Improving Tissue Oxygenation in Breast Reconstruction Surgery

The purpose of this trial is to evaluate the effects of perioperative hemodynamic therapy (guided by cardiac output monitoring) on tissue oxygenation during (and after) DIEP flap breast reconstruction surgery. We hypothesize that a low-dose, perioperative dobutamine infusion combined with goal-directed fluid therapy guided by cardiac output monitoring will improve flap perfusion (and, thus, oxygenation) in patients undergoing DIEP surgery.

The primary outcome is tissue oxygenation, measured via near-infrared spectroscopy (NIRS), 20 minutes following vascular re-anastomosis of the DIEP flap within the perfusion zone that is furthest away from the perforator vessels. Tissue oxygenation will be measured in the zone which is the farthest from the perforator vessels. This zone is the most vulnerable surgical area to ischemia and, therefore, the most likely to reflect the potential benefits of the proposed intervention.

Secondary outcomes include: (1) tissue oxygenation at baseline (preoperatively), hourly intraoperatively, 1, 2, 4, 8 hours postoperatively, as well as the morning of postoperative days 1 and 2; (2) the need for intraoperative surgical vascular re-intervention (i.e., re-anastomosis); (3) postoperative complications resulting from flap mal-perfusion (i.e., partial/total flap loss and/or fat necrosis); (4) the need for postoperative surgical re-intervention for flap-related issues; (5) the amount of intravenous fluids (crystalloids, colloids, blood products) and vasopressors (e.g., phenylephrine, ephedrine, norepinephrine, etc) administered intraoperatively as well as 4 hours postoperatively; (6) incidence of postoperative nausea and vomiting (PONV), infection, and hematoma; (7) hospital length of stay; and (8) overall patient satisfaction. Differences in perioperative pH, lactate and hemoglobin levels, will also be compared between groups.

Study Design and Duration This is a prospective, randomized controlled trial. Forty participants will be randomized to one of two groups (n=20/group) using computer-generated randomization. Patient randomization will be concealed in envelopes and opened only by the attending anesthesiologist prior to anesthesia induction. Blinding will be maintained until study completion (n=20/group) and verification that all outcome data has been successfully collected for all study participants. Each participant will be monitored perioperatively until postoperative day 2 (or until discharge from hospital) and will receive a 30 day follow-up telephone call.

Patient Population

Eligible consenting patients scheduled to undergo an elective DIEP flap breast reconstruction surgery under the care of Dr. Martou at the Kingston General Hospital site of Kingston Health Sciences Centre.

Intervention Group: The intervention will commence from the induction of general anaesthesia and continue until 4 hrs after surgery. Ringer's lactate (3ml/kg/hr) will be commenced upon admission to the operating room to satisfy maintenance fluid requirements. Cardiac output and stroke volume will be measured by minimally invasive cardiac output monitor (FloTrac system, Edwards Lifesciences Corporation, Irvine, CA, USA) which attaches to the arterial line already in place in this surgical population. No more than 500ml of intravenous fluid will be administered prior to commencing cardiac output monitoring. In addition to the maintenance fluid described previously, patients will receive 250ml fluid challenges with crystalloid as required until they are no longer fluid responsive. Albumin 5% will also be allowed for fluid challenges at the discretion of the attending anesthesiologist. The absence of fluid responsiveness will be defined as the absence of a sustained rise in stroke volume of at least 10% for 20 minutes or more, at which point and the patient will be considered fluid optimized. At this point, a low-dose dobutamine infusion at a fixed rate (2.5 μg/kg/min) will be commenced and maintained until 4h postoperative. The infusion rate will be halved and/or discontinued if the patient develops a tachycardia (heart rate ≥ 100bpm) for more than 30 minutes despite adequate anesthesia/analgesia and fluid status (based on the above mentioned intervention). Further fluid challenges will be performed by the attending anesthesiologist with the aim to maintain a maximal value of stroke volume throughout the case. Postoperatively, the patient will remain in the post-anesthetic care unit (PACU) for a minimum of 4 hrs (as per current standard of care) at the end of which, the cardiac output monitor will be disconnected from the arterial line, the dobutamine infusion will be discontinued, and the patient transferred to a level 2 critical care unit. Ringer's lactate at 2ml/kg/hr will be infused to satisfy maintenance fluid requirements until oral fluid intake is permitted by the surgical team, at which point the maintenance infusion will be stopped. The postoperative maintenance infusion rate will be reduced compared to the intraoperative period (3ml/kg/hr) to account for the reduction in insensible fluid losses in the postoperative period. Data collection and follow-up for such patients will be performed as per standard of care.

