Halogenated inhalational anaesthetics

The halogenated inhalational anaesthetics halothane, enflurane, isoflurane and desflurane can produce metabolic hepatocellular injury in humans to a variable extent. During metabolism of these anaesthetics, tissue acetylation occurs due to the formation of reactive intermediates. Proteins modified by acetylation may constitute neo-antigens with a potential for triggering an antibody-mediated immune response. The likelihood of suffering post-operative immune hepatitis depends on the amount of the anaesthetic metabolized and is thereby considerably less with enflurane, isoflurane or desflurane compared with halothane. Plasma inorganic fluoride concentrations are regularly increased after sevoflurane. Elevated inorganic fluoride concentrations have been associated with nephrotoxicity following methoxyflurane anaesthesia but not after sevoflurane. Another source of concern is the products of degradation from reactions with carbon dioxide absorbents. Most important is compound A, which has been shown to exhibit nephrotoxicity in rodents. However, no significant changes in renal function parameters have been reported in surgical patients.     

Risk factors for halothane hepatitis

Helothane hepatitis is a rare but sometimes fatal complication of halothane anaesthesia. Examination of case reports has pointed to a number of risk factors. Studies in animals and humans in the laboratory have provided evidence of a complex multifactorial basis for halothane hepatotoxicity, with the following factors playing a part: genetic predisposition; metabolism of halothane; repeated halothane anaesthetics; female sex; age of patient; intrahepatic hypoxia; and enzyme induction. Immunologic changes can be detected in a high percentage of cases of halothane hepatitis; however, studies establishing a cause-effect relationship are not available to determine if these changes cause, or result from, hepatic damage.     

Sevofluran in der Kinderanästhesie Maligne Hyperthermie

Inhalational anaesthesia is the most common anaesthesia technique in paediatric anaesthesia worldwide. Up to now the standard anaesthetic used is halothane. Because halothane is tolerated in the upper airways without side effects it is well suited for the inhalational induction of anaesthesia. However, halothane exerts side effects on the hepatic and the cardiovascular system. This review focuses on the replacement of halothane by sevoflurane in paediatric anaesthesia. Apart from its favorable pharmacological properties sevoflurane is also superior because of economical considerations. The following conclusions are drawn: (1) Halothane and sevoflurane do not cause irritations of the airways and are thus suitable for an inhalational induction. Sevoflurane should be administered in oxygen/nitrous oxide during induction of anaesthesia to reduce excitation. (2) The MAC values of sevoflurane are age dependent. In contrast to adult patients the MAC values of sevoflurane are only decreased by 20 to 25% in paediatric patients. The end-tidal concentration of sevoflurane necessary for intubation or insertion of a laryngeal mask is 2 to 4 Vol.%. (3) The blood/gas partition coefficient of sevoflurane is low, resulting in shorter induction times with sevoflurane compared to halothane. The so called priming technique with 8 Vol.% of sevoflurane results in shorter induction times. Consequently, times to recovery and psycho-motor functions are favourable for sevoflurane compared to halothane in paediatric patients. However, shorter recovery times lead to earlier perception of postoperative pain, requiring adequate pain management. (4) The hemodynamic stability after administration of sevoflurane is favourable to that after halothane in paediatric patients, leading to significantly less bradycardia. (5) In paediatric patients no negative effects on kidney function have been observed after administration of sevoflurane. There is no scientific basis for organotoxic effects, thus sevoflurane is suitable for low-flow and minimal-flow anaesthesia. (6) The duration of the action of muscle relaxants is increased to a greater extent in presence of sevoflurane compared to halothane. Consequently, the total dose of muscle relaxants can be reduced using sevoflurane. (7) Similar to the established inhalational anaesthetics sevoflurane triggers malignant hyperthermia (MH) and must not be used in patients in which MH is suspected or in which a predisposition for MH is known.     

