FAQ - Hyponatraemia

Send any comments to the maintainer Roger Caffin

Responses on this subject sent to BMJ included the following interesting exchanges. There were more, but they started to wander off the original subject. If you get to the end of this section, I imagine you will see what I mean. Reproduced with acknowledgments to BMJ.

 

From Dr Noakes

It is difficult for a patient not to receive intravenous fluids if he/she is having a major operation or has a critical illness but, as in the case of marathon runners (1), there is very little objective data to support the practice (2) even in shock.

There are two schools of thought, the "dry" school and the "wet" school. The "dry" school is based upon Francis Moore's classic work at Harvard on the metabolic response to surgery in which he identified salt and water retention with surgery and therefore the need to restrict fluids. The "wet" school, which has almost replaced by the "dry" school is based upon Tom Shires's [Cornell] finding of acute increases in extracellular fluid volume or "third-spacing" during major surgical procedures.

Subsequent studies in animals by George Zuidema [Univeristy of Michigan, Johns Hopkins] showed that resucitation from haemorrhagic shock with a combination of blood and isotonic salt solution achived better outcomes than resuscitation with blood alone. This lead to the current practice of administering large volumes of Ringer's lactate to shocked patients and even those having major surgery. There were disturbing anecdotal reports of an increase incidence of pulmonary oedema or "shock lung", a serious complication which I once saw occur in a young patient after an appendectomy. This was addressed by better monitoring, often with a pulmonary artery catheter. Despite concerns that have been raised about the practice it continues today, keeping patients "dry" being considered by many as being of historical interest only. It is time to revisit the issue.

Surprisingly capillary flow is not significantly reduced in shock and may even be increased in late shock and septic shock circumstances in which vasodilation is a dominant vascular feature (3,4). Capillary flow is a directly related to the persusion pressure from arteriolar to venular end and is inversely related to the resistance primarily of the precapillary sphincters. The vasoconstriction of the precapillary sphincters induced in shock by the release of endogenous vasoconstrictors, including vasopressin and angiotensin II, increases the pressure gradient between the interstitial space and the capillary blood (5). This causes an autotransfusion of interstitial fluid together with the autotransfusion of blood. The autotransfusion of blood is caused by the simultaneous constriction of splanchnic venous capacitance vessels by circulating catecholamines and sympathetic stimulation.

Tissue oxygenation may be improved in unresuscitated shock for the intercapillary distances are probably decreased. Intravenous infusions of fluid might, therefore, be detremental for they may decrease capillary flow rate by increasing venular outflow pressure and reverse the pressure gradient across capillaries. [The fall in venular outflow pressure appears to be an important determinant of the ability to maintain capillary flow during shock]. The reversal of the pressure gradient is responsible for the "third-spacing" described by Tom Shires. The likelihood of it occurring will increase as the permeability of the capillaries increases. The permability increase per se cannot be an important cause of oedema.

A prospective trial was conducted comparing immediate and delayed fluid resuscitation in 598 adults with penetrating torso injuries who presented with a pre-hospital systolic blood pressure of < or = 90 mm Hg (6). Patients assigned to the immediate-resuscitation group received standard fluid resuscitation before they reached the hospital and in the trauma center, and those assigned to the delayed-resuscitation group received intravenous cannulation but no fluid resuscitation until they reached the operating room. Among the 289 patients who received delayed fluid resuscitation, 203 (70 percent) survived and were discharged from the hospital, as compared with 193 of the 309 patients (62 percent) who received immediate fluid resuscitation (P = 0.04). This study provides strong support for the "dry"school.

Viewed in this context some degree of dehydration may benefit marathon runners by increasing the pressure gradient across their capillary beds, increasing capillary flow rates and decreasing intercapillary distances.

 

From BM Hegde

Very interesting. One of the reasons for the higher per capita death of war casualties in Vietnam compared to Falklands is supposed to be immediate fluid and blood replacement in Vietnam in the five-star American hospital in Saigon. There are other causes mentioned also in the audit.This fits in with the "dry hypothesis".

