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CASE REPORT |
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Year : 2014 | Volume
: 7
| Issue : 5 | Page : 661-664 |
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Persistent pulmonary hypertension and infantile hypertrophic pyloric stenosis in a neonate: Reduced nitric oxide levels could be a common etiological factor
Sudhir Malwade, Sharad Agarkhedkar, Himanshi Joshi
Department of Pediatrics, Padmashree Dr. D. Y. Patil Medical College, Hospital and Research Centre, Pimpri, Pune, Maharashtra, India
Date of Web Publication | 10-Sep-2014 |
Correspondence Address: Sudhir Malwade Associate Professor, Department of Pediatrics, Dr. D. Y. Patil Medical College, Hospital and Research Centre, Pimpri, Pune, Maharashtra India
Source of Support: None, Conflict of Interest: None | Check |
DOI: 10.4103/0975-2870.140488
Nitric oxide (NO) is an important mediator of biological functions. It is a potent vasodilator and has an effect on smooth muscle relaxation and proliferation. Absence or shortage of NO plays a role in the pathogenesis of persistent pulmonary hypertension and hypertrophic pyloric stenosis. A 3.2 kg male, full term baby, delivered through vaginal route in hospital settings presented with curdy white and non-bilious vomiting following feeds on 22 nd day of life. Baby had a history of neonatal intensive care unit admission for 4 days for respiratory distress due to meconium stained liquor. 2D echocardiography revealed pulmonary hypertension. On 22 nd day of life when vomiting began, baby was vigorous, irritable but examined well. Since, these two conditions occurred simultaneously in the same baby hence postulation that NO might have some role in both diseases. Keywords: Hypertrophic pyloric stenosis, nitric oxide, persistent pulmonary hypertension
How to cite this article: Malwade S, Agarkhedkar S, Joshi H. Persistent pulmonary hypertension and infantile hypertrophic pyloric stenosis in a neonate: Reduced nitric oxide levels could be a common etiological factor. Med J DY Patil Univ 2014;7:661-4 |
Introduction | | |
Since the breakthrough discovery in 1987 that the endothelium-derived relaxing factor was nitric oxide (NO), this colorless and odorless free radical gas became increasingly recognized as a key factor in human physiology and disease. It is endogenously produced by a group of enzymes known as nitric oxide synthases (NOS).
It's functions are diverse and involve smooth muscle relaxation, platelet inhibition, central and autonomic neurotransmission, tumor cell lysis, bacterial killing and stimulation of hormonal release. [1]
In humans, NO is a vital cellular signaling molecule having many physiological and pathological functions. NO is of critical importance as a mediator of vasodilation in blood vessels. Pulmonary arterial vasomotor tone is modulated by endothelin-1 (ET-1), NO and prostacyclin. NO synthetase of endothelial origin, under stress converts L-arginine to NO, which in turn raise the levels of cyclic guanosine monophosphate (cGMP) in pulmonary vascular smooth muscles. This rise in cGMP cause relaxation of smooth muscles mediated through protein kinase. [2]
Animal studies have shown that persistent pulmonary hypertension follows impaired endothelial release of NO and increased production of vasoconstrictors like ET-1. [3]
NO in pulmonary hypertension - NO is a potent pulmonary vasodilator that is produced locally in the lung and has an effect on smooth muscle relaxation and proliferation. It is involved in pulmonary neurotransmission, host defense, airway mucus secretion, inflammation and cytotoxicity. [1]
NO also causes relaxation of gastrointestinal smooth muscle. Impairment of neuronal nitric oxide synthase (nNOS) synthesis has been implicated in infantile hypertrophic pyloric stenosis. [4]
Significant progress in understanding of its biological effects has led to a better understanding of pathophysiology of persistent pulmonary hypertension and congenital hypertrophic pyloric stenosis and development of new therapies in recent years.
Case Report | | |
A male baby, weighing 3 kg, presented to us with history of projectile non-bilious vomiting on 22 nd day of life. The baby was delivered vaginally and was vigorous, weighing 3.2 kg. Antenatal scans were normal. There was no history of selective serotonin uptake inhibitor use in mother. Baby was admitted in neonatal intensive care unit for respiratory distress attributed to meconium stained liquor. Baby was initially put on 40% oxygen for 5 days, on 10% dextrose for 4 days feeds started on 2 nd day and gradually increased. Hemogram and X-ray were normal The baby's echocardiography revealed pulmonary artery hypertension of 42 mmHg, mean blood pressure being 54 mmHg with right to left shunt through patent foramen ovale (PFO) and patent ductus arteriosus (PDA). Baby was put on sildenafil and continued until 14 days. Baby got discharged at 6 th day of life.
