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Glyceryl trinitrate (GTN) is used to control arterial blood pressure during cardiopulmonary bypass (CPB) procedures, but its effects are often decreased during the period of extracorporeal support. The plasma and urine concentrations of GTN and glyceryl-1,2-dinitrate (1,2-GDN) and glyceryl-1,3-dinitrate (1,3-GDN) for male and female patients who received GTN during hypothermic CPB, and male and female patients who were given GTN during normothermic CPB, were measured by gas-liquid chromatography. During hypothermic CPB, the male and female subjects experienced significant decreases in GTN clearance (P < 0.05), 66% and 52%, respectively. Neither the males nor the females who underwent normothermic CPB experienced any significant change in GTN clearance. These results suggest that the lower core temperature during hypothermic CPB may decrease the biotransformation of GTN to GDNs and nitric oxide, thereby resulting in less dilation of blood vessels. Furthermore, the males in the hypothermic CPB group had significantly greater urinary concentrations of 1,3-GDN and 1,2-GDN than the females (P < 0.05), and the normothermic CPB males had a significantly greater urinary concentration of 1,2-GDN than the females in that group. The normothermic CPB males also had significantly higher plasma concentration of GTN at two time points, and 1,3-GDN at one time point, than the females. These data suggest that there may be a gender difference in GTN biotransformation.

The effectiveness of glyceryl trinitrate (nitroglycerin) in controlling myocardial ischemia and blood pressure during coronary artery bypass graft surgery is frequently lost during surgery, possibly as a result of drug sequestration by the cardiopulmonary bypass circuit. The objective of this study was to utilize a gas-liquid chromatographic assay to determine the extent of removal of glyceryl trinitrate from the priming fluid by the bubble and membrane oxygenators. The apparatus was maintained at either 25 or 37 degrees C, the two extreme temperatures experienced by the patient during bypass surgery. At apparent steady state, the circulating glyceryl trinitrate concentration was decreased by 20.6%, 46.6%, and 67.3% with the Maxima membrane oxygenator, Cobe membrane oxygenator, and Bentley bubble oxygenator, respectively. The three-layer defoaming filters that are used in the Bentley bubble oxygenator were studied by immersing each of the three filters in fluid containing 60 nM glyceryl trinitrate and monitoring the drug concentration in Plasmalyte. The filters sequestered approximately 90% of the glyceryl trinitrate from the bathing solution of which 31% was recovered with a single methanol wash of the polyurethane filter. These data demonstrate that the different oxygenators used in the cardiopulmonary bypass circuit remove glyceryl trinitrate to varying degrees from the circulating fluid.

Following the production of digitalis toxicity in dogs as manifested by ventricular tachycardia, the pharmacokinetics of lidocaine treatment of the arrhythmia were determined during pentobarbitone anaesthesia and pentobarbitone-halothane anaesthesia. The elimination rate constants, beta and Ke, and the biological half life T1/2beta were statistically significantly increased during halothane anaesthesia. The volume of distribution was unchanged. The results indicate that the therapeutic loading dose of lidocaine need not be altered during halothane anaesthesia but if a constant infusion is used, the rate of infusion would have to be decreased four fold to avoid toxic plasma levels of lidocaine.

Continuous intrathecal (IT) infusion via ALZET mini-osmotic pumps was used to induced spinal tolerance to morphine in the rat. Naloxone (1 mg/kg IP), injected on day 3 of continuous IT morphine (10 micrograms/hr), produced mild withdrawal symptoms in all morphine-treated animals. In rats pretreated with continuous IT morphine (10 micrograms/hr) or saline, systemic morphine (2, 4, 8, 10 and 15 mg/kg IP) produced equivalent, dose-dependent antinociception using the tail-flick and paw pressure tests. The rostral and caudal distribution of methylene blue dye in rat spinal cord was determined on days 1-7 of continuous IT infusion. The dye remained localized near the catheter tip throughout infusion; maximum distribution was 1.5 cm rostrally and 1.0 cm caudally. The data indicate that morphine, infused at the rate of 10 micrograms/hr, does not undergo extensive redistribution in the spinal cord. A sequential, double mini-osmotic pump technique for cross tolerance studies in rat spinal cord is described. In rats pretreated with continuous IT norepinephrine for 4 days, the antinociceptive actions of continuous IT morphine were reduced but not significantly different from saline-pretreated animals. These data suggest that morphine, injected into the spinal cord, does not produce behavioural analgesia by activation of local adrenergic systems.

