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Does Long-Term Furosemide Therapy Cause Thiamine Deficiency in Patients with Heart Failure? A Focused Review

Published:February 17, 2016DOI:https://doi.org/10.1016/j.amjmed.2016.01.037

      Abstract

      Diuretic therapy is a cornerstone in the management of heart failure. Most studies assessing body thiamine status have reported variable degrees of thiamine deficiency in patients with heart failure, particularly those treated chronically with high doses of furosemide. Thiamine deficiency in patients with heart failure seems predominantly to be due to increased urine volume and urinary flow rate. There is also evidence that furosemide may directly inhibit thiamine uptake at the cellular level. Limited data suggest that thiamine supplementation is capable of increasing left ventricular ejection fraction and improving functional capacity in patients with heart failure and a reduced left ventricular ejection fraction who were treated with diuretics (predominantly furosemide). Therefore, it may be reasonable to provide such patients with thiamine supplementation during heart failure exacerbations.

      Keywords

      Clinical Significance
      • Thiamine deficiency has been demonstrated to contribute to the development of heart failure.
      • Loop diuretics commonly are used to treat heart failure.
      • Furosemide therapy has been shown to produce thiamine deficiency.
      • Thiamine supplementation may increase left ventricular ejection fraction and improve function capacity in patients with systolic heart failure.
      Heart failure is an important public health problem affecting more than 5 million persons in the United States and 23 million individuals worldwide.
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      Diuretics commonly are used to reduce dyspnea and peripheral edema in both acute and chronic heart failure. Furosemide is the most frequently prescribed loop diuretic. Common side effects of furosemide therapy include hypovolemia and electrolyte depletion. Multiple studies have suggested that long-term furosemide therapy also may cause thiamine (vitamin B1) deficiency, although the exact mechanism remains unclear.
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      Urinary loss of thiamine is increased by low doses of furosemide in healthy volunteers.
      • Seligmann H.
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      • et al.
      Thiamine deficiency in patients with congestive heart failure receiving long-term furosemide therapy: a pilot study.
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      Furosemide-induced thiamine deficiency.
      • Zenuk C.
      • Healey J.
      • Donnelly J.
      • Vaillancourt R.
      • Almaki Y.
      • Smith S.
      Thiamine deficiency in congestive heart failure patients receiving long term furosemide therapy.
      Thiamine deficiency has been known to cause a clinical cardiac syndrome known as “wet beriberi.” Wet beriberi is a high cardiac output form of heart failure characterized by tachycardia, dyspnea, and peripheral edema.
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      Cardiac beriberi: two modes of presentation.
      In its severe form, thiamine deficiency can cause fulminant heart failure termed “shoshin beriberi,” with signs of cardiovascular collapse, metabolic acidosis, and severe hemodynamic instability.
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      Fulminant beriberi heart disease with lactic acidosis: presentation of a case with evaluation of left ventricular function and review of pathophysiologic mechanisms.
      In the absence of urgent treatment with intravenous thiamine, death may ensue.
