Response to a fluid load in athletes with a history of exercise induced hyponatremia.

PURPOSE: To determine whether athletes who had previously developed hyponatremia during an ultradistance triathlon show an impaired ability to excrete a large fluid load compared with athletes who had completed the same race without developing hyponatremia. METHODS: Six athletes who had developed hyponatremia ([Na] < 135 mmol x L(-1)) in the 1997 Ironman Triathlon (study cases) were compared with six athletes who completed the same race without hyponatremia (controls). All participants consumed 3.4 L of water over 2 h at rest. Weight, urine output, urine electrolytes, serum [Na(+)], hemoglobin, and hematocrit were measured every 30 min. Changes in plasma volume and residual fluid volume in the gut were estimated from these data. RESULTS: There were no significant differences between cases and controls in any parameters measured. Maximal rates of urine production (+/- SD) (1043 +/- 331 mL x h(-1) for cases, 878 +/- 168 mL x h(-1) for controls) were substantially behind the rate of fluid intake (1500 mL x h(-1)). Consequent to fluid retention, serum [Na(+)] fell progressively in both groups. Five cases and four controls developed hyponatremia. There was an inverse correlation between change in body weight and change in [Na(+)] (r = -0.67). Estimated changes in the intra- and extra-cellular fluid volumes could account for all the retained fluid, and there was little evidence for fluid accumulation in the bowel. CONCLUSION: When evaluated at rest, there does not appear to be any unique pathophysiological characteristic that explains why some athletes develop hyponatremia in response to fluid overload during prolonged exercise. Rather, hyponatremia was induced with equal effect in both cases and controls, consequent to progressive fluid overload of all the body fluid compartments and without evidence for fluid retention in the small bowel.

Fluid balance during and after an ironman triathlon.

OBJECTIVE: To record weight changes, fluid intake and changes in serum sodium concentration in ultradistance triathletes. DESIGN: Descriptive research. SETTING: Ironman triathlon (3.8 km swim, 180 km cycle, 42.2 km run). Air temperature at 1200 h was 21 degrees C, (relative humidity 91%). Water temperature was 20.7 degrees C. PARTICIPANTS: 18 triathletes. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Subjects were weighed and had blood drawn for serum sodium concentration [Na], hemoglobin, and hematocrit, pre-race, post-race, and at 0800 h on the morning following the race ("recovery"); subjects were also weighed at transitions. Fluid intake during the race was estimated by athlete recall. RESULTS: Median weight change during the race = -2.5 kg (p < 0.0006). Subjects lost weight during recovery (median = -1.0 kg) (p < 0.03). Median hourly fluid intake = 716 ml/h (range 421-970). Fluid intakes were higher on the bike than on the run (median 889 versus 632 ml/h, p = 0.03). Median calculated fluid losses cycling were 808 ml/h and running were 1,021 ml/h. No significant difference existed between pre-race and post-race [Na] (median 140 versus 138 mmol/L) or between post-race and recovery [Na] (median 138 versus 137 mmol/L). Plasma volume increased during the race, median + 10.8% (p = 0.0005). There was an inverse relationship between change in [Na] pre-race to post-race and relative weight change (r = -0.68, p = 0.0029). Five subjects developed hyponatremia ([Na] 128-133 mmol/L). CONCLUSIONS: Athletes lose 2.5 kg of weight during an ultradistance triathlon. most likely from sources other than fluid loss. Fluid intakes during this event are more modest than that recommended for shorter duration exercise. Plasma volume increases during the ultradistance triathlon. Subjects who developed hyponatremia had evidence of fluid overload despite modest fluid intakes.

Exercise-induced hyponatremia in ultradistance triathletes is caused by inappropriate fluid retention.