Durchblutung und Metabolismus von Leber und Splanchnikusgebiet unter Sevofluran

In common with other halogenated volatile anaesthetics, sevoflurane causes a dose-related cardiovascular depression and therefore the affection of blood flow of different organ systems is suggested. So far known, sevoflurane is not different compared to isoflurane in affecting liver and splanchnic blood flow. Concluded from former published studies there was no case of hepatic toxicity of sevoflurane been published so that this substance can be used in patients with reduced hepatic function. The primary organic metabolite of sevoflurane is hexafluorisopropanol (HFIP), which is readily and rapidly conjugated with glucuronic acid. No reactive intermediates are formed and HFIP appears to be an unlikely compound to form liver protein adducts. For this reasons sevoflurane ”hepatitis” is not expected. Like most other inhalation agents sevoflurane increase the neuromuscular blockade after treatment with muscle relaxants in anaesthesia. The MAC values of Sevoflurane where reduced after the application of nitrous oxide, benzodiazepines and opiates. From human studies we know that chronic drug therapy with isoniazid induces the metabolism of sevoflurane, enflurane and isoflurane, markedly increasing peak plasma fluoride concentrations. However, barbiturates as well as phenytoin do not influence the metabolism of sevoflurane because these agents do not induce the major hepatic defluorinating enzyme cytochrome P450 2E1. Obesity, untreated diabetes mellitus and alcohol abuse increase the hepatic content and activity of cytochrome P450 2E1 and therefore enhanced anaesthetic defluorination is to be suspected. Until now, there are no studies about sevoflurane anaesthesia in patients after liver transplantation but the extremely low hepatotoxic potential as compared to isoflurane provides no argument to avoid this substance for anesthesia in liver transplanted patients.     

New halogenated agents: should I change my practice?

Sevoflurane and Desflurane are relatively new halogenated agents which make induction and control of depth of anaesthesia easier, recovery rapid and of good quality and they have less side-effects and toxicity. In children sevoflurane could replace halothane because it provides smooth and rapid induction with less cardiovascular depression and arrhythmias. Desflurane is not used because of its pungent odour. In adults sevoflurane could be preferred to desflurane because it allows rapid induction and laryngeal mask insertion or tracheal intubation without myorelaxants, a similar time of recovery, no clinical evidence for renal and hepatic toxicity, no more costs for anaesthesia for a lower MAC.     

Early and late post-ischaemic recovery of contractile function is affected to different degrees by isoflurane and halothane in the anaesthetized rabbit model

The protective efficacy of halogenated anaesthetics on myocardial injury has never been compared during early reperfusion and late reperfusion in an in vivo animal model. We compared recovery of left ventricular function under isoflurane (0.5 MAC) and halothane (0.5 MAC) anaesthesia after a brief period of regional ischaemia (15 min) in acutely instrumented rabbits. Rabbits were instrumented for the measurement of regional segment length and left ventricular pressure. Rabbits receiving isoflurane showed greater recovery of systolic shortening fraction (%SS) both during early and late reperfusion compared with halothane anaesthesia. Isoflurane protected the post- ischaemic myocardium to a greater extent than halothane anaesthesia. Early recovery of contractile function may be a predictor of contractile recovery during the later stages of reperfusion.      

PONV: a problem of inhalational anaesthesia?

Even nowadays every third or fourth patient suffers from postoperative nausea and vomiting (PONV) after general anaesthesia with volatile anaesthetics. There is now strong evidence that volatile anaesthetics are emetogenic and that there are no meaningful differences between halothane, enflurane, isoflurane, sevoflurane, and desflurane in this respect. However, when propofol is substituted for volatile anaesthetics the risk for PONV is reduced by only about one fifth, indicating that there are other even more important causes for PONV following general anaesthesia. A main causative factor might be the use of perioperative opioids, but their impact--relative to other factors including volatile anaesthetics--has never been quantified. Patient-specific risk factors have also been shown to be clinically relevant; they are therefore included in the calculation of simplified risk scores that allow prediction of a patient's risk independent of the type of surgery. Although controversial, the well-known different incidences following certain types of surgery are most likely caused by patient-specific and anaesthesia-related risk factors. There is a common consensus that prophylaxis with anti-emetic strategies is rarely justified when the risk of PONV is low, while it is warranted in case of imminent medical risk associated with vomiting or in a patient with a high risk for PONV. A recently published large multicentre trial of factorial design, IMPACT, has demonstrated that various anti-emetic strategies are associated with a very similar and constant relative reduction rate of about 25-30% and that the main predictor for the efficacy of prophylaxis is the patient's risk for PONV. Interestingly, all anti-emetics (dexamethasone, droperidol and ondansetron) work independently, so that their combined benefit can be derived directly from the single effects. The effectiveness of the anti-emetics was also independent of a variety of risk factors, including volatile anaesthetics. This means that any anti-emetic prophylaxis for PONV induced by volatile anaesthetics is equally effective. Of course, the most logical approach for prevention would be the omission of volatile anaesthetics and nitrous oxide using a total intravenous anaesthesia with propofol. However, since volatile anaesthetics are probably not the most important risk factors, it might be even better--if appropriate--to avoid general anaesthesia by using a regional, opioid-free anaesthesia if PONV is a serious problem.     

