Neurotransmitters

From a neuroscience perspective, delirium is thought to be related to imbalances in the synthesis, release, and inactivation of neurotransmitters modulating the control of cognitive function, behavior, and mood.26,32 Three of the neurotransmitter systems involved in the pathophysiology of delirium are dopamine, γ-aminobutyric acid (GABA), and acetylcholine.^15,51,52 Whereas dopamine increases excitability of neurons, GABA and acetylcholine decrease neuronal excitability.¹⁵ An imbalance in one or more of these neurotransmitters results in neuronal instability and unpredictable neurotransmission. In general, an excess of dopamine and depletion of acetylcholine are two major physiologic problems believed to be central to delirium.⁵³ Other neurotransmitter systems thought to be involved in the development of delirium are serotonin imbalance, endorphin hyperfunction, and increased central noradrenergic activity.^26,51

Inflammatory Mediators

Other factors thought to be mechanistically deliriogenic in ICU patients are inflammatory abnormalities induced by endotoxins and cytokines.54–57 The inflammatory mediators produced in sepsis, such as tumor necrosis factor-α (TNF-α), interleukin 1, and other cytokines and chemokines, initiate a cascade that leads to endothelial damage, thrombin formation, and microvascular compromise.⁵⁸ Animal models show that these inflammatory mediators cross the blood-brain barrier,⁵⁹ increase vascular permeability in the brain,⁶⁰ and result in electroencephalography (EEG) changes consistent with those seen in septic patients with delirium.^61,62 Release of inflammatory mediators may occur from (1) decreased cerebral blood flow, a result of the formation of microaggregates of fibrin, platelets, neutrophils, and erythrocytes in the cerebral microvasculature, (2) cerebral vasoconstriction occurring in response to (α₁-adrenergic receptor activity⁶³; or (3) interference with neurotransmitter synthesis and neurotransmission.⁶⁴

Impaired Oxidative Metabolism

One hypothesis attempts to explain acute delirium as a behavioral manifestation of a “widespread reduction of cerebral oxidative metabolism resulting in an imbalance of neurotransmission.”⁶⁵ On the basis of a series of investigations in which they evaluated delirious patients using EEG, Engel and Romano⁶⁶ postulated that delirium is a state of “cerebral insufficiency,” that is, a global failure of cerebral oxidative metabolism. Their work showed that delirium is associated with diffuse slowing on EEG, a finding believed to represent a reduction in brain metabolism.

Cholinergic Deficiency

Blass and colleagues⁶⁷ offered a possible link between the state of cerebral insufficiency proposed by Engel and Romano⁶⁶ and the hypothesis of cholinergic blockade by suggesting that impaired oxidative metabolism in the brain results in a cholinergic deficiency. The finding that hypoxia impairs acetylcholine synthesis supports this hypothesis.⁶⁸ This reduction in cholinergic function leads to an increase in the level of glutamate, dopamine, and norepinephrine in the brain. Additionally, serotonin and GABA levels are reduced; all of these changes contribute to delirium.

Large Neutral Amino Acid in Delirium

Changes in the plasma levels of various amino acid precursors of cerebral neurotransmitters may affect their function, thus contributing to the development of delirium.⁶⁹ The amino acid entry into the brain is regulated by a sodium-independent large neutral amino acid transporter type 1 (LAT1).⁷⁰ The essential amino acid tryptophan, which is the precursor for serotonin, competes with several large neutral amino acids (LNAAs), such as tyrosine, phenylalanine, valine, leucine, and isoleucine, for transport across the blood-brain barrier via the LAT1 transporter.⁷⁰ This competition determines its uptake into the brain.⁷⁰ Recently, alterations in plasma tryptophan and tyrosine levels were identified as independent risk factors for the transition to clinical delirium.⁷¹ Increased activation of the kynurenine pathway, which is involved in the metabolism of tryptophan and the formation of neurotoxins, has also been linked to fewer days alive and without acute brain dysfunction in critically ill patients.⁷² Another amino acid that may play an important role in the pathogenesis of delirium is phenylalanine.⁶⁵ Like tryptophan, phenylalanine competes with the other LNAAs (tyrosine, tryptophan, valine, leucine, and isoleucine) for transport across the blood-brain barrier. An increase in the cerebral uptake of tyrosine and phenylalanine compared with the other LNAAs leads to greater availability of precursors for both dopamine and norepinephrine, two neurotransmitters that have been implicated in the pathogenesis of delirium.⁶⁵

