Relative adrenal insufficiency in etomidate-naive patients with septic shock.
A recent study reported that 77% of patients with septic shock had relative adrenal insufficiency. However, all patients were mechanically ventilated and received high-dose inotropes. In addition, at least 24% had prior exposure to etomidate, a drug known to suppress adrenal function. We studied the incidence of relative adrenal insufficiency in etomidate-naive patients with septic shock by analysing the adrenal response to high-dose short synacthen test in 113 consecutive patients from three university-affiliated intensive care units in Australia. Patients were allocated to three groups according to severity of illness and inclusion criteria of the trial of low dose hydrocortisone supplementation using information from patient records.
Of the 113 patients, 98 had septic shock (Group A). The incidence of relative adrenal insufficiency in this sub-population was 24.5%. Eighty-one per cent of patients with septic shock were mechanically ventilated (Group B). In this group, the incidence of relative adrenal insufficiency was 27.8%. Only 38 of the 98 patients with septic shock (39%) fulfilled inclusion criteria for the steroid supplementation trial (Group C). In this group, the incidence of relative adrenal insufficiency was only 34.2%. In all groups its presence was associated with a higher mortality.
We conclude that the incidence of relative adrenal insufficiency in etomidate-naive septic shock patients was lower than observed in the steroid supplementation trial. Further, in those who fulfilled inclusion criteria for the trial, the incidence of relative adrenal insufficiency was half that reported by the trial. Our observations raise concerns about the generalizability of the findings of the above trial to etomidate-naive patients.
Key Words: sepsis, septic shock, adrenal insufficiency, synacthen, hydrocortisone, etomidate
Septic shock is frequently managed in the intensive care unit (ICU) and is associated with a high mortality. Septic shock may be associated with a syndrome of acquired relative adrenal insufficiency (RAI), although there is controversy over the definition of this syndrome (1-5).
In a recent randomized placebo-controlled trial of patients with septic shock, it was demonstrated that seven days of treatment with hydrocortisone (50 mg every six hours parenterally) and fludrocortisone (50 [micro]g once daily enterally) resulted in a 46% reduction in 28 day mortality in the subset of patients with RAI (defined as an increase in cortisol of < 9 [micro]g/dl [250 nmol/1] following high dose short synacthen test [HDSST]) (6). The incidence of RAI in this study was 77% (229/299 patients).
The Surviving Sepsis Guidelines emphasise the importance of evidence-based medicine for the development of novel therapies to treat septic shock (7) such as steroid replacement therapy. An important aspect of any prospective randomized controlled trial is external validity. The external validity of the steroid replacement therapy trial (SRTT) to the wider population of septic shock remains unknown. Concern has been raised that the cohort of patients in the trial represented a small subset of all patients with sepsis. Specifically, all patients were at the severe end of the spectrum of septic shock, as they were mechanically ventilated, had significant organ dysfunction and were on high-dose vasopressors (8,9). In addition, at least 24% had been exposed to etomidate prior to undergoing HDSST Etomidate is known to suppress production of cortisol in response to corticotropin (6,10). In keeping with this, 68 of 72 patients exposed to etomidate failed to respond to the HDSST (11).
We sought to determine the external validity of the SRTT by conducting a retrospective assessment of septic patients with no prior exposure to etomidate from three Australian ICUs. Our primary outcome was the incidence of RAI in the subset of patients with severity of illness identical to those described in the SRTT As a secondary objective we also examined the proportion of septic patients to which the trial result could be applied.
One hundred and thirteen patients from three Australian intensive care units (ICUs) were identified from central electronic databases as undergoing a HDSST between December 2002 and November 2003. Patient charts were assessed to determine the indication for performing the HDSST The clinical diagnosis of sepsis/septic shock was based on previously published consensus criteria (12). As etomidate is not licensed for use in Australia, none of the patients had been exposed to the drug at any stage of their illness.
De-identified retrospective data analysis is classified as an audit activity and the need for informed consent for such studies is waived by the local Hospital Human Research Ethics Committees.
