Risk Factors and Outcomes in Patients With Hypernatremia and Sepsis

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Risk Factors for and Outcomes of Hypernatremia in Patients with Sepsis Hai-bin Ni M.D., Xing-xing Hu M.D., Xiao-fei Huang M.D., Ke-qin Liu M.D., Chen-bin Yu M.D., Xiao-meng Wang M.D., Lu Ke M.D.

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Cite this article as: Hai-bin Ni M.D., Xing-xing Hu M.D., Xiao-fei Huang M.D., Keqin Liu M.D., Chen-bin Yu M.D., Xiao-meng Wang M.D., Lu Ke M.D., Risk Factors for and Outcomes of Hypernatremia in Patients with Sepsis, Am J Med Sci, http://dx.doi.org/10.1016/j.amjms.2016.01.027 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Risk Factors for and Outcomes of Hypernatremia in Patients with Sepsis Hai-bin Ni,M.D.1*, Xing-xing Hu,M.D.1,Xiao-fei Huang,M.D.1 ,Ke-qin Liu,M.D.1, Chen-bin Yu ,M.D.1, Xiao-meng Wang, M.D.1 and Lu Ke,M.D.2

1 Department of Emergency, Jiangsu Province Hospital on Integration of Chinese and Western Medicine,Nanjing, China 2 Department of General Surgery, Jinling Hospital, Nanjing 210002, Nanjing University School of Medicine, Nanjing, China.

*Correspondence to: Hai-bin Ni, Department of Emergency, Jiangsu Province Hospital on Integration of Chinese and Western Medicine, Nanjing, 210028,Jiangsu Province, China

Telephone: +86-25-85638721

E-mail: [email protected]

Competing interests: None.

Fax: +86-25-85637831

Abstract Background

Hypernatremia is an uncommon but important electrolyte abnormality in ICU

patients. Sepsis is one of the most common causes of ICU admission, but few studies about the role of hypernatremia in sepsis has been published yet. In this study, we aimed to explore the risk factors for developing hypernatremia in patients with sepsis and the prognosis of sepsis patients with or without hypernatremia was also assessed. Methods

In this retrospective cohort study of 51 septic intensive care unit patients at

a single center, we examined the risk factors for the development of hypernatremia and the association of hypernatremia with clinical outcomes using univariate and multivariable analyses. Clinical outcomes such as mortality, hospital duration of patients with or without hypernatremia were also compared. Results APACHE II Score (Odds Ratio [OR], 1.15; 95% Confidence Interval [CI], 1.022-1.294) was found to be the only independent risk factor for hypernatremia in patients with sepsis. Moreover, patients developing hypernatremia during hospitalization showed significantly higher morbidity and mortality. Conclusions

APACHE II score may be an independent risk factor for hypernatremia in patients

with sepsis. Moreover, hypernatremia is strongly associated with worse outcome in sepsis. Key words: hypernatremia, sepsis, risk factors, prognosis

Introduction Acute disorders of blood sodium concentration, namely, dysnatremias (hyponatremia and hypernatremia) are commonly encountered in the intensive care unit (ICU) and have adverse impact on various organ systems mainly through alteration of effective plasma osmolality1, 2. Definition of hyponatremia and hypernatremia varies in different studies, but mostly hyponatremia is defined as a plasma sodium level less than 136mmol/l, while hypernatremia as greater than 145mmol/l.

In the literature, hyponatremia was much better studied and its clinical effects including brain oedema, increased intracranial pressure and gait disturbances were well described, although the mechanisms underlying its association with increased risk of death remain unclear3. In contrast, previous studies regarding the clinical relevance of hypernatremia were relatively limited4, 5. Actually, on ICU admission, the prevalence of hypernatremia was reported to be between 2%-9%1 and Lindner et al suggested that hypernatremia acquired during the ICU stay is an independent risk factor for death6. However, although sepsis and septic shock patients are commonly seen in the ICUs worldwide, no study about the role of hypernatremia in patients with sepsis was published yet.

