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Acute hepatic porphyria and anaesthesia: a practical approach to the prevention and management of acute neurovisceral attacks

2020; Elsevier BV; Volume: 21; Issue: 2 Linguagem: Inglês

10.1016/j.bjae.2020.09.005

2058-5357

Noamaan Wilson‐Baig, Michael N. Badminton, Danja Schulenburg‐Brand,

Alcoholism and Thiamine Deficiency

Learning objectivesBy reading this article you should be able to:•Describe the pathophysiology, clinical presentation and management of an acute attack of porphyria, including the appropriate use of haem arginate (HA).•Discuss the perioperative considerations for managing patients with latent or active porphyria presenting for elective and emergency surgery.•Know how to access the resources available for expert advice. In the UK, these include the National Acute Porphyria Service (NAPS) and the UK Porphyria Medicines Information Service (UKPMIS).Key points•Symptomatic active acute hepatic porphyria (AHP) is rare.•Anaesthesia can be given safely to patients with a diagnosis of AHP provided that porphyrinogenic medicines, prolonged fasting, dehydration and inadequate analgesia are avoided.•Acute attacks of porphyria should be managed with advice from a porphyria specialist. In the UK, this is provided by the National Acute Porphyria Service (NAPS).•Haem arginate (HA) treatment is indicated for severe complicated acute attacks or where the episode is not resolving after 12–18 h.•There are no specific risks of anaesthesia associated with the non-acute porphyrias. By reading this article you should be able to:•Describe the pathophysiology, clinical presentation and management of an acute attack of porphyria, including the appropriate use of haem arginate (HA).•Discuss the perioperative considerations for managing patients with latent or active porphyria presenting for elective and emergency surgery.•Know how to access the resources available for expert advice. In the UK, these include the National Acute Porphyria Service (NAPS) and the UK Porphyria Medicines Information Service (UKPMIS). •Symptomatic active acute hepatic porphyria (AHP) is rare.•Anaesthesia can be given safely to patients with a diagnosis of AHP provided that porphyrinogenic medicines, prolonged fasting, dehydration and inadequate analgesia are avoided.•Acute attacks of porphyria should be managed with advice from a porphyria specialist. In the UK, this is provided by the National Acute Porphyria Service (NAPS).•Haem arginate (HA) treatment is indicated for severe complicated acute attacks or where the episode is not resolving after 12–18 h.•There are no specific risks of anaesthesia associated with the non-acute porphyrias. The porphyrias are a group of mostly inherited conditions resulting from partial deficiency in the activity of enzymes involved in haem synthesis; with the exception of one cutaneous porphyria which is caused by an increase in activity of aminolaevulinic acid (ALA) synthase 2.1Bissell D.M. Anderson K.E. Bonkovsky H.L. Porphyria.N Engl J Med. 2017; 377: 862-872Crossref PubMed Scopus (139) Google Scholar,2Findley H. Philips A. Cole D. Nair A. Porphyrias: implications for anaesthesia, critical care, and pain medicine.Contin Educ Anaesth Crit Care Pain. 2012; 12: 128-133Abstract Full Text Full Text PDF Scopus (6) Google Scholar Clinical features depend on the quantity and type of haem biosynthetic intermediates that accumulate (Fig 1). Pathway intermediates include ALA, porphobilinogen (PBG) and porphyrinogens. The latter are oxidised and excreted as porphyrins. The main clinical presentations are characterised by either acute neurovisceral attacks, photosensitive skin features or both.1Bissell D.M. Anderson K.E. Bonkovsky H.L. Porphyria.N Engl J Med. 2017; 377: 862-872Crossref PubMed Scopus (139) Google Scholar,2Findley H. Philips A. Cole D. Nair A. Porphyrias: implications for anaesthesia, critical care, and pain medicine.Contin Educ Anaesth Crit Care Pain. 2012; 12: 128-133Abstract Full Text Full Text PDF Scopus (6) Google Scholar Four types of porphyria present with acute attacks.3Stein P.E. Badminton M.N. Rees D.C. Update review of the acute porphyrias.Br J Haematol. 2017; 176: 527-538Crossref PubMed Scopus (71) Google Scholar Three are autosomal dominant (AD): acute intermittent porphyria (AIP), hereditary coproporphyria (HCP) and variegate porphyria (VP). The fourth, an autosomal recessive acute porphyria, 5-aminolevulinate dehydratase deficiency porphyria is exceptionally rare and is not discussed further in this article.3Stein P.E. Badminton M.N. Rees D.C. Update review of the acute porphyrias.Br J Haematol. 2017; 176: 527-538Crossref PubMed Scopus (71) Google Scholar The non-acute porphyrias, erythropoietic protoporphyria, porphyria cutanea tarda, congenital erythropoietic porphyria and X-linked erythropoietic protoporphyria are not associated with any specific risks related to anaesthesia. AIP is the most common acute hepatic porphyria (AHP).1Bissell D.M. Anderson K.E. Bonkovsky H.L. Porphyria.N Engl J Med. 2017; 377: 862-872Crossref PubMed Scopus (139) Google Scholar,3Stein P.E. Badminton M.N. Rees D.C. Update review of the acute porphyrias.Br J Haematol. 