I wonder if you would let the readers know as to how much water one should drink in 24 hours, say in a hot and humid tropical weather. I do not know the answer. People advise two litres of water per day; I have a gut feeling that it might lead to hyponatraemia. I could be wrong. Would you enlighten me and the other readers please?

 

From Richard G Fiddian-Green

Exercise causes a gastric intramucosal acdosis in excess of any arterial acidosis present at the same time (1,2). The gastric intramucosal pH (pHi) which is normaly about 7.36 or 7.38 may fall below pH 7.0. The fall in pHi is accompanied by a rise in arterial lactate and is, therefore,unequivocally due to anaerobiosis (3). In patients having major surgery the fall in pHi is associated with the development of acute inflammatory changes in the mucosa (4). The abnormal gastric tonometric variables at the end of operation correlate with postoperative intensive care unit length of stay (r = 0.70, p = 0.0009) and multiple organ dysfunction score (r = 0.64, p = 0.0033)(5). Subjects with mesenteric vascular disease are especially sensitive to the stress of exercise (6).

In the Chicago marathon 75% of 34 subjects reported aspirin or ibuprofen (NSAID)ingestion before or during the race. Thirteen of the 26 NSAID users and 4 of the 8 non-users reported GI symptoms including the "trots". Those who had ingested ibuprofen but not aspirin had an increase in gastrointestinal permeability (7). In another study the urge to have a bowel movement (53%) and diarrhoea (38%) were the most common symptoms, especially among female runners (74% and 68% respectively) (8). The stool often has traces of blood (9).

Reperfusion of ischaemic gut mucosa, which occurs at the conclusion of the marathon, is especially important in causing mucosal injury (10) and may be accompanied by the release of myocardial depressant factors into the systemic circulation (11). These factors and/or other metabolites released upon reperfusion were almost certainly responsible for the sudden death of the original Marathon runner and of many deaths since including Jim Fix. The greatest danger from the systemic consequences of mucosal injury is likely, therefore, to be at the conclusion of the marathon. The drinking of fluids might alter this.

Overhydration may increase this risk of developing gut ischaemia and its systemic consequences by increasing the intercapillary distances and impairing mucosal oxygenation. Conversely some degree of dehydration may decrease the risk by decreasing the intercapillary distances and improving gut mucosal oxygenation.

 

From Gareth Williams

The recommendations as to fluid consumption during athletic endurance events should be welcomed by competitors at all levels.(1) However I am concerned that there may be other serious problems relating to fluid consumption at high level competitive sport.

Whilst taking part in a low-key endurance walking event last weekend, on a very hot day, I overheard other walkers talking about how, last year, a participant collapsed and had to be given intravenous fluid by the paramedics. Those who watch ultra-long distance cycling events on obscure satellite television stations may have noticed exhausted cyclists, who have retired from the race, being given intravenous fluids. This put me in mind of a Sports Medicine conference I attended last year during which we were reliably informed that intravenous hydration, at half-time, was not unknown in top level sport.

In hospital practice, apart from dire emergency, it is unknown to give intravenous fluid without knowing sodium and potassium levels, because of possibly fatal effects of hypokalaemia and hyponatraemia.

Let us suppose a professional sportsman had been suffering from diarrhoea and vomiting prior to an event and started the match with potassium or sodium depletion. Administration of intravenous fluids at the end of the first half would, surely, be even more likely to cause sudden death. This is a scenario which could easily take place in international sport.

I can find only two references in the literature to intravenous hydration in sport which appear to relate to Australian Rules Football. If this procedure is taking place in international sport on a regular basis then it is surely as dangerous as, for example anabolic steroid use which is of course banned.

It occurs to me that half-time intravenous hydration is unlikely to happen without the team doctor's knowledge. Maybe other reader's of this journal may be able to offer information about how widespread this procedure is in high level sport. Perhaps it is something the medical profession should take up with international sporting authorities.

Should a top athlete die suddenly on the field of play, it is submitted that the contributory role of possibly inappropriate intravenous hydration should be considered.

