After major thermal injury, situations may arise in which rapid onset of paralysis is required, such as for rapid-sequence induction of anesthesia or for treatment of laryngospasm. Use of succinylcholine is contraindicated because of concerns about hyperkalemia (1). Rocuronium has a fast onset time, an intermediate duration of action, and no hyperkalemia and may well be a suitable alternative to succinylcholine in these circumstances.
Patients with thermal injury are resistant to the action of nondepolarizing muscle relaxants (NDMRs) (2,3). This effect takes up to several days to manifest and can be observed even up to 18 mo after burn wounds have healed (4). Resistance to NDMRs occurs only when burn injury covers more than 30% of total body surface area (TBSA) (3). The molecular pharmacologic explanation for this is that burn injury causes proliferation of acetylcholine receptors (AChR) on the muscle membrane located under burn sites, as well as at sites distant from the injury (2,5–7). An increase in AChR numbers is usually associated with resistance to the neuromuscular blocking effects of NDMRs and an increased sensitivity to depolarizing muscle relaxants (8). The clinical implication of this observation is that burned patients require larger doses of NDMRs to achieve the desired effect. Rocuronium continues to be the drug of choice when succinylcholine is contraindicated and a rapid onset of paralysis is necessary. However, the pharmacodynamic behavior of rocuronium has not been established in severely burned patients.
This prospective study was conducted to assess the onset time and duration of action of neuromuscular block induced by a single dose of rocuronium (0.9 or 1.2 mg/kg) in patients with major burns when compared with unburned patients.
The study protocol was reviewed and approved by the institutional ethics committee for human research of Hangang Sacred Heart Hospital, Burn Center, Seoul, Korea. After careful explanation and discussion, written, informed consent was obtained from each patient or guardian. To minimize the operator bias, the study was conducted by several anesthesiologists within our department, all well experienced in the assessment of neuromuscular block.
This clinical trial was performed in adults, aged 18–59 yr with ASA physical status II or III, who were scheduled for elective surgery. Fifty-six evaluable patients were included with a history of major burn (>25% TBSA), approximately 50 days after the initial burn injury. The predetermined time for study was 2 wk to 3 mo after the injury. During this period, almost all patients, to a greater or lesser extent, were bedridden and continued to lose body weight but had no active ventilatory problems.
Another 44 unburned patients, matched to burn patients relative to age, weight, and sex, served as the controls. All patients had a Mallampati Class 1 or 2 upper airway anatomy and no anticipated difficulty with mask ventilation or tracheal intubation.
Patients who had 30% more than or less than expected body weight, who were wearing an artificial pacemaker, or who had a history of allergic reaction to neuromuscular blocking drugs were excluded, as were those with any history of hepatic, renal, neuromuscular, or endocrine disease; electrolyte imbalance; myasthenia gravis; or the use of drugs that might affect neuromuscular transmission. Subjects were also excluded if they were pregnant, required a rapid-sequence procedure, or had known or anticipated difficulties with intubation.
One hour before anesthesia, an 18- or 20-gauge IV catheter was placed, and premedication was administered that consisted of atropine 0.5 mg and midazolam 0.01 mg/kg IV. Upon arrival to the operating theater, routine monitors were applied, including electrocardiogram, noninvasive arterial blood pressure, and pulse oximetry. The administration of 100% oxygen via face mask for 3 min was initiated.
Whenever possible, an adductor pollicis area without any burn injury was chosen. Otherwise, healed wound lesions were selected. The monitoring arm was kept free from the inflation of the noninvasive blood pressure cuff or infusion of IV fluids and was placed on a wooden board for immobilization of that arm. The thumb was left freely movable, while the other fingers (digiti II–V) were loosely immobilized with a tape on the board so as not to distort the movement in the adductor pollicis muscle. Neuromuscular block was monitored with an acceleromyograph (TOF-Watch®; NV Organon, Oss, The Netherlands). Before the electrodes were applied, the skin was properly cleansed, degreased, and rubbed with an alcohol sponge. To stimulate the ulnar nerve, two electrodes were placed in parallel above the flexor carpi ulnaris tendon on the volar aspect of wrist and connected to the negative alligator clip distally and to the positive clip proximally. An acceleration transducer was attached at the volar aspect of the distal phalanx of the thumb.
