Rationale: Although associated with adverse outcomes in other cardiopulmonary conditions, the prognostic value of hyponatremia, a marker of neurohormonal activation, in patients with acute pulmonary embolism (PE) is unknown.
Objectives: To examine the associations between hyponatremia and mortality and hospital readmission rates for patients hospitalized with PE.
Methods: We evaluated 13,728 patient discharges with a primary diagnosis of PE from 185 hospitals in Pennsylvania (January 2000 to November 2002). We used random-intercept logistic regression to assess the independent association between serum sodium levels at the time of presentation and mortality and hospital readmission within 30 days, adjusting for patient (race, insurance, severity of illness, use of thrombolytic therapy) and hospital factors (region, size, teaching status).
Measurements and Main Results: Hyponatremia (sodium ≤135 mmol/L) was present in 2,907 patients (21.1%). Patients with a sodium level greater than 135, 130–135, and less than 130 mmol/L had a cumulative 30-day mortality of 8.0, 13.6, and 28.5% (P < 0.001), and a readmission rate of 11.8, 15.6, and 19.3% (P < 0.001), respectively. Compared with patients with a sodium greater than 135 mmol/L, the adjusted odds of dying were significantly greater for patients with a sodium 130–135 mmol/L (odds ratio [OR], 1.53; 95% confidence interval [CI], 1.33–1.76) and a sodium less than 130 mmol/L (OR, 3.26; 95% CI, 2.48–4.29). The adjusted odds of readmission were also increased for patients with a sodium of 130–135 mmol/L (OR, 1.28; 95% CI, 1.12–1.46) and a sodium less than 130 mmol/L (OR, 1.44; 95% CI, 1.02–2.02).
Conclusions: Hyponatremia is common in patients presenting with PE, and is an independent predictor of short-term mortality and hospital readmission.
Although associated with adverse outcomes in heart failure, pneumonia, and pulmonary hypertension, the prognostic value of hyponatremia, a marker of neurohormonal activation, in patients with acute pulmonary embolism (PE) is unknown.
In patients with acute PE, hyponatremia at presentation is common, and is associated with a higher risk of 30-day mortality and readmission.
A more recent study demonstrated that hyponatremia was also associated with right ventricular dysfunction and poor survival in patients with pulmonary arterial hypertension (7). In this study, the authors suggested that hyponatremia may result from neurohormonal activation, and be a consequence of more advanced right ventricular dysfunction (7).
Acute pulmonary embolism (PE) is a major health problem; in 2005, 140,000 patients were discharged with a primary diagnosis of PE from U.S. hospitals (8), with an estimated average 30-day mortality of 9% (9). Early death after PE is strongly associated with right ventricular dysfunction (10). Based on a previously observed association between abnormal sodium levels and mortality in patients with PE (9), we hypothesized that low serum sodium at baseline, a marker of neurohormonal activation, may indicate a worse prognosis in patients with this illness.
Our goal was to examine the association between hyponatremia and 30-day mortality and hospital readmission with a large, statewide sample of patients with acute PE. If found, such association may be useful to risk-stratifying patients with acute PE, given that serum sodium is a low-cost, routinely available laboratory parameter. Some of the results of this study have been previously reported in the form of an abstract (11).
We identified all patients with PE discharged from nongovernmental acute care hospitals in Pennsylvania (January 1, 2000 to November 30, 2002) with the Pennsylvania Health Care Cost Containment Council (PHC4) database (9). We included inpatients aged 18 years or older who were discharged with a primary International Classification of Diseases, 9th Clinical Modification diagnosis of PE or a secondary diagnosis for PE and one of the following primary diagnoses that represent complications or treatments of PE: respiratory failure; cardiogenic shock; cardiac arrest; secondary pulmonary hypertension; syncope; thrombolysis; and intubation/mechanical ventilation. A detailed methodological description is available in the online supplement.
Patient demographic characteristics and insurance status were abstracted from the PHC4 database (9). Baseline clinical and laboratory parameters were obtained by linking eligible patients to the MediQual Atlas database (9). We quantified severity of illness with the PE severity index (PESI), a validated prognostic model for patients with PE (9). The PESI comprises 11 routinely available clinical predictor variables. A total point score for a given patient is obtained by summing the points for each applicable predictor. Based on the total score, each patient is classified into one of five severity classes (I–V), with 30-day mortality ranging from 1.1 to 24.5%. We ascertained the hospital characteristics from the PHC4 database and from the Council of Teaching Hospitals of the Association of American Medical Colleges.
