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IV Ketorolac on Platelet Function Post-Cesarean Delivery (KetoPltAgg)

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ClinicalTrials.gov Identifier: NCT03805607
Recruitment Status : Not yet recruiting
First Posted : January 15, 2019
Last Update Posted : March 14, 2019
Sponsor:
Collaborator:
Society for Obstetric Anesthesia and Perinatology
Information provided by (Responsible Party):
John J. Kowalczyk, Beth Israel Deaconess Medical Center

Tracking Information
First Submitted Date  ICMJE January 8, 2019
First Posted Date  ICMJE January 15, 2019
Last Update Posted Date March 14, 2019
Estimated Study Start Date  ICMJE August 2019
Estimated Primary Completion Date December 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 27, 2019)
Platelet Aggregometry Percent Light Transmission [ Time Frame: 15 minutes after dosing of placebo or ketorolac ]
Platelet Aggregometry uses measurements platelet rich blood or serum samples and activating agents to analyze the percent change in light transmission as a marker of platelet aggregation.
Original Primary Outcome Measures  ICMJE
 (submitted: January 13, 2019)
Platelet Aggregometry [ Time Frame: 15 minutes after dosing of placebo or ketorolac ]
Platelet Aggregometry uses measurements platelet rich blood or serum samples and activating agents to analyze the percent change in light transmission as a marker of platelet aggregation.
Change History Complete list of historical versions of study NCT03805607 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: January 13, 2019)
  • Thromboelastogram parameters including Reaction time (R) [ Time Frame: 15 minutes after dosing of placebo or ketorolac ]
    Thromboelastogram parameters including Reaction time (R)
  • Thromboelastogram parameters including Angle (alpha) [ Time Frame: 15 minutes after dosing of placebo or ketorolac ]
    Thromboelastogram parameters including Angle (alpha)
  • Thromboelastogram parameters including Kinetics (K) [ Time Frame: 15 minutes after dosing of placebo or ketorolac ]
    Thromboelastogram parameters including Kinetics (K)
  • Thromboelastogram parameters including Maximum Amplitude (MA) [ Time Frame: 15 minutes after dosing of placebo or ketorolac ]
    Thromboelastogram parameters including Maximum Amplitude (MA)
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE IV Ketorolac on Platelet Function Post-Cesarean Delivery
Official Title  ICMJE Prospective Evaluation of the Effects of IV Ketorolac on Platelet Function Post-Cesarean Delivery
Brief Summary Cesarean delivery has become the most common surgical procedure in the US. Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to improve the quality of post-cesarean analgesia and markedly reduce opioid consumption. The effect of NSAIDs on healthy volunteers results in inhibition of platelet aggregation and prolonged bleeding time. However, in the obstetric population, the presence and degree of platelet inhibition after NSAID exposure is less clear. The investigators plan to use Platelet Aggregometry and Thromboelastography (TEG) to evaluate the effect of ketorolac on platelets.
Detailed Description

Cesarean delivery has become the most common surgical procedure in the US, with over 1.2 million cesarean deliveries performed each year. The addition of non-steroidal anti-inflammatory drugs (NSAIDs) to a post-cesarean analgesic regimen has been shown to improve the quality of post-cesarean analgesia and markedly reduce opioid consumption. As a result, fewer patients incur opioid related side-effects such as nausea and vomiting, respiratory compromise, sedation, and impaired breast-feeding.

The effect of NSAIDs on healthy volunteers is relatively well-described. Most commonly, NSAIDs inhibit membrane-bound cyclooxygenase 1 (COX-1), the enzyme responsible for the production of the platelet agonist thromboxane A2. This ultimately results in inhibition of platelet aggregation and prolonged bleeding time. However, in the obstetric population, the presence and degree of platelet inhibition after NSAID exposure is less clear. This has limited the incorporation of NSAIDs into protocols for postpartum analgesia following cesarean delivery.

Platelet Function Assessment 100 (PFA) assays, with collagen/epinephrine and collagen/ADP (adenosine diphosphate) as agonists, can reliably test for platelet inhibition. PFA has been utilized to examine the anti-platelet effects of platelet inhibitors including NSAIDs in studies involving non-obstetric patients. Similarly, platelet aggregometry has been used to evaluate the platelet inhibitory effects of NSAIDs. Thromboelastography (TEG) has been shown in numerous studies to represent in-vivo clot strength and function.

Research in this field is needed as physiologic changes of pregnancy combined with significant surgical blood loss and hemodilution at cesarean delivery may alter the effect on maternal platelet function. This has become more pressing as postpartum thromboprophylaxis is likely to be more commonly considered for patients after cesarean delivery. In their most recent unofficial guidelines, the American Society of Regional Anesthesia state that NSAIDs should not be used with thromboprophylaxis after patients received neuraxial blockade (ASRA App). However, to the best of our knowledge, there is limited data, only utilizing bleeding time,5 examining the potential platelet inhibitory effect of NSAIDs in a low-risk healthy cohort undergoing cesarean delivery.

Protocol:

Brief Study Protocol After obtaining Institutional Review Board (IRB) approval, patients will be randomly assigned to receive either IV ketorolac 30 mg (n=15) or normal saline (n=15) based on a pre-assigned randomization sequence. The assignment for each patient will be kept in sealed opaque envelopes. After obtaining written informed consent, an anesthesiologist not involved in the study will open the envelope and will prepare the study drug. The patient and the study investigators will be blinded to the study drug.

