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Neuromuscular blocking drugs seem to play a predominant role in the occurrence of adverse reactions during anesthesia. The Committee on Safety of Medicines in the United Kingdom reported that 10.8% (218 of 2014) of adverse drug reactions and 7.3% of deaths (21 of 286) were attributable to the neuromuscular blocking drugs.[360]
Neuromuscular blocking drugs interact with nicotinic and muscarinic cholinergic receptors within the sympathetic and parasympathetic nervous systems and at the nicotinic receptors of the neuromuscular junction.
Dose-response ratios comparing the neuromuscular blocking potency
of neuromuscular blockers (ED95
) with their potencies in blocking vagal
(parasympathetic) or sympathetic ganglionic transmission (ED50
) can be
constructed ( Table 13-11
).
These ratios are termed the
| Drugs | Vagus † | Sympathetic Ganglia † | Histamine Release ‡ |
|---|---|---|---|
| Benzylisoquinolinium Compounds | |||
| Mivacurium | >50 | >100 | 3.0 |
| Atracurium | 16 | 40 | 2.5 |
| Cisatracurium | >50 | >50 | None |
| Doxacurium | >50 | >100 | >4.0 |
| d-Tubocurarine | 0.6 | 2.0 | 0.6 |
| Metocurine | 3.0 | 16.0 | 2.0 |
| Steroidal Compounds | |||
| Rapacuronium | 2.0–3.0 | ? 5–20 | ? 3.0 |
| Vecuronium | 20 | >250 | None |
| Rocuronium | 3.0–5.0 | >10 | None |
| Pancuronium | 3.0 | >250 | None |
| Pipecuronium | 25 | >200 | None |
| Others | |||
| Alcuronium | 3.0 | 4.0 | None |
| Gallamine | 0.6 | >100 | None |
These autonomic responses are not reduced by slower injection of the relaxant. They are dose related and are additive over time if divided doses are given. If identical to the original dose, subsequent doses will produce a similar response; that is, no tachyphylaxis will occur. Such is not the case when the side effect of histamine release is in question. Cardiovascular responses secondary to histamine release are decreased by slowing the injection rate, and the response undergoes rapid tachyphylaxis. The autonomic effects of neuromuscular blocking drugs are summarized in Table 13-12 .
Quaternary ammonium compounds such as neuromuscular blockers are generally weak histamine-releasing substances relative to tertiary amines such as morphine. Nevertheless, when large doses of certain neuromuscular blockers are administered rapidly, erythema of the face, neck, and upper part of the torso may develop, as well as a brief decrease in arterial pressure and a slight to moderate increase in heart rate. Bronchospasm in this setting is very rare. The clinical effects of histamine are seen when plasma concentrations increase 200% to 300% above baseline values and involve chemical displacement of the contents of mast cell granules containing histamine, prostaglandin, and possibly other vasoactive substances.[361] The serosal mast cell, located in the skin and connective tissue and near blood vessels and nerves, is principally involved in the degranulation process.[361]
| Drug Type | Autonomic Ganglia | Cardiac Muscarinic Receptors | Histamine Release |
|---|---|---|---|
| Depolarizing Substance | |||
| Succinylcholine | Stimulates | Stimulates | Slight |
| Benzylisoquinolinium Compounds | |||
| Mivacurium | None | None | Slight |
| Atracurium | None | None | Slight |
| Cisatracurium | None | None | None |
| Doxacurium | None | None | None |
| d-Tubocurarine | Blocks | None | Moderate |
| Metocurine | Blocks weakly | None | Slight |
| Steroidal Compounds | |||
| Rapacuronium * | ? None | Blocks moderately | ? Slight |
| Vecuronium | None | None | None |
| Rocuronium | None | Blocks weakly | None |
| Pancuronium | None | Blocks moderately | None |
| Pipecuronium | None | None | None |
| Others | |||
| Alcuronium | Blocks weakly | Blocks weakly | None |
| Gallamine | None | Blocks strongly | None |
The side effect of histamine release is most often noted after administration of the benzylisoquinolinium class of muscle relaxants, although it has been reported with steroidal relaxants of low potency. The effect is usually of short duration (1 to 5 minutes), is dose related, and is clinically insignificant in healthy patients. Hatano and colleagues[362] showed that the hypotensive cardiovascular response to 0.6 mg/kg dTc in humans is prevented not only by antihistamines but also by nonsteroidal anti-inflammatory drugs (e.g., aspirin). These investigators concluded that the final step in dTc-induced hypotension is modulated by prostaglandins that are vasodilators.[362] The side effect may be reduced considerably by a slower injection rate. It is also attenuated by prophylaxis with combinations of H1 - and H2 -blockers. [363] If a minor degree of histamine release such as just described occurs after an initial dose of neuromuscular blocker, subsequent doses will generally cause no response at all, as long as they are not larger than the original dose. This observation is clinical evidence of tachyphylaxis, an important characteristic of histamine release. A much more significant degree of histamine release occurs during anaphylactic or anaphylactoid reactions, but these reactions are very rare.
