COVID-19 vaccines.
Introduction
With the emergence of the COVID-19 pandemic, there was a
need to rapidly investigate and carry out clinical trials allow-
ing the subsequent commercialization of effective vaccines
against SARS-CoV-2.
Comirnaty® (Pfizer-BioNTech) vaccine was the first vac-
cine against SARS-CoV-2 (developed using messenger RNA
technology) to be approved with conditional authorization
by the European Medicines Agency (EMA) based on a Phase
1/2/3 multicenter, multinational, randomized, placebo-con-
trolled, observer blind clinical trial that evaluated its efficacy
and safety in approximately 44 000 participants who received
2 doses of the vaccine.1
Concerning the safety analysis, during the course of the
aforementioned clinical trial, in approximately 21 744 par-
ticipants aged 16 years or more submitted to at least one dose
of the vaccine, the symptoms mostly identified were of mild
to moderate intensity. Mostly of these events were associated
with pain at the injection site (>80%), fatigue (>60%),
headache (>50%), myalgia and chills (>30%), arthralgia
(>20%), pyrexia and swelling at the injection site (>10%),
and whose frequency was more associated with older age.1-3
Also, information on the use of this vaccine in pregnancy is
still limited. Animal studies do not indicate direct or indirect
adverse effects with respect to pregnancy, embryonal/fetal
development, parturition, or postnatal development. It is not
known whether it is excreted in breast milk. Therefore, its
administration in pregnancy, until further evidence, should
only be considered when the potential benefits outweigh any
potential risks for the pregnant woman, fetus and/or infant.3,4
Thus, because clinical trials take place in a relatively short
period and because the enrolled population generally excludes
certain individuals with specific physiological conditions,
such as pregnancy, pediatric age and/or important comorbidi-
ties, it is crucial to keep on drug safety surveillance, namely
through its use in real life context, since it will be used in a
large number of individuals of several ages, physiological
conditions and comorbidities, that the rare (≥1/10 000 to
<1/1000) and very rare events (<1/10 000) may arise.
This post-authorization drug safety assessment can be
carried out either through phase IV clinical trials, develop-
ment of safety record databases, or development of active or
passive pharmacovigilance plans, namely through spontane-
ous notification of adverse events with further analysis of the
causal relationship between event and drug use.5
Current pharmacovigilance systems are able to identify
many of the main safety issues with medications.6 In the con-
text of passive pharmacovigilance (encouraging healthcare
professionals and others to notify safety issues), in which noti-
fication depends entirely on the initiative and motivation of
individuals to do so, the main objective is the early detection
of new adverse drug reactions (ADRs), rare and serious ADRs.
It has the advantage of being a comprehensive and cost-effec-
tive methodology, however, as the weak point is elevated
underreporting with one notification estimate of 6% of total
ADRs.6 In this methodology, several actions can be consid-
ered: sending and filling out reporting forms, which can be
collected regularly, individually or grouped, by phone, email
or web-based (electronic forms). Ease in reporting an adverse
event is a key factor in obtaining a good notification rate.7
The development and use of national electronic forms has
been a growing option for medicines agencies from several
countries around the world, as a way of increasing and accel-
erating the spontaneous reporting of adverse reactions. The
implementation of pharmacovigilance plans by the Hospital
Pharmacy has also been shown to be effective in detecting
adverse reactions both in the hospital and outpatient settings,
with special emphasis in the context of the COVID-19
pandemic.8-10
The aim of this study was to analyze the implementation
and the results of a web-form based pharmacovigilance plan
for the spontaneous notification of adverse events to the
Comirnaty® COVID-19 vaccine during its administration to
a population of healthcare professionals from a central uni-
versity hospital, within the scope of routine Hospital
Pharmacy activity, in collaboration with the Occupational
Health Service.
Methods
In Portugal and also at Centro Hospitalar Universitário
Lisboa Norte (CHULN), the vaccination process for health-
care professionals began on December 27th, 2020 and until
February 24th, 2021, a total of 4700 individuals have been
vaccinated, of which 4392 (93.4%) completed vaccination (2
doses). Data was gathered from December 28th, 2020 until
April 1st, 2021.
This is a single-center cross-sectional study, with data
collected over a period of 4 months. All eligible healthcare
professionals (those who had the disease COVID-19 for less
than 6 months or those who had signs and symptoms sugges-
tive of the disease on the day of vaccination were excluded)
within the scope of the vaccination plan of healthcare pro-
fessionals at the CHULN, were able to participate in this
study. The Comirnaty® vaccine was outlined to be adminis-
tered in 2 doses 21 days apart (per national government
guidance).4
746 Hospital Pharmacy 57(6)

Box 1.  Electronic Pharmacovigilance Form.

Pharmacovigilance Vaccine SARS-CoV-2

*Mandatory
  1.  Indicate the vaccine that was administered: *
  Comirnaty - (BioNTech / Pfizer)
  COVID-19 Vaccine AstraZeneca - (AstraZeneca)
  2.  Administration dose: *
 1st
 2nd
  3.  Enter your initials *
  4.  Indicate your gender *
 Male
 Feminine
  5.  Enter your date of birth *
  6.  Have you experienced any of these symptoms since the vaccination? *
  Injection site (pain, redness, swelling, itching)
 Chills
  Fatigue, drowsiness
  Head, joint, muscle, body pain
 Febrile
  Nausea, vomiting, diarrhea, abdominal pain
 Rash
  No symptoms
 Other:
  7.  Overall, rate the intensity of your symptoms: *
  Mild (Feels symptoms, but they are not disabling)
  Moderate (May cause limitations to daily activities)
  Severe (Symptoms that make daily activities difficult or impossible)
  8.  Authorizes contact by phone for subsequent submission of data to the
INFARMED- Portal RAM
 Yes
 No
  9.  Provide a phone contact
10.  Enter your email

Vaccines were mostly (95%) prepared by the Hospital
Pharmacy in a laminar flow cabinet, in individual pre-filled
syringes and administered at a vaccination center by the
nursing team. The administration was clinically supervised
by the Occupational Health Service medical team and an
allergist/immunologist with proper medical equipment for
any assistance in case of severe allergic adverse reaction,
supported by the emergency department medical team.
An electronic pharmacovigilance form was developed by
the Hospital Pharmacy Drug Safety Unit and was sent by
e-mail to CHULN healthcare professionals for spontaneous
notification of adverse events. This e-form was performed
with 8 pre-defined event options (according to the highest
frequency observed in development clinical trials), and an
open answer option for the description of other events and/or
symptoms not previously described in the form (Box 1).
During the course of the study, a question about the overall
intensity of symptoms in a pre-defined scale (mild, moder-
ate, or severe) was added.
At least one hospital pharmacist was always present at the
vaccination center. During the observation period (30 minutes
after administration of the vaccine), this pharmacist presented
the electronic pharmacovigilance form developed to the vac-
cinees, reinforcing for the importance of its voluntary and
individual ADR reporting, after receiving an email with a link
direct access to the form (in compliance with data protection
regulations and professional secrecy). He also explained the
most frequently expected possible adverse events.
The data were collected by a hospital pharmacist by
downloading the answers from the e-form sent. The obtained
adverse events reports were standardized according to physi-
ological and pathological condition, and submitted system-
atically to the pharmacovigilance department of the
Portuguese Medicines Regulatory Authority (INFARMED)
for further analysis and incorporation into the European
Database of Pharmacovigilance (EudraVigilance) of
COVID-19 vaccines. Adverse events of greater clinical rel-
evance and/or seriousness were additionally reported directly
Cruz et al 747
Figure 1.  Flow diagram of vaccinated healthcare professionals, submitted electronic forms and ADR reporting, according to first and
second dose of Comirnaty® vaccine.
to INFARMED web-form (Portal RAM), in accordance with
this institution guidance.11
Statistical descriptive analysis was performed using R/
RStudio software (version 4.0.2).
Results
About 4096 spontaneous notifications were made by health-
care professionals through filling the developed electronic
form (notification rate of 45%), and 23 directly to the
Occupational Health Service medical team (notification rate
of 0.25%), according with the study flow diagram (Figure 1).
Thus, within the scope of the implemented pharmacovigi-
lance plan, a total of 4119 notifications were obtained, with
1723 referring to the first dose and 2393 to the second dose,
and 3 not indicating which dose they referred to. About
14.6% (n = 251) and 8.36% (n = 200) reported having no
symptoms in the first and second doses, respectively.
The ages of the notifiers varied between 20 and 83 years
old (average of 40.9 years old), with around 78.1% belonging
to the female gender.
In Table 1 a description of the adverse events reported
with a frequency greater than 1% is shown, after excluding
notifications that did not report the respective dose and those
that reported having no symptoms.
Regarding the most clinically relevant events reported,
regardless of their frequency, the following stand out: tachy-
cardia (n = 19), dyspnea (n = 7), chest pain (n = 6), facial/
labial edema (n  = 6), lipothymia (n  = 5), bronchospasm
(n = 2), herpetic infection (n = 2), vasculitis (n = 2), arrhyth-
mia (n = 1), difficult to control arterial hypertension (n = 1),
gastritis (n = 1), and spontaneous abortion (n = 1).
The adverse events reported according to the first and sec-
ond dose with frequency n > 5 are shown in Figure 2.
The question regarding the overall intensity of symp-
toms was only incorporated later into the form, as men-
tioned earlier. Data was obtained for 2928 notifications
(71.1% of the initial sample), with 771 (26.3%) concerning
the first dose and 2157 (73.7%) the second dose. Of these,
70.0% were reported as having mild intensity (87.3%–first
dose, 63.8%–second dose), 25.8% as moderate (11.8%–
first dose, 30.7%–second dose), and only a low percentage
(4.27%) reported having symptoms of severe intensity
(0.91%–first dose, 5.47%–second dose) (Supplemental
Table 1).
The Figure 3 shows the events most frequently reported
according to the degree of intensity and dose administered,
generally showing an increase in the degree of intensity in
the second dose compared to the first dose and Table 2 details
the events reported with severe intensity.
In the analysis by age group, the highest frequency of
severe events occurred in the groups from 40 to 59 years in
both vaccine administrations. Of notice, the age group
between 60 and 69 years of age did not report any event of
severe intensity after the first dose, and after the second dose,
the percentage was the lowest (7.2%) among all (Table 3).
748 Hospital Pharmacy 57(6)

Table 1.  Adverse Events Reported by Healthcare Professionals During the vaccination process, no hospitalizations were
with a Frequency Greater Than 1%. recorded and no deaths were notified and/or recorded.
Reported adverse events N %
Discussion
Injection site (pain, redness, swelling, itching) 3350 91.40
From the analysis of the received notifications, it is high-
Head, joint, muscle, body pain 1621 44.23
lighted, in general, the higher frequency of notifications
Fatigue, drowsiness 1180 32.20
related to the second administered dose (54.5%). Reporting
Chills  751 20.49
Febrile  431 11.76
by gender (female: 78.1%) was in line with the WHO
Nausea, vomiting, diarrhea, abdominal pain  376 10.26 Working Paper in “Gender equity in the health workforce:
Adenomegaly  123  3.36 Analysis of 104 countries” that women account for 70% of
Rash   45  1.23 all workers in the health and social sector.12 At our hospital,
this rate is even higher (76.9%).

Figure 2.  Percentage of adverse events reported according to the first and second dose of the Comirnaty® vaccine.

Table 2.  Frequency and Percentage of Reported Adverse Events, in the Notifications That Mentioned the Degree of Intensity as Severe.
Severe reported adverse events N %
First dose
 Othersa   7 0.91
 Head, joint, muscle, body pain   5 0.65
 Injection site (pain, redness, swelling, itching)   4 0.52
 Chills   2 0.26
 Fatigue, drowsiness   2 0.26
Second dose
 Head, joint, muscle, body pain 110 5.10
 Fatigue, drowsiness  95 4.40
 Injection site (pain, redness, swelling, itching)  94 4.36
 Chills  76 3.52
 Febrile  76 3.52
 Nausea, vomiting, diarrhea, abdominal pain  40 1.85
 Adenomegaly  15 0.70
 Othersb  11 0.51
 Tachycardia   3 0.14
a
Adenomegaly; Arrhythmias; Dyspnea; Febrile; Paresthesias; Rash; Tachycardia (each, N = 1; 0.13%).
b
Bronchospasm; Dyspnea; Facial/labial edema; Hands and feet pain; Insomnia; Muscle weakness; Nasal obstruction; O2 desaturation; Paresthesias; Rash;
Rhinitis, rhinorrhea (each, N = 1; 0.05%)
Cruz et al 749

Figure 3.  Most frequently reported adverse events according to the degree of intensity and dose administered.

Table 3.  Frequency and Percentage of Severe Adverse Events In the second dose, events were, in general, more fre-
Notifications by Age Group. quently reported as moderate (30.7%) and severe (5.47%),
compared to the first dose (11.8% and 0.91%, respectively;
Nº Severe reported
Age group (years) Nº Reports adverse events % P < .01). The population aged with 60 years or older reported
7.2% of severe events in the second dose.
First dose Additional data (in process, n = 682) about the reports of
 20-29 162   3 1.86 the intensity of symptoms related with booster dose (third
 40-49 216  10 4.63 dose) show that 58.5% (n = 357) were reported as mild,
 50-59 136   7 5.15 31.8% (n = 190) as moderate, 10.0% (n = 61) as severe and
Second dose 0.3% (n = 2) as very severe (this degree of severity was
 20-29 428  87 20.3
reported only with the booster dose).
 30-39 639 136 21.29
The presence of adenomegaly (or lymphadenopathy) was
 40-49 491 175 35.64
reported more frequently compared to those occurred in clin-
 50-59 377  96 25.47
ical trials (3.4%; n = 123% vs 0.3%; n = 64, respectively),
 60-69 194  14 7.21
with n = 16 reported as severe in our study.1
Of note, it was the notification of gastrointestinal disor-
Regarding age, it was found that the highest percentage of ders (nausea, vomiting, diarrhea, abdominal pain) which, in
severe notifications occurred in the 40 to 49 age group being aggregate, corresponded to a frequency greater than 10%
less reported in age groups above 60 years-old (both doses), (10.3%; n = 376). About n = 40 were reported as having been
in line with what was observed in clinical trials in which the of severe intensity; all after the second dose.
incidence of systemic reactogenicity was higher between 16 Severe intensity of fatigue was reported at approximately
and 55 years.1 3.3% (n = 97/2928) compared to approximately 4% reported
The most frequently reported events were similar to those in phase 2/3 clinical trials, with the majority of cases occur-
previously reported in phase 2/3 trials, that showed a higher ring at the second dose. (4.4%; n = 95/2157).1
percentage of events reported after the second dose com- One case of miscarriage has been reported at 6 weeks’
pared to the first dose (70.3% and 29.7%, respectively).3,13 gestation, 1 month after the second administration, in a
We also noticed in this study that the frequency of injection woman with no history of previous abortions. Of note, there
site reactions was similar for the 2 administered doses (93.9% was a positive antiphospholipid antibody analysis 2 weeks
and 89.7%, respectively). after the abortion. This case was later notified by the Hospital
750 Hospital Pharmacy 57(6)
Pharmacy Drug Safety Unit to the Portuguese Medicines
Regulatory Authority (INFARMED) through the national
electronic pharmacovigilance web-form (Portal RAM –
INFARMED). According to studies carried out, namely on
data collected in the UK population, the percentage of abor-
tions in the first trimester in vaccinated women was not
higher than the percentage of abortions in unvaccinated
women. A causal relationship between abortion and the
Comirnaty® vaccine has not been established.14
The present electronic reporting methodology was applied
in a time period very close to administration (up to approxi-
mately 7 days after vaccine administration) and is therefore
not sensitive to the occurrence of adverse events later in
time. Thus, it is our intention to carry out a new evaluation,
using the same methodology, at 6 months and 1 year after
vaccine administration. Also, as a limitation, reported ADRs
in the present study were not clinically checked by a pharma-
covigilance health care professional, namely its cause effect
relationship.
Finally, it should be noted that, in the context of adher-
ence to notification through the use of this electronic form,
the rate reached of about 45% is quite significant, compared
to previously published studies.15 In a study that reported the
first French experience of reporting ADRs directly by indi-
viduals/patients after a mass immunization campaign with
vaccines against pandemic Influenza A (H1N1), out of 4746
notifications received during the study period, 1006 (21 .2%)
came directly from vaccinated individuals.16
Although some countries have already implemented legis-
lation that allows direct notification by the patient or target
individual of the drug (case of vaccines), this notification rate
is very variable, including countries such as Portugal, Malta,
and Hungary where this service was introduced more recently
and, consequently, the notification rate is still low.15,17 In one
of these studies, out of 50 countries included, direct patient
reporting systems exist in 44 and represent 9% of total report-
ing, with a total of 27 countries having a patient-specific
reporting form and 31 providing a form to fill out online in
order to improve compliance with the notification.15
Conclusion
In the present study, performed within the scope of the vac-
cination process for healthcare professionals, the profile of
reported adverse events related to the Comirnaty® vaccine
was similar to its previously carried out clinical development
program, except for the higher frequency of adenomegaly
and gastrointestinal disorders (nausea, vomiting, diarrhea,
abdominal pain). Noteworthy in this study, the notification of
a case of miscarriage.
Overall, the profile of reported adverse events was mild to
moderate in intensity, being less frequent and milder in older
adults than in younger adults, and more frequent and severe
after the second dose than after the first dose, although injec-
tion site reactions were similar at the 2 doses.
The development of pharmacovigilance activity through
the use of electronic forms by the Hospital Pharmacy, seemed
relevant to obtain a higher rate of adherence to spontaneous
adverse event reporting and, consequently, a greater and
faster knowledge of Comirnaty® vaccine safety profile.
Acknowledgments
Not applicable.
Contributorship Statement
The specific contribution of authors in the paper was:
Planning, conception and design, interpretation of data, paper
writing: João Paulo Garcia Lopes da Cruz.
Conduct the study, reporting, introduce the data: Cristina da
Conceição Ribeiro de Carvalho, Paula Alexandre da Cruz Silva,
Luis Filipe Campos Guerreiro.
Acquisition of data: Tatiana Vedes Bento, Leila Vanessa Carmo
Cardoso Martins Costa, Raquel Filipa Miguel Margarido Duarte
Simões, Rui Pedro Pinheiro Gonçalves Marques, Ana Cristina
Castro Fernandes, Luís Miguel Costa de Mendonça Galaio, Ana
Isabel B. Correia.
Statistical analysis and interpretation of data: Cristina da
Conceição Ribeiro de Carvalho, João Paulo Garcia Lopes da Cruz,
Paula Alexandre da Cruz Silva.
Medical validation of reporting data: Ana Isabel B. Correia, Luís
Miguel Costa de Mendonça Galaio.
Medical revision of the paper: Ema Maria S. Leite Resende.
Pharmaceutical revision of the paper: João Manuel Braz
Gonçalves.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
Ethics Approval Statement
This study was not submitted to the Ethics Committee as it was part
of normal pharmacovigilance activities, with all adverse events
reported through spontaneous notifications made by health profes-
sionals. This study was developed with the formal knowledge of the
Institutional Board.
ORCID iD
João Paulo Garcia Lopes da Cruz https://orcid.org/0000-0002-
3454-7229
Supplemental Material
Supplemental material for this article is available online.
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1113951
research-article2022
HPXXXX10.1177/00185787221113951Hospital PharmacyMunir et al

