Sedation and analgesia in children

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Chapter 100 Sedation and analgesia in children

All children, including preterm infants, feel and remember pain and discomfort.¹ Provision of adequate sedation and analgesia should therefore be a priority in the management of all critically ill children.

INDICATIONS AND BENEFITS

Pain in the paediatric intensive care unit (PICU) may be surgical in origin or due to the underlying illness or to procedures (e.g. central venous catheterisation, lumbar puncture and removal of drains). Sedation is frequently necessary to allow a child to tolerate an endotracheal tube and mechanical ventilation. It may also be needed to allow sleep in a brightly lit, noisy environment. As young children are unlikely to cooperate during investigations, such as an echocardiogram or computed tomographic (CT) scan, sedation is often necessary to prevent excessive movement.

In addition to its humane benefits, sedation and analgesia can suppress non-advantageous physiological responses to noxious stimuli. Analgesic suppression of the marked postsurgery stress response has been associated with significant improvements in postoperative morbidity and mortality.²^–⁴

ASSESSMENT

Adequacy of pain relief and sedation is dependent on an accurate assessment of the degree of discomfort. This is particularly difficult in the critically ill child who may be preverbal, developmentally delayed, intubated and/or paralysed, or simply uncooperative. Thorough assessment requires careful and frequent consideration of a number of factors. These include the nature of the noxious stimulus, variations in physiological parameters (e.g. heart rate and blood pressure) and interpretation of subjective clues (e.g. facial expressions and posture). Parental interpretations are reliable and should be included in the overall assessment.

Pain and sedation assessment tools should also be utilised. Neonates and infants are particularly difficult to assess and validated assessment tools, including the Premature Infant Pain Profile (PIPP) and CRIES scale, are helpful objective measures of pain in this group.⁵ The Multidimensional Assessment of Pain Scale (MAPS) has recently been validated as a tool for assessing postoperative pain in preverbal children.⁶ Established tools such as the Face, Legs, Activity, Cry and Consolability (FLACC) Scale have been modified to enhance the pain assessment of children with cognitive impairment.⁷ The COMFORT and the modified COMFORT ‘Behavior’ are validated observer reported sedation scales for children 1–3 years.⁸ In older children, self-reporting measurement scales can be used but these require a degree of patient cooperation.

The most challenging group of patients to manage optimally are those receiving muscle paralysis. Attempts to enhance the limited clinical parameters available for interpretation with an objective measure have centred on the bispectral index (BIS). Validation studies in the paediatric intensive care environment are limited and highlight the probable inaccuracy of current methods of assessing sedation in paralysed patients.⁹ In general it is preferable to err on the side of over- rather than undersedation in the paralysed patient.

APPROACH TO MANAGEMENT

The management of discomfort, anxiety and pain should be multifaceted. Recently published consensus guidelines from the United Kingdom Paediatric Intensive Care Society present a detailed analysis of the evidence for assessment and management strategies.¹⁰

Management can and should, whenever possible, begin prior to the child’s admission to intensive care. Orientation to the unit should be accompanied by a clear, age-appropriate explanation of the planned procedure or operation and the expected postoperative course. Parental presence during this phase and at other critical times is also important to help allay anxiety and fear. Close attention should also be paid throughout a child’s admission to potentially distressing physiological factors, such as hunger and urinary retention. In addition to these supportive measures, many paediatric patients require a pharmacological form of analgesia or sedation.

Sedation and analgesia should be tailored to the patient’s particular requirements. It is vital that there be continuous assessment and frequent adjustment of regimes so that optimal levels of sedation and adequate analgesia are delivered at all times. This requires a clear understanding by medical and nursing staff of the aims of management and of the pharmacology of the agents being administered. Relief of pain should be achieved with analgesic agents and care must be taken to avoid the overadministration of sedative agents when the patient’s primary need is for pain relief (Table 100.1). While emphasis should be on optimal comfort, consideration should also be given to minimising side-effects. A single drug may be effective but often a combination of medications and a combination of delivery methods (e.g. i.v./oral, i.v./epidural) will be useful and may avoid the side-effects of high doses of a single agent. A recent trend towards analgesia-based sedation, as an approach to managing the ventilated adult patient, has shown benefits when compared to hypnotic-based regimes.¹¹

