CLINICAL REVIEW

The pathophysiology of sepsis — 2021 update: Part 2,

organ dysfunction and assessment

Judith Jacobi, PharmD, FCCP,
MCCM, BCCCP, Visante, Lebanon, IN,
USA
Downloaded from https://academic.oup.com/ajhp/article/79/6/424/6397593 by Welch Medical Library, Johns Hopkins University user on 06 June 2022
Purpose. This is the second article in a 2-part series discussing the
pathophysiology of sepsis. Part 1 of the series reviewed the immunologic
response and overlapping pathways of inflammation and coagulation that
contribute to the widespread organ dysfunction. In this article (part 2),
major organ systems and their dysfunction in sepsis are reviewed, with
discussion of scoring systems used to identify patterns and abnormal vital
signs and laboratory values associated with sepsis.

Summary. Sepsis is a dysregulated host response to infection that pro-

duces significant morbidity, and patients with shock due to sepsis have
circulatory and cellular and metabolic abnormalities that lead to a higher
mortality. Cardiovascular dysfunction produces vasodilation, reduced car-
diac output and hypotension/shock requiring fluids, vasopressors, and
advanced hemodynamic monitoring. Respiratory dysfunction may require
mechanical ventilation and attention to volume status. Renal dysfunction
is a frequent manifestation of sepsis. Hematologic dysfunction produces
low platelets and either elevation or reduction of leukocytes, so consider-
ation of the neutrophil:lymphocyte ratio may be useful. Procoagulant and
antifibrinolytic activity leads to coagulation that is stimulated by inflam-
mation. Hepatic dysfunction manifest as elevated bilirubin is often a late
finding in sepsis and may cause reductions in production of essential pro-
teins. Neurologic dysfunction may result from local endothelial injury and
systemic inflammation through activity of the vagus nerve.

Conclusion. Timely recognition and team response with efficient use of

therapies can improve patient outcome, and pharmacists with a complete
understanding of the pathophysiologic mechanisms and treatments are
valuable members of that team.

Keywords: coagulopathy, inflammation, organ dysfunction, sepsis, septic

shock, SOFA score

Am J Health-Syst Pharm. 2022;79:424-436

P art 1 of this clinical review covered

Address correspondence to Dr. Jacobi
(jjacobi@visanteinc.com).
Twitter: @judijacobi
© American Society of Health-System
Pharmacists 2021. All rights reserved.
For permissions, please e-mail: journals.
permissions@oup.com.
https://doi.org/10.1093/ajhp/zxab393
the cellular-level impact of sepsis,
a dysregulated response to infection
leading to inflammation, coagulopathy,
endothelial injury, and a prolonged
anti-inflammatory state.1 Part 2 will
discuss the injury to multiple organs
that occurs in sepsis along with use of
biomarkers and measures to identify
the injury, with discussion of therapy
for adults. Sepsis is defined as a life-
threatening organ dysfunction due to
dysregulated host response to infec-
tion, and the term septic shock refers to
a subset of patients with circulatory and
cellular/metabolic abnormalities that
lead to higher mortality. The definition
of sepsis continues to evolve, with new
terms and definitions currently focusing
on sepsis, organ dysfunction, and septic
shock.2 The term severe sepsis is no longer
used. Pharmacists have key roles in the
management of patients with sepsis and
are well suited to provide input on all
aspects of therapy, as reviewed in de-
tail in the International Surviving Sepsis
Campaign Guidelines (SSCG).3 During
resuscitation, pharmacists can facilitate
timely and appropriate administration of
antimicrobials, fluids, vasoactive agents,

424 AM J HEALTH-SYST PHARM | VOLUME 79 | NUMBER 6 | MARCH 15, 2022

 PATHOPHYSIOLOGY OF SEPSIS, PART 2
and other supportive care therapies.
A  sepsis response team with pharma-
cist participation has been shown to
reduce order turnaround time, time
to antimicrobial administration, and
sepsis-related mortality.4 Pharmacists
should be familiar with the pathophysi-
ology of sepsis-induced organ dysfunc-
tion to maximize their involvement
and contributions to optimizing patient
outcomes. Prompt recognition of sepsis-
related organ dysfunction and an under-
standing of the underlying mechanisms
of injury can assist clinicians in the se-
lection and initiation of optimal thera-
peutic agents. Therapeutic interventions
are not discussed in detail in this paper
but guidance is available through nu-
merous other sources.3-5 Throughout the
hospitalization of a patient with sepsis,
pharmacists continue to contribute with
antimicrobial and fluid de-escalation,
therapeutic drug monitoring and dose
adjustment, interpreting coagulation
assays for optimal anticoagulation, and
other aspects of comprehensive medica-
tion management.
Diagnosis of sepsis
Signs and symptoms of sepsis
are nonspecific and include fever/
chills/rigor, confusion, anxiety, diffi-
cult breathing, fatigue/malaise, and
nausea/vomiting, so more specific
criteria that incorporate laboratory
testing, imaging, and physical examin-
ation have been established. The sys-
temic inflammatory response (SIRS)
criteria (fever/hypothermia, tachy-
cardia, tachypnea, and leukocytosis/
leucopenia) may indicate the pres-
ence of infection/inflammation but
are not predictive of outcome and are
nonspecific. Several other tools have
been devised to improve diagnostic
effectiveness, with varying degrees of
validity. These include the National
Early Warning Score (NEWS and
NEWS2), Sequential [Sepsis-related]
Organ Failure Assessment (SOFA) and
modified version, and the quick SOFA
(qSOFA).2,7-10 Versions of the NEWS
and NEWS2 appear to be more useful
in identifying severe sepsis and septic
shock during emergency department
KEY POINTS
• Systemic inflammation and
coagulopathy contribute to
multiple organ dysfunction in
sepsis that can be quantified
with validated scoring systems
such as the quick Sequential
Organ Failure Assessment
method for prognostication.
• Pharmacists should under-
stand the pathophysiology
of organ dysfunction to more
effectively manage medica-
tions that may be affected by
or contribute to the injury.
• Biomarkers are increasingly
useful in the assessment of
patients with sepsis, and more
precise descriptions of the
sepsis phenotype will facilitate
application of patient-specific
therapies.
triage, but these tools have not been en-
dorsed for this use and only the NEWS2
(Table 1) should be used.7-9 Artificial
intelligence strategies using decision
support and machine learning to iden-
tify patients with impending sepsis are
being tested, but it is too early to de-
termine their effectiveness and gener-
alizability.11 Thus a variety of tools and
clinical criteria are used to diagnose
sepsis. The Centers for Medicare and
Medicaid Services (CMS) sepsis core
measure (SEP-1) now includes patients
with an International Classification
of Diseases, 10th Revision, Clinical
Modification (ICD-10-CM) diagnostic
code for sepsis, severe sepsis, or septic
shock, leaving the choice of scoring
system up to each site.12 There are many
major organ systems that are the focus
of assessment and monitoring in sepsis,
including cardiovascular, respiratory,
renal, neurologic, hematologic, and
hepatic systems (Figure 1). The degree
of dysfunction may be quantified using
the SOFA, a validated intensive care
unit (ICU) mortality prediction scoring
AM J HEALTH-SYST PHARM | VOLUME 79
CLINICAL REVIEW
system, and the qSOFA (Table1).2,10 The
qSOFA is a modified approach that was
designed to identify patients with sepsis
who are at high risk for a poor outcome
(as indicated by a qSOFA score of ≥2) if
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treated outside the ICU but was not de-
signed for diagnosis of sepsis and has
less prognostic accuracy than the SOFA
score.10,13,14
Organ dysfunction
The source of organ dysfunction in
sepsis is multifaceted. As described in
part 1 of this series, the microcircula-
tion can be altered by increased leuko-
cyte adhesion, endothelial dysfunction,
microvascular thrombosis, increased
permeability, rheologic alterations, and
altered perfusion.1 These contribute to
organ dysfunction because of cellular
hypoxia and mitochondrial injury. For
clinicians, the focus is typically on clin-
ically measurable, macrovascular al-
terations such as reduced perfusion
pressure, redistribution of organ blood
flow, and shunting of oxygenated blood
through high-flow vessels and away
from lower-flow areas. Unfortunately,
bioenergetic failure at the cellular level
may persist after restoration of blood
flow to tissues, with continued inflam-
mation/coagulation of the endothelium.
Sepsis treatment
Early identification of sepsis and
prompt initiation of therapy are im-
portant factors influencing patient
outcomes. The SSCG place an em-
phasis on use of treatment bundles
following early identification, initi-
ation of diagnostic procedures and
therapy within 1 hour, and periodic
reassessment with specific targets for
fluid volume and other endpoints.3-5
Important elements in the 1-hour
bundle are to measure lactate, obtain
blood cultures prior to antimicrobials,
initiate broad-spectrum antibiotics,
start rapid fluid resuscitation for
hypotension or lactate elevation
(≥4  mmol/L), and vasopressors to
achieve or maintain a mean arterial
pressure (MAP) of ≥66 mm Hg. These
elements are illustrated in a variety of
tools available in the SSCG.5
| NUMBER 6 | MARCH 15, 2022 425
 CLINICAL REVIEW PATHOPHYSIOLOGY OF SEPSIS, PART 2

Figure 1. Sepsis-induced organ dysfunction and potential therapies. See Table 1 for specific laboratory abnormalities
that characterize each organ dysfunction.

