Abstract
Background and aims
Ascites and hyponatremia are important milestones of worsening portal hypertension in those with cirrhosis. The objective of our study was to evaluate the differences in clinical characteristics, resource utilization, and disposition of hospitalized cirrhotic patients with ascites with and without hyponatremia.
Methods
The National Inpatient Sample (NIS) database was used to identify all adult hospitalized patients with a diagnosis of cirrhosis and ascites with or without hyponatremia from 2016 to 2017 using ICD-10 codes.
Results
During the study period, 10,187 (7.6%) hospitalized patients with cirrhosis had ascites and hyponatremia and 34,555 (24.3%) had ascites but no hyponatremia. Elixhauser comorbidity score, excluding liver disease, was higher in hyponatremic patients (median 21 vs. 12, P < 0.001). Acute kidney injury (50.3% vs. 32.8%, P < 0.001) and sepsis (16.8% vs. 11.8%, P < 0.001) were more common in hyponatremic patients compared to those without hyponatremia. Similarly, acute respiratory failure, coagulopathy, hepatorenal syndrome, spontaneous bacterial peritonitis, acute (on chronic) liver failure, and liver cancer were more common in hyponatremic patients. Hyponatremia patients had a higher number of inpatient procedures, longer (6 days vs. 4 days, P < 0.001) hospital stay, and had higher hospital charges ($97,327 vs. $72,278, P < 0.01) than those without hyponatremia. Inpatient mortality was 38% higher in hyponatremic patients (9.8% vs. 7.1%, P < 0.001) compared to those without hyponatremia. Additionally, hyponatremic patients were less likely to have routine home discharges with self-care.
Conclusion
In conclusion, using a large and diverse national cohort of unselected patients, we were able to show that hyponatremia in patients with cirrhosis and ascites is associated with poor clinical outcomes and increased resource utilization.
Keywords: hyponatremia, cirrhosis, ascites, mortality, resource utilization
Abbreviations: AKI, Acute kidney injury; ALF, Acute liver failure; AHRQ, Agency for Healthcare Research and Quality; HCUP, Healthcare cost and Utilization Project; HE, Hepatic encephalopathy; HCC, Hepatocellular carcinoma; HRS, Hepatorenal syndrome; ICU, Intensive care units; NIS, National Inpatient Sample; SBP, Spontaneous bacterial peritonitis; SD, Standard deviation
Hyponatremia is the most frequent electrolyte abnormality encountered in hospitalized patients. The prevalence of hyponatremia (serum sodium <130 mEq/L) in hospitalized patients with cirrhosis is approximately 28–35% while a sodium less than 135 mEq/L is even more common (up to 57% of inpatients).1, 2, 3, 4 In the largest study (n = 997), serum sodium less than 135 mEq/L was seen 49.4% of patients; a majority of the studied patients (83.6%) were on diuretics at the time of hospitalization, most patients (93%) had either Child B or C cirrhosis and there was a clear association between hyponatremia and the severity of ascites.1 Although, hypovolemic hyponatremia (secondary to diuretic use and gastrointestinal losses) can occur in cirrhosis, in a majority of patients hyponatremia results from hypervolemia (dilutional).5,6 In patients with end-stage liver disease, hyponatremia is an indicator of worsening portal hypertension and is associated with a higher mortality.1,5,6 It has been suggested that for each 1 mmol/L decrease in serum sodium concentration between 125 mmol/L and 140 mmol/L, the mortality increases by 5%–10%.1
Hyponatremia in cirrhosis is also associated with an increased risk of complications such as refractory ascites requiring frequent large-volume paracentesis, spontaneous bacterial peritonitis (SBP), hepatorenal syndrome (HRS), and hepatic encephalopathy (HE).5, 6, 7 Hyponatremia also leads to poor quality of life and recurrent hospitalizations. Prior studies that evaluated hyponatremia in cirrhosis involved a highly selected group of patients mainly from tertiary care academic centers. The objective of our study was to evaluate the morbidity and resource utilization in a large unselected national cohort of hospitalized cirrhotic patients with ascites and with or without hyponatremia.
