What you need to know
Sepsis is a syndrome of life threatening infection with organ dysfunction, and most
guidelines do not advise use of corticosteroids to treat it in the absence of refractory
shock
Two new trials of corticosteroid treatment for sepsis came to differing conclusions
Corticosteroids may reduce the risk of death by a small amount and increase neuromuscular
weakness by a small amount, but the evidence is not definitive
This guideline makes a weak recommendation for corticosteroids in patients with sepsis;
both steroids and no steroids are reasonable management options
Fully informed patients who value avoiding death over quality of life and function
would likely choose corticosteroids
Do corticosteroids reduce death or improve recovery in people with sepsis or septic
shock? Our panel make a weak recommendation to give corticosteroids to people with
all types and severity of sepsis, based on new evidence. Because we are not certain
that they are beneficial, it is also reasonable not to prescribe them. Patients’ values
and preferences may guide this decision-making process.
This rapid recommendation was triggered by two trials, with differing conclusions
whose results might change practice:
ADRENAL (3658 patients who had septic shock) found no statistically significant difference
in 90 day mortality between the hydrocortisone and placebo groups.1
APROCCHSS (1241 patients who had septic shock) found that hydrocortisone plus fludrocortisone
reduced 90 day mortality.2
The trials are incorporated into a linked systematic review comparing corticosteroids
with placebo.3 This BMJ Rapid Recommendation promptly and transparently translates
this evidence using GRADE methodology for trustworthy guidelines. Sepsis is a life
threatening organ dysfunction from infection. Currently most guidelines advise against
giving corticosteroids in sepsis in the absence of refractory shock, but these guidelines
have not taken into account the new evidence. We do not anticipate that new clinical
trials will substantively alter the evidence suggesting a small but uncertain mortality
reduction. Box 1 shows publications linked in this Rapid Recommendation package. The
main infographic provides an overview of the absolute benefits and harms. The table
at the end of the article shows any evidence that has emerged since the publication
of this guideline.
Box 1
Linked articles in the BMJ Rapid Recommendation cluster
Lamontagne F, Rochwerg B, Lytvyn L, et al. Corticosteroid therapy for sepsis: a clinical
practice guideline. BMJ 2018;362:k3284
Summary of the results from the Rapid Recommendation process
Rochwerg B, Oczkowski SJ, Siemieniuk RAC, et al. Corticosteroids in sepsis: an updated
systematic review and meta-analysis. Crit Care Med 2018. doi:10.1097/CCM.0000000000003262
3
Review and meta-analysis of all available randomised trials that assessed corticosteroid
therapy for sepsis
MAGICapp (https://app.magicapp.org/public/guideline/EZ1w8n)
Expanded version of the results with multilayered recommendations, evidence summaries,
and decision aids for use on all devices
Current understanding
Sepsis is life threatening organ dysfunction caused by a dysregulated host response
to infection.4 In practice, a sepsis-related organ failure assessment (SOFA) score
of ≥2 in patients with infections is sepsis (table 1).4
5 Worldwide, about 30 million people are hospitalised with sepsis every year and up
to six million of them die.6
Table 1
Sepsis-related organ failure assessment (SOFA) score to help diagnose sepsis (adapted
from Vincent et al5)*
System or organ and measure
SOFA score
0
1
2
3
4
Respiratory:
PaO2/FiO2, mm Hg
≥400
300-399
200-299
100-199 with respiratory support
<100 with respiratory support
Coagulation:
Platelets, × 103/μL
≥150
100-149
50-99
20-49
<20
Liver:
Bilirubin, μmol/L (mg/dL)
<20 (1.2)
20-32 (1.2-1.9)
33-101 (2.0-5.9)
102-204 (6.0-11.9)
>204 (12.0)
Circulatory:
Mean arterial pressure, mm Hg
≥70
<70
Low dose dopamine or any dose dobutamine
Low-medium dose noradrenalin or adrenalin; medium dose dopamine
High dose noradrenalin, adrenalin, or dopamine
Central nervous system:
Glasgow Coma Scale score
15
13-14
10-12
6-9
<6
Renal:
Creatinine, μmol/L (mg/dL)
<110 (1.2)
110-170 (1.2-1.9)
171-299 (2.0-3.4)
300-440 (3.5-4.9)
>440 (5.0)
Urine output, mL/day
–
–
–
<500
<200
*
Our recommendation applies to patients with an infection and a SOFA score of ≥2.
PaO2 = partial pressure of oxygen (arterial). FiO2 = fraction of inspired oxygen.
