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Correction Hipernatremia
Correction Hipernatremia
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
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 Hypernatremia Correction and Cerebral Edema, Chauhan et al. 657
severe hypernatremia, which was defined if they had serum (nonalcoholic liver disease, CKD, ESKD, congestive heart
sodium .155 mmol/L at any time point during their hospital failure, diabetes mellitus type 2, depression, bipolar disor-
admission. We excluded patients aged ,18 years old and der, schizophrenia, epilepsy, stroke, myocardial infarction,
patients with no serum sodium values at any time points AIDS, chronic obstructive pulmonary disease, hyperten-
after the peak serum sodium level. The patients who had sion, and peripheral arterial disease), ICU type during
severe hypernatremia at hospital admission were labeled first admission, do-not-resuscitate (DNR) status, laboratory
“admission hypernatremia” and patients who developed values during peak sodium level (serum: creatinine, potas-
severe hypernatremia during their hospital stay were labeled sium, phosphorus, magnesium, osmolality, bicarbonate,
“hospital-acquired hypernatremia.” We considered only the and albumin; urine: sodium, potassium, and osmolality),
data from the patient’s first admission with hypernatremia. and diuretics use (thiazide and loop) (Table 1).
A study flow diagram is included in Supplemental Figure 1.
Statistical Analyses
Definition of Rapid Correction and Categories We conducted analysis to explore differences be-
For each study participant, we identified peak serum tween patients who experienced overall slow correc-
sodium level and calculated the overall rate of correction tion (#0.5 mmol/L per hour) versus rapid correction
using serum sodium values after the peak. We calculated (.0.5 mmol/L per hour) stratified by two groups: admission
rate of serum sodium correction was calculated using the hypernatremia and hospital-acquired hypernatremia. We
following formula: further divided correction rate categories during hospital
follow-up duration into patients with corrected sodium level
Overall serum sodium correction rate (those who achieved serum sodium of ,145 mmol/L) and
¼ ðpeak Naþ value-Naa Þmmol=L =ðtime at peak Naþ -timea Þh patients with uncorrected sodium level (those who did not
achieve a serum sodium level of ,145 mmol/L). We used the
Naa is the first corrected serum sodium value ,145 mmol/L Wilcoxon rank sum test for continuous variables and the
or the last serum sodium value before discharge in those Fisher exact test for categorical variables. We performed
patients who did not correct down to 145mmol/L. Kaplan–Meier curve to assess the survival rate difference in
Timea is the time at first corrected serum sodium patients between different sodium correction rates. We then
level ,145 mmol/L or the time of last available value in used unadjusted and adjusted logistic regression analysis to
those who did not achieve correction during their admis- determine the influence of hypernatremia correction rate at
sion. We also calculated serum sodium correction rate at different time points on mortality. An adjustment of age, sex,
24 hours using the same formula, where Naa is the serum DNR status, and Charlson comorbidity index was included
sodium value regardless of their corrected level at 24-hour, in the model. As a subgroup analyses, we identified patients
and timea is the time at which Naa was recorded at 24 hours. who had serum sodium $145 mmol/L for .48 hours in
Rapid hypernatremia correction was defined as an over- patients with hospital-acquired hypernatremia and consid-
all serum sodium correction rate of .0.5 and #0.5 mmol/L ered them as having chronic hypernatremia. Then we
per hour was considered slower hypernatremia correction compared mortality proportions between acute and
rate. Additionally, we did several subanalysis with varying chronic hypernatremia groups within the hospital-acquired
hypernatremia correction rates of .8, .10, and .12 mmol/L hypernatremia group and also between sex and median age
per 24 hours. groups among patients with hypernatremia at admission
and those with hospital-acquired hypernatremia. A P value
Definition of Neurologic Complications and of 0.05 was considered statistically significant for all
Chronic Hypernatremia comparisons. As this study was done on publicly available,
To determine the incidence of cerebral edema, seizures, deidentified data, it was considered exempt from institu-
and alteration of consciousness in the study population, we tional review board approval. The analysis was done using
used the International Classification of Diseases, Ninth SAS v9.4 (SAS Institute Inc., Cary, NC) and Stata/IC 15.1
Revision (ICD-9) diagnostic codes mentioned in Supple- software (StataCorp, College Station, TX).
