Document Title: PAEDIATRIC DEXMEDETOMIDINE INFUSIONS IN BURNS INTENSIVE CARE Document Reference/Register no: 15027 Version Number: 2.0 Document type: (Policy/ Guideline/ SOP) Guideline To be followed by: (Target Staff) Medical and Nursing staff, Burns ITU Ratification Issue Date: (Date document is uploaded onto the intranet) 14 th January 2019 Review Date: 13 th January 2022 Developed in response to: Best practice Review of local guidelines Contributes to HSC Act 2008 (Regulated Activities) Regulations 2014(Part 3); and CQC Regulations 2009 (Part 4) CQC Fundamental Standards of Quality and Safety: 9, 11 Issuing Division/Directorate: Burns and Plastics Author/Contact: (Asset Administrator) Dr Harish Bangalore, PICU Consultant Hospital Sites: (tick appropriate box/es to indicate status of policy review i.e. joint/ independent) MEHT BTUH SUH Consultation: (Refer to page 2) Approval Group / Committee(s): n/a Date: n/a Professionally Approved by: (Asset Owner) Ratification Group(s): Rebecca Martin, Burns ICU Consultant Documents Ratification Approval Group Chair s Action Date: 14 th December 2018 Date: 8 th January 2019 Executive and Clinical Directors (Communication of minutes from Document Ratification Group Date: January 2019 Distribution Method: Trust Intranet, Burns Reference Folder in Metavision
Consulted With: Post/ Approval Committee/ Group: Date: Joseph Hussey Burns ICU Consultant 14 th December 2018 Alison Felton Burns Pharmacist PICU Consultants Related Trust Policies (to be read in conjunction with) Document Review History: Version Authored/Reviewer: Summary of amendments/ Issue Date: No: Record documents superseded by: 1.0 Dr Saadia Mir 4 th January 2016 Dr Harish Bangalore 2.0 Dr Harish Bangalore Full review 14th January 2019 2
INDEX 1 Purpose 2. Equality Impact Assessment 3. Scope 4. Staffing and Training 5. Indications 6. Contraindications 7. Side Effects and Adverse Reactions 8. Overdosage 9. Published Use in the Paediatric Burns and Paediatric Intensive Care Population 10. Pharmacokinetics in children 11. Interactions 12. Precautions for Use 13. Drug Preparation 14. Dosage and Prescription 15. Compatibility 16. Infusion Regimen 17. Adjusting Other Sedatives 18. Stopping Dexmedetomidine 19. Audit 20. References 19. Appendix Appendix 1: Equality Impact Assessment Form 3
1. Purpose 1.1 To ensure safe practice in the use of Dexmedetomidine intravenous infusions for sedation of paediatric patients in the Burns Intensive Care Unit (ICU). 2. Equality Impact Assessment 2.1 The Trust is committed to the provision of a service that is fair, accessible and meets the needs of all individuals. (Refer to Appendix 1) 3. Scope 3.1 This clinical guideline is applicable to paediatric patients aged 1 month to 16 years requiring sedation on the Burns Intensive Care Unit (E220). 3.2 Dexmedetomidine is a sedative agent licensed for sedation in adult intensive care unit patients at a level not deeper than arousal in response to verbal stimulus. It is increasingly being used off-licence in the paediatric population and the paediatric burn population. 3.4 Dexmedetomidine is a highly selective alpha 2 receptor agonist which has approximately eight times the affinity for alpha-2 receptors than that of clonidine and has the advantage of being relatively free from respiratory depressant effects. 3.5 Dexmedetomidine can be used in paediatric patients irrespective of their mode of ventilation (invasive, non-invasive or self-ventilation). 4. Staffing and Training 4.1 This clinical guideline is for registered medical and nursing staff working within Burns ITU. 5. Indications 5.1 As an alternative to midazolam for sedation in overnight cases who will be ventilated for a short period of time (less than 48 hours). 5.2 As a bridge to extubation, where an attempt at decreasing sedation (especially in children on high dose sedation e.g. Midazolam > 4mcg/kg/min, Morphine >40 mcg/kg/hr) may risk unplanned extubation. Midazolam must be weaned after commencing dexmedetomidine, aiming for it to be stopped. 5.3 As an alternative to midazolam in children with ineffective sedation where delirium from benzodiazepines is suspected as the cause for rapid escalation or high dose requirements. Midazolam must be weaned after commencing dexmedetomidine, aiming for it to be stopped. 4