We defined hyponatremia as a baseline serum sodium level 135 mmol/L or lower. Although no commonly accepted cut-point exists for defining hyponatremia, most recent cardiopulmonary studies used a serum sodium level 134–136 mmol/L or less to define the threshold (2, 7, 12).
Our primary study outcome was all-cause mortality within 30 days of presentation, based on the National Death Index (13). To ascertain our secondary outcome, hospital readmission for any reason to any acute-care hospital in Pennsylvania within 30 days, we used the PHC4 database.
To compare baseline characteristics for patient discharges across three levels of serum sodium (<130, 130–135, >135 mmol/L), we performed Chi-square tests for categorical variables and Kruskal-Wallis tests for continuous variables. We used survival analyses and the log-rank test to compare the cumulative 30-day mortality and hospital readmission rates by sodium level. We also stratified our comparisons of mortality by sodium level and the five PESI severity classes.
We used multivariable logistic regression to examine the independent association between sodium level and mortality, after adjusting for patient race, insurance, severity of illness by using PESI severity class, thrombolytic therapy, and hospital region, size, and teaching status. To account for patient clustering within hospital, we used random-intercept logistic regression with the two levels defined by patient and hospital site. We used the same logistic model to examine the association between sodium level and readmission in patients discharged alive. We also examined whether the addition of serum sodium increases the prognostic performance of the PESI with net reclassification and integrated discrimination improvement (14).
Of the 17,733 patient discharges that met our inclusion criteria, we excluded 323 with only a secondary code indicative of PE (1.8%), 767 patient transfers from another hospital (4.3%), 265 subsequent transfers to another hospital (1.5%), 777 discharges without a match to key clinical findings (4.4%), 70 without a linkage to the National Death Index (0.4%), and 1,803 (10.2%) with an undocumented serum sodium at the time of presentation. The study cohort comprised 13,728 patient discharges with a diagnosis of PE from 185 Pennsylvania hospitals; 2,907 (21.1%) had hyponatremia (serum level ≤ 135 mmol/L). Of these, 2,598 (18.9%) had a sodium level 130 to 135 mmol/L and 309 (2.2%) had a sodium level less than 130 mmol/L. Compared with the 13,728 enrolled patients, the 1,803 excluded because of an undocumented serum sodium were significantly younger (median age, 64 versus 67 yr; P < 0.001), and were less likely to have a history of heart failure (10.7 versus 16.5%; P < 0.001) and chronic lung disease (14.7 versus 18.9%; P < 0.001). Compared with eligible patients with a documented serum sodium, these 1,803 excluded patients were also less likely to have a pulse of 110/minute or greater (11.1 versus 18.5%; P < 0.001), a systolic blood pressure less than 100 mm Hg (7.8 versus 10.8%; P < 0.001), a respiratory rate of 30/min or greater (8.3 versus 15.4%; P < 0.001), a body temperature of less than 36°C (14.4 versus 16.9%; P = 0.007), an altered mental status (5.9 versus 7.5%; P = 0.02), and an arterial oxygen saturation of less than 90% (3.9 versus 8.5%; P < 0.001) at presentation.
As shown in Table 1, patients admitted with lower serum sodium were older, more likely to have comorbid diseases (cancer, chronic lung disease, and heart failure), and more likely to have signs of clinical severity (tachycardia, hypotension, tachypnea, hypothermia, altered mental status, hypothermia, and hypoxemia). Consequently, there was a higher proportion of patients in PESI risk classes IV and V among patients with lower serum sodium. Patients with lower serum sodium were also significantly more likely to have hyperglycemia and elevated serum creatinine.
