Agitation in the ICU Have we swung the pendulum too far from benzodiazepines? Conflict of Interest The author of this presentation has no conflicts of interest to disclose Nina Vadiei, PharmD PGY1 Pharmacy Resident University Medical Center Brackenridge Seton Healthcare Family Clinical Adjunct Faculty University of Texas School of Pharmacy Objectives Provide an overview of ICU delirium and the 2013 Society of Critical Care Medicine (SCCM) Pain, Agitation, Delirium (PAD) Guidelines Analyze how the management of agitation has evolved Evaluate how sedation effects delirium outcomes Assess the role of benzodiazepines in the management of agitation Patient Case SS is a 35 year old male admitted s/p MVC driving reverse on I-35 diagnosed with traumatic brain injury and multiple rib fractures Placed on light sedation protocol with fentanyl and propofol Day 5, triglyceride level = 812 mg/dl What would Switched to dexmedetomidine you do? RASS = +2 A. Midazolam infusion B. Lorazepam intermittent bolus C. PRN quetiapine D. PRN haloperidol Why We Need Sedation Acute medical or surgical illness Underlying medical conditions Invasive interventions Mechanical ventilation Pain Anxiety Delirium Medication Hospital acquired illness Environmental stressors Sessler CN, et al. Chest 2008; 133; 552-65. The Balancing Act Oversedation Hypotension/bradycardia Prolonged mechanical ventilation Increased length of stay Complications Increased diagnostic testing Delirium Undersedation Hypertension/tachycardia Patient recall Agitation/anxiety Device removal Ventilator dysynchrony Pain/discomfort Jacobi J, et al. Crit Care Med 2002; 30: 119-41. Sessler CN, et al. Chest 2008; 133: 552-65. 1
Delirium Definition A syndrome characterized by the acute onset of cerebral dysfunction with a change or fluctuation of mental status, inattention, and either disorganized thinking or an altered level of consciousness. Classifications Hyperactive Mixed Hypoactive Agitation More often associated with hallucinations and delusions Mixed features of hyper and hypoactive Calm or lethargic More often associated with decreased alertness, apathy Overall Impact Delirium Predicts Mortality Objective Determine if delirium is an independent predictor of clinical outcomes Reintubation rate Length of stay Cost of care Mortality Longterm cognitive impact Design Population Interventions Single-center, prospective cohort study Mechanically ventilated MICU and coronary ICU patients Delirium group vs. No-delirium group Outcomes Primary: 6-month mortality, hospital LOS, overall LOS Secondary: Ventilator-free days, cognitive impairment at discharge Ely EW, et al. JAMA. 2004; 291(14): 1753-1762 Primary Outcomes Secondary Outcomes 6-month mortality Hospital LOS Overall LOS Ventilator-free days Cognitive Impairment 34% in delirium group died vs. 15% in no delirium group Delirium group spent median LOS 10 days longer Risk of remaining in hospital wards after ICU discharge 60% greater than those with no delirium Fewer days spent alive and free of ventilator (19 vs. 24) (p<0.001) Twice as many patients in delirium group with cognitive impairment at discharge (54.9% vs. 26.9%) (p=0.01) Ely EW, et al. JAMA. 2004; 291(14): 1753-1762 Ely EW, et al. JAMA. 2004; 291(14): 1753-1762 2
Overall Impact Long-Term Cognitive Impact Reintubation rate Length of stay Cost of care Mortality Long-term cognitive impact TBI = traumatic brain injury AD = alzheimer s disease Pandharipande PP, et al. NEJM 2013;369:1306-16. Etiology Disease-induced Shock, trauma, intra-cerebral hemorrhage, myocardial infarction, PE Iatrogenic or environmental Drug-induced Prolonged physical restraints and immobilization Drug and alcohol withdrawal Illicit or prescription drugs patients taking chronically Chronic alcohol use Demeure MJ et al. J Am Coll Surg. 2006; 203: 752-757 Risk Factors Paradigm Shift 2002 SCCM PAD Guidelines Benzodiazepine first-line sedative (midazolam/diazepam/lorazepam) (C) 2013 SCCM PAD Guidelines Avoidance of benzodiazepines (2B) Pandharipande P, et al. Crit Care Clin. 2006; 22: 313-327 Jakobi J, et al. Crit Care Med. 2002; 30(1): 119-141 3
