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.
Glucocorticoids influence the time course of neuromuscular block; in patients receiving long-term treatment with prednisolone, the duration of neuromuscular block was reduced following the administration of atracurium or rocuronium.1,2 In patients receiving pretreatment with betamethasone for several months, the neuromuscular blocking effect of vecuronium was also attenuated.3,4 Similar effects were described for dexamethasone and methylprednisolone in experimental settings.5,6 The interactions between corticosteroids and neuromuscular blocking agents (NMBAs) are not limited to one class of muscle relaxants (benzylisoquinolones or aminosteroids) or one glucocorticoid. However, the underlying pharmacologic mechanisms for the attenuation of the neuromuscular block remain unclear.6–9
All investigations described above were performed in patients receiving long-term treatment with glucocorticoids. It is not clear whether a single dose of a glucocorticoid might lead to a similar effect. Glucocorticoids, however, are frequently administered by anaesthesiologists to treat postoperative nausea and vomiting (PONV).10,11 The aim of the present study was to compare the time course of neuromuscular block in patients receiving dexamethasone for prophylaxis of PONV several hours before surgery, with patients receiving the drug immediately before induction of anaesthesia and with patients receiving dexamethasone only after all measurements had finished. The primary end point was the time from start of injection of rocuronium until recovery to a train-of-four ratio (TOF ratio) of 0.9.
Materials and methods
The study was randomised, unblinded, prospective and monocentre (ClinicalTrial.gov Identifier: NCT01782820). After obtaining approval from the local ethics committee (Ethikkommission der Ärztekammer Nordrhein, Düsseldorf, Germany, 20 September 2011, No. 2011272) and patients’ written informed consent, we studied female patients aged 18 to 50 years, American Society of Anesthesiologists physical status I or II, 50 to 90 kg body weight, undergoing elective laparoscopic gynaecological surgery under general anaesthesia.
C-reactive protein (CRP) concentration, haemoglobin concentration, serum sodium, calcium, and potassium concentration, white cell and platelet count, serum creatinine, internationalised normalised ratio (INR), glutamic-oxaloacetic transaminase (GOT), glutamic-pyruvic transaminase (GPT), gamma-glutamyl-transferase (GGT), alkaline phosphatase, bilirubin and cholinesterase were determined in all patients before surgery during routine preoperative evaluation. Patients with values outside the normal range [as defined in our department (Medizinische Laboratorien Duesseldorf, Duesseldorf, Germany)] were excluded from the study. Other exclusion criteria were expected difficulty with tracheal intubation [history of difficult intubation, reduced opening of the mouth (< 2 cm) and Mallampati Score of 4]; increased risk of pulmonary aspiration (gastro-oesophageal reflux, full stomach and intestinal obstruction); known allergies to the study drugs; pregnancy; neuromuscular disorders, intake of drugs affecting neuromuscular block such as furosemide, magnesium or cephalosporins; and hepatic or renal insufficiency.
Patients were randomly assigned to one of three groups according to a computerised allocation program: 36 patients received dexamethasone 8 mg intravenously 2 to 3 h prior to surgery (Group A), 36 patients received dexamethasone 8 mg intravenously immediately before induction of anaesthesia (Group B) and 36 patients served as control (Group C). In the latter group, dexamethasone was administered intravenously at the end of surgery when neuromuscular measurements had been finished.
Patients were premedicated with oral midazolam 7.5 mg. Anaesthesia was induced with continuous infusion of remifentanil 0.2 μg kg−1 min−1, and a single dose of fentanyl 2 μg kg−1 and propofol 2 to 3 mg kg−1. Directly after loss of consciousness, patients’ tracheas were intubated without NMBAs and their lungs ventilated to normocapnia (4.8 to 5.33 kPa) during the study period. Anaesthesia was maintained with continuous infusions of remifentanil 0.15 to 0.25 μg kg−1 min−1 and propofol 3 to 5 mg kg−1. Haemodynamic variables were maintained in a normal range (±20% of baseline values) by additional administration of propofol and remifentanil in case of tachycardia or arterial hypertension, and ephedrine or atropine were administered for hypotension or bradycardia. Core and surface temperature were measured and kept above 36°C (nasal) and 34°C (skin surface over the adductor pollicis) by warm blankets or convective warming devices.
