Peter C. Minneci, MD; Katherine J. Deans, MD; Steven M. Banks, PhD; Peter Q. Eichacker, MD; Charles Natanson, MD
Minneci PC, Deans KJ, Banks SM, Eichacker PQ, Natanson C. Meta-Analysis: The Effect of Steroids on Survival and Shock during Sepsis Depends on the Dose. Ann Intern Med. 2004;141:47-56. doi: 10.7326/0003-4819-141-1-200407060-00014
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Published: Ann Intern Med. 2004;141(1):47-56.
Previous meta-analyses demonstrated that high-dose glucocorticoids were not beneficial in sepsis. Recently, lower-dose glucocorticoids have been studied.
To compare recent trials of glucocorticoids for sepsis with previous glucocorticoid trials.
Systematic MEDLINE search for studies published between 1988 and 2003.
Randomized, controlled trials of sepsis that examined the effects of glucocorticoids on survival or vasopressor requirements.
Two investigators independently collected data on patient and study characteristics, treatment interventions, and outcomes.
The 5 included trials revealed a consistent and beneficial effect of glucocorticoids on survival (I2 = 0%; relative benefit, 1.23, [95% CI, 1.01 to 1.50]; Pâ€‰= 0.036) and shock reversal (I2 = 0%; relative benefit, 1.71 [CI, 1.29 to 2.26]; Pâ€‰< 0.001). These effects were the same regardless of adrenal function. In contrast, 8 trials published before 1989 demonstrated a survival disadvantage with steroid treatment (I2 = 14%; relative benefit, 0.89 [CI, 0.82 to 0.97]; Pâ€‰= 0.008). In comparison with the earlier trials, the more recent trials administered steroids later after patients met enrollment criteria (median, 23 hours vs. <2 hours; Pâ€‰= 0.02), for longer courses (6 days vs. 1 day; Pâ€‰= 0.01), and in lower total dosages (hydrocortisone equivalents, 1209 mg vs. 23â€‰975 mg; Pâ€‰= 0.01) to patients with higher control group mortality rates (mean, 57% vs. 34%; Pâ€‰= 0.06) who were more likely to be vasopressor-dependent (100% vs. 65%; Pâ€‰= 0.03). The relationship between steroid dose and survival was linear, characterized by benefit at low doses and increasing harm at higher doses (Pâ€‰= 0.02).
We could not analyze time-related improvements in medical care and potential bias secondary to nonreporting of negative study results.
Although short courses of high-dose glucocorticoids decreased survival during sepsis, a 5- to 7-day course of physiologic hydrocortisone doses with subsequent tapering increases survival rate and shock reversal in patients with vasopressor-dependent septic shock.
The relative survival benefits are shown with fixed-effects model and 95% CIs with glucocorticoid therapy in the sepsis trials. Both the fixed-effects estimate (to compare across studies) and the random-effects estimate (to generalize to other samples) of relative survival benefit are presented . (40). Meta-analysis of all 13 trials demonstrated variability (I2 = 70%) with no overall improvement in relative survival benefit (fixed-effects estimate, 1.01 [95% CI, 0.94 to 1.09]; random-effects estimate, 1.04 [CI, 0.90 to 1.20]). The effect of steroids in the trials published before 1989 compared with those published after 1997 significantly differed ( = 0.02). In the 4 trials published after 1997 (1 study did not report mortality data ), )the effect of steroids on the relative survival benefit was consistently beneficial (I2 = 0%) (fixed-effects estimate, 1.23 [CI, 1.01 to 1.50]; random-effects estimate, 1.19 [CI, 0.99 to 1.43]). The effects of steroids on the relative survival benefit in the 9 sepsis trials published before 1989 varied (I2 = 75%; fixed-effects estimate, 0.97 [CI, 0.89 to 1.04]; random-effects estimate, 0.97 [CI, 0.81 to 1.16]). Excluding 1 trial (16), which was a statistically significant outlier, yields a homogeneous group of 8 trials with a consistent harmful effect of steroids on survival (I2 = 14%; fixed-effects estimate, 0.89 [CI, 0.82 to 0.97]; random-effects estimate, 0.90 [CI, 0.80 to 1.02]). This excluded trial (16) had methodologic differences, including being performed by 1 investigator over an 8-year period and enrolling patients both prospectively and retrospectively. VA = Veterans Administration.
The relationship between the dose of steroids administered in the first 24 hours after enrollment in a sepsis trial and relative survival benefit (black circle) is presented. There is a linear relationship (that is, the relative survival benefit decreases with high-dose steroids but increases with lower doses) ( = 0.02). One study (white circle) was overly influential in our regression analysis, was a statistical outlier ( = 0.001) compared with the other trials, and was therefore excluded (35). This study was performed a decade before all of the other trials, included children, and had a high percentage of patients with meningitis.
The relative benefit (95% CI) and the hazard ratio (with 95% CI) of shock reversal for the sepsis trials published after 1997 are presented. Of note, in 3 of the 4 studies, the discontinuation of vasopressor therapy with steroid treatment statistically significantly improved. In the fourth trial, the effect of steroid therapy on vasopressor discontinuation was similar to the effect in the other trials (I2 = 0%; > 0.2).
