Sedation, Analgesia, and Neuromuscular Blockade in the Adult ICU Giuditta Angelini, MD University of Wisconsin Madison, WI Gil Fraser, PharmD, FCCM Maine Medical Center Portland, ME Doug Coursin, MD, FCCM

Objectives Participants should be able to: Describe the SCCM guidelines for sedation, analgesia, and chemical paralysis Describe the benefits of daily awakening/lightening and sedation titration programs Devise a rational pharmacologic strategy based on treatment goals and comorbidities Participants should be able to: Devise a rational pharmacologic strategy based on treatment goals and comorbidities

What We Know About ICU Agitation/Discomfort Prevalence 50% incidence in those with length of stay > 24 hours Primary causes: unrelieved pain, delirium, anxiety, sleep deprivation, etc. Immediate sequelae: Patient-ventilator dyssynchrony Increased oxygen consumption Self (and health care provider) injury Family anxiety Long-term sequelae: chronic anxiety disorders and post-traumatic stress disorder (PTSD)

Recall in the ICU Some degree of recall occurs in up to 70% of ICU patients. Anxiety, fear, pain, panic, agony, or nightmares reported in 90% of those who did have recall. Potentially cruel: Up to 36% recalled some aspect of paralysis. Associated with PTSD in ARDS? 41% risk of recall of two or more traumatic experiences. Associated with PTSD in cardiac surgery

Appropriate Recall May be Important Factual memories (even unpleasant ones) help to put ICU experience into perspective Delusional memories risk panic attacks and PTSD The optimal level of sedation for most patients is that which offers comfort while allowing for interaction with the environment.

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

Goals of Sedation in ICU 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 The specific individual goals of sedation are listed in this slide, taken from Dr Ramsay’s slide presentation on dexmedetomidine.com.

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 Speaker’s Notes: The characteristics of an ideal agent to be used for ICU sedation are listed. The lack of respiratory depression is particularly important because most of the available agents produce respiratory depression.

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

Sedation Causes for Agitation Sedatives

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

Oversedation Causes for Agitation Sedatives 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

Daily Goal is Arousable, Comfortable Sedation Sedation needs to be protocolized and titrated to goal: Lighten sedation to appropriate wakefulness daily. Effect of this strategy on outcomes: One- to seven-day reduction in length of sedation and mechanical ventilation needs 50% reduction in tracheostomies Three-fold reduction in the need for diagnostic evaluation of CNS

Protocols and Assessment Tools SCCM practice guidelines can be used as a template for institution-specific protocols. Titration of sedatives and analgesics guided by assessment tools: Validated sedation assessment tools (Ramsay Sedation Scale [RSS], Sedation-Agitation Scale [SAS], Richmond Sedation-agitation Scale [RSAS], etc.) - No evidence that one is preferred over another Pain assessment tools - none validated in ICU (numeric rating scale [NRS], visual analogue scale [VAS], etc.)

Sedating/Analgesia Options Rule out reversible causes of discomfort/anxiety such as hypoxemia, hypercarbia, and toxic/drug side effect. Assess comorbidities and potential side effects of drugs chosen. Target irreversible etiologies of pain and agitation.

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

Overview of SCCM Algorithm 1 2 3 4 Jacobi J, Fraser GL, Coursin D, et al. Crit Care Med. 2002;30:119-141.

Assess Pain Separately

Visual Pain Scales 0 1 2 3 4 5 6 7 8 9 10 Worst possible pain No pain

Hypertension Tachycardia Lacrimation Sweating Pupillary dilation 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

Address Pain

Opiates Benefits Risks Relieve pain or the sensibility to noxious stimuli Sedation trending toward a change in sensorium, especially with more lipid soluble forms including morphine and hydromorphone. Risks Respiratory depression NO amnesia Pruritus Ileus Urinary retention Histamine release causing venodilation predominantly from morphine Morphine metabolites which accumulate in renal failure can be analgesic and anti-analgesic. Meperidine should be avoided due to neurotoxic metabolites which accumulate, especially in renal failure, but also produces more sensorium changes and less analgesia than other opioids.

