Impact of Hyponatremia on Muscle Strength, Gait and Balance, and Cognitive Function: a Prospective Observational Study
Conditions: Hyponatremia
Sponsor: Bürgerspital Solothurn

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Impact of hyponatremia on muscle strength, gait and balance, and cognitive function:  
a prospective observational study 
 
 
 
 
 
 
 
v1.4, 14.05.2019 
Impact of hyponatremia on muscle strength, gait and balance, and 
cognitive function: a prospective observational study 
 
 
 
 
Research legislation: 
 Ordinance on human research with the exception of Clinical trials 
(HRO) [1]. 
 
 
Type of Research Project: 
Research project involving human subjects  
 
 
Risk Categorisation:  
A 
 
 
Project Leader: 
 
 
Gregor Lindner M.D.                                                                                                                                           
Department of General Internal Medicine                                                                                                         
Bürgerspital Solothurn  
Schöngrünstrasse 42  
4500 Solothurn                                                                                                                                                    
Switzerland                                                                                                                                                         
Tel: +41/32 627 31 21                                                                                                                                         
Email: lindner.gregor@gmail.com 
 
 
 
 
 

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Impact of hyponatremia on muscle strength, gait and balance, and cognitive function:  
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PROTOCOL SIGNATURE FORM    
 
 
Study Title 
Impact of hyponatremia on muscle strength, gait and 
balance, and cognitive function: a prospective 
observational study 
 
The project leader has approved the protocol version 1.4 (dated 14.05.2019), and confirms 
hereby to conduct the project according to the protocol, the Swiss legal requirements [30, 31], 
current version of the World Medical Association Declaration of Helsinki [32] and the principles of 
Good Clinical Practice.  
 
Project leader: 
 
Site  
Bürgerspital Solothurn  
Schöngrünstrasse 42  
4500 Solothurn                                                                                                                                                    
Switzerland       
 
Name: PD Dr. med. univ. Gregor Lindner 
Date: 
 _________________________ 
Signature:  ___________________________  
 
 
 
 
 
 

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Impact of hyponatremia on muscle strength, gait and balance, and cognitive function:  
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TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................. 3 
GLOSSARY OF ABBREVATIONS ............................................................................................. 4 
1 BACKGROUND AND PROJECT RATIONALE ........................................................................ 5 
2 PROJECT OBJECTIVES AND DESIGN .................................................................................. 6 
2.1 Hypothesis and primary objective ................................................................................... 6 
2.2 Primary and secondary endpoints ................................................................................... 6 
2.3 Project design ................................................................................................................. 7 
3 PROJECT POPULATION AND STUDY PROCEDURES ........................................................ 7 
3.1 Project population, inclusion and exclusion criteria ......................................................... 7 
3.2 Recruitment, screening and informed consent procedure ............................................... 7 
3.3 Study procedures ............................................................................................................ 7 
3.4 Withdrawal and discontinuation ....................................................................................... 8 
4 STATISTICS AND METHODOLOGY ...................................................................................... 8 
4.1. Statistical analysis plan .................................................................................................. 8 
4.2. Handling of missing data ................................................................................................ 8 
5 REGULATORY ASPECTS AND SAFETY ............................................................................... 8 
5.1 Local regulations / Declaration of Helsinki ....................................................................... 8 
5.2 Notification of safety and protective measures (HRO Art. 20) .......................................... 8 
5.3 Serious events (HRO Art. 21) .......................................................................................... 9 
5.4 Procedure for investigations involving radiation sources ................................................. 9 
5.5 Amendments ................................................................................................................... 9 
5.6 End of project .................................................................................................................. 9 
5.7 Insurance ........................................................................................................................ 9 
6 FURTHER ASPECTS .............................................................................................................. 9 
6.1 Overall ethical considerations ......................................................................................... 9 
6.2 Risk-Benefit Assessment ................................................................................................ 9 
6.3 Rationale for the inclusion of vulnerable participants ..................................................... 10 
7 QUALITY CONTROL AND DATA PROTECTION .................................................................. 10 
7.1 Quality measures .......................................................................................................... 10 
7.2 Data recording and source data .................................................................................... 10 
7.3 Confidentiality and coding ............................................................................................. 10 
7.4 Retention and destruction of study data and biological material .................................... 10 
8 FUNDING / PUBLICATION / DECLARATION OF INTEREST ............................................... 10 
9 REFERENCES ...................................................................................................................... 11 
Appendix 1: Schedule of assessments ................................................................................ 13 
 
