Summary

Seven patients were hospitalised with dizziness and deteriorating general condition. Tests for serum electrolytes revealed marked hyponatraemia in these patients. Diuretics taken by these patients for treatment of hypertension were suspected to be the major cause of the hyponatraemia, although other factors might have contributed. All seven patients recovered with cessation of the diuretics and sodium chloride supplement. As diuretics are recommended as first-line therapy for hypertension and are commonly prescribed, we should be aware of this potentially life-threatening complication. Since hyponatraemia developed in our patients after a duration of treatment ranging from 2 days to 14 years, it is prudent to monitor serum electrolytes for patients on diuretic therapy, particularly during circumstances when patients have reduced salt intake or increased risk of electrolytes loss.

摘要

七 位 因 頭 暈 和 全 身 狀 況 差 而 入 院 的 病 例 ， 血 電 解 質 檢 查 顯 示 嚴 重 低 鈉 血 症 ， 雖 然 可 能 有 其 他 原 因 ， 但 最 大 可 能 還 是 因 服 用 抗 血 壓 藥 物 — 利 尿 劑 而 引 發 。 停 止 利 尿 劑 和 補 充 氯 化 鈉 後 ， 七 位 病 人 均 得 以 康 復 。 因 抗 利 尿 藥 是 推 介 抗 高 血 壓 的 第 一 線 藥 物 ， 廣 泛 被 採 用 ， 我 們 要 警 惕 這 個 潛 在 的 致 命 的 併 發 症 。 低 鈉 血 症 可 發 生 在 病 人 服 用 利 尿 素 短 至 兩 日 ， 長 至 十 四 年 後 ， 尤 其 是 在 病 人 少 吃 鹽 和 有 增 加 電 解 質 流 失 的 風 險 情 況 下 ， 監 測 這 些 病 人 的 血 清 電 解 質 是 審 慎 而 精 明 的 做 法 。

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Introduction

Hypertension is an increasingly common problem in affluent societies like Hong Kong, particularly among the elderly with a reported prevalence rate of up to 60-80%.¹ Diuretics are recommended as a first-line therapy for hypertension, especially in the elderly.² Unfortunately, electrolyte imbalance due to diuretics is not uncommon and sometimes may be life-threatening. Patients suffering from severe diuretic-induced hyponatraemia have been reported locally³ and in western world.⁴ The simple daily dosage of most diuretics as anti-hypertensives and their wide availability in primary care clinics make them a commonly prescribed drug for hypertension. Indeed, in a study by Chang et al,⁵ thiazide diuretics including indapamide were commonly used as monotherapy for hypertension in specialist and general out-patient clinics. In a review by Sonnenblick,⁶ thiazides were responsible for severe diuretic-induced hyponatraemia in 94 percent of 129 case reports in literature between 1962 and 1990. We report on seven patients who presented with dizziness secondary to diuretic-induced severe hyponatraemia over a five-month period from June to November 2000.

Case 1

A 73 years old gentleman presented to the out-patient clinic in June 2000, with one-week history of dizziness and repeated vomiting not responding to treatment by a general practitioner. He had been hypertensive on indapamide 2.5mg daily for 14 years. On admission, the serum sodium level was 108mmol/L (normal range, 136-145mmol/L), and the serum potassium level was 2.8mmol/L (normal range, 3.5-5.1mmol/L). The serum and urine osmolality were 231mOsm/L (normal range, 280-300mOsm/L) and 454mOsm/L (normal range, 50-1200mOsm/L), respectively. The urine sodium concentration was 53mmol/L, suggesting inappropriate renal loss of sodium in the presence of diuretic despite a total body deficit. The indapamide was stopped and normal saline infusion and potassium chloride were given for replacement. The patient recovered with normalisation of serum sodium level after twelve days.

Case 2

An 85 years old gentleman was admitted for poor oral intake and deteriorating general condition in June 2000. He had been diagnosed to have hypertension and put on indapamide 2.5mg daily in a government general out-patient department (GOPD), one week before admission. Tests for blood biochemistry showed hyponatraemia of 110mmol/L and hypokalaemia of 2.0mmol/L. The serum and urine osmolality were 251mOsm/L and 371mOsm/L, respectively. The indapamide was stopped and sodium and potassium replacement was commenced. The serum sodium level was normalised after six days, together with patient recovery.

Case 3

A 75 years old gentleman was admitted due to exacerbation of chronic obstructive airway disease (COAD) in July 2000. The serum sodium and potassium levels were normal on admission. As his blood pressure was persistently above 190/100, he was put on Moduretic one tablet daily, which contained 50mg of hydrochlorothiazide and 5mg of amiloride. Two days later, the patient was found to be confused but with no focal neurological signs. Investigation showed that his serum sodium level had dropped to 109mmol/L and the serum potassium level had risen to 5.4mmol/L. The urinary sodium concentration was 202mmol/L, suggesting urinary loss of sodium. The serum osmolality was 243mOsm/L and the urine osmolality was 623mOsm/L. The test for thyroid stimulating hormone (TSH) was within normal range, thus excluding hypothyroidism. The sudden deterioration was considered to be secondary to moduretic-induced hyponatraemia. The patient recovered completely with cessation of the moduretic and four days of sodium chloride replacement, which normalised the serum sodium level.

