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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.[1] 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.[2] 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).[1] 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.[3] A similar study conducted in the United Kingdom found that vecuronium and atracurium were the most commonly used agents.[4]
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.[5] 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.[6] 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.[5]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.[7] 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.
Monitoring of Neuromuscular Blockade
Because of the variability in dose response of NMBAs in children, monitoring of neuromuscular function while administering a continuous infusion of an NMBA in the ICU is essential. Monitoring can be used to ensure adequate paralysis in critically ill patients while using the lowest dose possible to achieve the effect. The most commonly used method to monitor neuromuscular blockade in the operating room and in clinical studies for prolonged use of NMBAs is peripheral nerve stimulation or trainof- four (TOF) monitoring with the facial, ulnar, or peroneal nerve. This method involves the placement of electrodes over the peripheral nerves that deliver a total of four stimuli over 2 seconds. Patients can exhibit anywhere from zero to four twitches. The greater number of twitches indicates inadequate paralysis. One of the first studies to evaluate this method was a prospective, randomized, single-blind trial of 77 adults; the investigators found that peripheral nerve stimulation resulted in a significantly lower dose and mean infusion rate of the NMBA versus that of patients whose NMBA dosage was titrated by clinical parameters.[8] Currently the SCCM and the U.K. Working Group recommend using TOF monitoring in critically ill patients receiving continuous NMBAs, targeting a TOF response of one to two twitches.[1, 2] The U.K. Working Group also suggests that TOF monitoring be assessed at least once/day.[1]
Despite these recommendations, clinicians should be aware that there are some limitations to TOF monitoring in children. Even in moderate-sized ICUs, only a few patients are administered NMBAs at a given time, leading to unfamiliarity with TOF use. As a result of this unfamiliarity, user error may result in incorrect placement of the electrodes, leading to misinterpretation of the state of paralysis. Additional technical difficulties can occur in small children. Because of the size of the electrodes, it is possible to directly stimulate the muscle itself, leading to movement even though the neuromuscular junction is blocked.[6]
In addition to technical errors, other patient factors can affect TOF assessment in children. In children with acute illness, capillary leak syndrome and edema are common and may lead to incorrect function of TOF monitoring. Even though patients may have an adequate TOF response of one to two twitches through peripheral nerve stimulation, they may not have an adequate response in other areas of the body. For instance, some evidence supports that NMBAs have less effect on the diaphragm.[9]
Because of the limitations, the SCCM recommends that clinical monitoring must be used in conjunction with TOF monitoring.[2] This clinical monitoring should include observation of visual and tactile stimulation on muscle movement, as well as observation of breathing patterns (e.g., overbreathing the ventilator).[2] As part of this assessment, clinicians should evaluate the need for additional sedative or analgesic drugs. A previous set of guidelines from the SCCM have described use of an NMBA "drug holiday" in conjunction with TOF monitoring to assess the need for continued paralysis and adequacy of sedation or analgesia.[10] A drug holiday refers to cessation of the NMBA for a few to several hours on a daily basis. At this point, clinicians would restart the NMBA only when clinically necessary. In the 2002 SCCM guidelines, this practice was no longer routinely recommended for monitoring; however, it is still recommended to prevent postparalytic quadriparesis, a long-term complication associated with NMBAs.[2] Anecdotally, drug holidays are still used by clinicians for select patients. In fact, drug holidays are supported by the U.K. Working Group for patients in whom the practice is safe.
Nondepolarizing Agents
Pancuronium
Pancuronium was introduced in the late 1960s as the first bisquaternary aminosteroid NMBA and is classified as a long-acting agent.[11] It is primarily eliminated (80%) by renal excretion, with approximately 10% being excreted through the biliary route.[12] The active metabolite, 3-hydroxypancuronium, possesses one third to one half the potency of pancuronium.[2]
A number of specific adverse events have been attributed to pancuronium. Because of its long duration of action, pancuronium has been associated with prolonged paralysis and muscle atrophy after 1 week when given as intermittent doses or by continuous infusion.[13] In premature infants, pancuronium has also been associated with joint contractures, specifically in the hips and knees.[14] However, this effect does not appear to persist after discontinuation of the drug and resumption of spontaneous activity. Pancuronium has been associated with hemodynamic effects (e.g., tachycardia, hypertension) due to blockade of cholinergic receptors outside the neuromuscular junction. Although potentially detrimental in adult patients, these effects may be desired in the pediatric population and may offset the negative chronotropic effects of other agents used for sedation or analgesia.
