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RESEARCH ARTICLE
Chloride alterations in hospitalized patients:
Prevalence and outcome significance
Charat Thongprayoon
1,2
, Wisit Cheungpasitporn
1
, Zhen Cheng
1,3
, Qi Qian
1
*
1Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota,
United States of America, 2Department of Anesthesiology, Mayo Clinic Rochester, Minnesota, United States
of America, 3National Clinical Research Center of Kidney Disease, Jinling Hospital, Nanjing University
School of Medicine, Nanjing, China
*qian.qi@mayo.edu
Abstract
Serum Cl (sCl) alterations in hospitalized patients have not been comprehensively studied
in recent years. The aim of this study is to investigate the prevalence and outcome signifi-
cance of (1) sCl alterations on hospital admission, and (2) sCl evolution within the first 48 hr
of hospital admission. We conducted a retrospective study of all hospital admissions in the
years 2011–2013 at Mayo Clinic Rochester, a 2000-bed tertiary medical center. Outcome
measures included hospital mortality, length of hospital stay and discharge disposition.
76,719 unique admissions (18 years old) were studied. Based on hospital mortality, sCl
in the range of 105–108 mmol/L was found to be optimal. sCl <100 (n = 13,611) and >108
(n = 11,395) mmol/L independently predicted a higher risk of hospital mortality, longer hospi-
tal stay and being discharged to a care facility. 13,089 patients (17.1%) had serum anion
gap >12 mmol/L; their hospital mortality, when compared to 63,630 patients (82.9%) with
anion gap 12 mmol/L, was worse. Notably, patients with elevated anion gap displayed a
progressively worsening mortality with rising sCl. sCl elevation within 48 hr of admission
was associated with a higher proportion of 0.9% saline administration and was an indepen-
dent predictor for hospital mortality. Moreover, the magnitude of sCl rise was inversely cor-
related to the days of patient survival. In conclusion, serum Cl alterations on admission
predict poor clinical outcomes. Post-admission sCl increase, due to Cl-rich fluid infusion,
independently predicts hospital mortality. These results raise a critical question of whether
iatrogenic cause of hyperchloremia should be avoided, a question to be addressed by future
prospective studies.
Introduction
Chloride (Cl) is the most abundant anion in extracellular fluid, playing a fundamental role in
the maintenance of osmotic pressure, water distribution and acid–base balance [1]. Cl chan-
nels are expressed in almost all cells in the body. Dysfunctions in the Cl channel result in a
broad spectrum of diseases [2].
PLOS ONE | https://doi.org/10.1371/journal.pone.0174430 March 22, 2017 1 / 17
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OPEN ACCESS
Citation: Thongprayoon C, Cheungpasitporn W,
Cheng Z, Qian Q (2017) Chloride alterations in
hospitalized patients: Prevalence and outcome
significance. PLoS ONE 12(3): e0174430. https://
doi.org/10.1371/journal.pone.0174430
Editor: Yu Ru Kou, National Yang-Ming University,
TAIWAN
Received: December 17, 2016
Accepted: March 8, 2017
Published: March 22, 2017
Copyright: ©2017 Thongprayoon et al. This is an
open access article distributed under the terms of
the Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited.
Data Availability Statement: All relevant data are
within the paper.
Funding: The author(s) received no specific
funding for this work.
Competing interests: The authors have declared
that no competing interests exist.
Abbreviations: AG, anion gap; A
TOT
, total weak
non-volatile acids; CI, confidence interval; IQR,
interquartile range; LOS, length of hospital stay;
OR, odds ratio; sCl, serum chloride; SID, strong ion
Variations in electrolyte concentration drive changes in the ionization state of water mole-
cules that alter the hydrogen ion concentration [H
+
] and pH. Three independent factors
(strong ion difference [SID], A
TOT
(total weak non-volatile acids) and pCO
2
) determine the
plasma pH by changing the degree of water dissociation. An excess of plasma anions relative
to cations gives rise to acidosis, as disproportionate anion accumulation causes a fall in the
[OH
-
]. By contrast, an excess of cations lowers the [H
+
], leading to alkalosis [3]. Of the three
independent pH determinants, SID is dominant. SID is, however, cumbersome to calculate
and some SID components are not routinely measured in practice. Recently, serum sodium
(Na)-Cl difference (Diff
Na-Cl
) and Cl:Na ratio have been introduced as surrogates for SID.
They exhibit adequate receiver-operating characteristic curves in determining acid-base status
[4,5].
Hyperchloremia is a common feature in sepsis and a frequent etiology of metabolic acidosis
in critically ill patients [6]. Often, the source of the acidosis is multiple and at least partly iatro-
genic because 0.9% saline resuscitation is routinely used for sepsis and shock patients. Saline
infusion can produce hyperchloremia and metabolic acidosis. Mobilization of endogenous Cl
from tissue/cell may also contribute to hyperchloremia [7]. Additionally, acidosis in critically
ill patients can be due to the presence of anions that are not routinely measured (unmeasured
anions, UMAs), including lactate, β-hydroxybutyrate, acetoacetate, anions associated with ure-
mia and other toxins. UMAs can be quantified by calculating the anion gap (AG) [8] or strong
ion gap (SIG) [9,10]. AG corrected for albumin is an excellent surrogate for SIG [5].
Studies on the clinical impact of serum Cl (sCl) alterations are limited. Several publications
show that hypo- and hyperchloremia can both be associated with increased hospital mortality
in critically ill patients [11–15], patients with severe sepsis and septic shock [15,16], and in
post-surgery patients [14,17,18]. The studies, however, are limited by lack of data on anion-
gap and serum Na alterations. A recent study by Young et al. [19] compared buffered versus
non-buffered fluid administration for intensive care units (ICUs) patients and found no differ-
ence in the AKI occurrence and hospital mortality. The study, however, was commenced in
the ICUs after the participants were managed in various care settings (including the operation
rooms, regular hospital units and ICUs of another hospital) where they likely had received flu-
ids (amount unknown). There was no data on the patient volume status and no data on hyper-
chloremia with the study fluid (average of 2L) administration. Thus, it is unclear whether the
study results are related to serum Cl alterations. There has not been a comprehensive study on
the effects of sCl alterations upon hospital admission and consequences of sCl evolution after
admission.