Compromised blood brain barrier = Delirium, Encephalopathy

Downloaded from https://academic.oup.com/ajhp/article/79/6/424/6397593 by Welch Medical Library, Johns Hopkins University user on 06 June 2022
Acute lung injury = Hypoxia, Hypercarbia Intuba!on, Ven!la!on se"ngs

Myocardial dysfunc!on = Low perfusion Inotropes, Hemodynamic Monitoring

Acute kidney Injury = Low urine output Fluids, Renal Replacement Therapy

Immobility = Catabolism, Myopathy Early mobility, Nutri!on

Hepa!c injury = Coagulopathy, Cholestasis

Intes!nal injury = Altered microbiome Early enteral nutri!on

Bone marrow suppression= Cytopenias, Immunosuppression

Vasodila!on = Low blood pressure Judicious Fluids, Vasopressors

Concern that the suggested 1-hour
goal to initiate therapy is unreal-
istic has led the American College
of Emergency Physicians to develop
a new consensus-based report that
similarly emphasizes prompt rec-
ognition of sepsis and initiation of
diagnostic procedures and therapies
but without a specific administrative
timeline or prescriptive use of fluids
based on a volume target of 30 mL/kg,
as described in the SSCG and SEP-1
criteria.3,15 Previously, the Infectious
Diseases Society of America opposed
the broad criteria, citing concern for in-
appropriate antimicrobial utilization,
and suggested that the 1-hour target
for antimicrobial therapy be applied
only to patients with septic shock and
not for sepsis without shock.16 Clearly,
timely therapy should be applied to ap-
propriate patients and the systems and
processes of care evaluated to remove
barriers and causes of delayed care.
Quality assessment of these elements is
beneficial for target populations of in-
patients and emergency admissions, as
only a percentage of individual patients
are assessed for achievement of targets
with external data reporting.
Cardiovascular dysfunction
The cardiovascular system has
a prominent role in sepsis and its
dysfunction is often the first indi-
cation of impending critical illness.
Hypotension, reduced vascular tone,
and cardiac dysfunction are visible
signs of microvascular and cellular dys-
function. The signs of cardiovascular
stress may be subtle initially and are
due to compensatory mechanisms of
catecholamine and cortisol secretion
and activation of the renin-angiotensin-
aldosterone-system (RAAS) to correct
the perfusion deficit. Blood pressure
may not decline until the compensa-
tory mechanisms become inadequate,
although tachycardia and changes in
perfusion may be present with elevated
lactate levels (>2 mEq/L) and mot-
tled skin. The reduction in perfusion,
caused by endothelial injury with local
nitric oxide production (as described
in part 1 of this series), is worsened
by intravascular hypovolemia created
by endothelial/glycocalyx damage
and increased permeability leading
to fluid leakage and edema.1 Edema
creates a barrier to effective oxygen
diffusion into tissues that may persist
after restoration of perfusion.17 The
SOFA score point system adds 1 point
for each threshold of MAP less than
70 mm Hg and progressive increases in
vasopressor intensity (Table 1).2 Thus
high-dose norepinephrine contributes
4 points to the SOFA score. Fluid resus-
citation and vasopressors are the main-
stay of hypotension therapy; however,
the optimal balance is not easily de-
fined, as a higher volume in the first 24
hours was associated with nonsurvival,
but in other trials low-volume resusci-
tation was associated with lower mor-
tality, as described in a large review.18
The fundamentals of initial resuscita-
tion and patient assessment are be-
yond the scope of this paper but have
been reviewed recently.19 Once resusci-
tation has been initiated, the clinician
will need to strike a balance between
fluids and vasopressor dosing, and al-
though a perfect strategy has not been

426 AM J HEALTH-SYST PHARM | VOLUME 79 | NUMBER 6 | MARCH 15, 2022

 Table 1. Criteria to Screen for Sepsis or Assess Organ Dysfunction and Prognosis2,7
Measure Points Assigned

National Early Warning System (NEWS2) Criteria

3 2 1 0 1 2 3

Respiratory rate, breaths/min ≤8 – 9-11 12-20 – 21-24 ≥25

On supplemental oxygen – Yes – – – – –

SpO2 with hypercapnic ≤83 84-85 86-87 88-92 or ≥93 on room 93-94 on O2 95-96 on O2 ≥97 on O2
respiratory failure, % air

Temperature, °C ≤35 35.1-36.0 36.1-38.0 – 38.1-39.0 ≥39.1 –

Systolic BP, mm Hg ≤90 91-100 101-110 111-219 – – ≥220

Pulse, beats/min ≤40 41-50 – 51-90 91-110 111-130 ≥131

PATHOPHYSIOLOGY OF SEPSIS, PART 2

Consciousness New-onset – Alert – – –

confusion

Sequential Assessment of Organ Failure (SOFA)

0 1 2 3 4

PaO2/FIO2 ≥400 <400 <300 <200a <100a

Platelets × 103/µL ≥150 <150 <100 <50 <20

Bilirubin, mg/dL <1.2 1.2-1.9 2.0-5.9 6.0-11.9 >12

AM J HEALTH-SYST PHARM
Cardiovascular MAP ≥70 mm Hg MAP <70 mm Hg Dopamine or dobutamine Norepinephrine or Norepinephrine or

|
<5 epinephrine ≤0.1 µg/ epinephrine >0.1
µg/kg/min for ≥1 h kg/min for ≥1 h µg/kg/min for >1 h

Glasgow Coma Score 15 13-14 10-12 6-9 <6

Serum creatinine, mg/dL <1.2 1.2-1.9 2-3.4 3.5-4.9 >5

VOLUME 79
(or urine output mL/day) (<500) (<200)

|
Quick Sequential Organ Failure Assessment (qSOFA)

Respiratory rate, breaths/min ≥22

NUMBER 6
Systolic BP, mm Hg ≤100

Glasgow Coma Score ≤13

Abbreviations: BP, blood pressure; FIO2, fraction of inspired oxygen; MAP, mean arterial pressure; O2, oxygen; PaO2, partial pressure of oxygen; SpO2, oxygen saturation (percutaneous).
a
With respiratory support.

Calculate a sum of points within each scoring system to assess degree of illness or prognosis.

| MARCH 15, 2022

NEWS2: Total score of 0-4 indicates low clinical risk. For any individual item, score of 3 indicates low-medium risk; 5-6, medium risk; ≥7, high risk.7
SOFA: Scoring is based on worst value in prior 24 hours. Baseline score of ≥4 associated with high likelihood of clinical deterioration.13 The risk of mortality rises for every 2-point
increase when measured in an ICU population.14 For sequential measurement, a change of ≥2 points is considered significant for overall status (worsening or improvement).
CLINICAL REVIEW

427
Detailed advice on measuring SOFA score has been reported.2
qSOFA: A score of ≥2 points near the onset of infection is associated with a greater risk of death or prolonged ICU stay.2

