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1.
Measuring the impact of CFTR modulation on sweat chloride in cystic fibrosis: Rationale and design of the CHEC-SC study.
Zemanick, ET, Konstan, MW, VanDevanter, DR, Rowe, SM, Clancy, JP, Odem-Davis, K, Skalland, M, Mayer-Hamblett, N
Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society. 2021;(6):965-971
Abstract
BACKGROUND The Characterizing CFTR Modulated Changes in Sweat Chloride and their Association with Clinical Outcomes (CHEC-SC) study is a large epidemiologic study designed to determine the relationship between sweat chloride response and clinical outcomes in people with cystic fibrosis (CF) on commercially approved CFTR modulators. A challenge to study feasibility was capturing sweat chloride measurements before modulator initiation. We tested the hypothesis that historic sweat chloride approximated contemporary pre-modulator values to estimate CFTR modulator-induced changes, allowing a single-visit study design. METHODS GOAL and PROSPECT were multi-center prospective studies of individuals initiating ivacaftor or lumacaftor-ivacaftor. At enrollment, pre-modulator sweat chloride was measured and historic results recorded. Post-modulator sweat chloride was measured at 1, 3 and 6 months. For this analysis, differences between historic and pre-modulator sweat chloride were estimated. CFTR modulator-induced sweat chloride mean changes were compared using historic and pre-modulator sweat chloride. RESULTS Paired historic and pre-modulator sweat chloride (n=406 participants) revealed a non-significant mean change of -1.0 mmol/L (95% CI: -2.71, 0.66) over an average of 17.2 years. Calculating sweat response to ivacaftor or lumacaftor-ivacaftor using historic or pre-modulator values resulted in similar estimates of modulator response. Based on these results, the CHEC-SC study was designed with a single, post-modulator sweat chloride measurement. CONCLUSIONS Historic sweat chloride values provide a reliable estimate of pre-modulator sweat chloride for people starting on modulator therapy. The CHEC-SC study anticipates capturing approximately 5,000 sweat chloride values, providing an unprecedented understanding of sweat chloride across the CF population in the era of CFTR modulators.
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2.
Does Chloride Intake at the Early Phase of Septic Shock Resuscitation Impact on Renal Outcome?
Chapalain, X, Huet, O, Balzer, T, Delbove, A, Martino, F, Jacquier, S, Egreteau, PY, Darreau, C, Saint-Martin, M, Lerolle, N, et al
Shock (Augusta, Ga.). 2021;(3):425-432
Abstract
INTRODUCTION Fluid administration is one of the first lines of treatment for hemodynamic management of sepsis and septic shock. Studies investigating the effects of chloride-rich fluids including normal saline on renal function report controversial findings. METHODS This is a prospective, observational, multicenter study. Patients with septic shock, defined according to Sepsis-2 definition, were eligible. A "high-dose" of chloride was defined as a chloride intake greater than 18 g administrated within the first 48 h of septic shock management. The purpose of this study was to investigate the impact of cumulative chloride infusion within the first 48 h of septic shock resuscitation on acute kidney injury (AKI). RESULTS Two hundred thirty-nine patients with septic shock were included. Patients who received a "high-dose" of chloride had significantly higher Sequential Organ Failure Assessment score at the time of enrolment (P < 0.001). Cumulative chloride load was higher in patients requiring renal replacement therapy (RRT) (31.1 vs. 25.2 g/48 h; P < 0.005). Propensity score-weighted regression did not find any association between "high-dose" of chloride and AKI requiring RRT (OR: 0.97 [0.88-1.1]; P = 0.69). There was no association between "high-dose" of chloride and worsening kidney function at H48 (OR: 0.94 [0.83-1.1]; P = 0.42). There was also no association between "high-dose" of chloride and ICU length of stay (P = 0.61), 28-day mortality (P = 0.83), or hospital mortality (P = 0.89). CONCLUSION At the early stage of resuscitation of critically ill patients with septic shock, administration of "high-dose" of chloride (> 18 g/48 h) was not associated with renal prognosis.
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3.
Usefulness of chloride levels for fluid resuscitation in patients undergoing targeted temperature management after out-of-hospital cardiac arrest.
