Ketorolac for Analgesia followiNG Autologous Breast RecOnstructiOn
Ketorolac for Analgesia followiNG Autologous Breast RecOnstructiOn
Background: Ketorolac tromethamine is a nonsteroidal anti-inflammatory drug that has been
 shown to reduce breakthrough narcotic consumption following orthopaedic, neurosurgical, and
 obstetrical procedures. The morphine-sparing effect of ketorolac may reduce respiratory and
 central nervous system depression post operatively, while still providing adequate pain
 control for patients. Patients undergoing abdominally based microsurgical breast
 reconstruction may particularly benefit from ketorolac postoperatively, and ultimately be
 safely discharged from hospital sooner than their counterparts receiving standard of care.

 Research Question: In adult women post-mastectomy, undergoing abdominally based microsurgical
 breast reconstruction, does a postoperative regimen of intravenous ketorolac tromethamine, in
 addition to standard of care, reduce the length of postoperative hospital stay compared with
 an intravenous sham saline regimen?

 Study Design: A single center, explanatory, placebo-controlled, 1:1 allocation, 2-arm,
 parallel group, superiority, randomized, and double blinded, controlled trial.

 Population: The study population includes all females >18 years old post mastectomy
 consenting to abdominally based microsurgical breast reconstruction.

 Intervention and Comparator: The intervention will be ketorolac 30 mg IV every 6 hours
 postoperatively for 72 hours. The comparator will be a sham intravenous administration of
 normal saline.

 Outcomes: The primary outcome is hospital length of stay postoperatively. Secondary outcomes
 include visual analog scale for pain, breakthrough narcotic consumption, surgical drain
 outputs, hematoma, and other complications.

 Sample Size: Available data provided estimates for average length of hospital stay and
 standard deviation. A minimally clinically significant difference of 1 day was decided on due
 to expert opinion. Based on a power of 80% and alpha of 0.05, and inflated to account for
 attrition and efficiency losses, a total of 50 patients (25 per group) will be required for
 this study.
Breast reconstruction (BR) is commonly requested following mastectomy, and recent measures
 have been taken to ensure patient access is universal. Transferring autologous tissue from
 the abdomen using microvascular surgical techniques provides a reliable reconstruction method
 with high levels of patient satisfaction, and is routinely performed. However, the surgery is
 relatively complex and lengthy; operative times can exceed six hours and hospital stay ranges
 from 5-9 days. During each patient's postoperative course she must meet certain milestones
 before discharge. It has been shown that beyond the necessary monitoring of the viability of
 the free flap, pain and a patient's ability to mobilize are important modifiable barriers to
 discharge.

 Pain control following autologous BR is multimodal, but predominantly relies on opioids.
 Narcotics provide effective analgesia, but have a well-known side effect profile that
 includes drowsiness, nausea, vomiting, sedation, central nervous system and respiratory
 depression. Each of these potential adverse effects limits patients' mobility after surgery.
 Respiratory depression is particularly disadvantageous, as these patients have undergone
 major abdominal musculature dissection that also disrupts their mechanics of breathing 10 .
 This may have the counterproductive effect of limiting patient mobilization, and ultimately
 delay discharge. In a health care system where resources are at a premium and costs are
 climbing, any inexpensive intervention that allows for an earlier and safe discharge is
 worthy of consideration.

 No standard approach to postoperative pain control in free flap BR exists. Most protocols are
 institution dependent, and variably incorporate narcotics, nonsteroidal anti-inflammatory
 drugs (NSAIDs), acetaminophen and other agents. In addition, these medications are given via
 oral, intramuscular, or intravenous routes. Recent studies have investigated the use of
 transversus abdominis plane blocks as an analgesic adjunct, and patients are often provided
 with patient-controlled analgesia (PCA) pumps in the early postoperative period.

