The cerebral and systemic effects of movement in response to a noxious stimulus in lightly anesthetized dogs. Possible modulation of cerebral function by muscle afferents.

BACKGROUND: Afferentation theory predicts that agents or maneuvers that stimulate muscle stretch receptors (i.e., muscle afferents) will produce cerebral stimulation. From this theory it follows that, regardless of the source (e.g., drug effect, active muscle movement), increases in stretch receptor activity should result in a similar effect on the brain. The present study tested the hypothesis that active muscle movement in lightly anesthetized subjects would result in cerebral stimulation. METHODS: Studies were conducted in six dogs who were lightly anesthetized with halothane (0.70% end-expired). The following physiologic variables were quantified before and for 6 min after the initiation of a standardized (1-min duration) noxious stimulus to the trachea and the skin overlying the hind limb: cerebral blood flow, cerebral metabolic rate for oxygen (CMRO2), cerebral perfusion pressure, cerebral vascular resistance, electroencephalogram activity, electromyogram activity, arterial carbon dioxide partial pressure (PaCO2), central venous pressure, and serum epinephrine and norepinephrine concentrations. Response to stimulation was evaluated initially in unparalyzed dogs and later was evaluated in the same dogs after they were paralyzed with intravenous pancuronium (0.2 mg/kg). RESULTS: In unparalyzed dogs, stimulation produced episodes of coughing plus head and limb movement during the 6-min study period. Accompanying the movement was activation of the electromyogram, an increase in electroencephalogram frequency, and a reduction in electroencephalogram amplitude. There also was a 35% increase in cerebral blood flow, a 25% decrease in cerebral vascular resistance, and a 7% increase in CMRO2 versus the baseline values for each variable. There were no significant increases in either cerebral perfusion pressure, central venous pressure, PaCO2, or serum norepinephrine concentration to account for the cerebral effects; however, serum epinephrine concentrations increased by 61%. In pancuronium-paralyzed dogs, noxious stimulation resulted in a 5% increase in cerebral blood flow, a 7% decrease in cerebral vascular resistance, and an 5% increase in CMRO2 versus baseline levels. Electroencephalogram frequency was increased, but amplitude was unchanged. Central venous pressure, electromyogram activity, and serum norepinephrine concentration were unaffected. The serum epinephrine response was similar to that observed when the dogs were not paralyzed. CONCLUSIONS: These data support the hypothesis that active muscle movement in lightly anesthetized subjects has an effect on the brain that is mediated in part by muscle afferent receptors. This cerebral response was manifested as electroencephalogram activation, cerebral vasodilation unrelated to central venous pressure changes, and an increase in cerebral blood flow greater than that required to meet metabolic demands. Paralysis with pancuronium abolished movement induced by stimulation (and, thus, the muscle afferent response) and also attenuated the cerebral blood flow, cerebral vascular resistance, and electroencephalogram responses.

The effect of a platelet activating factor antagonist (BN 52021) on neurologic outcome and histopathology in a canine model of complete cerebral ischemia.

BACKGROUND: Research has demonstrated that platelet activating factor may modulate, in part, the severity of postischemic neurologic injury. The proposed mechanism involves a platelet activating factor-mediated release of cerebral cellular lipids and free fatty acids, resulting in increased cerebral edema and cell injury. The present study tested the hypothesis that a specific platelet activating factor antagonist, BN 52021, would improve neurologic outcome after 12 min of complete global cerebral ischemia in a canine model. METHODS: Using an established canine model of complete cerebral ischemia, dogs were assigned randomly to receive, in a blinded fashion, either 20 mg/kg BN 52021 intravenously (N = 8) or placebo (N = 7) 5 min before cerebral ischemia. After cerebral ischemia and recovery, neurologic assessment was performed by a blinded observer for 72 h. Immediately thereafter, the brains were harvested and later were evaluated histologically by a neuropathologist blinded to the treatment groups. RESULTS: Dogs were well matched for systemic physiologic variables during all portions of the study. One placebo-treated dog and one BN 52021-treated dog were not included in the statistical analysis because of failure to meet preestablished protocol criteria. BN 52021, when compared to placebo, affected neither neurologic functional recovery nor overall histopathology scores. Regional histopathology was improved in BN 52021-treated dogs in only 1 of 18 brain regions studied (i.e., the parietal cortex). When both treatment groups were combined, there was a significant correlation between neurologic function rank and histopathology rank. CONCLUSIONS: The present data demonstrate that the platelet activating factor antagonist BN 52021, at a dose of 20 mg/kg intravenously given 5 min before cerebral ischemia, did not protect the brain from injury in this canine model of complete global ischemia.

