EFFECTS OF ALTHESIN ON CEREBRAL BLOOD FLOW AND OXYGEN CONSUMPTION IN MAN

Cerebral circulation and metabolism during Althesin anaesthesiawere studied in seven healthy patients. Althesin was given ina single dose of 0.1 ml/kg and thereafter infused at a constantrate of 0.3 ml/kg/h. During Althesin infusion, the cerebralblood flow (CBF), the cerebral metabolic rate for oxygen (CMRo₂)were 29 ±10 ml/100 g/min and 1.7 ± 0.4 ml/100g/min, respectively. These values were significantly differentfrom those obtained in awake subjects in our laboratory (CBF:46±7 ml/100 g/min; CMRo₂: 3.1 ±0.6 ml/100 g/min).During CBF measurement, the mean cerebral perfusion pressure,cerebral vascular resistance (CVR) and arterial carbon dioxidetension (Pa_CO2) were 89±16mmHg,3.4±1.3 mm Hg/ml/100g/min, and 36±9mmHg, respectively. The relationship betweenCBF and .Pa_CO2 was studied and it was found that during Althesinanaesthesia reactivity of cerebral vessels to the alterationof Pa_CO2 was maintained. It is concluded that Althesin causedcerebral metabolic depression which was accompanied by a decreasein CBF and an increase in CVR.     

EFFECTS OF A DIAZEPAM-FENTANYL MIXTURE ON CEREBRAL BLOOD FLOW AND OXYGEN CONSUMPTION IN MAN

The effects of a mixture of diazepam and fentanyl on cerebralblood flow (c.b.f.) and cerebral metabolism of oxygen (CMRo₂)were studied in eight normal subjects and 13 patients with organicbrain disease. The coupling of flow and metabolism and the carbondioxide responsiveness of the c.b.f. were studied also. In thenormal subjects the injection of the mixture resulted in a significantdecrease in c.b.f. (34%), and a similar decrease in CMRo₂ (34.5%).The vasoreactivity of the brain to carbon dioxide was maintained.C.b.f. decreased in all patients with intracranial pathology.     

MYOCARDIAL BLOOD FLOW AND OXYGEN CONSUMPTION DURING HALOTHANE-NITROUS OXIDE ANAESTHESIA FOR CORONARY REVASCULARIZATION

The effects of halothane on myocardial blood flow and myocardialoxygen balance were studied in seven male patients with stableangina and normal left ventricular function. Patients were receivingmaintenance doses of ß-receptor antagonists and underwentcoronary artery bypass surgery. Anaesthesia consisted of halothaneand 50% nitrous oxide in oxygen. Halothane decreased myocardialblood flow and myocardial oxygen consumption by 29% and 32%,respectively, after induction of anaesthesia, and during sternotomy.Myocardial lnctatc production was not observed at any time.Cardiac index, stroke volume index, mean arterial pressure andmean diastolic arterial pressure were decreased significantlyafter induction of anaesthesia and during sternotomy. Heartrate remained unchanged. The global myocardial oxygen supplyand demand relationship was maintained. The results suggestthat halothane is a safe anaesthetic for coronary revascularizationin patients with unimpaired left ventricular function.     

EFFECT OF KETANSERIN ON GLOBAL CEREBRAL BLOOD FLOW AND CEREBRAL OXYGEN METABOLISM DURING MIDAZOLAM-FENTANYL OR ISOFLURANE ANAESTHESIA

