**1.2 Prevalence**

The prevalence of delirium is highly variable based on the population being evaluated. It has been reported to occur in 16–89% of hospitalized patients, and up to 50% of post-operative patients [5, 6]. Delirium is the most common manifestation of acute brain dysfunction during critical illness. Reports note that delirium affects 50–75% of patients who receive medical ventilation in the intensive care unit [5]. The prevalence in the transplant population has been reported to range from 12 to 47% of patients [7]. Patients undergoing liver transplant have a higher prevalence of developing delirium than other abdominal transplant recipients occurring in

**129**

medications.

*Delirium Management, Treatment and Prevention Solid Organ Transplantation*

approximately 45% of the liver recipients [8]. In a recent report by Haugen et al. only 0.8% of kidneys transplant recipients developed delirium [9]. The difference in prevalence of delirium in abdominal transplant recipients needs to be considered when developing preventive strategies to provide targeted interventions on high-

The pathophysiology associated with delirium development is multifactorial and is associated with complex interactions between systemic and cerebral physiology. The precise mechanisms are still being investigated, however many hypotheses exist for the underlying precipitating factor(s) that lead to delirium development. Examples of different hypotheses include inflammatory-mediated neuronal injury, altered cerebral perfusion, increased permeability of the blood brain barrier from endothelial dysfunction, and altered neurotransmitter balance [10]. In addition, the anatomic changes associated with advanced age including cerebral atrophy and changes in white matter density have been considered to contribute to the underlying mechanism of delirium, and also represent risk factors for delirium development [11]. Delirium pathophysiology is also believed to be associated with the systemic inflammatory cascade that occurs as a result of the stress response following an acute event, trauma or surgical intervention. The release of inflammatory mediators and cytokines (cortisol, c-reactive protein, interleukin-6, interleukin-8, etc.) following surgery likely play a significant role in the pathophysiologic link between surgery and delirium development [10]. Microglial cells have an intimate involvement in mediating the cerebral inflammatory response that occurs as a result of the systemic inflammatory response following surgery. The microglial cells up regulate the production of pro-inflammatory cytokines, which lead to disturbances in cognitive function and alterations in cerebral activity. In addition, over-activation of microglial cells can lead to neuronal apoptosis [10]. Thus, understanding the cellular and molecular pathways associated with microglial physiology may provide

opportunities for intervention and targeted therapy for delirium treatment. Endothelial cells serve as integral components of a competent blood brain barrier; however, in the setting of stress, surgery, inflammation, etc., endothelial function is altered leading to a reduction in the integrity of the highly selective blood brain barrier. This increases the risk of cerebral dysfunction and delirium development. Hughes et al. assessed biomarkers associated with the integrity of the blood brain barrier and endothelial dysfunction, and found that elevations in S1008, E-selectin and plasminogen activator-1 were associated with delirium in critical illness [12]. Endothelial dysfunction also up-regulates the coagulation pathways leading to microvascular thrombi formation, which consequently alters

Delirium is also linked to neurotransmitter dysfunction and deregulation. Acetylcholine is an important modulator of the systemic inflammatory response by decreasing the number of inflammatory cytokines. Critical illness and surgical stress create a physiologic environment that leads to depletion of acetylcholine stores and availability. A lack of acetylcholine receptor activation on the surface of microglial cells causes a lack of inhibition and leads to hyperactivation of microglial cells [10]. The acetylcholine association with delirium explains the pathophysiology involved with the increased risk of delirium in patients receiving anti-cholinergic medications. These medications exacerbate the depleted stores of acetylcholine that is associated with stress and post-surgical states. Hence, an important component of post-operative delirium prevention is to avoid the use of anti-cholinergic

cerebral blood flow further leading to cerebral dysfunction.

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

risk populations.

**1.3 Pathophysiology**

**Figure 1.** *Clinical symptomatology associated with delirium.*

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

approximately 45% of the liver recipients [8]. In a recent report by Haugen et al. only 0.8% of kidneys transplant recipients developed delirium [9]. The difference in prevalence of delirium in abdominal transplant recipients needs to be considered when developing preventive strategies to provide targeted interventions on highrisk populations.

