Monitoring neuromuscular block in infants and children

ABSTRACT

Neuromuscular blocking agents (NMBAs) have become a key component of anesthetic care as a means of facilitating endotracheal intubation, providing surgical relaxation of the skeletal musculature, and ensuring an immobile patient during surgical procedures. Although generally safe and effective, dosing of NMBAs and their reversal with acetylcholinesterase inhibitors (such as neostigmine) or encapsulating agents (such as sugammadex) require monitoring, including a means to quantify the degree of neuromuscular (NM) block and residual NM function. Although clinical evaluations (head lift, hip flexion, and grip strength) or respiratory parameters (tidal volume and vital capacity) have historically be used to assess return of muscle strength, these parameters have been shown to be insensitive means of detecting residual NM block and weakness. Furthermore, these subjective evaluations are not feasible during intraoperative anesthetic care and therefore cannot be used to guide initial and ongoing dosing of NMBAs, nor the adequacy of reversal. Assessing NM function using a peripheral nerve stimulator (PNS) and visual observation of the train-of-four (TOF) response was previously accepted as the standard monitor when administering NMBAs. However, subjective visual or tactile assessment is an indirect and insensitive measure of NM function, and measurement of the TOF ratio (T4/T1) is not feasible. It is generally accepted that a quantitatively determined TOF ratio ≥0.90 is the optimal method to document return of baseline NM function, avoid residual paralysis, and confirm the safe timing of tracheal extubation. The following educational review discusses the normal function of the NM junction, outlines clinical concerns of inadequate reversal of NM block, and reviews quantitative TOF monitoring with an emphasis on its use in the pediatric patient.

Introduction

Normal neuromuscular (NM) transmission begins with depolarization of the motor nerve axon and release of acetylcholine from the pre-synaptic nerve terminal. Acetylcholine is synthesized in the cytoplasm of the neuron from acetyl coenzyme A and choline and stored in synaptic vesicles (quanta) in the axonal terminals of the presynaptic membrane. Depolarization of the presynaptic axonal membrane opens calcium channels (P channel). The movement of calcium through the channels in the presynaptic membrane results in the movement of synaptic vesicles to and fusion with the membrane. This is followed by the release of acetylcholine into the synaptic cleft. After its release from the synaptic vesicles, acetylcholine diffuses across the synaptic cleft and binds to acetylcholine receptors on the postsynaptic membrane of the sarcolemma. This results in depolarization of the sarcolemma, the release of calcium from the sarcoplasmic reticulum (SR), and muscle contraction. Neuromuscular blocking agents (NMBAs) competitively block the acetylcholine receptor on the postsynaptic membrane, preventing muscle contraction and resulting in NM block. The P channel on the pre-synaptic membrane can be blocked by cations such as magnesium and lithium (calcium channel antagonists), but generally not to a clinically significant degree, although this effect potentiates the actions of nondepolarizing NMBAs as blockade of the inward movement of calcium prevents the release of acetylcholine into the synaptic cleft.

The acetylcholine receptor (nicotinic receptor on the sarcolemma) is a pentameric protein composed of five subunits. There are five possible subunits (alpha, beta, gamma, delta, and epsilon), each of that encoded by a different gene. The normal acetylcholine receptor found in adults includes two alpha subunits combined with one each of the beta, delta, and epsilon subunits. Binding of an acetylcholine molecule to each of the two alpha subunits is necessary for depolarization of the sarcolemma. During various stages of development or in pathologic disease states, the composition of the acetylcholine receptor may change. Immature and denervated acetylcholine receptors have a gamma subunit instead of the epsilon, while a demyelinated NM junction contains acetylcholine receptors composed of a pentamer of alpha subunits. The importance of these variants is that their response (opening of the ion channel) may be dramatically different from the normal adult variant of the acetylcholine receptor. These differences can have devastating consequences following the administration of the depolarizing NMBA, succinylcholine. The channel may remain open for a prolonged period, resulting in the release of intracellular potassium and systemic hyperkalemia. The acetylcholine receptor occupies the entire membrane from the outside of the muscle through the cell membrane to the inside and thereby regulates the transmembrane movement of ions. The receptor acts to convert the chemical stimulus (acetylcholine) into an electrical impulse that results in the depolarization of the sarcolemma. The depolarization of the sarcolemma (electrical impulse) results in the release of calcium from the SR and muscle contraction (mechanical response).

Activation of the acetylcholine receptor opens ion channels allowing the movement of small, positively charged cations such as sodium, potassium, and calcium. The sodium influx depolarizes the muscle membrane leading to the release of calcium from the SR and muscle contraction. Cessation of muscle contraction is mediated by the rapid metabolism of acetylcholine by the enzyme acetylcholinesterase that is present in the synaptic cleft. Once acetylcholine is metabolized, the sarcolemma can repolarize, thereby resetting the muscle for the next round of depolarization. Failure to metabolize acetylcholine that is bound to the receptor results in prolonged depolarization, inability to repolarize the sarcolemma, and cessation of further contraction.

Block of NM transmission with medications that are competitive antagonist for acetylcholine at the NM junction may be indicated in various clinical scenarios in the emergency department, operating rooms, and intensive care unit (ICU). These agents may be used to facilitate endotracheal intubation, provide surgical relaxation during operative procedures, and ensure a motionless patient during intraoperative anesthetic care. In the ICU setting, NMBAs may be administered to facilitate mechanical ventilation, prevent shivering in therapeutic hypothermia to decrease oxygen consumption, facilitate procedures along with deep sedation, and in the treatment of adult respiratory distress syndrome (ARDS).[1,2,3,4,5,6] The potential to interrupt NM transmission at the NM junction of skeletal muscle first became available during the first half of the 20^th century with the introduction of curare to anesthetic practice following isolation of the active chemical compound, tubocurarine, from plant samples obtained from South America.[7] The first clinical uses of a NMBA (curare) in clinical practice were to treat conditions associated with severe muscle hypertonicity (tetanus, strychnine poisoning, and rabies) or to prevent fractures and muscle contractions during electroconvulsive or Metrazol-induced convulsive therapy to treat psychiatry disturbances.[8,9] Its introduction into intraoperative practice was first officially recognized on January 23, 1942 when Dr. Harold Griffith and Enid Johnson at the Homeopathic Hospital in Montreal used it to supplement cyclopropane anesthesia during an appendectomy.[10,11] Curare was subsequently introduced into general anesthesia practice, and was quickly followed by the identification, synthesis, and clinical use of other NMBAs including gallamine, succinylcholine, and pancuronium.

