Analgesia and Sedation Guidelines for Paediatric Intensive Care Unit

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2 These clinical guidelines have been developed by a multidisciplinary working group in an attempt to achieve consistency in the choice and application of analgesic and sedative drugs in the PICU/CICU including ECMO patients. By working within these guidelines we hope to avoid under and over sedation by increasing clinical awareness of sedation related issues, as well as applying a scoring system to provide some objective assessment of the level of sedation. This in turn will help to minimise the risks of ICU psychosis, drug tolerance and withdrawal. These are guidelines only. Individual patients may deviate from the guidelines for clinical reasons following discussion with the PICU Consultant. If there is uncertainty about which pathway the patient should follow this can be discussed on an individual basis with the on-call PICU Consultant. Patients can move between pathways as their clinical condition changes. Please remember that there may be underlying clinical reasons for agitation, such as low cardiac output or mechanical airway obstruction. Patients with increased agitation, or those who have a sudden change in sedation score, should be assessed for underlying clinical or haemodynamic problems, in addition to reviewing their sedation requirements. Non pharmacological anxiolysis should always be employed in the paediatric patients, such as reducing noise and other noxious stimuli, giving reassurance and explanation around handling and procedures, and age-appropriate positioning etc. Ignoring these areas will lead to increased use of sedative drugs. Patient Population Following admission postoperative patients will be assessed and will enter one of three pathways, or Tracks. Non-surgical intubated patients can follow the appropriate pathway (usually Track 2), or be assessed on an individual basis. After Day 5 of admission the patients should transfer to a long stay pathway, where an active weaning programme is commenced.

3 Acute Admission Pathways: Guidelines for Analgesia and Sedation in Children on the Paediatric Child admitted to PICU Child assessed by Clinical fellow/picu Consultant Track 1: Extubation likely within 6-8 hours Track 2: Extubation likely within hours Track 3: Extubation unlikely within 48 hours Start regular paracetamol +/- diclofenac/ibuprofen (unless contraindicated) Commence morphine Consider midazolam boluses or low dose infusion (30-60 mcg/kg/hr) for anxiolysis Extubation delayed Commence morphine Consider midazolam infusion PRN: diazepam/alimemazine (Vallergan ) may be prescribed for breakthrough anxiety or if single dose nocturnal sedative required Start regular paracetamol +/- diclofenac/ibuprofen (unless contraindicated) Extubation delayed: START Clonidine Commence morphine Commence midazolam Commence clonidine PRN: diazepam/alimemazine (Vallergan ) may be prescribed for breakthrough anxiety or if single dose nocturnal sedative required Start regular paracetamol +/-diclofenac/ibuprofen (unless contraindicated) Pain management guidelines: Stage 1. Morphine micrograms/kg/hour + bolus and intermittent bolus of morphine 50 micrograms/kg Morphine should be commenced for analgesia

4 Stage 2. Stage 3. High dose morphine micrograms/kg/hour + bolus 100 micrograms/kg ** Fentanyl 1 4 micrograms/kg/minute + bolus 1 micrograms/kg ** Fentanyl can be used as 1 st line in a patient with Pulmonary hypertension for hours. NB: All patient should be on regular paracetamol and PRN Ibuprofen or diclofenac unless contraindicated. Sedation management guidelines: Stage 1. Midazolam micrograms/kg/hour + bolus Midazolam can be considered as a short acting anxiolytic in Track 1, either as low dose bolus (25 to 50 microgram/kg) that can be repeated, with or without low dose (30 to 100 microgram/kg/hr) short term intravenous infusion. Stage 2. Clonidine: micrograms/kg/hour or oral 1-5 micrograms/kg/dose NB: All patient should be on and PRN trimeprazine bolus for breakthrough anxiety or when nocturnal sedative is required unless contraindicated. If not sedated please Consult the PICU consultant The following drugs can only be used following discussion with PICU Consultant Fentanyl Ketamine Propofol for short term ventilation or detox to facilitate extubation Dexmedtomidine Chloral/Triclofos Nozinan (Levomepromazine) for ICU psychosis

