Serum sodium changes in marathon participants who use NSAIDs

Abstract

Introduction
The primary mechanism through which the development of exercise-associated hyponatraemia (EAH) occurs is excessive fluid intake. However, many internal and external factors have a role in the maintenance of total body water and non-steroidal anti-inflammatory medications (NSAIDs) have been implicated as a risk factor for the development of EAH. This study aimed to compare serum sodium concentrations ([Na]) in participants taking an NSAID before or during a marathon (NSAID group) and those not taking an NSAID (control group).

Methods
Participants in a large city marathon were recruited during race registration to participate in this study. Blood samples and body mass measurements took place on the morning of the marathon and immediately post marathon. Blood was analysed for [Na]. Data collected via questionnaires included athlete demographics, NSAID use and estimated fluid intake.

Results
We obtained a full data set for 28 participants. Of these 28 participants, 16 took an NSAID on the day of the marathon. The average serum [Na] decreased by 2.1 mmol/L in the NSAID group, while it increased by 2.3 mmol/L in the control group NSAID group (p=0.0039). Estimated fluid intake was inversely correlated with both post-marathon serum [Na] and ∆ serum [Na] (r=−0.532, p=0.004 and r=−0.405 p=0.032, respectively).

Conclusion
Serum [Na] levels in participants who used an NSAID decreased over the course of the marathon while it increased in those who did not use an NSAID. Excessive fluid intake during a marathon was associated with a lower post-marathon serum [Na].

Full text

WhatmoughS, etal. BMJ Open Sport Exerc Med 2018;4:e000364. doi:10.1136/bmjsem-2018-000364 1
Open access Original article
Serum sodium changes in marathon
participants who use NSAIDs
Steven Whatmough,1 Stephen Mears,2 Courtney Kipps1
To cite: WhatmoughS,
MearsS, KippsC. Serum
sodium changes in
marathon participants who
use NSAIDs. BMJ Open
Sport & Exercise Medicine
2018;4:e000364. doi:10.1136/
bmjsem-2018-000364
Accepted 12 November 2018
1Institute of Sport, Exercise
and Health, University College
London, London, UK
2Loughborough University,
Loughborough, UK
Correspondence to
Dr Steven Whatmough; steven.
whatmough@ nhs. net
© Author(s) (or their
employer(s)) 2018. Re-use
permitted under CC BY-NC. No
commercial re-use. See rights
and permissions. Published by
BMJ.
What are the new ndings?
►Over the course of a marathon, serum [Na] is more
likely to fall in participants who use an non-steroidal
anti-inammatory medication (NSAID) than in those
who don’t.
How might it impact on clinical practice in the near
future?
►A better understanding of the additional risks of us-
ing NSAIDs during exercise will inform future guide-
lines to make marathon running a safer activity
ABSTRACT
Introduction The primary mechanism through which the
development of exercise-associated hyponatraemia (EAH)
occurs is excessive uid intake. However, many internal
and external factors have a role in the maintenance of
total body water and non-steroidal anti-inammatory
medications (NSAIDs) have been implicated as a risk factor
for the development of EAH. This study aimed to compare
serum sodium concentrations ([Na]) in participants taking
an NSAID before or during a marathon (NSAID group) and
those not taking an NSAID (control group).
Methods Participants in a large city marathon were
recruited during race registration to participate in this
study. Blood samples and body mass measurements took
place on the morning of the marathon and immediately
post marathon. Blood was analysed for [Na]. Data collected
via questionnaires included athlete demographics, NSAID
use and estimated uid intake.
Results We obtained a full data set for 28 participants.
Of these 28 participants, 16 took an NSAID on the day
of the marathon. The average serum [Na] decreased by
2.1 mmol/L in the NSAID group, while it increased by 2.3
mmol/L in the control group NSAID group (p=0.0039).
Estimated uid intake was inversely correlated with both
post-marathon serum [Na] and ∆ serum [Na] (r=−0.532,
p=0.004 and r=−0.405 p=0.032, respectively).
