Although there are clearly defined risk factors for critical illness-associated CD, there is little understanding of the underlying pathophysiology. The precise mechanisms are unknown and there are likely to be multiple mechanisms at work in any given patient ( Figure 1 ) [5, 14, 15] . We have chosen to focus on two mechanisms that appear to have the greatest merit: neurotransmitter abnormalities and occult diffuse brain injury. In this bench-to-bedside review, we discuss the evidence supporting these mechanisms, potential markers that could be used to evaluate each mechanism in individual patients, and emerging therapies that may prevent or mitigate critical illness-associated CD. relative dopamine excess in the central nervous system (CNS). Antipsychotics such as haloperidol, which antagonize central dopamine receptors, can counteract the cognitive effects of anticholinergic medications, further supporting the anticholinergic hypothesis.