Article

Rate of Correction of Hypernatremia and Health

Outcomes in Critically Ill Patients
Kinsuk Chauhan,1 Pattharawin Pattharanitima,1 Niralee Patel,1 Aine Duffy,2 Aparna Saha,2 Kumardeep Chaudhary,2
Neha Debnath,1 Tielman Van Vleck,2 Lili Chan,1 Girish N. Nadkarni,1,2 and Steven G. Coca 1

Abstract
Background and objectives Hypernatremia is common in hospitalized, critically ill patients. Although there are no 1
Division of
clear guidelines on sodium correction rate for hypernatremia, some studies suggest a reduction rate not to Nephrology,
exceed 0.5 mmol/L per hour. However, the data supporting this recommendation and the optimal rate of Department of
hypernatremia correction in hospitalized adults are unclear. Medicine, and
2
Institute of
Personalized
Design, setting, participants, & measurements We assessed the association of hypernatremia correction rates
Medicine, Department
with neurologic outcomes and mortality in critically ill patients with hypernatremia at admission and of Genetics and
those that developed hypernatremia during hospitalization. We used data from the Medical Information Mart Genomics, Icahn
for Intensive Care-III and identified patients with hypernatremia (serum sodium level .155 mmol/L) on admission School of Medicine at
(n=122) and hospital-acquired (n=327). We calculated different ranges of rapid correction rates (.0.5 mmol/L Mount Sinai, New
York, New York
per hour overall and .8, .10, and .12 mmol/L per 24 hours) and utilized logistic regression to generate adjusted odds
ratios (aOR) with 95% confidence intervals (95% CIs) to examine association with outcomes.
Correspondence:
Dr. Steven G. Coca or
Results We had complete data on 122 patients with severe hypernatremia on admission and 327 patients who Dr. Girish N. Nadkarni,
developed hospital-acquired hypernatremia. The difference in in-hospital 30-day mortality proportion between Icahn School of
rapid (.0.5 mmol/L per hour) and slower (#0.5 mmol/L per hour) correction rates were not significant either in Medicine at Mount
Sinai, One Gustave L.
patients with hypernatremia at admission with rapid versus slow correction (25% versus 28%; P=0.80) or in Levy Place, New York,
patients with hospital-acquired hypernatremia with rapid versus slow correction (44% versus 40%; P=0.50). There NY 10029. E-mail:
was no difference in aOR of mortality for rapid versus slow correction in either admission (aOR, 1.3; 95% CI, steven.coca@mssm.
0.5 to 3.7) or hospital-acquired hypernatremia (aOR, 1.3; 95% CI, 0.8 to 2.3). Manual chart review of all suspected edu or girish.
nadkarni@mountsinai.
chronic hypernatremia patients, which included all 122 with hypernatremia at admission, 128 of the 327 hospital-
org
acquired hypernatremia, and an additional 28 patients with ICD-9 codes for cerebral edema, seizures and/or
alteration of consciousness, did not reveal a single case of cerebral edema attributable to rapid hyprnatremia correction.

Conclusions We did not find any evidence that rapid correction of hypernatremia is associated with a higher
risk for mortality, seizure, alteration of consciousness, and/or cerebral edema in critically ill adult patients with
either admission or hospital-acquired hypernatremia.
Clin J Am Soc Nephrol 14: 656–663, 2019. doi: https://doi.org/10.2215/CJN.10640918

Introduction and permanent neurologic damage from rapid correction

Hypernatremia is defined as increased serum sodium
concentration .145 mmol/L (1). It is a hyperosmolar
state in which there is a deficit in total body volume in
comparison to total body electrolytes (2). The inci-
dence of hypernatremia is reported to be up to 3% in
hospitalized patients and 9% in patients admitted to
the intensive care unit (ICU) (3,4). Acute hypernatremia
in ICU patients may have an independent association
with higher mortality and length of stay, although the
higher risk of mortality may reflect severity of related
illness and comorbid conditions (5).
There are no evidence-based guidelines on the appro-
priate sodium correction rate for hypernatremia. How-
ever, expert opinion suggests a reduction rate no more
than 0.5 mmol/L per hour, with an absolute change
of ,10 mmol/L per day to avoid cerebral edema, seizure,
(1,6–8). Although prior literature has documented the
association of cerebral edema and rapid hypernatremia
correction in children, the literature in adults is scant
(9,10). Contrary to the literature in children, two studies
in adults demonstrated that excessively slow rates of
correction are associated with a higher risk of mortality
and those with a greater reduction rate of sodium had
less mortality (11–13). Thus, the outcomes associated
with hypernatremia correction rate in hospitalized
adults are unclear.
We sought to determine the association between
rates of hypernatremia correction with mortality and
the incidence of neurologic outcomes in critically ill
patients with either hypernatremia present on admis-
sion or in those who developed hypernatremia during
hospitalization.

