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While primary hypertension (HTN) clearly occurs in children and adolescents, the approach of many providers to such patients can best be described as ambivalent: the condition may be recognised, but is not acted upon. Such ambivalence may stem from incomplete understanding of the effects of high blood pressure in the young, which in turn is related to the shortage of information on long-term outcomes of primary childhood HTN. However, other evidence on the short- and long-term effects of blood pressure elevation in childhood clearly shows that it is not a benign condition at all. Conclusion Childhood HTN warrants action to prevent adult cardiovascular disease.

J Clin Hypertens (Greenwich). 2012; 14:388–395. ©2012 Wiley Periodicals, Inc. As a result of the Food and Drug Administration (FDA) Modernization Act and the Best Pharmaceuticals for Children Act, the number of medications with FDA-approved pediatric labeling has increased. To assess the success of these initiatives, we examined whether antihypertensive drugs used by children with hypertension in 2008 had FDA-approved pediatric labeling and indications. Using a nationwide commercial insurer database, 2915 children with primary (n=2607) and secondary (n=308) hypertension were identified. Drug user rate and days of supply were calculated from pharmacy claims. Drugs were categorized based on pediatric labeling and indication and whether they were recommended for pediatric use. Antihypertensive drugs were used by 889 (34%) children with primary hypertension and 200 children (65%) with secondary hypertension. User rates were 44.3% in hypertensive children younger than 6 years, 30.9% in those 6 years to older than 12 years, and 38.1% in those 12 years to older than 18 years. Seven percent of drugs were neither labeled for pediatric use nor considered recommended for use in children. In children younger than 6 years, 29% of drugs used were not indicated for use in that age group. Despite recent legislative initiatives, many drugs used by hypertensive children still lack pediatric labeling. Additional efforts are needed to close the gap between the availability of drugs that are labeled and indicated for pediatric use and actual drug usage in children.

The prevalence of hypertension among all adolescents is approximately 3.5%, with somewhat higher rates of prehypertension. Obesity affects approximately 20% of adolescents in the United States, and the prevalence of hypertension is much higher among obese adolescents compared with nonobese adolescents. As in other populations, the evaluation of elevated blood pressure in obese adolescents should begin with a confirmation of the blood pressure elevation, followed by a focused diagnostic work-up to detect possible secondary causes of hypertension. Primary therapy for obesity-related hypertension in adolescents begins with weight loss, and may include antihypertensive medications if target-organ damage or other indications for drug therapy are present. The emphasis of management should be reduction of future cardiovascular risk.

J Clin Hypertens (Greenwich). Severe acute hypertension in pediatric patients requires prompt and controlled blood pressure (BP) reduction to prevent end-organ damage. The authors aimed to examine the efficacy and safety of isradipine, an orally administered second-generation dihydropyridine calcium channel blocker, for treatment of acute hypertension in hospitalized pediatric patients. A retrospective analysis of 391 doses of isradipine administered to 282 patients (58% boys) with acute hypertension and median age of 12.8 years (range, 0.1–21.9) was performed. Primary diagnoses included renal disease (n=154), malignancy (45), nonrenal transplant (37), neurologic disease (21), and other (25). The decrease in systolic BP was 16.3%±11.6% (mean ± SD) and diastolic BP was 24.2%±17.2%. BPs were significantly lower in all age groups and in all diagnosis categories following isradipine administration. The decrease in BP was the highest in children younger than 2 years. The mean increase in pulse after a dose was 7±17 beats per minute. Forty adverse events were reported in 33 patients, with emesis and nausea being the most common; 5 of these events were hypotension. The authors conclude that isradipine effectively reduces BP in a wide variety of hospitalized children and adolescents with acute hypertension. A lower initial dose of 0.05 mg/kg may be appropriate in children younger than 2 years. J Clin Hypertens (Greenwich). 2010;12:850–855.

