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Hyperchloremia and moderate increase in serum chloride are associated with acute kidney injury in severe… Suetrong, Bandarn; Pisitsak, Chawika; Boyd, John H; Russell, James A; Walley, Keith R Oct 6, 2016

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RESEARCH Open AccessHyperchloremia and moderate increase inserum chloride are associated with acutekidney injury in severe sepsis and septicshock patientsBandarn Suetrong1,2, Chawika Pisitsak1,3, John H. Boyd1, James A. Russell1 and Keith R. Walley1*AbstractBackground: Acute kidney injury and hyperchloremia are commonly present in critically ill septic patients. Ourstudy goal was to evaluate the association of hyperchloremia and acute kidney injury in severe sepsis and septicshock patients.Methods: In this retrospective cohort study in a provincial tertiary care hospital, adult patients with severe sepsis orseptic shock and serum chloride measurements were included. Serum chloride was measured on a daily basis for48 hours. Primary outcome was development of acute kidney injury (AKI) and association of AKI and serum chlorideparameters was analyzed.Results: A total of 240 patients were included in the study, 98 patients (40.8 %) had hyperchloremia. The incidenceof acute kidney injury (AKI) was significantly higher in the hyperchloremia group (85.7 % vs 47.9 %; p < 0.001).Maximal chloride concentration in the first 48 hours ([Cl-]max) was significantly associated with AKI. In multivariateanalysis, [Cl-]max was independently associated with AKI [adjusted odds ratio (OR) for AKI = 1.28 (1.02–1.62); p = 0.037]. Theincrease in serum chloride (Δ[Cl-] = [Cl-]max – initial chloride concentration) demonstrated a dose-dependent relationshipwith severity of AKI. The mean Δ[Cl-] in patients without AKI was 2.1 mmol/L while in the patients with AKI stage 1, 2and 3 the mean Δ[Cl-] was 5.1, 5.9 and 6.7 mmol/L, respectively. A moderate increase in serum chloride (Δ[Cl-]≥5 mmol/L) was associated with AKI [OR = 5.70 (3.00–10.82); p < 0.001], even in patients without hyperchloremia[OR = 8.25 (3.44–19.78); p < 0.001].Conclusions: Hyperchloremia is common in severe sepsis and septic shock and independently associated with AKI. Amoderate increase in serum chloride (Δ[Cl-] ≥5 mmol/L) is associated with AKI even in patients without hyperchloremia.Keywords: Chloride, Hyperchloremia, Acute kidney injury, Sepsis, Septic shockBackgroundAcute kidney injury (AKI) frequently occurs in patientswith severe sepsis and septic shock [1]. A small rise inserum creatinine (26.5 μmol/L) in critically ill patients isassociated with higher mortality, longer length of stay,greater need of vasopressor and mechanical ventilatorsupport and worse long-term outcomes [2–5]. Identify-ing risk factors for development of AKI in sepsis maytherefore be helpful to understand and avoid thisprofound complication.Intravenous fluid resuscitation to restore effective cir-culatory volume in severely ill septic patients is a main-stay of early therapy of severe sepsis and septic shock.The Surviving Sepsis Campaign International Guidelinesrecommends crystalloids as the initial fluid of choice forresuscitation of septic shock patients [6]. Normal 0.9 %saline solution (Saline), is the most common isotoniccrystalloid solution used for resuscitation globally [7–9].However, the electrolyte composition of Saline is quitedifferent from serum electrolyte composition; Saline has* Correspondence: Keith.Walley@hli.ubc.ca1Centre for Heart Lung Innovation, St. Paul’s Hospital, University of BritishColumbia, 1081 Burrard Street., Vancouver, BC V6Z 1Y6, CanadaFull list of author information is available at the end of the article© 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Suetrong et al. Critical Care  (2016) 20:315 DOI 10.1186/s13054-016-1499-750 % greater chloride than serum (154 vs 100 