The pathophysiology of the neuromuscular complications of systemic inflammatory response syndrome sepsis

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Retrospective and prospective studies (Bolton 1996) have failed to incriminate a variety of potential causes of critical illness polyneuropathy, including types of primary illness or injury, Guillain-Barre syndrome, medications including aminoglycoside antibiotics and neuromuscular blocking agents, and specific nutritional deficiencies. We have speculated that sepsis is the cause ( Bolton 1996). The severity of the polyneuropathy can be quantified from electrophysiological data. It tends to be more severe with time in the ICU and with increasing blood glucose and decreasing serum albumin concentrations. All these factors are recognized manifestations of the sepsis and multiple organ failure syndrome.

The microcirculation is disturbed in sepsis (Bolton 1996). Blood vessels supplying peripheral nerves lack autoregulation, rendering them particularly susceptible to such disturbances. Moreover, cytokines that are secreted in sepsis have histamine-like properties which may increase microvascular permeability ( Z.O.C.h.O.d.De..e.í a,l.:... 1987). The resulting endoneural edema could induce hypoxia by increase in intercapillary distance and other mechanisms. Severe energy deficits would result and induce a primary axonal degeneration, most likely distally, if highly energy-dependent systems involving axonal transport of structural proteins are involved. The predominantly distal involvement may explain why recovery time in some patients may be surprisingly short, conforming to the short length of nerve through which axonal regeneration takes place. It is also possible that cytokines themselves may have a direct toxic effect on peripheral nerve. To our knowledge, this as not been demonstrated in either humans or experimental animals. However, tumor necrosis factor decreases the resting transmembrane potential of skeletal muscle fibers in vitro and also induces muscle proteolysis in animals.

Disturbances of the microcirculation to nerve and muscle may also explain the effects of neuromuscular blocking agents and steroids. Neuromuscular blocking agents, notably vecuronium or its metabolite 3-desacetyl-vecuronium, could have a direct toxic effect on peripheral nerve axons through increased capillary permeability induced by the sepsis. These drugs may also cause functional denervation through their prolonged neuromuscular blocking action. The result would be denervation atrophy of muscle and a relatively pure motor neuropathy.

We have always been concerned that antibiotics, particularly aminoglycosides with their known neural toxicity, might cause critical illness polyneuropathy. They might gain access to the peripheral nerves as a result of increased capillary permeability. However, there has been no statistical proof that antibiotics cause peripheral nerve dysfunction in sepsis (Bolton 1996). Nonetheless, this possibility should be explored by fundamental experiments.

We suspect that many asthmatic patients who develop acute myopathy when they are treated with neuromuscular blocking agents and steroids suffer from systemic inflammatory response syndrome, since infection is often a precipitating event in acute severe asthma. Animal experiments ( Bolton 1996) have shown that a thick-filament myopathy similar to that seen in humans can be induced if the muscle is first denervated by nerve transection and then steroids are given. Thus, in humans, critical illness polyneuropathy and the additional effects of neuromuscular blocking agents would denervate muscle and then steroids would induce the typical myopathic changes. The rapidly evolving myopathy characterized by destruction of thick filaments throughout the muscle fibers and the acute necrotizing myopathy of intensive care may simply represent further stages of this process (Bolton 1996).

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