- Email: [email protected]
Anaesthetic management of an obstetric patient with variegate porphyria
156
Variegate porphyria and caesarean section
Anaesthetic management of an obstetric patient with variegate porphyria C. Harris, E. Hartsilver Department of Anaesthesia, Royal Devon and Exeter Hospital, Exeter, UK ABSTRACT Porphyria is an uncommon disease that can produce life-threatening attacks with a mortality rate of up to 10%, specifically as the result of administration of porphyrinogenic medications. In obstetric anaesthesia there are many situations where drugs are given in an emergency and it is therefore important to be prepared for complications to avoid inadvertently inducing an iatrogenic porphyric crisis. We discuss the case of a 20-year-old nulliparous woman with variegate porphyria who required an emergency caesarean section in labour, and the drugs that are commonly used in obstetric practice. c 2013 Elsevier Ltd. All rights reserved.
Keywords: Porphyria; Anaesthesia; Obstetrics; Pregnancy; Caesarean section
Introduction Porphyrias are predominately genetically-inherited diseases in which there is abnormal synthesis of the porphyrin molecule due to a defect in one of the enzymes in the biosynthetic pathway. The most biologically significant porphyrin-containing molecule is haem, which is produced when porphyrin binds to iron. Haem is found in haemoglobin, myoglobin and the cytochromes, including cytochrome P450. The porphyrin pathway is controlled by several enzymes and a deficiency in any one of these enzymes leads to an accumulation of the precursors to that enzymatic reaction. The excess of precursors is thought to result in the symptoms of the disease, as well as the reduction in the end product, haem.1 Different types of porphyrias arise from defects in various enzymes of the porphyrin pathway, resulting in the accumulation of different precursors and therefore varying clinical pictures. Porphyrias may be classified according to whether or not they cause acute symptoms. The acute porphyrias include acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP) and plumboporphyria (PP). The incidence of AIP in Europe is 1 in 20 000, with variegate porphyria being more common in South Africa where the incidence is approximately 1 in 300 of the Afrikaner population.1,2 VP is characterised by cutaneous photosensitivity; patients may present with the skin manifestations associated with the non-acute porphyrias, the characteristic presenting signs and symptoms of acute intermittent porphyria, or a combination of both. The highest incidence in the world is in South Accepted January 2013 Correspondence to: Emma Hartsilver, Department of Anaesthesia, Royal Devon and Exeter Hospital, Exeter, UK. E-mail address: [email protected]
Africa and results from the introduction of a single point-mutation in 1688 by a Dutch settler.1 The porphyrias of major relevance to anaesthetic practice are these acute forms where reactions to anaesthetic drugs may be life-threatening.1 Although porphyria is rare in the UK, it is important that anaesthetists have a clear understanding of drugs that should be avoided. This is particularly relevant in obstetric anaesthesia where the emergency nature of some procedures may provide little time to plan.
Case report A 20-year-old nulliparous woman with a diagnosis of VP was referred for an obstetric anaesthetic consultant review. She was diagnosed at the age of seven years after family screening when an aunt spent a period of time on an intensive care unit with a severe exacerbation of VP after an anaesthetic. As a teenager she was seen by a genetic counsellor where the implications of the disease were discussed. Since then she had been told to wear a medical alert bracelet and received yearly information from the Cardiff Porphyria Service regarding safe drugs.3 She was otherwise fit and well and had had no acute attacks of porphyria and no previous anaesthetics. A plan and safe drug guide was made and documented in her medical notes. The pregnancy proceeded uneventfully until at 38 weeks of gestation an ultrasound scan showed a breech presentation. At 38+2 weeks she had an external cephalic version which was complicated by a reduced fetal heart rate. Vaginal examination revealed a dilated cervix at 2–3 cm, so epidural analgesia using an infusion of 0.1% bupivacaine and fentanyl 2 lg/mL was commenced and labour was induced with oxytocin. The cardiotocogram became suspicious and a decision was made to
C. Harris, E. Hartsilver perform a category-2 caesarean section, which was performed under a spinal anaesthetic. This was carried out under full aseptic conditions. The skin was anaesthetised with 1% lidocaine 2 mL. A 25-gauge Whitacre needle was inserted and 0.5% hyperbaric bupivacaine 2.2 mL with diamorphine 300 lg administered. A 3230-g female infant was delivered in good condition with Apgar scores of 9 at both 1- and 5 min. A small placental abruption was diagnosed at delivery, and in addition the umbilical cord was wrapped loosely around the baby’s neck. Postoperatively, the patient was closely monitored in the recovery room for several hours using the hospital early warning score observation chart. Hourly observations including urine output, respiratory rate, blood pressure, pulse, temperature and conscious level were recorded for 12 h. These observations were then continued 4-hourly. She was encouraged to keep adequately hydrated and to consume a good calorific intake. She had no symptoms of an acute porphyria attack and was successfully discharged home after her second night in hospital. The patient and midwives were well informed regarding the porphyria. A midwife reviewed the patient at home daily for three consecutive days then on day 12 and day 14. She remained well when reviewed by her general practitioner six weeks later.
