Cases & Commentaries

Don't Push

Commentary By Herbert Y. Meltzer, MD

The Case

A 37-year-old HIV-positive woman was brought to
the emergency room by her family because she had exhibited altered
mentation for 3 days. The patient had been diagnosed with HIV
infection 3 years earlier. Her opportunistic infections included
thrush and Pneumocystis carinii pneumonia (PCP). She had
never received highly active antiretroviral therapy (HAART).
Nevertheless, her lowest CD4 count was 560 and her viral load was
low. The patient did not have any significant past surgical or
psychiatric history. Medications on admission included only
trimethoprim/sulfamethoxazole [Bactrim] for PCP prophylaxis.

The patient’s mental status deteriorated
rapidly after admission: she tossed about on her bed and had visual
and auditory hallucinations. Per the hospital’s safety
protocol, the planned lumbar puncture was put on hold because of
her agitation. Neurology and psychiatry consultations were sought.
The psychiatry team recommended haloperidol administered via
intravenous (IV) push 5 mg every 20 minutes until sedation was
achieved, so that the neurologist and psychiatrist could evaluate
the patient. However, after 3 doses of haloperidol, the
patient’s face turned pale and she started gasping for air.
The patient was connected to a cardiac monitor on a crash cart,
which showed polymorphic ventricular tachycardia ("torsade de
pointes") (Figure).

The patient received IV magnesium sulfate
immediately. In the cardiac intensive care unit, she required
placement of a transvenous pacemaker. She was able to return to a
regular medical floor 1 day later, and her mental status improved
without any intervention over the subsequent week.

The Commentary

The almost fatal outcome in this case directly
resulted from treatment with high and frequent doses of
haloperidol, administered according to a commonly used critical
care protocol that calls for multiple, sometimes escalating doses
of the drug, at 15-20 minute intervals.(1,2) The issue here is whether such a protocol was
appropriate and whether it provides the best balance of
effectiveness and safety, given the large number of new, "atypical"
antipsychotic agents now available.

Because this patient had no significant
psychiatric problems prior to developing an unspecified change in
mental status, hospitalization was indicated to rule out an
opportunistic central nervous system (CNS) infection, metabolic
derangement, or other cause of delirium. It would be helpful to
know whether she was already experiencing psychotic symptoms prior
to admission or whether definite signs of an organic process, such
as confusion and disorientation, were evident during the
evaluation. A recent onset of psychosis without organic symptoms
would be much less worrisome.

The prevalence of psychosis during the course of
HIV infection ranges from 0.5%-15%.(3) It
may be independent of HIV encephalopathy or dementia, or may be the
result of an underlying vulnerability to becoming psychotic under
stress. This woman is at the upper age of risk for developing
schizophrenia but well within the prime age range for a first
episode of mania. The stress of being HIV positive and attendant
changes in social and work function can contribute to the emergence
of vulnerability to these disorders.

Had psychotic symptoms alone been present during
the evaluation or right after admission, it would have been
appropriate to administer one of the atypical antipsychotic drugs
(eg, aripiprazole, olanzapine, quetiapine, risperidone, or
ziprasidone) orally, instead of oral, intramuscular (IM), or IV
haloperidol or other older, "typical" antipsychotic drugs.
Clozapine is a second-line treatment, reserved for patients who
fail to respond to one or two of the other atypical antipsychotic
drugs. The distinction between typical and atypical antipsychotic
drugs relates to their capacity to cause extrapyramidal symptoms
(EPS); the atypical drugs are much less likely to produce these
adverse effects. Because patients with AIDS are more susceptible to
developing EPS (4)
(possibly because AIDS compromises the dopaminergic and cholinergic
systems required for normal motor behavior [5]), atypical antipsychotic drugs are the treatment of
choice for HIV-related psychoses (6,7),
with or without dementia. Clozapine produces the least EPS of all
of the agents, and has been used in HIV-positive patients, despite
its ability to cause agranulocytosis in about 0.7% of
individuals.(8)

Oral antipsychotic medications require days to
weeks to take effect. Intramuscular medication reaches the brain
within 30 minutes (intravenous injection does so within minutes),
but only haloperidol and ziprasidone are currently available and
FDA-approved for IM use. Three issues must be considered in
choosing between them: (i) the risk of torsade de pointes; (ii) the
risk of EPS; and (iii) cost. Given repeatedly, IM haloperidol, 5
mg-10 mg, and IM ziprasidone, 20 mg, produce virtually the same
increases in QTc interval (2.2 ms). Intramuscular ziprasidone
produced greater improvement in agitation and psychopathology with
fewer EPS than IM haloperidol (9),
and is therefore the preferred choice when control of agitation
within 20 minutes to 2 hours is sufficient. Intramuscular
olanzapine (Zyprexa®) is expected to receive FDA approval in
the near future; it represents an equally preferable choice to
haloperidol in this setting.(10) If
sedation is required within minutes, IV lorazepam may be added.

