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Concise Critical Appraisal: Arginine Therapy in Hospitalized Children With Sickle Cell Anemia

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Daniel E. Sloniewsky, MD, FCCM
8/17/2022

Can arginine supplements improve the hemodynamics of children with severe pain or acute chest syndrome (ACS) related to sickle cell anemia? Although mortality rates in children with sickle cell disease (SCD) have improved over the past decade, ACS and vasoocclusive episodes (VOE) remain relatively common diagnoses in pediatric ICUs. This Concise Critical Appraisal explores an article in which Onalo et al completed the second phase of their work determining the role that L-arginine treatment may play in the cardiopulmonary status of children with SCD and VOE, with or without ACS. In the first phase of their work, the authors demonstrated decreased hospitalization time, decreased opioid use, and the absence of serious adverse events in children with SCD after receiving L-arginine therapy.

Although mortality rates in children with sickle cell disease (SCD) have improved over the past decade, acute chest syndrome (ACS) and vasoocclusive episodes (VOE) remain relatively common diagnoses in the pediatric intensive care unit (PICU). ACS, whether secondary to painful VOE or not, can lead to acute respiratory failure and the potential for chronic lung disease.1 Pulmonary hypertension (PH) is a known complication of pediatric SCD, particularly in the presence of ACS and in VOE. PH has been associated with increased morbidity and mortality.2 The etiology of PH has been linked to increased cellular adhesion and subsequent impaired nitric oxide (NO) signaling, which may be related to the depletion of L-arginine, a necessary NO substrate.3
 
Supplementation of L-arginine has been demonstrated to promote the formation of NO in animal models of PH and VOE, but studies in humans have been inconsistent, some even suggesting harm.4,5 This Concise Critical Appraisal explores an article in which Onalo et al6 completed the second phase of their work determining the role L-arginine treatment may play in the cardiopulmonary status of children with SCD and VOE, with or without ACS. In the first phase of their work, the authors demonstrated decreased hospitalization time, decreased opioid use, and the absence of serious adverse events in children with SCD after receiving L-arginine therapy.7
 
This study was a prospective double-blind placebo-controlled randomized controlled trial of oral arginine supplementation in children with SCD aged 5-17 years, hospitalized with VOE with or without ACD. The patients were recruited in Nigeria between 2017 and 2019. The primary goal of this study was to evaluate the effects of L-arginine supplementation on cardiopulmonary hemodynamics in this patient population. All subjects were homozygous for hemoglobin SS and had sickle-cell-related pain greater than or equal to 7 on a 0- to 10-point severity scale. Subjects with known or suspected congenital heart disease were excluded. Potential subjects were approached for consent as soon as they presented to the emergency department or within 6 hours of admission. Enrolled patients were randomized to an oral L-arginine or oral placebo arm using a block randomized design. The subjects underwent transthoracic echocardiography on hospital days 1 and 5 and had several measurements done, including tricuspid regurgitation velocity (TRV), which was used to estimate pulmonary artery systolic pressure.
 
Of the 66 patients included, more than 60% had elevated TRV. Of the 66 patients, 35 were in the L-arginine arm (22 completed the study) and 31 in the placebo arm (25 completed the study). The authors were first able to demonstrate that L-arginine supplementation increased blood L-arginine levels as well as global bioavailable arginine levels. They also demonstrated that median TRV decreased by 22% in  subjects receiving oral L-arginine supplementation compared to a 3.8% decrease in subjects receiving placebo. In subjects who had elevated TRV, the L-arginine-supplemented group had an 82% reduction compared to subjects in the placebo arm, who had a 25% decrease.
 
This work adds to a growing body of evidence suggesting the benefits of L-arginine supplements to children with SCD and PH, which are known mortality and morbidity risk factors. Limitations of this study addressed by the authors include the use of echocardiography to assess hemodynamics (with reported sensitivity of 83% and specificity of 72% in diagnosing PH)8 well as limited patient severity and trial power to examine clinical outcomes such as hospital length of stay. However, at their worst, the development of ACS and VOD in children with SCD, worsened by PH, can lead to cardiopulmonary collapse requiring mechanical ventilation, exchange transfusions, and death. It therefore seems reasonable, particularly in resource-challenged areas, to provide L-arginine in this patient population.
 
References

  1. Jain S, Bakshi N, Krishnamurti L. Acute chest syndrome in children with sickle cell disease. Pediatr Allergy Immunol Pulmonol. 2017 Dec;30(4):191-201. https://pubmed.ncbi.nlm.nih.gov/29279787/
  2. Dessap AM, Leon R, Habibi A, et al. Pulmonary hypertension and cor pulmonale during severe acute chest syndrome in sickle cell disease. Am J Respir Crit Care Med. 2008 Mar 15;177(6):646-53. https://pubmed.ncbi.nlm.nih.gov/18174543/
  3. Morris CR, Kato GJ, Poljakovik M, et al. Dysregulated arginine metabolism, hemolysis-associated pulmonary hypertension, and mortality in sickle cell disease. JAMA. 2005 Jul 6;294(1):81-90. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2065861/
  4. Schulman SP, Becker LC, Kass DA, et al. L-arginine therapy in acute myocardial infarction: the Vascular Interaction With Age in Myocardial Infarction (VINTAGE MI) randomized clinical trial. JAMA. 2006 Jan 4;295(1):58-64. https://pubmed.ncbi.nlm.nih.gov/16391217/
  5. Fike CD, Dikalova A, Slaughter JC, Kaplowitz MR, Zhang Y, Aschner JL. Reactive oxygen species: reducing strategies improve pulmonary arterial responses to nitric oxide in piglets with chronic hypoxia-induced pulmonary hypertension. Antioxid Redox Signal. 2013 May 10;18(14):1727-1738. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3619184/
  6. Onalo R, Cilliers A, Cooper P, Morris CR. Arginine therapy and cardiopulmonary hemodynamics in hospitalized children with sickle cell anemia: a prospective, double-blinded, randomized placebo-controlled clinical trial. Am J Respir Crit Care Med. 2022 Jul 1;206(1):70-80. https://pubmed.ncbi.nlm.nih.gov/35426778/
  7. Onalo R, Cooper P, Cilliers A, et al. Randomized control trial of oral arginine therapy for children with sickle cell anemia hospitalized for pain in Nigeria. Am J Hematol. 2021 Jan;96(1):89-97. https://pubmed.ncbi.nlm.nih.gov/33075179/
  8. Harrison A, Hatton N, Ryan JJ. The right ventricle under pressure: evaluating the adaptive and maladaptive changes in the right ventricle in pulmonary arterial hypertension using echocardiography (2013 Grover Conference series). Pulm Circ. 2015 Mar;5(1):29-47. https://pubmed.ncbi.nlm.nih.gov/25992269/


Daniel E. Sloniewsky, MD, FCCM
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Daniel E. Sloniewsky, MD, FCCM
Daniel E. Sloniewsky, MD, FCCM, is an associate professor in the Division of Pediatric Critical Care Medicine in the Department of Pediatrics at Stony Brook Long Island Children’s Hospital. Dr. Sloniewsky is an editor of Concise Critical Appraisal.
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Posted: 8/17/2022 | 0 comments


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