Sedation & Analgesia Dr Samir Sahu, Dr Niraj Mishra, Dr Samir Mishra, Dr D. Bindhani, Dr Sanghamitra Mishra, Dr Rakesh Roy

Pharmacological Principles Volume of Distribution Hydrophilic – low – morphine Lipophilic – high – midazolam Hepatic dysfunction – flow dependant – morphine P-450 – midazolam. Fentanyl Genetic variability – midazolam, Fentanyl

Analgesics Drug Onset Half-life Lipophylity Metabolism Active Metabolit Genetic Variation Fentanyl <1 min 2-4 hr +++ CYP3A4/5 Yes Morphine 5-10 min 3-4 hr ++ Glucoronidation

Opoids - Complications Hypotension Respiratory depression Gastric retention & ileus Constipation

Sedatives Drugs Onset Half-life Lipophil Metabolism Active Metabolites Genetic Midazolam 2-5 min 3-12 hrs +++ Hydroxyl Yes Lorazepam 5-20 min 10-20 hrs ++ Glucuroni No Diazepam 20-50 hrs Hydroxy Propofol 1-2 min 1.5-12.4 hrs

Benzodiazepines - complications Delirium Post traumatic stress disorder

Propofol Decreases ICP Not affected by renal & hepatic failure Hypotension Immunosuppressant effects Change Infusion sets every 12 hours Propofol related infusion syndrome (PRIS) (>83 mcg/kg/min>48 hrs)

Unwanted side-effects of sedative agents General Over sedation Delayed awakening/extubation Benzodiazepines Hypotension Respiratory depression Agitation/Confusion Clonidine Hypotension Rebound HTN Bradycardia Propofol Hypertriglyceridemia CVS depression Hypotension Opioids Abuse potential Respiratory depression Lack of orientation Constipation

Dexmedetomidine Highly selective alpha-2 agonist Anxiolysis, cooperative sedation without respiratory depression Onset – 15 min Peak concentration within 1 hr of infusion Hepatic metabolism Not significantly affected by renal failure

Overview of Current Sedative and Analgesic Agents Current choices for sustained sedation in the critically ill include the benzodiazepines (amnesia) the opiates (analgesia) Propofol (easily titratable and less likely to accumulate) (Semin Respir Crit Care Med. 2001;22(2):165-74)

Dexdine vs. Other Sedative/Analgesics Comparison of Clinical Effects   BDZ Propofol Opiods Haloperidol Dexdine Sedation  Anxiolytic Analgesic Maintain arousability during sedation & Facilitate weaning No respiratory depression Control Delirium

Dexdine vs. Other Sedative/Analgesics Comparison of Adverse Effects   BDZ Propofol Opiods Haloperidol Dexdine Prolonged weaning  Respiratory depression Hypotension Constipation Deliriogenic Tachycardia Morphine Bradycardia Fentanyl

What are your practices ?

Practices in different ICUs Short term sedation Long term sedation Analgesia Bolus/infusion

Current Sedation Practice Used in 70% of MV patients Trend towards lighter sedation guided by sedation assessment tool Nurse driven sedation protocol Daily sedation interruption

How often the target is achieved? Target of interventions (sedation) 2,3 Optimum sedation, (neither under- nor over-sedation) Free from anxiety & pain Calm & cooperative patient How often the target is achieved? Continuous sedation carries the risks associated with oversedation and may increase the duration of mechanical ventilation (MV)1,2 MV patients accrue significantly more cost during their ICU stay than non-MV patients 3 Sedation should be titrated to achieve a cooperative patient and daily wake-up2,3 1. Crit Care. 2000;4(suppl 1):S110, 2. NEJM 2000;342:1471-1477, 3. Crit Care Med.2005;33:1266-1271. 1. Crit Care. 2000;4(suppl 1):S110, 2. NEJM 2000;342:1471-1477, 3. Crit Care Med.2005;33:1266-1271.