No case of torsade de pointes from ziprasidone
has been reported even though more than 450,000 people have
received the oral formulation (A. Loebel, MD, oral communication,
Pfizer Inc., September 2003). This suggests the risk is low. Since
IM ziprasidone costs approximately 20 times more than IM
haloperidol, ziprasidone will likely prove cost effective only in
subgroups of patients at high risk for adverse effects from
haloperidol, such as AIDS patients.

The limited mental status data provided in the
case summary made the need for rapid and deep sedation difficult to
determine. The patient is described as "tossing in her bed" which,
unless she was restrained, suggests no more than moderate
agitation, no intent to harm herself or others, and enough
cognitive intactness to avoid wandering. The severity of visual and
auditory hallucinations is not described, but, even when severe,
these are not considered justification for IV haloperidol push
therapy. Consequently, an atypical antipsychotic (administered IM
or possibly orally) would likely have been adequate here,
especially since limb restraints could be added if necessary.

In my opinion, IV haloperidol push treatment
(1,2,11-14) to achieve rapid sedation of agitated
psychotic patients to facilitate medical work-up is generally
problematic. The initial basis for this practice was small,
uncontrolled studies, which indicated that massive doses of IV
haloperidol were sometimes necessary and well tolerated.(11,12)
This evolved into widely adopted recommendations for giving IV
haloperidol at doses of 2 mg IV (range 0.5-10 mg) and doubling the
dose every 20 minutes until adequate control is achieved.(1,2)
Dissemination of this practice has been accompanied by numerous
case reports of torsade de pointes (14-16), with an incidence of 3.6% in one
series.(16)
Given the clear risks, more evidence is needed before recommending
high-dose IV haloperidol rather than giving lower doses a chance to
work.

If high-dose IV haloperidol is to be used, or
might become a possibility, baseline QTc interval and serum
magnesium and potassium concentrations should be
measured.(14) If
the baseline QTc interval is 440 ms or longer, and patients have
electrolyte disturbance or are receiving other drugs which might
prolong QTc interval, IV haloperidol should be given cautiously.
Continuous cardiac monitoring during the course of IV haloperidol
push therapy is warranted.(1,2,14) Of note, another butyrophenone, droperidol, was
withdrawn from clinical use because of the high rate of torsade de
pointes in critical care patients.

Was it correct to discharge this patient without
any antipsychotic treatment after her mental status improved? The
rapid improvement suggests that the psychotic symptoms were not
related to underlying schizophrenia or mania. There is too little
information to draw firm conclusions about the basis for the mental
changes that preceded hospitalization. Most likely, this was a case
of HIV psychosis, not the sign of an adventitious CNS infection. In
such cases, with the psychosis clearing so rapidly, prophylactic
treatment with an antipsychotic drug is probably not indicated.
However, education of the patient and family to watch for early
signs of psychosis or other forms of psychopathology would be
indicated to avoid another costly and potentially dangerous visit
to an emergency room. Recurrent psychotic episodes would
necessitate continuous treatment with one of the newer
antipsychotic drugs.

Take-Home Points

  • Obtain a detailed history of the type
    and temporal course of mental status changes in HIV-positive
    patients before initiating medical workup and treatment of the
    changes.
  • Treat psychotic symptoms in HIV-positive
    patients with low oral doses of an atypical antipsychotic drug,
    such as aripiprazole, olanzapine, quetiapine, risperidone, or
    ziprasidone (or offer IM ziprasidone), depending on the clinical
    status of the patient and need for rapid control.
  • If sedation is truly urgent for medical
    or safety reasons, use IV push haloperidol but attempt to keep the
    dose as low as necessary.
  • Pretreatment ECG, measurement of QTc,
    and ongoing monitoring for development of torsade de pointes
    throughout course of treatment with IV haloperidol and during
    recovery is indicated.
  • Efficacy and safety of IM ziprasidone
    vs. IV haloperidol need to be studied in randomized clinical
    trials.

Herbert Y. Meltzer,
MD
Bixler Professor of Psychiatry and Professor of Pharmacology
Vanderbilt University School of Medicine

Disclosures:

The author is a consultant to the following
companies whose drugs are discussed here: Bristol Myers Squibb
(aripiprazole), Janssen (haloperidol, risperidone), Eli Lilly
(olanzapine), Novartis (clozapine), and Pfizer (ziprasidone). He
has received grant support from these companies, as well as from
Astra Zeneca (quetiapine).

References

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Figure

Figure. Electrocardiogram showing torsade de
pointes. Torsade de pointes, which generally occurs in patients
with prolonged QT intervals, is characterized by QRS complexes that
change amplitude and direction, or "twist."