Consensus guidelines for sustained neuromuscular blockade in critically ill children

Transcription

1 Pediatric Anesthesia : doi: /j x Consensus guidelines for sustained neuromuscular blockade in critically ill children STEPHEN PLAYFOR, IAN JENKINS, CAROLYNE BOYLES, IMTI CHOONARA, GERALD DAVIES, TIM HAYWOOD, GILLIAN HINSON, ANTON MAYER, NEIL MORTON, TANYA RALPH, ANDREW WOLF, UNITED KINGDOM PAEDIATRIC INTENSIVE CARE SOCIETY SEDATION, ANALGESIA AND NEUROMUSCULAR BLOCKADE WORKING GROUP Paediatric Intensive Care Unit, Royal Manchester Children s Hospital, Pendlebury, Manchester, UK Summary Background: The United Kingdom Paediatric Intensive Care Society Sedation, Analgesia and Neuromuscular Blockade Working Group is a multidisciplinary expert panel created to produce consensus guidelines on sedation, analgesia and neuromuscular blockade in critically ill children and forward knowledge in these areas. Neuromuscular blockade is recognized as an important element in the care of the critically ill and adult clinical practice guidelines in this area have been available for several years. However, similar clinical practice guidelines have not previously been produced for the critically ill pediatric patient. Methods: A modified Delphi technique was employed to allow the Working Group to anonymously consider draft recommendations in up to three Delphi rounds with predetermined levels of agreement. This process was supported by a total of four consensus conferences and once consensus had been achieved, a systematic review of the available literature was carried out. Results: A set of consensus guidelines was produced including six key recommendations. An evaluation of the existing literature supporting these recommendations is provided. Conclusions: Multidisciplinary consensus guidelines for maintenance neuromuscular blockade in critically ill children (excluding neonates) have been successfully produced and are supported by levels of evidence. The Working Group has highlighted the paucity of high quality evidence in these important clinical areas and this emphasizes the need for further randomized clinical trials in this area. Keywords: clinical guidelines; neuromuscular blockade; paediatric intensive care Correspondence to: Dr Stephen D Playfor MD, Consultant Paediatric Intensivist, Paediatric Intensive Care Unit, Royal Manchester Children s Hospital, Hospital Road, Pendlebury, Manchester M27 4HA, UK ( stephen.playfor@cmmc.nhs.uk) Journal compilation Ó 2007 Blackwell Publishing Ltd 881

2 882 S. PLAYFOR ET AL. Introduction Clinical practice guidelines have been available for sustained neuromuscular blockade in adult patients from the Society of Critical Care Medicine and the American College of Critical Care Medicine since 1995; these have since been updated in association with the American Society of Health-System Pharmacists (1). However, such clinical practice guidelines have not previously been published in the field of pediatric critical care. One of the reasons for this is the paucity of prospective randomized trials in the area of neuromuscular blockade in critically ill children. When attempting to create clinical practice guidelines in areas where the published evidence is weak, a widely used approach is to employ a modified Delphi technique to obtain consensus among a group of experts and then to support these conclusions with a critical review of the available literature. The United Kingdom Paediatric Intensive Care Society s Sedation, Analgesia and Neuromuscular Blockade Working Group is a multidisciplinary group established under the auspices of the United Kingdom Paediatric Intensive Care Society with the aim of forwarding knowledge in these areas. The group has previously produced consensus guidelines for analgesia and sedation in critically ill children (2). The Working Group was made up of thirteen UK pediatric intensive care unit (PICU) personnel including physicians, pharmacists, and nursing staff. The consensus guidelines produced by the group (and summarized in Appendix 1) refer exclusively to the practice of sustained neuromuscular blockade in the PICU; neuromuscular blockade to facilitate tracheal intubation or other procedures is not addressed, nor is neonatal intensive care. Physiology of the neuromuscular junction Nerves extend from the brainstem (in the case of cranial nerves) or from the spinal cord to muscle cells. Signals are transmitted along axons, which are insulated with myelin, at conduction speeds of upto mæs )1. Within most mammalian muscles each muscle fiber has a single region of contact with the axon of the motor neurone supplying it. This specialist structure is the neuromuscular junction where transmission is chemical rather than electrical as is the case in the axon. The role of the neuromuscular junction is to facilitate transmission of the electrical impulse from the nerve terminal to the motor endplate of the muscle. This is achieved by the transmission of 60 nm vesicles containing acetylcholine across the nm synaptic cleft. Binding of two acetylcholine molecules to the a units of the