GLOSSARY OF ABBREVATIONS 
 
BASEC 
Business Administration System for Ethical Committees 
CRF 
Case report form 
FOPH 
Federal Office of Public Health 

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Impact of hyponatremia on muscle strength, gait and balance, and cognitive function:  
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HRA 
Human Research Act 
HRO  
Ordinance on Human 
 
 
 

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Impact of hyponatremia on muscle strength, gait and balance, and cognitive function:  
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v1.4, 14.05.2019 
1 
BACKGROUND AND PROJECT RATIONALE  
Hyponatremia, defined as a serum sodium level below <136 mmol/L, is an often encountered 
disorder in hospitalized patients, with a prevalence of about 10% of patients presenting to the 
emergency department 1-3]. While the excess mortality seen in hyponatremic patients has long 
been attributed to the severity of the underlying disease, as it is potentially true in heart failure 
and other conditions, recent studies have shown that hyponatremia itself has a negative impact 
on patient outcomes, irrespective of the type and severity of the underlying disease 4-8]. Even a 
slight decrease of the serum sodium level was shown to be independently associated with 
adverse outcomes, such as mortality or increase in length of ICU/hospital stay 6, 8]. To date, the 
mechanisms leading to worse prognosis in patients with hyponatremia remain largely unknown. 
Evidence suggests that patients with hyponatremia may be more prone to falls resulting in an 
increased incidence of fractures in such patients 9-11]. In addition, chronic hyponatremia may be 
associated with decreased bone density and therefore a higher risk of fractures 12-14]. A small 
recent study showed an association between hyponatremia and psychomotor disturbances, such 
as attention deficits and gait difficulties 15]. 
The above mentioned effects of acute hyponatremia might be explained by cellular 
hyperhydration, the same mechanism that also leads to cerebral edema [3]. In chronic 
hyponatremia, compensatory mechanisms, such as a shift of organic and inorganic osmotically 
active substances from the intracellular to the extracellular space, have already occurred and 
decrease cellular edema [3, 16. However, resting membrane potential is a function of sodium and 
potassium concentrations. Thus, hyponatremia might directly influence nerve conduction velocity 
and muscle strength. 
In summary, limited evidence suggests that hyponatremia appears to influence neurologic 
functions leading to attention deficits, gait disturbances, and a higher risk of fractures. Given the 
low quality of existing data, the association between hyponatremia and these adverse outcomes 
must be further examined, preferably in an adequately powered prospective study.  
 
Preliminary studies 
I. In a large study including multiple intensive care units in Austria, our group demonstrated 
that even mild decreases in serum sodium (i.e., serum sodium 130 – 135 mmol/L) were 
associated with an increased mortality, adjusting for age, admission diagnosis, and 
severity of illness as measured by the Severe Acute Physiology Score (SAPS) II 6]. 
II. Another study by our group showed that hyponatremia at the time of hospital admission 
is often not noticed and consequently, not or inadequately treated during hospitalization 
11]. 
V. Refardt and coworkers demonstrated an increase in cognitive function but could not show 
an improvement in gait after correction of sodium levels [29]. 
VI. Vandergheynst and coworkers could show no improvement in strength after correction in 
moderate hyponatremia, but could show impaired nerve conduction with significant 
improvement through correction in severe hyponatremia [PMID 26835607]. 
VII. Albabtain and cowerkers found a correlation between hyponatremia and impaired 
cognitive function in patients with heart failure but none for impaired mobility [PMID 
27988787]. 
VIII. 
Murthy and coworkes did a metaanalysis regarding bone density and fractures in 
hyponatremia, showing a significantly increased risk for osteoporosis, all-site fractures, 
mortality and duration of hospital stay in Patients with hyponatremia [PMID 30720342]. 
IX. Usala and coworkers conducted a metaanalysis regarding osteoporisis and prevalence of 
fractures in diabetic patients with hyponatremia, showing a significantly increasd risk for 
osteoprosis and fractures in hyponatremia [PMID 30746503] 
X. Corona and coworkers showed in a metanalysis an increased risk for fractures even in 
mild hyponatremia [PMID 29920727]. 
 

