Kumar G. Belani

Naloxone, Meperidine, and Shivering

BackgroundMeperidine, which binds both μ and k opioid receptors, is reportedly more effective in treating shivering than are equianalgesic doses of morphine (a nearly pure μ-receptor agonist). Furthermore, butorphanol, a k-receptor agonist/antagonist, treats shivering better than does fentanyl, which mostly binds μ receptors. These data Indicate that much of meperidines special antishivering activity may be mediated by its k activity. Accordingly, the authors tested the hypothesis that the antishivering activity of meperidine will be minimally Impaired by low-dose naloxone (blocking most μ-receptors), but largely prevented by high-dose naloxone (blocking all μ and most k receptors). MethodsTwelve volunteers each participated on 2 days. On both days, shivering was induced by central venous Infusion of cold fluid. Twenty minutes later, six volunteers were given a placebo infusion of saline on one day, or an Infusion of 0.5 μg ± kg−1 ± min−1 naloxone hydrochloride (“low-dose,” designed to block μ receptors) on the other. The second group of six volunteers was given a saline bolus and infusion on one day, or a bolus of 11.5 μg/kg naloxone hydrochloride followed by an infusion of naloxone at 5 μg ± kg−1 ± min−1 (“high-dose,” designed to block both μ and k receptors) on the other day. The infusions were continued for the duration of the study. The order of the treatment days (saline vs. naloxone) was randomly assigned, and the study was double blinded. Fifteen minutes after the test infusion was started, all 12 volunteers were given an intravenous bolus of 1 mg/kg meperidine hydrochloride. Pupillary diameter and light reflex amplitude were used to quantify opioid-receptor agonist activity; shivering intensity was evaluated using oxygen consumption. ResultsAdministration of naloxone alone did not alter oxygen consumption, pupil size, or the pupillary light reflex. No pupillary constriction was detected in either group when naloxone and meperidine were combined; in contrast, meperidine alone decreased pupil size and amplitude of the light reflex 30%. The meperidine bolus decreased oxygen consumption nearly to control values when the volunteers were given saline placebo. Combined administration of meperidine and low-dose naloxone also significantly reduced oxygen consumption, but the reduction and the duration of the reduction was less than during saline. When the volunteers were given high-dose naloxone, meperidine only slightly reduced oxygen consumption, and the values rapidly returned to premeperidine levels. ConclusionsThese data Indicate that the antishivering property of meperidine is not fully mediated by μ-receptors. Although meperidine has well-known nonopioid actions, stimulation of k receptors seems a likely alternative explanation for much of the drugs antishivering action.

Leg Heat Content Continues to Decrease during the Core Temperature Plateau in Humans Anesthetized with Isoflurane

Background:Sufficient hypothermia during anesthesia provokes thermoregulatory responses, but the clinical significance of these responses remains unknown. Nonshivering thermogenesis does not increase metabolic heat production in anesthetized adults. Vasoconstriction reduces cutaneous heat loss, but the initial decrease appears insufficient to cause a thermal steady state (heat production equaling heat loss). Accordingly, the authors tested the hypotheses that: 1) thermoregulatory vasoconstriction prevents further core hypothermia; and 2) the resulting stable core temperature is not a thermal steady state, but, instead, is accompanied for several hours by a continued reduction in body heat content. Methods:Six healthy volunteers were anesthetized with isoflurane (0.8%) and paralyzed with vecuronium. Core hypothermia was induced by fan cooling, and continued for 3 h after vasoconstriction in the legs was detected. Leg heat content was calculated from six needle thermocouples and skin temperature, by integrating the resulting parabolic regression over volume Results:Core temperature decreased 1.0 ± 0.2°C in the 1 h before vasoconstriction, but only 0.4 ± 0.3° C in the subsequent 3 h. This temperature decrease, evenly distributed throughout the body, would reduce leg heat content 10 kcal. However, measured leg heat content decreased 49 ± 18 kcal in the 3 h after vasoconstriction Conclusions:These data thus indicate that thermoregulatory vasoconstriction produces a clinically important reduction in the rate of core cooling. This core temperature plateau resulted, at least in part, from sequestration of metabolic heat to the core which allowed core temperature to remain nearly constant, despite a continually decreasing body heat content.

Desflurane reduces the gain of thermoregulatory arteriovenous shunt vasoconstriction in humans

Background Thermoregulatory responses, such as arteriovenous shunt vasoconstriction, provide substantial protection against core hypothermia. A response can be characterized by its threshold (core temperature triggering response), gain (rate at which response intensity increases, once triggered), and maximum response intensity. Reduced gain decreases the efficacy of a thermoregulatory response at a given threshold because response intensity will increase more slowly than usual. The effects of general anesthesia on the gain of arteriovenous shunt vasoconstriction have not been reported. Accordingly, we tested the hypothesis that desflurane decreases the gain of centrally mediated vasoconstriction.