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 CLINICAL REVIEW
defined, the review authors provided
an algorithm for therapies, monitoring,
and endpoints.19 An initial bolus of
crystalloid fluids, with at least 30  mL/
kg given within the first 3 hours, is a
strong recommendation in the SSCG.3
The first large trial suggested that
the use of balanced crystalloids (lac-
tated Ringer’s solution or Plasma-Lyte
[Baxter Healthcare]) rather than 0.9%
sodium chloride injection reduced the
composite risk of mortality, new renal
replacement therapy (RRT), or per-
sistent renal dysfunction, but a second
large trial did not show a reduction
in mortality.20,21 The SSCG guidelines
on treatment of coronavirus disease
2019 (COVID-19) suggested the use of
balanced crystalloids over 0.9% sodium
chloride injection based on the initial
trial results (but characterized the trial
data as weak evidence), but equipoise
on fluid choice is likely to persist unless
the choice of a specific fluid or patient
characteristics are found to be im-
portant contributing factors.22 Albumin
is suggested (based on weak evidence)
as a fluid to consider for a patient re-
quiring large volumes of fluid to main-
tain MAP, but albumin is not suggested
for initial resuscitation.3 Synthetic col-
loids such as starches and gelatins are
not advised for intravascular volume
replacement. Ongoing fluid therapy
requirements may be variable over
time, and a standard total dose cannot
be defined; rather, individualization
and reassessment are needed. It is a
challenge at the bedside to determine
optimal fluid replacement volume.
Avoiding excessive fluid administration
is essential to minimize later compli-
cations.23 Hypervolemia may worsen
tissue edema, and venous congestion
may worsen organ dysfunction, as will
be discussed later in this article.
Norepinephrine is strongly re-
commended when a vasopressor is
needed to maintain a MAP of ≥65 mm
Hg. Clinicians should consider the
addition of vasopressin or epineph-
rine to achieve the MAP target or to
reduce the norepinephrine dose when
needed (a weak recommendation).3,4
Endpoints beyond MAP are needed.
428 AM J HEALTH-SYST PHARM | VOLUME 79
PATHOPHYSIOLOGY OF SEPSIS, PART 2
Tools for dynamic assessment of fluid
responsiveness include the passive
leg raise (PLR) and bioreactance with
stroke volume assessment for per-
sonalized and ongoing evaluation
of volume status. Use of these tools
has been shown to reduce the fre-
quency of renal and respiratory failure
compared with usual care.24 To test
if hemodynamics may improve with
additional fluid, a PLR procedure is
used to create a transient increase in
venous blood volume while the legs
are held at a 45-degree angle relative
to the horizontal upper body for 30 to
90 seconds. A positive response (a 10%
increase in stroke volume, as meas-
ured by a cardiac output monitor, or
a change in pulse pressure variation
of the arterial line) suggests potential
benefit of additional fluid; failure to
change this dynamic variable suggests
that additional volume resuscitation is
not needed.25 Dynamic assessments of
hemodynamics may require additional
invasive or noninvasive monitoring, as
reviewed elsewhere.26
The SSCG suggest monitoring
serum lactate (arterial or venous) as a
measure of severity of hypoperfusion,
with serial levels indicating progress to-
ward correcting the perfusion defect.3
A  lactate level of >2  mmol/L should
trigger repeated assessment, and a
level of >4  mmol/L is a sign of signifi-
cant hypoperfusion (type A  acidosis).
Metabolic acidosis with elevated lac-
tate is the result of a change in intra-
cellular pH that triggers transporters
to extrude lactate and hydrogen ions,
leading to extracellular accumulation
and diminished metabolic clearance.
The anion gap will be elevated by high
lactate levels.
Other causes of elevated lactate in-
clude type B, or accelerated, aerobic
glycolysis (eg, due to epinephrine in-
fusion or high-dose albuterol inhal-
ation therapy), hepatic insufficiency
with failure to metabolize lactate,
some toxins, and vigorous exercise/
seizures.27
During shock, concentrations of
endogenous vasopressors are variable.
Vasopressin concentrations rise within
| NUMBER 6 | MARCH 15, 2022
minutes but subsequently decline over
a period of hours, creating a relative
deficiency that can be corrected with a
low-dose infusion administered as hor-
mone replacement, leading to blood
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pressure improvement in at least a por-
tion of patients with inadequate cat-
echolamine response.28 Catecholamine
concentrations in shock are unpredict-
able and highly variable between pa-
tients, as is the response to exogenous
treatment.29 Norepinephrine is the pre-
ferred agent and is initiated with low
doses that are titrated to response while
continuing fluid resuscitation until PLR
results indicate a lack of fluid respon-
siveness.3,4 Epinephrine and angio-
tensin II are options for additional
vasoconstriction. Use of angiotensin
II has been reviewed recently and de-
scribed in patients with COVID-19 with
respiratory failure.30,31
Cardiac contractility and efficiency
are important components of car-
diovascular function. Dobutamine is
suggested as an adjunctive therapy
when poor perfusion persists despite
fluids and norepinephrine, but use of
dobutamine may be complicated by
its tendency to cause hypotension.3,4
While the left ventricle is responsible
for cardiac output and peripheral per-
fusion, there is increasing recognition
of the importance of right heart con-
tractility and risk of overdistention with
excess fluid administration.19 Right
ventricular (RV) dilation is best evalu-
ated with echocardiography, and resus-
citation should be done cautiously and
with close monitoring to avoid overload
in patients with poor RV contractility.
The usual endpoint for cardiovas-
cular resuscitation is achievement of
a MAP above 65  mm Hg (but below
85  mm Hg), although the higher
values may be beneficial in patients
with chronic hypertension.3 A  slightly
lower goal (60-65 mm Hg) is suggested
for adult patients with COVID-19.22
Although controversial, it has been
suggested that a low diastolic arterial
pressure (DAP) may worsen cor-
onary perfusion and that DAP should
be maintained above 50  mm Hg with
vasopressors.19 The MAP calculation
 PATHOPHYSIOLOGY OF SEPSIS, PART 2
gives a greater weight to DAP than sys-
tolic pressure, and although a low DAP
is associated with a poor outcome,
there is insufficient data to indicate
that use of vasopressors to raise DAP is
beneficial.32
Respiratory dysfunction
Injury to the lungs is common in
sepsis, whether it be due to direct or
indirect injury, and is identified in the
SOFA scoring system as the degree of
hypoxia, measured as the ratio of par-
tial pressure of oxygen (Pao2) to fraction
of inspired oxygen (Fio2), abbreviated
here as P/F (Table 1).2 A point is added
to the SOFA score as the ratio falls.
A P/F value of 75 and mechanical ven-
tilation for hypoxia would contribute
4 points to the SOFA score. The defin-
ition of acute respiratory distress syn-
drome (ARDS) severity has evolved and
currently relies on the Berlin criteria,
by which ARDS is categorized as mild
(P/F of ≤300), moderate (P/F of ≤200),
or severe (P/F of ≤100) based on the de-
gree of hypoxia despite the use of posi-
tive end-expiratory pressure (PEEP) or
continuous positive airway pressure
(CPAP) at a level of ≥5 cm H2O.33 Other
criteria include acute onset and bilat-
eral opacities on a chest radiograph not
attributed to heart failure or volume
overload. The incidence of ARDS in pa-
tients with sepsis depends on the popu-
lation and etiology of the insult but is
now generally less than 10%, much
lower than historically reported.
Respiratory distress may occur fol-
lowing direct injury from pneumonia/
aspiration or indirect injury from remote
infection/inflammation and widespread
endothelial injury producing ARDS, as
discussed in part 1.1 Disruption of the
alveolar-capillary membrane leads to
increased permeability and leakage
of protein-rich fluid into both the
interstitium and the alveolus, creating
a barrier to oxygen and carbon dioxide
diffusion and gas exchange.34 The alveoli
are normally able to reabsorb excess fluid
but in ARDS are unable to utilize lymph-
atic drainage if there is diffuse alveolar
damage (DAD). The inflammatory pro-
cess reduces production of surfactant
that is needed to reduce alveolar col-
lapse and inactivates existing surfactant.
With alveolar collapse and interstitial
fluid accumulation, the stiffening lungs
become more difficult to ventilate,
and improper ventilator settings with
high pressure or volumes can exacer-
bate the inflammatory injury (produ-
cing ventilator-induced lung injury and
worsening systemic inflammation). Low
tidal volumes (≤6  mL per kilogram of
ideal body weight) and plateau pressure
below 30 mm Hg are needed to improve
ARDS outcome.35 The classic finding of
hypoxia is the result of ventilation-to-
perfusion mismatching and right-to-left
intrapulmonary shunting (blood per-
fuses through lung areas without ad-
equate ventilation and gas exchange).
Another hallmark is impaired carbon di-
oxide elimination leading to hypercarbia
and respiratory acidosis. Experience
in treating viral ARDS in patients with
COVID-19 strongly reinforced the need
