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Recovery from rocuronium-induced neuromuscular block was longer in the larynx than in the pelvic limb of anesthetized dogs
Veterinary Anaesthesia and Analgesia 2017, xxx, 1e8
http://dx.doi.org/10.1016/j.vaa.2016.04.001
RESEARCH PAPER
Recovery from rocuronium-induced neuromuscular block was longer in the larynx than in the pelvic limb of anesthetized dogs Daniel M Sakai, Manuel Martin-Flores, Marta Romano, Chia T Tseng, Luis Campoy, Robin D Gleed & Jonathan Cheetham Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA Correspondence: Manuel Martin-Flores, 930 Campus Road, Box 32, Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA. Email: [email protected]
Abstract Objective To determine if neuromuscular monitoring at the pelvic limb accurately reflects neuromuscular function in the larynx after administration of rocuronium in anesthetized dogs. Study design Prospective experimental study. Animals Six healthy Beagle dogs. Methods Anesthesia was maintained in dogs with isoflurane and a continuous infusion of dexmedetomidine. Rocuronium (0.6 mg kg1) was administered intravenously to induce neuromuscular block. Train-of-four (TOF) impulses were applied to the left recurrent laryngeal nerve (RLn) and the peroneal nerve (Pn). The evoked TOF ratio (TOFR; T4:T1) was measured with electromyography (EMG) simultaneously at the larynx and at the pelvic limb. Spontaneous recoveries of T1 to 25% (T125%) and 75% (T175%) of twitch height, and to TOFR of 0.70 and 0.90 (TOFR0.90) at each EMG site were compared. Results Data from five dogs were analyzed. Times to T125% were similar at the pelvic limb and larynx when measured by EMG; time to T175% was slower at the larynx by 6 ± 4 minutes (p ¼ 0.012). The larynx had a slower recovery to TOFR0.70 (41 ± 13 minutes) and TOFR0.90 (45 ± 13 minutes) than did the pelvic limb [29 ± 8 minutes (p ¼ 0.011) and 33 ± 9 minutes (p ¼ 0.003), respectively]. When the pelvic limb EMG returned to TOFR0.70 and TOFR0.90, the larynx EMG TOFR0.70 and TOFR0.90 values were 0.32 ± 0.12 (p ¼ 0.001) and 0.38 ± 0.13 (p ¼ 0.001), respectively.
Conclusions and clinical relevance After administration of rocuronium, neuromuscular function assessed by EMG recovered approximately 36% slower at the larynx than at the pelvic limb. The results in these dogs suggest that quantitative neuromuscular monitoring instrumented at a pelvic limb may be unable to exclude residual block at the larynx in anesthetized dogs. Keywords airway obstruction, aspiration, complication, monitoring, residual paralysis. Introduction Residual neuromuscular block is the term used to describe the incomplete recovery of neuromuscular transmission in the postoperative period following the use of a neuromuscular blocking agent (NMBA). The incidence of residual neuromuscular block in humans has been reported to range between 2% and 64%, depending on the methods used, the NMBA administered and whether pharmacological reversal has been used (Murphy & Brull 2010). Residual paralysis has been associated with adverse respiratory events, such as postoperative hypoxemia and/or upper airway obstruction (Murphy et al. 2008a). In humans, the incidence of residual paralysis and its associated complications can be decreased with quantitative monitoring of neuromuscular function (Murphy et al. 2008b). Quantitative monitoring in a clinical setting is usually performed with electromyography (EMG) or acceleromyography (AMG). These monitors are available commercially and have been used previously in dogs (Sakai et al. 2015). However, neuromuscular monitoring evaluates the status of a
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Please cite this article in press as: Sakai DM, Martin-Flores M, Romano M et al. Recovery from rocuronium-induced neuromuscular block was longer in the larynx than in the pelvic limb of anesthetized dogs, Veterinary Anaesthesia and Analgesia (2017), http://dx.doi.org/10.1016/j.vaa.2016.04.001
Laryngeal neuromuscular block in dogs DM Sakai et al.
single nerveemuscle group and that information is frequently extrapolated to the entire skeletal musculature. Ideally, information about neuromuscular function obtained at one site should reflect the status of all motor units in the patient, or at least reflect the neuromuscular status of other nerveemuscle groups of clinical importance. However, the duration of neuromuscular block of distinct muscles is different (Ibebunjo & Hall 1994) and this discrepancy might differ between species. Return of laryngeal function is particularly important in the postoperative period, because both laryngeal adduction (to prevent aspiration) and abduction (for airway patency) require active laryngeal muscles. If return of neuromuscular function in the larynx were to lag behind that in the limb, results obtained from a limb might prompt premature removal of airway support and contribute to postoperative aspiration, hypoxemia and/or upper airway obstruction. In this investigation we measured the recovery time from rocuronium-induced neuromuscular block at the pelvic limb (one of the conventional sites of monitoring) and at the larynx in anesthetized dogs (site of clinical importance). The primary aim of this study was to compare recovery from rocuronium neuromuscular block at the pelvic limb and at the larynx by monitoring neuromuscular function using EMG. Concurrent measurements with AMG were obtained, as this technique is probably the most commonly used technique for quantitative neuromuscular monitoring in a clinical setting. We hypothesized that neuromuscular function returns faster at the pelvic limb than at the larynx after administration of rocuronium in anesthetized dogs. Materials and methods This investigation was approved by the Institutional Animal Care and Use Committee of Cornell University. Six healthy (based on regular physical examination and hematology) adult Beagle dogs were included. These dogs were participating in an unrelated research project that involved the surgical exposure of the left recurrent laryngeal nerve (RLn). The six intact female dogs were aged [mean ± standard deviation (SD)] 1.4 ± 0.2 years and weighed 7.4 ± 0.6 kg. Food but not water was withheld overnight prior to anesthesia. Each dog was administered dexmedetomidine (2 mg kg1; Dexdomitor; Pfizer Animal Health, NY, USA) and buprenorphine (20 mg kg1; Buprenex; Reckitt Benckiser Pharmaceuticals Inc., VA, USA) through a catheter in a cephalic vein. Anesthesia was 2
