EVITA study - RHC Glasgow Clinical SOP

EVITA uses a deferred consent process.

Deferred consent is an ethically approved approach commonly used in emergency research settings where participation in a time-sensitive clinical trial may need to begin before informed consent can be obtained from a parent, guardian, or patient.

As the medications used within EVITA are not experimental, this approach allows children and their families to focus on their immediate medical care during an emergency situation.

The deferred consent process has been approved by a Research Ethics Committee following consultation with parent and carers study group.

A member of the research team will approach families as soon as it is considered appropriate to discuss the study in full and seek informed consent for ongoing participation.

If you have any questions, please contact the Paediatric Research Team between 07:30 and 16:30:

• Nurse Hazel McPhail // hazel.mcphail@nhs.scot

• Nurse Louise Mutch // louise.mutch2@nhs.scot

• Dr Jen McKechnie // Jennifer.McKechnie2@nhs.scot

• Dr Ivory Huang // ivory.huang2@nhs.scot

Tel: 0141 232 7600 (87600)

or

Study PI - Dr Steve Foster // Steven.Foster@nhs.scot
Tel: 0141 452 4603

As part of the deferred consent model, there should be no approach of the participant or parent/guardian about the trial before the patient is randomised unless they specifically request information on the trial.

Posters are displayed within the ED / CDU common waiting areas / corridors / treatment areas. If the patient or parent/care has seen some information about the trial within the waiting room and asks about the EVITA study then the participant or parent/guardian should be given a copy of the summary leaflet.

Trial summary leaflets are available in ED / CDU / 2C in a green study folder that the CRF have created and are using to support nurse education in these areas. They can also be accessed and printed from this link – EVITA study Summary Participant Leaflet.

These summaries do not replace the main trial PIS that will be used by the CRF at time of written consent.

If the patient or patient family ask about the EVITA study then it is important to be honest and transparent, and the following guidance narrative is suggested:

Continuous ECG and saturation monitoring is necessary for patients on IV Magnesium Sulphate / IV Aminophylline / IV Salbutamol infusions.

• Standard clinical observations should be recorded on PEWS chart every 5 minutes for the first 15 mins and if improving then at 15 minutely intervals for the first hour after infusion commencing.

• Observations, including BP should be recorded hourly until the patient is felt to be improving.

• CBG /VBG should be repeated as clinically indicated.

• U&Es should be conducted a minimum of every 12 hours for patients on IV infusions.

Possible Side Effects of Intravenous Aminophylline

• Muscle tremors

• Tachycardia and palpitations

• Nausea and vomiting

• Agitation

• High doses can cause peripheral vasodilatation which can result in hypotension.

Possible Side Effects of Intravenous Salbutamol

• Hypokalaemia

• Hyperglycaemia - Concurrent administration of corticosteroids can exaggerate this effect.

• Lactic acidosis

• Muscle tremors and cramps

• Headache

• Hyperactivity

• Tachycardia and palpitations

• Nausea and vomiting

• Agitation

• High doses can cause peripheral vasodilatation which can result in hypotension.

MAGNESIUM SULPHATE (MgSO4)

Drug dose: 
The dose is 40mg/kg or 0.16mmols/kg (max. 2 grams)

Drug Preparation:
Draw up 0.08mls/kg 50% Magnesium Sulphate (40mg/kg) and dilute to 50mls with 0.9% saline
Run over 20-30 minutes. 

This cannot be run concurrently in the same IV cannula as IV AMINOPHYLLINE or SALBUTAMOL.  These can be given through the same IV cannula AFTER completion of MgSO4 following a suitable flush.  A separate IV cannula will need to be sited to run multiple IV therapies concurrently.

IV AMINOPHYLLINE

Drug dose:
The LOADING dose of aminophylline is 5mg/kg  (5mls/kg of 1mg/ml solution) over 20 minutes (Maximum dose 500mg).

Aminophylline LOADING should be prescribed using actual body weight unless patient is obese then use ideal body weight 

Drug preparation:
Add 20mls of aminophylline 25mg/ml to 480mls of 0.9% sodium chloride to give a concentration of 1mg/ml.

Aminophylline is compatible with I.V. fluids which contain potassium; maintenance I.V. fluids can be connected via a y-connector.

INFUSION Dose:  ideal body weight for height (See BNFc for guidance chart). 

