Neurohormonal Activation and Renal Chloride Avidity in Acute Heart Failure: Clinical Evidence Supporting the "Chloride Theory".

INTRODUCTION: Heart failure (HF) progression according to changes in the serum chloride concentration ([sCl-]) was recently proposed as the "chloride (Cl) theory" for HF pathophysiology. The present study examined the association of neurohormones and renal Cl avidity to determine their contribution to acute HF and their involvement to the "Cl theory." METHODS: Data from 29 patients with acute HF (48% men; 80.3 ± 12 years) were analyzed. Blood and urine samples were obtained before decongestive therapy. Clinical tests included peripheral blood, serum and spot urinary electrolytes, b-type natriuretic peptide (BNP), and plasma neurohormones. RESULTS: In the 29 patients, urinary Cl concentrations ([uCl-]) inversely correlated with log (plasma renin activity [PRA]) (r = -0.64, p = 0.0002) and log (plasma aldosterone concentration) (r = -0.50, p = 0.006). The [sCl-]‒[uCl-] difference positively correlated with log PRA (r = 0.63, p = 0.0002) and log (plasma aldosterone concentration) (r = 0.49, p = 0.008). Patients were divided into 2 groups according to the [sCl-]‒[uCl-] difference, an excretion (low renal Cl avidity) group and an absorption (high renal Cl avidity) group. Compared with the excretion group (-77 to ‒5 mEq/L; n = 14), the absorption group (1-84 mEq/L; n = 15) exhibited greater renal impairment (serum creatinine; 1.45 ± 0.63 vs. 1.00 ± 0.38 mg/d, p = 0.029) and cardiac burden (log BNP; 2.99 ± 0.3 vs. 2.66 ± 0.32 pg/mL, p = 0.008), higher log PRA (0.20 ± 0.58 vs. -0.25 ± 0.35 ng/mL/h, p = 0.018), and lower fractional urinary Cl excretion (1.34 ± 1.3 vs. 5.33 ± 4.1%, p < 0.001). CONCLUSION: Renal Cl avidity differs in acute HF, i.e., excretion (low renal Cl avidity) versus absorption (high renal Cl avidity) types, involving renin-aldosterone-angiotensin activity as the underlying mechanism, which provides the neurohormonal background for the "Cl theory." A version of this study was presented in part at the annual international scientific assembly (ACC.23) of the American College of Cardiology, March 4-6, 2023.

Effects of serum sodium and chloride levels in the outcome of critically ill pediatric patients in the post-operative period of liver transplantation.

BACKGROUND: Sodium and chloride disturbances have attracted increasing attention in recent years. Many pathophysiological effects are associated with hyperchloremia, including reduction in mean arterial pressure and acute renal disease. Pediatric patients undergoing liver transplantation are at risk of developing various electrolyte and biochemical abnormalities, with an impact on their postoperative outcomes. OBJECTIVE: To analyze the impacts of serum sodium and chloride levels on prognosis of Pediatric Liver Transplant receptors. METHODS: This was a retrospective analytical observational study performed in a single transplant reference center in Sao Paulo, Brazil. Included patients were pediatric patients who underwent liver transplantation between January 2015 and July 2019. Statistical regression analysis and General Estimating Equations analysis were performed to evaluate the impacts of sodium and chloride disturbances on the development of acute renal failure and mortality. RESULTS: A total of 143 patients were included in this study. The main diagnosis was Biliary Atresia (62.9%). Twenty-seven patients died (18.9%), and graft dysfunction was the main cause of death (29.6%). The only variable individually associated with 28-days mortality was PIM-3 score (HR 1.59, CI 95% 1.165-2.177, p = 0.004). Forty-one patients (28.6%) developed moderate or severe AKI. PIM-3 score (OR 3.052, 95% CI 1.56-5.97, p = 0.001), hypernatremia (OR 3.49, 95% CI 1.32-9.23, p = 0.012), and hyponatremia (OR 4.24, 95% CI 1.52-11.85, p = 0.006) were independently associated with the development of moderate/severe AKI. CONCLUSIONS: In pediatric patients after liver transplantation, PIM-3 score, and abnormal serum sodium levels were correlated with AKI development.

[Predictive value of serum chlorine and interleukin-6 combined with coagulation indexes on severity of severe acute pancreatitis].