Case 4

A 59 years old lady complained of dizziness for few days and was admitted into our Unit in September 2000. She had been treated for major depressive disorder in a psychiatric ward of another hospital and was discharged one week before. On top of the newly prescribed fluoxetine and nitrazepine from the psychiatrist, she was taking indapamide 2.5mg daily for hypertension diagnosed in a GOPD two weeks prior to the psychiatric admission. Tests for blood chemistry showed hyponatraemia of 110mmol/L and hypokalaemia of 2.6mmol/L. The serum and urine osmolality were 232mOsm/L and 151mOsm/L, respectively, but the renal sodium excretion was still high with the urine sodium concentration of 55mmol/L. In view of the psychiatric history and hyponatraemia, the serum TSH level was checked to rule out hypothyroidism, it was normal. The indapamide was stopped and sodium was replaced. Psychiatric drugs were withheld in view of the possibility of hyponatraemia causing her emotional disturbance. Unfortunately, despite normalisation of serum sodium level within six days, the patient still exhibited hallucination and delusional ideas, albeit to a lesser extent, she was subsequently transferred to a psychiatric hospital.

Case 5

A 75 years old gentleman was referred to our Hospital after unsuccessful treatment of nausea and vomiting by a private practitioner in September 2000. He also complained of bilateral lower limb weakness and dizziness. Serum biochemistry showed a sodium level of 100mmol/L and potassium level of 4.0mmol/L, with concomitant renal loss of sodium as reflected by a urinary sodium concentration of 103mmol/L. The serum osmolality and urine osmolality were 219mOsm/L and 385mOsm/L, respectively. As the patient was noted to have been recently put on indapamide slow-release (Natrilix SR 1.5mg) once daily for hypertension for one week, the medication was stopped. The patient recovered after sodium replacement for six days, which normalised the serum sodium level.

Case 6

An 85 years old lady presented with one-week history of dizziness and repeated vomiting to the Our Lady of Maryknoll Hospital in September 2000. The first serum sodium level was 113mmol/L and the serum potassium level was 2.8mmol/L and this was thought to be the cause of the dizziness. The urine sodium concentration was 92mmol/L, reflecting the lack of appropriate renal sodium conservation. The plasma and urine osmolality were 251mOsm/L and 437mOsm/L, respectively. As she was taking indapamide 2.5mg once daily for hypertension diagnosed two weeks before in a GOPD, which was likely to be the cause of hyponatraemia, the drug was stopped and the patient recovered after four days of sodium replacement.

Case 7

An 85 years old lady was admitted in October 2000 with a complaint of nausea and vomiting for one day. She had been started on Moduretic once daily for treatment of hypertension 5 days before admission. Her serum sodium level was noted to be 112mmol/L and potassium level was 4.2mmol/L on admission, with a urinary sodium concentration of 107mmol/L. The Moduretic was stopped and sodium replacement was commenced. She recovered after four days of sodium replacement, which normalised the serum sodium level.

Discussion

Our patients were mainly elderly with a mean age of 76.7, five out of seven were 75 years of age or older. The male to female ratio was 4:3 and their mean serum sodium level on presentation was 109mmol/L. The two patients mentioned in Chan's report³ were also elderly of 60 and 62 years of age, with indapamide induced hyponatraemia down to the levels of 104 and 103mmol/L, respectively. Ashouri reported eight patients with severe diuretic-induced hyponatraemia (mean sodium level 110mmol/L) in the elderly⁴ and noted that low body weight was an important cause of hyponatraemia. However, the mean body weight in our patients was 50.5kg, which is average amongst Chinese elderly.

Diuretic use was unlikely to be the only factor, as the first patient had been treated with indapamide for fourteen years without any problem. Concomitant illnesses resulting in reduced salt intake or increased sodium loss through repeated vomiting might have been a significant contributing factor. Indeed, five out of the seven patients did have similar complaints on admission (Table 1). Of course, hyponatraemia and repeat vomiting could either be the cause or the consequence. However, the fact that six out of the seven patients had been on diuretics for not more than two weeks and that the fifth patient had only been on the medication for two days yet developed hyponatraemia with serum sodium down to 100 mmol/L, points towards diuretic use as a major contributory factor. This is further supported by the normalisation of sodium levels by simple sodium supplement and IV fluid replacement.

