Dose Inflation When Using Precurarization

I read with great interest the meta-analysis by Schreiber et al.  1about the prevention of succinylcholine-induced fasciculation and myalgia. After reviewing carefully an abundant literature, the authors conclude that nondepolarizing neuromuscular blocking agents given before succinylcholine are effective in reducing fasciculations and myalgias. The meta-analysis also contains an analysis of the side effects that were reported in the studies, and the authors point out that the incidence of these side effects is not negligible. In particular, difficulty in breathing or swallowing is considered as potentially serious.

The incidence and magnitude of these neuromuscular side effects are most likely related to the dose given, and the meta-analysis by Schreiber et al.  1provides evidence of this dose relation for pancuronium. The same is probably valid for all nondepolarizing agents. The authors recommend that “… the smallest dose of each agent that has shown efficacy in these randomized trials should be given. These doses are unlikely to be above 10% of the respective ED⁹⁵.”1I agree. Most studies reporting adverse events involved doses that were clearly above 10% of the ED⁹⁵, and this applies especially to recent studies, using newer drugs. Of the six studies reporting difficulty in breathing or swallowing reported in Schreiber’s table 2, two involved multiple doses of pancuronium.2,3In the other four, the dose of rocuronium ranged from 0.06 to 0.1 mg/kg (0.2–0.33 × ED⁹⁵),4–6whereas the doses of cisatracurium (0.01 mg/kg),7vecuronium (0.01 mg/kg),5atracurium (0.05 mg/kg),5and mivacurium (0.02 mg/kg)5all represented approximately 0.2 × ED⁹⁵. The occurrence of breathing or swallowing difficulties is therefore not surprising.

The initial studies on precurarization involved d-tubocurarine, and the dose was 3 mg for an adult. This represented 0.043 mg/kg for the 70-kg adult, or less than 0.1 × ED⁹⁵. The ED⁹⁵of d-tubocurarine is 0.45–0.5 mg/kg. When other neuromuscular blocking agents were introduced, the potency ratio between these drugs and d-tubocurarine was not respected. The precurarization doses used in the studies quoted by Schreiber et al.  1were expressed as a fraction of their respective ED⁹⁵s and plotted against the year of their publication (fig. 1). The d-tubocurarine dose remained relatively constant throughout the last two decades of the 20th century, whereas the equivalent dose of other agents increased progressively. On average, the equivalent dose doubled between the late 1970s and the early 2000s (fig. 1).

Assuming that the studies were designed to reflect clinical practice, it follows that there has been a dangerous tendency to increase the precurarizing doses in the past 20–30 yr. Clinicians most likely administered the newer drugs in doses corresponding to the published values. Some of them certainly observed side effects or heard of complications arising from such a practice. As a result, precurarization has been abandoned by many practitioners. However, the numbers to treat to avoid fasciculations (1.2–2.5) and myalgia (3–5)1are low, thus justifying the use of nondepolarizing blocking drugs. In comparison, even the most effective antiemetics have higher numbers to treat, and we feel justified to use them as prophylaxis. The concluding statement of Schreiber et al.  1about nondepolarizing agents, which states that “[these drugs] should be used cautiously because the risk of potentially serious side effects is not negligible,” should be more specific. I would suggest that precurarization with a nondepolarizing blocking agent is both safe and effective, provided that the dose does not exceed 10% of the ED⁹⁵. d-Tubocurarine, 3 mg, is equivalent to 2 mg rocuronium, 1.5 mg atracurium, 0.5 mg mivacurium, 0.3 mg vecuronium, or 0.4 mg pancuronium.

Hôpital Maisonneuve-Rosemont and University of Montreal Montreal, Montreal, Quebec, Canada. francois.donati@umontreal.ca