for reduction of tidal volume and main-
tenance of plateau pressure despite the
need for higher PEEP levels (>10  cm
H2O), but unlike more traditional ARDS
therapy, in the context of COVID-19 it
is suggested that intubation be avoided
just for hypoxia, with the use of oxygen
therapy via modalities such as high-flow
nasal cannula and noninvasive positive
pressure ventilation.22 Prone positioning
of patients with hypoxia may improve
oxygenation.
An additional key component of
ARDS treatment is the identification
and correction of the inciting cause,
with adequate treatment of infection
(via use of antimicrobials and source
control), or elimination of other re-
mote or direct sources of lung injury
and inflammation (along with their
damage-associated molecular pat-
terns [DAMPs]), such as occur with
trauma, pancreatitis, and other in-
flammatory insults.1,34 Nonspecific
anti-inflammatory regimens of sys-
temic corticosteroids given for no
more than 7 to 10 days have emerged
as an important part of ARDS therapy
to reduce mortality, especially from
COVID-19, although there is no
consensus on the optimal dose or
AM J HEALTH-SYST PHARM | VOLUME 79
CLINICAL REVIEW
duration.22,36,37 If initiated after day 6
of ARDS, a higher dose and tapering
schedule have been suggested.37 Later
in the ARDS continuum there is pro-
coagulant factor accumulation and al-
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veolar fibrin deposition (this is called
the fibroproliferative phase) that can
lead to persistent hypoxemia and fi-
brosis. Controversy remains regarding
the use of systemic corticosteroids in
late ARDS (>2 weeks) due to increased
mortality risk.38
Fluid management is essential to
facilitate recovery, with avoidance of
initial overload and worsened alveolar
flooding followed by de-resuscitation
or diuresis to achieve negative fluid
balance while avoiding hypotension.39
A  full review of ARDS management is
beyond the scope of this paper, but re-
cent reviews are available.34,40
The incredible volume of patients
with ARDS due to COVID-19 has dem-
onstrated that some patients experi-
ence significant hypoxia but may not
have the classic “stiff ” lung associated
with classic ARDS.41 It is hypothesized
that the microvascular thrombosis
and endothelial injury are initially
more predominant than DAD; thus
an individualized approach to ven-
tilation is needed in patients with
COVID.22
Pharmacists play an important role
in fluid management, especially by
minimizing superfluous fluids during
administration of maintenance fluids
and large-volume secondary infusions
and assisting with the development/
implementation of de-resuscitation
protocols.39 Further, a patient with
ARDS may need sedation and neuro-
muscular blockade. Guidelines and
guidance documents are available
to describe these aspects in greater
detail.22,42,43
Renal dysfunction
Patients with sepsis often pre-
sent with low urine output, or oli-
guria (<0.5  mL/kg/h), and progressive
acute kidney injury (AKI), although
other causes should be ruled out and
nephrotoxins avoided unless essen-
tial for sepsis therapy. Renal SOFA
| NUMBER 6 | MARCH 15, 2022 429
 CLINICAL REVIEW
points are based on creatinine level,
although creatinine elevations may be
delayed. One point is added for rising
creatinine values above defined thresh-
olds (Table 1).2 A  creatinine value of
4  mg/dL would contribute 3 points
to the SOFA score. Urine microscopy
for sediment or signs of cellular injury
may help to establish the cause of AKI
but is not helpful to detect AKI or pre-
dict worsening. A separate renal injury
scoring system has been defined by
the Kidney Disease: Improving Global
Outcomes (KDIGO) guidelines; this
scoring system includes assessment
of both elevation in serum creatinine
and reduction in urine output to stage
the severity of AKI.44 The Risk, Injury,
Failure, Loss, and End-stage kidney dis-
ease (RIFLE) criteria similarly consider
both factors.45
AKI may occur in one-third of pa-
tients with sepsis; however, AKI itself
is a risk factor for the development
of sepsis.46 The initial oliguria may be
transient and respond to volume resus-
citation within 48 hours or become pro-
longed or permanent (ie, unresolved at
ICU discharge). Use of 0.9% sodium
chloride injection as a resuscitation
fluid often causes hyperchloremia and
may cause a higher rate of major ad-
verse renal events (the composite of
mortality, new RRT, or persistent renal
dysfunction known as major adverse
kidney events [MAKE]), and thus use
of balanced crystalloids (eg, lactated
Ringer’s or Plasma-Lyte) has been sug-
gested by the SSCG COVID-19 task
force.20,22 A recent large trial did not
replicate the initial findings, although
renal outcomes were secondary meas-
ures assessed at different time points
from the first trial, so trial design may
have influenced comparability..21 Only
15% to 20% of patients in both land-
mark studies had sepsis, so focused
research on that population may be
warranted.20,21
Poor outcome is associated with
the length of renal dysfunction. In an
audit of patient outcome for 28 days in
the ICU setting, patients with oliguria
on admission were older and sicker,
with more comorbidities and other
430 AM J HEALTH-SYST PHARM | VOLUME 79
PATHOPHYSIOLOGY OF SEPSIS, PART 2
organ dysfunction and greater need
for RRT, than those without oliguria.47
The duration of oliguria may be more
important than its initial presence, as
persistent oliguria during an ICU stay
led to new RRT in almost half of the pa-
tients despite a more positive daily fluid
balance. Fluid overload contributes to
high venous pressures, renal conges-
tion, and a higher risk of AKI.48
Renal dysfunction in sepsis is the
result of a complex interplay of factors:
microcirculatory alterations, endothe-
lial inflammatory injury and interstitial
edema, hypoperfusion due to hypo-
volemia and hypotension, ischemia
and reperfusion, exogenous nephro-
toxins, and a complex array of other
factors.46 As discussed in part 1 of this
series, inflammatory mediators such
as DAMPs circulate and are filtered by
the kidney.1 Toll-like receptors in the
renal tubular epithelial cells bind these
mediators, leading to local oxidative
stress injury, production of reactive
oxygen species, and mitochondrial in-
jury. Energy consumption is altered,
and cell-cycle arrest is induced as
renal cells prioritize cell survival over
usual filtration and reabsorption func-
tions. Markers of this cell-cycle arrest
are released into the urine and include
tissue inhibitor of metalloproteinase 2
(TIMP-2) and insulin-like growth factor
binding protein 7 (IGFBP7).49 A  com-
mercial assay for these biomarkers is
available (Nephrocheck; bioMérieux)
and may provide an early warning of
impending AKI, but proper timing
and a systematic response, such as the
KDIGO bundle, are essential to miti-
gate the insult.44,50 The KDIGO bundle
includes avoidance of nephrotoxins,
ensured volume status and renal perfu-
sion pressure, use of functional hemo-
dynamic monitoring, monitored urine
output and creatinine levels, avoid-
ance of hyperglycemia, and consider-
ation of alternatives to radiocontrast
procedures. Unfortunately, real-world
use of the AKI marker and bundle
have not been shown to have a con-
sistent impact on renal outcomes.50
Other AKI markers include cystatin C
for glomerular filtration and neutrophil
| NUMBER 6 | MARCH 15, 2022
gelatinase–associated lipocalin (NGAL)
for tubular injury, but optimization
of the timing for the measurement of
these biomarkers and response to ele-
vations remain challenging in the clin-
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ical setting.49
The kidneys are sensitive to changes
in other organs. Alteration of the intes-
tinal microbiome and dysbiosis con-
tribute to renal and other organ injury
from factors such as direct bacterial
translocation following gut epithelial
apoptosis (programmed cell death) and
release of toxic mediators from injured
gut mucosa, with lymphatic transport
to remote organs.51 Microbial diversity
is altered by the broad-spectrum anti-
biotics and also by other therapies,
including proton pump inhibitors,
opioids, and vasopressors, and by use
of parenteral feeding.52 Additionally,
reduced production of short-chain
fatty acids by intestinal bacteria from
nondigestible dietary carbohydrates
may lead to alterations in renal cell
signaling and increased autophagy of
renal cells.53
Hypoperfusion of the kidneys ac-
tivates the RAAS as a compensatory
mechanism to raise blood pressure.
Renin leads to the formation of angio-
tensin I, a precursor of angiotensin
II. The conversion of angiotensin I  to
angiotensin II requires the angiotensin-
converting enzyme (ACE). This process
may be impaired in patients taking
ACE inhibitors and may also be im-
paired in patients with severe vasodila-
tory shock, leading to high renin levels
and abnormal ratios of angiotensin
I  to angiotensin II.54 High renin levels
are associated with hypotension and
renal arteriolar dilation leading to ad-
verse renal outcomes in septic shock,
and early measurement may be pre-
dictive of MAKE at discharge.55,56 While
a full understanding of how renin levels
may predict outcome is evolving, this
biomarker may be useful to identify
patients who are at risk for poor renal
outcomes or may benefit from therapy
with exogenous angiotensin II for re-
