Thiamine supplementation, Congestive heart failure and Furosemide.

Dr. Adrienne Zarifis, ND

Inquiry:

Congestive heart failure (CHF) is a progressive condition by which the heart has decreased cardiac performance, such as reduced cardiac output, leading to compensatory mechanisms designed to preserve tissue perfusion and cellular metabolism. The term ‘congestive’ refers to the physical findings associated with the condition, as symptomatic individuals will have varying symptoms depending on what chamber(s) are affected.
CHF affects more than 5 million people in the United States alone, with over 550,000 people diagnosed each year, and it is the most common inpatient diagnosis in patients >65 years old. That being said, it is a massive public health concern costing the nation 32$ billion/year, and although the availability of effective and proven therapies such as loop diuretics and other cardiovascular pharmaceuticalsfor CHF have increased life expectancy, the mortality rates remain high with an approximate 50% 5 year survival rate [5, 7].
One drug in particular, Furosemide (a loop diuretic) is known to deplete thiamine (B1), which happens to be paramount in cardiovascular health, and knowing the risk of cardiovascular pathology associated with thiamine deficiency such as ‘Wet Beriberi’, the correlation between the two make for an interesting review. Thiamine deficiency is known to cause heart failure, as it is an important coenzyme for many reactions, includingATP production and acid-base regulation (to prevent lactic acidosis).
In my personal experience, I have had a family member go through the diagnosis of CHF with a prescription of Furosemide, after briefly learning about the risks of Furosemide and Thiamine depletion worsening CHF in Dr. Rouchotas 2nd year Clinical Nutrition class. I have a strong interest in integrative cardiology and due to the safety profile, wide availability and cost effectiveness of thiamine, I felt this intervention is not widely recognized and would be an important to investigate the physiological benefits of supplementation.

Initial Pub med search
"heart failure"[MeSH Terms] OR congestive heart failure[Text Word] = 103257
("thiamine"[MeSH Terms] OR thiamine[Text Word]) AND ("thiamine"[MeSH Terms] OR vitamin B1[Text Word]) = 10156
"thiamine" [MeSH terms] AND "heart failure" [MeSH terms] = 102
"furosemide"[MeSH Terms] OR furosemide[Text Word] =14920
"furosemide"[MeSH Terms] OR furosemide[Text Word] AND "thiamine" [MeSH terms] AND "heart failure" [MeSH terms] =14

Limits: Clinical trial, systematic review, observational study, Humans, Review, Meta-analysis
"heart failure"[MeSH Terms] OR congestive heart failure[Text Word] = 29152
("thiamine"[MeSH Terms] OR thiamine[Text Word]) AND ("thiamine"[MeSH Terms] OR vitamin B1[Text Word]) =609
"thiamine" [MeSH terms] AND "heart failure" [MeSH terms] =13
"furosemide"[MeSH Terms] OR furosemide[Text Word] AND "thiamine" [MeSH terms] AND "heart failure" [MeSH terms =4

My research strategy involved researching PubMed, accessed through CCNM student database sign in. If the article was unavailable through free full text directly through this, I emailed the LRC staff @ CCNM to retrieve the articles for me. All articles were found in full text through CCNM LRC staff. My backup plan was to use my sisters log-on at UoGuelph, but was not needed.

Discussion:
What is CHF and who is affected by it ?
Congestive heart failure is a condition where the heart cannot pump sufficient oxygenated blood to the organs and periphery, which manifests in varying symptoms based on the predominant chamber affected. Left sided heart failure is associated with elevated pulmonary capillary pressure leading to respiratory symptoms such as shortness of breath, pleural effusion,and marked interstitial edema of the small airways which may interfere with ventilation, elevating PCO2. Right sided heart failure is associated more so with elevated systemic venous pressures, leading to marked peripheral edema, elevated jugular venous pressure and organ dysfunction [Merck Manual]. LV failure normally preceeds RV failure, and LV failure is associated with 2 types which are medicated differently; systolic failure leading to reduced left ventricular ejection fraction, and diastolic failure which is due to stiffening of the ventricle [American heart association]. Heart failure, simply put, is a result of either excess volume or pressure load, muscle damage (MI, infections ) or filling restriction ( stenotic valves). Causes for this condition include cardiovascular diseases such as long standing hypertension, valvular disease, previous MI, high output states like hyperthyroid, alcoholism, pre-exisiting LSHF leading to RSHF. Those with the highest risk include people who are obese, smokers/pre-existing lung conditions like COPD, diabetic, physically inactive, and the elderly. As mentioned previously, as CHF does progressively worsen, there are conventional treatments that attempt to halt this process [First Consult].

