Therapeutic Paralysis



Therapeutic Paralysis


J. Matthias Walz

Raimis Matulionis

Khaldoun Faris



Despite the routine use of neuromuscular blocking agents (NMBA) in the intensive care unit (ICU), limited data are currently available to guide the clinician with respect to appropriate indications, choice of agents, and the depth of neuromuscular blockade necessary to achieve a desired therapeutic effect.

The most common indications for the use of NMBAs in the ICU include emergency or elective intubations, optimization of patient-ventilator synchrony, the management of increased intracranial pressure, reduction of oxygen consumption and the treatment of muscle spasms associated with tetanus. According to the American College of Critical Care Medicine and the Society of Critical Care Medicine clinical practice guidelines for sustained neuromuscular blockade in the adult critically ill patient, they should be used only when all other means of optimizing a patient’s condition have been used. This recommendation is based on concern that the administration of NMBAs may worsen patient outcome when administered during a course of critical illness, particularly if the patient is receiving systemic steroids at the same time [1, 2, 3 and 4]. In a recent international multicenter trial, 13% of patients on mechanical ventilation received NMBAs for at least 1 day, which was associated with longer duration of mechanical ventilation, longer weaning time and stay in the ICU, and higher mortality [5].

In addition to the pharmacology of the most commonly administered agents, we will briefly review the biology of the neuromuscular junction (NMJ), its alterations during the course of critical illness, and the resulting implications for the use of depolarizing and nondepolarizing NMBAs. Recommendations for administration of NMBAs to ICU patients based on available evidence will be provided.


Pharmacology of NMBAs

The NMJ consists of the motor nerve terminus, acetylcholine (ACh), and the muscle end-plate. In response to neuronal action potentials, ACh is released from presynaptic axonal storage vesicles into the synapse of the NMJ. Both the presynaptic membrane and postsynaptic end-plate contain specialized nicotinic ACh receptors (nAChRs). The chemical signal is converted into an electrical signal by binding of two ACh molecules to the receptor, causing a transient influx of sodium and calcium, and efflux of potassium from muscle cells. This depolarization propagates an action potential that results in a muscle contraction. Unbound ACh is quickly hydrolyzed in the synapse by the enzyme acetylcholinesterase to acetic acid and choline, thus effectively controlling the duration of receptor activation. A repolarization of the motor end-plate and muscle fiber then occurs.


The Nicotinic Acetylcholine Receptor

The nAChR is built of five subunit proteins forming an ion channel. This ionic channel mediates neurotransmission at the NMJ, autonomic ganglia, spinal cord, and the brain. During early development, differentiation and maturation of the NMJ and transformation of the nAChR takes place: Fetal nAChRs gradually disappear with a rise of new, functionally distinct, mature nAChRs.

These mature nAChRs (also termed adult, innervated, σ-containing) have a subunit composition of α2βσδ in the synaptic muscle membrane. The only structural difference from the fetal nAChR is in substitution of the γ for the σ subunit, although functional, pharmacologic, and metabolic characteristics are quite distinct. Mature nAChRs have a shorter burst duration and a higher conductance to Na+, K+, and Ca2+ and are metabolically stable with a half-life averaging about 2 weeks. The 2 α, β, δ, and σ/γ subunits interact to form a channel and an extracellular binding site for ACh and other mediators as well. As mentioned previously, simultaneous binding of two ACh molecules to αδ and ασ subunits of a nAChR initiates opening of the channel and a flow of cations down their electrochemical gradient. In the absence of ACh or other mediators, the stable closed state (a major function of σ and γ subunits) normally precludes channel opening [6].

Adult skeletal muscle retains the ability to synthesize not only adult, but also fetal (often called immature or extrajunctional) type nAChRs. The synthesis of fetal nAChRs might be triggered in response to altered neuronal input such as loss of nerve function or prolonged immobility, or in the presence of certain disease states. The major differences between fetal and adult type of nAChRs is that fetal receptors migrate across the entire membrane surface and adult ones are mostly confined to the muscle end-plate. Secondly, these fetal nAChRs have much shorter half-life and are more ionically active with prolonged open channel time that exaggerates the K+ efflux. Lastly, these receptors are much more sensitive to depolarizing agents such as succinylcholine and resistant to nondepolarizing neuromuscular blockers.


The functional difference between depolarizing and nondepolarizing neuromuscular blockers lies in their interaction with AChRs. Depolarizing neuromuscular blockers are structurally similar to ACh and bind to and activate AChRs. Nondepolarizing neuromuscular blockers are competitive antagonists. There is emerging evidence pointing to yet another variant nAChR subunit (α7 acetylcholine receptors [α7nAChRs]), recently described to be expressed in muscle also [7]. These receptors not only bind ACh and succinylcholine, but also agonists such as choline and nicotine, as well as antagonists such as pancuronium, cobra toxin, and α-bungarotoxin [8].


