Centronuclear myopathy (CNM), also called myotubular myopathy, is a congenital disease characterised by centrally placed nuclei and generalised muscle weakness.1 CNM exists in X-linked recessive, autosomal-recessive and autosomal-dominant forms. The severity of muscular weakness and associated complications such as respiratory failure is greatest for the X-linked form and mildest for the autosomal-dominant form.1 From observations in France, the incidence of confirmed X-linked CNM is reported to be approximately 2/100 000 male births per year; however, the overall incidences of other forms of CNM are unknown.1
Hyperkalaemia and even fatal rhabdomyolysis have been associated with the use of neuromuscular blocking agents such as succinylcholine (SCh) in patients with other myopathies and some diseases that affect muscle development, such as Duchenne muscular dystrophy.2–8 Little is known about CNM because its rarity means that there is very little objective information available regarding the use of neuromuscular blocking agents in these individuals. From the available reports, it is apparent that neuromuscular blocking agents are usually avoided.9–11 Some anaesthesiologists have even opted to remove SCh from the operating room when anaesthetising patients with X-linked CNM, presumably to avoid accidental use.12 Administration of SCh to patients with unrecognised myopathies has been reported, in some cases with fatal results.6,13 To our knowledge, there are no reports on the effects of SCh in patients with CNM.
Autosomal-recessive CNM has been described in Labrador retriever dogs.14 Clinical signs and histological characteristics of CNM in these animals are identical to those encountered in man.15 To our knowledge, the canine model is the only naturally occurring model available and it reflects very closely the changes that occur with autosomal-recessive CNM in humans.15 The rarity of CNM and the potentially lethal consequences of hyperkalaemia exclude prospective investigations into the use of SCh in patients, and accordingly, we have chosen to use canine CNM as a model for a prospective investigation into the effects of agents used during general anaesthesia in man.
In this pilot investigation, we compared the kalaemic and neuromuscular effects of SCh in dogs with CNM against those in control animals. We hypothesised that the increase in blood potassium (K+) after SCh administration would be greater in CNM dogs than in normal control animals and that the duration of neuromuscular block would be longer in the affected animals.
Materials and methods
Six purpose-bred adult Labrador retriever dogs with diagnosed autosomal-recessive CNM, weighing 20.4 to 33.3 kg, and a group of six healthy adult purpose bred beagles, weighing 7.1 to 11.3 kg were used. Sample size was limited by the availability of animals with CNM. Autosomal-recessive canine CNM was diagnosed through DNA testing by an independent laboratory (DDC Veterinary, Fairfield, Ohio, USA). None of the dogs were receiving any type of medication before this study. All procedures were approved by the Cornell Institutional Animal Care and Use Committee (Protocol number 2012-0088; 19 July 2012).
General anaesthesia and neuromuscular monitoring
Food but not water was withheld overnight prior to anaesthesia. A catheter was placed in a cephalic vein and dexmedetomidine (Dexdomitor; Orion Corporation, Espoo, Finland) 2 μg kg−1 was administered intravenously (i.v.). General anaesthesia was induced with i.v. propofol (Propoflo; Abbott Laboratories, North Chicago, Illinois, USA) 2 mg kg−1. The trachea was intubated and the lungs were ventilated to normocapnia with isoflurane (Isothesia; Butle Schein Animal Health, Dublin, Ohio, USA) (end-tidal concentration 1.3 to 1.5%) in oxygen. Dexmedetomidine 2 μg kg−1 h−1 and lactated Ringer's solution (5 ml kg−1 h−1) were infused throughout the procedure. The electrocardiogram, SpO2, capnography, end-tidal isoflurane concentration, systemic arterial blood pressure waveform and oesophageal temperature were monitored continuously. Oesophageal temperature was maintained between 37°C and 38°C by the use of a forced warm air device.
Neuromuscular function was assessed on a thoracic limb with acceleromyography (AMG; TOF Watch SX, Organon, Ireland) as described previously.16 Briefly, with the dog in left lateral recumbency, the dependent limb was held extended and slightly elevated so that the carpus and manus (paw) could flex freely during nerve stimulation. A 150 g elastic preload was applied to the paw to facilitate return of the carpus to an extended position during neuromuscular monitoring. Stimulating needles were placed subcutaneously over the ulnar nerve and the acceleration transducer was taped to the palmar aspect of the paw. After at least 30 min of general anaesthesia and 15 min of single twitch stimulation (0.1 Hz, pulse duration 0.2 ms, 50 mA), the AMG monitor was calibrated (CAL 2). Single twitch stimulation was then resumed.
After the single twitch signal had been stable for at least 3 min, SCh 0.3 mg kg−1 was administered i.v. as a fast bolus through a free-flowing infusion of the isotonic crystalloid solution. This dose produces complete neuromuscular block in normal dogs.17,18 During recovery from SCh, the changes in the height of the single twitch were recorded until no further increases were observed for at least 5 min. The average of the first six values for single twitch amplitude after the recovery plateau was established was used as the final single twitch amplitude. All values for single twitch after administration of SCh were normalised to this final single twitch value.19
Arterial blood was sampled 5 min before and 5 min after injection of SCh for analysis of electrolytes, glucose and acid–base status with a point-of-care device (i-STAT system; Abbott Point of Care Inc, Princeton, New Jersey, USA). Blood samples were obtained from the arterial catheter and analysed immediately.