Control group: Patients in the control group will also receive a baseline infusion of Ringer's lactate at 3ml/kg/hr to satisfy maintenance fluid requirements, which will be commenced upon admission to the operating room. The anesthetic management will otherwise be according to standard practice. This will include 250ml fluid challenges with a crystalloid administered at the discretion of the attending anesthesiologist, which is generally guided by pulse rate, arterial pressure, urine output, and/or core-peripheral temperature gradient. Albumin 5% will also be allowed for fluid challenges at the discretion of the attending anesthesiologist. No specific cardiac output monitoring device will be used to guide fluid therapy. Likewise, perioperative dobutamine will not be used unless clinically indicated to improve cardiac function. It will not be used as described in this protocol (i.e., intervention group) as it is not currently part of our standard practice in these surgeries; and there is not yet documented evidence to support its use in all DIEP flap patients. We are hoping that this study addresses this gap in knowledge and provides evidence as to whether there is benefit to indicate using it as part of standard of care. Postoperative care will be similar to the intervention group (except for the cardiac output monitoring and dobutamine infusion in PACU).

A tissue oximeter device (SnapshotNIR, KENT Imaging, Calgary, Canada) will be used in all patients. This is a portable non-invasive monitor that measures tissue oxygen saturation using near-infrared spectroscopy (NIRS) technology. Measurements are taken within seconds upon hovering the monitor over the skin area where the oxygen levels are intended to be measured. Upon admission to the operating room, pre-operative, baseline measurements will be recorded over the abdominal flap, followed by sequential recordings upon induction and hourly thereafter until completion of the surgical procedure. The surgical team, led by Dr. Martou, will guide the measurements to ensure that they are consistently taken from the same surgical area throughout the case. Furthermore, the surgical team will have access to the intraoperative KENT measurements, which will be used to guide surgical decision-making in an attempt to reduce postoperative flap (perfusion-related) complications and ensure the best possible surgical outcomes. The attending anesthesiologist, however, will be blinded to the KENT measurements throughout the perioperative period, whereas the surgical team will be blinded to group allocation, i.e., intervention vs. control. The ischemic period during which the flap is transferred (reflected by a fall in the oxygen saturation of the flap21) as well as the time of flap revascularization (characterized by increased oxygen saturation21) will be recorded. Upon completion of the surgical procedure, another NIRS-based monitor (Somanetics INVOS 5100C Cerebral/Somatic Oximeter, Medtronic, Minneapolis, USA) will be utilized. A sticker will be applied over the flap for continuous monitoring of the graft oxygenation for up to 48h postoperative. Postoperative measures will be recorded at incremental time periods including 1, 2, 4, and 8h, as well as on the morning of postoperative days 1 and 2, by the KENT device as well as the continuous monitor (Somanetics INVOS). All measures will be consistently taken at the same location.22 Note that intraoperative oximetry continuous monitoring with the Somanetics INVOS Oximeter is not possible as the sensors cannot be sterilized.