Clinicians typically manage sepsis with early, broad spectrum antibiotics. They may
provide supportive treatment such as vasoactive drugs and mechanical ventilation.
They track and adjust treatment based on clinical signs and laboratory data.7 Septic
shock is the most severe form of sepsis. These patients experience profound circulatory,
metabolic, and cellular abnormalities.4
8 They require vasopressors to maintain perfusion pressure and have elevated serum
lactate concentrations despite adequate fluid repletion.
It is possible that corticosteroids help improve the dysregulated immune response
caused by sepsis9 and increase blood pressure if it is low.10 Some clinicians have
found this biological rationale, and results of early studies, compelling. Others
disagree and do not use corticosteroids.11
Most professional organisations recommend against corticosteroid use in the absence
of refractory shock.12
Table 2 summarises current professional society guidelines.
Table 2
Current recommendations for corticosteroid therapy in patients with sepsis
Society
Recommendation regarding corticosteroid use
In sepsis
In septic shock
Other situations
“Surviving Sepsis” for SCCM and ESICM, 20167
Against
In favour for hypotension refractory to fluid resuscitation and vasopressor
History of adrenal insufficiency or corticosteroid use
CIRCI guidelines for SCCM and ESICM, 201812
13
Against
In favour for shock not responsive to fluid and at least moderate dose vasopressor
Acute respiratory distress syndromeCommunity acquired pneumoniaBacterial meningitisHistory
of adrenal insufficiency or corticosteroid use
CAEP, 200814
Against
In favour for haemodynamically unstable patients not responsive to fluid resuscitation
and vasopressor
NICE, 201715
Not mentioned
Not mentioned
Not mentioned
JSICM, 201816
Against
In favour for shock not responsive to initial fluid resuscitation and vasoactive drugs
SCCM = Society of Critical Care Medicine. ESICM = European Society for Intensive Care
Medicine. CIRCI = critical illness-related corticosteroid insufficiency. CAEP = Canadian
Association of Emergency Physicians. NICE = National Institute for Health and Care
Excellence (UK). JSICM = Japanese Society for Intensive Care Medicine.
How this recommendation was created
Our international panel included sepsis survivors, family caregivers of patients who
had sepsis, intensivists, internists, nurses, an endocrinologist, physiotherapists,
trialists, and methodologists (see appendix 1 on bmj.com). They decided on the scope
of the recommendation and the outcomes that are most important to patients. The panel
judged death and quality of life to be the most important outcomes. Myocardial infarction,
stroke, duration of stay in hospital and in the intensive care unit (ICU), superinfections,
and neuromuscular weakness (such as ICU-acquired weakness) were also identified as
important outcomes for patients.
Surrogate outcomes such as time to shock reversal, organ dysfunction measured by the
sepsis-related organ failure assessment (SOFA) score, hyperglycaemia, and hypernatraemia
were less important to the panel. This view is consistent with GRADE recommendations
to focus on patient-important outcomes rather than surrogates.29
Subgroups of interest—The panel wanted to know whether the effect of corticosteroids
differed in people with sepsis, compared with people who had septic shock, pneumonia,
acute respiratory distress syndrome, or were at higher risk of death.3
30 They also wanted to know whether the type of corticosteroid or its dose influenced
outcomes.
The panel met by videoconference to discuss the evidence and formulate a recommendation.
No panel member had financial conflicts of interest; intellectual and professional
conflicts were minimised and managed (see appendix 2 on bmj.com).
The panel requested a systematic review of randomised controlled trials on the impact
of corticosteroid therapy for patients who have sepsis, including those who have septic
shock.3 This review examines the two latest, as well as previous studies, on corticosteroids
in sepsis. The aim was to resolve apparently conflicting evidence.
The panel followed the BMJ Rapid Recommendations procedures for creating a trustworthy
recommendation,31 including using the GRADE approach to critically appraise the evidence
and create recommendations (see appendix 3 on bmj.com).32 The panel considered the
balance of benefits, harms, and burdens of corticosteroids, the quality of the evidence
for each outcome, expected variations in patient values and preferences, and acceptability
of corticosteroids.33 Determining patient values and preferences occurred before the
panel received the results of the meta-analysis to reduce the risk that opinions regarding
outcome importance will be data driven. According to the GRADE approach, recommendations
can be strong or weak and for or against a course of action.33 High quality evidence
of an effect on surrogate outcomes do not trigger strong recommendations.
The evidence
The linked systematic review identified 42 randomised controlled trials (RCTs) comparing
corticosteroids with no corticosteroids (typically placebo).3
Figure 2 provides an overview of the trials and participants.