6. Contraindications 6.1 Previous allergy to dexmedetomidine or other alpha-2 agonists. 6.2 Second- or third-degree heart block. 6.3 Uncontrollable hypotension. 6.4 Acute cerebrovascular disorders. 7. Side Effects and Adverse Reactions 7.1 The most frequently reported adverse reactions ( 1/10) with dexmedetomidine are hypotension, hypertension and bradycardia, occurring in approximately 25%, 15% and 13% of adult patients respectively. 7.2 Other common ( 1/100 to <1/10) adverse effects include: hyperglycaemia, hypoglycaemia, agitation, myocardial ischaemia or infarction, tachycardia, nausea, vomiting, dry mouth, withdrawal syndrome, hyperthermia. 7.3 Uncommon ( 1/100 to <1/100) adverse effects include: metabolic acidosis, hypoalbuminaemia, hallucination, atrioventricular block, decreased cardiac output, dyspnoea, abdominal distention, thirst. 7.4 Most adverse effect data in children has been obtained from short term exposure. 8. Overdosage 8.1 Overdosage reactions are predominantly cardiovascular including hypo/hypertension and bradycardia. Deep sedation may also occur. 8.2 When overdosage is suspected, reduce or stop the infusion and treat the cardiovascular effects as clinically indicated. Cases of sinus arrest have reversed spontaneously or with administration of atropine/glycopyrrolate. 9. Published Use in the Paediatric Burns and Paediatric Intensive Care Population 9.1 In one of the largest paediatric observational studies, dexmedetomidine was used as an addition agent in 65 children with burns after failing to achieve adequate sedation with opioids and benzodiazepines. Initiated at a dose of 0.2mcg/kg/hour, the average duration of infusions was 11 days (range, 2-50) and the mean dose was 0.5mcg/kg/hour (range, 0.1-2). All patients achieved adequate sedation after initiation of dexmedetomidine and no significant hypotension or bradycardia was observed. 9.2 Lin et al described their experience of dexmedetomidine in eleven paediatric burn patients in a retrospective review covering three-years. It was used for initial sedation and as a sole agent in six patients, five of whom also received continuous 5
neuromuscular blockade. The median initial dose was 0.39 mcg/kg/hr (range, 0.1 1.16) median infusion dose 0.57 mcg/kg/hr (range, 0.11 1.17) and median duration was 40 hours (range, 1-356). No loading dose was given. In the majority of cases, other sedatives (mainly benzodiazepines) were either discontinued before or weaned off after starting dexmedetomidine only one case required increasing amounts of other sedatives. Opiate therapy continued. No adverse events or clinically significant rebound hypertension or tachycardia on withdrawal of the infusion was noted. 9.3 Fagin et al compared dexmedetomidine and midazolam for sedation in severe paediatric burn injury. Data on twenty-one children who received dexmedetomidine as the sole agent for sedation was retrospectively compared to children who had received midazolam the latter were handpicked to match the dexmedetomidine group according to age and TBSA burn injury. Nine had received midazolam infusions at some point (eight prior to starting dexmedetomidine and one after starting dexmedetomidine) but none received the two drugs simultaneously. Mean dose in the dexmedetomidine group was 0.44 mcg/kg/hour and mean dose in the midazolam group was 0.44mcg/kg/hour. Duration of treatment with dexmedetomidine was 22.5 days (range, 1-103) and with midazolam 20.1 days (range, 2-116). One patient had bradycardia directly attributable to dexmedetomidine and was resolved by reducing its dose. Thirteen patients were weaned off mechanical ventilation during the infusion. There was a trend for hypotensive episodes being more common in the midazolam group. There was no evidence of withdrawal symptoms in the dexmedetomidine group. 9.4 Czaja and Zimmerman performed a retrospective observational study on the use of dexmedetomidine in a general medical and surgical PICU. A dexmedetomidine infusion policy and protocol was in place within this unit. Only intubated patients received the drug although infusions could be maintained for up to 12 hours postextubation, infusions were initiated at 0.2mcg/kg/hour and increased at half-hour intervals to a maximum of 0.7mcg/kg/hr. No bolus doses were administered and infusions were allowed to continue for a full 48 hours before being held for 24-48 hours. Data from 121 patients were examined. The main indications were 1) to improve sedation during ventilation either as a sole agent or to facilitate a decrease in other medications and/or 2) to expedite extubation by allowing a decrease in other longer-acting sedatives. Mean dose was 0.55mcg/kg/hour (range, 0.15-0.7) and average duration was 25.8 hours (range, 20 min to 60 hr) infusions were discontinued without a taper. Hypotension requiring intervention occurred in 16% and bradycardia requiring intervention occurred in 12%, the latter responding in almost all to a decrease in the infusion rate. This study also demonstrated a decrease in the mean dose of benzodiazepines and opiates after the infusion by 42% and 36% respectively. 