We have studied the effect of ketanserin on cerebral blood flow(CBF), cerebral oxygen metabolism (CMRO₂) and cerebrovascularcarbon dioxide reactivity in 19 adult patients undergoing lumbardisc operation – 10 during midazolam-fentanyl anaesthesia(group A) and nine during isoflurane anaesthesia (group B).Measurements were made in each patient whilst awake, duringanaesthesia, during anaesthesia with ketanserin and during anaesthesiawith ketanserin and hyperventilation. CBF was measured by thei. v. xenon-133 technique. CMRO₂ was calculated as the productof CBF and the cerebral arterio-venous oxygen content difference.In the awake state, CBF was 52 and 51 ml/100g min_–1 andCMRo₂ 3.8 and 3.5 ml/100 g min_–1 in groups A and B, respectively.After induction of anaesthesia, CBF decreased 37% in group Aand 22% in group B (P < 0.05); CMRo₂ decreased 26% in groupA and 51% in group B (P < 0.05). Adding ketanserin did notchange CBF or CMRo₂ in either group. The carbon dioxide reactivityof the cerebral vessels during anaesthesia with ketanserin was15.4%kPa^–1 in group A and 24%kPa^–1 in group B. Weconcluded that ketanserin, in a clinically recommended dose,administered during midazolam-fentanyl or isoflurane anaesthesiahad no effect on global CBF, CMRo₂ or the relationship betweenthe two factors. Cerebrovascular carbon dioxide reactivity waspreserved.     

EFFECTS OF NIMODIPINE ON CEREBRAL BLOOD FLOW AND NEUROPSYCHOLOGICAL OUTCOME AFTER CARDIAC SURGERY

Thirty-five patients undergoing cardiac surgery requiring cardiopulmonarybypass (CPB) were allocated randomly in a prospective double-blindstudy to receive either nimodipine 0.5 µg kg^–1 min^–1or placebo. Cerebral blood flow (CBF) was measured during andimmediately after CPB. Neuropsychological tests were performed6 months after surgery to determine any relationship betweenischaemic damage and CBF and administration of nimodipine. Therewere no differences in CBF between the nimodipine (n = 18) andplacebo groups (n = 17). Significant changes in neuropsychologicaltests were found in six patients tested 6 months after surgerybut there were no conclusive signs of ischaemic damage. Thenimodipine-treated group performed better in tests of verbalfluency and visual retention, suggesting that some memory functionswere preserved better in this group.     

EFFECTS OF ENFLURANE AND HALOTHANE ON LIVER BLOOD FLOW AND OXYGEN CONSUMPTION IN THE GREYHOUND

The effect of increasing inspired concentrations of halothane0.5, 1.0, 1.5, 2.0% and cdurane 1.0, 1.5, 2.0, 3.0% on the hepaticcirculation, were investigated in two groups of anasthetizedgreyhounds. Hepatic arterial a d portal venous blood flow weremeasured continuously using electromagnetic flow probes. Meanarterial pressure and cardiac output were monitored throughouteach investigation. At equiptent anaesthetic concentrationsthere were similar and dose-dependcnt decreases in hepatic arterial,portal venous and total liver blood flows in b t h groups. Enfluraneproduced a more marked decrease in mean arterial pressure thanhalothane because of a significant decrease in systemic vascularresistance. Hepatic arterial resistance decreased significantlywith enflurane but was unchanged in the group receiving halothane.Nather drug affected hepatic oxygen consumption significandy.     

EFFECT OF INCREASED CONCENTRATIONS OF CARBON DIOXIDE DURING HALOTHANE ANAESTHESIA ON LIVER BLOOD FLOW AND HEPATIC OXYGEN CONSUMPTION

The effects of hypercapnia (during halothane anaesthesia) onthe hepatic circulation and hepatic oxygen consumption wereinvestigated in anaesthetized greyhounds. The administrationof 1% halothane alone caused significant decreases in both hepaticarterial and portal venous blood flows. Hepatic oxygen consumptiondid not change significantly. When carbon dioxide was addedto the inspired gas mixture during the continued administrationof halothane, hepatic arterial blood flow showed a further decrease(P< 0.01), while portal venous flow increased markedly. Thisresulted in an overall increase in total liver blood flow. Hepaticoxygen supply increased also. However, hepatic oxygen consumptionincreased during the periods of hypercapnia. Thus, althoughthe hypercapnia increased the oxygen supply to the liver, therewas no improvement in the supply: demand ratio. ^*Present address: Department of Anaesthesia, Stobhill Hospital,Glasgow     