A recent report suggests that there may be advantages of intraaortic (IA) versus intravenous (IV) administration of protamine for reversal of heparin at the end of cardiopulmonary bypass. Because complete haemodynamic measurements were not performed in that study, we prospectively and randomly assessed the effects of protamine sulphate administered via either route. Patients were studied in the period immediately following cardiopulmonary bypass. Heparin, 300 units.Kg-1, plus 150 units.Kg-1 when required, was administered to keep the activated clotting time > 400 sec. Protamine 3 mg.Kg-1 was injected over 30 sec. intravenously in the IV group (n = 5) and into the ascending aorta in the IA group (n = 5). There was a significant decrease in arterial blood pressure (28.6 per cent) from 109.2 ±5.6 mmHg (S.E.) systolic to 78.0 ± 9.0 mmHg observed in the IA group one minute post protamine, which returned to baseline by 2.5 min (analysis of variance p < 0.05). No significant hypotension was observed in the IV group. There was no significant change in heart rate, left alrial pressure, central venous pressure, systemic vascular resistance or cardiac index with either IA or IV protamie. In contrast to our recent study in pigs there was no significant change in pulmonary artery pressure, pulmonary vascular resistance or cardiac output with protamine. Results indicate that there are no haemodynamic benefits of IA vs IV injection of protamine. Une elude recente a suggere qu’il pourrait etre avantageux d’administrer la protamine par voie intra-aortique a la fin de la circulation extra-corporelle. Cependant, celte etude ne comporte pas de mesures precises des consequences hemodynamiques d’un tel procede. Nous avons donc decide d’etudier les effets cardiovasculaires du sulfate de protamine selon qu’il est administre par voie intra-veineuse (IV) ou intra-aortique (1A) et ceci de facon prospective et aleatoire. Dix patients ont ete etudies immediatement apres le sevrage de la circulation extra-corporelle. Les patients avaient recu de l’heparine 300 unites.Kg-1 plus 150 unites.Kg-1 au besoin pour maintenir un temps de coagulation active (ACT) plus grand que 400 sec. La protamine, 3 mg.Kg-1, a ete injectee en 30 sec. par voie intra-veineuse (N = 5) ou intra-aortique (N = 5). On a note une minute apres l’injection intra-aortique, une diminution significative de la pression arterielle (28.6 pour cent), la syndique passant de 109.2 ±5.6 mmHg (ET) a. 78 ± 9 mmHg et un retour aux valeurs de controle a2.5 min. (analyse de variancep < 0.05). Par contre, il n’y a pas eu d’hypotension significative dans le groupe IV. Dans les deux groupes, il n’y a pas eu de changement significatif de la frequence cardiaque, des pressions auriculaire gauche et veineuse centrale, de la resistance peripherique ou de l’index cardiaque. Contrairement a notre elude recente chez leporc, il n’y a pas eu, associe a la protamine, de changement significatif dans la pression arterielle, la resistance vasculaire pulmonaire ou le debit cardiaque. Les resultats obtenus indiquent qu’il n’est pas avantageux d’administrer la protamine par voie intra-aortique plutot que par voie intra-veineuse.

Noradrenergic and serotonergic neurons, originating in the brainstem and terminating in the dorsal horn, modulate the spinal processing of nociception. The inhibitory effects of norepinephrine (NE) and serotonin (5-HT) on elements of nociceptive transmission may be direct, or secondary to the release of neuromodulators such as opioid peptides. Two major criteria have been used in pharmacological studies of spinal opioid and monoamine interactions: the ability of opioid antagonists to attenuate the antinoceceptive effects evoked by stimulating the release of endogenous NE and 5-HT in the lumbar spinal cord, or by the intrathecal injection of exogenous NE and 5-HT; and the development of cross tolerance between opioids and each of NE and 5-HT. Evidence regarding the spinal interaction between opioids and monoamines in mediating behavioural analgesia is reviewed. Recent results from this laboratory indicate that IT (−)naloxone but not (+)naloxone produces dose-dependent antagonism of IT NE-induced antinociception in the rat. This effect was not due to hyperalgesia. In rats made tolerant to spinal morphine using continuous IT infusion, the antinociceptive effect of continuous IT NE was significantly attenuated. However, no cross tolerance was observed between morphine and 5-HT. Observations from a variety of studies support the hypothesis of a spinal opioid link which contributes, in part, to NE-induced antinociception. However, this interaction remains to be conclusively established.