Fig 2
Characteristics of patients and trials included in systematic review of the use of
corticosteroids for treating sepsis3 CAP = community acquired pneumonia. ARDS = acute
respiratory distress syndrome.
The systematic review includes total of 10 194 patients who had sepsis. Of the 42
trials included, 24 restricted enrolment to patients who had septic shock. The typical
patient was critically ill—a median of 32% of participants died within the first month.
The most common sources of sepsis were pulmonary infections (median 44%) and abdominal
infections (median 17%). Most of the RCTs used hydrocortisone alone (n=26), others
used hydrocortisone plus fludrocortisone (n=2), methylprednisolone (n=6), prednisolone
(n=3), or dexamethasone (n=3) (see fig 2). Although most of the clinical trials included
patients who had septic shock, many included patients who did not (16 trials, 2241
patients). The linked systematic review provides detailed trial descriptions, including
risk of bias assessments and patient characteristics.3
Subgroups of patients
Corticosteroids did not seem to be more or less effective in particular clinical subgroups,
for example:
Septic shock
Pneumonia
Acute respiratory distress syndrome (ARDS)
Higher baseline risk of death
Different corticosteroid drugs (such as hydrocortisone, methylprednisolone)
Different corticosteroid doses
Different corticosteroid regimens (such as single agents or corticosteroid combinations
such as hydrocortisone plus fludrocortisone)
More recent v older trials
Trials with higher v lower risk of bias.
Older studies tended to use much higher doses of corticosteroids for a shorter time
than are typically used now; the pooled evidence from these older studies is imprecise
(few events), and the linked meta-analysis was underpowered to detect important subgroup
differences such as by dose. All tests for relative subgroup effects may be underpowered
to detect true differences because the effect sizes are small, especially for mortality.
Therefore, we cannot be certain that a true subgroup effect does not exist. Future
meta-analyses of individual patient data may help to identify populations that benefit
more or less from corticosteroids. Until such time, we can only conclude that the
evidence applies to all subgroups.
Understanding the recommendation
The main infographic provides an overview including the benefits and harms, and our
certainty in the evidence for each outcome.
Absolute benefits and harms
There was better survival in the group taking corticosteroids, but this was not certain.
This drives the weak rather than strong recommendation.
Mortality
Corticosteroids may reduce mortality in the first month after admission to an intensive
care unit (ICU) by approximately 2%. However, the panel had low certainty that this
is true. The confidence interval crosses the line of no difference, and the results
were inconsistent, with some RCTs showing a mortality reduction and others showing
none.
The effect on longer term mortality (from 60 days to 1 year) was similar. Fewer studies
reported this outcome, so, although the results were consistent in the RCTs that did
report this outcome, the panel also had low certainty that corticosteroids reduce
longer term mortality.
Quality of life
No RCT reported quality of life outcomes at any time point. The ADRENAL study investigators
are collecting quality of life data at six months, but these data have not been published.17
Outcomes of some interest
Corticosteroids may reduce the length of ICU and hospital stay by less than a day
each (moderate quality evidence). The impact of corticosteroids on other patient-important
outcomes such as stroke and myocardial infarction was extremely uncertain. They may
increase the risk of neuromuscular weakness by a small amount (low quality evidence
from seven RCTs). Possible explanations include the toxic effects on nerve and muscle
cells, and hyperglycaemia from corticosteroid use.18 Weakness may compromise patients’
ability to function independently19 and delay recovery.20
In two of the seven RCTs evaluating weakness, it was prospectively evaluated one month
after enrolment.2
21 Evaluations of neuromuscular weakness, especially in RCTs that relied on investigator
identification, were unreliable. The panel therefore believed that the RCTs probably
underestimated the risk of neuromuscular weakness.
Outcomes of less importance
Corticosteroids probably increase the risk of hyperglycaemia and hypernatraemia. Corticosteroids
probably improve organ function at day 7 and the chance of shock reversal at day 7.
Patient subgroups
Our recommendation applies to all patients with sepsis. There was no meaningful difference
in the efficacy of corticosteroids in different groups of patients including those
with septic shock, pneumonia, acute respiratory distress syndrome, or other sources
of sepsis, or those who were sicker. However, the absolute reduction in mortality
from corticosteroids will be greater in patients with a higher risk of death. The
absolute harm (such as neuromuscular weakness) will also be greater in sicker patients.
The analysis of a subgroup effect showed no convincing evidence of such an effect.
Based on published criteria for credible subgroup effects,22 in the absence of a subgroup
effect, the interpretation of the effect of corticosteroids in any particular subgroup
should be guided by the effect in the overall population of septic patients.
