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▲ Lamivudine, the negative enantiomer of 2′-deoxy-3′-thiacytidine, is a dideoxynucleoside analog that prevents hepatitis B virus (HBV) DNA synthesis by competitively inhibiting the viral reverse transcriptase and DNA polymerase stages of HBV replication and by terminating proviral DNA chain extension. ▲ A dose-ranging study established that once daily oral lamivudine 3 mg/kg up to a maximum of 100 mg/day has the optimum efficacy and tolerability profile for achieving a maximal reduction in serum HBV DNA levels in children aged 2 to 12 years and adolescents aged 13 to 17 years with chronic HBV infection and active viral replication (chronic hepatitis B). ▲ Significantly more children and adolescents with chronic hepatitis B receiving lamivudine demonstrated a virologic response (undetectable serum hepatitis Be antigen and undetectable HBV DNA level) [23 vs 13%; p=0.04] and/or biochemical response (55 vs 12%; p < 0.001) compared with placebo in a large, randomized, doubleblind, 52-week phase III study. Despite the emergence of YMDD-variant HBV in 19% of lamivudine-treated children and adolescents, serum alanine aminotransferase and HBV DNA levels remained below baseline in these patients. ▲ Oral lamivudine is generally well tolerated by children and adolescents with chronic hepatitis B, with a similar tolerability profile to placebo at the recommended once daily dosage of 3 mg/kg up to a maximum of 100 mg/day.

