Abstract
Introduction
Inhaled nitric oxide (NO) may be beneficial in the treatment of pulmonary hypertension, both of the newborn and in the adult respiratory distress syndrome. Up to now, serious systemic side effects have not been reported.
Objective
The effect of inhaled NO on superoxide anion production by neutrophils.
Design
Prospective study of a consecutive series of 15 neonates and infants.
Setting
Neonatal and paediatric ICUs with a total of 17 beds (university hospital).
Measurements and results
Superoxide anion production was determined by a flow cytometric method using dihydrorhodamine 123 (DHR) as an oxidative probe after the priming of neutrophils withN-formyl-methionyl-leucylphenylalanine (fMLP) or withEscherichia coli. The generated fluorescence was expressed as relative fluorescence intensity (RFI). Inhalation of NO for more than 24 h reduced the superoxide anion production by neutrophils stimulated withE. coli to below baseline values before NO inhalation (mRFI=158±25 vs 222±24;P=0.03). This decrease was more pronounced after more than 72 h (mRFI=133±17). At this time, superoxide anion production by fMLP-stimulated neutrophils was also decreased (mRFI=40±3, vs 57±5;P=0.03). The reduced capacity of superoxide production persisted throughout therapy with NO and lasted up to more than 4 days after the end of NO inhalation.
Conclusion
The results suggest that inhalation of NO in patients with pulmonary hypertension causes reduced superoxide anion production by neutrophils stimulated withE. coli or with fMLP. To determine the clinical importance of this systemic side effect with respect to bacterial infections, a randomized controlled study is necessary.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Pepke-Zaba, J, Higenbottam TW, Dinh-Xuan AT, Stone D, Wallwork J (1991) Inhaled nitric oxide as a cause of selective pulmonary vasodilatation in pulmonary hypertension. Lancet 338: 1173–1174
Rossaint R, Falke KJ, López F, Slama K, Pison V, Zapol WM (1993) Inhaled nitric oxide for the adult respiratory distress syndrome. N Engl J Med 328: 339–405
Journois D, Pouard P, Mauriat P, Malhere T, Vouhe P, Safran D (1994) Inhaled nitric oxide as a therapy for pulmonary hypertension after operations for congenital heart defects. J Thorac Cardiovasc Surg 107: 1129–1135
Zayek M, Wild L, Roberts JD, Morin FC (1993) Effect of nitric oxide on the survival rate and incidence of lung injury in newborn lambs with persistent pulmonary hypertension. J Pediatr 123: 947–952
Roberts JD, Polaner DM, Lang P, Zapol WM (1992) Inhaled nitric oxide in persistent pulmonary hypertension of the newborn. Lancet 340: 818–819
Kinsella JP, Neish SR, Shaffer E, Abman SH (1992) Low dose inhalational nitric oxide therapy in persistent pulmonary hypertension of the newborn. Lancet 340: 819–820
Levin DL, Heymann MA, Kitterman JA, Gregory GA, Phibbs RH, Rudolph AM (1976) Persistent pulmonary hypertension of the newborn. J Pediatr 89: 626–633
Moncada S, Higgs A (1993) Thel-arginine-nitric oxide pathway. N Engl J Med 329: 2002–2012
Gruetter CA, Gruetter DY, Lyon JE, Kadowitz PJ, Ignarro LJ (1981) Relationship between cyclic guanosine 3′: 5′-monophosphate formation and relaxation of coronary arterial smooth muscle by glyceryl trinitrate, nitroprusside, nitrate, and nitric oxide: effects of methylene blue and methemoglobin. J Pharmacol Exp Ther 219: 181–186
Naeda N, Laraizumi K, Kon K, et al. (1987) A kinetic study on function impairment of nitric oxide exposed rat erythrocytes. Environ Health Perspect 73: 171–177
Mellion BT, Ignarro LJ, Ohlstein EH, Pontecorvo EG, Hyman AL, Kadowitz PJ (1981) Evidence for the inhibitory role of guanosine 3′5′-monophosphate in ADP-induced human platelet aggregation in the presence of nitric oxide and related vasodilators. Blood 57: 946–955
Kubes P, Suzuki M, Granger DN (1991) Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc Natl. Acad Sci USA 88: 4651–4655
Clancy RM, Leszczynska-Piziak J, Abramson SB (1992) Nitric oxide, an endothelial cell relaxation factor, inhibits neutrophil superoxide anion production via a direct action on the NADPH oxidase. J Clin Invest 90: 1116–1121
Cummings JJ, D'Eugenio DB, Gross SJ (1989) A controlled trial of dexamethasone in preterm infants at high risk for bronchopulmonary dysplasia. N Engl J Med 320: 1505–1510
