Efficacy and Safety of Intravenous Midazolam and Ketamine as Sedation
for Therapeutic and Diagnostic Procedures in Children
Robert I. Parker, MD*; Rosemary A. Mahan, RN, CPNP*; Debra Giugliano, RN*;
and Margaret M. Parker, MD
ABSTRACT. Objective. We have used the combina-
tion of midazolam, a short-acting benzodiazepine, and
ketamine, a dissociative anesthetic, to provide con-
scious sedation for invasive or lengthy procedures.
Methods. A total of 350 procedures (74 lumbar punc-
tures, 97 bone marrow aspirations or biopsies, 84 radio-
therapy sessions, and 95 imaging studies) were per-
formed on 68 children, 4 months to 17 years of age, in
both inpatient and ambulatory settings. All patients had
an intravenous line in place and were monitored for
heart rate and O2 saturation by pulse oximetry for the
duration of the procedure and recovery time. Blood pres-
sure was monitored periodically (every 5 to 30 minutes).
Oxygen and suction equipment was available during the
procedure. In addition to the individual performing the
procedure, a second staff member trained in airway man-
agement (eg, physician, nurse practitioner, or registered
nurse) was present to monitor vital signs and respiratory
status. Patients were sedated initially with midazolam
(0.05 to 0.1 mg/kg intravenously; maximum single dose of
2 mg, maximum total dose of 4 mg), followed by ket-
amine (1 to 2 mg/kg intravenously). During lengthy pro-
cedures, additional doses of ketamine (0.5 to 1 mg/kg)
were given as necessary. Effectiveness of the sedation,
recovery time, and adverse events associated with the
sedative regimen were documented.
Results. All patients were effectively sedated with
this regimen. Four patients experienced transient de-
crease in O2 saturation (<85%) requiring temporary in-
terruption of the procedure and oxygen by blow-by; the
procedure was subsequently completed without incident
in each case. Two patients experienced significant agita-
tion during recovery from sedation. This side effect re-
solved spontaneously after 5 to 10 minutes in one patient
and was effectively treated with diphenhydramine hy-
drochloride in the other. Twenty-four lumbar punctures
were associated with transient decrease in O2 saturation
(88% to 92%), which improved by relief of neck flexion
and/or blow-by oxygen. No hypotension, bradycardia, or
respiratory depression requiring respiratory support or
reversal of sedation was noted. Anesthesia recovery time
ranged from <15 minutes to 120 minutes with >70% of
patients recovering within 30 minutes. Most patients
demonstrated an increase in oral secretions requiring
occasional suctioning. Transient sleep disturbances were
reported in only two patients.
From the Department of Pediatrics, *Pediatric Hematology/Oncology and
Pediatric Critical Care, State University of New York at Stony Brook,
New York.
Received for publication May 1, 1996; accepted Jun 24, 1996.
Address correspondence to: Robert I. Parker, MD, Hematology/Oncology,
Department of Pediatrics, SUNYStony Brook, HSC T-11, Room 060, Stony
Brook, NY 11794-8111.
PEDIATRICS (ISSN 0031 4005). Copyright 1997 by the American Acad-
emy of Pediatrics.
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Conclusions. This sedative regimen of intravenous
midazolam and ketamine was found to be safe and ef-
fective. Its use has greatly reduced patient and parent
anxiety for diagnostic and therapeutic procedures.
Pediatrics 1997;99:427 431; midazolam, ketamine, seda-
tion.
ABBREVIATION. DPT, Demerol/Phenergan/Thorazine cocktail.
