Background
Delirium is defined as a change in mental status, characterized by acute onset and fluctuating course, inattention, disorganized thinking, and altered level of consciousness [
1]. The incidence of delirium varies with the setting and the population analyzed and is reported to be as high as 82% in the intensive care unit (ICU) [
2]. Compounding this, the incidence ranges from 11% to 46% among all cardiac surgical patients and is even higher in the geriatric population undergoing cardiac surgery. In-hospital delirium confers a significant morbid burden and has been correlated with poor hospital outcomes, including significant increases in mortality [
2], nosocomial complications, and longer ICU and hospital stays [
3,
4]. Delirium has also been associated with debilitating long-term outcomes, including poor functional recovery, and accelerated cognitive decline with impaired cognitive function for up to 1 year after cardiac surgery [
5].
Risk factors for delirium in patients undergoing cardiac surgery include pre-existing cognitive dysfunction, depression, transient ischemic attacks, and abnormal serum albumin [
6]. The interplay between these pre-existing comorbid conditions and numerous perioperative factors, including postoperative pain, mechanical ventilation, use of deliriogenic analgesic and sedative drugs, and the inflammatory response to surgery and cardiopulmonary bypass, makes the elderly especially vulnerable to delirium. Despite this, delirium is deemed preventable in 30% to 40% of cases [
2]. Although the pathogenesis of postoperative delirium is not completely understood, modifiable factors such as perioperative sedation and opioid-based analgesia may contribute to the etiology [
7,
8].
Traditionally used sedatives and analgesics, namely benzodiazepines and opioids, have psychoactive properties. Midazolam, a benzodiazepine, acts via gamma-aminobutyric acid (GABA) receptors and is found to release deliriogenic mediators [
9]. Additionally, opioids such as morphine have long been known to cause delirium [
8]. However, dexmedetomidine, a selective alpha-2 receptor agonist, provides analgesia and sedation without causing respiratory depression and has no effect on the GABA receptors. Dexmedetomidine is also suggested to have an opioid-sparing effect [
10] and anti-inflammatory properties [
11]. Studies have also demonstrated reduction in mortality with the use of dexmedetomidine in cardiac surgery [
12]. Although these characteristics suggest dexmedetomidine to be a unique and promising drug for sedation following cardiac surgery, the studies investigating its effect on the incidence and duration of delirium have thus far shown mixed results. Non-standardized [
13] and insensitive outcome measurements in non-intubated patients [
14] have contributed to the mixed results. A recent meta-analysis suggested that the use of dexmedetomidine for sedation in cardiac surgery patients may reduce postoperative delirium [
9]. However, many of the studies included did not have a robust design and used various outcome measures and tools to assess delirium. Another study found no significant decrease in the incidence of postoperative delirium with the use of dexmedetomidine but was likely underpowered [
15]. A recent study compared postoperative sedation using dexmedetomidine versus propofol and the associated delirium incidence. They found lower incidence of delirium in the dexmedetomidine group compared with the propofol group [
16]. There are more studies that examine the role of dexmedetomidine in the incidence of postoperative delirium, but the results are contradicting. In a large trial that studied the use of intraoperative dexmedetomidine infusion, which was continued for 2 h into the postoperative period, in non-cardiac surgical patients, no difference was found in the incidence of postoperative delirium compared with the saline placebo [
17]. The authors have emphasized the importance of the timing of dexmedetomidine infusion. Another large trial compared the effect of dexmedetomidine infusion in the postoperative period to placebo. They found a significant decrease in delirium in the first seven postoperative days in the dexmedetomidine group [
18]. Hence, there is no clear consensus on the usefulness of dexmedetomidine in delirium prevention.
Postoperative pain following cardiac surgery is attributable to many factors, including the skin or sternal incision, sternal retraction, pericardial incision, chest tube sites, and leg incisions for graft harvesting [
19]. The current pain relief strategy primarily includes postoperative opioid administration (morphine or hydromorphone), although a multimodal balanced postoperative pain management strategy could prove advantageous. Although inadequate pain relief can increase the risk of postoperative delirium [
20], central nervous system properties of opioids can also increase this risk, especially in elderly patients [
21]. Non-steroidal anti-inflammatory drugs (NSAIDs), including acetaminophen, are the other agents used in a multimodal regimen. NSAIDs are generally avoided after cardiac surgery because of their deleterious effects on the gastric mucosa and kidney and increased risk of bleeding. Intravenous (IV) acetaminophen is a good alternative, and no bleeding risk is associated with its use. It inhibits cyclo-oxygenase and consequently the synthesis of pro-inflammatory cytokines [
22]. It also decreases production of inflammatory agents such as histamine and leukotrienes [
23]. In addition to its peripheral effects, it may also have effects on the central nervous system which contribute to its analgesic property [
24]. Billings et al. previously showed that perioperative administration of acetaminophen decreases lipid peroxidation during cardiopulmonary bypass [
25]. This study explores the effect of cardiopulmonary bypass and its inflammatory response leading to erythrocyte lysis and the effect of acetaminophen on its prevention [
25]. Although the context is different, the attenuation of lipid peroxidation with secondary inflammation and injury in the immediate postoperative period as seen with acetaminophen may be relevant to its effects on the central nervous system and subsequently on the incidence of delirium. The use of IV acetaminophen has been shown to decrease opioid consumption after surgeries such as hip and knee replacements, cesarean sections, and coronary artery bypass surgeries [
23,
26]. Despite these promising findings, IV acetaminophen has never been studied in the context of delirium prevention following cardiac surgery.