OBJECTIVE: To explore the predictive value of combined detection of serum interleukin-6 (IL-6), chloride (Cl-), D-dimer and fibrin degradation products (FDP) for severity of acute pancreatitis (AP). METHODS: From December 2020 to March 2022, 132 AP patients who met the criteria for inclusion were screened for retrospective analysis from 292 AP patients admitted in emergency surgery at the First Affiliated Hospital of Zhengzhou University and they were divided into severe acute pancreatitis (SAP) group and non-SAP group, with 63 in SAP group and 69 in non-SAP group, according to classification criteria. The data including lab results, abdominal doppler ultrasound and chest and abdominal CT, etc. The bedside index for severity in acute pancreatitis (BISAP) score was calculated. Multivariate Logistic regression analysis was carried out to find the risk factors for the severity of AP patients. The receiver operator characteristic curve (ROC) was drawn to judge the clinical predictive value of each factor. RESULTS: A total of 132 AP patients were enrolled. The serum IL-6, D-dimer, FDP levels and the BISAP score in SAP group were significantly higher than those in non-SAP group [serum IL-6 (ng/L): 62.73 (21.54, 187.47) vs. 8.22 (4.13, 14.70), D-dimer (mg/L): 5.36 (2.94, 8.25) vs. 0.94 (0.42, 2.21), FDP (mg/L): 13.54 (6.76, 22.45) vs. 3.20 (2.50, 6.10), BISAP score: 2.00 (1.00, 3.00) vs. 1.00 (0, 2.00), all P < 0.05], while the serum Cl- level was significantly lower than that of non-SAP group (mmol/L: 97.90±4.86 vs. 101.73±4.32, P < 0.05). Multivariate Logistic regression analysis showed that increased levels of IL-6 [odds ratio (OR) = 1.02, 95% confidence interval (95%CI) was 1.01-1.04], D-dimer (OR = 1.21, 95%CI was 1.05-1.40) and decreased Cl- level (OR = 0.88, 95%CI was 0.79-0.98) were risk factors for SAP (all P < 0.05). The ROC curve analysis showed that the area under the ROC curve (AUC) of IL-6, Cl-, D-dimer and FDP combined to predict the severity of AP patients was larger (0.89), and the sensitivity (82.50%) and specificity (85.50%) were higher. CONCLUSIONS: Compared with single index, the combined detection of serum IL-6, Cl-, D-dimer and FDP is more precise in determining the condition of AP.

Association of hyperchloremia with all-cause mortality in patients admitted to the surgical intensive care unit: a retrospective cohort study.

BACKGROUND: Serum chloride (Cl-) is one of the most essential extracellular anions. Based on emerging evidence obtained from patients with kidney or heart disease, hypochloremia has been recognized as an independent predictor of mortality. Nevertheless, excessive Cl- can also cause death in severely ill patients. This study aimed to investigate the relationship between hyperchloremia and high mortality rate in patients admitted to the surgical intensive care unit (SICU). METHODS: We enrolled 2131 patients from the Multiparameter Intelligent Monitoring in Intensive Care III database version 1.4 (MIMIC-III v1.4) from 2001 to 2012. Selected SICU patients were more than 18 years old and survived more than 72 h. A serum Cl- level ≥ 108 mEq/L was defined as hyperchloremia. Clinical and laboratory variables were compared between hyperchloremia (n = 664) at 72 h post-ICU admission and no hyperchloremia (n = 1467). The Locally Weighted Scatterplot Smoothing (Lowess) approach was utilized to investigate the correlation between serum Cl- and the thirty-day mortality rate. The Cox proportional-hazards model was employed to investigate whether serum chlorine at 72 h post-ICU admission was independently related to in-hospital, thirty-day and ninety-day mortality from all causes. Kaplan-Meier curve of thirty-day and ninety-day mortality and serum Cl- at 72 h post-ICU admission was further constructed. Furthermore, we performed subgroup analyses to investigate the relationship between serum Cl- at 72 h post-ICU admission and the thirty-day mortality from all causes. RESULTS: A J-shaped correlation was observed, indicating that hyperchloremia was linked to an elevated risk of thirty-day mortality from all causes. In the multivariate analyses, it was established that hyperchloremia remained a valuable predictor of in-hospital, thirty-day and ninety-day mortality from all causes; with adjusted hazard ratios (95% CIs) for hyperchloremia of 1.35 (1.02 ~ 1.77), 1.67 (1.28 ~ 2.19), and 1.39 (1.12 ~ 1.73), respectively. In subgroup analysis, we observed hyperchloremia had a significant interaction with AKI (P for interaction: 0.017), but there were no interactions with coronary heart disease, hypertension, and diabetes mellitus (P for interaction: 0.418, 0.157, 0.103, respectively). CONCLUSION: Hyperchloremia at 72 h post-ICU admission and increasing serum Cl- were associated with elevated mortality risk from all causes in severely ill SICU patients.