Original Article

Hospital Pharmacy

The Impact of Job Instruction Training

2022, Vol. 57(6) 752­–758
© The Author(s) 2022
Article reuse guidelines:
Within Pharmacy sagepub.com/journals-permissions
DOI: 10.1177/00185787221113951
https://doi.org/10.1177/00185787221113951
journals.sagepub.com/home/hpx

Faria Munir1 , Christopher Loucks2, and Petal Bartlett2

Abstract

Purpose: To provide pharmacy leaders and clinicians with the basic principles of a training method called job instruction (JI)
and its application within pharmacy as a strategy to teach routine pharmacy work. Summary: Job instruction is a reliable
way to teach a person to quickly learn how to perform a work standard correctly, safely, and efficiently. Job instruction
is a proven and successful technique for improving time to train, productivity, employee turnover and quality of work. In
healthcare, JI training is not well-known or widely utilized. Job Instruction was the strategy of choice to stabilize the variable
training practices within The University of Kansas Health System pharmacy enterprise, and a prospective, single center, multi-
cohort study was conducted to study its impact. Conclusion: The preliminary results of this study provide initial insight
into the applicability of job instruction in pharmacy. The study indicated the benefits of JI training within different teams to
standardize training practices, decrease error and safety event rates, and increase satisfaction of team members with on-
the-job training. The results of this study will be used to further analyze and optimize training practices in The University of
Kansas Health System pharmacy enterprise.

Keywords
staff development, pharmacy administration, education, pharmacy, teaching, pharmacy service, hospital, quality Improvement

Introduction development.6-8Job instruction is the core component of TWI

The field of healthcare is rapidly growing and changing, and
with this change comes the increased use of continuous
improvement methods. Healthcare institutions are moving
toward methods that help minimize waste with ongoing pro-
cess improvement along with finding opportunities for gen-
erating and sustaining value-added processes. Training
Within Industry (TWI) principles is one avenue to achieve
this. Training Within Industry is a precursor model to Lean
that aligns with common organizational goals at all levels
such as retaining skilled staff, increasing patient safety,
improving caregiver training, increasing the quality of care,
reducing waste, and establishing best practices.1-3 It was a
program developed in the United States during World War II
to support the increase in production needs by the Allied
forces. The purpose of TWI can be summarized by how it
was advertised in 1943, essentially to assist war production
industries by training each worker to make the fullest use of
their skill to enable production to keep pace with war
demands.4 By helping to establish methods to create work
standards and effective training processes, TWI principles
create a skilled and engaged workforce. During this time,
TWI methodologies were also applied in healthcare facili-
ties, due to the shortage of hospital workers during the war.5
The foundation of TWI principles contains 4 components:
job instruction (JI), job methods, job relations, and program
principles that focuses on the development and training of
standard job practices. The focus of JI is a way to quickly
teach a person a standard way to perform the work. As the
front line is engaged in the development of those standards,
JI is also a training tool that promotes the engagement, con-
tinuous improvement, and problem solving of existing team
members.7,8 The identification of work elements, key points,
and the reasons why a particular key point is “key” are the
elements behind how a task can be methodically broken
down to be done the “one best way” which is called a job
breakdown.8 The training process is essentially simplified
and broken down into vital functions, and is based around the
premise of “learning-by-doing.”2,3 Job breakdown sheets and
the 4-step instruction method are the foundation on which JI
training is built on.8 The 4-step method is illustrated in Figure
1. Participants who go through the formal JI training process
are taught to teach the current accepted standard and not
deviate from steps listed on the job breakdown form.2 This
1
University of Illinois Chicago College of Pharmacy, Chicago, IL, USA
2
The University of Kansas Health System, Kansas City, KS, USA
Corresponding Author:
Faria Munir, University of Illinois Chicago College of Pharmacy, 833 S
Wood St, Chicago, IL 60612, USA.
Email: fmunir@uic.edu
Munir et al 753
Figure 1.  The 4-step Method of Job Instruction.7
standardization of the job eliminates practice variation,
reduces errors, and increases productivity. An example tem-
plate of a job breakdown form is illustrated in Figure 2.
In healthcare, job instruction can help bridge the gap
in providing more effective training for new staff while
also continually updating best practices for veteran staff.5
For example, Virginia Mason Medical Center (VMMC), a
336-bed hospital, employed JI methodologies to train
staff on hand hygiene job breakdowns. Baseline audits
prior to JI at VMMC showed that only 83.5% of staff
were washing their hands properly and on a consistent
basis. After piloting JI training in 467 nurses at VMMC,
the reliability of hand hygiene in this pilot population
went above 98%.
The University of Kansas Health System (TUKHS) saw
an opportunity to incorporate JI in its training processes to
address variability, increase efficiency and productivity, and
decrease on the job errors. Integration of JI methodologies
into the pharmacy staff training model was the focus of this
pilot study. The goal of this study is not intended to teach
readers how to structure and implement JI training. The
intent is to report an example of JI implementation that will
help pharmacy health system leaders and clinicians under-
stand how applying JI concepts to routine clinical and opera-
tional tasks within a pharmacy department can lead to
positive impacts of change such as reduction in error rates
and increase in training satisfaction of staff.
Job Instruction Evaluation at The
University of Kansas Health System
The impact of JI training at TUKHS was evaluated as a pro-
spective, single center, multi- cohort study within the inpa-
tient and outpatient pharmacy departments. The University
of Kansas hospital in Kansas City where this study took
place is an academic medical center that staffs over 900
754 Hospital Pharmacy 57(6)

Job Breakdown Sheet

Title: Omnicell Restock Revision Date: 1.26.21

Operators who must adopt:
Departments who must adopt: Inpatient Pharmacy
Floor Technician
Metric: ___Decrease lead time by 50% Quality Mistake Safety
Check Proofing
___Decrease defects by 50%
_X_Decrease drug waste by 75%
_X_Local Metric (s): Monthly Cycle Count
Training Supplies Needed: Medication Training Bag, JIB, Blue Card
Training Equipment Needed: Kit Omnicell, Kit Scanner
Prior Training Needed: FT Orientation
Zero Steps: Put a small amount of each training med in at least 7 pockets, adjust expiration date on screen for each,
Run Critical Low Restock, Log in,Check Omnicell setting (Scan to Restock)
Simulation/Scenario: Use the Kit Omnicell and the “Special Restock” to simulate restocking medications. The trainer
will simuluate the restock of 3 medications. The trainer will then log out and allow the trainee to login and access the
restocks for their 4 practice restocks.
Introduction: “Over 80% of our dispensed medication from the pharmacy comes from automation. It is critical to make
sure the Omnicell is stocked with quality medication. The restocking process we are training today is about ensuring that
we have proper counts, no expired medication, and we are rotating the stock so the earliest expired is used first.”

Important Steps Key Points Reasons

(Advances the Work)
A logical segment of the
operation when something
happens to advance the work.
(quality, safety, knack) (for key points)
Anything in a step that might- Every Key Point must have a reason
1. Make or Break the Job
2. Injure the worker
3. Make the job easier to do

1 Access Restocks 1.1 Normal Restock 1.1 Populates the Restock lists
1.2 Choose Restock 1.2 Various Restock options

2 Scan Item Barcode

________________________ ________________________

3.1 Flashing light 3.1 Tells which bin to stock

3 Bin
3.2 Scan bin barcode if needed 3.2 Doesn’t always need scanning

4.1 Check the expiration dates and the count

in the bins first, change COUNT on
4.1 Check bin first screen if needed
4 Stock 4.2 Check restock product 4.2 Check the expiration dates and the count
4.3 Rotate of what you are restocking
4.3 “First in, first out”, earliest expiration
date is reflected on the screen

Simulation Considerations

Controlled Document: Yes

Approved by: Origin Date:
Owner: Pharmacy PMT

Figure 2.  TUKHS Job Breakdown Sheet Example.

Munir et al 755

Table 1.  TUKHS Pharmacy Training Modules Adapted from the Toyota Talent Development Process.8

Module Target Participants Duration Time Commitment

Module 1: Developing
Talent
Module 2: Identify
Critical Knowledge
Module 3: Transfer
Knowledge to Others
Module 4: Verify
Learning and Success
Leadership Complete Prior •  60 min meeting
TWI Master Trainer to Module 2 •  120 min training session
Leadership 2 Weeks •  Two 120 min training sessions
TWI Master Trainer
Leadership 3 Weeks •  60 min meeting
TWI Master Trainer •  20 to 30 min tasks (variable)
Training Team– (Training Week only) •  Weeklong training session (8 hours × 5 days)
Leadership 4 Weeks •  One 120 min training session
TWI Master Trainer •  Minimum of three 90-120 min meetings

Abbreviations: TUKHS, The University of Kansas Health System; TWI, Training Within Industry.

Table 2.  The 4 Levels of the Kirkpatrick Evaluation Model.9

Level 1: Reaction The degree to which participants find the training favorable, engaging, and relevant to their jobs
Level 2: Learning The degree to which participants acquire the intended knowledge, skills, attitude, confidence, and
commitment based on their participation in the training
Level 3: Behavior The degree to which participants apply what they learned during training when they are back on the job
Level 4: Results The degree to which target outcomes occur as a result of the training

inpatient beds. The study period was from May 1st, 2020 to
June 1st, 2021. There was a formal review by the Institutional
Review Board and this study was granted exemption status.
Training Within Industry training was launched by inter-
ested pharmacy areas to train current staff on JI methodol-
ogy; training consisted of a 9-week cohort course with a
targeted 1-week JI certification training for pharmacy lead-
ership and frontline trainers per cohort. Job Instruction fun-
damentals of job breakdown sheets and the 4-step instruction
method were utilized during a dedicated JI training week.
Table 1 showcases the schedule of the 9-week cohort course,
included the 1-week JI certification training embedded
within module 3 of the course. The course was taught by a
master trainer, which was a pharmacy department staff posi-
tion specifically created at TUKHS to develop and imple-
ment TWI-based training and education. Pharmacy staff
members who finished the 9-week cohort course would be
deemed certified JI trainers and go on to train pharmacy
staff members, in their respective pharmacy departments, on
various job breakdowns.
The primary objective was to evaluate if applying JI
training would impact 3 key areas of interest: the reduction
of error rates, increase in applied learning skills from train-
ing, and increase in job satisfaction of staff. Data was
obtained from conducted audits, survey responses, auto-
matic dispensing cabinet stockout reports, and an institu-
tional safety incident reporting portal. The Kirkpatrick
evaluation model was used to analyze the results of JI train-
ing on pharmacy department staff (see Table 2). This evalu-
ation methodology is a 4 level evaluation tool that it utilized
to create, deliver, measure and validate training standards.9
Levels 1, 2, and 3 focus on the impact of learning on the
participants; these levels assess whether participants
engaged with the content and acquired the intended knowl-
edge and skill. In this study, level 1 and 2 results were
assessed independently by the master trainer (and not
included within the scope of this study) and level 3 results
were assessed by a survey questionnaire that was distrib-
uted to pharmacy staff prior to JI training and post-JI train-
ing. Level 4 is dedicated to measuring the direct results of
the intended training (key performance indicators), which
are established prior to the training being initiated. One
focus of this pilot study was to track and report pre-speci-
fied key performance indicators for each job breakdown to
see what impact a standardized approach to training had on
these job functions.
Overall Cohort Results
Since the initiation of TWI cohorts and JI training within the
TUKHS pharmacy enterprise, there have been 8 total cohorts
that have completed their the 9-week training modules. A total
number of 67 pharmacy team members completed JI certifica-
tion since initiation of the program through the duration of this
study, which included pharmacists, pharmacy residents, and
pharmacy technicians (see Table 3). The fundamental skills of
creating job breakdowns are taught to JI trainers during the
cohort process, and cohorts will continue to write, validate,
and train to different job breakdowns as time goes on.
The following 3 charts (Figures 3-5) showcase results from
a survey questionnaire that was distributed to pharmacy staff
in the areas that completed JI training. The survey was given
to participants prior to the implementation of job instruction in
their area and then the same survey was given post-training to
compare differences in response. There were a total of 43 indi-
vidual responses collected in the pre-survey and 43 individual
756 Hospital Pharmacy 57(6)

Table 3.  Number of TUKHS Pharmacy Staff Members that are Job Instruction Trained.

Pharmacy Department

Acute Care Cancer Care Home Infusion Outpatient

Role Pharmacy Pharmacy Pharmacy Pharmacy Miscellaneous Grand Total
Front Line Team Member
  Pharmacist 8 1 0 2 0 11
  Technician 11 0 3 4 0 18
Leadership Team Member
  Pharmacy Leader 6 1 2 6 0 15
  Residents 0 0 0 0 4  4
  Technician Leader 6 4 3 6 0 19
Grand Total 31 6 8 18 4 67

Abbreviations: TUKHS, The University of Kansas Health System.

Figure 3.  Survey Questionnaire Results: Worker Assessment of the Trainer.

responses in the post-training survey. The data show that, with
newly certified trainers delivering the training, there was an
increase in not only applied learning skills but also staff satis-
faction in their training experience post JI implementation.
The Kirkpatrick Evaluation Model
Outcome Categorization
As a relatively new concept in the healthcare space, job
instruction has shown significant improvements in the way
we are training our pharmacy teams and the benefits that
standardized training can provide. There were many posi-
on a particular task. The following outcome results illustrate
the impact of JI in various areas within TUKHS pharmacy.
Post-JI training level 4 key indicator data was collected at
various timepoints (up to 6 months post-JI training). Each JI
cohort got to choose which key performance measures they
wanted to track for each job breakdown they created.
Examples of level 4 results from the Kirkpatrick evaluation
model from our cohorts included:
•• Intravenous (IV) room hood set-up audits (IV room
technician cohort)
|| 80% reduction in aseptic defects in setting up a stan-

tive impacts of change seen in reduction in error rates, dardized IV laminar or vertical flow hood 4 months
increase in applied learning skills from training, increase in post-training of IV room staff. Defect was defined
job satisfaction of staff, and the time to train a staff member as missing any step in the IV hood set-up protocol.
Munir et al 757

100
90
80
70
60
50
40
30
20
10
0
Presented the Operation (Important Steps, Key Points, Modeled the Operation 3+ times
Reasons)

Figure 4.  Survey Questionnaire Results: Worker Self-Assessment.

