Arterial Stiffness and General Anesthesia Induced Hypotension in Patients on Angiotensin-converting Enzyme Inhibitors

Background: Induction of anesthesia consists with administration of anesthetics followed by
endotracheal intubation. During the induction of anesthesia moderate hemodynamic disturbances
(either systemic arterial hyper- or hypo-tension) are common due to concurrent autonomic
nervous system suppression and from the stress response from endotracheal intubation.
Previous studies demonstrate that patients chronically treated with angiotensin converting
enzyme (ACE)-inhibitors have higher incidence of developing hypotension after induction of
general anesthesia, which typically, can be restored with small doses of adrenergic drugs
such as phenylephrine (100 to 200 mcg) to acceptable blood pressure levels. However, some
patients that develop hypotension may be refractory to those medications, which in turn poses
a significant challenge in controlling the hemodynamics of patients. The consequence of the
severe hypotension could be canceled surgery, ischemic stroke, myocardial infarction or even
death.

Interestingly, this refractory systemic hypotension does not occur in all anesthetized
patients prescribed ACE inhibitors. Notably, easily treatable systemic arterial hypotension
after induction of general anesthesia is not a clinical problem. Critical issue arises only
if the patient under general anesthesia does not respond to therapeutic doses of adrenergic
agonists. Therefore, identifying patients who will demonstrate refractory hypotension after
the induction of general anesthesia is a novel idea and has significant clinical implications
for peri-operative blood pressure control by anesthesiologists.

Thus, the overall goals of the proposed research will be to use preoperative non-invasive
measures of vascular stiffness to predict which patients might be at risk for severe
hypotension that is refractory to adrenergic vasoconstrictor medications following induction
of general anesthesia in patients chronically treated with angiotensin-converting enzyme
inhibitors.

Method/Design: The study will be human subject non-randomized observational study. This study
will be conducted at day of surgery administration area and main operation room at University
of Iowa Hospitals and clinics. Arterial stiffness will be measured at day of surgery
administration area prior to the surgery.

Carotid-Femoral Pulse Wave Velocity (Aortic Stiffness). Carotid-femoral pulse wave velocity
(cfPWV) will be determined by applanation tonometry using the Sphygmocor system by
sequentially recording ECG-gated carotid and femoral artery waveforms. Pulse wave signals
will be recorded by tonometers positioned at the base of the right common carotid artery and
over the right femoral artery. The time (t) between the feet of simultaneously recorded waves
will be determined as the mean of 10 consecutive cardiac cycles. PWV is calculated by the
system software from the distance between measurement points (D) and the measured time delay
(t) as follows: cfPWV = D/Δt (m/s) where D is distance in meters and t is the time interval
in seconds.

Prior to induction intravenous fluid administration will be restricted to less than 500 ml. A
standardized protocol will be followed which is commonly used by anesthesia providers. Prior
to induction of anesthesia, in addition to ASA standard monitors, neuromuscular twitch
monitor and Entropy monitor will be attached to the patient. Induction agents will include
1.5mg/kg propofol, 2µg/kg fentanyl, 100mg lidocaine, and 0.6 mg/kg rocuronium of lean body
weight. Inhaled anesthetic will be sevoflurane at 0.5 MAC with 5L/min of 100% oxygen starting
at mask ventilation till 10 minutes after tracheal intubation. Blood pressure will be
measured by a brachial cuff prior to induction and every minute after intubation for 10
minutes. If the systolic pressure drops below 90 mmHg or more than 25% from baseline, the
patient will be classified in the study as "Hypotensive." Conversely, if the patient's
systolic blood pressure does not drop below 90 mmHg more than 25% from baseline within 10
minutes of intubation, the patient will be classified as "Not Hypotensive." If the patient's
systolic blood pressure rises above 25% the baseline value, the anesthesiologist will
administer a bolus of 0.5mg/kg of propofol. This bolus will be repeated after the minute
blood pressure evaluations until the systolic blood pressure back to the baseline value.
These patients will be classified as "Not Hypotensive," but the administration of propofol
will be noted. In attempt to bring systolic blood pressure up to above 90 mmHg or more than
25% from baseline in "hypotensive" patients, the anesthetic provider will use 100µg
phenylephrine (or 5mg ephedrine if heart rate < 50bpm) within 10 minutes of intubation. If
over 200µg phenylephrine (10mg ephedrine) has been used without a return of the systolic
brachial blood pressure >90 mmHg or more than 25% from baseline, the patient will be
classified in the study as "Refractory Hypotensive." The study environment will be ended and
the provider can use whatever vasoactive drugs they deem appropriate, including more
phenylephrine, ephedrine, epinephrine, norepinephrine, or vasopressin, and/or fluid bolus.
The total given doses of each vasopressor medication will be recorded. Anesthetic induction,
blood pressure measurements, and medication to correct low and high blood pressure as
described above are all part of the patients' standard clinical procedures as performed by
the anesthesiologist. The patients who required more than 2 times laryngoscopy, required
other than standard anesthetics, or entropy >70 or <30, will be exclude from data analysis.

Inclusion Criteria:

- There will be three study populations. The first study population will include 60
adult patients over 50 years old and on ACE inhibitors for more than 3 months,
scheduled for surgery under general anesthesia in the second case in the Main
Operating Room at the UIHC. Patients who are taking angiotensin receptor inhibitors
will not be enrolled for the study.

The second study population will include 20 adult patients over 50 years old who are not
taking an ACE inhibitor and are currently taking a beta blocker, a calcium channel blocker,
or a diuretic for more than 3 months, scheduled for surgery under general anesthesia in the
Main Operating Room at the UIHC.

Exclusion Criteria:

We will exclude patients with diabetes (on insulin therapy), renal insufficiency (Cr>2.0),
history of arterial bypass (i.e. F-F bypass), history of carotid endoarterectomy,
angiotensin receptor inhibitor medication, heart rate <40 bpm or >100 bpm, atrial
fibrillation/flutter, history of ischemic stroke, transient ischemic attack, myocardial
infarction or coronary revascularization (any type) within 6 months, known left main or
3-vessel coronary disease positive myocardial perfusion study without subsequent
revascularization, angina or heart failure (>3 NYHA) class 3, known left ventricle ejection
fraction <30%, pulmonary hypertension (PA systolic >50mmHg), right ventricle dysfunction,
or a preoperative systolic blood pressure of >180 mmHg or <110 mmHg within 1 month prior to
surgery.