fractory vasodilatory shock, although
additional prospective data to support
this approach are needed.57 Common
 PATHOPHYSIOLOGY OF SEPSIS, PART 2
laboratory measurements of plasma
renin activity may not be adequate (the
active renin concentration has been
studied most recently for this purpose),
and elevated renin may be a marker for
a relative angiotensin II deficiency.54,56
This is a rapidly expanding area of re-
search that may help to understand the
mechanisms of renal injury.
Pharmacists routinely monitor for
renal dysfunction for the purpose of
medication dose adjustment. Elevated
creatinine may be present on admis-
sion and may improve with sepsis
therapy and volume expansion. Most
patients will either have improved
renal function with therapy or cre-
atinine elevation, volume overload,
and metabolic imbalance will often
lead to initiation of RRT. Loading doses
of antimicrobials are advised to achieve
optimal initial antimicrobial concen-
trations, and changes in creatinine and
urine output should be assessed in the
first 48 hours to guide ongoing doses.58
Use of inadequate initial antimicrobial
doses has been associated with poorer
outcomes and greater antimicrobial re-
sistance, and it has been suggested that
doses not be reduced in the first 2 days
for most agents.59 Equations to esti-
mate glomerular filtration rate (GFR)
in chronic renal function rely on stable
creatinine, so the tangent of change in
AKI is important, and these equations
should not be used without consid-
ering an overall assessment of the pa-
tient.60 Nevertheless, a patient with no
urine output, or anuria, will have neg-
ligible creatinine clearance or a GFR of
0 regardless of serum creatinine level.
Pharmacists should reassess patients
with AKI routinely to avoid nephro-
toxins, adjust doses for changing renal
function or during RRT, and monitor
for dose-related adverse effects, such as
neurologic injury from cefepime.61
Hematologic dysfunction
An important component of sepsis
identification is assessment of the
hematologic response to infection, and
while an elevation of the white blood
cell (WBC) count may be an obvious in-
dicator of infection, it is the least helpful
since leukopenia or WBC counts in the
normal range are also possible. Platelet
count may be a more valuable prog-
nostic factor in sepsis. The hematologic
SOFA assessment scores the degree of
thrombocytopenia, adding 1 point for
each value below a range of thresholds
(Table 1).2 A platelet count of 40,000/µL
would contribute 3 points to the SOFA
score. As described in part 1, platelets
are captured in thrombotic neutrophil
extracellular traps (NETs) and con-
sumed in microvascular thrombosis.1
Thrombocytopenia is present in ap-
proximately 40% of patients with septic
shock, and the degree of reduction
is a prognostic factor for mortality.62
Transfusion of platelets (<20,000/µL)
is not suggested unless a high risk of
bleeding or actual bleeding is present.3
Recent data appears to indicate that
a measure of platelet size such as mean
platelet volume may be useful for prog-
nosis, although it is not typically used in
clinical practice. A trend toward larger,
immature platelets is an independent
predictor of 90-day mortality.63 The
presence of platelet precursor cells,
or megakaryocytes, in cerebral blood
vessels of patients with COVID-19 and
lingering neurologic deficits, with a
similar finding in pulmonary vessels
of patients with DAD, has led to signifi-
cant additional research on these cells’
role in viral sepsis complications.64,65
Patients with neutropenia from
marrow-suppressing chemotherapy or
other therapies should have an abso-
lute neutrophil count assessment (this
is done by calculating the number of
mature and immature [band] neutro-
phils). An absolute neutrophil count
of <500/µL, defined as severe neutro-
penia, may lead to blunted inflamma-
tory response and failure to manifest
the usual focal signs of infection. The
presence of other immature granulo-
cytes (promyelocytes, myelocytes,
and metamyelocytes) is detected by
automated analyzers but, unless gran-
ulocyte levels are markedly elevated
(>3%), may not be helpful in the diag-
nosis of sepsis, and significant cutoff
values are not defined.66 Severe neutro-
penia also increases the risk of fungal
AM J HEALTH-SYST PHARM | VOLUME 79
CLINICAL REVIEW
infection, and pharmacists can play an
important role in monitoring for this
severe complication. Neutropenic pa-
tients with a slow clinical response may
need a longer course of antimicrobial
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therapies, as suggested in the SSCG.3
A new concept is to evaluate the
neutrophil-to-lymphocyte ratio (NLR).
The normal NLR is approximately 1
to 3, and values rise in proportion to
the degree of stress, but NLR may not
differentiate between infection or in-
flammation. Exogenous corticoster-
oids will also increase the NLR, and
active hematologic disorders will have
an unpredictable effect. Sepsis is likely
to produce an NLR of >10, but while a
higher NLR cutoff (eg, >10 vs >5) will
improve sensitivity for sepsis identi-
fication, it leads to lower specificity.
Response to therapy should produce a
decline in NLR. Farkas66 proposed that
septic shock is unlikely with an NLR
of <3 and unclear with an NLR of 3 to
10, but infection as the cause of shock
should be considered with an NLR of 10
to 15 and is likely at a level of >15.
Coagulopathy
Changes in coagulation are closely
tied with the hematologic system, as
described for platelet count. Activation
of coagulation and compensatory
thrombolysis contribute to elevation
of biomarkers, may alter typical meas-
ures of coagulation, and will alter a
thromboelastogram (TEG) result.
A  common biomarker is the D-dimer
which is elevated by fibrin formation
and degradation. Sensitivity varies be-
tween assays, and clinicians need to
be familiar with the values produced
locally and the normal values within a
research report.67 D-dimer elevation is
not specific for sepsis and may be al-
tered by malignancy, trauma, venous
thromboembolism, pulmonary em-
bolism, and ischemic stroke. Greater
D-dimer elevation in sepsis is asso-
ciated with worsening outcome as a
marker for more severe coagulopathy.
Patients with severe SARS-CoV-2 in-
fection have had significant D-dimer
elevations as a component of the
thrombotic and inflammatory process,
| NUMBER 6 | MARCH 15, 2022 431
 CLINICAL REVIEW
but this may have been a marker for
greater inflammation.68 When patients
with sepsis have an elevated D-dimer,
additional assessment of the coagula-
tion system through measurement of
platelet count, traditional measures of
coagulation (activated partial thrombo-
plastin time, prothrombin time, and fi-
brinogen level), and TEG is needed.
A  sepsis-induced coagulopathy (SIC)
scoring system has been developed
and can assist clinicians in identifica-
tion of this specific coagulopathy; the
SIC score is easier to use than other
scoring systems, such as the dissemin-
ated intravascular coagulopathy (DIC)
scoring systems (Table 2).69,70 The SIC
score, which has been validated in pa-
tients with septic shock, changes more
rapidly than the DIC score and has been
shown to be associated with poor out-
come, but additional research is needed
to understand its utility in other popu-
lations and determine if it is useful in
predicting which patients may benefit
from anticoagulation.70,71 Pharmacists
can use TEG to influence prescribing
of anticoagulants or procoagulants
and blood products, with guidance in
this area provided in a recent review.72
While clear criteria for TEG results and
need for anticoagulation are not avail-
able, some preliminary guidance in re-
lation to patients with COVID-19 has
been published.73
Empiric anticoagulation generally
increases the risk of bleeding but has
not been consistently shown to im-
prove outcome in sepsis or COVID-19,
Table 2. Sepsis Induced Coagulopathy (SIC) Scoring System69,a
Measure
Platelet count (cells × 109/L)
INR
SOFA score
Abbreviations: INR, International Normalized Ratio; SOFA, Sequential Organ Failure
Assessment.
a
A total SIC score of ≥4 indicates coagulopathy, but scoring should include at least 2 points
from the coagulation component (platelet count or INR).
432 AM J HEALTH-SYST PHARM
PATHOPHYSIOLOGY OF SEPSIS, PART 2
although research in this area is
ongoing.22,74 It is likely that traditional
laboratory tests alone are not ad-
equate to determine the populations
likely to benefit from anticoagulation.22
Description of patient phenotype rela-
tive to coagulation may improve the
ability to identify patients likely to
benefit.75
Hepatic dysfunction
The liver is an important organ
in sepsis for its contribution to clear-
ance of infectious agents and cellular
debris but may be injured by poor
perfusion, hypoxia, or inflammatory
injury. Bilirubin elevation is a SOFA
score measure, although changes in
this laboratory value typically lag the
other parameters by days (Table 1).2
One point is added to the SOFA score
above each threshold. A bilirubin level
of 4 mg/dL would contribute 2 points to
the SOFA score.
The liver is a major site for regu-
lation of the immune inflammatory
response. Cytokines trigger the pro-
duction of acute-phase proteins (eg,
C-reactive protein, complement fac-
tors, ferritin, haptoglobin) by the liver.
Various white cells (macrophages,
