Baseline characteristics in patients with hypernatremia
Systolic (p = 0.045) and diastolic (p = 0.004) blood pressures were significantly higher on admission day in patients with hypernatremia (n = 22, Table 1). However, no differences were observed in comorbidities, such as diabetes, hypertension, and dyslipidemia, and medications before admission between patients with and without hypernatremia. The incidence of atrial fibrillation was also not different (Table 1). Regarding laboratory data, there were no differences in BNP level; estimated glomerular filtration rate; albumin, blood sugar, and uric acid levels; renin activity; and aldosterone level between the two groups (Table 1). However, serum sodium level (p = 0.002) was significantly higher, and serum potassium level (p = 0.026) was significantly lower at baseline in patients with hypernatremia (Table 1). We did not observe differences in urine examination results at baseline. When we calculated serum osmolality by sodium, blood urea nitrogen, and blood sugar levels, patients exhibiting hypernatremia showed significantly higher calculated serum osmolality (p = 0.012, Table 2). There were no differences in the doses of tolvaptan (7.5 ± 3.8 vs. 8.1 ± 2.5 mg/day, p = 0.269) and carperitide (0.025 ± 0.010 vs. 0.025 ± 0.06 μg/min, p = 0.835) between patients with and without hypernatremia.
Table 1. Baseline characteristics of patients on admission day with and without hypernatremia in the initial three days after tolvaptan treatment
|
With hypernatremia
|
Without hypernatremia
|
P-value
|
N (%)
|
22(19)
|
95(81)
|
|
Age, years
|
78.5±12.2
|
77.3±11.3
|
0.661
|
Men, %
|
46
|
57
|
0.337
|
Body weight, kg
|
57.9±13.8
|
58.6±20.3
|
0.850
|
Body mass index, kg/m2
|
23.9±6.3
|
23,4±4.0
|
0.633
|
LVEF, %
|
44±18
|
45±19
|
0.869
|
Systolic blood pressure, mmHg
|
149±21
|
137±25
|
0.045
|
Diastolic blood pressure, mmHg
|
90±20
|
78±17
|
0.004
|
Heart rate, beats/min
|
95±24
|
87±23
|
0.152
|
NYHA, class
|
|
|
|
Ⅰ or Ⅱ, %
|
77
|
55
|
0.089
|
Ⅲ or Ⅳ, %
|
23
|
45
|
Medical history
|
|
|
|
Diabetes mellitus, %
|
36
|
42
|
0.623
|
Hypertension, %
|
73
|
64
|
0.452
|
Dyslipidemia, %
|
32
|
37
|
0.661
|
Atrial fibrillation, %
|
55
|
43
|
0.338
|
Coronary artery disease, %
|
23
|
25
|
0.806
|
Valvular disease, %
|
32
|
27
|
0.679
|
Cardiomyopathy, %
|
5
|
11
|
0.391
|
Medications before admission
|
|
|
|
ACEI/ARB, %
|
41
|
39
|
0.867
|
β-blocker, %
|
55
|
40
|
0.217
|
Ca channel blocker, %
|
50
|
39
|
0.347
|
Loop diuretics, %
|
45
|
53
|
0.548
|
MRA, %
|
23
|
13
|
0.230
|
Thiazide, %
|
0
|
7
|
0.192
|
Laboratory data at baseline
|
|
|
|
BNP, pg/mL
|
1043±758
|
1127±992
|
0.711
|
Hematocrit, %
|
35.3±8.2
|
34.7±7.5
|
0.722
|
Albumin, g/dL
|
3.9±0.5
|
3.7±0.5
|
0.182
|
Blood urea nitrogen, mg/dL
|
27.2±19.8
|
27.5±14.4
|
0.931
|
Serum creatinine, mg/dL
