Cognitive Dysfunction,Delirium,and Stroke in Cardiac Surgery Patients

Abstract

Neurologic injury in the form of cognitive decline, delirium, and stroke are common phenomena in patients undergoing cardiac surgery and continues to be one of the most common complication after cardiac surgery, in spite of improvements in mortality and and improved surgical and anesthetic techniques. These complications lead to a significant increase in length of stay in the intensive care unit, increased length of hospital admission, and functional impairment, resulting in not only profound negative effects on patients who experience these complications, but also to increased costs of medical care and delivery. We discuss each of these complications in regard to their risks factors, incidence, potential therapeutic modalities, and relevant intraoperative and postoperative considerations.

Keywords

brain injury cardiac anesthesia cardiac surgery cardiopulmonary bypass surgery cerebral metabolism critical care elderly patients inflammation near-infrared spectroscopy

Introduction

Neurologic morbidity is one of the most frequent complications after cardiac surgery. Despite an improvement in overall outcomes after cardiac surgery, the proportion of patients who suffer from neurologic morbidity has not changed. Anesthesiologists and critical care providers are uniquely positioned to assess and treat these conditions throughout the perioperative period. While the list of potential diagnoses is lengthy, this review will focus on 3 of the most commonly encountered neurological deficits: postoperative cognitive decline (POCD), delirium, and stroke.

Postoperative Cognitive Decline

Prevalence and Risk Factors

Soon after the advent of cardiopulmonary bypass (CPB), concerns were raised about the associated effects on patients’ cognition in the postoperative setting period. Patients—and caregivers—observed a noticeable decline in cognitive performance following cardiac surgery in a significant number of patients. These anecdotal concerns were subsequently confirmed via observational cohort studies. Shaw et al compared patients undergoing on-pump coronary artery bypass grafting (CABG) with those undergoing major surgery for peripheral vascular disease.¹ In this study, patients who underwent CABG had significantly higher rates of major neuropsychological complications after their cardiac surgery than those in the control vascular surgery group. The authors concluded that CPB was likely responsible for these increased disabilities. Most of the neuropsychological deficits appeared to persist beyond hospital discharge for up to 5 years.²

These findings and those of other landmark investigations² have described prevalence rates of POCD to be around 25% to 50% and have spurred numerous investigations into the specific pathophysiology of POCD following CPB. Inflammation has been frequently implicated.^3,4 Evidence for a systemic inflammatory response associated with CPB is unquestioned, and the early connection between CPB and POCD made inflammation a logical target. However, subsequent studies have cast doubts on the role of CPB on POCD. Kozora et al provided a detailed analysis of neurological outcomes in the ROOBY trial, a multicenter study designed to assess differences in outcome between on-pump and off-pump coronary bypass grafting.⁵ They found no significant differences in cognitive decline between the 2 groups at 1 year after surgery and attributed the decline to factors such as the patient’s prior cognitive score, age, education, and ethnicity. Similarly, interventions designed to ameliorate inflammation due to CPB have also had limited success. Infusion of lidocaine throughout the perioperative period was not shown to decrease the incidence of cognitive decline in patients requiring CPB.⁶ Although inflammation due to CPB may not be a key factor in POCD, the overall role of inflammation in the development of cognitive decline remains important. Patients with polymorphisms of C-reactive protein and P-selectin—proteins important in the inflammatory cascade—have been shown to be less likely to develop cognitive deficits.⁴

Cerebral ischemia has also been an active area of research, with equally mixed results. In a study looking at diffusion-weighted brain magnetic resonance imaging (MRI) following valvular heart surgery, 43% of patients had evidence of new ischemic embolic lesions postoperatively.⁷ Furthermore, there was a significant association between the degree of new ischemia and the severity of cognitive decline. A very similar study in a mixed cardiac surgery population (valvular or CABG requiring CPB) revealed that 32% of patients had new lesions on diffusion-weighted MRI. However, the incidence of POCD was identical in those with and without radiographic findings, with 88% of both groups demonstrating cognitive decline.⁸ It is interesting that both of these studies had similar rates of radiologic ischemia and POCD, yet differed in the correlation between the two. It is possible that the type of surgery (valvular vs coronary bypass) as well as unmeasured differences in the patient factors and the hospital course may play a role and thus contribute to the conflicting results; though, this remains unproven.

Ischemia is not limited to obstruction of flow and radiological evidence, however. Patients may have decreased cerebral oxygen delivery due to relative hypotension or hypoxemia. Patients undergoing on-pump coronary bypass grafting were less likely to develop POCD when they were maintained at a mean arterial pressure (MAP) of 80 to 90 mm Hg compared with those who had mean pressures between 60 and 70 mm Hg.⁹ A similar study that randomized patients to either a “high” mean pressure (90 mm Hg) or a “custom” mean pressure based on the patient’s baseline MAP did not demonstrate any difference in neurocognitive outcomes.¹⁰ The difference in outcome between these 2 studies could be explained in that all patients in the latter study were maintained at or above their baseline MAP, whereas a subset of patients in the low pressure arm of the former study may have been below their preexisting blood pressure.

Hypoxemia has also been a target for intervention. Measuring and optimizing cerebral oximetric saturations may improve cognitive outcomes. In one study, patients who were managed to maintain higher cerebral oxygen saturation had a decreased risk of developing early POCD, while time spent below 50% cerebral oxygen saturations was a risk factor for POCD.¹¹ Techniques used to optimize cerebral oxygen delivery include increased pump flows, increased MAP, and transfusion.¹¹ Providing surplus oxygen to maintain arterial hyperoxia has not been shown to have a positive impact on cognitive function following cardiac surgery.¹² There is a concern for providing excess oxygen delivery since oxygen free radicals have been implicated as part of the inflammatory milieu responsible for POCD, though in at least one study hyperoxia was not associated with significant cognitive decline.

Intraoperative and Postoperative Evaluation and Management

Perhaps the most striking aspect of these studies on POCD is the abundance of conflicting data. This is ultimately a reflection of the uncertainty surrounding the diagnosis itself.¹³ Early investigators realized the importance of a standardized criteria for evaluation, yet even more recent publications do not all use the same set of cognitive assessment measures, nor is there universal agreement about the timing of assessment.^14-16 These criteria generally (but not always) include multiple neuropsychological tests to assess executive function, memory, and learning, with POCD defined as a decline of 1 standard deviation in one or more domains of cognitive function. Another major criticism of the earlier investigations was a lack of adequate controls for preexisting cognitive deficits (a recognized risk factor for further postoperative deterioration) and other comorbidities.¹⁷ Subsequent studies have attempted to answer these questions. In a comparison between patients undergoing off-pump CABG or percutaneous coronary interventions, both groups displayed similar cognitive outcomes at 7.5 years following the procedure.¹⁸ Similarly, Selnes et al compared patients with coronary artery disease (CAD) treated with on-pump CABG, off-pump CABG, or medical management only.¹⁹ They included a non-CAD comparison group as well. At 6 years after enrollment, there was no significant cognitive difference between the 3 coronary disease groups although all 3 groups fared worse on cognitive testing than the non-CAD cohort. This suggests that it is patient-specific factors, rather than surgical intervention, which play the most important role in the development of cognitive decline. These data are complemented by data from patients who survive critical illness, whether it is after a surgical procedure or after being admitted to the medical intensive care unit (ICU). In these patients cognitive impairment is common, but again prior cognitive status, education, and then duration of delirium in the ICU were the main drivers associated with the decline in cognitive scores.²⁰

With the plethora of conflicting data, the clinician is left with few answers with regard to optimal management of cardiac surgical patients to reduce the risk of cognitive decline. Detailed preoperative neurocognitive testing is complex, time-consuming, and requires specialized training. While the available evidence does not allow for strong or very specific recommendations, clinicians in the operating room and in the ICU should focus on those patients who may be deemed at high risk, that is, the elderly, those with prior cognitive impairments, those with lower levels of education, and those who are at risk for delirium postoperatively.^21,22 In these patients, close attention to the basic tenets of management should be employed, including optimal hemodynamic management, prevention of hypoxemia, reduction of sedative (especially benzodiazepines) and analgesic medications that might predispose to delirium, and implementation of strategies that have been shown to decrease delirium burden (nonpharmacological and pharmacological as outlined in the delirium section below).