This 4‐week randomized, double blind, placebo‐controlled study (N=240), 1‐year open label trial (N=233), and single‐dose pharmacokinetic study (N=22) evaluated candesartan cilexetil (3 doses) in hypertensive children aged 6 to 17 years. Seventy‐one percent were 12 years of age or older, 71% were male, and 47% were black. Systolic (SBP)/diastolic (DBP) blood pressure declined 8.6/4.8–11.2/8.0 mm Hg with candesartan and 3.7/1.8 mm Hg with placebo (P.05). The response rate (SBP and DBP

A population pharmacokinetic study was conducted in 74 hypertensive children (mean age 10.4 +/- 4.4 years [mean +/- SD]) receiving amlodipine (mean dose 0.17 +/- 0.13 mg/kg/d) chronically. Multiple blood samples were obtained from each subject to characterize amlodipine pharmacokinetics. Plasma amlodipine concentrations were determined by liquid chromatography/mass spectrophotometry with multiple-reaction monitoring detection. Population pharmacokinetic analysis was performed using NONMEM. Amlodipine concentrations were similar in subjects dosed either once or twice daily. Amlodipine pharmacokinetics were well described by a 1-compartment model with first-order absorption and elimination. For a subject at the population median weight (45 kg), predicted apparent clearances (CL/F) were 23.7 L/h for males and 17.6 L/h for females, and the apparent volume of distribution (V/F) was 25.1 L/kg. Dosing frequency did not appear to affect amlodipine concentrations in children. Weight-adjusted CL/F and V/F of amlodipine in younger children were significantly greater than in older children, suggesting a need for higher doses when treating young children with amlodipine.

Because elevated blood pressure is one of the defining criteria of the metabolic syndrome, treatment of hypertension will be required in many, if not most, children and adolescents diagnosed with the metabolic syndrome. This review highlights several aspects of the approach to treatment of hypertension in young patients with the metabolic syndrome, including the definition of hypertension, use of nonpharmacologic measures, indications for instituting antihypertensive medications, and the potential adjunctive role that insulin-sensitizing agents may play in blood pressure reduction. The choice of antihypertensive agent is also discussed, along with consideration of the diabetogenic effects of various classes of antihypertensive agents. Consideration of all of these issues is important in achieving blood pressure control in children and adolescents with the metabolic syndrome, as appropriate treatment may help to forestall the development not only of type 2 diabetes but also of the cardiovascular disease that is frequently already present at the time of diagnosis of type 2 diabetes in adults.

Infection with parvovirus B19 (PV-B19) after solid organ transplantation may cause pure red cell aplasia (PRCA). Intravenous immunoglobulin (IVIg) may be of benefit in clearing the infection. Acute renal failure is a known adverse effect of IVIg administration. A 14-yr-old male received a cadaveric renal transplant. Three weeks after surgery he developed symptomatic anemia (hemoglobin 4.5 g/dL, reticulocyte count 0.2%). Anti-PV-B19 IgM and IgG titers, which had been negative pretransplant, were positive. He received two IVIg infusions as treatment for the PV-B19 infection. Four days after the IVIg infusions he developed non-oliguric acute renal failure (ARF) with a rise in serum creatinine from 1 to 1.8 mg/dL. Allograft biopsy showed changes consistent with an osmotic load. Anemia and the renal failure resolved after transfusions and IVIg. PV-B19 infection in immunosuppressed transplant recipients is associated with significant morbidity and may respond to IVIg therapy. High sucrose IVIg preparations may be associated with renal failure in renal allograft recipients. Adding PV-B19 testing of the donor and recipient to the standard pretransplant evaluation may be beneficial in diagnosing and managing a potential infection. If IVIg is to be used it may be safer to use a sucrose-free IVIg preparation.

Background: Introduction of the anti-CD-25 mAb basiliximab into renal transplant protocols has reduced the incidence of acute rejection. However, its side-effect profile is still unfolding. We report three adolescents who developed severe non-cardiogenic PE within 2 days of renal transplantation. Methods: Pretransplant cardiorespiratory evaluation was normal in all cases. Transplant immunosuppression consisted of basiliximab induction, corticosteroids, and tacrolimus. Patients received standard fluid management during and after the transplant surgery. Case reports: Patients 1 and 2 were 17- and 21-yr-old females. Pretransplant Hct values were 35 and 25% respectively. Each received 5-L normal saline during surgery. EBL was 200 and 500 mL in patients 1 and 2, respectively. There was immediate post-operative diuresis. Both developed non-cardiogenic PE by POD no. 2. BIPAP and PRVC were administered respectively. In both cases PE resolved within 1 wk. Patient 3 was a 19-yr-old male with pretransplant Hct of 43% who received a cadaveric renal transplant after 23.5-h cold-ischemia; 3.5 L normal saline was given during surgery. EBL was 100 mL. Non-cardiogenic PE ensued on POD no. 2 warranting assisted ventilation. The patient died following a sudden cardiopulmonary arrest on POD no. 3. Conclusions: Potential mechanisms for the development of PE include cytokine release from basiliximab with increased capillary permeability, volume overload and ischemic-reperfusion injury. Improved awareness of this potential complication, prudent fluid management, and efforts to minimize graft-ischemia are recommended to prevent further cases.