2017; 176: 527-538Crossref PubMed Scopus (71) Google Scholar A recent European study reported that the annual incidence of symptomatic acute porphyria is 0.2 per million (0.13 per million for AIP, 0.08 per million for VP and 0.02 per million for HCP) and the prevalence is 10 per million (one per 200,000 for AIP).4Elder G. Harper P. Badminton M. Sandberg S. Deybach J.C. The incidence of inherited porphyrias in Europe.J Inherit Metab Dis. 2013; 36: 849-857Crossref PubMed Scopus (147) Google Scholar However, interrogation of data from genome sequencing projects has identified the prevalence of pathogenic variants in the HMBS gene (causing AIP) to be as high as one in 1782.5Chen B. Solis-Villa C. Hakenberg J. et al.Acute intermittent porphyria: predicted pathogenicity of HMBS variants indicates extremely low penetrance of the autosomal dominant disease.Hum Mutat. 2016; 37: 1215-1222Crossref PubMed Scopus (70) Google Scholar Penetrance in the general population is therefore approximately 1%, rather than the 10–20% reported in families.5Chen B. Solis-Villa C. Hakenberg J. et al.Acute intermittent porphyria: predicted pathogenicity of HMBS variants indicates extremely low penetrance of the autosomal dominant disease.Hum Mutat. 2016; 37: 1215-1222Crossref PubMed Scopus (70) Google Scholar Clinicians are therefore more likely to encounter patients with asymptomatic latent porphyria diagnosed through family studies than overtly symptomatic patients with active disease. Few clinicians have experience in managing symptomatic acute porphyria. This article aims to provide anaesthetists and intensive care physicians with practical advice on managing patients with AHP. We discuss the pathogenesis, precipitating factors, clinical presentation, diagnosis and management of acute neurovisceral attacks. Specific measures to reduce the risk of perioperative acute attacks are also discussed. In each of the AD acute porphyrias, there is inheritance of a mutation causing partial deficiency in the respective enzyme activity with consequent accumulation of enzyme substrate. AIP, VP and HCP are caused by partial deficiencies in hydroxymethylbilane synthase (HMBS), protoporphyrinogen oxidase and coproporphyrinogen oxidase respectively (Fig 1). Haem supply in hepatic and other non-erythroid cells is regulated by the first enzyme in the pathway, ALA synthase 1 (ALAS1), which is subject to feedback inhibition by haem. An acute attack occurs when hepatic haem requirements are increased by physiological or environmental precipitants. ALAS1 and the pathway are induced and porphyrin precursors proximal to the deficient enzyme increase. Deficiency of HMBS becomes the rate limiting step in the pathway, resulting in accumulation of the metabolites ALA and PBG (Fig 1). In AIP, the HMBS deficiency is the primary defect, whereas in VP and HCP, HMBS deficiency is understood to be caused by accumulation of the enzyme substrates protoporphyrinogen and coproporphyrinogen (see Fig 1).6Meissner P. Adams P. Kirsch R. Allosteric inhibition of human lymphoblast and purified porphobilinogen deaminase by protoporphyrinogen and coproporphyrinogen. A possible mechanism for the acute attack of variegate porphyria.J Clin Invest. 1993; 91: 1436-1444Crossref PubMed Scopus (53) Google Scholar The excess ALA and PBG are released into the circulation. ALA is understood to be the metabolite most likely to be responsible for the acute neurological dysfunction associated with acute attacks.7Meyer U.A. Schuurmans M.M. Lindberg R.L. Acute porphyrias: pathogenesis of neurological manifestations.Semin Liver Dis. 1998; 18: 43-52Crossref PubMed Scopus (179) Google Scholar The regulatory mechanism for hepatic haem synthesis also provides a therapeutic target, as giving exogenous haem can downregulate ALAS1 activity and suppress the excess production of haem precursors. Precipitants implicated in causing acute attacks include:(i)Drugs (prescribed and illicit). Some commonly prescribed medications cause hepatic haem depletion by either induction or irreversible inhibition of cytochrome P450 enzymes resulting in upregulation of the haem biosynthetic pathway.8Hift R.J. Thunell S. Brun A. Drugs in porphyria: from observation to a modern algorithm-based system for the prediction of porphyrogenicity.Pharmacol Ther. 2011; 132: 158-169Crossref PubMed Scopus (36) Google Scholar(ii)Calorie restriction such as prolonged fasting, diets that exclude carbohydrates and severe gastrointestinal upset.2Findley H. Philips A. Cole D. Nair A. Porphyrias: implications for anaesthesia, critical care, and pain medicine.Contin Educ Anaesth Crit Care Pain. 2012; 12: 128-133Abstract Full Text Full Text PDF Scopus (6) Google Scholar,3Stein P.E. Badminton M.N. Rees D.C. Update review of the acute porphyrias.Br J Haematol. 2017; 176: 527-538Crossref PubMed Scopus (71) Google Scholar Under fasting conditions the transcriptional coactivator PGC-1α has been shown to act as a nutritional regulator of haem biosynthesis; it upregulates the pathway via induction of ALAS1.9Handschin C. Lin J. Rhee J. et al.Nutritional regulation of hepatic heme biosynthesis and porphyria through PGC-1alpha.Cell. 2005; 122: 505-515Abstract Full Text Full Text PDF PubMed Scopus (263) Google Scholar(iii)Fluctuating sex hormone concentrations associated with the menstrual cycle, in particular changing progesterone concentrations. Acute attacks are therefore frequently linked to the luteal phase of the menstrual cycle and may be caused by impaired 5α-reduction of steroid hormones.10Anderson K.E. Bradlow H.L. Sassa S. Kappas A. Studies in porphyria. VIII. Relationship of the 5 alpha-reductive metabolism of steroid hormones to clinical expression of the genetic defect in acute intermittent porphyria.Am J Med. 1979; 66: 644-650Abstract Full Text PDF PubMed Scopus (29) Google Scholar(iv)Although pregnancy is usually well tolerated, acute attacks have been reported, particularly during the first trimester.11Marsden J.T. Rees D.C. A retrospective analysis of outcome of pregnancy in patients with acute porphyria.J Inherit Metab Dis. 2010; 33: 591-596Crossref PubMed Scopus (24) Google Scholar(v)Excess alcohol consumption, particularly binge drinking, which leads to induction of ALAS1.12Doss M.O. Kühnel A. Gross U. Alcohol and porphyrin metabolism.Alcohol Alcohol. 