The acute intrathecal (i.t.) injection of 50, 100, 200, 250 and 300 nmol of oxymetazoline produced dose-dependent antinociception in rats assessed by tail flick and paw pressure tests. Significant antinociception was observed with all doses of oxymetazoline except 50 nmol in the paw pressure test. The ED50 values for i.t. oxymetazoline in the tail flick and paw pressure tests were 120 nmol (95% CI: 76-178 nmol) and 148 nmol (95% CI: 120-186 nmol), respectively. Oxymetazoline had a long duration of action; a single i.t. dose of 100 nmol significantly elevated tail flick latency and paw pressure threshold for 8 h. The alpha-adrenoceptor antagonist phentolamine, given i.t. 1 h after oxymetazoline, attenuated the antinociceptive effect in a dose-dependent manner. Phentolamine (50 micrograms i.t.) produced almost complete antagonism in the tail flick and paw pressure tests. These data indicate that oxymetazoline produces long lasting antinociception in the rat following i.t. injection, and that the effect is mediated by alpha-adrenoceptors in the spinal cord.

SUMMARY The increase in permeability of human erythrocytes to glucose produced by carbon dioxide was confirmed. The effect of certain membrane inhibitors was studied. It was found that while mercuric chloride inhibited the effect of carbon dioxide, ouabain and butanol did not. Inhalation anesthetics in therapeutic concentrations were found to inhibit the stimulatory effect of carbon dioxide. It was concluded that while the means by which carbon dioxide stimulates glucose entry into red cells remains undefined, the inhibitory effect of anesthetics is not related to their ability to “stabilize” membranes, to their effects on energy-linked metabolic processes, or to their interactions with sulfhydryl or amino groups in cell membranes. The inhibitory effect of anesthetics on carbon dioxide-stimulated glucose entry is compatible with the hypothesis that they act as competitive penetrating inhibitors of glucose transport mechanisms in human red cell membranes. The depressant effect of anesthetics on carbon dioxide-induced increases in respiration resemble their depressant effects on carbon dioxide-induced increases in glucose transport. This raises the possibility that anesthetics have as a common property inhibition of normal responses to carbon dioxide, including responses other than those involving pulmonary ventilation.

The haemodynamic responses to laryngoscopy and intubation after induction of anaesthesia with thiopentone alone or in combination with 1.5 mg.kg-1 lidocaine and/or 1.5 or 3.0 microgram.kg-1 fentanyl were measured in 150 patients over 64 years of age to determine whether lidocaine, fentanyl or both lidocaine and fentanyl attenuated the pressor response. Fentanyl reduced the rises in systolic, diastolic and mean arterial pressures, heart rate, and rate pressure product and lidocaine decreased the rises in arterial blood pressure and rate pressure product (P less than 0.05). Fentanyl decreased the incidence of marked fluctuations in haemodynamic variables, often seen in geriatric patients (P less than 0.05). The haemodynamic effects of lidocaine and fentanyl were independent of each other. Complications occurred in all groups. Lidocaine-treated patients had fewer cardiac dysrhythmias (P less than 0.05) and 34 per cent of them had tinnitus. Fentanyl-treated patients had a higher incidence of hypotension (P less than 0.05). Respiratory depression developed in only one per cent of the fentanyl-treated patients. Both lidocaine and fentanyl are recommended adjuncts to induction of anaesthesia with thiopentone in geriatric patients.

The objectives of this study were to investigate the duration of analgesia and the development of tolerance following continuous intrathecal administration of morphine and norepinephrine alone, and morphine followed by norepinephrine via mini-osmotic pumps in the rat. Analgesia was assessed by the tail-flick test. In single pump experiments morphine 1 microliter (10 micrograms)/h (7 days) and 0.5 microliter (10 micrograms)/h (14 days) produced analgesia with tolerance by days 5-7. Norepinephrine 1 microliter (15 micrograms)/h (7 days) produced analgesia equivalent to that of morphine with tolerance developing by day 3. Following continuous intrathecal morphine 1 microliter (10 micrograms)/h for 5 days, norepinephrine 1 microliter (15 micrograms)/h for 7 days failed to produce a significant increase in analgesia. This was in contrast to the increase in analgesia seen when the norepinephrine infusion followed a saline infusion. Determination of the norepinephrine concentration in the solution from the osmotic pumps verified that the norepinephrine is stable for the treatment period.