656 Copyright © 2019 by the American Society of Nephrology www.cjasn.org Vol 14 May, 2019
Clin J Am Soc Nephrol 14: 656–663, May, 2019
Materials and Methods
Study Design and Setting
We extracted data from the Medical Information Mart for
Intensive Care-III (MIMIC-III) database to identify patients
with hypernatremia. MIMIC-III is a publicly available critical
care database of patients from a large, single-center tertiary
care hospital (Beth Israel Deaconess Medical Center in
Boston, MA) from 2001 to 2012 (14). This database includes
patient demographics, vital signs, laboratory results, billing
codes, and notes. We included patients in the analysis with
severe hypernatremia, which was defined if they had serum
sodium .155 mmol/L at any time point during their hospital
admission. We excluded patients aged ,18 years old and
patients with no serum sodium values at any time points
after the peak serum sodium level. The patients who had
severe hypernatremia at hospital admission were labeled
“admission hypernatremia” and patients who developed
severe hypernatremia during their hospital stay were labeled
“hospital-acquired hypernatremia.” We considered only the
data from the patient’s first admission with hypernatremia.
A study flow diagram is included in Supplemental Figure 1.
Definition of Rapid Correction and Categories
For each study participant, we identified peak serum
sodium level and calculated the overall rate of correction
using serum sodium values after the peak. We calculated
rate of serum sodium correction was calculated using the
following formula:
Overall serum sodium correction rate
¼ ðpeak  Naþ   value-Naa Þmmol=L =ðtime at peak Naþ -timea Þh
Naa is the first corrected serum sodium value ,145 mmol/L
or the last serum sodium value before discharge in those
patients who did not correct down to 145mmol/L.
Timea is the time at first corrected serum sodium
level ,145 mmol/L or the time of last available value in
those who did not achieve correction during their admis-
sion. We also calculated serum sodium correction rate at
24 hours using the same formula, where Naa is the serum
sodium value regardless of their corrected level at 24-hour,
and timea is the time at which Naa was recorded at 24 hours.
Rapid hypernatremia correction was defined as an over-
all serum sodium correction rate of .0.5 and #0.5 mmol/L
per hour was considered slower hypernatremia correction
rate. Additionally, we did several subanalysis with varying
hypernatremia correction rates of .8, .10, and .12 mmol/L
per 24 hours.
Definition of Neurologic Complications and
Chronic Hypernatremia
To determine the incidence of cerebral edema, seizures,
and alteration of consciousness in the study population, we
used the International Classification of Diseases, Ninth
Revision (ICD-9) diagnostic codes mentioned in Supple-
mental Table 1. We also identified patients who had serum
sodium $145 mmol/L for .48 hours in patients with
hospital-acquired hypernatremia and considered them as
having chronic hypernatremia. We also presumed pa-
tients with hypernatremia at admission as having chronic
hypernatremia because the onset of higher serum sodium
was unknown. To identify the causes of these neurologic
Hypernatremia Correction and Cerebral Edema, Chauhan et al. 657
complications, we extracted medical resonance imaging,
computerized tomography imaging reports, and discharge
summary reports for the patients. Two independent clinicians
manually reviewed all reports to identify cause of cerebral
edema and to determine whether it was attributable to rapid
hypernatremia correction.
Assessment of Covariates
Additional data extracted included demographic char-
acteristics, additional comorbid conditions by ICD-9 codes
(nonalcoholic liver disease, CKD, ESKD, congestive heart
failure, diabetes mellitus type 2, depression, bipolar disor-
der, schizophrenia, epilepsy, stroke, myocardial infarction,
AIDS, chronic obstructive pulmonary disease, hyperten-
sion, and peripheral arterial disease), ICU type during
first admission, do-not-resuscitate (DNR) status, laboratory
values during peak sodium level (serum: creatinine, potas-
sium, phosphorus, magnesium, osmolality, bicarbonate,
and albumin; urine: sodium, potassium, and osmolality),
and diuretics use (thiazide and loop) (Table 1).
Statistical Analyses
We conducted analysis to explore differences be-
tween patients who experienced overall slow correc-
tion (#0.5 mmol/L per hour) versus rapid correction
(.0.5 mmol/L per hour) stratified by two groups: admission
hypernatremia and hospital-acquired hypernatremia. We
further divided correction rate categories during hospital
follow-up duration into patients with corrected sodium level
(those who achieved serum sodium of ,145 mmol/L) and
patients with uncorrected sodium level (those who did not
achieve a serum sodium level of ,145 mmol/L). We used the
Wilcoxon rank sum test for continuous variables and the
Fisher exact test for categorical variables. We performed
Kaplan–Meier curve to assess the survival rate difference in
patients between different sodium correction rates. We then
used unadjusted and adjusted logistic regression analysis to
determine the influence of hypernatremia correction rate at
different time points on mortality. An adjustment of age, sex,
DNR status, and Charlson comorbidity index was included
in the model. As a subgroup analyses, we identified patients
who had serum sodium $145 mmol/L for .48 hours in
patients with hospital-acquired hypernatremia and consid-
ered them as having chronic hypernatremia. Then we
compared mortality proportions between acute and
chronic hypernatremia groups within the hospital-acquired
hypernatremia group and also between sex and median age
groups among patients with hypernatremia at admission
and those with hospital-acquired hypernatremia. A P value
of 0.05 was considered statistically significant for all
comparisons. As this study was done on publicly available,
deidentified data, it was considered exempt from institu-
tional review board approval. The analysis was done using
SAS v9.4 (SAS Institute Inc., Cary, NC) and Stata/IC 15.1
software (StataCorp, College Station, TX).
Results
Study Cohort Characteristics
We identified 512 patients with severe hypernatremia
during their first admission to the ICU from 2001 to 2012. A
total of 449 patients were included in the main analysis
658 Clinical Journal of the American Society of Nephrology