Patient records were examined to obtain information regarding patient demographics, physiological derangement, clinical and radiological evidence of site of sepsis, the results of microbiological cultures, evidence of features of the systemic inflammatory response syndrome, APACHE II and SAPS II scores at ICU admission, central venous pressure (CVP) and the nature and doses of vasoactive medications (expressed in [micro]g/kg/min). We also assessed the ICU length of stay and the timing of the HDSST in relation to ICU admission. Finally, the serum albumin level on the day of the HDSST was also recorded.
Patients were assigned to one of three groups of increasing severity of illness (Figure 1). Group A included all patients with sepsis and requiring vasopressors (septic shock). Group B included all patients who were concurrently mechanically ventilated and on vasopressor therapy. Group C comprised patients fulfilling the inclusion criteria used for enrolment into the SRTT (6). Specifically, laboratory and clinical data in the eight-hour interval prior to testing with the HDSST were assessed. Patients were required to have (1) a documented site of infection; (2) a temperature >38.3[degrees]C or <35.6[degrees]C; (3) a heart rate >90 beats/min; (4) systolic blood pressure <90 mmHg or requirement of vasopressors; (5) need for mechanical ventilation and (6) one of urinary output <0.5 ml/kg for at least one hour or [P.sub.a][O.sub.2]:Fi[O.sub.2] ratio <280 mmHg or arterial lactate level > 2 mmol/1.
[FIGURE 1 OMITTED]
Details of cortisol assays
All three hospitals measure cortisol using a chemiluminescence assay. Two of the three hospitals use a Bayer instrument, with the third using a Beckman-Coulter instrument.
Results of HDSST
The adrenal response to HDSST was assessed as described in the SRTT Specifically, 250 [micro]g of synacthen was administered and cortisol levels were taken at 0, 30 and 60 minutes. RAI was defined as an increment (max) of less than 250 nmol/1(9 [micro]g/dl).
Data are presented as raw numbers with percentage for incidence data. Numerical data are presented as mean with 95% confidence intervals (CI) of the mean, or mean [+ or -]SD. Comparisons of proportions were performed using Fisher's exact test. A P<0.05 was taken to indicate statistical significance.
Features of the overall cohort
Of the 113 patients who underwent HDSST at the three institutions, fifteen did not meet consensus criteria for septic shock and were excluded from subsequent analysis (Figure 1).
Ninety-eight patients met the consensus criteria for septic shock (12) (Group A). Eighty-one percent of these patients (79/98) received both mechanical ventilation and vasopressor therapy (Group B). Only 39% (38/98) of the cohort of patients with septic shock fulfilled all inclusion criteria for the SRTT during the eight-hour period before undergoing the HDSST (Group C). Fifty-eight per cent of patients were male and the average age was 60 years (95% CI 56.2-63.8). Most patients had a respiratory focus of infection (Table 1). Sixty-eight per cent of patients were admitted for a medical reason and the ICU length of stay (av. [+ or -] SD) was 14.8[+ or -]37.9 days.
Characteristics of 98 patients with septic shock (Group A)
The average central venous pressure (CVP) for this population was 11.2 mmHg (95% CI 10.712.5). Ninety-seven patients received noradrenaline, seventeen patients received dopamine and only four received adrenaline. The average basal cortisol for this patient subgroup was 956 nmol/1 (95% CI 8071106). Twenty-four patients (24.5%) failed to have an increment of 250 nmol/1 following their HDSST On the day of the HDSST, the average ([+ or -]SD) serum albumin level was 22.9[+ or -]6.3 g/dl. The average ([+ or -] SD) time interval between the performance of the HDSST and admission to ICU was 2.2[+ or -]3.6 days, with 35% of patients undergoing the test within 24 hours of admission. The ICU and hospital mortality for group A were 24.5% and 38.8% respectively.
The majority (58.9%) of patients had either a respiratory or intra-abdominal focus of infection. Culture results were equally divided into gram positive (21%), gram negative (20%) and mixed organisms (21.7%). In 22.6% of patients, no organism was grown.