Anesthesia was induced with propofol 1.5–2.5 mg/kg and fentanyl 1–2 μg/kg IV. After the loss of eyelid reflex, TOF-Watch calibration was obtained. The ulnar nerve was stimulated via surface electrodes with 1-Hz single-twitch stimuli for 60 s (pulse width, 200 μs; square wave), and then 30-s tetanic contractions were administered for recruitment of neuromuscular junctions. This was followed by train-of-four (TOF) stimuli, automatically set to deliver 2 Hz, pulse width 200 μs, and square wave 1.5 s, repeated every 15 s. T1, the first twitch of the TOF expressed as a percentage of control response, and the TOF ratio (T4/T1) were used for evaluating the neuromuscular block. After TOF stabilization, the first twitch response was considered the baseline twitch height. A control TOF response was obtained for at least 3 min before the administration of rocuronium. After anesthesia induction and while TOF monitoring was being established, the airway was maintained with an oral airway and face mask without intubation; ventilation was assisted with supplemental oxygen. The end-tidal CO2 was controlled within a normocarbic level during this period.
Patients with and without burn injury were randomly assigned to receive rocuronium (Esmeron®; Organon International, Inc.) at 3 times (0.9 mg/kg) or 4 times (1.2 mg/kg) the 95% effective dose (ED95) administered within 5 s. Onset time was defined as the time from the beginning of drug administration to 95% depression of control twitch height. The time course of the neuromuscular block was assessed by using TOF stimulation and acceleromyography. The twitch responses shown in the TOF-Watch monitor screen and the time measured by digital stopwatch were written down serially.
An investigator who was unaware of the dosage performed tracheal intubation at T0 (complete twitch inhibition). Intubating conditions were assessed according to the guidelines for good clinical practice (9) and graded as excellent, good, or poor depending on vocal cord position and movement, ease of laryngoscopy, airway reaction, and movement of limbs.
Propofol- and fentanyl-based IV anesthesia was conducted with 66% nitrous oxide in oxygen, 0.1–0.15 mg/kg propofol, and occasional supplementation of fentanyl 0.5–1 μg/kg as needed. Vital signs were monitored every 3 min during the study period. The core and peripheral skin temperature were kept at ≥35°C and 32°C, respectively. Ventilation was adjusted to maintain normocarbia (end-tidal CO2, 35–40 mm Hg). Patients were allowed to recover spontaneously from the neuromuscular block to a TOF of ≥ 0.8.
For the recovery time variables, the clinical durations of action (10%, 25%, and 75%) were specified as the times from the start of drug injection until 10%, 25%, and 75% T1 recovery, respectively. The recovery was calculated by using the predose values as control (100%) values. The recovery index, or time from 25% to 75% twitch recovery, was also measured. Finally, the time from the start of drug injection to TOF ≥0.8 recovery was recorded.
Glycopyrrolate 7 μg/kg and neostigmine 50 μg/kg were administered IV for reversal of muscle paralysis at the end of surgery, even if TOF was ≥0.8. Patients were tracheally extubated at TOF ≥0.8 —the recovery of spontaneous ventilation, ability to open eyes on verbal command, and sustain head lift for at least 5 s.
All data are presented as mean data ± sd when applicable. SPSS 10.1 (SPSS Inc., Chicago, IL) was used for statistical analysis. Patient demographics recorded included age, sex, height in centimeters, weight in kilograms, and ASA classification. Type and degree of burns (%TBSA) and the days elapsed after injury were noted. Anesthesia and surgery data were also gathered. Any adverse events, regardless of the medications administered, were reported to the investigators within 24 h of the event. Demographic data were matched by using Student’s t-test. For analysis of onset time and duration of action, two-way analysis of variance with multiple comparison tests (the Scheffé method) was performed to test differences between the control and burn groups given the same dose of rocuronium, as well as between the control or burn groups given different doses. The scores for intubating conditions were compared by using Fisher’s exact test. P < 0.05 was considered statistically significant.
