The effects of a prophylactic bolus of lidocaine in focal cerebral ischaemia

In order to determine the cerebral protective effects of an intravenous bolus of 5 mg.kg-1 of lidocaine, the left middle cerebral artery (MCA) was transorbitally occluded in 19 cats. Ten animals received the lidocaine bolus and nine a similar volume of saline immediately before MCA occlusion. Somatosensory evoked potentials (SEP) were recorded before and after the lidocaine bolus as well as continually after MCA occlusion. After six hours of vessel occlusion and without reperfusion, the animals were sacrificed and the brains fixed for histology. Prior to MCA occlusion, lidocaine caused a statistically significant (p less than 0.01) reduction in the amplitude of the major cortical component of the SEP (10 +/- 1.2 microV vs 6.0 +/- 1.3 microV). Latency was unchanged. In the lidocaine group, SEP's persisted in 40 per cent immediately following occlusion whereas they disappeared in all of the control animals (p less than 0.05). Gradual recovery occurred in both groups and there were no differences at the end of the experiment although the amplitudes tended to be greater in the lidocaine group. There were no statistically significant differences in the histological size or severity of the infarcts between the groups. Although infarct size was not reduced, transient sparing of the SEP suggests that further studies of lidocaine by continuous infusion in models of temporary focal cerebral ischaemia may be warranted.     

Treatment of acute focal cerebral ischemia and recirculation with d-propranolol

The purpose of the investigation was to evaluate the effects of d-propranolol upon temporary cerebral ischemia followed by a period of reperfusion, that is, a situation analogous to major cerebral artery embolization. Twenty adult cats, lightly anesthesized with nitrous oxide, underwent 4 hours of right middle cerebral artery (MCA) occlusion and 2 hours of recirculation. Ten cats were untreated and 10 cats received d-propranolol, the weak beta-blocking isomer of racemic (d,l) propranolol. The d-propranolol was infused directly into the right carotid artery at doses of 2 mg/kg, given as a bolus immediately before MCA occlusion, and 0.33 mg/kg/hour, given continuously for 6 hours beginning immediately after MCA occlusion. Systemic arterial blood pressure was similar in both groups, but heart rate was transiently reduced in the treated group immediately after the bolus injection of d-propranolol and MCA occlusion. Regional cerebral blood flow (rCBF), measured by the xenon-133 clearance technique, was not significantly different in the ischemic, right hemisphere. Electroencephalographic (EEG) activity changes in the ischemic, right hemisphere were similar in both groups, but there was significant deterioration of EEG activity in the left, nonischemic hemisphere of untreated cats after MCA reopening. Swelling of the ischemic, right hemispheres was similar in both groups and more severe than in previous studies wherein there was no recirculation phase. Carbon perfusion and blood-brain barrier changes were also similar. The results of the study failed to show a protective effect despite theoretical beneficial actions of d-propranolol. Also, the study demonstrated that d-propranolol does not have a detrimental effect upon rCBF in acute focal cerebral ischemia.     

Effect of tirilazad mesylate given after permanent middle cerebral artery occlusion in rat

Summary The effect of the antioxidant drug tirilazad mesylate (U-74006F) on histopathological and neurological outcome 3 days after permanent middle cerebral artery (MCA) occlusion was evaluated in rats. Several previous studies have demonstrated the efficacy of tirilazad in reducing infarct size when administered before and during MCA occlusion, whereas post-treatment may be less effective in permanent focal ischaemia. We sought to determine if a protective effect of tirilazad could be demonstrated when administered after the insult only.U-74006F (3 mg/kg, i.v.) or sterile vehicle, was randomly given to rats 10 minutes and 3 hours after permanent MCA occlusion produced by transcranial proximal electrocauterization. Infarct volume and hemisphere volumes were estimated blindly from histological sections of defined levels of the brain after 72 h of ischaemia. Neurological score was determined blindly 1, 2, and 3 days after insult. There was no significant difference in infarct volume, volume of non-infarcted tissue, or neurological score between the tirilazad and placebo-treated rats.In conclusion, our results support the conception that post-treatment with tirilazad mesylate is not efficacious in reducing infarct size in permanent focal ischaemia, while pre-treatment, as reported by other groups, appears to be effective in both permanent and temporary focal ischaemia models. In temporary focal ischaemia, the limited data available suggest that also post-treatment with tirilazad may prove to be neuroprotective.     

