Analgesic Effect of IV Acetaminophen in Tonsillectomies

Phase 2

Completed

Conditions: Adenotonsillitis
Tonsillitis

Interventions: Drug: Acetaminophen (paracetamol)
Drug: Normal Saline Flush
Drug: Midazolam
Drug: Sevoflurane
Drug: Nitrous Oxide/Oxygen
Drug: Propofol
Drug: Morphine
Drug: Ondansetron
Drug: Dexamethasone

Registration Number: NCT01691690

Lead Sponsor: Nationwide Children's Hospital

Brief Summary: Acetaminophen (paracetamol) is a first-line antipyretic and analgesic for mild and moderate pain for pediatric patients. Its common use (particularly in oral form) is underscored by its wide therapeutic window, safety profile, over the counter accessibility, lack of adverse systemic effects (as compared with NSAIDS and opioids) when given in appropriate doses.

Although the exact anti-nociceptive mechanisms of acetaminophen continue to be elucidated, these mechanisms appear to be multi-factorial and include central inhibition of the cyclo-oxygenase (COX) enzyme leading to decreased production of prostaglandins from arachidonic acid, interference with serotonergic descending pain pathways, indirect activation of cannabinoid 1 (CB1) receptors and inhibition of nitric oxide pathways through N-methyl-D-aspartate (NMDA) or substance P. Of the above mechanisms, the most commonly known is that of central inhibition of COX enzymes by which the decreased production of prostaglandins diminish the release of excitatory transmitters of substance P and glutamate which are both involved in nociceptive transmission (Anderson, 2008; Smith, 2011).

To date, several studies have shown acetaminophen's opioid sparing effect in the pediatric population when given by the rectal or intravenous routes (Korpela et al, 1999; Dashti et al, 2009; Hong et al, 2010).

Detailed Description: Once enrolled, subjects will have a standardized anesthetic on the day of surgery:

1. Pre-medication with oral midazolam (0.5mg/kg to maximum dose of 20mg) given 15-20 minutes before induction

2. Inhalation induction with sevoflurane and a mixture of N20/02

3. Propofol 1-1.5 mg/kg to facilitate endotracheal intubation

4. Morphine 0.1 mg/kg given prior to intubation

5. Maintenance anesthesia with isoflurane, titrated to 0.8-1 Minimal Anesthetic Concentration (MAC) with a mixture of Air/02

6. Acetaminophen IV (15 mg/kg) vs. saline placebo infused intraoperatively (randomized by pharmacy)

7. Ondansetron (0.15 mg/kg, maximum dose of 4 mg) and dexamethasone (0.25 mg/kg, maximum dose of 20 mg) for postoperative nausea prophylaxis.

Following surgery and extubation, baseline vitals will be obtained and pain scores will be assessed in the post anesthesia care unit (PACU) via Faces, Legs, Activity, Cry, Consolability Scale (FLACC).The presence of emergence delirium will be assessed via Pediatric Agitation and Emergence Delirium scale (PAED). Those subjects whose pain score is assessed at \< 4 will receive standard postoperative care and no analgesics. Assessed pain scores \> 4 will receive 0.5mcg/kg fentanyl q10 minutes as needed. Variables such as time to extubation in the PACU, time to first analgesic delivery, pain scores, # times/total dose of opioids given, presence of sedation, nausea/vomiting, duration of oxygen requirement in PACU, whether or not patient was discharged to floor on oxygen and total PACU time will be recorded during the duration of the patient's PACU stay. Subjects will be discharged to the inpatient floor from the PACU once standard discharge criteria have been met.

Following discharge from the PACU, standardized analgesics will be given for breakthrough pain (oral oxycodone 0.1mg/kg q4hrs pro re nata (PRN) pain). Enrolled patients will be followed during the duration of their inpatient stay. Duration of oxygen requirement on the floor, pain scores and number of administered oxycodone doses on the floor will be monitored and recorded.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 250

Inclusion Criteria

Male or female patients aged 2 years and younger than 9 years old requiring postoperative admission for tonsillectomy or adenotonsillectomy.
Functional status as assigned by the American Society of Anesthesiology (ASA) classification of I (1), II (2) or III (3).
Have a parent/guardian who are able to provide written informed consent in accordance with Human Investigations Committee/Institutional Review Board (HIC/IRB) regulations.
Have parent/guardian who are compliant with routine medical care, capable of subjective evaluation and able to read, understand and sign the informed consent.