killer T cells, neutrophils, and mono-
cytes) accumulate in the liver and
contribute to the antimicrobial de-
fense through formation of NETs and
phagocytosis, as described in part 1.1
Local release of inflammatory cyto-
kines can lead to hepatocyte injury and
apoptosis manifesting as a continuum
Score Range
2 <100
1 ≥100, <150
2 >1.4
1 >1.2, ≤1.4
2 ≥2
1 1
| VOLUME 79 | NUMBER 6 | MARCH 15, 2022
from hepatocellular dysfunction to
fulminant hepatic failure. Liver per-
fusion is heavily dependent on portal
venous flow, and volume overload with
hepatic congestion can contribute to
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hypoperfusion and hypoxic hepatitis.
The liver is important for its meta-
bolic functions in synthesizing pro-
teins for immunity and coagulation as
well as for production of glucose and
other acute phase reactant proteins.76,77
When the liver fails, the mortality rates
may be above 50%. Clinically, pa-
tients with hypoxic hepatitis (formerly
called shock liver) manifest signs of
hepatocellular injury with initial lac-
tate dehydrogenase (LDH) elevation
and then rapidly elevated transaminase
levels; alanine aminotransferase (ALT)
and aspartate aminotransferase (AST)
levels can increase to as much as
10-fold above baseline.78 The AST rise is
initially greater than the rise in ALT, and
then both AST and LDH decline toward
baseline by about day 5 in survivors.
High bilirubin is a late finding and may
be multifactorial, involving cholestasis,
blood product transfusion, and/or hep-
atic congestion.
As with AKI, the pathophysiology
of hepatic injury is closely tied to
changes in the intestinal microbiome.
Inflammatory changes in the gut can
cause epithelial apoptosis and bac-
terial translocation and release of toxic
mediators, with lymphatic and portal
transport to the liver.79 As with AKI,
there is reciprocal injury and a higher
risk of new sepsis when existing hepatic
failure contributes to gut dysbiosis and
epithelial injury due to high levels of
circulating inflammatory cytokines and
impaired bacterial clearance. Reduced
secretion of bacteriostatic bile acids
and alterations in the bacterial metab-
olism of bile acids further contribute
to pathobiome development. Enteral
nutrition and interventions to re-
duce dysbiosis are important areas for
ongoing research in sepsis. Pharmacists
should be aware of patients with sig-
nificant hepatic injury and consider
avoiding hepatotoxins and reducing
doses of medications with significant
hepatic metabolism.
 PATHOPHYSIOLOGY OF SEPSIS, PART 2
Neurologic dysfunction
Changes in mental status and neuro-
logic function are a common part of
the sepsis syndrome and sepsis should
be suspected in a patient with acute
mental status changes. The SOFA score
incorporates the Glasgow Coma Score
(GCS) and various thresholds below the
normal value of 15. A patient with a GCS
of 11 would score 2 points (Table 1).2
Unfortunately, the GCS is a nonspecific
measure of neurologic status or prog-
nosis in sepsis. Patients may also ex-
hibit confusion, impaired cognition,
delirium, encephalopathic seizures,
and other signs. Systemic inflamma-
tion with elevated cytokine levels is
associated with neuroinflammation,
with evidence of blood-brain barrier
dysfunction.80 Microvascular coagula-
tion and perfusion alteration with dis-
turbances of cerebral autoregulation
also contribute to altered cerebral per-
fusion. The vagus nerve is an important
conduit for transmission of peripheral
inflammatory signals to the brain, so
avoidance of anticholinergic medica-
tions may be important to minimize de-
lirium development.81 Reactive oxygen
species associated with inflammation
induce neuronal and microglial apop-
tosis.1 Cytotoxic edema, occult seizures,
cerebral infarcts, and hemorrhages
have been reported and contribute to
chronic neurologic deficits (eg, fatigue,
musculoskeletal pain, neurocognitive
difficulty, mood disturbances) col-
lectively known as sepsis-associated
encephalopathy or delirium.80,82 The
long-term neurologic effects of COVID-
19 sepsis are common following more
severe illness, and significant research
is focused around clinical character-
ization of the many manifestations of
the disease and potential treatments.83
Pharmacists can contribute to the care
of patients through minimizing sed-
ation, reducing anticholinergic burden,
and promoting other interventions to
prevent delirium.42
Biomarkers in sepsis
A biomarker is a measurable value
that is indicative of normal or abnormal
biologic processes or pharmacologic
response to therapy. Vital signs such
as heart rate and blood pressure are
biomarkers, but the term is most often
applied to laboratory-measured sub-
stances. Lactate, d-dimer, and the
urinary biomarkers have already been
discussed. There is an ever-expanding
list of potential biomarkers in sepsis.
Clinicians need to consider what
sorts of tests are readily available and
whether the measure is a surrogate
endpoint with clinical relevance or
merely a marker of illness or severity.
Blood cultures are a gold-standard
biomarker for diagnosing bloodborne
infection, but rapid tests for patho-
genic cellular markers may speed the
rate of identification and initiation of
optimal therapy through use of poly-
merase chain reaction–based methods
to identify protein and cellular markers.
Some of these may be used on samples
of positive blood cultures, while others
are used for pathogen detection dir-
ectly from blood, cerebral spinal fluid,
respiratory specimen, or stool; ex-
amples of such tests include the BioFire
FilmArray System (BioFire Diagnostics,
Salt Lake City, UT) and Pheno system
(Accelerate Diagnostics, Inc., Tucson,
AZ).84,85 Tests for biomarkers of infec-
tion and/or inflammatory response,
such as procalcitonin (PCT) and
C-reactive protein (CRP), are the most
readily available. Elevated CRP levels
are produced by the liver in response
to inflammation but are nonspecific for
sepsis; when low, CRP levels are poten-
tially useful in excluding sepsis. Falling
levels during the first 48 hours may in-
dicate response to therapy. PCT is pro-
duced throughout the body in response
to bacterial toxins such as endotoxin
and cytokines. It modulates signaling
responses in innate immune cells,
leading to release of interleukin-17A,
thus serving as a both mediator and a
marker of bacterial sepsis.86 PCT is spe-
cific for bacterial infection (versus viral
or fungal infection) and may be most
useful when the concentration is low,
suggesting that antibacterial therapy
may not be needed. However, the de-
gree of PCT elevation has been correl-
ated with the probability of bacterial
AM J HEALTH-SYST PHARM | VOLUME 79
CLINICAL REVIEW
infection and may be a suitable trigger
for initial use of empiric antibacterial
therapy when used in conjunction
with clinical examination.87 A  con-
sensus breakpoint in critically ill pa-
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tients (PCT of ≥0.5 µg/L suggests a high
probability of bacterial infection and
potential need for antibiotics.88 The
PCT level should be rechecked in 1 to
2 days and therapy stopped if the PCT
level is less than 0.5 µg/L or declines by
80%. A PCT value of <0.5 µg/L suggests
a low probability of bacterial infection,
and while antibiotic use should be
based on clinical judgment, a persist-
ently low PCT value after 24 hours pro-
vides greater incentive to de-escalate
therapy, as suggested in the SSCG.3,88
Most challenging are the intermediate
levels, which are less definitive, and
the clinician must rely on judgment to
stop or continue therapy. Obtaining a
repeat value in 1 to 2 days is suggested
if therapy is continued. Other sepsis
biomarkers being researched include
presepsin, pentraxin-3, calprotectin,
adrenomedullin, angiopoietin, sTREM-
1, and CD64.89 Only a small number
have been studied in groups of more
than 300 patients, and a variety of sepsis
definitions and endpoints have been
used to define the populations, leading
to a lack of consensus on their role.90
Few of the biomarkers have better diag-
nostic value than PCT or CRP, but it is
likely that a panel of markers will be
needed to define a sepsis signature.
When reviewing data on new bio-
markers, the clinician must be aware of
the research goal (diagnostic vs prog-
nostic), population, and timing.
The next phase of biomarker re-
search delves into “omics” research—
genomics, transcriptomics, proteomics,
and metabolomics—to characterize
molecules that are modified in the
structure, function, and dynamics of a
patient or organism, thereby reflecting a
precision medicine perspective. This re-
search will usher in another component
to understanding the pathophysiology
of sepsis. We already have a diagnostic
biomarker that reports ribonucleic acid
(RNA) molecules altered by the host
response (SeptiCyte; ImmuneExpress,
| NUMBER 6 | MARCH 15, 2022 433
 CLINICAL REVIEW
Seattle, WA) and can differentiate be-
tween infection and inflammation in
heterogenous populations.91 Evaluation
of the impact of this assay on patient
outcome will help identify its diagnostic
utility in clinical practice.
Conclusion
Knowledge of the pathophysiology
of sepsis syndromes is continuously
evolving, especially during the COVID-
19 pandemic. Pharmacists who are
involved in the care of patients with
sepsis and septic shock should be fa-
miliar with the general mechanisms of
