Cardiopulmonary Bypass, Thoracic Surgery
Conditions
Keywords
cardiac surgery; brain injury; cerebral autoregulation
Brief summary
Neurological complications from cardiac surgery are an important source of operative mortality, prolonged hospitalization, health care expenditure, and impaired quality of life. New strategies of care are needed to avoid rising complications for the growing number of aged patients undergoing cardiac surgery. This study will evaluate novel methods for reducing brain injury during surgery from inadequate brain blood flow using techniques that could be widely employed.
Detailed description
Brain injury during cardiac surgery results primarily from cerebral embolism and/or reduced cerebral blood flow (CBF). The latter is of particular concern for the growing number of surgical patients who are aged and/or who have cerebral vascular disease. Normally, CBF is physiologically autoregulated (or kept constant) within a range of blood pressures allowing for stable cerebral O2 supply commensurate with metabolic demands. Cerebral autoregulation is impaired in patients undergoing cardiac surgery who have cerebral vascular disease and in many others due to other conditions. This could lead to brain injury since current practices of targeting low mean arterial blood pressure empirically (usually 50-70 mmHg) during cardiopulmonary bypass may expose patients with impaired cerebral autoregulation to cerebral hypoperfusion. The hypothesis of this proposal is that targeting mean arterial pressure during cardiopulmonary bypass to a level above an individual's lower autoregulatory threshold reduces the risk for brain injury in patients undergoing cardiac surgery. Monitoring of cerebral autoregulation will be performed in real time using software that continuously compares the relation between arterial blood pressure and CBF velocity of the middle cerebral artery measured with transcranial Doppler and with cerebral oximetry measured with near infrared spectroscopy. The primary end-point of the study will be a comprehensive composite outcome of clinical stroke, cognitive decline, and/or new ischemic brain lesions detected with diffusion weighted magnetic resonance (MR) imaging. Delirium assessed using a validated procedure that includes validated tools is a secondary outcome measure. Autoregulation is mediated by reactivity of cerebral resistance vessels. A secondary aim of this proposal is to evaluate whether near infrared reflectance spectroscopy can be used to trend changes in cerebral blood volume and provide a reliable monitor of vascular reactivity (the hemoglobin volume index). Assessments for extra-cranial and intra-cranial arterial stenosis will be performed using MR angiography to control for this potential confounding variable in the analysis. Finally, an additional aim of the study will be to assess whether preoperative transcranial Doppler examination of major cerebral arteries can identify patients who are prone to the composite neurological end-point. Near infrared oximetry is non-invasive, continuous, requires little care-giver intervention and, thus, could be widely used to individualize patient blood pressure management during surgery. Brain injury from cardiac surgery is an important source of operative mortality, prolonged hospitalization, increased health care expenditure, and impaired quality of life. Developing strategies to reduce the burden of this complication has wide public health implications.
Interventions
Blood pressure lowered or raised
Institutional standard of care.