Characteristics of ventilated patients with septic shock (Group B)
Seventy-nine of the 98 patients (81%) with septic shock received concurrent mechanical ventilation. The average CVP for this population was 11.6 (95% CI 10.6-12.5). The pattern of use of vasoactive drugs was similar to that seen in group A, as was the focus of infection and organisms obtained from culture results (Table 1). The average basal cortisol for this patient subgroup was 942 nmol/1(95% CI 776-1109). Twenty-two patients (27.8%) had RAI, and the ICU and hospital mortality for group B were 29.1% and 41.8% respectively.
Patients satisfying inclusion criteria for the multi-centre trial (Group C)
Of the 98 patients with septic shock, 38 (39%) satisfied all entry criteria for the SRTT during the eight-hour period before undergoing the HDSST This represented 48% (38/79) of the ventilator--and vasopressor-dependent population of patients. The major reason for failing to fulfil severity criteria was absence of fever (29/41 ineligible patients) in the eight-hour prior to undergoing HDSST Additional reasons for ineligibility included absence of tachycardia (6/41), advanced cancer (4/41) and age < 18 years (2/41).
The average basal cortisol for this patient subgroup was 994 nmol/1 (95% CI 778-1211, and 13 (34.2%) had a cortisol increment <250 nmol/1 following the HDSST The ICU and hospital mortality of this population were 34.2% and 39.5%, respectively.
The effect of RAI on ICU and mortality
In all three groups, the presence of RAI was associated with an increased ICU and hospital mortality (Table 1). In group A, in the presence of RAI, the odds ratio (OR) for ICU mortality was 3.1 (P=0.031; 95% CI 1.13-8.31) and that for hospital mortality was 1.85 (P=0.23; 95% CI 0.73-4.69). In group B, in the presence of RAI, the OR was 2.8 (P=0.057; 95% CI 0.99-8.00) for ICU mortality and a 1.59 (P=0.44; 95% CI 0.59-4.29) for hospital mortality. Finally, in group C, in the presence of RAI, the OR for ICU mortality was 6.4 (P=0.041; 95% CI 1.45-28.2) and that for hospital mortality was 4.11 (P=0.08; 95% CI 1.00-16.99).
We conducted a retrospective study of the adrenal response to a HDSST in a heterogeneous population of patients with septic shock who had not received the drug etomidate.
We found that the incidence of RAI in etomidate-naive patient with septic shock was much lower than that reported in a recent steroid replacement therapy trial (SRTT). In addition, we found that only 39% of all our patients with septic shock fulfilled the trial inclusion criteria and that, in these patients, the incidence of RAI was less than half that reported in the trial. These observations have clinical implications and require detailed discussion.
One possible explanation for the lower incidence on RAI observed in our cohort relates to the use of the drug etomidate in at least 24% of the patients enrolled into the SRTT Thus, 68 of the 72 patients who received etomidate in the eight-hour prior to undergoing the HDSST were non-responders (29.6% of all non-responders). Etomidate is known to inhibit the adrenal response to corticotropin via inhibition of 11[beta]-hydroxylase (6,10,13). In a recent study of 62 consecutive, acutely ill patients needing mechanical ventilation for more than 24 hours, 27 of the 62 (43.5%) patients failed to respond to a HDSST On multivariate analysis, only etomidate administration was related to relative adrenocorticoid deficiency (OR 12.21; 95% CI 2.99-49.74) (13)
We believe that exposure to etomidate combined with the severity of illness of the cohort in the SRTT may have led to an overestimation of the incidence of RAI when compared to a more heterogeneous population of patients with septic shock. Consistent with this notion, in another study involving 189 patients with septic shock using identical criteria for adrenal insufficiency, the estimated incidence of occult adrenal insufficiency was 54% (14).
Thus, at least some of the reduced mortality seen in the SRTT may relate to treatment of impaired cortisol production induced by etomidate. Following the amendment (July 1996) in the study by Annane and co-workers (6), patients receiving etomidate during the six hours preceding randomization were excluded. However, the paper did not report on the incidence of exposure to etomidate beyond six hours (15). A single dose of etomidate has been shown to interfere with cortisol synthesis for at least 24 hours in the critically ill (10,13). It is theoretically possible that a much greater proportion of patients received some etomidate in the 24 hours preceding randomization. If this were the case, then the SRTT might simply report on the adverse consequences of iatrogenic adrenal suppression without rescue replacement in a population of patients with septic shock.