Four patients in the control group and five in the burn injury group were excluded because of protocol violations or poor recording related to motion artifacts during the surgical procedure. Eventually, 44 controls and 56 burn-injured patients were included for the final analysis. Table 1 summarizes the demographic data, which show no significant differences between groups. All patients studied were within 20% of their ideal body weight. The average TBSA burn was more than 35%, and the time elapsed since the injury exceeded a month.
The time of onset to 95% neuromuscular block was significantly delayed in the burn injury groups compared with noninjured controls (115 versus 68 s for 0.9 mg/kg and 86 versus 57 s for 1.2 mg/kg doses, respectively; P < 0.05). The onset times within the two control groups were not significantly different. On the contrary, in the burn-injury group, an intubating dose of 1.2 mg/kg had a faster onset than the 0.9 mg/kg dose (Table 2).
The times taken from drug administration to intubation are summarized in Table 3. At both doses, the burned groups had a significantly longer time to intubate when compared with controls. The longer time to intubate was related to prolonged onset time in burned patients. Within the control groups, the increase in rocuronium dose did not shorten the intubation time. On the contrary, in the burned groups, the dose increase to 1.2 mg/kg significantly shortened the intubation time by approximately 30 s.
The recovery variables examined revealed a shorter duration of block after burn injury compared with controls for the same dose (Table 4). Time to reappearance of first twitch (T1); durations 10%, 25%, and 75%; and the time from injection to TOF 0.8 showed a shorter duration of neuromuscular block among the burn patients in comparison to controls at equipotent doses of rocuronium. Increasing the dosage from 0.9 to 1.2 mg/kg extended the duration of all the recovery variables observed in both the control and the burn-injured groups. The recovery indices (interval, 25%–75%) in both groups were, however, similar between the burn and control groups for equipotent doses.
Intubating conditions were excellent in most control patients, even with rocuronium 0.9 mg/kg. Increasing the dose to 1.2 mg/kg improved the excellent intubating conditions only marginally (65% versus 79%; P > 0.05). In contrast, in the burn group receiving rocuronium 0.9 mg/kg, more than 50% of patients had some diaphragmatic movement, nonsustained coughing, or slight movements in the upper extremities at the time of tracheal intubation, despite reportedly easy laryngoscopy. These conditions were improved when the burned patients were given the larger dose; the 1.2 mg/kg dose gave excellent conditions significantly more often than the 0.9 mg/kg dose in the burn groups (Fig. 1).
Our results have confirmed previous findings that burned patients are resistant to the neuromuscular effects of NDMRs. This was demonstrated as a delayed onset time and shortened duration of action compared with controls with both 0.9 and 1.2 mg/kg doses. This resistance or delayed onset of action in burned patients was overcome to some extent by dose escalation, which resulted in a more prolonged action compared with the smaller dose. Specific to healthy, nonburn patients, although increasing the dosages of rocuronium resulted in a more prolonged action, the onset time was not shortened significantly. This lack of change in onset time may reflect a ceiling effect of the drug.
The time to peak effect (i.e., latency to peak effect) is a function of a number of variables, including the dose administered, the plasma-effect site equilibration properties of the drug, and the potency of the drug. We have observed the expected decrease in potency of rocuronium in burn patients, i.e., a larger ED50. This decrease in potency means that a larger dose must be administered to burn patients to achieve the required therapeutic concentration to effect paralysis as quickly as in nonburned patients. In other words, the burn-induced decreased drug potency can be overcome by a larger dose. This larger dose possibly overcomes resistance related to the target organ changes. Given a large enough dose, the onset time of most drugs can be shortened substantially.