Inflammation

It is important to realize that although delirium may occur as a result of perturbations in other organ systems, the brain responds to systemic infections and injury with an inflammatory response of its own that also involves cytokine production, cell infiltration, and tissue damage.73,74 Reports indicate that local inflammation in the brain and subsequent activation of these central nervous system immune responses are accompanied by manifestations of systemic inflammation,^52,75,76 including production of large amounts of peripherally produced TNF-α, interleukin 10, and interferon-γ.^73,77–79 Thus, it is postulated that the brain can become an engine of inflammation, driving the development, resolution, or both, of MODS. Van Gool and associates propose that this self-propelling inflammation, in the context of microglial activation, could help explain the association between delirium and LTCI.⁸⁰ Surprisingly, van Gool points out that animal models have shown activated microglia can remain primed for months following injury, allowing ample time for ongoing injury long beyond the period of an ICU stay. This factors into hypothesis generation when designing neuroimaging studies in ICU survivors and will serve as fascinating topics for future study.

Sedatives and Analgesic Agents Contributing to Delirium

Sedative and analgesic medications are routinely administered to patients undergoing mechanical ventilation, in accordance with widely recognized clinical practice guidelines by the Society of Critical Care Medicine (SCCM),⁸⁹ in order to reduce pain and anxiety. Investigations have shown that continuous intravenous sedation is associated with prolonged mechanical ventilation and greater morbidity.⁹⁰ Similarly, associations between psychoactive medications and worsening cognitive outcomes have been reported in postoperative patients. Marcantonio and colleagues,⁹¹ studying postoperative patients in whom delirium developed, found an association between use of benzodiazepines and meperidine and the occurrence of delirium. Dubois and coworkers⁸³ have shown that opiates (morphine and meperidine) administered either intravenously or via an epidural catheter may be associated with the development of delirium in medical/surgical ICU patients. Studies such as these have generated concern about whether such drugs were actually responsible for the development of delirium or were given as a result of delirium.

Our group has studied this temporal relationship between the administration of sedatives and analgesics and delirium.⁹² To do so, one must make repeated cognitive assessments and must be able to assess the risk factors a patient is exposed to in between these assessments in order to study which of these factors is associated with a transition or a change in cognitive status to or from normal, delirium, or coma. In our study, lorazepam was found to be an independent risk factor for daily transition to delirium, and fentanyl, morphine, and propofol were associated with higher but not statistically significant odds ratios for such transition (Fig. 72.1).⁹² Increasing age and APACHE II (Acute Physiology and Chronic Health Evaluation II) scores were also independent predictors of transitioning to delirium (Figs. 72.2 and 72.3).⁹² Similar associations between another benzodiazepine, midazolam, and transition to delirium have been found in another study conducted in our trauma and surgical ICU patients.²¹

At this time it is not clear whether this association between benzodiazepines, and possibly opioids, and delirium is related to the pharmacokinetic properties of the agents or the pharmacodynamics of the drug. Benzodiazepines and propofol have high affinity for the GABA receptor in the central nervous system.⁹³ This GABA-mimetic effect can alter levels of numerous neurotransmitters believed to be deliriogenic.^64,94 Novel sedative agents that are GABA receptor-sparing (such as the α₂-agonists) may help reduce some of the cognitive dysfunction seen in ICU patients. It is important to note that the data for opioids and delirium are not as consistent as those for the benzodiazepines. Although meperidine has been associated with delirium in most of the published studies, evidence for both fentanyl and morphine has been less convincing.^83,91,95 Morrison and colleagues⁹⁵ conducted a prospective observational trial in patients who had undergone hip surgery and found that patients whose pain was well controlled with morphine were less likely to demonstrate delirium than those who received other opioids. These investigations point to the importance of the judicious use of psychoactive medications, with a focus on adequate analgesia.⁹⁶ One hopes that ongoing randomized controlled trials will pave the way to the development of sedation and analgesic guidelines for the prevention or reduction of the occurrence of delirium due to the administration of these psychoactive drugs.

