**2. Diagnosis**

#### **2.1 Risk factors**

Delirium is a very common complication following transplantation. It is important to have an appreciation for the risk factors linked to delirium development in order to optimize preventive measures and allow for early diagnosis. Advancing age and baseline cognitive impairment are the most commonly described risk factors for developing delirium [14, 15]. Certain medical conditions can also predispose patients to delirium. Sleep apnea, heart failure, diabetes and frailty have been shown to increase the risk of developing delirium [16]. Patients with lower cognitive and functional reserve likely have a reduced ability to maintain normal brain function in the setting of an acute stress event, such as surgery, sepsis or trauma. It is important to identify these risk factors that are present pre-operatively to help reduce the prevalence of delirium after transplant.

If cognitive dysfunction can predispose patients to delirium, an important question to answer when discussing delirium in transplant recipients is if surgery and/or anesthesia is an independent risk factor for post-operative cognitive defects (i.e. an unmodifiable risk factor for transplant recipients). A multicenter, prospective cohort study involving patients with surgical and nonsurgical critical illness was performed to evaluate if surgery and anesthesia was a risk factor for delirium. This study reported that surgery/anesthesia was not a risk factor for impairment of long-term global cognitive function or executive function after major non-cardiac surgery. In addition, increasing the level of exposure as measured by number of surgeries and duration of anesthesia was not associated with worse global cognitive or executive function. Cognitive impairment was highly prevalent at 3 and 12 months after hospital discharge in patients who suffered delirium. However, delirious patients who were exposed to general anesthesia and surgery suffered cognitive impairment at rates similar to those who did not undergo a surgical procedure. Postoperative cognitive impairment was associated with pre-existing cognitive deficits and level of education [3]. Based on these data, surgery and anesthesia does not appear to be an independent risk factor for delirium development and emphasizes the need for patient- and disease-focused risk stratification as transplant patients have many disease-specific risk factors that increase the incidence of delirium.

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**2.2 Screening**

*Delirium Management, Treatment and Prevention Solid Organ Transplantation*

Risk factors for delirium in patients undergoing liver transplantation include a history of alcohol abuse, pre-operative hepatic encephalopathy, pre-operative renal replacement therapy, intra-operative red blood cell transfusion volume and increasing Acute Physiologic and Chronic Health Evaluation II (APACHE II) scores upon intensive care unit admission. A study by Wang et al. showed that risk factors associated with delirium in liver transplant patients in the intensive care unit included history of alcohol abuse (Odds ratio: 6.40), preoperative hepatic encephalopathy (Odds ratio: 4.45), APACHE II score > 16 (Odds ratio: 1.73), and duration of endotracheal intubation for >5 days (Odds ratio: 1.81) [17]. Lescot et al. performed an observational study of liver transplant patients admitted to the intensive care unit after deceased donor transplant. Neither age nor etiology of cirrhosis was significantly associated with delirium [18]. Furthermore, delirium was not significantly associated with Model for End Stage Liver Disease score or Child-Pugh score. The median number of intraoperative transfused packed red blood cell units in patients with delirium was more than double that of in patients without delirium (P = 0.001). The risk of developing delirium was greater in patients with pre-transplant encephalopathy (P = 0.02) and in patients who underwent renal replacement therapy during the pretransplantation period (P < 0.01). In the logistic regression model, number of red blood cell transfusions, renal replacement therapy, and elevated APACHE scores were associated with increased risk of delirium. Interestingly, if a patient required renal replacement therapy, they had 13-fold greater odds of becoming delirious [18]. Haugen et al. evaluated 893 kidney transplant recipients and examined risk factors for developing postoperative delirium [9]. Risk factors in patients with end stage renal disease undergoing kidney transplantation include age greater than 65 (Odds ratio: 2.65, P = 0.004), frail patients (Odds ratio: 2.05, P = 0.04), and increasing comorbidities (two or more on the Charlson Comorbidity Index) (Odds ratio: 1.93 P = 0.05). In regards to delirium in pancreas transplant recipients, there are currently no organ specific factors detailed in the literature; however, the known risk factors for delirium associated with patients undergoing kidney transplantation can be theoretically applied to pancreas transplant recipients as these patients share

