Criteria abstracted from The Users' Guide to Medical Literature, from the Health Information Research Unit and Clinical Epidemiology and Biostatistics, McMaster University

Highlighted lines and questions below provide links to the pertinent description of criteria in The EBM User's Guide, now available at the Canadian Centres for Health Evidence

Article Reviewed:

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Risk factors of relative adrenocortical deficiency in intensive care patients needing mechanical ventilation.

Malerba G, Romana-Girard F, Cravoisy A, Dousset B, Nace L, Levy B, Bollaert P.

Intensive Care Medicine. 2005;31:388-392. [abstract]

Reviewed by A. Paige Davis MD, University of Iowa, Children's Hospital of Iowa

Review posted November 2, 2005

I. What is being studied?

Study objective:

The objective of this study was to evaluate the risk factors associated with relative adrenocortical insufficiency (RAI) in mechanically ventilated, critically ill patients.

Though the dangers of absolute adrenal deficiency have long been understood, the concept of RAI is more recent. The diagnosis of RAI developed as associations were made between inadequate serum cortisol levels and critically ill patient mortality rates (1). In multiple studies on patients with septic shock, an increase in serum cortisol less than 9 mcg/dl following corticotropin was strongly associated with death (2, 3). These findings have raised concern and controversy regarding use of stress steroid coverage in critically ill patients. Understanding the risk factors for RAI is necessary to optimize patient management.

Study design

1. This was a prospective observational cohort study in the multidisciplinary ICU of a university-affiliated teaching hospital.
2. To be included in the study, patients had to have undergone endotracheal intubation and mechanical ventilation for more than 24 hours.
3. Investigators evaluated 72 potentially eligible patients between 1 January 2000 and 1 September 2000. Patients with prior mechanical ventilation for more than six hours before admission to the ICU, a previous stay in another ICU, or needing steroids were excluded. Ten patients were excluded for recent or current steroid treatment (4 for asthma, 2 for COPD, 3 for cancer, 1 for chronic adrenocortical deficiency).
4. All of the 62 patients included in the study underwent a high-dose short corticotropin test 24 h after intubation (baseline cortisol level was drawn, 250 mcg corticotropin given IV and, 60 min later, stimulated cortisol level was drawn) as the method to diagnose RAI.
5. Patients were categorized as either 'responder' (absolute cortisol increase from 0 to 60 min > 90 mcg/l (9 mcg/dl or 250 nmol/l) or 'nonresponder' (absolute cortisol increase ≤ 90 mcg/l). The category of non-responder is consistent with the definition of RAI from the Surviving Sepsis Campaign (4).
6. ODIN (Organ Dysfunctions and/or Infection) scores were compared for each patient at the time of intubation and 24 hours after intubation (at the time of corticotropin test). Final diagnosis and mortality were also included in the study data set.

II. Are the results of the study valid?

Note: These questions follow from Randolph AG et al. Understanding articles describing clinical prediction tools. Crit Care Med 1998;26:1603-1612. [abstract]

1. Was a representative and well-defined sample of patients at a similar point in the course of the disease? Was follow-up sufficiently long and complete?

The cohort included a range of ages and diagnoses. All patients were adults aged 62 ± 17 years. No patients were excluded due to lack of follow-up or consent. All patients were apparently followed throughout the ICU stay. However, follow up is not directly mentioned in this article, except for brief statements regarding 1) patients who received hydrocortisone and 2) mortality.

2. Were all potential predictors included?

Yes. To evaluate the potential predictors of RAI in the critically ill, the authors assessed several variables, including: age in years; gender; diagnosis (cardiogenic shock, coma, severe sepsis, poisoning and postoperative care); and previous health status (assessed by two different scoring systems, the McCabe and Jackson system and the Knaus system). Sedatives used for intubation/ventilation were recorded (etomidate, combination fentanyl/midazolam, propofol, ketamine, sodium thiopental, or no sedative). The Organ Dysfunctions and/or Infection (ODIN) score was determined just prior to intubation (H0) and after 24 h of ventilation (H24). Other clinical and biochemical variables assessed included: heart rate and mean arterial pressure at H0 and H24; arterial pH, temperature, creatinine clearance, and serum potassium, protein, sodium, and glucose at H24. Treatment with vasopressor agents was recorded at H0 and H24.

3. Did the investigators test the independent contribution of each predictor variable?

Yes. Both patient groups (responders and non-responders) were compared using the same criteria. Each predictor variable for responders and non-responders was compared using univariate analysis for categorical variables and the Mann-Whitney nonparametric test for quantitative values. Variables with a p value less than 0.10 by univariate analysis were evaluated by logistic regression model for multivariate analysis. P values less than 0.05 were considered statistically significant.

4. Were outcome variables clearly and objectively defined?

RAI was the primary outcome and was clearly defined. Patients were categorized as either 'responder' (absolute cortisol increase from 0 to 60 min > 90 mcg/l or 'nonresponder' (absolute cortisol increase ≤ 90 mcg/l). Other outcomes are secondary (mortality).

