Glucocorticoid production is regulated by a circadian rhythm and is controlled by a negative feedback loop wherein cortisol inhibits the production of CRF and ACTH (Figure 1). The adrenal cortex itself is anatomically and functionally divided into 3 zones. The outer zona glomerulosa produces glucocorticoids including cortisol, and the intermediate zona fasciculata and the inner zona reticularis synthesize mineralocorticoids and androgens, respectively (Figure 2). Cortisol is then transported through the bloodstream predominantly (over 90%) bound to the cortisol-binding protein.4 The free fraction of cortisol then diffuses through the cell membrane and binds to its cytosolic receptor (GRα).5 GRα then acts as a transcription factor by activating or repressing DNA expression or by binding to specific regions of DNA called steroid-responsive elements.5
Glucocorticoids inhibit the maturation, differentiation, and proliferation of immune cells involved in inflammation. Glucocorticoids not only inhibit the expression of proinflammatory cytokines such as interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)-α, and interferon-γ, but also induce overexpression of anti-inflammatory cytokines such as IL-4 and IL-10. Furthermore, glucocorticoids inhibit the production of cyclo-oxygenase-2 and phospholipase A2 and diminish leukocyte recruitment to tissues. In addition to regulatory pathways described, many proinflammatory cytokines modulate in vitro production of glucocorticoids (Table 1).1
Systemically, glucocorticoids also stimulate gluconeogenesis, increase renal water and sodium reabsorption,6,7 and increase blood pressure and cardiac output, mainly through their influence on plasma volume.8–11
Surgery induces an increase in glucocorticoid production that correlates with the intensity of the surgical procedure. In general, an increase in total plasma cortisol begins in the immediate postoperative period, returns to its presurgery baseline on postoperative day 2, and is proportional to the extent of surgery12 with minor procedures having a low or an inexistent impact on the increase in cortisol levels.13–15 In a 2014 study by Dimopoulou et al,16 major general surgery caused an increase in postoperative levels of free cortisol and ACTH and lower levels of cortisol-binding protein and ACTH by the second postoperative day.
Sepsis is an inflammatory condition with elevated cortisol levels that persist during the septic period. Conversely, despite an initial rise in plasma levels, ACTH rapidly decreases within 3 to 5 days, resulting in a dissociation between ACTH and cortisol levels.17,18 A postmortem study of septic patients suggested a direct effect of sepsis on ACTH expression, independent of any CRF modulation.19
Despite increased cortisol production, adrenal function may be disturbed, and exogenous ACTH (cosyntropin) may result in little or no cortisol synthesis.20,21 Relative adrenal insufficiency (RAI) has thus been defined as an insufficiently high cortisol level in the context of physiological stress (such as septic shock). Although Annane et al20 has defined RAI as an increase of less than 9 μg/dL for total plasma cortisol 60 minutes after a 0.25-mg injection of cosyntropin in patients with septic shock, this test remains controversial.22,23
RAI in septic patients is associated with increased morbidity and mortality. In a landmark 2000 study, Annane et al20 found higher mortality in patients with septic shock with high levels of cortisol and a poor response to cosyntropin. The association between RAI and increasing morbidity and mortality in critically ill patients has been observed in other studies of septic or traumatized patients.25–28
In addition, several studies have observed improved outcomes with glucocorticoid supplementation in patients with septic shock.25,29,30 Oppert et al31 found a decrease in the duration of catecholamine use and in circulating levels of proinflammatory cytokines in patients with septic shock receiving hydrocortisone, which was particularly pronounced in cosyntropin test nonresponders.31 A 2002 prospective randomized double-blind study found that fludrocortisone and hydrocortisone infusions lowered mortality and the duration of vasopressor infusion in patients with septic shock. Finally, a meta-analysis conducted in 2009 on more than 2000 patients found a beneficial effect on survival (relative risk [RR] with 95% confidence interval = 0.84 [0.72–0.97]), duration of shock, and length of intensive care unit (ICU) stay without any increase in risk of infection, neuromyopathy, or gastrointestinal bleeding.32
More recent trials, however, have not been as positive. The 2008 CORTICUS (Corticosteroid Therapy of Septic Shock) trial observed a 46.7% incidence of RAI, faster reversibility of shock with hydrocortisone supplementation, but no difference in mortality.33 Another 2009 meta-analysis found similar results.34 More recently, a retrospective and multicenter study found no overall difference in mortality but greater survival in the subgroup with the highest APACHE scores.35
In conclusion, although the positive overall effect of hydrocortisone on mortality is questionable, its use may have benefit for the most serious cases of sepsis. In light of these conflicting data, the 2013 guidelines of the Surviving Sepsis Campaign have suggested the use of a hydrocortisone “stress dose” of 200 mg per day in patients with septic shock with a poor response to vasoconstrictors, but do not recommend a cosyntropin stimulation test.36
Several hypnotic agents commonly used in anesthesia and intensive care may affect the HPA axis. In this section, we discuss the clinical or experimental effects of common anesthetics on the HPA axis. Main effects are reported in Table 2.
