Introduction Of Halothane Research Articles

Beyond Ether and Chloroform—A Major Breakthrough With Halothane

BackgroundThe use of equipment powered by electricity in the operating room increased the risk of fires in the presence of flammable agents such as ether and cyclopropane. Chloroform was associated with cardiac arrhythmias and liver damage. The introduction of halothane in the late 1950s was heralded as a solution to many problems facing the specialty of anesthesia. We explore whether the manufacturer promptly reported halothane's adverse effects to regulatory agencies and practitioners. SourcesWe consulted documents submitted by Ayerst Laboratories to federal authorities through the Freedom of Information Act, promotional advertisements, package inserts, published articles, and textbooks. ResultsTwo major complications associated with the use of halothane, cardiac arrhythmias and the risk of hepatotoxicity, were disclosed by the manufacturer when the drug was first introduced to the US market. Reports appeared timely and complete; there was no apparent attempt to conceal or otherwise downplay these risks. ConclusionThe process of drug discovery and approval for clinical use has always been a lengthy, complex, and extremely expensive undertaking, with only a small minority of compounds receiving approval. The risk of adverse effects or drug interaction directly impacts commercial viability. In the case of halothane, the manufacturer disclosed major adverse effects, and the drug enjoyed decades of popularity until it was replaced by agents with a better drug profile.

Use of Volatile Anesthetics in Extracorporeal Circulation

Background and objectivesThe use of volatile anesthetics in cardiac surgery is not recent. Since the introduction of halothane in clinical practice, several cardiac surgery centers started to use these anesthetics constantly. ContentIn the last years a great number of studies have shown that the volatile anesthetics have a protecting effect against myocardial ischemic dysfunction. Experimental evidences have shown that the halogenated anesthetics have cardioprotective effects that cannot be only explained by coronary flow alterations or by the balance between myocardium available and consumed oxygen. In addition to that, the use of volatile anesthetics during extracorporeal circulation (ECC) in cardiac surgery plays an important role. Recent studies have proven that these agents have cardioprotective properties and produce better results when the volatile anesthetic is used during the whole surgery procedure, including ECC. The use of halogenated anesthetics through calibrated vaporizers adapted to the ECC circuit via oxygenator membranes has become popular. Therefore, the professionals involved such as anesthesiologists and perfusionists should learn specifcs in order to solve possible doubts.

The Introduction of Halothane into Clinical Practice: The Oxford Experience

This paper reviews the clinical situation in anaesthesia before the introduction of halothane into clinical practice in 1956, emphasising the limitations of agents available at the time. The background to the development of halogenated hydrocarbon compounds as anaesthesia agents is presented, including the involvement of Imperial Chemical Industries in England. The Nuffield Department of Anaesthetics was involved in the clinical trials and the designing and execution of these. The results of their work and the problems encountered are presented.

Effects of Halothane on Phosphatidylcholine, -ethanolamine, -glycerol, and -serine Monolayer Order at a Liquid/Liquid Interface

Vibrational sum-frequency spectroscopy has been employed to examine the vibrational spectra and determine the conformational order of diacylphosphatidyl lipid monolayers at a water-oil interface. These nonlinear vibrational spectra provide direct information about the orientation and the degree of order of the acyl chains of the lipid monolayers. Halothane was introduced into the lipid monolayers, and the resulting changes in acyl chain order were examined. Both neutral (zwitterionic) and charged lipid monolayers were studied in an effort to determine the likely sites of interaction between halothane and the lipid molecules. Two chain lengths (14 and 16 carbons) and four headgroups (choline, ethanolamine, glycerol, and serine) were studied. Each monolayer exhibits significant disorder, and the conformational order of each monolayer is perturbed after the introduction of halothane.