Baseline platelet count, coagulation parameters (activated partial thromboplastin time (APTT), prothrombin time (PT), Fibrinogen) and TEG parameters will be measured pre-operatively on the day of surgery. Routine lab work obtained at this time will require 10 ml of blood, while study related tests will require 5.4 ml. Each patient will undergo either spinal or combined spinal epidural anesthesia with our standard cesarean induction dose of hyperbaric intrathecal 0.75% bupivacaine 1.5 ml, intrathecal fentanyl 25 micrograms and intrathecal morphine 250 micrograms. 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 be allowed to proceed. At the completion of the surgery, Platelet Aggregometry and TEG parameters will be performed to assess for intraoperative changes to TEG and establish baseline Platelet Aggregometry values. A total volume of 18.9 ml of blood will be withdrawn for the study at this time. While under the effect of the spinal medication, meaning that the patient is unable to fill sharp in their feet, the patient may elect to have this blood and the subsequent blood drawn from their foot to avoid unnecessary pain. These blood draws would only be performed by an anesthesiologist and only if a suitable site was identified. Performing venipucture for lab draws in the feet is not known to increase the risk of complications from blood draws when compared to the upper extremity. The study drug will be administered upon completion of the case. Platelet Aggregometry and TEG parameters will be performed 10 min after study drug administration. An additional volume of 18.9 ml of blood will be withdrawn for the study at this time. After blood samples have been obtained, patients in each group will receive the alternate therapy (ie placebo group receives ketorolac and ketorolac receives placebo), allowing both groups to benefit from the analgesic effect of ketorolac. Supplemental analgesia will be administered according to a standard post-operative pain management protocol on labor and delivery.

Statistical analysis: Data will be assessed for normality using normality plots and the Kolmogorov-Smirnov test. Demographic, obstetric, and perioperative data will be presented as mean (SD) or median [interquartile range]. Between-group comparisons will be assessed using the unpaired t test and Mann-Whitney U test, where appropriate. Within-group before vs. after NSAID exposure changes will be assessed using the paired t test and Wilcoxon signed rank test, where appropriate. The percentage change from baseline for each PFA, TEG, and lab parameter will also be calculated.

Sample size justification: There is limited data on the affect of ketorolac on quantitative coagulation studies, particularly in the obstetric population. Based on available data from a prior study examining platelet inhibition of non-opioid analgesics, a PFA closure time ≥173 seconds can be used to classify platelet inhibition. Using the aforementioned data on epinephrine-induced PFA closure time, the investigators estimate that, before and after ketorolac exposure, 25% and 70% patients respectively would exhibit prolonged PFA closure times. With an alpha error of 0.05 and a beta error of 0.8, the investigators estimated that a sample size of 18 patients per group would provide 80% power. Additional studies have examined the affect of ketorolac on platelet aggregometry. Platelet aggregometry to collagen was diminished in the ketorolac group from preoperative to poststudy drug data points (90.8% +/- 7.6% to 60.5% +/- 32.5%; P < 0.01). With an alpha error of 0.05 and a beta error of 0.8, the investigators estimated that a sample size of 19 patients per group would provide 80% power.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Randomized Double-blind Placebo Controlled Study
Masking: Triple (Participant, Care Provider, Investigator)
Masking Description:
Placebo (normal saline) or ketorolac in syringe prepared by the investigational pharmacy with study patient number and blinding key maintained by investigational pharmacy until time of unblinding.
Primary Purpose: Diagnostic
Condition  ICMJE
  • Cesarean Section Complications
  • Postoperative Pain
  • Coagulation Defect; Postpartum
  • Nonsteroidals (NSAIDs)Toxicity
  • Postpartum Hemorrhage
Intervention  ICMJE
  • Drug: Ketorolac Tromethamine 30 MG/ML
    Ketorolac 30 mg
    Other Names:
    • ketorolac
    • Ketorolac Tromethamine
    • Ketorolac Injectable Solution
  • Drug: Placebos
    Normal Saline
    Other Names:
    • Placebo
    • Normal Saline
Study Arms  ICMJE
  • Placebo Comparator: Placebo
    1 ml of normal saline
    Intervention: Drug: Placebos
  • Experimental: Ketorolac
    30 mg of ketorolac in 1 ml
    Intervention: Drug: Ketorolac Tromethamine 30 MG/ML
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: January 13, 2019)
40
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE February 2020
Estimated Primary Completion Date December 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Pregnant
  • Undergoing routine, scheduled cesarean section
  • Gestation >37 weeks
  • Singleton gestation
  • Intraoperative anesthesia - 1.5 ml of intrathecal bupivicaine 0.75%, 25mcg of intrathecal fentanyl and 250 mcg of intrathecal morphine via Spinal or Combined Spinal Epidural

Exclusion Criteria:

  • Pre-eclampsia with severe features or HELLP
  • Allergy to NSAIDs
  • Pre-existing bleeding disorder
  • Other major risk factor for postpartum hemorrhage (placenta accreta, large uterine fibroid)
  • Chronic kidney disease
  • Plt count less than 100k
  • Gastric ulcer or gastric bleeding
  • Pre-existing uterine bleeding or disseminated intravascular coagulation
  • Patient or Obstetrician refusal
  • Intraoperative exclusion criteria - Postpartum hemorrhage (EBL >1000 ml) or unplanned intraoperative extension of surgery
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years to 45 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE
Contact: John J Kowalczyk, MD 617-667-3112 jkowalcz@bidmc.harvard.edu
Contact: Phil Hess, MD 617-667-3112 phess@bidmc.harvard.edu
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03805607
Other Study ID Numbers  ICMJE 2018P000625
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: Individual participant data (IPD) will not be shared.
Responsible Party John J. Kowalczyk, Beth Israel Deaconess Medical Center
Study Sponsor  ICMJE Beth Israel Deaconess Medical Center
Collaborators  ICMJE Society for Obstetric Anesthesia and Perinatology
Investigators  ICMJE Not Provided
PRS Account Beth Israel Deaconess Medical Center
Verification Date March 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP