Introduction
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The utility of steroids in sepsis has been debated passionately for decades. There is hope that steroids might improve mortality, but also fear that they could increase infectious complications. Practice varies widely. What does the data truly indicate?
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Four misconceptions and one truth
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Misconception #1: Stress-dose steroids decrease mortality
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This belief is based on the first modern RCT of stress-dose steroids in sepsis by Annane et al. 2002. This study randomized 299 patients with severe vasopressor-refractory shock to placebo versus stress-dose steroids. Patients were also divided into two subgroups depending on whether they responded to an ACTH stimulation test. Their hypothesis was that patients who failed to respond normally to the ACTH stimulation test had inadequate adrenal function and would improve with stress dose steroids. The primary outcome was 28-day mortality (additional details in TheBottomLine blog here).
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Analysis of the raw data reveals no mortality benefit for steroid among any of the patient subgroups (see the unadjusted p-values, which I have added to the table below on the right column). Most notably, 28-day mortality was not significantly reduced among patients who didn’t respond to the ACTH stimulation test (p=0.11, highlighted red box).
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Here is where things get murky. The authors went on to perform an adjusted mortality analysis using a regression model derived from a prior study. The adjusted analysis yielded lower p-values, with a value of p=0.04 for the primary outcome (red box above). The remainder of the paper, and nearly all of the subsequent medical literature, has focused exclusively on the p-values from the adjusted analysis.
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This may not be valid. There is generally no need to perform an adjusted analysis of an RCT. The entire concept of a RCT is that randomization will naturally account for random variation, making an adjusted analysis unnecessary. An adjusted analysis may rarely be performed if there is a considerable imbalance between the groups at baseline, but in this study the groups appear fairly well matched at baseline. There is no explanation in the manuscript as to why an adjusted analysis was performed.
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Currently the ACTH stimulation test in sepsis has been abandoned, partially because it is erratic. Therefore, the non-responder subgroup analysis is no longer clinically relevant to us. The data which are most relevant today are the results from all patients combined. These results are negative regardless of which statistical analysis is used. Therefore, from our perspective today there is unequivocally no mortality benefit.
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As shown below, a meta-analysis failed to find any mortality benefit in anysubset from any study (1). Note that this meta-analysis used the uncorrected data from the Annane 2002 study.
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Thus, no study has convincingly shown a mortality benefit in any group of patients. It is possible that a mortality benefit exists which is too small to detect in these studies. It is possible that a yet-unidentified subgroup of patients experiences a mortality improvement. However, no mortality benefit has ever been clearly proven.
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Misconception #2: Stress-dose steroids increase the risk of secondary superinfection
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Concerns regarding superinfection with stress-dose steroid are largely based on the CORTICUS trial, the second major RCT of steroids in sepsis. This study randomized 499 patients with septic shock to receive stress dose steroids or placebo. The primary endpoint was 28-day mortality, with no difference observed between groups (for additional details see TheBottomLine here). The authors also evaluated the occurrence of 25 adverse events, most notably:
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This data was reported in the paper as follows:
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This description is misleading. As shown in the table above, there were no statistically significant differences in the rate of superinfection, new sepsis, or new septic shock. In order to overcome this lack of statistical significance, the authors seem to have created a post-hoc combined adverse outcome of “new episodes of sepsis or septic shock.” The validity of creating this combined outcome is questionable, and the statistical analysis of this combination outcome remains unimpressive (2).
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As shown below, meta-analysis by Sligl 2009 failed to detect any change in the rate of superinfection among any study or the pooled results.
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Thus, no study or meta-analysis has shown an increase in superinfections. This possibility certainly hasn't been excluded. However, if this risk exists, it doesn't seem to be of substantial clinical significance.
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Truth: Stress-dose steroid reduces the duration of septic shock
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Steroids consistently improve hemodynamic stability, thereby allowing earlier withdrawal of vasopressors and decreasing the duration of shock. As shown in the meta-analysis below by Sligl 2009, this is reproducible across multiple studies and patient populations.
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For example, the duration of septic shock among patients in the CORTICUS trial is shown below. Among all patients, steroids decreased the median time to shock reversal from 5.8 days to 3.3 days (p<0.001).
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Misconception #3: The Annane et al. and CORTICUS studies conflict each other
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It is widely believed that the Annane et al. and CORTICUS trials conflict with each other. Annane et al. is perceived as supporting the use of steroids, whereas CORTICUS does not.
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However, the actual datafrom these two studies are entirely consistent. The raw data from both studies shows no mortality benefit with steroids, faster shock resolution, and no increase in superinfection. The Forrest plots above illustrate that in every single case the point estimates from both studies overlap, indicating statistical agreement. If these two studies had been statistically analyzed and written in a less imaginative way, they would look and sound nearly identical.
