patient behaviour case based presentation: delirium s. mountain ahd april 17, 2008

Patient Behaviour Case Patient Behaviour Case Based Presentation: DeliriumBased Presentation: Delirium

S. MountainS. MountainAHD April 17, 2008AHD April 17, 2008

The CaseThe Case

► It is a gray day in January, and you are on It is a gray day in January, and you are on morning rounds, leading your large and morning rounds, leading your large and inquisitive team from bedside to bedside.inquisitive team from bedside to bedside.

► You arrive at bed 17, and find your patient You arrive at bed 17, and find your patient deeply sedated, on A/C, not overriding the deeply sedated, on A/C, not overriding the vent. This is a bit of a surprise to you, as vent. This is a bit of a surprise to you, as yesterday the patient was weaning nicely on yesterday the patient was weaning nicely on moderately high PSV, and you were hopeful moderately high PSV, and you were hopeful to wean and possibly extubate him today.to wean and possibly extubate him today.

The CaseThe Case

►The patient is a 72 year old ex-logger, The patient is a 72 year old ex-logger, who lives in a single room hotel on the who lives in a single room hotel on the Downtown East Side. He presented 5 Downtown East Side. He presented 5 days ago with pneumonia, and was days ago with pneumonia, and was intubated for rapidly progressive intubated for rapidly progressive hypoxemic respiratory failure. He has hypoxemic respiratory failure. He has progressed well both clinically and progressed well both clinically and radiographically, and is now requiring radiographically, and is now requiring 40% FiO2, and a PEEP of 10 with good 40% FiO2, and a PEEP of 10 with good blood gases.blood gases.

The CaseThe Case

► When you inquire of the nurse, and your team, as When you inquire of the nurse, and your team, as to why he is so sedated, you are told that last night, to why he is so sedated, you are told that last night, as his sedation was turned off in anticipation of as his sedation was turned off in anticipation of extubation today, he became extremely agitated. extubation today, he became extremely agitated. He started bucking and coughing on the vent, He started bucking and coughing on the vent, which was alarming continuously, and was pulling which was alarming continuously, and was pulling at all his lines and tubes. He dislodged his NG tube, at all his lines and tubes. He dislodged his NG tube, and since the resident was concerned that he might and since the resident was concerned that he might pull his ETT, he ordered the patient to be started pull his ETT, he ordered the patient to be started back on morphine and midazolam infusions to back on morphine and midazolam infusions to settle him. He has required large amounts of both settle him. He has required large amounts of both throughout his ICU stay, and is now on infusions of throughout his ICU stay, and is now on infusions of 15 mg of each medication, and has settled nicely.15 mg of each medication, and has settled nicely.

The CaseThe Case

►The nurse says to you, “Doctor, clearly The nurse says to you, “Doctor, clearly this patient is delirious, and cannot be this patient is delirious, and cannot be safely weaned from his sedation.” At safely weaned from his sedation.” At this statement one of the more this statement one of the more animated medical students looks animated medical students looks puzzled. You note her confusion, and puzzled. You note her confusion, and ask what she is thinking. “Well,” she ask what she is thinking. “Well,” she says, “how can you tell if a patient is says, “how can you tell if a patient is delirious in the ICU?”delirious in the ICU?”

Naisan:Naisan:

1. What is delirium? What1. What is delirium? Whattypes of delirium are there?types of delirium are there?What are the diagnostic criteria?What are the diagnostic criteria?

2. What is a RASS score? How2. What is a RASS score? Howis it calculated?is it calculated?

Delirium: DefinitionDelirium: Definition

►Delirium is an organic mental Delirium is an organic mental syndrome defined as an acute, syndrome defined as an acute, potentially reversible impairment of potentially reversible impairment of consciousness and cognitive function consciousness and cognitive function that fluctuates in severity that fluctuates in severity

Hansen-Flaschen J Crit Care Clin 1994 Oct;10(4):659-71.Hansen-Flaschen J Crit Care Clin 1994 Oct;10(4):659-71.

DSM IV CriteriaDSM IV Criteria

► Disturbance of consciousness with reduced ability to focus, Disturbance of consciousness with reduced ability to focus, sustain, or shift attention. sustain, or shift attention.

► A change in cognition or the development of a perceptual A change in cognition or the development of a perceptual disturbance that is not better accounted for by a preexisting, disturbance that is not better accounted for by a preexisting, established, or evolving dementia. established, or evolving dementia.

► The disturbance develops over a short period of time (usually The disturbance develops over a short period of time (usually hours to days) and tends to fluctuate during the course of the hours to days) and tends to fluctuate during the course of the day. day.

► There is evidence from the history, physical examination, or There is evidence from the history, physical examination, or laboratory findings that the disturbance is caused by a laboratory findings that the disturbance is caused by a medical condition, substance intoxication, or medication side medical condition, substance intoxication, or medication side effect. effect.

DSM IV CriteriaDSM IV Criteria

► Additional features that may accompany Additional features that may accompany delirium and confusion include the following:delirium and confusion include the following: Psychomotor behavioral disturbances such as Psychomotor behavioral disturbances such as

hypoactivity, hyperactivity with increased hypoactivity, hyperactivity with increased sympathetic activity, and impairment in sleep sympathetic activity, and impairment in sleep duration and architecture. duration and architecture.

Variable emotional disturbances, including fear, Variable emotional disturbances, including fear, depression, euphoria, or perplexity.depression, euphoria, or perplexity.