A SHEEP PREPARATION FOR STUDYING INTERACTIONS BETWEEN BLOOD FLOW AND DRUG DISPOSITION: III: EFFECTS OF GENERAL AND SPINAL ANAESTHESIA ON REGIONAL BLOOD FLOW AND OXYGEN TENSIONS

In awake unrestrained sheep the infusions i.v. of five drugs(cefoxitin, pethidine, chlormethiazole, tocainide and lignocaine)with potentially flow-limited clearance were shown to have nosignificant haemodynamic effects of their own, nor to have anyeffects on arterial or venous oxygen tensions. Under generalanaesthesia (1.5% end-tidal halothane), haemodynamic changessimilar to those previously documented in man occurred. Cardiacoutput and hepatic blood flow were decreased to 70%, and renalblood flow to 50% of control vahies; heart rate was unchangedand mean arterial pressure decreased by an average of 10%. Hepaticand renal vein oxygen tensions were decreased significantly.Under spinal anaesthesia, apart from a 10% decrease in hepaticblood flow, there were no significant changes in any haemodynamicvariables or in the arterial or in any of the venous oxygentensions. The i.v. infusion of adequate volumes of saline atthe time of blockade probably contributed to the maintenanceof these indices at their baseline values     

THE EFFECTS OF CLINICAL CONCENTRATIONS OF HALOTHANE ON THE BLOOD FLOW AND OXYGEN UPTAKE OF THE CEREBRAL CORTEX

Clinical concentrations of halothane vaporized in nitrous oxide-oxygencaused vasodilatation in the cerebral cortex of anaesthetizeddogs at constant arterial carbon dioxide tension. The vasodilatoryaction on the cerebral circulation was greater the higher theconcentration of halothane. Consequently 2 per cent halothaneincreased blood flow through the cerebral cortex more than did0.5 per cent halothane. However, the administration of 4 percent halothane reduced mean blood pressure so markedly thatblood flow was not elevated above the control value. The oxygenuptake of the cerebral cortex was depressed by halothane andthis depression was greater with 2 per cent halothane than with0.5 per cent. These results are discussed with reference tothe effects of halothane on intracranial pressure and on theoxygenation of the brain.     

EFFECTS OF NITROUS OXIDE AND VOLATILE ANAESTHETICS ON CEREBRAL BLOOD FLOW

Nitrous oxide and halogenated anaesthetic agents are often administeredconcurrently during neuroanaesthesia. To assess the interactiveeffects of these agents on cerebral blood flow (CBF), we havemeasured CBF by ¹⁴C-iodoantipyrine autoradiography, in normocapnicrats receiving either 0.5 or 1.0 MAC of volatile agent alone(halothane or isoflurane) or 0.5 MAC of volatile agent+0.5 MACnitrous oxide. CBF (global and regional) was significantly greaterat 1.0 MAC compared with 0.5 MAC, regardless of how 1.0 MACwas achieved (agent alone or agent+nitrous oxide) (P < 0.05).The addition of 0.5 MAC nitrous oxide to 0.5 MAC halothane resultedin flows similar to those produced by 1.0 MAC halothane alone.In contrast, the addition of nitrous oxide to 0.5 MAC isofluraneresulated in flow values significantly greater than those measuredduring 1.0 MAC isoflurane alone. We conclude that the use ofnitrous oxide, as opposed to an increased dose of volatile agent,has no advantage in respect of minimizing anaesthetic-inducedincreases in cerebral blood flow.     