 

From Richard G Fiddian-Green

Whilst the benefits of carbohydrate loading in marathon runners, which is intended to increase glycogen stores, are equivocal fructose loading might enhance performance significantly by increasing the capacity for ATP resynthesis by anaerobic means and potentially limit the risks of over-hydration addressed in this paper. The capacity of the liver for metabolising lactate and other metabolites may, however, be the ultimate determinant of performance in marathion runners.

Unlike glucose fructose does not require insulin to enter muscle or liver cells. Neither does fructose stimulate the release of insulin, as glucose does, certainly in aerobic conditions. Fructose also enhances the rate of lipolysis in adipose tissues and the availability of free fatty acids for the synthesis of acetyl coenzyme A and of glycerol for entry into the Embden-Meyhoff pathway in anaerobic tissues (1,2). Insulin, which is released by glucose, does the reverse in adequately perfused and oxygenated tissues.

Fructose competes unsuccessfully with glucose for hexokinase, the enzyme catalysing the formation of fructose-6-phosphate from both glucose and from fructose. The relative rates of reactions in aerobic conditions are 20/1. Fructose may, however, also enter the Embden-Meyhoff pathway by being catalysed by fructokinase an enzyme that does not catalyse glucose reactions but is not present in muscle. In by-passing the phosphofructokinase step fructose bypasses the fructokinase pathway and escapes the negative feedback controls hypoxia, a fall in pH and a fall in [ATP]/[AMP] exerts upon the rate and direction of metabolism within the glyocolytic pathway (3). Indeed this pathway evades all of the negative feed back controls exerted upon glucose metabolism as the severity of anaerobiosis increases.

To circumvent the inhibitory controls in anaerobiosis glucose may be converted to fructose by activating the polyol pathway. The first enzyme in the polyol pathway, aldose reductase, reduces glucose to sorbitol, which is then converted to fructose by sorbitol dehydrogenase [if as is likely it also exists in man]. Thus fructose may be the preferred substrate by muscle in marathon runners the glucose being used for reductive biosynthesis, if necessary, and more importantly to provide substrate for the brain.

An intravenous infusion of fructose has a half-life of 18 minutes, half that of glucose. Its metabolic pathways bypass the pentose phosphate shunt, its synthesis of the NADPH and hence reductive biosynthesis of fatty acids in adipocytes, cholesterol and the steroid hormones in the liver, and other important products of reductive biosynthesis including cytochrome P450, reduced glutathione, nitric oxide and tetrahydrofolate all of which use ATP.

In anaerobiosis in exercising muscle phosphofructokinase is inhibited initially by the fall in pH induced by the accompanying unreversed ATP hydrolysis and later by the fall in [ATP] and rise in [AMP]. Concurrently fructose-6-phosphatase is upregulated so that F-6-phosphate accumulates. Gluconeogenesis is thus stimulated promoting a rise in blood glucose from synthesis in the liver from the lactate, glycerol and amino acids. Glycogenolysis may also be inhibited further preserving the glucose generated by gluconeogenesis for consumption by the brain. Thus in anaerobiosis of exercising muscle fatty acids become the preferred substrate for muscle and the glucose entering the blood is preserved for uptake and utilisation by the glial cells interposed between capillaries and neurons. The glial cells traffic nutrient from capillaries to neurons.

Glial cells do not require insulin for their glucose uptake from blood even in normoxic conditions. In a sense, therefore, glucose behaves like fructose in glial cells presumably with the same purpose, increasing the rate of substrate utlisation for ATP resynthesis. In the normal course of events ATP resynthesis in glial cells occurs by anaerobic means. The lactate generated by glial cells is, however, used as substrate by adjacent and oxygenated neurons. As with lactate generated by exercising muscle which is converted into glucose in the liver (Cori cycle)the neurons may rely upon an adequately oxygenated and normal functioning liver to complete their metabolic functions if also supported by anaerobic rather than aerobic means. These circumstances may exist in some patients with isolated head injuries or strokes.