induced with propofol (2 mg kg1; PropoFlo; Abbott Laboratories, IL, USA) administered intravenously (IV). An EMG-capable tracheal tube (NIM EMG endotracheal tube; Medtronic Xomed, FL, USA) was inserted orally, and the cuff was inflated and connected to a rebreathing circle system (Ohmeda Modulus SE; GE Healthcare, WI, USA). Anesthesia was maintained with isoflurane (Forane; Arkema Inc., PA, USA) in oxygen at an end-tidal isoflurane concentration (FE0 Iso) of 1.3e1.5%. Dexmedetomidine (2 mg kg1 hour1) was infused IV (Medfusion 3500; Smiths Medical ASD Inc., MN, USA). The lungs were ventilated mechanically (Ohmeda 7900; GE Healthcare) to maintain the end-tidal carbon dioxide tension (PE0 CO2) at 35e45 mmHg (4.7e6.0 kPa). A balanced electrolyte solution (5 mL kg1 hour1; Plasma-Lyte A; Abbott Laboratories) and meloxicam (0.2 mg kg1; Metacam; Boehringer Ingelheim Vetmedica, Inc., MO, USA) were administered IV. Monitoring during anesthesia included continuous electrocardiography, hemoglobin oxygen saturation (SpO2), PE0 CO2, FE0 Iso, oscillometric noninvasive arterial pressure (neonatal size 3, placed above one carpus; 3 minute duty cycle) and rectal temperature (Cardell Touch; Midmark Corp., OH, USA). Temperature was maintained at 38e39 C with a forced-air warming device. Dogs remained in dorsal recumbency for the duration of anesthesia. Neuromuscular monitoring with EMG at the larynx After clipping and aseptic preparation of the skin, a lateral approach to the larynx was made in a standard fashion ventral to the right linguofacial vein. The subcutaneous fascia was divided bluntly and the RLn identified, running on the caudolateral aspect of the cricoid cartilage, and a cuff electrode (2 mm diameter, MED-EL; Ardiem Medical Inc., PA, USA) was placed around the left RLn. The ground electrode of the EMG tracheal tube was placed on the dog's forehead. Supramaximal current (1e3 mA; Model 2100 Isolated Pulse Stimulator; A-M Systems, WA, USA) was applied to the RLn though the cuff electrode in a train-of-four (TOF) pattern (2 Hz, 0.2 ms pulse duration) repeated every 15 seconds throughout the experiment. Three consecutive, indirectly evoked TOF electromyograms were stored (computer files recorded with Sierra Wave; Cadwell Laboratories, Inc., WA, USA) every 2 minutes throughout the experiment for post hoc measurement. Stimulation of the RLn produced an EMG signal that was detected by the electrodes on the tracheal tube (Fig. 1a); an artifact (representing the stimuli) followed
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Please cite this article in press as: Sakai DM, Martin-Flores M, Romano M et al. Recovery from rocuronium-induced neuromuscular block was longer in the larynx than in the pelvic limb of anesthetized dogs, Veterinary Anaesthesia and Analgesia (2017), http://dx.doi.org/10.1016/j.vaa.2016.04.001
Laryngeal neuromuscular block in dogs DM Sakai et al.
by a typical biphasic EMG curve was displayed in real time on the Sierra Wave monitor (Fig. 1b). The amplitudes of the first (T1) and fourth (T4) EMG curves in each TOF (Fig. 1) were measured (MATLAB Version R2013b; The MathWorks, Inc., MA, USA), and the TOF ratio (TOFR; T4:T1) was calculated. The median of the three measurements was used for analysis. The surgical wound was closed in two layers using absorbable sutures. Neuromuscular monitoring with EMG at the pelvic limb The left or right (selected randomly by ballot) peroneal nerve (Pn) was stimulated with an EMG monitor
(M-NMT module of Datex-Ohmeda AS/3; GE Healthcare) using 25 gauge, 2.5 cm needles (PrecisionGlide; Becton, Dickinson and Company, NJ, USA) inserted subcutaneously 2 cm apart where the Pn crosses the lateral head of the gastrocnemius muscle at the level of the femorotibial joint. The hair over the belly of the cranial tibial muscle was clipped and the skin cleansed with Nuprep Skin Prep Gel (Weaver and Company, CO, USA) before attaching adhesive silver/silver chloride electrodes (Conmed Cleartrace; Conmed Corporation, NY, USA), which were secured in place with cohesive flexible bandage (Vetrap 2 inch; 3M, MN, USA). The ground electrode was placed in the opposite side of the limb. The EMG monitor was calibrated with the ‘start-up’ function, a process whereby
Figure 1. Electromyographic (EMG) monitoring of neuromuscular function at the larynx. (a) Schematic representation of an evoked EMG recorded at the larynx after stimulation of the recurrent laryngeal nerve showing three train-of-four (TOF) (2 Hz) stimuli at 15 second intervals. The first (T1) and fourth (T4) response of each train were used to calculate the TOF ratio (TOFR; T4:T1). (b) The first response (T1) to the TOF with the timescale expanded. The amplitude of each response is the difference between the peak (maximum) and valley (minimum) voltage obtained after the electrical stimulus (artifact). The lines on the original recordings have been made darker for a better view. © 2017 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved., ▪, 1e8
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Please cite this article in press as: Sakai DM, Martin-Flores M, Romano M et al. Recovery from rocuronium-induced neuromuscular block was longer in the larynx than in the pelvic limb of anesthetized dogs, Veterinary Anaesthesia and Analgesia (2017), http://dx.doi.org/10.1016/j.vaa.2016.04.001
Laryngeal neuromuscular block in dogs DM Sakai et al.
the supramaximal current (up to 70 mA) is automatically detected. Thereafter, TOF stimulation (similar to that applied to the RLn) was initiated. The EMG monitor measures the T1 and the TOFR, and expresses both as percentages of calibration values. Neuromuscular monitoring with AMG at the pelvic limb An AMG monitor (TOF Watch SX; Organon Ltd, Ireland) was placed on the contralateral pelvic limb in five dogs. Stimulating needles (25 gauge, 2.5 cm PrecisionGlide needle) were placed as described for EMG monitoring. The acceleration transducer was taped onto the dorsal aspect of the metatarsus. That limb was held fixed to the surgical table proximal to the tarsus to avoid excessive movement and the tarsus was allowed to flex freely. The AMG monitor was calibrated (CAL 2 function), a process whereby supramaximal current (up to 60 mA) is detected and the response of the evoked muscle twitch set to 100%. Train-of-four stimulation occurred every 15 seconds during the experiment. In order to reduce background noise of stimuli occurring simultaneously at the larynx and at the pelvic limbs, a lag of 5 seconds was introduced between the sites. The values of three consecutive indirectly evoked EMG T1 and TOFR, and AMG T1 and TOFR were recorded every 2 minutes; the median of the three measurements was used for statistical calculations.
Neuromuscular block and data collection After instrumentation for neuromuscular monitoring, rocuronium bromide (0.6 mg kg1; Zemuron; Merck & Co. Inc., NJ, USA) was administered IV over 5 seconds. Neuromuscular function was allowed to recover spontaneously and no acetylcholinesterase inhibitors were used. Neuromuscular function was monitored during recovery from rocuronium until no further increase in the TOFR could be observed for at least 5 minutes. All values obtained with EMG at the larynx and pelvic limb were normalized to the final T1 and TOFR values, i.e. when T1 and TOFR no longer increased (Fuchs-Buder et al. 2007). The time until the TOFR recovered to 0.70 (TOFR0.70) and 0.90 (TOFR0.90) was measured for each monitor. In addition, the time for T1 to return to 25% (T125%) and to 75% (T175%), and the recovery index (time interval between T125% and T75%) were measured for each of the two EMG monitors. Because laryngeal EMG data were recorded every 2 minutes, values closest to target outcomes could be missed; hence, for each dog, the values for T1 and TOF ratio were subjected to nonlinear curve fitting against time (Course Lowess curve, Prism 6; GraphPad Software Inc., CA, USA) (Fig. 2). The times for T125%, T175%, TOFR0.70 and TOFR0.90 were then interpolated from the curves. For AMG monitoring, the time when the TOFR returned to 0.9 was recorded.