Kong, T, Chung, YE, Lee, HS, You, JS, Chung, HS, Park, I, Chung, SP
The American journal of emergency medicine. 2021;:69-76
Abstract
OBJECTIVE Chloride is an important electrolyte in the body. In this study, we aimed to evaluate the associations between chloride levels on emergency department (ED) admission and neurologic outcomes by stratifying patients undergoing targeted temperature management (TTM) after out-of-hospital cardiac arrest (OHCA) into three groups (hyper/normo/hypochloremia); we also assessed the effect of changes in chloride levels from baseline over time on outcomes. METHODS This retrospective, observational cohort study of 346 patients was conducted between 2011 and 2019. The chloride levels were categorized as hypochloremia, normochloremia, and hyperchloremia by predetermined definitions. The primary endpoint was poor neurologic outcomes after hospital discharge. We evaluated the associations between chloride levels on ED admission and neurologic outcomes and assess the effect of changes in chloride levels over time on clinical outcomes. RESULTS On ED admission, compared with normochloremia, hypochloremia was significantly associated with unfavorable neurologic outcomes (OR, 2.668; 95% CI, 1.217-5.850, P = 0.014). Over time, unfavorable neurologic outcomes were significantly associated with increases in chloride levels in the hyperchloremia and normochloremia groups after ED admission. The rates of poor neurologic outcomes in the hyperchloremia and normochloremia groups were increased by 14.2% at Time-12, 20.1% at Time-24, and 9.3% at Time-48 with a 1-mEq/L increase in chloride levels. CONCLUSION In clinical practice, chloride levels can be routinely and serially measured cost-effectively. Thus, baseline chloride levels may be a promising tool for rapid risk stratification of patients after OHCA. For fluid resuscitation after cardiac arrest, a chloride-restricted solution may be an early therapeutic strategy.
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4.
Females with Cystic Fibrosis Demonstrate a Differential Response Profile to Ivacaftor Compared with Males.
Secunda, KE, Guimbellot, JS, Jovanovic, B, Heltshe, SL, Sagel, SD, Rowe, SM, Jain, M
American journal of respiratory and critical care medicine. 2020;(8):996-998
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5.
Urinary chloride concentration as a prognostic marker in critically ill patients.
Komaru, Y, Doi, K, Matsuura, R, Yoshida, T, Miyamoto, Y, Yoshimoto, K, Nangaku, M
Nephrology (Carlton, Vic.). 2020;(5):384-389
Abstract
AIM: Associations have been reported among serum chloride concentration, mortality and incidence of acute kidney injury (AKI) in intensive care units (ICU). This study aimed to examine associations among urinary chloride, mortality, and AKI incidence in ICU patients. METHODS A retrospective observational study was conducted among medical-surgical ICU in a tertiary hospital wherein 170 consecutive ICU patients were evaluated from October 2015 to March 2016 and 116 patients were enrolled. Serial data of serum and urine electrolytes from day 1 to day 4 of ICU admission were examined. The primary and secondary outcomes were ICU mortality and incidence of AKI in the ICU, respectively. RESULTS Among the 116 enrolled patients, 15 (13%) died during their ICU stay. Although serum and urinary sodium and potassium on day 1 did not significantly differ between ICU survivors and non-survivors, urinary chloride concentration on day 1 was significantly lower in non-survivors. Receiver operating characteristic analysis showed that the cutoff value of day 1 urinary chloride concentration for prediction of ICU mortality was 53 mEq/L. The lower urinary chloride concentration group on day 1 showed a significantly lower survival rate, even in long-term follow-up, compared with the higher urinary chloride group. Addition of day 1 urinary chloride concentration improved prediction of AKI incidence in the ICU by Sequential Organ Failure Assessment score alone. CONCLUSION Lower urinary chloride concentration was associated with increased mortality and incidence of AKI in the ICU. Further investigation is necessary to clarify the mechanism of urinary chloride regulation.
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6.
The association between serum chloride levels and chronic kidney disease progression: a cohort study.
