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

AnalgesicsDrug Onset Half-life Lipophylit

yMetabolism

Active Metabolit

Genetic Variation

Fentanyl <1 min 2-4 hr +++ CYP3A4/5 Yes Yes

Morphine 5-10 min 3-4 hr ++ Glucoronidation

Yes Yes

Opoids - Complications

• Hypotension• Respiratory depression• Gastric retention & ileus • Constipation

SedativesDrugs Onset Half-life Lipophil Metabolism Active

MetabolitesGenetic

Midazolam 2-5 min 3-12 hrs +++ Hydroxyl Yes Yes

Lorazepam 5-20 min 10-20 hrs ++ Glucuroni No Yes

Diazepam 2-5 min 20-50 hrs +++ Hydroxy Yes Yes

Propofol 1-2 min 1.5-12.4 hrs

+++ HydroxyGlucuroni

No Yes

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)

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Unwanted side-effects of sedative agents

PropofolHypertriglyceridemia

CVS depressionHypotension

ClonidineHypotension

Rebound HTN

Bradycardia

BenzodiazepinesHypotension

Respiratory depressionAgitation/Confusion

OpioidsAbuse potential

Respiratory depressionLack of orientation

Constipation

GeneralOver sedation

Delayed awakening/extubation

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

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Overview of Current Sedative and Analgesic Agents

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Dexdine vs. Other Sedative/AnalgesicsComparison of Clinical Effects

  BDZ Propofol Opiods Haloperidol Dexdine

Sedation Anxiolytic    

Analgesic    

Maintain arousability during sedation & Facilitate weaning

  

  

  

No respiratory depression

     

Control Delirium      

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Dexdine vs. Other Sedative/AnalgesicsComparison 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

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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 

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 AgentsAuthors 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)

Mida>Propofol(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

Daily interruption

Protocol 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% 88%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 SurveyApollo 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 Mida Mida

Admn infusion bolus Bolus

Daily int yes Yes

Safety scree yes No

Scale Ramsay Ramsay RASS

Delirium common uncommon Rare

Protocol yes Yes No

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.

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

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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

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

CT in ICU sedation- 1

P= .01

3.7 days

5.6 days

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Dexmedetomidine-treated patients spend less time on ventilator

Dexmedetomidine

Midazolam

P= .01

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40

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60

70

80

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Enrollment 1 2 3 4 5 6

Treatment Day

Dexmedetomidine reduces the prevalence of Delirium

Dexmedetomidine

Midazolam

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 YOUDexdine

Dexmedetomidine Hydrochloride

Macleods Pharmaceuticals Ltd

21st May 2010; Bhubaneshwar