The hypotension seen with atracurium and mivacurium is due to histamine release. dTc causes hypotension through histamine release and ganglion blockade.[364] [365] [366] [367] More than any other neuromuscular blocker, the ganglion-blocking and histamine-releasing effects of dTc occur closer to the dose required to achieve neuromuscular blockade. [219] [368] Dowdy and coworkers[369] proposed that hypotension is not caused by dTc itself but by the preservative in its formulation. However, in anesthetized patients, Stoelting[370] [371] disproved this theory. The safety margin for histamine release is about three times greater for atracurium and mivacurium and two times greater for metocurine than for dTc.[215] [361] [362] [367] [372] Rapid administration of atracurium in doses greater than 0.4 mg/kg and mivacurium in doses greater than 0.15 mg/kg has been associated with transient hypotension from histamine release ( Fig. 13-24 ).
Pancuronium causes a moderate increase in heart rate and, to a lesser extent, cardiac output, with little or no change in systemic vascular resistance. [373] [374] Pancuronium-induced tachycardia has been attributed to (1) a vagolytic action,[373] [375] probably as a result of inhibition of M2 receptors,[376] and (2) sympathetic stimulation involving both direct (blockade of neuronal uptake of norepinephrine) and indirect (release of norepinephrine from adrenergic nerve endings) mechanisms.[377] [378] [379] [380] Vercruysse and associates[381] suggested that both gallamine and pancuronium augment the release of norepinephrine in vascular tissues under vagal control. In studies in humans, Roizen and colleagues[382] surprisingly found a decrease in plasma norepinephrine levels after the administration of either pancuronium or atropine. They postulated that the increase in heart rate or rate-pressure product occurs because pancuronium (or atropine) acts through baroreceptors to reduce sympathetic outflow.[382] More specifically, the vagolytic effect of pancuronium increases the heart rate and, hence, blood pressure and cardiac output, which in turn influence the baroreceptors to decrease sympathetic tone. Support for this concept is provided by
Figure 13-24
Dose response to mivacurium in patients under nitrous
oxide-oxygen-opioid anesthesia. Maximum changes at each dose are shown (n
= 9 subjects per group). A, With fast injection,
a 15% to 20% decrease in arterial pressure occurred at 2.5 to 3 ×
ED95
(0.20 to 0.25 mg/kg). B,
The changes were less than 10% when slower injection (30 seconds) was performed.
(Redrawn from 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 70:386–394, 1989.)
Gallamine, dTc, and succinylcholine actually reduce the incidence of epinephrine-induced dysrhythmias.[386] Possibly because of enhanced atrioventricular conduction,[387] the incidence of dysrhythmias from pancuronium appears to increase during halothane anesthesia.[373] Edwards and collaborators[388] observed a rapid tachycardia (more than 150 beats/min) that progressed to atrioventricular dissociation in two patients anesthetized with halothane who received pancuronium. The only factor common to these two patients was that both were receiving tricyclic antidepressants.
Several case reports[389] [390] have described severe bradycardia and even asystole after vecuronium or atracurium administration. All these cases were associated with opioid administration. Subsequent studies have indicated that vecuronium or atracurium alone does not cause bradycardia. [391] When combined with other drugs that do cause bradycardia (e.g., fentanyl), nonvagolytic relaxants such as vecuronium, cisatracurium, and atracurium allow this mechanism to occur unopposed. The moderate vagolytic effect of pancuronium is often used to counteract opioid-induced bradycardia.
