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Medical Grand Rounds

STEROIDS IN THE ACUTELY ILL: EVOLVING RECOMMENDATIONS AND PRACTICE

Stephen M. Pastores, MD, MACP, FCCP, FCCM
Cleveland Clinic Journal of Medicine September 2022, 89 (9) 505-511; DOI:
https://doi.org/10.3949/ccjm.89gr.22002
Stephen M. Pastores
Program Director, Critical Care Medicine; Vice-Chair of Education, Department of
Anesthesiology and Critical Care Medicine, Memorial Sloan Kettering Cancer
Center; Professor of Medicine in Anesthesiology and Medicine, Weill Cornell
Medical College, New York, NY; researcher and member of guidelines committees on
the use of corticosteroids in acutely ill patients
* Find this author on Google Scholar
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* Search for this author on this site
* For correspondence: pastores@mskcc.org

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ABSTRACT

Critical illness-related corticosteroid insufficiency (CIRCI) is a state of
systemic inflammation involving dysregulation of the
hypothalamic-pituitary-adrenal axis, altered cortisol metabolism, and tissue
resistance to corticosteroids. Many conditions may be associated with CIRCI,
including sepsis, septic shock, acute respiratory distress syndrome, and severe
community-acquired pneumonia. Recommendations and practice for diagnosing and
treating this condition have evolved as information has emerged. Here, the
author reviews the current thinking.

KEY POINTS

* Guidelines suggest giving intravenous (IV) hydrocortisone 200 mg/day (50 mg
IV every 6 hours or as a continuous infusion) to patients who have septic
shock and ongoing need for vasopressor therapy to maintain adequate blood
pressure, but not to those who have sepsis without septic shock.

* Guidelines suggest giving IV methylprednisolone 1 mg/ kg/day or dexamethasone
20 mg/day to those with acute respiratory distress syndrome, provided it is
early (within 72 hours of onset) and severe (with a PaO2/FiO2 ratio < 200).

* Dexamethasone 6 mg IV once daily for up to 10 days is recommended for
hospitalized patients with COVID-19 who require supplemental oxygen,
noninvasive respiratory support, or invasive mechanical ventilation.

* Using and tapering steroids should always be guided by clinical response and
side effects.

The term circi, or critical illness-related corticosteroid insufficency, was
coined in 2008 by an international multidisciplinary task force of the Society
of Critical Care Medicine and the European Society of Intensive Care Medicine
when they released the guidelines for the diagnosis and treatment of CIRCI.1 The
guidelines were updated in 20172,3 and are being updated for publication in
2023.

Recommendations have evolved as new information has been generated with regards
to what causes CIRCI, how to diagnose it, who should receive corticosteroid
treatment, and what regimens to use.

THREE MAIN MECHANISMS

In 2008, we described CIRCI as a syndrome of inadequate corticosteroid activity
for the severity of the patient’s illness, that may occur with a decrease in
adrenal steroid production (adrenal insufficiency) or from tissue resistance to
glucocorticoids with or without adrenal insufficiency. To these mechanisms we
now add alterations in cortisol metabolism.

During critical illness, production of adrenocorticotropic hormone (ACTH) is
often low, while cortisol levels tend to be normal or, usually, high. The
diurnal rhythm in cortisol levels (normally lower in the evening and higher in
the morning) is also lost.

More than 90% of circulating cortisol is bound to corticosteroid-binding
globulin, which tends to fall during critical illness. Only 5% to 10% of
cortisol is free and biologically active.

Normal total cortisol levels are between 5 and 24 μg/dL.

Cortisol is a lipophilic hormone that enters cells passively and binds to
specific glucocorticoid receptors in the cytoplasm, or to membrane sites.
Cortisol is metabolized primarily in the liver by 5 alpha/beta-reductases and in
the kidneys by the 11-beta-hydroxysteroid dehydrogenase (11-beta-HSD) type 2
enzyme. During severe stress states, the expression and activity of these enzyme
systems is reduced, leading to decreased clearance of cortisol. Upon binding of
glucocorticoid, the glucocorticoid receptor undergoes a conformational change,
dissociates from the chaperone proteins, and enters the nucleus and
mitochondria, where it binds to positive (transactivation) or negative
(cis-repression) specific DNA regions termed glucocorticoid responsive elements
to regulate transcription and translation of target genes in a cell- and
gene-specific manner. Nuclear factor kappa B is the major transcription protein
that glucocorticoids inhibit, and this inhibition is responsible for
downregulating the actions of proinflammatory cytokines such as tumor necrosis
factor-alpha, interleukin 1, and interleukin 6. Glucocorticoids also act through
a nongenomic pathway.

