Mechanism of age-related and nitrous oxide-associated anesthetic sensitivity: the role of brain catecholamines.

To provide a neurochemical basis for differences in their anesthetic requirements, the authors examined mice selectively bred for resistance (HI) and susceptibility (LO) to nitrous oxide anesthesia for brain levels of catecholamines. Concentrations of norepinephrine and dopamine in whole brain were 26% and 13% higher (P less than 0.001), respectively, in HI mice than in LO mice. Whole-brain levels of 3,4-dihydroxyphenylacetic acid, a major metabolite of dopamine, were the same for both HI and LO groups of mice. The authors then analyzed portions of the HI and LO mice brains for concentrations of norepinephrine and dopamine. A significant correlation was found between norepinephrine content in the medulla and nitrous oxide requirement. In other regions of the brain (cerebellum, cerebral cortex, hippocampus, pons, midbrain, hypothalamus), no significant differences in norepinephrine or dopamine levels could be detected. Differences in anesthetic requirements between resistant and susceptible mice decrease from 0.99 to 0.53 atm as they aged from 100 days to 600 days old, paralleling the decline in differences in norepinephrine levels in medulla oblongata between HI and LO mice from 1.6 to 0.73 ng/mg protein. Thus, the difference in anesthetic requirement between HI and LO mice may arise from alterations in catecholamine content in specific regions of the brain.

Narcotics decrease heart rate during inhalational anesthesia.

We determined the heart rate (HR) response to enflurane, halothane, and isoflurane and the effects of narcotics on this response in 81 healthy patients scheduled for elective surgery. Patients were randomly assigned to one of six treatment groups: one of the three anesthetics (approximately 0.9 MAC) in 60% nitrous oxide, and either 0.15 mg/kg of intramuscular morphine 30-60 min before induction or 1 microgram/kg of IV fentanyl 10 min after skin incision. All patients received diazepam, 10 mg orally, 60-90 min before anesthesia, a rapid sequence intravenous induction, and mechanically controlled ventilation. During inhalational anesthesia and the first 10 min of surgery, no significant change in HR occurred in any group (compared to the preinduction HR), although patients given morphine premedication tended to have a decreased HR and those not given morphine premedication tended to have an increased HR. These trends partially account for significant differences that emerged between groups after induction of anesthesia. Patients given morphine premedication and halothane had lower HR (64 +/- 3 SEM) than patients given isoflurane (80 +/- 3) or enflurane (84 +/- 3) and no morphine premedication. Patients anesthetized with enflurane and morphine premedication had lower HR (71 +/- 3) than patients given enflurane without morphine premedication. Administration of fentanyl 10 min after incision (these patients had received no morphine) significantly decreased HR in the presence of any of the vapors. We conclude that inhalational anesthetics used in the clinical setting we employed do not significantly increase heart rate, and that prior administration of morphine or concurrent administration of fentanyl may significantly decrease HR.

Intraoperative detection of myocardial ischemia in high-risk patients: electrocardiography versus two-dimensional transesophageal echocardiography.

Because acute segmental wall motion abnormalities (SWMAs) of the left ventricle are highly sensitive and specific indicators of myocardial ischemia, this study compared the incidence and significance of ischemia, as detected by two-dimensional transesophageal echocardiography and surface electrocardiography, during anesthesia and surgery in patients at high risk of myocardial ischemia. During surgery, 24 of the 50 patients studied had new SWMAs, whereas only six had ST segment changes. All patients with ST segment changes also had new SWMAs: in three instances, SWMAs occurred before the ST segment change, and in three instances, they occurred simultaneously. All three patients who had intraoperative myocardial infarctions also had persistent intraoperative SWMAs, whereas only one patient had ST segment changes. Ten healthy patients requiring noncardiovascular surgery were monitored similarly; none of these had SWMAs, ST segment changes, or myocardial infarction. This study demonstrates the superiority of two-dimensional transesophageal echocardiography over electrocardiography for the intraoperative detection of myocardial ischemia. Furthermore, when new SWMAs persist to the conclusion of surgery, myocardial infarction is likely to have occurred.

Monitoring with two-dimensional transesophageal echocardiography. Comparison of myocardial function in patients undergoing supraceliac, suprarenal-infraceliac, or infrarenal aortic occlusion.