Discussion Haem synthesis is controlled by an efficient negative feedback mechanism. A reduction in the concentration of haem stimulates the initial enzyme, d-aminolaevulinic acid (ALA) synthase, in the metabolic pathway to produce many of the initial precursors to haem. Thus any increase in haem utilisation, for example drugs that
Table 1
157 use the P450 cytochrome as part of their metabolism, will stimulate the pathway.1 Inheritance of a faulty gene leads to a 50% decrease in the activity of its affected enzyme allowing for some normal haem production. Carriers, therefore, may remain asymptomatic and only about 10–15% will express the clinical features of the disease. The increase in oestrogen and progesterone particularly in the first and second trimesters leads to an increased risk of exacerbations during pregnancy. The frequency of attacks during pregnancy in patients with acute porphyria has been reported in the range of 24–95%.1 Acute attacks of AIP in pregnancy are associated with miscarriage, hypertension, low birthweight infants and a maternal mortality of 2–42%.2 However, with greater understanding of the disease and its precipitating factors, close management of these patients during pregnancy is more frequently associated with a good outcome.2,4 Porphyria attacks may be precipitated by fasting, dehydration, stress, infection and hormonal changes. Further risk factors during pregnancy include starvation from hyperemesis gravidarum or during labour and smoking. The most important trigger factors in relation to anaesthesia, however, are the enzyme-inducing drugs. There are other mechanisms by which drugs can also interfere with this pathway, meaning many different drugs have the potential to induce an exacerbation.1 Acute exacerbations can present clinically with different symptoms which range from mild autonomic instability and electrolyte disturbances to severe attacks that may be fatal. The presenting symptoms and signs of an acute porphyric crisis are listed in Table 1.1,5 Acute attacks are diagnosed by raised concentrations of the pathway intermediates in urine, faeces and blood.
Symptoms and signs of acute exacerbations of porphyria
Abdominal pain Diffuse, usually extends into lower back and thighs, continuous, severe Vomiting Diarrhoea Autonomic instability Hypertension and tachycardia Photosensitivity Bullous skin rash in VP and HCP Agitation Electrolyte abnormalities Including hyponatraemia, hypomagnesaemia, hypokalaemia and hypochloraemia Seizures Tonic–clonic. May be associated with hyponatraemia and encephalopathy Paralysis Acute motor neuropathy, quadriparesis, cranial nerve paralysis. Lower motor neurone palsy with profound paralysis, hypotonia and absent reflexes Renal failure Particularly with chronic attacks of AIP Respiratory paralysis and coma
VP: variegate porphyria; HCP: hereditary coproporphyria; AIP: acute intermittent porphyria.
158 Crudely, this can be done by eye as porphyrin precursors, porphyrinogens, are colourless, but when exposed to light and oxygen they will convert spontaneously to porphyrins, which make urine turn to the colour of port wine. Biochemical assays of the precursors allow the type of porphyria to be established. Levels of the precursor ALA can be 5–20 times normal and levels of porphobilinogen may be 20–50 times normal.6 Management of a porphyric crisis should include rapid recognition and withdrawal of any potentially porphyric-inducing drugs, adequate hydration and calorific intake, and consideration of a dextrose infusion if oral intake is insufficient. Fluid balance and electrolytes should be carefully monitored as crises can induce electrolyte imbalance. Seizures, which are often secondary to hyponatraemia, may be safely treated with diazepam. Management of pain, nausea and tachycardia is symptomatic. Treatment of the underlying disease and muscle weakness is undertaken by the administration of haem arginate, 3 mg/kg given as an infusion over 15–20 min daily for four consecutive days.5,7 Haem arginate consists of haem complexed with the amino acid arginine to form a stable compound. By replenishing haem stores, the negative feedback inhibits the initial rate-limiting enzyme of the haem synthetic pathway, ALA synthase. The formation of porphyrins and the precursors ALA and PBG is almost immediately reduced to low levels, and the symptoms improve.2,5 The older treatment of haematin commonly caused thrombophlebitis and changes to coagulation and fibrinolysis.6 Haem arginate has fewer side effects and is safe during pregnancy. Patients with signs of respiratory insufficiency during an acute attack require immediate intubation and ventilation. Motor neuropathy is fully reversible but slow to recover and in some cases may take many months.5 Porphyria is a life-threatening disease that can be initiated by many precipitants, but one of the main concerns to physicians is iatrogenic inducement of a porphyric crisis secondary to administration of drugs. There are many situations throughout pregnancy and delivery where medication may be indicated. The Norwegian Porphyria Centre (NAPOS),8 in collaboration with the British Porphyria Association and the Welsh Medicines Information Centre (WMIC), has developed a multi-language drug database for acute porphyrias. It classifies drugs into non-porphyrinogenic (NP), probably non-porphyrinogenic (PNP), possibly porphyrinogenic (PSP), probably porphyrinogenic (PRP), porphyrinogenic (P) and not yet classified (NC). This database along with information from the WMIC has been used for the basis of the recommendations.3,8 Table 2 classifies the commonly-used anaesthetic, obstetric and resuscitation drugs into safe to use (NP and PNP) and those which should be avoided (PRP and P) for rapid reference. Other rarer drugs can be