5 Oral Enteral Sedation: Early use of enteral sedation is preferred. The agreed drugs in preferred order are: 1 st Clonidine 2 nd Trimeprazine 3 rd Diazepam or Lorazepam (if not on midazolam) 4 th Chloral hydrate (if not on any other benodiazepine) Long stay Pathway On Day 5 of admission patients should transfer to the long-stay pathway. Symptoms of withdrawal are far less likely if opiates and benzodiazepines are given for less than 5 days, and therefore at this stage active weaning of opiates and benzodiazepines is a priority. By combining active weaning and sedation scoring we hope to significantly reduce the administration of opiates and benzodiazepines, and as a consequence the incidence of tolerance and withdrawal. This weaning is likely to be facilitated by the presence of effective concentrations of clonidine. Please refer to: Oral Morphine and Clonidine Weaning Guidelines The following aspects of care should be reviewed in the Long Stay patient. 1. Is there an active weaning programme for opiates and benzodiazepines? 2. Is the patient on clonidine? 3. Is there a day-night cycle? 4. Is there an attempt to use non-pharmacological measures to alleviate sedation e.g. noise reduction, non-noxious handling, position, music etc.? 5. Is there a need for a drug with antipsychotic properties (e.g Trimeprazine or Levomepromazine) consider in the older patient with extended length of stay. SEDATION SCORING & SEDATION HOLIDAYS: 1. Sedation therapy should be discussed on all patients on the morning ward round. 2. The total amount of sedative drugs given in the previous 24 hours should be clearly stated (infusion and boluses). 3. Patients in PICU > 48hrs should have a daily sedation holiday, unless they are receiving muscle relaxants.

6 The sedation holiday is designed to make sure that patients are clearing their sedative drugs. It will commence following discussion on the morning ward round, unless there is a specific contraindication. Sedation holidays should occur even when sedation scores are thought to be adequate. Sedation Holidays Midazolam stopped at 10am following discussion on morning ward round Measure COMFORT Score Comfort Score > 26 within 6 hours: Restart midazolam at same dose Comfort Score > 26 between 6 and 12 hours: Restart midazolam but reduce dose by 20% Comfort Score > 26 between 12 and 24 hours: Restart midazolam but reduce dose by 40% Comfort Score still < 26 at 24 hours Stop Morphine When a patient reaches a COMFORT score at the upper end of the acceptable range sedative drugs will be recommenced at the same rate, if target score achieved within 6 hours, or at a reduced rate if there is a delay in achieving target score. COMFORT SCORE Acceptable range CS >26 within 6hrs restart same dose CS >26 within 6-12 hrs reduce dose by 20% CS > 26 within hrs reduce dose by 40%

7 If a patient is thought to be in distress during a sedation holiday drugs should be recommenced immediately and a bolus dose considered. This information must be relayed to the medical staff and discussed on the daily sedation review the following morning. Under Sedation: Comfort score >26 or greater than target comfort score 1) Morphine bolus 50 microgram/kg review comfort score in 20 minutes 2) Comfort score still not in target range give another bolus of morphine 50 microgram/kg review comfort score in 20 minutes 3) Comfort score still not in target range give morphine bolus 50 microgram/kg and increase the back ground rate by 20% review comfort score in 20 minutes 4) Comfort score still not in target range give midazolam bolus 50 microgram/kg only if child is cardiovascularly stable 5) Comfort score still not in target range contact PICU consultant Over sedation: Comfort score < 17 or less than target range 1) Review in an hour 2) If the score is till < 17 decrease sedation by 20% Patient about to have an accidental extubation: Call for help and bolus 100 microgram/kg of morphine +/- midazolam if child is cardiovascularly stable and increase the back ground rate by 20% Drug Dosing Information: MORPHINE Morphine is the first line analgesic in the early postoperative period. Start rate Range Bolus Neonates 15 microgram/kg/hr 5-40 microgram/kg/hr 50 microgram/kg Children < 40kg 30 microgram/kg/hr microgram/kg/hr 50 microgram/kg Children > 40kg 2 mg/hr mg/hr 1-2 mg Morphine is pure μ/κ/δ-agonist. It is a single agent with both analgesia and sedation properties. This is available in parenteral and enteral preparations. Reduce doses in renal or hepatic failure, and in prematurity.

