Train-of-Four To Monitor Neuromuscular Blockade?
2004; Elsevier BV; Volume: 126; Issue: 4 Linguagem: Inglês
10.1378/chest.126.4.1018
ISSN1931-3543
Autores Tópico(s)Healthcare Decision-Making and Restraints
ResumoICU-acquired weakness is an unfortunately common and serious occurrence among critically ill patients.1Murray MJ Cowen J DeBlock H et al.Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient.Crit Care Med. 2002; 30: 142-156Crossref PubMed Scopus (260) Google Scholar2Gehr LC Sessler CN Neuromuscular blockade in the Intensive Care Unit.Semin Respir Crit Care Med. 2001; 22: 175-188Crossref PubMed Scopus (13) Google Scholar3Deem S Lee CM Curtis JR Acquired neuromuscular disorders in the intensive care unit.Am J Respir Crit Care Med. 2003; 168: 735-739Crossref PubMed Scopus (73) Google Scholar4De Jonghe B Sharshar T Lefaucheur JP et al.Paresis acquired in the intensive care unit: a prospective multicenter study.JAMA. 2002; 288: 2859-2867Crossref PubMed Scopus (1073) Google Scholar5Fletcher SN Kennedy DD Ghosh IR et al.Persistent neuromuscular and neurophysiologic abnormalities in long-term survivors of prolonged critical illness.Crit Care Med. 2003; 31: 1012-1016Crossref PubMed Scopus (323) Google Scholar6Rudis MI Guslits BJ Peterson EL et al.Economic impact of prolonged motor weakness complicating neuromuscular blockade in the intensive care unit.Crit Care Med. 1996; 24: 1749-1756Crossref PubMed Scopus (87) Google Scholar ICU-acquired weakness has multiple causes1Murray MJ Cowen J DeBlock H et al.Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient.Crit Care Med. 2002; 30: 142-156Crossref PubMed Scopus (260) Google Scholar but is generally attributed to the following three conditions: ICU-acquired polyneuropathy; ICU-acquired myopathy; and prolonged neuromuscular blockade.3Deem S Lee CM Curtis JR Acquired neuromuscular disorders in the intensive care unit.Am J Respir Crit Care Med. 2003; 168: 735-739Crossref PubMed Scopus (73) Google Scholar The latter two conditions may be attributable to the use of neuromuscular blocking agents (NMBAs). Monitoring of the depth and duration of chemical paralysis is important to optimize neuromuscular blockade for each individual patient and to avoid complications of therapy.1Murray MJ Cowen J DeBlock H et al.Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient.Crit Care Med. 2002; 30: 142-156Crossref PubMed Scopus (260) Google Scholar2Gehr LC Sessler CN Neuromuscular blockade in the Intensive Care Unit.Semin Respir Crit Care Med. 2001; 22: 175-188Crossref PubMed Scopus (13) Google Scholar7Sladen RN Neuromuscular blocking agents in the intensive care unit: a two-edged sword.Crit Care Med. 1995; 23: 423-428Crossref PubMed Scopus (36) Google Scholar In a 2002 clinical practice guideline,1Murray MJ Cowen J DeBlock H et al.Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient.Crit Care Med. 2002; 30: 142-156Crossref PubMed Scopus (260) Google Scholar in previous guidelines,8Shapiro BA Warren J Egol AB et al.Practice parameters for sustained neuromuscular blockade in the adult critically ill patient: an executive summary: Society of Critical Care Medicine.Crit Care Med. 1995; 23: 1601-1605Crossref PubMed Scopus (103) Google Scholar and in other reviews,2Gehr LC Sessler CN Neuromuscular blockade in the Intensive Care Unit.Semin Respir Crit Care Med. 2001; 22: 175-188Crossref PubMed Scopus (13) Google Scholar3Deem S Lee CM Curtis JR Acquired neuromuscular disorders in the intensive care unit.Am J Respir Crit Care Med. 2003; 168: 735-739Crossref PubMed Scopus (73) Google Scholar7Sladen RN Neuromuscular blocking agents in the intensive care unit: a two-edged sword.Crit Care Med. 1995; 23: 423-428Crossref PubMed Scopus (36) Google Scholar the use of peripheral nerve stimulation testing by periodically evaluating the response to a “train-of-four” (TOF) stimulation is recommended, in combination with clinical assessment, for all patients receiving NMBAs. However, the added value of TOF monitoring has been critically examined in only a few controlled trials that directly compare TOF testing with clinical evaluation alone,9Rudis 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: 575-583Crossref PubMed Scopus (109) Google Scholar10Strange C Vaughan L Franklin C et al.Comparison of train-of-four and best clinical assessment during continuous paralysis.Am J Respir Crit Care Med. 1997; 156: 1556-1561Crossref PubMed Scopus (50) Google Scholar and these studies have arrived at contrasting conclusions. In this issue of CHEST (see page 1267), Baumann and colleagues report the results of a single-center randomized, controlled trial that prospectively compared the titration of cisatracurium by TOF monitoring to clinical evaluation alone. They found no difference in recovery time after the cessation of NMBA administration or in the total NMBA dosage given. No cases of ICU-acquired weakness were observed. They concluded that TOF testing is unnecessary when careful clinical assessment is performed, but they limit this recommendation to patients who are receiving the agent they used, cisatracurium, and a related agent, atracurium. The evaluation of neuromuscular blockade begins with the indication for therapeutic paralysis and the desired level of muscle relaxation. Although common indications include the control of intracranial pressure, the control of muscle spasm, the control of intractable agitation, and the reduction in oxygen consumption, the majority of patients, including those in the study by Baumann et al, receive NMBAs to optimize patient-ventilator synchrony1Murray MJ Cowen J DeBlock H et al.Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient.Crit Care Med. 2002; 30: 142-156Crossref PubMed Scopus (260) Google Scholar9Rudis 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: 575-583Crossref PubMed Scopus (109) Google Scholar10Strange C Vaughan L Franklin C et al.Comparison of train-of-four and best clinical assessment during continuous paralysis.Am J Respir Crit Care Med. 1997; 156: 1556-1561Crossref PubMed Scopus (50) Google Scholar and potentially to improve oxygenation.11Gainnier M Roch A Forel JM et al.Effect of neuromuscular blocking agents on gas exchange in patients presenting with acute respiratory distress syndrome.Crit Care Med. 2004; 32: 113-119Crossref PubMed Scopus (239) Google Scholar The depth of neuromuscular blockade that is necessary to achieve the desired clinical goals, which range from synchronous respiration, to apnea, or even complete paralysis, varies considerably. The goals of monitoring include measures of effectiveness (ie, how well we are achieving our clinical goals), as well as safety (ie, whether we are avoiding overdosage), and otherwise reducing the likelihood of prolonged neuromuscular blockade and/or ICU-acquired myopathy. Although both the clinical assessment and measurement of the TOF are routinely utilized, survey data from 10 to 15 years ago indicated the use of TOF monitoring in only 8.3 to 41% of ICUs.12Appadu BL Greiff JM Thompson JP Postal survey on the long-term use of neuromuscular block in the intensive care.Intensive Care Med. 1996; 22: 862-866Crossref PubMed Scopus (22) Google Scholar13Hansen-Flaschen JH Brazinsky S Basile C et al.Use of sedating drugs and neuromuscular blocking agents in patients requiring mechanical ventilation for respiratory failure: a national survey.JAMA. 1991; 266: 2870-2875Crossref PubMed Scopus (292) Google Scholar14Kleinpell R Bedrosian C McCormick L et al.Use of peripheral nerve stimulators to monitor patients with neuromuscular blockade in the ICU.Am J Crit Care. 1996; 5: 449-454PubMed Google Scholar All patients who receive NMBAs should undergo periodic clinical assessment,1Murray MJ Cowen J DeBlock H et al.Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient.Crit Care Med. 2002; 30: 142-156Crossref PubMed Scopus (260) Google Scholar but what exactly is meant by this term? Experts consider the observation of skeletal muscle movement and respiratory effort as the foundation of clinical assessment.1Murray MJ Cowen J DeBlock H et al.Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient.Crit Care Med. 2002; 30: 142-156Crossref PubMed Scopus (260) Google Scholar Clinical evaluation could more precisely focus on the assessment of the adequacy of muscle relaxation to achieve specific goals (ie, the observation of synchronous breathing, apnea, or absence of movement) as measures of efficacy. In the study by Baumann et al, clinical assessment consisted of evaluating patient-ventilator dyssynchrony, including “bucking” the ventilator or high peak airway pressures, which prompted the increasing of the NMBA dosage. Apnea was not the goal except in patients undergoing inverse ratio ventilation, and the frequency of the use of this modality was not stated. In other prospective studies that were designed to compare clinical assessment to TOF, Strange et al10Strange C Vaughan L Franklin C et al.Comparison of train-of-four and best clinical assessment during continuous paralysis.Am J Respir Crit Care Med. 1997; 156: 1556-1561Crossref PubMed Scopus (50) Google Scholar considered “best clinical assessment” to be ventilator synchrony and the absence of clinical movement, and Rudis and colleagues9Rudis 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: 575-583Crossref PubMed Scopus (109) Google Scholar considered “clinical efficacy” to be the absence of movement or spontaneous breathing. Since deep tendon reflexes (DTRs) disappear as 100% blockade is achieved,15Tavernier B Rannou JJ Vallet B Peripheral nerve stimulation and clinical assessment for dosing of neuromuscular blocking agents in critically ill patients.Crit Care Med. 1998; 26: 804-805Crossref PubMed Scopus (7) Google Scholar the routine testing of DTRs could be incorporated into the clinical evaluation. Clinical assessment also might include specific dose-reduction titration strategies. For