Acute Brain Dysfunction in the Critically Ill Patient :   Data from recent delirium studies Pratik Pandharipande, MD, MSCI...
… The biggest problem is that “doctors are focused only on the organs that got patients into the hospital, ignoring newly ...
Delirium <ul><li>Disturbance of consciousness </li></ul><ul><li>Rapid onset </li></ul><ul><li>Fluctuating course </li></ul...
Prevalence of ICU Delirium   <ul><li>60-80% MICU/SICU/TICU ventilated patients develop delirium  </li></ul><ul><li>20-50% ...
Key Points: ICU Delirium <ul><li>$15k to $25k higher hospital costs </li></ul><ul><li>Longer hospital stays </li></ul><ul>...
Long-term cognitive impairment (LTCI) after ICU survival <ul><li>10 cohorts (~500 pts) and the largest with neuropsycholog...
0 10 20 30 40 50 60 0 5 10 15 20 Days of ICU Delirium Cognitive Function at 12 months (predicted mean T-score) Girard TD, ...
Delirium risk factors
Risk Factors, Prevention,  and Treatment <ul><li>Aging </li></ul><ul><li>Baseline dementia </li></ul><ul><li>Psychiatric d...
Probability of transitioning from normal   to delirium after lorazepam Lorazepam Dose (mg) Delirium Risk Pandharipande et ...
Midazolam and fentanyl as risk factors for delirium Pandharipande et al., J Trauma.2008:65;34-41 Surgical Trauma Users Non...
Sedatives/analgesics in delirium Pandharipande et al. unpublished data
Delirium in surgical ICU patients <ul><li>134 surgical and trauma adult patients requiring mechanical ventilation  </li></...
ARDS Patients Larson MJ. JINS 2007;13:595-605
Psychological outcomes <ul><li>Pts with delusional but not factual recall of ICU experience at 2 weeks scored highly for P...
 
How do we prevent/ treat delirium ?  1. Prevention protocols 2. Changing sedation paradigms - Reducing exposure -Changing ...
Prevention protocols <ul><li>Reorientation, continuity of care givers </li></ul><ul><li>Improving sleep architecture </li>...
Reduce exposure to sedatives and analgesics <ul><ul><li>Protocol  and target based sedation and analgesia  </li></ul></ul>...
The ABC Trial (both groups get patient targeted sedation) Control Intervention
Benzodiazepines Study Day Daily Dose of Benzodiazepines 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 0 10 20 30 4...
Opiates Study Day Daily Dose of Opiates 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 0 2000 4000 6000 Usual Care+...
SBT- CONTROL SAT+SBT- INTERVENTION Treatment group No Yes Sepsis 0 10 20 Days of Delirium p =.74 Delirium duration in sept...
One-Year Survival Patients Alive (%) 0 0 20 40 60 80 100 60 120 180 240 300 360 Days Usual Care+SBT (n=168) SAT+SBT (n=167...
Long-Term Cognitive Outcomes Hospital Discharge 3-Month Follow-Up 12-Month Follow-Up 1.86 (1.04, 3.34) 2.01 (1.09, 3.71) 2...
Changing sedation paradigms MENDS SEDCOM
MENDS Study Double blind randomized controlled trial Vanderbilt University Medical Center and Washington Hospital Center P...
Brain Dysfunction Delirium/Coma-Free Days 0 2 4 6 8 10 12 p =.01 Delirium-Free Days p =.09 p =.001 Coma-Free Days Dexmedet...
Risk of developing delirium
Septic subgroup analysis
Pandharipande et al. Critical Care 2008, 12(Suppl 2):P275   0.016 67% (35,85) 35% (0,60) Days at Physician RASS goal Effic...
28-Day Survival, Sepsis Patients 0 7 14 21 28 0 20 40 60 80 100 Days Patients Alive (%) Dexmedetomidine Lorazepam Pandhari...
Data on antipsychotics and delirium in the ICU
Olanzapine vs. haloperidol: treating delirium in a critical care setting  Skrobik et al, ICM 2004;30:444-49
Risperidone and delirium <ul><li>Double blind randomized trial (DBRT)  </li></ul><ul><li>Single dose (1 mg) of risperidone...
MIND Multicenter Double Blind RCT Girard T, Pandharipande P et al. in review MV Surgical, Medical and Trauma ICU patients ...
Delirium rates in MIND Girard T, Pandharipande P et al. in review
Conclusion <ul><ul><li>Delirium occurs in majority of mechanically ventilated patients and is associated with worse outcom...