The use of etomidate for sedation has been shown to be an independent risk factor for death in ICU patients (16). There is also evidence from animal models that this detrimental effect can be partially reversed by glucocorticoid therapy (17). Indeed, a recent editorial suggested that the use of etomidate should be abandoned in the ICU (18). Because of concerns about safety, etomidate has never been licensed for use in Australia.
In the present study, the average CVP among ventilated patients with septic shock was 11.6 mmHg, suggesting adequate fluid replacement therapy. However, the predominant vasoactive drug used in the current study was noradrenaline (97/98 of septic shock patients). Only 21% of septic shock patients in the current study received dopamine and/or adrenaline. This is in contrast to the study by Annane and co-workers where more than 90% of patients (273/299) received dopamine and only 31% (94/299) received noradrenaline. The less frequent use of vasoactive agents with [beta]-adrenergic activity in our study may partly explain the lower incidence of tachycardia in our septic cohort.
The average basal cortisol in our cohort was higher than that seen in the SRTT (994 versus 722 nmol/1). High basal cortisol levels in patients with sepsis have previously been associated with increased mortality". However the overall hospital mortality of Group C in our study was lower than that of the SRTT (39.5% versus 61% for the intervention arm of SRTT).
Concerns have been raised about the high mortality seen in the SRTT (8) (198/299 or 66%). For example, in a recent study involving 100,554 intensive care admissions in Paris, the crude mortality for septic shock in the year 2000 was found to be 55.9% (19). Further, in the study examining the effect of activated protein C therapy in patients with severe sepsis, the mortality of the placebo arm was 30.8% (20). Finally, in a recent Australian study, mortality at 28 days for patients with severe sepsis was 32.4% (21). The overall hospital mortality of our cohort of septic shock patients requiring both mechanical ventilation and vasopressor therapy was 41.8%. However, in patients with RAI, the mortality was 50% for patients mechanically ventilated and on vasopressors (Group B), and 61.5% in patients fulfilling the inclusion criteria for the SRTT (Group C). These observations highlight the extreme severity of illness in the cohort of patients in the SRTT
An alternate explanation for the lower incidence of RAI in our cohort compared with the SRTT may be that the patients in the later study were sicker. Although the patients in Group C of our present study had identical entry criteria to that of the SRTT, the patients in the later study had higher SAPS and APACHE scores and were on higher doses of inotropes. Thus, patients in the SRTT were on a mean dose of 11 [micro]kg/kg/min dopamine, and/or 0.9 [micro]kg/kg/min adrenaline, and/or 1 [micro]kg/kg/min noradrenaline within eight hours of the onset of septic shock.
Concerns have also been raised that the recent study of the role of steroid supplementation in septic shock patients with RAI examined a highly selected subgroup of the entire population of septic patients (8). Consistent with this, only 39% of the 98 patients in the present study fulfilled severity criteria for this study during the eight-hour period prior to undergoing the HDSST The major reason for ineligibility into the study was a lack of fever. We believe that the routine use of paracetamol in our patient cohort contributed to this. Data on the use of antipyretics were not reported in the SRTT.
Our findings have implications for the design of future investigations into the potential benefits of steroid therapy in septic shock and make the exclusion of the drug etomidate an important component of such trials. They add further information to support the notion that etomidate use is associated with adrenal suppression and that the trial of steroid replacement may have reflected the effects of a particular intervention in a very unique biological and clinical setting.
Our observations suggest that the need for steroid supplementation may be applicable to as little as 13.3% (34.2% of 38/98) of patients with septic shock if etomidate is not used. These observations will affect sample size calculations and recruitment rates if it is this subgroup of patients who might yet benefit from steroid therapy. In addition, as the incidence of HDSST responders in this group of patients would be 66% instead of 23%, any potential adverse effects of steroid supplementation in septic patients without RAI may have been underestimated or not recognised in the original trial. Therefore, we believe there is a need for larger randomized controlled trials evaluating the role of steroid therapy in etomidate naive patients with septic shock.