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      Thiamine supplementation for treatment of heart failure. A review of the literature.
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      • Jones M.R.
      • McCallister R.G.
      Fulminant beriberi heart disease with lactic acidosis: presentation of a case with evaluation of left ventricular function and review of pathophysiologic mechanisms.
      It is important for physicians to be aware that furosemide may cause thiamine deficiency and potentially cause worsening of preexistent heart failure.
      The major dietary sources of thiamine are unprocessed rice, wheat germ, cereal grains, nuts, seeds, liver, beef, pork, poultry, fish, orange juice, and tomato juice.
      • DiNicolantonio J.J.
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      Thiamine supplementation for treatment of heart failure. A review of the literature.
      • Gubler J.C.
      Thiamine.
      • Suter P.M.
      • Vetter W.
      Diuretics and vitamin B1. Are diuretics a risk factor for thiamin malnutrition?.
      In contrast, dairy products, fruits, and most vegetables are low in thiamine content.
      • DiNicolantonio J.J.
      • Niazi A.K.
      • Lavie C.J.
      • O'Keefe J.H.
      • Ventura H.O.
      Thiamine supplementation for treatment of heart failure. A review of the literature.
      • Gubler J.C.
      Thiamine.
      • Suter P.M.
      • Vetter W.
      Diuretics and vitamin B1. Are diuretics a risk factor for thiamin malnutrition?.
      Animals are prone to thiamine deficiency because they do not synthesize or store a sufficient amount of thiamine and therefore are dependent on regular dietary intake.
      • DiNicolantonio J.J.
      • Niazi A.K.
      • Lavie C.J.
      • O'Keefe J.H.
      • Ventura H.O.
      Thiamine supplementation for treatment of heart failure. A review of the literature.
      • Suter P.M.
      • Vetter W.
      Diuretics and vitamin B1. Are diuretics a risk factor for thiamin malnutrition?.
      According to the 1980 Committee on Dietary Allowance, Food, and Nutrition Board, the recommended daily allowance of thiamine for adults aged ≥19 years is 1.2 mg per day for men and 1.0 mg per day for women.
      • Anderson S.H.
      • Vickery C.A.
      • Nicot A.D.
      Adult thiamine requirements and continuing need fortify processed cereates.
      Thiamine deficiency clearly is an important health care problem in underdeveloped countries. However, it is not uncommon to encounter thiamine deficiency in developed countries. According to the Boston Nutritional States Survey, 15% of an elderly population who did not receive thiamine supplements had low thiamine levels.
      • Sadowski J.A.
      Riboflavin.
      Institutionalization and poverty have been associated with poor thiamine intake in the elderly.
      • Bianchetti A.
      • Rozzini R.
      • Carabellese C.
      • Zanetti O.
      • Trabucchi M.
      Nutritional intake, socioeconomic conditions, and health status in a large elderly population.
      • O'Rourke N.P.
      • Bunker V.W.
      • Thomas A.J.
      • Finglas P.M.
      • Bailey A.L.
      • Clayton B.E.
      Thiamine status of healthy and institutionalized elderly subjects: analysis of dietary intake and biochemical indices.
      Other independent risk factors for thiamine deficiency include excessive alcohol intake, malabsorption and eating disorders, various catabolic diseases, trauma, surgery, prolonged nausea and vomiting, and frequent use of processed foods.
      • DiNicolantonio J.J.
      • Niazi A.K.
      • Lavie C.J.
      • O'Keefe J.H.
      • Ventura H.O.
