To evaluate the association of severe vitamin D deficiency with clinically important outcomes in children with septic shock.
Methods:
We enrolled children ≤17 years with septic shock prospectively over a period of 6 months. We estimated 25-hydroxyvitamin D [25 (OH) D] levels at admission and 72 hours. Severe deficiency was defined as serum 25 (OH) <10 ng/mL. We performed univariate and multivariate analysis to evaluate association with clinically important outcomes.
Results:
Forty-three children were enrolled in the study. The prevalence of severe vitamin D deficiency was 72% and 69% at admission and 72 hours, respectively. On univariate analysis, severe vitamin D deficiency at admission was associated with lower rates of shock reversal, 74% (23) versus 25% (3); relative risk (95% confidence interval [CI]): 2.9 (1.09-8.08), at 24 hours and greater need for fluid boluses (75 vs 59 mL/kg). On multivariate analysis, nonresolution of shock at 24 hours was significantly associated with severe vitamin D deficiency after adjusting for other key baseline and clinical variables, adjusted odds ratio (95% CI): 12 (2.01-87.01); 0.01.
Conclusion:
The prevalence of severe vitamin D deficiency is high in children with septic shock admitted to pediatric intensive care unit. Severe vitamin D deficiency at admission seems to be associated with lower rates of shock reversal at 24 hours of ICU stay. Our study provides preliminary data for planning interventional studies in children with septic shock and severe vitamin D deficiency.
MaddenKFeldmanHASmithEM. Vitamin D deficiency in critically ill children. Pediatrics. 2012;130(3):421–428.
2.
McNallyJDMenonKChakrabortyP. The association of vitamin D status with pediatric critical illness. Pediatrics. 2012;130(3):429–436.
3.
RippelCSouthMButtWWShekerdemianLS. Vitamin D status in critically ill children. Intensive Care Med. 2012;38(12):2055–2062.
4.
EbenezerKJobVAntonisamyBDawoduAManivachaganMNSteinhoffM. Serum vitamin D status and outcome among critically ill children admitted to the pediatric intensive care unit in South India. Indian J Pediatr. 2016;83(2):120–125.
5.
SankarJLothaWIsmailJAnubhutiCMeenaRSSankarMJ. Vitamin D deficiency and length of pediatric intensive care unit stay: a prospective observational study. Ann Intensive Care. 2016;6(1):3.
6.
WangTTNestelFPBourdeauV. Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol Baltim Md. 2004;173(5):2909–2912.
7.
GombartAFBorregaardNKoefflerHP. Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1,25-dihydroxyvitamin D3. FASEB J. 2005;19(9):1067–1077.
8.
LiuPTStengerSLiH. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science. 2006;311(5768):1770–1773.
9.
VerwayMBouttierMWangTT. Vitamin D induces interleukin-1β expression: paracrine macrophage epithelial signaling controls M. tuberculosis infection. PLoS Pathog. 2013;9(6):e1003407.
10.
RockettKABrookesRUdalovaIVidalVHillAVKwiatkowskiD. 1,25-dihydroxyvitamin D3 induces nitric oxide synthase and suppresses growth of Mycobacterium tuberculosis in a human macrophage-like cell line. Infect Immun. 1998;66(11):5314–5321.
11.
JefferyLEWoodAMQureshiOS. Availability of 25-hydroxyvitamin D(3) to APCs controls the balance between regulatory and inflammatory T cell responses. J Immunol Baltim Md. 2012;189(11):5155–5164.
12.
HewisonM. Vitamin D and immune function: an overview. Proc Nutr Soc. 2012;71(1):50–61.
13.
MoraJRIwataMvon AndrianUH. Vitamin effects on the immune system: vitamins A and D take centre stage. Nat Rev Immunol. 2008;8(9):685–698.
14.
De HaanKGroeneveldAde GeusH. Vitamin D deficiency as a risk factor for infection, sepsis and mortality in the critically ill: systematic review and meta-analysis. Crit Care Lond Engl. 2014;18(6):660.
15.
ArboledaJFUrcuqui-InchimaS. Vitamin D-regulated microRNAs: are they protective factors against dengue virus infection?[published online May 11, 2016]. Adv Virol. 2016;2016:1016840.
16.
CetinkayaMCekmezFBuyukkaleG. Lower vitamin D levels are associated with increased risk of early-onset neonatal sepsis in term infants. J Perinatol. 2015;35(1):39–45.
17.
PonnarmeniSKumar AnguranaSSinghiS. Vitamin D deficiency in critically ill children with sepsis. Paediatr Int Child Health. 2016;36(1):15–21.
18.
OnwunemeCCarrollADohertyD. Inadequate vitamin D levels are associated with culture positive sepsis and poor outcomes in paediatric intensive care. Acta Paediatr. 2015;104(10):e433–e438.
19.
WatsonRSCarcilloJALinde-ZwirbleWTClermontGLidickerJAngusDC. The epidemiology of severe sepsis in children in the United States. Am J Respir Crit Care Med. 2003;167(5):695–701.
20.
SankarJSankarMJSureshCP. Early goal-directed therapy in pediatric septic shock: comparison of outcomes “with” and “without” intermittent superior venacaval oxygen saturation monitoring: a prospective cohort study*. Pediatr Crit Care Med. 2014;15(4):e157–e167.
21.
