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.