We thank the Kidney News editors for the opportunity to respond to the Letters to the Editor (1, 2) regarding our invited commentary on hyponatremia correction (3). With a reference limit, our commentary could not provide the evidence demanded by the letter writers. Readers interested in that evidence can find it in our recent comprehensive review just published in CJASN (4). The review was authored by 24 hyponatremia experts from nine countries. All of the authors share our concern that the conclusions drawn from the study by MacMillan et al. (5) and the accompanying editorial by Ayus and Moritz (6) were unwarranted.
A major flaw in the study by MacMillan et al. (5) was that most of the patients studied were at extremely low risk of developing osmotic demyelination syndrome (ODS). In their letter, Topf et al. (1) ask for references. They need look no further than reviews written by Drs. Ayus and Moritz (7). Topf et al. (1) argue that ODS was found among patients whose initial serum sodium was between 120 and 129 mmol/L; the argument reveals another flaw: the study erroneously equated central pontine myelinolysis (CPM) with ODS. CPM has many causes—not just rapid correction of hyponatremia. The term “ODS” was introduced in 1986 (8) at a time when Ayus and others were recommending correction of severe hyponatremia by as much as 25 mmol/L within 12 hours (9). The purpose of the new term was to refocus attention away from the many causes of CPM to something that was occurring much too often in that era.
ODS describes a potentially crippling clinical syndrome of delayed neurological deterioration following rapid correction of severe, chronic hyponatremia. Patients with ODS do not always have CPM documented by imaging or autopsy (8), and patients with CPM do not always have ODS (10–12). The study by MacMillan et al. (5) looked for CPM in a population unlikely to have ODS; not surprisingly, the few cases found were unrelated to rapid correction of hyponatremia.
Citing a meta-analysis reporting a 3% ODS rate among patients with polydipsia (13), Topf et al. (1) also argue that their inclusion of patients with acute water intoxication did not minimize the true risk of ODS. However, all ODS cases in this meta-analysis either had chronic or unknown onset of hyponatremia. In contrast, a case series involving patients with psychosis and severe self-induced water intoxication (mean serum sodium of 110.9 ± 1.2 mmol/L) showed no neurological complications after correcting serum sodium by a mean of 21.6 ± 1.4 mmol/L per day (14).
Both letter writers (1, 2) cite evidence that slower correction of hyponatremia is associated with increased short-term mortality in critically ill patients (15). The association is unlikely to be causal. There is no evidence that hyponatremic fatalities were caused by inadequately treated cerebral edema (16). Series reporting deaths from herniation are based on litigation cases referred for an expert opinion (17). The true incidence of these catastrophes (which we all agree should be avoided) has been reported to be less common than CPM (18). It is implausible that a difference in correction rates of a few millimoles per liter was responsible for fatalities. It is far more likely that potentially fatal comorbidities affected correction rates (16). Rapid increases in the serum sodium concentration are usually caused by a spontaneous aquaresis in patients with easily reversible causes of hyponatremia who are free of an acute, life-threatening illness other than extremely low serum sodium concentrations. Hyponatremia corrects slowly in patients with shock, heart failure, acute kidney injury, advanced liver disease, and syndrome of inappropriate antidiuresis due to malignancies who cannot excrete dilute urine. In the study cited, the slow correction group consisted of nearly twice as many patients with heart and liver failure compared with the rapid correction group (15).
We do agree with the letter writers (1, 2) that a correction limit of 8 mmol/L per day is seldom necessary when the serum sodium concentration is higher than 120 mmol/L. At those levels, meticulous efforts to control the rate of correction are only needed in patients at heightened risk for ODS (e.g., alcohol use disorder, malnutrition, or advanced liver disease) and in patients with diabetes insipidus with desmopressin-induced hyponatremia who can rapidly become hypernatremic. We only wish that the study by MacMillan et al. (5) had limited its conclusion to that specific message.
Currently accepted therapeutic limits were proposed with the knowledge that limits are often inadvertently exceeded; they were meant to leave room for error (4). If adherence to those limits has made ODS much less common than it was when the disorder was first named (as demonstrated in some of the studies listed in the table provided in the letter by Moritz and Ayus [2]), that was the intent.
