Welcome to the Krampade Literature Library

This is our collection of literature covering the various subjects pertinent to Krampade®. Literature is open to the public or referenced from the public abstract through the US National Library of Medicine (NLM).


The core electrolyte in our formulations

Potassium Tissue Distribution
  • Distribution of Injected Radioactive Potassium in Rats; revolutionary 1940 study in which researchers injected radioactive potassium into rats, measuring the radiation emitted to determine where the potassium had been distributed in the body.  98% of potassium is found to be in tissues, which is rapidly removed from the blood.1
  • Distribution of Potassium in Liver, Kidney, and Brain of the Rat and Guinea Pig; is a 1955 study examining where inside the cell potassium is found in the liver, kidney, and brain.  65-85% is found in the soluble cytoplasm while 15-30% is found in the mitochondria.  The brain had much more in the mitochondria than the other tissues with an average of 27.4 mM versus 9.9 and 10.2 mM in kidney and liver respectively.2
Potassium Regulation
  • Potassium physiology; is a short review of potassium regulation and impacting factors such as the use of certain pharmaceuticals, such as beta blockers, on potassium secretion regulation.3
  • Regulation of Potassium Homeostasis; is a more recent 2015 review of potassium regulation more globally, including within muscle cells and various kidney cells, under a variety of conditions.4
Potassium Intake and Requirements
  • 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
Potassium Replacement
Potassium and Exercise
  • 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.
Potassium and Fatigue
  • 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
Potassium and Cardiovascular Health
Potassium and Kidney Function
Potassium and Cognition
Potassium and Immunity
  • 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.25
Potassium and Diabetes
Potassium and Heat Stress
  • 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.


Advantame Safety
Advantame and the Gut


Sodium Intake
Sodium Regulation
  • Sodium and Chloride; is a comprehensive review of sodium chloride intake, regulation, and corresponding health issues.  An obligatory minimum of 185 mg of sodium is required per day.  The rate of sodium loss is highly variable and is determined by the amount of sodium ingested.  Sodium balance can be maintained even under hot conditions and acclimation to heat is a rapid process in which sodium lost in sweat can decrease from, for example, 11.2 g per day to 1.6 g per day without a decrease in total body sodium.  This means that reduced sodium intake is unlikely to affect physical performance.  Other risk factors associated with high (above 2.3 grams per day) sodium intake include higher calcium excretion and hence kidney stone formation, increased blood pressure, higher incidence of cardiovascular disease, more severe asthma, higher risk of stomach cancer, and impeded post exercise lung function.  The upper limit of sodium consumption is established at 2.3 grams per day.
  • 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.
Sodium, Exercise, and Heat Stress
  • 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.
Sodium and Cognition
  • 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.
Sodium and Cardiovascular/Kidney Function
  • 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.