2000; 35: 109-125Crossref PubMed Scopus (54) Google Scholar(vi)Physiological stress including infection.13Hift R.J. Meissner P.N. An analysis of 112 acute porphyria attacks in Cape Town, South Africa.Medicine. 2005; 84: 48-60Crossref PubMed Scopus (107) Google Scholar Most patients with genetically proven but latent acute porphyria remain asymptomatic throughout their lifetime, although they remain at risk of becoming symptomatic when exposed to environmental triggers.3Stein P.E. Badminton M.N. Rees D.C. Update review of the acute porphyrias.Br J Haematol. 2017; 176: 527-538Crossref PubMed Scopus (71) Google Scholar The majority of symptomatic patients present between the ages of 15 and 40 yrs and are more likely to be female than male.4Elder G. Harper P. Badminton M. Sandberg S. Deybach J.C. The incidence of inherited porphyrias in Europe.J Inherit Metab Dis. 2013; 36: 849-857Crossref PubMed Scopus (147) Google Scholar In general, the older a patient with latent porphyria is, the less likely a first acute attack becomes. The clinical features of acute neurovisceral attacks are identical in all the AD acute porphyrias.3Stein P.E. Badminton M.N. Rees D.C. Update review of the acute porphyrias.Br J Haematol. 2017; 176: 527-538Crossref PubMed Scopus (71) Google Scholar Symptomatic AIP presents with acute attacks only, whilst in symptomatic HCP and VP photosensitive skin lesions manifesting as fragile skin and blistering in areas exposed to sun can occur during acute attacks or in isolation.3Stein P.E. Badminton M.N. Rees D.C. Update review of the acute porphyrias.Br J Haematol. 2017; 176: 527-538Crossref PubMed Scopus (71) Google Scholar Most symptomatic patients have one or a few attacks over a short period before the disease becomes inactive again. About 5% of symptomatic AIP patients suffer repeated severe debilitating attacks, but this is rare in VP and HCP.4Elder G. Harper P. Badminton M. Sandberg S. Deybach J.C. The incidence of inherited porphyrias in Europe.J Inherit Metab Dis. 2013; 36: 849-857Crossref PubMed Scopus (147) Google Scholar,14Gouya L. Ventura P. Balwani M. et al.EXPLORE: a prospective, multinational, natural history study of patients with acute hepatic porphyria with recurrent attacks.Hepatology. 2020; 71: 1546-1558Crossref PubMed Scopus (43) Google Scholar Acute neurovisceral crises relate to the central, peripheral and autonomic nervous systems.3Stein P.E. Badminton M.N. Rees D.C. Update review of the acute porphyrias.Br J Haematol. 2017; 176: 527-538Crossref PubMed Scopus (71) Google Scholar In more than 90% of cases, severe diffuse abdominal pain is the main presenting symptom, but back or leg pain may also be a prominent feature. There is usually associated gastrointestinal disturbance including nausea, vomiting and constipation, and autonomic features such as hypertension and tachycardia. Cardiac arrhythmias are a rare complication.1Bissell D.M. Anderson K.E. Bonkovsky H.L. Porphyria.N Engl J Med. 2017; 377: 862-872Crossref PubMed Scopus (139) Google Scholar,3Stein P.E. Badminton M.N. Rees D.C. Update review of the acute porphyrias.Br J Haematol. 2017; 176: 527-538Crossref PubMed Scopus (71) Google Scholar,13Hift R.J. Meissner P.N. An analysis of 112 acute porphyria attacks in Cape Town, South Africa.Medicine. 2005; 84: 48-60Crossref PubMed Scopus (107) Google Scholar Peripheral neuropathy is typically a motor neuropathy affecting distal muscles, but mild sensory symptoms such as paraesthesia have also been described.7Meyer U.A. Schuurmans M.M. Lindberg R.L. Acute porphyrias: pathogenesis of neurological manifestations.Semin Liver Dis. 1998; 18: 43-52Crossref PubMed Scopus (179) Google Scholar Seizures and psychiatric manifestations such as agitation, depression, insomnia, anxiety, confusion and psychosis are all features of the CNS effects associated with acute attacks. Hyponatraemia is common: it can be severe, develop rapidly and increase the risk of seizures.3Stein P.E. Badminton M.N. Rees D.C. Update review of the acute porphyrias.Br J Haematol. 2017; 176: 527-538Crossref PubMed Scopus (71) Google Scholar,13Hift R.J. Meissner P.N. An analysis of 112 acute porphyria attacks in Cape Town, South Africa.Medicine. 2005; 84: 48-60Crossref PubMed Scopus (107) Google Scholar Severe attacks can progress to motor paralysis. This may affect respiratory and pharyngeal muscles and also cause bladder dysfunction. Patients with a known diagnosis usually have a good understanding of their condition and are often able to recognise the symptoms of an impending acute attack. However, other causes such as postoperative complications, pregnancy-related complications or other intra-abdominal pathology should always be excluded, as clinical features are non-specific. Delays in diagnosis and treatment can lead to worse outcomes. The porphyrin precursors PBG and ALA are always increased during an acute attack of porphyria.15Deacon A.C. Elder G.H. ACP best practice no 165: front line tests for the investigation of suspected porphyria.J Clin Pathol. 