•• Automated dispensing cabinet cycle count audits

(inpatient floor technician cohort)
|| Up to 9% decrease in baseline defects of random

floor automatic dispensing cabinet pocket audits

1-month post-job instruction training implementa-
tion. Average number of monthly audits were 45
random inpatient floor cabinet pockets per month.
Baseline defects included: correct count in medi-
cation pocket, correct medication in pocket, and
correct expiration date entered
•• Automated dispensing cabinet stockouts (inpatient
floor technician cohort)
|| Stockouts create a delay in patient care and extra
workload for hospital team members. Baseline
stockout rate was 0.56 total stockouts per 100 dis-
penses, and post-JI training was 0.41 total stock-
outs per 100 dispenses.
•• Increase in job satisfaction of staff (all cohorts;
Figure 5)
|| There were no “Unsatisfied” or “Very Unsatisfied”
responses in the post-training survey given to staff
that assessed overall satisfaction as it related to the
pharmacy training they had received at TUKHS.
One component of this could be attributed to the
efficiency of the training process utilizing job
breakdowns. Average time to train a staff member
on one job breakdown is about 20 to 30 minutes
An example of Level 3 results from the Kirkpatrick
Evaluation Model from our cohorts included:
•• Pre- and post-JI survey (Figures 3 and 4)
Figure 5.  Survey Questionnaire Results: Worker Overall
Satisfaction Self-Assessment.
*No unsatisfied or very unsatisfied responses were reported in the post-
training survey results.
There was an increase in applied learning for both the trainer
and the worker in 3 of the 4 steps of the 4-step method,
excluding step number 4, as assessed by the self-reported sur-
veys given to those who were trained on a job breakdown by
a certified JI trainer. Step 4 was the follow-up step, and
included encouraging the worker to ask questions, connecting
the worker with someone who would support them if they
needed help once they started to do the task independently,
and periodically checking back in on them. This highlights an
opportunity for TUKHS to focus in on this critical step of the
process as we move forward. Examples of level 2 results from
the Kirkpatrick evaluation model from our cohorts included:
•• Creation of job breakdowns during the TWI cohort
process
758 Hospital Pharmacy 57(6)
|| The fundamental skills of creating job breakdowns
are taught to JI trainers during the cohort process,
and cohorts will continue to write, validate, and
train to different job breakdowns as time goes on.
For example: the IV room technician cohort has
created 13 job breakdowns that have gone through
the validation phase and are now part of the train-
ing plans of IV room pharmacy technicians.
Conclusion
The preliminary results of this study provide initial insight
into the applicability of job instruction training in pharmacy.
The pharmacy enterprise at TUKHS has and will continue to
benefit from TWI principles and JI training within different
teams to standardize training practices, decrease error and
safety event rates, and increase satisfaction of team members
with on-the-job training. The results of this study will be
used to further analyze and optimize training practices within
the pharmacy enterprise, and we hope these results encour-
age other institutions to adopt TWI and JI methodologies.
Having a dedicated TWI master trainer staff position was
necessary at TUKHS to implement TWI training methodolo-
gies. The master trainer took certified TWI coursework to
become knowledgeable in this area and worked closely with
the TUKHS pharmacy leadership team to set-up and imple-
ment JI training in different pharmacy departments within
this initial pilot. With the initiation of the JI training pro-
gram, the goal is to eventually have 100% of pharmacy staff
supported by a 1:8 ratio of certified JI trainers, which would
equate to 15 to 20% of pharmacy staff being JI trainer certi-
fied. These certified JI trainers would then be able to con-
tinue to train new and veteran employees on various job
breakdowns as time went on.
It is important to note that many of the TUKHS pilot
cohorts were conducted during the start of the COVID-19
pandemic. This led to prolonged training timelines due to a
multitude of reasons. One main reason was the shortage of JI
certified trainers for on-the-job training due to staffing needs.
There was also decreased engagement and accountability of
cohort leadership due to increased needs of daily operational
problem-solving. Some training sessions and touchbases
were also conducted via virtual sessions instead of originally
planned in-person sessions, which could have decreased
training impact and engagement.
Future program direction includes a continued emphasis
on increased accountability of all levels of management
involved in training. This will be done through increased
stakeholder engagement and understanding of TWI and JI
training prior to cohort implementation. Cohort specific met-
rics will also continue to be tracked to showcase the impact
of standardized training practices and increased employee
engagement.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
ORCID iD
Faria Munir https://orcid.org/0000-0001-6642-498X
References
1. What is training within industry (TWI)? TWI Institute.
Accessed May 31, 2022. https://www.twi-institute.com/twi-
training/
2. Pascual AA. Training Within Industry in the Emergency
Department: Team Development to Improve Patient Care and
Alleviate Staff Burnout. ProQuest Dissertations Publishing, 2017.
3. Donald D. Training Within Industry: The Foundation of Lean.
Productivity Press; 2005.
4. Labor Division. War Production Board. Training Within
Industry Service. The Training Within Industry Program,
Bulletin No. 1. U.S. Government Printing Office; 1943.
5. Graupp P. Getting to Standard Work in Health Care: Using
TWI to Create a Foundation for Quality Care. CRC Press;
2017.
6. Bianchi N, Giorcelli M. The dynamics and spillovers of man-
agement interventions: Evidence from the training within
industry program. J Polit Econ. 2022;130(6):1630-1675.
doi:10.1086/719277
7. Huntzinger J. The roots of lean: Training within industry: The
origin of Japanese management and kaizen. Target. 2002,
18(1). https://www.lean.org/downloads/105.pdf
8. Liker JK, Meier D. Toyota Talent: Developing Your People the
Toyota Way. McGraw-Hill; 2007:35-256.
9. Kirkpatrick JD, Kirkpatrick WK. Kirkpatrick’s Four Levels of
Training Evaluation. Atd Press; 2016.
1115664
research-article2022
HPXXXX10.1177/00185787221115664Hospital PharmacyPankey et al

Original Article

Hospital Pharmacy

Effect of Paralytic Agents on Post-

2022, Vol. 57(6) 759­–766
© The Author(s) 2022
Article reuse guidelines:
Intubation Sedation in the Emergency sagepub.com/journals-permissions
DOI: 10.1177/00185787221115664
https://doi.org/10.1177/00185787221115664

Department journals.sagepub.com/home/hpx

Jessica A. Pankey1 , Scott Christofferson1, Ginger Barrick1,

Brandon A. Knettel2 , and Christine Knettel1

Abstract

Purpose: This study aimed to evaluate the frequency at which postintubation sedation is administered following use of long-
acting paralytic agents compared to short-acting paralytic agents during rapid sequence intubation performed in the emergency
department. Methods: This retrospective, single-center study of intubated patients in the emergency department analyzed
the difference in time to administration of additional sedation following use of a short-acting paralytic (succinylcholine)
compared to use of a long-acting paralytic (rocuronium or vecuronium). A total of 387 patients were available for analysis.
The primary outcome was additional sedation given within 15 minutes following administration of a paralytic agent. The
secondary outcome sought to evaluate the incidence of hyperkalemia due to paralytic agents by comparing potassium level
before and after paralytic administration. Results: 46.9% of patients who received a short-acting paralytic agent received
additional sedation within 15 minutes, compared to 40.9% of patients who received a long-acting paralytic agent. The
Chi-square analysis comparing the short and long-acting paralytic groups showed no statistically significant difference (χ²
[1, N = 387] = 1.24, P = .266) in the frequency of additional sedation administered. Excluding patients who did not receive any
additional sedation, the mean time from paralytic administration to additional sedation in all patients was 20.03 ± 18 minutes.
No statistically significant difference was detected between groups regarding changes in potassium level. Conclusion:
The use of long-acting paralytic agents was not associated with increased time to administration of sedation compared to
shortacting paralytic agents. There is an opportunity to reduce the time to sedation administration for intubated patients
receiving both short- and long-acting paralytic agents.

Keywords
CPR, emergency medicine, analgesics, respiratory, critical care, anesthetics

Introduction persist well beyond the sedation duration of induction

In rapid sequence intubation (RSI), a rapid-acting sedative
(induction) agent is used in combination with a neuromus-
cular blocking (paralytic) agent to create optimal intubation
conditions. Based on the pharmacokinetic profiles of induc-
tion agents, commonly used agents include etomidate, ket-
amine, and propofol. These agents have a rapid onset and a
short duration of action, ranging from 3 to 10 minutes.1 The
paralytic agents used include succinylcholine, rocuronium,
and vecuronium. These agents produce similar intubation
success rates but vary in their duration of paralysis.
Succinylcholine is a short-acting paralytic with a duration of
action of 4 to 10 minutes, while rocuronium and vecuronium
are long-acting paralytics that have a duration of 30 to
60 minutes.2-4 Higher doses of these long-acting paralytics
can extend the duration of paralysis beyond an hour.2,3
Long-acting paralytics have a duration of action that can
agents. This creates potential for patients to be paralyzed
without adequate sedation if post-intubation sedation is not
administered promptly.
Current recommendations are for patients who undergo
intubation in the emergency department (ED) to receive
post-intubation sedation.5,6 Sedative agents that are com-
monly given following intubation include propofol, mid-
azolam, diazepam, lorazepam, or dexmedetomidine. Opioid
agents such as fentanyl, morphine, and hydromorphone are
1
UNC Rex Healthcare, Raleigh, NC, USA
2
Duke University, Durham, NC, USA
Corresponding Author:
Jessica A. Pankey, UNC Rex Healthcare, 4420 Lake Boone Trail, Raleigh,
NC 27607-7505, USA.
Email: jessica_pankey@unc.edu
760 Hospital Pharmacy 57(6)
commonly used for analgosedation, though these agents
may not be appropriate to provide sedation when used alone.
In the ED setting, the goal is to achieve appropriate sedation
quickly and efficiently. Methods used to estimate sedation,
such as the Richmond Agitation Sedation Scale (RASS),
cannot be used to assess a paralyzed patient. Currently, use
of technology to monitor the level of sedation in a paralyzed
patient, such as bispectral index (BIS) and spectral edge fre-
quency (SEF), is limited in EDs that do not have a desig-
nated ED intensive care unit. While analgesia is an important
component of RSI, additional sedatives are warranted to
ensure the patient is adequately sedated despite barriers to
assessment.
Appropriate sedation after intubation is important for
maintaining patient comfort, improving ventilator syn-
chrony, and reducing hypertension, hyperglycemia, or
hypoxemia related to physiologic stress and pain.1,5,6
Paralysis in the absence of sedation can lead to extreme dis-
comfort, panic, and PTSD.6 Paralytic agents may create a
perception of sedation due to lack of movement or patient
response, resulting in delayed post-intubation sedation
administration and increased risk of unintentional patient
awareness.
Multiple studies have demonstrated that intubated patients
often endure paralysis without sedation when long-acting
paralytics are used in the emergency setting.5,7,8 It has also
been demonstrated that patients undergoing RSI in the ED
frequently receive inadequate postintubation anxiolysis and
analgesia regardless of the paralytic agent used.9 Comparative
studies between short and long-acting paralytics have his-
torically focused on intubation conditions rather than post-
intubation care. Limited studies have evaluated the effect of
paralytic type on post-intubation sedative use.5,10 A retro-
spective analysis of data from the National Emergency
Airway Registry (NEAR) found that use of a short-acting
paralytic was associated with a higher odds of post-intuba-
tion sedation compared to a long-acting neuromuscular
blocking agent using a 15-minute endpoint for time to seda-
tion. This study included analgesic-only regimens as post-
intubation sedation, reporting fentanyl as the selected agent
for post-intubation sedation in 42.6% of patients.5 Another
retrospective study compared time between intubation and
sedative administration in patients who received succinyl-
choline or rocuronium as a paralytic.10 This study found a
greater delay in patients receiving rocuronium. However,
there were still significant delays in the time to sedative
administration in the short-acting paralytic group. The results
of these studies support the idea that patient movement likely
serves as a clinical reminder to prompt caretakers to admin-
ister additional sedation.5,10
The current study aims to further differentiate if the type
of paralytic agent used has an impact on the frequency at
which patients receive appropriate post-intubation sedation
by utilizing a defined endpoint and less stringent exclusion
criteria.
Methods
Objective
The objective of this study was to determine the difference
in sedation administered following long-acting paralytic
administration compared to short-acting paralytic adminis-
tration. Appropriate sedation was defined as an additional
sedative administered within 15 minutes of the paralytic
agent to capture the incidence at which patients may be par-
alyzed without sedation in both groups. Analgesic-only
medication regimens were not included as appropriate post-
intubation sedation, as optimal clinical practice suggests
concomitant analgesic and sedative agents be used prior to
and during neuromuscular blockade with the goal of achiev-
ing deep sedation.6 This study also sought to investigate fac-
tors that may impact choice of paralytic agent, such as
incidence of hyperkalemia or other effects on select labora-
tory values.
Study Design and Setting
We conducted a single-center retrospective analysis of
patients who underwent intubation at an emergency depart-
ment (ED) of a non-for-profit community hospital in Raleigh,
North Carolina. The ED has 41 beds and cares for approxi-
mately 65 000 patients annually. The site is a STEMI and
stroke center but is not a trauma/burn center. All ED intuba-
tions are performed only by Emergency Medicine board-cer-
tified attending physicians. The ED does not staff physician
residents. The site is staffed by ED trained pharmacists at all
times, with a clinical pharmacist present at >95% of intuba-
tions. The analysis compared 2 groups: patients who received
short-acting paralytics (succinylcholine) and patients who
received long-acting paralytics (rocuronium and vecuronium).
The study was approved by the study hospital’s institutional
review board prior to data collection. The requirement to
obtain informed consent from participants was waived due to
the retrospective nature of the study.
Selection of Participants
A list was generated of patients who underwent endotracheal
intubation in the emergency department between November
1, 2018 and October 31, 2020. Adults (≥18 years of age)
with documented administration of both induction agent and
paralytic agent were included in the analysis. Patients were
excluded if they were pregnant, involuntarily detained or
incarcerated, or if they expired while in the ED.
Data Collection and Outcomes
Data were collected from electronic medical records and
entered into a secure Research Electronic Data Capture
(REDCap) database. Objective data pertaining to the intuba-
tion were collected, including induction agent, paralytic
Pankey et al 761
agent, post-intubation sedation agent, and patient demo-
graphics. Data regarding the time of paralytic administration
and time of sedative medication administration were also
collected, which are recorded and entered into the electronic
record by the ED nurse.
The time from the administration of paralytic to the
administration of an additional sedative was measured in
minutes. A patient was considered to have received post-
intubation sedation if it was recorded that they received any
of the following within 90 minutes of paralytic administra-
tion: propofol, midazolam, dexmedetomidine, ketamine,
lorazepam, or diazepam. For the purposes of our analysis,
analgesic medications (eg, morphine or fentanyl) were not
included as sedation agents.
The primary outcome was successful administration of a
sedating agent within 15 minutes of administration of the par-
alytic agent. The secondary outcome was the change in potas-
sium level, which compared the potassium level prior to
paralytic administration to the level within 2 hours following
paralytic administration. Baseline characteristics included
age, weight, sex, and race/ethnicity. Laboratory variables
included potassium and serum creatinine, which were col-
lected prior to or within 2 hours following intubation.
Data Analysis
We used simple frequencies to summarize patient character-
istics, clinical data, and study outcomes, including the pri-
mary outcome of administration of post-intubation sedation
within 15 minutes of paralytic administration and the second-
ary outcome of change in potassium level. We conducted
2-sample t-tests and Pearson Chi-Square tests to assess
potential differences in patient characteristics for those who
met the primary outcomes versus those who did not. We also
used a Pearson Chi-Square test to assess potential differences
in the primary outcome (yes/no) among patients who
received long acting versus short acting paralytics. Finally,
we conducted a 2-sample t-test to compare changes in potas-
sium level in the long acting and short acting groups.
The sample size estimate was based on an estimated 20%
between-group difference in the primary outcome, according
to previous literature regarding ED sedation practices.5-8,10 A
desired sample of 450 patients was estimated, assuming a
power of 80% and an alpha level set at 0.05. Of the 545 par-
ticipants who underwent intubation during the study period,
387 eligible patients were included in this analysis.
Results
Characteristics of Study Subjects
During the study period, a total of 545 intubations were
performed by ED physicians. One hundred fifty-eight cases
were excluded from analysis: 83 expired while in the ED,
67 did not receive induction and/or paralytic agents, and
8 were otherwise ineligible for analysis (Figure 1). Of the
387 patients available for analysis, 128 patients (33.1%)
received a short-acting paralytic (succinylcholine) and 259
(66.9%) received a long-acting paralytic (rocuronium = 238,
vecuronium = 21). Patients frequently received etomidate
as the induction agent during RSI (89.1%). The mean age
was 63 ± 16 years with a median of 65 years (IQR 54, 76).
Two hundred fifteen (55.6%) participants were male. There
were no statistically significant baseline differences
between groups (Table 1).
Primary Outcome
Of the 128 total patients who received a short-acting para-
lytic, 60 (46.9%) received additional sedation within 15 min-
utes. Of the 259 total patients who received a long-acting
paralytic, 106 (40.9%) received additional sedation within
15 minutes (Figure 2). The Chi-square analysis comparing
the short and long-acting paralytic groups showed no statisti-
cally significant difference (χ² [1, N = 387] = 1.24, P = .266)
in the frequency of additional sedation administered within
15 minutes of paralytic.
In total, 166 out of 387 patients (42.9%) received addi-
tional sedation within 15 minutes of paralytic administra-
tion. Three hundred four (78.6%) of total patients received
additional sedation within 90 minutes following paralytic
administration, while 83 patients (21.4%) received no
additional sedation. Excluding patients who did not receive
any additional sedation, the mean time from paralytic
administration to the administration of additional sedation
was 20.03 ± 18 minutes. The median time was 14 minutes
(IQR 8,25).
Secondary Outcome
Only 25 patients had potassium levels recorded both prior
to paralytic administration and within 2 hours of paralytic
administration. Six of these patients had received a short-
acting paralytic and 19 had received a long-acting paralytic.
In the short-acting group, there was a mean change of
−0.117 ± 1.73 in potassium level. In the long-acting group,
there was a mean increase in potassium level of
0.026 ± 0.9938. This difference was not statistically sig-
nificant (t[23] = −0.256, P = .800), but this finding should
be interpreted with caution given the low sub-sample size.
Discussion
Many patients who are intubated in the ED are in critical
condition and often in pain or distress. Adequate sedation for
intubated patients relieves pain and anxiety.6,11 Patients who
have received paralytic agents may falsely appear comfort-
able while unable to communicate or even gesture. Paralysis
without sedation may cause significant distress, tachycardia,
hypertension, and can ultimately lead to worse patient
762 Hospital Pharmacy 57(6)
Figure 1.  Flow diagram of participant selection.
outcomes.7,11 Of the patients who did receive post-intubation
sedation, the median time to sedation was 14  minutes.
However, of the total study population, less than half of
patients received sedation within 15 minutes of paralytic
administration. While the limitations of this study make it
difficult to generate a precise estimate of the frequency of
non-sedation, the comparison of the 2 groups can determine
whether a difference exists when a patient is treated with a
short versus long-acting paralytic.
In this retrospective analysis, there was no difference
detected in the frequency at which patients received sedation
in the 15 minutes following paralytic administration whether
they had received a short-acting or long-acting agent. Patients
who received rocuronium or vecuronium for RSI were given
post-intubation sedation at a similar frequency compared to
patients who received succinylcholine. This result does not
support the hypothesis that long-acting paralytic use has
implications on post-intubation sedation. As the overall
Pankey et al 763

Table 1.  Participant characteristics (N = 387).