Usefulness of Incorporating Hypochloremia into the Get With The Guidelines-Heart Failure Risk Model in Patients With Acute Heart Failure.

Although hypochloremia is strongly associated with adverse prognosis in acute heart failure (AHF), it is unknown whether incorporating hypochloremia into the preexisting risk model improves the model performance. We calculated the Get With The Guidelines-Heart Failure (GWTG-HF) risk score in 1,428 patients with AHF (derivation cohort) and developed 2 risk scores incorporating brain natriuretic peptide (BNP) into the GWTG-HF risk score (GWTG-BNP risk score) and incorporating both BNP and hypochloremia (GWTG-BNP-Cl risk score). Hypochloremia was defined as <98 mmol/L. The external validation and comparison of model performance were performed in an independent group of 1,256 patients with AHF (validation cohort). All models were tested for in-hospital mortality. Hypochloremia was observed in 9.4% and 12.2% of the derivation and validation cohorts, respectively. Hypochloremia was an independent predictor of in-hospital mortality in the derivation cohort (odds ratio 2.02; p = 0.028). In the validation cohort, the GWTG-HF, GWTG-BNP, and GWTG-BNP-Cl risk scores demonstrated good discrimination (area under the curve: 0.742, 0.749, and 0.763, respectively). However, the GWTG-BNP-Cl risk score was more reliable than the GWTG-HF and GWTG-BNP risk scores in risk reclassification (net reclassification improvement: 0.491 and 0.408, respectively; p <0.01 for both). Moreover, this score demonstrated a good calibration of the GWTG-BNP-Cl model (Hosmer-Lemeshow test: p = 0.479). In conclusion, incorporating hypochloremia into the preexisting risk model improves the model performance.

Clinically Distinct Subtypes of Acute Kidney Injury on Hospital Admission Identified by Machine Learning Consensus Clustering.

BACKGROUND: We aimed to cluster patients with acute kidney injury at hospital admission into clinically distinct subtypes using an unsupervised machine learning approach and assess the mortality risk among the distinct clusters. METHODS: We performed consensus clustering analysis based on demographic information, principal diagnoses, comorbidities, and laboratory data among 4289 hospitalized adult patients with acute kidney injury at admission. The standardized difference of each variable was calculated to identify each cluster's key features. We assessed the association of each acute kidney injury cluster with hospital and one-year mortality. RESULTS: Consensus clustering analysis identified four distinct clusters. There were 1201 (28%) patients in cluster 1, 1396 (33%) patients in cluster 2, 1191 (28%) patients in cluster 3, and 501 (12%) patients in cluster 4. Cluster 1 patients were the youngest and had the least comorbidities. Cluster 2 and cluster 3 patients were older and had lower baseline kidney function. Cluster 2 patients had lower serum bicarbonate, strong ion difference, and hemoglobin, but higher serum chloride, whereas cluster 3 patients had lower serum chloride but higher serum bicarbonate and strong ion difference. Cluster 4 patients were younger and more likely to be admitted for genitourinary disease and infectious disease but less likely to be admitted for cardiovascular disease. Cluster 4 patients also had more severe acute kidney injury, lower serum sodium, serum chloride, and serum bicarbonate, but higher serum potassium and anion gap. Cluster 2, 3, and 4 patients had significantly higher hospital and one-year mortality than cluster 1 patients (p < 0.001). CONCLUSION: Our study demonstrated using machine learning consensus clustering analysis to characterize a heterogeneous cohort of patients with acute kidney injury on hospital admission into four clinically distinct clusters with different associated mortality risks.

Effects of salinity on gills' chloride cells, stress indices, and gene expression of Asian seabass (Lates calcarifer, Bloch, 1790).

A 2-week research was carried out to assess water salinity (WS) effects including 0, 15, 35, and 50‰ on osmoregulatory mechanisms and stress indices in Asian sea bass (34.4 g) juveniles. Except for fish reared at 50‰, in the other treatments, it gradually decreased to the prescribed WS during a 10-day period (- 5‰ a day). After a 10-day acclimation period, fish were reared at the prescribed WS for 2 weeks. Fish reared at 15 and 35‰ had higher chloride cell (CC) counts in the interlamellar region. The number of CC in the interlamellar region elevated with increment of WS up to 35‰, but they were pronouncedly reduced in 50‰ group. The diameter of CC in the interlamellar region was not affected by WS. The smallest nucleus diameter of CC in the interlamellar region was observed in fish reared at 15‰ (P < 0.05). The largest and the smallest amounts of serum aspartate aminotransferase were observed in fish reared at freshwater and 15‰, respectively. Fish reared at 35‰ had the highest serum sodium and potassium contents. Serum chloride content and total osmolality increased with increment of WS (P < 0.05). Serum cortisol and glucose contents gradually increased with elevation of WS up to 35‰; then, their contents remarkably decreased. The relative expression of insulin like growth factor-1 in the liver of fish reared at 35‰ was strikingly higher than that in the other groups. The relative expression of HSP70 gene in fresh water group was pronouncedly elevated compared to other treatments. The relative expression of interleukin-1ß in 15 and 35‰ groups was higher than that in the other groups; however, the relative expression of lysozyme gene in the liver of fish reared at fresh water was pronouncedly lower than that in the other treatments. The results of this study suggested rearing L. calcarifer at 15‰ closer to the isosmotic point and better provide its welfare.

