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Sedation and analgesia in the ICU
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Sedation and analgesia in the ICU Jill Zalieckas MD, MPH, Christopher Weldon MD, PhD
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Cite this article as: Jill Zalieckas MD, MPH, Christopher Weldon MD, PhD, Sedation and analgesia in the ICU, Seminars in Pediatric Surgery, http://dx.doi.org/ 10.1053/j.sempedsurg.2014.11.011 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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#8 SEDATION AND ANALGESIA IN THE ICU
Jill Zalieckas, MD, MPH Boston Children’s Hospital 300 Longwood Avenue Boston, MA 02115
Christopher Weldon, MD, PhD Boston Children’s Hospital 300 Longwood Avenue Boston, MA 02115 Corresponding Author: Christopher Weldon MD PhD Children's Hospital Boston 300 Longwood Ave, Fegan 3 Boston MA 02115 Work Phone: (617) 355-4503 Fax: (617) 730-0477 [email protected]
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Abstract
The alleviation of pain and anxiety is an important component of caring for the critically ill child. Sedation and analgesia regimens are utilized as adjuncts to procedures, facilitate mechanical ventilation, and assist with management of the critically ill child. Although sedation regimens have been used extensively across intensive care units, the data are lacking as to the best drugs, dosing, regimens, and short- and long-term safety profiles for use in the pediatric population. Sedation regimens continue to be a challenging aspect of the care of the critically ill child, and they have been associated with significant morbidity in this population. The following chapter will discuss the sedative use in the intensive care unit, morbidity associated with sedatives and analgesics, and the importance of establishing sedation and analgesia algorithms to reduce morbidity and mortality. Keywords: sedation, analgesia, intensive care, morbidity
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Introduction
The alleviation of pain and anxiety is an important component of caring for the critically ill infant and child. Children in the intensive care unit require sedation and analgesia as adjuncts to procedures, facilitate mechanical ventilation, and assist with post operative management and care. The goals of sedation are to ensure the patient’s safety, minimize physical discomfort and pain, control anxiety, minimize psychological trauma, and control behavior and movement.(1) Adequate sedation and analgesia also have benefits of reducing the stress response and catabolism associated with surgery (2). The approach to sedation and analgesia management has implications for a child’s overall hospital course in the intensive care unit. Specifically, ventilator days, ICU length of stay, risk of nosocomial infections, unplanned extubation, and risk of withdrawal are all morbidities that are increased with prolonged or ineffective sedation regimens (3,4). The following chapter outlines the impact of sedation regimens on morbidity in neonatal and pediatric ICUs and highlights the various pharmacologic agents commonly used for sedation and analgesia in the intensive care unit.
Impact of Sedation in the ICU Adult critical care literature highlights the importance of implementing a standard sedation/analgesia algorithm in order to reduce total sedative use and ICU morbidity. Sedation protocols may decrease morbidity, ICU length of stay, duration of mechanical ventilation, decreased duration of opioid and benzodiazepine infusion and total duration
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of sedative exposure. (4) Several pediatric studies have also demonstrated the impact of sedation on a child’s ICU course. The RESTORE trial was a prospective evaluation of sedation related adverse events among 22 PICUs. Inadequate pain or sedation management comprised 70% of reported adverse events in mechanically ventilated patients. (5) The relationship between sedation regimens and mechanical ventilation has been examined in several studies. In the randomized control trial by Randolph et al, sedative use in the first 24 hours of weaning was found to strongly influence length of time on the ventilator and extubation failure in infants and children (6). Payen et al also found continuous intravenous sedation was an independent risk factor for prolonged mechanical ventilation after multivariate analysis (7). Sedation regimens can also impact unplanned extubations. Lucas, et al reviewed the role of sedation in unplanned extubations. They found a significant reduction in rates of unplanned extubation following institution of a sedation algorithm. (8) The best practice recommendations include establishment of a sedation protocol and regular assessment of level of sedation to help reduce the rates of unplanned extubations, however a specific algorithm or sedation assessment tool was not identified. (8) Hartman, et al published a systematic review of pediatric sedation regimens in the intensive care unit in Pediatric Critical Care Medicine. The primary objective was to identify and evaluate the quality of evidence supporting sedatives and sedation regimens commonly used in the PICU to facilitate mechanical ventilation. Thirty-nine studies were included in the review, representing 39 sedation algorithms and 20 scoring systems used to evaluate level of sedation. Although sedation regimens have been used
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extensively across neonatal and pediatric intensive care units, the data are lacking as to the appropriate dosing, safety and protocols for use. (9) Use of sedation algorithms and focus on protocols for sedation are important to attempt to reduce the cumulative dose and duration of sedatives and analgesics used. Concerns regarding long term effects of analgesics and anesthetics have been illustrated in the literature. Animal studies have demonstrated opioids have caused neuroapoptosis and neurodevelopmental abnormalities. Other studies have suggested opioids increase apoptosis in human glial cells. The need to establish comprehensive sedation and analgesia protocols is essential to aid in reducing potential in hospital as well as developmental morbidity related to sedation and analgesia regimens. (10,11)
Opioids Opioids and benzodiazepines are traditionally used for sedation and analgesia in the intensive care unit. The CNS has 4 primary opioid receptors: μ, κ, δ, σ. μ agonists are most commonly used in pain management regimens. Opioids exert their clinical effects as a sedative and analgesic. Side effects include respiratory depression, nausea, vomiting, delayed gastric emptying, delayed intestinal motility, pruritus, constipation, miosis, tolerance, and physical dependence. Elimination half life is prolonged in neonates due to reduced hepatic activity and blood flow. Symptoms of opioid withdrawal include cramping, vomiting, diarrhea, tachycardia, hypertension, diaphoresis, restlessness, insomnia, movement disorders, reversible neurologic abnormalities, and seizures. (2,12,13)
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Morphine is the most commonly used opioid in the intensive care unit to manage pain. Dosing begins at 0.05-0.1mg/kg for both intermittent dosing as well as continuous infusions. The peak effect is observed within 20 minutes of administration, with a duration of action from 2-7 hours. Morphine should be used with caution in neonates because the half life elimination is prolonged, up to 9 hours in preterm neonates. Neonates have a decreased GFR, which leads to an accumulation of morphine 6glucouronide, which is the active metabolite of morphine. Accumulation of morphine 6glucouronide can cause respiratory depression. In addition to neonates, patients with renal failure, cirrhosis, and septic shock, should have morphine administered cautiously, as these disease processes result in decrease clearance of morphine and its active metabolites. (12,13,14) Fentanyl is another commonly used opioid in the intensive care unit, especially among infants. Fentanyl is 100 times more potent than morphine, and typical initial doses are from 1-5 mcg/kg for both intermittent dosing as well as continuous infusion. Compared to morphine, fentanyl has: less hemodynamic effects; rapid onset, less than 1 minute; and brief duration of action, ranging from 30-45 minutes. One must be aware of the risk of glottic and chest wall rigidity following rapid infusion of fentanyl in doses >5mcg/kg. (12) Methadone, another opioid commonly used in the intensive care unit, is helpful to treat or wean opioid dependent patients. The full analgesic effect occurs 3-5 days from drug initiation. Methadone has a slow elimination with long duration of action. Its active metabolite is morphine. EKG monitoring is necessary with methadone use, as it is associated with prolonged QT syndrome and torsades de pointes. Methadone can also
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have respiratory depressant effects. (12) Due to its properties, methadone is an important adjunct agent that can be used not only to wean opioid dependent patients, but also help prevent rapid escalation of opioid infusion in the long term sedation pathway. (12)
Benzodiazepines Benzodiazepines act by augmenting GABA (gamma amino butyric acid) transmission, which is an inhibitory neurotransmitter in the brain. Benzodiazepines have anxiolytic and amnestic properties but do not have analgesic effects. Clinical effects include decreased cerebral metabolism and blood flow, sedation, hypnosis, anxiolysis, anticonvulsant activity, anterograde amnesia, muscle relaxation, dose dependent respiratory depression, and decreased tidal volume. Use of benzodiazepines without opioid in presence of painful stimulus can cause hyperalgesia and agitation. Withdrawal symptoms include agitation, poor visual tracking, choreoathetoid and dyskinetic movements of face, tongue, and limbs, as well as depressed consciousness. (2,12) Midazolam, the most commonly used benzodiazepine, is short acting and rapidly crosses the blood brain barrier. The onset of action is achieved within 30 minutes and elimination half life is 6 hours. Typical dosing for sedation for mechanical ventilation ranges from 0.05-0.2mg/kg/hour. In addition to respiratory depression and hypotension, an additional side effect of midazolam is tolerance and withdrawal. In order to avoid dose escalation, lorazepam is another adjunct that can be used to avoid effects of tolerance and withdrawal. (12) Lorazepam can be used as an infusion or by intermittent dosing either intravenously or enterally. As an adjunct to midazolam infusion, lorazepam helps
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prevent dose escalation because of its prolonged duration of action at 2-4 hours. Enteral lorazepam is twice as potent as intravenous administration, therefore making it an effective agent to use during sedation wean. One caution with IV lorazepam is the risk of elevated osmolar gap metabolic acidosis and renal toxicity due to the inclusion of polyethylene glycol in its formulation. Lorazepam should not be used in children less than 6 months of age because of this toxicity. (2,12)
Adjuvant Therapies α-2 agonists have sedative and analgesic properties and are used as adjuncts to traditional opioid and benzodiazepine therapy for the critically ill child. Clonidine can be administered via enteral or transdermal route. Enteral dosing is 5mcg/kg/day. Transdermal patches range 100-300mcg per patch, and are changed every 7 days. Abrupt discontinuation of clonidine can cause rebound hypertension. Transdermal patches are typically weaned off over a period of 2-3 weeks. (2,12) Dexmedetomidine is another α-2 agonist, which has sedative and analgesic properties. Dexmedetomidine is being used in the ICU for several indications: 1. Adjunct to opioid and benzodiazepine infusions to avoid continuous escalation; 2. Facilitating weaning of other medications in anticipation of extubation; and 3. Provide sedation for spontaneously breathing children. Dexmedetomidine is highly lipid soluble and has effects on the CNS to decrease sympathetic tone and stimulates central parasympathetic outflow. It induces natural REM sleep and is associated with rapid and easy arousal. The elimination half life is 2-3 hours. Typical infusion rates are 0.2-2 mcg/kg/hour. Bolus dosing can cause rapid, transient decrease in heart rates and increased blood pressure.