|
1.8±2.3
|
1.3±0.8
|
0.110
|
eGFR, mL/min/1.73m2
|
44.6±20.9
|
46.6±18.6
|
0.654
|
Uric acid, mg/dL
|
6.5±2.4
|
6.4±2.3
|
0.817
|
Serum sodium, mEq/L
|
143±3
|
140±4
|
0.002
|
Serum potassium, mEq/L
|
3.9±0.5
|
4.3±0.6
|
0.026
|
Blood sugar, mg/dL
|
145±75
|
141±57
|
0.812
|
Serum osmolality, mOsm/L
|
295±9
|
291±11
|
0.139
|
Hormone at baseline
|
|
|
|
PRA, ng/mL/h
|
1.0±1.5
|
2.7±4.7
|
0.204
|
PAC, pg/mL
|
93±108
|
117±170
|
0.631
|
Adrenaline, pg/mL
|
75±138
|
58±133
|
0.690
|
Noradrenaline, pg/mL
|
1059±723
|
709±985
|
0.234
|
Dopamine, pg/mL
|
35±27
|
47±140
|
0.753
|
Urine examination at baseline
|
|
|
|
Urine urea nitrogen, mg/dL
|
478±397
|
478±405
|
0.999
|
Urine creatinine, mg/dL
|
71.3±64.9
|
86.0±90.8
|
0.579
|
Urine sodium, mEq/L
|
84.4±42.8
|
91.9±50.1
|
0.546
|
Urine potassium, mEq/L
|
27.0±18.4
|
29.7±26.3
|
0.733
|
Urine osmolality, mOsm/L
|
450±182
|
432±188
|
0.707
|
Abbreviations: NYHA, New York Heart Association; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; MRA, mineralocorticoid receptor antagonist; BNP, brain natriuretic peptide; eGFR, estimated glomerular filtration rate; PRA, plasma renin activity; PAC, plasma aldosterone concentration.
Table 2. Calculated parameters at baseline in patients with and without hypernatremia
|
With hypernatremia
|
Without hypernatremia
|
P-value
|
BUN/Cr
|
19.2±7.6
|
22.5±7.7
|
0.074
|
PAC/PRA
|
144±144
|
142±158
|
0.969
|
C-serum osmolality, mOsm/L
|
304±7
|
298±10
|
0.012
|
U-Osm/S-Osm
|
1.5±0.6
|
1.5±0.7
|
0.838
|
FENa, %
|
2.3±2.5
|
3.3±4.8
|
0.434
|
FEUN, %
|
36.8±12.9
|
34.8±12.6
|
0.623
|
FEK, %
|
18.1±18.3
|
15.1±10.4
|
0.442
|
TTKG
|
4.3±1.7
|
4.3±2.0
|
0.995
|
C-Serum osmolality = 2×Na + BUN/2.8 + blood sugar/18
FENa = (U-Na×S-Cr)/(U-Cr×S-Na)×100
FEUN = (U-UN×S-Cr)/(U-Cr×S-UN) ×100
FEK = (U-K× S-Cr)/(U-Cr ×S-K) ×100
TTKG = {U-K/(U-Osm/S-Osm)}/S-K
Abbreviations: U-, urine-; S-, serum-; C-, calculated; BUN/Cr, ratio of blood urea nitrogen to serum creatinine; PAC/PRA, ratio of plasma aldosterone concentration to plasma renin activity; U-Osm/S-Osm, ratio of urine osmolality to serum osmolality; FENa, fractional excretion of sodium; FEUN, fractional excretion of urea nitrogen; FEK, fractional excretion of potassium; TTKG, trans-tubular K gradient.
Regarding water balance calculated using the equation of (urine volume - water intake), dehydration obviously occurred during the first hospitalization day in patients with hypernatremia (p = 0.036, Table 3). In the multivariate regression analysis using significant factors observed in the univariate analysis, hypernatremia in the initial three days of hospitalization was independently associated with low serum potassium level (p = 0.034, Table 4). The cutoff serum potassium level at baseline was 3.8 mEq/L by the receiver operating characteristic curve analysis (Figure 1).
