SEDATION, AGITATION, DELIRIUM Daniel Lollar, MD

Transcription

1 SEDATION, AGITATION, DELIRIUM Daniel Lollar, MD

2 OVERVIEW Correctable causes of agitation Pain assessment opioids Agitation assessment BZNs, propofol, precedex comparisons Delirium haldol, antipsychotics Protocols

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4 PAIN causes of pain in the ICU are multiple, including surgeries, procedures, and discomfort from indwelling devices pain should be treated adequately as poor pain control can cause delirium and agitation pain should be assessed at regular intervals with a validated scale Recommended scales include the Behavior Pain Scale (BPS) and Critical Care Pain Observation Tool (CPOT) except for TBI

5 BEHAVIORAL PAIN SCALE Prospective evaluation of 30 pts in SICU TID evals by RN and LPN on 3-12 scale good interrater reliability based on physiologic score, response to painful stimuli and response to opiates has been repeated on sedated but non-intubated patients with consistent results

6 CRITICAL-CARE PAIN OBSERVATION TOOL Developed in 105 cardiac patients Each pt had assessments before, during and after a painful procedure κ for all of 9 assessments

7 PAIN MANAGEMENT Initial treatment of pain begins with preemptive and nonpharmaceutical interventions such as relaxation preemptive analgesia should be given in the form of local or systemic pharmacology before painful, invasive procedures IV opioids are first line therapy for non-neuropathic pain and all opioids are considered equally effective gabapentin or carbamazepine are equally effective for neuropathic pain Barr et al, Crit Care Med

8 OPIOIDS First used by the Sumerians around 3000 BC opium contains 20 alkaloids, ~10% morphine, 0.5% codeine morphine named after Morpheus, greek god of dreams heroin synthesized in 1874 in conjunction with hypodermic needles led to concerns for abuse Harrison Narcotic Act of 1914 prohibited non-medicinal use acts primarily in brainstem, amygdala, thalamus, medulla and spinal cord but also peripheral afferent pain tissues & GI tract

9 OPIOID PHARMACOLOGY three receptor subtypes: delta, kappa and mu (OP1, 2 and 3) G-protein coupled receptors absorbed well via IM and SQ, oral absorption limited by significant first pass effect tissue uptake based on a drug s lipophilicity undergoes hepatic metabolism via cytochrome P450, CYP3A4 and CYP2D6 most opioids and metabolites cleared by kidneys requiring dose adjustment in RF first line drug for dyspnea

10 NATURAL OPIOIDS morphine: primarily mu agonist SE include sedation, respiratory depression, ileus, itching 2/2 histamine, miosis active metabolite morphine-6-glucuronide cleared by kidney codeine: mu but also delta and kappa agonist antitussive at lower doses; analgesic at higher doses also induces non-ige mediated histamine release

11 SEMI-SYNTHETICS Hydrocodone, oxycodone- less n/v than morphine, oral administration only Hydromorphone- 8-10x more potent than morphine, less pruritis but more euphoria; no active metabolites Heroin- aka diacetylmorphine is morphine prodrug and lacks intrinsic opioid affects, however once in the CNS it is metabolized to active compounds

12 PHARMACOLOGY context sensitive half-life:: time it takes for a drug at steady state to reach half of its plasma concentration with constant infusion, drug distributes over central and peripheral compartments until it reaches equilibrium once equilibrium is reached, the drug is only removed by metabolism or excretion as the drug is removed, the drug moves from the peripheral compartments consistently into plasma, maintaining high plasma concentrations

13 SYNTHETICS fentanyl, sufentanil, alfentanil, remifentanil- short to ultra short acting 2/2 increasing lipophilicity fentanyl via gtt can accumulate in adipose tissue; longer exposure to infusion the longer the context-sensitive half life (300min after 12hrs) sufentanil can cause vocal cord closure alfentanil causes significant respiratory depression remifentanil metabolized by esterases meperidine has increased kappa activity metabolite normeperidine causes CNS excitation and seizures also blocks serotonin re-uptake and can interact with MAO-I causing serotonin syndrome