EFFECT OF HYPERCARBIA ON HEPATIC BLOOD FLOW AND OXYGEN CONSUMPTION IN THE GREYHOUND

The stability of a technique for measuring hepatic blood flowand oxygen consumption was established in six greyhounds anaesthetizedwith pentobarbitone (group A). Subsequently, the effects ofincreased Pa_CO2 were studied in another six animals (group B).With one exception (splenic blood flow) no significant changeswere observed in any of the indices measured in group A. Ingroup B, although hepatic arterial blood flow (HABF) decreasedwhen Pa_CO2 increased, both portal venous blood flow (PVBF) andtotal liver blood flow (HABF + PVBF) increased. However, thesechanges were much less marked after 20 min. Hepatic oxygen consumptionand splenic venous blood flow were unchanged with an increasein Pa_CO2     

PHARMACOKINETICS OF FLUMAZENIL AND MIDAZOLAM

.We have studied simultaneously the pharmaco-kinetics of flumazeniland midazolam in 12 healthy Chinese children, aged 5–9yr, undergoing circumcision. Two hours before operation eachpatient received midazolam 0.5 mg kg^-1 orally for pre-medicationand 0.5 mg kg^-1 i. v. during induction. Six minutes after cessationof anaesthesia, a bolus of flumazenil 10 ng kg^-1 was given i.v., followed by an infusion of flumazenil at 5 fig kg^-1 min^-1which was maintained until the child could identify himself.Midazolam data were consistent with a three-compartment modelwith a mean (SD) elimination half-life of 107 (30) min, totalbody clearance of 15.4 (3.2) ml min^-1 kg⁷ and apparent volumeof distribution at steady state of 1.9 (0.6) litre kg^-1. Flumazenildata were best interpreted by a mono-exponential function, witha mean terminal elimination half-life of 35.3 (13.8) min, atotal plasma clearance of 20.6 (6.9) ml minkg^-1 and apparentvolume of distribution at steady state of 1.0 (0.2) litre kg^-1.No unchange midazolam was detected in the 24-h urine sample,but 5.8–13.8% of the flumazenil dose was recovered unchanged.At the time of self identification, 4.5 (1.4) min after flumazeniladministration, the mean plasma concentrations of midazolamand flumazenil were 163.1 (43.7) and 29.9 (16.1) ngmt1, respectively.(Br. J. Anaesth. 1993; 70: 286–292)     

CEREBRAL BLOOD FLOW DURING HALOTHANE ANAESTHESIA

Cerebral blood flow has been measured in dogs using the methodof Lassen and Ingvar (1961), and Ingvar and Lassen (1962), whichinvolves measurement of the rate of clearance of krypton 85from an area of exposed cerebral cortex after injection intothe internal carotid artery. In every measurement during halothaneanaesthesia there was a considerable reduction in cerebral bloodflow compared with the flows obtained with nitrous oxide andoxygen. The average reduction in flow was 46 per cent and thiswas accompanied by an average increase in cerebrovascular resistanceof 50 per cent. Measurements were also made of the cerebraloxygen uptake (CMRO2) and halothane produced an average decreasein uptake of 49 per cent. Possible mechanisms for the observedresults are discussed.     

EFFECTS OF CERTAIN I.V. ANAESTHETICS ON LIVER BLOOD FLOW AND HEPATIC OXYGEN CONSUMPTION IN THE GREYHOUND

The effects of increasing concentrations of thiopentone, Althesinand etomidate on liver blood flow and hepatic oxygen consumptionwere investigated in the anaesthetized greyhound. All threeagents studied produced dose-related decreases in general cardiovascularindices such as mean arterial pressure, cardiac output and systemicvascularresistance; all three anaesthetics produced decreases in liverblood flow. During the low rates of infusion with Althesin andetomidate, significant decreases in hepatic arterial blood flowwere recorded at a time when the systemic circulation was notsignificantly affected. Indeed, during the low rates of infusionwith each of the three agents, hepatic arterial resistance andmesenteric vascular resistance increased by up to 40% abovebaseline values. During the high rates of infusion, hepaticarterial and mesenteric vascular resistances either returnedto or decreased below control values and the decreases in liverblood flow were a consequence of generalized cardiovasculardepression. Despite relatively unchanged hepatic oxygen consumption,all the anaesthetics produced significant decreases in the hepaticoxygen supply.     

