Preoperative Ephedrine Attenuates the Hemodynamic Responses of Propofol During Valve Surgery: A Dose Dependent Study

One hundred fifty ASA III-IV patients aged 18-55 years scheduled for elective valve surgery were included in this randomized double blinded placebo-controlled study at the author's center after obtaining of approval of the local ethical committee and a written informed consent from the participants. The sample size was determined by a prior power analysis indicated that 27 patients in each group would be a sufficiently large sample size to be adequate to detect a 20% changes in SVRI values, with a type-I error of 0.05 and a power of approximately 85%. We added 10% more patients to account for patients dropping out during the study. All operations were performed by the same surgeons. Participants were allocated randomly to five groups (n=30 for each) to receive saline [group 1] or ephedrine 0.07, 0.1 or 0.15 mg/kg [group 2, 3, and 4, respectively]and phenylephrine 1.5 ug/kg [group 5] 1 min before induction of anesthesia.

Patients with documented un-controlled hypertension, ischemic heart disease, left ventricular ejection fraction less than 45%, peripheral vascular disease, thyrotoxicosis, neurological, hepatic, and renal diseases, pregnancy, re-do or emergency surgery, allergy to the study medications, those requiring preoperative inotropic, vasopressor or mechanical circulatory or ventilatory support, and those who had electrocardiograph (ECG) characteristics that would interfere with ST segment monitoring, included baseline ST segment depression, left bundle-branch block, atrial fibrillation, left ventricular hypertrophy, digitalis effect, QRS duration >0.12 s, as well as pacemaker-dependent rhythms, were excluded from the study.

All routine medications except angiotensin-converting enzyme inhibitors were continued until the morning of the operation. All patients were premedicated with 0.03 mg/kg IV midazolam and fentanyl 1 µg/kg before invasive instrumentation. All patients were monitored with pulse oximetry, non invasive blood pressure and five leads electrocardiography (leads II and V5) (Life Scope Monitor, BSM-4113, Nihon Kohden Corp, Japan). Continuous ST segment trends were electronically measured at the J-point + 60 ms to exclude the T wave during the episodes of tachycardia. The tabulated and graphic ST segment data were reviewed by two investigators who are not involved in the study and are blinded to the patient's group for significant ischemic responses. The later were defined a reversible ST segment changes from baseline of either ≥ 1 mV ST-segment depression or ≥2 mV ST-segment elevation lasting for at least 1 minute. A radial artery catheter and a flow-directed balloon-tipped pulmonary artery catheter were placed under local anesthesia before induction. The final position of the pulmonary artery catheter tip was confirmed with portable chest x- ray film and pulmonary artery diastolic pressure > PAOP. CI was measured by thermodilution using ice cold injectate. Five measurements were performed, the lowest and highest readings were discarded, and the mean of the readings was recorded. Intravenous infusion of 5-7mL/Kg of 6% Hydroxyethyl Starch 130/0.4 (Voluven, Fresenius Kabi, Bad Hombourg, Germany) was given before induction of general anesthesia when the baseline PAOP was less than 10 mm Hg. End-tidal carbon dioxide monitoring and placement of a nasogastric tube, and rectal and nasopharyngeal temperature probes were done after induction of anesthesia.

Subjects were allocated randomly to four groups by drawing sequentially numbered sealed opaque envelopes containing a computer-generated randomization code. The subjects received intravenous injection of 0.1 mL/kg of a study solution containing either saline 0.9% solution [group 1 (n=30)], ephedrine 0.7 mg/mL [group 2 (n=30)], ephedrine 1 mg/mL [group 3 (n=30)] or ephedrine 1.5 mg/mL [group 4 (n=30)], or phenylephrine 15 mcg/mL [group 5 (n=30)]. All study solutions were injected over 1 min at 1 min before induction of anesthesia. The placebo and the ephedrine solutions were prepared in identical syringes labeled 'study drug' by the local pharmacy department before induction of anesthesia. The anesthesia providers were blinded to the study solution and were not involved in the study. All staff in the operating room were unaware of the randomization code.

Anesthesia was induced with fentanyl 5 µg/kg, propofol 2-2.5 mg/kg, and cisatracurium 0.2 mg/kg was given for muscle relaxation. After endotracheal intubation, the lungs were ventilated with a mixture of oxygen in air to maintain an arterial carbon dioxide tension at 4.5-6 kPa. Anesthesia was maintained with continuous infusions of propofol 4-6 mg/kg/ h, fentanyl 0.025 µg/kg/min, and cisatracurium 1-3 µg/Kg/ min to maintain suppression of the second twitch using a train-of-four stimulation. All patients received a slow injection of tranexamic acid 50 mg/kg before initiation of CPB. Target MAP and HR were within 20% from the mean baseline values. Hypotension (MAP ≤ 60 mm Hg ≥ 2-3 minutes) was treated with intravenous fluids; reduction of the infusion rate of propofol by 50%, or bolus doses of ephedrine 5 mg. Hypertension (MAP ≥ 20% from the mean baseline for ≥ 2-3 minutes) was treated with increasing of the infusion rate of propofol by 50%, or bolus doses of labetalol 20 mg, or nitroglycerin 0.05 mg. Tachycardia ≥20% from the baseline values for ≥1 minute was treated with the modulation of propofol infusion rate or boluses of esmolol 20 mg. Bradycardia (HR ≤ 40/min) was treated with atropine 0.5 mg.