Clinical trial NCT02509312
Conditions: Analgesia, Obstetrical Postpartum Hemorrhage Opioid Use Nonsteroidals (NSAIDs)Toxicity Coagulation Defect; Postpartum Postoperative Pain Ketorolac Adverse Reaction Blood Loss, Postoperative
Keywords: Analgesia, Obstetrical Blood Loss, Surgical Analgesics, Opioid/administration & dosage Cyclooxygenase Inhibitors/administration & dosage Cesarean Delivery Female Humans Ketorolac/administration & dosage Hydromorphone/administration & dosage Pain, Postoperative/drug therapy Pregnancy Morphine/administration & dosage Cesarean Section Complications Ketorolac
Sponsor: University Hospitals Cleveland Medical Center
Start date: 2016-05-01; Completion date: 2017-10-01
Enrollment: 70 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
In this randomized, double-blind control trial to evaluate the effect of ketorolac given at the time of cord clamp has on estimated blood loss and postcesarean pain control. Patients will be randomized to either placebo or ketorolac prior to surgery. Those randomized to ketorolac will receive ketorolac at cord clamp and three additional doses every 6 hours (total 4 doses/24 hours). Those in the placebo group will receive normal saline during those time periods. Our primary outcome is to assess whether intra-operative ketorolac increases the estimated blood loss during Cesarean delivery.

Detailed description:
Background:

Opioid analgesics are among the most common medication employed for post-cesarean delivery pain management. However, opioid side-effects such as, nausea, vomiting, urinary retention, and sedation are problematic and can adversely impact post-operative recovery. Non-steroidal anti-inflammatory medications have analgesic as well as anti-inflammatory properties making them an ideal alternative for opioid analgesics. Ketorolac, which can be given by either oral and parenteral routes, is frequently employed as a post-surgical analgesic in a variety of procedures including gynecologic and obstetric, and has comparable analgesic properties to opioids without the aforementioned side-effects.(1)

Additionally, two studies have specifically evaluated administration of ketorolac in the treatment of post-cesarean section pain in patients receiving either patient controlled intravenous analgesia or patient controlled epidural analgesia.(2, 3) However, due to the known inhibition of prostaglandin synthesis, several retrospective and observational studies have suggested that ketorolac and other non-steroidal anti-inflammatory drugs (NSAIDs) may be associated with an increase in estimated blood loss (EBL) and uterine atony.(4,5) This research showed in vivo defects in platelet function, however a recent meta-analysis in a variety of different surgical procedures suggest there is no clinically significant difference in EBL attributed to the administration of ketorolac compared to placebo.(6)

Despite this, there still exists significant resistance to the intraoperative and post-operative use of ketorolac due to concerns of increasing EBL. This is particularly true with regard to cesarean sections, which, due to the nature of the procedure is associated with an EBL higher than found in many other surgeries and possibly leading to increased morbidity. To our knowledge there have only been three previous studies that specifically examined the use of ketorolac with cesarean delivery.

El-Tahan et al, administered ketorolac preoperatively and focused on the blunting of sympathetic response to intubation of healthy patients undergoing cesarean section under general anesthesia. This study evaluated only a single low dose followed by intraoperative infusion. Although they did look at intraoperative EBL, they did not give additional postoperative doses or assess postoperative bleeding.(7) Lowder et al and Pavy et al looked at postoperative use of ketorolac on pain control and EBL, but no intraoperative dose of ketorolac was given.(2,3)

To our knowledge, there have been no studies that evaluated intraoperative ketorolac on post-operative opioid analgesic use and EBL during cesarean delivery with epidural analgesia and intra-epidural administration of morphine.

Screening/Eligibility Visit:

Patients admitted to MacDonald Women's Hospital for scheduled or non-scheduled, non-urgent Cesarean delivery will be screened for potential eligibility. Potential participants will be then be approached to confirm they meet inclusion and exclusion requirements. Patients will then be consented with an IRB-approved informed consent prior to enrollment.

Randomization \& Blinding:

Patients will be randomized to receive either ketorolac 30 mg in 1 ml (n=35) or normal saline 1 ml (n=35). Randomization will be performed by the Investigational Pharmacy in a block of four design. No one involved with patient care, enrollment or data collection will have access to the unblinding key until completion of the study. The randomization key will be kept in the Investigational Research Pharmacy, and they will prepare the medications accordingly. Upon arrival in the OR, the anesthesiologist will open an envelope that will contain the kit number corresponding to the patient's study identification number. The anesthesiologist or anesthetist will remove the assigned kit from the Omnicell. Patients, clinicians and study staff will be unaware of the patient's assigned study group. Upon study completion by all patients, the randomization key will be provided to the study staff upon request.

