Clonidine for Tourniquet-related Pain in Children (CLOTCH)

September 7, 2021 updated by: Nicola Groes Clausen, Odense University Hospital

Clonidine for Tourniquet-related Pain in Children: A Pilot Study

This study is designed as a randomized, placebo-controlled, double-blinded, clinical trial with two parallel groups.

This study investigates the association between a single dose of the drug, Clonidine, and the total amount of opioid administered under and 24 hours after surgery in children undergoing orthopedic limb surgery with the use of tourniquet.

The investigators hypothesize that administration of clonidine to children undergoing limb surgery with the use of inflatable tourniquets would reduce post-procedural pain.

This study is a pilot to obtain an effect size. Based on this the investigators will calculate a sample size for the main trial enabling us to reach a power of 0.8 with a significans level of 0.05.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Pediatric upper and lower limb surgery often requires fine tissue handling. The prevention of blood flow to a limb allows surgical procedures to be performed with improved accuracy, safety, and speed. Surgical tourniquets, compressing devices used to control venous and arterial circulation to an extremity, enable the surgeons to work in a bloodless operative field.

Tourniquet related complications comprise severe pain during and after the procedure.

In infants and children, surgical procedures are performed under general anaesthesia (GA), comprising standard analgesics and anesthesia maintenance drugs. If an inflatable tourniquet is used, supplementary opioid analgesics are often required to relieve postoperative pain. This clinical observation is in accordance with previously reported data. In adult patients, surgical extremity procedures requiring tourniquets are well known to be painful. As a consequence, infants and children are subjected to prolonged stays in the recovery department. Mobilization and referral to a more child friendly environment might be delayed.

Many interventions and different medications have been tried in order to improve postoperative analgesia in pediatric patients. Amongst these Clonidine, primarily an alpha-2 adrenoceptor agonist. Clonidine stimulates alpha-2 adrenoceptors in the brain stem, thus activating inhibitory neurons, resulting in reduced sympathetic outflow from the CNS.

In several studies' clonidine administered orally or rectally before anesthesia has shown to reduce opioid use and diminish level of pain. Additionally, clonidine reduces the occurrence of postoperative agitation. As an adjuvant to central or peripheral nerve blocks, clonidine effectively prolongs analgesia. The efficacy of clonidine has also been investigated in clinical studies with pediatric ADHD patients Tourette's syndrome and stuttering. The efficacy of Clonidine in these conditions has not been demonstrated.

Clonidine is a taste- and smell less fluid, completely opaque. Although clonidine has been widely studied in the pediatric population, the main outcome of investigations has been emergence delirium. In existing literature, the means of administration vary from intravenous, rectal, epidural or oral dosing. Intravenous single-bolus dosages range from 1.5 - 4 mcg/kg. One recent study included almost 400 patients and administered 3mcg/kg bodyweight without the occurrence of any severe events. Based on these results the investigators chose to administer 3mcg/kg bodyweight as a single bolus in our current study.

All outcomes are objective measures (mg/kg bodyweight, time endurance) or validated evaluation scales (FLACC/VAS score, PAED scale).

Morphine is widely used for postoperative pain relief, the intravenous administration being the most potent. However, morphine is known to have several side effects (prolonged sedation, nausea and vomiting, refusal of oral intake and concomitant dehydration) and may be dangerous for certain children, who experience serious respiratory depression. Hence, a reduction in total dose is crucial, especially after referral to the pediatric ward, where means of monitoring are reduced to intermittent observation and assessment of vital parameters (oxygen saturation by pulse oxymetri, heart rate and blood pressure) is only possible sporadically.

The same is true for pain and the assessment of pain using either FLACC or VAS scales.

Time-at-recovery should be held at a minimum of duration due to high turn-over in our operating facilities. Any unnecessary prolongation of recovery-time should hence be avoided.

Assessment of both primary and secondary outcomes are part of standard care and documentation of the conductance of anesthesia, recovery and post-recovery treatment at the pediatric ward. Hence, this information is readily available but will be registered in source-data sheets. After the individual participant has completed the study, the total amount of morphine administered at the pediatric ward from TREC-END to T24 will be registered by the study investigators.