Primary Prevention and Nonpharmacologic Approaches

In a trial of 852 general medical patients older than 70 years,¹⁰¹ implementation of strategies for primary prevention of delirium resulted in a 40% reduction in the odds for development of delirium (15% in control subjects vs. 9.9% in the intervention patients). The protocol focused on optimization of risk factors via the following methods: repeated reorientation of the patient by trained volunteers and nurses, provision of cognitively stimulating activities for the patient three times per day, a nonpharmacologic sleep protocol to enhance normalization of sleep/wake cycles, early mobilization activities and range-of-motion exercises, timely removal of catheters and physical restraints, institution of the use of eyeglasses and magnifying lenses, use of hearing aids and earwax disimpaction, and early correction of dehydration.¹⁰¹ Unfortunately, this intervention did not show sustained benefit during the 6 months of follow-up.¹⁰² Later studies of delirium were unable to reproduce this success in reducing the incidence of delirium.^103,104

Milisen and associates¹⁰⁵ and Lundstrom and coworkers,¹⁰⁶ who studied the implementation of multifactorial and multidisciplinary educational strategies, reported decreases in the duration and severity of delirium in patients cared for by staff who had received delirium-specific education.^105,106 Milisen and associates¹⁰⁵ measured the impact on delirium of implementing a nurse-led intervention program that involved delirium education for the nursing staff, systematic cognitive screening, availability of consultative services from a delirium resource nurse, and scheduled pain protocol on delirium. These researchers reported that although the program had no effect on the incidence of delirium, the duration and severity of delirium were significantly lower.¹⁰⁵ Lundstrom and coworkers¹⁰⁶ reported that in patients on a ward where the staff participated in specific educational activities focused on delirium and where the bedside nursing care was reorganized to provide more continuity of patient-centered care, duration of delirium and hospital stay were shorter and mortality rate was lower than in control patients. Cole and colleagues¹⁰⁴ found no difference in delirium rates between patients cared for by an intervention nurse and patients who received standard care. All of these nonpharmacologic “protocolization of care” studies focused on non-ICU patient populations. Clearly such investigations must be designed and conducted in the ICU (rather than simply extrapolated from non-ICU studies).

Although primary prevention of delirium is preferred, some delirium is inevitable in the ICU. In patients exhibiting delirium, the basic tenets of patient management, such as restoration of sleep/wake cycles, timely removal of catheters, early mobilization, minimization of unnecessary noise/stimuli, and frequent reorientation, should be applied liberally. Additionally, it should be emphasized that although sedative and analgesic agents have a very important role in patient comfort, health care professionals must also strive to achieve the right balance of administering these drugs through greater focus on reducing unnecessary or overzealous use. Instituting daily interruption of sedatives and analgesics, protocolizing their delivery, and instituting target-based sedation have all been shown to improve patient outcomes, although the studies reporting these results have not specifically looked at delirium rate or duration.107–109 Studies have also shown a benefit for pain control using morphine in the prevention of delirium, because pain itself can be a risk factor for the development of delirium. Family involvement can also be very helpful in reorienting and soothing some delirious patients. It is important to teach family members about the fluctuating course of delirium as well as how they can detect it. Preventive and management strategies for delirium in the ICU represent an important area for future investigation.