Delayed onset of malignant hyperthermia induced by isoflurane and desflurane compared with halothane in susceptible swine.

BACKGROUND: Desflurane (difluoromethyl 1-fluoro 2,2,2-trifluoroethyl ether) is a new inhalational anesthetic currently under investigation for use in humans. Recently, the authors showed that desflurane is a trigger of malignant hyperthermia (MH) in susceptible swine. To date, there has been no in vivo comparison of the relative ability of inhalational anesthetics to trigger MH. The effects of desflurane, isoflurane, and halothane on six MH-susceptible purebred and six MH-susceptible mixed-bred Pietrain swine were examined. METHODS: The animals were exposed to 1 MAC and 2 MAC (if MH was not triggered after 1 MAC hour) doses of each of the three volatile anesthetics in random sequence at 7-10-day intervals and changes in end-tidal CO2, arterial blood gases, serum lactate, core and muscle temperature, blood pressure, and heart rate were measured. RESULTS: There was a statistical difference between anesthetics in the time required to trigger MH; halothane exposure resulted in the fastest onset of an MH episode (20 +/- 5 min), compared with isoflurane (48 +/- 24 min) and desflurane (65 +/- 28 min), both of which required significantly longer exposures. There was no statistical difference between the MH purebred and mixed-bred swine in the time required to trigger MH (defined as a PaCO2 of 70 mmHg) with a given agent, and time to triggering was also independent of the order of exposure to the three anesthetics. Malignant hyperthermia susceptibility was confirmed in ten surviving animals, by both in vivo succinylcholine challenge and in vitro contracture testing. CONCLUSIONS: Although all three volatile anesthetics triggered MH, exposure to halothane resulted in significantly shorter times to MH triggering when compared with desflurane and isoflurane.

High-dose droperidol protects against experimental coronary thrombosis in dogs and pigs and attenuates aggregation of porcine platelets and Ca2+ mobilization in human platelets.

BACKGROUND: Activation of platelets after contact with thrombogenic substrates may be an early factor leading to coronary artery thrombosis and myocardial infarction. Haloperidol, a butyrophenone, possesses weak in vitro platelet inhibitory activity. Experiments were designed to determine whether droperidol, a butyrophenone adjunct to anesthesia, protected against experimental coronary thrombosis in intravenously anesthetized open-chest dogs and pigs, attenuated ex vivo porcine platelet aggregation, and inhibited agonist-induced increases in [Ca2+]i in human platelets. METHODS: In dogs and pigs, a lesion consisting of deendothelialization, deep vessel wall injury, and critical stenosis was created in the proximal circumflex arteries, resulting in coronary thrombus formation accompanied by decreased circumflex artery blood flow. Embolization of the thrombus restored flow, but the cycle then repeated, resulting in repetitive cyclical flow reductions (CFRs). These were measured using an electromagnetic flow probe. RESULTS: In dogs, droperidol 0.2 mg/kg intravenous rapidly abolished CFRs in all ten animals, with frequency decreasing from 0.22 +/- 0.01 cycles/min to 0. Droperidol 0.8 mg/kg intravenous rapidly abolished CFRs in seven of eight pigs, with frequency decreasing from 0.15 +/- 0.01 to 0.02 cycles/min (P < 0.005). In both species, additional doses of droperidol were effective against CFRs augmented with intravenous epinephrine, a catecholamine that stimulates thrombosis. Ex vivo platelet aggregation studies were performed in platelet-rich plasma obtained from pigs before and after droperidol 0.8 mg/kg intravenous. Pretreatment with the drug resulted in marked inhibition of aggregation evoked by collagen, modest attenuation of that elicited by adenosine diphosphate (ADP), but no effect on that evoked by arachidonic acid. In human platelets, apparent [Ca2+]i was estimated using the fluorescent indicator indo-1 and flow cytometry. Droperidol 10(-7), 10(-6), and 10(-5)M had a dose-dependent inhibitory effect on the amplitude of increases in [Ca2+]i evoked by 10(-5)M serotonin (plus 10(-7)M epinephrine). The higher droperidol concentration decreased the response to as much as 30% of control (P < 0.001). Droperidol lacked effect on Ca2+ mobilization elicited with 10(-6)M ADP. CONCLUSIONS: The results from three experimental models indicate that droperidol attenuates experimental coronary thrombosis in animals and suggest that this inhibition may result, in part, from a direct droperidol depressant effect on platelet activation and aggregation.

