Biphasic respiratory depression after fentanyldroperidol or fentanyl alone used to supplement nitrous oxide anesthesia.

Either fentanyl or Innovar (fentanyl, 0.05 mg/ml, and droperidol 2.5 mg/ml) was administered to supplement nitrous oxide anesthesia for operations on 29 patients. Both fentanyl and Innovar depressed the slope of the rebreathing CO2 response curve during operation to 42 per cent +/- 6 (mean of all intraoperative values, +/- SE) of the awake control value. Following the last injection of drug but with continuation of operation, the slope increased such that it was 77 per cent +/- 8 of control on the patients' arrival in the recovery room. The slope continued to increase to a peak of 103 per cent +/- 9 of control. Soon therafter respiratory depression recurred, as indicated by a decline in the slope to 55 per cent +/- 5 of control, with a subsequent gradual return to 85 per cent +/- 8 of control 230 minutes after the last injection. This biphasic response occurred in 90 per cent (26 of 29) of the patients treated either with fentanyl alone or with Innovar. Full recovery appeared to be more rapid with Innovar than with fentanyl alone. Droperidol did not augment and may have attenuated fentanyl-induced respiratory-depression.     

THE EFFECTS OF DROPERIDOL AND FENTANYL ON INTRACRANIAL PRESSURE AND CEREBRAL PERFUSION PRESSURE IN NEUROSURGICAL PATIENTS

The effects of droperidol and fentanyl on the intracranial pressure(i.c.p.) and cerebral perfusion pressure (c.p.p.) were studiedin eight anaesthetized normocapnic patients with intracranialspace-occupying lesions. The injection of droperidol resultedin a small and not significant increase in i.c.p. from 24.0to 27.2 mm Hg, while c.p.p. decreased from 75.9 mm Hg to 57.8mm Hg, as a result of a decrease in systemic arterial pressure.The addition of fentanyl produced no change in i.c.p., but afurther decrease in arterial pressure decreased c.p.p. from60.4 mm Hg to 47.8 mm Hg. In four patients values of c.p.p.less than 40 mm Hg were obtained. C.p.p. was increased by hyperventilationin all but one of these patients. It is concluded that droperidoland fentanyl should be used in patients with intracranial hypertensiononly if hypocapnia has been established and when the arterialpressure is normal or increased. ^*Present address: Department of Anaesthesia, Bornholm, Centralsygehüs,3700 Rønne, Denmark.     

Cardiovascular effects of minimal analgesic quantities of Innovar, fentanyl, and droperidol in man.

In volunteer human subjects not undergoing surgical operations and breathing spontaneously, the cardiovascular effects of Innovar and of its components, fentanyl and droperidol, were determined when the drugs were administered in minimal amounts necessary to reach an analgesic endpoint. This amount was fentanyl 5 mcg./kg. body weight combined with droperidol 0.22 mg./kg. Innovar, or its components when administered separately, produced minimal cardiovascular changes of consequence during the time of maximum analgesia (about 15 minutes). With the passage of time after administration of a single dose of Innovar, there were some changes in cardiac output, heart rate, and stroke volume, probably representing normal changes of sedated sleep. None of the changes, acute or delayed, was clinically significant. Analgesia could be achieved only when fentanyl was combined with droperidol; and although a certain amount of respiratory depression resulted from the combined drugs, the authors concluded that the observed cardiovascular changes probably represented primary drug effects.     

The Effect of Halothane Anaesthesia upon Cerebral Oxygen Consumption in the Rat

The influence of halothane (0.6 and 2%) upon cerebral (cortical) blood flow (CBF) and cerebral metabolic rate for oxygen (CMRo2) was studied in artificially ventilated rats, using a modified technique of Kety & Schmidt (1948). The values obtained in halothane anaesthesia were compared to those recorded in nitrous oxide anaesthesia, or to those measured in unanesthetized animals given an analgesic drug (fentanyl citrate). Although it could be confirmed that halothane induces vasodilatation in the brain, there were relatively small differences in CBF between the groups. The results demonstrate that, in the rat, halothane depresses CMRo2 in a dose-dependent way. With 0.6% halothane, CMRo2 was reduced by 20-30% and, with 2% halothane, CMRo2 was reduced by about 50%. Thus, in the rat the effect of 2% halothane upon metabolic rate is comparable to that observed in barbiturate anaesthesia.     

