Improving Tissue Oxygenation in Breast Reconstruction Surgery
Improving Tissue Oxygenation in Breast Reconstruction Surgery
Breast reconstruction is an integral part of breast cancer care. There are two main types of
 breast reconstruction: alloplastic (using implants), and autologous (using patient's tissue).
 The latter creates a more natural breast mound, and avoids long-term concerns requiring
 surgical re-intervention associated with implant-based surgery. The deep inferior epigastric
 perforator (DIEP) flap is the gold standard technique in autologous breast reconstruction.
 Complications that do occur with DIEP flap surgery often stem from poor flap
 perfusion/oxygenation. Hence, the development of strategies to enhance flap perfusion (e.g.,
 optimal perioperative fluid therapy) is essential. Current perioperative fluid therapy is
 usually guided by subjective criteria which leads to wide variations in fluids administered.
 We will randomly assign DIEP flap patients to receive optimal (cardiac output-guided) fluid
 therapy in combination with dobutamine (a medication which has potential to improve flap
 oxygenation) versus the current standard of care. Flap oxygenation will be monitored in all
 patients for up to 48 hours postoperatively. Optimal fluid therapy in combination with
 dobutamine may improve flap oxygenation and thereby, reduce complications.
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.
Inclusion Criteria:

 -  ASA I-III

 -  Undergoing elective DIEP flap surgery

 -  Competent to provide informed consent

 Exclusion Criteria:

 -  Dementia or neurological impairment

 -  Scheduled for DIEP flap combined with any other secondary surgical procedure

 -  Documented left ventricular dysfunction (ejection fraction < 40%)

 -  Contraindication to low-dose dobutamine

 -  Body mass index < 18 or > 40

 -  Pregnant or lactating

 -  Renal insufficiency (eGFR < 30)

 -  Known liver insufficiency (i.e., documented cirrhosis, coagulopathy and/or
 encephalopathy of hepatic origin)