educational session abstract 2010 ashp midyear clinical

EDUCATIONAL SESSION ABSTRACT 2010 ASHP Midyear Clinical Meeting

Anaheim, California

2231 Sedation Management in the Intensive Care Unit and Case Discussion Dasta, JF The Ohio State University, 500 West 12th Ave., Columbus, OH 43210, USA. Email: [email protected] In the 1990s, ICU patients received heavy sedation in an attempt to keep patients comfortable while receiving mechanical ventilation. However, more recent studies reveal that lower sedation dosages and daily interruption of sedatives results in better care and shortens the time on the ventilator and in the ICU. Although propofol has the advantage of being short acting, it can result in ADRs from lipid load and can result in metabolic acidosis and cardiac failure. Benzodiazepines which are commonly used are GABA‐mimetic and can increase the likelihood of developing delirium. Midazolam, in particularly, can have prolonged effects after being discontinued. Dexmedetomidine is not a GABA‐mimetic and may cause less delirium. It can cause hypotension and bradycardia. In addition, despite a higher acquisition cost, patients receiving dexmedetomidine have lower ICU costs compared to patients receiving midazolam. Learning Objectives:

1. Describe how sedation practice has changed in last 15 years. 2. List key findings influencing these changes. 3. Determine impact of dexmedetomidine on ICU costs.

SelfAssessment Questions: (True or False)

1. The use of heavy sedation was common in the 1990’s. 2. Mechanically ventilated ICU patients randomized to physical therapy and

lower dosages of sedatives had shorter stays in the MICU and hospital. 3. Large clinical trials of dexmedetomidine reveal that the drug should not be

administered beyond 24 hours. Answers: 1. (T); 2 (T); 3. (F)

Tuesday, December 7, 20109:00 AM – 11:00 AM

The Program Chair and presenters for this continuing pharmacy education activity report no relevant financial relationships except:

Joseph Dasta - Hospira and Eisai Pharmaceuticals consultant; France Foundation Speaker's Bureau member

John Devlin - Hospira and AstraZeneca research grant recipient

Joseph F. Dasta, M.Sc, FCCM, FCCPProfessor Emeritus, The Ohio State University

Adjunct Professor, The University of Texas

Describe how sedation practice has changed in last 15 years

List key findings influencing these hchanges

Determine impact of dexmedetomidine and propofol on total costs

71 yo white male admitted to ICU on December 7, 1995 with CAP

PMH: COPD, Heart failure, CKDF b il hi h hit bl d ll t Febrile, high white blood cell count

Agitated and on mechanical ventilator QUESTION- What level of sedation

do you think he is receiving?

A agitatedB calm and cooperativeC sedatedD S d t dD very SedatedE unarousable

Crit Care Med. 1999;27:1325-1329.

2010 ASHP Midyear Clinical Meeting Supplemental Handout

© 2010 American Society of Health-System Pharmacists Page 1 of 5

A agitatedB calm and cooperativeC sedatedD S d t dD very SedatedE unarousable

Crit Care Med. 1999;27:1325-1329.

A propofol only (new kid on the block)B benzodiazepine onlyC propofol and a benzodiazepineD i id d d ti ( )D opioid and sedative (s)

Years # Articles 1960-69 8 1970-79 80 1980-84 85 1985-89 197 1990-1994 613 1995-1999 991 2000-2004 1576 2005-2009 1838 SCCM sedation guidelines

(2010 database of articles) 18,874

Crit Care Clinics 2009;25:527

Crit Care Med 2009;37:3031 (with permission from LWW)



p = 0 03

p =0.47 Significant patient characteristics/metrics/outcomes

Light Deep P value

PTSD score ICU discharge*

52 57 0.39

PTSD score 4wks post ICU*

46 56 0.07p = 0.03

p = 0.024wks post ICU

Depression cases ICU discharge†

3 (5) 10 (19) 0.02

*Data presented in mean †Data presented as n (%) Event Scale-Revised PTSD

Single center, prospective, open label trial of 137 ICU patients requiring mechanical ventilation randomized to light (Ramsey 1-2) or deep (Ramsey 3-4) sedation at Geneva Hospital Switzerland. Extensive exclusion criteria, removing high risk patients and those with baseline cognitive dysfunction.

Crit Care Med. 2009 Sep;37(9):2527-34.

Before-after study in 57 MICU patients Intervention: Active OT/PT and lower sedation

target ICU days receiving BZ (50% vs. 25%) Daily midazolam equivalent dose (47 vs 15 mg) Daily midazolam equivalent dose (47 vs. 15 mg) More days alert and without delirium 2.1 fewer MICU days 3.1 fewer hospital days Hence “less” may be better than “more” Consistent with daily interruption data

Arch Phys Med Rehabil 2010;91:536

December 7, 2010 Same patient in the ICU Fancier ventilator

M t d t More pressure to reduce costs “My budget is more important than

your budget” Less reimbursement for bad care More ICU pharmacists on rounds

A agitatedB calm and Cooperative C sedatedD S d t dD very SedatedE unarousable

Crit Care Med 1999;27:1325-1329.

Nurses like to titrate drug For each shift, reduce dosage to talk with

patient, but often followed by bolus propofol to re-sedate the patient

One study showed propofol most common for “overrides” using smart pumps

Patient will be in ICU for several days

Why use a short acting drug like propofol?

Am J Health-Syst Pharm 2005; 62: 530

Apparently hard to manufacture

How many have experienced shortage??

Propoven© (approved importation)

▪ No preservative

▪ Contraindicated in peanut allergy High tryglycerides in 18%; of whom 10% develop

pancreatitis PRIS (Propofol-related infusion syndrome)

Recent study 1.1% incidence (18% mortality)

Few received >83 ug/kg/min

Crit Care Med 2010;38:S231; Crit Care 2009;13:R169



Following day 3 of propofol Depleted existing supply What are alternatives for this patient?

B di i Benzodiazepines Opioids Dexmedetomidine Fospropofol ??

GABA-mimetics are deliriogenic

Documented for lorazepam and midazolam Midazolam prolonged effect with long-term

therapypy Propylene glycol toxicity with lorazepam Easier to oversedate patients compared to

propofol or dexmedetomidine

Crit Care Med 2010;38:S231

Retrospective cohort from project IMPACT IV infusion drug usage analysis 2001 2.0% of patients 2007 7.2% of patients

C di i (1 4% 20 2%) Cardiac surgery patients (1.4% to 20.2%) 19% of ICUs 2001, 50% in 2007 31% received dexmedetomidine >24 hours 94 articles in humans published in the last year

Anesthesiology 2010;113:386

A patient doesn’t need to be in a coma to be adequately sedated

Cooperative sedation Loading dose usually not neededg y Dosage > 0.7 mcg/kg/hr safely given Duration > 24 hr doesn’t cause rebound Minimize hypotension with slow titration Cautious usage with beta-blocker/ccb Higher drug cost yet lower ICU cost compared

to midazolam infusionAnn Pharmacother 2009;43:2064-74

Dex duration: median 5 (2-6) vs. 3.5 (2-5) days Dex dosage: median 0.74 vs. mean 0.83 ug/kg/hr MENDS: Dex more time at target sedation SEDCOM: Dex equal time at target sedation MENDS: Dex lower delirium free and coma free MENDS: Dex lower delirium-free and coma free

days, lower coma-free days, lower % delirious Dex higher bradycardia in both SEDCOM: more hyperglycemia, lower tachycardia MENDS: NSD tachycardia, hypotension, ICU costs

JAMA 2009;301:489, Crit Care 2010; 14:R38, JAMA 2007;298:2644

p = 0.04

p = 0.55

p = 0.20

All patients

Single center analysis of adult patients expected to require mechanical ventilation for >48 hrs and who required >10 mg of lorazepam or a continuous infusion of a sedative to achieve adequate sedation, randomized to intermittent lorazepam or propofol titrated to Ramsay 2-3, with daily interruption in both groups

Crit Care Med. 2006 May;34(5):1326-32.



Two recent studies

This is a decision analysis model of a clinical trial

Direct costs were incorporated in the d l d dj t d t 2007 d llmodel and adjusted to 2007 dollars

ICU costs based on previously published data

Crit Care Med. 2008;36:706, Crit Care Med. 2005;33:1266Crit Care Med. 2008;36:706

Propofol group had lower costs $45,631 vs. $52,009

Three more ventilator-free daysP f l l tl Propofol was less costly or more effective in 94% and 90% of the 1000 simulations, respectively

Crit Care Med. 2008;36:706. Crit Care Med. 2008;36:706

• Median drug costs• Dex $1,166• Midazolam $60

• Total ICU patient savings with Dex: $9679

• Reduced ICU stay R d d MV

Adapted from Crit Care Med. 2010;38:497-503.

P < 0.01 P < 0.05

P < 0.01

• Reduced MV

Lighter degree of sedation is preferred Cautiously use propofol (lower dosage and shorter

duration) Limit exposure to GABA-mimetics Pharmacoeconomics (tool to help decisions)( p )

Assess your practice patterns compared to studies---do the findings apply to my hospital?

