Archive for June, 2014

Hyper and hypokalaemia in athletes

June 8, 2014

Potassium ions are of key importance for health and for athletic performance. The level of potassium in the blood must be regulated within fairly narrow limits: at concentrations above 12 mM there is a very high risk of sudden cardiac arrest*.  Steady state levels above 6.5 mM are considered dangerous in clinical practice, while levels below 3.5 mM are associated with slow repolarization of heart muscle and risk of various disturbances of cardiac rhythm, and also with risk of additional serious disorders such as high blood pressure and stroke (reviewed by Sica and colleagues). Low blood levels are also associated with fatigue of skeletal muscles, but so too is the loss of the normal gradient of potassium ions across muscle cell membranes that arises when potassium moves out of muscle cells into the extracelular fluid.

*[As summarised in the discussion with Michael below, the highest published potassium level in  a person who subsequently survived is 14 mM (possibly arising from muscle damage sustained during cardiac resuscitation.)  However survival after potassium exceeds 10 mM is very rare. ]

Potassium is lost from the body via the kidneys and in sweat. But more important than the maintenance of total body levels is the distribution between the inside of cells and the extra-cellular fluids (including blood plasma). While typical concentration outside of cells is around 4.5 mM, the concentration inside nerve and muscle cells is in the vicinity of 150 mM. About 98% of the body’s potassium is contained within cells. This gradient in ion concentration across the cell membrane is essential for conduction of neural impulses and for muscular contraction. Normal neural conduction and muscle contraction entail flow of potassium though ion channels in the cell membrane, thereby depleting intracellular levels and causing extracellular concentration to rise appreciably. This reduction in the gradient across the membrane contributes to fatigue. Extracellular levels of potassium are regulated by the renin-angiotensin-aldosterone hormonal system, which promotes potassium loss when levels are high.   Thus, higher extra-cellular levels promote potassium loss for the body. Molecular pumps that move potassium (K+) ions back into calls in exchange for sodium (Na+ ) ions minimise loss of potassium form cells during exercise and reducing fatigue, but continue to pump after exercise stops, resulting in a net fall of potassium below the pre-exercise levels.

The first concern of the athlete the development of effective Na/K pumping, and the second concern is ensuring that dietary intake is adequate so that total body store is not depleted. In long endurance races and even more catastrophic issue arises: damage to muscle cells during prolonged exercise can release potassium together with protein myoglobin, which damages the kidneys, and can result in potassium rising to dangerous levels. This is one of the causes of the rare sudden deaths that occur in the late stages of a marathon.   Thus, it is worthwhile understanding how training can promote effective Na/K pumping and the role of both electrolyte replacement and diet in maintaining the appropriate total body level of potassium.

 

The role of potassium in skeletal muscle contraction

The contraction of skeletal muscles is elicited by a rapid influx of Na+ and an equivalent efflux of K+ ions across cell membranes.  Skeletal muscles contain the largest pool of K+ in the body. During intense exercise, the Na/K-pumps cannot readily return K+ into the muscle cells. Therefore, the working muscles undergo a net loss of K+, while the K+ concentration in the arterial blood plasma can double in less than 1 minute. Even larger increases in K+ in interstitial tissues surrounding the muscle cells. This results in degradation in the electrical potential gradient across membranes, thereby resulting in loss of excitability and force. During continuous stimulation of isolated muscles, there is a strong correlation between the rise in extracellular K+ and the rate of force decline. These events present a major challenge for the Na/K-pumps.   Excitation of the muscle itself, together with the stimulating effects of adrenaline and insulin, increases the Na/K-pumping rate. If all available pumps are engaged, the rate of pumping can increase up to 20-fold above the resting transport rate within 10 seconds. Thus in working muscles, the Na/K-pumps play a dynamic regulatory role in the maintenance of excitability and force. Down-regulation of pump capacity reduces contractile endurance in isolated muscles. The Na/K-pump capacity is a limiting factor for contractile force and endurance, especially when their capacity is reduced as a result of de-training.

The pumping capacity of Na/K-pumps is influenced by hormones, such as thyroid hormone, adrenal steroids including cortisol, insulin, and by fasting and potassium-deficiency (as reviewed by Torben Clausen from University of Aarhus in Denmark). Thus, an adequate intake of dietary potassium is important. Good sources are leafy greens, dried apricots, yoghurt, salmon, mushrooms, and bananas. Perhaps even more importantly, physical inactivity degrades pumping capacity while training enhances it. High intensity interval training is especially effective in enhancing Na/K pump capacity. For example, Bangsbo and colleagues form Copenhagen reported that six to twelve 30-s sprint runs 3-4 times/week for 9 weeks produced a 68% increase in Na/K-pump units (p<0,05) and a significant reduction of blood plasma K+ level, compared with observations in a control group who continued with endurance training (approximately 55 km/Km). The intense sprint training was associated with significant improvement in performance. In those doing the intense sprints, 3-km time was reduced by 18 seconds from 10 min 24 sec to 10 min 6sec while 10-km time improved from 37 min18 sec to 36 min18 sec.