The Pupillary Light Reflex Effects of Anesthetics and Hyperthermia

BackgroundThe pupillary light reflex often is evaluated in the perianesthetic period to assess drug effects and brainstem function. Mild hypothermia alone or combined with isoflurane does not impair pupillary responses. Although perioperative hyperthermia is less common than hypothermia, abnormal increases in core temperature remain an important thermal disturbance. Accordingly, the pupillary effects of hyperthermia alone and hyperthermia combined with isoflurane and enflurane were evaluated. Additionally, the effects of nitrous oxide on pupillary responses were determined. MethodsThe pupillary light reflex was evaluated in 31 non-surgical volunteers participating in concurrent thermoregulatory studies. Pupillary reflexes were quantified using a portable infrared pupillometer during (1) hyperthermia alone (n = 9), (2) hyperthermia with 0.8% and 1.2% end-tidal isoflurane (n = 8), (3) hyperthermia with 1.7% end-tidal enflurane (n = 5), and (4) inhalation of 60% N2O (n = 9). ResultsMild hyperthermia alone (core temperature 38.5 ± 0.3° C) produced no clinically significant change in the pupillary light reflex. Pupillary responses were decreased markedly with 0.8% isoflurane, 1.2% isoflurane, and 1.7% enflurane when the volunteers were normothermic. Mild hyperthermia combined with isoflurane or enflurane dilated the pupil and increased the amplitude of the light reflex. Sixty-percent nitrous oxide decreased the pupillary reflex only 26 ± 4%. ConclusionsAnesthetic-induced inhibition of the pupillary response to light is reversed partially by core hyperthermia. In contrast to enflurane and isoflurane, 60% N2O has little effect on the pupil.

Thermoregulatory vasoconstriction during propofol/nitrous oxide anesthesia in humans: threshold and oxyhemoglobin saturation.

To determine the thermoregulatory effects of propofol and nitrous oxide, we measured the threshold for peripheral vasoconstriction in seven volunteers over a total of 13 study days. We also evaluated the effect of vasoconstriction on oxyhemoglobin saturation (Spo2). Anesthesia was induced with an intravenous bolus dose of propofol (2 mg/kg), followed by an infusion of 180 μg.kg−1.min−1 for 15 min, and maintained with 60% nitrous oxide and propofol (80–160 μg.kg−1.min−1). Central and skin surface temperatures and Spo2 (using two different pulse oximeters) were measured continuously; plasma propofol concentrations and arterial Po2 were measured at 15-min intervals. Volunteers were cooled with a circulating water blanket until definitive peripheral vasoconstriction was detected. The tympanic membrane temperature triggering vasoconstriction was considered the thermoregulatory threshold. Vasoconstriction developed on seven study days during propofol/nitrous oxide anesthesia at a central temperature of 33.3 ± 1.0°C (mean ± SD) and plasma propofol concentration of 3.9 ± 1.1 μg/mL. The thresholds during anesthesia were significantly lower than those during the control period (36.7 ± 0.3°C), but the correlation between plasma propofol concentrations and vasoconstriction thresholds was poor. On the remaining six study days, vasoconstriction did not develop despite central temperatures ranging from 32.1 to 32.7°C. Corresponding propofol concentrations were 4.1–10.9 μg/mL. These data suggest that anesthesia with propofol, in typical clinical concentrations, and 60% nitrous oxide substantially inhibits thermoregulatory vasoconstriction. Vasoconstriction increased Spo2by approximately 2% without a significant concomitant change in Po2. The observed increase in Spo2 probably reflects decreased transmission of arterial pulsations to venous blood in the finger.

EVIDENCE OF VENOUS STASIS AFTER ABDOMINAL INSUFFLATION FOR LAPAROSCOPIC CHOLECYSTECTOMY

Intraoperative venous stasis may increase the risk for perioperative deep vein thrombosis and pulmonary embolism. To determine if abdominal insufflation during laparoscopic cholecystectomy causes venous stasis, eight patients undergoing this procedure had their left common femoral veins examined by a duplex scanner before and after abdominal insufflation; the veins then were examined again before and after deflation. The right femoral veins were catheterized to measure femoral venous pressures. Abdominal insufflation to 14 millimeters of mercury pressure increased femoral venous pressures (10.2 +/- 4.1 millimeters of mercury to 18.2 +/- 5.1 millimeters of mercury; p < 0.001) and slowed peak blood velocities (24.9 +/- 8.5 centimeters per second to 18.5 +/- 4.5 centimeters per second; p < 0.05) without changing the cross-sectional areas (1.1 +/- 0.4 centimeter squared to 1.2 +/- 1.5 centimeter squared; p = NS) of the common femoral veins. Insufflation also reduced or eliminated pulsatility in the common femoral veins in 75 percent of the patients, indicating that insufflation was causing partial proximal venous obstruction. After 80 +/- 21 minutes of surgery, these changes remained significant. Deflation of the abdomen restored normal venous pulsatility in all patients, reduced femoral venous pressures (18.5 +/- 5.2 millimeters of mercury to 12.2 +/- 9.8 millimeters of mercury; p < 0.001), increased the peak blood velocities (14.2 +/- 6.8 centimeters per second to 28.1 +/- 16 centimeters per second; p < 0.05) and decreased the cross-sectional areas (1.4 +/- 0.6 centimeters squared to 0.9 +/- 0.4 centimeters squared; p < 0.05) of the common femoral veins, indicating venous decompression had occurred. The results suggest abdominal insufflation causes venous stasis during laparoscopic cholecystectomies. Measures shown to reduce intraoperative venous stasis, such as pneumatic compressive stockings, may benefit patients undergoing these procedures.

