Pain, Agitation and Delirium (PAD): An Overview of Recent Guidelines Brenda Pun, RN, MSN, ACNP Vanderbilt University Medical Center

Barr J, et al. Crit Care Med. 2013;41:263–306.

Pain, Agitation, and Delirium Are Interrelated Barr J, et al. Crit Care Med. 2013;41:263-306.

5 Key Themes 1. Goal = Light sedation 2. Sedative titration method = Daily Sedative Interruption or Targeted sedation 3. Avoid/Minimize Benzodiazepines 4. Early Mobility 5. No Med Recommendation for Delirium

#1: Light Sedation (rather than deep)

PAD Depth of Sedation Recommendations We recommend that sedative medications be titrated to maintain a light rather than a deep level of sedation in adult ICU patients, unless clinically contraindicated (+1B). Light Sedation: patient is arousable and able to purposefully follow simple commands Barr J, et al. Crit Care Med 2013; 41:263–306

Early Deep Sedation: Longer Ventilation, Reduced Survival Multicenter study (N=251) Deep sedation (RASS -3 to - 5) 76% within 4 hours of MV 68% at 48 hours Early deep sedation was independent predictor of time to extubation (P<0.001) Deeply sedated, 7.7 days Not deeply sedated, 2.4 days Early deep sedation was also an independent predictor of hospital death and 180-day mortality Survival Probability of death at 180 days Days Shehabi Y, et al. Am J Respir Crit Care Med. 2012;186:724-731.

Mental Health and Light vs Deep Sedation Sedation with midazolam Light: Ramsay 1-2, intermittent injection Deep: Ramsay 3-4, continuous infusion Results 4 weeks after ICU discharge the deep group: Higher PTSD Scores Trouble remembering the ICU Disturbing memories Patients: adults requiring mechanical ventilation Treggiari MM, et al. Crit Care Med. 2009 Sep;37(9):2527-2534.

#2: Sedative Titration Method Daily Sedative Interruption Light Targeted Titration

PAD Titration Recommendations We recommend either daily sedation interruption or a light target level of sedation be routinely used in mechanically ventilated adult ICU patients (+1B). Barr J, et al. Crit Care Med 2013; 41:263–306

Daily Sedation Interruption Methods: Hold sedation infusion until patient awake and then restart at 50% of the prior dose Results: Shorter time on the ventilatory Shorter stay in the ICU Fewer diagnostic tests to assess changes in mental status No increase in rate of agitated-related complications or episodes of patient-initiated device removal No increase in PTSD or cardiac ischemia Open eyes in response to voice Use eyes to follow investigator on request Squeeze hand on request Stick out tongue on request Kress JP, et al. N Engl J Med. 2000;342:1471-1477. Kress, JP, et al. AJRCCM 2003; 168: 1457-1461

Wake up and Breathe (ABC) Study The ABC protocol reduced…. Duration of mechanical ventilation by ~3 days ICU and hospital length of stay by ~4 days Duration of coma by ~1 day 32% lower likelihood of dying and a number needed to treat (NNT) of 7 to save a life at 1 year A: Spontaneous Awakening Trials B: Spontaneous Breathing Trials Girard TD, et al. Lancet. 2008;371:126-134.

Nursing-Implemented Sedation Protocol: Barnes Jewish Pilot Significant patient characteristics/metrics/outcomes Protocol Routine P value CIVS† 66 (40) 66 (42) 0.9 Duration CIVS, hrs* 3.5 ± 4 5.6 ± 6.4 0.003 Bolus† 118 (72) 127 (80) 0.14 Reintubated† 14 (8.6) 21 (13) 0.2 Trached† 10 (6.2) 21 (13.2) 0.04 *Data presented in median; †Data presented as n (%) CIVS: continuous intravenous infusion sedation P < 0.001 P = 0.13 P = 0.003 Single center, prospective, trial of 332 consecutive ICU patients requiring mechanical ventilation randomized to protocolized sedation (n = 162) or routine care (n = 159) at Barnes Jewish Hospital from 8/97 to 7/98. Protocol used goal orientated sedation to target Ramsey with bolus requirements before initiation of continuous infusion and uptitration of opioids and benzodiazepines. Brook AD, et al. Crit Care Med. 1999;27(12):2609-2615.