Delirium

Delirium is a form of acute brain dysfunction that has garnered increased interest within the critical care community over the past decade. Initially thought of as a normal part of critical illness, there is emerging evidence that delirium is a more significant problem.²³ It has been well established that delirium is associated with longer ICU and hospital length of stay.²¹ What may be more surprising—and more serious—is its association with long-term cognitive decline and even mortality.^20,24,25 The incidence of delirium in cardiac surgery and cardiology patients is around 30%,^21,26 and in critically ill patients delirium occurs in 50% to 70%²⁷ of patients representing a major source of morbidity and an area of intense focus. These findings have shifted the view that delirium is merely agitation, to an understanding that it is a marker of organic brain dysfunction.

Delirium is defined as an acute (hours to days) disturbance in attention that occurs over a short period of time and is accompanied by an acute decline in cognition that cannot be accounted for by a preexisting or evolving neurocognitive disorder such as dementia or stroke.²⁸ The onset of mental status change must be either acute or fluctuating (commonly referred to as a “waxing and waning” pattern). This distinction separates delirium from other cognitive disorders such as dementia, which is defined by its chronic progressive nature. Second, delirium is marked by inattention, which is considered the cardinal symptom of delirium.²⁹ Finally, patients with delirium must have either sleep–wake cycle disturbances, hallucinations, altered level of consciousness, or disorganized thinking.²⁷ Delirium is further classified into 3 psychomotor subtypes: hyperactive, hypoactive, and mixed-type.³⁰ Hyperactive delirium is characterized by increased restlessness, anxiousness, agitation, and combativeness. Hypoactive delirium is characterized by drowsiness, sedation, somnolence, or lethargy. Patients with mixed-type delirium fluctuate between hypoactive and hyperactive psychomotor activity. In critically ill patients, hypoactive and mixed-type are the commonly observed subtypes, while purely hyperactive delirium occurs in less than 2% of cases.^31,32 While the hyperactive type is perhaps more readily identifiable, the hypoactive type is far more prevalent in critically ill patients and portends worse outcomes.²⁶

Based on the above definition, patients must be arousable to verbal stimuli to meet diagnostic criteria. Patients who are unable to do so (because of either excessive sedation or innate brain dysfunction) are designated as comatose. Of note, patients may also be agitated or angry without having hyperactive delirium and this distinction should be made to guide management.³³ Recent validation of delirium monitoring instruments such as the Confusion Assessment Method (CAM), the CAM-ICU, and the Intensive Care Delirium Screening Checklist (ICDSC)^27,34 have provided clinicians with the ability to monitor for delirium without having to rely on a psychiatrist. These delirium assessments can also be performed in patients who are mechanically ventilated. Given that majority of delirium is missed unless a monitoring tool in used, hospitals should make delirium monitoring standard of practice as recommended by the recent Society of Critical Care Medicine (SCCM) pain, agitation and delirium guidelines.³³

Risk Factors and Intraoperative Management

Researchers have attempted to delineate risk factors related to postoperative delirium development. One clinical prediction rule tool identified a previous history of stroke or transient ischemic attacks, a lower baseline Mini-Mental Status Exam score, high scores on a geriatric depression screening tool, and abnormal serum albumin levels as independent risk factors for developing postoperative delirium in cardiac surgery patients.²² The same study noted a tendency toward older patients although this was not robust enough to be included in the final clinical prediction rule. Patients with low cardiac output states and a need for preoperative intra-arterial balloon pump support have displayed increased rates of delirium,²¹ and American Stroke Association physical score has been shown to be a significant risk factor as well.³⁵ These findings highlight the overall role of preoperative systemic disease in the development of postoperative delirium. Patients with preexisting cognitive deficits, cerebrovascular disease, and poor nutritional status have limited physiologic reserve and are more likely to manifest signs of brain end-organ dysfunction.

