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).

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.

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.

Diagnosing renal failure due to diethylene glycol in children in a resource-constrained setting.

BACKGROUND: In 2008, several Nigerian children developed acute kidney injury (AKI) after ingesting teething syrup contaminated with diethylene glycol (DEG). Because there are limited diagnostic facilities in resource-constrained countries, this study investigated whether AKI associated with DEG could be identified by other means. METHODS: This was a multicenter study. Information was obtained from hospital records. Clinicopathological features of all children with AKI over a 6-month period were reviewed. RESULTS: Sixty (50.4%) of 119 children ingested "My pikin" teething syrup. Compared to children who had not ingested it, they were significantly (p < 0.05) younger (11.95 vs. 31 months), more were anuric (98.3 vs. 74.6%), hypertensive (84 vs. 52%), had severe metabolic acidosis (46.7 vs. 20.5%), and died (96.6 vs. 71.2%). They developed increasing metabolic acidosis and multiorgan dysfunction despite peritoneal dialysis. Late presentation, financial difficulties, inadequate facilities for toxicology, and hemodialysis complicated management. CONCLUSIONS: Identifying AKI associated with DEG is difficult. Detailed drug history, increasing metabolic acidosis, and multiorgan deterioration despite peritoneal dialysis should arouse suspicion. Simple diagnostic tests need to be developed and facilities for hemodialysis of infants and financial support provided. Recurrences can be prevented by creating awareness, improving manufacturing practices, field-testing of drugs, and international monitoring of pharmaceuticals imported for manufacture.

Prevalence and outcome of neonatal tetanus in Zaria, Northwestern Nigeria.

INTRODUCTION: Neonatal tetanus is a highly debilitating disease with high mortality. Global efforts at eliminating the disease in developing countries are yielding results but slower than expected. The high case fatality of neonatal tetanus remains a therapeutic challenge to physicians and requires continuous evaluation. This study aimed to determine the incidence and outcome of neonatal tetanus in Zaria, northwestern Nigeria. METHODOLOGY: A retrospective study of neonatal tetanus was conducted at the Neonatal Unit of Ahmadu Bello University Teaching Hospital, Zaria, between January 2005 and December 2009. Data generated were analyzed using the Epi Info version 3.5.1 software and statistical significance was set at p < 0.05. RESULTS: Of the 2,692 newborns admitted during the study period, 20 had tetanus, giving an overall prevalence of 0.7%. There were 14 males and 6 females (male to female ratio 2.3:1). The mean age and weight at presentation were 8.3 ± 4.0 days and 2.7 ± 0.3 kg, respectively. The mean incubation period was 3.2 ± 2.0 days. Four infants (20.0%) survived, one was discharged against medical advice and 15 (75.0%) died. Factors associated with mortality were presentation at less than seven days of life, low Hendrickse score at presentation (p = 0.0005) and hypoglycaemia (p = 0.0374). CONCLUSION: The incidence and the mortality rate of neonatal tetanus appear to be lower than those previously reported by our centre for the same region. Therefore, the ongoing global efforts for disease elimination and further improvements in the quality of care should be sustained.