Statins for sepsis: a cautionary note

Abstract

There is a growing body of evidence that prior statin therapy lowers the incidence, severity and mortality of sepsis. A recent cohort analysis of 69,168 patients demonstrated reductions of broadly 20–25% [1], suggesting that patients with major infections should continue statin therapy. In their editorial in this journal Mekontso-Dessap and BrunBuisson [2] go further in speculating that statins should be investigated as adjuvant therapy for established sepsis (as opposed to a role in primary prevention). Whilst not wishing to discourage such investigations, we have concerns regarding statin use in the critically ill relating to their known neuromuscular toxicity potentially facilitating the development of critical illness weakness syndrome. Although statins rarely cause rhabdomyolysis, their neuromuscular adverse effects are not restricted to this presentation and include an axonal neuropathy as well as myalgia and weakness with or without a rise in creatine kinase [3]. The incidence of these less severe but nonetheless important effects is uncertain due to trial design resulting in underreporting as well as a focus on those associated with elevated creatine kinase. In the largest statin trial to date a run-in period effectively excluded the majority of patients developing side effects from inclusion in the trial. Indeed statins may result in a mild universal disturbance of muscle function. In professional athletes with hypercholesterolaemia 80% were unable to tolerate any statin because of perceived detrimental effects on performance [4]. The pathogenesis of statin-related myopathy and neuropathy is more likely to be a result of disruption of mevalonate metabolism and isoprenylation than of membrane consequences of a modest reduction in cholesterol. Prenylation is an integral step in the formation of a number of molecules critical to fundamental cellular processes, including mitochondrial function and structural components of the plasma membrane and cytoskeleton, and whose impairment is causal in several inherited muscle disorders. It may also account for the statins beneficial immuno-modulatory actions. There is good reason to believe that critically ill patients may be at particular risk of statin-associated myopathy. Principally this follows reduced statin metabolism (the incidence of myopathy is dose-related) and the additive effect of other processes inhibiting neuromuscular function. In a clinical advisory statement from the American College of Cardiology and others [5] patient groups perceived as being at increased risk of myopathy included advanced age, frailty, multisystem disease, chronic renal failure, the peri-operative period and alcohol abuse. Drugs associated with increased toxicity include cyclosporine, azole anti-fungals, macrolide antibiotics, amiodarone, verapamil and HIV protease inhibitors. It is clear that large numbers of critically ill septic patients fall into a higher risk category, and that many will be prescribed drugs which may increase their susceptibility. Any agent that may cause a myopathy or neuropathy and thus generate or exacerbate a critical illness weakness syndrome must be used with care. Intensivists caring for patients on a statin should be aware of the possibility of statin-associated neuromyopathy particularly in statinnaive patients, and if trials of statins as adjuvant therapy are to be performed, investigators must rigorously search for these complications.