ABC s of sedation: A B e tter use of C lonidine

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1 ABC s of sedation: A B e tter use of C lonidine for D exmedetomidine weaning Tina Chen, Pharm.D. PGY-1 Pharmacy Resident The Children s Hospital of San Antonio, San Antonio, TX Pharmacotherapy Education and Research Center University of Texas Health San Antonio January 5, 2018 Learning objectives : 1. To describe the advantages of dexmedetomidine use in a pediatric population. 2. To describe withdrawal symptoms from dexmedetomidine. 3. To describe the current challenges of using clonidine in the setting of sedation weaning. 4. To identify a pediatric candidate who may benefit from sedation weaning. 1

2 Introduction: Sedation in the pediatric population I. De finitions 1,2 A. Sedation: a continuum of various levels of consciousness i. Mild sedation: a. Able to provide appropriate response to all physical and verbal stimulation b. No loss of airway control or CV function c. Cognitive function possibly impaired ii. Moderate sedation, aka conscious sedation : a. Blunted response to light physical or verbal stimulation b. Usually no loss of respiratory control or CV function c. Cognitive function impaired-significant loss of orientation to environment iii. Deep sedation: a. Blunted response to painful physical stimuli b. Spontaneous ventilation often inadequate c. CV function may be impaired iv. General anesthesia: a. Unarousable, even with painful stimuli b. Requires respiratory assistance c. CV function impaired d. Only credentialed anesthesiologists are able to administer general anesthesia II. Significance A. Incidence of sedation and withdrawal 3,4 i. Over 55% of critically ill children require mechanical ventilation (MV) and sedation a. Most require MV for at least 5 days ii. Withdrawal symptoms occur in approximately 20% of children who required extended-period sedation a. Central nervous system (CNS): confusion, yawning, fever, seizures, hallucinations b. Gastrointestinal: poor feeding, loose stool, diarrhea c. Sympathetic symptoms: tachycardia, tremors, tachypnea, restlessness, diaphoresis III. Sedation in children 5 A. Goals for diagnostic and therapeutic procedures: i. Guard patient s safety and welfare ii. Minimize physical pain and discomfort iii. Control anxiety, minimize psychological trauma, maximize amnesia potential to allow safe completion of a procedure a. Child s ability to control own behavior for procedure depends on age and cognitive/emotional 6,7 behavior b. Children 6 years of age or under are at greater risk for adverse events 8 1. General anxiety 2. Separation anxiety 3. Apathy, aggression iv. Modify behavior and movement for safe completion of procedure 9 a. Reduces number of attempts at intubation b. Reduces stress on child and parent c. Reduces oxygen demand d. Prevents airway trauma and auto-extubation e. Provides comfort v. Return patient to state in which discharge is safe, as determined by recognized criteria B. Risk factors for increased sedation needs 10,11 i. Physically or mentally disabled Chen 2

3 a. Down Syndrome ii. Obesity iii. Obstructive sleep apnea (OSA) iv. Older age, over 7 years old v. Concurrent respiratory tract infection vi. Cardiovascular (CV) conditions vii. Cerebrovascular conditions C. Serious complications 5 i. Common for children to pass from intended level of sedation quickly to deeper, unintended level a. Rescue from a deeper level of sedation than intended is essential b. Recognition of various levels of sedation is essential c. Age and size appropriate cardiopulmonary support equipment must be available ii. Hypoventilation, hypoxemia iii. Laryngospasm iv. Seizures v. Sleep apnea vi. Allergic reactions vii. Airway compromise or obstruction iii. Hypotension and cardiopulmonary arrest, especially if inadequate recognition and treatment of respiratory compromise iv. Delays extubation v. Delirium vi. Tolerance to sedation drugs vii. Withdrawal IV. No standard of care for pediatric sedation 12 A. Generally, practitioners should use the least number of drugs and match drug to procedure type for safe practice i. Painful procedures: opioid analgesics or ketamine ii. Non-painful procedures: sedatives, hypnotics a. Computed tomography (CT) b. Magnetic resonance imaging (MRI) iii. Sedation and analgesia: single agent with both properties, or combination regimens iv. Anxiolytics and/or amnesia: patient specific goals B. Over-sedation associated with: i. Hypotension ii. Increased fluid requirements iii. Complications in assessing neurological status iv. Increased intensive care unit (ICU) or hospital length of stay C. Under-sedation associated with: i. Anxiety ii. Discomfort iii. Fear iv. Loss of vascular lines or mechanical ventilation D. Dosing regimens often composed of off-label use for medications i. Pharmacokinetic and pharmacodynamics data often not available E. Potential for adverse outcomes increases with increasing number of medications i. Multiple drugs often required 7 [Table I] Chen 3

