WAKE UP AND TREAT DELIRIUM : PITFALLS OF THE PAD GUIDELINES

WAKE UP AND TREAT DELIRIUM : PITFALLS OF THE PAD GUIDELINES Tudy Hodgman, Pharm D, FCCM, BCPS The goal of this discussion will be to review the literature published since the PAD guidelines were released and formulate an approach to individualized patient treatment for pain, agitation and delirium in the adult patient in the intensive care unit. I have no financial disclosures to make regarding the contents of this presentation OBJECTIVES Describe Early Goal Directed Sedation. Compare analgosedation to standard sedation approaches. Explain the approach to prevention and treatment of delirium. Review atypical antipyschotics and list common adverse reactions to these agents seen while treating delirium. Identify bedside issues with implementation of an effective program for PAD. Early Goal Directed Sedation (EGDS) o Early implementation after intubation o Goal directed to target LIGHT sedation (RASS -2 to 1) o Use of dexmedetomidine as the primary sedative o Minimizes use of benzodiazpepines Early Goal Directed Sedation (EGDS) Analgosedation Advantages o vent. weaning time o Vent. Time o ICU LOS ouse less hypnotics oless sedation o(? Less ADRx) Disadvantages opotential delirium orecall (unpleasant events) onightmares / hallucinations o? Immunosuppression owithdrawal o Hyperalgesia o Majority of trials used remifentanil Devabhakthuni S et al Ann Pharmacother 2012

PAIN Subjective Critically ill patients may be unable to self- report pain The ability to reliably assess pain is foundational for effective treatment Self reporting is GOLD standard PAIN ASSESSMENT If unable to self-report - Use a validated and reliable pain scale Behavioral Pain Scale (BPS) Critical Care Patient Observation Tool (CPOT) Facial expressions Body movements Muscle tension Compliance with ventilator Routinely monitor Identify and treat early rather than waiting until it becomes severe ( OR prior to procedures) Assess ALL PATIENTS for any TYPE of pain OPIOID OPIOID ADVERSE EFFECTS AGENT ONSET COMPARISON & DURATION USUAL DOSE COMMENT CNS effects (confusion, delirium) Sedation (often desirable) Mood changes Respiratory depression May increase time on ventilator Decreased GI motility Bowel regimens for constipation may be necessary Nausea, vomiting & constipation Abrupt discontinuation after prolonged use withdrawal Tolerance / Dependence Fentanyl Morphine Hydromorphone : 1-2 min Duration: 1-4 hr : 5-10 min Duration: 3-5 hr : 5-10 min Duration: 3-5 hr Bolus: 25-50 mcg IVP q 0.5-1 hr Infusion: 0.7-10 mcg/kg/hr Bolus: 2-4 mg IVP q 1-2 hr Infusion: 2-10+ mg/hr Bolus: 0.5-1 mg IVP q 1-2 hr Infusion: 0.5-3 mg/hr Agent of choice Rapid onset/offset Not an issue with renal failure Less hypotension Accumulate w morbid obesity Hypotension 2 histamine release Metabolite accumulation with renal failure Slower onset Not an issue with renal failure Use with intolerance to fentanyl or morphine Meperidine AVOID AVOID with long t ½ which can cause seizures Remifentanil : 1-1.5 min Duration: 5 min Bolus: 1 mcg/kg IVP Infusion: 0.5-1 mcg/kg/min Renal elimination Interacts with SSRI/ MAO Rapid onset / offset Metabolism by plasma esterases Chest wall rigidity $$$ Opioid ORAL options Equianalgesic Dose Codeine 120 mg 200 mg 15-60 mg every 4-6 h Oxycodone (OxyContin) Hydrocodone / APAP (Norco, Lorcet, Vicodin) N/A 20 mg 5-15 mg every 4-6 h (IR) N/A 30 mg 2.5-10 mg hydrocodone every 4-6 h Methadone N/A N/A 10-40 mg every 6-12 h Dosing Half-life Metabolism Adverse Effects 2.5-3 h Demethylation Glucuronidation 3-4.5 h CYP 2D6, 3A4 3-4.5 h CYP 2D6, 3A4 15-60 h N-demethylation CYP 3A4/5, 2D6, 2B6, 1A2 Histamine release Monitor all sources of acetaminophen Prolonged QTc Unpredictable PK/PD NON OPIOID ANALGESICS Use non-opioid opioid analgesics to: Amount of opioids or eliminate need for IV opioids Opioid related side effects Acetaminophen (Tylenol,, Ofirmev ) Analgesic and antipyretic effects Adverse Effects Hepatotoxicity Rash Neutropenia, leukopenia, pancytopenia NSAIDs Ibuprofen (Motrin) Ketorolac (Toradol)