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Enrique J. SÃ¡nchez-Delgado,
Hospital Metropolitano Vivian Pellas, Managua, Nicaragua
July 11, 2004
Low dose steroids stabilizes patient in sepsis.
Short after the inauguration of the Hospital Metropolitano Vivian Pellas in Managua, a 75 years old lady was received in the ER presenting chills, myalgias, hypotension and anuria, as well as low oxygen saturation, tachypnea and rales. She had been in treatment for congestive heart failure and atrial fibrillation, but presented with sinus rythmus. She had a plasty repair three years ago in USA for a mitral regurgitation, and the valve was fibrotic and calcified, difficulting the echo diagnosis for endocarditis. There was a marked leucocytosis, with left deviation and toxic granulations of the leucocytes, markedly elevated CRP and elevated creatinine. Both ACS or AMI were ruled out.
She was admitted to the ICU and treated for sepis, probable endocarditis, congestive heart failure and pre-renal renal failure.
Despite restoration of renal function, clearing of lung parenchima, recovering of oxygen saturation and appropiate antibiotic treatment, the hemodynamic pharmacologycal support with dopamine/dobutamine and properly regulated fluids were not enough to keep her blood pressure stable, and she had frecuent hypotensive episodes.
At the third day we decided to start with low dose hydrocortisone, 100 mg i.v. every 8 hours. She stabilized and could be continued with 100 mg a day until her release at the 8th. day with all her organ functions normalized to continue her treatment ambulatory, under supervision of her cardiologist.
David W Noble
Aberdeen Royal Infirmary
July 17, 2004
Corticosteroids for septic shock: - a question of interpretation.
The meta-analysis of Minneci and colleagues with regard to steroids for septic shock  has been interpreted too narrowly and may provide a misleading picture for practicing intensivists. I have three areas of concern. Firstly, the data analysis is retrospective, exploratory and uncorrected for multiple comparisons . Should then conclusions be less definitive than those actually offered? Secondly Bennett's low-dose steroid study is excluded from the low-dose steroid analysis. Although a rationale is provided, it remians the second largest study in this group even after pediatric patients have been excluded. Other quoted meta-analyses have not excluded this study. Thus to provide a more complete picture, sensitivity analyses are necessary and the authors should inform readers how exclusion or inclusion of this study would change results and conclusions. Finally, the trial that has the greatest impact on this aspect of the meta -analysis is fundamentally flawed in that a large percentage of patients were pharmacologically adrenalectomized with etomidate immediately prior to enrolment. With the widespread use of etomidate it is hardly surprising that so many shocked septic patients were unresponsive to corticotropin and benefited from hydrocortisone replacement therapy . Incorporation of this trial into the meta-analysis, without dealing with the confounding effects of etomidate, is problematic. Although surrogate measures promise much, currently there is insufficient scientifically sound outcomes data to mandate use of corticosteroids in septic patients. The meta-analysis of Minneci and colleagues has too many limitations, in that multiple comparisons, lack of sensitivity analyses and insufficient acknowledgement of individual study limitations has lead to narrow and unsustainable conclusions . Corticosteroids have serious adverse effects and our patients deserve decision making based on good and robust evidence. Support for the CORTICUS study must continue in the hope that intensive care practitioners can ultimately exercise truly evidence-based decision making . Corticosteroids for septic shock is not yet an evidence-based standard of care.
References. . Minneci PC, Deans KJ, Banks SM, Eichaker PQ, Natanson C. Meta- analysis: The effect of steroids on survival and shock during sepsis depends on the dose. Ann Intern Med 2004; 141: 47-56. . Pogue J, Yusuf S. Overcoming the limitations of current meta-analysis of randomised controlled trials. Lancet 1998; 351: 46-52. . Corticosteroids for septic shock "“ a standard of care? Bloomfield R, Noble DW. Br J Anaesth 2004; 93:178-80. . Eysenck HJ. Meta-analysis and its problems. BMJ 1994; 309: 789-92. . Luce JM. Physicians should administer low-dose corticosteroids selectively to septic patients until an ongoing trial is completed. Ann Intern Med 2004; 141: 70-82.
Robert G Badgett
University of Texas Health Science Center at San Antonio
July 30, 2004
Controversy due to heterogeneous mortality results among patients with normal adrenal responsiveness
The meta-analysis of corticosteroids for septic shock by Minneci et al is an important synthesis of this difficult topic (1). Could the authors please comment on the following two observations?
