Copyright Great Ormond Street Hospital. All rights reserved. Page 1 of 33

Transcription

1 Disclaimer: The Great Ormond Street Paediatric Intensive Care Training Programme was developed in 2004 by the clinicians of that Institution, primarily for use within Great Ormond Street Hospital and the Children s Acute Transport Service (CATS). The written information (known as Modules) only forms a part of the training programme. The modules are provided for teaching purposes only and are not designed to be any form of standard reference or textbook. The views expressed in the modules do not necessarily represent the views of all the clinicians at Great Ormond Street Hospital and CATS. The authors have made considerable efforts to ensure the information contained in the modules is accurate and up to date. The modules are updated annually. Users of these modules are strongly recommended to confirm that the information contained within them, especially drug doses, is correct by way of independent sources. The authors accept no responsibility for any inaccuracies, information perceived as misleading, or the success of any treatment regimen detailed in the modules. The text, pictures, images, graphics and other items provided in the modules are copyrighted by Great Ormond Street Hospital or as appropriate, by the other owners of the items. Copyright Great Ormond Street Hospital. All rights reserved. Analgesia, Sedation and Neuromuscular Blockade on PICU Author: Andy Petros 2004 Updated: Sophie Skellett, November 2006 Updated: Shruti Agrawal, March 2011 Updated: Reinis Balmaks, Emma Borrows January 2016 Associated clinical guidelines/protocols: Use of Train of Four in assessment of the muscle relaxed patient Scoring for neonatal abstinence NICU Withdrawal guidelines Local anaesthetic systemic toxicity Fundamental Knowledge: List of topics relevant to PIC that will have been covered in membership examinations. They will not be repeated here. Physiology: Afferent nociceptive pathways, dorsal horn, peripheral and central mechanisms, neuromodulatory systems, supraspinal mechanisms, Visceral pain, neuropathic pain Copyright Great Ormond Street Hospital. All rights reserved. Page 1 of 33

2 Information for Year 1 ITU Training (basic): Analgesia: Pain assessment Non-pharmacological interventions Non-opioids: Paracetamol and NSAIDs Opioids: Morphine, Fentanyl, Remifentanil, Codeine, Opioid toxicity, Tolerance and opioid-induced hyperalgesia NCA & PCAs Sedation: Distress assessment tools Non-pharmacological interventions Benzodiazepines: indications, complications, reversal agents Alpha-2 agonists Ketamine Propofol Thiopentone for barbiturate coma continuous EEG monitoring covered in CNS anatomy & physiology module Enteral sedation: antihistamines, chloral hydrate Neuromuscular blockade: Physiology: neuromuscular junctions Depolarising muscle relaxants: side effects and contra-indications Non depolarizing muscle relaxants: Vecuronium, Rocuronium, Atracurium, Cisatracurium Curriculum Notes for Year 1: Analgesia The most widely used definition of pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. 1 Analgesia is defined as the blunting or eradication of the sensation of pain or other noxious stimuli. Adequate analgesia should be provided to all critically ill children regardless of their need for sedation. Unrelieved pain has adverse physical and psychological consequences evoking a stress response characterised by tachycardia, hypercoagulability, immunosuppression and a persistent catabolic state. Longer-term, untreated pain increases the risk of post-traumatic stress disorder. Pain may also contribute to pulmonary complications in postoperative patients through reduced movement of the chest wall and diaphragm. Despite the importance of relieving pain, a study showed that 44% of children who remembered details of a PICU admission remembered being in pain. 1 Pain assessment tools Assessing whether a patient in the ICU is in pain may be difficult. The reference standard for the assessment of pain is self-reporting by the patient, but patients in the ICU may not be sufficiently interactive to give valid responses. 2 Whilst pain-related behaviours and physiological indicators of pain are neither sensitive nor specific to pain, their presence should be routinely documented, especially in those unable to communicate verbally. 1 Physiological and behavioural variables commonly measured are: - Blood pressure - Heart rate changes - Facial expression - Body movements - Presence of tears Copyright Great Ormond Street Hospital. All rights reserved. Page 2 of 33

3 - Intensity and quality of crying - Levels of adrenal stress hormones More specific pain assessment instruments are recommended by Paediatric Intensive Care Society (PICS) according to the age group: 1 - In neonates, infants and children under 3 years of age, behavioural observational scales are the primary tools available for pain assessment 1. FLACC scale by nurse or parent 3. Each category (Face, Legs, Activity, Cry and Consolability) is scored on the 0 2 scale, which results in a total score of = relaxed and comfortable; 1 3 = mild discomfort; 4 6 = moderate pain 7 10 = severe discomfort or pain or both. In GOSH PICU/CICU it is charted in CareVue under ICU Chart/Pain. Table 1 FLACC scale Categories Face Legs Activity Cry Scoring Occasional grimace or frown; withdrawn, disinterested No particular expression or smile Normal position or relaxed Lying quietly, normal position, moves easily No cry (awake or asleep) Uneasy, restless, tense Squirming, shifting back and forth, tense Moans or whimpers, occasional complaint Consolability Content, relaxed Reassured by occasional touching, hugging or being talked to; distractable Table 2 PAT score Parameters Posture/tone Frequent to constant frown, clenched jaw, quivering chin Kicking or legs drawn up Arched, rigid, or jerking Crying steadily, screams or sobs; frequent complaints Difficult to console or comfort 2. The Pain Assessment Tool (PAT) for neonates. 4 This scoring system is used in GOSH NICU (see CareVue ICU Chart/Pain) and is appropriate pain assessment tool for both term and preterm newborns. 5 The tool has 10 parameters that are scored on a scale of 0 to 2, the minimum and maximum scores being 0 and 20. Scores greater than 5 indicate that comfort measures such as tactile soothing, use of pacifier, and repositioning should be instituted, and scores greater than 10 require adjustment of the analgesia dose. Scoring Extended Digits widespread Shoulders raised off bed Flexed and/or tense Fists clenched Trunk guarding Limbs drawn to midline Head and shoulders resist posturing Cry No Yes When disturbed Doesn t settle after handling Loud Whimpering Whining Sleep pattern Relaxed Agitated or withdrawn Wakes with startle Easily woken Restless Squirming No clear sleep/wake pattern Eye aversion shut out Copyright Great Ormond Street Hospital. All rights reserved. Page 3 of 33

4 Expression Frown Shallow furrows Eyes lightly closed Grimace Deep furrows Eyes tightly closed Pupils dilated Colour Pink, well perfused Pale/dusky/flushed Palmar sweating Respirations Tachypnoea At rest Apnoea At rest or with handling Heart rate Tachycardia At rest Fluctuating Spontaneous or at rest Oxygen saturation Normal Desaturation with or without handling Blood pressure Normal Hypo-/hypertension at rest Nurse s perception No pain perceived by me I think the baby is in pain - In patients between 3 and 8 years of age, self-reporting techniques such as faces scales using either photographs or drawings of faces, may be used. Figure 1 Wong-Baker FACES Pain Rating Scale - Above the age of 8 years, competent children can usually use one-dimensional tools, such as the visual analogue scale (VAS) and numeric rating scale (NRS) in the same way as adult patients. The NRS is a 0 to 10 scale where the patient chooses a number that describes their pain, with 10 representing the worst possible pain. - Patients who cannot communicate should be assessed for the presence of pain-related behaviours and physiological indicators of pain (e.g. COMFORT [see Table 5], FLACC scale for special needs) Non-pharmacological interventions There are a number of non-pharmacological methods of pain reduction available that staff should consider in appropriate circumstances. These include: - Watching television: Bellieni et al. (2006) showed that TV watching was more effective than active distraction. This can be due either to the emotional participation of the mothers in the active procedure or to the distracting power of television. 6 - Parents: parents are powerful method of non-pharmacological pain relief available to the child. They instinctively provide comfort and therapeutic touch. Children may appear more distressed as they feel more comfortable expressing discomfort to their parents - Play: play can be used not only to distract but as a method to explain medical procedures reducing associated anxiety and hence pain. - Music: meta-analysis of 73 RCTs showed that in adult patients undergoing surgical procedures music reduces postoperative pain and analgesia needs, and increased patient satisfaction. Interestingly, subgroup analyses showed that choice of music and timing of delivery made little difference to outcomes. 7 Copyright Great Ormond Street Hospital. All rights reserved. Page 4 of 33