Non-opioid opioid analgesia NSAIDs Drug, route Dosing Time to Ketorolac (Toradol) PO, IM, IV 15-30 mg q 6 hr (MAX 5 days) > 50 kg: MAX 120mg/d IV/IM, 40mg/d PO Half-life Metabolism 10 min 2-6 hr Hydroxylation Conjugation Renal excretion Neuropathic pain Drug, route Dosing Time to Gabapentin (Neurontin) PO Carbamazepine (Tegretol) PO Initial: 100mg TID 300 1200mg TID *renally dosed (MAX 3600mg/day) Initial: 100mg BID 100 200 q 4 6 hr (MAX 1200mg/day) 2 4 hr 5 7 hr Half-life Prolonged in renal insufficiency 4 5 hr 25 65 hr but variable bc of autoinduction (complete in 3 5 weeks), then 12-17 h Metabolism Not metabolized CYP3A4 to active epoxide Induces hepatic enzymes < 50 kg &/or CrCL < 30ml/min: 60 mg/d IV/IM, 40 mg/d PO Drug, route Gabapentin (Neurontin) Side Effects and Considerations Sedation, sedation, confusion, dizziness, ataxia Ibuprofen (Motrin) PO, IV 400 mg PO q 4 hr (MAX 2.4 g/day) 400 800 mg IV q 6 hr over >30 min (MAX 3.2 g/day) PO 25 min PO 1.8-2.5 hr IV 2.2-2.4 hr Oxidation Carbamazepine (Tegretol) Adjust dosing in renal dysfunction Abrupt discontinuation associated with drug withdrawal syndrome, seizures Nystagmus, dizziness, diplopia, lightheadedness, lethargy (Rare: aplastic anemia, agranulocytosis, Stevens-Johnson syndrome or epidermal necrolysis with HLA-B1502 gene) Lexi-comp 2013 Multiple drug interactions due to hepatic enzyme induction All these choices, how do you choose? Propofol Dexmedetomidine Midazolam IV, IM, PO Lorazepam IV, IM, PO after IV Loading Dose Half- Life Initial Dosing- Intermittent 2-5 min 3-11 h 2-4 mg q 0.5-2 h 15-20 min 8-15 h 1-2 mg q 2-6h Initial Dosing- Continuous Infusion 2-4 mg/h (bolus before gtt) 1-2 mg/h (bolus before gtt) Titration Adjust by 1-2 mg/h q30min, bolus with each rate increase Adjust by 1 mg/h q30min; give bolus dose with each rate increase Bind the BZD site on the GABA receptor Potentiates GABA actions /Inhibits CNS Sedative / hypnotic Anxiolytic Induce anterograde amnesia Respiratory depression Diazepam (Valium) IV, PR, PO Alprazolam (Xanax) PO Chlordiazepoxide (Librium) PO Clonazepam (Klonopin) PO Half-Life Initial Dosing- Intermittent 2 5 min 20 120 h 0.03-0.1 mg/kg IV q 0.5-6h 1 2 h 12 15 h Start at 0.25-0.5 mg PO TID 0.5 4 h 20 80 h 5 25 mg PO 3-4 times daily Considerations Rapid onset Metabolites can prolong duration with repeated doses Accumulation avoid continuous dosing Anxiety and panic disorders Anxiety 1 4 h 18 50 h 0.5 mg PO TID Seizures Alcohol withdrawal Panic disorder Midazolam Lorazepam Adverse effects BP Quick onset, short duration is lessened by hepatic, renal impairment or with interacting drugs or length of use BP High doses toxicity (anion-gap metabolic acidosis, renal insufficiency (propylene glycol) Special Considerations Intermittent dosing preferred prolongs sedation, especially in patients with renal failure CYP 450 w more drug interactions Intermittent dosing preferred No active s Diazepam Pain, phlebitis at injection site, extremely long half life Short duration of effect Infusion requires large volume