In the present study, we explored the risk factors for hypernatremia in sepsis and the relationship between hypernatremia and clinical outcomes. Moreover, we also compared the prognosis of sepsis patients with or without hypernatremia to clarify the poor outcome of hypernatremia.

Materials and methods Patients Patients with a primary diagnosis of sepsis admitted to the ICU of the emergency department (ED) in Jiangsu integrative medicine hospital within 48 h after the onset of the disease were involved in this observational study. The study period extended from January 2012 to January 2013. Inclusion criteria for sepsis were defined according to the Surviving Sepsis Campaign(SSC) Guidelines 20127.Hypernatremia was defined as [Na+]> 145 mmol/L lasting for at least 48h to avoid laboratory error. n general, patients in the study ICU are treated in accordance with the Surviving Sepsis Campaign Guidelines from 2012.7, 8 and were followed until discharge from the hospital or hospital mortality.

Data collection

The risk factors analyzed in the present investigation included demographic metrics like age, gender and clinical parameters such as APACHE II score, hyperglycemia occurrence, blood urinary nitrogen (BUN) levels, white blood cells (WBC) levels, C-reactive protein (CRP) level, D-dimer, albumin levels and renal disease history (RDH) at admission. All the laboratory results were studied at the Central Laboratory of Jiangsu integrative medicine hospital. Moreover, clinical characteristics for each patient such as need of mechanical ventilation, ICU duration of stay, rate of complications including multiple organ dysfunction syndrome (MODS), infection, and mortality—were recorded to compare the prognosis of patients with or without hypernatremia. Infection was confirmed after the culture results. Hyperglycemia was defined serum glucose concentrations above 12 mmol/L (215 mg/dL). All data was collected by two research nurses and they were blinded to the patients’ clinical treatment. This study was approved by the ethic committee of Jiangsu Province

Hospital on Integration of Chinese and Western Medicine with fast track process (for observational studies). Statistical analysis

Results were expressed as the median (interquartile range) unless mentioned otherwise. Categorical variables were described in absolute numbers and in percentages. Continuous variables were compared using the Mann–Whitney U-test, and categorical data were analyzed with the chi-squared test. To identify risk factors for hypernatremia, several series of univariate logistics regression analyses using the 16 indices mentioned above were performed. Variables that showed statistical significance were tested in further multiple logistic regression analyses with the stepwise method. All statistical tests were two-tailed, and the significance level was set at P<0.05. Data were analyzed with SPSS 17.0 for Windows (SPSS Inc., Chicago, IL). Results Twenty four of the 51 sepsis patients (47.1%) developed hypernatremia during the study period. Table 1 shows the demographic and clinical characteristics of these patients.

Taking these significant variables together into the multiple logistic regression model, only one variable(APACHE II Score) is proved to be an independent risk factor for the development of hypernatremia (shown in Table 2).

Table 3 shows a variety of clinical variables with regard to the clinical outcomes. 15 out of all 51 patients died during hospitalization and 11 of which were in the hypernatremia group. The median

ICU duration was 19 days and 10 days in patient with or without hypernatremia, respectively. Patients with hypernatremia were more critically ill, as evidenced by higher rates of organ failure, higher in-hospital mortality. In the present study, most patients did not receive specific treatment aiming lower blood sodium level except distilled water given orally or dextrose given via venous line. In the hypernatremia group, 10 patients received distilled water 500ml/day orally while others received dextrose 250ml/day. The clinical impact was not well recorded (only the fluid intake and output were shown in table 4).

Discussion The clinical relevance of hypernatremia in critical ill patients has been repeatedly reported and the results suggested that development of hypernatremia is associated with mortality9-12. However, although sepsis is one of most common causes of ICU admission, the role of hypernatremia in sepsis patients has not been studied yet. In this study, we found that nearly half of the study patients developed hypernatremia during hospitalization and the outcome of these patients were significantly worse than those without hypernatremia. Moreover, regression analysis results suggest APACHII score is an independent risk factor for hypernatremia in sepsis patients.

