In the past month
we came across two drug studies done in emergency departments that gave us both
reassurance and reservations.
The first was a
study of a clinical decision rule about how long you need to observe patients
following opiate overdoses (Clemency 2019). The researchers did a validation study of
St. Paul's Early Discharge Rule, developed in 2000 at St. Paul’s Hospital in
Vancouver, BC but apparently not yet validated elsewhere. The rule was derived
to determine which patients could be safely discharged from the emergency
department after a 1‐hour observation period following naloxone
administration for opiate overdose (Christenson 2000). The rule suggested that, one hour after
the administration of naloxone for presumed opioid overdose, patients can be
safely discharged from the ED if they meet all six criteria:
·
Can mobilize as usual
·
Have a normal O2 saturation (>95%)
·
Have a normal respiratory rate (>10
and <20 breaths/min)
·
Have a normal temperature (>35.0
and <37.5°C)
·
Have a normal heart rate (>50
and <100 beats/min)
·
Have a GCS score of 15
In the current study
by Clemency and colleagues, a total of 538 patients received at least one
administration of prehospital naloxone, were transported to the study hospital,
and had a 1‐hour evaluation performed by a provider. Adverse events
(AE’s) occurred in 15.4% of patients. The rule exhibited a sensitivity of
84.1%, a specificity of 62.1%, and a negative predictive value of 95.6%. Only
one patient with a normal 1‐hour evaluation subsequently received
additional naloxone following a presumed heroin overdose.
There were no
deaths. The most frequent adverse events were:
·
Supplemental O2 for hypoxia 11,3%
·
Repeat naloxone for hypoventilation 3.0%
·
Assisted ventilation 2.6%
Both provider
judgement and the clinical prediction rule were predictive of adverse outcomes.
Among the 10 cases in which both provider judgment and the rule failed to
predict an AE, two patients received a repeat dose of naloxone after the
1‐hour evaluation and one patient was treated with artificial ventilation
(bilevel positive airway pressure).
The authors
attribute the expanded availability of intranasal naloxone as one of the key
differences between the derivation study and the current study (85.4% of patients
in the current study received IN naloxone). Also, 64.3% of patients in this
study had actual ED lengths of stays greater than 4
hours, compared to 28.8% of patients whom had hospital stays of greater than 4
hours in the derivation study.
The one patient who
received naloxone following a heroin overdose and had a normal 1‐hour
evaluation was given another dose of naloxone 5 hours
30 minutes after her first dose in the field. In that case, the repeat naloxone
administration occurred beyond the 4‐hour window they typically observe such
patients.
This validation
study did not include information on the route or type of opioid involved in
the exposure when determining the performance characteristics of the rule.
Our reservations
about the study have to do with long-acting and extended-release forms of
opioids that have become so widely available. The problem arises when the half life of the administered naloxone is exceeded by the half life of the opioid taken or when there is delayed
absorption of the opioid that allows “re-emergence” of opioid toxicity when
blood levels rise after the naloxone effect has disappeared. We’ve done several
columns on these drugs (see full list below). In our May 10, 2016 Patient
Safety Tip of the Week “Medical Problems in Behavioral Health” we mentioned we’ve seen patients who have
taken such drugs and been alert in the ED with low levels of drug in their
urine screen yet become obtunded due to opioid intoxication the following day
due to the delayed absorption of these drugs.
And, as one of the
cases in the Clemency study demonstrated, pulse oximetry does not provide a
good prediction of impending respiratory depression.
The Clemency study
is reassuring that the majority of opioid overdose
patients may be safely discharged after an hour if they meet the St. Paul's
Early Discharge Rule criteria. However, we’d be very reluctant to discharge
such patients that early if there is any doubt about the type of opioid (and
route of administration) that led to the overdose.
The second study we
came across compared 4 different pharmacologic agents (and 5 regimens) for
treatment of acute agitation in the emergency department (Klein 2018). Medications were administered according
to an a priori protocol in which the initial medication given was predetermined
in the following 3-week blocks: haloperidol 5 mg, ziprasidone 20 mg, olanzapine
10 mg, midazolam 5 mg, and haloperidol 10 mg (all doses administered
intramuscularly).
A total of 737 patients
were included in the study. The proportion of patients adequately sedated at 15
minutes (assessed by the Altered Mental Status Scale) was greater for patients
treated with midazolam than with haloperidol, olanzapine, and ziprasidone. Olanzapine
also resulted in a greater proportion of patients adequately sedated at 15
minutes compared with haloperidol and ziprasidone.
Adverse events were
uncommon: cardiac arrest (0), extrapyramidal adverse effects (2; 0.3%),
hypotension (5; 0.5%), hypoxemia (10; 1%), and intubation (4; 0.5%), and
occurred at similar rates in each group. Many patients required more than one dose
or more than one medication and this occurred more often when midazolam used.
The results sound
like a resounding endorsement of use of IM midazolam for acutely agitated
patients. But we have a few reservations. The median age of the patients was
40, and the underlying etiology was thought to be acute alcohol intoxication in
88%.
We are surprised at
the relative infrequency of serious adverse events. We suspect that we’d see
more AE’s in older patients or those with multiple comorbidities.
So
we’d probably say the real conclusion of this study is that IM midazolam in
safe and effective for management of relatively young males with acute alcohol
intoxication. The generalizability to other populations is certainly suspect.
And we would emphasize that even in the currently studied population, the potential
for respiratory depression due to the combined effects of alcohol and midazolam
merits close monitoring.
A second question is
whether adequate sedation at 15 minutes is the most
appropriate outcome measure. That certainly might help you get bloodwork
done and perhaps some other interventions. But probably more important would be
parameters like time to disposition or time to discharge.
So
you have 2 studies that statistically provide some reassurance on strategies for
managing certain patients in the ED setting but leave enough questions that
make it difficult to generalize about their use at this time.
Our prior
articles pertaining to long-acting and/or extended release preparations of
opioids:
References:
Clemency BM, Eggleston
W, Shaw EW, et al. Hospital Observation Upon Reversal (HOUR) With Naloxone: A
Prospective Clinical Prediction Rule Validation Study. Academic Emergency
Medicine 2019; 26(1): 7-15
https://onlinelibrary.wiley.com/doi/10.1111/acem.13567
Christenson J, Etherington J, Grafstein
E, et al. Early discharge
of patients with presumed opioid overdose: development of a clinical prediction
rule. Acad
Emerg Med 2000; 7(10): 1110-1118
https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1553-2712.2000.tb01260.x
Klein LR;
Driver BE; Miner JR; Martel ML et al. Intramuscular Midazolam, Olanzapine,
Ziprasidone, or Haloperidol for Treating Acute Agitation in the Emergency
Department. Ann Emerg Med 2018; 72(4): 374-385
https://www.annemergmed.com/article/S0196-0644(18)30373-1/abstract
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