Table 1. Characteristics of adults admitted to ICU with hypernatremia at admission and hospital-acquired hypernatremia by slower
versus rapid correction rate

Admission Hypernatremia, n=122; Hospital-Acquired Hypernatremia,

n (%) or Median (IQR) n=327; n (%) or Median (IQR)
Characteristic
#0.5 mmol/L per h .0.5 mmol/L per h #0.5 mmol/L per h .0.5 mmol/L per h

Total, n (%) 90 (74) 32 (26) 225 (69) 102 (31)

Age, yr, median (IQR) 83 (72–90) 80 (61–86) 64 (48–75) 58 (48–75)
Sex, n (%)
Men 48 (53) 8 (25) 149 (67) 66 (65)
Women 42 (47) 24 (75) 76 (34) 36 (35)
ICU first service, n (%)
Medical ICU 73 (81) 25 (78) 61 (27) 46 (45)
Surgical ICU 8 (9) 0 58 (26) 17 (17)
Coronary care unit 5 (6) 3 (9) 20 (9) 9 (9)
Trauma/surgical ICU 2 (2) 3 (9) 60 (27) 23 (23)
Cardiac surgery recovery unit 1 (1) 0 26 (12) 5 (5)
Admission type, n (%)
Elective 1 (1) 0 18 (8) 6 (6)
Urgent/emergency 89 (99) 32 (100) 207 (92) 96 (94)
Insurance, n (%)
Government 2 (2) 1 (3) 7 (3) 6 (6)
Medicaid 4 (4) 1 (3) 22 (10) 9 (9)
Medicare 75 (83) 22 (69) 105 (47) 42 (41)
Private 9 (10) 8 (25) 81 (36) 39 (38)
Self-pay 0 0 10 (4) 6 (6)
Race/ethnicity, n (%)
White 56 (62) 18 (56) 128 (57) 54 (53)
Black 17 (19) 4 (13) 23 (10) 19 (19)
Hispanic 3 (3) 3 (9) 8 (4) 3 (3)
Asian 6 (7) 3 (9) 4 (2) 4 (4)
Others/unknown 8 (9) 4 (13) 62 (28) 22 (22)
Charlson Comorbidity Index, n (%)
0 22 (24) 9 (28) 51 (23) 24 (24)
1 20 (22) 15 (47) 52 (23) 32 (31)
2 21 (23) 3 (9) 39 (17) 15 (15)
$3 27 (30) 5 (16) 83 (37) 31 (30)
Comorbidities, n (%)
CKD 19 (21) 1 (3) 20 (9) 11 (11)
ESKD 0 0 3 (1) 2 (2)
Liver disease (NA) 1 (1) 0 0 1 (1)
Congestive heart failure 22 (24) 7 (22) 47 (21) 21 (21)
Diabetes mellitus type 2 14 (16) 6 (19) 42 (19) 11 (11)
Depression 10 (11) 8 (25) 13 (6) 4 (4)
Bipolar disorder 3 (3) 1 (3) 14 (6) 4 (4)
Schizophrenia 1 (1) 0 1 (0.4) 0
Epilepsy 5 (6) 0 6 (3) 1 (1)
Stroke (infarction, ICH, SAH) 5 (6) 2 (6) 69 (31) 20 (20)
Myocardial infarction 11 (12) 0 23 (10) 6 (6)
HIV infection 1 (1) 1 (3) 0 1 (1)
Chronic obstructive pulmonary disease 6 (7) 5 (16) 22 (10) 6 (6)
Hypertension 27 (30) 10 (31) 76 (34) 29 (28)
Peripheral arterial disease 1 (1) 0 3 (1) 3 (3)
Laboratory values at peak sodium
level, median (IQR)
Creatinine, mg/dl 1.9 (1.3–2.9) 1.2 (0.8–2.1) 1.1 (0.8–1.6) 1.2 (1.0–2.0)
BUN, mg/dl 62 (40–85) 36 (27–64) 34 (20–52) 23 (15–54)
Potassium, mmol/L 3.9 (3.6–4.2) 3.8 (3.6–4.1) 3.8 (3.6–4.0) 3.8 (3.5–4.1)
Phosphorus, mg/dl 3.2 (2.4–3.9) 2.5 (2.2–3.8) 2.9 (2.3–3.8) 3.0 (2.3–3.9)
Magnesium, mg/dl 2.3 (2.1–2.7) 2.2 (2.0–2.4) 2.3 (2.0–2.5) 2.1 (1.9–2.3)
Serum osmolality, mOsm/kg 354 (345–367) 358 (352–365) 328 (323–337) 331 (320–345)
Serum bicarbonate, mmol/L 22 (19–25) 24 (20–28) 26 (23–29) 23 (19–26)
Serum bicarbonate #20 mmol/L, n (%) 31 (34) 11 (34) 30 (14) 29 (28)
Albumin, g/dl 2.8 (2.5–3.3) 3.0 (2.6–3.2) 2.9 (2.6–3.2) 2.9 (2.5–3.5)
Urine sodium, mmol/L 47 (20–75) 68 (46–109) 54 (33–82) 61 (30–112)
Urine potassium, mmol/L 65 (44–81) 43 (28–73) 39 (31–49) 25 (17–41)
Urine osmolality, mOsm/kg 514 (440–618) 632 (440–752) 489 (355–674) 440 (322–558)
Medications, n (%)
Thiazide diuretics 1 (1) 0 30 (13) 9 (9)
Loop diuretics 23 (26) 12 (38) 117 (52) 50 (49)
Clin J Am Soc Nephrol 14: 656–663, May, 2019
Table 1. (Continued)
Admission Hypernatremia, n=122;
n (%) or Median (IQR)
Characteristic
#0.5 mmol/L per h
In-hospital mortality, n (%) 25 (28)
DNR, n (%) 43 (48)
Length of stay, d, median (IQR) 3 (2–5)
ICU, intensive care unit; IQR, interquartile range; NA, non-alcoholic; ICH, intracerebral hemorrhage; SAH, subarachnoid hemorrhage;
DNR, do not resuscitate.
after excluding patients without follow-up serum sodium
values beyond their peak level. We also segregated patients
into those that presented with severe hypernatremia on
admission (n=122) and those who developed hospital-
acquired hypernatremia (n=327), respectively (Supplemen-
tal Figure 1). The baseline characteristics between admission
hypernatremia and hospital-acquired hypernatremia
groups are shown in Supplemental Table 2. Both groups
were significantly different with respect to key character-
istics, including age, sex, and ICU first service. The baseline
characteristics by correction rates in both groups are avail-
able in Table 1. A total of 32 (26%) and 102 (31%) patients
had correction .0.5 mmol/L per hour in admission and
hospital-acquired hypernatremia groups, respectively.
In the admission hypernatremia group, those with a
rapid correction had a higher proportion of female patients