OBJECTIVE: To study fluid and sodium balance during overnight recovery following an ultradistance triathlon in hyponatremic athletes compared with normonatremic controls. CASE CONTROL STUDY: Prospective descriptive study. SETTING: 1997 New Zealand Ironman Triathlon (3.8 Km swim, 180 Km cycle, 42.2 Km run). PARTICIPANTS: Seven athletes ("subjects") hospitalized with hyponatremia (median sodium [Na] = 128 mmol L(-1)). Data were compared with measurements from 11 normonatremic race finishers ("controls") (median sodium = 141 mmol L(-1)). INTERVENTIONS: None. MAIN OUTCOME MEASURES: Athletes were weighed prior to, immediately after, and on the morning after, the race. Blood was drawn for sodium, hemoglobin, and hematocrit immediately after the race and the following morning. Plasma concentrations of arginine-vasopressin (AVP) were also measured post race. RESULTS: Subjects were significantly smaller than controls (62.5 vs. 72.0 Kg) and lost less weight during the race than controls (median -0.5% vs. -3.9%, p = 0.002) but more weight than controls during recovery (-4.4% vs. -0.8%, p 0.002). Subjects excreted a median fluid excess during recovery (1,346 ml): controls had a median fluid deficit (521 ml) (p = 0.009). Estimated median sodium deficit was the same in subjects and controls (88 vs. 38 mmol L(-1), p = 0.25). Median AVP was significantly lower in subjects than in controls. Plasma volume fell during recovery in subjects (-5.9%, p = 0.016) but rose in controls (0.76%, p = NS). CONCLUSIONS: Triathletes with symptomatic hyponatremia following very prolonged exercise have abnormal fluid retention including an increased extracellular volume, but without evidence for large sodium losses. Such fluid retention is not associated with elevated plasma AVP concentrations.

A prospective study of exercise-associated hyponatremia in two ultradistance triathletes.

OBJECTIVE: To study fluid and sodium balance in two ultradistance triathletes. DESIGN: Prospective case study. SETTING: An ultradistance triathlon (3.8 km swim, 180 km cycle, 42.2 km run), and during overnight recovery. Ambient air temperature at 12:00 p.m. race day was 21 degrees C, with a relative humidity of 91%. Water temperature was 20.7 degrees C. SUBJECTS: Two female ultradistance triathletes, ages 30 and 39 years, who were participating in a larger study investigating weight and electrolyte changes in the Ironman triathlon. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Subjects were weighed and had blood drawn for serum sodium concentration, hemoglobin, hematocrit, arginine vasopressin, and aldosterone concentration prior to and after the race, and at 8:00 a.m. the following morning. Sodium and fluid intake and urinary output were measured during recovery. RESULTS: Both subjects developed mild hyponatremia (Na 131 and 130 mmol/L) during the race, with a weight gain (0.5 and 1.5 kg). Neither subject had large sodium losses (24 mmol and 20 mmol). Fluid consumption was 733 ml/h and 764 ml/h. Plasma volume increased during the race (25 and 16%). Arginine vasopressin (AVP) levels were not elevated in either subject (1.2 and 1.9 pmol/L). Both subjects demonstrated a water excess during the race (1.5 and 2.5 L), and lost weight during recovery (2.0 and 4.5 kg). CONCLUSIONS: Hyponatremia resulted from fluid retention in the extracellular space, without evidence of large sodium losses or inappropriate AVP secretion.

Diagnosis and prevention of hyponatremia at an ultradistance triathlon.

OBJECTIVE: To evaluate a method of medical care at an ultradistance triathlon, with the aim of reducing the incidence of hyponatremia. DESIGN: Descriptive research. SETTING: New Zealand Ironman triathlon (3.8 km swim, 180 km cycle, 42.2 km run). PARTICIPANTS: 117 of 134 athletes seeking medical care after the triathlon (involving 650 race starters). INTERVENTIONS: A prerace education program on appropriate fluid intake was undertaken. The number of support stations was decreased to reduce the availability of fluid. A body weight measurement before the race was introduced as a compulsory requirement, so that weight change during the race could be included in the triage assessment. An on-site laboratory was established within the race medical tent. MAIN OUTCOME MEASURES: Numbers of athletes and diagnoses, including the incidence of symptomatic hyponatremia (defined as symptoms of hyponatremia in association with a pretreatment plasma sodium concentration [Na] < 135 mmol/L); weight changes; and changes in [Na]. RESULTS: The common diagnoses in the 117 athletes receiving attention were exercise-associated collapse (27%), musculoskeletal complaints (26%), and dehydration (12%). There was a significant reduction in the number of athletes receiving medical care for hyponatremia, from 25 of the 114 athletes who received care in 1997 (3.8% of race starters) to 4 of the 117 athletes who received care in 1998 (0.6% of race starters). Mean weight change among athletes in the 1998 race was -3.1 kg, compared with -2.6 kg in 1997. CONCLUSION: A preventive strategy to decrease the incidence of hyponatremia, including education on fluid intake and appropriate placement of support stations, was associated with a decrease in the incidence of symptomatic hyponatremia.