APACHEII score is the most widely applied severity score for early recognition of patient at high risk for death, which is important for facilitating proper management for sepsis13,14. Therefore our results indicate that patients who were more critically ill at admission were at higher risk of developing hypernatremia. A variety of mechanisms may be involved in this phenomenon,

impairment of renal function in these patients and consequent renal water loss may play an important role, as evidenced by significantly higher level of BUN or creatinine in the hypernatremia group. Moreover, Osmotic diuresis caused directly by high blood urea concentration could lead to renal loss of free water and the consequent rise in serum sodium level in critically ill patients15, 16. Besides that, use of diuretics, especially loop diuretics, which is common in patients with acute kidney injury (AKI)17, could result in loss of hypertonicity in the renal medulla, which ultimately causes considerable losses of free water18.At last, extrarenal water losses caused by fever, which is commonly seen in sepsis patients may also contribute to occurrence of hypernatremia.

The prevalence of hypernatremia was 47%; higher than in previous studies in medical and surgical ICUs

6, 19, 20

, suggesting sepsis patients are more likely to develop hypernatremia when compared

with other ICU patients. Moreover, VAN DE Louw et al21 concluded that patients with hypernatremia showed much poorer outcome with higher mortality, more requirement of mechanical ventilation and higher rates of organ failure. Our findings are consistent with

theirs. Although hypernatremia may not be the main contributor to the poor outcome of these patients and a lot of other cofounders need to be considered, a series of adverse effects on physiologic functions caused by following hyperosmolar state such as cellular shrinking, impairment in glucose utilization and neuromuscular effects should affect the clinical outcome to some extent10, 22. For instance, it has been proved that neurologic impairment including muscle weakness and cramps caused by hypernatremia could prolong the need for mechanical ventilation and delay weaning23. In addition, it is noteworthy that most of the recent attention to electrolytes

in sepsis has focused on chloride24. Several studies had been repeatedly found that infusion of chloride-rich fluids can lead to a series of adverse clinical consequences. Therefore it is possible that elevation of chloride rather than hypernatremia resulted in worse outcome in this study and serum sodium just happened to increase when chloride was elevated25-27. Besides, some other findings in this study like higher rates of secondary infection cannot be well explained with the consequences of hypernatremia. Further studies are needed to clarify this issue.

Administration of free water is the most widely used treatment to correct hypernatremia and 5% dextrose solution are the most popular choice. Intermittent or continuous renal replacement therapy was another choice and its effect in treating hypernatremia had been shown by several studies 28, 29. Other measures include fluid resuscitation with balanced crystalloid in patient with hypovolemia and loop diuretics to induce natriuresis in addition to administration of 5% dextrose solution10.

There were several limitations need to be addressed. First of all, it is a single-center retrospective study with limited sample size, which may bring in some uncertainty to the conclusion. Secondly, as hypernatremia was not well recognized during the study period, the treatment of hypernatremia and the fluctuation of blood sodium level were not followed with full details, thus a

retrospective study was needed to collect more information on this topic. Most importantly, as hypernatremia could happen at any time during hospitalization, patients who were sicker and suffered longer ICU duration would probably be at higher risk of developing hypernatremia. Therefore the relationship we found between hypernatremia and worse outcome may be without

pathophysiological basis. Fortunately, in this study almost all hypernatremia (only two outliers) events were first detected within 96 hour after admission and most within 48 hours (18 of 24), thus it is reasonable to believe that hypernatremia could adversely affect the clinical outcome as most study patients stayed in ICU for more than 10 days.

In conclusion, we demonstrated that APACHE II score may be an independent risk factor for hypernatremia in patients with sepsis. Moreover, the clinical outcome of patients with hypernatremia was significantly poorer than the non-hypernatremia group.

