Postpartum patients have prolonged neuromuscular block after rocuronium (1), and it has been suggested that this could be a result of the decreased elimination of steroidal drugs during pregnancy (1,2). However, postpartum patients still have increased weight compared with the nonpregnant state, and drug administration according to total body weight (TBW) may result in a relative drug overdose, with consequent prolonged block. Lean body mass (LBM) has been advocated as a better predictor for drug dose calculations in obese patients (3,4). The purpose of the present study was to determine whether or not dosing by TBW as compared with LBM could largely account for the prolonged rocuronium block in postpartum patients.
The study was approved by the Clinical Research Ethics Committee, and all patients gave written informed consent. Neuromuscular block was compared between Postpartum and Control patients at two doses of rocuronium, 0.6 mg/kg TBW and 0.6 mg/kg LBM, so that 4 groups of patients were studied. From published data on rocuronium (1), power analysis (β = 0.1, α = 0.05) indicated that a sample size of 11 would be sufficient to detect a 4-min difference in clinical duration of neuromuscular block. Patients who were ASA physical status I between 25 and 45 yr of age were eligible for the study. Patients were excluded if they were known to have neuromuscular disease or were receiving medications with known or suspected effects on neuromuscular function. Patients taking oral contraceptive drugs were also excluded. Postpartum women were scheduled for elective tubal ligation 24–120 h after delivery, and Nonpregnant Control patients underwent gynecological laparoscopy.
Premedication was not prescribed. After routine monitors were applied, anesthesia was induced with propofol 2 mg/kg and alfentanil 5 μg/kg. Anesthesia was then maintained by a manually adjusted step-down infusion of the propofol (10 mg/mL) and alfentanil (50 μg/mL) mixture (1 mL · kg−1 · h−1 for the first 10 min, 0.8 mL · kg−1 · h−1 for the next 10 min, and 0.6 mL · kg−1 · h−1 thereafter). Neuromuscular block was measured by evoked adductor pollicis electromyography (Relaxograph; Datex, Helsinki, Finland). Methods were in accord with the Good Clinical Research Practice guidelines (5). Baseline calibration and measurement of neuromuscular block was performed with the hand fixed and the thumb placed under tension using an adhesive board and thumb restraint. The ulnar nerve was stimulated transcutaneously using a train-of-four pattern of stimulus every 10 s. The palmar skin temperature was maintained above 33°C with warm blankets. LBM was calculated according the formula:MATH where LBM and TBW are in kg and height is in cm (3,4).
The dose of rocuronium was allocated in a random double-blinded manner with the use of sealed envelopes. After an initial stabilization period of 15 min, rocuronium 0.6 mg/kg TBW or LBM was given over 5 s into a fast-running IV infusion of normal saline. The trachea was intubated after complete neuromuscular block had been achieved. Ventilation of the lungs was adjusted to maintain end-tidal carbon dioxide tension between 34 and 38 mm Hg. Neuromuscular block was permitted to diminish until there was at least 95% recovery of the first twitch response (T1). The study was completed before surgery started, and anesthesia was continued as required. Data from the Relaxograph were recorded and were coded to blind the investigator who calculated the times for standard indices of neuromuscular block (5). We measured the onset time (time from the start of rocuronium injection to 95% suppression of T1), duration of action (time from the start of rocuronium injection to 25% recovery of T1), and interval 25%–75% (time required from 25% to 75% recovery of T1).
Body mass index (BMI) was also calculated for all patients to allow comparison with other published data. The Mann-Whitney U-test was used to compare patient characteristics and indices of neuromuscular block between the Postpartum and Control groups at each of the two doses of rocuronium. Duration of block was compared with anthropometric variables by linear regression analysis. P values <0.05 were considered significant.
Patients’ characteristics are summarized in Table 1. Age and height of the Postpartum patients were similar to that of the Nonpregnant Controls. However, Postpartum patients were heavier than the Nonpregnant patients (P < 0.001) with a higher BMI (P < 0.001) and LBM (P < 0.05). T1 recovered spontaneously in all patients to between 96% and 100% of control.
When rocuronium was given by TBW, the onset times were similar in both groups but the duration and interval 25%–75% were longer in Postpartum women compared with Nonpregnant Controls (P < 0.001). After dosing by LBM, the duration of block and interval 25%–75% were similar between the Postpartum and Nonpregnant patients (Table 1).
Figure 1 shows the correlation between duration of rocuronium block and anthropometric variables. The duration of block increased linearly with TBW (Fig. 1A, r = 0.77, P < 0.001), LBM (Fig. 1B, r = 0.62, P = 0.002) and BMI (Fig. 1C, r = 0.74, P < 0.001) if rocuronium dose was administered according to TBW. In contrast, the duration was similar across the given range of TBW (Fig. 1C, P = 0.56), LBM (Fig. 1D, P = 0.80) and BMI (Fig. 1E, P = 0.41) when rocuronium was calculated on LBM.