4 Table I. Common sedation agents used in children 35 Class Drug Indications Onset of action T 1/2 Considerations Opioid analgesics Morphine Analgesic, sedation IV: 5-10 min 1-6 hours; shorter in older children -Highly hydrophilic -Caution in hepatic and renal dysfunction -Active metabolites Hydromorphone Analgesic, sedation IV: 5 min 2-3 hours -Hepatic metabolism -Improved safety for renal dysfunction Fentanyl Analgesic, sedation IV: 1 min 21 hours with long-term infusion -Highly lipophilic -Hepatic metabolism -Improved safety for renal dysfunction Benzodiazepines Midazolam Anxiolytic, sedation IV: 3-5 min 3-4 hours -Caution in hepatic and renal dysfunction -Active metabolites -High incidence of delirium Lorazepam Anxiolytic, sedation IV: 5-10 min hours -No hepatic or renal adjustments -High incidence of delirium Diazepam Anxiolytic, sedation IV: 4-5 min hours; longer in younger children -Active metabolites -Long T 1/2 but short clinical effect α 2 -agonists Dexmedetomidine Sedation IV: 5-10 min 2-4 hours; longer in younger children -Hepatic metabolism -Improved safety for renal dysfunction -No respiratory depression -No delirium NMDA antagonists Ketamine Analgesic, sedation IV: 30 sec Alpha: min Beta: 2-3 hours -Avoid in known intracranial pressure issues -No respiratory depression GABA agonists Propofol Sedation IV: sec 40 min, up to 4-7 hours with long-term infusion Barbiturates Pentobarbital Sedation IV: 3-5 min hours, dose dependent -Highly lipophilic -Hepatic metabolism -Triglyceride considerations -Risk of propofol related infusion syndrome (PRIS): refractory metabolic acidosis -Lipophilic -Negative inotrope -Profound sedation -Decreases intracranial pressure Sedation: Assessment I. Sedation Pre-assessment A. Baseline upper airway, lungs, CV, and neurological status B. Baseline vital signs i. Blood pressure (BP) ii. Heart rate (HR) Chen 4

5 iii. Respiratory rate (RR) iv. Oxygen saturation (O 2 sats) C. Comorbidities i. Respiratory conditions a. Infections b. Asthma c. OSA d. Prematurity e. Bronchopulmonary dysplasia II. Barriers to assessment A. Assessment of adequate sedation often accompanied by signs and symptoms that resemble pain: restlessness, agitation, increased muscle tone B. Children more prone to anxiety C. Physician fear of inducing deeper sedation, and thus, hypoxia, than intended D. Inadequate or inability to communicate III. Sedation Assessment Tools A. Withdrawal Assessment Tool-1 (WAT-1) 13, 14 [Appendix I] i. Advantages a. Excellent sensitivity of 87% and specificity of 88% for detecting iatrogenic withdrawal b. Simple to use 1. Easy to score 2. Objective items c. Assessment of motor disturbance, behavioral state disturbance, autonomic disturbance, and gastrointestinal symptoms d. Strong correlation between scores and nursing clinical judgement of withdrawal e. Validated in infants and children ii. Disadvantages a. Does not differentiate between opioid and BZD withdrawal E. Sophia Observation withdrawal Symptoms score (SOS) 15 [Appendix II] i. Advantages a. High sensitivity of 83% and specificity of 95% to detect opioid or BZD withdrawal syndrome in critically ill children b. Validated in children ii. Disadvantages a. Validated only in single-center trial F. COMFORT-behavioural scale (COMFORT-B) 16 [Appendix III] i. Accommodates both spontaneously breathing and ventilated patients ii. Advantages a. Pain and sedation assessment b. Assesses both behavioral and physiologic factors c. Detects changes in distress intensity due to treatment changes d. Validated in children iii. Disadvantages a. Cannot be used in pre-existing neurological disorders or fluctuations of neurological status b. Cannot be used for those receiving neuromuscular blocking agents (NMBs) G. Face, Legs, Activity, Cry, and Consolability scale (FLACC) 17 [Appendix IV] i. Advantages a. Provides easy method to quantify pain in nonverbal patients b. Validated in children ii. Disadvantages a. Cannot discriminate between pain, discomfort, withdrawal, or delirium Chen 5

