Prolonged neuromuscular block after mivacurium: case report

Abstracts

JUSTIFICATIVA E OBJETIVOS: Com a introdução de novos fármacos com ação de curta duração, houve aumento do número de procedimentos realizados em caráter ambulatorial. O mivacúrio com duração de ação entre 15 e 30 minutos e metabolismo enzimático tornou-se opção de bloqueador neuromuscular para estes procedimentos. O relato de caso tem como objetivo chamar a atenção para a ocorrência de bloqueio neuromuscular prolongado após administração do mivacúrio e as condutas que foram adotadas. RELATO DO CASO: Descreve-se um caso de paciente programado para procedimento de curta duração em regime ambulatorial e que apresentou bloqueio neuromuscular prolongado após administração do mivacúrio. O diagnóstico foi posteriormente confirmado pela demonstração de níveis reduzidos de atividade da colinestesterase plasmática. CONCLUSÕES: A investigação laboratorial pré-operatória, mesmo incluindo a dosagem da atividade da colinesterase, não previne a possibilidade do bloqueio neuromuscular prolongado devido à possibilidade de alteração qualitativa da atividade da enzima, não existindo recomendação para investigação sistemática. Ocorrendo esta complicação, deve-se sedar o paciente e manter ventilação mecânica até a completa recuperação da força muscular e realizar exames laboratoriais para o diagnóstico definitivo. É de responsabilidade do anestesiologista a coleta de amostra sangüínea para realização de testes quantitativos e qualitativos da colinesterase plasmática. Paciente e familiares devem ser orientados quanto à importância da investigação para classificação da variante atípica da colinesterase plasmática e suas implicações anestésicas.

BLOQUEADORES NEUROMUSCULARES; BLOQUEADORES NEUROMUSCULARES; COMPLICAÇÕES

CLINICAL REPORT

Prolonged neuromuscular block after mivacurium. Case report^*

Bloqueo neuromuscular prolongado después de administración de mivacúrio. Relato de caso

Karina Bernardi Pimenta, TSA, M.D.

Co-responsável do CET do Instituto Nacional do Câncer, Especialista em Terapia Intensiva pela AMIB; Anestesiologista do Serviço de Pneumologia CLEAR da Clínica São Vicente

^{Correspondence to}

SUMMARY

BACKGROUND AND OBJECTIVES: With the introduction of new drugs with short action, there has been increase in the number of outpatient procedures. Mivacurium, with duration of action of 15-30 minutes and enzymatic metabolism has become the neuromuscular blocker of choice for these procedures. This case report aim at calling the attention to prolonged neuromuscular block after mivacurium and its management approaches.

CASE REPORT: Patient scheduled for outpatient procedure presenting prolonged neuromuscular block after mivacurium. Diagnosis was confirmed by low plasma cholinesterase activity.

CONCLUSIONS: Preoperative laboratory screening, even including plasma cholinesterase activity testing, will not prevent the possibility of prolonged neuromuscular block due to possible qualitative enzymatic activity abnormality, and there is no recommendation for its systematic investigation. In the presence of this complication, patient should be sedated and maintained under mechanical ventilation until total muscle strength recovery. Laboratory tests should be requested for final diagnosis. It is the anesthesiologist's duty to collect blood samples for quantitative and qualitative plasma cholinesterase tests. Patient and relatives should be counseled about the importance of the investigation to classify the atypical variant of plasma cholinesterase and its anesthetic complications.

Key Words: COMPLICATIONS: prolonged neuromuscular block; NEUROMUSCULAR BLOCKERS, Nondepolarizing: mivacurium

RESUMEN

JUSTIFICATIVA Y OBJETIVOS: Con la introducción de nuevos fármacos con acción de corta duración, hubo aumento del número de procedimientos realizados en carácter ambulatorial. El mivacúrio con duración de acción entre 15 y 30 minutos y metabolismo enzimático se volvió opción de bloqueador neuromuscular para estos procedimientos. El relato de caso tiene como objetivo llamar la atención para la ocurrencia de bloqueo neuromuscular prolongado después de la administración del mivacúrio y las conductas que fueron adoptadas.

RELATO DEL CASO: Se describe un caso de paciente programado para procedimiento de corta duración en régimen ambulatorial y que presentó bloqueo neuromuscular prolongado después de administración del mivacúrio. El diagnóstico fue posteriormente confirmado por la demostración de niveles reducidos de actividad de la colinestesterasis plasmática.

CONCLUSIONES: La averiguación laboratorial pre-operatoria, mismo incluyendo la dosificación de la actividad de la colinesterasis, no precave la posibilidad del bloqueo neuromuscular prolongado debido a la posibilidad de alteración cualitativa de la actividad de la enzima, no existiendo recomendación para averiguación sistemática. Ocurriendo esta complicación, se debe sedar el paciente y mantener ventilación mecánica hasta la completa recuperación de la fuerza muscular y realizar exámenes laboratoriales para el diagnóstico definitivo. Es de responsabilidad del anestesista la colecta de muestra sanguínea para realización de tests cuantitativos y cualitativos de la colinesterasis plasmática. Paciente y familiares deben ser orientados en cuanto a la importancia de la averiguación para clasificación de la variante atípica de la colinesterasis plasmática y sus implicaciones anestésicas.

