1Department of Anaesthesia and Intensive Care, Worthing Hospital, Lyndhurst Road, Worthing, West Sussex BN11 2DH, UK. 2Department of Anaesthesia and Intensive Care Medicine, St Georges Hospital Medical School, Cranmer Terrace, London SW17 ORE, UK. 3Department of Anaesthesia and Intensive Care Medicine, St Georges Hospital, Blackshaw Road, London SW17 OQT, UK*Corresponding author
Accepted for publication: January 16, 2001
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Abstract |
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Br J Anaesth 2001: 86: 6506
Keywords: hormones, glucocorticoid, cortisol; hormones, growth; hormones, prolactin; hormones, adrenal; hormones, adrenocorticotrophic; intensive care; sedation, post-operative
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Introduction |
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The highly selective and potent 2 agonist dexmedetomidine is an effective agent for post-operative sedation and analgesia in the ICU.3 It is an imidazole compound and therefore has the potential to exert similar inhibitory effects to etomidate on cortisol synthesis. In vitro and in vivo animal studies have shown that dexmedetomidine inhibits cortisol synthesis at concentrations above 106 M, whereas therapeutic plasma concentrations of dexmedetomidine in patients are less than 109 M.4 Consequently, inhibition of steroidogenesis is unlikely to occur clinically, and this supposition is supported by the absence of hypocortisolism in human volunteers and surgical patients after i.v. or i.m. use.5 6 However, inhibition may become important clinically when dexmedetomidine is given as an infusion in the ICU patient, especially if changes in circulating inflammatory mediators [tumour necrosis factor
, immunoreactive corticostatin, interleukin 6 (IL-6)] have already impaired the adrenocortical response to adrenocorticotrophic hormone (ACTH).7
Attenuation of the cardiovascular and neuroendocrine responses to surgery may improve outcome by beneficial effects on organ function,8 although modulating the inflammatory response is probably more important in improving recovery.9 The modification of cardiovascular responses after surgery by dexmedetomidine has been described recently.3 The neuroendocrine effects of the 2-adrenoceptor agonist clonidine are well known10 11 but have not been observed during surgery.12 13 However, dexmedetomidine modified the pituitary hormonal response to gynaecological laparoscopy,6 possibly because of its higher selectivity for the
2-adrenoceptor. There has been little work on the effect of
2-adrenoceptor agonists on the inflammatory response. Although IL-6 production is suppressed in vitro by p-aminoclonidine,14 oral premedication with clonidine had no effect on the IL-6 response after pancreatobiliary surgery.15
We compared the effects of dexmedetomidine and propofol on adrenocortical function and the cardiovascular, endocrine and inflammatory responses in post-operative patients requiring sedation and ventilation in the ICU.
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Methods |
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The anaesthetic technique was decided by the individual anaesthetist and the dose of intra-operative analgesic was recorded. On arrival in the ICU, patients were allocated randomly, using sealed envelopes, to receive either dexmedetomidine or propofol infusions together with an alfentanil infusion for analgesia if required. Patients received a loading dose of dexmedetomidine 2.5 µg kg1 h1 over 10 min followed by a maintenance infusion of 0.22.5 µg kg1 h1 into a peripheral or central vein. Propofol was given undiluted as an infusion of 13 mg kg1 h1, and a bolus dose of 1 mg kg1 was given initially if required. Alfentanil was infused at 0.251.0 µg kg1 min1 if the patient complained of pain and analgesia was required. The level of sedation was measured and recorded hourly using the Ramsay sedation score16 and bispectral index17, and patients were maintained at a Ramsay sedation score >2 by adjustments to the sedative regimen. Bolus doses of atracurium were given to provide muscle relaxation and paracetamol was used as an antipyretic if necessary. No other sedative or analgesic agents were given.
Patients were ventilated mechanically with oxygen-enriched air to attain acceptable blood gases and extubation was undertaken when indicated clinically. The dexmedetomidine infusion could be continued up to a maximum of 24 h and patients were changed to propofol infusions if they still required sedation and ventilation after this time.