acetylcholine receptor at the motor endplate produces a conformational change in the receptor resulting in the opening of a central pore, which stays open for between 1 10 ms. This in turn results in the influx of some 10 5 sodium ions, which increases the membrane potential from )90 mv to approximately 0 mv. At this point potassium channels open and allow the efflux of potassium ions. When the endplate potential at the motor endplate reaches a threshold value of around from )50 mv voltage-dependent sodium ion channels of the adjacent muscle membrane open and the initiation of an action potential occurs. This action potential is propagated throughout the muscle fiber and results in muscle contraction. Current practice The practice of sustained neuromuscular blockade in PICU has been declining over the last 25 years; Merriman found that 91% of British units used neuromuscular blocking agents frequently in 1981 (3), but the practice remains fairly common and is more frequently reported than in studies of critically ill adults. More recently Martin et al. showed that these agents are used for long-term neuromuscular blockade in 14 16% of ventilatory support days in PICU and also that these children have a high overall mortality rate of 18% (4). Studies have shown the most commonly used agents for sustained neuromuscular blockade are vecuronium, pancuronium or atracurium (5,6). A large, recent prospective observational study of 338 critically ill children in 20 UK PICUs showed substantial variation in practice, but that vecuronium was the most commonly used agent (7). Methods A modified Delphi technique was used by our group to develop consensus. This is a well-

3 CONSENSUS GUIDELINES FOR SUSTAINED NEUROMUSCULAR BLOCKADE 883 established process which follows a series of predefined steps beginning with the formation of a panel of experts. A series of recommendations was drafted at an initial consensus conference and sent to all participants who had the opportunity to anonymously indicate their agreement on a linear nine point scale anchored at each end by Score 1; Disagree strongly and Score 9; Agree strongly. Panel members had the opportunity to add comments in order to highlight any areas of ambiguity or suggestions for improvement. Consensus agreement was predefined as 90% agreement among the group (scores of 7, 8 or 9 on the linear scale) once the two most extreme responses for agreement disagreement had been excluded. Draft recommendations which did not achieve consensus on this first round were rewritten in the light of any suggestions received and recirculated among the group with feedback of the mean group scores to allow individuals to see how their opinion compared with the rest of the panel. This process was repeated for a predetermined maximum of three rounds after which any outstanding recommendations would be classed as not achieving consensus. Rewriting of recommendations was undertaken in a series of three consensus conferences. Advantages of the Delphi technique include the anonymity of participants preventing the bandwagon or halo effects, in which participants succumb to the opinions of a dominant personality, and that participants have the time to carefully consider their responses. In addition an extensive search of the available literature was performed for supporting evidence. Relevant published studies were identified through broad searches of the Cochrane, MEDLINE, EMBASE, CINAHL, ProQuest, and ZETOC databases. Reference sections of retrieved documents were examined as were abstracts from meetings of relevant UK professional associations. The literature was critically evaluated by two investigators (SP and GH) and ranged in quality from prospective randomized controlled trials to expert opinion. Levels of evidence were assessed (Table 1) and grades of recommendation assigned (Table 2) according to the strength and quality of the scientific evidence using the revised Scottish Intercollegiate Guidelines Network (SIGN) grading system (8). Table 1 Levels of evidence Level Description of evidence 1++ High quality meta analyses, systematic reviews of RCTs, or RCTs with a very low risk of bias 1+ Well conducted meta analyses, systematic reviews of RCTs, or RCTs with a low risk of bias 1) Meta analyses, systematic reviews of RCTs, or RCTs with a high risk of bias 2++ High quality systematic reviews of case control or cohort or studies High quality case control or cohort studies with a very low risk of confounding, bias, or chance and a high probability that the relationship is causal 2+ Well conducted case control or cohort studies with a low risk of confounding, bias, or chance and a moderate probability that the relationship is causal 2) Case control or cohort studies with a high risk of confounding, bias, or chance and a significant risk that the relationship is not causal 3 Nonanalytic studies, e.g. case reports, case series 4 Expert opinion Table 2 Grades of recommendation Grade Description of evidence A At least one meta analysis, systematic review, or RCT rated as 1++, and directly applicable to the target