Betamethasone (Betapred®) as Premedication for Reducing Postoperative Vomiting and Pain After Tonsillectomy
Betamethasone (Betapred®) as Premedication for Reducing Postoperative Vomiting and Pain After Tonsillectomy
Betamethasone is currently given routinely in conjunction with tonsillectomy surgery at the
 majority of Ear, Nose & Throat clinics in Sweden. The scientific evidence regarding the
 effects of betamethasone in adults is limited when it comes to postoperative nausea (PONV),
 pain and postoperative bleeding.
Steroids are used routinely aiming to reduce pain and nausea, especially in surgery with high
 levels of postoperative pain. The majority of international studies on tonsillectomy (TE) are
 performed on dexamethasone which is used in large parts of the world. Use of steroids when TE
 is performed on children are also more studied on than on adults. Islam et al 2011
 demonstrated in a study that dexamethasone (8 mg) reduced postoperative nausea for 24 hours
 in a study population of both children and adults. Mc Kean et al 2006 studied the effect of
 10 mg dexamethasone on nausea in adults after TE during a seven-day period. Effect was seen
 during the first 24 hours but not the remaining days. With regard to postoperative pain, the
 research results differ in terms of what effect steroids have at TE. Mc Kean et al 2006
 showed significantly lower estimated pain on surgery day and day 4 to 7 after a single dose
 of dexamethasone peroperatively. Stewart et al 2002 has shown that, by means of
 preoperatively given dexamethasone (8 mg) and in decreasing dose over an 8 day period
 postoperative [2mgx2 for 4 days and then 2mgx1 for 4 days], the patient's estimated pain and
 consumption of additional pain relievers were reduced. Michele et al 1999, on the other hand,
 found no effect on pain over a 10 day period despite a relatively high peroperatively dose of
 dexamethasone (20 mg). There are, however, studies on children, suggesting that there is a
 dose-dependent relationship between dexamethasone and postoperative bleeding after TE in
 children. In a study by Czarnetzki et al 2008, 0.05, 0.15 and 0.5 mg / kg dexamethasone were
 used peroperatively. In this study it was seen that 0.5 mg / kg dexamethasone increased the
 risk of bleeding from 4% to 24%, which led to a premature termination of the study due to the
 bleeding risk. In 2012, a meta-analysis of the steroid effect on bleeding after tonsillectomy
 was conducted by Plante et al. Both studies on children and adults were included. No
 significant increase in the overall frequency of bleeding after tonsillectomy was seen. On
 the other hand, a significant increase in the number of haemorrhages that required operative
 action was noted. This could be interpreted as that the severity of bleedings was increased.
 It was recommended that systemic steroids should be used with caution until further studies
 have been performed. The investigators conducted a retrospective study on children with TE in
 Gällivare with and without betamethasone (69 patients in total) and found no evidence of
 increased bleeding risk, but also no effect on PONV. However, a significant effect on pain
 was found during the first 24 hours postoperative with the average dose of 0.15 mg / kg. When
 comparing different cortisone preparations, 8 mg of betamethasone corresponds to
 approximately 10 mg of dexamethasone. Bellis et al., 2014 performed a meta-analysis of
 dexamethasone and postoperative bleeding at TE in children, but considered that more studies
 are needed to determine the bleeding risk before any safe conclusions can be drawn. Thus,
 there are uncertainties with regard to the cortisone effect, both when it comes to the size
 of the dose and whether there really is an effect on PONV and / or postoperative pain or not.
 On the other hand one does not want to use high doses with risks of postoperative bleeding.
 Betamethasone has not been studied to the same extent as dexamethasone, and in Sweden
 betamethasone is preferably used preoperatively to counteract PONV and pain associated with
 certain operations. The results of previous studies are however not conclusive and there is
 no consensus of what doses that should be used. In Sweden 4 mg of betamethasone, given
 intravenously during the surgery, is routine at tonsillectomy surgery. However, in the
 literature there is very weak evidence that such a small dose have any effect. On the other
 hand, there are studies signaling that dexamethasone doses of 20 mg (= 16 mg betamethasone)
 reduced PONV, but increased postoperative hemorrhages after TE surgery.

