1590 SECTION XIV Pediatric Critical Care Anesthesia Principles in the Pediatric Intensive Care Unit Drug Elimination Half Life (h) Volume Distribution (SS; L/kg) Clearance (mL/kg/ min) Protein Binding[.]
1590 S E C T I O N X I V Pediatric Critical Care: Anesthesia Principles in the Pediatric Intensive Care Unit Opiate Antagonists Several opiate antagonists are available The most commonly used is naloxone, which is a specific and sensitive receptor antagonist of all opiate receptors It is administered in either low doses (1 mg/kg) for partial opiate reversal or to ameliorate opiate-induced pruritus, or in higher doses for full opiate reversal (10 mg/kg) or emergency reversal of opiate overdose (100 mg/kg) If the drug cannot be administered intravenously, then it can be given intramuscularly, TABLE 132.3 Opiate Pharmacokinetics Elimination Half-Life (h) Volume Distribution (SS; L/kg) Morphine 2.2 3.3 Meperidine 3.20 2.8 5.0 58 Fentanyl 3.10 3.2 10.0 79 Sufentanil 2.70 2.5 13.0 92 Alfentanil 1.20 0.3 2.8 89 Remifentanil 0.08 0.2 30.0 80 Drug Clearance (mL/kg/ min) Protein Binding (%) 15 30 SS, Steady state Incidental Pain Syndromes in the Pediatric Intensive Care Unit TABLE 132.4 Opiate Dose Equivalence Drug Oral Parenteral Morphine 0.5 mg/kg q4h 0.15 mg/kg q3h Hydromorphone 0.1 mg/kg q4h 0.02 mg/kg q4h Codeine 4.0 mg/kg q3h Hydrocodone 0.5 mg/kg q3h Oxycodone 0.5 mg/kg q3h Meperidine 5.0 mg/kg q2h Fentanyl intranasally, or into the midventral surface of the tongue.54 When naloxone is being used to antagonize a long-acting agonist, an infusion may be necessary because its half-life is only 30 to 81 minutes (mean of 64 12 minutes) In neonates, the half-life has been reported as 3.1 0.5 hours However, this prolonged effect is likely to be offset by a concomitant increase in the duration of action of the opioid for which the naloxone is given No effect is seen in the healthy patient in the absence of administered opioids; however, in the setting of sepsis in the ICU, a vasopressor effect may occur, presumably because of an interaction with endogenous opioids released in response to stress Nalmefene, a longer-acting antagonist, can be given through IV, IM, and SC routes It has a redistribution half-life of 41 minutes and a terminal half-life of 10.8 hours in adults and somewhat less in children Reappearance of the antagonized opioid is unlikely if nalmefene is given in an adequate dose.55 There has been a growing interest in the use of opiate antagonists in the management of opiate-induced ileus Naloxone can be given orally.56 However, there is evidence of a central effect that slightly reduces the efficacy of parenterally administered opiates Two opiate antagonists are available that have been approved for opiate-induced constipation Naloxegol is a PEGylated naloxone that does not cross the blood-brain barrier, inhibits opioid receptors in the GI tract, and improves motility.57 Methyl naltrexone is also approved for opiate-induced constipation These drugs are not routinely used; however, they may be added to bowel regimens to prevent opiate-induced bowel dysfunction 1.50 mg/kg q2h 1.50 mg/kg q2h Although the techniques used to sedate children are often applied in order to facilitate their PICU care, many children have pain that is related to their underlying condition Many options are available for controlling pain in the pediatric patient (Box 132.2) The pharmacologic management of pain should follow the traditional World Health Organization analgesic ladder, which begins with a nonopioid analgesic such as a nonsteroidal antiinflammatory drug or acetaminophen, followed by a weak opioid, such as hydrocodone added to the nonopioid, and then a strong opioid such as morphine or hydromorphone as needed When taken orally, a sustained-release preparation is useful once the dose TABLE 132.5 Summary of Opiate Dosing Drug Relative Potency Bolus Dose Initial Infusion Rate Active Metabolites Morphine 1.0 0.1 mg/kg 0.04 mg/kg/h M6G Meperidine 0.1 1.0 mg/kg N/A Normeperidine Fentanyl 100.0 1.0 mg/kg 1.0 mg/kg/h None Hydromorphone 7.0 0.015 mg/kg 0.005 mg/kg/h None Sufentanil 500.0 0.2 mg/kg 0.2 mg/kg/h None Remifentanil N/A N/A 0.1 mg/kg/min None Alfentanil 10.0 10 mg/kg 10 mg/kg/h None Methadone 1.0 0.1 mg/kg N/A None M6G, Morphine-6-glucuronide; N/A, not applicable CHAPTER 132 Sedation and Analgesia • BOX 132.2 Options for Controlling a Child’s Pain Analgesics Cognitive Opioids—weak, potent Nonsteroidal antiinflammatory drugs Nonopioids Imagery Distraction Hypnosis Choices and control