A combination of many different factors associated with burn injury might account for the aberrant responses to depolarizing muscle relaxants and NDMRs (8). Burn injury causes major systemic pathophysiologic changes and alterations of pharmacokinetic functions. Renal elimination of relaxants (e.g., d-tubocurarine [dTc]) is enhanced after burn injury (10) because of enhanced glomerular filtration (11). Circulating factors also decrease the potency of relaxants (12). Circulating plasma factors—such as α1-acid glycoprotein, prostaglandins, hydrolase, and cyclic nucleotides—have been suggested as possible alternatives that might alter the sensitivity of AChRs or the activity of NDMRs (8,13). Pharmacodynamic factors that alter relaxant responses include the upregulation of skeletal muscle AChRs (8,14). As previously reported and recently reviewed, immobilization and disuse due to long-term bed rest or the burn injury itself, inadequate nourishment, and possibly intensive care unit myopathy may also contribute to these changes (15).
By showing a strong correlation between the up-regulated AChRγ messenger RNA in local muscles of the rat and the increased ED50 of dTC, Ibebunjo and Martyn (16) suggested an additional potential mechanism to explain the hyposensitivity to NDMRs in burns. It was proposed that the increased expression of immature AChRs containing α2, β, δ, and γ receptors might play a role. There is evidence for a decreased affinity of NDMRs for immature (fetal) AChRs (17). These same receptors have increased sensitivity to ACh (8). These fetal-type receptors are proliferated at the neuromuscular junction (16) and, hence, express resistance to NDMRs (18).
On the basis of our data, the proper intubation dose for patients with major burns appears to be at least 3 times the ED95 of rocuronium (or even larger). Badetti et al. (19) proposed that the dose of vecuronium must be titrated to achieve effective paralysis and described different correcting factors depending on the extent of the burn injury. Even though intubations were possible in most patients within 90 seconds at 4 times the ED95, it was not clear to what extent the dose had to be increased to effect rapid onset of paralysis for rapid-sequence induction. Therefore, one should be aware of these confounding factors when contemplating rapid sequence induction.
In our study, the ceiling effect of onset time was demonstrated in nonburn controls, similar to other reports (20–22). Although our study was not a dose-finding study with different experimental settings, the general trend was similar to that seen in previous studies (23–26): shorter onset times and better intubating conditions are obtainable with increasing doses of NDMRs. This may well imply increased receptor occupation with more circulating drug. A ceiling effect may also be seen in burned patients if doses larger than 1.2 mg/kg are attempted. A similar ceiling effect was observed in burn patients when twice and 3 times the ED95 doses of a combination of pancuronium and metocurine were administered (27). The reasons for a ceiling effect are likely due to limits on circulation time. Burn patients indeed may show a ceiling effect at larger doses, when onset times reach the range of those in control patients. One exception to the larger dose requirement is mivacurium. Doses of 0.2 mg/kg (2 times the ED95) produced more than 95% block in approximately 90 seconds (28,29). The recovery was also prolonged. Because of the decreased pseudocholinesterase levels of burn (30), the normal intubating dose administered was a relative overdose in burn patients.
In our control groups, the recovery variables were much more prolonged compared with the other studies conducted in Western countries (20–22). All our patients were of Korean (Asian) origin. Previously, Collins et al. (31) observed differences in responses to relaxants between Chinese and Caucasian patients and attributed this interethnic discrepancy to the differences in serum α1-acid glycoprotein levels and muscle mass. Despite minimal metabolism of rocuronium and other steroid relaxants by the liver, their elimination can be altered by enzyme induction or inhibition (32,33). It is therefore possible that the prolonged recovery time seen in our Korean patients may have been related to reduced cytochrome P450 activity. Overall, Asians are more sensitive to NDMRs metabolized in the liver (34). Finally, this may also be due to the differences in experimental settings, such as the monitoring method. Some studies have disclosed large discrepancies between acceleromyographic and mechanomyographic measurements (35–37).
Our experimental limitation lies in the “softness” of the intubating condition end-points. These are very difficult to quantify and are subject to individual bias. The intersubject and intrasubject variability of these measurements has not been characterized. In addition, as for the timing of intubation, we observed in our preliminary studies that we could not intubate any of the burn patients at one minute after drug administration. Hence, the decision was made not to compare conditions at a specific time but to intubate after the twitch was ablated at the adductor pollicis.