2001; 54: 500-507Crossref PubMed Scopus (101) Google Scholar An increased concentration of PBG in a random urine sample collected in a plain universal container without preservatives, confirms an acute attack. As porphyrins and their precursors are sensitive to degradation by light, the urine sample should be protected from light before being sent to the laboratory. In the UK this requires close coordination with the local biochemistry department, as testing is not universally available locally. Samples should be tested urgently and so ideally a result should be available within 24 h of receipt in the laboratory.16Woolf J. Marsden J.T. Degg T. et al.Best practice guidelines on first-line laboratory testing for porphyria.Ann Clin Biochem. 2017; 54: 188-198Crossref PubMed Scopus (22) Google Scholar If qualitative testing is performed, positive results should be confirmed by quantitative testing.16Woolf J. Marsden J.T. Degg T. et al.Best practice guidelines on first-line laboratory testing for porphyria.Ann Clin Biochem. 2017; 54: 188-198Crossref PubMed Scopus (22) Google Scholar Provided the sample is collected during or soon after onset of symptoms, a normal PBG result excludes an acute porphyria attack and should prompt urgent consideration of alternative diagnoses.16Woolf J. Marsden J.T. Degg T. et al.Best practice guidelines on first-line laboratory testing for porphyria.Ann Clin Biochem. 2017; 54: 188-198Crossref PubMed Scopus (22) Google Scholar Urinary PBG excretion is significantly increased during an acute attack. Analytical methodologies, units and reference intervals differ between laboratories and countries but increases are typically greater than 10 times the upper reference limit.3Stein P.E. Badminton M.N. Rees D.C. Update review of the acute porphyrias.Br J Haematol. 2017; 176: 527-538Crossref PubMed Scopus (71) Google Scholar However, there is a sustained, sometimes marked, elevation of PBG excretion in between attacks in AIP, which can persist for several years making interpretation difficult.17Marsden J.T. Rees D.C. Urinary excretion of porphyrins, porphobilinogen and δ-aminolaevulinic acid following an attack of acute intermittent porphyria.J Clin Pathol. 2014; 67: 60-65Crossref PubMed Scopus (39) Google Scholar In this context qualitative testing of PBG in known AIP patients with active disease is unhelpful. Interpretation of the urinary PBG concentration requires knowledge of the patient's usual baseline excretion in between attacks and interpretation should be discussed with a porphyria specialist. In contrast, in both VP and HCP, urine PBG and ALA concentrations return to normal or near normal between acute attacks and therefore urine samples are best collected whilst patients are symptomatic. After the biochemical confirmation of an acute attack in a new patient with no family history or previous diagnosis of an AHP, confirmation and identification of the type of acute porphyria should follow. This requires porphyrin analysis of light-protected plasma and faecal samples in a specialist laboratory. The plasma porphyrin fluorescence emission wavelength and faecal porphyrin excretion patterns distinguish AIP, VP and HCP (Table 1).18Whatley S.D. Mason N.G. Woolf J.R. et al.Diagnostic strategies for autosomal dominant acute porphyrias: retrospective analysis of 467 unrelated patients referred for mutational analysis of the HMBS, CPOX or PPOX gene.Clin Chem. 2009; 55: 1406-1414Crossref PubMed Scopus (54) Google Scholar All patients who have experienced an acute attack should be referred to a porphyria specialist for follow-up.19Stein P. Badminton M. Barth J. Rees D. Stewart M.F. Best practice guidelines on clinical management of acute attacks of porphyria and their complications.Ann Clin Biochem. 2013; 50: 217-223Crossref PubMed Scopus (62) Google Scholar Genetic testing is usually offered to new patients to facilitate cascade testing of relatives to identify family members at risk. This is generally arranged through referral to a clinical geneticist. ALA, aminolaevulinic acid; Copro III, coproporphyrin III isomer; PBG, porphobilinogen; Proto, protoporphyrin. In practice, patients with acute porphyria fall into two distinct clinical subgroups; those with latent AHP and those with active or recently active AHP. The risk of developing an acute perioperative attack differs between the groups. Patients known to experience repeated acute attacks or who have recently had active disease are at the highest risk of developing symptomatic acute porphyria during the perioperative period. There has been extensive clinical experience with the use of local anaesthetic agents in patients with acute porphyria. Regional anaesthesia with either neuraxial or peripheral nerve blocks can be used safely in both groups.20James M.F. Hift R.J. Porphyrias.Br J Anaesth. 