Sevoflurane is an ether inhalation anaesthetic agent with low pungency, a non-irritant odour and a low blood: gas partition coefficient. It can be rapidly and conveniently administered without discomfort, and its low solubility facilitates precise control over the depth of anaesthesia and a rapid and smooth induction of, and emergence from, general anaesthesia. As an induction and maintenance agent for ambulatory and nonambulatory surgery in children, sevoflurane provides more rapid induction of, and emergence from, anaesthesia than halothane, and has similar or better patient acceptability. Time to discharge from the recovery area is usually at least as fast with sevoflurane as with halothane. While rapid emergence from sevoflurane lessens the time spent under anaesthesia, postoperative pain may be more intense and occur earlier than during more gradual emergence. Sevoflurane has been used successfully as an induction agent for tracheal intubation and laryngeal mask airway (LMA) insertion: time to LMA insertion is faster with sevoflurane than halothane, but the 2 drugs provide similar conditions for tracheal intubation. The pattern and incidence of induction and emergence events such as cough, laryngospasm and agitation/excitement is similar with sevoflurane and halothane; however, sevoflurane may cause less postoperative nausea and vomiting. At present, differences have not been consistently shown between the 2 drugs in their propensity to cause postoperative excitement or agitation. Compared with halothane, sevoflurane has low potential for arrhythmogenicity. Clinical experience does not substantiate concerns over the potential nephrotoxicity of the sevoflurane byproducts pentafluoroisopropenyl fluoromethyl ether (‘Compound A’) and plasma F− ions; no renal impairment has been documented in children receiving sevoflurane in clinical trials. The potential for sevoflurane hepatotoxicity also appears negligible. There are few trials comparing sevoflurane with agents other than halothane in paediatric anaesthesia. As well, pharmacoeconomic analyses are scarce and incompletely published; further studies are needed to determine whether shortened times to emergence will translate into cost savings. Conclusion: Sevoflurane is a preferred anaesthetic agent for induction and maintenance of paediatric anaesthesia because of its rapid induction and recovery characteristics, lack of pungency and agreeable odour, and acceptable cardiovascular profile. Although the issue of postoperative excitement requires clarification, sevoflurane anaesthesia can be considered a rational choice for ambulatory and nonambulatory surgery in children. Sevoflurane is a nonpungent ether inhalation anaesthetic agent. The anaesthetic potency of sevoflurane is age-dependent, sevoflurane being less potent in children than in adults. Concomitant use with nitrous oxide (N2O), clonidine, or opioids increases the potency of sevoflurane. The effects of sevoflurane on various body systems generally parallel those produced by other inhalation anaesthetics (most systems are depressed in a dose-related manner). The cerebrovasodilatory effect of sevoflurane was similar to that of halothane in 18 children. Sevoflurane also has cardiovascular depressant effects that are similar in type to those of desflurane and isoflurane in patients and healthy volunteers, although comparisons with halothane in children give variable results. Administration with N2O 60%, spontaneous ventilation or prolonged exposure to sevoflurane attenuate cardiovascular depression and myocardial contractility. Statistically significant increases in heart rate occur in infants and children aged ≤12 years during or soon after induction of anaesthesia with sevoflurane (see also Tolerability summary). Blood pressure is decreased in this population but to a lesser extent than with desflurane, a similar extent to that with isoflurane and generally to a similar or significantly lower extent versus halothane. Sevoflurane, in common with other inhalation anaesthetic agents, causes dose-dependent ventilatory depression which can lead to a decrease in blood pH and to apnoea. Sevoflurane caused greater respiratory depression or changes than halothane at 1 minimum alveolar concentration (MAC) in 30 infants aged 6 to 24 months. Comparison of sevoflurane and isoflurane (both at 1 MAC) in 40 children showed the 2 agents to produce a similar extent and pattern of respiratory depression. Sevoflurane has the advantage over several other inhalation anaesthetic agents, including desflurane, isoflurane and enflurane, of causing negligible airway irritation. Sevoflurane is degraded by CO2 absorbents (used in the anaesthesia circuit) to pentafluoroisopropenyl fluoromethyl ether (PIFE; ‘Compound A’), which is nephrotoxic in rats but has not been shown to cause clinically significant renal injury in patients undergoing anaesthesia. Many studies conducted in adults receiving sevoflurane anaesthesia have detected laboratory markers of renal injury but, overall, sevoflurane does not appear to be associated with a higher risk of renal toxicity than isoflurane, enflurane or propofol, even when sevoflurane is administered at low flow rates in comparisons with isoflurane. Because of its low blood: gas solubility, sevoflurane is rapidly taken up and eliminated. The alveolar ‘wash-in’ rate in children is about 50% higher with sevoflurane than with halothane when either is given with N2O. Like other fluorinated ethers, sevoflurane undergoes dose-independent hepatic biotransformation by cytochrome P450 (CYP) 2E1, principally to inorganic fluoride ions (F−) and hexafluoroisopropanol (HEIP). Up to 50% of plasma F− is cleared via uptake into bone. Sevoflurane undergoes negligible renal defluorination compared with methoxyflurane. Sevoflurane is eliminated more rapidly than halothane in children; the alveolar ‘washout’ rate is halved. Sevoflurane reduces time to induction and emergence compared with halothane in children undergoing ambulatory and nonambulatory surgery, although the clinical importance of the difference in time to induction has been questioned. Time to induction is reduced with increasing sevoflurane concentration, use of high concentration versus incremental concentrations and the addition of N2O. The rapid emergence from sevoflurane anaesthesia is desirable but appears to result in earlier and more intense discomfort or pain (as measured by objective pain/discomfort scores and use of postoperative analgesia). Time to discharge from the recovery area is generally at least as fast, and patient acceptability of the anaesthetic is at least as good, with sevoflurane as with halothane. Data are insufficient to allow any firm conclusions regarding the relative anaesthetic efficacy of sevoflurane compared with desflurane or propofol. Several clinical studies demonstrate that children can successfully undergo tracheal intubation without a muscle relaxant or LMA insertion while receiving sevoflurane induction anaesthesia. Although sevoflurane has been the subject of a number of theoretical cost analyses, detailed data are scarce and well designed formal cost effectiveness comparisons with other agents are not available. The incidence of adverse events occurring most often during induction and emergence — coughing, laryngospasm, breath-holding and agitation/excitement — is generally similar for sevoflurane and halothane. Available evidence does not consistently show differences between the 2 drugs in their propensity to cause postoperative excitement. EEG patterns for the 2 drugs have been shown to be dissimilar, but seizure-like movement seen during sevoflurane anaesthesia has not been causally related to the drug. Sevoflurane increases heart rate to a greater extent than halothane during induction but causes fewer instances of arrhythmias and bradycardia during anaesthesia. Sevoflurane may cause postoperative nausea and vomiting (PONV) less often than halothane; individual trials show a similar incidence of PONV for sevoflurane compared with desflurane, isoflurane and propofol. Despite elevated plasma F− levels, sevoflurane and other inhalation anaesthetic agents are not associated with nephrotoxicity. Numerous trials in children demonstrate that plasma F− levels remain below the theoretical ‘toxic threshold’ of 50 μmol/L (for methoxyflurane) during sevoflurane anaesthesia lasting up to 9 MAC · h, with no renal impairment evident. There have been no reports of PIFE-associated nephrotoxicity in children or adults anaesthetised with sevoflurane. The potential for hepatic injury with sevoflurane is expected to be negligible; sevoflurane does not generate antigenic trifluoroacetyl proteins and its organic metabolite HFIP has a low binding affinity for hepatic tissue and is rapidly glucoronidated and excreted. Increases in levels of serum glutathione S-transferase α seen in one series of children anaesthetised with sevoflurane or halothane were not evident in another group given sevoflurane. Like other inhalation anaesthetic agents, sevoflurane has the potential to cause malignant hyperthermia; only 2 such cases have been reported in children to date. Sevoflurane prolongs the duration of neuromuscular blockade induced by non-depolarising muscle relaxants such as vecuronium to a greater extent than halothane or isoflurane. Dosages of neuromuscular blockers should be reduced when sevoflurane anaesthesia is used. Agents such as isoniazid and alcohol that induce cytochrome P450 2E1 may increase sevoflurane metabolism. Whether sevoflurane may displace highly bound drugs such as phenytoin is unknown, but this interaction has occurred with other volatile fluorinated anaesthetics. Sevoflurane is synergistic with lidocaine (lignocaine) and procainamide in prolonging ventricular activation time. Sevoflurane is administered by inhalation with a vaporiser specifically calibrated for the agent. Delivery should be individualised according to the patient’s response. Sevoflurane concentrations needed to induce anaesthesia are greater in children than in adults. Inspired sevoflurane concentrations of 7 or 8% have been used successfully to induce anaesthesia in many studies in children. Sevoflurane is most often administered with N2O plus O2. Sevoflurane concentrations of 0.5 to 3% are sufficient to maintain anaesthesia during surgery. There are no flow rate restrictions in most countries where sevoflurane is approved. Sevoflurane is contraindicated in patients with known or suspected genetic susceptibility to malignant hyperthermia and should be used with caution in patients with renal insufficiency. Levels of the organic metabolite PIFE are higher when barium hydroxide lime rather than soda lime is used as a CO2 absorbent.

