David J. Miletich

Cardiovascular effects of intraperitoneal insufflation with carbon dioxide and nitrous oxide in the dog.

Cardiovascular changes caused by intraperitoneal insufflation with CO2 or N2O were measured in 15 mongrel dogs. Moderate progressive increases in intra-abdominal pressure (to 40 mm Hg) with either gas produced increases in mean arterial, right atrial, pleural, and femoral-vein pressures. Cardiac output and inferior vena caval flow were momentarily increased following the commencement of insufflation. However, both flows decreased precipitously as insufflation pressure was increased. At an intra-abdominal pressure of 40 mm Hg cardiac output and inferior vena caval flow were reduced more than 60 per cent in most cases. Peripheral resistance increased by approximately 200 per cent. Upon sudden release of abdominal pressure cardiac output and inferior vena caval flow increased but then returned to pre-insufflation values within seconds. Directly measured right atrial pressure increased with increasing insufflation pressure, but calculated transmural right atrial pressure decreased with the increase in intra-abdominal pressure. Insufflation with CO2. produced significant increases in PaCO2. However, cardiostimulatory effects due to elevated blood CO2. levels were not seen. The data from this study indicate that intraperitoneal insufflation produces serious hemodynamic alterations which are manifested by low cardiac output and elevated total peripheral resistance. In addition, directly measured right atrial pressure cannot be used clinically as an indicator of venous return to the heart since it reflects a composite of pleural and intra-abdominal insufflation pressures.

cardiovascular Effects of Centrally Administered Ketamine in Goats

&NA; The cardiovascular effects of centrally and peripherally administered ketamine were evaluated in unanesthetized goats and in goats anesthetized with pentobarbital. Small doses of ketamine (0.1 to 4 mg.) were injected directly into the central nervous system (CNS) of the unanesthetized goats via a temporal artery catheter, while cerebral blood flow (CBF), cardiac output (C.O.), systemic blood pressure (B.P.), and heart rate (H.R.) were continuously monitored. Administered by this route, ketamine produced an immediate increase in mean systemic B.P., C.O., and H.R. Changes in CBF were variable, increasing on some occasions and decreasing on others. Cardiovascular changes were not the result of alterations in blood gases, since these remained unchanged. When ketamine, 0.1 to 4 mg., was injected into the temporal artery of goats anesthetized with pentobarbital, no changes were observed in B.P., C.O., H.R. or CBF. Ketamine (2 mg./kg.) intravenously administered to unanesthetized goats produced anesthesia and an increase in B.P., C.O., H.R., CBF, and arterial carbon dioxide (Paco2) levels. Administered by the same route and dosage in mechanically ventilated goats previously anesthetized with sodium pentobarbital, ketamine did not produce any changes in cardiovascular or blood‐gas measurements. It was therefore concluded that ketamine produces peripheral sympathomimetic effects primarily by direct stimulation of CNS structures, and that when these structures are depressed by pentobarbital, the peripheral effects of ketamine are ameliorated.

Neurologic Outcome in Rats Following Incomplete Cerebral Ischemia during Halothane, Isoflurane, or N2O

Using rats in which incomplete cerebral ischemia was induced, the authors evaluated the effects of halothane (H) and isoflurane (I) on neurologic outcome compared to nitrous oxide (N2O) controls. Incomplete cerebral ischemia was produced by right carotid artery occlusion combined with hemorrhagic hypotension. Neurologic outcome was evaluated using a graded deficit score from 0 to 5 (0 = normal, 5 = death associated with stroke). Two levels of cerebral ischemia were tested. At moderate ischemia with hypotension of 30 mmHg, an FIO2 of 0.3, and ischemic periods of 30 or 45 min, N2O produced a deficit of 4.7–5.0 and a mortality rate of 90–100%. In contrast, halothane (1 MAC) and isoflurane (1 MAC) resulted in similar deficit scores (H = 1.1–1.8, I = 1.4–1.6) and mortality rates (H = 17–30%, I = 17–20%). Cerebral blood flow (CBF) measured with radioactive microspheres showed a 60–65% decrease in the ischemic hemisphere at this level of hypotension. With severe ischemia with hypotension = 25 mmHg, FIO2 = 0.2, and a 30-min period of ischemia, deficit scores increased to 3.0 and 3.9 with 1 MAC halothane and 1 MAC isoflurane, respectively. Morality rates also increased to 40% with halothane and 70% with isoflurane. Increasing the concentration of halothane or isoflurane to 2 MAC did not significantly improve outcome. Brain histology demonstrated extensive neuronal damage in striatal, hippocampal, and neocortical regions of N2O control treated rats, and less damage with little difference between H-and I-treated rats at each level of ischemia. Using this model of incomplete cerebral ischemia, halothane and isoflurane provided significantly better neurologic and histologic outcomes when compared to N2O controls, with little difference between the two volatile anesthetics.

