Ketofol (ketamine/propofol) as a superior sedative agent to mitigate cardiorespiratory effects and alleviate pain when used for procedural sedation and analgesia: a review

Authors: Papageorgiou L^1a*, Staikou Ch^2b

¹ MD, MSc, Anaesthesiology Resident
² MD, PhD, DESA, Professor in Anaesthesiology

^a Department of Anaesthesiology, General Hospital of Nicosia, Nicosia, Cyprus
^b 1^st Department of Anaesthesiology, Aretaieion Hospital of Athens, National and Kapodistrian University of Athens, Athens, Greece

*Correspondence: Thessalonikis street 9, Ormidhia, Larnaca, 7530, Cyprus. Tel. 00357-99599185. E-mail:

 

Abstract

Procedural sedation and analgesia (PSA) is often necessary in order to deal with anxiety, pain and stress that may accompany patients at the hospital during invasive, unpleasant and/or painful procedures. The literature has not presented firm conclusions regarding ideal sedative agents in terms of efficacy and safety in PSA or even present firm data regarding superiority of specific drugs over others which are considered the “gold-standard” in sedation (i.e. propofol). Ketofol is a combination of ketamine and propofol and is considered by many health-care professionals to cause less respiratory suppression and haemodynamic instability, ensuring better analgesia and often amnesia, and possibly improved patient satisfaction.

We reviewed the existing evidence regarding superiority of ketofol in mitigating cardiorespiratory effects when administered as a main agent for PSA in comparison to other drugs administered for such purposes underlying the safety and efficacy profile of this cocktail medication. We conducted three times an advanced Pubmed research using the following terms: “ketofol” or “ketamine and propofol” and “sedati*” and “analgesia or pain” in “Title/Abstract” of articles using filters, such as “clinical study”, “clinical trial”, “controlled clinical trial”, “meta-analysis”, “multicentre study”, “randomised controlled trial”, “review”, “systematic review”, “comparative study”, “observational study” in English language and in population of “Adult: 19+ years”. We found 46 articles appropriate to be included in this review.

We found limited evidence to support superiority of ketofol compared to other agents, specifically to propofol, the “gold-standard” drug in sedation; undoubtedly, propofol frequently leads to respiratory suppression, hypotension and bradycardia. It seems that the addition of ketamine to propofol in sub-dissociative doses is associated with less respiratory and haemodynamic complications during PSA, while achieving adequate analgesia and deeper sedation, possibly more amnesia and consequently high satisfaction in both patients and health-care professionals. Frequent side-effects of ketofol, such as increased psychomimetic complications, nausea and vomiting and perhaps more prolonged recovery do not outweigh its potential benefits during PSA. Therefore, we consider that it represents a good choice for PSA, especially in specific populations. Further research with large, well designed, randomised clinical trials is necessary to extract firm conclusions regarding superiority of ketofol against other agents used for PSA.

Introduction

Alleviation of anxiety, pain and stress is often necessary in patients who undergo invasive procedures which are unpleasant and sometimes painful as well.  The medical term “procedural sedation and analgesia” (PSA) refers to the administration of sedative, anxiolytic and analgesic drugs to people experiencing these stressful and painful procedures at the hospital under controlled conditions by well trained-health care professionals who monitor the patient and also deal with any complications that may occur during the procedure. It may also be required to provide amnesia and adequate operating conditions to minimize movement at specific time points. This need often becomes necessary only because of patients’ age¹.

An appropriate medication for PSA should provide rapid, deep, and consistent sedation with minimum adverse effects and complications. It should be associated with minimization of anxiety, maximization of amnesia and analgesia while maintaining haemodynamic stability, and also brief recovery time. Ideally, it should have an antidote and the property of being given orally which is especially important in children². There is no perfect agent as most medications used nowadays combine different sedative, analgesic, amnestic and dissociative properties.

Untreated pain and improper sedation may result in psychological distress such as post-traumatic stress disorder, major depression or delirium. For the alleviation of these symptoms fast-acting opioids can be combined with ketamine, propofol, dexmedetomidine or benzodiazepines, intravenously. Adjuvant drugs such as clonidine or non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol (acetaminophen) may also help³.

Propofol is one of the most popular agents mainly because of good efficacy, relative safety and rapid recovery, despite the risk of respiratory depression, apnoea, hypoxemia and hypotension⁴. Propofol exhibits antiemetic, anticonvulsant and amnestic properties⁵. It has no analgesic actions and therefore, it is usually combined with opioids for painful procedures.

Ketamine is a dissociative sedative agent with analgesic and amnestic properties, which does not cause significant respiratory suppression; patients receiving ketamine usually maintain spontaneous breathing⁶. This is an important beneficial feature of the drug, especially for patients who are continuously turned during wound dressing procedures and where analgo-sedation is often performed by practitioners who are not specialists in anaesthesiology⁷. The main disadvantages of ketamine are its psychomimetic effects and the development of post-operative dysphoria. In addition, it increases the risk for nausea and vomiting and can prolong recovery of patients. It is also important to note that ketamine has sympathomimetic effects, therefore it can increase the cardiac workload⁸.

Propofol has been combined with low dose ketamine to produce a mixture named “ketofol” in order to counteract the side effects of each medication when given alone, thus maintaining cardiovascular and respiratory stability^9,10. The use of lower doses of each drug, along with their synergistic effect reduces the adverse effects while achieving optimal PSA conditions^11,12. Various mixture strengths (mg: mg ratios) have been used ranging from 1:1 up to 1:10 ketamine-to-propofol ratios, but the optimal combination still remains unclear¹².

