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Recovery from neuromuscular block in dogs: restoration of spontaneous ventilation does not exclude residual blockade
Veterinary Anaesthesia and Analgesia, 2014, 41, 269–277
doi:10.1111/vaa.12109
RESEARCH PAPER
Recovery from neuromuscular block in dogs: restoration of spontaneous ventilation does not exclude residual blockade Manuel Martin-Flores, Daniel M Sakai, Luis Campoy & RD Gleed Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
Correspondence: Manuel Martin-Flores, Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Box 32, Ithaca, NY 14853, USA. E-mail: [email protected]
Abstract Objective To evaluate if return of spontaneous ventilation to pre-relaxation values indicates complete recovery from neuromuscular blockade. Study design Prospective, with each individual acting as its own control. Animals Ten healthy adult female Beagle dogs weighing 6.2–9.4 kg. Methods Dogs were anesthetized with propofol, dexemedetomidine and isoflurane. Spontaneous ventilation was assessed by measuring end-tidal CO2, expired tidal volume, peak inspiratory flow, respiratory rate and minute ventilation. Vecuronium 25 lg kg1 IV was administered and neuromuscular block was evaluated by measuring the train-of-four (TOF) ratio with acceleromyography in the hind limb. During spontaneous recovery from neuromuscular block, the TOF ratio when each ventilatory variable returned to baseline was recorded. Results This dose of vecuronium produced moderate neuromuscular block in all dogs, with TOF ratio values of 0–18% at maximal block. Expired tidal volume, peak inspiratory flow and minute ventilation returned to pre-relaxation values when the median TOF ratio was ≤ 20%. The median TOF ratio was 42% when the end-tidal CO2 returned to prerelaxation values.
Conclusions and clinical relevance Significant residual neuromuscular block could be measured at the hind limb with acceleromyography when ventilation had spontaneously returned to prevecuronium values. Monitoring spontaneous ventilation, including end-tidal CO2, expired tidal volume, peak inspiratory flow or minute ventilation cannot be used as a surrogate for objective neuromuscular monitoring, and this practice may increase the risk of postoperative residual paralysis. Keywords anaesthesia, neuromuscular blockade, residual blockade, vecuronium, ventilation.
Introduction Postoperative residual curarization (PORC) is a potential complication that arises in the immediate post-anesthesia period when recovery from neuromuscular block is incomplete (Murphy et al. 2005). In people, residual neuromuscular block increases the risk of adverse respiratory events following anesthesia, including upper airway obstruction and hypoxemia (Murphy et al. 2008). A strategy to minimize the risk of PORC is to monitor the degree of blockade prior to recovery from general anesthesia. Indeed, quantitative monitoring with acceleromyography (AMG) decreases the incidence of complications related to PORC in humans (Murphy et al. 2011), and is more precise than subjective visual assessment of the evoked muscular responses during nerve stimulation in anesthetized horses 269
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(Martin-Flores et al. 2008). The impact of residual neuromuscular block in animals has not been thoroughly investigated. Without the use of a nerve stimulator, the anesthetist might be inclined to judge recovery from neuromuscular block based on the presence and quality of spontaneous muscular activity. Particularly, evaluation of ventilation might be used to assess recovery (Alderson et al. 2007; Videira & Vieira 2011). There is, however, a potentially dangerous caveat with this approach: all muscle groups do not display the same sensitivity to neuromuscular blocking agents (NMBA). Substantial differences in duration of neuromuscular block between muscles have been documented; in particular the diaphragm recovers earlier than other more peripheral muscles (Ibebunjo & Hall 1994; Ibebunjo et al. 1999). In other words, ventilatory function could be restored while neuromuscular transmission in other muscles is still impaired. In people, forced vital capacity recovers to acceptable levels when the train-of-four (TOF) ratio is only 60%; that is, substantial neuromuscular block is still present by the time the forced vital capacity has recovered (Eikermann et al. 2004). To our knowledge, no formal studies have been carried out to investigate whether recovery of spontaneous ventilation is an adequate monitoring method for assessing recovery from modern NMBA in dogs. In the current investigation we evaluated the spontaneous recovery of several ventilatory variables following neuromuscular block while monitoring neuromuscular transmission with AMG at the peroneal (common fibular) nerve in dogs under general anesthesia. We hypothesized that during spontaneous recovery from vecuronium-induced neuromuscular block, ventilatory variables would return to pre-relaxation values before the acceleromyographic TOF ratio measured at the pelvic limb does, and hence that spontaneous ventilation is a poor indicator of appropriate recovery from neuromuscular block. Materials and methods This project was approved by the local IACUC (protocol 2011-0054). Ten healthy adult female Beagle dogs, with body weights between 6.2 and 9.4 kg were included in this investigation. After overnight fasting, an intravenous (IV) catheter was inserted into a cephalic vein and dexmedetomidine (Dexdomitor; Orion Corporation, Finland) 270
1 lg kg1 was administered IV. Following ~3 minutes of oxygen supplementation via face mask, propofol (Propoflo; Abbott Laboratories, IL, USA) 30–40 mg was administered IV and the trachea was intubated with a 6.5 or 7 mm internal diameter cuffed orotracheal tube. General anesthesia was maintained with isoflurane (Isothesia; Butler Schein Animal Health, OH, USA) in oxygen and a constant rate infusion of dexmedetomidine (1 lg kg1 hour1). Lactated Ringer’s solution was infused through the IV catheter. The inspired concentration of isoflurane was adjusted so that no response, other than the expected evoked muscle contractions, was seen during nerve stimulation. End-tidal isoflurane concentration was constant throughout the time of data collection. Monitoring during general anesthesia consisted of continuous ECG, pulse oximetry (SpO2), esophageal temperature and oscillometric arterial blood pressure measured every 3 minutes (Cardell MAX-12 HD; Midmark Corporation, OH, USA). Dogs were kept in left lateral recumbency and a blanket with circulating warm water and one with forced warm air were used to maintain esophageal temperature between 36.0 and 38.0 °C. All dogs were allowed to ventilate spontaneously throughout the experiment. Neuromuscular monitoring and block Quantitative neuromuscular transmission was monitored with AMG (TOF-Watch; Organon Ltd, Dublin, Ireland). Subcutaneous needles were inserted ~1 inch apart over the peroneal nerve on the right pelvic limb, and the acceleration sensitive crystal was taped to the dorsal aspect of the paw: the limb was supported in a horizontal position so that the tarsus would flex freely and unopposed during nerve stimulation. After at least 15 minutes of nerve stimulation with TOF stimulation every 15 seconds (2 Hz, 60 mA, pulse duration 0.2 milliseconds) to allow for stabilization and twitch potentiation, the AMG monitor was calibrated and nerve stimulation was resumed with TOF every 15 seconds. Immediately after baseline values had been obtained (see below), 25 lg kg1 vecuronium (Vecuronium Bromide; SUN Pharmaceutical Industries Ltd. Gujarat, India) was administered IV over 5 seconds into the catheter. The dose of vecuronium was chosen after pilot studies and was expected to produce partial block without causing apnea. The display on the accelerometer (either TOF count or TOF ratio) was recorded.