Residual Neuromuscular Block and Adverse Effects: Adult Studies

Various clinical outcomes have been proposed as benefits of monitoring NM block [Table 1] during perioperative care, although the majority have focused on the potential risk of residual NM block and its impact on the postoperative course. Shortly after their introduction of NMBAs into anesthetic practice, concerns were raised regarding their association with postoperative mortality.[12] The landmark study of Beecher and Todd analyzed 599,548 anesthetics and found that mortality was 6 times higher in patients who received intraoperative curare. In most of the patients (63%), the cause of death was respiratory failure. This became the first study to document the potential risk of postoperative residual paralysis related to NMBAs. Recognition of such problems led to changes in practice including the development and use of routine reversal agents (neostigmine) for NMBAs in the late 1950s and the recognition that clinical assessment of the reversal of NM block is inaccurate, paving the way for development of peripheral nerve stimulators (PNS) and the means to assess the train-of-four (TOF) response.

Table 1.

Why should the depth of neuromuscular block be monitored

1. Identify optimal timing of endotracheal intubation

2. Ensure adequate NM block based on the type of surgical procedure

3. Titrate redosing of NMBAs or adjustment of continuous infusion

4. Identify depth of NM block and guide choice of reversal agent (neostigmine or sugammadex)

5. Identify the appropriate dose of sugammadex

6. Document adequate reversal of NM block

7. Identify occurrence of recurarization

8. Ensure adherence to the current guidelines of the European and American Societies of Anesthesiologists

NMBAs=Neuromuscular blocking agents; NM=Neuromuscular

This response was needed as NMBAs had quickly become a key component of intraoperative anesthetic care and clinical studies demonstrated the lack of sensitivity and specificity of clinical assessment as a means of evaluating depth of NM block. Although clinical evaluation (head lift, hip flexion, and grip strength) or simple spirometry for evaluation of respiratory parameters (tidal volume, vital capacity, negative inspiratory force) have classically been used to assess return of adequate muscle strength, these parameters are an insensitive means of detecting residual NM weakness.[13,14,15] Furthermore, these evaluations are not feasible during intraoperative care and therefore cannot be used to guide ongoing dosing of NMBAs.

Investigations into the possibility of monitoring intraoperative NM block began during the 1960s and 1970s. Drs. Churchill-Davidson and Christie demonstrated the feasibility of stimulation of the ulnar nerve at the elbow and observation of the electromyograph (EMG) of the abductor digiti minima using electrodes applied over the muscle while Dr. Ron Katz reported the potential for intraoperative use of a nerve stimulator.[16,17] Further refinement led to the development and introduction of TOF monitoring.[18,19] The device developed by Dr. Hassan Ali used a novel pattern of neurostimulation with a regulated stimulus at 2 Hz for 2 s or a TOF.

Assessment of the degree of NM block is provided by assessing the TOF with measurement of the four responses and comparison of the amplitude of the height or amplitude of the last response (T4) to that of the first (T1) or the TOF ratio. At baseline, without the administration of a NMBA and with an intact NM junction, the height of T1 should equal T4 thereby giving a TOF ratio of 1. As there are progressive occupancy and block of acetylcholine receptors, the TOF ratio decreases. With 70–80% receptor occupancy, there is an initial decrease in TOF ratio, particularly T4. As block increases, T4 vanishes resulting in a TOF ratio of 0, and a TOF count of 3. Progressive increase in the degree of block results in sequential disappearance of the other responses of the TOF stimuli and a decrease in the TOF count. When the TOF count is zero, an increased stimulus (5-s, 50-Hz tetanic stimulus) can be used to generate a post-tetanic response. These patterns of response (TOF, TOF ratio, TOF count, and post-tetanic count [PTC]) are the patterns of neurostimulation that are used to assess the degree of NM block, assess the need for redosing, and evaluate the efficacy of reversal. A T4/T1 ratio ≥0.90 is the accepted threshold to ensure return of baseline NM function and return of skeletal muscle strength, to identify the correct timing of tracheal extubation, and ensure absence of residual paralysis.

Following the Beecher and Todd study and after development of appropriate tools to monitor the NM junction, additional studies verified the incidence of residual NM block and its perioperative consequences in adults.[20,21] Viby-Morgenson et al.[21] were among the first to demonstrate residual NM block in adults. In a random sampling from three operating room days at three different hospitals, the investigators identified a study cohort that included 72 adult patients, 20 to 86 years of age (mean age 57 years) undergoing various surgical procedures that required NM block. Administration of the NMBA and reversal with neostigmine was based only on clinical criteria. TOF was measured immediately after arrival in the post-anesthesia care unit (PACU) by ulnar nerve stimulation and gauging of the adduction of the thumb by a force displacement transducer. The TOF ratio was less than 60% in 16 of 72 (22%) patients and less than 70% in a total of 30 (42%) patients. The incidence of residual paralysis did not correlate with the NMBA used (curare, gallamine or pancuronium) or the type of anesthetic. The authors did not correlate the degree or frequency of residual NM block with perioperative complications. They did note that without TOF monitoring, the incidence of residual NM block was high, dosing of NMBAs was high, and that with these higher doses, reversal with a neostigmine dose of 2.5 mg was frequently inadequate. The authors opined that TOF monitoring was useful in evaluating residual NM block and recommended that NM block monitoring be used more extensively during anesthesia and in the PACU for titrating reversal with anticholinesterase medications.

Subsequent studies confirmed the significant incidence of residual NM block, identified its physiologic consequences [Table 2], and further identified its relationship with postoperative complications.[20] Kopman et al. identified that a TOF ratio ≥0.9 was necessary to ensure recovery from NM block in a study of 10 awake American Society of Anesthesiologists (ASA) physical status 1 volunteers, recovering from mivacurium-induced NM block.[22] At a TOF ratio of 0.70, grip strength averaged only 59% of control, and all subjects had significant signs and symptoms of residual NM block. The authors concluded that a TOF ratio ≥0.9 or even 1 was required to ensure complete recovery. These and other data refuted other suggestions that recovery could be defined at a lower TOF ratio (0.7).

