Porphyrias: implications for anaesthesia, critical care, and pain medicine telen Findley BMBS BMed Sci FRCA Anu Philips MBBS FRCA Duncan Cale PhD MRCP FRCPath Amanda Nair BM FRCA Revaidation Key points “The aut porpyras ae see incertae porpiyra, vanegte porphyrin heretary opropersnyra. and Sapsotewini sed debyertave detceney ‘Onl the sate porsyras Aeteriorte te acne etree Faring, dehy, fen, ane ‘matron of many degen lnggerteate ces therfore he ‘alr fers thule be checked Span cures bas Dagrosis of eve neurovsce ces equres a hgh index of apican coiplad wot of “rine er porpebiingen ‘Aca eres ay be fe rearenng (iiean be aborted by early ‘managements oterwe ‘uppercve Helen Findley BMBS BMed Sei FRA Specalty Regs in Anastasia Sheteld Tachng Hospis NHS Tt Sheil UK ‘Adu Pils MBBS FRCA Specialist Repstrar in Arwestia Sheed Teaching Hospias NHS Test Sheil UK Duncan Cole PhO MRCP FRCPith Clea Senior Lecture ia Mees Brochemisry and Metabolic Medine Department of infection. mmuraty ard Brochensry Car Uiversty Heth Park. Carl F140 UK ‘Amanda Naie BM FRCA Constant Anaesthetist Sheil Teaching Hosptial NHS Tet Norther Gener! Homa! Herries Road, Sheffield 5 7AU, UK Te 444 114 2714818 Foe +44 114 2269342 smal amanda ards (orcomespondence) 128 Definition ‘The porphyrias are a heterogeneous group of inherited disorders of haem biosynthesis. The ame porphyria is derived ffom the Greek word for purple, ‘porphyros’. This was the ‘name given (© the purple compound formed when blood was teated with concentrated sul- hutic acids! the disease was probably named porphyria due tothe red discolouration of urine in affected patients. Muliple classification systems exis; the most relevant to anaesthetists is acute and non- acute (Table 1). All acute porphyrias have the potential to develop acute neuroviseral crises. Precipitating factors are commonly encountered in the perioperative period; therefore, anaesthe- tists must be aware of the Wiggers and the ‘management of an acute crisis. Non-acute porphyrias do not deteriorate into acute crises, ate less relevant for anaesthetists, and will not ‘be mentioned further in this article, Pathogenesis Parphyrins are organic cyclical compounds found in many aspects of biological ie; the post important in humans is haem, the iro containing rng structure found in haemoglobin. myoglobin, and all of the cytochromes.” The haem biosynthetic patway is most sctve inthe liver and bone marrow. In the por phyrias, genetic defects cause deficiency of innermeary enzymes in his patway Fig. 1. Al acute porphyrias have the potential to develop acute netrovscen crises when a pre- cipsatng event occurs (Table 2). Precipitating factors incease the demand for haem in the liver, foe example, by inducing the acm ceasing cytochwme PASO family of cxzymcs, which results in an increased fox trough the pathway and accumalation of 1010p? substrate before the enzyme defect. All enzyme defects seen in the acute porphyrias result in the accumulation of Saminolaevolinie acid (ALA). In acute intermittent porphyria (AIP), vvatiegate porphyria (VP), and hereditary copro- ‘porphyria (HCP), porphobilinogen (PBG) is also elevated and levels are used to diagnose acute crises ‘The symptoms and signs of acute neurovise- feral crises are thought to result from neuro- Togical dysfunction in motor, sensory, and suwiogomic fibres and the central nervous system. The precise cause of neurological dys- fonction remains a matter of debate, There are ‘two main theories: the most widely held states that ALA is neurotoxic; the other proposes that ‘haem deficiency is responsible for neurological aysfunction Inheritance “The gene mutations causing AIP, VP. and HCP ae all inherited in an. autosomal-dominant ‘manncr, with variable expression” In all Uce ‘conditions, there isa eduction in speci imter- mediary enzyme activity to ~S0% of normal Iomever, 80% of carriers of the gene mutation will never manifest symptoms.’ ALA debyéra- tase deficiency is inherited as an autosomal secesive condition Epidemiology “The overall prevalence of acute porphyrias in European counties is 1-2 in 100000, with AIP being the most common. Inthe UK, the in- idence of newly diagnosed AIP is 0.16 per aillon per year,” equating to ~10 new cases er year inthe UK. “The prevalence of the diferent acute por- hyias also varies geographically. Owing to the founder effec, AIP is more common in -Aesace Aces pion 2 eng 202 ‘Coriuig Edveaton in Antes Cra Car & Pain | ohare 12 Number 32012 Se hater a aay Ono rey Pes onto rh rl of races ATARI MDUns pleas enat puraiipermasoratbepcom“able Presence faite eats and en ewe pores eee pape LA epee decency ———— [_esiceare rom) ) = Fig | Haem biosythev pathway and the enzyme defects invlved in Affereneporphyris. “Acate porphyrias are shown In bod Des ‘Alcohol northern Sweden, affecting up 9 1 per 1500.’ VP is about half as ‘common as AIP in Europe* but more widespread in the Afkaner ‘community in South Africa, where itis found in 1 per 250~500.° ALA dehydratase deficiency is extremely rare, with <10 cases reported since 1979. Implications of the acute porphyrias “The acue porphyras have significant implications de to their pro- pensty to develop potentially lifetheaening newrovisceral crises, Which can be tiggered by a mumber of facors including drugs (Table 2). Now-acute porphyria ae less concerning forthe anaes- thei a these patients do nt develop act rise. Syapons md sess te ewe Maybe midge ‘Abeta pin Reruren sete poly Anuer case of ate Astocined nana and_—_Endomeinpvic vomiting Intent dee [Abeae of tevecor ae bowel tome sexy Opiate adiction Cadionsco sion Tebyewda ekyanbytia ypereaon Wear Primal ‘nitan-Bare syctome Upper limbe>loner Pompei "espe tar (aly n VP and HCP apace rd Anaeathelists may be involved in the care of patients with diag- noses of porphytia in a number of settings: during acute crisis; during incidental surgery # for acute or chronic pain management Presentation of an acute crisis ‘The most common sympioms and signs of acute crisis are shown in Table 3. Almost all patients have severe abdominal pain, usvaly associated with a tachycardia. Neurological or psychiatric sy toms rarely occur in isolation. Skin lesions may be present during acute crtes in patients with VP and HCP. Other clues tothe disg- nosis include wine tha datkens on standing, hyponslraemia, or recent ingestion of tigger drugs (\ypically anticonvulsants, oral contraceptive pill, alcobel, or ict drugs). Continuing Education in Anaesthesia Critcal Cre & Pan | Voume [2 Number3 2012129Porphyrias Cises are four to five times more common in women and ‘usually occur in their early 3037 A family history of porphyria may not be presen, duc to previously undiagnosed disease in asymptomatic cars. Acute ctises may vary from a single attack that aborts quickly to those that go on to have frequent lifeshreatening attacks with rulisystem involvement, respiratory, and bulbar paresis. Less than 10% develop recarent sttacks* Symptoms and signs of acute crises also vary greatly and therefore can mimic ether conditions Patients having acute crises are frequently misdiagnosed, leading to inappropriate or delayed treatment. Acute porphyria should be excluded in any case of unexplained severe abdominal pan, espe- cially if associated with tachycardia and neurological symptoms. Implications for critical care Patients presenting with an acute crisis to critical care may not have an established diagnosis or may have been misdiagnosed with another condition. Critical care admissiom may be required for sup- pportive treatment, including respiratory support, control of seizures, or treatment of a precipitating infection. Diagnostic tests in acute porphyria “The key to making the diagnosis lies i having s high index of sus- Picion in patients presenting with abdominal pin. Acute porphyria can be effectively ruled out by checking PBG level in a fesh trine sample Urine mest be collected in universal container and ‘protected from light, as PBG will degrade rapidly when exposed to light’ increasing the likelihood of a false-negative result. All hos- pitas should have access to at leat semi-quantitaive assay 24 h 8 day. Increased urine PBG levels conti acute porphyria; levels ane usually 10 times normal within a weck of onset of an acute crisis.” A normal urine PBG level rales out AIP, VP, and HCP (but not ALA dehydratase deficiency) as @ cause of current symptoms, but PEG may be mildly elevated im latent AIP or AIP in remission, ‘Acute porphyria due to the rare condition of ALA dehydratase deficiency will no ext positive for wine PBG: therefore, specialist advice is waranted if porphyria is stomgly suspected ina patient With negative urine PBG. Cerebrospinal Bid samples in porphyria ae usually normal® ‘A posiive result should be discussed with the appropriate regional specialist centre, where further investigations are coordi- tated. Th orginal postive sample shouldbe sent to the specialist. ‘centre and a second, confirmatory sample may be useful, but is tot critical, and weaiment should not be delayed while waiting forts. EDTA blood $10 ml should also be collected, and a small faccal sample, both protected from light. These samples are less urgent, but should preferably be obtained when the patient i= unwell; they are used for biochemical analysis to determine the lype of acue porphysia. Once the type of porphyria has been ‘determined, DNA studies can identify the genetic mutation