PRECAUTIONS: BENZO S Hypotension upon initiation Caution if hemodynamically unstable Withdrawal Autonomic instability, altered perception, paresthesias, headaches, tremors, and seizures Taper off benzodiazepines if high doses or > 7 days of use Avoid use of flumazenil (BZD antagonist) for reversal withdrawal Propofol Adverse effects Respiratory depression Hypotension / bradycardia Pancreatitits Hypertriglyceridemia - Lipid-based emulsion - 1.1 kcal/ml - Check triglycerides 72 hours Propofol-related Infusion Syndrome (PRIS) Special Considerations Rapid onset / offset Requires a dedicated IV line Drug incompatibility Change tubing every 12 hours DEXMEDETOMIDINE (PRECEDEX ) Central, selective alpha-2 2 agonist Immediate onset, short duration (6 minutes) Has sedative, anxiolytic & analgesic effects but less amnesia May facilitate decreasing doses of analgesics, other sedatives Hepatic elimination, no dose adjustments for renal dysfunction Dexmedetomidine 15 min Peak 1 h Half- Life Adverse effects Hypotension Bradycardia Tachyphylaxis Initial Dosing Initial Dosing- Continuous Infusion 1.8-3 h NA 0.2 1.5 mcg/kg/h *do not bolus Minimal respiratory depression Loss of airway reflexes Titration Adjust by 0.1 mcg/kg/h q15 min Special Considerations Dose range listed in product labeling differs from that in literature - No bolus - Higher doses - > 24h administration $$$$$ MONITORING DEPTH OF SEDATION Richmond Agitation Sedation Scale (RASS) and the Sedation Agitation Scale (SAS) are the most valid and reliable tools assessing sedation More precise dosing Reduced use of sedatives & analgesics Shorter duration of mechanical ventilation Reduced need for vasopressors Reduced incidence of over-sedation AGITATION Agitation and anxiety occur frequently in critically ill patients Anxiety: : absence of a sense of well-being, exaggerated feelings of fear, nervousness, or apprehension Agitation: : combination of anxiety and increased motor activity

DELIRIUM TYPES OF DELIRIUM An acute brain dysfunction; a disturbance of consciousness and attention Can be hyperactive, hypoactive, or mixed Cardinal feature is inattention Underrecognized 60 80% prevalence of mechanically ventilated patients icudelirium.org DSM-IV, American Psychiatric Association 2000 Ely, SCCM 2012 Ely, JAMA 2004;291:1753 Pisani, AJRCCM 2009;180:1092 Maldonado. Anesthesiology 2003;99:A465 DELIRIUM OUTCOMES Delirium is strongly associated with mortality in adult patients Delirium is strongly associated with LOS in adults Delirium is moderately associated with development of post ICU cognitive impairment in adults DETECTING & MONITORING DELIRIUM Routine monitoring for delirium in all adult patients Confusion Assessment Method for the ICU (CAM-ICU) and the Intensive Care Delirium Screening Checklist (ICDSC) are the most valid and reliable tools in adults Routine monitoring is feasible in practice DELIRIUM RISK FACTORS Baseline risk factors associated with delirium Pre-existing existing dementia History of hypertension History of alcoholism Admission severity of illness Coma is an independent risk factor but linking a definitive relationship between subtypes of coma and delirium requires more study Opioids and delirium Conflicting evidence DELIRIUM RISK FACTORS may be a risk factor for delirium in adults Propofol and delirium insufficient data Vented patients are at risk for delirium, use of dexmedetomidine may be associated with lower incidence compared to benzodiazepines

