DISPOSITION OF ALFENTANIL IN BURNS PATIENTS

We have studied the disposition of alfentanil in six patients(who had suffered 10–30% surface area burns 5–21days previously) undergoing surgical debridement and graftingand compared the data with those from a control group of sixpatients matched for age, sex and weight undergoing body surfacesurgery of similar duration. Plasma samples were collected upto 480 min after an i. v. bolus of alfentanil 50 fig kg^–1.Drug concentrations were measured by radioimmunoassay and alfentanilbinding to plasma proteins by equilibrium dialysis. The burnspatients had significantly greater concentrations of alpha-1-acidglycoprotein (AAG) and smaller concentrations of albumin. Themean protein binding of alfentanil was 94.2 (SEM 0.05)% in theburns group and 90.7 (0.4)% in the control group (P = 0.004).There was a good correlation between AAG concentration and proteinbinding (r= 0.8). The volume of distribution and total clearanceof alfentanil were reduced significantly in the burns group.The clearance of the raction and the elimination half-life ofalfentanil were not decreased significantly. (Br. J. Anaesth.1992; 69: 447–450) ^*Present address: Department of Anaesthesia, Western Infirmary,Dumbarton Road, Glasgow Gil 6NT.     

EFFECTS OF INCREMENTAL DOSES OF ALFENTANIL AND PROPOFOL ON THE BREATHING OF ANAESTHETIZED PATIENTS

Incremental doses of alfentanil and propofol were given to anaesthetizedhealthy patients undergoing routine orthopaedic surgery. Ventilationwas recorded by respiratory inductance plethysmography and analysedby microcomputer. Alfentanil affected primarily expiratory time.The onset of effect lasted 82 s (range 25–173 s); offsetwas exponential, with a half-life of 146 s (range 62–260s). Alfentanil also reduced tidal volume, but the effect wasless obvious and less consistent. Propofol affected primarilytidal volume. The onset of effect lasted 34 s (range 17–69s); offset was linear, with a time to 50% recovery of 92 s (range47–161 s). Propofol had little effect on expiratory time.The drugs had little effect on inspiratory time. Three patientsshowed periods when the distribution of expiratory times wasbimodal; the mechanism for this is unknown.     

HEPATIC DISPOSITION OF METHOHEXITONE IN PATIENTS UNDERGOING CORONARY BYPASS SURGERY

In order to clarify the relative contribution of hepatic metabolismto the short term disposition of metho-hexitone, we have measuredhepatic blood flow during induction of anaesthesia with a 1.5-mgkg^–1 i. v. bolus dose of methohexitone. Median hepaticclearance was 1.01 litre min^–1 and hepatic extraction87%. As a consequence of the high hepatic extraction, the hepaticclearance of methohexitone was closely dependent on hepaticplasma flow. (Br. J. Anaesth. 1992; 69: 478–481)     

VENTILATORY EFFECTS OF MEPTAZINOL AND PETHIDINE IN ANAESTHETIZED PATIENTS

The ventiiatory effects of three doses of mep-tazinol (20 mg,30 mg and 48 mg) were studied in anaesthetized patients andcompared with those of pethidine 20 mg. Minute volume, tidalvolume, ventilatory frequency, inspiratory and expiratory timeswere measured and mean inspiratory flow rates calculated. Eachpatient received a first dose of drug which was followed after5 min by a second identical dose. After the first injectionthe ventilatory effects of meptazinol were dose-dependent andmeptazinol 20 mg had an effect similar to pethidine 20 mg. Followingrepeated injection the effects on ventilation were markedlydifferent between the drugs. Carbon dioxide retention and othercompensatory mechanisms attenuate the ventilatory depressionof meptazinol, but these may be inadequate in the anaesthetizedpatient.     

EFFECTS OF ALFENTANIL AND FENTANYL ON INDUCTION OF ANAESTHESIA IN PATIENTS WITH SEVERE PREGNANCY-INDUCED HYPERTENSION

Forty patients with severe pregnancy-induced hypertension presentingfor Caesarean section under general anaesthesia were allocatedrandomly to receive either fentanyl 2.5 µg kg^–1or alfentanil 10 µg kg^–1 as part of the anaestheticinduction sequence. In all patients, the cardiovascular responseto tracheal intubation was measured. Both drugs attenuated theresponse equally but did not abolish it in all patients. Alfentanil10 µg kg^–1 is a suitable alternative to fentanyl2.5 µg kg^–1 for patients with pregnancy-inducedhypertension.     

HEPATIC AND EXTRAHEPATIC DISPOSITION OF PROPOFOL IN PATIENTS UNDERGOING CORONARY BYPASS SURGERY

In order to clarify the relative contribution of the liver tothe short term disposition of propofol, hepatic blood flow wasmeasured during induction of anaesthesia with an i.v. bolusdose of propofol 2 mg kg^–1. Total clearance of the drugwas 2390 (SD 340) ml min^–1, hepatic extraction 82% andhepatic clearance 1060 (260) ml min^–1. During the 60-minperiod of observation, hepatic extraction of propofol increasedfrom 79% to 92%. It is concluded that, within 1 h, only 44%of the administered dose is removed by the liver. Consequently,drug accumulation may occur with repeated dosing or infusionof propofol. The increase in extraction results presumably fromslow release of propofol from the soy-bean emulsion. Results presented in part at the 29th Spring Meeting of theGerman Association of Pharmacology, March 8–11, Mainz,FRG. (Abstract (No. 490) in Naunyn-Schmiedebergs Archives ofPharmacology 1988; 337 (Suppl.): R123.)     

HEPATIC AND RENAL DISPOSITION OF PANCURONIUM AND GALLAMINE IN PATIENTS WITH EXTRAHEPATIC CHOLESTASIS

The plasma clearance of pancuronium in patients with extrahepaticcholestasis was 16% lower than in a control group (1.47±0.11ml min^–1 kg^–1 v. 1.76±0.21 ml min^–1kg^–1), but the difference was not significant. A significantincrease in the elimination half-life T^ß of pancuronium(from 141 to 224 min) and a significant increase in the volumeof the peripheral compartment (V₂ was found in patients withextrahepatic cholestasis when compared with control patients.There was a significantly lower cumulative biliary excretionof pancuronium (0.3±0.3% v. 10.9±3.2% in the controls)during the 48-h period of observation. The biotransformationand cumulative urinary excretion patterns of pancuronium revealedno significant differences between the two groups of patients.The increase of T^ß pancuronium in patients with extrahepaticcholestasis was mainly a consequence of the increase in thevolume of distribution. No significant differences in the plasmaclearance, T^ß or in the volume of distribution wereobserved with gallamine in the patients with extrahepatic cholestasiswhen compared with the control patients. The cumulative urinaryexcretion of gallamine during 48 h in both groups of patientswas approximately 100%. We concluded that in patients with cholestasisand normal glomerular filtration, gallamine is probably morereliable than pancuronium for neuromuscular blockade.     

EFFECTS OF ALFENTANIL ON CEREBRAL VASCULAR REACTIVITY IN DOGS

The effects of high dose alfentanil on the cerebral vascularresponses to alterations in mean arterial pressure (MAP), arterialoxygen tension (Pa^O2) and arterial carbon dioxide tension (Pa^CO2)were studied in 17 dogs, using the cerebral venous outflow technique.In six animals anaesthetized with sodium pentobarbitone 30 mgkg^–1 i.v., bolus injection of alfentanil 0.32 mg kg^–li.v. decreased MAP without a change in cerebral blood flow (CBF).In another group of animals(n = 5) anaesthetized with pentobarbitone30mg kg^–1 i.v. the CBF responses to changes in MAP. Pa^O2,and Pa^CO2 were studied. In a third group of animals (n = 6)anaesthetized with alfentanil 0.32 mg kg^–1 i.v. plus pentobarbitone1–2 mg kg^–1 i.v. and an infusion of alfentanil 0.32mg kg^–1h^–1 the CBF responses to alterations inMAP, Pa^O2, and Pa^CO2 were studied and compared with the barbiturate-anaesthetizedanimals. The CBF responses to hypercapnia and hypoxia in thealfentanil-anaesthetized animals were not different from thoseobserved in animals anaesthetized with barbiturate only. Thelower and upper limits of cerebral autoregulation in alfentanil-anaesthetizedanimals were not different from those observed in animals anaesthetizedwith barbiturate only. The data suggest that alfentanil, indoses sufficient to cause profound analgesia and anaesthesia,does not alter cerebral reactivity to changes in Pa^O2, Pa^CO2and MAP.     

