Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Low vasopressin and progression of neonatal sepsis to septic shock: a prospective cohort study


The study objective was to analyze the association between low plasma vasopressin and progression of sepsis to septic shock in neonates < 34 weeks gestation. Septic neonates of < 34 weeks gestation were consecutively enrolled; moribund neonates and those with major malformations were excluded. Subjects were monitored for progression of sepsis to septic shock over the first 7 days from enrolment. Plasma vasopressin levels and inducible nitric oxide synthase levels were measured at the onset of sepsis (T0), severe sepsis (T1), and septic shock (T2). Primary outcome was plasma vasopressin levels at the point of sepsis in those who progressed to septic shock in comparison with matched nested controls in the non-progression group. Forty-nine (47%) enrolled subjects developed severe sepsis or septic shock. Plasma vasopressin levels (pg/ml) at the onset of sepsis were significantly low in those who progressed to septic shock (median (IQR), 31 (2.5–80) versus 100 (12–156); p = 0.02). After adjusting for confounders, vasopressin levels were independently associated with progression to septic shock (adjusted OR (95% CI), 0.97 (0.96, 0.99); p = 0.01).

Conclusion: Preterm septic neonates who progressed to septic shock had suppressed vasopressin levels before the onset of shock. Low vasopressin levels were independently associated with progression to septic shock.

What is known:
• In animal sepsis models and adult septic patients, exuberant production of nitric oxide metabolites and low vasopressin levels have been reportedly associated with progression to septic shock.
• Vasopressin levels have been variably reported as low as well as elevated in children with septic shock.
What is New:
• Preterm neonates who progressed from sepsis to septic shock had significantly lower levels of vasopressin before the onset of shock in comparison with those who did not progress.
• Low vasopressin levels independently predicted the progression from sepsis to septic shock in this population.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3



Cerebrospinal fluid


Inducible nitric oxide synthase


Inter-quartile range


Mean difference


Organ dysfunction


Odds ratio


Receiver operating characteristic curve


Risk ratio


Systemic inflammatory response syndrome


Score for neonatal acute physiology


  1. 1.

    Aird WC (2003) The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome. Blood 101(10):3765–3777.

  2. 2.

    Singer M (2014) The role of mitochondrial dysfunction in sepsis-induced multi-organ failure. Virulence 5(1):66–72.

  3. 3.

    Kilbourn RG, Griffith OW (1992) Overproduction of nitric oxide in cytokine-mediated and septic shock. J Natl Cancer Inst 84(11):827–831.

  4. 4.

    Levy B, Collin S, Sennoun N, Ducrocq N, Kimmoun A, Asfar P, Perez P, Meziani F (2010) Vascular hyporesponsiveness to vasopressors in septic shock: from bench to bedside. Intensive Care Med 36(12):2019–2029.

  5. 5.

    Landry DW, Levin HR, Gallant EM, Ashton RC Jr, Seo S, D’Alessandro D, Oz MC, Oliver JA (1997) Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation 95(5):1122–1125.

  6. 6.

    Choi SJ, Jefferies HE, Wills BC et al (2003) Vasopressin deficiency in pediatric septic shock. Pediatr Crit Care Med 4

  7. 7.

    Rosenzweig EB, Starc TJ, Chen JM, Cullinane S, Timchak DM, Gersony WM, Landry DW, Galantowicz ME (1999) Intravenous arginine-vasopressin in children with vasodilatory shock after cardiac surgery. Circulation 100(19 Suppl):II182–II186.

  8. 8.

    Leclerc F, Walter-Nicolet E, Leteurtre S, Noizet O, Sadik A, Cremer R, Fourier C (2003) Admission plasma vasopressin levels in children with meningococcal septic shock. Intensive Care Med 29(8):1339–1344.

  9. 9.

    Lodha R, Vivekanandhan S, Sarthi M, Kabra SK (2006) Serial circulating vasopressin levels in children with septic shock. Pediatr Crit Care Med 7(3):220–224.

  10. 10.

    Brealey D, Brand M, Hargreaves I, Heales S, Land J, Smolenski R, Davies NA, Cooper CE, Singer M (2002) Association between mitochondrial dysfunction and severity and outcome of septic shock. Lancet 360(9328):219–223.

  11. 11.