Information Role play Anesthetics Regional block Epidural anesthesia Topical anesthesia Physical Behavioral Biofeedback Relaxation therapy Thermal Massage Physical therapy Transcutaneous electrical nerve stimulation requirement has been determined The required dose can be variable in the patient taking opioids for a prolonged period; not appreciating this variability is a common cause for therapeutic failure In addition, once a dose requirement is known, the analgesic should be given to preempt pain rather than to relieve pain as required At each level of analgesic use, the addition of adjuvant medications should be considered Adjuvant drugs fall into six groups: antidepressant, anticonvulsant, neuroleptic, steroid, stimulant, and local anesthetic Of the tricyclic antidepressants, nortriptyline is available in a liquid form The tricyclic antidepressants are indicated for neuropathic pain, particularly when the patient describes a burning pain Anticonvulsant agents, gabapentin, pregabalin, and carbamazepine can be useful for neuropathic pain as well These drugs often work best when the pain is described as shooting or lancinating Neuropathic pain may result from tumor invasion, vincristine therapy, cytomegalovirus infection, or human immunodeficiency infection Neuroleptic drugs, including chlorpromazine and trimeprazine, may be useful in the management of nausea, anxiety, and pruritus Steroids benefit mood, inflammation, nausea, appetite, nerve swelling/entrapment, and vasculitis When opioid sedation is interfering with quality of life, a stimulant such as an amphetamine may restore energy and alertness while allowing ongoing analgesia from the opioid Pain can sometimes be managed by local anesthetic, placed by peripheral nerve block, topically, or as a neuraxial block Patient-controlled analgesia (PCA) has become the mainstay of postoperative pain relief in children because of its efficacy and safety However, its use is limited by the child’s ability to understand how to use the PCA pump Proxy PCA (PCA-P) has been used for younger children or those with cognitive impairment.58 The use of PCA by the nurse or the caregiver may override the safety net that the PCA has The use of PCA-P has been associated with greater need for rescue interventions; however, it is often used in sicker children When PCA-P is used, careful evaluation and rigorous monitoring are needed Sickle Cell Crisis Pain in patients with sickle cell disease differs from that experienced by patients with cancer or acquired immune deficiency syndrome in that intermittent episodes of severe pain occur, requiring urgent intensive treatment.59 Chronic pain is present 1591 because of long-term tissue and bone damage from periods of ischemia during past crises, including persistent myocardial ischemia Patients may be receiving long-acting opioids or may have had repeated exposure to opioids with past crises Chest crises result from the sickling of erythrocytes in the pulmonary microvasculature and result in hypoxia to the rest of the body and local lung damage The systemic hypoxia worsens the crisis; thus, it is self-perpetuating Chest radiograph changes may lag other symptoms, and an associated paralytic ileus may be present Poor pulmonary function may incorrectly discourage the practitioner from using adequate opioid analgesics out of concern for worsening the hypoxia However, it is important not to underestimate the need for pain relief and to appreciate that past opioid exposure may have resulted in tolerance to opioids It is important that the pain is assessed early and quickly treated Pain must be reevaluated often to ensure that additional doses are given in a timely manner.60 When considering the use of PCA, appropriate dosing must be employed as well Inadequately low dosing will result in unsatisfactory analgesia in patients who are not opiate naïve These patients require frequent pain reevaluation to ensure that the PCA is programmed properly If IV access is difficult to obtain, morphine may be given subcutaneously or orally Ketamine has anecdotally been suggested as an adjunct in sickle cell pain crisis, with purported improvement in pain scores and a reduction in opiate requirements.61 Intranasal fentanyl has also been used with a reduction in pain within 20 minutes However, the analgesic effect was not sustained for long and the use of intranasal opiates may complicate the dosing of subsequent parenteral opiates Its use in the emergency department reduces the time to parenteral opiate when compared to IV