Sadan et al. Journal of Intensive Care (2020) 8:32 https://doi.org/10.1186/s40560-020-00449-0 RESEARCH Open Access Low-chloride- versus high-chloride- containing hypertonic solution for the treatment of subarachnoid hemorrhage– related complications: The ACETatE (A low ChloriE hyperTonic solution for brain Edema) randomized trial Ofer Sadan1*, Kai Singbartl2, Jacqueline Kraft1, Joao McONeil Plancher1, Alexander C. M. Greven3, Prem Kandiah1, Cederic Pimentel1, C. L. Hall1, Alexander Papangelou4, William H. Asbury5, John J. Hanfelt6 and Owen Samuels1 Abstract Background: Recent reports have demonstrated that among patients with subarachnoid hemorrhage (SAH) treated with hypertonic NaCl, resultant hyperchloremia has been associated with the development of acute kidney injury (AKI). We report a trial comparing the effect of two hypertonic solutions with different chloride contents on the resultant serum chloride concentrations in SAH patients, with a primary outcome aimed at limiting chloride elevation. Methods: A low ChloridE hyperTonic solution for brain Edema (ACETatE) trial is a single-center, double-blinded, double-dummy, randomized pilot trial comparing bolus infusions of 23.4% NaCl and 16.4% NaCl/Na-acetate for the treatment of cerebral edema in patients with SAH. Randomization occurred when patients developed hyperchloremia (serum Cl− ≥ 109 mmol/L) and required hyperosmolar treatment. Results: We enrolled 59 patients, of which 32 developed hyperchloremia and required hyperosmolar treatment. 15 patients were randomized to the 23.4% NaCl group, and 17 patients were randomized to the 16.4% NaCl/Na- acetate group. Although serum chloride levels increased similarly in both groups, the NaCl/Acetate group showed a significantly lower Cl− load at the end of the study period (978mEq vs. 2,464mEq, p < 0.01). Secondary outcome analysis revealed a reduced rate of AKI in the Na-acetate group (53.3% in the NaCl group vs. 11.8% in the Na- acetate group, p = 0.01). Both solutions had similar effects on ICP reduction, but NaCl/Acetate treatment had a more prominent effect on immediate post-infusion Na+ concentrations (increase of 2.2 ± 2.8 vs. 1.4 ± 2.6, (p < 0.01)). Proximal tubule renal biomarkers differed in concentration between the two groups. (Continued on next page) * Correspondence: [email protected] 1Department of Neurology and Neurosurgery, Division of Neurocritical Care, Emory University Hospital and Emory University School of Medicine, 1364 Clifton Rd. NE, Atlanta, GA 30322, USA Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. 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 in a credit line to the data. Sadan et al. Journal of Intensive Care (2020) 8:32 Page 2 of 10 (Continued from previous page) Conclusions: Our pilot trial showed the feasibility and safety of replacing 23.4% NaCl infusions with 16.4% NaCl/Na- acetate infusions to treat cerebral edema in patients with SAH. The degree of hyperchloremia was similar in the two groups. 16.4% NaCl/Na-acetate infusions led to lower Cl− load and AKI rates than 23.4% NaCl infusions. Further multi-center studies are needed to corroborate these results. Trial registration: clinicaltrials.gov # NCT03204955, registered on 6/28/2017 Keywords: Cerebral edema, Subarachnoid hemorrhage, Hyperosmolar therapy, Hyperchloremia, Acute kidney injury, Neurocritical care Introduction Therefore, the question arises as to whether avoiding Aneurysmal subarachnoid hemorrhage (aSAH), a life- further worsening of hyperchloremia by differential use of threatening condition that results from a rupture in a hypertonic solutions might be a better strategy for the pre- cerebral artery [1]. Although a relatively rare type of vention of AKI in aSAH patients. At our institution, we stroke, it carries a disproportionally high risk for mortal- began utilizing a compound solution that replaces part of ity and morbidity. For example, even with treatment im- the NaCl solution with sodium-acetate, offering a lower provements in recent years, aSAH in-hospital mortality chloride load per dose. Further analysis of the previously − rates remain around 20% [2]. published cohort allowed us to identify a Cl concentra- Aside from CNS-related complications such as hydro- tion of 109 mmol/L as a threshold