Figure 2. Example of the recovery from rocuronium-induced neuromuscular block at the pelvic limb (open circles) and at the larynx (black triangles) in one dog. Train-of-four ratio (TOFR) values were normalized to the last value obtained at 60 minutes for each site of monitoring; hence the last value of each curve is always unity. A nonlinear curve (Course Lowess curve, Prism 6; GraphPad Software Inc., CA, USA) was fitted for each site to allow target times to be obtained by interpolation. In this example, when the pelvic limb reached TOFR0.90, the laryngeal TOFR was 0.30. 4
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Please cite this article in press as: Sakai DM, Martin-Flores M, Romano M et al. Recovery from rocuronium-induced neuromuscular block was longer in the larynx than in the pelvic limb of anesthetized dogs, Veterinary Anaesthesia and Analgesia (2017), http://dx.doi.org/10.1016/j.vaa.2016.04.001
Laryngeal neuromuscular block in dogs DM Sakai et al. Table 1 Recovery times of neuromuscular function in five anesthetized dogs after administration of rocuronium (0.6 mg kg1) measured at the larynx and at the pelvic limb with electromyography (EMG). Data are presented as mean ± standard deviation and median (range) for parametric and nonparametric data, respectively Recovery times (minutes)
Laryngeal EMG
Pelvic limb EMG
p-value
Recovery Recovery Recovery Recovery Recovery
41.2 ± 13.3 45.4 ± 12.7 26.2 (4.8e29.7) 32.3 ± 10.0 11.9 ± 9.7
28.7 ± 7.6 32.8 ± 9.1 15.5 (8.3e21.3) 24.4 ± 6.1 5.5 ± 1.0
0.011 0.003 0.418 0.020 0.656
to TOFR0.70 to TOFR0.90 to T125% to T175% index
TOF, train-of-four; T1, first twitch of train-of-four; TOFR0.70, spontaneous recovery time to TOF ratio of 0.70; TOFR0.90, spontaneous recovery time to TOF ratio of 0.90; T125%, spontaneous recovery time to T1 of 25% of baseline height; T175%, spontaneous recovery time to T1 of 75% of baseline height; recovery index, time from T125% to T175%.
Recovery from general anesthesia The dogs were allowed to recover from anesthesia after the surgical wound closure. The IV catheter was removed and the dogs were returned to their housing facility when they were able to ambulate without weakness or ataxia. Statistical analysis Data were confirmed for normality with the KolmogoroveSmirnov test. The times to reach target values (TOFR0.70, TOFR0.90, T125% and T175%) and the recovery index were compared between laryngeal EMG and pelvic limb EMG with paired t-tests (two-tailed) for parametric data, or Wilcoxon signed rank test for nonparametric results (Prism 6; GraphPad Software Inc., CA, USA). A one-sample t-test was used to test the significance of differences between EMG-derived TOFR in the larynx and EMG-derived TOFR in the limb when the latter values were 0.7 and 0.9 (Minitab 16.2.4; Minitab Inc., PA, USA). Significance was set at p < 0.05. Results are summarized as mean ± SD and median (range) for parametric and nonparametric data, respectively. Lastly, the time to reach a TOFR of 0.9 with AMG was also measured and reported in reference to the recovery time for TOFR0.90 measured at the larynx. Only descriptive results of AMG values are presented. Results All dogs recovered from anesthesia without complications. Rocuronium (0.6 mg kg1) administration resulted in complete neuromuscular block at all monitored sites in all animals. Technical difficulties in one dog prevented data collection from the laryngeal EMG after the rocuronium was administered; this dog was excluded from statistical and descriptive analysis.
The TOFR measured with EMG at the pelvic limb reached values of 0.7 and 0.9 significantly and consistently faster than at the larynx (Table 1). When the EMG TOFR measured at the pelvic limb reached 0.7 and 0.9, the TOFR values measured at the larynx were 0.32 ± 0.12 (p ¼ 0.002) and 0.38 ± 0.13 (p ¼ 0.001), respectively. The recovery time to T175% was significantly faster at the pelvic limb than at the larynx (p ¼ 0.020) (Table 1). The recovery indices at both sites were not significantly different. The recovery time for a TOFR 0.9 measured with AMG (n ¼ 4) at a pelvic limb was 34.7 ± 7.4 minutes. At that time, the TOFR measured at the larynx with EMG was 0.36 ± 0.12. Discussion The main outcome of this study was that spontaneous recovery of neuromuscular function was slower at the larynx than at the pelvic limb. Neuromuscular monitoring in anesthetized animals is usually performed at an extremity. The results of our work suggest that the current, clinically accepted technique of monitoring neuromuscular function in pelvic limbs cannot ensure that the recovery of laryngeal function is adequate. While data regarding the clinical implications of residual block in animals are lacking, results in humans show an association between residual block (measured at the adductor pollicis muscle) and negative respiratory outcomes, including hypoxia and upper airway obstruction, in the immediate postoperative period (Murphy et al. 2008b). Furthermore, without objective monitoring or routine reversal, residual block is a common finding in humans (Mortensen et al. 1995). In a clinical setting, an assumption is made that what is being measured on a limb regarding neuromuscular
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Laryngeal neuromuscular block in dogs DM Sakai et al.