Possibility of Venous Serum Cl- Concentration ([Cl-]s) as a Marker for Human Metabolic Status: Correlation of [Cl-]s to Age, Fasting Blood Sugar (FBS), and Glycated Hemoglobin (HbA1c).

The HCO3- concentration in venous serum ([HCO3-]s) is a factor commonly used for detecting the body pH and metabolic conditions. To exactly detect [HCO3-]s, the venous CO2 pressure should be kept as it is in the vein. The [HCO3-]s measurement is technically complicated to apply for huge numbers of almost heathy persons taking only basic medical examinations. The summation of [HCO3-]s and the venous serum Cl- concentration ([Cl-]s) is approximately constant; therefore, we studied if [Cl-]s could be a marker detecting metabolic conditions instead of [HCO3-]s. Venous blood was obtained from persons taking basic medical examinations (the number of persons = 107,630). Older persons showed higher values of [Cl-]s, fasting blood sugar (FBS), and glycated hemoglobin (HbA1c) than younger ones. [Cl-]s showed positive correlation to age and negative correlation to FBS and HBA1c. The negative correlation of [Cl-]s to FBS/HbA1c was obvious in persons with high FBS/HbA1c, leading us to an idea that persons with high FBS/HbA1c show high [HCO3-]s, which might be caused by low activity of carbonic anhydrase in the lung observed in persons with diabetes mellitus under acidotic conditions. Taken together, an easily measured serum electrolyte, [Cl-]s, could be a useful marker estimating metabolic conditions.

Hyperchloremia is associated with poor renal outcome after coronary artery bypass grafting.

BACKGROUND: Hyperchloremia is associated with the risks of several morbidities and mortality. However, its relationship with acute kidney injury (AKI) and end-stage renal disease (ESRD) in patients undergoing coronary artery bypass grafting (CABG) remains unresolved. METHODS: A total of 2977 patients undergoing CABG between 2003 and 2015 were retrospectively reviewed from two tertiary hospitals. Patients were categorized by serum chloride levels into normochloremia (95-105 mmol/L), mild hyperchloremia (106-110 mmol/L), and severe hyperchloremia (> 110 mmol/L). The odds ratios (ORs) for AKI and hazard ratios (HRs) for ESRD were calculated after adjustment for multiple covariates. The death-adjusted risk of ESRD was additionally evaluated. RESULTS: Postoperative AKI occurred in 798 patients (26.5%). The hyperchloremia group had a higher risk of AKI than the normochloremia group, wherein the risk was incremental depending on the severity of hyperchloremia, as follows: ORs were 1.26 (1.06-1.51) and 1.95 (1.52-2.51) in the mild and severe hyperchloremia groups, respectively. During a median period of 7 years (maximum 15 years), 70 patients (2.3%) had ESRD. The severe hyperchloremia group was at an elevated risk of ESRD compared with the normochloremia group, with an HR of 2.43 (1.28-4.63). Even after adjusting for the competing risk of death, hyperchloremia was associated with the risk of ESRD. CONCLUSIONS: Preoperative hyperchloremia is associated with poor renal outcomes such as AKI and ESRD after CABG. Accordingly, serum chloride should be monitored in patients undergoing CABG.

Risk factors for recurrent positive results of the nucleic acid amplification test for COVID-19 patients: a retrospective study.

