This article is accompanied by the following Invited Commentary:
Fuchs-Buder T. Residual neuromuscular blockade and postoperative pulmonary outcome. The missing piece of the puzzle. Eur J Anaesthesiol 2014; 31:401–403.
Acute porphyria in a patient can be challenging for the anaesthesiologist. Most, but not all, anaesthetic drugs are well tolerated. The safety of some medications is unknown. We present a case of a 70-year-old woman with variegate porphyria, one of the acute porphyrias, who underwent abdominal vascular surgery and received sugammadex for reversal of residual neuromuscular blockade. There were no adverse effects. This is the first report of the successful use of sugammadex in a patient with acute porphyria.
The term porphyria refers to a group of inborn errors of metabolism resulting in enzyme defects in the biosynthetic pathway of haem. This results in the accumulation of haem precursors. Depending on the involved enzyme, a specific form of porphyria is produced. The acute form of porphyria is potentially life-threatening. Acute porphyria usually presents with severe and poorly localised abdominal pain. Other features include urinary symptoms, peripheral neuropathy and proximal motor weakness that can affect the respiratory muscles. There may also be increased circulating catecholamine levels resulting in tachycardia, hypertension, sweating, restlessness and tremor. Neuropsychiatric symptoms such as anxiety, agitation or hallucination may also be present. Hyponatremia may occur due to hypothalamic involvement leading to SIADH.1,2
Drugs can elicit an attack of acute porphyria. Most medication used by the anaesthesiologist is considered well tolerated. However, the safety of newer drugs in acute porphyria is unknown. We present a case of administration of sugammadex to a patient with variegate porphyria. It appears that this is the first report of the successful use of sugammadex in a patient with acute porphyria.
The publication of the following data was approved by our local review board and the patient gave her written consent.
We present a case of a 70-year-old female patient with variegate porphyria who was scheduled for abdominal aortic surgery. The indication for surgery was an occluded right common iliac artery with multiple stenoses in the left iliac artery and an occluded left femoral artery with subsequent intermittent claudication and pain at rest (Fontaine stage III).
She was diagnosed with porphyria in 1997 following investigation of a cousin who had fallen ill as a result of variegate porphyria. Diagnosis was confirmed by DNA analysis, which revealed R59W mutation on the PPOX gene. Other past medical history included hypertension, COPD (GOLD stage 2) with frequent exacerbations due to tobacco use, renal impairment and osteoporosis. Her medication consisted of aspirin, esomeprazol, labetalol, lisinopril, tiatropium and a combination of salmeterol and fluticasone. The patient had undergone anaesthesia for appendicectomy, breast cancer and aortic valve replacement without any complications. These procedures had taken place after the patient was diagnosed with porphyria.
The fasting regimen in our hospital is 6 h for solid food and 2 h for clear fluids. Patients scheduled for abdominal surgery receive carbohydrate-enriched drinks. The patient was premedicated with 10 mg oxazepam.
Prior to surgery, an epidural catheter was placed between the seventh and eighth thoracic vertebrae, without complications. According to the Dutch Guidelines on Neuraxial Anaesthesia and Anticoagulants, aspirin was not discontinued, and the intraoperative use of heparin is allowed if administered more than 60 min after the epidural puncture.3
The prophylactic antibiotic regimen in our hospital for abdominal surgery consists of 1 g cefazolin and 500 mg metronidazole, which was administered preoperatively. General anaesthesia was induced with 120 mg propofol, 15 μg sufentanil and 50 mg rocuronium. Anaesthesia was maintained with sevoflurane (end-tidal 1.5%) while incremental doses of sufentanil (in total 30 μg) and rocuronium were given intravenously. Epidural anaesthesia was provided by a continuous infusion with a mixture of bupivacaine 0.125% and 1 μg ml−1 sufentanil at 6 ml h−1. Arterial and central venous catheters were inserted for haemodynamic monitoring and administration of vasoactive agents.
The intraoperative course was uneventful; an infusion of noradrenaline (0.13 μg kg−1 min−1) was started for hypotension. Surgery lasted for almost 3 h. At the end of the procedure, the surgeon required deeper muscle relaxation for abdominal closure and 10 mg rocuronium was administered, resulting in a cumulative perioperative total of 80 mg.
When emerging from anaesthesia her vital signs were stable and she was weaned from the noradrenaline infusion. Her temperature was 35.9°C. The patient had residual muscle relaxation with a train-of-four (TOF) ratio of 47%. Sugammadex 200 mg was administered intravenously, which in this patient was equivalent to approximately 4 mg kg−1. This improved the TOF ratio to 90% within 2 min. The patient's trachea was extubated shortly afterwards. Adequate postoperative analgesia was achieved with epidural anaesthesia and oral acetaminophen.
In the postoperative course no signs of acute porphyria were noted and the patient appeared comfortable with stable vital parameters. No cutaneous lesions were seen. Blood results showed a mildly low sodium measurement of 134 mmol l−1, without signs of SIADH.