Table 100.1 Single dose and infusion rates of sedative and analgesic drugs*

Drug	Bolus dose	Infusion rate
Morphine	0.1–0.2 mg/kg i.v.	10–40 μg/kg per hour
Fentanyl	1–2 μg/kg i.v.	1–10 μg/kg per hour
Remifentanil	0.1–0.5 μg/kg i.v.	0.1–0.5 μg/kg per min
Midazolam	0.1–0.2 mg/kg i.v.	50–200 μg/kg per hour
Midazolam	0.5 mg/kg (oral)	50–200 μg/kg per hour
Ketamine	1–2 mg/kg i.v.	10–20 μg/kg per min (sedation)
Ketamine	1–2 mg/kg i.v.	4 μg/kg per min (analgesia)
Propofol	1–3 mg/kg i.v.	< 4 mg/kg per hour (short term)
Clonidine	1–2 μg/kg i.v.	0.1–2 μg/kg per hour
Clonidine	4 μg/kg (oral)	0.1–2 μg/kg per hour
Dexmedetomidine	0.5–1 μg/kg i.v.	0.2–1.0 μg/kg per hour

Note: Some infusion rates are described per minute and others per hour.

PAEDIATRIC PHARMACOLOGICAL CONSIDERATIONS

Differences in drug handling between children and adults should be considered. Drug distribution, rates of drug metabolism and relative organ blood flows differ in children, particularly in young infants. These differences may result in greater concentrations of free drug and differing volumes of distribution. Neonates have relatively larger total body water, extracellular fluid volume, blood volume and cardiac output and significantly less body fat than adults. Their blood–brain barrier is less efficient and allows more ready entry of some drugs to the brain. Mixed-function oxidases mature quickly to adult levels by 6 months of age, and acetylation and glucuronidation mechanisms mature by about 3 months. Renal blood flow and glomerular filtration rate are low in the immediate neonatal period. However, both increase significantly in the first 2–3 days and reach adult values by around 5 months. Tubular secretory capacity reaches adult levels by 6 months of age. In general therefore, drug metabolism and clearance are relatively mature by 6 months of age but great care is required when dealing with the neonate and young infant.

NON-OPIOID AGENTS

MIDAZOLAM

Midazolam is water soluble, and has a rapid onset of action. Metabolism occurs in the liver and by 6 months of age is comparable to that of an adult. The standard i.v. sedative dose is 0.1–0.2 mg/kg and this is effective for uncomfortable procedures, such as echocardiography and cardioversion. The oral route (0.5 mg/kg) may also be useful though there is a 15-minute delay to onset of sedation. Nasal administration (0.2 mg/kg) can be useful in children who do not have established i.v. access and in whom oral agents are not appropriate. Although midazolam may be effective as the sole sedative agent for ventilated patients, higher doses, and often additional agents, are commonly required in young children (1–4 years).¹² 50–200 μg/kg per hour, in combination with an opioid (morphine 10–40 μg/kg per hour), is usually effective in facilitating mechanical ventilation. Dose-related respiratory depression occurs and hypotension can be significant in hypovolaemic patients and in those with depressed myocardial function. During continuous infusion, accumulation can occur, particularly in young infants (under 6 months) and in patients with liver dysfunction. The use of midazolam in neonatal intensive care is controversial as there are concerns regarding its safety and effectiveness as a long-term sedative in the newborn.¹³

KETAMINE

Ketamine is a dissociative anaesthetic agent with sedative, analgesic and amnesic properties. Biotransformation occurs by the microsomal enzyme system. Thus, there is little metabolism in the newborn and clearance is less and elimination half-life greater in infants than in older children and adults.¹⁴ Ketamine’s usefulness in preterm infants, to a postconceptual age of 51 weeks, is limited because of an increased risk of postanaesthetic apnoea. An initial i.v. dose of 1–2 mg/kg is usually adequate to induce deep sedation. Cardiovascular disturbance is minimal and ketamine is therefore particularly useful as the induction agent in status asthmaticus and in patients with a compromised haemodynamic state, such as tamponade. Prolonged sedation for ventilated children can be achieved with a continuous infusion of 10–15 μg/kg per min and analgesia can be provided by an infusion of 4 μg/kg per min. Concomitant use of an antisialogogue, such as glycopyrrolate, helps control the often seen increase in respiratory tract secretions. The unpleasant emergent phenomena, seen frequently in adults, probably occur less often in children. The traditional practice of concurrently administering a benzodiazepine with the aim of minimising these effects has minimal demonstrable benefit.¹⁵

