Systemic analgesia
Local anaesthesia
Low-dose opioids (in order of increasing potency)
Local anaesthesia
Codeine, morphine, fentanyl, alfentanil, remifentanil
Lignocaine, bupivacaine,
L-bupivacaine, ropivacaine
High-dose opioids
Routes
NMDA antagonists
Topical:
Ketamine
EMLA, LAT gel, amethocaine
Alpha-2 agonists
Infiltration
Clonidine, dexmedetomidine
Nonsteroidal anti-inflammatory drugs
Regional blockade
Diclofenac, ibuprofen, ketorolac
Epidural
Paracetamol
Spinal
Adjuncts to central blocks
Clonidine, opioids
39.2.2.1 Opioids
Opioids remain the mainstay of analgesia in paediatric intensive care. Morphine, one of the main active ingredients of opium, was first isolated in the 1800s and is still in use today. Other drugs from this group that are used in PIC include fentanyl, alfentanil and remifentanil.
Pharmacokinetics of the opioids are age dependant and related to the maturity of hepatic and renal elimination routes. They are also highly influenced by the effect of the primary disease process on organ function, drug compartments and fluid balance (Rigby-Jones et al. 2007; Lynn et al. 1998). For the critically ill child in general, there is a combination of an increase in volumes of distribution but a fall in drug clearance as alluded to earlier in the chapter. As a result, drug requirements are high in the initial phases with significant context-sensitive half-time, but once a true steady state is reached, drug accumulation can occur due to reduced clearance. Care therefore must be taken to provide adequate drug loading early on, but once a steady state is reached, infusion rates need to be adjusted to reflect the reduced clearance, particularly if there are reductions in hepatic or renal function. A guideline to the opioid choices and dose ranges are given in Table 39.2.
Table 39.2
Opioid analgesia
Drug | Indications | Dose | Elimination | Comments |
|---|---|---|---|---|
Fentanyl infusions | Analgesia | 1–5 μg/kg/h | Metabolised in the liver | Large bolus doses can cause hypotension |
Intense analgesia/anaesthesia in ventilated patients | 5–15 μg/kg/h | Neonates may have long elimination half-lives with delayed recovery | ||
Bolus fentanyl | Control of pulmonary hypertension | 10–50 μg/kg | Ventilatory depression | |
Morphine | Analgesia with sedation Controlled analgesia in the extubated patient | Loading dose: 50–200 μg/kg Infusion: 5–80 μg/kg/h Neonates: lower infusion rates 5–20 μg/kg/h | Hepatic followed by renal excretion of active metabolite (morphine-6-glucuronide) | Delayed recovery in neonates Nausea and vomiting can be a problem in older children Reduced doses may be needed with renal impairment due to accumulation of morphine-6-glucuronide |
Oral morphine | Longer-term analgesia once absorption has recovered | 200–500 μg/kg 4 hourly | Oral doses need to be larger than IV doses due to reduced bioavailability and first-pass metabolism | |
Alfentanil | Given by infusion Rapid-offset drug useful for fast-track surgery | Loading dose: 50–100 μg/kg Infusion: 0.5–4 μg/kg/min | Metabolised in the liver. Highly protein bound with a small volume of distribution | Its small volume of distribution and short elimination half-life make its offset very rapid |
Remifentanil | Given by infusion in ventilated patients Intense rapid onset/offset (largely independent of age or duration of infusion) | Analgesia: 0.1–0.4 μg/kg/min | Metabolised rapidly by plasma and tissue cholinesterases | Alternative analgesia is required before the infusion is stopped |
Anaesthesia: 0.5–1.5 μg/kg/min | Not suitable in the extubated spontaneously breathing patient | |||
Codeine Phosphate | Oral medication | Neonate: 0.5–1 mg/kg 4–6 hourly | Hepatic and renal clearance | Also used for treatment of diarrhoea due to constipating effects |
Child up to 12 years: 0.5–1 mg/kg max 240 mg per day | Poor activity below 5 years | |||
Over 12 years: 30–60 mg | Inactive in approx 10 % patients | |||
Tramadol | Oral medication | Over 12 years 50–100 mg every 4–6 h maximum 400 mg/day | Hepatic and renal clearance | Only in patients over 12 years old Nausea and vomiting, constipation Respiratory depression in large doses |
Neonates have both pharmacodynamic and pharmacokinetic susceptibility to sedatives and opioids, and this may deter the clinician from providing effective dosing. However, unless effective plasma concentrations of the drug have already been achieved during surgery, initial loading doses of the drug may need to be given in the intensive care unit. In contrast, with older infants and young children, it can be difficult to provide effective analgesia and sedation without resorting to large drug doses, often in combination with multiple sedative drugs. This reflects increased volumes of distribution and large clearance values that may equal or exceed that of adults, compared to relative pharmacodynamic drug resistance in neonates. It is not until adolescence that responses and handling of the drugs approach that of the adult.
