Arginine Therapy and Cardiopulmonary Hemodynamics in Hospitalized Children with Sickle Cell Anemia: A Prospective, Double-blinded, Randomized Placebo-controlled Clinical Trial.

Rationale: Acute changes in cardiopulmonary hemodynamics that include tricuspid regurgitant jet velocity (TRV) elevation measured by Doppler echocardiography are often encountered during sickle cell vasoocclusive pain and acute chest syndrome (ACS). Arginine and nitric oxide depletion develop in patients with these complications. Arginine administration may therefore improve nitric oxide bioavailability and potentiate pulmonary vasodilatation. Objectives: To evaluate effects of l-arginine supplementation on Doppler indices of cardiopulmonary hemodynamics in children with sickle cell anemia experiencing pain. Methods: This was a prospective, double-blinded, randomized placebo-controlled trial of oral arginine in children with sickle cell anemia age 5-17 years hospitalized with severe pain and/or ACS. Measurements and Main Results: Blood biomarkers and Doppler echocardiographic indices of cardiopulmonary hemodynamics were measured before and after supplementation. The mean change in TRV, pulmonary artery systolic pressure, mean pulmonary artery pressure, and other indices of cardiopulmonary hemodynamics were tested with paired Student's t test and correlated with markers of arginine bioavailability using Pearson correlation. Sixty-six children were randomized into arginine versus placebo groups. An elevated TRV ⩾ 2.5 m/s was seen in 40 (61%) patients. A Day 5 Doppler echocardiogram was performed in 47 patients who remained hospitalized. A greater reduction in median TRV occurred in the arginine group than placebo (22.2%, n = 22 vs. 3.8%, n = 25; p < 0.01). A larger percentage increase in global arginine bioavailability was associated with a lower TRV after 5 days of supplementation (r = -0.533; P = 0.001). Significant differences in multiple indices of cardiopulmonary hemodynamics and mean N-terminal pro B-type brain natriuretic peptide were also noted after arginine therapy. Conclusions: Oral arginine supplementation improves cardiopulmonary hemodynamics during sickle cell disease vasoocclusive pain and ACS.Clinical trial registered with Pan African Clinical Trial Registry https://pactr.samrc.ac.za/Search.aspx (PACTR201611001864290).

Randomized control trial of oral arginine therapy for children with sickle cell anemia hospitalized for pain in Nigeria.

Low arginine bioavailability is associated with vaso-occlusive painful crisis (VOC) severity in sickle cell anemia (SCA) and predicts need for pediatric hospitalization. Intravenous arginine therapy has opioid-sparing effects and was found to significantly decrease pain scores in children hospitalized with SCA-VOC in a phase-two randomized placebo-controlled trial (RCT). Efficacy of oral arginine is unknown. Our objective was to determine the safety and efficacy of oral arginine therapy in Nigerian children with SCA. A double-blind RCT of oral L-arginine-hydrochloride (100 mg/kg TID) was conducted in children with SCA-VOC, aged 5-17 years, hospitalized at two Nigerian sites. The primary outcome measure was analgesic usage, quantified by difference in the mean Analgesic Medication Quantification Scale (MQS). Secondary outcomes included daily pain scores, time-to-crisis-resolution and length-of-hospital-stay. An intention-to-treat analysis was performed. Sixty-eight children (age 5-17 years, mean 10.6 ± 0.4 years; 56% male), were randomized to receive L-arginine (35 patients) or placebo (33 patients). The mean total MQS for the arginine group was 73.4 (95% CI, 62.4-84.3) vs 120.0 (96.7-143.3) for placebo (P < .001). The mean rate of decline in worst pain scores was faster in the arginine arm vs placebo (1.50 [1.23-1.77] vs 1.09 [0.94-1.24] point/d, P = .009). Children receiving arginine had a shorter time-to-crisis-resolution (P = .02), shorter hospital-stay (P = .002) and experienced no serious adverse event. Pain control was more rapid, total analgesic requirement was significantly reduced, and most notably, time-to-crisis-resolution and length-of-hospital-stay were shorter in children with SCA-VOC receiving arginine vs placebo. Given the established safety and low cost, oral arginine is a promising adjuvant therapy for SCA-VOC management.

Cardiovascular changes in children with sickle cell crisis.