Table 2.

Clinical and physiologic impact of residual neuromuscular block

1. Clinical and subjective signs and symptoms of weakness

2. Impaired hypoxic ventilatory response

3. Decreased inspiratory flow rates

4. Impairment of pharyngeal coordination and swallowing dysfunction

5. Impairment of upper airway dilator muscles and reduction of upper airway volume

6. Impaired upper airway function with obstruction

7. Impaired airway protective reflexes with risk of aspiration

8. Prolonged post-anesthesia care unit stay

9. Postoperative hypoxemia

10. Prolonged postoperative mechanical ventilation

11. Increased pulmonary complications (atelectasis, pneumonia, and respiratory failure)

Additional studies confirmed that residual NM block was not only related to the use of first generation, long-acting NMBAs (pancuronium) or repeated dosing, but that residual NM block may occur even following a single dose of an intermediate acting NMBAs (rocuronium, vecuronium, or atracurium) as Debaene et al.[23] reported a TOF ratio <0.7 in 10% of patients and <0.9 in 37% of the patients 2 hours after administration of a single dose of an intermediate acting NMBA. Two other studies sought to demonstrate the potential for postoperative complications related to use of NMBA, failure to implement monitoring, and/or inadequate reversal of NM block.[24,25] However, a clear association was difficult to prove due to the retrospective nature of the study, variations in clinical practice, and challenges associated with propensity matching for comorbid conditions and patient status.

Work in this area has continued over the past 10–15 years with continued evidence demonstrating an alarming incidence of postoperative residual NM as well as attempting to further define and prove the association between residual NM block and adverse perioperative outcomes. A series of studies under the acronym RECITE (Residual Cubanization and its Incidence at Tracheal Extubation) noted a high incidence of residual NM block (TOF ratio <0.9) from various countries.[26,27,28] The RECITE-US study measured the TOF ratio in a cohort of 255 patients following abdominal surgery in the United States.[26] The majority of patients (64.7%) had a TOF ratio <0.9 at the time of tracheal extubation, despite reversal of rocuronium with neostigmine and the use of qualitative peripheral nerve stimulation. Similar findings were observed in RECITE trials performed in Canada and China.[27,28] These findings suggest that residual NM block remains a common anesthetic concern, especially when quantitative monitoring and sugammadex are not used.

Additional studies have continued to demonstrate the impact of residual NM block on respiratory function. In a multicenter study from Spain, adult patients with a TOF ratio <0.9 in the PACU had an increased risk for postoperative adverse respiratory events (odds ratio [OR] 2.57) and a higher incidence of the need for tracheal reintubation.[29] A subsequent group of investigators demonstrated that the most significant independent predictor for an adverse respiratory event during early recovery from anesthesia and surgery was residual NM block (OR: 6.4).[30] A retrospective cohort study demonstrated that patients with a TOF ratio <0.9 had a three-times higher risk of ICU admission than those with TOF ratios ≥0.9.[31] These outcomes translate into adverse patient outcomes, the need to escalate care, and higher hospital costs.

Other investigators have demonstrated the impact of the clinical decision not to reverse NM block, the incidence of residual NM block, and its association with adverse postoperative outcomes. Bulka et al.[32] reported a 2.3 increased risk of postoperative pneumonia in patients who did not receive a reversal agent (neostigmine) after surgery. In a similar cohort of 11,355 surgical patients, the incidence of postoperative respiratory complications (failure to wean, occurrence of pneumonia, or need for tracheal reintubation) was significantly higher in patients who did not receive a reversal agent (neostigmine) for NM block.[33] A final database investigation determined that when comparing patients who did not receive neostigmine with those who did, there was a higher incidence of major complications (6.05% vs. 1.7%) including the need for tracheal reintubation (4.6% vs. 0.8%) or unplanned ICU admissions (3.2% vs. 0.8%).[34]

Residual Neuromuscular Block and Adverse Effects: Pediatric Studies

While the incidence of residual NM block has been investigated extensively in adult patients, information regarding this phenomenon and its impact on postoperative outcome has been less well demonstrated in pediatric-aged patients.[35,36,37] In a prospective trial of pediatric-aged patients who received intraoperative NM block with rocuronium (49%), cis-atracurium (27%), mivacurium (22%), atracurium (2%), residual NM block, defined as TOFR ratio less than 0.9, was measured just prior to tracheal extubation and again in the PACU using acceleromyograph (AMG).[35] The incidence of residual NM block was 48.2% (136 of 282 patients) in the OR and 26.9% (32 of 119 patients) in the PACU. Risk factors for residual NM block in the OR included the interval between NMBA administration and the TOF measurement, as well as the NMBA used (being more common with rocuronium or cis-atracurium and less common with mivacurium). There was an 8% risk reduction in the incidence of residual NM block with each increased year of age.

Further work has confirmed the potential for residual NM block, its association with the agent used for reversal of NM block, as well as the inadequacy of qualitative TOF monitoring.[35] In a prospective trial of 74 children (2–17 years of age) who presented for elective surgery and received rocuronium for NM block, the TOF was assessed with both a qualitative and quantitative (EMG-based) TOF monitor. Residual block was reversed with either neostigmine or sugammadex. Qualitative TOF monitoring and clinical assessment failed to detect residual NM block in 29.7% of patients in the neostigmine reversal cohort, while no residual NM block occurred in the sugammadex reversal group. A correlation between increasing patient weight and the incidence of postoperative residual block was observed in the neostigmine cohort. In another prospective study, 37.5% of pediatric patients who received neostigmine for reversal had a TOF ratio <90% prior to tracheal extubation.[37] However, having a TOF ratio <90% in children did not appear to be as clinically significant as that reported in the adult literature. In this specific cohort of patients, no adverse clinical effects were noted beyond the findings of TOF ratio <0.90.