5 Analgesic agents Preventing pain is felt to be more effective than treating established pain. When patients are administered drugs on an as needed basis, they may receive less than the prescribed dose and often experience significant delays in receiving treatment. For background pain, analgesics should therefore be administered by continuous infusion or on a planned intermittent basis, with additional boluses being given as required for breakthrough pain or prior to painful procedures. Doses of analgesics recommended by PICS are summarized in Appendix 1. Non-opioids NSAIDS Non-steroidal anti-inflammatory drugs (NSAIDs) provide analgesia via the nonselective, competitive inhibition of cyclooxygenase (COX), a critical enzyme in the inflammatory cascade which produce prostaglandins. 1 Prostaglandins do not produce pain, they sensitise peripheral nerve endings to agents such as histamine and bradykinins. Whilst the administration of NSAIDs may reduce opioid requirements in adult and paediatric post-surgical pain by 15 30%, the analgesic benefit of NSAIDs has not been systematically studied in critically ill children. 1 Recent RCT comparing morphine and ibuprofen for post-tonsillectomy analgesia showed no difference in analgesic effectiveness or rates of post-tonsillar haemorrhage, but the use of ibuprofen reduced the risk of oxygen desaturation. 8 Care should be taken in renal compromise, patients with history of asthma and clotting and platelet disorders. Paracetamol This is not an anti-inflammatory but has centrally acting analgesic and antipyretic properties. It is metabolised in the liver and renally excreted. Paracetamol is an analgesic used to treat mild to moderate pain. In combination with an opioid, paracetamol produces a greater analgesic effect than higher doses of the opioid alone and has an opioid sparing effect in both children and adults. 1 Opioids Opioids mediate analgesia by interacting at a variety of central and peripheral opioid receptors. Six major categories of opioid receptors and their subtypes have been described: μ, κ, δ, nociceptin, σ, and ε. Binding of opioids to their receptors leads to inhibitory G protein (G i2α and G 0 ) signal transduction which downregulates adenylate cyclase (AC) and camp production and by regulation of rectifying K + channel causes hyperpolarization of the neuronal membrane. As a result, signal transduction from activated opioid receptors lowers neuronal excitability, reduces action potential duration, and decreases neurotransmitter release, which leads to opioid analgesia. Morphine and fentanyl are the two most commonly used opioids in PICUs for both maintenance and breakthrough analgesia recommended by PICS. 1 Morphine Morphine is an opiate, and its primary therapeutic actions are sedation and analgesia; anxiolysis and euphoria also may occur. Morphine has a relatively long duration of action of around two hours when administered as a single dose of 0.1 mg kg -1, and administration by either continuous infusion or repeated intermittent doses may therefore be considered in the PICU. The half-life of morphine, however, is 6.5 hours in term neonates and 9 hours in the preterm child because of reduced clearance. Morphine has the lowest lipid solubility of all the opioids, which accounts for its slow entry into the brain and subsequent delayed onset of clinical effect. It is also the most widely used of the opioids and relieves visceral, somatic and neuropathic pain with peak analgesic effect occurring 20 min after intravenous administration. Metabolism of morphine produces an active metabolite, morphine-6-glucuronide, which may delay drug elimination in renal disease, and the analgesically inactive metabolite morphine-3-glucuronide, which fails to bind to opioid receptors and is considered to be antianalgesic. Morphine removal from the body is slow and quantitatively different in newborns (who preferentially form more morphine-3- glucuronide) but adjusts toward adult values within the first months of life. Morphine stimulates the release of significant amounts of histamine and inhibits compensatory sympathetic Copyright Great Ormond Street Hospital. All rights reserved. Page 5 of 33

6 responses. The vasodilation produced by morphine may result in hypotension, particularly with bolus administration. 1 Fentanyl Fentanyl is a synthetic opioid phenylpiperidine with approximately 100 times the analgesic potency of morphine. It is highly lipid soluble, which accounts for its rapid onset of action of 2-3 minutes. Fentanyl causes less histamine release than morphine, and as such is associated with a reduced incidence of hypotension. However, fentanyl can reduce cardiac output by decreasing heart rate which is an advantage in cardiovascular conditions where ablation of the stress and/or pressor response is desirable. When given intravenously fentanyl has a relatively short half-life of min because of rapid redistribution to peripheral compartments. With prolonged administration there is accumulation in these peripheral compartments, which increases the context sensitive half time and tolerance may rapidly develop. The longer half-life of fentanyl in neonates, and the consequent lower rate of fentanyl elimination, are due to the lower expression of CYP3A4 in neonatal liver, which metabolizes fentanyl. 10 Ketoconazole and erythromycin are potent inhibitors of fentanyl metabolism and must not be used in association with fentanyl. 1 Fentanyl has no active metabolites and does not cross-react in patients with morphine allergy. 1 Remifentanil Remifentanil is a synthetic opioid, a phenylpiperidine derivative that acts as a pure μ-receptor agonist, equipotent to fentanyl. It has cardiorespiratory effects similar to other opioids. Remifentanil s half-life is short (3 min) in all age groups as it is metabolised by plasma and tissue esterases and has a very small volume of distribution. The effects of remifentanil therefore dissipate rapidly even after prolonged infusion, giving it a short, context-sensitive half-time. Remifentanil is an ideal agent for neurosedation as it can be stopped and allow the child to awake to get a window of awareness consciousness. Remifentanil has also been used to provide ongoing analgesia in the PICU. 1 It has been compared with midazolam alone, midazolam with fentanyl, fentanyl alone, and morphine. Although remifentanil has been associated with a reduced duration of mechanical ventilation and ICU stay in small adult trials, it has not yet been evaluated in a large, heterogeneous population of critically ill patients, its prolonged use is associated with rapid development of tolerance and relatively high cost and is currently not a common choice in most ICUs. 1,2 It may have more potential for procedural analgesia in critical care, given its rapid onset and offset times and effective blunting of airway reflexes. Respiratory and cardiovascular depressant effects must be anticipated when remifentanyl is used. 1 Codeine Until recently, codeine was commonly prescribed for postoperative pain management. However, on August 15, 2012, after the publication of three codeine-related fatalities post tonsillectomy, the US Federal Drug Administration issued a Drug Safety communication advising practitioners that codeine use in certain children after tonsillectomy and/or adenoidectomy may lead to rare but lifethreatening respiratory failure and death. Further investigation revealed 13 cases of death or life threatening overdose in children receiving standard, appropriate codeine doses and the majority of these cases (8/13) were related to tonsillectomy patients. 8 MHRA/CHM advice states that codeine should only be used to relieve acute moderate pain in children older than 12 years and only if it cannot be relieved by other painkillers. 11 Opioid Toxicity Overdose of opioids will cause respiratory depression and apnoea, hypotension and CNS depression. These effects can be reversed immediately by intravenous naloxone which is an opioid antagonist, antagonising the µ and κ receptors. Naloxone is a competitive inhibitor, so the dose may have to be tailored to the dose of opioid given rather than the child s weight. The dose may have to be repeated or an infusion started in some cases as the half-life of naloxone is short. This should be used carefully in children requiring on going analgesia because the analgesic effect of opioids is also antagonised. Naloxone can also be used to reverse the respiratory depression in neonates whose mothers have received opioid analgesia prior to birth. Dosage: - Neonate 10 µg kg -1 IV - Child (1 month 12 years) 10 µg kg -1 IV dose or 5-20 µg kg -1 h -1 IV infusion. Copyright Great Ormond Street Hospital. All rights reserved. Page 6 of 33

7 Tolerance and opioid-induced hyperalgesia Figure 2 Algorithm for management of diminished opioid analgesia 9 - Opioid-induced hyperalgesia occurs even in the absence of opioid tolerance, as demonstrated in opioid addicts, normal adult volunteers, and those who receive opioid therapy. Proposed mechanisms include the sensitization of primary afferent neurons, enhanced production and release of excitatory neurotransmitters, decreased reuptake of excitatory neurotransmitters, sensitization of second-order neurons, and descending facilitation from the rostral ventromedial medulla associated with upregulation of the central dynorphin and glutamatergic systems 9 - Opioid tolerance occurs in 35% to 57% of PICU patients and often results in a prolonged hospital stay or other complications. Although opioid-induced hyperalgesia and tolerance use similar mechanisms, tolerance primarily results from receptor desensitization and upregulation of the camp pathway. Other mechanisms such as neuroimmune activation, production of antiopioid peptides, or activation of the spinal dynorphin system also contribute to opioid tolerance. Duration of opioid receptor occupancy is clearly important for the development of tolerance. Opioid tolerance rarely occurs after therapy for less than 72 hours. Continuous infusions of opioids seem to induce tolerance more rapidly than intermittent therapy. Indirect evidence has suggested that opioid tolerance develops earlier in preterm versus term newborns. Greater tolerance occurs with the use of synthetic or short-acting opioids. Infants who received fentanyl during extracorporeal membrane oxygenation required more supplemental analgesia, frequently developed opioid withdrawal, and required longer durations of opioid weaning compared with morphine treated infants. Procedural changes such as the daily interruption of sedatives, nurse-controlled sedation, sequential rotation of analgesics (although associated with some concerns), or the use of epidural/intrathecal opioids in paediatric patients may decrease the incidence of opioid tolerance and withdrawal. 9 Copyright Great Ormond Street Hospital. All rights reserved. Page 7 of 33