administration, without any noted complications.62 Codeine is the only schedule opiate in the United States, and its use is still common In a study looking at CYP2D6 genotypes in a sickle cell population, approximately 7% of patients were possible or actual ultra-rapid metabolizers and 1.4% were poor metabolizers While safe in typical subjects, codeine must be avoided in both of these subsets.63 Anecdotal success also has been reported with nebulized morphine.64 Opiate Tolerance The use of opiate infusions in the ICU is associated with the potential for the development of tolerance or dependence.53 This can be due to receptor desensitization or upregulation of the postreceptor pathways, which mostly results in a physiologic dependency state The need to wean sedatives to facilitate ventilation weaning and extubation further compounds this problem, resulting in iatrogenic withdrawal syndrome (IWS), which has been shown to delay patient recovery and prolong hospitalization IWS can occur if an opiate is discontinued abruptly Withdrawal effects have been correlated to the total dose and duration of fentanyl infusion A fentanyl infusion of days or a total cumulative dose of 1.6 mg/kg during the hospital stay was associated with a 50% chance of developing narcotic withdrawal, whereas a fentanyl infusion of days or longer or a total cumulative fentanyl dose of 2.5 mg/kg or more during the hospital stay had a 100% incidence of withdrawal.65 The rising plasma fentanyl levels caused by increased dosing suggested that increased metabolism or clearance is not responsible for the development of tolerance A study of patients in a PICU conducted to determine the degree of opiate tolerance showed a significant increase in opiate dosing required for adequate sedation.66 Opiate dosage increased by about 80% 1592 S E C T I O N X I V Pediatric Critical Care: Anesthesia Principles in the Pediatric Intensive Care Unit per week for the first weeks of opiate use No difference in the rate of opiate increase was found with respect to age, postoperative status, mode of ventilation, and use of NMBAs.66 For patients considered to be at risk of withdrawal, several options are available If circumstances allow, it is better to start the treatment for withdrawal prevention before the patient develops symptoms and signs of withdrawal Opiate withdrawal is not usually a serious medical problem; although highly uncomfortable, it is rarely life-threatening and is self-limited However, treatment should begin as early as possible for patient comfort The hypersympathetic state associated with opiate withdrawal may be detrimental to the patient The signs and symptoms of withdrawal are nonspecific; other causes—such as infection, hypoglycemia, hypocalcemia, hyperthyroidism, and hypoxia—should be excluded Because of the nonspecific nature of the symptoms of opiate withdrawal, several scoring systems have been described to aid with the diagnostic process The Finnegan score is based on 31 variables and is lengthy The Lipsitz score is shorter and easier to use Both of these scoring systems, however, were devised for use with neonates; several of the measurements are not appropriate for patients in the PICU The Withdrawal Assessment Tool-1 (WAT1) has been developed and validated in a PICU population.67 The score is quick and easy to calculate (Table 132.6), usually done once a shift IWS is considered when the WAT-1 score is or greater The risk of withdrawal with respect to this tool appears to be related to both opiate dosing and duration.68 The score has features typical of opiate withdrawal, such as sweating, yawning, and loose stools The score also takes into account agitation, TABLE 132.6 WAT-1 Withdrawal Assessment Tool Symptom/Sign Score Assigneda Loose stools Vomiting or gagging Temperature 37.8°C Awake and distressed prior to stimulation Moderate or severe tremor Sweating Uncoordinated/repetitive movements Repeated yawning or sneezing Poststimulation (in order, if no response) Call patient’s name If no response, touch patient’s arm If no response, perform a planned uncomfortable procedure Startle response Increased muscle tone How quickly does the child settle? a 2–5 minutes minutes Maximum score of 12 tremor, and uncoordinated movements, which are more often associated with BZD withdrawal The signs related to sympathetic overactivity that may be associated with opiate withdrawal, such as tachycardia and hypertension, were not found to be specific enough to be included in this assessment tool The tool appears