### **1.3 Pathophysiology**

*Perioperative Care for Organ Transplant Recipient*

disorder. Delirium is characterized by reduced capacity to direct, focus, sustain, or shift attention, as well as reduced orientation to the environment [1, 3]. These symptoms must present acutely and fluctuate throughout the day. Importantly, the diagnosis of delirium identifies the constellation of symptoms representing altered

Delirium can be classified into three subtypes based on psychomotor behavior: hyperactive, hypoactive and mixed type delirium. Delirium is under diagnosed due to inconsistent screening, but also because delirium has varying and inconsistent presentations especially in patients suffering from hypoactive delirium. Hypoactive delirium is characterized by slowed mentation, lethargy, and decreased movement, whereas hyperactive delirium is marked by agitated behavior, confusion and difficulty with re-orientation. Without consistent, evidence-based screening methods, hypoactive delirium is more likely to be overlooked compared to hyperactive delirium. In addition, the different forms of delirium carry different prognosis. In a study of patients admitted to the intensive care unit after elective operations, patients that suffered from hypoactive delirium had an increased six-month mortality compared to patients with other subtypes of delirium (32 vs. 8.7%, P = 0.04) [4]. Therefore, it is important understand the various forms of delirium and the clinical

scenarios in which it can present to allow timely diagnosis and management.

The prevalence of delirium is highly variable based on the population being evaluated. It has been reported to occur in 16–89% of hospitalized patients, and up to 50% of post-operative patients [5, 6]. Delirium is the most common manifestation of acute brain dysfunction during critical illness. Reports note that delirium affects 50–75% of patients who receive medical ventilation in the intensive care unit [5]. The prevalence in the transplant population has been reported to range from 12 to 47% of patients [7]. Patients undergoing liver transplant have a higher prevalence of developing delirium than other abdominal transplant recipients occurring in

brain function, but does not identify the etiology (**Figure 1**).

**128**

**Figure 1.**

*Clinical symptomatology associated with delirium.*

**1.2 Prevalence**

The pathophysiology associated with delirium development is multifactorial and is associated with complex interactions between systemic and cerebral physiology. The precise mechanisms are still being investigated, however many hypotheses exist for the underlying precipitating factor(s) that lead to delirium development. Examples of different hypotheses include inflammatory-mediated neuronal injury, altered cerebral perfusion, increased permeability of the blood brain barrier from endothelial dysfunction, and altered neurotransmitter balance [10]. In addition, the anatomic changes associated with advanced age including cerebral atrophy and changes in white matter density have been considered to contribute to the underlying mechanism of delirium, and also represent risk factors for delirium development [11].

Delirium pathophysiology is also believed to be associated with the systemic inflammatory cascade that occurs as a result of the stress response following an acute event, trauma or surgical intervention. The release of inflammatory mediators and cytokines (cortisol, c-reactive protein, interleukin-6, interleukin-8, etc.) following surgery likely play a significant role in the pathophysiologic link between surgery and delirium development [10]. Microglial cells have an intimate involvement in mediating the cerebral inflammatory response that occurs as a result of the systemic inflammatory response following surgery. The microglial cells up regulate the production of pro-inflammatory cytokines, which lead to disturbances in cognitive function and alterations in cerebral activity. In addition, over-activation of microglial cells can lead to neuronal apoptosis [10]. Thus, understanding the cellular and molecular pathways associated with microglial physiology may provide opportunities for intervention and targeted therapy for delirium treatment.

Endothelial cells serve as integral components of a competent blood brain barrier; however, in the setting of stress, surgery, inflammation, etc., endothelial function is altered leading to a reduction in the integrity of the highly selective blood brain barrier. This increases the risk of cerebral dysfunction and delirium development. Hughes et al. assessed biomarkers associated with the integrity of the blood brain barrier and endothelial dysfunction, and found that elevations in S1008, E-selectin and plasminogen activator-1 were associated with delirium in critical illness [12]. Endothelial dysfunction also up-regulates the coagulation pathways leading to microvascular thrombi formation, which consequently alters cerebral blood flow further leading to cerebral dysfunction.

Delirium is also linked to neurotransmitter dysfunction and deregulation. Acetylcholine is an important modulator of the systemic inflammatory response by decreasing the number of inflammatory cytokines. Critical illness and surgical stress create a physiologic environment that leads to depletion of acetylcholine stores and availability. A lack of acetylcholine receptor activation on the surface of microglial cells causes a lack of inhibition and leads to hyperactivation of microglial cells [10]. The acetylcholine association with delirium explains the pathophysiology involved with the increased risk of delirium in patients receiving anti-cholinergic medications. These medications exacerbate the depleted stores of acetylcholine that is associated with stress and post-surgical states. Hence, an important component of post-operative delirium prevention is to avoid the use of anti-cholinergic medications.

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 as benzodiazepines [13].

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.