Conclusion Serum [Na] levels in participants who used
an NSAID decreased over the course of the marathon while
it increased in those who did not use an NSAID. Excessive
uid intake during a marathon was associated with a lower
post-marathon serum [Na].
INTRODUCTION
Exercise-associated hyponatraemia (EAH) is
a potentially life-threatening cause of collapse
during and after endurance exercise.1 2 It is
defined as a serum sodium concentration
([Na]) below that of the laboratory reference
range (commonly 135 mmol/L) during or
up to 24 hours following prolonged physical
activity.3
Risk factors in the development of EAH
tend to be related to fluid balance. In most
cases, EAH is caused by overhydration during
exercise which can result in a haemodilution
and subsequent decrease in blood sodium
concentration.4 5 Non-steroidal anti-inflam-
matory medications (NSAIDs) indirectly
potentiate the water retention effects of
vasopressin through reduction in prosta-
glandin synthesis and subsequent reduced
renal blood flow.6 7 Change in body mass
can be used as a marker of hydration status
after prolonged endurance exercise, such
as a marathon. Participants who do not lose
weight, or indeed gain weight, over the course
of the marathon are likely to be overhydrated
and are at greater risk of developing EAH.8–10
The American College of Sports Medicine
recommend aiming for <2% body mass loss
during sporting events to maintain hydration
status.11 12
Despite the well-documented medical risks
of using NSAIDs, NSAIDs are widely avail-
able without prescription. Previous studies
have found that between 30% and 50% of
competitors will use NSAIDs before or during
events.13–17 Several authors have observed
an association between NSAID use and
development of EAH,14 18 19 although other
studies specifically investigating EAH risk
factors have found no correlation between
use of NSAIDs and EAH.7 20 21 This uncer-
tainty in the relationship between NSAIDs
and EAH prompted the Third International
EAH Consensus Conference to recommend
further research in this area.3
The aim of this study was to compare the
effect of NSAID use on changes in serum
[Na] following a marathon. It was hypothe-
sised that participants using NSAIDs before
or during a marathon would have a greater
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Open access
reduction in serum [Na] (post-marathon serum [Na] –
pre-marathon serum [Na]) than participants who did not
use an NSAID.
METHODS
Study setting
This study took place during a 26.2 mile city marathon
which runs annually in late spring in the UK. The average
daytime temperature on race-day was 6°C (3°C–10°C),
the average humidity was 58% (31%–88%) and there was
0.2 mm of rainfall.22 There were several drinks stations
along the route including water in 250 mL bottles every
mile from mile 3 to mile 25 and 380 mL sports drinks
at miles 5, 10, 15, 19 and 23. Final instructions from the
marathon organisers which included guidelines on safe
drinking habits (eg, to drink according to thirst) and
recommendations to avoid NSAID use during the mara-
thon were sent to all participants in print and were also
available to read online.
Study design
A sample size calculation was used to calculate the
number of participants required in the study in order to
compare the change in serum [Na] from pre-marathon
sampling to post-marathon sampling (∆ serum [Na]) in
participants taking NSAIDs (NSAID group) and partic-
ipants not taking NSAIDs (control group). A mean ∆
serum [Na] difference of 3 mmol/L was deemed signifi-
cant. The SD was set at 2 mmol/L as this value has been
used in previous research.23 The result found a sample
size of 10 participants per group allowed 90% statistical
power (1 - beta) with a significance level set at 5%.
Marathon participants were approached at random
during marathon registration, which took place over the
4 days prior to the marathon and invited to participate in
the study. All registered entrants in the marathon were
eligible for our study, and we deemed that participation
in the marathon implied that participants were fit and
healthy. Participants under 18 years of age were ineligible
to enter the marathon and therefore were not included
our study. Consent for participation and blood testing was
obtained. Participants completed a brief demographic
questionnaire.
On the day of the marathon, immediately prior to
starting, all participants completed a brief questionnaire
had their body mass measured wearing race clothing and
running shoes on a Seca 803 Clara Digital Scale, accurate
to 0.1 kg, and had a 5 mL blood sample drawn.