Positive retests of COVID-19 represent a public health concern because of the increased risk of transmission. This study explored whether factors other than the nucleic acid amplification test (NAAT) contribute to positive retest results. Patients with COVID-19 admitted to the Guanggu district of the Hubei Maternal and Child Health Hospital between February 17 and March 28, 2020, were retrospectively included. The patients were grouped into the negative (n = 133) and positive (n = 51) retest groups. The results showed that the proportion of patients presenting with cough was higher (P < 0.001) and the proportion of patients with dyspnea was lower (P = 0.018) in the positive than in the negative retest group. The positive retest group showed shorter durations between symptom onset and hospitalization (P < 0.001) and symptom onset and the first positive NAAT (P = 0.033). The positive retest group had higher basophil counts (P = 0.023) and direct bilirubin (P = 0.032) and chlorine concentrations (P = 0.023) but lower potassium concentrations (P = 0.001) than the negative retest group. Multivariable regression analysis showed that coughing (OR = 7.59, 95% CI 2.28-25.32, P = 0.001) and serum chloride concentrations (OR = 1.38, 95% CI 1.08-1.77, P = 0.010) were independently associated with a positive retest result. Coughing and serum chloride concentrations were independent risk factors for positive NAAT retest results. Patients with a hospital stay of < 2 weeks or a short incubation period should stay in isolation and be monitored to reduce transmission. These results could help identify patients who require closer surveillance.

Serum Sodium Concentration and Mental Status in Children With Diabetic Ketoacidosis.

OBJECTIVES: Diabetic ketoacidosis (DKA) is typically characterized by low or low-normal serum sodium concentrations, which rise as hyperglycemia resolves. In retrospective studies, researchers found associations between declines in sodium concentrations during DKA and cerebral injury. We prospectively investigated determinants of sodium concentration changes and associations with mental status alterations during DKA. METHODS: Using data from the Pediatric Emergency Care Applied Research Network Fluid Therapies Under Investigation in Diabetic Ketoacidosis Trial, we compared children who had declines in glucose-corrected sodium concentrations with those who had rising or stable concentrations. Children were randomly assigned to 1 of 4 intravenous fluid protocols that differed in infusion rate and sodium content. Data from the first 4, 8, and 12 hours of treatment were analyzed for 1251, 1086, and 877 episodes, respectively. RESULTS: In multivariable analyses, declines in glucose-corrected sodium concentrations were associated with higher sodium and chloride concentrations at presentation and with previously diagnosed diabetes. Treatment with 0.45% (vs 0.9%) sodium chloride fluids was also associated with declines in sodium concentration; however, higher rates of fluid infusion were associated with declines in sodium concentration only at 12 hours. Frequencies of abnormal Glasgow Coma Scale scores and clinical diagnoses of cerebral injury were similar in patients with and without declines in glucose-corrected sodium concentrations. CONCLUSIONS: Changes in glucose-corrected sodium concentrations during DKA treatment are influenced by the balance of free-water loss versus sodium loss at presentation and the sodium content of intravenous fluids. Declines in glucose-corrected sodium concentrations are not associated with mental status changes during treatment.

Moroccan Bee Bread Improves Biochemical and Histological Changes of the Brain, Liver, and Kidneys Induced by Titanium Dioxide Nanoparticles.

Titanium dioxide nanoparticles (TiO2) were used in various fields such as food industry, cosmetics, medicine, and agriculture. Despite the many advantages of nanotechnology, the adverse effects of nanoparticles are inevitable. The present study was conducted to evaluate the protective effect of bee bread on titanium dioxide (TiO2) nanoparticle toxicity. Male rats were randomly divided into four groups: Group 1 received daily by gavage (10 mL/kg bw) of distilled water, Group 2 received bee bread ethanolic extract (100 mg/kg bw), Group 3 received TiO2 (100 mg/kg bw) and distilled water (10 mL/kg bw), and Group 4 received TiO2 (100 mg/kg bw) and bee bread ethanolic extract (100 mg/kg bw). All treatments were given daily by gavage during 30 days. At the end of the experiment period, blood samples were collected to analyze fasting blood glucose, lipid profile (TC, TG, LDL-C, HDL-C, and VLDL-C), liver enzymes (AST, ALT, and LDH), total protein, urea, albumin, creatinine, sodium, potassium, and chloride ions. In addition, histological examinations of the kidneys, liver, and brain were investigated. The results showed that the subacute administration of TiO2 alone (100 mg/kg bw) had induced hyperglycemia (309 ± 5 mg/dL) and elevation of hepatic enzyme levels, accompanied by a change in both lipid profile and renal biomarkers as well as induced congestion and dilatation in the hepatic central vein and congestion in kidney and brain tissues. However, the cotreatment with bee bread extract restored these biochemical parameters and attenuated the deleterious effects of titanium nanoparticles on brain, liver, and kidney functions which could be due to its rich content on functional molecules. The findings of this paper could make an important contribution to the field of using bee bread as a detoxifying agent against titanium dioxide nanoparticles and other xenobiotics.

Effects of intravenous magnesium sulfate on serum calcium-regulating hormones and plasma and urinary electrolytes in healthy horses.

