Non-Opioid Adjuncts in the +4 = Combative, violent Difficult - PDF document

Richmond Agitation-Sedation Scale (RASS) Ely EW, JAMA 2003:289(22):2983 Non-Opioid Adjuncts in the • +4 = Combative, violent Difficult Patient • +3 = Very agitated, pulls at catheters • +2 = Agitated, fights the ventilator • +1 = Restless Daniel Burkhardt, M.D. • 0 = Alert and calm Associate Professor • -1 = Drowsy, >10 sec. eye open to voice • -2 = Light sedation, <10 sec. eye open to voice Department of Anesthesia and Perioperative Care • -3 = Moderate sedation, movement to voice University of California San Francisco • -4 = Deep sedation, movement to touch daniel.burkhardt@ucsf.edu • -5 = Unarousable, no response to touch What is pain: sensory and How to "Sedate" in the ICU emotional experience • Identify goals: – Analgesia • Pain is whatever the patient says it is – Anxiolysis • Sledgehammer – Amnesia • Don't have to give opioids – Hypnosis – Paralysis • Choose a drug and titrate to effect • Anticipate side effects

"Analgesia" Opioids Sources of Pain in the ICU • The mainstay of analgesic therapy • Surgical incisions • Do NOT reliably produce amnesia, anxiolysis, or • Tissue injury from malignancy, infection, ischemia hypnosis • Indwelling catheters and monitors • Lots of side effects (itching, nausea, constipation, • Discomfort from lying in bed in one position for hours or days • ICU sedation algorithms always start with “Does the patient have urine retention, myoclonus, respiratory pain?  Treat it.” depression) • If you can’t ask the patient: • Very little direct organ toxicity – Guarding of wound – Pupil size (to assess opioid tolerance) – Trial of therapy Opioid effect on pain is a Tramadol spectrum • Up and down with dose • Weak opioid agonist • Up and down with reversal • Made DEA Schedule IV in August 2014 – Tiny doses of naloxone • ? some antidepressant effect • Up and down with stimuli • May not add much coadministered with – Epidural clog conventional opioids • Fail opioid for toxicity, not because it doesn't do anything

Opioids: How to Reduce Side Tylenol Effects • If the patient is comfortable, decrease the dose • 4 mg too much • Change opioids – Fentanyl and Dilaudid may be better than morphine • IV available • Add non-opioid adjuncts to reduce opioid dose needed – $35 per vial – NSAIDS (PO or IV), acetaminophen (PO or IV), – Insurance carve-out neuropathic pain treatments (PO only), regional anesthesia, dexmedetomidine, ketamine, isoflurane etc. • Reduce the source of pain – Tracheostomy, for example Cardiovascular Safety of NSAIDs NSAIDS Trelle S et al. BMJ 2011 • Renal • 31 RCT with 116K patients • MI (Rate Ratio) • Bone – Naprosyn 0.82 (0.37 to 1.67) – Ibuprofen 1.61 (0.5 to 5.77) • GI bleed – Rofecoxib 2.12 (1.26 to 3.56) • MI / CVA • Cardiovascular Death (Rate Ratio) – Naprosyn 0.98 (0.41 to 2.37) – Naprosyn better – Ibuprofen 2.39 (0.69 to 8.64) • SAIDS – Rofecoxib 1.58 (0.88 to 2.84)

Pregabalin: Postop Pain Metaanalysis Other non-opioid adjuncts Mishriky BM et al. Brit J Anaes 2014 • Gabapentin / pregabalin • 55 RCTs with 4155 patients – Don’t have to load pregabalin as much • Significant reduction in – Gabapentin can start at 300 - 600 mg po TID as an inpatient – Pain score at rest (-0.38) • Tricyclic’s – Pain with movement (-0.47) – Sleep more with amitriptyline than nortriptyline – Morphine equivalents (-8.27 mg) • Cymbalta (duloxetine) for diabetic neuropathy • Ketamine – PONV (RR 0.62, 0.48-0.80) • Local Anesthetics (Regional, IV, Lidocaine patch) – Pruritus (RR 0.49, 0.34-0.70) • Dexmedetomidine • Significant increase in – Sedation (RR 1.46, 1.08-1.98) – Dizziness (RR 1.33, 1.07-1.64) – Visual disturbance (RR 3.52, 2.05-6.04) Ketamine: A Unique Sedative Case: The Last Resort • 25 year old male with severe pancreatitis and • Phencyclidine derivative (like PCP) ARDS. Progressive worsening of hypoxia and • NMDA receptor antagonist agitation since admission 2 weeks ago. • Dissociative hypnotic, amnestic • Analgesic • Oxygen saturation 85% on FiO2=1.0 and – The only potent analgesic without much respiratory depression PEEP=20. Frequent coughing leading to – One of the few non-opioid analgesics that can be given IV desaturations down to 60% despite fentanyl at • Classically used for brief procedures (such as dressing changes) on 1000 mcg/hr IV and midazolam 20 mg/hr IV. unintubated patients • Little to no tolerance

