Preoperative Ephedrine Attenuates the Hemodynamic Responses of Propofol During Valve Surgery: A Dose Dependent Study
Condition: Hypotension; Valve Surgery
MeSH terms: Hypotension
Study type: Interventional
Phase: Phase 2

Summary: 
      The prophylactic use of small doses of ephedrine may be effective in obtunding of the
      hypotension responses to propofol with minimal hemodynamic and ST segment changes. The
      investigators aimed to evaluate the effects of small doses of ephedrine on hemodynamic
      responses of propofol anesthesia for valve surgery.

      There is widespread interest in the use of propofol for the induction and maintenance of
      anesthesia for fast track cardiac surgery. However, its use for induction of anesthesia is
      often associated with a significant rate related transient hypotension for 5-10 minutes. This
      is mainly mediated with decrease in sympathetic activity with minor contribution of its
      direct vascular smooth muscle relaxation and direct negative inotropic effects.

      Ephedrine has demonstrated as a vasopressor drug for the treatment of hypotension in
      association with spinal and general anesthesia. Prophylactic use of high doses of ephedrine
      [10-30 mg] was effective in obtunding the hypotensive response to propofol with associated
      marked tachycardia. However, the use of smaller doses (0.1-0.2 mg/kg) was successfully
      attenuated, but not abolished, the decrease in blood pressure with transient increase in
      heart rate. This vasopressor effect is mostly mediated by β-stimulation rather than
      α-stimulation and also indirectly by releasing endogenous norepinephrine from sympathetic
      nerves.

      Because the effect of decreasing the dose of ephedrine from 0.1 to 0.07 mg/kg may be
      clinically insignificant, the investigators postulated that the prophylactic use of small
      dose of ephedrine may prevent propofol-induced hypotension after induction of anesthesia for
      valve surgery with minimal in hemodynamic, ST segment, and troponin I changes.

      The aim of the present study was to investigate the effects of pre-induction administration
      of 0.07, 0.1, 0.15 mg/kg of ephedrine on heart rate (HR), mean arterial blood pressure (MAP),
      central venous and pulmonary artery occlusion pressures (CVP and PAOP, respectively), cardiac
      (CI), stroke volume (SVI), systemic and pulmonary vascular resistance (SVRI and PVRI,
      respectively), left and right ventricular stroke work (LVSWI and RVSWI, respectively)
      indices, ST segment, and cardiac troponin I (cTnI) changes in the patients anesthetized with
      propofol-fentanyl for valve surgery.
    

Detailed description: 
      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.

      The cardiopulmonary bypass (CPB) lines, oxygenator, and venous reservoir were primed. Heparin
      sodium 300 IU/kg was given after pericardiotomy to achieve celite-activated clotting time
      became higher than 480 s. Standard CPB technique was established with the ascending aorta
      cannula and the bicaval venous cannulae. During CPB, the non-pulsatile pump flow rate was 2.4
      L min/ m2 using a twin roller pump and a hollow fiber membrane oxygenator, perfusion pressure
      was 50-80 mmHg, arterial carbon dioxide tension was 35-40 mmHg, unadjusted for temperature
      (α-stat), arterial oxygen tension was 150-250 mmHg, and moderate systemic hypothermia
      (nasopharyngeal temperature 33-34°C) was maintained. Myocardial viability was preserved with
      topical hypothermia and cold blood antegrade cardioplegia administered intermittently into
      the aortic root.

      Before separation from CPB, all patients were rewarmed (nasopharyngeal temperature 37°C,
      bladder temperature 36°C) and epinephrine and nitroglycerine infusions were used to as needed
      after CPB. Heparin was neutralized after discontinuation of CPB with protamine sulfate.

      After surgery propofol 1-2 mg/kg/ h was used for sedation in the ICU and morphine 0.05 µg/kg
      was used as needed for analgesia. Propofol infusion was discontinued and ventilator weaning
      was started once patients were awake and cooperative, hemodynamically stable without high
      doses of inotropic support, no severe arrhythmias, body core temperature >35.5°C, bleeding
      <100 mL/h, urine output> 0.5 mL/kg/h, and arterial oxygen tension >100 mm Hg with oxygen
      concentration <0.5.

      Primary outcome variables include the changes in hemodynamic variables namely; HR, MAP, CI,
      SVRI, LVSWI, and ST segment changes. Secondary outcome variables were CVP, PAOP, RVSWI, and
      troponin I changes, and the need for vasoactive drugs. Anesthesia providers were not involved
      in the assessment of the patients. Other anesthesiologists who were blinded to the study
      group and were not in the operative room performed the assessment.

      HR, MAP, CI, SVI, CVP, PAOP, SVRI, PVRI, LVSWI, and RVSWI changes were recorded before
      (baseline), and 5 min after induction, 5, 10, 15, and 30 min after endotracheal intubation;
      and 15 min after sternotomy. The changes in hemodynamic data were calculated as percentages
      of the baseline measurements. The numbers and total time of intra-operative ischemic episodes
      were recorded in each group. Venous blood samples were drawn before, 3, 12, 24, and 48 hours
      after CPB to measure cardiac troponin I. Blood samples were centrifuged at 3,000 rpm for 10
      min and serum samples stored at-20°C. Two specific monoclonal antibodies were used to avoid
      the cross-reactivity with human skeletal muscle for the measurement of cTnI. The upper
      reference limits for cTnI in a control population was 0.6 µg/L. The number of patients who
      received rescue doses of labetalol, ephedrine, atropine and esmolol, times from induction to
      intubation (I-T) and to skin incision (I-S) and all major complications (hypoxemia
      (SaO2<90%), arrhythmias, respiratory failure, and cardiovascular events) were recorded in
      each group.

      Data were tested for normality using the Kolmogorov-Smirnov test. Repeated-measures analysis
      of variance was used for analysis of serial changes in the hemodynamic and cTnI data at
      different times after administration of study solution. Fisher exact test was used for
      categorical data. Repeated measure analysis of variance (ANOVA) was used for continuous
      parametric variables and the differences were then corrected by post-hoc Bonferoni test. The
      Kruskal-Wallis one-way ANOVA was performed for intergroup comparisons for the non-parametric
      values and post hoc pairwise comparisons was done using the Wilcoxon rank sum t test.
      Univariate analyses of the preoperative risk factor, namely EuroSCORE for the frequency of
      significant hypotension and ST segment changes after propofol anesthesia were performed.
      Univariate predictors were examined in a stepwise manner into a multivariate logistic
      regression model, with entry and retention set at a significance level of p < 0.05 to assess
      the independent impact of this risk factor on the outcome. Data were expressed as mean (SD),
      number (%), or median [range]. A value of p < 0.05 was considered to represent statistical
      significance.
    

Intervention name(s): Ephedrine; Placebo; Phenylephrine
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Subjects were allocated randomly to five 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.; Subjects were allocated randomly to five 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.; Subjects were allocated randomly to five 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 15 mcg/ml of phenylephrine [group 5 (n=30)] All study solutions were injected over 1 min at 1 min before induction of anesthesia. The placebo, the ephedrine, and the phenylephrine solutions were prepared in identical syringes labeled 'study drug' by the local pharmacy department before induction of anesthesia.
Intervention MeSH terms: Phenylephrine; Oxymetazoline; Ephedrine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Care Provider, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Ephedrine; phenylephrine; hypotension; propofol; anesthesia; cardiac valve surgery