The aim of this study is to investigate the prevalence and outcome significance of (1) sCl
alterations upon hospital admission, and (2) sCl evolution within 48 hr following the hospital
admission in recent years.
Materials and methods
The Institutional Review Board approved the study and waver of consent. All participants had
provided Mayo Clinic with research authorization. Participant records were de-identified and
analyzed anonymously. Adults (age >18 years) admitted to Mayo Clinic Rochester between
January 1, 2011 and December 31, 2013 were enrolled (Fig 1). Patients without admission sCl
(24hr of admission) were excluded. For patients with multiple admissions, data from the
first admission were analyzed. Charlson comorbidity index [20] was computed for each patient
at the index admission. Clinical data, including principal diagnosis based on the ICD-9 (Inter-
national Classification of Diseases, 9th Revision) codes, were extracted from our institutional
electronic database. sCl values were grouped, based on hospital mortality data (Fig 2) into:
Chloride alterations in hospitalized patients
PLOS ONE | https://doi.org/10.1371/journal.pone.0174430 March 22, 2017 2 / 17
difference; SIG, strong ion gap; UMA, unmeasured
anion.
<95, 95–100, 100–105, 105–108 (optimal), 108–113, 113–118 and >118 mmol/L. Acid-base
status was determined (Box 1). Diff
Na-Cl
and Cl:Na ratio were used as surrogates for SID [4,5],
and AG (Na-Cl-HCO
3
) used to estimate UMAs.
Serum Cl measurement
In out institution, sCl is measured using the Roche Cobas 8000 ISE analytics, which utilizes an
indirect potentiometric assay with an ion-selective electrode (ISE). The electrode has a selec-
tive membrane in contact with both the test solution (patient’s sample) and an internal filling
solution (containing the test ion at a fixed concentration). The membrane electromotive force
is determined by the difference in concentration of the test ion in the two solutions. In our
experience, such method for sCl measurement has imprecision (coefficient of variation) of
1–2% across the measurable range. The quality control program in our clinical laboratory is
designed to minimize between instrument bias and between lot shifts to 3 mmol/L.
Fig 1. The study flow chart.
https://doi.org/10.1371/journal.pone.0174430.g001
Chloride alterations in hospitalized patients
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Statistical analysis
Continuous and categorical variables are reported as means±SDs and counts with percentages,
respectively. Baseline characteristics among groups were compared, using ANOVA for contin-
uous and Chi-square for categorical variables. Missing data were not imputed; lower counts
were reported. Hospital mortality and sCl were modeled using smoothing splines to allow for
non-linear effects. The restricted cubic spline with 4 knots was used with sCl when fitting the
model; plot constructed using the design library, R version 3.0 (Free software Foundation, Cal-
ifornia) [21]. Multivariable logistic and linear regressions were performed to assess the associa-
tions between sCl and clinical outcomes (mortality, length of hospital stay [LOS] and
Fig 2. Hospital mortality analyzed by restricted cubic spline.
https://doi.org/10.1371/journal.pone.0174430.g002
Chloride alterations in hospitalized patients
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discharge disposition). Odds ratio (OR) and 95% confidence interval (CI) were reported. Two-
tailed p of <0.05 was considered significant. Unless specified, JMP statistical software (version
9.0, SAS Institute Inc., NC) was used for analyses.
We hypothesized that patients with sCl increase (>4 mmol/L) received higher proportion
of Cl-rich fluids (0.9% saline) than patients with minimal sCl change (-2 to 0 mmol/L). How-
ever, comparison of the two groups using the whole dataset would likely cause over-power,
resulting a statistical significant but (possibly) clinically meaningless or misleading result. To
avoid such a possibility, we did a preliminary testing of 15 patients in each of the two groups
(samples randomized) to assess the difference in the percentage of 0.9% saline between the two
groups. The testing showed a difference to be approximately 20%, and a power calculation
yielded a total of 150 patients needed to generate a >85% power. We, therefore, included 200
patients (100 patients in each group of randomized sample) for analysis.
Results
1. Patients characteristics
76,719 unique patients from a total of 147,358 hospital admissions were enrolled. 55,523
(72.4%) had repeat sCl measurements within 48 hours (Fig 1). 23.6% (n = 18,066) of the
76,719 had an optimal sCl level (105–108 mmol/L) based on hospital mortality (Table 1, Figs 2
and 3). 61.6% (n = 47,258) patients had sCl <105 mmol/L, and 14.9% (n = 11,395) patients
had sCl >108 mmol/L on admission.
Acid-base profile was assessed. With increasing sCl, Diff
Na-Cl
declined progressively from
38.6±5.1 to 24.1±6.7 mmol/L; Cl:Na ratios increased from 0.70±0.03 to 0.84±0.04. AG and
HCO
3
declined (Table 1). In patients with sCl <95 mmol/L, their Diff
Na-Cl
was 38.6±5.1, Cl:Na
ratio 0.70±0.03, HCO
3
27.0±5.5 and AG 11.6±4.9 mmol/L, suggesting the presence of mixed
hypochloremic alkalosis and AG acidosis. In those with sCl >118 mmol/L, Diff
Na-Cl
was 24.1
±6.7, Cl:Na ratio 0.84±0.04, HCO
3
19.0±5.8 and AG 5.1±6.9 mmol/L. These changes are con-
sistent with a dominant presence of hyperchloremic acidosis. Acid-base alterations were fur-
ther delineated based on the patients’ AG (detailed below).
Box 1. Definition of acid-base alterations:[5,42,43]
• Hypochloremic alkalosis:
Cl:Na ratio <0.75
Diff
Na–Cl
>37 mmol/L
• Hyperchloremic acidosis:
Cl:Na ratio >0.77
Diff
Na–Cl
:<32 mmol/L
• Mixed alterations:
AG >12 mmol/L
Cl:Na ratio 0.75–0.77
Diff
Na–Cl
32–37 mmol/L
Chloride alterations in hospitalized patients
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2. Clinical outcomes
2-a. Hospital mortality. Initial determination of hospital mortality (Fig 2) showed that
the lowest mortality risk was with sCl in the range of 105–108 mmol/L (designated as optimal
sCl value). Concordant changes in the hospital mortality (in %) were noted (Fig 3).