Several recent articles have examined the impact of intraoperative management on the risk of developing delirium. A large, multicenter, randomized-control trial (DECS) evaluated the impact of intraoperative high-dose dexamethasone on delirium following cardiac surgery and found a significant decrease in postoperative delirium.³⁶ However, delirium was identified based on antipsychotic use at discharge, which may not be an accurate surrogate marker. Sauër et al looked at a single-center subset of patients in the DECS trial who were evaluated daily for delirium using a dedicated assessment tool (the CAM-ICU).³⁷ In this subset, the authors found no significant difference in the incidence of delirium. In another subgroup analysis study, investigators looked at the incidence of delirium in cardiac surgical patients enrolled in the BAG-RECALL trial.³⁵ They found that patients who were managed using a Bispectral Index (BIS) monitor had a lower incidence of delirium than those who were managed simply by monitoring end tidal concentrations of volatile anesthetics. Patients in the BIS group actually received larger average volatile anesthetic doses; it is unclear as to whether this increased dose is protective or simply a marker of patients who were less ill and therefore able to tolerate more volatile anesthetic.

Blood transfusion has been implicated as a risk factor in the development of delirium.^21,35 However, the risk may be related to more than simply the need for blood products. Brown et al examined the age of allogenic red blood cell transfusions to determine what influence this had on incidence of delirium.³⁸ Every day of storage >14 days was associated with a slightly increased risk of delirium, although there was no difference overall in patients who received blood that was exclusively less than or more than 14 days old, thus making the interpretation of these results challenging.

Postoperative Management

The primary step in managing delirium is detection. A standardized screening protocol is critical because hypoactive delirium can easily go undetected otherwise.²⁶ While there have been a number of validated tools, the SCCM guidelines recommends the use of the CAM-ICU or the ICDSC, which have been shown to be both efficient and accurate and require little training.²⁷ Patients can be screened by nursing staff or other clinicians in several minutes. Furthermore, testing can be completed in patients who are mechanically ventilated or otherwise unable to speak. Large implementation studies have shown that nurses and health care providers can perform testing in less than 5 minutes.³⁹

Once delirium is detected, management should follow a stepwise approach. The Society of Critical Care Medicine has published guidelines on the management of pain, agitation, and delirium, which recommend first ensuring that pain control is adequate.³³ Once that has been achieved, there are several potential nonpharmacologic therapies. Adjustments to the patient environment, such as turning on lights, providing glasses or hearing aids, and reorienting patients to their surroundings, have been frequently advocated for their simplicity and have been shown to be effective in reducing delirium in ward patients.⁴⁰ Unfortunately, there is little evidence for their efficacy in the ICU. One promising study examined rates of delirium before and after instituting an aggressive system of reorienting patients to place and time, using the patient’s first name, and sensory stimulation and found that the incidence of delirium decreased from 35% to 22%.⁴¹ Other studies have shown a benefit of improving sleep hygiene and reducing delirium duration.⁴² Even without strong evidence, these measures are reasonable given the ease and safety with which they can be implemented. Early mobilization is another important intervention. Early physical therapy and mobilization was successful at reducing delirium duration in a cohort of mechanically ventilated patients.⁴³ Finally, minimizing physical restraints is also important. These devices have been associated with increased delirium in the 24 hours following use and should be utilized only when absolutely necessary for patient safey.²⁶

The next step in delirium management is pharmacotherapy. Benzodiazepines have been implicated in the development of delirium as early as on postoperative day 1, and should be minimized in the operating room and avoided in the ICU when possible.^26,33,44 Alternative sedatives such as propofol and dexmedetomidine should therefore be considered as first-line sedatives after pain is controlled.^33,44 Antipsychotics, most notably haloperidol, have long been used in the intensive care unit to control agitated delirium. Somewhat surprisingly, the evidence for its use in critically ill patients is scant and it is not even included in professional guidelines.³³ Implementation of a standardized screening and treatment protocol with haloperidol in cardiac surgical patients has not been shown to have any impact on the incidence or resolution of delirium.⁴⁵