Age 2-<12yrs – 1mg/kg/hr = 1ml/kg/hr
Age >12 years – 0.5mg/kg/hr = 0.5ml/kg/hr

Drug preparation:  As per loading dose drug preparation above.

IV SALBUTAMOL

Salbutamol for injection comes in 2 concentrations: 
500 micrograms in 1ml or 5mg in 5ml (1mg/ml). 
Use the correct concentration for LOADING and INFUSION dosing.

The LOADING dose of salbutamol is 15 micrograms/kg  (maximum 250 micrograms) slow injection over 5-10 minutes.

Drug Preparation:
Use 500 micrograms in 1ml concentration for LOADING preparation

For intravenous injection dilute to a concentration of 50microgram/ml with 0.9% NaCl by adding 9mls to 1ml of 500microgram/ml salbutamol injection

Example:
For any child over 16kgs then loading dose is maximum 250 micrograms

15kg child – LOADING dose = 15 x15mg = 225micrograms – Solution diluted to 50microgram/ml. Give the 4. 5mls final solution over 5-10 minutes

The INFUSION dose for salbutamol for the EVITA trial is 1micrograms/kg/min to a maximum of 20mcg/min. 

Drug Preparation:
Use 5mg in 5ml (1mg/ml) concentration for INFUSION preparation
Dilute to a concentration of 200micrograms per ml with 0.9% saline (add 40mls of 0.9% saline to 10mls of salbutamol 5mg/5ml to give 10mg (10,000micrograms) in 50mls)

Example:
20kg child – infusion dose is 1microgram/kg/min  = 20microgram/min
Solution is 200microgram/ml – 20/200 =0.1. Run infusion at 0.1 mls/min (6mls/hr)

IV SALBUTAMOL CANNOT BE RUN CONCURRENTLY WITH IV AMINOPHYLLINE OR MAGNESIUM SULPHATE. SEPARATE CANNULAS MUST BE SITED TO RUN MULTIPLE IV THERAPIES CONCURRENTLY

EVITA STUDY - CLINICAL REVIEW REQUIREMENTS PROFORMA should be completed for all recruited patients and remain with the clinical notes. This is available in the EVITA folder or can be printed from this hyperlink.

After starting an intravenous infusion the child should be reviewed (by physician or ANP) a minimum of every 30 minutes for the first 2 hours and as clinically indicated thereafter.

The following should be recorded in medical notes with each review:

• Conscious Level.

• Oxygen saturations and oxygen requirement in litres/minute.
  Significant hypoxia (SpO₂ <92%, or significant oxygen requirement >6l/min to maintain normal oxygen saturation) is indicative of severe asthma.

• Heart rate– Compare to normal range for age.
  Increasing tachycardia can denote worsening asthma but remember that B2-agonists increase heart rate. 
  In life-threatening asthma a drop in heart rate can be a pre-terminal sign

• Respiratory Rate– Compare to normal range for age.

• Blood Pressure

• Posture / position of patient.

• Ability to talk in words, phrases or sentences

• Degree of Respiratory Distress / Use of accessory muscle and recession

  • None / Mild / Moderate / Severe

• Air entry- including any clinical suspicion of pneumothorax or significant collapse and amount of wheezing including biphasic or silent chest.

• Wheeze

  • None / Expiratory only / Inspiratory and expiratory / Heard without stethoscope or silent chest

• Overall assessment of asthma severity:

  • Mild / Moderate / Acute severe / Life threatening (see chart below)

• Clinical plan detailing ongoing care – for example: Continue / escalation in care / de-escalation in care and reasoning behind this decision.

For the study the assessments above require to be conducted at the following time points from randomisation time: 

1. IV Magnesium Sulphate arm

At clinical review after the completion of the IV Magnesium Sulphate infusion, if the treating clinician feels the patient meets the criteria for further escalation in care for acute wheeze, then the indications should be clearly documented in the patient’s notes.

The clinician should then follow the existing RHCG guidelines which identifies IV Aminophylline as the next step– Acute wheeze: escalation to intravenous therapy for Acute Wheeze Integrated Care Pathway (ICP) for patients over 2 years old

At clinical review after the completion of the IV Magnesium Sulphate infusion if the treating clinician feels the patient has improved then this should be clearly documented in the patient’s notes and further management of the acute wheeze should continue with inhaled bronchodilators as per current RHCG practice.

2. IV Aminophylline arm

At clinical review during the infusion of the IV Aminophylline, if the treating clinician feels the patient meets the criteria for further escalation in care for acute wheeze, then the indications should be clearly documented in the patient’s notes. 