Conventional treatment for CHF?
Congestive heart failure can be exacerbated acutely and/or simply get to a severe enough stage, requiring hospitalization. Immediate hospitalization is needed when the patient presenting with pulmonary edema leading to respiratory distress while seated, any patient without known hypoxemia reaching arterial desaturation of <90%, a systolic BP of <75mmHg, or presenting with confusion due to suspected hypoperfusion. Urgent hospitalization is required if the patient has severe liver distention/tense ascites, renal dysfunction, new onset atrial fibrillation or increasing dyspnea non-responsive to diuretics.

The goals of conventional treatment in non emergent CHF is to improve cardiac function, reduce the risk of death and ultimately, improve quality of life. This can be achieved multiple medications, and non drug treatments. The most predominant medications used are diuretics, as renal sodium handling is a major target in order to reduce the ‘load’ on the vascular system. ACE inhibitors, angiotensin-2 R antagonists, B blockers, aldosterone antagonists, hydralazine+oral nitrate, digoxin, anticoagulations and antiplatelet agents may also be included in the treatment plan, depending on patients individul health status. Lifestyle changes can be made when feasible, which can include dietary modifications such as low sodium and reduced fluid intake, again, to reduce the ‘load’ on the system. Specific modification can be made depending on the patients causative and risk factors in the diagnosis of their HF.

Naturopathic Treatment for CHF?

If patients with cardiovascular disease are supplemented with complementary nutritional therapies, it should be evident that not only a reduction in mortality (4% reduction) is possible, but a reduction in morbidity and quality of life.
Not only is diet addressed, but therapeutic doses of nutritional treatments are considered. L-Carnitine shows to increase ATP production, encourages vasodilation, helps to sustain cardiac contractions (increase LVEF), and an overall cardio-protective effect against hypoxia and oxidative stress. CoQ10, as needed by all metabolically active tissues which include the heart, is a key component in CHF as it has been shown to increase LVEF, improve clinical signs (edema, cyanosis, etc), andincrease exercisecapacity. Heart friendly fats such as fish oils, high in an EPA:DHA ratio (2:1 or 3:1), taurine and D – ribose ( a source of energy for cardiac myocytes after ischemia) have all been shown to reduce mortality, andimprove cardiac function. Cardioprotective herbal preparations such as Hawthorn (Crataegus species), have been shown to decrease left ventricular work, decrease the consumption of oxygen index, and increase coronary sinus blood oxygen concentrations, resulting in a decrease in oxygen consumption.
The underlying cause of the CHF must be addressed in order to minimize the staging of the disease, and the vast amount of complementary therapies available to help patients suffering from CHF can support this process, both at the root and symptomatic improvement. [8]

title; reference; research design; methodology; summary of results with duration of study, dosage of intervention, efficacy of intervention; limitations)

Title of Article

Thamine deficiency in patients with Congestive heart failure receiving long term furosemide therapy

Reference

Seligmann, H. "Thiamine Deficiency in Patients with Congestive Heart Failure Receiving Long-term Furosemide Therapy: A Pilot Study." The American Journal of Medicine 91.2 (1991): 151-55.

Design

Pilot study

methodology

39 hospitalized patients;
23 (10 men, 13 women) in treatment group were diagnosed with CHF undergoing long term pre-admission furosemide therapy (mean age 70; 38-80years) and 16 controls (7 men, 9 women) with no diagnosis of CHF and no use of diuretics ( mean age 69 years; 50-78).
Heart failure ranking based on the New York Heart Association (NYHA) rated at a ‘functional class 2’, and was caused by ischemic heart disease in 18 patients, valvular insufficiency in 2 and idiopathic dilated cardiomyopathy in 3. All 23 patients received a combination therapy including digoxin, ACE inhibitors, nitrates and in particular interest – furosemide at a dose between 80-240mg for 3-14 months.
6/23 treatment group received 100mg bid of IV thamine hydrochloride (200mg/daily total) for 7 days.
5/6 LVEF was assessed prior to and at the end of the7 days via electrocardiographic evaluation.
All 6 were assessed after 12 hours of cessation of IV thiamine therapy, via TPPE and thiamine excretion.
Oral Thiamine supplementation of 200mg daily in an out-patient setting was then continued in the 6 patients as well as the other 15 who did not partake in the IV treatment, and no assessment took place.
Exclusion criteria: identifiable causes of thiamine deficiency other than CHF and furosemide therapy such as alcoholism, malnutrition, malabsorption, folate deficiency, increased distilled carbohydrate intake, prolonged diarrheal disease, dialysis, major catabolic ad physiologic stress state (such as MI or pulmonary edema), prolonged fever, acute infection, thyrotoxicosis, liver disease,uremia, insulin dependant diabetes mellitus, hypoproteinemia, hypomagnesemia, or hypophosphatemia and anyone who supplemented any sort of vitamins prior to the study.