It should be emphasised that for anaerobic metabolism to be an efficient generator of ATP in exercising muscle any lactate, and probably NAD, glutamate and NH4, needs to be washed into the systemic circulation so that they can be metabolised in the liver. The lactate is converted to glucose in the liver (Cori cycle), the NAD to NADH by the conversion of glutamate into alpha ketoglutarate in the Krebs cycle [this may occur primarily within the brain] and the NH4 into amino acids in the liver for synthesis, additional fuel for the Krebs cycle or convesion into urea and excretion in urine. The kidneys may also dispose of the NH4.

In glial cells glutamate and NH4 is converted into glutamine and transported to the oxygenated neurons. The lactate enters the Krebs cycle by being converted into pyruvate. The glutamine is converted back into glutamate which is either released into the synaptic clefts and taken up again by glial cells or used to form NADH from NAD and alpha ketoglutarate which is consumed in the Krebs cycle. The disposal of lactate and NH4 and replenishment of NADH are necessary for the ATP resynthesis by anaerobic means not be inhibited to their accumulation in accordance with the law of mass action. In the cases of regional intracerebral anaerobiosis, as may occur with isolated head injuries and strokes, an adequately oxygenated liver [and to a lesser degree kidneys] becomes essential if anaerobic metabolism is to generate the ATP needed for the brain to survive.

An intravenous administration of fructose has the potential to increase ATP resynthesis in both anaerobic tissues without interfering with gluconeogenesis or with fatty acid utilisation by muscle. Fructose, but not glucose if phosphofructokinase is inhibited, is metabolised to form fructose 1,6 bisphoglycerate an intermediate metabolite within the Embden-Meyhoff pathway. If it, instead of fructose, were to be administered intravenously two moles of ATP would be preserved increasing from 2 to 4 moles the net yield of ATP generated from one mole of glucose (or for that matter fructose) in the Emden-Meyerhoff pathway. [There would, however, be a need to replenish the NADH from NAD for the conversion of pyruvate to lactate, a reaction that could take place in adequately oxygenated liver if it is impaired within the glycolytic pathway in anaerobiosis as would seem. [This may occur in the Embden-Meyhoff pathway but befoire the synthesis of fructose 1,6 bisphoglycerate and can be suppressed in oxidative stress, notably that induced by cytokines].

If phosphofructokinase is inhibited and glucose is made to pass throught the pentose phosphate shunt the phosphofructokinase step is bypassed in glycolysis preserving one mole ATP normally used in the metabolism of glucose. The net yield of ATP from glucose in anaerobic metabolism may, therefore, be increased from 2 to 3 moles, but this increase is probably off-set by the ATP consumed in the reducitve biosynthetic pathways. In other words enough ATP may be resynthesised in anaerobioisis from glucose alone for reductive biosynthesis to proceed and for the basic metabolic needs for cell survival to be met.

Glycolytic turnover and hence yield of ATP by anaerobic means may increase by four or even as much as eight times in hypoxic conditions. This may be the product of increased extraction of nutrient from each unit of flowing capillary blood, and increased rate of capillary blood flow and of the 10% increase in metabolic rate that occurs with each degree of rise in regional temperature that occurs with exercise, an increase in metabolic activity or inflammation [the Q10 effect]. Thus the net yield of ATP in anerobiosis, regardless of whether glucose of fructose is the substrate, is much greater than commonly supposed. It may even be as high as 16 moles or 24 moles for each mole of substrate utilised. As the yield from aerobic metaolism may also be increased from 38 moles by these influences the net yield from anaerobic metabolism in any given set of circumstances remains much lower than that from aerobic metabolism. It is, however, sufficient to meet the needs of highly metabolically active physicological processes such as wound healing.

Honey has been applied to wounds for millenia. Its reduces the risk of infection and enhances wound healing in burns, ulcers, and other cutaneous wounds (4). As Willmore, Hunt and others have shown wounds replenish their ATP by anaerobic means even in hyperoxic conditions. As honey contains large amounts of fructose, fructose could be one of its active ingredients. This deduction is consistent with frutose being the preferred carbohydrate substrate in anaerobic metabolism and suggests that the supplementary supplies of fructose in honey may promote wound healing by enhancing the yield of ATP from anaerobic metabolism. In which case spermatazoa might depend upon the high concentations of fructose in semen and ova upon the high concentrations of fructose in follicular fluid to survive and thrive in the hostile microaerophilic environments of the vagina, oviduct (i.e. Fallopian tube)and uterus.