Patients and parents find lumbar puncture and
bone marrow examinations uncomfortable and anx-
iety-producing. In addition, many radiologic studies
and radiotherapy treatments require young patients
to be sedated to obtain optimum results. Commonly
used sedatives such as chloral hydrate and intramus-
cular narcotic and phenothiazine cocktails, including
Demerol/Phenergan/Thorazine (DPT), are largely
ineffective and have a prolonged recovery time.15
Intravenous agents such as propofol generally re-
quire anesthesiology support because of the high risk
of respiratory depression. In many institutions, an-
esthesiology support with endotracheal intubation of
patients is used during these procedures. This often
makes these procedures more difficult to obtain on a
timely schedule and more anxiety-producing for
both parents and patients. To minimize these prob-
lems, we instituted a program in which the hematol-
ogy/oncology and/or critical care staff would pro-
vide sedation services for these procedures. We
chose to use a combination of ketamine, a dissocia-
tive anesthetic, and the short-acting benzodiazepine
midazolam to provide sedation, because the pharma-
cology of these agents in children is well understood;
they each have short durations of action and produce
relatively little respiratory depression and, in the
case of midazolam, a pharmacologic antagonist is
available.6 12
METHODS
Sedation was delivered according to guidelines developed in
concert with the critical care medicine division and are in accord
with those published recently by the American Academy of Pedi-
atrics.13 Patients were instructed that the meal immediately pre-
ceding the procedure be a light one and to intake nothing by
mouth for 4 hours before sedation. In the case of urgent proce-
dures, we required that the patients have nothing but clear liquids
within 4 hours of the procedure and to be NPO for 1 to 2 hours
before the procedure. All patients had an intravenous line in place
for the duration of sedation and recovery. In addition to the
person performing the procedure, a second individual trained in
airway management (ie, bag/mask ventilation) was in attendance
to monitor the patient. Continuous monitoring of heart rate and O2
PEDIATRICS Vol. 99 No. 3 March 1997 427
saturation by pulse oximetry was obtained for the duration of
sedation and the recovery period, with blood pressure being mon-
itored at a minimum of every 15 to 30 minutes. In most cases,
blood pressure was monitored every 5 minutes; however, for
some imaging procedures, this was not possible and in these cases,
blood pressure was monitored after the initiation of sedation and
then at least every 15 to 30 minutes thereafter. Respiratory rate
was monitored with each blood pressure determination and at the
time of any documented O2 desaturation. Oxygen and suction
equipment was available for the duration of the sedation and the
recovery period. After the procedure requiring sedation, the pa-
tient was monitored by the nursing staff until able to walk (if
age-appropriate), drink clear liquids (if desired by the patient and
if not nauseated), and give age-appropriate responses to verbal
commands.
In all patients, sedation was initiated with midazolam (initial
dose of 0.05 to 0.1 mg/kg) to minimize the incidence of frightening
hallucinations or nightmares that might be caused by ketamine.
The maximum single dose of midazolam administered was 2 mg,
with a maximum total dose of 4 mg. Two to 5 minutes later,
sedation was continued with ketamine (1.0 to 2.0 mg/kg initial
dose). Subsequent doses of ketamine (0.5 to 1.0 mg/kg) were
administered as needed, to a total dose of 6 mg/kg in most cases.
In general, children weighing up to 20 kg received 0.1 mg/kg
midazolam followed by an initial dose 1.0 mg/kg ketamine. A
second dose of ketamine (1.0 mg/kg) was given after 2 to 3
minutes if adequate sedation had not been achieved. Subsequent
doses of 0.5 to 1.0 mg/kg ketamine were then given during the
procedure, depending on the response to the previous doses and
the anticipated time needed to complete the procedure. For chil-
dren weighing .20 kg, a single dose of 2.0 mg of midazolam was
given, followed by 0.5 to 1.0 mg/kg ketamine. This dose of ket-
amine was repeated after 2 to 3 minutes if needed. Patients weigh-
ing .70 kg received 4 mg of midazolam, followed by one or two
50-mg doses of ketamine. Additional doses of midazolam or a
single dose of ketamine .50 mg were rarely given. For lengthy
procedures (eg, magnetic resonance imaging studies, nuclear
scans) and in patients who developed tolerance to ketamine, this
maximum dose occasionally was exceeded. In these circum-
stances, subsequent doses of ketamine were titrated to the clinical
effect observed and the anticipated need for additional sedation.