Intravenous magnesium sulfate (MgSO4) is used in equine practice to treat hypomagnesemia, dysrhythmias, neurological disorders, and calcium dysregulation. MgSO4 is also used as a calming agent in equestrian events. Hypercalcemia affects calcium-regulating hormones, as well as plasma and urinary electrolytes; however, the effect of hypermagnesemia on these variables is unknown. The goal of this study was to investigate the effect of hypermagnesemia on blood parathyroid hormone (PTH), calcitonin (CT), ionized calcium (Ca2+), ionized magnesium (Mg2+), sodium (Na+), potassium (K+), chloride (Cl-) and their urinary fractional excretion (F) after intravenous administration of MgSO4 in healthy horses. Twelve healthy female horses of 4-18 years of age and 432-600 kg of body weight received a single intravenous dose of MgSO4 (60 mg/kg) over 5 minutes, and blood and urine samples were collected at different time points over 360 minutes. Plasma Mg2+ concentrations increased 3.7-fold over baseline values at 5 minutes and remained elevated for 120 minutes (P < 0.05), Ca2+ concentrations decreased from 30-60 minutes (P < 0.05), but Na+, K+ and Cl- concentrations did not change. Serum PTH concentrations dropped initially to rebound and remain elevated from 30 to 60 minutes, while CT concentrations increased at 5 minutes to return to baseline by 10 minutes (P < 0.05). The FMg, FCa, FNa, FK, and FCl increased, while urine osmolality decreased from 30-60 minutes compared baseline (P < 0.05). Short-term experimental hypermagnesemia alters calcium-regulating hormones (PTH, CT), reduces plasma Ca2+ concentrations, and increases the urinary excretion of Mg2+, Ca2+, K+, Na+ and Cl- in healthy horses. This information has clinical implications for the short-term effects of hypermagnesemia on calcium-regulation, electrolytes, and neuromuscular activity, in particular with increasing use of Mg salts to treat horses with various acute and chronic conditions as well as a calming agent in equestrian events.

Abnormal serum chloride is associated with increased mortality among unselected cardiac intensive care unit patients.

PURPOSE: We sought to describe the association between serum chloride levels and mortality among unselected cardiac intensive care unit (CICU) patients. MATERIALS AND METHODS: We retrospectively reviewed adult patients admitted to our CICU from 2007 to 2015. The association of dyschloremia and hospital mortality was assessed in a multiple variable model including additional confounders, and the association of dyschloremia and post-discharge mortality were assessed using Cox proportional-hazards analysis. RESULTS: 9,426 patients with a mean age of 67±15 years (37% females) were included. Admission hypochloremia was present in 1,384 (15%) patients, and hyperchloremia was present in 1,606 (17%) patients. There was a U-shaped relationship between admission chloride and unadjusted hospital mortality, with increased hospital mortality among patients with hypochloremia (unadjusted OR 3.0, 95% CI 2.5-3.6, p<0.001) or hyperchloremia (unadjusted OR 1.9, 95% CI 1.6-2.3, p<0.001). After multivariate adjustment, hypochloremia remained associated with higher hospital mortality (adjusted OR 2.1, 95% CI 1.6-2.9, p <0.001). Post-discharge mortality among hospital survivors was higher among patients with admission hypochloremia (adjusted HR 1.3, 95% CI 1.1-1.6; p<0.001). CONCLUSION: Abnormal serum chloride on admission to the CICU is associated with increased short- and long-term mortality, with hypochloremia being a strong independent predictor.

Base-excess chloride; the best approach to evaluate the effect of chloride on the acid-base status: A retrospective study.

To practically determine the effect of chloride (Cl) on the acid-base status, four approaches are currently used: accepted ranges of serum Cl values; Cl corrections; the serum Cl/Na ratio; and the serum Na-Cl difference. However, these approaches are governed by different concepts. Our aim is to investigate which approach to the evaluation of the effect of Cl is the best. In this retrospective cohort study, 2529 critically ill patients who were admitted to the tertiary care unit between 2011 and 2018 were retrospectively evaluated. The effects of Cl on the acid-base status according to each evaluative approach were validated by the standard base excess (SBE) and apparent strong ion difference (SIDa). To clearly demonstrate only the effects of Cl on the acid-base status, a subgroup that included patients with normal lactate, albumin and SIG values was created. To compare approaches, kappa and a linear regression model for all patients and Bland-Altman test for a subgroup were used. In both the entire cohort and the subgroup, correlations among BECl, SIDa and SBE were stronger than those for other approaches (r = 0.94 r = 0.98 and r = 0.96 respectively). Only BECl had acceptable limits of agreement with SBE in the subgroup (bias: 0.5 mmol L-1) In the linear regression model, only BECl in all the Cl evaluation approaches was significantly related to the SBE. For the evaluation of the effect of chloride on the acid-base status, BECl is a better approach than accepted ranges of serum Cl values, Cl corrections and the Cl/Na ratio.