example, Strange et al10Strange C Vaughan L Franklin C et al.Comparison of train-of-four and best clinical assessment during continuous paralysis.Am J Respir Crit Care Med. 1997; 156: 1556-1561Crossref PubMed Scopus (50) Google Scholar mandated that at least once every 12 h the atracurium infusion rate be reduced to allow patient movement, after which patients were maintained in a slightly higher state of paralysis. Rudis and colleagues9Rudis 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: 575-583Crossref PubMed Scopus (109) Google Scholar required titration to the minimum effective dose by decreasing the vecuronium infusion rate every 2 to 3 h until the patient was breathing above the preset ventilatory rate, then increasing the infusion by 0.02 mg/kg/h. Baumann et al did not specify a strategy, per se. None of these studies9Rudis 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: 575-583Crossref PubMed Scopus (109) Google Scholar10Strange C Vaughan L Franklin C et al.Comparison of train-of-four and best clinical assessment during continuous paralysis.Am J Respir Crit Care Med. 1997; 156: 1556-1561Crossref PubMed Scopus (50) Google Scholar incorporated a formal “drug holiday” strategy in which the drug infusion was stopped daily. This technique permits the periodic evaluation of the neurologic status, reassessment of the ongoing need for neuromuscular blockade, and assessment of the adequacy of analgesia and sedation, and should reduce the accumulation of the drug and active metabolites. The use of daily NMBA interruption has been recommended in some guidelines and reviews,1Murray MJ Cowen J DeBlock H et al.Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient.Crit Care Med. 2002; 30: 142-156Crossref PubMed Scopus (260) Google Scholar2Gehr LC Sessler CN Neuromuscular blockade in the Intensive Care Unit.Semin Respir Crit Care Med. 2001; 22: 175-188Crossref PubMed Scopus (13) Google Scholar3Deem S Lee CM Curtis JR Acquired neuromuscular disorders in the intensive care unit.Am J Respir Crit Care Med. 2003; 168: 735-739Crossref PubMed Scopus (73) Google Scholar but is based solely on expert opinion. There are numerous techniques that are designed to test the depth of neuromuscular blockade using peripheral nerve stimulation; however, the TOF approach is considered to be the easiest and most reliable method for the ICU setting.1Murray MJ Cowen J DeBlock H et al.Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient.Crit Care Med. 2002; 30: 142-156Crossref PubMed Scopus (260) Google Scholar Four equal electrical charges are delivered every 0.5 s from the nerve stimulator device that is attached to leads overlying a superficial nerve, usually the ulnar or facial nerve, and the contraction of the innervated muscle (ie, the adductor pollicis or obicularis occuli muscle, respectively) is graded subjectively by palpation or observation. Guidelines1Murray MJ Cowen J DeBlock H et al.Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient.Crit Care Med. 2002; 30: 142-156Crossref PubMed Scopus (260) Google Scholar support the titration of NMBAs, so that one to two of four twitches are present, as Baumann and coworkers did. What is the evidence that TOF testing improves outcomes? Investigators have reported16Mascia MF Koch M Medicis JJ Pharmacoeconomic impact of rational use guidelines on the provision of analgesia, sedation, and neuromuscular blockade in critical care.Crit Care Med. 2000; 28: 2300-2306Crossref PubMed Scopus (129) Google Scholar17Frankel H Jeng J Tilly E et al.The impact of implementation of neuromuscular blockade monitoring standards in a surgical intensive care unit.Am Surg. 1996; 62: 503-506PubMed Google Scholar that the implementation of practice guidelines that include the routine measurement of TOF is associated with fewer episodes of prolonged weakness compared to the baseline period. However, three prospective trials have provide the best evidence.9Rudis 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: 575-583Crossref PubMed Scopus (109) Google Scholar10Strange C Vaughan L Franklin C et al.Comparison of train-of-four and best clinical assessment during continuous paralysis.Am J Respir Crit Care Med. 1997; 156: 1556-1561Crossref PubMed Scopus (50) Google Scholar Rudis and colleagues9Rudis 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: 575-583Crossref PubMed Scopus (109) Google Scholar randomly assigned 77 patients who received vecuronium by continuous infusion to TOF monitoring (goal, one of four twitches) or clinical assessment. Patients assigned to TOF testing required less vecuronium, had more rapid recovery to four of four twitches and to spontaneous breathing, and had fewer episodes of “delayed recovery” (ie, defined as > 4 h from drug discontinuation to four of four twitches) after an infusion averaging 50-h duration. They noted that renal dysfunction, which was present in 20% of patients, was strongly predictive of slower clinical recovery. Four