We found only one study that evaluated the dosage requirements and efficacy of pancuronium given by continuous infusion for neuromuscular blockade in critically ill children. This was a prospective, open-label study conducted in 25 children (Table 1).[12] Patients not receiving an NMBA before arrival to the pediatric ICU received a bolus dose of pancuronium 0.1 mg/kg followed by a continuous infusion of 0.05 mg/kg/hour when the first twitch of the TOF returned. The dose was increased or decreased by 0.01 mg/kg/hour in an effort to maintain one to two twitches of the TOF. Additional bolus doses equivalent to the current hourly dose were administered before an increase in infusion rate. After discontinuation of the infusion, the time until return of neuromuscular function (i.e., normal TOF and sustained tetanus to 50 Hz) was recorded. Fourteen patients received an initial bolus dose of pancuronium. These patients had a statistically significant increase in heart rate (mean ± SD 122 ± 37 vs 141 ± 41 beats/min, p<0.05) and systolic blood pressure (102 ± 33 vs 144 ± 28 mm Hg, p<0.05) from baseline. These changes in heart rate and blood pressure may be of minimal clinical significance in patients with stable heart function; however, in patients with cardiovascular instability, these effects could result in further detriment.
This patient cohort had a wide variability in pancuronium dosing and duration of use. Patients requiring 5 or more days of continuous neuromuscular blockade required a significant increase in dose on day 5 compared with day 1 (mean 0.083 vs 0.059 mg/kg/hr, p=0.03). Also, patients receiving anticonvulsants had an increased infusion requirement (mean ± SD 0.056 ± 0.03 vs 0.14 ± 0.06 mg/kg/hr, p<0.05). After discontinuation of pancuronium, return of neuromuscular function was observed after 35–75 minutes. No episodes of prolonged paralysis were noted; however, this study included a small sample size.
Vecuronium
Vecuronium, a structural derivative of pancuronium, is a monoquaternary aminosteroid NMBA that was introduced in the 1980s. Vecuronium has 1.2–1.5 times greater potency and a shorter duration of action than pancuronium.[27] Unlike pancuronium, vecuronium does not cause catecholamine or histamine release. Vecuronium is categorized as an intermediateacting NMBA. Hepatobiliary clearance is the primary route of elimination, accounting for approximately 50% of the dose.[28] An active metabolite, 3-desacetylvecuronium, is formed by hydrolysis and is 50–70% as potent as the parent compound.[6] This metabolite is cleared primarily by renal elimination.
A prospective study of continuous-infusion vecuronium, given to facilitate mechanical ventilation, was conducted in 11 infants and children and four neonates.[15] All patients received a bolus dose followed by initiation of a continuous infusion (Table 1). The degree of neuromuscular blockade was assessed with TOF monitoring, and a 10% adjustment in dose was made to maintain one twitch of TOF. There was a wide range in the duration of infusion in both age groups. The mean dose was not statistically significantly different between the infantschildren group and the neonate group, with 0.14 ± 0.05 mg/kg/hour and 0.11 ± 0.05 mg/kg/hour, respectively (p<0.4). Recovery time after discontinuation ranged from 27–80 minutes for all patients. Only in the infants-children group was there a positive correlation between duration of infusion and time to recovery (r=0.76, p<0.01). No adverse cardiovascular or toxic effects were noted.
