ΣΧΟΛΗ ΕΠΙΣΤΗΜΩΝ ΥΓΕΙΑΣ-ΙΑΤΡΙΚΗ ΣΧΟΛΗ

ΑΡΕΤΑΙΕΙΟ ΝΟΣΟΚΟΜΕΙΟ
Α΄ ΑΝΑΙΣΘΗΣΙΟΛΟΓΙΚΗ ΚΛΙΝΙΚΗ
ΚΕΝΤΡΟ ΠΟΝΟΥ & ΠΑΡΗΓΟΡΙΚΗΣ ΑΓΩΓΗΣ

“Ketofol (ketamine/propofol) as a superior sedative

agent to mitigate cardiorespiratory effects and
alleviate pain when used for procedural sedation and
analgesia, a review.”

Name: Papageorgiou Lampriani

Supervising Professor: Chryssoula Staikou, MD, PhD, DESA, Professor in

Anaesthesiology, NKUA
 Introduction
Figure 1: 3D structure of propofol Figure 2: 3D structure of ketamine
(https://pubchem.ncbi.nlm.nih.gov/compound/ (https://pubchem.ncbi.nlm.nih.gov/compound/Ketamine
Propofol#section=3D-Conformer) #section=3D-Conformer

 Definition: Procedural Sedation and Analgesia (PSA) refers to the administration of sedative,
anxiolytic and analgesic drugs to people experiencing stressful and painful procedures at the hospital
under controlled conditions by well-trained health care professionals who can monitor the patient during
this duration and deal with unnecessary complications if these arise.
 Most frequently used sedatives: propofol, ketamine, benzodiazepines, opioids, dexmedetomidine ( +/-
adjuvants: NSAIDs, clonidine, paracetamol etc.)

A mixture of propofol: ketamine used in different ratios (e.g. propofol:

KETOFOL
ketamine 1:1, 1:2. 1:3, 1:4 etc.)
 Advantages and disadvantages of most frequently used sedatives
DRUGS ADVANTAGES
• The “gold-standard” in sedation due to short half-life and
duration of action (2-10 minutes)
• Rapid regain of consciousness w/o residual drowsiness
• Role as an IV anaesthetic, a sedative, a radical scavenger,
an antiemetic, an anti-convulsant
• Easy, predictable and versatile titration, rapid start of
PROPOFOL action (dose-depended depression of level of
consciousness)
 Analgesic properties
 Normal pharyngeal and laryngeal reflexes
 Transient or minimal respiratory suppression
 Cardiovascular and respiratory stimulation
(sympathomimetic effects, bronchodilatation)
 Anti-depressant effects
KETAMINE
DISADVANTAGES
• No analgesic nor muscle-relaxant properties
• Frequent SEs: apnoea and respiratory suppression,
hypotension and other haemodynamic changes, pain on
injection, involuntary movements
• Caution is required in elderly, debilitated, frail, hypovolemic
patients
• High dosage for a prolonged time can cause PRIS
• High risk for nausea and vomiting
• High risk for emergence reactions (dream-like states,
hallucinations, confusion, anxiety, agitation, delirium)
• Dysphoria and unpleasant feeling on awakening
• Increased risk for psychotic episodes
• Prolongation of recovery
• CI for schizophrenia, ophthalmologic disorders, ischemic
cardiac disease, valvular aneurysm, increased intracranial
pressure, history of sensitivity to ketamine
DRUGS ADVANTAGES
• Combined with other sedatives to provide optimum sedation and
analgesia to patients (not pure sedatives, mainly analgesic effects)
• Strong and broad spectrum analgesic properties
OPIOIDS • Feeling of pleasure when used
• Pharmacological properties of anxiolysis, sedation , hypnosis,
muscle relaxation, amnesia and anti-convulsant activity
• Midazolam: fast onset and short duration of action (compared to
BENZO- other benzodiazepines), many routes available
DIAZE-
PINES
• Sedative, anxiolytic, sympatholytic and opioid sparing properties
• Easy transition from sleep to wakefulness (conscious sedation)
• Resembles natural sleep
• Minimal respiratory suppression (even in high doses)
• Prevention of delirium
DEXME- • Some analgesic effect
DETO- • Organ protective effects against ischaemic and hypoxic injury
MIDINE including cardioprotection, neuroprotection, renoprotection
• Safely used through tracheal extubation
DISADVANTAGES
• Common SEs: sedation, respiratory suppression, dizziness, nausea and
vomiting, physical dependence, tolerance, constipation
• Less common SEs: delayed gastric emptying, hyperalgesia, muscle
rigidity, immunologic and hormonal dysfunction and myoclonus
• Common SEs: lethargy, drowsiness, fatigue, impaired motor
coordination, dizziness, vertigo, slurred speech, blurry vision, mood
swings, euphoria, erratic or even hostile behaviour (increased risk for
delirium in geriatric patients)
• Can cause respiratory suppression and haemodynamic changes
• Tolerance, dependence and withdrawal effects associated w/ long term
use
• Not versatile use nor easy or predictable titration
• Can cause significant bradycardia and hypotension
• Needs time to reach desired sedation level
• Prolongation of awakening and discharge time possible
• Not so versatile or easy in titration (bolus can be given in the beginning
within a 10 minute frame). Boluses of propofol might be necessary to
cover for prolonged start of action or incomplete sedation level
METHODS
174 articles [( 3 times advanced Pubmed research (66, 58, 50 articles
sequentially)] using keywords such as “ketofol” or “ketamine and
propofol” and “sedati*” and “analgesia or pain” in “Title/Abstract” of
articles using filters such as “ books and documents”, “clinical study”,
“clinical trial”, “controlled clinical trial”, “meta-analysis”, “multicentre
study”, “randomised controlled trial”, “review”, “systematic review” in
English language and in population of “Adult: 19+ years”

71 were
excluded
(duplicates)
103 articles were screened for further
analysis

53 articles
were excluded
(irrelevant)

50 articles were included in this review

(35 RCTs, 6 reviews, 3 review and
metanalysis, 3 comparative studies, 2
multicentre studies, 1 cohort study)

Figure 3: Flow diagram for ketofol review

RESULTS

1.) Reviews and meta-analyses comparing ketofol with propofol

 Jalili et al., 2016 (ketofol vs propofol, 18 trials):

 reduced respiratory complication profile for ketofol (RR=0.31, 14 trials, p=0.001)
 reduced cardiovascular complication profile w/ less hypotension (RR=0.11, 9 trials, p=0.04) and
bradycardia (RR=0.47, 8 trials, p=0.008) in favour of ketofol vs propofol
 psychomimetic complications more frequent in ketofol group (RR=1.95, 13 trials, p=0.15)
 muscle rigidity less observed for ketofol vs propofol (RR=0.52, 2 trials, p=0.56)
 N+V more frequent in ketofol group (RR=1.23, 12 trials, p=0.72)

• Ghojazadeh et al., 2019 (ketofol vs propofol, N=1250 pts, 5 studies):

 beneficiary respiratory AEs profile for ketofol
 improved sedation quality for ketofol (2 studies)
 similar haemodynamic profile for the two agents
 2.) Reviews and meta-analyses comparing ketofol with ketamine
 Zaki et al. 2022 (ketofol vs ketamine), 6 studies:
 Respiratory profile similar between the two agents.
 Nature and extend of SEs were similar between the groups except nausea and vomiting (more frequently related to ketamine)
(p<0.05).
 Shorter recovery time for ketofol vs single agents.

3.) Systematic reviews comparing ketofol with other sedative agents

 M. Thomas et al., 2011 (propofol vs ketamine vs ketofol 1:1, 10 trials): Patients at great risk to develop respiratory
complications and hypotension are great candidates for the combination of propofol and ketamine compared to either agent
given as solo sedatives.
 Kendra S. et al., 2011 (propofol vs ketofol, ketamine for PSA and RSI, 6 studies): No evidence to support the superiority of
the combination of ketamine and propofol in comparison to propofol alone for PSA.
 Wakai et al., 2015 (propofol vs alternative drugs, 10 studies, N=813 pts): No firm conclusions can be drawn regarding the
comparative effects of administration of propofol w/ or w/o adjunctive analgesics or about any alternative interventions on
AEs and participant satisfaction.
 Barends et al., 2018 (commonly used and new drugs for ambulatory sedation): The properties that would constitute an ideal
sedative have not yet combined in one drug. No definite answers as to which drug is best suited in a specific situation/
scenario.
 G. Loh et al. 2007 (propofol vs ketofol, 11 trials): Fewer patients in the ketofol group experienced respiratory and
haemodynamic compromise compared to propofol although not significantly different between the groups. More nausea and
 4.) Randomised Clinical Trials (RCTs) comparing ketofol with propofol and ketamine

 Ferguson et al., 2016 (ketofol 1:1 vs propofol, N=573 pts): Respiratory complication rate and the need for
intervention and depth of sedation were all similar between the groups. Hypotension was more strongly
related to P group (difference 7%). Patient satisfaction was rated high for both groups.
 Andolfatto et al., 2012 (ketofol 1:1 vs propofol, N=284 pts): Ketofol did not result in reduced respiratory AE
profile compared to propofol (difference 2%, p=0.8), although depth of sedation was more consistent in the
case of ketofol.
 Baykal et al., 2016 (ketofol vs propofol, N=95 pts): Respiratory depression, hypotension and nausea and
vomiting less likely to happen in the of ketofol compared to propofol.
 Phillips et al., 2010 (ketofol vs propofol, N=28 pts): Ketofol might be a wiser choice for PSA since it is less
related to hypotension and deviation from target sedation offering patient comfort and safety.
 Henry et al. 2011 (ketofol vs propofol, N=220 pts): Respiratory depression was similar between
the groups although sedation quality was better in the case of ketofol, so as satisfaction of health
care professionals.
 Frey et al., 1999 (ketofol vs propofol, N = 70 pts): PK group exhibited faster onset of sedation and
less supplemental sedation. The addition of ketamine to propofol improved the quality of sedation
and time to acceptable depth of sedation.
 Frizelle et al., 1997 (ketofol vs propofol, N=40 pts): Sedation scores, supplemental sedation,
respiratory complications, administration of fluids and vasopressors, emergence and recovery
phenomena were all similar between the groups (under spinal anaesthesia and supplemented with
PSA).
 Lemoel et al., 2017 (ketofol 1:1 vs ketamine, N=152 pts): Recovery reactions and the need for any
intervention were 22% less for ketofol. Emesis was less observed for ketofol (3-fold reduction)
compared to ketamine.
 Mortero et al., 2001 (ketofol vs propofol, N=39 pts): The addition of small-dose ketamine on
propofol may mitigate hypoventilation caused by propofol producing positive effects on mood
without perceptual changes post-operatively and may provide earlier recovery of cognition.
 Piper et. al., 2009 (propofol+ketamine vs propofol+saline, N=48 pts): Patients in group A
(ketamine + propofol) had higher satisfaction scores in terms of pain management despite less
opioid consumption.
 Lian Tian et al., 2020 (propofol vs propofol +ketamine 0.25 mg/kg, N=200 pts): Cognitive
functions were more impaired when ketamine was added to propofol for PSA being associated
with less respiratory suppression and hypotension (p<0.05).
 Wang et. al, 2012 and Yalcin et al., 2012 (propofol vs ketamine vs ketofol, N=48 pts and N=90
pts): Ketamine and propofol combination might be a first line agent for sedation for patients with
major depressive disorder who will undergo ECT as treatment.
 5.) RCTs comparing different ratios of ketofol (and other agents)

 Miner et al., 2015 (propofol vs ketofol 1:1 vs ketofol 1:4, N=271 pts): Airway and respiratory events were all
similar between the groups. Recovery agitation was more frequent in the ketofol groups whereas efficacy, depth
and time of sedation and recall and satisfaction did not have significant differences between the groups.
 Ayatollahi et al., 2016 (ketofol 1:1 vs ketofol 1:3, N=100 pts): There was no significant change in the
haemodynamic profile between the two groups while there was a reduction in the hallucination and vomiting
rate and recovery duration time in the ketofol 1:3 group compared to 1:1 ratio.
 Sanatkar et al., 2015 (ketofol ratios 1:2 vs 1:4, N=80 pts): Respiratory depression was greater in ketofol 1:4 so
as hemodynamic changes possibly because the dose of propofol in the mixture was more increased.
 Badrinath et al., 2000 (group 1: propofol +placebo vs group 2: propofol + ketamine 0.94 mg/ml vs group 3:
propofol + ketamine 1.88 mg/ml vs group 4: propofol + ketamine 2.83 mg/ml, N=100 pts):The combination of
propofol and subanaesthetic dose of ketamine is a safe sedative/analgesic mixture during monitored anaesthesia
care whereas ketamine may be a useful adjuvant to propofol sedation especially where procedure is expected to
be painful.
6.) RCTs comparing ketofol with other sedative agents and opioids

 Shuang et al., 2019 (PSa: propofol + saline vs PSu: propofol+sufentanil vs PD:

propofol+dexmedetomidine vs PK:propofol +ketamine, N=120 pts): The combination of PK
succeeded the most haemodynamic and respiratory stability profile in elderly patients who
required PSA to undergo invasive procedures compared to the other agents.
 Kramer et al., 2012 (PR: propofol+remifentanil vs KP: ketamine+propofol, N=37 pts):
Respiratory and haemodynamic stability were similar between the groups except the preoperative
and intraoperative values of HR and MAP but these were not clinically significant.
 Paola Fabbri et al. 2012 (GR: propofol+remifentanil vs GK:propofol+remifentanil+ketamine,
N=322 pts): Respiratory suppression was less observed in the GK group compared to GR.
Intraoperative conditions were better in the case ketamine was added to the sedative regimen.
 Aminiahidashti et al., 2018 (PF: propofol+fentanyl vs PK: propofol + ketamine, N=136 pts): The
pain score was significantly lower in the PF group and that analgesia caused by fentanyl was
significantly superior compared to ketamine (p=0.0).
• Aynur Akin et al., 2005 (PF vs KP, N=40 pts): Respiratory depression was less in the KP group;
this finding was not statistically significant
• Messenger et al., 2008 (PF vs KP, N=63 pts): Patients receiving fentanyl had a 5.1 times the odd of
having a more serious intrasedation event compared to those who had ketamine.
• Akhondzadeh et al., 2016 (PF vs KP, N=98 pts): Rate of apnoea was 32% and 63% in PK and PF
groups respectively (p<0.05).
• Fructher et al., 2017 (KPM: ketamine + propofol + midazolam vs FPM: fentanyl + propofol +
midazolam, N=80 pts): Ketamine is as effective as fentanyl providing adequate analgesia for FFB, a
potent bronchodilator achieving respiratory and haemodynamic stability, therefore its use should be
encouraged for such a purpose.
• Oncul et al., 2016 (KP: ketamine+propofol vs R: remifentanil, N=60 pts): Respiratory depression
was more prominent in the case of remifentanil (16.6% vs 3.3%, p=0.08), whereas satisfaction of
patients was similar and time to recovery was significantly greater in the KP group compared to the
R group.
• Hacer S. Turk et al., 2014 (AP: alfentanil+propofol vs KP: ketamine+propofol (1:2), N=70 pts):
Ketofol succeeded more in establishing haemodynamic stability and good quality of sedation
compared to opioid and propofol combination in elective colonoscopy and required less propofol
dose.
• Hwang et al., 2005 (AP vs KP, N=276 pts): Haemodynamic stability was observed during
sedation with KP. Saturation fell from 98% to 87% and 88% to PK and PA groups respectively
(p<0.01). This fall was not statistically different between the groups. A higher percentage of PK
patients presented amnesia compared to PA (82% vs 61%, p<0.01).
• M Bahreini et al., 2021 (KP: ketamine+propofol vs TF: thiopental + fentanyl, N=96 pts):
Patient’s and provider’s satisfaction rate was greater in KP compared to TF group. Amnesia was
also greater in favor of ketofol. Transient hypoxia was observed in 2.1% and 8.1% in the KP and
TF groups leading to 4.2% and 8.1% airway interventions respectively.
7.) RCTs comparing ketofol with dexmedetomidine

 Sruthi et al., 2018 (D: dexmedetomidine vs KP: ketamine:propofol 1:3, N=50 pts): There were no
significant differences between the groups regarding respiratory, haemodynamic or any other
complications. The time for RSS>3 was significantly less for ketofol (260 vs 460 secs, p=0.00*)
whereas there was a significant decrease of HR in the D group while no significant haemodynamic
change was noted for KP group.
 Elkalla et al,, 2020 (P:propofol vs D:dexmedetomdine vs KP:ketofol, N=60 pts): Oxygen
desaturation (<90%) was more evident in group P as compared to groups D and K (70%, 35%, 30%
respectively, p=0.021).
 Mona Blough El Mourad et al., 2021 (P vs D vs KP, N=75 pts): The time onset and offset of
sedation, duration of TOE procedure and the need for rescue propofol were less in the P and K
groups compared to group D (p<0.05). MAP, HR and CO were significantly decreased in groups P
and D compared to baseline and group K. Hypoxia was more frequently observed in group P.
 8.) A cohort study comparing a premixed type of ketofol to sequential administration of
propofol/ ketamine

• Andrew Greer et al., 2017 (mixed vs sequential ketofol, N=563 pts): Procedural memory was
uncommon for both types (mixed or sequential). Nevertheless, the premixed type was associated
with more unpleasant memory. Association with sex, opioids, moderate sedation and propofol
dose was shown. Respiratory events were more frequent in the premixed type (difference between
the groups 5%).
DISCUSSION
The combination of reduced risk of respiratory and haemodynamic
ketamine and propofol compromise in comparison to propofol.

The addition of increased risk of nausea and vomiting, psychomimetic

ketamine effects, recovery agitation and emergence phenomena.
leading to prolonged recovery time.

Analgesia of ketamine
≠ analgesia of opioids

• Several limitations exist in the majority of the studies which were mentioned in this review:
 the number of patients who participated in a lot of studies was quite limiting.
 all comparator variables between the studies were not the same.
 the types of the procedures were frequently different, the demographic data of the patients and their status also.
 Patients who are candidates to develop respiratory or haemodynamic compromise during
sedation with propofol are good candidates to receive ketofol instead, especially where the
intervention is expected to be painful. This is of course true in case no contraindications exist
for the administration of ketamine.

• Contraindications of use of ketamine:

 a history of schizophrenia or any other psychotic behaviour or epilepsy
 reduced level of consciousness or a history of recent trauma or intracranial bleeding
 a history of uncontrolled hypertension (>190/110 mmHg)
 a history of abdominal or thoracic or any other unsecured aneurysm
 a history of heart failure or recent myocardial infarction or stroke (last 6 months)
 a history of pregnancy
 a known hypersensitivity to any of the medication or substances provided
 a history of raised intracranial pressure (ICP) or intraocular pressure (IOP)
 a status ASA IV or more
 CONCLUSIONS
• There is no strong evidence to support superiority of ketofol compared to other available agents, and
specifically to propofol which is considered the “gold-standard” drug in sedation.
• The addition of ketamine in sub-dissociative doses to propofol is associated with less respiratory and
haemodynamic effects during sedation, achieving analgesia and deeper and more consistent sedation
levels and perhaps more amnesia to patients, being related to very good satisfaction scores not only to
patients but to health-care professionals also.
• Frequent side-effects of ketofol such as increased psychomimetic complications, agitation, nausea and
vomiting and perhaps more prolonged recovery do not outweigh its potential benefits during PSA.
• We consider that its use should be encouraged in cases where there are no contraindications for the use of
ketamine, especially when interventions by physicians are expected to be painful.
• The literature can not provide answers as to what ratio of ketamine: propofol is the best analogy in the
mixture to minimize the risk of respiratory suppression and cardiovascular changes during PSA.
• There is no ideal sedative agent nowadays and in every case we need to individualise as the main dogma
applies in medicine.
Thank you