(75% versus 47%; P=0.01), Charlson Comorbidity Index
score of 1 (47% versus 22%; P=0.03), comorbid conditions
such as depression (25% versus 11%; P=0.06), and a lower
proportion of CKD (3% versus 21%; P=0.02).
Although patients in the hospital-acquired hypernatremia
group who experienced rapid correction had no difference
in sex or CKD status, they had a shorter median length of
stay (4 days [interquartile range (IQR), 2.2–8.8] versus
7 days [IQR 3.1–14.7]; P=0.002) and lower proportion of
stroke (20% versus 31%; P=0.04) (Table 1) compared with
those in the slower correction group. In patients with
hospital-acquired hypernatremia with rapid correction
rate, the median serum bicarbonate was significantly
lower (26 versus 23 mmol/L; P=0.02) and the number of
patients with serum bicarbonate #20 mmol/L were signif-
icantly higher in the rapid correction group (28%) compared
with slower correction group (14%; P=0.002).
There were some missing values for first care unit,
marital status, and laboratory values at the time of peak
sodium level, but they were used only for descriptive
purposes.
Serum Sodium Level and Correction of Hypernatremia
In the rapid serum sodium correction group of patients
with hospital-acquired hypernatremia, the time to correc-
tion to serum sodium ,145 from peak serum sodium was
14.7 hours (IQR, 9.2–18.9). The median rate of correction was
higher in patients with hospital-acquired hypernatremia
(0.9; IQR, 0.6–1.6 mmol/L per hour) compared with those
with admission hypernatremia (0.7; IQR, 0.6–1.4) (Table 2).
The peak serum sodium concentration in patients with
Hypernatremia Correction and Cerebral Edema, Chauhan et al. 659
Hospital-Acquired Hypernatremia,
n=327; n (%) or Median (IQR)
.0.5 mmol/L per h #0.5 mmol/L per h .0.5 mmol/L per h
8 (25) 90 (40) 45 (44)
12 (38) 61 (27) 23 (23)
3 (2–9) 7 (3–5) 4 (2–9)
admission hypernatremia was 163 mmol/L (IQR, 159–168),
which was significantly higher than the peak serum sodium
in those with hospital-acquired hypernatremia (158 mmol/
L; IQR, 156–161; P,0.001). Similarly, rate of correction was
higher at 24 hours in patients with admission hypernatremia
(0.5 mmol/h; IQR, 0.3–0.7 mmol/h) compared with those
with hospital-acquired hypernatremia (0.4 mmol/h; IQR,
0.2–0.7 mmol/h; P=0.05) (Supplemental Table 3).
Association of Serum Sodium Correction Rate with In-
Hospital Mortality
The in-hospital mortality proportion was not significantly
different between patients with admission hypernatremia
with rapid correction versus slow correction (25% versus
28%; P=0.80) (Table 1). Similarly, the in-hospital mortality
rate was not significantly different between patients with
hospital-acquired hypernatremia with rapid correction ver-
sus slow correction (44% versus 40%; P=0.50) (Table 1).
In multivariable analysis, rapid correction and 24-hour serum
sodium correction rate was not associated with mortality in
patients with admission hypernatremia (adjusted odds ratio
[aOR], 1.3; 95% confidence interval [95% CI], 0.5 to 3.7; and
aOR, 0.7; 95% CI, 0.3 to 1.6, respectively) (Table 3). Similarly,
among patients with hospital-acquired hypernatremia there
was no association between higher overall and 24-hour
serum sodium correction rate and mortality (aOR, 1.3;
95% CI, 0.8 to 2.3; and aOR, 1.4; 95% CI, 0.9 to 2.4,
respectively) (Table 3).
The Kaplan–Meier curves for 30-day survival for the rapid
versus slow correction rate groups are shown in Figure 1, A
and B and none of these curves were significantly different.
Incidence of in-hospital mortality by rapid versus slow cor-
rection rates by different cut-offs (.8, .10, and .12 mmol/L
in 24 hours) for both groups of patients are presented in
Figure 2, A and B. In subanalysis using different cut-offs of
rapid correction (.8, .10, and .12 mmol/L at 24 hours),
results for 30-day survival estimates were also largely
consistent in both groups of patients (Supplemental
Figure 2, A–C). In fact, there was a trend toward lower
mortality in some of the rapid correction rate groups that
did not reach statistical significance (Supplemental Figure
2, A and B). The mortality proportions in admission and
hospital-acquired hypernatremia groups were not signif-
icantly different among sexes in both slower and rapid
correction groups.
In subgroup analyses, the mortality rates in admission
and hospital-acquired hypernatremia groups were not
660 Clinical Journal of the American Society of Nephrology

