Effects of dialysis duration on brain perfusion and cognitive function in end-stage renal disease - short vs. long hemodialysis

Cardiovascular disease, as the leading cause of mortality, and cognitive
decline are common in patients with end-stage renal disease (ESRD) undergoing
conventional hemodialysis (CHD), which is usually performed 3 times per week
for about 4 hours. A serious side effect is intradialytic hypotension (IDH),
which occurs in approximately 20% of the dialysis sessions (1, 2). Recurrent
arterial hypotension endangers perfusion of the heart (coronary circulation)
and the brain, and is associated with poor survival. A transient reduction in
cerebral blood flow (CBF) occurs during hemodialysis (HD), correlating with
intradialytic decline in cognitive dysfunction (3). Nocturnal hemodialysis
(NHD; 8 hours) is associated with better hemodynamic tolerance and blood
pressure (BP) control, with the majority of the patients no longer requiring
antihypertensive medication (4). NHD has the advantage of slow ultrafiltration
rate with a reduced incidence of IDH, potentially resulting in preserved CBF
and cognitive function.
For the brain as a highly metabolic active organ, constancy of oxygen supply by
maintaining CBF is a prime requirement. CBF is under tight autoregulatory
control and impairment of CBF control exposes the brain to episodic
hypoperfusion. A reduction in CBF in itself may contribute to progression of
vascular cognitive impairment. Recent data indicate that cerebral ischemia
during HD is a common phenomenon (5) and correlates with the decline in
executive cognitive function (6). Notably, intradialytic hemodynamic
instability was associated with the development of brain white matter lesions
after 1 year (7). Whether or not intrinsic CBF control is impaired in patients
with ESRD remains to be determined.
Improvement of hemodynamic stability (defined as smaller reduction in BP during
dialysis) with NHD vs. CHD has the potential to limit the intradialytic decline
in CBF and cognitive function in ESRD patients.

Primary objective:
To test in patients with ESRD whether a longer HD session (8 hours) compared
with CHD limits the decline in cerebral blood flow.

Secondary objectives:
1) to investigate whether a longer dialysis session is associated with superior
hemodynamic stability, defined as a smaller reduction in blood pressure during
dialysis (pre-post), compared with CHD.
2) to test whether a longer dialysis session is associated with less
intradialytic cognitive decline compared with CHD.
3) to assess cerebrovascular autoregulatory capacity, blood pressure
variability and cardiovascular autonomic function during long vs. short HD
sessions.

A cross-over design will be used consisting of 2 parts:
A) CHD vs. extended HD (4 vs. 8 hours at daytime), and B) NHD vs. CHD (8 hours
at night vs. 4 hours at daytime).
For each part 8 patients will be enrolled. Patients will be recruited from the
dialysis center Diapriva Buitenveldert B.V. The dialysis center has access to
a mobile cerebro- and cardiovascular bedside monitoring, recording and storage
unit as designed and in use in the Laboratory for Clinical Cardiovascular
Physiology (LCCP, Amsterdam UMC, location AMC).

Part A) Eight patients receiving CHD treatment will be asked to undergo a
longer HD session at daytime (extended HD) on the first dialysis day of the
week (Monday or Tuesday), extending the HD treatment time to 8 hours.
Intradialytic hemodynamic measurements will be performed at both visits in
random order (CHD > extended HD or extended HD > CHD) with an interval of 2
weeks.
Part B) Eight patients receiving NHD treatment will be asked to undergo CHD
treatment at daytime on the first dialysis day of the week, shortening the HD
treatment time to 4 hours. Intradialytic hemodynamic measurements will be
performed at both visits in random order (CHD > NHD or NHD > CHD) with an
interval of 2 weeks.

The following measurements will be performed during dialysis:
-Systemic hemodynamic variables: Beat-to-beat non-invasive continuous arterial
BP monitoring (finger plethysmography contralateral to the AV fistula arm) and
automated oscillometric non-invasive BP (NIBP) measurement, heart rate, stroke
volume and cardiac output (pulse contour analysis). NIBP measurements will be
performed every 30 min during daytime dialysis and only twice during NHD (at
the start of dialysis treatment and at the end).
-Cerebrovascular hemodynamic variables: CBF velocity (middle cerebral artery
blood flow velocity by transcranial Doppler ultrasonography) and end-tidal CO2
(PETCO2). Static cerebrovascular autoregulation will be assessed in the time
domain by relating the changes in CBF velocity to changes in BP during
dialysis. Dynamic cerebrovascular autoregulation, measured prior to and after
dialysis, will be quantified in the frequency domain expressed as the arterial
pressure-to-CBF velocity transfer function coherence, phase shift and gain.
-BP variability: Cardiac baroreflex sensitivity will be evaluated during the
first half hour and last half hour of the dialysis session (very short-term BP
variability). Also standard deviation (SD) and coefficient of variation (CV) of
the BP values from the NIBP measurements will be estimated (short-term BP
variability).
-Cardiovascular autonomic function: Cardiovascular sympathetic and
parasympathetic function and postural BP response (orthostatic hypotension)
will be assessed prior to and after dialysis.
-Cognitive function will be assessed during the last hour of both HD sessions
using a validated neuropsychological protocol.
All measurements will be performed on the first dialysis day of the week
(Monday or Tuesday after the long interdialytic interval) to account for
different interdialytic weight gain, which determines the ultrafiltration rate,
throughout the week.

A longer HD session (8 hours) will be compared with a conventional HD session
(4 hours)

The burden for the subjects will be minimal: Measurement of CBF velocity by
transcranial Doppler and continuous non-invasive BP measurement using finger
plethysmography are generally well-tolerated. Blood sampling will be performed
from the arterial lines of the extracorporeal circuit before and after dialysis
(no venipuncture). Evaluation of cognitive functioning (using a test battery)
during dialysis is limited to 30-45 min. Patients regularly treated with NHD
could encounter an increased prevalence of IDH during CHD, which they would
also encounter if one of their dialysis sessions is scheduled at daytime for
personal reasons. No extra risks are to be expected with participation. Whereas
the benefit for patients is as yet unknown, in terms of cerebral perfusion and
cognitive function, improvement of hemodynamic stability with NHD has the
potential to limit the intradialytic reduction in CBF with preserved cognitive
function in ESRD patients, which will improve the prospects and quality of life
in this patient population. This study addresses the underlying mechanism(s) of
HD-related brain decay and opens the discussion on preservation of cognitive
function as a highly relevant objective in this frail patient group.