Volatile anaesthetics and the atmosphere: atmospheric lifetimes and atmospheric effects of halothane, enflurane, isoflurane, desflurane and sevoflurane

The atmospheric lifetimes of the halogenated anaesthetics halothane, enflurane, isoflurane, desflurane and sevoflurane with respect to reaction with the hydroxyl radical (OH.) and UV photolysis have been determined from observations of OH. reaction kinetics and UV absorption spectra. Rate coefficients for the reaction with OH radicals for all halogenated anaesthetics investigated ranged from 0.44 to 2.7 x 10(-14) cm3 molec-1 s-1. Halothane, enflurane and isoflurane showed distinct UV absorption in the range 200-350 nm. In contrast, no absorption in this wavelength range was detected for desflurane or sevoflurane. The total atmospheric lifetimes, as derived from both OH. reactivity and photolysis, were 4.0-21.4 yr. It has been calculated that up to 20% of anaesthetics enter the stratosphere. As a result of chlorine and bromine content, the ozone depletion potential (ODP) relative to chlorofluorocarbon CFC-11 varies between 0 and 1.56, leading to a contribution to the total ozone depletion in the stratosphere of approximately 1% for halothane and 0.02% for enflurane and isoflurane. Estimates of the greenhouse warming potential (GWP) relative to CFC-12 yield values of 0.02-0.14, resulting in a relative contribution to global warming of all volatile anaesthetics of approximately 0.03%. The stratospheric impact of halothane, isoflurane and enflurane and their influence on ozone depletion is of increasing importance because of decreasing chlorofluorocarbons globally. However, the influence of volatile anaesthetics on greenhouse warming is small.      

Comparison of the effects of sevoflurane and halothane on the quality of anaesthesia and serum glutathione transferase alpha and fluoride in paediatric patients

We have compared sevoflurane and halothane anaesthesia in paediatricpatients with reference to induction and recovery. We also assessedhepato-cellular integrity by measurement of serum gluta-thionetransferase alpha (GSTA) concentration and sevoflurane metabolismby serum fluoride concentration. Fifty unpremedicated 5–12-yr-oldchildren were allocated randomly to induction of anaesthesiavia a face mask with 66% nitrous oxide in oxygen and sevoflurane(up to 7%) or halothane (up to 3.5%). Anaesthesia was maintainedfor 1.8 h at 1–1.2 MAC of the volatile agent. Childrenreceiving sevoflurane had significantly faster induction andrecovery variables than those receiving halothane. There wasa small postanaesthetic increase in GSTA in both groups, suggestingthat halothane and sevoflurane may disturb hepato-cellular integrity.Serum concentrations of fluoride were significantly greaterafter sevoflurane than after halothane anaesthesia. There wereno clinical signs or symptoms of hepatic or renal disturbance.Children tolerated sevoflurane better than halothane, whichmay have been because of the non-pungency of sevoflurane andthe rapid psycho-motor recovery after anaesthesia.     

Serum glutathione S-transferase alpha as a measure of hepatocellular function following prolonged anaesthesia with sevoflurane and halothane in paediatric patients

We studied the effects of prolonged anaesthesia (4.3-7.7 h) with sevoflurane and halothane on hepatic function in 14 paediatric patients. Hepatic function was assessed using serum concentrations of liver-specific glutathione S-transferase alpha (GSTA) before and 0, 3 and 15 h after the end of anaesthesia. A transient significant increase in GSTA over baseline was observed in the sevoflurane group, but not in the halothane group, and the difference between the groups was not significant. These data suggest that, although statistically insignificant, the use of sevoflurane for prolonged anaesthesia in paediatric patients is more likely than halothane to be involved in damage to hepatic function.     