© 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 41, 269–277
Ventilatory function and recovery from neuromuscular block M Martin-Flores et al.
Respiratory values The spontaneous respiratory rate (fR), partial pressure of end-tidal carbon dioxide (PE′CO2) and endtidal percentage of isoflurane (FE′Iso) were measured from the tracheal tube with a side-stream gas analyzer (Datex-Ohmeda AS/3; Datex-Ohmeda Instrumentation Corp, Helsinki, Finland). Expired tidal volume (V_ T ) and peak inspiratory flow (Pif) were measured at the connection between the tracheal tube and the circle breathing circuit (NICO2; Respironics Novametrix, CT, USA). fR, PE′CO2, FE′Iso, V_ T , and Pif were recorded immediately after each TOF. Subsequently, minute ventilation (V_ E ) was calculated as the product of V_ T and fR. V_ T , Pif and V_ E were indexed to each animal’s weight for analysis. Analysis To minimize the effects of twitch-to-twitch variation of TOF values and breath-to-breath variation of ventilation values, the median of the five consecutive measurements immediately prior to vecuronium administration was used for baseline for each dog. A similar procedure was used when neuromuscular block was maximal and when recovery from neuromuscular block was complete; neuromuscular block was considered maximal as soon as five consecutive AMG readings at the lowest level were recorded; recovery from block was considered complete as soon as the TOF ratio equaled or exceeded baseline values for at least five consecutive readings. In addition to the values obtained at baseline, maximal block and complete recovery (see above), values for all variables were also recorded every 15 seconds (immediately following each TOF) throughout the recovery phase of neuromuscular block i.e., from the time TOF ratio started to increase over time until complete recovery. Data are summarized as median (minimum, maximum). Values for fR, PE′CO2, VT, Pif, and V_ E were normalized to baseline and expressed as a fraction of that value. Accordingly, and as an example, if for dog #1 baseline V_ T was 10 mL kg1 and during maximal neuromuscular blockade it decreased to 4 mL kg1, then its fractional value during maximal block was 0.4 (4 mL kg1/ 10 mL kg1). Values for TOF ratio were also normalized to baseline but they were expressed as a percentage rather than a simple fraction (e.g.; 69/ 98 9 100 = 70%).
Due to the internal program logic of the TOFWatch monitor, a TOF count (0–4) is displayed by the monitor when neuromuscular block is deep, and a TOF ratio is displayed if block is less intense. Specifically, a TOF count is reported when the magnitude of the first component of the TOF (T1) is <20% of baseline, and a TOF ratio is calculated when T1 is ≥ 20% of baseline (Martin-Flores et al. 2012b). Therefore, AMG results ranging from 0 to 4 represent TOF counts (0–4 counts), and actual TOF ratios are expressed in percentage (%). The TOF ratio when fR, V_ T , Pif and V_ E returned to, or exceeded 0.7 and 1.0 of their respective baseline values was recorded. If a variable returned to 0.7 or 1.0 of baseline when only a TOF count was displayed by the AMG monitor, then a TOF ratio of 0% was assigned. Since it is expected that the PE′CO2 would accumulate during partial neuromuscular block, and then decrease towards baseline during recovery from neuromuscular block, then the TOF ratio when PE′CO2 returned to 1.3 (i.e. 30% above baseline) and 1.0 of baseline were recorded. Values for all variables during maximal block and recovery were compared with those at baseline with the Wilcoxon Signed Rank Test (Statistix 9.0; Analytical Software, FL, USA). Bonferroni adjustments were imposed for multiple comparisons. Differences were considered significant when p < 0.05. Results All dogs recovered uneventfully from general anesthesia, and the TOF ratio returned to baseline before the orotracheal tube was removed. Apnea was not seen in any individual, even though a TOF count of zero was seen in two dogs. Desaturation never occurred; furthermore, SpO2 was never <99% for any dog at any time during anesthesia. Absolute magnitudes for TOF ratio, E′Iso, fR, PE′CO2, VT, Pif and V_ E at baseline, maximal depth of neuromuscular block and recovery are summarized in Table 1. In five dogs, VT and Pif decreased to values below the minimum sensitivity of the respiratory monitor (30 mL and 0.5 L minute1, respectively) during the period of maximal neuromuscular blockade; a value of zero was assigned in those cases. When VT, Pif and V_ E returned to or exceeded 0.7 and 1.0 of baseline, median TOF ratio ranged between 14 and 20% (Table 2 and Fig. 1). Endtidal CO2 returned to 1.3 of baseline in all individuals, but reached 1.0 of baseline in only seven dogs. The TOF ratio when that occurred was
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Ventilatory function and recovery from neuromuscular block M Martin-Flores et al.
(a)
(b)
Figure 1 Values displayed by the TOF-Watch monitor when tidal volume (VT) (a), peak inspiratory flow (Pif) (b) and minute ventilation (V_ E ) (c) first returned to or exceeded 0.7 (▲) and 1.0 (○) of their baseline value in dogs recovering spontaneously from neuromuscular block induced by intravenous vecuronium (25 lg kg1). The TOF-Watch displays TOF count (C0 to C4) when neuromuscular block is intense and TOF ratio (%) when block is less. There was substantial residual impairment of neuromuscular transmission when tidal volume, peak inspiratory pressure and minute ventilation had returned to baseline.
17% and 42%, respectively (Table 2 and Fig. 2). The fR returned to 0.7 of its baseline value when the median TOF ratio was 13%, but only returned to 1.0 in two individuals, hence results for that variable are not reported (Table 2). The time lag between the return of a ventilatory variable to or in excess of baseline, and the return of the TOF ratio to baseline, is presented in Table 2. An example of the relationship between the acceleromyographic TOF ratio at the peroneal nerve and PE′CO2, VT, Pif and V_ E during baseline, maximal block and recovery are illustrated in Fig. 3.
