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Rapid Responses: Rapid Responses published:
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Is it appropriate to withhold beneficial therapy in critical illness?
- Peter C. Minneci, Katherine J. Deans, Steven M. Banks, Peter Q. Eichacker, and Charles Natanson. (23 August 2004)
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DO LOW DOSES OF CORTICOSTEROIDS FOR SEVERE SEPSIS AND SEPTIC SHOCK INDEED LOWER MORTALITY?
- Jack J. Ligtenberg, Jan G. Zijlstra (3 September 2004)
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Thesis is worthless without anti-thesis!
- Djillali Annane (6 September 2004)
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Corticosteroids for sepsis and septic shock - Credible evidence………..or not?
- David W Noble (13 September 2004)
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Re: Corticosteroids for sepsis and septic shock - Credible evidence………..or not?
- Peter C. Minneci, Katherine J. Deans, Steven M. Banks, Peter Q. Eichacker, and Charles Natanson. (20 September 2004)
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Peter C. Minneci, Physician Critical Care Medicine Dept., National Institutes of Health, Bldg 10, Rm 7D43, Bethesda, MD 20892, Katherine J. Deans, Steven M. Banks, Peter Q. Eichacker, and Charles Natanson.
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In the recent meta-analysis by Annane et al., long courses (greater than or equal to 5 days) of low dose corticosteroids (less than or equal to 300 mg of hydrocortisone or equivalent) led to an overall 11% reduction in mortality in patients with severe sepsis and septic shock without an increase in the incidence of adverse events (1). However, the authors recommend withholding steroid therapy from septic patients that respond normally to corticotropin stimulation testing (“responders”). This recommendation is based on the fact that only two trials provided data on corticotropin stimulation testing with each trial using a different definition for adrenal insufficiency (2,3). The authors state that in one trial, too few patients had adrenal insufficiency to draw any conclusions (3), and in the other trial, benefit from corticosteroids was only demonstrated in patients with an abnormal response to corticotropin stimulation testing (“nonresponders”) (2). In beneficial clinical trials or meta-analyses, it is important to examine the data for subgroups of patients that may have been harmed or whose response was significantly different to the treatment. This is particularly prudent when physiologic principles or preclinical data suggest that a subgroup might behave differently or suffer an adverse effect related to treatment. Recommendations to exclude subgroups of patients from receiving a beneficial therapy such as corticosteroids for septic shock must have a clear objective basis such as increased mortality or increased complications from the therapy. Five clinical trials show a strong clinical benefit of corticosteroids in septic shock (1). Based on the currently available studies, we maintain that there are insufficient empirical findings to justify a recommendation to withhold steroid therapy from any subgroup of patients with septic shock. In a previous meta- analysis of the same trials (4), we performed a subgroup analysis of the results of the three published clinical sepsis trials of steroids that reported mortality data based on the results of corticotropin stimulation testing (2,3,5). A trend toward harmful effects of steroid therapy was found in one trial reporting outcomes of “responders” to corticotropin stimulation testing (2). However, that trend was not seen in the two other trials where beneficial effects of steroids were observed in both “responders” and “nonresponders” to corticotropin stimulation testing (3,5). Importantly, the effects of steroids on survival in “responders” and “non-responders” were not significantly different within each of these three trials and when combined (4). Withholding steroids from any subgroup would result in one additional death for every nine patients that should have been treated. Therefore, since the currently available data does not demonstrate a consistent trend towards harm or a different effect of steroids in this subgroup of patients, we believe that there is no objective basis to recommend withholding this beneficial therapy. Corticosteroids should be considered for all patients with septic shock. References: 1. 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. 2. Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM, 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. 3. Bollaert PE, Charpentier C, Levy B, Debouverie M, Audibert G, Larcan A. Reversal of late septic shock with supraphysiologic doses of hydrocortisone. Crit Care Med 1998;26(4):645-50. 4. 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. 5. Yildiz O, Doganay M, Aygen B, Guven M, Keleutimur F, Tutuu A. Physiological-dose steroid therapy in sepsis [ISRCTN36253388]. Crit Care 2002;6(3):251-9. Competing interests: None declared |