Pharmacology of Selected Analgesics Agent Dose (iv) Half-life Metabolic pathway Active metabolites Fentanyl 200 g 1.5-6 hr Oxidation None Hydromorphone 1.5 mg 2-3 hr Glucuronidation Morphine 10 mg 3-7 hr Yes (Sedation in RF) Meperidine 75-100 mg 3-4 hr Demethylation & hydroxylation Yes (neuroexcitation in RF) Codeine 120 mg 3 hr Demethylation & Glucuronidation Yes ( analgesia, sedation) Remifentanil 3-10 min Plasma esterase Keterolac 2.4-8.6 hr Renal

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

Opioids Onset Peaks Duration Morphine 2 min 20 min 2-7 hr Fentanyl 30 sec 5-15 min 30-60 min

Opiate Analgesic Options: Fentanyl, Morphine, Hydromorphone Rapid onset X Rapid offset X* Avoid in renal disease X** Preload reduction Avoid in hemodynamic instability Equivalent doses 100 mcg 1.5 mg 10 mg * Offset prolonged after long-term use ** Active metabolite accumulation causes excessive narcosis

Morphine Metobolism Morphine 80% 10% Morphine-3-G Normorphine Antianalgesic Neurotoxicity Analgesic (40X)

Sample Analgesia Protocol Numeric Rating Scale

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;2:656-659 Crit Care Med 1999;27:1325-1329 J Clin Psychopharmacol 1990;10:244-251 Crit Care Med 1999;27:1271-1275

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

The Riker Sedation-Agitation Scale Score Description Definition 7 Dangerous agitation Pulling at endotracheal tube, trying to strike at staff, thrashing side to side 6 Very agitated Does not calm despite frequent verbal commands, biting ETT 5 Agitated Anxious or mildly agitated, attempting to sit 4 Calm and cooperative Calm, awakens easily, follows commands 3 Sedated Difficult to arouse, awakens to verbal stimuli, follows simple commands 2 Very sedated Arouse to physical stimuli, but does not communicate spontaneously 1 Unarousable Minimal or no response to noxious stimuli

The Motor Activity Assessment Scale Score Description Definition 6 Dangerous agitation Pulling at endotracheal tube, trying to strike at staff, thrashing side to side 5 Agitated Does 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 Unresponsive Does 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 Monitoring                  

BIS Range Guidelines BIS Awake 100 Responds to normal voice Axiolysis 80 Responds to loud commands or mild prodding/shaking Moderate sedation 60 Low probability to explicit recalls Unresponsive to verbal stimuli 40 Burst suppression Deep Sedation 20 Flat line EEG

Address Sedation Yes

Choose the Right Drug Benzodiazepines Propofol -2 agonists

Sedation Options: Benzodiazepines (Midazolam and Lorazepam) Pharmacokinetics/dynamics Lorazepam: onset 5 - 10 minutes, half-life 10 hours, glucuronidated Midazolam: onset 1 - 2 minutes, half-life 3 hours, metabolized by cytochrome P450, active metabolite (1-OH) accumulates in renal disease Benefits Anxiolytic Amnestic Sedating Risks Delirium NO analgesia Excessive sedation: especially after long-term sustained use Propylene glycol toxicity (parenteral lorazepam): significance uncertain - Evaluate when a patient has unexplained acidosis - Particularly problematic in alcoholics (due to doses used) and renal failure Respiratory failure (especially with concurrent opiate use) Withdrawal

Sedation Options: Propofol Pharmacology: GABA agonist Pharmacokinetics/dynamics: onset 1 - 2 minutes, terminal half-life 6 hours, duration 10 minutes, hepatic metabolism Benefits Rapid onset and offset and easily titrated Hypnotic and antiemetic Can be used for intractable seizures and elevated intracranial pressure Risks Not reliably amnestic, especially at low doses NO analgesia! Hypotension Hypertriglyceridemia; lipid source (1.1 kcal/ml) Respiratory depression Propofol Infusion Syndrome - Cardiac failure, rhabdomyolysis, severe metabolic acidosis, and renal failure - Caution should be exercised at doses > 80 mcg/kg/min for more than 48 hours - Particularly problematic when used simultaneously in patient receiving catecholamines and/or steroids

Sample Sedation Protocol Sedation-agitation Scale Riker RR et al. Crit Care Med. 1999;27:1325.