Table 1 Median and (range) values for train-of-four (TOF) ratio, end-tidal isoflurane concentration (E′Iso), end-tidal carbon dioxide pressure (PE′CO2), expired tidal volume (VT), peak inspiratory flow (Pif), respiratory rate (fR) and minute ventilation (V_ E ) at baseline, during maximal neuromuscular block and after recovery from nondepolarizing neuromuscular block with vecuronium 25 lg kg1 in dogs
(c) Baseline TOF ratio (%) E0 Iso (%) PE0 CO2 (mmHg) PE0 CO2 (kPa) VT (mL kg1) Pif (mL kg1 second1) fR (bpm) V_ E (mL kg1 minute1)
96 (81, 100)
Maximum block
Recovery
0 (0, 18)*
94 (91, 100)
1.5 (1.1, 1.7) 1.55 (1.1, 2) 46 (42, 50) 46 (34, 57)
1.55 (1.1, 1.8) 46 (42, 50)
6.1 (5.5, 6.7)
6.1 (4.5, 7.6)
6.1 (5.6, 6.7)
10 (9, 15) 27 (20, 40)
2 (0, 7)* 9 (0, 22)*
11 (9, 17)* 26 (20, 43)
21 (15, 36) 238 (141, 395)
20 (13, 31) 36 (0, 186)*
20.5 (13, 32) 241 (154, 351)
*Significantly different from baseline. All p < 0.01.
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© 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 41, 269–277
Ventilatory function and recovery from neuromuscular block M Martin-Flores et al. Table 2 Median and (range) of the acceleromyographic train-of-four ratio measured at the pelvic limb when end-tidal carbon dioxide (PE′CO2), expired tidal volume (VT), peak inspiratory flow (Pif), respiratory rate (fR) and minute ventilation (V_ E ) returned to 0.7 and 1.0 of their respective baseline value. The lag between each variable returning to baseline and the time TOF ratio returned to 100% is also presented
Ventilatory variables
TOF ratio (%) when ventilatory variable is 0.7 of baseline
TOF ratio (%) when ventilatory variable is 1.0 of baseline
Lag between ventilatory variable returning to baseline and TOF ratio reaching 100% (minutes)
PE′CO2 VT Pif fR V_ E
17 14 17 13 17
42 17 17 – 20
3 4 5.3 – 4.25
a
(0, (0, (0, (0, (0,
46) 32) 46) 91) 24)
(15, 80) (0, 100) (0, 46) (7, 63)
(0.75, 4.5)a (0, 7) (2.5, 8.5) (1.5, 8.5)
n = 7.
Figure 2 Values displayed by the TOF-Watch monitor when end-tidal carbon dioxide first returned to or exceeded 1.3 (▲) and 1.0 (○) of baseline value in dogs recovering spontaneously from neuromuscular block induced by intravenous vecuronium (25 lg kg1). The TOF-Watch displays TOF count (C0 to C4) when neuromuscular block is intense and TOF ratio (%) when blockade is less intense. There was substantial residual impairment of neuromuscular transmission even when end-tidal carbon dioxide had returned to baseline.
Discussion The results of this experiment show that restoration of ventilation cannot be used to exclude PORC in anesthetized dogs during spontaneous recovery from neuromuscular block, even when ventilatory variables have returned to magnitudes similar to those
measured before the NMBA was administered. All ventilatory variables measured returned to their baseline value when the acceleromyographic TOF ratio was ≤20%, with the exception of PE′CO2, in which case the TOF ratio was 42% when that variable reached its baseline value. In people, an acceleromyographic TOF ratio ≥90% is required so that recovery from neuromuscular block may be considered adequate (Eriksson et al. 1992, 1993, 1997; Kopman et al. 1997). Residual neuromuscular block is associated with laryngeal dysfunction leading to an increased risk of tracheal aspiration, a reduction in upper airway dimensions and function, and an increased incidence of postoperative hypoxemia (Eriksson et al. 1997; Eikermann et al. 2007; Murphy et al. 2008). A value for adequate recovery during AMG monitoring in dogs has not been established, however, it is evident that a TOF ratio ≤20% indicates that recovery is far from complete, at least in the muscle being monitored. In the absence of a ‘minimal acceptable TOF ratio’ in dogs above which recovery may be considered adequate, full restoration of neuromuscular transmission should be the goal; it is only in this way that even subtle residual block can be avoided. Ventilatory variables returned to baseline values early in the course of recovery from NMB, and returned to values in excess of baseline in some individuals (Figs 1 & 2). Values in excess of baseline often occurred transiently (Fig. 3). The tidal volume measured at recovery from neuromuscular block had a median value significantly higher than at baseline. In some dogs, the first measurable value during the recovery phase of NMB was already equal or higher than 1.0 of baseline, such as observed for
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Figure 3 Relationship between train-of-four (TOF) ratio [%, (vertical lines)] and ventilatory variables (○) during baseline, maximal block and recovery in one dog. Panels (a) through (d) are VT, Pif, V_ E and PE′CO2, respectively. The TOF counts that were measured when the TOF ratio was zero are indicated [(♦), 1–4].
Pif (Fig. 1). In at least one individual, every ventilatory variable returned to, or exceeded 0.7 and 1.0 of baseline, before four twitches could be detected (TOF count ≤ 3). The PE′CO2 returned to baseline values when the TOF ratio was 42%. Although this parameter appears to be superior to the previous ones for assessing recovery from neuromuscular block, a TOF ratio <50% clearly indicates that recovery is still incomplete. There was significant variability in the TOF ratio when PE′CO2 returned to baseline; TOF ratio ranged between 15 and 80% at the time PE′CO2 returned to baseline. In some dogs PE′CO2 remained within normal limits during deep block. Moreover, the median value of PE′CO2 for all dogs during maximal depth of block was no different from those obtained at baseline (Table 1). This finding was unexpected: given that a significant decrease in VT was measured during maximal depth of neuromuscular block, and no increase in fR was present, high levels of PE′CO2 were expected. It is possible that increases in PE′CO2 were not observed as an artifact of our monitoring technique: a sidestream monitor was used to measure this parameter. Because sidestream capnographs remove a sample of gas for analysis, it is possible that during low VT states when expiratory flow is low, the sample aspirated is diluted by gas from the inspiratory limb of the breathing system, and thence, falsely low values of PE′CO2 are reported (Bhavani-Shankar et al. 1992). These findings further illustrate the limitations in using 274
PE′CO2 as a parameter to assess neuromuscular block, especially when a sidestream apparatus is utilized. Since PE′CO2 and not VT or V_ E is likely more commonly monitored during general anesthesia in dogs, it is important to acknowledge the limitation of using such parameter as a surrogate for assessing recovery from neuromuscular block. Tidal volume and peak expiratory flow fell below the minimum sensitivity of the respiratory monitor in five dogs; in those cases a value of zero for both variables was assigned. As a consequence, a value of zero also resulted for minute ventilation in those animals. However, breathing never ceased; capnographic evidence of ventilation, albeit small, could be seen at all times in every dog. Data regarding respiratory rate were also variable: fR returned to 0.7 of its baseline value in all dogs when the TOF ratio was 13%, but only in two dogs did it return to actual baseline values (TOF ratio were 90% for both animals). Consequently, and due to the reduced sample size, the TOF ratio at the time fR returned to baseline was not analyzed. Put together, these data show that respiratory variables are unreliable indicators of depth of neuromuscular blockade. At any time during recovery from NMB, when the TOF ratio may vary between 0 and 100%, a respiratory variable could be measured to be not different from pre-relaxation values. The current guidelines for monitoring small animals under general anesthesia by the American College of Veterinary Anesthesia and Analgesia recommend
© 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia, 41, 269–277
Ventilatory function and recovery from neuromuscular block M Martin-Flores et al. that neuromuscular function should be monitored whenever NMBA are used (ACVAA). These guidelines also suggest that in addition to peripheral nerve stimulation, monitoring of the respiratory function can be used to assess recovery from neuromuscular block. More specifically, that ‘recovery of neuromuscular function may be assumed if the evoked response (twitch and/or tetanic fade) to a nerve stimulus, and respiratory tidal volume as measured with a spirometer, return to at least 70% of preblockade status…’ and that ‘End tidal CO2 may also be used as an indication of adequate ventilation in spontaneously ventilating patients’. Our results are at odds with the recommendation that tidal volume can be used to assess recovery from non-depolarizing block. The same principle would apply for peak inspiratory flow or minute ventilation. Although PE′CO2 may certainly indicate adequate ventilation, this was not the case during the time of maximal block in some of our dogs, when PE′CO2 was normal despite significant reductions in VT and V_ E . Furthermore, adequate ventilation does not indicate appropriate recovery from neuromuscular block in muscles other than those involved in ventilation. The time lag between the respiratory variables normalized to baseline values, and the moment at which the TOF ratio recovered completely, was brief: between 3 and 5 minutes. This represents a period of increased risk of PORC; as judged by return of respiratory functions these dogs could have been considered recovered from neuromuscular block and extubated. Although this period was indeed short in these dogs, several factors can increase the period of partial NMB under clinical situations, such as changes in pH, temperature, electrolytes, and interactions with other drugs (Ono et al. 1990; Heier et al. 1994; Nagahama et al. 2006; Yoshida et al. 2006). A case of prolonged partial block in a dog receiving vecuronium and magnesium sulfate during isoflurane anesthesia, and a long lasting partial block after vecuronium was administered to horses have been reported (Martin-Flores et al. 2011, 2012a). A case of unexpectedly long paralysis in a horse receiving vecuronium and atracurium has also recently been reported (Gurney & Mosing 2012). The dose of vecuronium chosen for this project was selected after pilot studies. The objective was to achieve substantial neuromuscular block while avoiding apnea so that mechanical ventilation would not be necessary. Although apnea and desaturation did not occur in the dogs during this
study, it is important to point out that these animals were intubated and supplemented with ~98% O2. The effects of this level of blockade on efficiency of ventilation, oxygenation and airway patency in a non-intubated dog breathing room air are not known, however, low degrees of neuromuscular block affect laryngeal function and ventilatory response to hypoxia in humans (Eriksson et al. 1992; Sundman et al. 2000). In nine of the ten dogs, vecuronium 25 lg kg1 produced a twitch reduction of >80%. Although data for the first twitch of the TOF (T1) was not collected, the AMG monitor displayed TOF counts and not TOF ratios during the deepest level of block in nine dogs. TOF Watch monitors display a TOF count and not a ratio when T1 is <20% of control; therefore it can be safely assumed that T1 depression was more than 80% in these nine dogs (MartinFlores et al. 2012b). In the remaining dog, maximal T1 depression was not assessed, and the lowest value was a TOF ratio of 18%. Bom et al. (2009) reported an ED90 of vecuronium in dogs of 90 lg kg1, although no description of the anesthetic technique used is mentioned. Kariman & Clutton (2008) showed that complete paralysis in dogs can be induced with 50 lg kg1 vecuronium during halothane anesthesia. Our results and those of Kariman & Clutton (2008) suggest that under inhalational anesthesia the ED90 of vecuronium in dogs is likely much lower than 90 lg kg1. Some limitations should be considered: First, in the current experiment we only evaluated female dogs. In human patients, signs of residual neuromuscular block differ slightly between the sexes (Heier et al. 2011). We are unaware of whether such differences can be demonstrated between male and female dogs. Second, PE′CO2 was used as a surrogate for PaCO2. While capnography is commonly used for assessing ventilation in anesthetized animals, differences may exist between PE′CO2 and PaCO2. As mentioned above, it is possible that under the circumstances of our experiment (i.e., when VT was low), PE′CO2 did not faithfully represent PaCO2. In addition, a small delay exist when the value for PE′CO2 is obtained with a sidestream capnograph. Last, other parameters might be measured in order to assess recovery from neuromuscular block in the absence of objective neuromuscular monitoring, such as inspiratory force (Mason & Betts 1980). We conclude that during spontaneous recovery from vecuronium-induced neuromuscular block, substantial residual impairment of neuromuscular
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transmission can be measured with AMG even when the PE′CO2, expired tidal volume, peak inspiratory flow, and minute ventilation have returned to baseline values. Consequently, these ventilatory variables do not adequately assess recovery from nondepolarizing neuromuscular block, nor can they be used to assess the level of neuromuscular block or exclude residual paralysis prior to tracheal extubation in anesthetized dogs. Assessing recovery from neuromuscular block on the basis of spontaneous ventilation alone carries an increased risk of postoperative residual curarization. Acknowledgements The authors would like to thank Dr. Robert F Gilmour, PhD, for his generosity, making this investigation possible. References ACVAA. Small animal monitoring guidelines. Available at www.acva.org Alderson B, Senior J, Jones R et al. (2007) Use of rocuronium administered by continuous infusion in dogs. Vet Anaesth Analg 34, 251–256. Bhavani-Shankar K, Moseley H, Kumar AY et al. (1992) Capnometry and anaesthesia. Can J Anaesth 39, 617– 632. Bom A, Hope F, Rutherford S et al. (2009) Preclinical pharmacology of sugammadex. J Crit Care 24, 29–35. Eikermann M, Groeben H, H€ using J et al. (2004) Predictive value of mechanomyography and accelerometry for pulmonary function in partially paralyzed volunteers. Acta Anaesthesiol Scand 48, 365–370. Eikermann M, Vogt F, Herbstreit F et al. (2007) The predisposition to inspiratory upper airway collapse during partial neuromuscular blockade. Am J Respir Crit Care Med 175, 9–15. Eriksson L, Lennmarken C, Wyon N et al. (1992) Attenuated ventilatory response to hypoxaemia at vecuronium-induced partial neuromuscular block. Acta Anaesthesiol Scand 36, 710–715. Eriksson L, Sato M, Severinghaus J (1993) Effect of a vecuronium-induced partial neuromuscular block on hypoxic ventilatory response. Anesthesiology 78, 693– 699. Eriksson L, Sundman E, Olsson R et al. (1997) Functional assessment of the pharynx at rest and during swallowing in partially paralyzed humans: simultaneous videomanometry and mechanomyography of awake human volunteers. Anesthesiology 87, 1035–1043. Gurney M, Mosing M (2012) Prolonged neuromuscular blockade in a horse following concomitant use of
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doi:10.1111/vaa.12109
RESEARCH PAPER
Recovery from neuromuscular block in dogs: restoration of spontaneous ventilation does not exclude residual blockade Manuel Martin-Flores, Daniel M Sakai, Luis Campoy & RD Gleed Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA
Correspondence: Manuel Martin-Flores, Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Box 32, Ithaca, NY 14853, USA. E-mail: [email protected]
Abstract Objective To evaluate if return of spontaneous ventilation to pre-relaxation values indicates complete recovery from neuromuscular blockade. Study design Prospective, with each individual acting as its own control. Animals Ten healthy adult female Beagle dogs weighing 6.2–9.4 kg. Methods Dogs were anesthetized with propofol, dexemedetomidine and isoflurane. Spontaneous ventilation was assessed by measuring end-tidal CO2, expired tidal volume, peak inspiratory flow, respiratory rate and minute ventilation. Vecuronium 25 lg kg1 IV was administered and neuromuscular block was evaluated by measuring the train-of-four (TOF) ratio with acceleromyography in the hind limb. During spontaneous recovery from neuromuscular block, the TOF ratio when each ventilatory variable returned to baseline was recorded. Results This dose of vecuronium produced moderate neuromuscular block in all dogs, with TOF ratio values of 0–18% at maximal block. Expired tidal volume, peak inspiratory flow and minute ventilation returned to pre-relaxation values when the median TOF ratio was ≤ 20%. The median TOF ratio was 42% when the end-tidal CO2 returned to prerelaxation values.
