Susan A. Rice

Halothane, isoflurane, and enflurane MAC in pregnant and nonpregnant female and male mice and rats.

The MAC of halothane, isoflurane, and enflurane was determined using the tail-clamp technique in pregnant female, nonpregnant female, and male Swiss Webster mice (n = 216) and Sprague-Dawley rats (n = 112). Mean MAC values (+/-SD) for halothane, isoflurane, and enflurane in mice were 0.95 +/- 0.07%, 1.34 +/- 0.10%, and 1.95 +/- 0.16%, respectively; values in rats were 1.03 +/- 0.04%, 1.46 +/- 0.06%, and 2.21 +/- 0.08%, respectively, all significantly higher than in mice. Neither the sex of the animals nor whether female animals were pregnant influenced the results.

Prolonged administration of isoflurane to pediatric patients during mechanical ventilation.

We undertook a prospective study of the effectiveness and potential toxicities of isoflurane sedation in pediatric patients undergoing mechanical ventilation who required large doses of opioids for sedation were considered eligible. Ten patients (ages 3 wk to 19 yr) received continuous isoflurane sedation for a mean duration of 131 minimum alveolar concentration (MAC)-hours (range 13-497 MAC-hours). The mean peak inorganic fluoride (F-) concentration was 11.0 microM, and the highest F- concentration was 26.1 microM after 441 MAC-hours. Only one patient had a measured F- concentration greater than 20 microM. No abnormalities were noted in serum creatinine or osmolality. Creatinine clearances were available for five patients who received a mean of 193 MAC-hours of isoflurane (range 33-497 MAC-hours), and only one patient had a persistent decrease from baseline of more than 20%. Five patients demonstrated an abstinence syndrome which consisted of nonpurposeful movements and extreme agitation. All of these patients had received at least 70 MAC-hours of isoflurane. Our experience indicates that isoflurane can effectively provide sedation to pediatric patients for prolonged periods without significant adverse effects on cardiovascular, hepatic, or renal function.

Fetal morphology in mice exposed to halothane.

: The teratogenic potential of subanesthetic and anesthetic exposure to halothane was studied in Swiss/ICR mice. Two treatment regimens were employed: daily exposure of males and females for nine weeks prior to conception and on days 1 through 17 of pregnancy; and exposure of females only on days 6 through 15 of pregnancy. Mice were exposed to subanesthetic concentrations of halothane for 0.025, 0.1, 0.4, and 1.2 MAC hours/day; anesthetic exposure was 4.0 MAC hours/day. Fetal morphologic development was normal at the two lowest exposures. Exposures of 0.4 MAC hours/day and more were associated with decreased fetal ossification. At the 1.2 MAC hour/day exposure, renal pelvic masturation was retarded and the incidence of skeletal variants was increased. The incidences of major malformations and minor anomalies were not increased following exposure to subanesthetic concentrations of halothane. Anesthetic exposure to 4.0 MAC hours/day was lethal to both dams and embryos, and resulted in major developmental malformations in surviving fetuses. These effects were probably due to altered maternal physiologic status. It is concluded that exposure of mice to subanesthetic concentrations of halothane does not result in important morphologic abnormalities in their offspring.

Inorganic fluoride and prolonged isoflurane anesthesia in the intensive care unit

Isoflurane is a safe anesthetic for routine as well as for prolonged surgical procedures. It has also been employed in the intensive care unit (ICU) to treat conditions such as refractory status asthmaticus (1) or status epilepticus (2). These situations may require the administration of isoflurane for extended periods of time, well beyond the limits of documented safety. We report a case of prolonged isoflurane administration resulting in potentially nephrotoxic serum concentrations of inorganic fluoride (F-).

Carcinogenicity of halothane in Swiss/ICR mice.