to be accurate, with an area under the curve of 94% (sensitivity of 87% and specificity of 88%).67,68 The other tool that has also been validated in the PICU for withdrawal assessment is the Sophia Observational Score (SOS).69 It is quite similar to the WAT-1, as it uses 15 items and includes both abnormal heart rate and respiratory rate Additional components include inconsolable crying, hallucinations, and sleep disorder The accuracy of the score appears to be very similar to the WAT-1, with an area under the curve of 95% (sensitivity of 83%, specificity of 93%) Both scores have good intra- and interrater reliability and should be useful in the management of opiate withdrawal as well as BZD withdrawal in the PICU Several therapeutic options are available for the prevention and treatment of opiate withdrawal Drugs from the same class are preferable The FDA has approved methadone for the treatment of opiate withdrawal Other agents that may be useful include morphine, clonidine, dexmedetomidine, phenobarbital, paregoric, chlorpromazine, the transdermal clonidine patch,70 and SC fentanyl Paregoric contains morphine plus papaverine, noscapine, camphor (a CNS stimulant), ethanol (45%), benzoic acid (which competes with bilirubin-binding sites), and glycerin (which causes diarrhea) Paregoric has been used for neonatal withdrawal, but because of its composition, it may cause adverse effects Chlorpromazine may be useful for GI adverse effects, but hypothermia and hypotension may occur Haloperidol may be of use, having minimal respiratory depression and no active metabolites It also offers cardiovascular stability Phenobarbital has been used for hyperactive behavior; however, it can cause significant CNS depression, induces drug metabolism, and is tolerance/ dependence forming Methadone is the most suitable agent for treating opiate withdrawal It has an oral bioavailability of 80% to 90% and an elimination half-life of 12 to 24 hours It is equipotent to morphine Methadone has inactive metabolites and is less sedating than morphine while remaining an effective analgesic Because of its higher bioavailability and reduced first-pass metabolism, the effect of oral doses is more predictable than that of morphine Methadone has been extensively used in the outpatient management of opiate addiction The convenience of the oral route, the less-frequent dosing because of its longer half-life, and the ease of calculating doses because of its equal potency to morphine make methadone attractive for use in the management of opiate withdrawal in children However, significant variability exists in recommendations regarding the methadone dose that should be used to prevent opiate withdrawal in children Several factors are important in the dosing of methadone for withdrawal from fentanyl After prolonged IV administration, fentanyl has a potency 100 times that of methadone; it has a metabolic half-life approximately one-quarter that of methadone; and if given intravenously, it has a bioavailability 20% greater than orally administered methadone A study assessing the effectiveness of a fentanyl-methadone conversion protocol found that administering 2.4 times the daily fentanyl dose as methadone successfully prevented withdrawal symptoms.71 In that study, methadone was given intravenously for 24 hours; the fentanyl dose was decreased by 50% on day and by another 50% on day 2, then discontinued On day 3, methadone CHAPTER 132 Sedation and Analgesia was converted to oral dosing Methadone was given intravenously initially (with the possibility of administering additional doses, as needed) because it could take up to days to reach a steady state with scheduled oral dosing due to its long half-life The duration of methadone treatment varied from to weeks, depending on the duration of the preceding opiate infusion Methadone was weaned by 3% to 15% per day with no signs of withdrawal.71 To date, there have been no published cases of respiratory arrest when methadone has been used for opiate weaning The incidence, risk factors, and best management strategy for opiate withdrawal in the PICU are still open to debate Several articles have suggested risk factors for withdrawal Younger age, higher level of critical illness, duration, and cumulative dose are important patient variables,72 but not all studies demonstrate these same risk factors Postoperative patients appear to be less likely to develop tolerance, as postoperative patients who received morphine rather than fentanyl However, in nonsurgical patients, the