transmission reliably indicates the status of other important muscle groups, such as those responsible for ventilation and protection of the upper airway. This assumption appears to be true in humans and in goats (Ibebunjo & Hall 1994; Kirov et al. 2004). The results of the present study show that, in dogs, spontaneous recovery of neuromuscular function at the larynx occurs substantially later than at the pelvic limb; laryngeal recovery occurred around 12 minutes later than pelvic limb recovery, i.e. recovery time was 36% longer at the larynx. In one dog, the larynx recovered 17 minutes later than the pelvic limb. The results agree with a previous study in dogs administered vecuronium (Iwasaki et al. 1994). In that experiment, the recovery of single twitch height (supramaximal intensity, 0.1 Hz, 0.2 ms) was slower in the cricothyroid (laryngeal adductor) than in the cranial tibial muscles (Iwasaki et al. 1994). Similar results have also been observed in cats, where recovery times of the posterior cricoarytenoid, lateral cricoarytenoid, and the vocal muscles were longer than for the cranial tibial muscle (Michalek-Sauberer et al. 2000). The data obtained previously in cats and dogs, and our current results suggest that measurements from the pelvic limb cannot be extrapolated reliably to the laryngeal musculature in these species. Thus decisions regarding advisability of removing the orotracheal tube, and whether neuromuscular blockade can, or should, be reversed pharmacologically, ought not to be based on observations at the pelvic limb. The present study does not suggest a mechanism responsible for the disparity between the observations in dogs and what has been reported in humans. Several factors can affect the duration of neuromuscular block in a given muscle, including distribution of fiber sizes, endplate size, ratio of endplate size to fiber size (Ibebunjo et al. 1996), muscle temperature (Bigland et al. 1958) and concentration that produces 50% block (Plaud et al. 1995). It is possible that any of these factors, or a combination of several, accounts for the observations. In this study, neuromuscular function was measured at the larynx and at the pelvic limb simultaneously with EMG. This monitoring technique has been used previously in humans to quantify neuromuscular function simultaneously in different muscles (Hemmerling et al. 2000). An EMGcapable tracheal tube was placed between the arytenoid cartilages and vocal cords of the dogs so that the recording electrode remained in contact with those structures. Stimulation of the RLn resulted in 6
muscle activation; the evoked EMG response was then recorded and quantified. The use of EMG, while infrequent for neuromuscular monitoring in clinical veterinary practice, allowed measurement at different sites simultaneously with one technique. When the EMG on the pelvic limb measured a TOFR0.90, the TOFR measured at the larynx was still only 0.45. While the study did not allow an evaluation of laryngeal function, the presence of fade measured at the larynx raises concern about the dogs' ability to abduct the larynx and maintain a patent airway if extubation were to occur at that time. In humans, even mild levels of residual block result in increased incidence of aspiration of solids into the trachea (Sundman et al. 2000). Until more data are available, avoiding recovery from anesthesia and extubation in the presence of fade at the larynx is probably the safest course of action. Two primary recovery outcomes, return to TOFR0.70 and TOFR0.90, were used in this study. These values have been used as indicators of adequate neuromuscular function (Viby-Mogensen et al. 1979; Kopman et al. 1997). Moreover, a recovery to TOFR0.70 of preblock levels in twitch amplitude or tetanic fade is suggested as an adequate end point of recovery of neuromuscular function by the monitoring guides published by the American College of Veterinary Anesthesia and Analgesia (http://acvaa.org). Different authors have suggested that, in humans, a TOFR of at least 0.90 should be the target (Eriksson et al. 1997; Eikermann et al. 2003, 2007; Heier et al. 2010), and some have suggested that a TOFR of 1.0 should be used when AMG monitoring is employed (Capron et al. 2004; Piccioni et al. 2014). The increase in the threshold TOFR from 0.70 to 0.90 was made, at least in part, in response to results showing that laryngeal dysfunction might be of clinical relevance when the TOFR measured at the adductor pollicis is < 0.9 (Eriksson et al. 1997; Eikermann et al. 2003). Our results suggest that a TOFR of 0.9 measured at a pelvic limb in dogs is probably inadequate to assume effective laryngeal function. The dogs in the present study were also instrumented with an AMG monitor on the contralateral pelvic limb, the reason being that an AMG monitor is more commonly used to quantify the neuromuscular status of veterinary patients in a clinical setting. When the AMG recorded a TOFR > 0.9, the TOFR measured at the larynx was only 0.36. A recent study compared EMG with AMG in dogs and was found that both monitors are not interchangeable (Sakai et al. 2015). Nevertheless, the observation that substantial fade was
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Please cite this article in press as: Sakai DM, Martin-Flores M, Romano M et al. Recovery from rocuronium-induced neuromuscular block was longer in the larynx than in the pelvic limb of anesthetized dogs, Veterinary Anaesthesia and Analgesia (2017), http://dx.doi.org/10.1016/j.vaa.2016.04.001
Laryngeal neuromuscular block in dogs DM Sakai et al.
measured at the larynx with EMG at the time when adequate recovery was assessed by AMG at the pelvic limb raises a clinically important question: can adequate recovery of laryngeal function be assumed when neuromuscular monitoring is conducted in a limb with AMG? Our results suggest that recovery of neuromuscular function measured with AMG at a pelvic limb might not ensure that laryngeal function has also been restored. Several limitations should be acknowledged. The gold standard for neuromuscular measurements is isometric force of contraction. Measuring force of contraction at the larynx is technically difficult, whereas apparatus for measuring EMG activity at the larynx is easily available. Contemporary measurements of EMG at the limb and the larynx had the virtue of allowing direct comparison of values obtained by similar methods. Measurements of laryngeal EMG can only provide information on the degree of muscle cell activation, and the extent to which protective laryngeal reflexes might actually be depressed can only be inferred. Data from only five dogs were presented in this study, a number considered to be small for a research study. Nonetheless, all dogs reacted in the same way and statistical differences were obtained. In summary, spontaneous recovery of neuromuscular function after administration of rocuronium in isoflurane-anesthetized dogs was approximately 36% slower at the larynx than at the pelvic limb. When EMG monitoring at the pelvic limb indicated that neuromuscular function had been restored, a substantial fade was still measured at the larynx. Conventional, quantitative neuromuscular monitoring instrumented at a pelvic limb might not be reliable for excluding residual block at the larynx in anesthetized dogs. Acknowledgements This work was funded by the Resident Research Grants Program of the College Research Council at Cornell University. Authors' contributions DMS: design, data acquisition, data management, statistical analysis and preparation of manuscript. MMF: design, data management, statistical analysis and preparation of manuscript. MR: data acquisition, revision of manuscript. CTT: data acquisition, revision of manuscript. LC: interpretation of data, revision of manuscript. RDG: interpretation of data, revision of manuscript. JC: design, surgery, revision of manuscript.
