Porphyrias
2000; Elsevier BV; Volume: 85; Issue: 1 Linguagem: Inglês
10.1093/bja/85.1.143
ISSN1471-6771
Autores Tópico(s)Neonatal Health and Biochemistry
ResumoBr J Anaesth 2000; 85: 143–53 The porphyrins play a critical role in biology, being involved in a wide range of reactions related to oxygen utilization, transport, storage or formation. The synthetic pathway involved in the production of the porphyrins is complex and is governed by a sequence of enzymes. A defect in any of these enzymes results in accumulation of the preceding intermediaries and produces one form or another of the diseases known as the porphyrias. This review briefly outlines porphyrin synthesis, the diseases that arise from errors in porphyrin metabolism and the anaesthetic implications of these disorders. The porphyrins are cyclic structures formed by the linkage of four pyrrole rings through methene (–CH=) bridges. The porphyrin ring can, via the nitrogen atom of the pyrrole subunits, form complexes with many metals, giving metalloporphyrins. These compounds are widely distributed throughout the plant and animal kingdoms where they are essential for photosynthesis, oxygen transport, electron transport, the reduction of molecular oxygen and various hydroxylation reactions. Of the metalloporphyrins, the most biologically important are those containing iron (to form haem) and magnesium (to form chlorophyll). The porphyrins are highly coloured and exhibit red fluorescence in ultraviolet light. The porphyrin precursors, the porphyrinogens, which are linked by methyl (CH2) bridges (Fig. 1), are colourless. When exposed to light and oxygen, they spontaneously convert to porphyrins. In human physiology, haem is the most important of the porphyrins. In its biologically active form, haem is bound to various proteins to form haemoproteins, which include haemoglobin, myoglobin and all of the cytochromes (including the P450 series) together with numerous other compounds involved in oxidation and hydroxylation reactions. The biosynthesis of haem commences with formation of δ-aminolaevulinic acid (ALA) by the condensation and subsequent decarboxylation of two freely available molecules—succinyl co-enzyme A (succinyl CoA) and the amino acid glycine—in a step catalysed by the enzyme ALA synthetase. This process occurs in the mitochondria (where succinyl CoA is produced in the citric acid cycle); ALA synthetase appears to be the most important rate-limiting enzyme in porphyrin biosynthesis. The next step in porphyrin biosynthesis occurs outside the mitochondria where two molecules of ALA condense under the influence of the enzyme ALA dehydratase to form the monopyrrole subunit of the porphyrin ring, porphobilinogen (PBG). The enzyme PBG deaminase catalyses the condensation of four molecules of PBG to form hydroxymethylbilane, which is then converted into the first of the porphyrinogens, uroporphyrinogen, under the influence of uroporphyrinogen cosynthetase. The stepwise decarboxylation and conversion of uroporphyrinogen acetate groups to methyl substituents results in the formation of coproporphyrinogen which then re-enters the mitochondria where oxidation and chelation with ferrous iron result in the production of haem. These steps together with the relevant enzymes are illustrated in Fig. 2. The porphyrin biosynthetic pathway operates very efficiently and <2% of the porphyrin precursors are produced in excess of that required for haem synthesis. Consequently, the finding of increased concentrations of porphyrin intermediates in urine or stool indicates an abnormality of production, with a partial block somewhere in the enzymatic chain. The control of the production of haem is effected primarily through ALA synthetase. This enzyme has a low endogenous activity and also has a very short half-life, making it ideally suited to a regulatory role. The formation of ALA synthetase is controlled by the concentration of haem itself, which forms a negative feedback loop, thus ensuring that the level of haem production matches requirements closely. The concentration of haem required to suppress enzyme production is extremely low, of the order of 10−7 M, while that required to inhibit enzyme activity is of the order of 10−5 M. However, the concentration of haem generated within the mitochondrion is insufficient to inhibit the enzyme, so ALA synthetase control is thought to be exerted by a volatile 'free haem pool' within the cytosol.38Moore MR McColl KE Rimington C Goldberg A Disorders of Porphyrin Metabolism. Plenum, London1987Crossref Google Scholar It is also possible that some measure of control is exerted by the availability of glycine. ALA synthetase is readily inducible and can respond rapidly to increased haem requirements such as those resulting from the administration of drugs which require cytochrome P450 for their metabolism. Thus the availability and activity of the enzyme depend on the intracellular level of haem, and the demand for