Sedation Options: Dexmedetomidine Alpha-2-adrenergic agonist like clonidine but with much less imidazole activity Has been shown to decrease the need for other sedation in postoperative ICU patients Potentially useful while decreasing other sedatives to prevent withdrawal Benefits Does not cause respiratory depression Short-acting Produces sympatholysis which may be advantageous in certain patients such as postop cardiac surgery Risks No amnesia Small number of patients reported distress upon recollection of ICU period despite good sedation scores due to excessive awareness Bradycardia and hypotension can be excessive, necessitating drug cessation and other intervention

Benzodiazepines Onset Peaks Duration Diazepam 2-5 min 5-30 min >20 hr Midazolam 2-3 min 5-10 min 30-120 min Lorazepam 5-20 min 30 min 10-20 hr

Propofol Onset Peaks Duration Propofol 30-60 sec 2-5 min short

3-5 g/kg/min antiemetic 5-20 g/kg/min anxiolytic Propofol Dosing 3-5 g/kg/min antiemetic 5-20 g/kg/min anxiolytic 20-50 g/kg/min sedative hypnotic >100 g/kg/min anesthetic

Problems with Current Sedative Agents Midazolam Propofol Opioids Prolonged weaning X - Respiratory depression Severe hypotension Tolerance Hyperlipidemia Increased infection Constipation Lack of orientation and cooperation

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

Loading infusion 0.25-1 g/kg (10-20 min) DEX: Dosing Maintenance infusion 0.2-0.7 g/kg/hr

Use Continuous and Combined Infusion Load Maintenance Plasma Level

Repeated Bolus Plasma levels

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

Continuous Infusion Regimens Fentanyl 25-250 g/h Midazolam 0.5-5 mg/hr Propofol 15-50 g/kg/min

Sedation Analgesia Propofol Benzodiazepines Opioids Patient Comfort Choose the Right Drug Sedation Analgesia Amnesia Hypnosis Anxiolysis Propofol Benzodiazepines Opioids Patient Comfort -2 agonists

Altered Pharmacology Midazolam and Age Harper et al. Br J Anesth, 1985;57:866-871

Overdose (prolonged infusion) Delayed Emergence Overdose (prolonged infusion) pK derived from healthy patients Drug interaction Individual variation Delayed elimination Liver (Cp450) Kidney dysfunction Active metabolites

Opiate and Benzodiazepine Withdrawal Frequency related to dose and duration 32% if receiving high doses for longer than a week Onset depends on the half-lives of the parent drug and its active metabolites Clinical signs and symptoms are common among agents CNS activation: seizures, hallucinations, GI disturbances: nausea, vomiting, diarrhea Sympathetic hyperactivity: tachycardia, hypertension, tachypnea, sweating, fever No prospectively evaluated weaning protocols available 10 - 20% daily decrease in dose 20 - 40% initial decrease in dose with additional daily reductions of 10 - 20% Consider conversion to longer acting agent or transdermal delivery form

Significance of ICU Delirium Seen in > 50% of ICU patients Three times higher risk of death by six months Five fewer ventilator free days (days alive and off vent.), adjusted P = 0.03 Four times greater frequency of medical device removal Nine times higher incidence of cognitive impairment at hospital discharge

Acute onset of mental status changes or a fluctuating course Delirium Acute onset of mental status changes or a fluctuating course & 2. Inattention 3. Disorganized Thinking or 4. Altered level of consciousness Courtesy of W Ely, MD

Risk Factors for Delirium Primary CNS Dx Infection Metabolic derangement Pain Sleep deprivation Age Substances including tobacco (withdrawal as well as direct effect)

Diagnostic Tools: ICU Routine monitoring recommended by SCCM Only 6% of ICUs use Confusion Assessment Method (CAM-ICU) or Delirium Screening Checklist (DSC) Requires Patient Participation Cognitive Test for Delirium Abbreviated Cognitive Test for Delirium CAM-ICU Ely. JAMA. 2001;286: 2703-2710.

Delirium Screening Checklist No Patient Participation Delirium Screening Checklist Bergeron. Intensive Care Med. 2001;27:859.