Pharmacologic Therapy

Medications should be used for delirium only after adequate attention has been given to correction of modifiable contributing factors (e.g., sleep disturbance, restraints), as discussed previously. It is important to remember that delirium could be a manifestation of an acute, life-threatening problem that requires immediate attention (such as hypoxia, hypercarbia, hypoglycemia, metabolic derangement, or shock). After such concerns have been addressed, pharmacologic management should be considered. It should be recognized that although agents used to treat delirium are intended to improve cognition, they all have psychoactive effects that may further cloud the sensorium and promote a longer overall duration of cognitive impairment. Therefore, until we have outcomes data that confirm beneficial effects of treatment, these drugs should be used judiciously in the smallest possible dose and for the shortest time necessary, a practice infrequently adhered to in most ICUs. Indeed, some cases prove refractory to all “cocktail” approaches to sedation and delirium therapy, and in these cases, a trial of complete cessation of all psychoactive drugs should be considered. Some reports have described the utility of dexmedetomidine (an α₂-agonist) as an adjunct to assist with weaning patients from all psychoactive medications.¹¹⁰ Preliminary results from a prospective, randomized, yet unblinded trial in postoperative patients who had undergone cardiac surgery showed that sedation with dexmedetomidine at sternal closure was associated with an 8% incidence of postoperative delirium compared with 50% for either propofol or benzodiazepines.¹¹¹

Benzodiazepines, which are used most commonly in the ICU for sedation, are not recommended for the management of delirium because of the likelihood of oversedation, exacerbation of confusion, and respiratory suppression. However, they remain the drugs of choice for the treatment of delirium tremens (and other withdrawal syndromes) and seizures. The amnestic qualities of benzodiazepines make these agents especially useful when noxious or unpleasant procedures are required. It is likely, however, that residual accumulation of these drugs may lead to prolonged delirium long after they have been discontinued. In certain populations, particularly elderly patients with underlying dementia, benzodiazepines may increase confusion and agitation. In such cases, one may try to take advantage of the sedative effects of haloperidol in lieu of continuing the benzodiazepine therapy.

Currently, no drugs are approved by the U.S. Food and Drug Administration (FDA) for the treatment of delirium. The SCCM guidelines⁸⁹ recommend haloperidol as the drug of choice, with the acknowledgment that this recommendation is based on sparse outcome data from nonrandomized case series and anecdotal reports (i.e., level C data). Nevertheless, haloperidol is a “typical” butyrophenone antipsychotic, which is the most widely used neuroleptic agent for delirium.¹¹² It does not suppress the respiratory drive and works as a dopamine receptor antagonist by blocking the δ₂-opioid receptor, resulting in treatment of positive symptoms (hallucinations, unstructured thought patterns, etc.) and producing a variable sedative effect. There are data to suggest that haloperidol may have some anti-inflammatory properties,^113,114 though this is theoretical in terms of a helpful pharmacologic effect on disease (such as septic delirium) at this point and requires further study.

In the non-ICU setting, the recommended starting dose of haloperidol is 0.5 to 1.0 mg orally or parenterally, with repeated doses every 20 to 30 minutes until the desired effect is achieved. In the ICU, a recommended starting dose would be 2 to 5 mg every 6 to 12 hours (intravenous, intramuscular, or oral), with maximal effective doses usually in the neighborhood of 20 mg/day. This dose range will usually be adequate to achieve the “theoretically optimal” 60% δ₂-receptor blockage¹¹⁵ while avoiding complete δ₂-receptor saturation associated with the adverse effects cited later. Because of the urgency of the situation in many ICU patients—due to the potential for inadvertent removal of central lines, endotracheal tubes, or even aortic balloon pumps—much higher doses of haloperidol or a sedative are often used. Unfortunately, there are few data from formal pharmacologic investigations to guide dosage recommendations in the ICU. Once calm, the patient can usually be managed with much lower maintenance doses of haloperidol.

Neither haloperidol nor similar agents (i.e., droperidol and chlorpromazine) have been extensively studied for ICU use.⁸⁹ Newer “atypical” antipsychotic agents (e.g., risperidone, ziprasidone, quetiapine, and olanzapine) may also prove helpful for delirium.¹¹⁶

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