Serum Sodium Level (mmol/L)
|Characteristics||All Patients (n = 13,728)||<130 (n = 309)||130–135 (n = 2598)||>135 (n = 10,821)||P Value|
|Age, yr||67 (52–77)||71 (59–79)||68 (55–78)||67 (52–77)||<0.001|
|Male sex||5,525 (40.2)||122 (39.5)||1,099 (42.3)||4,304 (39.8)||0.06|
|White||11,166 (81.3)||249 (80.6)||2,149 (82.7)||8,768 (81.0)|
|Black||1,459 (10.6)||34 (11.0)||252 (9.7)||1,173 (10.8)|
|Other/unknown||1,103 (8.0)||26 (8.4)||197 (7.6)||880 (8.1)|
|None/unspecified||197 (1.4)||1 (0.3)||37 (1.4)||159 (1.5)|
|Government||7,685 (56.0)||205 (66.3)||1,513 (58.2)||5,967 (55.1)|
|Medicaid||1,013 (7.4)||25 (8.1)||204 (7.8)||784 (7.2)|
|Private||4,833 (35.2)||78 (25.2)||844 (32.5)||3,911 (36.1)|
|History of cancer||2,669 (19.4)||105 (34.0)||685 (26.4)||1,879 (17.4)||<0.001|
|Chronic lung disease||2,602 (18.9)||68 (22.0)||540 (20.8)||1,994 (18.4)||0.009|
|Heart failure||2,266 (16.5)||80 (25.9)||494 (19.0)||1,692 (15.6)||<0.001|
|Physical examination findings|
|Pulse ≥ 110 beats per minute||2,542 (18.5)||87 (28.2)||596 (22.9)||1,859 (17.2)||<0.001|
|Systolic blood pressure < 100 mm Hg||1,484 (10.8)||65 (21.0)||417 (16.0)||1,002 (9.3)||<0.001|
|Respiratory rate ≥ 30 breaths/minute||2,111 (15.4)||69 (22.3)||446 (17.2)||1,596 (14.7)||<0.001|
|Altered mental status*||1,024 (7.5)||39 (12.6)||218 (8.4)||767 (7.1)||<0.001|
|Temperature < 36°C||2,316 (16.9)||64 (20.7)||403 (15.5)||1,849 (17.1)||0.03|
|Arterial oxygen saturation < 90%†||1,165 (8.5)||30 (9.7)||250 (9.6)||885 (8.2)||0.04|
|Glucose > 250 mg/dl||1,000 (7.3)||54 (17.5)||335 (12.9)||611 (5.6)||<0.001|
|Creatinine > 1.5 mg/dl||1,809 (13.2)||67 (21.7)||412 (15.9)||1,330 (12.3)||<0.001|
|Troponin ≥ 0.1 ng/ml||4,497 (32.8)||106 (34.3)||817 (31.4)||3,574 (33.0)||0.26|
|PESI risk class||<0.001|
|I||2,531 (18.4)||12 (3.9)||334 (12.9)||2,185 (20.2)|
|II||2,894 (21.1)||45 (14.6)||463 (17.8)||2,386 (22.0)|
|III||3,018 (22.0)||65 (21.0)||578 (22.2)||2,375 (21.9)|
|IV||2,253 (16.4)||70 (22.6)||512 (19.7)||1,671 (15.4)|
|V||3,032 (22.1)||117 (37.9)||711 (27.4)||2,204 (20.4)|
|Thrombolysis||329 (2.4)||6 (1.9)||75 (2.9)||248 (2.3)||0.19|
|Types of hospitals attended|
|Pittsburgh and surrounding areas||3,174 (23.1)||66 (21.4)||509 (19.6)||2,599 (24.0)|
|Northwest Pennsylvania||947 (6.9)||20 (6.5)||187 (7.2)||740 (6.8)|
|Southern Laurel Highlands||713 (5.2)||11 (3.6)||124 (4.8)||578 (5.3)|
|North central Pennsylvania||942 (6.9)||21 (6.8)||211 (8.1)||710 (6.6)|
|South central Pennsylvania||2,187 (15.9)||57 (18.4)||451 (17.4)||1,679 (15.5)|
|Northeast Pennsylvania||841 (6.1)||23 (7.4)||179 (6.9)||639 (5.9)|
|Eastern Pennsylvania||1,366 (9.9)||19 (6.1)||288 (11.1)||1059 (9.8)|
|Surrounding Philadelphia||2,037 (14.8)||36 (11.6)||314 (12.1)||1,687 (15.6)|
|Philadelphia||1,521 (11.1)||56 (18.1)||335 (12.9)||1,130 (10.4)|
|Average annual volume of PE, quartiles||0.02|
|<10||747 (5.4)||8 (2.6)||147 (5.7)||592 (5.5)|
|10–20||1,569 (11.4)||30 (9.7)||257 (9.9)||1,282 (11.8)|
|21–42||3,517 (25.6)||87 (28.2)||686 (26.4)||2,744 (25.4)|
|>42||7,895 (57.5)||184 (59.5)||1508 (58.0)||6,203 (57.3)|
|Hospital size and teaching status||<0.001|
|Large nonteaching (≥350 beds)||2,748 (20.0)||73 (23.6)||615 (23.7)||2,060 (19.0)|
|Small nonteaching (<350 beds)||7,542 (54.9)||149 (48.2)||1337 (51.4)||6,056 (56.0)|
| Teaching||3,438 (25.1)||87 (28.2)||646 (24.9)||2,705 (25.0)|
Overall, 1,308 of 13,728 patients (9.5%) died at 30 days. As shown in Figure 1, patients with a serum sodium of greater than 135, 130–135, and less than 130 mmol/L had a cumulative 30-day mortality of 8.0, 13.6, and 28.5% (P < 0.001), respectively. Mortality in these three groups diverged 1 day after admission, and the difference continued to increase over the 30-day follow up. Mortality was also significantly increased among patients with lower serum sodium, stratified by each of the five PESI risk classes at presentation (Table 2).