Conclusions and clinical relevance Significant residual neuromuscular block could be measured at the hind limb with acceleromyography when ventilation had spontaneously returned to prevecuronium values. Monitoring spontaneous ventilation, including end-tidal CO2, expired tidal volume, peak inspiratory flow or minute ventilation cannot be used as a surrogate for objective neuromuscular monitoring, and this practice may increase the risk of postoperative residual paralysis. Keywords anaesthesia, neuromuscular blockade, residual blockade, vecuronium, ventilation.
Introduction Postoperative residual curarization (PORC) is a potential complication that arises in the immediate post-anesthesia period when recovery from neuromuscular block is incomplete (Murphy et al. 2005). In people, residual neuromuscular block increases the risk of adverse respiratory events following anesthesia, including upper airway obstruction and hypoxemia (Murphy et al. 2008). A strategy to minimize the risk of PORC is to monitor the degree of blockade prior to recovery from general anesthesia. Indeed, quantitative monitoring with acceleromyography (AMG) decreases the incidence of complications related to PORC in humans (Murphy et al. 2011), and is more precise than subjective visual assessment of the evoked muscular responses during nerve stimulation in anesthetized horses 269
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(Martin-Flores et al. 2008). The impact of residual neuromuscular block in animals has not been thoroughly investigated. Without the use of a nerve stimulator, the anesthetist might be inclined to judge recovery from neuromuscular block based on the presence and quality of spontaneous muscular activity. Particularly, evaluation of ventilation might be used to assess recovery (Alderson et al. 2007; Videira & Vieira 2011). There is, however, a potentially dangerous caveat with this approach: all muscle groups do not display the same sensitivity to neuromuscular blocking agents (NMBA). Substantial differences in duration of neuromuscular block between muscles have been documented; in particular the diaphragm recovers earlier than other more peripheral muscles (Ibebunjo & Hall 1994; Ibebunjo et al. 1999). In other words, ventilatory function could be restored while neuromuscular transmission in other muscles is still impaired. In people, forced vital capacity recovers to acceptable levels when the train-of-four (TOF) ratio is only 60%; that is, substantial neuromuscular block is still present by the time the forced vital capacity has recovered (Eikermann et al. 2004). To our knowledge, no formal studies have been carried out to investigate whether recovery of spontaneous ventilation is an adequate monitoring method for assessing recovery from modern NMBA in dogs. In the current investigation we evaluated the spontaneous recovery of several ventilatory variables following neuromuscular block while monitoring neuromuscular transmission with AMG at the peroneal (common fibular) nerve in dogs under general anesthesia. We hypothesized that during spontaneous recovery from vecuronium-induced neuromuscular block, ventilatory variables would return to pre-relaxation values before the acceleromyographic TOF ratio measured at the pelvic limb does, and hence that spontaneous ventilation is a poor indicator of appropriate recovery from neuromuscular block. Materials and methods This project was approved by the local IACUC (protocol 2011-0054). Ten healthy adult female Beagle dogs, with body weights between 6.2 and 9.4 kg were included in this investigation. After overnight fasting, an intravenous (IV) catheter was inserted into a cephalic vein and dexmedetomidine (Dexdomitor; Orion Corporation, Finland) 270
1 lg kg1 was administered IV. Following ~3 minutes of oxygen supplementation via face mask, propofol (Propoflo; Abbott Laboratories, IL, USA) 30–40 mg was administered IV and the trachea was intubated with a 6.5 or 7 mm internal diameter cuffed orotracheal tube. General anesthesia was maintained with isoflurane (Isothesia; Butler Schein Animal Health, OH, USA) in oxygen and a constant rate infusion of dexmedetomidine (1 lg kg1 hour1). Lactated Ringer’s solution was infused through the IV catheter. The inspired concentration of isoflurane was adjusted so that no response, other than the expected evoked muscle contractions, was seen during nerve stimulation. End-tidal isoflurane concentration was constant throughout the time of data collection. Monitoring during general anesthesia consisted of continuous ECG, pulse oximetry (SpO2), esophageal temperature and oscillometric arterial blood pressure measured every 3 minutes (Cardell MAX-12 HD; Midmark Corporation, OH, USA). Dogs were kept in left lateral recumbency and a blanket with circulating warm water and one with forced warm air were used to maintain esophageal temperature between 36.0 and 38.0 °C. All dogs were allowed to ventilate spontaneously throughout the experiment. Neuromuscular monitoring and block Quantitative neuromuscular transmission was monitored with AMG (TOF-Watch; Organon Ltd, Dublin, Ireland). Subcutaneous needles were inserted ~1 inch apart over the peroneal nerve on the right pelvic limb, and the acceleration sensitive crystal was taped to the dorsal aspect of the paw: the limb was supported in a horizontal position so that the tarsus would flex freely and unopposed during nerve stimulation. After at least 15 minutes of nerve stimulation with TOF stimulation every 15 seconds (2 Hz, 60 mA, pulse duration 0.2 milliseconds) to allow for stabilization and twitch potentiation, the AMG monitor was calibrated and nerve stimulation was resumed with TOF every 15 seconds. Immediately after baseline values had been obtained (see below), 25 lg kg1 vecuronium (Vecuronium Bromide; SUN Pharmaceutical Industries Ltd. Gujarat, India) was administered IV over 5 seconds into the catheter. The dose of vecuronium was chosen after pilot studies and was expected to produce partial block without causing apnea. The display on the accelerometer (either TOF count or TOF ratio) was recorded.