All the opioids are associated with tolerance, resulting in increasing opioid requirements to maintain adequate analgesia/sedation, and this is accelerated by high-dose opioid techniques’ “acute tolerance”. This effect has been shown to be more pronounced in the shorter acting and more potent opioids such as fentanyl and remifentanil (Guignard et al. 2000). Neonates undergoing ECMO require five times the initial fentanyl infusion rate by day 6 to achieve the same level of sedation due to a combination of enhanced elimination (Arnold et al. 1991) and pharmacodynamic tolerance (Greeley 1998).
Once the alimentary route is effective, there is some evidence that oral opioid administration results in reduced longer-term tolerance (Nestler 2001; Eisch et al. 2000; Pu et al. 2002). Certainly, the use of enteral drug administration reduces infection risk associated with long-term intravenous access and line manipulations (Pronovost et al. 2006) and should be used in preference where possible. Morphine undergoes considerable first-pass metabolism through the liver if absorbed through the alimentary system, and therefore, the dose requirements are considerably greater than by intravenous routes with total daily doses needing to be increased by a factor of five to ten in order to achieve the same level of analgesia compared to the intravenous route.
39.2.2.1.1 Morphine
Morphine has a lower opioid receptor affinity and is more water soluble compared to drugs such as fentanyl. These properties confer relatively low potency and slower onset (10–15 min to maximal effect) due to the time required for the drug to reach an adequate effector site concentration. This also explains the long duration of effect and relatively slow clinical offset with a single dose lasting several hours. This can be used as an advantage in transition periods for a patient such as in the immediate postoperative phase. A loading dose of 100–200 μg/kg (or more in the ventilated morphine-naive patient) followed by an infusion with a rate of 10–80 μg/kg/h will provide a reliable level of analgesia for the majority.
Early drug dosing may be needed in the postoperative patient to achieve effective drug concentrations, while infusion rates may need to be moderated with time to reflect the increased volumes of distribution and any reduced hepatic and renal clearance. Reduced renal function regardless of cause will significantly increase the effective half-life of morphine in a patient. This is due to the accumulation of the active metabolite of morphine, morphine-6-glucuronide, in these patients. Conversely all patients have the potential for tolerance to opioids requiring increased doses to achieve the same level of sedation or analgesia.
Intravenous morphine infusions can be adjusted to allow patients to self-ventilate. Adequate regular monitoring using appropriate behavioural scoring such as the COMFORT score (Ambuel et al. 1992; van Dijk et al. 2000) will allow dose adjustment to prevent excessive sedation and respiratory depression. Nausea and vomiting are more usually associated with older children, particularly females, but can usually be controlled with antiemetics and should not prevent the use of adequate analgesia.
Patient-controlled analgesia with morphine can be a useful tool in the extubated child that is able to understand the principle (usually by the age of 5 or 6 years). The usual technique is to have a low background infusion of 5 mcg/kg/h combined with a demand dose of 20 mcg/kg with a lockout time of 5 min (Doyle et al. 1993). This approach leads to analgesia better matched to pain and reduced side effects. For the younger age group, this principle can be applied, and nurse-controlled analgesia has been used successfully using a higher background infusion and a smaller bolus dose. As discussed above, oral morphine should replace intravenous morphine if and when required, provided the alimentary system is functional.
39.2.2.1.2 Fentanyl
Fentanyl is a potent opioid with a faster onset and offset than morphine due to its high receptor affinity and increased fat solubility allowing rapid delivery to the receptor sites. Initial offset with the drug is primarily by continued uptake into the peripheral stores, making it a short-acting drug for single-dose or short-term infusion. However, after 12 h when peripheral stores are largely saturated, the drug has a slow offset (terminal half-life of 3 h in the older child but up to 17 or more hours in the preterm neonate (Katz and Kelly 1993; Collins et al. 1985)) which can then delay recovery if the effects have not been monitored with behavioural scoring or regular drug “holidays”. Infusion rates of 1–5 μg/kg/h are sufficient to provide analgesia. For sick infants where it is being used to maintain anaesthesia, reduce metabolic demand and provide haemodynamic stability, rates of 10–20 μg/kg/h can be used. These higher doses provide blunting of haemodynamic and pulmonary responses to procedures such as endotracheal suctioning and physiotherapy – useful in an unstable patient.
In neonates, high-dose fentanyl alone is considered sufficient to provide complete anaesthesia and sedation. However, infants and children require the addition of hypnotic drugs such as a benzodiazepine, chloral hydrate or clonidine to ensure adequate sedation as well as analgesia.
39.2.2.1.3 Alfentanil
Alfentanil is an opiate that is highly protein bound which results in a small volume of distribution. The result of this is a much shorter elimination half-life than fentanyl with less potential for accumulation (Bower and Hull 1982). Alfentanil is metabolised in the liver to inactive compounds. It is less potent than fentanyl, but its rapid onset and offset makes it a useful drug both in the operating theatre and intensive care unit. As with morphine and fentanyl, the pharmacokinetics are highly age dependant, and the younger-age child has a shorter elimination half-life than adults (Goresky et al. 1987; Meistelman et al. 1987), while the neonate has prolonged elimination (Davis et al. 1989).
39.2.2.1.4 Remifentanil
This drug is the exception to the opioid class as it is metabolised by plasma and tissue cholinesterases and therefore does not rely on hepatic and renal function. It has a very short half-life of 3–6 min after a single injection and is relatively age independent unlike the other drugs in the group (Ross et al. 2001). Due to this rapid and efficient way of clearing the drug, there is a predictable offset of drug action even in infusions and peripheral accumulation does not occur. However, in common with high-efficacy rapid-offset drugs, it leads rapidly to acute tolerance. While this is a controllable effect for use in the operating theatre or for procedural pain in PICU (Guignard et al. 2000), it precludes its use in PICU as a longer-term analgesic that can be used over days (Vinik and Kissin 1998).
Remifentanil provides intense opioid analgesia with limited sedative effects. Analgesia is initially provided by doses of 0.1–0.4 μg/kg/min, but for surgical procedures, doses in the order of 1 μg/kg/min are needed in order to completely obtund stress responses (Weale et al. 2004). Due to the potency of the drug, it is difficult to use in a self-ventilating child as with other high-efficacy opioids chest wall rigidity can occur on initial exposure to the drug. This can result in significant respiratory impairment and should be watched out for in the unparalysed ventilated neonate. Bradycardia and hypotension have been reported in neonates on initial exposure to the drug (Weale et al. 2004).
Adult studies suggest that large intraoperative doses of remifentanil are associated with increased postoperative morphine requirements (Guignard et al. 2000). This means loading with longer-acting opiates is necessary prior to stopping a remifentanil infusion. The major barriers to further investigation of this drug in clinical practice are its high cost and drug tolerance.
One study looking at fast-track paediatric cardiology patients found remifentanil was no better than fentanyl in terms of recovery and was associated with a significant (30 %) reduction in heart rate compared to fentanyl (Friesen et al. 2003). Remifentanil potentially has use via the intranasal route for procedures in PICU. Given as a single dose intranasally, it provides an excellent pharmacokinetic profile providing increased analgesia for 15 min. This approach avoids fluctuant levels and the attendant side effects of single-dose intravenous or infusion administration of remifentanil. Verghese et al. have reported this technique for intubation during inhalational anaesthesia with 5 % sevoflurane after a single dose of 4 μg/kg of remifentanil (Verghese et al. 2008). This exciting new approach would allow modulation of analgesia for physiotherapy, tube change, etc., without having to change existing background infusions of sedation and analgesia or break into the intravenous circuit to give additional bolus doses.
39.2.2.1.5 Codeine Phosphate
Codeine is a simple analgesic that can be administered orally, rectally or intramuscularly. It should not be used intravenously due to the risks of profound hypotension and grand mal seizures. It is commonly used for postoperative analgesia in the paediatric setting for moderate pain, having a place on the World Health Organisation’s analgesia ladder. It is most commonly used in conjunction with paracetamol and can in addition be used with nonsteroidal anti-inflammatory drugs (NSAIDs).
Codeine has a low affinity for opioid receptors; 10 % of the drug is metabolised to morphine. There is genetic variability in the amount of morphine metabolised by the cytochrome P-450 enzyme CYP2D6, so patients experience differing analgesic effects (Sasada 2003). An estimated 7–10 % of Caucasians have low levels of the enzyme resulting in poor metabolism and therefore lower levels of active metabolites and reduced analgesic benefits (Tremlett et al. 2010). Conversely some individuals show enzyme duplication and become ultrarapid metabolisers, producing abnormally high levels of morphine and therefore being at greater risk of respiratory depression (Tremlett et al. 2010). Approximately 50 % of the drug undergoes first-pass metabolism following rapid oral absorption. Peak plasma levels occur after an hour in adults with varying rates of clearance in the paediatric population (Tremlett et al. 2010).
The most common side effect of codeine is slowed gut motility that can lead to constipation but has been used as a treatment (Sasada 2003). Some patients experience respiratory depression following codeine administration. The primary mode of metabolism is within the liver, and therefore, caution with dosage needs to be considered in those with hepatic impairment (Sasada 2003). The recognised problem of respiratory depression has resulted in codeine being withdrawn from use both in neonates and breastfeeding mothers.
While there are many theoretical reasons why codeine should no longer be used, it is still prescribed both within and outside the PICU (Tremlett et al. 2010). Familiarity and well-recognised dosing regimens convey an advantage as well as the availability of oral preparations. It has a limited role in the PICU setting as it is generally agreed that codeine is not a substitute for the more reliable and potent analgesic properties of morphine (Tremlett et al. 2010). It is the author’s view that oral morphine should be started in preference to codeine where possible.
39.2.2.1.6 Tramadol
Tramadol is a synthetic opioid used in the management of moderate to severe pain. It can be administered orally, intravenously or intramuscularly. The dose for children is 1–2 mg/kg every 4–6 h (Sasada 2003). Eighty five percent is metabolised by the liver; 90 % of the dose is excreted in the urine. Hepatic or renal failure is a contraindication to its use (Sasada 2003). In the UK, tramadol is not licensed for use in children less than 12 years of age.
One major disadvantage of tramadol in paediatrics is the high incidence of nausea in children. As with codeine, the active metabolite is formed via the CYP2D6 enzyme system resulting in a varied analgesic effect depending on the patient’s underlying genetics.
39.2.2.2 Non-opioid Analgesics
There are a variety of drugs within this group, the most common of which are discussed below. Table 39.3 summarises this group including doses and the most clinically relevant side effects.
Table 39.3
Non-opioid analgesia
Drug | Indications | Dose | Comments |
|---|---|---|---|
Paracetamol | Hyperthermia Co-analgesia with opioids | 0–3 months loading dose: oral 20 mg/kg, rectal 30 mg/kg Maintenance 15 mg/kg/dose Maximum daily dose (see Table 39.4) | Significant but low analgesic potency Reduced doses may be needed in the critically ill fluid-restricted child to avoid hepatic dysfunction and toxicity |
Diclofenaca | Opioid-sparing analgesia Not used under 1 year or in children with significant asthma | 1 mg/kg/dose or rectal maximal daily dose 3 mg/kg/day | Has effects on gastric mucosa and platelet function Can be nephrotoxic |
Ibuprofena | Not used under 3 months or in children with significant asthma | 10 mg/kg/dose oral or rectal maximal daily dose 40 mg/kg/day | As above |
Ketamine | Alternative intravenous analgesia to opioids (NMDA receptor antagonist) | IV infusion 10–45 μg/kg/min | Can be used in spontaneously breathing children. Associated with dysphoria when used as a sole agent. May provide useful bronchodilation |
Clonidine | Less analgesic potency than morphine but can be used as co-analgesia (orally), for longer-term sedation or for withdrawal from opioids (α-2-agonist) | Intravenous: 0.5–3.0 μg/kg/h Oral: 2–5 μg/kg 4 hourly | Can cause hypotension and bradycardia Rebound hypertension has been described in adults |
39.2.2.2.1 α-2 Adrenoceptor Agonists
39.2.2.2.1.1 Clonidine
Clonidine is an α-2 receptor agonist that has a predominantly central action within the central nervous system to modify sympathetic outflow and alter pain transmission and perception. It has multiple actions and has been used as a nasal decongestant and antihypertensive agent in the past, but in intensive care, it has become of interest as an analgesic and a sedative agent. The drug is fat soluble with high bioavailability (>90 %), making it useful by both intravenous and oral routes. Intravenous doses of 2 μg/kg/h have been used in combination with low-dose midazolam to provide effective postoperative analgesia in paediatric cardiac patients without significant effects on heart rate, arterial blood pressure or cardiac index (Ambrose et al. 2000). It can produce significant hypotension and bradycardia in the adult population in intensive care, and this has been used clinically as a biofeedback loop to regulate infusion rate. Low-dose clonidine [1 μg/kg/h] can give a significant opioid-sparing effect with subsequent improvement in ventilatory function and conscious level (Lyons et al. 1996).
