Chloride Imbalance in Preterm Infants

The Impact of Chloride Imbalance on BPD Development and Mortality in Preterm Infants

In adults and children low or high blood chloride levels are linked to the risk of death. The aim of this observational study is to determine whether there is a relationship between low or high blood chloride levels and the risk of death or long-term lung problems. We will also learn the risk factors and associated conditions of high or low blood chloride levels. We will include infants born before 32 weeks of pregnancy or have a birth weight of less than 1500 grams in the study. The main question it aims to answer is:

Is there a relationship between low or high blood chloride levels in the first 4-6 weeks of life and risk of death or long-term lung problems in premature babies? We will examine the medical reports of babies who were followed up in neonatal intensive care unit over the past 5 years.

Study Overview

• Status: Not yet recruiting
• Conditions: Bronchopulmonary Dysplasia (BPD); Mortality Prediction; Chloride Disorder
• Intervention / Treatment: Other: Incomplete response; Other: Complete response; Other: Bad response

Detailed Description

Chloride balance usually parallels that of sodium, and it is strictly correlated to the extracellular volume balance. In addition plasma chloride and bicarbonate concentrations are inversely regulated through the chloride-bicarbonate exchange pump in renal collecting ducts, independent of sodium. Consequently, plasma chloride levels are closely correlated with pH (hypochloremia/metabolic alkalosis, hyperchloremia/metabolic acidosis).

In adults, dyschloremia is associated with mortality, acute kidney injury, and prolonged hospital stay. Hyperchloremia is often associated with severe sepsis. It has been shown that resuscitation with high-chloride fluids (eg: saline solution) instead of balanced fluids (e.g., Ringer's lactate) increases the need for inotropes in critically ill adults. Similarly, hyperchloremia in septic pediatric patients is linked to acute renal injury requiring dialysis, increased inotropic support, and mortality. In 1979, infants fed with chloride-deficient formula were reported to develop impaired head growth and neurologic sequelae.

Although serum chloride is routinely measured in neonatal intensive care units, its clinical significance is often overlooked. For this reason unlike sodium, literature on chloride metabolism in preterm infants is exceedingly limited.

Advancements in perinatal care over the past 50 years have significantly improved survival rates in preterm infants. However, a large proportion of very preterm infants who survive the neonatal period develop bronchopulmonary dysplasia (BPD). BPD, a chronic lung disease, manifests clinically through persistent respiratory support and/or oxygen dependency. Despite efforts to optimize neonatal care -such as controlled oxygen usage, non-invasive ventilation, volume-guarantee techniques, high-frequency ventilation, and caffeine therapy- BPD remains the most common complication among preterm infants and is associated with increased morbidity and mortality.

It has been suggested that extracellular volume expansion (edema) plays a role in the pathophysiology of BPD. Perlman et al.'s 1986 study demonstrated that infants who died from BPD exhibited hypochloremia, metabolic alkalosis, and complications like inadequate head growth, more frequently than those who survived. These findings highlight the critical importance of chloride imbalance in neonates, similar to findings in adult and pediatric populations.

This study aims to investigate the relationship between chloride balance and two major outcomes-mortality and the development of BPD-in preterm infants. Infants <32 weeks postmentruel age (PMA) or weighing less than 1500 grams will be enrolled in the study. We also plan to explore the relationship of dyschloremia with other outcomes of prematurity (eg: patent ductus arteriosus, ventilator dependency, retinopathy of prematurity (ROP), necrotizing enterocolitis, intraventricular hemorrhage, periventricular leukomalacia, hospital stay. Lastly we plan to explore the risk factors and clinical/laboratory conditions that are associated with chloride level abnormalities.

If this study yields findings that underscore the clinical significance of chloride levels in preterm infants, similar to adults and children, then close monitoring of chloride balance and appropriate interventions could potentially reduce mortality and BPD incidence in preterm infants. Conversely, if results indicate that chloride balance lacks clinical significance in preterm infants, this will also contribute valuable information to the current literature.

• Study Type: Observational
• Enrollment (Estimated): 500

Contacts and Locations

• Study Contact: Name: Murat Köstü; Phone Number: +905323932616; Email: murat.kostu@saglik.gov.tr

Study Locations

• Turkey
  • Istanbul, Turkey
    • Kanuni Sultan Suleyman Education and Research Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Study population includes infants admitted to the Neonatal Intensive Care Unit at Kanuni Sultan Suleyman Training and Research Hospital over the past 5 years.

Description

Inclusion Criteria:

• Infants born <32 weeks PMA or <1500 grams
• Infants admitted to NICU within the first 24 hours

Exclusion Criteria:

• Infants with major congenital anomalies
• Infants with chromosomal anomalies
• Infants who have undergone enterostomy operation
• Infants admitted to NICU after the first 24 hours