Variegate porphyria and caesarean section checked for safety on the NAPOS drug database and the WMIC online.3,8 Many drugs required in obstetric anaesthesia are safe to use in porphyria but notable exceptions include diclofenac, cyclizine and ergometrine. If general anaesthesia is required, thiopentone is unsafe, but there have been several published cases of propofol being used without harm.3,8–10 For maintenance of anaesthesia, the agents of choice would be isoflurane or desflurane. Propofol infusion has also been used without complications.9 Neuraxial anaesthesia may be safely undertaken in porphyria patients. Careful neurological assessment should be made before anaesthesia and peripheral neuropathy from previous porphyric exacerbations documented to allow for assessment of changes should an attack occur. Previously, many local anaesthetic agents were considered to be unsafe, so procaine was preferentially used because of its short duration of action, and spinal anaesthesia was recommended because of the lower dose required. More recently, however, both bupivacaine and lidocaine have been put on the safe drug list; however, because of a lack of pharmacokinetic information, repeated high doses of lidocaine should only be used with caution and should be administered in glucose solution if used as a continuous infusion.3 Several cases have reported the use of both spinal anaesthesia and epidural analgesia using either lidocaine and/ or bupivacaine without precipitating an acute attack.9–11 Obstetric complications such as preeclampsia, postpartum haemorrhage, preterm labour and premature rupture of membranes all require the administration of medications. Commonly-used drugs such as methyldopa, hydralazine, ergometrine and some antibiotics are not recommended for use in patients with porphyria. However, no drug should be restricted if it is likely to be of major clinical benefit or required in a life-threatening situation. An acute exacerbation of porphyria can be managed and should not be fatal provided early recognition and treatment. The use of cell salvage is yet to be evaluated and reported upon in cases of porphyria. The concern is that the stress and hypothermia created by an extracorporeal circuit may increase the risk of a crisis. Cardiopulmonary bypass however, has been used without provoking an exacerbation.1 Starvation and dehydration are also known to be risk factors for the initiation of acute attacks of porphyria. Therefore, preoperative fasting should be kept to the recommended minimum and intravenous fluids should be considered if starvation is prolonged.1 Overall, with good obstetric and anaesthetic care, most patients with porphyria should have an asymptomatic uncomplicated pregnancy. We recommend that, as with this case, patients with porphyria should be seen by the obstetric anaesthetist and obstetrician early in the antenatal period. A clear management plan for preg-
Omeprazole
Co-amoxiclav, gentamicin, teicoplanin
Unfractionated heparin, Low-molecularweight heparin
Prochlorperazine
Labetalol
Bupivacaine
Suxamethonium, rocuronium
Terbutaline
Oxytocin
Adrenaline
Magnesium sulphate, tranexamic acid, adenosine, insulin
Antacids
Antibiotics
Anticoagulants
Antiemetics
Antihypertensives
Local anaesthetics
Muscle relaxants
Tocolytics
Uterotonics
Vasopressors
Others
Neostigmine, glycopyrrolate, atropine
Phenylephrine
Carboprost, misoprostol
Atosiban, betamethasone
Atracurium, vecuronium
Lidocaine*
Nifedipine
Ondansetron, granisetron, metoclopramide
Cefuroxime
Ranitidine
Fentanyl, remifentanil, alfentanil, paracetamol, codeine, tramadol, ibuprofen
Nitrous oxide, isoflurane, desflurane
Probably not porphyrinogenic
Intravenous administration of lidocaine should be avoided.
Morphine, pethidine
Analgesics
*
Propofol
Non porphyrinogenic
Recommendations for commonly-used drugs in patients with porphyria
Anaesthetics
Table 2
Ephedrine
Dexamethasone
Sevoflurane
Possibly porphyrinogenic
Cyclizine
Clarithromycin
Diclofenac
Halothane
Probably porphyrinogenic
Methylergometrine
Methyldopa, hydralazine
Erythromycin
Thiopentone
Porphyrinogenic
Sugammadex, chlorphenamine
Metaraminol
Ergometrine
Bupivacaine/fentanyl mixture
Not yet classified
C. Harris, E. Hartsilver 159
160
Psychogenic paresis after dural puncture
nancy, labour and delivery should be documented in the hospital and hand-held patient notes. This should include advice to avoid excessive fasting and dehydration, and a list of safe drugs and those drugs that should be avoided. The patient and midwife should also receive clear instructions regarding the possible signs and symptoms of an acute attack of porphyria during pregnancy, labour and in the postnatal period.