haem by metabolic processes. This fact is of great relevance in the development of the porphyrias, in which an increase in haem requirements in the face of a partial block in the synthetic pathway results in the overproduction of ALA synthetase, and consequently of the pathway intermediates before the block. The enzyme PBG deaminase also seems to have a regulatory role that is of relevance in some porphyric conditions. Under normal circumstances, an increase in production of ALA results in an increase in activity of PBG deaminase, thus enabling the synthetic pathway to continue efficiently. However, in acute forms of the disease, there appears to be a concomitant failure of PBG deaminase to respond appropriately, with a resultant accumulation of the early components of the metabolic pathway. Recent work has shown that coproporphyrinogen and protoporphyrinogen, both of which are produced in excess in variegate porphyria, can also inhibit PBG deaminase.34Meissner PN Enzyme studies in variegate porphyria. PhD thesis. University of Cape Town, Cape Town1990Google Scholar The porphyrias can be classified by the main site of the defect (hepatic or erythropoietic), by the enzyme defect (Fig. 2) or by whether or not they cause acute symptoms (Table 1). The latter method of classification is particularly useful for anaesthetic practice as only the acute forms of the porphyrias are of major anaesthetic relevance, since these are the conditions that may result in life-threatening reactions to drugs. All the hepatic porphyrias except for porphyria cutanea tarda are acute porphyrias.Table 1Classification of the porphyriasType of porphyriaExamplesAcuteacute intermittent porphyria (AIP); variegate porphyria (VP); hereditary coproporphyria (HC); plumboporphyria (PP)Non-acuteporphyria cutanea tarda (PCT); erythropoietic porphyrias: congenital erythropoietic porphyria (CEP); erythropoietic protoporphyria (EPP) Open table in a new tab The acute porphyrias include acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP) and the very rare plumboporphyria (PP). With the exception of PP, which is recessive, these porphyrias are inherited as non-sex-linked, autosomal dominant conditions with variable expression. Like many inherited conditions, they have a patchy distribution. The overall frequency of AIP in Europe is estimated to be one per 20 000, with one per 10 000 in Northern Sweden and an even higher incidence in Lapland. VP is particularly common in the Afrikaner community in South Africa where the prevalence has been estimated at between one in 250 and one in 500,12Dean G The Porphyrias: A Story of Inheritance and Environment. 2nd edn. Pitman Medical, Bristol1971Google Scholar but the disease is recognized worldwide and in Britain is thought to be about a third as prevalent as AIP.17Elder GH Hift RJ Meissner PN The acute porphyrias.Lancet. 1997; 349: 1613-1617Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar The true incidence of these conditions is hard to estimate as many individuals remain asymptomatic throughout their lives; this is particularly true of HCP where more than half the affected individuals may be symptom-free. The enzyme defects in porphyria are deficiencies rather than absolute deficits. In most patients with clinically expressed porphyria, the level of enzyme reduction is generally of the order of 50%,26Jackson S Genetic and metabolic diseases. Inborn errors of metabolism.in: Katz J Benumof J Kadis L Anaesthesia and Uncommon Diseases. 3rd edn. WB Saunders, Philadelphia1990: 84-99Google Scholar suggesting that the defective allele produces essentially no enzyme activity. This may be why homozygotes are extremely rare, as complete failure to produce haem is probably incompatible with life. Increasingly, however, families are being identified in which mutations appear to encode proteins with some residual activity. Where such a family marries into another carrying a more typical mutation for the same defect, compound heterozygotes may result; such patients express low levels of enzyme and characteristically are phenotypically severely affected. Although there is no direct influence of gender on the pattern of inheritance, attacks occur more frequently in women and are most frequent in the third and fourth decades. Few cases have been reported before puberty, and attacks are rare after the menopause,29Kantor G Rolbin SH Acute intermittent porphyria and caesarean delivery.Can J Anaesth. 1992; 39: 282-285Crossref PubMed Scopus (26) Google Scholar although presentation has occurred between the ages of 7 and 75 yr.27Jensen NF Fiddler DS Striepe V Anesthetic considerations in porphyrias.Anesth Analg. 1995; 80: 591-599PubMed Google Scholar Acute attacks of porphyria are most commonly precipitated by events that decrease haem concentrations, thus increasing the activity of ALA synthetase and stimulating the production of porphyrinogens. Acute exacerbations may be precipitated by a number of factors, including physiological hormonal fluctuations (such as those occurring with menstruation), fasting, dehydration, stress and infection.14Disler PB Moore MR Drug therapy in the acute porphyrias.Clin Dermatol. 