In conclusion, the resistance of burn-injured patients to NDMRs can have significant clinical implications. Anesthesiologists, especially when contemplating rapid-sequence induction of anesthesia, should be aware that in major burn injury, the routine recommended intubating dose of rocuronium might not provide adequate muscle relaxation. Even with larger doses, onset may be slower than expected, or the effect may be unpredictable. For rapid-sequence induction in burned patents, we recommend a rocuronium dose of 1.2 mg/kg. Its duration of action, however, could be quite variable; therefore, monitoring of neuromuscular function is clinically essential to specifically determine the dose requirement and the adequacy of reversal in patients with major burns.
1. Gronert GA, Theye RA. Pathophysiology of hyperkalemia induced by succinylcholine. Anesthesiology 1975;43:89–99.
2. Martyn J, Goldhill DR, Goudsouzian NG. Clinical pharmacology of muscle relaxants in patients with burns. J Clin Pharmacol 1986;26:680–5.
3. Dwersteg JF, Pavlin EG, Heimbach DM. Patients with burns are resistant to atracurium. Anesthesiology 1986;65:517–20.
4. Marathe PH, Dwersteg JF, Pavlin EG, et al. Effect of thermal injury on the pharmacokinetics and pharmacodynamics of atra-curium in humans. Anesthesiology 1989;70:752–5.
5. Pavlin EG, Haschke RH, Marathe P, et al. Resistance to atra-curium in thermally injured rats: the roles of time, activity, and pharmacodynamics. Anesthesiology 1988;69:696–701.
6. Ward JM, Martyn JA. Burn injury induced nicotinic acetylcholine receptor changes on muscle membrane. Muscle Nerve 1993;16:348–54.
7. Kim C, Hirose M, Martyn JAJ. D-Tubocurarine accentuates the burn-induced upregulation of nicotinic acetylcholine receptors at the muscle membrane. Anesthesiology 1995;8:309–15.
8. Martyn JAJ, White DA, Gronert GA, et al. Up and down regulation of skeletal muscle acetylcholine receptors. Anesthesiology 1992;76:822–43.
9. Viby-Mogensen J, Englbaek J, Eriksson LI, et al. Good clinical research practice in pharmacodynamic studies of neuromuscular blocking agents. Acta Anaesthesiol Scand 1996;40:59–74.
10. Martyn JA, Matteo RS, Greenblatt DJ, et al. Pharmacokinetics of d-tubocurarine in patients with thermal injury. Anesth Analg 1982;61:241–6.
11. Martyn JA, Greenblatt DJ, Abernethy DR. Increased cimetidine clearance in burn patients. JAMA 1985;253:1288–91.
12. Storella RJ, Martyn JAJ, Bierkamper GG. Anti-curare effect of plasma from patients with thermal injury. Life Sci 1988;43:35–40.
13. Martyn JA. Clinical pharmacology and drug therapy in the burned patients. Anesthesiology 1986;65:67–75.
14. Kim C, Fuke N, Martyn JAJ. Burn injury to rat increases nicotine acetylcholine receptors in the diaphragm. Anesthesiology 1988;68:401–6.
15. Roitberg B. ICU neuropathy and myopathy. Surg Neurol 2003;59:146–7.
16. Ibebunjo C, Martyn JAJ. Disparate dysfunction of skeletal muscles located near and distant from burn site in the rat. Muscle Nerve 2001;24:1283–94.
17. Schuetze SM, Role LW. Developmental regulation of nicotinic acetylcholine receptors. Ann Rev Neurosci 1987;10:403–57.
18. Martyn JA. Basic and clinical pharmacology of the acetylcholine receptor: implications for the use of neuromuscular relaxants. Keio J Med 1995;44:1–8.
19. Badetti C, Pascal L, Bernini V, Manelli JC. Resistance au vecuronium chez le brule: influence de la surface brulee sur la dose efficace 95. Ann Fr Anesth Reanim 1996;15:135–41.