Objective: To provide an updated list of the highly toxic medications in North America that can kill a 10kg toddler upon ingestion of 1–2 dose units. Methods: All drugs available in North America were reviewed and their reported lethal doses in children or adults (where no pediatric data existed) were identified. The dose units of drugs available in North America were subsequently identified, followed by those dose units that could kill a toddler upon ingestion of 1–2 dose units or teaspoonfuls. Results: Tricyclic antidepressants, antipsychotics, quinine derivatives, calcium channel blockers, opioids, and oral hypoglycemics can kill a toddler with 1–2 dose units. This list of drugs was responsible for 40% of toddler fatalities reported to the American Association of Poison Control Center Toxic Exposure Surveillance System between 1990–2000. Conclusion: Drugs that can kill a toddler with 1–2 dose units should be known to clinicians as such exposures warrant immediate and intensive management. A new system of special labeling of these drugs should be considered.

The development of cluster of differentiation (CD)-19-targeted chimeric antigen receptor (CAR) T cells for the treatment of pre-B-cell acute lymphoblastic leukemia (B-ALL) is an exciting new advancement in the field of pediatric oncology. Tisagenlecleucel and axicabtagene ciloleucel are the first US FDA-approved CD19-targeted CAR T cells. While various different CD19 CAR T cells are in development, tisagenlecleucel is the only CAR T cell approved for pediatric patients. The multicenter phase II trial that led to the approval of tisagenlecleucel demonstrated excellent responses in individuals with highly refractory disease. Other high-risk groups of patients with B-ALL who experience poor outcomes with standard therapy may also benefit from treatment with tisagenlecleucel. After receiving CAR T cells, patients must be closely monitored for unique toxicities, including cytokine release syndrome, neurotoxicity, and B-cell aplasia. The management of patients with relapsed or refractory disease after administration of CD19 CAR T cells can be challenging, and treatment options vary according to the characteristics of the disease present at relapse. In the many patients who experience a complete response, CAR T cells can lead to a durable remission. This review describes the current design and manufacturing of CAR T cells. Data in the selection and management of pediatric patients are highlighted, as are areas where further studies are needed.