BACKGROUND: Sickle cell anaemia is characterised by frequent, sometimes serious events referred to as "crisis". Cardiopulmonary consequences such as pulmonary hypertension and myocardial ischaemia may accompany a serious crisis. OBJECTIVE: To determine the cardiovascular changes that occur during a severe sickle cell crisis. METHODS: A cross-sectional comparative study of sickle cell anaemia in children (5-17 years) admitted during a severe crisis (cases) and those in steady state (controls) was conducted over a 2-year period. Effects of the crisis on the cardiopulmonary system were assessed. The diagnosis of myocardial ischaemia was made using electrocardiography and serological cardiac biomarkers, while cardiac dysfunction and the presence of pulmonary hypertension were determined using echocardiography. The presence of systemic hypertension and tachycardia was also evaluated. RESULTS: A total of 176 patients were recruited, 92 in steady state (male:female ratio, 1.2:1) and 84 in severe crisis (male:female ratio, 1.3:1). The mean age was 10.4 ± 3.2 years for steady state and 10.5 ± 3.4 years for those in crisis. The mean heart rate in crisis was higher than in steady state (p < 0.0001). The blood pressures (systolic, p < 0.0001, diastolic, p < 0.0001, mean, p < 0.0001) as well as myocardial ischaemia scores (p < 0.0001) were higher in patients with crisis than in those in steady state. Similarly, conduction abnormalities, pulmonary hypertension, and ventricular dysfunction were more prevalent in the crisis than in the steady state. CONCLUSION: The present data suggest that sickle cell crisis results in a derangement of clinical, electrocardiographical, and echocardiographical parameters in children with sickle cell anaemia. Further research on these cardiovascular events may improve the overall care of these patients.

Review of children with Takayasu's arteritis at a Southern African tertiary care centre.

IntroductionTakayasu's arteritis is a rare idiopathic arteritis causing stenosis or aneurysms of the aorta, pulmonary arteries, and their branches. It usually occurs in women, but has been described in children. OBJECTIVE: The objective of this study was to determine the clinical presentation, demographic profile, vascular involvement, origins, management, and outcome of children diagnosed with Takayasu's arteritis at a Southern African tertiary care centre between 1993 and 2015. METHODS: This is a retrospective analysis of all children with Takayasu's arteritis captured on a computerised electronic database during the study period. RESULTS: A total of 55 children were identified. The female:male ratio was 3.2:1, and the mean age was 9.7±3.04 years. Most originated outside the provincial borders of the study centre. The majority presented with hypertension and heart failure. In all, 37 (67%) patients had a cardiomyopathy with a mean fractional shortening of 15±5%. A positive purified protein derivative test was documented in 73%. Abdominal aorta and renal artery stenosis were the predominant angiographic lesions. A total of 23 patients underwent 30 percutaneous interventions of the aorta, pulmonary, and renal arteries: eight stents, 22 balloon angioplasties, and seven had nephrectomies. All patients received empiric tuberculosis treatment, immunosuppressive therapy, and anti-hypertensive agents as required. Overall, there was a significant reduction in systolic blood pressure and improvement in fractional shortening (p<0.05) with all treatments. CONCLUSION: Takayasu's arteritis is more common in girls and frequently manifests with hypertension and heart failure. The abdominal aorta and renal arteries are mostly affected. Immunosuppressive, anti-hypertensive, and vascular intervention therapies improve blood pressure control and cardiac function.

Anti-inflammatory treatment for carditis in acute rheumatic fever.