PathophysiologyPathophysiology

► ““Delirium is a syndrome of global cerebral Delirium is a syndrome of global cerebral insufficiency analogous to organ system insufficiency analogous to organ system failures observed in sites remote from the failures observed in sites remote from the brain”brain”

► Neurotransmitter imbalancesNeurotransmitter imbalances GABA, serotonin, acetylcholine, dopamineGABA, serotonin, acetylcholine, dopamine

► InflammationInflammation► Neuroanatomic lesionsNeuroanatomic lesions► Electrophysiologic changesElectrophysiologic changes

Stevens RD & Nyquist PA Crit Care Clin 2007

Delirium subtypesDelirium subtypes► Hypoactive delirium Hypoactive delirium

more common in older more common in older patients patients

withdrawal, flat affect, withdrawal, flat affect, apathy, lethargy, apathy, lethargy, decreased decreased responsivenessresponsiveness

may be misdiagnosed may be misdiagnosed as depressionas depression

► MixedMixed

► HyperactiveHyperactive “ “ICU psychosis”ICU psychosis” rarerarePeterson et al. J Am Geriatr Soc 2006

Yoan:Yoan:

3. Are there validated 3. Are there validated methods to diagnose methods to diagnose delirium in the ICU? What is delirium in the ICU? What is the CAM-ICU, what is the the CAM-ICU, what is the evidence for it, and how evidence for it, and how does it work?does it work?

►Several validated methods:Several validated methods: Intensive Care Delirium Screening Intensive Care Delirium Screening

checklistchecklist►Bergeron et al Int Care Med 2001Bergeron et al Int Care Med 2001

Confusion assessment method in the ICUConfusion assessment method in the ICU►Ely at al JAMA 2001Ely at al JAMA 2001

ICDSICDSCC

Main differences (Poldermans Main differences (Poldermans ICM 2007)ICM 2007)

ICDSCICDSC► Decreased LOC, Decreased LOC,

sedation: not possible sedation: not possible to assess: no deliriumto assess: no delirium

► Few exclusions (if will Few exclusions (if will die in < 24h)die in < 24h)

► Steps:Steps: No steps, all criteria No steps, all criteria

get pointsget points > 4 /8 points = > 4 /8 points =

DeliriumDelirium► Validation: 875 pts, Validation: 875 pts,

ICM 2007ICM 2007

CAM-ICUCAM-ICU► Decreased LOC = part Decreased LOC = part

of Dx criteria for of Dx criteria for deliriumdelirium

► Many exclusion criteria Many exclusion criteria (> 50% pts)(> 50% pts)

► Steps: Steps: 1.1. FluctuateFluctuate2.2. InattentionInattention3.3. Decreased LOCDecreased LOC4.4. Decreased mentationDecreased mentation

► Validation: 275 pts, Validation: 275 pts, CCM2004CCM2004

The Case - ContinuedThe Case - Continued

► At this point one of the senior medicine residents, who At this point one of the senior medicine residents, who is clearly trying to impress the juniors with his cynicism is clearly trying to impress the juniors with his cynicism and world weary attitude, chimes in. “Of course,” he and world weary attitude, chimes in. “Of course,” he declares, “all the patients in the ICU are delirious declares, “all the patients in the ICU are delirious because of the effects of the sedatives. It doesn’t because of the effects of the sedatives. It doesn’t matter, because they all get better as soon as you wake matter, because they all get better as soon as you wake them up anyway.”them up anyway.”

► Concerned that he does not quite seem to grasp the Concerned that he does not quite seem to grasp the prevalence, impact, or nature of critical care brain prevalence, impact, or nature of critical care brain dysfunction, you decide to do him a favour and set him dysfunction, you decide to do him a favour and set him straight.straight.

4. How common is delirium in the 4. How common is delirium in the ICU? How about in older ICU? How about in older patients, or patients with patients, or patients with dementia?dementia?

5. What is the impact of delirium 5. What is the impact of delirium on critically ill patients in terms on critically ill patients in terms of mortality, cost, length of stay, of mortality, cost, length of stay, etc.?etc.?

Delirium - EpidemiologyDelirium - Epidemiology

►Develops in 50 – 80% of mechanically Develops in 50 – 80% of mechanically ventilated patientsventilated patients

►Estimated to be unrecognized in 66% - Estimated to be unrecognized in 66% - 84% of patients (ICU, hospital ward, ER)84% of patients (ICU, hospital ward, ER)

► Independent predictor of:Independent predictor of: prolonged ICU and hospital LOSprolonged ICU and hospital LOS higher 6 month mortalityhigher 6 month mortality higher costshigher costs higher rate of cognitive dysfunctionhigher rate of cognitive dysfunction

Impact of Delirium in ICUImpact of Delirium in ICU

CAM-Ely et al JAMA 2001

ICDSC-Skrobik et al, ICM 2007

CAM-Millbrand + Ely JAMA 2004

Delirium as a Predictor of Mortality in Delirium as a Predictor of Mortality in Mechanically Ventilated Patients in the Mechanically Ventilated Patients in the

Intensive Care Unit Intensive Care Unit

Ely EW et al Ely EW et al JAMA.JAMA. 2004;291:1753-1762. 2004;291:1753-1762.

