Continuous-Infusion Neuromuscular Blockers in Pediatrics
Continuous-Infusion Neuromuscular Blockers in Pediatrics
Neuromuscular blocking agents (NMBAs) are often administered as a prolonged (> 24 hrs) continuous infusion in infants and children in the intensive care unit for a variety of reasons including facilitation of oxygenation and ventilation. No guidelines on the use of NMBAs in pediatric patients are available yet in the United States; however, pediatric guidelines are available in the United Kingdom. Based on a 2007 U.S. survey, the most commonly used nondepolarizing NMBAs for sustained neuromuscular blockade in critically ill children are pancuronium and vecuronium. Recent national drug shortages involving NMBAs have been reported for atracurium, cisatracurium, pancuronium, rocuronium, and vecuronium. Therefore, to explore alternative options for neuromuscular blockade, we conducted a literature search to identify articles evaluating prolonged use (> 24 hrs) of NMBAs administered by continuous infusion. The search was limited to English-language articles in the MEDLINE (1950–August 2010), EMBASE (1988–August 2010), International Pharmaceutical Abstracts (1970–August 2010), and Cochrane Library (1996-August 2010) databases. Relevant abstracts, reference citations, and manufacturers' product information were also reviewed. A total of 13 reports representing 208 children were included in the analysis. Many of the reports described wide interpatient variability in dosing for the specific NMBAs evaluated. Selection of the most appropriate NMBA should be based on the patient's clinical status, potential adverse effects, and pharmacoeconomics. All patients receiving sustained neuromuscular blockade should be monitored routinely to ensure that dosing is appropriate in order to obtain the desired level of blockade. The goal is to use the lowest dose possible in an effort to limit adverse effects or prolonged blockade.
Neuromuscular blocking agents (NMBAs) are often administered as a prolonged (> 24 hrs) continuous infusion in the neonatal and pediatric intensive care units (ICUs) to facilitate intubation for mechanical ventilation, reduce intracranial pressure, decrease oxygen consumption, control ventilation to permit oxygenation in patients with pulmonary hypertension, and eliminate shivering with induced hypothermia. Although available for adult patients, clinical practice guidelines for sustained neuromuscular blockade in pediatric patients have not been established in the United States because of the paucity of robust clinical data. However, consensus guidelines for use in the United Kingdom were established in 2007 by the United Kingdom Paediatric Intensive Care Society Sedation, Analgesia, and Neuro-muscular Blockade Working Group (U.K. Working Group). Results of a survey conducted in 2007 found that the most commonly used agents in the United States for sustained neuromuscular blockade in critically ill children are vecuronium and pancuronium, with nearly half of those surveyed using continuous infusions. A similar study conducted in the United Kingdom found that vecuronium and atracurium were the most commonly used agents.
Acetylcholine is the neurotransmitter responsible for muscle movement by binding to the postsynaptic nicotinic receptors on the sarcolemma of skeletal muscle. This receptor is composed of five subunits, and acetylcholine binds with two of the alpha subunits of the receptor. Activation of this receptor results in depolarization of the muscle membrane, in turn resulting in muscle contraction. Muscle contraction ends when acetylcholine is metabolized by acetylcholinesterase and repolarization of the sarcolemma occurs. The NMBAs can be differentiated by their mechanism of action at the nicotinic receptor. Depolarizing agents, such as succinylcholine, mimic endogenous acetylcholine by binding to the nicotinic receptor at the neuromuscular junction and initially cause muscle contraction. However, compared with endogenous acetylcholine, these agents persist for a longer duration due to their resistance to acetylcholinesterase. This effectively results in sustained depolarization of the sarcolemma and corresponding paralysis. Succinylcholine is not routinely recommended for continuous infusion in the ICU setting because of adverse effects such as tachycardia, ventricular arrhythmias, and hypertension secondary to stimulation of sympathetic ganglia. The agent has also been associated with hyperkalemia.
Nondepolarizing agents—pancuronium, vecuronium, rocuronium, atracurium, and cisatracurium—competitively antagonize the neuromuscular junction and block the action of acetylcholine, resulting in muscle paralysis. These agents can be further classified according to their chemical structure (aminosteroid vs benzylisoquinolinium) or the duration of activity (short, intermediate, or long-acting). There are a number of NMBAs on the market, and differences exist among the agents, including potency, onset time, duration of action, adverse-effect profile, route of metabolism, and cost. Selection of the most appropriate agent can be influenced by any one of these factors.
Over the past year, several national drug shortages have been reported for atracurium, cisatracurium, pancuronium, rocuronium, and vecuronium. At our institution, vecuronium and cisatracurium are the most common agents used for prolonged neuromuscular blockade. The shortages forced us to explore supporting evidence for alternative NMBAs for continuous infusion in children, including dosage recommendations, dosage adjustments, and adverse events.
We therefore conducted a literature search of MEDLINE (1950–August 2010), EMBASE (1988-August 2010), International Pharmaceutical Abstracts (1970–August 2010), and the Cochrane Library (1996–August 2010) databases by using the following key words: child, neonate, paralysis, cisatracurium, vecuronium, atracurium, rocuronium, and pancuronium. Results were limited to human studies published in the English language. Relevant abstracts from the Society of Critical Care Medicine ([SCCM] 2006–2010), reference citations from relevant articles, and product information from the NMBA manufacturers was also reviewed. Articles were reviewed for prolonged use (> 24 hrs) of NMBAs administered by continuous infusion. However, articles describing intermittent dosing or shortterm continuous infusion of NMBAs were evaluated and included if considered relevant to the discussion.