opiate chosen was not significant.73 Of patients receiving opiates for more than days, 35% required the dose to be doubled by 14 days Most of these increased dose requirements occurred within to days Starting at a lower dose was also a risk factor for increased dose requirements In this study, however, the opiate doses used were very low, with a peak fentanyl dose of only mg/kg per hour Thus, these factors may not apply in patients receiving higher doses.72 Of interest, the concomitant use of midazolam infusions also was associated with increased opiate needs; whether this reflects a patient factor or a drug effect is unknown Caution should be taken when interpreting these data given the multicenter nature of the study with the lack of a sedation protocol in these institutions.72 There is some belief, but little evidence, that using sedation protocols can reduce this problem Intermittent rather than continuous infusions can reduce the risk However, this option has to be balanced against the primary aim of sedation, which is patient comfort and safety Finally, hospital-based factors can play a part It would appear prudent to initiate the conversion from fentanyl/morphine to methadone in the ICU environment in the event that problems arise and to ensure that an adequate dose is given Once stabilized, the patient may be transferred out of the ICU and ultimately home, with a clear plan for decreasing the methadone dose over time The weaning plan should involve the primary pediatrician as an additional safeguard An alternative to fentanyl equivalence-based methadone dosing has also been reported.74 In this study, the patients received either a fixed low dose (0.1 mg/kg) of methadone or a high dose (fentanyl dose [mg/kg per hour] 0.1 weight) of methadone The methadone was tapered in a fixed manner irrespective of the duration of fentanyl infusion There was no difference in the success (about 60%) of the methadone taper between groups However, four times as many patients in the high-dose methadone group became oversedated The success rate of either of these protocols appears to be poor, possibly due to the fairly rapid wean of the methadone irrespective of the duration of opiate exposure Of note, the peak fentanyl dosing was low (4 mg/kg per hour) and the cumulative dose was also low (0.59 mg/kg), both below what are considered high risk for IWS This is an important consideration because, if using the high-dose strategy, the methadone dose based on a much higher fentanyl rate would expose the patient to very high doses of methadone and risk respiratory depression Also, methadone accumulates over several days—this respiratory depression could occur when the child is not being monitored as closely, after transfer to the floor This study supports the use of the lowest dose possible to prevent 1593 withdrawal, which is safer and allows for a shorter methadone taper period If the dose is found to be insufficient, small (25%) adjunct doses of methadone can be given to control the withdrawal symptoms Then, if needed, the methadone dose can be modified to reflect the patient’s actual requirements In younger children, an every 8- or 12-hour dosing schedule may not be adequate; a change to an every 6-hour regimen may be required in the initial few days Again, caution must be observed with respect to drug accumulation during this period The purpose of methadone is to prevent withdrawal symptoms and keep the child comfortable The methadone dose to prevent withdrawal is usually lower than the sedation dose Patient safety is paramount—opiate withdrawal, although unpleasant, is not life-threatening and, with appropriate assessment and timely intervention, can be corrected quickly Excessive sedation should be avoided Lofexidine has been used as an oral adjunct during outpatient opiate withdrawal and is approved by the FDA for that purpose.75 a2-Agonists are appropriate for opiate withdrawal in the ICU setting.76 There have been several reports of either SC or IV dexmedetomidine infusions (0.5 mg/kg per hour) that have demonstrated the ability to reduce the symptoms of opiate withdrawal in PICU patients.76 If already on dexmedetomidine, extubating on a lower infusion rate may result in a lower dose of methadone required to alleviate withdrawal symptoms The use of a clonidine patch also has been evaluated in the PICU Clonidine has been shown to be effective in the management of nicotine, opiate, and alcohol withdrawal It decreases sympathetic outflow from the CNS and has a synergistic effect