Despite higher acquisition cost, dexmedetomidine lowers ICU cost compared to midazolam infusions and propofol lowers cost compared to intermittent lorazepam




Anaheim, California

2232 Pain Management in the Intensive Care Unit and Case Discussion Erstad, B.L. University of Arizona College of Pharmacy, 1703 E. Mabel St., Tucson, Arizona, USA Email: [email protected] This presentation uses embedded multiple choice questions as an active learning strategy for discussing pain management in the intensive care unit. The talk begins with a case of a patient admitted to an intensive care unit after trauma. The case leads into a brief discussion of pain assessment followed by general principles of pain management in the critically ill patient. The important distinction between analog‐sedation and sedato‐analgesia will be discussed next since this has applicability not only for the care of the critically ill patient, but also for interpretation of research trials involving combinations of sedatives and analgesics. The next portion of the presentation pertains to adverse effects of opioids with special consideration of opioid‐induced bowel dysfunction, immunomodulation, and serotonin syndrome. The last portion of the presentation addresses the unique issues associated with non‐opioid analgesic use in the critically ill patient. Learning Objectives:

1. Describe the implications of using an analgo‐sedation versus a sedato‐analgesia approach when caring for a critically ill opioid tolerant patient

2. Discuss the pros and cons of using an opioid‐only versus an opioid‐sparing approach when caring for a critically ill opioid tolerant patient

SelfAssessment Questions:

1. Which of the following statements is true regarding a trial of ventilated patients that compared a no sedation regimen (analgesia‐based regimen with minimal sedation prn) to a sedative‐based regimen with prn analgesia?

a. The length of stay was higher in the no sedation group (i.e., the analgesia‐based regimen)

b. The length of stay was lower in the no sedation group (i.e., the analgesia‐based regimen)

c. The incidence of delirium was the same in both the no sedation and the sedation groups

d. The number of healthcare workers needed to care for patients was similar in both groups

2. In the only randomized controlled trial that compared IV infusions of midazolam to IV infusions of a combined midazolam + fentanyl, what was the result?

a. Fewer daily dose adjustments in the midazolam only group b. Drug costs were significantly less in the midazolam only group


Anaheim, California

c. Significantly less ventilator asynchrony in the combined group d. Significantly less time to sedation in the combined group

3. Which of the following conditions is most likely to be responsive to an opioid tapering strategy?

a. Opioid tolerance b. Subtherapeutic opioid doses c. Opioid‐induced hyperalgesia d. Inadequate pain control

Answers: 1. b; 2. c; 3. c

Pain Management in the Intensive Care Unit and Case Discussion

Brian L. Erstad, Pharm.D., FASHPProfessor

University of Arizona

Disclosures

The author of this presentation has no disclosures concerning possible financial or personal relationships with commercial entities that may have a direct or indirect interest in thethat may have a direct or indirect interest in the subject matter of this presentation

Overview of Presentation

Case presentation General principles of pain management in ICU Analgo-sedation versus sedato-analgesia OpioidsOpioids General comparisons

Adverse effects

Conversions Non-opioid analgesics/adjuncts

33 y/o obese man with leg injury 2 days PTA from MVA

PMH: not significant per patient but difficult to elicit due to painFH/SH/DH t bl t

Case Presentation

FH/SH/DH: not able to assess Afebrile but tachycardia with severe pain Initial BP 170/70 mm Hg Swollen leg with subcutaneous

emphysema and two bullae WBC 18.1 x 109/L with 29% bands

Case Continued… Case Continued…

Started on broad spectrum antibiotics –taken to OR Extensive debridement for necrotizing fasciitis

Recovery room: respiratory distress requiring reintubation, bradycardia, hypotension

All cultures grew Group A Streptococcus Prolonged ICU and hospital stay with

multiple trips to OR for further debridements Postop course also complicated by severe

pain and renal dysfunction



Pain Management in the ICULack of high-level evidence for clinical decision making

Data typically extrapolated from studies in other settings

Substantial intra/inter-patient variability in response

Difficult to distinguish ADEs from other medical problems

Rapid titration of pain meds so risk of increased ADEs

Bioavailability concerns with non-IV routes

Unique considerations with specialized analgesia

Challenges with pain assessment

Pain Assessment Beyond scope of this presentation, but… Assessment itself may alter patient outcomes Post hoc analysis of prospective cohort of ventilated patients

who had pain assessed or not assessed on ICU day 2 Used propensity scoring to adjust for co-morbidities etc. Univariate analysis: patients with assessment had ↓ vent time

( 8 vs. 11 d) and ICU LOS (13 vs. 18 d), p<0.01 for both After adjustment for baseline characteristics, patients with

assessment had ↑ odds of weaning from ventilator (OR=1.4, 95%CI=1.00-1.98) and ICU DC (OR=1.43, 95%CI=1.02-2.00)

Assessment group also had ↑ use of nonopioids and fentanyl, ↓ sedation assessment and ↓ sedative use, ↓ NMBA use▪ Payen JP et al. Anesthesiology 2009;111:1308

Question

The trauma resident caring for the patient is talking to you about postop pain management and makes several questionable statements. Which of his following statements regarding fentanyl is true?

A. It offsets beneficial effects of dexmedetomidine on delirium

B. It is only opioid that has been associated with chest rigidity

C. Its duration of action is short regardless of dosing regimen

D. It is preferred over morphine in patients with renal failure

Analgo-Sedation vs. Sedato-Analgesia MENDS/SEDCOM trials Efficacy versus effectiveness No mandated daily sedative interruptions or

weaning protocols in either trial How might results change? How might results change?

Continuous infusions of benzodiazepines to match infusions of dexmedetomidine What about bolus dose benzodiazepines? What about a comparions to propofol?

Fentanyl boluses for pain (sedato-analgesia) 4-fold ↑ in requirements with dexmedetomidine in

MENDS but still had benefits with respect to delirium

Analgo-Sedation ICU Trial

Ventilated ICU patients (n=428) randomized to no sedation vs. sedation with daily interruption No sedation group given morphine 2.5-5 mg boluses

(no validated pain scale) with: ▪ Haloperidol for delirium (DSM IV), propofol prn (subjective)

Sedation group given morphine boluses plus:▪ Titrated propofol infusion changed to midazolam at 48 h)

Both ICU and hospital LOS ↓ in no sedation group (p=0.0316 and p=0.0039, respectively), but ↑delirium (p=0.0400)

and ↑ healthcare personnel (p=0.0247)

▪ Strom et al. Lancet 2010;375:475

Analgo-Sedation ICU Trial

Open-label (randomized) involving 105 mixed ICU patients expected to receive mechanical ventilation > 72 hours (protocol change after 30 patients)

Remifentanil (midazolam added) vs. midazolam-based (fentanyl or morphine added) regimen

Significant differences in favor of remifentanil for time Significant differences in favor of remifentanil for time to extubation (94 h vs. 147.5 h, p=0.033) and weaning time to extubation (0.9 h vs. 27.5 h, p<0.001)

No significant differences in time from study drug to start of weaning or until ICU discharge

No significant differences in ADEs (no bolus remifentanil)

▪ Breen et al. Crit Care 2005;9:R200



Question

The trauma resident is considering a sedation-only approach. He states that with enough sedation, he could knock out a horse so pain is not a major concern. In the only RCT that compared IV infusions of midazolam to IV infusions of combined midazolam +of midazolam to IV infusions of combined midazolam + fentanyl, what was the result?

A. Fewer daily dose adjustments in the midazolam only groupB. Drug costs significantly less in the midazolam only groupC. Significantly less ventilator asynchrony in combined groupD. Significantly less time to sedation in combined group

Sedation +/- Opioid

Adverse events of opioids must be considered in light of consequences of untreated pain

Example is RCT comparing IV infusions of midazolam vs. midazolam + fentanyl (co-sedation)y ( )

Patients enrolled if respiratory failure, expected mechanical ventilation > 48 h, and receiving a sedative but no opioid

Investigators cited surveys in Europe and US that found opioids routinely used ≈ 50% of time

▪ Richman et al. Crit Care Med 2006;34:1395

Midazolam vs. Midazolam/Fentanyl

Richman et al. Crit Care Med 2006;34:1395

p = 0.002

Midazolam vs. Midazolam/Fentanyl

Richman et al. Crit Care Med 2006;34:1395

p=0.04

Asynchrony

p=0.21

Time to sedate

p=0.79

Drug cost

PTSD if Inadequate Analgesia

Retrospective study of morphine use by military in Iraq Diagnosis by DSM-IV (credentialed providers) Assessed PTSD 1 – 24 months post-injury Excluded patients with severe TBI Two groups with/without PTSD had similar

characteristics other than morphine use Morphine use was lower in PTSD (60%) vs. non-PTSD

(76%) group, p<0.001 Limited information on dosing regimen or response

▪ Holbrook et al. NEJM 2010;362:110

Question

Using a numeric rating scale, the patient’s pain associated with line placements has increased during hospitalization with no obvious explanation. The trauma resident has heard of such a condition that might be responsive to an opioid tapering strategy. Your response is:

A. Opioid toleranceB. Subtherapeutic opioid dosesC. Opioid-induced hyperalgesiaD. Inadequate pain control



FIGURE 1 Diagrammatic representation of the neuronal mechanisms underlying opioid analgesia

Copyright ©2010 American Academy of Pediatrics

Anand, K. J. S. et al. Pediatrics 2010;125:e1208-e1225

FIGURE 2 Algorithm showing that clinical signs of diminished opioid analgesia may result from developing opioid tolerance, a worsening pain state, or opioid-induced hyperalgesia

Copyright ©2010 American Academy of Pediatrics

Anand, K. J. S. et al. Pediatrics 2010;125:e1208-e1225

Opioid Comparisons

Opioid t ½ß(h) Cl (mL/kg/min) Vc/Vdss(L) logPa

Morphineb 1.5-5 14 25/225 1.2metabolite renal failure 25-50 (6-glucuronide- slow CNS transfer but will

accumulate)Hydromorphoneb3 20 25/300 1.2Fentanylc 1 3 3 13 15/325 4 1Fentanylc 1.3-3 13 15/325 4.1Remifentanild 0.05 50 10/30 1.8

a log of octanol/water partition coefficientb glucuronidationc CYP3A4d degraded by plasma esterases so context sensitive half-time

Camu & Vanlsersberghe. Best Prac Res Clin Anesth 2002;16:475de Leon Casasola et al. Anesth Analg 1996;83:867

Opioid Comparisons

Opioid Cost Metabolism Adverse Effectsa

Morphine < $1 Demethylationb ↓ BP/HR; bronchospasm(active metabolite)

Hydromor < $1 Demethylationb Dosing errors?Fentanyl < $1 Demethylation Muscle rigiditycFentanyl < $1 Demethylation Muscle rigidityRemifent $10/mg Esterases Bradycardia/hypotension

a Refers to adverse effects that are somewhat unique to a particular opioid- does not include ADEs common to all opioids (e.g., CNS depression)

b Has 3-glucuronide metabolite that has neuroexcitatory effects in animal modelsc Possibly just a function of higher doses since noted with morphine and meperidine,

albeit less commonly; rigidity may not be seen as much in ICU vs. OR due to concomitant benzo or NMBA (or less likely, naloxone) use

Opioid Comparisons Complicated

Remifentanil compared to fentanyl-based analgesia Double-blind RCT involving 152 mixed ICU patients on

mechanical ventilation; opioids by continuous infusion Mean percent of hours in optimal sedation (SAS score

f 4) 88 3% d 89 3% ( )of 4) was 88.3% and 89.3% (ns) No significant difference in primary endpoint of ratio of

between-patient variability (unless 1 patient excluded from remifentanil group who failed to reach SAS of 4)

No significant differences in hemodynamic parameters or LOS from drug start to ICU discharge

▪ Muellejans et al. Crit Care 2004;8:R1-R11

Many Urban Myths Related to Opioid Comparisons

Anecdotal information often suggests differences in efficacy or adverse effect profiles of opioids

Some differences are legitimate with sound biological basis (e.g., normeperidine causing seizures)Oth t d diff ft idi ti Other noted differences often idiosyncratic

RCTs that have been performed typically do not show differences in efficacy or common toxicities RCT comparing morphine to hydromorphone PCA

No differences in efficacy or a number of adverse effects including N/V, pruritus▪ Hong et al. Anesth Analg 2008;107:1384



Opioid Adverse Drug Events (ADEs)

Allergy Arrhythmias Bowel dysfunction CNS/respiratory depression Cough

Immunomodulation Increased intracranial

pressure Myoclonus Nausea/vomitingg

Drug Interactions Dry mouth Endocrinopathy Hearing loss (sensorineural)

(methadone OD)*

Histamine release

g Neurotoxicity Pruritus Rigidity Serotonin syndrome Urinary retention Withdrawal

Adapted from Erstad et al. CHEST 2009;135:1075; * Christenson & Marjala. Ann Pharmacother 2010;44:207

Question

The trauma resident has heard that there is an opioid that can cause serotonin syndrome and asks which of the following agents is NOT a potential cause in a patient who meets the criteria using at least one of the two major systems typically used for diagnosis?

A. MorphineB. FentanylC. MeperidineD. TramadolE. All are potential causes

ADEs - Bowel Dysfunction

Double-blind RCT with 169 patients undergoing elective colon resection Patients randomized to bisacodyl 10 po or placebo

given twice daily on day 1 prior until POD 3 NGT removed at end of operation; opioids used as

2 d li GI t iti t t d POD 1p p

2nd line; GI nutrition started POD 1 Sig. diff. (p=0.007) in favor of bisacodyl using

composite endpoint (1st flatus, 1st defecation, 1st solid food); primarily due to time to defecation No diff. in secondary endpoints including LOS

Other options: mu-receptor antagonists but no substantial data in ICU patients; multimodal

▪ Zingg et al. Int J Colorectal Dis 2009;23:1175

ADEs - Opioid Immunomodulation

Overall Immune System HPA suppression Increased inflammatory

cytokines (IL-1ß, IL-4, IL-6, TNF-α) esp in presence of LPS ( d t i f ll f

GI Tract Colonization followed by

translocation of m.o. Immunosuppression more

dramatic with direct local (i i t it l) thLPS (endotoxin from wall of

gram-negative bacteria) Remifentanil discontinuation

risk factor for ICU infection¹Questions: Acute vs. chronic effects?Dose vs. duration effects?During vs. withdrawal effects?Chang et al. J Virology 2007;81:8406¹ Nseir et al. Crit Care 2009;13:R60

(i.e., intraperitoneal) than oral administration

Questions:Slowed transit vs. local vs. overall

immunosuppression?

Feng et al. Infect Immun 2006;74:5221

ADEs – Serotonin Syndrome

Two major systems used for diagnosis of syndrome Sternbach¹ and Hunter criteria² (diagnosis of exclusion) Symptoms include agitation, tremor, myoclonus, mental

status changes, diaphoresis, hyperreflexia, elevated temp Most case reports with phenylpiperidine opioid Most case reports with phenylpiperidine opioid

meperidine but also with phenylpiperidine fentanyl and diphenylheptane methadone Related compounds such as tramadol and dextromethorphan

also serotonin reuptake inhibitors Morphine doesn’t inhibit serotonin reuptake but has → S/S

Explanation for chest rigidity with fentanyl?³▪ ¹ Sternbach et al. Am J Psych 1991;148:705; ² Dunkley et al. Quart J

Med 2003;96:635; ³ Kirschner & Donovan. J Emerg Med 2010;38:477

Non-Opioid Analgesics/Adjuvants

NSAIDs/acetaminophen (IV forms becoming available) Muscle relaxants Anticonvulsants- neuropathic pain Antidepressants- neuropathic pain

C l it i b i ( t b l f ) Calcitonin- bone pain (vertebral fx) Lidocaine (various routes)- neuropathic pain Ketamine- NMDA antagonist; opioid sparing Adenosine (regulates pain transmission through

neuromodulation)- opioid sparing Corticosteroids- prolonged antihyperalgesic effects

even when given in single doses with opioids



Ketamine Little evidence for use outside of ED and OR,

particularly when given by continuous infusion in adults

Has been investigated in combination with opioids f i id i tifor opioid-sparing actions Subdissociative analgesia doses utilized

Small RCTs of morphine-ketamine combination (e.g., 1 mg of morphine + 5 mg of ketamine bolus doses by PCA) have found reductions in morphine doses and overall consumption while maintaining pain control

▪ Nesher et al. CHEST 2009;136:245

Example of Uncommon ADE

Conclusions Pain management in the ICU has unique issues

compared to management in other settings Much of the data extrapolated from studies in other areas

Increasing evidence that analgo-sedation is preferred to sedato-analgesia in the ICUO i id i th t d d f i f Opioids remain the standard of comparison for severe pain in the ICU Differences between opioids for dose-related ADEs often

overstated, but there are good reasons for choosing one over another (e.g., renal failure)

Nonopioid analgesics have a role but also have unique considerations when used in critically ill patients

Question

The trauma resident has heard you speak of the sedation versus no sedation study and wants to do the same study with analgesia. What is the most likely response by physician specialty to an RCT comparing pain control to no pain control in

ll ti t ith t i ?all patients with acute, severe pain?A. Pediatric intensivist: “Children aren’t little adults.”B. Psychiatrist: “And how does that make you feel?”C. EM doc: “Only if I can use anesthetic agents for

RSI!”D. Trauma doc: “Sounds great – let’s start enrollment

today.”E. All of the above




Anaheim, California

2233 Delirium Management in the Intensive Care Unit and Case Discussion Devlin, J.W. Northeastern University School of Pharmacy, Boston, MA, USA. Email: [email protected] Delirium, characterized by fluctuations in mental status such as inattention, disorganized thinking, hallucinations and disorientation, occurs in up to 80% of patients admitted to the ICU and is associated with higher mortality, a longer duration of mechanical ventilation and greater healthcare costs. Despite ICU guidelines recommending that ICU patients be routinely screened for delirium using a validated tool such at the Confusion Assessment Method for the ICU (CAM‐ICU) or the Intensive Care Delirium Screening Checklist (ICDSC), delirium screening is not routinely completed by health care providers, including critical care pharmacists. In addition, drug and non‐drug strategies shown to decrease the incidence of delirium in the ICU, are frequently not implemented. Recent data suggests that current critical care pharmacists’ practices and perceptions surrounding the recognition and treatment of delirium in the ICU are heterogeneous and frequently not evidence‐based. This program will focus on strategies that can be used by the ICU pharmacist to improve their ability to recognize delirium in their patients, to incorporate strategies know to reduce delirium in their practice and to provide evidence‐based guidance on how delirium should be treated should it occur. Learning Objectives:

1. Evaluate recent literature on the management of pain, and delirium in the ICU.

2. Apply key pharmacotherapy concepts to overcome barriers to optimizing pain, sedation, and delirium therapy in mechanically ventilated ICU patients.