Abstract and Introduction
Abstract
Neuromuscular blocking agents (NMBAs) are often administered as a prolonged (> 24 hrs) continuous infusion in infants and children in the intensive care unit for a variety of reasons including facilitation of oxygenation and ventilation. No guidelines on the use of NMBAs in pediatric patients are available yet in the United States; however, pediatric guidelines are available in the United Kingdom. Based on a 2007 U.S. survey, the most commonly used nondepolarizing NMBAs for sustained neuromuscular blockade in critically ill children are pancuronium and vecuronium. Recent national drug shortages involving NMBAs have been reported for atracurium, cisatracurium, pancuronium, rocuronium, and vecuronium. Therefore, to explore alternative options for neuromuscular blockade, we conducted a literature search to identify articles evaluating prolonged use (> 24 hrs) of NMBAs administered by continuous infusion. The search was limited to English-language articles in the MEDLINE (1950–August 2010), EMBASE (1988–August 2010), International Pharmaceutical Abstracts (1970–August 2010), and Cochrane Library (1996-August 2010) databases. Relevant abstracts, reference citations, and manufacturers' product information were also reviewed. A total of 13 reports representing 208 children were included in the analysis. Many of the reports described wide interpatient variability in dosing for the specific NMBAs evaluated. Selection of the most appropriate NMBA should be based on the patient's clinical status, potential adverse effects, and pharmacoeconomics. All patients receiving sustained neuromuscular blockade should be monitored routinely to ensure that dosing is appropriate in order to obtain the desired level of blockade. The goal is to use the lowest dose possible in an effort to limit adverse effects or prolonged blockade.
Introduction
Neuromuscular blocking agents (NMBAs) are often administered as a prolonged (> 24 hrs) continuous infusion in the neonatal and pediatric intensive care units (ICUs) to facilitate intubation for mechanical ventilation, reduce intracranial pressure, decrease oxygen consumption, control ventilation to permit oxygenation in patients with pulmonary hypertension, and eliminate shivering with induced hypothermia. Although available for adult patients, clinical practice guidelines for sustained neuromuscular blockade in pediatric patients have not been established in the United States because of the paucity of robust clinical data. However, consensus guidelines for use in the United Kingdom were established in 2007 by the United Kingdom Paediatric Intensive Care Society Sedation, Analgesia, and Neuro-muscular Blockade Working Group (U.K. Working Group). Results of a survey conducted in 2007 found that the most commonly used agents in the United States for sustained neuromuscular blockade in critically ill children are vecuronium and pancuronium, with nearly half of those surveyed using continuous infusions. A similar study conducted in the United Kingdom found that vecuronium and atracurium were the most commonly used agents.
Acetylcholine is the neurotransmitter responsible for muscle movement by binding to the postsynaptic nicotinic receptors on the sarcolemma of skeletal muscle. This receptor is composed of five subunits, and acetylcholine binds with two of the alpha subunits of the receptor. Activation of this receptor results in depolarization of the muscle membrane, in turn resulting in muscle contraction. Muscle contraction ends when acetylcholine is metabolized by acetylcholinesterase and repolarization of the sarcolemma occurs. The NMBAs can be differentiated by their mechanism of action at the nicotinic receptor. Depolarizing agents, such as succinylcholine, mimic endogenous acetylcholine by binding to the nicotinic receptor at the neuromuscular junction and initially cause muscle contraction. However, compared with endogenous acetylcholine, these agents persist for a longer duration due to their resistance to acetylcholinesterase. This effectively results in sustained depolarization of the sarcolemma and corresponding paralysis. Succinylcholine is not routinely recommended for continuous infusion in the ICU setting because of adverse effects such as tachycardia, ventricular arrhythmias, and hypertension secondary to stimulation of sympathetic ganglia. The agent has also been associated with hyperkalemia.
Nondepolarizing agents—pancuronium, vecuronium, rocuronium, atracurium, and cisatracurium—competitively antagonize the neuromuscular junction and block the action of acetylcholine, resulting in muscle paralysis. These agents can be further classified according to their chemical structure (aminosteroid vs benzylisoquinolinium) or the duration of activity (short, intermediate, or long-acting). There are a number of NMBAs on the market, and differences exist among the agents, including potency, onset time, duration of action, adverse-effect profile, route of metabolism, and cost. Selection of the most appropriate agent can be influenced by any one of these factors.
Over the past year, several national drug shortages have been reported for atracurium, cisatracurium, pancuronium, rocuronium, and vecuronium. At our institution, vecuronium and cisatracurium are the most common agents used for prolonged neuromuscular blockade. The shortages forced us to explore supporting evidence for alternative NMBAs for continuous infusion in children, including dosage recommendations, dosage adjustments, and adverse events.
We therefore conducted a literature search of MEDLINE (1950–August 2010), EMBASE (1988-August 2010), International Pharmaceutical Abstracts (1970–August 2010), and the Cochrane Library (1996–August 2010) databases by using the following key words: child, neonate, paralysis, cisatracurium, vecuronium, atracurium, rocuronium, and pancuronium. Results were limited to human studies published in the English language. Relevant abstracts from the Society of Critical Care Medicine ([SCCM] 2006–2010), reference citations from relevant articles, and product information from the NMBA manufacturers was also reviewed. Articles were reviewed for prolonged use (> 24 hrs) of NMBAs administered by continuous infusion. However, articles describing intermittent dosing or shortterm continuous infusion of NMBAs were evaluated and included if considered relevant to the discussion.