Single-Shot Sub-Dissociative Dose Ketofol versus Ketamine Alone for Emergency Department Procedural Sedation and Analgesia in Adult

Background

Procedural sedation and analgesia is a crucial component in the emergency department for a painful procedure. Many studies recently proved that the combination of Ketamine and Propofol is safe and effective for procedural sedation and analgesia (PSA) [1-4]. 

Propofol has a rapid onset of sedation and short duration of action. This nonbarbiturate, non opioid, sedative-hypnotic agent has amnestic but no analgesic properties [5]. Propofol is associated with a dose-depended risk of respiratory depression, and this risk appears to be heightened with concomitant opioid use [6]. Ketamine is a unique sedative agent that causes dissociation between the thalamic and limbic systems of the brain. At doses commonly used for procedural sedation (1 to 1.5 mg/kg), Ketamine produces a trance-like cataleptic state [7], whereas at sub dissociative doses (0.1 to 0.6 mg/kg; most commonly 0.3 mg/kg) it maintains potent analgesic and amnestic effects that are accompanied by preservation of protective airway reflexes, spontaneous respiration, and cardiopulmonary stability [8-10]. 

Many studies reveal that mixing Ketamine and Propofol will synergy the effect and balanced the side effect of each other [11-13]. Propofol can be associated with dose-dependent hypotension and respiratory depression [14]. Ketamine is known to preserve respiratory drive, and its sympathomimetic properties increase blood pressure [15]. Ketamine is emetogenic, and Propofol has intrinsic antiemetic properties [16]. Post procedural agitation is a common complication of ketamine sedation, where Propofol is known to be an anxiolytic [17]. Furthermore, the addition of Ketamine provides an analgesic effect that is lacking in a propofol-only procedural sedation and analgesia regimen [18]. 

The Mixture of Ketamine and Propofol at 50:50 and 30:70 ratios were physically compatible and chemically stable for up to 3 hours when stored in capped polypropylene syringes at room temperature with exposure to light [19].

Importance

If the combination of Ketamine/Propofol is safer or more effective than Ketamine alone, it would be preferred for procedural sedation and analgesia in ED.

Goals of this study

We want to compare the total sedation and full physiological recovery time (SRT) of Ketofol and Ketamine alone in ED for procedural sedation and analgesia according to the Quebec guideline (end of induction phase to end of physiologic recovery phase), (Figure 1) [20].

The secondary outcomes were the time of onset, hypoxia incidence, cardiovascular changes, adverse events, Visual analog pain scale, and patients' satisfaction scores.

 Figure 1: Sedation Time Interval.

Study design

This is a prospective randomized controlled trial of adults receiving procedural sedation and analgesia from April 2019 until September 2019 in the ED of a 700beds trauma center Rashid hospital with an annual census of 160,000 patient visits. The study was approved by the medical research committee of Dubai health authority, and informed consent was obtained from all participants or first-degree relative.

Selection of participants

Eligible patients were identified by the treating emergency physicians according to inclusion criteria. The inclusion criteria include patients aged 14 years old or older, and the American Society of Anaesthesiology class 1 to 2 status and patients of any country of origin. Exclusion criteria consisted of hemodynamic instability; pregnancy; head injury; intoxication; an allergy to egg, soy and study medicine; and other traditional ketamine contraindication.

Intervention

A hundred patients were randomized to either Ketamine/Propofol or Ketamine alone using a fixed 1:1 allocation ratio determined by a computer-based random number generator. Small, random block sizes of 4 were used to ensure equal allocation to each treatment arm.  All procedural sedation and analgesia events required the attendance of one certified emergency physician (treating doctor), two registered nurses and whenever possible, a second certified emergency physician (sedating doctor) assigned to the administration of the PSA medication was also present. Ketofol was prepared as a 0.5:1 mixture of 1ml of 50mg/ml Ketamine plus 10ml of 10mg/ml propofol plus 9ml normal saline into a single 20ml polypropylene syringe. Thus, each one milliliter of Ketofol solution contained 2.5mg ketamine and 5mg Propofol and the dosage given to the patients was 1ml of Ketofol solution per 5kg of patient body weight. 