References 1. James MFM, Hift RJ. Porphyrias. Br J Anaesth 2000;85:143–53. 2. Farfaras A, Zagouri F, Zografos G, Kostopoulou A, Sergentanis S, Antoniou S. Acute intermittent porphyria in pregnancy: a common misdiagnosis. Clin Exp Obstet Gynaecol 2010;37:256–60. 3. Welsh Medicines Information Centre (WMIC) Cardiff. http:// www.wmic.wales.nhs.uk [accessed January 2013]. 4. Aggarwal N, Bagga R, Sawhney H, Suri V, Vasishta K. Pregnancy with acute intermittent porphyria: a case report and review of literature. J Obstet Gynaecol Res 2002;28:160–2.
5. Porphyria South Africa online. Universities of Cape Town and KwaZulu-Natal. http://www.porphyria.uct.ac.za [accessed January 2013]. 6. Siegesmund M, van Tuyll van Serooskerken AM, PobleteGutie´rrez P, Frank J. The acute hepatic porphyrias: current status and future challenges. Best Pract Res Clin Gastroenterol 2010;24:593–605. 7. European Porphyria Initiative (EPNET). http://www.porphyriaeurope.com [accessed January 2013]. 8. NAPOS. The drug database for Acute Porphyria. http:// www.drugs-porphyria.org [accessed January 2013]. 9. Consolo D, Ouardirhi Y, Wessels C, Girard C. Obstetric anaesthesia and porphyrias. Ann Fr Anesth Reanim 2005;24:428–31. 10. Kantor G, Rolbin SH. Acute intermittent porphyria and caesarean delivery. Can J Anaesth 1992;39:282–5. 11. Dumas RP, Silva EF, Resende MA, Pantoja AV, Barros AC. Anaesthesia for caesarean section in pregnant women with acute intermittent porphyria and hypothyroidism-case report. Middle East J Anesthesiol 2011;21:405–7.
0959-289X/$ - see front matter c 2013 Elsevier Ltd. All rights reserved. doi:http://dx.doi.org/10.1016/j.ijoa.2013.01.005
Recurrent psychogenic paresis after dural puncture in a parturient J. Nguyen, R. Abola, J. Schabel Department of Anesthesiology, Stony Brook University Medical Center, Stony Brook, NY, USA ABSTRACT We describe the case of a 29-year-old parturient who, after undergoing elective cesarean delivery, displayed symptoms of lower extremity weakness and sensory deficit. Her past medical history was significant for asymptomatic Arnold Chiari Type I malformation and asthma. She had received spinal anesthesia that failed to achieve an adequate surgical level requiring conversion to general anesthesia. After tracheal extubation, she exhibited bilateral leg weakness that did not resolve over the next 4–6 h. An urgent magnetic resonance imaging scan revealed a normal spine with no evidence of hematoma. The lower extremity paresis persisted and a neurologist diagnosed psychogenic paresis, a type of conversion disorder. Interestingly, the patient’s postoperative leg paresis was not her first occurrence of neurological dysfunction after dural puncture. At 27 weeks of gestation, she had similar lower extremity symptoms after a lumbar puncture, performed to exclude meningitis for severe headache symptoms. Psychogenic paresis is not commonly reported in the medical literature and we found no reports of psychogenic paresis after spinal anesthesia in a parturient or recurrent psychogenic paresis. We review the various risk factors, etiology, neurological signs and symptoms, types, therapy and future management of a patient with recurrent conversion disorder. Published by Elsevier Ltd. Keywords: Psychogenic paresis; Conversion disorder; Parturient; Spinal anesthesia; General anesthesia
Introduction Psychogenic paresis is a type of conversion disorder that has been rarely reported in the medical literature, with Accepted January 2013 Correspondence to: Joy Schabel MD, Department of Anesthesiology, Stony Brook University Medical Center, Stony Brook, NY 117948480, USA. E-mail address: [email protected]
fewer than 20 cases cited involving anesthetic procedures. Recurrent psychogenic paresis following neuraxial procedures has not been previously described. This case report describes the presentation of recurrent psychogenic paresis in a parturient after spinal anesthesia for cesarean delivery. The various risk factors, etiology, neurological symptoms and signs, management and future anesthetic plan for patients with conversion disorder are reviewed.
