Acute intermittent porphyria (AIP) is a rare metabolic disorder which can be life-threatening when a porphyric crisis leads to generalized paralysis . Certain drugs are known to trigger such a crisis and other drugs have uncertain effects . Stress may also be a trigger factor . We describe a patient with AIP undergoing cardiac surgery involving hypothermic cardiopulmonary bypass. We present details of a seemingly safe anesthetic technique and porphobilinogen (PBG) measurements made in the perioperative period.
A 64-yr-old, 70-kg male with severe mitral regurgitation was admitted for elective mitral valve replacement surgery. He was diagnosed as having AIP at the age of 44 yr after his brother became seriously ill with AIP. His porphyric symptoms were mild, with occasional muscular weakness in the legs. He had never suffered an acute crisis.
On admission, his cardiac disease and porphyria were assessed, including a full neurologic examination. The only symptom related to his mitral valve disease was shortness of breath (New York Heart Association grade III).
Six hours preoperatively a 5% glucose infusion was started at 100 mL/hr. Premedication consisted of intramuscular morphine 10 mg with hyoscine 0.3 mg and oxygen was administered via face mask at the time of premedication.
At induction of anesthesia 15 micro gram/kg of fentanyl was given intravenously and a propofol infusion was started, decreasing from 6 mg/kg to 3 mg centered dot kg-1 centered dot h-1. On loss of consciousness, the latter dose continued throughout the operation. A bolus of 50 mg of atracurium was given followed by an atracurium infusion of 0.5 mg centered dot kg-1 centered dot h-1. After tracheal intubation, the lungs were ventilated to normocarbia with oxygen in air. Anticoagulation was achieved with heparin 300 U/kg to maintain an activated clotting time of more than three times control value. Cardiopulmonary bypass (CPB) was established with cooling of the core temperature to 32 degrees C. Myocardial protection was provided by a single dose of cold crystalloid cardioplegia. Hypothermia lasted for 55 min during an aortic cross-clamp interval of 60 min. During the 90 min of CPB, mean arterial pressure was maintained at 50 mm Hg with pump flow rates of 2.4 L centered dot min (-1) centered dot m-2 at 37 degrees C and 1.8 L centered dot min-1 centered dot m-2 at 32 degrees C. Hypotension during CPB was treated with metaraminol 0.5 mg in intermittent doses. Discontinuation of CPB was uneventful and residual anticoagulation was reversed by protamine 3 mg/kg.
The preoperative hemoglobin was 13.4 g/dL. After bypass this had decreased to 8.2 g/dL and 2 U of red cell concentrate was infused. The total duration of surgery was 2 h 45 min during which total doses of 690 mg propofol and 128 mg of atracurium were administered.
On completion of surgery, a morphine infusion was started at 2 mg/h and the propofol and atracurium infusions were discontinued. The patient regained consciousness 3 h after the end of surgery and his trachea was extubated uneventfully 1 h later. His postoperative period was not complicated by any signs or symptoms of AIP. He required diuretic therapy postoperatively, although this was probably not related to his AIP.
Samples from 24-h urine collections were taken for PBG on the day prior to surgery, before, during, and after CPB, and on the first 5 days after surgery, and were measured quantitatively using chromatography Table 1. Glucose levels were monitored throughout the procedure, using a glucometer. The levels were in the range of 9.0 to 17.0 mmol/L.
AIP has its highest incidence in Northern Europe (1:10,000) . It is an autosomal dominantly inherited metabolic disorder with variable expression leading to a disorder of the heme biosynthesis pathway in the liver. A partial deficiency of uroporphyrinogen I synthetase reduces heme production. This diminishes the negative feedback on delta-aminolevulinic acid (ALA) synthetase, the rate-limiting step. This in turn leads to an increase in precursors ALA and PBG Figure 1. These precursors cause the clinical symptoms. The reduction in negative feedback is mainly amplified by certain drugs (especially those that induce cytochrome P450) and alcohol, but other factors can be involved, including liver tumors, infection, fasting, and endogenous hormones . Steroid metabolites have been associated with acute attacks of AIP . Stress can be an important trigger for acute onset of AIP [3,7]. Both surgery and hypothermia can induce stress with an increase in cortisol levels [8,9]. We therefore avoided cooling the patient during CPB to temperatures below 32 degrees C. It is possible that, due to stress, an imbalance in steroid metabolites could cause an acute attack. The effect of cold cardioplegia in porphyria is unknown. There have been several case reports involving CPB and porphyria [10-12]. All used hypothermia of 30 degrees C or lower during bypass. One patient developed biochemical evidence of an acute crisis postoperatively . This might be related to hypothermic stress.