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Dexmedetomidine has been shown to cause bradycardia, sinus arrhythmias, heart block, nausea and vomiting. Dexmedetomidine has been used increasingly as an adjunctive sedative agent in the ICU given it is short acting and has minimal respiratory depression. Withdrawal with dexmedetomidine can occur after as short as 24 hours. Withdrawal symptoms include hypertension, vomiting, diarrhea, anxiety, and seizure. (12,15,16,17) Propofol, an alkylphenol, is an IV general anesthetic used as sedative to facilitate short term mechanical ventilation and procedures. Propofol has dose-proportional sedative/anesthetic effects with rapid onset, within a minute of injection. The sedative effects dissipate quickly with discontinuation of the infusion. Propofol is a potent vasodilator and has negative ionotropic effects. Typical dosing includes initial bolus 1-2 mg/kg and infusion doses of 75-250 mcg/kg/minute. Propofol should not be used for prolonged infusion in children. Propofol infusion syndrome (PRIS) is the presence of acute bradycardia resistant to treatment, which progresses to asystole. Hallmarks of PRIS include lactic acidosis, fatty liver enlargement, oliguria, elevated serum urea, elevated serum potassium, rhabdomyolysis and myoglobinuria. PRIS is associated with a high mortality rate and occurs with high doses of propofol for a prolonged duration. Risk factors for development of propofol infusion syndrome are poor oxygen delivery, sepsis, cerebral injury and high propofol dosage. Children are at higher risk of developing PRIS due to the low glycogen storage content and dependence on fat metabolism. (12,17) Treatment of PRIS involves stopping propofol infusion immediately and stabilizing the hemodynamic parameters. A challenge is that bradycardia is often resistant to external pacing or catecholamines. Carbohydrate substitution, hemodialysis, or ECMO have been used in the acute management of PRIS. Given the high risk profile
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of propofol infusion in children, it is not approved for prolonged sedation in the pediatric population. (18)
Managing Long Term Sedation and Analgesia Tolerance and dose escalation occur with benzodiazepine and opioid infusions. Providing optimal sedation and analgesia for prolonged durations can be challenging and require significant escalation of infusions. Several strategies can be employed to counter this issue. One is the use of adjuvant agents, namely α2 agonists. Dexmedetomidine has been used to improve sedation and analgesia in critically ill children. This has been used in burn patients, children recovering from cardiac surgery, as well as the general pediatric critically ill patient. Lam, et al published a retrospective series to evaluate the hemodynamic effects and safety of dexmedetomidine in critically ill infants with congenital heart disease. This study demonstrated that dexmedetomidine infusion was safe from a hemodynamic standpoint, and may aid in reducing vasopressors in children with catecholamine refractory shock. Although dexmedetomidine causes a decrease in heart rate, MAP, and CVP, all children in this study remained hemodynamically stable without dose escalation of vasopressors. (19) Daily Sedation Interruptions Clinical practice guidelines exist for the management of pain, agitation and delirium in adult patients in the intensive care unit as developed by a multi-institutional task force within the American College of Critical Care Medicine. A multidisciplinary approach to establish and use sedation and analgesia protocols is recommended in the ICU. Specific recommendations include daily sedation interruption or a light target level
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of sedation for adult mechanically ventilated patients.
Multiple RCTs in adults have
shown benefits of sedation holidays in decreasing ICU and hospital LOS. (20) Such guidelines do not exist in the pediatric population. Sedation protocols and sedation scales are associated with shorted time on mechanical ventilator, decreased ICU and hospital LOS as well as decreased delirium and long term cognitive dysfunction. Numerous studies have supported these findings. (20) A review conducted by Poh et al to evaluate the impact of sedation guidelines, protocols and algorithms on outcomes in pediatric ICUs determined that while there is limited data to guide practice, the presence of sedation guidelines and algorithms may decrease ICU LOS and medication dose, duration, and withdrawal. (21) Verlaat, et al report results of a randomized controlled trial of daily interruption of sedatives in the pediatric population. In this trial, sedatives were stopped daily and restarted when COMFORT-B score was ≥17 at the previously used infusion rate. This study resulted in decreased ventilator days, ICU length of stay, and lower use of morphine and midazolam in the intervention group. (22) A systematic review of sedation regimens in pediatric intensive care units performed by Hartman et al. found that the data are lacking in the pediatric literature to guide practice. As opposed to the adult literature, there is no standardization of care, resulting in limited data in the pediatric population. Therefore, a multi-institutional study is needed to answer questions on sedation and analgesia in the pediatric ICU, provide a thorough understanding of the options available, and establish an algorithm to drive practice. (9)
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Gupta, et al. published a randomized control trial of interrupted versus continuous sedative infusions in ventilated children, which examined the duration of mechanical ventilation, ICU LOS, days awake on sedative infusions, frequency of adverse events, total dose of sedatives and cost analysis. The daily interruptions involved discontinuing the sedative infusion every morning until the patient became fully awake or agitated or uncomfortable. At that point, the infusion was restarted at 50% less than the previous dose, and titrated for sedation. The intervention began 48 hours after intubation. Significant findings were decreased days on mechanical ventilation, ICU LOS, and total cost of sedation with daily interruptions. The percentage of awake days was significantly increased with daily interruptions. There was no significant difference in adverse events between groups, specifically no difference in unplanned extubations. (23)
Tolerance and Withdrawal Tolerance is receptor desensitization causing decreasing clinical effects after prolonged exposure due to upregulation of the cAMP pathway. Duration of therapy impacts the development of tolerance. Additionally, it is reported that infants exposed to opioids during this period of rapid brain development may develop long term tolerance. Shorter acting opioids can produce greater tolerance. Approaches to address tolerance include dose escalation, use of longer acting opioids, such as methadone, or addition of non opioid analgesics, such as dexmedetomidine or clonidine. (3,24) Dependence is the physiologic and biochemical adaptation of neurons, such that removing a drug precipitates withdrawal, which generally occurs after 2-3 weeks of continuous use. Dependence and withdrawal can lead to significant morbidity in critically
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ill patients. Withdrawal is the clinical syndrome that develops after stopping or reversing a drug after prolonged exposure to that drug. Symptoms are evident within 24 hours of drug cessation and peak within 72 hours. Opioid withdrawal occurs in over 50% of PICU patients and in 60% of all PICUs. Risk of withdrawal is over 50% after 5 days of continuous infusion or around the clock administration of an analgesic or sedative. Withdrawal can complicate medical treatment, increase morbidity, as well as prolong hospitalization. Although there is no gold standard tool to measure withdrawal symptoms, one tool that has been validated in children is the Withdrawal Assessment Tool (WAT-1) (table 4). Strategies for treatment of withdrawal include gradual wean of medications, use of adjunctive agents, such as dexmedetomidine, and conversion to long acting enteral medications (i.e. methadone, clonidine, lorazepam). (12)
Pain and Sedation Assessment Tools It is important to have a method of assessing response to treatment during the escalation phase as well as weaning phase of sedation and analgesia management in the ICU. There are numerous pain and sedation assessment tools available to monitor response to therapy. Some of the common tools are outlined below. State Behavioral Scale (SBS) is a sedation assessment instrument for infants and children on mechanical ventilation, which is a description of sedation-agitation continuum as measured by response to voice, gentle touch, and noxious stimuli. The scale ranges from -3 (unresponsive) to +2(agitated). (Table 1) (25)
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Face, Legs, Activity, Cry, Consolability behavior and pain assessment scale (FLACC) is validated for infants >34 weeks (Table 2). A score of 0-2 is given in each of the 5 categories. Total pain scores range from 0-10; 0-3 is indicative of mild pain; 4-6 moderate pain; and 7-10 severe pain. (26,27) The original COMFORT scale was validated as a measure for distress in ventilated pediatric ICU patients using physiologic parameters in addition to behavioral categories. A score of 1-5 is assigned in each of 5 behavioral categories (alertness, facial tension, muscle tone, agitation, and movement) and 3 physiologic variables (heart rate, respiration, and blood pressure). The scores are summated for a total of 8 (deep sedation) to 40 (alert and agitated). (12) (Table 3) The COMFORT-B scale, validated for ventilated as well as non ventilated patients, consists of 6 variables: alertness, agitation, respiratory response (if ventilated) or crying (if spontaneously breathing), body movements, facial tension, and muscle tone. Each category receives a rating of 1-5 and the individual scores are summated, for a total score of 6-30. A score of 17 or higher correlates with pain and requires intervention. (28) Withdrawal Assessment Tool (WAT-1) is an 11 item symptom assessment of opioid and benzodiazepine withdrawal focusing on motor, behavioral state, autonomic disturbances, and gastrointestinal symptoms. WAT-1 has been studied and validated in a multicenter prospective trial by Franck and Curley. (Table 4) Scoring begins on the first day of weaning, and is performed twice daily. Scores range from 0-12 and a score of 3 or higher had best sensitivity and specificity of clinically significant withdrawal. (24)
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Weaning Strategies Weaning sedation is another critical period in the care of the critically ill child. As is the case with initiation and escalation of sedation and analgesia, there is no clear evidenced based method to wean sedation. It is important to use one of the validated withdrawal assessment tools to aid in determining pace of wean for each patient. The weaning strategy described below is an example of a weaning strategy at the author’s institution. Infusions administered for less than 5 days are discontinued. WAT-1 scoring is performed to monitor for withdrawal. Infusions administered for greater than 5 days are weaned. If weaning for extubation, continuous infusions administered for 5-10 days are reduced by 50% if SBS score is less than target. Continuous infusions administered for greater than 10 days are reduced by 25% if SBS is less than target. WAT-1 scoring is performed after sedation weans, and rescue boluses administered for high WAT-1 scores (usually above 4). If safety or comfort issues prevent weaning for extubation, transitioning through extubation with propofol or dexmedetomidine infusion is considered. Propofol infusions are used for a maximum of 12 hours due to the risk of PRIS. After starting dexmedetomidine or propofol, opioid and benzodiazepine are weaned by 25-50%. In the post extubation period, opioid and benzodiazepine infusions are weaned every 8 hours by 10-20% of the original dose. WAT-1 scoring is completed, with goal score less than 5. If WAT-1 scores are greater than 5 and weaning is not possible, then rescue doses of opioid or benzodiazepine are given and adding a clonidine patch and/or transitioning to intermittent methadone and/or lorazepam is considered.
