Sedation and Analgesia in the PICU

1. Sedation and Analgesia in the PICU Wyn Wheeler, PharmD Pediatric Clinical Pharmacy Specialist Instructor – Society of Critical Care Medicine Pediatric Fundamentals of Critical Care Support Levine Children’s Hospital Office: 704.381.7170 Pager: 1885

2. Objectives • Discuss sedative options and their potential contribution to ICU length of stay, delirium, and duration of mechanical ventilation • Discuss differences apparent in neonatal and pediatric pain responses and compare properties of analgesics available for use in the intensive care population

3. Goals of sedation • Allow tolerance of the physical environment • Reduce autonomic response, reduce O2 consumption, achieve ventilator synchrony • Facilitate nursing care • Reduce anxiety • Potentially, can include utilization of amnesia • Maintain patient safety

4. Barbiturates • First developed at Bayer Pharmaceuticals under brand Veronol, allegedly named after the Italian city of Verona • Potentiate GABAA receptors by increasing Cl flow through the channel and inhibiting nerve transmission to the cortex • Can cause profound hypotension by decreasing systemic vascular resistance and myocardial contractility • No reversal agent • Phenobarbital: useful for seizures, treatment of withdrawal • Pentobarbital: reduces cerebral oxygen consumption and intracranial pressure, but can depress myocardial function. With continuous infusion, can cause leukocyte dysfunction and abdominal hypertension

5. Benzodiazepines • Anxiolytic, amnestic, anticonvulsant, and muscle relaxant properties • Promote cellular hyperpolarization through interactions between GABA and the GABAA receptor • Routinely replaced barbiturates due to lower toxicity in overdose • May decrease the ventilatory response to CO2 • Significant cardiovascular effects can occur when used in the presence of hypovolemia, or when used in conjunction with other agents that reduce systemic vascular resistance (e.g. opioids)

6. When grouped by half-life… • Short acting (1-12 hrs) • Midazolam*, triazolam, alprazolam* • Intermediate acting (12-40 hrs) • Clonazepam, lorazepam, temazepam • Long acting (40-250 hrs) • Diazepam*, chloradiazepoxide*, flurazepam* *presence of active metabolite

7. Alpha Agonists • Stimulation of alpha receptors in brain stem activates an inhibitory neuron, reducing sympathetic outflow (↓tone, ↓ HR) • Clonidine (t1/2 in kids: 8-12 hrs) • Dexmedetomidine • Higher affinity for alpha2 over alpha1 • “Arousable sedation,” less depression of respiratory function • Also stimulate alpha2 in dorsal horn of spinal cord analgesia • 2 hour t1/2 • Watch for hypotension/bradycardia

8. Ketamine • Dissociative anesthetic with analgesic and amnestic properties • Laryngospasm can occur in the presence of airway secretions or when adequate sedation has not yet been achieved • Cardiovascular collapse has developed during induction of children with depleted catecholamine stores • Systemic vascular resistance is usually maintained and balances increases in pulmonary vascular resistance or myocardial depression • Remember: consider premedication with atropine to offset sialorrhea • Concomitant benzodiazepines can help decrease emergence phenomena • Avoid if elevated intracranial pressure or seizures present

9. Propofol • Interacts with GABAA receptors • Possesses amnestic properties but no analgesic effects • Has negative inotropic and chronotropic effects • Propofol infusion syndrome (PRIS) • Cardiac failure, rhabdomyolysis, metabolic acidosis, renal failure • Risks include high dose propofol, concomitant steroids, increased catecholamine states • Controversial in the pediatric literature – best to stay < 4 mg/kg/hr, ensure adequate fat intake

10. Etomidate • Depresses reticular activating system and potentiates inhibitory neurotransmitters • Has been utilized in cases where impaired cardiovascular performance or increased intracranial pressure are evident • Has fallen out of favor due to potent adrenal suppression and an increase in mortality

11. Chloral Hydrate • First synthesized in 1832 and chemically differs from barbiturates • Modulates GABA receptor complex • Often used for EEG sedation to decrease artifact while improving organization of normal sleep features • Short onset • Metabolized by plasma esterases • High doses and chronic use are discouraged, due to adverse effects on respiratory and cardiac systems • Some products contain sodium benzoate (relative of benzoic acid) – implicated in neonatal gasping syndrome

13. Efficacy of sedation regimens to facilitate mechanical ventilation in the pediatric intensive care unit: A systematic reviewHartman ME, McCrory DC, Schulman SR – Pediatr Crit Care Med 2009 • In US, 11 different sedatives are commonly used, and 20% of surveyed PICUs state they use sedatives “routinely” • United Kingdom PICUs utilize midazolam and morphine most commonly • In one study, use of clonidine decreased morphine requirement • Ketamine in low doses appeared to be successful in maintaining sedation • Propofol was associated with increased morphine doses, and < 30% of patients remained sedated with 2.5 mg/kg/hr • Only midazolam, fentanyl, and chloral hydrate have been studied in a randomized controlled trial in pediatrics (midazolam being the most commonly used and best studied)