Logistic regression models were built to determine the contribution of sCl alterations to the
risk of mortality (Table 2). In both the unadjusted and adjusted models (Models 1 and 2), the
ORs for hospital mortality were significantly elevated in sCl <100 and >108 mmol/L. Dysna-
tremia, when disproportionate to Cl alterations, can independently alter patient mortality
[22,23]. We therefore further adjusted the model 2 for Na indifferences (model 3). The ORs
remained significant. These results are consistent with sCl alterations (outside 100–108 mmol/
L) being an independent predictor for hospital mortality.
2-b. Length of Hospital Stay (LOS) and discharge disposition. LOS and discharged to a
care facility are associated with patients’ long-term morbidity and mortality[24]. In fully
adjusted models, sCl <100 and >108 mmol/L were independently associated with elevated
risks for both (Table 2). It should be noted that LOS and hospital discharge disposition can be
affected by multiple factors and may not be strongly influenced by serum Cl alterations.
3. Patients with Anion Gap or >12 mmol/L
As the data from the entire cohort suggested the presence of mixed acid-base alterations, we
grouped patients based on their serum AG. The AG values were not adjusted for serum
Table 1. Baseline clinical characteristics.
Variables All Admission serum chloride level (mmol/L)
<95 95–100 100–105 105–108 108–113 113–118 >118 p
N 76,719 3,360 10,251 33,647 18,066 9,656 1,490 249
Age (year) 61.1±17.8 66±16 64±17 60±18 60±18 61±18 61±17 62±19 <0.001
Male 40,515 (53) 1,602 (48) 5,498 (54) 18,519 (55) 9,190 (51) 4,864 (50) 717 (48) 125 (50) <0.001
Caucasian 71,229 (93) 3,136 (93) 9,483 (93) 31,319 (93) 16,762 (93) 8,956 (93) 1,348 (90) 225 (90)
Principal Diagnosis
• Cardiovascular
• Endocrine/Metabolic
• Gastrointestinal
• Renal Disease
• Hematology/Oncology
• Infectious Disease
• Respiratory
• Injury/poisoning
• Other
16,275 (21)
2,084 (3)
7,118 (9)
2850 (4)
11,712 (15)
2,399 (3)
3,085 (4)
11,823 (15)
19,373 (25)
618
366
415
162
334
220
340
351
554
1,870
432
1,148
405
1,430
546
820
1,421
2,179
6,138
800
3,086
1,273
5,796
893
1,266
5,067
9,328
3,898
291
1,495
607
2,919
361
416
3,051
5,028
3,116
154
821
337
1,082
264
213
1,623
2,046
588
30
126
49
138
80
22
238
219
47
11
27
17
13
35
8
72
19
<0.001
Charlson Score 1.8±2.3 2.5±2.7 2.3±2.6 1.7±2.3 1.6±2.2 1.6±2.2 1.6±2.2 1.8±2.3 <0.001
eGFR (ml/min/1.73m
2
) 78.3±28.4 69±33 74±31 80±27 80±27 76±29 74±32 69±39 <0.001
Na (mmol/L) 138.0±4.0 129.1±5.9 134.8±3.4 137.9±2.7 139.6±2.5 140.6±2.7 142.3±3.5 145.6±7.8 <0.001
K (mmol/L) 4.2±0.6 4.2±0.8 4.2±0.6 4.3±0.5 4.2±0.5 4.2±0.6 4.1±0.7 3.8±1.1 <0.001
HCO
3
(mmol/L) 25.2±3.6 27.0±5.5 26.4±3.9 25.7±3.0 24.7±2.9 23.0±3.2 21.0±3.6 19.0±5.8 <0.001
Diff
Na-Cl
(mmol/L) 34.8±3.7 38.6±5.1 37.3±3.3 35.6±2.6 33.7±2.5 31.3±2.8 28.1±3.5 24.1±6.7 <0.001
Cl: Na ratio 0.75±0.03 0.70±0.03 0.72±0.02 0.74±0.01 0.76±0.01 0.78±0.02 0.80±0.02 0.84±0.04 <0.001
Anion Gap (mmol/L) 9.6±3.4 11.6±4.9 10.8±3.6 9.9±3.1 9.0±3.0 8.3±3.3 7.0±4.1 5.1±6.9 <0.001
Albumin (g/dL), n = 10,576 3.5±0.7 3.4±0.7 3.5±0.7 3.6±0.7 3.6±0.7 3.4±0.7 3.1±0.7 3.0±0.8 <0.001
Continuous data are presented as mean ±SD; categorical data are presented as count (%)
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Chloride alterations in hospitalized patients
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albumin because only 13.8% of the study patients had admission albumin values and the albu-
min variations were small (range: 3.0–3.6 g/dL) and could not have altered AG to a large
degree [25].
3-a. Characteristics of patients with AG 12 mmol/L. 82.9% (n = 63,630) of the patients
had AG 12 mmol/L. Patients with lower sCl were older and had higher Charlson scores
(Table 3). With increasing sCl, the Diff
Na-Cl
declined from 37.5±4.8 to 23.2±6.1 mmol/L, Cl:Na
ratio rose from 0.71±0.03 to 0.84±0.04, and HCO
3
declined from 28.5±5.1 to 19.5±5.5 mmol/
L. These results are consistent with the presence of alkalosis in patients with hypochloremia
and acidosis with hyperchloremia.
