QUANtification of Cardiovascular Autonomic Neuropathy (CAN) and the Effects of Anaesthesia on Haemodynamics and Cerebral Perfusion

Study Overview
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Brief Summary
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Rationale: Complications of chronic hyperglycaemia associated with Diabetes Mellitus type 2 (DM2) include macro- and microvascular angiopathy. Cerebral Autoregulation (CA), the capability of the brain to maintain constant cerebral blood flow (CBF) despite changes in blood pressure, is impaired early in DM2 implicating that CBF becomes dependent on blood pressure. In addition, 20-60% of all patients with DM2 suffers from cardiovascular autonomic neuropathy (CAN) resulting in more unstable blood pressure regulation. In patients without DM2 or CAN, induction of anaesthesia results in slightly decreased blood pressure, but cerebral perfusion is maintained through CA. In contrast, patients with DM2 and CAN may display greater reductions in blood pressure and cerebral perfusion may become jeopardized due to impaired CA. This could be an explanation for the increased incidence of stroke in patients with DM2. Objective: To study whether peri-operative haemodynamics fluctuate more in patients with DM2 and CAN. To study whether CAN further worsens cerebral perfusion in addition to impaired CA. Study design: Prospective, observational cohort trial. Study population: A total of 45 patients, 30 with DM2 and 15 healthy controls scheduled for elective, non-cardiothoracic surgery under general anesthesia and age 18 years and above will be included in the study. After inclusion, DM2-patients will be categorized in two groups (both 15 patients): patients with and patients without CAN. Given the prevalence of 20-60% CAN, we plan to screen at most 100 patients and include 15 patients in each study group. Intervention (if applicable): PRE-operative: chart review, short physical examination, autonomic function tests to determine the presence of CAN. These tests are simple physiological tests that can be performed on a regular ward and involve a Vasalva manoeuvre, 3 minute paced breathing with a frequency of 6·min-1 and tests for orthostatic hypotension. Also, we test the sensitivity of the cerebral vasculature to CO2 by measuring during one-minute hyperventilation and one minute CO2-rebreathing. Continuous blood pressure monitoring will be obtained using ccNexfin, a non-invasive monitor that comprises a single inflatable finger cuff. Cerebral perfusion will be assessed non-invasively using transcranial Doppler attached with a headband to the temporal skin area and (non-invasive) measurement of cerebral oxygenation using near-infrared spectroscopy (NIRS). INTRA-operative: we repeat the 3 minute paced breathing test and the CO2-reactivity test. Main study parameters/endpoints: Between group difference in haemodynamic parameters and cerebral perfusion parameters.

Official Title
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QUANtification of Cardiovascular Autonomic Neuropathy (CAN) and the Effects of Anaesthesia on Haemodynamics and Cerebral Perfusion

Conditions
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Anesthesia, Diabetes Mellitus, Type 2

Intervention / Treatment
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* Diagnostic Test: Paced breathing at 6, 10 and 15 breaths per minute


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Willing and able to give written informed consent Scheduled for elective, non-cardiothoracic surgery under general anesthesia Age 18 years and above Exclusion criteria: Day case surgery laparoscopic procedure DM type 1 Parkinson's disease uncontrolled cardiac arrhythmia Pure autonomic failure (formerly called idiopathic orthostatic hypotension) Multiple system atrophy with autonomic failure (formerly called Shy-Drager syndrome) Addison's disease and hypopituitarism pheochromocytoma peripheral autonomic neuropathy (e.g., amyloid neuropathy, idiopathic autonomic neuropathy) known cardiomyopathy extreme left ventricle hypertrophy or ejection fraction < 30% proven or suspected allergy for any of the medication used during induction of anaesthesia malignant hyperthermia unability to record transcranial doppler ultrasound due to anatomical variance.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Non-diabetic patients, n=15 Diabetic patients with cardiovascular autonomic neuropathy, n=15 Diabetic patients without cardiovascular autonomic neuropathy, n=15
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Non-diabetic patients<br>Study interventions include a medical history and short physical examination as well as autonomic function tests and cerebral autoregulation tests on the day before surgery. In addition we determine CO2 sensitivity of the cerebral vasculature by three minutes hyperventilation and three minutes CO2 rebreathing. Perioperatively, continuous measurement of heart rate, blood pressure, stroke volume and cardiac output is aquired using the ccNexfin monitor, a non-invasive device using a single finger cuff. Continuous monitoring of cerebral perfusion parameters using transcranial Doppler ultrasound (TCD) of the middle cerebral artery (MCA) and cerebral oxygenation using near-infrared-spectroscopy (NIRS) will be obtained. BRS and condition of CA will be determined preoperatively during autonomic function testing (see below) and 30 minutes after induction of anaesthesia. | Diagnostic Test: Paced breathing at 6, 10 and 15 breaths per minute<br> <br> |
| Active Comparator: Diabetic patients with cardiovascular autonomic neuropathy<br>Study interventions include a medical history and short physical examination as well as autonomic function tests and cerebral autoregulation tests on the day before surgery. In addition we determine CO2 sensitivity of the cerebral vasculature by three minutes hyperventilation and three minutes CO2 rebreathing. Perioperatively, continuous measurement of heart rate, blood pressure, stroke volume and cardiac output is aquired using the ccNexfin monitor, a non-invasive device using a single finger cuff. Continuous monitoring of cerebral perfusion parameters using transcranial Doppler ultrasound (TCD) of the middle cerebral artery (MCA) and cerebral oxygenation using near-infrared-spectroscopy (NIRS) will be obtained. BRS and condition of CA will be determined preoperatively during autonomic function testing (see below) and 30 minutes after induction of anaesthesia. | Diagnostic Test: Paced breathing at 6, 10 and 15 breaths per minute<br> <br> |
| Active Comparator: Diabetic patients without cardiovascular autonomic neuropathy<br>Study interventions include a medical history and short physical examination as well as autonomic function tests and cerebral autoregulation tests on the day before surgery. In addition we determine CO2 sensitivity of the cerebral vasculature by three minutes hyperventilation and three minutes CO2 rebreathing. Perioperatively, continuous measurement of heart rate, blood pressure, stroke volume and cardiac output is aquired using the ccNexfin monitor, a non-invasive device using a single finger cuff. Continuous monitoring of cerebral perfusion parameters using transcranial Doppler ultrasound (TCD) of the middle cerebral artery (MCA) and cerebral oxygenation using near-infrared-spectroscopy (NIRS) will be obtained. BRS and condition of CA will be determined preoperatively during autonomic function testing (see below) and 30 minutes after induction of anaesthesia. | Diagnostic Test: Paced breathing at 6, 10 and 15 breaths per minute<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in baroreflex sensitivty after induction of anesthesia | Baroreflex sensitivity (BRS; expressed as ms change in R-R-interval per mmHg blood pressure change) can be seen as a measure of hemodynamic homeostatic control. We calculate BRS preoperatively (baseline) and compare it to intra-operative values (after induction of anesthesia). | Pre-operative versus Intra-operative | 
| Change from baseline in dynamic cerebral autoregulation after induction of anesthesia | Dynamic Cerabral Autoregulation (dCA; expressed as MCAVmean-to-MAP phase lead) can be seen as the ability of the brain to compensate for blood pressure changes. We calculate dCA pre-operatively (baseline) and compare it to intra-operative values (after induction of anesthesia). | Pre-operative versus Intra-operative | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical outcome | The relationship between autonomic function tests and clinical outcome during 30-postoperative days (observational). Outcome measures include frequency of all adverse and serious adverse events. | Intra-operative till 30 days postoperative |