RESUMO
OBJECTIVES: The objective of this study was to determine the efficacy of balloon angioplasty (BA) by comparing the immediate and long-term outcomes of patients with and without re-coarctation after a Norwood procedure. BACKGROUND: Although BA has become the standard means for treating recurrent coarctation following a Norwood operation, it has been suggested that re-coarctation remains a significant cause of morbidity and mortality. METHODS: Patients who survived a Norwood operation from December 1986 through June 2001 were studied. Differences between groups were evaluated by t test and logistic regression. Survival differences were tested by log-rank tests using Kaplan-Meier survival curves. RESULTS: Fifty-eight of 633 patients underwent treatment for re-coarctation (9.2%). Thirty-five patients underwent BA (before 1988, 23 had surgery). Median age at catheterization was 6.6 months (1.9 to 35.6 months). Balloon angioplasty was successful (gradient <10 mm Hg) in 32 of 35 patients (92%). There were no BA-related deaths or neurologic complications. Recurrent obstruction after BA occurred in seven patients (20%); five underwent re-dilation. Kaplan-Meier estimates of freedom from recurrent obstruction after initial BA were 97% at one month, 79% at one year, and 79% at five years. There were no differences in survival between patients with re-coarctation treated by BA and patients who did not undergo treatment for re-coarctation. CONCLUSIONS: We found that 9.2% of patients underwent treatment for re-coarctation following a Norwood operation. Balloon angioplasty is effective, with low morbidity, no early mortality, and no difference in long-term survival when compared with patients who did not have re-coarctation. Recurrent coarctation following BA occurred in 17% of patients, usually within the first year after BA.
Assuntos
Angioplastia Coronária com Balão , Coartação Aórtica/etiologia , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Síndrome do Coração Esquerdo Hipoplásico/cirurgia , Coartação Aórtica/mortalidade , Coartação Aórtica/terapia , Pré-Escolar , Humanos , Lactente , Recidiva , Análise de SobrevidaRESUMO
BACKGROUND: Clinical trials in children with congenital heart disease are often limited by the absence of the following: (1) a primary outcome that can be observed in a reasonable period; (2) information regarding health-related quality of life; (3) knowledge of the correlation between health status and ventricular function and exercise performance; (4) a sufficient number of children at a single institution to provide adequate statistical power; and (5) procedural and management differences between and within institutions. METHODS: The NHLBI-funded Pediatric Heart Network designed a cross-sectional study of children aged 6 to 18 years, from 7 pediatric clinical centers, who had undergone a Fontan procedure as treatment for congenital heart disease. Health-related quality of life was measured by the Child Health Questionnaire and the Congenital Heart Adolescent and Teenager Questionnaire. Ventricular function was assessed by maximal exercise testing, echocardiography, cardiac magnetic resonance imaging, and B-type natriuretic peptide. The study was designed to detect a correlation of R > or = 0.30 between health status scores and measures of ventricular function and performance in a subcohort with all study measures completed. RESULTS: A total of 1078 children were screened by chart review; 644 (60%) were eligible. The consent rate was 85% and 546 children were enrolled. Acquisition of echocardiograms, B-type natriuretic peptide, and health status was > or = 94%; completion rates were lower for maximal exercise testing (76%) and cardiac magnetic resonance imaging (41%). CONCLUSIONS: This large study provides unique information regarding the relationship between health status and clinical measures in post-Fontan patients that will facilitate the design of future randomized trials.
