Preserved Sympathetic Response to Hypotension Despite Perioperative alpha (2) Agonist Administration (1997)

alpha2-adrenergic agonists are receiving attention as possible anesthetic adjuncts. They provide sedation [1] and may reduce both anesthetic and analgesic requirements [2-4]. A marked reduction in sympathetic activity appears to be their most pronounced effect, resulting in attenuated intraoperative blood pressure lability [2,5-8] and lower postoperative serum catecholamine levels [2,7,8]. There are concerns that these sympatholytic effects, although beneficial for patients at risk of myocardial ischemia, could adversely affect cardiovascular responses to hypotension and other life-threatening events. We report a case in which septic shock developed within 12 hours of surgery that had incorporated clonidine in the anesthetic plan. Despite the use of clonidine, serum epinephrine and norepinephrine levels increased markedly in response to hypotension, which suggests preserved sympathetic responsiveness. Case Report A 57-yr-old man with a history of insulin-dependent diabetes and a pancreatic pseudocyst was admitted to the Johns Hopkins Hospital with painless jaundice, pruritus, and weight loss. A peripancreatic abscess was discovered and treated with percutaneous drainage and antibiotics. The patient later underwent partial pancreatectomy and drainage of peripancreatic abscess. Preoperative vital signs were: temperature (T) 37.8-38.2 degrees C, respiratory rate (R) 24 breaths per minute, pulse (P) 84-90 bpm, arterial blood pressure (BP) 120-140/70-90 mm Hg, and weight 68.6 kg. Medications included insulin, gentamicin, metronidazole, and ceftriaxone. The patient consented to enroll in a trial evaluating the effects of clonidine on stress hormones after moderate upper abdominal, nonvascular surgery [9]. He received clonidine 0.2 mg per os and a 10.3-cm2 clonidine patch (Catapres-TTS) at 11 PM the night prior to surgery and clonidine 0.3 mg per os at 6:15 AM the morning of surgery. The operation began at 7:45 AM and concluded at 1:45 PM. Intraoperative medications included thiamylal, lidocaine, pancuronium, morphine (20 mg total, titrated over the first hour of the case), isoflurane (0.6%-0.8%), and intermittent boluses of labetalol (30 mg total) for hypertension. At the end of the procedure, neuromuscular block was reversed (glycopyrrolate 0.6 mg and neostigmine 3 mg). The patient was tracheally extubated and admitted to the surgical intensive care unit. Estimated intraoperative blood loss was 500 mL, urine output was 700 mL, and fluid replacement included 4.1 L lactated Ringer's solution and 2 units packed red blood cells. On arrival at the surgical intensive care unit, vital signs were T 37.5 degrees C, P 96 bpm, R 12 breaths per minute (spontaneous), BP 137/89 mm Hg, and central venous pressure 2 cm H2 O. Maintenance fluids were begun at 126 mL/h. Over the next several hours, diminishing urine output, decreasing BP, increasing heart rate, and low central venous pressure prompted aggressive fluid resuscitation (1 L hetastarch, 2 units packed red blood cells, and 6 L crystalloid in addition to maintenance fluids). There was no indication of active bleeding. Increasing fever (Tmax 39.4 degrees C at 1 PM) was treated with 1.2 g rectal acetaminophen. Despite these maneuvers, vital signs 18 h postoperatively were T 38.1 degrees C, P 130 bpm, R 22 breaths per minute, and BP 79/44 mm Hg. The clonidine patch was removed, and vasopressor support (phenylephrine) was begun. Blood samples were obtained immediately prior to induction, as well as at 1, 6, 12, and 18 h postoperatively for determination of clonidine, norepinephrine, and/or epinephrine concentrations (high-pressure liquid chromatography, electrochemical detection). Plasma clonidine concentrations (Figure 1) were between 1 and 2 ng/mL and were similar to those of the nonseptic patients (n = 35) enrolled in the parent study. In contrast, serum epinephrine levels, although similar to preoperative values, were dramatically higher postoperatively in our patient and did not follow the normal pattern of slow postoperative decline (Figure 2a). Preoperative norepinephrine levels were comparable to those seen in clonidine-treated nonseptic patients but increased markedly postoperatively (Figure 2b). Serum norepinephrine levels are presented in the context of hemodynamic and other vital signs data in Figure 3.Figure 1: Serum clonidine concentrations immediately prior to induction and 1 and 18 h after arrival at the surgical intensive care unit. Concentrations in our patient (hatched bars) were similar to those of a cohort of 35 patients who received the same clonidine regimen and who underwent similar surgery (solid bar).Figure 2: Serum epinephrine (a) and norepinephrine (b) concentrations of our septic patient (hatched bar) and those of a cohort of 35 similarly treated patients (solid bar) immediately prior to induction and 1, 6, 12, and 18 h after arrival at the surgical intensive care unit.Figure 3: The serum norepinephrine concentration levels of our patient are shown in the context of vital signs simultaneously measured preoperatively and 1, 6, 12, and 18 h after arrival at the surgical intensive care unit.Discussion This patient received a clonidine regimen that provided therapeutic plasma clonidine levels throughout the perioperative period and is associated with improved intraoperative hemodynamic stability [1]. Despite the presence of this alpha2 agonist, the patient was able to generate a sympathetic response to sepsis and hypotension. This suggests that anesthetically effective doses of clonidine do not prevent increases in serum catecholamines in response to life-threatening events in the perioperative period. Clonidine can reduce blood pressure by inhibiting lower brainstem stimulation of sympathetic preganglionic neurons [10-12], which inhibits spinal preganglionic neurons [13] or inhibits peripheral norepinephrine release [14]. However, clonidine does not prevent reflex modulation of efferent sympathetic nerve traffic [15-18]. This persistent baroreceptor sensitivity is associated with the preserved ability to mount a catecholamine response [19] and may explain why patients who receive clonidine do not experience severe orthostasis [20,21]. Although our patient's perioperative plasma clonidine levels were similar to those observed in patients who received the same clonidine regimen as part of a concurrent trial, the initial postoperative plasma catecholamine levels in our septic patient were higher than those seen in the nonseptic clonidine-treated patients. Furthermore, while the nonseptic patients had decreasing serum epinephrine concentrations and constant serum norepinephrine levels postoperatively [2,3,22], serum catecholamine levels continued to increase postoperatively in the septic patient. This rise in catecholamine levels was likely due to the sepsis-induced decrease in blood pressure and suggests that the sympathetic nervous system retains the capacity to respond to hemodynamic stress despite the presence of alpha2 agonist therapy. Data regarding the "normal" catecholamine response to septic hypotension are not available. We cannot exclude the possibility that clonidine particularly attenuated the hypotension-induced increase in sympathetic nervous system activity. Epidural clonidine, which achieves similar plasma levels and higher cerebrospinal fluid levels than systemic clonidine [23], blunts the epinephrine response to hemorrhage-induced hypotension in sheep but not the norepinephrine response [24]. By reducing baseline catecholamine levels [25], alpha2 agonists may also induce changes in adrenergic receptor expression and/or signal transduction that alter the perioperative hemodynamic response to catecholamine [26]. However, the marked increase in catecholamine concentrations in response to hypotension demonstrated by our patient strongly suggests that the perioperative use of clonidine does not abolish adrenergic responses to stress.