Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT04020172 |
| Other study ID # |
ANAE-341-19 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
Phase 1/Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
July 12, 2019 |
| Est. completion date |
July 2024 |
Study information
| Verified date |
April 2024 |
| Source |
Queen's University |
| Contact |
Glenio B. Mizubuti, MD, MSc, FRCPC |
| Phone |
+1 (613) 549-6666 |
| Email |
glenio.mizubuti[@]kingstonhsc.ca |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
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, however, do occur with DIEP flap surgery and 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 via
near-infrared spectroscopy in all patients for up to 48 hours postoperatively. Optimal fluid
therapy in combination with dobutamine may improve flap oxygenation and thereby, reduce
complications.
Description:
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), 45
minutes following vascular re-anastomosis of the DIEP flap within the perfusion zone that is
furthest away 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. In the case of bilateral DIEP flaps, the most vulnerable zone will be assessed
in both the left and right breasts.
Secondary outcomes include: (1) tissue oxygenation at baseline (preoperatively),
intra-operatively, 1, 2, 4, 8 hours postoperatively, as well as the morning of postoperative
days 1 and 2; (2) the amount of intravenous fluids (crystalloids, colloids, blood products)
and vasopressors (e.g., phenylephrine, ephedrine, norepinephrine, etc.) administered
intraoperatively and up to 4 hours postoperatively; (3) the need for intraoperative surgical
vascular re-intervention (i.e., re-anastomosis); (4) laboratory measures including
perioperative pH, serum lactate, and hemoglobin measures; (5) the incidence of postoperative
nausea and vomiting (PONV); (6) hospital length of stay; (7) any postoperative complications
including infection, hematoma and those resulting from flap mal-perfusion (i.e.,
partial/total flap loss and/or fat necrosis); (8) the need for postoperative intervention for
flap-related issues; (9) overall patient satisfaction; and (10) days alive and out of
hospital (DAOH) all up until 30 days postoperatively.
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 research staff (not otherwise involved with
data collection) and/or 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 unilateral or bilateral DIEP
flap breast reconstruction surgery under the care of Dr. Martou and/or Dr. Edmunds at the
Kingston General Hospital site of Kingston Health Sciences Centre.
Intervention Group:
The intervention will commence from the induction of general anesthesia and continue until 4
hours after surgery. Ringer's lactate (2 ml/kg/h) will be commenced upon admission to the
operating room to satisfy maintenance fluid requirements. Cardiac output (CO) and stroke
volume index (SVI) will be measured by one of two CO monitors: (1) FloTrac system, Edwards
Lifesciences Corporation, Irvine, CA, USA, which attaches to the arterial line already in
place in this surgical population; or (2) Starling SV system, Cheetah Medical, Vancouver, WA,
USA, a non-invasive CO monitor that utilizes 4 stickers placed on the patient's trunk. No
more than 500 ml of intravenous fluid will be administered at anesthesia induction. In
addition to the maintenance fluid described previously, patients will receive 250 ml 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 SVI of at least 10% for 20 minutes or more, at which point 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 postoperatively. The infusion rate
will be halved and/or discontinued if the patient develops tachycardia (heart rate ≥ 100 bpm)
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 SVI throughout the case.
Postoperatively, the patient will remain in the post-anesthetic care unit (PACU) for a
minimum of 4 hours (as per current standard of care) at the end of which, the CO monitoring
and the dobutamine infusion will be discontinued, and the patient transferred to a level 2
step-down critical care unit. Ringer's lactate at 2 ml/kg/h 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. 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 2
ml/kg/h 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 250 ml 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 CO monitoring device will be used to guide fluid therapy; however, a CO monitor will
be present in the operating room throughout the case to ensure adequate blinding of the
surgical team and the research staff with regards to which group the patient had been
randomized. 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 expect that this
study addresses this gap and provides evidence as to whether there is benefit to indicate
using it routinely. Postoperative care will be similar to the intervention group (except for
the CO monitoring and dobutamine infusion in PACU).