Mice of two strains, Crl:CD-1(1CR)Br and C57BL6, were exposed to nitrous oxide at concentrations of 50, 65 and 80 per cent for 34 or 68 hours. Cessation of nitrous oxide resulted in characteristic convulsions similar to those seen in alcohol withdrawal in all mice. These peaked in severity within 2-3 minutes after removal from nitrous oxide and declined over 6 hours. The severity and duration of these convulsions were related to the nitrous oxide concentration and duration of exposure. Naloxone or naltrexone produced no significant increase in severity of convulsions. The narcotic antagonists did not precipitate acute weight loss or characteristic jumping behaviour seen in animals dependent on opiates. These results demonstrate that chronic exposure to nitrous oxide results in development of physical dependence which resembles alcohol and not opiate dependence. Analgesia and physical dependence produced by nitrous oxide appear to be mediated through separate mechanisms.

Bis-[p-nitrophenyl] phosphate, BNPP, an enzyme inhibitor of the organophosphate class, has been used to inhibit the enzyme, carboxylic ester hydrolase EC 3.1.1.1. Esterases play a major role in the rapid metabolism of propanidid in vivo; in fact, the short duration of action of this intravenous anesthetic agent is due to this rapid hydrolysis. The duration of anesthesia with propanidid alone in healthy mongrel dogs was 10.1 +/- 2.1 (SEM) minutes. When the dogs were pretreated with BNPP, propanidid anesthesia time was prolonged to 38.2 +/- 7.9 (SEM) minutes. Measurements of serum propanidid concentration demonstrated that prolonged high levels of propanidid were associated with the extended anesthesia time. Therefore, BNPP can significantly alter the anesthetic action of propanidid by inhibition of the enzyme system responsible for the rapid hydrolysis of the agent. The experimental model used in the present study provides a means for investigation of effects of certain drugs when their metabolism is impaired.

During a coronary artery bypass operation arterial blood pressure measured with a Bentley Trantec model 800 transducer increased erroneously while continuous electrocautery was being used. This phenomenon has recurred infrequently, with fictitious hypotension being observed in one patient. To reproduce the problem of pressure offset during electrosurgery a bench test demonstrated that with peak to peak voltage of 20 volts from the electrosurgical unit, three of seven Bentley transducers had offsets as much as +/- 50 mmHg. It is important for anaesthetists to determine if electrosurgery units are functioning before treating apparent pressure drifts.

The acute intrathecal (i.t.) administration of 10, 25, 50, and 100 μg morphine and 7.5, 10, 15, and 30 μg (−)norepinephrine (NE) to the rat produced dose-dependent, long-lasting analgesia as assessed by the tail-flick and hot-plate tests. For i.t. morphine, maximum analgesia was observed 30–60 min after drug administration. The duration of analgesia in the tail-flick test ranged from 30 to 150 min; the duration of analgesia in the hot-plate test ranged from 60 to 120 min. For i.t. NE, maximum analgesia was observed 15–60 min after drug infusion. The duration of NE-induced analgesia in the hot-plate test ranged from 45 to 120 min and was 120 min in the tail-flick test. The effects of acute i.t. and intravenous (i.v.) infusions of morphine (10 μg) and NE (15 μg) on heart rate, blood pressure, arterial pH, partial pressure of oxygen [Formula: see text], partial pressure of carbon dioxide [Formula: see text], and standard bicarbonate were determined over 45 min in rats anesthetized with α-chloralose (70 mg/kg). Morphine significantly decreased [Formula: see text] throughout the experiment but did not affect blood pressure, heart rate, pH, [Formula: see text] and standard bicarbonate. A significant increase in blood pressure (137% of control) was observed 2.5 min after i.t. administration of NE. Intravenous NE produced a marked increase in blood pressure (246% of control) followed by a compensatory decrease in heart rate. There were no significant changes in blood gases with i.t. and i.v. NE. The data suggest that i.t. morphine and NE can produce effective analgesia with minimal effects on cardiovascular and respiratory function.

