Clinical trial NCT03035942
Conditions: Fractures, Bone Nausea and Vomiting, Postoperative Pruritus Morphine Adverse Reaction Satisfaction, Personal
Keywords: Intrathecal morphine Nausea and vomiting Quality of recovery Patient satisfaction Pruritus Postoperative pain
Sponsor: Pontificia Universidade Catolica de Sao Paulo
Start date: 2017-01-02; Completion date: 2019-11-04
Enrollment: 135 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The aim of this study is to evaluate not only the occurrence of side effects, but the quality of the recovery (QoR-40 Questionnaire) of patients submitted to spinal anesthesia with administration of low doses (0.1 mg) of intrathecal morphine for the surgical treatment of fractures in one of the lower limbs and who will receive prophylactic ondansetron (4mg), dexamethasone (8mg) or placebo.

Detailed description:
This randomised, double-blinded trial was approved by the Research Ethics Committee of the School of Medical and Health Sciences, Pontifical Catholic University of São Paulo (Sorocaba, São Paulo - Brazil), on June 14 2016, CAAE (Presentation Certificate for Ethical Appreciation) 58208015.7.0000.5373 (Chairperson Prof. J.A. Costa). On the day of surgery, after completion of the pre-anesthetic evaluation and due explanations of the study, consent will be obtained. No participant will take any pre-anesthetic medication before surgery. Subjects will be randomised using a computer-generated (www.random.org) table of random numbers into 3 groups: S (saline), D (dexamethasone 8 mg), or O (ondansetron 4 mg). Group assignments will be sealed in sequentially numbered opaque envelopes that were opened after patient inclusion in the study. All care providers, researchers, and patients will be blinded to group assignments. Study 5-mL syringes will be prepared by a nurse independent of the study. Normal saline (5 mL total volume), dexamethasone (made up to 5 mL with normal saline), or ondansetron 4 mg (made up to 5 mL with normal saline) will be drawn into each syringe which will be offered to the anesthesia provider after the opaque envelope was opened.

After arrival in the operating room, standard ASA (American Society of Anesthesiologists) monitors will be applied. Immediately after venoclysis,e.v. midazolam will be administered as titrated doses to achieve 3 or 4 on Ramsay scale. Spinal puncture will be performed with the patient in the seated position in the median or paramedian line at L3-L4 or L2-L3 interspace using a 26-gauge Quincke needle. Anesthesia will be established with a single bolus of 0.5% hyperbaric bupivacaine (17.5 mg if ≥ 70 kg or expected surgery duration \> 150 minutes and 15 mg if \< 70 kg) and preservative-free morphine 0.1 mg. Normal saline will be used for fluid replacement therapy. In case of failure of spinal anesthesia, the technique will be repeated or a general approach will be performed and the patient will be excluded from the study. Titrated doses of midazolam (up to 10 mg) or propofol continuous infusion will be administered to achieve perioperative sedation (≥4 on Ramsay scale). Supplemental oxygen 5 L/min via a vent mask will be administered during and after surgery.

Postanesthesia care unit (PACU) All patients will be transferred to the PACU. Data related to the occurrence of pain, nausea, vomiting, pruritus, urinary retention and time to Aldrete score ≥ 9 at the PACU will be recorded. Pain will be assessed every 15 minutes using a 0-10 numeric pain rating scale (NRS), where zero meant no pain and 10 the worst imaginable pain. Morphine (1 to 2 mg) was administered intravenously every 10 minutes to maintain the pain score below 4 (1 mg when the pain score was \<7 and 2 mg when it was ≥7). Postoperative nausea and vomiting (PONV) will be treated with dimenhydrinate (30 mg) intravenously. Pruritus will be classified as follow: 0 - no symptoms, 1 - 3 - mild symptoms, 3 - 7 moderate symptoms and 7 - 10 - severe symptoms. Nalbuphine 5 mg intravenously will be administered when score \> 4.

Ward Following discharge from the PACU (minimum stay 60 minutes and Aldrete score ≥ 9), all of the participants were given ketoprofen (100 mg) every 12 hours and dipyrone (30 mg.kg-1, maximum 1 g) every six hours intravenously. Whenever patients judged that their analgesia was insufficient, tramadol (100 mg) was administered intravenously at eight-hour minimum intervals as needed. Postoperative nausea and vomiting (PONV) were treated with dimenhydrinate (30 mg) intravenously. An investigator who was blinded to group assignment collected all postoperative outcome data 24 hours after surgical procedure. Subjects were asked to rate the higher score of pain (NRS) during the hospital ward stay. Tramadol consumption, occurrence of urinary retention and the number of nausea and vomiting episodes were also recorded. These findings were confirmed with the ward nursing staff. All subjects stayed at hospital for at least 24 hours.