Depolarizing Neuromuscular Blockers

Succinylcholine is the only depolarizing neuromuscular blocker in clinical use. Its use is limited to facilitating rapid-sequence intubation in the emergency setting. Succinylcholine mimics the effects of ACh by binding to the ACh receptor and inducing a persistent depolarization of the muscle fiber. Muscle contraction remains inhibited until succinylcholine diffuses away from the motor end-plate and is metabolized by serum (pseudo-) cholinesterase [9]. The clinical effect of succinylcholine is a brief excitatory period, with muscular fasciculations followed by neuromuscular blockade and flaccid paralysis. The intravenous dose of succinylcholine is 1 to 1.5 mg per kg and offers the most rapid onset of action (60 to 90 seconds) of the NMBAs. Recovery to 90% muscle strength after an intravenous dose of 1 mg per kg takes from 9 to 13 minutes [10]. Succinylcholine is also suitable for intramuscular administration; however, there are several limitations. Firstly, the required dose is higher (4 mg per kg) and time to maximum twitch depression is significantly longer (approximately 4 minutes). Secondly, the duration of action of succinylcholine after intramuscular injection is prolonged. It should be noted that the most frequent indication for intramuscular succinylcholine is for the treatment of laryngospasm in pediatric patients without intravenous access; however, the dose range listed here has also been verified in the adult population [11, 12].

Potential adverse drug events associated with succinylcholine include hypertension, arrhythmias, increased intracranial and intraocular pressure, hyperkalemia, malignant hyperthermia, myalgias, and prolonged paralysis [13]. Neuromuscular blockade can persist for hours in patients with genetic variants of pseudocholinesterase isoenzymes [14]. Contraindications to succinylcholine use include major thermal burns, significant crush injuries, spinal cord transection, malignant hyperthermia, and upper or lower motor neuron lesions. Caution is also advised in patients with open globe injuries, renal failure, serious infections, and near-drowning victims [15].


Nondepolarizing Nmbas

Nondepolarizing NMBAs function as competitive antagonists and inhibit ACh binding to postsynaptic nAChRs on the motor end-plate. They are categorized on the basis of chemical structure into two classes: benzylisoquinoliniums and amino- steroids. Within each of these classes, the therapeutic agents may further be categorized as short-acting, intermediate-acting, or long-acting agents. The benzylisoquinolinium agents commonly used in the critical care setting include mivacurium, atracurium, cisatracurium, and doxacurium, whereas the aminosteroid agents include vecuronium, rocuronium, pancuronium, and pipecuronium.

The nondepolarizing NMBAs are administered by the intravenous route and have volumes of distribution (Vds) ranging from 0.2 to 0.3 L per kg in adults.

A clinical relationship exists between the time to onset of paralysis and neuromuscular blocker dosing, drug distribution, and ACh-receptor sensitivity. An important factor to consider is Vd, which may change as a result of disease processes. Cirrhotic liver disease and chronic renal failure often result in an increased Vd and decreased plasma concentration for a given dose of water-soluble drugs. However, drugs dependent on renal or hepatic excretion may have prolonged clinical effect. Therefore, a larger initial dose but smaller maintenance dose may be appropriate.

Alterations in Vd affect both peak neuromuscular blocker serum concentrations and time to paralysis. The pharmacokinetic and pharmacodynamic principles of commonly used NMBAs are summarized in Table 24-1.


Mivacurium

Mivacurium is a short acting, nondepolarizing NMBA that is structurally related to atracurium. The time of onset is 2 to 4 minutes, with a clinical duration of 12 to 18 minutes. It is eliminated through hydrolysis by plasma cholinesterases and can be administered by bolus dose or continuous infusion [9, 16].


Atracurium

Atracurium is an intermediate-acting nondepolarizing agent. Neuromuscular paralysis typically occurs between 3 and 5 minutes and lasts for 25 to 35 minutes after an initial bolus dose. Atracurium undergoes ester hydrolysis as well as Hofmann degradation, a nonenzymatic breakdown process that occurs at physiologic pH and body temperature, independent of renal or hepatic function [17]. Renal and hepatic dysfunction should not affect the duration of neuromuscular paralysis. The neuroexcitatory metabolite laudanosine is renally excreted. Laudanosine is epileptogenic in animals and may induce CNS excitation in patients with renal failure who are receiving prolonged atracurium infusions. Atracurium may induce histamine release after rapid administration.