14. Randomized controlled trial of interrupted versus continuous sedative infusions in ventilated childrenGupta K, Gupta VK, Jayashree M, Singhi S -- Pediatr Crit Care Med 2012 Vol 13, No 2 (PAP)Posted 28 Jan 2011 • Prospective randomized controlled trial • Single-center referral/teaching PICU in North India • n=102 • Exclusion: mechanical ventilation < 48 hrs, peak inspiratory pressures > 28 mmHg • Group 1: continuous sedation (n=56) • Group 2: daily interruptions at 0800, and restart at 50% reduced dose (n=46) • Primary outcomes: length of mechanical ventilation, intensive care unit stay • Secondary outcomes: number/percentage of days awake on sedatives, frequency of adverse events, total dose of sedatives required

15. Outcomes Table 2. Continuous versus intermittent sedation: Primary and secondary outcomes _______________________________________________________________________________________________________________ Variable Continuous (n=56) Intermittent (n=46) p____ Length of mechanical ventilation (days), mean + SD (95% CI) 10.3 + 8.4 (8.04–12.58) 7.1 + 4.8 (5.63–8.46) .021a Number of days awake, mean + SD (95% CI) 2.3 + 4.7 (1.01–3.53) 3.7 + 3.9 (2.54–4.58) .103 Percentage of awake days, mean + SD (95% CI) 61.1 + 38 (50.80–71.32) 78.8 + 19.3 (73.02–84.47) .005a Duration of pediatric intensive care unit stay (days), mean + SD (95% CI) 14.1 + 9.8 (11.38–16.69) 10.7 + 6.1 (8.89–12.51) .048a Total dose of midazolam (mg/kg/day), mean + SD(95% CI) 11.0 + 6.9 (9.08–12.82) 7.1 + 4.7 (5.68–8.47) .002a Total cost of midazolam (rupees), mean + SD (95% CI) 13865 + 25338 (7015–20715) 4827 + 5445 (3210–6444) .020a Adverse events, n (%) 8 (14.3) 6 (13.0) .86b Pneumothorax, n (%) 7 (12.5) 5 (10.9) .79b Spontaneous extubation, n (%) 1 (1.8) 1 (2.2) .88b_____ pa < 0.05 by Student’s t test; pb < 0.05 by chi-square test

16. Outcomes Table 2. Continuous versus intermittent sedation: Primary and secondary outcomes _______________________________________________________________________________________________________________ Variable Continuous (n=56) Intermittent (n=46) p____ Length of mechanical ventilation (days), mean + SD (95% CI) 10.3 + 8.4 (8.04–12.58) 7.1 + 4.8 (5.63–8.46) .021a Number of days awake, mean + SD (95% CI) 2.3 + 4.7 (1.01–3.53) 3.7 + 3.9 (2.54–4.58) .103 Percentage of awake days, mean + SD (95% CI) 61.1 + 38 (50.80–71.32) 78.8 + 19.3 (73.02–84.47) .005a Duration of pediatric intensive care unit stay (days), mean + SD (95% CI) 14.1 + 9.8 (11.38–16.69) 10.7 + 6.1 (8.89–12.51) .048a Total dose of midazolam (mg/kg/day), mean + SD(95% CI) 11.0 + 6.9 (9.08–12.82) 7.1 + 4.7 (5.68–8.47) .002a Total cost of midazolam (rupees), mean + SD (95% CI) 13865 + 25338 (7015–20715) 4827 + 5445 (3210–6444) .020a Adverse events, n (%) 8 (14.3) 6 (13.0) .86b Pneumothorax, n (%) 7 (12.5) 5 (10.9) .79b Spontaneous extubation, n (%) 1 (1.8) 1 (2.2) .88b_____ pa < 0.05 by Student’s t test; pb < 0.05 by chi-square test

19. Strengths Single center similar to LCH Solid statistical analyses completed Authors correlated with adult data Weaknesses Investigators calculated that n=47 in each group was required for 80% power – was not reached Interrupted sedation group had a statistically significant reduced PIP/PEEP requirement at time of inclusion Analysis

20. ICU delirium • Some literature reports an incidence as high as 80% of critical care admissions • Risks: • Host factors – older age, hypertension, alcoholism • Precipitating factors – electrolyte disturbances, infection, hypoxemia, anemia, acidosis, medications

21. Medications as a cause… • Estimated 12% to 39% of all cases of delirium may be caused by medications alone • Benzodiazepines and opioids have had a demonstrated association in both medical and surgical ICUs • Often dose related • Benzodiazepine adverse effects may be linked to anticholinergic activity (+ muscarinic receptor affinity)

23. Analgesia • Must be considered in all ICU patients • Can reduce/eliminate the need for sedatives and paralytics, however are not efficient sedatives in and of themselves • Untreated pain has been linked to considerable morbidity • Hemodynamic instability • Psychological instability