Etomidate is often used in patients with cardiovascular instability because of its minimal effect on vascular tone and myocardial function.37,38 However, etomidate has been associated with high mortality in sedated ICU patients as a result of adrenal failure.39 In in vitro and in vivo studies, etomidate blocks the enzymatic activity of adrenocortical steroidogenesis decreasing production not only of cortisol, but also of aldosterone. Using radiolabeled precursors in cultures of murine adrenocortical cells, Wagner et al40 found that etomidate inhibited both 11β-hydroxylase and P450 side-chain cleavage (P450scc) resulting in accumulation of the precursor molecules, 11-deoxycorticosterone, and cholesterol and a decrease in corticosterone production. In human adrenocortical cells, Weber et al41 found that etomidate at concentrations close to clinical practice decreased 11β-hydroxylase activity by more than 70% with a milder effect on 17α-hydroxylase and 16α-hydroxylase. These data were confirmed in vivo on 14 patients with normal pituitary function who had minor surgery and received a single bolus of etomidate compared with thiopental for anesthetic induction. Etomidate lowered the final products of 11β-hydroxylation: corticosterone, cortisol, and aldosterone, with a rise in the levels of the precursors 11-deoxycortisol and 11-deoxycorticorticosterone 1 hour after drug administration.42 As a result of these studies, etomidate infusions are no longer used to maintain general anesthesia, but are reserved for induction, particularly in patients with cardiovascular instability.
However, a single dose of etomidate can inhibit adrenal function. In a prospective study, De Coster et al43 showed that an induction dose of 0.2 mg/kg of etomidate reduced total cortisol by more than 50% in healthy patients but that cortisol levels returned to normal within 6 hours. A 2010 meta-analysis of 20 studies also determined that the duration of adrenal dysfunction lasted only 4 hours after administration and had no impact on morbidity or mortality.44 However, a retrospective study analyzed more than 30,000 American Society of Anesthesiologists score III and IV patients who underwent general surgery and found both an increased 30-day mortality and an increased risk of cardiovascular morbidity in patients who received etomidate (versus propofol).45 Despite propensity matching, this retrospective analysis likely contained some selection bias with sicker patients in the etomidate group. Another retrospective study on 3127 patients induced with etomidate for cardiac surgery found no difference in morbidity or mortality.46
Unlike patients undergoing elective surgery, ICU patients often have a high level of baseline inflammatory stress, which may potentiate the duration of adrenal failure induced by etomidate. In an early study of 35 critically ill patients requiring surgery, anesthetic induction with etomidate induced RAI for at least 24 hours.47 A 2008 study of 40 nonseptic ICU patients found that etomidate induction produced RAI beginning 12 hours after administration and lasting 48 hours.48 In another study of 99 nonseptic ICU patients, RAI was observed in approximately 90% of patients treated with a single dose of etomidate.49