Cisatracurium

Cisatracurium and atracurium are similar intermediate-acting nondepolarizing agents. A bolus dose of 0.2 mg per kg of cisatracurium usually results in neuromuscular paralysis within 1.5 to 2.5 minutes and lasts 45 to 60 minutes. When compared with atracurium, cisatracurium is 3 times as potent and has a more desirable adverse drug event profile, including lack of histamine release, minimal cardiovascular effects, and less interaction with autonomic ganglia. Cisatracurium also undergoes ester hydrolysis as well as Hofmann degradation. However, plasma laudanosine concentrations after cisatracurium administration
are 5 to 10 times lower than those detected after administration of atracurium [18, 19].








TABLE 24-1. Pharmacokinetic and Pharmacodynamic Principles of Nondepolarizing Neuromuscular Blockersa


















































































































































































































  Benzylisoquinolinium Agents
  Cisatracurium
(Nimbex)
Atracurium
(Tracrium)
Doxacurium
(Nuromax)
Introduced 1996 1983 1991
95% Effective dose (mg/kg) 0.05 0.25 0.025–0.030
Initial dose (mg/kg) 0.1–0.2 0.4–0.5 Up to 0.1
Onset (min) 2–3 3–5 5–10
Duration (min) 45–60 25–35 120–150
Half-life (min) 22–31 20 70–100
Infusion dose (μ g/kg/min) 2.5–3.0 4–12 0.3–0.5
Recovery (min) 90 40–60 120–180
% Renal excretion Hofmann elimination 5–10 (Hofmann elimination) 70
Renal failure No change No change ↑Effect
% Biliary excretion Hofmann elimination Minimal Unclear
Hepatic failure Minimal to no change Minimal to no change ?
Active metabolites None but laudanosine None but laudanosine ?
Histamine hypotension No Dose-dependent No
Vagal block tachycardia No No No
Ganglionic block hypotension No Minimal to none No
Prolonged block reported Rare Rare Yes
  Aminosteroidal Agents
  Pancuronium
(Pavulon)
Vecuronium
(Norcuron)
Pipecuronium
(Arduan)
Rocuronium
(Zemuron)
Introduced 1972 1984 1991 1994
95% Effective dose (mg/kg) 0.07 0.05 0.05 0.30
Initial dose (mg/kg) 0.1 0.1 0.085–0.100 0.6–1.0
Onset (min) 2–3 3–4 5 1–2
Duration (min) 90–100 35–45 90–100 30
Half-life (min) 120 30–80 100
Infusion dose (μg/kg/min) 1–2 1–2 0.5–2.0 10–12
Recovery (min) 120–180 45–60 55–160 20–30
% Renal excretion 45–70 50 50+ 33
Renal failure ↑Effect ↑Effect ↑Duration Minimal
% Biliary excretion 10–15 35–50 Minimal <75
Hepatic failure Mild ↑ effect Mild ↑ effect Minimal Moderate
Active metabolites 3-OH and 17-OH pancuronium 3-desacetylvecuronium None None
Histamine hypotension No No No No
Vagal block tachycardia Modest to marked No No At high doses
Ganglionic block hypotension No No No No
Prolonged ICU block Yes Yes No No
↑, increased; ICU, intensive care unit.
aModified from Grenvik A, Ayres SM, Holbrook PR, et al: Textbook of Critical Care. 4th ed. Philadelphia, WB Saunders, 2000; and Watling SM, Dasta JF: Prolonged paralysis in intensive care unit patients after the use of neuromuscular blocking agents: a review of the literature. Crit Care Med 22(5):884, 1994.


Rocuronium

Rocuronium is the fastest onset, shortest-acting aminosteroidal NMBA. A bolus dose of 0.6 mg per kg usually results in neuromuscular paralysis within 60 to 90 seconds. It may be considered an alternative to succinylcholine for rapid-sequence intubation (0.8 to 1.2 mg per kg), although, even with large doses, the onset of action is slower as compared to succinylcholine [20]. Rocuronium is primarily eliminated in the liver and bile. Hepatic or renal dysfunction may reduce drug clearance and prolong recovery time.


Vecuronium

An initial intravenous bolus dose of 0.1 mg per kg of vecuronium typically results in neuromuscular paralysis within 3 to 4 minutes and lasts 35 to 45 minutes. Vecuronium lacks vagal effects
such as tachycardia and hypertension and produces negligible histamine release. Hepatic metabolism produces three active metabolites, the most significant being 3-desacetylvecuronium, with 50% to 70% the activity of the parent drug. Both vecuronium and its active metabolites are renally excreted. There is the potential for prolonged neuromuscular paralysis in patients with renal dysfunction receiving vecuronium by continuous infusion [21].

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Aug 27, 2016 | Posted by in CRITICAL CARE | Comments Off on Therapeutic Paralysis

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