III. What are the results?

1. What is(are) the prediction tool(s)?

The univariate analysis model showed the nonresponder group to include a higher percentage of males, higher overall illness severity scores (before and after intubation) and lower mean arterial pressure at H0 and H24. Of the biochemical variables assessed, only creatinine clearance was lower in the nonresponder patients.

The multivariate linear regression model identified two predictor variables:

1. Female gender had a protective effect on prevention of RAI (OR 0.13; 95% CI 0.03-0.57).
2. A single bolus of etomidate is an independent risk factor for RAI (OR 12.21; 95% CI 2.99-49.74, p = 0.001).

The mortality rate for nonresponders was 70.4%, vs. 31.4% in responders, which is consistent with other published data on relative adrenocortical insufficiency.

2. How well does the model categorize patients into different levels of risk?

The authors do not construct a model per se, except to identify the independent protective factor of female gender and risk factor of etomidate use. A model would, for example, offer a scoring system (composed of the predictors) that would yield a graded risk of RAI (the outcome) based upon the score. All we know from this study is that being female confers a roughly 1/6th risk of RAI, and use of etomidate results in an approximately 12-fold increased risk of RAI.

3. How confident are you in the estimates of risk?

With an odds ratio of 12.21 (> 1), the results show that etomidate use is associated with increased risk of relative adrenocortical insufficiency. The confidence interval for risk of RAI with etomidate use is wide. The odds ratio for use of etomidate may be as low as 3 or as high as 50. This is not very precise. The wide confidence interval suggests a small overall sample size (62 patients), as sample size is a main factor in determining precision. However, 45% of the population was exposed to etomidate and 70% of patients with RAI received etomidate. This should be an adequate percentage of the total population exposed to a medication to evaluate outcomes.

In 1983, Ledingham et al. published a retrospective study in The Lancet which documented increased mortality rates following etomidate use (5). Since that time, etomidate has been shown to be a selective inhibitor of adrenal 11-beta hydroxylase, which converts deoxycortisol to cortisol (6). Thus, it makes biological sense that etomidate could be a significant risk factor for RAI and, by extension, mortality. The Malerba, et al. article did not directly measure the relationship between etomidate exposure and mortality. Patients with RAI in this study had more than twice the mortality rate as responders (70.5 vs. 30%). The authors also expressed concern that this study was biased, in that sicker patients already predisposed to RAI received etomidate. By multivariate analysis, which should control for severity of illness, etomidate was an independent risk factor for RAI. Taking these factors together, one concludes that etomidate should be used with caution, if at all, in the critically ill patient population.

IV. Will the results help me in caring for my patients?

1. Does the tool maintain its prediction power in a new sample of patients?

This has not been studied in a new sample of patients.

2. Are your patients similar to those patients used in deriving and validating the tool(s)?

This was an adult ICU population and, therefore, not necessarily comparable to the pediatric ICU population. Mortality rates in severe sepsis and cardiogenic shock, among other variables, are different in the adult population compared to pediatric mortality rates.

3. Will the results lead directly to selecting or avoiding therapy?

At this point, it is difficult to assess whether this prediction tool improves clinical decision-making. Never the less, the evidence may be applied to PICU patients until definitive studies can be done to more fully answer the question: Does single dose etomidate cause an increased risk of RAI and mortality in the critically ill? Given the supportive data that already exists on the risk of RAI in intensive care patients, one may choose to avoid use of etomidate when possible. Based on the results of this study, one should consider evaluation for RAI in critically ill pediatric patients who have received etomidate.

4. Are the results useful for reassuring or counseling patients?

Not applicable.

References

1. Finlay WE, McKee JI. Serum cortisol levels in severely stressed patients. Lancet. 1982; 1: 1270. [citation]
2. Rothwell PM, Udwadia ZF, Lawler PG. Cortisol response to corticotropin and survival in septic shock. Lancet. 1991; 337: 582-3. [abstract]
3. Bollaert PE, Fieux F, Charpentier C, Levy B. Baseline cortisol levels, cortisol response to corticotropin, and prognosis in late septic shock. Shock. 2003; 19(1):13-5. [abstract]
4. Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J, Gea-Banacloche J, Keh D, Marshall JC, Parker MM, Ramsay G, Zimmerman JL, Vincent JL, Levy MM. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Intensive Care Medicine. 2004; 30(4):536-55. [abstract]
5. Watt I, Ledingham ImcA. Mortality amongst multiple trauma patients admitted to an intensive therapy unit. Anaesthesia. 1984; 39: 273-981. [abstract]
6. Wagner RL, White PF, Kan PB, Rosenthal MH, Feldman D. Inhibition of adrenal steroidogenesis by the anesthetic etomidate. New England Journal of Medicine. 1984; 310: 1415-1421. [abstract]

 

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