Brief Study Methods:

After obtaining written informed consent, the Investigation Research Pharmacy an envelope that will contain the kit number corresponding to the patient's study identification number. Basic demographic information is collected from the patient. Each patient will undergo combined spinal-epidural anesthesia with our standard cesarean induction dose of hyperbaric 0.75% bupivacaine 1.5 ml intrathecally and fentanyl 100mcg epidurally. The patient will be moved to the supine position with left lateral uterine displacement. When a T6 sensory level to pinprick is achieved, Cesarean delivery will proceed using the standard procedures established in our institution. Once the newborn is delivered and the cord is clamped, the first dose of the ketorolac/placebo will be administered by the anesthesiologist or anesthetist. Any additional medications required for sedation or pain control during the remainder of the surgery (hydromorphone and acetaminophen) will be given, as appropriate for patient comfort. Prior to the completion of the procedure, the patient will receive epidural morphine 3 mg per the standard protocols. Postoperatively, the patient will receive the corresponding three additional scheduled doses of ketorolac/placebo every 6 hours. Supplemental analgesia will be administered according to a standard post-operative pain management protocol on labor and delivery with acetaminophen and intravenous hydromorphone provided, as needed for pain control.

Exposures and their measurement:

Exposure: Ketorolac 30 mg IV or Normal Saline 1 ml (Placebo) IV

Measurements: See outcomes and their measurements

Outcomes and their measurement:

Primary outcome: Estimated Blood Loss (EBL) will be compared between groups. Secondary outcomes: Rate of Post-Partum Hemorrhage, Corrected Change in Hct on POD1, Uterotonic Doses, Units of Packed Reb Blood Cell Transfused, Hydromorphone Use, Total Hydromorphone Dose, Anti-emetic Doses, Pruritus Doses, Percentile Change in Systolic Blood Pressure at 6, 12, and 24 hours, Percentile Change in Diastolic Blood Pressure at 6, 12, and 24 hours, and Pain score at 0 and 15 minutes and 1, 6, 12 and 24 Hours post-Cesarean Delivery.

Confounders and their measurement:

Many confounders should be limited by the nature of an RCT in a select patient population and pre- and intra-operative exclusion criteria. Additional potential confounders, including intraoperative fluid volume administration and patient adherence to study medication, will be recorded. Posthoc analysis will be performed to determine if any differences between groups were significant.

Analysis plan:

Data will be assessed for normality using histograms, QQ plots and Shapiro-Wilk test. Demographic, obstetric, and perioperative data will be presented as mean (standard deviation), median \[interquartile range\] or count (percentage), as appropriate. Between-group comparisons will be assessed using the t-test and Wilcoxon signed-rank test, as appropriate. For dichotomized outcomes, a Chi-square test will be performed to assess the proportions between groups.

Sample size justification:

A priori power analysis was performed to determine the sample size. Based on our prior retrospective study, we knew that the mean estimated blood loss for uncomplicated Cesarean deliveries was 814 ml with a standard deviation of 242 ml. We set our difference between groups to 186 ml. This would detect an EBL of \>1,000 ml in the ketorolac group, a value large enough to classify the ketorolac group as post-partum hemorrhage and potentially escalate care and lead to additional maternal morbidity. With an alpha error of 0.05 and a power of 80%, we estimated that a sample size of 28 patients per group would be needed or 56 total patients enrolled. We had concern for loss after enrollment due to acuity, cases after 4 pm and exclusion criteria including intraoperative EBL and obstetric refusal. We planned for the loss of 20% of enrolled patients and increased the total study enrollment number to 70.

Arms: arm 1: Patients in this arm will be given ketorolac at cord clamp with standard dose of 30 mg, then 3 additional 30 mg doses every 6 hours arm 2: Patients in this arm will be given a placebo medication at cord clamp, and then 3 additional doses of placebo every 6 hours.
Interventions: intervention 1: Ketorolac intervention 2: Placebo
Intervention descriptions: intervention 1: Patients in the experimental arm will receive ketorolac 30 mg in 1 ml at the time of cord clamp and then for 3 more doses every 6 hours. intervention 2: Patients in the control arm will receive normal saline 1 ml at the time of cord clamp and then for 3 more doses every 6 hours.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
Official title: 
Prospective Effect of Intravenous Ketorolac on Opioid Use, EBL and 
Complications Following Cesarean Delivery 
NCT number: 
 