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Laryngeal neuromuscular block in dogs DM Sakai et al. adductor and abductor laryngeal muscles and tibialis anterior muscle in dogs. Br J Anaesth 72, 321e323. Kirov K, Motamed C, Decailliot F et al. (2004) Comparison of the neuromuscular blocking effect of cisatracurium and atracurium on the larynx and the adductor pollicis. Acta Anaesthesiol Scand 48, 577e581. Kopman AF, Yee PS, Neuman GG (1997) Relationship of the train-of-four fade ratio to clinical signs and symptoms of residual paralysis in awake volunteers. Anesthesiology 86, 765e771. Michalek-Sauberer A, Gilly H, Steinbereithner K et al. (2000) Effects of vecuronium and rocuronium in antagonistic laryngeal muscles and the anterior tibial muscle in the cat. Acta Anaesthesiol Scand 44, 503e510. Mortensen CR, Berg H, el-Mahdy A, Viby-Mogensen J (1995) Perioperative monitoring of neuromuscular transmission using acceleromyography prevents residual neuromuscular block following pancuronium. Acta Anaesthesiol Scand 39, 797e801. Murphy GS, Brull SJ (2010) Residual neuromuscular block: lessons unlearned. Part I: definitions, incidence, and adverse physiologic effects of residual neuromuscular block. Anesth Analg 111, 120e128. Murphy GS, Szokol JW, Marymont JH et al. (2008a) Residual neuromuscular blockade and critical respiratory events in the postanesthesia care unit. Anesth Analg 107, 130e137. Murphy GS, Szokol JW, Marymont JH et al. (2008b) Intraoperative acceleromyographic monitoring reduces
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the risk of residual neuromuscular blockade and adverse respiratory events in the postanesthesia care unit. Anesthesiology 109, 389e398. Piccioni F, Mariani L, Bogno L et al. (2014) An acceleromyographic train-of-four ratio of 1.0 reliably excludes respiratory muscle weakness after major abdominal surgery: a randomized double-blind study. Can J Anaesth 61, 641e649. Plaud B, Proost JH, Wierda JM et al. (1995) Pharmacokinetics and pharmacodynamics of rocuronium at the vocal cords and the adductor pollicis in humans. Clin Pharmacol Ther 58, 185e191. Sakai DM, Martin-Flores M, Tomak EA et al. (2015) Differences between acceleromyography and electromyography during neuromuscular function monitoring in anesthetized Beagle dogs. Vet Anaesth Analg 42, 233e241. Sundman E, Witt H, Olsson R et al. (2000) The incidence and mechanisms of pharyngeal and upper esophageal dysfunction in partially paralyzed humans: pharyngeal videoradiography and simultaneous manometry after atracurium. Anesthesiology 92, 977e984. Viby-Mogensen J, Jørgensen BC, Ording H (1979) Residual curarization in the recovery room. Anesthesiology 50, 539e541. Received 22 June 2015; accepted 15 April 2016. Available online xxx
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Please cite this article in press as: Sakai DM, Martin-Flores M, Romano M et al. Recovery from rocuronium-induced neuromuscular block was longer in the larynx than in the pelvic limb of anesthetized dogs, Veterinary Anaesthesia and Analgesia (2017), http://dx.doi.org/10.1016/j.vaa.2016.04.001
http://dx.doi.org/10.1016/j.vaa.2016.04.001
RESEARCH PAPER
Recovery from rocuronium-induced neuromuscular block was longer in the larynx than in the pelvic limb of anesthetized dogs Daniel M Sakai, Manuel Martin-Flores, Marta Romano, Chia T Tseng, Luis Campoy, Robin D Gleed & Jonathan Cheetham Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA Correspondence: Manuel Martin-Flores, 930 Campus Road, Box 32, Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA. Email: [email protected]
Abstract Objective To determine if neuromuscular monitoring at the pelvic limb accurately reflects neuromuscular function in the larynx after administration of rocuronium in anesthetized dogs. Study design Prospective experimental study. Animals Six healthy Beagle dogs. Methods Anesthesia was maintained in dogs with isoflurane and a continuous infusion of dexmedetomidine. Rocuronium (0.6 mg kg1) was administered intravenously to induce neuromuscular block. Train-of-four (TOF) impulses were applied to the left recurrent laryngeal nerve (RLn) and the peroneal nerve (Pn). The evoked TOF ratio (TOFR; T4:T1) was measured with electromyography (EMG) simultaneously at the larynx and at the pelvic limb. Spontaneous recoveries of T1 to 25% (T125%) and 75% (T175%) of twitch height, and to TOFR of 0.70 and 0.90 (TOFR0.90) at each EMG site were compared. Results Data from five dogs were analyzed. Times to T125% were similar at the pelvic limb and larynx when measured by EMG; time to T175% was slower at the larynx by 6 ± 4 minutes (p ¼ 0.012). The larynx had a slower recovery to TOFR0.70 (41 ± 13 minutes) and TOFR0.90 (45 ± 13 minutes) than did the pelvic limb [29 ± 8 minutes (p ¼ 0.011) and 33 ± 9 minutes (p ¼ 0.003), respectively]. When the pelvic limb EMG returned to TOFR0.70 and TOFR0.90, the larynx EMG TOFR0.70 and TOFR0.90 values were 0.32 ± 0.12 (p ¼ 0.001) and 0.38 ± 0.13 (p ¼ 0.001), respectively.
Conclusions and clinical relevance After administration of rocuronium, neuromuscular function assessed by EMG recovered approximately 36% slower at the larynx than at the pelvic limb. The results in these dogs suggest that quantitative neuromuscular monitoring instrumented at a pelvic limb may be unable to exclude residual block at the larynx in anesthetized dogs. Keywords airway obstruction, aspiration, complication, monitoring, residual paralysis. Introduction Residual neuromuscular block is the term used to describe the incomplete recovery of neuromuscular transmission in the postoperative period following the use of a neuromuscular blocking agent (NMBA). The incidence of residual neuromuscular block in humans has been reported to range between 2% and 64%, depending on the methods used, the NMBA administered and whether pharmacological reversal has been used (Murphy & Brull 2010). Residual paralysis has been associated with adverse respiratory events, such as postoperative hypoxemia and/or upper airway obstruction (Murphy et al. 2008a). In humans, the incidence of residual paralysis and its associated complications can be decreased with quantitative monitoring of neuromuscular function (Murphy et al. 2008b). Quantitative monitoring in a clinical setting is usually performed with electromyography (EMG) or acceleromyography (AMG). These monitors are available commercially and have been used previously in dogs (Sakai et al. 2015). However, neuromuscular monitoring evaluates the status of a
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Please cite this article in press as: Sakai DM, Martin-Flores M, Romano M et al. Recovery from rocuronium-induced neuromuscular block was longer in the larynx than in the pelvic limb of anesthetized dogs, Veterinary Anaesthesia and Analgesia (2017), http://dx.doi.org/10.1016/j.vaa.2016.04.001
Laryngeal neuromuscular block in dogs DM Sakai et al.