A tissue oximeter device (SnapshotNIR, KENT Imaging, Calgary, Canada) will be used for all
patients. This is a portable non-invasive monitor that measures tissue oxygen saturation
using near-infrared spectroscopy (NIRS) technology with the capability of saving images to
allow for subsequent analyses. Measurements are taken by holding the monitor at a
standardized (30-cm) distance from the skin area where the oxygen levels are to be measured.
Upon admission to the operating room, pre-operative, baseline measurements (with patients
breathing ambient air without supplemental oxygen) will be recorded over the abdominal flap
tissue, followed by recordings immediately post-induction, 1 hour post-induction, when the
abdominal flap is free (and still being perfused by the perforator arteries), prior to clamp
removal post-arterial re-anastomosis, and 45 minutes following re-anastomosis. All research
personnel dedicated to this study will receive pre-study training regarding perfusion zones
and the study outcomes to ensure that oxygenation measures are consistently taken from the
same surgical region in relation to the perfusion zones throughout each case. In addition,
the surgical team, led by Drs. Martou and Edmunds, will also assist with guiding the
intraoperative oxygenation measurements. The surgical team and attending anesthesiologist
will be blinded to the KENT oxygenation measurements throughout the perioperative period, and
surgery will be guided as per standard of care. The surgical team will also be blinded to
group allocation. The ischemic period during which the flap is transferred (reflected by a
fall in the oxygen saturation of the flap) as well as the time of flap revascularization
(characterized by increased oxygen saturation) will be recorded. Upon completion of the
surgical procedure, another NIRS-based monitor (Somanetics INVOS 5100C Cerebral/Somatic
Oximeter, Medtronic, Minneapolis, USA) may be applied to the freshly reconstructed graft at
the surgeon's discretion. If deemed appropriate, a sticker will be applied over the flap for
continuous monitoring of the graft oxygenation for up to 48 hours postoperatively. However,
if the surgeon requires the entirety of the graft to be exposed for visual monitoring (as per
standard care), a sensor will not be applied and postoperative measures will be recorded at
1, 2, 4, and 8 hours postoperatively, as well as on the morning of postoperative days 1 and 2
using the KENT device. All measures will be consistently taken at the same location. 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 one of two surgeons to minimize variability in
patient selection and surgical technique, both predictors of clinical outcomes in
microsurgery. 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 for guiding intravenous fluid therapy,
and interventions as described below. In the operating room, the ambient temperature will be
set at 20°C 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°C). 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 intravenous dexamethasone 4 mg on induction of general
anesthesia, and ondansetron 4 mg 15 minutes 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) and will be given an
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 contacted and/or their medical record accessed 30 days after surgery to determine
whether the patient experiences postoperative complications and/or required medical attention
(as per the informed consent). If the patient is successfully contacted, 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 CO monitoring to guide fluid administration intraoperatively and up to 4 hours
postoperatively, 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 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 tachycardia (heart rate ≥100 bpm) 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 (prior
to publication), the patient decides they want to withdraw their consent, 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 4
hours 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 (SAE) 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 seek permission to retain any data collected (especially demographic
information) for comparison of those who were versus were not withdrawn to determine whether
they differ in any respect (e.g. are older, 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 CO 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 NIRS, 45 minutes following vascular re-anastomosis of the DIEP flap
within the perfusion zone that is furthest away 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), 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, CO monitoring will be used to guide intravenous fluid
administration 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; (5) hospital length of stay; and (6) days alive and out of hospital (DAOH).
Differences in perioperative pH, lactate and hemoglobin levels will also be compared between
groups.
Statistical Analysis:
Data will be entered into REDCAP (version 10.6.12) and upon study completion, will be
exported to IBM SPSS (version 28.0 for Windows, Armonk, New York 2021) 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
criterion 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.