SCCM guidelines 2002 Short term < 24 – propofol or midazolam Long term >24 – lorazepam Analgesia – morphine or fentanyl

Commonly used Agents Authors Sedation Analgesia Comments Burry 2009(Canada) Mida>Propofol (24%) (19%) Fentanyl>morphine (22%) (16%) 40% antipsychotics O’Connor 2009 (Aus & NZ) Mida = Propofol Morphine>fentanyl Reschreiter 2008 (UK) <24 hr Propofol >24 hr Prop = mida Alfentanil> fentanyl or morphine Clonidine used for weaning Payen 2007 (France) (70%) (20%) Sufentanil=fentanyl (40%) (35%) 35% non opoids Ahmad 2007 (Malaysia) Midazolam Morphine Martin 2007 (Germany) <24hr propofol(83) >72 hr mida <24 hr Sufentanil >24 hr Remifentanil Ketamine Egerod 2006 (Danish) Propofol> Mida Fentanyl > Sufentanil Phenobarb & Clonidine

Intermittent Dosing Morphine (56%) Lorazepam (61%) Midazolam (56%) Haloperidol (81%)

Continuous Infusion France >90% Sweden 99% Australia >70% Canada - 26% in few patients, 38% in 25-75% of patients, 26% in most patients 64% continuous & 10% boluses (Tanios, 2009) Propofol(87%) & Fentanyl(96%) were more likely to administered as continuous infusion.

Do you practice daily interruption of Sedation ?

Daily Interruption Daily interruption of sedative infusion …....... Kress et al, N Eng J Med 2000 Stop infusion till patient is awake or agitated Restarted at half the original dose & titrated to clinical targets Reduced duration of MV Reduced duration of ICU stay Better assessment of patients sedation needs Reduces drug bioaccumulation

Safety Screen for Daily interruption No active seizure No alcohol withdrawal No agitation No paralysis No myocardial ischaemia Normal ICP

Daily Interruption Canada 40% Denmark 31% Germany 34%

Do you have a Sedation & Analgesia Protocol in your ICU ?

Sedation Protocols Australia 54% Germany 52% US 64% UK 80% Canada 43% Reduces duration of MV, ICU stay, reduces treatment delays, Improves communication, Standardizes therapy, increased dedicated education

Do you use any Sedation assessment scale in your ICU ?

Assessment Tools Ramsay(1974) – most commonly used RASS SAS

Protocols, Assessment Tools & Daily Interruptions Sedation Scale Patel, 2009 22% 71% 88% Ramsay 38% RASS 26% O’Connors,2009 (Aus & NZ) 20% 43% 8% Reschreiter, 2008 (UK) 62% 54% 75% (GCS 56%) SAS 25% RASS 8% Payen, 2007 (France) 78% 80% Ramsay 66% Martin, 2007 (Germany) 14% 38% 35%(Ramsay)

Pain Assessment Tools CPOT – Critical Care Pain Observation Tool

Delirium Assessment Tool CAM-ICU – confusion assessment method for the ICU

Local Survey Apollo Kalinga Cardiac Analgesia Fen/tra/p Tra/mor Fen Sedatives Mida Mida/Lora Mid MV 20-100% 0-20% 90-100 Short term Mida/pro Admn infusion bolus Bolus Daily int yes Yes Safety scree No Scale Ramsay RASS Delirium common uncommon Rare Protocol NMB intubation rarely post

Patient Assessment Is the patient comfortable ? Is the patient in pain ? Is the patient agitated ?

‘Wake up & Breath’ Girard et al, (Awakening & Breathing Controlled trial) :Lancet, 2008. 3.1 more ventilator free days ICU stay & Hospital stay reduced by 4 days

Safety screen for SBT No agitation SpO2 >88% with FiO2 50% PEEP < 8 No myocardial ischaemia No vasopressors Inspiratory effort

Determinants of Practice Cost Duration of action Familiarity Level of Experience Level of Education

Strøm et al,Lancet 2010;375:475-480. In the general intensive care unit of Odense University Hospital, Denmark, standard practice is a protocol of no sedation No sedation or intermittent sedation. The control group was sedated with 20 mg/mL of propofol for 48 hours and 1 mg/mL of midazolam thereafter, with daily interruption until awake. Both groups received bolus doses of 2.5 or 5 mg of morphine.

Strøm et al,Lancet 2010;375:475-480. Compared with the 58 remaining patients receiving interrupted sedation, the 55 patients receiving no sedation had significantly more days without ventilation (mean, 13.8 ± 11.0 days vs mean, 9.6 ± 10.0 days; mean difference, 4.2 days; 95% confidence interval [CI], 0.3 - 8.1; P = .0191).