8 Oral morphine dosing to be started as per BNFC and adjusted to effect/side effects unless patients have been on iv morphine for >5 days. Oral Morphine dose micrograms/kg every 4h age 1-3 months, micrograms/kg every 4h age 6-12 months and 200 micrograms/kg every 4h if over 1 year to a maximum of 10mg every 4hours Side Effects: Respiratory depression, hypotension, histamine release, pruritus (not an issue if child is on steroid), miosis, constipation and urinary retention (patients on morphine infusion do not always need in-dwelling urinary catheters), chest wall rigidity and withdrawal syndrome (see Weaning section)nb. Bolus doses of Morphine are required in addition to intravenous infusion in order to achieve effective plasma concentration in the early postoperative period. If a patient requires more than 3 boluses in a one hour period consider increasing the background rate by 20%. Please ensure that all bolus doses are recorded on PRN side of drug chart. Rarely some of the patient will need microgram/kg/hr before we consider Fentanyl MIDAZOLAM Midazolam is the first line sedative in the early postoperative period. The dose given should be titrated using the COMFORT score and daily sedation holidays. In patients with an expected PICU LOS greater than 48 hours clonidine should be given in order to facilitate weaning from midazolam. Start rate Range Bolus Neonates 50 microgram/kg/hr microgram/kg/hr 50microgram/kg Children < 40kg 50microgram/kg/hr microgram/kg/hr 50microgram/kg Children > 40kg 2 mg/hr mg/hr 1-2 mg A drug with a short half-life compared to Lorazepam/Diazepam, but which can accumulate due to lipid solubility and reduced clearance in critically ill children. It also has active metabolites which means its sedative effects can be long lasting. It should be used with caution in hypotensive children and neonates, and in liver failure. (N.B. 250microgram/kg/hr is too high for many infants and should not be the starting dose for infusions) Sublingual and Intranasal administration routes are possible for epilepsy or procedural purposes. Trisomy 21 patients and rarely other children can get

9 paradoxical agitation. Side Effects: Respiratory depression, hypotension, disinhibition, paradoxicalagitation, amnesia, mucosal irritant (acid taste), withdrawal syndrome. Active weaning should of midazolam should be in place by Day 5 of admission the aim to discontinue benzodiazepines whenever possible. CLONIDINE Clonidine has opiate and benzodiazepine sparing properties and should be commenced as a second line sedative in patients where PICU length of stay is expected to be greater than 48 hours. The suggested regimen allows a gradual increase in dose up to a maximum of 2 microgram/kg/hr over hours as clinically tolerated. (i) (ii) Postoperative cardiac patients 0-12 postop hours 0.5 microgram/kg/hr postop hours 1.0 microgram/kg/hr postop hours 1-2 microgram/kg/hr Once feeds are established consider changing to oral clonidine, following suggested dose conversion. Non cardiac, readmission, or long stay patients. Intravenous clonidine infusions can be titrated as above or started at 1.0 microgram/kg/hr and increased to 2 microgram/kg/hr Consider oral clonidine. Maintenance 2-3microgram/kg/dose 8 hourly Maximum 5microgram/kg/dose This centrally acting α agonist has sedative and analgesic effects. It potentiates opiates in addition to sedating patients. Remember to reduce concomitant midazolam/morphine infusion rates when using this drug. It also should be withdrawn gradually after prolonged use. Side effects: hypotension, bradycardia, opiate potentiation, withdrawal.

10 Oral Clonidine can be given even if patients are NBM unless there is a contraindication. Clonidine is compatible with morphine. There is no evidence about its compatibility with midazolam but the practice is to run all of them together. Fentanyl This is a fast-acting opiate, which causes less histamine release and pruritus than morphine. It is preferred in patients with pulmonary hypertension and asthma. It can also be useful as an alternative in children who are not settled on morphine. However remember that 1 microgram of fentanyl is equivalent to 100 microgram of morphine. Also that whilst fentanyl (strong μ-agonist/δ- agonist) is a better analgesic than morphine it is a poorer sedative drug since is does not act on kappa receptor; hence you need a higher equivalent dose to have a sedative effect. There is some evidence that fentanyl is less constipating than morphine in neonates, however it has also been shown to cause much more withdrawal than morphine. It has all the other side effects of morphine and should be reduced in renal and hepatic failure. One should try and limit its use to less than 5 days and try to convert to morphine when possible. Side Effects: (See morphine) In addition fentanyl is highly lipid soluble and so accumulates in fat stores and CNS. This means that long after an infusion is stopped fentanyl can continue to leach out of the fat stores and exert an effect. Fentanyl is also associated with chest wall rigidity. ** Fentanyl can be used as 1 st line in a patient with Pulmonary hypertension for hours. Propofol Dose: Bolus: 1-4mg/kg Infusion Rate: 2-4 mg/kg/hr Some patient may need intubation and ventilation only for few hours; they are fast tracked for early extubation. Such patient may arrive from operation theatre or from A&E on propofol. In such situation we will continue it till the patient is extubated instead of changing the drug. If the patient cannot be extubated and needs to continue sedation for more than 6-8 hours than propofol should be