The muscarinic cholinergic system plays an important role in regulating airway function. Five muscarinic receptors have been cloned.[392] [393] [394] Cloned m1, m2, m3, and m4 muscarinic receptors correspond to the pharmacologically defined M1 , M2 , M3 , and M4 receptors, respectively. [392] [394] [395] Three receptors (M1 to M3 ) exist in the airways.[396] [397] M1 receptors are under sympathetic control and mediate bronchodilation.[398] M2 receptors are located presynaptically ( Fig. 13-25 ) at the postganglionic parasympathetic nerve endings, and they function in
Figure 13-25
Muscarinic (M3
) receptors are located postsynaptically
on airway smooth muscle. Acetylcholine (ACh) stimulates M3
receptors
to cause contraction. M2
muscarinic receptors are located presynaptically
at the postganglionic parasympathetic nerve endings, and they function in a negative-feedback
mechanism to limit the release of acetylcholine.
Administration of benzylisoquinolinium neuromuscular blocking drugs (with the exception of cisatracurium and doxacurium) is associated with histamine release that may result in an increase in airway resistance and bronchospasm in patients with hyperactive airway disease.[401]
The frequency of life-threatening anaphylactic (immune mediated) or anaphylactoid reactions occurring during anesthesia has been estimated at between 1 in 1000 and 1 in 25,000 anesthetics with an approximately 5% mortality rate.[402] [403] [404] [405] Neuromuscular blocking drugs (especially succinylcholine) are the triggering agents in over 50% of these reactions.[360] [406] Anaphylactic reactions are mediated through immune responses involving IgE antibodies fixed to mast cells. Anaphylactoid reactions are not immune mediated and represent exaggerated pharmacologic responses in very rare and very sensitive individuals.
Neuromuscular blocking drugs contain two quaternary ammonium ions, which are the epitopes commonly recognized by specific IgE.[407] Cross-reactivity has been reported between neuromuscular blocking drugs and food, cosmetics, disinfectants, and industrial materials.[407] Cross-reactivity is seen in more than 60% of patients with a history of anaphylaxis to a neuromuscular blocking drug.[408]
Steroidal compounds (e.g., rocuronium, vecuronium, pancuronium, or pipecuronium) lack significant histamine release.[367] [409] Rocuronium at doses of 4 × ED95 (1.2 mg/kg) cause no significant histamine release.[410] Nevertheless, Laxenaire and Mertes[411] have reported a 29.2% (98/336 cases) incidence of anaphylaxis to rocuronium over a 2-year period in France. Rose and Fisher[412] classified rocuronium (and atracurium) as intermediate in risk for causing allergic reactions. They also noted that the increased number of reports of anaphylaxis with rocuronium is in the line with the market share.[412] Watkins[413] stated "The much higher incidence of rocuronium reactions reported in France is currently inexplicable and is likely to remain so if investigators continue to seek a purely antibody-mediated response as an explanation of all anaphylactoid reaction presentations." Currently, there are no standards against which diagnostic tests (skin prick test, intradermal test, or IgE testing) are performed. For instance, Laxenaire and Mertes [411] used a 1:10 dilution of rocuronium for intradermal skin testing, whereas Rose and Fisher[412] used a 1:1000 dilution. Levy and colleagues[414] showed that rocuronium in a 1:10 dilution can produce false-positive results in intradermal testing and suggested that rocuronium be diluted at least 100-fold to prevent false-positive skin tests. Levy and coworkers[414] also found that both rocuronium and cisatracurium at high concentrations (≥10-4 M) are capable of producing a wheal-and-flare response to intradermal testing associated with mild to moderate mast cell degranulation in the cisatracurium group only.
All neuromuscular blocking drugs can cause noncompetitive inhibition of histamine-N-methyltransferase, but concentrations required for inhibition far exceed those that would be used clinically, except for vecuronium, in which the effect becomes manifested at 0.1 to 0.2 mg/kg.[415] [416] This could explain the occurrence of occasional severe bronchospasm in patients after receiving vecuronium.[417] [418] [419]
The goals of treatment of anaphylactic reactions are to correct arterial hypoxemia, inhibit further release of chemical mediators, and restore intravascular volume. One hundred percent oxygen and intravenous epinephrine, 10 to 20 µg/kg, should be administered immediately. Early tracheal intubation with a cuffed tracheal tube should be considered in patients with rapidly developing angioedema. Fluids (crystalloid or colloid solutions, or both) must be administered concurrently. Norepinephrine or a sympathomimetic drug (phenylephrine) may also be necessary to maintain perfusion pressure until intravascular fluid volume can be restored. Dysrhythmias should be treated. The use of antihistamines and steroids is controversial.
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