During the last years the number of reports on complications associated with the long term use of neuromuscular blocking agent (NMBA) in the critically ill patient in the intensive care unit (ICU) has increased considerably. Not only the lack of dosing guidelines for these drugs but also the lack of knowledge of the pathophysiological changes of the critically ill have created several studies with the aim of better understanding the below mentioned problems.
Problems associated with the use of neuromuscular blocking
agents
Prolonged paralysis
The most frequently reported adverse events include among others
muscle atrophy, histological alterations consistent with pharmacological
denervation, prolonged residual paralysis due to neuromuscular
blockade as well as polyneuropathy and myopathy requiring ventilatory
support for up to four months after termination of the administration
of the muscle relaxant (1). The above complications have been
described for most available muscle relaxants. The use of excessive
doses or irrational combinations of neuromuscular blocking agents
is probably the most likely cause of prolonged paralysis in critically
ill patients. These complications are even more likely to occur
with the concomitant use of high dose corticosteroids and the
lack of neuromuscular monitoring (1).
Resistance development
Due to the constant blockade of the acetylcholine receptors, an
upregulation of the number of receptors occurs and contributes
to a substantial increase in muscle relaxant requirements. Although
the above changes occur in all CIU patients studied, resistance
development to NMBA occurs only in some. It was shown that the
number of acetylcholine receptors strongly correlated with the
amount of muscle relaxant needed in patients developing resistance
to different NMBA (2).
Critical illness polyneuropathy (CIP)
This syndrome was first described by Zochondre in 1987. The clinical
signs impose as muscle weakness with concomitant problems of weaning
patients from the ventilator, specially after sepsis and multiple
organ failure. Histological and electrophysiological signs consist
of axon degeneration with (in most cases) normal nerve conduction
velocity. Neurological changes are usually followed by myopathy,
so the term "polyneuromyopathy" was created (3). The
ethiology of CIP is still unclear, however, today it is considered
to be a part of the systemic inflammatory response syndrome (SIRDS)
of patients with multiple organ failure and or septic syndrome.
In most cases NMBA have not been involved at all.
Choice of neuromuscular blocking agent and dosing guidelines
Besides the time course profile, the side effects of the various
agents are an important factor in the choice of a particular compound.
A task force recruited from members of the American College of
Critical Care and the Society of Critical Care Medicine recently
recommended pancuronium as first choice muscle relaxant followed
by vecuronium as second choice if the patient is cardiovascular
unstable (4). If sustained muscle relaxation is preferred intermediate
acting compounds are better administered by continuos infusion,
adjusted to maintain the presence of one twitch of TOF. A detailed
summary on all muscle relaxants used in the ICU and dose ranges
reported in the current literature will be given in the lecture.
Pharmacokinetic considerations
Few pharmacokinetic studies have been performed with NMBA in the
ICU. The pharmacokinetics of vecuronium (and most of all its plasma
clearance) changed in the time course of long term administration
(5). For rocuronium, a considerable increase in the volume of
distribution was reported (6). In patients with renal or hepatic
failure, it has to be kept in mind that the elimination half live
of laudanosine, the major metabolite of atracurium and cisatracurium,
is increased 10-20 fold. Accumulation of laudanosine therefore
has to be expected (7). It should be kept in mind that not only
muscle relaxants are rarely studied in the ICU but relevant data
for ICU patients are lacking for most drugs administered to this
population.
Conclusion
Due to the wide variation of dose requirements of individual ICU
patients, the dose ranges of muscle relaxants reported in the
literature can only serve as a guideline for initiation of muscle
relaxation with the strong recommendation for individual dose
adjustment. For the assessment of the neuromuscular blockade a
peripheral nerve stimulator used in the train-of-four (TOF) mode
seems to be a suitable satisfactory method. However, it remains
an open question whether and how the confounding pathologic conditions
in the critically ill might affect neuromuscular transmission.
There seems to be a good agreement in studies in which neuromuscular
monitoring was carried out, that a partial block of 80% to 90%
in combination with adequate sedation and analgesia, will provide
optimal clinical conditions for the ventilatory management of
ICU patients without problems like prolonged paralysis
References
1. Agoston S et al. Anesthesiology Clinics of North America (Saunders)1994;345-359
2. Dodson BA et al. Crit. Care Med 1995:23:815-821
3. Lee C. Anesthesioloy 1995;83:237-240
4. Shapiro BA et al. Crit. Care Med 1995;23:1601- 5
5. Segredo V et al. Br.J.Anaesth. 1998;80:715-9
6. Sparr HJ et al. Br.J.Anaesth. 1998 ;78:267-73
7. Shearer ES et al. Anaesthesia 1991;46:750-755