Thromboxane synthetase inhibition in acute focal cerebral ischemia in cats

The purpose of this investigation was to study the effects of a selective thromboxane A2 (TXA2) synthetase inhibitor (TSI) upon the evolution of cerebral infarction in the cat. Adult cats, lightly anesthetized with nitrous oxide, underwent right middle cerebral artery (MCA) occlusion for 4 hours followed by a 2-hour period of reperfusion before sacrifice. Ten cats received 3 mg/kg TSI intravenously immediately before, and 10 cats received 3 mg/kg TSI intravenously immediately after MCA occlusion. Ten cats were used as controls receiving no treatment. The bleeding time was determined at baseline and at the end of each experiment. Electroencephalographic (EEG) recordings were obtained before and after MCA clipping and MCA release, and at hourly intervals thereafter. Regional cerebral blood flow (rCBF) was measured using the xenon-133 (133Xe) clearance technique before and after MCA occlusion, after MCA reopening, and before terminating each experiment. Thirty minutes before each cat was sacrificed, Evans blue dye and sodium fluorescein were given intravenously. The animals were then perfused with colloidal carbon and the brains removed and evaluated for midline shift. Evans blue dye and sodium fluorescein extravasation, carbon staining, and infarct size. The bleeding time, arterial blood pressure, rCBF changes, brain swelling, and vital dye extravasation were not statistically different between the three treatment groups. The EEG changes, carbon staining, and infarct size differences between the three groups also failed to reach statistical significance, but there was a suggestion that these parameters were adversely affected in the cats pretreated with TSI. Ten additional cats undergoing MCA occlusion and reperfusion were used for pharmacological studies. Five of them received 3 mg/kg TSI intravenously immediately after MCA occlusion, and serial drug and thromboxane B2 (TXB2) levels (a stable metabolite of TXA2) were determined. Another five cats were not treated and serial TXB2 levels were obtained. Production of TXA2 was inhibited by 95% in cats receiving TSI. In conclusion, thromboxane synthetase inhibition failed to modify favorably the evolution of cerebral infarction. When TSI was given before MCA occlusion, cerebral infarction tended to be more extensive.     

Improved neurological outcome in experimental focal cerebral ischemia treated with propranolol

Propranolol has been shown to exert a protective effect in experimental myocardial, renal, and early acute focal cerebral ischemia. However, propranolol was not found to reduce infarct size in nitrous oxide-anesthetized, paralyzed, mechanically ventilated cats subjected to 6 hours of acute focal ischemia. The objective of the current investigation was to study further the effects of racemic (d,l)-propranolol on the evolution of acute focal cerebral ischemia in awake, conscious cats. Adult cats were anesthetized with halothane and underwent the implantation of an occluding device around the right middle cerebral artery. After a 48-hour recovery period, the right middle cerebral artery was occluded for 6 hours and then reopened, allowing reperfusion for an additional 6 hours. Neurological examinations were conducted every 2 hours throughout each experiment. Ten cats received d,l-propranolol (2 mg/kg) 1 hour before occlusion, immediately before occlusion, and every 2 hours throughout each experiment. Eleven cats serving as controls were not treated. The neurological examination significantly improved over time in the treated group when compared to the untreated group (P = 0.01). Carbon filling defects, gross brain swelling, and infarct size were reduced in treated cats. The results of this study suggest that propranolol does have beneficial effects in acute focal cerebral ischemia.     