Methods
Study design and data source
This was a retrospective study using national inpatient sample (NIS) data of the years 2016 and 2017. The NIS is the largest publicly available all-payer inpatient administrative database developed by the Agency for Healthcare Research and Quality (AHRQ) for the Healthcare cost and Utilization Project (HCUP). It represents approximately 20% stratified sample of discharges from community hospitals but excludes long term acute care hospitals and rehabilitation facilities and contains information of more than 7 million hospital discharges annually. The database captures information about primary and secondary diagnoses during each hospital stay and also contains other valuable information such as severity and comorbidity measures. Information was extracted from the NIS database to identify all patients >18 years of age with a diagnosis of cirrhosis, ascites, and hyponatremia based on ICD-10 diagnostic codes (hyponatremia ICD10: E87.1, cirrhosis ICD 10: K74.60, K70.30, ascites ICD 10: R188). NIS database identifies serum sodium <135mEq/L as hyponatremia.
Variables
We obtained information on patient demographics (age, sex, race), patient disposition (discharged to home, home health services, or short-term facility), hospital characteristics (region of the country, bed-size, teaching status), and insurance status (Medicare, Medicaid and private insurance). We also examined the presence of complications such as acute respiratory failure, acute kidney injury (AKI), sepsis, and liver-related complications such as acute liver failure (ALF; most likely, most of them had acute-on-chronic liver failure and were coded as ALF in the absence of a code for acute on chronic liver failure), HE, esophageal variceal bleeding, portal vein thrombosis, SBP, HRS, and hepatocellular carcinoma (HCC); inpatient procedures such as upper endoscopy and paracentesis were also captured using ICD-10 codes (supplementary table 1).
Outcomes
Primary objectives were to characterize the differences in clinical characteristics, hepatic and nonhepatic complications, in-hospital mortality, and resource utilization of cirrhotic patients with ascites who have hyponatremia as compared to those without hyponatremia.
Statistical analysis
Descriptive statistics for characteristics of patients, stratified by those who died or were discharged alive, were presented as means and standard deviations (SDs) or median and interquartile range (IQR) as appropriate for continuous variables and frequencies for categorical variables. Differences in patient characteristics between two groups were assessed by using Chi-Square tests for categorical variables and T-tests for continuous variables; normality was checked for all continuous variables, and nonparametric Wilcoxon test was used when data were not normally distributed. A variable with P-value < 0.05 indicated a significant difference between the two groups.
Results
During the study period, 10,187 (7.6%) hospitalized patients with cirrhosis had ascites and hyponatremia, and 34,555 (24.3%) had ascites, but no hyponatremia; characteristics of these patients are shown in Table 1. Insurance status and hospital characteristics where they were admitted are shown in supplementary table 1. During the same study period, 97,370 (68.1%) patients were also admitted with cirrhosis, but without ascites nor hyponatremia; their characteristics are shown in supplementary table 2.
Table 1.
Patient Characteristics and Complications in Those With Cirrhosis and Ascites Stratified by the Presence or Absence of Hyponatremia.
| Variable | Cirrhosis with ascites and hyponatremia (n = 10,187) | Cirrhosis with ascites but no hyponatremia (n = 34,555) | P-value |
|---|---|---|---|
| Age (years), mean (SD) | 62.5 (12.1) | 63.8 (12.6) | <0.0001 |
| Male | 5539 (54.4%) | 18,310 (53.0%) | 0.013 |
| Race | |||
| White | 6796 (69.0%) | 21,469 (64.3%) | <0.001 |
| Black | 799 (8.1%) | 4085 (12.2%) | <0.001 |
| Hispanic | 1510 (15.3%) | 5440 (16.3%) | 0.024 |
| Asian/Pacific Islander | 344 (3.5%) | 973 (2.9%) | 0.003 |
| Other | 404 (4.1%) | 1442 (4.3%) | 0.36 |
| Elixhauser comorbidity score∗, Median (IQR) | 21 (13) | 12 (17) | <0.001 |
| Hepatocellular cancer | 1026 (10.1%) | 2438 (7.1%) | <0.001 |
| Nonhepatic complication | |||
| Acute kidney injury | 5121 (50.3%) | 11,344 (32.8%) | <0.001 |
| Congestive heart failure | 1900 (18.7%) | 6920 (20.0%) | <0.010 |
| Sepsis | 1708 (16.8%) | 4066 (11.8%) | <0.001 |
| Acute respiratory failure | 1240 (12.2%) | 3603 (10.4%) | <0.001 |
| Hepatic complications | |||
| Coagulopathy | 4743 (46.6%) | 13,169 (38.1%) | <0.001 |
| Hepatic encephalopathy | 2994 (29.4%) | 8289 (24.0%) | <0.001 |
| Hepatorenal syndrome | 1244 (12.2%) | 1957 (5.7%) | <0.001 |
| Spontaneous bacterial peritonitis | 1046 (10.3%) | 2294 (6.6%) | <0.001 |
| Acute liver failure | 832 (8.2%) | 1971 (5.7%) | <0.001 |
| Portal vein thrombosis | 595 (5.8%) | 1722 (5.0%) | <0.001 |
| Variceal bleeding | 332 (3.3%) | 1585 (4.6%) | <0.001 |
IQR: interquartile range; SD: standard deviation.