3. Apply key concepts in the selection of sedatives, analgesics, and antipsychotic agents in critically ill patients.


1. Which of the following delirium assessment tools has NOT been validated for use in mechanically ventilated adults?

a. CAM‐ICU b. MMSE c. ICDSC d. Neecham

2. Which of the following intervention has been shown in a randomized, controlled trial to improve outcome in ICU patients with delirium?

a. Reversal of metabolic abnormalities b. Quetiapine


Anaheim, California

c. Frequent orientation d. Haloperidol

Answers: 1. b; 2. b

Delirium Management in the Intensive Care Unit and Case Discussion

John W. Devlin, Pharm.D., FCCP, FCCM,

Associate Professor

Northeastern University School of Pharmacy,

Adjunct Associate Professor

Tufts University School of Medicine,

Boston, MA

Delirium Increases Mortality

With kind permission of Springer Science+Business Media Ouimet S, et al. Intensive Care Med 2007; 33:66-73.

Duration of Delirium Affects Mortality

With kind permission of the American Thoracic SocietyPisani M. Am J Respir Crit Care Med. 2009 Dec 1;180(11):1092-7.Shehabi Y. et al. Crit Care Med 2010 (ahead of press)

During the ICU/Hospital Stay

Sequelae of Delirium

- Increased mortality- 3x greater re-intubation rate- Average 10 additional days in hospital- Higher costs of care

After Hospital Discharge

- Increased mortality- Development of dementia - Long-term cognitive impairment- Requirement for care in chronic care facility- Decreased functional status at 6 months

Girard TD et al. Crit Care Med 2010; 38:1513-1520Milbrant EB, et al. Crit Care Med 2004;32:955-962.Jackson JC, et al. Neuropsychol Rev. 2004;14(2):87-98.Nelson JE, et al. Arch Intern Med. 2006; 166:1993-1999.Ely EW, et al. JAMA. 2004;291:1753-1762.

Prevalence of ICU Delirium

• 60-80% MICU/SICU/TICU ventilated patients develop delirium

• 20-50% of lower severity ICU patients develop delirium

H ti i d f t• Hypoactive or mixed forms most common

• Majority goes undiagnosed if routine monitoring is not implemented

Ouimet S, et al. Intensive Care Med. 2007;33:66-73

Dubois MJ, et al. Intensive Care Med 2001;27:1297-1304Ely EW, et al. Intensive Care Med. 2001;27:1892-1900.Ely EW, et al. JAMA. 2001;286,2703-2710.Pandharipande PP, et al. J Trauma. 2008;65:34-41.

.

Cardinal Symptoms of Delirium and Coma

With kind permission of Springer Science+Business Media Morandi A, et al. Intensive Care Med. 2008;34(10):1907-1915.



Current Practices and Perceptions of Critical Pharmacists Surrounding ICU Delirium

Identification, Prevention and Treatment

• Validated web/paper survey delivered to pharmacists practicing in clinical role in ICU ≥ 25% of their time in New England, TN and MI (n=457)

• 250/457 (55%) responded: – Practicing ≤ 10 years (61%)– Academic medical center (55%)– Medical ICU (33%)– Mixed medical-surgical ICU (37%)– ≥ 11 ICU beds (71%)– 0 hours of CE in 2009 related to ICU delirium (43%)

Devlin JW et al. Submitted to SCCM 2011 Congress

Survey: Symptoms Most Associated with Delirium

30

35

40

45

50

%

0

5

10

15

20

25

Agitation Disorganized Thinking

Fluctuating symptoms

Inattention Hallucinations Decreased LOC

%


Survey: Symptom Most Associated with Delirium

25

30

35

40

45

50

%

Frequency over Course of ICU

Admission in 600 patients (%)

Frequency in Pharmacist Survey (%)

Inattention 95 8

Disorganized thinking

89 17

Agitation 86 49

0

5

10

15

20

Agitation Disorganized Thinking


Inattention Hallucinations Decreased LOC

% Agitation 86 49

Altered LOC 85 6


69 11

Psychomotor slowing

52 N/A

Hallucinations 42 8

Marquis F et al. Crit Care Med 2007; 35:2522-37.

Confusion Assessment Method(CAM-ICU)

1. Acute onset of mental status changes or a fluctuating course

2 Inattention

and

or3. Altered level of

consciousness4. Disorganized

thinking

= DeliriumEly EW, et al. Crit Care Med. 2001;29:1370-1379.Ely EW, et al. JAMA. 2001;286:2703-2710.

2. Inattention

and

Intensive Care Delirium Screening Checklist

1. Altered level of consciousness

2. Inattention

3. Disorientation

4. Hallucinations

5. Psychomotor agitation or retardation5 syc o oto ag tat o o eta dat o

6. Inappropriate speech

7. Sleep/wake cycle disturbances

8. Symptom fluctuation

Bergeron N, et al. Intensive Care Med. 2001;27:859-864.

Ouimet S, et al. Intensive Care Med. 2007; 33:1007-1013.

Score 1 point for each component present during shift. • Score of 1-3 = Subsyndromal Delirium• Score of ≥ 4 = Delirium

ICDSC Score Predicts Patient Outcome:The Importance of Subsyndromal Delirium

Comparison of mortality, ICU LOS and outcome according to DSC score

50

60

70

DSC 0

DSC 1-3

DSC >3

DSC=0 (Neither Subsyndromal Delirium or Delirium)

DSC 1-3 (Subsyndromal Delirium)

DSC ≥ 4 (Delirium)

0

10

20

30

40

Dead (%) ICU LOS(mean)

Home Home withhelp

Convalesence Chronic care Other

%

LOS DaysICU

Home+help(%)

Convalescence(%)

Long Term Care(%)

Other(%)

Home nohelp(%)

%

Mortality (%)

With kind permission of Springer Science+Business Media Ouimet S et al. Intensive Care Med 2007; 33:66-73.



Survey: Delirium Screening

• Delirium status frequently or always discussed: 50%

• Delirium status screened ≥ 50% of the time: 18%

• Pharmacist screened for delirium ≥ 1 patient: 32%64% f d li i i ≤ 10% f ti t– 64% screen for delirium in ≤ 10% of patients

– Primary barrier to delirium screening: • Lack of time = 34%

• Is a nursing role = 24%

• Do not feel comfortable in using screening tool = 13%


Bedside RN Phase 1 Phase 2 Phase 3

Method delirium detection

No screening tool

ICDSC ICDSC

Education None Gave RN ICDSC validationpaper to read

Didactic lecture in classroom by ICU PharmD, web-based module with self ass’tquestions and bedside

19 RNS (30% nights) working in a STICU where delirium screening tool not yet implemented

paper to read the week before

questions and bedside teaching in at least 2 pts by ICU RN educator

Detection of delirium vs. validated judge (kappa)

0.403 0.624 0.735

Deliriumknowledge (out of 10)

6.1± 1.4` 6.5 ± 1.4 8.2 ± 1.4; p=0.001 (phase 2 vs phase 3)

Lin A, Russel B, Devlin JW et al. Submitted SCCM Congress 2011

Before MD use of DSC50 patients assessed

After MD use of DSC50 patients assessed

MD vs VJ -0.14 (-0.27 to -0.02) 0.67 (0.38 to 0.96)

Use of a Validated Delirium Assessment Tool Improves theAbility of Physicians to Identify Delirium in the ICU

MD vs RN -0.15 (-0.15 to -0.29) 0.58 (0.25 to 0.91)

RN vs VJ 0.65 (0.29 to 1.00) 0.92 (0.76 to 1.00)

Kappa Agreement0 to 0.2 = slight0.2 to 0.4 = fair0.4 to 0.6 = moderate0.6 to 0.8 = substantial0.8 to 1.0 = almost perfect

Kappa (95% CI)

Devlin JW et al. Crit Care Med. 2007: 35:2721-2724.