Median (Q1, Q3) or n (%)  

Received short-acting Received long-acting

  Full sample (N = 387) paralytic (n = 128) paralytic (n = 259) P-value
Demographics
 Age 65 (54, 76) 64 (53, 73) 66 (55, 77) .327
  Weight (Kg.) 79 (65, 95) 81 (68, 97) 79 (64, 94) .555
 Sex .847
 Male 215 (55.6%) 72 (56.3%) 143 (55.2%)  
 Female 172 (44.4%) 56 (43.8%) 116 (44.8%)  
 Race/Ethnicity .630
 White 255 (65.9%) 85 (66.4%) 170 (65.6%)  
 Black 94 (24.3%) 27 (21.1%) 67 (25.9%)  
 Asian 13 (3.4%) 6 (4.7%) 7 (2.7%)  
 Hispanic/Latino(a) 8 (2.1%) 4 (3.1%) 4 (1.5%)  
 Unknown 17 (4.4%) 6 (4.7%) 11 (4.2%)  
Clinical
 Induction .020
 Etomidate 345 (89.1%) 119 (93.0%) 226 (87.3%)  
 Propofol 17 (4.4%) 5 (3.9%) 12 (4.6%)  
 Midazolam 15 (3.9%) 2 (1.6%) 13 (5.0%)  
 Ketamine 7 (1.8%) 2 (1.6%) 5 (1.9%)  
 Lorazepam 3 (0.8%) 0 (0.0%) 3 (1.2%)  
 Paralytic N/A
 Rocuronium 238 (61.5%) 0 (0.0%) 238 (91.9%)  
 Succinylcholine 128 (33.1%) 128 (100%) 0 (0.0%)  
 Vecuronium 21 (5.4%) 0 (0.0%) 21 (8.1%)  
 Sedation .051
 Propofol 182 (47.0%) 51 (39.8%) 131 (50.8%)  
 Midazolam 96 (24.8%) 50 (39.1%) 46 (17.8%)  
 Lorazepam 21 (5.4%) 11 (8.6%) 10 (3.9%)  
 Dexmedetomidine 5 (1.3%) 2 (1.6%) 3 (1.2%)  
 None 82 (21.2%) 14 (10.9%) 68 (26.4%)  
Minutes to sedation (in patients who 14 (8, 25) 14 (9, 28) 14 (8, 24) .477
received post-intubation sedation)

Note. Comparisons across groups based on primary outcome utilized 2-sample t-tests for continuous variables and Chi-square tests for categorical variables.

frequency of patients receiving additional sedation within
15 minutes was lower than desired, this comparison offers
that there is an opportunity to improve sedation provision in
all intubated patients, regardless of the type of paralytic used.
Because sedatives commonly used for induction do not have
a duration of action longer than 15 minutes, protocols that
encourage prompt administration of sedation following RSI
would be beneficial.
Etomidate is the most frequently used induction agent. Its
brief duration of action is usually considered a positive char-
acteristic, but it may contribute to patients being paralyzed
and not adequately sedated.11 In this analysis, the mean time
to additional sedation following paralytic administration was
approximately 20 minutes. As this is longer than the duration
of action of etomidate, even patients who did receive addi-
tional sedation could have been paralyzed for several
minutes without being sedated. This was not exclusive to
patients who had received long-acting paralytics. When
administering the induction agent during RSI, the emergency
department staff should have an additional sedative already
available to be given within 10 minutes after intubation.
Many barriers can prevent prompt sedation following RSI
and paralytic use. Pharmacists play a vital role ensuring post-
intubation sedation, therefore decreasing time to adminis-
tration. The pharmacist’s knowledge of duration, dosage
calculations, and ability to procure drugs can help the team to
ensure timely administration. Beyond logistical factors
involving staffing and documentation, patient-specific fac-
tors such as hypotension or altered mental status may
decrease the likelihood of receiving post-intubation sedation.
In patients with pre- and post-intubation hypotension, physi-
cians may be hesitant to prescribe sedation due to fear of
764 Hospital Pharmacy 57(6)

Figure 2.  Time to additional sedation in patients who received a short-acting paralytic (left) and long-acting paralytic (right).
Percentages show the proportion of patients who received sedation within 15 minutes following paralytic administration, more than
15 minutes following paralytic administration, and patients who received no additional sedation.
Note. Patients who received sedation at an interval greater than 90 minutes following paralytic administration were considered to have not received any
additional sedation.

worsening hypotension.5,12 Physicians may also decide to
withhold additional sedation in patients with poor neurologic
status due to limited patient response. In patients with altered
mental status, it is possible that sedation is delayed due to the
caretaker’s belief that the patient is unable to perceive pain.
It is important to recognize that altered mental status does
not eliminate the need for sedation following intubation.5,7,12
Adequately assessing which patients are incapable of feeling
pain is very difficult in the emergency setting, especially in
patients given a paralytic. There is insufficient evidence on
the need for sedation in this subpopulation. Because it is
unclear how altered a person must be to not perceive pain or
distress, erring on the side of more sedation is important to
reduce discomfort of the patient.7 Lastly, the induction agent
of choice may influence the time to sedation. With mid-
azolam being used in 1.6% of patients who received a short-
acting paralytic and 5.0% of patients who received a
long-acting paralytic, it is possible that this expanded the
time needed to give appropriate sedation due to its longer
duration of action. However, to best ensure sedation for all
patients, a standard protocol for all induction agents is likely
a better approach to ensure timely sedation.
The secondary outcome of this analysis examined the
change in potassium level, measured before and after para-
lytic administration in a small sub-sample of patients. Most
patients did not have both pre- and post-paralytic potassium
levels available, limiting the utility of this analysis.
Succinylcholine is known to increase potassium, which may
restrict its use in select patients at risk for hyperkalemia.4
Those most at risk for hyperkalemia are trauma patients with
crush and burn injuries, and this population was not preva-
lent in our study. In this study, the data set showed a mean
decrease in potassium level in the group that had received
succinylcholine. However, there were only 6 patients who
had received succinylcholine available for analysis. In the
long-acting paralytic group, there was a mean increase in
potassium level. The difference between groups was not sta-
tistically significant due to the small sub-sample size. More
research is needed to better understand the reasons for choos-
ing long-acting paralytics over short-acting paralytics,
including both patient-specific factors and physician prefer-
ence. To better quantify the impact of paralytic type on labo-
ratory values, future studies are needed to assess these values
both prior to and following intubation in a larger sample of
patients.
Many aspects of our study increase its application to prac-
tice in the community. Our study had less stringent exclusion
criteria compared to previous studies, and patients with car-
diac or traumatic arrest were included in our analysis.
Additionally, because our study was conducted at a commu-
nity hospital, the results are likely a better reflection of all
sedation practices than results of studies conducted utilizing
data from the NEAR database, which represents a set of EDs
that are engaged in airway research. Further, our endpoint of
15 minutes was informed by the duration of action of etomi-
date, which is by far most frequently used in practice.
Pankey et al 765
Limitations
We acknowledge several limitations of this study. To begin,
because the study did not achieve our target sample size, we
did not reach statistical power. As no difference was detected
between groups, it is important to consider the risk of a type
II error.
Additionally, the study was a retrospective analysis,
which limits available data to what was recorded on the
patient’s chart. If additional sedation was not recorded, it was
assumed that no additional sedative had been given, which
may falsely elevate the number of patients designated as not
receiving additional sedative. It is also possible that the time
charted in the electronic medical record may not reflect the
actual time medication was administered, leading to a false
delay in administration of the sedative agent. The time
between when the medication was ordered and when it was
administered was not collected, limiting the opportunity to
identify logistical delays. The length of intubation time was
also not evaluated. Because a difficult airway may require a
longer intubation time, this could lead to delays in adminis-
tration of post-intubation sedation.
Furthermore, this study did not consider the reason for
lack of additional sedation. All indications for intubation
were included in the analysis, including cardiac or traumatic
arrest. It is likely that sedation was intentionally held in some
patients to evaluate neurological function. Data regarding the
indication for RSI and the initial Glasgow Coma Scale (GCS)
were not collected in this study due to its retrospective nature,
limiting the ability to understand why some patients did not
receive sedation.
Another possible limitation is that pharmacologic agents
considered appropriate for post-intubation sedation in this
study were not consistent with previous studies. In contrast to
prior studies looking at post-intubation sedation, patients
receiving analgesic-only medication regimens, such as fen-
tanyl or morphine alone, were not considered to have received
additional sedation. Although these agents are typically less
preferred in hemodynamically unstable ED patients due the
additional risk for respiratory depression with doses large
enough for sedation in RSI, the difference in acceptable seda-
tion agents may have led to inconsistent results between the
current study and previous analyzes.
Future Direction
This study showed that post-intubation care is not compro-
mised with the use of long-acting paralytics. While other
studies have suggested that long-acting paralytics may be
associated with greater delays in time to sedation, it must be
acknowledged that any delay, regardless of duration, puts
patients at risk for complications. The findings of this study
highlight the need to improve post-intubation care in all
patients. Future prospective studies are needed to investigate
the development of post-traumatic stress disorder as a result
of paralytic use without sedation. Studies are also needed to
evaluate the impact of implementing post-intubation care
protocols within institutions.
Conclusion
Patients who are intubated using long-acting paralytics do
not have greater delays in post-intubation sedation adminis-
tration compared with patients who were intubated using
short-acting paralytics in the emergency department. As the
study was underpowered, it is important to consider the risk
of a type II error. The frequency of sedation administered
within 15 minutes of a paralytic was lower than previously
expected and was not associated with the type of paralytic
used. Implementation of post-intubation sedation protocols
in the ED may help to improve post-intubation care.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
ORCID iDs
Jessica A. Pankey https://orcid.org/0000-0002-1626-5746
Brandon A. Knettel https://orcid.org/0000-0003-2986-1579
References
1. Schneider RE, Caro DA. Sedative and induction agents. In:
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Williams and Wilkins; 2004;189-199.
2. Rocuronium Bromide Injection. Package Insert. Baxter
Healthcare Corporation; 2019.
3. Vecuronium. Package Insert. Mylan; 2018.
4. Anectine (succinylcholine chloride) injection solution. Package
insert. Sandoz Inc; January 2021.
5. Lembersky O, Golz D, Kramer C, et al. Factors associated with
post-intubation sedation after emergency department intuba-
tion: a report from the National Emergency Airway Registry.
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2019.05.010
6. Murray MJ, DeBlock H, Erstad B, et al. Clinical practice
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critically ill patient. Crit Care Med. 2016;44(11):2079-2103.
doi:10.1097/CCM.0000000000002027
7. Chong ID, Sandefur BJ, Rimmelin DE, et al. Long-acting neu-
romuscular paralysis without concurrent sedation in emergency
care. Am J Emerg Med. 2014;32(5):452-456. doi:10.1016/j.
ajem.2014.01.002
8. Kendrick DB, Monroe KW, Bernard DW, Tofil NM. Sedation
after intubation using etomidate and a long-acting neuromuscular
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blocker. Pediatr Emerg Care. 2009;25(6):393-396. doi:10.1097/
PEC.0b013e3181a7923b
9. Bonomo JB, Butler AS, Lindsell CJ, Venkat A. Inadequate
provision of postintubation anxiolysis and analgesia in the
ED. Am J Emerg Med. 2008;26(4):469-472. doi:10.1016/j.
ajem.2007.05.024
10. Watt JM, Amini A, Traylor BR, Amini R, Sakles JC, Patanwala
AE. Effect of paralytic type on time to post-intubation sedative
use in the emergency department. Emerg Med J. 2013;30:893-
895. doi:10.1136/emermed-2012-201812
11. Oglesby AJ. Should etomidate be the induction agent of choice
for rapid sequence intubation in the emergency department?
Emerg Med J. 2004;21:655-659. doi:10.1136/emj.2003.009043
12. Groth CM, Acquisto NM, Khadem T. Current practices and
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1095767
case-report2022
HPXXXX10.1177/00185787221095767Hospital PharmacyVanDuyn et al

Case Report

Hospital Pharmacy

Omadacycline for a Carbapenem-

2022, Vol. 57(6) 767­–770
© The Author(s) 2022
Article reuse guidelines:
Resistant Enterobacter cloacae-Associated sagepub.com/journals-permissions
DOI: 10.1177/00185787221095767
https://doi.org/10.1177/00185787221095767

Wound Infection journals.sagepub.com/home/hpx

Dylan C. VanDuyn1 , Saloni Chadha2, Lauren A. Paul1,

Andrea R. Dressler1, Mario V. Beccari1,3 ,
and Rajinder P.S. Bajwa3

Abstract

Introduction: Carbapenem-resistant Enterobacteriaceae (CRE) are problematic pathogens because infections caused by
these organisms are associated with significant morbidity and mortality. These organisms often harbor multiple resistance
mechanisms, which makes it difficult to treat their associated infections. Treatment typically consists of intravenous
antibiotics that are selected based on the specific susceptibility pattern for the pathogen. Data on the use of oral antibiotics
for the treatment of infections caused by CRE are sparse. Case Presentation: In this case, a 62-year-old female presented
with a chronic left leg wound infection. She previously underwent surgical debridement and skin grafting, which were
unsuccessful. She was initially prescribed minocycline for the infection, but the wound got re-infected. At this time, the
wound had significant surrounding erythema, drainage, and slough. A wound culture was obtained and demonstrated growth
of carbapenem-resistant Enterobacter cloacae and methicillin-resistant Staphylococcus aureus. The patient was initiated on oral
omadacycline, and she responded with resolution of the cellulitis and wound drainage. Conclusion: This case demonstrates
that omadacycline may be beneficial as an oral medication for the treatment of complicated acute bacterial skin and skin
structure infections caused by carbapenem-resistant Enterobacter cloacae.

Keywords
anti-infectives, infectious diseases, outcomes research, pharmacists, education, skin