CIRCULATORY EFFECTS OF ATROPINE IN PATIENTS ANAESTHETIZED WITH NITROUS OXIDE AND TUBOCURARINE

Atropine was given intravenously in a dose of 0.012 mg/kg toten artificially ventilated patients anaesthetized with nitrousoxide and tubocurarine. The heart rate increased from a meanof 68 to a mean of 96 beats/min. This was accompanied by a 31per cent increase in cardiac output and a 12 per cent rise inmean arterial pressure. There was no significant change in strokevolume or left ventricular stroke work. Total peripheral resistancefell by 14 per cent and circulation time by 22 per cent. Useof 0.5 per cent halothane in the inspired mixture in five casesresulted in smaller increases in heart rate and cardiac outputthan were seen in the other five. The results were comparedwith those in an earlier report in which the patients breathedspontaneously during halothane-nitrous oxide anaesthesia (Farman,1967). The response to atropine depends not only on the effectof the drug on the heart, but also on the control state of thecirculation, both of which are heavily influenced by other anaestheticdrugs, by the arterial Pco₂ and by the mechanical effect ofartificial ventilation.     

CIRCULATORY EFFECTS OF ATROPINE IN PATIENTS ANAESTHETIZED WITH GALLAMINE TRIETHIODIDE AND NITROUS OXIDE

Circulatory responses to the intravenous injection of acceleratingdoses of atropine sulphate were studied in ten patients anaesthetizedwith nitrous oxide, oxygen and gallamine triethiodide and ventilatedartificially. Small but significant increases in heart rateand cardiac output were accompanied by lowering of total peripheralresistance and circulation time. Arterial pressures, strokevolumes and stroke work were unchanged. Initial heart ratesand pressures were high, due to the use of gallamine, and itis suggested that the control levels of cardiac output werealso high. This would account for the smaller changes seen comparedwith earlier reports of the effect of atropine in patients artificiallyventilated using tubocurarine and in those spontaneously breathingnitrous oxide, oxygen and halothane.     

PHARMACOKINETICS OF MIDAZOLAM IN ANAESTHETIZED CIRRHOTIC PATIENTS

The pharmacokinetics of midazolam were compared in cirrhoticpatients (n = 10) and control patients (n = 9), during generalanaesthesia. Total plasma clearance was 637 ± 223 mlmin^–1 (mean ± SD) in control patients and 402 ±170 ml min^–1 in cirrhotic patients (P<0.05). The totalvolume of distribution was similar. Elimination half-life was135 ±40 min in controls and 168±30min in cirrhosis(P<0.05). Protein binding was evaluated by equilibrium dialysisin both groups at two concentrations of midazolam: 20 and 500µg litre^–1. No saturation occurred, but the freefraction was 4.9±1.7% in cirrhotic patients, comparedwith 1.9±0.6% in controls (P < 0.01). Despite itsmainly hepatic elimination, midazolam disposition appears tobe only slightly impaired in cirrhotic patients.     

SOME EFFECTS OF THE STEROIDAL MUSCLE RELAXANT, DACURONIUM BROMIDE, IN ANAESTHETIZED PATIENTS

The neuromuscular blocking properties of a new steroidal drug,dacuronium bromide, were investigated in twenty-three anaesthetizedpatients. Dacuronium produced a competitive type of neuromuscularblock with a potency of approximately one-tenth that of tubocurarineand one-fiftieth that of pancuronium. When compared with thesedrugs its maximal action was apparent earlier and the recoveryfrom its effects was somewhat quicker. One patient showed thesyndrome of the return of block after apparent adequate antagonismby neostigmine. Its actions in anaesthetized patients are discussedand compared with its actions in animals.     