6 H. Richmond Agitation and Sedation Scale (RASS) 18, 19 [Appendix V] i. Advantages a. Able to detect changes in sedation status over consecutive days of use in ICU 1. Distinguishes between verbal and physical stimulation b. Able to distinguish between different levels of consciousness 1. Distinguishes between duration of eye contact c. Easy to use d. Logical ii. Disadvantages a. Not validated in children I. Confusion Assessment method for the ICU (CAM-ICU) 20,21 [Appendix VI] i. Advantages a. High specificity of 95% to detect delirium b. Can be performed in 2-3 minutes and requires little training c. Validated for critically ill, non-verbal (mechanically ventilated) patients ii. Disadvantages a. Recent study showed only moderate sensitivity of 50% b. Not validated in children Alpha 2-adrenergic agonists I. Pathophysiology 22 A. Presynaptic activation of α 2 -adrenoceptor inhibits norepinephrine (NE) release i. Causes termination of pain signals B. Postsynaptic activation of α 2 -adrenoceptor inhibits sympathetic activity i. Decreases BP and HR C. Agonism at α 2A -adrenoceptor in locus coeruleus i. Causes hypnotic and sedative effects II. Dexmedetomidine (DEX) A. Preferred sedation agent for pediatric patients in most institutions i. Selective α 2 -adrenergic agonist 23 a. Low plasma concentrations 1. Vasodilation of vascular smooth muscle, which lowers mean arterial pressure (MAP) and heart rate (HR) b. Higher plasma concentrations 1. Vasoconstriction in vascular smooth muscle, which increases MAP, but decline in HR c. Specificity of 1600:1 for the α 2 -receptor, compared to clonidine of 200:1 14 ii. Elimination half-life: 2-4 hours a. Short, compared to many other sedative agents iii. Metabolism a. CYP2A6 and glucuronidation B. Major advantages 24,25 i. Arousable sedation ii. Preserves respiratory drive iii. Decreased delirium incidence iv. Recent data shows neuroprotective effects C. Major disadvantages 26,27 i. Bradycardia ii. Hypotension D. DEX withdrawal syndrome Chen 6

