1579CHAPTER 131 Neuromuscular Blocking Agents commonly used by anesthesiologists in the operating room to monitor the degree of neuromuscular blockade, is peripheral nerve stimulation or TOF monitorin[.]
CHAPTER 131 Neuromuscular Blocking Agents commonly used by anesthesiologists in the operating room to monitor the degree of neuromuscular blockade, is peripheral nerve stimulation or TOF monitoring TOF monitoring involves placement of standard electrocardiographic electrodes over a peripheral nerve The nerves most commonly used are the facial, ulnar, or common peroneal, which result in corresponding movement in the muscles of the hand, face, or leg In some circumstances, direct stimulation of the muscle may occur, giving the false impression that an appropriate amount of neuromuscular blockade has not been achieved To avoid such problems, it may be appropriate to place the TOF monitor and assess the twitch response before the administration of the initial dose of the NMBA The electrodes of the TOF monitor are connected to a handheld peripheral nerve stimulator, which delivers two stimuli per second at 50 mA for seconds A total of four stimuli are administered over seconds—hence, the term train-of-four As this is painful, it should only be performed in patients who are anesthetized or sedated Depending on the number of acetylcholine receptors that are occupied by the nondepolarizing NMBA, there will be anywhere from zero to four responses or twitches Despite the availability of other more sophisticated machines to monitor the degree of neuromuscular blockade in the operating room and ICU setting, these monitors are generally used only for clinical research purposes In clinical practice in either the operating room or PICU, TOF monitoring remains the technique that provides the most useful information with limited requirements for training and equipment In clinical practice, the TOF monitoring is combined with clinical assessment at the end of the case to ensure that the patient is strong enough for tracheal extubation Following reversal of neuromuscular blockade, clinical assessment of strength is combined with neuromuscular monitoring These latter measures become necessary as residual weakness may be present despite apparent reversal using TOF monitoring Techniques of clinical assessment to evaluate the presence of residual neuromuscular blockade include measurement of negative inspiratory force (NIF) or maximum inspiratory pressure (MIP), hand grip, or head lift Although head lift and hand grip require the ability to follow a simple command, the measurement of NIF does not The technique involves measuring the inspiratory force that the patient can generate against an occluded airway The test can be completed with a simple manometer attached to the 15-mm adaptor of the endotracheal tube Initial studies suggested that an NIF of at least 220 cm H2O indicated sufficient muscle strength to maintain an adequate minute ventilation Subsequently, a value of 225 to 230 cm H2O became the generally accepted value for use in clinical practice However, subsequent work suggested that although strength was adequate to maintain minute ventilation, it may not be adequate to maintain upper airway patency Therefore, the use of voluntary responses (head lift for s or hand grip) was suggested as an adjunct to ensure adequate reversal of neuromuscular blockade In infants, reflex leg lift (both legs lifted off the operating room table) was shown to correlate with a mean NIF or MIP of 251 cm H2O Thus, the authors concluded that this was a sign of adequate reversal of neuromuscular blockade in infants.122 Given the variability of these responses and their correlation with reversal of neuromuscular blockade, the best clinical approach may be the use of several clinical maneuvers if TOF monitoring is not available The literature suggests that the ability to maintain a sustained head lift for seconds is the most sensitive clinical tool In the ICU setting, given the degree of neuromuscular blockade that is induced, voluntary measures of muscle strength are not 1579 adequate Therefore, titration of NMBAs should be guided by TOF monitoring The technique may allow the use of the lowest possible dose of agents and theoretically avoid complications such as prolonged blockade (see later discussion) In a prospective randomized trial in 77 adults, TOF monitoring (maintaining one twitch of the TOF) was compared with clinical parameters (patient breathing over the preset ventilator rate) as a means of titrating NMBAs.123 TOF monitoring resulted in a lower total dose and lower average infusion rate of vecuronium, as