Nitrous oxide markedly increases cerebral cortical metabolic rate and blood flow in the goat

Studies to date on the influence of N2O on cerebral blood flow (CBF) and metabolism in dogs, rodents, and humans have produced conflicting results. In the present study the authors have employed techniques in the awake, freely breathing nonstressed goat that allowed the authors to 1) serially obtain rapidly frozen cerebral cortical biopsy specimens (for labile metabolite assay) and 2) measure changes in cerebral O2 metabolism (CMRO2) and total and regional CBF (rCBF). Thus, with each animal utilized as its own control, the authors studied N2O effects on the above variables. Two determinations of the effects of 1 h of N2O (70% via a mask) on these variables were performed on each animal. Following introduction of N2O, PaCO2 and arterial blood pressure did not change, but arterial epinephrine levels declined over the 60-min period. Total CBF increased in the first 5 min of N2O exposure, reached a maximum of 165% control at 15 min, and then decreased to 143% control at 60 min. rCBF evaluations showed that much of this CBF increase was confined to cerebral cortical structures (188–246% control at 60 min). Over the same period cortical CMRO2 increased to 170% of control. No appreciable changes in the levels of high-energy phosphates or glycolytic intermediates were found at 60 min of N2O. The authors attribute the described changes solely to the presence of N2O and not to sympathoadrenal influences, altered ventilation, or anything related to the experimental preparation, and they conclude that N2O (at least in goats) is associated with a marked cerebral cortical “activation.”

Absence of autoregulation of cerebral blood flow during halothane and enflurane anesthesia.

The effects of halothane and enflurane anesthesia under conditions of normo-, hyper-, and hypocarbia on the autoregulation of cerebral blood flow (CBF) in the goat were evaluated. The goat was selected because of its unique arterial blood supply to the head and the development of a method by which CBF may be continuously measured. The study revealed that 1 MAC of halothane or enflurane anesthesia at normocarbia abolished cerebral autoregulation, CBF increasing or decreasing with increasing or decreasing peripheral blood pressure. Reduction of anesthesia to 0.5 MAC partially restored cerebral autoregulatory capability. The effect of 1 MAC and 0.5 MAC anesthesia on cerebral autoregulation of blood flow was potentiated by hypercarbia and antagonized by hypocarbia, indicating that the vascular response to blood CO2 fluctuations remained intact.

Captopril improves neurologic outcome from incomplete cerebral ischemia in rats.

We investigated the effects of the angiotensin-converting enzyme inhibitor captopril on neurologic outcome in a rat model of incomplete cerebral ischemia. Twenty male Sprague-Dawley rats were anesthetized with 70% nitrous oxide in oxygen and fentanyl (10 micrograms x kg-1 i.v. bolus, 25 micrograms x kg-1 x hr-1 i.v. continuous infusion). Animals in group 1 (n = 10) received no angiotensin-converting enzyme inhibitor while animals in group 2 (n = 10) were given 10 mg x kg-1 i.v. captopril 30 minutes prior to the ischemic period. Ischemia was produced by unilateral carotid artery ligation and hemorrhagic hypotension to 35 mm Hg for 30 minutes. Body temperature, arterial blood gases, and arterial pH were maintained constant. Neurologic outcome was evaluated every 24 hours for 3 days using a graded deficit score (0, normal; 18, stroke-related death). On the third day after ischemia, captopril significantly improved neurologic outcome (median deficit score = 4) compared with controls (median deficit score = 18) (p less than 0.05). These results suggest that reduced angiotensin II levels or increased tissue kinin concentrations may decrease ischemic brain injury.

Brain Lactate and Neurologic Outcome Following Incomplete Ischemia in Fasted, Nonfasted, and Glucose-loaded Rats

The neurologic outcomes following incomplete cerebral ischemia in rats treated by fasting, nonfasting, or glucose administration (6 ml/kg of 50% glucose solution intraperitoneal) were compared. Rats were anesthetized with 1.4% inspired isoflurane in air and incomplete ischemia was produced by temporary unilateral carotid occlusion and hypotension of 30 mmHg for 30 min. The rats were recovered and neurologic outcome was scored every 8 h for 3 days using a 6-point scale ranging from 0 (normal) to 5 (death associated with stroke). Brain histopathology was scored using a four-point scale on 19 of 30 rats surviving the 3-day postischemic neurologic examination and was correlated with neurologic deficit scores. Fasted rats had plasma glucose concentrations of 79 +/- 7 mg/100 ml (mean +/- SE) during ischemia and a significantly better neurologic outcome (P less than 0.001) than glucose-loaded rats (plasma glucose = 496 +/- 43 mg/100 ml). Nonfasted rats had blood glucose values (292 +/- 28 mg/100 ml) and deficit scores not significantly different from fasted but better than glucose-loaded rats (P = 0.054). Brain histology showed the greatest neuronal damage in caudate followed by hippocampus and cortical tissue. Histopathologic evaluation showed a correlation of r = 0.87 (P less than 0.01) with neurologic outcome. In separate experiments brain samples were collected at the end of the ischemic period in each of the experimental groups and regional tissue lactate and brain phosphocreatine and adenosinetriphosphate (ATP) concentrations were measured. Ischemic tissue lactate was similar in fasted, nonfasted, and glucose-loaded rats in caudate and hippocampus but was significantly higher in glucose loaded rats in cortical and thalamic tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of Methohexital and Isoflurane on Neurologic Outcome and Histopathology Following Incomplete Ischemia in Rats