Keys to Boosting Delirium Screening in Your ICU

• Make sure sedation assessment is regularly and reliably happening before tackling delirium screening

• Need buy-in from both RN and MD ICU managers• Education:

– Both didactic (e.g. web) and at bedside– Both day and night RNs

M k li i i f t bl ith “ t b i bl t• Make sure clinicians very comfortable with “not being able to evaluate” some patients or some delirium symptoms and that they document this fact in the flowsheet for the next shift

• RNs have been evaluating many of the symptoms for delirium for years…..they just do not realize it!

• Make sure all physicians (including housestaff) know how to use screening tool and that delirium status (that includes results of screening) is discussed on daily rounds.

Devlin JW et al. Crit Care 2008 12; R19Devlin JW et al. Intens Care Med 2007;33:929-40

Keys to Boosting Delirium Screening in Your ICU

• Make sure sedation assessment is regularly and reliably occurring before tackling delirium screening

• Need buy-in from RN and MD ICU managers• Education:

– Both didactic (e.g. web) and at bedside– Both day and night RNs

ICU Pharmacists Can Play a Key R l i B ti D li i S i

Both day and night RNs– Pharmacist can play important role

• Make sure clinicians very comfortable with “not being able to evaluate” some patients or some delirium symptoms and to document this fact for the next shift

• RNs have been evaluating for many of the symptoms for delirium for years and not realizing it.

• Make sure all physicians (including housestaff) know how to use screening tool and that delirium status (that includes results of screening) is discussed on daily rounds.

Devlin JW et al. Crit Care 2008 12; R19Devlin JW et al. Intens Care Med 2007;33:929-40

Role in Boosting Delirium Screening in Their ICU!

- AB is a 75 year old female admitted with septic shock secondary to community acquired pneumonia

- On ICU Day #4 the night nurse reported that AB:

1) was wildlyagitated at times (SAS=6) which necessitated the use of c ecess tated t e use ohand restraints.

2) only slept for brief periods

3) was orientated only to person and did not recognize her daughter the previous night during a visit

4) did not follow commands

AB is currently receiving midazolam @ 5mg/hr and fentanyl @ 100mcg/kg/hr





1) was wildlyagitated at times (SAS=6) which necessitated the use of

1. Altered level of consciousness = Yes

2. Inattention = Yes

3. Disorientation = Yes

4. Hallucinations = Unknown

5. Psychomotor agitation or retardation = Yes

which necessitated the use of hand restraints.




6. Inappropriate speech = Unknown

7. Sleep/wake cycle disturbances = Yes

8. Symptom fluctuation = Yes

ICDSC = 6….patient has delirium

Patient FactorsIncreased ageAlcohol useMale genderLiving aloneSmokingRenal disease

Environment

Predisposing DiseaseCardiac diseaseCognitive impairment

(e.g., dementia)Pulmonary disease

Acute IllnessLength of stayFeverMedicine service

Less Modifiable

DELIRIUMEnvironmentAdmission via ED or

through transferIsolationNo clockNo daylightNo visitorsNoiseUse of physical restraints

Lack of nutritionHypotensionSepsisMetabolic disorders Tubes/cathetersMedications:- anticholinergics- corticosteroids- benzodiazepines

Inouye SK et al. JAMA. 1996; 275: 852.

Dubois MJ, et al. ICM. 2001;27:1297-1304.

Ouimert S et al. ICM. 2007; 33:66-73.

Van Rompaey B et al. Crit Care. 2009; 13:R77.

More Modifiable

Survey: Medications Frequently or Always Associated with Delirium

60

70

80

90

%

0

10

20

30

40

50

Lorazepam Midazolam HD Methylpred Fentanyl Propofol Haloperidol Dexmedetomidine

%


Risk of Delirium With Benzodiazepines

eliri

um R

isk

MedicationTransitioning to Delirium Only OR (95% CI)

P Value

Lorazepam 1.2 (1.1-1.4) 0.003

Midazolam 1.7 (0.9-3.2) 0.09

Adapted from Pandharipande P, et al. J Trauma. 2008; 65:34-41.

Adapted from Pandharipande P, et al. Anesthesiol. 2006:104:21-26.

Lorazepam Dose, mg

De

Fentanyl 1.2 (1.0-1.5) 0.09

Morphine 1.1 (0.9-1.2) 0.24

Propofol 1.2 (0.9-1.7) 0.18

Midazolam

Dexmedetomidine

dexmedetomidine versus midazolam, P < 0.001

Reduced Delirium Prevalence with Dexmedetomidine vs Midazolam

SEDCOM

60

80

100

Del

irium

, %

Sample Size 118 229 109 206 92 175 77 134 57 92 42 60 44 34

Treatment Day

0

20

40

Baseline 1 2 3 4 5 6

Pat

ient

s W

ith

Adapted from Riker RR, et al. JAMA. 2009;301(5):489-499.

American Psychiatric Association Guidelines (1999)• “Antipsychotic medications are often the pharmacologic

treatment of choice” (Grade I = recommended with substantial clinical confidence)• “Haloperidol can be initiated at 1-2mg every 2-4 hrs and

titrated to higher doses for patients who continue to be agitated. Patients who require multiple boluses, continuous infusion may be useful”

• “Some physicians have used the newer (atypical)• Some physicians have used the newer (atypical) antipsychotics.”

SCCM Guidelines (2002)• “Haloperidol is the preferred agent for the treatment of

delirium in critically ill patients.” (Grade C recommendation)

Trzepacz P et al. APA .1999 (accessed April 4 2010)Jacobi J et al. Crit Care Med. 2002; 30:119-141.



Survey: First-Choice Delirium Treatment Options

60

70

80

• Delirium should always be managed with a medication: 85%

• Use ≥ 2 medications to treat delirium: 68%

Characteristics of Haloperidol Use (always or frequently)

• Oral: 23%; IV 93%

0

10

20

30

40

50

60

Haloperidol Atypical Antipsychotic Benzodiazepine Dexemedetomidine

%


• As needed: 93%; Scheduled: 61%; Infusion: 0%

• ≤ 4mg/day: 47%; 5-10mg/d: 56%; 11-20mg/d: 38%; ≥21mg/d: 9%

Survey: Treatment Patterns

Frequently or always used in a

patient with agitated delirium

(%)

Published RCT demonstrating

benefit (%)

Labeled by the FDA for delirium

treatment (%)

Haloperidol 87 42 34

Quetiapine 59 40 8

Lorazepam 47 3 3

Midazolam 32 0 1

Olanzapine 26 16 6

Dexmedetomidine 25 33 8


• Design: Double-blind, placebo-controlled, randomized trial • Setting: 6 tertiary medical centers • Patients: Mechanically ventilated adults with an abnormal level of

consciousness or who were receiving continuous sedatives/analgesicsNote: Patients had brain dysfunction but only 49% had delirium at baseline

• Intervention:– Haloperidol (5mg) vs ziprasidone (40mg) vs placebo – Max 14 days

D i t l i d if CAM ICU ti

Modifying the Incidence of Delirium (MIND) Trial

– Dose interval increased if CAM-ICU negative– Could give IM if NPO up to max 8 doses– Oversedation: ↓dose frequency when RASS ≥2 levels above target (after

holding sedation therapy)– If delirium reoccurred after d/c of study drug then restarted at last effective

dose (and weaned again as per above)• Primary outcome:

– Number of days patient alive without delirium or coma during the 21-day study period• Delirium = + CAM-ICU • Coma = RASS (-4) [ie. responsive to physical but not verbal stimulation] or RASS (-5) [ie. not

responsive to either]

Girard TD, et al. Crit Care Med. 2010;38(2):428-437.

MIND Trial Results

0 91716470% of days accurately sedated

0.90222Coma days

0.2821 (58)23 (77)24 (69)Resolution of delirium on study drug, n (%)

0.93444Delirium days

0.6612.515.014.0Delirium/coma-free days

P-valuePlacebo,

n = 36

Ziprasidone,

n = 30

Haloperidol, n = 35

Outcome

Girard TD, et al. Crit Care Med. 2010;38(2):428-437.

0.56000Average extrapyramidal symptoms score

0.816 (17)4 (13)4 (11)21-day mortality, n (%)

0.70

0.68

7.3

15.4

9.6

13.5

11.7

13.8

Length of stay, days

ICU

Hospital

0.2512.512.07.8Ventilator-free days

0.91716470% of days accurately sedated

• Design: Double-blind, placebo-controlled, randomized trial

• Setting: 3 academic medical centers

• Intervention:

Efficacy and Safety of Quetiapine in Critically Ill Patients with Delirium:

A Prospective, Multicenter, Randomized, Double-Blind, Placebo-Controlled Pilot Study

Intervention:– Quetiapine 50mg PO/NGT twice daily titrated to a maximum of 200mg twice

daily) vs Placebo

– PRN IV haloperidol protocolized and encouraged in each group

– Oversedation: hold study drug when SAS ≤ 2 (after holding sedation therapy)

• Primary outcome:– Time to first resolution of delirium (ie. first 12 hour period when ICDSC ≤ 3)

Devlin JW, et al. Crit Care Med. 2010;38(2):419-427.