mmol/L,respectively) [10]. Consequently, hyperchloremic meta-bolic acidosis is a common consequence of chloride-richsolution resuscitation [11, 12].Animal and human studies demonstrate that infusionof Saline results in decreased renal blood flow, reducedglomerular filtration rate, and delayed time to mictur-ition [13–15]. In an animal model of sepsis, resuscitationwith Saline resulted in a higher incidence of AKI com-pared to a balanced crystalloid solution with a morephysiologic chloride concentration [16]. A recent studyconducted by Yunos and colleagues [17] in critically illadults found that restriction of chloride-rich fluid wasassociated with a significant decrease in the incidence ofAKI and need for renal replacement therapy (RRT).However, a subsequent randomized controlled trial ofnormal saline vs. a balanced solution (Plasma-Lyte)found no difference in development of AKI. However,patients were unselected ICU patients, the exposure wasonly 2 L over the ICU stay, no renal biomarkers weremeasured, and the serum chloride was not reported.Thus it remains controversial how to manage fluids andchloride in the critically ill. To date, the association ofhyperchloremia and AKI has been observed in unse-lected critically ill patients [18] but not specifically inseptic patients [19, 20].Rapid volume resuscitation of septic patients withSaline rapidly changes serum chloride concentration.Despite all of the above work, it is unclear whether AKIassociated with chloride-rich volume resuscitation is dueto the absolute value of serum chloride rising above athreshold – hyperchloremia – or whether the change ofserum chloride concentration is more important. For ex-ample, a rapid increase in serum sodium concentration(rather than the absolute serum sodium concentration)can lead to central pontine myelinolysis.Accordingly we first tested the hypothesis that hyper-chloremia after volume resuscitation was associated withAKI in severe sepsis and septic shock patients. Second,we determined whether the change of serum chlorideconcentration resulting from volume resuscitation wasassociated with AKI in severe sepsis and septic shockpatients.MethodsStudy design and participantsThis study was a retrospective cohort study of patientswith severe sepsis or septic shock admitted to St. Paul’sHospital in Vancouver, a tertiary care referral hospital,from January 2011 to April 2015. We included all adultspatients with the following criteria: (1) 18 years or older;(2) diagnosis of severe sepsis (defined by two of four Sys-temic Inflammatory Response Syndrome (SIRS) criteriaplus a suspected or confirmed source of infection withat least one organ dysfunction or a lactate greater than4 mmol/L) or septic shock (defined by sepsis-inducedhypotension, tissue hypoperfusion or vasopressor re-quirement); and (3) initial serum chloride and dailyserum chloride concentration for the first 48 hours weremeasured. We excluded patients with pre-existingchronic renal failure or chronic use of RRT. Written in-formed consent was obtained from all patients or theirrepresentative and the study protocol was approved byour institutional ethics board.All of these patients were diagnosed via an institutionalsepsis protocol in the Emergency Department. Studyscreening was triggered by this protocol. Most of the re-suscitation was conducted by Emergency Departmentphysicians. The primary resuscitation fluid was Saline.Thirty-seven percent of these patients were admitted tothe ICU and managed by the attending intensivist.The treatment of these patients was evaluated and di-rected by attending physicians without a resuscitationguideline or protocol.Study variablesSerum chloride concentration was measured by indirectpotentiometry (ADVIA 1800 Chemistry System; SiemensHealthcare Diagnostic Inc., Oakville, ON, Canada). Theinitial chloride concentration, [Cl-]0 was the initial serumchloride