A prospective, dose-finding study with vecuronium continuous infusions was conducted in 12 infants and 18 children.[16] Patients did not receive a bolus dose, and the continuous infusion starting dose was based on patient age. There was a wide range in the duration of infusion. Neuromuscular blockade was assessed by using the TOFguard accelerometer (Organon Teknika, Cambridge, United Kingdom), and the dose was titrated by 10% to maintain one twitch of TOF. A statistically significant increase in dose was required for patients older than 1 year versus those younger than 1 year (mean ± standard error of mean [SEM] 98.7 ± 7.07 vs 54.7 ± 4.23 μg/kg/hr, p=0.0001). When comparing the mean infusion rate for the first 6 hours versus the final 6 hours, no statistically significant difference was noted (mean ± SEM 79.21 ± 6.62 vs 87.86 ± 7.11 μg/kg/hr). Therefore, the author suggested that tachyphylaxis requiring subsequent dose increase does not occur with prolonged duration of vecuronium and also noted that there was a statistically significant difference in recovery time after cessation of the infusion with a median recovery time of 45 minutes (interquartile range [IQR] 20–51 min) for infants and 65 minutes (IQR 55–103 min) for children (p=0.0019). The author noted that the time to spontaneous recovery was not influenced by duration of infusion.
One case series described one male and one female patient with prolonged paralysis after receipt of continuous-infusion vecuronium (Table 1).[17] Both patients received a continuous infusion without a bolus dose. After cessation of vecuronium, both patients were hypotonic with absent movement of the head and extremities and absent deep tendon reflexes. The female patient's deep tendon reflexes, extremity movements, and head movements returned to baseline at 5, 15, and 21 days after discontinuation of vecuronium, respectively, whereas the male patient's values returned to baseline 3 days after discontinuation. The female patient did receive high-dose corticosteroid therapy for 14 days while receiving vecuronium. Both patients' ICU length of stay and number of days requiring ventilator support were prolonged. This case series emphasized the morbidity associated with prolonged NMBA infusions and the need to assess concomitant risk factors for prolonged paralysis (e.g., drug therapy and electrolyte abnormalities).
Rocuronium
Rocuronium, introduced in 1994, is a desacetoxy analog of vecuronium.[6] It is classified as an intermediate-acting NMBA. It is approximately one sixth as potent but has a 2.5 times faster onset of action as vecuronium.[29]Rocuronium undergoes primarily hepatic metabolism to 17-desacetylrocuronium, which has minimal activity (5–10% activity of the parent compound).[2] Although rocuronium is primarily excreted through the biliary route, approximately 33% is excreted renally.[30] Like vecuronium, rocuronium causes negligible histamine release. It has been shown to have mild vagolytic activity resulting in tachycardia, although this adverse event may not be clinically significant.[18]
A prospective, open-label investigation was conducted to determine infusion requirements of rocuronium in 20 critically ill patients (Table 1).[18] Initial doses differed based on NMBA exposure. A bolus dose was administered if the patient was not currently receiving an NMBA or if the patient was receiving an NMBA and had one twitch of the TOF. Patients receiving a previous NMBA with no twitch noted were not given a bolus and were started on a continuous infusion when the first twitch was noted. In all cases, the initial starting dose of the continuous infusion was 0.6 mg/kg/hour; the infusion rate was titrated in increments of 0.1 mg/kg/hour to maintain one twitch of the TOF. Fourteen patients required a bolus dose, and a statistically significant, but not clinically significant, increase from baseline was noted in heart rate (mean ± SD 121 ± 31 vs 132 ± 42 beats/min, p<0.05) and blood pressure (systolic 104 ± 28 vs 112 ± 41 mm Hg, p<0.01; diastolic 62 ± 28 vs 68 ± 36 mm Hg, p<0.01). Wide variability in dosing requirements and duration of infusion was also noted, with higher doses noted in patients with the longest duration. A significant increase in dose requirements was noted after 5 days of therapy (0.67 vs 1.2 mg/kg/hr, p<0.05). Spontaneous recovery of neuromuscular function was noted within 24–44 minutes (mean ± SD 31 ± 12 min). The author noted that with the small number of patients, he was unable to evaluate dosing variability between age groups and concomitant disease states.