Several trials of corticosteroids for pneumonia or acute respiratory distress syndrome
have enrolled patients who did not have sepsis; we did not consider these trials.
Therefore, clinicians treating these conditions should also consider evidence23
24 and guidelines12 applicable to patients who have pneumonia and acute respiratory
distress syndrome.
Patient values and preferences
Fully informed patients who place a higher value on avoiding death than on quality
of life and function would be more likely to choose to receive corticosteroids. We
heard from our patient partners that most patients will want to reduce their risk
of death, even if this reduction is small and uncertain. This view is consistent with
the experiences of the rest of the panel. Most patients will likely be willing to
accept a small increased risk of weakness.
Patients (or their care givers and surrogate decision-makers) will probably vary in
how they would weigh the balance of expected desirable and undesirable consequences
from corticosteroids. We assume that most patients want to avoid death and will value
even a small, uncertain reduction in mortality. We judge that they will be less concerned
about the possible increase in weakness among survivors. There is also likely to be
a sizeable minority of patients who would place a large value on avoiding a very uncertain
but possible decline in quality of life and functional abilities even at the cost
of a small increase in risk of death.25 Shared decision making conversations about
specific interventions in patients with sepsis may not always be feasible, and could
delay care. However, clinicians should do their best to elicit each patient's values
and preferences. For example, they could talk about the patient’s goals of care with
the patient, their family, and friends.
Practical considerations
Figure 3 outlines the key practical issues for patients and clinicians discussing
corticosteroid treatment for sepsis.
Fig 3
Practical issues about use of corticosteroids for treatment of sepsis
The optimal corticosteroid drug, dose, and duration of treatment are uncertain. Hydrocortisone
was the most commonly used corticosteroid in the RCTs and is therefore a reasonable
choice. Differences among corticosteroids, if they do exist, are probably small; dexamethasone,
methylprednisolone, and prednisolone were also studied and produced similar results.
Adding an agent that has additional mineralocorticoid activity, such as fludrocortisone,
could be helpful, but that is highly speculative.
The typical hydrocortisone dose for an adult in the RCTs was 200-300 mg/day, given
either as an infusion or as boluses every six hours.26 If an infusion is chosen, a
bolus of 50-100 mg can be given before the infusion. In the RCTs the duration of treatment
was typically 7-14 days, or less for those who were rapidly improving.
Inflammation may recur after discontinuing corticosteroid therapy,27 especially when
it is stopped abruptly.28 Clinicians should carefully monitor all patients after discontinuing
corticosteroids. In patients who deteriorate after stopping corticosteroids (such
as development of shock or need for mechanical ventilation), reinitiating corticosteroid
therapy could be helpful, although this is highly speculative. Whether corticosteroids
should be tapered rather than stopped abruptly is unclear. Corticosteroid induced
adrenal suppression is probably duration dependent, and so patients who receive longer
courses of corticosteroids (such as >14 days) might be particularly likely to benefit
from a taper before discontinuing and an evaluation of hypothalamo-pituitary-adrenal
axis function if in doubt.12
Costs
Corticosteroids are typically inexpensive and widely available. The impact of corticosteroids
on the overall costs to patients and to health systems is uncertain and would be driven
mostly by ICU and hospital lengths of stay or prolonged periods of rehabilitation.
Future research
With the exception of the awaited analysis of quality of life in the ADRENAL trial,
there are currently no planned or ongoing RCTs in patients who have sepsis that are
likely to substantively change the overall effect estimates for the key outcomes.
Given remaining uncertainty regarding the effect of corticosteroids in different subgroups,
additional analyses of existing data to explore heterogeneity of treatment effects
are logical next steps before more patients are enrolled in similar trials. Such work
mandates individual patient-data meta-analyses that rely on investigators sharing
the data from their RCTs and cooperation among research networks.
It is possible that additional adaptive RCTs could help to resolve remaining uncertainty.
Key research questions to inform decision makers and future guidelines are:
What is the impact of corticosteroid therapy on quality of life in the short and long
term?
What is the impact of corticosteroid therapy on functional recovery?
What is the impact of corticosteroid therapy on healthcare costs?
Are there subgroups of patients with sepsis who benefit more or less from corticosteroid
therapy?
Are there differences between bolus and infusion dosing?
Does the addition of fludrocortisone improve outcomes?
Updates to this article
The final table shows evidence that has emerged since the publication of this article.
As new evidence is published, a group will assess the new evidence and make a judgment
on to what extent it is expected to alter the recommendation.
New evidence which has emerged after initial publication
Date
New evidence
Citation
Findings
Implications for recommendation(s)
There are currently no updates to the article.