Pseudohyperchloremia and Negative Anion Gap - Think Salicylate!

BACKGROUND: Pseudohyperchloremia results in a very low or negative anion gap. Historically, the most common cause of this artifact was bromide poisoning. Bromide salts have been removed from most medications and bromism has become very uncommon. More recently, the introduction of chloride ion selective sensing electrodes (Cl-ISE) has generated a new cause of pseudohyperchloremia-salicylate poisoning. We describe 5 such patients and quantitate the error generated by this measurement artifact. METHODS: The magnitude of artifactual hyperchloremia generated by high salicylate levels was quantified in 5 patients by measuring chloride concentration with several Cl-ISEs from different manufacturers and with Cl-ISEs of different "ages," and comparing these results to measurements with a chloridometer (coulometric titration), which is free of the salicylate artifact. RESULTS: Cl-ISEs from different manufacturers generated a wide range of artifactual chloride concentration elevation. Furthermore, the same Cl-ISE generated increasingly severe pseudohyperchloremia as it was repeatedly reused over time and "aged." CONCLUSIONS: Salicylate interferes with measurement of the blood chloride concentration when a Cl-ISE is used. The severity of this artifact is related to the salicylate level, the specific Cl-ISE, and the "age" of the electrode. Toxic blood salicylate levels can generate marked pseudohyperchloremia, and consequently, an artifactual very small or negative anion gap. The large anion gap metabolic acidosis typical of salicylate poisoning is masked by this artifact. Salicylate has become the most common cause of pseudohyperchloremia, and physicians should immediately consider salicylate poisoning whenever the combination of hyperchloremia and a very small or negative anion gap is reported by the laboratory.

Effect of 0.9% NaCl compared to plasma-lyte on biomarkers of kidney injury, sodium excretion and tubular transport proteins in patients undergoing primary uncemented hip replacement - a randomized trial.

BACKGROUND: Isotonic saline (IS) is widely used to secure perioperative cardiovascular stability. However, the high amount of chloride in IS can induce hyperchloremic acidosis. Therefore, IS is suspected to increase the risk of acute kidney injury (AKI). Biomarkers may have potential as indicators. METHODS: In a double-blinded, placebo-controlled study, 38 patients undergoing primary uncemented hip replacement were randomized to IS or PlasmaLyte (PL). Infusion was given during surgery as 15 ml/kg the first hour and 5 ml/kg the following two hours. Urinary samples were collected upon admission and the day after surgery. As surgery was initiated, urine was collected over the course of 4 h. Hereafter, another urine collection proceeded until the morning. Urine was analyzed for markers of AKI neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1). Arterious and venous blood samples for measurements of pH and plasma electrolytes including chloride (p-Cl) were collected as surgery was initiated, at the end of surgery and the following morning. RESULTS: IS induced an increase in p-Cl (111 ± 2 mmol/L after IS and 108 ± 3 after PL, p = 0.004) and a decrease in pH (7.39 ± 0.02 after IS and 7.43 ± 0.03 after PL, p = 0.001). Urinary NGAL excretion increased in both groups (ΔNGAL: 5.5 [4.1; 11.7] µg/mmol creatinine p = 0.004 after IS vs. 5.5 [2.1;9.4] µg/mmol creatinine after PL, p < 0.001). No difference was found between the groups (p = 0.839). Similarly, urinary KIM-1 excretion increased in both groups (ΔKIM-1: IS 115.8 [74.1; 156.2] ng/mmol creatinine, p < 0.001 vs. PL 152.4 [120.1; 307.9] ng/mmol creatinine, p < 0.001). No difference between the groups (p = 0.064). FENa increased (1.08 ± 0.52% after IS and 1.66 ± 1.15% after PL, p = 0.032). ENaC excretion was different within groups (p = 0.019). CONCLUSION: A significantly higher plasma chloride and a lower pH was present in the group receiving isotonic saline. However, u-NGAL and u-KIM-1 increased significantly in both groups after surgery despite absence of changes in creatinine. These results indicate that surgery induced subclinical kidney injury. Also, the IS group had a delayed sodium excretion as compared to the PL group which may indicate that IS affects renal sodium excretion differently from PL. TRIAL REGISTRATION: ClinicalTrials.gov Identifier:  NCT02528448 , 19/08/2015.

Effect of oral rehydration solution versus spring water intake during exercise in the heat on muscle cramp susceptibility of young men.

