This article is accompanied by the following Invited Commentary:
Fuchs-Buder T. Residual neuromuscular blockade and postoperative pulmonary outcome. The missing piece of the puzzle. Eur J Anaesthesiol 2014; 31:401–403.
Diabetes mellitus can be responsible for motor nerve dysfunction and degeneration, and this may alter the response to neuromuscular blocking drugs.1 Very few studies of the pharmacodynamics of neuromuscular blockers in diabetic mellitus type IIpatients (T2DM) are available. Earlier reports have shown a longer time to recovery from the effect of these drugs in patients with motor neurone disease, and a lower conduction velocity in the peroneal, ulnar and radial nerves in diabetic individuals than in healthy patients, despite the lack of diabetic neuropathy or nephropathy.2,3 Studies conducted by Saitoh et al.4–6 in T2DM patients given vecuronium showed a significant prolongation of neuromuscular function recovery. The results of experiments conducted with rocuronium were similar.7 A recent study8 of the profile of neuromuscular block by vecuronium using first dorsal interosseous electromyography has shown that recovery times to train-of-four (TOF) ratios of 0.70 (DURTOF70) and 0.90 (DURTOF90) were significantly longer in the T2DM group than in the control group. In the clinical setting, quantitative techniques may not be widely used, with many anaesthesiologists relying on visual or tactile assessment of the TOF ratio, or, in many cases, no neuromuscular monitoring at all.9 The data above suggest that the risk of developing residual neuromuscular block (RNMB) is greater in diabetic patients. No studies measuring this risk in diabetic patients after rocuronium are available.
The primary objective of this study was to analyse whether the time to achieve a TOF ratio of at least 0.9 from injection of rocuronium 0.6 mg kg−1 (DURTOF90) is prolonged in diabetic patients even in the absence of neuropathy or other complications of diabetes mellitus. Secondary objectives included an analysis of any correlation between glycosylated haemoglobin and fasting blood glucose levels (on the day of the preanaesthesia visit and on the day of surgery), and spontaneous recovery to a TOF ratio of at least 0.9 (DURTOF90), in the group of T2DM patients.
Patients and methods
Ethical approval for this study (Ethical Committee No. 15/2011) was provided by the Ethical Committee Hospital San Jorge de Huesca, Huesca, Spain, on 24 November 2011. All patients gave their consent after receiving extensive information about the study.
The study is a prospective, observational study of neuromuscular block induced by rocuronium in a group of T2DM patients compared with a group of healthy controls. The following observations were made: variables related to RNMB: spontaneous recovery to a TOF (TOF) ratio of at least 0.9 (DURTOF90, main variable), spontaneous recovery to a TOF ratio of at least 0.7 (DURTOF70) and time elapsed from reappearance of T2 to spontaneous recovery to a TOF ratio of at least 0.9 (T2-TOF90); pharmacodynamic variables related to neuromuscular blockade: reappearance of the first, second, third and fourth TOF responses (T1, T2, T3 and T4) and onset time (T1 = 0).
An analysis was also made to see whether a correlation existed between glycosylated haemoglobin (HbA1c) and fasting blood glucose levels, and spontaneous recovery to a TOF ratio of at least 0.9 (DURTOF90) in the T2DM patients. Blood samples were drawn on the day of the preanaesthesia visit and on the day of surgery.
Patients classified as American Society of Anesthesiology physical status (ASA PS) classes I, II or III, aged between 40 and 80 years, scheduled for surgery with an expected mean duration longer than 120 min under general anaesthesia were enrolled into the study. In the T2DM group, only those with no neurological symptoms without a diagnosis of diabetic neuropathy were enrolled. Patients with allergy to rocuronium, with myasthenia gravis, Guillain-Barré syndrome, Duchenne muscular dystrophy or similar, or receiving drugs that might interfere with neuromuscular transmission or the response to neuromuscular blockers, such as some anticonvulsants and antibiotics, were excluded from the study. An additional exclusion criterion was suspected difficult intubation (Mallampati III and IV, thyromental distance <6.5 cm, mouth opening <3.5 cm). Patients with serum creatinine levels higher than 1.5 mg dl−1 or creatinine clearance less than 60 ml min−1 1.73 m−2 (using the Cockcroft and Gault formula) were also excluded. Finally, patients with levels of glutamic-pyruvic transaminase (GPT) or glutamic-oxaloacetic transaminase (GOT) higher than 42 IU l−1 or a BMI of less than 18.5 kg m−2 or more than 30 kg m−2 did not participate in the study.