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Table 1 General characteristics of the patients Characteristic

Total(n=51)

Hypernatremia (n=24)

Non-

P value

Hypernatremia(n=27) Age, years(range)

74(66-80)

76.5(68.25-82.25)

72(48-80)

0.05

Gender, M/F

39/12

21/3

20/7

APACHE II score

18(14-23)

22(18.5-30)

16(14-19)

<0.001

Glasgow score

10(7-14)

7.5(7-10)

14(11-14)

<0.001

Hyperglycemia

10(19.6%)

4(16.6%)

6(22.2%)

0.09

Sepsis

27(52.9%)

10(41.6%)

17(62.9%)

0.13

Severe Sepsis

14(27.5%)

7(29.2%)

7(25.9%)

0.8

Septic Shock

10(19.6%)

7(29.2%)

3(11.1%)

0.11

BUN levels(mmol/lL)

9.9(6.7-18.3)

11.95(8.2-22.3)

8.1(6.1-12.2)

0.03

Creatinine levelsμ(mol/L)

131.5(68.4-175.3)

159.3(80.1-191.3)

112.0(64.8-145.4)

0.04

Sodion levels(mmol/L)

142(138-149)

143(137-149.5)

139(137-142)

<0.001

Chloride levels(mmol/L)

105(101-111)

109(103.5-117.8)

103(100-106)

<0.001

Bicarbonate(mmol/L)

19.3(17.5-23.4)

18.1(16.4-21.1)

21(19.1-24.2)

0.05

WBC levels(×10^9/L)

14.82(8.8-19.4)

15.42(12.37-20.93)

10.85(6.08-21.1)

0.475

CRP levels (mg/dl)

147(53-160)

130.5(40.3-160)

160(55-160)

0.761

D-D(mg/L)

1.03(0.63-3.49)

0.97(0.65-4.01)

1.03(0.62-2.44)

0.425

Alb (g/l)

29.1(27-33.4)

29.55(28.2-33.3)

29(25-34.3)

0.556

RDH

3/51

2/24

1/72

0.493

Severity of sepsis

Underlying infections Pneumonia

0.264 21

18

Urinary tract infection

1

2

Intrabdominal infection

1

6

Bloodstream infection

1

1

APACHE Acute Physiology and Chronic Health Evaluation,BUN blood urea nitrogen,WBC white blood cells,CRP c-reactive protein, D-D d-dimer,RDH renal disease history

Table 2 Independent prognostic factors in a multivariate logistic regression analysis of hypernatremia Variable

OR

95% CI

P value

Lower

Upper

Age

1.039

0.980

1.103

0.2

APACHE II

1.15

1.022

1.294

0.02

BUN

1.049

0.951

1.157

0.34

Hyperglycemia

0.263

0.06

1.14

0.07

Table 3 Clinical course and outcome of sepsis patients with or without hypernatremia Characteristic

Total(n=51)

Hypernatremi

Non-

a (n=24)

Hypernatremia(n=27)

P value

Hospital mortality, n

15(29.4)

11(45.8%)

4(14.8%)

<0.001

OF

35(68.6%)

22(91.6%)

13 (48.1%)

<0.001

ARDS

24(47.1%)

16(66.7%)

8(29.6%)

0.002

AKI

10(19.6%)

8(33.3%)

2(7.4%)

0.02

Shock

10(19.6%)

7(29.2%)

3(11.1%)

0.11

MODS, n

14 (27.4%)

7(29.1%)

7(25.9%)

0.8

15(29.4)

19(79.2%)

6(22.2%)

<0.001

Secondary Infection, n(%)

OF organ failure, MODS multiple organ dysfunction syndrome

Table 4 Fluid therapy in Hypernatremia and Non-Hypernatremia group Fluid intake(ml) Hypernatremia

Non-

(n=24)

Hypernatremia(n=

Fluid output (ml) P

Hypernatremia

Non-

(n=24)

Hypernatremia(n=

27) Day

1838(1480-243

1

5)

Day

1590(1300-210

2

0)

Day

1500(1300-198

3

0)

Tota

4907(3815-655

l

7)

1600(1490-2195)

1600(1490-1980)

1598(1390-1750)

4455(3215-6204)

P

27) 0.6

1539(1347-198

9

6)

0.1

1330(1190-187

3

0)

0.2

1470(1400-179

8

0)

0.3

4567(3319-580

4

5)

1209(1080-1736)

0.9 1

1117(1056-1670)

0.3 5

1363(1286-1650)

0.0 9

4018(3180-5409)

0.5 8