Neurocrit Care https://doi.org/10.1007/s12028-020-00928-0

ORIGINAL WORK (CLINICAL INVESTIGATION, BASIC SCIENCE) Hyperchloremia, not Concomitant , Independently Predicts Early Mortality in Critically Ill Moderate–Severe Traumatic Brain Injury Patients Kristen L. Ditch1* , Julie M. Flahive2, Ashley M. West3, Marcy L. Osgood4,5,6 and Susanne Muehlschlegel4,5,6

© 2020 Springer Science+Business Media, LLC, part of Springer Nature and Neurocritical Care Society

Abstract Background: Hypernatremia has been associated with mortality in neurocritically ill patients, with and without traumatic brain injury (TBI). These studies, however, lack concomitant adjustment for hyperchloremia as a physiologi- cally co-occurring fnding despite the associations with hyperchloremia and worse outcomes after trauma, , and intracerebral hemorrhage. The objective of our study was to examine the association of concomitant hypernatremia and hyperchloremia with in-hospital mortality in moderate–severe TBI (msTBI) patients. Methods: We retrospectively analyzed prospectively collected data from the OPTIMISM-study and included all msTBI patients consecutively enrolled between 11/2009 and 1/2017. Time-weighted average (TWA) and values were calculated for all patients to examine the unadjusted mortality rates associated with the burden of hyper- natremia and hyperchloremia over the entire duration of the intensive care unit stay. Multivariable logistic regression modeling predicting in-hospital mortality adjusted for validated confounders of msTBI mortality was applied to evalu- ate the concomitant efects of hypernatremia and hyperchloremia. Internal bootstrap validation was performed. Results: Of the 458 patients included for analysis, 202 (44%) died during the index hospitalization. Fifty-fve patients (12%) were excluded due to missing data. Unadjusted mortality rates were nearly linearly increasing for both TWA sodium and TWA chloride, and were highest for patients with a TWA sodium > 160 mmol/L (100% mortality) and TWA chloride > 125 mmol/L (94% mortality). When evaluated separately in the multivariable analysis, TWA sodium (per 10 mmol/L change: adjusted OR 4.0 [95% CI 2.1–7.5]) and TWA chloride (per 10 mmol/L change: adjusted OR 3.9 [95% CI 2.2–7.1]) independently predicted in-hospital mortality. When evaluated in combination, TWA chloride remained independently associated with in-hospital mortality (per 10 mmol/L change: adjusted OR 2.9 [95% CI 1.1–7.8]), while this association was no longer observed with TWA sodium values (per 10 mmol/L change: adjusted OR 1.5 [95% CI 0.51–4.4]). Conclusions: When concomitantly adjusting for the burden of hyperchloremia and hypernatremia, only hyperchlo- remia was independently associated with in-hospital mortality in our msTBI cohort. Pending validation, our fndings

*Correspondence: [email protected] 1 Department of Clinical Pharmacy, UMass Memorial Medical Center, 55 Lake Avenue North, Worcester, MA 01655, USA Full list of author information is available at the end of the article

This work was performed at the University of Massachusetts Medical School and its afliated university hospital, UMass Memorial Medical Center (Worcester, MA). may provide the rationale for future studies with targeted interventions to reduce hyperchloremia and improve outcomes in msTBI patients. Keywords: Traumatic brain injury, Hyperchloremia, Hypernatremia, Neurocritical care, Mortality

