Sumatriptan-induced cerebral vasoconstriction as treatment of experimental intracranial hypertension.

BACKGROUND: Increased intracranial pressure (ICP) is a major cause of mortality in severe head injuries and pharmacologically induced cerebral vasoconstriction has been suggested as a possible treatment. In the present study a porcine model of increased ICP was utilized to study the changes in cerebral haemodynamics and energy metabolism induced by a selective 5-hydroxytryptamine1 agonist (sumatriptan). METHODS: ICP was raised by inflation of two balloons covering both parieto-occipital regions extradurally. The animals were randomized into four groups receiving sumatriptan. 0.01 mg.kg-1 (A), 0.03 mg.kg-1 (B), 0.1 mg.kg-1 (C), and 0.5 mg.kg-1 (D) intravenously over 10 min. Measurements of cerebral blood flow (CBF), arterio-venous oxygen content difference (CavO2), and jugular venous pH (vpH) were performed 5, 20, 40, 60, and 75 min after start of the infusion. ICP, mean arterial pressure, and EEG were recorded continuously. Direct effects of sumatriptan were also compared in cortical arteries and veins in vitro. RESULTS: Significant decreases in ICP were obtained in groups A, B, and C while group D exhibited a progressive increase in ICP. Significant reductions in CBF, increase in CavO2, and slowing of EEG were observed in groups B, C, and D. Sumatriptan caused moderate constriction of the arteries and a more pronounced dilatation of veins in vitro. CONCLUSION: The results indicate that a low dose of sumatriptan has the potential to reduce a raised ICP. High doses of sumatriptan cause a further increase of ICP possibly by dilatation of intracerebral veins.

Cerebral vasoconstriction by indomethacin in intracranial hypertension. An experimental investigation in pigs.

BACKGROUND: Uncontrolled increase in intracranial pressure is the most significant cause of mortality in patients with severe traumatic brain lesions, and the efficacy of common non-surgical treatments has been questioned. Pharmacologically induced cerebral vasoconstriction aiming at a decrease of cerebral blood volume and brain edema has recently been suggested as an alternative. Limited clinical experience with indomethacin as a cerebral vasoconstrictor has been reported but dose- or concentration-effect relationships were not investigated. In particular, there is a lack of data showing whether a therapeutic window exists in which risk of cerebral ischemia is minimized. METHODS: In a porcine model of intracranial hypertension induced with two epidural balloons to a level of 26-28 mmHg, 18 animals were randomized into three groups receiving 0.1, 0.3, and 3.0 mg.kg-1.h-1 indomethacin, respectively, as an infusion during 80 min. Intracranial pressure, mean arterial blood pressure, and electrocortical activity were recorded continuously and measurements of cerebral blood flow, arteriovenous difference in oxygen content and cerebral venous pH were performed at 5, 20, 40, 60, and 75 min during and 10 min after the indomethacin infusion. Baseline measurements, performed before the indomethacin infusion, were used as an internal control. The infusions were pharmacokinetically designed to mimic the reported clinical conditions. RESULTS: An 11% mean decrease in intracranial pressure during the infusion, but no effects on cerebral blood flow, arteriovenous difference in oxygen content, venous pH, and electrocortical activity were observed in the group of animals receiving 0.1 mg.kg-1.h-1. When the rate of infusion was 0.3 and 3.0 mg.kg-1.h-1, the decrease in intracranial pressure was 20 and 25%, respectively, but this was accompanied by a decrease in cerebral blood flow and venous pH, an increase in arteriovenous difference in oxygen content, and a slowing of the electrocortical activity. All changes were statistically significant. CONCLUSIONS: Indomethacin, which is known to constrict precapillary resistance vessels, caused a decrease in intracranial pressure during experimental intracranial hypertension. This was accompanied by signs of cerebral ischemia when indomethacin was used in a dose that has previously been suggested for the treatment of increased intracranial pressure in patients.

Effects of dihydroergotamine on cerebral circulation during experimental intracranial hypertension.