3-b. Characteristics of patients with AG >12 mmol/L. 17.1% (n = 13,089) of the patients
had AG >12 mmol/L, consistent with the presence of UMAs (Table 4). For those with sCl <95
mmol/L, Diff
Na-Cl
was 40.8±4.9 mmol/L, Cl:Na ratio 0.69±0.03, HCO
3
24.3±5.2 mmol/L and
AG 16.5±4.3 mmol/L, consistent with the co-existence of UMA acidosis and hypochloremic
alkalosis. For patients with high sCl (from 108 to >118 mmol/L), Diff
Na-Cl
declined from 33.6
±3.2 to 31.3±7.1 mmol/L, Cl:Na ratios rose from 0.77±0.02 to 0.80±0.04, and HCO
3
reduced
from 18.9±3.7 to 15.0±6.4 mmol/L, consistent with the co-existence of duo acidoses due to
UMA and hyperchloremia.
Fig 3. Hospital mortality in percentage (%) among patients with various admission Cl levels.
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Chloride alterations in hospitalized patients
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3-c. Clinical outcomes. Consistent with previous publications [26–28], patients with ele-
vated AG had a higher overall hospital mortality than those without AG elevation, p<0.001.
Additionally, we noted a pattern of incremental mortality disparity with increasing sCl (Fig 4,
Table 5) that has never been described previously.
In patients with AG 12 mmol/L, hospital mortality risk was elevated as the sCl levels devi-
ated from 100–108 mmol/L in all Models (Table 5), consistent with a mortality significance in
hypo- and hyperchloremia. In patients with elevated AG, however, sCl <100 and >108 signifi-
cantly predicted hospital mortality in the unadjusted and adjusted (Models 1 and 2). When
further adjusted for dysnatremia, only high sCl (>108 mmol/L) significantly predicted hospital
mortality. These results suggest that hyperchloremia (duo acidoses of UMAs and hyperchlore-
mia), but not hypochloremia (mixed UMA acidosis and hypochloremic alkalosis), indepen-
dently predicted hospital mortality in patients with elevated AG.
Table 2. Clinical outcomes.
Outcome Admission serum chloride level (mmol/L)
<95 95–100 100–105 105–108 108–113 113–118 >118
Hospital mortality 127 (3.8) 226 (2.2) 355 (1.1) 164 (0.9) 164 (1.7) 53 (3.6) 24 (9.6)
Mortality, OR (95%CI)
Model 1: unadjusted 4.29 (3.39–5.42) 2.46 (2.01–3.02) 1.16 (0.97–1.40) 1 (ref) 1.89 (1.52–2.35) 4.03 (2.91–5.47) 11.64
(7.27–17.89)
Model 2# 2.63 (2.06–3.34) 1.66 (1.35–2.05) 1.11 (0.92–1.35) 1 (ref) 1.61 (1.29–2.01) 2.96 (2.12–4.05) 6.34
(3.84–10.09)
Model 3: Model 2 and Na 2.14 (1.59–2.87) 1.51 (1.21–1.89) 1.08 (0.89–1.30) 1 (ref) 1.65 (1.32–2.06) 3.14 (2.25–4.32) 7.26
(4.35–11.67)
Hospital LOS 5 (3–9) 5 (3–8) 4 (3–6) 4 (3–7) 5 (3–7) 6 (5–9) 6 (4–12)
LOS, relative prolongation
(95% CI)
Model 1: unadjusted 1.28 (1.25–1.32) 1.13 (1.11–1.15) 0.98 (0.97–0.99) 1 (ref) 1.15 (1.13–1.17) 1.45 (1.40–1.50) 1.53 (1.40–1.67)
Model 2# 1.25 (1.22–1.29) 1.11 (1.09–1.12) 0.98 (0.97–1.002) 1 (ref) 1.13 (1.11–1.15) 1.39 (1.34–1.45) 1.45 (1.33–1.58)
Model 3: Model 2 and Na 1.29 (1.26–1.34) 1.12 (1.10–1.14) 0.99 (0.97–1.01) 1 (ref) 1.12 (1.10–1.14) 1.39 (1.33–1.43) 1.42 (1.31–1.55)
Hospital survivor (n = 75,606) 3,233 10,025 33,292 17,902 9,492 1,437 225
Discharge disposition
- Home 2,203 (68) 7,398 (74) 27,123 (81) 14,590
(81)
7,558 (80) 1,072 (75) 139 (62)
- Home Health Care 305 (9) 856 (9) 1,897 (6) 994 (6) 568 (6) 96 (7) 12 (5)
- In-hospital rehab
+
13 (0.4) 45 (0.4) 91 (0.3) 75 (0.4) 36 (0.4) 12 (0.9) 1 (0.4)
- Skilled Nursing facility
+
686 (21) 1,680 (17) 4,066 (12) 2,191
(12)
1,299 (14) 247 (17) 69 (31)
- Swing bed
+
26 (0.8) 46 (0.4) 115 (0.3) 52 (0.3) 31 (0.3) 10 (0.7) 4 (2)
Discharge to short or long term
care facility, OR (95% CI)
Model 1: unadjusted 1.94 (1.77–2.13) 1.44 (1.35–1.54) 0.99 (0.94–1.04) 1 (ref) 1.13 (1.05–1.21) 1.55 (1.34–1.78) 3.29 (2.47–4.35)
Model 2# 1.46 (1.31–1.62) 1.16 (1.08–1.26) 0.97 (0.92–1.03) 1 (ref) 1.16 (1.08–1.26) 1.89 (1.61–2.20) 3.53 (2.53–4.88)
Model 3: Model 2 and Na 1.48 (1.30–1.69) 1.18 (1.08–1.28) 0.98 (0.92–1.04) 1 (ref) 1.16 (1.07–1.26) 1.88 (1.60–2.19) 3.49 (2.50–4.85)
#
model 2: Adjusted for age, sex, Charlson comorbidities score, eGFR and principal diagnosis.
+
discharge to short or long term care facility
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4. Post-admission Cl evolution and mortality significance
Cl evolution within the first 48hr of hospital admission (n = 55,523) showed that 17.2%
(n = 9,553) and 17.2% (n = 9,525) had Cl increase, by 2–4 and by >4 mmol/L, respectively,
while 12.2% (n = 6,776) and 9.3% (n = 5,138) had sCl decrease by the same degrees (Table 6).
Patients in all categories, except for cardiovascular diseases, showed Cl increase. With rising
sCl, hemoglobin concentrations fell, suggesting hemodilution.