well as a more rapid recovery once the infusion was discontinued A subsequent study in adults revealed a decreased incidence of persistent neuromuscular weakness when using TOF monitoring.124 Although data are lacking to clearly demonstrate the superiority of TOF monitoring in the PICU setting, its use is suggested as a means of titrating the administration of NMBA agents Of note are the significant interpatient variability that has been reported in the PICU setting and therefore the inability to ensure an appropriate dose without some monitoring modality The choice of the number of twitches to maintain has not been prospectively studied The majority of the clinical evidence suggests that maintaining one twitch of the TOF ensures an adequate degree of neuromuscular blockade while potentially limiting the incidence of persistent neuromuscular weakness However, the least amount of blockade that can be clinically tolerated is suggested In some patients, maintaining two twitches may be acceptable, especially with the use of an appropriate degree of sedation and analgesia When TOF monitoring is not in use or is not feasible, drug holidays are commonly employed in which the NMBA agent is temporarily discontinued until some clinical sign of neuromuscular function, such as motor movement, is noted At that time, if needed, the infusion is restarted or an additional bolus is administered No study has evaluated the best nerve (facial, ulnar, common peroneal) to monitor In clinical practice, any accessible nerve can be used However, several patient and technical factors may affect the response As such, whenever feasible, placement of the monitor before the institution of neuromuscular blockade is suggested to ensure that a TOF can be obtained before the administration of the NMBA If no response is obtained, the technique should be evaluated by first evaluating the monitor (faculty monitor, electrodes, or batteries) Is the electrode too far from the nerve (improper placement, edema, obesity)? If these technical problems are ruled out, the infusion can be decreased by 10% to 15%, and the TOF measured again in hours When two or more twitches are noted, if the patient is stable and a more profound degree of blockade is not required, ongoing observation is suggested If a deeper level of blockade is required, a bolus equivalent to the hourly infusion rate should be administered and the infusion increased by 10% to 15% Adverse Effects of Neuromuscular Blockade As with any medication used in the PICU patient with comorbid diseases, adverse effects may occur with NMBAs Perhaps the most devastating of these adverse effects is the inability to provide adequate ventilation following the administration of a medication that induces apnea Therefore, these medications should never be used if there is any suspicion that the airway cannot be controlled In rare circumstances, endotracheal intubation using direct laryngoscopy may be impossible In even rarer circumstances, adequate bag-mask ventilation cannot be provided In such scenarios, death or permanent CNS morbidity will result with the administration 1580 S E C T I O N X I V Pediatric Critical Care: Anesthesia Principles in the Pediatric Intensive Care Unit of NMBAs Measures to avoid such problems include an assessment of the airway before the administration of these agents and knowledge of the cannot intubate/cannot ventilate algorithm as outlined by the American Society of Anesthesiologists Various physical characteristics may suggest that direct laryngoscopy and endotracheal intubation will be difficult, including micrognathia, a short neck, limited neck mobility (flexion/extension), limited mouth opening, a large tongue, and a small mouth An additional tool is the Mallampati grade, which describes the ability to visualize the tip of the uvula and the tonsillar pillars.7,8 If there is a suspicion that endotracheal intubation using direct laryngoscopy will not be possible and there is time, other techniques to control the airway are suggested Some of the more commonly used approaches to the difficult airway in infants and children are described elsewhere.125 The techniques needed for the cannot intubate/cannot ventilate scenario should be understood and available in any situation in which NMBAs are being administered This should consist of alternative options for endotracheal intubation, including repositioning the patient or using a different type of laryngoscope—for example, indirect laryngoscopy, such as the Glidescope.7,8 Physicians using NMBAs should also have a working knowledge of the laryngeal mask airway, as it can be used to rescue patients when