BACKGROUND: Rheumatic heart disease remains an important cause of acquired heart disease in developing countries. Although prevention of rheumatic fever and management of recurrences have been well established, optimal management of active rheumatic carditis remains unclear. This is an update of a review published in 2003, and previously updated in 2009 and 2012. OBJECTIVES: To assess the effects, both harmful and beneficial, of anti-inflammatory agents such as aspirin, corticosteroids and other drugs in preventing or reducing further valvular damage in patients with acute rheumatic fever. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (2013, Issue 9 of 12), MEDLINE (Ovid, 1948 to 2013 October Week 1), EMBASE (Ovid, 1980 to 2013 Week 41) and Latin American Caribbean Health Sciences Literature (LILACS) (1982 to 17 October 2013). We last searched Index Medicus (1950 to April 2001) in 2001. We checked reference lists of identified studies and applied no language restrictions. SELECTION CRITERIA: Randomised controlled trials comparing anti-inflammatory agents (e.g. aspirin, steroids, immunoglobulins, pentoxifylline) versus placebo or controls, or comparing any of the anti-inflammatory agents versus one another, in adults and children with acute rheumatic fever diagnosed according to Jones, or modified Jones, criteria. The presence of cardiac disease one year after treatment was the major outcome criterion selected. DATA COLLECTION AND ANALYSIS: Two review authors extracted data and assessed risk of bias using the methodology outlined in the Cochrane Handbook of Systematic Reviews of Interventions. Standard methodological procedures as expected by The Cochrane Collaboration were used. MAIN RESULTS: No new studies were included in this update. Eight randomised controlled trials involving 996 people were selected for inclusion in the review. Researchers compared several steroidal agents such as corticotrophin, cortisone, hydrocortisone, dexamethasone, prednisone and intravenous immunoglobulin versus aspirin, placebo or no treatment. Six trials were conducted between 1950 and 1965; one was done in 1990 and the final study was published in 2001. Overall there were no observed significant differences in risk of cardiac disease at one year between corticosteroid-treated and aspirin-treated groups (six studies, 907 participants, risk ratio 0.87, 95% confidence interval 0.66 to 1.15). Similarly, use of prednisone (two studies, 212 participants, risk ratio 1.13, 95% confidence interval 0.52 to 2.45) compared with aspirin did not reduce the risk of heart disease after one year. Investigators in five studies did not report adverse events. The three studies reporting on adverse events reported substantial adverse events. However, all results should be interpreted with caution because of the age of the studies and the substantial risk of bias. AUTHORS' CONCLUSIONS: Little evidence of benefit was found when corticosteroids or intravenous immunoglobulins were used to reduce the risk of heart valve lesions in patients with acute rheumatic fever. The antiquity of most of the trials restricted adequate statistical analysis of the data and acceptable assessment of clinical outcomes by current standards. In addition, risk of bias was substantial, so results should be viewed with caution. New randomised controlled trials in patients with acute rheumatic fever are warranted to assess the effects of corticosteroids such as oral prednisone and intravenous methylprednisolone and the effects of other new anti-inflammatory agents. Advances in echocardiography will allow more objective and precise assessments of cardiac outcomes.

Anti-inflammatory treatment for carditis in acute rheumatic fever.

BACKGROUND: Rheumatic heart disease remains an important cause of acquired heart disease in developing countries. Although the prevention of rheumatic fever and the management of recurrences is well established, the optimal management of active rheumatic carditis is still unclear. This is an update of a review published in 2003 and previously updated in 2009. OBJECTIVES: To assess the effects of anti-inflammatory agents such as aspirin, corticosteroids, immunoglobulin and pentoxifylline for preventing or reducing further heart valve damage in patients with acute rheumatic fever. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials on The Cochrane Library (Issue 3, 2011), MEDLINE (1966 to Aug 2011), EMBASE (1998 to Sept 2011), LILACS (1982 to Sept 2011), Index Medicus (1950 to April 2001) and references lists of identified studies. No language restrictions were applied. SELECTION CRITERIA: Randomised controlled trials comparing anti-inflammatory agents (e.g. aspirin, steroids, immunoglobulins, pentoxifylline) with placebo or controls, or comparing any of the anti-inflammatory agents with one another, in adults and children with acute rheumatic fever diagnosed according to the Jones, or modified Jones criteria. The presence of cardiac disease one year after treatment was the major outcome criteria selected. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data. Risk of bias was assessed using methodology outlined in the Cochrane handbook. MAIN RESULTS: No new studies were included in this update. Eight randomised controlled trials involving 996 people were included. Several steroidal agents corticotrophin, cortisone, hydrocortisone, dexamethasone and prednisone, and intravenous immunoglobulin were compared to aspirin, placebo or no treatment in the various studies. Six of the trials were conducted between 1950 and 1965, one study was done in 1990, and the final study was published in 2001. Overall there was no significant difference in the risk of cardiac disease at one year between the corticosteroid-treated and aspirin-treated groups (six studies, 907 participants, relative risk 0.87, 95% confidence interval 0.66 to 1.15). Similarly, use of prednisone (two studies, 212 participants, relative risk 1.13, 95% confidence interval 0.52 to 2.45) compared to aspirin did not reduce the risk of developing heart disease after one year. Adverse events were not reported in five studies. The three studies reporting on adverse events all reported substantial adverse events. However, all results should be interpreted with caution due to the age of the studies and to substantial risk of bias. AUTHORS' CONCLUSIONS: There is little evidence of benefit from using corticosteroids or intravenous immunoglobulins to reduce the risk of heart valve lesions in patients with acute rheumatic fever. The antiquity of most of the trials restricted adequate statistical analysis of the data and acceptable assessment of clinical outcomes by current standards. Additionally there was substantial risk of bias, so results should be viewed with caution. New randomised controlled trials in patients with acute rheumatic fever to assess the effects of corticosteroids such as oral prednisone and intravenous methylprednisolone, and other new anti-inflammatory agents are warranted. Advances in echocardiography will allow for more objective and precise assessments of cardiac outcomes.