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Delirium in critically ill patients bogota043009

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  • Today, I am going to talk about a new frontier in critical care, brain injury, its prevalence, importance, methods of diagnosis, prognosis and opportunities for treatment.
  • Why should we be concerned? Delirium : disturbance of consciousness, rapid onset, fluctuating course, ability to receive, process, store and recall information is strikingly impaired Dementia : gradual onset, intellectual impairment, memory disturbance, no clouding of consciousness Psychosis : hallucinations/delusions, impaired reality testing, no clouding of consciousness
  • Predictors certainly include age and pre-existing impairment, but what else?
  • Studies such as these have generated interest in whether delirium caused patients to get increased sedation or vice versa
  • Note that the risk of delirium with no lorazepam was 60%, due to the other risk factors or other drugs. X axis is Lorazepam dose in mg. This is a univariate plot of delirium risk using LOWESS (locally weighted scatter plot smooth, which is derived using locally weighted linear regression to smooth data) versus lorazepam dose, though the odds ratios shown earlier are multivariate analysis
  • Histogram illustrating the proportion of time that patients were delirious in the surgical and trauma ICU while receiving midazolam, fentanyl or morphine (users) in comparison to those that were not exposed to the medications (non- users). Patients receiving midazolam spent a greater proportion of time with delirium than the non users in the surgical and trauma ICU.
  • Investigator initiated- D-RCT, with the investigators holding the FDA IND
  • Shifting gears slightly to the options available for treatment of delirium
  • Delirium in critically ill patients bogota043009

    1. 1. Acute Brain Dysfunction in the Critically Ill Patient : Data from recent delirium studies Pratik Pandharipande, MD, MSCI Anesthesiology/ Critical Care Vanderbilt University, Nashville, TN
    2. 2. … The biggest problem is that “doctors are focused only on the organs that got patients into the hospital, ignoring newly acquired brain problems…”
    3. 3. Delirium <ul><li>Disturbance of consciousness </li></ul><ul><li>Rapid onset </li></ul><ul><li>Fluctuating course </li></ul><ul><li>Inattention </li></ul><ul><li>Impaired ability to receive, process, store and recall information </li></ul><ul><li>Perceptual disturbances- illusions, hallucinations </li></ul>
    4. 4. Prevalence of ICU Delirium <ul><li>60-80% MICU/SICU/TICU ventilated patients develop delirium </li></ul><ul><li>20-50% of lower severity ICU patients develop delirium </li></ul><ul><li>Hypoactive or mixed forms most common </li></ul><ul><li>Majority goes undiagnosed if routine monitoring is not implemented </li></ul>Ely EW, ICM 2001;27:1892-900 Ely EW, JAMA 2001;286,2703-2710 Pandharipande J Trauma 2008;65(1):34-41 Ely EW, CCM 2001;29,1370-79 Pandharipande, ICM 2007;33(10):1726-31 Roberts B, Aust Crit Care. 2005;18(1):6, 8-9 Thomason J, Crit Care. 2005;9(4):375-81 Ely EW CCM 2004;32:106-112 Peterson JAGS 2006;54(3):479-84 Ouimet S, ICM 2007;33(1):66-73
    5. 5. Key Points: ICU Delirium <ul><li>$15k to $25k higher hospital costs </li></ul><ul><li>Longer hospital stays </li></ul><ul><li>3 times higher risk of death by 6 months </li></ul><ul><li>Prolonged neuropsychological dysfunction </li></ul>Milbrandt E et al, Crit Care Med 2004;32:955-962 Ely EW et al, JAMA 2004;291-1753-1762 Ouimet S, ICM 2007;33(1):66-73 Lin et al, Crit Care Med 2004;32:2254-59