Assessment of neuromuscular function
Neuromuscular transmission was assessed by acceleromyography (TOF Watch SX; Essex Pharma GmbH, Munich, Germany) at the adductor pollicis muscle using transcutaneous Ag/AgCl electrodes (ECG electrodes; Ambu Inc., Maryland, USA); neuromuscular stimulation started after induction of anaesthesia. To establish a control twitch height value of 100%, the acceleromyograph was calibrated in order to deliver supramaximal TOF stimuli (0.1 ms duration) at 2 Hz every 15 s. The first of the four responses was considered the twitch height (T1). To minimise movement-induced changes in twitch response, the patients’ hand was carefully fixed with tape on an arm board. After a 10-min period of stabilisation and a variation of the response of less than 2% for at least 3 min, the acceleromyograph was recalibrated and the control T1 was determined.
In all three groups, rocuronium 0.3 mg kg−1 was injected over a period of 5 s and the intravenous line flushed with Ringers’ solution. The following were measured: maximum T1 depression; onset time of neuromuscular block (time between the beginning of injection of rocuronium and maximum T1 depression); clinical duration (DUR 25%; time between administration of rocuronium and recovery to 25% twitch height of T1); recovery index (time interval from 25% to 7% twitch height recovery); duration TOF ratio 0.9 (time from injection of rocuronium to a recovery of neuromuscular block to a TOF ratio of 0.9).12 All data were recorded on a computer connected to the TOF Watch SX during the period of measurements (TOF-Watch SX Monitor Version 2.5.INT; Organon Ltd, Dublin, Ireland).
Statistical analysis was performed using the Sigma Plot 12.3 for Windows (Systat Software Inc., Chicago, Illinois, USA) software package. Data not normally distributed were compared using Kruskal–Wallis one-way analysis of variance on ranks, followed by Dunn's posthoc test for multiple comparisons (weight, BMI). Normally distributed data were compared using the one-way repeated measures analysis of variance, followed by the Holm–Sidak test for all pairwise multiple comparison procedures (all other data). All tests were two-tailed with a significance level of α equal to 0.05 and were corrected for multiple comparisons (Bonferroni correction). We calculated the sample size prospectively on the basis of the results of our previous study.1 We aimed at a power of 90% to detect a difference of 5 min (SD 10 min) in time to recovery of the TOF ratio to 0.9 at the 5% level; 33 patients per group were required.
Two patients in Group B were excluded because of technical problems with the equipment. In nine patients of Group A, seven patients of Group B and 10 patients of Group C, surgery finished before patients achieved complete recovery from the neuromuscular block; in these patients, anaesthesia was maintained until a TOF ratio of 0.9 (Fig. 1). Personal and laboratory data did not differ significantly between groups (Table 1). The mean ± SD time interval between administration of dexamethasone and injection of rocuronium was 165.9 ± 74.6 min in Group A and 14.4 ± 6.2 min in Group B.
Time course of neuromuscular block
The onset time and maximum T1 depression were similar in all groups. Although complete neuromuscular block developed in the majority of patients, five patients of Group A, three patients of Group B and six patients of Group C did not reach a maximum T1 depression of 5% or lower (Table 2). However, the groups differed significantly with regard to clinical duration, recovery index and duration to a TOF ratio of 0.9 (Table 2 and Fig. 2).
We have shown that dexamethasone 8 mg 2 to 3 hr prior to surgery shortened the duration of rocuronium-induced neuromuscular block by nearly 15 to 20% (recovery index and return to a TOF ratio of 0.9). Onset time and maximum neuromuscular block, however, were not affected. The administration of dexamethasone immediately before induction of anesthesia did not attenuate the rocuronium effect.
The dose of 8 mg of dexamethasone for prophylaxis of PONV is high. Many institutions use only 4 mg for this indication. However, dexamethasone improves analgesia and provides anti-inflammatory effects. In this context, the recommended dose varies from 1.25 to 20 mg.13 Thus, our concept seems to be an intermediate dose approach. The use of another dose – higher or lower – might have led to different results. However, the focus of the present investigation was on the timing, not on the dose of dexamethasone administration. Therefore, we are not able to make a statement with regard to the amount of dexamethasone necessary to influence neuromuscular block. The use of dexamethasone several hours prior to surgery is an experimental design and not a concept used in clinical routine. Nevertheless, the duration of many operations exceeds this time interval. In these cases, the effect of dexamethasone might become clinically relevant during anaesthesia. The administration of dexamethasone for prophylaxis of PONV is a routine measure in our department; therefore, the intention was to provide all patients with the drug, irrespective of the group. The injection after completion of measurements did not influence the results obtained. However, the patients received dexamethasone as early as possible in order to obtain its prophylactic effect in time.