Introduction Enterobacter cloacae complex (46%) compared to Klebsiella

Carbapenem-resistant Enterobacteriaceae (CRE) present a
critical problem throughout the world because infections
caused by these organisms are associated with significant
morbidity and mortality.1 In the United States (US), the CRE
epidemic began in 2001 with an outbreak of carbapenem-
resistant Klebsiella pneumoniae, which harbored Klebsiella
pneumoniae carbapenemase (KPC).1,2 Since then, KPC-
producing Klebsiella pneumoniae have emerged in various
communities across the country.2 Carbapenem resistance can
also occur in other species of Enterobacteriaceae, such as
Enterobacter cloacae. Although the rates of carbapenem
resistance in Klebsiella pneumoniae have decreased in cer-
tain areas of the country, the rates of carbapenem nonsuscep-
tibility and resistance in species of the Enterobacter cloacae
complex have increased throughout the last decade, reaching
>4% nonsusceptibility and 2.5% resistance in 2014 to 2015.
In addition, the proportion of isolates with intermediate sus-
ceptibility to carbapenems has been higher for species in the
pneumoniae (9%).
Infections caused by CRE are difficult to treat since the
genes encoding carbapenem resistance are typically located
on plasmids along with aminoglycoside and fluoroquino-
lone resistance determinants.3 Due to the limited antibiotic
options available, infections caused by carbapenemase-pro-
ducing organisms often require treatment with intravenous
antibiotics that are selected based on the specific suscepti-
bilities.4 Data on the use of oral antibiotics for the treatment
of infections caused by CRE are sparse. In this case, oral
omadacycline was used to treat carbapenem-resistant
1
D’Youville School of Pharmacy, Buffalo, NY, USA
2
St. Bonaventure University, St. Bonaventure, NY, USA
3
Niagara Falls Memorial Medical Center, Niagara Falls, NY, USA
Corresponding Author:
Mario V. Beccari, D’Youville School of Pharmacy, 320 Porter Avenue,
Buffalo, NY 14201, USA.
Email: beccarim@dyc.edu
768 Hospital Pharmacy 57(6)
Figure 1.  Infected left leg wound prior to omadacycline
treatment. This demonstrates surrounding erythema, drainage,
and slough on the base of the ulcer.
Enterobacter cloacae in a complicated acute bacterial skin
and skin structure infection (ABSSSI).
Case Presentation
Written informed consent was obtained from the patient for
publication of this case report and the accompanying images.
The patient was a 62-year-old Caucasian female with a past
medical history of obesity, deep vein thrombosis of the left
lower extremity on anticoagulation, venous insufficiency
involving both lower extremities, and necrotizing fasciitis of
the left lower extremity status post debridement in April 2019.
After the initial debridement, her wound failed to heal appro-
priately. Subsequently, the patient underwent surgical debride-
ment and skin grafting on 3 different occasions. Unfortunately,
the skin grafts failed, and the wound never healed.
The patient was seen for her chronic left leg wound infec-
tion in February 2020 at the Wound Care Center. A wound
culture was obtained and demonstrated growth of moderate
carbapenem-resistant Enterobacter cloacae and rare methi-
cillin-susceptible Staphylococcus aureus. She was initially
prescribed minocycline 200 mg by mouth twice daily for
10 days for the infection and ondansetron as needed for nau-
sea. She responded to minocycline with resolution of the cel-
lulitis, but she had significant nausea despite the use of
ondansetron. Once her infection improved, she was started
on local wound care and compression therapy. The patient’s
wound had slow improvement, and the left leg wound even-
tually got re-infected in May 2020. As shown in Figure 1, the
wound had significant surrounding erythema, drainage, and
slough on the base of the ulcer.
Another wound culture was obtained and demonstrated
growth of moderate carbapenem-resistant Enterobacter clo-
acae and methicillin-resistant Staphylococcus aureus. As
shown in Figure 2, this carbapenem-resistant Entero­bacter
cloacae was resistant to all traditional oral antibiotic options.
At that time, compression therapy was held, and she was
initiated on oral omadacycline. The patient received a load-
ing dose of 450 mg by mouth once daily on days 1 and 2.
Afterward, she received a maintenance dose of 300 mg by
mouth once daily from day 3 to day 10. The patient responded
to omadacycline with resolution of the cellulitis and wound
drainage. She then received local wound care, which involved
routine debridement and compression therapy using Profore
multi-layer dressings. As shown in Figure 3, the patient’s
wound continued to significantly improve by July 2020.
Discussion
To our knowledge, this is the first case report to demonstrate
successful use of oral omadacycline for the treatment of car-
bapenem-resistant Enterobacter cloacae in a complicated
ABSSSI. Traditionally, infections caused by CRE require
treatment with intravenous antibiotics.4 Although new anti-
biotics, such as ceftazidime-avibactam and plazomicin, have
been developed to treat carbapenemase-producing organ-
isms, intravenous use of these medications may cause
adverse reactions, administration difficulties, and increased
patient cost. Treatment with oral medications is often limited
by resistance genes encoded on plasmids.3 As shown in this
case, this carbapenem-resistant Enterobacter cloacae was
resistant to all of the oral antibiotics that are traditionally
used, so omadacycline was used for treatment.
Omadacycline received Qualified Infectious Disease
Product and Fast Track designations because of the need for
broad-spectrum antimicrobial medications with the ability to
combat multidrug-resistant organisms. This medication
received US Food and Drug Administration (FDA) approval
in October 2018 for the treatment of community-acquired
bacterial pneumonia (CABP) and ABSSSIs, and it is avail-
able in intravenous and oral formulations.5 For ABSSSI and
CABP, the US FDA identified the susceptibility breakpoint
for Enterobacteriaceae as a minimum inhibitory concentra-
tion (MIC) of ≤4 mg/L.6
Omadacycline is a semisynthetic aminomethylcycline
derived from minocycline.7 Its novel modification allows
it to overcome traditional tetracycline-based resistance
mechanisms and provides broad-spectrum coverage against
aerobic and anaerobic gram positive and gram negative
organisms, as well as atypical pathogens. It has also dem-
onstrated activity against multidrug-resistant organisms,
such as CRE.
The approval of omadacycline for ABSSSI was based on
a phase III non-inferiority trial, which compared it to line-
zolid.8 Patients in this study were initiated on the intrave-
nous formulation and allowed to transition to the oral
formulation after 3 days. Although this study showed non-
inferiority to linezolid for ABSSSIs, only 15.4% of patients
had a polymicrobial mixed gram positive and gram negative
infection. In addition, patients with an infection caused
solely by gram negative pathogens were excluded because
linezolid was used as the comparator.
VanDuyn et al 769
Figure 2.  Left leg wound Enterobacter cloacae susceptibilities prior to omadacycline treatment. This demonstrates growth of
carbapenem-resistant Enterobacter cloacae.
Figure 3.  Left leg wound after omadacycline treatment. This
demonstrates resolution of cellulitis and improvement in size.
A surveillance study assessed the activity of omadacycline
among clinical isolates from the US and Europe from 2016 to
2018.9 Omadacycline was tested against 49,000 bacterial iso-
lates from 73 different medical centers. In this study, carbape-
nem-resistant Escherichia coli had an MIC50 and MIC90 of 1
and 2  mg/L, respectively. However, carbapenem-resistant
Klebsiella pneumoniae had an MIC50 of 4 mg/L and an
MIC90 of 8 mg/L. For species in the Enterobacter cloacae
complex, omadacycline had an MIC50 and MIC90 of 2 and
4 mg/L, respectively. Against ceftazidime-non-susceptible
Enterobacter cloacae complex isolates, omadacycline was
less active with an MIC50 of 2 mg/L and an MIC90 of 8 mg/L.
None of the Enterobacter cloacae complex isolates were spe-
cifically classified as carbapenem-resistant in this study.
Despite the lack of data available regarding the use of
omadacycline for carbapenem-resistant Enterobacter cloa-
cae infections, this patient was treated with oral omadacy-
cline based on the data available in Enterobacter cloacae and
carbapenem-resistant Escherichia coli infections. Repeat
wound cultures were not obtained as documentation of bac-
terial clearance because chronic wounds caused by venous
insufficiency can remain colonized with bacteria. However,
this patient clinically responded to oral omadacycline with
resolution of the cellulitis and wound drainage. Therefore,
this case highlights the successful use of oral omadacycline
for the treatment of a complicated ABSSSI caused by car-
bapenem-resistant Enterobacter cloacae.
Conclusion
Omadacycline may be beneficial as an oral medication for
the treatment of complicated ABSSSIs caused by carbape-
nem-resistant Enterobacter cloacae. Additional data are
needed to investigate and confirm our findings.
Authors’ Note
The data represented in this manuscript were presented as a
poster at the virtual ASHP Midyear Clinical Meeting 2021 on
December 8, 2021.
770 Hospital Pharmacy 57(6)
Data Availability
The data used to support the findings of this study are available
from the corresponding author upon request.
Declaration of Conflicting Interests
The author(s) declared the following potential conflicts of interest
with respect to the research, authorship, and/or publication of this
article: Rajinder P.S. Bajwa has served on an advisory board for
Paratek Pharmaceuticals, which is the company that developed
omadacycline. All of the other authors declare that there are no
additional conflicts of interest.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
Ethical Approval
This work was carried out in accordance with The Code of Ethics of
the World Medical Association (Declaration of Helsinki) for exper-
iments involving humans, and the case was cleared through the
D’Youville College Institutional Review Board.
ORCID iDs
Dylan C. VanDuyn https://orcid.org/0000-0002-8860-417X
Mario V. Beccari https://orcid.org/0000-0003-4416-8035
References
1. Guh AY, Bulens SN, Mu Y, et al. Epidemiology of carbape-
nem-resistant Enterobacteriaceae in 7 US communities, 2012–
2013. JAMA. 2015;314:1479-1487.
2. Wilson BM, El Chakhtoura NG, Patel S, et al. Carbapenem-
resistant Enterobacter cloacae in patients from the US
Veterans Health Administration, 2006–2015. Emerg Infect
Dis. 2017;23:878-880.
3. Taylor E, Sriskandan S, Woodford N, Hopkins KL. High
prevalence of 16S rRNA methyltransferases among carbapene-
mase-producing Enterobacteriaceae in the UK and Ireland. Int
J Antimicrob Agents. 2018;52:278-282.
4. Clancy CJ, Potoski BA, Buehrle D, et al. Estimating the treat-
ment of carbapenem-resistant Enterobacteriaceae infections
in the United States using antibiotic prescription data. Open
Forum Infect Dis. 2019;6:ofz344.
5. Durães F, Sousa E. Omadacycline: a newly approved antibac-
terial from the class of tetracyclines. Pharmaceuticals (Basel).
2019;12:E63.
6. U.S. Food & Drug Administration. Omadacycline injection
and oral products: FDA identified breakpoints for omadacy­
cline for acute bacterial skin and skin structure infections
(ABSSSI). https://www.fda.gov/drugs/development-resources/
omadacycline-injection-and-oral-products. Published August
2020.
7. Barber KE, Bell AM, Wingler MJB, et al. Omadacycline enters
the ring: a new antimicrobial contender. Pharmacotherapy.
2018;38:1194-1204.
8. O’Riordan W, Green S, Overcash JS, et al. Omadacycline for
acute bacterial skin and skin-structure infections. N Engl J
Med. 2019;380:528-538.
9. Pfaller MA, Huband MD, Shortridge D, Flamm RK.
Surveillance of omadacycline activity tested against clinical
isolates from the United States and Europe: report from the
SENTRY antimicrobial surveillance program, 2016 to 2018.
Antimicrob Agents Chemother. 2020;64:e02488-e02519.
1095737
research-article2022
HPXXXX10.1177/00185787221095737Hospital PharmacyZuchowski et al

Case Report

Hospital Pharmacy

Mirabegron Associated Angioedema:

2022, Vol. 57(6) 771­–773
© The Author(s) 2022
Article reuse guidelines:
A Case Report sagepub.com/journals-permissions
DOI: 10.1177/00185787221095737
https://doi.org/10.1177/00185787221095737
journals.sagepub.com/home/hpx

Matthew T. Zuchowski1,2 , Jaylan M. Yuksel1,

and John Novi1

Abstract

Purpose: To review a case of angioedema associated with mirabegron. Summary: A 77-year-old woman presented to
the emergency department with swelling of the left anterior side of the tongue beginning 90 minutes prior to arrival. She
noticed tingling on her tongue while eating a hamburger, chips, and ice cream. The patient had no history of medication-
related allergies. Home medications include acetaminophen, aspirin, biotin, black cohosh, Co-enzyme Q-10, cranberry, fish
oil, multivitamin, alendronate, and mirabegron all taken orally. The patient reports being on mirabegron for 3 to 4 years but
recently decided to self-taper off the medication. Her initial laboratory test results were unremarkable. The patient was
diagnosed with left tongue angioedema, and she received methylprednisolone, epinephrine, famotidine, and 2 units of plasma.
After medication administration, the patient underwent a flexible nasopharyngeal laryngoscopy resulting in no significant
angioedema in the pharynx and hypopharynx with a small area of possible edema noted on the right base of tongue/lingual
tonsil. Patient’s symptoms improved with medication treatment and discontinuation of mirabegron. The use of Naranjo et
al. adverse-event probability scale revealed that mirabegron was the possible (score of 4) cause of the patient’s left tongue
angioedema. Conclusion: A 77-year-old woman developed drug induced tongue angioedema associated with mirabegron
after being compliant on this medication for 3 to 4 years. Patient was self-tapering her dose of mirabegron. This patient
responded well to medication treatment and discontinuation of drug. To our knowledge, this is the second case report of
mirabegron induced angioedema.

Keywords
mirabegron, angioedema, tongue

Key points: bradykinin). Mast cell degranulation is a process when mast

•• This is a rare case report of tongue angioedema caused
by miragebron.
•• The initial mirabegron package insert in 6/2012 did
not have angioedema listed as a possible ADR. Due to
post marking information reported, the package insert
was updated in 8/2015 to list angioedema as a rare but
serious ADR.
•• To date there is only 1 case report of mirabegron asso-
ciated angioedema.
Angioedema is defined by nonpitting edema of the dermis
and subcutaneous layers lasting from hours to 3  days.
Commonly, angioedema occurs in the lips, tongue, face, and
throat. Uncommonly, it can occur in the extremities, genitalia,
and viscera.1 Angioedema is a medical emergency, as it can
lead to life-threating airway swelling. The pathophysiology
behind angioedema is believed to be caused by either mast
cell degranulation (with a rapid release of histamine) or acti-
vation of the kallikrein-kinin cascade (with a rapid release of
cells are stimulated and release histamine.2 In angioedema
caused by mast cell degranulation, there is a rapid release of
histamine from the cells. Drug-induced, allergic angioedema
is a type I hypersensitivity reaction and is mediated by hista-
mine release. This type of angioedema has a rapid onset of
action and may present with an urticarial rash and often
resolves with medication treatment such as antihistamines.
Kallikrein-kinin cascade is an endogenous metabolic cascade
in which vasoactive kinins are released, specifically bradyki-
nin-related peptides.3 Overproduction of bradykinin can stim-
ulate an angioedema reaction. Drug-induced, non-allergic
angioedema is mediated by bradykinin. Urticarial rash is not
1
Upstate Community Hospital, Syracuse NY, USA
2
Albany College of Pharmacy and Health Sciences, Albany, NY, USA
Corresponding Author:
Matthew T. Zuchowski, Albany College of Pharmacy and Health Sciences,
106 New Scotland Avenue, Albany, NY 12208, USA.
Email: Matthew.zuchowski@acphs.edu
772 Hospital Pharmacy 57(6)
typically present in this type of angioedema. This reaction has
a gradual onset, unlike allergic angioedema. Symptoms will
subside after discontinuing the offending agent.4,5 Mirabegron,
a beta-3-agonist, is indicated for overactive bladder and uri-
nary incontinence.6 We describe a case of drug-induced
tongue angioedema related to use of mirabegron. A MEDLINE
search, without date limits, using the terms mirabegron and
angioedema or drug-induced angioedema identified 1 case
report.7
Case Report
A 77-year-old female with a body mass index of 19.01 kg/m2
arrived at the emergency department with complaints of left-
sided tongue swelling and tingling, tightness in the back of
her throat and difficulty speaking because of a lisp. Her
symptoms began after consuming a cheeseburger, potato
chips, and ice cream. Due to symptom progression, she pre-
sented to the emergency room 1.5 hours later. She has no pre-
vious history of allergies, angioedema, or anaphylaxis. Her
past medical history was significant for osteoporosis and
overactive bladder, both of which are not chronic degenera-
tive diseases. Vitals on admission include blood pressure:
182/95 mmHg, pulse: 98 BPM, respiratory rate: 18 breaths/
minute, SpO2: 98% on room air. Body temperature was
36.3°C. Given the patient was hemodynamically stable ana-
phylaxis was ruled out. On physical examination, patient’s
anterior tongue was significantly swollen concerning for
angioedema versus allergic reaction. The remainder of her
physical exam was unremarkable. Complete blood count and
differential, osmolality, and international normalized ratio
were all unremarkable. The basic metabolic panel was unre-
markable except for slightly elevated calcium at 10.8 mg/dL
and bicarbonate 31  mmol/L. COVID-19 and respiratory
pathogen were both unremarkable. Electrocardiogram
showed normal sinus rhythm without ST elevation or other
obvious signs of ischemia or arrhythmia. Patient received
intravenous methylprednisolone 125 mg, intravenous famoti-
dine 20 mg, and intramuscular epinephrine 0.3 mg shortly
after admission to the emergency department. Patient also
received 2 units of plasma 2 minutes after receiving the medi-
cations listed. After medications and plasma were adminis-
tered otolaryngology preformed a bedside flexible
pharyngo-laryngoscopy procedure with the following results:
no significant angioedema in pharynx/hypopharynx, small
area possible edema noted on the right base of the tongue/
lingual tonsil. Patient’s symptoms began to improve about
90 minutes after medications were administered and the
patient was discharged, with a total length of stay being
1 day, without any changes to her home medications. Her
home medications included the following: acetaminophen
500 mg twice daily, aspirin 81 mg daily, biotin 1000 μg daily,
black cohosh compound 1 tablet daily, Co-enzyme Q-10
1000 mg daily, cranberry 300 mg daily, fish oil 1000 mg
daily, multivitamin 1 tablet daily, alendronate 70 mg every
Friday, mirabegron 50 mg twice weekly on Monday and
Friday, all taken orally. She also used polyvinyl alcohol 1.4%
liquiform tear eye drops, 1 drop into both eyes as needed. Of
these medications, acetaminophen,8 alendronate,9 aspirin10
have been rarely associated with angioedema. This case
report will focus on mirabegron as possible cause. The
patient reports taking mirabegron for about 3 or 4 years and
up until recently she has been taking it as prescribed, once
daily. She has recently decided to self-taper off this medica-
tion and started to take it twice weekly. Due to the rapid onset
of her angioedema and her positive response to methylpred-
nisolone, famotidine, and epinephrine the patient was advised
to discontinue mirabegron on discharge. The patient was
scheduled to follow up with her primary care provider in
1 week post discharge to discuss whether to continue mirabe-
gron considering this occurrence. It was decided to discon-
tinue mirabegron. The Naranjo et al adverse-event probability
scale indicated a score of 4 which indicates possible causal-
ity of adverse drug reaction (ADR).11
Discussion
Mirabegron is indicated for overactive bladder and urinary
incontinence. It works by activating beta-3 adrenergic recep-
tors in the bladder resulting in relaxation of the detrusor
smooth muscle during the urine storage phase and increasing
bladder capacity. Data have shown that beta-adrenoceptors,
predominately the beta-3, mediate detrusor smooth muscle
tone, and promote the storage function of the human bladder.
Mirabegron is generally well tolerated with the most com-
mon side effects being increased blood pressure, dry mouth,
urinary tract infection, dizziness, headache, and constipation.
Serious, but rare, ADRs include hypersensitivity reactions
and head and neck angioedema (occurring in <1% of
patients).6 The initial mirabegron package insert in 6/201212
did not have angioedema listed as a possible ADR. Due to
post marking information reported, the package insert was
updated in 8/201513 to list angioedema as a rare but serious
ADR. To date there is only 1 case report of mirabegron asso-
ciated angioedema. This case study examines a 53-year-old
female who experienced dyspnea, dysphagia, and throat
tightness for 3 to 4 weeks. Through careful history taking the
team was able to reveal that she had increased her dose of
mirabegron from 25 to 50 mg 1 day prior to symptoms onset.
Three days after discontinuing mirabegron she reported
symptom resolution.7 Similarly, we report a patient who
recently changed her mirabegron dose who experienced
tongue angioedema. She was taking mirabegron 50 mg daily
for 3 to 4 years and recently cut back to 50 mg on Monday
and Fridays. She presented Friday evening and had received
her dose for the day. Based on the rapid onset of her tongue
swelling and response to treatment we propose the patient
experienced drug-induced allergic angioedema. We propose
the mechanism causing her angioedema was a type I hyper-
sensitivity mediated by mast cell degranulation and a rapid
Zuchowski et al 773
release of histamine. This is supported by the rapid onset and
response to antihistamines and corticosteroids.
Conclusion
A 77-year-old female developed tongue angioedema after self-
tapering her mirabegron. Drug-induced allergic angioedema is
a rare but is a medical emergency. This case report shows the
importance of obtaining an accurate medication history.
Author Contributions
Matthew T. Zuchowski, Jaylan M. Yuksel, and John Novi contrib-
uted to drafting the article, critically revising the article, and final
approval of the article.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
ORCID iD
Matthew T. Zuchowski https://orcid.org/0000-0002-2598-016X
References
1. Lewis LM. Angioedema: etiology, pathophysiology, current
and emerging therapies. J Emerg Med. 2013;45(5):789-796.
2. Kaplan AP. Angioedema. World Allergy Organ J. 2008;1(6):
103-113.
3. Moreau ME, Garbacki N, Molinaro G, Brown NJ, Marceau F,
Adam A. The kallikrein-kinin system: current and future phar-
macological targets. J Pharmacol Sci. 2005;99(1):6-38.
4. Agostoni A, Cicardi M. Drug-induced angioedema without
urticaria. Drug Saf. 2;24(8):599-606.
5. Kalambay J, Ghazanfar H, Martes Pena KA, Munshi RA,
Zhang G, Patel JY. Pathogenesis of drug induced non-aller-
gic angioedema: a review of unusual etiologies. Cureus.
2017;9(8):e1598.
6. Myrbetriq (Mirabegron) [Prescribing Information]. Astellas
Pharma US Inc;2021.
7. Davis H, Wallace T, Gilkerson C, Saunders E. Drug-induced
angioedema: a rare side effect of mirabegron. W V Med J. 1-3.
8. Deepthi A, Shaheen, Kumar H, Ashraf S, Deepak JH. Images
in medicine: an atypical presentation of unilateral tongue
angioedema caused by acetaminophen. J Clin Diagn Res.
2017;11(4):ZJ01-ZJ02.
9. Musette P, Kaufman JM, Rizzoli R, Cacoub P, Brandi ML,
Reginster JY. Cutaneous side effects of antiosteoporosis treat-
ments. Ther Adv Musculoskelet Dis. 2011;3(1):31-41.
10. Marshall LL. Angioedema associated with aspirin and rofe-
coxib. Ann Pharmacother. 2005;39(5):944-948.
11. Naranjo CA, Busto U, Sellers EM, et al. A method for estimat-
ing the probability of adverse drug reactions. Clin Pharmacol
Ther. 1981;30(2):239-245.
12. Approval Label, Myrbetriq. Orig-1 Drugs@FDA. 2012.
Accessed December 14,2021. https://www.accessdata.fda.gov/
drugsatfda_docs/label/2012/202611s000lbl.pdf
13.
Labeling-Package Insert. Suppl-6 Drugs@FDA. 2015.
Accessed December 14,2021. https://www.accessdata.fda.gov/
drugsatfda_docs/label/2015/202611s006lbl.pdf
1108715
research-article2022
HPXXXX10.1177/00185787221108715Hospital PharmacyRoss et al

