International Journal of Surgery Open 25 (2020) 52e58

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International Journal of Surgery Open

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Review Article

Evidence based guideline on use of ketofol (Ketamine and Propofol admixture) for
procedural sedation and analgesia (PSA) in pediatrics surgery: Review article
Siraj Ahmed Ali, Zemedu Aweke, Bedru Jemal*
Department of Anesthesia, College of Medicine and Health Sciences, Dilla University, Dilla, Ethiopia

a r t i c l e i n f o a b s t r a c t

Article history: Procedural sedation and analgesia (PSA) implies the state of drug induced tolerance of uncomfortable or
Received 11 May 2020 painful diagnostic, interventional medical and surgical procedures. Ketofol (ketamine and Propofol
Received in revised form mixture) is a good combination of drugs for PSA in painful procedures in pediatrics resulting in hemo-
19 June 2020
dynamic and respiratory safety. A combination of these drugs provides sedation, analgesia, and rapid
Accepted 20 June 2020
Available online 26 June 2020
recovery with hemodynamic stability and minimal respiratory depression. The objective of sedation
during such procedures is to reduce the discomfort of the patient and to facilitate the performance of the
procedure.
Keywords:
Ketofol
This systematic review was conducted according to the preferred reporting items for systematic re-
Sedation view and meta-analysis protocol (PRISMA). Evidences for this guideline development were searched
Analgesia from PubMed, Google Scholar, Google search, and Medline databases with keywords.
Pediatrics During the review of searched literature for the guideline, important concerns discussed were patient
selection and assessment (indication for PSA), monitoring of children including depth of sedation,
medication administration (a combination of the agents), and criteria for postoperative discharge.
Generally, in the presence of adequate resuscitation equipment and monitoring ketamine and Propofol
mixture can be used in the proportion of 1:1, 1:2, 1:3, and 1:4 safely with good respiratory and hemo-
dynamic stability.
© 2020 The Author(s). Published by Elsevier Ltd on behalf of Surgical Associates Ltd. This is an open
access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. Introduction low ketamine in combination helps to have decreased recovery

time and minimal side effects [2e4].
Procedural sedation and analgesia (PSA) implies the state of A randomized controlled trial by Shah et al. in 136 patients (age
drug induced tolerance of uncomfortable or painful diagnostic or 2 to 17), requiring procedural sedation and analgesia for manage-
interventional medical, dental, or surgical procedures. The objec- ment of isolated orthopedic extremity injury comparing ketamine/
tive of sedation during such procedures is to reduce the discomfort Propofol (n ¼ 67) with ketamine (n ¼ 69). The study concludes that
of the patient and to facilitate the performance of the procedure [1]. ketamine/Propofol (Ketofol) has short sedation time (13 vs 16 min
Ketamine is an anesthetic drug that is importantly analgesic p ¼ 0.04), reduced vomiting (2% vs 12%), and higher patient satis-
without respiratory depression, increased blood pressure, and faction scores (p < 0.05) compared to ketamine group. Patients
heart rate whereas Propofol has good sedation and rapid recovery with Ketofol group were induced with a bolus dose of 0.5 mg/kg
but causes respiratory depression, decreased blood pressure, and Propofol and 0.5 mg/kg ketamine, 1:1 combination [5].
heart rate. A combination of these drugs provides sedation, anal-
gesia, and rapid recovery with hemodynamic stability and minimal
respiratory depression. Ketofol (ketamine and Propofol mixture) is 1.1. Patient selection and assessment
a good combination of drugs for PSA in painful procedures in pe-
diatrics resulting in hemodynamic and respiratory safety. Use of In this document, patients considered for PSA are pediatric pa-
tients below the age of 18 years as defined by CRC adopted in 1989
ratified by Ethiopia in 1991 by the proclamation October 1992.
Systematic reviews and clinical practice guidelines strongly
* Corresponding author. support using PSA for a variety of painful procedures in both chil-
E-mail address: [email protected] (B. Jemal). dren and adults. Some of the most common indications for PSA are