PROPOFOL

Propofol is a rapidly acting hypnotic agent that is widely used in paediatric anaesthesia and intensive care for short- and longer-term sedation.^16,¹⁷ Although it has no analgesic properties its short half-life makes it an attractive agent for sedation. The half-life decreases with age, probably due to development of metabolising capacity and increasing hepatic flow.¹⁸ Sedation can be achieved in the spontaneously breathing patient, with an induction dose of 1 mg/kg, followed by intermittent smaller doses: 2–3 mg/kg per hour has delivered uncomplicated satisfactory sedation to ventilated children.¹⁹ However, propofol should be used with caution for sedation in the PICU because of the reported association between high dose (> 4 mg/kg per hour), prolonged (> 29 hours) infusions and a clinical syndrome (propofol infusion syndrome) consisting of metabolic acidosis, lipaemia, cardiac failure, arrhythmias and death.²⁰ The pathogenesis of this syndrome remains unclear, although it has been postulated that a disturbance of mitochondrial function leading to disordered hepatic lipid regulation underlies the disorder.²¹ Lipaemia may be an early indicator of developing problems and successful use of haemodialysis in the early phase is the only therapy described.²² There are sufficient concerns to limit the use of propofol in the PICU to short-term sedation in the stable ventilated child. Administration of propofol in the presence of shock, hypoxaemia or acute liver dysfunction, or for long-term, high-dose sedation cannot be recommended. It should be noted that the manufacturers advise against the use of propofol for sedation of children during intensive care.

THIOPENTAL

Thiopental is useful as an anaesthetic induction agent in critically ill children, although its hypotensive effects limit its use in shocked patients. The standard dose is 5 mg/kg, and this should be reduced to 2–3 mg/kg when hypotension is a risk. Thiopental is useful in the management of refractory status epilepticus and may have a role in difficult cases of raised intracranial pressure. In such cases, it is administered by continuous infusion (1–5 mg/kg per hour). Accumulation can lead to prolonged sedation.

CHLORAL HYDRATE

Chloral is an effective oral hypnotic and sedative agent with no analgesic effect. The hypnotic dose is 50 mg/kg and appropriate sedation may be achieved with lower doses. Gastric irritation can be a problem in some children. Toxic doses produce depression of respiration and cardiac contractility. Despite the disadvantage of delayed onset, chloral can be useful given prior to procedures, or as a supplemental sedative agent in the ventilated child and it can effectively induce nocturnal sleep. On a cautionary note, there is some evidence that it may not be suitable in acutely wheezing infants.²³

CLONIDINE AND DEXMEDETOMIDINE

Clonidine is an α₂-adrenoreceptor agonist with significant neurological, neuroendocrine and cardiovascular effects that result in sedation, analgesia and reduced sympathetic outflow. It is rapidly absorbed after oral administration and has a half-life of 9–12 hours. Metabolism is via the liver and kidney and approximately 50% is excreted unchanged in the urine. A single oral dose (4 μg/kg) can provide both preoperative sedation and postoperative analgesia following moderately painful surgery.²⁴ An i.v. infusion (0.1–2 μg/kg per hour) in combination with midazolam (50 μg/kg per hour) has been shown to produce effective sedation in ventilated children without haemodynamic disturbance.²⁵ Clonidine can also have a role in the management of the autonomic storms seen following severe traumatic brain injury and in the management of opioid withdrawal.