Different cerebral vasoconstrictors have recently been suggested for the treatment of raised intracranial pressure (ICP), in patients with severe traumatic brain lesions. Such treatment may be associated with severe side effects. A porcine model simulating an intracranial mass lesion was utilized to examine the haemodynamic cerebral effects of dihydroergotamine (DHE), a recently introduced pharmacological treatment for raised intracranial pressure. Intracranial hypertension was induced by inflation of two tonometric gastric balloons placed extradurally covering the parieto-occipital region bilaterally. The animals were randomized into one group with six animals receiving 1.0 mg of DHE i.v. followed by a continuous infusion of 0.2 mg/h (high dose) and another group of six animals receiving 0.15 mg i.v. followed by 0.03 mg/h (low dose). Measurements of cerebral blood flow (CBF) and arterio-venous difference in oxygen content (CaVO2) were performed by 5, 20 and 60 min after the DHE infusion. Intracranial pressure (ICP), mean arterial blood pressure (MAP) and cerebral electrical activity (EEG) were recorded continuously. In both groups infusion of DHE caused a lasting decrease in ICP probably achieved mainly by a decrease in cerebral blood volume due to constriction of both arterial and venous capacitance vessels. In the group treated with high-dose DHE, but not in that given low-dose DHE, a progressive increase in CaVO2, a fall in jugular venous pH and an increase in EEG delta activity were observed indicating cerebral hypoxia. The study supports the view that DHE may be a valuable tool in the pharmacological treatment of increased ICP in traumatic brain lesions but underscores the importance of a proper dosage.

Cerebral haemodynamic effects of dihydroergotamine in patients with severe traumatic brain lesions.

Dihydroergotamine (DHE) is used in our recently introduced therapy of post-traumatic brain oedema and is suggested to reduce ICP through reduction in both cerebral blood volume and brain water content. This study aims at increasing our knowledge of the mechanisms behind the ICP reducing effect of DHE by analysing cerebrovascular effects of a bolus dose of DHE in severely head injured patients (GCS < 8). Mean hemispheric cerebral blood flow (CBF) calculated from the clearance of i.v. 133Xenon, ICP, and cerebral arterio-venous difference in oxygen content (AVDO2), were measured before and after hyperventilation and after a bolus dose of DHE (4 micrograms/kg). The patients were divided into two groups, one with preserved and one with impaired cerebrovascular CO2-reactivity to hyperventilation, the latter being predictive of poor outcome. The haemodynamic effects of DHE were compared to those of hyperventilation. Regional CBF and brain volume SPECT measurements were performed in two patients. DHE increased cerebrovascular resistance (CVR) by about 20% and significantly reduced ICP in both groups of patients, resulting in unchanged AVDO2. Hyperventilation with preserved CO2-reactivity caused a similar decrease in ICP as by DHE but with a much larger increase in CVR (by 70%) and a substantial increase in AVDO2. Hyperventilation with impaired CO2-reactivity reduced ICP but otherwise had no significant cerebrovascular effects. The study supports the concept that the ICP reducing effect of DHE results more from constriction of the large veins than from arterial vasoconstriction, also implying a relatively smaller risk of ischaemia with DHE than with hyperventilation.

A porcine model for evaluation of cerebral haemodynamics and metabolism during increased intracranial pressure.

In patients with severe head injuries raised intracranial pressure (ICP) constitutes the most important cause of mortality. Several new therapies for increased ICP have recently been suggested and it is of importance to study the physiological effects of these treatments in animal experiments during steady state conditions. A porcine model for evaluation of cerebral haemodynamics and metabolism during increased ICP is presented. Intracranial hypertension was induced by inflation of two tonometric gastric balloons placed extradurally covering a major part of the parietooccipital region bilaterally. The distribution of the blood flow supplied by the carotid artery used for the cerebral blood flow (CBF) measurements was studied by intraarterial (i.a.) injection of 99mTc-HMPAO. The measurements showed that following ligation of the external carotid and the occipital artery no accumulation of tracer substance occurred in extracranial tissues during normal or increased ICP. Cerebral physiological variables (CBF, Cavo2, and ICP) were measured 5, 20 and 60 min after induction of intracranial hypertension. The results confirm that the experimental situation gives a reproducible increase in ICP (25-28 mm Hg) and that the physiological variables remain stable during the period of intracranial hypertension. We conclude that the model simulates the effects of an acute intracranial focal mass and is well suited for the evaluation of different pharmacological therapies of increased ICP.