Case Report

Hospital Pharmacy

Coronavirus Disease 2019-Related

2022, Vol. 57(6) 774­–778
© The Author(s) 2022
Article reuse guidelines:
Extensive Thrombosis in a Patient sagepub.com/journals-permissions
DOI: 10.1177/00185787221108715
https://doi.org/10.1177/00185787221108715

Receiving Therapeutic Anticoagulation journals.sagepub.com/home/hpx

With Dabigatran

Robert C. Ross1 , Andrew L. Hendrickson1, Miranda P. Boraas1,

Abbie N. Rosen1 , and Andrew J. Franck1

Abstract

Introduction and Objective: Coronavirus disease 2019 (COVID-19) is associated with respiratory failure and a
hypercoagulable state. Studies have shown the use of oral anticoagulants, specifically dabigatran, can significantly decrease
mortality from COVID-19. Dabigatran is an oral direct thrombin inhibitor commonly used for nonvalvular atrial fibrillation
and for the treatment or prevention of venous thromboembolism. The association of COVID-19-related extensive
thrombosis while receiving full therapeutic anticoagulation with dabigatran has not been well-established in current literature.
Case Report: We present a 73-year-old male patient with a history of persistent atrial fibrillation anticoagulated with
dabigatran presenting with an active COVID-19 infection admitted to the intensive care unit. On hospital day 7, he developed
extensive arterial and venous thromboembolisms. To our knowledge, this is the first published case of COVID-19-related
extensive thrombosis while receiving full therapeutic anticoagulation with dabigatran. Discussion: Guidelines recommend
prophylactic or therapeutic-dose anticoagulation with unfractionated heparin or low-molecular weight heparin for all patients
if no contraindications exist; however, recommendations for the use of therapeutic oral anticoagulants have not been well
established. Further studies are warranted to establish appropriate use of oral anticoagulants in the setting of COVID-19.
Conclusion: Evidence from this report suggests clinicians should closely monitor patients at risk for hypercoagulability
regardless of the anticoagulation therapy the patient may be receiving. Additionally, evidence from this case suggests a
possible inferiority in the anticoagulation ability of dabigatran in patients with active COVID-19.

Keywords
critical care, anticoagulants, COVID, pharmacokinetics

Introduction Dabigatran is an oral anticoagulant that acts by inhibiting

Coronavirus disease 2019 (COVID-19) is caused by
severe acute respiratory syndrome coronavirus 2 (SARS-
CoV-2) and is commonly associated with respiratory fail-
ure and a hypercoagulable state.1,2 The increased systemic
inflammatory response to COVID-19 is believed to be the
driving force for hypercoagulability, specifically increases
in the cytokine IL-6 leading to increased production of
fibrinogen and platelets.2,3 Changes in D-dimer, partial
thromboplastin time, platelet count, and fibrinogen may
present 4 to 10 days after hospitalization and indicate
potential COVID-19-induced alterations to coagulation.3
The use of direct oral anticoagulants (DOACs) prior to
being admitted with COVID-19 has been associated with
a significantly improved mortality, specifically with the
use of dabigatran.4
thrombin directly, which prevents the cleavage of fibrinogen
to fibrin, thrombin-induced platelet aggregation, and inhibits
the activation of factors V, VIII, XI, and XIII. It is commonly
used to prevent stroke and embolism in patients with non-
valvular atrial fibrillation (NVAF) or for the treatment or pre-
vention of venous thromboembolism (VTE).
There has been a case report of a patient developing pul-
monary embolism on dabigatran after recovering from a
COVID-19 infection.1 Here, we present a case that, to our
1
North Florida/South Georgia Veterans Health System, Gainesville, FL,
USA
Corresponding Author:
Robert C. Ross, North Florida/South Georgia Veterans Health System,
1601 SW Archer RD (119), Gainesville, FL 32608, USA.
Email: Robert.Ross1@va.gov
Ross et al 775
knowledge, is the first case report of COVID-19-related
extensive thrombosis while receiving full therapeutic antico-
agulation with dabigatran.
Case Report
The patient was a 73-year-old white male with a past medical
history of Guillain-Barre syndrome (diagnosed 17 months
prior to admission), hyperlipidemia, persistent NVAF (diag-
nosed 16 months prior to admission), and obesity (body mass
index [BMI] on admission was 33.3  kg/m2 [115 kg]).
Additionally, he had an extensive surgical history (all of
which occurred greater than 1 year prior to admission)
including a left tibia fracture repair, right knee replacement,
right rotator cuff repair, and left rotator cuff repair. He
reported no significant family history, had a previous smok-
ing history (quit 10 years prior to presentation), and reported
no use of alcohol or illicit drugs. He reported good medica-
tion adherence to his home medications, which included
dabigatran 150 mg by mouth twice daily, and metoprolol suc-
cinate 100 mg by mouth every morning and 50 mg by mouth
every evening. He also reported taking a non-prescription
fish oil supplement daily by mouth, dose unspecified. He
reported no known medication allergies or adverse drug
reactions.
The patient presented to the emergency department after
approximately 2 weeks of rhinorrhea, congestion, and non-
productive cough. He complained of worsening fatigue and
cough in the days leading to admission. He was found to be
COVID-19 positive by polymerase chain reaction (PCR)
testing. Of note, he had not received the COVID-19 vaccina-
tion due to his history of Guillain-Barre per advice from his
primary care physician. In the emergency department, he
was started on non-invasive positive pressure mechanical
ventilation for hypoxia and an intravenous (IV) diltiazem
infusion for his atrial fibrillation with rapid ventricular rate
(RVR). He was admitted to the medical intensive care unit
(MICU) for acute hypoxic respiratory failure secondary to
COVID-19 pneumonia. He was continued on metoprolol for
rate control and dabigatran to prevent stroke and systemic
embolism. His IV diltiazem infusion was converted to diltia-
zem extended-release oral formulation and the dose was
adjusted as indicated for rate control. He was initiated on
remdesivir daily for 5 days (1 dose of 200 mg IV, followed by
4 doses of 100 mg IV) and dexamethasone daily for 10 days
(1 dose of 6 mg IV, followed by 9 doses of 6 mg orally) for
the management of COVID-19.
Pertinent laboratory tests can be seen in Table 1 for the
first 8 days of the hospital stay. On hospital day 7, he reported
acute pain and paresthesia of the right leg from mid-tibia and
distally. Upon exam, his right foot was cold and pale com-
pared to his left side. Additionally, a pedal pulse could not be
palpated or located with bedside doppler ultrasound. Vascular
surgery was consulted, and a stat computed tomography
angiography (CTA) was ordered due to concern for acute
limb ischemia. The CTA showed moderate volume pulmo-
nary emboli, extensive arterial thrombus extending from the
distal aorta through the majority of the right iliac arteries,
and branch artery occlusions of large portions of the left kid-
ney. Vascular surgery recommended transitioning anticoagu-
lation to an IV unfractionated heparin (UFH) infusion given
the development of thrombus while anticoagulated on thera-
peutic dabigatran. Due to a high risk of repeat thrombosis,
surgical intervention was deferred. Since admission, he had
not missed any doses of dabigatran.
The patient was transitioned to an IV UFH infusion
(titrated to a goal anti-factor Xa level of 0.3-0.7 International
units/mL) from hospital day 7 until hospital day 12, at which
point he was converted to therapeutic enoxaparin (dosed as
1 mg/kg subcutaneously [SC] twice daily). On hospital day
16, he started warfarin and continued on therapeutic enoxa-
parin until his International Normalized Ratio (INR) was
within his goal range of 2.0 to 3.0. Due to the need for inva-
sive mechanical ventilation and requirement for amiodarone
for refractory atrial fibrillation, warfarin was discontinued,
and he was placed back on a therapeutic enoxaparin on hos-
pital day 27. He was later transitioned back to an IV UFH
infusion on day 30 after developing an acute kidney injury.
On hospital day 32, after days of developing progressive mul-
tiorgan failure, life-sustaining treatment was withdrawn, and
the patient died.
Discussion
Reports of VTE and arterial thromboembolism (ATE) have
been common since the start of the COVID-19 pandemic,
which have led to recommendations regarding the use of
anticoagulants for prophylaxis in this hypercoagulable
state.2,3,5 In the beginning of the pandemic, recommendations
using prophylactic-dose low-molecular-weight heparin
(LMWH) or UFH were not sufficient and led to breakthrough
thrombosis.5 This prompted further studies to compare the
use of therapeutic-dose versus intermediate dose versus pro-
phylactic dose anticoagulation.5,6 Current anticoagulation
recommendations for patients with COVID-19 receiving
intensive care unit level of care includes prophylactic-dose
UFH or LMWH for all patients as long as no contraindica-
tions exist, according to the Society of Critical Care
Medicine, Surviving Sepsis Campaign, and the National
Institutes of Health (NIH).6,7
Additionally, the NIH recommends full-strength LMWH/
UFH for non-critically ill patients over prophylactic-dose
and is preferred over the use of DOACs.6 This recommenda-
tion is based off multiple studies showing a significant ben-
efit using therapeutic dosing in patients with COVID-19. In
these studies, therapeutic dosing could have included any
LMWH at the manufacturer’s recommended therapeutic
dosing or UFH titrated to therapeutic effect based on partial
thromboplastin time (PTT) or anti-factor Xa monitoring per
institutional protocol. The preferred agent was enoxaparin at
776 Hospital Pharmacy 57(6)

Table 1.  Labs Collected During Hospital Days 1 to 8.

Lab test [reference range] Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8
AST (U/L) [0-45] 35 44 32 33
ALT (U/L) [0-40] 30 58 47 46
CRP (mg/dL) [<0.3-0.5] 14  
ANC (k/cmm) [1.8-7.8] 7.43 4.86 15.91  
PTT (sec) [23.0-37.7] 16.4 >200 67.0
PT (sec) [12.2-14.8] 39.3  
INR [0.9-1.2] 1.3  
WBC (k/cmm) [4.6-10.8] 8.35 5.28 12.19 11.13 13.0 17.29 14.39 15.08
Hgb (g/dL) [13.9-18] 18.4 16.3 16.1 14.9 16.1 17.4 15.3 15.2
HCT (%) [41-52] 52.3 46.7 46.1 42.5 45.7 49.6 42.9 42.8
Plt (k/cmm) [130-440] 164 141 198 184 210 205 160 165
Glucose (mg/dL) [65-99] 119 148 142 146 132 117 119 172
BUN (mg/dL) [9-20] 27 24 24 24 24 22 23 24
Creatinine (mg/dL) [0.5-1.2] 1.1 0.8 0.7 0.7 0.9 1.0 0.8 0.9
Sodium (mmol/L) [135-145] 138 136 138 140 139 139 135 134
Chloride (mmol/L) [23-32] 102 104 105 107 105 102 101 99
CO2 (mmol/L) [23-32] 19 21 20 20 21 22 24 22
Potassium (mmol/L) [3.5-5.0] 4.0 4.7 3.9 3.9 4.0 4.0 4.3 4.4

Note. ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CO2 = serum
bicarbonate; CRP = C-reactive protein; HCT = hematocrit; Hgb = hemoglobin; INR = international normalized ratio; Plt = Platelets; PT = prothrombin time;
PTT = partial thromboplastin time; WBC = white blood cells.