9.5 Chrysostomou et al retrospectively examined dexmedetomidine use in infants and neonates after cardiac surgery in a cardiac intensive care unit setting. It was started as an infusion at a dose of 0.1 1.25 mcg/kg/hour and was increased after twenty minutes by 0.1 0.3 mcg/kg/hr if sedation was inadequate. If after another twenty minutes sedation was still inadequate, a rescue agent was administered and the infusion was further increased to a maximum dose of 1.5 mcg/kg/hour. Boluses were administered on the physicians judgment. A total of 80 patients were examined. 25% had dexmedetomidine as the sole sedative/analgesic agent, around half required occasional rescue boluses and 27% required a fentanyl infusion. Mean starting dose 6
was 0.47 ± 0.29 mcg/kg/hour and mean maintenance dose was 0.66 ± 0.26 mcg/kg/hour with a mean duration of 25 ± 13 hours. Physician experience over time resulted in higher starting and maintenance doses in the last 40 patients with mean starting dose in this group being 0.6 ± 0.32 mcg/kg/hr and mean maintenance dose being 0.78 mcg/kg/hour. Hypotension occurred in 34% and bradycardia in 12.5%. 9.6 In a small randomised trial comprising of 30 patients, Tobias and Berkenbosch 12 demonstrated that the use of dexmedetomidine in paediatric ICU patients was superior to midazolam based on supplemental rescue dose requirements. They compared dexmedetomidine at two doses, 0.25 and 0.5 mcg/kg/hour with midazolam 0.22 mcg/kg/hour. At a dose of 0.25 mcg/kg/hour, dexmedetomidine was equivalent to midazolam and at the higher dose of 0.5 mcg/kg/hour, dexmedetomidine provided more effective sedation evidenced by fewer bolus doses of morphine, a decrease in 24hour supplemental morphine and a decrease in the total number of sedation assessment points outside the desired range. One patient was removed from the study because of bradycardia but there were no other adverse haemodynamic effects in the population. 10. Pharmacokinetics in Children 10.1 Dexmedetomidine exhibits a two-compartment disposition model. 10.2 Rapid redistribution half-life: ~ 7 minutes. 10.3 Elimination half-life:~2 hours (~1.5 hours in adults). 10.4 Volume of distribution: 1.5 2.2 L/kg (1.16-2.16 L/kg in adults). 10.5 Plasma clearance: 18.2 L/hr/70kg (term neonate), 42.1 L/kg/70kg (children), ~43 L/hour (adults). Clearance increases to reach 84.5% of the mature value by 1 year of age. 10.6 Protein binding: 94% (adults). 10.7 Metabolised in the liver to inactive metabolites. 10.8 The pharmacokinetics of dexmedetomidine are linear in adults in the dosing range 0.2 to 1.4 mcg/kg/hour and does not accumulate in treatments lasting up to 14 days. 11. Interactions 11.1 Co-administration with anaesthetics, sedatives, hypnotics and opioids is likely to lead to an enhancement of effects. 11.2 Enhanced hypotensive and bradycardic effects may be seen with other drugs that have these effects e.g. beta-blockers. 11.3 Dexmedetomidine has been shown to inhibit or induce some CYP450 enzymes invitro. An effect on drug substrates to these enzymes in-vivo cannot be excluded. The clinical significance of this is unknown. 7
12. Precautions for Use 12.1 Dexmedetomidine is not suitable in children with severe cardiovascular instability. 12.2 Dexmedetomidine reduces heart rate and blood pressure: continuous cardiac monitoring is required in all cases. 12.3 Hypotension may be greater in patients with pre-existing hypovolaemia or hypotension making children with burns a more vulnerable group: dose reduction, an intravenous fluid bolus or vasopressors may be required. DO NOT START DEXMEDETOMIDINE IF A CHILD IS HYPOVOLAEMIC AND/OR HYPOTENSIVE. 12.4 A loading dose is not recommended and is associated with increased adverse reactions. 12.5 Respiratory function must be monitored in non-intubated patients despite it being relatively free from respiratory depressant effects. 