Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03095742 |
| Other study ID # |
S-20150173 HLP |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
September 1, 2017 |
| Est. completion date |
September 3, 2020 |
Study information
| Verified date |
April 2022 |
| Source |
Odense University Hospital |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
In comatose patients resuscitated from out of hospital cardiac arrest (OHCA), neurological
injuries remain the leading cause of death. The in-hospital mortality is reported at 30-50%,
and the total mortality, although improved substantially over the last decade, remain to be
significant, in most countries at up to 90%. An adequate blood pressure must be maintained in
the post-cardiac arrest patient and helps to avoid further brain injury. The current trial
addresses strategies for neuroprotection using a design of two different target blood
pressure levels. "Normal MAP" (approximately 65 mmHg) vs. "high MAP" (approximately 75 mmHg).
Markers measuring global cerebral ischemia caused by cardiac arrest and consecutive
resuscitation, and reflecting the metabolic changes after successful resuscitation are
urgently needed to enable a more personalized resuscitation and post resuscitation care.
It is technically simple and feasible to place a microdialysis catheter in the jugular bulb
and monitor biochemical variables related to cerebral energy metabolism bedside. The LP ratio
obtained from microdialysis of cerebral venous blood may be a sensitive indicator of
impending cerebral damage and might play a critical role in detecting the early responses of
post resuscitation care. Aim of this study is to investigate the global cerebral metabolic
changes during CA and post-resuscitation care.
Description:
Microdialysis assessment of cerebral energy state during cardiac arrest and cardiopulmonary
resuscitation in humans
In comatose patients resuscitated from out of hospital cardiac arrest (OHCA), neurological
injuries remain the leading cause of death. The in-hospital mortality is reported at 30-50%,
and the total mortality, although improved substantially over the last decade, remain to be
significant, in most countries at up to 90%. The brain of a patient resuscitated after
cardiac arrest (CA) may have suffered ischemia and when spontaneous circulation is
re-established, the subsequent reperfusion may cause further damage. Brain ischemia and the
reperfusion injury lead to tissue degeneration and loss of neurological function, the extent
dependent on duration and density of the insult. Temperature control and Targeted Temperature
Management (TTM) targeting 33-36°C may mitigate this damage and is recommended in current
international guidelines. However, managing post cardiac arrest patients are much more
complicated than TTM alone, and blood pressure measurements and mechanical ventilation as
part of post resuscitation care is emphasized. An adequate blood pressure must be maintained
in the post-cardiac arrest patient. Episodes of hypotension can cause secondary injury, in
addition to any initial insult incurred during the arrest by the brain and other organs. Mean
arterial blood pressure (MAP) should be above 65 mmHg to reverse the acute shock state, and
may preferably 80 to 100 mmHg to optimize cerebral perfusion. When determining blood pressure
goals, clinicians must balance the metabolic needs of an ischemic brain with the potential
for overstressing a decompensated heart. Cerebral autoregulation is often impaired after
cardiac arrest, and brain perfusion declines when the MAP falls below 80 to 100 mmHg. Thus,
maintaining an adequate MAP helps to avoid further brain injury. However, blood pressure
goals have not been investigated in prospective clinical trials, and remain to be based on
observational data and extrapolation from experimental data. While experimental studies
suggest that high mean blood pressure targets are needed for maintaining cerebral blood flow,
registries on consecutive clinical cases undergoing post resuscitation care suggest that
lower blood pressure targets are used in clinical practice. But data RCT´s addressing
specific targets in post resuscitation care have not been performed. The current trial
addresses these strategies for neuroprotection in using design of two different target blood
pressure levels. Intervention: 1:1 randomization:
"Normal MAP" (approximately 65 mmHg) vs. "high MAP" (approximately 75 mmHg) Markers measuring
global cerebral ischemia caused by cardiac arrest and consecutive resuscitation, and
reflecting the metabolic changes after successful resuscitation are urgently needed to enable
a more personalized resuscitation and post resuscitation care.