Data Collection The baseline QoR-40 questionnaire was completed by the subjects after informed consent was obtained in the preoperative holding area and 24 hours after surgery by a blinded investigator. The QoR-40 questionnaire evaluates five dimensions of recovery (physical comfort - 12 items; emotional state - 7 items; physical independence - 5 items; physiological support - 7 items; and pain - 7 items). Each item was rated on a five-point Likert scale: none of the time, some of the time, usually, most of the time, and all the time. The total score on the QoR-40 ranges from 40 (very poor quality of recovery) to 200 (best quality of recovery).

The primary outcome of interest will be the QoR-40 score on postoperative day 1 (POD1).

Arms: arm 1: Dexamethasone 8 mg arm 2: Ondansetron 4 mg arm 3: Normal saline (5 mL total volume)
Interventions: intervention 1: Dexamethasone intervention 2: Ondansetron intervention 3: Saline
Intervention descriptions: intervention 1: Dexamethasone 8 mg (made up to 5 mL with normal saline) will be drawn into each syringe which will be offered to the anesthesia provider after the opaque envelope was opened and administered immediately after spinal anesthesia was performed. intervention 2: Ondansetron 4 mg (made up to 5 mL with normal saline) will be drawn into each syringe which will be offered to the anesthesia provider after the opaque envelope was opened and administered immediately after spinal anesthesia was performed. intervention 3: Normal saline (5 mL total volume) will be drawn into each syringe which will be offered to the anesthesia provider after the opaque envelope was opened and administered immediately after spinal anesthesia was performed.

Protocol documents:
Prot_002.pdf: 
Quality of Recovery after Dexamethasone, Ondansetron or Placebo Intrathecal 
Morphine Administration 
Official title: Role of dexamethasone or ondansetron in the quality of recovery after 
intrathecal morphine administration in patients undergoing lower limb surgery 
NCT03035942 
June 1st 2016 
 
Study protocol 
This randomised, double-blinded trial was approved by the Research Ethics Committee of the 
School of Medical and Health Sciences, Pontifical Catholic University of São Paulo (Sorocaba, 
São Paulo - Brazil), on June 14, 2016, CAAE 58208015.7.0000.5373 (Chairperson Prof. J.A. 
Costa). On the day of surgery, after completion of the pre-anesthetic evaluation and due 
explanations of the study, consent will be obtained. No participant will take any pre-anesthetic 
medication before surgery. Subjects will be randomised using a computer-generated 
(www.random.org) table of random numbers into 3 groups: S (saline), D (dexamethasone 8 
mg), or O (ondansetrona 4 mg). Group assignments will be sealed in sequentially numbered 
opaque envelopes that were opened after patient inclusion in the study. All care providers, 
researchers, and patients will be blinded to group assignments. Study 5-mL syringes will be 
prepared by a nurse independent of the study. Normal saline (5 mL total volume), 
dexamethasone (made up to 5 mL with normal saline), or ondansetrone 4 mg (made up to 5 mL 
with normal saline) will be drawn into each syringe which will be offered to the anesthesia 
provider after the opaque envelope was opened.  
After arrival in the operating room, standard ASA monitors will be applied. Immediately after 
venoclysis,e.v.  midazolam will be administered as titrated doses to achieve 3 or 4 on Ramsay 
scale. Spinal puncture will be performed with the patient in the seated position in the median or 


paramedian line at L3-L4 or L2-L3 interspace using a 26-gauge Quincke needle. Anesthesia will 
be established with a single bolus of 0.5% hyperbaric bupivacaine (17.5 mg if ≥ 70 kg or 
expected surgery duration > 150 minutes and 15 mg if < 70 kg) and preservative-free morphine 
0.1 mg. Normal saline will be used for fluid replacement therapy. In case of failure of spinal 
anesthesia, the technique will be repeated or a general approach will be performed and the 
patient will be excluded from the study. Titraded doses of midazolam (up to 10 mg) or propofol 
continuous infusion will be administered to achieve perioperative sedation (≥4 on Ramsay 
scale). Supplemental oxygen 5 L/min via a vent mask will be administered during and after 
surgery. 
 