responsible. Family members can then be offered genetic counsel- ling and screening, Management of an acute crisis (nce the diagnosis of an acute crisis has been made, management consists of removing potential precipitans, giving iv. haem srginate, and supportive measures Removing potential precipitants All drugs being administered should be reviewed, with reference to a regularly updated safe drog list However, in a life-threatening situation, emergency drugs should not be withheld due to concerns over their safety is porphyria; the acute porphyric atack can be treated if t occurs. Any intercurrent illness should be treated with the usual measures. Infection must be treated aggressively and should be actively excluded by septic sereen if no other obvious trigger is found. Paracetamol is safe as an antipyretic and analgesic?” Fasting will wigger continued production of porphyrins, 20 a catabolic state should be avoided by ensuring thatthe patient takes 200 g of glucose per day"? by cither administering carbohydrate nergy supplements orally or via a nasogastic tbe (eg. 25% MAXUUL, available from Nuticia) or through iv. infusion. If the later is used, we recommend the pharmacy to prepare 0.9% saline with 10% dextrse aded (2 lites provide 200 g of glucose in 24 1)? as these patiems are prone to hyponstraemia. Carbohydrate loading is also known to suppress hepatic ALA synthase activity sand has been wsed to aboet mild attacks.‘ LV. haem arginate 1. haem arginate therapy shoul be started as soon as posible, a itis associated with impeoved outcomes, including shorter hospital stay:* Hacm arginate aims to suppress hepatic production of ALA, and other porpbyrin peecrsrs by replenishing haem. The recom- mended dose of haem arginae is 3 mg kg” (10a maximum of 250 mg) once daily for 4 consecutive days and the course should be given in fll” Clinical improvement is usually rapid if weatment is started carly in the couse of an acute crisis; however, if eat ment is delayed and extensive neuronal damage has occured, the patient will be slow to cover. Treatment for longer than 4 days can be considered in these cases; however, there is no evidence for an improved outcome with longer cours of tretment.* Hiaem arginae should be administered as an iy. infusion over 30 min into a large vein cr via cena line” and should be thor- oughly Sushed with sale on completion of the dose. Hacm arzi- sae is isitant wo veins and may cause Uxombophlebis this may lead tothe loss of supericial veins and the consequent need for ceniral line. Hacm arginac should be diluted in 100 ml of 0956 sodium chloride in a glass botle: however, a pragmatic but wn- licensed approach, to avail delaying emergency treauneat, would be to use plastic containers of to administer in 100 ml of 2056 130 Continuing Eduction n Arseshesa Crtcal Care & Pain| Vole 12 Number 3 2012‘muman albumin, ensuring preparation occurs immediately before administration” Supportive measures ‘Acute crisis is commonly associated with abdominal pain, but can 'be associated with back pin or pain inthe limbs. Pain can be very severe and may require substantial dascs of opioids. Nausea and Vomiting are treated safely with prochlorperazine or ondansetron? Lorazepam and midazolam in low doses are safe for anxiety: in- somnia can be teated with zopiclone” Haloperidel i safe and ray be helpful in testing delirium. B-adrenergic blocking agents may be useful to contra tachycardia and hypertension; glyceryl trinitrate can also be used safely Controlled corection of hypond- ‘waemia may prevent seizures. Seizures can be safely terminated with boluses of benzodiazepines: however, prophylaxis canbe dif- ficult as many commonly used anticonvulsant drugs exacerbate acute porphyria. Levetracetam, clonazepam, gabapentin, and viga- ‘atrin are safe to use and magnesium sulphate may be used as an anticonvulsant? ‘Ventltory support is indicated if respiratory failure occurs. Evidence of functional impairment. fr example, inability to cough ‘or expectorate, are pragmatic markers of referal for cfitical care ‘opinion. The role of non-invasive ventilation is questionable: patents with respiratory failure may also have bulbar weakness and gastric paresis, leading to a signiicant risk of aspiration of gastric contents. For these reasons. aay patient with significant neurological deterioration should also be monitored closely. Sedation is safe using propofol and alfentanil infusions” The linical safety of prolonged midazslam infusion is unknown. ‘Clonidine is not thought to be porpinyrogenic within the normal therapeutic range; there is case report of its use during acute ‘Thromboembolic prophylaxis can be safely provided with any ‘of the low-molecular-weight