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Long term weaning is necessary after 10 days of continuous infusions. In patients that are predicted to have long-term intubation requirements, adjuvant medications can be initiated early to avoid not only the rapid escalation of medication, but also to aid in weaning in the long-term pathway. A multi-institutional prospective observational study evaluating opioid analgesia in pediatric ventilated patients demonstrated prolonged opioid exposure was associated with a doubling of opioid dose. Use of a sedation protocol was associated with reduced variability of opioid dosing. (29) Methadone has been used in the pediatric population for opioid weaning. Equivalent dosing of methadone divided every 6 hours is used for initial conversion of morphine infusions. Lorazepam is also used in intermittent dosing to reduce midazolam infusion requirements. (30)
Sample Sedation Algorithms
The literature supports sedation and analgesia algorithms in neonatal and pediatric intensive care units, however there is no consensus as to the agents or protocol to implement. The figures at the end of this chapter are examples of sedation and analgesia algorithms used at a high volume tertiary care center. They are meant for general suggestions for algorithms to follow, not absolute recommendations, as they have not been validated scientifically. Figure 1: NICU sedation & analgesia algorithm Figure 2: PICU short term extubation algorithm for anticipated intubation <3 days
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Figure 3: PICU long term extubation algorithm for anticipated intubation >3 days and/or chemically paralyzed Figure 4: NICU/PICU titration algorithm
Conclusion This chapter highlighted the common sedative and analgesics used in neonatal and pediatric intensive care units. Although sedation and analgesia algorithms have been used in neonatal and pediatric intensive care units, there is no consensus as to the specific agents or protocol to implement. It is important, however, to be mindful of the impact of sedation on morbidity and mortality. Prolonged sedation is associated with increased procedures, acquired neuromuscular disorders, length of mechanical ventilation, ICU length of stay and adverse events. Additionally, the effect of prolonged sedation on the developing brain is unclear. Therefore, it is recommended to establish and follow a sedation and analgesia algorithm for children in the intensive care unit. The information contained in this chapter is meant as a guideline for use. The following algorithms are general frameworks to assist in sedation and analgesia management however they may be individualized for each patient or for institutional protocols. In difficult cases, further assistance from pain treatment services may be helpful in guiding sedation and analgesia regimens.
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References
1. Cote CJ, Wilson S, et al. Guidelines for monitoring and management of pediatric patients during and after sedation for diagnostic and therapeutic procedures: an update. Pediatrics 2006; 118(6): 2587-2602 2. Vitali SH, Camerota AJ, Arnold JA. Anesthesia and analgesia in the neonate, in MacDonald MG, Seshia MM, Mullett MD (eds): Avery’s Neonatology. 6th edition. Philadelphia, PA, Lippincott Williams & Wilkins, 2005, pp 1557-1567 3. Anand KJ, Willson DF, Berger J, et al. Tolerance and withdrawal from prolonged opioid use in critically ill children. Pediatrics 2010; 125(5): e1208-1225 4. Deeter KH, King MA, Ridling D, et al. Successful implementation of a pediatric sedation protocol for mechanically ventilated patients. Critical Care Med 2011; 39(4): 683-688 5. Grant MJ, Scoppettuolo LA, Wypij D, Curley MA. Prospective evaluation of sedation related adverse events in pediatric patients ventilated for acute respiratory failure. Critical Care Medicine 2012; 40(4): 1317-1323 6. Randolph AG, Wypij D, Venkataraman ST, et al. Effect of mechanical ventilator weaning protocols on respiratory outcomes in infants and children. JAMA 2002; 288(20): 2561-2568 7. Payen V, Jouvet P, Lacroix J, et al. Risk factors associated with increased length of mechanical ventilation in children. Pediatric Critical Care Medicine 2012; 13(2): 152157
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8. Lucas da Silva, PS, Brunow de Carvalho W. Unplanned extubation in pediatric critically ill patients: a systematic review and best practice recommendations. Pediatric Critical Care Medicine 2010; 11(2): 287-294 9. Hartman, ME, McCrory DC, Schulman SR. Efficacy of sedation regimens to facilitate mechanical ventilation in the pediatric intensive care unit: a systematic review. Pediatric Critical Care Medicine 2009; 10(2): 246-255 10. Yu D, Liu B. Developmental anesthetic neurotoxicity: from animals to humans? J Anesth. 2013; 27: 750-756 11. Attarian S, Tran LC, Moore A, et al. The neurodevelopmental impact of neonatal morphine administration. Brain Sci 2014; 4: 321-334 12.Yaster, M, Easley RB, Brady KM. Pain and Sedation management in the critically ill child, in Nichols (ed): Rogers Textbook of Pediatric Intensive Care 4th Edition, Philadelphia, PA, Lippincott Williams & Wilkins, 2008, pp 136-164 13. Poss WB. Analgesia and sedation and the use of neuromuscular blocking agents, in Shanley TP (ed): Pediatric Multiprofessional Critical Care Review, Mount Prospect, IL, Society of Critical Care Medicine, 2008, pp 249-254 14. Berde CB, Sethna NF. Analgesics for the treatment of pain in children. NEJM 2002; 347(14): 1094-1103 15. Carney L, Kendrick J, Carr R. Safety and effectiveness of dexmedetomidine in the pediatric intensive care unit (SAD-PICU). Can J Hosp Pharm 2013; 66(1): 21-27 16. Hoy SM, Keating GM. Dexmedetomidine. Drugs 2011; 71(11): 1481-1501. 17. Wheeler, DS, Vaux KK, Ponaman ML, et al. The safe and effective use of propofol sedation in children undergoing diagnostic and therapeutic procedures: experience in a
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pediatric ICU and a review of the literature. Pediatric Emergency Care 2003; 19(6): 385392 18. Fudickar A, Bein B. Propofol infusion syndrome: update of clinical manifestation and pathophysiology. Minerva Anest 2009; 75: 339-344 19. Lam F, Bhutta AT, Tobias JD, et al. Hemodynamic effects of dexmedetomidine in critically ill neonates and infants with heart disease. Pediatr Cardiol 2012; 33: 1069-1077 20. Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med 2013; 41: 263-306 21. Poh YN, Poh PF, Buang SN, Lee JH. Sedation guidelines, protocols, and algorithms in PICUs: a systematic review. Ped Crit Care Med 2014; Epub 1-8 22. Verlaat CWM, Heesen GP, Vet NJ, et al. Randomized controlled trial of daily interruption of sedatives in critically ill children. Ped Anesth 2014; 24: 151-156 23. Gupta K, Gupta VK, Muralindharan J, Singhi S. Randomized controlled trial of interrupted versus continuous sedative infusions in ventilated children. Pediatric Critical Care Med 2012; 13(2): 131-135. 24. Franck LS, Harris SK, Soetenga DJ, et al. The Withdrawal Assessment Tool – Version 1 (WAT-1): an assessment instrument for monitoring opioid and benzodiazepine withdrawal symptoms in pediatric patients. Pediatric Critical Care Med 2008; 9(6): 573580 25. Curley MA, Harris SK, Fraser KA, et al. State Behavioral Scale (SBS) A sedation assessment instrument for infants and young children supported on mechanical ventilation. Pediatric Critical Care Med 2006; 7(2): 107-114
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26. Voepel-Lewis T, Merkel S, Tait AR, et al. The reliability and validity of the Face, Legs, Activity, Cry, Consolability observational tool as a measure of pain in children with cognitive Impairment. Anesth Analg 2002; 95:1224-1229 27. Ahn Y, Jun Y. Measurement of pain-like response to various NICU stimulants for high-risk infants. Early Human Development 2007; 83: 255-262 28. Boerlage AA, Ista E, Duivenvoorden HJ, et al. The COMFORT behavior scale detects clinically meaningful effects of analgesic and sedative treatment. European J of Pain 2014; Epub. 1-7 29. Anand KJS, Clark AE, Willson DF, et al. Opioid analgesia in mechanically ventilated children: Results from the multicenter MOTIF study. Pediatr Crit Care Med 2013; 14(1): 27-36 30. Jeffries SA, McGloin R, Pitfield AF, and Carr RR. Use of methadone for prevention of opioid withdrawal in critically ill children. Can J Hosp Pharm 2012; 65(1): 12-18
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Table 1. State Behavioral Score (SBS) Score -3
Description Unresponsive
-2
Responsive to noxious stimuli
-1
Responsive to gentle touch or voice
0
Awake and able to calm
+1
Restless and difficult to calm
+2
Agitated
Definition No spontaneous respiratory effort No cough or coughs only with suctioning No response to noxious stimuli Does not move Spontaneous yet supported breathing Coughs with suctioning Responds to noxious stimuli Occasional movement of extremities or shifting of position Spontaneous but ineffective non supported breaths Coughs with suctioning/repositioning Responds to touch/voice Able to pay attention but drifts off after stimulation Distresses with procedures Able to calm with comforting touch or voice when stimulus is removed Spontaneous and effective breathing Coughs when repositioned/occasional spontaneous cough Responds to voice/no external stimulus is required to elicit response Spontaneously pays attention to care provider Able to calm with comforting touch or voice when stimulus removed Spontaneous effective breathing/having difficulty breathing with ventilator Responds to voice/no external stimulus is required to elicit response Intermittently unsafe Does not consistently calm despite 5 minute attempt Restless, squirming May have difficulty breathing with ventilator Coughing spontaneously No external stimulus required to elicit response Spontaneously pays attention to care provider Unsafe (biting ETT, pulling at lines) Unable to console Increased movement (restless, squirming, or thrashing side to side, kicking legs)