Further work used the need for re-dosing of reversal agents (neostigmine or sugammadex) after the initial administration of neostigmine as a means of identify residual NM block in children.[38] The retrospective query of the EMR revealed that 101 of 6373 patients (1.58%) received rocuronium and additional reversal agents. Risk factors associated with re-dosing of reversal agent included time from the last dose of rocuronium to the initial dose of neostigmine (less than 28 min), a cumulative dose of rocuronium (more than 0.45 mg/kg), an initial neostigmine dose less than 0.05 mg/kg, and African American race.

Additional information regarding the incidence of residual NM block can be provided from a prospective study of 89 children, who presented for elective and urgent surgery.[39] Prior to the clinical decision to extubate the trachea at the completion of the surgical procedure, the TOF ration from the AMG was recorded. Quantitative monitoring was used in 65.2% of the cases, while qualitative monitoring was used in 5.6% of the cases. Residual NM block was present in nine children (10.1%) of the entire study cohort with the TOF ratio varying from 0.78 to 0.89 in eight children. The lowest TOF ratio was 0.48. The time from the last intraoperative dose of a NMBA agent prior to the TOF ratio measurement before tracheal extubation was significantly shorter in patients with a TOF ratio <0.90 versus TOF ratio ≥0.90 (median time of 88 versus 110 min). Although qualitative monitoring was used less frequently in the entire study cohort, residual NM block was significantly more frequent in patients with residual block (22.2% versus 3.8%). However, as noted in the majority of previous studies in pediatric-aged patients, there was no difference in adverse events when comparing the two groups.

Other investigators have suggested that the total dose of the intraoperative NMBA may correlate with the incidence of postoperative respiratory compromise.[40] In a retrospective hospital registry study involving a review of 7,216 surgical cases requiring endotracheal intubation in patients 0–10 years of age, patients were divided into three groups depending on the total intraoperative dose of NMBA that was based on the ED95 (median effective dose required to achieve a 95% reduction in maximal twitch response from baseline) of the NMBA. Based on this criterion, three groups were developed based on the ED95 multiples administered during surgery. One group received no NMBA and the two others that received medians of either 2 or 3.8 times the ED95 of the NMBA. Postoperative respiratory complications (defined as respiratory failure, pulmonary edema, tracheal reintubation, and pneumonia within 3 days of the procedure) were more frequent in patients who received higher doses of NMBAs. The OR in the highest NMBA group was 5.63 compared to the group that received no NMBA. The risk was highest in patients ≤1 year of age, higher ASA classification (more than 1), and surgery duration less than 90 minutes. The incidence was not modified by administration of neostigmine.

Although most of the studies have been performed in the operating room setting, information regarding the impact of residual NM block from the neonatal ICU setting has also been published recently.[41] In a prospective, observational study of 19 neonates who required NM block during their NICU course, recovery was evaluated using AMG after neurostimulation of the ulnar nerve. AMG was not used for clinical decision-making, including adjustment of the NMBA infusion. Outcomes included the time to recovery of the TOF ratio to >70%, >80%, and >90%. Enrolled patients had received either a rocuronium bolus (n = 10) or a vecuronium infusion (n = 9). The median time to recovery of the TOF ratio to >70% was 14 hours (range 4 to 22 hours) following a rocuronium bolus and 34 hours (range 3 to 119 hours) following cessation of the continuous vecuronium infusion. The need for tracheal reintubation occurred in three patients, all of whom had a TOF ratio less than 0.7.

In addition to residual NM block, Salaun et al.[42] have presented anecdotal information regarding the potential for “recurarisation” (more appropriately termed, “re-onset”) in pediatric-aged patients and the impact that lack of monitoring may have had. As opposed to residual NM block, where adequate reversal of block in not achieved, re-onset is the recurrence of NM block after a period of initial recovery of normal NM function. The authors reviewed and reported their own index case as well as six other cases from the literature.[42,43,44,45,46] The index case was a 3-week old, 3.5-kg infant who presented for pyloromyotomy. The initial and only dose of rocuronium was larger than intended due to a calculation error, so the patient received 2.3 mg/kg. At the completion of the 35-minute procedure, no response was noted after TOF stimulation at the posterior tibial nerve, but there were two responses noted after post-tetanic stimulation (PTC = 2). The TOF ratio was not monitored due to technical difficulties. Given these findings, residual NM block was reversed with sugammadex (4.3 mg/kg). Fifteen minutes later, the TOF count was 4/4, the infant was described as vigorous and moving all extremities, and his trachea was extubated. While in the PACU, 50 min after the administration of sugammadex, the infant became floppy and cyanotic with poor respiratory effort that required bag-valve-mask ventilation. The TOF count was not detectable at this time. A second dose of sugammadex was administered, which resulted in return of the TOF count to 4/4 and recovery of skeletal muscle and respiratory function. The authors postulated that the clinical findings were the result of excessive intraoperative rocuronium dosing, inadequate NM block monitoring, and inadequate sugammadex dosing. Their subsequent review of six additional cases in patients less than 2 years of age from four other published reports demonstrated a similar risk of recurarization related to these factors, including lack of NM monitoring (quantitative monitoring was used prior to the administration of rocuronium in only 1 of the 7 patients). To avoid such problems, the authors recommended several modifications of practice, including improved attention to dosing of NMBAs, especially in neonates and infants, given the altered pharmacodynamics of NMBAs in this population; use of quantitative NM block monitoring to ensure adequate reversal, a TOFR ≥0.9; and continued PACU quantitative NM monitoring for at least 60 min after the administration of sugammadex.

Given the potential for a higher incidence of residual NM block with neostigmine versus sugammadex, and in an effort to determine if differences in outcomes are based on the agent used to reverse residual NM block, the Pediatric Health Information System (PHIS) database was queried to determine if there were clinically significant differences in perioperative outcomes in children who received neostigmine versus sugammadex.[47] Using propensity score matching, a total of 33,819 children from the database were evaluated retrospectively. The study cohort included 23,312 (68.9%) who received neostigmine, and 10,361 (31.1%) who received sugammadex for reversal of NM block following non-cardiac surgery. No difference in the incidence of major postoperative pulmonary complications (postoperative pneumonia or respiratory failure) was noted based on the reversal agent used (3.1% in both groups).