Post-operative factors that contribute to delirium include inadequate pain control, need for mechanical ventilation, sedation levels, benzodiazepine use, poor sleep hygiene, electrolyte disturbances, and infections. Medication used to treat common post-operative symptoms such as nausea including prochlorperazine or phenergan are associated with delirium. Benzodiazepines are also strongly associated with a higher risk of delirium and should only be used in very select circumstances at reduced doses in young patients with chronic home benzodiazepine use. Opioids increase delirium risk and should be used in moderation. Pain control should focus on multimodal treatment protocols with opioid sparing when applicable. Medications that alter the cholinergic neurotransmitter pathway, such as diphenhydramine, promethazine, tricyclic antidepressants or prochlorperazine are strongly associated with delirium development and should be avoided. In addition, immunosuppressive medications, such as calcineurin inhibitors and steroids, can be associated with mental status changes [19]. In transplant recipients at high risk for developing delirium or patients who have developed delirium, an important step in managing and optimizing these patients is to review the medication list to limit and

Early diagnosis of post-operative delirium is paramount for prompt management and minimization of risk for improved speed of recovery. There are several

*DOI: http://dx.doi.org/10.5772/intechopen.86297*

similar demographics and disease processes.

discontinue any deliriogenic medication.

#### *Delirium Management, Treatment and Prevention Solid Organ Transplantation DOI: http://dx.doi.org/10.5772/intechopen.86297*

Risk factors for delirium in patients undergoing liver transplantation include a history of alcohol abuse, pre-operative hepatic encephalopathy, pre-operative renal replacement therapy, intra-operative red blood cell transfusion volume and increasing Acute Physiologic and Chronic Health Evaluation II (APACHE II) scores upon intensive care unit admission. A study by Wang et al. showed that risk factors associated with delirium in liver transplant patients in the intensive care unit included history of alcohol abuse (Odds ratio: 6.40), preoperative hepatic encephalopathy (Odds ratio: 4.45), APACHE II score > 16 (Odds ratio: 1.73), and duration of endotracheal intubation for >5 days (Odds ratio: 1.81) [17]. Lescot et al. performed an observational study of liver transplant patients admitted to the intensive care unit after deceased donor transplant. Neither age nor etiology of cirrhosis was significantly associated with delirium [18]. Furthermore, delirium was not significantly associated with Model for End Stage Liver Disease score or Child-Pugh score. The median number of intraoperative transfused packed red blood cell units in patients with delirium was more than double that of in patients without delirium (P = 0.001). The risk of developing delirium was greater in patients with pre-transplant encephalopathy (P = 0.02) and in patients who underwent renal replacement therapy during the pretransplantation period (P < 0.01). In the logistic regression model, number of red blood cell transfusions, renal replacement therapy, and elevated APACHE scores were associated with increased risk of delirium. Interestingly, if a patient required renal replacement therapy, they had 13-fold greater odds of becoming delirious [18].

Haugen et al. evaluated 893 kidney transplant recipients and examined risk factors for developing postoperative delirium [9]. Risk factors in patients with end stage renal disease undergoing kidney transplantation include age greater than 65 (Odds ratio: 2.65, P = 0.004), frail patients (Odds ratio: 2.05, P = 0.04), and increasing comorbidities (two or more on the Charlson Comorbidity Index) (Odds ratio: 1.93 P = 0.05). In regards to delirium in pancreas transplant recipients, there are currently no organ specific factors detailed in the literature; however, the known risk factors for delirium associated with patients undergoing kidney transplantation can be theoretically applied to pancreas transplant recipients as these patients share similar demographics and disease processes.

Post-operative factors that contribute to delirium include inadequate pain control, need for mechanical ventilation, sedation levels, benzodiazepine use, poor sleep hygiene, electrolyte disturbances, and infections. Medication used to treat common post-operative symptoms such as nausea including prochlorperazine or phenergan are associated with delirium. Benzodiazepines are also strongly associated with a higher risk of delirium and should only be used in very select circumstances at reduced doses in young patients with chronic home benzodiazepine use. Opioids increase delirium risk and should be used in moderation. Pain control should focus on multimodal treatment protocols with opioid sparing when applicable. Medications that alter the cholinergic neurotransmitter pathway, such as diphenhydramine, promethazine, tricyclic antidepressants or prochlorperazine are strongly associated with delirium development and should be avoided. In addition, immunosuppressive medications, such as calcineurin inhibitors and steroids, can be associated with mental status changes [19]. In transplant recipients at high risk for developing delirium or patients who have developed delirium, an important step in managing and optimizing these patients is to review the medication list to limit and discontinue any deliriogenic medication.