It is the practice of many pediatric renal transplant programs to convert' children taking cyclosporin A (CsA) to tacrolimus, although the indications for, outcome, and complications of this practice remain obscure. To better understand these aspects of tacrolimus conversion', a fax survey was sent to 119 North American pediatric renal transplant centers. Analyzable responses were received from 52 centers (44%), and included data from 1,815 pediatric renal transplants performed between 1991 and 98. Strong indications for tacrolimus conversion were: antibody-resistant rejection, CsA-resistant rejection, and CsA intolerance (strong indication in 72%, 65%, and 52% of centers, respectively). Steroid-resistant rejection and cosmetic side-effects were considered strong indications less often. Initial anti-rejection therapy was usually increased corticosteroid dose (47/52 centers). Antibody therapy was most commonly used for steroid-resistant rejection (44 centers). For steroid- and antibody-resistant rejection, tacrolimus conversion was most common (33 centers). Tacrolimus conversion for antibody-resistant rejection led to improvement of serum creatinine (SCr) in 27% of patients, stabilization of SCr in 46%, worsening of SCr in 11%, and graft loss in 16%. Reported complications after tacrolimus conversion included hyperglycemia, hyperkalemia, lymphoproliferative disorder, infection, and neurologic problems. We conclude that the major indication for tacrolimus conversion in pediatric transplant programs appears to be rejection. Outcome after tacrolimus conversion appears good, with the majority of patients experiencing stable or improved allograft function. These data provide direction for further study, including timing of tacrolimus conversion and interaction with other therapies.

Olson AD, Shope TC, Flynn JT. Pretransplant varicella vaccination is cost-effective in pediatric renal transplantation. Pediatr Transplantation 2001: 5: 44-50. # Munksgaard, 2001 Abstract: Because of the severe complications that may result from varicella zoster virus (VZV) infection following renal transplantation (Tx), transplanted varicella-susceptible children exposed to varicella are typically given varicella zoster immunoglobulin (VZIG) as prophylaxis or are admitted and treated with parenteral acyclovir if VZIG prophylaxis fails. As both VZIG and hospitalization are costly, prevention of varicella infection by vaccination could potentially result in significant cost savings in addition to decreasing morbidity and mortality. To test this hypothesis, we developed a decision-analysis model to evaluate the cost-effectiveness of vaccinating patients with chronic renal failure (CRF) against varicella prior to renal transplant. Under baseline assumptions, vaccination for varicella pretransplant was a cost-effective strategy, with a cost of $211 per patient vaccinated compared with $1,828 per patient not vaccinated. The magnitude of cost savings from vaccination was sensitive to variations in the cost of varicella vaccine, the percentage of patients hospitalized for treatment with acyclovir, and the percentage of patients exposed to varicella infection. One- and two-way sensitivity analyses confirmed that vaccination was the dominant cost-effective strategy under all conditions examined. We conclude that vaccination for varicella pretransplant is cost-effective for patients with CRF, and that the magnitude of cost savings is sensitive to the cost of hospitalization, the percentage of patients exposed to varicella, and the cost of varicella vaccination. Pending results of ongoing studies of the safety and efficacy of VZV vaccine in children with CRF, we recommend that VZV vaccine be given to all children with CRF.