https://doi.org/10.1016/j.ijso.2020.06.008
2405-8572/© 2020 The Author(s). Published by Elsevier Ltd on behalf of Surgical Associates Ltd. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).
 S.A. Ali et al. / International Journal of Surgery Open 25 (2020) 52e58 53

orthopedic injuries and reductions, wound debridement, burn care, During search using the keywords ketofol, pediatrics, sedation
abscess drainage, tube insertion, pediatric sexual assault exami- PubMed search engine yields many journals. Filtering tools of the
nations, and diagnostic imaging modalities [6]. database (clinical trials, Reviews, Full texts, Free-full texts) were used
Flower reviewed literature of prospective case series with 114 to exclude unrelated journals. Journals of adult populations, sedation
patients undergo PSA with “ketofol” shows the most common for reason other than procedural sedation, sedation with drugs other
indication (69.3%) was orthopedic [7]. than the topic of interests, and sedation in critically ill patients were
Generally, indications for procedural sedations in outpatient excluded from the review for developing this guideline.
bases or in main operation room can be classified into 1) Diagnostic Finally, we have reviewed 13 clinical trials, two systematic re-
imaging requiring sedation only 2) painful diagnostic procedures view and meta-analysis, two review article and five observational
(LP, sexual assault examination) 3) Painful therapeutic procedures using the following keywords: (Child OR Pediatrics) AND
(fracture/dislocation reduction, complex laceration repair, foreign (Conscious Sedation OR Deep Sedation OR Hypnotics) AND (Keta-
body removal, abscess drainage, etc). mine and propofol OR ketofol) AND Surgery AND Anesthesia
Patients who are classified ASA physical status I, II, and (ASA III (Fig. 1). A summary of the characteristics of the included studies can
patients with caution and may need consultation) are considered be viewed in Table 1. The reviewers independently appraised the
suitable candidates for PSA. Patients having anatomic airway ab- methodological quality of studies that met the inclusion criteria.
normalities (who needs special consideration and individual con- The included studies were appraised for quality using Oxford
cerns) are NOT considered as suitable for PSA [8e10]. Center for evidence based medicine to categorize them into level of
Peer-reviewed hospital based board review by John S. Rose et al. evidence and grades of recommendations. Finally, conclusion has
showed that patients assessment for undergoing PSA should drawn based on the level of evidence (Table 2).
consider past medical and anesthetic history, current medical his-
tory with physical examination and consent with a clear explana- 4. Discussion
tion of the procedure, risks, benefits and possible complications [6].
Patients planned to undergo PSA in OR or outside it (minor OR) 4.1. Equipment
must have a careful preoperative evaluation, laboratory tests
guided by underlying medical conditions should be obtained, the PSA should be performed in a setting where patients undergo-
risks, benefits, and possible complications of the proposed pro- ing PSA can easily be monitored and any adverse events can easily
cedure should be explained to the patients' parents or legal detected and managed in a timely manner. Source of oxygen,
guardian and consent should be obtained. Published guidelines monitoring for saturation of oxygen, monitoring for heart rate and
recommend that patients undergo PSA on elective bases should blood pressure, equipment, and drugs for cardiopulmonary resus-
follow ASA preoperative fasting guideline (as for general anes- citation (emergency cart) should be available [1,10].