population; or A systematic review of RCTs or a body of evidence consisting principally of studies rated as 1+, directly applicable to the target population, and demonstrating overall consistency of results B A body of evidence including studies rated as 2++, directly applicable to the target population, and demonstrating overall consistency of results; or Extrapolated evidence from studies rated as 1++ or 1+ C A body of evidence including studies rated as 2+, directly applicable to the target population and demonstrating overall consistency of results; or Extrapolated evidence from studies rated as 2++ D Evidence level 3 or 4; or Extrapolated evidence from studies rated as 2+ Results and recommendations Of seven draft recommendations generated, four achieved consensus in the first Delphi round and two achieved consensus in the second Delphi round. The only draft recommendation not to achieve consensus related to the clinical indications for sustained neuromuscular blockade. Dosing information and prescribing notes for recommended analgesic and sedative agents are given in Table 3. To avoid excessive dosing in obese

4 884 S. PLAYFOR ET AL. Table 3 Recommended neuromuscular blocking agents Drug Dosing information Notes Pancuronium Intravenous bolus; lgækg )1 Ædose )1 Reduce dosage in neonates Given as required, usually 4 6 h Vagolysis causes tachycardia Vecuronium Intravenous bolus; lgækg )1 Ædose )1 Reduce dosage in neonates Intravenous infusion; lgækgæ )1 Æh )1 Little histamine release Few cardiovascular effects Rocuronium Intravenous bolus; 600 lgækg )1 Ædose )1 Rapid onset Intravenous infusion; lgækg )1 Æh )1 Few cardiovascular effects Atracurium Intravenous bolus; lgækg )1 Ædose )1 May cause cardiovascular effects due to histamine release Intravenous infusion; mgækg )1 Æh )1 Relatively safe in renal or hepatic failure Cisatracurium Intravenous bolus; 150 lg kg )1Æ dose )1 Little histamine release Intravenous infusion; lgækg )1 Æh )1 Few cardiovascular effects Higher doses may be required children, doses should be calculated according to ideal body weight. Sustained neuromuscular blockade There are many recognized indications for the sustained administration of neuromuscular blocking agents in critically ill children. These may include the prevention of patient-ventilator dyssynchrony during mechanical ventilation, particularly when employing less physiological techniques such as deliberate hypo- or hyperventilation, inverse ratio ventilation or high frequency oscillatory ventilation. Sustained neuromuscular blockade may be instituted in the management of specific medical conditions, such as raised intracranial pressure, pulmonary hypertension, tetanus, malignant hyperthermia, neuroleptic malignant syndrome, and in other patients undergoing induced hypothermia in order to prevent shivering. Occasionally, specific surgical repairs may need to be protected in the immediate postoperative period such as tracheal reconstruction, cricoid split procedures, and vascular anastamoses. Owing to the diversity of clinical practice the Working Group was unable to reach consensus on the issue of clinical indications for sustained neuromuscular blockade. The decision to administer sustained neuromuscular blockade must be arrived at after careful consideration of risk vs benefit in each individual case. Complications of neuromuscular blockade Prolonged immobility may result in muscle atrophy, joint contractures, pressure sores, pulmonary atelectasis with associated pneumonia and corneal drying with potentially permanent corneal damage. Several neuromuscular blocking agents can produce ganglion and vagal blockade and result in liberation of significant amounts of histamine. Together these can produce adverse cardiovascular effects such as hypotension, tachycardia or bradycardia particularly after bolus dosing. The development of tolerance following prolonged infusions of neuromuscular blocking agents has been well described and there may be crossresistance between different agents (9). One possible mechanism to explain this observation is the formation of acetylcholine receptors along the muscle fiber distant to the neuromuscular junction with an increasing proportion of neuromuscular blocking agent being bound at these extrajunctional sites and therefore being clinically ineffective. The development of extrajunctional acetylcholine receptors may be stimulated by both prolonged infusions of neuromuscular blocking agents, even at doses insufficient to cause paralysis (10), or by prolonged immobility even in the absence of drug therapy. Accurate neurological assessment is not possible during the administration of neuromuscular blocking agents. In the absence of electroencephalography, seizure activity may go unrecognized and accurate assessment of analgesia and sedation status is impossible. Neurophysiological monitoring, such as the bispectral index (BIS) has been advocated in this clinical setting but there is currently insufficient evidence to recommend its routine use in critically ill children receiving neuromuscular blocking agents (2,11).