The U.S. Preventive Services Task Force (USPSTF) recently published their recommendation on pediatric hypertension screening. Based on an evidence review of the literature on 8 key questions, the USPSTF concluded that “there is no direct evidence to suggest that screening for hypertension in children reduces adverse cardiovascular outcomes in adults.” The implication of the USPSTF recommendation is that routine blood pressure (BP) measurement in asymptomatic children and adolescents is of little benefit. The USPSTF publication has provoked considerable alarm among the pediatric community, especially among specialists in cardiovascular and renal disease. There is general concern that the USPSTF report will be interpreted as grounds for abandoning BP measurements in childhood. Indeed, a recent “evidence-based” publication has recommended stopping BP measurement in children. In this issue of The Journal of Clinical Hypertension, Drs Lo, Malaga-Dieguez, and Trachtman propose a series of reasons why, in their opinion, the USPSTF may have done the subspecialty of pediatric hypertension a great service. We disagree and will consider these authors’ main points below. First, the authors conclude that “there is little risk of a policy that advocates deferring routine measurement of BP in asymptomatic children.” As a public health policy, it could be true that the child population risk may be small if BP measurement in asymptomatic children were abandoned. However, child health care is generally provided by physicians or other trained primary care providers, and the focus of primary care is to optimize health in the individual child, not the childhood population. It is well established that elevated BP is a risk factor for adverse health outcomes in individuals. There is sufficient observational data which confirm that this risk holds true for individual children as well as adults. Thus, abandonment of routine childhood BP measurement has the potential to increase risk in individual children by failing to detect conditions that are associated with elevated BP. In considering routine BP measurement from an economic perspective, the authors concur that “practice guidelines that help balance the benefits of a procedure or treatment are valuable even for seemingly innocuous tests such as measurement of BP in children.” It is unclear what the authors’ point is about the costs of routine BP measurement in all children vs the costs of evaluating and managing a child with symptomatic hypertension. All newborn infants undergo routine blood screening for inborn errors of metabolism and metabolic disorders; this screening is more invasive, laboratory costs are not trivial, and the conditions are rare. Relative to what is now standard newborn screening, the economic cost-benefit equation of childhood BP screening is not significant and hardly sufficient to abandon the practice. The authors question whether the USPST has abdicated its responsibility to promote cost-effective procedures that will improve the health of children and undermined efforts to educate doctors and lay people about the importance of hypertension. However, they consider it “premature to answer this question based on what is known.” As noted by Urbina and colleagues, the USFPTF recommendation ignores a substantial body of literature that includes many relevant observational studies, especially those that document intermediate outcomes associated with childhood hypertension such as cardiac hypertrophy, carotid artery thickening, and albuminuria. Thus, there is “evidence” well beyond that deemed acceptable to the USPSTF that contributes knowledge on the evolution of hypertension beginning in childhood. Lo and colleagues, like the USPSTF, have apparently failed to accept much that is known on target organ damage both among adults with known high BP in childhood and among hypertensive children. As an alternative to measuring BP and identifying hypertension, or prehypertension, in childhood, the authors suggest “we could advance global strategies to reduce weight, increase physical activity, and foster healthy lifestyle choices that will correct obesity and in all likelihood restore normal BP. . . .” While this approach may be theoretically plausible, little, if any, success has been achieved despite considerable efforts to approach these goals. Moreover the pace of success with global strategies is too slow for those adolescents who currently have hypertension with or without obesity. As estimated by Brady and colleagues, with elimination of BP screening, from 106,793 to 320,378 adolescents with primary hypertension would not be identified and, considering the number of missed diagnoses, this estimate could be higher. In addition, girls with obesity-associated hypertension who enter young adult childbearing years will have high-risk pregnancies and high-risk offspring. Address for correspondence: Bonita Falkner, MD, Department of Medicine and Pediatrics, Thomas Jefferson University, 833 Chestnut Street, Suite 700, Philadelphia, PA 19107 E-mail: bonita.falkner@jefferson.edu

The USPSTF methods are appropriately evidencebased and consist of a systematic search of pertinent literature and careful analysis of the available studies, but their primary question is essentially unanswerable. The Task Force attempted to find direct evidence that screening for essential HTN in children leads to decreased CV morbidity in adults. While direct evidence of correlation to “adverse health outcomes” can often be found for many screenable adult diseases where morbidity and mortality are relatively common, pediatric hypertension is likely a condition where direct evidence linking childhood BP to adult outcomes will never be available. Searching for direct evidence is therefore not an appropriate method of ascertaining future risk or benefit since children rarely develop severe CV outcomes. Any study attempting to directly answer the USPSTF question would necessarily have to follow both screened and unscreened children for many decades to determine the direct impact of early HTN detection. The report is also premature given the early state of evidence in pediatric hypertension. It was only 36 years ago that the first consensus report on BP in children was