Table 2. Distribution of the sodium level, difference, and correction time of adults admitted to ICU with hypernatremia at admission
and hospital-acquired

Admission Hypernatremia, n=122; Hospital-Acquired Hypernatremia,

Median (IQR) n=327; Median (IQR)
Variable
#0.5 mmol/L .0.5 mmol/L P #0.5 mmol/L .0.5 mmol/L
P Value
per h per h Value per h per h

Total, n (%) 90 (74) 32 (26) 225 (69) 102 (31)

Serum sodium, mmol/L
at peak 162.0 (159.0–168.0) 166.0 (158.5–169.5) 0.4 157.0 (156.0–160.0) 159.0 (157.0–164.0) ,0.001
at 24 h 156.0 (153.0–160.0) 152.0 (145.5–157.0) 0.1 153.0 (150.0–156.0) 146.0 (143.0–152.0) ,0.001
after correction or 144.0 (143.0–145.0) 144.0 (141.0–145.0) 0.9 145.0 (143.0–149.0) 144.0 (142.0–145.0) 0.02
last available
Serum sodium difference, mmol/L
at 24 h 7.5 (4.0–10.0) 13.0 (11.0–15.0) ,0.001 5.0 (3.0–7.0) 13.0 (8.0–19.0) ,0.001
at correction or last 18.0 (14.0–24.0) 25.0 (13.0–31.5) 0.1 13.0 (10.0–15.0) 16.0 (13.0–21.0) ,0.001
available
Serum sodium time difference, h
at 24 h 19.4 (16.0–21.8) 18.0 (15.0–20.5) 0.2 18.2 (11.9–21.9) 14.7 (9.2–18.9) ,0.001
at correction or last 69.2 (45.3–89.4) 24.0 (16.2–41.1) ,0.001 56.7 (34.1–88.8) 14.2 (6.7–23.4) ,0.001
available
Rate of sodium correction, mmol/L per h
at 0–24 h 0.4 (0.2–0.6) 0.7 (0.6–1.0) ,0.001 0.3 (0.2–0.4) 0.9 (0.6–1.6) ,0.001
Peak to normal 0.3 (0.2–0.4) 0.7 (0.6–1.4) ,0.001 0.2 (0.1–0.3) 0.9 (0.6–1.6) ,0.001
level or last
available