2000; 85: 143-153Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar In patients with a known diagnosis of latent acute porphyria, the risk of developing an acute perioperative attack is small, provided the appropriate precautions discussed below are followed. Patients with a family history of AHP requiring urgent anaesthesia, in whom preoperative testing is not possible, should be managed as if they are affected and definitive testing arranged after surgery. Patients with active or recently active acute porphyria are at higher risk of developing an acute attack in the perioperaitve period. As such they would be jointly managed with a porphyria specialist who should be able to provide detailed information about their current clinical status.19Stein P. Badminton M. Barth J. Rees D. Stewart M.F. Best practice guidelines on clinical management of acute attacks of porphyria and their complications.Ann Clin Biochem. 2013; 50: 217-223Crossref PubMed Scopus (62) Google Scholar Acute attacks are unusual after surgery now that barbiturate anaesthesia is rarely used. General anaesthesia may be safely undertaken provided only safe medicines are used (Table 2).21UK porphyria medicines information service. Provided by the Welsh Medicines Information Centre. 2019 Porphyria Safe List. Available from https://www.wmic.wales.nhs.uk/specialist-services/drugs-in-porphyria/(accessed 20 November 2020)Google Scholar Therefore, having a stock of haem arginate (HA) on site before surgery is rarely required. Perioperative stress should be reduced by effective premedication and pain control. Nausea and vomiting should also be addressed. Table 2 has been compiled using available safety information. It is not an exhaustive list and is intended for guidance only. Some medicines cannot be classified owing to a lack of safety information (Table 2). The UK Porphyria Medicines Information Service (UKPMIS) can be contacted for advice about specific agents that are not on this list.21UK porphyria medicines information service. Provided by the Welsh Medicines Information Centre. 2019 Porphyria Safe List. Available from https://www.wmic.wales.nhs.uk/specialist-services/drugs-in-porphyria/(accessed 20 November 2020)Google Scholar There is growing popularity for the use of ketamine, especially for induction of anaesthesia in patients who are haemodynamically unstable, and as an alternative analgesic. However, based on the available evidence, ketamine is not considered safe and should be avoided if possible.Table 2Medicines used regularly during the perioperative period. The evidence underpinning the classification for each drug can be reviewed in the Drug Database for Acute Porphyria (https://www.drugs-porphyria.org) by selecting the Info Tab to access a drug monographaIn an emergency, any drug considered essential to patient survival can be given. Omission of a medicine does not necessarily mean it is unsafe; further information can be obtained from UK Porphyria Medicines Information Service (UKPMIS) who can also be contacted by telephone. Information on medicine safety was collated from the UKPMIS safe drugs list,21 the Drug Database for Acute Porphyria (https://www.drugs-porphyria.org) and the American Porphyria Foundation Safe Drug list (https://www.porphyriafoundation.org/drugdatabase/) accessed 20 November 2020.SafeUnsafeNo data availableLocal anaesthesiaDentalArticaine with or without adrenaline (epinephrine)Lidocaine with or without adrenalineMepivacaine with or without adrenalinePrilocaine with or without felypressinRegional anaesthesiaBupivacainePrilocaineLevobupivacaineRopivacaineProcaineTopical anaesthesiaTetracaine eye drops (0.5–1%)Tetracaine gel (4%)Lidocaine gel 2%Lidocaine sprayOxybuprocaine eye drops (0.4%)General anaesthesiaInductionPropofolEsketamineEtomidateKetamineThiopentalInhalational agentsDesfluraneEnfluraneIsofluraneNitrous oxideSevofluraneHalothaneNeuromuscular blocking agents and reversal agentsAtracuriumCisatracuriumMivacuriumNeostigminePancuroniumRocuroniumSugammadexSuxamethoniumVecuroniumMedicines used during perioperative careAnalgesiaClonidineDiclofenacGabapentinIbuprofenKetoprofenKetorolacNaproxenOpioids (alfentanil, diamorphine, fentanyl, morphine, oxycodone, pethidine, remifentanil, tramadol)ParacetamolParecoxibPregabalinDexmedetomidineFlurbiprofenPapaveretumPentazocineAntibiotics/antifungals and antiviralsAciclovirAnidulafunginAminoglycosidesAmphotericinCaspofunginCefuroximeCeftriaxoneCo-amoxiclavLevofloxacinLinezolidMeropenemMetronidazolePenicillinsbThere are conflicting reports on the safety of flucloxacillin. Use only if there is no safe alternative.Piperacillin with tazobactamQuinolonesVancomycinClarithromycinClindamycinErythromycinFluconazoleItraconazoleRifampicinSulfamethoxazoleTrimethoprimAntiemeticsCyclizineDomperidoneGranisetronMetoclopramideOndansetronProchlorperazineCardiovascularACE inhibitorsAdenosineAdrenaline (epinephrine)AmlodipineAtenololAtropineBumetanideDigoxinDopamineEphedrineEplerenoneEsmololFurosemideGlyceryl trinitrateGlycopyrronium bromideLabetalolMetoprololMilrinoneNifedipineNimodipineNoradrenaline (norepinephrine)PhenylephrineAmiodaroneDiltiazemHydralazineIndapamideMethyldopaMetolazoneSpironolactoneVerapamilMetaraminolVasopressin EnoximoneCNSDiazepamFlumazenilHaloperidolLevetiracetamLorazepamMidazolamNaloxoneTemazepamZopicloneFlunitrazepamNitrazepamSodium valproatePhenytoinPhenobarbitalFibrinolytics, anticoagulantsAlteplaseApixabanClopidogrelHeparinLow molecular weight heparinsRivaroxabanStreptokinaseTenecteplaseTicagrelorWarfarinObstetrics