Letters to the Editor
review and meta-analysis. J Evid Based Med. 2020 March 13 patient population requiring high doses and pro-
[Epub ahead of print].
6. Cook TM, El-Boghdadly K, McGuire B, McNarry AF, Patel
A, Higgs A. Consensus guidelines for managing the air-
way in patients with COVID-19: guidelines from the
Difficult Airway Society, the Association of Anaesthetists
the Intensive Care Society, the faculty of intensive
care medicine and the royal college of anaesthetists.
Anaesthesia. 2020 March 27 [Epub ahead of print].
DOI: 10.1213/ANE.0000000000004883
Sedation of Mechanically Ventilated
COVID-19 Patients: Challenges and
Special Considerations
To the Editor
M
anagement of patient sedation and analgesia
to alleviate anxiety and pain and facilitate
mechanical ventilation is one of the key roles
of every intensivist. During the coronavirus disease
2019 (COVID-19) pandemic, unprecedented numbers
of patients require sedation in intensive care units
(ICUs) and other hospital locations due to their venti-
lator dependence. However, pharmacologic sedation
in mechanically ventilated patients with COVID-19
has thus far received very little attention in the critical
care literature, with minimal mention in the Society of
Critical Care Medicine’s COVID-19 guidelines or clin-
ical reviews.1,2 We propose that sedation of mechani-
cally ventilated patients with COVID-19 poses unique
challenges and has multiple important implications
that we would like to briefly outline:
Unusually high sedation requirements in a large
proportion of COVID-19 patients are observed in cur-
rent clinical experience. These high sedation require-
ments are likely related to younger age and good
health of many patients before the onset of COVID-
19, high respiratory drive, and intense inflamma-
tory responses previously linked to tolerance.3 This
translates into the need to administer combinations
of multiple agents (eg, propofol, ketamine, hydro-
morphone, dexmedetomidine, and midazolam),
increasing potential risks of side effects (eg, QT
interval prolongation, hypertriglyceridemia, hypo-
tension, and delirium) and requiring vigilance of the
ICU staff. When these are administered in combina-
tions, the typical requirements to ensure patient com-
fort and ventilator synchrony in adult patients range
between 25 and 50 µg/kg/min for propofol, 10 and
20 µg/kg/min for ketamine, 2 and 4 mg/h for hydro-
morphone, and 2 and 5 mg/h for midazolam. There
are currently no sedation guidelines specific for this
Funding: D.H. is supported by a Clinical Investigator Award from the
National Heart, Lung, and Blood Institute (K08HL141694).
e40   
www.anesthesia-analgesia.org
Copyright © 2020 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited.
longed drug administrations.
Deeper sedation levels may be required to facilitate
ventilator synchrony in patients with severe acute
respiratory distress syndrome (ARDS) and may also
be favored by ICU staff to reduce risk of patient self-
extubation, which is particularly problematic in this
population given the need for emergent reintubation
and risk of exposure to coronavirus. Subsequent tol-
erance to sedatives (eg, dexmedetomidine) from their
use early in the course of illness and high doses will
also limit the effectiveness of these drugs during ven-
tilator weaning.
Intermittent administration of certain drugs (eg,
narcotics) tailored to individual needs of each patient
may not always be feasible in situations of over-
whelmed health care systems (eg, when one nurse is
required to attend to multiple critically ill patients).
In these situations, continuous infusions of sedative
drugs are favored for their practicality, but this prac-
tice further increases the risks of side effects.
A subset of patients with severe ARDS is likely to
require prolonged sedation (often >2 weeks)4 to facili-
tate lung-protective mechanical ventilation or extra-
corporeal membrane oxygenation (ECMO) therapy
and subsequent weaning. These prolonged periods
of time may lead to drug accumulation (midazolam),
tolerance and tachyphylaxis (dexmedetomidine),
hypertriglyceridemia (propofol), QT interval pro-
longation (haloperidol), psychomimetic effects (ket-
amine), hyperalgesia or opioid dependence (fentanyl
and/or hydromorphone), and delirium (midazolam).
Increased precision in monitoring the depth of
sedation (eg, processed electroencephalogram [EEG])
is required in patients with high sedation require-
ments who also require neuromuscular blockade to
improve respiratory system compliance. While these
neuromonitoring technologies exist,5 they may not be
widely available given the number of patients who
would benefit. Patient awareness under these condi-
tions (eg, paralysis or prone position) may result in
significant psychological trauma.
Prolonged infusions of opioids that are often
required to facilitate strict lung-protective ventilation
are known to result in gut hypomotility, leading to
intolerance to feeding, interruptions in feeding, and
malnutrition during prolonged ICU stay. These gas-
trointestinal side effects of opioids may also result in
abdominal distension, which can impair ventilation
and/or contribute to nausea/vomiting, increasing
the risk of aspiration.
High doses of opioids, sometimes required to
facilitate lung-protective ventilation in patients with
ventilator dyssynchrony, may paradoxically compli-
cate ventilation management by inducing breathing
ANESTHESIA & ANALGESIA
 EE LETTERS TO THE EDITOR
patterns with large tidal volumes that may further
injure lungs.