Introduction Materials and Methods Hypernatremia independently predicts in-hospital Study Design mortality in patients with moderate–severe trau- We performed a retrospective analysis of prospectively matic brain injury (msTBI) and other neurocriti- collected data from the Outcome Prognostication in cally ill patients when peak serum sodium exceeds Traumatic Brain Injury (OPTIMISM)-study at the Uni- 160 mmol/L in some retrospective studies [1–3]. Con- versity of Massachusetts Medical School and its afliated sequently, some clinicians will exercise caution and university hospital UMass Memorial Medical Center. use 160 mmol/L as an upper sodium target when pre- All consecutive adult patients with msTBI [worst post- scribing hyperosmotic agents, such as mannitol and resuscitation Glasgow Coma Scale (GCS) in the frst 24 h hypertonic , for management of cere- without intoxication or sedation of 3–12] admitted to bral and elevated intracranial pressure (ICP) in the Neurological-Trauma-Intensive Care Unit (NTICU) these patients [1]. Limitations of these studies include between November 2009 and January 2017 were enrolled the evaluation of sodium in isolation of its chloride in the OPTIMISM-study [13] and analyzed. Tis study anion, marked heterogeneity of study populations, and was approved by the local institutional review board use of only peak or mean serum sodium with unknown (IRB) with written informed consent obtained from the duration or “burden” of hypernatremia over time. patient or surrogate decision-maker. For non-survivors, Known side effects of hyperosmotic therapy include the IRB granted a waiver for documentation of written not only hypernatremia, but also acute injury consent. Data were recorded in the local Research Elec- (AKI) and hyperchloremia [4–7]. Recent studies on tronic Data Capture platform [14]. Patients were man- hyperchloremia have revealed associations with mor- aged per the Brain Trauma Foundation guidelines with tality in patients with trauma, sepsis, intracerebral a protocolized treatment as previously described [15, hemorrhage, heterogeneous critically ill patients [7– 16]. Serum sodium and chloride values were obtained 10], and AKI in subarachnoid hemorrhage patients with a basic metabolic panel daily or more frequently [11]. A current knowledge gap exists in understanding per the treating clinical team if the patient was receiving the potential impact of hyperchloremia alone, as well hyperosmolar therapy. At our institution, we administer as the concomitant impact of hyperchloremia with intermittent doses of 1 g/kg of mannitol 20% (osmolar- hypernatremia, on mortality in patients with msTBI. ity 1098 mOsm/L) intravenously (IV) every 6 h, 15 mL Examining this impact using time-weighted aver- (60 mEq) or 30 mL (120 mEq) of 23.4% sodium chlo- age (TWA) sodium and chloride values, as opposed ride (NaCl) boluses (concentration, 4 mEq/mL, osmo- to peak or standard mean values, may reduce bias larity 8008 mOsm/L) IV every 6 h to achieve a goal because time is factored into the calculation. Peak ICP < 23 mmHg. Our clinical routine does not include values do not account for fluctuations in sodium and 3% NaCl bolus or infusions and therefore these were not chloride values throughout the day, and standard mean captured for this study. Total doses of mannitol and 23.4% values may be biased due to unequal time measure- NaCl were recorded by cross-referencing patients from ments or repeat testing due to an outlying value [12]. the OPTIMISM-study with the clinical pharmacy data- The primary objective of our current study was to base of administered drugs. We retrospectively obtained examine the concomitant association of hyperna- serum sodium and chloride values from an i2b2-based tremia and hyperchloremia with in-hospital mortal- semi-automated electronic medical record search algo- ity in msTBI patients utilizing TWA values. Given the rithm cross-linked to the OPTIMISM patients. Serum emerging data on the associations of hyperchloremia sodium and chloride were measured by AU5800 series with poor outcomes, we hypothesized that hyperchlo- analyzers (Beckman Coulter Inc, Brea, CA). We defned remia, along with hypernatremia, will be indepen- hypernatremia as any sodium value > 140 mmol/L. Tis dently associated with in-hospital mortality. value was chosen to capture those patients with border- line hypernatremia as they may be at risk of increased mortality based on previous retrospective literature [17, 18]. Hyperchloremia was defned as any chloride value > 110 mmol/L. Te exact date and time of all serum sodium and stay (LOS), osmotic