 Glucocorticoids may act via the following mechanisms: (1) anti-inflammatory effect; (2)
 direct central action at the solitary tract nucleus, (3) interaction with the
 neurotransmitter serotonin, and receptor proteins tachykinin NK1 and NK2, alpha-adrenaline,
 etc.; (4) maintaining the normal physiological functions of organs and systems; (5)
 regulation of the hypothalamic-pituitary-adrenal axis; and (6) reducing pain and the
 concomitant use of opioids, which in turn reduces opioid-related nausea and vomiting.

 2.2. Risk/Benefit evaluation One of the main problems after tonsillectomy is PONV and
 especially postoperative pain that can persist up to 10-14 days after the surgery. This long
 period of postoperative pain leads to weakness and dehydration due to difficulties to eat and
 drink after the operation. Sometimes hemorrhage after TE can be fatal, but normally the
 bleeding can be stopped with local anaesthesia or diathermy during general anaesthesia.
 Normally this type of bleeding occurs in 8-10% after TE. After TE the patients normally go
 home the same day as the surgery. In northern Sweden the distances from the Hospital with an
 ear, nose and throat (ENT) emergency unit to the home of the patients could be as far as
 3-400 kilometers. In this situation it is not advisory to give additional medications, which
 increases the risk of lethal hemorrhage.

 Benefits of 8 mg betamethasone:

 -  Reduced PONV

 -  Reduced pain => Less NSAID pain killers => Less risk of hemorrhage

 -  Reduced pain => Increased ability to eat and drink => less risk of postoperative
 infection => less risk of bleeding

 -  Reduced pain => Shorter sick leave => Socioeconomic benefits

 Risks of 8 mg betamethasone:

 -  Increased bleeding risk => more patients comes back to the hospital due to hemorrhage =>
 more patients need re-surgery with diathermy of the bleeding

 -  Patients with gastric ulcers have an increased risk of gastric bleeding

 A previous retrospective study showed a reduced pain postoperatively with 8 mg betamethasone,
 without any sign of increased postoperative hemorrhage. There are no studies that have showed
 an increased postoperative risk of hemorrhage with 10 mg of dexamethasone given to adults at
 TE surgery. On the other hand lower doses of dexamethasone, as for example 5 mg (= 4 mg of
 betamethasone), does not seem to have any clinical benefits. The aim of the present study is
 to evaluate if it is possible to register a beneficial effect of 8 mg betamethasone, given as
 a premedication orally, without increasing side effects as increased bleeding.

 In conclusion, the side effects are mild and probably very infrequent, while the positive
 effects are visible in almost all patients with less pain and a shorter recovery period after
 the surgery.

 3. STUDY OBJECTIVES AND ENDPOINTS 3.1. Primary objective The primary objective of this study
 is to verify if 8 mg of betamethasone at adolescents and adult TE operations can
 significantly reduce PONV.

 3.2. Secondary objective(s) The secondary objective is to verify that 8 mg of betamethasone
 in adolescents and adult TE operations reduces postoperative pain but does not increase the
 postoperative bleeding risks.

 4. STUDY DESIGN AND PROCEDURES 4.1. Overall study design and flow chart

 The study is a double-blind, placebo-controlled, randomized study in 100 volunteered patients
 over 12 years of age selected for elective tonsillectomy at the ENT clinic in Norrbotten.
 Patients fulfilling all of the inclusion and none of the exclusion criterias will be
 included. Enrollment will be continued until the required sample size is achieved (100
 subjects). Once informed consent is obtained, screening data will be collected to determine
 each subject´s eligibility for study participation. The total expected duration of the
 subject participation is maximum 95 days, from screening visit to end of follow-up. The
 active participation is 5 days (surgery at visit 2 and phone calls, 1 and 5 days after day of
 surgery). The study pharmaceutical (betamethasone) is a well-known substance and has been
 used in humans for many years for the same indications as in the present study. Thus it will
 be regarded as a phase IV study.
Inclusion Criteria:

 Signed informed consent Age over 12 years Planned for elective bilateral tonsillectomy

 Exclusion Criteria:

 -  • Insulin dependent diabetes mellitus

 -  NSAID or corticosteroid intolerance

 -  Pregnancy

 -  Gastric ulcer

 -  Immunodeficiency

 -  Treatment for chronic pain

 -  Psychiatric disorders