 Ketorolac tromethamine is an NSAID, which is approved by Health Canada for short-term pain
 control (Toradol, Hoffmann-La Roche Limited, 7070 Mississauga Road Mississauga, Ontario).
 Ketorolac provides better pain control than the most commonly used NSAIDs, and its potency is
 comparable to that of morphine. However, it does not have the same listed side effects of
 drowsiness and respiratory depression as do narcotics. Surgeons often cite concern regarding
 postoperative bleeding when using NSAIDs, however recent reviews have convincingly
 demonstrated the safety for use of NSAIDs in plastic surgery. A previous observational study
 has also shown the safety of ketorolac specifically following autologous BR. The routine
 addition of ketorolac following surgery has been shown to reduce patients' narcotic
 requirements in other fields of surgery, such as orthopaedics and gynaecology.

 Given the abovementioned advantages of ketorolac, and the particular propensity for
 abdominally based free flap BR patients to be negatively affected by narcotic side effects,
 we hypothesize that the addition of ketorolac to a routine multimodal postoperative analgesia
 regimen will reduce hospital stay by a day or more.

 The comparator for this study will be a placebo. Patients randomized both to the control
 group and those randomized to the intervention group will receive standard of care
 postoperatively, which will include pain control with scheduled acetaminophen and pro re nata
 oral and subcutaneous hydromorphone. In addition, control patients will receive a placebo
 with the same scheduling as the study drug, ketorolac. The rationale for this choice is to
 limit potential sources of bias, such as the patient and her care team, and maximize the
 accuracy of the primary outcome and patient-completed questionnaires that will serve as a
 secondary outcome. Other authors have previously successfully used placebos for ketorolac in
 their study design.

 The majority of surgeons at our institution currently do not employ ketorolac in their
 postoperative pain control regimen. Thus, there exists clinical equipoise for patients
 considering participating and potentially being randomized into the control group, when
 compared with declining participation and receiving usual care.

 This study will be single-centered and conducted in Nova Scotia, Canada. The Halifax
 Infirmary is a level III trauma center with multiple board certified Plastic surgeons who
 have undertaken extra training in microsurgery.

 Participants will be removed from the study upon request. Her data up until that point will
 be used for statistical analysis, however she would no longer receive the intervention.
 Modifications to intervention dosing would occur if a participant develops any drug
 hypersensitivity reaction. Additionally any major harm attributed to ketorolac will prompt a
 termination of the intervention.

 Each patient will undergo uni- or bilateral abdominally based free flap harvest,
 microsurgical anastomoses, and flap inset. Following randomization, the study drug will be
 sent to the main operating theatre, and attached to the patient's medical chart. At the
 conclusion of surgery, each patient will be administered their first dose of the study drug.
 Its content will depend on the patient's randomized group. If randomized to the ketorolac
 intervention group, the IV minibag will contain 30 mg of ketorolac tromethamine, or if in the
 control group it will be a sham normal saline IV minibag. They then will continue to receive
 their assigned drug every 6 hours for 72 hours. Patients all receive 1:1 care from nursing
 staff in the early postoperative period, and their nurse will administer all drugs given on
 the surgical ward.

 All patients who have enrolled will receive the usual care for the postoperative period. The
 study drug will be in addition to usual flap monitoring, patient vital sign monitoring,
 progression of mobilization, drain management, along with the other care provided for these
 patients. Patients also will have the same background analgesic and anti-emetics medications
 ordered postoperatively, which is included on a standardized pre-printed order form at the
 Halifax Infirmary for this particular surgery.

 Potential participants will first be introduced to the study following their initial
 consultation for BR. If the patient consents for abdominally based microsurgical BR, then the
 study will be reviewed, allowing time for any questions to be asked, and the risks and
 benefits to be discussed. The patient will be sent home with a study package that includes a
 copy of the study consent form and protocol. The study will be reviewed again at a
 preoperative appointment, allowing time for any follow up questions to be asked. This is a
 routine appointment intended for markings and patient questions regarding surgery, and the
 patient will officially be enrolled in the study if she wishes to participate at either
 time-point - the initial consultation or the preoperative appointment. Following the surgery,
 each patient will remain active in the study until her discharge from hospital. No follow up
 appointments or data will be scheduled or recorded for the purposes of the study (although
 follow up will occur as per usual with these patients and their respective surgeon).
 Therefore total enrolment time for each patient will be from the appointment immediately
 before surgery to her discharge from hospital.