Khatri, M, Zitovsky, J, Lee, D, Nayyar, K, Fazzari, M, Grant, C
BMC nephrology. 2020;(1):165
Abstract
BACKGROUND Limited data suggest serum chloride levels associate with mortality in heart failure, chronic kidney disease (CKD), and pulmonary arterial hypertension. Randomized trials have also shown that administration of crystalloid intravenous fluids with lower chloride concentration may have better renal outcomes. However, chloride has not been studied longitudinally for CKD progression. METHODS We used a prospective cohort of subjects with stage 3 and 4 CKD recruited from a nephrology clinic at a single medical center. Linear regression, linear regression with generalized estimating equations, and Cox proportional hazards models were created for outcomes of overall change in estimated glomerular filtration rate (eGFR), longitudinal changes in eGFR, and time to > 30% decline in eGFR, respectively. Baseline chloride was modeled continuously and categorically, and models were adjusted for potential confounders. RESULTS Median follow-up was 1.7 years. Baseline median age was 72 years and median eGFR was 35.7 mL/min/1.73m2. In multivariable analysis, higher serum chloride associated with worsened eGFR decline. Every 1 mEq/L increase in chloride associated with an overall eGFR decline of 0.32 mL/min/1.73m2 (p = 0.003), while the difference in eGFR decline in the highest quartile of chloride was 3.4 mL/min/1.73m2 compared to the lowest quartile (p = 0.004). No association between serum chloride and time to 30% decline in eGFR was observed in multivariable analysis (hazard ratio 1.05 per 1 mEq/L increase in serum chloride, p = 0.103). CONCLUSIONS In CKD patients, higher serum chloride associated with a modestly steeper rate of eGFR decline, and may be a useful biomarker to predict CKD progression. Further studies are needed to determine causality.
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7.
Perioperative Hyperchloremia and its Association With Postoperative Acute Kidney Injury After Craniotomy for Primary Brain Tumor Resection: A Retrospective, Observational Study.
Oh, TK, Kim, CY, Jeon, YT, Hwang, JW, Do, SH
Journal of neurosurgical anesthesiology. 2019;(3):311-317
Abstract
BACKGROUND Hyperchloremia is known to influence postoperative outcomes and may result in postoperative acute kidney injury (AKI). This study sought to investigate whether hyperchloremia was associated with postoperative AKI in patients who underwent surgery for primary brain tumor resection. MATERIALS AND METHODS This is a retrospective, observational study of patients who underwent craniotomy for primary brain tumor resection at a single tertiary care hospital between January 2005 and October 2017. Maximum levels of serum chloride (mmol/L) measured on postoperative days (PODs) 0 to 3 and increase in serum chloride (mmol/L), (maximum serum chloride-baseline serum chloride before surgery) were measured. We examined whether perioperative hyperchloremia was associated with postoperative AKI during PODs 0 to 3. Univariate and multivariate logistic regression analyses were used in this study. RESULTS A total of 726 patients were included in the analysis; of these, 39 (5.4%) were diagnosed with postoperative AKI during PODs 0 to 3. The risk of postoperative AKI was associated with maximum chloride levels (odds ratio, 1.10; 95% confidence interval, 1.02-1.19; P=0.015) and with an increase in serum chloride levels during PODs 0 to 3 (odds ratio, 1.11; 95% confidence interval, 1.04-1.19; P=0.004). CONCLUSIONS Our study shows that perioperative hyperchloremia during PODs 0 to 3 was associated with an increased risk of postoperative AKI during this period after craniotomy for primary brain tumor resection.
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8.
Acetazolamide as a potent chloride-regaining diuretic: short- and long-term effects, and its pharmacologic role under the 'chloride theory' for heart failure pathophysiology.
Kataoka, H
Heart and vessels. 2019;(12):1952-1960
Abstract
According to the "chloride theory" for heart failure (HF) pathophysiology, manipulation of the serum chloride concentration is an important therapeutic target. This study determined the short- and long-term effects of acetazolamide (Diamox), a potential chloride-regaining diuretic, on peripheral blood, serum electrolytes, and renal function. Effects of low-dose Diamox (250-500 mg/day) were evaluated in 30 HF patients for whom Diamox was added as de-novo/add-on decongestion therapy for acutely worsening HF (n = 18) or as modification therapy for serum hypochloremia in stable HF ( < 100 mEq/L; n = 12). Peripheral hematologic tests were performed at baseline, and at short- ( ≤ 10 days) and long-term ( ~ 60 days) time-points. In all 30 study patients of both groups, the serum chloride concentration increased in the short-term and even further over the long-term. The serum potassium concentration constantly decreased throughout the study period. Both the blood urea nitrogen and serum creatinine concentrations increased in the short-term, but returned to baseline levels over the long-term. Responders to Diamox (n = 13; defined by HF resolution and body weight loss ≥ 1 kg) in the decongestion group exhibited reduced serum b-type natriuretic peptide levels and a markedly increased serum chloride concentration, but the hemoglobin/hematocrit and serum creatinine concentrations did not change after treatment. In conclusion, acetazolamide is a potent candidate "chloride-regaining diuretic" for treating HF patients under the "chloride theory". Its effect to enhance the serum chloride concentration occurred within 10 days and persisted for at least ~ 60 days. Plasma volume and renal function were preserved under adequate diuretic treatment with acetazolamide.