Primate brain tolerance to temporary focal cerebral ischemia during isoflurane- or sodium nitroprusside-induced hypotension

Isoflurane has properties that suggest it may provide cerebral protection from ischemia. This study compared, in primates, neurologic outcome after a 45-min period of temporary focal ischemia during hypotension induced with either isoflurane or sodium nitroprusside (SNP). Fourteen macaque monkeys were studied. Seven animals received halothane and seven isoflurane anesthesia during surgical preparation. After transorbital exposure of the middle cerebral artery (MCA), in the halothane group, the inspired halothane was reduced to 0.75% and the mean blood pressure (BP) reduced to 50 mmHg by the infusion of SNP. In the isoflurane group, the isoflurane was titrated to reduce mean BP to 50 mmHg. Stable hypotension was maintained for 90 min, which included a 45-min period of MCA occlusion. Monitoring included intraarterial blood pressure, arterial blood gases, EEG, somatosensory evoked potentials (SEP), and temperature. After the procedure the animals were allowed to awaken and were assessed neurologically every 8 h. On the third postoperative day, they were reanesthetized and underwent magnetic resonance imaging (MRI) and SEP recording. Thereafter, they were killed with iv KCl and the brains fixed for neuropathology. All animals survived the surgical procedure, but two animals receiving halothane and none receiving isoflurane died prematurely (P less than 0.2). The SEP disappeared in all animals within 10 min of MCA occlusion and then returned partially or completely. There was no difference between groups in neurologic scores, in the size of the lesion as assessed by MRI (isoflurane 15.7 +/- 6%, halothane/SNP 10.5 +/- 4%), or in the extent or severity of the neuropathologic lesions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of nilvadipine on neuronal function in the ischemic cat brain.

The effect of nilvadipine, a dihydropyridine-type calcium entry blocker, on neuronal function during and following ischemia was investigated with a model of focal cerebral ischemia in cats and was compared with that of nicardipine. Drugs were given intravenously 30 minutes before occlusion of the left middle cerebral artery (MCA). Occlusion of the left MCA for 60 minutes was followed by reperfusion for 90 minutes. The amplitude of the somatosensory evoked potentials (SEPs), and the residual relative regional cortical blood flow in the left ectosylvian gyrus and the left posterior sigmoid gyrus, were higher or had a tendency toward higher values in the nilvadipine-treated (32 micrograms/kg) group than in other groups. After reperfusion, the amplitude of SEPs rapidly recovered in the nilvadipine-treated groups. When administered before MCA occlusion, nilvadipine improved neuronal function measured by SEPs both during and following the ischemic period. Thus, nilvadipine is effective against neuronal dysfunction in focal cerebral ischemia.     

Results of hyperbaric oxygen therapy during temporary middle cerebral artery occlusion in unanesthetized cats

We evaluated the effect of hyperbaric oxygen (HBO) therapy on neurological function and infarct size in 33 unanesthetized cats subjected to temporary 6-hour or 24-hour occlusion of the middle cerebral artery (MCA) 7 to 10 days after transorbital implantation of a vessel occluder. HBO therapy (100% oxygen at 1.5 atmospheres absolute) was administered for 40 minutes during or after 6-hour occlusions and before, during, and after 24-hour occlusions. Neurological function was graded on a scale of 0 to 10 every 30 minutes before, during, and after occlusion and HBO treatments until it stabilized and then daily until the cats were killed 10 days after occlusion. The results were compared with observations in 13 untreated controls and 6 cats that received 100% O2 at atmospheric pressure during a 6-hour MCA occlusion. HBO therapy during the 1st or 3rd hour of a 6-hour MCA occlusion resulted in a four-grade improvement of the initial neurological function; this effect persisted during the remainder of the occlusion. The average grade of neurological deficit at death was 94% less than in the untreated cats (P less than 0.03). Infarct size in the HBO-treated group was 58% less than in controls (P less than 0.03). There was no significant difference in infarct size between the untreated cats and those treated with 100% O2 at atmospheric pressure. HBO therapy during the 4th hour of a 6-hour MCA occlusion had no statistically significant effect on infarct size, even though the mean neurological deficit was 73% less than in controls (P less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)     

Quantification of burst suppression and bispectral index with 2 different bolus doses of thiopentone sodium