Prior to any kind of scheduled surgery, patients are seen at the outpatient's clinics at the Department of Orthopedic Surgery. If the patient is less than 15 years of age and is planned for extremity surgery with the use of surgical tourniquet, the surgeon will hand out parental information material. Further, he/she will inquire, whether parents will give their accept to receive a phone call 1-3 days prior to the date of surgery. If parents approve, study investigators will contact the parents and inform them about the study.

If parents agree to study participation, a written consent form will be presented on the day of surgery by one of the study investigators for the parents to sign before induction of anesthesia. Electronic patient records will not be accessed before written consent to study participation has been granted.

All of inclusion- and exclusion criteria are readily available in every anamnesis form filled out in the electronic patient data instrument at Odense University Hospital. Since inclusion criteria comprise 'scheduled procedures', female study participants at fertile ages will hence not be pregnant, since pregnancy is a contraindication against elective/non-urgent surgery with concomitant GA.

On surgery day, children will be prepared according to departmental standard. This includes fasting for meals 6 hours and for watery drinks 1 hour prior to anaesthesia induction and premedication with sedatives at the discretion of the anaesthetist in charge. In order to reduce pre-induction anxiety, parental presence will be allowed and encouraged. Choice of inductional technique (mask or intravenous), choice of airway management device (oral tube (portex (Smiths Medical International Ltd. Bound, Kent, CT21 6JL, UK) or Ruesch (Teleflex Medical, Westmeath, Ireland)) or laryngeal mask (AmbuR AuraStraightTM, Ambu A/S, Ballerup, Denmark) and means of anaesthesia maintenance are according to anaesthetists' preference. After induction, children will receive one i.v. line (BD VenflonTM Pro, Becton Dickinson Infusion Therapy AB, Helsingborg, Sweden) and a bolus of fentanyl (Fentanyl B.Braun; B.Braun Melsungen AG, Melsungen, Tyskland) 3mcg/kg. Maintenance fluid (Ringer's Acetate, Fresenius Kabi AB, Uppsala, Sweden) will be infused at a rate of 10ml/kg the first hour and then reduced to 5ml/kg/h. Monitoring will comprise electrocardiogram (ecg), non-invasive blood pressure (NIBP), puls oxymetri, esohageal temperature (IntelliVue MP70; ViCare Medical, Birkerød, Denmark). Children will be mechanically ventilated by pressure controlled ventilation (Siesta I TS, DAMECA, Denmark) aiming at end tidal carbon dioxide (CO2) of 4.5-5.5kPa. Flow of inspiratory oxygen FiO2 will be set at 45%. Anaesthesia depth will be clinically observed and adjusted as needed. All children will receive paracetamol i.v. (Para15mg/kg after induction. As it is not departmental standard, children will not receive ondansetron or steroid for prophylaxis of post-operative nausea and vomiting (PONV).

Tourniquet will be positioned, and inflation pressure applied according to surgeons' choice. At the time of tourniquet insufflation, children will receive either an intravenous bolus of Catapressan (CatapresR Ampoules 150 micrograms in 1ml, Solution for injection, Boehringer Ingelheim Ltd., Berkshire, UK)(3mcg/kg) or an equal quantity of IV saline (Natriumklorid B.Braun 9mg/ml, B.Braun Melsungen AG, Melsungen, Tyskland). Fentanyl will be supplemented by the anaesthetist as needed according to clinical judgement.

After surgery, children will be awake extubated and transferred to recovery. In recovery, children will be observed and monitored as per departmental standard comprising pulsoxymetri and pain assessment using the FLACC score (<6yrs) and VAS score (>6 yrs). Presence of nausea and vomiting will be registered and treated as per departmental standard. Children will be transferred to the pediatric ward when appropriate, that is in compliance with standards. On the 1st postoperative day the total consumption of opioids 24 hours after transferral to recovery will be summed up.

Peri-anaesthetic data collection: vital parameters (pulse, mean arteria pressure in mmHg, oxygen saturation) will be recorded every 5 minutes. Total amounts in mg/kg of Propofol (intravenous maintenance) or end-tidal sevoflurane/desflurane recorded at time of incision- time of tourniquet inflation and desuflation. Level of tourniquet pressure and total time of insufflation (total-tourniquet-time) will be recorded in minutes. Total amounts of fentanyl (mcg/kg) and infused fluid (ml/kg) will be registered. Adverse events (desaturation <90%, bradycardia and hypotension according to European Pediatric Life Support (EPLS) reference values for age) will be registered.