► Delirium was associated with a more than 3 times Delirium was associated with a more than 3 times higher risk of dying by 6 months higher risk of dying by 6 months (after adjusting for 11 covariates including preexisting (after adjusting for 11 covariates including preexisting

comorbidities, severity of illness, coma incidence and comorbidities, severity of illness, coma incidence and sedative and analgesic use)sedative and analgesic use)

► Each additional day spent in delirium was Each additional day spent in delirium was

associated with a 10% increased risk of deathassociated with a 10% increased risk of death

H.R. = hazard ratio. Data in parenthesis indicate confidence interval. H.R. = hazard ratio. Data in parenthesis indicate confidence interval. Ely EW et al.JAMA.2004Ely EW et al.JAMA.2004

Delirium in ICU patients is a risk factor for 6-month mortality.

Ely EW et al.JAMA.2004Ely EW et al.JAMA.2004

Delirium in ICU patients is a risk factor for prolonged hospital length of stay.

Milbrandt et al. Crit Care Med 2004Milbrandt et al. Crit Care Med 2004

Dave:Dave:

6. What are some conditions 6. What are some conditions that can contribute to the that can contribute to the development of delirium? development of delirium? What is the differential What is the differential diagnosis in this patient?diagnosis in this patient?

Risk factorsRisk factors► predisposing factorspredisposing factors

ageage male gendermale gender cognitive impairment or cognitive impairment or

dementiadementia poor functional statuspoor functional status malnutrition malnutrition substance or ethanol usesubstance or ethanol use coexisting medical coexisting medical

conditionsconditions History of smoking, History of smoking,

hypertensionhypertension genetic predisposition?genetic predisposition?

► precipitating factorsprecipitating factors primary neurologic disease primary neurologic disease infectioninfection shockshock hypoxiahypoxia electrolyte abnormalitieselectrolyte abnormalities surgerysurgery pharmacologic agentspharmacologic agents

► benzodiazepines, opiates, benzodiazepines, opiates, anticholinergicsanticholinergics

substance withdrawalsubstance withdrawal mechanical ventilationmechanical ventilation bladder and central venous bladder and central venous

catheterizationcatheterization restraintsrestraints sleep deprivationsleep deprivation

From: Stevens RD & Nyquist PA Crit Care Clin 2007

DDxDDx

► DeliriumDelirium► Drug reactionDrug reaction► WithdrawalWithdrawal► Dementia (Alzheimer’s, Lewy body dis.)Dementia (Alzheimer’s, Lewy body dis.)► SundowningSundowning► New infectionNew infection► Structural brain injury (infarct, bleed, neoplasm, etc.)Structural brain injury (infarct, bleed, neoplasm, etc.)► Underlying psychiatric illnessUnderlying psychiatric illness► NCSENCSE► Wernicke’sWernicke’s► Anton’s syndrome (cortical blindness and confabulation Anton’s syndrome (cortical blindness and confabulation

- focal occipital lesion).- focal occipital lesion).

Delirium Risk Factors- New Delirium Risk Factors- New StudiesStudies

► MIND-ICU Study: Delirium and Dementia in MIND-ICU Study: Delirium and Dementia in Veterans Surviving ICU CareVeterans Surviving ICU Care Vanderbilt University – ElyVanderbilt University – Ely Purpose: to define the epidemiology of and Purpose: to define the epidemiology of and

identify modifiable risk factors for long-term identify modifiable risk factors for long-term cognitive impairment and functional deficits of cognitive impairment and functional deficits of ICU survivorsICU survivors

► BRAIN ICU Study: Bringing to Light the Risk BRAIN ICU Study: Bringing to Light the Risk FactorsFactors Vanderbilt University – ElyVanderbilt University – Ely Purpose: to identify potentially modifiable risk Purpose: to identify potentially modifiable risk

factors of long-term cognitive impairment (i.e. factors of long-term cognitive impairment (i.e. development of delirium and exposure to development of delirium and exposure to sedative and analgesic medications) in ICU sedative and analgesic medications) in ICU patientspatients

Anesthesiology 2006;104:21-6


►The nurse, who is from Australia, is getting The nurse, who is from Australia, is getting annoyed at the amount of conversation at her annoyed at the amount of conversation at her bedside. She clearly has more important work bedside. She clearly has more important work to do. Somewhat disgruntled, and clearly to do. Somewhat disgruntled, and clearly missing the January sun, she grumbles “I don’t missing the January sun, she grumbles “I don’t know why the people in this country have such know why the people in this country have such ancient ideas about sedation anyway. At home, ancient ideas about sedation anyway. At home, we just put everyone on propofol, and that we just put everyone on propofol, and that treats all their delirium just fine. We never have treats all their delirium just fine. We never have any problems there at all.”any problems there at all.”


► Suspecting that her fading memories of Suspecting that her fading memories of home have caused her to have a somewhat home have caused her to have a somewhat rose-colored view of patient care, you rose-colored view of patient care, you nevertheless take this opportunity to review nevertheless take this opportunity to review prevention and treatment of ICU delirium prevention and treatment of ICU delirium with your team. Besides, you’re in no hurry with your team. Besides, you’re in no hurry to move on, since, as a well trained ICU to move on, since, as a well trained ICU Fellow, you have come to realize that eating Fellow, you have come to realize that eating lunch more than three times per week is a lunch more than three times per week is a luxury reserved for the weak.luxury reserved for the weak.

7. What are some non-7. What are some non-pharmacologic methods pharmacologic methods that can be used to prevent that can be used to prevent and treat delirium?and treat delirium?

