1999 Stockton Press All rights reserved 0268â3369/99 $15.00 http://www.stockton-press.co.uk/bmt. Case report. Acquired pseudocholinesterase deficiency after ...
Bone Marrow Transplantation, (1999) 24, 1367–1368 1999 Stockton Press All rights reserved 0268–3369/99 $15.00 http://www.stockton-press.co.uk/bmt
Case report Acquired pseudocholinesterase deficiency after high-dose cyclophosphamide V Koseoglu1, J Chiang2 and KW Chan1 Divisions of 1Pediatrics, 2Anesthesiology and Critical Care, University of Texas MD Anderson Cancer, Houston, TX, USA
Summary: Succinylcholine, a depolarizing neuromuscular blocking agent used in anesthesia is hydrolyzed in the plasma by the enzyme pseudocholinesterase (PSC). Conditions associated with reduced PSC activity lead to sustained action of succinylcholine and result in prolonged apnea. Cyclophosphamide is an inhibitor of PSC and its suppressive effect may be dose-dependent. We report a case of severe PSC deficiency after high-dose cyclophosphamide at 7 g/m2. The patient received succinylcholine during anesthesia 9 h after chemotherapy and developed prolonged apnea. This case highlights the potential risk of drug-induced PSC deficiency and cautions the use of depolarizing muscular relaxants soon after high-dose cyclophosphamide. Keywords: cyclophosphamide; prolonged apnea; pseudocholinesterase; succinylcholine
Succinylcholine is a depolarizing muscle relaxant commonly used during general anesthesia. After intravenous injection it is hydrolyzed and inactivated within a few minutes by the enzyme pseudocholinesterase (PSC). Reduced PSC activity allows the accumulation of succinylcholine in the synapses and neuromuscular junction, interfering with the regular sequences of nerve impulse conduction.1,2 As a result, prolonged apnea and cardiac arrythmia after general anesthesia have been reported.1–6 Conditions associated with reduced PSC activity include hereditary enzyme deficiency3,4 and acquired disease states such as disseminated cancer, chronic debilitating illnesses and malnutrition.2,5,7 Kaniaris et al7 showed that cancer patients with PSC activity of less than 40% of normal had delayed recovery after succinylcholine administration. A number of therapeutic agents (eg organophosphates, quinones, psychotropic drugs and alkylating agents) also interact with succinylcholine and potentiate neuromuscular blockade.1–3,7 Cyclophosphamide (CY) is an active chemotherapeutic agent for childhood leukemia and solid tumors. It is also used in many preparative regimens for hematopoietic stem Correspondence: Dr KW Chan, Division of Pediatrics, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Box 87, Houston, TX, USA Received 23 April 1999; accepted 5 August 1999
cell transplantation. Its major toxicities include myelosuppression and hemorrhagic cystitis. CY is a potent PSC inhibitor, reducing serum PSC concentration both in vitro and in vivo.5,8–10 However, clinically significant complications after depolarizing muscle relaxants are rarely reported in patients receiving CY.3,8 A search of the literature in English failed to reveal any report of a potential association in the past 10 years. Our institution does not have a policy regarding succinylcholine use in patients receiving alkylating agents. We report a patient with neuroblastoma who developed prolonged apnea after general anesthesia that included succinylcholine. The patient had received high-dose CY 1 day earlier and was found to have profound but transient PSC deficiency.
Case report A 2.-year-old girl was diagnosed with a left adrenal neuroblastoma with metastases to the pelvic bone and bone marrow. Exploratory laporatomy and left adrenalectomy were performed. She recovered uneventfully after general anesthesia that included rocuronium. She was started on chemotherapy consisting of cisplatin, etoposide, doxorubicin and CY every 3 weeks. The dose of CY was 1.2 g/m2 each course. Twenty days after the third course of chemotherapy, she had placement of a Quinton catheter (Sherwood Medical, St Louis, MO, USA) under general anesthesia without complications. The patient achieved a very good partial remission and was a candidate for autologous peripheral blood stem cell transplantation. The first phase of high-dose chemotherapy consisted of CY alone at a dose of 7 g/m2. The treatment was divided into four 1 h infusions given over an 8 h period (total dose: 3780 mg).10 Her liver enzymes and serum albumin level were within normal limits. Nine hours from the last infusion of CY, a double lumen central venous catheter was replaced under general anesthesia. She was given succinylcholine (1.8 mg/kg), fentanyl (2 mg/kg) and sodium thiopental (3.5 mg/kg). After the end of the procedure she did not regain spontaneous respiration and remained flaccid. Nerve stimulator studies confirmed neuromuscular blockade. Her PSC level was found to be severely depressed at 0.4 IU/l (normal: 1400–5600 IU/l). She required ventilatory support for 90 min before regaining normal breathing. Three weeks later, a repeat serum PSC level was 4533 IU/l.