All surgical procedures will be performed by the same surgeon to minimize variability in patient selection and surgical technique, both predictors of clinical outcomes in microsurgery.23 Elective DIEP flap surgical procedures and anesthetic management will all be completed in accordance with the standard of care. Perioperative management will be identical in both groups, apart from the hemodynamic monitoring and interventions as described below. In the operating room, room temperature will be set at 20oC and standard monitors will be applied. Invasive monitoring in the form of an arterial line will be established as per current practice. General anesthesia will be induced with propofol and fentanyl followed by rocuronium to facilitate endotracheal intubation; and maintained with sevoflurane (Etsevo=1.5-3.0%) and additional doses of fentanyl and/or hydromorphone administered at the discretion of the attending anesthesiologist. Extra doses of rocuronium will be administered throughout the case for muscle relaxation. A mean arterial pressure (MAP) ≥65 mmHg (or within 20% of baseline) will be targeted throughout the perioperative period. Likewise, all patients will receive standard measures to maintain oxygenation (SpO2 ≥95%), end-tidal CO2 (EtCO2) between 35-40 mmHg, hemoglobin (>8 g/dl), and heart rate (<100 bpm). A warming device (enFlow IV Fluid/Blood Warming System, GE Healthcare, Boston, MA, USA) will be used for intravenous fluids, as well as a forced-air patient warming system (3M Bair Hugger Normothermia System, 3M, St. Paul, MN, USA) in order to maintain normothermia (core temperature 36-37.5 oC). Arterial blood gasses will be checked every 2 hours (or more often at the discretion of the attending anesthesiologist) to specifically monitor the pH, SpO2, PaO2, PaCO2, base excess, hemoglobin, and lactate levels as surrogates for tissue perfusion perioperatively. Urine output will be recorded hourly. The total amount of vasopressor, perioperative fluid (crystalloids and Albumin 5%) and blood products, if any, will be recorded. In addition, the following demographic and surgical characteristics will be included: age, body mass index, preoperative hemoglobin and hematocrit, levels, American Society of Anesthesiologists classification, Charlson Comorbidity Index, and total surgical and anesthetic time. Prophylactic iv dexamethasone 4mg on induction of general anesthesia, and ondansetron 4mg 15 min prior to completion of the surgical procedure will be given for prevention of nausea and vomiting. All patients will be managed postoperatively in a high dependency unit (level 2 critical care) intravenous patient-controlled analgesia (IV-PCA) with hydromorphone (or an alternative in the case of adverse reactions) for post-operative pain management as per current standard of care. The postoperative goals (up to 48h postoperative) will be similar to the intraoperative period, namely: MAP ≥65 mmHg (or within 20% of baseline), SpO2 ≥95%, PaCO2 35-45 mmHg, hemoglobin >8 g/dl, core temperature between 36-37.5 °C, and heart rate <100 bpm. Patients will be called 30 days after surgery to document any occurrence of complications and they will be asked about their overall satisfaction.

Rescue Medication & Risk Management All anesthesia and surgical procedures are according to standard of care except for the low dose dobutamine infusion intraoperatively and potentially up to 4 hours postoperatively, the use of cardiac output monitoring intraoperatively, and non-invasive measurements of tissue oxygenation until 48 hours postoperatively. Patients will be intensively monitored and medications will be administered as considered medically necessary (conversely, no medications deemed medically necessary will be withheld as a result of study participation). The main potential side-effect associated with dobutamine is tachycardia. In order to mitigate this risk, our protocol proposes a very low-dose infusion. In addition, the dobutamine infusion rate will be halved and/or discontinued if the patient develops a tachycardia (heart rate ≥ 100bpm) for more than 30 minutes despite adequate anesthesia/analgesia and fluid status. In addition, all patients will be intensively monitored while in hospital for any adverse events/complications all of which will be carefully considered in terms of whether they are related to the study intervention or otherwise and action will be taken accordingly.