∗Elixhauser comorbidity score excluding liver disease.
Clinical characteristics
There were no clinically meaningful differences in age and gender between those with and without hyponatremia. Blacks were less than 34% less likely to be admitted with hyponatremia. Median comorbidity score (21 vs. 12, P < 0.001) was significantly higher in patients with hyponatremia compared to those without hyponatremia (Table 2). For the purpose of this study, we calculated the Elixhauser comorbidity score excluding liver disease.
Table 2.
Resource Utilization, Patient Disposition, and in-Hospital Mortality in Cirrhosis With Ascites Stratified by the Presence or Absence of Hyponatremia.
| Variable | Cirrhosis with ascites and hyponatremia (n = 10,187) | Cirrhosis with ascites but no hyponatremia (n = 34,555) | P-value |
|---|---|---|---|
| Procedures, hospital stay, disposition, in-hospital mortality, and costs | |||
| Paracentesis | 5392 (52.9%) | 15,226 (44.1%) | <0.001 |
| Upper Endoscopy | 1299 (12.8%) | 5180 (15.0%) | <0.001 |
| Total number of procedures, Median (IQR) | 2 (3) | 2 (2) | <0.001 |
| Length of stay (days), Median (IQR) | 6 (7) | 4 (5) | <0.001 |
| Patient Disposition | |||
| Discharged to home or self-care | 4028 (39.6%) | 17,158 (49.7%) | <0.001 |
| Transfer: short-term | 511 (5.0%) | 1198 (3.5%) | <0.001 |
| Transfer: other type | 2282 (22.4%) | 6535 (18.9%) | <0.001 |
| Home healthcare | 2198 (21.6%) | 6573 (19.0%) | <0.001 |
| Discharged against medical advice | 164 (1.6%) | 603 (1.8%) | 0.36 |
| In-hospital mortality | 995 (9.8%) | 2441 (7.1%) | <0.001 |
| Total charges in 2017 dollars, Mean (SD) | 97,328 (161,992) | 72,279 (118,554) | <0.001 |
IQR: interquartile range; SD: standard deviation.
Patients with hyponatremia were more likely to have AKI (50.3% vs. 32.8%, P < 0.001), acute respiratory failure (12.2% vs. 10.4%, P < 0.001) and sepsis (16.8% vs. 11.8%, P < 0.001). Patients with hyponatremia also had higher liver related complications such as coagulopathy (46.6% vs. 38.1%, P < 0.001), HE (29.4% vs. 24.0%, P < 0.01), HRS (12.2% vs. 5.7%, P < 0.001), SBP (10.3% vs 6.6%, P < 0.001), HCC (10.1% vs. 7.1%, P < 0.001) and acute liver failure (8.2% vs. 5.7%, P < 0.001) (Table 1). Portal vein thrombosis was numerically similar and there were fewer variceal bleeding in the hyponatremia group.
Length of hospital stay, disposition, and resource utilization
Patients with hyponatremia underwent a higher number of paracentesis (53% vs. 44%, P < 0.001), but fewer endoscopies (12.8% vs. 15.0, P < 0.001) than those without hyponatremia (Table 2). Patients with hyponatremia had a higher median length of hospital stay (6 days vs 4 days, P < 0.001) and 35% higher total hospital charges ($97,327 vs. $72,278, P < 0.001) compared to those without hyponatremia (Table 2).
Hyponatremic patients had a higher number of discharges to short-term care facilities (5.0% vs. 3.5%, P < 0.001), as well as a higher need for home health services upon discharge (21.6% vs.19.0%, P < 0.001), and they also had fewer routine home discharges with self-care than those without hyponatremia (39.6% vs. 49.7%, P < 0.001). The inpatient mortality was 38% higher in hyponatremic patients with ascites compared to those without hyponatremia (9.8% vs. 7.1%, P < 0.001). The in-hospital mortality of patients (n = 97,370) admitted with cirrhosis but without ascites or hyponatremia during the same period was 4.1%, and their mean total hospital charges were $59675 (Supplementary table 2).
