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Analgesia and sedation in paediatric intensive care unit. SB Bavdekar, MD Mahajan, KV ChanduDepartment of Paediatrics, Seth G. S. Medical College and K. E. M. Hospital, Parel, Mumbai, India., India
Correspondence Address: Source of Support: None, Conflict of Interest: None PMID: 0010734346 Keywords: Analgesia, Analgesics, Opioid, Child, Conscious Sedation, Diazepam, Human, Intensive Care Units, Pediatric, Lorazepam, Midazolam,
Physicians have traditionally been exquisitely insensitive to pain and anxiety suffered by children. This could be due to the widely held belief that neonates and young children do not feel pain. This has been proved to be untrue beyond doubt[1],[2],[3]. Other factors that could be responsible for pediatricians using analgesics and sedatives less frequently include the inability of children to express pain and anxiety[4], the wrong belief that children have no memory of pain, the exaggerated fears[5],[6],[7] about the adverse effects (respiratory depression, hypotension and addiction) of sedatives and hypnotic agents[8],[9],[10],[11], Physicians' inability to assess the degree of pain[12], the reluctance of children to demand a drug for relieving pain for the fear of administration of a painful injection and our ability to restrain children. In fact, in a paediatric intensive care unit (PICU) setting, several factors give rise to anxiety, fear and pain experienced in children during their stay. These include separation from parents, presence of unfamiliar people and machines, disruption of the usual sleep-wake cycle, invasive procedures and mechanical ventilation[13]. The role of pharmacologic intervention is beyond doubt, though many situations may be amenable to reassurance and compassionate behaviour. The major goal of sedation in PICU patients is to create a co-operative, reasonably calm, and pain-free patient who will not interfere in the delivery of ICU care. The suggested indications for sedation include[14]: a) Facilitation of Mechanical Ventilation: Ventilated patients require sedation so that chest wall compliance can be controlled, coughing due to endotracheal tube placement be suppressed and ventilatory dyssynchrony is avoided. Modern advances in ventilator technology and control modes lessened the need for heavy sedation during weaning but high-frequency jet ventilation, high levels of positive end-expiratory pressure (PEEP) and inverse ratio ventilation often require paralysis and sedation. b) To induce sleep and control agitation: Day night cycles are altered by ICU environment and pain and psychological stress render adequate sleep nearly impossible. c) To induce amnesia during paralysis and painful procedure. d) To decrease cellular Metabolism: Many critically ill patients exhibit a catabolic state. Sedation improves the balance between oxygen supply and demand by decreasing the global oxygen demand. Although there could be an overlap among agents used to minimize pain, anxiety and fear, these can be classified as: a) Agents for sedation: Benzodiazepines, barbiturates, ketamine, propofol, opioids, nitrous oxide, etomidate and inhalational anesthetic agents. b) Agents for analgesia: Opioids and non-steroidal anti-inflammatory agents.
Tobias and Rasmussen[13], have described criteria for an ideal sedative: rapid onset, predictable duration of activity, no active metabolites, rapid dissipation of effects on discontinuation of the agent, multiple options for drug delivery, limited effects on cardio-respiratory function, wide therapeutic index, non-interference with effects or metabolism by other drugs and non-affection of effect and duration in presence of organ failure. As expected, such as ideal agent does not exist. Benzodiazepines In most PICUs, benzodiazepines are the most commonly used sedatives. Their actions are supposed to be mediated through the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Benzodiazepines' anti-anxiety, sedative and amnestic actions are of great use in a PICU setting. They impair acquisition and encoding of new information (anterograde amnesia), while having little effect on retention or retrieval of previously stored information (retrograde amnesia)[15]. They have no intrinsic analgesic properties. Therefore, concomitant administration of an opioid is advocated in situations requiring analgesia. The commonly used benzodiazepines in PICU setting are diazepam, midazolam and lorazepam. They are compared in [Table - 1]. When these are used over a long time, they have a tendency to cause physical dependence. This can be minimized by tapering the doses over a period of days. All benzodiazepines are highly protein bound. Hypoalbuminemia, malnutrition and liver or renal disease may enhance the effects of benzodiazepines[16]. For short-term sedation, bolus injections can be given. Generally, intravenous boluses are preferred as titration of dose with clinical effect is possible. If intramuscular route is used, diazepam is best avoided due to its erratic absorption. Midazolam has a shorter half-life and is not an irritant and hence, is preferred by some over diazepam. Due to lack of clinically proven benefits, the choice of agent for short-term sedation usually depends on familiarity and cost. Long term (more than 24 hours) sedation can be achieved by intermittent intravenous administration of benzodiazepines. This approach is, however, problematic as it leads to peaks and valleys in drug concentration and effect, and the technique is time and labour intensive. Continuous intravenous infusions of benzodiazepines are safe if infusion pumps can be used. Midazolam's pharmacokinetic