Treatment of Delirium Correct inciting factor, but as for pain…relief need not be delayed while identifying causative factor Control symptoms? No evidence that treatment reduces duration and severity of symptoms Typical and atypical antipsychotic agents Sedatives? Particularly in combination with antipsychotic and for drug/alcohol withdrawal delirium No treatment FDA approved

Haloperidol No prospective randomized controlled trials in ICU delirium > 700 published reports involving > 2,000 patients The good: Hemodynamic neutrality No effect on respiratory drive The bad: QTc prolongation and torsades de pointes Neuoroleptic malignant syndrome - only three cases with IV haloperidol Extrapyramidal side effects - less common with IV than oral haloperidol

Mechanism of action unknown Less movement disorders than haloperidol Atypical Antipsychotics: Quetiapine, Olanzapine, Risperidone, Ziprasidone Mechanism of action unknown Less movement disorders than haloperidol Enhanced effects on both positive (agitation) and negative (quiet) symptoms Efficacy = haloperidol? One prospective randomized study showing equal efficacy of olanzapine to haldol with less EPS Issues Lack of available IV formulation Troublesome reports of CVAs, hyperglycemia, NMS Titratability hampered - QTc prolongation with ziprasidone IM - Hypotension with olanzapine IM

Neuromuscular Blockade (NMB) (Paralytics) in the Adult ICU Used most often acutely (single dose) to facilitate intubation or selected procedures Issues NO ANALGESIC or SEDATIVE properties Concurrent sedation with amnestic effect is paramount analgesic as needed Never use without the ability to establish and/or maintain a definitive airway with ventilation If administering for prolonged period (> 6 - 12 hours), use an objective monitor to assess degree of paralysis.

Neuromuscular Blockade in the ICU Current use in ICU limited because of risk of prolonged weakness and other complications Maximize sedative/analgesic infusions as much as possible prior to adding neuromuscular blockade Indications Facilitate mechanical ventilation, especially with abdominal compartment syndrome, high airway pressures, and dyssynchrony Assist in control of elevated intracranial pressures Reduce oxygen consumption Prevent muscle spasm in neuroleptic malignant syndrome, tetanus, etc. Protect surgical wounds or medical device placement

Neuromuscular Blocking Agents Two classes of NMBS: Depolarizers - Succhinylcholine is the only drug in this class - Prolonged binding to acetylcholine receptor to produce depolarization (fasciculations) and subsequent desensitization so that the motor endplate cannot respond to further stimulation right away Nondepolarizers - Blocks acetylcholine from postsynaptic receptor competitively - Benzylisoquinoliniums Curare, atracurium, cisatracurium, mivacurium, doxacuronium - Aminosteroids Pancuronium, vecuronium, rococuronium

Quick Onset Muscle Relaxants for Intubation Patients with aspiration risk need rapid onset paralysis for intubation. Not usually used for continuous maintenance infusions Rocuronium Nondepolarizer with about an hour duration and 10% renal elimination Dose is 1.2 mg/kg to have intubating conditions in 45 seconds Succinylcholine Depolarizer with a usual duration of 10 minutes All or none train of four after administration due to desensitization (can be prolonged in patients with abnormal plasma cholinesterase) Dose is 1 - 2 mg/kg to have intubating conditions in 30 seconds

Potential Contraindications of Succinylcholine Increases serum potassium by 0.5 to 1 meq/liter in all patients Can cause bradycardia, anaphylaxis, and muscle pain Potentially increases intragastric, intraocular, and intracranial pressure Severely elevates potassium due to proliferation of extrajunctional receptors in patients with denervation injury, stroke, trauma, or burns of more than 24 hours

Neuromuscular Blocking Agents Nondepolarizing muscle relaxants Pancuronium, vecuronium, cisatracurium All rapid onset (2 - 3 minutes) Differ in duration (pancuronium 1 - 2 hours, vecuronium 0.5 hours, cisatracurium 0.5 hours) Differ in route of elimination (pancuronium = renal/liver, vecuronium = renal/bile, cisatracurium = Hoffman degradation)

Neuromuscular Blocking Agents Infusion doses Pancuronium 0.05 - 0.1 mg/kg/h Vecuronium 0.05 - 0.1 mg/kg/h Cisatracurium 0.03 - 0.6 mg/kg/h Other distinguishing features Pancuronium causes tachycardia Vecuronium has neutral effects on hemodynamics but has several renally excreted active metabolites Elimination of cisatracurium is not affected by organ dysfunction, but it is expensive

Monitoring NMBAs Goal - To prevent prolonged weakness associated with excessive NMBA administration Methods: Perform NMBA dose reduction or cessation once daily if possible Clinical evaluation: Assess skeletal muscle movement and respiratory effort Peripheral nerve stimulation - Train of four response consists of four stimulae of 2 Hz, 0.2 msec in duration, and 500 msec apart. - Comparison of T4 (4th twitch) and T1 with a fade in strength means that 75% of receptors are blocked. - Only T1 or T1 and 2 is used for goal in ICU and indicates up to 90% of receptors are blocked.