Our study has several strengths and limitations. It is multi-centre in design, involves a heterogeneous group of patients with septic shock and provides a population where lack of exposure to etomidate is certain. It also provides details on vasopressor use and mechanical ventilation and data on ICU and hospital outcome. Nonetheless, this is a retrospective observational study and does not examine the role of steroid supplementation in patients with septic shock and concurrent RAI. However, the aim of the study was to demonstrate the incidence of RAI in a heterogeneous population of patients with septic shock who had not been exposed to the drug etomidate.
Second, it is possible that we may have missed septic patients undergoing HDSST, or that the study population may not be representative of the population of etomidate-naive patients with septic shock. However, we have studied patients from three university-affiliated hospitals who have demographics and infections similar to those reported by the SRTT, the patients were consecutive and the HDSST was confirmed using the central laboratory electronic records. Thus, it is unlikely many patients were missed.
Third, our study examines the adrenal response in 98 patients, one third of the cohort examined in the SRTT Despite the smaller size however, we were able to demonstrate clear differences in the incidence of RAI and mortality between our cohort and the reference study. Fourth, there was a higher incidence of negative cultures in our study. This may relate to the different intensity of searches for positive cultures in prospective studies compared to routine clinical practice. Fifth, we are unable to comment on the timing of the HDSST in relation to the onset of shock. In the SRTT the HDSST was performed within eight hours of the onset of shock. However, we believe that the RAI associated with septic shock is unlikely to be a transient phenomenon that is present within eight hours of the onset of shock but not present thereafter.
Our study does not report the incidence of RAI using alternate diagnostic criteria, such as low baseline cortisol or response to low dose SST (1-5), and does not report on levels of free cortisol. However, the aim of our study was to determine the external validity of the SRTT to etomidate-naive patients with sepsis and not to ascertain the incidence of RAI in this cohort according to various diagnostic criteria.
The nature and dose of the vasopressor therapy in our study differs substantially from that of the comparative study. It is unknown whether individual catecholamines influence adrenal responsiveness to synacthen.
Finally, patients in our cohort were selected on the basis of whether they had undergone a HDSST during the study period. This is imperfect methodology. Our study does not indicate the total number of septic patients admitted to the three units over the twelve month period, or the outcome of patients not subjected to a HDSST
In conclusion, our observations suggest that the patient cohort studied in the recent multicentre prospective randomized placebo controlled trial investigating the role of treatment with low-dose hydrocortisone may represent a small and extremely ill portion of the overall population of patients with septic shock. The incidence of relative adrenal insufficiency in this population was significantly higher than that seen in our population of etomidate-naive patients. Our observations raise concerns regarding the external validity and generalizability of the findings of the steroid therapy trial to the broader population of septic shock patients, especially in the absence of exposure to etomidate.
A prospective study is required to confirm whether the findings from our present study are applicable to all patients presenting with sepsis, rather than selecting the patient cohort on the basis of whether they had undergone a HDSST A randomized controlled trial in etomidate naive HDSST non-responders would also help better understand the role of steroid supplementation in septic shock.
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D. JONES *, M. HAYES [dagger], S. WEBB [double dagger], C. FRENCH [section], R. BELLOMO **
Department of Intensive Care, Royal Perth Hospital, Perth, Western Australia, Department of Intensive Care, Western Hospital, Melbourne, and the Departments of Intensive Care and Surgery, Austin Hospital, Melbourne, Victoria, Australia
* B.Sc. (lions), M.B., B.S., Australian and New Zealand Intensive Care Research Centre (ANZIC-RC) and Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria.
[dagger] M.B., B.Ch., B.A.O., M.R.C.S., Department of Anaesthesia, Mater Misericordiae Hospital, Dublin, Ireland.
[double dagger] M.B., B.S., Ph.D., M.P.H., F.R.A.C.P, F.J.F.I.C.M., Department of Intensive Care, Royal Perth Hospital and School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia.