Sponsors
Study design
Eligibility
Inclusion criteria
* Male or female patients undergoing primary or re-operative Coronary Artery Bypass Graft (CABG) and/or valvular surgery or ascending aorta surgery that requires Cardio-pulmonary bypass (CPB) who are at high risk for neurologic complications (stroke or encephalopathy) as determined by a Johns Hopkins risk score of \>0.02
Exclusion criteria
* Contraindication to MRI imaging (e.g., permanent pacemaker, cerebral arterial vascular clips) * Liver function test before surgery more than twice the upper limit of institutional normal * Pre-existing renal dysfunction defined as an estimated glomerular filtration rate of ≤60 mL/min, or current renal dialysis * Emergency surgery * Inability to attend outpatient visits * Visual impairment or inability to speak and read English. The patient will be excluded from further study if an adequate temporal window for Transcranial Doppler (TCD) monitoring can not be identified before surgery.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Composite Neurological Outcome of Clinical Stroke or New Ischemic Brain Lesion on Diffusion Weighted MRI or Neurocognitive Dysfunction 4 to 6 Weeks After Surgery. | Up to 6 weeks post-operative | The composite neurological outcome was composed of clinical stroke, or new ischemic lesions detected on postoperative brain diffusion weighted magnetic resonance imaging(DWI), or cognitive decline from baseline to 4-6 weeks after surgery. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Postoperative Delirium | Postoperative days 1-4 | Assessed with Confusion Assessment Method or Confusion Assessment Method-ICU along with adjudication by team of experts |
| Multiple Inotropic Drugs>24 Hours After Surgery | 7 days after surgery | Use of multiple inotropic drugs greater than 24 hours after the planned surgical procedure until discharge from the hospital. |
| Mechanical Lung Ventilation>24 Hours After Surgery | Up to 28 days after surgery. | Subjects need for mechanical lung ventilation more than 24 hours after planned surgical procedure. |
| Insertion of Intra-aortic Balloon Pump | 7 days after surgery | Procedural insertion of intra-aortic balloon pump within 7 days after surgical procedure |
| Postoperative Atrial Fibrillation | Up to 28 days after surgery. | Clinical diagnosis of postoperative atrial fibrillation from date of surgical procedure to discharge from the hospital. |
| Sepsis | Up to 28 days after surgery. | Clinical diagnosis of sepsis from time of surgical procedure to discharge from the hospital. |
| Acute Kidney Injury Within 7 Days After Surgery. | 7 days after surgery | Subject developed acute kidney injury within 7 days after surgical procedure. Based on Kidney disease: Improving Global Outcomes (KDIGO) classification system. |
| New Renal Replacement Therapy | Up to 28 days after surgery. | Subjects requiring new renal replacement therapy prior to discharge from hospital |
| Multisystem Organ Failure After Surgery | Up to 28 days after surgery. | Subject diagnosis of multisystem organ failure after surgery. |
| Mortality | 28 days | Subject death within 28 days after surgical procedure |
Countries
United States
Contacts
Northwestern University
Participant flow
Pre-assignment details
After obtaining written informed consent, 468 were randomized to the two groups. 237 in the autoregulation group were randomized after consent and 5 subjects withdrew consent. 231 in the usual care group were randomized after consent and 3 subjects withdrew consent.
Participants by arm
| Arm | Count |
|---|---|
| Usual Care Group Blood pressure targets during cardiopulmonary bypass based on institutional standards of empiric management.
Control group: Institutional standard of care. | 228 |
| Autoregulation Group Blood pressure management based on cerebral autoregulation data.
blood pressure maintenance based on cerebral blood flow autoregulation measurement: Blood pressure lowered or raised | 232 |
| Total | 460 |
Baseline characteristics
| Characteristic | Usual Care Group | Total | Autoregulation Group |
|---|---|---|---|
| Age, Continuous | 70.8 years STANDARD_DEVIATION 8 | 70.4 years STANDARD_DEVIATION 7.6 | 70.0 years STANDARD_DEVIATION 7.3 |
| Aortic cross-clamp (time in minutes) | 73 Minutes | 71 Minutes | 69 Minutes |