thesia) whereas emergency patients should be based on the risk There must be resuscitation equipment and drugs (emergency
and benefit analysis [11,12]. cart), NIBP apparatus, stethoscope, and pulse oxymetry in a place
This guideline is intended to be used by anesthetists for thera- where PSA for pediatrics will be administered.
peutic and diagnostic procedures in pediatrics patients with pro- Recommendation: Appropriate resuscitation equipment (Age-
cedural sedation and/or analgesia in a major operating theatre or appropriate endotracheal tubes, laryngoscopes, suction devices, and
minor operating rooms. bag-valve mask ventilation device, source of oxygen, and vascular
access materials) must be available for management of complication,
respiratory support, and cardiopulmonary resuscitation. (Grade A).
2. Justification
4.2. Combination of the drugs
Procedural sedation and analgesia can be safely used for
outpatient procedures or inpatients bases in pediatrics diagnostic
Different systematic review and meta-analysis of RCTs to deter-
and therapeutic procedures with the combination of ketamine and
mine the combination of ketamine and Propofol for procedural
Propofol as studies show there safety use having good sedation,
sedation and analgesia showed the range of 1:10 to 1:1 ketamine:
hemodynamic stability and rapid recovery with minimal compli-
Propofol can be used depending on the patients' characteristics. The
cations [2,5,13].
doses required using the combination of the drugs is less than the dose
We face different cases of pediatrics therapeutic and diagnostic
of the individual drugs required to obtain the required level of sedation
procedures such as removal of foreign body from trachea or
and the combined drug had lower frequency of adverse effect in pa-
esophagus requiring sedation in our institution and there is vari-
tients undergoing PSA compared to the individual drugs [15,23,24].
ability of technique for sedation between anesthetists as some uses
A randomized double-blind study done by Ayatollahi et al. in 60
inhalational sedation while others use ketamine only or other,
pediatric patients (age 3e12) undergoing bone marrow aspiration
which needs practice guideline to make it uniform. The combina-
or lumbar puncture with a combination of ketamine: Propofol 1:2
tion of ketamine and Propofol for PSA can be safely used in pedi-
and 1:3. The study showed that patients in a group undergo
atrics procedures.
sedation with 1:2 ketamine: Propofol combination has prolonged
Therefore, it is important to develop a guideline that helps
recovery time compared to group undergo sedation with 1:3 ke-
professionals to manage procedures in pediatrics with PSA using a
tamine: Propofol combination (11.3 vs 8.0 min P-value <0.001) and
combination of Propofol and ketamine in different concentrations.
hallucination (P-value ¼ 0.05). However, patients in both groups
were hemodynamically stable [2].
3. Methodology Five RCT on combination of ketamine and propofol compared to
individual drug for procedural sedation and analgesia reported that
This systematic review was conducted according to the ketofol improve patient recovery and comfort by limiting the
preferred reporting items for systematic review and meta-analysis incidence of psychodysleptic events. Ketofol results in less hemo-
protocol (PRISMA). Evidences for this guideline development were dynamic instability, lower incidence of vomiting and adverse res-
searched from PubMed, Google Scholar, Google search, and Med- piratory events, better sedation, and enhanced patient comfort
line databases with keywords. [25e29].
54 S.A. Ali et al. / International Journal of Surgery Open 25 (2020) 52e58

Fig. 1. Flow chart for selection of studies by PRISMA.

Other observational studies show that Ketamine Propofol moderate, deep, or general anesthesia as defined by American So-
combination of 1:2-1:1 is effective procedural sedation and anal- ciety of Anesthesiologists (ASA) (See Appendix 3).
gesia in pediatrics for emergency procedures [16] [30e33]. Children who undergo sedation should be continuously monitored
Generally, ketamine and Propofol mixture can be used in the by the anesthetist administering the sedation. These may help to
proportion of 1:1, 1:2, 1:3, and 1:4 safely with good respiratory and detect complications of sedation early (before decompensated cardiac
hemodynamic stability. state and brain hypoxia) and manage in a timely manner. Clinical
Recommendation: Any proportion of 1:1, 1:2, 1:3, or 1:4 combi- monitoring (observing pattern of breathing, the color of mucosa and
nations can be used. Based on the above evidence we recommend blood), respiratory monitoring (capnography, pulse oximetry), car-
using a low proportion of ketamine in combination with the drugs in diac monitoring (NIBP, HR, ECG), level of consciousness (response to
PSA for pediatrics. (Grade A). verbal command if applicable based on the level of intended sedation,
response to tactile or light tap stimulation) are mandatory during
sedation of children for every procedure. Sedation in pediatrics is
4.3. Documentation difficult from that of adults and maybe a continuum. It can be easy to
advance beyond the intended level of sedation to the next level even
In PSA clear documentation of procedure and the patients’ to the level of general anesthesia and rescue to the safety of the next
characteristics including baseline determination of vital signs in level as a maximum of cardiopulmonary resuscitation equipment
pre-sedation, time based recorded of the medication, the patients (including emergency cart) must be available [1,8,9,17].
monitored hemodynamic physiologic status, time and condition of A study done on 154 children receiving procedural sedation
the child at discharge should be documented [1,8]. showed that hypoventilation is common in pediatrics procedural
Recommendation: Use the standard Anesthesia Record with the sedation and can be easily detected by capnography [18]. Other
level of sedation during PSA of Pediatrics. (Grade A). study done in pediatrics undergo sedation showed that inclusion of
capnography in routine monitoring for adequate sedation could
4.4. Monitoring during PSA improve safety [19].
Pulse oxymetry, blood pressure, and heart rate monitoring with
The children undergo PSA should be monitored to obtain the audible and appropriately set alarms must be applied during and
desired level of sedation based on the procedure indicated. The after the procedure during PSA in pediatrics. Other monitoring may
level of sedation desired for the planned procedure may be mild, be required based on the patients’ condition.
 S.A. Ali et al. / International Journal of Surgery Open 25 (2020) 52e58 55

Table 1
A summary of the included evidence/studies.

No Authors Agent Dose Sample procedure Study design Comment

(ketamine:
propofol)

1 Ayatollahi V et al. Ketofol 1:2/1:3 60 Bone RCT Lower doses of Ketamine in these
Marrow Aspiration combinations have lower psycho mimetic
side effects, and shorter recovery time.
2 Mehtapet al. Ketofol 1:1 60 Ultrasound guided RCT ketamine-propofol combinations for
transbronchial needle sedation during EBUS-TBNA were effective
aspiration and safe without remarkable side effects
3 Shah Aet al. ketofol 1:1 140 orthopedic extremity RCT Ketofol for pediatric orthopedic reductions
injury produced slightly faster recoveries while
also demonstrating less vomiting, higher
satisfaction scores, and similar efficacy and
airway complications compared to
ketamine alone
4 Mehtapet al. 1:2/1:4 80 undergoing RCT ketofol mixture prepared in the proportion
colonoscopy 1 : 2 provides suitable hemodynamic
conditions and sufficient sedation in
elective colonoscopy.
5 Smischnew NJ et al. ketofol 1:2 80 Induction of GA RCT Ketofol is associated with improved
hemodynamic stability
6 Andolfatto G et al. ketofol 1:1 284 ED Procedural Sedation RCT Ketofol for ED procedural sedation does not
and Analgesia result in a reduced incidence of adverse
respiratory events compared with propofol
alone. Induction time, efficacy, and sedation
time were similar; however, sedation depth
appeared to be more consistent with ketofol
7 Langhan ML et al. ketamine different 154 Procedural Sedation RCT Capnography may improve the quality of
and Analgesia care among children during sedation.
8 Lemoel et al. ketofol 1:1 152 orthopedic injury RCT ketofol for ED procedural sedations
improves patient recovery and comfort by
limiting the incidence of psychodysleptic
events and unpleasant recoveries
9 Willman EV ketofol 1:1 114 Different emergency observational Ketofol procedural sedation and analgesia is
procedure effective and appears to be safe for painful
emergency procedures.
10 David & Shipp ketofol 1:2 220 Different emergency RCT The combination of ketamine and propofol
procedure provide less propofol administration and
better sedation quality
11 Ferguson et al. ketofol 1:1 591 Varity of emergency RCT Ketofol and propofol resulted in a similar
incidence of adverse respiratory events
12 Andolfatto and Willman ketofol 1:1 728 orthopedic procedure observational Ketofol is an effective PSA agent in adult ED
procedures patients. Recovery times are short and
adverse events are few
13 Andolfatto and Willman ketofol 1:1 219 Varity of emergency observational Pediatric PSA using ketofol is highly
procedures effective. Recovery times were short;
adverse events were few
14 W. Phillips et al. ketofol 1:1 28 RCT Ketofol results in less hypotension, better
sedation, and enhanced patient comfort
and safety. Ketofol provides an attractive
combination for procedural sedation
15 Roback et al. ketamine 1 mg/kg IV 225 Orthopedic Procedures RCT IV ketamine group had lower incidence of
vomiting and shorter length of sedation
16 Sharieff et al. ketofol 1:2 20 Fracture observational The combination of ketamine and propofol
Reduction provided effective sedation with rapid
recovery and no clinically significant
complications
17 Mora Capin A et al. Variable drug Variable doses 20 pediatric emergency RCT The inclusion of capnography to routine
procedure monitoring for adequate sedation
procedures could improve safety
18 David H et al. Variable drugs Variable doses 1341 Variable procedure observational In children without serious adverse effects
during procedural sedation and analgesia,
discontinuation of monitoring and
discharge from the ED may be safe
approximately 30 min after final
medication administration.
Systematic review and Meta-analysis
19 Yan et al. Ketofol/propofol 1:4-1:2 6 article Variable procedure Systematic review Ketofol had a lower frequency of adverse
and meta-analysis respiratory events in patients undergoing
PSA compared to propofol alone
20 M. Jalili et al. Ketofol/propofol 1:10-1:1 18 article Variable procedure Systematic review ketofol is significantly effective for
and meta-analysis reduction of respiratory and cardiovascular
complication
21 James R et al. Variable drugs Variable doses e pediatric emergency Review article Medications, such as ketamine, fentanyl,
procedure etomidate, propofol and midazolam can be
utilized whenever clinically appropriate
(continued on next page)
56 S.A. Ali et al. / International Journal of Surgery Open 25 (2020) 52e58