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 Results
having chronic hypernatremia. We also presumed pa- Study Cohort Characteristics
tients with hypernatremia at admission as having chronic We identified 512 patients with severe hypernatremia
hypernatremia because the onset of higher serum sodium during their first admission to the ICU from 2001 to 2012. A
was unknown. To identify the causes of these neurologic 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
#0.5 mmol/L per h .0.5 mmol/L per h #0.5 mmol/L per h .0.5 mmol/L per h
Table 1. (Continued)
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
Downloaded from http://journals.lww.com/cjasn by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1A
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 admission hypernatremia was 163 mmol/L (IQR, 159–168),
values beyond their peak level. We also segregated patients which was significantly higher than the peak serum sodium
into those that presented with severe hypernatremia on in those with hospital-acquired hypernatremia (158 mmol/
admission (n=122) and those who developed hospital- L; IQR, 156–161; P,0.001). Similarly, rate of correction was
acquired hypernatremia (n=327), respectively (Supplemen- higher at 24 hours in patients with admission hypernatremia
tal Figure 1). The baseline characteristics between admission (0.5 mmol/h; IQR, 0.3–0.7 mmol/h) compared with those
hypernatremia and hospital-acquired hypernatremia with hospital-acquired hypernatremia (0.4 mmol/h; IQR,
groups are shown in Supplemental Table 2. Both groups 0.2–0.7 mmol/h; P=0.05) (Supplemental Table 3).
were significantly different with respect to key character-
istics, including age, sex, and ICU first service. The baseline Association of Serum Sodium Correction Rate with In-
characteristics by correction rates in both groups are avail- Hospital Mortality
able in Table 1. A total of 32 (26%) and 102 (31%) patients The in-hospital mortality proportion was not significantly
had correction .0.5 mmol/L per hour in admission and different between patients with admission hypernatremia
hospital-acquired hypernatremia groups, respectively. with rapid correction versus slow correction (25% versus
In the admission hypernatremia group, those with a 28%; P=0.80) (Table 1). Similarly, the in-hospital mortality
rapid correction had a higher proportion of female patients rate was not significantly different between patients with
(75% versus 47%; P=0.01), Charlson Comorbidity Index hospital-acquired hypernatremia with rapid correction ver-
score of 1 (47% versus 22%; P=0.03), comorbid conditions sus slow correction (44% versus 40%; P=0.50) (Table 1).
such as depression (25% versus 11%; P=0.06), and a lower In multivariable analysis, rapid correction and 24-hour serum
proportion of CKD (3% versus 21%; P=0.02). sodium correction rate was not associated with mortality in
Although patients in the hospital-acquired hypernatremia patients with admission hypernatremia (adjusted odds ratio
group who experienced rapid correction had no difference [aOR], 1.3; 95% confidence interval [95% CI], 0.5 to 3.7; and
in sex or CKD status, they had a shorter median length of aOR, 0.7; 95% CI, 0.3 to 1.6, respectively) (Table 3). Similarly,
stay (4 days [interquartile range (IQR), 2.2–8.8] versus among patients with hospital-acquired hypernatremia there
7 days [IQR 3.1–14.7]; P=0.002) and lower proportion of was no association between higher overall and 24-hour
stroke (20% versus 31%; P=0.04) (Table 1) compared with serum sodium correction rate and mortality (aOR, 1.3;
those in the slower correction group. In patients with 95% CI, 0.8 to 2.3; and aOR, 1.4; 95% CI, 0.9 to 2.4,
hospital-acquired hypernatremia with rapid correction respectively) (Table 3).
rate, the median serum bicarbonate was significantly The Kaplan–Meier curves for 30-day survival for the rapid
lower (26 versus 23 mmol/L; P=0.02) and the number of versus slow correction rate groups are shown in Figure 1, A
patients with serum bicarbonate #20 mmol/L were signif- and B and none of these curves were significantly different.
icantly higher in the rapid correction group (28%) compared Incidence of in-hospital mortality by rapid versus slow cor-
with slower correction group (14%; P=0.002). rection rates by different cut-offs (.8, .10, and .12 mmol/L
There were some missing values for first care unit, in 24 hours) for both groups of patients are presented in
marital status, and laboratory values at the time of peak Figure 2, A and B. In subanalysis using different cut-offs of
sodium level, but they were used only for descriptive rapid correction (.8, .10, and .12 mmol/L at 24 hours),
purposes. results for 30-day survival estimates were also largely
consistent in both groups of patients (Supplemental
Serum Sodium Level and Correction of Hypernatremia Figure 2, A–C). In fact, there was a trend toward lower
In the rapid serum sodium correction group of patients mortality in some of the rapid correction rate groups that
with hospital-acquired hypernatremia, the time to correc- did not reach statistical significance (Supplemental Figure
tion to serum sodium ,145 from peak serum sodium was 2, A and B). The mortality proportions in admission and
14.7 hours (IQR, 9.2–18.9). The median rate of correction was hospital-acquired hypernatremia groups were not signif-
higher in patients with hospital-acquired hypernatremia icantly different among sexes in both slower and rapid
(0.9; IQR, 0.6–1.6 mmol/L per hour) compared with those correction groups.
with admission hypernatremia (0.7; IQR, 0.6–1.4) (Table 2). In subgroup analyses, the mortality rates in admission
The peak serum sodium concentration in patients with 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
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
significantly different among sex and age (by median) residents, and physician attendings. We manually reviewed
categories (#69 versus .69 years) in both slower and rapid all these notes starting from the peak serum sodium level
correction groups (Supplemental Table 4). In patients with through discharge and were unable to find any documen-
hospital-acquired hypernatremia, the mortality proportion tation of an adverse event related to serum sodium correc-
was higher in patients who had acute hypernatremia, tion. Rather than correction of hypernatremia, our manual
specifically in a group defined by a 48-hour interval (47% chart review revealed that the top five major primary causes
versus 32%; P=0.01). There is no significant difference in of worsening mental status, seizures, or cerebral edema
mortality proportion between slower and rapid correction were intracerebral hemorrhage, stroke, epilepsy, brain
group in any duration of hypernatremia development tumors, and brain trauma.