8 Table 3 Definition of terms and underlying mechanisms 9 Term Definition Primary Mechanism Tolerance Decreasing clinical effects of a drug after prolonged exposure to it Upregulation of the camp pathway; desensitization of opioid receptors; Dependence Withdrawal Tachyphylaxis Addiction A physiologic and biochemical adaptation of neurons such that removing a drug precipitates withdrawal or an abstinence syndrome A clinical syndrome that manifests after stopping or reversing a drug after prolonged exposure to that drug Rapid loss of drug effects caused by compensatory neurophysiologic mechanisms A chronic, relapsing syndrome of psychological dependence and craving a drug for its psychedelic, sedative, or euphoric effects; characterized by compulsion, loss of control, and continued use of a substance despite harmful effects other mechanisms Activation of second-messenger protein kinases; changes in neurotransmitter levels; changes in neuronal networks Superactivation of AC; opioid receptor coupling to Gs protein; activation of excitatory amino acid receptors Exhaustion of synaptic neurotransmitters; activation of antagonist signaling systems; activation of NMDA receptors and inos Activation of dopaminergic reward systems in nucleus accumbens; mechanisms associated with tolerance and dependence PCA/NCA Although they are popular, simple continuous infusions of analgesia are very limited by the fact that for pharmacokinetic reasons changes in infusion rate will only change the level of analgesia very slowly. In addition, this lag effect can lead to analgesic drug accumulation and escalation of the total dose of analgesia to unnecessarily high levels. Because there is so much variation in the amount of analgesia individual patients need, getting the right dose with a continuous infusion is very difficult. PCA: patient-controlled analgesia. Superior pain relief has been achieved through the use of PCA. This method of delivery uses computerized infusion pumps that deliver a specific amount of the analgesic (usually morphine) IV or epidurally continuously. Bolus administration of the drug on top of this background is also available when the PCA is activated by the patient to treat break through pain. Lockout periods and dose limits can be programmed. PCA is effective in the management of pain in non-sedated children aged 7 years and older, but occasionally as young as 5 years, 1 but younger ages will find this more difficult (they will find it difficult to understand and may lack the manual dexterity or strength to operate the pump); for this group NCA (see below) is more appropriate. NCA: nurse- or parent-controlled analgesia uses PCA technology i.e. specially designed microcomputer controlled infusion pumps to allow safe delivery of analgesia. The pumps will only allow a pre-determined amount of analgesia to be given within safe limits. However, the effectiveness of NCA, and its safety, depend on a number of factors: - NCA patient selection and education - Correct NCA equipment set-up - Appropriate supervision and monitoring of NCA Monitto and Greenburg 2000 studied the use of NCA in children. 12 They concluded that NCA appears to provide superior analgesia to that reported when PRN dosing of analgesics in young children is assessed by objective measures. Although NCA was safe in the large majority of patients studied, some patients did experience opioid-induced side effects, most notably respiratory compromise. They reported a 1.7% incidence of apnoea and episodes of desaturation requiring treatment with naloxone. They did however allow parents and or nurses to determine pain levels and dosing and did not study the effect of this use of different groups on doses given. Copyright Great Ormond Street Hospital. All rights reserved. Page 8 of 33

9 At Great Ormond Street Hospital there is a Pain Control Team available for advice and for initiating PCA and NCA. The assessment for infusion doses is based on the patient s requirements and careful pain assessments. The details of this service and further information regarding NCAs and PCAs can be found on their website on the GOSH intranet. Sedation The provision of adequate sedation and analgesia is a crucial component of critical care management. Sedation and analgesia reduce pain, anxiety, and agitation; allow nursing and invasive procedures to be performed safely; and enhance synchronization with mechanical ventilation. Despite the importance of ensuring comfort throughout critical care stay, sedation therapy is often suboptimal and seldom systematically evaluated in PICU patients. Optimal sedation is described as a level of sedation at which the patient is sedated but easily arousable, free from pain and anxiety, and could tolerate nursing and medical procedures. Achieving optimal sedation may help avoid risks associated with oversedation (e.g., prolonged mechanical ventilation and extubation failure) and problems of undersedation (e.g. agitation, anxiety-induced hypertension, and unplanned extubation). Suboptimal sedation may potentially prolong length of stay in ICU and lead to increased morbidity. 14 Given the multiple side-effects of sedation, it should be used only when pain and delirium have been addressed with the use of specific pharmacologic and non-pharmacologic strategies. 2 Children are usually sedated through a combination of hypnotics (e.g., midazolam) and analgesics (e.g., morphine or fentanyl). Regrettably, there is little evidence from randomized trials on the efficacy of these drugs for sedation in critically ill children. Other frequently used sedatives are ketamine, clonidine, propofol, barbiturates, chloral hydrate, first-generation antihistamines, and dexmedetomidine in different combinations. 15 Assessment To achieve the optimal level of sedation in individual patients, doses of sedatives are individually titrated to effect. Several clinical assessment tools have been developed (Ramsay sedation scale, COMFORT scale, COMFORT-B scale, State Behaviour Scale (SBS), Richmond Agitation Sedation Scale (RASS)) to titrate depth of sedation. The COMFORT score, 16 which is composed of eight variables (each with five categories), has been validated and is commonly used to assess sedation level in critically ill children (Table 5). 14,15 Total scores can range between A score of generally indicates adequate sedation and pain control (i.e. patient is "somnolent, responsive to the environment but untroubled by it, no excessive movement"). 15,17 Deeper levels of sedation are reserved for select patients who are receiving neuromuscular blocking agents or have a specific clinical condition (e.g. head injury, pulmonary hypertension). 1 Use of this system, however, is complicated and time consuming. A simpler sedation assessment is available by using Richmond Agitation-Sedation Scale (RASS) which has been demonstrated to have excellent interrater reliability. 18 Both of these scales are currently used at GOSH PICU/NICU/CICU and their assessment is charted in CareVue ICU Chart/Pain. Table 5 COMFORT score Alertness Deeply asleep 1 Lightly asleep 2 Drowsy 3 Fully awake and alert 4 Hyper-alert 5 Calmness / Agitation Calm 1 Slightly anxious 2 Anxious 3 Very anxious 4 Panicky 5 Copyright Great Ormond Street Hospital. All rights reserved. Page 9 of 33

10 Respiratory response No coughing no spontaneous breathing 1 Spontaneous breathing with no resistance to the ventilator 2 Occasional cough or resistance to the ventilator 3 Actively breathing against the ventilator 4 Fights ventilator coughing or choking 5 Physical Movement No movement 1 Occasional slight movement 2 Frequent slight movement 3 Vigorous movement limited to extremities 4 Vigorous movement include torso and head 5 Blood pressure MAP Baseline Blood pressure below baseline 1 Blood pressure consistently at baseline 2 Infrequent elevation of 15% or more (1-3) 3 Infrequent elevation of 15% or more (more than 3) 4 Sustained elevation of >15% 5 Heart rate Baseline Heart Rate below baseline 1 Heart rate consistently at baseline 2 Infrequent elevations of 15% or more (1-3) 3 Frequent elevations of 15% or more (>3) 4 Sustained elevation of more than 15% 5 Muscle Tone Muscle totally relaxed, no muscle tone 1 Reduced muscle tone 2 Normal muscle tone 3 Increased muscle tone and flexion of fingers and toes 4 Extreme muscle rigidity and flexion of fingers and toes 5 Facial Muscles Facial muscles totally relaxed 1 Facial muscle tone normal, no tension 2 Tension evident in some facial muscles 3 Tension evident throughout facial muscles 4 Facial muscle contorted / Grimacing 5 Table 6 RASS scale Score Classification (RASS) +4 Combative Overtly combative or violent; immediate danger to staff +3 Very agitated Pulls on or removes tube(s) or catheter(s) or has aggressive behaviour toward staff +2 Agitated Frequent non-purposeful movement or patient ventilator dyssynchrony +1 Restless Anxious or apprehensive but movements not aggressive or vigorous 0 Alert and calm -1 Drowsy Not fully alert, but has sustained (more than 10 seconds) awakening, with eye contact, to voice -2 Light sedation Briefly (less than 10 seconds) awakens with eye contact to voice -3 Moderate Any movement (but no eye contact) to voice sedation -4 Deep sedation No response to voice, but any movement to physical stimulation -5 Unarousable No response to voice or physical stimulation Neurophysiological monitors Given the difficulties involved in the subjective assessment of sedation during deep sedation or during the administration of neuromuscular blocking agents there are clearly potential benefits in the objective measurement of sedation using neurophysiological techniques such as the bispectral index (BIS) or auditory evoked potentials. Considerable interest exists in the use of electroencephalogram (EEG) analysis tools such as BIS, which uses a digital scale from 100 Copyright Great Ormond Street Hospital. All rights reserved. Page 10 of 33