      Thiamine supplementation for treatment of heart failure. A review of the literature.
      • Gubler J.C.
      Thiamine.
      • Bianchetti A.
      • Rozzini R.
      • Carabellese C.
      • Zanetti O.
      • Trabucchi M.
      Nutritional intake, socioeconomic conditions, and health status in a large elderly population.
      • O'Rourke N.P.
      • Bunker V.W.
      • Thomas A.J.
      • Finglas P.M.
      • Bailey A.L.
      • Clayton B.E.
      Thiamine status of healthy and institutionalized elderly subjects: analysis of dietary intake and biochemical indices.
      A variety of drugs have been associated with thiamine deficiency, including antibiotics (penicillins, cephalosporins, fluoroquinolones, tetracyclines, sulfa-containing drugs, aminoglycoside) and phenytoin.
      • DiNicolantonio J.J.
      • Niazi A.K.
      • Lavie C.J.
      • O'Keefe J.H.
      • Ventura H.O.
      Thiamine supplementation for treatment of heart failure. A review of the literature.
      As a water-soluble vitamin, thiamine is excreted in the urine. Thus, it is not surprising that multiple studies have suggested that diuretics may facilitate thiamine deficiency.
      • DiNicolantonio J.J.
      • Niazi A.K.
      • Lavie C.J.
      • O'Keefe J.H.
      • Ventura H.O.
      Thiamine supplementation for treatment of heart failure. A review of the literature.
      • Rieck J.
      • Halkin H.
      • Almog S.
      • et al.
      Urinary loss of thiamine is increased by low doses of furosemide in healthy volunteers.
      • Seligmann H.
      • Halkin H.
      • Rauchfleisch S.
      • et al.
      Thiamine deficiency in patients with congestive heart failure receiving long-term furosemide therapy: a pilot study.
      • Yui Y.
      • Itokawa Y.
      • Kawai C.
      Furosemide-induced thiamine deficiency.
      • Zenuk C.
      • Healey J.
      • Donnelly J.
      • Vaillancourt R.
      • Almaki Y.
      • Smith S.
      Thiamine deficiency in congestive heart failure patients receiving long term furosemide therapy.
      • Suter P.M.
      • Vetter W.
      Diuretics and vitamin B1. Are diuretics a risk factor for thiamin malnutrition?.
      Because diuretics, and in particular the loop diuretic furosemide, represent the cornerstone of pharmacotherapy of heart failure, it has been postulated that their long-term use may cause thiamine deficiency, thereby reducing ventricular function with a subsequent worsening of heart failure symptoms and signs. Indeed, various studies have reported the prevalence of thiamine deficiency in patients with heart failure to range from 0% to 98%.
      • DiNicolantonio J.J.
      • Niazi A.K.
      • Lavie C.J.
      • O'Keefe J.H.
      • Ventura H.O.
      Thiamine supplementation for treatment of heart failure. A review of the literature.
      The wide variation in prevalence values may reflect variability in age, risk factors, dietary intake, and severity of heart failure.
      This is a focused review of the interrelationship of furosemide use, thiamine deficiency, and heart failure. We discuss the pathophysiology and biochemistry of thiamine deficiency as they relate to heart failure in patients receiving furosemide therapy, describe the results of clinical and experimental studies that address the relation of furosemide therapy and thiamine deficiency, and provide recommendations concerning the role of thiamine in the prevention and management of heart failure in patients receiving furosemide therapy. This focused review used a MEDLINE search using the terms “thiamine deficiency,” “furosemide,” and “heart failure” to identify relevant articles from the past 25 years. A total of 24 articles were identified that met the search criteria.