When the aorta must be temporarily occluded at the suprarenal or supraceliac levels during surgery, the resulting large increase in afterload may make the myocardium ischemic, even though systemic and pulmonary artery pressures and cardiac output are maintained at normal levels. These traditional indices of myocardial well-being do not appear to be sufficiently sensitive, since cardiac complications are still the most frequent cause of perioperative death and morbidity after aortic reconstruction. To evaluate two-dimensional transesophageal echocardiography as a monitor of myocardial well-being, we studied 24 American Society of Anesthesiologists physical status class III or IV adult patients who were undergoing aortic reconstruction and occlusion at the supraceliac (n = 12), suprarenal-infraceliac (n = 6), or infrarenal (n = 6) level. In addition to traditional monitors, we used a gastroscope tipped with a special 3.5 MHz two-dimensional echocardiographic transducer (Diasonics) that was placed in the esophagus to give a cross-sectional view of the left ventricle through the base of the papillary muscles. The hemodynamic effects of clamping the aorta were managed by administration of vasodilating drugs, anesthetics, and fluids to keep systemic and pulmonary arterial pressures normal. Occlusion at the supraceliac level caused major increases in left ventricular end-systolic and end-diastolic areas, decreases in ejection fraction, and frequent wall motion abnormalities; these changes were not detected by conventional monitoring devices. Occlusion at the suprarenal-infraceliac level caused similar but smaller changes, and occlusion at the infrarenal level caused only minimal cardiovascular effects. We conclude that the two-dimensional transesophageal echocardiogram offers promise as an intraoperative monitoring device.

Potencies of barbiturates in mice selectively bred for resistance or susceptibility to nitrous oxide anesthesia.

To test the possibility that mice selectively bred for resistance (HI mice) and susceptibility (LO mice) to nitrous oxide anesthesia have general differences in central nervous system sensitivity to other depressants, we examined the effects of four barbiturates in these two lines of mice. LO mice given intraperitoneal injections of barbital (275 mg/kg), hexobarbital (120 mg/kg), pentobarbital (65 mg/kg), or secobarbital (50 mg/kg) had significantly (16-46%) longer sleep times than HI mice. Concentrations of barbiturates were significantly (12-73%) greater in the serum and 3-55% greater in the brain on awakening in HI mice than in LO mice. The largest separations in potency between the HI and LO lines occurred with pentobarbital and hexobarbital and the smallest separations with barbital and secobarbital. We concluded that HI and LO mice do have a general resistance and susceptibility to barbiturates, but that the magnitude of the difference in central nervous system sensitivity between the two lines varies among barbiturates.

Age-dependent alterations in nitrous oxide requirement of mice.

To determine the relationship of nitrous oxide requirement to age in mice, the authors repeatedly tested the righting-reflex response in stock CD-1 mice at 50 to 703 days of age. Over this age range, nitrous oxide requirement (+/- SE) progressively decreased from 1.48 +/- 0.02 atm to 1.09 +/- 0.06 atm. A second set of experiments measured changes in nitrous oxide requirement with age in mice selectively bred for resistance (HI mice) and susceptibility (LO mice) to nitrous oxide anesthesia. When tested at two months of age, selected HI and LO mice had nitrous oxide ED50 values of approximately 2.0 and 1.1 atm, respectively. At 11 to 14 months, the nitrous oxide ED50 of the HI mice had decreased to approximately 1.5 atm. In contrast, the nitrous oxide ED50 of the LO mice showed a much smaller decrease over this age range. Thus, the separation in nitrous oxide requirement between the HI and LO lines tended to disappear with age. By correlating the difference in anesthetic requirement between the HI and LO mice with biochemical and biophysical alterations in the central nervous system, studies on aging that use selectively bred lines may be helpful in investigating the mechanism of anesthetic action and the mechanism by which aging affects anesthetic action.

Effects of halothane, isoflurane, enflurane, thiopental, and fentanyl on blood gas values in rats exposed to hypoxia.