Effects of hypotensive treatment with alpha 2-agonist and beta 1-antagonist on cerebral haemodynamics in severely head injured patients.

Therapy of post-traumatic brain oedema often includes preservation of high arterial blood pressure to avoid secondary ischaemic injuries to the brain. This practice can be questioned since high arterial blood pressure may aggravate brain oedema through raised hydrostatic capillary pressure, causing fluid filtration across the damaged blood-brain barrier. This latter view is in agreement with our clinical experience and therefore hypotensive therapy with an alpha 2-adrenergic agonist (clonidine) and a beta 1-adrenergic antagonist (metoprolol) has become part of our treatment protocol for severely head injured patients to decrease the post-traumatic brain oedema. The present study is an attempt to analyse whether there are any direct local cerebrovascular effects of the hypotensive agents used, which also might influence intracranial pressure. Severely head injured patients were investigated. Heart rate, mean arterial blood pressure, intracranial pressure, cerebral blood flow and arteriovenous difference in oxygen content were measured before and after a bolus dose of clonidine (six patients) and metoprolol (nine patients). Clonidine decreased mean arterial blood pressure and cerebrovascular resistance without affecting other parameters measured. Metoprolol decreased heart rate and mean arterial pressure, but had no effect on the cerebrovascular parameters. The results show that clonidine and metoprolol have no, or only minor, direct influence on local cerebral haemodynamics in severely brain injured patients. This implies that if there is an intracranial pressure reducing effect of these drugs, as suggested, this must be due to other mechanisms, namely a reduction in capillary hydrostatic pressure secondary to decreased arterial blood pressure and heart rate.

Distribution of cerebral blood flow during anesthesia with isoflurane or halothane in humans.

BACKGROUND: Halothane and isoflurane have been shown to induce disparate effects on different brain structures in animals. In humans, various methods for measuring cerebral blood flow (CBF) have produced results compatible with a redistribution of CBF toward deep brain structures during isoflurane anesthesia in humans. This study was undertaken to examine the effects of halothane and isoflurance on the distribution of CBF. METHODS: Twenty ASA physical status patients (four groups, five in each) anesthetized with either isoflurane or halothane (1 MAC) during normo- or hypocapnia (PaCO2 5.6 or 4.2 kPa (42 or 32 mmHg)) were investigated with a two-dimensional CBF measurement (CBFxenon, intravenous 133xenon washout technique) and a three-dimensional method for measurement of the regional CBF (rCBF) distribution with single photon emission computer-aided tomography (SPECT; 99mTc-HMPAO). In the presentation of SPECT data, the mean CBF of the brain was defined as 100%, and all relative flow values are related to this value. RESULTS: The mean CBFxenon level was significantly influenced by the PaCO2 as well as by the anesthetic used. At normocapnia, patients anesthetized with halothane had a mean CBFxenon of 40 +/- 3 (SE) ISI units. With isoflurane, the flow was significantly (P < 0.01, 33 +/- 3 ISI units) less than with halothane. Hypocapnia decreased mean CBFxenon (P < 0.0001) during both anesthetics (halothane 24 +/- 3, isoflurane 13 +/- 2 ISI units). The effects on CBFxenon, between the anesthetics, differed significantly (P < 0.01) also during hypocapnia. There were significant differences in rCBF distribution measured between the two anesthetics (P < 0.05). During isoflurane anesthesia, there was a relative increase in flow values in subcortical regions (thalamus and basal ganglia) to 10-15%, and in pons to 7-10% above average. Halothane, in contrast, induced the highest relative flow levels in the occipital lobes, which increased by approximately 10% above average. The rCBF level was increased approximately 10% in cerebellum with both anesthetics. Changes in PaCO2 did not alter the rCBF distribution significantly. CONCLUSIONS: There is a difference in the human rCBF distribution between halothane and isoflurane with higher relative flows in subcortical regions during isoflurane anesthesia. However, despite this redistribution, isoflurane anesthesia resulted in a lower mean CBFxenon than did anesthesia with halothane.

The effect of thiopental on cerebral blood flow, and its relation to plasma concentration, during simulated induction of anaesthesia in a porcine model.