CIRCI IS COMMON

The incidence of CIRCI varies widely, depending on the population studied and
the diagnostic criteria used: 20% to 60% of patients with septic shock in a
medical intensive care unit, 21% to 75% of patients with human immunodeficiency
virus infection who are critically ill, and 15% to 50% of patients with
traumatic brain injury.4,5

The common clinical features are hemodynamic instability despite adequate fluid
resuscitation, and fever and inflammation without an obvious source of infection
that does not respond to empiric antimicrobial therapy. Other, nonspecific signs
and symptoms can include altered mental status, gastrointestinal symptoms,
hypoglycemia, eosinophilia, hyponatremia, and hyperkalemia. Hyponatremia and
hyperkalemia are less common than in patients with primary adrenal
insufficiency, in whom they may be more prominent.

Many conditions can be associated with CIRCI: sepsis, septic shock, acute
respiratory distress syndrome (ARDS), major trauma, severe bacterial pneumonia,
bacterial meningitis, and nonseptic shock states such in patients
cardiopulmonary bypass, post cardiac arrest, cardiogenic shock, and burns.

NO SINGLE TEST CAN RELIABLY DIAGNOSE CIRCI

In 2008, the Corticosteroid Guideline Task Force recommended two ways of testing
for CIRCI in the critically ill:

* The cosyntropin stimulation test (an increase in the total serum cortisol
from baseline of less than 9 μg/dL 60 minutes after giving an intravenous
(IV) 250-μg dose of cosyntropin, a synthetic formulation of natural ACTH)

* A random total plasma cortisol level (of less than 10 μg/dL).

However in 2017, we concluded that no single test can reliably diagnose the
syndrome, and we could not reach a consensus (> 80% agreement) on whether the
ACTH stimulation test is superior to random cortisol for the routine diagnosis
of CIRCI.

If the ACTH stimulation test is used, we recommend that the high dose of
cosyntropin (250 μg IV) be used for testing rather than the low dose (1 μg),
because the latter has mediocre sensitivity in critically ill patients. This was
a weak recommendation based on low-quality evidence.

We advised against measuring plasma free cortisol. We found no randomized trial
that compared serum total vs free cortisol levels to diagnose CIRCI. A
prospective study of 112 critically ill adults with treatment-insensitive
hypotension, published after the 2008 recommendations, found a good correlation
between serum concentrations of free and total cortisol before and after 250 μg
ACTH stimulation testing.6 Measurement of free cortisol is cumbersome to perform
and may not be widely available in hospital laboratories, and so for practical
purposes we felt that measurement of total cortisol would be preferable for most
clinicians.

We also suggested against the use of salivary cortisol levels, as it would not
be cost-effective, practical, or feasible given that it is tested by enzyme
immunoassay, which may not be routinely available at most centers.

Most importantly, we emphasized that if corticosteroids are clinically indicated
in acutely ill or critically ill patients, there is no need to do a cosyntropin
stimulation test.

Patients already on steroids (ie, ≥ 5 mg of prednisone or 20 mg of
hydrocortisone per day for at least 3 weeks) are at risk of
hypothalamic-pituitary-adrenal axis suppression. Cosyntropin stimulation testing
is recommended only for those who are more likely to develop either permanent,
secondary adrenal insufficiency or CIRCI, to confirm or deny need for permanent
replacement therapy or to monitor their recovery during the final phases when
tapering the corticosteroid. Dexamethasone does not interfere with the cortisol
response or with the cortisol assay. However, if someone is taking
hydrocortisone, it should be discontinued the evening before stimulation
testing.

DIFFERENT GLUCOCORTICOID PREPARATIONS

The biologic rationale for glucorticoid use in acutely ill patients relates to
its potent anti-inflammatory effects and to its effects on cardiovascular tone,
including enhanced vasoconstrictor responde to exogenous catecholamines and
inhibition of cyclo-oxygenase-2 and inducible nitric oxide synthase.
Hydrocortisone tends to be preferred as replacement therapy, as it has a short
duration of action which allows the hypo-thalamic-pituitary-adrenal axis to
recover between doses. However, prednisone, dexamethasone, and
methylprednisolone are the agents we generally use, particularly in those with
severe inflammation including bacterial pneumonia and ARDS.

SIDE EFFECTS

Steroids are not benign drugs. They can be associated with several side effects,
most notably hyperglycemia, but also hypernatremia, neuromuscular weakness,
myopathy, superinfections, upper gastrointestinal bleeds, arrhythmias, and
steroid-induced psychosis.

