Nutritional Requirements and Intake

Potassium

• Potassium and the Diet; is a quick facts sheet outlining what you need and how activity can other conditions affect this number.  A good example is how 1-2 hours of exercise makes you lose about a banana's worth of potassium.  Another exceedingly important point is that there is no tolerable upper oral intake limit on potassium in healthy individuals.⁵
• Canadian Dietary Intake Data for Adults from Ten Provinces, 1990-1997  ; is a dataset showing that Canadians are generally low in potassium consumption and high in sodium consumption.⁶
• Potassium; is the USDA dietary reference intake for potassium.  This goes into quite a bit of detail as to what is needed each day and why.  Highlights include that 4.7 grams of potassium reduces salt-sensitive hypertension (high blood pressure), higher potassium intake and lower sodium intake lowers blood pressure, stroke risk, increases bone density, and decreases kidney stone formation.⁷
• Potassium Intake of the U.S. Population; is a convenient publication by the USDA that outlines what was found in the comprehensive NHANES study on potassium intake.  This robust document shows how men and women chronically under-consume potassium through life, with men consuming ~3172 mg per day and women consuming ~2408 mg per day.⁸
• The rates of absorption of the radioactive isotopes of sodium, potassium, chlorine, bromine, and iodine in normal human subjects; is a revolutionary study in 1938 that measured gamma radiation emitting from hands after ingestion of salts made radioactive using a cyclotron.  The salts were aged to isolate a specific atom, taking advantage of the variable half-lives.  The salts other than potassium took 3-6 minutes to be detectable while potassium took 6 to 15 minutes to be detectable.⁹
• Pharmacokinetics and effects on fecal blood loss of a controlled release potassium chloride tablet; examined potassium chloride solution in comparison with a controlled release tablet of potassium chloride in humans on a controlled diet.  The solution was taken up much faster after ingestion with peak urine content at 2 hours.  Potassium given chronically was virtually all taken up by the body.  Potassium depleted subjects took up KCl solution and, over the first couple days, presumably incorporated potassium into tissues (such as heart, which started to have a slightly abnormal rhythm) and returned blood levels to normal.¹⁰
• Pharmacokinetics of potassium chloride in wax-based and syrup formulations; is a 1985 study that examined a small sample of men on potassium changes in plasma and subsequent excretion in urine.  The syrup, which is most similar to Krampade, peaked in plasma concentration at a median of 60 minutes after ingestion and was completely excreted in 36 hours and was much more bioavailable than the wax-based pill form.¹¹
• New Guidelines for Potassium Replacement in Clinical Practice; argues the point that every effort should be made to keep serum potassium levels above 4.0 mmol despite 3.5 mmol being considered clinically normal.

Sodium

• Sodium intake status in United States and potential reduction modeling: an NHANES 2007-2010 analysis; is a comprehensive study that shows both men and women have significantly higher sodium intake of ~4400 and ~3000 mg per day respectively, than the 2300 mg per day limit.  Overall sodium intake has remained unchanged from 2001-2010, though intake per kg food has decreased.
• The effect of sodium balance on sweat sodium secretion and plasma aldosterone concentration; is a foundational study that demonstrates that sodium balance can be maintained under extreme  conditions, 104°F for extended periods, independent of sodium intake, in this case 1.5, 4.0, or 8.0 grams per day.  The only discernible affect of high sodium intake is a lowering of aldosterone levels under the hot conditions relative to the low sodium intake group.

Magnesium

Magnesium Deficiency; is a review of the magnesium needed and consequences of too little.  Magnesium is mainly found in bone and inside cells, with a small amount in serum.  The daily requirement is between 220-400 mg per day while the average American consumes 240-370 mg per day.  It is important to note that magnesium absorption is limited and is only about 30-40% of what is consumed, on average and this is further compromised when Vitamin D deficient.  Magnesium excretion is tightly regulated by the kidney.  Signs of magnesium deficiency are variable, but include neurological changes in behavior and personality, heart disease, impairment of parathyroid hormone secretion, and tetany.  Magnesium deficiency often leads to other electrolyte imbalances especially lower potassium levels.  It is important to note that those with both magnesium and potassium deficiency require magnesium to be replaced in order for potassium to be replaced.  This is part of why there is a synergistic effect felt from Krampade 2.0, which contains both magnesium and potassium.