1985; 3: 112-124Abstract Full Text PDF PubMed Scopus (22) Google Scholar Though pregnancy was thought to represent a particular risk in the porphyric patient, with acute attacks reportedly occurring in a high proportion of pregnant patients (24–95%) with AIP,29Kantor G Rolbin SH Acute intermittent porphyria and caesarean delivery.Can J Anaesth. 1992; 39: 282-285Crossref PubMed Scopus (26) Google Scholar more recent experience suggests that the rate in pregnancy is lower. Frequent spontaneous abortion (6–12%) and hypertension may, however, complicate pregnancy in the patient with AIP and there is an increased incidence of low-birthweight infants. Nevertheless, enzyme-inducing drugs are by far the most important trigger factors, particularly in relation to anaesthesia. Acute attacks are characterized by severe abdominal pain, autonomic instability, electrolyte disturbances and neuropsychiatric manifestations; they may range from a mild disturbance to fulminating attacks with a fatal outcome.17Elder GH Hift RJ Meissner PN The acute porphyrias.Lancet. 1997; 349: 1613-1617Abstract Full Text Full Text PDF PubMed Scopus (141) Google Scholar Neuromuscular weakness, which may progress to quadriparesis and respiratory failure, is the most prominent and potentially lethal neurological manifestation, but sensory losses also occur. Central nervous system involvement with upper motor neuron lesions, cranial nerve palsies and involvement of the cerebellum and basal ganglia are less commonly seen. Permanent neurological lesions, especially parasympathetic dysfunction, can occur, particularly in AIP, although this is rarely seen unless the attacks have been multiple or of long duration. Though psychiatric disturbances were believed to occur in a high percentage of overt sufferers from the condition, the current belief is that these have been greatly exaggerated. Seizures may occur during an acute attack. Gastrointestinal symptoms are the most common and typically present with severe abdominal pain with vomiting and occasionally diarrhoea. Clinical examination of the abdomen is remarkably normal considering the severity of the symptoms,15Eales L Day RS Blekkenhorst GH The clinical and biochemical features of variegate porphyria: an analysis of 300 cases studied at Groote Schuur Hospital, Cape Town.Int J Biochem. 1980; 12: 837-853Crossref PubMed Scopus (81) Google Scholar since there is no peritonism. Abdominal pain is thought to relate directly to the autonomic neuropathy, though there may be a contribution from abnormal bowel function with alternating areas of spastic and relaxed bowel. Ganglionic blockade may, therefore, be helpful in this condition,6Campos JH Stein DK Michel MK Moyers JR Anesthesia for aortic valve replacement in a patient with acute intermittent porphyria.J Cardiothorac Vasc Anesth. 1991; 5: 258-261Abstract Full Text PDF PubMed Scopus (8) Google Scholar though it is seldom necessary, since the abdominal complaints commonly abate promptly with resolution of the attack. Dehydration and electrolyte abnormalities of Na+, K+ and Mg2+ may be severe and careful fluid and electrolyte management is essential. Cardiovascular instability—with tachycardia and arterial pressure changes of hypertension or, less commonly, hypotension—occurs, particularly in AIP, and permanent hypertension may result. Between attacks, complete remission is the norm, and many subjects with the genetic defect remain asymptomatic. This is particularly important when planning a drug regimen in patients potentially at risk, as patients with so-called 'silent' (or latent) porphyria may have their first symptoms precipitated by injudicious administration of triggering agents. In all the acute porphyrias, acute attacks are characterized by markedly increased concentrations of ALA and PBG in the urine, though in PP the elevation is limited to ALA since the enzyme defect here lies before the step in which PBG is synthesized. Drugs may trigger an acute attack of porphyria in many ways, most of which depend on an increased demand for haem production or a failure of haem inhibitory feedback as the final common pathway. Thus drugs may induce the transcription of ALA synthetase directly through mRNA or may interfere with the negative feedback control which haem exerts on ALA synthetase production. Drugs may interfere with the haem synthetic pathway, thus reducing the level of haem production, or they may increase the demand for haem by increasing utilization, for example through increased demand for oxidative processes mediated through the cytochromes. This multitude of potential pathways and the great variety of drug structures make it impossible to predict which agents are likely to be porphyrinogenic. The only properties of drugs which are clearly linked to porphyrinogenicity are lipid solubility11De Matteis F Aldridge WN Haem and Haemoproteins. Springer-Verlag, Berlin1978Crossref Google Scholar and membrane fluidization.42Neilson IR Singer MA Marks GS Association between the membrane-fluidizing properties and porphyrin-inducing activity of alfaxolone and related steroids.Mol Pharmacol. 