The mechanism of neurologic derangement seen with AIP is unclear in humans, although demyelination can occur throughout the nervous system . Theoretical explanation involves: 1) neurotoxicity due to excessive porphyrin precursors; 2) impaired heme biosynthesis within neural tissue; 3) depletion of cofactors from the heme biosynthesis defect; and 4) abnormal products from porphyrin precursors . In animal preparations, high concentrations of ALA and PBG inhibit synaptic transmission, inhibit sodium-and potassium-dependent adenosine triphosphatase, and interfere with gamma-aminobutyric acid metabolism . ALA has a structural similarity to gamma-aminobutyric acid and glutamic acid , which can lead to disturbance in neurophysiologic mechanisms . This seems to support the first theory. Furthermore, ALA can form free radicals, leading to oxidation of membranes and damage to deoxyribonuclease .
Clinical onset is usually during or after puberty and is more marked in women. Symptoms include abdominal pain (which is colicky in character), nausea, vomiting, and constipation. These symptoms are probably due to autonomic involvement. Inappropriate antidiuretic hormone secretion and mental disturbances leading to delirium, coma, or seizure are due to central nervous system involvement. Peripheral nervous involvement leads to predominantly motor neuropathy. Labile hypertension, tachycardia, and sweating are the only clues to the onset of a porphyric crisis during anesthesia and are caused by autonomic involvement.
Indicators of an AIP crisis are an increase in ALA and PBG and, on long standing of urine, a brown-red coloration (due to porphyrinogens reacting with light being oxidized to porphyrins) . A slightly increased PBG level was present preoperatively, which decreased during surgery and slowly increased back to baseline level postoperatively. These data demonstrate that, with the use of this management regimen in this patient, there was no evidence of significant increase of urinary concentration of heme metabolites or risk of a clinical porphyric crisis.
Treatment of a crisis is difficult, and there is no specific prophylaxis. A large carbohydrate load (2000 kcal/24 h) is beneficial , as glucose suppresses the synthesis of ALA synthetase and is beneficial in acute attacks. A preoperative infusion of glucose was commenced to avoid fasting. The use of heme therapy in the form of hematin or heme-arginate to suppress ALA synthetase in the liver mitochondria has been recommended [17,18]. There is evidence of a reduction of urinary excretion of ALA, PBG, and uroporphyrinogen during an acute crisis of AIP , but there is little improvement in clinical signs and symptoms, despite lower ALA and PBG levels during treatment . This might be due to the rapid return to high levels as soon as treatment is stopped. The addition of tinprotoporphyrin might clinically improve patients, by inhibiting heme oxygenase, thereby reducing the breakdown of heme resulting in a negative feedback on ALA synthetase activity . In our patient we aimed to avoid low hemoglobins in view of the possible trigger from low heme concentrations on ALA synthetase. Cimetidine has been used in animal models causing a 50% reduction in ALA synthetase activity, but further human studies are needed for evaluation in patients .
Acute attacks in porphyric patients are mainly pharmacologically induced . It is therefore important for anasthetists to know which drugs to avoid Table 2. In the previous case reports involving CPB [10-12], either fentanyl with or without diazepam, pancuronium, and nitrous oxide in oxygen, or sufentanil, atracurium, and isoflurane in oxygen were used. We decided to use fentanyl, atracurium, and propofol in doses which permit early tracheal extubation. We avoided using inhaled anesthetics for induction or maintenance, in view the safety record of these drugs Table 2 and the possible stunning effect on the heart after bypass. Fentanyl has been safely used on many occasions in AIP . Atracurium has been used previously without adverse effect . Our data show no increase in PBG's, and this might help in choosing a muscle relaxant which is safe to use when others may be relatively contraindicated. Propofol is said to be safe as a drug for induction of anesthesia , and several reports have confirmed the safe use of propofol infusions for maintenance of anesthesia [24-26], although a recent case report showed an increase in ALA and PBG . Our experience supports the view that propofol is a safe drug.
In summary, we describe the anesthetic management of a patient undergoing mitral valve replacement and discuss the underlying molecular defects, theoretical explanations of symptoms, and detection and treatment of AIP.
