Attack of the catabolic pathways: muscle wasting in the ICU

Critical care or intensive care units (ICUs) began to emerge in major academic medical centres in the years following World War II (E. P. Didier, personal communication (see Acknowledgements below); Didier, 1970). At the same time, there was a parallel emergence of what might be described as high-tech surgery which included most notably the development of open heart surgery which is now routine. All of this required translation of basic physiological techniques including invasive monitoring of pressures throughout the cardiovascular system, measurement of arterial blood gases, and mechanical ventilation, along with administration of drugs in attempts to maintain some semblance of physiological homeostasis in the patients. As progress continued, these techniques were applied to patients with a wide variety of severe illnesses and facilitated additional impressive surgical interventions, permitting patients to survive illnesses like pneumonia and sepsis that were frequently fatal in earlier eras. So, by any stretch of the imagination, ICUs and the medical advances they have facilitated are clear demonstrations of how broad-based physiological principles, techniques and interventions can be translated into medical practice. Intensive care is also sometimes flippantly referred to as ‘expensive care’ inside the walls of academic medical centres (Halpern, 2009). This euphemism reflects the high cost of care for these patients because it requires significant equipment and around the clock attention and intervention by skilled teams of physicians, nurses, and other hospital personnel (Didier, 1970). While the cost of ICU care is a great challenge to policy makers, at another level the vast sums spent taking care of critically ill patients demonstrate the potential life-saving powers of the integrated use of expertise and technology in complex patients. Additionally, one unforeseen ‘side effect’ of ICUs has been what happens after the patient recovers from their acute condition or conditions. Finally, the complex nature of the critically ill patient is also a great challenge in the design of clinical trials to improve outcomes because generating a large pool of relatively homogeneous subjects who can participate in well-controlled standardized interventions is very difficult in these patients. These issues are amplified by the challenges associated with informed consent and just the unpredictable nature and ‘rollercoaster’ clinical course in many patients admitted to ICUs. With this information as a background, Constantin and colleagues have performed an outstanding study on the general syndrome of muscle wasting in the ICU, described in a recent issue of The Journal of Physiology (Constantin et al. 2011). As they point out, muscle wasting, and loss of muscle strength (especially respiratory muscle strength) is a major issue for patients in critical care units in the short term. In addition to general and respiratory muscle weakness, muscle wasting also leads to acute disruptions in metabolic control (diabetes) in many ICU patients. In the medium term it can also make weaning patients from mechanical ventilation problematic. In the longer term (especially in older patients) muscle wasting poses a significant challenge for the rehabilitation of these patients and resumption of the normal activities of daily living. Along these lines, the main findings from Constantin et al. are that a suite of molecular events occurs early on in the course of critical illness that promote muscle protein breakdown via activation of a number of catabolic pathways. Additionally, while there is an increase in the transcription of at least some anabolic pathways in skeletal muscle, this transcription does not appear to generate a major bump in the proteins that synthesize skeletal muscle and any anabolic changes are overwhelmed by a broad-based catabolic attack. From both basic science and clinical perspectives, these finding are important for the following reasons. First, the ten patients studied at some level are typical of ICU patients at teaching hospitals. They have a wide variety of conditions, multiple co-morbidities, and are unified primarily by the fact that they tend to be older. In this context, it is interesting to note that there appears to be a generic catabolic response irrespective of the clinical syndrome that lands the patient in the ICU. Second, the finding of a relatively generic set of defects in the catabolic/anabolic pathways and their regulation is important because this suggests that perhaps a common set of anti-catabolic strategies will have broad-based success in these patients. Third, is there a strategy of either anti-catabolic drugs (myostatin inhibitors?) that might be useful in these patients, and how would any pharmacological or physiological strategies interact with nutritional support in the ICU? As noted above, mechanistic clinical studies and clinical trials are especially difficult in ICU patients. However, over the last 10–20 years physiologically based strategies have been developed and tested in the ICU and led to improved outcomes in these complex patients. A key example relates to how mechanical ventilators have been used in the treatment of the adult respiratory distress syndrome (Gillette & Hess, 2001). The change towards less aggressive ventilator strategies was based on a number of studies and observations in small groups of patients that then led to larger trials. These trials and the parallel generation of ICU research networks have facilitated and improved outcomes in ICU patients. Thus, perhaps the data from Constantin et al. will ultimately lead to a comprehensive set of strategies and interventions in critically ill patients designed to preserve their muscle mass, quicken their recovery, and facilitate their rehabilitation. If this happens, it will be another demonstration of the link between understanding the physiology of complex medical conditions and treatment strategies that improve outcomes (Joyner, 2011).