Tuesday, September 26, 2017
Lorazepam, Haloperidol, and Delirium
by Drew Rosielle
JAMA Internal Medicine has published a double-blind, randomized, placebo-controlled trial of adding lorazepam to haloperidol in patients with advanced cancer and agitated delirium. (We had a heads up about this trial because it was presented at ASCO earlier this year.) If there ever was a sort of consensus in HPM about how we should be treating delirium, my sense is that it’s been shattered by the recent RCT of low-dose haloperidol vs risperidone for delirium in Australian palliative care unit patients, showing those drugs worsened delirium symptoms. So, it seems like we should all see what we can learn from this newly published investigation.
JAMA Internal Medicine has published a double-blind, randomized, placebo-controlled trial of adding lorazepam to haloperidol in patients with advanced cancer and agitated delirium. (We had a heads up about this trial because it was presented at ASCO earlier this year.) If there ever was a sort of consensus in HPM about how we should be treating delirium, my sense is that it’s been shattered by the recent RCT of low-dose haloperidol vs risperidone for delirium in Australian palliative care unit patients, showing those drugs worsened delirium symptoms. So, it seems like we should all see what we can learn from this newly published investigation.
The authors note that to be best of their knowledge there
has never been a RCT involving a benzodiazepine compared with placebo for
delirium. The one kind of famous (if you are a delirium geek) trial which
looked at benzos, which was the trial I was directed to when I asked why not benzos for delirium when I was
training, involving a 3-way
comparison of lorazepam, haloperidol, and chlorpromazine for delirium in
hospitalized patients with AIDS, and registered 6 (!) patients in the
delirium arm (lorazepam patients did worse). It had no placebo arm.
In fact, there is a lack of high quality drug trials in the
delirium world which involve genuine placebo arms, ie, an arm in which there
was no active pharmacologic treatment. I have wondered if we’ve made a huge
mistake by doing trials which assumed haloperidol was the standard of care,
without robust data to actually support that, and so have just done comparison
trials of haloperidol with other agents, or like this study, a benzo or placebo
added to haloperidol, when then underlying question, does haloperidol or other antipsychotics actually help (compared with
placebo) remains open. See for instance this recent
review for a nice summary of what’s out there (noting that this even predated
the damning low-dose haloperidol/risperidone/placebo trial): it’s not
convincing, it’s not the sort of
thing you’d read and say the book is
closed on this question, we can no
longer have equipoise about comparing antipsychotics to placebo in delirium
trials.
I was going to get to this point later in the blog post, but
I realize I’m already there, so I’ll say it now: delirium is an international
health crisis, it is real, it can be devastating (lead to permanent cognitive
changes), leads to far worse outcomes for our patients (longer hospital stays,
not being discharged home), costs billions of dollars, sucks shit for the
patients and families going through it, and we don’t have a real inkling about
actual, effective drug treatment for it. There are some inklings about
chemoprophylaxis, but nothing definitive. Multidimensional prevention programs
seem good, I like those, I’m 100% for those, but we need a lot more. If we can
do a bloody RCT of
simvastatin for chemoprophylaxis of delirium, surely we can do large,
multicenter, patient-diverse (dementia, surgical patients, ICU patients,
advanced cancer patients, dying patients), high quality, placebo-controlled
trials of a variety of drugs, drug-classes – especially testing the ones people
are actually using, and dosing strategies to see if there are any effective
disease-modifying agents out there!
Which is why I’m just delighted our friends at MD Anderson
did this study as it was well-done, although small, and adds to our
understanding.
The subjects (N~60) were patients at MD Anderson’s
palliative care unit; all had advanced cancer, and all had agitated delirium
(RASS score of 2 or more; it looks like they changed the protocol to 1 or more
mid-study – there’s a lengthy supplement involving the protocol changes). All
had received haloperidol as a primary treatment for delirium – it looks like
they used a protocol of 2 mg IV q4h scheduled + 2 mg IV q1h as needed. The
patients were followed with q2 hourly RASS assessments and then received 3mg IV
lorazepam or placebo if they continued to have an agitated RASS (mean RASS
score prior to being the study drug was 1.6). Importantly, the patients also received a 2 mg prn dose of haloperidol
as well regardless of which group they were assigned too. Of note, all the
patients studied had delirium for at least 2 days prior to enrollment – these were
patients with persistent delirium who didn’t get better quickly after routine
interventions. After enrollment the median observation time was 6.4 h (after a
median of 6.4 h, the patients had an agitation episode leading to being given
the study drug). Median haloperidol doses prior to receiving the study drug
were 5-7 mg in the prior 24h.
