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Objectives: This study evaluated the effectiveness, recovery time, and adverse event profile of intravenous (IV) ketofol (mixed 1:1 ketamine–propofol) for emergency department (ED) procedural sedation and analgesia (PSA) in children.
Methods: Prospective data were collected on all PSA events in a trauma-receiving, community teaching hospital over a 3.5-year period, from which data on all patients under 21 years of age were studied. Patients receiving a single-syringe 1:1 mixture of 10 mg/mL ketamine and 10 mg/mL propofol (ketofol) were analyzed. Patients received ketofol in titrated aliquots at the discretion of the treating physician. Effectiveness, recovery time, caregiver and patient satisfaction, drug doses, physiologic data, and adverse events were recorded.
Results: Ketofol PSA was performed in 219 patients with a median age of 13 years (range = 1 to 20 years; interquartile range [IQR] = 8 to 16 years) for primarily orthopedic procedures. The median dose of medication administered was 0.8 mg/kg each of ketamine and propofol (range = 0.2 to 3.0 mg/kg; IQR = 0.7 to 1.0 mg/kg). Sedation was effective in all patients. Three patients (1.4%; 95% confidence interval [CI] = 0.0% to 3.0%) had airway events requiring intervention, of which one (0.4%; 95% CI = 0.0% to 1.2%) required positive pressure ventilation. Two patients (0.9%; 95% CI = 0.0% to 2.2%) had unpleasant emergence requiring treatment. All other adverse events were minor. Median recovery time was 14 minutes (range = 3 to 41 minutes; IQR = 11 to 18 minutes). Median staff satisfaction was 10 on a 1-to-10 scale.
Conclusions: Pediatric PSA using ketofol is highly effective. Recovery times were short; adverse events were few; and patients, caregivers, and staff were highly satisfied.
ACADEMIC EMERGENCY MEDICINE 2010; 17:194–201 © 2010 by the Society for Academic Emergency Medicine
There has been increasing interest in the use of propofol, a nonopioid nonbarbiturate sedative-hypnotic, for pediatric procedural sedation.1–3 Propofol’s advantages include its rapid onset, short recovery time, and antiemetic effects.4,5 Additionally, the ability to reliably produce sedation and amnesia makes it well-suited to emergency department (ED) practice.4 However, propofol use can be limited by dose-dependent respiratory depression and hypotension. Propofol also lacks any analgesic effect, and thus some clinicians may combine an analgesic medication with propofol sedation for painful procedures. While providing analgesia prior to procedural sedation is considered standard care, the provision of narcotic analgesia during procedural sedation is controversial. It has been shown that the addition of alfentanil, an ultra-short-acting opioid, during procedural sedation with propofol does not result in a difference in reported pain or recall immediately after the procedure, but is associated with an increase in the proportion of patients requiring stimulation to induce breathing.6
Procedural sedation and analgesia (PSA) in children is commonly accomplished using intravenous (IV) or intramuscular (IM) ketamine, a dissociative sedative known to reliably produce analgesia and amnesia.7 There are numerous reports of ketamine’s efficacy and safety in pediatric PSA.4,8,9 Ketamine has been shown to provide analgesia in acutely painful conditions in the ED setting10 and may represent an analgesic option with fewer adverse effects than fentanyl when combined with propofol sedation.11–13
The combination of ketamine and propofol has received interest as a PSA regimen that allows the provision of PSA using drug doses lower than typically required for each agent alone, while the nauseant and psychic recovery effects of ketamine are counterbalanced by the sedative and antiemetic effects of propofol.14,15 Its use in children has been documented in cardiac catheterization procedures using each component drug in separate syringes,16 as well as administered as a mixture in a single syringe.17 Ketamine–propofol mixture has been shown to display stable hemodynamic parameters in human volunteers.18 Ketamine and propofol mixed in polypropylene syringes in a 1:1 ratio and in a 3:7 ratio have been shown to be physically and chemically compatible at room temperature, with a stable and predictable concentration.19
Ketamine–propofol combination appears to provide rapid, reliable, and effective ED PSA with short recovery times and few adverse events. The published data on its use in children are limited to two small series of 20 patients20 and 28 patients.21 Our goal was to evaluate the effectiveness, adverse effect profile, and recovery time of IV mixed ketamine and propofol (“ketofol”) for the provision of ED PSA in children. ED staff and patient/guardian satisfaction were also assessed.