Subarachnoid hemorrhage and endothelial L-arginine pathway in small brain stem arteries in dogs.

BACKGROUND AND PURPOSE: Experiments were designed to determine the effect of subarachnoid hemorrhage on endothelium-dependent relaxations in small arteries of the brain stem. A "double-hemorrhage" canine model of the disease was used, and the presence of vasospasm in the basilar artery was confirmed by angiography. METHODS: Secondary branches of both untreated basilar arteries (inner diameter, 324 +/- 11 microns; n = 12) and arteries exposed to subarachnoid hemorrhage for 7 days (inner diameter, 328 +/- 12 microns; n = 12) were dissected and mounted on glass microcannulas in organ chambers. Changes in the intraluminal diameter of pressurized arteries were measured using a video dimension analyzer. RESULTS: In untreated arteries, 10(-11) to 10(-7) M vasopressin, 10(-10) to 10(-6) M bradykinin, and 10(-9) to 10(-6) M calcium ionophore A23187 caused endothelium-dependent relaxations. At 10(-6) and 3 x 10(-4) M the nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) abolished relaxations to vasopressin and produced small but significant rightward shifts of the concentration-response curves to bradykinin and A23187. At 10(-3) M L-arginine prevented the inhibitory effect of L-NAME. Subarachnoid hemorrhage abolished relaxations to vasopressin but did not affect relaxations to bradykinin or A23187. CONCLUSIONS: These studies suggest that in small arteries of the brain stem vasopressin causes relaxations by activation of the endothelial L-arginine pathway. This mechanism of relaxation is selectively inhibited by subarachnoid hemorrhage. Preservation of endothelium-dependent relaxations to bradykinin and A23187 is consistent with the concept that small arteries are resistant to vasospasm after subarachnoid hemorrhage.

Cerebral vascular autoregulation and CO2 reactivity following onset of the delayed postischemic hypoperfusion state in dogs.

A small number of animal studies have suggested that during the delayed postischemic hypoperfusion state, CO2 reactivity of the cerebral vasculature is lost whereas autoregulation is retained. These findings, however, are inconsistent with the bulk of experimental evidence which demonstrates that CO2 reactivity is more robust and may be retained in pathologic circumstances which abolish autoregulation. These opposing viewpoints were therefore further evaluated in 18 dogs in which complete global ischemia was induced by cerebrospinal fluid (CSF) compression for periods of 12 (n = 12) and 18 (n = 6) min. Following 45 min of reperfusion and with onset of the delayed postischemic hypoperfusion state, autoregulation and CO2 reactivity were evaluated using a continuous measurement of CBF (by sagittal sinus outflow). CO2 reactivity was tested over a PaCO2 range of 20 to 60 mm Hg; autoregulation was tested over a blood pressure range of 60 to 140 mm Hg. Results demonstrated that after both 12 and 18 min of complete global ischemia, autoregulation and CO2 reactivity of the cerebral vasculature were both present, but attenuated. In the case of CO2 reactivity, the slope of the CBF response was decreased approximately 75%. In the case of autoregulation, the response in some dogs was incomplete as compared with their preischemic response.