12.6 No dose adjustment is required for children with renal impairment. 12.7 Dexmedetomidine should be used with caution in children with hepatic impairment. 12.8 To avoid inadvertent dexmedetomidine bolusing, do not co-administer with any other drug infusion or fluid that may be bolused. 12.9 Some patients receiving dexmedetomidine have been observed to be arousable and alert when stimulated; this alone should not be considered as evidence of lack of efficacy. 13. Drug Preparation 13.1 Dexmedetomidine is available in the United Kingdom as Dexdor (Orion Pharma). 13.2 Dexmedetomidine is a clear, colourless solution available in 2ml, 4ml and 10ml vials containing 200 micrograms, 400 micrograms and 1000 micrograms of dexmedetomidine respectively. Each 1ml concentrate in any size vial contains 100 micrograms of dexmedetomidine. 13.3 Dexdor should be diluted to 4 micrograms/ml for intravenous infusion in children. 13.4 A 2ml ampoule containing 200 micrograms should be diluted with 48ml of 0.9% sodium chloride or 5% glucose to achieve the required concentration of 4 micrograms/ml. 13.5 Shake gently to mix well. Do not use if there is any particulate matter or discolouration. 13.6 Shelf life after dilution: chemical and physical in-use stability has been demonstrated for 24 hours at 25 o C. From a microbiological perspective, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to the 8
use are the responsibility of the user and would not normally be longer than 24 hours at 2-8 o C. 14. Dosage and Prescription 14.1 Do not use Dexmedetomidine as a bolus dose for sedation on the BITU. 14.2 Dosing and prescribing has been extrapolated using data from the paediatric burns population in conjunction with existing guidelines from a UK paediatric intensive care unit. 14.3 The dose range, within the scope of this clinical guideline, is 0.2-1.2 micrograms/kg/hour, delivered by a continuous intravenous infusion. 14.4 After dose adjustment, a new steady state sedation level may not be reached for up to one hour. 14.5 No dose adjustment is required for children with renal impairment. 14.6 Use with caution in children with hepatic impairment. 14.7 Clonidine should ideally be stopped before commencing dexmedetomidine. Caution must be taken in children on long-term clonidine due to the risk of cardiovascular rebound effects. In these special cases, consider continuing clonidine or tapering off slowly. 14.8 Baseline heart rate and blood pressure must be documented before commencing the infusion. 14.9 To prescribe the infusion: Drug Diluent Volume Calculate Rate of Infusion DEXMEDETOMIDINE 200 micrograms Sodium chloride 0.9% or Glucose 5% 50 mls 0.025 ml/kg/hour =0.1 micrograms/kg/hour ml/hour =0.2 1.2 micrograms/kg/hour 15 Compatibility 15.1 Dexdor is compatible when administered with the following: lactated Ringers, 5% glucose, 0.9% saline, 20% mannitol, thiopental sodium, etomidate, vecuronium bromide, pancuronium bromide, succinylcholine, atracurium besylate, mivacurium chloride, rocuromium bromide, glycopyrrolate bromide, phenylephrine hydrochloride, atropine sulphate, dopamine, noradrenaline, dobutamine, midazolam, morphine sulphate, fentanyl citrate, and a plasma-substitute. 15.2 Dexmedetomidine should not be bolused. It should not therefore be co-administered with any other drug infusion or fluid that may be bolused. 9
16. Infusion Regimen (intubated or non-intubated patients) 16.1 Dexmedetomidine infusion should be commenced only on the advice of a Burns ITU Consultant. 16.2 Dexmedetomidine infusion may be administered via peripheral or central venous access. 16.3 Baseline heart rate and blood pressure must be documented before commencing dexmedetomidine infusion. 16.4 Initiate infusion at 0.2mcg/kg/hr and titrate infusion by 0.1 0.3 mcg/kg/hr every halfhour to a maximum infusion rate of 1.2 mcg/kg/hr to achieve target sedation level (RASS 0 to -3). 16.5 If heart rate is less than 20% of baseline, request medical review and consider reducing the dexmedetomidine infusion by 25%. Consider atropine if life threatening bradycardia. 16.6 If mean arterial pressure (MAP) is less than 20% of baseline, request medical review and consider reducing the dexmedetomidine infusion by 25%. Consider fluid bolus +/- vasopressor if clinically indicated. 16.7 If satisfactory sedation level is not achieved with the maximum dose, consider alternative drugs. 