Variegate porphyria and caesarean section
Anaesthetic management of an obstetric patient with variegate porphyria C. Harris, E. Hartsilver Department of Anaesthesia, Royal Devon and Exeter Hospital, Exeter, UK ABSTRACT Porphyria is an uncommon disease that can produce life-threatening attacks with a mortality rate of up to 10%, specifically as the result of administration of porphyrinogenic medications. In obstetric anaesthesia there are many situations where drugs are given in an emergency and it is therefore important to be prepared for complications to avoid inadvertently inducing an iatrogenic porphyric crisis. We discuss the case of a 20-year-old nulliparous woman with variegate porphyria who required an emergency caesarean section in labour, and the drugs that are commonly used in obstetric practice. c 2013 Elsevier Ltd. All rights reserved.
Keywords: Porphyria; Anaesthesia; Obstetrics; Pregnancy; Caesarean section
Introduction Porphyrias are predominately genetically-inherited diseases in which there is abnormal synthesis of the porphyrin molecule due to a defect in one of the enzymes in the biosynthetic pathway. The most biologically significant porphyrin-containing molecule is haem, which is produced when porphyrin binds to iron. Haem is found in haemoglobin, myoglobin and the cytochromes, including cytochrome P450. The porphyrin pathway is controlled by several enzymes and a deficiency in any one of these enzymes leads to an accumulation of the precursors to that enzymatic reaction. The excess of precursors is thought to result in the symptoms of the disease, as well as the reduction in the end product, haem.1 Different types of porphyrias arise from defects in various enzymes of the porphyrin pathway, resulting in the accumulation of different precursors and therefore varying clinical pictures. Porphyrias may be classified according to whether or not they cause acute symptoms. The acute porphyrias include acute intermittent porphyria (AIP), variegate porphyria (VP), hereditary coproporphyria (HCP) and plumboporphyria (PP). The incidence of AIP in Europe is 1 in 20 000, with variegate porphyria being more common in South Africa where the incidence is approximately 1 in 300 of the Afrikaner population.1,2 VP is characterised by cutaneous photosensitivity; patients may present with the skin manifestations associated with the non-acute porphyrias, the characteristic presenting signs and symptoms of acute intermittent porphyria, or a combination of both. The highest incidence in the world is in South Accepted January 2013 Correspondence to: Emma Hartsilver, Department of Anaesthesia, Royal Devon and Exeter Hospital, Exeter, UK. E-mail address: [email protected]
Africa and results from the introduction of a single point-mutation in 1688 by a Dutch settler.1 The porphyrias of major relevance to anaesthetic practice are these acute forms where reactions to anaesthetic drugs may be life-threatening.1 Although porphyria is rare in the UK, it is important that anaesthetists have a clear understanding of drugs that should be avoided. This is particularly relevant in obstetric anaesthesia where the emergency nature of some procedures may provide little time to plan.
Case report A 20-year-old nulliparous woman with a diagnosis of VP was referred for an obstetric anaesthetic consultant review. She was diagnosed at the age of seven years after family screening when an aunt spent a period of time on an intensive care unit with a severe exacerbation of VP after an anaesthetic. As a teenager she was seen by a genetic counsellor where the implications of the disease were discussed. Since then she had been told to wear a medical alert bracelet and received yearly information from the Cardiff Porphyria Service regarding safe drugs.3 She was otherwise fit and well and had had no acute attacks of porphyria and no previous anaesthetics. A plan and safe drug guide was made and documented in her medical notes. The pregnancy proceeded uneventfully until at 38 weeks of gestation an ultrasound scan showed a breech presentation. At 38+2 weeks she had an external cephalic version which was complicated by a reduced fetal heart rate. Vaginal examination revealed a dilated cervix at 2–3 cm, so epidural analgesia using an infusion of 0.1% bupivacaine and fentanyl 2 lg/mL was commenced and labour was induced with oxytocin. The cardiotocogram became suspicious and a decision was made to
C. Harris, E. Hartsilver perform a category-2 caesarean section, which was performed under a spinal anaesthetic. This was carried out under full aseptic conditions. The skin was anaesthetised with 1% lidocaine 2 mL. A 25-gauge Whitacre needle was inserted and 0.5% hyperbaric bupivacaine 2.2 mL with diamorphine 300 lg administered. A 3230-g female infant was delivered in good condition with Apgar scores of 9 at both 1- and 5 min. A small placental abruption was diagnosed at delivery, and in addition the umbilical cord was wrapped loosely around the baby’s neck. Postoperatively, the patient was closely monitored in the recovery room for several hours using the hospital early warning score observation chart. Hourly observations including urine output, respiratory rate, blood pressure, pulse, temperature and conscious level were recorded for 12 h. These observations were then continued 4-hourly. She was encouraged to keep adequately hydrated and to consume a good calorific intake. She had no symptoms of an acute porphyria attack and was successfully discharged home after her second night in hospital. The patient and midwives were well informed regarding the porphyria. A midwife reviewed the patient at home daily for three consecutive days then on day 12 and day 14. She remained well when reviewed by her general practitioner six weeks later.