No dantrolene protection in a dog model of complete cerebral ischaemia.

Intracellular free calcium is believed to play a major role in the ischaemic cascade which leads to cell death. Calcium channel blockers, which in part inhibit the influx of extracellular calcium, have been shown to be neuroprotective in both complete and focal cerebral ischaemia models. Dantrolene, an agent used in the treatment of malignant hyperthermia, is known to inhibit the release of stored intracellular calcium. Assuming that reduced levels of intracellular free calcium would improve neurologic outcome, we studied the neuroprotective potential of dantrolene. A complete cerebral ischaemia model was used to examine ten anesthetized dogs. Five were given intravenous dantrolene and five were given equal volumes of saline prior to the ischaemic event. Simultaneous occlusion of the venae cavae and ascending aorta provided eleven minutes of complete cerebral ischaemia as monitored by electroencephalography. Arterial blood gases and serum glucose levels were drawn prior to ischaemia, 5 and 20 minutes post-ischaemia, and following extubation. Forty-eight hours following the ischaemic event, neurologic outcomes were scored. No significant differences were observed between the two groups. All ten dogs had equally significant increases in serum glucose levels at 5 and 20 minutes post-ischaemia. The average neurologic outcome of the five dantrolene-treated dogs equalled the average of the five controls. These results suggest that dantrolene, alone, is not neuroprotective during complete cerebral ischaemia.

The effect of profound levels of hypothermia (below 14 degrees C) on canine cerebral metabolism.

The goal of this study was to determine the temperature coefficient (Q10) for canine CMRO2 at temperatures below 14 degrees C. Eight dogs were anesthetized with halothane for surgical preparation. The animals were placed on total cardiopulmonary bypass and CBF was measured by direct sagittal sinus outflow. Duplicate measurements were taken at 37, 13, and 7 degrees C. The EEG became isoelectric at a temperature of 12.0 +/- 0.8 degrees C. The Q10 between 13 and 7 degrees C was 2.19 +/- 0.59. With rewarming to 37 degrees C, cerebral metabolic variables returned to control levels. Brain biopsies taken at the end of the study yielded normal values for brain energy stores. We conclude that the Q10 for CMRO2 at temperatures between 7 and 37 degrees C can be profoundly affected by the state of cerebral function as reflected by the EEG. In the absence of EEG activity, an expected Q10 value of 2.2 reflects only the direct effect of temperature on the rates of biologic reactions.

Ischemia-reperfusion does not affect reactivity of isolated canine basilar artery.

The effect of ischemia-reperfusion on endothelium-dependent relaxations and reactivity of vascular smooth-muscle cells was studied in rings of basilar arteries obtained from six dogs exposed to 12 min of complete global cerebral ischemia followed by 100 min of reperfusion. Three sham-operated control dogs served as controls. Ischemia was induced either by an increase in intracranial pressure or by aortic occlusion. The rings were suspended for isometric tension recording in physiological salt solution. Ischemia-reperfusion did not affect endothelium-dependent relaxations to vasopressin and bradykinin. In rings without endothelium relaxations to sodium nitroprusside, molsidomine (SIN-1), and papaverine as well as contractions to 5-hydroxytryptamine and KCl were preserved. These results demonstrate that in large canine cerebral arteries, ischemia-reperfusion of these durations does not affect relaxations mediated by activation of endothelium or direct relaxations and contractions of vascular smooth-muscle cells.

Postischemic canine cerebral blood flow is coupled to cerebral metabolic rate.