From adult studies, it is suggested that the use of α-2 agonists is associated with a noticeable lack of drug tolerance and withdrawal (Mirski et al. 1995). In order to reduce opiate requirements postoperatively, some units load patients with clonidine at a dose of 5 μg/kg followed by maintenance doses of 2–4 μg/kg every 4 h. Similar doses are used in children that have been ventilated for prolonged periods who have become tolerant of opiates. This approach has been adapted from the use of oral clonidine in neonatal abstinence syndrome, although a Cochrane Review found insufficient randomised trial evidence to support this practice (Hoder et al. 1984). The therapeutic ratio for clonidine in children appears to be high, and single oral doses of up to 10 μg/kg have been tolerated without apnoea, bradycardia or hypotension (Fiser et al. 1990).
Although the classical withdrawal symptoms seen with drugs such as midazolam do not occur with clonidine, some concerns still remain about rebound hypertension and agitation, but as yet there are not enough cumulative or prospective data with which to answer these questions.
39.2.2.2.1.2 Dexmedetomidine
As with clonidine, dexmedetomidine’s main actions are sedation, anxiolysis and analgesia. It has a purer alpha-2 agonist effect with less alpha-one receptor action (vasoconstriction) and is undergoing evaluation within the United States. The drug is delivered intravenously: dosages involve an initial load at 1 μg/kg for 10 min before reducing the infusion to 0.2–0.7 μg/kg/h. It is only advised for short-term use; infusions are usually stopped within 24 h. The drug is 94 % protein bound with extensive hepatic clearance. The main side effects, as with clonidine, are hypotension and bradycardia (Sasada 2003).
39.2.2.2.2 Non-competitive NMDA Receptor Antagonist
39.2.2.2.2.1 Ketamine
Ketamine is an anaesthetic agent that can provide analgesia and unconsciousness. When given by continuous infusion, it can be used for perioperative pain (Vardi et al. 2002; Green et al. 2001), for procedural pain (Vardi et al. 2002; Green et al. 2001) and as an alternative analgesic to opioids. It usually maintains blood pressure and heart rate after administration due to its indirect sympathomimetic effects despite a limited negative effect on cardiac performance, and this has made it a popular agent for induction of anaesthesia in the child with critical cardiac performance (e.g. cardiomyopathy). Ketamine is associated with hallucinogenic properties and dysphoria that can be offset by combining it with a benzodiazepine.
Ketamine is often selected as an alternative to opioids for analgesia/sedation in the ventilated child with life-threatening bronchospasm, due to its associated bronchodilatory properties. There are limited publications that describe the successful use of ketamine in asthma, but this has never been tested in a large-scale prospective comparative trial (Nehama et al. 1996; Mannix and Bachur 2007). The place of ketamine as an analgesic infusion in PICU remains limited, but it has proved a valuable alternative to opioids in schemes that allow for cyclical rotation of sedative/analgesic combinations (See Fig. 39.1). Doses up to 2.7 mg/kg/h have been described (Nehama et al. 1996; Hartvig et al. 1993; Tobias et al. 1990; Rock et al. 1986).
39.2.2.2.3 Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
NSAIDs can be given in combination with opioids and paracetamol as part of a balanced analgesic regimen to reduce the opioid requirements and their attendant side effects (Mather and Peutrell 1995; Issioui et al. 2002). However, their side effects, including gastrointestinal irritation, prolonged bleeding time due to suppressed platelet function, bronchospasm and renal impairment. Their use therefore needs to be considered with care in the individual PICU patient. The majority of drugs in this class are not licensed for use in children. The most commonly used are ibuprofen (only given over the age of 3 months) and in the older child diclofenac.