It is technically simple and feasible to place a microdialysis catheter in the jugular bulb
and monitor biochemical variables related to cerebral energy metabolism bedside. The LP ratio
obtained from microdialysis of cerebral venous blood may be a sensitive indicator of
impending cerebral damage and might play a critical role in detecting the early responses of
post resuscitation care. Aim of this study is to investigate the global cerebral metabolic
changes during CA and post-resuscitation care.
Aim: The study aim to (I) investigate whether the LP ratio obtained by microdialysis (MD) of
the cerebral venous outflow reflects a derangement of global cerebral energy state during the
peri-cardiac arrest period and (II) investigate the correlation between LP ratio and
neurological outcome among patients with cardiac arrest and (III) investigate the correlation
between LP ratio and the randomized blood pressure targets.
Design: The trial was a sub-study in the Blood Pressure and Oxygenation Targets after
Out-of-Hospital Cardiac Arrest-trial (BOX, clinicaltrials.gov NCT03141099). This single
center randomized trial allocated 60 comatose out-of-hospital cardiac arrest patients
undergoing TTM, to normal or high blood pressure target during ICU stay. Secondary a
descriptive prospective cohorte study, measuring LP ratio obtained by microdialysis (MD) of
the cerebral venous outflow, during the peri-cardiac arrest period.
Primary outcome: Analysis will compare the two target blood pressure groups with respect to
LP ratio.
Secondary outcomes: Cerebral Performance Category (CPC) when discharged from hospital, time
to death, daily cumulated vasopressor requirement during ICU stay and need for combination of
vasopressors and inotropic agents or mechanical circulatory support. All end-points are
correlated to the randomized blood pressure groups. A stratified analysis by the following
pre-defined design variables will also be performed: sex, age above median, median time to
ROSC, known hypertension, known COPD, shockable primary rhythm.
Method: Interventions are considered emergency procedures and study blood pressure
measurement using the study blood pressure modules should be commenced as soon as possible
after sustained ROSC, screening and randomisation. Study target blood pressure will be
blinded. Patients will be mechanically ventilated, sedated (propofol/fentanyl) and when
necessary paralysed with neuromuscular blocking agents to reduce shivering and subsequent
heat-generation and energy consumption. The core body temperature will be set as quickly as
possible at the predefined target temperature, according to intervention allocation, with 4°C
intravenous solutions, and commercially available cooling devices at the discretion of the
treating physician. The target core temperature is then maintained for 24 h. After the
maintenance period core temperature is gradually raised to normothermia of 37°C with a
rewarming rate of no more than 0.5°C/hour. Body temperature is then maintained at
normothermia 37 ±0.5°C for as long the as patient is comatose until 72 hours from sustained
ROSC in treatment groups, using pharmacological treatment and temperature management systems
when applicable.
The study is targeting low-normal paO2 of 9.5 kPa during TTM and when mechanical ventilation
is needed. The target PaO2 is reached by adjusting FiO2 and PEEP on the ventilator as long as
the patient in on controlled ventilation. Patients ventilation is adjusted, targeting
normocapnia of paCO2 of 4,5 - 6,0 in all patients. Serial arterial blood gas analyses will be
performed open label using the commercially available equipment adjusted to 37 °C
(alpha-stat).
MD catheter (CMA 67, MDialysis AB, Stockholm, Sweden) is placed in a retrograde direction
into the jugular bulb. A second identical MD catheter is inserted into one brachial artery.
Both catheters are inserted through a peripheral intravenous 17 GA cannula using ultrasound
guidance. The positioning of the catheter in the jugular bulb above the inlet of the common
facial vein is verified on lateral neck radiograph according to accepted principles. MD
catheters are perfused by MD pumps (CMA 106, MDialysis AB, Stockholm, Sweden) at 0.3 μL/min.