Ketamine prepared as a mixture of 2ml of 50mg/ml Ketamine plus 18ml intra-lipid solution in 20 ml polypropylene syringe. Thus, each milliliter of ketamine solution contained 5mg Ketamine also the dosage given to the patients was 1ml of Ketamine solution per 5kg of patient body weight. The total calculated dose of Ketofol or Ketamine must be given with a one minute. All procedures were performed in the ED in an area equipped with continuous Oxygen saturation, cardiac monitoring and complete airway and resuscitation cart. 

Preprocedural analgesia was administered by the emergency doctor according to the clinical judgment to control the patient's pain when arrival to the ED but a minimum 30-minute washout period between administering any opioid analgesic and the commencement of the procedural sedation and analgesia procedure was mandated. Patients were given supplemental oxygen if pulse oximetry value less than 90% and do not improve by vigorous tactile stimulation and airway repositioning.

Data collection and processing

The standardized procedural and analgesia datasheet was used for all procedures conducted and was completed by the registered nurse and supervised and signed by attended emergency physician. The information collected included three stages.

The first stage: include presedation documentation like ID number, chief complaint, fasting time for liquid and food, vital signs cardio respiratory examination. 

Second stage: include sedation documentation type of procedure performed, any pre procedural medication, weight, the total dose of procedural medication, time of onset, vital sign( pulse rate, respiratory rate, oxygen saturation, systolic, diastolic and mean blood pressure) recorded by the cardio respiratory monitor (NIHON KOHDEN TEC -8300 series), modified Ramsay sedation scale (Table 1), available online at http://www.annemergmed.com) and visual analogue scale every 5 minutes and any adjunctive medication was given. 

Third stage: post sedation documentation or recovery time (recovery time was define as the time when the procedure is completed till a cumulative score of 9, with minimum scores of 2 for the respiratory and oxygen saturation parameters according to the modified Aldrete Recovery Scale (Table 2), available online at http://www.annemergmed.com), patient satisfaction, recall of procedure and agreement about the sedation, lastly the fate of the patient. 

All adverse events are reported according to the Quebec guidelines 14 and documented by the attending physician on standardized datasheet with specific events checkboxes and free-text area for any other events could be recorded. 

Table 1: Ramsay Sedation Scale. 

Table 2:  Modified Aldrete Recovery Scale*.

Primary data analysis

Data are reported using descriptive statistics (IBM SPSS STATISTICS19). Continuous variables are expressed as mean ± SD. Differences in the average (SRT) in minutes between the two groups of patients were tested using t-test.  The results were considered to be significant if p < .05 and are presented with 95% CIs. 

Since the results of the F test (Levene’s test) for evaluating the equality of variance has a p-value of 0.002, which indicates that the variances are significantly different, The independent samples t-test assuming unequal variances was performed to test the hypothesis that the average SRT time in minutes of the two groups of patients given Ketamine and Ketofol was equal.”

Characteristics of the study subjects

This study was conducted during six months, in which 100 patients were enrolled for procedural sedation and analgesia with Ketofol and Ketamine for a painful procedure in the ED. The two groups were similar in demographics and baseline characteristics (Table 3). 

Table 3: Baseline characteristics of study subjects. 

The most commonly performed procedures were orthopedic, comprising 95% of both groups and mostly shoulder dislocation 49% secondly elbow dislocation 22 % and thirdly Colles` fracture, (Table 4). 57% of the study patients were from South Asia country, and 13% were from UAE (Table 5). 

Table 4: Diagnosis. 

Table 5: Nationality. 

Three patients with epilepsy, two with diabetic mellitus, two asthmatic and 88% without any prior medical history, and (Table 6). 32% of the patients are given narcotics, and 19% were given Voltaren as preprocedural pain management. 8% of the patients were given Maxolon as post procedural treatment. Only three patients required an additional dosage of Ketofol to complete the intended procedure, and seven patients required an additional dosage of Ketamine only. 

Table 6: Present illness. 

