Cardiac sympathetic innervation and coronary blood flow regulation during general anesthesia

The central hypothesis in the present project is that general anesthesia may
alter autonomic control such that perioperative coronary blood flow (CBF) is
significantly disturbed. These disturbances in coronary blood flow may
contribute to the development of myocardial ischemia in the perioperative
period. Furthermore, patients with an intrinsically altered autonomic
sympathetic innervation, like diabetics, are even more prone to develop
perioperative disturbances in coronary blood flow. Here we will investigate the
direct effects of general and locoregional anesthesia on the CBF. Furthermore,
we aim to evaluate whether diabetic subjects and patients undergoing a thoracic
sympathectomy show more disturbed CBF responses to anesthesia as compared to
healthy subjects.

1. Does general anesthesia affect autonomic sympathetic control of coronary
blood flow in healthy subjects?
2. Does acute inhibition of autonomic sympathetic innervation by means of a
thoracic epidural or a thoracic sympathectomy additionally impair coronary
blood flow in healthy, anesthetized subjects?
3. Are patients with an intrinsically impaired autonomic control more prone to
develop anesthesia-induced coronary flow disturbances as compared to healthy
subjects?

Open, prospective observational study with invasive measurements

Coronary blood flow measurements: Coronary blood flow measurements (CBF) are
part of routine clinical care in the department of Cardiology (dr. Otto Kamp).
CBF measurements will be performed by non-invasive ultrasound measurements. CBF
will be determined by measuring coronary blood flow at resting conditions,
during maximal coronary dilatation (by infusing adenosine 140 microgram/kg/min)
and during sympathetic stimulation by performing the cold pressure test
(immersing the patient*s hand and forearm in ice water). Both adenosine
exposure and the cold pressure test may be related to discomfort but with low
risk for the patient. Patients will undergo three contrast echo's (pre-, intra-
and postoperatively) and patientgroup 2b will undergo a fourth contrast echo 6
weeks postoperatively to study the long term effects of a thoracic
sympathectomy. CBF measurements will be performed by an experienced echo
technician who performs these measurements routineously. Patients will be
informed about the discomfort they may experience by adenosine and the cold
pressure test in order to reduce anxiety and stress during the actual
measurements. Despite the possible discomfort of CBF measurements we believe
that the burden for the subjects is in proportion to the potential value of the
present study.

Assessment of autonomic function: All subjects undergo non-invasive
cardiovascular reflex tests that are already part of outpatient clinical
routine in the department of Endocrinology. The tests will not add up tot
patient discomfort, except that for standardization issues and limitations of
capacity at the preassessment clinic measurements have to be made at fixed
times (morning) and at a separate day in the week before the scheduled surgery.
Discomfort from this issue is kept as low as possible by planning coronary flow
measurements on the same day.
Blood sampling from an intravenous catheter: In the preoperative phase, blood
drawing will be performed by a venapunction. Although venapunction may cause
hemorrhages, this risk will be minimized since all blood will be drawn by an
experienced physician. Perioperative blood sample drawing from a peripheral
intravenous catheter placement is standard perioperative procedure in all
surgical patients, and will therefore not add up to patient discomfort in the
present study.

Oral glucose tolerance test: All healthy subjects will undergo a oral glucose
tolerance test to exclude the presence of diabetes mellitus or impaired glucose
tolerance. Glucose levels will be measured before and 2 hours after ingestion
of 75 grams of glucose. This test will not add up to patient discomfort.

Intraoperative and postoperative monitoring. Intraoperative hemodynamic
parameters (blood pressure, heart rhythm, BIS monitoring, ventilation, blood
oxygen saturation) are part of routine monitoring during anesthesia and will
not add up to patient discomfort. Perioperative holter-ECG monitoring will be
instituted before anesthesia and be continued in the postoperative phase, but
will not add up to patient discomfort.

Thoracic epidural anesthesia: Epidural anesthesia will be instituted before
anesthesia conform standard of care, only when epidural analgesia is indicated
for the type of surgery.

Sevoflurane anesthesia: The present study requires sevoflurane mask induction
of anesthesia, which can be safely be performed in adult patients. Patients
will be informed about the procedure and will receive adequate premedication.