Connecting the Dots BZD = Delirium = Mortality Patient Case SS is a 35 year old male admitted s/p MVC driving reverse on I-35 diagnosed with traumatic brain injury and multiple rib fractures Placed on light sedation protocol with fentanyl and propofol Day 5, triglyceride level = 812 mg/dl What would Switched to dexmedetomidine you do? RASS = +2 A. Midazolam infusion B. Lorazepam intermittent bolus C. PRN quetiapine D. PRN haloperidol Rise of Antipsychotics Used mostly for acute agitation PAD guidelines recommendations Haloperidol (C) Quetiapine (C) High variability in prescribing patterns Scant evidence-based recommendations regarding appropriate medical management Heterogeneity between trials Swan et al. Critical Care. 2012; 16: R84 Devlin JW, SkrobikY, Harv Rev Psychiatry. 2011; 19(2): 59-67 Rise of Antipsychotics % Respondent Use 90 80 70 60 50 40 30 20 10 0 Atypical AP Haloperidol 2001 2007 Ely EW, et al. Crit Care Med. 2004; 32:106-112 Patel RP, et al. Crit Care Med. 2009; 37: 825-832 Limited Antipsychotic Evidence Design Population Interventions Duration Results Conclusion Placebo- Intubated Haloperidol 2.5 mg IV 14 days or Same # days alive, Haloperidol shown randomized- patients > 18 Q8H (n=71) delirium free for delirium-free in both to be nonsuperior to double-blind- yo 2 consecutive groups (p=0.53) placebo for the placebo 0.9% saline placebo days treatment of controlled IV Q8H (n=70) delirium; patients single-center more at risk for oversedation Limited Antipsychotic Evidence Design Population Interventions Duration Results Conclusion Placebo- MICU and SICU Haloperidol 5 mg IV Q12H 14 days No difference in Ziprasidone nonsuperior randomized- patients x 24H, then Q6H (n=35) duration of delirium to haloperidol in the double-blind- (p=0.66) or secondary treatment of ICU placebo Ziprasidone 40 mg Q12H x outcomes (p=0.25) delirium controlled 24H, then Q6H (n=30) single-center Placeborandomizeddouble-blindplacebo controlled multi-center Adult ICU patients with delirium Quetiapine 50 mg Q12H; in 50 mg increments based on PRN haloperidol requirements (n=18) Placebo (n=18) Until delirium resolution, discharge, or 10 days Quetiapine shorter Quetiapine resolves time to first resolution many ICU delirium of delirium (p=0.001), symptoms faster less time agitated than placebo (p=0.02), fewer days requiring PRN haloperidol (p=0.05) Page VJ, et al. Lancet. 2013; 1(7): 515-523 Devlin JW, et al. Crit Care Med. 2010; 38(2): 419-27 Placeborandomized control trial Placebodouble blindrandomized control trial Mixed-floor, ICU + Oncology patients Mixed-floor, ICU + Oncology patients Olanzapine 5 mg daily (n=28) Haloperidol 2.5-5 mg Q8H (n=45) Risperidone 0.5 mg BID (n=12) Haloperidol 0.75 mg BID (n=12) 5 days Both agents reduced delirium symptoms (p=0.83) and benzodiazepine use (p=0.90) 7 days No difference in efficacy or response rate (p=0.35) Olanzapine noninferior to haloperidol in the treatment of ICU delirium Risperidone noninferior to haloperidol in the treatment of ICU delirium Girard TD, et al. Crit Care Med. 2010; 38(2): 428-37 Skrobik YK, et al. Intensive Care Med. 2004; 30(3): 444-9 Hans CS, et al. Psychosomatics. 2004; 45(4): 297-301 4