Recovery: FLACC/VAS score will be recorded at arrival and discharge. If pain is present during recovery, scores will be registered before and after intervention. Total amount of analgesics will be registered. Occurrence of PONV will be registered as well as interventions undertaken against. Occurrence of emergency delirium will be registered. Time-to-discharge will be registered (in minutes).

Children will be transferred to the pediatric ward when appropriate, that is in compliance with standards. On the 1st postoperative day the total consumption of opioids 24 hours after transferral to recovery will be summed up.

The investigators chose the parallel-group design for the CLOTCH-Study. In accordance with ICH-GCP recommendations on statistical principles for clinical trials (E9), the primary analyses will be differences in primary and secondary outcomes adjusted for stratification variables (i.e. means of anaesthesia maintenance (TIVA or Inhalational), tourniquet-time and tourniquet pressure level, age groups <1year, 1-6years, >6years). The investigators will assess and report all outcomes as "intention-to-treat" analysis including all randomised children meeting the inclusion criteria and not fulfilling the exclusion criteria with a standing consent to participate. Complete case analysis will be carried out if the overall level of missing data is less than 5%. However, if exceeding the limit of 5% missing data and if Littles' test is statistically significant, multiple imputation will be used and considered the primary result of the trial to reduce bias from complete case analysis. Little's test tests the null hypothesis that the missing data is Missing Completely At Random (MCAR). A p-value of less than 0.05 is usually interpreted as being that the missing data is not MCAR (i.e. is either Missing At Random or non-ignorable). The investigators will present "worst-case" and "best-case" scenarios. p < 0.05 will be considered statistically significant. For each group, all children will be analysed for the primary outcome. For each primary and secondary outcome, the results and estimated effect sizes with 95% confidence interval will be provided. The investigators will exclude patients with major protocol violations defined as failure to receive the total drug dose. The investigators will carry out statistical analyses before revealing the code of allocation.

The trial offers benefits for the population, which the minor study participant represents. These comprise

  • Improved strategies for treatment of pain after use of surgical tourniquets for extremity surgery
  • Reduced anxiety and discomfort postoperatively due to reduced pain levels
  • Accelerated mobilization postoperatively - a major factor in order to prevent immobility related complications (pulmonary infections, obstipation)
  • Reduced-time-to-oral-intake, which is extremely important in all age groups, but crucial for infants, who have a high metabolism and hence are at high risk of complications due to anaerobic energy production.

Study Type

Interventional

Enrollment (Anticipated)

20

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Denmark
    • Fyn
      • Odense, Fyn, Denmark, 5000
        • Recruiting
        • Odense University Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

3 months to 15 years (CHILD)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • ASA I + II
  • Scheduled for GA and planned for relevant surgical procedure (according to table 1)
  • Planned use of surgical tourniquet on upper and/or lower extremity

Exclusion Criteria:

  • parental consent missing
  • ASA classification >II
  • Known diagnosis of QT-prolongation syndrome
  • known allergies to clonidine
  • known allergies or intolerance to morphine
  • daily use of pain killers
  • under treatment with antihypertensive and antiarrythmic medications
  • status of current or previous prematurity
  • planned for peripheral or central nerve block in addition to general anaesthesia

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: SUPPORTIVE_CARE
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: TRIPLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
PLACEBO_COMPARATOR: Control group
IV Saline (Natriumklorid B.Braun 9mg/ml, B.Braun Melsungen AG, Melsungen, Tyskland) in an equal quantity as the study drug is administered at tourniquet inflation
Other: Saline
controlgroup receiving saline
EXPERIMENTAL: Intervention group
Catapressan (CatapresR Ampoules 150 micrograms in 1ml, Solution for injection, Boehringer Ingelheim Ltd., Berkshire, UK)(3mcg/kg) is administered at tourniquet inflation
Drug: Catapresan
The intervention is either a single intravenous bolus of 3mcg/kg Catapresan (150mcg/1ml) or an equal amount of saline at the time of tourniquet inflation.
Other Names:
  • Clonidine