Regarding the properties of the specific agents in ketofol mixture, ketamine provides analgesia and usually maintains respiratory stability with intact airway reflexes. This is very important since propofol frequently leads to loss of airway reflexes and causes significant respiratory suppression. On the other hand, ketamine causes nausea and vomiting, whereas propofol acts as an antiemetic. Additionally, ketamine causes sympathetic stimulation with tachycardia and hypertension while propofol causes hypotension and usually bradycardia. Finally, analgesia offered by ketamine has an opioid sparing action, therefore less opioid-associated side-effects¹³.

Despite the abovementioned advantages of ketofol, there are studies which showed that the addition of ketamine to propofol presents no benefits so ever. In fact, adding ketamine might just complicate things; while in addition, ketamine may prolong recovery and cause agitation. Thus, a number of investigators suggest that there is no reason to use the combination since propofol is just as safe and efficient¹⁴.

In this review, we present the data from current literature that answer the question whether ketofol is superior to propofol or other sedative/analgesic agents used for PSA regarding cardio-respiratory effects in adult patients. Also, we present the existing data that suggest the ideal analogy of ketamine/ propofol in the ketofol mixture.

Methods

We collected and analysed data relevant to the question about ketofol superiority over other sedatives used in PSA in terms of oxygenation, ventilation and cardiovascular stability (i.e. safety profile). We also analysed data regarding the efficacy profile of ketofol in terms of providing satisfactory sedation, analgesia and amnesia.

We performed three times an “advanced research” in Pubmed database using the keywords: “ketofol” OR “propofol/ketamine” OR “ketamine AND propofol” AND “sedati*” AND “analgesia” OR “pain” to be screened in “Title/Abstract” using filters such as “books and documents”, “clinical study”, “clinical trial”, “clinical trial, phase I”, “clinical trial, phase II”, “clinical trial, phase III”, “clinical trial, phase IV”, “comparative study”, “controlled clinical trial”, “meta-analysis”, “multicentre study”, “observational study”, “pragmatic clinical trial”, “randomised controlled trial”, “review” and “systematic review”. Additional filters we used were: “English language” and “adult: 19+ years” population”.

Articles published up to January 23^rd 2023 were retrieved. Of the 237 articles identified, 98 were duplicates and were excluded. Therefore, 139 articles were screened in relevance to the subject to end up including 46 articles in the present review. Of these 46 studies, 3 were “Reviews and Meta-analyses”, 5 were “Reviews”, 34 were “Randomised Controlled Trials” (RCTs) and 4 were “Comparative Studies” (Fig.1). 

 

The primary outcome in most studies was respiratory suppression. Secondary outcomes included haemodynamic stability [blood pressure (BP) and heart rate (HR) compared to baseline values], recovery time, procedure time, total dosage of propofol required, depth and consistency of sedation, time to reach desired level of sedation, satisfaction score of patients and health-care professionals, nausea and vomiting rate, emergence reactions and any other side-effects rate, Visual Analogue Scale (VAS) score, amnesia rate and discharge time.

Results

Studies comparing ketofol with propofol

One of the most important meta-analyses regarding comparison of ketofol to propofol belongs to Jalili et al. and was published in 2016 (Table 1).

 

This study was based on 18 trials. According to their results, the risk of respiratory complications appeared decreased in the case of ketofol around 70% compared to propofol (RR=0.31 in 14 trials, p=0.001). The same applied for cardiovascular complications. Hypotension was less likely to occur with ketofol, up to 90% reduction (RR=0.11 in 9 trials, p=0.04), whereas risk for bradycardia presented 50% reduced with ketofol compared to propofol (RR=0.47 in 8 trials, p=0.008). Nevertheless, psychomimetic complications were more frequent with ketofol (RR=1.95 in 13 trials, p=0.15), so as nausea and vomiting rates (RR=1.23 in 12 trials, p=0.72)¹⁵.

Ghojazadeh et al. published more recently a meta-analysis based on 5 studies (n=1250 pts). According to their results, the respiratory adverse effects were decreased when ketofol was used instead of propofol for PSA. Additionally, ketofol produced better sedation, whereas the haemodynamic profile was similar between the comparators¹⁶. Another, older review had presented similar results regarding decreased respiratory effects of ketofol compared to propofol, but this finding was not significantly different between the groups¹⁷. In agreement with the above, Thomas et al. suggested that patients at high risk of developing respiratory complications and hypotension on PSA are good candidates for the ketamine/propofol combination compared to either drug alone¹⁸.

On the other hand, Wakai and colleagues suggested that no firm conclusions could be drawn regarding efficacy, adverse events (AEs) and participants’ satisfaction when administering propofol with or without adjunctive analgesic agents. The researchers however mentioned limitations associated with the comparator and sample size of studies included in their review¹. Another important truth in the field came in light in 2018 by Barends et al., who declared that the properties of an ideal sedative have not yet been combined in one drug and that the selection of the drugs for ambulatory sedation depends on many factors such as procedure type, patient characteristics and expectations of both patients and health-care providers¹⁹.

The findings of the RCTs we identified are presented in Table 2.

A few studies showed no significant differences between ketofol and propofol regarding respiratory effects^20-25. It should be noted though, that a number of these studies employed a very small number of participants. However, most of the researchers who conducted these trials seemed to agree that the addition of ketamine to propofol reduced the likelihood for hypotension.

Interestingly, some of the studies claimed that sedation depth was more consistent in the case of ketofol compared to propofol²⁴, whereas the difference between targeted and baseline sedation was less for ketofol rather than propofol²². In fact, ketofol exhibited shorter time to reach deep sedation compared to propofol, but at the cost of longer recovery²⁶. In general, sedation of better quality was achieved with ketamine/propofol combination compared to propofol alone. This was one of the main reasons why some health-care professionals reported to be more satisfied with ketofol rather than propofol²³.

Cognitive functions were more impaired when ketamine was added to propofol for PSA according to a RCT with 200 patients who received sedation for colonoscopy²⁷. Meanwhile, ketofol was shown in some studies to improve mood in the long-term possibly due to the anti-depressant effects of ketamine²⁸. This finding was confirmed by two RCTs that compared ketofol versus propofol and ketamine when used for sedation in patients with major depressive disorder scheduled for electroconvulsive treatment (ECT) sessions. Apparently, ketofol was associated with longer mean seizure time and seizure energy index compared to propofol and shorter recovery time and less side-effects compared to ketamine. In addition, the Hamilton Depression Rating Scale (HDRS) scores gave earlier and better results in the case of presence of ketamine. The researchers concluded that ketofol might be a first line agent for PSA in patients undergoing ECT as treatment for major depressive disorder^29,30.

Satisfaction was rated high by patients and providers in the majority of the studies regarding both ketofol and propofol, without significant differences between the two agents. However, emergence delirium was more strongly associated with ketofol compared to propofol (3% difference in a study of 573 patients who underwent painful procedures at the Emergency Department)²⁵. Paradoxically, one study showed that nausea and vomiting were more frequent with propofol use compared to ketofol (17% vs 4.2%, p=0.041), possibly due to an increased consumption of opioid analgesics²⁶.

Studies comparing ketofol with ketamine

Hany et al. published recently a meta-analysis of 6 studies comparing the effects of ketofol versus ketamine³¹. They found no significant differences in desaturation rates (p=0.1) and other respiratory effects between the groups. Ketofol showed less nausea and vomiting compared to ketamine (p<0.05). The nature and extent of other side-effects (SEs) were found similar between the two agents except nausea (Table 1). Clinicians’ satisfaction was not influenced by the agent, although ketofol appeared to have significantly shorter recovery time compared to ketamine. Interestingly, in both ketofol and ketamine groups the levels of sedation corresponded to the bi-spectral index (BIS) values.

Kendra Sih et al. included 6 studies in their review investigating ketamine when used as a supplement for PSA and rapid sequence induction (RSI) purposes. Adequate sedation, high patient satisfaction and lack of pain and procedural recall were reported in the majority of studies as a result of the use of ketamine for PSA. Recovery agitation was common but could be minimised with premedication midazolam. Lastly, they concluded that there was not enough evidence to support the superiority of a combination of ketamine and propofol over propofol alone for adult patients and that ketamine can be safely used for PSA and RSI, although not a first line agent for the latter³².

Lemoel et al. published the results of a RCT which included 152 adult patients with orthopaedic injuries who required PSA to undergo invasive and painful procedures (Table 2). They randomly allocated patients in two groups: ketamine (K) and ketofol [K/P (1:1)]. One of their results was the reduction of recovery reactions with the use of ketofol [22% less in K/P (1:1) compared to K group, p<0.01]. The risk for emesis was three-fold decreased in the case of ketofol compared to ketamine, whereas satisfaction scores, respiratory effects, hypotensive episodes and other AEs did not have significant differences between the two agents³³.

Studies comparing ketofol with other sedative agents and opioids

Most studies that compare the effects of opioids versus ketofol underlie the improved analgesia provided by opioids at the cost of increased risk of respiratory compromise. Specifically, a study in 2008 showed that patients who received fentanyl had a 5.1 times the odd of having a more serious intrasedation event compared to those who had ketamine as an addition to propofol³⁴ (Table 3).

 

Similarly, there are studies which report that the rate of respiratory complications was significantly increased when opioid was added to the sedative regimen^34-38. When remifentanil was compared to ketofol, the respiratory depression risk increased almost five times more. The same risk increase applied regarding tachycardia rate in remifentanil compared to ketofol³⁹. Interestingly, there was an RCT which showed that only the presence of ketamine in the combination can actually help to mitigate the risk of respiratory effects of the sedative regimens. Specifically, when remifentanil/propofol was compared to ketofol/remifentanil for sedation purposes, the risk for respiratory complications was significantly reduced when ketamine was present in the regimen⁴⁰. Nevertheless, there were studies which showed no significant differences between the opioid combination and ketofol groups or the samples were too small to extrapolate safe conclusions regarding this effect^41-45. Of course, the intervention performed so as the status and the comorbidities of the patient play a major role to this.

Maintenance of haemodynamic stability favours ketofol over opioid/sedative combination^{36,37,42,46,47}. It has to be noted though, that some of these findings were not statistically significant. Furthermore, there were many researchers also who reported that the episodes of haemodynamic change were not clinically important in the majority of the cases^36,42. Other studies reported that the haemodynamic variables did not present significant differences between the groups^35,39,44,45  but none in favour of an opioid and a sedative combination compared to ketofol regarding this outcome.

It is generally accepted that the analgesia provided by opioids is superior to the analgesia provided by ketamine despite the many side-effects of opioids³⁶. Nevertheless, this was not verified by some of the studies which mentioned that analgesia caused by ketamine was as efficient as analgesia caused by opioids and the intervention was managed to be successfully completed in all cases^35,43,45. It depends however on the level of pain caused by the intervention. Interestingly, there was a study which showed that pain was less in the ketamine/propofol group compared to the midazolam/fentanyl group⁴³. A RCT with adult patients who required deep sedation for endoscopic retrograde cholangiopancreatography (ERCP) showed that the addition of ketamine to the propofol and remifentanil combination not only was related to less SEs during or after the procedure but could also create better conditions for the intervention to be successfully completed⁴⁰. Nevertheless, quite often health-care professionals realized that pain could not be dealt enough with ketamine ending up administrating opioids. Indeed, opioids were used in a lot of the studies mentioned in this review, regardless of the agents being compared.

Amnesia was also greatly achieved in the case of ketofol, probably being improved compared to the opioid combination⁴². The same applied regarding sedation depth which was more consistent with ketofol. Nevertheless, there were studies with contrary findings³⁶. Patient satisfaction was rated high in the majority of the studies, both in the ketofol and the opioid regimen groups^{39,42,44,45,47}. One study however showed that the satisfaction rate of the patients was better in the case of opioid use⁴¹. Satisfaction rates for health care professionals were also rated high, without significant differences between the groups^42-45,47. Time to recovery and discharge seemed to appear longer in the case of ketofol^{37,39,41,44,46}. The same applied regarding nausea and vomiting⁴¹ and hallucination rates³⁷. Nevertheless, there were studies which showed that post-operative nausea and vomiting was similar between the comparators⁴⁴  or even being strongly associated with the use of opioids compared to the ketofol group³⁷.

Studies comparing ketofol with dexmedetomidine

When dexmedetomidine was compared to ketofol no significant differences were found regarding respiratory suppression rates⁴⁸ (Τable 4).

This finding underlies the safety profile of ketofol regarding respiratory effects, since dexmedetomidine is not strongly associated with respiratory depression. Differences in desaturation and hypoxia episodes were more evident when propofol became “player” of the “comparison game”^49,50. Dexmedetomidine was associated with longer time to reach sufficient sedation level, prolonged recovery time and increased requirements of rescue propofol compared to ketofol to reach the goal sedation level⁴⁸. Similarly, there are studies which showed that bradycardia and hypotension episodes were frequent in patients who received dexmedetomidine for sedation^48-51. This is not a finding though which has been confirmed by all researchers. In fact, these haemodynamic changes were not clinically important in most of the cases.

Ketofol was the only drug which was able to achieve haemodynamic stability by maintaining (and perhaps increasing) blood pressure (BP), heart rate (HR) and cardiac output (CO) during sedation when it was compared with propofol and dexmedetomidine^49,50. Providers’ satisfaction levels seemed to rank higher in the case of ketofol, possibly due to that reason. Nevertheless, psychomimetic complications were more frequent when ketamine was present in the mixture⁴⁹. The same applied regarding agitation which presented strongly associated to the use of ketamine, whereas the incidence of agitation was lower when dexmedetomidine or propofol was added to ketamine for comparison⁵².

Interestingly, the combination of ketamine and dexmedetomidine (K/D) has been compared to ketofol when administered for sedation in patients after cardiac surgery [coronary artery by-pass graft (CABG)]. Group K/D exhibited reduced time of weaning and extubation compared to ketofol group, whereas fentanyl consumption was significantly less with K/D compared to ketofol. Both these findings were statistically significant. Haemodynamics and length of stay in the Intensive Care Unit (ICU) were comparable between the groups in this study⁵³. Similarly, the combination of dexmedetomidine and propofol (D/P) has been compared to ketofol. This was a small study performed in patients who required sedation to undergo upper gastrointestinal endoscopy. Their findings were that D/P and ketofol are appropriate and safe sedatives with minimal AEs when used for such purposes. Nevertheless, D/P appeared superior to ketofol in terms of sedation depth, while ketofol proved superior in terms of early recovery⁵⁴.

Another RCT compared all possible combinations. It was performed in 120 elderly patients who required sedation to undergo gastrointestinal endoscopy. The comparators were propofol/saline (P/Sa, control group), propofol /sufentanil (P/Su), propofol/ dexmedetomidine (P/D) and ketofol. The area under the curve (AUC) for HR was lowest in the P/D group, whereas the AUC for saturation (SaO₂) was higher in groups P/D and ketofol. The P/D group exhibited the highest incidence of bradycardia and hypotension whereas the control group presented the highest rate of hypoxia episodes. Propofol consumption was lowest in the ketofol group. Apparently, the ketofol group succeeded the most haemodynamic and respiratory stability in elderly patients as shown by this study⁵¹.

Studies comparing different ratios of ketofol (and other agents)

Different ratios of ketamine/propofol combination were compared in various studies but the ideal analogy to the mixture still remains undetermined. Most studies in this domain were performed in children, possibly because ketamine is more frequently used to children compared to the adult population for sedation. We identified 5 studies which compared different ratios of ketofol in adult population (Τable 5).

As expected, the higher the dosage of ketamine, thus less propofol in the mixture, the more reduced the risk of respiratory suppression and haemodynamic compromise. On the other hand, the increased dose of ketamine is associated with more nausea and vomiting, psychomimetic complications, agitation and prolonged recovery⁵⁵. In most studies, the need for opioid rescue appeared inversely analogous to the ketamine dose; meaning that higher doses of ketamine in the mixture were associated with less need for opioids^56,57.

In a large RCT performed in patients ASA I-III undergoing interventional radiological procedures under sedation, the groups of propofol, ketofol (1:1) and ketofol (1:4) were used. Paradoxically, the airway and respiratory AEs did not appear to have significant differences between the groups. The same applied regarding other outcomes, including efficacy, time and depth of sedation, reported pain, recall and general satisfaction⁵⁸. On the contrary, when ketofol (1:2) was compared to ketofol (1:4) in another study, the haemodynamic change was more pronounced as the dose of propofol increased in the mixture, meaning it was greater in group (1:4) compared to the (1:2) group. In the same way, respiratory depression was less evident for group (1:2). Nevertheless, it is important to mention that in this study the doses of ketamine and propofol in the ratio (1:4) were 2.25 mg/ml and 9 mg/ml respectively. The doses became 4.5 mg/ml and 9 mg/ml for the ratio (1:2) respectively⁵⁷. Therefore, we can easily realise that there is great discrepancy even regarding the doses in the mixture between the studies, regardless of the ratios of the two drugs present.

Interestingly, a study comparing the ratios (1:1) and (1:2) showed that the number of over-sedated patients increased as the dosage of ketamine decreased in the mixture, because these patients required more extra propofol (rescue) to complete the intervention⁵⁹.

DISCUSSION

Most of the researchers agree that the combination of ketamine and propofol is associated with a reduced risk of respiratory and haemodynamic compromise in comparison to propofol^15,18,26,27. The addition of subanaesthetic doses of ketamine provides not only sufficient analgesia with preservation of a patent airway, breathing and reflexes but is also associated with reduced dose of propofol in the mixture, therefore less risk of developing apnoea, hypotension and bradycardia¹⁴. Regarding side effects, many researchers seem to agree that the addition of ketamine leads to increased risk of nausea and vomiting, psychomimetic effects, recovery agitation and emergence phenomena and finally prolonged recovery time^15,17. Nevertheless, premedication with midazolam can mitigate the latter phenomena³².

There are a few studies which showed no difference between ketofol and propofol regarding respiratory^20-25 and haemodynamic complications¹⁶. The same applied for other side-effects, time of sedation, recovery time and satisfaction of patients and health-care professionals^24,27.

In relation to other sedative agents, ketofol seems to present both advantages and disadvantages. Apparently, the analgesia provided by ketamine in the mixture of ketofol is not sufficient in comparison to opioid analgesia³⁶. Nevertheless, it is considered a successful opioid sparing option, which is especially important in cases where administration of many opioids should be avoided. It is well known that opioids present synergistic effects with other sedatives and can lead to increased risk of respiratory and haemodynamic compromise, especially in opioid naive patients.

Regarding benzodiazepines, the use of midazolam may lead to prolongation of awakening. Also, titration to optimal sedation with midazolam is neither so versatile nor predictable. Respiratory effects are also frequent with this drug. Administration of midazolam can end up extremely problematic in specific populations, such as geriatric patients where prolongation of recovery and delirium are frequent and obese or sleep apnoea patients where respiratory effects, mainly hypoventilation, hypercapnia, apnoea and easy loss of airway consist issues of extreme clinical significance⁶⁰.

Similarly to dexmedetomidine, ketofol is also not frequently associated with respiratory suppression. Though a very useful and advantageous agent, dexmedetomidine appears to have some drawbacks. Bradycardia, hypotension and even hypertension can occur during its use⁶¹. Additionally, dexmedetomidine requires some time to reach target sedation level and frequently needs boluses of propofol to achieve that. On the contrary, ketofol seems to require less propofol rescue while at the same time it can achieve sedation of higher quality and in less time than dexmedetomidine⁴⁸. Furthermore, ketofol was the only sedative in some studies which was able to succeed cardiovascular stability during its’ use for sedation purposes while maintaining and perhaps increasing arterial pressure, heart rate and cardiac output^49,50. Nevertheless, the dosage of ketamine should be taken into consideration during its use since there are many cases where increase of cardiac workload is not desirable nor expected, especially in people with non stable coronary artery disease.

Several limitations exist in the majority of the studies which were included in the present review. Specifically, the sample size was small in several studies, while in addition, the comparator variables were not the same. Additionally, the types of the procedures were frequently different, the demographic data of the patients and their status also; even the dosages of the drugs were different among ketofol mixtures, regardless of the ratios present. Therefore, caution is needed for the extrapolation of safe conclusions and generalization of the findings to different populations and procedures. It is well known that the selection of drugs for PSA depends on many factors, such as the procedure type, patient characteristics, expectations of both patients and the health-care providers¹⁹. Unfortunately, all properties that would constitute an ideal sedative have not yet been combined in one drug¹⁹. There is no golden recipe and drug combinations should be tailored to each individual case.

Nevertheless, literature agrees that ketofol is associated with less respiratory and haemodynamic suppression in comparison to propofol which is considered the “gold-standard” in sedation¹⁵. Therefore, patients at risk of respiratory or haemodynamic compromise during sedation with propofol are good candidates to receive ketofol instead¹⁸, especially where the intervention is expected to be painful. This is suggested only when ketamine is not contraindicated; known contraindications of ketamine are history of schizophrenia or other psychotic behaviour or epilepsy, reduced level of consciousness, recent trauma or intracranial bleeding, raised intracranial pressure, uncontrolled hypertension (>190/110 mmHg) or high risk coronary artery disease, moderate or severe hepatic dysfunction, history of heart failure or recent myocardial infarction or stroke (last 6 months), pregnancy or known hypersensitivity, raised intraocular pressure and  history of thyrotoxicosis⁶².

Finally, the literature has not provided an answer regarding the optimal ratio of ketamine: propofol in the ketofol mixture in order to maintain respiratory and haemodynamic stability while providing adequate sedation and analgesia, but without prolonging recovery. Most studies designed to answer that question have been performed in children. The most relevant study belongs to Coulter et al. and involved patients in good health, aged between 2 and 20 years who received ketofol (ratios from 1:1 up to 1:10) for PSA. The investigators concluded that the optimal ratio of ketamine: propofol is 1:3 for intermittent doses and 1:4 for a continuous infusion⁶³. It is possible that the same ratios may apply to adult population as well, but perhaps not to elderly or fragile patients with significant co-morbidities.

Conclusions

There is no strong evidence in the literature to support the superiority of ketofol compared to other available agents, and specifically propofol which is considered the “gold-standard” in sedation. The literature is also inconclusive regarding the ideal ratio of ketamine: propofol in terms of ketofol optimal efficacy and safety. It seems that the addition of ketamine in sub-dissociative doses to propofol is associated with less respiratory and haemodynamic effects during sedation, better analgesia, deeper and more consistent sedation, perhaps more amnesia in patients and also high satisfaction in both patients and health care providers. Frequent side-effects of ketofol such as increased psychomimetic effects, agitation, nausea and vomiting and perhaps prolongation of recovery may not outweigh its potential benefits during PSA. Therefore, we consider that ketofol use should be encouraged in cases where there are no contraindications for ketamine, especially when interventions are expected to be painful and when the risk of respiratory depression is high. Definitely, more large well-designed randomised clinical trials are necessary to extract robust conclusions regarding superiority of ketofol against other agents during PSA.

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Addittional materials: No

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Acknowledgements:
Not applicable

Authors’ contributions:
PL searched the literature, drafted the paper and is the lead author. SC contributed to the planning of the review, the critical revision of the draft and the writing of the final version of the paper.

Funding:
Not applicable.

Availability of supporting data:
The datasets analyzed during the current article are available from the corresponding author on reasonable request.

Ethical approval and consent to participate:
No IRB approval required.

Consent for publication:
Patients consents were obtained

Competing interests:
The authors declare that they have no competing interests.

Received: February 2023, Accepted: February 2023, Published: March 2023.

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References

1. Wakai A, Blackburn C, McCabe A, Reece E, O’Connor G, Glasheen J, et al. The use of propofol for procedural sedation in emergency departments. Cochrane Database Syst Rev. 2015;2015(7):Cd007399.
2. Mahajan C, Dash HH. Procedural sedation and analgesia in pediatric patients. J Pediatr Neurosci. 2014;9(1):1-6.
3. O’Connor RE, Sama A, Burton JH, Callaham ML, House HR, Jaquis WP, et al. Procedural sedation and analgesia in the emergency department: recommendations for physician credentialing, privileging, and practice. Ann Emerg Med. 2011;58(4):365-70.
4. Frazee BW, Park RS, Lowery D, Baire M. Propofol for deep procedural sedation in the ED. Am J Emerg Med. 2005;23(2):190-5.
5. Lundström S, Twycross R, Mihalyo M, Wilcock A. Propofol. J Pain Symptom Manage. 2010;40(3):466-70.
6. Gao M, Rejaei D, Liu H. Ketamine use in current clinical practice. Acta Pharmacol Sin. 2016;37(7):865-72.
7. Gregoretti C, Decaroli D, Piacevoli Q, Mistretta A, Barzaghi N, Luxardo N, et al. Analgo-sedation of patients with burns outside the operating room. 2008;68(17):2427-43.
8. Zanos P, Moaddel R, Morris PJ, Riggs LM, Highland JN, Georgiou P, et al. Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms. Pharmacol Rev. 2018;70(3):621-60.
9. Willman EV, Andolfatto G. A prospective evaluation of “ketofol” (ketamine/propofol combination) for procedural sedation and analgesia in the emergency department. Ann Emerg Med. 2007;49(1):23-30.
10. Arora S. Combining ketamine and propofol (“ketofol”) for emergency department procedural sedation and analgesia: a review. West J Emerg Med. 2008;9(1):20-3.
11. Andolfatto G, Willman E. A prospective case series of single-syringe ketamine-propofol (Ketofol) for emergency department procedural sedation and analgesia in adults. Acad Emerg Med. 2011;18(3):237-45.
12. Slavik VC, Zed PJ. Combination ketamine and propofol for procedural sedation and analgesia. 2007;27(11):1588-98.
13. Lee EN, Lee JH. The Effects of Low-Dose Ketamine on Acute Pain in an Emergency Setting: A Systematic Review and Meta-Analysis. PLoS One. 2016;11(10):e0165461.
14. Green SM, Andolfatto G, Krauss BS. Ketofol for procedural sedation revisited: pro and con. Ann Emerg Med. 2015;65(5):489-91.
15. Jalili M, Bahreini M, Doosti-Irani A, Masoomi R, Arbab M, Mirfazaelian H. Ketamine-propofol combination (ketofol) vs propofol for procedural sedation and analgesia: systematic review and meta-analysis. Am J Emerg Med. 2016;34(3):558-69.
16. Ghojazadeh M, Sanaie S, Paknezhad SP, Faghih SS, Soleimanpour H. Using Ketamine and Propofol for Procedural Sedation of Adults in the Emergency Department: A Systematic Review and Meta-Analysis. Adv Pharm Bull. 2019;9(1):5-11.
17. Loh G, Dalen D. Low-dose ketamine in addition to propofol for procedural sedation and analgesia in the emergency department. Ann Pharmacother. 2007;41(3):485-92.
18. Thomas MC, Jennett-Reznek AM, Patanwala AE. Combination of ketamine and propofol versus either agent alone for procedural sedation in the emergency department. Am J Health Syst
19. Barends CRM, Absalom AR, Struys M. Drug selection for ambulatory procedural sedation. Curr Opin Anaesthesiol. 2018;31(6):673-8.
20. Frizelle HP, Duranteau J, Samii K. A comparison of propofol with a propofol-ketamine combination for sedation during spinal anesthesia. Anesth Analg. 1997;84(6):1318-22.
21. Frey K, Sukhani R, Pawlowski J, Pappas AL, Mikat-Stevens M, Slogoff S. Propofol versus propofol-ketamine sedation for retrobulbar nerve block: comparison of sedation quality, intraocular pressure changes, and recovery profiles. Anesth Analg. 1999;89(2):317-21.
22. Phillips W, Anderson A, Rosengreen M, Johnson J, Halpin J. Propofol versus propofol/ketamine for brief painful procedures in the emergency department: clinical and bispectral index scale comparison. J Pain Palliat Care Pharmacother. 2010;24(4):349-55.
23. David H, Shipp J. A randomized controlled trial of ketamine/propofol versus propofol alone for emergency department procedural sedation. Ann Emerg Med. 2011;57(5):435-41.
24. Andolfatto G, Abu-Laban RB, Zed PJ, Staniforth SM, Stackhouse S, Moadebi S, et al. Ketamine-propofol combination (ketofol) versus propofol alone for emergency department procedural sedation and analgesia: a randomized double-blind trial. Ann Emerg Med. 2012;59(6):504-12.e1-2.
25. Ferguson I, Bell A, Treston G, New L, Ding M, Holdgate A. Propofol or Ketofol for Procedural Sedation and Analgesia in Emergency Medicine-The POKER Study: A Randomized Double-Blind Clinical Trial. Ann Emerg Med. 2016;68(5):574-82.e1.
26. Baykal Tutal Z, Gulec H, Derelı N, Babayıgıt M, Kurtay A, Inceoz H, et al. Propofol-ketamine combination: a choice with less complications and better hemodynamic stability compared to propofol? On a prospective study in a group of colonoscopy patients. Ir J Med Sci. 2016;185(3):699-704.
27. Tian L, Luan H, Zhu P, Zhang Z, Bao H. A randomized controlled trial for measuring effects on cognitive functions of adding ketamine to propofol during sedation for colonoscopy. Medicine (Baltimore). 2020;99(36):e21859.
28. Mortero RF, Clark LD, Tolan MM, Metz RJ, Tsueda K, Sheppard RA. The effects of small-dose ketamine on propofol sedation: respiration, postoperative mood, perception, cognition, and pain. Anesth Analg. 2001;92(6):1465-9.
29. Yalcin S, Aydoğan H, Selek S, Kucuk A, Yuce HH, Karababa F, et al. Ketofol in electroconvulsive therapy anesthesia: two stones for one bird. J Anesth. 2012;26(4):562-7.
30. Wang X, Chen Y, Zhou X, Liu F, Zhang T, Zhang C. Effects of propofol and ketamine as combined anesthesia for electroconvulsive therapy in patients with depressive disorder. J ect. 2012;28(2):128-32.
31. Zaki HA, Shallik N, Shaban E, Bashir K, Iftikhar H, Mohamed Khair Y, et al. An Analytical Comparison Between Ketamine Alone and a Combination of Ketamine and Propofol (Ketofol) for Procedural Sedation and Analgesia From an Emergency Perspective: A Systematic Review and
32. Sih K, Campbell SG, Tallon JM, Magee K, Zed PJ. Ketamine in adult emergency medicine: controversies and recent advances. Ann Pharmacother. 2011;45(12):1525-34.
33. Lemoel F, Contenti J, Giolito D, Boiffier M, Rapp J, Istria J, et al. Adverse Events With Ketamine Versus Ketofol for Procedural Sedation on Adults: A Double-blind, Randomized Controlled Trial. Acad Emerg Med. 2017;24(12):1441-9.
34. Messenger DW, Murray HE, Dungey PE, van Vlymen J, Sivilotti ML. Subdissociative-dose ketamine versus fentanyl for analgesia during propofol procedural sedation: a randomized clinical trial. Acad Emerg Med. 2008;15(10):877-86.
35. Akhondzadeh R, Ghomeishi A, Nesioonpour S, Nourizade S. A comparison between the effects of propofol-fentanyl with propofol-ketamine for sedation in patients undergoing endoscopic retrograde cholangiopancreatography outside the operating room. Biomed J. 2016;39(2):145-9.
36. Aminiahidashti H, Shafiee S, Hosseininejad SM, Firouzian A, Barzegarnejad A, Kiasari AZ, et al. Propofol-fentanyl versus propofol-ketamine for procedural sedation and analgesia in patients with trauma. Am J Emerg Med. 2018;36(10):1766-70.
37. Seleem WM, El Hossieny KM, Abd-Elsalam S. Evaluation of Different Sedatives for Colonoscopy. Curr Drug Saf. 2020;15(1):20-4.
38. Bahreini M, Talebi Garekani M, Sotoodehnia M, Rasooli F. Comparison of the efficacy of ketamine- propofol versus sodium thiopental-fentanyl in sedation: a randomised clinical trial. Emerg Med J. 2021;38(3):211-6.
39. Oncul S, Gaygusuz EA, Yilmaz M, Terzi H, Balci C. Comparison of ketamine-propofol and remifentanil in terms of hemodynamic variables and patient satisfaction during monitored anaesthesia care. Anaesthesiol Intensive Ther. 2016;48(2):116-21.
40. Fabbri LP, Nucera M, Marsili M, Al Malyan M, Becchi C. Ketamine, propofol and low dose remifentanil versus propofol and remifentanil for ERCP outside the operating room: is ketamine not only a “rescue drug”? Med Sci Monit. 2012;18(9):Cr575-80.
41. Akin A, Guler G, Esmaoglu A, Bedirli N, Boyaci A. A comparison of fentanyl-propofol with a ketamine-propofol combination for sedation during endometrial biopsy. J Clin Anesth. 2005;17(3):187-90.
42. Hwang J, Jeon Y, Park HP, Lim YJ, Oh YS. Comparison of alfetanil and ketamine in combination with propofol for patient-controlled sedation during fiberoptic bronchoscopy. Acta Anaesthesiol Scand. 2005;49(9):1334-8.
43. Nejati A, Moharari RS, Ashraf H, Labaf A, Golshani K. Ketamine/propofol versus midazolam/fentanyl for procedural sedation and analgesia in the emergency department: a randomized, prospective, double-blind trial. Acad Emerg Med. 2011;18(8):800-6.
44. Kramer KJ, Ganzberg S, Prior S, Rashid RG. Comparison of propofol-remifentanil versus propofol-ketamine deep sedation for third molar surgery. Anesth Prog. 2012;59(3):107-17.
45. Fruchter O, Manevich Y, Carmi U, Rozengarten D, Kramer MR. Prospective Randomized Trial Evaluating Ketamine for Adult Bronchoscopy. J Bronchology Interv Pulmonol. 2017;24(4):279-84.
46. Türk H, Aydoğmuş M, Ünsal O, Işıl CT, Citgez B, Oba S, et al. Ketamine versus alfentanil combined with propofol for sedation in colonoscopy procedures: a randomized prospective study. Turk J Gastroenterol. 2014;25(6):644-9.
47. Kılıc E, Demiriz B, Isıkay N, Yıldırım AE, Can S, Basmacı C. Alfentanil versus ketamine combined with propofol for sedation during upper gastrointestinal system endoscopy in morbidly obese patients. Saudi Med J. 2016;37(11):1191-5.
48. Sruthi S, Mandal B, Rohit MK, Puri GD. Dexmedetomidine versus ketofol sedation for outpatient diagnostic transesophageal echocardiography: A randomized controlled study. Ann Card Anaesth. 2018;21(2):143-50.
49. Elkalla RS, El Mourad MB. Respiratory and hemodynamic effects of three different sedative regimens for drug induced sleep endoscopy in sleep apnea patients. A prospective randomized study. Minerva Anestesiol. 2020;86(2):132-40.
50. El Mourad MB, Shaaban AE, El Sharkawy SI, Afandy ME. Effects of Propofol, Dexmedetomidine, or Ketofol on Respiratory and Hemodynamic Profiles in Cardiac Patients Undergoing Transesophageal Echocardiography: A Prospective Randomized Study. J Cardiothorac Vasc Anesth. 2021;35(9):2743-50.
51. Yin S, Hong J, Sha T, Chen Z, Guo Y, Li C, et al. Efficacy and Tolerability of Sufentanil, Dexmedetomidine, or Ketamine Added to Propofol-based Sedation for Gastrointestinal Endoscopy in Elderly Patients: A Prospective, Randomized, Controlled Trial. Clin Ther. 2019;41(9):1864-77.e0.
52. Azizkhani R, Kouhestani S, Heydari F, Majidinejad S. A comparative study of dexmedetomidine and propofol to prevent recovery agitation in adults undergoing procedural sedation with ketamine: A randomized double-blind clinical trial. Am J Emerg Med. 2021;50:167-72.
53. Mogahd MM, Mahran MS, Elbaradi GF. Safety and efficacy of ketamine-dexmedetomidine versus ketamine-propofol combinations for sedation in patients after coronary artery bypass graft surgery. Ann Card Anaesth. 2017;20(2):182-7.
54. Tekeli AE, Oğuz AK, Tunçdemir YE, Almali N. Comparison of dexmedetomidine-propofol and ketamine-propofol administration during sedation-guided upper gastrointestinal system endoscopy. Medicine (Baltimore). 2020;99(49):e23317.
55. Ayatollahi V, Vafaiyan M, Hatami M, Behdad S. Two Different Concentrations of Ketofol for Procedural Sedation and Analgesia in Closed Reduction of Nasal Fracture. J Craniofac Surg. 2016;27(4):996-1000.
56. Badrinath S, Avramov MN, Shadrick M, Witt TR, Ivankovich AD. The use of a ketamine-propofol combination during monitored anesthesia care. Anesth Analg. 2000;90(4):858-62.
57. Sanatkar M, Abianeh SH, Ghazizadeh S, Rahmati J, Ghanbarzadeh K, Fathi HR, et al. The Comparison of Infusion of Two Different Sedation Regimens with Propofol and Ketamine Combination During Plastic and Reconstructive Surgery. Aesthetic Plast Surg. 2015;39(1):141-6.
58. Miner JR, Moore JC, Austad EJ, Plummer D, Hubbard L, Gray RO. Randomized, double-blinded, clinical trial of propofol, 1:1 propofol/ketamine, and 4:1 propofol/ketamine for deep procedural sedation in the emergency department. Ann Emerg Med. 2015;65(5):479-88.e2.
59. Erden IA, Pamuk AG, Akinci SB, Koseoglu A, Aypar U. Comparison of two ketamine-propofol dosing regimens for sedation during interventional radiology procedures. Minerva Anestesiol. 2010;76(4):260-5.
60. Ronald MD, Lars EI, Lee FA, Jeanine W-KP, Neal CH, William YL. Miller’s Anesthesia. Eighth ed. Philadelphia: Elsevier Saunders; Copyright: 2015. 837-43 p.
61. Ronald MD, Lars EI, Lee FA, Jeanine W-KP, Neal CH, William YL. Miller’s Anesthesia. Eighth ed. Philadelphia: Elsevier Saunders; Copyright: 2015. 854-9 p.
62. Schwenk ES, Viscusi ER, Buvanendran A, Hurley RW, Wasan AD, Narouze S, et al. Consensus Guidelines on the Use of Intravenous Ketamine Infusions for Acute Pain Management From the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, and the American Society of Anesthesiologists. Reg Anesth Pain Med. 2018;43(5):456-66.
63. Coulter FL, Hannam JA, Anderson BJ. Ketofol dosing simulations for procedural sedation. Pediatr Emerg Care. 2014;30(9):621-30.

 

 

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Citation: Papageorgiou L, Staikou Ch. Ketofol (ketamine/propofol) as a superior sedative agent to mitigate cardiorespiratory effects and alleviate pain when used for procedural sedation and analgesia: A review. Greek e j Perioper Med. 2023; 22 (a): 3-32.

 

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