Chronic lymphocytic leukemia

Altered Mental Status: Delirium and ComaDr. Mohammad Aljawadi PharmD, Msc, PhDPHCL 478Clinical Pharmacy DepartmentCollege of Pharmacy King Saud UniversityAPRIL 2015In ICUs: This is what we usually see

This is what might happeningIntroduction Altered mental status is very common in ICUsSevere disease processes Iatrogenic Altered metal status can be due to brain dysfunctionAcute: Coma and Delirium Chronic: Subsequent long-term cognitive impairment after discharge In ICU: Acute Brain Dysfunction Coma is characterized by unresponsiveness to physical or verbal stimuli.Delirium is an acute and fluctuating disorder of consciousness characterized by inattention, disorganized thinking, and perceptual disturbances with hypoactive and hyperactive subtype

Acute Brain Dysfunction

EtiologyDespite increasing research in the field, the multifactorial pathophysiological processes of delirium and coma remain poorly understood. Numerous hypotheses: Neurotransmitter imbalance (eg, dopamine, -aminobutyric acid, and acetylcholine) Inflammatory perturbations (eg, tumor necrosis factor-, interleukin-1, and other cytokines and chemokines)Impaired oxidative metabolismCholinergic deficiencyChanges in various amino acid precursors

IncidenceThe incidence of acute brain dysfunction is common in the ICUBetween 50% and 80% of patients with critical illness developing delirium depending on the severity of illness and the need for mechanical ventilationStill underdiagnosed Consequences of Acute Brain DysfunctionLonger weaning time from mechanical ventilatorPatients without delirium compared to those with delirium (3.6 days vs. 10.7days)Increased Hospital length of Stay ( an additional 1.18 days compared to non-delirious patients)Increased ICU mortality Increased Readmission after hospital discharge Higher ICU and hospital costs

Delirium and MortalityDeath among patients without delirium compared to those with delirium (15 of 126 [11.9%] vs. 69 of 228 [30.3%])Each additional day of delirium increases the risk of dying.

Number of delirious days was associated with increased risk of 1 year post-ICU mortality (hazard ratio, 1.10; 95% confidence interval, 1.021.18).

Days in ICUHazard of Death 1HR: 1.70; (95% CI, 1.27-2.29)2HR: 2.69; (95%CI, 1.58-4.57)3HR: 3.37; (95%CI, 1.92-7.23)Consequences of brain dysfunction after discharge Among patients who survive their critical illness, up to 75% experience long-term cognitive impairmentLonger periods of acute brain dysfunction in the hospital are associated with greater degrees of cognitive decline 1 year after hospital dischargeDiagnosis of Acute Brain DysfunctionTo diagnose delirium in the ICU:The validation of the Confusion Assessment Method for the ICU (CAM-ICU)The Intensive Care Delirium Screening Checklist (ICDSC)Many scales are used to assess the level of sedation and agitation of patients in ICU:Ramsay scaleRiker Sedation-Agitation ScaleMotor activity assessment scaleGlasgow Coma ScaleRichmond Agitation-Sedation Scale (RASS)

We use one of these with CAM-ICU or ICDSC to diagnose delirium

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FYIRiker Sedation-Agitation Scale

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Diagnosis criteria To diagnose delirium:RASS score of 3 or higher ( -2 , -1, 1, 2, 3, 4)Feature 1 of CAM-ICU (acute change or fluctuation in mental status)Feature 2 of CAM-ICU (inattention) One of the following: Feature 3 (disorganized thinking) OR Feature 4 (altered level of consciousness of CAM-ICU)Diagnosis criteria Coma:RASS score of -4 or -5

Risk factors:

Source: Delirium in the intensive care unit;Timothy D Girard, Pratik P Pandharipande,andE Wesley ElyLet us focus on themIn the only study to date to examine whether there is agenetic predisposition to ICU delirium in some patients, Elyand coworkers [38] evaluated the association betweenapolipoprotein E (APOE) genotype and duration of deliriumamong 53 mechanically ventilated medical ICU patients.Patients with the APOE4 polymorphism (a risk factor forAlzheimers disease) were delirious for twice as long as thosewithout the APOE4 polymorphism (median [interquartilerange]: 4 [3 to 4.5] days versus 2 [1 to 4] days; P = 0.05).Larger studies are ongoing to confirm this association.