      Biochemical Considerations

      Thiamine is a water-soluble vitamin that is present in the body in an unphosphorylated form and as a monophosphate, diphosphate, and triphosphate. Thiamine plays a vital role in numerous cellular functions. The most important of those related to the heart involve thiamine diphosphate, also known as “thiamine pyrophosphate.” In the pentose phosphate pathway, thiamine pyrophosphate serves as a coenzyme to transketolase, facilitating the conversion of glucose-6-phosphate to ribose-5-phosphate, which in turn contributes to nucleic acid synthesis. In the citric acid (Kreb's) cycle, thiamine pyrophosphate serves as a coenzyme to the pyruvate dehydrogenase complex in the conversion of pyruvate to acetyl coenzyme A and then to alpha-ketoglutarate. Thiamine pyrophosphate also serves as a coenzyme to alpha-ketoglutarate dehydrogenase in the conversion of alpha-ketoglutarate to succinate, which facilitates adenosine triphosphate production.

      Quantifying Body Thiamine Status

      Various laboratory tests are available to quantify body thiamine status. These include tests that directly measure thiamine levels in the serum, plasma, and urine, as well as high-performance liquid chromatography.
      • DiNicolantonio J.J.
      • Niazi A.K.
      • Lavie C.J.
      • O'Keefe J.H.
      • Ventura H.O.
      Thiamine supplementation for treatment of heart failure. A review of the literature.
      Other laboratory tests provide an indirect estimation of thiamine status, including the thiamine pyrophosphate effect. The thiamine pyrophosphate effect measures erythrocyte ketolase activity when thiamine diphosphate is added to serum in vitro.
      • DiNicolantonio J.J.
      • Niazi A.K.
      • Lavie C.J.
      • O'Keefe J.H.
      • Ventura H.O.
      Thiamine supplementation for treatment of heart failure. A review of the literature.
      • Brian M.
      Thiamine deficiency and erythrocyte metabolism.
      This is an actual representation of tissue thiamine level. Measurement of thiamine pyrophosphate effect is widely available.
      • DiNicolantonio J.J.
      • Niazi A.K.
      • Lavie C.J.
      • O'Keefe J.H.
      • Ventura H.O.
      Thiamine supplementation for treatment of heart failure. A review of the literature.
      • Doolman R.
      • Dinbar A.
      • Sela B.A.
      Imposed measurement of transketolase activity in the assessment of “TPP effect”.
      Thiamine pyrophosphate effect >15% suggests that thiamine deficiency is present, and thiamine pyrophosphate effect >25% suggests that severe thiamine deficiency is present.
      • Lubetsky A.
      • Winaver J.
      • Seligmann H.
      • et al.
      Urinary thiamine excretion in the rat: effects of furosemide, other diuretics, and volume load.
      The urine thiamine level provides information about the adequacy of thiamine intake, but does not quantify tissue thiamine stores.
      • Lubetsky A.
      • Winaver J.
      • Seligmann H.
      • et al.
      Urinary thiamine excretion in the rat: effects of furosemide, other diuretics, and volume load.
      The plasma or serum thiamine level does not accurately represent body thiamine status because it contains only a fraction of total body thiamine.
      • Lubetsky A.
      • Winaver J.
      • Seligmann H.
      • et al.
      Urinary thiamine excretion in the rat: effects of furosemide, other diuretics, and volume load.