A second IV cannula should be sited and a bolus of IV Magnesium Sulphate should be given as per the existing RHCG guidelines (Acute wheeze: escalation to intravenous therapy for Acute Wheeze Integrated Care Pathway (ICP) for patients over 2 years old). 
This is in addition to the continuation of the IV Aminophylline infusion.
IV Magnesium Sulphate cannot be run concurrently in the same IV cannula as IV AMINOPHYLLINE or SALBUTAMOL.
These can be given through the same IV cannula AFTER completion of MgSO4 following a suitable flush.
A separate IV cannula is needed to run multiple IV therapies concurrently.

At clinical review after the completion of the IV Magnesium Sulphate infusion, the treating clinician feels the patient meets the criteria for yet further escalation in care for acute wheeze, then the clinician should refer to the existing RHCG guidelines (Acute wheeze: escalation to intravenous therapy for Acute Wheeze Integrated Care Pathway (ICP) for patients over 2 years old) and follow the guidance on commencing IV Salbutamol bolus and infusion. The treating consultant should be requested to attend the patient AND urgent PICU review requested.

At clinical review during the infusion of the IV Aminophylline if the treating clinician feels the patient has improved then this should be clearly documented in the patient’s notes and further management of the acute wheeze should continue as per the existing RHCG guidelines including de-escalation of care guidance.

3. IV Salbutamol arm

At clinical review during the infusion of the IV Salbutamol, if the treating clinician feels the patient meets the criteria for further escalation in care for acute wheeze, then the indications should be clearly documented in the patient’s notes.

• For patient  LESS than 20kg in weight:

  1. Increase IV Salbutamol infusion to maximum of 2mcg/kg/min. 

  2. If after infusion dose increase, the clinician feels the patient meets further criteria for yet further escalation then a second IV cannula should be sited and a bolus of IV Magnesium Sulphate should be given as per the existing RHCG guidelines (Acute wheeze: escalation to intravenous therapy for Acute Wheeze Integrated Care Pathway (ICP) for patients over 2 years old). 
     This is in addition to the continuation of the IV Salbutamol infusion. 
     The treating consultant should be informed AND PICU review requested.

• For patient EQUAL OR MORE than 20kg in weight (on max 20 mcg/min infusion):

  1. Increase IV Salbutamol infusion to 1mcg/kg/min. 

  2. If after initial infusion dose increase, the clinician feels the patient meets further criteria for yet further escalation then increase salbutamol infusion dose to MAXIMUM 2mcg/kg/min.
     The treating consultant should be informed AND PICU review requested.

  3. If after further infusion dose increase, the clinician feels the patient meets further criteria for yet further escalation a second IV cannula should be sited and a bolus of IV Magnesium Sulphate should be given as per the existing RHCG guidelines (Acute wheeze: escalation to intravenous therapy for Acute Wheeze Integrated Care Pathway (ICP) for patients over 2 years old). 
     This is in addition to the continuation of the IV Salbutamol infusion. 

At clinical review during the infusion of the IV Salbutamol if the treating clinician feels the patient has improved then this should be clearly documented in the patient’s notes and further management of the acute wheeze should continue as per the existing RHCG guidelines including de-escalation of care guidance.

Remember that if a child is improving care can be de-escalated at any time

The half-life of IV AMINOPHYLLINE is on average 7-9 hours but is often shorter in younger children and can be longer in patients with hepatic impairment.

The half-life of IV SALBUTAMOL is 4-6 hrs.

Criteria for reducing IV infusions used for acute severe asthma / wheeze:

• Normal ability to speak

• No increase in respiratory effort

• Reduction in oxygen requirement

• Significant improvement in peak flow (if applicable)

• Rate should be halved and reviewed again for discontinuation after 6 hours
  Some patients may require a slower reduction and rate should then be halved every 9-12 hours.

• The decision to reduce and discontinue the infusion should be clearly documented in the notes. The change in rate and discontinuation of infusion needs to be documented (with timing) on the infusion chart.

Rebound bronchospasm can occur as the infusion is reduced and stopped.
Nebulised salbutamol and ipatropium bromide should be continued during this process - consider 2 hourly nebulised salbutamol.

Patients who have required intravenous therapy for wheeze should be monitored in hospital for at least 24 hours post the discontinuation of all intravenous therapy.