富硒酵母对大鼠肝纤维化形成的影响

目的 评价富硒酵母对大鼠肝纤维化形成的影响。方法 用４０％ＣＣＩ４３个月诱导大鼠肝纤维化形成，同时每天分别给邓定硒酵母５０ｍｇ／ｋｇ或秋水仙碱０．１ｍｇ／ｋｇ。检测大鼠血甭丙氨酸氨基转换酶（ＡＬＴ）、白蛋白（ＡＬＢ）层粘蛋白（ＬＮ）、透明质酸（ＨＡ）和Ⅳ型原的（ＣⅣ）水平以及肝脏纤维化程度和羟脯氨酸（ＨＹＰ）的含此评价所用药物对大鼠肝纤维化形成的影响。结果 富硒酵母对ＣＣＩ４所致大鼠血清ＡＬＴ，Ｌ     

INFLUENCE OF SUXAMETHONIUM ON THE POTENCY OF ORG NC 45 IN ANAESTHETIZED PATIENTS

The non-depolarizing neuromuscular block produced by Org NC45was potentiated by the previous administration of suxamethonium1 mg kg^–1, shown by twitch depression of 91.3±2.4%when the same dose of Org NC 45 was administered after recoveryfrom suxamethonium compared with the control value of 71.9±6.5%.The recovery index was also prolonged from 8.1±0.3 to10.4±1.0min after suxamethonium. The dose-response curvesfor Org NC 45 showed a 1.66 potentiation factor for ED₅₀ and1.73 for ED_9.5, caused by the previous administration of suxamethonium.This interaction is likely to occur in the plasma.     

DISPOSITION OF NALBUPHINE IN PATIENTS UNDERGOING GENERAL ANAESTHESIA

The pharmacokinetics of nalbuphine 20 mg i.v. were studied in10 patients undergoing lower abdominal or body surface surgery.Blood sampling was carried out for 600 min after injection anddrug concentrations were measured by HPLC using electrochemicaldetection. Disposition was best described as a triexponentialfunction, with a mean elimination half-life of 135.5 min. Meanresidence time, clearance, and volumes of distribution, V^ssand V^ß, were determined by a model independent method,and gave mean values of 149·7 min (MRT), 1095 ml min^–1(Cl), 159·9 litre (V^ss) and 207.1 litre(V^ß).     

PULMONARY KINETICS OF FENTANYL AND ALFENTANIL IN SURGICAL PATIENTS

The pulmonary kinetics of fentanyl and alfentanil were studiedquantitatively in two groups of five and six surgical patients,respectively, after the induction of anaesthesia. A mixtureof one of the opioids and indocyanine green was administeredas a bolus. From measurements of the concentrations of the dyein plasma and the opioids in blood, central blood volume andthe amount of drug which passed through the pulmonary circulationwere calculated. The pulmonary release of fentanyl and alfentanilwas calculated from the arterial-mixed venous blood concentrationdifferences. Fentanyl 43.0–86.9% (median 70.9%) and 35.9–79.8%of alfentanil (median 58.6%) were sequestered by the lung onfirst passage of the opioid- containing blood through the pulmonarycapillaries. During the following 14 min, fentanyl was released,apparently from two binding sites (: 0.22 (0.16–0.27) min; : 5.78 (3.65–13.86) min). Initially, there was a rapid releaseof alfentanil (: 0.28 (0.08–0.51) min). However, 1–3 min after injection, the arterial-mixedvenous blood concentration difference of alfentanil disappeared,although considerable amounts of drug were still present inthe lung of five of the six patients studied. It may be expectedthat a temporary pulmonary sequestration of fentanyl and alfentanilhas considerable impact on the time course of their pharmacologicaleffects, on the time necessary to reach their maximum effectand on the intensity and (in case of fentanyl) the durationof these effects.     