1980; 18: 144-147PubMed Google Scholar Some chemical groupings, such as the allyl groups which form the basis of the barbiturates, and certain steroid structures have also been incriminated in the induction of porphyria (steroids can enhance the induction of ALA synthetase). It is of interest that it is only the acute forms of the disease that are affected by enzyme induction, so this is the only form of the disease of pharmacogenetic importance. It is not clear why the manifestations of the non-acute forms of porphyria are not apparently affected by enzyme-inducing drugs. Even such potent inducers of ALA synthetase as the anticonvulsants do not exacerbate or precipitate porphyria cutanea tarda (PCT) or the erythropoietic porphyrias. The only apparent drug association with PCT is that of oestrogen-containing compounds. They may exacerbate the biochemical and skin manifestations of this condition, but acute attacks are never encountered in PCT. There are occasional reports of other agents being implicated in either the causation or exacerbation of the non-acute porphyrias, but Moore and colleagues concluded that the evidence for induction of these conditions by drugs other than oestrogens is weak.38Moore MR McColl KE Rimington C Goldberg A Disorders of Porphyrin Metabolism. Plenum, London1987Crossref Google Scholar. These conditions will, therefore, not be considered further. For more information about the non-acute porphyrias, see the review by Paslin.45Paslin DA The porphyrias.Int J Dermatol. 1992; 31: 527-539Crossref PubMed Scopus (12) Google Scholar Notably, there is no excess excretion of ALA or PBG in these conditions, whereas these changes are the hallmarks of the acute porphyrias. The pathogenesis of the acute porphyrias is unclear, although there are several possibilities. The excessive production of ALA is common to all of the acute forms and in all but the very rare plumboporphyria there is a defect in PBG deaminase, either in terms of an absolute reduction of enzyme activity, or in terms of a failure to increase its level in response to increased demand. Thus it is possible that ALA or PBG, or both, may be directly neurotoxic, although the severity of the symptoms does not correlate well with the increase in either of these substances. Nevertheless, the accumulation of these two compounds appears likely to have some effect on symptomatology. An alternative, but not exclusive, hypothesis is that the failure of haem production results in an acute haem deficiency within the nerve cell, and that this is the chief cause of the neuronal lesions, although the toxicity of ALA and PBG may still be relevant.38Moore MR McColl KE Rimington C Goldberg A Disorders of Porphyrin Metabolism. Plenum, London1987Crossref Google Scholar It has also been suggested that haem deficiency results in a secondary reduction in the activity of haem-containing enzymes such as tryptophan oxygenase, with consequent disturbances in the production and metabolism of potential neurotransmitters such as serotonin. The defective enzyme in this condition is porphobilinogen deaminase and the gene encoding this enzyme is located on chromosome 11. PBG deaminase deficiency can, in most cases, be detected in red cells between attacks. Of all the porphyrias, this one produces the most severe symptoms, and is the one in which an acute attack is most likely to be fatal. It has been reported that hypertension and impaired renal function are significantly more common in porphyric subjects than in their non-porphyric relatives, and that hypertensive complications and renal failure are the most frequent causes of death in patients with porphyria.9Church SE McColl KE Moore MR Youngs GR Hypertension and renal impairment as complications of acute porphyria.Nephrol Dialysis Transplant. 1992; 7: 986-990PubMed Google Scholar This condition is characterized by cutaneous photosensitivity in which bullous skin eruptions occur on exposure to sunlight as a result of the conversion of porphyrinogens to porphyrins. The characteristic skin lesion is one of excessive fragility, especially on sun-exposed surfaces such as the face and hands, where bullae and erosions with subsequent pigmented 'tissue paper' scarring are frequently seen. The name of this condition derives from the fact that patients may present with the skin manifestations associated with the non-acute porphyrias, or the disorders characteristic of AIP or combinations of both. The enzyme defect is at the level of protoporphyrinogen oxidase but there is also a reduced amount of PBG deaminase. The gene encoding this enzyme is on chromosome 1. The incidence of VP in South Africa is the highest in the world: in some areas it may be as high as one in 250 of the white population.12Dean G The Porphyrias: A Story of Inheritance and Environment. 