Effects of halothane and sevoflurane on the paediatric respiratory pattern

Using a respiratory inductive plethysmograph, we investigated the effects of halothane and sevoflurane on the paediatric respiratory pattern under spontaneous breathing. We measured tidal volume per weight, respiratory rate, partial pressure of end-expiratory carbon dioxide (Pet_CO2), rib cage contribution to ventilation (%RC) and phase shift between rib cage and abdominal movements at 0.5, 1.0 and 1.5 MAC of these inhalational anaesthetics in oxygen. Both of these anaesthetics increased Pet_CO2 significantly with increase in depth of anaesthesia; sevoflurane produced more profound respiratory depression than halothane at high MAC. Both agents decreased %RC significantly with increase in depth of anaesthesia; paradoxical respiration occurred in the halothane group at high MAC. The profound respiratory depression of sevoflurane is due to both decreased tidal volume and decreased respiratory rate. The paradoxical respiration under halothane may be attributed to the potent suppression of intercostal muscle function and may be partly due to compensatory sparing effect on respiratory rate, which leads to the increase in airway flow and airway resistance.     

Sevoflurane versus halothane: effect of oxycodone premedication on emergence behaviour in children

BACKGROUND: Clinical studies have provided conflicting conclusions about whether the frequency of emergence agitation is increased in children following sevoflurane anaesthesia. The purpose of the study was to determine a frequency and duration of agitation with halothane and sevoflurane anaesthesia and whether oxycodone premedication affected the incidence of emergence agitation in children. METHODS: We measured and compared halothane and sevoflurane recovery in 130 patients using a 5-point scale measuring emergence behaviour every 10 min during the first 60 min of recovery or until discharge. RESULTS: We used this 5-point scale to assess the presence or absence of emergence agitation and found a frequency of emergence agitation of more than 40% in children who received halothane and sevoflurane anaesthesia. CONCLUSIONS: Oxycodone reduced the frequency of agitation in children who received halothane, but not in the children who received sevoflurane anaesthesia.     

Enflurane Hepatitis. A Report of a Case with a Previous History of Halothane Hepatitis

"Enflurane hepatitis" has only recently been accepted as a disease entity. As far as the authors know, this paper is the first report on enflurane hepatitis in a patient with a previous history of halothane hepatitis. Our conclusion is that a potent halogenated inhalation agent should never be given to a patient if a prior administration of another such agent has led to the development of hepatic injury.     

Case report: Fatal hepatic failure after aortic valve replacement and sevoflurane exposure

PURPOSE: To report a case of lethal hepatotoxicity possibly caused by sevoflurane. CLINICAL FEATURES: A 76-yr-old woman with a history of four previous minor surgical procedures developed acute liver failure after general anesthesia with sevoflurane, sufentanil and propofol for aortic valve replacement. After an uneventful procedure the patient was extubated 4.5 hr after surgery. On the second postoperative day, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) increased. On the third postoperative day liver failure occurred, ALT peaked at 10504 UxL(-1) and AST at 15516 UxL(-1), and coagulopathy with an international normalized ratio of 4.6 developed. Liver transplantation was considered but rejected as a therapeutic option. The patient died three days after the operation in multiple organ failure triggered by hepatic failure. Other possible causes for liver failure were excluded. CONCLUSIONS: Sevoflurane hepatitis as a cause for liver failure may be implicated in this patient undergoing valve surgery. Unlike other halogenated anesthetic drugs, sevoflurane is not metabolized to hepatotoxic trifluoroacetyl proteins. However, compound A may react with proteins and may be transformed into antigenic material. We suggest that all halogenated anesthetics may be implicated with acute liver injury.     