Summary of Results

TPPE was returned to normal (<15%) in all 6 patients receiving parenteral Thiamine treatment, from 27% down to 4.5%.
Electrocardiogram on the last day showed a functional capacity improvement by at least one NYHA class (all 5 patients), systolic and diastolic BP increased by 10mmhg on average (all 5 patients), LVEF increased by 13% (24%-->37%) in 4 patients. No significant change in cardiac output.

Limitations & Quality of research

-The study was first limited by its design; Pilot study; as other variables within the populations studied were not thoroughly addressed such as the combination therapy’s dosage and potential effect on thiamine status.

-Size of study; only 6 patients were assessed before and after, as the other 15 were discharged as outpatientwith an oral prescription

-results were limited to IV therapy as follow-up was not performed after the daily oral supplementation

-exclusion criteria was thorough

Conclusions

Thiamine deficiency could be correlated with long term furosemide use, and is an important factor to address as the metabolic and hemodynamic features of heart failure are aggravated by a thiamine deficiency. Restoration ofnormal values of Thiamineis essential in managing CHF.

Title of Article

Thiamine supplementation in symptomatic chronic heart failure

Reference

Schoenenberger, A. W. "Thiamine Supplementation in Symptomatic Chronic Heart Failure: A Randomized, Double-blind, Placebo-controlled, Cross-over Pilot Study." Clinical Research in Cardiology 101.3 (2012): 159-64.

Design

Randomized, double-blind, placebo controlled, cross-over pilot study

Methodology

9 outpatients with symptomatic heart failure and an LVEF of <40% were randomized to two groups. The treatment group (6 patients) received 300mg/day of Thiamine and the control group (4 patients) got an identical pill in size, shape and colour once a day, for 28 days. The randomization centre and examination centre were two separate hospitals. 28 days of treatment or placebo was followed by a 6 week washout period, treatment group (4) and control group (5, 1 declined to continue). All patients had prescriptions for ACE inhibitors or angiotensin receptorblocker, and a diuretic, doses were not changed during the study other than for one patient to address edematous legs.
Functional status encompassing general health and dyspnea (day, night and exercise induced), was assessed via a visual analogue scale, dietary intake was self – recorded, free thiamine was measured via high pressure liquid chromatography, ECG’s were taken, echocardiography was performed and LVEF was determined via the Simpson method.

Inclusion criteria encompassed symptomatic heart failure with at least one of the following symptoms or objective findings; shortness of breath or orthopnea, positive hepatojugular reflex, interstitial transudation on chest radiography, or elevated brain natriuretic peptide (BNP) >39ng/L.
Exclusion criteria: acute HF, vitamin supplemented patients, renal failure (creatinine >250nmol/L) and fertile women.

Summary of Results

Free thiamine increased from day 1 to day 29, from 73 ng/mL to 133 ng/mL (normal range is 28-85ng/mL). The primary outcome, a change in LVEF, was achieved as the Thiamine group went from day 29.5% up to 32.8% (Pvalue 0.015) whereas the control group demonstrated a slight decrease from 29.5% down to 28.8%. The difference between the two groups end points was statistically significant, at a pvalue of 0.024.
There was also a decrease in right atrium area in the Thiamine group,from 16.7cm2 to 14.8cm2 (pvalue 0.026). There was non-significant changes in the 6 minute walking test, which was 549 to 624m, but at a value of 0.084 it was close.
No significant changes were found from baseline to day 29 in placebo.

Limitations& Quality of research

The sample size of the study was analyzed and a power of 0.80 which translates to 22 subjects would prove to be ideal for a parallel group study, and when converting that number to match a cross-over design, ½ the amount is needed (maybe even ¼), so the 9 subjects which were analyzed in the end could be low if 11 are needed.

Follow up period was short. This along with a small sample size is a limitation as significant changes in secondary outcomes were not possible. Long term effects such as mortality and morbidity were not possible to measure.