injury, parameters to identify sepsis-
related organ dysfunction, and guide-
line udpates as they are published. The
Surviving Sepsis Campaign Guidelines
for treatment of COVID-19 are an ex-
ample of this evolving knowledge, with
periodic updates being published.
Addendum
During the publication process, the up-
dated guidelines from the Surviving Sepsis
Campaign were released, and the reader
should consult them for the latest therapy
guidance.92
Disclosures
Dr. Jacobi has a consulting relationship with
La Jolla Pharmaceuticals and Visante and
an advisory board membership with Pfizer
Hospital Products Division. There was no out-
side funding for the preparation of the article
manuscript. The author is responsible for all
content.
References
1. Jacobi J. The pathophysiology of sepsis
— 2021 update: Part 1, immunology and
coagulopathy leading to endothelial in-
jury. Am J Health-Syst Pharm. Published
online October 4, 2021. https://doi.
org/10.1093/ajhp/zxab380
2. Singer M, Deutschman CS,
Seymour CW, et al. The third inter-
national consensus definitions for
sepsis and septic shock (Sepsis-3).
JAMA. 2016;315(8):801-810.
3. Rhodes A, Evans LE, Alhazzani W, et al.
Surviving Sepsis Campaign: inter-
national guidelines for management of
sepsis and septic shock: 2016. Crit Care
Med. 2017;45(3):486-552.
4. Rhodes A, Dellinger RP, Schorr CA,
Levy MM. A users guide to the 2016
Surviving Sepsis Guidelines. Crit Care
Med. 2017;45(3):381-385.
434 AM J HEALTH-SYST PHARM | VOLUME 79
PATHOPHYSIOLOGY OF SEPSIS, PART 2
5. Society of Critical Care Medicine.
Hour-1 bundle: initial resuscita-
tion for sepsis and septic shock.
Published January 11, 2019.
Accessed April 22, 2021. https://
www.sccm.org/getattachment/
SurvivingSepsisCampaign/Guidelines/
Adult-Patients/Surviving-Sepsis-
Campaign-Hour-1-Bundle.pdf
6. Beardsley JR, Jones CM, Williamson J,
et al. Pharmacist involvement in a
multidisciplinary initiative to reduce
sepsis-related mortality. Am J Health-
Syst Pharm. 2016;73(3):143-149.
7. Royal College of Physicians.
National Early Warning Score
(NEWS). Published December 19,
2017. Accessed July 27, 2021. www.
rcplondon.ac.uk/projects/outputs/
national-early-warning-score-news-2
8. Usman OA, Usman AA, Ward MA.
Comparison of SIRS, qSOFA, and NEWS
for the early identification of sepsis
in the Emergency Department. Am J
Emerg Med. 2019;37(8):1490-1497.
9. Melhammar L, Linder A, Tverring J,
et al. NEWS2 is superior to qSOFA in
detecting sepsis with organ dysfunction
in the emergency department. J Clin
Med. 2019;8(8):1128.
10. Seymour CW, Liu VX, Iwashyna TJ, et al:
Assessment of clinical criteria for sepsis:
for the Third International Consensus
Definitions for Sepsis and Septic Shock
(Sepsis-3). JAMA. 2016;315(8):762-774.
11. Pepic I, Feldt R, Ljungström L, et al.
Early detection of sepsis using artificial
intelligence: a scoping review protocol:
a scoping review protocol. Sys Rev.
2021;10:28.
12. Centers for Medicare and Medicaid
Services. Severe sepsis and septic
shock management bundle (composite
measure) Revision 6. Accessed July
27, 2021. https://cmit.cms.gov/CMIT_
public/ViewMeasure?MeasureId=1017#
tab1
13. López-Izquierdo R, del Brio-Ibañez P,
Martín-Rodríguez F, et al. Role of
qSOFA and SOFA scoring systems for
predicting in-hospital risk of deteri-
oration in the emergency depart-
ment. Int J Environ Res Public Health.
2020;17:8367.
14. Raith EP, UDY AA, Bailey M, et al.
Prognostic accuracy of the SOFA score,
SIRS criteria, and qSOFA score for
in-hospital mortality among adults
with suspected infection admitted
to the intensive care unit. JAMA.
2017;317(3):290-300.
15. Yealy DM, Mohr NM, Shapiro NI, et al.
Early care of adults with suspected
sepsis in the emergency department
and out-of-hospital environment: a
consensus-based task force report.
| NUMBER 6 | MARCH 15, 2022
Ann Emerg Med. Published on-
line April 9, 2021. doi.org/10.1016/j.
annemergmed.2021.02.006.
16. IDSA Sepsis Task Force. Infectious
Diseases Society of America (IDSA)
position statement: Why IDSA did
Downloaded from https://academic.oup.com/ajhp/article/79/6/424/6397593 by Welch Medical Library, Johns Hopkins University user on 06 June 2022
not endorse the Surviving Sepsis
Campaign Guidelines. Clin Infect Dis.
2018;66(10):1631-1635.
17. De Backer, D, Orbegozo, C D,
Donadello K, Vincent, JL.
Pathophysiology of microcirculatory
dysfunction and the pathogenesis of
septic shock. Virulence. 2014;5:73-79.
18. Tigabu BM, Davari M, Kebriaeezadeh A,
Mojtahedzadeh M. Fluid volume, fluid
balance and patient outcome in severe
sepsis and septic shock: a systematic
review. J Crit Care. 2018;48:153-159.
19. Cinel I, Kasapoglu US, Gul F,
Dellinger RP. The initial resusci-
tation of septic shock. J Crit Care.
2020;57:108-117.
20. Semler MW, Self WH, Wanderer JP,
et al. Balanced crystalloids versus saline
in critically ill adults. N Engl J Med.
2018;378:829-839.
21. Zampieri FG, Machado FR, Biondi RS,
et al. Effect of intravenous fluid treat-
ment with a balanced solution vs.
0.9% saline solution on mortality in
critically ill patients. The BaSICS ran-
domized clinical trial. JAMA. Published
online August 10, 2021. doi.10.1001/
jama.2021.11684.
22. Alhazzani W, Evans L, Alshamsi F, et al.
Surviving Sepsis Campaign Guidelines
on the management of adults with
coronavirus disease-2019 (COVID-19)
in the ICU: first update. Crit Care Med.
2021;49(3):e219-e234.
23. Sakr Y, Birri PNR, Kotfis K, et al. Higher
fluid balance increases the risk of death
from sepsis: Results from a large inter-
national audit. Crit Care Med. 2017;
4(3):, 386-94.
24. Douglas IS, Alapat PM, Corl KA, et al.
Fluid responsiveness evaluation
in sepsis hypotension and shock:
a randomized clinical trial. Chest.
2020;158(4):1431-1445.
25. Monnet X, Rienzo M, Osman D, et al.
Passive leg raising predicts fluid respon-
siveness in the critically ill. Crit Care
Med. 2006;34(5):1402-1407.
26. Lopez CN, Sulaica EM, Donahue KR,
Wanat MA. Updates in hemo-
dynamic monitoring: a review
for pharmacists. J Pharm Pract.
2021;8971900211003436.
doi:10.1177/08971900211003436.
27. Suetrong B, Walley KR. Lactic acidosis
in sepsis: It’s not all anaerobic. Chest.
2016;149(1):252-261.
28. Sharshar T, Blanchard A, Paillard M,
et al. Circulating vasopressin levels
 PATHOPHYSIOLOGY OF SEPSIS, PART 2
in septic shock. Crit Care Med.
2003;31(6):1752-1758.
29. Calzia E, Georgieff M, Huber-lang M,
Radermacher P. Epinephrine kinetics in
septic shock — a means to understand
variable catecholamine efficiency. Crit
Care. 2009;13:177.
30. Heavner MS, McCurdy MT,
Mazzeffi MA, et al. Angiotensin II and
vasopressin for vasodilatory shock: a
critical appraisal of catecholamine-
sparing strategies. J Intensive Care Med.
2021;36(6):635-645.
31. Leisman DE, Mastroianni F, Fisler G,
et al. Physiologic response to angio-
tensin II treatment for coronavirus dis-
ease 2019-induced vasodilatory shock:
a retrospective matched cohort study.
Crit Care Explor. 2020;2(10):e0230.
doi:10.1097/CCE.0000000000000230
32. Magder S. Diastolic arterial pressure is
important in septic shock: con. J Crit
Care. 2019;51:241-243.
33. Ranieri VM, Rubenfeld GD,
Thompson BT, et al; ARDS Definition
Task Force. Acute respiratory distress
syndrome: the Berlin definition. JAMA.
2012;307(23):2526-2533.
34. Matthay MA, Zemans RL,
Zimmerman GA, et al. Acute respira-
tory distress syndrome. Nature Rev.
2019;5:18.
35. The Acute Respiratory Distress
Syndrome Network. Ventilation with
lower tidal volumes as compared with
the acute respiratory distress syndrome.
N Engl J Med. 2000;342:1301-1308.
36. Chaudhuri D, Sasaki K, Karkar A, et al.
Corticosteroids in COVID-19 and non-
COVID-19 ARDS: a systematic review
and meta-analysis. Intensive Care Med.
Published online April 19, 2021. doi.
org/10.1007/s00134-021-06394-2
37. Annane D, Pastores SM, Rochwerg B,
et al. Guidelines for the diagnosis and
management of critical illness-related
corticosteroid insufficiency (CIRCI) in
critically ill patients (part 1): Society
of Critical Care Medicine (SCCM) and
European Society of Intensive Care
Medicine (ESICM) 2017. Crit Care Med.
2017;45(12):2078-2088.
38. National Heart, Lung, and Blood
Institute Acute Respiratory Distress
Syndrome (ARDS) Clinical Trials
Network. Efficacy and safety of cortico-
steroids for persistent acute respira-
tory distress syndrome. N Engl J Med.
2006;354:1671-1684.
39. Bissell BD, Donaldson JC, Morris PE,
Neyra JA. A narrative review of pharma-
cologic de-resuscitation in the critically
ill. J Crit Care. 2020;59:156-162.
40. Kaku S, Nguyen CD, Htet NN, et al.
Acute respiratory distress syndrome:
etiology, pathogenesis, and summary
of management. J Intensive Care Med.
2020;35(8):723-737.
41. Grasselli G, Tonetti T, Protti A, et al.
Pathophysiology of COVID-19-
associated acute respiratory distress
syndrome; a multicentre prospective
observational study. Lancet Resp Med.
2020;8(12):1201-1208.
42. Devlin JW, Skrobik Y, Gélinas C, et al.
Clinical practice guidelines for the pre-
vention and management of pain, agi-
tation/sedation, delirium, immobility,
and sleep disruption in adult patients in
the ICU. Crit Care Med. 2018;46(9):e825
-e873.
43. Murray MJ, DeBlock H, Erstad B, et al.
Clinical practice guidelines for sus-
tained neuromuscular blockade in the
adult critically ill patient. Crit Care Med.
2016;44(11):2079-2103.
44. Kidney Disease: Improving Global
Outcomes (KDIGO) Acute Kidney