#### **2.2 Screening**

Early diagnosis of post-operative delirium is paramount for prompt management and minimization of risk for improved speed of recovery. There are several

*Perioperative Care for Organ Transplant Recipient*

as benzodiazepines [13].

**2. Diagnosis**

**2.1 Risk factors**

Additional neurotransmitter imbalances associated with the development of delirium include dopamine, serotonin, and norepinephrine [1, 10]. Elevated levels of dopamine and norepinephrine are associated with hyperactive delirium [13]. Increased norepinephrine levels contribute to agitation, impaired attention and cerebral dysfunction. Increased serotonin levels are also linked to cerebral dysfunction and increased risk of delirium. Gamma-aminobutyric acid (GABA) is the primary neurotransmitter associated with inhibitory pathways in the brain. Dysregulation of GABA is associated with delirium. The administration of drugs that are mechanistically involved in activation or inhibition of the GABA receptor or altering levels of other important neurotransmitters are associated with delirium, and efforts should be made to minimize patient exposure to these medications, such

Overall, the pathophysiology linked to delirium is complex and incompletely understood. Importantly, delirium is the clinical manifestation that results from the interaction of multiple different dysfunctional systemic and cerebral physiologic pathways. As the understanding of the pathophysiology that leads to delirium improves, targeted pharmacologic agents can be developed and tested in clinical scenarios.

Delirium is a very common complication following transplantation. It is important to have an appreciation for the risk factors linked to delirium development in order to optimize preventive measures and allow for early diagnosis. Advancing age and baseline cognitive impairment are the most commonly described risk factors for developing delirium [14, 15]. Certain medical conditions can also predispose patients to delirium. Sleep apnea, heart failure, diabetes and frailty have been shown to increase the risk of developing delirium [16]. Patients with lower cognitive and functional reserve likely have a reduced ability to maintain normal brain function in the setting of an acute stress event, such as surgery, sepsis or trauma. It is important to identify these risk factors that are present pre-operatively to help

If cognitive dysfunction can predispose patients to delirium, an important question to answer when discussing delirium in transplant recipients is if surgery and/or anesthesia is an independent risk factor for post-operative cognitive defects (i.e. an unmodifiable risk factor for transplant recipients). A multicenter, prospective cohort study involving patients with surgical and nonsurgical critical illness was performed to evaluate if surgery and anesthesia was a risk factor for delirium. This study reported that surgery/anesthesia was not a risk factor for impairment of long-term global cognitive function or executive function after major non-cardiac surgery. In addition, increasing the level of exposure as measured by number of surgeries and duration of anesthesia was not associated with worse global cognitive or executive function. Cognitive impairment was highly prevalent at 3 and 12 months after hospital discharge in patients who suffered delirium. However, delirious patients who were exposed to general anesthesia and surgery suffered cognitive impairment at rates similar to those who did not undergo a surgical procedure. Postoperative cognitive impairment was associated with pre-existing cognitive deficits and level of education [3]. Based on these data, surgery and anesthesia does not appear to be an independent risk factor for delirium development and emphasizes the need for patient- and disease-focused risk stratification as transplant patients have many disease-specific risk factors that increase the incidence of delirium.

reduce the prevalence of delirium after transplant.

**130**

validated screening tools for assessing for the presence of delirium. The gold standard for diagnosis of delirium is a formal evaluation performed by a psychiatrist using The Diagnostic and Statistical Manual of Mental Disorders criteria; however, the application and feasibility of a formal psychiatric evaluation is not clinically practical [1]. More commonly used methods of delirium screening utilize nursing expertise for frequent and consistent bedside screening. The Richmond Agitation Sedation Scale (RASS) is a widely used screening tool to evaluate and communicate patients' level of sedation and arousal [20]. With an appropriate level of consciousness, there are many validated tools for delirium screening. Importantly, a patient must be arousable to voice (i.e. RASS score of −1) to be able to screen for delirium. The most commonly used tool for screening is the Confusion Assessment Method for Intensive Care Unit (CAM-ICU) [21]. The CAM-ICU (**Figure 2**) is an abbreviated version of the Confusion Assessment Method. The CAM-ICU tool screens for acute changes in mental status, inattention, disorganized thinking and altered level of consciousness in a condensed approach ideal for a fast paced clinical setting. The CAM-intensive care unit screening tool requires less than 2 min to complete and in addition to being rapidly applied, has been shown to be 93% sensitive and 98% specific for diagnosing delirium [21].