and gynaecologyAtosibanCarboprostMisoprostolOxytocinErgometrinedUse if required in an obstetric emergency.MifepristoneRespiratoryAminophyllineBeclometasoneBudesonideIpratropiumSalbutamolSalmeterolTerbutalineTiotropiumMiscellaneousAcetazolamideAcetylcysteineChlorphenamineContrast media (gadolinium-based, gastrografin, iodine-based)DexamethasoneGlucagonHydrocortisoneHyoscineInsulinsMagnesiumProtaminecProtamine is considered safe by the American Porphyria Foundation (https://www.porphyriafoundation.org/drugdatabase/).Proton pump inhibitorsSodium bicarbonateTranexamic acidDantrolenePhentolaminea In an emergency, any drug considered essential to patient survival can be given. Omission of a medicine does not necessarily mean it is unsafe; further information can be obtained from UK Porphyria Medicines Information Service (UKPMIS) who can also be contacted by telephone. Information on medicine safety was collated from the UKPMIS safe drugs list,21UK porphyria medicines information service. Provided by the Welsh Medicines Information Centre. 2019 Porphyria Safe List. Available from https://www.wmic.wales.nhs.uk/specialist-services/drugs-in-porphyria/(accessed 20 November 2020)Google Scholar the Drug Database for Acute Porphyria (https://www.drugs-porphyria.org) and the American Porphyria Foundation Safe Drug list (https://www.porphyriafoundation.org/drugdatabase/) accessed 20 November 2020.b There are conflicting reports on the safety of flucloxacillin. Use only if there is no safe alternative.c Protamine is considered safe by the American Porphyria Foundation (https://www.porphyriafoundation.org/drugdatabase/).d Use if required in an obstetric emergency. Open table in a new tab The requirement to use ‘safe medicines’ must be highlighted in the patient's medical record. However, in a life-threatening emergency, no medicine should be withheld if there is no acceptable alternative, even if it is known to be porphyrinogenic. The partial enzyme deficiencies associated with AHPs do not affect haem synthesis for erythropoiesis. Anaemia is therefore not a feature of the acute porphyrias and should be managed as for any other patient. The risk of allergic reactions in patients with AHP is the same as in the general population and standard management practices should be followed. Thromboprophylaxis should be given as for any patient, using safe anticoagulants when required (Table 2). There are no reports of increased risk of venous thromboembolism in patients with AHP. Where possible, fasting times for elective procedures should be kept to a minimum by scheduling patients early on theatre lists. As for any patient requiring general anaesthesia for elective procedures, fasting in relation to solid food and particulate liquids should be for at least 6 h. Patients should be allowed to drink clear fluids up to 2 h before surgery as clear fluids containing carbohydrates prevent a catabolic state. Urgent procedures should proceed without fasting delay. Fasting intervals for elective procedural sedation should follow local protocols. Although they traditionally are identical to that recommended for elective general anaesthesia, a recent international multidisciplinary consensus statement on fasting before procedural sedation advises that each patient and procedure should be stratified for aspiration risk so that a graded fasting period can be recommended.22Green S.M. Leroy P.L. Roback M.G. et al.An international multidisciplinary consensus statement on fasting before procedural sedation in adults and children.Anaesthesia. 2020; 75: 374-385Crossref PubMed Scopus (18) Google Scholar After surgery, acute porphyria symptoms can be masked by analgesic medicines and mimic complications. Normal eating and drinking should be established before discharge and patients should be given open access to return to hospital if required. If it is not possible to establish postoperative eating and drinking as per usual protocols, i. v. Fluids containing glucose, for example, glucose 5% with saline 0.9% or a similar crystalloid, should be continued according to local protocols to limit catabolism until oral intake is established. In patients who are unable to eat and drink for a prolonged period after surgery, advice must be sought from a dietician, and calories provided enterally via the nasogastric route or i. v. as total parental nutrition. The majority of patients with AHP have normal pregnancies with no clinical issues relating to porphyria.11Marsden J.T. Rees D.C. A retrospective analysis of outcome of pregnancy in patients with acute porphyria.J Inherit Metab Dis. 2010; 33: 591-596Crossref PubMed Scopus (24) Google Scholar Acute attacks that have occurred during pregnancy have been safely treated with HA without adverse outcomes.3Stein P.E. Badminton M.N. Rees D.C. Update review of the acute porphyrias.Br J Haematol. 