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Rather than the data itself, it is primarily the data interpretation and press surrounding these studies which is conflicting. Annane et al. performed an adjusted analysis which seemed to show a mortality benefit, causing enormous excitement about steroids. CORTICUS reported no mortality benefit and focused on some trends among the adverse events, splashing cold water on the enthusiasm generated by Annane et al.
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Misconception #4: The benefit of steroids is limited to patients with vasopressor-refractory shock
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This misconception is a direct consequence of the misconception that Annane et al. was a positive study whereas CORTICUS wasn't (misconception #3). It is commonly believed that the reason for this “difference” is that patients in Annane et al. were sicker at enrollment (Annane et al. required patients to have vasopressor-refractory shock, whereas CORTICUS did not). This has led to the common belief that steroids should be reserved for patients with vasopressor-refractory shock.
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In fact, Annane et al. and CORTICUS revealed similar clinical benefits from steroids (faster shock reversal). Within CORTICUS, steroids caused an improvement in hemodynamic stability and possibly renal function (more on this below). Thus, benefits of steroids do not seem so be restricted to patients with vasopressor-refractory shock.
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Patients with more severe sepsis might benefit more from steroids than patients with milder sepsis. As shown above the side-effects from steroids are probably roughly stable, whereas the benefit may be greater for patients with more severe disease. However, the point at which benefits might outweigh risks is unknown.
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Conclusions
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The use of steroids in sepsis may be similar to their use in COPD
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Thus, steroids in sepsis are neither as awesome nor as scary as is often believed. Steroids won't improve mortality, but neither will they lead to terrible superinfections. The primary benefit of steroids may simply be to reduce the duration of shock. This shouldn't be a huge surprise because stress dose steroids (200 mg/day hydrocortisone) are equivalent of 50 mg prednisone daily, a commonly used dose which is fairly safe in short courses.
Thus, steroids in sepsis are neither as awesome nor as scary as is often believed. Steroids won't improve mortality, but neither will they lead to terrible superinfections. The primary benefit of steroids may simply be to reduce the duration of shock. This shouldn't be a huge surprise because stress dose steroids (200 mg/day hydrocortisone) are equivalent of 50 mg prednisone daily, a commonly used dose which is fairly safe in short courses.
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This may be similar to the role of steroids in patients with COPD exacerbation. Steroids don’t improve mortality in COPD. Compared to placebo, steroids reduced the average length of hospitalization by merely 1.2 days (Niewoehner 1999). Nonetheless, steroids are an accepted treatment for COPD exacerbation.
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The debate about steroids in sepsis has been focused on whether steroids effect mortality. This might be the wrong question. A more relevant and practical question may be whether it is worth using steroids in order to reduce the duration and severity of septic shock.
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Reducing shock duration could have meaningful consequences. Prompt resolution of shock could improve organ perfusion and function. For example, a post-hoc analysis of CORTICUS showed that patients with renal failure who received steroids had a significantly higher likelihood of renal recovery (figure above; Moreno 2011). As discussed previously here, renal recovery in septic shock appears to be critical for achieving good outcomes.
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For now, how should we use steroids?
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The precise risk/benefit balance remains unclear. Steroids are proven to improve hemodynamics and speed shock resolution, which might facilitate recovery among the most unstable patients. However, steroids do have a number of potential side-effects including myopathy, hyperglycemia, and peptic ulcer disease.
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The above approach may be reasonable. Some patients have indications or contraindications for steroids, but mostly it may be a matter of clinical judgment. Individual patient characteristics may tip the risk/benefit balance one way or the other. In the absence of definitive evidence, judgment is needed.
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Unfortunately, clinical judgment is nebulous and leads to variation between practitioners. However, this is the nature of critical care medicine. The most that we can ask of ourselves and our colleagues is to carefully consider the situation and make our best call.
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- Misconception #1 = Stress-dose steroids can improve mortality. (Evidence: There is no convincing data that stress-dose steroids improve mortality.)
- Misconception #2 = Stress-dose steroids increase risk of superinfection. (Evidence: There is no statistically significant increase in the rate of superinfection.)
- Misconception #3 = Annane et al. and CORTICUS, the two major trials investigating stress dose steroids in septic shock, obtained conflicting results. (Evidence: The raw data from these studies is consistent.)
- Misconception #4 = The benefit of stress dose steroid is restricted to patients with vasopressor-refractory septic shock. (Evidence: There is no clear demarcation of which patients may or may not benefit from steroids.)
- Truth = Stress-dose steroids consistently reduce the duration of septic shock.
- Overall this may be similar to the utility of steroids in COPD exacerbations: a treatment which hastens recovery and improves organ function without affecting mortality.