ICU, intensive care unit; IQR, interquartile range.

significantly different among sex and age (by median)
categories (#69 versus .69 years) in both slower and rapid
correction groups (Supplemental Table 4). In patients with
hospital-acquired hypernatremia, the mortality proportion
was higher in patients who had acute hypernatremia,
specifically in a group defined by a 48-hour interval (47%
versus 32%; P=0.01). There is no significant difference in
mortality proportion between slower and rapid correction
group in any duration of hypernatremia development
(Supplemental Table 4).
residents, and physician attendings. We manually reviewed
all these notes starting from the peak serum sodium level
through discharge and were unable to find any documen-
tation of an adverse event related to serum sodium correc-
tion. Rather than correction of hypernatremia, our manual
chart review revealed that the top five major primary causes
of worsening mental status, seizures, or cerebral edema
were intracerebral hemorrhage, stroke, epilepsy, brain
tumors, and brain trauma.

Manual Review of Potential Neurologic Complications due Discussion

to Correction of Hypernatremia
We conducted a manual chart review of all available
imaging reports, physician progress notes, and discharge
summaries among the admission hypernatremia group
and found no patients that had documented worsening
mental status, seizures, or generalized cerebral edema due
to correction of serum sodium. Among 327 hospital-acquired
hypernatremia group, 128 were defined to have chronic
hypernatremia. Similarly, in the manual chart reviews of
patients with chronic hypernatremia, no patients experi-
enced worsening mental status, seizures, or generalized
cerebral edema due to correction of serum sodium. Moreover,
among the 327 patients with hospital-acquired hypernatremia,
there were 28 additional patients in addition to the 128 defined
as having chronic hypernatremia that had ICD-9 codes for
cerebral edema, seizures, and/or alteration of consciousness.
None of these 128 patients had these symptoms secondary
to hypernatremia correction. Additionally, 47 out of 122
patients with admission hypernatremia and 128 patients with
hospital-acquired hypernatremia had progress notes avail-
able in the database from nursing staff, intensivists, physician
In the largest cohort published to date to determine the
effect of hypernatremia correction rate in critically ill patients
(11–13), we found that rapid correction of both admission
and hospital-acquired hypernatremia occurred in a third of
patients, and that rapid correction .0.5 mmol/L per hour or
.12 mmol/L per day was not associated with in-hospital
mortality or cerebral edema. In fact, there were no cases of
cerebral edema in the 78 patients who had serum sodium
correction of .12 mmol/L per day.
The target rate of sodium reduction in hypernatremia
treatment that is widely used in clinical practice is
0.5 mmol/L per hour, with a maximum rate of 10 mmol/L
per day (1,6–8). However, the data to support this rate of
correction is negligible (9). The studies in adults with
hypernatremia showed that rapid sodium correction rates
associated with less mortality (11,13). Alshayeb et al. (12)
and Ates et al. (13) used .0.134 and $0.25 mmol/L per
hour as a rapid hypernatremia correction rates, respec-
tively. However, the definitions of rapid correction rates
in these studies are ,0.5 mmol/L per hour and could be
considered as slow correction rates.
Clin J Am Soc Nephrol 14: 656–663, May, 2019 Hypernatremia Correction and Cerebral Edema, Chauhan et al. 661

Table 3. Measures of association and 95% CIs for overall correction rate and at 24 hours with the mortality outcome

Admission Hypernatremia Hospital-Acquired Hypernatremia

OR (95% CI) OR (95% CI)

Variables
Events, Events,
Unadjusted Adjusteda Unadjusted Adjusteda
N (%) N (%)

Overall sodium correction rate

#0.5 90 (74) Ref Ref 225 (69) Ref Ref
.0.5 32 (26) 0.9 (0.3 to 2.2) 1.3 (0.5 to 3.7) 102 (31) 1.2 (0.7 to 1.9) 1.3 (0.8 to 2.3)
At 24-h sodium correction rate
#0.5 62 (23) Ref Ref 203 (77) Ref Ref
.0.5 58 (33) 0.5 (0.2 to 1.3) 0.7 (0.3 to 1.6) 118 (67) 1.3 (0.8 to 2.1) 1.4 (0.9 to 2.4)

95% CI, 95% confidence interval; OR, odds ratio; Ref, reference.
a
Adjusted by age, sex, do-not-resuscitate status, and Charlson Comorbidity Index score.