Following complete global cerebral ischemia and reperfusion, a brief period of reactive hyperemia is followed by a prolonged period of low flow commonly referred to as the delayed postischemic hypoperfusion state. It is generally assumed that this low-flow state may be injurious because of inadequate substrate delivery, thus implying that flow is no longer coupled to metabolic needs. This relationship of CBF to CMRO2 was examined in six anesthetized dogs that were subjected to 12 min of complete ischemia induced either by CSF compression or aortic occlusion. Following reperfusion and onset of the low-flow state, which stabilized at 45 min postischemia, control normothermic (37 degrees C) measurements of CBF and CMRO2 were determined. Thereafter, femoral arterial blood was circulated through a heat exchanger (42.5 degrees C), and brain temperature was increased to 40 degrees C and measurements were repeated. The brain was then cooled back to 37 degrees C for a final set of normothermic measurements. Thereafter, brain biopsies were taken to determine the energy state of the brain. CMRO2 changed approximately 6%/degrees C. CBF paralleled the change in CMRO2. Accordingly, the ratio of CBF to CMRO2 remained constant throughout at a value of 8 to 9, demonstrating maintained coupling. The brain energy state was normal at the end of the study. The authors conclude that postischemic CBF is modulated by the brain's metabolic needs.

The relationship among canine brain temperature, metabolism, and function during hypothermia.

Cerebral protection by hypothermia is commonly attributed to cerebral metabolic suppression. However, at temperatures below 28 degrees C, the relationship of temperature to cerebral metabolic rate of oxygen consumption (CMRO2) has not been well characterized. Accordingly, the relationship between brain temperature and CMRO2 was determined in eight dogs during cooling from 37 to 14 degrees C while the EEG was continuously monitored. Cardiopulmonary bypass was initiated and control measurements were made at 37 degrees C during anesthesia with nitrous oxide 50-60% inspired and morphine sulfate 2 mg.kg-1 intravenously (iv). Upon cooling to 27 degrees C, the nitrous oxide was discontinued and the morphine was antagonized with naloxone 2 mg iv. Measurements were repeated at 27, 22, 18, and 14 degrees C and in four dogs again at 37 degrees C after nitrous oxide 50-60% had been reestablished at 27 degrees C along with administration of morphine sulfate 2 mg.kg-1. For each temperature interval, the temperature coefficient (Q10) for CMRO2 was calculated (Q10 = CMRO2 at x degrees C divided by CMRO2 at [x - 10] degrees C). Between 37 and 27 degrees C the Q10 was 2.23, but between 27 and 14 degrees C the mean Q10 was doubled to 4.53. With rewarming to 37 degrees C, CBF and CMRO2 returned to control levels, and brain biopsies revealed a normal brain energy state. During cooling, the EEG developed burst suppression at or below 22 degrees C. With further cooling, the periods of suppression increased; however, burst activity continued in seven of eight dogs even at 14 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

Pretreatment with U74006F improves neurologic outcome following complete cerebral ischemia in dogs.

We examined the 21-aminosteroid U74006F, a potent inhibitor of lipid peroxidation, for potential neuroprotective effects in a canine model of complete cerebral ischemia. Two 1.5-mg/kg boluses were administered to six dogs, the first bolus 15 minutes prior to a 12-minute episode of complete cerebral ischemia and the second bolus after 11 minutes of ischemia, 1 minute prior to reperfusion. Using this dosage regimen, plasma U74006F levels of greater than 0.3 microgram/ml were maintained for up to an hour postischemia. An additional six animals received equal volumes of the citrate vehicle solution. At 24 and 48 hours postischemia, the dogs were neurologically evaluated by an observer blinded as to treatment selection. All six U74006F-treated animals had a normal neurologic outcome at 48 hours postischemia, while the citrate vehicle-treated animals all suffered moderate to severe neurologic deficits. The difference in outcome was significant at both 24 and 48 hours (p less than 0.005). Although U74006F is a 21-aminosteroid, it is not reported to possess glucocorticoid activity. This is supported by the present finding that no changes in plasma glucose concentration were observed following administration of the drug. The systemic vitamin E levels of citrate vehicle-treated animals decreased significantly (from 4.10 +/- 0.46 micrograms/ml to 2.95 +/- 0.38 micrograms/ml, p less than 0.05), whereas the vitamin E levels in U74006F-treated animals did not decrease significantly. These results suggest that U74006F may be of benefit in improving neurologic outcome when administered prior to an episode of complete cerebral ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