 

The effect of potassium on the heart

Unlike the situation in skeletal muscle, under normal circumstances, in the heart the rise in intracellular Na+ concretion associated with activation of the muscle activate the Na/K pump adequately to completely compensate for the increased K+ release (evidence reviewed by Sejersted).  Thus, whereas the K+ shifts during intense exercise can contribute substantially to fatigue in skeletal muscle in the heart, the K(+) balance is normally controlled much more effectively. This might not be the case during abnormal circumstances such as ischemia.

If there is serious elevation of blood levels of potassium due to muscle damage (see the section on rhabdomyolysis below) or due to dietary excess in the presence of a disorder of the renin-angiotension –aldosterone mechanism that normally regulates potassium, there is a risk of serious reduction of the electrical gradient across the heart muscle membrane essential for conduction of the excitation signal thought the heart muscle. The consequence can be cardiac arrest, which is usually fatal.

Conversely, when blood levels of potassium are low, due to serious loss and failure of dietary replacement, the re-establishment of the electrical gradient is slower. This delayed re-polarization is, manifest as an increase in the interval between the Q wave and the T wave in the electro cardiogram. The delayed re-polarization can lead to rhythm disturbances due to alteration of the conduction pathways. The most serious of these is the rare but potentially fatal rhythm disturbance known as Torsade de Pointes. However, because of the normally tight regulation of sodium and potassium ion level by the renin-angiotensin aldosterone system, this is very unlikely in otherwise healthy individuals.

 

Regulation of potassium levels by the renin-angiotensin-aldosterone system

Renin is an enzyme secreted by the kidneys that acts on a substance called angiotensinogen that is produced in the liver. Renin splits angiotensinogen releasing the peptide angiotensin, which has various actions in the body directed towards retaining sodium, conserving blood volume and maintaining blood pressure. One of the important actions of angiotensin is stimulation of release of the steroid hormone, aldosterone, from the adrenal glands. Aldosterone acts on the kidney to promote retention of sodium and excretion of potassium. During exercise, aldosterone production is increased, thereby decreasing urine production and conserving fluid volume, while promoting excretion of potassium. This helps reduce the accumulation of potassium in blood due to efflux from active skeletal muscle, but contributes to the fall in potassium levels after exercise ceases. Maintenance of blood volume by moderate fluid intake is likely to minimise excessive engagement of the renin-angiotensin-aldosterone system.

On one occasion when I made an overly ambitious attempt to find a novel route across a mountain ridge for my return journey during a long run in the Sierra Nevada in southern Spain on a hot dry day with an inadequate supply of water, I became quite dehydrated. I was somewhat alarmed to experience an increase in ectopic heart beats. I suspect that the dehydration had led to excessive activity of the renin-angiotensin-aldosterone system, depletion of potassium and consequent disturbance of heart rhythm. I am now much more careful about hydration during long runs.

For runs greater than 20 Km, I generally prepare a drink containing 4 tablespoons of sugar and one quarter of a teaspoon of salt in four cups of water, together with lemon juice to make it palatable. I do not add any potassium salts to this mixture, as any added potassium might promote excessive activation of the renin-angiotensin-aldosterone system, thereby defeating the purpose. I adjust rate of intake to keep just ahead of appreciable thirst. Typically I find that consuming a mouthful of this drink per Km keeps me adequately hydrated.

 

Rhabdomyolysis

Rhabdomyolysis is a condition produced by the breakdown of muscle, resulting in the release of the protein myoglobin, along with potassium in to the blood stream. The myoglobin damages the kidney with multiple adverse consequences including failure of potassium excretion.   In extreme cases the increase in blood potassium can produce fatal cardiac arrest.   In slightly less extreme cases, the kidney failure is nonetheless a serious medical emergency. Severe rhabdomyolysis arises rarely as a result of the muscle damage sustained during endurance events. However, some evidence indicates that mild degrees are not uncommon in males. For example a study by Maxwell and Bloor that tested for evidence of muscle damage after a 14 mile run at 8 min/mile pace in three groups of well-conditioned male athletes who had undergone training regimes differing in volume of running for a period of one months, found that the 14 mile run produced evidence of substantial muscle damage, including increases in serum myoglobin ranging from of 52-405%. The increases were most marked in those who had trained less for 8 miles/day on alternate days. Rhabdomyolysis is much less in females, possible because oestrogen stabilises muscle membranes.