After crossing the finish line, participants had their
body mass measured using the same scales. A second 5
mL venous blood sample was drawn, and participants
completed a brief questionnaire documenting estimated
fluid intake, medication use, and where appropriate,
NSAID dose.
Data regarding intended NSAID use were collected at
race registration and again at the start line. Questions
regarding participants knowledge of NSAID risk and safe
dose were asked on the post-marathon questionnaire in
order to reduce response bias. No instructions were given
to participants with regards to NSAID use or NSAID dose.
Risk awareness was categorised as correct if participants
were able to name at least one correct risk or side effect
from any NSAID. Dose awareness was categorised as
correct if participants knew the maximum dose of the
NSAID they had used. Maximum daily doses of medica-
tion were obtained from the British National Formulary.24
Doses of NSAIDs are presented relative to the maximum
daily recommended dose.
Fluid intake was estimated from the participants recall
of the number of water and sports drink bottles picked up
at fluid stations over the course of the marathon. Further-
more, it was based on the assumption that all bottles were
completely consumed.
Venous blood samples were collected from an antecu-
bital vein in a seated position into a Startstedt-Monovette
Z-Gel vacutainer system. Blood samples were stored
upright for 30–60 min before being centrifuged (2500
rpm for 10 min) using a Hettich Zentrifugen Rotofix
32. Thereafter bloods were stored upright in a cooling
bag for transport to the laboratory for analysis. Sodium,
potassium, urea and creatinine concentrations were
measured in duplicate using indirect ion selective elec-
trode (Siemens ADVIA 2400, Siemens, Berlin: Germany;
CV<1.1%).
Outcome measures
The laboratory’s normal reference range for [Na] was
133–146 mmol/L. NSAID use was a key independent vari-
able. Other variables included age, body mass change,
estimated fluid intake, marathon time and number of
previous marathons.
Statistical analysis
Statistics were calculated using IBM SPSS V.23. Contin-
uous variables, categorical and non-parametric variables
were compared using t-tests, χ2 tests and Mann-Whitney
U tests, respectively. Pearson’s correlation coefficient was
used to analyse relationships between variables. Multivar-
iate analysis, using analysis of variance, further analysed
the dependent variable ‘change in serum [Na] with the
independent variables ‘NSAID use’ and ‘percentage mass
change’. Statistical significance was defined as p<0.05.
Data were recorded as mean±SD, unless stated otherwise.
RESULTS
Recruitment
A total of 109 participants were recruited during mara-
thon registration. A subset of 41 participants reported
to the research station at the start line for pre-marathon
baseline tests. All 41 participants completed the mara-
thon and 28 participants returned for data collection
after crossing the finish line. Therefore, a complete
dataset for 28 participants was obtained. There were
no significant differences in age, gender, body mass,
number of previous marathons or finish times between
the 28 participants who completed the study and the 13
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Table 1 Participant demographics, body mass, uid intake and marathon time data
Complete finish line cohort
(n=28)
NSAID group
(n=16)
Control group
(n=12) P value*
Age (years) 45±9 43±8 47±11 0.316
Male:female 21:7 10:6 11:1 0.058
Body mass (kg) 79.0±16.8 77.8±18.8 80.8±14.4 0.649
Caucasian ethnicity, n (%) 23 (82.1) 13 (81.2) 12 (100) 0.112
Number of prior marathons completed 6±13 4±10 7±16 0.532
Estimated uid intake during the marathon (L) 1.4±1.5 1.7±1.6 1.0±1.5 0.309
Race time (min) 276.0±48.0 276.8±45.6 281.0±58.7 0.834
Absolute body mass change (kg) −1.6±1.3 −1.4±1.3 −1.9±1.2 0.376
Relative body mass change (%) −2.1±1.5 −1.9±1.6 −2.3±1.4 0.568
*P values are given for analysis between the NSAID and control groups. NSAID, non-steroidal anti-inammatory medications.