Some studies have found worsened outcomes with single-dose etomidate use in critically ill patients. In a subgroup analysis of polytraumatized patients in the HYPOLYTE (Hydrocortisone Polytraumatise) study, patients treated with a single dose of etomidate had an excess risk of nosocomial acquired pneumonia at 28 days.50,51 In the 2008 CORTICUS study, etomidate was associated with a 44% to 61% increase in RAI33 and a 28% increase in mortality.52 However, selection bias is highly likely because the initial study was not designed to explore the association between etomidate and mortality. Other studies have not replicated the CORTICUS result. One prospective observational study on 106 septic patients found no effect of etomidate on mortality or length of hospital stay.53 Another more recent cohort study of 102 ICU patients with septic shock found no differences in life-threatening complications or mortality between patients who received a single dose of etomidate and those who received another hypnotic agent.54 Because both studies were small, a lack of power may have limited their ability to identify a difference. Larger meta-analyses have been similarly mixed. A systematic review of 14 studies and 2854 patients found an RR of RAI after etomidate administration of 1.64 (1.52–1.77) with an increased RR of mortality of 1.19 (1.10–1.30).55 A 2012 meta-analysis by Chan et al56 also identified an RR of mortality of 1.20. In contrast, a more recent (2015) meta-analysis by Gu et al57 included 5552 septic patients (2 randomized controlled studies and 16 observational studies) and found adrenal insufficiency with etomidate (RR = 1.42 [1.22–1.94]) but no difference in mortality (RR = 1.05 [0.79–1.39]). Another meta-analysis by Bruder et al58 did not show an association between mortality and etomidate but a rise in RAI (odds ratio = 2.37 [1.61–3.47]) 12 hours after administration and a small increase in Sequential Organ Failure Assessment dysfunction scores. Unfortunately, many of the studies included in these meta-analyses were either not designed to evaluate the specific impact of etomidate on mortality or heterogeneous in methodology and inclusion criteria. As a result, no consensus currently exists regarding the use of this agent in inflammatory conditions. Although the specific effects of etomidate on enzymatic function are well known, the molecular mechanism of steroidogenesis inhibition is not clear. Crystallographic studies have suggested the role of the imidazole ring, which interacts with the heme of P450 cytochrome and may thus inhibit the activity of such enzymes59,60 (Figure 3). A 2013 in vitro study found that etomidate inhibits the incorporation of a radiolabeled analog of etomidate (azi-etomidate) by 11β-hydroxylase, suggesting that physical affinity and the direct effect of etomidate may play a role.61 A new anesthetic, carboetomidate, substitutes a carboxyl group for the imidazole group.61 Unlike etomidate, this analog has a low affinity for 11β-hydroxylase and can fit into the heme-containing active site pocket but not interact with the heme iron. Cotten et al62 demonstrated that carboetomidate had a 3-fold lower inhibition of steroidogenesis in vitro compared with etomidate and no significant adrenal effect in vivo. These findings await confirmation in humans.
In summary, strong in vitro data show etomidate interferes with normal steroidogenesis via inhibition of adrenal function. Its use in elective surgery for patients without pre-existing morbidities likely does not induce clinically significant adrenal suppression. Conversely, the impact of etomidate for morbid or ICU patients, especially septic patients, is seriously debated. In light of existing data, etomidate cannot be considered risk-free, and an adverse effect on outcomes in septic, critically ill patients may be possible. Hence, etomidate should be chosen cautiously in these patients and practitioners should consider alternative agents when possible.