STEROIDS TO TREAT SEPTIC SHOCK

Corticosteroids have been used in septic shock for nearly 6 decades, and
practice has changed as information has emerged.

1976—Schumer7 performs the first randomized controlled trial, using very large
doses of steroids, ie, dexamethasone 3 mg/ kg or methylprednisolone in doses of
nearly 2 g daily, in 172 patients with clinical septic shock and finds a
reduction in mortality.

1980s—Bone et al8 and Sprung et al9 find that high-dose methylprednisolone (30
mg/kg daily) does not increase survival, and it induces superinfections in many
patients. For the next 15 years, steroids are avoided in patients with septic
shock.

2002—Annane et al10 find that the combination of hydrocortisone 50 mg IV every 6
hours plus flud-rocortisone 50 μg enterally daily is associated with a lower
mortality rate, especially in those who do not respond to the cosyntropin
stimulation test. However, patients who do respond derive no benefit. In the
next few years, cosyntropin stimulation testing becomes popular, and
nonresponders get hydrocortisone plus fludrocortisone.

2008—The Corticosteroid Therapy of Septic Shock (CORTICUS) trial11 finds no
benefit to the use of hydrocortisone 50 mg IV every 6 hours in terms of
survival, but shock reversal is faster. Response to the cosyntropin stimulation
test does not seem to matter. Many clinicians begin to abandon the stimulation
test in patients deemed to already have an indication for corticosteroids, ie,
refractory septic shock.

2016—The Hydrocortisone for Prevention of Septic Shock (HYPRESS) trial,12 with
380 patients, finds that hydrocortisone 200 mg/day IV for 5 days does not
prevent progression from sepsis to septic shock, indicating steroids should not
be used for patients with sepsis who are not in refractory shock.

2018—The Adjunctive Corticosteroid Treatment in Critically Ill Patients With
Septic Shock (ADRENAL) trial,13 in 3,800 patients, finds that hydrocortisone 200
mg by IV infusion for 7 days compared with placebo was not associated with
survival benefit, but shock reversal is faster, duration of mechanical
ventilation is shorter, and fewer blood transfusions are needed, with relatively
few side effects, mainly hyperglycemia.

2018—The Activated Protein C and Corticosteroids for Human Septic Shock
(APROCCHSS) trial,14 in 1,241 patients, uses the combination of hydrocortisone
200 mg IV in divided doses (50 mg IV every 6 hours) and fludrocortisone 50 μg
enterally daily for 7 days. At 90 days, fewer patients in the steroid group had
died, shock reversal was faster, and the steroid regimen was found to be safe;
hyperglycemia was the most common adverse reaction. At 180 days, the survival
benefit remained.

2019—A Cochrane meta-analysis15 finds that corticosteroid therapy “probably”
reduces hospital mortality (by about 9%), and results in large reductions in
length of stay in the intensive care unit (by about 1 day) and in the hospital
(by about 1 and one-half days). Corticosteroid therapy was associated with
increased risk of hyperglycemia, hypernatremia, and muscle weakness but no
increased risk of superin-fection and little or no difference in
gastrointestinal bleeding, neuropsychiatric, stroke, or cardiac events.

2020—Enter artificial intelligence. Pirracchio et al16 enter data from about
2,500 patients from 4 septic shock clinical trials into an artificial
intelligence program to attempt to more precisely determine who should receive
corticosteroids, based on multiple patient variables. This seems to be where the
future lies. They found that strategies to treat all patients with
corticosteroids or to treat no one were associated with a worse outcome. In
contrast, an individual estimation-based treatment strategy always yielded a
positive net benefit.

2017 GUIDELINES

The 2017 guidelines3 were issued just before the results of the ADRENAL and
APROCCHSS trials were published. Our suggestions at that time were as follows:

Consider the use of IV hydrocortisone less than 400 mg/day for at least 3 days
in patients in septic shock who already got adequate fluid resuscitation and
still need moderate to high-dose vasopressor therapy (conditional
recommendation, low quality of evidence).

Do not use corticosteroids in adult patients with sepsis who are not in
refractory shock (conditional recommendation, moderate quality of evidence).

> Steroid use should always be guided by clinical response and tapered slowly to
> avoid the rebound phenomenon

SURVIVING SEPSIS CAMPAIGN GUIDELINES 2021

Recommendations from the Surviving Sepsis campaign17 published in 2021 are
similar, suggesting intravenous corticosteroids (eg, hydrocortisone 200 mg per
day in divided doses or as continuous infusion) for adult patients in septic
shock who continue to need vasopressor therapy (norepinephrine or epinephrine ≥
0.25 μg/kg/minute at least 4 hours after initiation) (weak recommendation;
moderate-quality evidence).