2017; 176: 527-538Crossref PubMed Scopus (71) Google Scholar However some general precautions should be taken during labour and delivery. They include avoiding prolonged fasting and use of medicines from the safe drug list. Stress should be minimised by providing good analgesia during labour. Early epidural anaesthesia should be considered. No alteration in epidural drug therapy is required in patients with porphyria. If symptoms suggestive of porphyria occur, including seizures, pregnancy-related causes should be excluded first following local maternity service guidelines. In a clinical emergency, no medicine should be restricted if it is likely to be of clinical benefit in a life-threatening situation. This includes the use of ergometrine. Acute porphyria very seldom manifests before puberty. For asymptomatic children with a known diagnosis of porphyria, as confirmed by family testing, adhering to non-porphyrinogenic medication as a precaution is recommended. There are no other specific requirements, but if concern is expressed by the family then the case should be discussed with a porphyria specialist.23National acute porphyria service contact details: Cardiff porphyria service. www.cardiff-porphyria.org. King’s College Hospital porphyria service. Available from https://www.kch.nhs.uk/service/a-z/porphyria (accessed 20 November 2020)Google Scholar Case reports mention a theoretical risk of an acute porphyric crisis during cardiopulmonary bypass as a result of stress caused by blood loss, hypothermia and the use of large numbers of medicines required during anaesthesia and surgery.20James M.F. Hift R.J. Porphyrias.Br J Anaesth. 2000; 85: 143-153Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar,24Saberi K. Salehi M. Rahmanian M. Bakhshandeh A.R. Mahlabani M. Anesthetic implication of tricuspid valve replacement in a patient with acute intermittent porphyria.Ann Card Anaesth. 2016; 19: 367-371Crossref PubMed Scopus (1) Google Scholar However, there is currently no evidence that these factors directly precipitate acute attacks. Several reports describe successful surgery in patients requiring cardiopulmonary bypass provided the general measures outlined above are followed.24Saberi K. Salehi M. Rahmanian M. Bakhshandeh A.R. Mahlabani M. Anesthetic implication of tricuspid valve replacement in a patient with acute intermittent porphyria.Ann Card Anaesth. 2016; 19: 367-371Crossref PubMed Scopus (1) Google Scholar In the initial phase, especially in mild acute attacks (mild pain, no neuropathy, no hyponatraemia), patients may respond to conservative measures that they can initiate at home. However, if neurological features develop or the patient fails to respond to initial conservative measures within 12–18 h, then admission for monitoring, treatment with parenteral analgesia, fluid replacement and possibly i. v. HA are indicated. As few clinicians have experience with managing an acute attack, advice should be sought from a porphyria specialist. Specialist support is provided in the UK through the National Acute Porphyria Service (NAPS) who provide 24-h clinical advice.23National acute porphyria service contact details: Cardiff porphyria service. www.cardiff-porphyria.org. King’s College Hospital porphyria service. Available from https://www.kch.nhs.uk/service/a-z/porphyria (accessed 20 November 2020)Google Scholar The following should be considered in patients experiencing an acute attack of porphyria3Stein P.E. Badminton M.N. Rees D.C. Update review of the acute porphyrias.Br J Haematol. 2017; 176: 527-538Crossref PubMed Scopus (71) Google Scholar,19Stein P. Badminton M. Barth J. Rees D. Stewart M.F. Best practice guidelines on clinical management of acute attacks of porphyria and their complications.Ann Clin Biochem. 2013; 50: 217-223Crossref PubMed Scopus (62) Google Scholar:(i)Remove or treat precipitating factors and use non-porphyrinogenic medicines. A safe medicines list is provided by UKPMIS.21UK porphyria medicines information service. Provided by the Welsh Medicines Information Centre. 2019 Porphyria Safe List. Available from https://www.wmic.wales.nhs.uk/specialist-services/drugs-in-porphyria/(accessed 20 November 2020)Google Scholar(ii)Exclude other causes of abdominal pain including surgical, gynaecological, obstetric or postoperative complications.(iii)Conservative measures and increased oral carbohydrate intake may be sufficient to treat mild attacks.9Handschin C. Lin J. Rhee J. et al.Nutritional regulation of hepatic heme biosynthesis and porphyria through PGC-1alpha.Cell. 2005; 122: 505-515Abstract Full Text Full Text PDF PubMed Scopus (263) Google Scholar(iv)Pain, nausea and vomiting are prominent features. Pain is usually severe and nearly always requires parenteral opioids, often in large doses.13Hift R.J. Meissner P.N. An analysis of 112 acute porphyria attacks in Cape Town, South Africa.Medicine. 2005; 84: 48-60Crossref PubMed Scopus (107) Google Scholar Consider patient-controlled analgesia and seek advice from the local pain team as required. Antiemetics such as cyclizine, ondansetron and prochlorperazine are not porphyrinogenic.(v)Heart rate and blood pressure should be monitored and an ECG performed to identify any arrhythmias. Hypertension and tachycardia should be managed with atenolol, propranolol or labetalol. Nifedipine is a safe alternative.(vi)Ventilatory frequency and oxygen saturations should be monitored. An arterial blood gas should be taken if there is concern about respiratory function.(vii)Observe for signs of motor neuropathy, including muscle weakness, bladder and bowel dysfunction. Progressive neuropathy is a medical emergency. Affected patients should be transferred to a high dependency unit or ICU, with access to specialist neurology and metabolic advice. Convulsions can be terminated with i. v. lorazepam or diazepam. Safe anticonvulsants should be prescribed for ongoing use (e.g. levetiracetam).