Elsevier

The American Journal of Cardiology

Volume 184, 1 December 2022, Pages 72-79
The American Journal of Cardiology

Relation of Low Chloride Concentration to Diuretic Efficiency and Transplant-Free Survival in Children Hospitalized With Heart Failure

https://doi.org/10.1016/j.amjcard.2022.08.023Get rights and content

Serum chloride plays an important role in fluid homeostasis and is associated with impaired diuretic responsiveness and mortality in adults with heart failure (HF). We sought to characterize the relationship of serum chloride and diuretic efficiency (DE) and to determine its prognostic importance in children hospitalized with acute decompensated HF (ADHF).

We studied DE, defined as net fluid output/kg+constant per mg of loop diuretic/kg, in 200 children hospitalized with ADHF. Median serum chloride at admission was 102 mmol/L (interquartile range 99 to 105 mmol/L), and hypochloremia (chloride ≤96 mmol/L) was present in 16% of the population at admission. Serum chloride correlated with serum sodium (r = 0.66; p < 0.001) and bicarbonate (r = −0.39; p < 0.001). In the adjusted analysis, lower chloride was associated with reduced DE (p < 0.001). Serum sodium was associated with DE on the unadjusted analysis; however, the association was eliminated when added to the model with chloride (p = 0.442). Lower chloride was also associated with features of inadequate decongestion during hospitalization: a positive fluid balance (p = 0.003), greater cumulative loop diuretic dose per weight (p = 0.001), addition of a thiazide diuretic during hospitalization (p < 0.001), less weight loss (p = 0.025), and longer length of stay (p = 0.003). Chloride concentration was independently associated with death or transplant 1 year after admission (hazard ratio 0.94; p < 0.001). As a dichotomous variable, hypochloremia was independently associated with reduced DE (p < 0.001) and decreased 1-year transplant-free survival (hazard ratio 2.3, p < 0.001).

Lower serum chloride at hospital admission is strongly and independently associated with impaired DE and reduced transplant-free survival in children hospitalized with ADHF.

Introduction

Diuretic resistance occurs frequently in adults who are hospitalized with acute decompensated heart failure (ADHF), resulting in incomplete decongestion, persistent symptoms, and worsening renal function. Not surprisingly, patients with refractory ADHF are at increased risk of rehospitalization and mortality.1,2 Because serum chloride plays an important role in tubuloglomerular feedback, fluid homeostasis, and acid-base balance, its impact on diuretic responsiveness has recently been studied in adults with heart failure (HF).3,4 As a biomarker alone, low serum chloride at hospital admission predicts mortality in adults with acute and chronic HF.4, 5, 6, 7 Mechanistically, hypochloremia due to chloride depletion is linked to neurohormonal activation and diuretic resistance, begging the question as to whether chloride replacement might result in improved decongestion.3

Unlike in adults, our understanding of the mechanisms and risk factors for diuretic resistance in children remains very limited. A lack of chronic co-morbidities in this population means classic age-related risk factors for impaired diuresis, such as diabetes and chronic kidney disease, do not apply. Likewise, the impact of reduced filtration and excretion on diuretic response in the immature kidney is not known. Furthermore, the specific role of serum chloride in diuretic response has never been studied in pediatric HF. These knowledge gaps have important implications because approximately 1/3 of pediatric patients who are hospitalized with ADHF have a poor initial response to loop diuretics, resulting in a positive fluid balance and increased risk of mortality or the need for mechanical circulatory support (MCS).8

Early identification of children at risk of poor diuretic response may result in modifications in treatment that lead to improved outcomes. Thus, the primary aim of this study was to determine whether low serum chloride at admission is associated with reduced diuretic efficiency (DE) in children hospitalized with ADHF. Secondary aims were to define the association of serum chloride concentration with clinical features of impaired decongestion and transplant-free survival.

Section snippets

Methods

We performed a retrospective cohort study of all children hospitalized at a single institution from March 2011 to December 2019 with a primary diagnosis of ADHF. We defined ADHF as the gradual or rapid worsening of HF signs and symptoms resulting in a need for hospitalization and urgent therapy. We required that the diagnosis of HF be attributable to ventricular dysfunction. All subjects were identified by physicians from the HF and cardiac transplant service using the daily HF census at our

Results

During the study period, 326 consecutive hospitalizations for ADHF were reviewed. A total of 200 patients met the study criteria and were included in the analysis. Baseline patient characteristics and associations with serum chloride concentration by tertile are shown in Table 1. The median age of the cohort was 7.3 years (interquartile range [IQR] 1.3, 13.1 years), and the median weight was 21.0 kg (IQR 9.1, 52.5 kg). There was no difference in age or weight across tertiles of chloride

Discussion

The primary finding of this study is that lower chloride concentration at admission is independently associated with diminished loop DE and decreased transplant-free survival in children hospitalized with ADHF. In addition, patients with lower serum chloride were more likely to develop clinical features of impaired decongestion during the hospitalization and experienced longer lengths of stay. Importantly, new onset hypochloremia and serum chloride at treatment Day 4 were also independently

Conclusions

Among a cohort of children hospitalized with ADHF, lower serum chloride concentration was independently associated with impaired loop DE and diminished transplant-free survival, consistent with findings in adult patients and suggestive of an important role for chloride in cardiorenal regulation of pediatric HF. Lower serum chloride at admission was also associated with clinical features of impaired decongestion and longer hospital length of stay. Younger children and those receiving loop

Disclosures

The authors have no conflicts of interest to declare.

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    Funding: XXX.

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