Placebo

f P

ati

en

ts w

ith

De

liri

um

Log-Rank P = 0.001

Patients with First Resolution of Delirium

Quetiapine

Pro

po

rtio

n o

Day During Study Drug Administration

Used with permission of Wolters-Kluwer Health




Quetiapine(n=18)

Placebo(n=18)

P value

Time of study drug administration (hours) 102 (84-168) 186 (108-228) 0.04

Time in delirium (hours) 36 (12-87) 120 (60-195) 0.006

Time spent agitated (SAS ≥ 5) (hours) 6 (0-38) 36 (11-66) 0.02

Percent of time spent in delirium after ICU discharge

0 (0-0) 14 (0-47) 0.05

Subject placement after hospital discharge (%)

Home / rehabilitation center 89 56

Clinical Outcomes

Home / rehabilitation center 89 56

0.06Chronic care facility / another acute care hospital / death

11 44


• Five episodes of somnolence and one episode of hypotension were observed that were felt to be possibly related to the administration of quetiapine.

• No episodes of EPS were experienced during the study drug period.

• The number of subjects with QTc prolongation as determined by a > 60 msec increase from baseline (39 vs. 44%, p=0.74), QTc > 500 msec (22 vs. 28%, p=1.0), or other CPMP definitions (50 vs. 72%, p=0.31) was similar between the quetiapine and placebo groups.

Many differences between the two studies:• Presence of delirium at study entry

• Presence of coma at study entry

• Inclusion of patients with active alcohol withdrawal

• Time course in ICU stay when randomized

• Method of antipsychotic discontinuation

• Use of haloperidol in placebo group

Why did Patient Outcome Improve in Quetiapine Study but not in MINDS Study?

• Use of haloperidol in placebo group

• Two-fold difference in dose of atypical antipsychotic administered

Devlin JW et al Harvard Rev Psychiatry (2010 in press)Pisani MA et al. Am J Respir Crit Care Med 2009; 180: 1092-7.Trzepacz PT et al. J Psychosomatic Res 2008; 65: 299-307Gareri P, et al. Clin Drug Invest. 2003; (5):287-322.

5-HT2A serotonergic

ά1-adrenergic

H1-histaminic

D2 dopamine

ά2-adrenergic

Dexmedetomidine vs Haloperidol for the Treatment of Delirium

Open Access Journal – Permission not required Reade RC et al. Crit Care 2009; 13:R75

Haloperidol: 0.5-2mg/hr infusion to maintain RASS=0Dexmedetomidine: 0.2 – 0.7 mcg/kg/hr to maintain RASS=0

Methodologic Considerations for Studies Investigating Antipsychotic Therapy For

Delirium Prevention or Treatment in the ICU.

• Interventions shown to reduce delirium in the ICU are maximized.• Patients with conditions know to mimic delirium are excluded.• Underlying causes for delirium are reversed when possible prior to

randomization.• Use of a placebo arm that does not involve antipsychotic administration.• Stratification based on the presence of positive versus negative delirium

symptoms.• Antipsychotic dosing strategy based on formalized dose-response

testing.• Avoidance of a level of sedation where patient is unarousable.• Adequate size to measure differences in standard ICU patient

outcomes (e.g. duration of mechanical ventilation). • Evaluation of post-ICU neurocognitive outcomes.

Devlin JW et al Harvard Rev Psychiatry (2010 in press)

Pharmacological Considerations When Treating Delirium

• Pharmacological therapy should be considered ONLY after underlying causes of delirium are reversed/treated

• Pharmacological therapy should be reserved for g pypatients with severe agitation that will affect patient/caregiver safety

• The underlying cause (s) of the delirium may affect response to antipsychotic therapy

Inouye SK. N Engl J Med. 2006; 354:1157-1165.Trzepacz PT, et al. Semin Clin Neuropsych .2000; 5:132-148.Dubois MJ, et al. Intensive Care Med. 2001; 27:1297-1304. Skrobik Y, et al. Crit Care Clinics. 2009 25:585-587.



1) was wildlyagitated at times (SAS=6) which necessitated the use of

Treatment of AB’s delirium:

1. Remove any reversible factors causing her delirium.

Change midazolam to dexmedetomidine if patient is hemodynamically stable

2 If patient remains agitatedc ecess tated t e use ohand restraints.




2. If patient remains agitated, haloperidol 1-2 mg IV q4-6h prn if QTc remains ≤ 500 msec and is not more than ≥ 60 msec above baseline.

3. If delirium persists 24-48 hrs hours after #1 and #2 implemented, consider quetiapine 50mg PO/NGT q12h




Anaheim, California

2234 Implementation of Best Practices Protocols, Guidelines, Education, and Metrics Szumita, P.M. Brigham & Women’s Hospital, 75 Francis Street; L‐2 Pharmacy Administration, Boston, MA 02115, USA. Email: [email protected] Anger, K.E. Brigham & Women’s Hospital, 75 Francis Street; L‐2 Pharmacy Administration, Boston, MA 02115, USA. Email: [email protected] Optimal management of pain, sedation, and delirium in the intensive care unit (ICU) is an essential component to improving patient satisfaction and outcomes. Recent literature highlights the positive impact on patient outcomes when implementing strategies such as routine assessment of pain, sedation, and delirium; goal oriented sedation practices; and daily sedation interruption. Clinical practitioners are faced with many barriers when charged with implementing best practices. ICU pharmacists have traditionally played an integral role in the management of sedation therapy and can become involved as local champions to improving practice within their institution. This interactive discussion will evaluate literature on best practice, identify barriers, and evaluate implementation strategies for improving the management of pain, sedation, and delirium in the ICU setting. Learning Objectives:

1. Evaluate recent literature on the management of pain, and delirium in the ICU.

2. Apply key pharmacotherapy concepts to overcome barriers to optimizing pain, sedation, and delirium therapy in mechanically ventilated ICU patients.

3. Apply key concepts in the selection of sedatives, analgesics, and antipsychotic agents in critically ill patients.


1. Implementation of an ICU sedation protocol or guideline is associated with which of the following outcomes:

a. Increased nosocomial infection rate b. Decreased length of mechanical ventilation c. Decreased incidence of ICU delirium d. Increased hospital length of stay

2. Which of the following strategies has been shown to improve outcomes in mechanically ventilated ICU patients:

a. Implementation of routine daily sedation interruption


Anaheim, California

b. Implementation of a validated sedation assessment tool and use of

goal oriented therapy c. Reduction in the use and duration of continuous infusion

benzodiazepine therapy d. Addition of early physical and occupational therapy during daily

sedation interruption periods e. All of the above

Answers: 1. b; 2. e

Kevin Anger PharmD, BCPSClinical Pharmacy Specialist

Brigham and Women’s Hospital

Paul Szumita PharmD, BCPSClinical Pharmacy Practice Manager

Brigham and Women’s Hospital

Evaluate recent literature on the management of pain, and delirium in the ICU.

Apply key pharmacotherapy concepts to overcome barriers to optimizing pain, sedation, and delirium therapy in mechanically ventilated ICU patients.

Apply key concepts in the selection of sedatives, analgesics, and antipsychotic agents in critically ill patients.

The author of this presentation has no disclosures concerning possible financial or personal relationships with commercial entities that may have a direct or indirectentities that may have a direct or indirect interest in the subject matter of this presentation

Use of guideline or protocol that incorporates goal oriented administration of sedatives, analgesics, and antipsychotics Sedation and Pain scale with frequent assessment Routine assessment of ICU delirium

Development of a pharmacotherapy plan based upon patient specific PK and PD characteristicspatient specific PK and PD characteristics Avoidance of long acting continuous infusion sedative agents Dose minimization strategies

Daily interruption of sedatives and analgesics with spontaneous breathing trial “Wake up and breath” Early physical therapy and occupational therapy during interruption

Sessler CN, Chest. 2008 Feb;133(2):552-65.Schweickert WD, Kress JP. Crit Care. 2008;12 Suppl 3:S6.

Which component of a guideline or protocol do you think is the most important?

a) Assessment toolsa) Assessment toolsb) Drug selection for specific patient

populationsc) Dose limitation strategiesd) Daily Sedation Interruption (DSI)

Timeless Recommendations

Use of sedation guidelines, algorithms, or protocols is recommended

Routine use of validated sedation, pain and delirium assessment

Recommendations Likely to Change

Lorazepam is first line for most patients via intermittent i.v. or continuous infusion

Midazolam for short term use onlypain, and delirium assessment tools scales

Therapeutic plan development with use of sedation/analgesia goals

Analgesia before sedation Daily interruption strategies Fentanyl or hydromorphone preferred

for hemodynamic instability or renal insufficiency

Propofol is the preferred sedative when rapid awakening is important

Midazolam for short-term use only Haloperidol is the preferred agent

for the treatment of delirium in critically ill patients

Jacobi J, et al. Crit Care Med. 2002 Jan;30(1):119-41



71

88

76

50

60

70

80

90

100

po

nd

en

ts

Patel RP, et al. Crit Care Med. 2009;37(3):825–32.