Pharmacist Enforced Adherence to an ICU Sedation Guideline Significant patient characteristics/metrics/outcomes RPh Control P value Alcohol/drug overdose† 15 (19.2) 6 (7.7) 0.03 Lorazepam equivalents/vent day, mg* 65.2 ± 114.1 74.8 ± 76.1 0.54 Fentanyl equivalents/vent day, mcg* 102.5 ± 328 400 ± 1026 0.02 *Data presented in mean ; †Data presented as n (%) P = 0.002 P = 0.0004 102.5 ± 328 Single center trial of 156 adult MICU patients requiring mechanical ventilation before (n = 78) and after (n = 78) implementation of RPh enforced guideline sedation management at Boston Medical Center. Guideline addressed use of agent selection, goal oriented therapy, and dose limitation strategies. Marshall J, et al. Crit Care Med. 2008;36(2):427-433.

#3: Avoid/Minimize Benzodiazepine use

PAD Choice of Sedative Recommendations We suggest that analgesia-first sedation be used in mechanically ventilated adult ICU patients (+2B). We suggest that sedation strategies using nonbenzodiazepine sedatives (either propofol or dexmedetomidine) may be preferred over sedation with benzodiazepines (either midazolam or lorazepam) to improve clinical outcomes in mechanically ventilated adult ICU patients (+2B). We suggest that in adult ICU patients with delirium unrelated to alcohol or benzodiazepine withdrawal, continuous IV infusions of dexmedetomidine rather than benzodiazepine infusions be administered for sedation to reduce the duration of delirium in these patients (+2B). Barr J, et al. Crit Care Med 2013; 41:263–306

Analgosedation Analgesia Sedation vs. Hypnotic Sedation Analgesic first sedation + supplement with hypnotic sedative Treats pain + provides sedation Remifentanil Fentanyl Morphine Not appropriate for drug or alcohol withdrawal Park G, et al. Br J Anaesth. 2007;98:76-82. Rozendaal FW, et al. Intensive Care Med. 2009;35:291-298.

Analgosedation Study Results Patients receiving analgosedation had More days without ventilation (13.8 vs 9.6 days, P = 0.02) Shorter stay in ICU (HR 1.86, P = 0.03) Shorter stay in hospital (HR 3.57, P = 0.004) More agitated delirium (N = 11, 20% vs N = 4, 7%, P = 0.04) No differences found in Accidental extubations Need for CT or MRI Ventilator-associated pneumonia Strøm T, et al. Lancet. 2010;375:475-480.

PAD Choice of Sedative Recommendations We suggest that analgesia-first sedation be used in mechanically ventilated adult ICU patients (+2B). We suggest that sedation strategies using nonbenzodiazepine sedatives (either propofol or dexmedetomidine) may be preferred over sedation with benzodiazepines (either midazolam or lorazepam) to improve clinical outcomes in mechanically ventilated adult ICU patients (+2B). We suggest that in adult ICU patients with delirium unrelated to alcohol or benzodiazepine withdrawal, continuous IV infusions of dexmedetomidine rather than benzodiazepine infusions be administered for sedation to reduce the duration of delirium in these patients (+2B). Barr J, et al. Crit Care Med 2013; 41:263–306

Propofol vs. Benzodiazepines Randomized Trial ICU Comparator Superior Ronan et al.1995 Surgical Midazolam Propofol Chamorro et al. 1996 General Hsiao et al. 1996 Equivalent Kress et al. 1996 Medical Barrientos-Vega et al. 1997 Searle et al. 1997 Cardiac Weinbroum et al. 1997 Both Sanchez-Izquierdo-Riera JA, et al. 1998 Trauma Hall et al. 2001 Mixed Carson et al. 2006 Lorazepam Outcomes improved by propofol: sedation quality, ventilator synchrony, time to awakening, variability of awakening, time to extubation from discontinuation of sedation, overall time to extubation, ventilator days, ICU LOS among survivors, costs of sedation

