1. Catrina Crisp MD MSc, Ganga Devaiah MS,
Randomized Controlled Trial of Intravenous Acetaminophen for Post-Cesarean Delivery Pain Control
Brie Altenau MD,
Catrina Crisp MD MSc, Ganga Devaiah MS,
Donna Lambers MD,
Department of OB/GYN
TriHealth Hospitals
Thank you for the opportunity to present our research. There are no potential conflicts of interest or disclosures to report.
Funding for our study was obtained from the General Medical Education Quality Improvement Grant.

2. Background Multimodal management of postoperative pain
Cesarean deliveries – intrathecal morphine, oral or intravenous narcotics, and NSAIDS
Per ACOG a goal of post operative pain management is to use the least amount of narcotics necessary
Opioids
abuse potential with rise in incidence
Adverse effects: nausea, sedation, and pruritus
Currently in the United States a multimodal management approach is used for treatment of post operative pain. In the Obstetric field, this is applied to Cesarean Delivery patients by utilizing intrathecal morphine and oral or intravenous narcotic analgesics in combination with traditional NSAIDS. Per ACOG, a goal of post cesarean pain management should be to use the least amount of narcotic medications necessary.
Unfortunately opioid medications have abuse potential, with a rise in the incidence over recent years. Secondary to these concerns, a reduction in reliance on narcotic medications has been encouraged.
In addition, narcotic medications have common adverse effects such as nausea, sedation, and pruritus.
Bateman Am J Obstet Gynecol 2016;215(3)
Booth Anesth Analg. 2016;122(4)
ACOG Practice Bulletin 36 Obstet Gynecol. 2002;100(1)

3. Background IV formulation of acetaminophen
International in 2002
United States in 2011
Successful integration in pediatrics, orthopedics, plastics, and cardiology
Obstetrics- improved pain and reduced adverse effects, only international sites
An additional tool for non-narcotic management of pain is intravenous acetaminophen. It has been available internationally since 2002 and became available in the US in It has demonstrated successful integration into multimodal regimens in many fields of medicine including: pediatrics, orthopedics, plastics, and cardiology. Studies evaluating its utility in obstetrics have revealed improved pain management with reduced narcotic adverse effects, however these are from international sites where obstetric care may differ than in the United States. Therefore…
Rosaeg Can J Anaesth. 1997;44(8)
Alhashemi Can J Anaesth. 2006;53(12)
Kilicaslan Agri. 2010;22(1)
Omar RMJ. 2011;36(4
Ozmete J Clin Anesth. 2016;33
Inal Internet J Anesth. 2007;15(1)

4. Hypothesis
The hypothesis of this study is that administration of IV acetaminophen at the time of cesarean delivery and 48 hours post-operatively will reduce the amount of narcotics consumed.

5. Secondary Outcomes Incidence of opioid-related medication side effects
Evaluation of patient-reported pain scores
Secondary outcomes included the incidence of opioid- related side effects and the evaluation of patient reported pain

6. Material and Methods IRB Approved Study: Hatton #13068
ClinicalTrials.gov NCT:
Study Population:
Inclusion: ≥ 18yrs; scheduled procedure, spinal/epidural using intrathecal morphine
Exclusion: weight<50kg; allergy to study medications; positive drug screen; liver dysfunction
This was an IRB approved study registered with the US National Institute of Health Clinical Trials Registry.
The study population was enrolled from a large academic referral center.
Inclusion Criteria consisted of age 18yrs or older, scheduled cesarean procedure, and patient ability to receive spinal anesthesia using intrathecal morphine.
Exclusion criteria included weight < 50kg, allergy to study medications, positive drug screen, and liver dysfunction.

7. Material and Methods
Informed consent was obtained from all study participants
Randomization: assigned on the day of their surgery by pharmacist
Patient data was extracted from electronic medical records
Primary author
Electronic code
Written informed consent was obtained from all study participants.
Randomization was assigned to participants on the day of their surgery by the pharmacist on duty utilizing a previously developed randomization schedule.
All patient data/information was extracted from Electronic Medical Records by myself. The same information was extracted from EPIC using a specifically designed software program. Extracted information was compared between researcher and the software program, and this was used to adjust and calibrate the program code until this could be used to accurately extract study information for statistical analysis

8. Material and Methods Standardized pre and post operative order sets
Study drug preparations
1g IV acetaminophen in 100mL NS
100mL of NS
1st dose given 30 to 60 minutes prior to incision
For this study, standardized pre and post operative order sets were used. The Study Drug was either 1g of IV acetaminophen prepared in 100ml of NS or placebo of 100ml of NS. The study drug was administered preoperatively within minutes of incision.