      Effect of Furosemide on Body Thiamine Status

      In 1980, Yui et al
      • Yui Y.
      • Itokawa Y.
      • Kawai C.
      Furosemide-induced thiamine deficiency.
      reported that thiamine deficiency may result from a long-term decrease in transketolase activity and serum thiamine levels, and a surge in thiamine pyrophosphate effect in rats treated with intraperitoneal administration of furosemide for 4 weeks.
      A study reported by Seligmann et al
      • Seligmann H.
      • Halkin H.
      • Rauchfleisch S.
      • et al.
      Thiamine deficiency in patients with congestive heart failure receiving long-term furosemide therapy: a pilot study.
      in 1991 suggested that urinary loss of thiamine may be the main cause for thiamine deficiency related to chronic diuretic therapy in patients with heart failure. Twenty-three patients with heart failure who were treated with furosemide (80-240 mg per day) for 3 to 14 months were found to have thiamine deficiency compared with 16 individuals who did not have heart failure and did not receive furosemide. There was a significantly higher mean thiamine pyrophosphate effect in the furosemide-treated group compared with a control group (27.7% ± 2.5% vs 7.1% ± 1.6%, P < .001). Despite lower plasma thiamine levels, the urine thiamine levels were inappropriately elevated in furosemide-treated patients (410 ± 95 μg/g of creatinine), which was approximately twice that of the control group (236 ± 69 μg/g of creatinine). These findings suggest that furosemide may increase urinary thiamine excretion, resulting in a decrease in plasma thiamine levels.
      • Rieck J.
      • Halkin H.
      • Almog S.
      • et al.
      Urinary loss of thiamine is increased by low doses of furosemide in healthy volunteers.
      It was unclear whether this was the result of a direct effect of furosemide or of increased urine volume.
      Other studies have suggested that sustained diuresis may contribute to thiamine deficiency via urinary losses irrespective of the type of intervention. In a 1999 study, Rieck et al
      • Rieck J.
      • Halkin H.
      • Almog S.
      • et al.
      Urinary loss of thiamine is increased by low doses of furosemide in healthy volunteers.
      measured urine thiamine levels in 6 healthy adults after administration of single intravenous doses of furosemide (1 mg, 3 mg, 10 mg) and isolated intravenous infusion of 750 mL of normal saline. Single furosemide doses and intravenous normal saline infusion were administrated at 1-week intervals, each followed by a washout period. Mean urinary flow rates increased from baseline (51 ± 17 mL/h) with successive increases in furosemide dosage (89 ± 29 mL/h with 1 mg, 110 ± 38 mL/h with 3 mg, and 183 ± 58 mL/h with 10 mg, P < .002 for the trend). Normal saline infusion increased the urinary flow rate to 104 ± 35 mL/h. Mean urinary thiamine excretion rates increased to a similar extent with each intervention over a 6-hour period (6.4 ± 5.1 nmol/h to 11.6 ± 8.2 nmol/h, P < .01). Urinary thiamine excretion rates then returned to baseline over the following 18 hours. The thiamine excretion rate was positively and significantly associated with urinary flow rate (P < .001). However, there were no significant differences in thiamine excretion observed among the various doses of furosemide. This suggests that urinary thiamine loss is linked to persistent urinary flow >100 mL/h rather than the mode of intervention.
      • Howland J.
      Biomolecules.
      These findings support routine surveillance for thiamine deficiency in patients who are at risk of excessive diuresis, including long-term diuretic users, alcoholic patients, and patients with psychogenic polydipsia. A study reported by Lubetsky et al
      • Lubetsky A.
      • Winaver J.
      • Seligmann H.
      • et al.
      Urinary thiamine excretion in the rat: effects of furosemide, other diuretics, and volume load.
      in 1999 showed that urinary thiamine excretion is a flow-dependent mechanism, common to various diuretic agents, including furosemide, acetazolamide, mannitol, hydrochlorothiazide, and amiloride. They produced similar increments in urine thiamine excretion proportional to the urine flow rate, irrespective of the diuretic used.
      • Lubetsky A.
      • Winaver J.
      • Seligmann H.
      • et al.
      Urinary thiamine excretion in the rat: effects of furosemide, other diuretics, and volume load.
      Unlike previous investigations, a Canadian prospective study reported by Zenuk et al
      • Zenuk C.
      • Healey J.
      • Donnelly J.
      • Vaillancourt R.
      • Almaki Y.
      • Smith S.
      Thiamine deficiency in congestive heart failure patients receiving long term furosemide therapy.
      in 2003 suggested that thiamine deficiency may be more severe in patients receiving higher doses of furosemide. Severe thiamine deficiency was detected in 24 of 25 patients (96%) who received 80 mg or more of furosemide per day compared with 4 of 7 patients (57%) receiving lower doses of furosemide. It was unclear whether there was a difference in urinary thiamine excretion levels between groups.