profile makes it attractive for use as a continuous intravenous infusion, though certain problems like tachyphylaxis and prolonged effect even after its discontinuation have been reported[16]. Ketamine Ketamine is an intravenous anaesthetic agent. It has sedative hypnotic, amnestic and analgesic actions. Its exact mechanism of action is not known. It has been shown to block afferent impulses associated with the affective emotional component of pain perception in reticular formation. It is metabolised in the liver and excreted in urine. Termination of its effects is probably due to redistribution from the brain to other tissues. Nevertheless, dosages need to be adjusted in presence of hepatic dysfunction. The major advantages of ketamine lie in its amnestic and analgesic actions, its relative cardiovascular stability and its limited effects on respiratory mechanics. Ketamine, in fact improves pulmonary compliance and relieves bronchospasm. However, elevations of PaCO2 have been reported[17]. Intrinsically, Ketamine has direct negative inotropic properties. But, in most patients its indirect sympathomimetic effects overshadow them leading to increase in the heart rate and blood pressure. It increases salivary and bronchial gland secretions through central cholinergic receptors. Its effects on protective airway reflexes are controversial[13]. Aspiration has been reported following ketamine administration[18]. Ketamine should be used cautiously in children with pulmonary hypertension and avoided in those with raised intracranial pressure, severe cardiovascular disease, congestive cardiac failure or severe, uncontrolled hypertension. The side effects of ketamine that have received maximum attention include its ability to produce dissociative state in sub hypnotic doses and to lead to emergence phenomena or hallucinations. These are dose- related and occur more commonly in older patients. They can be prevented by prior administration of benzodiazepines. The excessive bronchial secretions can also be avoided by prior administration of anti-sialogogue agents. Other adverse effects include tonic and clonic muscle movements, tremor, vomiting, nystagmus and skin rash. Propofol Propofol is a short acting sedative hypnotic agent and an intravenous anaesthetic agent. It does not have analgesic properties. Its mechanism of action has not been well defined. It became a popular agent in intensive care units due to its rapid onset of action, quick recovery time and lack of active metabolites. It is well tolerated in patients with adequate cardiac reserve but its hemodynamic effects such as negative inotropy, vasodilation, hypotension and bradycardia preclude its use in hemodynamically unstable patients. Its hypotensive effects may be potentiated by opioid analgesics while concomitant use of other drugs causing bradycardia (fentanyl, succinylcholine) can lead to asystole. It is also a respiratory depressant producing apnoea. Other adverse effects include hyperlipidaemia, opisthotonic posturing, myoclonic movements and convulsion. In addition, lipid emulsion in which propofol is delivered has given rise to anaphylactoid reactions and has served as a suitable culture medium for bacteria. Its use has resulted in unexplained metabolic acidosis and fatal cardiac failure in some children with respiratory infections. These events have led to a decline in its popularity. It is no longer recommended for continuous infusion in the PICU patients. It may still be a valuable sedation agent, however, for brief, invasive procedures. Barbiturates Barbiturates are one of the oldest class of agents used for sedation in the PICUs. They act as sedatives by inhibiting the ascending conduction in the reticular formation at the thalamic level. In part, their sedative action is also related to their ability to enhance or mimic the inhibitory synaptic action of gamma aminobenzoic acid (GABA). As sedating agents, barbiturates have several limitations. They possess a low degree of selectivity and therapeutic index. They depress all excitable tissues in the central nervous system (CNS). In the periphery, they depress autonomic ganglia and decrease nicotinic excitation by choline esters leading to hypotension. They are potent respiratory depressants and have negative inotropic actions. They also lack analgesic properties. Another problem that limits their use is that the solution is alkaline, making it incompatible with several other medications and intravenous solutions. In the PICU, barbiturates are more frequently used as anticonvulsant agents (phenobarbitone) and for lowering raised intracranial pressure (pentobarbital) than as sedative agents. Short-acting agents like methohexital and thiamylal are hardly used nowadays except for rapid sequence induction for endotracheal intubation[20]. Inhalation Anaesthetic Agents The inhalational anaesthetic agents in common clinical use include halothane, enflurane, isoflurane and nitrous oxide. Anaesthetic agents are supposed to act by interfering with the physiological functioning of nerve cell membranes in the brain via an action at the lipid matrix of the membrane. Except for a few centres in Europe, these agents are not used extensively in the PICUs as sedative agents. Although advocates of this mode of sedation emphasize its rapid awakening upon discontinuation, the rapid onset of action and the ease of control of depth of sedation; the limitations are formidable. Halothane, enflurane and isoflurane have significant potential for hepatotoxicity and have the associated risks of cardiac arrhythmias, circulatory depression and emergence delirium. Cerebral vasodilatation may occur with