Exercise and Fatigue

Potassium

• Plasma K+ changes during intense exercise in endurance-trained and sprint-trained subjects; is a 1994 study examining the differences in potassium regulation during treadmill sprints to exhaustion and non-exhaustion.  The sprint-trained athletes tended to have more potassium released into the plasma from muscles, but also cleared potassium from the plasma faster.¹²
• Potassium Regulation During Exercise and Recovery in Humans: Implications for Skeletal and Cardiac Muscle; is a review from 1994 on potassium flows during exercise and recovery.  Peak potassium in blood is strongly correlated to exhaustion and a plateau of potassium in the plasma is found in non-exhaustive exercise.  This is followed by rapid loss of potassium in the blood after exercise stops and an extended period of having less potassium in the plasma than before exercise began.¹³
• K+ balance in humans during exercise; is a 1996 study that examines potassium efflux rate out of exercising tissues at various exercising intensities.  High intensity exercise has a rapid increase of potassium until exhaustion while non-exhaustive reaches a plateau.  Low-intensity exercise does not have a significant change in plasma potassium concentration which indicates a redistribution of potassium from the exercised muscle into other tissues.  Adrenaline increases the plasma potassium concentration and arterial potassium is the primary factor for interstitial potassium concentration.  Hence, adding exogenous potassium shifts the balance driving potassium back into cells and delays fatigue.¹⁴
• Potassium regulation during exercise and recovery; is a 1991 study that also examines the loss of potassium from muscles and subsequent gain of potassium in plasma.  The rate of loss is directly proportional to exercise intensity and potassium loss is a direct contributor to muscle exhaustion.  Repeated bouts of exercise extend the length of time to potassium reuptake by the cells resulting in increased recovery time required prior to another bout of exercise.  Adding an external source of potassium, such as Krampade, is likely to speed recovery.¹⁵
• Skeletal Muscle Resting Membrane Potential in Potassium Deficiency; is a groundbreaking 1973 study examining what was observed in man, specifically soldiers during basic training, on animal models.  Dogs had significantly depressed action potential, -54.8 mV prior to potassium depletion versus -90.1 mV in the same dogs after potassium depletion.  The dogs had observed muscle cell death due to necrosis and some had signs of paralysis.
• On the Mechanism of Rhabdomyolysis in Potassium Depletion; mimics potassium depletion observed in soldiers using a dog model.  This study confirmed that the suspected rhabdomyolysis (muscle cell death) in soldiers was caused by necrosis as a result of decreased blood flow to potassium depleted muscles during exercise.  The blood flow only increased 19% when dogs were potassium deficient, drastically less than 136% increase in the same dogs with normal potassium.  Potassium infusion increased blood flow in resting muscles of both normal (90%) and depleted dogs (63%), but potassium depleted dogs lagged behind when exercised (50% increase in potassium infused normal dogs versus  a 4% decrease in potassium depleted dogs).  This result indicates that external potassium increases performance whether the subject is potassium deficient or normal.  Tissue slices demonstrated significant muscle cell deformity and death and immune cell infiltration.  Blood indicators of rhabdomyolyisis in the dogs mirrored that seen in Army recruits and football players that had signs of rhabdomyolysis and were potassium depleted.
• Pathophysiology of Intense Physical Conditioning in a Hot Climate; is a revolutionary study done by the US Army to determine a cause of the masive numbers of soldiers suffering from heat injury in the late 1960s.  These otherwise healthy young men had complications of rhabdomyolysis and renal failure when suffering heat stroke.  The study found that during the first 2 weeks of basic training in the heat, recruits lost 20% of their total body potassium despite consuming 4100 mg potassium per day.  While potassium loss decreased considerably when not training after a recruit became potassium depleted, training increased aldosterone production and potassium loss remained the same when training and already potassium depleted.  Interestingly, increased sodium intake had no effect on potassium loss during training, but did show increased sodium loss in urine and sweat.  This study demonstrates that to combat heat injury significantly increasing potassium intake is a key component of combating heat injury.
• Dog Days and Siriasis: How to Kill a Football Player; is a commentary directed toward trainers and coaches of football players and military personnel.  It goes through data of heat injury and how important it is to get enough potassium as even moderate potassium deficiency leads to potentially devastating effects of both health and training outcomes in young people working in the heat.
• Plasma potassium changes with high intensity exercise; investigates how potassium fluxes in muscle tissue during repeated bouts of intense exercise. Repeated bouts of exhaustive exercise resulted in lower peak plasma potassium and also less time to reach exhaustion.  Muscles become hyperpolarized after cessation of exercise for at least 3 minutes resulting in difficulty of triggering a muscle contraction.
• Role of exercise-induced potassium fluxes underlying muscle fatigue: a brief review; is a 1990 review of the proposed cause of muscle fatigue, focusing on the site of muscle fatigue which is identified as the membrane.  The key component of muscle fatigue in exercise higher than 2 contractions per second (aka moderate to intense exercise) is the loss of potassium from inside the cell, decreasing the membrane potential, and hence, eventually lead to the inability to contract e.g. exhaustion.¹⁶
• Role of Interstitial Potassium; is a 1995 review of the unique role of interstitial (the space between tissues and blood vessels) potassium.  When exercising the concentration of potassium in this compartment increases which both promotes and postpones fatigue.  Higher interstitial potassium reduces the excitability of both muscle cells and motor neurons which reduces muscle contraction strength and frequency.  However, interstitial potassium also increases respiration rate and blood flow to the muscle which increases the amount of fuel/nutrients available (oxygen, sugars, fats, etc) which slows fatigue.¹⁷
• Potassium and fatigue: the pros and cons; is a 1996 paper examining the conflicting data on whether calcium or potassium is the source of fatigue in exercise.  The source of fatigue likely varies depending on the intensity of exercise.  Intense and moderate exercise likely has the source of fatigue due to depletion of potassium and the reduction of the ability to repolarize  the membrane (activation of the muscle firing mechanism) while low-intensity exercise fatigue is likely due to depletion of ATP (fuel).¹⁸
• Dynamics and Consequences of Potassium Shifts in Skeletal Muscle and Heart During Exercise; is a comprehensive 2000 review of potassium dynamics in skeletal muscle and heart.  The heart has much better regulation of potassium and maintains homeostasis much better than skeletal muscle due to a much higher rate of pumping sodium out and potassium back into the cell.  Otherwise, the findings are similar in that potassium shift from inside to outside the cell is the core cause of skeletal muscle fatigue during moderate to intense exercise.¹⁹
• Elevated muscle glycogen and anaerobic energy production during exhaustive exercise in man; is a 1992 study that determined that increased muscle glycogen stores results in more potassium being released during a single bout of exercise and faster potassium recovery after a single bout of exercise.  Interestingly, there was no difference in subsequent bouts.
• The inhibitory effect of shakuyakukanzoto on K+ current in H9c2 cells; is a 2014 study using a model skeletal muscle cell in which it was found that inhibiting or downregulating potassium channels prevented tetany, or cramping, in cell culture.  Thus, maintaining intracellular potassium levels are critical for maintaining normal muscle function.²⁰
• Effect of potassium (K) depletion on the response to exercise in the dog; is a presentation showing that potassium depleted dogs do not have increased lactate levels after exercise and cardiac output was actually higher (3.7 L/min) during rest than after exercise (2.9 L/min), the inverse of dogs with normal potassium levels (2.8 L/min during rest to 4.1 L/min after exercise).  These findings suggest that potassium depletion alters glycolysis (the ability to utilize sugar) in the muscle.  The alteration of cardiac output indicates that muscles can be subject to ischemic necrosis and contributes to hyperthermia (heat stress) as heat generated from muscle contractions cannot be adequately dissipated to the environment through the skin.
• Exertional Rhabdomyolysis; is an editorial that postulates that the core cause of exertional rhabdomyolysis lies in potassium deficiency of the tissues.  Potassium deficiency causes blood flow to not increase during exercise resulting in ischemic necrosis, or cell death from a lack of oxygen, in the muscle tissue.  Hence, it is important to keep tissue potassium levels high to avoid this condition.
• Potassium deficiency syndrome in the rat and the dog; a description of the muscle changes in the potassium-depleted dog; is a foundational 1950 study and describes how skeletal muscle rapidly degenerates in the potassium depleted dog.  However, when given more dietary potassium and restoring tissue potassium levels, the degeneration of skeletal muscle is completely reversible.
• Nutritional deficiency syndrome with diarrhea resulting in hypopotassemia, muscle degeneration, and renal insufficiency report of case with recovery; is a case study of a man with 2 months of diarrhea which resulted in severe potassium deficiency.  He had severe myolysis, or muscle cell death.  Upon increasing dietary potassium intake, the individual recovered.
• Myoglobinuria and hypokalemia in regional enteritis; is a case study of a man suffering from Crohn's disease and diarrhea became severely hypokalemic.  Modest exercise resulted in pain in the calf muscle and indications of muscle cell death (rhabdomyolysis) were seen in his urine.  This was confirmed by biopsy in which striation of the cells was lost.  This was reversed and did not return once dietary potassium was increased

