Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT04645121 |
| Other study ID # |
H-20031445 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
November 25, 2020 |
| Est. completion date |
June 1, 2022 |
Study information
| Verified date |
June 2022 |
| Source |
Rigshospitalet, Denmark |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
The study is a case-control study with the primary aim of objectifying the volume status of
patients receiving hemodialysis. Volume status will be assessed at dry weight and evaluated
by a carbon monoxide rebreathing method, that measures blood volume, and bioimpedance that
measures total body water. Case-control subjects will be matched on gender, age and weight.
Secondary aims are to evaluate the carbon monoxide rebreathing method. Blood volumes obtained
by the carbon monoxide rebreathing method will be correlated to blood volumes obtained by
radioactive labelling of erythrocytes and albumin. In addition, it will be investigated
whether hemoglobin is a valid marker of anemia in patients receiving hemodialysis by
measuring the erythrocyte volume and the hemoglobin mass by the carbon monoxide rebreathing
method and correlating this to the hemoglobin concentration measured before and after
dialysis.
Description:
Aim:
1. To combine a carbon monoxide rebreathing method and bioimpedance which allows to
objectively measure the amount of fluid in the bloodstream (intravascular) and
throughout the body, and thereby test the actual amount of fluid in the body when
patients are hydrated according to their clinical dry weight.
2. To validate carbon monoxide rebreathing method in hemodialysis patients compared against
a radioactive labeling of erythrocytes and albumin (the gold standard).
3. To investigate whether hemoglobin is a valid marker of anemia in this patient population
by measuring the erythrocyte volume and hemoglobin mass by the carbon monoxide
rebreathing method and correlating this to the hemoglobin concentration.
Background:
Anemia and overhydration are challenging conditions in patients on hemodialysis.
Overhydration is associated with hypertension, cardiomyopathy and increased mortality. In
assessing the patient's volume status, blood pressure, body weight and peripheral edema are
used as indicators. To achieve a more accurate estimate, these measures have been combined
with various techniques, such as relative changes in blood volume (measured with blood volume
sensor (BVS)) and bioimpedance. These methods are used to varying degrees in everyday
clinical practice.
In case of overhydration, fluid is distributed intravascularly and can thereby expand blood
volume. The primary clinical problem with an expanded blood volume is hypertension and
increased risk of cardiovascular complications. Measurement of the intravascular volume can
therefore have great clinical relevance, but currently there are no direct measures for this
implemented in the clinical daily routine. Various techniques have been used for research
purposes. These include fluorescent dilution techniques, radioactive labeling of erythrocytes
and albumin, as well as infusion of dialysate during dialysis where changes in BVS
measurements can be used to calculate the intravascular volumes.
Bioimpedance can be used to measure the total water phase and the intra- and extracellular
volume. The method has been shown to be useful in the diagnosis of overhydration in
hemodialysis patients. Overhydration detected by bioimpedance in hemodialysis patients has
been shown to correlate to increased mortality. Bioimpedance is a non-invasive, painless and
practically useful way of assessing the volume status.
Anemia is another significant challenge in patients on hemodialysis. The majority of patients
on hemodialysis have a significant decrease in endogenous erythropoietin production, which
causes anemia and requires treatment with an erythrocyte stimulant (ESA). The basis for
anemia diagnosis and the decision on ESA treatment in hemodialysis patients is based on
pre-dialysis hemoglobin (measured at dialysis start-up). Upon overhydration, fluid
distributed to the intravascular space will lead to dilated plasma volume (PV) and dilution
of hemoglobin. This dilution and thus artificial decrease in hemoglobin makes pre-dialysis
hemoglobin difficult to interpret in patients on dialysis. Time-averaged hemoglobin,
calculated on the basis of pre-dialysis and post-dialysis hemoglobin, has been shown to
correlate better with the actual hemoglobin of hemodialysis patients, but the value has not
gained ground in practice.
The carbon monoxide rebreathing method is a well-proven technique for determining
intravascular volume, (blood volume, BV), PV and red blood cell volume (RBCV). In renally
healthy patients, the method is validated against a radioactive labeling technique (gold
standard) where high correlation (r = 0.97) has been demonstrated between the two methods.
The carbon monoxide rebreathing method has also been shown to be able to detect even very
small changes in blood volume. The method is safe and requires 6 minutes of carbon monoxide
inhalation. A prerequisite for using the carbon monoxide rebreathing method is a normal
diffusion of gas over the lungs, which allows uptake into the blood. Dialysis patients may be
significantly overhydrated and possible accumulation of water in the alveoli may decrease the
diffusion of carbon monoxide and affect the method. Against this background, the method is to
be validated against a radioactive labeling technique.
The validity of the carbon monoxide rebreathing method in hemodialysis patients has not been
performed which is important if the method is to be implemented clinically and for research
purposes.
Method:
Case-control study with 25 patients in each group. The case group consists of hemodialysis
patients and the control group consists of healthy individuals with eGFR above 60
ml/min/1.73m2. Subjects were matched on gender, age (+/- 5 years) and (weight +/- 10kg).
Hemodialysis group: 25 hemodialysis patients are included. Immediately before the start of
dialysis, the total body water is measured by bioimpedance and blood samples are taken. A
normal hemodialysis lasts 3-4 hours and during this period the patient undergoes fluid
extraction corresponding to their estimated dry weight. 30 minutes after the dialysis is
completed, the total boby water is measured with bioimpedance and the blood volume, plasma
volume and erythrocyte volume are measured by carbon monoxide rebreathing method. In 10
participants, blood volume, plasma volume and the erythrocyte volume are measured by a
radioactive labeling of erythrocytes and albumin, where blood is taken at the beginning of
dialysis and cleaned at the end of dialysis. Hemoglobin and hematocrit are measured
pre-dialysis, post-dialysis and 30 minutes after cessation of dialysis. Participation in the
study involving the radioactive labeling of erythrocytes and albumin may be omitted if a
participant does not wish the study.
Control group: Includes 25 patients with eGFR above 60 ml/min/1.73m2 and without severe heart
failure, liver failure or lung disease. In all participants, the intravascular volume is
measured by carbon monoxide rebreathing method and the total body water by bioimpedance. In
10 participants, blood volume is measured by a radioactive label of erythrocytes and albumin.
Hemoglobin and other standard samples are measured.
If a participant after inclusion must be withdrawn, the patient is replaced by a new
participant until a number of 25 participants in each group is achieved. If a matched
participant cannot be found for an included participant, the person in question is withdrawn
and replaced by a new one.
Statistics:
Blood volume in patients hemodialysis has been found to be 73.4 ml / kg (SD 15 ml / kg) and
from the predicted normal blood volume has been found to be 59.0 ml / kg (SD 9.3 ml / kg). In
a two-sided unpaired t-test with α = 0.05, SD = 15 and a power of 90%, a sample size of 23
patients in each group will show a significant difference. A dropout rate of approximately 2
patients is assumed and a total of 25 are included in each group.
After completion of the study and data completion the results are analysed according to
primary and secondary endpoints. Results are reported as mean values with confidence interval
or median and interquartile range. Data are analysed with parametric (normally distributed
data) or non-parametric statistics (non-normal distributed data). A 95 % confidence interval
is accepted as statistically significant (p < 0.05). Analysis are performed as a per protocol
analysis.