laryngoscopy, endotracheal intubation, and bag-valve-mask ventilation fail.126 Other adverse effects from NMBAs relate to the elimination of protective physiologic functions Eye care with the use of artificial tears or a moisturizing eye ointment at fixed intervals during the administration of NMBAs is necessary to avoid drying and damage to the cornea Repositioning of the patient at frequent intervals is necessary to avoid pressure sores For prolonged immobility, the use of special mattresses may be considered as an adjunct to frequent patient moving Passive range of motion may also be implicated with splinting to prevent forearm and ankle contractures while sequential compression devices may be indicated to prevent deep vein thrombosis Ineffective coughing and clearance of secretions mandates the implementation of suctioning protocols to limit the risk of nosocomial pneumonias Alterations in normal physiologic respiratory parameters include a decrease in functional residual capacity, increase in dead space, and ventilation-perfusion ratios that may result in ventilatory issues, for example, hypoxemia or hypercarbia and the need to adjust ventilatory parameters Although these agents prevent movement, they provide no degree of sedation or analgesia As such, monitoring sedation using clinical scoring systems is generally not feasible Therefore, some other measure of the depth of sedation may be required In the majority of clinical situations, physiologic parameters such as heart rate and blood pressure are used as a means of titrating sedative and analgesic agents However, issues arise in critically ill patients in whom alterations in heart or blood pressure may not occur in response to stress or pain In this patient population, exogenous vasopressors may be in use and thereby eliminate the reliability of physiologic parameters In the operating room setting, the availability of depth of anesthesia monitors is recommended, and it is suggested that their use be considered in patients at high risk for awareness Despite the rare occurrence of such events, means for their prevention of awareness during the use of neuromuscular blocking agents in the PICU appear indicated given the consequences of such problems In the operating room setting, various depth of sedation or anesthesia monitors are currently available To date, there are no data in the PICU to demonstrate their efficacy in preventing recall during the use of neuromuscular blocking agents The bispectral (BIS) index is a processed electroencephalographic parameter expressed as a numeric value ranging from (isoelectric electroencephalogram) to 100 (awake, eyes open, no sedative agent) In the pediatric population, its intraoperative use has been suggested to decrease the incidence of awareness.127 In the PICU population, the BIS value has been shown to generally correlate with the depth of sedation assessed using various clinical scoring systems.128,129 In one such study, BIS monitoring was used to evaluate the depth of sedation in a cohort of 12 PICU patients receiving NMBAs.130 BIS monitoring was used for a total of 476 hours and revealed that the desired depth of sedation (BIS number 50–70) was achieved 57% of the time The BIS number demonstrated a deeper than desired depth of sedation (BIS number #49) 35% of the time and an inadequate depth of sedation in patients receiving neuromuscular blockade (BIS number 71) 8% of the time At the time that additional sedation was administered by the bedside nurse who was not allowed to view the monitor, the BIS number was 71 or greater 64% of the time, 50 to 70 during 31% of the time, and 49 or less 5% of the time Although no long-term follow-up or assessment of awareness was pursued, the authors concluded that physiologic parameters are not a viable means of assessing the depth of sedation during the use of NMBAs The adverse effect that has received the most attention in the adult population with the administration of NMBAs is residual neuromuscular paralysis In clinical practice, it appears that there are two distinct entities that may account for prolonged neuromuscular paralysis: (1) prolonged recovery from neuromuscular blockade related to excessive dosing or delayed clearance of the parent compound or metabolites due to renal or hepatic issues and (2) what is now termed the acute quadriplegic myopathy syndrome (AQMS).130–133 Potential concern regarding such problems was first reported in 1992 with the use of vecuronium in patients with renal insufficiency.131 Complications related to excessive dosing or inadequate clearance of an active metabolite generally resolve spontaneously