Intravenous Acetaminophen in Craniotomy

• ClinicalTrials.gov Identifier: NCT01598701
• Recruitment Status: Completed
• First Posted: May 15, 2012
• Results First Posted: June 19, 2018
• Last Update Posted: June 19, 2018
• Sponsor: The University of Texas Health Science Center, Houston
• Collaborator: Mallinckrodt
• Information provided by (Responsible Party): Carlos Artime, The University of Texas Health Science Center, Houston

Study Description

Brief Summary:

The purpose of this study is to assess the use of intravenous Acetaminophen (OFIRMEV) as an effective adjunct therapeutic agent in patients undergoing craniotomy.

Condition or disease	Intervention/treatment	Phase
Postoperative Pain	Drug: Acetaminophen; Drug: Placebo	Phase 4

Detailed Description:

General anesthesia will be induced by bolus administration of propofol (1.5-2.5 mg/kg IV), and fentanyl (2-3 µg/kg IV). Neuromuscular blockade will be achieved with bolus administration of rocuronium, vecuronium, or succinylcholine. Once the endotracheal tube is secured in place, the patient will be mechanically ventilated to an end-tidal CO2 of 35 mmHg. Additional procedures will include radial arterial line placement for invasive arterial blood pressure monitoring, as well as additional large-bore peripheral IV placements, or central line placement, if indicated. Anesthesia will be maintained with desflurane, propofol, and remifentanil.

Once general anesthesia has been induced, but prior to the first surgical incision, the first dose of the interventional agent will be administered. Repeat doses will be administered every 6 hours until 24 hours from the time that the patient enters the PACU, for a total of up to 6 doses. Once the patient has been positioned and prepped for surgery, the surgeon will infiltrate the scalp with bupivacaine 0.5% with epinephrine 1:200,000 (15-20 ml) before skin incision.

No other opioids or agents with analgesic properties (e.g., ketorolac, dexmedetomidine, ketamine) will be administered at any time during the operation. Additional medications that will be routinely administered for this procedure include dexamethasone 8-12mg IV prior to incision, and ondansetron 4mg IV at skin closure. Anticonvulsant drugs will be administered at the surgeon's request.

Emergence and extubation will occur at the completion of the case per standard guidelines. The time of remifentanil infusion discontinuation and time of extubation will be noted. If necessary, extubation may occur in the post anesthesia recovery unit (PACU); otherwise, extubation will occur in the operating room.

The patient will then be taken directly to the PACU. Inability to extubate a patient within two hours of completion of surgery will result in their withdrawal from the study. Once in the PACU, immediate postoperative vital signs will be recorded, including blood pressure, heart rate, respiratory rate, oxygen saturation, and RASS score.

Pain scores will be assessed using the visual analog scale (VAS) upon entering the PACU or upon extubation in PACU (0 hours), and then again at 1, 2, 4, 8, 12, 16, 20, and 24 hours post-operatively. The VAS will be a 10 cm scale on a numerical scale of 0 (no pain) to 10 (severe pain) that the patient will point to in order to indicate their current level of pain. Pain scores will be measured while the patient is at rest. Post-operative nausea will also be recorded on a 10 cm numeric rating scale (NRS) at the same time intervals, with 0 indicating no nausea and 10 indicating severe nausea. All day-time VAS and NRS measurements will be made by a research assistant. Night-time measurements will be made by the nurse on the unit.

While in the PACU, the time until the patient receives their first dose of analgesic medicine will be recorded. Patients will be given a 2mg nurse-administered dose of morphine upon request or if they report a pain score of ≥4/10, and will continue to be given morphine doses based on clinical assessment by the PACU/intensive care nurse, who will be blind to patient group allocation. The nurse will objectively assess the patient's pain score at least once an hour using the VAS pain scale, and an assessment of pain ≥4/10 will warrant an additional 2mg dose of morphine. Morphine dosage requirements will be recorded for 24 hours post-operatively. If morphine requirement is greater than 10mg in a 30 minute period or the patient develops an allergic reaction, pruritus, renal insufficiency, drowsiness, nausea/vomiting, or clinically relevant reason to change medication, the PACU supervising physician or ICU physician may use their clinical discretion to change the opioid rescue medication to hydromorphone (0.3mg doses). The reason for changing medication will be reported by the physician and recorded. The morphine equivalent of hydromorphone will be estimated to be 7 times the hydromorphone dose. The PACU/ICU nurses will also record any episodes of emesis, use of rescue anti-emetic medicine, and the occurrence of any other side effects.

A post-operative neurologic examination will take place in the PACU. Criteria for a neurological exam to be complete is the patient's ability to successfully lift each leg off of the bed for more than two seconds on command, and to be able to hold up two fingers on each hand on command. If these criteria are not met prior to transferring the patient from the PACU to the ICU, a post-operative neurologic complication will be considered and the patient will be withdrawn from the study.

The time until the patient is ready to be discharged from the PACU will also be noted. Patients with a modified Aldrete score of ≥ 8 (see Appendix 1) will be considered ready for discharge. These criteria will be assessed by either the research assistant or PACU staff.

At the end of the 24 hour post-operative time period, a patient interview will be conducted. At this interview the patient will asked about their subjective satisfaction with their analgesic protocol, as well as any adverse effects they may have noticed. The 24 hour morphine consumption will also be recorded at this time.