INTRODUCTION

Mivacurium, due to its fast hydrolysis by plasma cholinesterase has short duration of action (15 to 30 min) as compared to other nondepolarizing agents and is a good choice for short procedures ¹. Succinylcholine and mivacurium are more slowly degraded in patients with decreased plasma cholinesterase and may induce prolonged postoperative apnea ².

This report aimed at describing a case of prolonged neuromuscular block after mivacurium and the anesthetic implications for patients susceptible to this phenomenon.

CASE REPORT

Female, Egyptian patient, 62 years old, 72 kg, physical status ASA II, to be submitted to bronchofibroscopy with flexible scope under general anesthesia to investigate a pulmonary node. Patient had been submitted to epidural anesthesia with sedation for liposuction without intercurrences. Patient denied allergies, asthma and the use of regular medication, and physical evaluation was normal. There was nothing outstanding in her family history. Procedure was scheduled in outpatient regimen.

Patient was not premedicated. Venous 20G catheter was installed in the operating room for lactated Ringer's infusion. Monitoring consisted of ECG at D_II lead, pulse oximetry, noninvasive blood pressure and capnography.

Anesthesia was induced with propofol (1.5 mg.kg^-1), alfentanil (500 µg), mivacurium (0.1 mg.kg^-1) and lidocaine (1 mg.kg^-1), followed by laryngeal mask n. 4, without intercurrences. Anesthesia was maintained with 100 to 140 µg.kg^-1.min^-1 propofol continuous infusion. Ventilation was manually controlled with normocapnia between 35 and 40 mmHg and 99% SpO₂. At the end of the investigation, which lasted 15 minutes, propofol continuous infusion was withdrawn and we waited for anesthetic superficialization to pharmacologically antagonize the neuromuscular blockade.

Thirty minutes after mivacurium administration low tidal volume and increased P_ETCO₂ were observed. Patient was given 1 mg.kg^-1 bolus propofol and neuromuscular transmission was monitored by acceleromyography. TOF stimulation with 2 Hz every 20 seconds was applied and no muscle response was observed. We decided for midazolam administration, return to propofol continuous infusion varying from 50 to 75 µg.kg^-1.min^-1 and wait for neuromuscular function recovery to antagonize the neuromuscular blockade. Ninety minutes after initial mivacurium dose there was no motor response to TOF even after neostigmine (0.05 mg.kg^-1) and atropine (0.015 mg.kg^-1). A second and third dose of neostigmine (0.025 mg.kg^-1) and atropine (0.007 mg.kg^-1) were administered at 30-minute intervals, however still with no response.

Muscle strength recovery T₄/T₁ 50% was observed 140 minutes after the first neostigmine dose and 230 minutes after initial mivacurium dose. Neostigmine and atropine were then administered with return to spontaneous ventilation and tidal volume between 450 and 475 mL and capnometry of 38 mmHg. Blood sample was collected for arterial gases analysis (pH 7.30; paO₂ 174 mmHg; pCO₂ 43 mmHg; Bic 21.20 mEq/L; BE - 5.2 mEq/L; SatO₂ 99%) when sedation was withdrawn and laryngeal mask was removed. Patient was referred to the ICU with Aldrete's recovery index = 9 and blood was again collected for plasma cholinesterase measurement.

Lab results have shown 2878 UI plasma cholinesterase, being 4,650 to 10,500 the normal values for females (kinetic colorimetric method). Patient was discharged from ICU 14 hours later.

DISCUSSION

This case report calls the attention to changes in plasma cholinesterase, the function of which is still undefined and which may be affected by different diseases, drugs, inheritance and ethnic variations.

Plasma cholinesterase is a very important enzyme for Anesthesiology due to its involvement with the metabolism of succinylcholine and other drugs, such as mivacurium ³.

Neuromuscular blockade duration after succinylcholine and mivacurium is primarily determined by hydrolysis through plasma cholinesterase ⁴.

Patients with pseudocholinesterase variations may present prolonged neuromuscular blockade after succinylcholine or mivacurium. In these situations, biochemical investigation is needed to identify quantitative mutation changes in patients and their relatives.

Ostergaard et al. have shown that heterozygous patients for the atypical gene have up to 50% increase in duration neuromuscular blockade ^2,3.

Alles et al. ⁵ have shown in 1940 that cholinesterase found in erythrocytes was different from cholinesterase found in human plasma. Two years later, Mendel et al. ⁶ have shown two types of cholinesterase, one highly specific for acetylcholine and called true or specific cholinesterase, and pseudocholinesterase or nonspecific cholinesterase able to hydrolyze choline and aliphatic esters ³.