a dose of 1 mg/kg SC twice daily. Further, typical prophylac-
tic dosing was enoxaparin 40  mg SC daily or heparin
5000 units SC 2 to 3 times daily based on institutional proto-
col. Regarding safety, a non-significant increase in non-fatal
bleeding (defined based on International Society on
Thrombosis and Haemostasis [ISTH] criteria as fatal bleed-
ing, symptomatic bleeding in a critical area or organ, or
bleeding causing a drop in hemoglobin of at least 20 g/L) was
observed for the therapeutic dosing group.8,9
One concern with using DOACs compared to LMWH or
UFH in general is the increased drug interactions present;
however, most of these interactions lead to increased sys-
temic concentrations. Decreased systemic concentrations of
dabigatran can occur with the concomitant use of medica-
tions that increase the gastric pH or induce the P-glycoprotein
efflux pump.10 Medications that increase the gastric pH (eg,
magnesium or aluminum-containing antacids) decrease the
absorption of dabigatran, whereas medications that induce
the P-glycoprotein efflux pump (eg, carbamazepine, phe-
nytoin) may reduce the bioavailability of dabigatran by
increasing drug efflux back into the intestinal lumen for
excretion.10 From hospital admission to the development of
extensive thrombus, our patient did not receive any concom-
itant medications that could have explained any change in
the systemic concentration of dabigatran. Of note, the
patient did not receive any stress ulcer prophylaxis. Our
patient did not have risk factors present to indicate an
increased risk of clinically important gastrointestinal bleed-
ing (eg, at least 48 hours of mechanical ventilation, platelets
<50 k/mm3, INR > 1.5, PTT > 2 times baseline), so stress
ulcer prophylaxis was not indicated.11 Another major con-
cern with dabigatran is the storage of the medication.
Dabigatran must be stored in its original packaging to mini-
mize product breakdown from moisture and avoid a loss of
potency.10 While our patient’s home storage conditions of
dabigatran are unknown, our facility uses manufacturer blis-
ter packs of dabigatran while inpatient to control for these
storage conditions. The last major concern with the use of
DOACs involves their efficacy in the obese patient popula-
tion, especially with our patient having a BMI of 33.3 kg/m2.
Dabigatran has been reported to have significantly reduced
plasma concentrations by about 20% in patients weighing
more than 100 kg compared to patients weighing 50 to
100 kg10,12 While there is limited data on therapeutic failure
of dabigatran in patients with a BMI 30 to 40 kg/m2, the
available case reports of patients with a BMI greater than
40 kg/m2 supports the idea of increased body weight signifi-
cantly contributing to the diminished effect of dabigatran.
The definitive reason for the lack of therapeutic efficacy of
dabigatran in our patient case remains unclear, although the
elevated BMI could have played a significant role.
While the findings in this case are noteworthy, this case
report also has some important limitations. Most importantly,
several coagulation/inflammatory tests (D-dimer, C-reactive
protein (CRP), ferritin, and fibrinogen) were not collected at
baseline and have limited data during his admission; how-
ever, these inflammatory markers can also be elevated in the
absence of an active thrombosis and would not definitively
indicate a thrombus. Additionally, the PTT, prothrombin
time (PT), and INR were not continuously collected during
Ross et al 777
the first 7 days of admission to determine any changes in his
coagulable state. These tests are not specific in assessing the
anticoagulation effects of DOACs; however, elevations in
these values may have shown some therapeutic effect of dabi-
gatran. While not validated for determining therapeutic antico-
agulation, an alternative approach that may warrant future
studies is the use of thromboelastography (TEG) monitoring
in patients with hypercoagulable states. Studies assessing the
use of TEG monitoring in COVID-19 patients have reported it
to be an effective strategy in guiding goal-directed anticoagu-
lation of COVID-19 patients to improve patient outcomes.13,14
Another important limitation to consider in this case report
involves effects of COVID-19 that have not been studied that
could have played a role in this thrombosis event. For exam-
ple, it has been shown certain infections such as human immu-
nodeficiency virus (HIV) have been shown to increase the
expression of P-glycoprotein and increase the efflux of sub-
strate medications.15 While different in etiology and patho-
physiology, both HIV and COVID-19 are associated with
increased synthesis of pro-inflammatory cytokines leading to
prolonged inflammation.16 Similar to COVID-19, evidence
suggests patients with chronic HIV infection are associated
with a significantly increased risk of VTE; however, whether
the increased systemic inflammatory response is the driving
force of hypercoagulability has yet to be determined.2,3,16,17
Due to the hypercoagulable state in HIV patients, it is recom-
mended to use either LMWH or warfarin rather than DOACs
for VTE treatment.17 Although the increased expression of
P-glycoprotein has not yet been confirmed in COVID-19, it
would help account for a decreased serum concentration of
dabigatran and explain the thrombosis event.
As described in the case, extensive ATE and VTE devel-
oped in the presence of a COVID-19 infection despite receiv-
ing therapeutic anticoagulation with dabigatran. While
several studies have evaluated the use of anticoagulation in
the setting of COVID-19, recommendations for the use of
therapeutic DOACs in this setting have not been well estab-
lished. One study of 497 patients compared the use of antico-
agulation prior to admission with COVID-19 to assess for
overall survival and thrombotic events. Although this study
saw a low proportion of patients (less than 6%) in each group
with thrombotic events, hazard ratios showed a significantly
improved survival with the prior use of DOACs compared to
no anticoagulation. In a secondary analysis, this study also
found survival was significantly improved in patients over
the age of 70 who were previously prescribed a DOAC.
Additionally, all patients prescribed dabigatran in this study
survived; thus, the authors of the study identified dabigatran
as a potentially beneficial treatment needing further investi-
gation.4 Because this finding is in opposition of our patient
case, further investigation is warranted as it remains unclear
how to properly manage the anticoagulation regimen for
patients on a DOAC with COVID-19 to prevent VTE or ATE
events.
Conclusion
In conclusion, this case is the first to associate therapeutic
failure of dabigatran leading to extensive thrombosis with an
active COVID-19 infection. Evidence from this report sug-
gests clinicians should closely monitor patients at risk for
hypercoagulability regardless of the anticoagulation therapy
the patient may be receiving. Additionally, evidence from
this case suggests a possible inferiority of dabigatran-based
therapeutic anticoagulation in patients with COVID-19.
Further studies are warranted to establish appropriate antico-
agulation in the setting of COVID-19.
Acknowledgments
This material is the result of work supported with resources and
facilities of the U.S. Department of Veterans Affairs. The contents
do not represent the views of the U.S. Department of Veterans
Affairs or the United States Government. The authors have no con-
flicts of interest to disclose. Portions of this project have been
reported previously in abstract form.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect
to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
ORCID iDs
Robert C. Ross https://orcid.org/0000-0001-9721-6163
Abbie N. Rosen https://orcid.org/0000-0001-5196-8853
Andrew J. Franck https://orcid.org/0000-0003-3112-1334
References
1. D’Elia E, Gori M, Grosu A, et al. An unexpected case of recur-
rence of pulmonary embolism in a patient recovered from
COVID19 in full regimen dose of direct oral anticoagulant
drug. BMC Pulm Med. 2021;21:102. doi:10.1186/s12890-021-
01453-2
2. Hadid T, Kafri Z, Al-Katib A. Coagulation and anticoagula-
tion in COVID-19. Blood Rev. 2021;47:100761. doi:10.1016/j.
blre.2020.100761
3. Gómez-Mesa JE, Galindo-Coral S, Montes MC, Muñoz
Martin AJ. Thrombosis and coagulopathy in COVID-19.
Curr Probl Cardiol. 2021;46:100742. doi:10.1016/j.cpcar-
diol.2020.100742
4. Buenen AG, Sinkeldam M, Maas ML, Verdonschot M, Wever
PC. Prior use of anticoagulation is associated with a better sur-
vival in COVID-19. J Thromb Thrombolysis. 2021;52:1207-
1211. doi:10.1007/s11239-021-02486-4
5. Giannis D, Douketis JD, Spyropoulos AC. Anticoagulant
therapy for COVID-19: what we have learned and what are
the unanswered questions? Eur J Intern Med. 2022;96:13-16.
doi:10.1016/j.ejim.2021.11.003
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6. COVID-19 Treatment Guidelines Panel. Information on
COVID-19 treatment, prevention and research. National
Institutes of Health. Updated: May 31, 2022. Accessed January
24, 2022. https://www.covid19treatmentguidelines.nih.gov/
7. Surviving Sepsis Campaign Panel. COVID-19 guidelines.
Society of Critical Care Medicine. 2020. Accessed January 24,
2022. https://sccm.org/SurvivingSepsisCampaign/Guidelines/
COVID-19
8. Spyropoulos AC, Goldin M, Giannis D, et al. Efficacy and
safety of therapeutic-dose heparin vs standard prophylactic or
intermediate-dose heparins for thromboprophylaxis in high-
risk hospitalized patients with COVID-19: the HEP-COVID
randomized clinical trial. JAMA Intern Med. 2021;181:1612-
1620. doi:10.1001/jamainternmed.2021.6203
9. The ATTACC, ACTIV-4a, and REMAP-CAP Investigators.
Therapeutic anticoagulation with heparin in noncritically ill
patients with COVID-19. N Engl J Med. 2021;385:790-802.
doi:10.1056/NEJMoa2105911
10. Pradaxa (dabigatran etexilate mesylate) [package insert].
Boehringer Ingelheim Pharmaceuticals, Inc.; 2011.
11. Barletta JF, Bruno JJ, Buckley MS, Cook DJ. Stress ulcer pro-
phylaxis. Crit Care Med. 2016;44(7):1395-1405. doi:10.1097/
CCM.0000000000001872
12. Sebaaly J, Kelley D. Direct oral anticoagulants in obesity: an
updated literature review. Ann Pharmacother. 2020;54:1144-
1158. doi:10.1177/1060028020923584
13. Thomas AV, Lin KP, Stillson JE, et al. A case series of
thromboelastography-guided anticoagulation in COVID-19
patients with inherited and acquired hypercoagulable states.
Case Rep Med. 2021;2021:5568982. doi:10.1155/2021/556
8982
14. Hartmann J, Ergang A, Mason D, Dias JD. The role of TEG
analysis in patients with COVID-19-associated coagulopathy:
a systematic review. Diagnostics. 2021;11:172. doi:10.3390/
diagnostics11020172
15. Lopez P, Velez R, Rivera V, Rodriguez N, Yamamura Y.
Characteristics of p-glycoprotein (pgp) upregulated in chronic
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2005;2:142.
16. Illanes-álvarez F, Márquez-Ruiz D, Márquez-Coello M,
Cuesta-Sancho S, Girón-González JA. Similarities and dif-
ferences between HIV and SARS-CoV-2. Int J Med Sci.
2021;18(3):846-851. doi:10.7150/ijms.50133
17. Bibas M, Biava G, Antinori A. HIV-associated venous thrombo-
embolism. Mediterr J Hematol Infect Dis. 2011;3(1):e2011030.
doi:10.4084/MJHID.2011.030
1104367
case-report2022
HPXXXX10.1177/00185787221104367Hospital PharmacyAnderson et al

Case Report

Hospital Pharmacy

Calcium and Phosphate Solubility Curve

2022, Vol. 57(6) 779­–785
© The Author(s) 2022
Article reuse guidelines:
Equation for Determining Precipitation sagepub.com/journals-permissions
DOI: 10.1177/00185787221104367
https://doi.org/10.1177/00185787221104367

Limits in Compounding Parenteral journals.sagepub.com/home/hpx

Nutrition

Collin Anderson1 , Larry Eggert2, Kristie Fitzgerald3,

Daniel Jackson4, and Fred Farr1

Abstract

Clinicians have published research and reports on calcium and phosphate solubility within parenteral nutrition (PN) for
over 40 years. Foundational empirical laboratory investigation in the 1980s motivated by the prevalence of neonatal rickets
and osteomalacia in the Neonatal Intensive Care Unit (NICU) population led to precipitation curves that have guided PN
prescribing and compounding. Over subsequent decades, numerous publications have expanded the knowledge of factors
influencing calcium and phosphate solubility in formulating optimal and safe PN admixtures. Failure to adhere to known
principles has led to serious injury and death. Known solubility curves are derived from empiric analysis of a finite number
of conditions and concentrations, whereas custom PN orders vary widely and rarely match the admixture composition in
the data set used to derive the published precipitation curves. Various commercial platforms have been developed to aid
the pharmacist in assessing the potential for precipitation when evaluating a PN order. Some applications plot the calcium
and phosphate concentrations of the prescribed PN against known published graphs most similar to the order, allowing
the pharmacist to judge the risk of precipitation. Other approaches use intellectually protected trade secret algorithms to
determine calcium and phosphate solubility across a continuum of conditions. This publication reports equations that have
been used successfully for over 2 decades in our regional network of NICUs and shared with others to determine safe
prescribing limits for calcium and phosphate concentrations using an electronic PN prescribing program.

Keywords
nutrition, nutritional support, intravenous therapy, pediatrics

Prescribing and compounding parenteral nutrition PN admix-
tures is a high-risk process due to the complexity of the large
number of components, the wide range of concentrations, and
the various additives prescribed to meet clinical demands of
therapy.1 To help guide professionals in the safe provision of
PN therapy, the American Society for Parenteral and Enteral
Nutrition (A.S.P.E.N.) has published recommendations.2
These guidelines emphasize the need for all formulations to
be evaluated for risk of calcium and phosphate precipitation.
Early work within PN formulations determined pH to be a
predominant factor in calcium and phosphate solubility.3 At
lower pH, the monobasic phosphate ion (H2PO4−) prevails
allowing solubility with calcium 60-fold greater than the
dibasic phosphate ion (HPO42−), which predominates at
higher pH.4 In addition to the pH and calcium/phosphate con-
centrations, the amino acid concentration, amino acid prod-
uct, form of calcium utilized, and temperature also influence
calcium and phosphate solubility.5 Since amino acid solutions
are the principle acidic component of PN, amino acid
composition and pH are linked variables. Studies show that
the precipitation curves became more favorable, that is, cal-
cium-phosphate solubility increases, with increased amino
acid concentrations and decreased pH.6,7 Original research
studied various amino acid products at discrete concentra-
tions within PN.3,6,8-11 Historically, the pharmacist would
compare an individual patient’s order against the most closely
matched reference precipitation curves from published
sources. Over time software was developed that would auto-
matically plot the calcium and phosphate concentrations of a
1
Primary Children’s Hospital, Salt Lake City, UT, USA
2
Intermountain Healthcare, Salt Lake City, UT, USA
3
Salt Lake Community College, Salt Lake City, UT, USA
4
University of Utah Health, Salt Lake City, UT, USA
Corresponding Author:
Collin Anderson, Primary Children’s Hospital, 100 N Mario Capecchi
Drive, Salt Lake City, UT 84113-1100, USA.
Email: collin.anderson@imail.org
780 Hospital Pharmacy 57(6)
Table 1.  Assigned Amino Acid Factor Values by Source Product.
Commercial amino acid product Assigned amino acid factor
Aminosyn PF, Premasol, 200
TrophAmine
Aminosyn II, Clinisol, Travasol 100
prescribed PN against known curves.12 Because an ordered
PN rarely matches the published curves within the software,
the pharmacist must still make a judgment regarding the
potential for precipitation of the ordered product. Industry has
developed certain intellectually protected algorithms based
on published precipitation curves.13 These unpublished algo-
rithms are used to stop an order from being placed that would
have a high potential for precipitation. We report equations
utilized in an electronic PN prescribing program to prospec-
tively determine if an order for PN is likely to precipitate.
Methods
Equations were developed according to mathematical prin-
ciples to match the general hyperbolic shape of published
curves, incorporating those elements most strongly influenc-
ing the buffering capacity and pH of a PN admixture.
A numeric value, referred to as the precipitation limit, is
assigned to each PN order according to the following
formulas:
Equation 1: 2-in-1 PN that will be run separate from fat
emulsion
Precipitation limit = AAF + ( CYS*AAF ) /100
Equation 2: 2-in-1 PN with y-site administration with fat
emulsion
Precipitation limit = AAF + ( CYS*AAF ) /
100 − ( FIR*FIT*FPP*AAF ) / ( AA*WT*1000 )
Equation 3: 3-in-1 PN
Precipitation limit = AAF + ( CYS*AAF ) /
100 − ( FAT*AAF ) / ( AA*10 )
AAF = amino acid factor (a constant empirically assigned to
an amino acid product based on its reported pH and pub-
lished precipitation curves, see Table 1). CYS = cysteine
amount ordered in mg/g amino acid; FIR = fat emulsion infu-
sion rate in mL/h; FIT = fat emulsion infusion time in h/d;
FPP = % fat emulsion of the commercially provided product
(usually 20); FAT = fat emulsion amount ordered in g/kg;
AA = amino acid amount ordered in g/kg; WT = weight in kg.
A solution factor is assigned to each PN order:
Equation 4: Solution factor
( calcium gluconate in mEq/L)0.863 * 
Solution Factor =  /
( inorganic phosphate in mmol/L )1.19 
 
( final AA% )
The solution factor value is compared to the precipitation
limit value. The calcium and phosphate within the PN admix-
ture is considered compatible if the solution factor value is
less than the precipitation limit value.
Example for 2-in-1 PN with y-site administration with fat
emulsion
1 kg neonate
3.5 g/kg of amino acid (Trophamine or Premasol)
40 mg cysteine per g of amino acids
3 g/kg of fat emulsion (20%) run over 24 hours (0.63 mL/
hour) y-site administration with PN
Calcium 3.6 mEq/kg
Phosphates 1.8 mmol/kg
Volume of 2-in-1 PN 120 mL/kg
Precipitation limit = 200 + (40 * 200)/100 − (0.63 * 24 * 20 
* 200)/(3.5 * 1 * 1000) = 262.7
Solution factor = (300.863 * 151.19)/2.92 = 161.8
The solution factor value (161.8) is less than the precipita-
tion factor value (262.7), therefore the calcium and phos-
phate within the solution is determined to be compatible at
standard storage and administration temperatures.
Example for 3-in-1 PN
30 kg adolescent
1.6 g/kg of Travasol
0.9 g/kg of fat emulsion (20%)
Calcium 1 mEq/kg
Phosphates 0.9 mmol/kg
Volume of 3-in-1 PN 75 mL/kg
Precipitation limit = 100 + (0 * 100)/100 – (0.9 * 100)/
(1.6 * 10) = 94.4
Solution factor = (13.330.863 * 121.19)/2.13 = 84.4
The solution factor value (84.4) is less than the precipita-
tion factor value (94.4), therefore the calcium and phosphate
within the PN is determined to be compatible at standard
storage and administration temperatures.
Discussion
Published calcium and phosphate precipitation curves are a
key safety component of PN. Some have suggested develop-
ment of probability-based curves and logistic regression
analysis be applied when developing new curves.14 The phar-
macist is responsible for assessing calcium and phosphate
solubility during verifying and compounding of PN orders.
Anderson et al 781
Figure 1.  TrophAmine 1.5% and 2% with 10% dextrose
parenteral nutrition original published curves.
Original precipitation curves were developed using a small
number of representative PN admixtures at finite concentra-
tions of calcium and phosphate. Custom PN order combina-
tions are vast and therefore do not match the limited number
of published PN calcium and phosphate curves. Extrapolation
of published results is required to make a determination
regarding compatibility for any admixture that deviates from
the representative samples. In practice a unique PN order
rarely matches the exact precipitation curve parameters that
were tested in the laboratory. For example each of the origi-
nal TrophAmine precipitation curves, which continue to be
referenced today, were compiled from 20 distinct data points.
In reality practitioners are required to make daily judgment
calls in the precipitation potential of a vast number of PN
orders that fail to match the exact conditions tested in the
laboratory. Figure 1 shows the original 2% and 1.5%
TrophAmine curves. If a patient has an order for a 1.8%
TrophAmine, 17% dextrose, with 20 mEq/L of calcium and
20 mmol/L of phosphate, there is not a curve to reference for
this admixture. The practitioner can use the 1.5%
TrophAmine, 10% dextrose curve, and deem the formula
incompatible because the calcium and phosphate are in the
incompatible zone. Alternatively, the practitioner could look
at the 2% TrophAmine, 10% dextrose curve, and deem the
formula compatible.
Approximately 4 decades ago a team at our institution
began developing equations to define limits for calcium and
phosphate additives that apply to a continuum of custom PN
orders. The equations evaluate calcium gluconate and inor-
ganic phosphate concentrations and incorporate the driving
factors of source amino acid, amino acid concentration in the
final product, addition of cysteine with its pH lowering
effect, and the addition of alkaline fat emulsions. Dextrose
concentration was shown to have a lesser effect on calcium
and phosphate solubility than amino acid concentration in
early studies.15,16 The equations presented herein do not
include dextrose as a variable and were conservatively devel-
oped to maintain solubility regardless of dextrose amount.
They have been successfully utilized in practice in admix-
tures containing 0% to 30% dextrose. The calculations were
developed to accommodate a continuum of amino acid, fat
emulsion and cysteine concentrations within a PN order and
were built into the computerized ordering software to pre-
vent order submission when pre-defined calcium and phos-
phate concentration limits are exceeded. Rather than rely on
inconsistent extrapolation of the finite number of published
curves to an infinite number of PN formulations, the equa-
tions provide a consistent approach to evaluating precipita-
tion potential based on the published curves. The equations
were developed to match the general hyperbolic shape of the
published curves. Key to this approach was assigning an
amino acid factor to each amino acid product. The larger the
amino acid factor, the more the equation curve moves up and
to the right. The amino acid factors were assigned based on
published precipitation curves for each individual amino
acid product. The factor was assigned conservatively to
ensure a buffer between the original precipitation curve and
the assigned precipitation limit according to the developed
equation. Development of the equations allows for the sys-
tematic and consistent evaluation of numerous combinations
of PN admixtures, for which there are no exact matches
within published literature. Validation of the equation’s util-
ity in predicting the solubility of calcium and phosphate
within PN has occurred in their actual use in clinical practice.
Over their decades of use in our multi-hospital healthcare
system, caring for both inpatient and homecare patients,
there has not been a report of calcium and phosphate precipi-
tation related to the utilization of the equations. Our system
has utilized filters, according to recommendations of national
societies, and these filters have not occluded nor shown signs
of calcium and phosphate precipitates.
To provide an example of the empirical calculations
to literature precipitation limits, Figures 2 to 9 compare his-
torical TrophAmine published curves with program curve
limits as dictated by equations 1 through 4.6 The original
TrophAmine curves were based on microscopy visualized of
precipitation in a set of PN admixtures. Equations developed
for the computerized physician order entry system were con-
structed to be slightly more restrictive than the published
precipitation curves to allow for variability in compounding
accuracy in the original test formulations as well as in cur-
rent clinical practice. Application of the equations results in
hyperbolic curves, which follow the general shape of the
finite point determinations from the original research.
The empirically developed equations account for continu-
ous concentrations of amino acid, fat emulsion, cysteine,
782 Hospital Pharmacy 57(6)
Figure 2.  TrophAmine 1.5% with 10% dextrose parenteral
nutrition.
Figure 3.  TrophAmine 1.5% with 10% dextrose and 12%
Intralipids parenteral nutrition.
calcium, and phosphates seen within custom PN orders. For
example, Figures 10 and 11 illustrate how defined calcium
and phosphate limits within the prescribing software are
influenced by changes in the final amino acid or cysteine
concentrations, respectfully. The program calculations allow
precipitation potential to be evaluated at any point within the
continuum of amino acid concentrations. The empiric curves
have been used in practice with the historical generic cyste-
ine product as well as the 2019 FDA approved product at
Figure 4.  TrophAmine 1.5% with 10% dextrose and cysteine
(40 mg/g amino acids) parenteral nutrition.
variable doses during shortages and as our institution
changed dosing strategies based on new package labeling
and current research.17-19 The equations have also been used
in practice across vitamin and trace element product refor-
mulations that manufacturers have made in response to
requests from the PN community as well as with the various
FDA approved fat emulsions.
The equations presented herein have been used to guide
risk of precipitation in hundreds of thousands of PN orders in
real world settings both within the hospital and for home care
preparations. Within our acute care settings the admixtures
have been utilized with 24 hours hang times and nurses are
trained to avoid hanging admixtures next to heat sources.
Homecare products undergo typical storage under refrigera-
tion prior to being brought to room temperature for infusion
within the patients’ home environments. The PN ordering
program places a hard stop on any admixture for which the
solution factor exceeds the precipitation factor. The practitio-
ner is therefore able to adjust the PN order at time of entry,
with feedback prompts, to achieve a calcium/phosphate com-
patibility before the order is sent to the compounding phar-
macist. Practical utilization of the empiric calculations has
occurred over a broad range of PN orders for more than
20 years.7
Conclusion
Ensuring calcium and phosphate solubility within PN is criti-
cal for patient safety and outcomes. Published calcium and
phosphate solubility curves provide a foundation for safe
Anderson et al 783