Injury Work Group. KDIGO clinical
practice guideline for acute kidney in-
jury. Kidney Int. 2012;2(suppl):1-138.
45. Bellomo R, Ronco C, Kellum JA, et al.
Acute renal failure — definition, out-
come measures, animal models, fluid
therapy, and information technology
needs: the Second International
Consensus Conference of the Acute
Dialysis Quality Initiative (ADQI)
Group. Crit Care. 2004;8(4):R204-R212.
46. Peerapornratana S, Manrique-
Caballero CL, Gómez H, Kellum J. Acute
kidney injury from sepsis: current con-
cepts, epidemiology, pathophysiology,
prevention and treatment. Kidney Int.
2019;96(5):1083-1099.
47. Vincent J-L, Fergusin A, Pickkers P,
et al. The clinical relevance of oliguria
in the critically ill patient: analysis of a
large observational database. Crit Care.
2020;24:171.
48. Ostermann M, Joannidis M. Acute
kidney injury 2016: diagnosis and diag-
nostic workup. Crit Care. 2016;20:299.
49. McCullough PA, Shaw AD, Haase M,
et al. Diagnosis of acute kidney injury
using functional and injury biomarkers:
workgroup statements from the
Tenth Acute Dialysis Quality Initiative
Consensus Conference. Contrib
Nephrol. 2013;182;13-29.
50. Kane-Gill SL, Peerapornratana S,
Wong A, et al. Use of tissue inhibitor
of metalloproteinase 2 and insulin-
like growth factor binding protein
7 [TIMP2]-[IGFBP7] as an AKI risk
screening tool to manage patients
in the real-world setting. J Crit Care.
2020;57:97-101.
51. Gong J, Noel S, Pluznick JL, et al.
Gut microbiota-kidney cross-talk in
acute kidney injury. Semin Nephrol.
2019;39(1):107-116.
AM J HEALTH-SYST PHARM | VOLUME 79
CLINICAL REVIEW
52. Le Bastard Q, Al-Ghalith GA,
Grégoire M, et al. Systematic review:
human gut dysbiosis induced by
non-antibiotic prescription medi-
cations. Aliment Pharmacol Ther.
2018;47(3):332-345.
Downloaded from https://academic.oup.com/ajhp/article/79/6/424/6397593 by Welch Medical Library, Johns Hopkins University user on 06 June 2022
53. Huang W, Zhou L, Guo H, et al. The
role of short-chain fatty acids in
kidney injury induced by gut-derived
inflammatory response. Metabolism.
2017;68:20-30.
54. Bellomo R, Forni LG, Busse LW, et al.
Renin and survival in patients given
angiotensin II for catecholamine-
resistant vasodilatory shock. Am J Resp
Crit Care Med. 2020;202(9):1253-1261.
55. Nguyen M, Denimaal D, Dargent A,
et al. Plasma renin concentration is as-
sociated with hemodynamic deficiency
and adverse renal outcome in septic
shock. Shock. 2019;52(4):e22-e30.
56. Flannery AH, Ortiz-Soriano V, Li X,
et al. Serum renin and major adverse
kidney events in critically ill patients:
a multicenter prospective study. Crit
Care. 2021;25:294.
57. Chow JH, Wallis M, Lankford AS,
et al. Treatment of renin-angiotensin-
aldosterone system dysfunction with
angiotensin II in high-renin septic
shock. Semin Cardiothorac Vasc Anesth.
2021;25(1):67-73.
58. Crass RL, Rodvold KA, Mueller BA,
Pai MP. Renal dosing of antibiotics: are
we jumping the gun? Clin Infect Dis.
2019;68(9):1596-1602.
59. González de Molina FJ, Ferrer R.
Appropriate antibiotic dosing in severe
sepsis and acute renal failure factors to
consider. Crit Care. 2011;15(4):175.
60. Bragadottir G, Redfors B, Ricksten S-E.
Assessing glomerular filtration rate
(GFR) in critically ill patients with acute
kidney injury – true GFR versus urinary
creatinine clearance and estimating
equations. Crit Care. 2013;17:R108.
61. Khan A, DeMott JM, Varughese C,
Hammond DA. Effect of cefepime on
neurotoxicity development in critically
ill adults with renal dysfunction. Chest.
2020;158(1):157-163.
62. Zhao L, Zhao L, Wang YY, et al. Platelets
as a prognostic marker for sepsis. a
cohort study from the MIMIC-III data-
base. Medicine. 2020;99(45):e23151.
63. Vardon-Bounes F, Gratacap M-P,
Groyer S, et al. Kinetics of mean
platelet volume predicts mortality in
patients with septic shock. PloS One.
2019;14(10):e0223553.
64. Nauen DW, Hooper JE, Stewart CM,
Solomon IH. Assessing brain capil-
laries in coronavirus disease 2019.
JAMA Neurol. Published online
February 12, 2021. doi:10.1001/
jamaneurol.2021.0225.
| NUMBER 6 | MARCH 15, 2022 435
 CLINICAL REVIEW
65. Valdivia-Mazeyra MF, Salas C, Nieves-
Alonso JM, et al. Increased number
of pulmonary megakaryocytes in
COVID-19 patients with diffuse alveolar
damage: an autopsy study with clinical
correlation and review of the literature.
Virchows Arch. 20201;478:487-496.
66. Farkas JD. The complete blood count
to diagnose septic shock. J Thorac Dis.
2020;12(suppl 1):S16-S21.
67. Linkins L-A, Lapner ST. Review of
d-dimer testing: good, bad, and ugly.
Int J Lab Hem. 2017;39(suppl 1):98-103.
68. Al-Samkari H, Karp Leaf RS, Dzik WH,
et al. COVID-19 and coagulation:
bleeding and thrombotic manifest-
ations of SARS-CoV-2 infection. Blood.
2020:136(4):489-500.
69. Iba T, Di Nisio M, Levy J, et al. New cri-
teria for sepsis-induced coagulopathy
(SIC) following the revised sepsis
definition: a retrospective analysis
of a nationwide survey. BMJ Open.
2017;7(9):e017046.
70. Iba T, Arakawa M, Di Nisio M, et al.
Newly proposed sepsis-induced
coagulopathy precedes International
Society on Thrombosis and
Haemostasis overt-disseminated
intravascular coagulation and predicts
high mortality. J Intensive Care Med.
2020;35(7):643-649.
71. Tanaka C, Tagami T, Kudo S, et al.
Validation of sepsis-induced
coagulopathy score in critically ill
patients with septic shock: post hoc
analysis of a nationwide observa-
tional study in Japan. Int J Hematol.
2021;114(2):164-171.
72. Gilbert BW, Bissell BD, Santiago RD,
Rech MA. Tracing the lines: a review
of viscoelastography for emergency
medicine clinicians. J Emerg Med.
2020;59(2):201-215.
73. Stillson JE, Bunch CM, Gillespie L,
et al. Thromboelastography-guided
management of anticoagulated
COVID-19 patients to prevent
436 AM J HEALTH-SYST PHARM | VOLUME 79
PATHOPHYSIOLOGY OF SEPSIS, PART 2
hemorrhage. Semin Thromb Hemost.
2021;47:442-446.
74. University of Manitoba. Heparin
anticoagulation in septic shock clinical
trial protocol. Published February 4,
2021. Accessed July 30, 2021.
www.centerwatch.com/clinical-
trials/listings/207622/heparin-
anticoagulation-in-septic-shock/
75. Kudo D, Goto T, Uchimido R, et al.
Coagulation phenotypes in sepsis
and effects of recombinant human
thrombomodulin: an analysis of three
multicentre observational studies. Crit
Care. 2021;25:114.
76. Nesseler N, Launey Y, Aninat C, et al.
Clinical review: The liver in sepsis. Crit
Care. 2012;16:235.
77. Lescot T, Karvellas C, Beaussier M,
et al. Acquired liver injury in the
intensive care unit. Anesthesiology.
2012;117:898-904.
78. Aboelsoud MM, Javaid AI, Al-Qadi MO,
Lewis JH. Hypoxic hepatitis — its bio-
chemical profile, causes and risk factors
of mortality in critically-ill patients: a
cohort study of 565 patients. J Crit Care.
2017;41:9-15.
79. Sun J, Zhang J, Wang X, et al. Gut-liver
crosstalk in sepsis-induced liver injury.
Crit Care. 2020;24:614.
80. Lamar CD, Hurley RA, Taber KH.
Sepsis-associated encephalopathy:
review of the neuropsychiatric mani-
festations and cognitive outcomes.
J Neuropsychiatry Clin Neurosci.
2011;23(3):236-241.
81. Egberts A, Moreno-Gonzalez M, Alan H,
et al. Anticholinergic drug burden and
delirium: a systematic review. J Am Med
Dir Assoc. 2021;22:65-73.
82. Sweis R, Ortiz J, Biller J. Neurology
of sepsis. Curr Neurol Neurosci Rep.
2016;16:21.
83. Huang C, Huang L, Li X, et al. 6-month
consequences of COVID-19 patients
discharged from hospital: a cohort
study. Lancet. 2021;397:220-232.
| NUMBER 6 | MARCH 15, 2022
84. Rello J, van Engelen TSR, Alp E, et al.
Towards precision medicine in sepsis:
a position paper from the European
Society of Microbiology and Infectious
Diseases. Clin Microbiol Infect.
2018;24:1264-1272.
Downloaded from https://academic.oup.com/ajhp/article/79/6/424/6397593 by Welch Medical Library, Johns Hopkins University user on 06 June 2022
85. Wilke M, Heinlein W, Stiefenhofer L,
Bodmann K-F. Clinical and economical
improvements after introducing rapid
identification of bacteria and early anti-
biotic susceptibility testing in sepsis and
bloodstream infections. Results of the
PHENOMENON study. GMS Infect Dis.
2020;8:doc25.
86. Baranowsky A, Appelt J, Kleber C, et al.
Procalcitonin exerts a mediator role in
septic shock through the calcitonin-
gene-related peptide receptor. Crit Care
Med. 2021;49(1):e41-e52.
87. Gregoriano C, Heilmann E, Molitor A,
Schuetz P. Role of procalcitonin use in
the management of sepsis. J Thorac Dis.
2020;12(suppl 1):s5-s15.
88. Schuetz P, Beishuizen A, Broyles M,
et al. Procalcitonin (PCT)-guided anti-
biotic stewardship: an international
experts’ consensus on optimized
clinical use. Clin Chem Lab Med.
2019;57(9):1308-1318.
89. Kin M-H, Choi J-H. An update on
sepsis biomarkers. Infect Chemother.
2020;52(10):1-18.
90. Pierrakos C, Velissaris D, Bisdorff M,
et al. Biomarkers of sepsis: time for a
reappraisal. Crit Care. 2020;24:287.
91. Miller RR, Lopansri BK, Burke JP, et al.
Validation of a host response assay,
SeptiCyte Lab, for discriminating sepsis
from systemic inflammatory response
syndrome in the ICU. Am J Resp Crit
Care Med. 2018;198(7):903-913.
92. Evans L, Rhodes A, Alhazzani W, et al.
Surviving Sepsis Campaign: inter-
national guidelines for the manage-
ment of sepsis and septic shock. Crit
Care Med. Published online October
4, 2021. https://doi.org/10.1097/
CCM.0000000000005337