concentration measured at the time that the pa-tient fulfilled diagnostic criteria for severe sepsis or sep-tic shock (above). Serum chloride concentration wasmeasured at least daily for the first 48 hours and themaximal serum chloride concentration during this timeperiod was designated as [Cl-]max. The increase in serumchloride, Δ[Cl-], was the difference between maximalserum chloride level and initial serum chloride level(Δ[Cl-] = [Cl-]max - [Cl-]0). Hyperchloremia was definedas [Cl-]max ≥ 110 mmol/L [20].The Acute Physiology and Chronic Health Evaluation II(APACHE II) score was determined by using clinical andlaboratory data on the first day of enrollment. AKI wasdiagnosed and classified by Kidney Disease ImprovingGlobal Outcomes (KDIGO) consensus criteria by anincrease in serum creatinine concentration > 50 %from a baseline creatinine concentration measured within3 months prior to enrollment [21]. If a previous serumcreatinine was not available, it was calculated by assumingthat the glomerular filtration rate (GFR) of the patient was75 mL/min per 1.73 m2 and serum creatinine concentra-tion was computed using the modified 4-variable Modifi-cation of Diet in Renal Disease (MDRD) formula [22].Study outcomesThe primary outcome was development of AKI byKDIGO criteria. The secondary outcomes were require-ment of RRT and 28-day mortality.Suetrong et al. Critical Care  (2016) 20:315 Page 2 of 8Statistical analysisDemographic and clinical data were compared between pa-tients with hyperchloremia and without hyperchloremia.Continuous data were reported by using mean ± standarddeviation (SD) or median (interquartile range) and categor-ical data as percentage. We used t tests to comparenormally distributed continuous data and Wilcoxonsigned-rank tests for non-normally distributed data. Forcategorical variables, a chi-square test was used.Logistic regression was used to test for association ofchloride parameters ([Cl-]0, [Cl-]max and Δ[Cl-], hyper-chloremia) with AKI, RRT, and 28-day mortality. Univar-iate logistic regression was used to test for unadjustedassociation between chloride parameters and AKI.Multivariate logistic regression was used to test for asso-ciations between chloride parameters and AKI afteradjusting for potentially confounding covariates. Inde-pendent variables with p < 0.1 in univariate models wereincorporated as covariates into the multivariate regres-sion model. These variables consisted of demographicdata (age, gender), underlying diseases (hypertension,congestive heart failure, chronic obstructive pulmonarydisease) and clinical severity at presentation (APACHE IIscore, serum lactate, requirement of vasopressor, mech-anical ventilator requirement).All analyses were performed using SPSS, version 20(SPSS, Chicago, IL, USA). A two-sided p value less than0.05 was considered to be statistically significant.ResultsPatient characteristicsIn this study, 275 patients with severe sepsis and septicshock were enrolled. Thirty-five patients were excludedbecause they had pre-existing chronic renal failure. Thus,240 patients were eligible for further evaluation (Fig. 1).Of these, 98 patients (40.8 %) had hyperchloremia withinthe first 48 hours of resuscitation and 142 patients(59.2 %) did not have hyperchloremia. Demographics,baseline characteristics and clinical outcome of patientswith hyperchloremia and without hyperchloremia areshown in Table 1. Patients with hyperchloremia had ahigher heart rate and APACHE II score, vasopressor andventilator requirement. Comorbidities, serum lactate andfluid intake/output were not different between the twogroups. Baseline serum creatinine also was not signifi-cantly different in both groups. Notably, there was nodifference in serum chloride before full resuscitationbetween those patients who developed hyperchloremia([Cl-]0 104.3 ± 7.7 mmol/L) and those who did not ([Cl-]0103.7 ± 4.6 mmol/L, p = 0.51).Univariate analysisSerum chloride and acute kidney injuryThe initial serum chloride, [Cl-]0, before full resuscita-tion was not associated with development of AKI [oddsratio 1.01 (0.97–1.05); p = 0.51]. The incidence of AKIwas significantly higher in the hyperchloremia group (84of 98 = 85.7 % versus 68 of 142 = 47.9 %; p < 0.001). Themaximum chloride concentration within the first48 hours, [Cl-]max, was associated with AKI with an oddsratio 1.14 per mmol [Cl-] (95 % CI 1.08–1.20, p < 0.001)(Table 2). Non-significant trends for patients with hyper-chloremia, compared to those without hyperchloremia,included a need of RRT (7.1 % versus 3.5 %; p = 0.206)and 28-day mortality (6.1 % versus 1.4 %; p = 0.066).Increase in serum chloride and severity of AKIThe increase in serum chloride, Δ[Cl-] (= [Cl-]max - [Cl-]0),was strongly associated with AKI. The odds ratio for de-velopment of AKI for Δ[Cl-] was 1.25 per mmol Δ[Cl-](95 % CI 1.16–1.36; p < 0.001), which was a stronger effectthan for [Cl-]max. Importantly, Δ[Cl-] remained signifi-cantly associated with development of AKI even in thosepatients who were never hyperchloremic with an odds ra-tio of 1.37 per mmol Δ[Cl-] (95 % CI 1.20–1.56). A dose-response relationship of Δ[Cl-] and severity of AKI wasobserved; the greater the Δ[Cl-], the more severe the AKIstage. The mean Δ[Cl-] in patients without AKI was2.06 mmol/L, for AKI stage 1 Δ[Cl-] was 5.14 mmol/L, forAKI stage 2 Δ[Cl-] was 5.88 mmol/L, and for AKI stage 3Δ[Cl-] was 6.70 mmol/L (Fig. 2).Moderate increase in serum chloride and AKISince AKI stage 1, 2, and 3 were all associated with amean Δ[Cl-] ≥ 5 mmol/L we used this value as a threshold.A moderate increase in serum chloride (Δ[Cl-] ≥ 5 mmol/L) identified patients with an odds ratio of developing anyAKI of 5.70 (3.00–10.82); p < 0.001 and an odds ratio ofdeveloping more severe AKI (AKI stage 2 and 3) of 3.40(1.95–5.94); p < 0.001. Interestingly, in patients withouthyperchloremia, Δ[Cl-] ≥ 5 mmol/L was also associatedwith AKI (OR = 8.25, 95 % CI 3.44–19.78; p < 0.001) andFig. 1 Flow chart of the patients with severe sepsis and septic shockin the study. [Cl-]max maximal chloride concentration in the first48 hours, AKI acute kidney injury, CRF chronic renal failureSuetrong et al. Critical Care  (2016) 20:315 Page 3 of 8more severe AKI (AKI stage 2 and 3) (OR = 4.8, 95 % CI2.1–10.7; p < 0.001) (Table 3).Multivariate analysisTo adjust for baseline differences we incorporated age,gender and all potentially confounding variables [withp < 0.1 in univariate logistic regression analysis; hyper-tension, congestive heart failure, chronic obstructivepulmonary disease (COPD), APACHE II score, serum lac-tate, vasopressor and ventilator requirement] into themultivariate model. [Cl-]max remained significantly associ-ated with AKI (OR = 1.35, 95 % CI 1.09–1.66, p = 0.006).Norepinephrine dosage was included quantitatively inthe multivariable model and, while associated withAKI in the univariate analysis, it sufficiently covariedwith other factors in the multivariate model (e.g.,mean arterial pressure, APACHE II score) so that thisassociation was not significant in the multivariatemodel. In contrast serum chloride remained an inde-pendent predictor of AKI (Table 4).Table 1 Demographic and clinical variables and outcome of patients classified by serum chloride statusVariable HyperchloremiaN = 98No hyperchloremiaN = 142pDemographicsAge, yr, mean ± SD 57.5 ± 15.1 52.9 ± 18.4 0.05Male, % 46.9 55.6 0.38Underlying diseasesHypertension, % 36.7 28.2 0.074Ischemic heart disease, % 6.1 5.6 0.65CHF, % 4.1 8.5 0.10DM, % 21.4 21.1 0.71COPD, % 21.4 18.3 0.086Cirrhosis, % 7.1 4.9 0.082Malignancy, % 4.1 5.6 0.20HIV, % 11.2 9.2 0.56Chronic steroid treatment, % 5.1 6.3 0.91Clinical parameters at presentationMAP, mean ± SD 85 ± 21 89 ± 17 0.12HR, mean ± SD 104 ± 22 96 ± 21 0.003aLactate, mean ± SD 2.9 ± 2.8 2.5 ± 2.4 0.29Creatinine(mg/dL), median (IQR) 1.0 (0.7-1.4) 0.9 (0.4-1.4) 0.49APACHE II score, mean ± SD 11.3 ± 5.0 7.8 ± 5.4 <0.001aClinical parameters at 24 hrVasopressor, % 31 11 <0.001aMechanical ventilator, % 64 32 <0.001aFluid intake, mean ± SD 4959 ± 3,417 4691 ± 2,341 0.71Urine output, mean ± SD 2416 ± 1,146 2554 ± 1,463 0.644Chloride parametersInitial chloride ([Cl-]0), mean ± SD 104.3 ± 7.7 103.7 ± 4.6 0.51Maximal Cl in 48 hours ([Cl-]max) 104.4 ± 3.7 114.4 ± 3.6 <0.001aIncrease in serum Cl (Δ[Cl-]) 3.2 ± 4.2 6.1 ± 5.0 <0.001aClinical outcomeAKI, % 85.7 47.9 <0.001aRRT, % 7.1 3.5 0.20628-day mortality, % 6.1 1.4 0.066SD standard deviation, CHF congestive heart failure, DM diabetes mellitus, COPD chronic obstructive pulmonary disease, HIV human immunodeficiency virus, MAPmean arterial pressure, HR heart rate, IQR interquartile rate, APACHE Acute Physiology and Chronic Health Evaluation, [Cl-]0 initial chloride concentration, [Cl-]maxmaximal chloride concentration in the first 48 hours, Δ[Cl-] increase in serum chloride; AKI acute kidney injury, RRT renal replacement therapyaIndicates statistical significance, p < 0.05Suetrong et al. Critical Care  (2016) 20:315 Page 4 of 8Serum sodium and bicarbonate and AKITo test an alternative explanation that serum chloride wassimply a marker of the degree of volume resuscitation, werepeated the multivariate analysis using alternative elec-trolytes that would similarly covary with Saline volume re-suscitation. The multivariable analysis was repeated usinginitial and maximal serum sodium and initial and maximalserum bicarbonate. None of these variables were signifi-cant independent predictors of AKI (Table 4).DiscussionThe main result of this study is hyperchloremia is com-mon and significantly associated with AKI in severe sep-sis and septic shock patients. Although initial serumchloride concentration before volume resuscitation didnot correlate with development of AKI, maximal serumchloride concentration in the first 48 hours ([Cl-]max)and the increase in serum chloride (Δ[Cl-]) were signifi-cantly associated with AKI. Because the patients in thehyperchloremia group had higher APACHE II score,vasopressor and ventilator requirement that might resultin higher AKI than the patients in the normochloremiagroup rather than by hyperchloremia, we use a multivari-ate logistic regression model to minimize the effect ofthese confounders. After several potential confounderssuch as age, gender, hypertension, congestive heart failure,COPD, APACHE II score, serum lactate, vasopressor andventilator requirement were adjusted for in the multivari-ate logistic regression model, [Cl-]max remained independ-ently associated with AKI. Moreover, an increase in serumchloride was associated with AKI and more severe AKI(AKI stage 2 and 3). Importantly, Δ[Cl-] ≥ 5 mmol/L wasassociated with the development of AKI even in the pa-tients who never developed hyperchloremia. Thus, thesedata suggest that a rapid change in serum chloride con-centration may be more important than the absolute valueof serum chloride in causing AKI.To our knowledge this is the first report of the associ-ation of a moderate increase in serum chloride (Δ[Cl-] ≥5 mmol/L) and development of AKI in severe sepsis andseptic shock, even in patients without hyperchloremia.Our results are consistent with a retrospective study ofunselected critically ill patients in which there was an as-sociation of maximal chloride concentration and the de-velopment of AKI [18]. Our study used serum chlorideconcentration in the first 48 hours to define hyperchlor-emia and found the association of [Cl-]max with the de-velopment of AKI in severe sepsis and septic shock. Weobtained chloride measurements prior to significant vol-ume resuscitation and found that this initial serumchloride concentration ([Cl-]0) was not associated withdevelopment of AKI. Previous