Clinical trial NCT01691690: Analgesic Effect of IV Acetaminophen in Tonsillectomies
Official title: Analgesic Effect of Single Dose Intravenous Acetaminophen in Pediatric Patients Undergoing Tonsillectomy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Adenotonsillitis
Tonsillitis
Lead sponsor: Nationwide Children's Hospital
Sponsor class: OTHER
First posted: 2012-09-25
Enrollment: 250
Sex: ALL
Minimum age (years): 2
Maximum age (years): 9
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

1. Male or female patients aged 2 years and younger than 9 years old requiring postoperative admission for tonsillectomy or adenotonsillectomy.
2. Functional status as assigned by the American Society of Anesthesiology (ASA) classification of I (1), II (2) or III (3).
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.
4. 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:

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

Primary outcomes:
measure: FLACC Pain Score Greater Than or Equal to 4
timeFrame: 0-60 mins post-operatively
Secondary outcomes:
measure: Analgesics Administered After Arrival to Inpatient Ward and Number of Participants Requiring Each
timeFrame: 8-12 hours post-operatively
measure: Time of First Opioid Analgesia in PACU
timeFrame: 0-90 minutes post-operatively
Other outcomes:
Locations:
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
Study officials:
affiliation: Nationwide Children's Hospital
name: Arlyne Thung, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Anderson BJ. Paracetamol (Acetaminophen): mechanisms of action. Paediatr Anaesth. 2008 Oct;18(10):915-21. doi: 10.1111/j.1460-9592.2008.02764.x.
citation: Smith HS. Perioperative intravenous acetaminophen and NSAIDs. Pain Med. 2011 Jun;12(6):961-81. doi: 10.1111/j.1526-4637.2011.01141.x. Epub 2011 May 31.
citation: Korpela R, Korvenoja P, Meretoja OA. Morphine-sparing effect of acetaminophen in pediatric day-case surgery. Anesthesiology. 1999 Aug;91(2):442-7. doi: 10.1097/00000542-199908000-00019.
citation: Dashti GA, Amini S, Zanguee E. The prophylactic effect of rectal acetaminophen on postoperative pain and opioid requirements after adenotonsillectomy in children. Middle East J Anaesthesiol. 2009 Jun;20(2):245-9.
citation: Hong JY, Kim WO, Koo BN, Cho JS, Suk EH, Kil HK. Fentanyl-sparing effect of acetaminophen as a mixture of fentanyl in intravenous parent-/nurse-controlled analgesia after pediatric ureteroneocystostomy. Anesthesiology. 2010 Sep;113(3):672-7. doi: 10.1097/ALN.0b013e3181e2c34b.