Fructose-1,6-bisphosphate, the intermediary product of fructose in the Emden-Meyerhoff pathway, has a neuroprotective effect when administered intravenously immediately before or after inducing hypothermic circulatory arrest in a porcine model (5). Animals treated with it have significantly better postoperative behavioral scores. The administration of the fructose-1,6-bisphosphate was also associated with lower intracranial pressures and lower venous creatine kinase isoenzyme MB measured during rewarming (P =.01 and P =.001, respectively). Among the treated animals, brain glucose, pyruvate and lactate levels tended to be higher, brain glycerol levels tended to be lower, and the histopathologic score of the brain was significantly lower (P =.04). This raises the possibility that fructose loading and especially fructose 1,6-bisphosphate loading might enhance the performance of marathon runners. But, apart from oral fructose causing gastrointestinal upsets, there may be a risk.

Fructose may cause a metabolic acidosis when administered to patients in shock (2). This is not surprising for hepatic metabolism is likely to be impaired in shock and with it the ability to metabolise lactate and NH4 and to replenish NADH. [Hence perhaps the rise in CSF glutamine and NH4 in liver failure]. As the gastric intramucosal pH, which falls in severe exercise, may correlate closely with hepatic venous lactates this could be an indication of an inadequacy of hepatic oxygenation (6). Fructose loading might, therefore, be dangerous in the many marathon runners who develop a gastric intramucosal acidosis.

On the other hand catalytic quantities of fructose (<10% of total carbohydrate flux) enhance liver glucose uptake in a dose dependent manner. The primary fate of the glucose is glycogen synthesis[possibly because fructose may inhibit glyogenolysis](7). The ability of fructose to augment liver glucose uptake is not impaired by the presence of marked insulin resistance such as in type 2 diabetes or infection. [This is not surprising since fructose uptake is not dependent upon insulin]. Fructose is a potent acute regulator of liver glucose uptake and glycogen synthesis. Furthermore inclusion of catalytic quantities of fructose in a carbohydrate meal improves glucose tolerance. Fructose-1,6-diphosphate administration also attenuates post-ischemic ventricular dysfunction (8)in addition to having a neuroprotective effect in the porcine model of circulatory arrest(5). But these observations appear to have been made in circumstances in which the liver is adequately oxygenated and not in those, such as shock, in which it has been inadequately oxygenated.

In the absence of inhibitory controls might an intravenous infusion of fructose and especially of fructose-1,6-bisphosphate, which has the potential to double the capacity for ATP resynthesis in anaerobiosis, induce a lactic acidosis? Only if the adequacy of hepatic tissue oxygenation is impaired or if there is preexisting hepatic disease which compromises the ability to metabolise lactate and NH4 and replenish NADH? The co-existing presence of renal disease can be expected to increase the risk.

There may indeed be the potential to enhance performance in marathon runners with fructose loading by either or intravenous means. If accompanied by bicarbionate loading to off-set the degree of any gastric intramucosal acidosis that develops in anaerobiosis the potential to enhance performance could be much greater. Phosphate loading to accommmodate the increased rate of ATP resynthesis might be an additional benefit. It is needed to prevent complications from the development of the hypophosphataemia induced by the increase in rate of resynthesis apparently occurring with the commensement of feeding in burned patients and possibly malnourished children (9,10).

If it enhances performance in marathon runners fructose or fructose-1,6-bisphosphate loading might be of partcular benefit to patients by limiting the degree of irreversible cellular damage induced by, for example, head injuries, strokes, and acute coronary artery occlusions. Maintining the adequacy of hepatic tissue oxygenation and function is likely to be an especially important determinant of benefit in these circumstances. There will, however, be no benefit if tissue perfusion in the region in question, be it muscle , brain or heart, and nutrient transport to remainder of the body including the liver is not maintained. These potentail benefits might, however, be off-set by an widening of the intercapiiary distances that might be induced by overhydration.

 

© BMJ I would imagine