2nd edn. Pitman Medical, Bristol1971Google Scholar This has been shown to result from the introduction of a single point-mutation by a Dutch settler in 1688.35Meissner PN Dailey TA Hift RJ et al.A R59W mutation in human protoporphyrinogen oxidase results in decreased enzyme activity and is prevalent in South Africans with variegate porphyria.Nature Genet. 1996; 13: 95-97Crossref PubMed Scopus (171) Google Scholar This condition is far less common than VP and AIP. Acute attacks appear to be considerably less severe, and the prognosis better. The defective enzyme is coproporphyrinogen oxidase, encoded by a gene on chromosome 9. As in VP, cutaneous photosensitivity is characteristic, though it tends to be less severe in the interval between acute attacks than it is in VP. This, the rarest of the acute porphyrias, results from a deficiency of ALA dehydratase, which is encoded by a gene on chromosome 9. It is associated with an excess of urinary ALA analogous to that found in lead poisoning (hence the name), although lead concentrations in the blood are normal. Unlike the other acute porphyrias, the mutation is recessive, and the disease presents early in life, with all clinically manifest cases being homozygotes.19Goldberg A Moore MR McColl KE Brody MJ Porphyrin metabolism and the porphyrias.in: Weatherall DJ Ledingham JGG Warrell DA Oxford Textbook of Medicine. 2nd edn. Oxford University Press, Oxford1987: 9.136-9.145Google Scholar No references to anaesthesia for patients with this condition have been published. It might be expected that the cytochrome-mediated metabolism and high lipid solubility of many anaesthetics would make many of them porphyrinogenic, and anaesthesia has certainly been implicated in the triggering of a number of severe porphyric reactions. Nevertheless, most porphyrics can be anaesthetized with relative safety provided that appropriate precautions are taken. The mainstay of safe anaesthetic management of the porphyric patient depends on the detection of susceptible individuals, and the identification of potentially porphyrinogenic agents. Neither of these is simple or readily achievable. Laboratory identification of porphyric subjects is not easy, as many of them show only subtle or even no biochemical abnormalities during asymptomatic phases. The identification of potentially porphyric patients must, therefore, begin with knowledge of the local prevalence of the condition and then rely on the recognition of a suggestive personal or family history. Any suggestion of porphyria in the patient's history should be taken seriously and appropriate laboratory investigations undertaken. Where the urgency of the situation precludes full biochemical evaluation, the patient should be managed with an anaesthetic technique appropriate for a porphyric patient. The most appropriate test for the diagnosis of porphyria will vary according to the type of porphyria expected and the patient's circumstances. Thus, when the actual mutation is known in the family, DNA analysis is most appropriate. In the absence of this knowledge, determination of erythrocyte PBG activity is probably the most appropriate screening test for patients with suspected AIP, as detection of elevated ALA and PBG in urine is less sensitive. In the case of possible VP, HCP or a suspected acute attack, biochemical analysis of urine, stool and plasma porphyrin profiles is indicated. Direct enzyme activity estimates are problematic in these patients, because activity is expressed not in erythrocytes but only in nucleated cells such as fibroblasts or leukocytes, and then in such low amounts that standard assays are unreliable. The biochemical tests vary in their ability to identify porphyric patients depending on the type of the condition and whether or not the individual is in remission or suffering an attack; their interpretation is listed in Table 2. It must be remembered that prepubertal children who carry the gene will be asymptomatic, but are still at risk from an acute attack if improperly managed.45Paslin DA The porphyrias.Int J Dermatol. 