Delirium after cardiac surgery is associated with serious long-term medical consequences [1
] and high costs [3
]. It affects approximately 30% of cardiac surgery patients, although reported incidences are variable [4
]. Delirium is an acute and fluctuating state of confusion and disorientation, characterized by changes in attention, cognition, consciousness, and perception, and is often associated with changes in sleep patterns. Diagnosis is typically based on clinical assessments of patient symptoms, which are defined by the Diagnostic and Statistical Manual
fourth, text-revised (DSM-IV TR) edition [12
Factors that have previously been identified as key, independent predictors of delirium after cardiac surgery include advanced age, pre-operative cognitive decline, atrial fibrillation, previous delirium as well as a sizeable list of other conditions and co-morbidities [13
]. Given that many of these risk factors are non-modifiable, emphasis recently has been on identifying risk factors that can be modified so that the incidence or severity of postoperative delirium may be reduced. A focus of such modifiable risk factors includes medications that cardiac surgery patients consume before, during, and after surgery. Interestingly, it seems that while some medications may be associated with a higher rate of delirium, others may be associated with a significantly reduced rate of delirium. Despite a growing number of studies that include perioperative drug use in their investigations, the influence of drugs on the development of delirium after cardiac surgery has not been the subject of critical review.
Critical examination of perioperative drugs is important because these agents may have pharmacological actions (particularly within neural tissues) that can greatly influence the etiology of postoperative delirium. One popular theory for delirium etiology is the neurotransmitter hypothesis. This theory postulates that decreased neuronal metabolism from oxygen deprivation during cardiac surgery alters neuro-transmitter function and causes generalized dysfunction in the brain [16
]. In particular, the neurologically ubiquitous cholinergic system is believed to be deficient in the delirious patient [18
]; additionally, there may also be excesses of dopamine, norepinephrine, and glutamate, while serotonin and GABA levels may be increased or decreased [16
]. Therefore, cardiac medications such as digoxin, furosemide or nifedipine (which have relatively significant anticholinergic properties), and other medications like selective serotonin reuptake inhibitors (SSRIs), antipsychotics, or benzodiazepines, may pay important contributions to delirium etiology through these neurotransmitter pathways.
It is important to emphasize that most studies that have collected data on perioperative use of medications in delirious patients are prospective or retrospective observational studies, and therefore cannot imply direct causal relationships between the medications that were studied and the outcome of delirium. Even though the majority of these observational studies use multivariate logistic regression analyses to identify drugs that may independently increase or decrease the risk of delirium, such techniques cannot account for all the reasons why groups differ in the rates of delirium; depending on the covariates that are being controlled for in the regression models, there may be significant cross-study differences in the results.
Another challenge of using the observational study design for delirium research is in determining the influence of intraoperative drugs on delirium. The reason for this is because behavioural abnormalities that appear immediately following surgery may be attributed to the residual effects of anesthesia, and patients may experience a form of delirium known as emergence delirium
, which is a state of short-lived, self-limiting agitation that is attributable to substance use [20
]. In the literature, emergence delirium is not consistently defined, and its etiological and pathological distinction from postoperative delirium is not consistently differentiated (compare, for example, [20
] to [21
]). For this reason, a couple of the studies that were reviewed for this synopsis did not commence their assessments of delirium in patients until the second day after surgery [5
]. Nevertheless it has been suggested that intraoperative factors reliably contribute to the development of postoperative delirium because the first symptoms almost always occur in the period shortly after awakening from sedation [13
Similarly, it is also difficult to establish the role of postoperative drugs on delirium with such observational designs. Even though delirium is defined by the DSM-IV-TR as having multifactorial etiology (which includes preoperative, intraoperative, and postoperative factors) the role of postoperative factors on delirium is frequently downplayed in studies because they are not commonly considered ‘predictors’ of delirium, despite the fact that they are potentially modifiable. For instance, Afonso et al
], Katznelson et al
] and Redelmeier et al
] did not include any postoperative variables in their investigations, while Tan et al
], Shehabi et al
], and Tully et al
] focused primarily on pre- and intraoperative factors in their studies. Thus, studies that look at postoperative medications as potential factors that influence delirium are limited in number.
Other studies that have looked at the influence of drugs on delirium are randomized controlled trials (RCTs). These studies, which are more robust, are typically designed to investigate the prophylactic effectiveness of certain medications like dexmedetomidine or rivastigmine to prevent delirium in vulnerable individuals. Unlike observational studies, well-controlled RCTs can suggest that any observed differences in the rates of delirium are due to differences in drug administration.
In this review, delirium after cardiac surgery is considered distinct from other types of postoperative deliria for a number of reasons. For one, different surgical populations often have different medication profiles and require different anesthesia techniques. Thus, the pharmacological triggers of delirium will vary depending on surgery. Secondly, the use of cardiopulmonary bypass (CPB) in cardiac surgeries requires special consideration since its use is associated with postoperative effects on neurological function and an increase in delirium [13
]. Lastly, it is unknown if the pathophysiology of different postoperative deliria differs: research has shown that predictors of delirium appear to vary depending on surgery type, and levels of certain biomarkers for delirium also appear to vary with different forms [23
The purpose of this article hence is to synthesize the evidence in the literature for drugs that have been shown to be associated with either a higher or a lower rate of delirium after cardiac surgery. We also discuss studies that have attempted to use certain drugs for strategic prevention of postoperative delirium.