Sedation: Choosing the Right Drug for the Right Patient

Sedation: Choosing the Right Drug for the Right Patient Kimberly Varney Gill, Pharm.D., BCPS VCU Health System VCU School of Pharmacy Associate Professor of Critical Care Medicine

Objectives 1. Discuss a general sedation strategy 2. Review commonly used sedatives 3. Present individual uses for specific sedative medications

Sedation Strategy New Goal: Awake, but Comfortable

Sedation Strategy New Goal: Awake, but Comfortable I. Medication Reconciliation and Patient History 1. Restart home psych / pain medications if not contraindicated, to prevent drug withdrawal 2. Identify specific disease states which direct toward a particular class of sedatives. (pain indication? EtOH abuse? Opiate / bzd abuse?)

Sedation Strategy New Goal: Awake, but Comfortable I. Medication Reconciliation and Patient History 1. Restart home psych / pain medications if not contraindicated, to prevent drug withdrawal 2. Identify specific disease states which direct toward a particular class of sedatives. (pain indication? EtOH abuse? Underlying psych disorder?) II. Drug or Delivery Method 1. Analgesia 1 st : A1 method 1,2 2. PRN only method 4 3. Patient Controlled Sedation (PCS) / PCA method 3 4. Shorter acting infusion agents: propofol, dexmedetomidine 5. Anti-psychotics over benzos for hyperactive delirium 1 Breen D, Wilmer A, Bodenham A, et al. Crit Care 2004;8:R21-30. 2 SCCM Sedation and Analgesia Guidelines 2002. 3 Chian LL et al. Chest. 2010 Nov;138(5):1045-53 4 Strom T et al. Lancet 2010. Feb 6;375(9713):475-80

Sedation Strategy III. Monitoring and Mobilization 1. RASS to lighter goal: -1 to -2 may be more appropriate. REASSESS daily 1 2. Daily interruption in appropriate pts 3. Delirium assessment 4. Daily mobilization protocol 2 1 Patel SB, Kress JP. Sedation and Analgesia in the mechanically ventilated patient. Am J Resp and Crit Care Med Oct 20, 2011. 2 Schweickert WD et al.. Early physical and occupational therapy in critically ill patients. Lancet 2009;373:1874-1882.

Sedation Strategy III. Monitoring and Mobilization 1. RASS to lighter goal: -1 to -2 may be more appropriate. REASSESS daily 2. Daily interruption in appropriate pts 3. Delirium assessment 4. Daily mobilization protocol IV. Weaning to Extubate 1. Pairing daily interruption with spontaneous breathing trial (ABC Trial) 1 2. Observe for withdrawal from pre-hosp exposure, or ICU exposure to continuous sedative meds of >/= 3 days 3. If withdrawal: transition to longer acting agents (oral route). PLAN FOR TAPERING OFF POST-ICU should be well documented to avoid inadvertent long-term / post hospital exposure to anxiolytics/antipsychotics/opiates. 1 Girard T et al. ABC Trial. Lancet 2008;371:126-34.

Analgesia Before Sedation Patients experience pain in the ICU Endotracheal tube suctioning Repositioning Insertion of lines and tubes Desired outcomes have not been achieved; report of pain (50-65%) same now as data from 17 yrs ago Szokol JW, Vender JS. Crit Care Clin 2001, 17:821 842.

Characteristic Analgesia First Remifentanyl-based vs Standard hypnotic-based sedation in the ICU: a randomised trial 1 Remifentanil (n = 57) Control (n = 48) Number (%) of pts extubated 29 (51%) 16 (33%) Hours from start of study drugs to weaning - (Difference) Hours from start of study drugs to extubation - (Difference) Hours from weaning time until extubation - (Difference) Hours from start of study drugs until ICU discharge - (Difference) 83.0 (- 15.0) 94.0 (- 53.5) 0.9 (- 26.6) 187.3 (- 22.5) P 98.0 0.523 147.5 0.033 27.5 <0.001 209.8 0.326 1 Des Breen et al. Decreased duration of mechanical ventilation when comparing analgesia-based sedation with standard hypnotic-based sedation. Critical Care Dec 2005 9:R200-210