| Cardiopulmonary bypass duration | 107 Minutes | 105 Minutes | 103 Minutes |
| Current tobacco use | 22 Participants | 46 Participants | 24 Participants |
| Duration of hospitalization (days) | 8 Days | 7 Days | 7 Days |
| Duration of ICU admission (hours) | 44.1 Hours | 44 Hours | 44 Hours |
| Highest Grade of Formal Education (median,[inter-quartile range]) | 14.0 Years | 14 Years | 14.5 Years |
| History of anemia | 101 Participants | 209 Participants | 108 Participants |
| History of a prior stroke | 25 Participants | 44 Participants | 19 Participants |
| History of atrial fibrillation | 53 Participants | 102 Participants | 49 Participants |
| History of chronic obstructive lung disease | 31 Participants | 52 Participants | 21 Participants |
| History of diabetes | 101 Participants | 209 Participants | 108 Participants |
| History of hypertension | 213 Participants | 420 Participants | 207 Participants |
| History of myocardial infarction | 65 Participants | 139 Participants | 74 Participants |
| Logistic EuroSCORE (median,[interquartile range]) | 5.3 score on a scale 0-2 good >=5 high risk | 5.19 score on a scale 0-2 good >=5 high risk | 5.08 score on a scale 0-2 good >=5 high risk |
| Mini-Mental State Exam | 28 score on a scale (30 good- 0 poor) | 28 score on a scale (30 good- 0 poor) | 28 score on a scale (30 good- 0 poor) |
| Obstructive sleep apnea | 41 Participants | 77 Participants | 36 Participants |
| Race/Ethnicity, Customized African American | 24 participants | 52 participants | 28 participants |
| Race/Ethnicity, Customized Asian | 0 participants | 4 participants | 4 participants |
| Race/Ethnicity, Customized Caucasian | 189 participants | 273 participants | 184 participants |
| Race/Ethnicity, Customized Hispanic | 3 participants | 5 participants | 2 participants |
| Race/Ethnicity, Customized Multiple | 0 participants | 2 participants | 2 participants |
| Race/Ethnicity, Customized Native American | 1 participants | 4 participants | 3 participants |
| Race/Ethnicity, Customized Other | 10 participants | 19 participants | 9 participants |
| Region of Enrollment United States | 228 Participants | 460 Participants | 232 Participants |
| Sex/Gender, Customized Female | 67 participants | 129 participants | 62 participants |
| Sex/Gender, Customized Male | 160 participants | 330 participants | 170 participants |
| Sex/Gender, Customized Missing designation | 1 participants | 1 participants | 0 participants |
| Type of surgery Aortic Root Replacement | 2 Participants | 4 Participants | 2 Participants |
| Type of surgery Aortic Valve Replacement (AVR) | 41 Participants | 89 Participants | 48 Participants |
| Type of surgery Aortic Valve Replacement, Mitral Valve Replacement (AVR/MVR) | 9 Participants | 14 Participants | 5 Participants |
| Type of surgery Coronary Aertery Bypass Graft, Aortic Valve Replacement (CABG/AVR) | 35 Participants | 61 Participants | 26 Participants |
| Type of surgery Coronary Artery Bypass Graft, Aortic Valve Replacement, Mitral Valve Replacement (CABG/AVR/MVR) | 3 Participants | 6 Participants | 3 Participants |
| Type of surgery Coronary Artery Bypass Graft (CABG) | 109 Participants | 226 Participants | 117 Participants |
| Type of surgery Coronary Artery Bypass Graft, (CABG) / Aortic Root Replacement | 1 Participants | 1 Participants | 0 Participants |
| Type of surgery Coronary Artery Bypass Graft, Mitral Valve Replacement CABG/MVR) | 6 Participants | 15 Participants | 9 Participants |
| Type of surgery Mitral Valve Replacement (MVR) | 19 Participants | 41 Participants | 22 Participants |
| Type of surgery Transcatheter Aortic Valve Replacement (TAVR) | 3 Participants | 3 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 12 / 228 | 5 / 232 |
| other Total, other adverse events | 34 / 228 | 19 / 232 |
| serious Total, serious adverse events | 133 / 228 | 121 / 232 |
Outcome results
Composite Neurological Outcome of Clinical Stroke or New Ischemic Brain Lesion on Diffusion Weighted MRI or Neurocognitive Dysfunction 4 to 6 Weeks After Surgery.
The composite neurological outcome was composed of clinical stroke, or new ischemic lesions detected on postoperative brain diffusion weighted magnetic resonance imaging(DWI), or cognitive decline from baseline to 4-6 weeks after surgery.