Table 1: Demographic data of patients
Patient	Sex	Age	Duration of diuretic use	Culprit drug	Lowest sodium (mmol/L)	Lowest potassium (mmol/L)	Vomiting as symptom
Case 1	M	73	14 years	Indapamide 2.5mg	108	2.8	Yes
Case 2	M	84	1 week	Indapamide 2.5mg	110	2.0	Yes
Case 3	M	75	2 days	Moduretic	109	5.4	No
Case 4	F	59	2 weeks	Indapamide 2.5mg	110	2.6	No
Case 5	M	75	1 week	Indapamide slow-release 1.5 mg	100	4.0	Yes
Case 6	F	85	2 weeks	Indapamide 2.5mg	113	2.8	Yes
Case 7	F	85	5 days	Moduretic	112	4.2	Yes

The triad of low serum osmolality, inappropriately high urine osmolality and high urinary sodium concentration in our patients was also compatible with the diagnosis of the syndrome of inappropriate secretion of anti-diuretic hormone (SIADH). However, diuretic intake could result in salt wasting and the same pattern of serum and urine chemistry. In practice, the diagnosis of SIADH could not be made if there was a history of diuretic intake. Moreover, all patients except the third patient had no identifiable condition that might predispose them to SIADH. Indeed, all except the third patients' chest x-ray did not reveal any active lung lesion. The classical management for patients suffering from SIADH is fluid restriction. Instead, all our patients responded promptly to volume repletion with normal saline infusion, with normalisation of serum sodium, in contrast to the typical poor response amongst patients suffering from SIADH. However, Friedman⁷ in his prospective trial of re-challenging patients who had history of thiazide induced hyponatraemia, found that these patients re-developed hyponatraemia. They also had weight gain as compared with weight loss in controls who did not develop hyponatraemia with challenge of single dose thiazide. This suggested that the hyponatraemia might result from a combination of loss of body sodium and dilution by increased body water.

Severe hypothyroidism is another possible cause for hyponatraemia,⁸ as a result of inability to excrete water load in the absence of adequate thyroid hormone. Although only the second and third patients had been screened with serum TSH level, none of our patients had any signs suggestive of hypothyroidism. More importantly, all of our patients responded to sodium repletion without any thyroid hormone replacement.

Hypertensive elderly patients have twice the risk of cardiovascular complications as compared with younger patients.⁹ Well-designed large scale randomised trials have established the benefit of treating elderly patients suffering from both systolic and diastolic hypertension.^9-15 The latest recommendation of both the World Health Organisation and the Joint National Committee on Detection, Evaluation, and Diagnosis of High Blood Pressure of United States recommended diuretics and beta-blockers as the first-line medications.^2,16 Diuretics have been used for over 30 years and are well tolerated with proven efficacy in reduction of cardiovascular and cerebrovascular morbidity. Thiazide diuretics are the most commonly used group.¹⁷ Biochemical derangements are the major side effects of this class of drug, which generally correlate with the dosage. However the blood pressure dose response curve is relatively flat.¹⁸ In fact, Moduretic contains a relatively high dose of hydrochloro-thiazide (50mg), which was responsible for the hyponatraemia in the second and seventh patients. A recent trend and recommendation has been the use of low dose diuretic as monotherapy. Another class of drug can be added if optimal blood pressure cannot be achieved, instead of increasing the dosage of diuretics.^19,20 However, the use of Natrilix SR, which contains only 1.5mg of indapamide, still caused hyponatraemia in the fifth patient. Indeed, Chan et al reported a drug 'Adelphane-Esidrex' as the cause of hyponatraemia and hypokalaemia in an 89 years old lady,²¹ with the serum sodium and potassium levels down to 121mmol/L and 2.5mmol/L, respectively. The drug contains only 10mg of hydrochlorothiazide, on top of 0.1mg of reserpine and 10mg of dihydralazine.

Although five out of our seven patients developed hyponatraemia secondary to indapamide as compared with hydrochlorothiazide in the other two, it may just be related to the fact that indapamide was more commonly used, particularly in GOPD.⁵ In fact, the elegant re-challenge trial of Freidman⁶ with just single dose thiazide on patients with history of thiazide induced hyponatraemia suggested idiosyncrasy in individual susceptible patients as the major reason for the adverse reaction.

Besides thiazide diuretics, both loop diuretic and potassium-sparing diuretic can induce electrolyte disturbances. Severe electrolyte imbalance associated with either of these is, however, seldom reported.⁷ One major reason is probably the short duration of loop diuretic, which actually renders them unsuitable for treatment of hypertension. In addition, side effects, including potential hyperkalaemia, mean that potassium-sparing diuretic are rarely used alone for treatment of hypertension.

In light of the time-honoured proven efficacy and tolerability, low cost, and general availability in the GOPD, diuretics remain a good choice for treating hypertension, especially in the elderly. Nevertheless, the patients should be advised to withhold diuretic treatment temporarily and seek medical advice if they develop vomiting or diarrhoea. Serum electrolytes should be monitored, particularly if they present with reduced salt intake, vomiting or altered sensorium, with institution of appropriate treatment measures for diuretic-induced hyponatraemia.

Key messages

1. Diuretics are commonly used for treating hypertension, particularly in elderly patients in primary care settings.
2. They have proven effectiveness and good safety record over a number of years.
3. Life-threatening electrolyte disturbances secondary to diuretics are rare but possible given their frequency of prescription.
4. Physicians' continuous alertness and prompt action, if suspicious, are warranted.
5. Electrolyte monitoring after initiation, periodically afterwards and additional checking during inter-current illness will ensure that patients gain maximal benefit from the therapy without serious adverse reactions.

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References