CEREBRAL VASODILATATION BY HALOTHANE ANAESTHESIA IN MAN AND ITS POTENTIATION BY HYPOTENSION AND HYPERCAPNIA

In ten young normal adults the cerebral blood flow and oxygenuptake during normotensive and normocapnic halothane anaesthesia(1 per cent) were studied by means of the ⁸⁵Kr inhalation method.Compared with a similar group studied when awake, a significantincrease of 27 per cent in cerebral blood flow was found duringanaesthesia while the oxygen uptake was reduced by 26 per cent.After discussing previous conflicting reports, it is concludedthat halothane per se acts as a cerebral vasodilator. Ten patientsfrom the neurological service with and without cerebrovasculardisease were studied when awake and during hypotensive hypercapnichalothane anaesthesia (1 per cent). In five cases a third studywas made during either hypotension (three cases) or hypercapnia(two cases) alone. Cerebral blood flow was measured by the ¹³³Xeinjection method. The results suggested a potentiation of thecerebral vasodilatation of halothane by hypotension and/or hypercapniaeven in patients with cerebrovascular disease. The very highblood flows found during normotensive, moderately hypercapnichalothane anaesthesia indicated a sort of controlled cerebralhyperoxygenation, the application of which is discussed.     

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.     

Dose-response relation and time course of action of pipecuronium bromide in humans anesthetized with nitrous oxide and isoflurane, halothane, or droperidol and fentanyl

The dose-response of pipecuronium bromide, the time course of its neuromuscular blocking effects, and the reversibility of the residual block by neostigmine and edrophonium have been investigated in patients undergoing various types of anesthesia. The estimated doses of pipecuronium required for 95% depression of the twitch height were 44.6, 46.9, and 48.7 micrograms.kg-1 during anesthesia with nitrous oxide (65%) and isoflurane (group 1), halothane (group 2), or droperidol/fentanyl (group 3), respectively. The potentiating effects of the volatile anesthetics were reflected by the significant prolongation of the duration of both initial (50.0 +/- 4.3, 36.0 +/- 3.3, and 29.0 +/- 2.0 minutes) and maintenance doses (56.0 +/- 2.5, 49.5 +/- 3.3, and 41.2 +/- 1.6 minutes) of pipecuronium during anesthesia with nitrous oxide and isoflurane, halothane, or droperidol/fentanyl, respectively. Both edrophonium chloride (0.5 mg.kg-1) and neostigmine methylsulphate (40 micrograms.kg-1) promptly reversed the residual block induced by pipecuronium. No side effects attributable to pipecuronium were seen in this study.     

SURVIVAL OF BLED DOGS AFTER HALOTHANE AND ETHER ANAESTHESIA

Sixty spontaneously-breathing atropinized dogs anaesthetizedwith 79 per cent ethylene/21 per cent oxygen were bled to amean aortic blood pressure of 40 mm Hg for 90 minutes, and theirsurvival observed during and after an additional 30 minutesof halothane or di-ethyl ether anaesthesia followed by bloodreplacement. Blood volumes were reduced approximately 40 percent by an average haemorrhage of 46.3 ml/kg. It is concludedthat: (a) Survival experiments did not demonstrate a deleteriouseffect of 1.5 per cent halothane due to its hypotensive actionin oligaemia when compared with lighter planes of ether anaesthesia,(b) Maintenance of a normal minute volume will not suffice foradequate oxygenation of the arterial blood during anaesthesiawith either agent after haemorrhage with air as carrier gas.(c) Enrichment of the inspired oxygen to 30 per cent ensuresadequate arterial oxygenation when pulmonary ventilation isreduced by 1.5 per cent halothane after haemorrhage of thisseverity, and a survival rate insignificantly different fromthat resulting when 100 per cent oxygen is used as carrier gas. ^*Present address: University College Hospital, London.     