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Three-hundred pediatric patients underwent procedural sedation during the study period. In two patients, the data collection form was lost and was not recoverable. Twelve data sheets (4%) were missing demographic data and were completed by accessing the health records system. Age and ASA class of the patients in each PSA group are detailed in Table 2. Of the 298 patients in whom prospective data were obtained, 219 (73%) received ketamine and propofol mixed 1:1 in the same syringe (ketofol). Demographics and comorbid conditions of patients receiving ketofol PSA are listed in Table 3. The majority of procedures performed with ketofol PSA were orthopedic (Table 4). Of the 219 ketofol PSA events, one (0.4%) did not include a physician satisfaction score, two (0.9%) did not include an RN satisfaction score, and 15 (7%) did not include a patient or caregiver satisfaction score.
Table 2. All PSA Regimens (n = 298 PSA Events)
|PSA Regimen||No. of PSA Events||Age, yr, Median (Range) (IQR)||ASA Class 1 + 2, n (%)||ASA Class 3, n (%)||Comorbid Conditions, n (%)|
|Ketofol IV||219||13 (1–20) (8.0–16.0)||209 (95)||10 (5)||22 (10)|
|Ketamine IV + propofol IV||6||9 (5–18) (6.8–12.0)||6 (100)||0 (0)||0 (0)|
|Ketamine IM||27||2 (1–12) (1.7–3.5)||27 (100)||0 (0)||4 (15)|
|Ketamine IV||19||3.5 (0.5–9) (2.0–5.5)||19 (100)||0 (0)||2 (11)|
|Propofol IV||24||17 (4–20) (13.5–19.0)||16 (67)||8 (33)||10 (42)|
|Fentanyl IV + midazolam IV||3||17 (10–17) (13.5–17.0)||2 (67)||1 (33)||1 (33)|
Table 3. Characteristics of ED Patients Receiving IV Ketofol for PSA
|Characteristic||Subjects (n = 219)|
| Median (range) (IQR)||13 (1–20) (8–16)|
|Distribution, n (%)|
| 0–35 months||3 (1)|
| 3–7 yr||41 (19)|
| 8–13 yr||80 (37)|
| 14–20 yr||95 (43)|
| Male sex, n (%)||159 (73)|
|Comorbid medical conditions, n (%)|
| None||197 (90)|
| Asthma||11 (5)|
| Concurrent multisystem trauma||4 (2)|
| Alport syndrome||1 (0.4)|
| Bipolar disorder||1 (0.4)|
| Congenital hip dysplasia||1 (0.4)|
| Depression||1 (0.4)|
| Dysrhythmia||1 (0.4)|
| Hypertension||1 (0.4)|
| Ulcerative colitis||1 (0.4)|
Table 4. Procedures Performed With Ketofol PSA (n = 219)
|Procedures Performed||n (%)|
| Fracture reduction||155 (71)|
| Dislocation||20 (9)|
|Chest tube||9 (4)|
|Incision and drainage||9 (4)|
|CT scan||2 (0.9)|
|Foreign body removal||2 (0.9)|
|Hernia reduction||2 (0.9)|
|Lumbar puncture||2 (0.9)|
|Pelvic examination||1 (0.5)|
The median dose of ketofol used was 0.8 mg/kg each of ketamine and propofol (range = 0.2 to 3.0 mg/kg; IQR = 0.7–1.0 mg/kg). Of the patients receiving ketofol for PSA, 212 (96%) received less than 1.5 mg/kg each of ketamine and propofol, while 149 (68%) received less than 1.0 mg/kg each of ketamine and propofol. Administration of morphine for analgesia while awaiting the procedure was documented in 94 patients receiving ketofol PSA (43%), the median dose being 0.1 mg/kg (range = 0.02 to 0.23 mg/kg; IQR = 0.05 to 0.10 mg/kg). Premedication with hydromorphone (0.03 mg/kg IV), midazolam (0.1 mg/kg PO), and codeine (1.5 mg/kg PO) occurred in one patient each. Nitrous oxide was administered as a premedication in two patients.