Atypical antipsychotics have been increasingly used to prevent and treat postoperative delirium. Many of the drugs in this class have been evaluated, including ziprasidone, quetiapine, and risperidone. Of these, risperidone is of special note in cardiac surgical patients because its utility has been specifically evaluated in this patient population. Patients older than 65 who displayed subsyndromal delirium after CPB were randomized to 0.5 mg of risperidone every 12 hours or placebo. Patients in the placebo arm were more than twice as likely to develop full delirium symptoms.⁴⁶ Furthermore, giving a single 1 mg dose of sublingual risperidone to patients at initial postoperative awakening in the ICU decreased the incidence of delirium from 31.7% to 11.1%.⁴⁷ Other small studies have shown that other atypical antipsychotics are also safe and effective in critically ill patients,^48-50 though larger placebo controlled trials are required to assess the risk and benefit ratio of administration of antipsychotic medications. At the time of this review, they should be considered for symptomatic relief of agitated/hyperactive delirium, with little evidence to suggest any beneficial role in patients with hypoactive delirium.

In summary, a framework for the good sedation and delirium practices in ICU patients is the “ABCDE bundle,” which comprises of strategies that would help reduce sedation, liberate patients from mechanical ventilation, and reduce the burden of delirium.⁵¹ The individual elements of this bundle are the daily Awakening and Breathing (AB) coordinated trials, Choosing (C) the right sedative, Delirium monitoring (D), and Early mobility (E). This framework has been studied recently and shown to reduce duration of mechanical ventilation and delirium in critically ill patients⁵² and should be considered in the management of critically ill patients.

Stroke

Stroke continues to be one of the most debilitating and devastating complications of cardiac surgery. Although there is some evidence to suggest that the incidence may be decreasing slightly,⁵³ the overall rate of stroke has remained remarkably constant at between 1% and 3%. Postoperative stroke places a major burden on patients, their families, and the health care system. In cardiac surgery patients who developed stroke, in-hospital mortality increased from 4% to 38%.⁵⁴ Even when patients survive to discharge, they have increased hospital length of stay and are more likely to need to be discharged to a nursing home or a rehabilitation center. Thirty-day mortality is also increased in these patients.⁵⁵ Prompt neurologic evaluation and management is critical to optimizing clinical outcomes.

Risk Factors and Prevention

Much work has been done to delineate the factors that lead to the development of stroke following cardiac surgery. Stroke is differentiated from other types of neurologic dysfunction (such as cognitive decline or delirium) based on the presence of focal neurologic deficits. The diagnosis can be further refined based on duration of signs and symptoms. A transient ischemic attack (TIA) is an episode that lasts less than 24 hours with complete resolution. If symptoms persist beyond this, the event is a stroke.⁵⁶ Although resolution of symptoms may seem reassuring, it is important to note that patients who experience a TIA have approximately a 5% chance of developing a subsequent stroke within the next 24 hours.⁵⁷ In a broader sense, the differentiation between focal and generalized brain dysfunction has important implications beyond simply taxonomy. Roach et al looked at neurologic injury in a large prospective cohort of patients undergoing on-pump coronary bypass surgery and divided them into 2 types.⁵⁸ Type I included patients with focal deficits (ie, stroke), whereas type II patients had declines in cognitive function, delirium, or coma. There was little overlap in the risk factors between the 2 groups, leading the authors to hypothesize that there are different pathophysiologic patterns responsible for these complications.

Unfortunately, many of the risk factors for stroke following cardiac surgery are nonmodifiable. Age has consistently been identified as one of the critical determinants of stroke risk.⁵⁸ Octogenarians are almost twice as likely to develop a stroke as those less than age 80. The type of surgery also affects the incidence of stroke. Coronary artery bypass carries the lowest risk, followed by combined CAB and aortic valve replacement. The highest incidence is in patients who undergo combined CAB and mitral valve replacement.⁵⁹ It is unclear whether this is related to the procedure itself or rather to the duration of CBP; pump time of greater than 120 minutes has been demonstrated to be an independent risk factor of stroke in several studies.^53,60