Prevention is the BEST treatment for delirium Treatment options Non-pharmacologic Pharmacologic Antipsychotics Atypical antipsychotics DELIRIUM PREVENTION Early mobilization should be performed whenever feasible to delirium incidence No recommendation for use of pharmacologic agents to prevent delirium No recommendation for combined non- pharmacologic and pharmacologic agents to prevent delirium Neither haloperidol or antipsychotics prevent delirium No recommendation for prophylactic use of dexmedetomidine to prevent delirium DELIRIUM TREATMENT Little data that treatment with haloperidol reduces delirium Atypical antipsychotics may reduce the duration of delirium Do not use antipsychotics in patients at risk for torsades de pointes (history of long QT, patients with meds which QT or patients with prior torsades de pointes) Dexmedetomidine instead of benzodiazepines be used for patients with delirium to reduce its duration Receptors ANTIPSYCHOTICS PROPERTIES Olanzapine Quetiapine Risperidone Ziprasidone Aripiprazole Haloperidol α1, H1, M1 α1, H1, M1 α1, α2, H2 α1 α1, H1 Bioavailability 60 73 70-85 60 87 65% Half life (H) 33 6 3-24 6.6 47-68 20 Renal adjustment No No Yes No No No Dosage form PO, SL, IM PO PO, IM PO, IM PO, IM PO, IM Daily dose (mg) 10 to 20 250 to 600 3 to 6 40 to 80 10 to 30 1.5 to 30 DA Adverse effect Anticholinergic effects Comparative Risk of Adverse Effects of Antipsychotic Medications* Aripiprazole (Abilify) Clozapine (Clozaril) Olanzapine (Zyprexa) Quetiapine (Seroquel) Risperidone (Risperdal) 0 +++ + + 0 0 Dyslipidemia 0 +++ +++ ++ + 0 EPS + 0 + 0 ++ + Hyperprolactinemia 0 0 + 0 +++ + Neuroleptic malignant syndrome Postural hypotension Prolonged QT interval + + + + + + + +++ + ++ ++ + + + + + + ++ Sedation + +++ ++ ++ + + Ziprasidone (Geodon) Protocols and the use of assessment tools Protocol design PAD protocol, algorithms and guidelines Implementation of protocols Use of assessment tools CONSISTENTLY Documentation of assessment Consistency from days to nights Seizures + +++ + + + + Sexual dysfunction + + + + ++ + Type 2 DM + ++ ++ + + + Weight gain 0 +++ +++ ++ ++ 0 NOTE: 0 = rare; + = lower risk; ++ = medium risk; +++ = higher risk. FGAs = first-generation antipsychotics; SGAs = second-generation antipsychotics; EPS= extrapyramidal symptoms * Effects are approximate, and relative to other antipsychotic medications rather than absolute risk of an adverse effect occurring. MUENCH, J. HAMER, AM. Am Fam Physician. 2010 Mar 1;81(5):617-622.

GUIDELINE MANAGEMENT & IMPLEMENTATION Daily interruption or light target level of sedation be used Analgesia be implemented as first sedative Sleep should be promoted to protect the normal sleep cycle GUIDELINE MANAGEMENT & IMPLEMENTATION Multidisciplinary team plus: Provider education Preprinted +/or computerized protocols and order forms ICU rounds checklist be used to assess pain, agitation and delirium ROUTINELY TAKE HOME POINTS QUESTIONS?? Treat pain first Evaluate the pharmacology of agents to select optimal therapy to avoid delirium when possible Sedation: lighter is better than deeper Promote sleep Identify your goal and routinely reassess therapy Use a multi-disciplinary approach