Porphyrias are a group of diseases with overproduction of haem precursors as a result of insufficiency of one or more enzymes that regulate haem synthesis due to acquired or hereditary deficiency [1-3]. Anaesthesiologists must be especially careful about the rarely seen acute porphyrias, which include acute intermittent porphyria, variagate porphyria, hereditary coproporphyria and plumboporphyria, because some anaesthetic drugs can cause life-threatening encephalopathy and muscle paralysis, which may be irreversible and difficult to treat . Some studies show that opioids can be used safely in porphyria [1-3]. This correspondence is the first in which remifentanil has been safely given to a patient with acute intermittent porphyria.
A 39-yr-old female (gravida 9, parity 8) was admitted for emergency Caesarean section because of acute fetal distress. The fetus, of 36 weeks' gestation, was identified with obstetric ultrasonography. There was a variable deceleration of the fetal heart rate from a baseline of 140-160 to 60-70 beats min−1 with a non-stress test. The patient had previously been investigated, and porphobilinogen and coproporphyrin were present in her urine and acute intermittent porphyria had been diagnosed.
During the induction of anaesthesia, the patient had no problems relating to her porphyria. Anaesthesia was induced with propofol 200 mg intravenously (i.v.) and vecuronium 8 mg was given i.v. to facilitate tracheal intubation. Anaesthesia was maintained with isoflurane 0.7-1.0%. After delivery, remifentanil 1.5 mg kg−1 was given i.v. followed by an infusion of 0.5 μg kg−1 min−1. At the end of surgery, all anaesthetics were discontinued and the patient was extubated after antagonism of residual neuromuscular blockade. The procedure was uneventful, and she was delivered of a live female, weight 2850 g, with Apgar scores of 6 and 9, at 1 and 5 min, respectively. The postpartum course was uneventful. On the first postpartum day, samples from 24 h urine collections were assayed for porphobilinogen revealing concentrations of 6 mg dL−1 (n = 3). Abdominal pain, nausea, anxiety, confusion, hypertension, tachycardia and electrolyte imbalance were not seen during the patient's 3 day hospital stay.
The porphyrias are a group of heterogeneous diseases that are a result of inherited or acquired enzymatic defects of haem biosynthesis. Porphyrins are the basic substances in the productive pathway. Haem, the ferrous iron complex of protoporphyrin IX, is the form in which haemoproteins bind to various proteins. Haem is the prosthetic group of haemoglobin and myoglobin and all cytocromes which play roles in oxidation and hydroxylation [1-3]. Porphyrias occur due to the deficiency of one specific enzyme in the haem biosynthetic pathway and are characterized by the accumulation of porphyrin intermediate substances. Precursor substances, succinyl CoA and glycine produce the δ-aminoleuvilinic acid (ALA) with a reaction catalysed by ALA synthetase. The rate of reaction is controlled by the end-product haem. Porphobilinogen is produced with two ALA molecules. This product is the protoporphyrin used in haem synthesis. Other porphyrins have no physiological functions, they are reactive oxidants and excreted in the urine [1-3]. The haem concentration within the mitochondria is low in all the porphyrias and therefore increased ALA synthetase activity leads to porphyrins accumulating in the tissues .
Although there is no gender predilection in genetic inheritance, acute attacks are seen more often in females. Attacks in very few cases are reported before puberty or after the menopause . Conditions with decreased haem concentrations cause acute attacks because of increases in ALA synthetase activity. These conditions include physiological hormone irregularities, starvation, dehydration, stress and infections. Acute attacks are characterized with abdominal pain, autonomic instability, electrolyte imbalance and neuropsychiatric manifestations. Neuromuscular weakness can lead to quadriparesia and respiratory failure, and also death. The abdominal pain results from the intestinal dysfunction of autonomic neuropathy. Dehydration and electrolyte abnormalities can be severe and must be corrected [1-4]. Tachycardia and hypertension are seen especially in patients with acute intermittent porphyria .
Pregnancy in patients with acute intermittent porphyria has been associated with a 24-95% incidence of acute attacks of porphyria, resulting in a considerable maternal mortality rate (42%) and high rates of spontaneous abortion (12%), hypertension (16%) and low birth-weight infants . Patients are asymptomatic between crises. Silent, or latent, porphyric patients may experience their first acute attack of porphyria after exposure to drugs; the mechanisms involved mostly depend on an increased demand for haem production or a failure of the haem inhibitory feedback as the final pathway. Thus drugs may induce the transcription of ALA synthetase directly through mRNA or may interfere with the negative feedback control which haem exerts on ALA synthetase production. Drugs may interfere with the haem synthetic pathway, thus reducing the amount of haem production, or they may increase the demand for haem by increasing utilization. It is difficult to predict which drugs can cause acute attacks because of various effect pathways and variations in the structures of drugs. It is interesting that only in acute porphyria can an acute attack be induced with drugs .
Since acute attacks in porphyria patients are induced commonly with drugs, the anaesthesiologist needs to know which drugs may precipitate reactions. It has been established which agents are safe from case reports. The criterion is whether or not an acute reaction has developed clinically or whether there are porphyrins or metabolites in the urine or faeces [1-3]. Attacks can be induced by factors such as starvation, infection, fever and preoperative stress. Benzodiazepines can be used to prevent preoperative stress [1,2]. Either regional or general anaesthesia may be given to a patient with acute intermittent porphyria. The patient should be seen before the operation and the risks of porphyria and anaesthesia explained. Thiopental or other barbiturates must never be used for the induction of anaesthesia, even though such well-known triggers do not always precipitate reactions [1,2,4]. Although Kasraie and Cousins  claimed that propofol increased the concentration of porphobilinogen and ALA, and in most studies its safety has been confirmed [1,2,5]. All the opioids except pentazocine can be used during the maintenance of anaesthesia. Most studies show that volatile anaesthetics, e.g. N2O, halothane, enflurane and isoflurane, can be used safely, but there are no clinical data regarding sevoflurane or desflurane [1,2]. Regional anaesthesia is not contraindicated as long as the possibility of autonomic dysfunction is considered [1,2,5]. Ester- or amide-type local anaesthetics have been used by the spinal and epidural routes without any problems [1,2].
Remifentanil is a new opioid that is now in regular clinical use in many countries. Its metabolism by non-specific esterases in blood and tissues gives it a pharmacokinetic profile unlike that of any other opioid. The resulting hydrolysis of remifentanil renders the compound inactive. The clinical advantage of the drug lies in its extremely rapid clearance, and therefore offset of effect, which is independent of excretory organ function . This pharmacokinetic profile of remifentanil can be advantageous in porphyric patients because it does not interfere with haem metabolism.
We chose propofol to induce anaesthesia and isoflurane to maintain anaesthesia in this patient because they were judged to be safe. We preferred the short-acting analgesic remifentanil for its pharmacokinetics. We believe, on the basis of this single case, that remifentanil, with the other agents we describe, may be suitable for use in patients with acute intermittent porphyria, although the clinical data do not allow any definite conclusion.
H. I. Toprak
M. O. Ersoy
Department of Anaesthesiology and Reanimation; Inonu University; Medical Faculty; Turgut Ozal Medical Centre; Malatya, Turkey
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