Delirium PreventionDelirium Prevention

►NonpharmacologicNonpharmacologic Risk factor modificationRisk factor modification

►Reorientation, cognitively stimulating Reorientation, cognitively stimulating activities, early mobilization, rom exercises, activities, early mobilization, rom exercises, removal of catheters and restraints, glasses, removal of catheters and restraints, glasses, hearing aids, reduce noise, adequate hearing aids, reduce noise, adequate hydrationhydration

ProtocolsProtocols SleepSleep

► APPENDIX 5---NON-PHARMACOLOGICAL INTERVENTIONS FOR DELIRIUM MANAGEMENTAPPENDIX 5---NON-PHARMACOLOGICAL INTERVENTIONS FOR DELIRIUM MANAGEMENT►

► VibrationVibration► DistractionDistraction► Position patient in a position that minimizes discomfortPosition patient in a position that minimizes discomfort► Apply heat or coldApply heat or cold► RelaxationRelaxation► MassageMassage► Therapeutic touchTherapeutic touch► AcupressureAcupressure► Minimize stimulation (Take conversations away from the bedside)Minimize stimulation (Take conversations away from the bedside)► Minimize tethers (Lines, tubes, and monitoring devices)Minimize tethers (Lines, tubes, and monitoring devices)► Provide set rest periods—aim for one 90 minute uninterrupted rest period during day.Provide set rest periods—aim for one 90 minute uninterrupted rest period during day.► Provide 1:1 or 1:2 nursing care as needed. Have a “patient sitter” prn.Provide 1:1 or 1:2 nursing care as needed. Have a “patient sitter” prn.► Plan care in clumps of timePlan care in clumps of time► Maximize comfort (Is bowel care needed?)Maximize comfort (Is bowel care needed?)► Hunt for the underlying cause (Refer to “ICU DELERIUMS" Appendix 4)Hunt for the underlying cause (Refer to “ICU DELERIUMS" Appendix 4)► Maximize rest and sleep periods – preferably without drugs, (e.g. dim room lighting, private room, close Maximize rest and sleep periods – preferably without drugs, (e.g. dim room lighting, private room, close

doors to reduce noise, turn down bedside alarm volume on monitor, diminish faceplate lights on pumps, doors to reduce noise, turn down bedside alarm volume on monitor, diminish faceplate lights on pumps, reduce nuisance alarms, etc.)reduce nuisance alarms, etc.)

► Provide frequent calm reassurance and reorientationProvide frequent calm reassurance and reorientation► Make sure patient is wearing his glasses and/or hearing aidesMake sure patient is wearing his glasses and/or hearing aides► Keep familiar objects in the patient’s line of sightKeep familiar objects in the patient’s line of sight► Play familiar musicPlay familiar music► Use family support if they help calm the patientUse family support if they help calm the patient► Provide adequate nutrition and hydrationProvide adequate nutrition and hydration► Assess for electrolyte imbalanceAssess for electrolyte imbalance► Establish and maintain a clear day/night pattern—i.e. sleep during night and awake during day except Establish and maintain a clear day/night pattern—i.e. sleep during night and awake during day except

for either short naps or 1-90min. rest period.for either short naps or 1-90min. rest period.► Use plain language in face to face communications with patientUse plain language in face to face communications with patient► Ask questions that can be answered with “Yes” or “No” either verbally or non-verbally.Ask questions that can be answered with “Yes” or “No” either verbally or non-verbally.► Establish a consistent approach to care and provide it in a calm unhurried mannerEstablish a consistent approach to care and provide it in a calm unhurried manner► Provide cognitively stimulating activities several times a dayProvide cognitively stimulating activities several times a day► Consider consults to Nutrition, OT, Speech Therapy, Gerontology, Psychiatry, Social Work, Chaplain prn.Consider consults to Nutrition, OT, Speech Therapy, Gerontology, Psychiatry, Social Work, Chaplain prn.► Early mobilization and/or frequent Range-of-Motion exercisesEarly mobilization and/or frequent Range-of-Motion exercises

Gord:Gord:

8. 8. What pharmacologic agents What pharmacologic agents exist in Canada to treat ICU exist in Canada to treat ICU delirium? Which is best? What delirium? Which is best? What is the evidence?is the evidence?

Treatment of DeliriumTreatment of Delirium

►No drugs have FDA-approval for the No drugs have FDA-approval for the treatment of delirium treatment of delirium

►The American Psychiatric Association The American Psychiatric Association and the Society of Critical Care and the Society of Critical Care Medicine clinical practice guidelines Medicine clinical practice guidelines (Jacobi J, et al., Crit Care Med 2002; (Jacobi J, et al., Crit Care Med 2002; 30:119-141) recommend haloperidol 30:119-141) recommend haloperidol for the treatment of delirium (level C for the treatment of delirium (level C data).data).

Treatment of DeliriumTreatment of Delirium

►Atypical antipsychotics may be as Atypical antipsychotics may be as effective as haloperidol, and may be effective as haloperidol, and may be associated with fewer side effects associated with fewer side effects (Stevens and Nyquist Crit Care Clin (Stevens and Nyquist Crit Care Clin 2007)2007)

►Several studies on use of antipsychotics Several studies on use of antipsychotics to treat delirium in ICU patients are to treat delirium in ICU patients are currently underway currently underway

Olanzapine vs Haldol:treating delirium in a critical Olanzapine vs Haldol:treating delirium in a critical care setting (Skrobik et al Int Care Med 2004)care setting (Skrobik et al Int Care Med 2004)

Olanzapine vs Haldol:treating delirium in a critical Olanzapine vs Haldol:treating delirium in a critical care setting (Skrobik et al Int Care Med 2004)care setting (Skrobik et al Int Care Med 2004)

►Treatment alternative; no real Treatment alternative; no real difference found. difference found.