Assuntos
Ensaios Clínicos como Assunto/métodos , Estudos Transversais , Técnica de Fontan/estatística & dados numéricos , Cardiopatias Congênitas/epidemiologia , Cuidados Paliativos/métodos , Adolescente , Criança , Ensaios Clínicos como Assunto/tendências , Feminino , Técnica de Fontan/tendências , Cardiopatias Congênitas/cirurgia , Humanos , Imageamento por Ressonância Magnética/métodos , Imageamento por Ressonância Magnética/tendências , Masculino , Estudos Multicêntricos como Assunto/métodos , Estudos Multicêntricos como Assunto/tendências , Cuidados Paliativos/tendências , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto/tendências , Inquéritos e QuestionáriosRESUMO
PURPOSE: To determine whether an angiotensin-converting enzyme (ACE) inhibitor, enalapril, prevents cardiac function deterioration (defined using maximal cardiac index [MCI] on exercise testing or increase in left ventricular end-systolic wall stress [LVESWS]) in long-term survivors of pediatric cancer. PATIENTS AND METHODS: This was a randomized, double-blind, controlled clinical trial comparing enalapril to placebo in 135 long-term survivors of pediatric cancer who had at least one cardiac abnormality identified at any time after anthracycline exposure. RESULTS: There was no difference in the rate of change in MCI per year between enalapril and placebo groups (0.30 v 0.18 L/min/m(2); P =.55). However, during the first year of treatment, the rate of change in LVESWS was greater in the enalapril group than in the placebo group (-8.59 v 1.85 g/cm(2); P =.033) and this difference was maintained over the study period, resulting in a 9% reduction in estimated LVESWS by year 5 in the enalapril group. Six of seven patients removed from random assignment to treatment because of cardiac deterioration were initially treated with placebo (P =.11), and one has died as a result of heart failure. Side effects from enalapril included dizziness or hypotension (22% v 3% in the placebo group; P =.0003) and fatigue (10% v 0%; P =.013). CONCLUSION: Enalapril treatment did not influence exercise performance, but did reduce LVESWS in the first year; this reduction was maintained over the study period. Any theoretical benefits of LVESWS reduction in this anthracycline-exposed population must be weighed against potential side effects from ACE inhibitors when making treatment decisions.
Assuntos
Antraciclinas/toxicidade , Enalapril/administração & dosagem , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/tratamento farmacológico , Neoplasias/tratamento farmacológico , Adolescente , Adulto , Antraciclinas/uso terapêutico , Criança , Pré-Escolar , Progressão da Doença , Método Duplo-Cego , Teste de Esforço , Tolerância ao Exercício/efeitos dos fármacos , Feminino , Seguimentos , Insuficiência Cardíaca/fisiopatologia , Testes de Função Cardíaca/efeitos dos fármacos , Humanos , Modelos Lineares , Masculino , Neoplasias/patologia , Probabilidade , Prognóstico , Valores de Referência , Medição de Risco , Índice de Gravidade de Doença , Sobreviventes , Resultado do TratamentoRESUMO
PURPOSE: As the number of pediatric cancer survivors increases, so does the number of survivors previously exposed to anthracyclines as part of their cancer therapy. Because screening is costly, some have suggested that health-related quality of life (HRQL) measures might be useful in focusing screening tests on those patients with cases most likely to display positive findings. This study reports on the predictive ability of HRQL measures to detect patients with abnormalities on serial cardiac testing. METHODS: Using 127 patients from the ACE-Inhibitor after Anthracycline (AAA) Trial, this study compared serial measures of the Short Form-36 (SF-36; for ages > 13 years) and Child Health Questionnaire-Child Form 87 (CHQ-CF87; for ages < or = 13 years) to serial cardiac performance tests including echocardiographic shortening fraction, left ventricular end systolic wall stress (LVESWS), LVESWS-index, and maximal cardiac index (MCI; a measure of cardiac output at peak exercise). RESULTS: Generally, there was no clinically or statistically significant correlation between any HRQL measure and any cardiac function measure except between MCI and vitality and physical functioning. For each of these measures, the correlation between MCI was statistically significant (P < .006), but each HRQL subscale could explain no more than 7% of the variation in MCI. HRQL measures were not predictive of any other cardiac function measure. CONCLUSION: HRQL measures should not be used in isolation as a screen for cardiac function abnormalities in patients exposed to anthracylines who already have a mild degree of ventricular dysfunction. Patient history appears to be no substitute for cardiac testing in this cohort.