The perfusates are collected in microvials and analyzed every one hour for 72 hours by
enzymatic photometric techniques and displayed bedside (Iscus, Mdialysis AB, Stockholm,
Sweden). The analyses include the variables routinely monitored during intracerebral
microdialysis: glucose, pyruvate, lactate, glutamate and glycerol.
Neurological status, according to the CPC-scale, and survival are evaluated every day in the
intensive care unit and/or at day 1, 2, 3, 4, 5, 6, 7 and at hospital (including local
hospital) discharge, whichever comes first.
The Danish Regional Committee on Health and Research Ethics approved the study. Trial
registration: S-20150173 HLP.
Perspectives The prognosis of patients who are admitted in a comatose state following
successful resuscitation after cardiac arrest remains uncertain. Although the introduction of
therapeutic hypothermia (TH), targeted temperature management (TTM) and improvements in
post-resuscitation care have significantly increased the number of patients who are
discharged home with minimal brain damage, short-term assessment of neurological outcome
remains a challenge. The need for early and accurate prognostic predictors is crucial,
especially since sedation and TH/TTM may alter the neurological examination and delay the
recovery of motor response for several days. The development of additional tools, including
electrophysiological examinations (electroencephalography and somatosensory evoked
potentials), neuroimaging and chemical biomarkers, may help to evaluate the extent of brain
injury in these patients. Accurate prognostication of comatose patients treated with TH/TTM
can be obtained only 72 to 96 hours after CA and requires a multimodal approach.
Markers measuring cerebral ischemia caused by cardiac arrest and consecutive resuscitation,
and reflecting the metabolic changes after successful resuscitation are urgently needed to
enable a more personalized resuscitation and post resuscitation care. The LP ratio obtained
from microdialysis of cerebral venous blood may play a critical role in detecting the early
responses of post resuscitation care, and may predict in hospital and long term prognosis in
patients affected by brain injury after CA.
During the peri-cardiac arrest period the LP ratio obtained by microdialysis of the cerebral
venous outflow may reflects a derangement of global cerebral energy state. The LP ratio
obtained from microdialysis of cerebral venous blood in humans may be a sensitive indicator
of impending cerebral damage among patients with cardiac arrest. Further, the study
investigates the correlation between LP ratio and the randomized blood pressure targets. In
the future this might optimize and individualize the management of post cardiac arrest
patients.
Appendix:
Pre-defined methodological substudy conducted prior to the MICA-RCT:
This single-center prospective feasibility study explores the possibilities to use
microdialysis (MD) for continuous monitoring of cerebral energy metabolism by analyzing the
draining cerebral venous blood. Eighteen comatose patients (same inclusion criteria as
MICA-study but without the MAP intervention) )will be continuously monitored with jugular
bulb and radial artery (reference) MD following resuscitation. This feasibility study was
designed to investigate whether bedside JBM reflects secondary brain injury after OHCA, and
may be implemented as a clinical tool with implications for early prognosis and
individualized treatment improving patient outcome. Therefore, we tested the hypothesis
whether the lactate/pyruvate (LP) ratio monitored in the cerebral venous outflow reflected
brain energy metabolism after cardiac arrest and hence was different from the LP ratio
monitored in arterial blood.
The primary objective was to compare time-averaged means of microdialysis parameters
(intervals of 12 hours) of the jugular venous and the arterial blood during
post-resuscitation care. Secondary objectives of clinical interest were to compare (i)
neuro-metabolic patterns between patients with unfavorable and favorable neurological outcome
(ii) total duration of cerebral desaturation and clinical outcome.
Risks and discomforts: Few. The retrograde MD catheter is inserted under ultrasound guidance
and is associated with a small (<2%) risk of localized bleed which can be managed by manual
compression. Accidental arterial puncture occurs and is managed by manual compression.
Strokes and air emboli are extremely rare and symptoms are usually transient. The blood drawn
for blood gas analyses is not associated with increased risk, the volume needed is
approximately 50 ml total and thus not associated with increased risks.