Dexmedetomidine is a selective α₂-agonist that has many of the properties of clonidine and may produce less respiratory depression. It is metabolised in the liver and, in adults, has an elimination half-life of 2 hours. It has provided satisfactory sedation and analgesia with minimal respiratory or haemodynamic disturbance in postoperative ventilated and spontaneously breathing adult patients. Respiratory stability during infusion has been sufficient to allow successful extubation of patients who had previously failed because of agitation.²⁶ Use is approved and recommended by the manufacturer for the sedation of adult patients for up to 24 hours. In the paediatric population studies are limited. 0.5–1 μg/kg followed by an infusion of 0.5–1 μg/kg per hour has provided adequate sedation for non-invasive procedures.²⁷ 1 μg/kg followed by 0.1–2 μg/kg per hour, added to an opioid/benzodiazepine regime, has also been shown to improve patient comfort without significant respiratory depression.²⁸ As with clonidine, bradycardia has been seen during continuous infusion.^25,²⁹

OPIOID ANALGESICS

MORPHINE

Morphine is frequently used to provide analgesia and as part of a sedative regime for children on mechanical ventilation. Marked variation in pharmacokinetics in the neonatal period has been demonstrated, but infants over 1 month of age eliminate morphine efficiently and should not be more sensitive to respiratory depression than adults. Clearance and half-life (2 hours) are at adult values by 6 months of age.³⁰ The active metabolite is renally excreted and can therefore accumulate in renal failure. The standard i.v. dose is 0.1–0.2 mg/kg and an infusion rate of 20–40 μg/kg per hour provides safe postoperative pain relief in spontaneously breathing patients. With careful titration of dose to effect, higher rates can be administered, particularly to the child on mechanical ventilation. Patient-controlled analgesia devices delivering fixed doses of opioid, with or without a background infusion, can be used successfully by the majority of school-aged children and may occasionally be appropriate in intensive care. Histamine-related side-effects, in particular nasal itch, may warrant a change of opioid and fentanyl is an alternative.

FENTANYL AND ALFENTANIL

Fentanyl has theoretical advantages over morphine in certain situations because of its rapid onset and its systemic and pulmonary hemodynamic stability. Termination of the effects of a single dose is by redistribution. Clearance is more rapid in neonates and infants compared to adults and does not change with time during continuous infusion. However, after prolonged infusion, unchanged fentanyl is returned to the circulation from peripheral compartments, resulting in a prolonged terminal elimination half-life of approximately 21 hours.³¹ The effective dose for painful procedures is 1–2 μg/kg. Fentanyl is useful as an anaesthetic agent in patients with labile pulmonary vasculature, as it can blunt changes in pulmonary vascular resistance seen with stimulation.⁴ However, it does not prevent the increase in pulmonary vascular pressure caused by hypoxia.³² Infusions of 1–5 μg/kg per hour produce effective sedation in neonates on mechanical ventilation; 1–10 μg/kg per hour is required for analgesia in older children. Tolerance, noted in both neonates and older children, can develop rapidly.³³ Fentanyl’s short duration of action makes it suitable for use in epidural regimens.

Alfentanil, because of its shorter duration of action, may have advantages for analgesia or sedation for very short procedures.

REMIFENTANIL

Remifentanil is a synthetic opioid with potent analgesic properties, rapid onset of action, and, following initial redistribution, a short half-life of around 8 minutes. Metabolism occurs via non-specific esterases and is therefore relatively independent of renal and hepatic mechanisms. The short duration of action allows rapid emergence from general anaesthesia, thereby facilitating extubation or assessment of the patient’s neurological state.³⁴ Postoperative pain needs to be managed with an alternative analgesic regime and an opioid should be administered prior to discontinuing remifentanil.

Infusions of 0.1–0.5 μg/kg per min have produced satisfactory analgesia and sedation in ventilated adult patients and there is evidence that ventilation times are shorter and weaning from ventilation more rapid in comparison to standard sedation regimes.^11,³⁵ Although remifentanil is widely used in paediatric anaesthesia there are few data available on its use in children in intensive care. Uncomplicated and successful use in the induction and sedation of a ventilated preterm neonate has been described.³⁶ As metabolism is relatively independent of renal and hepatic mechanisms, remifentanil could be considered for use in patients with liver and/or renal impairment who do not have continuing pain and in whom rapid termination of sedation is required.

PARACETAMOL AND NON-STEROIDAL ANTI-INFLAMMATORY DRUGS

The addition to an analgesic regime of either paracetamol or a non-steroidal anti-inflammatory drug (NSAID) should be considered provided there are no contraindications.