First the meta-analysis has led to conflicting opinions between the authors and the editorialist about safety and efficacy of continuing corticosteroids among patients with normal adrenal response to corticotropin stimulation testing ('responders') (2). Close examination of Table 3 reveals significant heterogeneity exists in the mortality data among the responders, I2=58% (3). These three studies should not be pooled, either mathematically or informally. The trail by Annane is the outlier and is the only study that suggests harm from corticosteroids among responders. Although the degree of harm (absolute increase in mortality of 8%) is insignificant, its magnitude is similar to the benefit realized in the nonresponders to the corticotropin stimulation testing and the insignificance may be due to smaller sample size. In addition to being the only study to suggest harm among the responders, this study had the largest difference between the results of the nonresponders and responders. Irregardless of whether the small studies by Yildiz and Boleart should be discarded, one must explain the results of the Annane study. One difference in the Annane study is the higher proportion of nonresponders which suggests sicker patients. A second difference is the cotreatment with fludrocortisone. Until more studies establish the correct explanation, it seems premature to continue corticosteroids for responders when the best study suggests harm. In addition, fludocortisone should be considered for cotreatment.
Second, the recent study by Hamrahian (4) suggests the free cortisol level may better predict adrenal sufficiency and should be used in further research of this topic rather than the response in the total cortisol level.
References: 1. Minneci PC, Deans KJ, Banks SM, Eichacker PQ, Natanson C. Meta-analysis: the effect of steroids on survival and shock during sepsis depends on the dose. Ann Intern Med. 2004;141:47-56. PMID: 15238370 [Full text] 2. Luce JM. Physicians should administer low-dose corticosteroids selectively to septic patients until an ongoing trial is completed. Ann Intern Med. 2004;141:70-2. PMID: 15238374 [Full text] 3. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557-60. PMID: 12958120 4. Hamrahian AH, Oseni TS, Arafah BM. Measurements of serum free cortisol in critically ill patients. N Engl J Med. 2004;350:1629-38. PMID: 15084695
Katherine J Deans
Critical Care Medicine Department, National Institutes of Health
September 1, 2004
Corticosteroids in sepsis: should therapy be based on response to ACTH testing?
In Response: Drs. Noble and Badgett raise important concerns about the findings of our meta-analysis (1). In response to Dr. Noble, a properly performed meta- analysis is similar to a clinical trial in that they are both prospective studies with inclusion criteria, endpoints, and analytic strategies defined prior to the beginning of the study. Furthermore, in a meta- analysis with significant heterogeneity, it is essential to partition the dataset into homogeneous groups to explain the heterogeneity of the data (2). This is not considered an analysis of multiple comparisons, but rather a fundamental technique of meta-analysis. In our study, the significantly heterogeneous effects of steroids on survival were explained by partitioning the trials by year of publication. Based on this division, the Bennett study was included in the set of trials published before 1989 (1). Subsequent descriptions of the trials were based on differences between the sets of trials, and sensitivity analyses were performed within each of these sets (1). Finally, the use of etomidate in the trial by Annane et al (3) is concerning. However, low-dose steroids remain significantly beneficial when this trial is removed (relative survival benefit, 1.36 [95% CI, 1.04 to 1.79]; P= 0.03). Moreover, recently available data from the trial by Chawla et al. also demonstrate a consistent beneficial effect of steroids on survival (RSB, 1.82 [95% CI, 0.80 to 4.00]; P>0.2) (4).
In response to Dr. Badgett's concern of heterogeneity in mortality data among "responders", these 3 trials are not different based on traditionally used significance cutoffs (P=0.15). However, even if the studies are not combined because of the concerning I2 value, there was no consistent trend towards harm in the trials and there were no significantly different treatment effects of steroids in "responders" and "nonresponders" within the individual trials. Categorizing septic patients as "responders" and "nonresponders" to corticotropin stimulation testing is based on a classification system that has not been validated. Moreover, the validity of these subgroups needs to be reassessed based on recent data which suggests that total cortisol levels may not accurately reflect adrenal function in critically ill patients (5).
Withholding steroids may potentially harm one out of every nine eligible patients. Low-dose steroids have demonstrated a consistent beneficial effect on survival in five trials and a significant improvement in survival in two meta-analyses (1, 4). This beneficial effect remains when the Annane trial is excluded (3). Furthermore, there was no increase in adverse events with steroid therapy reported in these trials or meta- analyses. The currently available data indicate that low-dose steroids should be considered for all patients with vasopressor-dependent septic shock. Treatment decisions should be based on individual patient risk- benefit profiles and not on a categorization system which has not been validated, which uses total cortisol levels of questionable value, and which has produced inconsistent and nonsignificant results in clinical trials.
References: 1. Minneci PC, Deans KJ, Banks SM, Eichacker PQ, Natanson C. Meta- analysis: the effect of steroids on survival and shock during sepsis depends on the dose. Ann Intern Med. 2004;141(1):47-56. 2. Thompson SG. Why sources of heterogeneity in meta-analysis should be investigated. Bmj. 1994;309(6965):1351-5. 3. Annane D, Sebille V, Charpentier C, et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002;288(7):862-71. 4. Annane D, Bellissant E, Bollaert PE, Briegel J, Keh D, Kupfer Y. Corticosteroids for severe sepsis and septic shock: a systematic review and meta-analysis. Bmj. 2004. 5. Hamrahian AH, Oseni TS, Arafah BM. Measurements of serum free cortisol in critically ill patients. N Engl J Med. 2004;350(16):1629-38.
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