Assuntos
Antraciclinas/efeitos adversos , Coração/fisiologia , Qualidade de Vida , Sobreviventes , Adolescente , Adulto , Criança , Pré-Escolar , Método Duplo-Cego , Ecocardiografia , Feminino , Testes de Função Cardíaca , Humanos , Lactente , Masculino , Neoplasias/tratamento farmacológico , Valor Preditivo dos TestesRESUMO
OBJECTIVE: Mechanical cardiorespiratory support is occasionally required before or after pediatric thoracic organ transplantation. Extracorporeal membrane oxygenation is the most commonly used mechanical support technique in children. The goal of this study was to examine the indications for initiation and outcomes after peritransplant use of extracorporeal membrane oxygenation. METHODS: A retrospective study was conducted of 65 patients who received peritransplant extracorporeal membrane oxygenation between November 1994 and June 2000. The pretransplant group included 45 patients (average age, 38 months) supported with extracorporeal membrane oxygenation and listed for transplantation (31 heart, 8 lung, and 6 heart-lung), and the post-transplant group included 20 patients (average age, 83 months) who required extracorporeal membrane oxygenation after thoracic organ transplantation (12 heart, 6 lung, and 2 heart-lung transplants). Hospital course and outcomes were evaluated. RESULTS: With regard to pretransplant extracorporeal membrane oxygenation, patients listed for heart transplants were more likely to survive to transplantation than were those listed for lung or heart-lung transplants (12/31 [39%] vs 1/14 [7%], P =.03). There was no difference in long-term survival between heart transplant patients after extracorporeal membrane oxygenation and those without extracorporeal membrane oxygenation (12-month actuarial survival, 83% vs 73%; P =.68). Patients who survived for prolonged periods on extracorporeal membrane oxygenation (>250 hours) typically received heart transplants (7/8 [88%]). With regard to post-transplant extracorporeal membrane oxygenation, patients receiving lung or heart-lung transplants had better short-term outcomes than those receiving heart transplants (63% survived to discharge vs 33%). All 3 patients with early graft dysfunction receiving lung transplants survived to discharge. CONCLUSIONS: Long-term outcomes among those undergoing heart transplantation after support with an extracorporeal membrane oxygenator are comparable with those of patients not receiving extracorporeal membrane oxygenation. Extracorporeal membrane oxygenation can be a useful post-transplant support device, particularly in patients undergoing lung transplants.
Assuntos
Oxigenação por Membrana Extracorpórea , Transplante de Coração , Transplante de Pulmão , Criança , Pré-Escolar , Oxigenação por Membrana Extracorpórea/efeitos adversos , Feminino , Transplante de Coração-Pulmão , Humanos , Lactente , Masculino , Cuidados Pós-Operatórios , Cuidados Pré-Operatórios , Reoperação , Estudos RetrospectivosRESUMO
BACKGROUND: Thoracic organ transplantation is a life-changing event for a child and family from both a physical and a psychosocial perspective. Accurate pre-transplantation counseling and effective post-transplantation follow-up depend on a good understanding of post-transplantation health status, especially as perceived by families. METHODS: The Child Health Questionnaire-Parent Form 50 (CHQ-P50), an instrument that assesses parent-reported health status of pediatric patients, was administered to 47 pediatric thoracic organ transplant recipients (41 heart, 6 lung) 5 to 18 years of age. RESULTS: Transplant recipients scored lower on the Physical Health Summary (PhS) score than the general population, as evidenced by a lower median score (50.6 vs 55.1, p < 0.0001) and a difference in the distribution of quartiles (p = 0.001), skewed toward the lower quartiles of the general population. The distribution of PhS scores in transplant recipients was comparable to scores of 3 groups of pediatric patients with other chronic health conditions (juvenile rheumatoid arthritis, epilepsy and asthma). The distribution of the Psychosocial Health Summary (PsS) scores was similar to that of the general population, but the median score was lower (51.5 vs 53.2, p = 0.02). Transplant patients clearly scored lower than the general population on 4 of 12 sub-scales, including those assessing general health, physical functioning, family activities and parental emotional impact. No difference was found in sub-scales reflecting self-esteem, mental health, behavior, pain, peer interactions, family cohesion or parental time demands. CONCLUSIONS: Thoracic organ transplantation in children ages 5 to 18 years is associated with an ongoing deficit in parent-perceived physical health status.