EFFECTS OF DIAZEPAM AND MIDAZOLAM ON RECOVERY FROM ANAESTHESIA IN OUTPATIENTS

Sixty patients were randomly allocated in an open study to receiveeither midazolam or diazepam (Diazemuis) with fentanyl and etomidatefor induction and maintenance of anaesthesia during day-staygynaecological surgery. The excitatory effects of etomidatewere controlled by the benzodiazepine-fentanyl combination inboth groups. No significant difference in the quality of recovery(as judged by Trieger test analysis), amnesia, incidence ofrecall of pain on injection of etomidate or nausea and vomitingcould be demonstrated between the groups. There was a high degree(97%) of patient acceptance.     

CEREBRAL BLOOD FLOW AND METABOLISM DURING ETOMIDATE ANAESTHESIA IN MAN

The effects of etomidate on regional cerebral blood flow (rc.b.f.)and cerebral metabolic rate for oxygen (CMRo₂) were studiedin seven patients undergoing diagnostic carotid angiography.Following determination of baseline rc.b.f. while awake, thepatients were anaesthetized with a single dose of etomidate15 mg. Thereafter an infusion of etomidate (2 or 3 mg min–¹)was administered. Etomidate decreased both rc.b.f.₁₀ (mean decrease34%) and CMRo₂ (mean decrease 45%). It was concluded that etomidateis a potent cerebral metabolic depressant. Furthermore, thecerebrovascular reactivity to carbon dioxide was maintainedunder etomidate anaesthesia.     

EFFECTS OF FENTANYL, DROPERIDOL, AND INNOVAR ON CANINE CEREBRAL METABOLISM AND BLOOD FLOW

The effects of droperidol and fentanyl given individually andin combination (Innovar) on the rate of cerebral oxygen consumption(CMRo,) and cerebral blood flow (c.b.f.) were studied in dogsanaesthetized with nitrous oxide (70 percent) and oxygen. Fentanyl(0.006 mg/kg) decreased both the CMRo, and the c.b.f. (meandecreases at 15 minutes were 18 per cent and 47 percent, respectively).The duration of effect was approximately 30 minutes. Droperidol(0.3 mg/kg) produced a decrease of 40 per cent in c.b.f. dueprimarily to a 30-40 per cent increase in cerebrovascular resistance,and this effect persisted for the period of observation (60minutes). No significant change in CMRo, occurred after droperidolwas administered. With the combination drug (Innovar), the effectswere partially additive. After 15 minutes, CMRo, had decreased23 per cent; c.b.f. had decreased 50 per cent; and cerebralvascular resistance had increased 85 per cent. After 30 minutes,the effects of Innovar were indistinguishable from those ofdroperidol alone. No significant changes occurred in the rateof cerebral glucose consumption or the oxygen-glucose index.The effect of increased and decreased Paooj on c.bi. after Innovarwas compared widi that observed during halothane anaesthesia.With halothane, hypercapnia (Pacoi=60 tnm Hg) increased c.b.f.40 per cent and hypocapnia (Pace = 20 mm Hg) decreased c.b.f.40 per cent. Innovar at normocapnia reduced the c.b.f. 65 percent. With hypercapnia, the c.bi. doubled, but with hypocapnia,little further reduction in c.b.f. occurred. It is concludedthat droperidol is a potent cerebral vasoconstrictor, that thiseffect dominates when it is given in combination with fentanyl,that hypocapnia causes little further reduction in c.b.f., andthat the reduction in c.bi. produced by Innovar is not accompaniedby alterations in normal cerebral metabolic pathways     