Hepatocellular integrity during and after isoflurane and halothane anaesthesia in surgical patients

Subclinical disturbance in hepatocellular integrity, indicated by glutathione transferase Alpha (GSTA), has been associated with halothane, sevoflurane and propofol, but not with isoflurane anaesthesia. We anaesthetized 82 patients with isoflurane or halothane at 1 MAC for superficial surgery. GSTA concentration were measured with a sensitive time-resolved immunofluorometric assay in serum samples. GSTA concentrations increased from a baseline value of geometric mean 1.8 micrograms litre-1 (95% confidence intervals 1.4-2.2 micrograms litre-1) to a peak of 4.3 (3.3-5.7) micrograms litre-1 in the isoflurane group and from 2.1 (1.6-2.9) micrograms litre-1 to 6.2 (4.1- 9.5) micrograms litre-1 in the halothane group. The change in GSTA was significant within groups but the difference between groups was not significant. Two patients exhibited an unexpectedly large increase in GSTA (peaks 370 and 620 micrograms litre-1) and a mild increase in alanine aminotransferase after halothane anaesthesia. We conclude that hepatocellular integrity was mildly disturbed after isoflurane and halothane anaesthesia but there was no difference between anaesthetics. Halothane anaesthesia may be associated with more advanced hepatocellular disturbance in some cases.      

Anaesthetic-induced myocardial preconditioning: fundamental basis and clinical implications

OBJECTIVE: Volatile halogenated anaesthetics offer a myocardial protection when they are administrated before a myocardial ischaemia. Cellular mechanisms involved in anaesthetic preconditioning are now better understood. The objectives of this review are to understand the anaesthetic-induced preconditioning underlying mechanisms and to know the clinical implications. DATA SOURCES: References were obtained from PubMed data bank (http://www.ncbi.nlm.nih.gov/entrez/query.fcgi) using the following keywords: volatile anaesthetic, isoflurane, halothane, sevoflurane, desflurane, preconditioning, protection, myocardium. DATA SYNTHESIS: Ischaemic preconditioning (PC) is a myocardial endogenous protection against ischaemia. It has been described as one or several short ischaemia before a sustained ischemia. These short ischaemia trigger a protective signal against this longer ischaemia. An ischemic organ is able to precondition a remote organ. It is possible to replace the short ischaemia by a preadministration of halogenated volatile anaesthetic with the same protective effect, this is called anaesthetic PC (APC). APC and ischaemic PC share similar underlying biochemical mechanisms including protein kinase C, tyrosine kinase activation and mitochondrial and sarcolemnal K(ATP) channels opening. All halogenated anaesthetics can produce an anaesthetic PC effect. Myocardial protection during reperfusion, after the long ischaemia, has been shown by successive short ischaemia or volatile anaesthetic administration, this is called postconditioning. Ischaemic PC has been described in humans in 1993. Clinical studies in human cardiac surgery have shown the possibility of anaesthetic PC with volatile anaesthetics. These studies have shown a decrease of postoperative troponin in patient receiving halogenated anaesthetics.     

Neue Inhalationsanästhetika

Recently, two new halogenated volatile anaesthetics, sevoflurane and desflurane, have been approved for clinical use in Germany. Their low solubility in blood is the most important common property, and this represents the most obvious difference from the inhalational anaesthetics currently used. Extensive clinical and experimental evaluations have confirmed the superior pharmacokinetic properties predicted. Both sevoflurane and desflurane provide more rapid emergence from anaesthesia, permit easier titration of the anaesthetic dose during maintenance and offer more rapid recovery from anaesthesia. For sevoflurane, there are additional advantages: a pleasant odor, negligible airway irritation, and excellent pharmacodynamic characteristics that even provide cardiovascular stability comparable to isoflurane. A certain disadvantage and source of potential nephrotoxicity result from the metabolism of sevoflurane (2–5%) to anorganic fluoride and degradation to compound A in carbon dioxide absorbents. The extensive clinical data reported to date have revealed no evidence that sevoflurane has adverse renal effects. New insight into the pathomechanism of nephrotoxicity associated with either production of fluoride or compound A may well support clinical experience. Desflurane strongly resists in vivo metabolism and because of this it appears to be devoid of toxicity. Nevertheless, potential side-effects may result from degradation in dry absorbents and subsequent release of CO, from its extreme pungency and irritating airway effects. Thus, desflurane is not recommended for induction of anaesthesia, especially in children. The tendency for desflurane transiently to stimulate sympathetic activity, especially at concentrations above 1.0 MAC, limits its application in patients with cardiac disease.     