Metabolic suppression caused by barbiturates is a major mechanism responsible for their cerebral protective potential. Maximal cerebral metabolic suppression is believed to coincide with electroencephalographic burst suppression. However, many neurosurgical procedures associated with cerebral ischemic threat are still performed in the absence of electroencephalogram monitoring, especially in developing nations. The present study was designed to assess the degree of burst suppression with 2 different doses of thiopentone sodium administered on the background of isoflurane anesthesia intraoperatively. Forty-one patients without any intracranial pathology undergoing elective spinal surgery under a general anesthetic consisting of N2O (60%) in O2 (40%) and isoflurane to maintain a bispectral index (BIS) value of 45 were randomized to receive a thiopentone bolus of either 3 or 5 mg/kg. BIS, burst suppression ratio (BSR), systolic blood pressure, and heart rate were recorded before the bolus and every 15 seconds for first 2 minutes and every 30 seconds for another 8 minutes. During the 10-minute study period after the administration of thiopentone bolus, BIS values were significantly lower in the group that received thiopentone 5 mg/kg compared with the group that received thiopentone 3 mg/kg (P<0.02). BSR>25% was seen in 7 out of 21 patients in the 3 mg/kg group and 10 out of 20 patients in the 5 mg/kg group. There was a statistically insignificant prolongation of the duration of burst suppression with thiopentone 5 mg/kg [243 s (range 75 to 435 s)] compared with thiopentone 3 mg/kg [171 s (30 to 465 s)]. The number of patients who had a BSR >50% was higher among patients who received thiopentone 5 mg/kg as compared with those who received a dose of 3 mg/kg [9/20 vs. 3/21(P<0.02)]. We conclude that thiopentone in a bolus dose of 3 to 5 mg/kg produces only a short duration of incomplete burst suppression. Also, in this dose range, burst suppression does not occur consistently in all patients. The present data suggest that bolus doses of thiopentone in the range of 3 to 5 mg/kg may have very limited value in providing significant metabolic suppression required for intraoperative cerebral protection during temporary ischemic episodes.     

Failure of naloxone to affect focal incomplete cerebral ischemia and collateral blood flow in cats

Focal incomplete cerebral ischemia was created in 20 adult cats by retro-orbital middle cerebral artery (MCA) occlusion under halothane anesthesia. Arterial blood flow (CBF), bilateral electroencephalographic (EEG) recordings, and systemic arterial blood pressure (SABP) were monitored for the 1st hour of occlusion. Ten animals were treated with 10 mg/kg of naloxone within 10 minutes of MCA clipping, followed by a continuous infusion of naloxone at 2 mg/kg/hr for the duration of the occlusion (8 hours). Ten animals were treated in a similar fashion with physiological saline (control). Blood flow was restored after 8 hours. The brains were examined at the time of death or 7 days after the occlusion period. There was no difference between the two groups regarding cerebral infarction size or distribution, neurological outcome, SABP, PaCO2, or CBF. Minor changes in EEG amplitude observed in the naloxone-treated group appear to represent interaction of the drug with halothane after prolonged administration. The authors conclude that naloxone did not modify the outcome of focal cerebral ischemia in the cat.     

Treatment of acute focal cerebral ischemia with intermittent, low dose mannitol

The object of this investigation was to study the effects of intermittent, low dose mannitol therapy on conscious cats after acute left middle cerebral artery (MCA) occlusion. A simple implanted device was applied to the proximal left MCA of 40 adult cats using microsurgical techniques. In the acute experiments, 10 cats were untreated and 10 cats received mannitol (0.5 g/kg intravenously) immediately before occlusion and again 3, 6, and 9 hours later. They subsequently underwent intra-arterial perfusion with colloidal carbon and buffered paraformaldehyde 12 hours after occlusion. The plasma osmolality immediately before perfusion was 316 +/-2 (SD) milliosmoles in untreated cats and 331 +/- 5 milliosmoles in treated cats. Gross swelling, impaired carbon filling, and breakdown of the blood-brain barrier (BBB) to fluorescein were seen in the left MCA territory of 8 untreated cats and 1 treated cat. The mean percentage of gray matter cross sectional area where severe ischemic neuronal alterations predominated was 45 +/- 12% in untreated and 14 +/- 16% in treated cats (p less than 0.01). The mean capillary luminal diameter in the left sylvian cortex was 4.5 +/- 1.0 mu in untreated cats (control, 6.5 +/- 1.0 mu) and 5.5 +/- 1.0 mu in treated cats. In the subacute experiments, 10 cats were not treated and 10 cats received mannitol as in the acute experiments. The cats were killed with a large bolus of sodium pentobarbital 48 hours after left MCA occlusion. Gross swelling and breakdown of the BBB were less severe in treated cats. The mean cross sectional area of infarcted tissue was 55 +/- 12% in untreated cats and 33 +/- 21% in treated cats (p less than 1.0). The findings of this study indicate that intermittent, low dose mannitol therapy delays the onset of ischemic cerebral injury and may reduce the size of the eventual infarct or convert a potential infarct into a so-call "transient ischemic attack." (Neurosurgery, 5: 684--691, 1979).     