Post-anesthetic apnea after high-dose CY V Koseoglu et al
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Discussion We observed prolonged apnea due to acquired cholinesterase deficiency in a child recently treated with high-dose CY. Such a phenomenon is rare but has been reported. Immediately after an intravenous injection of 250–2500 mg of CY to a 70 kg person, plasma PSC activity was reduced by 35–70%.6 In some patients this suppression has lasted for several days. A similar inhibitory effect was also reported after prolonged oral treatment with low doses of cyclophosphamide.8,11,12 The rapidity of enzyme inhibition in vitro suggests a direct effect rather than an interference with synthesis.9 The exact nature of PSC inhibition has not been clearly defined. Cyclophosphamide exerts its action by irreversible alkylation and this activity lasts an average of 7.7 h.13 As the biologic half-life of PSC is 8–14 days, it may take 2 or more weeks before enzyme activity returns to normal. In a murine model a significant drop in PSC serum concentration was seen 2–3 weeks after a single dose of CY which persisted for another week.14 Apnea has been reported even if CY was withdrawn 2 weeks before anesthesia.8 However, respiratory depression due to PSC deficiency rarely exceeds 240 min.2,4 Al-Jafari et al9 suggested that the CY effect on PSC is reversible, after demonstrating inhibition did not vary according to the length of preincubation in vitro. Walker et al8 showed that CY inhibits PSC in a concentration-dependent manner. At a concentration of 0.6 mg per ml of plasma CY had no effect on PSC activity in vitro, while a serum concentration of 6.0 mg per ml was inhibitory. Such a concentration of CY is normally not achieved with standard dosage but is seen with doses used for stem cell transplantation. The clinical relevance of PSC deficiency is also controversial.3,11 Individuals with complete absence of enzyme function due to mutant variants lead a normal life but will develop apnea lasting 70–120 min after receiving a depolarizing agent.2,5 A reduction in plasma PSC activity of more than 70% may result in marked decrease in vivo hydrolysis of succinylcholine.6 However the rare occurrence of prolonged apnea after succinycholine suggested that simple quantitative reduction of PSC might not be the most significant reason for the respiratory complication.3,11 Other coexisting factors such as abnormal enzyme genotype might account for the prolonged neuromuscular blockade in some of the cases reported previously.2,4 Prolonged apnea after anesthesia is extremely rare in patients receiving CY despite its extensive use. In the case described, the complication developed 9 h after the completion of high-dose CY. The temporal association between chemotherapy and prolonged apnea is highly suggestive that the two events are causally related. Similarly we had observed a low PSC level in a patient with severe aplastic anemia after he received four daily doses of CY at 50 mg/kg/day before transplantation (PSC level: pretreatment 5262 IU/l, 24 h after the last CY dose 1220 IU/l). Treatment of PSC deficiency includes ventilation support, and transfusion with human acetylcholinesterase concentrate, if necessary. Our patient recovered fully with assisted ventilation alone, without the administration of acetylcholinesterases. We conclude that doses of CY used for stem cell trans-
plantation are high enough to cause severe PSC suppression. Prolonged apnea can occur in these patients if they are given succinylcholine, independent of tumor dissemination, hepatic dysfunction and low albumin level. As short repeated anesthetics using succinylcholine become more popular, we suggest caution in anesthetizing transplant patients soon after they have received CY. Postponement of surgery should be considered. If not possible, PSC levels should be checked before general anesthesia and succinycholine or any depolarizing agent should be given with great care. A short acting nondepolarizing muscle relaxant such as atracurium or rocuronium may be preferable in these situations. Proper monitoring of patients with a peripheral nerve stimulator to differentiate the effects of PSC deficiency and other causes of flaccidity are essential to ensure maximal safety.2,11,15
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