Hospital mortality risk was elevated in patients with sCl increase (>2 mmol/L) in fully
adjusted models (Table 7). When patients were grouped based on their admission sCl, sCl
increases in all groups (>4 for admission sCl<105, >2 for admission sCl 105–108, and 0–2 for
admission sCl >108 mmol/L) independently predicted hospital mortality (Table 8).
To investigate whether the sCl elevation was contributed by Cl-rich fluid administration,
we selected 100 patients with minimal sCl change (-2 to 0 mmol/L) and 100 with sCl increase
(>4 mmol/L) from the randomized samples (JMP statistical software was used for the ran-
domization) based on the preliminary power calculation. The proportion of 0.9% saline infu-
sion (volumes of infused saline/the total fluid infusion) in the two groups was 37.9 and 59.1%,
respectively, p<0.0001, consistent with a larger proportion Cl-rich fluid administration in
patients with sCl elevation. An inverse relationship between the magnitude of post-admission
sCl increase and the days of patient survival was also found (Fig 5). Our observations were
Table 3. Baseline clinical characteristics of patients with AG 12.
Variables All Admission serum chloride level (mmol/L)
<95 95–100 100–105 105–108 108–113 113–118 >118 p
N 63,630 2,178 7,368 27,742 15,985 8,755 1,380 222
Age (year) 61.4±17.7 69±15 65±17 61±18 60±18 61±18 61±17 62±19 <0.001
Male 33,483 (53) 998 (46) 3,922 (53) 15,291 (55) 8,113 (51) 4,384 (50) 662 (48) 113 (51) <0.001
Caucasian 59,199 (93) 2,044 (94) 6,859 (93) 25,862 (93) 14,852 (93) 8,127 (93) 1,254 (91) 201 (91) 0.01
Principal Diagnosis
• Cardiovascular
• Endocrine/Metabolic
• Gastrointestinal
• Renal Disease
• Hematology/Oncology
• Infectious Disease
• Respiratory
• Injury/poisoning
• Other
13,113 (21)
1,500 (2)
5,844 (9)
2,166 (3)
9,729 (15)
1,872 (3)
2,617 (4)
10,060 (16)
16,729 (26)
403
218
253
77
227
138
277
221
364
1,275
246
836
242
1,040
392
670
1,076
1,591
4,696
631
2,553
1,011
4,785
719
1,076
4,256
8,015
3,309
250
1,316
509
2,566
304
371
2,743
4,617
2,821
126
745
273
974
226
196
1,478
1,916
563
21
116
41
127
65
21
218
208
46
8
25
13
10
28
6
68
18
<0.001
Charlson Score 1.8±2.3 2.5±2.7 2.3±2.7 1.7±2.3 1.6±2.2 1.6±2.2 1.6±2.2 1.7±2.2 <0.001
eGFR (ml/min/1.73m
2
) 79.8±26.8 74±29 76±29 82±26 81±26 78±28 76±30 73±38 <0.001
Na (mmol/L) 137.8±3.8 128.1±5.8 134.3±3.3 137.6±2.6 139.3±2.4 140.4±2.5 142.0±3.2 144.7±7.1 <0.001
K (mmol/L) 4.2±0.5 4.2±0.7 4.2±0.6 4.3±0.5 4.2±0.5 4.2±0.5 4.1±0.7 3.8±1.1 <0.001
HCO
3
(mmol/L) 25.7±3.2 28.5±5.1 27.5±3.3 26.4±2.6 25.2±2.6 23.4±2.8 21.4±3.2 19.5±5.5 <0.001
Diff
Na-Cl
(mmol/L) 34.3±3.4 37.5±4.8 36.7±3.1 35.3±2.5 33.5±2.4 31.0±2.7 27.8±3.2 23.2±6.1 <0.001
Cl: Na ratio 0.75±0.02 0.71±0.03 0.73±0.02 0.74±0.01 0.76±0.01 0.78±0.02 0.80±0.02 0.84±0.04 <0.001
Anion Gap (mmol/L) 8.5±2.4 8.9±2.5 9.2±2.2 8.9±2.2 8.3±2.3 7.6±2.6 6.4±3.4 3.7±5.9 <0.001
Albumin (g/dL), n = 7,866 3.5±0.7 3.3±0.6 3.4±0.7 3.6±0.7 3.6±0.7 3.4±0.7 3.1±0.7 2.9±0.8 <0.001
Continuous data are presented as mean±SD; categorical data are presented as count (%)
https://doi.org/10.1371/journal.pone.0174430.t003
Chloride alterations in hospitalized patients
PLOS ONE | https://doi.org/10.1371/journal.pone.0174430 March 22, 2017 9 / 17
similar to a report showing sCl increase, induced by 0.9% saline, to be inversely related to the
survival time in septic rodents [29].
Discussion
In this large, single center study of all hospital admission, sCl alterations are not only common,
but also independently associated with elevated risks for hospital mortality, LOS and discharge
to a care facility. Furthermore, in adjusted analysis, post-admission sCl increase, associated
with a higher percentage saline infusion, independently predicted fewer days of patient sur-
vival, when compared to patients without sCl increase.
sCl is responsible for about one third of the extracellular fluid tonicity and two-thirds of all
anionic charges in plasma. Because of its high concentration, sCl is the most important anion
to balance the extracellular cations. An increase in sCl out of proportion to Na causes SID
reduction and hyperchloremic acidosis. In critically ill patients, saline-driven hyperchloremic
acidosis is becoming increasingly recognized and is caused by non-physiological Cl (154
mmol/L) in 0.9% saline. Hypochloremia disproportionate to Na in the absence of UMA, con-
versely, engenders alkalosis. Acidosis caused by accumulation of UMAs can be detected using
SIG[3], which can be accurately reflected by AG corrected for serum albumin [30].
In this study, the distributions of admission sCl are associated with the disease categories
with a known propensity for acid-base alterations. For example, most cardiovascular
Table 4. Baseline clinical characteristics of patients with AG >12.