Effect of opiate antagonists on middle cerebral artery occlusion infarct in the rat

The authors examined the effect of the opiate antagonists naloxone and thyrotropin-releasing hormone (TRH) on neurological outcome and the size of areas of cerebral infarction in a rat model of focal cerebral ischemia. The middle cerebral artery (MCA) was permanently occluded in 66 adult Sprague-Dawley rats. The rats were randomly divided into three groups. In 20 Group I rats, TRH in normal saline was administered initially as a 2-mg/kg bolus followed by continuous infusion of 2 mg/kg/hr for 4 hours. In 20 Group II rats, naloxone in normal saline was administered initially as a 2-mg/kg bolus followed by continuous infusion of 2-mg/kg/hr for 4 hours. In 26 Group III rats, physiological saline was administered as an initial 0.5-cc bolus followed by continuous infusion of 0.5 cc/hr for 4 hours. All solutions were given in volumes of 0.5 cc for the bolus and 0.5 cc/hr for continuous infusion, and all infusions were begun within 10 minutes of MCA occlusion. Twenty-four hours after treatment, the rats underwent a careful neurological examination and were then sacrificed immediately. The size of areas of cerebral infarction was evaluated using 2,3,5-triphenyltetrazolium chloride staining techniques. The neurological grade of the rats correlated with the size of infarcted areas among all grades, irrespective of treatment (p less than 0.01). Neither naloxone nor TRH improved neurological function or reduced the size of infarction compared to saline-treated control rats. Treatment with TRH caused a significant increase in mean arterial blood pressure during infusion, but naloxone had no effect. These results suggest that neither TRH nor naloxone are effective in the treatment of acute focal cerebral ischemia.     

Transcranial Doppler sonography in experimental Cushing response

Summary Searching for the early warning symptoms of brain ischaemia, transcranial Doppler sonography (TCD) was used in cats during the Cushing response. The study was performed on seven cats.The intracranial pressure was increased by means of different rate lumbar infusions. The TCD changes of middle cerebral artery (MCA) and basilar artery (BA) flows were analyzed at the stage of the slightest but significant systemic blood pressure increase. The first symptos of Cushing phenomenon were accompanied by BA flow pattern alternations while the MCA flow remained unchanged.The study suggests the necessity of BA TCD monitoring in cases at risk from brain stem ischaemia. It was shown also that in such cases the MCA TCD study can be misleading.     

Pentothal protection for delay cerebral revascularization.

Thiopentone (20 mg/kg/bolus and 20 mg/kg/three hours) was effective in preventing infarction in five dogs with six hours of middle cerebral occlusion. Nine control animals sustained massive to large infarctions. Utilizing this regime therapeutic blood levels were rapidly attained for over 12 hours without side effects. From the experimental and human experience with focal cerebral ischaemia, there appears to be a finite grace period in which cerebral revascularization can be undertaken. In canine and primate models this time has been about five hours, following which the infarction process may not be reversible (Sundt et al. 1977, Laha et al. 1978). Seeking to prolong this grace period, thiopentone was selected as an ideal drug for this purpose, and its effect on the revascularized canine middle cerebral distribution was evaluated at six hours following embolectomy.     