    Aydemir O, Ozcan B, Yucel H, Bas AY, Demirel N (2015) Asymmetric dimethylarginine and L-arginine levels in neonatal sepsis and septic shock. J Matern Fetal Neonatal Med 28(8):977–982.

  12. 12.

    Barrett LK, Singer M, Clapp LH (2007) Vasopressin: mechanisms of action on the vasculature in health and in septic shock. Crit Care Med 35(1):33–40.

  13. 13.

    Dunser MW, Wenzel V, Mayr AJ, Hasibeder WR (2003) Management of vasodilatory shock: defining the role of arginine vasopressin. Drugs 63(3):237–256.

  14. 14.

    Treschan TA, Peters J (2006) The vasopressin system: physiology and clinical strategies. Anesthesiology 105(3):599–612; quiz 639-540.

  15. 15.

    Shivanna B, Rios D, Rossano J, Fernandes CJ, Pammi M (2013) Vasopressin and its analogues for the treatment of refractory hypotension in neonates. Cochrane Database Syst Rev 3:CD009171.

  16. 16.

    Goldstein B, Giroir B, Randolph A, International Consensus Conference on Pediatric S (2005) International pediatric sepsis consensus conference: definitions for sepsis and organ dysfunction in pediatrics. Pediatr Crit Care Med 6(1):2–8.

  17. 17.

    Wynn JL, Wong HR (2010) Pathophysiology and treatment of septic shock in neonates. Clin Perinatol 37(2):439–479.

  18. 18.

    SN T (2005) Johns Hopkins: the Harriet lane handbook - a manual for pediatric house officers, 17th edn. Elsevier Mosby, Philadelphia

  19. 19.

    Singh SA, Dutta S, Narang A (2003) Predictive clinical scores for diagnosis of late onset neonatal septicemia. J Trop Pediatr 49(4):235–239.

  20. 20.

    Chiesa C, Natale F, Pascone R, Osborn JF, Pacifico L, Bonci E, De Curtis M (2011) C reactive protein and procalcitonin: reference intervals for preterm and term newborns during the early neonatal period. Clin Chim Acta 412(11–12):1053–1059.

  21. 21.

    Dellinger RP, Levy MM, Rhodes A, Annane D, Gerlach H, Opal SM, Sevransky JE, Sprung CL, Douglas IS, Jaeschke R, Osborn TM, Nunnally ME, Townsend SR, Reinhart K, Kleinpell RM, Angus DC, Deutschman CS, Machado FR, Rubenfeld GD, Webb S, Beale RJ, Vincent JL, Moreno R, Surviving Sepsis Campaign Guidelines Committee including The Pediatric S (2013) Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med 39(2):165–228.

  22. 22.

    Richardson DK, Corcoran JD, Escobar GJ, Lee SK (2001) SNAP-II and SNAPPE-II: simplified newborn illness severity and mortality risk scores. J Pediatr 138(1):92–100.

  23. 23.

    Youden WJ (1950) Index for rating diagnostic tests. Cancer 3(1):32–35.<32::aid-cncr2820030106>;2-3

  24. 24.

    Alvarez S, Boveris A (2004) Mitochondrial nitric oxide metabolism in rat muscle during endotoxemia. Free Radic Biol Med 37(9):1472–1478.

  25. 25.

    Boveris A, Alvarez S, Navarro A (2002) The role of mitochondrial nitric oxide synthase in inflammation and septic shock. Free Radic Biol Med 33(9):1186–1193

  26. 26.

    Carson DS, Howerton CL, Garner JP, Hyde SA, Clark CL, Hardan AY, Penn AA, Parker KJ (2014) Plasma vasopressin concentrations positively predict cerebrospinal fluid vasopressin concentrations in human neonates. Peptides 61:12–16.

  27. 27.

    Stewart JM, Zeballos GA, Woolf PK, Dweck HS, Gewitz MH (1988) Variable arginine vasopressin levels in neonatal congestive heart failure. J Am Coll Cardiol 11(3):645–650.

  28. 28.

    Carrara M, Baselli G, Ferrario M (2015) Mortality prediction model of septic shock patients based on routinely recorded data. Comput Math Methods Med 2015:761435.

  29. 29.