that differentiates be- cephalus, cerebral edema, or delayed cerebral ischemia, tween patients at high versus low risk for AKI [16]. systemic complications account for up to 40% of all deteri- Focusing on at-risk patients, this trial aimed to reduce orations during inpatient care [3]. Acute kidney injury in exacerbations of hyperchloremia in aSAH patients aSAH patients is associated with a greater than four-fold treated with hypertonic saline who developed mild increase in hospital mortality, along with less favorable hyperchloremia by using a double-blind, double-dummy, neurological recovery in patients who survive [4–6]. pragmatic approach. Among critically ill patients, it has been suggested that hyperchloremia can precipitate or worsen AKI and in- Methods crease the need for renal replacement therapy [7–9]. Patient population and problem investigated Prospective comparative studies between isotonic NaCl Our trial protocol has been published previously [16] and balanced crystalloid solutions have consistently and was approved by the Emory University institutional shown an association between isotonic NaCl infusions, review board (IRB). We utilized a single-center double- an increased risk for AKI, and subsequent poor outcome blinded, double-dummy, pilot design to compare NaCl in critically ill patients [10–13]. 23.4% and NaCl/Na-acetate 16.4% (Table 1) for the Hyperosmolar therapy is a cornerstone in the treat- treatment of cerebral edema in patients with aneurysmal − ment of aSAH-related cerebral edema, which is neces- SAH and evolving hyperchloremia (serum Cl ≥ 109 sary in approximately 20–30% of SAH patients [14]. mmol/L). Osmotherapy commonly includes infusions of hypertonic sa- All patients admitted to the Emory University Hospital line, which has a significantly higher chloride concentrations Neuroscience Critical Care Unit, Atlanta, GA, between in comparison with standard NaCl 0.9% solution. It is of no June 25, 2017, and June 24, 2018, were screened. Adult surprise, therefore, that in a recently published retrospective patients with a diagnosis of aSAH, or their legally autho- analysis of SAH patients, we observed correlations between rized representatives, were approached for consent, ex- hyperchloremia and AKI, and between AKI and increased cluding those with a poor prognosis (e.g. brain death, or morbidity and mortality. We identified treatment with progressing towards brain death) and known end-stage hypertonic NaCl as a risk factor for the development of renal disease. hyperchloremia [5]. We were not, however, able to demon- strate a dose-response relationship between chloride load Intervention and comparison and the subsequent development of hyperchloremia. Instead, After enrollment, patients who required hyperosmolar − a great variability in chloride exposure was observed [5]. The therapy and had developed hyperchloremia (i.e., Cl ≥ large variability appeared to be related to a high incidence of 109 mmol/L) were ultimately randomized to infusions of cerebral salt-wasting syndrome in our study population, 23.4% NaCl or 16.4% NaCl/Na-acetate. As a pragmatic resulting in the need for extensive sodium and volume re- protocol, the decision on initiation of hyperosmolar placement with intravenous (IV) fluids, particularly with therapy was made by the attending physician. The indi- NaCl solutions of various concentrations [15]. cations were either cerebral edema evident on imaging, Sadan et al. Journal of Intensive Care (2020) 8:32 Page 3 of 10 Table 1 Composition of the two hypertonic solutions compared in the trial NaCl (standard treatment) group NaCl/Na-acetate (alternate treatment) group Solution components (per dose) Sodium chloride Sodium chloride and sodium acetate Na Concentration [%] 23.4 16.4 NaCl pre-mixed solution, 4 mEq/ml [ml] 30 20 Na-acetate pre-mixed solution, 2 mEq/ml [ml] 0 30 Volume [ml] 30 50 Sodium content [mEq/dose] 120 140 Chloride content [mEq/dose] 120 80 Acetate content [mEq/dose] 0 60 or increase in intracranial pressure, or both. All other IV with either NaCl 23.4% (30 mL) or NaCl/Na-acetate fluids administered to the patients were balanced IV so- 16.4% (50 mL), between the pre-randomization concen- lution (PlasmaLyte®), in all groups, apart from carrier so- tration and