therapy administration, and AKI. chloride values obtained during the patient’s NTICU Patients with missing data for any of the variables in the stay were recorded to calculate TWA sodium and chlo- multivariable logistic regression model were excluded ride values for each patient. Using a model previously from the analysis. TWA sodium and TWA chloride val- described for reporting TWA [12], we ues were added to the adjusted model frst separately, and applied the trapezoidal rule to calculate TWA sodium then in combination, to explore the association with in- and chloride values (Supplement 1). Te TWA eliminates hospital mortality. Te variables TWA sodium and TWA the bias created by unequal serum sodium and chloride chloride were evaluated for collinearity. We reported measurements because the diference in time associated adjusted odds ratios (OR) and corresponding 95% con- with each measurement is factored into the calculation fdence intervals. Model discrimination was described [12]. by the c-statistic, and model calibration was assessed by the Hosmer–Lemeshow goodness-of-ft test. An alpha Outcome measures level < 0.05 indicated statistical signifcance. Because dia- Te primary outcome of this study was in-hospital mor- betes insipidus (DI) is not recorded as a pre-specifed tality. We defned NTICU-acquired AKI according to complication in the OPTIMISM cohort, we were not the 2004 Risk, Injury, Failure, Loss of kidney function, able to classify patients with DI. Terefore, we performed and End-stage classifcation as well as the a post hoc sensitivity analysis excluding all brain dead 2011 Kidney Disease: Improving Global Outcomes Clini- patients as DI usually occurs near brain death. We inter- cal Practice Guideline as any of the following: increase in nally validated our multivariable models using 100 boot- strap samples and corrected our C-statistic for optimism, serum creatinine by ≥ 0.3 mg/dL (≥ 26.5 µmol/L) within 48 h, three time increase in baseline serum creatinine, as commonly applied to multivariable prediction models [22]. All analyses were performed using SAS 9.4 software decrease in glomerular fltration rate ≥ 50%, urine out- put < 0.5 mL/kg/h for 24 h, or anuria for 12 h [19, 20]. (SAS Institute Inc, Cary, NC), including a SAS macro for Radiological images were adjudicated using a method our bootstrap validation [23, 24]. previously described [13]. Results Statistical analysis We identifed 502 msTBI patients consecutively enrolled Baseline characteristics were compared in a univariate in the OPTIMISM-study between November 2009 and analysis between survivors and non-survivors. Percent- January 2017. Tirty-nine were excluded for GCS ≥ 13. ages were reported for categorical variables. Means and Five patients were excluded because their trauma cause standard deviations were calculated for normally distrib- was hanging, with resultant hypoxic-ischemic brain uted continuous variables, and medians and interquar- injury. Because these patients lacked TBI, they were tile ranges (IQR) were calculated for skewed continuous excluded from OPTIMISM. Our total cohort consisted variables. Using clinically meaningful groups of hyper- of 458 patients: 202 non-survivors and 256 survivors natremia and hyperchloremia severity, we explored the (Fig. 1). Te patients had a mean age of 51 (SD 22) years, relationship between unadjusted mortality rates and and 71% were male. Te most common causes of trauma TWA sodium and TWA chloride values. Diferences were falls (47%) and high-velocity injuries involving a between survivors and non-survivors were compared using the Chi-square test for categorical variables, and the t test or Wilcoxon rank sum test for normally or non-normally distributed continuous variables, respec- tively. Te multivariable logistic regression analysis was adjusted for the IMPACT-model [21] variables: age, admission motor GCS, pre-admission hypoxia (oxygen saturation < 90%) or pre-admission hypotension (sys- tolic < 90 mmHg), admission Marshall- computed