11 stopped and midazolam started. It is also useful for preparing children with significant sedation requirements for extubation. The patients established sedation regime is replaced by a propofol infusion for 6-8 hours prior to extubation, giving the other agents time to wear off. Propofol has a rapid offset when used in this way, facilitating controlled extubation. It has respiratory depressant actions which make it difficult to use, without anaesthetic skills, for procedural purposes. It also causes a predictable and significant drop in blood pressure. We will use it for older children or young adults, with maximum dose of 4 mg/kg/hr provided lactate is less than 4 with normal blood ph. Side effects: Respiratory Depression, Hypotension, Metabolic Acidosis, Bradycardia, Convulsions. Trimeprazine/Alimemazine This is a phenothiazine derivative, sedating antihistamine drug which is enterally administered (PO/NG). It has anxiolytic properties and can help to induce natural sleep. Hypersensitivity to this drug (rash, bronchospasm and anaphylaxis) is more common than the other agents in this guideline. It should be avoided in significant hepatic impairment. Dose: 1-4 mg/kg 6hrly Side Effects: hypotension, anticholinergic (dry mucosa, urinary retention and constipation), paradoxical agitation. Chloral Hydrate Administered enterally (PO/PR) it exerts its effects via its major liver metabolite TrichloroEthanol, which is further degraded to TrichloroAcetic Acid (TCA) prior to renal excretion. It has a variable, age-dependent half-life (prems and neonates metabolise and excrete the drug much more slowly than larger children) and it accumulates with repeated dosing. It is safest for short term or procedural sedation. The metabolite TCA has been shown to be carcinogenic in animal studies. With its high fatality index its use is decreasing rapidly. If aspirated Chloral is very irritant to Airway Mucosa. It should also be avoided in children following upper GI surgery as it aggravates peptic ulceration and can cause haemorrhagic gastritis.

12 Chloral should also be avoided in hepatic or renal impairment and in cardiac arrhythmias (it can precipitate SVT, VT and Torsade). It interacts with Frusemide which displaces TCA from its albumin binding resulting in agitation, flushing, sweating and tachycardia. TCA also displaces Bilirubin from its Albumin binding aggravating jaundice. Finally, Chloral can cause acute dystonia by sudden withdrawal and should be weaned gradually following prolonged use. Dosage: 10-50mg/kg every 6hours. Higher doses should be avoided in neonates, infants and prolonged use. (30mg/kg 6hrly top dose for use>24hours) max 1-2g/day. Side Effects: Respiratory depression, hypotension, nausea/vomiting, arrhythmia, seizures, gastritis, paradoxical agitation, withdrawal syndrome. Dexmedtomidine Awaiting TAS re-application. On named patient basis and with approval. Dexmedetomidine is a selective alpha2-adrenergic agonist. It is structurally related to clonidine, but has a much greater affinity for alpha2-receptors over alpha1-receptors (with a ratio of 1,600:1, compared to 200:1 for clonidine). Dexmedetomidine has activity at a variety of locations throughout the central nervous system. The sedative and anxiolytic effects of dexmedetomidine result primarily from its activity in the locus ceruleus of the brainstem. Stimulation of alpha2-adrenergic receptors at this site reduces central sympathetic output, resulting in increased firing of inhibitory neurons. The presence of dexmedetomidine at alpha2-adrenergic receptors in the dorsal horn of the spinal cord modulates release of substance P and produces its analgesic effects. Dosage: 0.7 to 1.4 micrograms/kg/hour for hours Side effects: hypotension, bradycardia. Hence can t be used if clonidine is stopped because of these side effects. Paracetamol ALL patients should be given regular (NOT PRN) paracetamol for a minimum of 48 hours after surgery unless contraindicated (extremely rare).