9. Material and Methods
Blinded administration of study drug via premixed IV bags marked as “Study Drug”
Total of 6 doses of the study drug, first dose preoperatively, then every 8 hours to complete a total of 48 hours
Nurses recorded patient self-reported pain scores via Faces Pain Scale at time of study drug administration
For the purposes of blinding, IV acetaminophen and placebo were packaged in identical IV bags and labeled as “study drug” as IV acetaminophen is normally packaged in a glass bottle.
Participants would then receive nurse administered doses every 8 hours for a total of 6 doses, spanning 48 hours. Prior to study drug infusion the nurse would routinely ask the patient to rate their pain, based on the Revised Faces Pain Scale and chart this information in the patients electronic medical records.
Feese Am J Obstet Gynecol. 2013;209(6)

10. Material and Methods Breakthrough pain medications Recorded in EMR
Oxycodone
Ibuprofen
Recorded in EMR
Pain scores
Postoperative care medications
Additionally, patients received Oxycodone and Ibuprofen for breakthrough pain management. Prior to any administration of analgesic medication the nurse would have the patient rate their pain to record in the EMR. Frequently used post-operative care medications such as anti-emetics and stool softeners were also recorded.

11. Material and Methods
For statistical analysis we used a 30% reduction in total postoperative narcotic consumption as significant (71.44mg to 50mg)
100 participants (50 per arm)
A power calculation was completed based on previous data. We considered a 30% reduction in total post operative oxycodone consumption from 71.44mg to 50 mg in the IV acetaminophen group when compared to placebo to be clinically significant. The power calculation determined that 45 patients per study arm would be required to detect the 30% reduction with 80% power and a significance level of To account for patient drop out or exclusion after consent, 100 patients (50 per arm) were randomized. 100 total randomized patients also gave the study adequate power to detect a clinically relevant mean difference in patient-reported pain scores between groups.
(If need to address additional questions regarding statistics and power of study) A clinically relevant change in 0-10 pain rating scales for pain has been listed as 2 points5. To detect a 2 point difference in pain with 80% power and a significance level of 0.05, 66 patients would be required. Therefore, the 100 patients needed to detect the narcotics consumption outcome was more than adequate to also assess the outcome of pain. The study was approved to consent up to 150 patients in order to account for patients who were excluded after consent due to spontaneous labor; non-scheduled cesarean section; and positive drug screen.

12. Consort Flowchart
A total of 133 patients were consented from March 2014 through April 2016 with 1 delivering prior to randomization.
The remaining 132 patients were randomized into the study drug and placebo arms
Despite the large volume of potential study participants, limits in research staff, availability to approach patients prior to scheduled procedure, patient hesitance for exposure to a new medication, and the unpredictable nature of obstetrics were all factors that impacted the amount of patients consented for the study.

13. Consort Flowchart
From the randomized patients a total of 7 were excluded or withdrawn from both arms of the study for non-scheduled cesarean or vaginal delivery.
An additional 21 patients were excluded or withdrawn from the study for positive drug screens, choice, medical exclusion, or protocol deviation. A total of 104 patients completed the study with 57 patients in the IV acetaminophen arm, and 47 patients in the placebo arm

14. Demographic and Clinical Characteristics
Review of patient demographics revealed no difference in baseline characteristics including patient age, body mass index, gravity, parity, ethnicity, recorded comorbidities, or number of prior cesarean deliveries. Gestational age at time of cesarean section was found to be 39 weeks for both groups
If asked:
Non-parametric data points (BMI, gravidity, parity), can’t be statistically analyzed using mean
Not evenly distributed data points – additional characteristics, EBL etc can’t use parametric analysis
timing of discharge was not dependent on control of patient pain but rather on additional factors not related to pain control.

15. Comparison of Breakthrough Medications during Inpatient Stay
When evaluating medications administered by anesthesia during the cesarean section and immediately postop, total amounts of IV morphine, fentanyl, and ketorolac (IV and intramuscular) were not different between study arms. (CLICK)
A significant difference (CLICK) was found in the amount of narcotic medication required for pain management in post cesarean patients.
If questioned about large range of (SD) standard deviation so closely approaches the mean values This happened because there is a wide variation in the data which is expected since there is a wide variation in the pain levels experienced by the patients. Since the standard deviations are below the means, we can still use the t-test to test for differences

16. Total Oxycodone Consumption, mg
The IV acetaminophen study arm received nearly 20 mg less of oxycodone. On average the acetaminophen group received a total of 47mg of oxycodone during the hospitalization while the placebo group received a total of 65mg of oxycodone (p = 0.034).