Serum Sodium Level* (mmol/L)
|PESI risk class||<130||130–135||>135||P-Value|
|I||0/12 (0.0)||10/334 (3.0)||22/2,185 (1.0)||0.02|
|II||7/45 (15.6)||28/463 (6.0)||62/2,386 (2.6)||<0.001|
|III||16/65 (24.6)||52/578 (9.0)||134/2,375 (5.6)||<0.001|
|IV||15/70 (21.4)||73/512 (14.3)||156/1,671 (9.3)||<0.001|
|V||50/117 (42.7)||190/711 (26.7)||493/2,204 (22.4)||<0.001|
After adjustment for patient race, insurance, severity of illness by PESI risk class, administration of thrombolytic therapy, hospital region, and hospital size and teaching status (Table 3), the odds of 30-day mortality remained significantly increased for patients with a sodium level of 130–135 mmol/L (odds ratio [OR], 1.53; 95% confidence interval [CI], 1.33–1.76) and a sodium level less than 130 mmol/L (OR, 3.26; 95% CI, 2.48–4.29). When the PESI risk class was replaced in the model with the 11 variables comprising the PESI and laboratory parameters (serum glucose > 250 mg/dl, serum creatinine > 1.5 mg/dl, and serum troponin ≥ 0.1 ng/ml), or when the 5,951 patients with a history of cancer, chronic lung disease, or heart failure were excluded from analysis, the results remained similar.
Adjusted Odds Ratio*
95% Confidence Interval
|30-d all-cause mortality||<0.001|
|Serum sodium > 135 mmol/L||1.00||—|
|Serum sodium 130–135 mmol/L||1.53||1.33–1.76|
|Serum sodium < 130 mmol/L||3.26||2.48–4.29|
|30-d hospital readmission rate†||<0.001|
|Serum sodium > 135 mmol/L||1.00||—|
|Serum sodium 130–135 mmol/L||1.28||1.12–1.46|
|Serum sodium < 130 mmol/L||1.44||1.02–2.02|
Patient reclassifications for 30-day mortality are summarized in Table 4. For 38 of 1,308 patients (2.9%) who died within 30 days of admission, classification improved with serum sodium level in addition to the PESI. Conversely, 154 of 12,420 patients (1.2%) who were alive within 30 days of admission were reclassified up. The net reclassification improvement was estimated at 1.7% (P < 0.001), corresponding to a modest, but statistically significant, improvement. The integrated discrimination improvement was also statistically significant (0.009; P < 0.001).
PESI without Serum Sodium Level Frequency
PESI with Serum Sodium Level*
|Patients who died by 30 d, %|
|Patients who were alive by 30 d, %|
The 30-day readmission rate was estimated in 12,762 patients, after the exclusion of 840 patients who died in the hospital, 91 who were still hospitalized at 30 days after admission, and 35 with unknown readmission status. Of these, 1,596 (12.5%) were readmitted within 30 days. As shown in Figure 2, patients with a sodium level greater than 135, 130–135, and less than 130 mmol/L had a cumulative 30-day readmission rate of 11.8, 15.6, and 19.3% (P < 0.001), respectively. After adjustment (Table 3), patients with a sodium level 130–135 mmol/L (OR, 1.28; 95% CI, 1.12–1.46) and a sodium level less than 130 mmol/L (OR, 1.44; 95% CI, 1.02–2.02) had significantly increased odds of 30-day readmission. When the PESI risk class was replaced in the model with the 11 variables comprising the PESI and laboratory parameters (serum glucose > 250 mg/dl, serum creatinine > 1.5 mg/dl, and serum troponin ≥ 0.1 ng/ml), or when the 5,951 patients with a history of cancer, chronic lung disease, or heart failure were excluded from analysis, the results were unchanged.
Our results demonstrate that a substantial proportion of patients with PE (21.1%) are hyponatremic at the time of presentation. After adjusting for potential patient- and hospital-related confounders, and the administration of thrombolytic therapy, we found that patients with hyponatremia had a significantly higher 30-day mortality than patients without hyponatremia, and that the mortality rate increased with the severity of hyponatremia. The higher mortality among patients with hyponatremia was observed across all PESI risk classes. Similarly, we also observed a significant association between hyponatremia and 30-day hospital readmission. To our knowledge, our study represents the first to demonstrate the prognostic importance of hyponatremia in patients with PE.