5 CONSENSUS GUIDELINES FOR SUSTAINED NEUROMUSCULAR BLOCKADE 885 One of the most widely reported complications associated with the administration of neuromuscular blocking agents is that of critical illness polyneuropathy and myopathy (CIPNM). The administration of neuromuscular blocking agents may be an independent risk factor for the development of these complications in septic patients (12) although critically ill children may develop features of CIPNM without having received neuromuscular blocking agents. The use of neuromuscular blocking agents should be restricted to situations where the benefits outweigh the possible risks, doses of these agents should be minimized and ideally avoided altogether if a diagnosis of CIPNM is made (13). When it is judged safe to do so intermittent discontinuation of neuromuscular blocking agents allows for an accurate assessment of the level of analgesia and sedation, facilitates neurological examination of the patient and serves to reduce the total dose of agents being administered. Recommendations Ensure adequate analgesia and sedation before commencing neuromuscular blocking agents. (Grade of recommendation = D). The need for neuromuscular blocking agents should be regularly reviewed and they should be discontinued as soon as possible (Grade of recommendation = D). Whenever it is safe to do so, continuous infusions of neuromuscular blocking agents should be discontinued at least once every 24 h until spontaneous movement returns and the levels of analgesia and sedation can be assessed (Grade of recommendation = C). Commonly used neuromuscular blocking agents Pancuronium Pancuronium is a nondepolarizing neuromuscular blocking agent with a long duration of action. It may cause vagolysis and sympathomimetic effects which can result in tachycardia and hypertension. Vecuronium Vecuronium is a monotertiary, monoquaternary derivative of pancuronium that is slightly more potent than the parent compound. Although it does not have a rapid onset of action, vecuronium is notable for its relative lack of unwanted effects, even in high doses (14). The major route of elimination is hepatobiliary, and metabolites have some neuromuscular blocking activity; the renal excretion of these metabolites explains the accumulation that may be seen in patients with renal failure. Differences in the volume of distribution result in a longer duration of action in younger children. Rocuronium Rocuronium has the benefit of a rapid onset of action which is approximately half that of vecuronium. When used to provide sustained neuromuscular blockade rocuronium is reported to have minimal cardiovascular effects, although in high doses it may cause some vagolysis. In addition, owing to its rapid onset of action, rocuronium is a common choice for facilitating tracheal intubation in circumstances where a nondepolarizing neuromuscular blocking agent is indicated. It should be remembered however that neuromuscular blocking agents have differential effects on different muscle groups, and the onset of laryngeal adductor paralysis with rocuronium is significantly slower than with suxamethonium. Atracurium Atracurium, a bisquaternary tetrahydropapaverum derivative, is one of the benzylisoquinolinium family of drugs. It is not a pure drug and can form 10 different isomers; in the commercial preparation three isomers predominate: trans trans, cis trans, and cis cis. Single doses of atracurium have a relatively rapid onset of action and conditions suitable for tracheal intubation can usually be achieved within 90 s of the intravenous injection of lgækg )1, with an elimination half time of 21 min. The unique metabolism of atracurium gives this agent particular advantages as a neuromuscular blocking agent for prolonged use in the critically ill. The drug is broken down primarily by two purely chemical mechanisms; Hofman degradation (a nonenzymatic base-catalyzed reaction) and nonspecific ester hydrolysis via plasma cholinesterase. Although some organ uptake has been demonstrated and 10% of the drug is excreted in the urine, the effects of atracurium have not been shown to be prolonged in renal or hepatic failure. There is a strong correlation between rectal temperature and the offset time of atracurium; prolonged moderate