Procedural sedation and analgesia was considered effective in all patients receiving ketofol. Three patients (1.4%; 95% CI = 0.0% to 3.0%) experienced airway events requiring intervention, while two patients (0.9%; 95% CI = 0.0% to 2.2%) required intervention for unpleasant emergence reactions. Two patients (0.9%; 95% CI = 0.0% to 2.2%) were treated with diphenhydramine for rash. Two patients (0.9%; 95% CI = 0.0% to 2.2%) developed transient bradycardia. Neither episode was considered significant, as there were no signs of decreased perfusion or hypotension, and no intervention was required. Of the two patients (0.9%; 95% CI = 0.0% to 2.2%) in this series experiencing central apnea, one was a 15-year-old acutely intoxicated with alcohol. This patient was judged to require emergent joint reduction as there was evidence of neurovascular compromise and tenting of the skin. The patient presented in an agitated state, and 10 mL of ketofol (0.7 mg/kg each of ketamine and propofol) was administered over a 2-minute period with no preprocedural analgesics. Minimum oxygen saturation was 84% and normalized within 1 minute after vigorous sternal rubbing. The second person experiencing central apnea was an 18-year-old patient with asthma undergoing ankle reduction who received 0.8 mg/kg each of ketamine and propofol over 2 minutes. Morphine 2 mg (0.03 mg/kg) and 25 mg of dimenhydrinate (0.4 mg/kg) were administered 30 minutes prior to the sedation. Apnea resolved in less than 1 minute with vigorous stimulation. The patient was not hypoxic at any time. Neither patient experienced any adverse sequelae. Obstructive apnea was noted in a 2-year-old who experienced laryngospasm during laryngoscopy for possible foreign body. This patient received 1.4 mg/kg each of ketamine and propofol in a single dose over 15 seconds. Laryngospasm occurred after manipulation of the airway and was easily managed with bag-valve-mask ventilation for 15 seconds. Minimum O2 saturation was 86%, and the patient recovered uneventfully. A final diagnosis of croup was made. All other events did not require treatment and were considered minor in nature. No patient required endotracheal intubation or admission to the hospital as a result of PSA. No patient became hypotensive or had vomiting. Adverse events are detailed in Table 5.
Table 5. Ketofol PSA Adverse Events (n = 219 Ketofol PSA Events)
|Age (yr)/Sex (Weight, kg)||Coexisting Medical Conditions||Procedure||Ketofol Components||Preprocedural Medications||Adverse Event(s)||Intervention|
|Ketamine (mg/kg)||Propofol (mg/kg)|
| 2/Female (10.5)||None||Laryngoscopy||1.4||1.4||None||Laryngospasm/hypoxia (min O2 sat 86%)||Bag-valve-mask × 15 seconds|
| 18/Male (60)||Asthma||Ankle fracture/dislocation||0.8||0.8||MS 2 mg IV||Apnea > 20 seconds (min O2 sat 98%)||Vigorous stimulation|
| 15/Male (72)*||Acute alcohol intoxication||Ankle fracture/dislocation||0.7||0.7||None||Apnea/hypoxia (min O2 sat 84%) (agitation)||Sternal rubbing|
| 18/Male (100)||None||Elbow dislocation||0.6||0.6||None||Partial airway obstruction||Airway positioning|
| 12/Male (42)||None||Wrist fracture||1.2||1.2||None||Partial airway obstruction||Airway positioning|
| 16/Male (68)||Dysrhythmia (unstable)||Cardioversion||0.8||0.8||None||Partial airway obstruction||Airway positioning|
| 16/Female (61)||None||Patellar dislocation||0.6||0.6||None||Partial airway obstruction||Airway positioning|
|Central nervous system events|
| 16/Male (64)||Ulcerative colitis||Wrist fracture||1.1||1.1||Hydromorphone 2 mg IV||Unpleasant tremors||Midazolam 2 mg IV|
| 18/Female (45)||Congenital hip dysplasia||Hip dislocation||0.4||0.4||MS 5 mg IM||Unpleasant emergence||Midazolam 0.5 mg IV|
| 15/Male (72)*||Alcohol intoxication||Ankle fracture/dislocation||0.7||0.7||None||Agitation, (central apnea, hypoxia [84%])||None for agitation|
| 8/Male (55)*||None||Supracondylar fracture||0.6||0.6||None||Unpleasant emergence, rash||None for emergence|
| 14/Male (60)||None||Wrist fracture||1.3||1.3||MS 4 mg IV||Unpleasant emergence||None|
| 12/Male (43)||None||Wrist fracture||0.8||0.8||None||Unpleasant emergence||None|
| 8/Male (55)*||None||Supracondylar fracture||0.6||0.6||None||Unpleasant emergence, rash||Diphenhydramine 25 mg IV|
| 13/Male (61)||None||Wrist fracture||1.1||1.1||MS 2 mg IV||Rash (minor)||Diphenhydramine 50 mg IV|
| 11/Male (36)||None||Forearm fracture||1.0||1.0||MS 2.5 mg IV||Bradycardia (HR 56; no hypotension)||None|