Thiopentone and methohexital, but not pentobarbitone, reduce early focal cerebral ischemic injury in rats

PURPOSE: Although barbiturates are considered to be cerebral protectants, little is known regarding the relative efficacy of different barbiturates to reduce ischemic brain injury. In a model of middle cerebral artery occlusion (MCAo), we compared the relative effects of 1.0 and 0.4 burst-suppression doses of thiopentone, methohexital, and pentobarbitone on cerebral infarct. METHODS: During isoflurane anesthesia, MCAo was achieved via a temporal craniotomy. Thirty minutes before MCAo the rats were randomized to receive one of the following which was maintained throughout the study. Halothane (n=20)-1.2 MAC halothane, thiopentone (n=20), methohexital (n=20), or pentobarbitone (n=20). The first ten animals in each barbiturate group received the respective barbiturate in a dose sufficient to maintain burst-suppression of the electroencephalogram (3-5 bursts x min(-1)). The subsequent ten animals in each barbiturate group received 40% of the burst-suppression dose. After 180 min of MCAo and 120 min of reperfusion, cerebral injury was assessed. RESULTS: For the burst-suppression animals, injury volume (mm3, mean +/- SD) was less in the thiopentone group (88 +/- 14) than the halothane (133 +/- 17), methohexital (126 +/- 19), or pentobarbitone (130 +/- 17) groups (P <0.05). For 0.4 burst-suppression animals, injury volume was less for the methohexital group (70 +/- 22) than the halothane (124 +/- 24), thiopentone (118 +/- 15), or pentobarbitone (121 +/- 20) groups (P <0.05). CONCLUSIONS: These data are inconsistent with the longstanding assumption that electrophysiologically comparable doses of the various classes of barbiturates have equivalent protective efficacy. They in turn suggest that mechanisms other than, or at least in addition to, metabolic suppression may contribute to the protective effect of barbiturates.     

Effect of Ascorbic Acid on Infarct Size in Experimental Focal Cerebral Ischaemia and Reperfusion in a Primate Model

Summary  Temporary occlusion of major cerebral blood vessels occasionally becomes necessary during surgical procedures. Ascorbic acid (Vitamin C) is an important non-enzymatic scavenger of free radicals and its protective effect on the brain in permanent focal cerebral ischaemia has been proven in a primate model of focal cerebral ischaemia [16]. Additional damage caused by reperfusion of the infarcted area has been shown in the rat model [22].  This study was undertaken to study the efficacy of ascorbic acid in decreasing infarct size in ischaemic reperfused brain.  Maccaca radiata monkeys in the treated group were given two grams of ascorbic acid, parentally immediately before clipping the middle cerebral artery and the control group was given placebo. Reperfusion was done after four hours. Mean infarct size in all the three brain slices in the ascorbic acid pretreated group was 7.3%±2.7 and in the placebo group 22.1±6.7 under similar conditions. The mean infarct size in the ascorbic acid pretreated group of monkeys was significantly lower when compared with the placebo group (p=0.0003).     

A comparison of the area of histochemical dysfunction after focal cerebral ischaemia during anaesthesia with isoflurane and halothane in the rat

The investigations that have thus far evaluated the cerebral protective properties of isoflurane have provided conflicting results. Protection would be most likely to occur in the circumstances of incomplete cerebral ischaemia in which there is a penumbral zone of marginal perfusion. The present investigation sought to evaluate further the protective properties of isoflurane in that circumstance. Middle cerebral artery occlusion (MCAO) was performed in Sprague-Dawley rats anaesthetized with 1.2 MAC concentrations of either halothane or isoflurane. At the end of four hours of MCAO, the brains were removed, sectioned and incubated in the histochemical stain 2-3-triphenyltetrazolium (TTC). An image analysis system was used to measure the area of reduced or absent TTC staining in four coronal planes spanning the distribution of the middle cerebral artery. There was no difference between halothane and isoflurane anaesthetized animals with respect to the area of brain with evidence of histochemical dysfunction. It is concluded that isoflurane is not protective (relative to the status of halothane anaesthetized control animals) when administered at 1.2 MAC concentration during four hours of focal (incomplete) cerebral ischaemia in the rat.     