(viii)Fluid balance should be carefully monitored, especially if the patient is vomiting. Sodium chloride 0.9% or similar crystalloids may be needed to correct dehydration and electrolyte disturbance. Fluid replacement with glucose only solutions (e.g. glucose 5%) should be avoided as there is a risk of exacerbating hyponatraemia. In patients unable to tolerate oral calories, glucose 5% with sodium chloride 0.9% or similar crystalloids are suitable.(ix)Routine laboratory investigations tend to be normal, apart from hyponatraemia, or evidence of an infection, which could be a precipitating factor. Hyponatraemia occurs in up to 40% of cases and can be severe.3Stein P.E. Badminton M.N. Rees D.C. Update review of the acute porphyrias.Br J Haematol. 2017; 176: 527-538Crossref PubMed Scopus (71) Google Scholar The exact mechanism of hyponatraemia during an acute attack is unclear. The syndrome of inappropriate antidiuresis as well as renal and or gastrointestinal related sodium loss have all been described. A cause should be sought in each patient with specific attention to intravascular volume status. Hyponatraemia exclusively caused by an acute attack of porphyria typically does not respond to fluid restriction alone and may require hypertonic saline.(x)A random urine sample for urinary PBG should be collected and sent for laboratory analysis as described earlier.16Woolf J. Marsden J.T. Degg T. et al.Best practice guidelines on first-line laboratory testing for porphyria.Ann Clin Biochem. 2017; 54: 188-198Crossref PubMed Scopus (22) Google Scholar Human haemin, available in the UK as HA (Normosang, Recordati Rare Diseases, Paris, France), is a specific therapy for severe acute neurovisceral attacks irrespective of the type of AHP (https://www.porphyriafoundation.org/drugdatabase/). Indications for the use of HA include progressive neuropathy, hyponatraemia, convulsions and persistent pain and vomiting unresponsive to conservative measures.19Stein P. Badminton M. Barth J. Rees D. Stewart M.F. Best practice guidelines on clinical management of acute attacks of porphyria and their complications.Ann Clin Biochem. 2013; 50: 217-223Crossref PubMed Scopus (62) Google Scholar Despite reducing severity and duration of attacks in addition to progression of neuropathy, HA will not reverse established nerve damage. The recommended dose of HA is 3 mg kg−1 (maximum 250 mg) once daily on 4 consecutive days. HA is supplied as a concentrated haem solution which is diluted in saline immediately before infusion and given over 30–40 min (Table 3).25Summary of product characteristics - normosang® (haem arginate) Recordati rare diseases. Available from https://www.medicines.org.uk/emc/product/6235 (accessed 20 November 2020)Google Scholar In the UK, HA is obtained through NAPS.23National acute porphyria service contact details: Cardiff porphyria service. www.cardiff-porphyria.org. King’s College Hospital porphyria service. Available from https://www.kch.nhs.uk/service/a-z/porphyria (accessed 20 November 2020)Google ScholarTable 3Practical information on giving haem arginate.25Summary of product characteristics - normosang® (haem arginate) Recordati rare diseases. Available from https://www.medicines.org.uk/emc/product/6235 (accessed 20 November 2020)Google ScholarGiving haem arginateEstablish venous access•Large i.v. cannula OR:•Peripherally inserted central catheter (PICC) OR:•Central venous catheterEquipmentGiving set with 15–20 μm inline filterPreparation•Dilute immediately before giving•3 mg kg−1 (maximum 250 mg) in 100 ml saline 0.9% once daily for four consecutive days•Do not exceed 5 mg kg−1 dailyInfusion•Infuse over 30–40 min•Monitor infusion site continuously for extravasationAftercare•Flush using 250 ml sodium chloride 0.9% solution:•Three to four 10 ml boluses initially, then:•Remaining volume under gravityOther•Alternate arms daily if peripheral infusion•Stop infusion immediately in case of extravasation Open table in a new tab The main adverse effect of acute treatment with HA is local perivascular irritation and thrombophlebitis. This effect can be minimised by infusion through a large bore cannula or central venous catheter in addition to flushing with 250 ml sodium chloride 0.9% after the infusion. Frequent peripheral use may cause phlebitis of peripheral veins, whilst central venous catheters can become obstructed with haem deposits after repeated doses. Despite being a rare condition, it is essential for anaesthetists to consider the practical implications of managing surgical patients with AHP. The variable and non-specific symptoms can make the diagnosis of an acute attack challenging. Advice on the management of these patients can be sought from NAPS.23National acute porphyria service contact details: Cardiff porphyria service. www.cardiff-porphyria.org. King’s College Hospital porphyria service. Available from https://www.kch.nhs.uk/service/a-z/porphyria (accessed 20 November 2020)Google Scholar In the perioperative period, precipitating factors should be avoided and drugs should be chosen from a safe list such as that provided by UKPMIS.21UK porphyria medicines information service. Provided by the Welsh Medicines Information Centre. 2019 Porphyria Safe List. Available from https://www.wmic.wales.nhs.uk/specialist-services/drugs-in-porphyria/(accessed 20 November 2020)Google Scholar