►May be useful in :May be useful in : Parkinson’sParkinson’s Prolonged QTProlonged QT Oropharyngeal dysfunctionOropharyngeal dysfunction

►Limited by:Limited by: Only available enterallyOnly available enterally

New TrialsNew Trials

ORIC-1: Optimizing recovery from ORIC-1: Optimizing recovery from intensive care: mechanical ventilation and intensive care: mechanical ventilation and deliriumdelirium

►University of Pittsburgh and NHLBI – University of Pittsburgh and NHLBI – Mildebrandt EBMildebrandt EB

►Purpose – to determine if treating delirious icu Purpose – to determine if treating delirious icu pts with haloperidol improves mortalitypts with haloperidol improves mortality

►Delirious mechanically ventilated pts will be Delirious mechanically ventilated pts will be treated with haldol 5mg iv q 12 h or placebotreated with haldol 5mg iv q 12 h or placebo

New TrialsNew Trials A pilot study of haloperidol to treat critical illness A pilot study of haloperidol to treat critical illness

deliriumdelirium► University of Colorado – Douglas ISUniversity of Colorado – Douglas IS

Randomized controlled trial of dexmedetomidine Randomized controlled trial of dexmedetomidine for the treatment of ICU deliriumfor the treatment of ICU delirium

► Brigham and Women’s Hospital – Weinhouse, GLBrigham and Women’s Hospital – Weinhouse, GL► Comparison of dex to haldol and lorazepamComparison of dex to haldol and lorazepam

A comparison of dexmedetomidine and A comparison of dexmedetomidine and haloperidol in patients with icu-associated haloperidol in patients with icu-associated agitation and deliriumagitation and delirium

► Austin Health – Bellomo RAustin Health – Bellomo R

9. What new sedative agents 9. What new sedative agents exist that may impact our exist that may impact our future care of agitated future care of agitated patients? Remind us of the patients? Remind us of the evidence for or against their evidence for or against their use; i.e. what are the pros use; i.e. what are the pros and cons?and cons?

Dexmedetomidine Dexmedetomidine (Precedex(Precedex®)®)

•Alpha-2 receptor agonist

•Reduced release of NE and inhibition of postsynaptic activation

•CNS excitation is attenuated, esp. in locus coeruleus

In a study of 8 female surgical patients, Precedex was infused postoperatively by computer-controlled infusion protocol (CCIP) for 60 minutes, targeting a plasma concentration of 600 pg/mLPlasma norepinephrine concentrations decreased on average by 72% (range 40% to 97%) Plasma epinephrine decreased by 72% (range 47% to 92%)

DexmedetomidineDexmedetomidine►““cooperative sedation”cooperative sedation”►Therapeutic uses: Therapeutic uses:

ICU sedationICU sedation►adults and peds, drug withdrawal, ventilator adults and peds, drug withdrawal, ventilator

weaningweaning Perioperative usePerioperative use

►sympatholysis, analgesic and sedative sympatholysis, analgesic and sedative propertiesproperties

NeurosurgeryNeurosurgery►potential to decrease cerebral blood flow, potential to decrease cerebral blood flow,

optimize cerebral O2 supply, optimize cerebral O2 supply, neuroprotection (reduces glutamine neuroprotection (reduces glutamine release), decrease ICP (in animal studies)release), decrease ICP (in animal studies)

For outpatient procedural sedation For outpatient procedural sedation ►no respiratory depressionno respiratory depression

DexmedetomidineDexmedetomidine

►Adverse reactions:Adverse reactions: Hypotension – at lower dosesHypotension – at lower doses Hypertension – at higher doses (activation Hypertension – at higher doses (activation

of peripheral alpha-2b receptors)of peripheral alpha-2b receptors) NauseaNausea BradycardiaBradycardia Dry mouthDry mouth

Effect of Sedation With Dexmedetomidine vs Lorazepam on Acute Brain Dysfunction in Mechanically Ventilated Patients

The MENDS Randomized Controlled Trial Pratik P. Pandharipande

, MD, MSCI; Brenda T. Pun, RN, MSN, ACNP; Daniel L. Herr, MD; Mervyn Maze, MB, ChB; Timothy D. Girard, MD, MSCI; Russell R. Miller, MD, MPH;

Ayumi K. Shintani, MPH, PhD; Jennifer L. Thompson, MPH; James C. Jackson, PsyD; Stephen A. Deppen, MA, MS; Renee A. Stiles, PhD; Robert S. Dittus

, MD, MPH; Gordon R. Bernard, MD; E. Wesley Ely, MD, MPH

JAMA. 2007;298(22):2644-2653.

Objective: To determine whether dexmedetomidine reduces the duration of delirium and coma in mechanically ventilated ICU patients while providing adequate sedation as compared with lorazepam.