tomography (CT) classifcation, admission pupillary reactivity, and presence of epidural hematoma or traumatic subarachnoid hemorrhage on admission CT. In addition to these variables, we also included vari- ables with a p value of < 0.2 in the univariate analysis that Fig. 1 Flowchart. Shown is a fowchart depicting how the fnal ana- remained independently associated with outcome includ- lyzed cohort was derived. GCS Glasgow Coma Scale ing: duration of mechanical ventilation, ICU length of moving vehicle (40%). Te median dose of mannitol was optimism-corrected C-statistics remained high (> 0.94) 108 grams/day (IQR 100, 178), and median dose of 23.4% for all three multivariable models (Supplemental Table 4). NaCl was 165 mEq/day (IQR 120, 276). Baseline charac- teristics and diferences between survivors and non-sur- Discussion vivors are shown in Table 1. In our cohort, both crude sodium and chloride TWA val- Te rate of unadjusted, in-hospital mortality increased ues had a near linear increase in mortality rates. When to over 75% when TWA sodium was 151–160 mmol/L, evaluating the association of sodium and chloride in and to 100% for TWA values > 160 mmol/L (Fig. 2a). Te combination, as seen physiologically in patients, only rate of unadjusted, in-hospital mortality was 94% for hyperchloremia independently predicted in-hospital TWA Cl values > 125 mmol/L (Fig. 2b). Te relationship mortality. We believe that these fndings are not sim- between serum sodium and TWA, peak, ply a refection of disease severity, because our fndings and mean measurements and unadjusted in-hospital persisted even after adjusting for the IMPACT-model mortality are shown in Supplemental fgure 3, panel A variables as validated confounders of TBI mortality [21], and panel B, respectively. osmotic therapy administration, ICU LOS, duration of Retained variables in the fnal adjusted model included mechanical ventilation, and AKI. Our fndings suggest the IMPACT-variables, duration of mechanical ventila- that hyperchloremia may be more relevant than previ- tion, ICU LOS, osmotic therapy administration, and AKI. ously known, possibly even more relevant than hyperna- Fifty-fve patients (12%) had missing data for “duration tremia, when assessing early mortality after msTBI. of mechanical ventilation” (n = 34), chloride (n = 13), To our knowledge, this study is the frst to examine the or sodium (n = 8) and were excluded for our complete relationship between hyperchloremia and hospital mor- case analysis. Te OR and 95% CI for all variables in tality in patients with msTBI. Tis study contributes to the adjusted model evaluating TWA sodium and TWA the growing body of the literature evaluating the poten- chloride separately are shown in Supplemental Table 2. tial detrimental efects of hyperchloremia in critically ill Individual analysis of TWA sodium and TWA chloride patients. Previous studies have reported an association values resulted in signifcant associations with in-hospital between hyperchloremia and AKI or mortality in vari- mortality (per 10 mmol sodium/L change: adjusted OR ous critically ill populations including septic, intracranial 4.0 [95% CI 2.1–7.5]; per 10 mmol chloride/L change: hemorrhage, subarachnoid hemorrhage, trauma, medi- adjusted OR 3.9 [95% CI 2.2–7.1]). When TWA sodium cal, and surgical patients [7–11, 26–28]. TBI patients are and TWA chloride values were evaluated in combina- subject to a high chloride burden secondary to the use of tion in the multivariable model, only TWA chloride inde- isotonic for maintenance fuids and hyperosmotic pendently predicted in-hospital mortality (per 10 mmol therapy to manage cerebral edema. One study retrospec- chloride/L change: adjusted OR 2.9 [95% CI 1.1–7.8]), tively evaluated the impact of hyperchloremia on clinical while TWA sodium was no longer independently associ- outcomes in intracerebral hemorrhage patients. In-hos- ated with in-hospital mortality (per 10 mmol sodium/L pital mortality was signifcantly higher in patients with change: adjusted OR 1.5 [95% CI 0.51–4.4]) (Table 2). moderate hyperchloremia (≥ 115 mmol/L) in a propen- Collinearity between TWA sodium and TWA chloride sity-matched cohort and was an independent predictor was confrmed (Pearson correlation coefcient = 0.86, of mortality in that study (OR 4.4 [95% CI 1.4–13.5]) [7]. p < 0.01), but its presence does not afect the direction In our adjusted model, TWA chloride (when evaluated of the estimate nor the independent association of each without sodium) resulted in a similar OR for hospital variable with the outcome [25]. mortality (OR 3.9 [95% CI 2.2–7.1]). Te results of the post hoc sensitivity analysis exclud- Te underlying biological explanation as to why hyper- ing all brain dead patients (n = 51) are shown in Sup- chloremia, but not hypernatremia, had an independ- plemental table 3a–3c. Te exclusion of 51 brain dead ent association with hospital mortality in our study is patients resulted in a reduction of the full cohort by unknown. Tere are several potential explanations for 13% to n = 352 and a reduction of non-survivors by 27% the association of hyperchloremia and worse outcomes to n = 135. As in the primary analysis, when including in critically ill patients. In animal models, chloride-rich TWA sodium and TWA chloride separately into the fully solutions decreased the glomerular fltration rate through adjusted multivariable model, both remained independ- renal vasoconstriction, decreased fbrinogen levels, and ent predictors of in-hospital mortality (Supplemental increased blood loss [29–31]. In critically ill patients, a table 3a and 3b). When including both variables simul- chloride restrictive strategy of fuid hydration was associ- taneously, hyperchloremia was no longer independently ated with a decrease in AKI [32]. We adjusted our mor- associated with mortality (Supplemental table 3c). Our tality model for AKI, and yet hyperchloremia remained results were validated internally with bootstrapping, and independently associated with mortality. Additionally, Table 1 Baseline characteristics

Characteristic Total cohort (n 458) Non-survivors (n 202) Survivors (n 256) p value = = = Age (years), mean (SD) 51 (22) 57 (22) 47 (21) < .0001 Male, n (%) 326 (71) 149 (74) 177 (69) 0.28 Race, n (%) 0.06 White/Caucasian 417 (91) 181 (90) 236 (92) Black or African-American 18 (3.9) 6 (3.0) 12 (4.7) Asian 10 (2.2) 5 (2.5) 5 (2.0) American Indian or Alaska Native 1 (0.22) 0 (0) 1 (0.39) Unknown or not documented 11 (2.4) 2 (0.78) 9 (4.5) Ethnicity, n (%) 0.10 Hispanic or Latino 37 (8.1) 12 (5.9) 25 (9.8) Not Hispanic or Latino 396 (86) 175 (87) 221 (86) Unknown or not documented 25 (5.5) 15 (7.4) 10 (3.9) Motor Glasgow Coma Scale, median (IQR) 4 (1, 5) 1 (1, 4) 5 (3, 5) < .0001 Injury Severity Scale, median (IQR) 27 (25, 38) 27 (26, 38) 29 (21, 36) 0.03 Cause of trauma, n (%) < .0001 High-velocity injury involving moving vehicle 182 (40) 61 (30) 121 (47) Fall 215 (47) 109 (54) 106 (41) Assault 34 (7.4) 10 (5.0) 24 (9.4) Gun shot wound 27 (5.9) 22 (11) 5 (2.0) Marshall head CT grading on frst CT, n (%) < .0001 Difuse injury Type II 263 (57) 66 (33) 197 (77) Difuse injury Type III 60 (13) 48 (24) 12 (4.7) Difuse injury Type IV 25 (5.5) 19 (9.4) 6 (2.3) Non-evacuated mass lesion 110 (24) 69 (34) 41 (16) Duration of ventilation (days), median (IQR) 5 (1, 12) 2 (1, 6) 9 (3, 17) < .0001 ICU length of stay (days), median (IQR) 7 (2.2, 17) 2.5 (1, 6) 14 (6.6, 22) < .0001 Pupillary reactivity, n (%) < .0001 None 124 (27) 93 (46) 31 (12) One 38 (8.3) 16 (7.9) 22 (8.6) Both 296 (65) 93 (46) 203 (79) Pre-hospital hypotension, n (%) 58 (13) 42 (21) 16 (6.3) < .0001 Pre-hospital hypoxia, n (%) 36 (7.9) 21 (10) 15 (5.9) 0.07 Mannitol dose grams/day, median (IQR) 108 (100, 178) 125 (100, 200) 100 (88, 169) 0.08 23.4% NaCl dose mEq/day, median (IQR) 165 (120, 276) 180 (120, 300) 120 (120, 240) 0.04 Peak serum sodium (mmol/L), mean (SD) 151 (14) 155 (16) 149 (10) < .0001 Mean serum sodium (mmol/L), mean (SD) 144 (9.0) 147 (11) 142 (5.4) < .0001 