Curley MA, Harris SK, Fraser KA, et al. State Behavioral Scale (SBS) A sedation assessment instrument for infants and young children supported on mechanical ventilation. Pediatric Critical Care Med 2006; 7(2): 107114
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Table 2. FLACC Behavioral Pain Assessment Tool Category
Description
Face
0 - no particular expression or smile 1 - occasional grimace/frown, withdrawn or disinterested 2 - frequent/constant quivering chin, clenched jaw
Legs
0 - Normal position or relaxed 1 – uneasy, restless, tense 2 – kicking or legs drawn up
Activity
0 – lying quietly, normal position, moves easily 1 – squirming, shifting back and forth, tense 2 – arched, rigid or jerking
Cry
0 – no cry 1 – moans or whimpers 2 – crying steadily, screams or sobs
Consolability
0 – content and relaxed 1 – reassured by occasional touching,being talked to, distractible 2 – difficult to console or comfort
Score (0-2)
Voepel-Lewis T, Merkel S, Tait AR, et al. The reliability and validity of the Face, Legs, Activity, Cry, Consolability observational tool as a measure of pain in children with cognitive Impairment. Anesth Analg 2002; 95:1224-1229
24 Table 3. COMFORT Scale Scor
Alertnes
Agitation
Respirator
Physical
Muscle
Facial
Mean
e
s
/
y Response
Movement
Tone
Tension
Arterial
Calmness
Heart rate
blood pressure
1
Deeply
Calm
asleep
2
No cough
No
Totally
Totally
Any low
Any
or
spontaneou
relaxed, no
relaxed
observation
observation
spontaneou
s
tone
s respiration
movement
low
Lightly
Slightly
Spontaneou
Occasional
Reduced
Normal
All 6
All 6
asleep
anxious
s
slight
tone
tone, no
observation
observation
respiration,
movement
tension
s within
s within
baseline
baseline
minimal response to ventilator 3
Drowsy
Anxious
Occasional
Frequent,
Normal
Tension
1-3
1-3
cough or
slight
tone
in some
observation
observation
resistance
movement
facial
s high
s high
to ventilator 4
muscles
Fully
Very
Actively
Vigorous
Increased
Tension
4-5
4-5
awake
anxious
breathes
movement
tone with
throughou
observation
observation
against
of
flexion of
t facial
s high
s high
ventilator
extremities
fingers/toe
muscles
and alert
s 5
Hyperalert
Panicky
Fights
Vigorous
Extreme
Facial
All 6
All 6
ventilator,
movement
rigidity
muscles
observation
observation
coughing or
including
and
contorted
s high
s high
choking
head/torso
flexion of
and
fingers/toe
grimacing
s
25 Boerlage AA, Ista E, Duivenvoorden HJ, et al. The COMFORT behavior scale detects clinically meaningful effects of analgesic and sedative treatment. European J of Pain 2014; Epub. 1-7
26
Table 4. Withdrawal Assessment Tool Version 1 (WAT -1) Information from patient record in previous 12 hours
Score
Any loose/watery stools (No= 0; Yes = 1) Any vomiting/wretching/gagging (No= 0; Yes = 1) Temperature >37.8 ‘C (No= 0; Yes = 1) 2 minute pre-stimulus observation State SBS/= +1 or awake/distressed = 1 Tremor none/mild = 0; moderate/severe = 1 Any sweating (No= 0; Yes = 1) Uncoordinated/repetitive movement none/mild = 0 moderate/severe = 1 Yawning or sneezing none or 1 = 0 >/= 2 = 1 1 minute stimulus observation Startle to touch none/mild = 0 moderate/severe = 1 Muscle tone normal = 0 Increased =1 Post – stimulus recovery Time to gain calm state (SBS 5 min = 2 Total score (0-12) Curley MA, Harris SK, Fraser KA, et al. State Behavioral Scale (SBS) A sedation assessment instrument for infants and young children supported on mechanical ventilation. Pediatric Critical Care Med 2006; 7(2): 107114
27 Figure 1. NICU ANALGESIA AND SEDATION ALGORITHM
Pain
PLUS
Fentanyl 2mcg/kg dose IV or morphine 0.02mg/kg/dose IV q 15 minutes until pain controlled
Exhibiting signs of discomfort despite multiple bolus dosing (as assessed by FLACC or PIPP scale)
fentanyl infusion 2-5mcg/kg hr IV or Morphine 0.02-0.1 mg/kg/hr IV
Exhibiting signs of discomfort requiring rescue prn bolus dose equal to total of 1 hour infusion dose
Acetaminophen 15 mg/kg PR for 72 hours >44 weeks q4h 33-44 weeks q8h 28-32 weeks q12h
Agitation
Midazolam 0.03-0.1mg/kg/dose IV q1h prn
Exhibiting signs of agitation despite bolus dosing
midazolam infusion 0.03-0.1 mg/kg IV >3 nonprocedural boluses in 8 hours or >1 bolus dose in 1 hour
>3 nonprocedural boluses in 8 hours or >1 bolus dose in 1 hour
Increase infusion and bolus doses by 10% Increase infusion and bolus doses by 10%
28 Figure 2. PICU SHORT TERM EXTUBATION ALGORITHM (<3 days) Pain
Agitation
Morphine 0.05-0.1mg/kg/dose IV q2h prn
Exhibiting signs of discomfort requiring rescue boluses
Morphine 0.05 mg/kg/dose IV q2h prn
Midazolam 0.05-0.1mg/kg/dose IV q1h prn
Exhibiting signs of agitation requiring rescue boluses
Midazolam 0.05 mg/kg/dose IV q1h prn
>3 non procedural boluses in 8hrs
>3 non procedural boluses in 8hrs
Increase bolus dose to Morphine 0.15-0.2 mg/kg/dose IV q2h
Increase bolus dose to midazolam 0.15-0.2 mg/kg IV q1h
Unable to capture despite increase in sedation boluses, Consider additional agent to avoid further escalation:
Dexmedetomidine gtt 0.2- 2 mg/kg/h
29 Figure 3.PICU LONG TERM EXTUBATION ALGORITHM (>3 days or chemically paralyzed)
Morphine 0.05 mg/kg/hr IV to maintain comfort
AND
Exhibiting signs of discomfort requiring rescue boluses
Midazolam 0.05 mg/kg/hr IV to reduce physiologic stress and anxiety
Exhibiting signs of agitation requiring rescue boluses
Morphine 0.05 mg/kg/dose IV q1h prn
Midazolam 0.05 mg/kg/dose IV q1h prn
>3 non procedural boluses in 8hrs or SBS greater than target
Increase infusion of narcotic or benzodiazepine by 10%
>3 non procedural boluses or SBS > target
Increase other infusion by 10%
Repeat if >3 non procedural boluses in 8hrs or SBS > target
Consider clonidine patch or dexmedetomidine infusion if continuing to escalate on infusions without adequate sedation
30 Figure 4. NICU/PICU TITRATION ALGORITHM No longer actively resuscitating, weaning ventilator or plateaued
Titrate narcotic and benzodiazepine infusions for minimum effective dose
<3 non procedural boluses in 8hrs
Decrease infusion of narcotic by 10%
SBS goal maintained
Decrease benzodiazepine infusion by 10%
No procedural boluses within 8 hrs
Transition midazolam to intermittent lorazepam
3 or more non procedural boluses in 8hrs
Start methadone (1/4 of hourly morphine infusion as methadone dose q4h)
Sedation and analgesia in the ICU Jill Zalieckas MD, MPH, Christopher Weldon MD, PhD
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PII: DOI: Reference:
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Seminars in Pediatric Surgery
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Cite this article as: Jill Zalieckas MD, MPH, Christopher Weldon MD, PhD, Sedation and analgesia in the ICU, Seminars in Pediatric Surgery, http://dx.doi.org/ 10.1053/j.sempedsurg.2014.11.011 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
#8 SEDATION AND ANALGESIA IN THE ICU
Jill Zalieckas, MD, MPH Boston Children’s Hospital 300 Longwood Avenue Boston, MA 02115
Christopher Weldon, MD, PhD Boston Children’s Hospital 300 Longwood Avenue Boston, MA 02115 Corresponding Author: Christopher Weldon MD PhD Children's Hospital Boston 300 Longwood Ave, Fegan 3 Boston MA 02115 Work Phone: (617) 355-4503 Fax: (617) 730-0477 [email protected]
2
Abstract
The alleviation of pain and anxiety is an important component of caring for the critically ill child. Sedation and analgesia regimens are utilized as adjuncts to procedures, facilitate mechanical ventilation, and assist with management of the critically ill child. Although sedation regimens have been used extensively across intensive care units, the data are lacking as to the best drugs, dosing, regimens, and short- and long-term safety profiles for use in the pediatric population. Sedation regimens continue to be a challenging aspect of the care of the critically ill child, and they have been associated with significant morbidity in this population. The following chapter will discuss the sedative use in the intensive care unit, morbidity associated with sedatives and analgesics, and the importance of establishing sedation and analgesia algorithms to reduce morbidity and mortality. Keywords: sedation, analgesia, intensive care, morbidity
3
Introduction
The alleviation of pain and anxiety is an important component of caring for the critically ill infant and child. Children in the intensive care unit require sedation and analgesia as adjuncts to procedures, facilitate mechanical ventilation, and assist with post operative management and care. The goals of sedation are to ensure the patient’s safety, minimize physical discomfort and pain, control anxiety, minimize psychological trauma, and control behavior and movement.(1) Adequate sedation and analgesia also have benefits of reducing the stress response and catabolism associated with surgery (2). The approach to sedation and analgesia management has implications for a child’s overall hospital course in the intensive care unit. Specifically, ventilator days, ICU length of stay, risk of nosocomial infections, unplanned extubation, and risk of withdrawal are all morbidities that are increased with prolonged or ineffective sedation regimens (3,4). The following chapter outlines the impact of sedation regimens on morbidity in neonatal and pediatric ICUs and highlights the various pharmacologic agents commonly used for sedation and analgesia in the intensive care unit.