11 (completely awake) to 0 (isoelectric EEG), where a number less than 40 is suggestive of a deep hypnotic effect. BIS has been found to reliably differentiate between inadequate and adequate levels of sedation, but appears to be relatively insensitive for differentiating between adequate and excessive sedation. Many factors encountered during critical illness, including drugs (such as opioid analgesics, ketamine and nitrous oxide), body temperature variation, hypotension and even critical illness itself, may alter the BIS score. Electrical interference from PICU equipment or pacemakers and muscle activity at lighter levels of sedation may confound BIS and auditory evoked potential scores. All in all, there is insufficient evidence to support the routine use of the BIS monitor in the PICU. 1 Protocols and Guidelines In a systematic review 19 that included 19 adult studies (four RCTs and 15 observational studies) that investigated the effect of protocolized sedation in adult ICUs, the authors found a strong association between the use of a systematic approach to sedation with reduced duration of mechanical ventilation, ICU and hospital length of stay, and costs. In paediatrics, several observational before-after studies reported on the association between initiation of sedation protocol and reduced PICU length of stay, frequency of unplanned extubation, prevalence of patients experiencing drug withdrawal, total exposure to sedatives. 14 However, a large pragmatic randomized trial conducted in 31 PICUs in the US involving almost 2,500 children failed to demonstrate reduction in length of mechanical ventilation by using a nurse-directed sedation protocol. 20 No sedation The use of sedatives is associated with longer durations of mechanical ventilation and ICU stay. Numerous studies have confirmed the link between sedation and other adverse patient consequences including delirium, delayed mobilization, long-term psychological morbidity, and cognitive impairment. 41 In general, patients in paediatric ICU are more frequently oversedated than undersedated. For example, in pooled data from 15 studies patients were optimally sedated in 57.6 % of the observations, undersedated in 10.6 % of the observations, and oversedated in 31.8 % of the observations. 15 The Clinical Practice Guidelines from the Society of Critical Care Medicine for the Management of Pain, Agitation, and Delirium in Adult Patients in the Intensive Care Unit recommend either daily interruption of sedation or titration to achieve minimal sedation be routinely used in mechanically ventilated adults unless clinically contraindicated. 21 Singlecentre randomized controlled trial in paediatric intensive care unit showed that the length of mechanical ventilation, duration of ICU stay, and total dose of midazolam were reduced in children who underwent daily interruption of sedation. 22 There is also a single-centre randomized controlled study showing increased ventilator free days and decreased length of ICU stay in adults receiving no sedation. 23 However, meta-analysis of nine adult RCTs failed to demonstrate statistical difference in duration of mechanical ventilation or ICU stay in patients managed with and without daily interruption of sedation. 41 Non-pharmacological interventions Sympathetic nursing of critically ill children and careful attention to simple environmental factors enhances comfort and can reduce the need for pharmacological analgesic and sedative agents. These are some of the strategies used in the PICU and recommended by PICS 1 : - Massage and relaxation - Viewing of videos - Music therapy - Play specialist distraction - Presence of relatives - Special mattresses - Noise reduction - Maintenance of patient s dignity and respect - Maintenance of daily schedule (together with the use of clocks, calendars and lighting changes to maintain day-night orientation) Evidence that any of these methods promotes sleep is low or very low with best support in metaanalysis for ear plugs and eye masks. 24 Copyright Great Ormond Street Hospital. All rights reserved. Page 11 of 33

12 Doses of sedatives recommended by PICS are summarized in Appendix 1 Enteral sedation Where the enteral route is available, enteral sedatives such as the hypnotic agents chloral hydrate or triclofos sodium, and sedating antihistamines such as promethazine or alimemazine (trimeprazine), can be introduced. Chloral hydrate and promethazine have been shown to be more effective than intravenous midazolam in providing maintenance sedation in critically ill children. - Antihistamines are classed as sedating and non-sedating according to their potential for CNS depression. The sedating antihistamines include trimeprazine and promethazine; both are more sedating than chlorpheniramine and cyclizine. Sedating antihistamines have significant anti-muscarinic activity and should not be used in neonates or older children with glaucoma. - Chloral hydrate was the first synthetic drug employed for its sedative-hypnotic effect. Unlike opioids, it produces sedation without significant adverse effects on cardiovascular or respiratory function at therapeutic doses. 25 Chloral hydrate is rapidly absorbed from the gastrointestinal tract and is converted to the active metabolite trichloroethanol. The drug starts to act within min, being metabolised in the liver and other tissues and excreted in the urine and bile. Duration of action is min but may be prolonged in renal or hepatic disease and in neonates. Gastrointestinal irritation is the most commonly reported adverse effect. Triclofos sodium is believed to cause fewer gastrointestinal disturbances than chloral hydrate. 1 Benzodiazepines Midazolam Mechanism of action Metabolism Half-life Advantages Disadvantages Uses Benzodiazepines act by facilitating gamma amino butyric acid (GABA) the main inhibitory neurotransmitter in the central nervous system. GABA normally opens chloride channels, hyperpolarise neurones and decrease their excitability. Benzodiazapines facilitate GABA by increasing the frequency of the chloride channel opening. Metabolized by hepatic oxidation, with renal excretion of active metabolite 3 to 11 hr; active metabolite accumulates with prolonged infusion Midazolam is the recommended agent for the majority of critically ill children requiring intravenous sedation. 1 Midazolam is an excellent agent for inducing antegrade amnesia without impairing the ability to retrieve previously learned information; an effect which can be achieved even when sedation is minimally evident. Its advantage is that it has a number of routes of administration which has given it an important role in the acute treatment of seizure disorders. Midazolam has the shortest elimination half-life of the benzodiazepine group. Following a single bolus intravenous injection in healthy adult patients, the time to peak sedation is 5 10 min with a duration of action of min. Metabolite 1-hydroxymidazolam can accumulate in the critically ill. Little information has been published on its effectiveness and safety when administered to critically ill neonates. There have been reports on increased adverse neurological outcomes, but causality has not been clearly demonstrated. It has been questioned whether midazolam is safe and effective sedative in neonates. 26 Most common sedative in the PICU Benzodiazepine antagonists: Flumazenil is a specific benzodiazepine antagonist. Flumazenil is given intravenously and should be given in small aliquots as large doses can precipitate seizures, cardiac arrhythmias and acute withdrawal symptoms. It has a half-life of only 1 hour so may need to be given as an infusion or the actions of the benzodiazepines can recur. Copyright Great Ormond Street Hospital. All rights reserved. Page 12 of 33