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9.
CHOLESTEROL AND CHLORIDE IN ACUTE HEART FAILURE.
Radulović, B, Potočnjak, I, Dokoza Terešak, S, Trbušić, M, Vrkić, N, Huršidić Radulović, A, Starčević, N, Milošević, M, Degoricija, V, Frank, S
Acta clinica Croatica. 2019;(2):195-201
Abstract
Detecting predictors of poor outcome is crucial for understanding the underlying pathophysiology of heart failure (HF) and thus creating new therapeutic concepts. It is well established that low serum lipid levels are associated with unfavorable outcomes in HF patients. Several studies examined the association between serum lipids and established predictors of mortality in HF patients. The aim of the present study was to examine the association of serum lipid and chloride concentrations, as well as their impact on survival in acute heart failure (AHF). The present study was performed as a prospective, single-centre, observational research. The study included 152 patients with AHF. Spearman's correlation coefficient revealed a significant positive correlation of serum chloride levels with serum levels of total cholesterol (ρ 0.221, p=0.006), low-density lipoprotein cholesterol (LDL-c) (ρ 0.187, p=0.015) and high-density lipoprotein-cholesterol (HDL-c) (ρ 0.169, p=0.038). Binary logistic regression revealed a significant association of chloride, total cholesterol and LDL-c serum levels measured at admission with hospital survival (OR 1.077, CI 1.01-1.154, p=0.034), (OR 1.731, CI 1.090-2.748, p=0.020) and (OR 1.839, CI 1.033-3.274, p=0.038), respectively, as well as with 3-month survival (OR 1.065, CI 1.002-1.131, p=0.042), (OR 1.625, CI 1.147-2.303, p=0.006) and (OR 1.711, CI 1.117-2.622, p=0.014), respectively. In conclusion, positive statistical association between serum cholesterol (total cholesterol, LDL-c and HDL-c) and chloride levels may suggest their similar modulation by AHF pathophysiology. Serum levels of total cholesterol, LDL-c and chloride contribute to patient survival.
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10.
223Ra-chloride therapy in men with hormone-refractory prostate cancer and skeletal metastases: Real-world experience.
Boni, G, Mazzarri, S, Cianci, C, Galli, L, Farnesi, A, Borsatti, E, Bortolus, R, Fratino, L, Gobitti, C, Lamaj, E, et al
Tumori. 2018;(2):128-136
Abstract
BACKGROUND Radium-223 (223Ra) chloride, an alpha emitter, has been shown to improve overall survival (OS) and pain control, and to delay skeletal-related events, in patients with castration-resistant prostate cancer (CRPC) and bone metastases. Our retrospective observational study presents the first Italian experience on the efficacy and safety of 223Ra therapy in routine clinical practice. METHODS A total of 83 patients with metastatic CRPC were treated with 223Ra at 3 Italian centers between August 2013 and August 2016. 223Ra-chloride (55 kBq/kg) was administered every 4 weeks for a total of 6 cycles. Primary endpoints were OS and progression-free survival (PFS). Secondary endpoints included toxicity, pain evaluation using numeric rating scale (NRS), symptomatic skeletal-related events and biomarkers response. RESULTS Patients had a median age of 75 (range 53-89) years. The majority of men showed a Gleason score of 7, 8, or 9. Forty-one patients completed 6 treatment cycles; 33 stopped treatment before completing 6 cycles. Nine were still receiving therapy at the time of data collection. At the end of therapy, NRS pain scores significantly improved ( p < .000001). OS was a mean of 10.1 months, while median OS had not been attained. According to Kaplan-Meier estimation, OS and PFS were 17.5 and 7.7 months, respectively. There was a significant correlation between OS and PFS with the number of 223Ra cycles; patients receiving all 6 cycles experienced the major benefit from the therapy. 223Ra was well-tolerated. CONCLUSIONS 223Ra alpha therapy is an important therapeutic option for men with CRPC and symptomatic skeletal metastases.