Unlike hyponatremia, where the risks of osmotic de-
myelination syndrome are well described and often
studied in patients with rapid correction of serum sodium
in all age groups (15), there have been no convincing
reports of cerebral edema after rapid correction of
hypernatremia in adults. Clinicians and trainees often
extrapolate the data from hyponatremia and apply it to
hypernatremia. Most often, correction of the serum
sodium is a matter of increasing the rate of free water
We found no neurologic complications associated with
rapid hypernatremia correction. This is in contrast to the
study in neonates, which reported seizures due to cerebral
edema in the rapid correction group. There is a possible
A 1.0
P = 0.87
0.8
Survival Probability

administration, especially in vulnerable patients who do

not have access to or the capacity to ask for free water. 0.6
Trepidation in the rate of correction leads to longer length
of stay without any balancing benefit or evidence-based 0.4
justification.
0.2
We performed multiple sensitivity analysis to determine
the effect of varying rates of hypernatremia correction on 0
in-hospital mortality. For the admission hypernatremia
0 10 20 30
group, mortality rates were consistently lower in those
Days
with rapid correction (.8, .10, and .12 mmol/L) at
Rate ≤ 0.5 mmol/L/hour
24 hours, with no difference in mortality overall. For the
Rate > 0.5 mmol/L/hour
hospital-acquired hypernatremia group, there was no
clinically important difference in in-hospital mortality in B 1.0
all rate groups at 24 hours and at overall. All previous P = 0.21
studies have been done in the patients with hypernatremia 0.8
Survival Probability