Atracurium
Atracurium, introduced in 1983, is a bisquaternary ammonium benzylisoquinolinium. Atracurium is classified as an intermediate-acting NMBA and is distinctive with regard to its route of metabolism. The drug is metabolized by two chemical mechanisms, Hofmann elimination and nonspecific ester hydrolysis. Hofmann elimination is dependent on pH and temperature; alterations in these two variables can decrease elimination (e.g., hypothermia, acidosis).[31]
A number of adverse events have been proposed with atracurium. Several are primarily related to histamine release with bolus dosing and include hypotension, tachycardia, bronchospasm, erythema, and rash.[31] In addition, there is a theoretical concern of precipitation of seizures secondary to formation of laudanosine, a long-acting metabolite produced by Hofmann elimination and hydrolysis. Laudanosine is both hepatically and renally eliminated and could accumulate in patients with renal or hepatic insufficiency.[29] Results of an animal study demonstrated that high concentrations (17 μg/ml) of laudanosine resulted in convulsions.[32] We found only one report of a patient who had a seizure while receiving atracurium.[33]
A case report describes an infant who received atracurium by continuous infusion after surgery for a total of 7 days (Table 1).[19] The atracurium infusion was started without a bolus dose, and the dose was titrated by 0.1–0.2 mg/kg/hour to maintain one to two twitches of the TOF. After 72 hours, a significant increase in dose was noted, and by day 7, the patient required a maximum of 1.8 mg/kg/hour. Recovery from paralysis was achieved 25 minutes after discontinuation of the infusion. Laudanosine concetrations were also collected to determine whether increased dose requirements of atracurium resulted in increased laudanosine accumulation. The laudanosine concentration was reported to be relatively constant throughout the 7-day infusion despite a 3-fold increase in dose. An electroencephalogram was obtained but did not demonstrate any abnormalities. The authors suggested that laudanosine accumulation is likely not a concern in patients without hepatic failure.
A dose-finding study with atracurium as a continuous infusion was conducted in 12 children receiving mechanical ventilation (Table 1).[20] Treatment was started as an atracurium infusion without a bolus dose, and the dose was titrated by clinical assessment and TOF stimulation of the ulnar nerve. The dose was increased with patient movement and decreased when the patients exhibited zero twitches of TOF. The mean duration of infusion was 98 hours, and the mean ± SEM infusion rate was 1.6 ± 0.08 mg/kg/hour. All patients had progressively increased dose requirements; seven patients required a mean ± SEM infusion rate of 1.72 ± 0.15 mg/kg/hour after 72 hours of exposure. Time to full recovery after discontinuation of the infusion was evaluated in seven patients with a mean ± SEM time of 23.7 ± 3.1 minutes (range 10–35 min). The mean dose in this study is higher than that of some adult studies. This is thought to be due to the increased clearance of atracurium in children compared with adults, coupled with the requirement for a greater degree of neuromuscular blockade to facilitate mechanical ventilation in this population.
The offset time after discontinuation of atracurium infusion was investigated in 20 children receiving mechanical ventilation (Table 1).[21] Patients were given a bolus dose followed by a continuous infusion. A total of 35 assessments were made among the 20 children by using TOF stimulation of the ulnar nerve. At the time of discontinuation, the mean dose was 1.41 mg/kg/hour and mean duration of infusion was 55.7 hours. The mean recovery time was determined to be 28.7 minutes (range 8–56 min). No correlation was found between the dose at discontinuation and the offset time; however, the duration of infusion was negatively correlated with offset time (rs= −0.338, p=0.047), suggesting that development of tolerance occurs after prolonged infusions (i.e., 48–72 hrs). The focus of this study was mainly on time of offset of atracurium, so the investigators did not specifically evaluate adverse events.