6 886 S. PLAYFOR ET AL. hypothermia has a very significant effect on the offset time of atracurium when given by infusion to critically ill children (15). Clearance of atracurium also tends to be faster in children than in adults. Cisatracurium Cisatracurium was introduced into clinical practice in 1996 and is the R-cis, R -cis isomer of atracurium. This agent has a similar profile to atracurium; being free from significant vagolytic or sympatholytic properties and with a slower onset of action but three to four times the potency of atracurium. Cisatracurium is therefore less likely to stimulate histamine release hepatic disease. It has been suggested that recovery of neuromuscular function after discontinuation of neuromuscular blocking drug infusion in infants and children is significantly faster with cisatracurium than vecuronium (16,17). Comparative studies There are no prospective, randomized, controlled trials demonstrating a long-term advantage to administering sustained neuromuscular blockade to critically ill children, and similarly no trials demonstrating an advantage of one particular agent over any other in this clinical setting. Vernon and Witte have demonstrated that sustained neuromuscular blockade reduced oxygen consumption and energy expenditure in critically ill children, but concluded that this effect is of only modest magnitude in patients who were already sedated (18). Recommendations Atracurium or vecuronium given by continuous infusion are the recommended agents for the majority of critically ill children requiring neuromuscular blockade. Intermittent doses of pancuronium may be considered. (Grade of recommendation = D) Monitoring of neuromuscular blockade Transcutaneous electrical stimulation of the ulnar nerve using train-of-four (TOF) pattern stimulation is the most commonly used objective method of monitoring the degree of neuromuscular blockade. Peripheral nerve stimulation can be difficult to perform, particularly in small children where it is easy to produce direct stimulation of muscle groups, and results may be variable depending on other factors including peripheral edema, hemodynamic status, hydration, acid base derangements and electrolyte disturbances. While there is no evidence that the routine use of TOF monitoring can reduce the incidence of prolonged weakness after neuromuscular blockade it is recommended practice in adult patients (1) where it has been demonstrated to reduce the total dose requirements for neuromuscular blocking agents, facilitate faster recovery of neuromuscular function and spontaneous ventilation (19), and allows cost savings (20). Recommendations Where continuous infusions are employed the degree of neuromuscular blockade being provided should be assessed at least once every 24 h with train-of-four monitoring. Administered doses of neuromuscular blocking agents should be titrated to provide the optimum level of neuromuscular blockade (Grade of recommendation = C). Conclusions This paper details the consensus clinical guidelines of a multi-disciplinary expert panel on the provision of sustained neuromuscular blockade in critically ill children. These recommendations were produced according to accepted consensus methodology but it should be noted that the quality of evidence available in the literature to support these recommendations is poor. There is a need for prospective, randomized, controlled trials in this clinical area. Conflict of interest None. Financial support None. References 1 Murray MJ, Fowen J, DeBlock H et al. Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient. Crit Care Med 2002; 30:

7 CONSENSUS GUIDELINES FOR SUSTAINED NEUROMUSCULAR BLOCKADE Playfor S, Jenkins I, Boyles C et al. Consensus guidelines on sedation and analgesia in critically ill children. Intensive Care Med 2006; 32: Merriman HM. The techniques used to sedate ventilated patients. Intensive Care Med 1981; 7: Martin LD, Bratton SL, Quint P et al. Prospective documentation of sedative, analgesic, and neuromuscular blocking agent use in infants and children in the intensive care unit: A multicenter perspective. Pediatr Crit Care Med 2001; 2: Rhoney DH, Murry KR. National survey on the use of sedatives and neuromuscular blocking agents in the pediatric intensive care unit. Pediatr Crit Care Med 2002; 3: Playfor SD, Thomas DA, Choonara I. Sedation and neuromuscular blockade in paediatric intensive care: a review of current practice in the UK. Paediatr Anaesth 2003; 13: Jenkins IA, Playfor S, Bevan C et al. Current United Kingdom sedation practice in pediatric intensive care. Pediatr Anesth 2007; 17: Harbour R, Miller J. A new system for grading recommendations in evidence based guidelines. BMJ 2001; 323: Fish DN, Singletary TJ. Cross-resistance to both atracuriumand vecuronium-induced neuromuscular blockade in a critically ill patient. Pharmacotherapy 1997; 17: Hogue CJ, Ward JM, Itani MS et al. Tolerance and upregulation of acetylcholine receptors following chronic infusion of d- tubocurarine. J Appl Physiol 1992; 72: Playfor SD. The use of bispectral index monitors in paediatric intensive care. Critical Care 2005; 9: Garnacho-Montero J, Madrazo-Osuna J, Garcia-Garmendia JL et al. Critical illness polyneuropathy: Risk factors and clinical consequences. A cohort study in septic patients. Intensive Care Med 2001; 27: Bolton CF. Neuromuscular manifestations of critical illness. Muscle Nerve 2005; 32: Fahey MR, Morris RB, Miller RD et al. Clinical pharmacology of ORG NC45 (NorcuronTM): a new non-depolarizing muscle relaxant. Anesthesiology 1981; 55: Playfor SD, Thomas DA, Choonara I. The effect of induced hypothermia on the duration of action of atracurium when given by infusion to critically ill children. Paediatr Anaesth 2000; 10: Burmester M, Mok Q. Randomised controlled trial comparing cisatracurium and vecuronium infusions in a paediatric intensive care unit. Intensive Care Med 2000; 31: Reich DL, Hollinger I, Harrington DJ. Comparison of cisatracurium and vecuronium by infusion in neonates and small infants after congenital heart surgery. Anesthesiology 2004; 101: Vernon DD, Witte MK. Effect of neuromuscular blockade on oxygen consumption and energy expenditure in sedated, mechanically ventilated children. Crit Care Med 2000; 28: Rudis MI, Sikora CA, Angus E et al. A prospective, randomized, controlled evaluation of peripheral nerve stimulation versus standard clinical dosing of neuromuscular blocking agents in critically ill patients. Crit Care Med 1997; 25: Zarowitz BJ, Rudis MI, Lai K et al. Retrospective pharmacoeconomic evaluation of dosing vecuronium by peripheral nerve stimulation versus standard clinical assessment in critically ill patients. Pharmacotherapy 1997; 17: Accepted 23 May 2007 Appendix 1. Summary of recommendations 1. Ensure adequate analgesia and sedation before commencing neuromuscular blocking agents (Grade of recommendation = D). 2. The need for neuromuscular blocking agents should be regularly reviewed and they should be discontinued as soon as possible (Grade of recommendation = D). 3. Whenever it is safe to do so, continuous infusions of neuromuscular blocking agents should be discontinued at least once every 24 h until spontaneous movement returns and the levels of analgesia and sedation can be assessed (Grade of recommendation = C). 4. Atracurium or vecuronium given by continuous infusion are the recommended agents for the majority of critically ill children requiring neuromuscular blockade. Intermittent doses of pancuronium may be considered (Grade of recommendation = D). 5. Where continuous infusions are employed the degree of neuromuscular blockade being provided should be assessed at least once every 24 h with train-of-four monitoring. Administered doses of neuromuscular blocking agents should be titrated to provide the optimum level of neuromuscular blockade (Grade of recommendation = C).