    6. 6. Long-term cognitive impairment (LTCI) after ICU survival <ul><li>10 cohorts (~500 pts) and the largest with neuropsychological testing was 74 patients </li></ul><ul><li>Summary: ~2 out of 3 ICU survivors leave the ICU with long-term cognitive impairment that equates to mild/moderate dementia (sometimes severe) </li></ul><ul><li>Deficits tend to be diffuse and occur in domains including memory, attention/concentration, language, executive functioning </li></ul>Rothenhausler, Gen Hosp Psych 2001;23:90-96 Hopkins, AJRCCM 1999;160:50-56 Jackson, Crit Care Med 2003;31;1226-34 Hopkins, JINS 2004; 10:1005-1017 Hopkins, AJRCCM 2005; 171:340-347 Marquis, AJRCCM 2000;161:A383 (Curtis) Al Saidi, AJRCCM 2003:167:A737 (Herridge) Sukantarat, Anaesthesia 2005;60:847-853 Suchyta, AJRCCM 2004; 169:A18 Christie, AJRCCM 2004; 169:A781
    7. 7. 0 10 20 30 40 50 60 0 5 10 15 20 Days of ICU Delirium Cognitive Function at 12 months (predicted mean T-score) Girard TD, et al. 2008, unpublished data p =.005 Delirium and Long-Term Cognitive Outcomes
    8. 8. Delirium risk factors
    9. 9. Risk Factors, Prevention, and Treatment <ul><li>Aging </li></ul><ul><li>Baseline dementia </li></ul><ul><li>Psychiatric disorders </li></ul><ul><li>Underlying illness </li></ul><ul><ul><li>Inflammation </li></ul></ul><ul><ul><li>Coagulation </li></ul></ul><ul><li>Metabolic Disturbances </li></ul><ul><li>Hypoxemia </li></ul><ul><li>Genetic Predisposition (?) </li></ul><ul><li>Psychoactive Medications </li></ul><ul><li>Sleep Deprivation </li></ul>Inouye, JAMA 1996;275:852-57 Dubois, Intens Care Med 2001;27:1297-1304 Inouye, NEJM 1999;340:669-676 Jacobi, Crit Care Med 2002;30:119-141 Milbrandt, Crit Care Med. 2005;33:226-9 Ouimet S. Int Care Med 2007;33:66-73
    10. 10. Probability of transitioning from normal to delirium after lorazepam Lorazepam Dose (mg) Delirium Risk Pandharipande et al. Anesthesiology 2006: 124:21-6 OR 1.2 (1.1-1.4), P=0.003
    11. 11. Midazolam and fentanyl as risk factors for delirium Pandharipande et al., J Trauma.2008:65;34-41 Surgical Trauma Users Non-Users Midazolam Daily Midazolam Use (Exc. Coma Days) % Days Delirious 0 20 40 60 80 100 p=0.014 p=0.031 Surgical Trauma Users Non-Users Fentanyl Daily Fentanyl Use (Exc. Coma Days) % Days Delirious 0 20 40 60 80 100 p=0.007 p=0.936
    12. 12. Sedatives/analgesics in delirium Pandharipande et al. unpublished data
    13. 13. Delirium in surgical ICU patients <ul><li>134 surgical and trauma adult patients requiring mechanical ventilation </li></ul><ul><li>63% developed delirium </li></ul><ul><li>Delirium was associated with more MV days (9.1 vs. 4.9 days, p < 0.01), longer ICU stay (12.2 vs. 7.4 days, p < 0.01), longer hospital stay (20.6 vs. 14.7 days, p < 0.01). </li></ul><ul><li>Greater cumulative lorazepam dose (p = 0.012), and higher cumulative fentanyl dose (p = 0.035) were administered in the delirium group. </li></ul>Lat I. Crit Care Med. April 2009 (epub)
    14. 14. ARDS Patients Larson MJ. JINS 2007;13:595-605
    15. 15. Psychological outcomes <ul><li>Pts with delusional but not factual recall of ICU experience at 2 weeks scored highly for PTSD related symptoms and panic attacks at 8 weeks (p = 0.023 and 0.014 respectively). </li></ul>Jones C et al. Crit Care Med 2001; 29: 573
    16. 17. How do we prevent/ treat delirium ? 1. Prevention protocols 2. Changing sedation paradigms - Reducing exposure -Changing medications 3. Antipsychotics
    17. 18. Prevention protocols <ul><li>Reorientation, continuity of care givers </li></ul><ul><li>Improving sleep architecture </li></ul><ul><li>Reducing exposure to deliriogenic medications </li></ul><ul><li>Cognitive stimulation </li></ul><ul><li>Role of geriatrician visits or trained personnel in neuropsychological disorders </li></ul>Inouye et al. NEJM 1999; 9(340):669-676
    18. 19. Reduce exposure to sedatives and analgesics <ul><ul><li>Protocol and target based sedation and analgesia </li></ul></ul><ul><ul><li>Daily awakening trials </li></ul></ul>Mascia et al. CCM 2000; 28: 2300-2306 Brook et al. CCM 1999; 27: 2609-2615 Kress et al. NEJM 2000; 342: 1471-1477 Brattebo et al. BMJ 2002; 324: 1386-1389