STOPPING STEROIDS

If the patient no longer needs vasopressor therapy, is out of shock, and is
maintaining adequate blood pressure for at least 12 to 24 hours, it is probably
time to consider tapering or discontinuing steroids.

An exception is in patients who have an underlying endocrine disorder or
indication for using corticosteroids: in those patients you have to taper the
corticosteroids back to their usual dose. This has to be done carefully. One
recommendation is to decrease by 10 to 20 mg over several days to weeks,
depending on how much they required for maintenance therapy.

Steroid use should always be guided by clinical response and tapered slowly to
avoid the rebound phenomenon.

STEROID USE IN ACUTE LUNG INJURY AND ARDS

The ARDS Network study18 showed that corticosteroids should not be used in
patients in the late phase of ARDS, ie, after 2 weeks on a ventilator. But what
about early?

Meduri et al19 performed a randomized, double-blind placebo-controlled trial in
91 patients with severe early ARDS (within 72 hours), 66% of whom had sepsis.
They randomized these patients in a 2:1 ratio to methylprednisolone infusion 1
mg/ kg/day vs placebo. They tapered the steroid slowly, keeping the same dose
for 14 days, cutting it in half on day 15 to day 21, in half again from day 21
to 28, and then stopping. More importantly, they did surveillance with frequent
bronchoscopies to rule out infection, and they avoided neuromuscular blockade so
as not to accentuate neuro-muscular weakness, a side effect of steroids.

The primary outcome was a reduction in the Lung Injury Score or successful
extubation by day 7, both of which were achieved. There were also significant
reductions in the duration of mechanical ventilation, length of stay in the
intensive care unit, and mortality.

The 2017 guidelines3 gave a weak recommendation for the use of
methylprednisolone 1 mg/kg/day in patients with ARDS, specifically patients
receiving at least 50% FiO2 on mechanical ventilation with positive
end-expiratory pressure of 10 cm H2O or more who have a PaO2/FiO2 ratio under
200. The tradeoff is hyperglycemia. We felt there was no increased risk of
neuromuscular weakness, gastrointestinal bleeding, or nosocomial infection.

Villar et al20 performed a study in 277 patients who had moderate to severe
ARDS, with PaO2/FiO2 ratios less than 200 despite lung-protective ventilation
and other strategies to optimize them on mechanical ventilation; 77% of these
patients had either pneumonia- or sepsis-associated ARDS. They randomized the
patients to dexamethasone 20 mg/day for 5 days, and then 10 mg/day on days 6 to
10, and then stopped the steroid shortly after that in most patients. The study
was conducted over 5 years. The trial was stopped by the Data and Safety
Monitoring Board due to low enrollment rate after enrolling nearly 90% of the
planned sample size. The investigators found significant benefits with
dexamethasone in terms of ventilator-free days, all-cause mortality at day 60,
and duration of mechanical ventilation.

STEROIDS IN SEVERE BACTERIAL PNEUMONIA

In 2017, we suggested using corticosteroids in hospitalized patients with severe
community-acquired pneumonia who required mechanical ventilation or vasopressor
therapy (conditional recommendation, moderate quality of evidence).21

This was largely based on a trial by Torres et al,22 published in 2015, in
patients with severe community-acquired pneumonia and a high systemic
inflammatory response, with C-reactive protein levels greater than 15 mg/L,
requiring mechanical ventilation or vasopressor therapy. Corticosteroid therapy
was associated with improvement in survival. Hyperglycemia was the most common
adverse effect.

A Cochrane review23 in 2017 looked at 17 randomized controlled trials involving
2,264 patients and showed corticosteroids to significantly reduce mortality and
morbidity rates in patients with severe community-acquired pneumonia, but not in
those with nonsevere community-acquired pneumonia.

COVID-19

The initial flulike symptoms of COVID-19 are usually associated with
bioreplication, and by the time the patients come to the hospital with
respiratory symptoms they usually are already at risk with a severe inflammatory
response that can progress to ARDS and the need for invasive mechanical
ventilation. These patients have elevations in proinflammatory markers and
inflammatory cytokines such as C-reactive protein, IL-6, and IL-1.

In April 2020, we argued in favor of corticosteroid therapy in patients with
severe COVID-19-associated ARDS based on available observational evidence at
that time and the extremely high mortality associated with the disease, and in
favor of not waiting for the results of the randomized controlled trials.24

The Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial25 published its
results a few months later. It was large, with 6,425 patients, of whom 2,104
received dexamethasone 6 mg IV daily for up to 10 days, and the rest usual care.
Dexamethasone reduced mortality by one-third in those who required mechanical
ventilation and by one-fifth in those receiving supplemental oxygen. However,
there was no benefit in patients who were not receiving respiratory support, and
there was even the suggestion of harm that could not be excluded.

