Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT06130033 |
| Other study ID # |
H23-00172 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
June 1, 2023 |
| Est. completion date |
June 1, 2026 |
Study information
| Verified date |
November 2023 |
| Source |
University of British Columbia |
| Contact |
Mypinder Sekhon, MD PhD |
| Phone |
6048754111 |
| Email |
myp[@]mail.ubc.ca |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
The purpose of this study is to better understand what happens in the brain during the dying
process.
This is a prospective observational study conducted at the end of life in the ICU at VGH. At
the time of withdrawal of life sustaining therapies the investigators will monitor brain
blood flow and oxygenation. The investigators will also collect blood samples to measure
biomarkers of brain dysfunction.
This may help us to determine when blood flow to the brain stops and when brain function
ceases. This information may provide researchers and the medical community as a whole with
important information as to the best timing for organ donation. This study is the first step
in commencing a research program related to improving the organ donation process. Our goal is
to determine how best to provide high quality organs to those who would otherwise die without
an organ transplant.
Description:
MAIN STUDY
PURPOSE The goal of this project is to characterize the cerebrovascular physiology of
circulatory death during withdrawal of life sustaining therapies in humans.
JUSTIFICATION Death is defined as the permanent loss of brain function following absence of
cerebral blood flow (CBF). Such physiology can result from two clinical scenarios: a) absent
CBF in patients with a beating heart (neurological brain death) or b) after natural
circulatory arrest. In the latter scenario, eventual cessation of innate cardiac output leads
to absent CBF, brain tissue oxygenation and irreversible loss of brain function. Pertinent to
solid organ transplantation, death must occur prior to consideration of organ donation. In
the setting of circulatory death, withdrawal of life-sustaining therapies (WLST) is
undertaken and organ donation commences after the declaration of death. This process is
termed controlled donation after cardiac death (DCD). Due to the scarcity of available organ
donation opportunities, the emergence of DCD has provided increased access to life-saving
solid organ transplants for recipients. However, challenges remain with respect to successes
of DCD graft organ function and optimal recipient outcomes. Principally, the timeliness from
WLST to circulatory death declaration is crucial to graft viability with prolonged periods
associated with worse graft organ ischemia, function and adverse recipient outcomes. To this
extent, the determination of the precise timing of death determination during DCD is
imperative to inform timely diagnosis of death and optimize retrieval of high-quality grafts
for solid organ transplant recipients.
The characterization of the cerebrovascular physiology of circulatory death in humans has
knowledge gaps. Current guidelines define a pulse pressure < 5mmHg (systolic - diastolic
blood pressure) using radial arterial line monitoring as the acceptable threshold for timing
of circulatory death. Although pragmatic, this definition assumes that in vivo hemodynamic
physiology generated by the heart (reflected by the arterial line) is simultaneously
reflected in the cerebral circulation. It is well known that systemic hemodynamics do not
necessarily correlate with cerebral hemodynamics during critical illness. Pathophysiologic
sequelae (e.g. elevated intracranial pressure) in critically ill acutely brain injured
patients who undergo WLST suggest that cerebral perfusion may cease before systemic
hemodynamics (detected by radial arterial line monitoring) deteriorate irreversibly. As such,
it is plausible that cerebral perfusion ceases before a pulse pressure < 5mmHg is achieved
thereby setting the conditions by which the physiologic requirement of circulatory death is
present (absent CBF) but the clinical definition has not (pulse pressure < 5mmHg) been
reached. Clinically, this scenario would expose viable graft organs to prolonged ischemia and
negatively affect solid organ transplant recipient outcomes
HYPOTHESES AND AIMS
OBJECTIVES and associated HYPOTHESIS Aim 1 (Cerebral Hemodynamics): To determine the pulse
pressure (measured with an in situ radial arterial catheter) at which cerebral hemodynamics
cease (measured with transcranial Doppler derived middle [MCA-Fv] and posterior cerebral
artery blood flow velocities [PCA-Fv]) following WLST. The investigators hypothesize that
cerebral hemodynamics will cease when the pulse pressure is > 5mmHg.
Sub-aim 1b: To assess the agreement between the timing of circulatory death determined by
invasive neuromonitoring (absent CBF using invasive neuromonitoring) and transcranial Doppler
derived indices (absent MCA-Fv and PCA-Fv). The investigators hypothesize that there will be
strong agreement.
Aim 2 (Brain Oxygenation): To determine the pulse pressure at which brain oxygenation
(measured with jugular venous bulb oximetry and near infrared spectrscopy) ceases following
WLST. The investigators hypothesize that brain oxygenation will cease when the pulse pressure
is > 5mmHg.
Sub-aim 2b: To assess the agreement between the timing of circulatory death determined by
invasive neuromonitoring (absent brain tissue oxygen tension using invasive neuromonitoring)
and with jugular venous bulb oximetry (SjvO2 0%) and near infrared spectroscopy (0%). The
investigators hypothesize that there will be strong agreement.