Paracetamol is useful for mild to moderate pain and is an effective supplement to opioids for more severe pain. Enteral preparations, though useful, are prone to erratic absorption. The intravenous preparation Perfalgan is a more useful drug in the intensive care setting and has been shown to reduce opioid requirements in adults with few side-effects following orthopaedic surgery.³⁷ Data in children and neonates are limited. The recommended initial i.v. dose is 15 mg/kg (30 mg/kg p.o. or rectal) and the total daily i.v. dose should be limited to 60 mg/kg (90 mg/kg p.o.). Lower i.v. doses (7.5 mg/kg 6-hourly) are recommended for neonates. Contraindications to paracetamol include liver dysfunction and care must be taken to avoid liver injury in all children.

NSAIDs should also be considered as supplemental analgesics. Care should be taken, however, regarding the risk of bleeding, particularly in the postoperative period and in the highly stressed patient in whom gastric bleeding is more likely. Ketorolac (0.6 mg/kg) can be given i.v. and therefore has the potential to reduce the dose of opioid required in the immediate postoperative period when enteral medications are not appropriate.

INHALED AGENTS

NITROUS OXIDE

Nitrous oxide is a potent analgesic agent. It is useful in intensive care during short painful procedures such as removal of surgical drains. A mixture of 50% nitrous oxide with oxygen provides analgesia in awake and cooperative patients. It is unsuitable for repeated or continuous use because of toxicity and administration to younger children may cause distress because of the need for application of a mask.

ISOFLURANE

Isoflurane has been used for long-term sedation in intensive care in adults. As elimination is independent of hepatic and renal mechanisms, there are theoretical advantages in many critically ill patients. However, an association between isoflurane sedation and neurological abnormalities has been reported in children.³⁸ These abnormalities, although reversible, were a considerable clinical problem and make this technique unsuitable.

DRUG WITHDRAWAL SYNDROMES

Opioid withdrawal is a recognised problem and symptoms include poor feeding, tremors, agitation, poor sleeping, tachycardia, diarrhoea, sweating, increased muscle tone, dystonic posturing and seizures. It occurs particularly following prolonged high-dose infusions. The risk of withdrawal following a fentanyl infusion is associated with the duration of infusion and the total dose. Infusion for > 5 days or a total dose > 1.5 mg/kg was associated with greater than 50% incidence.³⁹

Benzodiazepine withdrawal (agitation, anxiety, sweating, tremor) is also seen and the risk following a midazolam infusion is associated with a total dose > 60 mg/kg.⁴⁰ Careful attention to weaning an infusion in high-risk patients can minimise withdrawal symptoms. Longer-term pharmacological management is occasionally required and is best managed by administering the agent from which the patient is withdrawing. Methadone, benzodiazepines and clonidine have been used via i.v., oral and subcutaneous routes.⁴¹ Recent evidence suggests that short-term (5-day) opioid weaning programmes can be successful.⁴² Although withdrawal can be a significant problem, adequate sedation or analgesia should not be withheld because of fears of the development of drug dependence.

LOCAL ANAESTHESIA

Local anaesthesia can produce effective analgesia without systemic effects and therefore has significant advantages in many patients, particularly the postoperative group. In the intensive care setting, it can be used as the sole method of providing analgesia or in combination with i.v. agents. The risk of toxicity is related both to the dose and to the rapidity of absorption, which is dependent on local blood flow. Metabolism of the amide local anaesthetics (lidocaine, bupivacaine) is via the cytochrome P-450 system and their half-life is longer in infants less than 6 months of age. Unbound drug does not produce analgesia but is potentially toxic as infants have lower levels of the binding protein α-glycoprotein.⁴³ The use of local anaesthesia in infancy therefore requires careful assessment and close monitoring.

EMLA

EMLA, an emulsion of lidocaine and prilocaine, is effective in reducing the pain associated with percutaneous procedures.⁴⁴ It needs to be applied to the skin 60 minutes beforehand and thus is unsuitable for urgent procedures. Systemic absorption of the prilocaine component and subsequent methaemoglobinaemia can occur. Neonates, because of their relative deficiency of methaemoglobin reductase, are particularly at risk and EMLA should be used with caution in this group.

LOCAL INFILTRATION

Optimal analgesia for some painful procedures is possible, particularly in older children, with careful local infiltration and minimal sedation. The total dose of local anaesthetic agent infiltrated must be monitored and maximum doses not exceeded. The total dose of lidocaine should not exceed 4 mg/kg (7 mg/kg if combined with adrenaline).