The quality of the sedation was assessed both by the medical staff
based on the ability to perform the procedure as planned and by
the parents based on their perception of their childs comfort level
during the procedure. Patients were judged to be optimally se-
dated, acceptably sedated, or to have failed sedation. Recov- spiratory rates from 16 to 24 breaths per minute but
ery from sedation, as measured by level of awareness, fluency of
age-appropriate speech, ability to walk unassisted (if appropriate),
and lack of double vision, was assessed at 15 minutes, 30 minutes,
and then every 30 minutes thereafter. Recovery time was mea-
sured from the completion of the procedure.
RESULTS
Sedation was provided to 68 children, 4 months to
17 years of age, for a total of 350 procedures. These
procedures included 74 lumbar punctures, 97 bone
marrow aspirations and/or biopsies, 95 imaging
studies, and 84 radiotherapy sessions. All children
were acceptably sedated (ie, sedated to a degree
that the planned procedure could be performed to
the physicians and parents satisfaction), and .90%
of the time the child was judged to be optimally
sedated (ie, sedation resulting in the optimal per-
formance of the procedure as judged by the parents
and medical staff). The level of sedation ranged from
conscious sedation to deep sedation for all pa-
tients.13 As we gained experience with this regimen,
we initiated sedation with smaller drug doses. Con-
sequently, the proportion of children who were un-
der deep sedation was continually decreasing dur-
ing the study period. At present, approximately two
thirds to three quarters of the children sedated with
428 SEDATION WITH INTRAVENOUS MIDAZOLAM AND KETAMINE
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this regimen are able to respond to verbal stimuli or
are talking during the procedure.
No serious complications were encountered; no
patient required intubation, bag/mask ventilation,
or pharmacologic reversal of sedation for respiratory
depression. No patient was documented to experi-
ence any significant degree of hypotension or hyper-
tension (ie, change in systolic blood pressure of .10
mm Hg or diastolic blood pressure of .5 mm Hg).
Mild tachycardia (increase in heart rate of 10 to 15
beats per minute) was noted in most patients after
ketamine administration. Respiratory rates were
largely unchanged during sedation. Although most
children experienced a mild decrease in respiratory
rate (ie, a decrease of three to four breaths per
minute), this may be explained by the decrease in
anxiety produced by the sedation.
The most common adverse event with this se-
dation protocol was a mild decrease in O2 saturation,
as measured by pulse oximetry (Table 1). Most seda-
tion events (245/350; 70.0%) produced a transient
drop in O2 saturation of between 2% and 6% within
1 to 2 minutes after receiving ketamine. Subse-
quently, the O2 saturation would return to baseline
within 1 to 2 minutes. This drop could be attenuated
by decreasing the rate of subsequent ketamine injec-
tions. Four patients (1.1%) experienced a significant
drop in O2 saturation (,85%) that required interrup-
tion of the procedure and/or mild stimulation to
improve respiratory effort. None of these patients
had an underlying condition that would explain the
hypoxemia, although one of the children had been
given diphenhydramine hydrochloride by a parent
before the procedure. This childs respiratory rate
did drop into the low- to mid-teens before the onset
of the O2 desaturation. The other three children who
experienced significant desaturation maintained re-
did appear to have a decrease in the strength of
inspiration. Approximately one third of the patients
undergoing lumbar punctures (24/74; 32.4%) was
associated with a drop in O2 saturation to between
88% and 94% upon neck flexion. This generally re-
mitted when neck extension was allowed and did
not return with the neck in flexed position when O2
by blow-by was administered. Blood pressure was
measured at the time of any documented desatura-
tion and then every 5 minutes thereafter until O2
saturation had returned to baseline for at least 10
minutes. No patient was documented to have a sig-
nificant drop in systolic or diastolic blood pressure
alone or in association with a drop in O2 saturation.