For our primary outcome, “The average SRT ( minutes ) of the group of patients given Ketamine ( M = 27.4 min , SD = 9.1, N = 50 ) is significantly different from the group of patients given Ketofol ( M = 19.7 min, SD = 5.0, N = 50 ), t ( 76 ) = 5.24, p < 0.0001, 95% confidence Interval is ( 4.78, 10.63 ), (Figure 2). The number of patients discharged over time is more in the Ketofol group than the ketamine group, and patients are discharged sooner in the Ketofol group (20 min) compared to the Ketofol group (30min), (Figure 3).

 Figure 2: RST time (mins) by treatment group for 100 procedural sedations. Circles indicate outliers. 

Figure 3: Number of discharges over time. 

For our secondary outcome, The average time of onset (sec) of the group of patients given Ketamine ( M = 47.8 sec, SD = 23.4, N = 50 ) is significantly different from the group given Ketofol ( M = 35.5 sec, SD  = 13.6, N = 50 ), t ( 98 ) = 3.202, p = 0.002, 95% confidence Interval is ( 4.6, 19.9 ), (Figure 4).

 Figure 4: Time of onset (sec) by treatment group for 100 procedural sedations. Asterisks indicate extreme cases. 

The hypoxia incidence was 21.6% in Ketofol group compared to 34% in the Ketamine group but patient in either group not required bag-valve ventilation, tracheal intubation, or any airway intervention other than airway repositioning or increased oxygen supplement. The average percentage of oxygen saturation of the patients' given Ketamine is lower than the average for the Ketofol patients, except at 5 minutes (Figure 5). However, the patients' average respiratory rate given Ketamine is more or less the same as the Ketofol patients' a (Figure 6).

 Figure 5: The average percentage of oxygen saturation of the patients given Ketamine is lower than the average for the Ketafol patients, except at 5 minutes. 

Figure 6: The average Respiratory rate of the patients given Ketamine is more or less the same as the average for the Ketafol patients. 

Cardiovascular changes are compared between two groups during procedural sedation and analgesia and summarized as the average pulse rate of the patients given Ketamine is consistently more than the average for the Ketofol patients, except at 30 minutes after treatment (Figure 7).

 Figure 7: The average pulse rate of the patient given Ketamine is consistently more than the average for the Ketafol patients, except at 30 minutes after treatment. 

The average SBP of the patients given Ketamine is more than the average for the Ketofol patients up to 25 minutes, and the average is lower than the Ketofol group after 25 minutes after treatment (Figure 8).The average diastolic BP of the patients given Ketamine is more than the average for the Ketofol patients up to 30 minutes, and the average is lower than the Ketofol group from 40 minutes after treatment (Figure 9). The average MAP of the patients given Ketamine is more than the average for the Ketofol patients up to 30 minutes, and the average is lower than the Ketofol group from 40 minutes after treatment (Figure 10).

Figure 8: The average SBP of the patients given Ketamine is more than the average for the Ketafol patient’s up to 25 minutes and the average is lower than the Ketafol group after 25 minutes after treatment.

Figure 9: The average Diastolic BP of the patients given Ketamine is more than the average for the Ketafol patient’s up to 30 minutes and the average is lower than the Ketafol group from 40 minutes after treatment.

Figure 10: The average MAP of the patients given Ketamine is more than the average for the Ketafol patients’ up to 30 minutes and the average is lower than the Ketafol group from 40 minutes after treatment. 

Just 4 (8%) patients given Ketofol experienced post procedural adverse events compared with 26 (52%) given Ketamine experienced post procedural adverse events (Table 7). During PSA, visual analogue pain scaleis summarized in (Table 8), revealing 82% of Ketofol patients and 72% Ketamine patients showing zero visual analogue scales. Patient satisfaction score (0=unsatisfied; 10=satisfied) 90% of the Ketofol patients gave a ten score for satisfaction, and 56% of the Ketamine patients gave a ten score for satisfaction. 

Table 7: Adverse Events Table. 

Table 8: Visual analog scale by Treatment group.