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Respiratory values The spontaneous respiratory rate (fR), partial pressure of end-tidal carbon dioxide (PE′CO2) and endtidal percentage of isoflurane (FE′Iso) were measured from the tracheal tube with a side-stream gas analyzer (Datex-Ohmeda AS/3; Datex-Ohmeda Instrumentation Corp, Helsinki, Finland). Expired tidal volume (V_ T ) and peak inspiratory flow (Pif) were measured at the connection between the tracheal tube and the circle breathing circuit (NICO2; Respironics Novametrix, CT, USA). fR, PE′CO2, FE′Iso, V_ T , and Pif were recorded immediately after each TOF. Subsequently, minute ventilation (V_ E ) was calculated as the product of V_ T and fR. V_ T , Pif and V_ E were indexed to each animal’s weight for analysis. Analysis To minimize the effects of twitch-to-twitch variation of TOF values and breath-to-breath variation of ventilation values, the median of the five consecutive measurements immediately prior to vecuronium administration was used for baseline for each dog. A similar procedure was used when neuromuscular block was maximal and when recovery from neuromuscular block was complete; neuromuscular block was considered maximal as soon as five consecutive AMG readings at the lowest level were recorded; recovery from block was considered complete as soon as the TOF ratio equaled or exceeded baseline values for at least five consecutive readings. In addition to the values obtained at baseline, maximal block and complete recovery (see above), values for all variables were also recorded every 15 seconds (immediately following each TOF) throughout the recovery phase of neuromuscular block i.e., from the time TOF ratio started to increase over time until complete recovery. Data are summarized as median (minimum, maximum). Values for fR, PE′CO2, VT, Pif, and V_ E were normalized to baseline and expressed as a fraction of that value. Accordingly, and as an example, if for dog #1 baseline V_ T was 10 mL kg1 and during maximal neuromuscular blockade it decreased to 4 mL kg1, then its fractional value during maximal block was 0.4 (4 mL kg1/ 10 mL kg1). Values for TOF ratio were also normalized to baseline but they were expressed as a percentage rather than a simple fraction (e.g.; 69/ 98 9 100 = 70%).
Due to the internal program logic of the TOFWatch monitor, a TOF count (0–4) is displayed by the monitor when neuromuscular block is deep, and a TOF ratio is displayed if block is less intense. Specifically, a TOF count is reported when the magnitude of the first component of the TOF (T1) is <20% of baseline, and a TOF ratio is calculated when T1 is ≥ 20% of baseline (Martin-Flores et al. 2012b). Therefore, AMG results ranging from 0 to 4 represent TOF counts (0–4 counts), and actual TOF ratios are expressed in percentage (%). The TOF ratio when fR, V_ T , Pif and V_ E returned to, or exceeded 0.7 and 1.0 of their respective baseline values was recorded. If a variable returned to 0.7 or 1.0 of baseline when only a TOF count was displayed by the AMG monitor, then a TOF ratio of 0% was assigned. Since it is expected that the PE′CO2 would accumulate during partial neuromuscular block, and then decrease towards baseline during recovery from neuromuscular block, then the TOF ratio when PE′CO2 returned to 1.3 (i.e. 30% above baseline) and 1.0 of baseline were recorded. Values for all variables during maximal block and recovery were compared with those at baseline with the Wilcoxon Signed Rank Test (Statistix 9.0; Analytical Software, FL, USA). Bonferroni adjustments were imposed for multiple comparisons. Differences were considered significant when p < 0.05. Results All dogs recovered uneventfully from general anesthesia, and the TOF ratio returned to baseline before the orotracheal tube was removed. Apnea was not seen in any individual, even though a TOF count of zero was seen in two dogs. Desaturation never occurred; furthermore, SpO2 was never <99% for any dog at any time during anesthesia. Absolute magnitudes for TOF ratio, E′Iso, fR, PE′CO2, VT, Pif and V_ E at baseline, maximal depth of neuromuscular block and recovery are summarized in Table 1. In five dogs, VT and Pif decreased to values below the minimum sensitivity of the respiratory monitor (30 mL and 0.5 L minute1, respectively) during the period of maximal neuromuscular blockade; a value of zero was assigned in those cases. When VT, Pif and V_ E returned to or exceeded 0.7 and 1.0 of baseline, median TOF ratio ranged between 14 and 20% (Table 2 and Fig. 1). Endtidal CO2 returned to 1.3 of baseline in all individuals, but reached 1.0 of baseline in only seven dogs. The TOF ratio when that occurred was
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Ventilatory function and recovery from neuromuscular block M Martin-Flores et al.
(a)
(b)
Figure 1 Values displayed by the TOF-Watch monitor when tidal volume (VT) (a), peak inspiratory flow (Pif) (b) and minute ventilation (V_ E ) (c) first returned to or exceeded 0.7 (▲) and 1.0 (○) of their baseline value in dogs recovering spontaneously from neuromuscular block induced by intravenous vecuronium (25 lg kg1). The TOF-Watch displays TOF count (C0 to C4) when neuromuscular block is intense and TOF ratio (%) when block is less. There was substantial residual impairment of neuromuscular transmission when tidal volume, peak inspiratory pressure and minute ventilation had returned to baseline.
17% and 42%, respectively (Table 2 and Fig. 2). The fR returned to 0.7 of its baseline value when the median TOF ratio was 13%, but only returned to 1.0 in two individuals, hence results for that variable are not reported (Table 2). The time lag between the return of a ventilatory variable to or in excess of baseline, and the return of the TOF ratio to baseline, is presented in Table 2. An example of the relationship between the acceleromyographic TOF ratio at the peroneal nerve and PE′CO2, VT, Pif and V_ E during baseline, maximal block and recovery are illustrated in Fig. 3.
Table 1 Median and (range) values for train-of-four (TOF) ratio, end-tidal isoflurane concentration (E′Iso), end-tidal carbon dioxide pressure (PE′CO2), expired tidal volume (VT), peak inspiratory flow (Pif), respiratory rate (fR) and minute ventilation (V_ E ) at baseline, during maximal neuromuscular block and after recovery from nondepolarizing neuromuscular block with vecuronium 25 lg kg1 in dogs
(c) Baseline TOF ratio (%) E0 Iso (%) PE0 CO2 (mmHg) PE0 CO2 (kPa) VT (mL kg1) Pif (mL kg1 second1) fR (bpm) V_ E (mL kg1 minute1)
96 (81, 100)
Maximum block
Recovery
0 (0, 18)*
94 (91, 100)
1.5 (1.1, 1.7) 1.55 (1.1, 2) 46 (42, 50) 46 (34, 57)
1.55 (1.1, 1.8) 46 (42, 50)
6.1 (5.5, 6.7)
6.1 (4.5, 7.6)
6.1 (5.6, 6.7)
10 (9, 15) 27 (20, 40)
2 (0, 7)* 9 (0, 22)*
11 (9, 17)* 26 (20, 43)
21 (15, 36) 238 (141, 395)
20 (13, 31) 36 (0, 186)*
20.5 (13, 32) 241 (154, 351)
*Significantly different from baseline. All p < 0.01.