Impact of Sedation in the ICU Adult critical care literature highlights the importance of implementing a standard sedation/analgesia algorithm in order to reduce total sedative use and ICU morbidity. Sedation protocols may decrease morbidity, ICU length of stay, duration of mechanical ventilation, decreased duration of opioid and benzodiazepine infusion and total duration
4
of sedative exposure. (4) Several pediatric studies have also demonstrated the impact of sedation on a child’s ICU course. The RESTORE trial was a prospective evaluation of sedation related adverse events among 22 PICUs. Inadequate pain or sedation management comprised 70% of reported adverse events in mechanically ventilated patients. (5) The relationship between sedation regimens and mechanical ventilation has been examined in several studies. In the randomized control trial by Randolph et al, sedative use in the first 24 hours of weaning was found to strongly influence length of time on the ventilator and extubation failure in infants and children (6). Payen et al also found continuous intravenous sedation was an independent risk factor for prolonged mechanical ventilation after multivariate analysis (7). Sedation regimens can also impact unplanned extubations. Lucas, et al reviewed the role of sedation in unplanned extubations. They found a significant reduction in rates of unplanned extubation following institution of a sedation algorithm. (8) The best practice recommendations include establishment of a sedation protocol and regular assessment of level of sedation to help reduce the rates of unplanned extubations, however a specific algorithm or sedation assessment tool was not identified. (8) Hartman, et al published a systematic review of pediatric sedation regimens in the intensive care unit in Pediatric Critical Care Medicine. The primary objective was to identify and evaluate the quality of evidence supporting sedatives and sedation regimens commonly used in the PICU to facilitate mechanical ventilation. Thirty-nine studies were included in the review, representing 39 sedation algorithms and 20 scoring systems used to evaluate level of sedation. Although sedation regimens have been used
5
extensively across neonatal and pediatric intensive care units, the data are lacking as to the appropriate dosing, safety and protocols for use. (9) Use of sedation algorithms and focus on protocols for sedation are important to attempt to reduce the cumulative dose and duration of sedatives and analgesics used. Concerns regarding long term effects of analgesics and anesthetics have been illustrated in the literature. Animal studies have demonstrated opioids have caused neuroapoptosis and neurodevelopmental abnormalities. Other studies have suggested opioids increase apoptosis in human glial cells. The need to establish comprehensive sedation and analgesia protocols is essential to aid in reducing potential in hospital as well as developmental morbidity related to sedation and analgesia regimens. (10,11)
Opioids Opioids and benzodiazepines are traditionally used for sedation and analgesia in the intensive care unit. The CNS has 4 primary opioid receptors: μ, κ, δ, σ. μ agonists are most commonly used in pain management regimens. Opioids exert their clinical effects as a sedative and analgesic. Side effects include respiratory depression, nausea, vomiting, delayed gastric emptying, delayed intestinal motility, pruritus, constipation, miosis, tolerance, and physical dependence. Elimination half life is prolonged in neonates due to reduced hepatic activity and blood flow. Symptoms of opioid withdrawal include cramping, vomiting, diarrhea, tachycardia, hypertension, diaphoresis, restlessness, insomnia, movement disorders, reversible neurologic abnormalities, and seizures. (2,12,13)
6
Morphine is the most commonly used opioid in the intensive care unit to manage pain. Dosing begins at 0.05-0.1mg/kg for both intermittent dosing as well as continuous infusions. The peak effect is observed within 20 minutes of administration, with a duration of action from 2-7 hours. Morphine should be used with caution in neonates because the half life elimination is prolonged, up to 9 hours in preterm neonates. Neonates have a decreased GFR, which leads to an accumulation of morphine 6glucouronide, which is the active metabolite of morphine. Accumulation of morphine 6glucouronide can cause respiratory depression. In addition to neonates, patients with renal failure, cirrhosis, and septic shock, should have morphine administered cautiously, as these disease processes result in decrease clearance of morphine and its active metabolites. (12,13,14) Fentanyl is another commonly used opioid in the intensive care unit, especially among infants. Fentanyl is 100 times more potent than morphine, and typical initial doses are from 1-5 mcg/kg for both intermittent dosing as well as continuous infusion. Compared to morphine, fentanyl has: less hemodynamic effects; rapid onset, less than 1 minute; and brief duration of action, ranging from 30-45 minutes. One must be aware of the risk of glottic and chest wall rigidity following rapid infusion of fentanyl in doses >5mcg/kg. (12) Methadone, another opioid commonly used in the intensive care unit, is helpful to treat or wean opioid dependent patients. The full analgesic effect occurs 3-5 days from drug initiation. Methadone has a slow elimination with long duration of action. Its active metabolite is morphine. EKG monitoring is necessary with methadone use, as it is associated with prolonged QT syndrome and torsades de pointes. Methadone can also
7
have respiratory depressant effects. (12) Due to its properties, methadone is an important adjunct agent that can be used not only to wean opioid dependent patients, but also help prevent rapid escalation of opioid infusion in the long term sedation pathway. (12)
Benzodiazepines Benzodiazepines act by augmenting GABA (gamma amino butyric acid) transmission, which is an inhibitory neurotransmitter in the brain. Benzodiazepines have anxiolytic and amnestic properties but do not have analgesic effects. Clinical effects include decreased cerebral metabolism and blood flow, sedation, hypnosis, anxiolysis, anticonvulsant activity, anterograde amnesia, muscle relaxation, dose dependent respiratory depression, and decreased tidal volume. Use of benzodiazepines without opioid in presence of painful stimulus can cause hyperalgesia and agitation. Withdrawal symptoms include agitation, poor visual tracking, choreoathetoid and dyskinetic movements of face, tongue, and limbs, as well as depressed consciousness. (2,12) Midazolam, the most commonly used benzodiazepine, is short acting and rapidly crosses the blood brain barrier. The onset of action is achieved within 30 minutes and elimination half life is 6 hours. Typical dosing for sedation for mechanical ventilation ranges from 0.05-0.2mg/kg/hour. In addition to respiratory depression and hypotension, an additional side effect of midazolam is tolerance and withdrawal. In order to avoid dose escalation, lorazepam is another adjunct that can be used to avoid effects of tolerance and withdrawal. (12) Lorazepam can be used as an infusion or by intermittent dosing either intravenously or enterally. As an adjunct to midazolam infusion, lorazepam helps
8
prevent dose escalation because of its prolonged duration of action at 2-4 hours. Enteral lorazepam is twice as potent as intravenous administration, therefore making it an effective agent to use during sedation wean. One caution with IV lorazepam is the risk of elevated osmolar gap metabolic acidosis and renal toxicity due to the inclusion of polyethylene glycol in its formulation. Lorazepam should not be used in children less than 6 months of age because of this toxicity. (2,12)
Adjuvant Therapies α-2 agonists have sedative and analgesic properties and are used as adjuncts to traditional opioid and benzodiazepine therapy for the critically ill child. Clonidine can be administered via enteral or transdermal route. Enteral dosing is 5mcg/kg/day. Transdermal patches range 100-300mcg per patch, and are changed every 7 days. Abrupt discontinuation of clonidine can cause rebound hypertension. Transdermal patches are typically weaned off over a period of 2-3 weeks. (2,12) Dexmedetomidine is another α-2 agonist, which has sedative and analgesic properties. Dexmedetomidine is being used in the ICU for several indications: 1. Adjunct to opioid and benzodiazepine infusions to avoid continuous escalation; 2. Facilitating weaning of other medications in anticipation of extubation; and 3. Provide sedation for spontaneously breathing children. Dexmedetomidine is highly lipid soluble and has effects on the CNS to decrease sympathetic tone and stimulates central parasympathetic outflow. It induces natural REM sleep and is associated with rapid and easy arousal. The elimination half life is 2-3 hours. Typical infusion rates are 0.2-2 mcg/kg/hour. Bolus dosing can cause rapid, transient decrease in heart rates and increased blood pressure.