Sodium

• Responses to moderate and low sodium diets during exercise-heat acclimation; is a clinical study that examines how sodium intake effects exercise performance and other physiological variables such as heart rate and body temperature in extreme heat (106°F).  There was no difference in performance or other variables outside of sodium content in sweat and urine in which the low sodium diet (~1.6 grams per day) versus the moderate sodium diet (~3.2 grams per day).  Interestingly the potassium content of sweat and urine was the same regardless of sodium intake.  This study therefore indicates that increasing sodium intake has no bearing on performance or heat acclimatization.
• The Effect of the Sodium Chloride Intake on the Work Performance of Man During Exposure to Dry Heat and Experimental Heat Exhaustion; is a clinical study in which unacclimatized men walked in 120°F heat over the course of 3 days.  There were 3 groups, high (11.7 g), medium ( 5.9 g), and low (2.3 g) sodium intake (note that all are at or above the FDA upper intake limit of 2.3 g per day).  It was noted that there were no differences between the high and medium diets, but the low sodium intake diet had higher heart rate and weight loss.  The sodium balance was negative for the groups, but recovered quickly in two days as subjects adapted to the heat.  This indicates that there is no need to have sodium intake higher than 6 g over the first few days of heat acclimatization.
• Aldosteronism in Man: Some Clinical and Climatological Aspects Part I; is a revolutionary review of studies done to determine the process of adapting to working in hot environments, namely humid, tropical heat.  Increased aldosterone production begins almost immediately and there is a fast, sharp drop in urinary sodium.  Sweat glands also see a sharp drop in sodium and over the course of a few days the sweat content is as much as 95% lower than prior to adaption to working in the heat.  Even with low sodium intake (1.2 g per day) the body is able to maintain sodium balance by altering urinary and sweat sodium secretion without any drop in performance.  This series of studies indicates that while important, sodium is well conserved by the body even under the harshest conditions and that the sodium content of urine and sweat is dependent on sodium content of the diet.