Figure 5.  TrophAmine 1.5% with 10% dextrose, 12% Intralipids, and cysteine (40 mg/g amino acids) parenteral nutrition.

Figure 7.  TrophAmine 2% with 10% dextrose and 12%

Intralipids parenteral nutrition.
Figure 6.  TrophAmine 2% with 10% dextrose parenteral nutrition.
784 Hospital Pharmacy 57(6)
Figure 8.  TrophAmine 2% with 10% dextrose and cysteine
(40 mg/g amino acids) parenteral nutrition.
Figure 9.  TrophAmine 2% with 10% dextrose, 12% Intralipids,
and cysteine (40 mg/g amino acids) parenteral nutrition.
administration of PN. Equations have been developed to pre-
dict calcium and phosphate solubility across a continuum of
conditions. These equations have been successfully utilized
within an electronic PN prescribing program for more than 2
decades across numerous facilities.
Figure 10.  Predicted calcium and phosphate program limits at
varying TrophAmine concentrations, 2-in-1 parenteral nutrition
solution.
Figure 11.  Predicted calcium and phosphate program limits
at varying cysteine concentrations, 3% TrophAmine 2-in-1
parenteral nutrition solution.
Declaration of Conflicting Interests
The author(s) declared the following potential conflicts of interest with
respect to the research, authorship, and/or publication of this article:
Collin Anderson: Consultant for Baxter on a limited basis (<10 hours
per year) for a product which is not a part of this manuscript.
Anderson et al 785
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
ORCID iD
Collin Anderson https://orcid.org/0000-0001-9441-3663
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and phosphorus solubility in neonatal intravenous feeding
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1108719
research-article2022
HPXXXX10.1177/00185787221108719Hospital PharmacyRaimonde and Dennis

Case Report

Hospital Pharmacy

Carvedilol-Induced Thrombocytopenia:
2022, Vol. 57(6) 786­–789
© The Author(s) 2022
Article reuse guidelines:
A Case Report sagepub.com/journals-permissions
DOI: 10.1177/00185787221108719
https://doi.org/10.1177/00185787221108719
journals.sagepub.com/home/hpx

Angelina R. Raimonde1 and Anthony K. Dennis1

Abstract

Thrombocytopenia is a commonly encountered complication of hospitalized patients, and can be caused by many factors
including infections, surgery, and medications. Drug-induced thrombocytopenia (DITP) should be considered when a patient
presents with an unexpected occurrence of thrombocytopenia. Many drugs can induce thrombocytopenia either as a direct
effect on thrombopoiesis within the bone marrow or by drug-dependent antibody-mediated destruction of platelets within
the circulation. We present the case of a 44-year-old female who presented with 2 weeks of nausea, vomiting, and headaches
occurring with her hemodialysis sessions. On admission she was found to be thrombocytopenic with a platelet count of 35 K/µL.
Her last known normal platelet count was 299 K/µL from 2 months prior. A thorough work up of her thrombocytopenia was
found to be unremarkable. Her newly started carvedilol was thought to be the most likely cause based on the rapid platelet
recovery upon drug discontinuation and negative workup of other potential causes.

Keywords
carvedilol, thrombocytopenia, beta-blocker, platelets, heparin-induced thrombocytopenia

Introduction carbamazepine, ceftriaxone, ibuprofen, mirtazapine, oxali-

Thrombocytopenia is defined as a platelet count less than
150 000 per microliter (K/µL) and can be caused by many
factors ranging from inherited conditions, cancer and its
associated treatment, infections, surgery, and medication
use. The associated risk of bleeding is of concern when the
platelet count becomes as low as 10 to 20 K/µL, which would
warrant increased monitoring and work-up of the thrombo-
cytopenia. The first sign of symptomatic thrombocytopenia
is usually external bleeding evidenced by skin bruising,
known as purpura or petechiae, prolonged bleeding from
minor cuts, vaginal bleeding, and/or oral and nasal bleeding.
The concern for more serious internal bleeding increases
when patients experience blood in their urine or stool.
Determining the underlying cause of the thrombocytopenia
can be challenging due to the many factors that can cause it.1
Drug-induced thrombocytopenia (DITP) should always
be considered when a patient presents with an unexpected
occurrence of severe thrombocytopenia. Many drugs can
induce thrombocytopenia either as a direct effect on throm-
bopoiesis within the bone marrow or by drug-dependent
antibody-mediated destruction of platelets within the circula-
tion.2-4 A systematic review of individual patient data found
that over 300 drugs have been associated with causing
thrombocytopenia, including quinine, quinidine, trime-
thoprim/sulfamethoxazole, vancomycin, penicillin, rifampin,
platin, glycoprotein IIb/IIIa inhibitors, and heparin.3
Chemotherapeutic agents commonly cause thrombocytope-
nia due to their direct effects on hematopoietic stem cells.
Additionally, linezolid has been found to cause dose-depen-
dent thrombocytopenia due to myelosuppression, and hepa-
rin induces thrombocytopenia due to antibodies present
within circulation.3,4 Of these drugs, beta blockers are not
usually associated with thrombocytopenia. We report the
case of a female patient with new onset thrombocytopenia
after the recent initiation of carvedilol.
Case Presentation
A 44-year-old Caucasian female presented with 2 weeks of
nausea, vomiting, and headaches occurring with her hemodi-
alysis sessions. Her past medical history included end-stage
renal disease (ESRD) on hemodialysis 3 times weekly,
Crohn’s disease, type 1 diabetes mellitus, osteomyelitis of
the right lower extremity status post right below-the-knee
1
Rush University Medical Center, Chicago, IL, USA
Corresponding Author:
Angelina R. Raimonde, Department of Pharmacy, Rush University Medical
Center, 1653 Congress Pkwy, Chicago, IL 60612-3801, USA.
Email: angelina_r_raimonde@rush.edu
Raimonde and Dennis 787
amputation, and recently diagnosed hypertension. Upon pre-
sentation to the emergency department, she was found to
have thrombocytopenia of unknown origin that necessitated
further workup. Her platelet count was 35 K/µL on admis-
sion, and her last known normal platelet count was 299 K/µL
from 2 months prior. Her prior to admission medication list
included carvedilol 12.5 mg twice daily, which was started
approximately 2 weeks prior to admission, cyanocobalamin
1000 mcg IM once monthly, and insulin lispro via insulin
pump. She was admitted to an outside hospital 1 month prior
to admission for the amputation of her right lower extremity
and received vancomycin and cefepime as pre- and post-
operative antibiotics. The patient had no personal or family
history of autoimmune disorders, thrombocytopenia or
hematologic malignancy.
Her complete blood count (CBC) with differential was
found to be within normal limits, except for the following: red
blood cells (RBC) 3.98, hemoglobin 11.6, mean corpuscular
hemoglobin concentration (MCHC) 29.9, and red cell distribu-
tion width (RDW) 16.7. Her basic metabolic panel (BMP) was
also within normal limits, except for abnormal serum creati-
nine and blood urea nitrogen (BUN) due to ESRD. GI/liver
labs, iron studies (despite iron saturation of 19), and vitamin
B12 level were all within normal limits. A peripheral smear and
morphology of the patient’s platelets was performed and
resulted in normal appearing platelets with normal granularity.
The initial differential diagnoses included drug-induced throm-
bocytopenia (DIT) versus heparin-induced thrombocytopenia
(HIT) versus thrombotic thrombocytopenic purpura (TTP) ver-
sus immune thrombocytopenic purpura (ITP). The prospective
work-up included hemolysis labs, HIV panel, HCV and HBV
panels, autoimmune profile, hematology consult, and HIT-
antibody since the patient believed unfractionated heparin was
used during her dialysis sessions. Given the patient’s normal
bilirubin, haptoglobin, and only mildly elevated LDH, throm-
botic angiopathies, such as TTP and hemolytic uremic syn-
drome (HUS), were ruled out.
A 4 T-score of 5 was calculated, which is categorized as
intermediate risk. She received 2 points for having a platelet
fall greater than 50% and a platelet nadir of greater than
20 000. She received one point for a platelet fall consistent
with days five through 10, but not clear as the patient did
state she received heparin with her hemodialysis sessions.
She received zero points for active thrombosis. Finally, she
received 2 points for not having any alternative causes of
thrombocytopenia. Per the HIT protocol at Rush University
Medical Center, a HIT-antibody was ordered on day 1 of hos-
pitalization, which resulted as negative with an optical den-
sity of 0.191. No serotonin-release assay (SRA) was ordered
per the protocol, since HIT was deemed unlikely based on
the negative HIT-antibody.
On day 2 of hospitalization, carvedilol was held as a
possible cause of thrombocytopenia since this was the only
new medication for the patient and had been started
approximately 2 weeks prior to the patient’s presentation.
Further work-up for ITP was unremarkable due to the lack
of platelet clumping or morphologic abnormalities. HIV
panel resulted as undetectable, as were hepatitis C virus
antibody and hepatitis B surface antigen. Helicobacter
pylori antigen was also not detected. Thyroid-stimulating
hormone (TSH) was 2.18. Her autoimmune profile (C reac-
tive protein, rheumatoid factor, C3, C4, and antinuclear
antibodies screen) was unremarkable, and immunoglobulin
G antibody was less than 14 and within normal limits. By
the third day of hospitalization, the patient’s platelets had
more than doubled to 86, and continued to rise to 189 by
discharge. Amlodipine was started prior to discharge to
replace carvedilol, and this was well tolerated.
Discussion
Drug-induced thrombocytopenia typically occurs around 5
to 10 days after initial drug administration with a median
platelet nadir of about <20 × 109/L2. Determining the
offending drug can be difficult since patients are typically on
several medications at a time. Bakchoul et al2 discuss 5 clini-
cal criteria that may help in the establishment of probable
drug-induced thrombocytopenia: (1) exposure to the drug
occurred prior to thrombocytopenia; (2) recovery was com-
plete and sustained upon discontinuation of that drug; (3) the
drug was the only new drug started prior to the thrombocyto-
penic episode or other drugs were continued or reintroduced
after discontinuation of the suspected drug with sustained
normal platelet counts; (4) other causes of thrombocytopenia
were ruled out, and (5) re-exposure to the suspected drug
resulted in recurrent thrombocytopenia. Similarly, the
Naranjo et al5 adverse drug reaction probability scale is one
of the most widely used causality assessment tools. This
scale consists of 10 questions that, when totaled, provide a
final score that is associated with one of 4 categories of like-
lihood that the drug was associated with the reaction: doubt-
ful, possible, probable, or definite. Treatment of drug-induced
thrombocytopenia necessitates drug discontinuation and
monitoring of platelets, but in instances of significant dis-
ease, high doses of intravenous immunoglobulin can be
given to patients at high risk of bleeding or with evidence of
bleeding. However, only 2 case reports have been published
about using intravenous immunoglobulin in these instances.6,7
Upon discontinuation of the suspected drug, platelet counts
can start to improve after 4 to 5 half-lives of the drug and/or
drug metabolite.2
The mechanism behind beta-blocker-associated throm-
bocytopenia is not fully understood, but its proposed mecha-
nism may be immunologic in nature owing to positive
platelet-reactive antibody testing or reduced platelet pro-
duction.8,9 Metoprolol, sotalol, labetalol, carvedilol, ateno-
lol, and propranolol are the 6 beta blockers that have been
tested at the Wisconsin Blood Center for platelet-reactive
788 Hospital Pharmacy 57(6)
Table 1.  Platelet trend during admission.
Day 1 Day 2 Carvedilol stopped Day 3 Day 4
35 44   86 95
43
antibodies between 1995 and 2018.10 Only atenolol and pro-
pranolol yielded positive results. Furthermore, no standard
testing assays, criteria for differentiating positive and nega-
tive results, and data on sensitivity and specificity of these
assays have been established.11
The Naranjo score for our patient was 6, suggesting a
probable association between carvedilol and the patient’s
thrombocytopenia. After a thorough literature search on
PubMed using the search terms “thrombocytopenia, beta
blockers, carvedilol,” 2 case reports were found regard-
ing thrombocytopenia with carvedilol use. Alex et al12
reported their patient was also recently started on
carvedilol and experienced a platelet drop of about
151 000 within 19 days of therapy initiation. Once the
patient had been switched from carvedilol to metoprolol,
the platelet count improved in as little as 24 hours.
Similarly, their Naranjo score was 8, indicating carvedilol
was the probable cause of their patient’s thrombocytope-
nia. James et al13 reported the case of a hospitalized
patient who was initiated on ceftriaxone, doxycycline,
metformin, insulin, furosemide, carvedilol, losartan, and
nebulizer treatments. By day 3, the patient had progres-
sive thrombocytopenia, with a negative work up for
Dengue and chronic liver disease. Ceftriaxone, doxycy-
cline and furosemide were held on day 5, however plate-
lets continued to decline. It was not until carvedilol was
held that the platelets began to recover over the next 24 to
48 hours. Platelets had returned to normal at her 14 days
follow up visit.14 Our patient also displayed rapid recov-
ery of her platelets the day after discontinuing carvedilol,
as shown in Table 1. Her platelets had doubled from day
one to day three and continued to uptrend throughout the
remainder of her inpatient stay. Carvedilol has a half-life
of about 6 hours, so platelet recovery within 24 hours
seems appropriate. The carvedilol package insert reports
a 1% to 3% incidence of thrombocytopenia from the clin-
ical trials.
Conclusion
A 44-year-old female developed new onset thrombocytope-
nia after the recent initiation of carvedilol for newly diag-
nosed hypertension. Carvedilol was determined to be the
most likely cause based on the rapid platelet recovery upon
drug discontinuation, and negative workup of other potential
causes. Prior to hospital discharge, the patient was trialed on
Day 5 Day 6 Day 7 Day 8 Day 9
128 139 171 153 189
amlodipine for blood pressure management, which was well
tolerated. Carvedilol-induced thrombocytopenia is rare, and
not well understood as there have only been 2 other cases
reported in the literature to date.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship, and/or publication of this
article.
Funding
The author(s) received no financial support for the research, author-
ship, and/or publication of this article.
Ethics
Informed consent was obtained from the study subject.
ORCID iDs
Angelina R. Raimonde https://orcid.org/0000-0003-3265-1628
Anthony K. Dennis https://orcid.org/0000-0002-8146-4813
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