The effect of opioids on thermoregulatory responses in humans and the special antishivering action of meperidine.

In summary, both mu-receptor and combined mu/kappa-receptor opioids impair thermoregulatory control. Alfentanil, a pure mu-receptor agonist slightly increased the thresholds for sweating and markedly decreased the thresholds for vasoconstriction and shivering. However, the vasoconstriction-to-shivering range remained normal during alfentanil administration as it does during general anesthesia. Meperidine, a combined mu- and kappa-receptor agonist, also slightly increased the threshold for sweating and reduced the thresholds for vasoconstriction. However, meperidine reduced the shivering threshold twice as much as the vasoconstriction threshold, thus significantly increasing the vasoconstriction-to-shivering range. Furthermore, shivering during meperidine administration, once triggered, was of low intensity suggesting that the drug also decreased the gain of shivering. The special antishivering action of meperidine appears to result, at least in part, from its kappa-receptor activity.

Surgical Aspects of Pancreas Transplantation

According to the International Pancreas Transplantation Registry’s 2000 Midyear Update, the number of pancreas transplants performed worldwide has steadily increased since 1995. Pancreas graft survival rates at 1 year now range between 70% for pancreas transplant alone (PTA) recipients and 85% for simultaneous pancreas and kidney (SPK) recipients.1 These excellent, much improved outcomes have been achieved thanks to a marked decrease in immunologic graft loss and in technical failures over the last 10 years.

Is dantrolene safe to administer in sepsis? The effect of dantrolene after endotoxin administration in dogs and rats

Hyperthermia from septic shock may be indistinguishable from malignant hyperthermia. Dantrolene may be given in septicemia if the diagnosis is unclear. To determine if dantrolene is safe to use in sepsis, two studies were performed. In study 1, 18 anesthetized dogs in which profound septic shock was induced with 5 mg/kg of intravenous Escherichia coli endotoxin were randomized to receive (30 min later) intravenous injections of 10 mg/kg of dantrolene solution, the diluent of dantrolene, or maintenance intravenous fluids alone. The use of dantrolene solution and the diluent of dantrolene resulted in similar but transient statistically significant increases in the cardiac filling pressures and cardiac outputs and decreases in the vascular resistances compared with the control dogs. In a second study, 185 rats were randomized into five equal groups. Groups 1, 2, and 3 received 15 mg/kg of intraperitoneal Escherichia coli endotoxin followed 30 min later by 10 mg/kg of dantrolene solution, the diluent of dantrolene, or normal saline. Groups 4 and 5 received normal saline followed by dantrolene or normal saline. The survival of groups 1, 2, and 3 was less at 24 h (P < 0.0001) than that of either control group, but was not significantly different from one another. The results suggest dantrolene can be administered safely under clinical conditions where the cause of hyperthermia and shock cannot clearly be ascribed to malignant hyperthermia or septicemia.

Hemodynamic and Metabolic Manifestations of Acute Endotoxin Infusion in Pigs with and without the Malignant Hyperthermia Mutation

BACKGROUND The hypermetabolic state induced by acute endotoxemia and malignant hyperthermia (MH) may be indistinguishable. The aims of this study were (1) to investigate the differences between MH and sepsis, (2) to determine whether acute endotoxemia can trigger MH, and (3) to establish the effects of dantrolene in these two disorders. METHODS Three groups of swine were studied. All pigs were invasively monitored and initially anesthetized with nontriggering agents. A placebo MH-susceptible group (n = 5) received normal saline whereas the endotoxin groups (MH-susceptible, n = 6; MH-negative, n = 4) received intravenous endotoxin (250 microg/kg total) during 2.5 h. Halothane (1.5%) and succinylcholine (2-4 mg/kg) were then administered, followed by two doses of dantrolene (4 mg/kg total). RESULTS Endotoxin infusion resulted in pulmonary hypertension and systemic hypotension in pigs with and without the MH mutation, but did not trigger MH. Halothane and succinylcholine triggered MH, evidenced by a markedly higher oxygen consumption in the MH-susceptible pigs that received endotoxin (325+/-196 ml/min) and those that did not (374+/-110 ml/min) compared to the MH-negative pigs (69+/-15 ml/min, P<0.0009), as well as muscular rigidity in the susceptible animals. Dantrolene reversed these changes. Three of the six MH-susceptible pigs that received endotoxin died; two died soon after triggering and one after dantrolene administration. In contrast, none of the MH-negative pigs or the MH-susceptible pigs that did not receive endotoxin died (0 of 9 vs. 3 of 6, P = 0.044). CONCLUSION Endotoxemia does not trigger MH, but may worsen outcome if it occurs.