Hyponatremia in ultradistance triathletes.

PURPOSE: Hyponatremia ([plasma sodium] <135 mmol x L(-1)) is a potentially serious complication of ultraendurance sports. However, the etiology of this condition is still uncertain. This observational cohort study aimed to determine prospectively the incidence and etiology of hyponatremia in an ultradistance triathlon. METHODS: The subjects consisted of 605 of the 660 athletes entered in the New Zealand Ironman triathlon (3.8-km swim, 180-km cycle, and 42.2-km run). Subjects were weighed before and after the race. A blood sample was drawn for measurement of plasma sodium concentration after the race. RESULTS: Complete data on pre- and postrace weights and plasma sodium concentrations were available in 330 race finishers. Postrace plasma sodium concentrations were inversely related to changes in body weight (P = 0.0001). Women (N = 38) had significantly lower plasma sodium concentrations (133.7 vs 137.4 mmol x L(-1); P = 0.0001) than men (N = 292) and lost significantly less relative weight (-2.7 vs -4.3%; P = 0.0002). Fifty-eight of 330 race finishers (18%) were hyponatremic; of these only 18 (31%) sought medical care for the symptoms of hyponatremia (symptomatic). Eleven of the 58 hyponatremic athletes had severe hyponatremia ([plasma sodium] < 130 mmol x L(-1)); seven of these 11 severely hyponatremic athletes were symptomatic. The relative body weight change of the 11 severely hyponatremic athletes ranged from 2.4% to +5%; eight (73%) of these athletes either maintained or gained weight during the race. In contrast, relative body weight changes in the 47 athletes with mild hyponatremia ([plasma sodium] 130-134 mmol x L(1)) were more variable, ranging from -9.25% to +2.2%. CONCLUSIONS: Hyponatremia is a common biochemical finding in ultradistance triathletes but is usually asymptomatic. Although mild hyponatremia was associated with variable body weight changes, fluid overload was the cause of most (73%) cases of severe, symptomatic hyponatremia.

Improved efficacy with nonsimultaneous administration of first doses of gentamicin and ceftazidime in vitro.

First doses of aminoglycoside and beta-lactam antibiotics, when used in combination, are usually given simultaneously; however, nonsimultaneous administration may be more efficacious. We used a dynamic in vitro model, which simulates in vivo serum kinetics, to assess the effect of spacing the first doses of gentamicin and ceftazidime used against Pseudomonas aeruginosa ATCC 27853 and two clinical isolates of P. aeruginosa, PA1 and PA2. The following dose regimens against P. aeruginosa ATCC 27853 were compared: (i) gentamicin given alone, (ii) ceftazidime given alone, (iii) gentamicin and ceftazidime given simultaneously, (iv) gentamicin followed by ceftazidime at 15 or 50 min or at 2, 4, or 8 h, and (v) ceftazidime which was followed by gentamicin at 4 h. The effects of regimen iii and the 4-h interval in regimen iv against PA1 and PA2 were also compared. Initial peak concentrations used were 8 mg/liter for gentamicin and 80 mg/liter for ceftazidime, with drug half-lives of 2.5 and 1.8 h, respectively. Compared with simultaneous administration, nonsimultaneous administration (regimens iv and v) produced greater overall bacterial killing and was associated with a delay in bacterial regrowth (p < 0.005) of up to 6.6 to 8.3 h, regardless of the order in which the drugs were given. The optimal interval between gentamicin and ceftazidime doses, which maximized initial bactericidal effect and the time before regrowth, appeared to be 2 to 4 h.