Benzodiazepine a Infusions Appropriate Use Status Epilepticus Alcohol Withdrawal Patients < 65 yrs Chronic outpt benzo use Use Caution or Avoid Use Older population (>65 yrs) Treatment of delirium b Hepatic failure, cirrhosis End-stage renal failure No hepatic failure No end stage renal failure A midazolam and lorazepam b avoid infusion or prn use Patel SB, Kress JP. Sedation and Analgesia in the mechanically ventilated patient. Am J Resp Crit Care Med Oct 2011.

Propofol Mechanism of Action - sedative and hypnotic properties; no analgesic properties - GABA A receptor agonist; NMDA receptor blockade - Highly lipophilic with high Vd Short acting agent Adult Dose: 5-100 mcg/kg/min Onset ~ 30 seconds; Duration ~ 3-10 minutes (may be prolonged in obese, elderly) Titration fast, ~ every 5-10 minutes Monitoring BP, HR, RR Triglycerides > 500 mg/dl (~ 10 %) 10% Lipid emulsion: 1.1 kcal/ml; the calories count PRIS McKeage K, Perry CM: Propofol: a review of its use in ICU sedation. CNS Drugs 2003, 17(4):235 272.

Propofol Use has steadily increased over last 10 years. 1 IV infusion sedation almost doubled 2001-2007: 39% to 68% Attributed to increased use of propofol 2001-2007: 31% to 55% Meta-analysis of Propofol from 1966-2007 2 16 controlled studies, 1386 patients on mechanical ventilation Endpoint Mortality Length of ICU stay (med-long term sedation Duration of mech ventilation (4 studies) Propofol vs Control No difference Decreased LOS vs sedatives; No diff LOS compared to midazolam Shorter duration vs control 1 Wunsch, H ET all. Project IMPACT data. Crit Care Med Dec 2009;3031-39. 2 Ho KM, Ng, KY. Propofol Meta-Analysis. Int Care Med Nov 2008;34(11):1969-79.

PRIS 36 yo female adm to MICU for severe sepsis/resp failure requiring intubation, secondary to strep pneumoniae. PMH included substance abuse, HIV, and hep C, schizoaffective, and DM. Abx, fluids, and pressors were started. Sedation included propofol 30 mcg/kg/min, and midazolam infusion. Renal and hepatic lab values WNL. Day 7 Morbilliform rash on neck, shoulders, chest AST 115 ALT 536 Amylase 294 Lipase 608 CK 36,327 TGs 1005 Sinus tach Abd CT showed hepatomegaly w/ fatty infiltration of liver Orsini J et al. Am J Health-Syst Pharm Vol 66 May15, 2009

PRIS Total dose of propofol over 8 days 35,200 mg (avg 49 mcg/kg/min). Propofol stopped and phenobarb was added. Laboratory test values normalized, and rash and tachycardia resoved within 72 hrs of propofol discontinuation. Orsini J et al. Am J Health-Syst Pharm Vol 66 May15, 2009

PRIS High mortality, must stop infusion Lipemic serum may be an indicator Rhabdomyolysis, heart failure, renal failure, liver failure, high triglycerides, metabolic acidosis, lactic acidosis, arrhythmias Dose and time related (> 50 mcg/kg/min), for 48hrs Labs: lactate, TGs, CK, SCr, LFTs, pancreatic enzymes, ECG, echocardiogram Roberts RJ et al. Crit Care 2009;13(5):R169

Propofol Place in Therapy Along with an opiate, patients on mechanical ventilation (out to 7-10 days..) Effective to prevent alcohol withdrawal Preferred over midazolam in patients with renal failure, hepatic failure If on a longer acting infusion, can consider switching to propofol as pt gets closer to extubation (shorter acting) Monitor for hypertriglyceridemia, PRIS Riker R, Gilles F Crit Care Clinics. 2009(25):527-38.

