Sedation, Analgesia and Paralysis in ICU Mazen Kherallah, MD, FCCP

ICU Sedation ICU sedation is a complex clinical problem Current therapeutic approaches all have potential adverse side effects Agitated patients are often hypertensive, increase stress hormones, and require more intensive nursing care

The Need for Sedation Anxiety Pain Acute confusional status Mechanical ventilation Treatment or diagnostic procedures Psychological response to stress

Patient comfort and Control of pain Anxiolysis and amnesia Blunting adverse autonomic and hemodynamic responses Facilitate nursing management Facilitate mechanical ventilation Avoid self-extubation Reduce oxygen consumption Goals of sedation in the ICU

Characteristics of an ideal sedation agents for the ICU Lack of respiratory depression Analgesia, especially for surgical patients Rapid onset, titratable, with a short elimination half-time Sedation with ease of orientation and arousability Anxiolytic Hemodynamic stability

The Challenges of ICU Sedation Assessment of sedation Altered pharmacology Tolerance Delayed emergence Withdrawal Drug interaction

Sedation Sedatives Causes for Agitation

Undersedation Sedatives Causes for Agitation Agitation & anxiety Pain and discomfort Catheter displacement Inadequate ventilation Hypertension Tachycardia Arrhythmias Myocardial ischemia Wound disruption Patient injury

Oversedation Sedatives Causes for Agitation Prolonged sedation Delayed emergence Respiratory depression Hypotension Bradycardia Increased protein breakdown Muscle atrophy Venous stasis Pressure injury Loss of patient-staff interaction Increased cost

Correctable Causes of Agitation Full bladder Uncomfortable bed position Inadequate ventilator flow rates Mental illness Uremia Drug side effects Disorientation Sleep deprivation Noise Inability to communicate

Causes of Agitation Not to be Overlooked Hypoxia Hypercarbia Hypoglycemia Endotracheal tube malposition Pneumothorax Myocardial ischemia Abdominal pain Drug and alcohol withdrawal

Altered Pharmacology Midazolam and Age Harper et al. Br J Anesth, 1985;57:

Delayed Emergence Overdose (prolonged infusion) –pK derived from healthy patients –Drug interaction –Individual variation Delayed elimination –Liver (C p450 ) –Kidney dysfunction –Active metabolites

Morphine Metobolism 80%10%

Withdrawal Withdrawal from preoperative drugs Sudden cessation of sedation –Return of underlying agitation Hyperadrenergic syndrome –Hypertension, tachycardia,sweating Opioid withdrawal –Salivation, yawning, diarrhea

Drug Interactions Diazepam-Morphine Interaction Synergism Antagonism Morphine Diazepam ED 50 isobologram Righting reflex In rats Kissin et al. Anesthesiology. 1989, 70:

Strategies for Patient Comfort Set treatment goal Quantitate sedation and pain Choose the right medication Use combined infusion Reevaluate need Treat withdrawal

Set Treatment Goal SedationAnalgesia AmnesiaAnxiolysisHypnosis Patient Comfort

Quantitate Sedation & Analgesia Subjective measure Objective measures

Sedation Scoring Scales Ramsay Sedation Scale (RSS) Sedation-agitation Scale (SAS) Observers Assessment of Alertness/Sedation Scale (OAASS) Motor Activity Assessment Scale (MAAS) BMJ 1974;2: Crit Care Med 1999;27: J Clin Psychopharmacol 1990;10: Crit Care Med 1999;27:

The Ramsay Scale ScaleDescription 1Anxious and agitated or restless, or both 2Cooperative, oriented, and tranquil 3Response to commands only 4Brisk response to light glabellar tap or loud auditory stimulus 5Sluggish response to light glabellar tap or loud auditory stimulus 6No response to light glabellar tap or loud auditory stimulus

The Riker Sedation-Agitation Scale ScoreDescriptionDefinition 7 Dangerous agitationPulling at endotracheal tube, trying to strike at staff, thrashing side to side 6 Very agitatedDoes not calm despite frequent verbal commands, biting ETT 5 AgitatedAnxious or mildly agitated, attempting to sit 4 Calm and cooperative Calm, awakens easily, follows commands 3 SedatedDifficult to arouse, awakens to verbal stimuli, follows simple commands 2 Very sedatedArouse to physical stimuli, but does not communicate spontaneously 1 UnarousableMinimal or no response to noxious stimuli

The Motor Activity Assessment Scale ScoreDescriptionDefinition 6 Dangerous agitationPulling at endotracheal tube, trying to strike at staff, thrashing side to side 5 AgitatedDoes not calm despite frequent verbal commands, biting ETT 4 Restless and cooperative Anxious or mildly agitated, attempting to sit 3 Calm and cooperative Calm, awakens easily, follows commands 2 Responsive to touch or name Opens eyes or raises eyebrows or turns head when touched or name is loudly spoken 1 Responsive only to noxious stimuli Opens eyes or raises eyebrows or turns head with noxious stimuli 0 UnresponsiveDoes not move with noxious stimuli

