Is mild hypernatremia an independent predictor of poor clinical outcome in neurocritically ill patients?

Background: Hypernatremia is a common complication encountered during the treatment of neurocritically ill patients. However, it is unclear whether clinical outcomes correlate with the severity of hypernatremia in such patients. Therefore, we investigated the impact of hypernatremia on mortality of these patients, depending on the degree of hypernatremia. Methods: Among neurosurgical patients admitted to the intensive care unit (ICU) in a tertiary hospital from January 2013 to December 2019, patients who were hospitalized in the ICU for more than 5 days and whose serum sodium levels were obtained during ICU admission were included. Hypernatremia was dened as the highest serum sodium level exceeding 150 mEq/L observed. We classied the patients into four subgroups according to the severity of hypernatremia and performed propensity score matching analysis. Results: Among 1,146 patients, 353 patients (30.8%) showed hypernatremia. Based on propensity score matching, 290 pairs were included in the analysis. The hypernatremia group had higher rates of in-hospital mortality and 28-day mortality in both overall and matched population (both p < 0.001 and p = 0.001, respectively). In multivariable analysis of propensity score-matched population, moderate and severe hypernatremia were signicantly associated with in-hospital mortality (adjusted odds ratio [OR]: 4.58, 95% condence interval [CI]: 2.15 – 9.75 and adjusted OR: 6.93, 95% CI: 3.46 – 13.90, respectively) and 28-day mortality (adjusted OR: 3.51, 95% CI: 1.54 – 7.98 and adjusted OR: 10.60, 95% CI: 5.10 – 21.90, respectively) compared with the absence of hypernatremia. However, clinical outcomes, including in-hospital mortality and 28-day mortality, were not signicantly different between the group without hypernatremia and the group with mild hypernatremia (p = 0.720 and p = 0.690, respectively). The mortality rates of patients with moderate and severe hypernatremia were signicantly higher in both overall and matched population. Interestingly, the mild hypernatremia group

Hypernatremia is caused by increased sodium intake, loss of free water, or both [5]. Under normal conditions, thirst is the primary defense mechanism against the development of hypernatremia [5]. However, this mechanism is disrupted in critically ill patients because their consciousness is generally disturbed by sedation or delirium [4,5]. Moreover, neurocritically ill patients are more likely to develop hypernatremia than patients in general ICUs for several reasons, including impaired thirst mechanisms, altered mentality, and hormonal abnormalities resulting from brain injury [4,9]. In addition, hypernatremia may be induced by treating elevated intracranial pressure (ICP) with hyperosmolar therapies, such as mannitol and hypertonic saline, and control of ICP may be correlated with serum sodium concentration [4,9,10]. However, it is unclear whether hypernatremia can be prevented in patients with intracranial hypertension, even by reducing or discontinuing hyperosmolar agents.
A limited number of studies reported that clinical outcomes correlated with the severity of hypernatremia in neurocritically ill patients [11]. It is unknown whether hypernatremia itself is associated with poor prognosis, or is a symptom associated with neurocritical illness. Therefore, the objective of this study was to investigate the impact of hypernatremia on mortality of neurocritically ill patients, depending on the degree of hypernatremia. In addition, we evaluated whether hypernatremia per se was associated with poor prognosis when severity and factors other than hypernatremia were controlled by propensity score matching.

Study population
This is a retrospective, single-center, observational study. Patients admitted to the neurosurgical ICU in a tertiary, referral hospital (Samsung Medical Center, Seoul, Republic of Korea) from January 2013 to December 2019 were eligible. This study was approved by the Institutional Review Board of Samsung Medical Center (approval number: SMC 2020-09-082).We included patients (1) who were hospitalized in the ICU for more than 5 days, and (2) whose serum sodium concentrations were obtained during the ICU admission. We excluded patients (1) with hypernatremia (serum sodium > 150 mEq/L) on ICU admission, (2) with insu cient medical records, (3) those who were admitted to departments other than neurosurgery, and (4) those who were transferred to other hospitals and with unknown prognoses (Fig. 1).

De nitions and endpoints
In this study, baseline characteristics of comorbidities, ICU management, and laboratory data were collected retrospectively using Clinical Data Warehouse. Our center constructed the "Clinical Data Warehouse Darwin-C" designed for investigators to search and retrieve de-identi ed medical records from the electronic archives. It contains data pertaining to more than four million patients. The clinical and laboratory data were extracted from the Clinical Data Warehouse Darwin-C after nalizing the patient list in this study. The levels of serum sodium were measured at least once every morning in all patients. Additional laboratory tests were performed if patients underwent hyperosmolar therapy or when attending physicians or neurosurgeons needed additional tests throughout the day. Hypernatremia was de ned as the highest serum sodium level exceeding 150 mEq/L during ICU stay [11]. We also classi ed the patients to determine the association between clinical outcomes and severity of hypernatremia. Patients were divided into four subgroups: no hypernatremia (≤ 150 mEq/L), mild hypernatremia (151-155 mEq/L), moderate hypernatremia (156-160 mEq/L), and severe hypernatremia (> 160 mEq/L) [11]. Acute Physiology and Chronic Health Evaluation (APACHE) II score was calculated with worst values recorded during the initial 24 h in the ICU admission [12,13]. If the patient was intubated, the verbal score of Glasgow Coma Scale (GCS) was estimated using the eye and motor scores as reported previously [14]. The primary endpoint was in-hospital mortality and the secondary outcome was 28-day mortality.