halothane. They may also alter the metobolism of lignocaine, beta-adrenergic blocking agents and benzodiazepines. Concurrent use of phenytoin increases the risk of halothane hepatotoxicity. It must be remembered that the excellent safety record of these agents spanning many years pertains only to short duration use in the operating rooms. The effects of prolonged administration remain unknown. Long-term administration can lead to fluoride toxicity, which can manifest with nephrogenic diabetes insipidus and decreased glomerular filtration rate[13]. There are problems of feasibility, too. Use of these agents will mandate installation of scavenging devices to prevent environmental pollution and neurologic injury in individuals administering them. Installation of such systems can involve prohibitive costs. Additionally, anaesthetists who are not usually involved in Indian PICU settings will have to play a more active role. As compared to halothane, enflurane and isothane, nitrous oxide is relatively easy and inexpensive to use. Its major disadvantage is the need to install scavenging devices to prevent environmental pollution. Prolonged exposure to nitrous oxide can lead to reduced fertility, increased risk of spontaneous abortion and chronic myeloneuropathy in health workers. It has abuse potential and hence precautions are required in storing nitrous oxide. It is contraindicated in patients with altered mental status or respiratory failure. Due to its low solubility in blood, it diffuses easily into air-containing spaces such as a pneumothorax. It can alter cerebral blood flow and produce a rise in intracranial pressure. Prolonged exposure can cause bone marrow suppression, megaloblastic anaemia and alterations in white cell function. Because of these limitations, prolonged use of nitrous oxide is not recommended, although it may have some role in sedation during brief invasive procedures. It should be administered only by persons trained in administering it and under proper monitoring, because the delivery of a hypoxic gas mixture is possible with improper use or equipment malfunction. Miscellaneous Agents Several other agents have been used with varying degrees of success for sedation in the PICU. Phenothiazines (e.g., chlorpromazine) and butyrophenones (e.g., Haloperidol) are "major tranquillizers" used in the treatment of psychiatric disturbances. They have not been associated with great success as sedatives and combinations may in fact, result in prolonged sedation, hypotension and respiratory depression. The side effects include vasodilatation, extrapyramidal reactions (oculogyric crisis, stiffness), tardive dyskinesias and dysphoria. Anti-histamines with most effective sedative properties include promethazine, diphenhydramine and hydroxyzine. They are well tolerated orally and side effects are few. However, the degree of sedation leaves much to be desired. Chloral hydrate, a sedative-hypnotic agent, is still commonly used in children. Its CNS effects are due to its active metabolite trichloroethanol but the mechanism of these effects is not known. As there is no parenteral formulation available, oral or rectal administration is required. Though readily absorbed from the gastrointestinal tract, the onset of action may be delayed upto 20 minutes. This makes chloral hydrate unsuitable for control of acutely agitated patient in the PICU. It may be effective as one-time dose for brief, non-painful procedures like computed tomography. Repeated dosing may lead to accumulation of trichloroethanol and trichloroacetic acid metabolites. These may increase the potential for excessive CNS depression. It should not be used in infants younger than 3 months, children with hepatic impairment or those with severe renal dysfunction. Prolonged use may result in psychic and physical dependence. Following prolonged administration, chloral hydrate should be withdrawn gradually so as to avoid the possibility of precipitating withdrawal symptoms. The dosages of commonly used sedatives are provided in [Table - 2]. Opioids Opioid analgesics continue to be the mainstay of pain management in the PICUs. Opioids diminish both the sensation of noxious stimulation (nociception) and the emotional component of subjective stress (suffering)[21]. They also suppress autonomic responses to noxious stimulation such as hypertension, tachycardia and perspiration[21],[22]. In addition to providing analgesia they also have sedative properties, which come in handy when patients demonstrate agitation as a result of pain. Opioids do not provide amnesia. Opioids exert their pharmacological actions by binding with opioid receptors. The opioid analgesics commonly used in PICU include morphine, hydromorphone, meperidine, methadone, and codeine. Pentazocine, nalbuphine, butorphanol and propoxyphene have been touted as having advantages of a lowered risk of respiratory depression, biliary spasm and abuse. But, they are associated with a higher incidence of dysphoria, may precipitate withdrawal in patients receiving narcotics and are significantly less potent analgesics[9],[21],[22]. Morphine is a poorly lipid soluble, inexpensive, well-studied agent, which is metabolised by conjugation. It shares the safe haemodynamic profile of opioid analgesics. But as it causes release of histamine, it may cause some vasodilation and lead to decrease in blood pressure especially, in hypovolaemic patients. Meperidine seems to be a relatively poor choice for analgesia. Although accompanying sedation could be beneficial, several other CNS effects occur including tremors, muscle twitchings, dysphoria, agitation and seizures[13],[23]. In older children, the