In rats pretreated with phenobarbital breathing 10% oxygen, subanesthetic doses of halothane, isoflurane, enflurane, thiopental, and fentanyl caused hepatic injury. Because hypoxia per se can produce such injury, we hypothesized that the anesthetic-induced injury resulted from increased hypoxemia secondary to respiratory depression. Male Sprague-Dawley rats were pretreated with phenobarbital; half of the rats were fed and the other half were deprived of food for the 24 h before study. Isoflurane anesthesia was given for the placement of a catheter into the femoral artery. After 1 h of recovery, the rats were exposed to 10% oxygen. Control samples were obtained and halothane, isoflurane, enflurane, thiopental, or fentanyl was administered. Rats given food had higher PaCO2 and lower pH values than starved rats. Also, arterial oxygen saturation (SaO2) tended to be lower in rats given food. At concentrations of 0.15-0.2 MAC or higher, halothane, isoflurane, and enflurane slightly increased PaCO2 values relative to values for a control group exposed only to hypoxia. However, SaO2 and PaO2 did not show significant drug-induced changes. Fentanyl transiently decreased PaO2 and SaO2. Thiopental caused no changes. Thus, we conclude that subanesthetic doses of anesthetics may depress the ventilatory response to hypoxia but that this depression is inconsistent and appears to be too small to cause hepatic damage.

Hepatic injury induced by anesthetic agents in rats.

Recent studies on rats pretreated with phenobarbital indicate that anesthetic agents may produce hepatic injury even when metabolism of the anesthetic is almost negligible. This implies that anesthesia per se may cause hepatic injury. To evaluate this possibility, we determined the amount of hepatic injury produced by halothane, enflurane, isoflurane, thiopental, and fentanyl in rats pretreated with phenobarbital. Anesthetics were administered in doses ranging from 0.04-1.1 MAC (or their equivalent for thiopental or fentanyl) and were given with 10% oxygen for 2 h. Liver specimens taken 24 h later were examined microscopically for hepatic injury. At concentrations of 5-40% of MAC, all anesthetics produced more hepatic injury than did control conditions (i.e., exposure to only 10% oxygen for 2 h). There were no systematic differences among agents, nor did starvation before anesthetic exposure produce a difference among agents. Therefore, mechanisms other than anesthetic metabolism are needed to explain hepatic injury produced by anesthetic agents.

Effect of oxygen concentration, hyperthermia, and choice of vendor on anesthetic-induced hepatic injury in rats.

Although hypoxic rats exposed to anesthetics may develop hepatic injury, divergent results have been obtained. These discrepancies might be due to different levels of hypoxia, hypothermia, or choice of vendor. Male Sprague-Dawley rats purchased from Zivic-Miller were pretreated with phenobarbital for 4 days. After 24 h without phenobarbital, they were exposed to 2 h of hypoxia and halothane, enflurane, isoflurane, thiopental, or fentanyl. Rectal temperature was kept between 36.5 degrees C and 38.5 degrees C. All agents given in 10% oxygen produced more hepatic injury than did control conditions (exposure to 10% oxygen alone) (P less than 0.01). Only halothane given in 12% and 14% oxygen produced hepatic injury. No agent given in 20% or 100% oxygen demonstrated hepatotoxicity. In a separate study, rectal temperatures were kept between 32 degrees C and 34 degrees C during 2 h of exposure to 0.3 MAC halothane, enflurane, or isoflurane in 10% oxygen. Hypothermia prevented hepatotoxicity by enflurane and isoflurane, but not by halothane. Finally, although livers of rats obtained from Zivic-Miller were injured, specific pathogen-free rats from Charles River were not injured or were less injured by enflurane, thiopental, or fentanyl. Apparently, minor changes in experimental conditions can substantially affect results; hepatic hypoxia per se, anesthetic metabolism (especially that of halothane), and perhaps anesthesia itself may produce hepatic injury.

MAC values of thiopental and fentanyl in rats.

A comparison of the effects of thiopental or fentanyl with those of inhaled anesthetics requires the establishment of a comparable level of anesthetic potency. Accordingly, using the response of male Sprague-Dawley rats to tail-clamping, we determined the ED50S for thiopental and fentanyl. Half of the rats were pretreated with phenobarbital. After subcutaneous injection of various doses of thiopental or fentanyl, each rat was tested for movement in response to tail-clamping at 15-min intervals for 2 h. In untreated rats, the maximal effect of thiopental (i.e., the lowest ED50 value was 107 +/- 10 mg/kg, mean +/- SEM) occurred 75 min after injection. Although higher values were found at other times, differences from the nadir were relatively small. In rats pretreated with phenobarbital, the lowest value (130 +/- 8 mg/kg) occurred at 60 min. The lowest ED50S for fentanyl (52 +/- 7 micrograms/kg for control rats, and 73 +/- 14 micrograms/kg for pretreated rats) were found at 15 min.