1992; 31: 527-539Crossref PubMed Scopus (12) Google ScholarTable 2Summary of major biochemical findings in the acute porphyrias. Note that the findings described in the quiescent phase apply only to those with biochemically expressed disease; silent carriers will demonstrate no abnormality on urine and faecal testing, yet carry the gene and are at risk of an acute attackDisorderPhaseUrinaryALA and PBGUrinary porphyrinsFaecal porphyrinsAIPquiescentincreasedmild increasenormalacutevery highvery highas aboveHCPquiescentnormalcoproporphyrin III often increasedincreased coproporphyrin IIIacutehighincreasedas aboveVPquiescentnormalnormalincreased pentacarboxylic porphyrin III, coproporphyrin III and protoporphyrin IXacutehighhighas above Open table in a new tab The identification of drugs likely to be hazardous to the porphyric patient is also far from clear-cut. The labelling of drugs as safe or unsafe in porphyria is based on anecdotal experience of the use of the agents in porphyric patients and reports of the induction of acute attacks, or on measurements of porphyrins or their precursors in urine or faeces. Drugs may be tested for in cell culture models for their ability to induce ALA synthetase activity or for effects on porphyrin synthesis. Alternatively, their actions on the porphyrin synthetic pathway in animal models of porphyria can be investigated; in these models, porphyria is mimicked by administering known porphyrinogenic agents, such as the enzyme-blocking drug dicarbethoxy-dihydrocollidine (DDC). Both cell culture and animal models tend to overestimate the porphyrinogenicity of drugs. A summary of anaesthetic drugs for their perceived safety has been published previously.22Harrison GG Meissner PN Hift RJ Anaesthesia for the porphyric patient.Anaesthesia. 1993; 48: 417-421Crossref PubMed Scopus (47) Google Scholar However, as there are often conflicting reports of the safety of anaesthetic drugs in clinical practice, and since other factors such as infection or stress may precipitate a porphyric crisis coincidentally with the administration of anaesthesia, it is extremely difficult to assess the porphyrinogenic potential of anaesthetic agents with precision. Thus, any attempted classification of anaesthetic agents with regard to their porphyrinogenicity is far from ideal, and inevitably somewhat arbitrary. In view of the difficulties clinicians experience in interpreting such terms as 'possibly safe' and 'probably unsafe' in drug lists, the Porphyria Drug Safety Database held at the University of Cape Town has been reviewed and modified to reflect the terms listed in Table 3, which give a clearer indication of the relative desirability of drugs. Those drugs most applicable to anaesthesia are listed in Table 4. The information presented in this table was obtained by examining data from the literature (itself based on clinical experience as well as animal and in vitro experiments), from personal experience and by the examination of drugs for structure, structural similarity and routes of metabolism. As such it represents both compromise and intuition unsubstantiated by hard data, and the recommendations cannot be guaranteed to prove valid under all circumstances. The list should serve as a guide only, and the authors cannot accept responsibility for errors or for any adverse experience. More information on specific agents may be obtained from the authors.Table 3Recommendations applied to drugs in the Porphyria Drug Safety DatabaseCategoryDescriptionUseThe drug is likely to be safe and may be used freely.Use with caution (UWC)Though safety is not established beyond doubt, the evidence suggests that the drug is unlikely to prove unsafe in practice. It may be used provided no safer alternative is available or suitable.Use with extreme caution only (UWECO)There is evidence to suggest that the drug may yet prove unsafe in practice, or grounds to suspect this may be so, or too little evidence to suggest that it may be safe. Such drugs should only be used if the expected benefits strongly outweigh the risks, and an adverse outcome must be anticipated.AvoidThere is evidence that such drugs have precipitated acute attacks in patients, or other grounds for believing that the risk of an acute attack is high.No data/avoid (ND/avoid)There is too little evidence to draw a conclusion, and it is wisest to regard the drug as potentially hazardous and avoid its use. Open table in a new tab Table 4Recommendations for the use of anaesthetic drugs in the acute porphyrias (adapted from 24Hift RJ Meissner PN Meissner DM Petersen LA Porphyria: A Guide for Patients and Doctors. University of Cape Town, Cape Town1999Google Scholar). The terms used for the recommendations are explained in Table 3, and should be read in conjunction with the text. *There are no published data on these drugs; their recommendations are based on a comparison with drugs of the same classDrugsRecommendationInhalational agentsNitrous oxideUseCyclopropaneUseHalothaneUseEnfluraneUWCIsofluraneUWCSevoflurane*UWCDesflurane*UWCIntravenous induction agentsPropofolUseKetamineUWCBarbituratesAvoidEtomidateAvoidAnalgesicsAcetaminophenUseAlfentanilUseAspirinUseBuprenorphineUseCodeineUseFentanylUsePethidine (meperidine)UseMorphineUseNaloxoneUseSufentanilUseDiclofenacUWECOKetorolac*UWECOPhenacetinUWECOTilidineUWECOPentazocineAvoidNeuromuscular blocking drugsTubocurarineUsePancuroniumUseSuccinylcholineUseAlcuroniumUWCAtracuriumUWCRocuronium*UWCMivacurium*UWCVecuroniumUWCNeuromuscular block reversal agentsAtropineUseGlycopyrrolateUseNeostigmineUseLocal anaesthetic
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