: A simplified in-vivo bioassay system was used to test the carcinogenic potential of halothane in Swiss/ICR mice. Halothane was tested only at its maximum tolerated dose, and histologic examination was performed only on tumor masses and other grossly abnormal tissues found at necropsy. Two groups, each of 15 timed pregnant mice, were exposed to either halothane, 500 ppm (0.05 per cent), or compressed air for two hours on days 10--19 of pregnancy. Five days after birth the offspring were similarly exposed, three times weekly, for 78 weeks. After a ten-week, no-treatment, observation period, all remaining mice were examined by necropsy. Mice dying or killed in extremis before final sacrifice at 88 weeks of age also underwent complete gross necropsy unless extensive cannibalism or autolysis precluded examination. The incidences of malignant tumors, hepatomas or modular hyperplasias, and benign tumors in halothane-treated mice were 7, 6, and 20 per cent, respectively; there were similar incidences of these lesions in control animals. It is concluded that under the conditions of this experiment, lifetime administration of halothane at its maximum tolerated dose is not associated with an increased incidence of neoplasia in Swiss/ICR mice.

Metabolism by Rat Hepatic Microsomes of Fluorinated Ether Anesthetics Following Isoniazid Administration

The possibility that enflurane defluorination is increased following treatment with isoniazid was investigated in male Fischer 344 rats. The effects of various isoniazid dosage regimens on the hepatic microsomal defluorination rates of enflurane were compared with those of several other ether anesthetics, and the conditions for production of maximal enflurane defluorination rates were determined. Seven to ten days of treatment with 50 mg/kg/ day isoniazid (Nydrazid®) resulted in maximal rates of defluorination of methoxyflurane, enflurane, isoflurane, and sevoflurane with no overt sign of toxicity. Compared with saline treatment of control rats, isoniazid increased defluorination of enflurane 370 per cent, methoxyflurane 259 per cent, sevoflurane 283 per cent, and isoflurane 168 per cent. Previous studies have shown that while the enzyme inducer phenobarbital increased in vitro rates of methoxyflurane defluorination approximately 1000 per cent, the rate of enflurane defluorination remained unchanged or increased by 100 per cent at most. In this study, enhanced hepatic microsomal defluorination was not associated with an increase in cytochrome P-450 per mg protein. Anesthetic defluorination rates were not altered by treatment with chlorobutanol, the preservative contained in Nydrazid.

Halothane hepatotoxicity in Fischer 344 rats pretreated with isoniazid

Male Fischer 344 rats were used to investigate the hepatic effects of exposure to halothane under normoxic conditions (FIO2 = 0.21) in isoniazid-treated rats. Animals were treated with saline or isoniazid (50 mg/kg) for 7 days and then were exposed to either 1% halothane or air for 2 hr. One-half of the rats from each treatment and exposure group were killed 24 hr postexposure; the remaining were killed 4 days postexposure. Twenty-four hours following halothane exposure, serum transaminase levels were significantly elevated in isoniazid- compared with saline-treated rats (i.e., aspartate aminotransferase = twofold; alanine aminotransferase = seven-fold). Cholesterol levels were significantly depressed by halothane exposure in both saline- and isoniazid-treated rats. Other serum parameters indicative of hepatic and renal function were not different: alkaline phosphatase, total protein, total bilirubin, hematocrit, uric acid, creatinine, urea nitrogen, Na+, K+, Ca2+, and inorganic phosphate. Neither saline-treated nor isoniazid-treated rats exposed to air exhibited histologic evidence of hepatic damage. Halothane-exposed rats, however, showed a circumscribed disruption of cellular morphology. The most severe lesions were observed with isoniazid-treated animals with extensive pericentral hepatocellular necrosis and infiltration by leucocytes and Kupffer cells. Serum concentrations of two products of the oxidative metabolism of halothane, trifluoroacetic acid and bromide, were significantly elevated in isoniazid- compared with saline-treated rats. Serum levels of fluoride, a product of reductive metabolism, were not different. These results strongly suggest that hepatic injury following halothane administration can be produced by intermediates of oxidative metabolism.