    Langley RJ, Tsalik EL, van Velkinburgh JC, Glickman SW, Rice BJ, Wang C, Chen B, Carin L, Suarez A, Mohney RP, Freeman DH, Wang M, You J, Wulff J, Thompson JW, Moseley MA, Reisinger S, Edmonds BT, Grinnell B, Nelson DR, Dinwiddie DL, Miller NA, Saunders CJ, Soden SS, Rogers AJ, Gazourian L, Fredenburgh LE, Massaro AF, Baron RM, Choi AM, Corey GR, Ginsburg GS, Cairns CB, Otero RM, Fowler VG Jr, Rivers EP, Woods CW, Kingsmore SF (2013) An integrated clinico-metabolomic model improves prediction of death in sepsis. Sci Transl Med 5(195):195ra195.

  30. 30.

    Zuev SM, Kingsmore SF, Gessler DD (2006) Sepsis progression and outcome: a dynamical model. Theor Biol Med Model 3:8.

  31. 31.

    Kumar D, Kumar A, Singh S, Tilak R (2015) Candidemia-induced pediatric sepsis and its association with free radicals, nitric oxide, and cytokine level in host. J Crit Care 30(2):296–303.

  32. 32.

    Wang L, Zhu YP, Li MX (2011) Role of hypoxia-inducible factor-1alpha endothelin-1 and inducible nitric oxide synthase in the pathogenesis of hypoxia-induced pulmonary hypertension of the newborn. Zhongguo Dang Dai Er Ke Za Zhi 13(1):8–11

  33. 33.

    Bidegain M, Greenberg R, Simmons C, Dang C, Cotten CM, Smith PB (2010) Vasopressin for refractory hypotension in extremely low birth weight infants. J Pediatr 157(3):502–504.

  34. 34.

    Bondi DSOK (2017) Vasopressin and hemodynamic effects on the neonate. NeoReviews 18(8):e460–e471.

  35. 35.

    Ikegami H, Funato M, Tamai H, Wada H, Nabetani M, Nishihara M (2010) Low-dose vasopressin infusion therapy for refractory hypotension in ELBW infants. Pediatr Int 52(3):368–373.

  36. 36.

    Meyer S, Gottschling S, Baghai A, Wurm D, Gortner L (2006) Arginine-vasopressin in catecholamine-refractory septic versus non-septic shock in extremely low birth weight infants with acute renal injury. Crit Care 10(3):R71.

  37. 37.

    Rios DR, Kaiser JR (2015) Vasopressin versus dopamine for treatment of hypotension in extremely low birth weight infants: a randomized, blinded pilot study. J Pediatr 166(4):850–855.

  38. 38.

    Choong K, Kissoon N (2008) Vasopressin in pediatric shock and cardiac arrest. Pediatr Crit Care Med 9(4):372–379.

  39. 39.

    Morgenthaler NG, Muller B, Struck J, Bergmann A, Redl H, Christ-Crain M (2007) Copeptin, a stable peptide of the arginine vasopressin precursor, is elevated in hemorrhagic and septic shock. Shock 28(2):219–226.

Download references

Financial information

The study was supported by an institute special research grant (Postgraduate Institute of Medical Education and Research, Chandigarh – PGIMER/Spl research grant/2016) and dissertation grant (Indian council of medical research – 3/2/March-2016/PG-Thesis-HRD(19)).

Author information

Abhishek Somasekhara Aradhya collected the data, analyzed the data, drafted the initial manuscript and reviewed the manuscript.

Venkataseshan Sundaram conceptualized and designed the study, designed the data collection tool, supervised the conduct of the study, analyzed the data, and critically edited the manuscript.

Naresh Sachdeva contributed to the study design and conducted an analysis of metabolic and molecular parameters and critically edited the manuscript.

Sourabh Dutta, Shiv Sajan Saini, and Praveen Kumar contributed to designing the study and the data collection tool and critically reviewed the data analysis.

All authors read and approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Correspondence to Venkataseshan Sundaram.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in the current study involving human participants were in accordance with the ethical standards of the institutional research committee (Institute Ethics Committee, PGIMER) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Communicated by Daniele De Luca

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Aradhya, A.S., Sundaram, V., Sachdeva, N. et al. Low vasopressin and progression of neonatal sepsis to septic shock: a prospective cohort study. Eur J Pediatr (2020).

Download citation


  • Vasopressin
  • Neonate
  • Sepsis
  • Septic shock
  • Inducible nitric oxide synthase