Consequences Cholinesterase inhibitors mentioned as possibly beneficial in American Psychiatric Association guidelines Off label use support by case series Maarten M, et al. first multicenter, randomized, placebocontrolled trial Mortality higher in rivastigmine group (n=12 vs. n=4, p=0.07) Study immediately halted! Rivastigmine use also associated with more severe delirium type and longer ICU stay Is there risk in using antipsychotics for agitation? Maarten M, et al. Lancet. 2010; 376: 1829-1837 Off Label Use in Elderly Atypical antipsychotics commonly used for off label conditions Agitation, dementia, anxiety Associated with increased mortality Only small improvement in global symptoms Other risks: QT prolongation, hypotension, extrapyramidal symptoms Maher AR, et al. JAMA. 2011; 306 Swan et al. Critical Care. 2012; 16:R84 Devlin JW, SkrobikY, Harv Rev Psychiatry. 2011; 19(2): 59-67 Have we swung the pendulum too far? Benzodiazepines Antipsychotics Patient Case SS is a 35 year old male admitted s/p MVC driving reverse on I-35 diagnosed with traumatic brain injury and multiple rib fractures Placed on light sedation protocol with propofol Day 5, triglyceride level = 812 mg/dl What would Switched to dexmedetomidine you do? RASS = +2 A. Midazolam infusion B. Lorazepam intermittent bolus C. PRN quetiapine D. PRN haloperidol Now what? Timeline of Benzodiazepine Use Recommended first-line for acute agitation in 2002 PAD guidelines 2013 guidelines suggest avoiding use as sedative to improve clinical outcomes Since 2013 guideline release, new studies warrant reconsideration Jakobi J, et al. Crit Care Med. 2002; 30(1): 119-141 5
Sedative Choice Outcomes Sedative Choice Outcomes Objective Design Population Interventions Outcomes To assess global cognition and executive function 3 and 12 months after discharge Multicenter, prospective cohort study Patients admitted to ICU with respiratory failure or shock Duration of delirium and use of sedative or analgesic medication Prevalence and severity of long-term cognitive impairment 3 and 12 months after discharge Delirium Duration Longer duration of delirium independently associated with worse global cognition and executive function (p=0.001) (-6.3 [-10.3 to -2.3]) Medication Use No independent association between higher doses of benzodiazepines and worse long-term cognitive scores Pandharipande P, et al. NEJM. 2013; 369;14 Pandharipande P, et al. NEJM. 2013; 369;14 Inflammation and Delirium Inflammation and Delirium Objective Design Population Interventions Outcomes To compare biological and drug treatment characteristics in patients with coma and/or delirium while in the ICU Single-center, prospective cohort study ICU patients admitted > 24 hours receiving IV fentanyl or IV midazolam Levels of inflammatory mediators present and doses of fentanyl and midazolam Correlation of clinical variables with delirium and association of inflammatory mediators with coma or delirium Midazolam correlation with incidence of delirium Time to first occurrence of delirium unrelated to administered doses of midazolam (p=0.4) Duration of delirium not associated with cumulative midazolam dose (p=0.25) Inflammatory mediators association with delirium 100% delirious patients vs. 33% comatose patients plasma IL-6 conc > 40 pg/ml 29% delirious vs. 7% comatose plasma IL-1B concentration above detectable level Skrobik, et al. Crit Care Med. 2013; 41(4): 999-1008 Skrobik, et al. Crit Care Med. 2013; 41(4): 999-1008 Sedation Depth and Mortality Outcomes Objective Design Population Interventions Outcomes To evaluate the relationship between early deep sedation, time to extubation, delirium, and long-term mortality Multicenter, prospective longitudinal cohort study MICU/SICU patients intubated 24 hours Deep vs. light sedation level at 48 hours (midazolam, propofol, and dexmedetomidine used) Time to extubation, subsequent delirium, in-hospital mortality, and 180-day mortality Extubation Deeply sedated patients had longer time to extubation (p=0.008) Delirium Time to delirium after 48 hours significantly shorter with deep sedation (p<0.001) Mortality Higher hospital (p=0.004) and 180-day mortality (p=0.001) Shehabi Y, et al. Intensive Care Med. 2013; 39:910 918 Shehabi Y, et al. Intensive Care Med. 2013; 39:910 918 6
