Question 1: We already
prescribe paracetamol/acetaminophen to our patients with acute stroke; so why do a trial?
Answer: What we do now probably does not work at all.
The usual daily dose of paracetamol (4 g daily), does not seem to lower body
temperature in normothermic patients with acute stroke in any appreciable
amount. It is unlikely that treatment started after 12 hours will benefit your
patients. We therefore need a trial that establishes whether high dose
paracetamol (6g daily) started within 12 hours from onset of symptoms, improves
outcome in patients with acute stroke. The results of such a trial would change
current practice.
Question 2: Is it ethical to
have a placebo arm in this trial?
Answer: PAIS has been designed to find out whether
paracetamol in a higher dose than usual (i.e. 6 g daily) improves outcome in patients with
acute stroke. Lower doses than 6, given later than 12 hours after onset of symptoms are
not likely to improve outcome at all. High doses of paracetamol carry a risk of masking
fever and infections, and a small risk of hepatic complications.
Because we simply do not know whether this treatment
improves outcome in patients with acute stroke, a placebo controlled trial can be
considered ethical. This was also the opinion of the central medical ethics committee of
the University Medical Center in Utrecht, who approved of the study protocol.
Question 3: What if my patient
really develops a fever, with body temperature exceeding 38.5ºC, what should I do?
Answer: When you think that your patient's fever needs to
be treated symptomatically, you should do as you please. When you consider giving
non-study paracetamol, the study medication should be stopped. Note however, that the
effect of treating fever on outcome in general is unknown.
Question 4: Is it safe to
administer 6000 mg paracetamol daily?
Answer: The main safety concern with paracetamol
(acetaminophen) is the risk of damage to the liver. In the two phase II studies
of high dose paracetamol we conducted (PAPAS & PISA) liver failure did not
occur, and transient increases in transaminases were just as common in patients
taking placebo or low dose paracetamol.Nevertheless, because of this concern,
chronic liver disease and alcoholism
are exclusion criteria. We recommend that at least ASAT, ALAT, AF bilirubin are measured
at baseline, and that the study medication be stopped when levels exceed two times the
upper limit of normal.