studies found a relation-ship between initial chloride concentration and develop-ment of AKI, although these initial measurements mayhave followed a substantial saline resuscitation [19, 20].More recently, a double-blind randomized trial evaluat-ing the effect of Saline versus Plasma-Lyte in the inten-sive care unit (the SPLIT trial) demonstrated nodifference of AKI incidence and severity between thetwo groups [23]. However, most patients were postoper-ative (71 %) and only 4 % of patients were diagnosed assepsis. Overall incidence of AKI by KDIGO criteria waslower (27 %) compared to what we observed (63 %) inour sepsis/septic shock population. The volume of crys-talloid solution used in that trial (2000 mL) was muchless than the average volume that was infused in our pa-tients (4825 mL). This study did not report serum chlor-ide concentrations so it is unknown whether this smallvolume of Saline resuscitation over an extended periodof time was sufficient to cause either hyperchloremia orΔ[Cl-] ≥ 5 mmol/L.We did not find a statistically significant associationbetween hyperchloremia and need for RRT although weobserved a trend in this direction. A previous studyfound a similar statistically significant trend in the asso-ciation of chloride restrictive strategy and reduction ofRRT requirement [17]. However, we excluded the pa-tients with pre-existing chronic renal failure and need ofRRT in our study was lower (5 % vs 10 %). Second, aTable 2 Univariate logistic regression model to test associationof AKI and initial serum chloride ([CL-]0), maximal serum chloridein first 48 hours ([Cl–]max), and increase in serum chloride(Δ[Cl-] = [Cl-]max–[CL-]0)Variable AKI stage 1 to 3 p AKI stage 2 and 3 pOdds ratio (95 % CI) Odds ratio (95 % CI)[CL-]0 1.01 (0.97–1.05) 0.478 0.99 (0.95–1.03) 0.562[Cl-]max 1.14 (1.08–1.20) <0.001a 1.07 (1.02–1.12) 0.006aΔ[CL-] 1.25 (1.16–1.36) <0.001a 1.14 (1.07–1.21) <0.001aAKI acute kidney injury, [Cl-]0 initial chloride concentration, [Cl-]max maximalchloride concentration in the first 48 hours, Δ[Cl-] increase in serum chloride,CI confidence intervalaIndicates statistical significance, p <0.05Fig. 2 Increase in serum chloride and AKI severity. The mean increasein serum chloride (Δ[Cl-]) in AKI stage 1, 2 and 3 is significantly higherthan in patients without AKI (p < 0.05) and these data suggest a dose-response relationship between Δ[Cl-] and AKI stage. Δ[Cl-] increase inserum chloride, AKI acute kidney injury,Suetrong et al. Critical Care  (2016) 20:315 Page 5 of 8smaller sample size in our study limited the statisticalpower of detection. Moreover, our populations wereexclusively severe sepsis or septic shock while in the pre-vious study only 7 % were severe sepsis or septic shock.Normal saline solution was originally called “indiffer-ent” saline because it was recognized that human eryth-rocytes did not lyse in the 0.9 % NaCl solution [24].Despite being called “normal saline” solution, it has a nearphysiological concentration of sodium (154 mmol/L) butsupraphysiologic concentration of chloride (154 mmol/Lor 1.5 times of normal serum chloride concentration) [25].Infusion of 0.9 % NaCl is significantly associated withhyperchloremic metabolic acidosis in both healthy volun-teers and various types of patient [26–35]. The clinicalsignificance of iatrogenic hyperchloremic metabolic acid-osis remains uncertain. The hospital mortality is muchhigher in lactic acidosis than in hyperchloremic acidosis(56 % vs 29 %) compared with the hospital mortality of pa-tients without acidosis (26 %) [36].Supraphysiologic serum chloride concentration hasdetrimental effects on renal function. In animal models,infusion of 0.9 % NaCl resulted in renal vasoconstrictionand decreased renal blood flow and glomerular filtrationrate [13, 37–39] possibly due to chloride-inducedthromboxane release [38] and augmented response torenal