23Psychoactive Medications The temporal association of psychoactive medications with delirium in critically ill patients has been examined in different ICU cohortAmong mechanically ventilated patients: Lorazepam be an independent risk factor for the daily development of delirium Propofol, morphine, and fentanyl were associated with higher but not statistically significant odds ratios for delirium development in the same cohort. In surgical, trauma, and burn ICU patients, midazolam has been associated with increased delirium incidence.Delirium potential: Benzodiazepines vs. Opioids ?

Delirium potential: Benzodiazepines vs. Opioids ?Opioids:The effects on acute brain dysfunction are not as consistently demonstrated as the effects of benzodiazepines.Insufficient pain relief has been shown to be a risk factor for delirium In a prospective cohort study that enrolled delirium free-patients with hip fractures,:Doses 10 mg a day.

Thus, opiates may be protective of acute brain dysfunction in patients at high risk for pain but may be detrimental if used excessively to achieve sedation.

Depth of sedation: The dilemma between too much or to littleDepth of sedation: The dilemma between too much or to littleUnder-sedation and inadequate pain relief:Hyperactive stress responseTachycardia, increased oxygen consumption, hypercoagulability, immunosuppression, hypermetabolism, and increased endogenous catecholamine activity.Agitation can lead to the removal of medical devices (e.g., endotracheal tubes, intravascular lines), creating life-threatening situations. Posttraumatic stress disorder (PTSD) after discharge Over-sedation is the norm in ICUs, however, it has its own consequences: Higher probability of developing deliriumLonger duration of mechanical ventilation and ICU length of stayIncreased use of radiological evaluations of mental statusThe presence of burst suppression on electroencephalograms, associated with deep sedation, has been shown to be an independent predictor of mortality in critically ill patientsDepth of sedation: The dilemma between too much or to littleTo reduce deep sedation, multiple strategies have been evaluated to decrease patients psychoactive drug exposure.Target-based sedationProtocolizing sedative drug deliveryDaily interruptions of sedationsdecrease sedative administration and improve patient outcomesThe Awakening and Breathing Controlled Trial:Spontaneous Breathing Trials (SBTs)Spontaneous Awakening Trials (SATs) + SBTOutcomes:Spontaneous breathingICU discharge Hospital DischargeSelf-extubation 12-months mortalitySedation discontinuation based on a pre-specified protocol Mechanically Ventilated Patients The Awakening and Breathing Controlled Trial:Patients in the intervention group were :spontaneously breathing more than the control group (147 days vs. 116 days; mean diference 31 days, 95% CI 07 to 56; p=002) anddischarged from intensive care earlier (median time in intensive care 91 days vs 129 days; p=001)discharged from the hospital earlier (median time in the hospital 149 days vs 192 days; p=004).

More patients in the intervention group self-extubated than in the control group (16 patients vs six patients; 60% difference, 95% CI 06% to 118%; p=003), but the number of patients who required reintubation after self-extubation was similar (five patients vs three patients; 12% difference, 95% CI 52% to 25%; p=047)

12-months mortality: patients in the intervention group were less likely to die than were patients in the control group (HR 068, 95% CI 050 to 092; p=001). For every seven patients treated with the intervention, one life was saved (number needed to treat was 74, 95% CI 42 to 355).What about after discharge:Interrupted sedation methods have not been associated with an increase in long-term neuropsychological outcomes PTSD.Sedating agents have been associated with increased PTSD symptomsNumber of days of sedation in the ICU is associated with a greater likelihood of depression and PTSD.Delusional memories of the ICU stay are more likely to result in PTSD than factual, even if painful, memories.Patients with recall of their ICU stay have been shown to manifest less cognitive dysfunction than patients who have complete amnesia for their ICU experience.