This study aims to assess the role of postoperative pharmacological interventions in decreasing the incidence of delirium. We hypothesize that the use of postoperative acetaminophen and dexmedetomidine will result in a decrease in the incidence of postoperative delirium after cardiac surgery.
Discussion
Significance
This is a large, randomized, controlled, double-blinded study that aims to assess whether there is a relationship between IV acetaminophen and postoperative delirium and whether this relationship is dependent on the sedative used. Study outcomes are measured by using tools that are tested and proven to be sensitive in identifying delirium. They are designed to detect any cognitive changes in the past 24 h and hence are performed on a daily basis. We have also incorporated a cognitive assessment to measure postoperative cognitive decline over the course of the immediate and extended postoperative period. Furthermore, the follow-up at two time points may provide insight into the long-term effects of the study intervention on delirium and neurocognition. If the benefits proposed are substantiated, this can have a significant impact on patient care and satisfaction following cardiac surgery, as it involves modifiable factors that could be easily incorporated into clinical practice.
Limitations
This trial is designed to study the role of postoperative pharmacological intervention, and any sedative intervention in the preoperative and intraoperative period is left to the discretion of the treating provider. This may have a potential to impact the outcome. As with any study assessing changes over time, there is the potential for loss to follow-up to occur. This limitation is minimized by the fact that it may largely impact our secondary rather than the primary outcome. Furthermore, in an effort to mitigate non-response, we have established wide windows to allow for completion of the follow-up assessments and have also limited the number of follow-up assessments to two. Additionally, we have accounted for dropouts in our sample size calculations. Another potential limitation of this study is the inability to blind the choice of sedative used (propofol or dexmedetomidine) to the study team members. This study includes only one academic medical center and its patient population. While we are located in an urban area, the study population may not be a completely representative sample of those who undergo these types of procedures. Furthermore, clinical care guidelines may differ from those of other hospitals, especially in terms of sedation and pain management. Despite these limitations, this study will provide further insight into the utility of IV acetaminophen with or without dexmedetomidine in reducing the incidence of postoperative delirium following cardiac surgery.
Ethics and dissemination
The drugs used in the study are US Food and Drug Administration–approved for sedation and analgesia and are routinely used as standard of care in the cardiac postoperative setting. In the tightly monitored environment of the cardiovascular ICU, if any drug-related adverse event occurs, it can be detected early and managed effectively. Thus, it is expected that the benefits of the intervention would far outweigh the anticipated risks associated with them.
Phlebotomy is associated with a small risk of pain and bruising. So whenever possible, blood draws are performed via existing arterial or central venous lines inserted for the purpose of surgery or are obtained at the same time as blood draws for other clinical lab work. As for the volume, a maximum of 80 cm3 of blood is drawn over the duration of hospital stay, which is considered minimal risk.
There is chance of patient fatigue with daily cognitive assessments. To overcome this, the patients are placed on an alternate day assessment pattern once they are CAM-negative (delirium-free) for three consecutive days.
This study has been approved by the Committee on Clinical Investigations Institutional Review Board at Beth Israel Deaconess Medical Center (Protocol 2014-P-000413). Written informed consent will be obtained from all subjects prior to initiation of study procedures.
We have planned to present the results of this study in national/international meetings and to publish them in scientific journals. The datasets used or analyzed during the current study will be available from the corresponding author upon reasonable request. There are no plans to individually notify participants regarding the results of this study.
Trial status
The trial is ongoing and currently recruiting.
Acknowledgments
The authors would like to thank Kristin Brierly and Valerie Banner-Goodspeed from the Center for Anesthesia Research Excellence (CARE) within the Department of Anesthesia at Beth Israel Deaconess Medical Center, who supported the protocol development, implementation, and compliance adherence of this clinical trial.