"As Horas" - diário fotográfico hospitalar

Nerve regeneration

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A reunião terá lugar no Serviço de Anestesiologia do Hospital de Santo António, no dia 27 de Maio, Quarta-feira, entre as 16h e as 18h.

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Overdosing with Neuromuscular Blocking Drugs: a Universal Foible

Jennifer M. Hunter, MD


"What is it in the psyche of anesthesiologists that makes them use much more of a drug than is necessary to produce the desired effect? Is it simply a human failing or just laziness? Why is it that although the recommended dose of, for instance, atracurium is 0.5 mg/kg, so many anesthesiologists give at least 0.6–0.9 mg/kg at the beginning of anesthesia? Is it because they want a more rapid onset of action? Undoubtedly, it will be slightly faster, albeit only by a matter of seconds, with the larger dose. Do they want a longer clinical duration of action (25% recovery of the twitch response) of about 47 min after atracurium 0.9 mg/kg instead of 32 min after atracurium 0.6 mg/kg for any particular patient? I doubt it. It is "bucket anesthesia": rapidly and carelessly pouring an excessive, and inexact, amount of the requisite drug into a patient, as if to cover every eventuality, without any consideration of how long that dose is likely to produce a clinical effect. Do they give any thought to the variability of effect of a dose of any nondepolarizing drug given on a weight-related basis? Do they acknowledge that the standard deviation of 20% recovery (when an incremental dose can be given or reversal effected) from atracurium 0.5 mg/kg is 11 min, for a mean time of 43 min?¹ How do they know that their patient is not at the upper end of that range of effect? They are probably relying on the spontaneous breakdown of the drug in the plasma by Hofmann degradation and ester hydrolysis. Remember the variable effect Katz showed in 1967 with tubocurarine 0.1 mg/kg. In 7% of patients, complete ablation of the four twitches of the train-of-four (TOF) response occurred, even with this very low dose.²

Only recently, it has been clearly demonstrated that all anesthesiologists use an unnecessarily large dose of succinylcholine.³ Succinylcholine 0.6 mg/kg will still have a rapid onset (81 s) and even 0.4 mg/kg may suffice, with maximum block at a mean of 105 s. More importantly, clinical recovery will be faster at 6.6 min after succinylcholine 0.4 mg/kg and 7.6 min after 0.6 mg/kg, compared with 9.3 min after succinylcholine 1.0 mg/kg.³ Thus, following preoxygenation, recovery of respiration could occur before hypoxic damage ensued if a smaller dose of succinylcholine had been used and intubation had failed. Even with succinylcholine, however, there is a range in the clinical recovery times of 5–6 min.³

The practice of using an excessive dose of muscle relaxant is made worse by the tendency to give a generous increment every 30 min ("on the half hour" in UK terminology). No thought is given to monitoring neuromuscular block to determine the degree of recovery prior to the increment. Nor is detection of the second twitch of the TOF response ascertained, as it should be, before another often excessive bolus is given, for instance, atracurium 15–20 mg.

It is not surprising that when surgery finishes somewhat earlier than expected, which occasionally happens, and an anticholinesterase such as neostigmine has been given, recovery from block is slow and incomplete, with all the potential complications that have been described.⁴ For if neostigmine 2.5 mg is given when the first twitch of the TOF response has recovered to 10% after vecuronium 0.1 mg/kg, it takes 3.9 min for T₁/T₀ to reach 70% and 9.2 min for the TOF ratio to reach 0.7, when the patient can probably be extubated safely. How many anesthesiologists wait 10 min after giving neostigmine before they extubate their patient? But if neostigmine 2.5 mg is not given until T₁/T₀= 0.5, it takes only 1.2 min for T₁/T₀ to reach 0.7, and only 2.1 min for the TOF ratio to do so.⁵

Anesthesiologists should realize that the art of their practice is to give a sufficient amount, but no more, of a neuromuscular blocking drug and its antagonist, and to give both drugs at an appropriate time. Only then will the desired effect of the drug be achieved and fewer side effects encountered. For instance, anesthesiologists do not want to produce unnecessary histamine release and subsequent hypotension from mivacurium by giving too large a dose (0.3 mg/kg) too rapidly, over 10–15 s.⁶ A 33% fall in mean arterial pressure can be anticipated in such circumstances. Nor do they wish to see the tachycardia and hypertension that result from administration of a large dose of that now archaic drug, pancuronium. Do they want an incomplete reversal when too much vecuronium has been given too frequently to a patient with either acute or chronic renal dysfunction?⁸ I see about three such cases a year in my hospital, so such occurrences must be common.