In the preanaesthesia room, all patients were given intravenous (i.v.) midazolam 10 to 20 μg kg−1. An electrocardiograph, a noninvasive blood pressure monitor, a pulse oximeter, bispectral index (BIS), a capnograph and an expiratory gas analyser were attached in the operating room. Anaesthesia was induced with an i.v. bolus of fentanyl 1 to 2 μg kg−1 and propofol 2 to 2.5 mg kg−1. After induction, once preparation and calibration for neuromuscular block monitoring was completed, rocuronium 0.6 mg kg−1 was administered over 5 s. Once the first TOF response was equal to 0 (T1 = 0), orotracheal intubation was performed by direct laryngoscopy. Anaesthesia was maintained with sevoflurane in oxygen/air to maintain an FiO2 of 0.4 and an end-tidal concentration of sevoflurane (EtSev) of 1.5% for a BIS ranging from 40 to 60. Ventilation was adjusted to maintain end-tidal CO2 concentrations (EtCO2) ranging from 30 to 35 mmHg. Patients received thermal protection with hot air blankets. Crystalloid fluid therapy was infused according to our current clinical protocol. When heart rate or blood pressure increased more than 15% above baseline values, fentanyl boluses of 50 to 100 μg were administered. When heart rate or blood pressure decreased by more than 15% of baseline values, patients were treated with increased fluid, atropine or ephedrine as needed. In the event of poor tolerance of mechanical ventilation, propofol 20 to 30 mg by bolus was administered. Anaesthesia was maintained in this manner until study completion. The study was terminated when a TOF ratio equal to 0.9 was reached, regardless of the surgery time remaining.
Monitoring of neuromuscular block
After induction of anaesthesia, monitoring of neuromuscular function by percutaneous stimulation of the ulnar nerve at the wrist was begun. A TOF Watch SX neurostimulator (Organon Ltd, Ireland) and paediatric skin electrodes (Neotrode, Conmed, Utica, New York, USA) were used. The information collected was downloaded in real time to a personal computer (PC) using TOF Watch SX Monitor v2.5 software (Organon Ltd, Ireland).
The monitoring procedure was based on recommendations from the 2007 Stockholm revision of good clinical practice research in pharmacodynamic studies of neuromuscular blocking drugs.10 Before placing the electrodes, the skin was cleaned with alcohol to decrease resistance. Skin electrodes were then applied 3 to 6 cm apart. Finally, neuromuscular electrodes were connected in the recognised fashion: the negative electrode distal and the positive electrode proximal. The skin temperature sensor was placed on the thenar eminence. The recommended peripheral skin temperature is at least 32°C. The hand adapter device was used to prevent the staircase phenomenon. The piezoelectric acceleration sensor was placed at the union of the two phalanges of the thumb in the space reserved by the hand adapter for that purpose. The hand and forearm were fastened strongly to the armrest to facilitate thumb movement and avoid interference.
The sequence used to calibrate the device and stabilise response was as follows: 50 Hz tetanic stimulus for 5 s (tetanic preconditioning); 0.2 ms pulses in TOF stimulation mode (four 2 Hz stimuli 15 s apart) for 2 to 5 min until a stable response was obtained; calibration of the TOF Watch SX in its CAL2 mode; and TOF stimulation mode (four 2 Hz stimuli 15 s apart) until the end of the study. After this sequence, rocuronium 0.6 mg kg−1 was administered.
Personal and clinical variables
The following were recorded: sex, age, weight, height, BMI, ASA classification and type of surgery. Laboratory tests included blood glucose at the preanaesthesia visit and on the day of surgery; potassium (mEq l−1); creatinine (mg l−1); creatinine clearance (ml min−1); and haemoglobin (g dl−1). In diabetic patients, the last HbA1c measurement and hypoglycaemic treatment received were recorded.
The following times from rocuronium injection (0.6 mg kg−1) were recorded: onset time, occurrence of the first (T1), second (T2), third (T3) and fourth (T4) TOF response, time to achieve a TOF ratio of at least 0.7 (DURTOF70) and time to achieve a TOF ratio of at least 0.9 (DURTOF90). Time from occurrence of T2 to a TOF ratio of at least 0.9 (T2-TOF90) was also recorded.
The sample size required to test the null hypothesis using a two-sided Student's t test for two independent samples was estimated. Means and standard deviations were obtained after the first 10 cases of each of the study groups. The mean in the control group was 85.0 min, compared with a mean of 112.8 min in the T2DM group, with a standard deviation of 33.2 min in both groups. These findings are similar to those from similar studies.11–15 Thus, assuming a 5% significance level and a 90.0% power, it was concluded that at least 31 patients had to be recruited in both the control and T2DM groups.
For comparing means, Student's t test was used when conditions of homogeneity and normality of variances were met between the two groups, and a nonparametric Mann–Whitney test for samples not meeting these conditions. Analysis of variance (ANOVA) was used for repeated measures with Bonferroni correction when required. Analysis of association between two quantitative variables was performed using Pearson's correlation coefficient. SPSS v 15.0 was used for statistical data analysis.
A total of 71 patients were recruited: 32 patients diagnosed with T2DM and 39 healthy controls who met inclusion and exclusion criteria between January and September 2012. Data were collected by the same observer in all cases. Patients of both groups were matched in terms of weight, age and sex (Table 1). No statistically significant differences were seen between the laboratory values of both groups (Table 2).