Variables All Admission serum chloride level (mmol/L)
<95 95–100 100–105 105–108 108–113 113–118 >118 p
N 13,089 1,182 2,883 5,905 2,081 901 110 27
Age (year) 59.8±18.2 62±17 61±18 59±18 59±19 61±19 61±19 67±20 <0.001
Male 7,032 (54) 604 (51) 1,576 (55) 3,228 (55) 1,077 (52) 480 (53) 55 (50) 12 (44) 0.08
Caucasian 12,030 (92) 1,092 (92) 2,624 (91) 5,457 (92) 1,910 (92) 829 (92) 94 (85) 24 (89)
Principal Diagnosis
• Cardiovascular
• Endocrine/Metabolic
• Gastrointestinal
• Renal Disease
• Hematology/Oncology
• Infectious Disease
• Respiratory
• Injury/poisoning
• Other
3,162 (24)
584 (4)
1,274 (10)
684 (5)
1,983 (15)
527 (4)
468 (4)
1,763 (13)
2,644 (20)
215
148
162
85
107
82
63
130
190
595
186
312
163
390
154
150
345
588
1,442
169
533
262
1,011
174
190
811
1,313
589
41
179
98
353
57
45
308
411
295
28
76
64
108
38
17
145
130
25
9
10
8
11
15
1
20
11
1
3
2
4
3
7
2
4
1
<0.001
Charlson Score 1.9±2.4 2.5±2.8 2.2±2.6 1.7±2.2 1.8±2.3 2.0±2.4 1.9±2.5 2.1±2.4 <0.001
eGFR (ml/min/1.73m
2
) 70.7±34.2 58±37 69±36 75±32 73±32 62±36 51±37 37±30 <0.001
Na (mmol/L) 138.6±4.5 131.0±5.5 136.3±3.2 139.4±2.7 141.4±2.6 142.9±3.3 145.6±5.1 153.3±8.7 <0.001
K (mmol/L) 4.3±0.7 4.3±0.9 4.3±0.7 4.3±0.6 4.3±0.6 4.2±0.8 4.1±1.0 3.9±0.8 <0.001
HCO
3
(mmol/L) 22.5±3.9 24.3±5.2 23.7±3.8 22.8±3.1 21.1±3.0 18.9±3.7 16.0±4.8 15.0±6.4 <0.001
Diff
Na-Cl
(mmol/L) 37.4±3.6 40.8±4.9 38.9±3.1 37.3±2.6 35.6±2.6 33.6±3.2 31.3±4.9 31.3±7.1 <0.001
Cl: Na ratio 0.73±0.03 0.69±0.03 0.72±0.02 0.73±0.01 0.75±0.01 0.77±0.02 0.79±0.03 0.80±0.04 <0.001
Anion Gap (mmol/L) 14.9±2.6 16.5±4.3 15.1±2.8 14.6±2.1 14.5±2.0 14.7±2.3 15.2±2.7 16.3±3.6 <0.001
Albumin (g/dL), n = 2,710 3.6±0.7 3.5±0.8 3.6±0.6 3.8±0.6 3.7±0.7 3.4±0.7 3.4±0.7 3.2±0.8 <0.001
Continuous data are presented as mean±SD; categorical data are presented as count (%)
https://doi.org/10.1371/journal.pone.0174430.t004
Chloride alterations in hospitalized patients
PLOS ONE | https://doi.org/10.1371/journal.pone.0174430 March 22, 2017 10 / 17
Fig 4. Hospital mortality in percentage (%) among patients with AG 12 and >12 mmol/L with various admission Cl levels.
https://doi.org/10.1371/journal.pone.0174430.g004
Table 5. Hospital mortality in patients with AG 12 or >12 mmol/L and with various serum Cl concentrations.
Outcome Admission serum chloride level (mmol/L)
<95 95–100 100–105 105–108 108–113 113–118 >118
AG 12 (n = 63,630)
Hospital mortality 80 (3.7) 139 (1.9) 238 (0.9) 122 (0.8) 119 (1.4) 40 (2.9) 18 (8.1)
- Model 1: unadjusted 4.96 (3.71–6.58) 2.50 (1.96–3.20) 1.13 (0.91–1.40) 1 (ref) 1.79 (1.39–2.31) 3.88 (2.67–5.52) 11.47
(6.65–18.70)
- Model 2# 2.87 (2.13–3.85) 1.59 (1.24–2.05) 1.06 (0.85–1.33) 1 (ref) 1.55 (1.20–2.00) 2.96 (2.02–4.24) 6.76
(3.81–11.39)
- Model 3: Model 2 and Na 1.90 (1.30–2.76) 1.32 (1.002–1.73) 0.99 (0.79–1.25) 1 (ref) 1.62 (1.25–2.09) 3.29 (2.24–4.74) 8.28
(4.62–14.09)
AG >12 (n = 13,089)
Hospital mortality 47 (4.0) 87 (3.0) 117 (2.0) 42 (2.0) 45 (5.0) 13 (11.8) 6 (22.2)
- Model 1: unadjusted 2.01 (1.32–3.08) 1.51 (1.05–2.21) 0.98 (0.69–1.42) 1 (ref) 2.55 (1.66–3.93) 6.51 (3.26–12.21) 13.87
(4.89–34.29)
- Model 2# 1.58 (1.02–2.45) 1.30 (0.89–1.92) 1.01 (0.71–1.46) 1 (ref) 2.11 (1.36–3.27) 4.14 (1.99–8.13) 5.87
(1.91–16.20)
- Model 3: Model 2 and Na 0.92 (0.54–1.56) 0.99 (0.66–1.50) 0.91 (0.63–1.32) 1 (ref) 2.30 (1.48–3.58) 5.45 (2.59–10.84) 11.54
(3.59–33.62)
#
model 2: Adjusted for age, sex, Charlson comorbidities score, eGFR and principal diagnosis.
https://doi.org/10.1371/journal.pone.0174430.t005
Chloride alterations in hospitalized patients
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admissions had hypochloremia which is consistent with frequent loop and thiazide diuretics
use. Loop and thiazide diuretics disproportionately excrete Cl in relation to Na (in 2:1 and 1:1
ratio, respectively), leading to hypochloremic alkalosis. Patients with gastrointestinal diseases
were predominantly hypochloremic, which could have been related to gastric alkalosis in
patients with upper gastrointestinal and biliary diseases. Admissions due to respiratory dis-
eases were predominantly hypochloremic, potentially related to a degree of compensatory
metabolic alkalosis in the setting of ventilatory insufficiency. Admissions under the category of
endocrine/metabolic diseases frequently had hypochloremia, which could have represented
patients with uncontrolled diabetes and ketoacidosis (hypochloremia in the setting of
ketoacidosis).