24. Goals of analgesia • Anticipation • Treatment • Reassessment • Use of adjunctive measures • Open communication • Reassurance • Parental presence

25. Pediatric pain response • Framework of nervous system detectable in 7th week of gestation • High density of substance P in the fetal brainstem; endogenous opioids are released in response to the stress of birth • Nociceptive nerve terminals are dense in the neonate • Shorter transmission distances compensate for lack of myelination • Mu receptor is predominant in first 2 weeks, which may explain increased respiratory depression in infants receiving opioids • NMDA receptors are immature and can be more sensitive to stimulation

26. Non-opioids • Nonsteroidal anti-inflammatory agents • Ketorolac • Ibuprofen • Caldolor  – nonformulary at CHS facilities • Acetaminophen • Ofirmev now on market – nonformulary at CHS facilities • Tramadol • Inhibits reuptake of serotonin and norepinephrine in addition to agonism at the mu receptor

27. Opioids Reduces first-pass metabolism • Derived from opium • Morphine, codeine, thebaine (nonanalgesic), papaverine (vasodilator) C3 methylation Acetylation of both hydroxyls Facilitates transport across BBB

28. Phenanthrenes Morphine Hydromorphone Oxymorphone Codeine Hydrocodone Oxycodone Phenylheptylamines Methadone Levomethadyl acetate Propoxyphene Phenylpiperidines Meperidine Fentanyls (alfentanil, sufentanil, remimfentanil) Diphenoxylate Loperamide Morphinians Levorphanol Butorphanol Classes of opioids

29. Fentanyl Synthetic, phenylpiperidine class Rapid onset, more lipophilic, less histamine release 100 times more potent than morphine Tachyphylaxis is common Rigid chest syndrome when given rapid IV push Morphine Phenanthrene class Longer duration of action than fentanyl Active metabolites Morphine-6-glucuronide Also active Morphine-3-glucuronide Excitatory effect ? Anti-analgesic effect Common ICU opioids

30. Side effects • Respiratory depression • CO2 curve is flattened and shifted to the right • Narcotic bowel syndrome • GI disturbance • Pruritis • Physical tolerance/dependence • Tend to occur after 5-7 days of continuous use

31. Methadone • Longer acting synthetic opiate • T½ estimated at 19 hrs in children • Lower tolerance/dependence potential • Has affinity for both the mu and NMDA receptors • Good oral bioavailability

32. Evaluation of an opiate weaning protocol using methadone in pediatric intensive care unit patientsRobertson RC, Darsey E, Fortenberry JD, Pettignano R, Hartley G -- Pediatr Crit Care Med 2000 • Time series, prospective study • 20-bed medical/surgical PICU in an academic children’s hospital • N=20 • Conclusion: use of a protocol reduced time required for weaning without an increase in withdrawal symptoms

33. Reversal • Naloxone • May not reverse hypotension • Use in patients physically dependent on opioids can precipitate abstinence syndrome and unopposed sympathetic activity • Flumazenil • Competitive inhibitor of BZD binding site on GABA • Can precipitate seizures – use with caution

34. References • Castro CB, Chiste MA, Vizioli JF, Cordova NM, Ohlweiler L, Lago IS, et al. Comparison between the EEG of natural sleep and the induced by chloral hydrate in relation to paroxysmal changes and baseline rhythm. Arch Neuro Psychiatr 1994; 52: 326-9 • Hartman ME, McCrory DC, Schulman SR. Efficacy of sedation regimens to facilitate mechanical ventilation in the pediatric intensive care unit: A systematic review. Pediatr Crit Care Med 2009; 10(2):246-255 • Vasile B, Rasulo F, Candiani A, Latronico N. The pathphysiology of propofol infusion syndrome: a simple name for a complex syndrome. Intensive Care Med 2003 Sep;29(9): 1417-25 • Gupta K, Gupta VK, Jayashree M, Singhi S. Randomized controlled trial of interrupted versus continuous sedative infusions in ventilated children. Pediatr Crit Care Med 2012 Vol 13, No 2 (PAP)Posted 28 Jan 2011 • Delirium in the intensive care unit: Medications as risk factors. Alexander E. Crit Care Nurse 2009 Feb; 29(1):85-87 • Yaster M, Maxwell L: Opioid agonists and antagonists. In: Pain in Infants, Children, and Adolescents. Schechter NL, Berde CB, Yaster M (Eds). Baltimore, Williams & Wilkins, 1993, p 145-171 • Robertson RC, Darsey E, Fortenberry JD, Pettignano RP, Hartley, G. Evaluation of an opiate-weaning protocol using methadone in pediatric intensive care unit patients. Pediatr Crit Care Med 2000; 1(2):119-123 • Pediatric Multiprofessional Critical Care Review. Society of Critical Care Medicine 2008.