Baby was breastfeeding well post discharge up until 3 weeks of life, when he began to have non-bilious projectile vomiting just after the feeds, there was no history of loose motions and decreased urine output. Peristalsis was well heard in all quadrants and there was a visible olive shaped mass in the abdomen which was more prominent after feeding.
The baby's saturation on room air was 88%, after initial oxygen provision, no further oxygen was needed, baby was vigorous. Heart rate was normal. There was a loud P2 with absent murmur. There were signs of Grade 2 dehydration, sugar was normal.
Neurologically the baby was normal. Blood gas was consistent with metabolic alkalosis. Septic screen was negative.
Ultrasonography showed a distended stomach with pylorus hypertrophied, tubular, 4.5 mm thick and length 15 mm testes were descended. There were no other midline defects.
The baby was kept nil by mouth. Fluid given was 10% dextrose plus electrolytes plus calcium a per neonatal requirement. The baby underwent Ramstedt pyloromyotomy successfully [Figure 1]. He was discharged on full enteral feeds.
Discussion | | |
Persistent pulmonary hypertension of newborn (PPHN) is defined as the failure of the normal circulatory transition at birth resulting in marked pulmonary hypertension with right to left shunting through the fetal channels (PFO and PDA) causing severe hypoxemia. [5] Pulmonary hypertension is defined as a mean pulmonary arterial pressure of >25 mmHg as per the British Cardiac Society Guidelines and Medical Practice Committee, 2001 and tricuspid regurgitation with a Doppler velocity of more than 2.5 m/s.
Severe PPHN has been estimated to occur in 2 out of 1000 live born infants and some degree of pulmonary hypertension complicates the course of more than 10% of all neonates with respiratory failure. [6]
Several vasoactive substances are known to modulate the vasomotor tone of the pulmonary arteries, including ET-1, NO and prostacyclin (PGI2). Vasoconstriction is also promoted by basal production of vasodilators like prostacyclin and NO proving their role in persistent pulmonary hypertension. NO acts through cGMP which leads to a decrease in calcium influx and relaxation of smooth muscle cells by stimulating protein kinase G. Many experimental studies have demonstrated impaired endothelin release of NO and increased production of vasoconstrictors, e.g., ET-1 in newborns with pulmonary hypertension. [7]
Other factors which have been associated with PPHN are black and Asian males as well as SSRI intake during the third trimester of pregnancy.
Genetic factors may increase susceptibility to pulmonary hypertension. Although persistent pulmonary hypertension of newborn is often associated with perinatal distress and meconium staining, idiopathic persistent pulmonary hypertension of the newborn can present without signs of acute perinatal distress.
Congenital hypertrophic pyloric stenosis-also known as infantile hypertrophic pyloric stenosis (IHPS), is the most common cause of intestinal obstruction in infancy. Usual age of presentation is 3 rd week of life, vomiting is non-bilious, projectile and neonate is usually not sick except mild to moderate dehydration. IHPS occurs secondary to hypertrophy and hyperplasia of the muscular layers of the pylorus, causing a functional gastric outlet obstruction. [8] The pyloric canal becomes lengthened and the whole pylorus becomes thickened.
The causes of infantile hypertrophic pyloric stenosis are multifactorial. Both environmental factors and hereditary factors are believed to be contributory. Possible etiologic factors include deficiency of NOS containing neurons, abnormal myenteric plexus innervations, nfantile hypergastrinemia and exposure to macrolide antibiotics.