Malignant hyperthermia: advances in clinical management and diagnosis

Malignant hyperthermia: advances in clinical management and diagnosis

The Effect of a Right-to-Left Intracardiac Shunt on the Rate of Rise of Arterial and End-Tidal Halothane in Children

In this prospective study, we evaluated the effect of a right-to-left intracardiac shunt on the rate of rise of end-tidal and arterial halothane concentration in children. Six children aged 23-43 mo undergoing surgical closure of atrial fenestration after Fontan procedure were given 0.8% inspired halothane. End-tidal halothane was recorded at 1-min intervals after the introduction of halothane. Arterial halothane concentrations were determined 0, 1, 3, 5, 10, and 15 min after the introduction of halothane. The sampling was performed before and after closure of the atrial fenestration. The ratio of pulmonary to systemic blood flow (Qp/Qs) increased in this patient population, from 0.58 +/- 0.04 to 0.88 +/- 0.12 (P = 0.01). The rate of rise of end-tidal halothane did not change significantly with a decrease in the magnitude of the right-to-left intracardiac shunt after closure of the atrial fenestration. The ratio of arterial to inspired halothane concentrations at 1, 3, 5, 10, and 15 min were lower before closure of the atrial fenestration compared with after closure (P < 0.05). We conclude that the presence of a right-to-left intracardiac shunt significantly slows the rate of rise of arterial halothane in the face of a constant inspired concentration. The rate of rise of end-tidal halothane is not significantly affected in the presence of a right-to-left intracardiac shunt. Implications: In this prospective study, we found a slower rate of rise of halothane in arterial blood in children with right-to-left intracardiac shunting. Induction of anesthesia by inhalation of volatile anesthetics may therefore be slower in these children. (Anesth Analg 1999;88:759-62)

The effect of a right-to-left intracardiac shunt on the rate of rise of arterial and end-tidal halothane in children.

In this prospective study, we evaluated the effect of a right-to-left intracardiac shunt on the rate of rise of end-tidal and arterial halothane concentration in children. Six children aged 23-43 mo undergoing surgical closure of atrial fenestration after Fontan procedure were given 0.8% inspired halothane. End-tidal halothane was recorded at 1-min intervals after the introduction of halothane. Arterial halothane concentrations were determined 0, 1, 3, 5, 10, and 15 min after the introduction of halothane. The sampling was performed before and after closure of the atrial fenestration. The ratio of pulmonary to systemic blood flow (Qp/Qs) increased in this patient population, from 0.58 +/- 0.04 to 0.88 +/- 0.12 (P = 0.01). The rate of rise of end-tidal halothane did not change significantly with a decrease in the magnitude of the right-to-left intracardiac shunt after closure of the atrial fenestration. The ratio of arterial to inspired halothane concentrations at 1, 3, 5, 10, and 15 min were lower before closure of the atrial fenestration compared with after closure (P < 0.05). We conclude that the presence of a right-to-left intracardiac shunt significantly slows the rate of rise of arterial halothane in the face of a constant inspired concentration. The rate of rise of end-tidal halothane is not significantly affected in the presence of a right-to-left intracardiac shunt. In this prospective study, we found a slower rate of rise of halothane in arterial blood in children with right-to-left intracardiac shunting. Induction of anesthesia by inhalation of volatile anesthetics may therefore be slower in these children.

Respiratory sinus arrhythmia and clinical signs of anaesthesia in children

We have investigated changes in respiratory sinus arrhythmia (RSA) and compared these with clinical signs of anaesthesia in children. Children aged 3-10 yr were anaesthetized by gaseous induction with halothane and nitrous oxide. Multiple heart rate variability (HRV) spectra were obtained by power spectral analysis of continuous epochs of time from before introduction of halothane (baseline) until the pupils were central and fixed (stage 3). Measurement of RSA was performed by integration of the area under the spectral curve within the range of the respiratory frequency +/- 0.15 Hz. In all patients RSA decreased continuously during induction unless stimulation occurred with insertion of an airway. Values of RSA were compared at three times: baseline, loss of pharyngeal tone and stage 3. The decrease in RSA from baseline to loss of pharyngeal tone and from loss of pharyngeal tone to stage 3 was significant (P = 0.003 and P = 0.018, respectively). These results show that RSA can be related to the clinical signs of anaesthesia and has potential as a measure of depth of anaesthesia in children.