Ketamine is a viable alternative to etomidate as a hypnotic agent for induction of anesthesia in patients with cardiovascular instability. Ketamine administration activates sympathetic nervous system activity and produces a rise in heart rate, blood pressure, and cardiac output.63 In vivo studies in healthy volunteers have shown that ketamine administration also increases total cortisol levels.64,65 However, interactions among the sympathetic nervous system, the endocrine system, and analgesic properties of ketamine complicate in vivo study of its specific effects on steroidogenesis. During minor surgery, ketamine lowers cortisol levels in association with a decrease in circulating catecholamines.65 Both direct and indirect effects are possible because ketamine acts on N-methyl-d-aspartate receptors, which are distributed throughout the HPA axis.66–68 A direct effect of ketamine on proinflammatory cytokine production (IL-6, IL-8, TNF-α) has also been suggested69–73 and has been observed during gynecologic surgery.65
As a result of its hemodynamic and immunomodulating properties, ketamine may be an effective substitute for etomidate in patients with septic shock. In a prospective, multicenter study, Jabre et al74 randomized 655 patients requiring prehospital intubation to ketamine or etomidate and found no difference in mortality but a higher risk of RAI with etomidate (odds ratio = 6.7 [3.5–1 2.7]). However, because only 16% of patients in this study were septic, these results cannot be applied to septic ICU patients.
Because current data do not indicate an adverse effect of ketamine on the HPA axis, it is a reasonable induction agent in septic patients with a high risk of RAI. However, further clinical trials are warranted to evaluate both etomidate and ketamine for induction of anesthesia during septic shock.
Benzodiazepines have anxiolytic, hypnotic, myorelaxant, and amnesic properties. However, benzodiazepines are well-known inhibitors of cortisol production both in vitro and in vivo. In bovine adrenal cultures, midazolam and diazepam inhibit cortisol and aldosterone production in a concentration-dependent manner. This inhibition is present in doses administered for anxiolysis during anesthesia and a 3- to 6-fold decrease in cortisol production is possible with midazolam and diazepam at concentrations similar to those obtained with continuous administration in the ICU.75–77
In vivo, inhibition of cortisol production may be mediated by reduced CRF production and also by direct inhibition of adrenal enzymes.77–80 Thus, an anxiolytic dose of alprazolam can decrease ACTH production and total cortisol in healthy subjects.78 A 2002 study suggested that the effect of benzodiazepines on the HPA axis was mediated predominantly via CRF because ACTH production did not change with alprazolam treatment in the presence of human CRF. This study also suggested a peripheral effect of benzodiazepines because adrenal cortisol production was reduced despite cosyntropin administration.79
Benzodiazepines thus inhibit both the hypothalamic and adrenal compartment of the HPA axis. In addition to direct inhibition of the HPA axis, benzodiazepines can also inhibit catecholamine release, which inhibits steroid production.81 Crozier et al80 compared the effects of etomidate, midazolam, and methohexital on adrenal function in healthy subjects after minor surgery and found that midazolam induced a decrease in cortisol levels similar to etomidate and also a decrease in ACTH and circulating catecholamines. Conversely, some in vitro data suggest a stimulatory effect of benzodiazepines on steroidogenesis but only at very high doses.82
The mechanisms by which benzodiazepines affect steroid synthesis are incompletely understood. Midazolam and diazepam inhibit both 17 and 21 hydroxylation and, to a lesser extent, 11β hydroxylation of steroids.76,77 Moreover, midazolam can inhibit the uptake of Ca2+ by glomerulosa cells and thus limit cyclic adenosine monophosphate mediated ACTH enhancement of steroidogenesis.76,77 Conversely, the presence of peripheral benzodiazepine receptors in the adrenal cortex suggests that benzodiazepines may directly stimulate steroid production by facilitating the transfer of cholesterol to the inner mitochondrial membranes and enhancing the P450scc enzyme.83,84 A local environment rich in high-density lipoprotein cholesterol could thus favor steroidogenesis. However, conditions have only been realized in vitro, and clinical studies actually argue for an inhibitory effect of benzodiazepines on the HPA axis through both hypothalamic and adrenal inhibition. Thus, midazolam should theoretically be avoided in conditions likely to cause adrenal insufficiency such as sepsis. However, randomized studies comparing propofol and midazolam in critically ill patients have not found differences in clinical outcomes.85–87 In a small prospective randomized trial, Aitkenhead et al85 found no differences in morbidity or mortality and no differences in cortisol levels at baseline or after cosyntropin administration. However, very few patients were admitted for sepsis. In the absence of conclusive evidence, midazolam is unlikely to affect the HPA axis in a clinically meaningful way.