Alkalosis is known to increase the occurrence of arrhythmia and mortality in critically ill
patients [31]. Clinical effects of acidosis, however, have not been consistent across studies.
Table 6. Baseline characteristics in patients with Cl evolution within 48 hours of hospital admission.
variables Change in serum chloride within the first 48 hours of hospital admission (mmol/L)
<-4 -4 to -2 -2 to 0 0 to 2 2 to 4 >4 p
N 5,138 6,776 11,751 12,780 9,553 9,525
Age (year) 60.3±17.1 63.3±16.7 63.8±16.7 63.8±17.1 63.9±17.4 63.0±17.9 <0.001
Male 2,890 (56) 3,873 (57) 6,643 (57) 7,051 (55) 4,917 (51) 4,486 (47) <0.001
Caucasian 4,739 (92) 6,331 (93) 11,004 (94) 11,940 (93) 8,868 (93) 8,785 (92) <0.001
Principal Diagnosis
• Cardiovascular
• Endocrine/Metabolic
• Gastrointestinal
• Renal Disease
• Hematology/Oncology
• Infectious Disease
• Respiratory
• Injury/poisoning
• Other
2,096
61
285
102
577
74
137
835
971
2,215
121
464
157
971
118
237
1,069
1,424
3,344
230
947
315
1,700
306
507
1,808
2,594
3,240
291
1,220
380
1,686
417
651
2,064
2,831
2,053
327
1,272
333
1,138
465
582
1,399
1,984
1,662
618
1,558
548
1,004
857
585
1,265
1,428
<0.001
Charlson Score 1.6±2.2 1.9±2.4 2.0±2.4 2.0±2.4 2.0±2.4 2.2±2.5 <0.001
eGFR (ml/min/1.73m2) 79.0±28.1 75.2±28.1 74.9 (28.1) 74.9±28.7 74.0±29.5 71.1±32.3 <0.001
Na (mmol/L) 139.7±3.6 139.1±3.4 138.6±3.6 137.8±3.9 137.0±4.1 135.2±5.3 <0.001
HCO
3
(mmol/L) 23.6±3.7 24.6±3.6 25.1±3.5 25.3±3.6 25.4±3.8 25.0±4.4 <0.001
Anion Gap (mmol/L) 7.7±3.8 8.9±3.3 9.3±3.2 9.7±3.3 10.1±3.4 11.2±4.2 <0.001
Change in Hemoglobin (g/dL) -0.8±1.6 -0.8±1.4 -0.9±1.3 -1.0±1.3 -1.1±1.3 -1.4±1.4 <0.001
Continuous data are presented as mean±SD; categorical data are presented as count (%)
https://doi.org/10.1371/journal.pone.0174430.t006
Table 7. Hospital mortality in patients with Cl evolution within 48 hours of hospital admission.
Outcome Change in serum chloride within the first 48 hours of hospital admission (mmol/L)
<-4 -4 to -2 -2 to 0 0 to 2 2 to 4 >4
Hospital Mortality 68 (1.3) 78 (1.2) 155 (1.3) 178 (1.4) 179 (1.9) 305 (3.2)
Mortality, OR (95%CI)
- Unadjusted 1.00 (0.75–1.33) 0.87 (0.66–1.14) 1 (ref) 1.06 (0.85–1.31) 1.43 (1.15–1.78) 2.47 (2.04–3.01)
- Adjusted# 1.14 (0.85–1.52) 0.91 (0.68–1.19) 1 (ref) 1.03 (0.83–1.28) 1.33 (1.07–1.66) 2.10 (1.72–2.58)
#
adjusted for age, sex, Charlson Comorbidities Score, eGFR, principal diagnosis
https://doi.org/10.1371/journal.pone.0174430.t007
Chloride alterations in hospitalized patients
PLOS ONE | https://doi.org/10.1371/journal.pone.0174430 March 22, 2017 12 / 17
Transient acidosis in healthy adults is well tolerated. Effects of acidosis in ill adults are contro-
versial. Acidemia can shift the O
2
dissociation curve to enhance tissue O
2
delivery. There is,
however, strong evidence of a poor prognosis in critically ill patients with lactic acidosis, while
hyperchloremic acidosis might not exert a mortality significance [32]. Our results show that
sCl alterations (outside the range of 100–108 mmol/L) in patients without AG elevation
Table 8. Hospital mortality in subgroups of patients with various serum Cl levels.
Outcome (n = 55,523) Change in serum chloride within the first 48 hours of hospital admission (mmol/L)
<-4 -4 to -2 -2 to 0 0 to 2 2 to 4 >4
Serum Cl <105 mmol/L (n = 33,515)
Hospital Mortality 13 (1.3) 30 (1.2) 88 (1.5) 120 (1.4) 133 (1.8) 237 (2.8)
Unadjusted OR (95%CI) 0.85 (0.45–1.47) 0.84 (0.54–1.25) 1 (ref) 0.98 (0.75–1.30) 1.25 (0.95–1.64) 1.96 (1.54–2.53)
#
Adjusted OR (95%CI) 0.87 (0.46–1.52) 0.86 (0.56–1.30) 1 (ref) 1.00 (0.76–1.33) 1.24 (0.94–1.64) 1.84 (1.43–2.39)
Serum Cl 105–108 mmol/L (n = 12,447)
Hospital Mortality 8 (0.7) 15 (0.7) 29 (0.8) 19 (0.6) 26 (1.6) 37 (4.4)
Unadjusted OR (95%CI) 0.89 (0.38–1.85) 0.83 (0.43–1.53) 1 (ref) 0.74 (0.41–1.32) 2.03 (1.19–3.46) 5.59 (3.42–9.20)
#
Adjusted OR (95%CI) 0.95 (0.40–1.99) 0.82 (0.43–1.51) 1 (ref) 0.69 (0.38–1.23) 1.80 (1.04–3.10) 4.35 (2.61–7.31)
Serum Cl >108 mmol/L (n = 9,561)
Hospital Mortality 47 (1.6) 33 (1.6) 38 (1.8) 39 (3.0) 20 (3.1) 31 (9.8)
Unadjusted OR (95%CI) 0.90 (0.58–1.39) 0.89 (0.55–1.42) 1 (ref) 1.72 (1.10–2.72) 1.77 (1.01–3.04) 6.07 (3.70–9.89)
#
Adjusted OR (95%CI) 1.11 (0.72–1.75) 0.96 (0.59–1.55) 1 (ref) 1.61 (1.01–2.56) 1.51 (0.84–2.63) 4.33 (2.55–7.31)
#
Adjusted for age, sex, Charlson comorbidities score, eGFR and principal diagnosis.