Table 2 A comparison of athlete blood results in the non-steroidal anti-inammatory medication (NSAID) and control groups
[a]. These were then subdivided into those taking an NSAID the morning of the marathon (mNSAID group) [b] and those taking
an NSAID during the marathon (dNSAID group) [c]
[a] NSAID use before or during the marathon
NSAID group (n=16) Control group (n=12) P value
Pre-marathon [Na] (mmol/L) 142.8±4.1 140.2±4.4 0.114
Post-marathon [Na] (mmol/L) 140.8±4.4 142.5±1.8 0.161
∆ [Na) (mmol/L) −2.1±5.7 2.3±4.7 0.039
[b] NSAID use the morning of the marathon
NSAID group (n=11) Control group (n=17) P value
Pre-marathon [Na] (mmol/L) 142.2±4.6 141.4±4.3 0.633
Post-marathon [Na] (mmol/L) 141.4±3.7 141.6±3.6 0.874
∆ [Na] (mmol/L) −0.8±4.7 0.2±6.3 0.639
[c] NSAID use during the marathon
NSAID group (n=8) Control group (n=20) P value
Pre-marathon [Na] (mmol/L) 144.0±2.6 140.8±4.6 0.074
Post-marathon [Na] (mmol/L) 140.9±4.9 141.8±3.0 0.566
∆ [Na] (mmol/L) −3.1±6.3 1.0±5.1 0.081
∆, Change from pre-marathon to post-marathon; [Na], Sodium concentration.
participants who did not attend the research station after
the finish line.
NSAID use and their effect on serum biochemistry
At race registration, 50 of the 109 (45.9%) participants
stated that they intended to use an NSAID on race day
and/or during the marathon. At the start line, 11/28
(39%) participants had used an NSAID on the morning
of the marathon. Also, 8 of the 28 (29%) participants
used an NSAID during the marathon. In total, 16 of the
28 (57.1%) participants completing the study used an
NSAID either before or during the marathon, or both.
Participants were grouped into those who took
an NSAID before or during the marathon (‘NSAID
group’) and those who did not take an NSAID (‘control
group’). The NSAID group comprised 6 females and 10
males. The control group (n=12) had only one female
(table 1).
Both groups finished the marathon in similar times
(p=0.834) and estimated consuming similar volumes
of fluid per person (p=0.309). There was no significant
difference in absolute or relative body mass change
between groups (p=0.376 and 0.568, respectively) over
the course of the marathon. There was no difference
in either pre-marathon or post-marathon serum (Na)
between groups (table 2). However, serum (Na) levels
in the NSAID group decreased by an average of 1.5%
compared with an average 1.6% increase in serum (Na)
in the control group. No differences were seen in either
pre-marathon or post-marathon serum potassium, urea
or creatinine between groups; nor were changes in these
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Table 3 Comparisons of non-steroidal anti-inammatory medication (NSAID) knowledge in the NSAID and control group
NSAID group (n=16) Control group (n=12) P value
Correct awareness of NSAID risks, n (%) 8 (50) 5 (41.7) 0.662
Correct awareness of NSAID safe dose, n (%) 6 (37.5) 4 (33.3) 0.820
Consumed more than recommended safe limit of NSAID, n (%)* 6 (37.5) – –
*Dose exceeding the maximum safe limit for a single dose as per the British National Formulary.24
parameters over the course of the marathon significant
(data not shown).
There was a significant difference in the change in
serum [Na] between the NSAID and control groups
(p=0.039, table 2). Multiple linear regression suggested
a possible correlation between the dependent variable ∆
serum [Na] and the independent variables percentage
body mass change (beta=−0.34, p=0.057) and NSAID use
(beta=−0.35, p=0.051); however, this did not quite reach
significance. Participants who used an NSAID during the
marathon tended to reduce serum [Na] over the course
of the marathon. However there was no difference in
serum [Na] between those who used an NSAID on the
morning of the marathon (mNSAID group) and those
who used an NSAID during the marathon (dNSAID
group) (table 2).
Athlete knowledge of NSAIDs
Ibuprofen was the most commonly used NSAID (n=14).