The cerebral effects of pancuronium and atracurium in halothane-anesthetized dogs

Pancuronium decreases the minimal alveolar anesthetic concentration (MAC) of halothane in humans, while atracurium has a metabolite, laudanosine, which is a known cerebral stimulant. To determine if these muscle relaxants significantly alter cerebral function, their effects on cerebral metabolic rate (CMRo2), cerebral blood flow (CBF), intracranial pressure (ICP), EEG, and the cerebral energy state were studied in halothane-anesthetized dogs. Group A dogs (n = 6) were maintained at 0.86% end-expired (1.0 MAC) halothane. Thereafter, a sequence of 1) pancuronium 0.1 mg . kg-1; 2) reversal of neuromuscular blockade with neostigmine plus glycopyrrolate; and 3) pancuronium 0.2 mg . kg-1 produced no changes in CMRo2, CBF, ICP, or EEG. Group B dogs (n = 6) also were maintained at 0.86% end-expired halothane and received the following in sequence: 1) atracurium 0.5 mg . kg-1; 2) reversal of neuromuscular blockade with neostigmine plus glycopyrrolate; 3) atracurium 1.0 mg . kg-1; and 4) atracurium 2.5 mg . kg-1. There were no changes in CMRo2, CBF, or ICP; EEG evidence of cerebral arousal occurred in only one dog with the final dose of atracurium. Group C dogs (n = 6) received tetracaine spinal anesthesia and the minimal halothane concentration (mean +/- SE = 0.69 +/- 0.03% end-expired) that would maintain an "anesthetic" EEG pattern. Each Group C dog received the following in sequence: 1) atracurium 1.0 mg . kg-1, and 2) atracurium 2.5 mg . kg-1. EEG evidence of cerebral arousal occurred in all six Group C dogs. Arousal was not accompanied by significant increases in CBF, CMRo2, or ICP.(ABSTRACT TRUNCATED AT 250 WORDS)     

THE EFFECT OF NEUROLEPTANALGESIA WITH INNOVAR ON THE METABOLIC RATE OF MAN

The metabolic rate of eight healthy adults did not change significantlyafter the introduction of neuroleptanalgesia with Innovar. Averageoxygen consumption decreased from the control value of 133 ml/min/sq.m±22(standard deviation) which is 98.6 per cent of predicted basalmetabolic rate, to 127±37 8 minutes after the injectionof Innovar (93.2 per cent), and was 141±17 25 to 30 minutesafter injection (105.5 per cent). Ventilation was controlled,keeping end-tidal carbon dioxide constant. Carbon dioxide excretionand the respiratory quotient did not change. Anatomical deadspaceand the ratio of deadspace to tidal volume both rose after induction.This study offers no support for the theory that Innovar "protects"by reducing metabolic demand for oxygen in man.     

THE RESPIRATORY EFFECTS OF INNOVAR GIVEN FOR PREMEDICATION

Innovar, a mixture of a synthetic, short-acting narcotic (fentanyl)and a long-acting butyrophene (droperidol), was given to sixhealthy post-prandial volunteers, to determine the impact onrespiratory function of the usual pre-anaesthetic dose employed.No significant alteration in spirometric pulmonary functiontests followed the injection. Ventilation decreased, especiallyalveolar ventilation; end-tidal and mixed venous (oxygenated)carbon dioxide tensions rose reciprocally, by 5–6 mm Hg.Oxygen and carbon dioxide exchange rates were close to predictedbasal rate. In comparison with equivalent dosage of fentanylalone, Innovar is approximately equipotent in respiratory effect.     