Impact of Highly Active Antiretroviral Therapy on paediatric Human Immunodeficiency Virus-associated left ventricular dysfunction within the Johannesburg teaching hospital complex.

OBJECTIVE: To analyse the outcome of children with left ventricular dysfunction placed on Highly Active Antiretroviral Therapy. METHOD: This study is a retrospective review of records of Human Immunodeficiency Virus-positive children with left ventricular dysfunction. Demographic data were collected. Left ventricular fractional shortening, CD4 percentage, viral load, and nutritional status were compared before and during antiretroviral therapy. RESULTS: We reviewed the records of 34 Human Immunodeficiency Virus-positive children with left ventricular dysfunction. In all, 18 patients received antiretroviral therapy (group one) and 16 were antiretroviral therapy naive (group two). The median age of group one at initial visit was 94 months, with a male-to-female ratio of 1:1. Of those, 17 children showed improved left ventricular function on treatment, with an increase in fractional shortening (median: 17-33.5%; p less than 0.0001). There was no significant statistical difference between the groups regarding initial fractional shortening. In group one, the CD4 percentage improved (median: 12% to 30.5%; p less than 0.0001), with viral load suppression (median: 24,900 copies per millilitre to less than 25 copies per millilitre; p less than 0.0001). There was weight gain in group one (median z-score: -1.70 to -1.32; p equal to 0.0083). Proper statistical analysis in group two was not possible because of poor follow-up of patients. CONCLUSION: The findings are in keeping with other reports that have shown improvement in left ventricular function in patients with Human Immunodeficiency Virus-associated cardiomyopathy treated with Highly Active Antiretroviral Therapy. Recovery of myocardial function is associated with improvement in immunological and nutritional statuses.

Improving Access to Pediatric Cardiac Care in the Developing World: the South African Perspective.

Purpose of Review: The paper outlines the current status of health care and pediatric cardiac services in South Africa and the challenges faced in providing pediatric cardiac care in the country. Recent Findings: As infant and child mortality rates in South Africa and most of Sub-Saharan Africa continue to decline, establishing and improving the infrastructure to manage congenital heart disease increases in importance. Summary: South Africa has well-established pediatric cardiac units in most major centers in the country. These have been able to train sufficient numbers of pediatric cardiologists to double the number in the country in just over a decade as well as train fellows from surrounding countries. A significant proportion of funding for this training comes from non-government sources. The number of pediatric cardiologists is however still far less than required with services spread unevenly throughout the country. Pediatric cardiac surgical services remain severely constrained with an urgent need to train more pediatric cardiac surgeons. Further progress depends not only on focussing resources on cardiac disease but also improvements in the health care systems and socioeconomic conditions in general.

Early presentation of endomyocardial fibrosis in a 22-month-old child: a case report.

We present an unusual, biopsy-proven case of endomyocardial fibrosis in a 22-month-old male child, which progressed rapidly resulting in death. The patient was born to a father originating from Mozambique, where the disease is endemic but who had not himself travelled there, suggesting a genetic link. Other remarkable features were the presence of a right ventricular diverticulum, and a positive Mycoplasma pneumoniae immunoglobulin M enzyme-linked immunosorbent assay test.