Heart rate, arterial pressure, central venous pressure and oxygen saturation measurements were monitored continuously. Blood samples were obtained from all patients immediately on arrival in the ICU and before administration of sedative or analgesic infusions, and 2, 4, 6, 8, 12 and 24 h after commencement of sedative infusions, provided the patient had not been extubated and the sedative infusion had not been discontinued. In addition, after cessation of the infusion, a short ACTH stimulation test was performed in those patients who had received dexmedetomidine; blood samples were collected 30 and 60 min after administration of synthetic ACTH 250 µg i.v. (Synacthen; CIBA-Geigy, Macclesfield, UK). Samples were centrifuged immediately and serum was stored at 70°C, before analysis in duplicate. Serum concentrations of cortisol, ACTH, insulin, growth hormone (GH), prolactin and IL-6 were measured with commercially available enzyme-linked immunoassay (ELISA) kits. Serial glucose measurements were performed immediately on the ICU using a blood gas analyser (ABL 625; Radiometer, Copenhagen, Denmark), which was calibrated and referenced daily. IL-6 measurements were only performed at baseline and 2, 6, 8 and 12 h after admission to the ICU. The lower limits of sensitivity of the assays were 8.3 nmol litre1 for cortisol (Milenia Cortisol, Diagnostic Products, CA, USA), 0.27 pmol litre1 for ACTH (Active ACTH, Diagnostic Systems Laboratories, London, UK), 0.11 mIU litre1 for growth hormone (MedgenixHGHEASIA, Biosource, Nivelles, Belgium), 7.6 mIU litre1 for prolactin (FertigenixPRLEASIA, Biosource, Nivelles, Belgium), 0.15 mIU litre1 for insulin (MedgenixINSEASIA, Biosource, Nivelles, Belgium) and 0.70 pg ml1 for IL-6 (Quantikine IL-6; R&D systems, Abingdon, UK). Intra- and inter-assay coefficients of variation were 6.9 and 8.0% respectively for cortisol, 8.6 and 6.6% for ACTH, 3.6 and 7.1% for GH, 6.1 and 8.3% for prolactin, 5.3 and 9.8% for insulin, and 4.2 and 6.4% for IL-6. The morning reference range for cortisol was 138 690 nmol litre1.
Sample size was determined from previous work, which indicated that with 20 patients there was a power of 90% to detect a 20% decrease in heart rate at a significance level of 5%. Cardiovascular data are shown as mean (SEM) values and comparisons were made by analysis of variance for repeated measures, followed by post hoc Bonferroni testing. Other data are shown as median values (interquartile range), and non-parametric analysis was undertaken. Analysis of serial measurements for unequal time points was performed with a two-stage method that used summary measures for cortisol, ACTH, prolactin, insulin and glucose concentrations.18 The area under the curve was calculated for each patient and between-group comparisons were made using the MannWhitney U-test. Insulin concentrations at several time points were less than the sensitivity of the assay and so data were ranked and the groups compared using the KruskalWallis test. The ratios of IL-6 concentrations at 2, 6, 8 and 12 h relative to baseline were calculated and then compared using the MannWhitney U-test. P<0.05 was accepted as significant. All analysis was carried out using the Statview for Windows software package (version 4.57; Abacus Concepts, Berkeley, CA, USA).
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Results |
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Haemodynamics
Patients receiving dexmedetomidine had significantly lower heart rates compared with the propofol group (P=0.034), but there were no differences in arterial pressure between the two groups (systolic, P=0.6, diastolic P=0.36) (Fig. 1).
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Two patients in the propofol group and one receiving dexmedetomidine required an insulin infusion to control blood glucose concentration and so were excluded from the analysis of the insulin results. Of the remainder, three patients in the dexmedetomidine group and one patient in the propofol group had insulin concentrations below the sensitivity of the ELISA assay for the whole study period. Insulin concentrations were consistently lower in the dexmedetomidine group, but this was statistically significant only at 2 h (P=0.021).
Serum concentrations of GH increased from baseline in patients receiving dexmedetomidine in the ICU, although this rise was not statistically significant. There was no significant change in the propofol group. There was a statistically significant difference between the groups overall for GH secretion (P=0.036) (Table 3).
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Discussion |
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Imidazole compounds are potent, non-selective inhibitors of cytochrome P450 enzymes, through the binding of the unhindered nitrogen in the imidazole ring to the catalytic haem iron atom of the protoporphyrin in the resting cytochrome P450 enzyme.23 Dexmedetomidine does not inhibit cytochrome P450 enzymes, including those involved in steroidogenesis, at therapeutic concentrations.4 6 It is difficult to show that a new drug does not affect adrenocortical function in the critically ill because many other factors may be influencing steroidogenesis, including the pathology and other medications. A single test of adrenal function in the ICU remains elusive, and so we assessed steroidogenesis by measuring sequential cortisol and ACTH concentrations and by performing an adrenal cortex stimulation test at the end of the dexmedetomidine infusion.
Hypocortisolism, defined as a serum cortisol concentration below the lower limit of the normal range (<138 nmol litre1), is probably an inappropriate definition for patients in the ICU. Because surgery, intercurrent illness and ICU interventions will stimulate the hypothalamicpituitary adrenal axis, various investigators have suggested lower cortisol limits of 400 or 500 nmol litre1 to be appropriate measures of adrenal insufficiency in these patients.24 The majority of patients studied would fall into this category at some time in the ICU, a finding reported recently in other ICU patients.25 These authors concluded that relative dysfunction of the adrenal glands is a frequent occurrence in the ICU patient, although it is unclear what an appropriate circulating cortisol value is in these patients. The exaggerated ACTH response at low concentrations of cortisol seen with etomidate,26 implying maximal ACTH secretion in order to overcome complete inhibition of cytochrome P450 enzymes, was not seen in this study.