| 14/Female (66)||None||Wrist fracture||1.0||1.0||None||Bradycardia (HR 58; no hypotension)||None|
| 6/Male (23)||None||Lumbar puncture||0.7||0.7||Midazolam 3 mg IV||Rigidity during procedure (not interfering)||None|
| 13/Male (36)||None||Elbow dislocation||0.8||0.8||MS 2.5 mg IV||Diplopia||None|
| 15/Female (91)||None||Ankle fracture/dislocation||0.8||0.8||MS 3 mg IV||Vocalized during procedure||None|
Median recovery time from ketofol PSA was 14 minutes (range = 3 to 41 minutes; IQR = 11 to 18 minutes). Of the 219 patients receiving ketofol, 196 (90%) had recovered within 20 minutes, and 218 (99%) recovered in less than 30 minutes. Median total sedation time for ketofol PSA events was 18 minutes (range = 5 to 62 minutes; IQR = 13 to 22 minutes). Median satisfaction scores for ketofol PSA were 10 for physicians (n = 218; range = 5 to 10; IQR = 10 to 10) and 10 for nurses (n = 217; range = 5–10; IQR = 10 to 10). Of the 204 (93%) patient/guardian scores completed, 202 (99%) stated they would choose the same PSA regimen in the future.
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Only two studies have been previously published on the use of ketamine–propofol combination for ED PSA in children. A prospective observational pilot study of 20 pediatric patients undergoing orthopedic reductions using separate syringe ketamine–propofol PSA showed that the combination of ketamine and propofol provided effective, predictable deep sedation. Fifteen percent of patients had mild, easily correctable respiratory depression (95% CI = 5% to 36%).20 Single-syringe ketamine and propofol mixed in a 1:1 ratio was used in a case series of 114 patients, which included 28 pediatric patients, undergoing primarily orthopedic ED procedures. Ketamine–propofol combination was judged to be highly effective, with short recovery times and a low incidence of adverse effects.21 This series represents an extension of this previous data set. Thirteen percent of this study’s ketamine–propofol series (28 of 219 patients) were captured from the previous study population.
Most patients in this case series received ketamine in subdissociative doses and propofol in doses far less than those usually required for deep sedation in children. Pediatric PSA with IV ketamine alone is reliably achieved with a dose of 1.5 mg/kg, while lower doses frequently require repeating.26–30 It is postulated that by combining ketamine with propofol, clinicians have the ability to provide deep sedation using lower doses of ketamine, which may allow for more rapid recovery. As expected, the median recovery time of 14 minutes documented in this series was longer than most recovery times reported for propofol alone and shorter than those reported for IV ketamine alone. Previous ED studies using IV ketamine alone have shown median recovery times of 25,28 58,31 and 103 minutes.32 Median recovery time using propofol alone in children has been reported to be between 5 and 15 minutes.4 In an observational pilot study with 20 children receiving a fixed dose of ketamine at 0.5 mg/kg and a fixed dose of propofol of 1.0 mg/kg, patients were deemed to be suitable for discharge in a median time of 38 minutes (range = 30 to 59 minutes; IQR = 35 to 41 minutes).20
This study confirms the short recovery time experienced by patients receiving mixed, titrated ketamine and propofol. Ninety percent of patients receiving mixed 1:1 ketamine–propofol PSA had recovered in less than 20 minutes, and 99% were recovered within 30 minutes. It is logical to expect that more rapid recovery may assist in ED patient flow, although total time in the ED was not specifically measured in this series, and no firm conclusions regarding the effects on patient flow can be made.
Sedation with propofol alone in children requires total doses of propofol from 2.833 to 3.5 mg/kg.34 Pediatric cardiology studies have shown that the use of ketamine reduces the dose of propofol required to achieve adequate sedation.35 The median dose of propofol in this series of 0.8 mg/kg was low in comparison to studies using propofol alone for deep sedation. The rate of adverse airway events when using propofol are known to be dose-dependent, with studies showing the rate of hypoxia to be from 1.5% (95% CI = 1.4% to 1.7%)1 to 5%.34 Two patients in this series (0.9%; 95% CI = 0.0% to 2.2%) developed hypoxia. Larger studies are necessary to determine if this difference could be statistically or clinically significant.