Heat Stress

Potassium

• • Potassium Losses in Sweat Under Heat Stress; is a study of people acclimatized to tropical conditions and not performing any physical activity were placed in environmental chambers set at 104°F at various humidities for 2 hours.  They ate a consistent diet containing 6300 mg of sodium and 3800 mg of potassium.  The subjects lost about 4500 mg of potassium per day, despite not being active and having a high sodium diet.  This indicates that even when at rest and fully acclimatized to the heat, excessive potassium loss continues in spite of higher sodium intake.

• • Effect of low-potassium diet on rat exercise hyperthermia and heatstroke mortality; is a US Army study in which rats are subjected to a low-potassium diet to mimic the potassium losses seen in humans during basic training in the heat.  The rats fed the low-potassium diet had much slower growth than control.  Potassium deficient rats could barely generate half the work of control rats during exercise while simultaneously having more than double the heat gain (increase in body temperature).  This would indicate that severe potassium deficiency in tissues decreases performance while simultaneously increasing heat gain and, hence, increased susceptibility to heat stress.

• • Salt Loading as a Possible Factor in the Production of Potassium Depletion, Rhabdomyolysis, and Heat Injury; is a hypothesis based upon the review of literature that would be later investigated by the authors and proofed.  The preponderance of evidence indicated that potassium depletion in tissues is the primary driver of heat injury, which ranges from heat cramps to heat stroke.  Furthermore, high sodium loads appear to drive more potassium loss and make heat injury more prevalent despite excessive fluid intake.  Indeed, studies indicated that people can work in the heat well with low-sodium intake and high potassium intake and be more resistant to heat stress.

• • On the trail of potassium in heat injury; is an extensive review of the literature conducted by the US Army Research Institute of Environmental Medicine that brings together the overriding observation of potassium deficiency being a prevalent component of heat injury.

• • Effect of Restricted Potassium Intake on its Excretion and Physiological Responses During Heat Stress; is a paper studying potassium conservation in heat unacclimated humans working in tropical heat for 3 hours per day for 3 days (this was done during the winter so excessive sweating only occurred during the study).  The potassium lost through sweat was unchanged whether subjects consumed the baseline (3300 mg), medium (2150 mg), or low (1750 mg) diet.  About 40 percent of the subjects had cardiac abnormalities likely resulting from low potassium in the cardiac muscle.  This study indicates that the body does not conserve potassium even when intake is reduced.  Thus it is imperative that even in winter potassium intake is adequate to prevent potassium depletion.

• • Cardiovascular and Metabolic Manifestations of Heat Stroke and Severe Heat Exhaustion; is a 1979 clinical study examining the differences between heat stroke and heat exhaustion.  One key difference is those with heat stroke had less serum potassium than those with heat exhaustion.  It is important to note that serum potassium is a poor indicator of potassium in the body, meaning those with heat stroke likely had far less potassium in their tissues compared to those with heat exhaustion.

• • Potassium Deficiency as the Result of Training in Hot Weather; is a component of a 1993 report on the problems of heat stress and fluid replacement in the military.  This chapter focuses on the previous research that details how potassium deficiency contributes extensively to heat injury.  However, the report also notes that a viable solution achieve adequate potassium intake was impractical and the best solution was to train less in the heat.

• • Heat stroke: a clinic-pathologic study of 125 fatal cases; is a large survey of fatal heat stroke case studies in the early 1940s.  In those that measured serum potassium, 27 of 44 had hypokalemic potassium levels.  This indicates that low serum potassium, and hence very low tissue potassium levels, is a risk factor for heat injury.

• • Desert climate, physiological and clinical observations; is a study of British soldiers in Iraq in 1943.  Temperatures were consistently over 100°F daily.  One particular finding was that a large number of men became polyuric, or expelled large volumes of urine, in conjunction with insatiable thirst and overall weakness and increased fatigue.  This was not treatable with vasopressin, an antidiuretic that is used to slow urine production, and strongly suggests that these men were suffering from potassium deficiency.

• • Potassium Depletion in Heat Stroke: A Possible Etiologic Factor; is a 1966 case study of fatal heat stroke in which the tissue potassium levels of the patient was significantly depressed.  Authors suggest, based on prevailing case evidence, that potassium is likely required for sweat gland function.

Sodium

• • Responses to moderate and low sodium diets during exercise-heat acclimation; is a clinical study that examines how sodium intake effects exercise performance and other physiological variables such as heart rate and body temperature in extreme heat (106°F).  There was no difference in performance or other variables outside of sodium content in sweat and urine in which the low sodium diet (~1.6 grams per day) versus the moderate sodium diet (~3.2 grams per day).  Interestingly the potassium content of sweat and urine was the same regardless of sodium intake.  This study therefore indicates that increasing sodium intake has no bearing on performance or heat acclimatization.

• • Serum sodium abnormalities during nonexertional heatstroke: incidence and prognostic values; is a 2012 clinical study of patients admitted to emergency rooms with a high core body temperature above 101°F.  Patients frequently had low (35% of total patients) or high (17% of total patients) sodium, but only hypernatremia, that is having higher than normal serum (blood) sodium, was an independent risk-factor for patient death due to heatstroke.  This indicates that it is important to limit sodium intake and prevent hypernatremia.

