Once written informed consent has been obtained for the patient to participate in the trial the patient will be randomised to treatment with haloperidol or placebo. All members of the research team will be blinded to whether a patient is allocated to receive haloperidol or placebo. Patients will be randomised in the operating theatre post anaesthetic care unit (PACU) – the “recovery area” – a qualified member of the theatre recovery staff using a secure internet programme. This will be provided by Sealed Envelope Company -www.sealedenvelope.com. This is a fully audited internet service, which allows real-time access and unblinding if required. The randomisation log will be maintained in the PACU where study drugs are kept and stored in a locked cupboard.
3.9 Trial procedures
Active ingredient: Haloperidol
Trade name: Haloperidol
Excipient:: Lactic acid, sodium hydroxide and water for injections.
Container: Clear glass ampoules
Pharmaceutical form: Sterile injection
Manufacturer: Janssen Pharmaceutica
3.9.2 Control (placebo) treatment
Name: Sodium Chloride injection BP 0.9%
Concentration: 9 mg/ml
Container: Clear plastic ampoules
Pharmaceutical form: Sterile injection
3.9.3 Treatment preparation and supply
Study drugs will be prepared in PACU, which is in close proximity, but separate from the ICU. Once a patient has been enrolled in the trial and allocated a study number the PACU nurse in charge will be informed. The patient will be then allocated to receive haloperidol 2.5mgs 8 hourly or placebo 0.5 mls 0.9% saline according to the randomisation programme. No one on the study team will have access to this information. The randomisation will be recorded in the study allocation logbook. The drug will be ordered on the prescription chart as HOPE study drug to be given at 8am, 16.00 and midnight.
Boxes of haloperidol 5mgs/ml and saline 0.9% ampoules will be kept in and identified as HOPE study drugs in a separate locked drug cupboard on PACU. The ICU pharmacist will supply and replace these as necessary. The use and replacement of boxes will be recorded in the study allocation logbook and accountability kept in the same locked cupboard.
All the nurses who prepare and administer the study drugs will have been passed as competent for intravenous drug handling. When the study drug is due the prescription chart will be brought from ICU to PACU. The ampoule of the study drug according to randomisation will be then be checked by the 2 nurses or 1 nurse and an anaesthetist for name of drug and expiry date. The drug will be immediately drawn up using sterile precautions, labelled with a HOPE study label identifying the patient by name, date of birth, hospital number and study number. The same nurse will then immediately bring the capped syringe to the ICU patient. No clinicians working on the ICU or on the study team will be involved in the preparation of the blinded syringe. At the bedside the nurse who prepared the drug and ICU nurse responsible for that patient will then check the patient’s wrist label against the prescription chart and the syringe label. Using sterile precautions the nurse who prepared the drug will then administer the study drug as a slow intravenous injection, 1-2 minutes followed by a saline flush and initial as given on prescription chart. This will be documented in a separate study drug administration book kept in ICU and the study drug accountability form stored securely in the PACU where study drugs are prepared with the randomisation log and study drugs.
This process will be repeated for each individual trial patient.
3.9.5 Treatment reduction
If a patient is oversedated first all sedatives and analgesics should be stopped until the patient reaches target sedation goal and then restarted at half the rate according to routine practice. The study drug will be continued.
If patient is still oversedated 24 hours later, then the study drug dose will stopped until the patient reaches the target sedation score. If the patient still screens positive for delirium the study drug will be restarted at half the dose – 1.25 mgs haloperidol or 0.25 mls 0.9% saline placebo, same frequency.
If the patient is not on sedatives or analgesics the study drug will be stopped until the patient reaches target sedation score. If the patient still screens positive for delirium the study drug will be restarted at half the dose, same frequency.
Dystonia is non-life threatening and a typically transient and dose related extrapyramidal symptom of antipsychotics. If a patient develops extrapyramidal symptoms including dystonia and scores less than 3 points on three or more categories of the modified Simpson-Angus scale the study drug will be halved. If it persists or the patient requires symptomatic treatment (procyclidine or equivalent) the study drug will be terminated
The attending clinician can decide to halve the dose of study drug on safety grounds e.g. hypotension, akathisia.
Treatment termination is defined as discontinuing the trial drug without intention to restart the drug at a later date. Trial drug will be terminated in the following circumstances:
Oversedation despite stopping additional sedative and analgesic drugs and halving the study drug dose.
Development of QTc > 500 msecs
Score of 3 points or more on three or more categories of the modified Simpson-Angus scale.
Discharge from the ICU
Discontinuation of active treatment
Request to withdraw from PerLR or patient
Decision by attending clinician that the drug should be stopped on safety grounds.
14 days after randomisation