Discussion Haem synthesis is controlled by an efficient negative feedback mechanism. A reduction in the concentration of haem stimulates the initial enzyme, d-aminolaevulinic acid (ALA) synthase, in the metabolic pathway to produce many of the initial precursors to haem. Thus any increase in haem utilisation, for example drugs that
Table 1
157 use the P450 cytochrome as part of their metabolism, will stimulate the pathway.1 Inheritance of a faulty gene leads to a 50% decrease in the activity of its affected enzyme allowing for some normal haem production. Carriers, therefore, may remain asymptomatic and only about 10–15% will express the clinical features of the disease. The increase in oestrogen and progesterone particularly in the first and second trimesters leads to an increased risk of exacerbations during pregnancy. The frequency of attacks during pregnancy in patients with acute porphyria has been reported in the range of 24–95%.1 Acute attacks of AIP in pregnancy are associated with miscarriage, hypertension, low birthweight infants and a maternal mortality of 2–42%.2 However, with greater understanding of the disease and its precipitating factors, close management of these patients during pregnancy is more frequently associated with a good outcome.2,4 Porphyria attacks may be precipitated by fasting, dehydration, stress, infection and hormonal changes. Further risk factors during pregnancy include starvation from hyperemesis gravidarum or during labour and smoking. The most important trigger factors in relation to anaesthesia, however, are the enzyme-inducing drugs. There are other mechanisms by which drugs can also interfere with this pathway, meaning many different drugs have the potential to induce an exacerbation.1 Acute exacerbations can present clinically with different symptoms which range from mild autonomic instability and electrolyte disturbances to severe attacks that may be fatal. The presenting symptoms and signs of an acute porphyric crisis are listed in Table 1.1,5 Acute attacks are diagnosed by raised concentrations of the pathway intermediates in urine, faeces and blood.
Symptoms and signs of acute exacerbations of porphyria
Abdominal pain Diffuse, usually extends into lower back and thighs, continuous, severe Vomiting Diarrhoea Autonomic instability Hypertension and tachycardia Photosensitivity Bullous skin rash in VP and HCP Agitation Electrolyte abnormalities Including hyponatraemia, hypomagnesaemia, hypokalaemia and hypochloraemia Seizures Tonic–clonic. May be associated with hyponatraemia and encephalopathy Paralysis Acute motor neuropathy, quadriparesis, cranial nerve paralysis. Lower motor neurone palsy with profound paralysis, hypotonia and absent reflexes Renal failure Particularly with chronic attacks of AIP Respiratory paralysis and coma
VP: variegate porphyria; HCP: hereditary coproporphyria; AIP: acute intermittent porphyria.
158 Crudely, this can be done by eye as porphyrin precursors, porphyrinogens, are colourless, but when exposed to light and oxygen they will convert spontaneously to porphyrins, which make urine turn to the colour of port wine. Biochemical assays of the precursors allow the type of porphyria to be established. Levels of the precursor ALA can be 5–20 times normal and levels of porphobilinogen may be 20–50 times normal.6 Management of a porphyric crisis should include rapid recognition and withdrawal of any potentially porphyric-inducing drugs, adequate hydration and calorific intake, and consideration of a dextrose infusion if oral intake is insufficient. Fluid balance and electrolytes should be carefully monitored as crises can induce electrolyte imbalance. Seizures, which are often secondary to hyponatraemia, may be safely treated with diazepam. Management of pain, nausea and tachycardia is symptomatic. Treatment of the underlying disease and muscle weakness is undertaken by the administration of haem arginate, 3 mg/kg given as an infusion over 15–20 min daily for four consecutive days.5,7 Haem arginate consists of haem complexed with the amino acid arginine to form a stable compound. By replenishing haem stores, the negative feedback inhibits the initial rate-limiting enzyme of the haem synthetic pathway, ALA synthase. The formation of porphyrins and the precursors ALA and PBG is almost immediately reduced to low levels, and the symptoms improve.2,5 The older treatment of haematin commonly caused thrombophlebitis and changes to coagulation and fibrinolysis.6 Haem arginate has fewer side effects and is safe during pregnancy. Patients with signs of respiratory insufficiency during an acute attack require immediate intubation and ventilation. Motor neuropathy is fully reversible but slow to recover and in some cases may take many months.5 Porphyria is a life-threatening disease that can be initiated by many precipitants, but one of the main concerns to physicians is iatrogenic inducement of a porphyric crisis secondary to administration of drugs. There are many situations throughout pregnancy and delivery where medication may be indicated. The Norwegian Porphyria Centre (NAPOS),8 in collaboration with the British Porphyria Association and the Welsh Medicines Information Centre (WMIC), has developed a multi-language drug database for acute porphyrias. It classifies drugs into non-porphyrinogenic (NP), probably non-porphyrinogenic (PNP), possibly porphyrinogenic (PSP), probably porphyrinogenic (PRP), porphyrinogenic (P) and not yet classified (NC). This database along with information from the WMIC has been used for the basis of the recommendations.3,8 Table 2 classifies the commonly-used anaesthetic, obstetric and resuscitation drugs into safe to use (NP and PNP) and those which should be avoided (PRP and P) for rapid reference. Other rarer drugs can be