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Impact of hyponatremia on muscle strength, gait and balance, and cognitive function:  
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2 
PROJECT OBJECTIVES AND DESIGN  
2.1 Hypothesis and primary objective  
Our broad objective is to prospectively examine in a prospective study whether an association 
exists between hyponatremia and psychomotor deficits. The specific aims are: 
A) To measure muscle strength by use of a dynamometer in patients presenting with 
moderate to severe hyponatremia (serum sodium ≤ 125 mmol/L) at the emergency 
department before and after correction of hyponatremia (serum sodium ≥ 135 mmol/L). 
B) To test for balance and gait disorders before and after correction of hyponatremia 
C) To investigate whether presence of hyponatremia is associated with cognitive impairment 
that isreversible after correction of serum sodium. 
Our hypothesis is that hyponatremia is associated with reduced muscle strength, impaired 
balance, and cognitive impairment, and that the correction of the serum sodium will lead to an 
improvement of these parameters. 
2.2 Primary and secondary endpoints 
A) Muscle strength in pounds and kilogram before and after correction of hyponatremia. 
B) Results for the Tinetti performance-oriented mobility assessment (POMA) to evaluate 
static and dynamic balance abilities during and after correction of hyponatremia. 
C) Results for the Montreal Cognitive Assessment (MOCA) test to assess mild cognitive 
impairment before and after correction of hyponatremia.  
 
Muscle strength at handgrip will be measured at time of presentation at our clinic with a serum 
sodium ≤ 125 mmol/L and 24 to 48 hours after correction of hyponatremia at a serum sodium ≥ 
135 mmol/L using the Jamar ® hydraulic hand dynamometer, Lafayette Instrument, Lafayette, IN, 
USA. Strength will be measured in pounds and kilograms thrice at baseline and after correction 
of hyponatremia, respectively. The best result of each test will be used for the analysis. The test 
will be conducted by either Drs. Woitok or Lindner. 
The Tinetti POMA, a simple, easily administered test, will be used to measure patients’ gait and 
balance taking about 10 to 15 minutes [19]. Scoring of the Tinetti Assessment Tool is done on a 
three point ordinal scale with a range of 0 to 2. A score of 0 represents the most severe 
impairment, while a 2 would represent patient independence. The individual scores are then 
combined to form three measures; an overall gait assessment score, an overall balance 
assessment score, and a gait and balance score. The test has been validated in several studies 
and found to be a useful screening tool for gait instabilities and prediction of falls [20-22]. The 
Tinetti POMA form is shown in the Appendix. The test will be performed at baseline and 24 to 48 
hours after correction of hyponatremia. The test will be conducted by either Drs. Woitok and 
Lindner. 
The MOCA is a 30-point test administered in about 10 minutes designed to identify mild cognitive 
impairment [23]. The test is validated for a large variety of diseases ranging from frontotemporal 
dementia to HIV or chronic obstructive pulmonary disease [24-27]. The MOCA form is shown in 
the Appendix. The test will be performed at baseline and 24 to 48 hours after correction of 
hyponatremia. The test will be conducted by either Drs. Woitok and Lindner. 
2.3 Project design  
We will conduct a single-center, prospective, observational study at the General Hospital 
Solothurn. The study will be conducted at the Department of Emergency Medicine, where patients 
will be screened for hyponatremia, and the Department of General Internal Medicine, where 
screening will occur both in the inpatient and outpatient services. 

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Impact of hyponatremia on muscle strength, gait and balance, and cognitive function:  
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3 
PROJECT POPULATION AND STUDY PROCEDURES 
3.1 Project population, inclusion and exclusion criteria  
Sample size was calculated on basis of the MOCA test. To achieve a power of 90% and a two-
sided alpha level of 0.05, the sample size needed to detect a difference of 5 points (shown 
difference between normal individuals and those with mild cognitive impairment) between the 
baseline and post-correction MOCA scores would be 44 patients [23]. Thus, we plan to enroll a 
total of 50 patients. 
Inclusion criteria 
Consecutive patients aged 18 years or above presenting with moderately to severe hyponatremia 
(serum sodium ≤ 125 mmol/L after correction for blood glucose), who give informed consent. 
Exclusion criteria 
 
Patients who do not give or are not able to give informed consent. 
 
Patients with concomitant Potassium dysregulation (K+<3.5 mmol/l or K+>5.0 mmol/l) 
 
