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Ketofol: A Sedation Alternative

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Propofol Formula
Ketamine Formula

We describe the experience of pain as “an unpleasant sensory and emotional experience” (1). As an essential facet of patient care, sedation and analgesia are of equal importance in the critical care setting for intubated and ventilated patients. The mismanagement of sedation and analgesia can lead to psychological and physiological consequences leading to an increased length of hospital admission and poor patient outcome resulting in long-term disability (1). When caring for patients who will ultimately require intubation and respiratory management via mechanical ventilation, the goals to consider are:

  • limiting patient recall
  • manage pain
  • maintain adequate cerebral oxygenation
  • cerebral perfusion pressure (CPP)
  • facilitate stable hemodynamics
  • relax the brain
  • eventually, allow for a quick recovery from the anesthetic agents following extubation

(2,3)

Common medications used for sedation in the critical care transport medicine environment are: Propofol, Ketamine and Versed. This article seeks to introduce an alternative to these medications by examining the concept of combining Ketamine and Propofol, referred to as Ketofol. What follows is a brief individual overview of Propofol and Ketamine before discussing Ketofol and its pharmacodynamic effects on the neurological and cardiovascular system in addition to its effects on airway management.

Propofol

Known to be a short-acting hypnotic sedative, it interacts with the neurotransmitter γ-aminobutyric acid, commonly referred to as GABA. Propofol directly stimulates GABAA receptors to produce the desired amnesic effect. Propofol helps create a rapid loss of consciousness, rapid emergence from sedation, anxiolysis, amnesia, and preventing nausea. The downside to Propofol is that its side effects induce hypotension, bradycardia, widening of the QRS complex, respiratory depression, apnea, and decrease cerebral blood flow (2).

Ketamine

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Described as a dissociative anesthetic, Ketamine is an N-methyl-D-aspartate amino acid (commonly referred to as NMDA) receptor antagonist. It provides amnestic and analgesic effects by inhibiting afferent pain sensory inputs with a decrease in spinothalamic transmission leading to a reduction in the stimulation of sympathetic response to pain stimulation. Ketamine is rapidly distributed and absorbed into the brain while metabolism occurs in the liver with an elimination half-life of 2-3 hours (2,4). Ketamine causes minimal respiratory depression in addition to being a potent bronchodilator. It has become a favourite in hemodynamically unstable patients due to the lack of cardio depression. Despite Ketamine’s safety profile, it too has unwanted side effects. These include the production of delirium, increased intracranial pressure (albeit found to be transient), increased production of oral secretions, and increased heart rate and blood pressure (also found to be transient) (4).

Mixology 101 – Ketofol

Ketofol results from mixing Ketamine and Propofol and can be mixed in various ratios; commonly 1:1, 2:1 or 3:1 (5). The rationale for combining these two medications is to obtain a mixture that offers the best of both worlds while limiting the unwanted side effects. The combination also facilitates a decrease in the dose of each medication required for the production of sedation while lessening the adverse effects that can occur when administering each drug alone. The net benefit of Ketofol administration results in the potential to decrease the instance of nausea and vomiting while providing more profound sedation and analgesia (in combination with fentanyl) as well as more excellent hemodynamic stability (2,3,5).

Effect of Ketofol on Jugular Venous Oxygen Saturation (SjVO2)

Bhaire et al. (2019) observed a statistically significant lower SjVO2 chronicling in patients who received Propofol than those who received Ketofol at 1-h, 2-h and 6-h time points. A dip in the SjVO2 at 2 hours did occur in the propofol group following the initiation of the study drug and was significantly lower than baseline (P = 0.001). Bhaire et al. (2019) noted observing “the lesser fall and lesser fluctuation in SjVO2 values in patients who received Ketofol”. Similar to the Bhaire et al. (2019) study, other studies have revealed the maintenance of anesthesia with Propofol is associated with “significantly lower levels of SjVO2 compared to inhalation anesthetic agents” (3). The study did not produce a change in SjVO2 by administering different ketamine doses to patients who were already receiving Propofol. Therefore, Bhaire et al. (2019) state the results of their study concerning the effect of Ketofol on SjVO2 are comparable with previous studies examined.

Effect of Ketofol on Brain Relaxation

Bhair et al. (2019) are not aware of any studies which have evaluated the effect of Ketofol on brain relaxation. However, in their research, the quality of brain relaxation in both groups was similar (P = 0.887). Additionally, in both groups, patients were found to have a good brain condition. Bhaire et al. (2019) commented that many studies have shown intravenous anesthetics facilitate an increase in the reduction of ICP compared to inhalational drugs; however, “various anesthetic techniques have not shown any difference in brain relaxation.

Effect of Ketofol on Hemodynamic Stability

Anesthesia has significant complications. These include hemodynamic instability due to induction, intubation, surgical intervention, stress, hypovolemia, and anesthesia agents. The difficulties are more prominent in patients with a history of ischemic heart disease, valvular heart disease and other cardiomyopathies (4,5).