Dexmedetomidine vs Benzodiazepines Trials with better outcomes with Dex Population Outcome Improved   Pandharipande et al/2007 Mixed ICU More accurate sedation, more delirium/coma-free days   Riker et al/2009 Lower prevalence of delirium, earlier extubation   Ruokonen et al/2009 Shorter duration of mechanical ventilation   Maldonado et al/2009 Cardiac surgery Lower incidence and duration of delirium   Esmaoglu et al/2009 Eclampsia Shorter ICU length of stay   Dasta et al/2010 Lower ICU costs   Jakob et al/2012 General ICU Lighter sedation, fewer ventilation days Relatively consistent answer: more accurate sedation, more days without Delirium or coma, shorter duration of MV support and ICU stay Trials with better outcomes with Benzo’s = None Ely EW, et al. Chest. 2012;142(2);287-289.

#4: Early Mobility

Early Mobility in the ICU Early exercise = progressive mobility Study design: paired SAT/SBT protocol with PT/OT from earliest days of mechanical ventilation Wake Up, Breathe, and Move Schweickert WD, et al. Lancet. 2009;373:1874-1882.

Early Mobility Study Results: Return to independent functional status at d/c (59% vs 35%) Decrease in ICU and Hosp Delirium (2 vs 4 days) Decrease in time on Vent 6/10 back to independent functional status vs 4/10. For every 10 patients 2 more were back to baseline. Schweickert WD, et al. Lancet. 2009;373:1874-1882.

#5: No medication recommendation for the treatment of delirium

During the ICU/Hospital Stay After Hospital Discharge Delirium Risks Increased mortality Longer intubation time Average 10 additional days in hospital Higher costs of care During the ICU/Hospital Stay Increased mortality Development of dementia Long-term cognitive impairment Requirement for care in chronic care facility Decreased functional status at 6 months After Hospital Discharge 28

PAD Treatment of Delirium Recommendations There is no published evidence that treatment with haloperidol reduces the duration of delirium in adult ICU patients (No Evidence). Atypical antipsychotics may reduce the duration of delirium in adult ICU patients (C). We do not recommend administering rivastigmine to reduce the duration of delirium in ICU patients (–1B). Barr J, et al. Crit Care Med 2013; 41:263–306

The MIND Study Design: Randomized and double-blind Haloperidol Ziprasidone Placebo n = 35 n = 32 n = 36 Design: Randomized and double-blind Multisite (6 centers), 103 MV patients PO/IM delivery of study drug Results: No difference in any outcome No difference in any side effect To demonstrate the feasibility of a double-blind, placebo-controlled, randomized trial of antipsychotics in mechanically ventilated ICU patients To test the hypothesis that antipsychotics are efficacious and safe for the prevention and treatment of ICU delirium Girard TD, et al. Crit Care Med. 2010;38(2):428-437.

PAD Treatment of Delirium Recommendations There is no published evidence that treatment with haloperidol reduces the duration of delirium in adult ICU patients (No Evidence). Atypical antipsychotics may reduce the duration of delirium in adult ICU patients (C). We do not recommend administering rivastigmine to reduce the duration of delirium in ICU patients (–1B). Barr J, et al. Crit Care Med 2013; 41:263–306