(Supplemental Table 4).
Table 3. Measures of association and 95% CIs for overall correction rate and at 24 hours with the mortality outcome
Events, Events,
Unadjusted Adjusteda Unadjusted Adjusteda
N (%) N (%)
.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- We found no neurologic complications associated with
myelination syndrome are well described and often rapid hypernatremia correction. This is in contrast to the
studied in patients with rapid correction of serum sodium study in neonates, which reported seizures due to cerebral
in all age groups (15), there have been no convincing edema in the rapid correction group. There is a possible
reports of cerebral edema after rapid correction of
hypernatremia in adults. Clinicians and trainees often
extrapolate the data from hyponatremia and apply it to A 1.0
hypernatremia. Most often, correction of the serum P = 0.87
sodium is a matter of increasing the rate of free water 0.8
Survival Probability
A 50
40
P = 0.02 P = 0.09 P = 0.14
20
WnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC1y0abggQZXdgGj2MwlZLeI= on 11/06/2023
10
0
≤8 vs >8 mmol/L/24 hours ≤10 vs >10 mmol/L/24 hours ≤12 vs >12 mmol/L/24 hours
B 50
P = 0.19 P = 1.00 P = 0.55
40
Mortality Rate (%)
30
20
10
0
≤8 vs >8 mmol/L/24 hours ≤10 vs >10 mmol/L/24 hours ≤12 vs >12 mmol/L/24 hours
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 These results, however, should be interpreted in light of
volume rapidly increases during the first 6 years of life, and some limitations. First, we were unable to identify the exact
then progressively increases until age 15 years. In general, timing of the onset of hypernatremia among patients with
the ratio of brain volume to cranial vault size was greatest admission hypernatremia. Animal studies have shown that
around age 6 years. In adults, the brain volume gradually increasing concentration of idiogenic osmoles plays an
reduces from age 45 years and reaches the lowest volume at important role in the regulation of intracellular osmolality
age 86 years (17–19). These differences between children and during the course of hypernatremia. However, this change
adults limit brain adaptation and can potentially explain the occurs only in chronic hypernatremia (20). Therefore, the
edema associated with rapid hypernatremia correction seen patients with chronic hypernatremia were theoretically
only in infants. more susceptible for neurologic complication and their
Our study has several advantages. First, to the best of outcomes may differ from acute hypernatremia after rapid
our knowledge, this is the largest adult cohort study focusing sodium reduction. Nevertheless, we could not find any
on the neurologic complications and mortality after instances of neurologic complications from hypernatremia
hypernatremia correction in critically ill adults. Second, correction regardless of chronicity of the onset. Second, we
we conducted a comprehensive manual review of neuro- included patients with sodium level $155 mmol/L and
logic outcomes where the imaging reports and discharge patients with lower sodium levels were not included.
summaries were available. Third, the previous studies Theoretically, the adverse effects of rapid hypernatremia
were done entirely in patients with hypernatremia present correction in patients with mild hypernatremia is less than
on admission, whereas we included patients with both what we found in our study; however, we could not find
admission and hospital-acquired hypernatremia and dem- any neurologic complications associated with rapid correc-
onstrated the distinct differences in cohort characteristics tion. Third, the types of fluids used to correct hypernatremia
and outcomes. Finally, we accounted for many factors was not evaluated in this study, and it could be one of
(including comorbidity burden and DNR status) that may the confounding factors. However, the evidence to suggest
confound the association between hypernatremia correc- that treatment with different fluid administration strategies
tion and mortality. would have an influence on outcomes in critically ill patients
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Supplemental Table 4. Mortality rates of adults admitted to ICU Received: September 5, 2018 Accepted: February 15, 2019
with hypernatremia at admission and patients with hospital-
acquired hypernatremia by slower versus rapid correction rate. K. Chauhan, P.P., G.N.N., and S.G.C. contributed equally to this work.
Supplemental Figure 1. Selection of patients with hypernatremia
Published online ahead of print. Publication date available at www.
from the MIMIC‐III database.
cjasn.org.
Supplemental Figure 2. Thirty‐day survival patterns by rapid
versus slow correction rate in admission and hospital-acquired See related editorial, “Evidence for Managing Hypernatremia: Is It
hypernatremia groups. Just Hyponatremia in Reverse?,” on pages 645–647.