Ketamine: Problems Ketamine: Last Resort Sedative • Increases BP and HR via sympathetic stimulation • For continuous sedation in the ICU – But actually a direct negative inotrope – 1 - 10 mcg/kg/min IV used in post-op patients for pain • May increase in ICP, also because of sympathetic relief (typically keep dose < 5 for awake patients) stimulation – Up to 20 - 30 mcg/kg/min IV used at UCSF for – But not in patients who are sedated and mechanically "impossible to sedate" intubated patients to avoid ventilated (Himmelseher S Anes Analg 2005) paralysis • Causes unpleasant dreams and hallucinations • Low dose IV (< 5 mcg/kg/min) is used anywhere in the – Consider benzo use if dose is > 5 mcg/kg/min IV hospital • Increases bronchodilation by sympathetic stimulation • Oral ketamine used on outpatients – But also increases secretions Dexmedetomidine Dexmedetomidine vs. Lorazepam (Pandharipande PP et al. JAMA 2007) • 103 adult medical and surgical ICU patients requiring mechanical ventilation • Selective alpha-2 agonist (IV infusion) for >24 hrs prospectively randomized to: • Sedation, anxiolysis, analgesia, sympatholysis – Lorazepam 1 mg/hr IV titrated between 0-10 (no boluses allowed) – Dexmedetomidine 0.15 mcg/kg/hr titrated between 0-1.5 • Not reliably amnestic at low doses • All patients received fentanyl boluses or infusion if necessary • Still arousable for neuro exam • Continued until extubation or until FDA mandated endpoint of 120 hours • Dexmedetomidine group did better • No significant respiratory depression – More delirium and coma free days (7.0 vs. 3.0, p=0.01) – Can be used on extubated patients – Trend toward lower 28 day mortality (17% vs. 27%, p=0.18) • Dexmedetomidine group received significantly more fentanyl (575 vs. 150 • No more hemodynamically stable than propofol mcg/24h, p=0.006)

Dexmedetomidine vs. Midazolam Dexmedetomidine vs. Midazolam (Riker RR et al. JAMA 2009) Riker RR et al. JAMA 2009 • PDBRCT 375 intubated med/surg ICU patients expected to require • Dex group did better ventilation for at least 3 more days – Less delirium (54% vs. 76.6%, p<0.001) • Dex 0.2 - 1.4 mcg/kg/hr vs Midaz 0.02 - 0.1 mg/kg/hr until extubation – Shorter time to extubation (3.7 vs. 5.6 days, p=0.01) or 30 days • No difference • Excluded (among other things) hypotension defined as SBP < 90 – ICU LOS (5.9 vs. 7.6 days, p=0.24) despite 2 vasopressors – 30 day mortality (22.5% vs 25.4%, p=0.60) • Also – Study drug boluses prn • Dex had more bradycardia (42.2% vs. 18.9%, p<0.001) – Open-label midazolam 0.01-0.05 mg/kg iv q10-15min prn agitation – Fentanyl 0.5-1 mcg/kg iv q15mr prn pain – Haloperidol 1-5 mg iv q10-20min prn delirium Dex vs. Propofol Dex Adrenal Suppression Jakob SM et al. JAMA 2012 • Riker RR et al. JAMA 2009 • RDBRCT 500 ICU pt. on mechanical ventilation who need >24 h sedation. Rx for up to 14 days. – Mean dose of 0.83 mcg/kg/hr x 3.5 days – Dex 0.2 – 1.4 mcg/kg/hr (mean 0.925 x 42h) – 1/244 dex patients had adrenal insufficiency (0/122 in – Propofol 5 – 67 mcg/kg/hr (mean 29.2 x 47h) midaz group) – Fentanyl for pain, bolus midazolam for rescue • Pandharipande PP et al. JAMA 2007 • No difference – Mean dose 0.74 mcg/kg/hr x 5 days – Vent duration (D vs. P) 4.0 vs. 4.9 d (p=0.24) – ICU LOS, mortality, hemodynamics – No difference in cortisol or ACTH levels 2 days after – Neurocognitive AE requiring rx: 28.7% vs. 26.8% (p=0.689) discontinuation – CAM-ICU Positive: 11.9% vs. 13.9% (p=0.393) • Dex had less critical illness polyneuropathy (0.8% vs. 4.4% p=0.02)

Non-pharmacologic adjuncts Hospital Drug Acquisition Costs Drug only ... does not include preparation, etc. All costs are for 24 hours for a 70 kg patient • Exercise / PT – Improve sleep • Propofol 75 mcg/kg/min = $75 • The gold standard: cure the underlying • Dexmedetomidine 1 mcg/kg/hr = $500 disease – MICU patients needed 1 mcg/kg/hr (Venn RM et al. ICM 2003) – CABG patients on a 0-0.7 mcg/kg/hr dex protocol only reduced their Propofol dose – Remove the painful stimulus from 20 to 5 mcg/kg/min • Midazolam 2 mg/hr = $10 • Trach the intubated ICU patient • Remove foley, NG tube, etc. • Fentanyl 50 mcg/hr = $7 • Remifentanil 0.10 mcg/kg/min = $250 ERAS Epidural Analgesia Significantly Speeds Return of Bowel Function in Abdominal Surgery Early Recovery After Surgery Jorgensen H et al. Cochrane 2008 • Epidural local anesthetic infusion significantly reduced time to return of GI function compared to systemic opioids by 37 hours (CI 56-18) • Tylenol, Gabapentin, Celebrex/Diclofenac – First flatus (36 hr) and first stool (45 hr) subgroups also significant PO in preop • Lots of problems – Substantial heterogeneity • Thoracic Epidural – Only 7 studies and 319 patients • Minimize Opioids – Old studies (1996 – 1999) – Pain worse in epidural group (1.5 VAS) • Epid LA/opioid combo vs. systemic opioids only reduced time to recovery by 9.3 hours (NS)