The cerebral and systemic hemodynamic and metabolic effects of desflurane-induced hypotension in dogs.

The cerebral and systemic hemodynamic and metabolic effects of hypotension induced with desflurane were examined in 11 dogs. During a steady-state baseline period under 1 MAC desflurane (7.2%), the following were measured or derived: arterial, pulmonary artery, and pulmonary artery occlusion pressures; arterial, mixed venous, and sagittal sinus blood gases; cardiac index and cerebral blood flow (CBF); whole-body and cerebral O2 consumption; systemic and cerebral vascular resistance; intracranial pressure; and blood glucose and lactate concentrations. After the baseline period, hypotension to a mean arterial pressure (MAP) of 50 mmHg was produced by 15.5% (2.2 MAC), and hypotension to an MAP of 40 mmHg was produced by 17.1% (2.4 MAC) for 1 h. During this hypotensive period all measurements were taken at 5- or 15-min intervals. At the end of the hypotensive period, brain biopsy specimens were taken for measurement of cerebral concentrations of ATP, phosphocreatine, and lactate to determine whether there was any metabolic evidence of cerebral ischemia. Desflurane-induced hypotension produced a significant, 40-50% decrease in cardiac index with a significant change in systemic vascular resistance at the lower blood pressure, but produced little change in heart rate. Even though whole-body O2 consumption did not decrease, adequate peripheral perfusion was maintained with the lower cardiac output, as evidenced by lack of accumulation of blood lactate. Induced hypotension caused a significant, 50 (at MAP = 50 mmHg) to 64% (at MAP = 40 mmHg) decrease in cerebral perfusion pressure, accompanied by a significant, 36 (at MAP = 50 mmHg) to 60% (at MAP = 40 mmHg) decrease in CBF.(ABSTRACT TRUNCATED AT 250 WORDS)

The response of the canine cerebral circulation to hyperventilation during anesthesia with desflurane.

Arterial CO2 tension (PaCO2) is an important factor controlling cerebral blood flow (CBF) and cerebral vascular resistance (CVR) in animals and humans. The normal responsiveness of the cerebral vasculature to PaCO2 is approximately 2 ml.min-1.100 g-1.mmHg-1. This study examined the effect of desflurane, a new volatile anesthetic, on the responsiveness of the cerebral vasculature to changes in PaCO2. Mean arterial pressure (MAP), CBF, CVR, intracranial pressure (ICP), and cerebral metabolic rate for O2 (CMRO2) were measured in five dogs anesthetized with desflurane (0.5-1.5 MAC) at normocapnia (PaCO2 = 40 mmHg) and at two levels of hypocapnia (PaCO2 = approximately 30 and approximately 20 mmHg). Under desflurane anesthesia, similar changes in CBF and CVR occurred with hyperventilation at all MAC levels of desflurane. At 0.5 MAC, CBF decreased significantly, from 81 +/- 6 to 40 +/- 3 ml.min-1.100 g-1 (P less than 0.05, mean +/- SE) when PaCO2 was decreased from 40 to 24 mmHg; i.e., the CBF decreased approximately 2.6 ml.min-1.100 g-1.mmHg-1. At 1.0 MAC desflurane, CBF decreased significantly, from 79 +/- 10 to 43 +/- 5 ml.min-1.100 g-1 with hyperventilation (2.0 ml.min-1.100 g-1.mmHg-1); at 1.5 MAC desflurane, CBF decreased from 65 +/- 6 to 38 +/- 2 ml.min-1.100 g-1 with hyperventilation (1.6 ml.min-1.100 g-1.mmHg-1). Despite the significant decreases in CBF with hyperventilation, there was no significant change in ICP. Dose-dependent decreases in MAP were observed with increasing concentrations of desflurane but were not significantly affected by ventilation.(ABSTRACT TRUNCATED AT 250 WORDS)

Desflurane is a trigger of malignant hyperthermia in susceptible swine.