Impact of oral L-arginine supplementation on blood pressure dynamics in children with severe sickle cell vaso-occlusive crisis.

Sickle cell anaemia (SCA) patients generally have lower blood pressures compared to those with the AA haemoglobin genotype. However, during vaso-occlusive crises (SCA-VOC), blood pressures (BP) may elevate transiently to levels beyond the 95th percentile. The risk of stroke or even death increases with increasing systolic BP in SCA. Therefore, interventions targeted at BP reduction may be essential during severe vaso-occlusive episodes. Reduction in BP was achieved with arginine therapy in a meta-analysis of randomized controlled trials (RCT) in non-sickle cell adults. The impact of oral arginine (given for pain control) on the BP of children with SCA-VOC has not been documented. METHODS: A double-blind RCT of oral L-arginine hydrochloride as adjuvant therapy for pain reduction was conducted in children with SCA-VOC, aged 5-17 years, over a 2-year period. The mean change in BP and the time to achieve BP <90th percentile was added as part of the outcome variables. The anthropometry, pain scores and mercury sphygmomanometry were done following standard procedures. BP percentiles were generated using the Fourth Report guidelines. Differences in the time to normalization of BP in the treatment arms were tested with Kaplan-Meier analysis. RESULTS: Sixty-six children (57.6% male) were randomized into L-arginine (35 patients) or placebo (31 patients) arm. The prevalence of hypertension (BP ≥95th percentile) at presentation tended to increase as the pain scores increased, from a prevalence of 50% in patients with a score of 7 to 65% in those with score of 10 (systolic hypertension) and from 44.4% in patients with pain score of 7 to 50% in patients with pain score of 10 (diastolic hypertension). Patients that received arginine recorded a 12.8±3.2 mmHg decline in mean systolic BP compared to the placebo group, where a mean difference of 7.6±1.5 mmHg was observed, P<0.001. Similarly, the mean diastolic BP reduced by 13% in the arginine group and 7.5% in the placebo group, P<0.001. Children who received arginine tended to achieve BP normalization much faster than the placebo group (P=0.112), and no serious adverse events were documented related to the hypertension or arginine administration. CONCLUSIONS: High blood pressure (≥95th percentile) is common amongst children with SCA-VOC and are mostly asymptomatic. Administration of oral arginine given for pain control achieves a reduction of the BP at a faster rate in children compared to placebo and it is safe.

A retrospective review of right-sided hearts at a South African tertiary hospital.

BACKGROUND: A right-sided heart (RSH) has three main causes: dextrocardia, dextroposition and dextroversion. It may be associated with cardiac malformation, extra-cardiac abnormalities and adverse patient outcomes. The aim of this study was to determine the prevalence, demographics, associated cardiac malformations (ACM) and outcome of paediatric patients diagnosed with a RSH at a South African tertiary hospital. METHODS: A retrospective review was performed over a 22-year period. RESULTS: RSH comprised 1% of the paediatric cardiology referrals. Dextrocardia was the most frequent cause (58.1%) and the majority of these patients had ACM (81.5%). More than a third (40.9%) were diagnosed with dextroposition, secondary to extra-cardiac factors. Dextroversion was the least common cause (1.1%). Over a quarter of all patients were confirmed dead at the time of the study; most had been diagnosed with dextrocardia. Two-thirds of the patients were lost to follow up. CONCLUSIONS: A RSH is an unusual occurrence. Dextrocardia, the most common cause, is frequently associated with ACM and extra-cardiac abnormalities. It is therefore important to timeously elucidate the cause of a RSH.

Transcatheter closure of the patent ductus arteriosus at a public sector hospital in Soweto, South Africa: a review of patient outcomes over 15 years.