After the study is completed, patients may receive IV or oral acetaminophen therapy at the discretion of the primary physician.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 100 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Supportive Care
• Official Title: The Opioid-Sparing and Analgesic Effects of IV Acetaminophen in Craniotomy: A Prospective, Randomized, Placebo-Controlled, Double-Blind Study
• Actual Study Start Date: May 2, 2012
• Actual Primary Completion Date: March 30, 2016
• Actual Study Completion Date: March 30, 2016

Arms and Interventions

Arm	Intervention/treatment
Experimental: Intravenous Acetaminophen; Patients will be receive doses of 1000 mg/100 mL of IV Acetaminophen (OFIRMEV). The drug will be infused over 15 minutes.	Drug: Acetaminophen; Intravenous Acetaminophen, 1000 mg/100mL, Every 6 hours, Infused over 15 minutes.; Other Name: OFIRMEV
Placebo Comparator: Placebo; Patients will be given 100 mL normal saline placebos at scheduled time intervals in place of IV acetaminophen.	Drug: Placebo; 100 mL 0.9% Sodium Chloride; Other Name: 0.9% Sodium Chloride

Outcome Measures

Primary Outcome Measures :

1. Post-Operative Opioid Requirement [ Time Frame: 24 hours post-operatively ]
   Opioid Consumption will be monitored in the first 24 post-operative hours. All non-opioid analgesics are disallowed. Total opioid consumption was calculated based on morphine equivalents (MEs), where 1 mg of IV morphine was equivalent to 1 ME, and 1 mg IV hydromorphone was calculated as 7 MEs.

Secondary Outcome Measures :

1. Post-Operative Pain [ Time Frame: 24 Hours Post-Operatively ]
   Patients will be assessed for pain using a Visual Analogue Scale (VAS) Scale at set time points after surgery (0,1,2,4,8,12,16,20,24 hours post-operatively). The Visual Analogue Scale (VAS) scale was measured on a scale of 0 - 10 (0 = no pain, 1-3 = mild, 4-6 = moderate, 7-10 = severe). Higher values on the VAS represent a worse outcome. The two rows below report: 1. the average VAS score for the least amount of pain reported per group and 2. the average VAS score of the worst amount of pain reported per group.
2. Post-Operative Side Effects [ Time Frame: 24 Hours Post-Operatively ]
   Patients will be monitored for 24 hours post-operatively to detect the incidence of any drug or opioid-related side effects. These side effects were not considered to be adverse events.
3. Time to Extubation at Emergence From Anesthesia [ Time Frame: Time from of discontinuation of anesthetic to time of extubation, an average of 7 minutes ]
4. Time for Patient to Meet Post-anesthesia Care Unit (PACU) Discharge Criteria [ Time Frame: From time of entry to PACU to time to meet PACU discharge criteria, an average of 12 minutes ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 120 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Adults
• Undergoing Craniotomy for Supratentorial Tumor Resection
• Weight between 50 and 120 kilograms
• ASA Physical Status I-III
• Be able to communicate verbally
• Be able to use Visual Analog Score

Exclusion Criteria:

• Allergies to acetaminophen, morphine or any of the anesthetic agents required by the protocol.
• Use of opioids, tramadol, benzodiazepines, or gabapentin on a daily basis for > 7 days prior to the day of surgery.
• Use of acetaminophen, NSAIDs, or any other analgesic medication in the 12 hours immediately prior to study enrollment.
• Hepatic insufficiency (elevated transaminases > 1.5 times the upper limit of normal) or renal insufficiency (plasma creatinine > 2mg/dl).
• Known or suspected history of alcohol or illicit drug abuse.
• Pregnant or breast-feeding.
• Surgical plan for infratentorial (suboccipital) craniotomy.
• Plan for neurophysiologic monitoring that precludes the use of neuromuscular blockade.
• Inability to communicate due to a language barrier, impaired consciousness, cognitive defect or intellectual disability.
• Uncontrolled Hypertension

Contacts and Locations

Locations

United States, Texas

Memorial Hermann Hospital - Texas Medical Center

Houston, Texas, United States, 77030

Sponsors and Collaborators

The University of Texas Health Science Center, Houston

Mallinckrodt

Investigators

• Principal Investigator: Carlos A. Artime, MD; University of Texas Health Sciences Center at Houston
• Principal Investigator: Sam D. Gumbert, MD; University of Texas Health Sciences Center at Houston

More Information

Publications of Results:

Artime CA, Aijazi H, Zhang H, Syed T, Cai C, Gumbert SD, Ferrario L, Normand KC, Williams GW, Hagberg CA. Scheduled Intravenous Acetaminophen Improves Patient Satisfaction With Postcraniotomy Pain Management: A Prospective, Randomized, Placebo-controlled, Double-blind Study. J Neurosurg Anesthesiol. 2018 Jul;30(3):231-236. doi: 10.1097/ANA.0000000000000461.

• Responsible Party: Carlos Artime, Assistant Professor - Anesthesiology, The University of Texas Health Science Center, Houston
• ClinicalTrials.gov Identifier: NCT01598701
• Other Study ID Numbers: HSC-MS-12-0055
• First Posted: May 15, 2012
• Results First Posted: June 19, 2018
• Last Update Posted: June 19, 2018
• Last Verified: May 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• 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.: No

Keywords provided by Carlos Artime, The University of Texas Health Science Center, Houston:

Acetaminophen; Intravenous Acetaminophen; Opioid Requirement; Pain; Post-Operative Pain; Craniotomy; Post-Craniotomy Pain

Additional relevant MeSH terms:

Pain, Postoperative; Postoperative Complications; Pathologic Processes; Pain; Neurologic Manifestations; Acetaminophen; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Antipyretics