 A computer-generated algorithm will be used to randomize patients in a 1:1 allocation into
 the intervention or control group during surgery. Randomization will be stratified by
 laterality of the reconstruction (i.e. bi- or unilateral) because this could affect
 participant pain levels. Randomization will be managed and maintained by a third party
 service, not otherwise involved in the study, in the hospital pharmacy department. Allocation
 methods will not be disclosed to study investigators. Following randomization, the study drug
 will be sent to the main operating theatre, and given at the conclusion of the surgery. Both
 the intervention and control drug will be of the same storage and opacity to prevent
 identification by the patient or care providers. From there, the patient will then be
 administered the same drug according to the randomization result, based on delivery by the
 third party pharmacy service.

 Randomization will be carried out within the pharmacy department placing patients into either
 the intervention or control group. The intervention and control intravenous drugs will be
 prepared in the same style IV minibag with the same volume and opacity of fluid. The fluids
 will be of similar viscosity. Once similar appearances and features are confirmed the
 prepared drug will be sent to the operating theatre or the ward as required depending on the
 time point.

 During the conduction of this study all involved trial participants, clinicians, data
 collectors, event adjudicators, and data analysts will be blinded to the grouping of
 patients. All study medications will be stored in the hospital pharmacy department by a third
 party. Following randomization, treatment drugs will be dispensed by the pharmacy and then
 administered by nursing staff. The third party service will maintain records linking a
 patient unique identifier to her study group. Post hoc analysis to assess whether staff could
 identify between the intervention and placebo will be conducted.

 Harms will be classified as either minor or major. Minor harms will include surgical site
 infection and those listed from prior clinical trials on the drug monograph, namely:

 Common Clinical Trial Adverse Drug Reactions (>1%): Dyspepsia, abdominal pain, nausea,
 constipation, diarrhea, flatulence, gastrointestinal fullness, peptic ulcers, headache,
 dizziness, somnolence, edema

 Less Common Clinical Trial Adverse Drug Reactions (≤ 1%): Eructation, stomatitis, vomiting,
 anorexia, duodenal ulcer, gastritis, increased appetite, melena, mouth ulceration, rectal
 bleeding, sore mouth, abnormal dreams, anxiety, depression, dry mouth, insomnia, nervousness,
 paresthesia, tinnitus, taste perversion, abnormal vision, blurred vision, deafness,
 lacrimation disorder, weight gain, alkaline phosphatase increase, BUN increased, excessive
 thirst, generalized edema, hyperuricemia, pruritus, rash, burning sensation, asthenia, pain,
 back pain, face edema, hernia, arthralgia, myalgia, joint disorder, chest pain, chest pain
 substernal, migraine, dyspnea, asthma, epistaxis, hematuria, increased urinary frequency,
 oliguria, polyuria, anemia, purpura

 No major harms are anticipated. Major harms will include but are not limited to (* indicates
 possible association with oral ketorolac from drug monograph, <1%):

 Surgical site hemorrhage requiring re-exploration in the main operating theatre
 Gastrointestinal hemorrhage* Pulmonary embolus Death

 Any harm identified by care providers during enrolment of the study will be communicated to
 the principal and sub investigators. Minor harms will be communicated within 5 days. Any
 major harm will be communicated to the research ethics board within 24 hours. Complications
 will be managed medically in standard fashion, and the research will have no bearing on
 patient care. Emergency unblinding will be available to the patients' care providers at all
 times, as above.
Inclusion Criteria:

 -  Patients 18 years of age or older will be offered inclusion if they are scheduled to
 undergo unilateral or bilateral postmastectomy abdominally based free flap BR
 postmastectomy, either in a delayed fashion or at the time of initial mastectomy(ies).

 Exclusion Criteria:

 -  Patients will be excluded if they meet any of the exclusion criteria: male; revision
 surgery; a planned pedicled flap reconstruction; any previous diagnosis of chronic
 renal disease, gastric ulcers, or bleeding disorder; acetaminophen, NSAID or specific
 ketorolac sensitivity or allergy; pregnancy; or opioid tolerance defined as
 preoperative opioid use greater than 50 mg.