The reversible effect of an induction dose of thiopental on the cerebral blood flow (CBF) was characterized by repeated 133Xe washout measurements during stable physiological conditions in anaesthetized pigs. A thiopental effect corresponding to induction of light and transient anaesthesia was confirmed by electroencephalography (EEG). The concentration (arterial plasma) -effect (-% CBF) relationship of thiopental was estimated using a sigmoidal Emax model. The injection caused a rapid 36 +/- 4.5% (mean +/- s.d.) drop in CBF, with return to baseline by 80 min. According to the pharmacodynamic model, the maximal effect of thiopental (Emax) in this experimental set-up was a 58% lowering of the CBF and the concentration at half-maximal effect (EC50) was 25 micrograms.ml-1. This study provides a complete characterization of the effect of thiopental on the CBF, including the time-course and concentration-effect relationship. A comparison to limited data in the literature suggests that the findings in the pigs constitute a fair approximation of the action of thiopental during the clinical induction of anaesthesia.

Influence of halothane and isoflurane on the contractile responses to potassium and prostaglandin F2 alpha in isolated human pial arteries.

Volatile anaesthetics may modulate cerebrovascular resistance, but their direct actions on human cerebral arteries are unknown. In the present study, we have evaluated the effects of halothane and isoflurane at different MAC (0.4, 1.0 and 2.0) on contractions induced by depolarization (potassium) or receptor stimulation (prostaglandin F2 alpha) in isolated ring segments of human pial arteries. Neither halothane nor isoflurane had significant effects on potency (unaffected EC50 value) or the maximum response (Emax) in potassium-contracted arteries, even though there was a general tendency to attenuation of Emax. Similarly, the potency of prostaglandin F2 alpha was unchanged (unaffected EC50 value). However, the Emax value for prostaglandin F2 alpha at normocapnia (mean PCO2 4.3 (SEM 0.1) kPa, pH 7.41 (0.01)) and addition of halothane (0.4, 1.0 and 2.0 MAC) was significantly attenuated to 96 (2)%, 91 (3)% and 84 (4)% at the respective MAC concentrations. Isoflurane at 2 MAC and normocapnia also reduced Emax to 94 (3)%. During hypocapnia (PCO2 2.7 (0.1) kPa, pH 7.64 (0.01)), the vasodilator effect of halothane was reduced, whereas isoflurane at 0.4 and 1.0 MAC enhanced the contraction induced by prostaglandin F2 alpha.

Low-dose midazolam antagonizes cerebral metabolic stimulation by ketamine in the pig.

In order to test the hypothesis that low-dose midazolam reduces excitatory cerebral symptoms by attenuating ketamine-induced increases in the cerebral metabolic rate for oxygen (CMRO2), we compared the cerebral effects of a combination of an anesthetic dose of ketamine hydrochloride (10.0 mg.kg-1 i.v.) and a subanaesthetic dose of midazolam maleate (0.25 mg.kg-1 i.v., n = 6; or 0.10 mg.kg-1 i.v., n = 6) with results recently obtained with ketamine (10.0 mg.kg-1 i.v.) in normoventilated pigs anaesthetized with fentanyl, nitrous oxide and pancuronium. Cerebral blood flow (CBF) was measured with the intra-arterial 133Xe clearance technique, and CMRo2 was calculated from CBF and the cerebral arteriovenous oxygen content difference (CaVO2). The CMRO2 did not increase significantly. In contrast, the maximal increase in cerebral CaVo2 (by 56-59% at 10 min; P < 0.01) was similar to that induced by ketamine, since CBF was more depressed (by 35-45% at 1 min: P < 0.001) by ketamine-midazolam than by ketamine only. Midazolam was found to increase CVR (P < 0.01) and further depress CBF (P < 0.01), and to antagonize the ketamine-induced increase in CMRO2 (P < 0.05). Ketamine-induced effects on mean arterial pressure (MAP) and spectral electroencephalographic (EEG) voltage were not significantly altered by midazolam. The pharmacokinetics of ketamine, as measured during an 80-min period, were not affected by the concomitant administration of midazolam. We propose that a ketamine-midazolam combination comprising a low-dose fraction (1/100-1/40) of midazolam is superior to ketamine alone for anaesthetic use.

Cerebral pharmacodynamics of anaesthetic and subanaesthetic doses of ketamine in the normoventilated pig.