39.2.2.2.4 Paracetamol
In isolation paracetamol has limited analgesic potency, but using adequate loading and maintenance regimens can optimise its effectiveness. Children over 3 months of age can be given loading doses of 20 mg/kg orally or 40 mg/kg rectally, followed by regular doses of up to 15 mg/kg every 4 h to provide effective plasma concentrations of the drug (Anderson et al. 2002). The maximum daily oral dosage of the drug in children is 90 mg/kg/day. However, it is generally accepted that in patients who are fluid restricted with reduced cardiac output, dosages should be reduced as hepatic impairment and liver failure can develop when a dose of 90 mg/kg/day is continued in a sick child over several days (Morton and Arana 1999). In neonates, the maximum daily dose is reduced further to 60 mg/kg/day and lower still in preterm infants (Arana et al. 2001). Rectal preparations have reduced and more variable bioavailability than the oral route, and intravenous route may be preferable if the oral route is not available. The duration of use of paracetamol varies with age and can be seen in Table 39.4 (Arana et al. 2001).
Age of patient | Maximum daily dose (mg/kg/day) | Maximum duration of treatment (h) |
|---|---|---|
Preterm 28–32 weeks | 35 | 48 |
Preterm 32–36 weeks | 60 | 48 |
0–3 months | 60 | 48 |
>3 months | 90 | 72 |
39.2.2.2.5 Local Analgesia Techniques
Afferent pain conduction can be eliminated with effective local anaesthesia applied to the appropriate area with minimal side effects. These can provide an important adjunct to any analgesia or sedation regimen to reduce the drug requirements for background medication or procedural pain. These can be given by a wide variety of routes including topically, infiltration, peripheral nerve blocks or central continuous blocks (epidural or spinal).
Topical anaesthesia is used regularly on the general paediatric wards and in the emergency department. The use of these agents in PICU is often ignored except in non-intubated patients. Procedures seemingly minor such as venous cannulation can be incredibly distressing to the sedated child, often resulting in an increase in baseline rates of sedative infusions. If agents such as Ametop and EMLA are applied in advance of an anticipated procedure, as a routine, the use of intravenous analgesia and sedation can be minimised. Newer, faster-acting agents are now available. Included in this group is lidocaine-adrenaline-tetracaine gel (LAT gel), which is effective for use in as little as 10 min (Ernst et al. 1997; Chipont Benabent et al. 2001). This agent is finding increasing favour in the emergency department for wound suturing, with good effect. It has been suggested that its use should be extended to other areas, such as PICU, due to its rapid onset of action and excellent analgesic effects. Care does need to be given to its site of use due to the adrenaline component.
Regional anaesthesia remains under utilised in PICU. It can facilitate early extubation and rapid mobilisation following surgery or allow lower levels of systemic analgesia and sedation thereby reducing side effects (Scott et al. 2001; Staats and Panchal 1997; Loick et al. 1999). Included in the realms of regional anaesthesia are intravertebral nerve blocks. These can be applied directly to the nerves by surgeons in theatres following thoracotomies and if necessary repeated in PICU or continued via a catheter. Epidural and spinal catheter techniques for major postoperative chest, abdominal and pelvic surgery have been compared to opioid techniques and can reduce pain, stress response and side effects in comparison to opioids in the short term (Wolf et al. 1998; Humphreys et al. 2005).
39.3 Sedation
39.3.1 Indications
Sedation is a broad term when used in the context of PICU. It comprises many features that may include:
1.
Unconsciousness (virtual anaesthesia) or reduction in conscious level
2.
Reduced awareness
3.
Loss of explicit and implicit memory
4.
Compliance with the need to lie in a confined space attached to monitors and invasive lines
The ideal sedative should have a rapid onset, easy administration, predictable duration of action, few side effects and a rapid recovery.
Sedation needs may be low-dose long-term administration, but in addition, the degree of sedation may need to be increased to allow potentially distressing procedures such as physiotherapy, radiological scanning or minor surgical procedures to take place.
Different drugs fulfil these roles to different extents. For example, benzodiazepines provide anterograde amnesia with reduced or complete unconsciousness at different doses, while phenothiazines and butyrophenones (chlorpromazine and haloperidol) used as major tranquillising drugs in schizophrenia have psychotropic properties that render the patient disinterested in activity. In addition, some of the analgesic drugs described above have dual effects on the reduction of pain and consciousness: ketamine provides analgesia and a dissociative anaesthesia/sedation, clonidine produces analgesia and a calmed relaxed state and morphine has additional sedative properties. Therefore, selection of a sedative regimen needs to be individualised rather than generic.