Four days after her initial operation, the patient developed a wound dehiscence of the rectus abdominal muscle, which was closed under general anaesthesia after rapid sequence induction with propofol and rocuronium and balanced maintenance anaesthesia with sufentanil and sevoflurane without complications. A week later she was discharged from the hospital.
Porphyria is a group of disorders involving the haem biosynthesis, characterised by excessive excretion of porphyrins or their precursors. Porphyria is classified as either hepatic or erythropoietic (depending on the site of accumulation of porphyrins) or as acute (neuropsychiatric), cutaneous, or both based on the symptoms.2,4,5 Only acute forms of porphyria are relevant to the management of anaesthesia. The three main types of acute porphyria are acute intermittent porphyria, variegate porphyria and hereditary coproporphyria. An attack of acute porphyria often presents with severe abdominal pain. Autonomic nervous system instability, electrolyte disturbances, dehydration, skeletal muscle weakness, tachycardia and hypertension can also occur.
Acute porphyria in a patient can be challenging for the anaesthesiologist.6 Preoperative fasting can cause an acute porphyria attack. The patient in this case was specifically instructed to strictly adhere to the fasting regimen to prevent an acute porphyria attack.
There are several drugs that can cause an attack of acute porphyria. The metabolism of many drugs may be altered in patients with porphyria. This can not only lead to an accumulation of nonmetabolised drugs but can also result in an accumulation or secretion of haem components. It is impossible to predict which drugs are unsafe in porphyria, as many drugs can provoke an acute attack. Several online databases that provide detailed information on the safety of medication in acute porphyria are available: American Porphyria Foundation Drug Safety Database (www.porphyriafoundation.com); Cape Town Drug List (web.uct.ac.za/depts/porphyria); European Drug List (www.porphyria-europe.org); the Nordic drug database (www.drugs-porphyria.org); and the French database (www.porphyrie.net/medicaments).
Barbiturates and etomidate are well known to be contraindicated in acute porphyria. However, most of the remaining drugs used in modern anaesthesia are considered to be well tolerated. For some drugs, the risks are either unknown or there are conflicting data available. The medication that the patient received for her chronic conditions is considered well tolerated in one or more databases concerning acute porphyria.
This patient received metronidazole as part of antibiotic prophylaxis. The information given by the above-mentioned databases varies from ‘unsafe’ to ‘probably nonporphyrinogenic’. It is probably safest to avoid any medication that has such conflicting advice unless there is no reasonable alternative.
The evidence for these lists is drawn from three main sources: clinical reports; experimental systems; and drug metabolism data. The response to unsafe drugs is variable. There are case reports of porphyria patients who suffered no adverse effects after encountering a drug on the unsafe drugs list. Sugammadex is not present on any of the databases because there are no available data as yet. That means that the use of sugammadex in patients with porphyria is not yet recommended, or can only be used with caution when it is judged essential for treatment. The question is whether sugammadex is a drug with expected risks in acute porphyria. Sugammadex is a gamma-cyclodextrin in which the aminosteroid neuromuscular blocking drugs (rocuronium, vecuronium, pancuronium) are encapsulated, forming a tightly bound, inactive complex.7,8 Sugammadex has a small volume of distribution (11 to 14 l)9 and it is not hepatically metabolised. Up to 80% of the administered drug is eliminated unchanged in the urine within 24 h.8,10 The cyclodextrin structure does not dissociate and it does not interact with aminolevulinic acid (ALA)-synthetase. The chance of interference with the haem components is, therefore, small. Nevertheless, it is difficult to predict whether sugammadex induces ALA-synthetase, which can lead to porphyria. For that reason, clinical reports are needed to prove the safety of sugammadex in patients with porphyria. This case report can contribute to the evidence.
Sugammadex has several advantages over the traditional neuromuscular blockade reversal agents such as neostigmine. It provides fast reversal with no postoperative residual neuromuscular blockade when the appropriate dose is administered.8,9,11 It is associated with much greater cardiovascular and autonomic stability than the neostigmine-atropine combination.9,12
In this case, as the surgery had been uncomplicated, the patient was cardiovascularly stable and normothermic. Immediate postoperative extubation was attempted in light of her preoperative respiratory status. Residual muscle relaxation, however, needed to be reversed. Neostigmine has the potential to cause bronchoconstriction that was to be avoided in this patient with frequent COPD exacerbations. In our hospital, atropine is the anticholinergic agent used concomitantly with neostigmine with the deleterious potential of causing tachycardia. Consideration was given to the advantages and disadvantages of administering neostigmine-atropine versus sugammadex. In the end, the decision was made to reverse muscle relaxation with sugammadex 200 mg (approximately 4 mg kg−1). According to dosage schemes for sugammadex, 2 mg kg−1 should probably have been sufficient for normalisation of the TOF ratio.
In conclusion, we present a patient with variegate porphyria, a form of acute porphyria, who was scheduled for abdominal aortic surgery. The residual neuromuscular block was reversed with sugammadex. The postoperative course was uneventful; specifically, there were no signs of an acute porphyria attack. To the best of our knowledge, this is the first publication of the use of sugammadex in a patient with acute porphyria.
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