Cisatracurium
Cisatracurium was introduced in 1995 and is the cis-isomer of atracurium.[22] It is classified as an intermediate-acting benzylisoquinolinium advantages over atracurium, such as increased potency (4 times as potent), minimal or no histamine release resulting in no significant cardiovascular adverse events, and higher autonomic:neuromuscular blockade ratio.[34] The metabolism of cisatracurium is dependent on Hofmann degradation and not renally or hepatically eliminated.[22] With regard to the theoretical concern for accumulation of laudanosine and precipitation of seizures, the Hofmann degradation of cisatracurium results in 5–10 times lower concentrations of laudanosine than atracurium.[34]
In the first prospective study to evaluate dose requirements of continuous cisatracurium, all 15 critically ill children received a bolus followed by a continuous infusion; the infusion was titrated in increments of 1 μg/kg/minute as needed to maintain one twitch of the TOF (Table 1).[22] If an increase in rate was required, patients received a bolus dose equivalent to the hourly dose before increasing the rate. The author noted a wide variability in the duration of infusion and dosing requirements. There was less variability when evaluating the dose requirements over the first 3 days (1.4–8.1 μg/kg/min). All patients required a statistically significant increase in dose after 3 days of therapy (p<0.01). Infusion requirements were significantly decreased in a patient requiring intentional hypothermia, likely due to the fact that Hofmann elimination is affected by temperature. No significant differences in infusion requirements were noted in patients with organ dysfunction compared with those with normal function. After discontinuation, spontaneous return of neuromuscular function was achieved in 14–33 minutes. No statistically significant differences in cardiovascular effects were noted.
One case report describes an infant who received a continuous infusion of cisatracurium for a total of 40 days.[23]This infant was noted to have hepatic and renal dysfunction during the course of the ICU stay. Cisatracurium was begun with a bolus dose followed by a continuous infusion (Table 1). The dose was titrated to maintain one twitch on the TOF. If a dose increase was required, a bolus dose was administered followed by a 15–20% increase in infusion rate. The patient required an increase in dose throughout therapy with a maximum dose of 22.3 μg/kg/minute. No specific adverse events were addressed in the report.
An open-label, prospective study was conducted in 11 critically ill children receiving cisatracurium.[24] For eight of the patients, the authors had pharmacodynamic and plasma concentration data. Each of these patients received a bolus dose followed by continuous infusion (Table 1). Doses were increased by 1 μg/kg/minute or decreased by 0.25 μg/kg/minute to maintain one twitch of the TOF. If an increase in rate was required, a bolus dose of 100 μg/kg was administered before the increase in rate. Similar to one of the previously discussed studies,[22] there was wide interpatient variability in dose and duration of infusion. The mean maximum infusion rate was significantly greater than the mean initial rate (p=0.015), suggesting development of tachyphylaxis. Full neuromuscular recovery was achieved in a mean ± SD of 74.8 ± 32 minutes. Cisatracurium and laudanosine concentrations were obtained at steady state after initiation of infusion, at steady state after change in infusion rate, on a daily basis if no change in rate, and after discontinuation of infusion. The authors reported that, in general, laudanosine concentrations declined as cisatracurium concentrations declined, suggesting no accumulation. No significant hemodynamic changes were noted in this study during administration of the bolus dose or continuous infusion.
Cisatracurium Versus Vecuronium
A prospective, randomized, double-blind study was conducted to compare the infusion requirements, recovery characteristics, and pharmacokinetics of cisatracurium and vecuronium in children aged 2–163 days after congenital heart surgery (Table 1).[25] Patients were randomly assigned to cisatracurium or vecuronium, and a continuous infusion was started. Doses were adjusted by 25–100% to maintain one twitch of TOF. Because of the small size of the patients, the magnitude of the electromyographic response was too small to be detected by the monitor, so visual observation of thumb movement was used to determine TOF response. The median duration of infusion was not statistically significantly different between the two groups (p=0.16). The mean infusion rate was 0.066 mg/kg/hour (range 0.03–0.18 mg/kg/hr) for vecuronium and 2.8 μg/kg/minute (range 0.75–11.5 μg/kg/min) for cisatracurium. The spontaneous recovery time after discontinuation of infusion was significantly longer for vecuronium-treated patients than for cisatracurium-treated patients (180 min [range 75–435 min] vs 30 min [range 0–45 min], p<0.05). After discontinuation of vecuronium, 3-hydroxy-vecuronium concentrations were obtained, and a median half-life of 354 minutes (range 152–1046 min) was calculated. The median half-life of 3-hydroxy-vecuronium is approximately 4-fold that of the parent compound in this patient population. Although time to recovery was significantly different, no significant differences were noted in time to extubation, post–neuromuscular blockade ICU length of stay, or post–neuromuscular blockade hospital length of stay. The investigators suggested that the prolonged recovery time with vecuronium may have been associated with decreased clearance and accumulation of its active metabolite.