- Which patients may benefit from stress dose steroid remains unclear. For now, careful consideration of each patient with clinical judgment may be a reasonable approach.
Stay tuned for the culmination of this three-week series on septic shock next week.
Notes
(1) To add to the confusion, there are numerous meta-analyses of these studies which come to opposing conclusions. Some meta-analyses were more inclusive, including smaller studies and studies of patients with more variable characteristics. Most recently there have been three meta-analyses which focused on higher-quality studies with less bias: Sligl 2009, Wang 2014, and the Position statement of the American Academy of Emergency Medicine (Sherwin 2012). These three studies are generally in agreement and appear to represent the highest quality meta-analytic data at this point.
(2) A total of 26 statistical tests were performed on various adverse outcomes. Given this many tests, the odds of one or more test being “positive” at the p<0.05 level is 74%! To reduce the likelihood of obtaining a false-positive test among several tests, the p-value of each individual test must be reduced based on the number of tests (e.g. using a Bonferroni correction, which in this case would suggest that any individual test would require a p-value of <0.05/26 or <0.002 to be deemed “significant”). Thus, the statistical results for the combined adverse outcome of “new sepsis or new septic shock” is still not statistically significance.
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- Vasopressors
- Fluids: Empty IVC in early sepsis doesn’t prove volume depletion
- Renoresuscitation: Overall conceptualization & strategy
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The universal theory of sepsis is very exciting. Murine research which seemed unproductive will now make sense. Drugs like anti-TNF alpha as APC may now be found to work with specific hybrid phenotypes. This is the most exciting time for sepsis since the heady days of the early 1990s. This time though we have all learned and the road is wide open ahead of us.
I will explain the theory of "sepsis" as a group of hybrid phenotypes which presents an alternative to the theory that sepsis is a unified condition of immune imbalance triggered by infection and defined by thresolds. Beta strep is a human pathogen. Humans are its primary prey. Its 'genotype codes for conversion of human proteins into proteins which defeat the human immune system (like a beaver genotype codes for building a dam) to make the environment safe for its babies. (Just like the beaver). As the beaver dam is the extended phenotype of the beaver and the braches are its… Read more »
Very nice review and thoughtful, intriguing explanations. One question is: Given that shock is so mortal, why, if shock duration is reduced by steroids, don't steroids reduce mortality. The obvious answer would be that some adverse effect of steroids offsets the benefit of shock duration reduction. However it is certainly more complicated than that. The problem might be that sepsis is not a unified condition. In other words there is no unified condition of "sepsis". Rather sepsis (like cancer) is actually comprised of a group of phenotypes. Toxic shock due to a specific type of toxigenic strain of beta strep… Read more »
Excellent breakdown, it’s imperative we continue to think of these adjunct therapies as only a piece of the bigger picture with our patients and their recovery. Way to keep an eye on the big picture.
great stuff. keep up the great work!
Simple simple concept. Anytime you feel the need to give steroids, pretend you are a DR and test for Vitamin C levels. Both are stress hormones. Vitamin C deficit impedes production of the body’s natural steroids. Giving steroids is an unacknowledged admission of a significant Vite C deficit. Steroids are not a lasting answer because it leaves the real problem unanswered, Vite C deficit.
Gee, this is so difficult. Steroids don’t affect mortality because they are a poorly constructed band aid, not an answer. To administer the steroids and expect long term results is pathetic. WHAT is causing the need for the steroids? SCURVY! Adrenal glands become exhausted in the presence of extreme Vite C deficiency. They cannot produce the necessary steroid in sufficient quantity. Supplying steroid barely does CRAP! Restoring the ABILITY of the ADRENALS to produce the needed steroids is an answer NOT a poorly constructed band aid. Isepsis.com
I disagree. The numbers are pretty clear. Patients who received steroids were 10% less likely to die. That’s significant in my book. 68% of patients without steroids died in the ICU compared to 60% mortality of patients who received steroids… again pretty clear cut to me. I don’t understand this P value mumbo jumbo shenanigans. It seems pretty straight forward. Not saying you are not correct here with this P value stuff, it’s probably above my paygrade, but it definitely is not convincing to me. To anonymous who talked about sepsis have multiple phenotypes… that sounds like a good approach.… Read more »
Excellent and engaging review. I understand why mortality is a common end-point in critical care studies. However, when interpreting data, we have to be careful to say that mortality is the only value that matters (which you discussed nicely). Is the patient on permanent dialysis or not? Is the patient walking out of the hospital or are they being discharged to an LTAC? It gets frustrating when people dismiss x, y, or z thing because it didn’t demonstrate a short-term mortality benefit. There is a difference between not being dead and being truly alive and well. Thanks for thinking thoughtfully… Read more »