All patients developed some degree of increased
TABLE 1. Complications
Type of Complication Incidence
O2 saturation ,85% 4/350 (1.1%)
O2 saturation of 88%94% during lumbar 24/74 (32.4%)
puncture (neck flexion)
Macular rash/flushing 8/68 (11.8%)
Agitation 2/68 (2.9 %)
Sleep disturbance 2/68 (2.9 %)
Vomiting (nonlumbar puncture procedures) 8/276 (2.9%)
oral secretions, with some patients requiring oral
suctioning during or after the procedure; in no pa-
tient did the oral secretions interfere with respiratory
effort. Consequently, the administration of an anti-
sialagogue was not felt to be necessary. An erythem-
atous macular rash was noted at least once in eight
(12%) patients. The appearance of the rash was tem-
porally related to the injection of ketamine. No pa-
tient developed urticaria or wheezing or any other
sign of laryngospasm. Only two patients (3%) expe-
rienced significant agitation during recovery from
sedation, and two patients were reported to have
transient sleep disturbances (eg, nightmares); both of
these patients received ketamine with subsequent
procedures at a reduced dose without repeat sleep
disturbances. Vomiting at recovery from sedation
was noted in 8 (2.9%) of 276 patients receiving non-
lumbar puncture procedures. In all patients who ex-
perienced vomiting, this occurred at a point in recov-
ery from sedation in which they were able to sit up
and were talking. No episodes of aspiration were
either observed or suspected. Seven of these eight
patients also experienced anticipatory nausea and
vomiting with chemotherapy.
Recovery time ranged from 15 to 120 minutes, with
.70% of patients having recovered by 30 minutes
(Table 2). Recovery time was shortest for patients
undergoing radiotherapy sessions and in patients
who had been sedated previously, because we were
able to decrease the amount of medication given for
the procedure in most cases. Recovery occurred
within 15 minutes for all of the radiotherapy ses-
sions. Sixty-six of the 115 patients who took at least
60 minutes to recover were patients who had under-
gone lumbar punctures for intrathecal therapy. Be-
cause our practice is to routinely keep patients in a
supine or Trendelenberg position for at least 60 min-
utes after completion of intrathecal chemotherapy,
these patients were often documented to have re-
covered near or at the end of this period.
DISCUSSION
In our experience, the combination of midazolam
and ketamine provides safe, effective sedation for
procedures in children. With the recognition of the
limitations and risks of standard lytic cocktails used
to provide sedation in children, newer short-acting
agents such as midazolam, propofol, fentanyl, and
ketamine have been used to provide preanesthesia
and procedural sedation in children with good re-
sults.6,7,14 20 In general, all of these agents have been
shown to be both effective and relatively safe when
used with appropriate monitoring. Midazolam and
ketamine have been used separately to provide se-
TABLE 2. Recovery Time
Time No. (%)
,15 minutes 136 (38.9)
1530 minutes 124 (35.4)
3060 minutes 38 (10.9)
6090 minutes 68 (19.4)
90120 minutes 5 (1.4)
.120 minutes 0 (0)
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dation for invasive procedures in pediatric oncology
patients with good results.6,21 This combination con-
sists of a good anxiolytic and sedative agent (mida-
zolam) with a second agent that has both sedative
and analgesic properties (ketamine). Although both
midazolam and ketamine have been shown to be
effective when used as single agents for sedation and
analgesia, significant variation in the sedative re-
sponse to midazolam has been reported previously.22
The use of high doses of midazolam is more likely to
produce respiratory depression. When ketamine is
used as a single agent, there is a significant incidence
of dysphoric reactions that both the patient and par-
ents may find unpleasant. The use of a benzodiaz-
epine with ketamine has been shown to result in
more rapid onset of analgesia and fewer and less
severe dysphoric reactions, as well as the need for
less ketamine administration, more amnesia of the
procedure, and less risk of respiratory depression
resulting from the lower dose of midazolam admin-
istered.12,15,16,2327 The addition of midazolam to ket-
amine has also been shown to reduce or eliminate
many of the undesirable cardiovascular effects ob-