Delirium + Haloperidol PRN Quetiapine vs. Placebo Delirium + Haloperidol PRN Quetiapine (n = 18) Placebo (n = 18) Design: Randomized, double-blind, placebo-controlled Multisite (3 centers), 36 ICU patients PO delivery of study drug Results: Faster delirium resolution & Less agitation Greater rate of transfer to home or rehabilitation Titrated in response to Haldol dosing q50mg intervals every 12 hrs. IV prn Haldol 1-10,mg up to q2hrs no other antipsychotics or continuous infusions allowed. 10 day treatment Dosing info From article: The study drug was continued until one of the following occurred: (1) the subject was deemed by the attending intensivist, based on their clinical judgment, to no longer demonstrate signs of delirium and, therefore, to no longer require scheduled therapy with an antipsychotic agent; (2) 10 days of therapy had elapsed; (3) ICU discharge occurred; or (4) an adverse event potentially attributable to the study drug occurred that warranted discontinuation of the study drug. Allowing the attending intensivist to discontinue study drug once the subject no longer had signs of delirium was consistent with existing clinical practice in our institutions. In situations in which 10 days of therapy was reached or the subject was ready to transfer out of the ICU while still receiving study drug, the subject’s treatment assignment was revealed to the attending intensivist (but not the study team) to help determine the best course of therapy (which could include continued therapy with quetiapine). Limitations: patient safety (3, 41, 44, 48, 49). A number of potential limitations of our study must be considered when evaluating the results. Although adequate to demonstrate a difference in our primary outcome, our sample size was not large enough to reliably detect differences in any of the efficacy or safety outcomes. In addition, the multiple analyses that were completed may have contributed to an inflated type 1 error. Therefore, our investigation should be considered a pilot study. The rigorous study inclusion criteria that we chose lead to only 14% of To accommodate the varying duration of delirium seen in clinical practice, we did not require a minimum duration of study drug treatment, instead allowing the subject’s intensivist to discontinue study drug when delirium was thought to have resolved or the subject was ready to transfer from the ICU. Given its fluctuating nature, considering delirium resolved when first noted to be absent may be premature, but it is a reasonable and reproducible event. In addition, study drug may have been discontinued prematurely in subjects with hypoactive delirium, although the optimal way to treat these patients is not well-defined (3, 50–53). Whereas the same “as-needed” haloperidol dosing protocol was used for all study patients, the average dose of haloperidol that was administered was lower than the dose recommended in some guidelines and may reflect increasing safety concerns among clinicians regarding the use of high-dose haloperidol therapy (9, 54). The greater use of haloperidol in patients receiving placebo could have diminished the treatment effect of quetiapine that was observed. Devlin JW, et al. Crit Care Med. 2010;38(2):419-427.

PAD Treatment of Delirium Recommendations There is no published evidence that treatment with haloperidol reduces the duration of delirium in adult ICU patients (No Evidence). Atypical antipsychotics may reduce the duration of delirium in adult ICU patients (C). We do not recommend administering rivastigmine to reduce the duration of delirium in ICU patients (–1B). Barr J, et al. Crit Care Med 2013; 41:263–306

Rivastigmine for Delirium? FDA approved for dementia of Alzheimer’s or Parkinson’s Cholinesterase inhibitor Result Mortality (vs placebo): 22% vs 8%, P = 0.07 Delirium (vs placebo): 5 vs 3 days, P = 0.06 Conclusion: Need RCTs for delirium as endpoint Don’t use rivastigmine for ICU delirium Survival (%) Time (days after inclusion) Lancet. 2010 Nov 27;376(9755):1829-37. Epub 2010 Nov 4. Effect of rivastigmine as an adjunct to usual care with haloperidol on duration of delirium and mortality in critically ill patients: a multicentre, double-blind, placebo-controlled randomised trial. van Eijk MM, Roes KC, Honing ML, Kuiper MA, Karakus A, van der Jagt M, Spronk PE, van Gool WA, van der Mast RC, Kesecioglu J, Slooter AJ. Source Department of Intensive Care Medicine, University Medical Centre, Utrecht, Netherlands. Abstract BACKGROUND: Delirium is frequently diagnosed in critically ill patients and is associated with adverse outcome. Impaired cholinergic neurotransmission seems to have an important role in the development of delirium. We aimed to establish the effect of the cholinesterase inhibitor rivastigmine on the duration of delirium in critically ill patients. METHODS: Patients (aged ≥18 years) who were diagnosed with delirium were enrolled from six intensive care units in the Netherlands, and treated between November, 2008, and January, 2010. Patients were randomised (1:1 ratio) to receive an increasing dose of rivastigmine or placebo, starting at 0·75 mL (1·5 mg rivastigmine) twice daily and increasing in increments to 3 mL (6 mg rivastigmine) twice daily from day 10 onwards, as an adjunct to usual care based on haloperidol. The trial pharmacist generated the randomisation sequence by computer, and consecutively numbered bottles of the study drug according to this sequence to conceal allocation. The primary outcome was the duration of delirium during hospital admission. Analysis was by intention to treat. Duration of delirium was censored for patients who died or were discharged from hospital while delirious. Patients, medical staff, and investigators were masked to treatment allocation. Members of the data safety and monitoring board (DSMB) were unmasked and did interim analyses every 3 months. This trial is registered with ClinicalTrials.gov, number NCT00704301. FINDINGS: Although a sample size of 440 patients was planned, after inclusion of 104 patients with delirium who were eligible for the intention-to-treat analysis (n=54 on rivastigmine, n=50 on placebo), the DSMB recommended that the trial be halted because mortality in the rivastigmine group (n=12, 22%) was higher than in the placebo group (n=4, 8%; p=0·07). Median duration of delirium was longer in the rivastigmine group (5·0 days, IQR 2·7-14·2) than in the placebo group (3·0 days, IQR 1·0-9·3; p=0·06). INTERPRETATION: Rivastigmine did not decrease duration of delirium and might have increased mortality so we do not recommend use of rivastigmine to treat delirium in critically ill patients. http://www.accessdata.fda.gov. Accessed March 2012. Van Eijk MM, et al. Lancet . 2010;376(9755):1829-1837.