[section] M.B., B.S., F.A.N.Z.C.A, F.J.F.I.C.M., Department of Intensive Care, Western Hospital, Melbourne, Victoria.
** M.B., B.S., M.D., F.R.A.C.P, F.J.F.I.C.M., Departments of Intensive Care and Surgery, Austin Hospital, Melbourne, Victoria.
Address for reprints: Prof. Rinaldo Bellomo, Department of Intensive Care and Department of Medicine, Austin Hospital, Studley Rd, Heidelberg, Vic. 3084.
TABLE 1 Characteristics and outcome of 98 etomidate-naive patients with septic shock. Description Group A Group B On vasopressors On vasopressors AND ventilated Number of patients 98 79 Mean (95% CI) Age years 60 (56.2-63.8) 59 (54.8-63.2) Percent female 41.5 36.7 APACHE II at ICU admission 23.4 23.4 SAPS II at ICU admission 46.9 48.2 Site of infection (% of overall) Respiratory 40 46 Abdomen 18.9 21.5 Urinary tract 6.6 1.3 Soft tissue 11.3 8.9 Endocarditis 2.8 3.8 More than one site 14.2 18.9 Culture results (% of overall) Gram positive 21 23 Gram negative 20 15 Viral 1.9 2.5 Fungal 7.5 10.1 Mixed 21.7 26.6 Culture negative 22.6 24.1 Average (95% CI) basal cortisol (nmol/1) 956 (807-1106) 942 (776-1109) Proportion (%) with serum cortisol increase <250 nmol/1 (9 [micro] g/dl) following HDSST 24/98 (24.5%) 22/79 (27.8%) Average (95% CI) CVP mm Hg 11.2 (10.7-12.5) 11.6 (10.6-12.5) Vasoactive drugs. Number of patients (mean dose in [micro]g/kg/min) Dopamine 17 (3.84) 16(3.4) Adrenaline 4(0.2) 4(0.2) Noradrenaline 97 (0.34) 78 (0.35) ICU mortality (%) Overall 24/98 (24.5%) 23/79 (29.1%) Without RAI 14/74 (18.9%) 13/57 (22.8%) With RAI 10/24 (41.7%) 10/22 (45.5%) Hospital mortality (%) Overall 38/98 (38.8%) 33/79 (41.8%) Without RAI 26/74 (35.1%) 22/57 (38.5%) With RAI 12/24 (50.0%) 11/22 (50.0%) Description Group C Fulfill all criteria for study by Annane et al Number of patients 38 Mean (95% CI) Age years 56 (53.6-58.4) Percent female 26 APACHE II at ICU admission 23.6 SAPS II at ICU admission 48 Site of infection (% of overall) Respiratory 42 Abdomen 23.7 Urinary tract 2.6 Soft tissue 15.8 Endocarditis 0 More than one site 13.2 Culture results (% of overall) Gram positive 24 Gram negative 13 Viral 0 Fungal 7.9 Mixed 31.6 Culture negative 23.7 Average (95% CI) basal cortisol (nmol/1) 994 (778-1211) Proportion (%) with serum cortisol increase <250 nmol/1 (9 [micro] g/dl) following HDSST 13/38 (34.2%) Average (95% CI) CVP mm Hg 11.2 (9.9-12.6) Vasoactive drugs. Number of patients (mean dose in [micro]g/kg/min) Dopamine 9(3) Adrenaline 2(0.2) Noradrenaline 38 (0.36) ICU mortality (%) Overall 13/38 (34.2%) Without RAI 5/25 (20.0%) With RAI 8/13 (61.5%) Hospital mortality (%) Overall 15/38 (39.5%) Without RAI 7/25(28%) With RAI 8/13 (61.5%) CI, confidence interval: HDSST, high dose short synacthen test: CVP, central venous pressure.
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|Author:||Jones, D.; Hayes, M.; Webb, S.; French, C.; Bellomo, R.|
|Publication:||Anaesthesia and Intensive Care|
|Date:||Oct 1, 2006|
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