Ketofol: A Friend or Foe in Procedural Sedation and Analgesia

By Prof James Roelofse, Dept of Anaesthesiology and Critical Care, University of Free State. MB.ChB, MMED, PhD, NDBA (USA)

 

 

I must confess that ketofol (a mixture of Ketamine and propofol) is a friend of mine. Moreover, everyone will have differing views. In a world where we do not yet have an ideal sedative drug, ketofol is an excellent alternative to the ideal drug for procedural sedation and analgesia (PSA). Foe, I’m not sure; I do have concerns when we mix Ketamine and propofol in the same syringe, especially the problem of sterility. Ketamine and propofol are both core PSA agents. 

So far, an ideal intravenous anaesthetic agent has not been found (1). Combining Ketamine and propofol has several ideal sedative, amnesic and analgesic properties. Many clinical studies have been done to evaluate the use of ketofol (2). To date, there is significant interest in ketofol as an agent for PSA.

 

A debate on the merits of ketofol has been going on for quite a while. It is a significant combination in sedation practice used by many different sedation practitioners for various procedures. We do have problems as far as mixing the two drugs in the same syringe is concerned. If this is an issue, then we can solve the problem by giving the two drugs independently. So what is ketofol, and why are some practitioners concerned about its use? Ketofol is a combination of two drugs, racemic Ketamine and propofol. It can be administered as a combination in the same syringe or independently in two separate syringes, following the other. Ketofol (the combination) can also be used as boluses for PSA or as an intravenous infusion with different ratios in adults and children.

 

An important question is why we use Ketamine and propofol. Both drugs have unique characteristics we can exploit in our practice to get as close as possible to the ideal drug. Their actions complement each other. Ketamine preserves respiratory drive and protects against hypoventilation (3).

Its sympathomimetic properties increase blood pressure, but propofol does not. The addition of Ketamine provides analgesia that is lacking in a propofol-only regimen.

Several synergies are apparent between the two drugs. Ketamine can cause nausea and vomiting, according to many practitioners. I believe one sees it rarely with low doses; it is dose-dependent. Ketamine provides amnesia, usually with propofol at 5mg/kg/hr.

 

Propofol

 

Propofol is a sedative/hypnotic with antiemetic properties that could counter Ketamine-associated recovery agitation and emesis. Ketamine adds analgesia to the purely sedative action of propofol. Hallucinations are rarely seen with propofol.

Propofol is associated with a dose-dependent risk of respiratory depression, which is heightened with concomitant opioid use. This can be problematic for the clinician wishing to provide analgesia with opioids, as propofol has no intrinsic analgesic properties.

 

The issues around ketofol for the 

sedation practitioner:

 

• Can we mix Ketamine and propofol (ketofol) in the same syringe? 

   Is it safe? Or is independent dosing of the two drugs more acceptable, especially in children?

   Sterility can be a significant problem when mixing drugs.

• In the mixtures, which ratio is the best? In literature many different ratios are used, e.g.,1:1, 1:2, 1:4, 1:5, 1:6.7, 1:10. 

 The Sedation practitioner should decide which ratio is best for his patients. There is enough literature to come to a reasonable conclusion about which one to use.

  Accumulation of Ketamine with continuous infusion is quite a topic under discussion, as Ketamine has a long context-sensitive half-life which may affect recovery after the procedure.

• Some clinicians would argue against mixing drugs in the same syringe, although it is

  common practice in anaesthesia. We must answer the question whether there are anystudies on the compatibility of propofol and Ketamine in the same syringe.

 

Significant research has been done on the compatibility of propofol and Ketamine in the propofol-ketamine mixture. 

No visible incompatibility was detected. 

One study shows that both drugs were stable in a 1:1 mixture of Ketamine and propofol. (4). The combination is chemically stable and physically compatible when mixed in capped polypropylene syringes.

An emergency department also evaluated the stability of ketamine-propofol mixtures (5). Mixtures of propofol and Ketamine of 50:50 and 30:70 ratios were physically compatible and chemically safe.

 

An excellent study on the compatibility of injectable ketofol with selected other drugs during simulated Y-site injection was done. Propofol injectable emulsion was compatible with 98 0f 112 drugs tested. It was compatible with Ketamine (6).

 

So, why are we so concerned about single-syringe administration? One can say the separation of fat or the separation of emulsion phases, “oily droplets”, precipitation, and 

sterility concerns.

 

Propofol pharmacokinetics

 

Propofol is a non-opioid, non-barbiturate, sedative/hypnotic with a rapid onset and short duration of action (half-life of 4.4min in adults, children 9min) due to rapid equilibration between the blood and the brain. With a rapid metabolic clearance from the blood, propofol is an ideal drug for sedation in adults and children.