vasoconstrictors such as angiotensin II [40]. Fur-thermore, the tubuloglomerular feedback mechanisminitiated by detection of chloride at the macula densa re-sults in afferent arteriolar vasoconstriction, mesangialcontraction and decreased glomerular filtration rate [41].In healthy human volunteers, infusion of normal salinecaused reductions in renal artery blood flow, renal cor-tical perfusion [14] and delayed first micturition [15, 27].Saline infusion resulted in a higher incidence of AKIwhen compared with balanced crystalloids [17, 42, 43].In an animal model of sepsis, resuscitation of septic ani-mals with Saline resulted in not only higher incidence ofAKI and greater severity of AKI but also higher inflam-matory mediator concentrations (IL-6) when comparedto Plasma-Lyte [16]. Interestingly, the study of effect ofan acute Saline infusion on fluid and electrolyte metab-olism revealed that the human body required 2 days torestore electrolyte and fluid balance to equilibrium [44].There are several limitations to this study. First, it wasa retrospective cohort study so the association of hyper-chloremia with AKI does not necessarily imply causality.Second, we were not able to determine the amount ofchloride administered from the medical records so theanalysis is based on the consequence – the change inserum chloride concentration. Hyperchloremia may havenegative effects on renal function and cause AKI. Alter-natively, increased severity of shock would lead to AKIand increased administration of Saline without a causalTable 3 Univariate logistic regression model to test association of AKI and increase in serum chloride (ΔCL = [Cl-]max - CL0) in allpatients and patients without hyperchloremiaVariable AKI stage 1 to 3 p AKI stage 2 and 3 pOdds ratio (95 % CI) Odds ratio (95 % CI)All patientsΔ[Cl-] 1.25 (1.16–1.36) <0.001a 1.14 (1.07–1.20) <0.001aΔ[Cl-]≥ 5 mmol/l 5.70 (3.00–10.82) <0.001a 3.40 (1.95–5.94) <0.001aPatients without hyperchloremiaΔ[Cl-] 1.37 (1.20–1.56) <0.001a 1.25 (1.13–1.38) <0.001aΔ[Cl-]≥ 5 mmol/l 8.25 (3.44–19.78) <0.001a 4.77 (2.13–10.70) <0.001aAKI acute kidney injury, Δ[Cl-] increase in serum chloride, [Cl-]max maximal chloride concentration in the first 48 hours, [Cl-]0 initial chloride concentration, CIconfidence intervalaIndicates statistical significance, p < 0.05Table 4 Multivariate logistic regression of association of AKIwith initial serum chloride ([Cl-]0), maximal serum chloride([Cl-]max), initial serum sodium (Na0) and maximal serumsodium(Namax)OR 95 % confidence interval pAge 0.99 0.95 1.04 0.776Sex (male) 0.40 0.09 1.77 0.228Hypertension 0.68 0.13 3.70 0.656APACHE II 1.55 1.19 2.03 0.001aSerum lactate 1.60 0.84 3.04 0.155Norepinephrine dosage 1.06 0.82 1.36 0.680Ventilator requirement 3.95 0.57 27.44 0.165[Cl-]0 0.87 0.70 1.10 0.240[Cl-]max 1.28 1.02 1.62 0.037aΔ[Cl-] 1.32 1.07 1.61 0.008aNa0 1.01 0.76 1.35 0.825Namax 1.03 0.81 1.31 0.825Multivariate logistic regression model was adjusted by incorporating allpotentially confounding factors including age, gender, underlying diseases,initial serum lactate, APACHE II score and requirement of vasopressorand ventilatorAKI acute kidney injury, OR odds ratio, APACHE Acute Physiology and ChronicHealth EvaluationaIndicates statistical significance, p < 0.05Suetrong et al. Critical Care  (2016) 20:315 Page 6 of 8relationship between the two. Second, these results do notaddress the mechanism or pathophysiology of hyperchlor-emia and AKI. Finally, the small sample size significantlylimits power to detect an association of hyperchloremia orΔ[Cl-] with RRT and 28-day mortality.ConclusionsHyperchloremia is common in severe sepsis and septicshock patients and is independently associated with AKI.Initial serum chloride concentration is not associated withthe development of AKI while hyperchloremia, defined asthe maximum serum chloride concentrations measure-ment in the