The History of Cyprane

The following fascinating account of apparatus history holds special interest for the Editor. With the advent of the value of trichloroethylene as an analgesic, an apparatus similar in concept to the Cyprane inhaler (Duke University Inhaler) was designed in the United States} and found favor. Later, with the introduction of halothane in 1956, as noted in the subsequent article, the Fluotec vaporizer was developed, which revolutionized the safe delivery of potent anesthetic drugs. Mr. Fraser Sweatman, a personal friend from Toronto, Ontario, bought the Cyprane Company and carried on the distribution of the Fluotec until his company was absorbed by the British Oxygen Company. And so the merger continues. WI! are much indebted to Dr. RS. Edmundson and the Proceedings of the History of Anaesthesia Society for permission to reprint this paper in the Bulletin (proc HAS 15:41-42, 1994). . -Editor

New Antiemetic Drugs

In an editorial, Kapur [4] described perioperative nausea and vomiting as the big "little problem following ambulatory surgery." In contrast to the attitudes of some physicians, patients put a high value on freedom from nausea and emesis in the postoperative period and are willing to accept some pain and drowsiness as the cost of controlling PONV [85]. Until recently, there had been little change in the incidence of postoperative emesis since the introduction of halothane into clinical practice in 1956. However, the introduction of the IV anesthetic agent propofol and of the NSAID ketorolac, plus abandonment of the policy of insisting that patients drink before discharge, appear to have contributed to a recent decline in the incidence of emesis. With the availability of new antiserotonin drugs, the incidence of recurrent (intractable) emesis could be further decreased, particularly if combination therapy is used. Further research into the mechanisms of this common postoperative complication may help in improving the management of emetic sequelae in the future. Improvements in antiemetic therapy could have a major impact for surgical patients, particularly those undergoing ambulatory surgery. Just as pain is no longer considered an unavoidable part of the postoperative experience, so should nausea and vomiting be considered an avoidable side effect.

Postoperative nausea and vomiting. Its etiology, treatment, and prevention.

In a recent editorial, Kapur described perioperative nausea and vomiting as "the big 'little problem' following ambulatory surgery."257 Although the actual morbidity associated with nausea is relatively low in health outpatients, it should not be considered an unavoidable part of the perioperative experience. The availability of an emesis basin for every patient in the postanesthesia recovery unit is a reflection of the limited success with the available therapeutic techniques.257 There had been little change in the incidence of postoperative emesis since the introduction of halothane into clinical practice in 1956. However, newer anesthetic drugs (e.g. propofol) appear to have contributed to a recent decline in the incidence of emesis. Factors associated with an increased risk of postoperative emesis include age, gender (menses), obesity, previous history of motion sickness or postoperative vomiting, anxiety, gastroparesis, and type and duration of the surgical procedure (e.g., laparoscopy, strabismus, middle ear procedures). Anesthesiologists have little, if any, control over these surgical factors. However, they do have control over many other factors that influence postoperative emesis (e.g., preanesthetic medication, anesthetic drugs and techniques, and postoperative pain management). Although routine antiemetic prophylaxis is clearly unjustified, patients at high risk for postoperative emesis should receive special considerations with respect to the prophylactic use of antiemetic drugs. Minimally effective doses of antiemetic drugs can be administered to reduce the incidence of sedation and other deleterious side effects. Potent nonopioid analgesics (e.g., ketorolac) can be used to control pain while avoiding some of the opioid-related side effects. Gentle handling in the immediate postoperative period is also essential. If emesis does occur, aggressive intravenous hydration and pain management are important components of the therapeutic regimen, along with antiemetic drugs. If one antiemetic does not appear to be effective, another drug with a different site of action should be considered. With the availability of new antiserotonin drugs, the incidence of recurrent (intractable) emesis could be further decreased. Research into the mechanisms of this common postoperative complication may help in improving the management of emetic sequelae in the future. As suggested in a recent editorial, improvement in antiemetic therapy could have a major impact for surgical patients, particularly after ambulatory surgery. Patients as well as those involved in their postoperative care look forward to a time when the routine offering of an emesis basin after surgery becomes a historical practice.