Dexmedetomidine (Precedex ) Central alpha 2 agonist Sedation / Analgesia ( opiate requirements ~ 25-30%) HR and BP NO effect on respiratory drive Mimics non-rem sleep Dosing and Monitoring Starting dose: 0.2 mcg/kg/hr 1.4 mcg/kg/hr (optional bolus) Titration up: every 30 mins Titration down: every 2-4 hrs; maybe longer if on for several days Peak effect (steady state): ~2-4 hours if no bolus given Monitor for bradycardia, hypotension Ann Pharmacother. 2009;43:1707-13., Acta Anaesthesiol Scand. 2008;52:289-94.

N Ohtani et al. Peri-operative effects of dexmedetomidine. J Anesth Sept 2011 Tian-Zhi Guo et al. Anesthesiology 1996;84(4):873-881. Dexmedetomidine for Pain Dexmedetomidine produces antinociception via -2 A,C agonist activity in the locus ceruleus, and dorsal horn in the spinal cord. decreased opiate and anesthesia requirements peri- and postoperatively, and in the intensive care unit

Dexmedetomidine for Pain Palliative care: intractable pain control and decreased delirium at end of life Opioid-induced hyperalgesia (OIH): opiates in high dose and with prolonged exposure can have pronociceptive /antinociceptive properties Unable to achieve pain control despite escalating opioid doses Dexmedetomidine provides pain control via a different mechanism which acts synergistically with opioids. Coyne PJ et al. Dexmedetomidine: its role for intractable pain and dosing guideline. J of Pain and Pall Care Pharmacother Dec 2010;24(4):384-386. E Prommer. Dexmedetomidine: role in palliative care medicine. Am J Hosp P Med 2011;28(4):276-283. Belgrade M, Hall S. Dexmedetomidine for OIH. Pain Med Dec 2010;11(12):1819-1826.

Alcohol Withdrawal Neurotransmitter Long term EtOH Removal of EtOH Targeted Drug Therapy GABA(a) (inh) 1 GABA receptors inhibitory fxn leading to anxiety and seizures Benzos, Barbs Carbamazepine Propofol Glutamate (excit) 2 glutamate via NMDA receptors excitatory function from elevated receptor levels Propofol Calcium channel blockers Norepinephrine brain adrenergic (excit) 3 output noradren levels to above pre-etoh levels (early in w/dr) Clonidine Dexmedetomidine 1 Muzyk AJ et al. Annals of Pharm May 2011, Vol 45:649-57. 2 Davis KM et al. J Biomed Sci 2000;8:7-19. 3 Patkar AA et al. Alcohol Alcohol 2003;38:224-31.

Alcohol Withdrawal Neurotransmitter Long term EtOH Removal of EtOH Targeted Drug Therapy GABA(a) (inh) 1 GABA receptors inhibitory fxn leading to anxiety and seizures Benzos, Barbs Carbamazepine Propofol Glutamate (excit) 2 glutamate via NMDA receptors excitatory function from elevated receptor levels Propofol Calcium channel blockers Norepinephrine brain adrenergic (excit) 3 output noradren levels to above pre-etoh levels (early in w/dr) Clonidine Dexmedetomidine 1 Muzyk AJ et al. Annals of Pharm May 2011, Vol 45:649-57. 2 Davis KM et al. J Biomed Sci 2000;8:7-19. 3 Patkar AA et al. Alcohol Alcohol 2003;38:224-31.

Dexmedetomidine in Alcohol Withdrawal 30 year old male hx of chronic alcohol abuse admitted for AMS and agitation. Last EtOH intake was 24 hrs previous. Pt went into withdrawal on hosp d 2. Lorazepam IM bolus, midazolam gtt titrated to 12 mg/hr Pt remained altered with episodes of severe agitation, tremors. Dexmed initiated at 0.2 mcg/kg/hr titrated to 0.7 mcg/kg/hr. Total of 39 hrs of dexmed. Midazolam titrated down after 3 hrs of dexmed; mental status, tremors/agitation improved. Midaz stopped after 14 hrs of overlap with dexmed. Patient on oxazepam by day 3; discharged home day 5. Darrouj J, et al. Annals of Pharmacotherapy. Nov 2008 Vol 42(11);1103-5.