There are still divergent opinions regarding the pharmacodynamic effects of ketamine on the brain. In this study, the cerebral blood flow (CBF), cerebral metabolic rate for oxygen (CMRO2) and electroencephalographic (EEG) activity were sequentially assessed over 80 min in 17 normoventilated pigs following rapid i.v. infusions of anaesthetic (10.0 mg.kg-1; n = 7) or subanaesthetic (2.0 mg.kg-1; n = 7) doses of ketamine or of its major metabolite norketamine (10.0 mg.kg-1; n = 3). The animals were continuously anaesthetized with fentanyl, nitrous oxide and pancuronium. CBF was determined by the intra-arterial 133Xe technique. Ketamine (10.0 mg.kg-1) induced an instant, gradually reverting decrease in CBF, amounting to -26% (P < 0.01) at 1 min and -13% (P < 0.05) at 10 min, a delayed increase in CMRO2 by 42% (P < 0.01) at 10 min and a sustained rise in low- and intermediate-frequency EEG voltage by 87% at 1 and 97% at 10 min (P < 0.0001). It is concluded that metabolically formed norketamine does not contribute to these effects. Considering the dissociation of CBF from CMRO2 found 10-20 min after ketamine (10.0 mg.kg-1) administration, it is suggested that ketamine should be used with caution for anaesthesia in patients with suspected cerebral ischaemia in order not to increase the vulnerability of brain tissue to hypoxic injury. Ketamine (2.0 mg.kg-1) had no significant effects on CBF, CMRO2 or EEG. It therefore seems that up to one fifth of the minimal anaesthetic i.v. dose can be used safely for analgesia, provided that normocapnaemia is preserved.

Cerebral blood flow during carotid endarterectomy determined by three dimensional SPECT measurement; relation to preoperative risk assessment.

Cross-clamping of the carotid artery during carotid endarterectomy implies a risk of developing an ischaemic insult. To evaluate the effects of carotid artery occlusion on cerebral blood flow (CBF), both hemispheric and regional CBF (rCBF) were investigated using intravenously (i.v.) administered 133Xenon with 3 min clearance recording time for two-dimensionally (hemispheric CBF) and 99m-technetium-hexamethylpropylene amine oxime (99mTC-HMPAO) for three-dimensionally single photon emission computed tomography (SPECT) measurements (rCBF). Thirteen patients scheduled to undergo carotid endarterectomy anaesthetised with fentanyl/isoflurane participated in the study. Preoperative evaluation included investigation of rCBF with SPECT in all participants. Two intraoperative 133Xe CBF measurements were performed in each patient, before and after occlusion of the carotid artery. The preoperative rCBF measurement constituted the reference, for technical reasons, for the intraoperative investigations of rCBF during cross-clamping, which was completed immediately after the hemispheric measurements. The increase in preoperative risk evaluation as described by Sundt et al. and modified by Cho et al. corresponded excellently to a decrease in hemispheric CBF due to cross-clamping. A significant decrease in rCBF (p < 0.005) was present between patients with high and low preoperative risk score for the region of the middle cerebral artery. In this region, a correlation between decrease in rCBF and corresponding decrease in hemispheric CBF was also present. The present study demonstrates that the vascular regions of the ipsilateral middle cerebral artery are the most vulnerable vascular area during cross-clamping in individuals with high preoperative risk score.(ABSTRACT TRUNCATED AT 250 WORDS)

Cerebral haemodynamic and electrocortical CO2 reactivity in pigs anaesthetized with fentanyl, nitrous oxide and pancuronium.

Cerebral haemodynamic, metabolic and electrocortical reactivity to alterations in arterial CO2 tension (PaCO2) was assessed in seven mechanically ventilated juvenile pigs to test an experimental model designed for cerebral pharmacodynamic and pharmacokinetic studies. The animals were anaesthetized with fentanyl, nitrous oxide and pancuronium and sequentially normo- and hyperventilated over a 100-min period. Five measurements were made at 25-min intervals. The cerebral blood flow (CBF) was measured with the intra-arterial 133Xe technique and the cerebral metabolic rate for oxygen (CMRO2) determined from CBF and the cerebral arteriovenous oxygen content difference. A linear correlation (r = 0.845) was found between CBF and PaCO2. The cerebrovascular reactivity to hypocapnia (delta CBF/delta PaCO2) was maintained throughout the experimental period and amounted to (95% confidence interval) 9.1 (7.1-11.1) ml x 100 g-1 x min-1 x kPa-1 within the PaCO2 range 3.3-6.3 kPa. The CMRO2 was not influenced by hyperventilation. The baseline electroencephalographic (EEG) pattern was stable at normocapnia (mean PaCO2 5.6 kPa), whereas spectral values for delta and total average voltage increased significantly (P < 0.05) at extensive hypocapnia (3.5 kPa). Maintenance of cerebral CO2 reactivity and spectral EEG voltage at a stable plasma level of fentanyl is complementary to the cerebral haemodynamic and metabolic stability previously found at sustained normocapnia in this model.