Monitoring Sedation During Paralysis Bispectral index is based on cumulative observation of a large number of clinical cases correlating clinical signs with EEG signals. While used to titrate appropriate sedation (and amnesia) in anesthetized patients to the least amount required, not proven to achieve this goal. Increased potential for baseline neurologic deficit and EEG interference in ICU patients No randomized controlled studies to support reliable use in ICU. Other neuromonitoring (awareness) modalities are likely to be developed. Cessation of NMB as soon as safe in conjunction with other patient parameters should be a daily consideration.

Complications of Neuromuscular Blocking Agents Associated with inactivity: Muscle wasting, deconditioning, decubitus ulcers, corneal drying Associated with inability to assess patient: Recall, unrelieved pain, acute neurologic event, anxiety Associated with loss of respiratory function: Asphyxiation from ventilator malfunction or accidental extubation, atelectasis, pneumonia Other: Prolonged paralysis or acute NMBA related myopathy - Related to decreased membrane excitability or even muscle necrosis - Risk can be compounded by concurrent use of steroids.

Sample NMBA Protocol

References Jacobi J, et al. Crit Care Med. 2002;30:119-141. Jones, et al. Crit Care Med. 2001;29:573-580. Cammarano, et al. Crit Care Med. 1998;26:676. Ely, et al. JAMA. 2004;292:168.

Case Scenario #1 22-year-old male with isolated closed head injury who was intubated for GCS of 7 He received 5 mg of morphine, 40 mg of etomidate, and 100 mg of succinylcholine for his intubation. He is covered in blood spurting from an arterial catheter that was just removed, and he appears to be reaching for his endotracheal tube. What sedative would you use and why? What are the particular advantages in this situation? How could you avoid the disadvantages of this drug?

Case Scenario #1 - Answer Propofol will rapidly calm a patient who is displaying dangerous behavior without need for paralysis. Titratable and can be weaned quickly to allow for neurologic exam Can treat seizures and elevated ICP which may be present in a head trauma with GCS of eight or less Minimizing dose and duration will avoid side effects.

Case Scenario #2 54-year-old alcoholic who has been admitted for Staph sepsis Intubated in the ICU for seven days and is currently on midazolam at 10 mg/hour His nurse was told in report that he was a “madman” on the evening shift. Currently, he opens his eyes occasionally to voice but does not follow commands nor does he move his extremities to deep painful stimulation. Is this appropriate sedation? What would you like to do? How would you institute your plan of action?

Case Scenario #2 - Answer This patient is oversedated. Not only can a neurologic exam not be performed, but it would be unlikely to be able to perform a wakeup test within one 24-hour period. Given the need to examine the patient, midazolam should be stopped immediately. Rescue sedatives including midazolam should be available if agitation develops. Flumazenil should be avoided.

Case Scenario #3 62-year-old, 65-kg woman with ARDS from aspiration pneumonia Her ventilator settings are PRVC 400, RR 18, PEEP 8, and FIO2 100%. She is dyssynchronous with the ventilator and her plateau pressure is 37 mm Hg. She is on propofol at 50 mcg/kg/min, which has been ongoing since admit four days ago. She is also on norepinephrine 0.1 mcg/kg/min and she was just started on steroids. What do you want to do next? Do you want to continue the propofol? Why or why not? What two iatrogenic problems is she likely at risk for?

Case Scenario #3 - Answer This patient needs optimization of her sedatives, and potentially chemical paralysis to avoid complications of ventilator dyssynchrony and high airway pressures. If you continue to use propofol, higher doses are required and the patient is already on norepinephrine. In addition, if paralysis is used, you do not have reliable amnesia. She is at risk for propofol infusion syndrome and critical illness polyneuropathy.

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

Barr, Donner. Crit Care Clin. 1995;11827 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

Acute management Prolonged management Treat Withdrawal Resume sedation Beta-blockade, dexmedetomidine Prolonged management Methadone 5-10 mg VT bid Clonidine 0.1-0.2 mg VT q8h Lorazepam 1-2 mg IV q8h