Premature Withdrawal / Discontinuation Criteria One of the limitations of a dobutamine infusion is tachycardia. The infusion rate will be halved and/or discontinued if a patient develops a tachycardia (heart rate ≥ 100bpm) for more than 30 minutes despite adequate anesthesia/analgesia and fluid status (based on the above mentioned intervention). If the reduced dose does not correct the tachycardia, then the infusion will be turned off. In addition, if at any point attending staff raises concerns about the patient being at an increased risk because of study participation, the intervention will be stopped and the patient removed from the investigation. Also if at any point the patient decides they want to withdraw their consent (even afterwards), they will be excluded from the study and none of the information collected from them will be used for research purposes. The study intervention only applies during surgery and potentially for 4hrs after. All study participants will be in a fully monitored setting for the duration of study intervention and beyond for up to 48 hours postoperatively. They will have immediate access to any additional care or intervention if required. Adverse events and serious adverse events will be monitored and documented. Study staff will mandatorily report all SAE's and serious unexpected adverse drug reactions (SUSARs) to the investigator for evaluation as soon as they become aware of it. All adverse events will be immediately reported to the Queen's University Health Sciences and Affiliated Teaching Hospitals Research Ethics Board and to the Health Canada, Therapeutic Products Directorate.

If patients are withdrawn from the study, we will continue to enroll patients consecutively until we have met our stipulated sample size of 20 patients per group. For patients who are withdrawn, we will retain any data collected (especially demographic information) and so we can compare those who were withdrawn to those who completed the study to determine if they differ in this respect (e.g. are older, all male etc.). However, if at any point the patient decides they want to withdraw their consent (even afterwards), they will be excluded from the study and none of the information collected from them will be used for study purposes.

Efficacy Variables and Analysis Our primary objective is to establish whether the use of minimally invasive cardiac output monitoring for guidance of intravenous fluid administration, combined with low-dose dobutamine infusion (via a treatment algorithm), will increase tissue oxygenation in patients undergoing DIEP flap surgery, measured by near-infrared spectroscopy (NIRS). The primary outcome is tissue oxygenation, measured via near-infrared spectroscopy (NIRS), 20 minutes following vascular re-anastomosis of the DIEP flap within the perfusion zone that is furthest away from the perforator vessels. Tissue oxygenation will be measured in the zone which is the farthest from the perforator vessels. This zone is the most vulnerable surgical area to ischemia and, therefore, the more likely to reflect the potential benefits of the proposed intervention.

Tissue oxygenation will also be measured at baseline (preoperatively), hourly intraoperatively, 1, 2, 4, 8 hours postoperatively, as well as the morning of postoperative days 1 and 2;

Safety Variables and Analysis:

Invasive monitoring in the form of an arterial line will be established in all patients for intensive monitoring (hemodynamics etc.), as per standard perioperative care for this surgical procedure. In addition, cardiac output monitoring will be used to guide intravenous fluid administration (including dobutamine) in the intervention group. Other safety variables collected will include postoperative complications resulting from flap mal-perfusion (i.e., partial/total flap loss and/or fat necrosis); (2) the need for surgical re-intervention for flap-related issues; (3) the amount of intravenous fluids (crystalloids, colloids, blood products) administered intraoperatively; (4) incidence of postoperative nausea and vomiting, infection, and hematoma; and (5) hospital length of stay. Differences in perioperative pH, lactate and hemoglobin levels will also be compared between groups.

Statistical Analysis

Data will be collected in a password protected Excel file designed for the study, and entered into IBM SPSS (version 25.0 for Windows, Armonk, New York 2018) for statistical analysis. Descriptive analyses, including means, standard deviations, medians and quartiles for continuous data, and frequencies and percentages for categorical data, will be completed for all demographic and surgical characteristics, and study outcomes. The underlying distributions of all continuous data will be assessed for normality using the Shapiro Wilk test. Tissue oxygenation will be compared using independent samples t-tests if the data are normally distributed, or the Mann-Whitney U in the event that they are not. Secondary outcomes will be compared between the two groups using the Fisher's Exact or Pearson chi-square tests (as appropriate depending on cell sizes) for categorical data, and independent samples t-tests (or the Mann-Whitney U depending on the underlying distribution) for continuous data. Repeated measures ANOVA, with group as a factor, will be used to compare the tissue oxygenation over time (baseline, 1, 2, 4 and 8 hours post-operatively; as well as baseline, post-operative day 1 and day 2 data). A p-value of <0.05 will be used as the criteria for statistical significance and no adjustment will be made for multiple comparisons. The possibility of a type I error will be acknowledged and the actual p-values will be presented for all comparisons.