Additional Findings Covariates adjusted for Sedatives used, diagnosis, age, APACHE II score, vasopressors, dialysis Found that cumulatitve midazolam dose in first 48 hours associated with RASS -3 to -5 Irrespective of sedative choice, early deep sedation was independently associated with delayed extubation and higher mortality Sedation Depth and Mortality PAD guidelines Greatest difference in time to awakening seen when deep sedation was the goal of therapy 2002 2013 Shehabi, et al. Early deep sedation predicts outcomes irrespective of sedative choice Shehabi Y, et al. Intensive Care Med. 2013; 39:910 918 Shehabi Y, et al. Intensive Care Med. 2013; 39:910 918 If sedation depth rather than sedative choice predicts outcomes Why were benzodiazepines shown to be less favorable than other sedative agents? PK/PD Sedatives Drug MOA T ½ Active-Metabolites Midazolam GABAa agonist 3-11 hr Yes* Lorazepam GABAa agonist 8-15 hr No Diazepam GABAa agonist 20-120 hr Yes* Propofol GABAa agonist 30-60 min No Dexmedetomidine Alpha 2 agonist 2 hr No *Active metabolites prolong sedation, especially in renal failure Reade MC, et al. NEJM. 2014; 370: 444-54 PK/PD Implications PK/PD Implications ICU Length of Stay Mechanical Ventilation Duration Delirium Prevalence All-cause Short-Term Mortality Carson 2006 Jakob 2012 Pandharipande 2007 Riker 2009 Roukonen 2009 Weinbroum 1997 Carson 2006 Jakob 2012 Pandharipande 2007 Riker 2009 Pandharipande 2007 Riker 2009 Carson 2006 Jakob 2012 Pandharipande 2007 Riker 2009-10 - 5 5 10-10 - 5 5 10 Non-BZD BZD Non-BZD BZD 0.01 0.1 10 100 0.01 0.1 10 100 Non-BZD BZD Non-BZD BZD Fraser, et al. Crit Care Med. 2013; 41(9): S30-38 Fraser, et al. Crit Care Med. 2013; 41(9): S30-38 7
Continuous Infusion Sedation Importance of Timing Jakob 2012 Pandharipande 2007 Riker 2009 Dexmedetomidine CI vs. Propofol CI or Midazolam CI Dexmedetomidine CI vs. Lorazepam CI Dexmedetomidine CI vs. Midazolam CI Methodological inconsistency in timing of delirium assessments regarding sedative administration Medication not always completely stopped prior to assessment Different sedatives = different half-lives Benzodiazepines take longer to clear Roukonen 2009 Weinbroum 1997 CI = continuous infusion Dexmedetomidine CI vs. Midazolam CI vs. Propofol CI Propofol CI vs. Midazolam CI Fraser, et al. Crit Care Med. 2013; 41(9): S30-38 Sedation stopped 0 2 4 6 8 10 12 14 Hours Propofol Midazolam Patel SB, et al. Am J Respir Crit Care Med. 2014; 189(6): 659-665 CAM-ICU Assessment CAM-ICU Assessment Feature 1 Is patient different than his/her baseline mental status? OR has patient had fluctuation in mental status in past 24 hours Feature 2 SAVEAHAART Feature 3 Present if RASS anything other than 0 (alert and calm) Feature 4 Ability to answer yes/no questions Copyright 2002, E. Wesley Ely, MD, MPH and Vanderbilt University, all rights reserved Feature 1 Is patient different than his/her baseline mental status? OR has patient had fluctuation in mental status in past 24 hours Feature 2 SAVEAHAART CAM-ICU Positive (delirium present) Feature 3 Present if RASS anything other than 0 (alert and calm) Feature 4 Ability to answer yes/no questions Copyright 2002, E. Wesley Ely, MD, MPH and Vanderbilt University, all rights reserved CAM-ICU Assessment Looking more closely Feature 1 Is patient different than his/her baseline mental status? OR has patient had fluctuation in mental status in past 24 hours Feature 2 SAVEAHAART CAM-ICU Positive (delirium present) Feature 3 Present if RASS anything other than 0 (alert and calm) Feature 4 Ability to answer yes/no questions Copyright 2002, E. Wesley Ely, MD, MPH and Vanderbilt University, all rights reserved Lorazepam is an Independent Risk Factor for Transitioning to Delirium in Intensive Care Unit Patients Anesthesiology. 