A significant prolongation of DURTOF90 was seen in the T2DM group compared with the control group. DURTOF70 and T2-TOF90 times were also significantly longer in diabetic patients (Table 3). All other recovery times of neuromuscular function were also prolonged in diabetic patients (occurrence of T1, T2, T3, T4). Only onset time showed similar values in both groups (Table 4).
Correlation between HbA1c, glycaemia and pharmacodynamic variables in the type 2 diabetes mellitus group
Blood glucose levels were significantly elevated in the T2DM group compared with the controls. In the T2DM group, no correlation was found between DURTOF90 and HbA1c, and glucose levels either at the preanaesthesia visit or on the day of surgery. There was no correlation between HbA1c and other pharmacodynamic variables.
There were no significant differences in DURTOF90 between T2DM patients treated with oral hypoglycaemic drugs or insulin.
Our results support the hypothesis that mean DURTOF90 is significantly prolonged in diabetic patients after a standard clinical bolus of rocuronium giving a higher risk of RNMB. Nitahara et al.8 reached the same conclusion using a 0.1 mg kg−1 bolus of vecuronium comparing two groups of 14. In common with the patients in our study, DURTOF70 and DURTOF90 values were significantly longer in the diabetic group. However, the patient groups analysed by Nitahara had a difference in their mean age that was not significant, but amounted to a significant bias in interpretation of results. Despite this, our findings support such results and provide new evidence of the higher risk of RNMB in diabetic patients. Our study used rocuronium because in our practice it is more commonly used than vecuronium. DURTOF90 is a standard variable in pharmacodynamic studies of neuromuscular blockade in recent years. Our control group had a DURTOF90 consistent with that reported by other studies, considering mean age, anaesthetic procedure and rocuronium dose used.11–20
Our results are also in agreement with Saitoh in the significantly longer times to reappearance of T1, T2, T3 and T4 in diabetic patients.4–6 Saitoh also found a significantly lower TOF ratio at 120 min in the diabetic group. He suggested that the reason for these findings was because diabetes mellitus has a greater impact on neuromuscular transmission at the postsynaptic membrane than at the presynaptic nerve endings. However, research conducted by Constantini et al.21 on the pathophysiology of the neuromuscular junction in diabetic rats showed both metabolic and transmission changes in these animals. This challenged Saitoh's hypothesis because changes in both glucose transport and acetylcholine release were seen in the presynaptic nerve endings.4–6 In our study, and in the study by Nitahara et al.,8 differences in pharmacodynamic variables between the diabetic and control groups became more evident with time. However, Nitahara found no statistically significant time differences from injection of vecuronium 0.1 mg kg−1 to a TOF ratio equal to 0.25. In the present study, significant time differences to reappearance of T1 were found.
Nitahara maintained anaesthesia with TIVA, although this study used sevoflurane, which may suggest a greater sensitivity of diabetic patients to the effect of sevoflurane. This hypothesis is also supported by Saitoh's findings,6 but additional research would be needed to confirm it.
Results of this study show that T2-TOF90 time is significantly prolonged in the group of diabetic patients, in agreement with previous reports with vecuronium.8 Reappearance of T2 marks the time at which the effect of rocuronium and other neuromuscular blockers may be reversed with anticholinesterase agents. Both vecuronium and rocuronium can be reversed with sugammadex, a novel molecule that inactivates the neuromuscular blocker by encapsulation. When T2 reappears, administering sugammadex 2 mg kg−1 will restore neuromuscular function.
As expected, mean blood glucose levels were higher in the diabetic than in the control group both at the preanaesthesia visit and on the day of surgery. This finding was also made in the studies by Saitoh, Alper and Atallah and colleagues.4–7,22 Sustained hyperglycaemia may be involved in the pathogenesis of subclinical neuropathy, leading to prolongation of the effect of neuromuscular blockers. Earlier studies in diabetic patients did not seek a relationship between glycaemic control and characteristics of the neuromuscular block, probably because of the small numbers in the diabetic groups. The sample size of this study allowed for analysis of such a relationship but, contrary to expectations, no correlation was found between blood glucose levels, HbA1C and DURTOF90. It may be that for this to succeed, a larger sample size is required. HbA1c only indicates glycaemic control in the last 4 or 6 weeks, and neurological damage from sustained hyperglycaemia occurs over years, rather than months. The same may be said of blood glucose levels at the preanaesthesia visit and on the day of surgery, which only show glyacemic control at a given time.
Our conclusion is that time to recovery from neuromuscular block to a TOF ratio of at least 0.9 following administration of rocuronium 0.6 mg kg−1, similar to all other measurements of residual neuromuscular block, is significantly prolonged in diabetic patients without nephropathy or clinical signs of neuropathy than in healthy controls. Times to reappearance of T1, T2, T3 and T4 are also significantly delayed. Markers of poorer glycaemic control do not correlate with DURTOF90. Finally, the nature of treatment does not appear to influence the risk of residual neuromuscular block.
Acknowledgements relating to this article
Assistance with the study: We would like to thank Sofía Perea, Pharm D, PhD, for editorial assistance.
Financial support and sponsorship: none.
Conflicts of interest: none.
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