The primary outcome was RASS score 8 h after the single dose
of study drug.
The results are fascinating as hell. To begin with,
lorazepam looks really, really good when you are looking simply at the primary
outcome of reduction in the RASS score. The RASS score went down rapidly as you’d
expect – it was markedly lower in the lorazepam group by half an hour – and remained
markedly lower than the placebo group at hour 8: -2.5 for lorazepam, -0.5 for
the placebo group (all this was very statistically significant by all the usual
tests). Of note, -2 on the RASS is light sedation (briefly awakens with eye
contact to voice, but less than 10 seconds); -3 is movement or eye opening to
voice but no eye contact.
Ie, these patients were pretty sedated, and much more so than
the haloperidol/placebo-only patients.
One may also observe that the placebo patients having a RASS
of -0.5 at 8 h means the median state of the placebo patients at 8 hours was
something between ‘alert & calm’ and ‘mildly drowsy.’
Got that? While the RASS was a lot lower in lorazepam, the
placebo patients’ median RASS could be considered, in fact, a really good outcome, and arguably, a better outcome, than the lorazepam
group.
Of course, the reality is much more complicated than that
(most delirious patients just don’t go back to normal and stay there), but it’s
a good reminder that when using something like the RASS as an outcome, lower is
not necessarily better: 0 is normal, and for many patients would be the most
desirable outcome. (Notably, the authors address all this explicitly in their
discussion.)
Figure 2b in the study is probably more helpful in
understanding what happened to these patients than the actual primary outcome
graph. What you can see is that at 8 h, in the lorazepam group, basically half
the patients were deeply sedated (RASS -3 or less), and half were mildly
sedated. In the placebo group, about a third
were agitated, and the most of the rest in the mildly to moderately sedated
range. If you want, you can actually see what happened to individual patients
in the supplement online.
In the secondary findings, they note that many more nurses
and caregivers in the lorazepam group than the placebo group judged the patient
to be comfortable after the study drug was administered (~80 vs ~30%). The lorazepam
group also had fewer ongoing doses of rescue medicines also. Median survival
for both groups was ~70 h. I.e., you can
essentially understand this to be a study of patients with terminal delirium.
What does all this mean?
It means that lorazepam effectively and rapidly sedates people,
better than haloperidol, at the doses studied.
We’ve discussed this on the blog a little before, but this
study helps us think about delirium and delirium outcomes better - what outcome
we are actually aiming for in these patients. As I implied in the opening
discussion of this blog post, I myself am at a point at which I do not consider
there to be any active, disease-modifying drug treatment for delirium that I
can get behind. By disease-modifying I mean drugs which would return patients
to a more normal state of consciousness (i.e. push people closer to 0 on the
RASS), and/or reduce the duration of delirium, and/or its long-term adverse
outcomes. I think there is hope for antipsychotics, especially used in higher
doses than the Australian study, but I don’t think there are any available data
which convince me these should be a routine part of our care for delirious
patients. We need well-powered, meticulously designed, placebo-controlled, and
multi-institutional studies of haloperidol/other antipsychotics.
Until then, it’s just hope, and I honestly don’t know what
to do.
I want to be clear, though – with the above I am talking
about disease-modifying treatments
for delirium. We clearly have, however, rapid & effective ways for reducing
the distressing behaviors of agitation by
sedating patients.
And I think it’s important that we keep in mind there is a
difference between these two goals (sedation vs disease-modification). For our
patients near the end of life sedation is often appropriate & acceptable. For
some of our patients and their families it is in fact desirable - as this study
showed, caregivers as a whole really preferred the moderately to deeply sedated
state lorazepam gave these agitated, dying patients. It’s what I would want for
myself, or my close loved ones, when close to death.
Sedation however is just not a ‘treatment for delirium,’ in
the way that I used to hope low-dose haloperidol was.
Lorazepam has had a bad rap for ‘delirium’ historically. All
of us have seen patients become agitated after getting it. Undoubtedly it is a
common cause of delirium in
hospitalized patients. While I don’t have any data to support this claim, I
think much of the bad rap comes from patients who were given small doses of
lorazepam, anxiolytic doses, leading to confusion and disinhibition. They weren’t
given sedating doses of lorazepam, which is not a hard thing to do, and quite
predictably sedates most people. To me, what this study does is help clarify
that lorazepam very much does have a role in agitated delirium in patients near
the end of life, when the immediate therapeutic goal is sedation. When we do
it, however, we should do it right, and use the 3 mg dose like they did in this
study, after of course clarifying prognosis and treatment goals with appropriate
surrogates.