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psychosis, euphoric, disorientation, and altered motor activity, awake but agitated and actively hallucinating,” while warning
1–6
among others. One pediatric study of 745 patients published to “decide ahead of time if you’re going high or low, but don’t
in 2009 defined “delirium” as a child “who cried on awaken- get stuck in the middle.” 15
7
ing and did not settle easily.” A 2014 Cochrane review of
sevoflurane emergence defined emergence delirium (ED) and Are Abnormal Behavioral Reactions
emergence agitation (EA) under the umbrella of EA, and de-
fined it as “restless(ness), may cause self-injury or may disrupt Unique to Ketamine?
8
the dressing or surgical site of indwelling devices.” Emergence No. Volatile gas anesthetics (VGA) and other medications are
has also been referred to as post-operative negative behavior well-known to cause similar symptoms. An extensive litera-
(PONB), which includes emergence delirium, discomfort, tem- ture review in 2015 noted emergence reactions with all general
perament and pain. In one large pediatric study, where 91% of anesthetics, and reiterated the current lack of understanding
patients displayed PONB within 15 minutes of extubation, the of the phenomena. A 2014 Cochrane review was completed
6
authors concluded that it is nearly impossible to distinguish specifically to study which medications and strategies could
between emergence delirium and pain. 9 reduce sevoflurane emergence agitation in children and several
other studies over the past several years have evaluated strat-
While the definition of EA is unclear at best, the definitions egies to combat VGA emergence phenomena in children. 8,16–26
of such reactions in the setting of ketamine are even murkier. However, these studies generally reach the same conclusion
In 2011, Green and Krauss found “ketamine-induced recov- – that emergence phenomena occur across the spectrum of an-
ery reactions are too complex to simply classify as present or algesic, sedative, and anesthetic medications.
absent. Instead, they exhibit a dramatic spectrum of severity
while exhibiting a wide and not necessarily proportionate Perhaps surprisingly, even benzodiazepines can cause agitation
range of patient agreeability. Vivid dreams or hallucinations and delirium in what is defined as a “benzodiazepine para-
need not always be feared or avoided.” Furthermore, trying doxical reaction.” A case report demonstrated a 27-year-old
10
to discern which reactions are clinically important is incredi- woman undergoing MRI who became increasingly more agi-
bly difficult, and can be summed up as “what counts as im- tated with repeated doses of midazolam intended for anxioly-
27
portant is difficult to define.” 11 sis. Her agitation resolved with administration of propofol.
A similar case report of a 4-year-old girl who received oral
Perhaps the largest misconception regarding emergence reac- midazolam to facilitate closure of a facial laceration demon-
tions is that they only occur as a medication is wearing off. strated the same phenomena, which resolved with flumazenil
28
This is not certainly the case, as these same reactions can occur administration. In 2004, a review of 38 cases of paradoxical
during administration or shortly after. In the case of ketamine, reactions to midazolam in adults was published, the majority
we will refer to this as “incomplete dissociation.” A 2006 re- of which resolved with the administration of either an alter-
29
view of the use of ketamine for nonanesthesiologists noted native sedating medication or flumazenil. One anesthesia
that dissociation with ketamine is “either present or absent,” study of emergence reactions that did not involve ketamine
and that ketamine “is given as a single bolus . . . rather than found that “preoperative benzodiazepines is a significant risk
12
as repeated small doses titrated to effect.” Increasing military factor for emergence delirium in the PACU. Use of benzodi-
experience with ketamine has taught us that this view of the azepines before surgery nearly doubled the risk of emergence
dissociative state is incomplete. delirium.” 30

Ketamine is frequently given in lower doses to control pain, Interestingly, ketamine is sometimes used to treat emergence
often referred to as “analgesic dose” or “subdissociative” ket- reactions from VGA, and has shown efficacy in limited pub-
amine. However, some patients enter into a state of “incom- lished studies. 4,18,28 In one recent study, children undergoing
plete dissociation” at a lower than expected dose, and there is VGA sedation were pretreated with ketamine or midazolam.
a paucity of literature discussing this phenomenon. The signs When comparing these two medications in their ability to pre-
and behavior observed in this state are difficult to distinguish vent significant emergence reactions, ketamine significantly
from an emergence reaction. The 2011 American College of outperformed midazolam, with no incidence of emergence
Surgeons (ACEP) Clinical Practice Guideline (CPG) acknowl- reactions. In another study of patients undergoing rhino-
31
edges that “in smaller doses, ketamine exhibits analgesia and plasty, pretreatment with ketamine decreased the incidence of
disorientation.” This definition is nearly identical to that of emergence agitation fivefold. Ketamine has similarly demon-
32
emergence reactions. 13 strated success in patients with prior emergence reactions
from propofol sedation. It is common practice in emergency
30
In 2015, two papers addressed these phenomena directly. A departments and prehospital settings to treat severe agitation
review of four studies relating to low dose (subdissociative) secondary to nearly any organic or inorganic cause with ket-
ketamine use in the ED found that “it was difficult to con- amine, as its general lack of respiratory depression and low
clude whether these events were related to dissociation or side effect profile make it an ideal drug for this use. 33–35
an emergence reaction.”2 The second study, a review of 500
cases, similarly concluded that “it is now apparent that mild What Is the Danger in Coadministering
dysphoric effects of LDK (low dose ketamine) occasionally
occur with doses lower than what is traditionally considered Midazolam With Ketamine?
the dissociative range.” This phenomenon was addressed Cardiovascular collapse and respiratory depression. Ketamine
14
by the military community directly when the Prolonged Field is favored in remote and austere locations due to its favorable
Care Working Group published recommendations regarding hemodynamic profile and its lack of respiratory depression.
ketamine dosing. They similarly acknowledged that emer- Its ability to provide everything from analgesia to complete
gence reactions can occur in “the mid-range where they’re still dissociation without compromising respiratory drive makes it

50 | JSOM Volume 21, Edition 4 / Winter 2021