9
Dexmedetomidine has been shown to cause bradycardia, sinus arrhythmias, heart block, nausea and vomiting. Dexmedetomidine has been used increasingly as an adjunctive sedative agent in the ICU given it is short acting and has minimal respiratory depression. Withdrawal with dexmedetomidine can occur after as short as 24 hours. Withdrawal symptoms include hypertension, vomiting, diarrhea, anxiety, and seizure. (12,15,16,17) Propofol, an alkylphenol, is an IV general anesthetic used as sedative to facilitate short term mechanical ventilation and procedures. Propofol has dose-proportional sedative/anesthetic effects with rapid onset, within a minute of injection. The sedative effects dissipate quickly with discontinuation of the infusion. Propofol is a potent vasodilator and has negative ionotropic effects. Typical dosing includes initial bolus 1-2 mg/kg and infusion doses of 75-250 mcg/kg/minute. Propofol should not be used for prolonged infusion in children. Propofol infusion syndrome (PRIS) is the presence of acute bradycardia resistant to treatment, which progresses to asystole. Hallmarks of PRIS include lactic acidosis, fatty liver enlargement, oliguria, elevated serum urea, elevated serum potassium, rhabdomyolysis and myoglobinuria. PRIS is associated with a high mortality rate and occurs with high doses of propofol for a prolonged duration. Risk factors for development of propofol infusion syndrome are poor oxygen delivery, sepsis, cerebral injury and high propofol dosage. Children are at higher risk of developing PRIS due to the low glycogen storage content and dependence on fat metabolism. (12,17) Treatment of PRIS involves stopping propofol infusion immediately and stabilizing the hemodynamic parameters. A challenge is that bradycardia is often resistant to external pacing or catecholamines. Carbohydrate substitution, hemodialysis, or ECMO have been used in the acute management of PRIS. Given the high risk profile
10
of propofol infusion in children, it is not approved for prolonged sedation in the pediatric population. (18)
Managing Long Term Sedation and Analgesia Tolerance and dose escalation occur with benzodiazepine and opioid infusions. Providing optimal sedation and analgesia for prolonged durations can be challenging and require significant escalation of infusions. Several strategies can be employed to counter this issue. One is the use of adjuvant agents, namely α2 agonists. Dexmedetomidine has been used to improve sedation and analgesia in critically ill children. This has been used in burn patients, children recovering from cardiac surgery, as well as the general pediatric critically ill patient. Lam, et al published a retrospective series to evaluate the hemodynamic effects and safety of dexmedetomidine in critically ill infants with congenital heart disease. This study demonstrated that dexmedetomidine infusion was safe from a hemodynamic standpoint, and may aid in reducing vasopressors in children with catecholamine refractory shock. Although dexmedetomidine causes a decrease in heart rate, MAP, and CVP, all children in this study remained hemodynamically stable without dose escalation of vasopressors. (19) Daily Sedation Interruptions Clinical practice guidelines exist for the management of pain, agitation and delirium in adult patients in the intensive care unit as developed by a multi-institutional task force within the American College of Critical Care Medicine. A multidisciplinary approach to establish and use sedation and analgesia protocols is recommended in the ICU. Specific recommendations include daily sedation interruption or a light target level
11
of sedation for adult mechanically ventilated patients.
Multiple RCTs in adults have
shown benefits of sedation holidays in decreasing ICU and hospital LOS. (20) Such guidelines do not exist in the pediatric population. Sedation protocols and sedation scales are associated with shorted time on mechanical ventilator, decreased ICU and hospital LOS as well as decreased delirium and long term cognitive dysfunction. Numerous studies have supported these findings. (20) A review conducted by Poh et al to evaluate the impact of sedation guidelines, protocols and algorithms on outcomes in pediatric ICUs determined that while there is limited data to guide practice, the presence of sedation guidelines and algorithms may decrease ICU LOS and medication dose, duration, and withdrawal. (21) Verlaat, et al report results of a randomized controlled trial of daily interruption of sedatives in the pediatric population. In this trial, sedatives were stopped daily and restarted when COMFORT-B score was ≥17 at the previously used infusion rate. This study resulted in decreased ventilator days, ICU length of stay, and lower use of morphine and midazolam in the intervention group. (22) A systematic review of sedation regimens in pediatric intensive care units performed by Hartman et al. found that the data are lacking in the pediatric literature to guide practice. As opposed to the adult literature, there is no standardization of care, resulting in limited data in the pediatric population. Therefore, a multi-institutional study is needed to answer questions on sedation and analgesia in the pediatric ICU, provide a thorough understanding of the options available, and establish an algorithm to drive practice. (9)
12
Gupta, et al. published a randomized control trial of interrupted versus continuous sedative infusions in ventilated children, which examined the duration of mechanical ventilation, ICU LOS, days awake on sedative infusions, frequency of adverse events, total dose of sedatives and cost analysis. The daily interruptions involved discontinuing the sedative infusion every morning until the patient became fully awake or agitated or uncomfortable. At that point, the infusion was restarted at 50% less than the previous dose, and titrated for sedation. The intervention began 48 hours after intubation. Significant findings were decreased days on mechanical ventilation, ICU LOS, and total cost of sedation with daily interruptions. The percentage of awake days was significantly increased with daily interruptions. There was no significant difference in adverse events between groups, specifically no difference in unplanned extubations. (23)
Tolerance and Withdrawal Tolerance is receptor desensitization causing decreasing clinical effects after prolonged exposure due to upregulation of the cAMP pathway. Duration of therapy impacts the development of tolerance. Additionally, it is reported that infants exposed to opioids during this period of rapid brain development may develop long term tolerance. Shorter acting opioids can produce greater tolerance. Approaches to address tolerance include dose escalation, use of longer acting opioids, such as methadone, or addition of non opioid analgesics, such as dexmedetomidine or clonidine. (3,24) Dependence is the physiologic and biochemical adaptation of neurons, such that removing a drug precipitates withdrawal, which generally occurs after 2-3 weeks of continuous use. Dependence and withdrawal can lead to significant morbidity in critically
13
ill patients. Withdrawal is the clinical syndrome that develops after stopping or reversing a drug after prolonged exposure to that drug. Symptoms are evident within 24 hours of drug cessation and peak within 72 hours. Opioid withdrawal occurs in over 50% of PICU patients and in 60% of all PICUs. Risk of withdrawal is over 50% after 5 days of continuous infusion or around the clock administration of an analgesic or sedative. Withdrawal can complicate medical treatment, increase morbidity, as well as prolong hospitalization. Although there is no gold standard tool to measure withdrawal symptoms, one tool that has been validated in children is the Withdrawal Assessment Tool (WAT-1) (table 4). Strategies for treatment of withdrawal include gradual wean of medications, use of adjunctive agents, such as dexmedetomidine, and conversion to long acting enteral medications (i.e. methadone, clonidine, lorazepam). (12)
Pain and Sedation Assessment Tools It is important to have a method of assessing response to treatment during the escalation phase as well as weaning phase of sedation and analgesia management in the ICU. There are numerous pain and sedation assessment tools available to monitor response to therapy. Some of the common tools are outlined below. State Behavioral Scale (SBS) is a sedation assessment instrument for infants and children on mechanical ventilation, which is a description of sedation-agitation continuum as measured by response to voice, gentle touch, and noxious stimuli. The scale ranges from -3 (unresponsive) to +2(agitated). (Table 1) (25)
14
Face, Legs, Activity, Cry, Consolability behavior and pain assessment scale (FLACC) is validated for infants >34 weeks (Table 2). A score of 0-2 is given in each of the 5 categories. Total pain scores range from 0-10; 0-3 is indicative of mild pain; 4-6 moderate pain; and 7-10 severe pain. (26,27) The original COMFORT scale was validated as a measure for distress in ventilated pediatric ICU patients using physiologic parameters in addition to behavioral categories. A score of 1-5 is assigned in each of 5 behavioral categories (alertness, facial tension, muscle tone, agitation, and movement) and 3 physiologic variables (heart rate, respiration, and blood pressure). The scores are summated for a total of 8 (deep sedation) to 40 (alert and agitated). (12) (Table 3) The COMFORT-B scale, validated for ventilated as well as non ventilated patients, consists of 6 variables: alertness, agitation, respiratory response (if ventilated) or crying (if spontaneously breathing), body movements, facial tension, and muscle tone. Each category receives a rating of 1-5 and the individual scores are summated, for a total score of 6-30. A score of 17 or higher correlates with pain and requires intervention. (28) Withdrawal Assessment Tool (WAT-1) is an 11 item symptom assessment of opioid and benzodiazepine withdrawal focusing on motor, behavioral state, autonomic disturbances, and gastrointestinal symptoms. WAT-1 has been studied and validated in a multicenter prospective trial by Franck and Curley. (Table 4) Scoring begins on the first day of weaning, and is performed twice daily. Scores range from 0-12 and a score of 3 or higher had best sensitivity and specificity of clinically significant withdrawal. (24)
15
Weaning Strategies Weaning sedation is another critical period in the care of the critically ill child. As is the case with initiation and escalation of sedation and analgesia, there is no clear evidenced based method to wean sedation. It is important to use one of the validated withdrawal assessment tools to aid in determining pace of wean for each patient. The weaning strategy described below is an example of a weaning strategy at the author’s institution. Infusions administered for less than 5 days are discontinued. WAT-1 scoring is performed to monitor for withdrawal. Infusions administered for greater than 5 days are weaned. If weaning for extubation, continuous infusions administered for 5-10 days are reduced by 50% if SBS score is less than target. Continuous infusions administered for greater than 10 days are reduced by 25% if SBS is less than target. WAT-1 scoring is performed after sedation weans, and rescue boluses administered for high WAT-1 scores (usually above 4). If safety or comfort issues prevent weaning for extubation, transitioning through extubation with propofol or dexmedetomidine infusion is considered. Propofol infusions are used for a maximum of 12 hours due to the risk of PRIS. After starting dexmedetomidine or propofol, opioid and benzodiazepine are weaned by 25-50%. In the post extubation period, opioid and benzodiazepine infusions are weaned every 8 hours by 10-20% of the original dose. WAT-1 scoring is completed, with goal score less than 5. If WAT-1 scores are greater than 5 and weaning is not possible, then rescue doses of opioid or benzodiazepine are given and adding a clonidine patch and/or transitioning to intermittent methadone and/or lorazepam is considered.