Other Clinical Reasons to Monitor Neuromuscular Block

While most of the literature has focused on safety concerns and the potential for postoperative respiratory complications related to inadequate reversal of NM block, other investigators have provided additional information regarding alternative potential improvements in clinical care related to NM block monitoring [Table 3]. Several studies have demonstrated significant pharmacodynamic variation in the onset, the duration, and overall dosing requirements for NM block in both adult and pediatric patients.[48,49,50,51] Various authors have suggested the potential utility of NM block monitoring to demonstrate the appropriate time for endotracheal intubation, regardless of the NMBA used.[52,53,54] In a prospective study of 250 adults, the intubating conditions after rocuronium (0.6 mg/kg) were improved and incidence of sore throat was decreased when endotracheal intubation was performed at TOF count = 0 (no twitches in the TOF) compared to TOF count = 1 (one twitch of the TOF).[52] The conditions for endotracheal intubation were graded as excellent in 87.9% of patients in group TOF count = 0 compared to 80.1% in group TOF count = 1. The time to achieve TOF count = 0 was 142.98 ± 27.04 s compared to 122.38 ± 30.76 s to achieve TOF count = 1. In a subsequent study in adults, conditions for endotracheal intubation were compared between a preset time interval (2 minutes after the administration of 0.6 mg/kg rocuronium) versus a TOF count ≤ 1 using an EMG-based quantitative NM block monitor.[53] Ideal conditions for endotracheal intubation were more common with the TOFR measurement than with a set time interval (61 of 84 or 73% versus 47 of 83 or 57%, P = 0.036). In a meta-analysis of data from 8,008 pediatric-aged patients in 105 trials, although both succinylcholine in a dose ≥1.5 mg/kg and rocuronium in a dose ≥0.9 mg/kg provided similar conditions for endotracheal intubation, the onset time was variable and not consistently within 60 s.[54]

Table 3.

Additional benefits offered for intraoperative neuromuscular block monitoring.

1. Endotracheal intubation time:

a. Assessment of intubation readiness

b. Improvement of conditions for endotracheal intubation

c. Decreased incidence of postoperative sore throat

2. Assessment of maintenance dosing:

a. Timing of intermittent dosing

b. Adjustment of continuous infusions

3. Improvement in intraoperative surgical conditions.

4. To guide sugammadex dosing based on TOF count.

5. Differentiating type of block between depolarizing and non-depolarizing agents (fade is not present with depolarizing NMBAs).

6. Optimizing intraoperative neurophysiologic monitoring to ensure stable level of block.

NMBAs=Neuromuscular blocking agents; TOF=Train-of-four

Quantitative monitoring improves intraoperative conditions during various procedures such as minimally invasive surgery.[55,56,57,58,59] In adults undergoing laparoscopic gynecologic surgery, deep NM block with rocuronium administered to maintain a PTC between 1 and 2 provided improved procedural conditions, as assessed by surgeon, when compared to a lighter plane of NM block with a TOF count of 1–3.[57] Additionally, the length of stay in the PACU was slightly shorter in the group that received deeper NM block (13 versus 22 min). Other investigators have demonstrated in adult laparoscopic surgery that deep NM block increases the intra-abdominal space during insufflation and also lowers insufflation pressures.[60] Similarly, during major laparoscopic procedures in pediatric patients 2–14 years of age, the maximum and mean intra-abdominal pressure, the peak inspiratory pressure, and mean airway pressure were significantly lower in the deep NM block group (PTC 1–2) when compared to the moderate NM block group (TOF count 1–2).[61] Intraoperative conditions assessed using the Leiden Surgical Rating Scale were better, and the dose of rocuronium was significantly higher in the deep NM block group.

Based on previous data suggesting a correlation between the total dose of NMBA administered intraoperatively and its relationship to the incidence of postoperative respiratory complications, monitoring of NM block may be indicated during prolonged procedures, when higher doses of NMBAs are administered, when repeated does of a NMBA are administered, or when a continuous infusion is administered.[62] Given differences in pharmacodynamics and pharmacokinetics, there may be significant variation in the infusion requirements during intraoperative care, providing further support for the use of TOF monitoring to adjust the dose and maintain the desired level of NM block.[63]

The limited published data support similar variability in pediatric patients in both the ICU and the operating room settings. The first study to evaluate the administration of rocuronium by continuous infusion in the Pediatric ICU (PICU) was published in 1996.[64] In the study cohort of 20 pediatric patients, continuous infusion requirements varied from 0.3 to 0.8 mg/kg/hour with an average infusion rate of 0.76 ± 0.3 mg/kg/hour during the first 24-hours, and from 0.3 to 2.2 mg/kg/hour (0.95 ± 0.4 mg/kg/hour) when all patients and all infusion days were considered. A significant increase in infusion requirements was noted over time as some patients required ongoing NM block for more than 48 hours. The higher infusion requirements and increased variability in the PICU setting may be the result of several factors, including the inaccuracy of qualitative monitoring used in the study, difference in patient characteristics and comorbid conditions, associated sedative and anesthetic agents (volatile anesthetic agents for intraoperative care versus midazolam infusions for sedation in the ICU setting), and duration of infusion (hours in the operating room versus days in the ICU). Choi et al.[65] reported lower, albeit still variable, intraoperative infusion rates in children receiving continuous infusions of rocuronium in the only study using an EMG-based TOF monitoring in pediatric-aged patients. Their study cohort included 66 children who were randomized to receive either continuous infusion or intermittent bolus injections. In the continuous infusion group, an initial rocuronium dose of 0.6 mg/kg was administered for endotracheal intubation followed by a rocuronium infusion starting at 0.3 mg/kg/hr. The infusion was titrated in increments of 0.1 mg/kg/hour to maintain a TOF count of 2 during surgery using a quantitative EMG-based device (Datex-Ohmeda E-NMT ElectroSensor, GE Healthcare, Waukesha, WI, USA). Rocuronium infusion requirements were lower in the continuous infusion group when compared to the intermittent bolus dosing group (0.294 ± 0.06 versus 0.366 ± 0.054 mg/kg/hour, P = 0.001). The authors suggested that the lower requirement seen with continuous infusion may be related to the mechanism of action of non-depolarizing NMBAs. NM block becomes evident when 70–80% of the acetylcholine receptors are occupied, resulting in a moderate block. Therefore, to achieve complete block, only a minimal supplemental dose of rocuronium is needed. The margin between moderate and complete block is so narrow that with intermittent injection administration, there is a chance of administering greater doses than required. The excessive dose of rocuronium can result in higher plasma concentrations and cause a slower decay of the plasma concentration of rocuronium through the processes of distribution and elimination. A continuous infusion titrated to the individual’s requirement mitigates this risk and minimizes the occurrence of higher plasma concentrations and redistribution of the drug into body compartments other than the effect compartment.[66]