13 Dosage: Oral 15mg/kg po QDS (TDS if premature til term corrected, maximum dose 1g) If oral dosing is not possible IV is the second choice. Intravenous dose 7.5mg/kg QDS to 1 month corrected age then 15mg/kg to maximum 1g. Intravenous paracetamol is 2-5x cheaper than PR equivalent doses. It has also been shown to be more effective, have a quicker onset of action and more reliable absorption. It can have an equal analgesic effect to opiates. Therefore the PR route is not recommended. Ibuprofen: Should be used next unless there is a contraindication or caution. Doseage: 5mg/kg po QDSa consider staggering with paracetamol doses. Usually to be prescribed PRN but consider regular for 24 hours and review daily. Contraindications include abnormal renal function (beware post-bypass), gastrointestinal bleeding and co-medication with aspirin. Use caution in co-medication with steroids/captopril/heparin/warfarin and age <3 months (especially < 1 month). Diclofenac PR is an alternative only if po ibuprofen cannot be given. Oral drugs can often be given even if a child is not fed check with a doctor. It is no more effective than ibuprofenf but avoids the oral route. PR Diclofenac dosing bases on BNFC doses and available suppositories: WEIGHT DOSE 8-12 kg 12.5mg BD kg 12.5mg TDS kg 25mg BD kg 25mg TDS kg 50mg BD >50kg 50mg TDS

14 Annexure A Under sedation: Comfort score >26 or greater than target comfort score 1) Morphine bolus 50 microgram/kg review comfort score in 20 minutes 2) Comfort score still not in target range give another bolus of morphine 50 microgram/kg review comfort score in 20 minutes 3) Comfort score still not in target range give morphine bolus 50 microgram/kg and increase the back ground rate by 20% review comfort score in 20 minutes 4) Comfort score still not in target range give midazolam bolus 50 microgram/kg only if child is cardiovascularly stable 5) Comfort score still not in target range contact PICU consultant Over sedation: Comfort score < 17 or less than target range 3) Review in an hour 4) If the score is till < 17 decrease sedation by 20% Patient about to have an accidental extubation: Call for help and bolus 100 microgram/kg of morphine +/- midazolam if child is cardiovascularly stable and increase the back ground rate by 20% TIME SCORE ACTION RESCORE SIGNATURE

15 References: 1. Current United Kingdom sedation practice in pediatric intensive care Pediatric Anesthesia : Intravenous clonidine infusion in infants after cardiovascular surgery Pediatric Anesthesia : Intravenous clonidine infusion in critically ill children: dose-dependent sedative effects and cardiovascular stability. Br J Anaesth 2000; 84: Use of oral clonidine for sedation in ventilated paediatric intensive care patients. Intensive Care Med 2004; 30: Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial Lancet 2008; 371: Alpha-2-Agonist Sedation Vs GABA Agonists May Shorten Time on Mechanical Ventilation JAMA. 2009; 301: Assessing distress in pediatric intensive care environments: The COMFORT scale. J Pediatr Psychol 1992; 17: The reliability and validity of the COMFORT scale as a postoperative pain instrument in 0 to 3-year-old infants. Pain 2000; 84: An item analysis of the COMFORT scale in a pediatric intensive care unit. Pediatr Crit Care Med 2002;3(2): Dexmedetomidine use in a pediatric cardiac intensive care unit: Can we use it in infants after cardiac surgery? Pediatric Critical Care Medicine: November Volume 10 - Issue 6 - pp A dose-response study of dexmedetomidine administered as the primary sedative in infants following open heart surgery. Pediatr Crit Care Med Jun;14(5): Perioperative Use of Dexmedetomidine is Associated with Decreased Incidence of Ventricular and Supraventricular Tachyarrhythmias after Congenital Cardiac Surgery Ann Thorac Surg. Sep 2011; 92(3): Acknowledge Previous Authors May 2009: Dr A Vora Dr S Nichani S Wheeler A Hall R Patel A Sutton N. Chotai Post-operative pain guideline Designed for paediatric patients at Glenfield Hospital after cardiothoracic surgery Oral Morphine and Clonidine Weaning Guideline UHL Childrens Hospital mainly PICU/CICU/HDU/Ward30