BACKGROUND: Methods of closing patent ductus arteriosus (PDA) have evolved over time. We review this development in our setting. METHODS: This was a retrospective analysis of children who had transcatheter PDA closure at Chris Hani Baragwanath Hospital between 1993 and 2008. RESULTS: Over 15 years, 1 254 PDAs were diagnosed, of which 293 required intervention; 139 patients had transcatheter closure, the median age was 1.8 years (interquartile range = 1-4.5 years) and 66% were female (92/139). Mean PDA diameter was 3.2 mm (standard deviation = 1.6 mm), with an average 2:1 shunt. Transcatheter closure was performed using COOK® Flipper coils (n = 93) or Amplatzer™ devices (n = 46). Early occlusion rates for coils were 52% (39/75) and late occlusion occurred in 91% (68/75) of patients. For Amplatzer devices, early occlusion rates were 94% (33/35) and late occlusion was 100%. Amplatzer™ devices, available since 2003, were overwhelmingly used in the later years. CONCLUSIONS: Transcatheter PDA closure was safe and effective in this setting, with outcomes similar to reports elsewhere.

Percutaneous endovascular occlusion of symptomatic coronary arteriovenous fistulas with cyanoacrylate.

We describe four cases with symptomatic coronary artery fistulas that were treated primarily with endovascular cyanoacrylate embolization. Coils were also used as adjunctive embolic agents in two of these cases. All four cases showed symptomatic improvement after closure of the fistulas. Complications occurred in three cases including transient ST-segment elevation in one, symptomatic pulmonary embolization in a second, and transient pleuritic chest pain, pericarditis and acute renal failure in a third. The technical aspects of all four cases are given together with a review of the use of cyanoacrylate as an embolic material. We conclude that cyanoacrylate embolization could be considered as an alternative technique for the endovascular closure of coronary artery fistulas but must also caution that the use of this embolic agent is hazardous and should be restricted to practitioners experienced in its usage.

Cortical hyperostosis in an infant on prolonged prostaglandin infusion: case report and literature review.

The common side effects associated with the use of prostaglandins in newborn infants include apnoea, hyperthermia, diarrhoea, skin flushing and oedema. Periosteal reaction or cortical thickening of the bones, also known as cortical hyperostosis, is associated with a prolonged use of prostaglandins. This is a radiological diagnosis; therefore, its occurrence is most likely underestimated. We describe an infant who developed cortical hyperostosis simulating osteomyelitis with elevated alkaline phosphatase. The radiologic changes were initially attributed to congenital syphilis. This occurred after a prolonged infusion of prostaglandin E(1) for a cyanotic congenital heart disease.

Rheumatic fever and rheumatic heart disease in Gauteng on the decline: Experience at Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa.

BACKGROUND: The incidence of rheumatic fever (RF) and its complications has waned over the past three to four decades throughout the Western world, but RF remains a problem in developing countries and in the indigenous populations of some well-resourced countries. A marked decline in children presenting with acute rheumatic fever (ARF) and chronic rheumatic heart disease (RHD) has been observed over the past two decades at Chris Hani Baragwanath Academic Hospital (CHBAH) in southern Gauteng Province, South Africa, which mainly serves the periurban population of Soweto. OBJECTIVES: To analyse the observed decline in ARF and RHD, and consider the reasons for the decrease. METHODS: Review of children with ARF and RHD captured on a computerised database of all children seen in the Paediatric Cardiology Unit at CHBAH during 1993 - 2010. RESULTS: The records of 467 children with ARF and RHD were retrieved from the database. The majority provided addresses in Gauteng, Soweto and North West Province. The number of children documented to have ARF or RHD declined from 64 in 1993 to 3 in 2010. One-third of the patients underwent surgery, the majority mitral valve repair. Most of the patients requiring surgery had addresses in parts of Gauteng other than Soweto and other provinces, with relatively few originating from Soweto. CONCLUSION: The decline in the number of children with ARF and RHD presenting to CHBAH may be attributed to an improvement in socioeconomic conditions and better access to medical care for the referral population over the past two decades.

Fontan procedure for univentricular hearts: have changes in design improved outcome?

The Fontan operation has undergone numerous design changes in the last 30 years, which have resulted in an improved morbidity and mortality of patients with a univentricular heart. However, good patient selection and a staged approach to the Fontan operation have also contributed greatly to a better outcome in these patients.

Vasculopathy of the large arteries in children infected by the human immune deficiency virus.

We report on two children with advanced acquired immune deficiency syndrome presenting with vasculopathy involving the large vessels. Both patients had extensive involvement of the aorta and its branches. One patient presented with heart failure, and mild systemic hypertension secondary to renal arterial stenosis, while the other patient manifested with gangrene of both arms.