Assessment of a computerized system for the diagnosis of iron deficiency.

The aim of this study was to develop a computer expert system that could reproduce a pathologist's diagnosis of iron deficiency from the data obtained from blood tests. 275 cases were collected for construction and testing of the expert system. The expert system used a combination of fuzzy set logic and cut-off points from 14 parameters to arrive at one of 5 diagnostic categories graded from "iron deficient" to "no evidence of iron deficiency". The agreement between pathologist and expert system was 0.91 (Spearman rank correlation coefficient) in the learning population; this dropped to 0.79 in the test population. Absolute agreement on diagnostic category was reached in 71% of cases. In no case was there disagreement by more than 3 grades.

Haemoglobin Manukau beta 67[E11] Val-->Gly: transfusion-dependent haemolytic anaemia ameliorated by coexisting alpha thalassaemia.

Haemoglobin Manukau (beta 67 Val-->Gly) is a novel haemoglobin variant presenting in two brothers as nonspherocytic haemolytic anaemia which became transfusion dependent by 6 months of age. The severity of clinical expression seems to be modulated by coexisting alpha thalassaemia: the severely affected children have a normal complement of alpha globin genes with an unusual genotype (-alpha 3.7/alpha alpha alpha 3-7), while their father, who carries the abnormal gene with minimal symptoms, has homozygous alpha+ thalassaemia (-alpha 3.7/-alpha 3.7). Another unusual feature of this case is the association of the beta 67 Val-->Gly mutation with modification of beta 141 Leu to a residue (believed to be hydroxyleucine) that is not detected by standard amino acid analysis. This finding offers an explanation for the previous report of an association of another mutation at this site (Hb Sydney beta 67 Val-->Ala) with Hb Coventry (deletion of beta 141 Leu).

Elevated levels of acute phase plasma proteins in major depression.

Levels of acute phase and other plasma proteins were measured in 21 men with major depression, 28 men with alcohol dependence, and 12 men who acted as controls. The depressed men had significantly elevated levels of the acute phase proteins, haptoglobin and alpha-1-antichymotrypsin, and of immunoglobulin G. The elevations in haptoglobin and alpha-1-antichymotrypsin were highly correlated with each other, and were correlated with the severity of depression and negatively correlated with the thyroid stimulating hormone response to thyrotropin. The alcoholic men had elevated haptoglobin levels, but significantly decreased levels of immunoglobulin G. These findings provide further evidence for an inflammatory response during depression.

Comparison of gentamicin dosing regimens using an in-vitro model.

An in-vitro model which simulates in-vivo pharmacokinetics was used to compare the efficacy against Pseudomonas aeruginosa of dosing regimens of gentamicin which achieve different peak/trough concentrations but use the same total dose over 24 h. First exposure to gentamicin produced a rapid bactericidal effect which was proportional to the initial peak concentration. Subsequent doses of gentamicin produced a smaller bactericidal effect. Regrowth occurred with all dosing regimens, even after very high initial concentrations (26 mg/L). The time to reach bacterial counts above starting values was prolonged in relation to peak concentrations. Regrowth was also demonstrated in continuous infusion experiments which maintained very high concentrations (26 mg/L), although an inhibitory effect was evident compared with single dose experiments and the experiments mimicking in-vitro pharmacokinetics. There was little evidence of a post-antibiotic effect. The data supports the use of larger initial and longer interval bolus dosing compared with current recommendations.

Prediction of the site of signal peptidase cleavage in normal and variant human preproalbumin.

We describe the use of a template for the recognition site of signal peptidase to give score predictions for cleavage at normal and aberrant sites in human and chicken preproalbumin. As expected, the highest score obtained for human preproalbumin was at the normal cleavage site between -7 Ser and -6 Arg. The mutation in preproalbumin Kaikoura (-2 Arg----Cys) introduced an aberrant cleavage site in the propeptide between the new -2 Cys and -1 Arg. Although the new site had a lower template score (6.88) than the normal site (9.99), it is cleaved in vivo about five times faster. The presence of minor proportions of des-Asp and des-Asp-Ala-albumin in normal human plasma was not found to correlate with possible aberrant signal peptidase cleavage. These truncated albumin species, therefore, appear to be generated through cleavage of mature albumin in circulation. Chicken preproalbumin had only one probably signal peptidase cleavage site, the one utilised in vivo. Template scores should be regarded as qualitative predictions rather than definitive quantitative indicators.