Our results differ from those of Aho and colleagues, who noted that the cortisol response was attenuated during gynaecological laparoscopy.6 Pre-operative samples provided baseline cortisol values in this study and were lower than those found in our post-operative patients. It is possible that there were small differences in the endocrine response in the dexmedetomidine group that we were unable to detect with the power of the study; our sample size would be expected to show a 50% change in cortisol values based on Ahos work ( value 0.05, ß value 0.8).
An ACTH stimulation test is used clinically to diagnose relative adrenal insufficiency, because isolated normal or high cortisol measurements may not reflect the patients ability to respond to further physiological stress and low cortisol levels do not necessarily imply functional adrenal insufficiency. However, the usefulness and interpretation of this test in both post-operative27 and intensive care7 patients remains controversial. There is no agreement in intensive care medicine on the criteria that should be used in evaluating the changes in cortisol after ACTH stimulation. Therefore, it is not surprising that our patients sedated with dexmedetomidine showed differing pass rates depending on the method used to interpret the test. Five patients failed to show an incremental rise in cortisol >200 nmol litre1 after ACTH stimulation (Table 1), reflecting the inadequacy of this criterion in diagnosing adrenocortical dysfunction. The majority of patients had high normal or high basal cortisol values and the magnitude of the incremental rise was inversely proportional to the basal cortisol concentration.27 It is notable that over 30% of healthy volunteers failed to meet this criterion in one study.28 There are several criteria in the literature for diagnosing adrenal hypofunction based on the peak cortisol concentration after ACTH stimulation.27 We chose the lowest value (400 nmol litre1) and a commonly used value (550 nmol litre1). Two patients failed to meet two of our selected criteria, but both these patients had an uneventful post-operative ICU and hospital recovery with no clinical suspicion of adrenocortical insufficiency.
Dexmedetomidine failed to modulate the remaining hormonal response to surgery, with the exception of a transient decrease in insulin and augmentation of GH secretion. Alpha-2 adrenoceptor agonists can cause hyperglycaemia in humans12 29 and even the wild boar.30 The mechanism is thought to involve postsynaptic 2-adrenoceptor stimulation of pancreatic beta cells, which inhibits insulin release, although activation of hepatic glycogenolysis and an increase in GH may be involved.31 Hyperglycaemia was not found after surgery when oral clonidine was given,32 and this may reflect attenuation of the sympathoadrenal response. We found no differences in glucose concentrations between the groups, and there were no differences in the requirements for exogenous insulin infusion.
Agonists of the 2-adrenoceptor, including dexmedetomidine, are known to stimulate GH secretion.5 Increased protein turnover and a negative nitrogen balance are characteristic features of patients in the ICU, and this may prolong ventilation as a result of respiratory muscle weakness and delay mobility. This may be attributable partly to resistance to GH and the decreased production and action of insulin-like growth factor.33 It was thought that GH therapy may be beneficial in the critically ill, but a recent large multicentre study showed that mortality was increased at least two-fold by the use of large doses of GH in these patients.34 We found an increase in GH in the dexmedetomidine group that was within the physiological range, and this may be advantageous for patients in the ICU.
Dexmedetomidine may influence the inflammatory response and there is some evidence that this has a beneficial effect on outcome.9 IL-6 is the principal cytokine released after surgery, and the response is modulated partly by endogenous corticosteroids.35 In this study, any interaction between IL-6 and cortisol would have been similar in the two groups. Circulating IL-6 concentrations reflect the inflammatory response to surgical trauma, and the similarity of baseline concentrations indicates that the severity of surgery was equivalent in the groups. IL-6 usually peaks about 12 h after surgery,8 and it is notable that patients receiving dexmedetomidine showed a continuing decline in IL-6 concentrations (Table 3). The lack of a statistically significant difference between the groups may be the result of the small sample size, and further investigation is warranted. According to our results, a sample size of 40 would have an 80% power of detecting a 50% difference in IL-6 ( value 0.05).
In conclusion, dexmedetomidine infusions did not inhibit adrenal steroidogenesis when used for short-term sedation in intubated and ventilated post-operative patients in the ICU. Dexmedetomidine attenuated the heart rate response to surgical trauma compared with propofol and may decrease the inflammatory response to surgical trauma. However, dexmedetomidine had only minor effects on the other endocrine changes.
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