Limitations of the Study

It was a single-center study in which patients were enrolled as a convenience sample according to predetermined inclusion and exclusion criteria. The paediatric population was not included in the study as PSA requirement is more in this age group. The sample size was near minimum for adequate power (95%) with a confidence interval (10%).The study did not contain a Propofol only arm, and thus we are unable to comment on whether Ketofol has any advantage over Propofol alone.

To our knowledge, this is the first prospective randomized controlled study comparing single-shot sub-dissociative dose ketofol versus Ketamine alone for adults’ procedural sedation and analgesia in the emergency department setting. The typical PSA should provide credible onset with an expected depth of sedation, a short duration of action and rapid, uneventful recovery. 

The total sedation time and full physiological recovery (SRT) of Ketofol group were significantly faster than in the Ketamine group, but how far it is of clinical value? So if we compare the recovery times from procedural sedation and analgesia induced by intravenous ketamine range between 50 – 110 minutes [21], to that induced by Ketofol range between 8-15 minutes [1, 12, 22]. As a result, we had hypothesized a 10-minutes difference as clinically meaningful, shown in (Figure 3), where the number of patients discharged overtime is 10 minutes more in the Ketofol group than the ketamine group. 

The incidence of hypoxia in Ketofol group was 21.6% which was acceptable compared to the incidence of hypoxia with 3-arm randomized trial done by Miner et al [23]. They report the incidence as Propofol alone was 29%, Ketofol formulation: 1:1 was 19%, and 1:4 was 32%. Higher incidence of hypoxia in the ketamine group (34%), Miner et al [23] detected a higher rate of subclinical respiratory depression in patients sedated with Ketamine than in patients sedated with Propofol. It is well known that rapid intravenous infusion of Ketamine has the potential to cause apnea [24]. Ketamine is an attractive PSA drug, especially in paediatric age group but in massive doses or combined with other sedative agents; however, respiratory depression and apnea can occur [25-27]. Independent idiosyncratic effects seen after iatrogenic administration include laryngospasm, hypersalivation, and bronchorrhea [28-30]. Generally, the average percentage of oxygen saturation of the patients given Ketofol is higher than the average for the Ketamine patients. It justified by rapid onset and extremely short half-life of Propofol and sub dissociative doses of Ketamine which do not have anaesthetic effects but rather has analgesic effects [30], except at 5 minutes when the maximum effect of the Propofol induces mild respiratory depression but of no significant clinically. In Fact, during PSA in adults’ breathing room air, desaturation detectable by pulse oximeter usually occurs before overt changes in capnometry are identified [31]. 

There were no reported cases of significant cardiovascular adverse events in this study in either treatment group. The average of the pulse rate, systolic blood pressure, diastolic blood pressure, and mean arterial blood pressure is consistently normal more in Ketofol group than Ketamine patients. Indicates that the patients with Ketofol group are cardiovascular stable than Ketamine group except after 30 minutes when the patient of Ketofol group start wake up and probably feel of the pain there are an increase in pulse rate, systolic blood pressure, diastolic blood pressure and mean arterial blood pressure. 

The adverse events of our trail show an effective synergy between Ketamine and Propofol agents. Patients in the Ketamine group exhibited nausea and vomiting in 10% of cases, the incidence of which is estimated to be between 5% and 15% in adults [24], compared with only 2% of cases in the Ketofol group similar finding in Shah et al. [18]. The incidence of problematic recovery agitation in adults receiving Ketamine is estimated to be between 10% and 20% [24].Our study was 20% in the Ketamine group compared to 6% in Ketofol group this difference confirm the blunting effect of the Propofol in inhibiting the emergence reaction of the Ketamine. The same blunting effect was justified about muscle hypertonicity during the Ketamine group PSA, which was 4% compared with nil in the Ketofol group.

In conclusion, when compared with Ketamine alone for adult procedural sedation and analgesia in emergency department setting, the Ketofol with rapid onset of action, faster recoveries with essential cardio respiratory stability, less adverse events, and more comfortable the patient during the procedure and better score of patient satisfaction.