Newer drugs in intensive care

Abstract

Systems for monitoring the efficacy and safety of new drugs in the general population are now reasonably well-established, but it is only in the last few years that the pharmaceutical industry and the medical profession have recognized the need to assess drugs formally in critically ill patients, rather than making assumptions based on simple pharmacokinetic studies in patients with stable failure of single organ systems such as chronic renal failure or cirrhosis. Two examples have drawn attention to this problem: the hypnotic agent etomidate (Hypnomidate) and morphine-based opioids. Etomidate was used for infusion-sedation of critically ill patients by clinicians who assumed that its safety in anaesthetic practice would apply in intensive care; and it was not until Watt and Ledingham (1984) reported the association of such infusions with an increase in mortality in multiple trauma patients that the potent inhibitory effect of etomidate on adrenal cortical function was discovered (Lambert et al, 1983). Old drugs used in new surroundings are potentially even more hazardous, as they may escape the vetting procedures applied to new drugs: the accumulation of active morphine metabolites in renal failure (Osborne et al, 1986) is still not recognized by some clinicians. Some pharmaceutical companies are now applying for product licences specifically for intensive care, and this is a welcome development. In time it should be possible to develop a standardized approach to the investigation of new drugs in critically ill patients, but there are difficulties that need to be resolved. The assessment of drugs in patients with multiple organ failure (MOF) may be complicated by polypharmacy, changes in drug receptors, altered plasma protein and tissue binding, changes in regional blood flow and drug distribution, accumulation of either the parent compound or potentially active metabolites, and the effect of haemofiltration on drug clearance. Two particular difficulties include the measurement of tissue (as opposed to plasma) drug levels, and the absence of accurate non-invasive measures of hepatic blood flow and hepatocellular function. Pharmacodynamic studies, particularly those which use survival as an end-point, must stratify for severity of illness to reduce bias (Knaus et al, 1984). In this brief review, we have selected new drugs of relevance to intensive care practice, and have included some older compounds, which are either