ARTERIAL WASHIN OF HALOTHANE AND ISOFLURANE IN YOUNG AND ELDERLY ADULT PATIENTS

We have studied the effect of age on washin of isoflurane and halothane by comparing end-tidal (PE') and arterial (Pa) partial pressures of the agents in young (18-32 yr) and elderly (63-82 yr) healthy patients for 20 min after introduction of the agents, before surgery. PE' was measured by infra-red analysis and Pa by gas chromatography. Washin of isoflurane occurred at the same rate in the young and elderly, with no significant difference between young and elderly in PE' or Pa as proportions of the inspired partial pressure (PI). After 20 min of isoflurane administration, mean Pa/PI in the young was 0.57 (95% confidence limit (CL) 0.53-0.62) and 0.55 in the elderly (95% CL 0.51-0.59). Washin of halothane was slower in the elderly than in the young, with Pa/PI significantly less in the elderly from 10 min after introduction of halothane. The difference between age groups, however, was small: mean Pa/PI after 20 min of halothane administration 0.45 (95% CL 0.41-0.49) in the young and 0.38 (95% CL 0.35-0.41) in the elderly. Washin of isoflurane was significantly faster than that of halothane in both young and elderly subjects. For isoflurane, the PE'-Pa gradient was small relative to Pa and did not differ significantly between young and elderly. For halothane, PE'-Pa in the young did not differ significantly from that for isoflurane. In the elderly, PE'-Pa for halothane was significantly greater than in the young and than PE'-Pa for isoflurane.

The effects of halothane on sympathetic ganglionic transmission.

The effects of halothane on ganglionic transmission were studied in the stellate ganglion of the guinea pig using intracellular recordings in vitro. Depression of synaptic transmission is one of the actions common to many general anesthetics. The aim of this study was to investigate which of the processes involved in synaptic transmission are affected by halothane in concentrations comparable to those used during surgical anesthesia. The neurons of the stellate ganglion were depolarized using preganglionic nerve stimulation, postganglionic nerve stimulation, and intracellular stimulation before ad after introduction of halothane (vaporizer settings of 0.75% and 1.5% produced bath concentrations of 8 and 18 mg/dl, respectively). Halothane at both concentrations depressed sympathetic ganglionic transmission which was induced by stimulation of preganglionic nerves. Axonal transmission and the excitability of the postganglionic neurons to direct intracellular stimulation was far less sensitive to halothane than synaptic transmission. The depression of ganglionic transmission seen in the present study was most likely due to a decrease in transmitter release although alterations in postsynaptic receptor properties could have been involved as well. The decrease in sympathetic activity resulting from depression of ganglionic transmission probably contributes to the arterial hypotension seen during halothane anesthesia, along with direct myocardial depression, inhibition of catecholamine release from the adrenal medulla, direct action on vascular smooth muscle, and central sympathetic depression.

Halothane, hypocapnia, and cerebrospinal fluid pressure in neurosurgery.

Recent studies by McDowall, Jennett, Barker, and Fitch [1–4] demonstrated that halothane may increase intracranial pressure, especially in patients with intracranial space-occupying lesions, and suggested that hypocapnia may not prevent such increases. A subsequent editorial [5] concluded that halothane is relatively contraindicated for intracranial surgery. The validity of this conclusion may be questioned because in the patients studied by the McDowall group, the levels of hypocapnia were inconstant, awake cerebrospinal fluid pressure (CSFP) was not measured, and the effect of halothane was observed for only 10 min. The present study was designed to examine the effect of continuous administration of halothane on CSFP at a constant level of hypocapnia induced either before or together with the introduction of halothane. In addition, the combined effect of droperidol, fentanyl, nitrous oxide, and hypocapnia on CSFP was examined.

Recurrent Hepatitis in Patients Receiving Multiple Halothane Anesthetics for Radium Treatment of Carcinoma of the Cervix Uteri

Severe acute hepatocellular jaundice occurred in 6 women who had received multiple halothane anesthetics for radium treatment of carcinoma of the cervix uteri at the Queensland Radium Institute between March 1964 and October 1966. In 5 of the 6 patients recurrent episodes of otherwise unexplained fever, bilirubinuria, or jaundice followed separate exposures to halothane. Two patients died in acute hepatic coma. Treatment of this carcinoma has not been altered significantly in this center in the past 12 years except for the introduction of halothane as the anesthetic of choice in 1961. Most patients receive two or sometimes three radium insertions at weekly intervals under general anesthesia. No case of acute hepatocellular jaundice occurred in this unit before 1961 or after 1966. The use of halothane as an anesthetic for radium insertions was stopped in October 1966; since then an additional 320 patients have been treated without a further instance of hepatocellular jaundice. Fever developing later than the 5th postoperative day after an anesthetic was significantly more common after the use of halothane than other anesthetic agents. A prospective study of 50 patients receiving multiple nonhalothane anesthetics for radium treatment of carcinoma of the cervix uteri revealed none with late postoperative fever and no biochemical or clinical evidence to indicate liver damage.