13 Alpha-2 agonists Clonidine Mechanism of action Metabolism Half-life Advantages Disadvantages Uses Dexmedetomidine Mechanism of action Metabolism Half-life Advantages Disadvantages Uses Clonidine is an α-adrenergic agent that acts specifically on α 2 -receptors. The α 2 -receptors are located presynaptically and inhibit the released of noradrenaline from sympathetic nerves. Stimulation of these receptors decreases sympathetic tone, resulting in decreases in blood pressure and heart rate. Sedation and analgesia is mediated by centrally located α 2A - receptors (locus coeruleus, brain stem nuclei, cerebral cortex, septum, hypothalamus, and hippocampus). Hepatic, urinary excretion 9 hr Sedation without causing respiratory depression, and exert anxiolytic effects that are comparable with those of benzodiazepines. 1 Reduce the requirement for other sedative agents and improve haemodynamic and sympathoadrenal stability. Clonidine blocks the symptoms of withdrawal by decreasing the amount of norepinephrine released into the synaptic cleft and reducing the firing rate of noradrenergic neurons within the locus coeruleus. Adverse effects associated with the use of clonidine include dry mouth, bradycardia, hypotension, and headache. Withdrawal of clonidine after prolonged administration has been associated with hypertension and seizures, and abrupt discontinuation should be avoided. 1 In total, six RCTs have been published comparing α-2 agonists to other sedatives. Meta-analysis of these trials showed that clonidine has an opiate and benzodiazepine sparing effect, particularly, in neonates 26 The therapeutic effects of dexmedetomidine are mediated throughout the CNS: with the sedative and anxiolytic effects resulting from its activity in the locus coeruleus and the analgesic effects from the dorsal horn of the spinal cord. These actions result in sedation, anxiolysis, and analgesia coupled with minimal concern for respiratory depression times more active at the α 2 -receptors than at the α 1 -receptors and is thus eight times more selective than clonidine. Hepatic, urinary excretion 2 hr Dexmedetomidine seemingly provides a qualitatively different type of sedation in which patients are more interactive and so potentially better able to communicate their needs. As compared with lorazepam and midazolam, in adults dexmedetomidine resulted in less delirium and a shorter duration of mechanical ventilation but not reduced stays in the ICU or hospital. 2 Prolonged infusions of dexmedetomidine can be tolerated safely and are associated with minimal clinically significant hemodynamic effects. Dexmedetomidine infusions may decrease the overall opioid and benzodiazepine burden. Dexmedetomidine compared to other sedatives has a potential to reduce length of mechanical ventilation in postoperative paediatric patients. 26 Prolonged infusions of dexmedetomidine may be associated with rebound tachycardia, hypertension, and withdrawal symptoms with rapid discontinuation, suggesting a need for weaning of the infusion. Currently, at GOSH dexmedetomidine is used in children and term neonates, but not in preterm infants due to unclear pharmacokinetics and effect on neurodevelopment. Recent phase II/III clinical trial demonstrated that dexmedetomidine is effective and safe preterm newborns. 28 Copyright Great Ormond Street Hospital. All rights reserved. Page 13 of 33

14 Ketamine Ketamine Mechanism of action As a phencyclidine derivative, ketamine is in a unique class that induces a functional disorganization between the thalamoneocortical and limbic systems, producing a dissociative state. The primary anaesthetic properties of ketamine are due to its antagonism of CNS N-methyl-Daspartate (NMDA) receptors. Ketamine due to its effects on µ and κ opioid receptors is also a potent analgesic. Ketamine promotes central sympathetic stimulation and inhibition of neuronal catecholamine uptake. Metabolism Hepatic (cytochrome P450) Half-life hr Advantages Disadvantages Uses Barbiturates Data from several small clinical trials and observations suggest that ketamine decreases airway resistance, improves dynamic compliance, and preserves functional residual capacity, minute ventilation and tidal volume. The ability of ketamine to antagonize bronchospasm may be related to its vagolytic and direct smooth muscle relaxant effects. Additionally, ketamine does not result in significant perturbations in blood pressure, heart rate, or vascular resistance. Nevertheless, ketamine has several significant side effects: hypersalivation, emergence reaction, negative inotropy in heart failure physiology, and pro-convulsant properties. 29 There are data to suggest that the traditional view of increase in intracranial pressure with use of ketamine is not founded on evidence and it is perfectly safe to use it as an induction agent in patients with head trauma. 30 Ketamine may be a safe and effective tool for maintenance sedation of mechanically ventilated patients, however data from large prospective trials are missing. 29 As maintenance sedation agent it is usually used in status asthmaticus. Thiopentone Mechanism of action Metabolism Half-life Advantages Disadvantages Uses Thiopentone binds at a distinct binding site associated with a Cl - ionopore at the GABA A receptor. It lowers ICP through two distinct mechanisms: suppression of metabolism and alteration of vascular tone. Barbiturate therapy improves coupling of regional blood flow to metabolic demands resulting in higher brain oxygenation with lower cerebral blood flow and decreased ICP from decreased cerebral blood volume. Hepatic, will accumulate faster in liver failure hr Lowers ICP, decreases brain oxygen consumption, potent anticonvulsant Barbiturates must be given cautiously to haemodynamically unstable patients because they all directly depress the myocardium and the arterial vascular tree and cause significant hypotension. The solution is highly alkaline and extravasation causes severe tissue necrosis and pain. Management of patients with severe head injuries with raised ICP and intractable seizure disorders. The infusion should be titrated with continuous EEG monitoring to achieve burst suppression. Electrical silence offers no further advantage and leads to increased numbers of complications. Thiopentone can also be used when conventional sedation is ineffective or the patient develops tachyphylaxis requiring high doses of opioids and/or benzodiazepines. However, its use in these circumstances is associated with high incidence of complications. 32 Copyright Great Ormond Street Hospital. All rights reserved. Page 14 of 33

15 Propofol Propofol Mechanism of action Metabolism Half-life Advantages Disadvantages Uses The action of propofol involves a positive modulation of the inhibitory function of GABA through GABA A receptors Hepatic, mainly by glucuronidation Initial distribution phase t 1/2α = min. Second redistirubtion phase t 1/2β =21-70 min. In the adult ICU population, propofol has been compared with midazolam for long-term sedation. Both agents provide good sedation, but propofol has the advantage of being more titratable with a faster recovery. Despite the increased drug cost, the use of propofol can reduce overall ICU costs because of a reduction in ventilator weaning time. 33 The longer-term administration of propofol by continuous infusion has been associated with the propofol infusion syndrome, a rare but frequently fatal complication characterised by acidosis, bradyarrhythmia and rhabdomyolysis that has been reported in both children and adults. 1 It is for this reason propofol in not recommended as maintenance sedative in paediatric intensive care unit. Propofol has a role as a short acting hypnotic agent that can be given in low doses to achieve short acting and controlled sedation. Propofol is not considered an analgesic, so opioids such as fentanyl may be combined with propofol to alleviate pain if intended procedure requires it. 25 Neuromuscular blockade Physiology of the neuromuscular junction Nerves extend from the brainstem (in the case of cranial nerves) or from the spinal cord to muscle cells. Signals are transmitted along axons, which are insulated with myelin, at conduction speeds of up to m s -1. Within most mammalian muscles each muscle fibre has a single region of contact with the axon of the motor neurone supplying it. This specialist structure is the neuromuscular junction where transmission is chemical rather than electrical as is the case in the axon. The role of the neuromuscular junction is to facilitate transmission of the electrical impulse from the nerve terminal to the motor endplate of the muscle. This is achieved by the transmission of 60 nm vesicles containing acetylcholine across the nm synaptic cleft. Binding of two acetylcholine molecules to the a units of the acetylcholine receptor at the motor endplate produces a conformational change in the receptor resulting in the opening of a central pore, which stays open for between 1 10 ms. This in turn results in the influx of some 10 5 sodium ions, which increases the membrane potential from -90 mv to approximately 0 mv. At this point potassium channels open and allow the efflux of potassium ions. When the endplate potential at the motor endplate reaches a threshold value of around from -50 mv voltage-dependent sodium ion channels of the adjacent muscle membrane open and the initiation of an action potential occurs. This action potential is propagated throughout the muscle fibre and results in muscle contraction. 37 Use of muscle relaxants has fallen from about 90% of patients in the 80's to < 10% of patients in the 00's in the UK. Use has declined since synchronised modes of ventilation have become available. Despite this there are many recognized indications for the sustained administration of neuromuscular blocking agents in critically ill children. These may include the prevention of patient-ventilator dyssynchrony during mechanical ventilation, particularly when employing less physiological techniques such a deliberate hypo- or hyperventilation, inverse ratio ventilation or high frequency oscillatory ventilation. Sustained neuromuscular blockade may be instituted in the management of specific medical conditions, such as pulmonary hypertension, tetanus, malignant hyperthermia, neuroleptic malignant syndrome, and in other patients undergoing induced hypothermia in order to prevent shivering. Occasionally, specific surgical repairs may need to be protected in the immediate postoperative period such as tracheal reconstruction, cricoid split procedures, and vascular anastamoses. 37 Muscle relaxation is also commonly used during patient transfer. Neuromuscular-blocking agents have been suggested to reduce ICP by a variety Copyright Great Ormond Street Hospital. All rights reserved. Page 15 of 33