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Infants without dyschloremia; Infants with serum chloride levels within reference range before 36 weeks PMA	Other: Incomplete response; Infants died before 36 weeks PMA, infants diagnosed to have BPD at 36 weeks PMA and infants developed major complications before 36 weeks PMA: >Stage 2 necrotizing enterocolitis according to Bell classification; Hemodynamically significant patent ductus arteriosus; >Grade 2 intraventricular hemorrhage,; Retinopathy of prematurity, ICROP classification stage >2; >Stage 2 cystic periventricular leukomalacia; Ventricular dilatation/hydrocephalus requiring intervention; Other: Complete response; Infants discharged before 36 weeks PMA and infants who reached 36 weeks PMA without BPD and major complications: >Stage 2 necrotizing enterocolitis according to Bell classification; Hemodynamically significant patent ductus arteriosus; >Grade 2 intraventricular hemorrhage,; Retinopathy of prematurity, ICROP classification stage >2; >Stage 2 cystic periventricular leukomalacia; Ventricular dilatation/hydrocephalus requiring intervention; Other: Bad response; Infants died before 36 weeks PMA and infants diagnosed to have BPD at 36 weeks PMA
Infants with dyschloremia; Infants with serum chloride levels <96 mEq/l and >110 mEq/l before 36 weeks PMA	Other: Incomplete response; Infants died before 36 weeks PMA, infants diagnosed to have BPD at 36 weeks PMA and infants developed major complications before 36 weeks PMA: >Stage 2 necrotizing enterocolitis according to Bell classification; Hemodynamically significant patent ductus arteriosus; >Grade 2 intraventricular hemorrhage,; Retinopathy of prematurity, ICROP classification stage >2; >Stage 2 cystic periventricular leukomalacia; Ventricular dilatation/hydrocephalus requiring intervention; Other: Complete response; Infants discharged before 36 weeks PMA and infants who reached 36 weeks PMA without BPD and major complications: >Stage 2 necrotizing enterocolitis according to Bell classification; Hemodynamically significant patent ductus arteriosus; >Grade 2 intraventricular hemorrhage,; Retinopathy of prematurity, ICROP classification stage >2; >Stage 2 cystic periventricular leukomalacia; Ventricular dilatation/hydrocephalus requiring intervention; Other: Bad response; Infants died before 36 weeks PMA and infants diagnosed to have BPD at 36 weeks PMA

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
BPD	BPD at 36 weeks PMA	From enrollment to the end of 36 weeks PMA

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mortality	Mortality within 36 weeks PMA	From enrollment to the end of 36 weeks PMA

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
NEC	>Stage 2 necrotizing enterocolitis according to Bell classification within 36 weeks PMA	From enrollment to the end of 36 weeks PMA
PDA	Hemodynamically significant patent ductus arteriosus within 36 weeks PMA	From enrollment to the end of 36 weeks PMA
IVH	>Grade 2 intraventricular hemorrhage within 36 weeks PMA	From enrollment to the end of 36 weeks PMA
ROP	Retinopathy of prematurity, ICROP classification stage >2 at 36 weeks PMA	From enrollment to the end of 36 weeks PMA
PVL	>Stage 2 cystic periventricular leukomalacia at 36 weeks PMA	From enrollment to the end of 36 weeks PMA
Hydrocephalus	Ventricular dilatation/hydrocephalus requiring intervention at 36 weeks PMA	From enrollment to the end of 36 weeks PMA

Collaborators and Investigators

• Sponsor: Kanuni Sultan Suleyman Training and Research Hospital

Publications and helpful links

General Publications

• Thebaud B, Goss KN, Laughon M, Whitsett JA, Abman SH, Steinhorn RH, Aschner JL, Davis PG, McGrath-Morrow SA, Soll RF, Jobe AH. Bronchopulmonary dysplasia. Nat Rev Dis Primers. 2019 Nov 14;5(1):78. doi: 10.1038/s41572-019-0127-7.
• Perlman JM, Moore V, Siegel MJ, Dawson J. Is chloride depletion an important contributing cause of death in infants with bronchopulmonary dysplasia? Pediatrics. 1986 Feb;77(2):212-6.
• Chutorian AM, LaScala CP, Ores CN, Nass R. Cerebral dysfunction following infantile dietary chloride deficiency. Pediatr Neurol. 1985 Nov-Dec;1(6):335-41. doi: 10.1016/0887-8994(85)90067-0.
• Khan AH, Gai J, Faruque F, Bost JE, Patel AK, Pollack MM. Pediatric Mortality and Acute Kidney Injury Are Associated with Chloride Abnormalities in Intensive Care Units in the United States: A Multicenter Observational Study. J Pediatr Intensive Care. 2020 Nov 23;11(2):91-99. doi: 10.1055/s-0040-1719172. eCollection 2022 Jun.
• Kalikkot Thekkeveedu R, Ramarao S, Dankhara N, Alur P. Hypochloremia Secondary to Diuretics in Preterm Infants: Should Clinicians Pay Close Attention? Glob Pediatr Health. 2021 Feb 4;8:2333794X21991014. doi: 10.1177/2333794X21991014. eCollection 2021.
• Iacobelli S, Kermorvant-Duchemin E, Bonsante F, Lapillonne A, Gouyon JB. Chloride Balance in Preterm Infants during the First Week of Life. Int J Pediatr. 2012;2012:931597. doi: 10.1155/2012/931597. Epub 2012 Mar 8.

Study record dates

Study Major Dates

• Study Start (Estimated): April 15, 2025
• Primary Completion (Estimated): April 15, 2026
• Study Completion (Estimated): October 15, 2026

Study Registration Dates

• First Submitted: April 7, 2025
• First Submitted That Met QC Criteria: April 15, 2025
• First Posted (Actual): April 23, 2025

Study Record Updates

• Last Update Posted (Actual): April 23, 2025
• Last Update Submitted That Met QC Criteria: April 15, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: Mortality; Bronchopulmonary dysplasia; Preterm infant; Chloride imbalance
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Infant, Premature, Diseases; Infant, Newborn, Diseases; Lung Injury; Ventilator-Induced Lung Injury; Bronchopulmonary Dysplasia
• Other Study ID Numbers: Murat Kostu

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: We are not sure that local ethics committee that approved our study will allow IPD sharing

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No