    19. 20. The ABC Trial (both groups get patient targeted sedation) Control Intervention
    20. 21. Benzodiazepines Study Day Daily Dose of Benzodiazepines 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 0 10 20 30 40 50 60 70 Usual Care+SBT SBT+SAT
    21. 22. Opiates Study Day Daily Dose of Opiates 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 0 2000 4000 6000 Usual Care+SBT SBT+SAT
    22. 23. SBT- CONTROL SAT+SBT- INTERVENTION Treatment group No Yes Sepsis 0 10 20 Days of Delirium p =.74 Delirium duration in septic patients in ABC study Girard et al. Personal communication p =.02
    23. 24. One-Year Survival Patients Alive (%) 0 0 20 40 60 80 100 60 120 180 240 300 360 Days Usual Care+SBT (n=168) SAT+SBT (n=167) p =.01 NNT=7 Girard TD, et al. Lancet 2008;371:126-34
    24. 25. Long-Term Cognitive Outcomes Hospital Discharge 3-Month Follow-Up 12-Month Follow-Up 1.86 (1.04, 3.34) 2.01 (1.09, 3.71) 2.23 (1.13, 4.41) 0.04 0.02 0.02 Time of Cognitive Assessment Odds Ratio (95% CI) P-value 0 1 2 3 4 Favors Control Favors Intervention Jackson JC, et al. 2008, in submission
    25. 26. Changing sedation paradigms MENDS SEDCOM
    26. 27. MENDS Study Double blind randomized controlled trial Vanderbilt University Medical Center and Washington Hospital Center Pandharipande P et al. JAMA Dec 2007
    27. 28. Brain Dysfunction Delirium/Coma-Free Days 0 2 4 6 8 10 12 p =.01 Delirium-Free Days p =.09 p =.001 Coma-Free Days Dexmedetomidine Lorazepam Pandharipande PP, et al. JAMA 2007;298:2644-53
    28. 29. Risk of developing delirium
    29. 30. Septic subgroup analysis
    30. 31. Pandharipande et al. Critical Care 2008, 12(Suppl 2):P275 0.016 67% (35,85) 35% (0,60) Days at Physician RASS goal Efficacy of sedation <0.03 68% 95% Prevalence of coma 0.52 79% 70% Prevalence of delirium <0.003 10 (9, 12) 7 (1,9) Coma free days 0.007 10 (8, 11) 7.5 (4, 8) Delirium free days 0.002 8 (4,10) 1.5 (1,4) Delirium and coma free days Brain Dysfunction (N=19) (N=20) P value Dexmedetomidine Lorazepam Outcome variable MENDS: Patients Outcomes in Septic subgroup
    31. 32. 28-Day Survival, Sepsis Patients 0 7 14 21 28 0 20 40 60 80 100 Days Patients Alive (%) Dexmedetomidine Lorazepam Pandharipande et al. Critical Care 2008, 12(Suppl 2):P275 HR 0.3 (0.1- 0.9). P=0.04
    32. 33. Data on antipsychotics and delirium in the ICU
    33. 34. Olanzapine vs. haloperidol: treating delirium in a critical care setting Skrobik et al, ICM 2004;30:444-49
    34. 35. Risperidone and delirium <ul><li>Double blind randomized trial (DBRT) </li></ul><ul><li>Single dose (1 mg) of risperidone administered after cardiac surgery </li></ul><ul><li>Reduced the incidence of postoperative delirium </li></ul><ul><ul><li>11.1% vs.31.7%, P=0.009 </li></ul></ul><ul><ul><li>RR=0.35, 95% CI=0.16-0.77) </li></ul></ul>Prakanrattana et al. Anaesth Intensive Care 2007 Oct;35(5):714-9 .
    35. 36. MIND Multicenter Double Blind RCT Girard T, Pandharipande P et al. in review MV Surgical, Medical and Trauma ICU patients PO haloperidol PO ziprasidone Placebo
    36. 37. Delirium rates in MIND Girard T, Pandharipande P et al. in review
    37. 38. Conclusion <ul><ul><li>Delirium occurs in majority of mechanically ventilated patients and is associated with worse outcomes </li></ul></ul><ul><ul><li>Easy to diagnose in ICU with new validated instruments </li></ul></ul><ul><ul><li>Sedatives and analgesics may be modifiable risks factors </li></ul></ul><ul><ul><li>Avoiding benzodiazepines/ using alpha 2 agonists may reduce delirium </li></ul></ul><ul><ul><li>No difference between typical and atypical antipsychotics in delirium management in ICU patients (risperidone in 1 study) </li></ul></ul><ul><ul><li>Prevention protocols with emphasis on restoring sleep may help </li></ul></ul>

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