Some aspects of the metabolic and physiological response to critical illness

Abstract

Patients suffering from extreme degrees of illness consistently show major metabolic and physiological changes. The type and magnitude of these changes have been quantified to a variable extent, but many aspects have not been adequately measured or reported. Clinical management of such patients is often based on extrapolating results from treatment of mild or moderate degrees of illness, yet the validity of this approach has not been confirmed. The catabolic state in severe illness, if prolonged or extreme, is potentially harmful to the patient. It is likely, however, that the breakdown of protein (from skeletal muscle and other tissues) is useful as a source of fuel and substrates for vital metabolic functions, such as immune responses and wound healing. It has proven difficult to establish a cause-and-effect relationship for these concepts. The role of cytokines in the genesis of the metabolic and physiological response to critical illness is now becoming clearer. One of these cytokines—tumour necrosis factor-α, or TNFα—is thought to be the primary trigger in an amplification cascade that results in activation of the inflammatory response. This response is beneficial when controlled, but overwhelming activation can result in organ dysfunction and even death. The hypothesis that the cytokine response can be modified beneficially (“immunotherapy”) has been tested and proven in animal models, particularly when treatment is given prophylactically or soon after the primary insult. Clinical trials with patients with sepsis, with mortality reduction as the end point, have also been performed but have failed to live up to early hopes It has been unclear from such trials to what degree physiological abnormalities are prevented or reversed. Expert opinion has suggested the need to better quantify aspects of metabolism and physiology in patients with severe sepsis. This thesis reports on some aspects of studies on two sets of critically ill patients. The first involved attenuating the early activation of the cytokine cascade in patients with severe sepsis using cA2, a neutralising antibody to TNFα, given as early as practical after diagnosis. Outcomes examined included a number of vital metabolic, physiological, and functional variables. Similar investigations were performed on a group of patients after major trauma. The results from the work allow us to extend our understanding about critical illness, and challenge us to re-examine certain assumptions about the role of immunotherapy in critically-ill patients. In brief, overall mortality was unaltered by the cA2 agent. The peak concentrations of cytokines, including endogenous antagonist molecules, were remarkably high in these patients. Although the anti-TNFα antibody was effective in reducing levels of immunoreactive TNFα, the concentrations of “downstream” pro-inflammatory cytokines did not alter. These findings suggest very early activation of the cytokine cascade, and perhaps recruitment of parallel mediator systems. Blockade of TNFα, in patients with severe sepsis did not alter the volumes of fluid needed to resuscitate patients, or reduce the dramatic expansion of the extracellular fluid compartment seen with such illness. The catabolic loss of protein stores over a three week period was almost 15%, a threshold which has important clinical implications. In examining biochemical markers of recovery, it was found that plasma proteins (such as transferrin, prealbumin, and insulin-like growth factor-1) which correlate well to changes in body protein stores in mild and moderate illness, do not perform similarly for patients with critical illness. The healing of experimental wounds was unaltered by cA2 treatment (the first time this has been shown in humans), but was found to be impaired in inflammatory illness of this severity when compared to injured patients. This conflicts to some extent with long-held views of the “biological priority” of wound healing, yet confirms experimental data. Remarkable similarities in metabolic and physiological responses were demonstrated for the patients intensively studied in this thesis, and the group of patients suffering from major trauma. Possible reasons for these similarities are discussed. Evidence for the maintenance of cardiac function in critical illness is presented. Preliminary investigations into the role of oxidative stress injury and evidence in support of changes in cellular hydration are also described. A theme that emerges from this work is that although whole-body catabolism is profound in critically ill patients, the composition and function of different tissues and organ systems are preserved or even enhanced during this period. The immune system for example is shown to be markedly synthetic, as is the liver (albeit with different production lines than in the normal state). Cardiac mass is unaltered in these patients. The healing of wounds goes on, but at a slower pace than normal. In summary, these studies suggest that immunotherapy in severe sepsis may be thwarted by the early and massive activation of the systemic inflammatory response, such that many treatments will do “too little, too late”. Further characterisation of certain aspects of the metabolic and physiological response to critical illness have been gained from these studies. Finally, preliminary evidence of some new concepts in critically ill patients is presented.