• • The Effect of the Sodium Chloride Intake on the Work Performance of Man During Exposure to Dry Heat and Experimental Heat Exhaustion; is a clinical study in which unacclimatized men walked in 120°F heat over the course of 3 days.  There were 3 groups, high (11.7 g), medium (5.9 g), and low (2.3 g) sodium intake (note that all are at or above the FDA upper intake limit of 2.3 g per day).  It was noted that there were no differences between the high and medium diets, but the low sodium intake diet had higher heart rate and weight loss.  The sodium balance was negative for the groups, but recovered quickly in two days as subjects adapted to the heat.  This indicates that there is no need to have sodium intake higher than 6 g over the first few days of heat acclimatization.

• • Aldosteronism in Man: Some Clinical and Climatological Aspects Part I; is a revolutionary review of studies done to determine the process of adapting to working in hot environments, namely humid, tropical heat.  Increased aldosterone production begins almost immediately and there is a fast, sharp drop in urinary sodium.  Sweat glands also see a sharp drop in sodium and over the course of a few days the sweat content is as much as 95% lower than prior to adaption to working in the heat.  Even with low sodium intake (1.2 g per day) the body is able to maintain sodium balance by altering urinary and sweat sodium secretion without any drop in performance.  This series of studies indicates that while important, sodium is well conserved by the body even under the harshest conditions and that the sodium content of urine and sweat is dependent on sodium content of the diet.

• • Cardiovascular and Metabolic Manifestations of Heat Stroke and Severe Heat Exhaustion; is a 1979 clinical study examining the differences between heat stroke and heat exhaustion.  It is important to note that there was no difference in serum sodium between the heat stroke and heat exhaustion groups.  This would indicate that changes in sodium content is not a primary driver along the progression of heat stress.

Muscle Function

Potassium

• Potassium deficiency syndrome in the rat and the dog; a description of the muscle changes in the potassium-depleted dog; is a foundational 1950 study and describes how skeletal muscle rapidly degenerates in the potassium depleted dog.  However, when given more dietary potassium and restoring tissue potassium levels, the degeneration of skeletal muscle is completely reversible.
• Nutritional deficiency syndrome with diarrhea resulting in hypopotassemia, muscle degeneration, and renal insufficiency report of case with recovery; is a case study of a man with 2 months of diarrhea which resulted in severe potassium deficiency.  He had severe myolysis, or muscle cell death.  Upon increasing dietary potassium intake the individual recovered.
• Myoglobinuria and hypokalemia in regional enteritis; is a case study of a man suffering from Crohn's disease and diarrhea became severely hypokalemic.  Modest exercise resulted in pain in the calf muscle and indications of muscle cell death (rhabdomyolysis) was seen in his urine.  This was confirmed by biopsy in which striation of the cells was lost.  This was reversed and did not return once dietary potassium was increased.

Magnesium

• Skeletal muscle injury after magnesium depletion in the dog; is a 1982 study examining severe magnesium deficiency on dogs. Magnesium deficiency resulted in increases in intramuscular sodium and a drop in phosphorous.  Potassium levels did not change.  The muscle became hyperpolarized The muscle cells have morphological changes; swelling of the mitochondria and sarcoplasmic reticulum as well as degredation of the characteristic sarcomere banding pattern of the skeletal muscle.  These morphological changes are followed by cell death and necrosis of the tissue.  The reasons for this is unknown, but could be due to a variety of factors including impaired energy production (magnesium is a critical catalyst of many enzymatic reactions involved in ATP synthesis), maintaining electrical neutrality, and/or leaky cells.
• The Myopathy of Experimental Magnesium Deficiency; is a 1984 review of what was known about how magnesium deficiency effects muscle cells.  There are a variety of animals used experimentally, and differences in species show variable results, but dogs are closest to humans.  Magnesium deficiency results in higher amounts of calcium, sodium, and chloride inside cells while phosphorous levels drop.  The drop in phosphorous levels due to magnesium deficiency is actually higher than that in phosphorous deficient dogs.  Magnesium deficiency mirrors what is seen in alcoholism, with the exception of magnesium not dropping inside muscles during magnesium deficiency, but dropping in alcoholism.