Variegate porphyria and caesarean section checked for safety on the NAPOS drug database and the WMIC online.3,8 Many drugs required in obstetric anaesthesia are safe to use in porphyria but notable exceptions include diclofenac, cyclizine and ergometrine. If general anaesthesia is required, thiopentone is unsafe, but there have been several published cases of propofol being used without harm.3,8–10 For maintenance of anaesthesia, the agents of choice would be isoflurane or desflurane. Propofol infusion has also been used without complications.9 Neuraxial anaesthesia may be safely undertaken in porphyria patients. Careful neurological assessment should be made before anaesthesia and peripheral neuropathy from previous porphyric exacerbations documented to allow for assessment of changes should an attack occur. Previously, many local anaesthetic agents were considered to be unsafe, so procaine was preferentially used because of its short duration of action, and spinal anaesthesia was recommended because of the lower dose required. More recently, however, both bupivacaine and lidocaine have been put on the safe drug list; however, because of a lack of pharmacokinetic information, repeated high doses of lidocaine should only be used with caution and should be administered in glucose solution if used as a continuous infusion.3 Several cases have reported the use of both spinal anaesthesia and epidural analgesia using either lidocaine and/ or bupivacaine without precipitating an acute attack.9–11 Obstetric complications such as preeclampsia, postpartum haemorrhage, preterm labour and premature rupture of membranes all require the administration of medications. Commonly-used drugs such as methyldopa, hydralazine, ergometrine and some antibiotics are not recommended for use in patients with porphyria. However, no drug should be restricted if it is likely to be of major clinical benefit or required in a life-threatening situation. An acute exacerbation of porphyria can be managed and should not be fatal provided early recognition and treatment. The use of cell salvage is yet to be evaluated and reported upon in cases of porphyria. The concern is that the stress and hypothermia created by an extracorporeal circuit may increase the risk of a crisis. Cardiopulmonary bypass however, has been used without provoking an exacerbation.1 Starvation and dehydration are also known to be risk factors for the initiation of acute attacks of porphyria. Therefore, preoperative fasting should be kept to the recommended minimum and intravenous fluids should be considered if starvation is prolonged.1 Overall, with good obstetric and anaesthetic care, most patients with porphyria should have an asymptomatic uncomplicated pregnancy. We recommend that, as with this case, patients with porphyria should be seen by the obstetric anaesthetist and obstetrician early in the antenatal period. A clear management plan for preg-
Omeprazole
Co-amoxiclav, gentamicin, teicoplanin
Unfractionated heparin, Low-molecularweight heparin
Prochlorperazine
Labetalol
Bupivacaine
Suxamethonium, rocuronium
Terbutaline
Oxytocin
Adrenaline
Magnesium sulphate, tranexamic acid, adenosine, insulin
Antacids
Antibiotics
Anticoagulants
Antiemetics
Antihypertensives
Local anaesthetics
Muscle relaxants
Tocolytics
Uterotonics
Vasopressors
Others
Neostigmine, glycopyrrolate, atropine
Phenylephrine
Carboprost, misoprostol
Atosiban, betamethasone
Atracurium, vecuronium
Lidocaine*
Nifedipine
Ondansetron, granisetron, metoclopramide
Cefuroxime
Ranitidine
Fentanyl, remifentanil, alfentanil, paracetamol, codeine, tramadol, ibuprofen
Nitrous oxide, isoflurane, desflurane
Probably not porphyrinogenic
Intravenous administration of lidocaine should be avoided.
Morphine, pethidine
Analgesics
*
Propofol
Non porphyrinogenic
Recommendations for commonly-used drugs in patients with porphyria
Anaesthetics
Table 2
Ephedrine
Dexamethasone
Sevoflurane
Possibly porphyrinogenic
Cyclizine
Clarithromycin
Diclofenac
Halothane
Probably porphyrinogenic
Methylergometrine
Methyldopa, hydralazine
Erythromycin
Thiopentone
Porphyrinogenic
Sugammadex, chlorphenamine
Metaraminol
Ergometrine
Bupivacaine/fentanyl mixture
Not yet classified
C. Harris, E. Hartsilver 159
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Psychogenic paresis after dural puncture
nancy, labour and delivery should be documented in the hospital and hand-held patient notes. This should include advice to avoid excessive fasting and dehydration, and a list of safe drugs and those drugs that should be avoided. The patient and midwife should also receive clear instructions regarding the possible signs and symptoms of an acute attack of porphyria during pregnancy, labour and in the postnatal period.