17. Pain Score Comparison Prior to and After each Dose of Study Drug/Placebo
Lastly, when analyzing pre and post study drug administration patient reported pain scores, both the IV acetaminophen and placebo groups were not found to be different. In both study arms, the pain scores overall were low with median pain scores between 0 and 4.

18. Comments
Multimodal analgesia has traditionally used oral acetaminophen
Oral route
Subject to first pass effect
Slow uptake following major intra-abdominal surgery
Increased time to systemic levels
As an oral medication, acetaminophen is subject to the first pass effect from the gastrointestinal tract and subsequently takes time to achieve appreciable systemic levels Following major intra-abdominal surgery such as cesarean delivery, the GI tract can be slow to resume normal activity resulting in reduced uptake of oral acetaminophen, and diminishing its effectiveness
Groudine J Perianesth Nurs. 2011;26(2)
Singla Pain Pract. 2012;12(7)

19. Comments IV acetaminophen has improved pharmacokinetic attributes
No first pass effect
Fast onset of action
Addition of IV acetaminophen to Post Cesarean Multi-modal pain management decreased narcotic medication consumption
The parenteral form is not reliant on this metabolism, and is able to quickly attain therapeutic levels in the plasma and subsequently the CSF(cerebral spinal fluid) where it has its mechanism of action for pain relief. We believe this favorable pharmacokinetic profile allows for IV acetaminophen’s improved effects in the cesarean delivery setting, allowing patients to achieve adequate anesthesia with less oxycodone, while pursing more pressing matters such as caring for and bonding with their newborn

20. Strengths Double blinded, randomized, placebo-controlled trial
Standardized pre & post operative care
Strengths of this study included its design as a double blinded, randomized placebo-controlled trial and use of standardized order sets to provide care to patients in the pre and post operative settings.

21. Limitations
Inability to use patient reported events to monitor for decrease in opioid related side effects
Inability to regularly record pain scores 1 hour following administration of study drug to determine decrease in patient perceived pain
One limitation of this study was the use of proxy medications to detect for the occurrence of narcotic associated adverse effects in the postoperative setting, which only revealed their routine application in all patients and not specific events
The secondary outcome of decreased patient perceived pain was unable to be demonstrated as a result of the inability to routinely collect 1 hour post study drug administration pains scores.
One limitation of this study was the administration of specific medications as a proxy to detect for occurrence of narcotic associated adverse effects Unfortunately for this study, the proxy medications chosen had multiple purposes in the postoperative setting. This gave false positive results of adverse effects that were in fact routine use of medications in the recovery period, possibly leading to no difference in arms when a true difference may exist.
Another limitation was the inability to routinely collect post study drug administration patient reported pain scores at consistent time intervals. Lacking these specifically timed data points, the inability to demonstrate reduced patient perceived pain is not surprising due to the variation in time of collection following study drug adminstration.

22. Conclusion
IV acetaminophen in the post-operative period following cesarean delivery resulted in a significant decrease in oral narcotic consumption for pain control
In conclusion, iv acetaminophen patients required less total narcotic.
The results demonstrate that the addition of IV acetaminophen to a multimodal postoperative pain management regimen significantly decreased the total amount of narcotic medications required. Given the impact of narcotics, consideration should be given to routinely incorporating this medication into post-cesarean delivery multi-modal pain management, as a tool to decrease narcotic requirement in the postoperative period.
THANK YOU  I look forward to your questions

23. Sincere Thanks! Donna Lambers MD Catrina Crisp MD MSc Ganga Devaiah MS
Peggy Walsh RN and Rita Doerger RN
Michaela Eschenbacher MPH
Michael Thierauf
General Medical Education Quality Improvement Fund
Labor & Delivery and Mother Baby Unit Nurses
TriHealth OB/GYN Residents
Sincere thanks to everyone involved.

24. References
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26. Questions?
Thank you! I look forward to your questions!

27. Thank you! I look forward to your questions!

28. Mean CSF Values

29. Mean Plasma Values