first 48 hours, is associated with developmentof AKI. Our most striking finding is the association ofmoderate increase in serum chloride (Δ[Cl-] ≥ 5 mmol/L)and AKI even in patients who had serum chloride withinthe normal range. Finally, there is a continuing need forRCTs of intravenous fluid in sepsis and septic shock thataddress the risks of saline vs. balanced solutions for devel-opment of AKI. Perhaps serum chloride could be a bio-marker for response to various intravenous fluids.Abbreviations[Cl-]0: initial chloride concentration; [Cl-]max: maximal chloride concentrationin the first 48 hours; Δ[Cl-]: increase in serum chloride; AKI: acute kidneyinjury; APACHE: Acute Physiology and Chronic Health Evaluation;CI: confidence interval; COPD: chronic obstructive pulmonary disease;CRF: chronic renal failure; GFR: glomerular filtration rate; KDIGO: KidneyDisease Improving Global Outcomes; MDRD: Modification of Diet in RenalDisease; Na0: initial serum sodium; Namax: maximal serum sodium in first48 hours; OR: odds ratio; RRT: renal replacement therapy; SD: standarddeviation; SIRS: systemic inflammatory response syndromeAcknowledgementsNot applicable.FundingNot applicable.Availability of data and materialsNot applicable.Authors’ contributionsJB contributed to study conception and design, prepared and collected dataand helped to draft the manuscript. JR participated in study conception anddesign, and helped to draft and revise the manuscript. CP participated in studyconception and design, and performed statistical analysis. BS participated instudy conception and design, collected data, performed statistical analysis,and drafted and revised the manuscript. KW participated in study conceptionand design, and helped to draft and revise the manuscript. All authors madesubstantial contribution. All authors read and approved the final version of themanuscript.Competing interestsThe authors declare that they have no competing interests.Consent for publicationNot applicable.Ethics approval and consent to participateThis study was approved by the University of British Columbia, ethicsapproval H11-00505, and all patients gave written informed consent to theuse of both their clinical and analytical data. In a blinded, observational,cohort study, patients with suspected sepsis were identified when theattending Emergency Department physician activated the InstitutionalSevere Sepsis Order Set.SupportCanadian Institutes for Health Research.Author details1Centre for Heart Lung Innovation, St. Paul’s Hospital, University of BritishColumbia, 1081 Burrard Street., Vancouver, BC V6Z 1Y6, Canada. 2Departmentof Pediatrics, Faculty of Medicine, Thammasat University, Pathum Thani,Thailand. 3Department of Anesthesiology, Ramathibodi Hospital, Faculty ofMedicine, Mahidol University, Bangkok, Thailand.Received: 29 June 2016 Accepted: 19 September 2016References1. Poukkanen M, Vaara ST, Pettilä V, et al. Acute kidney injury in patients withsevere sepsis in Finnish Intensive Care Units. Acta Anaesthesiol Scand. 2013;57:863–72.2. Lopes JA, Jorge S, Resina C, et al. Acute kidney injury in patients with sepsis:a contemporary analysis. Int J Infect Dis. 2009;13:176–81.3. 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Effects of an acute saline infusion on fluidand electrolyte metabolism in humans. Am J Physiol. 1992;262:F744–54.•  We accept pre-submission inquiries •  Our selector tool helps you to find the most relevant journal•  We provide round the clock customer support •  Convenient online submission•  Thorough peer review•  Inclusion in PubMed and all major indexing services •  Maximum visibility for your researchSubmit your manuscript atwww.biomedcentral.com/submitSubmit your next manuscript to BioMed Central and we will help you at every step:Suetrong et al. Critical Care  (2016) 20:315 Page 8 of 8

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