The tendency to encourage the use of larger doses of a nondepolarizing muscle relaxant, such as rocuronium 1.2 mg/kg or cisatracurium 0.4 mg/kg,⁸ to increase the rate of onset of block may at first seem attractive. But do not forget that prolonged neuromuscular block is then being produced. Twenty-five percent recovery of the first twitch of the TOF, when it is appropriate to give an anticholinesterase, takes 67 ± 25 (mean ± SD) min¹⁰ following rocuronium 1.2 mg/kg and 91 ± 3.3 (mean ± SE) min after cisatracurium 0.4 mg/kg.⁸ Few anesthesiologists appreciate the length of action of the neuromuscular blocking drugs they use.

Never forget the old days of recurarization. This phenomenon should no longer occur except in patients with undiagnosed neuromuscular disorders such as myasthenia gravis and amyotrophic lateral sclerosis, or in the hypothyroid patient. It could be considered a sign of negligence for a patient to experience residual curarization in the recovery room. For now there are drugs that are broken down independent of organ function, such as atracurium, cisatracurium, and mivacurium. If the correct dose of these drugs is used, neuromuscular block is monitored, and the anticholinesterase is given only when the second twitch of the TOF response is detectable; then residual block should never be seen. In the days of tubocurarine and pancuronium, it was more understandable if patients had impaired clearance of these long-acting drugs from reduced renal or hepatic function (which can occur in the hypovolemic shocked patient as well as in the patient with chronic organ dysfunction).

Remember too that organ function deteriorates with increasing age. The older the patient, the lower the rate of clearance and the longer the elimination half time of a neuromuscular blocking drug, even if it primarily undergoes organ-independent elimination. How many anesthesiologists consider the age of their patients before selecting the dose of a neuromuscular blocking drug? It is inappropriate to use the same dose in a 20-year-old patient as in an 80-year-old patient, even if they are of the same sex and weight. If succinylcholine is given to intubate a patient, the duration of action of the nondepolarizing agent will also be potentiated.

The clearance of many nondepolarizing neuromuscular blocking drugs is lower in women, so they may need a smaller dose to achieve an effect similar to that in men.⁹ Ethnicity is also important; different races metabolize drugs at different rates. This difference is augmented by the different rates of alcohol consumption and cigarette smoking in different cultures, as these substances stimulate hepatic enzyme induction and faster metabolism of drugs cleared by the liver. Thus the nonsmoking, non–alcohol-consuming, nonwhite, vegetarian lady will be more sensitive to the effect of a neuromuscular blocking drug than an overweight white man who smokes and who drinks a large amount of alcohol every day. In addition, it is uncertain whether in adults it is necessary to give a dose of neuromuscular blocking drugs such as atracurium, which undergo organ-independent elimination on a weight-related basis. Atracurium 25 mg will be sufficient in most adult females, and atracurium 30 mg in adult males.

So remember, there is no rationale for using excessive doses of neuromuscular blocking drugs. By taking pride in giving a good anesthetic in which the dose of all drugs used is tailored to a particular patient, anesthesiologists can achieve an ideal effect, for both the well-being of their patients and the smooth running of their practice."

"Right conduct can never, except by some rare accident, be promoted by ignorance or hindered by knowledge"(Bertram Russell, 1929).

1. Hunter JM, Jones RS, Utting JE: Comparison of vecuronium, atracurium and tubocurarine in normal patients and in patients with no renal function. Br J Anaesth 1984;56:941. [PMID: 6147153]

2. Katz RL: Neuromuscular effects of d-tubocurarine, edrophonium and neostigmine in man. Anesthesiology 1967;28: 327.

3. Kopman AF, Zhaku B, Laik S: The intubating dose of succinylcholine: The effect of decreasing doses on recovery time. Anesthesiology 2003;99:1050. [PMID: 14576537]

4. Savarese JJ: A current practice of relaxation. In: Clinical Anesthesiology, 3rd ed. McGraw-Hill, 2002 (Chapter 9).

5. Jones JE, Hunter JM, Utting JE: Use of neostigmine in the antagonism of residual neuromuscular blockade produced by vecuronium. Br J Anaesth 1987;59:1454. [PMID: 2891365]

6. Savarese JJ, Ali HH, Basta SJ, et al: The cardiovascular effects of mivacurium chloride (BW B1090U) in patients receiving nitrous oxide–opiate-barbiturate anesthesia. Anesthesiology 1989;70:386. [PMID: 2564261]

7. Cody MW, Dormon FM: Recurarization after vecuronium in a patient with renal failure. Anaesthesia 1987;42:993. [PMID: 2890315]

8. Belmont MR, Lien CA, Quessy S, et al: The clinical neuromuscular pharmacology of 51W89 in patients receiving nitrous oxide/opioid/barbiturate anesthesia. Anesthesiology 1995;82:1139. [PMID: 7741288]

9. Parker CJR, Hunter JM, Snowdon SL: Effect of age, sex and anaesthetic technique on the pharmacokinetics of atracurium. Br J Anaesth 1992;69:439. [PMID: 1467071]