Sedation in ICU Patients

Sedation in ICU Patients• Old agents for sedation– Benzodiazepines– Opioids– Propofol• Problems with delerium• New agents– Dexmedetomidine– Ketamine– Fospropofol

Traditional ICU Sedation• Opioids• Benzodiazepines– Midazolam– Lorazepam– Diazepam• Propofol

GABA Receptor

Lorazepam Dose and Probability ofDeliriumPandharipande. Anesthesiology 2006

Effect of Midazolam on Delirium

Avoiding GABA Agonist relatedDelirium• Don’t sedate• Target appropriate sedation levels• Daily interruption of sedation– Drug holidays

Effect of Daily Interruption ofSedationP < 0.0001Kress, NEJM, 2000

Effect of Daily Interruption ofSedationP = 0.02Kress, NEJM, 2000

Delirium: A never event?• Delirium proposed by CMS as a “Never Event”2008• “Never Events” are errors in medical care that areclearly identifiable, preventable, and serious inconsequences and indicate a problem in the safetyof a healthcare facility• Medicare List of Unreimbursed PreventableConditions

Delirium• Incidence in Surgical and Thoracic Intensive CareUnits– 11% to 80%• Each additional day of delirium– Increases the risk of prolonged hospitalization by 20%– Increases the likelihood of a poor functional status at 3and 6 months• Delirium is associated with $15k to $25k higherhospital costs• Delirious patients have a 5X increase in selfextubation

Modifiable Risk Factors• Lack of social interaction• Frequent nursing care• Medications• Pain• Sleep disturbance

Treatment StrategiesMaldonado. Crit Care Clin. 2008

Reduction in Mortality with HaloperidolMilbrandt Crit Care Med 2005

Haloperidol Side Effects• Prolongation of QT interval– Torsade de Pointes ventricular tachycardia• Extrapyramidal side effects– Very rare with IV use of haloperidol• Neurolept malignant syndrome– Again very rare with IV use

Pharmacologic Profiles ofAntipsychoticsCasey. J Clin Psych. 1997

Effect of Quetiapine on Incidence andDuration of Delirium• 36 adult intensive care unit patients withdelirium• Quetiapine 50mg BID• Increased by 50mg every 12 hrs ifhaloperidol required• Reduced incidence and duration ofdelirium.Devlin, Crit Care Med 2010

Effect of Quetiapine on Incidence andDuration of DeliriumDevlin, Crit Care Med 2010

Risperidone and Delirium• Double-blind randomized trial• Single dose (1 mg) of risperidoneadministered after cardiac surgery– sublingual• Reduced the incidence of postoperativedelirium– 11.1% vs. 31.7%, P=.009– RR=0.35, 95% CI=0.16-0.77Prakanrattana, et al. Anaesth Intensive Care. 2007

Dexmedetomidine• α2-receptor agonist• Properties similar to natural sleep– sedated but arousable• Analgesic properties• Side effects– Hypotension– Bradycardia– Sinus arrest– No respiratory depression• Short distribution half-life (t½) - 6 minutes• Terminal elimination half-life (t½) - 2 hours

MENDS• Maximizing Efficacy of Targeted Sedation andReducing Neurological Dysfunction Study• 106 adult mechanically ventilated medical andsurgical ICU patients• Titrated to RASS• Randomized to dexmedetomidine or lorazepam• t1/2 of unconjugated lorazepam is 12 hours• Major metabolite, lorazepam glucuronide, t1/2about 18 hoursPandharipande, JAMA, 2007

MENDSPandharipande, JAMA, 2007

SEDCOM• Safety and Efficacy of DexmedetomidineCompared With Midazolam Study Group• Prospective, double-blind, randomized trial• 68 centers in 5 countries• 375 medical/surgical ICU patients• Expected mechanical ventilation for morethan 24 hoursRiker, JAMA, 2009

SEDCOM: Prevalence of DeliriumRiker, JAMA, 2009

SEDCOM: Time to ExtubationRiker, JAMA, 2009

SEDCOMRiker, JAMA, 2009

Dexmedetomidine for Sedation afterCPB for Valve SurgeriesMaldonado, Psychosomatics, 2009

Fast Track Cardiac Surgery• Recovery room extubation• CABG +/- valve• Dexmedetomidine vs propofol sedation• Retrospective• Patients were matched according to surgerytype and left ventricular ejection fractionBarletta, Pharmacotherapy, 2009

Fast Track Cardiac SurgeryBarletta, Pharmacotherapy, 2009

Ketamine for Intubation on the ICU?• Etomidate is the least cardiac depressantinduction agent– Known to cause adrenal suppression oninfusion• Ketamine is sympathomimetic– Raises BP and heart rate– Can cause hallucinations

Etomidate vs Ketamine forIntubation• Emergency intubation– 12EDs and 65 ICUs in France• 469 patients• No difference in:– SOFA scores– Probability of being on ventilation– Vasopressors requirementJabre, Lancet, 2009

Etomidate vs Ketamine forIntubationKetamineEtomidateP=0.36Jabre, Lancet, 2009

Adrenal Effects of Etomidate vsKetamine16(11-15) 25(17-34)18(12-29) 33(25-41)19(14-30) 38(28-48)9 mcg/dL,10 mcg/dL,9 mcg/dLJabre, Lancet, 2009

Propofol• Risks– Not reliably amnestic, especially at low doses– No analgesia!– Hypotension– Respiratory depression– Propofol Infusion Syndrome• Cardiac failure, rhabdomyolysis, severe metabolic acidosis,and renal failure• Caution should be exercised at doses > 80 mcg/kg/min formore than 48 hours• Problematic when used simultaneously with catecholaminesand/or steroids

Propofol• Formulated in 10% Intralipid– Egg phosphatid and soy lecithin– Emulsion which is miscible with aqueoussolutions– Lipid load (1.1 kcal/ml)– Hypertriglyceridemia– Medium for bacterial overgrowth

Fospropofol

Fospropofol• Pro-drug of propofol• Aqueous solubility• No lipid emulsion• Slower onset• Less hypotension and respiratory depressionfor procedures

FospropofolAlkalinePhosphatasePropofol Formaldehyde Phosphate

Fospropofol Side Effects• Anal and genital– Itching– Burning– Paresthesia• Phosphate

Fospropofol• Formaldehyde metabolized to formate• Formate in high concentrations:– Acidosis– Ketonemia– Acetonuria– Respiratory compromise– Blindness