We thank Mr. S. A. M. Nashef for his surgical expertise.
1. Bonkovsky HL, Bloomer JR. The porphyrias. Dis Mon 1989;35:5-54.
2. Harrison GG, Meissner PN, Hift JR. Anaesthesia for the porphyric patient. Anaesthesia 1993;48:417-21.
3. Eales L. Porphyria and the dangerous life-threatening drugs. S Afr Med J 1979;56:914-17.
4. Lip GYH, McColl KEL, Moore MR. The acute porphyrias. Br J Clin Pract 1993;47:39-43.
5. Moore MR, McColl KEL, Fitzsimmons EJ, Goldberg A. The porphyrias. Blood Rev 1990;4:88-96.
6. Gillette PN, Bradlow HL, Gallagher TF, Kappas A. A new biochemical lesion in acute intermittent porphyria: deficiency of steroid-5 alpha reductase activity [abstract]. J Clin Invest 1970;49:34-5A.
7. McColl KEL, Moore MR, Goldberg A. Porphyrin metabolism in the porphyrias. In: DJ Weatherall, ed. Blood and its disorders, Oxford, UK: Blackwell Scientific Publications, 1980:838-65.
8. Cope CL. Adrenal steroids and disease. Philadelphia: JB Lippincott, 1972:197.
9. Cardens H. Effects of stress upon plasma estradiol and progesterone levels and the rate of oviductal embryo transport in the rat. Biol Res 1992;25:15-20.
10. Campos GH, Stein DK, Michel NK, Moyers JR. Anaesthesia for aortic valve replacement in a patient with acute intermittent porphyria. J Cardiothorac Vasc Anesth 1991;5:258-61.
11. Roby HP, Harrison GA. Anaesthesia for coronary artery bypass in a patient with Porphyria variegata. Anaesth Intensive Care 1982;10:276-8.
12. Shipton EA, Roelofse JA. Anaesthesia in a patient with variegated porphyria undergoing coronary bypass surgery. S Afr Med J 1984;65:53-4.
13. Gibson JB, Goldberg A. The neuropathology of acute porphyria. J Pathol 1956;71:495-509.
14. Moore MR. The pathogenesis of acute porphyria. Mol Aspects Med 1990;11:49-57.
15. Vickers MD, Jones RM. Genetics and inherited disease. In: Vickers MD, Jones RM, eds. Medicine for anaesthetists. Oxford, UK: Blackwell Scientific Publications, 1989:327-49.
16. Straka JG, Rank JM, Bloomer JR. Porphyria and porphyrin metabolism. Annu Rev Med 1990;41:457-69.
17. Lamon JM, Frykholm BC, Hess RA, Tschudy DP. Hematin therapy for acute porphyria. Medicine 1979;58:252-69.
18. Tokala O. Haem arginate--new compound for acute porphyrias. Helsinki: WHO, 1988.
19. McColl KEL, Moore MR, Thompson GG, et al. Treatment with haematin in acute hepatic porphyria. QJ Med 1981;198:161-74.
20. Herrick AL, Moore MR, McColl KEL, et al. Controlled trial of haem arginate in acute hepatic porphyria. Lancet 1989;1:1295-7.
21. Dover SB, Moore MR, Fitzsimmons EJ, et al. Tin protoporphyrin prolongs the biochemical remission produced by heme arginate in acute hepatic porphyria. Gastroenterology 1993;105:500-6.
22. Marcus DL, Nadel H, Lew G, Freedman ML. Cimetidine suppresses chemically induced experimental hepatic porphyria. Am J Med Sci 1990;300:214-7.
23. Wetterberg L, Doss M, Nawrocki P. Supplement to the proceedings of the first international meeting on porphyrins in human disease. Freiburg, Germany: 1976:191-202.
24. Riggs JD, Petts V. Anaesthesia in the porphyric patient. Anaesthesia 1993;48:1009-10.
25. Cooper R. Anaesthesia for porphyria using propofol [letter]. Anaesthesia 1988;43:611.
26. Mitterschiffthaller G, Theiner A, Hetzel H, Fuith LC. Safe use of propofol in a patient with acute intermittent porphyria. Br J Anaesth 1988;60:109-11.
27. Elcock D, Norris A. Elevated porphyrins following propofol anaesthesia in acute intermittent porphyria. Anaesthesia 1994;49:957-8.