16 of mechanisms including a reduction in airway and intrathoracic pressure with facilitation of cerebral venous outflow and by prevention of shivering, posturing, or breathing against the ventilator. Reduction in metabolic demands by elimination of skeletal muscle contraction has also been suggested to represent a benefit and is often used in the management of low cardiac output state. 31 Risks of neuromuscular blockade include the potential devastating effect of hypoxemia secondary to inadvertent extubation. Prolonged immobility may result in muscle atrophy, joint contractures, pressure sores, pulmonary atelectasis with associated pneumonia and corneal drying with potentially permanent corneal damage. Several neuromuscular blocking agents can produce ganglion and vagal blockade and result in liberation of significant amounts of histamine. Together these can produce adverse cardiovascular effects such as hypotension, tachycardia or bradycardia particularly after bolus dosing. 31 Neuromuscular blockade also poses a risks of masking seizures and causes immobilization stress (if neuromuscular blockade is used without adequate sedation/analgesia). One of the most widely reported complications associated with the administration of neuromuscular blocking agents is that of critical illness polyneuropathy and myopathy. Myopathy is most commonly seen with the combined use of non-depolarizing agents and corticosteroids. Incidence of this complication varies between 1% and over 30% of cases. 31 PICS recommendations for on-going neuromuscular blockade: - Ensure adequate analgesia and sedation before commencing neuromuscular blocking agents - The need for neuromuscular blocking agents should be regularly reviewed and they should be discontinued as soon as possible - Atracurium or vecuronium given by continuous infusion are the recommended agents for the majority of critically ill children requiring neuromuscular blockade. Intermittent doses of pancuronium may be considered - Whenever it is safe to do so, continuous infusions of neuromuscular blocking agents should be discontinued at least once every 24 hours until spontaneous movement returns and the levels of analgesia and sedation can be assessed Depolarizing muscle relaxants Suxamethonium acts by mimicking acetylcholine at the neuromuscular junction but hydrolysis is much slower than for acetylcholine; depolarisation is thereby prolonged resulting in neuromuscular blockade. Its action cannot be reversed and recovery is spontaneous (if neostigmine is given it will potentiate this block). Suxamethonium is the most commonly used depolarizing muscle relaxant especially for rapid sequence induction (RSI) technique in both controlled and emergency settings. Suxamethonium has been the preferred muscle relaxant because it has a rapid onset of 40 to 60 seconds and a short duration, lasting only six to 10 minutes. Bradycardia is a frequent occurrence with suxamethonium use and concomitant use of atropine reduces this and the excessive salivation which also occurs. Prolonged paralysis may be seen in patients with low or atypical plasma cholinesterase. Suxamethonium depolarizing action can lead to hyperkalaemia, possibly inducing fatal cardiac arrhythmias. As a result, it is contraindicated in patients with major burns (beyond 48 hours and for up to 6 months or more), major crush injuries (beyond 48 hours), severe abdominal sepsis, denervation syndromes (such as amyotrophic lateral sclerosis or Guillain Barré Syndrome), muscular dystrophy and major nerve or spinal cord injuries. It is also contraindicated in patients with known hyperkalaemia, a history of malignant hyperthermia or previous allergic reaction to suxamethonium. Suxamethonium use has also been associated with variable increases in intracranial pressure and to a lesser extent intraocular pressure and should be administered with drugs that help mitigate these side effects. 38 When compared to rocuronium in a meta-analysis of 50 RCTs suxamethonium was better in establishing excellent and clinically acceptable intubation conditions during RSI there was no difference in failed intubations. However, this finding depended on the dose of rocuronium used, and there was no difference between the agents when larger ( mg kg -1 ) doses are used. It should be noted that rocuronium has a longer duration of action compared to suxamethonium, and that increasing the dose of rocuronium increases also its duration of action (73 ± 32 minutes for 1.2 mg kg -1 dose) which can result in an increased incidence of adverse outcomes (i.e. increased duration of paralysis in a patient who cannot be successfully intubated). No difference between the two agents was also found in pooled data from five paediatric trials. It must be noted that these trials were underpowered for an equivalence trial. 38 Copyright Great Ormond Street Hospital. All rights reserved. Page 16 of 33

17 Non-depolarizing muscle relaxants Also known as competitive muscle relaxants these compete with acetylcholine for receptor sites at the neuromuscular junction. Their action may be reversed by anticholinesterases such as neostigmine. Divided into 2 groups: aminosteroid (pancuronium, rocuronium, vecuronium) and benzylisoquinolinium (atracurium, cisatracurium, mivacurium). Non-depolarizing muscle relaxants have a slower onset of action than suxamethonium and they are not considered to be triggers for malignant hyperthermia. Benzylisoquinolinium group agents are associated with histamine release which can cause skin flushing, hypotension, tachycardia, bronchospasm. Most aminosteroid ND muscle relaxants cause little or no histamine release. Table 7 Non-depolarizing muscle relaxants recommended by PICS 37 Drug Dosing information Notes Pancuronium -1 Intravenous bolus; µg kg -1 dose Given as required, usually 4 6 h Reduce dosage in neonates Vagolysis causes tachycardia Vecuronium -1 Intravenous bolus; µg kg -1 dose -1 Intravenous infusion; µg kg -1 h Reduce dosage in neonates Little histamine release Few cardiovascular effects Rocuronium -1 Intravenous bolus; 600 µg kg -1 dose -1 Intravenous infusion; µg kg -1 h Rapid onset Few cardiovascular effects Atracurium -1 Intravenous bolus; µg kg -1 dose -1 Intravenous infusion; mg kg -1 h May cause cardiovascular effects due to histamine release Relatively safe in renal or hepatic failure Cisatracurium -1 Intravenous bolus; 150 µg kg -1 dose -1 Intravenous infusion; µg kg -1 h Little histamine release Few cardiovascular effects Higher doses may be required Vecuronium Vecuronium is the preferred drug for continuous muscle relaxation. It is a derivative of pancuronium that is slightly more potent than the parent compound. Although it does not have a rapid onset of action, vecuronium is notable for its relative lack of unwanted effects, even in high doses. The major route of elimination is hepatobiliary, and metabolites have some neuromuscular blocking activity; the renal excretion of these metabolites explains the accumulation that may be seen in patients with renal failure. Differences in the volume of distribution result in a longer duration of action in younger children. Rocuronium Rocuronium is a steroid-based non-depolarizing muscle relaxant, which has been proposed for creating intubating conditions. Rocuronium has the benefit of a rapid onset of action which is approximately half that of vecuronium. When used to provide sustained neuromuscular blockade rocuronium is reported to have minimal cardiovascular effects, although in high doses it may cause some vagolysis. In addition, owing to its rapid onset of action, rocuronium is a common choice for facilitating tracheal intubation in circumstances where a non-depolarizing neuromuscular blocking agent is indicated. If an alternative agent to suxamethonium is required for RSI, rocuronium 1 mg kg -1 can be used to create acceptable intubation conditions but it must be kept in mind that the length of paralysis will be significantly prolonged. The introduction of suggamadex to facilitate reversal of non-depolarizing muscle relaxants may decrease the incidence of this complication, but this drug is not currently widely available and is expensive. 38 The only absolute contraindication to rocuronium is allergy. Care must be taken with people who have myasthenia gravis or myasthenic syndrome, hepatic disease, neuromuscular disease, carcinomatosis, or severe cachexia, as the duration of action may be profoundly increased. It should be remembered however that neuromuscular blocking agents have differential effects on different muscle groups, and the onset of laryngeal adductor paralysis with rocuronium is significantly slower than with suxamethonium. 37 Atracurium Atracurium, a bisquaternary tetrahydropapaverum derivative, is one of the benzylisoquinolinium family of drugs. It is not a pure drug and can form 10 different isomers; in the commercial preparation three isomers predominate: trans trans, cis trans, and cis cis. Single doses of atracurium have a relatively rapid onset of action and conditions suitable for tracheal intubation Copyright Great Ormond Street Hospital. All rights reserved. Page 17 of 33