      It is further evident that not only urinary losses but also lack of thiamine supplementation can be a major predictor of thiamine deficiency in patients with heart failure. In a large prospective, cross-sectional observational study reported by Hanninen et al
      • Hanninen S.A.
      • Darling P.B.
      • Sole M.J.
      • Barr A.
      • Keith M.E.
      The prevalence of thiamin deficiency in hospitalized patients with congestive heart failure.
      in 2006, thiamine deficiency was severe in patients with heart failure who did not receive thiamine supplementation. A total of 100 patients with New York Heart Association (NYHA) class I to IV heart failure and various degrees of left ventricular systolic dysfunction were treated with furosemide (median dose 60 mg per day) for a mean duration of 14 months. Urinary thiamine levels and erythrocyte thiamine pyrophosphate analysis by high-performance liquid chromatography were used to assess thiamine status. One third of patients with heart failure were found to be thiamine deficient compared with 12% of controls (P = .007), and the percentage difference was even more pronounced when thiamine supplement users were excluded (37.2% vs 12.2%, P = .02). These results suggest that use of thiamine supplementation may reduce the severity of thiamine deficiency in this group of patients. The same study showed that the frequency of thiamine deficiency is proportional to the severity of systolic heart failure. Forty percent of patients in NYHA classes III and IV with left ventricular systolic dysfunction were thiamine deficient compared with 24% of patients with NYHA class I and II heart failure and left ventricular systolic dysfunction (P = .03) when thiamine supplement users were excluded.
      • Hanninen S.A.
      • Darling P.B.
      • Sole M.J.
      • Barr A.
      • Keith M.E.
      The prevalence of thiamin deficiency in hospitalized patients with congestive heart failure.
      Although the majority of the studies demonstrated that urinary thiamine losses are responsible for lower thiamine levels in furosemide users, one study suggested that furosemide may directly inhibit thiamine uptake at the cellular level.
      • Zangen A.
      • Botzer D.
      • Zanger R.
      • Shainberg A.
      Furosemide and digoxin inhibit thiamine update in cardiac cells.
      Zangen et al
      • Zangen A.
      • Botzer D.
      • Zanger R.
      • Shainberg A.
      Furosemide and digoxin inhibit thiamine update in cardiac cells.
      reported the effect of furosemide on thiamine uptake by cardiac cells in a rat model. Their findings suggest that furosemide can reduce intracellular thiamine pyrophosphate levels by directly inhibiting uptake or by blocking intracellular phosphorylation. An additive effect on cardiac cell thiamine uptake was noted when digoxin was used concomitantly with furosemide.
      Although there is considerable evidence linking furosemide to thiamine deficiency, a similar association was not found with the aldosterone antagonist spironolactone. Spironolactone has been shown to decrease long-term mortality in patients with systolic heart failure and is one of the most widely used drugs in patients with heart failure and a reduced left ventricular ejection fraction. In 2008, Rocha et al
      • Rocha R.M.
      • Silva G.V.
      • de Albuquerqe D.L.
      • Tura B.R.
      • Albanesi Filho F.M.
      Influence of spironolactone therapy on thiamine blood levels in patients with heart failure.
      reported the results of a study of the effect of spironolactone on furosemide-treated patients with heart failure. Patients with heart failure who received both spironolactone and furosemide had significantly higher thiamine levels than patients with heart failure treated with furosemide alone (277.2 ± 89.8 pmol/mL vs 154.7 ± 35.7 pmol/mL, P < .001).
      • Rocha R.M.
      • Silva G.V.
      • de Albuquerqe D.L.
      • Tura B.R.
      • Albanesi Filho F.M.
      Influence of spironolactone therapy on thiamine blood levels in patients with heart failure.
      It was not clear whether this was a direct result of spironolactone therapy. Little information exists concerning the effects of other loop diuretics on thiamine pyrophosphate effect or on serum or urine thiamine levels. Speculation exists that bumetanide and torsemide also may produce thiamine deficiency, but studies specifically focusing on the effects of these drugs on body thiamine status are lacking.
      • Doshi S.
      • Velpandian T.
      • Seth S.
      • Maulik S.K.
      • Bhargava B.
      • Bahl V.K.
      Prevalence of thiamine deficiency in patients on long-term diuretic therapy.
      It is certainly possible that thiamine deficiency in patients with heart failure treated with loop diuretics is not unique to furosemide.