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Ventilatory function and recovery from neuromuscular block M Martin-Flores et al. Table 2 Median and (range) of the acceleromyographic train-of-four ratio measured at the pelvic limb when end-tidal carbon dioxide (PE′CO2), expired tidal volume (VT), peak inspiratory flow (Pif), respiratory rate (fR) and minute ventilation (V_ E ) returned to 0.7 and 1.0 of their respective baseline value. The lag between each variable returning to baseline and the time TOF ratio returned to 100% is also presented
Ventilatory variables
TOF ratio (%) when ventilatory variable is 0.7 of baseline
TOF ratio (%) when ventilatory variable is 1.0 of baseline
Lag between ventilatory variable returning to baseline and TOF ratio reaching 100% (minutes)
PE′CO2 VT Pif fR V_ E
17 14 17 13 17
42 17 17 – 20
3 4 5.3 – 4.25
a
(0, (0, (0, (0, (0,
46) 32) 46) 91) 24)
(15, 80) (0, 100) (0, 46) (7, 63)
(0.75, 4.5)a (0, 7) (2.5, 8.5) (1.5, 8.5)
n = 7.
Figure 2 Values displayed by the TOF-Watch monitor when end-tidal carbon dioxide first returned to or exceeded 1.3 (▲) and 1.0 (○) of baseline value in dogs recovering spontaneously from neuromuscular block induced by intravenous vecuronium (25 lg kg1). The TOF-Watch displays TOF count (C0 to C4) when neuromuscular block is intense and TOF ratio (%) when blockade is less intense. There was substantial residual impairment of neuromuscular transmission even when end-tidal carbon dioxide had returned to baseline.
Discussion The results of this experiment show that restoration of ventilation cannot be used to exclude PORC in anesthetized dogs during spontaneous recovery from neuromuscular block, even when ventilatory variables have returned to magnitudes similar to those
measured before the NMBA was administered. All ventilatory variables measured returned to their baseline value when the acceleromyographic TOF ratio was ≤20%, with the exception of PE′CO2, in which case the TOF ratio was 42% when that variable reached its baseline value. In people, an acceleromyographic TOF ratio ≥90% is required so that recovery from neuromuscular block may be considered adequate (Eriksson et al. 1992, 1993, 1997; Kopman et al. 1997). Residual neuromuscular block is associated with laryngeal dysfunction leading to an increased risk of tracheal aspiration, a reduction in upper airway dimensions and function, and an increased incidence of postoperative hypoxemia (Eriksson et al. 1997; Eikermann et al. 2007; Murphy et al. 2008). A value for adequate recovery during AMG monitoring in dogs has not been established, however, it is evident that a TOF ratio ≤20% indicates that recovery is far from complete, at least in the muscle being monitored. In the absence of a ‘minimal acceptable TOF ratio’ in dogs above which recovery may be considered adequate, full restoration of neuromuscular transmission should be the goal; it is only in this way that even subtle residual block can be avoided. Ventilatory variables returned to baseline values early in the course of recovery from NMB, and returned to values in excess of baseline in some individuals (Figs 1 & 2). Values in excess of baseline often occurred transiently (Fig. 3). The tidal volume measured at recovery from neuromuscular block had a median value significantly higher than at baseline. In some dogs, the first measurable value during the recovery phase of NMB was already equal or higher than 1.0 of baseline, such as observed for
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Figure 3 Relationship between train-of-four (TOF) ratio [%, (vertical lines)] and ventilatory variables (○) during baseline, maximal block and recovery in one dog. Panels (a) through (d) are VT, Pif, V_ E and PE′CO2, respectively. The TOF counts that were measured when the TOF ratio was zero are indicated [(♦), 1–4].
Pif (Fig. 1). In at least one individual, every ventilatory variable returned to, or exceeded 0.7 and 1.0 of baseline, before four twitches could be detected (TOF count ≤ 3). The PE′CO2 returned to baseline values when the TOF ratio was 42%. Although this parameter appears to be superior to the previous ones for assessing recovery from neuromuscular block, a TOF ratio <50% clearly indicates that recovery is still incomplete. There was significant variability in the TOF ratio when PE′CO2 returned to baseline; TOF ratio ranged between 15 and 80% at the time PE′CO2 returned to baseline. In some dogs PE′CO2 remained within normal limits during deep block. Moreover, the median value of PE′CO2 for all dogs during maximal depth of block was no different from those obtained at baseline (Table 1). This finding was unexpected: given that a significant decrease in VT was measured during maximal depth of neuromuscular block, and no increase in fR was present, high levels of PE′CO2 were expected. It is possible that increases in PE′CO2 were not observed as an artifact of our monitoring technique: a sidestream monitor was used to measure this parameter. Because sidestream capnographs remove a sample of gas for analysis, it is possible that during low VT states when expiratory flow is low, the sample aspirated is diluted by gas from the inspiratory limb of the breathing system, and thence, falsely low values of PE′CO2 are reported (Bhavani-Shankar et al. 1992). These findings further illustrate the limitations in using 274
PE′CO2 as a parameter to assess neuromuscular block, especially when a sidestream apparatus is utilized. Since PE′CO2 and not VT or V_ E is likely more commonly monitored during general anesthesia in dogs, it is important to acknowledge the limitation of using such parameter as a surrogate for assessing recovery from neuromuscular block. Tidal volume and peak expiratory flow fell below the minimum sensitivity of the respiratory monitor in five dogs; in those cases a value of zero for both variables was assigned. As a consequence, a value of zero also resulted for minute ventilation in those animals. However, breathing never ceased; capnographic evidence of ventilation, albeit small, could be seen at all times in every dog. Data regarding respiratory rate were also variable: fR returned to 0.7 of its baseline value in all dogs when the TOF ratio was 13%, but only in two dogs did it return to actual baseline values (TOF ratio were 90% for both animals). Consequently, and due to the reduced sample size, the TOF ratio at the time fR returned to baseline was not analyzed. Put together, these data show that respiratory variables are unreliable indicators of depth of neuromuscular blockade. At any time during recovery from NMB, when the TOF ratio may vary between 0 and 100%, a respiratory variable could be measured to be not different from pre-relaxation values. The current guidelines for monitoring small animals under general anesthesia by the American College of Veterinary Anesthesia and Analgesia recommend