DIFFERENTIAL EFFECTS OF VECURONIUM ON DIAPHRAGM AND GENIOHYOID MUSCLE IN ANAESTHETIZED DOGS

We have examined the sensitivity of the geniohyoid, an upperairway dilating muscle, to vecuronium in 12 anaesthetized dogsundergoing mechanical ventilation of the lungs and comparedit with that of the diaphragm. Dogs were allocated randomlyto two groups: pentobarbitone alone (group 1, n = 7); pentobarbitonecombined with 0.2 MAC (0.44%) of enflurane anaesthesia (group2, n = 5). Supramaximal single twitch stimulations (0.1 Hz)were applied to the phrenic nerves in the upper thorax and thegeniohyoid branches of the hy-poglossal nerves at the neck.The evoked responses were assessed by the transdiaphragmaticpressure (Pdi) and the isometric force of the geniohyoid muscles(Tgh) until complete recovery of these variables after i.v.administration of vecuronium 0.02 mg kg^–1. In both groups,the magnitude of the depression of twitch response was greaterand time required to reach control amplitude was longer in thegeniohyoid than the diaphragm. The depression of Tgh. was significantlygreater in group 2 than in group 1, whereas no change was observedin Pdi between the two groups. We conclude that the geniohyoidis more sensitive to vecuronium than the diaphragm and the differentialeffects of vecuronium are facilitated by a low concentrationof enflurane.     

CARDIOVASCULAR EFFECTS OF PROPOFOL IN THE ANAESTHETIZED DOG

This study was designed to investigate if propofol producedcardiovascular effects by indirect actions or by indirect actionssecondary to depression of the central nervous system. Experimentswere performed on chloralose anaesthetized dogs in which allneurogenic cardiovascular reflexes were abolished by bilateralvagotomy and common carotid ligatures, in combination with i.v. bretylium and propranolol. Bolus doses of propofol followedby infusions at rates up to 160 mg kg^–1 h^–1 producedblood concentrations of propofol from 1.99 to 112 µg ml–1.Infusions of hydroxyethyl starch given to maintain central venouspressures and pulmonary artery occlusion pressures at controlvalues were used as an index of changes in capacitance. Bloodconcentrations of propofol less than 10 µg ml^–1caused an increase in mean capacitance of 8.0 (SEM 1) ml kg^–1with no significant changes in systemic vascular resistance,pulmonary vascular resistance or intropic state of the heart.We conclude that anaesthesia with propofol may be accompainedby decreased cardiac output secondary to reduction in preloadby a direct venodilator effect. Our experiments indicate thatcardiac output and arterial pressure are preserved well at normalanaesthetic blood concentrations of propofol if the preloadis maintained.     

CARDIOVASCULAR EFFECTS OF ALFENTANIL ANAESTHESIA

In 30 patients undergoing cardiac surgery, anaesthesia was inducedwith alfentaml 125 µg kg^–1 and maintained with aninfusion of alfentanil 0.5 mg kg^–1 h^–1 until thestart of cardiopulmonary bypass, and alfentanil 0 25mg kg^–1h^–1thereafter until the end of surgery. Pancuronium was given andthe lungs ventilated with air in oxygen. In the majority ofpatients, there were no tignifiranr changes in cardiovascularmeasurements throughout the study, although two received sodiumnitroprusside for the control of hypertension, and in one patienthypertension was so severe that the method of anaesthesia wasabandoned. Transient hypotension occurred on induction in onepatient. Twenty-six patients required alfentanil supplementationbefore bypass. These results indicate that anaesthesia withan alfentanil infusion provides satisfactory cardiovascularstability for cardiac surgery.     

PHARMACOKINETICS OF PHENOPERIDINE IN ANAESTHETIZED PATIENTS UNDERGOING GENERAL SURGERY

The pharmacokinetics of phenoperidine have been studied in fiveanaesthetized patients receiving a 2-mg bolus dose i.v. Plasmaconcentrations were measured using a sensitive radioimmunoassaymethod. The distribution of phenoperidine was described accordingto a two-compartment open model. The mean distribution half-life(T) for the five patients was short (2.2 min); the mean eliminationhalf-life (T^ß) was 193 min. The mean whole body clearancewas 22 ml min^-1 kg^-1 and the apparent steady state distributionvolume (V^SS) was 5.7 litre kg^-1. Secondary concentration peaksoccurred in all patients; in two patients these were substantialand occurred 80 min after injection.