Aside from its use to document adequate reversal and avoid the potential for residual NM block, current dosing guidelines for sugammadex strongly support the use of quantitative TOF monitoring as dosing recommendations are based on the TOF findings. A dose of 2 mg/kg is recommended for moderate block, defined as ≥two twitches of the TOF while 4 mg/kg is suggested for deep NM block, defined as 1–2 post-tetanic twitches.[67,68] Subsequent to its release for clinical use, more robust investigations into dosing has suggested that lower doses may be feasible in some patients when quantitative TOF of monitoring is used to guide dosing, thereby resulting in cost savings.[69,70,71,72] In a cohort of 97 adults following cardiac surgery, sugammadex was administered in 50-mg increments every 5 min to achieve a TOF ratio ≥0.9 using an EMG-based quantitative monitor.[71] NM block was monitored with EMG in the ICU until sedation was discontinued before tracheal extubation, or for a maximum of 7 hours. Although there was a correlation between the depth of NM block and the sugammadex dose required for reversal, there was a large variation in the dose required at any depth of NM block. Eighty-four of 97 patients (87%) required less than the recommended dose, while 13 of 97 (13%) required more. The authors concluded that when using quantitative TOF monitoring, the dose of sugammadex is frequently less than the recommended dose.

Are We Monitoring the Depth of Neuromuscular Block?

Despite improvements in technology with the development of suitable monitors for use even in neonates and infants, there tends to be limited use of these monitors in pediatric-aged patients and perhaps a resistance to their introduction into our clinical practice. Various surveys have demonstrated that, especially in the United States, there has not been widespread acceptance of qualitative or quantitative monitors of NM block. With the introduction of sugammadex and its recommended dosing guidelines (which are based on TOF monitoring), a QI project was initiated to evaluate adherence to monitoring recommendations and to evaluate the efficacy of an educational program aimed at increasing the use of such monitoring.[73] A retrospective review of 100 patients in the preintervention analysis revealed that TOF monitoring was used in only 30% of the patients. In the post-intervention analysis following departmental-wide educational initiatives, TOF monitoring increased to only 45% in the 75 patients reviewed. The significant (yet low) improvement led the authors to conclude that additional interventions are needed. Similar findings were reported by Faulk et al.[74] in their survey study that was sent to 3,245 members of the Society for Pediatric Anesthesia. Despite a low response rate of 13%, the authors noted that only 40% of participants always assessed NM block using the TOF. Use was inversely correlated with years of practice.

In a more recent retrospective study in a study cohort of 2,923 children less than 2 years of age, which was aimed to assess the risk of recurarisation, residual NM block, or the need for sugammadex redosing, only 43.7% of patients had TOF monitoring used intraoperatively.[75] No difference was noted in the use of TOF monitoring when comparing those who required redosing of sugammadex versus those who did not (40.7% versus 43.8%). The most recent of the studies evaluating intraoperative practices for TOF monitoring involved a survey of 287 practicing ASA from Italy.[76] Overall, NM block monitoring was used in 33% of patients while a higher percentage (41%) reported using it based on the patient’s ASA physical status and for major surgical procedures. However, 26% said they never use it while AMG was the monitor used most frequently (70%).

Given these data, one would wonder why most of the practicing ASA and pediatric ASA may choose not to use TOF monitoring of any type. Various reasons and speculations have been provided to explain the lack of universal TOF monitoring TOF in children as well as the lack of adoption of quantitative over qualitative monitors [Table 4]. Although many reasons have been cited for the lack of monitoring, several of these concerns have recently been challenged or refuted with information led by the publication of guidelines for NM block monitoring in children from the European Society for Anesthesia and Intensive Care in collaboration with the European Society for Pediatric Anesthesia.[77] The feasibility of NM block monitoring even in neonates and infants has been supported by improvements in technology with prospective studies demonstrating the clinical feasibility of quantitative TOF monitoring.[78,79,80,81] Additionally, to facilitate operating room efficiency, preoperative sensor placement has been evaluated to allow for rapid movement into the operating room, initiation of TOF monitoring, and anesthetic induction.[82]

Table 4.

Reasons for lack of universal monitoring of neuromuscular block in children

1. Lack of suitable equipment including pediatric sized sensors.

2. Cost of equipment and sensors.

3. Lack of suitable equipment when the limb is tucked and there may not free movement of the involved extremity or digit.

4. Technological limitations as older devices may require stabilization periods.

5. Clinical practice and beliefs that clinical signs (hip flexion, negative inspiratory force) can be used to determine need for redosing or adequacy of reversal of NM block.

6. Lack of formalized educational processes in training programs with incorporation of monitoring into standard ASA intraoperative monitoring guidelines.

7. Lack of experience with use of these devices, especially in practitioners with a long history of clinical practice.

8. Clinical impression or misinformation that children recover from NMBAs more quickly than adults.

9. Lack of evidence-based medicine to clearly show outcomes differences in pediatric-aged patients.

10. Until recently, lack of formal guidelines regarding intraoperative NM block monitoring.

11. Interference with normal OR routine with delays related to sensor placement and calibration prior to anesthetic induction.