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Jack J. Ligtenberg, intensivist University Medical Center Groningen, NL-9700RB Groningen, Netherlands, Jan G. Zijlstra
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EDITOR – In their systematic review Djillali Annane et al. analyse 16 trials of corticosteroid treatment in severe sepsis and septic shock, published from 1955 until 2003.1 As expected, since 11 of the older trials (1558 of 2023 reviewed patients) use high dose corticosteroids, an effect on 28 day mortality could not be shown. However, based on a subanalysis of 5 more recent trials all with low dose corticosteroids (> 5 day treatment, 465 patients), they conclude that long course low dose steroid treatment does have a positive effect on mortality (RR 0.83, 95% CI 0.70- 0.97, P=0.02). This conclusion is remarkable, because not one of these 5 trials separately were able to show this positive effect. Even the largest study (300 patients2) did not find an effect on mortality for the whole treated group: p=0.09 for 28-day mortality and p=0.12 for hospital mortality. 2;3 Furthermore, one of the included low dose steroid trials has only been published in abstract format 5 years ago. 4 Since the description of the relative adrenal insufficiency sydrome in the late nineties, it has by now been unequivocally proven that low dose corticosteroid suppletion helps in restoring hemodynamic stability in catecholamine dependent septic shock patients; shock reversal.5 We feel, that strong evidence for a positive effect on mortality is still lacking, although it appears to become more likely. To make future meta-analysis more clear, high dose studies should not be included because these studies are basically different from low dose steroid studies. Furthermore, in our view this meta-analysis does not give support for threshold values to start or withdraw low dose steroid therapy. There is no evidence anyhow to base a treatment strategy on cortisol levels.6 Let’s hope that the ongoing Corticus study will be able to tell us, if low dose steroid therapy is indeed the long-awaited tool to improve prognosis of septic shock patients. Jack J.M. Ligtenberg
Intensive and Respiratory Care Unit (ICB), Dept of Internal Medicine, University Medical Center, P.O. Box 30.001, NL-9700RB, Groningen, The Netherlands References 1. 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;329:480. 2. Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002;288:862-71. 3. Zijlstra JG, Horst ICC, Tulleken JE, van der Werf TS, Ligtenberg JJM. Corticosteroids for septic shock. JAMA 2003;289:42. 4. Chawla K et al. Hydrocortisone reverses refractory septic shock. Crit Care Med. 1999;27 (suppl):A33. 5. Ligtenberg JJM, Zijlstra JG. Relative Adrenal Insufficiency Syndrome. In Vincent JF, ed. Yearbook of Intensive Care and Emergency Medicine 2002, pp 492-8. Berlin: Springer, 2002. 6. Ligtenberg JJ, Tulleken JE, Werf TS, Zijlstra JG. Unraveling the mystery of adrenal failure in the critically ill. Crit Care Med 2004;32:1447-8. Competing interests: None declared |
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Djillali Annane, MD 92380 garches, France
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Drs Minneci and Ligtenberg remarks about the recent systematic review on corticosteroids for severe sepsis and septic shock (1) well illustrate how diversely physicians may interpret evidence based findings. On the one side, Dr Minneci and colleagues argued that the evidence is so strong that all patients with septic shock should be replaced with corticosteroids regardless of their hormonal status. In theory, I would tend to agree with their statement as the relative risk of death estimated from five randomised trials was of 0.83 (95%CI: 0.70 to 0.97) in favour of corticosteroids at dose ranging from 200 to 300 mg per day for at least five days. In practice, these trials were set up with the rationale that septic shock may be associated with adrenal dysfunction, and the various authors chose a prolonged treatment with hydrocortisone (the natural hormone) at doses that mimic maximal stress in healthy subjects. Secondly, the largest trial accounting for 70% of the patients included in the meta- analysis showed benefit from one week treatment with hydrocortisone and fludrocortisone only in patients who failed to increase their cortisol levels by 250 nmol/L (or more) after 250µg of corticotrophin (2). Finally, adrenal function was not available in all studies, and when available it was not used to stratify treatments allocation. Thus, it may be hazardous to rule out that in sepsis corticosteroids effects may depend on adrenal function. On the other side, Drs Ligtenberg and Zijlstra argued that the evidence is not strong enough to recommend using corticosteroids in septic shock, although recognising their unquestionable positive effects on haemodynamic. How much evidence is enough? Five well designed randomised trials very consistently showed that a prolonged treatment with replacement doses of corticosteroids reduced by 11% one month septic shock lethality (1). Two additional randomised trials recently yielded similar survival benefits from