All subjects were on other medications, and no description ( dose of any of the drugs) were given.

Measurement ofThiamine levels usingPlasms Free Thiamine levels may miss a subclinical deficiency and determinations of free thiamine in plasma do not necessarily reflect a direct relationship to the level in the blood and tissues. Using TPPE is more sensitive as it reflects the saturation status of transketolase with coenzyme B1.

2 out of 9 patients had dilated cardiomyopathy, due to excess alcohol consumption which is a known causative factor for Thamine depletion.

Conclusions

High dose (pharmacological dose rather than nutritional) Thiamine reaching higher than normal values in plasma, demonstrated a significant increase in LVEF, in patients taking diuretics ( as well as ACE inhibitors or angiotensin receptor blockers). A longer follow-up with more subjects is needed in order to better assess long term effects and secondary outcomes.

Title of Article

Improved left ventricular function after Thiamine supplementation in patients with congestive heart failure receiving long term furosemide therapy

Reference

Design

Randomized double-blind placebo controlled

Methods

27 inpatients with chronic CHF, and a NYHA functional class between 2-4 , currently taking 80mg of furosemide or more for at least 3 months. Other drugs were also being taken, such as digoxin, nitrates, ACE inhibitors.
15 patients received IV 100mg BID Thamine HCl (200mg total), and 15 received saline solution.
Common ward dietwith estimated sodium content of 100mEq/d and thiamine content of 1-1.5mg/d.
Any other drugs that were taken 5 days prior to the study, were allowed to continue at the same dosages, and remained consistent for the 7 weeks of the study. No new drugs or supplements (other than Thiamine) were added.

After the 1 week IV for treatment group, ALL patients were given 200mg/day or oral Thiamine, while keeping all other medications constant, and were evaluated at the outpatient clinic at 3 and 6 weeks.

Echocardiographic exam, and TPPE % were measured at baseline, end of1st week, end of 6th week marks.

Exclusion criteria: patients taking diuretics other than furosemide. Valvular heart disease, atrial fibrillation, recent MI, heart failure induced by acute myocardial ischemia, LVEF >45%, recent thiamine or multivitamin supplements, other causes of thiamine deficiency (malabs, malnut, alcoholism), malignancy, myeloproliferative disorders, acute infection, thyrotoxicosis, liver disease, uremia, anemia, insulin dependant diabetes mellitus.

Summary of Results

After week 1 of IV therapy, TPPE reduced from 11.7% (+/- 6.5%) to 5.4% (+/- 3.2%) (pvalue <0.01). No change in placebo. Plasma Thiamine levels increased to 90.4 (+/- 63 ug/L) (pvalue <0.001) from 4.3 and did not change in placebo group.

After 6 weeks of oral thiamine in both groups, LVEF increased 22%, from 28% to 32% (pvalue <0.01). NYHA functional class decreased from 2.6 to 2.2 in 27 patients completing all 7 weeks. TPPE decreased in 22 of 27, to 4.2% (pvalue <0.01). No such changes were observed in placebo. Plasma thiamine levels were 50.2 ug/L, significantly higher than baseline (pvalue 0.001). Urinary output increased from 1731 to 2389mL from day 1 to day 29, respectively (pvalue <0.02) and daily sodium excretion increased from 84 to 116mEq/d (pvalue <0.05), in treatment groups and not placebo.

Limitations and Quality of research

One patient developed nausea and insomnia during IV therapy, and dosage was cut in half which halted to nausea.

Small sample size due to strict exclusion criteria

All drugs were kept constant during the study therefore contribute Thiamine to the positive change in hemodynamics.

Diet was accounted for and controlled which was important as it eliminated dietary thiamine differences between individuals and groups.

It would be useful to have evaluated patients via electrocardiography to estimate LVEF, after the one week IV therapyAND compare that to after the 28 days, to see if the group who received IV therapy had a significantly better improvement in LVEF. This would help determine whether or not it is beneficial to begin patients on IV for 7 days followed by oral supplementation OR if oral supplementation is suffice.

Conclusions

TPPE significantly decreased in patients after the 1 week 200mg/day IV supplementation of Thiamine, and LVEF increased significantly after 6 weeks of oral supplementation of 200mg/day of Thiamine in both groups, both with the same dietary intake of Thiamine, which demonstrates the dietary Thiamine was not sufficient to change TPPE.

Therefore, Thiamine levels were associated with significantly increased LVEF In some patients with moderate to severe CHF who had been on high dose furosemide for >3months (80mg or >).