Neonates are a special group in that morphine alone can often provide enough analgesia and sedation so that a second sedative agent is not required. However, outside this period, almost always an analgesic and a sedative drug are necessary. In the special case where a child needs to receive muscle relaxants, the need for a sedative drug given at adequate dose becomes mandatory to prevent awareness.
In the past, patients in adult intensive care have been given an opioid in combination with a low dose of an anaesthetic agent to ensure pain relief, haemodynamic stability and tolerance to the constraints of ITU. The potentially lethal side effects of anaesthetic drugs over days have only emerged after reviews of death rates and analysis of recurring adverse events. These have included immunomodulation by barbiturates (Galley et al. 2000; Sanders et al. 2009), adrenocortical suppression by etomidate (Fraser et al. 1984) and more recently, mitochondrial dysfunction with propofol in both adults as well as children (Vasile et al. 2003).
Where possible sedation via the enteral route is beneficial. When a patient is able to tolerate feeds and absorb medications via this route, it enables sedation to be given regularly without the need for an infusion and the complications associated with the intravenous route. Many useful sedation agents are well absorbed and tolerated via the enteral route including benzodiazepines, clonidine and chloral hydrate. An additional advantage to oral sedation is it can be weaned gradually and continued following discharge from intensive care if necessary.
39.3.2 Choice of Drug
Table 39.5 summarises the major drugs in this section that are outlined in detail below:
Table 39.5
Sedative drugs
Drug | Benefits | Dose | Comments |
|---|---|---|---|
Benzodiazepines | |||
Midazolam | Provide amnesic benefit in addition to sedation | Infusion max dose of 200 μg/kg/h Intranasal midazolam 0.1 mg/kg/nostril | High risk of withdrawal with prolonged or high-dose (>100 μg/kg/h) use Helps control seizures |
Lorazepam | Oral drug useful in midazolam withdrawal | Oral: 0.02–0.06 mg/kg IV: 0.05–0.2 mg/kg, then 0.01–0.1 mg/kg/h | |
Diazepam | Rectal for status epilepticus | Rectal doses: Neonate: max 2.5 mg 1 month–2 years: 5 mg 2–12 years: 5–10 mg 12–18 years: 10 mg | Risk of respiratory depression – particularly with repeated doses |
Propofol | Short-term action – rapid wake up | Infusion: Max 4 mg/kg/h Titrate to effect Check for rising lactate or acidosis, limit infusion duration | Hypotension Risk of propofol infusion syndrome Lipid load with infusion Contraindicated by FDA |
Phenothiazines (chlorpromazine hydrochloride) | Dissociated sedation | Oral or PR: 0.5–2 mg/kg IV: 0.25–1 mg/kg | Risk of extrapyramidal side effects |
Butyrophenones (Haloperidol) | Dissociated sedation | Infusion: 1 month–12 years 25–85 μg/kg per day 12–18 years 1.5–5 mg per day | Risk of extrapyramidal side effects |
Clonidine | Helpful with withdrawal Analgesic properties with an opiate-sparing effect | Intravenous: 0.5–3.0 μg/kg/h Oral: 2–5 μg/kg 4 hourly | Can cause hypotension and bradycardia Rebound hypertension has been described in adults |
Volatile agents | Rapid clearance for quick wake up | Dose titrated to effect Depends on delivery system and gas flows | Can help with bronchospasm and seizures Requires vapouriser and scavenger systems |
Chloral hydrate | Well tolerated | 25–50 mg/kg oral or per rectum 4–6 hourly | Delayed clearance in neonates – be wary with regular dosing |
39.3.2.1 Benzodiazepines
39.3.2.1.1 Midazolam
Currently, midazolam is the most common sedative agent in use in PICU (Jenkins et al. 2007). Acutely it can provide effective conscious sedation and amnesia, but used over time, it is a drug associated with major side effects resulting in significant morbidity. Benzodiazepines are associated with tolerance resulting in escalating doses and eventual withdrawal when they are stopped, which are features of all the commonly used sedative agents (Mirski et al. 1995). However, this has been especially noted with midazolam, with data reporting an incidence as high as 35 % with this drug (Fonsmark et al. 1999; Hughes et al. 1994). The duration of symptoms of withdrawal has been found to be as long as 1 week in some patients and can raise concerns about neurological injury while the symptoms continue. Limiting the dose of midazolam to 100 mcg/kg/h can reduce the risks of tolerance and withdrawal, but recent data demonstrated that there was no difference in the incidence of these side effects when the drug was stopped abruptly rather than weaned off over days (Jenkins et al. 2007). It has been shown that any of the commonly used sedative agents in PICU can produce tolerance, physical dependency and withdrawal after prolonged use (Tobias 2000). Midazolam has the advantage of being reversed by flumazenil if necessary.