Statistical analyses
All data are presented as means ± standard deviations for continuous variables and frequencies and proportions for categorical variables. Data were compared using Student's t-test for continuous variables and the chi-square test or Fisher's exact test for categorical variables.
Propensity score matching was used to control the selection bias and the confounding detected in this observational study. Each patient with hypernatremia was matched to one of the control patient with the nearest neighbor matching within calipers determined by the propensity score. A caliper width of 0.2 of the standard deviation of the logit of the propensity score was used for the matching [15]. To determine the effectiveness of propensity score matching in controlling the differences between patients with and without hypernatremia, the standardized mean differences (SMDs) were calculated for each variable before and after matching. SMDs less than 10% were considered successful propensity scores matching and balancing the groups.
To conduct doubly robust estimation to improve causal inference, we combined the propensity score matching and regression methods. The propensity score-matched population was subjected to multiple logistic regression analysis with stepwise variable selection. The variables included in the propensity score estimation and the other multivariable analyses were age, sex, comorbidities, cause of ICU admission, utilization of organ support modalities, including mechanical ventilators, continuous renal replacement therapy and vasopressors, ICP monitoring devices, hyperosmolar therapy, GCS, and APACHE II score on ICU admission. The cumulative incidences of mortality were calculated by Kaplan-Meier estimates and compared using a log-rank test. All tests were two-sided and p values less than 0.05 were considered statistically signi cant. Statistical analyses were performed with R Statistical Software (version 4.0.2; R Foundation for Statistical Computing, Vienna, Austria).

Baseline characteristics
A total of 12,743 patients were admitted to the neurosurgical ICU during the study period and 1,146 patients were included in the analysis. In the study population, 353 patients (30.8%) had hypernatremia (Fig. 1).The mean age of all patients was 50.0 ± 22.9 years. The study included 597 (52.1%) male patients. Malignancy (56.4%) and hypertension (34.1%) were the most common comorbidities. Brain tumors (39.1%) and intracerebral hemorrhage (18.2%) were the most common reasons for ICU admission. Age and APACHE II score on ICU admission were higher in patients with hypernatremia compared with those without hypernatremia (both p < 0.001). However, malignancy was more common in the group with hypernatremia than in the group without (p < 0.001). Vasopressors and mechanical ventilators were more commonly used in patients with hypernatremia compared with those without hypernatremia (both p < 0.001). Although the frequency of mannitol use was similar between the two groups (p = 0.293), glycerin was more frequently used in the hypernatremia group (p < 0.001). The mean value of maximum serum sodium level was higher in the hypernatremia group than in the group without hypernatremia (160.2 ± 8.6 mEq/L vs. 141.9 ± 5.8 mmol/L, p < 0.001). The mean value of minimum serum sodium level was also higher in the hypernatremia group than in the non-hypernatremia group (144.3 ± 12.9 mEq/L vs. 135.1 ± 5.8 mEq/L, p < 0.001). However, there were no signi cant differences in the length of stay in the ICU and hospital between the two groups (p = 0.970 and p = 0.232, respectively). After propensity score matching, 290 pairs of data were generated by 1:1 individual matching without replacement. No signi cant imbalance was found in the baseline characteristics between the matched data pairs (Table 1). In the overall study population, the rates of in-hospital mortality and 28-day mortality were higher in the hypernatremia group compared with the non-hypernatremia group (45.6% vs. 15.5% and 43.6% vs. 13.5%, both p < 0.001) ( Table 1). Clinical outcomes in the propensity score-matched population were similar to those of the entire population. In the propensity scorematched population, the rates of in-hospital mortality and 28-day mortality were also higher in the hypernatremia group compared with the non-hypernatremia group (40.3% vs. 26.9% and 37.9% vs. 24.8%, both p = 0.001) ( Table 1).
In multivariable analysis of propensity score-matched population, the clinical outcomes, including in-hospital mortality and 28day mortality, were not signi cantly different between non-hypernatremia and mild hypernatremia groups (p = 0.720 and p = 0.690, respectively) (  Table 2).
In survival analysis, the mortality rates of patients with moderate and severe hypernatremia were signi cantly higher compared with those with mild hypernatremia and without hypernatremia in the overall population and propensity score-matched population (Fig. 2). Especially, the mild hypernatremia group of matched population showed the best survival rate in the Kaplan-Meier curve. However, the mortality rate of patients with mild hypernatremia was not signi cantly lower compared with those without hypernatremia (16.1% vs. 27.6%, log-rank test, p = 0.163).