Time-weighted average serum sodium (mmol/L), mean (SD) 144 (9.0) 148 (11) 141 (4.6) < .0001 Peak serum chloride (mmol/L), mean (SD) 121 (14) 125 (16) 118 (12) < .0001 Mean serum chloride (mmol/L), mean (SD) 112 (9.2) 116 (11) 109 (5.7) < .0001 Time-weighted average serum chloride (mmol/L), mean (SD) 112 (9.6) 117 (11) 108 (5.4) < .0001 AKI, n (%) 146 (32) 87 (43) 59 (23) < .0001 Presence of SAH, n (%) 341 (74) 155 (77) 186 (73) 0.32 Presence of EDH, n (%) 18 (3.9) 3 (1.5) 15 (5.9) 0.02 Mode of death, n (%) Brain death 54 (27) Cardiac arrest 15 (7.4) Withdrawal of life-sustaining treatments 133 (66)

Shown are baseline characteristics by survivors and non-survivors. p values < 0.05 were considered statistically signifcant and shown in bold AKI , CT computed tomography, EDH epidural hematoma, GCS Glasgow Coma Scale, ICP intracranial pressure, IQR interquartile range, ICU intensive care unit, ISS Injury Severity Scale, SAH subarachnoid hemorrhage, NaCl sodium chloride Fig. 2 Crude mortality rates for time-weighted average (TWA) serum sodium and chloride values. a The crude mortality rates for TWA sodium values. b The crude mortality rates for TWA chloride values

Table 2 Adjusted model for in-hospital mortality by TWA limiting chloride exposure through use of balanced solu- sodium and TWA chloride values tions decreased the rate of hyperchloremic acidosis in Risk factor OR (95% CI) healthy volunteers and during perioperative care [33, 34]. We did not collect information on coagulation param- Age per 1 year change 1.05 (1.03–1.08) eters, base defcit upon admission to the ICU, blood Motor GCS 1 versus 6 3.3 (0.72–15) transfusions, or pH to assess hyperchloremic acidosis or Motor GCS 2 versus 6 5.2 (0.64–42) blood loss in our cohort. Terefore, we cannot extrapo- Motor GCS 3 versus 6 2.7 (0.19–39) late any direct biological explanations for the associations Motor GCS 4 versus 6 2.7 (0.55–14) of hyperchloremia with mortality in our study. Motor GCS 5 versus 6 1.5 (0.32–7.0) Tere are two explanations for the fndings in our post Duration of mechanical ventilation 1.3 (1.1–1.4) hoc sensitivity analysis after excluding patients who ICU LOS 0.70 (0.62–0.80) died from brain death. First, the exclusion of 51 brain Pre-hospital hypoxia 1.3 (0.32–5.2) dead patients resulted in a large reduction of our cohort Pupils none versus both 3.6 (1.2–10) and non-survivors (13 and 27%, respectively), therefore Pupils one versus both 0.86 (0.27–2.7) reducing the power of the post hoc sensitivity analysis. Pre-hospital hypotension 4.5 (1.1–19) Second, patients with brain death were likely driving the Marshall CT-classifcation III versus II 3.4 (0.85–14) results of our main analysis. We merely used brain death Marshall CT-classifcation IV versus II 2.6 (0.26–27) as an indicator of DI, but we cannot reliably conclude Marshall CT-classifcation non-evacuated mass lesion 4.7 (1.8–12) that DI was driving our fnding in the full cohort because versus II we could not specifcally classify DI in the OPTIMISM Presence of SAH 2.2 (0.92–5.3) cohort. Another explanation is that severely injured Presence of EDH 0.18 (0.02–1.4) patients may also have been treated very aggressively Osmotic therapy given 1.8 (0.76–4.2) early on with large amounts of hypertonic saline, result- AKI 3.4 (1.4–8.5) ing in hyperchloremia and hypernatremia. We want to TWA sodium per 10 mmol/L change 1.5 (0.51–4.4) point out that patients who are dead on arrival are not TWA chloride per 10 mmol/L change 2.9 (1.07–7.8) enrolled into the OPTIMISM-study. Even if death occurs Shown is the multivariable model for in-hospital mortality (n 403a, with 186 = within a few days of admission (brain dead patients had in-hospital deaths) with time-weighted average sodium and chloride values in the multivariable model. IMPACT-variables were forced into the model to adjust a mean ICU LOS of 2.7 days), the fact that hyperchlo- for known predictors of mortality after msTBI. For this model: C-statistic 0.96 = remia was independently associated with