heperins and stress ulcer prevention ‘using iv. omeprazole or ranitidine is safe? Prognosis ‘A study in the USA, published in 1996, showed a mortality of 14% in patients admitted to hospital with an acute crisis. Neatly all the patients who died had advanced porphyria and required ‘mechanical ventilation However, more recent studies have ve a high index of pion in pater wth unexganad abdominal ple ‘Send urine, protected frm it fo FOG ay Remove ores ggg foto. Gree hem arg 3g yf cays Hy requre ge doses f morphine to cont pa ntemstes—pochorperasne an enna ae fe Conzlacycarda an hyperterion wih ecg ges ‘Sears ay be avoid by coven hypenaacma are est With atone, aban vet so Sedation wi root ad alenan! isle Fg 2 Key principles of investigation and management of aeuteporplyrias suggested that acute crises are rarely fatal* Acute porphyria, whether symptomatic or not, carries an increased risk of hyperten- sion, hepatocellular carcinoma, and chronic renal failure. ® Implications for anaesth General principles ‘Any patient with suspected or confirmed acute porphyria undergo- ing surgery requires a full medical history, including detailed family history. and a thorough physical examination, along with careful neurological assessment. Particular attention should be given to the presence of peripheral neuropathy and autonomic instability, as they will influence the anaesthetic technique and also indicate active disease, with increased risk of acute criss, However, most patients will have a negative family history and no clinical evidence of diseae, Acute porphyrias can be wiggered by a number of factors present in the perioperative period (Table 2), Safe anaesthetic man- agement of these paticas requires knowledge of the type of por- phyria and susceptibility to an acute crisis, awareness of the clinical features of an attack, and knowledge of safe pharmaco- logical intervention. ‘All team members involved in the perioperative period should bee informed of the patent's condition and implications of the disease. The patient can be admitted on the day of surgery, provid- ing a thorough preoperative assessment has taken place. Ideally, preoperative assessment should be done by a senior anaesthetist {involved in the case a this may allay anxiety and aid in setting up a rapport. Anxiolysis with benzodiazepines or phenothiazines is recommended. Fasting periods should be minimized, but remain in sccordance with Jocal protocols, and i.v. dextrose saline infusion should be given to avoid calorie restriction. Patents should be monitored after operation for symptoms and signs of an acute crisis, and are therefore not suitable for day-case surgery. Monitoring of urine PBG levels is not necessary roatinely, although may be useful as an early marker of acute crisis in those patients who have recurrent acute attacks. In the event of an acute crisis, teatment is as advised in the previous section, Regional anaesthesia There it no absolute contradiction to the use of regional anaesthe- sia in porphyria. However, a thorough neurelogical and cardiovas- cular examination must be carried out by a senior clinician before ‘regional lechnique is undertaken, to diagnose pre-existing neuro- logical deficits, and the presence of autonomic neuropathy Untreated bypovolaemia and autonomic instability in the presence of central neutoaxial block may precipitate severe cardiovascular instability There have been various reports of regional anaesthesia being used successfully in patents with porphyria and we conclude that there is no evidence that a general anaesthetic is safer than a regional anaesthetic. [Arseshess Crocs) Care & an |oune |Z Number3 2012131Porphyrias “able 4 Safe rote of cnmeniy sed éugs in amestes Adare am hp drs orp ncordng ter dasa The ae rus re ne rohynegnt pss no porpiegw or probably na porpyriegeie The poy porpyinagee Uncaiad dug Propel ‘Neoromuscular Backing Agen and Revers ‘Ailes plang mui lane Byetowaptose Asia Dimer Sedative premedication Feyiicne Mazer hppa en sed ely) General anaesthesia There are many agents available to allow a safe general anaesthetic in a patient with acute porphyria, but a safe technique must be sccompanied by team awareness of the implications of the condi- tion, appropriate preoperative preparation, and the availability of expert advice, ideally including a porphyria specalis, Depending on the patient and surgical completes, the provision for critical care admission may be advised Classifying drugs as porphyria safe or unsafe is too simplistic the duration of exposure and the absolute dose dictate whether an cute crisis triggered and the severity of the crisis, Multiple con- founding factors in the perioperative period mean that the