Discussion
In this study, we investigated the severity and impact of hypernatremia on mortality of neurocritically ill patients, depending on the degree of hypernatremia. Major ndings of this study were as follows. First, poor clinical outcomes were more common in patients with hypernatremia compared with those without hypernatremia in overall and propensity score-matched population.
Second, patients with mild hypernatremia in the matched population showed the best survival rate. Finally, multivariable analysis revealed that moderate and severe hypernatremia, use of vasopressors and GCS on ICU admission were signi cantly associated with in-hospital mortality and 28-day mortality in neurocritically ill patients. Speci cally, mild hypernatremia was not associated with poor clinical outcomes in this study.
In neurocritically ill patients, hyperosmolar therapy, including mannitol, glycerin or hypertonic saline, are frequently used to control intracranial hypertension [9,16]. Hypernatremia may occur due to the use of these agents [4,9,10,16]. Mild hypernatremia is the goal of serum sodium when hypertonic saline is used to lower ICP continuously [16]. Neurocritically ill patients are frequently subjected to hyperosmolar therapy. Hyperosmolar therapy and associated acute kidney injury can aggravate hypernatremia [11,17,18]. In addition, hypothalamic dysfunction due to brain injury can contribute to hypernatremia [11,19]. Therefore, hypernatremia occurs easily in patients with severe neurological disease compared with those manifesting benign disease. Eventually, it is not easy to determine whether hypernatremia itself is associated with a poor prognosis, or patients with hypernatremia show poor prognosis because of their neurocritical illness. Therefore, a propensity score matching method was used to adjust for this confounder in this study. In brief, moderate and severe hypernatremia were signi cantly associated with poor clinical outcomes in neurocritically ill patients.
In this study, neurocritically ill patients with mild hypernatremia did not manifest worse outcomes compared to those without hypernatremia. However, patients with moderate or severe hypernatremia had worse prognosis than those without hypernatremia. In neurocritically ill patients with mild hypernatremia, favorable clinical outcomes may be associated with the ICP-lowering effect induced by mild hypernatremia with fewer complications than those detected during moderate and severe hypernatremia. Therefore, hyperosmolar agents may not be reduced or discontinued to maintain normal level of serum sodium in case of mild hypernatremia during treatment of patients with intracranial hypertension.
This study has several limitations. First, this was a retrospective review of medical records and the data extracted from Clinical Data Warehouse. The nonrandomized nature of registry data may have resulted in selection bias. Laboratory studies, including serum sodium levels, were not protocol-based. Second, hypernatremia was easily induced with hypertonic saline. Although, a small number of patients used hypertonic saline in this study, they could not be identi ed from Clinical Data Warehouse due to technical challenges. Third, the distribution of neurosurgical diseases differed from that of the general neurosurgical ICU, and the proportion of patients with brain tumors was particularly high. Although this study still provides valuable insight, prospective large-scale studies are needed to con rm the safety and effectiveness of mild hypernatremia in neurocritically ill patients to arrive at evidence-based conclusions.

Conclusions
In this study, moderate and severe hypernatremia were associated with poor clinical outcomes in neurocritically ill patients. However, prognosis of the patients with mild hypernatremia was similar to those without hypernatremia. Therefore, mild hypernatremia may be allowed during the active management of intracranial hypertension using hyperosmolar therapy. Further, it may not be necessary to reduce or discontinue hyperosmolar agents to control mild hypernatremia.

Key Messages
Moderate and severe hypernatremia are independently associated with poor clinical prognosis in neurocritically ill patients.
Neurocritically ill patients with mild hypernatremia did not manifest worse outcome compared to those without hypernatremia in this study.
Mild hypernatremia group in the propensity score-matched population showed the best survival rate.
Mild hypernatremia may be allowed during active management of intracranial hypertension using hyperosmolar therapy.
Abbreviations APACHE II, acute physiology and chronic health evaluation II; CI, con dence interval; GCS, Glasgow coma scale; ICP, intracranial pressure; ICU, intensive care unit; OR, odds ratio; SMD, standardized mean difference.
Ethics approval and consent to participate This study was approved by the Institutional Review Board of Samsung Medical Center (approval number: SMC 2020-09-082).
Patients' records were reviewed and published according to the Declaration of Helsinki. Informed consent was waived because of the retrospective nature of this study.

Consent for publication
Not applicable. This study does not contain individual or personal data in any form (including individual details, images, or videos).

Availability of data and materials
Our data are available on the Harvard Dataverse Network (http://dx.doi.org/10.7910/DVN/LVJEDX) as recommended repositories of critical care.

Competing interests
The authors declare that they have no competing interests.

Funding
Not applicable.

Figure 1
Study ow chart. ICU, intensive care unit; Na, sodium level.