for analgesia, both at the central and spinal levels In one report, a sustained-release transdermal clonidine hydrochloride patch (mean, 5.8 mg/kg per day; range, 4.2–8.5 mg/kg per day) was applied to consecutive patients after tracheal reconstructive operations and days of mechanical ventilation before discontinuation of sedative infusions and scheduled extubation.71 One patch had to be removed because of hypotension The transdermal clonidine patch seemed to be safe and efficacious in preventing withdrawal Its use is attractive because of its noninvasive approach However, the use of a transdermal patch prevents titration of the effect In addition, problems with bradycardia, hypotension, hypothermia, sedation, and dysrhythmia may occur A confounding issue in many publications and in the clinical management of opiate withdrawal is the potential for simultaneous BZD withdrawal Most researchers have not been able to successfully separate these two issues The symptoms of BZD withdrawal differ from those of opiate withdrawal because the BZD symptoms generally include less sympathetic activation BZD withdrawal symptoms are characterized by agitation and a movement disorder If BZD withdrawal is a concern, low-dose lorazepam or diazepam should be added to the withdrawal management strategy (Table 132.7) A prospective study of BZD withdrawal77 following lorazepam infusion (up to 0.3 mg/kg per hour) documented BZD withdrawal syndrome in approximately 25% of the children This withdrawal occurred even when using a 6-day tapering of the lorazepam dose All of the children had been previously weaned off fentanyl infusions No predisposing risk factors were found for BZD withdrawal with respect to BZD or opiate dosing or duration Rapid Opiate Detoxification There are various strategies for rapid opiate detoxification in the ICU These have employed a form of deep sedation (with propofol 1594 S E C T I O N X I V Pediatric Critical Care: Anesthesia Principles in the Pediatric Intensive Care Unit TABLE 132.7 Pharmacokinetics of Benzodiazepines Elimination Half-Life (h) Volume Distribution (SS; L/kg) Clearance (mL/kg/ min) Protein Binding (%) 46.60 1.13 0.4 97.8 Midazolam 3.00 1.09 7.5 94.0 Lorazepam 14.50 1.10 1.1 91.0 Flumazenil 0.67 1.20 15.3 50.0 Drug Diazepam SS, Steady state or another anesthetic agent) to facilitate opioid withdrawal in patients addicted to the recreational use of opiates.78 The patients are given high doses of opiate antagonists to displace all opiates from their receptors while under heavy sedation to reduce the occurrence and effects of the sympathetic stimulation observed with short-term opiate withdrawal These procedures have been safely performed in the ICU However, major complications can occur when these procedures were not performed with full ICU support.79 The effectiveness and safety of 1-day opiate detoxification are still a matter of debate.80 If used, it should be combined with a comprehensive support plan to optimize long-term success In the PICU, deep sedation with propofol has been used to facilitate rapid opiate weaning of ventilator-dependent patients.81 The use of propofol for up to days allowed a reduction of fentanyl dosing from 24 to mg/kg per hour (a 65% reduction), with no signs or symptoms of opiate withdrawal or metabolic acidosis.81 Opiate antagonists were not used for this rapid weaning process However, concern has been raised regarding the longterm administration of propofol, especially in the PICU patient, given the potential for propofol infusion syndrome Benzodiazepines BZDs are among the most commonly used agents for sedation in the ICU They augment the function of the GABA type A (GABAA) receptor at the postsynaptic membrane This pentameric protein controls a chloride channel, the opening of which leads to an inhibitory effect due to hyperpolarization of the cell membrane.82,83 BZDs bind to BZD receptors, which are usually found as part of the GABAA receptor in the CNS, enhancing the effect of endogenous GABA.84 Peripheral BZD receptors are not usually associated with the GABAA receptor but are a binding site for diazepam and midazolam.85 These 18-kDa proteins are associated with regulation of cellular proliferation, immunomodulation, porphyrin transport, heme biosynthesis, and anion transport In particular, they seem to be important in the regulation of steroid synthesis and apoptosis, and they have a significant effect on the hypothalamic-pituitary-adrenal axis.86 These latter effects may be pertinent to the physiologic care of patients