death is still an (corrected for optimism after bootstrap validation: 0.95); Hosmer–Lemeshow goodness-of-ft p value < 0.0001 important fnding, even in patients who progressed to AKI acute kidney injury, CT computed tomography, EDH epidural hemorrhage, brain death. GCS Glasgow Coma Scale, SAH subarachnoid hemorrhage, TWA​ time-weighted Te C-statistics of our models indicate that the model average, ICU Intensive care unit, LOS length of stay discrimination is very high in our cohort (all > 0.96; a Data were missing for 55 patients (34 were missing number of days mechanically ventilated, and 21 were missing sodium or chloride values) bootstrap validation optimism-corrected > 0.94), raising a question about a “too-good-to-be-true” C-statistic. not afect the direction of the estimate nor the associa- We adjusted all models for pre hoc selected IMPACT- tion with outcome. Finally, we did not exclude patients variables, which in our cohort highly discriminate dead with or adjust for central , which has from alive patients (C-statistic of IMPACT-variables been associated with increased mortality in patients with alone 0.88). Addition of more predictors to a model usu- severe TBI [46]. ally results in better discrimination and, hence, growing Ideally, we would have liked to establish the biologi- C-statistics. Internal bootstrap validation showed only a cal mechanism between hyperchloremia and AKI in our minimal decrease in the C-statistics after correction for cohort by performing a separate analysis with AKI as the optimism (Supplemental Table 4). outcome and adjusting for confounders of AKI in the Our study has several important strengths and limi- ICU (e.g., CT contrast dye exposure, , type tations. Strengths included the analysis of a rigorously, and levels of antibiotics, and vasopressor use and prospectively and consecutively enrolled contemporary doses, daily fuid balance, timing of sepsis). However, the msTBI patient cohort from the OPTIMISM-study with OPTIMISM-study does not collect this data and a post adherence to the National Institute of Health TBI Com- hoc retrospective chart review would have lacked the mon Data Elements [35] and weekly adjudication of CT necessary scientifc rigor to reliably establish an unbiased scans, ICU complications and outcomes. Tis allowed us biological link between AKI and hyperchloremia in our to evaluate the efects of hypernatremia and hyperchlo- cohort. We are considering this approach for a future remia while reliably adjusting for known confounders study. of mortality, ICU LOS, duration of mechanical ventila- Our study lacks external validation, but we are search- tion, AKI, and osmotic therapy administration. Our rig- ing for an existing moderate–severe TBI cohort with pre- orous methods also increase the generalizability of our specifed ICU complications collected. fndings. While we recognize that TWA is not a practi- cal metric for a clinician to calculate at the bedside, the Conclusions strength of using TWA values in our study lies in the Hyperchloremia and hypernatremia are common in ability to reduce bias caused by unequal times of sodium patients with msTBI. Our data showed that hyperchlo- and chloride measurements and repeat testing [12]. Our remia, but not hypernatremia, was independently associ- study is limited by its partially retrospective design. We ated with in-hospital mortality in msTBI patients when did not assess cumulative fuid balance or pre-ICU fuid the burden of sodium and chloride was quantifed using administration. Both negative and positive fuid bal- TWA calculations. Pending external validation, our ances are associated with worse neurological outcomes results may provide the rationale for future research in TBI patients [36, 37]. Although our clinical practice is with targeted interventions to reduce hyperchloremia in to maintain euvolemia with isotonic fuids, fuid manage- msTBI patients with the ultimate goal to improve out- ment strategies prior to the ICU admission or during the comes of these