single nerveemuscle group and that information is frequently extrapolated to the entire skeletal musculature. Ideally, information about neuromuscular function obtained at one site should reflect the status of all motor units in the patient, or at least reflect the neuromuscular status of other nerveemuscle groups of clinical importance. However, the duration of neuromuscular block of distinct muscles is different (Ibebunjo & Hall 1994) and this discrepancy might differ between species. Return of laryngeal function is particularly important in the postoperative period, because both laryngeal adduction (to prevent aspiration) and abduction (for airway patency) require active laryngeal muscles. If return of neuromuscular function in the larynx were to lag behind that in the limb, results obtained from a limb might prompt premature removal of airway support and contribute to postoperative aspiration, hypoxemia and/or upper airway obstruction. In this investigation we measured the recovery time from rocuronium-induced neuromuscular block at the pelvic limb (one of the conventional sites of monitoring) and at the larynx in anesthetized dogs (site of clinical importance). The primary aim of this study was to compare recovery from rocuronium neuromuscular block at the pelvic limb and at the larynx by monitoring neuromuscular function using EMG. Concurrent measurements with AMG were obtained, as this technique is probably the most commonly used technique for quantitative neuromuscular monitoring in a clinical setting. We hypothesized that neuromuscular function returns faster at the pelvic limb than at the larynx after administration of rocuronium in anesthetized dogs. Materials and methods This investigation was approved by the Institutional Animal Care and Use Committee of Cornell University. Six healthy (based on regular physical examination and hematology) adult Beagle dogs were included. These dogs were participating in an unrelated research project that involved the surgical exposure of the left recurrent laryngeal nerve (RLn). The six intact female dogs were aged [mean ± standard deviation (SD)] 1.4 ± 0.2 years and weighed 7.4 ± 0.6 kg. Food but not water was withheld overnight prior to anesthesia. Each dog was administered dexmedetomidine (2 mg kg1; Dexdomitor; Pfizer Animal Health, NY, USA) and buprenorphine (20 mg kg1; Buprenex; Reckitt Benckiser Pharmaceuticals Inc., VA, USA) through a catheter in a cephalic vein. Anesthesia was 2
induced with propofol (2 mg kg1; PropoFlo; Abbott Laboratories, IL, USA) administered intravenously (IV). An EMG-capable tracheal tube (NIM EMG endotracheal tube; Medtronic Xomed, FL, USA) was inserted orally, and the cuff was inflated and connected to a rebreathing circle system (Ohmeda Modulus SE; GE Healthcare, WI, USA). Anesthesia was maintained with isoflurane (Forane; Arkema Inc., PA, USA) in oxygen at an end-tidal isoflurane concentration (FE0 Iso) of 1.3e1.5%. Dexmedetomidine (2 mg kg1 hour1) was infused IV (Medfusion 3500; Smiths Medical ASD Inc., MN, USA). The lungs were ventilated mechanically (Ohmeda 7900; GE Healthcare) to maintain the end-tidal carbon dioxide tension (PE0 CO2) at 35e45 mmHg (4.7e6.0 kPa). A balanced electrolyte solution (5 mL kg1 hour1; Plasma-Lyte A; Abbott Laboratories) and meloxicam (0.2 mg kg1; Metacam; Boehringer Ingelheim Vetmedica, Inc., MO, USA) were administered IV. Monitoring during anesthesia included continuous electrocardiography, hemoglobin oxygen saturation (SpO2), PE0 CO2, FE0 Iso, oscillometric noninvasive arterial pressure (neonatal size 3, placed above one carpus; 3 minute duty cycle) and rectal temperature (Cardell Touch; Midmark Corp., OH, USA). Temperature was maintained at 38e39 C with a forced-air warming device. Dogs remained in dorsal recumbency for the duration of anesthesia. Neuromuscular monitoring with EMG at the larynx After clipping and aseptic preparation of the skin, a lateral approach to the larynx was made in a standard fashion ventral to the right linguofacial vein. The subcutaneous fascia was divided bluntly and the RLn identified, running on the caudolateral aspect of the cricoid cartilage, and a cuff electrode (2 mm diameter, MED-EL; Ardiem Medical Inc., PA, USA) was placed around the left RLn. The ground electrode of the EMG tracheal tube was placed on the dog's forehead. Supramaximal current (1e3 mA; Model 2100 Isolated Pulse Stimulator; A-M Systems, WA, USA) was applied to the RLn though the cuff electrode in a train-of-four (TOF) pattern (2 Hz, 0.2 ms pulse duration) repeated every 15 seconds throughout the experiment. Three consecutive, indirectly evoked TOF electromyograms were stored (computer files recorded with Sierra Wave; Cadwell Laboratories, Inc., WA, USA) every 2 minutes throughout the experiment for post hoc measurement. Stimulation of the RLn produced an EMG signal that was detected by the electrodes on the tracheal tube (Fig. 1a); an artifact (representing the stimuli) followed
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Please cite this article in press as: Sakai DM, Martin-Flores M, Romano M et al. Recovery from rocuronium-induced neuromuscular block was longer in the larynx than in the pelvic limb of anesthetized dogs, Veterinary Anaesthesia and Analgesia (2017), http://dx.doi.org/10.1016/j.vaa.2016.04.001
Laryngeal neuromuscular block in dogs DM Sakai et al.
by a typical biphasic EMG curve was displayed in real time on the Sierra Wave monitor (Fig. 1b). The amplitudes of the first (T1) and fourth (T4) EMG curves in each TOF (Fig. 1) were measured (MATLAB Version R2013b; The MathWorks, Inc., MA, USA), and the TOF ratio (TOFR; T4:T1) was calculated. The median of the three measurements was used for analysis. The surgical wound was closed in two layers using absorbable sutures. Neuromuscular monitoring with EMG at the pelvic limb The left or right (selected randomly by ballot) peroneal nerve (Pn) was stimulated with an EMG monitor
(M-NMT module of Datex-Ohmeda AS/3; GE Healthcare) using 25 gauge, 2.5 cm needles (PrecisionGlide; Becton, Dickinson and Company, NJ, USA) inserted subcutaneously 2 cm apart where the Pn crosses the lateral head of the gastrocnemius muscle at the level of the femorotibial joint. The hair over the belly of the cranial tibial muscle was clipped and the skin cleansed with Nuprep Skin Prep Gel (Weaver and Company, CO, USA) before attaching adhesive silver/silver chloride electrodes (Conmed Cleartrace; Conmed Corporation, NY, USA), which were secured in place with cohesive flexible bandage (Vetrap 2 inch; 3M, MN, USA). The ground electrode was placed in the opposite side of the limb. The EMG monitor was calibrated with the ‘start-up’ function, a process whereby
Figure 1. Electromyographic (EMG) monitoring of neuromuscular function at the larynx. (a) Schematic representation of an evoked EMG recorded at the larynx after stimulation of the recurrent laryngeal nerve showing three train-of-four (TOF) (2 Hz) stimuli at 15 second intervals. The first (T1) and fourth (T4) response of each train were used to calculate the TOF ratio (TOFR; T4:T1). (b) The first response (T1) to the TOF with the timescale expanded. The amplitude of each response is the difference between the peak (maximum) and valley (minimum) voltage obtained after the electrical stimulus (artifact). The lines on the original recordings have been made darker for a better view. © 2017 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved., ▪, 1e8
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Please cite this article in press as: Sakai DM, Martin-Flores M, Romano M et al. Recovery from rocuronium-induced neuromuscular block was longer in the larynx than in the pelvic limb of anesthetized dogs, Veterinary Anaesthesia and Analgesia (2017), http://dx.doi.org/10.1016/j.vaa.2016.04.001
Laryngeal neuromuscular block in dogs DM Sakai et al.
the supramaximal current (up to 70 mA) is automatically detected. Thereafter, TOF stimulation (similar to that applied to the RLn) was initiated. The EMG monitor measures the T1 and the TOFR, and expresses both as percentages of calibration values. Neuromuscular monitoring with AMG at the pelvic limb An AMG monitor (TOF Watch SX; Organon Ltd, Ireland) was placed on the contralateral pelvic limb in five dogs. Stimulating needles (25 gauge, 2.5 cm PrecisionGlide needle) were placed as described for EMG monitoring. The acceleration transducer was taped onto the dorsal aspect of the metatarsus. That limb was held fixed to the surgical table proximal to the tarsus to avoid excessive movement and the tarsus was allowed to flex freely. The AMG monitor was calibrated (CAL 2 function), a process whereby supramaximal current (up to 60 mA) is detected and the response of the evoked muscle twitch set to 100%. Train-of-four stimulation occurred every 15 seconds during the experiment. In order to reduce background noise of stimuli occurring simultaneously at the larynx and at the pelvic limbs, a lag of 5 seconds was introduced between the sites. The values of three consecutive indirectly evoked EMG T1 and TOFR, and AMG T1 and TOFR were recorded every 2 minutes; the median of the three measurements was used for statistical calculations.