 It should also be noted that exercise induced rhabdomyolysis does not always lead to increased levels of potassium. In a series cases of exercise indices rhabdomyolysis reported by Sinert and colleagues there were no cases of hyperkalaemia.

 

Conclusion

Efficient regulation of potassium is essential for both good athletic performance and for health. One key issue for endurance athletes is maintaining the capacity of the Na/K-pumps that return potassium excreted by muscle cells as result of muscular activation back into the muscle cells. Inadequate pumping results in fatigue. Training, especially high intensity interval training, enhances the activity of the Na/K pumps. Potassium is lost from the body during exercise and dietary replacement of potassium is necessary though this is not generally an issue provide diet is reasonably well balanced.   However, sustained potassium depletion has adverse effects including heart rhythm disturbances, increased blood pressure and risk of stroke.

The renin-angiotensin-aldosterone system acts to maintain fluid volume during exercise, but promotes potassium loss. It is important to avoid serious dehydration to minimise the risk of excessive activation of the renin-angiotensin-aldosterone system.

In rare instances, muscle damage during endurance events results in life-threatening rhabdomyolysis. This can lead to a dangerous excess of potassium in the blood.  More common is moderate muscle damage that leads to accumulation of myoglobin.  However, training reduces this risk.

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Cortisol and the stress response

June 2, 2014

Cortisol, a steroid hormone produced by the adrenal gland, plays a key role in mobilizing the body’s resources to cope with stressful challenges, including the challenge of running. Among its many roles is the regulation of blood glucose. When demands are high, cortisol acts to conserve glucose for the brain by minimizing uptake of glucose into other tissues and by promoting the production of glucose in the liver.   Because healing is not a priority when dealing with an acute challenge, cortisol suppresses inflammation and the immune system. In a healthy person, cortisol levels return to normal over a time scale of 30-60 minutes after the stress resolves. However if the transient surge of cortisol required to deal with acute stress is not switched off, cortisol inhibits healing by suppressing the formation of collagen while promoting breakdown of protein, thereby damaging many tissues of the body.

Recent evidence from a study by Skoluda and colleagues indicates that endurance athletes tend to have persistently high levels of cortisol. This increases in proportion to training volume. Thus the regulation of cortisol is potentially of great importance not only for ensuring that an athlete obtains benefits from training, but also for long term health.

The relationship between cortisol and inflammation is complex. In the short term cortisol suppresses inflammation, but sustained elevation of cortisol can lead to a suppression of the receptors that mediate the effects of cortisol on body tissues, and consequently, sustained elevation of cortisol can actually promote chronic inflammation which in turn damages tissues by laying down non-functional fibrous tissue as described in my recent post.

Although excessive cortisol is harmful, reduced ability to generate cortisol when required can be even more harmful. Addison’s disease, a rare condition in which the adrenal gland is damaged by autoimmune attack, is characterised by non-specific symptoms such as weakness and fatigue, and can be result in fatal inability to respond to stress. There is some evidence that sustained stress can reduce the capacity of the adrenal glands to produce cortisol when required, though the concept of adrenal fatigue, popularized by some alternative-medicine practitioners, remains an ill-defined entity.

Cortisol production is regulated by a feedback mechanism that takes account of information about the overall metabolic state of the body. This feedback system acts via the hypothalamo-pituitary-adrenal axis (HPA). The release of cortisol from the adrenal glands is stimulated by a hormone, ACTH, that is produced in the pituitary gland. The release of ACTH is in turn stimulated by a hormone, corticotrophin releasing factor, that is secreted by the hypothalamus. Information about the state of the body is funnelled via the amygdala and hippocampus in the temporal lobe of the brain, to the hypothalamus. This complex feedback system allows a diverse array of neural and hormonal signals to control cortisol release in a way that balances the catabolic effects of cortisol, promoting tissues breakdown, with the anabolic effects of other hormones, such as DHEA (a steroid hormone produced in the adrenal glands) and growth hormone, produced in the pituitary gland, that play a role in promoting the repair and strengthening of damaged tissues.  Thus many complex, interacting processes are involved in ensuring the optimal balance between mobilising body resources to deal with acute challenge and subsequent healing. Factors such as levels of ongoing stress from life circumstances and age contribute to the balance.