Adverse events in this series were few and mostly self-limited (Table 5). Nearly half of the study patients received narcotic analgesia while awaiting their procedure. No clear relationship between adverse events and preprocedural analgesia was apparent. A large series of pediatric propofol sedations occurring outside the operating room showed airway events (stridor, laryngospasm, airway obstruction, wheezing, or central apnea) requiring intervention (oral/nasal airway placement, bag-mask ventilation, or endotracheal intubation) to occur in 1 in 70 patients.1 A meta-analysis of 32 studies on ketamine for ED PSA showed apnea to occur in 0.8% of patients and laryngospasm to occur in 0.3% of patients.36
It is thought that the sedative effects of propofol may mitigate adverse events such as recovery agitation and vomiting that are associated with ketamine use. In this series two patients (0.9%; 95% CI = 0.0% to 2.2%) aged 18 and 16 years had emergence phenomena treated with midazolam, and no patients experienced vomiting during or after PSA. A meta-analysis of 32 ED studies on pediatric ketamine PSA reported the overall incidence of emesis and clinically important recovery agitation to be 8.4 and 1.4%, respectively.37
This series constitutes the largest clinical experience of the combination of ketamine and propofol for ED pediatric PSA published to date. The provision of PSA with mixed ketamine and propofol appears to provide rapid, reliable, and effective PSA with short recovery times and few adverse events. It was well liked by care providers. The use of this medication combination is theoretically compelling, as the sedative effects of propofol are thought to balance the nauseant and psychomimetic effects of ketamine. The ability to achieve deep sedation with lower doses of ketamine may provide for shorter recovery times compared to using ketamine alone. As well, ketamine provides an analgesic effect during propofol PSA that may result in fewer adverse airway events when compared to the use of fentanyl with propofol.6,11
The differing mechanisms of action of ketamine and propofol, and the difference in duration of action of the two drugs, has called into question the rationale for same-syringe titration of these two agents.11,15 The sedative effect of propofol occurs in a progressive, dose-dependent fashion. In contrast, ketamine displays a “dissociative threshold,” usually between IV doses of 1.0 and 1.5 mg/kg. As well, ketamine is known to have a longer duration of action than that of propofol. While using fixed doses of ketamine and propofol has also been shown to reliably produce deep sedation,11,20 this series, and previously reported series,21 has demonstrated that the differences in kinetics and duration of action between ketamine and propofol do not mitigate the effectiveness of using a titrated, same-syringe ketamine–propofol combination for ED PSA in children and adults. In ED practice, PSA must be performed for a variety of conditions and in patients who may have variable responses to sedatives and analgesics. The amount of medication necessary to achieve adequate sedation is also dependent on the painfulness of the condition being treated and on the amount of anxiety being experienced by the patient. Titrating ketamine and propofol together may be a way of addressing these differences in a simple and effective fashion.
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The dosing of PSA medications was intentionally not standardized. While this strengthens the study in terms of its applicability to ED practice, there are variations in individual practice patterns that could affect measured parameters, such as drug doses, recovery times, and adverse events. Selection bias may have existed, as the choice to use ketofol PSA was left up to the discretion of the treating physician.
It is possible that the presence of two EPs during PSA could have led to a reduction in the frequency of adverse events. This may have led to bias in the reported rates of complications.
While data on adverse events were collected prospectively, and the absence of an explicit list of complications was specifically queried by means of check-boxes as well as a free-text area on the chart, there may be variability in individual physicians’ tolerance for events that are considered “adverse.” This may have led to recording bias. Also, the small size of our series precludes any definitive statements on safety and the incidence of rare adverse effects.
Of patients receiving ketofol PSA, 124 (57%) were 13 years of age or less, and 44 (20%) were under 8 years of age; thus, the effectiveness and safety of ketofol in the youngest age groups remains uncertain. The number of children younger than 2 years of age captured in this case series was small, and thus these results cannot be applied to this age group. Of the 15 children under the age of 2 years receiving PSA during the study period, 10 (67%) received IM ketamine alone, two (13%) received IV ketamine alone, and three (20%) received IV ketofol. We believe that this reflects a preference for the IM route given the challenges of IV access in small children rather than any increase in the perceived risks of ketofol PSA in this age group. This view is supported by noting that when ketamine alone was the PSA agent of choice, it was given almost exclusively by the IM route. Also, of the 16 ASA class 3 patients, nine (56%) received ketofol, while propofol alone and ketamine alone were chosen in five patients (31%) and one patient (6%), respectively. Ketofol was not compared in a randomized, blinded fashion to other PSA regimens, and thus no comment can be made regarding its effectiveness and safety when compared to other PSA regimens.