Onset and recovery times in the two Nonpregnant groups were similar to that reported in other studies (6,7). The total dose of rocuronium given, and hence the duration of block, was less in our LBM groups compared with the TBW groups. It could be argued that the shorter duration of block might have made it more difficult to detect differences in duration. An alternative study design would have been to give a larger dose (approximately 0.85 mg/kg LBM) to the LBM groups. However, the duration of block should be similar for a given dose whenever the dose is calculated according to LBM.
Prolonged block may be attributable to pharmacokinetic or pharmacodynamic reasons. There are no data on rocuronium disposition or dose-response relationship in the postpartum period. However, the elimination of vecuronium and pancuronium is actually increased during cesarean delivery (8), and an in vitro study using phrenic nerve-hemidiaphragm preparation showed no difference in the neuromuscular blocking effects of vecuronium between pregnant and nonpregnant rats (2). Although changes in rocuronium elimination cannot be excluded, we believe that considerations of body weight are sufficient to account clinically for the prolonged block.
Changes in body composition may also alter duration of neuromuscular block. In this regard, obesity is associated with a decrease in the proportion of muscle mass to TBW. Thus, administration of neuromuscular blocking drugs according to TBW will result in drug overdose. Pühringer et al. (9) compared the time course of rocuronium block in obese patients (BMI >28) with subjects of ideal body weight (BMI 20–24). Although the difference did not reach statistical significance (P = 0.07), the median (range) duration of block in the obese patients, 31.5 (21–61) min, tended to be longer than the controls, 26 (20–36) min. Similar findings of prolonged block have also been reported with vecuronium (10,11) and atracurium in obesity (12). Body weight will not have returned to nonpregnant values in postpartum patients who are still 10%–20% heavier than normal. Given that over half of our Postpartum patients had a BMI >28, it would not be surprising that rocuronium block is longer compared with Nonpregnant Controls. Although the weight gain during pregnancy may be different from nonpregnant obesity, our results suggest that dose adjustment according to LBM will prevent delayed recovery from rocuronium block.
In summary, neuromuscular block is prolonged in the postpartum period after standard doses of rocuronium. Calculating the dose by LBM would give a more consistent duration of block.
We thank Mr. Bryan Ng, BSc, for his technical assistance in data collection.
1. Pühringer FK, Sparr HJ, Mitterschiffthaler G, et al. Extended duration of action of rocuronium in postpartum patients. Anesth Analg 1997; 84: 352–4.
2. Khuenl-Brady KS, Koller J, Mair P, et al. Comparison of vecuronium- and atracurium-induced neuromuscular blockade in postpartum and nonpregnant patients. Anesth Analg 1991; 72: 110–3.
3. Morgan DJ, Bray KM. Lean body mass as a predictor of drug dosage. Implications for drug therapy. Clin Pharmacokinet 1994; 26: 292–307.
4. Bouillon T, Shafer SL. Does size matter? Anesthesiology 1998; 89: 557–60.
5. Viby-Mogensen J, Engbaek J, Eriksson LI, et al. Good clinical research practice (GCRP) in pharmacodynamic studies of neuromuscular blocking agents. Acta Anaesthesiol Scand 1996; 40: 59–74.
6. Booij LHDJ. A dose finding study with rocuronium bromide. Eur J Anaesthesiol 1994; 11 (Suppl 9): 16–9.
7. Khuenl-Brady KS, Sparr H. Clinical pharmacokinetics of rocuronium bromide. Clin Pharmacokinet 1996; 31: 174–83.
8. Dailey PA, Fisher DM, Shnider SM, et al. Pharmacokinetics, placental transfer and neonatal effects of vecuronium and pancuronium administered during cesarean section. Anesthesiology 1984; 60: 569–74.
9. Führinger FK, Khuenl-Brady KS, Mitterschiffthaler G. Rocuronium bromide: time course of action in underweight, normal weight, overweight and obese patients. Eur J Anaesthesiol 1995; 12 (Suppl 11): 107–10.
10. Schwartz AE, Matteo RS, Ornstein E, et al. Pharmacokinetics and pharmacodynamics of vecuronium in the obese surgical patient. Anesth Analg 1992; 74: 515–8.
11. Kirkegaard-Nielsen H, Helbo-Hansen HS, Toft P, Severinsen IK. Anthropometric variables as predictors for duration of action of vecuronium-induced neuromuscular block. Anesth Analg 1994; 79: 1003–6.
12. Kirkegaard-Nielsen H, Helbo-Hansen HS, Lindholm P, et al. Anthropometric variables as predictors for duration of action of atracurium-induced neuromuscular block. Anesth Analg 1996; 83: 1076–80.