served when ketamine is administered as a single
agent (eg, hypertension, myocardial depression, in-
creased pulmonary pressure). These drugs have the
advantage over many other sedative and analgesic
agents in that therapeutic plasma levels can be ob-
tained with oral, rectal, sublingual, nasal, and intra-
muscular administration.21,2326,28 34 This ability to
achieve therapeutic drug levels via different routes
of administration, albeit with different doses, pro-
vides an added degree of flexibility in the use of
these drugs. Although we only report our experience
with the intravenous administration of the combina-
tion of midazolam and ketamine, we believe that this
combination should be equally effective and safe
when administered transmucosally. Our results are
similar to those reported by others who have used
this combination by other routes for sedation or pre-
anesthesia.15,23,24,26,28
Although we observed minimal adverse events
with this sedative/analgesic combination, some de-
gree of hypoxemia did occur in many patients (Table
1). Most episodes of significant O2 desaturation oc-
curred in patients undergoing lumbar puncture and
may, in part, be attributable to the neck flexion used
for the procedure. Because we do not routinely mon-
itor O2 saturation during lumbar puncture in nonse-
dated patients, we do not know how often transient
hypoxemia occurs in nonsedated patients undergo-
ing lumbar puncture. However, neck flexion should
be minimized during procedures performed with
sedation to minimize any airway obstruction. Be-
cause intravenous midazolam has been demon-
strated to produce mild hypoxemia in some re-
ports23,35 but not in others,8 we must assume that
administration of this agent contributed to the noted
decrease in percent hemoglobin oxygen saturation.
The risk of hypoxemia appears to increase when a
narcotic agent (eg, fentanyl) is administered with
midazolam,17,36 whereas ketamine does not appear to
increase this risk.23 Hypoxemia generally has not
been reported in studies in which midazolam and/or
ARTICLES 429
ketamine was administered via a transmucosal
route.21,25,28 Although midazolam has a specific an-
tagonist that reverses the sedative and respiratory
depressant actions of the drug,9 there is no such
agent for ketamine. Because of the short half-life of
flumazenil, the midazolam antagonist, rebound se-
dation and respiratory depression may occur in pa-
tients to whom large doses of the agent have been
administered.10,11 Consequently, we limited the use
of midazolam to a maximum total dose of 4 mg. With
this dose, we noted no significant respiratory depres-
sion, and no patient required therapy with flumaze-
nil. The rapidity of recovery with this sedation/an-
algesia therapy that we experienced also limited the
need for the active antagonism of midazolam to
shorten recovery time.
We were able to provide effective sedation with
this regimen in which most children recovered from
the effects of sedation within 30 minutes, allowing
for more effective use of services. The cost of the
midazolam and ketamine used in this regimen is
approximately two to three times that for a standard
DPT cocktail (2 mg/kg demerol, 2 mg/kg phener-
gan, 1 mg/kg thorazine). Because the absolute dollar
differences are small (approximately $5 for midazo-
lam/ketamine vs $2 for DPT for a 20-kg child), the
shorter recovery time, better efficacy, and high pa-
tient and parent satisfaction experienced with this
midazolam/ketamine regimen make it more cost-
and resource-efficient than the various DPT cock-
tails. Although midazolam is more expensive than
propofol when delivered as a continuous infusion for
sedation,37 the need for anesthesia support in nonin-
tubated patients makes propofol a less desirable
agent for short sedation episodes, in our opinion. We
did not perform a formal cost analysis of this seda-
tive regimen, although the major cost is for the per-
sonnel time for monitoring during sedation. Al-
though this form of monitoring has not been
performed routinely when children receive intra-
muscular agents (eg, DPT), hypoxemia can be pro-
duced with these regimens,25 and it may be appro-
priate to monitor any child who receives parenteral
sedation. In this case, the shorter recovery time of
this regimen would make it more cost-effective than
traditional intramuscular DPT regimens.