Antimicrobial effects of lomefloxacin in vitro.

The MIC of lomefloxacin was determined for 554 isolates from the urinary tract. Some of the more resistant strains of Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, and Pseudomonas aeruginosa were studied in a dynamic in-vitro model in order to study dosing strategies. The model simulated, in Mueller-Hinton broth, the profile of plasma lomefloxacin concentrations in volunteers. Bacteria were exposed to a range of lomefloxacin concentration profiles achievable by oral dosing. The first dose of lomefloxacin was rapidly bactericidal in a dose-dependent manner for all strains. On re-exposure, a dose-dependent inhibitory effect was observed. Drug-resistant mutants were readily isolated from all bacteria tested on lomefloxacin-containing plates. These occurred at a high frequency in P. aeruginosa (10(-1)), but less frequently in K. pneumoniae (10(-3)). P. mirabilis (10(-5)), and E. coli (10(-6)). The number of resistant mutants isolated tended to be lower with use of higher drug concentrations. The results suggest that lomefloxacin dosing regimens ensuring maintenance of a high serum concentration: MIC ratio will result in maximal antibacterial effects and minimal problems with resistant strains.

P1 variant antithrombins Glasgow (393 Arg to His) and Pescara (393 Arg to Pro) have increased heparin affinity and are resistant to catalytic cleavage by elastase. Implications for the heparin activation mechanism.

The heparin affinity of normal and two P1 variants of antithrombin-III (AT) was studied by gradient elution with NaCl in Tris buffer on heparin-Sepharose. At pH 7.4 normal AT eluted at [Na+] 0.78 mol/l and the variants both showed increased affinity with AT Pescara eluting at [Na+] 0.86 mol/l and AT Glasgow at [Na+] 0.92 mol/l. We have earlier proposed a model for heparin activation in which the native state of AT maintains a salt bridge involving the P1 Arg-393 residue. Binding of heparin induces a higher heparin affinity conformation in which the salt bridge is disrupted to reveal the reactive centre for inhibition of thrombin. The Glasgow and Pescara variants, lacking a reactive centre P1 basic residue, would be unable to form this salt bridge, and we suggested that the high affinity conformation which they adopt as their native state would resemble the heparin induced conformation. To examine this model, we measured the heparin induced fluorescence of two P1 variants and tested the susceptibility of their reactive loops to catalytic cleavage. Both variants had fluorescence spectra indistinguishable from normal AT. In the absence of heparin, neither variant was more susceptible than normal to catalytic cleavage by human neutrophil elastase. These findings suggest that the conformation of these P1 variants is different to that of fully heparinized normal AT.

Novel human proalbumin variant with intact dibasic sequence facilitates identification of its converting enzyme.

We describe here the identification of a new genetic variant of human proalbumin with an N-terminal sequence of Arg-Gly-Val-Phe-Arg-Arg-Val-Ala-His-Lys-. Proalbumin Blenheim (10%) and mature albumin Blenheim (38%) with an initial sequence of Val-Ala-His-Lys-make up nearly half the serum albumin in affected individuals. Despite retaining an intact dibasic processing site, proalbumin Blenheim (1 Asp----Val) enters the circulation unprocessed. The observed ratio of proalbumin to albumin can be accounted for by proteolysis in the periphery. Employed as a potential substrate, proalbumin Blenheim provides a unique means of identifying the physiologically relevant proalbumin convertase. In vitro studies showed that the variant is readily cleaved by trypsin. However, it is not cleaved by the proposed proalbumin convertase, a membrane-bound Ca2+-dependent proteinase prepared from rat liver Golgi vesicles, which gives authentic cleavage of normal human proalbumin.