Through at least the mid-1990s, children were often referred to as ‘therapeutic orphans’ for whom many treatments were administered without the benefit of appropriate studies to guide drug labeling for dosing and other critical therapeutic decisions. At that time, there were no incentives for manufacturers to pursue such work, nor regulatory requirements to compel these studies. Congress addressed this by including an important provision titled the Best Pharmaceuticals for Children Act (BPCA) in the 1997 Food and Drug Administration Modernization and Accountability Act. This was complemented by another key piece of legislation, the Pediatric Research Equity Act (PREA) in 2003. The former Act and its successors created an incentive for firms to study on-patent drugs in pediatric populations by extending the market exclusivity of a medicine by 6 months. The latter was a requirement that provided the US FDA with the authority to require studies of drugs in children if an adult indication also occurs in children. In the current paper, we consider the effects of both pieces of legislation in terms of the health, societal, and economic benefits they have likely imparted and will continue to provide in the future. We conclude that the gains have been substantial — both in terms of safer and more effective use of medicines in children and in terms of new research that has been incentivized by the BPCA exclusivity provision. We estimate the gross economic benefits from the latter alone to be approximately $US360 billion.

Neonatal sepsis is uncommon (2–4 per 1000 live births in developed countries), but the rate increases dramatically in premature newborns and those born to mothers with infections or prolonged rupture of the fetal membranes. While infections caused by organisms contracted from the mother at birth have decreased in the past two decades, there has been an increase in nosocomial infections. Today, most infants with sepsis have been hospitalized in neonatal intensive care units for weeks or months because of extreme prematurity, or because of a congenital malformation or surgical condition. Antimicrobial therapy is usually begun prior to the isolation of a pathogen and is based upon knowledge of the likely microbes in the particular clinical situation. The number of antimicrobial agents that can be safely used in neonates is relatively small, and dose administration usually needs to be adjusted based upon birthweight and post-gestational age. The decision whether to treat with antimicrobials should be made with consideration of the history, physical examination, and laboratory data. One should also consider the effects of the use of antimicrobials on the flora of the care unit. Bacterial resistance in the resident flora of the unit has become a major problem where there has been indiscriminate use of broad-spectrum agents.

Ranibizumab (Lucentis®) is a monoclonal antibody fragment targeted against VEGF-A that is the first approved anti-VEGF agent for the treatment of retinopathy of prematurity (ROP). In the pivotal, randomized, phase III RAINBOW trial in infants with ROP, the majority of intravitreal ranibizumab recipients experienced treatment success at 24 weeks, with a numerically greater treatment success rate in the ranibizumab 0.2 mg (80% of patients) than laser therapy (66%) group without reaching statistical significance for superiority. Long-term effects on vision following ranibizumab treatment are not yet known, but interim analyses from the RAINBOW extension study do not show evidence of degraded vision. Adverse reactions to ranibizumab in pediatric patients were consistent with the known safety profile in adults, with most adverse reactions attributed to the intravitreal injection procedure. Furthermore, systemic VEGF suppression was not observed in clinical trials, which is congruent with the rapid systemic clearance of ranibizumab. Overall, ranibizumab is an effective and generally well tolerated treatment for ROP and is not associated with systemic VEGF suppression. Although results for its long-term effects on vision are not yet available, ranibizumab is a promising alternative option to laser therapy for treating ROP.

The onset of psychosis during pregnancy presents difficult management decisions. A complete and thorough physical and obstetric examination is always warranted to look for possible physiological precipitants. The treatment of pregnant patients with psychotic symptomatology requires close contacts between family members, non-physician professionals involved in the patient’s care (e.g. social workers, case managers and home healthcare nurses), and the physicians overseeing the patient’s management (e.g. internists, obstetricians and psychiatrists). In mild and less disabling cases it may be possible to avoid medication intervention but this approach risks adverse behaviour consequences resulting from a possible worsening of the patient’s symptomatology. Avoiding medication requires an environment in which the patient has strong social supports. Risks are present whether medication is initiated or not, and treatment decisions require a careful assessment of the risks and benefits involved. Initiating medication raises the possibility of obstetric, teratogenic, neurobehavioural and neonatal toxic effects. Research on the risks imposed by antipsychotic drug use during pregnancy is incomplete and raises questions regarding appropriate management. The first trimester represents a period of increased susceptibility to medication-induced teratogenesis. The use of low potency phenothiazines during the first trimester may increase the risk of congenital abnormalities by an additional 4 cases per 1000 (odds ratio = 1.21, p = 0.04) The pharmacological profiles of antipsychotic medications also present adverse effects which need to be considered during pregnancy (hypotension, sedation, etc.). Less is known about the risk of adverse consequences resulting from the use of newer atypical antipsychotic medications. Electroconvulsive therapy is another treatment modality and its use may circumvent the need to introduce antipsychotic medication during pregnancy. It must be stressed that, given current knowledge, no treatment regimen can be considered completely safe. Ultimately many factors must be evaluated when treating psychosis during pregnancy, however, no decision is risk-free.