MENDSMENDS► Double blind randomized controlled trialDouble blind randomized controlled trial► 106 ventilated pts – med and surg - 106 ventilated pts – med and surg -

randomized to continuous infusion of randomized to continuous infusion of either lorazepam or dexmedetomidineeither lorazepam or dexmedetomidine

► Infusion titrated to goal RASS set by Infusion titrated to goal RASS set by medical teammedical team

► Infusion continued until extubation or 120 Infusion continued until extubation or 120 hrs at which point pts were sedated hrs at which point pts were sedated according to standard practice for that ICUaccording to standard practice for that ICU

► Apparent pain treated with fentanyl bolus Apparent pain treated with fentanyl bolus or infusionor infusion

► If max dose of study drug did not give If max dose of study drug did not give adequate sedation, fentanyl infusion could adequate sedation, fentanyl infusion could be startedbe started

► For sudden agitation – propofol bolusesFor sudden agitation – propofol boluses

MENDSMENDS

► Daily cessation of sedatives and spontaneous Daily cessation of sedatives and spontaneous breathing trials – not mandatedbreathing trials – not mandated

► Primary outcomes:Primary outcomes: delirium-free and coma-free days, efficacy delirium-free and coma-free days, efficacy

of sedation regimenof sedation regimen► Secondary outcomes:Secondary outcomes:

lengths of stay with ventilation, in ICU, in lengths of stay with ventilation, in ICU, in hospital, neuropsych testing post-ICU, 28 hospital, neuropsych testing post-ICU, 28 day mortality, 12 month survivalday mortality, 12 month survival

► CAM-ICU performed twice dailyCAM-ICU performed twice daily

Screening, Enrollment, and RandomizationScreening, Enrollment, and Randomization

Pandharipande, P. P. et al. JAMA 2007;298:2644-2653.

Time to Death Within 28 Days of Enrollment for All PatientsTime to Death Within 28 Days of Enrollment for All Patients



Median infusion rate for dex was .74ug/kg/hr (.39 – 1.04 ug/kg/hr)

Median infusion rate for lorazepam was 3 mg/hr (2.2 – 6mg/hr)

Fentanyl Dose While Receiving Study Drug According to Depth of Fentanyl Dose While Receiving Study Drug According to Depth of Target SedationTarget Sedation


The difference in fentanyl dosage was more notable when patients were more deeply sedated.

MENDSMENDS

►Safety – no more adverse events with Safety – no more adverse events with dexmedetomidinedexmedetomidine

►Cost – overall costs were more for Cost – overall costs were more for dexmedetomidine, but P values were dexmedetomidine, but P values were not significantnot significant

MENDSMENDS

►Conclusion: Conclusion: Sedation with dexmedetomidine infusion Sedation with dexmedetomidine infusion

resulted in 4 more days alive without resulted in 4 more days alive without delirium or coma and significantly more delirium or coma and significantly more time at the desired level of sedation as time at the desired level of sedation as compared with lorazepam infusioncompared with lorazepam infusion

Dexmedetomidine was safeDexmedetomidine was safe

New trialsNew trials► Dexmedetomidine Versus Midazolam for Dexmedetomidine Versus Midazolam for

Continuous Sedation in the ICU (MIDEX)Continuous Sedation in the ICU (MIDEX)► Dexmedetomidine Versus Propofol for Dexmedetomidine Versus Propofol for

Continuous Sedation in the ICU (PRODEX)Continuous Sedation in the ICU (PRODEX)

► Both trials sponsored by Orion PharmaBoth trials sponsored by Orion Pharma► various centres in Europevarious centres in Europe► Purpose: to show that dexmedetomidine is at Purpose: to show that dexmedetomidine is at

least as effective as midazolam/propofol for least as effective as midazolam/propofol for sedation, and that it is associated with sedation, and that it is associated with shorter duration of mechanical ventilationshorter duration of mechanical ventilation


► A Pilot Study of Effect of Dexmedetomidine on A Pilot Study of Effect of Dexmedetomidine on Sleep and Inflammation in Critically Ill PatientsSleep and Inflammation in Critically Ill Patients University of Arizona – ParthasarathyUniversity of Arizona – Parthasarathy Purpose – to assess the short-term effect of Purpose – to assess the short-term effect of

sympatholysis on sleep quality and inflammation in sympatholysis on sleep quality and inflammation in critically ill patientscritically ill patients

► Oral Melatonin in Critically Ill High-Risk Oral Melatonin in Critically Ill High-Risk PatientsPatients University of Milan – MistralettiUniversity of Milan – Mistraletti Purpose – to analyze the potential of oral melatonin Purpose – to analyze the potential of oral melatonin

as a sedative and free-radical scavenger for as a sedative and free-radical scavenger for critically ill patients and secondarily for preventing critically ill patients and secondarily for preventing delirium during their ICU stay and PTSD after ICU delirium during their ICU stay and PTSD after ICU dischargedischarge


““The MIND Study: Modifying the Incidence of The MIND Study: Modifying the Incidence of Delirium” or “Delirium in the ICU: a Prospective Delirium” or “Delirium in the ICU: a Prospective randomized Trial of Placebo vs. Haloperidol vs. randomized Trial of Placebo vs. Haloperidol vs. Ziprasidone Ziprasidone

► Vanderbilt – ElyVanderbilt – Ely► a pilot study of feasibility to begin assessing the role of a pilot study of feasibility to begin assessing the role of

antipsychotics in management of ICU deliriumantipsychotics in management of ICU delirium► aims of study are:aims of study are:

determine whether antipsychotics reduce incid and determine whether antipsychotics reduce incid and duration of delirium in high risk mech vent ptsduration of delirium in high risk mech vent pts

determine whether antipsychotics reduce severity of determine whether antipsychotics reduce severity of neuropsych dysfn at hospital dischg in high risk mech vent neuropsych dysfn at hospital dischg in high risk mech vent ptspts