Ketamine and midazolam decrease cerebral blood flow and consequently their own rate of transport to the brain: an application of mass balance pharmacokinetics with a changing regional blood flow.

Mass balance pharmacokinetics, with simultaneous blood sampling from an artery and the internal jugular vein, was used to characterize the cerebral uptake of ketamine, norketamine, and midazolam in normoventilated pigs. Intravenous injections of ketamine or midazolam decreased the cerebral blood flow (CBF) by one third, as measured by intermittent 133Xe washout. By means of pharmacodynamic models, the effects on the CBF could be predicted from the arterial drug concentrations. The high-resolution CBF vs. time curves thus generated allowed the calculation of cerebral drug levels from arterio-venous concentration gradients in spite of a continuously changing regional blood flow. By their effects on the CBF, ketamine and midazolam decrease their own rate of transport to the brain, the immediate 30-35% drops in CBF giving similar reductions in initial net influx of drug. Physiological pharmacokinetic models assuming a constant regional blood flow are therefore not appropriate. Under clinical conditions, the CBF is determined mainly by the effects of the anesthetics and by the arterial CO2 tension. CBF changes in either direction influence the transport of drugs to the brain and may consequently result in impaired or exaggerated drug effects.

Modulation by carbon dioxide and pH of the contractile responses to potassium and prostaglandin F2 alpha in isolated human pial arteries.

Variation of PCO2 with concomitant changes in extracellular pH (pHo) may modulate cerebrovascular resistance, but the direct actions of carbon dioxide and pHo on human cerebral arteries are unknown. In this study, we have evaluated the effects of different carbon dioxide tensions (2.7, 4.2 and 7.2 kPa) with either fixed (pHo = 7.44) or concomitant changes in pHo, on contractions induced by depolarization (potassium) or receptor stimulation (prostaglandin F2 alpha) in isolated human pial arteries. Isolated changes in PCO2 had no significant effect on either potency (unchanged EC50 value) or the maximum response (Emax) in potassium-contracted arteries. Hypercapnia with uncompensated pHo significantly decreased both EC50 and Emax values, whereas uncompensated hypocapnia significantly increased the EC50 value without any effect on Emax. Concentration-response curves induced by prostaglandin (PG) F2 alpha were shifted significantly to the right (increased EC50 = decreased potency) during both hypo- and hypercapnia, independent of changes in pHo. The maximal responses were enhanced significantly during hypocapnia (Emax = 110 (SEM 2)%), but this enhancement was converted into a slight attenuation when pHo was compensated (Emax = 92 (4)%). Hypercapnia, with or without compensation of pHo, decreased the Emax values to 69 (16)% and 73 (9)%, respectively. We conclude that hypocapnia increases contractility in human pial arteries--an effect which is reversed by compensation of pHo. In contrast, the hypercapnic decrease of PGF2 alpha-induced contractions appears to be independent of pHo. The results confirm a relationship between contractility and pHo, but do not exclude a direct action of carbon dioxide in receptor-stimulated arteries.

A porcine model for sequential assessments of cerebral haemodynamics and metabolism.

