The PSNet Collection. Patient Safety Training and Education. Improvement Resources. About PSNet. All Content. Current Weekly Issue. Past Weekly Issues. Curated Libraries. The Fundamentals. Continuing Education. Training Catalog. Editorial Team. Technical Expert Panel. Copy URL. Take the Quiz. Case Objectives Recognize that thiazide diuretics can lead to serious adverse events. State how commonly used thiazide diuretics can contribute to hyponatremia.
Discuss risk factors that predispose to the development of thiazide-induced hyponatremia. List other common adverse effects of thiazide diuretics. Describe precautionary measures that may reduce the risks associated with thiazide diuretics. The Case A year-old woman with morbid obesity and a past medical history of chronic obstructive pulmonary disease, hypertension, heart failure with preserved ejection fraction, diabetes mellitus, and a previous hospitalization for hyponatremia was seen by her primary care provider for a routine visit.
The Commentary by Tobias Dreischulte, MPharm, MSc, PhD This case illustrates how a commonly used medicine can lead to severe adverse events when not used judiciously and cautiously, especially in vulnerable patients. Take-Home Points Despite being widely used and recommended by guidelines, thiazide diuretics are a class of medicines that may cause severe harm if used inappropriately. The main adverse effects of thiazides include hyponatremia, hypokalemia, hypomagnesemia, and hypercalcemia.
Thiazide-induced hyponatremia is an often underestimated risk that requires proactive management by clinicians and patients.
A number of readily identifiable risk factors may predispose patients to thiazide-induced hyponatremia, and these should trigger precautionary measures. These measures include using low starting doses and intensified monitoring around the time of treatment initiation.
References 1. Department of Health and Human Services. Readers should not interpret any statement in this report as an official position of AHRQ or of the U. None of the authors has any affiliation or financial involvement that conflicts with the material presented in this report.
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Edit your case as a draft. Your name will not be publicly associated with the case. Already have a PSNet Account? Track and save your case in My Cases. Get email alerts when new content matching your topics of interest publishes. Increasing salt intake may worsen HTN, and a change in dietary habits decreasing water intake and increasing protein intake is difficult to implement for the elderly individual.
Overall, TD-induced hyponatremia is a significant clinical problem among elderly hypertensives which prohibits their use in a significant proportion at best and may have serious adverse outcomes if not recognized or treated in a worst case scenario.
Knowing the pathophysiology of TD-induced hyponatremia in elderly HTN patients, there is a case for a proof-of-concept clinical trial to test a unique, simple to understand and administer, and relatively affordable approach to rectify this adverse event.
Provision of a concentrated dietary supplement which is high in protein should increase free water excretion by the kidneys by providing an increased solute load in the form of urea, the metabolic end product of protein catabolism. This approach should result in the slow correction of TD-induced hyponatremia. Direct ingestion of urea itself has been used and reported to result in an increase of serum sodium levels on the basis of uncontrolled case series [ 9 , 10 ].
Unfortunately, its bitter taste limits its long-term use, which protein supplements could potentially overcome. There are no prospective trials on the use of protein supplementation nor any data on the possible estimate of benefit of protein supplementation for mild TD-induced hyponatremia. Before embarking on a definitive trial, we describe here the protocol for a proof-of-concept feasibility trial. This trial would establish the feasibility of enrolling participants with this condition, as well as provide pilot estimates about safety and potential efficacy which would be needed to design the larger prospective trial.
The study design is an open-label, single-arm, prospective clinical trial see Fig. In this proof-of-concept study, we will assess feasibility, safety, and potential efficacy of an intervention of standardized dietary supplement of a bottle mL of protein supplement Nepro, Abbott Inc. A total of 40 consecutive patients with TD-induced hyponatremia over the period of 12—18 months will be recruited for this study from the Renal HTN clinic at the Ottawa Hospital.
This clinic has about patients with hypertension, and TDs are among the most common drug class used. With diagnosed HTN treated with thiazide hydrochlorothiazide or thiazide-like chlorthalidone and indapamide diuretic.
Other causes of hyponatremia liver cirrhosis, uncontrolled hypothyroidism, adrenal insufficiency. Patients with generalized volume overload who may require immediate changes in diuretic therapy at the discretion of treating HTN specialist. Patients taking drugs which may interfere with urinary sodium excretion such as carbamazepine, loop diuretics, potassium sparing diuretics, mineralo- and glucocorticosteroids, selective serotonin receptor inhibitors, tricyclic antidepressants, amiodarone, and lithium.
This is based on the following calculations: mL bottle of Nepro contains 19 g of protein which will generate mmol of urea, mg of sodium equals to 11 mmol, mg of potassium equals to 6 mmol, and 3 mmol of calcium for a total of mosmol compare with mosmol with 15 g of urea given every day. Thus, in theory, over the period of 2 to 4 weeks, the calculated free water excess should be completely eliminated in most patients.