► Your latest diatribe on delirium seems to have lulled Your latest diatribe on delirium seems to have lulled some of your less enthusiastic residents into a small some of your less enthusiastic residents into a small coma of their own. You decide to get back to the task coma of their own. You decide to get back to the task at hand, in order to wake them up. Now that you have at hand, in order to wake them up. Now that you have established how you are going to treat this patient’s established how you are going to treat this patient’s delirium, you ask the resident in charge how they delirium, you ask the resident in charge how they would like to go about weaning this patient from would like to go about weaning this patient from sedation and ventilation. The resident says, “I don’t sedation and ventilation. The resident says, “I don’t know, but you’d think there would be some kind of know, but you’d think there would be some kind of protocol or something, isn’t there?”protocol or something, isn’t there?”

► ““Well,” you say, “as a matter of fact...”Well,” you say, “as a matter of fact...”

Steve:Steve:

10. Is there any recent evidence to 10. Is there any recent evidence to show standardized sedation or show standardized sedation or ventilator weaning protocols ventilator weaning protocols reduce the incidence of delirium reduce the incidence of delirium or coma? What other impacts or coma? What other impacts have they been shown to have have they been shown to have (i.e. what is the evidence for or (i.e. what is the evidence for or against their use?)against their use?)

Prevention - ProtocolsPrevention - Protocols

► Sedation/analgesia/delirium protocolsSedation/analgesia/delirium protocols

► Outcomes can be improved by:Outcomes can be improved by: Daily interruption of sedation and sedation Daily interruption of sedation and sedation

protocolsprotocols Ventilator weaning protocols including Ventilator weaning protocols including

spontaneous breathing trialsspontaneous breathing trials

► ABC trialABC trial

Notice that pt APACHE score wasn’t that high.

Lancet 2008;371:126-34

ABC TrialABC Trial

► Multicentre, randomized controlled trialMulticentre, randomized controlled trial

► Purpose: to assess the efficacy and safety of Purpose: to assess the efficacy and safety of a protocol of daily spontaneous awakening a protocol of daily spontaneous awakening trials (SATs) paired with spontaneous trials (SATs) paired with spontaneous breathing trials (SBTs) versus a standard breathing trials (SBTs) versus a standard SBT protocol in patients receiving patient-SBT protocol in patients receiving patient-targeted sedation as part of usual caretargeted sedation as part of usual care

ABC TrialABC Trial► 4 large centres4 large centres

► Inclusion criteriaInclusion criteria 18 yrs or older18 yrs or older Mechanical ventilation > 12 hrsMechanical ventilation > 12 hrs Full ventilatory support or weaningFull ventilatory support or weaning

► Exclusion criteriaExclusion criteria Admitted post cardiopulmonary arrest, ventilated >2 Admitted post cardiopulmonary arrest, ventilated >2

weeks, moribund, withdrawal of life support, profound weeks, moribund, withdrawal of life support, profound neuro deficit, enrolled in another trialneuro deficit, enrolled in another trial

ABC TrialABC Trial

►Patients randomly assigned to Patients randomly assigned to management with either paired SAT management with either paired SAT and SBT protocols or usual care and SBT protocols or usual care including patient-targeted sedation including patient-targeted sedation and an SBT protocoland an SBT protocol

ABC Trial

ABC TrialABC Trial

►Primary endpointPrimary endpoint Number of days breathing without Number of days breathing without

assistance (had to last at least 48 hrs) assistance (had to last at least 48 hrs) during the 28-day study periodduring the 28-day study period

►Secondary endpointsSecondary endpoints Time to discharge from ICU and hospitalTime to discharge from ICU and hospital All-cause 28 day mortalityAll-cause 28 day mortality 1 year survival1 year survival Duration of coma and deliriumDuration of coma and delirium

ABC TrialABC Trial

►Patients were assessed using RASS Patients were assessed using RASS and CAM-ICUand CAM-ICU

ConclusionsConclusions

►Compared to usual care, a paired Compared to usual care, a paired sedation and ventilator weaning sedation and ventilator weaning protocol consisting of daily SATs plus protocol consisting of daily SATs plus SBTs resulted in:SBTs resulted in: more time off mechanical ventilationmore time off mechanical ventilation less time in comaless time in coma less time in the ICU and hospital less time in the ICU and hospital improved 1-year mortalityimproved 1-year mortality

CriticismCriticism

►There were more failures of SBT in There were more failures of SBT in controls - too sedated?controls - too sedated?

►Could stress of repeated SBTs Could stress of repeated SBTs contribute to worse outcomes?contribute to worse outcomes?


► The SOMNUS Study: Sedation Optimization The SOMNUS Study: Sedation Optimization Via Monitoring Neurological StatusVia Monitoring Neurological Status Vanderbilt – Watson and ElyVanderbilt – Watson and Ely Purpose: To show that a combine strategy of Purpose: To show that a combine strategy of

RASS clinical targeting plus BIS guided sedation RASS clinical targeting plus BIS guided sedation in mechanically ventilated, critically ill patients in mechanically ventilated, critically ill patients will decrease time on mechanical ventilation, will decrease time on mechanical ventilation, decrease duration of ICU delirium and coma and decrease duration of ICU delirium and coma and will improve subacute neurocognitive function will improve subacute neurocognitive function when compared to sedation guided by RASS when compared to sedation guided by RASS targeting alonetargeting alone


► Now that you are finally ready to leave the bedside and Now that you are finally ready to leave the bedside and move on to the next patient, you realize you forgot to move on to the next patient, you realize you forgot to address the patient’s sleep disturbance. When you address the patient’s sleep disturbance. When you mention it, one of the residents says “I thought we were mention it, one of the residents says “I thought we were trying to wake this guy up. Why are you so worried trying to wake this guy up. Why are you so worried about his sleep now? Let’s just get him awake so we can about his sleep now? Let’s just get him awake so we can extubate him.”extubate him.”