 Strategies for optimising the stress response

In summary, an athlete requires healthy adrenal glands which can generate enough cortisol to meet the challenge of stress but then to switch off cortisol production to promote recovery. The simple principle is that for optimum training benefit and long term health, we need to avoid excessive stress. However, the best way of achieving this is likely to determined by individual’s genes and life circumstances. While each individual has to find what works for him or her, there are several issues likely to be relevant to most athletes.

1)      Avoiding over-training. As demonstrated by Skoluda, the sustained excess of cortisol is greater in those who train more. Both volume and intensity matter though it is noteworthy that prolonged duration of exercise promotes increase in cortisol, whereas high intensity promotes hormones such as growth hormone and anabolic steroid hormones that promote strengthening of tissues. Consistent with this, some evidence indicates that the over-training syndrome is more strongly linked to high volume training than to high intensity training.

2)      Recovery from training and racing is crucial.   Not only does inadequate recovery increase the risk of persisting inflammation (as discussed in my previous post) but it impedes the transition from the cortisol induced catabolic state to the anabolic state required to rebuild and strengthen body tissues. This raises the major question of how best to determine if recovery is adequate. Subjective indices such as the Profile of Mood States, and autonomic measures such as resting heart rate and heart rate variability provide a guide, but no single test provides the full answer.  This is an issue I will return to again in the near future.

3)      Resistance training promotes the release of anabolic hormones and has many other beneficial effects on metabolism including increased sensitively to insulin. The major metabolic benefits of resistance training can be achieved by two 15 minute sessions per week.

4)      Life-stress and relaxation. Many of us have relatively limited control over the pressures of work and other responsibilities. However the way we react to these pressures is largely under our own control. Sleep plays a cardinal role. During sleep, cortisol levels fall while release of growth hormone is promoted. During our waking hours we can do a great deal to minimise stress. In recent years, the practice of Mindfulness has been proven to be effective in treating clinical disorders including anxiety and depression. It is a technique derived from Eastern meditative practices in which the aim is cultivation of a calm, non-judgmental awareness of one’s present physical and mental state.   Accumulating evidence indicates that this mental state is the optimum state for individuals such as US Navy Seals for whom remaining calm and focussed under intense pressure is crucial. Some studies show that Mindfulness lowers cortisol levels, while other studies have found evidence of beneficial reduction in stress and improved sleep but did not observe significant reduction of cortisol levels. Mindfulness is a knack that can be acquired by practice. Although the evidence for its effectiveness is still preliminary, my own experience is that it is effective in lowering mental and physical tension. I practice it at any time when I feel pressure is building, and also experiment with employing it while running to promote a constructive focussed mental state.

5)      Fuelling before and during training is a debateable topic. Some evidence indicates that training in a fasting state leads to improved endurance performance, perhaps mediated by the development of increased capacity to utilise fat as fuel, but overall the studies have yielded mixed results, as I have discussed in a previous post. I suspect this is because training in a fasted state also promotes increased cortisol levels that might be harmful. I have made appreciable gains in fitness in the past following training in a fasted state, but suffered one of the few serious muscle strains I have ever experienced after three weeks of high volume training predominantly in a fasted state.   This is mere anecdote, but when combined with the mixed evidence from scientific studies, leads me to conclude that training in a fasted state should be done cautiously, ensuring that overall stress levels are not excessive.

6)      Long term nutrition.  In light of the mechanism by which the hypothalamo-pituitary axis (HPA) adjusts cortisol levels in order to maintain metabolic homeostasis, it would be expected that a diet that promotes healthy energy metabolism would also be expected to promote healthy regulation of cortisol. As discussed in several of my recent posts, there is growing evidence that a Mediterranean diet promotes healthy metabolism. In accord with this, the available evidence indicates that a Mediterranean diet does promote healthy regulation of cortisol. For example a study of Spanish women found that those who chose a dietary pattern closer to the Mediterranean diet, with high mono-unsaturated fatty acid intake, showed more stable regulation of cortisol by the HPA.

 Conclusions

The evidence obtaind by Skoluda indicating that endurance athletes suffer sustained elevation of cortisol suggests that taking steps to maintain healthy regulation of cortisol is likely to result not only in a better response to endurance training but also in better long term health. This might be achieved by avoidance of over-training, ensuing good recovery, incorporation of some resistance training into the schedule and a number of life-style adaptations including adequate sleep, stress reduction via strategies such as Mindfulness, and a healthy diet, such as the Mediterranean diet.