What Sedation Scales Do Provide a semiquantitative “score” Standardize treatment endpoints Allow review of efficacy of sedation Facilitate sedation studies Help to avoid oversedation

What Sedation Scales Don’t Do Assess anxiety Assess pain Assess sedation in paralyzed patients Predict outcome Agree with each other

BIS Monitoring

BIS Range Guidelines Awake Responds to loud commands or mild prodding/shaking Low probability to explicit recalls Unresponsive to verbal stimuli Burst suppression Flat line EEG Responds to normal voice Axiolysis Moderate sedation Deep Sedation BIS

Pain Assess Pain Separately

Visual Pain Scales No pain Worst possible pain

Signs of Pain Hypertension Tachycardia Lacrimation Sweating Pupillary dilation

Principles of Pain Management Anticipate pain Recognize pain –Ask the patient –Look for signs –Find the source Quantify pain Treat: –Quantify the patient’s perception of pain –Correct the cause where possible –Give appropriate analgesics regularly as required Remember, most sedative agents do not provide analgesia Reassess

Nonpharmacologic Interventions Proper position of the patient Stabilization of fractures Elimination of irritating stimulation Proper positioning of the ventilator tubing to avoid traction on endotracheal tube

Choose the Right Drug Benzodiazepines Propofol Opioids  -2 agonists

Choose the Right Drug SedationAnalgesia AmnesiaAnxiolysisHypnosis Benzodiazepines

OnsetPeaksDuration Diazepam2-5 min5-30 min>20 hr Midazolam2-3 min5-10 min min Lorazepam5-20 min30 min10-20 hr

Choose the Right Drug SedationAnalgesia AmnesiaAnxiolysisHypnosis Propofol

OnsetPeaksDuration Propofol30-60 sec2-5 minshort

Propofol Dosing 3-5  g/kg/min antiemetic 5-20  g/kg/min anxiolytic  g/kg/min sedative hypnotic >100  g/kg/min anesthetic

Choose the Right Drug SedationAnalgesia AmnesiaAnxiolysisHypnosis Opioids

Pharmacology of Selected Analgesics AgentDose (iv)Half-lifeMetabolic pathwayActive metabolites Fentanyl 200  g hrOxidationNone Hydromorphone1.5 mg2-3 hrGlucuronidationNone Morphine10 mg3-7 hrGlucuronidationYes (Sedation in RF) Meperidine mg 3-4 hrDemethylation & hydroxylation Yes ( neuroexcitation in RF) Codeine120 mg3 hrDemethylation & Glucuronidation Yes ( analgesia, sedation) Remifentanil3-10 minPlasma esteraseNone Keterolac hrRenalNone

Opioids Lipid Solubility Histamine Release Potency Morphine+/-+++1 Hydromorphone++5 Fentanyl+++-50

Opioids OnsetPeaksDuration Morphine2 min20 min2-7 hr Fentanyl30 sec5-15 min30-60 min

Problems with Current Sedative Agents MidazolamPropofolOpioids Prolonged weaningX-X Respiratory depressionX-X Severe hypotensionXX- ToleranceX-X Hyperlipidemia-X- Increased infection-X- Constipation--X Lack of orientation and cooperation XXX

Choose the Right Drug SedationAnalgesia AmnesiaAnxiolysisHypnosis  -2 agonists

Alpha-2 Receptors Brain (locus ceruleus) Spinal Cord Peripheral vasculature Sedation Anxiolysis Sympatholysis Analgesia Vasoconstriction

DEX: Dosing Loading infusion  g/kg (10-20 min) Maintenance infusion  g/kg/hr

Use Continuous and Combined Infusion Plasma Level Load Maintenance

Repeated Bolus Plasma levels

Opioid + Hypnotic Infusion Fentanyl + Midazolam or Propofol Analgesia Amnesia Anxiolysis Hypnosis

Continuous Infusion Regimens Fentanyl  g/h Midazolam mg/hr Propofol  g/kg/min

Choose the Right Drug SedationAnalgesia AmnesiaAnxiolysisHypnosis  -2 agonists Primary Adjunct sedation Propofol

Choose the Right Drug SedationAnalgesia AmnesiaAnxiolysisHypnosis  -2 agonists Primary Adjunct sedation Midazolam

Choose the Right Drug SedationAnalgesia AmnesiaAnxiolysisHypnosis  -2 agonists Primary Adjunct analgesia Morphine

Choose the Right Drug SedationAnalgesia AmnesiaAnxiolysisHypnosis  -2 agonists Primary Adjunct analgesia Fentanyl

Reassess Need Use sedation score as endpoint Initiate sedation incrementally to desired level Periodically (q day) titrate infusion rate down until the patient begins to emerge Gradually increase infusion rate again to desired level of sedation Barr, Donner. Crit Care Clin. 1995;11827

Treat Withdrawal Acute management –Resume sedation –Beta-blockade, dexmedetomidine Prolonged management –Methadone 5-10 mg VT bid –Clonidine mg VT q8h –Lorazepam 1-2 mg IV q8h