over time with clearance of the parent compound or its metabolites In clinical practice, prolonged recovery is defined as a recovery time of more than 100% of the predicted parameter In distinction, AQMS presents with acute paresis, myonecrosis with increased plasma markers demonstrating muscle breakdown, such as CPK, and abnormal electromyography (EMG) with the demonstration of reduced compound motor action potential amplitude, decreased motor nerve conduction, and evidence of acute denervation Clinical findings include flaccid paralysis, relative preservation of extraocular movements, decreased deep tendon reflexes, respiratory insufficiency, intact sensory function, and normal findings in the cerebrospinal fluid.132–134 Recovery may require weeks to months, with the need for prolonged rehabilitation care, and tracheostomy with chronic ventilatory support, all of which may significantly affect the cost of ICU care Although initially reported only with aminosteroid compounds, it has been subsequently also reported with the benzylisoquinolinium derivatives.135,136 Given that CPK values are elevated in up to 50% of patients with AQMS, periodic screening of patients receiving ongoing neuromuscular blockade may be indicated As problems have been noted more commonly following the prolonged, continuous infusion of NMBAs, it has also been suggested that drug holidays or periodic interruption of the infusion be considered However, there are no data to demonstrate that this practice will alter the incidence of AQMS, and even the periodic withdrawal of neuromuscular blockade must be considered on a risk-benefit ratio Termination of CHAPTER 131 Neuromuscular Blocking Agents the use of NMBAs is suggested whenever it is clinically feasible given their adverse effect profile Other factors and comorbid processes that may contribute to the development of AQMS include nutritional deficiencies; coadministration of other medications (cyclosporine, corticosteroids, aminoglycosides); hyperglycemia; hepatic or renal insufficiency; and electrolyte disturbances The association is most profound with the coadministration of NMBAs and corticosteroids, suggesting a heightened awareness in such patients.135 In addition to AQMS, other conditions to consider in the differential diagnosis of patients with prolonged weakness following the use of NMBAs include neuromuscular conditions (myasthenia gravis, Eaton-Lambert syndrome, Guillain-Barré syndrome); acquired or primary myopathic conditions (mitochondrial myopathy, steroid myopathy); central nervous system injury; spinal cord injury; critical illness polyneuropathy; disuse atrophy; and electrolyte or metabolic disturbances Critical illness polyneuropathy may be confused with AQMS It is a combined motor and sensory neuropathy that results from ischemia of the microvasculature of the nerves, which is seen most commonly in patients with multisystem organ failure EMG demonstrates a pattern different from that seen in AQMS Summary: Neuromuscular Blocking Agents in the PICU In addition to their use in the operating room, specific situations that mandate the use of NMBAs in the PICU may arise Although these agents are generally administered as intermittent bolus doses in the operating room, a more stable baseline level of neuromuscular blockade may be desired in the PICU; therefore, a continuous infusion may be used When choosing an agent for use in the PICU population, the major issues are cardiovascular effects, metabolism, and cost Because many of the patients in the PICU have some degree of hemodynamic instability, agents that cause excessive histamine release should be avoided Additionally, the presence of hepatic or renal insufficiency may affect metabolism or elimination or the parent compound as well as its metabolites In the absence of end-organ dysfunction, pancuronium offers an inexpensive means of achieving neuromuscular blockade Its vagolytic effect will result in tachycardia with an increase in heart rate of 10 to 20 beats per minute above baseline Given its duration of action, intermittent dosing is feasible With its availability in generic form, vecuronium provides another cost-effective option in the PICU setting while eliminating the tachycardia that is seen with pancuronium Although vecuronium and pancuronium are generally effective and inexpensive in patients without end-organ dysfunction, significant alterations in infusion requirements occur in patients with renal insufficiency/failure (pancuronium and vecuronium) or hepatic insufficiency/failure (vecuronium) Atracurium or cis-atracurium may be a more appropriate choice in patients with hepatic