► You’re a bit concerned that the resident may have You’re a bit concerned that the resident may have missed the entire point of the conversation up to now. missed the entire point of the conversation up to now. Unfortunately, you don’t have time to review the whole Unfortunately, you don’t have time to review the whole thing. So you decide to make a few well informed thing. So you decide to make a few well informed comments about sleep in the ICU instead.comments about sleep in the ICU instead.

11. How does sleep 11. How does sleep disturbance impact disturbance impact cognitive function in cognitive function in critically ill patients?critically ill patients?

Delirium Prevention - SleepDelirium Prevention - Sleep► Critically ill patients have severe sleep deprivation Critically ill patients have severe sleep deprivation

and disrupted sleep architectureand disrupted sleep architecture

► Adverse consequences of sleep deprivation include: Adverse consequences of sleep deprivation include: increased risk for cognitive dysfunction and deliriumincreased risk for cognitive dysfunction and delirium reduced cellular and humoral immunityreduced cellular and humoral immunity elevated inflammatory cytokineselevated inflammatory cytokines

► Multiple causes, many potentially modifiable, Multiple causes, many potentially modifiable, including: including: psychoactive medications (sedatives and analgesics)psychoactive medications (sedatives and analgesics) mechanical ventilationmechanical ventilation

► Limitation of the above study was that sleep quantity Limitation of the above study was that sleep quantity and quality was assessed subjectively by nursing and quality was assessed subjectively by nursing staff and that it can only infer correlation, not staff and that it can only infer correlation, not causality. Other negative impacts of poor sleep; causality. Other negative impacts of poor sleep; increased catecholamines, impaired immunological increased catecholamines, impaired immunological function, potentially increased BP, potentially function, potentially increased BP, potentially increased cardiac arrythmias, long term alteration of increased cardiac arrythmias, long term alteration of sleep cycles, may impact overall morbidity and sleep cycles, may impact overall morbidity and mortality.mortality.

► Problems with assertion of a causal link between Problems with assertion of a causal link between lack of sleep and delirium; studies are correlational, lack of sleep and delirium; studies are correlational, healthy volunteers exposed to sleep deprivation healthy volunteers exposed to sleep deprivation show none of the aspects of delirium, sleep show none of the aspects of delirium, sleep disturbances may be a consequence rather than a disturbances may be a consequence rather than a cause of delirium, disturbance of sleep tends to cause of delirium, disturbance of sleep tends to correlate with the degree of illness and is therefore correlate with the degree of illness and is therefore a strong confounder, some studies have found no a strong confounder, some studies have found no correlation between sleep disturbance and delirium.correlation between sleep disturbance and delirium.(From McGuire 2000) (From McGuire 2000)

12. What ventilator 12. What ventilator strategies have been strategies have been explored to improve sleep explored to improve sleep in the ICU? Do they work?in the ICU? Do they work?

► 11 pt had sleep polysomnography during PS or AC ventilation. 11 pt had sleep polysomnography during PS or AC ventilation. PS led to hypocapnia with resultant hypoventilation and more PS led to hypocapnia with resultant hypoventilation and more periods of wafefulness than AC.periods of wafefulness than AC.

►Also adding dead space ventilation Also adding dead space ventilation decreased periods of wakefulness.decreased periods of wakefulness.

Apparently this study shows that PSV is associated with more apneas during sleep.

Discusses the nuances of altering ventilation settings during sleep.

Sleep and mechanical Sleep and mechanical ventilationventilation

►Bosma et al 2007 Crit Care Med: Bosma et al 2007 Crit Care Med:

PAV resulted in better quality of sleep PAV resulted in better quality of sleep compared to PSVcompared to PSV

reduction in patient-ventilator asynchroniesreduction in patient-ventilator asynchronies

PAV responds to the normal down-PAV responds to the normal down-regulation of respiratory muscles during regulation of respiratory muscles during sleep and therefore preserves the sleep and therefore preserves the physiologic increase in PaCO2physiologic increase in PaCO2

SummarySummary

► Delirium (mixed and hypoactive) is very common Delirium (mixed and hypoactive) is very common and is associated with significant long term and is associated with significant long term morbidity and mortalitymorbidity and mortality

► We may be able to improve on our current methods We may be able to improve on our current methods of monitoring for, preventing, and treating deliriumof monitoring for, preventing, and treating delirium Sedation/analgesia/delirium protocolSedation/analgesia/delirium protocol

► Alter how we monitor deliriumAlter how we monitor delirium► Consider adding vent weaning protocolConsider adding vent weaning protocol

PAV during sleepPAV during sleep MedicationsMedications

► Dexmedetomidine?Dexmedetomidine?► Antipsychotics – should we use them more?Antipsychotics – should we use them more?

patient behaviour case based presentation: delirium s. mountain ahd april 17, 2008

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