Desflurane (difluoromethyl 1-fluoro 2,2,2-trifluoroethyl ether: CF2-H-O-CFH-CF3) is a potent inhalation anesthetic agent being investigated for possible clinical use. The authors examined the effects of this agent on normal swine and those from a special breeding program that were considered purebred for susceptibility to malignant hyperthermia (MH). Animals were exposed to 1 or 2 MAC or both doses of desflurane and observed for changes in end-tidal CO2, arterial blood gases, lactate, catecholamines, core temperature, blood pressure, and heart rate. All normal swine tolerated exposure to desflurane without clinical signs of MH, but significant changes in heart rate and blood pressure were noted. In contrast, of six MH susceptible swine tested, two had unequivocal MH reactions to deflurane, defined by significant increases of end-tidal CO2 (greater than 50 mmHg), an increase in PaCO2 (greater than 70 mmHg), a decrease in blood pH (less than 7.30), an increase in blood lactate concentration, and an increase in core temperature. Two other susceptible swine showed equivocal signs of MH but not until desflurane had been administered for 40-60 min. Finally, two other susceptible swine showed no signs of MH after 60 min of exposure to 2 MAC desflurane. These latter four animals all developed episodes of MH immediately after intravenous succinylcholine (2 mg/kg). The increased PaCO2, blood lactate concentrations, and temperature, and the decrease in pH induced by desflurane, were successfully treated with dantrolene and supportive measures. All surviving animals were biopsied 1 to 2 weeks after the exposure to desflurane for in vitro contracture testing to confirm MH susceptibility.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of suxamethonium on the cerebrum following disruption of the blood-brain barrier in dogs.

We have studied the effects of suxamethonium 1.0 mg kg-1 i.v. on cerebral blood flow (CBF), cerebral metabolic rate (CMRO2), and the electroencephalogram (EEG) in dogs anaesthetized with halothane (1.0 MAC) following blood-brain barrier (BBB) disruption with intracarotid (i.c.) mannitol. The combination produced a transient increase in CBF, while CMRO2 did not change. These responses were similar to those produced by i.c. mannitol plus i.v. saline. Suxamethonium produced desynchronization of the EEG that persisted longer than that produced by saline. In only one of the six animals was the desynchronization sustained (90 min) beyond that found in dogs with a normal BBB. We conclude that disruption of the BBB did not enhance the cerebral stimulating effects of i.v. suxamethonium, and did not increase the likelihood of seizure activity following suxamethonium.

The effects of intravenous succinylcholine on cerebral function and muscle afferent activity following complete ischemia in halothane-anesthetized dogs.