 

Propofol is one of the most widely used drugs for procedural sedation in adults and children, owing to its known advantages, but some concerns remain regarding respiratory and/or cardiac complications in patients receiving propofol.

Propofol is an intravenously administered sedative-hypnotic agent with advantages 

including rapid onset and offset of action.

 Due to its known advantages, propofol is commonly used to relieve anxiety and to sedate patients. Nausea and emergency delirium are possible side effects of propofol.

   For children, it is also known that propofol has a strong sedative effect that could be categorised as deep sedation or general anaesthesia.

Researchers claim that adding Ketamine to propofol infusion will prolong recovery unless infusion rates are decreased. 

They suggest an optimal ratio of 1:5 for a 30min procedure and a 1:6.7 ratio for a 95min procedure (7).

Adding Ketamine to propofol can result in an extremely delayed awakening of over 4 hours when a ratio of 1:1 is used for lengthy procedures. This decreased to a delay of 50min when a 1:10 ratio was used.

 

The implications of all this

 

• To improve postoperative recovery, infusion rates should be reduced as there is a possibility of accumulation of Ketamine for longer procedures.

• Ketamine has a long context-sensitive half-life.

• The above simply means we need to give less Ketamine or use some other drug, e.g. Propofol, in its place after 30 -60min of administration.

• A propofol/ketamine ratio of 1:10 ketamine/propofol is believed to be the best ratio.

 

 

How to use Ketamine and propofol

 

• There is no standard dosing regimen as practitioners use different ratios and different doses for different procedures, also depending on the level of sedation required.

• Drugs may be premixed in the same syringe or dosed sequentially with Ketamine administered first to prevent the risk of injection-site pain with propofol.

 

Ketofol doses

 

• Sedation practitioners do use different ratios. It isn’t easy to give ketofol doses.

• A 1:10 mixture is popular for continuous infusion and boluses in adults and children:

20mg ketamine and 200mg propofol in a 20cc syringe.

• A TCI (target-controlled infusion) can be used with an infusion pump starting at levels between 1-2 mcg/ml, depending on the age of the patient and type of procedure. We often start with a level of 2 mcg/ml in small children.

• Using TIVA 2-4mg/kg/hr in an infusion pump is also possible for sedation.

• Boluses in children and adults using a 1:2 mixture of Ketamine and propofol for shorter procedures are very popular. Using a 10ml syringe where 50mg ketamine and 100mg propofol are mixed, a bolus of 0.3 – 0.5mg/kg of Ketamine can be used and repeated after 15 minutes. 

Do we need a BIS monitor for children? Maybe not, as long as you know that this mixture can significantly drop the level of consciousness if we use a rapid intravenous administration. 

Titration is always a good option as it eliminates the guesswork.

Independent dosing, if you prefer this technique:

 

• Independent dosing means Ketamine and propofol are used in two separate syringes (8). Separating the administration of Ketamine and propofol may provide the sedation consistency of Ketamine with the rapid recovery time inherent in propofol boluses.

• The issue of one syringe or two is an interesting one because the differing pharmacokinetics of the two drugs does lead to the logical conclusion that they are best titrated separately.

• In children, an independent dosing technique is probably better for bolus administration if there is no objective way of monitoring the level of consciousness.

• We live in an ever-changing and demanding environment where the sedation practitioner is expected to provide a safe, pain-free and ‘dream-like’ patient with no side effects undergoing various procedures. Ketofol should be considered as part of the armamentarium of the sedation practitioner in providing safe and effective PSA for procedures outside the operating room.

• The question of “Why not use one drug instead of two independently?” remains unanswered. There is no perfect drug, so we will need to find the perfect combination to achieve the perfect sedation. More consideration should probably be given to a strategy to start PSA using ketofol, followed by propofol monotherapy. 

This is especially so in patients on psychotropic drugs and in young children.

• A substantial body of prospective data demonstrates the effectiveness of the single-syringe combination. The recovery time with the single-syringe combination (8 minutes; range 7 to 10 minutes) is longer than that of propofol alone (6 minutes; range 2 to 8 minutes), as one would surmise, but only by a median of 2 minutes. This is probably of no clinical significance.

 

To conclude, which one, ketofol or propofol?

 

Some research says propofol is better than ketofol. 

I leave this to you, dear reader to decide. Can we say which one depends on the procedure done and whether the patient is an adult or child? Let us look at the study objectives.  The research was done to determine whether emergency physician–provided deep sedation with 1:1 ketofol versus propofol results in fewer adverse respiratory events requiring physician intervention when used for procedural sedation and analgesia (9).