Discussion
In this nationwide analysis, we found that 7.6% of patients with cirrhosis admitted to US hospitals had ascites with hyponatremia, and 24.3% had ascites without hyponatremia. As expected, hyponatremic patients were sicker with higher rates of hepatic and nonhepatic complications. They also used more hospital resources resulting in 35% higher hospital charges than those with ascites and no hyponatremia. Patients with hyponatremia had higher in-hospital mortality, with 1 in 10 dying during the hospitalization. Moreover, those who were discharged were less likely to have home discharges with self-care.
Consistent with other published data, we found that patients with hyponatremia had higher rates of hepatic and nonhepatic complications.1,8, 9, 10 Patients with hyponatremia had 50% higher inpatient hospital stay and required more inpatient procedures resulting in increased hospital charges confirming observations of previous studies.11,12 Additionally, a higher proportion of patients with hyponatremia were discharged to skilled nursing facilities, acute rehabilitation units and required more home health services compared to those without hyponatremia. We did not examine readmission rates in those with hyponatremia, but a recent study had reported 1.37 times greater odds for 30-day readmission due to any cause and 2.68 times greater odds for hyponatremia related hospital readmission rates.13 These observations clearly suggest that the true burden of managing hyponatremic patients with cirrhosis with ascites and hyponatremia is under estimated.
Previous studies had reported a mortality of 2–6% in hospitalized patients with hyponatremia, irrespective of underlying disease, with a higher mortality (up to 18%) in those admitted to the intensive care units (ICU).11,14, 15, 16 Only a limited number of studies have analyzed the outcomes of patients with cirrhosis and hyponatremia, and most of those studies focused on mortality rates. One small study that analyzed critically ill cirrhotic patients found that patients with Na <135 mEq/L (n = 67) at the time of ICU admission had 73% in-hospital mortality.17 Another study of 57 hospitalized patients with cirrhosis and hyponatremia (defined as Na < 130 mEq/L) reported a mortality of 26% with a higher mortality (48%) in those with severe hyponatremia (<125 mEq/L).18 In our study, hyponatremia was defined as Nc < 135 mEq/L and due to the limitations of the NIS database, we were unable to determine mortality rates based on the severity of hyponatremia. However, in a large unselected patient population, we found that in-hospital mortality was 9.8% in ascites and hyponatremia. In contrast, those with ascites and no hyponatremia had a mortality rate of 7.1%, and those with cirrhosis but without ascites or hyponatremia had mortality rates of 4.1%, showing an incremental increase in mortality rates with ascites and hyponatremia.
The use of an administrative database has a few limitations, including coding errors resulting in misclassification and potential bias. Another shortcoming is that the NIS reports every hospitalization as a separate encounter and not as a unique patient. It is possible that many of these patients were re-admitted and were counted multiple times, which may have skewed the mortality rates. The NIS datasets also do not provide laboratory data, which precluded us from calculating severity indices such as the model for end-stage liver diseases or Child-Turcotte-Pugh scores. The chronology of the onset of complications before or after hospitalization also could not be ascertained. Nonetheless, the reliability of the NIS database has been extensively validated and provides an excellent national cross-sectional image.
In conclusion, using a large and diverse national cohort of unselected patients, we were able to show that hyponatremia in patients with cirrhosis and ascites is associated with poor clinical outcomes and increased resource utilization. Although hyponatremia could be a reflection of the severity of portal hypertension, future studies should explore whether optimal management of hyponatremia could improve the short-term outcomes of hospitalized patients.
Credit authorship contribution statement
PJT contributed to the conception and design, the acquisition, analysis, interpretation of the data, the drafting of the article or critical revision for important intellectual content. JJA contributed to the drafting of the manuscript and revision. TZ did the statistical analysis, and all authors approved the final version and agreed to be accountable for all aspects of the work.
Conflicts of interest
The authors have none to declare.
Funding
None.
Footnotes
Supplementary data to this article can be found online at https://doi.org/10.1016/j.jceh.2021.10.145.
Appendix A. Supplementary data
The following is the supplementary data to this article:
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