The ultimate objective To reduce the incidence and duration of acute and long-term brain dysfunction in critically ill patients.ABCDEs:Awakening and Breathing trialsChoice of sedationDelirium monitoring and managementEarly ExerciseManagement of Delirium:Choice of SedativesNon-Pharmacological Pharmacological Choice of Sedatives:Study ComparatorsFavorsOutcome and its resultPropofol vs. BDZsPropofolLower ventilator daysOpioids (morphine or remifentanil) vs. BDZsmorphine or remifentanilLower ventilator days

Dexmedetomidine vs. lorazepam(MENDS study)dexmedetomidinedecrease the duration of brain organ dysfunction, with a lower likelihood of delirium development on subsequent daysDexmedetomidine vs. midazolam (SEDCOM study)Dexmedetomidine Reduction in delirium incidence and shorter time on mechanical ventilationDexmedetomidine vs. morphine(DEXCOM study)Dexmedetomidine reduced the duration but not the incidence of deliriumDexmedetomidine: Selective alpha2-adrenoceptor agonist Alpha2-Adrenergic Agonist;Sedative Dexmedetomidine:

Non-pharmacological:Orientation Provide visual and hearing aids. Encourage communication and reorient patient repetitively.Have familiar objects from patients home in the room. Attempt consistency in nursing staff.Allow television during day with daily news. Allow nonverbal music. Environment Maintain sleep hygiene: Keep lights off at night, on during the day. Consider sleep aids (zolpidem, mirtazapine).Control excess noise (staff, equipment, visitors) at night. Ambulate or mobilize patient early and often.Clinical parameters: maintain systolic blood pressure >90 mm hg. Maintain oxygen saturations >90%. Treat underlying metabolic derangements and infections

Risk factors:

Pharmacological Therapy:Only after minimizing contributing factors and optimizing treatment of the underlying physiological abnormalities

Antipsychotics:Lack of large RCT comparing typical or atypical antipsychotics to placeboSmall studies and case reports consist the constitute the best data available While tapering or discontinuing sedatives, consider: Typical: Haloperidol 2 to 5 mg IV initially (0.5-2 mg in elderly) and then q 6 hours. Guideline for max haloperidol dose is 20 mg/day. Atypical:Olanzapine, quetiapine, risperidone, ziprasidone, or abilifideDiscontinue if high fever, QTc prolongation, or drug-induced rigidity.

Comparative Effectiveness: Study Comparators Favors OutcomesOlanzapine vs. HaloperidolNo difference Severity of delirium symptomsQuetiapine vs. PlaceboQuetiapine Resolution of delirium Risperidone vs. PlaceboRisperidone Reduced the incidence of deliriumziprasidone vs. Haloperidol vs. placebo (MIND Study)No difference

number of days patients were alive without delirium or coma.Rivastigmine vs. HaloperidolNo difference Duration of delirium, rivastigmine may increase ICU mortality Points regarding Haloperidol:Onset of action 15 to 20 minutes after intravenous infusion.Duration of effect: re-dosing may be needed 4 to 12 hours after symptoms have been controlled with the initial doses.Highly protein bound, has a large volume of distribution, is metabolized hepatically by CYP3A4, CYP2D6, and glucuronidation (many many many drug interactions)Adverse effect:Rare but serious : polymorphic ventricular tachycardia (including torsades de pointes) The QT interval should be monitored every shift (ie, every 8 to 12 hours) and haloperidol should not be given if the corrected QT interval exceeds 500 msec (normal in males: 460 msec; females: 480 msec)Extrapyramidal side effects are less common with IV intravenous haloperidol than among those receiving oral haloperidolDeath in elderly??? (may not be applicable in the ICU)Antipsychotics:They have psychoactive effects that may further cloud the sensorium and promote a longer overall duration of cognitive impairment.The lowest effective dose for the shortest possible time may be the most important delirium management recommendation

Not in the ICUs

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