Effects on Airway Management

We categorize laryngoscopy and intubation as noxious stimuli. Critical care practitioners still misunderstand them. If we were to examine a scale classifying noxious stimuli, we would find skin incisions in the middle of the gage; it is classified as more stimulating than electrical pain but is far less rousing than laryngoscopy and intubation. Therefore, the depth of sedation is paramount in the clinical responses to noxious stimuli. Because of its classification, intubation requires more opioid and hypnotic agents to overcome the most refractory response, hypertension and tachycardia. Kayahal et al. (2017) note that Ketofol appears to suppress the sensation of pain and decrease the hemodynamic response better than Propofol alone, leading to a decrease in the need for increasing the dosing of opioids (4).

The main observable impact of Ketofol is on trending blood pressure, for both systolic and diastolic in addition to heart rate. In their work, Kayahal et al. (2017) monitored the trending of a stable pattern following induction, through intubation and into post-intubation time. The hypothesis of this effect is due to the decrease in sympathetic stimulation by the somatic pain stimulatory input. A significant barrier to hemodynamic stability is the overactivation of the sympathetic nervous system (4).

Aslan et al. (2019) also noted similar findings between their ketofol and propofol groups. Their comparison of Erdoğan et al. (2013) compared the effects of Propofol and Ketofol measured on laryngeal mask airway (LMA) condition insertion and hemodynamics in elderly patients. Aslan et al. (2019) found fewer patients requiring push dose pressors such as ephedrine. The total dose of ephedrine required was significantly lower in addition to observing a considerably higher systolic arterial pressure (SAP) in the Ketofol group as compared to the propofol group. This finding correlates to Ketamine’s stimulation of the nervous system and inhibition of norepinephrine reuptake (5).

Ketofol appears to be an alternative to Propofol alone; from the outset of induction, intubation and post-intubation management of a ventilated patient. This strategy could have significant positive implications in the short-term care during transport and long-term management during intensive care unit admission. The immediate benefits patients experience when appropriate sedation and pain management are applied translate into increased hemodynamic stability and suitable cerebral oxygenation. The negative aspects of poorly managing sedation and analgesia have dire consequences for the patient (physiologically and psychologically) and overburden the health care system due to the longer length of admission. Limiting or eliminating these negative aspects will help both, patients and the overall system in which we work.  

References

  1. Jones GE, Machen I. Pre-hospital pain management: the paramedics’ perspective. Accident and Emergency Nursing. 2003;11(3):166–72.
  2. Meyer A. Propofol, Ketamine, and Ketofol Use for Procedural Sedation. International Student Journal of Nurse Anesthesia [Internet]. 2018 Summer [cited 2021 May 24];17(2):48–53. Available from: https://search-ebscohost-com.ezproxy.tru.ca/login.aspx?direct=true&db=ccm&AN=134820275&site=eds-live&scope=site
  3. Bhaire V, Panda N, Luthra A, Chauhan R, Rajappa D, Bhagat H. Effect of combination of ketamine and propofol (ketofol) on cerebral oxygenation in neurosurgical patients: A randomized double-blinded controlled trial. Anesthesia: Essays & Researches [Internet]. 2019 Oct [cited 2021 May 24];13(4):643–8. Available from: https://search-ebscohost-com.ezproxy.tru.ca/login.aspx?direct=true&db=a9h&AN=140432269&site=eds-live&scope=site
  4. Hamid Kayalha, Mohammad Kolahdoozha, Siamak Yaghoobi, Marzieh Beygom Khezri, Seyed Amir Mohajerani, Alireza Jahangirifard. Effect of Ketofol instead of Propofol on hemodynamic stabilization for induction of Anesthesia in Laparatomy. Journal of Cellular and Molecular Anesthesia [Internet]. 2017 May 1 [cited 2021 May 24];2(2):50–4. Available from: https://search-ebscohost-com.ezproxy.tru.ca/login.aspx?direct=true&db=edsdoj&AN=edsdoj.4a18dcaffd2f496dacec9476708ecfe4&site=eds-live&scope=site
  5. Duygu Demiroz Aslan, Muharrem Ucar, Mehmet Ali Erdogan, Mukadder Sanli, Nurcin Gulhas, Cemil Colak, et al. Effects of ketofol and propofol on intubation conditions and hemodynamics without the use of neuromuscular blockers in patients undergoing tympanomastoidectomy. Medicine Science [Internet]. 2019 Jun 1 [cited 2021 May 24];8(2):381–4. Available from: https://search-ebscohost-com.ezproxy.tru.ca/login.aspx?direct=true&db=edsdoj&AN=edsdoj.7c30760f04314732b1276d1ec115a9cc&site=eds-live&scope=site
Chris Farnady

Chris Farnady

Chris is a graduate of Loyalist College’s Primary Care Paramedic program (Bancroft, ON), Durham College’s (Oshawa, ON) Advance Care Paramedic and currently pursuing his Bachelor of Health Science from Thompson Rivers University. Chris began his prehospital care career in 1997 working as an EMR in Alberta’s oil and gas industry and has enjoyed the privilege of working as a Primary Care and Advanced Care Paramedic in Ontario, Northern Manitoba and Alberta. In April 2018 Chris accepted a position with Advanced Paramedic Ltd. and returned to Northern Alberta as an Advanced Care Flight Paramedic for Alberta Health Services’ transport medicine program. In his time away from work, Chris enjoys being at home with his wife and two children. Chris can be reached for comment at chris.farnady@gmail.com.

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