Survey of 1,384 ICU practitioners between October 2006 and May 2007, distributed to ICU practitioners in 41 North American hospitals, seven international critical care meetings and courses, and the American Thoracic Society e-mail database

34

0

10

20

30

40

50

Protocol/Guideline Sedation Scale Daily interruptionpolicy

Delirum Screeningtool

% R

es

p

Which of the following do you find the largest barrier to the use of guideline or protocols for sedation, analgesia, and delirium in the ICU setting?

a) Sedation protocols are not applicable to all subgroups of ICU patients

b) Compliance of bedside practitioners

c) Lack of evidence suggesting benefit

d) Lack of ICU resources

64

4040

50

60

70

po

nd

en

ts

Site Variable Respondents % P value

Protocol Availability

University 64%

NON University

64%

Tanios MA, et al. J Crit Care. 2009 Mar;24(1):66-73.

Multidisciplinary, web-based survey to determine current use of sedation protocols and DSI and the perceived barriers to each, and administered it to members of the Society of Critical Care Medicine. Of the 12,994 SCCM members surveyed, 916 (7.1%) responded.

0

10

20

30

Protocol/Guideline Daily interruptionpolicy

% R

es

Community 65%

VA 37%

≥ 20 beds 72% 0.03

≤ 5 beds 43%

6.0%

8.0%

11.0%

15.0%

38.0%

Protocol not accessible when needed

Use may cause oversedation

Prefer more control than a protocol offers

Lack of nursing acceptance

Lack of physician order

2.0%

3.0%

4.0%

4.0%

6.0%

6.0%

0% 5% 10% 15% 20% 25% 30% 35% 40%

No proven benefit

Possibility for undersedation

Not appropriate for select patients*

Inconvenient to coordinate

Protocols are difficult to use

Protocol not accessible when needed

Tanios MA, et al. J Crit Care. 2009 Mar;24(1):66-73.

* Responders cited examples such as neurosurgical, head trauma, and pediatric patients

Phase I:

Development

Phase II:

Implementation

Phase III:

Continuous Quality Improvement (CQI)

1. Periodic Metric

1. Creation of the “physical champion(s)”

2. Multidisciplinary Committee

3. Data synthesis

4. Protocol drafting

Assessment

2. Guideline update with current literature

3. Publication of efficacy, safety, and compliance data

■ Benchmarking against other institutions

■ Assistance in guideline development

1. Pilot Analysis

■ Efficacy, Safety, Adherence

2. Endorsement of protocol from institutional credible bodies

3. Education to all ICU clinicians

4. Integration with electronic documentation and clinical monitoring systems

Protocol“A detailed plan of a scientific

or medical experiment, treatment, or procedure”

Policy implementation for compliance metrics

1. Assessment tools2. Daily Interruption

Guideline“A standard or principle by

which to make a judgment or determine a policy or course of action”

Flexibility to fit clinical assessment

1. Agent selection2. Dosing strategies3. Monitoring (labs,

EKG)

Fusion of both strategies



Policy on Pain, Sedation, and Delirium assessment tools/technology Goal Orientated administration of pharmacotherapy

Pharmacotherapy selection based upon patient specific parameters

Dose Limitation Strategies Avoidance of continuous infusion therapy Recommendations for bolus therapy Daily Sedation Interruption policy: Clear inclusion/exclusion criteria

Monitoring and Safety considerations Special Patient Populations Neuromuscular Blockade Frequent Neurocognitive Assessment/ Elevated intracranial

pressure Therapeutic Hypothermia Palliative Care

Default sedation goal documented in medication order

Change of default sedation goal requires documentation of reason

What aspects of a sedation protocol do you think provide the greatest degree of improvement in patient outcomes?

a) Reduced use of continuous infusions

b) Daily interruption strategies

c) Systematic titration to goal sedation

d) Benzodiazepine dose reduction

What outcomes have improved as a result of implementation of sedation protocol or guideline?

a) Reduced ICU LOS

b) Reduced hospital LOS

c) Reduced duration of mechanical ventilation

d) Reduced the incidence of nosocomial infection

e) All of the above

Significant patient characteristics/metrics/outcomes

CIVS NO CIVS

P value

Age* 49 61 <0.001

PaO2/FiO2* 175 232 0.005185 vs 55 hrs; P<0 001

Single center, retrospective evaluation of 240 mechanically ventilated MICU patients stratified by continuous intravenous sedation (n = 93) or interrupted/no continuous IV sedation n = 149) at Barnes Jewish Hospital from August to December 1997.

Kollef MH, et al. Chest. 1998;114:541-548.

NMB† 12 (13) 0 <0.001

Reintubation† 14(15) 7 (5) 0.005

ICU LOS* 13.5 4.8 <0.001

Hospital LOS* 21 12.8 <0.001

Bolus therapy† 66 (71) 64 (43) <0.001

*Data presented in mean†Data presented as n (%)

185 vs 55 hrs; P<0.001



14

20

15

20

25

Tim

e (

da

ys)

Protocol n = 162

Routine n = 159

p = 0.13

p < 0.001Significant 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

2.3

5.74.8

7.5

0

5

10

Duration of MV ICU LOS Hospital LOS

Med

ian

T

p = 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

Brook AD, et al. Crit Care Med. 1999;27(12): 2609–15.

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 up titration of opioids and benzodiazepines.

17

11

21

15

20

25

Tim

e (d

ays)

Protocol n = 197

Control n = 226

p = 0.004

p = 0.003

p = 0.001


Protocol Control P value

Daily midazolam, mg*

44 31 92 59 0.001

Duration midazoam, hrs**

3 5 0.18

4.25

8

11

0

5

10


Med

ian

T

p

Reintubated† 11 (6) 29 (13) 0.01

VAP diagnosis† 12 (6) 34 (15) 0.005

*Data presented in mean ** Data presented in median†Data presented as n (%)

Single center, prospective, before-after trial of 423 ICU patients requiring mechanical ventilation for > 48 hours before (n=226) and after (n=197) implementation of sedation protocol at Bocage University Hospital from 5/99 to 12/03. Protocol used goal orientated sedation to target Q3hr Cambridge scale with bolus requirements before initiation of continuous infusion and up titration of midazolam

Quenot JP, et al. Crit Care Med. 2007 Sep;35(9):2031-6.

12

18

15

20

25

Tim

e (d

ays

)

Protocol n = 58

Control n = 61 p = 0.04


Protocol Control P value

Propofol infusions†

52 (90) 49 (81) 0.25

Propofol,mcg* 10,057 14,616

19,23222,477

0.01

1.2

4.13.2

5.9

0

5

10


Me

dia

n T p = 0.21

p = 0.03MSO4,mcg* 1,641±

1,2502,465±1

,242<0.001

Lorazepam infusions†

8 (16) 24 (39) 0.003

*Data presented in mean ** Data presented in median†Data presented as n (%)CIVS; Continuous intravenous infusion sedation

Single center, retrospective, before-after trial of 143 Trauma ICU patients requiring mechanical ventilation before (n=75) and after (n=68) implementation of sedation protocol at the University Hospital in Cincinnati between during 6-11/04 and 6-1/06. Protocol focused on light goal oriented sedation, limit the useand duration of continuous infusion sedation, increase awareness of delirium. No DSI required.

Robinson BR, et al. J Trauma. 2008 Sep;65(3):517-26.

42

63

40

50

60

70

80

ain

or

agit

atio

n (

%)

Post implemenation n = 130

Control n = 100

p < 0.01


Pre Post P value

Mechanical Ventilation, hrs*

120 65 0.01

Duration CIVS, hrs*

84 48 0.03

p < 0.01

12

29

0

10

20

30

Pain Agitation

Inci

den

ce o

f p

a hrs

Duration CIVI Opioid, hrs*

96 60 0.02

Nosocomial infection†

17 (17) 11 (8) <0.05

*Data presented in median hrs; †Data presented as n (%)CIVS; Continuous intravenous infusion sedation

Chanques G, et al. Crit Care Med. 2006;34(6):1691–9.

Single center, prospective, Two-phase, controlled study of 230 ICU patients requiring > 24hr stay before (n = 100) and after (n = 130) implementation of a pain and sedation Montpellier University hospital in France. Education and encouragement of use of pain scale and sedation assessment tools.

27

55

30

40

50

60

me

(d

ay

s)

Protocol n = 561

PRE protocol n = 572

p < 0.001 Significant patient characteristics/metrics/outcomes

Protocol PRE P value

Delirium† (34.2) (34.7) 0.9

Subsyndromal Delirium†

(24.6) (33) 0.009

Lorazepam i l t

2.75 7 94

5.79 31 78

0.02

5.9 5.37.5 6.3

0

10

20


Me

an T

i

p = 0.009p = 0.01

equivalents, mg*

7.94 31.78

MSO4 equivalents, mg*

22.3 ±40.1

103.5 ±239.2

<0.001

*Data presented in mean †Data presented as n (%)Subsyndromal delirium; max ICDSC 1-2 in ICU

Skrobik Y, et al. Anesth Analg. 2010 Aug;111(2):451-63.

Single center, observational trial of 1,133 adult ICU patients requiring > 24hrs of ICU care before (PRE) (n = 572) and after (n = 561) implementation of a protocol for pain, sedation, and delirium management at Hospital Maisonneuve-Rosemont from 8/03 to 11/05. Protocol used goal orientated sedation to target RASS and NRS.