The total dose of ibuprofen taken on the day of the
marathon ranged from 200 to 1800 mg (for reference
the recommended maximum daily dose is 2400 mg24).
One participant used two different NSAIDs during the
marathon (ibuprofen and diclofenac). Reasons given
for taking NSAIDs included treating a pre-existing
injury (n=7), prophylactic pain management (n=6) and
perceived improvements in performance (n=3). 37.5%
of the participants who used an NSAID were aware of the
safe dose and 50% were aware of at least one NSAID-re-
lated risk. There were no differences in safe NSAID dose
knowledge and NSAID risk awareness between the two
groups (table 3).
Other risk factors for EAH
Fluid intake was expressed relative to pre-marathon
body mass (fluid intake/body mass) and compared
with post-marathon serum [Na] and change in serum
[Na]. Significant correlations were found in both cases
(R=−0.581, p=0.001 and R=−0.448, p=0.017). However,
there was no significant differences in fluid intake/
body mass between the NSAID and control groups.
Those in whom the serum [Na] fell over the course of
the marathon were relatively inexperienced compared
with participants in whom the serum [Na] did not fall
(average of 2 previous marathons vs 12 previous mara-
thons, respectively, p=0.063). There were no significant
differences in marathon experience between the
NSAID and control groups (table 1).
There were no other significant differences in between
these two groups, including gender, race time, body mass
or age. Other than NSAIDs, no participants were taking
any regular medications.
Incidence of EAH
One of the 28 participants (3.5%) had a post-race serum
[Na] of 130 mmol/L meeting the criteria for EAH. The
pre-race serum [Na] was 146. This participant reported
using 800 mg ibuprofen and estimated consuming 5 L of
fluid during the marathon and lost only 0.3% body mass.
The race time for this participant was 4 hours 56 min.
The participant remained asymptomatic and reported no
subsequent effects (personal correspondence).
Correlations of serum sodium concentration
Estimated fluid intake and body mass changes were
inversely correlated with both post-marathon serum [Na]
and ∆ serum [Na] (figure 1). There were no significant
correlations between estimated fluid intake and either
absolute body mass change (r=0.110, p=0.579) or rela-
tive body mass change (r=0.161, p=0.396). Furthermore,
marathon time did not correlate with either absolute or
relative body mass change (r=0.008, p=0.966 and r=0.000,
p=0.998, respectively).
Finally, no significant correlations were identified
between race time and ∆ serum [Na] and post-marathon
[Na] (r=−0.257, p=0.186 and r=0.032, p=0.871, respec-
tively).
Discussion
Our main findings were a high prevalence of NSAID
use among marathon participants before or during
the marathon. Participants who consumed an NSAID
before or during the marathon demonstrated a signifi-
cantly greater reduction in serum [Na] over the course
of the marathon compared with those participants
who did not use an NSAID (table 2). Fluid intake and
change in body mass both correlated with post-mara-
thon serum [Na] and with ∆ serum [Na] (figure 1).
One participant met the criteria for EAH.
Prevalence of NSAID use at marathons
The marathon provides written medical guidance to
all participants which includes specific advice on fluid
intake and recommendations to avoid using NSAIDs
before or during the race. Despite this, 57% of this
small study cohort used an NSAID on marathon day.
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Figure 1 Correlations between changes in serum (Na), body mass changes and estimated uid intake. Pearson’s correlation
coefcient and regression analysis for the respective graphs are illustrated in the underlying table.
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Participants in this present study commonly cited
prophylactic pain management as a reason for using
NSAIDS, although previous research has shown that
NSAIDs do not prevent delayed onset muscle sore-
ness (DOMS) after a marathon.13 This lack of benefit
could be explained by the short half-life of NSAIDs.25
The half-life of ibuprofen is only 2 hours, and there-
fore it is unlikely to exert much analgesic effect past 4
hours, the average duration of a marathon.26 This short
half-life may be a reason participants take more than
one dose during a marathon, and thus consume doses
above the recommended safe maximum. Also, 50%
of athletes using NSAIDs were unaware of the risks of
NSAID use, and 37.5% of NSAID users consumed doses
greater than the recommended safe maximum.