Table 3. Water balance in patients with and without hypernatremia
|
|
With hypernatremia
|
Without hypernatremia
|
P-value
|
Total urine volume (BL to day 3), mL
|
|
10610±5327
|
8816±4062
|
0.096
|
Total water intake (BL to day 3), mL
|
|
3530±1643
|
2799±1591
|
0.089
|
Urine volume – water intake, mL
|
|
|
|
|
From BL to day 1
|
|
2188±1583
|
1507±1189
|
0.036
|
From days 1 to 2
|
|
1978±1589
|
1700±1480
|
0.465
|
From days 2 to 3
|
|
1681±2051
|
1389±1221
|
0.427
|
Abbreviation: BL, baseline.
Table 4. Multivariate regression analysis of factors predicting hypernatremia
|
OR
|
95%CI
|
P-value
|
Systolic blood pressure, mmHg
|
0.99
|
0.965 - 1.020
|
0.678
|
Diastolic blood pressure, mmHg
|
1.04
|
0.994 - 1.080
|
0.094
|
Serum sodium level, mEq/L
|
1.14
|
0.878 - 1.480
|
0.326
|
Serum potassium level, mEq/L
|
0.28
|
0.085 - 0.907
|
0.034
|
C-serum osmolality, mOsm/L
|
1.09
|
0.981 - 1.210
|
0.109
|
Total urine volume
- water intake (BL to day 1), mL
|
1.00
|
1.000 - 1.000
|
0.095
|
Abbreviations: OR, odds ratio; CI, confidence interval; C, calculated; BL, base line.
Characteristics of patients with hypernatremia in those with low potassium level at baseline
There were no significant differences in the renin activity and aldosterone level and medications with loop diuretics, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and aldosterone antagonists between patients with serum potassium level ≤3.8 mEq/L at baseline with and without hypernatremia (Table 5). However, patients with hypernatremia exhibited significantly higher diastolic pressure on admission day (p = 0.004) among those with serum potassium level ≤3.8 mEq/L (Table 5). The ratio of aldosterone level to renin activity tended to be high in patients with hypokalemia with hypernatremia.
Table 5. Baseline characteristics of patients whose baseline potassium level ≤3.8 mEq/L stratified based on the presence or absence of hypernatremia
|
With hypernatremia
(n=10)
|
Without hypernatremia
(n=19)
|
P-value
|
Serum sodium, mEq/L
|
144±2
|
142±2
|
0.080
|
ACEI/ARB, %
|
60
|
53
|
0.717
|
MRA, %
|
30
|
26
|
0.840
|
Loop diuretics, %
|
50
|
58
|
0.697
|
FENa, %
|
2.3±2.1
|
3.7±5.6
|
0.624
|
FEUN, %
|
42.0±8.5
|
39.8±9.0
|
0.665
|
FEK, %
|
12.6±7.2
|
14.7±10.1
|
0.684
|
TTKG
|
3.6±1.8
|
4.0±1.6
|
0.677
|
PRA, ng/mL/h
|
0.5±0.4
|
3.5±5.9
|
0.241
|
PAC, pg/mL
|
57.3±31.0
|
80.1±53.6
|
0.353
|
PAC/PRA
|
186±211
|
114±112
|
0.353
|
Systolic blood pressure, mmHg
|
157±22
|
139±22
|
0.050
|
Diastolic blood pressure, mmHg
|
97±20
|
75±17
|
0.004
|
Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; MRA, mineralocorticoid receptor antagonist; FENa, fractional excretion of sodium; FEUN, fractional excretion of urea nitrogen; FEK, fractional excretion of potassium; TTKG, trans-tubular K gradient; PRA, plasma renin activity; PAC, plasma aldosterone concentration; PAC/PRA, ratio of plasma aldosterone concentration to plasma renin activity;.