The distribution of all variables was tested for normality (Shapiro–Wilk test, Minitab 16.2.4). Whole blood potassium concentration before and after SCh administration were compared within groups with the paired t-test. The increase in K+ concentration relative to baseline was compared between groups with the two-sample t-test. The sensitivity (gain) of the AMG monitor and all recovery variables [return of single twitch to 25, 75 and 90% of the final single twitch height and recovery index (interval between ST 25 and 75%)] were compared between groups with two-sample t-tests. Differences were considered significant when P value was less than 0.05. All parametric data are summarised as mean (SD). Descriptive statistics [nonparametric distribution; median (IQR)] for electrolytes other than K+, acid–base variables and glucose before and after SCh administration are also presented.
All dogs recovered uneventfully from general anaesthesia. A transient decrease in arterial blood pressure of at least 20% was observed in two CNM dogs following SCh. These changes were self-limiting and required no intervention.
Kalaemic, other electrolytic, acid–base and glucose effects of succinylcholine
In two animals from the control group, venous blood samples were used in lieu of arterial samples because of failure of the arterial catheter. Following SCh administration, K+ increased by 0.5 (0.4) mmol l−1 [16% (1.15)] in the CNM group and by 0.7 (0.4) mmol l−1 [18% (1.2)] in control dogs; each was a significant increase from baseline; P = 0.03 and 0.01, respectively (Fig. 1). However, the percentage increase from baseline was not different between groups (P = 0.47). Other electrolyte, acid–base and glucose values obtained before and after Sch administration are summarised in Table 1. There was a little change after SCh was given.
Neuromuscular effects of succinylcholine
Onset time was 1.4 (0.4) min for CNM and 1.7 (0.6) min for control dogs (P = 0.47). Times to 25, 75 and 90% recovery were significantly longer (P ≤ 0.001) for CNM dogs than for controls (Fig. 2). The recovery index was not significantly different between the treatment groups [CNM 8.3 (3.5) vs. control 3.9 (2.1) min; P = 0.15].
Performance of acceleromyography
Calibration of the AMG required several attempts in dogs affected with CNM, in which the evoked excursion of the paw was minimal. After calibration, the AMG reports the value of sensitivity (gain) required to set the control response to 100%. The sensitivity after calibration was significantly greater for CNM dogs [CNM 481 (30) vs. control 308 (80); P = 0.003], suggesting that signal amplification by the AMG monitor was larger in those animals. In one dog with CNM, the gain had to be increased manually to its maximum (512) because calibration failed after several attempts. We did not encounter any problems during AMG calibration in control animals.
In three out of six dogs with CNM, the AMG monitor reported single twitch values between 10 and 20% at a time when neuromuscular block was expected to be maximal and when evoked motor response could neither be seen nor palpated (Fig. 3). Such erroneous measurements were not observed in the control dogs (Fig. 3).
Our results show that the increase in K+ after SCh was similar for the two groups of dogs. No electrocardiographic signs consistent with hyperkalaemia, such as tall T waves, absence of P waves or wide QRS complexes, were observed at any time.20 In two CNM dogs, we observed a transient decrease in arterial blood pressure after SCh, which resolved spontaneously. This might have been due to histamine release, but no other signs such as flushing of the mucous membranes, urticaria or signs of bronchospasm were observed. As the highest K+ concentrations recorded did not exceed the normal limit for dogs (5.5 mmol l−1), it appears unlikely that an increase in K+ was responsible for these haemodynamic changes.20 Moreover, the increment in K+ observed in both groups after SCh is in agreement with previous reports in man (0.5 to 1 mmol l−1).21 In our study, K+ was measured 5 min after SCh administration; we chose 5 min because in humans, the increase in K+ induced by SCh peaks at 3 to 4 min.2,22,23
Succinylcholine-induced hyperkalaemia has been reported in a variety of pathological states including muscle trauma (inflammatory or thermal), upper and lower motor neurone defects and severe infection,2–5 when SCh may be contraindicated. In patients with disease of this nature, upregulation of extrajunctional (fetal or immature) acetylcholine receptors and also an isoform of the acetylcholine receptor, known as α7AChR, is observed. Upon interaction with SCh, depolarisation of extrajunctional and α7AChR occurs resulting in an exaggerated efflux of K+.23 As we did not observe hyperkalaemia in dogs with CNM, it is unlikely that significant upregulation of these receptors occurred. Recent observations of endplates of an individual affected with CNM found a reduced number of acetylcholine receptors per endplate and a reduction in the acetylcholine receptor index. The authors also observed formation of immature endplate regions that could potentially express immature acetylcholine receptors.24
Succinylcholine is usually avoided in patients with malignant hyperthermia, as it is known to trigger the condition. The skeletal muscle ryanodine receptor (RYR1) gene has been implicated in the development of MH and recent evidence has shown that RYR1 mutations can also be involved in the development of some forms of myopathies with central nuclei or in patients presenting with mixed diseases that include both core and central nuclei.25,26 In at least one instance, malignant hyperthermia has developed in an anaesthetised patient with CNM.27 Although many cases of CNM remain genetically unresolved,28 it has been suggested that RYR1 mutations might be common in individuals with CNM and that they should be considered at risk for developing malignant hyperthermia.26 Our experience with dogs with autosomal-recessive CNM provided no evidence of any signs of malignant hyperthermia being triggered by SCh or isoflurane. Of note, this group of dogs has been anaesthetised at least four times with isoflurane or sevoflurane for different unrelated investigations; no complications indicative of malignant hyperthermia were observed.