Few data exist on the effect of propofol on adrenal function in humans. In 1 study of bovine adrenal cell cultures, propofol decreased cortisol production by 10% to 20% at doses similar to those currently used for anesthesia. This inhibition is less than with etomidate.88,89 Neither animal nor human studies show significant inhibition of cortisol production or an altered response to tetracosactide.85,90,91 Thus, inhibition of in vitro steroidogenesis is unlikely to be clinically relevant and the use of propofol, either for anesthesia or sedation in ICU, probably does not interfere with the HPA axis.
Thiopental weakly inhibits cortisol production in vitro and in vivo. In bovine adrenal cultures, thiopental induced a 30% to 40% decrease in cortisol production.88,89 In healthy subjects undergoing minor surgery, Duthie et al showed that cortisol levels remained unchanged 4 hours after injection of thiopental.92 Similarly, Crozier et al80 demonstrated that methohexital did not affect the production of cortisol or ACTH compared with etomidate or midazolam during minor surgery. Like propofol, barbiturates probably do not significantly affect adrenal function.
Few studies have investigated the specific effect of inhaled anesthetics on HPA axis function. In a porcine model, sevoflurane increased total cortisol and ACTH levels after induction of anesthesia when compared with propofol.93 Similarly, the use of volatile agents during hysterectomy increased ACTH and total plasma cortisol levels compared with propofol and midazolam.94 This increase was not influenced by the agent used and occurred concomitantly with catecholaminergic activation.95 Insufficient data exist to determine the effect of volatile anesthetics on HPA function.
Dexmedetomidine is a selective agonist of adrenergic α-2 receptors with analgesic, anxiolytic, and sedative actions. Few studies have examined the effects of this drug on HPA function. Structurally, dexmedetomidine contains an imidazole ring like etomidate, and thus may mimic etomidate with respect to its effect on steroidogenesis. In murine adrenocortical cultures, concentrations above 10−6 M significantly inhibited corticosterone production.96 However, at concentrations closer to clinical practice (10–7 to 10-8M), dexmedetomidine (unlike etomidate) did not inhibit steroidogenesis. These results were supported in a dog model of dexmedetomidine sedation where no change in cortisol level was seen.96 Very few data are available in humans. In 1 1992 study, preoperative intramuscular administration of 3 different doses (0.6, 1.2, and 2.4 μg/kg) before laparoscopy decreased cortisol and circulating catecholamine levels.97 In a single-center randomized study on 20 ICU patients who had major abdominal pelvic surgery, patients sedated with dexmedetomidine did not differ from those receiving propofol in total cortisol, ACTH, or response to cosyntropin injection.98 However, these studies focused only on short-term dexmedetomidine administration. Thus, dexmedetomidine may have only modest effects on HPA function. More human studies are needed to evaluate the long-term effects of dexmedetomidine on adrenal function, particularly during septic shock.
Very few studies have investigated the effect of local anesthetics on the HPA axis. Experimental data argue for a stimulatory effect of lidocaine on hypothalamic–pituitary function. In rat hypothalamic cultures, lidocaine or procaine increases CRF production.99 In pituitary cell cultures, most local anesthetics potentiate the effect of CRF on POMC transcription.100 The characterization of in vivo effects is more difficult because of the multiple pathways involved in HPA regulation. Kling et al99 showed that administration of procaine to healthy subjects induced a rise in ACTH and cortisol plasma levels. Nevertheless, subjects also had stress with anxiety, dysphoria, and sensorial distortion related to procaine administration. Moreover, the use of intravenous lidocaine during surgery diminishes perioperative hypnotic consumption, postoperative pain, and opioid consumption and decreases inflammatory mediator release.101,102 These factors complicate analysis of the impact of local anesthetics on HPA function. Existing data are mixed. In a randomized study of 40 patients undergoing laparoscopic colectomy, Kaba et al101 showed that intravenous lidocaine did not affect cortisol plasma levels. However, another study of 90 patients who received intravenous lidocaine for cesarean delivery found a 30% reduction in plasma cortisol levels but also a concomitant reduction in heart rate and blood pressure, suggesting reduced overall surgical stress.103 The epidural administration of local anesthetics presents similar difficulties in interpretation as a result of stress effects of pain. Li et al104 randomized 90 patients undergoing gastrectomy to epidural ropivacaine or placebo and found a decrease in cortisol levels but also levels of TNF-α, IL-6, and catecholamines. In another study, the use of epidural bupivacaine for radical cystectomy was associated with lower levels of cortisol but also ACTH and aldosterone.105 Overall, local anesthetics seem to have little effect on HPA function.