PACU 
All patients will be transferred to the PACU. Data related to the occurrence of pain, nausea, 
vomiting, pruritus, urinary retention and time to Aldrete score ≥ 9 at the PACU will be 
recorded. Pain will be assessed every 15 minutes using a 0-10 numeric pain rating scale (NRS), 
where zero meant no pain and 10 the worst imaginable pain. Morphine (1 to 2 mg) was 
administered intravenously every 10 minutes to maintain the pain score below 4 (1 mg when the 
pain score was <7 and 2 mg when it was ≥7). PONV will be treated with dimenhydrinate (30 
mg) intravenously. Pruritus will be classified as follow: 0 – no symptoms, 1 - 3 – mild 
symptoms, 3 - 7 moderate symptoms and 7 - 10 – severe symptoms. Nalbuphine 5 mg 
intravenously will be administered when score > 4.  
 
Ward 
Following discharge from the PACU (minimum stay 60 minutes and Aldrete score ≥ 9), all of 
the participants were given ketoprofen (100 mg) every 12 hours and dipyrone (30 mg.kg-1, 
maximum 1 g) every six hours intravenously. Whenever patients judged that their analgesia was 


insufficient, tramadol (100 mg) was administered intravenously at eight-hour minimum 
intervals as needed. Postoperative nausea and vomiting (PONV) were treated with 
dimenhydrinate (30 mg) intravenously. An investigator who was blinded to group assignment 
collected all postoperative outcome data 24 hours after surgical procedure. Subjects were asked 
to rate the higher score of pain (NRS) during the hospital ward stay. Tramadol consumption, 
occurrence of urinary retention and the number of nausea and vomiting episodes were also 
recorded. These findings were confirmed with the ward nursing staff. All subjects stayed at 
hospital for at least 24 hours. 
 
Data Collection 
The baseline QoR-40 questionnaire was completed by the subjects after informed consent was 
obtained in the preoperative holding area and 24 hours after surgery by a blinded investigator. 
The QoR-40 questionnaire evaluates five dimensions of recovery (physical comfort – 12 items; 
emotional state – 7 items; physical independence – 5 items; physiological support - 7 items; and 
pain – 7 items). Each item was rated on a five-point Likert scale: none of the time, some of the 
time, usually, most of the time, and all the time. The total score on the QoR-40 ranges from 40 
(very poor quality of recovery) to 200 (best quality of recovery).  
The primary outcome of interest will be the QoR-40 score on POD1. 
 

SAP_001.pdf: 
Quality of Recovery after Dexamethasone, Ondansetron or Placebo Intrathecal 
Morphine Administration 
NCT03035942 
February 1st, 2018 
 
Statistical analysis 
The primary outcome was the QoR-40 score 24 hours after surgery. Murphy et al 
evaluated the quality of recovery in patients undergoing laparoscopic cholecystectomy 
with or without IV dexamethasone.1 The sample size estimated to achieve 80% power 
to detect a 17-point difference in QoR-40 was 30 subjects per group. A difference of 10 
points represents a 15% improvement in the quality of recovery.2,3Considering possible 
dropouts, one hundred thirty-five subjects were finally randomized into three groups. 
The Shapiro–Wilk test was used to test the hypothesis of a normal distribution. Ordinal 
and continuous data that were not normally distributed are presented as median and 
range and were compared using the Kruskal-Wallis test. Dunn's multiple comparisons 
test was used to compare groups whenever a difference was detected. Treatment 
comparisons were tested at a 1.67% level (Bonferroni comparison). Statistical 
significance (p-value) was assessed by means of a two-tailed test in all instances; values 
below 0.05 were considered statistically significant. Statistical analysis was performed 
using O IBM SPSS Statistics, version 22. 
1. Murphy GS, Szokol JW, Greenberg SB, Avram MJ, Vender JS, Nisman M, 
Vaughn J. Preoperative dexamethasone enhances quality of recovery after 


laparoscopic cholecystectomy: effect on in-hospital and postdischarge recovery 
outcomes. Anesthesiology 2011; 114: 882-90. 
2. Myles PS, Weitkamp B, Jones K, Melick J, Hensen S. Vality and reliability of a 
postoperative quality of recovery score: the QoR-40. Br J Anaesth. 2000; 84:11-15. 
3. Castro-Alves LJS, de Azevedo VFL, Braga TFF, Gonçalves AC, de Oliveira GS. 
The effect of neuroaxial versus general anesthesia techniques on postoperative 
quality and analgesia after abdominal hysterectomy: a prospective, randomized, 
controlled trial. Anesth Analg 2011; 113: 1480-6