Using a rat model of incomplete cerebral ischemia the effects of isoflurane (iso) and methohexital (metho) were compared with those of 70% nitrous oxide controls (N2O). Two levels of incomplete cerebral ischemia were produced by right carotid occlusion plus hypotension for 30 min: moderate = 30 mmHg, FIO2 = 0.30; severe = 25 mmHg, FIO2 = 0.20. The iso doses (1 and 2 MAC) and metho doses (0.01 and 0.1 mg.kg-1.min-1) were tested at each ischemic level. These iso and metho doses were selected because without ischemia they produced similar decreases in cerebral oxygen consumption (CMRO2) compared with that produced in N2O controls. In the absence of ischemia, the electroencephalogram (EEG) was suppressed by 0.01 mg.kg-1.min-1 metho and 1 MAC iso and showed burst-suppression with 0.1 mg.kg-1.min-1 metho and 2 MAC iso. The EEG was further depressed by ischemia under all anesthetic conditions. Neurologic outcome was evaluated for 3 days following incomplete cerebral ischemia by using a graded deficit score (0 = normal, 5 = death associated with stroke). Following moderate ischemia all four anesthetic treatments improved outcome compared with N2O controls, but after severe ischemia only 2 MAC iso significantly improved outcome. Neurohistopathology was evaluated on a scale of 0 to 40, 24 h after ischemia. The neurohistopathology score was significantly improved by all four anesthetic treatments compared with N2O following moderate ischemia and was better with 2 MAC iso compared with 0.1 mg.kg-1.min-1 metho after both moderate and severe ischemia. These results show that both iso and metho improve outcome from cerebral ischemia compared with that associated with N2O, but only 2 MAC iso resulted in an improved outcome following severe ischemia. This difference in outcome between the two anesthetics may be related to greater neuronal depression with iso, which may occur with little difference in cerebral metabolic depression.

The Effect of Ketamine on Catecholamine Metabolism in the Isolated Perfused Rat Heart

The effects of ketamine infusion on the uptake and release of norepinephrine and on formation of deaminated metabolites in the isolated, perfused rat heart were studied. Hearts were removed from animals during light ether anesthesia, transferred to a modified Langendorff perfusing apparatus, and perfused with Krebs-Ringer solution containing various doses of ketamine and 200 µg/ml of DL-norepinephrine—14C. Norepinephrine uptake was determined after perfusion for 1, 2, 4, 6, and 20 minutes. At the end of each period the ketaminetreated hearts contained less DL-norepinephrine—14C per gram of heart tissue than control hearts. The reduction was proportional to the dose of ketamine. On an equal-dose basis, ketamine was approximately 80 per cent as effective as cocaine in blocking the uptake of norepinephrine. Norepinephrine release was determined after perfusing hearts for 4 minutes with perfusate containing 200 µg/ml of DL-norepinephrine—14C, then perfusing with solution containing ketamine but free of norepinephrine for 20 minutes. After 10 minutes of perfusion a decrease in myocardial DL-norepinephrine began to appear, and at 20 minutes the decrease was significant. Ketamine infusion did not alter myocardial levels of intracellular deaminated metabolites of norepinephrine, indicating that the effects of ketamine are primarily membrane-related. The results of this study suggest that the sympathomimetic-like effects of ketamine seen in both man and animals may be due to inhibition of the reuptake processes for endogenously released norepinephrine.

Sodium Nitroprusside and Cerebral Blood Flow in the Anesthetized and Unanesthetized Goat

The effects of sodium nitroprusside (SNP) on total, ipsilateral cerebral blood flow (CBF) in the unanesthetized and anesthetized goat was evaluated under four conditions: 1) bolus injection of SNP into the cerebral circulation via the temporal artery; 2) continuous infusion of SNP into the temporal artery in amounts too small to affect the peripheral circulation (0.57–1.14 µg/kg/min); 3) intravenous infusion of SNP; 4) continuous intravenous infusion of SNP with a bolus injection of angiotensin. Small doses (20, 40, and 80 µg) of SNP injected directly in the cerebral circulation of the awake goat produced immediate increases of 21 ± 8, 36 ± 8, and 48 ± 10 per cent, respectively, in CBF lasting 1 to 3 min without causing peripheral cardiovascular changes. The effects of SNP were attenuated by 1.5 per cent halothane anesthesia. Continuous infusion of SNP into the temporal artery in amounts too small to cause peripheral cardiovascular effects produced sustained increases in CBF averaging 31 ± 8 per cent; CBF returned to preinfusion values upon cessation of infusion. Intravenous infusion of SNP in both anesthetized and unanesthetized animals in recommended clinical dosages (3–8 µg/kg/min) produced hypotension but did not significantly alter CBF. However, upon injection of angiotensin (1.43 µg/kg), both peripheral blood pressure and CBF increased sharply, suggesting that SNP may impair autoregulation of CBF. The results of this study indicate that SNP dilates the cerebral vascular system in a way that is probably similar to its effects on other vascular beds.