2006. Lack of delirium assessments Lack of power A randomized trial of intermittent lorazepam verus propofol with daily interruption in mechanically ventilated patients Crit Care Med. 2006. Propofol group had more rapid awakening, leading to better performance of spontaneous breathing trials and earlier extubation Lorazepam group had earlier resumption of sedation Carson SS, et al. Crit Care Med. 2006; 34: 5 Pandharipande P, et al. Anesthesiology. 2006; 104 :21 6 8
Is Delirium Dichotomous? Sedation-Related Delirium Objective To compare rapidly-reversible, sedation-related delirium and persistent delirium Design Single-center, prospective cohort study Yes vs. No Heterogenous Population Adult intubated MICU patients Interventions Delirium type (none vs. rapidly-reversible vs. persistent) Outcomes Primary: Proportion of days with no delirium vs. rapidly-reversible vs. persistent Secondary: Number of ventilator, hospital, ICU days, 1-year mortality Patel SB, et al. Am J Respir Crit Care Med. 2014; 189(6): 659-665 Sedation-Related Delirium Sedation-Related Delirium ND RRD Mixed PD P-value Days MV 2.4 (1.3-3.1) 2.5 (1.6-2.8) 5.1 (2.2-12.0) 6.2 (3.7-12.0) <0.001 ICU LOS 4.0 (2.4-8.1) 4.5 (2.2-7.2) 9.7 (6.0-17.7) 13.1 (8.8-19.1) <0.001 Hospital LOS 8.1 (7.7-16.9) ND=no delirium RRD=rapidly-reversible delirium PD=persistent delirium 6.7 (3.8-16.4) 26.8 (9.8-50.0) 25.4 (13.6-29.6) <0.001 Patel SB, et al. Am J Respir Crit Care Med. 2014; 189(6): 659-665 % Discharged 100 80 60 40 20 0 ND RRD MD PD Home Other Institution Died/Hospice Patel SB, et al. Am J Respir Crit Care Med. 2014; 189(6): 659-665 Sedation-Related Delirium Rapidly reversible delirium persistent delirium Sedative-induced delirium sepsis-related delirium Persistent Sicker group, higher ages, more sepsis, likely more encephalopathy, 1-year mortality (p<0.001) Rapidly-reversible No difference in discharge disposition or mortality risk from patients with no delirium Future Considerations Benzodiazepines when administered intermittently may still have a role to play in the treatment of agitation PRN use in previous large randomized-controlled studies (PRODEX/MIDEX/Sedcom) Shown to be effective in achieving goal sedation Sedcom trial % PRN benzodiazepine use 63% Dexmedetomidine vs. 49% Midazolam (p=0.02) Patel SB, et al. Am J Respir Crit Care Med. 2014; 189(6): 659-665 9
Timeline of Benzodiazepine Use Recommended first-line for acute agitation in 2002 PAD guidelines 2013 guidelines suggest avoiding use as sedative to improve clinical outcomes Since 2013 guideline release, new studies Use of PRN benzodiazepines warrant reconsideration Patient Case SS is a 76 year old male admitted for acute respiratory failure requiring intubation Placed on light sedation protocol with fentanyl and propofol Day 5, TG level = 812 mg/dl Switched to dexmedetomidine RASS = +2, unable to achieve RASS -1 to -2 What would you do? Jakobi J, et al. Crit Care Med. 2002; 30(1): 119-141 Solution PRN benzodiazepines! Conclusions ICU Delirium has significant impact on outcomes in critically ill patients Major shift in prescribing patterns when literature identified BZD routine use to be an independent risk factor of increased mortality Minimal evidence to support routine use of antipsychotics to treat ICU delirium Studies