https://doi.org/10.1371/journal.pone.0174430.t008
Fig 5. Days of patient survival relating to Cl increase within 48 hours of admission.
https://doi.org/10.1371/journal.pone.0174430.g005
Chloride alterations in hospitalized patients
PLOS ONE | https://doi.org/10.1371/journal.pone.0174430 March 22, 2017 13 / 17
independently predicted poor outcomes, including hospital mortality. The farther away from
100–108 mmol/L, the worse the prognosis. For those with elevated AG, however, only hyper-
chloremia, >108 mmol/L, was independently associated with higher mortality. Intriguingly,
the difference in mortality between the two AG groups grew progressively with rising Cl
(Fig 4). It is tempting to speculate that in patients with hypochloremia and without AG eleva-
tion, metabolic alkalosis was dominant, accounting for the mortality risk [31]. In patients with
hypochloremia and AG elevation, the dual pathology of hypochloremic alkalosis and AG aci-
dosis potentially offsets the net pH change and thus might have attenuated the mortality conse-
quences. By the same token, in patients with simultaneous AG and serum Cl elevations, the
presence of dual AG and hyperchloremic acidoses likely escalated the acidosis severity and
worsened mortality. Although lactic acidosis in critical illness is often assumed to reflect tissue
hypoperfusion and has been used to direct fluid resuscitation strategies, our study suggests
that sCl concentrations are an additional independent predictor for poor outcome.
The post-admission sCl evolution was informative. Except for the cardiovascular category,
the majority of patients showed sCl increase. Importantly, regardless of admission sCl values,
sCl increase was across the board linked to elevated hospital mortality (Tables 7and 8). Given
the evidence of hemodilution (hemoglobin reduction), the disproportionate sCl increases are
consistent with Cl-rich fluid administration. This possibility was confirmed in random sam-
ples of patients with and without sCl increase. Notably, the only patient category that did not
show sCl increase was cardiovascular, which is consistent with clinical practice as fluid infu-
sion for these patients is typically avoided. Cl increase in septic rodents shortens their survival
time [29]. Such inverse relationship was also demonstrated in our cohort (Fig 5). These results
suggest that post-admission sCl increase associated with 0.9% saline infusion is detrimental,
consistent with the known detrimental effects of hyperchloremia on multiple organ systems
[33–40].
There are several limitations in this study. First, although the sample size is large, this is a
retrospective cohort study. The data, however, are recent and thus reflect current practice. The
short 3-year study duration avoided major change in practice style. Second, the study lacks
granularity to examine clinical manifestations of sCl alterations. Clinical manifestations, how-
ever, were not a study objective. Third, the cut-off for AG was 12 mmol/L, which was arbitrary.
Given that only 17.1% of the total cohort had higher AG, we decided to use a relatively high
cut-off to ensure specificity in determining the presence of UMAs. Fourth, the nature of the
UMAs was not investigated. Published studies suggest that UMAs are mostly lactic acids and
ketoacids, and despite an exhaustive search, not all identities of UMAs can be determined [41].
Fifth, we used surrogates for SID and SIG. Although both surrogates have been extensively val-
idated [5], there could still be a degree of decreased precision. The use of surrogates, however,
allowed us to analyze the acid-base status in the vast majority of admissions, minimizing
patient selection bias. Sixth, we did not consider the other two independent components
(A
TOT
and pCO
2
) in the Steward model. Among these components, however, SID is by far the
dominant and independent determinant. It is not influence by changes in pCO
2
and A
tot
[3].
Moreover, most published studies evaluating acid-base balance use SID almost exclusively,
making our results comparable with existing publications. Taken together, the robust results
from this large contemporary patient sample show unequivocally that Cl alterations impart
major outcome significance.
Conclusions
sCl alterations outside of 100–108 mmol/L range are common at hospital admission and can
independently predict poor clinical outcomes, including hospital mortality. Post-admission
Chloride alterations in hospitalized patients
PLOS ONE | https://doi.org/10.1371/journal.pone.0174430 March 22, 2017 14 / 17
sCl increase, associated with Cl-rich 0.9% saline infusion, is not only associated with higher
hospital mortality, but is also inversely correlated with days of patient survival. Given that sCl
values are routinely obtained and available for vast majority of patients, attention should be
paid to the sCl value. Although our study results do not establish causality, they do raise an
important question of whether Cl-rich fluids compromise patient outcomes. This question
should be addressed with future prospective randomized trials.
Acknowledgments
The authors are grateful for the input from Mayo Clinic Laboratory Medicine, specifically Dr.
NA Baumann, Ph.D.
Author Contributions
Conceptualization: CT WC ZC QQ.
Data curation: CT WC ZC QQ.
Formal analysis: CT WC QQ.
Investigation: CT WC ZC QQ.
Methodology: CT WC QQ.
Project administration: QQ.
Resources: QQ.
Software: CT.
Supervision: QQ.
Validation: CT WC ZC QQ.
Visualization: CT WC ZC QQ.
Writing – original draft: CT WC QQ.
Writing – review & editing: CT WC ZC QQ.
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