Cardiovascular Function

Potassium

• Potassium Feeding Reduces Hyperactive Central Nervous System Pressor Responses in Dahl Salt-Sensitive Rats; is a 1981 study using a salt-sensitive rat model of high blood pressure.  Adding 2% potassium chloride reduced the change in mean blood pressure in these rats compared to the normal controls.  This indicates that potassium supplementation could be beneficial to those with salt sensitivity.²¹
• Double-Blind, Placebo-Controlled Trial of Potassium Chloride in the Treatment of Mild Hypertension; is a 1987 study that indicated there could be a decrease in systolic blood pressure when patients are given 120 mEq or ~4680 mg of potassium each day.  Interestingly, the study indicated that the African-American population could be especially sensitive to increases of potassium decreasing blood pressure.²²
• Cardiac arrhythmias induced by hypokalaemia and potassium loss during maintenance digoxin therapy; is a clinical study in which patients with advanced congestive heart failure on digoxin therapy were subjected to a low-potassium diet.  Within one week half the patients had developed arrhythmias.  It is concluded that hypokalaemia can contribute significantly to the development of arrhythmia for those on digoxin therapy.
•  Effect of increased potassium intake on cardiovascular risk factors and disease: systematic review and meta-analysis; is a comprehensive review of 22 randomized control studies.  It concludes that there is high quality evidence that by increasing potassium consumption there is a correlating decrease in blood pressure, especially in hypertensive individuals.  Furthermore, there is moderate evidence that increased potassium intake is correlated with a 24% lower risk of stroke.  Increased potassium intake is defined in this study as ~3500 mg per day. which is below the 4700 mg per day recommended.²³
• Cardiac Necrosis Accompanying Potassium Deficiency and Administration of Corticosteroids; is a study examining how deprivation and addition of magnesium, sodium, and potassium chloride, alone or in combination, affects heart lesions.  Cardiac necrosis correlates with decreased skeletal muscle potassium and increase skeletal muscle sodium.  Addition of potassium in the animals' drinking water is the only electrolyte that prevents the formation of cardiac necrosis in these animals.

Sodium

• Dietary Sodium and Health: More Than Just Blood Pressure; is an interesting review of sodium literature.  High sodium intake stiffens arterial endothelial cells and also damages the pericellular matrix which can lead to atherosclerosis.  High sodium intake also increases the mass of the left ventricle of the heart independent of blood pressure which increases the risk of cardiovascular complications such as heart attack or stroke, but can be reduced by decreasing sodium intake.  High sodium intake also decreases plasma flow in and filtration rate while increasing protein excretion in the kidney.  This proteinuria affect can be reduced by reducing sodium intake.  When sodium intake is chronically high the sympathetic nervous system may become disrupted resulting in salt-sensitive hypertension.  The amount of sodium required to maintain homeostasis in most adults is only 500 mg, far below the 2300 mg upper limit and the 4400 and 3000 mg ingested by men and women on average respectively.
• Effect of Plasma Sodium on Aldosterone Secretion during Angiotensin 2 Stimulation in Normal Humans; is a small clinical trial that demonstrated that small increases of sodium can substantially alter aldosterone secretion, but only when Angiotensin 2 levels are elevated.

Kidney Function

Potassium

• Potassium depletion in permanent inhabitants of hot areas; is a study examining how miners that live and work in the heat (113-117°F) become potassium deficient.  These miners are unable to concentrate their urine with none above 1200 mOsm/kg and 30% below 800 mOsm/kg, but when supplemented with 8 grams of potassium per day for 1 week their kidney function recovered and their urine concentration became normal with 21% of miners having urine above 1200 mOsm/kg and only 7% below 800 mOsm/kg.
• The Renal Lesions of Electrolyte Imbalance: The Structural Alterations in Potassium-Depleted Rats; is a 1957 study that examined anatomical changes in the rat kidney as a result of potassium depletion.  During the early stage of potassium depletion the kidneys developed lesions in the collecting tubules.  These developed into swelling and hyperplasia (excessive cell division rate) in which the mitochondrial pattern changes and cell death occurs while rapid division attempts to maintain kidney function.  These disturbances can be linked to an inability to concentrate urine.
• The Renal Lesions of Electrolyte Imbalance: The Combined Effect on Renal Architecture of Phosphate Loading and Potassium Depletion; is an extension of the 1957 study in which lower dose phosphate loading and potassium depletion are examined together.  The potassium depletion acts synergistically with the moderate phosphate load and exasperates the phosphate-specific alterations in kidney anatomy seen in high dose phosphate loading.
• A Prospective Study of Dietary Calcium and Other Nutrients and the Risk of Symptomatic Kidney Stones; is a 1993 study that shows that increasing potassium intake lowers the incidence of kidney stone formation.
• Potassium deficiency in chronic renal failure; is a clinical trial of patients with chronic kidney disease, which is defined as the gradual loss of kidney function.  All subjects with chronic kidney disease had significantly lower intracellular (determined via muscle biopsy) potassium than control.  Furthermore, all but 2 had significantly higher intracellular sodium than controls.  This study indicates that chronic potassium deficiency is a common component of chronic kidney disease.

Sodium

• Dietary Sodium and Health: More Than Just Blood Pressure; is an interesting review of sodium literature.  High sodium intake stiffens arterial endothelial cells and also damages the pericellular matrix which can lead to atherosclerosis.  High sodium intake also increases the mass of the left ventricle of the heart independent of blood pressure which increases the risk of cardiovascular complications such as heart attack or stroke, but can be reduced by decreasing sodium intake.  High sodium intake also decreases plasma flow in and filtration rate while increasing protein excretion in the kidney.  This proteinuria affect can be reduced by reducing sodium intake.  When sodium intake is chronically high the sympathetic nervous system may become disrupted resulting in salt-sensitive hypertension.  The amount of sodium required to maintain homeostasis in most adults is only 500 mg, far below the 2300 mg upper limit and the 4400 and 3000 mg ingested by men and women on average respectively.
• Effect of Plasma Sodium on Aldosterone Secretion during Angiotensin 2 Stimulation in Normal Humans; is a small clinical trial that demonstrated that small increases of sodium can substantially alter aldosterone secretion, but only when Angiotensin 2 levels are elevated.