Harkavy KL, Scanlon JW, Chowdhry PK, Grylack LJ (1989) Dexamethasone therapy for chronic lung disease in ventilator- and oxygen-dependent infants: a controlled trial. J Pediatr 115: 979–983
Bass DA, Parce JW, Dechatelet LR, Szejda P, Seed MC, Thomas M (1983) Flow cytometric studies of oxidative product formation by neutrophils: a graded response to membrane stimulation. J Immunol 130: 1910–1917
Smith JA, Weidemann MJ (1993) Further characterization of the neutrophil oxidative burst by flow cytometry. J Immunol Methods 162: 261–268
Theodorsson-Norheim E (1986) Kruskal-Wallis test: BASIC computer program to perform nonparametric oneway analysis of variance and multiple comparisons on ranks of several independent samples. Comput Methods Programs Biomed 23: 57–62
Peltola H, Jaakola M (1988) C-reactive protein in early detection of bacteremic versus viral infections in immunocompetent compromised children. J Pediatr 113: 641–646
Pourcyrous M, Bada, HS, Korones SB, Baselski V, Wong SP (1993) Significance of serial C-reactive protein responses in neonatal infection and other disorders. Pediatrics 92: 431–435
Kinsella JP, Abman SH (1993) Inhalational nitric oxide therapy for persistent pulmonary hypertension of the newborn. Pediatrics 91: 997–998
Bone RC (1993) A new therapy for the adult respiratory distress syndrome. N Engl J Med 328: 431–432
Finer NN, Etches PC, Kamstra B, Tierney AJ, Peliowski A, Ryan CA (1994) Inhaled nitric oxide in infants referred for extracorporeal membrane oxygenation: dose response. J Pediatr 124: 302–308
Babior BM (1984) The respiratory burst of phagocytes. J Clin Invest 73: 599–601
Dewald B, Baggiolini M, Curnutte JT, Babior BM (1979) Subcellular localization of the superoxide-forming enzyme in human neutrophils. J Clin Invest 63: 21–29
Tauber AI (1987) Protein kinase C and the activation of the human neutrophil NADPH-oxidase. Blood 69: 711–720
Combadiere C, Benna JE, Pedruzzi E, Hakim J, Perianin A (1993) Stimulation of the human neutrophil respiratory burst by formyl peptides is primed by a protein kinase inhibitor, staurosporine. Blood 82: 2890–2898
Curnutte JT, Whitten DM, Babior BM (1974) Defective superoxide production by granulocytes from patients with chronic granulomatous disease. N Engl J Med 290: 593–597
Bass DA, Olbrantz P, Szejda P, Seeds MC, McCall CE (1986) Subpopulations of neutrophils with increased oxidative product formation in blood of patients with infection. J Immunol 136: 860–866
Elbim C, Chollet-Martin S, Bailly S, Hakim J, Gougerot-Pocidalo MA (1993) Priming of polymorphonuclear neutrophils by tumor necrosis factor α in whole blood: identification of two polymorphonuclear neutrophil subpopulations in response to formyl-peptides. Blood 82: 633–640
Balazovich KJ, Almeida HI, Boxer LA (1991) Recombinant human G-CSF and GM-CSF prime human neutrophils for superoxide production through different signal transduction mechanisms. J Lab Clin Med 118: 576–584
Sullivan GW, Carper HT, Mandell GL (1993) The effect of three human recombinant hematopoietic growth factors (granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, and interleukin-3) on phagocyte oxidative activity. Blood 81: 1863–1870
Nielson CP, Bayer C, Hodson S, hadjokas N (1992) Regulation of the respiratory burst by cyclic 3′,5′-AMP, an association with inhibition of arachidonic acid release. J Immunol 149: 4036–4040
Moncada S (1992) Thel-arginine: nitric oxide pathway. Acta Physiol Scand 145: 201–227
Ialenti A, Ianaro A, Moncada S, Di Rosa M (1992) Modulation of acute inflammation by endogenous nitric oxide. Eur J Pharmacol 211: 177–182
Nathan CF (1987) Neutrophil activation on biological surfaces: massive secretion of hydrogen peroxide in response to products of macrophages and lymphocytes. J Clin Invest 80: 1550–1556
Author information
Authors and Affiliations
Additional information
The study was supported in part by a grant (39-1993, 40-1994) from the Fakultät für Klinische Medizin Mannheim, Universität Heidelberg
Rights and permissions
About this article
Cite this article
Gessler, P., Nebe, T., Birle, A. et al. A new side effect of inhaled nitric oxide in neonates and infants with pulmonary hypertension: Functional impairment of the neutrophil respiratory burst. Intensive Care Med 22, 252–258 (1996). https://doi.org/10.1007/BF01712246
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF01712246