or renal failure because these conditions not alter dosing requirements of either agent.137 In the PICU setting, like the operating room, adjustment of the dose based on monitoring with a peripheral nerve stimulator is recommended Regardless of the agent used, significant interpatient variability with up to 10-fold variations in infusion requirements may be noted This results from not only interpatient variability but also multiple associated conditions that may increase or decrease the sensitivity to NMBAs (Boxes 131.6 and 131.7) On the basis of this knowledge, the recommended doses (Table 131.1) for the various NMBAs are starting guidelines The 1581 • BOX 131.6 Factors That Increase Sensitivity to Neuromuscular Blocking Agents Medications Inhalational anesthetic agents Local anesthetic agents Antibiotics (aminoglycosides) Antiarrhythmic agents (quinidine, procainamide) Calcium channel blockers b-adrenergic antagonists Chemotherapeutic agents (cyclophosphamide) Diuretics (furosemide) Dantrolene Lithium, magnesium Cyclosporine Underlying Disorders Electrolyte disturbances (hypokalemia, hypermagnesemia, hypocalcemia) Hypothermia Respiratory acidosis Metabolic alkalosis Myasthenia gravis Eaton-Lambert syndrome Muscular dystrophy Multiple sclerosis Amyotrophic lateral sclerosis Poliomyelitis • BOX 131.7 Factors That Decrease the Sensitivity to Neuromuscular Blocking Agents Medications Anticonvulsant agents (phenytoin, carbamazepine) Aminophylline Underlying Conditions Hypercalcemia Burns Prolonged administration of neuromuscular blocking agents TABLE Suggested Starting Guidelines for the Continuous 131.1 Infusion of Neuromuscular Blocking Agents Agent Dose Comments Pancuronium 0.06–0.08 mg/kg/h Vagolytic effect, primary renal excretion Vecuronium 0.1–0.15 mg/kg/h No cardiovascular effects, hepatic metabolism to active metabolites, which are renally excreted Rocuronium 0.6–0.8 mg/kg/h Mild vagolytic effect, hepatic metabolism Atracurium 1.0–1.5 mg/kg/h Mild histamine release, non–organ-dependent elimination Cis-atracurium 0.2 mg/kg/h No cardiovascular effects, non–organ-dependent elimination 1582 S E C T I O N X I V Pediatric Critical Care: Anesthesia Principles in the Pediatric Intensive Care Unit infusion should be increased or decreased as needed to maintain one twitch of the TOF or provide the required depth of neuromuscular blockade An additional problem that occurs in the ICU patient who receives NMBAs for a prolonged period is the development of tachyphylaxis or an increased dose requirement over time The primary cause is an upregulation of acetylcholine receptors in patients who are chronically exposed to NMBAs Dodson et al demonstrated an increased density of acetylcholine receptors in muscle from patients who had received prolonged infusions of NMBAs.138 Prolonged neuromuscular blockade, like partial or complete deafferentation, leads to proliferation of acetylcholine receptors at the neuromuscular junction This requires that the dose of the NMBA be increased over time to maintain the same amount of neuromuscular blockade Given their adverse effect profile, it is recommended that NMBAs be administered only when aggressive attempts at sedation have failed to provide the desired level of patient immobilization An ongoing assessment regarding the need for continuing such therapy is suggested, with discontinuation of the medication as early as is feasible Specific protocols should be in place to ensure appropriate care of the patient receiving neuromuscular blockade, with attention to the provision of adequate sedation and analgesia, eye care, prevention of pressure sores, and pulmonary toilet Key References Black AE, Flynn PE, Smith HL, Thomas ML, Wilkinson KA, Association of Pediatric Anaesthetists of Great Britain and Ireland Development of a guideline for the management of the unanticipated difficult airway in pediatric practice Paediatr Anaesth 2015;25:346-362 deBacker J, Hart N, Fan E Neuromuscular 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Br J Anaesth 1989;62:184-187 ... noted This results from not only interpatient variability but also multiple associated conditions that may increase or decrease the sensitivity to NMBAs (Boxes 131.6 and 131.7) On the basis of this... scenario should be understood and available in any situation in which NMBAs are being administered This should consist of alternative options for endotracheal intubation, including repositioning... patients in whom alterations in heart or blood pressure may not occur in response to stress or pain In this patient population, exogenous vasopressors may be in use and thereby eliminate the reliability