Myocardial contractility and ischaemia in the isolated perfused rat heart with propofol and thiopentone

The effects of propofol and thiopentone on myocardial contractility and global ischaemia were evaluated using an isolated non-working perfused rat heart preparation. Contractility was assessed using a tension transducer linked to the cardiac apex, and the contractility was expressed as a ratio of the deflection size before and after infusion of the drug. Ischaemia-induced leakage of myocardial proteins and ions (potassium and magnesium) was assessed by comparing the concentrations in the effluent perfusate immediately before and after 60 min of isothermic ischaemia, in the presence of propofol, thiopentone or plain Krebs' buffer solution (control). Mean contractility ratios of 1.15 and 1.3 were obtained with control and propofol groups respectively (NS), but were reduced to 0.5 in the thiopentone group (P less than 0.001). The magnitude of the post-ischaemic leakage of proteins and potassium was similar in each group; however, the post-ischaemic leakage of magnesium was greater in the thiopentone group than in the propofol or control groups. These data suggest that, compared with thiopentone, propofol is not a potent negative inotrope, and that it may cause less disturbance of myocardial magnesium homeostasis during myocardial ischaemia.     

Thiopentone pharmacokinetics during cardiopulmonary bypass with a nonpulsatile or pulsatile flow

To evaluate possible factors affecting the pharmacokinetics of thiopentone during cardiopulmonary bypass (CPB), the present study was undertaken in patients scheduled for coronary artery bypass grafting and with in vitro experiments. The effects of nonpulsatile and pulsatile flow during CPB on the distribution and elimination of thiopentone were compared in 30 patients anaesthetized with fentanyl. The initial rapid phases of distribution of thiopentone were studied in 17 patients undergoing a nonpulsatile or pulsatile perfusion, to whom thiopentone 6 mg/kg was given as a rapid intravenous bolus during CPB. In order to study later distribution and early elimination of thiopentone, 13 patients perfused with a nonpulsatile or pulsatile flow received 6 mg/kg of the drug as a 15-min intravenous infusion before CPB. No differences in the pharmacokinetic parameters characterizing distribution and elimination of thiopentone were found between the patients undergoing nonpulsatile or pulsatile perfusion. As measured in 10 of the patients receiving the drug before the institution of CPB, no difference in plasma thiopentone level was observed in blood samples drawn simultaneously from a radial arterial cannula and a pulmonary artery catheter before, during and after CPB. This suggests that thiopentone is not sequestered in lungs during CPB. In vitro binding of thiopentone to the CPB equipment was studied in 6 experiments using a closed circuit. After a 60-min circulation time, only 50% of the predicted thiopentone level was recovered from the perfusate. It is concluded that replacing a nonpulsatile perfusion with a pulsatile one has no effect on the distribution and elimination of thiopentone in patients undergoing CPB. During CPB, thiopentone is sequestered in the extracorporeal circuit but not in the lungs.     

The effect of allopurinol on focal cerebral ischaemia: an experimental study in rabbits

In this experimental study, the neuroprotective effect of the xanthine oxidase inhibitor allopurinol on focal cerebral ischaemia created by permanent middle cerebral artery occlusion (MCAO) was investigated. Using high performance liquid chromatography (HPLC), we measured hypoxanthine, xanthine, and uric acid (UA) levels in rabbit brains following focal cerebral ischaemia. Rabbits were randomly and blindly assigned into four groups of eight animals each. The control groups received 2% carboxymethylcellulose solution, while 10% allopurinol 150 mg/kg was given to the treatment group 1 h before ischaemia. Each group was subdivided into two groups which were sacrificed 4 h or 24 h after ischaemia, respectively. UA and xanthine values of the rabbits in the control groups were quite high at both times and highest after 24 h, particularly in the centre of the ischaemia. A significant decrease in UA and xanthine values was observed in rabbits that were given allopurinol (P<0.05). According to our results, it was concluded that allopurinol pretreatment protects neural tissue in the early period after arterial occlusion and prevents cerebral injury in the late period, especially in the perifocal area, possibly by preventing the formation of free radicals with xanthine oxidase inhibition. Received: 22 June 1998 / Accepted: 21 February 2000