A meta-analysis conducted by the World Health Organization Rapid Evidence
Appraisal for COVID-19 Therapies Working Group26 showed that the mortality rate
at 28 days was significantly lower in patients with COVID-19 pneumonia and ARDS
who got corticosteroid therapy, compared with those who did not receive
corticosteroids (32.7% vs 41.5%, respectively).

IS VIRAL SHEDDING A PROBLEM?

In the influenza H1N1 and SARS epidemics, when steroids were given very early,
they were associated with adverse outcomes. However, by the time patients with
COVID-19 come to the hospital and need supplemental oxygen or mechanical
ventilation, they are usually in a very proinflammatory phase, and at that point
there is probably already less likelihood of delay in SARS-CoV-2 viral
clearance.

Cano et al27 reviewed 73 studies involving 21,350 patients, which showed there
was clearly a benefit of using corticosteroids in terms of mortality in very
sick patients with COVID-19. They did not find any significant impact on viral
shedding.

> The mortality rate is significantly lower in severely ill patients with
> COVID-19 who receive dexamethasone

LOW VS HIGH DOSE OF DEXAMETHASONE IN COVID-19

Why not use a higher dose of dexamethasone? Dexamethasone 6 mg is equivalent to
only about 30 mg of methylprednisolone. Would 12 mg be better than 6 mg?

Two randomized controlled trials28,29 did not show a statistically significant
benefit in terms of survival at 28 days in patients who received 12 mg compared
with those who received 6 mg. Therefore, 6 mg of dexamethasone is still most
commonly given. In my own practice, I occasionally either double the dose if
patients are on 6 mg and not clinically responding and remain very hypoxic, or
switch to methylprednisolone 1 mg/kg/day, and see if they respond. You can
double it up to 2 mg per kg depending on inflammatory markers if they have ARDS.

Comparing dexamethasone and methylprednisolone, I favor methylprednisolone
because it resides longer in the lung and is more potent as an anti-inflammatory
agent, but always start with 6 mg of dexamethasone and then move from there
depending on how sick the patient is.

The National Institutes of Health guidelines30 recommend the following:

* Remdesivir, dexamethasone, or both for hospitalized patients who require
supplemental oxygen

* Dexamethasone with or without remdesivir for patients who require oxygen
through a high-flow nasal cannula or noninvasive ventilation (plus either
baricitinib or IV tocilizumab for patients with rapidly increasing oxygen
needs and systemic inflammation)

* Dexamethasone for those requiring mechanical ventilation or extracorporeal
membrane oxygenation (plus IV tocilizumab for those within 24 hours of
admission to the intensive care unit).

Chaudhuri et al31 did a systematic review and meta-analysis of 2,826 patients
treated with steroids for COVID-19 and non-COVID-19 ARDS in 18 randomized
controlled trials. They concluded the use of corticosteroids “probably” reduces
mortality in patients with ARDS of any etiology, and patients who got a longer
course of corticosteroids (more than 7 days) had higher rates of survival than
those who got a shorter course.

DISCLOSURES

Dr. Pastores has disclosed serving as advisor or review panel participant for
AbbVie Pharmaceuticals, as research investigator with bioMerieux, Eisai, and
Revimmune, receiving royalty fees as textbook editor for McGraw-Hill.

FOOTNOTES

* Medical Grand Rounds articles are based on edited transcripts from Medicine
Grand Rounds presentations at Cleveland Clinic. They are approved by the
author but are not peer-reviewed.

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* Steroids in COVID-19: An overview
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* Blood purification for sepsis: an overview
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Cleveland Clinic Journal of Medicine
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Steroids in the acutely ill: Evolving recommendations and practice
Stephen M. Pastores
Cleveland Clinic Journal of Medicine Sep 2022, 89 (9) 505-511; DOI:
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* Article
* ABSTRACT
* THREE MAIN MECHANISMS
* CIRCI IS COMMON
* NO SINGLE TEST CAN RELIABLY DIAGNOSE CIRCI
* DIFFERENT GLUCOCORTICOID PREPARATIONS
* SIDE EFFECTS
* STEROIDS TO TREAT SEPTIC SHOCK
* STEROID USE IN ACUTE LUNG INJURY AND ARDS
* STEROIDS IN SEVERE BACTERIAL PNEUMONIA
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