7 i. Result of sympathetic nervous system overactivity 28,29,30 a. Tachycardia, nervousness, agitation, headache, hypertension, seizures ii. Risk factors a. Higher cumulative doses b. Abrupt discontinuation c. Prolonged infusion iii. Management a. Reinitiation of DEX b. Clonidine-limited data in pediatrics E. ICU sedation (infants, children, adolescents) i. Loading dose: mcg/kg/hr intravenously over 10 minutes ii. Maintenance dose: mcg/kg/hr intravenously initially, titrate to desired sedation level III. Clonidine A. Widespread and increasing use as a sedative in pediatric ICU settings, but limited data exists on efficacy, dosing, and safety 31 i. Mixed α 1 and α 2 -adrenergic agonist a. Predominant effects at the postsynaptic α 2 -adrenoceptor in locus coeruleus inhibits sympathetic outflow 1. Peripheral vasoconstriction 2. Decreases systolic blood pressure 3. Decreases heart rate 4. Decreases cardiac output 5. Dose dependent sedation ii. Shares potassium channel with opioid receptors a. Hyperpolarization of neuronal membrane 1. Possibly contributes to analgesia via hyperpolarization of neuronal membrane b. Place in therapy 1. PICU/NICU for sedation, analgesia, neonatal abstinence syndrome iii. Elimination half-life: 8-12 hours iv. Metabolism: hepatic a. Inactive metabolites v. Major advantages a. Lowers blood pressure b. Many formulations available: immediate and extended release tablet, epidural injection, transdermal c. Analgesic properties vi. Major disadvantages 26,27 a. Long half-life b. Hypotension c. Bradycardia d. Potential for dependency vii. Enteral dosing in critically ill infants and children 32 a. Sedation and analgesia: 2-20 mcg/kg/day, divided every 6-8 hours b. Neonatal abstinence syndrome: 5-12 mcg/kg/day c. Drug withdrawal: 2-8 mcg/kg/day, based on published reports 1. Capino and colleagues performed a literature review of clonidine doses used in published reports and studies and recommended starting dose of 5-8 mcg/kg/day as transdermal patch, or in divided doses every 8 hours given orally Chen 7

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13 Evidence-based summary I. The most significant role clonidine currently has in the ICU setting is as an adjunct sedative to limit the dose of opioids and benzodiazepines II. Although very limited data exists at this time, clonidine is an easily accessible, easy to administer drug which acts on the same α 2 -adrenoceptor as dexmedetomidine, so it should in theory be useful in weaning dexmedetomidine for patients at high risk of having withdrawal symptoms A. The little data that exists for clonidine for sedation weaning suggests further exploration is needed. Even though the data is controversial at this time and lacking in strong conclusion, for a patient who is experiencing withdrawal symptoms, having the option is better than none at all B. Clonidine s long half-life and many available routes of administration render it an option that should be explored in larger, randomized prospective trials Final recommendations I. Clonidine should be considered to aid in dexmedetomidine weaning in pediatric patients who are at risk for withdrawal, namely, those who have had infusion times of at least 5 days II. Clonidine can be used as adjunct therapy to limit the use of opioid and BZD agents in the ICU setting III. Standardized weaning protocol should be applied to each practice site with critically ill patients A. Healthcare personnel should be familiar with and comfortable managing oversedation symptoms in patients and withdrawal symptoms B. Each institution should utilize validated and reliable sedation assessment tools for their particular population C. Due to variable degrees of treatment options and lack of standardized sedation protocol, sedation weaning must be individualized to each patient Suggested protocol for weaning DEX Chen 13

14 Appendix I. Withdrawal Assessment Tool-1 (WAT-1) and Instructions 36 Studies have shown that a WAT-1 score of 3 or higher has the best sensitivity and specificity in relation to indicating clinically significant withdrawal 13 Chen 14

15 Appendix II. Sophia Observation withdrawal Symptoms scale and Instructions 15 Chen 15

16 16 Appendix III. COMFORT-behavioural scale (COMFORT-B) Appendix IV. Face, Legs, Activity, Cry, Consolability scale (FLACC) 37 Chen 16

17 Appendix V. The Richmond Agitation and Sedation Scale 38 Appendix VI. Confusion Assessment Method for the ICU (CAM-ICU) 39 Chen 17

