Ignite Creation Date:
2024-05-05 @ 9:59 PM
Last Modification Date:
2024-10-26 @ 10:12 AM
Study NCT ID:
NCT01006863
Status:
COMPLETED
Last Update Posted:
2020-09-02
First Post:
2009-10-30
Brief Title:
Preoperative Ephedrine Attenuates the Hemodynamic Responses of Propofol During Valve Surgery A Dose Dependent Study
Sponsor:
King Faisal University
Organization:
King Faisal University
Study Overview
Official Title:
Preoperative Ephedrine Attenuates the Hemodynamic Responses of Propofol During Valve Surgery A Dose Dependent Study
Status:
COMPLETED
Status Verified Date:
2020-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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 01-02 mgkg 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 01 to 007 mgkg 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 007 01 015 mgkg 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
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 01-02 mgkg 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 01 to 007 mgkg 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 007 01 015 mgkg 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 authors 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 005 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 n30 for each to receive saline group 1 or ephedrine 007 01 or 015 mgkg group 2 3 and 4 respectivelyand phenylephrine 15 ugkg 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 012 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 003 mgkg IV midazolam and fentanyl 1 µgkg 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 patients 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 5-7mLKg of 6 Hydroxyethyl Starch 13004 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 01 mLkg of a study solution containing either saline 09 solution group 1 n30 ephedrine 07 mgmL group 2 n30 ephedrine 1 mgmL group 3 n30 or ephedrine 15 mgmL group 4 n30 or phenylephrine 15 mcgmL group 5 n30 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 µgkg propofol 2-25 mgkg and cisatracurium 02 mgkg 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 45-6 kPa Anesthesia was maintained with continuous infusions of propofol 4-6 mgkg h fentanyl 0025 µgkgmin and cisatracurium 1-3 µgKg min to maintain suppression of the second twitch using a train-of-four stimulation All patients received a slow injection of tranexamic acid 50 mgkg 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 005 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 40min was treated with atropine 05 mg
The cardiopulmonary bypass CPB lines oxygenator and venous reservoir were primed Heparin sodium 300 IUkg 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 24 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 33-34C 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 37C bladder temperature 36C 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 mgkg h was used for sedation in the ICU and morphine 005 µgkg 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 355C bleeding 100 mLh urine output 05 mLkgh and arterial oxygen tension 100 mm Hg with oxygen concentration 05
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 3000 rpm for 10 min and serum samples stored at-20C 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 06 µgL 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 SaO290 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 005 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 005 was considered to represent statistical significance
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 012 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 003 mgkg IV midazolam and fentanyl 1 µgkg 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 patients 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 5-7mLKg of 6 Hydroxyethyl Starch 13004 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 01 mLkg of a study solution containing either saline 09 solution group 1 n30 ephedrine 07 mgmL group 2 n30 ephedrine 1 mgmL group 3 n30 or ephedrine 15 mgmL group 4 n30 or phenylephrine 15 mcgmL group 5 n30 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 µgkg propofol 2-25 mgkg and cisatracurium 02 mgkg 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 45-6 kPa Anesthesia was maintained with continuous infusions of propofol 4-6 mgkg h fentanyl 0025 µgkgmin and cisatracurium 1-3 µgKg min to maintain suppression of the second twitch using a train-of-four stimulation All patients received a slow injection of tranexamic acid 50 mgkg 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 005 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 40min was treated with atropine 05 mg
The cardiopulmonary bypass CPB lines oxygenator and venous reservoir were primed Heparin sodium 300 IUkg 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 24 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 33-34C 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 37C bladder temperature 36C 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 mgkg h was used for sedation in the ICU and morphine 005 µgkg 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 355C bleeding 100 mLh urine output 05 mLkgh and arterial oxygen tension 100 mm Hg with oxygen concentration 05
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 3000 rpm for 10 min and serum samples stored at-20C 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 06 µgL 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 SaO290 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 005 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 005 was considered to represent statistical significance
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None