A prospective, randomized, double-blind trial was conducted in 37 children to compare efficacy and recovery profiles of vecuronium and cisatracurium continuous infusions (Table 1).[26] Patients were randomly allocated to one of the treatment groups, and they received a bolus dose, if indicated, followed by a continuous infusion. Doses were increased or decreased by 25% to maintain one twitch in the TOF response. Increases in infusion rate were accompanied by a bolus dose equivalent to the current hourly dose. The mean ± SD infusion rate of cisatracurium was 3.9 ± 1.3 μg/kg/minute with a median duration of 63 hours (IQR 23–88 hrs), whereas the vecuronium mean ± SD infusion rate was 0.16 ± 0.08 mg/kg/hour with a median duration of 40 hours (IQR 27–72 hrs). No statistically significant difference in duration of infusion was noted between the groups (p=0.65). In patients receiving more than 24 hours of vecuronium, three patients (19%) received a significant decrease in dose, and one patient (6%) required a significant increase in dose. Contrasting this, four patients (29%) receiving cisatracurium for more than 24 hours required a statistically significant increase in dose.
These results suggest accumulation of vecuronium that requires dosage reduction for prolonged use and development of tachyphylaxis for cisatracurium after prolonged use. The median recovery time to TOF ratio of more than 70% (i.e., ≥ three twitches) was significantly shorter with cisatracurium than with vecuronium (52 vs 123 min, p=0.001). One patient with head injury and no organ dysfunction had a prolonged recovery time after discontinuation of vecuronium and required 27 hours to recover. No relationship between recovery time and duration of infusion was noted. No significant hemodynamic effects or adverse effects were noted, but the study was not powered to detect such effects. The authors noted that a higher vecuronium dose was required in this population compared with that in a previously discussed study,[16] but they propose that the higher dosing scheme may reflect that they had a higher median age compared with the other study.
Drug Selection and Administration
Table 2 includes a summary of the dosing regimens used in the studies evaluated. It is important to note that many of the studies reported a wide interpatient variability in dosing requirements. This variability in dosing requirements can be secondary to a variety of factors, including administration of other drugs that are known to potentiate (e.g., corticosteroids, amino-glycosides, magnesium) or antagonize (e.g., phenytoin, carbamazepine) the effects of the NMBAs.[6] All of the studies included in Table 1, except for the vecuronium studies, reported development of tachyphylaxis after 3–5 days of therapy, requiring an increase in dose to achieve the desired level of paralysis. The drug therapy profiles of patients receiving prolonged neuromuscular blockade should be screened for agents known to agonize or antagonize NMBAs, and clinical monitoring should be performed at regular intervals to assess for development of tachyphylaxis. The SCCM's adult guidelines for sustained neuromuscular blockade recommend that if a patient develops tachyphylaxis to one agent, the clinician should try another NMBA.[2] A reasonable approach would be to use an NMBA from a different class if tachyphylaxis develops.
Dosage adjustments or avoidance of agents may need to be considered in select patient populations. Because of its vagolytic activity, pancuronium should be avoided in children with cardiovascular dysfunction or children with unstable hemodynamic congenital heart defects. Dosage adjustments should be made in children with renal or hepatic dysfunction based on the pharmacokinetic principles of the selected NMBA and the active metabolites that are formed. Cisatracurium and atracurium may be used in patients with renal and/or hepatic dysfunction without a need to modify dosing because they are eliminated by Hofmann elimination rather than reliance on hepatic enzymes or organ function. One caveat to these agents is that this Hofmann elimination is a pH- and temperature-dependent process.[31] Therefore, critically ill children undergoing induced hypothermia or with altered temperature regulation in some disease states and/or acidosis (e.g., septic shock) may have decreased elimination of these agents. The other NMBAs can be used in patients with organ dysfunction. However, clinicians should use the lowest possible dose and monitor frequently to limit accumulation of these agents.