severe sepsis and septic shock with hydrocortisone (3,4). Then, to erase the reduction in mortality shown in these seven trials, the ongoing CORTICUS trial would have to demonstrate a 10% (or more) increase in mortality with hydrocortisone as compared to placebo. How likely is this to occur? God only knows! Drs Ligtenberg and Zijlstra also questioned the validity of the suggested diagnosis algorithm based on base-line cortisol levels of less than 415 nmol/L or cortisol increase after 250 µg of corticotrophin of less than 250 nmol/L (5). In theory, I would tend to agree with their statement as this decision tree has not been tested in randomised trials. In practice, would it be ethical not to treat a patients with septic shock and low base -line cortisol levels? In those with high cortisol levels and not responding to corticotrophin test, a large trial has shown that they were more likely to draw benefit from cortisol replacement than those with an appropriate response to corticotrophin. Thus, one may argue that, so far, the proposed algorithm is the one with the strongest rationale. References 1- 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;329:480. 2- Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM et al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA 2002;288:862-71. 3- Oppert M, Schiendler R, Husung C, Offermann K, Graef KJ, Barkow D, et al. Improvement of septic shock with low dose hydrocortisone is associated with improved cytokine levels. Intensive Care Med 2003; 29: S155. 4- Confalonieri M, Rubino R, Carbone G, Potena A, Piattella M, Puccio G, et al. Hydrocortisone Infusion (HI) in Patients with Severe Community- Acquired Pneumonia (SCAP): Results of Randomized Clinical Trial. Am J Respir Crit Care Med 2004; A782. 5- Cooper MS, Stewart PM. Corticosteroid insufficiency in acutely ill patients. N Engl J Med. 2003;348:727-34. Competing interests: None declared |
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David W Noble, Consultant in Anaesthesia and Intensive Care Aberdeen Royal Infirmary, UK, AB25 2ZN
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As clinicians we want to provide our patients with the best available therapies based on good scientific evidence. Currently corticosteroids are being championed as inexpensive and effective interventions for sepsis and septic shock. One “landmark” study and two meta-analyses seem to underpin the rationale for giving steroids unselectively or selectively to patients with sepsis or septic shock [1-3]. However the presented evidence requires close scrutiny.
A high proportion of patients in the potentially landmark study of Annane and co-workers received the powerful long-acting adrenal suppressant, etomidate [1]. It is then hardly surprising that hydrocortisone replacement was of value in these chemically adrenalectomised and shocked patients. Scientifically inferences are difficult when an adrenal suppressant has been used in a study investigating adrenal function and the validity of these observations must be in doubt as a result [4]. Cognisance of this is essential when interpreting the original study as well as for the systematic reviews which have incorporated it. The two recently published systematic reviews, which do incorporate this study, also point to the value of low-dose steroids [2, 3]. However, some trials have been selectively omitted from their analyses. Minneci et al, with some explanation [2], exclude the CSG trial which is the largest published study of low dose steroids. Annane et al have omitted both the CSG trial as well that of Wagner which is the third largest study [3]. One explanation given for their omission in the full text is the high prevalence of adrenal insufficiency found in studies after 1992. Why is there this difference? Is it methodological or could etomidate-induced adrenal suppression have played a result in these other recent trials too? Regardless of mechanism these omitted trials would substantially affect results, discussion and conclusions. It is then somewhat surprising and disappointing that neither systematic review has adequately used sensitivity analysis, addressed these issues and formally presented such analyses to readers given their inclusion would almost double the patients available for analysis. The results with all studies presented below show no statistically significant benefit of low-dose corticosteroids. The older trials on their own are also presented to allow readers to assimilate the utility of steroids where there is not a high incidence of adrenal insufficiency. This analysis suggests steroids could be harmful in such situations. These might include countries such as Australia where etomidate is not available and iatrogenic adrenal suppression therefore not an issue. Currently, although there is undeniable promise for the use of low dose steroids in patients with sepsis and septic shock, the credibility of current evidence should not be taken for granted or overemphasised and ongoing trials such as CORTICUS require continued support[4]. I eagerly await better scientific evidence to better guide my own clinical practice.