of the 42 patients (TOF group, 1 patient; control group, 3 patients) who underwent thorough neurologic examinations before and after receiving vecuronium had prolonged weakness lasting until death, which was likely due to acute myopathy, or hospital discharge.9Rudis 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: 575-583Crossref PubMed Scopus (109) Google Scholar The authors subsequently estimated a cost savings of $738 per vecuronium-treated patient with TOF testing.18Zarowitz 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: 327-332PubMed Google Scholar In a prospective, but nonrandomized study of 36 patients who received continuous atracurium, Strange et al10Strange C Vaughan L Franklin C et al.Comparison of train-of-four and best clinical assessment during continuous paralysis.Am J Respir Crit Care Med. 1997; 156: 1556-1561Crossref PubMed Scopus (50) Google Scholar found no difference in the total dosage or recovery time between the TOF testing group (goal, three of four twitches) and the clinical evaluation group. Recovery time averaged < 1 h in both groups despite an average of 125 h of atracurium infusion. No episodes of prolonged weakness or myopathy were observed. Finally, Baumann and colleagues randomized 30 patients who received continuous cisatracurium to undergo TOF testing (goal, one to two twitches) or clinical evaluation, demonstrating no difference in total dosage or recovery time. Recovery times averaged < 1 h despite an average of 61 h of cisatracurium infusion, and no episodes of prolonged paralysis (ie, fewer than four of four twitches at 3 h after infusion cessation) or acute myopathy were reported. How does one reconcile the different results from these prospective trials? Although some differences in study design, target TOF, clinical dosing, and evaluation are apparent, the most likely explanation lies with the NMBA tested. The benzylisoquinolinium agents, atracurium and cisatracurium, are metabolized by Hofmann degradation, an end-organ-independent process, to inactive metabolites. Prospective clinical trials19Pearson AJ Harper NJ Pollard BJ The infusion requirements and recovery characteristics of cisatracurium or atracurium in intensive care patients.Intensive Care Med. 1996; 22: 694-698Crossref PubMed Scopus (24) Google Scholar20Newman PJ Quinn AC Grounds RM et al.A comparison of cisatracurium (51W89) and atracurium by infusion in critically ill patients.Crit Care Med. 1997; 25: 1139-1142Crossref PubMed Scopus (33) Google Scholar21Prielipp RC Coursin DB Scuderi PE et al.Comparison of the infusion requirements and recovery profiles of vecuronium and cisatracurium 51W89 in intensive care unit patients.Anesth Analg. 1995; 81: 3-12PubMed Google Scholar22Lagneau F D'Honneur G Plaud B et al.A comparison of two depths of prolonged neuromuscular blockade induced by cisatracurium in mechanically ventilated critically ill patients.Intensive Care Med. 2002; 28: 1735-1741Crossref PubMed Scopus (47) Google Scholar for the use of atracurium and cisatracurium in ICU patients have documented mean recovery times to 70% TOF (ie, the amplitude of fourth twitch > 70% of amplitude of first twitch [a standard marker of recovery in research]) of 46 to 57 min and 45 to 75 min, respectively. Interestingly, even when intentionally dosed to achieve zero of four twitches, the recovery time for cisatracurium averaged only 75 min despite the administration of 50% higher doses than those used to achieve a goal of two of four twitches.22Lagneau F D'Honneur G Plaud B et al.A comparison of two depths of prolonged neuromuscular blockade induced by cisatracurium in mechanically ventilated critically ill patients.Intensive Care Med. 2002; 28: 1735-1741Crossref PubMed Scopus (47) Google Scholar By contrast, in a randomized, controlled trial of vecuronium vs cisatracurium, 70% TOF averaged 387 min with vecuronium, vs 68 min for cisatracurium, and delayed recovery (ie, > 2 h) was observed in 13 of 30 vecuronium-infused patients vs only 2 of 22 cisatracurium-infused patients.21Prielipp RC Coursin DB Scuderi PE et al.Comparison of the infusion requirements and recovery profiles of vecuronium and cisatracurium 51W89 in intensive care unit patients.Anesth Analg. 1995; 81: 3-12PubMed Google Scholar It is noteworthy that delayed recovery occurred despite the titration of vecuronium to a TOF of ≥ 1.21Prielipp RC Coursin DB Scuderi PE et al.Comparison of the infusion requirements and recovery profiles of vecuronium and cisatracurium 51W89 in intensive care unit patients.Anesth Analg. 