Assuntos
Nível de Saúde , Transplante de Coração , Transplante de Coração-Pulmão , Transplante de Pulmão , Pais/psicologia , Adolescente , Criança , Doença Crônica , Feminino , Transplante de Coração/fisiologia , Transplante de Coração-Pulmão/fisiologia , Humanos , Transplante de Pulmão/fisiologia , Masculino , Aptidão Física , Estresse Psicológico , Inquéritos e Questionários , Fatores de TempoRESUMO
OBJECTIVE: Critical congenital heart disease has been proposed as a target of newborn screening. This study aimed to define the incidence and timing of significant physiologic compromise attributable to critical congenital heart disease as well as the distribution of vulnerable lesions. These descriptive parameters must be defined to evaluate the impact and feasibility of any proposed screening strategy. METHODS: A retrospective cohort study of neonates who had critical congenital heart disease and were admitted to a single institution was conducted. Critical congenital heart disease was defined as congenital heart disease that required invasive intervention or resulted in death in the first 30 days of life. Significant physiologic compromise was defined by severe metabolic acidosis, seizure, cardiac arrest, or laboratory evidence of renal or hepatic injury before invasive intervention. Significant physiologic compromise was classified as potentially preventable when it occurred as a result of undiagnosed congenital heart disease after 12 hours of life. RESULTS: Significant physiologic compromise occurred in 76 (15.5%) of 490 patients, and potentially preventable significant physiologic compromise occurred in 33 (6.7%) of 490 patients. Most (83%) significant physiologic compromise as a result of unrecognized congenital heart disease occurred after 12 hours of age. A total of 90.9% of cases of potentially preventable significant physiologic compromise had aortic arch obstruction. The incidence of potentially preventable significant physiologic compromise as a result of congenital heart disease in the general population is estimated to be 1 per 15,000 to 1 per 26,000 live births. CONCLUSIONS: The incidence and timing of significant physiologic compromise as a result of critical congenital heart disease seems amenable to postnatal screening. Any viable screening strategy must be sensitive for lesions with aortic arch obstruction.
Assuntos
Causas de Morte , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/epidemiologia , Triagem Neonatal/métodos , Estudos de Coortes , Estado Terminal , Feminino , Mortalidade Hospitalar/tendências , Hospitais Pediátricos , Humanos , Incidência , Recém-Nascido , Masculino , Pennsylvania/epidemiologia , Estudos Retrospectivos , Medição de Risco , Análise de SobrevidaRESUMO
BACKGROUND: Risk factors for tricuspid regurgitation (TR) after adult orthotopic heart transplantation (OHT) have been reported, although there are no pediatric data. METHODS: This study was a single-center retrospective analysis of patients Assuntos
Transplante de Coração/efeitos adversos
, Insuficiência da Valva Tricúspide/epidemiologia
, Adolescente
, Criança
, Pré-Escolar
, Feminino
, Humanos
, Lactente
, Recém-Nascido
, Masculino
, Prevalência
, Estudos Retrospectivos
, Fatores de Risco
, Resultado do Tratamento
, Insuficiência da Valva Tricúspide/etiologia
RESUMO
Homozygous familial hypercholesterolemia (hoFH) is caused by mutations in the low-density lipoprotein receptor gene and is characterized by severe hypercholesterolemia from birth and onset of premature cardiovascular disease (CVD) during childhood. The onset and progression of CVD using currently available testing methods in children with hoFH have not been fully characterized. A large cohort of patients with hoFH referred to our subspecialty clinic was studied. Thirty-nine patients (22 aged < or =16 years) underwent extensive cardiovascular, lipid, and genetic evaluation. Sixteen children < or =16 years without known CVD when first evaluated were followed up longitudinally for up to 8 years. CVD was clinically evident in 88% of subjects aged >16 years and 9% of those < or =16 years. Markers of atherosclerosis correlated significantly with age at which lipid-lowering treatment was initiated (abnormal coronary angiogram, abnormal aortic valve using echocardiography, and high calcium score using electron beam computed tomography; all p <0.01; abnormal carotid Doppler result; p = 0.03). Twenty of 22 children had no clinical evidence of coronary artery disease, yet 7 of these children had angiographically confirmed mild coronary artery disease (<50%) and 8 had mild to moderate aortic regurgitation using echocardiography. Of noninvasive tests, only evaluation of aortic valve regurgitation using echocardiography predicted the presence of angiographic coronary stenosis (p <0.001). During follow-up, 7 children developed progression of coronary and/or aortic valvular disease during their teenage years and 4 required surgical interventions. In conclusion, in these patients aggressive lipid-lowering treatment initiated in early childhood is warranted. Careful coronary and valvular surveillance strategies and coronary revascularization when appropriate are also warranted in this high-risk population.