Hepatic Effects of Halothane,Isoflurane or Sevoflurane Anaesthesia in Dogs

The effects of halothane, isoflurane and sevoflurane anaesthesia on hepatic function and hepatocellular damage were investigated in dogs, comparing the activity of hepatic enzymes and bilirubin concentration in serum. An experimental study was designed. Twenty‐one clinically normal mongrel dogs were divided into three groups and accordingly anaesthetized with halothane (n = 7), isoflurane (n = 7) and sevoflurane (n = 7). The dogs were 1–4 years old, and weighed between 13.5 and 27 kg (18.4 ± 3.9). Xylazine HCI (1–2 mg/kg) i.m. was used as pre‐anaesthetic medication. Anaesthesia was induced with propofol 2 mg/kg i.v. The trachea was intubated and anaesthesia maintained with halothane, isoflurane or sevoflurane in oxygen at concentrations of 1.35, 2 and 3%, respectively. Intermittent positive pressure ventilation (tidal volume, 15 ml/kg; respiration rate, 12–14/min) was started immediately after intubation and the anaesthesia lasted for 60 min. Venous blood samples were collected before pre‐medication, 24 and 48 h, and 7 and 14 days after anaesthesia. Serum level of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and gamma‐glutamyltransferase (GGT), lactate dehydrogenase (LDH GGT) activities and bilirubin concentration were measured. Serum AST, ALT and GGT activities increased after anaesthesia in all groups. In the halothane group, serum AST and ALT activities significantly increased all the time after anaesthesia compared with baseline activities. But in the isoflurane group AST and ALT activities increased only between 2 and 7 days, and in the sevoflurane group 7 days after anaesthesia. GGT activity was increased in the halothane group between 2 and 7 days, and in the isoflurane and sevoflurane groups 7 days after anaesthesia. All dogs recovered from anaesthesia without complications and none developed clinical signs of hepatic damage within 14 days. The results suggest that the use of halothane anaesthesia induces an elevation of serum activities of liver enzymes more frequently than isoflurane or sevoflurane from 2 to 14 days after anaesthesia in dogs. The effects of isoflurane or sevoflurane anaesthesia on the liver in dogs is safer than halothane anaesthesia in dogs.     

Adsorption of carbon dioxide gas

OBJECTIVES: To analyse the various methods for carbon dioxide absorption in anaesthesia, the available absorbents and their modes of use. DATA SOURCES: We searched the Medline and Internet databases for papers using the key words: carbon dioxide absorption, soda-lime, zeolite. We also had correspondence and contacts with soda lime manufacturers. STUDY SELECTION: All types of articles containing data on CO2 absorption. DATA EXTRACTION: The articles were analysed for the benefits and adverse effects of the various absorbents. DATA SYNTHESIS: Carbon dioxide absorption enables the use of low flow anaesthesia, and a decreased consumption of medical gases and halogenated anaesthetics, as well as reduced pollution. Chemical absorbents (soda-lime and barium hydroxide lime (Baralyme) may produce toxic compounds: carbon monoxide with all halogenated anaesthetics and compound A with sevoflurane. Simple measures against desiccation of the lime prevent carbon monoxide production. The toxicity of compound A, shown in the rat, has not been proven in clinical anaesthesia. Recent improvements in manufacture processes have decreased the powdering of lime. Moreover, filters inserted between the anaesthesia circuit and the patient abolish the risk for powder inhalation.     

Drugs and the liver

The liver and its diseases can affect drug metabolism, and drugs can modify liver function. Ethanol produces dose-dependent liver damage and is the commonest cause of cirrhosis, and aspirin has been associated with Reye’s syndrome in children, which involves fatty degeneration of the viscera and liver failure. Most inhalational anaesthetic agents have been associated with postoperative liver dysfunction, but much of the literature concerns halothane. Halothane-associated hepatitis has been attributed to a direct effect of halothane or a metabolite upon liver cells, whereas fulminating hepatic failure has been attributed to an immune reaction following repeat halothane exposure.