17. Adjusting Other Sedatives 17.1 Benzodiazepines should be discontinued within as soon as possible at least within 24 hours for initiating Dexmedetomidine. 17.2 On commencing dexmedetomidine, benzodiazepine infusions should be weaned over 24 to 48 hours, unless prolonged use is suspected to lead to withdrawal symptoms, in which case existing protocols should be followed. 17.3 Opiate infusions should be continued for burn pain, although a dose reduction may be appropriate. 17.4 Clonidine should ideally be stopped prior to commencing dexmedetomidine. Caution must be taken in children on long-term clonidine due to the risk of cardiovascular rebound effects. In these special cases, consider continuing clonidine or tapering off slowly. 18. Stopping Dexmedetomidine 18.1 Dexmedetomidine may be continued during extubation, although a dose reduction may be appropriate. 10
18.2 When sedation is no longer required, dexmedetomidine infusion may be stopped without a taper. If preferred, after prolonged treatment, the infusion may be reduced over 12-24 hours. 18.3 Do not alter the infusion rate of dexmedetomidine during routine daily sedation holds. 19. Audit 19.1 The use of this guideline will be monitored by review of any reported incidents and annual audit. 19.2 Any significant complications related to dexmedetomidine infusions will be reviewed at the monthly Burns Mortality and Morbidity meetings and the minutes distributed to the Burns MDT. 20. References Plambech MZ, Afshari A. Dexmedetomidine in the pediatric population: a review. Minerva Anestesiologica 2015;81(3): 320-332 Mason KP, Lerman J. Dexmedetomidine in children: current knowledge and future applications. Anesthesia & Analgesia 2011;113(5): 1129-1142 Booth R, Petros A. Guideline for the use of dexmedetomidine for sedation in PICU (version 1). Great Ormond Street Hospital Clinical Guidelines. 2012 Lin H, Faraklas I, Sampson C, Saffle JR, Cochran A. Use of dexmedetomidine for sedation in critically ill mechanically ventilated pediatric burn patients. Journal of Burn Care & Research 2011;32(12): 98-103 Walker J, MacCallum M, Fischer C, Kopcha R, Saylors R, McCall J. Sedation using dexmedetomidine in pediatric burn patients. Journal of Burn Care & Research 2006;27(2): 206-210 Fagin A, Palmieri T, Greenhalgh D, Sen S. A comparison of dexmedetomidine and midazolam for sedation in severe pediatric burn injury. Journal of Burn Care & Research 2012;6(33): 759-763 Shank ES, Sheridan RL, Ryan CM, Keaney TJ, Martyn J. Hemodynamic responses to dexmedetomidine in critically injured pediatric burned patients: a preliminary study. Journal of Burn Care & Research 2013;34(3): 311-317 Dexdor SPC. Orion Pharma (UK) Limited. http://www.dexdor.eu/. Last accessed 18 August, 2015. Potts AL, Anderson BJ, Warman GR, Lerman J, Diaz SM, Vilo S. Dexmedetomidine pharmacokinetics in pediatric intensive care a pooled analysis. Pediatric Anaesthesia 2009;19(11): 1119-1129 Czaja AS, Zimmerman JJ. The use of dexmedetomidine in critically ill children. Pediatric Critical Care Medicine 2009;10(3): 381-386 11
Chrysostomou C, De Toledo JS, Avolio T, Motoa MV, Berry D, Morell VO, Orr R, Munoz R. Dexmedetomidine use in a pediatric cardiac intensive care unit: can we use it in infants after cardiac surgery? Pediatric Critical Care Medicine 2009;10(6): 654-659 Tobias JD, Berkenbosch JW. Sedation during mechanical ventilation in infants and children: dexmedetomidine versus midazolam. Southern Medical Journal 2004;97(5): 451-455 12
Appendix 1: Preliminary Equality Analysis This assessment relates to: (please tick all that apply) A change in a service to patients A change to an existing policy A change to the way staff work A new policy Questions Something else (please give details) Answers 1. What are you proposing to change? Point 14.1; 17.1 and Appendix 1 2. Why are you making this change? (What will the change achieve?) 3 year review as per process 3. Who benefits from this change and how? Patients and clinicians 4. Is anyone likely to suffer any negative impact as a result of this change? If no, please record reasons here and sign and date this assessment. If yes, please complete a full EIA. 5. a) Will you be undertaking any consultation as part of this change? b) If so, with whom? Preliminary analysis completed by: No Refer to pages 1 and 2 Name Harish Bangalore Job Title Date 10/12/2018 13