trigger fora crisis may be unclear. Much wrk has been done to develop CContinung Eeveaton in Anaeshasia Crea Care & Pan databases based on intemational experience. Table 4 gives a list of commonly used drugs and their safety profile Cardiopulmonary bypass has been caried out successfully in ‘ients with porphyria, despite the physiological stress imposed by hypothermia, pump-induced haemolysis, blood loss, and expos- lure to numerous drugs, all of which could tigger development of Implications for pain management Management of acute pain associated with neurovisceral crisis is fone of the most important aspects of managing patients with por- pPhytia, Patients having acute painful crises have high disease Voume 12 Number 32012Porphyrias activity and are therefore at risk of major deterioration if an unsafe analgesic is used. Based on collective clinical experience, the safety profile of different analgesics is wll known, so even severe pain should be manageable with safe and effective agents, Table 4 ‘etal the safety profile of common analgesics. The safety of any agent should be confirmed using one of the drug databases listed in the Sources of further information section. For severe pain associated with an acute crisis, iv. morphine via a patien-controlled analgesia system (PCAS) provides rapid ‘onset, itatable, effective, and safe analgesia. Meperidine can also ‘be used safely; there is less experience using fentanyl PCAS, but it is reported as safe to use.’ Offering regular prochlorpeazine or ‘ondansetron can help manage opiidsinduced nausea, iclofenac should not be used as it is probably porphyto- genic. Other simple analgesics, in accordance with the WHO analgesic ladder, are safe to use” and are helpful, in addition to ‘morphine, during an acute crisis and to control pain between ‘A small minority of patients will experience chronic neuropath- ic pein, associated with an ongoing level of disease. activity. Gabapentin, pregabalin, and amitrypilline are safe drugs to teat ‘neuropathic pain.” ‘Patients with undiagnosed porphyria may also. present at ‘hronic pain clinic for management of chronic abdominal, pelvic, ‘or back pain. If these patiems have any neurological, psychiatric, for other astocited features fisted im Table 3, a urine sample should be checked for PBG to exclude acute porphyria (see the previous section). Ie is important to appreciate that abdominal pain in patients known to have porphyria may be dae to aditional pathologies, for ‘example, appendicitis. A carefol history, examination, and focused ‘investigations should highlight these patients. Summary Although relatively uncommon, anaesthetists may be involved with the care of patients with porphyria during elective or emergency surgery, supportive weatment inertial care during an acute crisis or for pain management. The variable and non-specific symptoms and signs of the condition require clinicians to actively consider the diagnosis and to have a low threshold for checking urinary PUG levels. Anaesthetists should be aware of the perioperative factors that may tigger or worsen an acute crisis, and in particular should know where to source up-to-date information on the safety of indi vidual drogs. Management with iv. haem arginate together with supportive measures can improve outcome, Sources of further information wow cardiff porphyria ore vworw.wmic.walecas uk/pomphyria info.php wow drugs-porphyria.org wow porpbyria-europe.com wow porpyia org.uk Declaration of interest None declared. References 1. Murphy PC. Acute itermizene porpiyr: the anaesthetic problem and te background, Br] Anoet 1964" 36:80 2. James ME HR Roepe. Br) Ancerh 2000 85: 143-53 3. Expert opinion. European Porphyria Network (EPNET). Arable trom worporpinriaeurope cor (ecesed [7 Februar 2011) 4. Anderson KE. Bloomer JR, Bonkovsky HL et al Recommendacons for the diagnosis and trenton: of the ate porphyria. An Inte Med 2005; 142: 439-50 5. Dephach JC. Parker S.Bacninton M, Sandberg §. Elder G. European Porplyra. Network (PNET) for Information, epiemilogel dat quay and egy of servic. Orph) Rare Dis 2010; Supa. 1) 16 6 Puy H. Gooya L. Deybac JC Porphyrin, Lancet 2010; 375: 924-37 7. Thadant H, Deacon A Peters T Disgrous and management of porphyria be Med ] 2000, 320: 1647-51 8, Deacon AC Eder GH Fron ine ters fr the inveriton of suspected porphyria jin Pte! 2001 4500-7 9. Expert opinion. Wiles Meticines Information Cente. Aralabe trom vworawantcwalesshakiporphyria info php (accessed 19 fanry 2012) 10, Expert opinion. The Norwegan Porplyrn Centre (NAPOS), Avaisbe from wonwedrugsporphyra rgimenographphpid=3897 (accessed 7 February 2011) Please see multiple choice questions 17-20. Araeshess Voume |2Number3 2012133 cee kPa