Although there were no differences between groups in onset time, our results show moderately longer duration of neuromuscular blockade in dogs with CNM; the recovery of the single twitch to 90% was delayed in the CNM dogs by nearly 10 min. The difference in the recovery index between groups did not quite reach significance, but it is possible that our sample size is too small to detect such a difference. We chose a dose of SCh of 0.3 mg kg−1 in our investigation. Although this dose might appear lower than that typically used in humans, in dogs it is commonly used to produce complete block;17,18 the return of the first twitch of the TOF to 80% of baseline after 0.3 mg kg−1 SCh takes 20 to 30 min.17,18 It is possible that the longer duration of neuromuscular block observed in the CNM dogs could be attributed to breed differences (Labrador retriever vs. beagle), but no breed-specific alterations in the time-course of neuromuscular blockers have been reported for dogs. Furthermore, when duration of SCh was compared between greyhounds and mixed breed dogs, no differences were observed.29 It appears that the differences in recovery times that we observed between control and CNM dogs are relatively benign, especially if the extent of neuromuscular blockade is being measured objectively.
Acceleromyographic monitoring in dogs with CNM proved challenging. Several attempts were required before calibration could be performed. This was not the case in the control animals, nor has it been our experience when using similar protocols in earlier work. In one dog, calibration was not possible and the gain was manually increased to its maximum. During calibration of the AMG, the signal (gain) is amplified so that the response can be set to 100%. It follows that small evoked responses might require higher signal amplification. When signal amplification is high, the potential for erroneous measurements arising from background noise, such as movement from surgical table, increases. In dogs with CNM, the sensitivity used by the AMG was significantly higher than in the control group, indicating higher signal amplification. In these dogs, erroneous results were observed at the time of complete block; the AMG displayed twitch heights of up to 20% when no visible or palpable twitch could be detected (Fig. 3). This observation suggests that AMG monitoring might be prone to erroneous measurements whenever the evoked response is very small (and signal amplification high), as is the case in many patients with neuromuscular disease. Similar difficulties have been reported when calibrating an AMG monitor on neonates and small infants and whether the sensitivity of the AMG monitor is adequate for patients producing small responses is in question.30 Presumably, our experience of myopathic dogs represented an exaggeration of that observation.
Our study has limitations. The sample size is small reflecting the availability of animals with CNM and because this is an animal model with small numbers, our findings cannot be extrapolated directly to humans. Nevertheless, this study adds information that might be relevant to anaesthesiologists presented with patients with this rare condition. The dogs in this study were autosomal-recessive; we cannot exclude the possibility that autosomal-dominant individuals might behave differently. Weakness in individuals with CNM can worsen mildly with time.1 We cannot speculate on how progression of the disease might affect the duration and effects of SCh. We compared groups of dogs of different breeds and different size and weight; the control group was composed of beagles, which were smaller than the Labradors with CNM. Beagles are commonly used for research purposes, and to our knowledge, no breed-related differences in the response to neuromuscular blockers have been reported in dogs. We did not measure cholinesterase activity in either group, and hence, we cannot comment on whether that could have influenced the duration of action of SCh. However, it is noteworthy that duration of SCh in the beagles is in accord with previous reports.16,17 Whole blood K+ concentrations were only measured at baseline and 5 min after SCh administration and it is possible that higher values of K+ could have gone unnoticed. However, no electrocardiographic changes indicative of hyperkalaemia were observed at any point in any of the dogs. Rhabdomyolisis has been reported after SCh was given to patients with other myopathies.6 Although specific biomarkers for muscle injury were not measured in these experiments, all of the animals returned quickly to their pre-experimental condition and none had signs of muscle pain, suggesting that any muscle injury was minimal in these animals.
In summary, SCh 0.3 mg kg−1 resulted in similar onset but longer duration of action in dogs with autosomal-recessive CNM than in control ones. Autosomal-recessive CNM did not exacerbate the increase in K+ ordinarily seen after succinylcholine in these animals. Although our sample size is too limited to evaluate the incidence of succinylcholine-induced hyperkalaemia, extrapolation of these findings suggests that increased duration of action should be expected if succinylcholine is given to a patient with autosomal-recessive CNM.
Acknowledgements relating to this article
Assistance with the study: none.
Financial support and sponsorship: this work was supported by the Section of Anesthesiology, College of Veterinary Medicine, Cornell University.
Conflicts of interest: none.
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