NCT02509312 
Document date: 
2/28/2022 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Basic study design: 
Randomized Control Trial: Double‐Blind Placebo‐Controlled Trial 
Study population and assembly of patients: 
We will study 70 healthy (ASA 1 or 2) women between 18 and 45 years old with singleton term 
pregnancies undergoing or non‐scheduled, non‐urgent primary or repeat Cesarean delivery between 37‐
42 weeks gestational age with neuraxial anesthesia with combined spinal‐epidural placed for surgery.  
Exclusion criteria are as follows: unable or unwilling to provide informed consent, urgent or emergent 
Cesarean delivery, multiple fetal gestations (>1 intrauterine pregnancy), patients undergoing Cesarean 
delivery for bleeding such as placental abruption or actively bleeding placenta previa or vasa previa, 
contraindication to NSAID use eg: allergy, chronic renal disease, acute or chronic platelet dysfunction 
(e.g.: idiopathic thrombocytopenic purpura, HELLP syndrome), platelets <100k, history of peptic ulcer 
disease, inherited or acquired coagulopathies or bleeding disorder, (disseminated intravascular 
coagulopathy, hemophilia), suspected or proven placenta accreta, increta or percreta, inability to 
receive epidural morphine, patients with a diagnosed chronic pain disorder on chronic adjunct or opioid 
analgesia, use of general anesthesia during procedure. 
Intraoperative exclusion criteria include an EBL > 1000 ml prior to cord clamp. 
Randomization & Blinding: 
Patients will be randomized to receive either ketorolac 30 mg in 1 ml (n=35) or normal saline 1 ml 
(n=35). Randomization will be performed by the Investigational Pharmacy in a block of four design. No 
one involved with patient care, enrollment or data collection will have access to the unblinding key until 
completion of the study. The randomization key will be kept in the Investigational Research Pharmacy, 
and they will prepare the medications accordingly. Upon arrival in the OR, the anesthesiologist will open 
an envelope that will contain the kit number corresponding to the patient's study identification number. 
The anesthesiologist or anesthetist will remove the assigned kit from the Omnicell. Patients, clinicians 
and study staff will be unaware of the patient's assigned study group. Upon study completion by all 
patients, the randomization key will be provided to the study staff upon request. 
Brief Study Methods: 
After obtaining written informed consent, the Investigation Research Pharmacy an envelope that will 
contain the kit number corresponding to the patient's study identification number. Basic demographic 
information is collected from the patient. Each patient will undergo combined spinal‐epidural anesthesia 
with our standard cesarean induction dose of hyperbaric 0.75% bupivacaine 1.5 ml intrathecally and 
fentanyl 100mcg epidurally. The patient will be moved to the supine position with left lateral uterine 
displacement. When a T6 sensory level to pinprick is achieved, Cesarean delivery will proceed using the 
standard procedures established in our institution. Once the newborn is delivered and the cord is 
clamped, the first dose of the ketorolac/placebo will be administered by the anesthesiologist or 
anesthetist. Any additional medications required for sedation or pain control during the remainder of 
the surgery (hydromorphone and acetaminophen) will be given, as appropriate for patient comfort. 
Prior to the completion of the procedure, the patient will receive epidural morphine 3 mg per the 
standard protocols. Postoperatively, the patient will receive the corresponding three additional 


scheduled doses of ketorolac/placebo every 6 hours. Supplemental analgesia will be administered 
according to a standard post‐operative pain management protocol on labor and delivery with 
acetaminophen and intravenous hydromorphone provided, as needed for pain control.  
Exposures and their measurement: 
Exposure: Ketorolac 30 mg IV or Normal Saline 1 ml (Placebo) IV 
Measurements: See outcomes and their measurements 
Outcomes and their measurement: 
Primary outcome: Estimated Blood Loss (EBL) will be compared between groups. 
Secondary outcomes: Rate of Post‐Partum Hemorrhage, Corrected Change in Hct on POD1, Uterotonic 
Doses, Units of Packed Reb Blood Cell Transfused, Hydromorphone Use, Total Hydromorphone Dose, 
Anti‐emetic Doses, Pruritus Doses, Percentile Change in Systolic Blood Pressure at 6, 12, and 24 hours, 
Percentile Change in Diastolic Blood Pressure at 6, 12, and 24 hours, and Pain score at 0 and 15 minutes 
and 1, 6, 12 and 24 Hours post‐Cesarean Delivery. 
Confounders and their measurement: 
Many confounders should be limited by the nature of an RCT in a select patient population and pre‐ and 
intra‐operative exclusion criteria. Additional potential confounders, including intraoperative fluid 
volume administration and patient adherence to study medication, will be recorded. Posthoc analysis 
will be performed to determine if any differences between groups were significant. 
Analysis plan: 
Data will be assessed for normality using histograms, QQ plots and Shapiro‐Wilk test. Demographic, 
obstetric, and perioperative data will be presented as mean (standard deviation), median [interquartile 
range] or count (percentage), as appropriate. Between‐group comparisons will be assessed using the t‐
test and Wilcoxon signed‐rank test, as appropriate. For dichotomized outcomes, a Chi‐square test will be 
performed to assess the proportions between groups.  
Sample size justification: 
A priori power analysis was performed to determine the sample size. Based on our prior retrospective 
study, we knew that the mean estimated blood loss for uncomplicated Cesarean deliveries was 814 ml 
with a standard deviation of 242 ml. We set our difference between groups to 186 ml. This would detect 
an EBL of >1,000 ml in the ketorolac group, a value large enough to classify the ketorolac group as post‐
partum hemorrhage and potentially escalate care and lead to additional maternal morbidity. With an 
alpha error of 0.05 and a power of 80%, we estimated that a sample size of 28 patients per group would 
be needed or 56 total patients enrolled. We had concern for loss after enrollment due to acuity, cases 
after 4 pm and exclusion criteria including intraoperative EBL and obstetric refusal. We planned for the 
loss of 20% of enrolled patients and increased the total study enrollment number to 70.