Higher than normal plasma Thiamine status was needed to reach the significant changes in LVEF (50.2 +/- 32.4ug/mL) (normal range is 2.3-14.3 ug/mL) (pvalue <0.01 compared to baseline) and normal TPPE (4.2%+/- 4.4%) was needed (normal is <15%) (pvalue 0.001 compared to baseline). Plasma Free Thiamine is not a good representation of Thiamine levels in tissues, and TPPE is more sensitive.

Thiamine supplementation in patients with clinically normal thiamine status may be able to reverse the underlying subclinical deficiency and improve cardiac function.

Title of Article

Reversal of Refractory Congestive Heart Failure

after Thiamine Supplementation

Reference

Design

Case report and review of literature

Number of articles/ methodology

Despite maximal medical management, which

included enalapril, carvedilol, digoxin, furosemide,

metolazone, and a strict sodium-restricted diet; his condition had been progressively worsening. He had no other medical problems and denied the use of tobacco, alcohol, recreational drugs, and other nonprescribed medications. His dietary history showed a proportionalconsumption of animal products and vegetables.

LVEF estimated at 15%, and a depressed right ventricular function with a right ventricular systolic pressure of 55 mm Hg by Doppler assessment. S3 gallop. Severe mitral regurgitation and moderate tricuspid regurgitation.
Patient had gone into shock and was brought back to satisfactory arterial pressure.
TPPE was >25% (normal is <15%, severely deficient considered >25%)
100mg IV administered Thiamine began.

Summary of Results

3 days post IV Thiamine, electrocardiography was performed and an increase in LVEF from 15% baseline to 25% was recorded,mitral regurgitation reduced from severe to moderate, and moderate tricuspid regurgitation to mild.

5 days after IV supplementation, patient was walking on his own, S3 gallop was gone, diuretic was tapered, and outpatient CHF medications were re-started. He was discharged with an oral Thiamine supplement (dosage not recorded).

Limitations

The methods used in this case report do not allow us to establish a scientific cause-effect relationship between the improvements and Thiamine supplementation, as chance alone could be the case in a single case report.

However, case reports may exert

significant influence on clinical management because they can be useful references when approaching similar patients in the future.

TPPE was not re-evaluated after supplementation.

Conclusions

Thiamine deficiency and thus, supplementation, plays an important role in worsening CHF, and overall deterioration of cardiac function.

Title of Article

Thiamine supplementation for the treatment of heart failure

Reference

Design

Systematic review

Number of articles/ methodology

20 articles met the inclusion criteria and were included in the systematic review. A mix of different study designs were used, and reviewed.

Outcomes measured were varying dependant on the study analyzed, and included increase in LVEF, decrease in right ventricular area, hospitalization times, dyspnea, functional capacity score based on NYHA, urinary output and quality of life.

Summary of Results

Supplementation of Thiamine, oral or IV, between200-300mg dailywas shown to improve cardiac function including significant LVEF increase in all studies and functional class NYHA decrease, right ventricular area decreased, urinary output (in mL) increase, and sodium excretion increase.

It was found that patients with low Thiamine status (TPPE >15%) had a lower LVEF, and when thiamine status normalized(TPPE<15%), LVEF increased. Plasma free thiamine is not an accurate assessment of Thiamine cellular uptake, TPPE is the most sensitive marker.

Acute decompensated HF, treated within 30 minutes with 100mg IV thiamine showed no difference in hospitalization time or dyspnea, compared to placebo.

IV thiamine of 50mg/kg administerd incrementally over 2 minutes to patients who were mechanically ventilated for either cardiac, renal or pulmonary impairment was shown to increase systolic BP 20mmHg and mean rise in CVP of 3mmHg.

Limitations

-Not all studies used the most sensitive marker for Thiamine activity in tissues (TPPE), which skews baseline and post treatment thiamine levels therefore making it difficult to apply results.

-One study was looking at micronutrient supplementation and not Thiamine on its own.

-One single dose of 100mg IV thiamine has not been shown to increase TPPE enough to change LVEF

-not all studies were relevant to heart failure, and not all interventions were thiamine alone.

Conclusions

Thiamine deficiency is known to have negative effects on cardiac function, an supplementation is shown to improve LVEF, however it is not known whether this is due to an elimination of thiamine deficiency or a positive effect on the CV system. More RCTs with longer follow up times are needed to address mortality and morbidity after Thiamine supplementation.

