Curing the Septic Diaphragm with the Ventilator

Franco Laghi, M.D.

Loyola University Medical Center and Hines VA Hospital, Maywood, Illlinois

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After overcoming the perils of sepsis, prolonged mechanical ventilation may be required because of profound weakness of the respiratory muscles. But prolonged mechanical ventilation can cause death, and the victory over sepsis becomes pyrrhic. Why does sepsis weaken the respiratory muscles? What can we do to lessen the problem?

Over the past decade, our understanding of how sepsis harms the respiratory muscles has advanced tremendously. Nitric oxide and its metabolites have attracted particular attention. In animals, inhibitors of nitric oxide synthase largely prevent the impaired contractility (1, 2) and the injury to muscle sarcolemma caused by sepsis (1). In the septic diaphragm, continued contractions of the muscle aggravate the injury to the sarcolemma (3). This synergism between sepsis and repeated muscle contraction has caused investigators to wonder whether the early institution of mechanical ventilation might minimize the muscle injury.

In the current issue (pp. 221-228) of the American Journal of Respiratory and Critical Care Medicine, Ebihara and coworkers (4) show that commencing ventilation at the time of infusing endotoxin into rats partially prevents the impaired contractility caused by sepsis. Mechanical ventilation also prevented the injury to the sarcolemma of the cells of the diaphragm. Surprisingly, mechanical ventilation did not reduce the increase in expression of inducible nitric oxide synthase. Does this mean that nitric oxide is less important than we thought in causing the muscle injury seen in sepsis? I believe not. The apparent paradox is only on the surface. In their study, Ebihara and coworkers (4) also tease out the effects of oxidative stress and mechanical stress on the sarcolemma. They conclude that oxidative stress combined with the stress to the muscle caused by repeated stretching makes the sarcolemma more fragile. And the interaction is not just additive, it is synergistic.

An interesting finding is that sepsis did not impair diaphragmatic endurance. How can we reconcile a decrease in diaphragmatic force with preserved endurance? It could mean that sepsis impairs all fiber types equally and it affects the diaphragm in an all-or-none fashion. Once a fiber is damaged by sepsis it is incapable of generating meaningful tension. The new data are consistent with other research showing that nitric oxide originates not only in the muscle fibers (2) but also in the inflammatory cells that enter the muscles (5). As such, it is likely that nitric oxide and its metabolites affect equally all of the fiber types in the diaphragm. The view that nitric oxide has a generalized action, however, contrasts with the findings of Gath and coworkers (2). These investigators reported that expression of the inducible nitric oxide synthase protein is limited to slow twitch fibers that are resistant to fatigue. This finding fits neatly with the decrease in endurance they saw in septic animals. Why are the two sets of data in conflict? Two possibilities are the species and the methods. Ebihara and coworkers (4) studied rats and Gath and coworkers (2) studied guinea pigs. Ebihara and coworkers (4) stimulated their muscle strips directly, whereas Gath and coworkers (2) stimulated the phrenic nerves. This technical difference is important because a constitutive nitric oxide synthase may be acting mainly at the neuromuscular junction (2). By sidestepping the neuromuscular junction, the adverse effects of sepsis on the respiratory muscles may be underestimated in the experiment of Ebihara and coworkers (4).

Is there evidence that these processes occur in septic patients? Inducible nitric oxide has been found in the muscles of septic patients and its expression is proportional to the severity of the sepsis (6). The muscles of septic patients are also less contractile than normal (6). Unlike animals, the impaired contractility is not reversed by inhibitors of nitric oxide synthase (6). Also exposing a piece of normal muscle to the amount of peroxynitrite produced in a septic muscle decreases force irreversibly (6). These data (6) suggest that respiratory muscle dysfunction in septic patients can be prevented only if counteracting steps are begun early. The new data also shed light on why early use of noninvasive ventilation can improve outcome in patients with lung infection (7, 8). The ventilator could be preventing the type of injury to the diaphragm seen by Ebihara and coworkers (4).

Is nitric oxide the main fuel for respiratory muscle damage in sepsis? Should we confine our focus to nitric oxide and the associated sarcolemmal injury? Most definitely no. First, the new data indicate that preventing sarcolemmal injury does not completely protect against the muscle dysfunction of sepsis. Nitric oxide has negative effects on other cellular components, such as inhibiting mitochondria, DNA strand breakage, and the proteins involved in excitation-contraction coupling. Second, nitric oxide may have protective effects in sepsis (3, 9). In mice without the inducible (9) or a constitutive form of nitric oxide synthase (3), endotoxin causes a greater decline in diaphragmatic contractility than in mice with normal levels of the enzyme. In these mice, nitric oxide may be acting as an antioxidant (3) and so protects the muscle against the reactive oxygen species that arise during sepsis (10). Third, pathways other than nitric oxidefree radical production (10), ubiquitin-proteasome proteolysis (11), and a decrease in nicotinic acetylcholine receptors (12)may be damaging the respiratory muscles in sepsis. Dysregulation of the microcirculation and of the Krebs cycle may also be contributing to the muscle injury.

What can we make of the metabolic maze that accompanies sepsis? Despite the advances, we are only scratching the surface. The complexity of the metabolic pathways indicates that any silver bullet used to cure the septic diaphragm will have to be assembled from many components. And as shown by Ebihara and coworkers (4), the early institution of mechanical ventilation will be a vital part.

	References

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