It is important to consider the clinical significance of
the small changes in serum [Na] observed in this study.
A difference in 4.4 mmol/L is unlikely to be of clinical
significance. This difference may be of greater clinical
significance when combined with other risk factors, such
as increased fluid intake.
The effect of NSAIDs on serum sodium concentration
In the present study serum [Na] decreased by 2.1 mmol/L
in NSAID users over the course of the marathon, while it
increased by 2.3 mmol/L in non-NSAID users (p=0.039).
This appears to contrast with a large cohort study of
>400 participants which found no association between
NSAID use and the development of EAH.7 However, it
should be noted that the definition of NSAID use in in
this large cohort study included use up to 7 days prior to
the marathon and did not differentiate between NSAID
use in the days prior to the marathon and use during the
marathon.7
A subgroup analysis was performed on the effect
of NSAID use prior to or during the marathon. In a
subgroup analysis on participants in this study, serum
[Na] fell further in participants who used an NSAID
during the marathon (3.1 mmol/L) compared with those
who only used an NSAID before starting the marathon
(0.8 mmol/L)(table 2). This affect may be a consequence
of the short half-life of NSAIDs.26 No significant correla-
tions were found between serum [Na] and the dose of
NSAIDs used.
The NSAID group did consume 0.7 L more fluid than
the control group. Furthermore, the NSAID group lost
0.4% less weight than the control group. Despite both
these differences not reaching clinical significance, this
may present a confounder.
Fluid intake, body mass changes and serum sodium
concentrations
Body mass change is commonly used in field-based
studies as marker of hydration and is used as a surrogate
measure for fluid balance during a race. Several authors
have described inverse correlations between body mass
change and serum [Na].7 8 21 27 28 Furthermore, studies
have described inverse correlations between fluid intake
and serum [Na].12 29 Our study replicated these findings,
providing further evidence to show inverse relationships
between serum [Na] indices and estimated fluid intake,
and between serum [Na] and body mass change. There
was no difference in either estimated fluid intake or body
mass change between those who used NSAIDs and those
who did not use NSAIDs.
Incidence of EAH
One participant met the criteria for EAH. He estimated
that he had consumed approximately 5 L and 800 mg
of ibuprofen before and during the marathon. His
race time was 4 hours 56 min, slightly slower than the
average race time of all study participants 4 hours 38
min. Given increased fluid intake is a significant factor
in the development of EAH; this is likely to have signifi-
cantly influenced his serum [Na] during and after the
marathon. It is interesting to note that several other
athletes in this study estimated that they had consumed
similar volumes of fluid, but did not use NSAIDs, yet their
serum [Na] were not significantly affected adding further
weight to the possible role of NSAIDs in the development
of EAH.
Limitations and implications for future research
Participants were presumed medically fit and healthy as
they were taking part in a marathon. As a result, uniden-
tified comorbidities may have been present. Normal
pre-race serum [Na] reduced the likelihood that partici-
pants were truly unwell on the day of the marathon.
Fluid intake during the marathon relied on athlete
recall which is subject to bias. To minimise this limitation,
body mass was measured immediately before and after
the marathon to complement fluid intake data. Data
regarding NSAID use were also collected retrospectively.
Furthermore, NSAID type and dose was not controlled or
accounted for in the main analysis.
There was large dropout rate between race registration
and the start of the marathon. In addition, 13 partici-
pants did not attend the finish line research station for
data collection. Attempts were made to contact partic-
ipants who did not attend for post-race testing. Several
cited difficulties locating the research station among
busy crowds. This loss to follow-up resulted in small final
groups and therefore accuracy of results may have been
affected.
Although the same scales were used to measure partic-
ipants body mass, running shoes were not removed.
Accumulation of fluid (eg, sweat) within the fabric of the
clothes and shoes may have affected apparent post-mar-
athon body mass potentially underestimating body mass
loss. This may offer an explanation for the lack of body
mass changes seen in some participants.