The effects of iv succinylcholine (SCh) on cerebral blood flow (CBF), the electroencephalogram (EEG), muscle afferent activity (MAA), electromyographic activity (EMG), and PaCO2 were tested in six halothane-anesthetized dogs (1.0 MAC) more than 1 h after a 10-min period of complete cerebral ischemia. All dogs received treatments of both iv SCh (1.0 mg.kg-1) and saline placebo in a random sequence. Fasciculations and substantial increases in EMG activity were observed in all dogs following SCh administration. At the onset of fasciculations, there was an increase in MAA to a peak value of 353 +/- 74% of control (mean +/- SE; n = 5 for MAA; n = 6 for all other variables) at the 1-min measurement point. Thereafter, MAA gradually declined toward control values. There were delayed increases in PaCO2 throughout the 45-min study period, achieving values of 106 +/- 1% to 118 +/- 4% of control (an increase in PaCO2 of 2-7 mmHg). Despite the increases in MAA and PaCO2, there were no significant increases in CBF during the study. The control EEG 1-h after complete cerebral ischemia, but immediately before administering the drug treatments, consisted predominantly of a delta rhythm, denoting cerebral dysfunction. In one dog, SCh administration produced transient attenuation of the delta rhythm, a change consistent with cerebral stimulation. In the remaining five dogs, SCh had no effect on the EEG. Treatment with saline placebo did not affect any variable measured. The authors conclude that, in the electrically dysfunctioning brain (e.g., as occurs following resuscitation from complete cerebral ischemia), the cerebral (i.e., CBF and EEG) response to iv SCh is attenuated when compared to the previously reported response in normal brain.

The cerebral functional, metabolic, and hemodynamic effects of desflurane in dogs.

The effects of 0.5-2.0 MAC (3.6-15%) desflurane on cerebral function, metabolism, and hemodynamics and on systemic metabolism and hemodynamics were examined in dogs. Desflurane produced a significant dose-related decrease in cerebral vascular resistance from 1.53 +/- 0.21 mmHg.ml-1.min.100 g at 0.5 MAC to 0.50 +/- 0.03 mmHg.ml-1.min.100 g at 2.0 MAC desflurane. This was accompanied by an increase in cerebral blood flow (CBF) from 61 +/- 7 ml.min-1.100 g-1 at 0.5 MAC to 78 +/- 3 ml.min-1.100 g-1 at 1.5 MAC desflurane. At 2.0 MAC desflurane CBF was 52 +/- 2 ml.min-1.100 g-1 but was associated with a decrease in mean arterial pressure (MAP) to 43 +/- 2 mmHg. When MAP was increased to 73 +/- 3 mmHg with phenylephrine, CBF increased to 87 +/- 3 ml.min-1.100 g-1 at this concentration. At 0.5 MAC desflurane, intracranial pressure (ICP) was 15 +/- 5 mmHg, higher than normal, but did not change significantly with increasing concentrations of desflurane. Increasing concentrations of desflurane initially produced on the EEG the common pattern sequence of increasing depth of anesthesia with decreasing frequency and increasing amplitude progressing to burst suppression and then at 2.0 MAC desflurane to regular attenuation with interruption by periodic polyspiking, a pattern similar to that seen with isoflurane. At both 1.5 and 2.0 MAC the EEG pattern initially observed at that concentration changed to one with faster background activity with time.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of dizocilpine maleate (MK-801), an antagonist of the N-methyl-D-aspartate receptor, on neurologic recovery and histopathology following complete cerebral ischemia in primates.

The present study was designed to determine if the noncompetitive excitatory amino acid antagonist, dizocilpine maleate, when administered after a 17 min period of complete cerebral ischemia in primates, would improve postischemic neurologic function and hippocampal histopathologic outcome when compared to placebo-treated animals. Ten pigtail monkeys were anesthetized and subjected to complete cerebral ischemia using an established neck tourniquet model. Five minutes postischemia, five monkeys received dizocilpine 300 micrograms/kg i.v. over 5 min, followed by an infusion of 150 micrograms/kg/h for 10 h. This produced plasma levels of the drug in excess of 30 ng/ml for the duration of the infusion. An additional five monkeys were treated with an identical volume of saline placebo. All monkeys received intensive care for the initial 24 to 48 h postischemia. At 96 h postischemia, there was no significant difference in neurologic function between the two groups (p = 0.53, with the placebo group having the numerically better outcome). There also was no significant difference between hippocampal histopathology scores between dizocilpine and placebo-treated monkeys. The authors conclude that dizocilpine is not an efficacious therapy in the treatment of neurologic injury that occurs following complete cerebral ischemia in this primate model.