Cerebral metabolism and the electroencephalogram during hypocapnia plus hypotension induced by sodium nitroprusside or trimethaphan in dogs

The effects on cerebral metabolism and the electroencephalogram (EEG) of combining hypocapnia with hypotension have been only incompletely examined. The present study examined the possibility that hypocapnia may worsen the cerebral metabolic and EEG disturbances caused by hypotension. Cerebral metabolism and the EEG were studied at three levels of hypotension during hypocapnia (PaCO2 = 20 mm Hg) in dogs under light halothane anesthesia. A sequential decrease of the mean arterial pressure (MAP) to 60, 50, and 40 mm Hg (30 minutes at each level) was achieved with sodium nitroprusside (SNP) (n = 12) or trimethaphan (TMP) (n = 12). With SNP-induced hypotension plus hypocapnia, the power of the alpha and beta 2 spectra of the EEG decreased at MAP less than or equal to 60 mm Hg. Cerebral metabolic values were unchanged at a MAP of 60 or 50 mm Hg. Brain tissue phosphocreatine and the cerebral energy charge decreased, and the lactate/pyruvate ratio increased at a MAP of 40 mm Hg. With TMP-induced hypotension plus hypocapnia, power decreased in the alpha and beta 2 spectra of the EEG at MAP less than or equal to 60 mm Hg. Cerebral metabolic values were unchanged at a MAP of 60 mm Hg. At MAP less than or equal to 50 mm Hg, power in the beta 1 spectrum, brain tissue phosphocreatine, and the cerebral energy charge all decreased. At a MAP of 40 mm Hg, the cerebral glucose value decreased and the lactate/pyruvate ratio increased.(ABSTRACT TRUNCATED AT 250 WORDS)     

OXYGEN AND ANAEMIA: THEIR EFFECTS IN MICE, ON INDUCTION TIME AND SURVIVAL TIME WITH HALOTHANE ANAESTHESIA

This paper reports the results of five studies on female miceto investigate the effects of halothane anaesthesia in air and100 per cent oxygen on induction time, survival time and sensitivityto halothane, in bled and unbled mice. Studies on the effectof anaemia on induction time and survival time showed that reductionsof haemoglobin content significantly reduced induction timesin mice anaesthetized with 10 per cent halothane in air and100 per cent oxygen (2 1./min), but did not significandy affectthe survival times in the same groups of mice. The use of 100per cent oxygen instead of air as the anaesthetic vehicle causeda highly significant increase in induction times and survivaltimes in both bled and unbled mice. Toxicity studies to determinethe halothane concentrations required to kill 50 per cent and99 per cent of mice in 30 minutes were used to confirm the resultsof the above survival studies. One study showed that in unbledmice, the mice were significantly more sensitive to halothane/airanaesthesia than to halothane/100 per cent oxygen anaesthesia.Other studies showed that a mean haemoglobin reduction of 31per cent did not significandy affect the mouse sensitivity tohalothane/100 per cent oxygen anaesthesia, but a reduction of45 per cent significantly increased the sensitivity of the bledmice to halothane/100 per cent oxygen. Body weight was shownto have a highly significant effect on induction time and survivaltime with 10 per cent halothane/100 per cent oxygen, but a non-significanteffect with 10 per cent halothane/air.     

Effect of enflurane and fentanyl on the clinical characteristics of long-term succinylcholine infusion