in the ICU BZD receptors are bound by a family of endogenous peptides called endozepines, which have similar effects to the BZDs.87,88 The expression of this diazepam-binding inhibitor may be relevant to the development of dependence not only on BZDs but also on alcohol and opioids Therefore, it may be relevant in the drug dependence commonly seen in patients in the PICU who are given these agents continuously.89 Naturally occurring BZDs have been detected with structures similar to those used clinically.90 Subsets of GABAA receptors have been shown to have different effects Type receptors are responsible for sedation and anterograde amnesia, whereas type receptors mediate anxiolysis It may be possible to develop selective subtype receptor agonists to provide anxiolysis without sedation, amnesia, or dependence The general pharmacologic effects of BZDs are sedation, anxiolysis, euphoria (limbic system), anticonvulsive, reduced skeletal muscle tone (through spinal BZD receptors), and neuroendocrine effects They impair acquisition and encoding of new information, providing antegrade amnesia They not have any analgesic properties and little direct effect on ICP Their effects are dose dependent Patient cofactors—including age, concurrent disease, and any co-sedation therapy—influence responses to BZDs Paradoxical reactions are reported, in which agitation rather than calm is observed.91 In healthy patients, BZDs have few cardiovascular adverse effects However, profound cardiovascular depression may be observed in a critically ill patient Thus, BZDs should be used judiciously until the patient response is known.92 Midazolam has been most often associated with this effect,93 and research in dogs has shown both negative inotropy and chronotropy, especially when the sympathetic response has been abolished.94 Specific Benzodiazepines Diazepam The first widely used BZD in the ICU was diazepam Because of its low solubility in water, it is available in the IV or IM form dissolved in propylene glycol This formulation may cause pain and thrombophlebitis with peripheral IV use A lipid emulsion that has fewer adverse effects is available in the United Kingdom Diazepam is inexpensive and effective for short-term sedation; in such cases, accumulation is less of a concern Diazepam may be given orally because it has good absorption, but absorption is less predictable when given rectally or intramuscularly It is highly lipid soluble, with a long half-life (24 hours) Metabolism by oxidative biotransformation generates several hypnotically active metabolites with a long elimination half-life, including oxazepam (half-life, 10 hours) and N-dimethyldiazepam (half-life, 93 hours) Delayed recovery has been reported in neonates after receiving diazepam, possibly because of the long half-life of dimethyldiazepam.95 Prolongation of effects occurs in patients when clearance is reduced because of hepatic dysfunction and when metabolism is inhibited by drugs such as cimetidine and omeprazole BZDs are used as first-line therapy for pediatric convulsive seizures or status epilepticus Diazepam has been safely used rectally or intravenously to prevent and treat seizures.96,97 Recent evidence supports that other BZDs (midazolam and lorazepam) are more effective than diazepam for treating convulsive seizure or status epilepticus.98–100 Diazepam is used in the treatment for spasticity in children with cerebral palsy and other illnesses.101 In a recent randomized prospective follow-up study, Goyal et al.102 compared outcome of oral diazepam and baclofen in children with spastic cerebral palsy The mean Modified Ashworth Scale (MAS) score improved from 1.96 0.4 at baseline to 1.63 0.40 and 1.41 0.36 at month and months for diazepam and from 1.84 0.64 to 1.57 0.59 and 1.31 0.48, respectively for baclofen (P 0001) There was a significant improvement in the range of motion in both groups Both diazepam and baclofen were safe to use.102 ... indicated for neuropathic pain, particularly when the patient describes a burning pain Anticonvulsant agents, gabapentin, pregabalin, and carbamazepine can be useful for neuropathic pain as well... of these increased dose requirements occurred within to days Starting at a lower dose was also a risk factor for increased dose requirements In this study, however, the opiate doses used were... evidence, that using sedation protocols can reduce this problem Intermittent rather than continuous infusions can reduce the risk However, this option has to be balanced against the primary aim