Drug holidays could be used to allow the clinician to assess how long it takes the patient to recover and to avoid NMBA accumulation. There are no specific recommendations provided by clinical trials or consensus guidelines regarding drug holidays. The median time to recovery for the agents was approximately 30 minutes. So, a reasonable approach would be to implement a drug holiday for 30–60 minutes in clinically stable patients. For patients who do not have signs of spontaneous recovery at the end of the drug holiday, clinicians may consider reducing the dose by 50% and titrating according to their clinical examination and TOF monitoring.
Special consideration should also be made for obese pediatric patients (i.e., those with ≥ 95th percentile for body mass index for age and sex according the Centers for Disease Control and Prevention definition[40]). Because dosing is weight based, the NMBA regimen could result in supratherapeutic doses and prolonged neuromuscular blockade. Two studies have been conducted in obese adults to evaluate the pharmacokinetic differences with vecuronium and rocuronium.[41, 42] Both studies reported a lower volume of distribution and prolonged duration of action in this population. The authors of these studies recommend using ideal body weight (IBW) for calculation of doses in obese adults. Although this recommendation is for adults, the United Kingdom guidelines for sustained neuromuscular blockade in critically ill children also recommend use of IBW for obese children.[1] As an overall recommendation, dosing should be started based on IBW for children with a body mass index greater than or equal to the 95th percentile for age and sex, and this dose can be titrated upward if needed based on clinical monitoring to achieve the desired level of blockade.
Table 2 also shows a comparison of the time to recovery of the selected NMBAs based on the clinical reports included in this article. It must be noted that there is a wide range of time to recovery with some of the agents. There appears to be a correlation between prolonged time to recovery, extended duration of use, and higher dose requirements. Based on the trials reviewed, vecuronium appears to have the longest time to recovery.
Because of concerns for health care costs, clinicians should carefully consider the economic implications when selecting an NMBA. The estimated cost/day (Table 2) includes the cost based on a 10-kg child receiving the range of initial doses extracted from the clinical reports in Table 1. It should be noted that this cost may vary based on the preferred pricing at individual institutions. However, this provides a rough estimate for comparison of the selected agents. The actual cost of the drug is one of many factors that may affect the total pharmacoeconomics of NMBAs. For instance, patients with a prolonged time of recovery may have an overall longer hospital or ICU stay, contributing to increased hospital cost. None of the studies that were included in this article was powered to detect differences in cost. One group of authors found that TOF monitoring reduces overall cost/patient by 40% compared with that for patients who did not receive TOF monitoring.[43] The SCCM guidelines for adults recommend that institutions should perform a careful economic analysis by using their own specific data when selecting NMBAs.[2]
The recommended intravenous concentrations found in the literature for the selected NMBAs (Table 2) should be used, if possible, based on data for stability. However, many critically ill neonates, infants, and children may have fluid overload and require more concentrated solutions. Anecdotally, clinicians have used alternative concentrations based on their experience with that specific agent.
Conclusion
The use of continuous neuromuscular blockade for more than 24 hours in critically ill pediatric patients is a common practice. Recent drug shortages have forced clinicians to consider alternative agents. When selecting an NMBA, clinicians should carefully consider the patient's clinical status (renal, cardiac, and hepatic dysfunction), potential adverse effects, and pharmacoeconomics. Most of the available evidence for prolonged neuromuscular blockade in pediatric patients is with cisatracurium, atracurium, and vecuronium. Clinicians should carefully monitor all patients receiving prolonged neuromuscular blockade; decisions should be made after clinical examination and by using either TOF monitoring or drug holidays, with the goal of avoiding elevated NMBA concentrations in order to decrease ICU morbidity, measured as increased ventilator days, ICU length of stay, and myopathy.
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