Abstract
Hyponatremia is the most common electrolyte abnormality encountered in clinical practice. Several medications are associated with hyponatremia. Proton pump inhibitors were reported to cause hyponatremia in one large Swedish population-based study and small observational studies or case reports. This article presents the results of a single-center retrospective case-control study based on a US patient population that examined the association between the use of proton pump inhibitors and significant hyponatremia. Cases were 792 hospitalized patients with hyponatremia, extracted from 473,000 patient encounters over 6 years, and matched controls were 774 hospitalized patients with normal serum sodium levels whose risk factors for hyponatremia were comparable to those of the study cases. The results showed that use of proton pump inhibitors for at least 30 days prior to hospital admission was significantly higher in patients with hyponatremia than in patients who had normal serum sodium levels (32.7% vs 23.3%, respectively, odds ratio 1.6, P < 0.001). Also, proton pump inhibitor use was nonsignificantly higher among patients with recurrent hyponatremia in subsequent hospitalizations compared with patients who did not have recurrence of hyponatremia (35.5% vs 30.4%, respectively, odds ratio 1.3, P = 0.13). To our knowledge, no prior US population-based study addressing such an association has been published.
Keywords: Hyponatremia, proton pump inhibitors, syndrome of inappropriate antidiuretic hormone secretion
Hyponatremia, defined as a serum sodium concentration <135 mmol/L, is the most common electrolyte abnormality encountered in clinical practice. Hyponatremia can occur in different clinical settings as well as with several medications.1 Proton pump inhibitors (PPIs) were reported to cause hyponatremia in small observational studies2,3 and multiple case reports, in addition to one large Swedish population-based study.4 No population-based studies have examined the association between PPIs and hyponatremia in the US to date.
METHODS
This single-center retrospective case-control study was conducted in a 385-bed community hospital located in Annapolis, Maryland, with 20,000 to 25,000 admissions annually. Out of 473,000 adult patient encounters between July 2015 and July 2021, a total of 792 adult patients had a diagnosis of hyponatremia at the time of hospitalization or emergency department visit. A cutoff serum sodium of <130 mmol/L was used for patient inclusion, since milder hyponatremia would less likely require hospital admission, aggressive treatment, or frequent laboratory testing. Patients who developed hyponatremia later during hospital admission or who were admitted for elective surgical procedures were excluded. Matched controls were 774 adult patients with normal serum sodium at the time of hospitalization for any acute medical condition. Controls were selected based on the presence of similar, or more, risk factors for hyponatremia compared with the study cases. The frequency of PPI use as home medication at least 30 days before admission among patients with hyponatremia was compared with its use among matched controls. The use of PPIs was also compared between patients who had recurrent or persistent hyponatremia in a subsequent hospitalization or emergency visit, within 6 months, and those who did not have recurrence of hyponatremia. Data were set into a 2 × 2 table, and the ratio of the odds of hyponatremia in PPI users divided by the odds of hyponatremia in non-PPI users was calculated; if the ratio was >1, then hyponatremia is associated with PPI use. The results were evaluated at 95% confidence interval (CI), at a significance level of P < 0.05 (Supplementary Material). The Luminis Health Clinical Research Committee reviewed the protocol of this project and determined that it was exempt under 45 CRF part 46.104, Category 4(iii). The request for a waiver of HIPAA authorization was approved.
RESULTS
Among hospitalized patients, the use of PPIs was significantly higher in patients with hyponatremia than in patients who had normal serum sodium levels (32.7% vs 23.3%, respectively, odds ratio 1.6, 95% CI 1.3–2.0, P < 0.001). The most frequently used PPI in the two groups of patients was pantoprazole. The prior-to-admission home medications were verified by the hospital pharmacy staff at the time of hospitalization in 82.7% of all patients (cases and controls). Table 1 lists the results obtained from the two groups of patients. In addition, the use of PPIs was nonsignificantly higher among patients with recurrence or persistence of hyponatremia in a subsequent hospitalization or emergency visit, within 6 months, compared with patients who did not develop recurrence of hyponatremia (35.5% vs 30.4, respectively, odds ratio 1.3, 95% CI 0.9–1.7, P = 0.13).
Table 1.
Association between the use of proton pump inhibitors and significant hyponatremia
| Variable | Hyponatremia |
|
|---|---|---|
| Yes (n = 792) | No (n = 774) | |
| Age (years): mean (range) | 69 (20–102) | 69 (24–102) |
| Males | 38.3% (304) | 44.9% (347) |
| Females | 61.7% (489) | 55.1% (427) |
| Proton pump inhibitor use | 32.7% (259) | 23.2% (180) |
| Minimum of daily omeprazole 20 mg equivalent* | 95% (246/259) | 94% (169/180) |
| Once-daily dosing | 89.6% (232/259) | 86.7% (156/180) |
| Pantoprazole | 48.3% (125/259) | 46.7% (84/180) |
| Omeprazole | 31.7% (82/259) | 29.4% (53/180) |
| Esomeprazole | 7.7% (20/259) | 10% (18/180) |
| Lansoprazole | 7.7% (20/259) | 6.7% (12/180) |
| Dexlansoprazole | 2.7% (7/259) | 3.9% (7/180) |
| Rabeprazole | 1.9% (5/259) | 3.3% (6/180) |
| Other medications causing hyponatremia | 63.8% (506) | 69.6% (539) |
| Pharmacy-verified medications | 76.4% | 87.5% |
| Congestive heart failure | 14.3% (113) | 20.5% (159) |
| Chronic lung disease | 22% (175) | 29.3% (227) |
| Diabetes mellitus or other endocrine disorders | 44.7% (354) | 49.6% (384) |
| Chronic kidney disease | 15.7% (124) | 20.9% (162) |
| Malignancy (current) | 17% (135) | 17.4% (135) |
| Chronic liver disease | 6.3% (50) | 11.9% (92) |
| Central nervous system disorders | 21% (166) | 22.1% (171) |
| Alcohol abuse | 14.4% (114) | 13.4% (104) |
| Mental health disorders | 37% (293) | 40.7% (315) |
Minimum of daily pantoprazole 40 mg, esomeprazole 20 mg, lansoprazole 30 mg, dexlansoprazole 60 mg, or rabeprazole 20 mg.
DISCUSSION
Our study results indicate that the use of PPIs for at least 30 days is significantly associated with hyponatremia in hospitalized patients and is nonsignificantly associated with higher rates of recurrence, or persistence, of hyponatremia in a subsequent hospitalization within 6 months. The percentage of the specific type of PPI used was similar in patients with hyponatremia and in controls, with a similar order of frequency of their use, indicating a possible similar effect of all PPIs. Risk factors including medical conditions or medications that are known to cause hyponatremia were comparable between the two groups, or even higher among controls.
Other than case reports and small observational studies,2,3 only one large Swedish population-based study, by Falhammar et al, has recently suggested an association between any newly initiated PPI treatment and hospitalization due to hyponatremia.4 To our knowledge, no prior US population-based study has been published that addressed the association between PPIs and significant hyponatremia. The limitation of our study is that the sample size is relatively smaller than that of the Falhammar et al study.
The mechanism of PPI-induced hyponatremia is believed to be secondary to syndrome of inappropriate antidiuretic hormone secretion5–8 or less likely due to salt-losing nephropathy.9 Numerous other adverse kidney outcomes have been linked to PPI use, including risk for hypomagnesemia, acute kidney injury, and acute interstitial nephritis, among others.10
In conclusion, it would be reasonable to hold PPIs and to switch to a different class of acid suppressants, if necessary, if hyponatremia develops during therapy.
Supplementary Material
References
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