Opioid derivatives are commonly used for general anesthesia. Their effects are mainly exerted through δ, μ, and κ receptors. These receptors have all been identified in the hypothalamus, pituitary, and adrenal glands and exert a modulatory effect on the HPA axis.106 In this review, we focus only on the effects of acute opioid administration. For a complete review, see Vuong et al.106 In rodents, acute morphine administration induces a rise in CRF, ACTH, and cortisol plasma levels.107–109 Interestingly, in addition to hypothalamic–pituitary stimulation, opioid peptides directly stimulate μ receptors in the zona glomerulosa, resulting in production of corticosterone independent of ACTH.110 Effects of opioids on the HPA axis in humans are mixed. Administration of oral morphine in healthy subjects decreased ACTH and cortisol levels despite CRF stimulation.111 Moreover, administration of the antagonist naloxone to healthy subjects was associated with an increase in ACTH and cortisol levels after CRF stimulation, whereas morphine blunted their production.112,113 Similarly, oral morphine administered to patients in pain returned elevated cortisol and ACTH levels to normal.114
Taken together, these data argue for the inhibitory effect of opioids on HPA function when used clinically, although the mechanisms responsible are poorly understood. In rats, morphine administration reduced the expression of the prohormone convertase in the hypothalamus.115 Because prohormone convertases are responsible for converting POMC into ACTH, this finding suggests that posttranscriptional regulation of ACTH production by opioids may account for opioid effects on the HPA axis. The effects of opioids during surgery are more difficult to assess because of operative stress. In a randomized study, 60 patients undergoing laparoscopic colectomy received either epidural anesthesia with ropivacaine or intravenous analgesia with remifentanil. Although both strategies reduced circulating catecholamines, remifentanil infusion was associated with a reduction in perioperative cortisol and ACTH levels compared with those observed at induction.116 Similar results were observed in 12 patients during cholecystectomy. High doses of fentanyl reduced cortisol levels, but this reduction was also associated with a significant drop in adrenaline levels, potentially obscuring the independent effect of opioids on HPA function.117 However, experimental and clinical data both argue overall that opioids inhibit the HPA axis. Clinically, opioid-induced modulation of the stress response must be weighed against the weak functional inhibition of the HPA axis.
In conclusion, most anesthetic agents, at least in vitro, modify HPA axis activity at 1 or more levels. The clinical relevance of this interaction depends on the hypnotic agent administered. Etomidate is the drug most studied because of its well-known inhibitory effect on HPA axis function. However, the clinical impact of etomidate remains unclear and probably depends on patient morbidities and inflammatory status. Alternative drugs such as ketamine, which have a smaller impact on HPA function, should be considered for induction of anesthesia in inflammatory conditions. Although midazolam, dexmedetomidine, and propofol suppress the HPA axis in vitro, the clinical impact of this effect is unclear and no recommendation can be made for any 1 agent, particularly for long-term sedation. The effects of opioids and local anesthetics on HPA function are similarly unclear, in part because they treat pain, which itself may affect stress hormone production. More clinical trials are needed to investigate the adrenal effects of anesthetic agents.
The authors are grateful to Nikki-Sabourin-Gibbs, Rouen University Hospital, for editing the manuscript.
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