Helpful Approach to Delirium Management Stop THINK Lastly Medicate

What to THINK if positive for delirium Toxic Situations CHF, shock, dehydration Deliriogenic meds (tight titration) New organ failure (liver, kidney, etc) Hypoxemia; Infection/sepsis (nosocomial), Immobilization Nonpharmacological interventions K+ or Electrolyte problems

Pain, Agitation, and Delirium Are Interrelated Barr J, et al. Crit Care Med. 2013;41:263-306.

PAD Interdisciplinary Team Integrated Approach to PAD MD Champion RN Champion RT Champion Pharmacy Champion Physical Therapy Champion Hospital Administrators Family Patient Courtesy J Barr, MD

Teach your team how to Communicate and Think!

If you give a man a fish, he will eat for a day If you give a man a fish, he will eat for a day. If you teach a man to fish, he will eat for a lifetime. Chinese Proverb

Start with the Foundation: Assessment Pain CPOT BPS Agitation SAS RASS Delirium CAM-ICU ICDSC Barr J, et al. Crit Care Med. 2013;41:263-306.

Brain Road Map Where is the patient going? (Target Sedation Level) 2. Where is the patient now? (Current PAD Assessnent) 3. How did they get there? Drug exposures © Brian Sloan via Flickr

Brain Road Map Script for Rounds Investigate (Ask these questions) Report (only takes 10 seconds) Where is the patient going? Target level of consciousness (RASS/SAS) Where is the patient now? Actual level of consciousness Delirium assessment (CAM-ICU/ICDSC) Pain Assessment Scale (BPS/CPOT) How did they get there? Drug exposures Without appropriate cognitive status information, management may not match the needs of the patient.

Brain Road Map Example Investigate (Ask these questions) Report (only takes 10 seconds) Where is the patient going? Target/Goal is RASS -1/0 Where is the patient now? Currently: RASS is -3 (-3 and -4 for past 6 hrs) CAM-ICU positive CPOT of 4 How did they get there? Propofol infusion 40 mcg/kg/min & intermittent fentanyl for pain Without appropriate cognitive status information, management may not match the needs of the patient.

5 Key Themes 1. Goal = Light sedation 2. Sedative titration method = Daily Sedative Interruption or Targeted sedation 3. Avoid/Minimize Benzodiazepines 4. Early Mobility 5. No Med Recommendation for Delirium

www.ICUdelirium.org Questions? Brenda.Pun@vanderbilt.edu The website is a great resource. www.ICUdelirium.org Brenda.Pun@vanderbilt.edu