Assuntos
Doenças Cardiovasculares/diagnóstico , Homozigoto , Hiperlipoproteinemia Tipo II/fisiopatologia , Adolescente , Adulto , Biomarcadores , Doenças Cardiovasculares/diagnóstico por imagem , Doenças Cardiovasculares/fisiopatologia , Criança , Pré-Escolar , Angiografia Coronária , Progressão da Doença , Teste de Esforço , Feminino , Humanos , Hiperlipoproteinemia Tipo II/genética , Lactente , Estudos Longitudinais , Masculino , Medição de Risco , Fatores de Tempo , Ultrassonografia , Adulto JovemRESUMO
OBJECTIVES: We characterized a large cohort of children who had a Fontan procedure, with measures of functional health status, ventricular size and function, exercise capacity, heart rhythm, and brain natriuretic peptide (BNP). BACKGROUND: The characteristics of contemporary Fontan survivors are not well described. METHODS: We enrolled 546 children (age 6 to 18 years, mean 11.9 years) and compared them within pre-specified anatomic and procedure subgroups. History and outcome measures were obtained within a 3-month period. RESULTS: Predominant ventricular morphology was 49% left ventricular (LV), 34% right ventricular (RV), and 19% mixed. Ejection fraction (EF) was normal for 73% of subjects; diastolic function grade was normal for 28%. Child Health Questionnaire mean summary scores were lower than for control subjects; however, over 80% of subjects were in the normal range. Brain natriuretic peptide concentration ranged from <4 to 652 pg/ml (median 13 pg/ml). Mean percent predicted peak O2 consumption was 65% and decreased with age. Ejection fraction and EF Z score were lowest, and semilunar and atrioventricular (AV) valve regurgitation were more prevalent in the RV subgroup. Older age at Fontan was associated with more severe AV valve regurgitation. Most outcomes were not associated with a superior cavopulmonary connection before Fontan. CONCLUSIONS: Measures of ventricular systolic function and functional health status, although lower on average in the cohort compared with control subjects, were in the majority of subjects within 2 standard deviations of the mean for control subjects. Right ventricular morphology was associated with poorer ventricular and valvular function. Effective strategies to preserve ventricular and valvular function, particularly for patients with RV morphology, are needed.
Assuntos
Técnica de Fontan , Cardiopatias Congênitas/cirurgia , Adolescente , Fatores Etários , Criança , Pré-Escolar , Estudos de Coortes , Estudos Transversais , Exercício Físico/fisiologia , Feminino , Nível de Saúde , Coração/fisiologia , Cardiopatias Congênitas/sangue , Cardiopatias Congênitas/patologia , Cardiopatias Congênitas/fisiopatologia , Ventrículos do Coração/patologia , Humanos , Masculino , Peptídeo Natriurético Encefálico/sangue , Fatores Sexuais , Resultado do Tratamento , Função Ventricular/fisiologiaRESUMO
OBJECTIVES: To determine physical activity levels in paediatric patients who underwent the Fontan procedure, and their relationship to functional status and exercise capacity. STUDY DESIGN: We studied 147 patients (ages 7-18 years) at a median of 8.1 years after Fontan, as part of the Pediatric Heart Network cross-sectional study of Fontan survivors. Assessment included medical history, self-reported physical activity, parent-completed Child Health Questionnaire (CHQ), cardiopulmonary exercise testing and physical activity level measured by accelerometry (MTI Actigraph). RESULTS: Measured time spent in moderate and vigorous activity was markedly below normal at all ages, particularly in females, and was not significantly related to self-reported activity levels, or to maximum Vo2, Vo2 at anaerobic threshold or maximum work rate on exercise testing. Lower measured activity levels were significantly related to lower perceived general health but not to self-esteem, physical functioning, social impact of physical limitations or overall physical or psychosocial health summary scores. Reduced exercise capacity was more strongly related than measured activity levels to lower scores in general health, self-esteem and physical functioning. CONCLUSIONS: Physical activity levels are reduced after Fontan, independent of exercise capacity, and are associated with lower perceived general health but not other aspects of functional status.