2.3

2.6

2

2.5

3

3.5

4

Tim

e (d

ays)

Pre Implementation n = 369

Post Implementation n = 400

p = 0.25

p = 0 13


Pre Post P value

Sepsis Pneumonia†

40(10.8) 26 (6.5) -

Trauma† 59 (15.4) 80 (19 8)

-

1.161

0

0.5

1

1.5

Duration of MV ICU LOS

Med

ian

T p = 0.13 (19.8)

Cardiac Surgery†

84 (22.8) 110 (27.5)

-

*Data presented in median†Data presented as n (%)Incomplete data set for appropriate metric assessment

Single center, before after analysis of 769 Mixed ICU patients requiring > 6 hrs of mechanical ventilation before (n=369) and after (n=400) implementation of Q6hr Richmond Agitation-Sedation Scale (RASS) and the Behavioral Pain Scale (BPS) assessments at Royal Perth Hospital.

Williams TA, et al. Am J Crit Care. 2008 Jul;17(4):349-56.



15

23

1215

20

25

ime

(d

ay

s)

DSI n = 36

Sedation Algorithm n = 38

p = 0.0003

p = 0.001

p < 0.0001

6.7

3.9

8

0

5

10

Mechanical Ventilation ICU LOS Hospital LOS

Me

dia

n T

Single center trial of 74 adult MICU patients on mechanical ventilation randomized to sedation therapy guided by new sedation algorithm or daily interruption of sedation with no algorithm.

de Wit M, et al. Crit Care. 2008;12(3):R70.

For audience members who have a protocol or guideline in place, when was the last time it was updated?

a) < 1 yeara) < 1 yearb) 1-3 yearsc) 3- 5 yearsd) > 5 years

14.7 14.9

11.712.9

19.2

15

20

25

ime

(d

ay

s)

DSI with SBT n = 167

SBT alone n = 168 p = 0.01

p = 0.02

p = 0.04

Girard TD,et al. Lancet. 2008 Jan 12;371(9607):126-34.

Four center trial of 336 mechanically ventilated patients randomized to management with a DSI followed by an SBT or with sedation per usual care plus a daily SBT.

2

9.1

3

0

5

10

Coma Ventilator freedays

ICU LOS Hospital LOS

Me

an

Ti

p = 0.002

13.5

6 1

7.9

12.9

8

10

12

14

16

Tim

e (

days)

PT/OT with DSI n = 49

DSI alone n = 55

p = 0.02

p = 0.08p = 0.02

p = 0.93

All patients

23.4

5.9

4

6.1

0

2

4

6

Duration of ICUDelirium

MechanicalVentilation

ICU LOS Hospital LOS

Med

ian

T

Schweickert WD, et al. Lancet. 2009 May 30;373(9678):1874-82.

Two center trial of 104 adult patients on mechanical ventilation for less than 72 h, randomized to early exercise and mobilization (PT and OT) during periods of daily interruption of sedation or to daily interruption of sedation with therapy as ordered by the primary care team

Physicians Pharmacists Nurses Information systems personnelInformation systems personnel Respiratory Therapists Physical Therapists Occupational Therapists

11.810 6

19.8

15

20

25

Tim

e (d

ays

)

RPh intervention n = 78

Control n = 78

p = 0.002

p = 0.001

p = 0.0004


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

5.37

8.910.6

0

5

10


Me

dia

n T

nt day,mg

Fentanyl equivalents/vent day,mcg*

102.5 ±328

400 ±1026

0.02

*Data presented in mean †Data presented as n (%)

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 Feb;36(2):427-33



45.1

85.4

44.1

66.7

60

80

100

smen

ts (

%)

PRE intervention n = 57

POST intervention n = 54

p < 0.05 Significant patient characteristics/metrics/outcomes

PRE POST P value

Organ dysfunctions/ patient*

1.8 0.9 2.2 1.1 0.03

Duration of MV hrs*

120 118

166 170

0.10

p < 0.05

p < 0.05

21.3

31.4

0

20

40

Sedation orderwith Goal

RASS at Goal RASS within 1of goal

As

ses

s MV, hrs 118 170

ICU LOS, days*

9.3 9.1 10.6 9.8

0.48

Midazolam vent day,mg*

25 32 22 24 0.56

Fentanyl vent day,mcg*

648 765

784 911

0.4

*Data presented in mean †Data presented as n (%)Drug dosing in midazolam and fentanyl equivalents

Single center trial of 111 adult MICU patients requiring mechanical ventilation for ≥ 12 hours before (n = 57) and after (n = 54) systematic implementation of a guideline for pain, sedation, and delirium management at Brigham and Women’s Hospital. Guideline addressed agent selection, use of goal oriented therapy, and dose limitation strategies.

DeGrado, J, et al. Crit Care Med. 2008 Dec;36(S12):A556

Metric Variable Assessment Metric Target

Sedation Assessment Q3hr or more frequent 100%

Pain Assessment Q3hr or more frequent 100%

Delirium Assessment Q12-Q24hr 100%

Daily Interruption Daily after 48 hours 100%

Time in target goal % of assessments ≥ 70%??

Time in target +/- 1 of RASS goal

≥ 80%??

Assessment “comatose”

‘never event’?? ?

Incidence of delirium Patient population dependant

0%

Days in delirium ?

Implementation of best practices for pain, sedation, and delirium management by means of protocols and guidelines is associated with improvement in patient outcomes

Continuous quality assessment and improvement initiatives can provide clinicians with valuable information needed to address barriers and improve outcomes

Weinert CR, Calvin AD. Epidemiology of sedation and sedation adequacy for mechanically ventilated patients in a medical and surgical intensive care unit. Crit Care Med. 2007 Feb;35(2):393-401.

Williams TA, Martin S, Leslie G, et al. Duration of mechanical ventilation in an adult intensive care unit after introduction of sedation and pain scales. Am J Crit Care. 2008 Jul;17(4):349-56.

Chanques G, Jaber S, Barbotte E, et al. Impact of systematic evaluation of pain and agitation in an intensive care unit. Crit Care Med. 2006 Jun;34(6):1691-9.

Pun BT, Gordon SM, Peterson JF, et al. Large-scale implementation of sedation and delirium monitoring in the intensive care unit: a report from two medical centers. Crit Care Med. 2005 Jun;33(6):1199-205.

MacLaren R, Plamondon JM, Ramsay KB, et al. A prospective evaluation of empiric versus protocol-based sedation and analgesia. Pharmacotherapy. 2000 Jun;20(6):662-72.

Mascia MF, Koch M, Medicis JJ. Pharmacoeconomic impact of rational use guidelines on the provision of analgesia sedation and neuromuscular blockade in critical care Crit Care Med 2000 Jul;28(7):2300 6analgesia, sedation, and neuromuscular blockade in critical care. Crit Care Med. 2000 Jul;28(7):2300-6.

Kollef MH, Levy NT, Ahrens TS, et al. The use of continuous i.v. sedation is associated with prolongation of mechanical ventilation. Chest. 1998; 114:541-548.

Swart EL, van Schijndel RJ, van Loenen AC, et al. Continuous infusion of lorazepam versus medazolam in patients in the intensive care unit: sedation with lorazepam is easier to manage and is more cost-effective. Crit Care Med. 1999 Aug;27(8):1461-5.

Barrientos-Vega R, Mar Sánchez-Soria M, Morales-García C, et al. Prolonged sedation of critically ill patients with midazolam or propofol: impact on weaning and costs. Crit Care Med. 1997 Jan;25(1):33-40.

Robinson BR, Mueller EW, Henson K, et al. An analgesia-delirium-sedation protocol for critically ill trauma patients reduces ventilator days and hospital length of stay. J Trauma. 2008 Sep;65(3):517-26.

Devlin JW, Holbrook AM, Fuller HD. The effect of ICU sedation guidelines and pharmacist interventions on clinical outcomes and drug cost. Ann Pharmacother. 1997 Jun;31(6):689-95.

Puntillo KA, Wild LR, Morris AB, et al. Practices and predictors of analgesic interventions for adults undergoing painful procedures. Am J Crit Care. 2002 Sep;11(5):415-29

Puntillo KA, White C, Morris AB, et al. Patients' perceptions and responses to procedural pain: results from Thunder Project II. Am J Crit Care. 2001 Jul;10(4):238-51.

Skrobik Y, Ahern S, Leblanc M, et al. Protocolized intensive care unit management of analgesia, sedation, and delirium improves analgesia and subsyndromal delirium rates. Anesth Analg. 2010 Aug;111(2):451-63.

Marshall J, Finn CA, Theodore AC. Impact of a clinical pharmacist-enforced intensive care unit sedation protocol on duration of mechanical ventilation and hospital stay. Crit Care Med. 2008 Feb;36(2):427-33.

Strøm T, Martinussen T, Toft P. A protocol of no sedation for critically ill patients receiving mechanical ventilation: a randomised trial. Lancet. 2010 Feb 6;375(9713):475-80.



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