Time frame: Up to 6 weeks post-operative
Population: Subjects who completed neurological testing and MRI testing
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Usual Care Group (Control) | Composite Neurological Outcome of Clinical Stroke or New Ischemic Brain Lesion on Diffusion Weighted MRI or Neurocognitive Dysfunction 4 to 6 Weeks After Surgery. | 79 Participants |
| Autoregulation Group | Composite Neurological Outcome of Clinical Stroke or New Ischemic Brain Lesion on Diffusion Weighted MRI or Neurocognitive Dysfunction 4 to 6 Weeks After Surgery. | 70 Participants |
Acute Kidney Injury Within 7 Days After Surgery.
Subject developed acute kidney injury within 7 days after surgical procedure. Based on Kidney disease: Improving Global Outcomes (KDIGO) classification system.
Time frame: 7 days after surgery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Usual Care Group (Control) | Acute Kidney Injury Within 7 Days After Surgery. | 56 Participants |
| Autoregulation Group | Acute Kidney Injury Within 7 Days After Surgery. | 62 Participants |
Insertion of Intra-aortic Balloon Pump
Procedural insertion of intra-aortic balloon pump within 7 days after surgical procedure
Time frame: 7 days after surgery
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Usual Care Group (Control) | Insertion of Intra-aortic Balloon Pump | 19 Participants |
| Autoregulation Group | Insertion of Intra-aortic Balloon Pump | 14 Participants |
Mechanical Lung Ventilation>24 Hours After Surgery
Subjects need for mechanical lung ventilation more than 24 hours after planned surgical procedure.
Time frame: Up to 28 days after surgery.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Usual Care Group (Control) | Mechanical Lung Ventilation>24 Hours After Surgery | 22 Participants |
| Autoregulation Group | Mechanical Lung Ventilation>24 Hours After Surgery | 13 Participants |
Mortality
Subject death within 28 days after surgical procedure
Time frame: 28 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Usual Care Group (Control) | Mortality | 12 Participants |
| Autoregulation Group | Mortality | 5 Participants |
Multiple Inotropic Drugs>24 Hours After Surgery
Use of multiple inotropic drugs greater than 24 hours after the planned surgical procedure until discharge from the hospital.
Time frame: 7 days after surgery
Population: 228 in the usual care group and 232 in the autoregulation group were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Usual Care Group (Control) | Multiple Inotropic Drugs>24 Hours After Surgery | 13 participants |
| Autoregulation Group | Multiple Inotropic Drugs>24 Hours After Surgery | 6 participants |
Multisystem Organ Failure After Surgery
Subject diagnosis of multisystem organ failure after surgery.
Time frame: Up to 28 days after surgery.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Usual Care Group (Control) | Multisystem Organ Failure After Surgery | 7 Participants |
| Autoregulation Group | Multisystem Organ Failure After Surgery | 2 Participants |
New Renal Replacement Therapy
Subjects requiring new renal replacement therapy prior to discharge from hospital
Time frame: Up to 28 days after surgery.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Usual Care Group (Control) | New Renal Replacement Therapy | 6 Participants |
| Autoregulation Group | New Renal Replacement Therapy | 4 Participants |
Postoperative Atrial Fibrillation
Clinical diagnosis of postoperative atrial fibrillation from date of surgical procedure to discharge from the hospital.
Time frame: Up to 28 days after surgery.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Usual Care Group (Control) | Postoperative Atrial Fibrillation | 89 Participants |
| Autoregulation Group | Postoperative Atrial Fibrillation | 79 Participants |
Postoperative Delirium
Assessed with Confusion Assessment Method or Confusion Assessment Method-ICU along with adjudication by team of experts
Time frame: Postoperative days 1-4
Population: Delirium was measured day 1-4. 232 in the autoregulation group were assessed and 228 were assessed in the usual care group.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Usual Care Group (Control) | Postoperative Delirium | 34 Participants |
| Autoregulation Group | Postoperative Delirium | 19 Participants |
Sepsis
Clinical diagnosis of sepsis from time of surgical procedure to discharge from the hospital.
Time frame: Up to 28 days after surgery.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Usual Care Group (Control) | Sepsis | 7 Participants |
| Autoregulation Group | Sepsis | 2 Participants |