References 1. James MFM, Hift RJ. Porphyrias. Br J Anaesth 2000;85:143–53. 2. Farfaras A, Zagouri F, Zografos G, Kostopoulou A, Sergentanis S, Antoniou S. Acute intermittent porphyria in pregnancy: a common misdiagnosis. Clin Exp Obstet Gynaecol 2010;37:256–60. 3. Welsh Medicines Information Centre (WMIC) Cardiff. http:// www.wmic.wales.nhs.uk [accessed January 2013]. 4. Aggarwal N, Bagga R, Sawhney H, Suri V, Vasishta K. Pregnancy with acute intermittent porphyria: a case report and review of literature. J Obstet Gynaecol Res 2002;28:160–2.
5. Porphyria South Africa online. Universities of Cape Town and KwaZulu-Natal. http://www.porphyria.uct.ac.za [accessed January 2013]. 6. Siegesmund M, van Tuyll van Serooskerken AM, PobleteGutie´rrez P, Frank J. The acute hepatic porphyrias: current status and future challenges. Best Pract Res Clin Gastroenterol 2010;24:593–605. 7. European Porphyria Initiative (EPNET). http://www.porphyriaeurope.com [accessed January 2013]. 8. NAPOS. The drug database for Acute Porphyria. http:// www.drugs-porphyria.org [accessed January 2013]. 9. Consolo D, Ouardirhi Y, Wessels C, Girard C. Obstetric anaesthesia and porphyrias. Ann Fr Anesth Reanim 2005;24:428–31. 10. Kantor G, Rolbin SH. Acute intermittent porphyria and caesarean delivery. Can J Anaesth 1992;39:282–5. 11. Dumas RP, Silva EF, Resende MA, Pantoja AV, Barros AC. Anaesthesia for caesarean section in pregnant women with acute intermittent porphyria and hypothyroidism-case report. Middle East J Anesthesiol 2011;21:405–7.
0959-289X/$ - see front matter c 2013 Elsevier Ltd. All rights reserved. doi:http://dx.doi.org/10.1016/j.ijoa.2013.01.005
Recurrent psychogenic paresis after dural puncture in a parturient J. Nguyen, R. Abola, J. Schabel Department of Anesthesiology, Stony Brook University Medical Center, Stony Brook, NY, USA ABSTRACT We describe the case of a 29-year-old parturient who, after undergoing elective cesarean delivery, displayed symptoms of lower extremity weakness and sensory deficit. Her past medical history was significant for asymptomatic Arnold Chiari Type I malformation and asthma. She had received spinal anesthesia that failed to achieve an adequate surgical level requiring conversion to general anesthesia. After tracheal extubation, she exhibited bilateral leg weakness that did not resolve over the next 4–6 h. An urgent magnetic resonance imaging scan revealed a normal spine with no evidence of hematoma. The lower extremity paresis persisted and a neurologist diagnosed psychogenic paresis, a type of conversion disorder. Interestingly, the patient’s postoperative leg paresis was not her first occurrence of neurological dysfunction after dural puncture. At 27 weeks of gestation, she had similar lower extremity symptoms after a lumbar puncture, performed to exclude meningitis for severe headache symptoms. Psychogenic paresis is not commonly reported in the medical literature and we found no reports of psychogenic paresis after spinal anesthesia in a parturient or recurrent psychogenic paresis. We review the various risk factors, etiology, neurological signs and symptoms, types, therapy and future management of a patient with recurrent conversion disorder. Published by Elsevier Ltd. Keywords: Psychogenic paresis; Conversion disorder; Parturient; Spinal anesthesia; General anesthesia
Introduction Psychogenic paresis is a type of conversion disorder that has been rarely reported in the medical literature, with Accepted January 2013 Correspondence to: Joy Schabel MD, Department of Anesthesiology, Stony Brook University Medical Center, Stony Brook, NY 117948480, USA. E-mail address: [email protected]
fewer than 20 cases cited involving anesthetic procedures. Recurrent psychogenic paresis following neuraxial procedures has not been previously described. This case report describes the presentation of recurrent psychogenic paresis in a parturient after spinal anesthesia for cesarean delivery. The various risk factors, etiology, neurological symptoms and signs, management and future anesthetic plan for patients with conversion disorder are reviewed.