KaurGVinayakNMittalKKaushikJSAamirM. Clinical outcome and predictors of mortality in children with sepsis, severe sepsis, and septic shock from Rohtak, Haryana: a prospective observational study. Indian J Crit Care Med. 2014;18(7):437–441.
22.
WagnerCLGreerFR; American Academy of Pediatrics Section on Breastfeeding; American Academy of Pediatrics Committee on Nutrition. Prevention of rickets and vitamin D deficiency in infants, children, and adolescents. Pediatrics. 2008;122(5):1142–1152.
23.
HolickMFBinkleyNCBischoff-FerrariHA. Endocrine Society. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(7):1911–1930.
24.
RossACMansonJEAbramsSA. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know?J Clin Endocrinol Metab. 2011;96(7):53–58.
25.
ThomasMKLloyd-JonesDMThadhaniRI. Hypovitaminosis D in medical inpatients. N Engl J Med. 1998;338(12):777–783.
26.
QuraishiSABittnerEAChristopherKBCamargoCA. Vitamin D status and community-acquired pneumonia: results from the Third National Health and Nutrition Examination Survey. PLoS One. 2013;8(11):e81120.
27.
MuheLLulsegedSMasonKESimoesEA. Case–control study of the role of nutritional rickets in the risk of developing pneumonia in Ethiopian children. Lancet. 1997;349(9068):1801–1804.
28.
QuraishiSACamargoCA. Vitamin D in acute stress and critical illness. Curr Opin Clin Nutr Metab Care. 2012;15(6):625–634.
29.
de PaulaFJRosenCJ. Vitamin D safety and requirements. Arch Biochem Biophys. 2012;523(1):64–72.
30.
QuraishiSADe PascaleGNeedlemanJS. Effect of cholecalciferol supplementation on vitamin D status and cathelicidin levels in sepsis: a randomized, placebo-controlled trial. Crit Care Med. 2015;43(9):1928–1937.
31.
RaoDSVillaneuvaAMathewsM. Histologic evolution of vitamin D – depletion in patients with intestinal malabsorption or dietary deficiency. In: FrameBPottsJT, eds. Clinical Disorders of Bone and Mineral Metabolism. Amsterdam, Netherlands: Excerpta Medica; 1983:224–226.
32.
MatthewsLRAhmedYWilsonKLGriggsDDDannerOK. Worsening severity of vitamin D deficiency is associated with increased length of stay, surgical intensive care unit cost, and mortality rate in surgical intensive care unit patients. Am J Surg. 2012;204(1):37–43.
33.
CecchiABonizzoliMDouarS. Vitamin D deficiency in septic patients at ICU admission is not a mortality predictor. Minerva Anestesiol. 2011;77(12):1184–1189.
34.
AmreinKSchnedlCHollA. Effect of high-dose vitamin D3 on hospital length of stay in critically ill patients with vitamin D deficiency: the VITdAL-ICU randomized clinical trial. JAMA. 2014;312(15):1520–1530.
35.
DellingerRPLevyMMRhodesA. Surviving Sepsis Campaign Guidelines Committee including The Pediatric Subgroup. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 2013;39(2):165–228.
36.
AsakuraHAoshimaKSugaY. Beneficial effect of the active form of vitamin D3 against LPS-induced DIC but not against tissue-factor-induced DIC in rat models. Thromb Haemost. 2001;85(2):287–290.
37.
MøllerSLaigaardFOlgaardKHemmingsenC. Effect of 1,25-dihydroxy-vitamin D3 in experimental sepsis. Int J Med Sci. 2007;4(4):190–195.
38.
EquilsONaikiYShapiroAM. 1,25-Dihydroxyvitamin D inhibits lipopolysaccharide-induced immune activation in human endothelial cells. Clin Exp Immunol. 2006;143(1):58–64.
39.
JengLYamshchikovAVJuddSE. Alterations in vitamin D status and anti-microbial peptide levels in patients in the intensive care unit with sepsis. J Transl Med. 2009;7:28.
40.
LeafDERaedADonninoMWGindeAAWaikarSS. Randomized controlled trial of calcitriol in severe sepsis. Am J Respir Crit Care Med. 2014;190(5):533–541.
41.
BustosB RRodríguez-NuñezIPeña ZavalaRSoto GermaniG. Vitamin D deficiency in children admitted to the paediatric intensive care unit [in Spanish]. Rev Chil Pediatr. 2016;87(6):480–486.
42.
AlvesFSFreitasFGBafiATAzevedoLCMachadoFR. Serum concentrations of vitamin D and organ dysfunction in patients with severe sepsis and septic shock. Rev Bras Ter Intensiva. 2015;27(4):376–382.
43.
KrishnanAOcholaJMundyJ. Acute fluid shifts influence the assessment of serum vitamin D status in critically ill patients. Crit Care. 2010;14(6):R216.
44.
NguyenHBEsheteBLauKHSaiAVillarinMBaylinkD. Serum 1,25-dihydroxyvitamin D: an outcome prognosticator in human sepsis. PLoS One. 2013;8(5):e64348.
45.
PletzMWTerkampCSchumacherU; CAPNETZ-Study Group. Vitamin D deficiency in community-acquired pneumonia: low levels of 1,25 (OH) 2 D are associated with disease severity. Respir Res. 2014;15:53.
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