20. Magorian T, Flannery KB, Miller RD. Comparison of rocuronium, succinylcholine, and vecuronium for rapid-sequence induction of anesthesia in adult patients. Anesthesiology 1993;79:913–8.
21. Wright PMC, Caldwell JE, Miller RD. Onset and duration of rocuronium and succinylcholine at the adductor pollicis and laryngeal adductor muscles in anesthetized humans. Anesthesiology 1994;81:1110–5.
22. Schultz P, Ibsen M, Østergaard D, Skovgaard LT. Onset and duration of action of rocuronium: from tracheal intubation, through intense block to complete recovery. Acta Anaesthesiol Scand 2001;45:612–7.
23. Kirkegaard-Nielsen H, Caldwell J, Berry PD. Rapid tracheal intubation with rocuronium: a probability approach to determining dose. Anesthesiology 1999;91:131–6.
24. Woolf RL, Crawford MW, Choo SM. Dose response of rocuronium bromide in children anesthetized with propofol: a comparison with succinylcholine. Anesthesiology 1997;87:1368–72.
25. McCourt KC, Salmela L, Mirakhur RK, et al. Comparison of rocuronium and suxamethonium for use during rapid sequence induction of anaesthesia. Anaesthesia 1998;53:867–71.
26. Andrews JI, Kumar N, Van den Brom RHG, et al. A large sample randomized trial of rocuronium versus succinylcholine in rapid sequence induction of anaesthesia along with propofol. Acta Anaesthesiol Scand 1999;43:4–8.
27. Hagen J, Martyn J, Szyfelbein SK, Goudsouzian NG. Cardiovascular and neuromuscular responses to high-dose pancuronium-metocurine in pediatric burned and reconstructive patients. Anesth Analg 1986;65:1340–4.
28. Martyn JAJ, Goudsouzian NG, Chang YC, et al. Neuromuscular effects of mivacurium in 2- to 12-yr-old children with burn injury. Anesthesiology 2000;92:31–7.
29. Martyn JAJ, Chang Y, Goudsouzian NG, Patel SS. Pharmacodynamics of mivacurium chloride in 13- to 18-yr-old adolescents with thermal injury. Br J Anaesth 2002;89:580–5.
30. Viby-Mogensen J, Hanel HK, Hansen E, et al. Serum cholinesterase activity in burned patients. I. Biochemical findings. Acta Anaesthesiol Scand 1975;19:159–68.
31. Collins LM, Bevan JC, Bevan DR, et al. The prolonged duration of rocuronium in Chinese patients. Anesth Analg 2000;91:1526–30.
32. Soriano SG, Sullivan LJ, Venkatakrishnan K, et al. Pharmacokinetics and pharmacodynamics of vecuronium in children receiving phenytoin or carbamazepine for chronic anticonvulsant therapy. Br J Anaesth 2001;86:223–9.
33. van Miert MM, Eastwood NB, Boyd AH, et al. The pharmacokinetics and pharmacodynamics of rocuronium in patients with hepatic cirrhosis. Br J Clin Pharmacol 1997;44:139–44.
34. Bertilsson L. Geographical/interracial differences in polymorphic drug oxidation: current state of knowledge of cytochromes P450 (CYP) 2D6 and 2C19. Clin Pharmacokinet 1995;29:192–209.
35. Harper NJN, Martlew R, Strang T, Wallace M. Monitoring neuromuscular block by acceleromyography: comparison of the Mini-Acceleromyography with the Myograph 2000. Br J Anaesth 1994;72:411–4.
36. Heier T, Hetland S. A comparison of train-of-four monitoring: mechanomyography at the thumb vs. acceleromyography at the big toe. Acta Anaesthesiol Scand 1999;43:550–5.
37. McCluskey A, Meakin G, Hopkinson JM, Baker RD. A comparison of acceleromyography and mechanomyography for determination of the dose response curve of rocuronium in children. Anaesthesia 1997;52:345–9.