Several explanations are possible for the association between hyponatremia and increased 30-day mortality in patients with PE. Hyponatremia is a well known marker of neurohormonal activation in patients with left ventricular heart failure, and reflects nonosmotic release of vasopressin consequent to activation of the sympathetic and renin–angiotensin–aldosterone system axis (6, 15). Neurohormonal activation has also been demonstrated in patients with pulmonary arterial hypertension, and occurs in proportion to the degree of right ventricular dysfunction (16, 17). Therefore, hyponatremia may indicate neurohormonal activation in the context of PE-related pulmonary arterial hypertension and subsequent right heart dysfunction, a known factor of adverse prognosis in patients with PE (10). Indeed, a prior prospective study of patients with chronic pulmonary arterial hypertension demonstrated a strong association between hyponatremia and the presence of right ventricular dysfunction and short-term survival (7). Future prospective studies should examine whether hyponatremia reflects neurohormonal activation and right ventricular dysfunction in patients with acute PE.
Another explanation for the observed association between hyponatremia and adverse outcomes may be the presence of unmeasured prognostic factors that are unrelated to right ventricular dysfunction. In a recent study of middle-aged and elderly community subjects without a history of heart failure, hyponatremia was an independent predictor of death, regardless of concomitant diuretic use, renal and hepatic disease, and hyperglycemia (18). In large, retrospective and prospective cohort studies, hyponatremia also significantly increased short-term mortality in unselected inpatients (19–22). Indeed, the relationship between hyponatremia and adverse outcomes is incompletely understood because of its association with a multitude of underlying disease states, and its multiple causes with different pathophysiologic mechanisms (23).
Our study also shows that, after adjustment for patient and hospital characteristics and the administration of thrombolytic therapy, hyponatremia in the acute phase of PE is an independent predictor for future hospital admissions, reinforcing the prognostic importance of a low serum sodium level. Our findings are consistent with the results from prior studies that found significantly higher hospital readmission rates in hyponatremic patients with acute myocardial infarction and heart failure (2, 12, 24).
Our findings have both clinical and research implications. Clinically, patients with PE who are hyponatremic at presentation carry a higher risk of short-term mortality and hospital readmission, and may, therefore, potentially benefit from more intensive surveillance in the hospital and after discharge. Further research is warranted to determine whether correction of hyponatremia (e.g., with vasopressin receptor antagonists or other treatments) is associated with improved outcomes for patients with PE. Evidence suggests that patients with left ventricular heart failure who have persistent hyponatremia have a significantly higher risk of short-term mortality or hospitalization for heart failure than patients in whom hyponatremia was corrected (24). Similarly, resolution of admission hyponatremia during hospitalization appears to attenuate the increased mortality risk conferred by hyponatremia among unselected inpatients (21).
Our work has several potential limitations. First, patients in the study sample were identified by use of International Classification of Diseases, 9th Clinical Modification codes for PE rather than standardized radiographic criteria, and patient eligibility may, therefore, be subject to study selection biases due to hospital coding procedures. In prior studies, up to 96% of patients with specific codes for PE had objectively documented disease on the basis of chart review criteria (25–27). Second, our sample excluded 10.2% of younger, healthier, and less severely ill patients in whom serum sodium was not measured at the time of admission. However, because hyponatremia adversely affects outcomes across the full spectrum of severity of illness (PESI risk classes I–V), the exclusion of these lower-risk patients is unlikely to change our study results. Third, because measures of right ventricular function and neurohormonal activation were not available in our database, we could not examine whether these factors are linked to the pathophysiology of hyponatremia. Moreover, we had no information about diuretic use and hypervolemic hyponatremic states, such as cirrhosis or nephrotic syndrome. Thus, we could not explore whether these conditions are associated with the higher observed mortality among patients with hyponatremia. Fourth, because we had no information on sodium levels after hospital discharge, the prognostic implications of transient versus persistent hyponatremia could not be analyzed. Finally, we can only detect associations, not causality, from these data. Thus, we cannot determine whether hyponatremia has a specific effect on the pathophysiology of PE, or if it is simply a marker of adverse outcome.
In conclusion, in this large sample of patients hospitalized with acute PE, hyponatremia at presentation was common, and was associated with a higher risk of 30-day mortality and readmission. Hyponatremia may serve as an easy-to-use marker to identify patients with PE who are at high risk of adverse medical outcomes. Future studies should examine whether hyponatremia reflects neurohormonal activation and right ventricular dysfunction in patients with acute PE, and whether correction of this electrolyte abnormality is associated with improved patient outcomes.
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