HAEMODYNAMIC EFFECTS OF MIDAZOLAM AND THIOPENTONE DURING INDUCTION OF ANAESTHESIA FOR CORONARY ARTERY SURGERY

The cardiovascular effects of thiopentone 3 mgkg^–1 andmidazolam 0.3mgkg ^–1 were observed during inducuon ofanaesthesia in 16 premedicated patients about to undergo myocardialrevascularizanon. There were no significant changes in eithergroup in cardiac output or central venous pressure. The heartrate in both groups showed an increase at 3 nun and thereafterreturned to control values. After 3 min, there was a significantdecrease in both arterial pressure and peripheral resistanceby 12% and 15% (mean values) respectively from control valuesin the group receiving midazolam, whereas after thiopentonethe peripheral resistance increased by approximately 13% andwas not affected by a further dose of thiopentone 1 mg kg^–1.     

A SHEEP PREPARATION FOR STUDYING INTERACTIONS BETWEEN BLOOD FLOW AND DRUG DISPOSITION: VI: EFFECTS OF GENERAL OR SUBARACHNOID ANAESTHESIA ON BLOOD FLOW AND CHLORMETHIAZOLE DISPOSITION

Blood flow through and chlormethiazole extraction ratios acrosslungs, liver, kidneys and gut were measured in awake unrestrainedsheep (controls) and with the same animals anaesthetized with1.5% halothane or whilst undergoing high thoracic subarachnoidblockade with amethocaine. In the control-drug studies, chlormethiazoleinfused to sub-sedative blood concentrations produced no significantchanges in haemodynamics or in the kinetics of iodohippurate(renal and hepatic blood flows). Chlormethiazole was eliminatedpredominantly by the liver (mean extraction ratio and clearance,respectively, 0.90 and 1.3 litre min^–1) and lungs (0.15;0.6 litre min^–1). Renal clearance was absent or neglible(>0.1 litre min^–1). Because of pulmonary clearance,mean total body clearance was derived from analysis of pulmonaryarterial concentrations. Under general anaesthesia, there weresignificant reductions in mean cardiac output, hepatic and renalblood flow (to 54%, 63% and 43% of control); chlormethiazolemean hepatic extraction ratios and clearance were reduced, respectively,to 82% and 56% of control, and its pulmonary and renal clearanceswere abolished. With subarachnoid anaesthesia there were nosignificant changes in haemodynamics or in chlormethiazole extractionratios or clearances.     

ANTAGONISM OF THE HYPNOTIC EFFECT OF MIDAZOLAM IN CHILDREN: A RANDOMIZED, DOUBLEBLIND STUDY OF PLACEBO AND FLUMAZENIL ADMINISTERED AFTER MIDAZOLAM-INDUCED ANAESTHESIA

In a randomized, double-blind study, we administered placeboand flumazenil to 40 healthy Chinese boys, aged 3–12 yr,undergoing circumcision. The children received midazolam 0.5mg kg^–1 orally for premedication and 0.5 mg kg^–1i.v. during induction. After operation the patients were given0.1 ml kg^–1 of a blinded solution followed by 0.05 mlkg^–1 min^–1 until either they awoke or the 10-mlampoule of solution was empty. Efficacy of antagonism of midazolamwas assessed by times to eye opening and self identification,modified Steward coma scale, a post-box toy completion-timeratio and qualitatively by an independent observer. The differencebetween flumazenil and placebo was both clinically and statisticallydifferent in the first 2h. Children receiving flumazenil awokeapproximately four times faster and identified themselves nearlythree times sooner; 65% of this group could complete the post-boxtoy at 10 min, compared with none of the placebo group. Therewere no cases of resedation, but one child did not awaken for30 min after i.v. administration of flumazenil 1.0 mg. The meantotal dose of flumazenil administered was 0.024 (SD 0.019) mgkg^–1. Flumazenil rapidly antagonized midazolam-inducedhypnosis in children and was associated with minimal changein cardio-respiratory variables.