References
- 1.↑
Topf JM, et al. We should continually think about our approach to hyponatremia. Kidney News, August 2023; 15(8):20.
- 2.↑
Moritz ML, Ayus JC. Re-evaluating hyponatremia treatment guidelines: Rapid correction of severe hyponatremia is associated with improved outcomes without ODS. Kidney News, August 2023; 15(8):21–22.
- 3.↑
Rondon-Berrios H, Sterns RH. We do not need to rethink our approach to overcorrection of hyponatremia. Kidney News, May 2023; 15(5):14–15. https://www.kidneynews.org/view/journals/kidney-news/15/5/article-p14_6.xml
- 4.↑
Sterns RH, et al.; PRONATREOUS Investigators. Treatment guidelines for hyponatremia: Stay the course. Clin J Am Soc Nephrol (published online ahead of print June 28, 2023). doi: 10.2215/CJN.0000000000000244; https://journals.lww.com/cjasn/Abstract/9900/Treatment_Guidelines_for_Hyponatremia__Stay_the.180.aspx
- 5.↑
MacMillan TE, et al. Osmotic demyelination syndrome in patients hospitalized with hyponatremia. NEJM Evid 2023; 2:1–9. https://evidence.nejm.org/doi/full/10.1056/EVID-oa2200215
- 6.↑
Ayus JC, Moritz ML. Hyponatremia treatment guidelines—have they gone too far? NEJM Evid 2023; 2. doi: 10.1056/EVIDe2300014; https://evidence.nejm.org/doi/full/10.1056/EVIDe2300014
- 7.↑
Ayus JC, Moritz ML. Misconceptions and barriers to the use of hypertonic saline to treat hyponatremic encephalopathy. Front Med (Lausanne) 2019; 6:47. doi: 10.3389/fmed.2019.00047
- 8.↑
Sterns RH, et al. Osmotic demyelination syndrome following correction of hyponatremia. N Engl J Med 1986; 314:1535–1542. doi: 10.1056/NEJM198606123142402
- 9.↑
Ayus JC, et al. Rapid correction of severe hyponatremia with intravenous hypertonic saline solution. Am J Med 1982; 72:43–48. doi: 10.1016/0002-9343(82)90575-7
- 10.↑
Bergin PS, Harvey P. Wernicke's encephalopathy and central pontine myelinolysis associated with hyperemesis gravidarum. BMJ 1992; 305:517–518. doi: 10.1136/bmj.305.6852.517
- 11.
Chang Y, et al. Central pontine and extrapontine myelinolysis associated with acute hepatic dysfunction. Neurol Sci 2012; 33:673–676. doi: 10.1007/s10072-011-0838-3
- 12.↑
Chintagumpala MM, et al. Hodgkin's disease associated with central pontine myelinolysis. Med Pediatr Oncol 1993; 21:311–314. doi: 10.1002/mpo.2950210416
- 13.↑
Rangan GK, et al. Clinical characteristics and outcomes of hyponatraemia associated with oral water intake in adults: A systematic review. BMJ Open 2021; 11:e046539. doi: 10.1136/bmjopen-2020-046539
- 14.↑
Cheng JC, et al. Long-term neurologic outcome in psychogenic water drinkers with severe symptomatic hyponatremia: The effect of rapid correction. Am J Med 1990; 88:561–566. doi: 10.1016/0002-9343(90)90518-i
- 15.↑
Kinoshita T, et al. Effects of correction rate for severe hyponatremia in the intensive care unit on patient outcomes. J Crit Care (published online ahead of print May 13, 2023). doi: 10.1016/j.jcrc.2023.154325; https://www.sciencedirect.com/science/article/abs/pii/S0883944123000746?via%3Dihub
- 16.↑
Chawla A, et al. Mortality and serum sodium: Do patients die from or with hyponatremia? Clin J Am Soc Nephrol 2011; 6:960–965. doi: 10.2215/CJN.10101110
- 17.↑
Halperin ML. Postoperative hyponatremia. Neurology 1997; 48:548; author reply 548–549. doi: 10.1212/wnl.48.2.548
- 18.↑
Wijdicks EF, Larson TS. Absence of postoperative hyponatremia syndrome in young, healthy females. Ann Neurol 1994; 35:626–628. doi: 10.1002/ana.410350520