Title of Article

Thiamine status, diuretic medications and the management of congestive heart failure

Reference

Design

methodology

6 healthy adults (21 years – 27 years) were recruited for the study. Physical exam, ECG, routine lab tests and medical history were taken. No volunteer was smoker or drank alcohol. Unrestricted diets and no medications or vitamin supplements.
4 study days. 24 hours pre-intervention urine collection, and overnight fast at home. Subjects arrived at 6am and 7 am the diuretic intervention (furosemide at either 1mg, 3mg or 10 mg IV admin) or saline solution placebo was administered (750ml IV admin), all over 20 mins.
spontaneously voided urine collected over 6 hour period. 10 am light meal, with 200mL tea or coffee. 1 pm subjects went home and collected all urine until 7 am next day. No changes to diet were recommended during this time.
Urinary concentrations of sodium, creatinineand potassium were determined by routine screening. Urinary thiamine was measured using high pressure liquid chromatography. Non compliane was monitored by completeness of urine collection at home which was accounted for by creatinine excretion.

Summary of Results

Creatinine excretion did not differ on pre-intervention days and intervention days – which indicate compliance of urine collection at home.

Furosemide induced dose dependant increases in Urine flow rates which were highly correlated with thiamine excretion.

Limitations & quality of research

Self-collection not monitored at home from 1pm-7am next day.

Healthy subjects versus congestive heart failure patients.

Conclusions

Thiamine, heart failure and Furosemide.

Thiamine (Vitamin B1) is a vital part of the energy systems,as it is an important coenzyme in oxidation-reduction reactions, such as glucose metabolism,the pentose shunt and the citric acid cycle. There are 4 forms of Thiamin in the human body, and most relevant to CHF, Thiamine Pyrophosphate (thiamine diphosphate), as it is a coenzyme to pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase and transketolase (TK). Recommended dietary intake of Thiamine is between 1.0-1.5mg/day and can be attained through a diet rich in foods with the highest levels such as whole grains, soybeans, pork and tuna.
Thiamine deficiency can lead to 2 syndromes; dry beriberi (neurological effects) due to cerebral hypoperfusion from a disruption in the blood-brain barrier, and wet beriberi( cardiovascular effects) to which it is hypothesized a depletion in ATP, leading to a rise in adenosine in the plasma causing increased systemic vasodilation, flushing and headaches. Not only are the cardiac myocytes depleted of their energy source (ATP), a lack of Thiamine coenzyme prevents important reactions, such as pyruvate->acetyl CoA---> ATP, from going forward, leading to cellular acidosis (->lactic acidosis) and increased intracellular free fatty acids (-> ketone formation). Overall, the lack of ATP leads to a weakened heart muscle and heart failure and the entire cardiovascular system is severely affected.
As discussed, Thiamine deficiency can be the cause of heart failure and aggravate pre-existing heart failure. It can be caused by insufficient dietary requirements, age, trauma, surgery, alcoholism, infections, or the most prevalent statistic of them all, those taking diuretics; as it has been shown that 91% of patients taking diuretics are deficient in Thiamine.
One loop diuretic in particular, Furosemide has not only been shown to deplete thiamine levels via the increase in urinary flow rate as Thiamine is a water soluable B vitamin and thus positively correlated with urinary flow rate[10], but has also been shown to exhibit a dose-dependent inhibition onthiamine uptake into cardiac cells [9]. It is most interesting to note the vicious cycle created by the use of the gold standard in diuretics for CHF, Furosemide, and the correlation with depleting Thiamine, knowing a deficiency in Thiamine can lead to cardiovascular disease such as heart failure.

-Does research favour a particular dose of Thiamine?
Depending on the individual health status of the patient, the research demonstrates different doses and methods of administration.
Acute exacerbation of congestive heart failure can be treated with 100mg of IV Thiamine, and was shown to reverse refractory congestive heart failure in one case report [4,8]. An oral dose between 200-300mg/day for 28 days was shown to be sufficient to increase LVEF(the primary outcome)up to 22%.

-What are some areas that remain unassessed by current research?