Pregnant or Lactating females 
 
3.2 Recruitment, screening and informed consent procedure 
If a serum sodium of 125 mmol/L is detected in a blood sample sent from the Department of 
Emergency Medicine or General Internal Medicine, the Center for Laboratory Medicine will notify 
the study team (Drs. Lindner and Woitok) responsible for patient enrollment using a dedicated 
pager. Then, a member of the study team will approach potential participants, inform them about 
the study goals and procedures, obtain informed consent, and enroll them into the study.  Patients 
enrolled in the Department of Emergency Medicine needing hospitalization will primarily 
hospitalized in the Department of General Internal Medicine, unless hospitalization at specialist 
ward is indicated. 
3.3 Study procedures 
Upon recruitment the following data will be collected: 
a.) Clinical data 
Of all patients included in the study, we will collect data on age, sex, comorbidities, and current 
medications taken by the patients.  
b.) Serum sodium measurements 
Measurements of serum sodium will be performed through the Center for Laboratory Medicine of 
the General Hospital Solothurn. Sodium determination will be performed by use of ion-selective 
electrode using the ICT (Na+, K+, Cl-) Sample Diluent Kit, Abbott Laboratories, Chicago, IL, USA. 
Additionally, serum osmolality, potassium, magnesium, calcium, creatinine, albumin and 
hemoglobin as well as urine osmolality, sodium, potassium, creatinine and urea will be measured. 
All of these parameters are standard measurements in case of a severe electrolyte disorder and 
are part of clinical practice in the care for patients with electrolyte disorders. All laboratory 
parameters will be measured at baseline and after correction of serum sodium. In order to avoid 
multiple blood drawings for the patient the parameters mentioned above will be reordered from 
blood already taken for serum sodium determination. 
c.) Physical and cognitive measurements 
Afterwards muscle strength, Tinetti score and MOCA score will be measured. Upon correction of 
hyponatremia these measurements will be repeated. The study is then completed for the 
individual participant. 
See also Appendix 1. 

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3.4 Withdrawal and discontinuation 
Patients are excluded from the project in case of withdrawal of informed consent. Endpoint-
specific datasets will be included if complete (see Section 4.2.). Additional patients will be enrolled 
to compensate for drop-outs. Since the blood samples used are part of clinical routine no further 
steps are taken, the blood samples will be handled according to usual clinical routine. 
4 
STATISTICS AND METHODOLOGY 
4.1. Statistical analysis plan 
Data will be presented as means and standard deviation or medians and interquartile range as 
appropriate. Wilcoxon signed ranked tests will be used to compare results on muscle strength, 
Tinetti score and MOCA scores, since those are not normally distributed and samples will be 
dependent since every patient serves as his own control. A p-value of ≤ 0.05 will be considered 
statistically significant. Statistics will be calculated using IBM SPSS Statistics 25, IBM, Armonk, 
New York, USA. 
Based on general Patient count and prevalence of Hyponatremia, the enrollment of the sample 
size of 50 patients seems realistic in a 12-month period, starting on 01 June 2019. 
4.2. Handling of missing data  
Partially missing data (e.g. a missing Tinetti-Assesment) would be left out in the specific 
calculation, but data for the other Endpoints would be used, if complete. If there would be no 
complete sets of data for any Endpoint the data set would be discarded. Reasons for missing 
measurements will be stated in the publication. 
5 
REGULATORY ASPECTS AND SAFETY 
5.1 Local regulations / Declaration of Helsinki 
This research project will be conducted in accordance with the protocol, the Declaration of 
Helsinki [32], the principles of Good Clinical Practice, the Human Research Act (HRA) and the 
Human Research Ordinance (HRO) [30] as well as other locally relevant regulations. The Project 
Leader acknowledges his responsibilities as both the Project Leader and the Sponsor. 
5.2 Notification of safety and protective measures (HRO Art. 20) 
The project leader is promptly notified (within 24 hours) if immediate safety and protective 
measures have to be taken during the conduct of the research project. The Ethics Committee will 
be notified via BASEC of these measures and of the circumstances necessitating them within 7 
days. 
5.3 Serious events (HRO Art. 21) 
If a serious event occurs, the research project will be interrupted and the Ethics Committee 
notified on the circumstances via BASEC within 7 days according to HRO Art. 211. 
                                                        
1 A serious event is defined as any adverse event where it cannot be excluded, that the event is attributable to the 
sampling of biological material or the collection of health-related personal data, and which: 
a. requires inpatient treatment not envisaged in the protocol or extends a current hospital stay; 
b. results in permanent or significant incapacity or disability; or 
c. is life-threatening or results in death. 