The dose of rocuronium used in our study (0.3 mg kg−1) is substantially lower than the doses administered routinely. However, the GCRP guidelines recommend the use of low doses in order to assess onset and time course of the neuromuscular block.12 Tracheal intubation without muscle relaxants might lead to a higher incidence of vocal cord damage or difficult intubation conditions and is not recommended for routine clinical situations. With hindsight, initial placement of a laryngeal mask airway and secondary tracheal intubation after establishment of the neuromuscular block might have been a better design.
Several investigations have demonstrated an attenuation of the neuromuscular blocking effect of vecuronium,3,4 atracurium1 and rocuronium2 in the presence of glucocorticoid co-medication. Long-term co-medication affects only a small group of patients. In contrast, single-dose dexamethasone is frequently administered during anaesthesia because of its antiemetic, anti-inflammatory and analgesic properties.10,11,13 Of note, dexamethasone is usually injected prior to surgery at the induction of anaesthesia because of the delayed onset of its desired effects.14,15 According to our results, dexamethasone requires time to produce its effect on neuromuscular block; in Group B, no attenuation of the neuromuscular block was observed in patients receiving dexamethasone about 15 min prior to the administration of rocuronium. Thus, dexamethasone probably does not produce a direct antagonistic effect at the motor end plate. Glucocorticoids possess a direct facilitatory effect at the impulse generating end of the motor nerve axon16 and act presynaptically stimulating synthesis17 and release of acetylcholine.5,18 Recently, a study19 has demonstrated a counteracting effect of a high single dose of glucocorticoid on rocuronium in rats. The authors postulate an inhibition of the calpain system, a protein belonging to the family of calcium-dependent, nonlysosomal cysteine proteases and the caspase-3 system playing a role in apoptosis. However, measurements were performed 24 h after administration of methylprednisolone. The time interval from injection of the glucocorticoid to onset of the effect was not exactly defined and it is not clear whether these mechanisms are able to explain our results.
The clinical duration of neuromuscular blockade was shorter in Group A (dexamethasone 2 to 3 h before surgery) than in Group B (dexamethasone before induction of anaesthesia). Recovery index and recovery to a TOF ratio of 0.9 were shorter in Group A than in Groups B and C (Fig. 2). We found no difference between Group B and Group C. We believe that dexamethasone had no effect on the duration of rocuronium neuromuscular block in Group B because 15 min did not allow enough time to produce an effect, whereas 2 to 3 h were long enough. We are not able to define the exact time interval required to develop the effect on neuromuscular block.
In our previous study,2 we found a significant reduction of the clinical duration as well as recovery index and TOF ratio 0.9 following a rocuronium-induced neuromuscular block in patients with long-term glucocorticoid medication (∼25 to 30%), which was more pronounced than the present data. In addition, the difference between groups with regard to return to a TOF ratio of 0.9 after rocuronium 0.3 mg kg−1 was nearly 10 min in the previous investigation, whereas we recorded a difference of 6 min in the present study. These findings support the hypothesis that the effects of glucocorticoids on the duration of the neuromuscular block would have been even more pronounced if the time interval from injection of the glucocorticoid to administration of rocuronium had been longer. On the contrary, a single dose of dexamethasone 8 mg might not be equivalent to long-term use of glucocorticoid medication in the previous investigations. A direct comparison of the two studies is difficult because we used different equipment; data in the previous study were obtained using electromyography whereas the measurements in the present investigation were performed with acceleromyography. TOF ratios obtained with acceleromyography are often slightly higher than those measured with other methods and the techniques cannot be used interchangeably.12
A shorter duration of neuromuscular block reduces the risk of postoperative residual curarisation (PORC) but increases the possibility of an insufficient neuromuscular block. In certain situations, such as during neurosurgery, dexamethasone is administered in high doses (up to 40 mg) or long term in order to reduce intracranial pressure. In these cases, neuromuscular block might be even more attenuated than observed in the present setting. Neuromuscular monitoring is mandatory if deep neuromuscular block is necessary.