critically ill patients. ICU were not quantifed. We did not collect blood glu- Electronic supplementary material cose levels in our study. Hyper- and hypoglycemia are The online version of this article (https​://doi.org/10.1007/s1202​8-020-00928​-0) strongly associated with mortality and worse functional contains supplementary material, which is available to authorized users. outcomes in TBI patients [38–40]. It is unlikely that our results are infuenced by large diferences in glucose lev- Author details els between cohorts since all patients were managed with 1 Department of Clinical Pharmacy, UMass Memorial Medical Center, 55 2 a blood glucose goal of 6.1–7.8 mmol/L which is in line Lake Avenue North, Worcester, MA 01655, USA. Department of Population and Quantitative Health Sciences, UMass Medical School, Worcester, MA, USA. with the Society of Critical Care Medicine insulin guide- 3 Department of Clinical Pharmacy, Yale New Haven Hospital, New Haven, CT, line recommendations for TBI patients [41]. Twelve USA. 4 Department of Neurology, University of Massachusetts Medical School, 5 percent of our cohort had missing data for three of the Worcester, MA, USA. Department of Anesthesia/Critical Care, University of Massachusetts Medical School, Worcester, MA, USA. 6 Department of Sur- variables included in our multivariable models (dura- gery, University of Massachusetts Medical School, Worcester, MA, USA. tion of mechanical ventilation, sodium and chloride). We performed a complete case analysis and did not perform Acknowledgments We thank our research patients and families for their participation in the sensitivity analyses with multiple imputation methods to OPTIMISM-study. We also thank Dr. Wiley Hall, Dr. Raphael Carandang, and impute missing data; hence, our results may be biased. Ms. Irina Mechikow for the assistance in the data collection of the OPTIMISM However, based on the statistical literature, even multi- patients. ple imputation methods do not protect from bias [42– Author Contributions 45]. Another limitation is that TWA sodium and TWA KLD, SM, and MLO were responsible for the study design, analysis, and inter- chloride were collinear, which can afect the variance of pretation of results. KLD was responsible for the writing of the manuscript. MLO, JMF and SM also contributed to writing the manuscript and critically the estimated regression coefcients. However, this does revised the manuscript. AMW was responsible for the clinical data for patients and review of the manuscript. JMF was responsible for the statistical analysis 14. Harris PA, Taylor R, Thielke R, et al. Research electronic data capture of results. SM oversaw study design and provided expertise regarding analysis (REDCap): a metadata-driven methodology and workfow process for and interpretation of results. SM was responsible for the funding of the study. providing translational research informatics support. J Biomed Inform. 2009;42:377–81. Source of Support 15. Brain Trauma Foundation. Guidelines for the management of severe This study was supported by: NIH/NICHD 5K23HD080971 (PI: Muehlschlegel) traumatic brain injury. J Neurotrauma. 2007;24:S1–106. and NIH UL1TR000161 (CTSA; PI: Luzuriaga). Dr. Muehlschlegel is supported by 16. Carney N, Totten AM, O’Reilly C, et al. Brain trauma foundation, american grants NIH/NICHD 5K23HD080971 (PI); UMass Memorial Medical Group PACE- association of neurological surgeons joint section on neurotrauma and Prize 2018 (co-PI); DARPA HR001117S0032-WASH-FP-031 (consultant). critical care: guidelines for the management of severe trauma brain injury, fourth Edition. Neurosurgery. 2017;80:6–15. Conflict of Interest 17. Darmon M, Diconne E, Souweine B, et al. Prognostic consequences of The remaining authors have disclosed that they do not have any conficts of borderline dysnatremia: pay attention to minimal serum sodium change. interest. Crit Care. 2013;17(1):R12. 18. Tsipotis E, Price LL, Jaber BL, et al. 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