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Ventilatory function and recovery from neuromuscular block M Martin-Flores et al. that neuromuscular function should be monitored whenever NMBA are used (ACVAA). These guidelines also suggest that in addition to peripheral nerve stimulation, monitoring of the respiratory function can be used to assess recovery from neuromuscular block. More specifically, that ‘recovery of neuromuscular function may be assumed if the evoked response (twitch and/or tetanic fade) to a nerve stimulus, and respiratory tidal volume as measured with a spirometer, return to at least 70% of preblockade status…’ and that ‘End tidal CO2 may also be used as an indication of adequate ventilation in spontaneously ventilating patients’. Our results are at odds with the recommendation that tidal volume can be used to assess recovery from non-depolarizing block. The same principle would apply for peak inspiratory flow or minute ventilation. Although PE′CO2 may certainly indicate adequate ventilation, this was not the case during the time of maximal block in some of our dogs, when PE′CO2 was normal despite significant reductions in VT and V_ E . Furthermore, adequate ventilation does not indicate appropriate recovery from neuromuscular block in muscles other than those involved in ventilation. The time lag between the respiratory variables normalized to baseline values, and the moment at which the TOF ratio recovered completely, was brief: between 3 and 5 minutes. This represents a period of increased risk of PORC; as judged by return of respiratory functions these dogs could have been considered recovered from neuromuscular block and extubated. Although this period was indeed short in these dogs, several factors can increase the period of partial NMB under clinical situations, such as changes in pH, temperature, electrolytes, and interactions with other drugs (Ono et al. 1990; Heier et al. 1994; Nagahama et al. 2006; Yoshida et al. 2006). A case of prolonged partial block in a dog receiving vecuronium and magnesium sulfate during isoflurane anesthesia, and a long lasting partial block after vecuronium was administered to horses have been reported (Martin-Flores et al. 2011, 2012a). A case of unexpectedly long paralysis in a horse receiving vecuronium and atracurium has also recently been reported (Gurney & Mosing 2012). The dose of vecuronium chosen for this project was selected after pilot studies. The objective was to achieve substantial neuromuscular block while avoiding apnea so that mechanical ventilation would not be necessary. Although apnea and desaturation did not occur in the dogs during this
study, it is important to point out that these animals were intubated and supplemented with ~98% O2. The effects of this level of blockade on efficiency of ventilation, oxygenation and airway patency in a non-intubated dog breathing room air are not known, however, low degrees of neuromuscular block affect laryngeal function and ventilatory response to hypoxia in humans (Eriksson et al. 1992; Sundman et al. 2000). In nine of the ten dogs, vecuronium 25 lg kg1 produced a twitch reduction of >80%. Although data for the first twitch of the TOF (T1) was not collected, the AMG monitor displayed TOF counts and not TOF ratios during the deepest level of block in nine dogs. TOF Watch monitors display a TOF count and not a ratio when T1 is <20% of control; therefore it can be safely assumed that T1 depression was more than 80% in these nine dogs (MartinFlores et al. 2012b). In the remaining dog, maximal T1 depression was not assessed, and the lowest value was a TOF ratio of 18%. Bom et al. (2009) reported an ED90 of vecuronium in dogs of 90 lg kg1, although no description of the anesthetic technique used is mentioned. Kariman & Clutton (2008) showed that complete paralysis in dogs can be induced with 50 lg kg1 vecuronium during halothane anesthesia. Our results and those of Kariman & Clutton (2008) suggest that under inhalational anesthesia the ED90 of vecuronium in dogs is likely much lower than 90 lg kg1. Some limitations should be considered: First, in the current experiment we only evaluated female dogs. In human patients, signs of residual neuromuscular block differ slightly between the sexes (Heier et al. 2011). We are unaware of whether such differences can be demonstrated between male and female dogs. Second, PE′CO2 was used as a surrogate for PaCO2. While capnography is commonly used for assessing ventilation in anesthetized animals, differences may exist between PE′CO2 and PaCO2. As mentioned above, it is possible that under the circumstances of our experiment (i.e., when VT was low), PE′CO2 did not faithfully represent PaCO2. In addition, a small delay exist when the value for PE′CO2 is obtained with a sidestream capnograph. Last, other parameters might be measured in order to assess recovery from neuromuscular block in the absence of objective neuromuscular monitoring, such as inspiratory force (Mason & Betts 1980). We conclude that during spontaneous recovery from vecuronium-induced neuromuscular block, substantial residual impairment of neuromuscular
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transmission can be measured with AMG even when the PE′CO2, expired tidal volume, peak inspiratory flow, and minute ventilation have returned to baseline values. Consequently, these ventilatory variables do not adequately assess recovery from nondepolarizing neuromuscular block, nor can they be used to assess the level of neuromuscular block or exclude residual paralysis prior to tracheal extubation in anesthetized dogs. Assessing recovery from neuromuscular block on the basis of spontaneous ventilation alone carries an increased risk of postoperative residual curarization. Acknowledgements The authors would like to thank Dr. Robert F Gilmour, PhD, for his generosity, making this investigation possible. References ACVAA. Small animal monitoring guidelines. Available at www.acva.org Alderson B, Senior J, Jones R et al. (2007) Use of rocuronium administered by continuous infusion in dogs. Vet Anaesth Analg 34, 251–256. Bhavani-Shankar K, Moseley H, Kumar AY et al. (1992) Capnometry and anaesthesia. Can J Anaesth 39, 617– 632. Bom A, Hope F, Rutherford S et al. (2009) Preclinical pharmacology of sugammadex. J Crit Care 24, 29–35. Eikermann M, Groeben H, H€ using J et al. (2004) Predictive value of mechanomyography and accelerometry for pulmonary function in partially paralyzed volunteers. Acta Anaesthesiol Scand 48, 365–370. Eikermann M, Vogt F, Herbstreit F et al. (2007) The predisposition to inspiratory upper airway collapse during partial neuromuscular blockade. Am J Respir Crit Care Med 175, 9–15. Eriksson L, Lennmarken C, Wyon N et al. (1992) Attenuated ventilatory response to hypoxaemia at vecuronium-induced partial neuromuscular block. Acta Anaesthesiol Scand 36, 710–715. Eriksson L, Sato M, Severinghaus J (1993) Effect of a vecuronium-induced partial neuromuscular block on hypoxic ventilatory response. Anesthesiology 78, 693– 699. Eriksson L, Sundman E, Olsson R et al. (1997) Functional assessment of the pharynx at rest and during swallowing in partially paralyzed humans: simultaneous videomanometry and mechanomyography of awake human volunteers. Anesthesiology 87, 1035–1043. Gurney M, Mosing M (2012) Prolonged neuromuscular blockade in a horse following concomitant use of
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