Our three groups did not differ from each other concerning onset time and maximum depression of T1 depression. This observation might be related to the study design. The guidelines for studies assessing onset time and maximum block recommend using subparalysing doses of muscle relaxant.12 We used rocuronium 0.3 mg kg−1 (1 × ED95) leading to complete neuromuscular block in nearly all patients and may be the reason why we did not observe differences.
In conclusion, a single dose of dexamethasone 8 mg attenuated rocuronium-induced neuromuscular block by 15 to 20% with a latency of 2 to 3 h. The effect might be negligible in short procedures.
Acknowledgements relating to this article
Assistance with the study: none
Financial support and sponsorship: none.
Conflicts of interest: none.
1. Soltesz S, Mencke T, Mey C, et al. Influence of a continuous prednisolone medication on the time course of neuromuscular block of atracurium in patients with chronic inflammatory bowel disease. Br J Anaesth
2. Soltesz S, Mencke T, Stunz M, et al. Attenuation of a rocuronium-induced neuromuscular block in patients receiving prednisolone. Acta Anaesthesiol Scand
3. Parr SM, Robinson BJ, Rees D, Galletly DC. Interaction between betamethasone and vecuronium. Br J Anaesth
4. Parr SM, Galletly DC, Robinson BJ. Betamethasone-induced resistance to vecuronium: a potential problem in neurosurgery? Anaesth Intensive Care
5. Dalkara T, Onur R. Facilitatory effects of dexamethasone on neuromuscular transmission. Exp Neurol
6. Kindler CH, Verotta D, Gray AT, et al. Additive inhibition of nicotinic acetylcholine receptors by corticosteroids and the neuromuscular blocking drug vecuronium. Anesthesiology
7. Dal Belo CA, Leite GB, Fontana MD, et al. New evidence for a presynaptic action of prednisolone at neuromuscular junctions. Muscle Nerve
8. Fischer JR, Baer RK. Acute myopathy associated with combined use of corticosteroids and neuromuscular blocking agents. Ann Pharmacother
9. Leeuwin RS, Veldsema-Currie RD, van Wilgenburg H, Ottenhof M. Effects of corticosteroids on neuromuscular blocking actions of d-tubocurarine. Eur J Pharmacol
10. De Oliveira GS, Almeida MD, Benzon HT, McCarthy RJ. Perioperative single dose systemic dexamethasone for postoperative pain: a meta-analysis of randomized controlled trials. Anesthesiology
11. De Oliveira GS Jr, Castro-Alves LJ, Ahmad S, et al. Dexamethasone to prevent postoperative nausea and vomiting: an updated meta-analysis of randomized controlled trials. Anesth Analg
12. Fuchs-Buder T, Claudius C, Skovgaard LT, et al. Good clinical research practice in pharmacodynamic studies of neuromuscular blocking agents II: the Stockholm revision. Acta Anaesthesiol Scand
13. Waldron NH, Jones CA, Gan TJ, et al. Impact of perioperative dexamethasone on postoperative analgesia and side-effects: systematic review and meta-analysis. Br J Anaesth
14. Holte K, Kehlet H. Perioperative single-dose glucocorticoid administration: pathophysiologic effects and clinical implications. J Am Coll Surg
15. Wang JJ, Ho ST, Tzeng JI, Tang CS. The effect of timing of dexamethasone administration on its efficacy as a prophylactic antiemetic for postoperative nausea and vomiting. Anesth Analg
16. Hall ED. Glucocorticoid effects on the electrical properties of spinal motor neurons. Brain Res
17. Veldsema-Currie RD, Wolters E, Leeuwin RS. The effect of corticosteroids and hemicholinium-3 on choline uptake and incorporation into acetylcholine in rat diaphragm. Eur J Pharmacol
18. Dreyer F, Peper K, Sterz R, et al. Drug-receptor interaction at the frog neuromuscular junction. Prog Brain Res
© 2014 European Society of Anaesthesiology
19. Maes K, Testelmans D, Thomas D, et al. High dose methylprednisolone counteracts the negative effects of rocuronium on diaphragm function. Intensive Care Med