We present a physiologically stable porcine model designed for sequential assessments of pharmacological effects on mean hemispheric cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMRO2) at sustained normocapnia. The dynamic influence of continuously administered fentanyl (0.040 mg.kg-1.h-1 i.v.), nitrous oxide (70%) and pancuronium (0.30 mg.kg-1.h-1 i.v.) on these variables was studied in eight normoventilated pigs. CBF was reliably assessable at 10-min intervals by clearance of intra-arterially injected 133Xe, monitored by an extracranial scintillation detector. CMRO2 was calculated from CBF and the simultaneously measured cerebral arteriovenous difference in blood oxygen content. The intracerebral distribution of a contrast medium injected into the external and internal carotid arteries was studied by angiography, and the cerebral venous outflow was investigated by measurements of the distribution of an intra-arterially administered non-diffusible tracer, [99mTc]pertechnetate, to the internal and external jugular veins. After a 3-h equilibration period, CBF and CMRO2 were determined on six occasions over a study period lasting 1 h 40 min. The mean ranges of these variables were 56-60 and 1.9-2.0 ml.100 g-1.min-1, respectively. We conclude that the model enables repeated assessments of CBF and CMRO2 under stable physiological background conditions and thus valid cerebral pharmacodynamic investigations of drugs given for anaesthesia.

Complications and side effects during thiopentone therapy in patients with severe head injuries.

This study reports all complications and side effects occurring in 38 patients with severe traumatic brain lesions treated with barbiturate coma because of a dangerous increase in intracranial pressure. The treatment was induced by intravenous infusion of thiopentone (5-11 mg.kg-1) followed by a continuous infusion of 4-8 mg.kg-1.h-1. The subsequent rate of thiopentone infusion was governed by the level of the intracranial pressure with the intention of keeping ICP below 20 mmHg (2.7 kPa). The duration of treatment was 1-15 days. Arterial hypotension occurred in 58%, hypokalemia in 82%, respiratory complications in 76%, infections in 55%, hepatic dysfunction in 87% and renal dysfunction in 47% of the patients. Twenty patients survived. Mortality in 17 patients was caused by an untreatable increase in intracranial pressure. In one patient complications due to barbiturate treatment may have contributed to the fatal outcome. In none of the other cases were the noted complications and side effects associated with any permanent symptoms or dysfunctions.

Human brain temperature during anesthesia for intracranial operations.

The intraventricular and rectal temperatures were registered in nine patients subjected to major surgery of the brain. Copper-constantan thermocouples were introduced into the lumen of an intraventricular catheter also used for perioperative monitoring of intracranial pressure. During anesthesia, the intraventricular temperature was higher than rectal temperature, the mean difference being 0.30 +/- 0.24 degrees C. No significant changes in intraventricular temperature were seen during different stages of the operations. It is concluded that during routine anesthesia rectal temperature can be relied on for a reasonable estimation of human brain temperature. It should be observed, however, that in the postoperative period, both rectal and intraventricular temperature rose considerably. In three patients, the intraventricular temperature rose as much as 2.5-4 degrees C, thus increasing the temperature gradient between rectum and brain. The relevance of these findings are discussed.

Oxygen modulates contractile responses to potassium and prostaglandin F2 alpha in human pial arteries.

Oxygen may modulate cerebrovascular resistance, but its direct influence on human pial arteries is unknown. We have investigated the effects of varying oxygen tension (73, 30 and 8 kPa) in depolarized (potassium) and receptor stimulated (prostaglandin F2 alpha) isolated human pial arteries. Control responses were obtained at an oxygen tension of 30 kPa. Contractions induced by prostaglandin F2 alpha and potassium showed no significant difference in potency (unaffected EC50 values) at the different oxygen concentrations. In contrast, the maximum contractions (Emax) were dependent on the oxygen tension. Potassium-induced contractions were enhanced (Emax = 107 (SE 3)% of control contractions (P less than or equal to 0.01)) at an oxygen tension of 73 kPa, whereas a reduction in tension to 8 kPa had no significant effect (97 (2)%). Prostaglandin F2 alpha-induced contractions were enhanced at 73 kPa (115 (6)%) (P = 0.02) and depressed at 8 kPa (96 (2)%) (P = 0.02). Reduction in oxygen tension induced a relaxation in depolarized and in receptor stimulated arteries, regardless of whether or not oxygen was replaced by nitrogen or by helium. Low oxygen tension relaxed arteries despite pretreatment with 2,4-dinitrophenol, an agent which blocks oxidative phosphorylation. It is concluded that a reduction in oxygen tension exerted a direct, although small, depressant effect on human pial arteries, and that this effect was not mediated exclusively by hyperpolarization or by inhibition of oxidative phosphorylation.