14 ANTAGONISTS: CENTRAL AND PERIPHERAL Naloxone- antagonizes mu, kappa and delta receptors iv and im formulations should be administered repeatedly at low doses Naltraxone- antagonizes mu receptors only long acting (>24hr), po administration only Alvimopan- peripheral mu antagonist po administration, hosptial availability only SE include hypokalemia and anemia

15 AGITATION sedation should be kept light associated with improved neurologic outcomes not associated with increased MI 2/2 stress response sedation should be stopped every day and neurologic exam performed sedation should be monitored regularly using Richmond Agitation Sedation Scale (RASS) or Sedation Agitation Scale (SAS) objective measures of brain function should only be used in paralyzed patients

16 RICHMOND AGITATION- SEDATION SCORE (RASS)

17 RASS cont

18 RIKER SEDATION AGITATION SCORE (SAS)

19 Conclusion: there is a strong correlation between the RASS and SAS; either can be used to assess need for CAM-ICU

20 BENZODIAZEPINES causes allosteric modulation of GABAA receptor increasing inhibitory effects effects include amnesia (including antegrade) and sedation side effects include prolonged sedation and predisposition to delirium, abrupt cessation can cause seizures metabolized by the liver most commonly used ICU drugs midazolam (Versed) and lorazepam (Ativan)

21 VERSED AND ATIVAN Versed has high lipid solubility causing rapid onset (2 minutes) and rapid clearance metabolized by cytochrome P450 system and has active metabolite (1-hydroxymidazolam) Ativan has onset of minutes with half life of up to 6 hrs metabolized by glucuronidation and has no active metabolites prepared in polyethylene glycol which can cause lactic acidosis, delirium, hypotension and MOFS- max dose 2mg/hr for 70kg adult time to emergence with Versed can be 30hrs versus 4.4hrs with Ativan

22 PROPOFOL also binds GABAA receptors, different one from BZDs, acts as sodium channel blocker and may have endocannibinoid action 1-2 minute onset, awakening occurs within 10-15min developed for procedural sedation but awakening short even with prolonged infusion loading dose 5 mcg/kg/min; maintenance at 5-50 mcg/kg/min, dosed based on ideal weight PIS can be triggered with doses of >85mcg/kg/min for > 48hr in conjunction with pressors and/or steroids

23 PROPOFOL +/- Pros: does not accumulate decreases intracranial pressure no dose adjustment for renal or hepatic insufficiency provides 1kcal/mL in lipid emulsion Cons: respiratory depression hypotension 2/2 vasodilation hypertriglyceridemia green urine from phenolic metabolites PIS- bradycardia HF, LA, rhabdo and ARF with 30% mortality

24 67 pts from mixed ICU prospectively randomized to midazolam or propofol; protocol: bolus followed by infusion, intermittent morphine for pain propofol associated with twice the rate of SBP drop >20%, longer time to sedation goal trend toward shorter vent times, shorter time in ICU propofol was 4-5x more costly

25 open label RCT propofol gtt vs intermittent ativan to goal Ramsay score pts from MICU enrolled 2.6 fewer ventilator days overall; 4 fewer ICU days in survivors, equivalent mortality same amount of adverse events (self extubations 3 v 1, nss)

26 open label RCT propofol gtt vs intermittent ativan to goal Ramsay score pts from MICU enrolled 2.6 fewer ventilator days overall; 4 fewer ICU days in survivors, equivalent mortality same amount of adverse events (self extubations 3 v 1, nss)

27 DEXMEDETOMIDINE post-synaptic α-2 receptor agonist with sedative, amnestic and analgesic properties maintains arousal despite deep sedation (pts can be assessed and extubated without stopping infusion) Dosing: loading 1mcg/kg over 10min*, maintenance mcg/kg/hr Systemic effects include bradycardia and BP as well as decreased NE levels pts with HF* and arrhythmias especially susceptible