Neuromuscular block and data collection After instrumentation for neuromuscular monitoring, rocuronium bromide (0.6 mg kg1; Zemuron; Merck & Co. Inc., NJ, USA) was administered IV over 5 seconds. Neuromuscular function was allowed to recover spontaneously and no acetylcholinesterase inhibitors were used. Neuromuscular function was monitored during recovery from rocuronium until no further increase in the TOFR could be observed for at least 5 minutes. All values obtained with EMG at the larynx and pelvic limb were normalized to the final T1 and TOFR values, i.e. when T1 and TOFR no longer increased (Fuchs-Buder et al. 2007). The time until the TOFR recovered to 0.70 (TOFR0.70) and 0.90 (TOFR0.90) was measured for each monitor. In addition, the time for T1 to return to 25% (T125%) and to 75% (T175%), and the recovery index (time interval between T125% and T75%) were measured for each of the two EMG monitors. Because laryngeal EMG data were recorded every 2 minutes, values closest to target outcomes could be missed; hence, for each dog, the values for T1 and TOF ratio were subjected to nonlinear curve fitting against time (Course Lowess curve, Prism 6; GraphPad Software Inc., CA, USA) (Fig. 2). The times for T125%, T175%, TOFR0.70 and TOFR0.90 were then interpolated from the curves. For AMG monitoring, the time when the TOFR returned to 0.9 was recorded.
Figure 2. Example of the recovery from rocuronium-induced neuromuscular block at the pelvic limb (open circles) and at the larynx (black triangles) in one dog. Train-of-four ratio (TOFR) values were normalized to the last value obtained at 60 minutes for each site of monitoring; hence the last value of each curve is always unity. A nonlinear curve (Course Lowess curve, Prism 6; GraphPad Software Inc., CA, USA) was fitted for each site to allow target times to be obtained by interpolation. In this example, when the pelvic limb reached TOFR0.90, the laryngeal TOFR was 0.30. 4
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Please cite this article in press as: Sakai DM, Martin-Flores M, Romano M et al. Recovery from rocuronium-induced neuromuscular block was longer in the larynx than in the pelvic limb of anesthetized dogs, Veterinary Anaesthesia and Analgesia (2017), http://dx.doi.org/10.1016/j.vaa.2016.04.001
Laryngeal neuromuscular block in dogs DM Sakai et al. Table 1 Recovery times of neuromuscular function in five anesthetized dogs after administration of rocuronium (0.6 mg kg1) measured at the larynx and at the pelvic limb with electromyography (EMG). Data are presented as mean ± standard deviation and median (range) for parametric and nonparametric data, respectively Recovery times (minutes)
Laryngeal EMG
Pelvic limb EMG
p-value
Recovery Recovery Recovery Recovery Recovery
41.2 ± 13.3 45.4 ± 12.7 26.2 (4.8e29.7) 32.3 ± 10.0 11.9 ± 9.7
28.7 ± 7.6 32.8 ± 9.1 15.5 (8.3e21.3) 24.4 ± 6.1 5.5 ± 1.0
0.011 0.003 0.418 0.020 0.656
to TOFR0.70 to TOFR0.90 to T125% to T175% index
TOF, train-of-four; T1, first twitch of train-of-four; TOFR0.70, spontaneous recovery time to TOF ratio of 0.70; TOFR0.90, spontaneous recovery time to TOF ratio of 0.90; T125%, spontaneous recovery time to T1 of 25% of baseline height; T175%, spontaneous recovery time to T1 of 75% of baseline height; recovery index, time from T125% to T175%.
Recovery from general anesthesia The dogs were allowed to recover from anesthesia after the surgical wound closure. The IV catheter was removed and the dogs were returned to their housing facility when they were able to ambulate without weakness or ataxia. Statistical analysis Data were confirmed for normality with the KolmogoroveSmirnov test. The times to reach target values (TOFR0.70, TOFR0.90, T125% and T175%) and the recovery index were compared between laryngeal EMG and pelvic limb EMG with paired t-tests (two-tailed) for parametric data, or Wilcoxon signed rank test for nonparametric results (Prism 6; GraphPad Software Inc., CA, USA). A one-sample t-test was used to test the significance of differences between EMG-derived TOFR in the larynx and EMG-derived TOFR in the limb when the latter values were 0.7 and 0.9 (Minitab 16.2.4; Minitab Inc., PA, USA). Significance was set at p < 0.05. Results are summarized as mean ± SD and median (range) for parametric and nonparametric data, respectively. Lastly, the time to reach a TOFR of 0.9 with AMG was also measured and reported in reference to the recovery time for TOFR0.90 measured at the larynx. Only descriptive results of AMG values are presented. Results All dogs recovered from anesthesia without complications. Rocuronium (0.6 mg kg1) administration resulted in complete neuromuscular block at all monitored sites in all animals. Technical difficulties in one dog prevented data collection from the laryngeal EMG after the rocuronium was administered; this dog was excluded from statistical and descriptive analysis.
The TOFR measured with EMG at the pelvic limb reached values of 0.7 and 0.9 significantly and consistently faster than at the larynx (Table 1). When the EMG TOFR measured at the pelvic limb reached 0.7 and 0.9, the TOFR values measured at the larynx were 0.32 ± 0.12 (p ¼ 0.002) and 0.38 ± 0.13 (p ¼ 0.001), respectively. The recovery time to T175% was significantly faster at the pelvic limb than at the larynx (p ¼ 0.020) (Table 1). The recovery indices at both sites were not significantly different. The recovery time for a TOFR 0.9 measured with AMG (n ¼ 4) at a pelvic limb was 34.7 ± 7.4 minutes. At that time, the TOFR measured at the larynx with EMG was 0.36 ± 0.12. Discussion The main outcome of this study was that spontaneous recovery of neuromuscular function was slower at the larynx than at the pelvic limb. Neuromuscular monitoring in anesthetized animals is usually performed at an extremity. The results of our work suggest that the current, clinically accepted technique of monitoring neuromuscular function in pelvic limbs cannot ensure that the recovery of laryngeal function is adequate. While data regarding the clinical implications of residual block in animals are lacking, results in humans show an association between residual block (measured at the adductor pollicis muscle) and negative respiratory outcomes, including hypoxia and upper airway obstruction, in the immediate postoperative period (Murphy et al. 2008b). Furthermore, without objective monitoring or routine reversal, residual block is a common finding in humans (Mortensen et al. 1995). In a clinical setting, an assumption is made that what is being measured on a limb regarding neuromuscular
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Laryngeal neuromuscular block in dogs DM Sakai et al.