39.3.2.1.2 Diazepam
Diazepam possesses both anxiolytic and amnesic properties. It can be painful if given intravenously but can also be given orally and rectally. It has a rapid predictable onset and as with midazolam can be reversed with flumazenil (Pershad et al. 1999). Diazepam has some mild muscle relaxation and anticonvulsant properties. It is relatively lipid soluble and water insoluble, and when taken orally, its availability is about 100 %. The sedative level of diazepam is attained some 30 min after oral administration, with the deepest sedative effects occurring after 60–90 min. In neonates, the volume of distribution is increased, and patients with hepatorenal function impairment will have reduced clearance rates of the drug; therefore, care needs to be given with the dosing in PICU due to the potential for the sedative effects of diazepam to be prolonged by a build-up of active metabolites.
39.3.2.1.3 Lorazepam
Lorazepam is a potent long-acting agent that is a useful drug in PICU, particularly in long-term ventilated patients on oral sedation therapies.
Peak plasma concentration of lorazepam is reached within 3 h of ingestion with a slow offset (Greenblatt et al. 1979). Patients experiencing symptoms of withdrawal following cessation of intravenous administration of midazolam for a prolonged period can also benefit from oral lorazepam. The acute withdrawal symptoms can be counteracted with the lorazepam, and the dose gradually reduced as the patient recovers. As the drug is well absorbed and tolerated via the oral route, the complications of needing ongoing intravenous access are avoided.
39.3.2.2 Propofol
Propofol was widely used in PICU but is contraindicated by both US and UK regulatory authorities due to life-threatening complications including metabolic acidosis, rhabdomyolysis and cardiac and renal failure. This syndrome termed propofol infusion syndrome (PIS) (Parke et al. 1992; Bray 1998; Hanna and Ramundo 1998; Cray et al. 1998; Wolf et al. 2001; Mehta et al. 1999) is related to suppression of fat metabolism at a mitochondrial level while continuing to deliver a fat load contained in the propofol emulsion. However, despite the concerns, it continues to be used in specific cases for short-term use at low dose (<4 mg/kg/h). Patients should be closely monitored for rising lactate, acidosis, reduced urine output or dysrhythmias. Haemofiltration to remove the lipid and propofol and provision of adequate carbohydrate intake to suppress further beta oxidation has been recommended as an acute treatment for PIS (Wolf and Potter 2004).
When used as a short-term anaesthetic agent, it can initially cause profound hypotension on first exposure. This brings with it a particular risk for those patients who have cardiovascular compromise secondary to sepsis or underlying cardiac defect. This group are recognised to decompensate when given propofol and potentially spiral into cardiac arrest. While low-dose propofol provides excellent sedation for procedures, it needs to be used with caution as there is a fine line between sedation, anaesthesia and loss of airway control.
39.3.2.3 Chloral Hydrate
Chloral hydrate is a widely used sedative hypnotic. It is commonly used as an adjunct in neonatal and paediatric intensive care. Doses of 25–50 mg/kg can be given either orally or rectally. It is rapidly absorbed from the GI tract and converted to the active metabolite trichloroethanol (TCE). In neonates the parent drug also contributes to the sedation and hypnotic action. The half-life of TCE is 8–12h but is estimated to be three to four times longer in neonates and infants (Pershad et al. 1999). For this reason neonatal doses may need to be revised, particularly with multidose regimens.
Chloral hydrate is a CNS depressant which at therapeutic doses has only mild influence on blood pressure and respirations with no impairment on airway protection reflexes giving it a good safety profile with the correct dosing range. In overdose the majority of adverse effects occur via the cardiovascular system with a spectrum of arrhythmias that can be fatal. It has a wide safety margin, being detoxified by the liver and eliminated by the kidneys; therefore, hepatorenal disease will affect drug clearance.
Drug interactions are recognised with chloral hydrate exhibiting synergistic effects when given in combination with other sedative drugs. In combination with warfarin, there can be an unpredictable reaction with potential hypoprothrombinaemia due to competition for protein binding. By the same mechanism furosemide in combination with chloral hydrate can lead to vasomotor instability (Pershad et al. 1999).
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