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5.4 Procedure for investigations involving radiation sources 
This Study does not involve radiation sources. 
5.5 Amendments 
Substantial changes to the project set-up, the protocol and relevant project documents will be 
submitted to the Ethics Committee for approval according to HRO Art. 18 before implementation. 
Exceptions are measures that have to be taken immediately in order to protect the participants.  
5.6 End of project 
Upon project termination, the Ethics Committee is notified within 90 days. All health-related data 
are anonymized upon termination of data analysis. 
5.7 Insurance 
In the event of project-related damage or injuries, the liability of the Bürgerspital Solothurn 
provides compensation, except for claims that arise from misconduct or gross negligence. 
6 
FURTHER ASPECTS 
6.1 Overall ethical considerations 
This is a prospective, observational study. No invasive interventions will take place and thus, there 
is no potential harm for the patients. Laboratory parameters will be re-ordered from blood samples 
already taken as a part of clinical routine, so no additional blood drawings are necessary for study 
purposes. Only patients who are able to give informed consent by themselves will be included in 
the study. There will be no compensation for the patients, neither monetary nor in another way.  
6.2 Risk-Benefit Assessment  
Hyponatremia is a commonly encountered problem in hospitalized patients and is associated with 
significant morbidity and mortality [1, 2, 10]. The present study could give more insight into the 
impact of this electrolyte disorder on important body functions, such as muscle strength, gait and 
balance, and cognition. If hyponatremia is associated with these conditions, specific preventive 
measures could be taken to avoid complications, such as falls and fractures, which are associated 
with significant mortality, morbidity, and a socioeconomic burden [18]. Additionally, if the negative 
influence of hyponatremia on psychomotricity was shown, it could help increase physicians’ 
awareness to correct hyponatremia and eliminate predisposing factors for this condition [17]. 
Since it is an observational study no specific risks are expected. 
6.3 Rationale for the inclusion of vulnerable participants  
Vulnerable Participants are not included in the Study. 
 
7 
QUALITY CONTROL AND DATA PROTECTION 
7.1 Quality measures  
All data handling will be undertaken directly by the investigators. For quality assurance the Ethics 
Committee may visit the research sites. Direct access to the source data and all project related 
files and documents must be granted on such occasions. 

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7.2 Data recording and source data 
Data will be collected on paper CRFs and transferred to a Microsoft Excel file by the 
investigators. The Paper CRFs will be subsequently stored in a lockable bin. The Excel file will 
be stored on a dedicated drive accessible only by the study team. The dedicated drive is part of 
the Hospital IT Structure and thus subject to data backup procedures. 
7.3 Confidentiality and coding 
Project data will be handled with uttermost discretion and is only accessible to authorized 
personnel who require the data to fulfil their duties within the scope of the research project. On 
the CRFs and other project specific documents, participants are only identified by a unique 
participant number. The Code will not include any parts able to identify a subject like name or 
date of birth. 
All patient data will be stored in a lockable bin in an office room at the General Hospital Solothurn. 
Patient data will be entered into a Microsoft Excel database, Microsoft Corporation, Redmond, 
WA, USA, and stored electronically on a password-protected computer. Electronic patient data 
will be encrypted and only the investigators (Drs. Woitok and Lindner) will be able to identify 
patients by use of a personal identification number for every patient enrolled in the study. Data 
will be published anonymously. 
7.4 Retention and destruction of study data and biological material 
Health related data are stored for 10 years after publication of the research project. The blood 
samples are part of clinical routine and will be handled according to clinical routine. No blood 
samples will be stored for study purposes. 
8  FUNDING / PUBLICATION / DECLARATION OF INTEREST 
There is no funding for the project. The Investigators declare no conflict of interest. 
9 
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Impact of hyponatremia on muscle strength, gait and balance, and cognitive function:  
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11. Hoorn EJ, Rivadeneira F, van Meurs JB, Ziere G, Stricker BH, Hofman A, Pols HA, Zietse R, 
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Impact of hyponatremia on muscle strength, gait and balance, and cognitive function:  
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Clifford DB, Ances BM, (2013) The Alzheimer's disease-8 and Montreal Cognitive 
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30. Ordinance on Human Research with the Exception of Clinical trials (HRO) 
https://www.admin.ch/opc/en/classified-compilation/20121177/index.html  
31. Human Research Act (HRA) 
http://www.admin.ch/opc/en/classified-compilation/20121176/201401010000/810.305.pdf  
32. Declaration of Helsinki  
(https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-
medical-research-involving-human-subjects ) 
33. STROBE statement (http://www.jclinepi.com/article/S0895-4356(07)00436-2/pdf) 
 
 
 

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Impact of hyponatremia on muscle strength, gait and balance, and cognitive function:  
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Appendix 1: Schedule of assessments  
 
 
 
Time 
0 
Corrected sodium  
Visit 
Screening/1st visit  2nd visit 
oral and written Information 
+ 
 
Written consent 
+ 
 
check inclusion-/ 
exclusion criteria 
+ 
 
Medical history 
+ 
 
Participant Characteristics  
+ 
 
Serum sodium measurements 
+ 
+ 
MOCA 
+ 
+ 
Tinetti Assessment 
+ 
+ 
Grip Strength 
+ 
+