28 double blind PRCT of 106 pts in medical and surgical ICUs lorazepam gtt vs dexmedetomidine gtt, titrated to RASS levels dexmedetomidine pts had more alive days without coma or delirium (by CAM-ICU) by median of 4 days, lower prevalence of coma (63% vs 92%), and more time at sedation goal 28 day mortality was less (17% vs 27%) post-icu neuropsychological test results were better 4 v 2 self-extubations, $22K more expensive (not stat significant)

29 double blind PRCT on 375 med/surg ICU pts Precedex vs Versed gtt, titrated to RASS goal no difference in time at RASS goal delirium (based on CAM ICU) ~25% lower in dexmed group, time on mech vent 1.9d shorter, length of ICU stay similar incidence of bradycardia higher while rate of tachycardia and hypertension lower

30 6 trials totaling 1235 pts comparing a BZ to a nonbz sedative (propofol or Precedex) nonbz protocol associated with decreased ICU stay (1.6d, CI ), duration of mechanical ventilation (1.9d, CI ) did not evaluation rate of delirium or mortality

31 DELIRIUM Should be assessed at regular intervals with ICU-CAM predisposing factors include age >65y/o, those with underlying cognitive impairment, those with severe illness defining characteristic is inattention and can be hyper- or hypo-active in type (ie not all delirious pts are agitated) also marked by waxing and waning awareness, disorganized behavior and confusion, slowed thinking MUST have an organic cause MUST be a change from baseline; absence of dementia

32 - Developed from the CAM based on expert opinion and DSM-III by Inouye - 38 ventilated and non-ventilated pts in mixed ICU - Results compared to DSM-IV dx by delirium experts - Inter-rater reliability

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34 BUTYROPHENONES Haldol low propensity to cause hypotension therefore useful in acute setting and in hypovolemic pts terminal half life approximately 24 hrs can be given PO as well as IV and IM, can also be given as gtt treatment of EPS is administration of IV anticholinergic (benztropine or Benadryl); EPS effects are dose related so may cont drug at lower dose Droperidol most potent antiemetic, dosage 1.25mg 2-3x/d

35 ATYPICAL ANTIPSYCHOTICS Less effects on dopaminergic or cholinergic rcpts; acts to block 5- HT2 rcpts and are α-2 antagonists (can cause hypotension) much lower incidence of EPS but more likely to cause hypotension and sedation Quetapine (Seroquel): odds ratio of prolonging QT is 0.17 over placebo, requires a gradual discontinuation Olanzapine (Zyprexa): reduces insulin sensitivity, increase fat accumulation not recommended to use as prophylaxis against delirium

36 SO HOW DO WE PUT IT ALL TOGETHER?

37 140 intubated pts randomized to no sedation vs. propofol x 48hr followed by midazolam gtt, intermittent morphine for pain no sedation group had 4 fewer vent days, 2 fewer days in ICU and 3.6 fewer hospital days of note, protocol included a person assigned to verbally comfort and assure patient, no restraints, and daily mobilization despite ventilator

38 ICU wide improvement program implementing a new sedation protocol in ALI pts important aspects: sedation to targeted RASS, required failure of intermittent dosing prior to starting gtts, addition of CAM ICU implementation resulted in 50% reduction of BZN and opiate gtts, median RASS improvement from -4 to -1.5

39 CRITICAL CARE GUIDELINES very good primer on drug pharmacology fairly conservative recommendations specific recommendations based on discrete literature no specific recommendations regarding drugs, just drug classes

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41 CONCLUSION pain, agitation and delirium should be regularly assessed and any therpay should be targeted to specific end points ICU patients should be started on an analgesia first regimen ICU patients should be started on a intermittent dosing regimen BZN should be avoided, especially as an infusion, in preference to dexmedetomidine or propofol except in pts with seizures or withdrawal delirium should be assessed regularly and symptoms treated with haldol Reassurance and mobilization should be used as adjuncts

42 REFERENCES Gabrielli, Layton, Yu, Civetta, Taylor & Kirby s Critical Care, 4th edition Vincent, Abraham, Moore, Textbook of Critical Care, 6th edition Marino, ICU Book, 4th edition