Female gender is a known risk factor for EAH, and
the higher proportion of females to males in the NSAID
group than the control group may have skewed the
results. It is possible the increased risk related to female
gender represents an association due to volume of fluid
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relative to females’ smaller size rather than a risk factor
per se.
Further research is required to establish if NSAIDs
taken post-event cause similar effects on serum sodium
levels in the 24 hours following exercise.
CONCLUSION
Fifty-seven percent of a cohort of 28 marathon partici-
pants used NSAIDS before or during a marathon despite
cautionary advice from the marathon organisers to avoid
their use. There was a significant reduction in serum [Na]
over the course of the marathon in participants who used
NSAIDS while athletes who did not use NSAIDs demon-
strated an increase in serum [Na]. Estimated fluid intake
and changes in body mass were inversely correlated with
both post-marathon serum [Na] and ∆ serum [Na]. Only
half the athletes using NSAIDs were aware of the risks of
NSAID use, and 37.5% of NSAID users consumed doses
greater than the recommended safe maximum.
Acknowledgements In addition to the authors of this paper Dr Alex Maxwell,
Angela McIllMurray, Dr Bethan Grifths, Dr Emily Kidd, Jenny Baker, Dr Jonathan
Hall, Nikhil Patel, Dr Rachel Parker and Dr Tom Lyon assisted during data collection.
The project was awarded the British Association of Sports Medicine (BASEM) 2016
Research Bursary, which helped towards the expenses of the project. University
College London (UCL) provided the remaining funds for the projects expenses. The
authors would like to thank all participants, helpers, BASEM and UCL.
Contributors SW: data collection, analysis and article write up. SM: data collection
and review/editing of article. CK: supervisor, review/editing of article.
Funding This project received funding from the University College London (UCL)
and the British Association of Sport and Exercise Medicine (BASEM).
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval UCL Research Ethics Committee.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement All collated data are available to all researchers who
provide a methodologically sound proposal and have the appropriate approval.
Data will be available immediately following publication, for 5 years. Proposals
should be directed to steven. whatmough@ nhs. net. To gain access, data requestors
will need to sign a data access agreement.
Open access This is an open access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which
permits others to distribute, remix, adapt, build upon this work non-commercially,
and license their derivative works on different terms, provided the original work is
properly cited, appropriate credit is given, any changes made indicated, and the
use is non-commercial. See: http:// creativecommons. org/ licenses/ by- nc/ 4. 0/.
REFERENCES
1. Ayus JC, Varon J, Arieff AI, etal. Hyponatremia, cerebral edema, and
noncardiogenic pulmonary edema in marathon runners. Ann Intern
Med 2000;132:711–4.
2. Thompson J-A, Wolff AJ. Hyponatremic encephalopathy in a
marathon runner. Chest 2003;124:313S.
3. Hew-Butler T, Rosner MH, Fowkes-Godek S, etal. Statement of the
third international exercise-associated hyponatremia consensus
development conference, Carlsbad, California, 2015. Clin J Sport
Med 2015;25:303–20.
4. Spasovski G, Vanholder R, Allolio B, etal. Clinical practice guideline
on diagnosis and treatment of hyponatraemia. Nephrology Dialysis
Transplantation 2014;29(suppl_2):i1–i39.
5. Verbalis JG, Goldsmith SR, Greenberg A, etal. Hyponatremia
treatment guidelines 2007: expert panel recommendations. Am J
Med 2007;120(11 Suppl 1):S1–S21.
6. Knechtle B, Knechtle P, Rüst CA, etal. Regulation of electrolyte and
uid metabolism in multi-stage ultra-marathoners. Horm Metab Res
2012;44:919–26.
7. Almond CS, Shin AY, Fortescue EB, etal. Hyponatremia among
runners in the Boston Marathon. N Engl J Med
2005;352:1550–6.
8. Noakes TD, Sharwood K, Speedy D, etal. Three independent
biological mechanisms cause exercise-associated hyponatremia:
evidence from 2,135 weighed competitive athletic performances.
Proc Natl Acad Sci U S A 2005;102:18550–5.