NERVE BLOCKS

Femoral nerve blockade is a simple technique that produces effective analgesia in cases of femoral shaft fracture. A single injection is effective for approximately 3 hours and longer term analgesia can be provided by a continuous infusion of bupivacaine (0.125%) at 0.2–0.3 ml/kg per hour through a fine catheter placed adjacent to the femoral nerve.⁴⁵ As this technique can decrease opioid requirements, it is particularly useful in trauma patients who have suffered a coexistent head injury.

Intercostal nerve blocks may be useful after thoracotomies and liver transplants in children.⁴⁶ A single dose of 0.125% bupivacaine (maximum single dose 2 mg/kg) can produce up to 8 hours of analgesia. The dose must be carefully limited, because the relatively high blood flow to the area increases the risk of toxicity. Continuous infusions via an intercostal catheter can provide ongoing pain relief. These require careful monitoring in the PICU, particularly regarding maximal dose. There is a risk of pneumothorax with this technique and it should therefore be avoided when there is significant coexistent lung disease.

EPIDURAL ANALGESIA

Caudal, lumbar and thoracic epidural anaesthesia can provide effective control of postoperative pain in children.^47,⁴⁸ The procedures must be performed by skilled experienced staff who clearly understand the risks and benefits. A complication rate of 1.5 per 1000 has been reported, with dural puncture and intravascular injection seen most commonly.⁴⁹ Other risks include cord injury, epidural infection and excessive motor blockade. Infants under 6 months are at highest risk because of their size and immature metabolism.

Many epidural catheter insertions are performed in the operating theatre and general anaesthesia is a prerequisite in most paediatric patients. PICU care may subsequently be required because of the nature of the surgery (e.g. thoracotomy, liver transplant) or because of underlying patient factors (e.g. neurological disorders, morbid obesity, age). Epidurals have been used in paediatric cardiac surgery without clear benefit over conventional postoperative analgesia.⁵⁰ Particular indications for commencing epidural analgesia in the PICU include burns in a suitable distribution (e.g. abdomen and lower limbs) and blunt chest trauma with rib fractures. Contraindications include shock, hypovolaemia, meningitis, coagulopathy and local skin infection.

Bupivacaine is the most commonly used local anaesthetic. A single dose should not exceed 2.5 mg/kg and the maximum infusion rate is 0.4 mg/kg per hour (0.2 mg/kg per hour in infants). Opioids (morphine and fentanyl) may be added and have a synergistic effect, thereby allowing less local anaesthetic agent to be used. Epidural opioids can cause sedation and respiratory depression.

REFERENCES

1 Anand KJS, Hickey PR. Pain in the foetus and neonate. N Engl J Med. 1987;317:1321-1329.

2 Anand KJS, Ward-Platt MP. Neonatal and paediatric responses to anaesthesia and operation. Int Anesthesiol Clin. 1988;26:218-225.

3 Anand KJS, Hickey PR. Halothane-morphine compared with high dose sufentanil for anaesthesia and postoperative analgesia in neonatal cardiac surgery. N Engl J Med. 1992;326:1-9.

4 Hickey P, Hansen DD, Wessell DL, et al. Blunting of stress response in the pulmonary vasculature of infants by fentanil. Anesth Analg. 1985;64:1137-1142.

5 McNair C, Ballantyne M, Dionne K, et al. Postoperative pain assessment in the neonatal intensive care unit. Arch Dis Child Fetal Neonatal Ed. 2004;89:F537-541.

6 Ramelet AS, Rees N, McDonald, et al. Development and preliminary psychometric testing of the Multidimensional Assessment of Pain Scale: MAPS. Paediatr Anaesth. 2007;17:333-340.

7 Malviya S, Voepel-Lewis T, Burke C, et al. The revised FLACC observational pain tool: improved reliability and validity for pain assessment in children with cognitive impairment. Paediatr Anaesth. 2006;16:258-265.

8 Ista E, van Dijk M, Tibboel D, et al. Assessment of sedation in pediatric intensive care patients can be improved by using the COMFORT ‘behavior’ scale. Pediatr Crit Care Med. 2005;6:58-63.

9 Aneja R, Heard AM, Fletcher JE, et al. Sedation monitoring of children by the Bispectral Index in the paediatric intensive care unit. Pediatr Crit Care Med. 2003;4:60-64.