Aim 3 (Cardiac Output): To determine the agreement between the timing of absence of cardiac
output (measured via a right heart catheter) and the pulse pressure < 5mmHg from a radial
arterial line. The investigators hypothesize that there will be strong agreement.
RESEARCH DESIGN This is a prospective observational study of the evaluation of the
cerebrovascular physiology of circulatory death.
STATISTICAL ANALYSIS Our sample size is one of convenience. We will enroll 50 participants.
Discrete variables will be summarized by frequencies and percentages. Continuous variables
will be summarized by mean (SD) or median (IQR) if data are skewed.
Aim 1: The pulse pressure at which MCA-Fv and PCA-Fv cease will be summarized as a median and
range across the cohort. The percentage of patients exhibiting absent CBF with a pulse
pressure of > 5mmHg will be stated as well. Sub Aim 1b: The agreement between the pulse
pressure at which CBF ceases (detected by invasive neuromonitoring) will be compared against
the pulse pressure at which MCA-Fv and PCA-Fv cease using a Bland-Altman analysis. Linear
regression analysis will also be used to conduct agreement analysis as part of this aim.
Further, receiver operating curve analysis will be used to assess the diagnostic accuracy of
the non-invasive neuromonitoring techniques against the gold standard comparator (invasive
neuromonitoring guided CBF measurement).
Aim 2: The pulse pressure at which SjvO2 % reaches zero will be summarized as a median and
range across the cohort. The percentage of patients exhibiting SjvO2 )% with a pulse pressure
of > 5mmHg will be stated as well. Sub Aim 2b: The agreement between the pulse pressure at
which SjvO2 % and regional saturation of oxygen percent reach zero will be compared against
the pulse pressure at which brain tissue oxygen tension cease (detected by invasive
neuromonitoring) using a Bland-Altman analysis. Linear regression analysis will also be used
to conduct agreement analysis as part of this aim.
Aim 3: The agreement between the time of pulselessness detected by absent cardiac output (by
the right heart catheter) versus pulse pressure < 5mmHg (at the radial artery) will be
analyzed using a Bland-Altman analysis. Linear regression analysis will also be used to
conduct agreement analysis as part of this aim.
Sex Based Analysis: Assessing sex-related differences will encompass an exploratory analysis
to inform future hypothesis generation. In our neuromonitoring patients, the proportion of
patients has been approximately 60% male and 40% female. The investigators expect a similar
ratio of males to females in the current study. Data will be stratified by sex, across all
patients and within each study group. Further, for both study groups the investigators will
assess differences between males and females by including an interaction term group*sex into
our linear mixed models.
PATHOLOGY SUB STUDY
PURPOSE To perform post-mortem pathological examination of nervous system tissue (brain and
spinal cord)
HYPOTHESIS The investigators hypothesize that the brain will show histological features
correlated with early cessation of blood perfusion such as abnormalities in and around small
vessels and in the blood-brain barrier, tissue edema, and markers of early cellular necrosis,
and that these changes will not be present, or will be present to a much lesser extent, in
the spinal cord of the same individuals.
JUSTIFICATION AND OBJECTIVES Post-mortem brain and spinal cord autopsy will be obtained in
patients to provide a tissue correlate and context to the neuromonitoring data. The
investigators will evaluate whether two distinct areas of the central nervous system (brain
and spinal cord) with different blood supply show the same degree of histopathological
changes. Specifically, pathologic examination will be undertaken to provide macroscopic
evaluation of the middle and posterior cerebral arteries for signs of vascular pathology
(e.g. intravascular thrombi, vasoconstricted state) to provide mechanistic explanations for
the anticipated results. Examination will also be undertaken in the regions of anterior and
posterior circulation to assess microvascular pathology that could explain the
cerebrovascular physiologic results. This will also be compared to the spinal cord which has
a different blood supply from the brain. Specifically, the formalin fixed samples will be
used for hematoxylin and eosin and special stains to assess for abnormalities in and around
small vessels and in the blood-brain barrier, tissue edema, and markers of early cellular
necrosis.
RESEARCH DESIGN This single-center prospective post-mortem pathological analysis of patients
who underwent WLST will describe the pathologic characteristics of neurological injury in the
neurovascular unit.
STATISTICAL ANALYSIS The pathology tissue analysis will be used to draw descriptive analyses
pertaining to the macrovascular and microvascular abnormalities present on post-mortem
examination. The change in the concentrations of the arterial and cerebral arterio-venous
gradients of the brain biomarkers will be analyzed before WLST and immediately following
circulatory death using a one-way ANOVA analysis. Comparisons between the pulse pressure at
which cerebral hemodynamics, brain oxygenation and neural electrical activity cease will be
conducted between patients with an antecedent acquired brain injury versus those without
using a paired T-test.