NMBAs=Neuromuscular blocking agents; NM=Neuromuscular; ASA=Anesthesiologists

Monitoring Neuromuscular Block

The need to monitor NM block was first suggested by outcome data provided by Beecher and Todd in 1954, which was followed in the 1960s and 1970s by the introduction of both qualitative and quantitative monitors in clinical practice.[12,16,17,18,19] These concerns were supported by the early recognition that clinical signs (head lift, grasp, negative inspiratory force) of the degree of recovery from NM block are inaccurate.[83] Although a significant advancement from no monitoring, concerns remain with qualitative monitoring using a PNS, including the inability to count the twitch response, visually assess the TOF count, and inability to accurately assess a TOF ratio.[84] Despite these significant limitations, qualitative monitoring remains the more commonly used modality in operating rooms throughout the United States. With qualitative monitoring, even experienced anesthesia professionals are unable to reliably detect fade when the TOF ratio exceeds 0.4. Furthermore, evidenced-based protocols that incorporate targeted NMBA administration, routine NM block antagonism, and qualitative monitoring with a PNS can still result in residual NM block in a significant percentage of patients.[85] The qualitative assessment of NM block with a PNS monitor cannot confirm successful reversal, as it does not measure the TOF ratio.[86] Given the current technology available, qualitative monitoring with a PNS may be best applied when there is limited or no availability of a quantitative TOF monitor (see below).

With quantitative NM block monitors, a more direct assessment of the degree of NM block can be obtained on a scale from complete NM block to acceptable recovery [Table 5].[87] These measurements can be used to assess onset of NM block and recovery to guide the need for redosing or adjustment of the infusion during intraoperative care. Additionally, documentation of TOF ratio can be used to guide dosing of the reversal agent, as well as documentation of successful recovery with a TOF ratio ≥0.9. Quantitative monitors can be generally classified based on the method employed to obtain the TOF measurement. When considering the techniques to monitor NM block, the initial discussion begins with mention of mechanomyography (MMG), considered by many to be the “gold” (reference) standard for monitoring NM block.[88] As novel devices are developed for quantitative monitoring of NM block, they are compared to MMG to demonstrate their efficacy and accuracy. MMG measures the force of isometric muscle contraction in response to standard TOF neurostimulation. The technique of MMG including its set-up and calibration are generally described as cumbersome and not suitable for clinical practice.[88,89] These devices were previously not generally considered for clinical use due to the time required for set-up and calibration as well as being limited commercially; however, there has recently been a resurgence of interest in this technology with a commercially available apparatus that may increase its clinical applicability.[90] The potential clinical applicability of the device was demonstrated in a prospective trial in 33 adults during anesthesia care with the MMG device on one arm and an EMG-based device on the other. The MMG device used was the TOF^3D (MIPM, Mammendorf, Germany), a battery-powered, stand-alone device for quantitative NM monitoring, equipped with a three-dimensional acceleration sensor for measuring muscle response. For MMG, the device uses a newly developed sensor to measure muscle force in one dimension using an electrically isolated force transducer integrated into a handgrip that has been shaped to fit into the palm of the patient palm and secured with an adjustable elastic strap to hold it in place. The thumb is placed in a dedicated sensor tray located on the top of the handgrip such that the device functions with the arms at the side. Positioning of the hand and thumb allows for isometric contraction of the adductor pollicis brevis after stimulation of the ulnar nerve at the wrist. Although the authors concluded that the TOF^3D mechano-sensor was not less precise than EMG during baseline, they noted that better hand fixation was necessary to improve the precision of the MMG. While not commercially available, every new device is compared to one of the legacies MMG devices, or to a newly manufactured (prototype) monitor.

Table 5.

Depth of neuromuscular block using quantitative monitors

Depth of neuromuscular block	Defining parameters
Complete	TOF count=0; post-tetanic count=0
Deep	TOF count=0; post-tetanic count ≥1
Moderate	TOF count 1–3
Shallow	TOF count=4; TOFR less than 0.4
Minimal	TOF count=4; TOFR 0.4–0.9
Recovery	TOF count=4; TOFR ≥0.9

TOF=Train-of-four; TOFR=Train-of-four ratio

Three other types of quantitative NM block monitors are in more widespread clinical use with commercially available devices to measure TOF using kinemyography (KMG), AMG, and EMG.[91,92] Two of these devices (KMG and AMG) use a piezo-electrode device. With KMG, an electrical current is generated in response to deformation of a mechano-sensor that is placed in the webspace between the thumb and the forefinger. Deformation of the sensor occurs in response to neurostimulation of the ulnar nerve following contraction of the adductor pollicis muscle, which generates an electrical current that is measured to provide the TOF.[93,94,95] When attempting to use the device in clinical practice, concerns raised include the need for various sizes of the handpiece, especially when applying the technique in pediatric-aged patients, the limitation of sizes for smaller patients less than 10 kg, and that the device can only be used on the hand, making it less useful in settings where the arms are unavailable for intraoperative monitoring (e.g., robotic, cardiac, laparoscopic procedures).

AMG measures the acceleration of the muscle during neurostimulation using a piezoelectric transducer attached to the thumb.[96,97,98] When a force is applied to the piezoelectric crystal, an electrical impulse is generated that can then be analyzed and measured. The force of muscle contraction is estimated based on the physics principle (second law of motion) which equates force with the product of mass and acceleration. In this case, the mass equals the thumb; acceleration of the thumb is used to measure force and hence the height of the TOF twitches. Similar to KMG, these devices may incorporate a hand adaptor that stabilizes the thumb and improves accuracy of the measurement.[99] With the limitations previously noted with MMG; for many years, AMG was the primary quantitative modality used to evaluate depth of NM block in the operating rooms.[100,101,102] When compared to MMG, AMG devices were easier to set-up and use, did not require prolonged calibration times, and were more portable (battery operated). However, similar to KMG, AMG devices are limited to use on the hand, generally require free movement of the thumb, and may have limited applicability in smaller pediatric patients due to device size and design. More importantly, as AMG devices have been used in clinical practice, a significant limitation is that the baseline TOF ratio measurement, obtained prior to the administration of a NMBA, is generally greater than 1.[103,104,105] As such, it has been recommended that all subsequent TOF ratios obtained after administration of a NMBA or after a reversal agent, should be compared to the baseline value (i.e., normalized), and not merely calculated from the TOF that is obtained at that moment. If these calculations are not possible, it has been recommended that a TOFR = 1.0 be considered the threshold of recovery, rather than TOFR ≥0.9.[106]