Assuntos
Atitude Frente a Saúde , Técnica de Fontan/reabilitação , Atividade Motora , Adolescente , Criança , Exercício Físico/psicologia , Teste de Esforço/métodos , Feminino , Indicadores Básicos de Saúde , Cardiopatias Congênitas/cirurgia , Humanos , Masculino , Período Pós-Operatório , AutoimagemRESUMO
This paper examined the role of metabolites in causing muscle fatigue. Previous studies have shown that Pi (H2PO4-, HPO4-2) and H+ may be important factors in causing fatigue. A key question is the potential interaction between metabolic end-products and calcium related excitation-contraction coupling fatigue (ECC). An in vivo rat muscle model was used to measure tension development and metabolic end-products in response to electrical stimulation. Two stimulation protocols were used, high intensity stimulation followed by a medium intensity stimulation (High Group), and low intensity stimulation followed by a medium intensity stimulation (Low Group). Metabolic fatigue was based on concentrations of (H2PO4-measured with phosphorus magnetic resonance spectroscopy. ECC fatigue was measured as the fatigue in excess of metabolic fatigue, and as the relative decline of force at low compared to high stimulation frequencies. During the initial stimulation period, the High Group had greater metabolic fatigue (p < 0.001) and greater ECC fatigue (p = 0.007). During the second stimulation period and recovery, the High Group had no difference in metabolic fatigue (p = 0.07) and greater ECC fatigue (p = 0.015). These results present a method for determining the relative amounts of metabolic and ECC fatigue, and suggest that metabolites can increase the amount of ECC fatigue.
Assuntos
Fadiga Muscular/fisiologia , Músculo Esquelético/metabolismo , Análise de Variância , Animais , Estimulação Elétrica , Metabolismo Energético , Concentração de Íons de Hidrogênio , Contração Isométrica/fisiologia , Modelos Lineares , Espectroscopia de Ressonância Magnética , Fosfocreatina/metabolismo , Fósforo/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVE: To review and describe pneumatosis intestinalis (PI) in children who have undergone thoracic organ transplantation and evaluate potential risk factors. METHODS: We retrospectively reviewed abdominal radiographs obtained from June 1992 through September 2000 in all pediatric (age <21 years) thoracic organ recipients who survived at least 1 week after transplantation. In this group, a case was defined as an episode of radiographically confirmed PI; those without PI were assigned as controls. Variables analyzed included demographic data, gastroenteritis history (stool cultures or symptoms of gastroenteritis), and transplant-related factors (ie, graft type, rejection history, immunosuppression regimen). Significance was defined as P <.05. RESULTS: Over this 8-year period, PI occurred in 8 (7%) of 116 patients (0.86% annual risk). No child had >1 diagnosed episode of PI. Of these 8 cases, 7 presented with 1 or more abdominal symptoms. Three of these children had rotavirus antigen isolated in their stool, 2 others were noted to have stool positive for Clostridium difficile toxin, and in the other 3, no pathogen was identified. All cases were treated with a regimen of intravenous antibiotics and total parenteral nutrition. There were no deaths; however, 1 patient developed an Aspergillus pulmonary infection during his course of antibiotic therapy, and another underwent an exploratory laparotomy without bowel resection. Significant risk factors included black race (unadjusted odds ratio: 16), younger age at presentation (age <5 years; unadjusted odds ratio: 9), higher steroid dose (steroid dose >0.5 mg/kg/d; unadjusted odds ratio: 7), and a higher tacrolimus level at presentation (tacrolimus level >1; unadjusted odds ratio: 6). PI did not occur with a steroid dose <0.4 mg/kg/d. Variables not associated with increased risk for developing PI included gender, graft type, total white blood cell count, recent antibiotic use, concurrent use of an antimetabolite, cytomegaloviral infection, past use of extracorporeal membrane oxygenation, and graft rejection history. CONCLUSIONS: Significant risk factors for the development of PI in our pediatric thoracic organ transplantation population included black race, younger age, higher daily steroid dosing, and a high tacrolimus level at presentation. In the children diagnosed with PI, there were no related deaths, significant gastrointestinal sequelae, or complications. These findings suggest that in this population, PI will often have a benign course when treated aggressively, and that steroid dosing should be reduced to <0.5 mg/kg/d whenever possible.