1995; 81: 3-12PubMed Google Scholar Prolonged neuromuscular blockade with vecuronium has been well-described.23Segredo V Caldwell JE Matthay MA et al.Persistent paralysis in critically ill patients after long-term administration of vecuronium.N Engl J Med. 1992; 327: 524-528Crossref PubMed Scopus (436) Google Scholar24Watling SM Dasta JF Prolonged paralysis in intensive care unit patients after the use of neuromuscular blocking agents: a review of the literature.Crit Care Med. 1994; 22: 884-893Crossref PubMed Scopus (139) Google Scholar25Hansen-Flaschen J Cowen J Raps EC Neuromuscular blockade in the intensive care unit: more than we bargained for.Am Rev Respir Dis. 1993; 147: 234-236Crossref PubMed Scopus (165) Google Scholar Vecuronium is an aminosteroid, related to pancuronium, that undergoes hepatic hydrolysis to three metabolites, of which 3-desacetyl-vecuronium is estimated to be 50 to 80% as active as the parent compound and accumulates in patients experiencing renal failure.1Murray MJ Cowen J DeBlock H et al.Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient.Crit Care Med. 2002; 30: 142-156Crossref PubMed Scopus (260) Google Scholar26Caldwell JE Szenohradszky J Segredo V et al.The pharmacodynamics and pharmacokinetics of the metabolite 3-desacetylvecuronium (ORG 7268) and its parent compound, vecuronium, in human volunteers.J Pharmacol Exp Ther. 1994; 270: 1216-1222PubMed Google Scholar Segredo et al23Segredo V Caldwell JE Matthay MA et al.Persistent paralysis in critically ill patients after long-term administration of vecuronium.N Engl J Med. 1992; 327: 524-528Crossref PubMed Scopus (436) Google Scholar previously documented a strong relationship between plasma 3-desacetylvecuronium levels and prolonged neuromuscular blockade and/or myopathy. Additionally, up to 35% of a vecuronium dose is renally excreted, 50% is excreted in bile,1Murray MJ Cowen J DeBlock H et al.Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient.Crit Care Med. 2002; 30: 142-156Crossref PubMed Scopus (260) Google Scholar and drug clearance changes in an unpredictable fashion during prolonged infusion.27Segredo V Caldwell JE Wright PM et al.Do the pharmacokinetics of vecuronium change during prolonged administration in critically ill patients?.Br J Anaesth. 1998; 80: 715-719Crossref PubMed Scopus (19) Google Scholar A correlation between prolonged neuromuscular blockade and renal insufficiency has been documented in many studies,9Rudis 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: 575-583Crossref PubMed Scopus (109) Google Scholar17Frankel H Jeng J Tilly E et al.The impact of implementation of neuromuscular blockade monitoring standards in a surgical intensive care unit.Am Surg. 1996; 62: 503-506PubMed Google Scholar23Segredo V Caldwell JE Matthay MA et al.Persistent paralysis in critically ill patients after long-term administration of vecuronium.N Engl J Med. 1992; 327: 524-528Crossref PubMed Scopus (436) Google Scholar but not all.21Prielipp RC Coursin DB Scuderi PE et al.Comparison of the infusion requirements and recovery profiles of vecuronium and cisatracurium 51W89 in intensive care unit patients.Anesth Analg. 1995; 81: 3-12PubMed Google Scholar Accordingly, the current recommendations support using atracurium or cisatracurium instead of vecuronium or pancuronium in patients who have renal or hepatic dysfunction.1Murray MJ Cowen J DeBlock H et al.Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient.Crit Care Med. 2002; 30: 142-156Crossref PubMed Scopus (260) Google Scholar2Gehr LC Sessler CN Neuromuscular blockade in the Intensive Care Unit.Semin Respir Crit Care Med. 2001; 22: 175-188Crossref PubMed Scopus (13) Google Scholar Acute quadriplegic myopathy syndrome (AQMS) is a devastating cause of ICU-acquired weakness that has been attributed to the prolonged use of NMBAs, usually in the setting of concomitant corticosteroid administration.1Murray MJ Cowen J DeBlock H et al.Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient.Crit Care Med. 2002; 30: 142-156Crossref PubMed Scopus (260) Google Scholar2Gehr LC Sessler CN Neuromuscular blockade in the Intensive Care Unit.Semin Respir Crit Care Med. 2001; 22: 175-188Crossref PubMed Scopus (13) Google Scholar3Deem S Lee CM Curtis JR Acquired neuromuscular disorders in the intensive care unit.Am J Respir Crit Care Med. 2003; 168: 735-739Crossref PubMed Scopus (73) Google Scholar6Rudis MI Guslits BJ Peterson EL et al.Economic impact of prolonged motor weakness complicating neuromuscular blockade in the intensive care unit.Crit Care Med. 1996; 24: 1749-1756Crossref PubMed Scopus (87) Google Scholar24Watling SM Dasta JF Prolonged paralysis in intensive care unit patients after the use of neuromuscular blocking agents: a review of the literature.Crit Care Med. 1994; 22: 884-893Crossref PubMed Scopus (139) Google Scholar28Leatherman JW Fluegel WL David WS et al.Muscle weakness in mechanically ventilated patients with severe asthma.Am J Respir Crit Care Med. 1996; 153: 1686-1690Crossref PubMed Scopus (217) Google Scholar AQMS is characterized by prolonged weakness of the limb and trunk muscles with sparing of the extraocular musculature. Abnormal compound motor action potentials but generally intact sensory nerve conduction is found on testing.29David WS Roehr CL Leatherman JW EMG findings in acute myopathy with status asthmaticus, steroids and paralytics: clinical and electrophysiologic correlation.Electromyogr Clin Neurophysiol. 