NO and congenital hypertrophic pyloric stenosis - the muscular layer here is deficient in the quantity of nerve terminals, NOS activity, messenger ribonucleic acid production for NOS and interstitial cells of Cajal. It is postulated that this abnormal innervation of the muscular layer leads to failure of relaxation of pyloric muscle; increased synthesis of growth factors; and subsequent hypertrophy, hyperplasia and obstruction. NO has been demonstrated as a major inhibitory nonadrenergic, non-cholenergic neurotransmitter in the GI tract, causing relaxation of smooth muscle of the myenteric plexus upon its release. Impairment of this nNOS synthesis has been implicated in IHPS and achalasia, diabetic gastroparesis and Hirschsprung disease. [8]
NOS is one of the most regulated enzymes in biology, the different forms of NO synthetase have been classified as follows: [9]
Chromosomally the eNOS and n NOS had no connection that could be explained. Brouwers and Waals-van de Wal presented a neonate with pulmonary hypertension caused by meconium aspiration syndrome followed by hypertrophic pyloric stenosis and pyloromyotomy performed. [10] They state that shortage of NO plays a role in the pathogenesis of both hypertrophic pyloric stenosis and persistent pulmonary hypertension. This association has not been described before and can be explained by a lowered plasma concentration of arginine leading to deficient NO synthesis in the affected organ systems. The precursor of NO is arginine, a urea-cycle intermediate. Hecker et al. stated that low concentrations of arginine correlates with the presence of persistent pulmonary hypertension in newborns. Endothelial cells generate NO from precursor l-arginine, an amino acid supplied by urea cycle. [11] Theoretically a link exists between NO production and the urea cycle. Carbamoyl-phosphate synthetase catalyzes the rate determining step of the urea cycle. Genetic variations in the activity of this enzyme affect the downstream availability of the urea cycle intermediates. [12]
They described a C-to-A nucleotide transversion in exon 36 of the gene that encodes carbamoyl-phosphate synthase, resulting in the substitution of asparagines for threonine at position 1405 (T1405N), which is in the critical N-acetylglutamate-binding domain. [13] Low concentrations of urea cycle intermediates and NO precursors arginine and citrulline correlates with the presence of pulmonary hypertension in neonates. The distribution of the polymorphism at position 1405 in carbamoyl-phosphate synthetase varies between infants with and those without persistent pulmonary hypertension.
Conclusion | | |
NO plays a diverse role in human physiology and disease. Babies recovering from severe PPHN if develops feeding intolerance, a possibility of CHPS should be kept in mind. Further studies are required to prove the correlation between hypertrophic pyloric stenosis and persistent pulmonary hypertension, if and when it occurs together.
References | | |
1. | Tonelli AR, Haserodt S, Aytekin M, Dweik RA. Nitric oxide deficiency in pulmonary hypertension: Pathobiology and implications for therapy. Pulm Circ 2013;3:20-30. |
2. | Schmidt HH, Schmidt PM, Stasch JP. NO- and haem-independent soluble guanylate cyclase activators. Handb Exp Pharmacol 2009;191:309-39. |
3. | Villamor E, Le Cras TD, Horan MP, Halbower AC, Tuder RM, Abman SH. Chronic intrauterine pulmonary hypertension impairs endothelial nitric oxide synthase in the ovine fetus. Am J Physiol 1997;272:L1013-20. |
4. | Takahashi T. Pathophysiological significance of neuronal nitric oxide synthase in the gastrointestinal tract. J Gastroenterol 2003;38:421-30. [PUBMED] |
5. | Cabral JE, Belik J. Persistent pulmonary hypertension of the newborn: Recent advances in pathophysiology and treatment. J Pediatr (Rio J) 2013;89:226-42. |
6. | Steinhorn RH. Neonatal pulmonary hypertension. Pediatr Crit Care Med 2010;11:S79-84. [PUBMED] |
7. | Persistent newborn pulmonary hypertension. Available from: http://www.emedicine.medscape.com/article/898437. [Last updated on 2013 Sep 13; Last cited on 2013 Sep 23]. |
8. | Aspelund G, Langer JC. Current management of hypertrophic pyloric stenosis. Semin Pediatr Surg 2007;16:27-33. |
9. | Nitric oxide synthetase. Available from: http://www.Wikipedia, en.wikipedia,.org/wiki/Nitric_oxide_synthase. [Last cited on 2013 Jul 23]. |
10. | Brouwers AG, Waals-van de Wal CM. Hypertrophic pyloric stenosis and pulmonary hypertension in a neonate. A common mechanism? Acta Paediatr 2009;98:1064-5. |
11. | Hecker M, Sessa WC, Harris HJ, Anggård EE, Vane JR. The metabolism of L-arginine and its significance for the biosynthesis of endothelium-derived relaxing factor: Cultured endothelial cells recycle L-citrulline to L-arginine. Proc Natl Acad Sci U S A 1990;87:8612-6. |
12. | NORD Guides for Physicians. The physician′s guide to urea cycle disorders. Available from: http://www.nordphysicianguides.org/wpcontent/uploads/2012/02/NORD_Physiian_Guide_to_Urea_Cycle_Disorders.pdf.]. [Last cited on 2013 Jul 23]. |
13. | Summar ML, Gainer JV, Pretorius M, Malave H, Harris S, Hall LD, et al. Relationship between carbamoyl-phosphate synthetase genotype and systemic vascular function. Hypertension 2004;43:186-91. |
[Figure 1]
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