after release of new SCCM guidelines suggest ICU delirium not linked to sedative choice but rather to sedation depth ICU delirium is not dichotomous, meaning treatment efficacy may be impacted by delirium classification Intermittent BZD use is still a valid option for management of agitation in the ICU and warrants future studies Acknowledgements Dr. Mitchell J. Daley, PharmD, BCPS Dr. Manasa S. Murthy, PharmD, BCPS THANK YOU!!! Agitation in the ICU Have we swung the pendulum too far from benzodiazepines? Nina Vadiei, RPh, PharmD PGY1 Pharmacy Resident University Medical Center Brackenridge Seton Healthcare Family Clinical Adjunct Faculty University of Texas School of Pharmacy 10
1 STEP Level of Consciousness Assessment Scale Label Description RICHMOND AGITATION-SEDATION SCALE (RASS) +4 COMBATIVE Combative, violent, immediate danger to staff +3 VERY AGITATED Pulls to remove tubes or catheters; aggressive +2 AGITATED Frequent non-purposeful movement, fights ventilator +1 RESTLESS Anxious, apprehensive, movements not aggressive 0 ALERT & CALM Spontaneously pays attention to caregiver -1 DROWSY Not fully alert, but has sustained awakening to voice (eye opening & contact >10 sec) -2 LIGHT SEDATION Briefly awakens to voice (eyes open & contact <10 sec) -3 MODERATE SEDATION Movement or eye opening to voice (no eye contact) If RASS is -3 proceed to CAM-ICU (Is patient CAM-ICU positive or negative?) -4 DEEP SEDATION No response to voice, but movement or eye opening to physical stimulation -5 UNAROUSABLE No response to voice or physical stimulation If RASS is -4 or -5 STOP (patient unconscious), RECHECK later V O I C E T O U C H Sessler, et al., Am J Repir Crit Care Med 2002, 166: 1338-1344 Ely, et al., JAMA 2003; 286, 2983-2991
CAM-ICU Worksheet Feature 1: Acute Onset or Fluctuating Course Is the patient different than his/her baseline mental status? OR Has the patient had any fluctuation in mental status in the past 24 hours as evidenced by fluctuation on a sedation/level of consciousness scale (i.e., RASS/SAS), GCS, or previous delirium assessment? Feature 2: Inattention Letters Attention Test (See training manual for alternate Pictures) Directions: Say to the patient, I am going to read you a series of 10 letters. Whenever you hear the letter A, indicate by squeezing my hand. Read letters from the following letter list in a normal tone 3 seconds apart. S A V E A H A A R T or C A S A B L A N C A or A B A D B A D A A Y Errors are counted when patient fails to squeeze on the letter A and when the patient squeezes on any letter other than A. Feature 3: Altered Level of Consciousness Present if the Actual RASS score is anything other than alert and calm (zero) Feature 4:Disorganized Thinking Yes/No Questions (See training manual for alternate set of questions) 1. Will a stone float on water? 2. Are there fish in the sea? 3. Does one pound weigh more than two pounds? 4. Can you use a hammer to pound a nail? Errors are counted when the patient incorrectly answers a question. Command Say to patient: Hold up this many fingers (Hold 2 fingers in front of patient) Now do the same thing with the other hand (Do not repeat number of fingers) *If the patient is unable to move both arms, for 2 nd part of command ask patient to Add one more finger An error is counted if patient is unable to complete the entire command. Score Either question Yes Number of Errors >2 RASS anything other than zero Combined number of errors >1 Check here if Present Overall CAM-ICU Feature 1 plus 2 and either 3 or 4 present = CAM-ICU positive Criteria Met Criteria Not Met CAM-ICU Positive (Delirium Present) CAM-ICU Negative (No Delirium) Copyright 2002, E. Wesley Ely, MD, MPH and Vanderbilt University, all rights reserved