1998; 38: 371-376PubMed Google Scholar There is evidence for the following two mechanisms as its cause: (1) widespread myonecrosis that may result in elevated serum creatine phosphokinase levels30Fischer JR Baer RK Acute myopathy associated with combined use of corticosteroids and neuromuscular blocking agents.Ann Pharmacother. 1996; 30: 1437-1445Crossref PubMed Scopus (34) Google Scholar31Douglass JA Tuxen DV Horne M et al.Myopathy in severe asthma.Am Rev Respir Dis. 1992; 146: 517-519Crossref PubMed Scopus (268) Google Scholar; and (2) selective myosin loss that is accompanied by marked reductions in myosin messenger RNA.32Larsson L Li X Edstrom L et al.Acute quadriplegia and loss of muscle myosin in patients treated with nondepolarizing neuromuscular blocking agents and corticosteroids: mechanisms at the cellular and molecular levels.Crit Care Med. 2000; 28: 34-45Crossref PubMed Scopus (199) Google Scholar Originally reported to occur with the aminosteroid agents pancuronium and vecuronium,30Fischer JR Baer RK Acute myopathy associated with combined use of corticosteroids and neuromuscular blocking agents.Ann Pharmacother. 1996; 30: 1437-1445Crossref PubMed Scopus (34) Google Scholar32Larsson L Li X Edstrom L et al.Acute quadriplegia and loss of muscle myosin in patients treated with nondepolarizing neuromuscular blocking agents and corticosteroids: mechanisms at the cellular and molecular levels.Crit Care Med. 2000; 28: 34-45Crossref PubMed Scopus (199) Google Scholar33Giostra E Magistris MR Pizzolato G et al.Neuromuscular disorder in intensive care unit patients treated with pancuronium bromide: occurrence in a cluster group of seven patients and two sporadic cases, with electrophysiologic and histologic examination.Chest. 1994; 106: 210-220Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar an association with benzylisoquinolinium agents also has been reported in case reports.28Leatherman JW Fluegel WL David WS et al.Muscle weakness in mechanically ventilated patients with severe asthma.Am J Respir Crit Care Med. 1996; 153: 1686-1690Crossref PubMed Scopus (217) Google Scholar32Larsson L Li X Edstrom L et al.Acute quadriplegia and loss of muscle myosin in patients treated with nondepolarizing neuromuscular blocking agents and corticosteroids: mechanisms at the cellular and molecular levels.Crit Care Med. 2000; 28: 34-45Crossref PubMed Scopus (199) Google Scholar34Davis NA Rodgers JE Gonzalez ER et al.Prolonged weakness after cisatracurium infusion: a case report.Crit Care Med. 1998; 26: 1290-1292Crossref PubMed Scopus (45) Google Scholar35Marik PE Doxacurium-corticosteroid acute myopathy: another piece to the puzzle.Crit Care Med. 1996; 24: 1266-1267Crossref PubMed Scopus (24) Google Scholar Interestingly, in a number of controlled trials AQMS was not reported following atracurium or cisatracurium infusion in > 200 cases, compared to 5 of 107 cases of vecuronium-infused patients.9Rudis 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: 575-583Crossref PubMed Scopus (109) Google Scholar10Strange C Vaughan L Franklin C et al.Comparison of train-of-four and best clinical assessment during continuous paralysis.Am J Respir Crit Care Med. 1997; 156: 1556-1561Crossref PubMed Scopus (50) Google Scholar19Pearson AJ Harper NJ Pollard BJ The infusion requirements and recovery characteristics of cisatracurium or atracurium in intensive care patients.Intensive Care Med. 1996; 22: 694-698Crossref PubMed Scopus (24) Google Scholar20Newman PJ Quinn AC Grounds RM et al.A comparison of cisatracurium (51W89) and atracurium by infusion in critically ill patients.Crit Care Med. 1997; 25: 1139-1142Crossref PubMed Scopus (33) Google Scholar21Prielipp RC Coursin DB Scuderi PE et al.Comparison of the infusion requirements and recovery profiles of vecuronium and cisatracurium 51W89 in intensive care unit patients.Anesth Analg. 1995; 81: 3-12PubMed Google Scholar22Lagneau F D'Honneur G Plaud B et al.A comparison of two depths of prolonged neuromuscular blockade induced by cisatracurium in mechanically ventilated critically ill patients.Intensive Care Med. 2002; 28: 1735-1741Crossref PubMed Scopus (47) Google Scholar It appears that the avoidance of overdose using TOF-based drug titration is not protective since most of the more recently reported cases of AQMS developed despite TOF monitoring.9Rudis 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: 575-583Crossref PubMed Scopus (109) Google Scholar21Prielipp RC Coursin DB Scuderi PE et al.Comparison of the infusion requirements and recovery profiles of vecuronium and cisatracurium 51W89 in intensive care unit patients.Anesth Analg. 