Neurological Function

Potassium

• Potassium signalling in the brain: its role in behaviour; is a 2000 review examining how glial cells (the non-neuronal cells of the brain) redistribute potassium and alter the behavior of animals.²⁴
• Potassium Treatment for Premenstrual Syndrome; is a pilot study to examine if potassium supplementation of 600 mg can have an effect on women suffering from PMS.  This study was done with women in their 50s and 8 of 11 had their PMS symptoms resolved after potassium supplementation.
• Potassium: A New Treatment for Premenstrual Syndrome; is a small study of 7 women with severe PMS and were supplemented with 600 mg of potassium daily.  PMS symptoms, as ascertained by survey, diminished with each cycle and were absent by the 4^th cycle after starting potassium supplementation in all 7 participants.

Sodium

• Dietary salt promotes neurovascular and cognitive dysfunction through a gut-initiated TH17 response; is a pioneering study in mice that shows how high sodium intake may increase the risk of neurodegenerative disease via constriction of blood vessels in the brain.  This occurs as the sodium increases TH17 production from T-helper cells (a type of immune cell) in the gut.  TH17 then inhibits nitric oxide production (normally causes vasodialation) and results in restricted blood flow in the brain.  The high salt animals had significant cognitive decline, but were able to recover when the high sodium diet was removed.

Cramps

Night time leg and foot cramps

• Nocturnal leg cramps: Prevalence and associations with demographics, sleep disturbance symptoms, medical conditions, and cardiometabolic risk factors; is a large study from the National Health and Nutrition Examination Survey in 2005-2006 and 2007-2008.  30% of the population suffers from nighttime leg cramps with 6% being severe.  This kind of cramp increases in frequency and severity with age, lower overall health, and professions that are more blue-collar.
• Muscle Cramps Do Not Improve With Correction of Vitamin D Insufficiency; is a clinical study examining idiopathic cramping in women between 60 and 75 years of age.  The only significant difference in nutrition between those that suffered from cramps and those that did not is their potassium intake.  Women suffering from idiopathic cramps consumed significantly less potassium than those that did not.  This indicates that low potassium consumption is the primary difference between those that do and those that do not suffer from idiopathic cramps.

Menstrual Cramps

• The Prevalence and Risk Factors of Dysmennorrhea (menstrual cramps); is a meta-analysis of 15 studies conducted from 2002-2011 across the world. The range of those menstruating women suffering from menstrual cramps is wide, from 16% (Japan) to 91% (Iran), with 2% (United States) to 29% (Japan) having debilitating pain.  Women with a family history had a much higher likelihood of suffering from menstrual cramps.  Younger women and those with more stress also had a moderately higher likelihood of suffering from menstrual cramps.  Mitigating factors are having had children or using oral contraceptives.
• Productivity loss due to menstruation-related symptoms: a nationwide cross-sectional survey among 32,748 women; is a large study examining how menstrual cramps affect productivity. The findings are startling with the average woman losing 9 days of productivity due to menstrual cramps.
• Primary dysmenorrhea and its effect on quality of life in young girls; is a cross-sectional study of 310 women in India between 18-25 years of age. 2% of these women reported menstrual cramps and 91% had PMS, including 40.4% suffering from leg cramps.  These women are more than 4 times as likely to be absent, more than 3 times as likely to have reduced physical activity and concentration, and more than twice as likely to have poor work satisfaction and skipping of meals.
• Prevalence of menstrual pain in young women: what is dysmenorrhea?; is a cross-sectional study of 408 Italian women with an average age of 23 years. 1% of women reported menstrual pain, with 43.1% reporting this pain occurred with each menstrual period.  55.2% of these women used medication to help temper the pain and, despite medication use, 25.3% of women experience absenteeism.  This demonstrates that even with the use of medication, about 1 in 4 young women miss work or school due to menstrual cramps.

Exercise and other cramps

• Tetany induced by hypokalemia in the absence of alkalosis; is a case study in which an individual had tetany (muscle cramps) as a sole result of potassium deficiency.