Over the past decade, there has been renewed interest in EMG-based devices to monitor the TOF response.[107,108] Following neurostimulation, EMG signals (compound motor action potentials) are recorded by surface electrodes placed over the target muscles. After amplification and filtering, the EMG signals are used to quantify the twitch height and provide a TOF pattern.[109,110,111] Interest in these devices has been driven by the availability of several commercially available devices, which allow reliable bedside measurement of the response to NMBAs, while avoiding some of the potential confounding factors and limitations that have been noted with other quantitative devices. The latest generation of EMG-based devices have simplified set-up and allowed their use in patients when there is limited access to the extremities with the potential for restricted movement of the thumb such as may occur with minimally invasive surgery, robotic procedures or when both extremities are tucked under surgical drapes such as cardiac procedures or smaller infants. Additionally, with the availability of smaller sensors, application of these devices in neonates and infants has been reported. As with other devices, non-comparative studies as well as prospective, comparative trials have demonstrated that validity and efficacy of EMG-based devices in both adult and pediatric patients for TOF monitoring during intraoperative care.[78,79,80,81,103,112,113,114,115,116,117]

Summary

In the operating room, NMBAs may be used as a single dose to facilitate endotracheal intubation or by repeated doses or a continuous infusion to provide ongoing NM block. Following the development and introduction of the first NMBAs for intraoperative anesthetic use, Beecher and Todd identified the potential for increased postoperative morbidity and mortality related to their use and suggested that quantitative monitoring of the NM junction was needed to guide intraoperative administration and document adequate recovery. More recently, significant evidence has accumulated in the adult population related to the potential adverse effects related to residual NM block. These concerns have led to the recent publication of guidelines from the ASA, ESAIC, and ESPA recommending the routine use of quantitative TOF monitoring. The need for quantitative monitoring is driven by evidence-based medicine demonstrating the inadequacy of clinical assessment of residual NM block as well as the improved accuracy of quantitative versus qualitative monitoring. The visual or tactile assessment of the TOF responses (qualitative measurement) and assessment of clinical signs (tidal volume, grip strength, tongue depressor test, etc.) are insensitive and cannot be used to provide the needed data to document adequate reversal such as a TOF ratio ≥0.90.

Continued improvements in technology have resulted in several different and acceptable devices for quantitative TOF monitoring in the OR including AMG, KMG, and EMG. While the correlation and performance of these devices may vary between studies, in general all three of these methods have been used successfully as quantitative monitors of NM function for clinical practice to guide administration and reversal of NM block. EMG-based monitors may allow for improved monitoring in situations where there is limited access to the extremity (arms tucked) and when free movement of the muscle group may not be possible. Additionally, the sensors for EMG monitoring may be placed on the foot when upper extremities are not available, and have also been successfully used in neonates and infants.

Although there are significant regional and hospital-based differences in practice, surveys, particularly from the Unites States, have demonstrated that universal use of quantitative monitoring has not been implemented. This less-than-ideal practice continues, despite the ongoing evidence-based medicine demonstrating the potential for adverse effects related to residual NM block, especially in adults. The practice may be even more varied in pediatric-aged patients, in whom the data demonstrating the potential negative physiologic impact of resulting residual NM dysfunction is less robust. Yet, it seems that quantitative monitoring should definitely be considered in various clinical scenarios [Table 6]. In addition, recent reports of residual NM block or re-onset of NM block, particularly in neonates and infants, have emphasized the need for continued evaluation and perhaps evolution of our practice with attention to not only quantitative NM block monitoring, but also closer attention to our dosing parameters for NMBAs, including both the initial and subsequent doses, especially in neonates and infants. As pointed out and emphasized by other authors, the initial dose of rocuronium in neonates and infants needs to be lower than our usual dose for older patients (0.3–0.4 mg/kg versus 0.6–1 mg/kg) while subsequent doses should be 15–20% of the initial dose and whenever possible, guided by quantitative TOF monitoring. Wachtendorf et al.[118] have recently reported that in a study cohort of 163,402 adult patient cases between 2010 and 2024, rocuronium dose increased by 45.1% after the introduction of sugammadex. Although rocuronium was associated in a dose-dependent manner with a higher postoperative respiratory complication risk, this association was attenuated when sugammadex was administered and abolished with quantitative, but not qualitative, NM block monitoring.

Table 6.

Neuromuscular block monitoring in pediatric-aged patients

1. For prolonged cases or when repeated doses of NMBAs are administered.

2. To titrate continuous infusions of NMBAs intraoperatively.

3. In neonates and infants where variable pharmacokinetics and pharmacodynamics impact the potential for residual neuromuscular block.

4. Patients with neuromuscular diseases or disorders.

5. Patients with end-organ dysfunction (renal or hepatic) that impacts the pharmacokinetics of NMBAs.

6. To guide dosing of sugammadex for reversal of residual NM block.

7. To document adequate reversal of NM block (TOFR ≥0.9)

TOFR=Train-of-four ratio; NMBAs=Neuromuscular blocking agents; NM=Neuromuscular

As noted in our review, the data are robust and underscore the potential deleterious adverse physiologic effects of residual NM block in adults; however, we need more robust and larger cohort studies in pediatric-aged patients to further define the risk. These outcome data can be combined with cost analyses to evaluate the economic advantage of quantitative NM block monitoring. Future technologic improvements may allow for monitors that are incorporated into the anesthesia workstation with integrated modules that facilitate seamless communication and recording of objective measurements into the electronic medical record. Ongoing evaluation of the needs of our individual practices will prove invaluable when choosing a monitoring modality and integrating it into the daily routine of our operating rooms. This should be supported by educational processes and availability of monitoring devices to encourage their use. All of this should encourage adoption of the recent guidelines published by the ESPA for monitoring of NM block in infants and children.

Abbreviation

EMG = electromyography

KMG = kinemyography

AMG = acceleromyography

MMG = mechanomyographic

PICU = Pediatric Intensive Care Unit

ICU = Intensive Care Unit

PACU = Post Anesthesia Care Unit

TOF = train-of-four

ARDS = adult respiratory distress syndrome

NM = neuromuscular

NMBA = neuromuscular blocking agent

SR = sarcoplasmic reticulum

PTC = post tetanic count

PNS = peripheral nerve stimulator

OR = odds ratio

Conflicts of interest

There are no conflicts of interest to declare.

Funding Statement

Nil.