18 can usually be achieved within 90 seconds of the intravenous injection of µg kg -1, with an elimination half time of 21 min. The unique metabolism of atracurium gives this agent particular advantages as a neuromuscular blocking agent for prolonged use in the critically ill. The drug is broken down primarily by two purely chemical mechanisms: Hofman degradation (a nonenzymatic base-catalyzed reaction) and nonspecific ester hydrolysis via plasma cholinesterase. Although some organ uptake has been demonstrated and 10% of the drug is excreted in the urine, the effects of atracurium have not been shown to be prolonged in renal or hepatic failure. There is a strong correlation between rectal temperature and the offset time of atracurium; prolonged moderate hypothermia has a very significant effect on the offset time of atracurium when given by infusion to critically ill children. Clearance of atracurium also tends to be faster in children than in adults. 37 Cisatracurium Cisatracurium is the R-cis, R -cis isomer of atracurium. This agent has a similar profile to atracurium; being free from significant vagolytic or sympatholytic properties and with a slower onset of action but three to four times the potency of atracurium. Cisatracurium is less likely to stimulate histamine release. It has been suggested that recovery of neuromuscular function after discontinuation of neuromuscular blocking drug infusion in infants and children is significantly faster with cisatracurium than vecuronium. 37 Copyright Great Ormond Street Hospital. All rights reserved. Page 18 of 33

19 Information for Year 2 ITU Training (advanced): Analgesia: Regional anaesthesia: Local anaesthetic systemic toxicity, topical anaesthesia, central neuraxial blockade Sedation: Withdrawal syndrome: opiate and benzodiazepine withdrawal, assessment Delirium Neuromuscular blockade: Monitoring neuromuscular blockade Sedation and analgesia for procedures Painless imaging Painful procedures Consideration choosing specific agents: sucrose, midazolam, ketamine, chloral hydrate, nitrous oxide, sevoflurane, propofol, opioids Curriculum Notes for Year 2: Regional anaesthesia Local anaesthetics (LA) are widely used in children for the short-term relief of painful procedures by subcutaneous or topical administration. Regional techniques can be used to provide epidural anaesthesia and peripheral nerve blocks, and these techniques are being used more frequently in the critical care environment as they enable effective analgesia with fewer systemic side effects such as respiratory depression and they are morphine sparing. 1 LAs cause reversible interruption of the conduction of impulses in peripheral nerves. The primary electrophysiological effect of these compounds is to cause a local decrease in the rate and degree of depolarisation of the nerve membrane. These effects are due to blockade of sodium channels, thereby impairing sodium ion flux, across the membrane. The drugs used vary widely in their potency, toxicity, duration of action, stability, solubility in water and ability to penetrate mucous membranes. These variations determine their suitability for use by various routes e.g., topical (surface), infiltration, plexus, epidural or spinal block. LAs do not rely on the systemic circulation to transport them to their site of action, but uptake into the systemic circulation is important in terminating their action and producing toxicity. Following most regional anaesthetic procedures, maximum arterial plasma concentrations develop within about 10 to 25 minutes; so careful watching for toxic effects is necessary during the first 30 minutes after injection. Great care must be taken to avoid accidental intravascular injection. 11 LAs may be applied to the skin, the eye, the ear, the nose and the mouth as well as other mucous membranes. In general, cocaine, amethocaine, lignocaine and prilocaine are the most useful and effective LAs for this purpose. When used to produce topical anaesthesia, they usually have a rapid onset of action (5-10 min) and a moderate duration of action (30-60 min). Cocaine is a potent vasoconstrictor and is useful in the reduction of bleeding as well as topical anaesthesia. There are two classes of LAs drugs defined by the nature of the carbonyl-containing linkage group. The ester agents include cocaine, procaine, amethocaine and chloroprocaine, whilst the amides include lignocaine, prilocaine, mepivacaine and bupivacaine. There are important practical differences between these two groups of LA agents. Esters are relatively unstable in solution and are rapidly hydrolysed in the body by plasma cholinesterase (and other esterases). One of the main breakdown products is para-amino benzoate (PABA) which is associated with allergic phenomena and hypersensitivity reactions. In contrast, amides are relatively stable in solution, are slowly metabolised by hepatic amidases and hypersensitivity reactions to amide LAs are extremely rare. In current clinical practice esters have largely been superseded by the amides. Copyright Great Ormond Street Hospital. All rights reserved. Page 19 of 33

20 Toxicity Toxic effects associated with LAs usually result from excessively high plasma concentrations. Toxic effects initially include a feeling of inebriation and light-headedness followed by sedation, circumoral paraesthesia and twitching: convulsions can occur in severe reactions. LAs are also cardiotoxic (in high enough systemic doses) causing severe bradyarrythmias, sinus arrest, a negative inotrope effect and depressed contractility. When prolonged analgesia is required a long acting LA is preferred to limit toxicity. LA injections should be given slowly so that possible inadvertent intravascular injection can be rapidly detected. LA should not be injected into inflamed or infected tissues (increased absorption will occur with increased risks of toxicity). 11 Immediate management includes stopping injecting the LA, establishing the airway if necessary (hyperventilation may help by increasing plasma ph in the presence of metabolic acidosis), CPR if circulatory arrest, seizure control: benzodiazepine, thiopental or propofol in small incremental doses. Lipid intravenous emulsion should be considered in any patient with systemic toxicity and it is part of treatment of circulatory arrest (20% lipid emulsion bolus 1.5 ml kg 1 over 1 min followed by infusion 15 ml kg 1 h 1 ). 13 Most LAs cause vasodilatation (except cocaine). The use of vasoconstrictors in combination limits systemic absorption and hence toxicity; it will also prolong the duration of action. Adrenaline is commonly used (concentration 5 mcg ml). Adrenaline containing solutions should never be used for infiltration around end-arteries i.e. penis, ring block of fingers or other areas with a terminal vascular supply as the intense vasoconstriction may lead to severe ischemia and necrosis. Topical anaesthesia Surface anaesthesia Effectively absorbed from mucous membranes and is a useful surface anaesthetic in concentrations of 1 5%. Solutions of Lignocaine 1% used otherwise; duration of action when combined with adrenaline is 90 minutes. Surface preparations: - Lignocaine gel 1% for mucocutaneous anaesthesia: mouth ulcers, urethral catheterisation (combined with chlorhexidine). - Lignocaine ointment 5%: local relief anal fissures, haemorrhoids, herpes zoster. - Lignocaine solution 4%: spray for bronchoscopy. - Lignocaine cream: (children over 1 year). EMLA cream is a eutectic mixture of LAs which may be used to provide surface anaesthesia of the skin. It is a mixture of the base forms of lignocaine 2.5% and prilocaine in equal proportions in an emulsion. Cutaneous contact (usually under an occlusive dressing) should be maintained for at least 60 minutes prior to venepuncture. Infiltration local anaesthesia Conduction anaesthesia can be divided into minor nerve blockade (e.g. ulnar, radial or intercostal), and major blockade of deeper nerves or trunks with a wide dermatomal distribution (e.g. brachial plexus blockade). For each individual agent the duration of anaesthesia will be determined more by the total dose of the drug rather than the volume or concentration of drug used. Infiltration techniques are used to provide anaesthesia for minor surgical procedures. Amide anaesthetics with a moderate duration of action are commonly used (lignocaine, prilocaine and mepivacaine). The site of action is at unmyelinated nerve endings and onset is almost immediate. The duration of LA is variable. Procaine has a short duration of action (15-30 min), while lignocaine, mepivacaine and prilocaine have a moderate duration of action ( min). Bupivacaine has the longest duration of action (approximately 200 min). The addition of adrenaline (1 in 200,000) will prolong the duration of anaesthesia. - Lignocaine: Injection of Lignocaine into the skin locally to minimise the pain of chest drain insertion, stitching, lumbar puncture etc. Neonates: up to 3 mg kg -1 (0.3 ml kg -1 of 1% solution) 4 hourly max. Child 1 month 12 years: up to 4 mg kg -1 (0.4 ml/ kg -1 1% solution) 4 hourly max. Child years: up to 200 mg, max 4 hourly - Bupivacaine: Bupivacaine has a long duration of action (3 7 hours). It has a slow onset of action taking up to 30 minutes for full effect. Often used in lumbar epidural blockade. It is the principal drug for spinal anaesthesia. Preparations with and without adrenaline are available. Copyright Great Ormond Street Hospital. All rights reserved. Page 20 of 33