Other screening tools include the Nursing Delirium Symptom Checklist (NuDESC) [22], Confusion Assessment method (CAM) [23] and the Intensive Care Delirium Screening Checklist (ICDSC) [24]. The multiple, validated tools available speaks to the importance for using a tool of any type to achieve consistent screening. More important than which tool to use is having a program in place for regular, routine, and consistent screening. If delirium is not screened for using a validated screening tool, delirium may be missed up to 75% of the time [25–28], especially in the setting of hypoactive delirium. Given the fluctuating course of critically

**133**

*Delirium Management, Treatment and Prevention Solid Organ Transplantation*

etiologies and ultimately directed delirium management.

ill patients and delirium, it is important that screening be performed in a serial, repeatable and consistent manner to achieve timely diagnosis and prevent under diagnosis. Routine implementation of validated screening tools allows for rapid and dependable evaluation and subsequent work up to identify potential underlying

Following a positive screening evaluation for delirium, working through a differential diagnosis to identify treatable underlying causes is essential. In the transplant population in the setting of immunosuppression, infection is an extremely important diagnosis to consider and rule out in a timely manner. Immunosuppressed patients do not have a robust systemic inflammatory response as compared to non-immunosuppressed, post-operative patients, so infections present in a more discreet and subtle manner, often with mental status changes as the only clinical symptomatology. In a patient with new onset delirium, initial work up should include a comprehensive laboratory evaluation including a complete blood count, comprehensive metabolic panel, liver function tests, lipase and amylase. In the post-transplant recipient where renal dysfunction and electrolyte fluctuations are common, a basic metabolic panel should also be obtained to ensure that uremia or an underlying electrolyte disturbance is not present. Hormone dysregulation should also be considered as a cause of delirium with laboratory evaluation of thyroid function and the pituitary–adrenal axis. The patient's medication list should also be reviewed to ensure that medication toxicity is not contributing or exacerbating the mental status changes. However, in the immunosuppressed, post-operative transplant recipient with clinical decompensation highlighted by new onset mental

status changes, sepsis needs to be at the top of the differential diagnosis.

underlying infection is contributing to the mental status changes.

to determine if percutaneous drainage or open drainage is needed.

Mental status changes are often the initial presenting symptom of an underlying infection or sepsis in the transplant population. Blood cultures, urine cultures, and a chest x-ray should be obtained to rule out bacteremia, urinary tract infection or pneumonia, respectively. In addition, based on the operative details and time since surgery, cross sectional axial imaging should be considered to rule out a deep space infection or other possible surgical complications. Importantly, early initiation of broad-spectrum antibiotics is strongly recommended if there is any concern that an

If surgical drains are present, evaluating the character of the abdominal fluid is important to rule out intra-abdominal pathology. Organ specific evaluation of surgical drains is an important step in evaluating for potential infectious sources. In the setting of liver transplant, drains should be evaluated for elevated bilirubin to rule out a biloma and anastomotic biliary complication. In pancreas recipients, drain amylase and bilirubin should be obtained to evaluate for a pancreatic parenchyma leak and/or an enteric anastomotic leak. If clinically applicable in kidney transplant recipients, drain fluid should be checked for creatinine to evaluate for a possible urine leak. Drain fluid studies should be correlated with high resolution, axial imaging to further define the anatomic location of potential fluid collections

Furthermore, the work up should include placing the patient on a pulse oximeter to obtain an oxygen saturation and obtain an arterial blood gas to ensure that hypoxia or hypercarbia is not causing or contributing to the mental status changes. Myocardial infarctions and cerebral vascular events can also present with delirium. An electrocardiography, troponins and a possible echocardiography should be obtained if there is a concern for a cardiac event. If there is clinical suspicion for a stroke based on neurologic exam, a non-contrast and subsequently

*DOI: http://dx.doi.org/10.5772/intechopen.86297*

**2.3 Delirium work up**

#### **Figure 2.**

*Delirium screening tool and flowchart outlining the confusion assessment method for the intensive care unit [2].*

ill patients and delirium, it is important that screening be performed in a serial, repeatable and consistent manner to achieve timely diagnosis and prevent under diagnosis. Routine implementation of validated screening tools allows for rapid and dependable evaluation and subsequent work up to identify potential underlying etiologies and ultimately directed delirium management.