Anesthetic Metabolism and Renal Function in Obese and Nonobese Fischer 344 Rats Following Enflurane or Isoflurane Anesthesia

This study was designed to determine the nephrotoxic potential of prolonged anesthesia with enflnrane or isoflurane in obese and nonobese Fischer 344 rats. Weight-paired rats received either a regular chow diet or Potters high fat diet for 16 weeks. The chow-fed (nonobese) rats gained 20% in body weight compared with 45% for the Potters-fed (obese) rats. Exposure of nine pairs of rats to 2.0% enflurane for 4 h resulted in significantly elevated peak serum F levels (62 ± 11 μM vs. 27 ± 6 μM; P < 0.001) in obese compared with nonobese rats and clinical signs of F−-induced nephrotoxicity (i.e., polyuria) confirmed by decreased creatinine and urea nitrogen clearances in the obese rats. Exposure of nine pairs of rats to 1.4% isoflurane for 4 h produced significantly elevated peak serum F− levels (27 ± 8 μM vs. 9 ± 0.4 μM; P < 0.001) in obese compared with nonobese rats and subclinical nephrotoxicity in obese rats manifested by significantly decreased creatinine and urea nitrogen clearances, but without polyuria. This study suggests that obese patients may be at risk of developing F−-induced nephrotoxicity following prolonged enflurane anesthesia. Isoflurane may have significant potential for subclinical F−-induced nephrotoxicity in obese patients, to a degree that might affect renal clearance of some drugs in the postoperative period.

Thymidine and methionine syntheses in pregnant rats exposed to nitrous oxide.

The dose-dependent effects of nitrous oxide on thymidine and methionine syntheses were investigated in pregnant rats. Female Sprague-Dawley rats were exposed on day 9 of gestation to 0.75%, 7.5%, or 75% nitrous oxide for 24 h. Immediately and 72 h after exposure, a deoxyuridine-suppression test was performed on maternal bone marrow and a methionine synthetase assay was performed on maternal liver to assess thymidine and methionine syntheses, respectively. Inhibition of thymidine synthesis was seen after exposure to 7.5% and 75%, but not after 0.75%, nitrous oxide. Recovery was complete 72 h after exposure. Methionine synthetase activity was abolished at all concentrations of nitrous oxide tested and did not return to control values 72 h after exposure. Fetal weight and gross appearance were not affected by exposure to nitrous oxide; however, the observed decrease in thymidine and methionine syntheses after nitrous oxide exposure may account for its teratogenic effects.

Longitudinal distribution of pulmonary vascular resistance after endotoxin administration in sheep.

Background and MethodsPulmonary hypertension may increase pulmonary capillary pressure and exacerbate pulmonary edema in acute respiratory failure. The effects of pulmonary hypertension on pulmonary capillary pressure depend on the longitudinal distribution of pulmonary vascular resistance. Since pulmonary hypertension occurs during acute respiratory failure, we hypothesized that acute respiratory failure may produce time-dependent changes in the longitudinal distribution of pulmonary vascular resistance. Therefore, we measured pulmonary capillary pressure and the longitudinal distribution of pulmonary vascular resistance in an animal model of acute respiratory failure. Escherichia coli endotoxin (2.5 to 5.0 μg/kg) was administered over a 1-hr period in eight anesthetized sheep. Pulmonary and systemic hemodynamics, including pulmonary artery occlusion pressure (PAOP), pulmonary capillary pressure, and the longitudinal distribution of pulmonary vascular resistance, were measured over the next 5 hrs. Pulmonary capillary pressure was estimated by analysis of the pressure decay following pulmonary artery balloon inflation. ResultsEndotoxin administration resulted in sustained pulmonary hypertension for the subsequent 5 hrs of the study. Pulmonary capillary pressure was increased 7 mm Hg above baseline at 0.5 and 0.75 hrs during the infusion of endotoxin but returned to baseline values at 1.5 hrs. Despite sustained pulmonary hypertension, pulmonary capillary pressure remained at baseline values for the duration of the study. Similar to pulmonary capillary pressure, pulmonary venous (or postcapillary) resistance was increased approximately four-fold over baseline at 0.5 and 0.75 hrs after initiating endotoxin administration, but returned to baseline values by the end of endotoxin administration and remained at baseline values throughout the remainder of the study. In contrast, pulmonary arterial (or precapillary) resistance remained at values approximately three times baseline during the infusion and throughout the duration of the study. ConclusionsIn this experimental model of acute respiratory failure, the effects of endotoxin on the longitudinal distribution of pulmonary vascular resistance are time-dependent. If these data from animals can be extrapolated to humans, we speculate that the importance of pulmonary venoconstriction in exacerbating pulmonary edema may vary over time in patients with acute respiratory failure. (Crit Care Med 1992; 20:119)