16
Long term weaning is necessary after 10 days of continuous infusions. In patients that are predicted to have long-term intubation requirements, adjuvant medications can be initiated early to avoid not only the rapid escalation of medication, but also to aid in weaning in the long-term pathway. A multi-institutional prospective observational study evaluating opioid analgesia in pediatric ventilated patients demonstrated prolonged opioid exposure was associated with a doubling of opioid dose. Use of a sedation protocol was associated with reduced variability of opioid dosing. (29) Methadone has been used in the pediatric population for opioid weaning. Equivalent dosing of methadone divided every 6 hours is used for initial conversion of morphine infusions. Lorazepam is also used in intermittent dosing to reduce midazolam infusion requirements. (30)
Sample Sedation Algorithms
The literature supports sedation and analgesia algorithms in neonatal and pediatric intensive care units, however there is no consensus as to the agents or protocol to implement. The figures at the end of this chapter are examples of sedation and analgesia algorithms used at a high volume tertiary care center. They are meant for general suggestions for algorithms to follow, not absolute recommendations, as they have not been validated scientifically. Figure 1: NICU sedation & analgesia algorithm Figure 2: PICU short term extubation algorithm for anticipated intubation <3 days
17
Figure 3: PICU long term extubation algorithm for anticipated intubation >3 days and/or chemically paralyzed Figure 4: NICU/PICU titration algorithm
Conclusion This chapter highlighted the common sedative and analgesics used in neonatal and pediatric intensive care units. Although sedation and analgesia algorithms have been used in neonatal and pediatric intensive care units, there is no consensus as to the specific agents or protocol to implement. It is important, however, to be mindful of the impact of sedation on morbidity and mortality. Prolonged sedation is associated with increased procedures, acquired neuromuscular disorders, length of mechanical ventilation, ICU length of stay and adverse events. Additionally, the effect of prolonged sedation on the developing brain is unclear. Therefore, it is recommended to establish and follow a sedation and analgesia algorithm for children in the intensive care unit. The information contained in this chapter is meant as a guideline for use. The following algorithms are general frameworks to assist in sedation and analgesia management however they may be individualized for each patient or for institutional protocols. In difficult cases, further assistance from pain treatment services may be helpful in guiding sedation and analgesia regimens.
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References
1. Cote CJ, Wilson S, et al. Guidelines for monitoring and management of pediatric patients during and after sedation for diagnostic and therapeutic procedures: an update. Pediatrics 2006; 118(6): 2587-2602 2. Vitali SH, Camerota AJ, Arnold JA. Anesthesia and analgesia in the neonate, in MacDonald MG, Seshia MM, Mullett MD (eds): Avery’s Neonatology. 6th edition. Philadelphia, PA, Lippincott Williams & Wilkins, 2005, pp 1557-1567 3. Anand KJ, Willson DF, Berger J, et al. Tolerance and withdrawal from prolonged opioid use in critically ill children. Pediatrics 2010; 125(5): e1208-1225 4. Deeter KH, King MA, Ridling D, et al. Successful implementation of a pediatric sedation protocol for mechanically ventilated patients. Critical Care Med 2011; 39(4): 683-688 5. Grant MJ, Scoppettuolo LA, Wypij D, Curley MA. Prospective evaluation of sedation related adverse events in pediatric patients ventilated for acute respiratory failure. Critical Care Medicine 2012; 40(4): 1317-1323 6. Randolph AG, Wypij D, Venkataraman ST, et al. Effect of mechanical ventilator weaning protocols on respiratory outcomes in infants and children. JAMA 2002; 288(20): 2561-2568 7. Payen V, Jouvet P, Lacroix J, et al. Risk factors associated with increased length of mechanical ventilation in children. Pediatric Critical Care Medicine 2012; 13(2): 152157
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8. Lucas da Silva, PS, Brunow de Carvalho W. Unplanned extubation in pediatric critically ill patients: a systematic review and best practice recommendations. Pediatric Critical Care Medicine 2010; 11(2): 287-294 9. Hartman, ME, McCrory DC, Schulman SR. Efficacy of sedation regimens to facilitate mechanical ventilation in the pediatric intensive care unit: a systematic review. Pediatric Critical Care Medicine 2009; 10(2): 246-255 10. Yu D, Liu B. Developmental anesthetic neurotoxicity: from animals to humans? J Anesth. 2013; 27: 750-756 11. Attarian S, Tran LC, Moore A, et al. The neurodevelopmental impact of neonatal morphine administration. Brain Sci 2014; 4: 321-334 12.Yaster, M, Easley RB, Brady KM. Pain and Sedation management in the critically ill child, in Nichols (ed): Rogers Textbook of Pediatric Intensive Care 4th Edition, Philadelphia, PA, Lippincott Williams & Wilkins, 2008, pp 136-164 13. Poss WB. Analgesia and sedation and the use of neuromuscular blocking agents, in Shanley TP (ed): Pediatric Multiprofessional Critical Care Review, Mount Prospect, IL, Society of Critical Care Medicine, 2008, pp 249-254 14. Berde CB, Sethna NF. Analgesics for the treatment of pain in children. NEJM 2002; 347(14): 1094-1103 15. Carney L, Kendrick J, Carr R. Safety and effectiveness of dexmedetomidine in the pediatric intensive care unit (SAD-PICU). Can J Hosp Pharm 2013; 66(1): 21-27 16. Hoy SM, Keating GM. Dexmedetomidine. Drugs 2011; 71(11): 1481-1501. 17. Wheeler, DS, Vaux KK, Ponaman ML, et al. The safe and effective use of propofol sedation in children undergoing diagnostic and therapeutic procedures: experience in a
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pediatric ICU and a review of the literature. Pediatric Emergency Care 2003; 19(6): 385392 18. Fudickar A, Bein B. Propofol infusion syndrome: update of clinical manifestation and pathophysiology. Minerva Anest 2009; 75: 339-344 19. Lam F, Bhutta AT, Tobias JD, et al. Hemodynamic effects of dexmedetomidine in critically ill neonates and infants with heart disease. Pediatr Cardiol 2012; 33: 1069-1077 20. Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med 2013; 41: 263-306 21. Poh YN, Poh PF, Buang SN, Lee JH. Sedation guidelines, protocols, and algorithms in PICUs: a systematic review. Ped Crit Care Med 2014; Epub 1-8 22. Verlaat CWM, Heesen GP, Vet NJ, et al. Randomized controlled trial of daily interruption of sedatives in critically ill children. Ped Anesth 2014; 24: 151-156 23. Gupta K, Gupta VK, Muralindharan J, Singhi S. Randomized controlled trial of interrupted versus continuous sedative infusions in ventilated children. Pediatric Critical Care Med 2012; 13(2): 131-135. 24. Franck LS, Harris SK, Soetenga DJ, et al. The Withdrawal Assessment Tool – Version 1 (WAT-1): an assessment instrument for monitoring opioid and benzodiazepine withdrawal symptoms in pediatric patients. Pediatric Critical Care Med 2008; 9(6): 573580 25. Curley MA, Harris SK, Fraser KA, et al. State Behavioral Scale (SBS) A sedation assessment instrument for infants and young children supported on mechanical ventilation. Pediatric Critical Care Med 2006; 7(2): 107-114
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26. Voepel-Lewis T, Merkel S, Tait AR, et al. The reliability and validity of the Face, Legs, Activity, Cry, Consolability observational tool as a measure of pain in children with cognitive Impairment. Anesth Analg 2002; 95:1224-1229 27. Ahn Y, Jun Y. Measurement of pain-like response to various NICU stimulants for high-risk infants. Early Human Development 2007; 83: 255-262 28. Boerlage AA, Ista E, Duivenvoorden HJ, et al. The COMFORT behavior scale detects clinically meaningful effects of analgesic and sedative treatment. European J of Pain 2014; Epub. 1-7 29. Anand KJS, Clark AE, Willson DF, et al. Opioid analgesia in mechanically ventilated children: Results from the multicenter MOTIF study. Pediatr Crit Care Med 2013; 14(1): 27-36 30. Jeffries SA, McGloin R, Pitfield AF, and Carr RR. Use of methadone for prevention of opioid withdrawal in critically ill children. Can J Hosp Pharm 2012; 65(1): 12-18