Table 1 (continued )

No Authors Agent Dose Sample procedure Study design Comment

(ketamine:
propofol)

22 Slavik VC et al. Ketamine and 1:10e1:2 23 article Variable procedure Review article The available evidence does not support the
Propofol use of this combination for patients
undergoing procedural sedation.

Guideline

Society Year Clinical setting

23 Australian and new zealand college of anesthetists 2014 Procedural sedation and analgesia for
diagnostic and interventional medical,
dental or surgical procedure
24 American academy of pediatric dentistry 2011 Monitoring and management of pediatric
patients during and after sedation for
diagnostic and therapeutic procedures.
25 Emergency Medicine Society of South Africa 2009 Practice guideline for procedural sedation
in the emergency center
26 American Society of Anesthesiologists 2011 Practice guideline for preopeartive fatsing
and the use of pharmacologic agents to
reduce the risk of pulmonary aspiration
27 American Society of Anesthesiologists 2012 Preanesthesia Evaluation
28 American Society of Anesthesiologists 2010 Standards for basic anesthetic monitoring

Recommendation: use the ASA Standards for basic anesthetic 4.6. Recovery and discharge
monitoring: approved by ASA House of Delegates, amended on October
2010. (Grade A). Recovery after sedation should be under supervision and can be
in area where sedation was administered or other area having well
4.5. Assessment of level of sedation monitoring of the child during recovery. They should be monitored
during recovery time until they rich Aldrete score of 9e10. Children
Studies show that frequent monitoring of patients level of undergo PSA should be discharged based on clear discharge criteria
sedation or depth helps to detect and manage adverse effects and and authorized by the practitioner who administered the drugs, or
decreases the risk of serious complications of sedation including another appropriately qualified practitioner [1,8].
death. Monitoring level of sedation can avoid the unnecessary Patients should be discharged when consciousness level
depth of sedation and awareness during PSA. Level of sedation returned to pre-sedation level, stable vital sign, and hemodynamic
during PSA is usually monitored with clinical observation, which is status (within 20% of baseline) including no evidence of hypoxia or
performed by judging a sedated patient's response to increasing hypotension. Studies show that the greatest concern for adverse
levels of stimulation or processed electroencephalogram-based events during PSA is 10 min following the last administration of
depth of anesthesia (DoA) monitoring devices commonly used sedation and removal of painful stimuli, adverse events are rare
bispectral index (BIS). The use of BIS monitoring for assessing after 25 min. If there were no adverse events during PSA, patients
sedation reflects trends rather than rather than specific end point can be safely discharged after 30 min of receiving the last dose of
for amnesia, sedation and analgesia, so that clinical assessment of medication.[22]
level of sedation is primary for monitoring level of sedation Pediatrics patients undergo PSA can be discharged safely after
[20,21,28]. 30 min of the last dose of medication when no o adverse effects
The level of sedation must be monitored using the Modified occurred and appropriately monitored after the procedure.
RAMSEY Sedation Scale or Modified Observers Assessment of Recommendation: Recovery after PSA must be under supervision
Alertness/Sedation Scale (MOAA/S) (See Appendix 4 and 5). and near the area of sedation administered or PACU and discharge
Recommendation: Patients level of sedation should be assessed must be after 30 min following last administration sedative medica-
with clinical observations of patients’ response using the Modified tion and reaching Aldrete Discharge score of 9 to 10 (see Appendix 6).
RAMAY Sedation Scale (Grade A). (Grade A).

Table 2
Level of evidence and grade of recommendations.

Level of evidences Grading criteria Grade of recommendation

1a Systematic reviews of RCTs including meta-analysis A

1b Individual RCT with narrow confidence interval A
1c All or non-studies- met when all participants died before the Rx become available but some now survive on it, B
or when some patients died before the Rx
becomes available, but non now died on it.
2a Systematic review of cohort study B
2b Individual cohort including low quality RCT
2c Outcome research study C
3a Systematic review of case control studies C
3b Individual case control study C
4 Case series, poor quality cohort and case control studies C
5 Expert opinion D

Sources: Hierarchy of evidences used in NICE technology appraisal Oxford Center for evidence based medicine level of evidences: http//www.cebm.net
 S.A. Ali et al. / International Journal of Surgery Open 25 (2020) 52e58 57

Fig. 2. Summary of using Ketofol for PSA in pediatrics.

5. Conclusion Author's contribution

Ketamine and propofol admixture (ketofol) can be safely used Siraj Ahmed conceived the idea design of the project. Bedru
for procedural sedation and analgesia in pediatrics patients. Based Jemal, and Zemedu Awoke, involved in searching strategy, data
on our review of available evidences, ketamine, and propofol pro- extraction, quality assessment, analysis and manuscript prepara-
portion of 1:10 to 2:1 depending on the patient's condition. The tion. All authors have approved the submitted version and any
dose required using the combination of the drugs is less than the substantially modified version that involves the author's contri-
individual drugs required to obtain the required level of sedation. bution to the study; agreed both to be personally accountable for
Sedation should be monitored continuously during the procedure the author's own contributions and to ensure that questions related
by the anesthetist administering sedation (Fig. 2). to the accuracy or integrity of any part of the work, even ones in
which the author was not personally involved, are appropriately
Consent for publication investigated, resolved, and the resolution documented in the
literature.
Not applicable.

Conflict of interest statement

Ethical approval
None.
Ethical approval is not required.

Funding Guarantor

Not applicable. Bedru Jemal.

58 S.A. Ali et al. / International Journal of Surgery Open 25 (2020) 52e58

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admixture (ketofol) is associated with improved hemodynamics as an injuc-
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