The characteristics of the neuromuscular block produced by prolonged succinylcholine infusion were compared in 40 patients anaesthetized with either nitrous oxide with enflurane (1-2 per cent inspired) or nitrous oxide and fentanyl. Neuromuscular transmission was monitored using train-of-four stimulation and the infusion rate was adjusted to keep the first twitch at 10-15 per cent of its control value. Initially, all patients, exhibited a depolarizing-type block all twitches of the train-of-four being roughly the same size, and the infusion rates were similar in the enflurane (54 microgram X kg-1/min) and the fentanyl (58 microgram X kg-1/min) groups. Tachyphylaxis developed later in both groups and correlated well with the onset of phase II block (dual block). This occurred sooner and at a lower cumulative dose in the enflurane group. Fourth to first twitch ratios decreased to 50, 25 and 0 per cent in 31, 46 and 59 minutes in the enflurane group, at cumulative succinylcholine doses of 2.2, 3.2 and 4.2 mg X kg-1 respectively. Corresponding figures for the fentanyl group were 52, 73 and 86 minutes, with dose of 3.4, 5.0 and 5.9 mg X kg-1. Infusion rates increased markedly after establishment of dual block, but were similar with enflurane (0.99 mg X kg-1/min) and fentanyl (1.12 mg X kg-1/min). Ten minutes after stopping the infusion fourth to first twitch ratios failed to reach 50 per cent in most patients given enflurane who had received more than 6 mg X kg-1 succinylcholine over more than 90 minutes. Corresponding figures for fentanyl patients were 13 mg x kg-1 and 150 minutes. The block in all 15 patients (9 enflurane, 6 fentanyl) who did not recover spontaneously was successfully antagonized with atropine and neostigmine.     

Effect of halothane,enflurane and isoflurane on the end-systolic pressure-length relationship

Myocardial contractility was measured using the end-systolic pressure-length (ESPL) relationship in dogs subjected to increasing concentrations of halothane (0.5-2 per cent), enflurane (0.77-2.6 per cent) or isoflurane (0.70-2.13 per cent), combined with an infusion 7 micrograms X kg-1 X min-1 of fentanyl, after induction of anaesthesia with 15 mg X kg-1 thiopentone. The relationship between the concentrations of the different drugs and contractility (ESPL) can best be described by ESPL = a + b/(MAC fraction) where "a" is a constant and "b" is the slope of the curve relating ESPL to MAC. At 1.0 MAC values, the ESPL for halothane (69.04 +/- 25.83 mmHg X mm-1) did not differ from that of isoflurane (63.19 +/- 17.36 mmHg X mm-1). However, the myocardial contractility during 1.0 MAC halothane and isoflurane anaesthesia was better preserved than that of enflurane (38.66 +/- 9.73 mmHg X mm-1: p less than 0.01, p less than 0.05 respectively).     

THE HYPERGLYCAEMIC RESPONSE TO DIFFERENT TYPES OF SURGERY AND ANAESTHESIA

The rise in blood sugar during anaesthesia without surgery andduring surface, thoracic and intra-abdominal surgery, was measured.In patients anaesthetized primarily with thiopentone there wasno significant rise without surgery and the rise was, in general,proportional to the stress of surgery, the largest being duringintra-abdominal operations. Findings were similar in anotherseries of patients anaesthetized primarily with propanidid.Five anaesthetic techniques were also compared during intra-abdominalsurgery. In all nitrous oxide and tubocurarine were used andthere was a bigger rise in patients in whom anaesthesia wasinduced with propanidid than in those who had thiopentone. Theaddition of 1 per cent halothane or phenoperidine 5 mg to thethiopentone/nitrous oxide/tubocurarine technique, led to a significantlysmaller response. When a technique using droperidol/fentanyl/tubocurarinewas employed the hyperglycaemic response was similar to thatwith thiopentone induction.     

THE EFFECT OF HALOTHANE ON BACTERIAL GROWTH RATE

The growth rate of four species of non-pathogenic bacteria inbroth was estimated spectrophotometrically. Exposure to halothane(1–10 per cent) vaporized in air produced a dose-dependentdepression of growth rate, but for all species the effect wasnegligible at clinical concentrations of halothane. The ED₅₀was within the range 7–8 per cent halothane for threespecies: 50 per cent inhibition was not obtained with 10 percent halothane in the fourth species. Inhibition of divisionwith 10 per cent halothane was delayed by 20–25 minuteswhich was close to the mean generation time. The effect wasfully reversible although there was again a lag of about 20minutes before division was resumed after withdrawal of halothane.     