There is no prior empiric data about the possible efficacy of this intervention. Hence, we have designed this as a proof-of-concept study. The primary outcomes of the study will be threefold 1 feasibility and 2 safety, in terms of compliance and loss to follow-up and 3 potential efficacy. For feasibility, we will examine the number of patients who are eligible and the proportion of those eligible who actually consent for the study.
For safety, we will examine the proportion of patients who tolerate the Nepro supplement for the duration of the study and who are able to comply with the daily supplementation for the period of study. Secondary outcomes will include changes in urine osmolality, urine sodium, urea, and potassium excretions and plasma potassium, urea, office blood pressure, and body weight.
Plasma sodium, potassium, urea, creatinine, osmolality, and urinary counterparts from h urine collection will be assessed at baseline and at 4 weeks post dietary intervention, which will serve to provide estimates of potential efficacy. Office blood pressure will be evaluated at same time points. All patients will be informed that they can withdraw from the study at any time. Patients who agree to participate to the study will provide a written informed consent.
The study is a proof-of-concept trial, with no prior known efficacy estimates of the intervention. Hence, though no formal sample size estimation is possible, data from this trial will help us to estimate the definitive large trial. A definitive trial in this area will be a randomized controlled trial RCT comparing protein supplementation as described in this project with standard of care.
The data from the present project with respect to the rate of recruitment will allow a decision on whether this RCT is feasible. We will apply the following specific criteria to make the decision that a definitive trial is worth pursuing, depending on funding. Lastly, the recruitment rate will help determine the number of sites and length of recruitment period for a definitive trial.
A trial management group involving the principal investigators MR, SH , two co-investigators BM, PM , and a study coordinator will review, implement, and supervise all aspects of this pilot trial. The study coordinator, under the supervision of the principal investigators SH, MR , will be responsible for receiving, processing, editing, and storing and all the data. All investigational product supplies in the study will be stored in a secure, safe place, under the responsibility of the investigator.
The statistical analysis will be conducted by the investigators SH and TR. The results will be disseminated via conferences and publication in an open access publication and the trial registry; decision for publication lies with the investigators.
This is a new approach to identify and test potentially effective method for treatment of TD-induced hyponatremia in elderly hypertensive patients. If successful, this approach will be tested in a large RCT.
This treatment would be easily available to family physicians and would reduce number of consults referred to HTN Clinics. A negative study outcome also has significant implications for health care delivery and use of resources. A definitive trial on this topic would compare the protein supplement strategy to the current standard of care fluid restriction, advice to increase protein intake , with thiazide withdrawal as rescue for severe or intractable cases.
Such an RCT would require a sample size of over patients under the assumptions described in the methods, and the current project will demonstrate the feasibility of doing such a definitive RCT.
The study design has certain limitations. Given its pilot feasibility design, it will be inherently underpowered to demonstrate any efficacy; however, the purpose is that the potential efficacy data will allow planning of an appropriately powered trial.
Secondly, the intervention might be unsuccessful in increasing sodium levels for a few reasons. This may result in either an increase without normalizing sodium levels or a longer time to increase sodium levels back to normal. However, there are no human studies evaluating the chronic effect of mild protein loading leading to extra urea generation on mild chronic hyponatremia.
Additionally, it is possible that participants might concomitantly also increase water intake, which may negate any effect of the intervention, which we will capture by measurement of h urinary volumes at baseline and end of study.
Lastly, any efficacy data based on change from baseline will be susceptible to regression to the mean given the single-arm study and will be interpreted with caution. This trial has received grant funding from the Ottawa Hospital Academic Medical Organization and obtained approval from the institutional review board the Ottawa Health Sciences Research Ethics Board , and recruitment began in December and is still ongoing. Diagnosed hypertension in Canada: incidence, prevalence and associated mortality.
Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. JAMA , 24 Treatment of hypertension in patients 80 years of age or older. N Engl J Med. Systolic hypertension in China Syst-China collaborative group. J Hypertens , 16 12 Pt 1 Lancet , Thiazide-induced hyponatremia.
Electrolyte Blood Press. Risk of thiazide-induced hyponatremia in patients with hypertension. Am J Med. Mann SJ. The silent epidemic of thiazide-induced hyponatremia. J Clin Hypertens Greenwich. Urea for hyponatremia? Kidney Int. Article PubMed Google Scholar. Treatment of the syndrome of inappropriate secretion of antidiuretic hormone with urea in critically ill patients.
Am J Nephrol. Thiazide-associated hyponatremia, report of the hyponatremia registry: an observational multicenter international study. Pilot Feasibility Stud. Download references. The trial has received peer-reviewed competitive funding from the Ottawa Hospital Academic Medical Organization.
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