18 References : 1. Meredith JR, O'keefe KP, Galwankar S. Pediatric procedural sedation and analgesia. J Emerg Trauma Shock. 2008;1(2): Delirium: symptoms and causes. Mayo Clinic. Rochester, Minn. Sept Accessed 18 Dec Farias JA, Fernández A, Monteverde E, et al. Mechanical ventilation in pediatric intensive care units during the season for acute lower respiratory infection: a multicenter study. Pediatr Crit Care Med. 2012; 13(2): Birchley G. Opioid and benzodiazepine withdrawal syndromes in the paediatric intensive care unit: a review of recent literature. Nurs Crit Care. 2009; 14(1): Cote CJ, Wilson S. Guidelines for Monitoring and Management of Pediatric Patients Before, During, and After Sedation for Diagnostic and Therapeutic Procedures: Update Pediatrics. 2016; 138(1). doi: /jphp Joffe AR, Hogan J, Sheppard C, et al. Chloral hydrate enteral infusion for sedation in ventilated children: the CHOSEN pilot study. Crit Care. 2017;21(1): Baarslag MA, Allegaert K, Knibbe CA, et al. Pharmacological sedation management in the paediatric intensive care unit. J Pharm Pharmacol. 2016; 69(5): Pearce JI, Brousseau DC, Yan K, et al. Behavioral Changes in Children After Emergency Department Procedural Sedation. Acad Emerg Med. 2017; doi: /acem Cosentino C, Fama M, Foà C, et al. Unplanned extubations in intensive care unit: evidences for risk factors. A literature review. Acta Biomed. 2017;88(5-S): Yoshikawa F, Tamaki Y, Okumura H, et al. Risk factors with intravenous sedation for patients with disabilities. Anesth Prog. 2013;60(4): Grunwell JR, Mccracken C, Fortenberry J, et al. Risk factors leading to failed procedural sedation in children outside the operating room. Pediatr Emerg Care. 2014; 30(6): Kozin ED, Cummings BM, Rogers DJ, et al. Systemwide change of sedation wean protocol following pediatric laryngotracheal reconstruction. JAMA Otolaryngol Head Neck Surg. 2015;141(1): Franck LS, Harris SK, Soetenga DJ, et al. The Withdrawal Assessment Tool-1 (WAT-1): an assessment instrument for monitoring opioid and benzodiazepine withdrawal symptoms in pediatric patients. Pediatr Crit Care Med. 2008;9(6): Lardieri AB, Fusco NM, Simone S, et al. Effects of clonidine on withdrawal from long-term dexmedetomidine in the pediatric patient. J Pediatr Pharmacol Ther. 2015;20(1): Ista E, de Hoog M, Tibboel D, et al. Psychometric evaluation of the Sophia Observation withdrawal symptoms scale in critically ill children. Pediatr Crit Care Med Oct; 14(8): doi: /PCC.0b013e31829f5be Ista E, Van dijk M, Tibboel D, et al. Assessment of sedation levels in pediatric intensive care patients can be improved by using the COMFORT "behavior" scale. Pediatr Crit Care Med. 2005;6(1): Voepel-lewis T, Zanotti J, Dammeyer JA, et al. Reliability and validity of the face, legs, activity, cry, consolability behavioral tool in assessing acute pain in critically ill patients. Am J Crit Care. 2010;19(1): Ely EW, Truman B, Shintani A, et al. Monitoring sedation status over time in ICU patients: reliability and validity of the Richmond Agitation-Sedation Scale (RASS). JAMA. 2003;289(22): Sessler CN, Gosnell MS, Grap MJ, et al. The Richmond Agitation-Sedation Scale: validity and reliability in adult intensive care unit patients. Am J Respir Crit Care Med. 2002;166(10): Ely EW, Margolin R, Francis J, et al. Evaluation of delirium in critically ill patients: validation of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). Crit Care Med. 2001;29(7): Guenther U, Popp J, Koecher L, et al. Validity and reliability of the CAM-ICU Flowsheet to diagnose delirium in surgical ICU patients. J Crit Care. 2010; 25(1): Gertler R, Brown HC, Mitchell DH, et al. Dexmedetomidine: a novel sedative-analgesic agent. Proc (Bayl Univ Med Cent). 2001;14(1): Colin PJ, Hannivoort LN, Eleveld DJ, et al. Dexmedetomidine pharmacodynamics in healthy volunteers: 2. Haemodynamic profile. Br J Anaesth. 2017;119(2): Scibelli G, Maio L, Sasso M, et al. Dexmedetomidine: Current Role in Burn ICU. Transl Med UniSa. 2017;16: Mishina T, Aiba T, Hiramatsu K, et al. Comparison between dexmedetomidine and midazolam as a sedation agent with local anesthesia in inguinal hernia repair: randomized controlled trial. Hernia. 2017; doi: /s Chen 18

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