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Table 1. State Behavioral Score (SBS) Score -3
Description Unresponsive
-2
Responsive to noxious stimuli
-1
Responsive to gentle touch or voice
0
Awake and able to calm
+1
Restless and difficult to calm
+2
Agitated
Definition No spontaneous respiratory effort No cough or coughs only with suctioning No response to noxious stimuli Does not move Spontaneous yet supported breathing Coughs with suctioning Responds to noxious stimuli Occasional movement of extremities or shifting of position Spontaneous but ineffective non supported breaths Coughs with suctioning/repositioning Responds to touch/voice Able to pay attention but drifts off after stimulation Distresses with procedures Able to calm with comforting touch or voice when stimulus is removed Spontaneous and effective breathing Coughs when repositioned/occasional spontaneous cough Responds to voice/no external stimulus is required to elicit response Spontaneously pays attention to care provider Able to calm with comforting touch or voice when stimulus removed Spontaneous effective breathing/having difficulty breathing with ventilator Responds to voice/no external stimulus is required to elicit response Intermittently unsafe Does not consistently calm despite 5 minute attempt Restless, squirming May have difficulty breathing with ventilator Coughing spontaneously No external stimulus required to elicit response Spontaneously pays attention to care provider Unsafe (biting ETT, pulling at lines) Unable to console Increased movement (restless, squirming, or thrashing side to side, kicking legs)
Curley MA, Harris SK, Fraser KA, et al. State Behavioral Scale (SBS) A sedation assessment instrument for infants and young children supported on mechanical ventilation. Pediatric Critical Care Med 2006; 7(2): 107114
23
Table 2. FLACC Behavioral Pain Assessment Tool Category
Description
Face
0 - no particular expression or smile 1 - occasional grimace/frown, withdrawn or disinterested 2 - frequent/constant quivering chin, clenched jaw
Legs
0 - Normal position or relaxed 1 – uneasy, restless, tense 2 – kicking or legs drawn up
Activity
0 – lying quietly, normal position, moves easily 1 – squirming, shifting back and forth, tense 2 – arched, rigid or jerking
Cry
0 – no cry 1 – moans or whimpers 2 – crying steadily, screams or sobs
Consolability
0 – content and relaxed 1 – reassured by occasional touching,being talked to, distractible 2 – difficult to console or comfort
Score (0-2)
Voepel-Lewis T, Merkel S, Tait AR, et al. The reliability and validity of the Face, Legs, Activity, Cry, Consolability observational tool as a measure of pain in children with cognitive Impairment. Anesth Analg 2002; 95:1224-1229
24 Table 3. COMFORT Scale Scor
Alertnes
Agitation
Respirator
Physical
Muscle
Facial
Mean
e
s
/
y Response
Movement
Tone
Tension
Arterial
Calmness
Heart rate
blood pressure
1
Deeply
Calm
asleep
2
No cough
No
Totally
Totally
Any low
Any
or
spontaneou
relaxed, no
relaxed
observation
observation
spontaneou
s
tone
s respiration
movement
low
Lightly
Slightly
Spontaneou
Occasional
Reduced
Normal
All 6
All 6
asleep
anxious
s
slight
tone
tone, no
observation
observation
respiration,
movement
tension
s within
s within
baseline
baseline
minimal response to ventilator 3
Drowsy
Anxious
Occasional
Frequent,
Normal
Tension
1-3
1-3
cough or
slight
tone
in some
observation
observation
resistance
movement
facial
s high
s high
to ventilator 4
muscles
Fully
Very
Actively
Vigorous
Increased
Tension
4-5
4-5
awake
anxious
breathes
movement
tone with
throughou
observation
observation
against
of
flexion of
t facial
s high
s high
ventilator
extremities
fingers/toe
muscles
and alert
s 5
Hyperalert
Panicky
Fights
Vigorous
Extreme
Facial
All 6
All 6
ventilator,
movement
rigidity
muscles
observation
observation
coughing or
including
and
contorted
s high
s high
choking
head/torso
flexion of
and
fingers/toe
grimacing
s
25 Boerlage AA, Ista E, Duivenvoorden HJ, et al. The COMFORT behavior scale detects clinically meaningful effects of analgesic and sedative treatment. European J of Pain 2014; Epub. 1-7
26
Table 4. Withdrawal Assessment Tool Version 1 (WAT -1) Information from patient record in previous 12 hours
Score
Any loose/watery stools (No= 0; Yes = 1) Any vomiting/wretching/gagging (No= 0; Yes = 1) Temperature >37.8 ‘C (No= 0; Yes = 1) 2 minute pre-stimulus observation State SBS/= +1 or awake/distressed = 1 Tremor none/mild = 0; moderate/severe = 1 Any sweating (No= 0; Yes = 1) Uncoordinated/repetitive movement none/mild = 0 moderate/severe = 1 Yawning or sneezing none or 1 = 0 >/= 2 = 1 1 minute stimulus observation Startle to touch none/mild = 0 moderate/severe = 1 Muscle tone normal = 0 Increased =1 Post – stimulus recovery Time to gain calm state (SBS 5 min = 2 Total score (0-12) Curley MA, Harris SK, Fraser KA, et al. State Behavioral Scale (SBS) A sedation assessment instrument for infants and young children supported on mechanical ventilation. Pediatric Critical Care Med 2006; 7(2): 107114
27 Figure 1. NICU ANALGESIA AND SEDATION ALGORITHM
Pain
PLUS
Fentanyl 2mcg/kg dose IV or morphine 0.02mg/kg/dose IV q 15 minutes until pain controlled
Exhibiting signs of discomfort despite multiple bolus dosing (as assessed by FLACC or PIPP scale)
fentanyl infusion 2-5mcg/kg hr IV or Morphine 0.02-0.1 mg/kg/hr IV
Exhibiting signs of discomfort requiring rescue prn bolus dose equal to total of 1 hour infusion dose
Acetaminophen 15 mg/kg PR for 72 hours >44 weeks q4h 33-44 weeks q8h 28-32 weeks q12h
Agitation
Midazolam 0.03-0.1mg/kg/dose IV q1h prn
Exhibiting signs of agitation despite bolus dosing
midazolam infusion 0.03-0.1 mg/kg IV >3 nonprocedural boluses in 8 hours or >1 bolus dose in 1 hour
>3 nonprocedural boluses in 8 hours or >1 bolus dose in 1 hour
Increase infusion and bolus doses by 10% Increase infusion and bolus doses by 10%
28 Figure 2. PICU SHORT TERM EXTUBATION ALGORITHM (<3 days) Pain
Agitation
Morphine 0.05-0.1mg/kg/dose IV q2h prn
Exhibiting signs of discomfort requiring rescue boluses
Morphine 0.05 mg/kg/dose IV q2h prn
Midazolam 0.05-0.1mg/kg/dose IV q1h prn
Exhibiting signs of agitation requiring rescue boluses
Midazolam 0.05 mg/kg/dose IV q1h prn
>3 non procedural boluses in 8hrs
>3 non procedural boluses in 8hrs
Increase bolus dose to Morphine 0.15-0.2 mg/kg/dose IV q2h
Increase bolus dose to midazolam 0.15-0.2 mg/kg IV q1h
Unable to capture despite increase in sedation boluses, Consider additional agent to avoid further escalation:
Dexmedetomidine gtt 0.2- 2 mg/kg/h
29 Figure 3.PICU LONG TERM EXTUBATION ALGORITHM (>3 days or chemically paralyzed)
Morphine 0.05 mg/kg/hr IV to maintain comfort
AND
Exhibiting signs of discomfort requiring rescue boluses
Midazolam 0.05 mg/kg/hr IV to reduce physiologic stress and anxiety
Exhibiting signs of agitation requiring rescue boluses
Morphine 0.05 mg/kg/dose IV q1h prn
Midazolam 0.05 mg/kg/dose IV q1h prn
>3 non procedural boluses in 8hrs or SBS greater than target
Increase infusion of narcotic or benzodiazepine by 10%
>3 non procedural boluses or SBS > target
Increase other infusion by 10%
Repeat if >3 non procedural boluses in 8hrs or SBS > target
Consider clonidine patch or dexmedetomidine infusion if continuing to escalate on infusions without adequate sedation
30 Figure 4. NICU/PICU TITRATION ALGORITHM No longer actively resuscitating, weaning ventilator or plateaued
Titrate narcotic and benzodiazepine infusions for minimum effective dose
<3 non procedural boluses in 8hrs
Decrease infusion of narcotic by 10%
SBS goal maintained
Decrease benzodiazepine infusion by 10%
No procedural boluses within 8 hrs
Transition midazolam to intermittent lorazepam
3 or more non procedural boluses in 8hrs
Start methadone (1/4 of hourly morphine infusion as methadone dose q4h)