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Total morphine T24
Time Frame: Through time spent in the Post-Anaesthesia Care Unit (PACU), i.e. from end-of-incision time to time of transferal from PACU to the paediatric ward, maxium up to 24 hours
Total amount of i.v. morphine in milligram (mg) administered per kg bodyweight from end-of-incision-time (T0) through the first 24 hours postoperatively (T24).
Through time spent in the Post-Anaesthesia Care Unit (PACU), i.e. from end-of-incision time to time of transferal from PACU to the paediatric ward, maxium up to 24 hours

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Morphine recovery to transferal to pediatric ward
Time Frame: Through time spent at the paediatric ward, i.e. from time of transferal from PACU to the paediatric ward to time of discharge up to 24 hours after end-of-incision-time
Total amount of i.v. morphine in mg administered per kg bodyweight during recovery, i.e. from end-of-incision-time (T0) to time at transferal to the paediatric ward (TREC-END)
Through time spent at the paediatric ward, i.e. from time of transferal from PACU to the paediatric ward to time of discharge up to 24 hours after end-of-incision-time
Morphine at pediatric ward to T24
Time Frame: Through time spent in the Post-Anaesthesia Care Unit (PACU), i.e. from end-of-incision time to time of transferal from PACU to the paediatric ward, maximum up to 24 hours
Total amount of i.v. morphine in mg administered per kg bodyweight in the paediatric ward from time at transferal to the paediatric ward (TREC-END) until 24-hours after end-of-incision-time (T24)
Through time spent in the Post-Anaesthesia Care Unit (PACU), i.e. from end-of-incision time to time of transferal from PACU to the paediatric ward, maximum up to 24 hours
Total time at recovery
Time Frame: Through time spent in the Post-Anaesthesia Care Unit (PACU), i.e. from end-of-incision time to time of transferal from PACU to the paediatric ward, maximum up to 24 hours
The total time spent in recovery at PACU (TREC-total)
Through time spent in the Post-Anaesthesia Care Unit (PACU), i.e. from end-of-incision time to time of transferal from PACU to the paediatric ward, maximum up to 24 hours
Maximal pain
Time Frame: Through time spent in the Post-Anaesthesia Care Unit (PACU), i.e. from end-of-incision time to time of transferal from PACU to the paediatric ward, maximum up to 24 hours

For children between the ages of 2 months and 7 years, maximal pain during recovery at PACU will be assessed using the 'Face, Legs, Activity, Cry, Consolability' (FLACC) scale ranging from score 1-10.

For children above 7 years pain during recovery at PACU was assessed by a Visual Analog Score (VAS) also ranging from 1 to 10.
Through time spent in the Post-Anaesthesia Care Unit (PACU), i.e. from end-of-incision time to time of transferal from PACU to the paediatric ward, maximum up to 24 hours
Occurrence of emergence delirium(ED)
Time Frame: Through time spent in the Post-Anaesthesia Care Unit (PACU), i.e. from end-of-incision time to time of transferal from PACU to the paediatric ward, maximum up to 24 hours
Occurrence of ED assessed by Paediatric Anaesthesia Emergence Delirium (PAED) scale (1-5). 5 representing highest level of emergence delirium.
Through time spent in the Post-Anaesthesia Care Unit (PACU), i.e. from end-of-incision time to time of transferal from PACU to the paediatric ward, maximum up to 24 hours

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Odense University Hospital

Collaborators

Odense Patient Data Explorative Network

Investigators

  • Principal Investigator: Nicola G. Clausen, Ph.D., Department of Anaesthesiology and Intensive Care at Odense University Hospital
  • Study Director: Tom G. Hansen, Ph.D., Department of Anaesthesiology and Intensive Care at Odense University Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

March 1, 2021

Primary Completion (ANTICIPATED)

December 20, 2021

Study Completion (ANTICIPATED)

January 1, 2022

Study Registration Dates

First Submitted

May 25, 2020

First Submitted That Met QC Criteria

September 21, 2020

First Posted (ACTUAL)

September 25, 2020

Study Record Updates

Last Update Posted (ACTUAL)

September 10, 2021

Last Update Submitted That Met QC Criteria

September 7, 2021

Last Verified

September 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NC12547

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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