transmission reliably indicates the status of other important muscle groups, such as those responsible for ventilation and protection of the upper airway. This assumption appears to be true in humans and in goats (Ibebunjo & Hall 1994; Kirov et al. 2004). The results of the present study show that, in dogs, spontaneous recovery of neuromuscular function at the larynx occurs substantially later than at the pelvic limb; laryngeal recovery occurred around 12 minutes later than pelvic limb recovery, i.e. recovery time was 36% longer at the larynx. In one dog, the larynx recovered 17 minutes later than the pelvic limb. The results agree with a previous study in dogs administered vecuronium (Iwasaki et al. 1994). In that experiment, the recovery of single twitch height (supramaximal intensity, 0.1 Hz, 0.2 ms) was slower in the cricothyroid (laryngeal adductor) than in the cranial tibial muscles (Iwasaki et al. 1994). Similar results have also been observed in cats, where recovery times of the posterior cricoarytenoid, lateral cricoarytenoid, and the vocal muscles were longer than for the cranial tibial muscle (Michalek-Sauberer et al. 2000). The data obtained previously in cats and dogs, and our current results suggest that measurements from the pelvic limb cannot be extrapolated reliably to the laryngeal musculature in these species. Thus decisions regarding advisability of removing the orotracheal tube, and whether neuromuscular blockade can, or should, be reversed pharmacologically, ought not to be based on observations at the pelvic limb. The present study does not suggest a mechanism responsible for the disparity between the observations in dogs and what has been reported in humans. Several factors can affect the duration of neuromuscular block in a given muscle, including distribution of fiber sizes, endplate size, ratio of endplate size to fiber size (Ibebunjo et al. 1996), muscle temperature (Bigland et al. 1958) and concentration that produces 50% block (Plaud et al. 1995). It is possible that any of these factors, or a combination of several, accounts for the observations. In this study, neuromuscular function was measured at the larynx and at the pelvic limb simultaneously with EMG. This monitoring technique has been used previously in humans to quantify neuromuscular function simultaneously in different muscles (Hemmerling et al. 2000). An EMGcapable tracheal tube was placed between the arytenoid cartilages and vocal cords of the dogs so that the recording electrode remained in contact with those structures. Stimulation of the RLn resulted in 6
muscle activation; the evoked EMG response was then recorded and quantified. The use of EMG, while infrequent for neuromuscular monitoring in clinical veterinary practice, allowed measurement at different sites simultaneously with one technique. When the EMG on the pelvic limb measured a TOFR0.90, the TOFR measured at the larynx was still only 0.45. While the study did not allow an evaluation of laryngeal function, the presence of fade measured at the larynx raises concern about the dogs' ability to abduct the larynx and maintain a patent airway if extubation were to occur at that time. In humans, even mild levels of residual block result in increased incidence of aspiration of solids into the trachea (Sundman et al. 2000). Until more data are available, avoiding recovery from anesthesia and extubation in the presence of fade at the larynx is probably the safest course of action. Two primary recovery outcomes, return to TOFR0.70 and TOFR0.90, were used in this study. These values have been used as indicators of adequate neuromuscular function (Viby-Mogensen et al. 1979; Kopman et al. 1997). Moreover, a recovery to TOFR0.70 of preblock levels in twitch amplitude or tetanic fade is suggested as an adequate end point of recovery of neuromuscular function by the monitoring guides published by the American College of Veterinary Anesthesia and Analgesia (http://acvaa.org). Different authors have suggested that, in humans, a TOFR of at least 0.90 should be the target (Eriksson et al. 1997; Eikermann et al. 2003, 2007; Heier et al. 2010), and some have suggested that a TOFR of 1.0 should be used when AMG monitoring is employed (Capron et al. 2004; Piccioni et al. 2014). The increase in the threshold TOFR from 0.70 to 0.90 was made, at least in part, in response to results showing that laryngeal dysfunction might be of clinical relevance when the TOFR measured at the adductor pollicis is < 0.9 (Eriksson et al. 1997; Eikermann et al. 2003). Our results suggest that a TOFR of 0.9 measured at a pelvic limb in dogs is probably inadequate to assume effective laryngeal function. The dogs in the present study were also instrumented with an AMG monitor on the contralateral pelvic limb, the reason being that an AMG monitor is more commonly used to quantify the neuromuscular status of veterinary patients in a clinical setting. When the AMG recorded a TOFR > 0.9, the TOFR measured at the larynx was only 0.36. A recent study compared EMG with AMG in dogs and was found that both monitors are not interchangeable (Sakai et al. 2015). Nevertheless, the observation that substantial fade was
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Please cite this article in press as: Sakai DM, Martin-Flores M, Romano M et al. Recovery from rocuronium-induced neuromuscular block was longer in the larynx than in the pelvic limb of anesthetized dogs, Veterinary Anaesthesia and Analgesia (2017), http://dx.doi.org/10.1016/j.vaa.2016.04.001
Laryngeal neuromuscular block in dogs DM Sakai et al.
measured at the larynx with EMG at the time when adequate recovery was assessed by AMG at the pelvic limb raises a clinically important question: can adequate recovery of laryngeal function be assumed when neuromuscular monitoring is conducted in a limb with AMG? Our results suggest that recovery of neuromuscular function measured with AMG at a pelvic limb might not ensure that laryngeal function has also been restored. Several limitations should be acknowledged. The gold standard for neuromuscular measurements is isometric force of contraction. Measuring force of contraction at the larynx is technically difficult, whereas apparatus for measuring EMG activity at the larynx is easily available. Contemporary measurements of EMG at the limb and the larynx had the virtue of allowing direct comparison of values obtained by similar methods. Measurements of laryngeal EMG can only provide information on the degree of muscle cell activation, and the extent to which protective laryngeal reflexes might actually be depressed can only be inferred. Data from only five dogs were presented in this study, a number considered to be small for a research study. Nonetheless, all dogs reacted in the same way and statistical differences were obtained. In summary, spontaneous recovery of neuromuscular function after administration of rocuronium in isoflurane-anesthetized dogs was approximately 36% slower at the larynx than at the pelvic limb. When EMG monitoring at the pelvic limb indicated that neuromuscular function had been restored, a substantial fade was still measured at the larynx. Conventional, quantitative neuromuscular monitoring instrumented at a pelvic limb might not be reliable for excluding residual block at the larynx in anesthetized dogs. Acknowledgements This work was funded by the Resident Research Grants Program of the College Research Council at Cornell University. Authors' contributions DMS: design, data acquisition, data management, statistical analysis and preparation of manuscript. MMF: design, data management, statistical analysis and preparation of manuscript. MR: data acquisition, revision of manuscript. CTT: data acquisition, revision of manuscript. LC: interpretation of data, revision of manuscript. RDG: interpretation of data, revision of manuscript. JC: design, surgery, revision of manuscript.
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Please cite this article in press as: Sakai DM, Martin-Flores M, Romano M et al. Recovery from rocuronium-induced neuromuscular block was longer in the larynx than in the pelvic limb of anesthetized dogs, Veterinary Anaesthesia and Analgesia (2017), http://dx.doi.org/10.1016/j.vaa.2016.04.001