High-dose thalamonal-rohypnol for premedication. A randomized double-blind study

The combination of fentanyl and droperidol, Innovar, was compared to flunitrazepam (1-2 mg) in a higher dosage (2.5-5 ml) for i.m. premedication. We measured psychological (ESB) and physiological (blood pressure, heart rate, p.cortisol) stress parameters before and after premedication. Side effects were registered. The day after surgery the patients were asked about the quality of premedication. Flunitrazepam reduced anxiety; Innovar did not. After Innovar the feeling of weakness increased significantly compared to flunitrazepam. Two patients panicked and refused operation. Other severe side effects were not observed. There were slight advantages for flunitrazepam on physiological stress. Patients were more satisfied with flunitrazepam than with Innovar premedication. The results show that Innovar also in a higher dosage cannot be recommended for premedication.     

Autoregulation of cerebral blood flow during normocapnia and hypocapnia in dogs

The effect of hypocapnia on autoregulation of cerebral blood flow (CBF) and the lower limit of autoregulation (LLA) was determined in dogs anesthetized with nitrous oxide (66%) and halothane (0.2%, end-expired concentration). CBF and cerebral vascular resistance (CVR) were determined during both normocapnia and hypocapnia (PaCO2 21-22 mmHg) at control cerebral perfusion pressure (CPP) and after reducing CPP (by hemorrhage) to 80%, 60%, 50%, and 40% of control. At control CPP hypocapnia decreased CBF from 75 +/- 5 to 48 +/- 3 ml.100 g-1.min-1 (mean +/- SEM, P less than 0.05). During both normocapnia and hypocapnia CVR decreased and CBF did not change as CPP was reduced to 60% of control. When CPP was reduced to 50% or 40% of control, CVR remained decreased and CBF fell sharply. The LLA during hypocapnia, 61 +/- 2% of control CPP, was not different than that during normocapnia, 59 +/- 3% of control CPP. Below the LLA the CBF-CPP slopes differed from zero but did not differ between hypocapnia and normocapnia. Hypocapnia does not produce a substantial shift of the LLA, and over the range of CPP values studied here, autoregulatory cerebral vasodilation only partially abolishes hypocapnia-induced cerebral vasoconstriction. The results suggest that when cerebral autoregulation is intact and in the absence of cerebrovascular disease, hypocapnia does not reduce global CBF to a level that is likely to produce ischemia and remains a useful therapeutic treatment so long as CPP remains above the LLA.     

Halothane does not decrease amiloride-sensitive alveolar fluid clearance in rabbits

Halothane decreases alveolar fluid clearance (AFC), a function required for efficient gas exchange in the rat. Further, halothane decreases amiloride-sensitive Na(+) transport in rat alveolar type II cells, a process responsible for a significant portion of AFC. We tested the hypothesis that halothane would decrease amiloride-sensitive AFC in rabbits. Rabbits anesthetized with 1.8% halothane had 5% albumin in 0.9% NaCl instilled into the right lung with (n = 11) or without (n = 11) 1 mM amiloride present in the instillate. Similarly, animals anesthetized with IV fentanyl and droperidol were administered 5% albumin solution with (n = 11) or without (n = 11) amiloride. At 90 min after instillation, alveolar fluid samples were obtained, and AFC was determined by changes in fluid protein concentration. Rabbits anesthetized with halothane or fentanyl and droperidol in the absence of amiloride had similar AFC values (35% +/- 12% and 35% +/- 7%, respectively, mean +/- SD). Rabbits anesthetized with halothane or fentanyl and droperidol in the presence of amiloride had similar AFC values (20% +/- 10% and 16% +/- 12%, respectively) that were significantly less than the groups not administered amiloride (P < 0.01). Unlike the rat, the ability of the rabbit to clear fluid from the alveolar space through amiloride-sensitive pathways is not decreased by halothane anesthesia. Implications: Unlike the rat, the ability of the rabbit to clear fluid from the alveolar space through amiloride-sensitive pathways is not decreased by halothane anesthesia.