Currently, there areno long-term studies demonstrating the effects of Thiamine supplementation on patients with congestive heart failure, taking Furosemide. Therefore, there is a gap in knowledge at the moment whether or not the increases in LVEF, normalization of TPPE levels, decrease inarea of artria, improvement in exercise parameters, and other outcomes, actually have an effect on mortality, and if this does in fact increase life span. However, it has been found that among HF patients in sinus rhythm, higher LVEFs were associated with a linear decrease in mortality up to an LVEF of 45%. However, increases above 45% were not associated with further reductions in mortality[11]. It may be deduced from other studies that if Thiamine can incrementally increase LVEF, there could be a reduction in mortality.
Although a couple of the studies addressed the differences in TPPE levels before and after IV administration of Thiamine, LVEF has yet to be measured between 2 groups that (group 1)received IV thiamine followed by oral supplementation and (group 2) just oral thiamine, which would help practitioners decide whether or not IV administration yields a significant benefit when combined with oral supplementation, or if oral supplementation is suffice.
It would be of utmost importance to see a study focusing not only on the physical findings but also on the subjective findings such as quality of life improvements as this was not a major focus in any of the studies reviewed.
Ideally, it would be important to see more RCTs with a larger sample size in order to be able to apply the effects to the general population.

How do these findings support, or modify the Naturopathic management of the Congestive Heart Failure cases?

As an ND, when treating a patient whose survival is dependent on conventional medication, such as those with congestive heart failure, it is paramount to take those medications into consideration when treating the person as a whole. One cannot simply look at the patient as an organic system, one must look at all the exogenous factors as well as it was proven highlighted in this review that these exogenous factors have the power to not only exacerbate disease but cause disease.
As ND’s we are taught that many if not all medications come with side effects that have the potential to be managed. It is therefore most interesting to the vicious cycle created by the use of the gold standard in diuretics for treatment of CHF, Furosemide, and the correlation with depleting Thiamine, knowing a deficiency in Thiamine can lead to cardiovascular disease such as heart failure. Knowing this now, it is a top priority to supplement patients with Thiamine when taking Furosemide in order to halt the progression of congestive heart failure.
The primary outcomes were positively correlated with thiamine supplementation in all studies reviewed here as they demonstrate a correction of subclinical thiamine deficiency and an increase in LVEF%, and it is hypothesized that the mechanism of action via Thiamine could be either due to direct myocardial pharmacological action of Thiamine at the cellular level or a diuretic response (increase sodium and water excretion, relieving the ‘load’ on the vascular system) to thiamine. Regardless of the MOA, Thiamine proved itself worthy of improved cardiac function and functional capacity. Significant outcomes outlined in the studies include; increased LVE, impoved functional class according to NYHA, increased diuresis (increased sodium and water excretion), and normalization of a previous subclinical thiamine deficiency.
Knowing the background of thiamine and the risks of deficiency leading to BeriBeri, in not only those on Furosemide, but also related to lack of dietary intake, Thiamine can be used preventatively and therapeutically.
I would not feel comfortable leaving Thiamine out of a therapeutic regimen in those with heart failure, and taking Furosemide, and based on the review to date it makes for an essential addition to the patients daily supplementation.

Works Cited

Seligmann, H. "Thiamine Deficiency in Patients with Congestive Heart Failure Receiving Long-term Furosemide Therapy: A Pilot Study." The American Journal of Medicine 91.2 (1991): 151-55.
Schoenenberger, A. W. "Thiamine Supplementation in Symptomatic Chronic Heart Failure: A Randomized, Double-blind, Placebo-controlled, Cross-over Pilot Study." Clinical Research in Cardiology 101.3 (2012): 159-64.
Shimon, H. "Improved Left Ventricular Function after Thiamine Supplementation in Patients with Congestive Heart Failure Receiving Long-term Furosemide Therapy." The American Journal of Medicine 98.5 (1995): 485-90.
Mendoza, C. E., F. Rodriguez, and D. G. Rosenberg. "Reversal of Refractory Congestive Heart Failure after Thiamine Supplementation: Report of a Case and Review of Literature." Journal of Cardiovascular Pharmacology and Therapeutics 8.4 (2003): 313-16. Web.
Dinicolantonio, J. J. "Thiamine Supplementation for the Treatment of Heart Failure: A Review of the Literature." Congestive Heart Failure 19.4 (2013): 214-22.
Brady, J.a, C.l Rock, and M.d Horneffer. "Thiamin Status, Diuretic Medications and the Management of Congestive Heart Failure." Journal of the American Dietetic Association 93.9 (1993): A9. Web
"Heart Failure Fact Sheet." Centers for Disease Control and Prevention. Centers for Disease Control and Prevention, 03 Dec. 2013. Web. 10 Nov. 2014.
-Prousky, Jonathan. Textbook of Integrative Clinical Nutrition. S.l.: Canadian College Of Natur, 2013. Print.