BACKGROUND: Muscle cramp is a painful, involuntary muscle contraction, and that occurs during or following exercise is referred to as exercise-associated muscle cramp (EAMC). The causes of EAMC are likely to be multifactorial, but dehydration and electrolytes deficits are considered to be factors. This study tested the hypothesis that post-exercise muscle cramp susceptibility would be increased with spring water ingestion, but reduced with oral rehydration solution (ORS) ingestion during exercise. METHODS: Ten men performed downhill running (DHR) in the heat (35-36 °C) for 40-60 min to reduce 1.5-2% of their body mass in two conditions (spring water vs ORS) in a cross-over design. The body mass was measured at 20 min and every 10 min thereafter during DHR, and 30 min post-DHR. The participants ingested either spring water or ORS for the body mass loss in each period. The two conditions were counter-balanced among the participants and separated by a week. Calf muscle cramp susceptibility was assessed by a threshold frequency (TF) of an electrical train stimulation to induce cramp before, immediately after, 30 and 65 min post-DHR. Blood samples were taken before, immediately after and 65 min after DHR to measure serum sodium, potassium, magnesium and chroride concentrations, hematocrit (Hct), hemoglobin (Hb), and serum osmolarity. Changes in these varaibles over time were compared between conditions by two-way repeated measures of analysis of variance. RESULTS: The average (±SD) baseline TF (25.6 ± 0.7 Hz) was the same between conditions. TF decreased 3.8 ± 2.7 to 4.5 ± 1.7 Hz from the baseline value immediately to 65 min post-DHR for the spring water condition, but increased 6.5 ± 4.9 to 13.6 ± 6.0 Hz in the same time period for the ORS condition (P < 0.05). Hct and Hb did not change significantly (P > 0.05) for both conditions, but osmolarity decreased (P < 0.05) only for the spring water condition. Serum sodium and chloride concentrations decreased (< 2%) at immediately post-DHR for the spring water condition only (P < 0.05). CONCLUSIONS: These results suggest that ORS intake during exercise decreased muscle cramp susceptibility. It was concluded that ingesting ORS appeared to be effective for preventing EAMC.

False-negative diagnosis of high anion gap in patients with end-stage kidney disease.

The traditional anion gap (AG) equation is widely used, but its misdiagnosis in end-stage kidney disease (ESKD) patients has not been investigated fully. Diagnostic accuracy to detect high AG was cross-sectionally evaluated using 3 AG equations in 1733 ESKD patients with an eGFR less than 15 mL/min/1.73 m2. The prevalence of high AG was 67.9%, 92.1% and 97.4% by the traditional, albumin-adjusted AG (aAG) and full AG equations, respectively. The sensitivity, specificity, accuracy and Kappa coefficient obtained with the traditional AG vs aAG equation were 0.70 vs 0.94, 0.98 vs 0.93, 0.7 vs 0.94, and 0.103 vs 0.44, respectively. Next, we created a subcohort comprising only patients with high full AG and investigated how the traditional AG equation leads to misdiagnoses. Multivariable-adjusted regression analysis in 1688 patients revealed that independent factors associated with a false-negative AG diagnosis were ARB use, eGFR, blood leukocyte count, serum chloride, bicarbonate, ionized calcium, potassium, albumin and phosphate. 93.2% of our subcohort prescribed any of RAAS inhibitors, Loop diuretics or Alkali which could increase either serum chloride or bicarbonate. Frequent use of these possible AG-reducing medications may conceal high AG state in patients with ESKD unless they have incidental inflammation which may increase AG value.

Sex and Age-Specific Hematology and Biochemistry Reference Intervals of Live Iberian Hares (Lepus granatensis) and Comparison with Postmortem Sampling.

Hematology and serum biochemistry reference intervals were estimated for the Iberian hare (Lepus granatensis). Most parameters differed significantly between hunted and livetrapped Iberian hares. Significant differences were found for sex (red blood cell count, mean corpuscular volume, total protein, albumin, uric acid, triglycerides, cholesterol, chloride) and age classes (red blood cell count, hematocrit, mean corpuscular hemoglobin, glucose, calcium, and sodium). Sex- and age-specific reference intervals were estimated for these parameters. Red blood cell count, hemoglobin concentration, mean corpuscular hemoglobin, urea, and potassium show seasonal variations, with the lowest values in summer and the highest in winter. Creatinine, calcium, sodium, and phosphorus achieve their highest values in summer and stable baseline values throughout the rest of the year. These reference intervals can be used as baseline to monitor health, physiology, ecology, and nutrition of Iberian hare populations.