dysphoretic response may be manifested by complaints of "not feeling well and restlessness, whereas agitation and uncontrolled crying may be the only manifestation in a younger child or infant. The CNS toxicity is due to a metabolite of meperidine, viz. normeperidine. This metabolite has a long half-life. It is dependent on renal excretion and toxic levels can accumulate with renal insufficiency, co-administration of phenobarbital or other microsomal enzyme inducers and use of large doses. Methadone is an effective, yet seldom used, opioid. Its major advantages include long plasma half-life providing a steady-state serum concentration without a continuous or patient controlled analgesia technique. In addition to providing routine analgesia in the PICU setting, it may also be used to slowly taper opioid therapy in patients who have developed tolerance following prolonged opioid administration[13]. Fentanyl, a synthetic opioid, is highly lipid soluble, considerably more potent than morphine and readily and extensively metabolised by the liver to inactive metabolites. Its major advantages include a shorter duration of action than morphine and its inability to cause significant histamine release, thereby decreasing the propensity to cause vasodilatation, hypotension and pruritus. The two caveats as regards to fentanyl (and its derivatives sufentanil and alfentanil) are the possible effects on intracranial pressure and the occurrence of chest wall rigidity. The latter is an idiosyncratic reaction and can be reversed with naloxone or neuromuscular blocking agents. Fentanyl is most commonly used for short painful procedures such as bone marrow aspirations and dressing changes. It is often administered as an intravenous infusion for sedation and analgesia in patients who have undergone cardiothoracic surgery. Other issues, which need attention while prescribing opioids, are the route and mode of administration. Intramuscular dosing is associated with erratic serum plasma levels due to variability in uptake and absorption. Additionally, children will deny pain to avoid a 'shot'. Intravenous administration ensures complete bio-availability, immediate effect and painless delivery. Intravenous infusion is preferred over intermittent dosing when analgesia is required for a longer period. Infusion avoids peak and trough levels, thereby preventing occurrence of alternating periods of over sedation and under sedation. Subcutaneous administration should be considered when drug incompatabilities preclude the intravenous route. This route has generally been used in terminal cancer patients. A novel approach to narcotic delivery is the recent development of transdermal fentanyl. This route has been extensively studied in adults, but its use in children is still anecdotal. It is mainly used for alleviation of chronic pain as steady-state concentrations may be reached at eight hours. Another alternative is to use a patient controlled analgesia pump. This method of drug delivery employs a computer - controlled infusion pump that permits the patient to administer a small bolus dose by pressing a button. After the dose is given, a "lock-out" mechanism is activated, preventing a repeat dose before a specified time period elapses. Over dosage is avoided by selecting a cumulative maximum dose for a longer time period. Patient-controlled analgesia has been applied to children as young as five years. It requires an awake, co-operative patient who is able to comprehend its purpose and is able to push the button when additional analgesia is required. Another option is to include a low basal infusion rate especially at night. Contraindications to patient controlled analgesia use include inability to push the button (weakness or immobilisation), inability to understand the technique (young age, type and state of illness), inability to provide frequent surveillance and management by experienced professionals, or a patient's or family's refusal to take responsibility for providing analgesia. Non-Steroidal Anti-inflammatory Agents The use of non-steroidal anti-inflammatory agents (NSAIDs) in the PICU has been limited by the need for oral administration. Ketorolac and indomethacin are available as parenteral preparations. Intravenous Indomethacin had been shown to improve analgesia and decrease narcotic requirements following surgery[24] while ketorolac has been found to be efficacious for post-surgical, inflammatory, musculoskeletal pain and in patients with pleuritic-type pain or vaso-occlusive crisis due to sickle cell disease[13],[25].
There are many factors that induce fear, anxiety and pain in children admitted to PICU. Effective and safe drugs and proven regimens are now available, to relieve and ameliorate pain and anxiety in the vast majority of these patients. Although a 'cookbook' approach is impossible because of the diversity of patient and clinical scenarios, certain general remarks can be made. Benzodiazepines are the most commonly used sedatives in the PICU. Ketamine and Propofol can be used for specific purposes. The role of barbiturates in sedation is showing a declining trend. Amongst the analgesic agents, morphine is an efficacious and cost-effective drug for patient with stable cardiovascular function. Newer methods of administration such as, transcutaneous administration, patient-controlled anxiolysis / anaesthesia may simplify issues of sedation and analgesia in children.
Authors thank Dr. R G Shirahatti, Dean, Seth GS Medical College and King Edward Memorial Hospital for his permission to publish this article.
[Table - 1], [Table - 2], [Table - 3]
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