In 1979, the Commission on Biochemical Nomenclature ⁷ has named nonspecific cholinesterase as plasma or serum cholinesterase, pseudocholinesterase, butyrylcholine esterase or type S cholinesterase. True cholinesterase is called acetylcholinesterase the function of it is hydrolyze acetylcholine neurotransmitter. It is found in all excitable tissues, are them muscles or nerves, central or peripheral, cholinergic or adrenergic, motor or sensory, in most erythrocytes and placental tissues. Plasma cholinesterase has a wide expression in central and peripheral nervous systems, liver and plasma. Enzymes differ in their biochemical properties. Acetylcholinesterase has high affinity for acetylcholine, is rapidly degraded and is inhibited by high acetylcholine concentrations. Plasma cholinesterase has low affinity for acetylcholine and is not inhibited by its high concentrations.

Reasons for plasma cholinesterase activity variation may be physiological, acquired or inherited.

Among physiological changes there are 20% activity decrease in the first semester of gestation, which is maintained until delivery. There is also decreased activity in neonates, especially low-weight neonates.

Sensitivity to succinylcholine is not affected by 30% decrease in plasma cholinesterase activity ⁸.

Some diseases determine decrease in plasma cholinesterase activity, such as hepatitis, cirrhosis, cholecystitis, cancer with distant metastasis (especially pulmonary, genito-urinary system and primary intestinal cancer), malnutrition, severe heart failure, renal failure, uremia and extensive burns ^9-12.

Plasmaferesis, oral contraceptives, noncompetitive cholinesterase inhibitors (echothiophate, organo- phosphorates and cyclosphamide), competitive cholinesterase inhibitors (neostigmine, edrophonium and pyridostigmine), metoclopramide and pancuronium are also responsible for pseudocholinesterase activity decrease ^13-16.

Metoclopramide inhibits plasma cholinesterase in up to 70% of its normal value ^3,17. Although being controversial to prevent postoperative nausea and vomiting, it is still often used in the perioperative period. Studies have shown 30% delay in muscle strength recovery after metoclopramide administration, probably due to decreased plasma clearance of mivacurium and increased bioavailability ¹⁸.

As to hereditary changes, it is established that the frequency of atypical homozygous is one in 3 thousand to 1 in 10 thousand patients, which are sensitive to succinylcholine. Heterozygous are one in 25 and do not present significant sensitivity to succinylcholine or ester-derived drugs, unless there are other factors contributing to increased sensitivity, such as associated diseases or the administration of anticholinesterase drugs ^19,20.

Caucasians, Egyptians, Indians, Turkish, Jews, Iranians and Iraquians are included in ethnic distribution ²¹.

In addition to succinylcholine, other drugs are affected by enzymatic activity changes, such as mivacurium, chloroprocaine, aspirin, methylprednisolone and cocaine. Atracurium presents double metabolism both by plasma cholinesterase and by Hoffman's degradation, which is the spontaneous temperature and pH-dependent inactivation not counterindicating its use in patients with plasma cholinesterase deficiencies ²².

Management of patients with prolonged apnea after succinylcholine or mivacurium primarily involves diagnosis and beginning of treatment. Peripheral nerve stimulator is critical to show neuromuscular blockade depth and differentiate it from anesthetic overdose as the reason for apnea. Although there might be plasma cholinesterase inhibition by anticholinesterase drugs, it has been already confirmed the benefit of the antagonism of mivacurium neuromuscular blockade both for patients with normal cholinesterase and homozygous patients for atypical cholinesterase ². Fresh plasma and red cells concentrate may be indicated to accelerate muscle strength recovery, however these are questionable approaches due to blood transfusion risks. It should be stressed that waiting for total spontaneous recovery does not pose risks for patients.

Plasma cholinesterase has more than 10 known variants and the frequency in which mivacurium and succinylcholine are used increases the possibility of facing one of those uncommon genetic variants throughout our clinical activity. Preoperative lab investigation of plasma cholinesterase activity does not prevent this incident, since there may be only qualitative changes in activity ²³. Regardless of the reason for prolonged neuromuscular blockade, controlled ventilation and sedation should be maintained until muscle strength recovery. Then it is important to counsel patients and relatives about the need for extensive investigation to determine the variant carried by the patient.

In our case, there has been prolonged apnea caused by significant quantitative decrease in plasma cholinesterase of potential ethnic origin.

REFERENCES

Submitted for publication February 21, 2005

Accepted for publication June 14, 2005

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^*

Received from Clínica São Vicente, Rio de Janeiro, RJ

Publication Dates

• Publication in this collection
  13 Feb 2006
• Date of issue
  Oct 2005

History

• Accepted
  14 June 2005
• Received
  21 Feb 2005