Exclusion Criteria

Male or female patients age greater than 9 years.
Have an American Society of Anesthesiologists Physical Status > IV (4)(severe disease that is life threatening).
Have a known hypersensitivity or allergy to acetaminophen.
Have a known allergy or intolerance to morphine or fentanyl.
Have received chronic opioid analgesic therapy prior to surgery.
Have renal disease.
Have hepatic disease.
Are morbidly obese (% BMI > 95).

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
IV Acetaminophen	Acetaminophen (paracetamol)	Patients will receive pre-medication with oral midazolam Participants of this experimental arm of the study will receive Acetaminophen IV to evaluate opioid-sparing effect and pain score reduction..
IV Acetaminophen	Morphine	Patients will receive pre-medication with oral midazolam Participants of this experimental arm of the study will receive Acetaminophen IV to evaluate opioid-sparing effect and pain score reduction..
Saline placebo infused intraoperatively	Dexamethasone	For this arm Morphine will be administered to manage pain.
IV Acetaminophen	Nitrous Oxide/Oxygen	Patients will receive pre-medication with oral midazolam Participants of this experimental arm of the study will receive Acetaminophen IV to evaluate opioid-sparing effect and pain score reduction..
Saline placebo infused intraoperatively	Normal Saline Flush	For this arm Morphine will be administered to manage pain.
Saline placebo infused intraoperatively	Nitrous Oxide/Oxygen	For this arm Morphine will be administered to manage pain.
IV Acetaminophen	Midazolam	Patients will receive pre-medication with oral midazolam Participants of this experimental arm of the study will receive Acetaminophen IV to evaluate opioid-sparing effect and pain score reduction..
IV Acetaminophen	Sevoflurane	Patients will receive pre-medication with oral midazolam Participants of this experimental arm of the study will receive Acetaminophen IV to evaluate opioid-sparing effect and pain score reduction..
Saline placebo infused intraoperatively	Ondansetron	For this arm Morphine will be administered to manage pain.
IV Acetaminophen	Propofol	Patients will receive pre-medication with oral midazolam Participants of this experimental arm of the study will receive Acetaminophen IV to evaluate opioid-sparing effect and pain score reduction..
IV Acetaminophen	Ondansetron	Patients will receive pre-medication with oral midazolam Participants of this experimental arm of the study will receive Acetaminophen IV to evaluate opioid-sparing effect and pain score reduction..
IV Acetaminophen	Dexamethasone	Patients will receive pre-medication with oral midazolam Participants of this experimental arm of the study will receive Acetaminophen IV to evaluate opioid-sparing effect and pain score reduction..
Saline placebo infused intraoperatively	Midazolam	For this arm Morphine will be administered to manage pain.
Saline placebo infused intraoperatively	Sevoflurane	For this arm Morphine will be administered to manage pain.
Saline placebo infused intraoperatively	Propofol	For this arm Morphine will be administered to manage pain.
Saline placebo infused intraoperatively	Morphine	For this arm Morphine will be administered to manage pain.

Primary Outcome Measures

Name	Time	Method
FLACC Pain Score Greater Than or Equal to 4	0-60 mins post-operatively	The Face, Legs, Activity, Cry, Consolability scale or FLACC scale is a measurement used to assess pain for children between the ages of 2 months and 7 years or individuals that are unable to communicate their pain. The scale is scored in a range of 0-10 with 0 representing no pain. 5 pain measurements were performed at 0, 5, 15, 30, and 60 minutes after PACU arrival. This is the number of participants who reached a FLACC score \>/= 4 at one or more time points.

Secondary Outcome Measures

Name	Time	Method
Time of First Opioid Analgesia in PACU	0-90 minutes post-operatively	Mean time to first drug administration among patients requiring opioid analgesia in the PACU.
Analgesics Administered After Arrival to Inpatient Ward and Number of Participants Requiring Each	8-12 hours post-operatively	Analgesics administered after arrival to the inpatient ward included hydrocodone/acetaminophen, oxycodone, NSAIDS, acetaminophen, and morphine.