1995; 81: 3-12PubMed Google Scholar34Davis NA Rodgers JE Gonzalez ER et al.Prolonged weakness after cisatracurium infusion: a case report.Crit Care Med. 1998; 26: 1290-1292Crossref PubMed Scopus (45) Google Scholar35Marik PE Doxacurium-corticosteroid acute myopathy: another piece to the puzzle.Crit Care Med. 1996; 24: 1266-1267Crossref PubMed Scopus (24) Google Scholar There are potential technical and interpretative problems with TOF testing.1Murray MJ Cowen J DeBlock H et al.Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient.Crit Care Med. 2002; 30: 142-156Crossref PubMed Scopus (260) Google Scholar36Rudis MI Guslits BG Zarowitz BJ Technical and interpretive problems of peripheral nerve stimulation in monitoring neuromuscular blockade in the intensive care unit.Ann Pharmacother. 1996; 30: 165-172Crossref PubMed Scopus (29) Google Scholar The presence of perspiration or tissue edema can interfere with nerve stimulation, and direct muscle stimulation can misleadingly result in muscle contraction despite effective chemical blockade.36Rudis MI Guslits BG Zarowitz BJ Technical and interpretive problems of peripheral nerve stimulation in monitoring neuromuscular blockade in the intensive care unit.Ann Pharmacother. 1996; 30: 165-172Crossref PubMed Scopus (29) Google Scholar37Tschida SJ Hoey LL Mather D et al.Train-of-four: to use or not to use.Pharmacotherapy. 1995; 15: 546-550PubMed Google Scholar38Murray MJ Monitoring of peripheral nerve stimulation versus standard clinical assessment for dosing of neuromuscular blocking agents.Crit Care Med. 1997; 25: 561-562Crossref PubMed Scopus (8) Google Scholar Variations in management such as visual vs palpation assessment, and the use of facial vs ulnar nerve stimulation likely reduce the consistency of interpretation.39Lagneau F Benayoun L Plaud B et al.The interpretation of train-of-four monitoring in intensive care: what about the muscle site and the current intensity?.Intensive Care Med. 2001; 27: 1058-1063Crossref PubMed Scopus (16) Google Scholar Finally, thermal injury has been described.38Murray MJ Monitoring of peripheral nerve stimulation versus standard clinical assessment for dosing of neuromuscular blocking agents.Crit Care Med. 1997; 25: 561-562Crossref PubMed Scopus (8) Google Scholar The training of ICU nurses regarding TOF is widely performed,14Kleinpell R Bedrosian C McCormick L et al.Use of peripheral nerve stimulators to monitor patients with neuromuscular blockade in the ICU.Am J Crit Care. 1996; 5: 449-454PubMed Google Scholar and should improve the accuracy and reliability of testing. TOF testing requires additional time to perform,18Zarowitz 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: 327-332PubMed Google Scholar and may not be consistently performed, interpreted, and documented. Despite these limitations and limited evidence, TOF testing has achieved broad acceptance because of expert recommendation, its relative simplicity and low cost, its low risk, and its incorporation into successful strategies for managing neuromuscular blockade.1Murray MJ Cowen J DeBlock H et al.Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient.Crit Care Med. 2002; 30: 142-156Crossref PubMed Scopus (260) Google Scholar2Gehr LC Sessler CN Neuromuscular blockade in the Intensive Care Unit.Semin Respir Crit Care Med. 2001; 22: 175-188Crossref PubMed Scopus (13) Google Scholar3Deem S Lee CM Curtis JR Acquired neuromuscular disorders in the intensive care unit.Am J Respir Crit Care Med. 2003; 168: 735-739Crossref PubMed Scopus (73) Google Scholar6Rudis MI Guslits BJ Peterson EL et al.Economic impact of prolonged motor weakness complicating neuromuscular blockade in the intensive care unit.Crit Care Med. 1996; 24: 1749-1756Crossref PubMed Scopus (87) Google Scholar16Mascia MF Koch M Medicis JJ Pharmacoeconomic impact of rational use guidelines on the provision of analgesia, sedation, and neuromuscular blockade in critical care.Crit Care Med. 2000; 28: 2300-2306Crossref PubMed Scopus (129) Google Scholar17Frankel H Jeng J Tilly E et al.The impact of implementation of neuromuscular blockade monitoring standards in a surgical intensive care unit.Am Surg. 1996; 62: 503-506PubMed Google Scholar The simple numerical score enhances clarity and improves communication among caregivers. Thus, the removal of TOF testing from the box of ICU-monitoring tools, even for selected cases as suggested by Baumann and colleagues, requires careful consideration. Given the unreliable recovery profile of vecuronium,21Prielipp RC Coursin DB Scuderi PE et al.Comparison of the infusion requirements and recovery profiles of vecuronium and cisatracurium 51W89 in intensive care unit patients.Anesth Analg. 1995; 81: 3-12PubMed Google Scholar the use of TOF testing, in concert with clinical assessment, should improve dosing, shorten the recovery time, and reduce the likelihood of complications in this setting,9Rudis 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: 575-583Crossref PubMed Scopus (109) Google Scholar and is thus recommended. In contrast, the added value of TOF testing to clinical assessment during atracurium or cisatracurium blockade is unproven for preventing delayed recovery or AQMS, or even for reducing the dosage of drug administered.10Strange C Vaughan L Franklin C et al.Comparison of train-of-four and best clinical assessment during continuous paralysis.Am J Respir Crit Care Med. 1997; 156: 1556-1561Crossref PubMed Scopus (50) Google Scholar It is likely, however, that TOF testing would allow more precise dosing, even for atracurium and cisatracurium, when deep neuromuscular blockade (ie, for apnea or complete paralysis) is performed and clinical assessment is less reliable.22Lagneau F D'Honneur G Plaud B et al.A comparison of two depths of prolonged neuromuscular blockade induced by cisatracurium in mechanically ventilated critically ill patients.Intensive Care Med. 2002; 28: 1735-1741Crossref PubMed Scopus (47) Google Scholar Reliance on clinical assessment alone would highlight some practical issues. As noted above, there is considerable variability and subjectivity in performing, interpreting, and documenting a periodic clinical assessment, and thus standardization of the evaluation among caregivers would be important. Simplicity and clarity of documentation, similar to that for TOF testing, also would be useful. Finally, it would be important to confirm that the elimination of TOF testing, as an additional safety measure, did not inadvertently reduce the vigilance with which these critically ill and complex patients are monitored. Recommendations for the administration of NMBAs to ICU patients are offered in Table 1, recognizing that many are based primarily on expert opinion or limited data.1Murray MJ Cowen J DeBlock H et al.Clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient.Crit Care Med. 2002; 30: 142-156Crossref PubMed Scopus (260) Google Scholar2Gehr LC Sessler CN Neuromuscular blockade in the Intensive Care Unit.Semin Respir Crit Care Med. 2001; 22: 175-188Crossref PubMed Scopus (13) Google Scholar Baumann and colleagues are to be commended for challenging the status quo with their well-done prospective study. Further research is needed to optimize our use of these valuable but potentially hazardous drugs, and to develop strategies to prevent AQMS and/or recognize it an early stage.Table 1Recommendations for Administration of NMBAs to ICU Patients*DVT = deep venous thrombosis. Modified from Gehr and Sessler,2 with permission.1. Develop, utilize, and document a standardized approach for administering and monitoring NMBA2. Use NMBA only after optimizing ventilator settings and sedative and analgesic medication administration3. Establish the indications and clinical goals of neuromuscular blockade, and evaluate at least daily4. Select the best NMBA based upon patient characteristics: A. Use intermittent NMBA therapy with pancuronium, doxacurium, or other suitable agent if clinical goals can be met B. If continuous infusion is required and renal or hepatic dysfunction is present, select atracurium or cisatracurium, and avoid vecuronium5. Use the lowest effective dose for the shortest possible time (< 48 h if possible), particularly if corticosteroids are concomitantly administered6. Administer adequate analgesic and/or sedative medication during neuromuscular blockade, and monitor clinically or by bispectral array EEG7. Systematically anticipate and prevent complications, including provision of eye care, careful positioning, physical therapy, and DVT prophylaxis8. Avoid the use of medications that affect NMBA actions. Promptly recognize and manage conditions that affect NMBA actions9. Adjust NMBA dosage to achieve clinical goals (ie, patient-ventilator synchrony, apnea, or complete paralysis)10. Periodically (ie, at least once or twice daily) perform NMBA dosage reduction, and preferably cessation (drug holiday) if clinically tolerated, to determine whether neuromuscular blockade is still needed, and to perform physical and neurologic examination11. Periodically perform and document a clinical assessment in which spontaneous respiration as well as limb movement and/or the presence of DTRs are observed during steady-state infusion and/or during dosage reduction/cessation. With deep blockade, muscle activity may be present only during dosage reduction/cessation12. Perform and document scheduled (ie, every 4–8 h) TOF testing for patients receiving vecuronium NMBA and/or undergoing deep neuromuscular blockade (ie, apnea or complete paralysis), and adjust dosage to achieve ≥ 1/4 twitches. If clinical goals cannot be met when ≥ 1/4 twitches are present during steady-state infusion, demonstrate ≥ 1/4 twitches during dosage reduction/cessation. Consider TOF testing in all patients* DVT = deep venous thrombosis. Modified from Gehr and Sessler,2Gehr LC Sessler CN Neuromuscular blockade in the Intensive Care Unit.Semin Respir Crit Care Med. 2001; 22: 175-188Crossref PubMed Scopus (13) Google Scholar with permission. Open table in a new tab Download .doc (.04 MB) Help with doc files Supplementary appendix
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