References. [1]. 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: 862-71. [2]. Minneci PC, Deans KJ, Banks SM, Eichacker PQ, Natanson C. Meta-analysis: The effects of steroids on survival and shock during sepsis depends on the dose. Annals of Internal Medicine 2004; 141: 47-56. [3]. Annane, Bellisant E, Bollaert PE, Briegel J, Keh D, Kupfer Y. Corticosteroids for severe sepsis and septic shock: a systematic review and meta-analysis. BMJ 2004; 329: 480-4. [4]. Bloomfield R, Noble DW. Editorial III. Corticosteroids for septic shock – a standard of care? British Journal of Anaesthesia 2004; 93:178-80. Competing interests: None declared |
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Peter C. Minneci, Physician Critical Care Medicine Dept, National Institutes of Health, Bldg 10 Rm 7D43, Bethesda, MD 20892, Katherine J. Deans, Steven M. Banks, Peter Q. Eichacker, and Charles Natanson.
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The analysis of the low dose steroid trials presented by Dr. Noble demonstrates a nonsignificant beneficial effect of steroids on survival in seven clinical trials. However, the overall survival estimate that he reports is based on combining studies that demonstrated significant heterogeneity (p=0.03; I2 = 57%). When performing meta-analyses, significant heterogeneity across trials mandates further investigation 1. Sensitivity analyses with systematic partitioning of studies will identify statistically significant outliers. In addition, the trials should be examined for clinical differences that may account for the variable treatment effects. In the seven trials presented by Dr. Noble, the Cooperative Study Group (CSG) is a statistically significant outlier (p=0.03) 2. Furthermore, both this trial and that by Wagner are clinical outliers. Both trials were performed over 30 years before the other five trials at a time when supportive care measured were poorly defined. These two trials examined patient populations that were less severely ill than the other 5 trials (mean control mortality rates, range) (Wagner + CSG: 17%, 2 – 23%; other 5 trials: 62%, 30 – 69%). Partitioning the trials based on the year of study publication or the severity of illness of the patients studied, yields two homogeneous groups of trials (both I2 = 0%). In the earlier trials of less severely ill patients (Wagner + CSG), steroids were significantly harmful (Relative survival benefit, 95% CI) (0.56, 0.34 to 0.90, p = 0.02). In contrast, in the recent trials which focused on more severely ill patients with vasopressor-dependent septic shock, steroids were significantly beneficial (1.25, 1.05 to 1.49, p = 0.01). The contrasting effects of steroids on survival based on severity of illness is consistent with the effects of other agents with anti- inflammatory properties in sepsis 3. Dr. Noble again raises concerns about the Annane trial 4. Sensitivity analyses of the five recent trials demonstrate that steroids have a statistically significant beneficial effect on survival whether or not the trial by Annane is included. Therefore, after examining all seven low dose steroid trials, the heterogeneity within the results can be accounted for both clinically and statistically and the results are consistent with the effects of other anti-inflammatory agents in sepsis 3. Based on the results of the five recent trials, low dose steroids should be considered for severely ill patients with vasopressor-dependent septic shock 5 6. References: 1. Thompson SG. Why sources of heterogeneity in meta-analysis should be investigated. Bmj 1994;309(6965):1351-5. 2. Bennett IL, Finland M, Hamburger M, Kass EH, Lepper M, Waisbren BA. The effectiveness of hydrocortisone in the management of severe infection. JAMA 1963;183:462-465. 3. Eichacker PQ, Parent C, Kalil A, Esposito C, Cui X, Banks SM, et al. Risk and the efficacy of antiinflammatory agents: retrospective and confirmatory studies of sepsis. Am J Respir Crit Care Med 2002;166(9):1197 -205. 4. Annane D, Sebille V, Charpentier C, Bollaert PE, Francois B, Korach JM, 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. 5. 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. 6. 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. Competing interests: None declared |
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