Short summary

The objective of this double-blinded RCT study is to investigate the association between single dose clonidine administration (3mcg/kg) prior to limb tourniquet inflation and the total amount of opioid (mcg/kg) administered peri-operatively, during recovery and 24 hours postoperatively (first outcome). This study is a pilot to obtain an effect size. Based on this we 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.

Rationale

Surgical tourniquets - usage and related complications

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. The underlying pathophysiology might relate to vascular endothelial dysfunction and decreased endothelial dilatation following ischemia-reperfusion-injury (IRI). IRI is caused by blood supply returning to tissue after a period of ischemia or lack of oxygen (anoxia or hypoxia). IRI involves a complex cascade of responses and local inflammation resulting in swelling and pain. Pain related to use of surgical tourniquets In infants and children, surgical procedures are performed under general anaesthesia (GA), comprising standard analgesics and anaesthesia 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.

Clonidine - a substance to alleviate tourniquet-pain?

Many interventions and different medications have been tried in order to improve postoperative analgesia in paediatric 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.(9) In several studies clonidine administered orally or rectally before anaesthesia 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 paediatric ADHD patients Tourette's syndrome and stuttering. The efficacy of clonidine in these conditions has not been demonstrated. Clonidine affects several areas of the nervous system. Clonidine causes central hypotensive and anti-arrhythmogenic effects. The stimulation of alpha-2 adrenoceptors in the locus coeruleus may be responsible for the hypnotic effects of clonidine as this region of the brain helps regulate wakefulness. Clonidine can also decrease transmission of pain signals at the spine. Finally, clonidine can affect regulators of blood pressure in the ventromedial and rostral-ventrolateral areas of the medulla.

Clonidine side effects and drug interactions Along with its beneficial effects, clonidine may cause some unwanted effects. These are described mainly after the use of daily oral dosages for treatment of neurological diseases (e.g. Tourette's syndrome). Those effects comprise

• drowsiness

• lightheadedness

• dizziness

• headache

• dry mouth

• nausea (upset stomach)

• vomiting (throwing up) (common) and

• tiredness

• weakness

• constipation (hard stools)

• diarrhea (loose stools)

• dry eyes

• blurred vision

• nightmares (occasional)

Since clonidine overall reduces the central nervous system sympathetic outflow, clonidine may decrease blood pressure and lower pulse rate. Hence, if antihypertensive or arrythmogenic medications are taken, the additive intake of clonidine might result in bradycardia and hypotension. Equally to every medication, clonidine might provoke signs of an allergic reaction to clonidine: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Study medication and -dose

Clonidine is a taste- and smell less fluid, completely opaque. Although clonidine has been widely studied in the paediatric population, the main outcome of investigations has been ED. 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 we chose to administer 3mcg/kg bodyweight as a single bolus in our current study.

Pharmacodynamic properties

Clonidine acts by reducing sympathetic outflow and decreases peripheral and renal vascular resistance, heart rate and blood pressure. Renal blood flow and glomerular filtration rate remain essentially unchanged. Normal postural reflexes are intact and therefore orthostatic symptoms are mild and infrequent. Slowing of the pulse has been observed in most patients given clonidine, but the drug does not alter normal haemodynamic response to exercise.

Pharmacokinetic properties

The pharmacokinetics of clonidine is dose proportional in the range of 100-600 micrograms. Clonidine is well absorbed and no first pass effect exists. It is rapidly and extensively distributed into tissues and crosses the blood-brain barrier as well as the placental barrier. The plasma protein binding is 30-40%. The mean plasma half-life of clonidine is 13 hours ranging between 10 and 20 hours.

We hypothesize that administration of clonidine to paediatric patients undergoing limb surgery with the use of inflatable tourniquets (TQ) would reduce post-procedural pain.

The objective of the study is to investigate the association between single dose clonidine administration (3mcg/kg) prior to limb TQ inflation and the total amount of opioid (mcg/kg) administered peri-operatively (from induction to extubation) during recovery and 24 hours postoperatively (first outcome).

This study is a pilot to obtain an effect size. Based on this we 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.

Primary outcomes

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).

Secondary outcomes

• 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)

• 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)

• Total time-at-recovery (TREC-total)

• Maximal pain during recovery assessed by FLACC* and VAS* score

• Occurrence of ED** assessed by PAED*** scale

*FLACC score if age <6 yrs, VAS if age > 6 yrs

**Emergence delirium

***Paediatric Anaesthesia Emergence Delirium

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

Description of the cohort

Children < 15 yrs and classified according to American Society of Anesthesiologists (ASA) I + II scheduled for elective lower or upper extremity surgery in GA with planned use of tourniquet will be included.

Inclusion criteria

• Children age 0 - <15 years

• ASA I + II

• Scheduled for GA and planned for relevant surgical procedure

• Planned use of surgical tourniquet on upper and/or lower extremity

Exclusion criteria

• parental consent missing

• ASA-classification >2

• 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

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.

Parents will be informed prior to surgery. If informed consent is granted, children will be randomized to either intervention or control. Participation in the study expires at T24 (= 24hours after end-of-incision-time). Each participant will be included in the study from anaesthesia induction to T24.

Data and biological material

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 (Ambu® 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 clonidine ("Clonidin-ratiopharm® Ampullen", 150 micrograms in 1ml, ratiopharm GmbH, Ulm, Germany) (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 and application of relevant splint, brace or cast as decided by the surgeon, 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 or discharged from hospital in case of ambulatory surgery 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.

Collaborating researchers and departments

Orthopaedic Research Unit

Dept. of Orthopaedic Surgery and Traumatology

• Karina Liv hansen
• Uggi Balle
• Julie Ladeby Eriksen

OPEN, Open Patient data Explorative Network, Odense University Hospital, Region of Southern Denmark