To some extent, the effectiveness of this sedation/
analgesia therapy was dependent on the degree of
preprocedure anxiety experienced by the patient. Pa-
tients who were less anxious before the procedure
were more readily sedated with smaller doses of
midazolam and required less ketamine to maintain
adequate sedation. This points out the value of non-
pharmacologic anxiety-relieving techniques in the
management of procedure-related anxiety. The value
of nonpharmacologic antianxiety techniques is atten-
tuated additionally by the observation that postseda-
tion nausea and vomiting in the nonlumbar puncture
patients was limited largely to patients who also
experienced anticipatory nausea and vomiting with
chemotherapy.
We believe that two reasons this sedative regimen
has been shown to be safe and effective in our insti-
tution are the requirements for pulse-oximetry mon-
430 SEDATION WITH INTRAVENOUS MIDAZOLAM AND KETAMINE
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itoring and for the presence of a second individual
trained in airway management during the procedure
to monitor the patient. We initially used this regimen
in controlled settings that allowed for optimal pa-
tient monitoring (eg, patient or procedure rooms)
while we were still learning how best to administer
this therapy. Once we had adequate experience, we
then began administering sedation in less controlled
settings such as in the magnetic resonance imaging
or radiotherapy suite. This has allowed us to use the
least amount of drug necessary while sedating the
child adequately to accomplish the procedure in
most cases. Although we believe that this drug and
monitoring regimen can safely provide effective se-
dation and analgesia for children undergoing diag-
nostic and therapeutic procedures, the goal should
always be to provide the smallest doses of medica-
tion necessary in the safest setting. Minimizing the
amount of drug administered results in a shorter
recovery time and decreased risks of significant car-
diorespiratory side effects and adverse drug interac-
tion.7,8,38 To provide this form of sedation/analgesia
with an appropriate level of safety, certain patients
may need to be excluded from consideration. Pa-
tients with intrinsic or extrinsic airway abnormalities
that may increase the risk of obstruction or make it
difficult to produce adequate mask ventilation may
not be suitable candidates for intravenous sedation
of this type. Likewise, because of the hemodynamic
and central nervous system effects of ketamine, in-
dividuals who have experienced adverse reactions to
ketamine (eg, laryngospasm, hypersensitivity reac-
tions) or who have uncontrolled hypertension, in-
creased intracranial or intraocular pressure, hyper-
thyroidism, or a history of psychiatric disorders may
not be candidates for sedation with this regimen.
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ARTICLES 431
Efficacy and Safety of Intravenous Midazolam and Ketamine as Sedation for
Therapeutic and Diagnostic Procedures in Children
Robert I. Parker, Rosemary A. Mahan, Debra Giugliano and Margaret M. Parker
Pediatrics 1997;99;427
DOI: 10.1542/peds.99.3.427
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned, published, and
trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove
Village, Illinois, 60007. Copyright 1997 by the American Academy of Pediatrics. All rights
reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

Downloaded from pediatrics.aappublications.org at USD and Wegner Hlth Sci Info Ctr on March 12, 2015
Efficacy and Safety of Intravenous Midazolam and Ketamine as Sedation for
Therapeutic and Diagnostic Procedures in Children
Robert I. Parker, Rosemary A. Mahan, Debra Giugliano and Margaret M. Parker
Pediatrics 1997;99;427
DOI: 10.1542/peds.99.3.427

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/99/3/427.full.html

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright 1997 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

Downloaded from pediatrics.aappublications.org at USD and Wegner Hlth Sci Info Ctr on March 12, 2015