The provision of analgesia and sedation in the PICU: current practice and recent advances

Current practice  Sedation of children in requiring intensive care in Europe has favoured a combination of a sedative drug, mainly midazolam, and an analgesic, usually morphine. In North America fentanyl is often employed as the first line analgesic. Postoperatively, the need for analgesia is obvious but for other patients analgesic drugs are used as an adjunct to spare the dose of a pure sedative. Propofol, although an undoubtedly useful drug, has been used widely albeit with concerns regarding its safety in children (1) and even in adults (2). This debate was curtailed recently (3) and is no longer a viable alternative, at least in the UK. However, even the more established drugs are not free from generating problems: Tolerance and Tachyphlaxis Classically seen with local analgesics and opioids, this is also observed with midazolam (4) and dose rate does not relate reliably to adequacy of sedation (5) Withdrawal This is seen with almost all classes of drugs used in sedation in PICU. Not only as ‘expected’ with opioids and the benzodiazepines, but also with propofol (6), isoflurane (7) and barbiturates (8). Many of these reactions may be mediated through NMDA receptors and this can be modified by the use of ketamine (8). Some of these reactions can have long drawn out symptoms and necessitate tapering regimens that may fast up to three weeks (8, 9, 10). The incidence of such phenomena varies from 17 to 35% in published data, particularly where midazolam was concerned (9,10) Immune effects Morphine has titratable effects in decreasing the proliferation of stimulated human lymphocytes, and it also suppresses killer cell cytotoxicity. Selective α, κ and δ agonists decrease immunoglobulin production by B lymphocytes (1l). Sedative sparing strategies  Clinical observation systems should be objective and reproducible in a quantitative form so that assessments of sedation can be made independently of varying individuals or units. The COMFORT score is validated but has 5 scores in each of 8 categories (12) so we use a simpler version in our unit (13). The EEG is difficult to interpret and suppression of waveforms is non linear with concentration of propofol (14). In paediatric patients we found that propofol levels varied widely, given the same dose, and that there was no correlation between these levels, the EEG and the level of clinical sedation (15). The use of muscle relaxants may reduce the total sedative requirement, but may lead to overdosage where awareness is feared (8). They affect thoracic compliance (16) and lead to more nosocomial infections (16,17), and increase the length of ventilation and length of stay (17). Drug ‘holidays’ can be achieved with reduced length of stay and length of ventilation in adults (18) but this would be problematic in children. However, cycling of drug regimens can be used to good effect. We vary drug regimens every week in a three week cycle, switching from morphine/midazolam (week 1) to ketamine/promethazine (week 2) to clonidine/chloral (week 3). Analgesia can be delivered in short acting form as a bolus for specific procedures, e.g. physiotherapy and as regional blockade, epidurally or spinally, even for thoracic and cardiac procedures (19, 20). Dealing with sequelae  Withdrawal is the most obvious side effect and can be extremely distressing for the child, the parents and for the clinical staff. A good outcome from the acute illness can be frustratingly marred by unwelcome neurological side effects that range from jitteriness, irritability, refusal to feed/drink, to outright myoclonus, ataxia and vomiting (8). Gradual tapering of sedatives is one approach but substitution by a drug from the same class or by a drug from a different class with similar effects can be beneficial. The partial α 2 agonist drug clonidine has proved to be very useful in either combating withdrawal or being used as a primary sedative (21, 22). Dexmedetomidine, a drug first used in veterinary anaesthesia, is being evaluated as a first line sedative in adults. It is a pure α 2 agonist and may be more prone to hypotensive and bradycardic episodes (23). Clonidine has some α 1 activity that may be more protective in this regard. Other agents can be used to combat withdrawal and drugs used in clinical practice include chlorpromazine, lorazepam, oramorph and methadone. Sleep deprivation plays a part in withdrawal. Diurnal variation is disturbed and this is associated with abnormal steroid and melatonin secretion (24). Future Developments for Evaluation  Lorazepam may have advantages over midazolam, with shorter return to consciousness (25). Further study of α 2 agonists is needed. Remifentanil as a primary sedative/analgesic agent looks promising, especially in view of its pharmacokinetic profile. We are evaluating its use as a procedural bolus drug. Eltanolone/pregnanolone and other such drugs are being evaluated as a possible substitute for propofol. Regional analgesia is being looked at in our unit, not only for its beneficial effect intraoperatively (20), but as a means of sparing opioid administration on PICU. Melatonin needs evaluating in re‐establishing sleep patterns in children in intensive care together with its specific sleep inducing properties (26).