9. Hoffman MD, Fogard K, Winger J, etal. Characteristics of 161-
km ultramarathon nishers developing exercise-associated
hyponatremia. Res Sports Med 2013;21:164–75.
10. Bruso JR, Hoffman MD, Rogers IR, etal. Rhabdomyolysis and
hyponatremia: a cluster of ve cases at the 161-km 2009 Western
States Endurance Run. Wilderness Environ Med
2010;21:303–8.
11. Casa DJ, Clarkson PM, Roberts WO, etal. American College of
Sports Medicine roundtable on hydration and physical activity:
consensus statements. Curr Sports Med Rep
2005;4:115–27.
12. Montain SJ, Cheuvront SN, Sawka MN, etal. Exercise associated
hyponatraemia: quantitative analysis to understand the aetiology. Br
J Sports Med 2006;40:98–105.
13. Küster M, Renner B, Oppel P, etal. Consumption of analgesics
before a marathon and the incidence of cardiovascular,
gastrointestinal and renal problems: a cohort study. BMJ Open
2013;3:e002090.
14. Wharam PC, Speedy DB, Noakes TD, etal. NSAID use increases the
risk of developing hyponatremia during an Ironman triathlon. Med
Sci Sports Exerc 2006;38:618–22.
15. Martínez S, Aguiló A, Moreno C, etal. Use of non-steroidal anti-
inammatory drugs among participants in a mountain ultramarathon
event. Sports 2017;5:11.
16. Joslin J, Lloyd JB, Kotlyar T, etal. NSAID and other analgesic use by
endurance runners during training, competition and recovery. South
African Journal of Sports Medicine 2013;25:101–4.
17. Gorski T, Cadore EL, etal. Use of nonsteroidal anti-inammatory
drugs (NSAIDs) in triathletes: Prevalence, level of awareness, and
reasons for use. Br J Sports Med 2009.
18. Davis DP, Videen JS, Marino A, etal. Exercise-associated
hyponatremia in marathon runners: a two-year experience. J Emerg
Med 2001;21:47–57.
19. Cairns RS, Hew-Butler T. Incidence of exercise-associated
hyponatremia and its association with nonosmotic stimuli of arginine
vasopressin in the GNW100s ultra-endurance marathon. Clin J Sport
Med 2015;25:347–54.
20. Page AJ, Reid SA, Speedy DB, etal. Exercise-associated
hyponatremia, renal function, and nonsteroidal antiinammatory
drug use in an ultraendurance mountain run. Clin J Sport Med
2007;17:43–8.
21. Scotney B, Reid S. Body weight, serum sodium levels, and renal
function in an ultra-distance mountain run. Clin J Sport Med
2015;25:341–6.
22. Meteorological-Ofce. Meteorological ofce archive. [Online]
[Accessed 6 June 2018].
23. Stachenfeld NS, Taylor HS. Sex hormone effects on body uid and
sodium regulation in women with and without exercise-associated
hyponatremia. J Appl Physiol 2009;107:864–72.
24. Joint Formulary Committee. British National Formulary (online).
London: BMJ Group and Pharmaceutical Press, 2018.
25. Nieman DC, Henson DA, Dumke CL, etal. Ibuprofen use,
endotoxemia, inammation, and plasma cytokines during
ultramarathon competition. Brain Behav Immun 2006;20:578–84.
26. Bushra R, Aslam N. An overview of clinical pharmacology of
Ibuprofen. Oman Med J 2010;25:155–661.
27. Jones BL, OʼHara JP, Till K, etal. Dehydration and hyponatremia in
professional rugby union players: a cohort study observing english
premiership rugby union players during match play, eld, and gym
training in cool environmental conditions. J Strength Cond Res
2015;29:107–15.
28. Sharwood K, Collins M, Goedecke J, etal. Weight changes, sodium
levels, and performance in the South African Ironman Triathlon. Clin
J Sport Med 2002;12:391–9.
29. Kipps C, Sharma S, Tunstall Pedoe D, etal. The incidence of
exercise-associated hyponatraemia in the London marathon. Br J
Sports Med 2011;45:14–19.
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