      Effect of Thiamine Supplementation on Left Ventricular Systolic Function and Functional Capacity

      Relatively few studies have assessed the effect of thiamine supplementation on cardiac function and functional capacity in patients with heart failure who were treated chronically with loop diuretics. Shimon et al
      • Shimon I.
      • Almog S.
      • Vered Z.
      • et al.
      Improved left ventricular function after thiamine supplementation in patients with congestive heart failure receiving long-term furosemide therapy.
      reported the results of a randomized, double-blind, placebo-controlled study of 30 patients with NYHA class II to IV heart failure. Patients were treated with thiamine or a placebo. Thiamine-treated patients received 200 mg of thiamine intravenously daily for 1 week and then oral thiamine (200 mg/d) for 6 weeks. In thiamine-treated patients, the mean left ventricular ejection fraction increased from 28% ± 9% to 32% ± 9% (P < .05) after 1 week of intravenous thiamine therapy. After 6 weeks of oral thiamine therapy, left ventricular ejection fraction improved from 27% ± 10% to 33% ± 11% (P < .01). Mean NYHA functional class improved from 2.6 ± 0.6 at baseline to 2.2 ± 0.7 (P < .01) after oral thiamine administration. After 6 weeks of oral thiamine administration, there was a significant increase in the mean serum thiamine level. In this study, thiamine administration increased left ventricular systolic function in patients with subclinical and overt thiamine deficiency.
      Schoenenberger et al
      • Schoenenberger A.W.
      • Schoenenberger-Berzius R.
      • Aufdermaus C.
      • Suter P.M.
      • Vergopoulos A.
      • Enne P.
      Thiamine supplementation in symptomatic heart failure: a randomized, double-blind, placebo controlled, cross-over pilot study.
      reported the results of a randomized, placebo-controlled, crossover study of 9 patients with mild to moderate heart failure who were treated chronically with various diuretics. Patients were randomized to receive oral thiamine 300 mg/d or a placebo for 28 days followed by a 6-week washout period and then crossover and continued therapy for 28 days. During the initial treatment period and after crossover, mean left ventricular ejection fraction was significantly higher in thiamine-treated patients than in placebo-treated patients (32.8% vs 28.8%, P = .024), an absolute increase of 3.9%.
      In a study of 19 patients with acute decompensated heart failure reported by Smithline,
      • Smithline H.A.
      Thiamine for the treatment of acute decompensated heart failure.
      administration of intravenous thiamine (100 mg) within 30 minutes of presentation was associated with no significant difference in dyspnea score during the first 4 hours or duration of hospitalization.
      In Seligmann et al's
      • Seligmann H.
      • Halkin H.
      • Rauchfleisch S.
      • et al.
      Thiamine deficiency in patients with congestive heart failure receiving long-term furosemide therapy: a pilot study.
      study of 23 patients with heart failure who received furosemide and 16 controls with heart failure who did not receive furosemide, the mean thiamine pyrophosphate effect and urinary thiamine levels were significantly higher in furosemide-treated patients than in those not treated with furosemide. Among 6 patients who received thiamine supplementation (200 mg intravenously for 2 days, then 100 mg orally twice per day for 7 days, and then 200 mg orally per day long term), normalization of thiamine pyrophosphate effect was associated with a mean improvement in NYHA functional class of 1.0, and mean left ventricular ejection fraction increased in 4 of the 5 patients who underwent echocardiography (from 24.0% ± 4.3% to 37.0% ± 2.4%).
      The aforementioned studies suggest that thiamine administration is associated with improvement of left ventricular ejection fraction. A meta-analysis of randomized, double-blind, placebo-controlled trials addressing this issue supported this contention (average increase in left ventricular ejection fraction of 3.28%).
      • Shimon I.
      • Almog S.
      • Vered Z.
      • et al.
      Improved left ventricular function after thiamine supplementation in patients with congestive heart failure receiving long-term furosemide therapy.
      • Schoenenberger A.W.
      • Schoenenberger-Berzius R.
      • Aufdermaus C.
      • Suter P.M.
      • Vergopoulos A.
      • Enne P.
      Thiamine supplementation in symptomatic heart failure: a randomized, double-blind, placebo controlled, cross-over pilot study.
      • DiNicolantonio J.J.
      • Lavie C.J.
      • Niazi A.K.
      • O'Keefe J.H.
      • Hu T.
      Effects of thiamine on cardiac function in patients with systolic heart failure: systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials.
      Thiamine supplementation also may improve functional capacity in patients with heart failure and a reduced left ventricular rejection fraction treated with a loop diuretic (mainly furosemide). However, study populations in these investigations were small. Thiamine deficiency was present in most but not all patients in these studies. Moreover, it is not clear that thiamine supplementation improves the symptoms and signs of heart failure in patients with acute decompensated heart failure or heart failure with a preserved left ventricular ejection fraction, whether or not they are treated with loop diuretic. Clearly, further research in this area is warranted.

      Conclusions

      Thiamine and its ester forms are important co-factors in cellular energy production and play a vital role in myocardial contractility. Existing evidence suggests that furosemide may increase urinary excretion and its cellular uptake of thiamine. Review of the literature suggests that thiamine supplementation may improve left ventricular systolic function and functional capacity in patients with heart failure and a reduced left ventricular ejection fraction treated with furosemide. Because diagnosing and treating thiamine deficiency are relatively easy, safe, and inexpensive, healthcare providers should consider thiamine supplementation as a routine practice in the management of such patients.

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