 

Conclusion: Ketofol and propofol resulted in a similar incidence of adverse respiratory events requiring the intervention of the sedating physician. Although propofol resulted in more hypotension, the clinical relevance of this is questionable, and both agents are associated with high levels of patient satisfaction.

 

We live in an ever-changing and demanding environment where the sedation practitioner is expected to provide a safe, pain-free and ‘dream-like’ patient with no side effects undergoing a variety of procedures. Ketofol should be considered as part of the armamentarium of the sedation practitioner in providing safe and effective PSA for procedures outside the operating room. The question of “Why not use one drug instead of two?” remains unanswered. 

 

There is no perfect drug, so we will need to find the perfect combination to achieve the perfect sedation.

More consideration should probably be given to a strategy to start PSA using ketofol, followed by propofol monotherapy. This is especially so in patients on psychotropic drugs and in young children.

 

In a patient at low risk of cardiovascular compromise who needs brief sedation, there is not enough information to discern a difference between ketofol at a ratio of 1:2 (higher ketamine proportions have demonstrated prolonged recovery times) and propofol, and there is no safety or analgesic benefit detected for Ketamine to justify the risk of recovery agitation.

 

For compromised patients at risk of hypotension, however, Ketamine and propofol are likely superior to propofol. Given the lower rate of the reported recovery agitation noted in a study in the issue of AEM (America et al.) and the equivocal rate of hypotension between Ketamine and propofol, it appears that ketofol is the better choice for patients at risk for hypotension.

What do we need to consider when we want to avoid the separation of substances (phases of emulsion) in ketofol? 

 

One can call these safety measures.

  Use a new syringe for every patient.

  Use of particular ratios of mixtures, e.g., 1:1, 1:2 or 1:10, probably the best

  Look at the ratios we are using and see if there is any precipitation before

  Administration. We can call this self-study.

  Sterility remains one of our biggest concerns. Ensure that all healthcare professionals that prepare and administer propofol for sedation carefully follow the 

    recommendations for handling and use.

 

Ketamine is one of the most significant drugs available for PSA, and we discover more about this drug. A problem with significant drugs is that you may find people using it for other purposes—one of our biggest problems centres around the drug’s recreational use.

  Ketamine causes dissociative sedation. A good question to ask is what dissociation is. Ketamine dissociates the thalamic-neocortical and limbic systems (emotional brain).

  The dissociative state is characterised by sedation, intense analgesia, amnesia, intact protective reflexes, e.g., coughing and swallowing, and stable cardiovascular and respiratory systems.

 

Ketamine has nearly all the characteristics we exploit/want for procedural sedation,

 

Which makes Ketamine such an attractive and popular drug and ideal to combine with other drugs, e.g., propofol. 

References

 

1. Pandit JJ (2011) Intravenous anesthetic agents. Anesth Intens CareMed 12(4): 144-150

2. Green S, Roback M, Krauss B, et al. Predictors of airway and respiratory adverse events with ketamine sedation

     in the emergency department: an individual-patient

   data meta-analysis of 8,282 children. Ann Emerg Med. 2009;54(2):158-68.

3. Gildasio S, De Oliveira P, Fitzgerald N, et al. The effect of ketamine on hypoventilation during deep sedation with midazolam and propofol. European J of Anaesthesia

     2013; 30:1-9.

4. Calimaran A, Lancaster K, Lerant A, et all. Compatibility of Propofol and Ketamine in Propofol-Ketamine mixture

5. Donnelly R, Willman E, Andolvatto G. Stability of ketamine-propofol mixtures for Procedural Sedation and Analgesia in the emergency department. Can J of Hosp Pharm 2008, 16(6): 426-430

6. Lawrence A, Trissel A, Doward L et al. Compatibility of propofol injectable emulsion with selected drugs during simulated Y-site administration. Am J Health-Syst Pharm 1997; 54: 1287-89

7. Coulter F, Hannam J, Anderson B. Ketofol simulations for dosing in pediatric anesthesia. Pediatric Anesthesia

     ISSN: 1155

8. Shy B, Strayer R, Howland M. Independent dosing of ketamine and propofol may improve procedural

     sedation compared with the combination propofol. http://dx.doi.org/10.1016/j.annemergmed.2012.07.130

9. Ferguson Ian et al. Propofol or Ketofol for Procedural Sedation and Analgesia in Emergency Medicine—The POKER Study: A Randomized Double-Blind Clinical Trial. Ann Emerg Med 2016;68:574-582.

 

Latest News

0 Comments