In the rat, the continuous intrathecal (i.t.) infusion of clonidine (0.4 microgram/hr) significantly increased the tail-flick latency (TF) and the threshold for paw pressure (PP) withdrawal for 5 days and decreased the systolic blood pressure (up to 24 mm Hg) for 7 days. The antinociceptive effect of continuous intrathecal infusion of clonidine (0.4 microgram/hr) in the tail flick and paw pressure tests was not attenuated in rats that were tolerant to morphine. The acute intrathecal administration of clonidine (2.7 micrograms) and morphine (1.0 microgram) resulted in a synergistic interaction in the tail-flick and paw pressure tests. A synergistic interaction was also observed during the continuous intrathecal infusion of morphine (1.25 micrograms/hr) and clonidine (0.2 microgram/hr) in the tail-flick and paw pressure tests. Individually, these doses of morphine and clonidine had no antinociceptive effect. However, intrathecal infusion together yielded peak tail-flick and paw pressure responses comparable to that of 0.4 microgram/hr clonidine alone, without affecting systolic blood pressure. No delay in the onset of tolerance to the analgesic effect was observed with the combination as compared with clonidine (0.4 microgram/hr) alone. The data indicate that clonidine-induced spinal analgesia is independent of endogenous opioid systems linked to mu-receptors in the spinal cord, and that optimization of spinal analgesia (e.g. synergism) can be achieved during continuous intrathecal infusion without affecting cardiovascular activity.

Massive endobronchial hemorrhage due to balloon-tipped catheter rupture of a branch of the pulmonary artery in a fully heparinized patient undergoing cardiopulmonary bypass is potentially lethal. Death occurs due to asphyxiation. Endobronchial intubation (double-lumen endotracheal tube) appears to be a simple and effective method for control of the airway and tamponade of the bleeding site, which allows for completion of the surgical procedure until protamine sulphate reversal can be achieved.

Ten studies were performed to examine the time course of arterial and venous thiopenlal concentrations following the administration of thiopental (4mg.kg-1 over 3 min) for cerebral protection during carotid occlusion in nine patients undergoing elective carotid endarterectomy; in five patients the time course of EEC change was also studied. The arterial and venous thiopental concentrations were similar with no evidence of a sustained arterial-venous gradient. The average arterial concentration was 20.1 μg.ml-1 ± 10 (SD) at 2 min after thiopental, and fell rapidly to 13.0 μg.ml-1 ± 3.2 at 5 min, 10.7 μg.ml-1 ± 4.4 at 10minand 6.2 μg-ml-1 at 30 min. After thiopental the EEG record showed an increase in delta activity and in four patients a burst suppression pattern was seen. The duration of burst suppression activity was variable (130 to 367 seconds) but in all instances cortical activity had returned to the pre-lhiopental level by five to ten minutes. Thus concentrations of thiopental of 10-30 μg.ml-1 were associated with EEG burst suppression and both were seen only within the first five minutes after drug administration. In contrast the carotid artery was occluded for considerably longer (26 ± 4) minutes. We conclude that, since there was no sustained arterial-venous gradient, either arterial or venous concentrations are adequate for the study of thiopental pharmacokinetics. However, using burst suppression as an index of cerebral protection with thiopental it appears that the administration of thiopental (4mg.kg-1 over three minutes) before carotid occlusion is not adequate to protect for the duration of the carotid endarterectomy procedure.

The bond(s) which join halothane-diethyl ether azeotrope can be broken by gas chromatography, soda lime, water, and blood,in vitro and in the body. Soda lime breaks the bonding probably in a manner similar to that in gas chromatography. It is postulated that water, blood, and the body break the bonding by extractive distillation. Halothane-diethyl ether ratios in expired breath during azeotrope anaesthesia increased, indicating a greater proportional uptake of diethyl ether by the body; and the ratio tended to decrease during recovery, indicating a greater proportional elimination of diethyl ether. During recovery from azeotrope anaesthesia, expired diethyl ether concentrations were below the minimum flammability limit even without taking into consideration reformation of azeotrope in expired breath, which in itself would decrease the likelihood of flammability. Arterial and venous blood concentrations of halothane and diethyl ether during light azeotrope anaesthesia were determined. The diethyl ether blood concentrations are well below those reported for diethyl ether analgesia.