Prolonged infusions of high doses of sedatives and
analgesics in large numbers of patients have already
resulted in drug shortages at hospital, regional, and
state levels. In these situations, providing sedation
with less commonly used agents (barbiturates, meth-
adone, clonidine, chlorpromazine, and propranolol)
may need to be considered. The use of inhalational
anesthetics (eg, isoflurane), at least in locations with
appropriately designed scavenging systems, such as
operating rooms converted to ICUs, may be a ratio-
nal alternative that is supported by their documented
safety6 and potential anti-inflammatory and lung-pro-
tective effects.
Attention must be paid to the potential interaction
between sedative drugs and other agents adminis-
tered as part of clinical trials (there are >300 clinical
COVID-19 trials currently ongoing worldwide). For
instance, significant QT prolongations may result
from combinations of hydroxychloroquine and halo-
peridol. Administration of barbiturates may increase
metabolism of hydroxychloroquine. In patients with
high fevers, dexmedetomidine may need to be dis-
continued to help delineate the cause of the fever.
In summary, management of sedation in ICU
patients with COVID-19 needs to reflect individual
properties and side effect profiles of agents, unique
patient characteristics (prolonged intubation and
virus shedding), and health care system limitations
(large numbers of patients, ICU patients in emergency
rooms and operating rooms, and drug shortages).
Potential for interactions with investigational drugs
used in clinical trials (some blinded to ICU staff)
needs to be considered. The collective clinical expe-
rience from the United States and from other highly
affected areas around the world should be quickly
leveraged to formulate recommendations and guide-
lines to increase patient safety and provider aware-
ness of these unique challenges.
Dusan Hanidziar, MD, PhD
Edward A. Bittner, MD, PhD
Department of Anesthesia, Critical Care and Pain Medicine
Massachusetts General Hospital
Boston, Massachusetts
dhanidziar@partners.org
REFERENCES
1. Alhazzani W, Møller MH, Arabi YM, et al. Surviving sep-
sis campaign: guidelines on the management of critically
ill adults with Coronavirus Disease 2019 (COVID-19). Crit
Care Med. 2020 March 27 [Epub ahead of print].
2. Greenland JR, Michelow MD, Wang L, London MJ. COVID-
19 infection: implications for perioperative and critical care
physicians. Anesthesiology. 2020 March 27 [Epub ahead of
print].
July 2020 • Volume 131 • Number 1 www.anesthesia-analgesia.org e41
Copyright © 2020 International Anesthesia Research Society. Unauthorized reproduction of this article is prohibited.
3. Martyn JAJ, Mao J, Bittner EA. Opioid tolerance in critical
illness. N Engl J Med. 2019;380:365–378.
4. Bhatraju PK, Ghassemieh BJ, Nichols M, et al. COVID-19 in
critically ill patients in the Seattle region - case series. N Engl
J Med. 2020 March 30 [Epub ahead of print].
5. Fahy BG, Chau DF. The technology of processed electroen-
cephalogram monitoring devices for assessment of depth of
anesthesia. Anesth Analg. 2018;126:111–117.
6. Jerath A, Panckhurst J, Parotto M, et al. Safety and efficacy
of volatile anesthetic agents compared with standard intra-
venous midazolam/propofol sedation in ventilated critical
care patients: a meta-analysis and systematic review of pro-
spective trials. Anesth Analg. 2017;124:1190–1199.
DOI: 10.1213/ANE.0000000000004887
COVID-19 Putting Patients at Risk
of Unplanned Extubation and Airway
Providers at Increased Risk of
Contamination
To the Editor
C
oronavirus 2019 (COVID-19) puts patients
at increased risk of experiencing unplanned
extubation (UE), and both UE and subsequent
reintubation put providers at increased risk of viral
contamination. The increased patient surge that has
occurred during this COVID-19 pandemic and the
associated less-than-ideal provider/patient ratios put
patients at increased risk for UE. In addition, patient
proning, a common procedure in critically ill COVID-
19 adult respiratory distress syndrome (ARDS)
patients, is a risk factor for UE.
UE includes any unintentional and uncontrolled
removal of an endotracheal tube, such as self-extu-
bation (when a patient pulls his or her own tube)
and accidental extubation (when an external force
is applied to the endotracheal tube during patient
movement or during nursing care and results in
dislodgement of the tube). Before the COVID-19
pandemic, the incidence of UE in the adult inten-
sive care unit (ICU) setting ranged in the literature
from 0.8% to 35.8%, with a median rate of 7.3%.1
With an average 1.65 million adult patients requir-
ing mechanical ventilation per year in the United
States, approximately 120,000 adult patients experi-
enced these types of UE each year before the current
pandemic.2
With the massive surge of patients requiring
intubation and mechanical ventilation that is occur-
ring with this COVID-19 pandemic, statistically we
should also expect an increase in number of incidents
of UE. According to the Center for Disease Control
Conflicts of Interest: A. Kanowitz is the founder of Securisyn Medical, which
markets securement devices for endotracheal tubes. The remaining author
declares no conflicts of interest.