Diabetes and Diebetics

Potassium

• Effects of potassium supplements on glucose metabolism in African Americans with prediabetes: a pilot trial; is a clinical trial in which participants averaged 2456 mg of potassium per day in their normal diet.  Participants were given an additional 1500 mg of potassium for 12 weeks bringing them to an average of 3956 mg per day, which is still short of the 4700 mg per day recommended.  The potassium supplementation resulted in a significant decrease in fasting glucose, showing that increased potassium intake may help with controlling prediabetes.
• Serum an Dietary Potassium and Risk of Incident Type 2 Diabetes: The Atherosclerosis Risk in Communities (ARIC) Study; is a large clinical study that demonstrated that individuals with a plasma potassium level below 4.5 mEq/L have a higher incident rate of becoming type 2 diabetic.  This rate increases when low serum potassium is combined with diuretic use and is measurable over an extended time period.
• Potassium intake and risk of incident type 2 diabetes mellitus: theCoronary Artery Risk Development in Young Adults (CARDIA) Study; is a large clinical study that young people with low urinary potassium levels have a higher incidence of developing type-2 diabetes.  Furthermore, those with low potassium intake also have higher incidence of developing type-2 diabetes.
• Serum potassium is a predictor of incident diabetes in African Americans with normal aldosteron: the Jackson Heart Study; is another clinical trial focusing on African Americans that showed that subjects with serum potassium above 4.3 mmol/L have significantly lower risk of developing type-2 diabetes than those with serum potassium lower than 4.1 mmol/L.
• Evidence for a role of endogenous insulin and glucagon in the regulation of potassium homeostasis; is an animal study examining how potassium infusion interacts with insulin, glucagon, and glucose in normal and alloxan-induced diabetic dogs.  In normal dogs, potassium infusion caused both insulin and glucagon levels in increase in serum while glucose was level.  Potassium infusion in the alloxan-diabetic dogs caused hyperkalemia and rises in serum glucose and glucagon.  However, hyperkalemia was prevented by the addition of insulin to the alloxan-diabetic dogs and serum glucose was decreased.  In normal dogs, infusion of potassium results in a decrease in serum glucose during a hyperglycemic state caused by contemporaneous glucose infusion.

Immune Function

Potassium

• K+ regulates Ca2+ to drive inflammasome signaling: Dynamic visulization of ion flux in live cells; is a 2015 study studying macrophages, a kind of white blood cell, and the coordination of potassium and calcium to drive inflammasome formation to create reactive oxygen species as a part of innate immunity, but also macrophage mediate chronic inflammatory diseases.  High extracellular potassium inhibits inflammasome formation which is induced by having too much calcium in the mitochondria.

Advantame

Advantame Safety

• A two-generation reproductive toxicity study of the high-intensity sweetener advantame in CD rats; is a 2011 study examining whether Advantame poses any teratogenic risks (risks to unborn).  There were no adverse effects for reproductive health or development.
• Acute and multiple-dose studies to determine the safety, tolerability, and pharmacokinetic profile of advantame in healthy volunteers; is a 2011 study examining how high levels of Advantame affect human subjects.  This study showed that even at very high quantities ingested, Advantame was not quantifiable in the blood, indicating that it passes through the gut.
• Chronic oral toxicity of N-[N-[3-(3-hydroxy-4-methoxyphenyl)propyl]-a-aspartyl]-L-phenylalanine 1-methyl ester, monohydrate (advantame) in the dog; is a 2011 study that followed dogs consuming about 2100 mg/kg body weight Advantame daily for a year.  No changes were seen in a plethora of factors indicating Advantame is safe to use chronically.
• Chronic toxicity and carcinogenicity of N-[N-[3-(3-hydroxy-4-methoxyphenyl)propyl]-a-aspartyl]-L-phenylalanine 1-methyl ester, monohydrate (advantame)in the rat; is a 2011 study that followed rats consuming upwards of 3400mg/kg body weight of Advantame per day for 2 years.  There was no observed adverse effect in the rats after the 2 year period.
• Evaluation of the teratogenic potential of N-[N-[3-(3-hydroxy-4-methoxyphenyl)propyl]-a-aspartyl]-L-phenylalanine 1-methyl ester, monohydrate (advantame)in the rat and rabbit; is a 2011 study that examined if Advantame could harm the offspring of rats and rabbits.  There was no direct effects observed on fetal health indicating Advantame is safe for use during pregnancy.
• In vitro and in vivo assessment of the mutagenic activity of N-[N-[3-(3-hydroxy-4-methoxyphenyl) propyl]-a-aspartyl]-L-phenylalanine 1-methyl ester, monohydrate (advantame); is a 2011 study that evaluated whether Advantame can cause genetic mutations in both bacteria and mammalian cells.  There were no mutations in any tested cell line indicating that there is not mutagenic potential of Advantame.
• Pharmacokinetics and metabolism of N-[N-[3-(3-hydroxy-4-methoxyphenyl) propyl]-a-aspartyl]-L-phenylalanine 1-methyl ester, monohydrate (advantame) in the rat, dog, and man; is a 2011 study that examined the metabolic fate using radiolabeled Advantame.  More than 90% is passed through the gut in humans and metabolites found are consistent across species.

Advantame and the Gut

• Measuring Artificial Sweeteners Toxicity Using a Bioluminescent Bacterial Panel; is a 2018 study that examined the FDA approved artificial sweeteners for their toxic effects on gut bacteria, specifically genotoxic, cytotoxic, and membrane toxicity.  Interestingly, Advantame was the only FDA approved sweetener to not have any toxic effects, but did enhance growth indicating it could be a prebiotic.
• Effects of Sweeteners on the Gut Microbiota: A Review of Experimental Studies and Clinical Trials; is a 2019 review of the literature in this somewhat new field.  Advantame is one of the few high intensity sweeteners that did not affect the gut microbiota.