Another important surgical consideration is the presence of noncoronary vascular disease. Atheroma in the ascending aorta is a significant risk factor due to cannulation and manipulation during surgery. Traditionally, the aorta was assessed for atheroma by surgical palpation. But newer techniques involving either epiaortic ultrasound or transesophageal echocardiography have become the diagnostic standard. Patients who had an intimal thickness of less than 2 mm by ultrasound had a lower risk of neurologic dysfunction (although not specifically stroke) than those with a thickness greater than 2 mm. In addition, only patients in the latter group had postoperative ischemic lesions on MRI.⁶¹ Peripheral vascular disease is also an important risk factor,⁵⁸ especially plaques and stenosis in the carotid arteries. This has led to investigations of the possible benefits of carotid endarterectomy at the time of cardiac surgery. A recent meta-analysis including 12 studies of nearly 25 000 patients concluded that a staged and combined procedural approach had very similar outcome. The decision on timing of carotid endarterectomy and cardiac surgery therefore depends largely on the unique situation at each surgical center.⁶²

Development of postoperative atrial fibrillation also confers a greater risk of stroke. With an overall incidence of atrial fibrillation occurring in approximately 30% of cardiac surgical patients, this is of no small significance.⁶³ Atrial fibrillation has been shown to increase the risk of developing stroke 2-fold, and is also a risk factor in the development of postdischarge stroke.⁶⁴ There are published guidelines to support the prevention of atrial fibrillation in cardiac surgical patients, but there is insufficient evidence to recommend rhythm control for stroke prevention once fibrillation has occurred.⁶⁵

Evaluation and Management

The importance of early recognition and management of stroke cannot be overestimated. At many centers, a dedicated “stroke team” or rapid response group may exist to facilitate rapid evaluation and treatment and should be utilized immediately. The first step is to obtain a detailed and accurate neurologic examination, including both cranial and peripheral nerves. The National Institutes of Health Stroke Scale (NIHSS) is an extremely useful adjunct in this regard. The NIHSS is useful for not only for prognosticating outcome but also for inclusion in possible therapeutic interventions in stroke patients.⁶⁶

Timely imaging is the next step in the acute management of postoperative stroke, with both computed tomography (CT) and MRI serving complementary roles. CT can often be obtained more quickly than MRI, and some centers have portable scanners that eliminate the need for patient transport. This is especially helpful in unstable patients or those with mechanical devices such as intra-arterial balloon pumps that make transport both more difficult and more dangerous. While a CT of the head without intravenous contrast is useful for identifying hemorrhagic strokes, it has very low sensitivity for acute ischemic events. In this regard, either CT angiography or MRI is preferred. This is of significance because the great majority of postoperative strokes are ischemic in nature.⁵³ Patients with ventricular assist devices or other implanted cardiac appliances are not eligible for MRI.

If the physical exam and imaging confirm a cerebral ischemic event, the patient may be a candidate for interventional therapies. While systemic thrombolysis is generally contraindicated following cardiac surgery, targeted endovascular treatments exist. Intra-arterial thrombolytics, such as tissue plasminogen activator, can be injected directly at the site of clot burden and have been shown to be safe and efficacious in this patient population.^67,68 Patients may also be eligible for endovascular mechanical clot retrieval. However, these therapies are generally only indicated within the first 6 hours after onset of symptoms, which demonstrates the need for efficient stroke management from the entire health care team.⁶⁹

Medical management remains the mainstay of treatment for most stroke patients. Many of these are summarized in recently updated guidelines,⁷⁰ but a few will be highlighted here. Blood pressure control is an important early goal. Most evidence suggests that permissive hypertension up to a systolic blood pressure of 220 mm Hg is acceptable in the absence of other organ injury. That limit may need to be judiciously reduced in many cardiac surgical patients due to either decreased left ventricular function or the risk of bleeding at fresh suture lines. Uncertainty surrounds the optimal time to start (or reinstate) antihypertensives, but there is generalized consensus that 24 to 48 hours is probably a safe starting point.⁷¹ Hyperthermia should be aggressively avoided either through pharmacological means or by active cooling. Furthermore, hyperglycemia worsens outcomes in patients with cerebral ischemia. Serum glucose should be maintained below 200 mg/dL; this must be balanced against the well-documented risks associated with hypoglycemia.⁷²

Conclusion

Neurologic complications occur frequently in the cardiac surgical population. Ultimately, it is important for providers to understand the entire perioperative course of these patients because this will help identify those at highest risk. Although many patients with postoperative cognitive decline will improve without specific therapies, this puts a tremendous burden on patients, caregivers, and society. Both delirium and stroke require rapid assessment and treatment to optimize outcomes.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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