Zangen, A. "Furosemide and Digoxin Inhibit Thiamine Uptake in Cardiac Cells." European Journal of Pharmacology 361.1 (1998): 151-55.
Rieck, J. "Urinary Loss of Thiamine Is Increased by Low Doses of Furosemide in Healthy Volunteers." Journal of Laboratory and Clinical Medicine 134.3 (1999): 238-43. Web.
Curtis, Jeptha P. "The Association of Left Ventricular Ejection Fraction, Mortality, and Cause of Death in Stable Outpatients with Heart Failure." Journal of the American College of Cardiology 42.4 (2003): 736-42. Web.

Appendix A

Appraiser Adrienne Zarifis

Citation (Title):Thiamine supplementation in symptomatic chronic heart failure; randomized, double blind, placebo controlled, cross over pilot study.
Schoenberger, AW.

ARE THE RESULTS OF THIS TRIAL VALID? What is the risk of bias?

Was assignment of patients to treatment groups randomized?

Was the randomization process concealed from investigators (was the trial allocation concealed?) Note: this refers to both blinding of the investigators from the treatment, but also blinding from the process of randomization itself

-random allocation to either treatment or placebo controlled group

-random allocation process generated by a computerized random number generator

Were patients in the treatment and control groups similar with respect to known prognostic factors at the start of the trial?

Baseline characteristics for primary outcomes were not significantly different between thiamine treatment group and placebo.

All patients were outpatients at the same hospital, treated with diuretics for symptomatic heart failure

Heart failure was due to dilated cardiomyopathy due to excess alcohol consumption in 3 patients and CAD in 6 patients.

Blinding: were patients aware of group allocation? Were clinicians aware of group allocation? What about outcome assessors?

The study was double blinded; so subjects and clinicians were both blinded. Outcome assessors (echocardiography) were also blinded.

Was follow up complete and appropriate in length for the outcomes examined?

Follow up time was appropriate in order to assess LVEF and other outcomes, however mortality was not able to be assessed as it was only a 28 day period. Previous studies have followed a similar time frame of 28 days.

It is much anticipated to see a longer term RCT performed, in order to see if greater effects are seen with longer supplementation.

WHAT ARE THE RESULTS OF THE TRIAL?

Calculate the results for 1 major outcome. How large was the treatment effect? How precise was the treatment effect?

LVEF is the major outcome and Thiamine showed a treatment effect of 3.9% in absolute terms. (pvalue >0.024)

Chart not applicable to my data.

Control Event Rate

(CER)

Experimental Event Rate

(ERR)

Relative Risk (RR)

RR = EER/CER

Relative Risk Reduction (RRR)

(1-RR)x100 or [(CER-EER)/CER]

Absolute Risk Reduction

(ARR)

ARR = CER-EER)

Number Needed to Treat (NNT)

NNT = 1/ARR

p-value

Are the outcome measures clinical (hospitalization, stroke, death, etc) or physiologic (BP reading, HbA1c, LDL levels, etc)?

Outcome measures are physiological, LVEF%, TPPE%, BNP, area of left and right atria, BNP, exercise test, weight, dyspnea.

If the outcomes are physiologic, are they established surrogate markers of clinically important outcomes (i.e. BP reduction correlating with decreased mortality rate)?

Yes, the primary outcome in this study is appropriate as a surrogate marker, as LVEF% is characteristically decreased in congestive heart failure (LVEF <40%). Among HF patients in sinus rhythm, higher LVEFs were associated with a linear decrease in mortality up to an LVEF of 45%. However, increases above 45% were not associated with further reductions in mortality.[11]

Were important adverse events reported?

No adverse events reported.

CAN I APPLY THE RESULTS OF THIS TRIAL TO MY PATIENT(S)?

Is the intervention feasible in my practice setting?

Yes. Thiamine is a safe, readily available in oral supplement form and cost effective treatment for patients of any income status.
IV thiamine would only be required in an acute inpatient status and would be done in a hospital setting.

Are the potential benefits worth the possible harms and cost?

There are no harms associated with Thiamine supplementation at the dose between 200-300mg recorded.

Longer studies would have to be performed in order to assess mortality.

Research paper review by Adrienne Zarifis; dedicated in memory to Herman.
Herman was only 10 months old, a beautiful Slovakian mountain dog and battled CHF from a congenital heart defect. He was put on furosemide. He passed away August 21 2013. I supplemented him with B1 and COQ10 after reading the research and guided me to this paper review. It is amazing how heartbreak can guide you to do greater good.