at admission, and our results are consistent with them

(11–13). However, patients who developed hospital- 0.6
acquired hypernatremia were significantly different from
those with admission hypernatremia with higher 0.4
comorbidity burden and DNR status. The median serum
bicarbonate in the hospital-acquired hypernatremia group 0.2
with rapid correction group was significantly lower than the
patients in slower correction group. Although we did not 0
evaluate the fluid administration in our study, it is possible 0 10 20 30
that there are differences in bicarbonate therapy in rapid Days
versus slower serum sodium correction groups in patients Rate ≤ 0.5 mmol/L/hour
with hospital-acquired hypernatremia. However, Zhang Rate > 0.5 mmol/L/hour
et al. (15) showed that the bicarbonate therapy in patients
with metabolic acidosis was not associated with the mor-
Figure 1. | Thirty-day survival curves for the rapid versus slow cor-
tality outcome using the same MIMIC-III database. Another rection rate groups are not significantly different. Figure 1A and 1B
randomized controlled study by Jaber et al. (16) showed represents admission and hospital-acquired hypernatremia patients
similar results. Thus, we hypothesized that the differences respectively. Thirty-day survival patterns by rapid versus slow cor-
in bicarbonate level in hospital-acquired hypernatremia rection rate in patients with (A) admission and (B) hospital-acquired
would not affect the mortality outcome. hypernatremia.
662 Clinical Journal of the American Society of Nephrology
A 50
40
P = 0.02
Mortality Rate (%)
30
20
10
0
≤8 vs >8 mmol/L/24 hours
Slower correction group
B 50
P = 0.19
40
Mortality Rate (%)
30
20
10
0
≤8 vs >8 mmol/L/24 hours
Slower correction group
Figure 2. | Incidence of in-hospital mortality rates are lower in rapid correction rate group versus slow correction rate group but not
significantly different by various cut-offs of correction rates Figure 2A and 2B represents admission and hospital-acquired hypernatremia
patients respectively. In-hospital mortality proportions in patients with (A) admission and (B) hospital-acquired hypernatremia.
explanation for this conflicting outcome. The human brain
volume rapidly increases during the first 6 years of life, and
then progressively increases until age 15 years. In general,
the ratio of brain volume to cranial vault size was greatest
around age 6 years. In adults, the brain volume gradually
reduces from age 45 years and reaches the lowest volume at
age 86 years (17–19). These differences between children and
adults limit brain adaptation and can potentially explain the
edema associated with rapid hypernatremia correction seen
only in infants.
Our study has several advantages. First, to the best of
our knowledge, this is the largest adult cohort study focusing
on the neurologic complications and mortality after
hypernatremia correction in critically ill adults. Second,
we conducted a comprehensive manual review of neuro-
logic outcomes where the imaging reports and discharge
summaries were available. Third, the previous studies
were done entirely in patients with hypernatremia present
on admission, whereas we included patients with both
admission and hospital-acquired hypernatremia and dem-
onstrated the distinct differences in cohort characteristics
and outcomes. Finally, we accounted for many factors
(including comorbidity burden and DNR status) that may
confound the association between hypernatremia correc-
tion and mortality.
P = 0.09 P = 0.14
≤10 vs >10 mmol/L/24 hours ≤12 vs >12 mmol/L/24 hours
Rapid correction group
P = 1.00 P = 0.55
≤10 vs >10 mmol/L/24 hours ≤12 vs >12 mmol/L/24 hours
Rapid correction group
These results, however, should be interpreted in light of
some limitations. First, we were unable to identify the exact
timing of the onset of hypernatremia among patients with
admission hypernatremia. Animal studies have shown that
increasing concentration of idiogenic osmoles plays an
important role in the regulation of intracellular osmolality
during the course of hypernatremia. However, this change
occurs only in chronic hypernatremia (20). Therefore, the
patients with chronic hypernatremia were theoretically
more susceptible for neurologic complication and their
outcomes may differ from acute hypernatremia after rapid
sodium reduction. Nevertheless, we could not find any
instances of neurologic complications from hypernatremia
correction regardless of chronicity of the onset. Second, we
included patients with sodium level $155 mmol/L and
patients with lower sodium levels were not included.
Theoretically, the adverse effects of rapid hypernatremia
correction in patients with mild hypernatremia is less than
what we found in our study; however, we could not find
any neurologic complications associated with rapid correc-
tion. Third, the types of fluids used to correct hypernatremia
was not evaluated in this study, and it could be one of
the confounding factors. However, the evidence to suggest
that treatment with different fluid administration strategies
would have an influence on outcomes in critically ill patients
Clin J Am Soc Nephrol 14: 656–663, May, 2019
with hypernatremia is limited. Fourth, only 47 patients
had progress notes available for a detailed manual chart
review to assess potential complications. However, we
did manually review all imaging reports and discharge
summaries for patients with chronic hypernatremia. Finally,
we lacked an external validation cohort or a cohort with
noncritically ill patients.
In conclusion, we did not find any evidence that rapid
correction of hypernatremia was associated with a higher risk
for mortality, seizure, alteration of consciousness, and/or
cerebral edema in critically ill adult patients with either
admission or hospital-acquired hypernatremia. These find-
ings point toward the fact that the fears of rapid correction of
hypernatremia may be overstated and clinicians should
consider correcting the serum sodium level with free-water
administration to shorten the length of stay in this vulnerable
patient population.
Acknowledgments
Dr. Chan reports grants from the National Institutes of Health
(5T32DK007757-18), outside the submitted work. Research reported
in this publication was supported by the National Institute of Dia-
betes and Digestive and Kidney Diseases of the National Institutes
of Health.
The content is solely the responsibility of the authors and does
not necessarily represent the official views of the National Institutes
of Health.
Disclosures
Dr. Coca reports personal fees and other from RenalytixAI, per-
sonal fees from CHF Solutions, personal fees from Quark, personal
fees from Takeda, personal fees from Janssen, personal fees and other
from pulseData, and personal fees from Goldfinch, outside the sub-
mitted work. Dr. Nadkami reports personal fees and other funding
from RenalytixAI, personal fees and other funding from pulseData,
research funding from Goldfinch, outside the submitted work, and
personal fees from BioVie, outside the submitted work. Dr. Van
Vleck reports personal fees from Clinithink, outside the submitted
work. Dr. Chan, Dr. Chauhan, Dr. Chaudhary, Dr. Debnath,
Dr. Duffy, Dr. Patel, Dr. Pattharanitima, and Dr. Saha have nothing
to disclose.
Supplemental Material
This article contains the following supplemental material online at
http://cjasn.asnjournals.org/lookup/suppl/doi:10.2215/
CJN.10640918/-/DCSupplemental.
Supplemental Table 1. List of International Classification of Dis-
eases, Ninth Revision (ICD-9) codes used.
Supplemental Table 2. Characteristics of adults admitted to ICU
with hypernatremia at admission versus hospital acquired.
Supplemental Table 3. Distribution of the sodium level, difference,
and correction time of adults admitted to ICU with hypernatremia at
admission versus hospital‐acquired.
Supplemental Table 4. Mortality rates of adults admitted to ICU
with hypernatremia at admission and patients with hospital-
acquired hypernatremia by slower versus rapid correction rate.
Supplemental Figure 1. Selection of patients with hypernatremia
from the MIMIC‐III database.
Supplemental Figure 2. Thirty‐day survival patterns by rapid
versus slow correction rate in admission and hospital-acquired
hypernatremia groups.
Hypernatremia Correction and Cerebral Edema, Chauhan et al. 663
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Received: September 5, 2018 Accepted: February 15, 2019
K. Chauhan, P.P., G.N.N., and S.G.C. contributed equally to this work.
Published online ahead of print. Publication date available at www.
cjasn.org.
See related editorial, “Evidence for Managing Hypernatremia: Is It
Just Hyponatremia in Reverse?,” on pages 645–647.