21 Central neuraxial blockade Epidural anaesthesia Is commonly used during surgery, often combined with general anaesthesia, because of its protective effect against the stress response of surgery. It is often used when postoperative pain relief is essential. An epidural is a specialised procedure performed by an appropriately trained doctor, usually an anaesthetist. The needle is inserted through the skin into the epidural space. A fine plastic catheter is threaded through it, and the needle is removed. The catheter is taped in place and LA and analgesics are infused through it. LA solutions are deposited in the epidural space between the dura mater and the periosteum lining the vertebral canal (Figure 3). The epidural space contains adipose tissue, lymphatics and blood vessels. The injected LA solution produces analgesia by blocking conduction at the intradural spinal nerve roots. The quality and extent of the blockade produced by each agent is determined by the volume as well as the total dose of the drug. Epidural catheters can be placed in either the cervical, thoracic or lumbar regions. Epidural infusions are usually run for 2-3 days and rarely for longer than 5 days. Bupivacaine (0.5%) or lignocaine ( %) are usually used to produce extradural anaesthesia. Repeated administration of lignocaine or mepivacaine into the epidural space may result in a diminished response with each subsequent dose (tachyphylaxis) Figure 3 Sagittal section of the spine Spinal anaesthesia The introduction of LA solutions directly into the cerebrospinal fluid (CSF) produces spinal anaesthesia. The LAs do not have to cross tissue or diffusion barriers and also the central attachments of the ventral and dorsal nerve roots are unmyelinated, which allows rapid uptake of the free base. There is a faster onset of action and a smaller dose is required as compared to epidural anaesthesia. Spinal anaesthesia produces a similar clinical effect with a dose approximately ten times smaller than that needed for extradural anaesthesia. The greatest challenge in spinal anaesthesia is to control the spread of LA through the cerebrospinal fluid (CSF) to provide a block which is adequate for the proposed surgery without unnecessary extensive spread, and increased risk of complications. Solutions of amethocaine (0.2%), Copyright Great Ormond Street Hospital. All rights reserved. Page 21 of 33

22 lignocaine (5%), prilocaine (5%) bupivacaine (0.5%) and mepivacaine (4%) are commonly used to produce spinal anaesthesia. Prilocaine and mepivacaine have a slightly longer duration of action than lignocaine; bupivacaine has the longest duration of action. The following analgesics may be separately added to the LA solution to improve analgesia: Fentanyl, Morphine, Clonidine. Assessment of sensory level It is important to assess sensory block (Figure 4): - To ensure the spinal/epidural/caudal anaesthesia is covering the patient's pain - To ensure the block is not too extensive, which may increase the risk of complications - Assessment should be performed on both sides of the body as blocks may be uneven or unilateral. Ice or ethyl chloride spray, which produces a cold sensation, can be used to assess the level. Once ascertained the level of the block must be documented. Record both the upper and lower limits of the block: eg T7-L1 L = R or R: T7-L1 L: T10-L2 - Regular assessments should take place and in addition if the rate of epidural/spinal is increased or the patient complains of pain then the level should be reassessed. Epidurals and spinals are placed and monitored by the pain team who should be contacted if there are any problems or if the level of the block is higher than expected. Figure 4 Dermatome assessment ( Children's Pain Management Service, The Royal Children's Hospital, Melbourne) Sedation Withdrawal Iatrogenic withdrawal can occur with the abrupt discontinuation or too rapid weaning of opioids and/or benzodiazepines. An estimated 10 34% of all PICU patients are at risk for iatrogenic withdrawal and for those exposed to greater than 5 to 10 days of opioids and benzodiazepines the risk is between %. 34 Withdrawal syndrome is thought to be related to the total drug doses received: a total dose of midazolam of > 60 mg kg -1 and a total fentanyl dose of >1.5 mg kg -1 are significantly associated with the occurrence of withdrawal syndromes. Therefore, strategies to reduce the incidence of withdrawal syndrome begin by making efforts to reduce the total doses of benzodiazepines and opioids administered by using sedation and pain-scoring systems and through the application of non-pharmacological interventions. 1 The potential for Copyright Great Ormond Street Hospital. All rights reserved. Page 22 of 33

23 opioid and benzodiazepine withdrawal syndrome should be considered after 7 days of continuous therapy. When subsequently discontinued, the doses of these agents may need to be routinely tapered. 1 It is standard practice in many units to taper doses off by daily increments of 5 10% of the initial dose. There is, however, little evidence to support this practice. Neurologic signs of opioid withdrawal include anxiety, agitation, grimacing, insomnia, increased muscle tone, abnormal tremors, and choreoathetoid movements. Gastrointestinal symptoms include vomiting, diarrhoea, and poor appetite, whereas autonomic signs include pupillary dilatation, tachypnoea, tachycardia, fever, goose pimples on the skin, sweating, pyrexia, and hypertension. 9 The mainstay of pharmacologic management is gradual opioid weaning. In the acute situation, most opioids are given as continuous intravenous infusions. These infusions can be substituted with long-acting enterally administered agents or subcutaneous infusions, which have the advantages of ease of use, decreased need for intravenous access, and early PICU discharge. Therapy must be directed by regular assessments for signs of opioid withdrawal. Pharmacologic agents commonly used to treat or prevent opiate withdrawal include the following 9 : Methadone is an effective analgesic for paediatric patients. It has a prolonged half-life, inhibits tolerance by multiple mechanisms Buprenorphine is a long-acting μ-opioid partial agonist with potent analgesic properties and naloxone-reversible respiratory depression Clonidine is an α2-adrenergic receptor agonist with potent analgesic effects; because α2- adrenergic and μ-opioid receptors activate the same K + channel via inhibitory G proteins, clonidine has been used to treat opioid withdrawal Dexmedetomidine is an α2-adrenergic agonist with eightfold greater affinity than clonidine Gabapentin was developed as an anticonvulsant but reduces neuropathic pain via effects on α2-δ calcium channels Propofol can be used for preventing benzodiazepine and opioid withdrawal as suggested by the results of preclinical and clinical studies 34 Benzodiazepine withdrawal symptoms are similar but also include agitation, visual hallucinations, facial grimacing, small amplitude choreic or choreoathetoid movements, and seizures. 34 Withdrawal assessment, especially, in preverbal or nonverbal children, can be challenging. The WAT-1 (Figure 5) scale is used to identify iatrogenic withdrawal syndrome. The 11-item WAT-1 consists of direct observation of the patient for two minutes, patient assessment using a progressive stimulus routinely performed to assess level of consciousness, and assessment of post-stimulus recovery. Available evidence identifies iatrogenic withdrawal as a WAT-1 Score of Copyright Great Ormond Street Hospital. All rights reserved. Page 23 of 33

24 Figure 5 Withdrawal Assessment Tool version 1 34 Delirium Delirium is acute cerebral dysfunction caused by systemic illness or the effects of treatment. American Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) lists four domains of delirium: (i) disturbance of consciousness, (ii) change in cognition, (iii) development over a short period, and (iv) fluctuation. The most common feature of delirium, thought by many to be its cardinal sign, is inattention. Delirium is a nonspecific but generally reversible manifestation of acute illness that appears to have many causes, including recovery from a sedated or oversedated state. 2 About one in three to five children have delusional memories from their PICU stay and they are associated with use of benzodiazepines and opiates for more than two days. 35,36 In addition, delusional memories are associated with post-traumatic stress syndrome while factual memories are not. 35 The pathophysiology of delirium that is associated with critical illness remains largely uncharacterized and may vary depending on the cause. The increased risk associated with the use of GABA A agonists and anticholinergic drugs led to the suggestion that the GABAergic and cholinergic neurotransmitter systems play a contributory role. Alternative hypotheses include excess dopaminergic activity and direct neurotoxic effects of inflammatory cytokines. 2 There are two distinct forms of delirium, hypoactive and agitated (or hyperactive). When individual patients intermittently have both forms, it is termed mixed delirium. The hypoactive form is characterized by inattention, disordered thinking, and a decreased level of consciousness without agitation. 2 Several screening tools are currently available: Delirium Rating Scale (DRS), Pediatric Confusion Assessment Method for the ICU (pcam-icu), Pediatric Anesthesia Emergence Delirium (PAED), Cornell Assessment of Pediatric Delirium (CAPD). 36 Cornell Assessment of Pediatric Delirium (Figure 6) scores orientation, arousal, and appropriate cognition from 0 to 32 with score 9 indicating delirium with sensitivity of 94.1% and specificity of 79.2%. 36 Unfortunately, these scoring tools perform best in older children and delirium assessment is much more difficult in infants. There is some evidence that delirium can be prevented. Outside the ICU, repeated reorientation, noise reduction, cognitive stimulation, vision and hearing aids, adequate hydration, and early mobilization can reduce the incidence of delirium in hospitalized patients. Haloperidol prophylaxis in patients undergoing hip surgery reduced the severity and duration of delirium. Among patients in the ICU, the duration of delirium was cut in half with early mobilization during interruptions in sedation. 2 Copyright Great Ormond Street Hospital. All rights reserved. Page 24 of 33