Strøm et al,Lancet 2010;375:475-480. Patients in the no-sedation group also had a shorter stay in the intensive care unit (hazard ratio [HR], 1.86; 95% CI, 1.05 - 3.23; P = .0316) and a shorter stay in the hospital for the first 30 days studied (HR, 3.57; 95% CI, 1.52 - 9.09; P = .0039). Accidental extubations, the need for computed tomography or magnetic resonance imaging brain scans, and ventilator-associated pneumonia were similar in both groups. However, the no-sedation group had more frequent agitated delirium than the intermittent sedation group (n = 11 [20%] vs n = 4 [7%]; P = .0400).

Strøm et al,Lancet 2010;375:475-480. In an accompanying editorial, Dr. Laurent Brochard, from Centre Hospitalier Albert Chenevier–Henri Mondor, and Université Paris-Est, Créteil, France, notes the study limitations but calls the overall results "impressive and promising." "Use of this strategy will mean that more attention needs to be paid in the daily care of patients, and caregivers will need increased empathy towards patients," Dr. Brochard writes. "Hopefully, these findings will prove beneficial to patients."

Sangeeta Mehta, SLEAP Investigators and the Canadian Critical Care Trials Group. JAMA. Published online October 17, 2012. for critically ill patients receiving mechanical ventilation....a sedation protocol that targeted light sedation, daily sedation interruption did not reduce the duration of mechanical ventilation, offered no additional benefits for patients, and may have increased both sedation and analgesic use and nurse workload.

Included surgical and medical patients. Sangeeta Mehta, SLEAP Investigators and the Canadian Critical Care Trials Group. JAMA. Published online October 17, 2012. A sedation strategy adding daily interruption to a control group strategy of protocolized sedation that targeted light sedation, which is likely superior to "usual care" of an earlier era. Reflecting "actual practice in ICUs with variable workloads and ICU staffing models. Included surgical and medical patients. The most commonly administered medications to facilitate sedation were midazolam and fentanyl

Sangeeta Mehta, SLEAP Investigators and the Canadian Critical Care Trials Group. JAMA. Published online October 17, 2012. The 2 groups also had similar outcomes for durations of stay in the ICU or hospital, hospital mortality, rates of unintentional extubation, delirium, or tracheostomy. The interruption group had higher mean daily doses of benzodiazepines and opioids. Nurse workload was estimated to be higher in the interruption group vs the control group. Evidence existed that interruption of sedation was more effective for surgical or trauma patients vs medical patients.

Pharmaco-economics Cost of drugs Reduced ventilator days Reduced ICU days

CT in ICU sedation- 1 Dexdine vs Midazolam DXMD(0.2-1.4 µg/kg/hour) or Midazolam (0.02-0.1mg/kg/hour) N: 375, adult mechanically ventilated patients; Duration: > 24 hr 10 20 30 40 50 60 70 80 % of patient suffering from Delirium Enrollment 1 2 3 4 5 6 Treatment Day Dexmedetomidine reduces the prevalence of Delirium Dexmedetomidine Midazolam 3.7 days 5.6 days 2 4 6 Time to extubation in days Dexmedetomidine-treated patients spend less time on ventilator Dexmedetomidine Midazolam P= .01 P= .01 DXMD therapy significantly reduced (vs Midazolam) Median time to extubation by 1.9 days (3.7 vs 5.6 days, P= .01) Incidence of delirium by 22.6% (P < .001) Significantly less tachycardia & HTN requiring treatment JAMA 2009;301(5):489-499

A Cost-Minimization Analysis of Dexmedetomidine Compared With Midazolam for Long-term Sedation in the Intensive Care Unit Dasta JF, Kane-Gill SL, Pencina M, et al Crit Care Med.2010; Patients who received dexmedetomidine experienced less delirium, fewer nosocomial infections, less tachycardia and hypertension (but more bradycardia), and a shorter time to extubation than patients treated with midazolam. From these data, it appears that the use of dexmedetomidine may be more cost effective, despite higher drug acquisition costs, than the commonly used benzodiazepine anxiolytic medications.

Summary Chose your drugs according to availability, costs & overall benefits Develop a protocol (Protocolized target-based sedation & analgesia) Practice daily interruption of continuous sedation Use an assessment tool to stay at your goal (Indentify goals using validated tools for pain, agitation & sedation Nurse driven protocol

THANK YOU Dexdine Dexmedetomidine Hydrochloride Good evening everybody. At the outset, I would like to thank you all for sparing your valuable time for this CME on Dexdine. Dexdine, Dexmedetomidine Hydrochloride, the sedative that ensures patient comfort and safety Macleods Pharmaceuticals Ltd 21st May 2010; Bhubaneshwar