Dexmed 4 ½ hrs mcg/kg/hr 1.2, 1, 0.6, 0.5, 0.25, off Patient had been on high dose dexmed for roughly 7 days. Dexmed was titrated off over 4 ½ hrs. Lorazepam also decreased slightly (from q4h to q6). Next morning 10 am, pt having rigors, tachy 130s, hypertsn 160s, extreme anxiety. Gave 2 mg midazolam, HR decreased to 110s; gave dexmed full bolus, HR to 70s and SBP to 105/65. Patient calm and sedated. Total dexmed infusion time was 32 days; pt eventually started on PO phenobarb and clonidine to wean off infusion medications. Dexmed was not successfully weaned off until clonidine was initiated.

Dexmedetomidine Place in Therapy Short-medium term sedation and analgesia Pain requiring increased opiate dosing with concerns for respiratory depression; intractable pain, palliative care Substance abuse withdrawal w/ benzo, barb Decrease benzodiazepine use* Cost: ~60 $ per bag (~ 350-750 $ / day) Concerns Still FDA approved for only 24 hours Case reports of severe withdrawal when weaned too quickly from long term use (>7 days) Titration down can be tricky when on drug for several days.? Consider PO clonidine if withdrawal occurs. Arain SR, Ebert TJ: Anesth Analg 2002, 95:461 466.

Delirium in the ICU Cause(s) of delirium is usually multifactorial, therefore needing a multicomponent approach to targeting treatment of delirium. Expected based on disease state(s)? Correctable diseaserelated cause? Drug related? Attempt to correct underlying pathophysiology and/or removing medications that may be causing delirium DRUGS causing delirium and/or altered mental status Benzodiazepines, opiates, propofol, dexmedetomidine, antipsychotics 1 Devlin J et al. Crit Care Med 2010 Feb:38(2):419-27.

Delirium * Non-pharmacologic therapy Normalizing ICU atmosphere: sleep, light, alarms, family visitation Discontinue medications contributing to delirium Antipsychotics May be beneficial for hyperactive delirium 1 Haloperidol, quetiapine, olanzapine, ziprasidone have been published with some efficacy Adverse effects: sedation, QTc prolongation, EPS Medication reconciliation If treatment drugs are started, need to plan for taper or discontinue before ICU or hospital discharge** 1 Devlin J et al. Crit Care Med 2010 Feb:38(2):419-27.

Summary Think through sedation strategy on a case by case basis. Use individual drug characteristics to base decision.

Questions

PRN method study, Lancet 2010 Outcome data No sedation (n=55) Sedation (n=58) p value Days w/o MV 13 8 (11 0) 9 6 (10 0) 0 0191 * Length of stay (days) Intensive care unit 13 1 (5 7) 22 8 (11 7) 0 0316 * Hospital 34 (17 65) 58 (33 85) 0 0039 * Mortality Intensive care unit 12 (22%) 22 (38%) 0 06 Hospital 20 (36%) 27 (47%) 0 27 Drug doses (mg/kg) Propofol (per h of infusion) ** 0 (0 0 515) 0 773 (0 154 1 648) 0 0001 Midazolam (per h of infusion) 0 (0 0) 0 0034 (0 0 0240) <0 0001 Morphine (per h of MV) 0 0048 (0 0014 0 0111) 0 0045 (0 0020 0 0064) 0 39 Haloperidol (per day of MV) 0 (0 0 0145) 0 (0 0) 0 0140 Tracheostomy 16 (29%) 17 (29%) 0 98 Ventilator-associated pneumonia 6 (11%) 7 (12%) 0 85