Review article: Intravenous vs intramuscular ketamine for pediatric procedural sedation by emergency medicine specialists: a review

Ketamine is a general anesthetic agent widely used for pediatric procedural sedation outside the operating theater by nonanesthesiologists. In a setting where efficacy and safety of the agent are paramount, there are conflicting recommendations in terms of optimal mode of parenteral administration, as well as optimal dosage and need for the coadministration of adjunctive agents to decrease side effects. We investigated existing evidence to determine whether ketamine should be best administered intravenously or intramuscularly. This analysis was made difficult by limited direct comparisons of both modes of parenteral administration and a lack of consistent definitions for key outcomes such as ‘effectiveness,’‘adverse events,’‘hypoxia,’‘ease of completion of the procedure,’ and ‘satisfaction’ across studies that have evaluated ketamine. Based on large data sets, the safety and efficacy of both modes of administration are broadly similar. Although data on head to head comparisons of intravenous and intramuscular ketamine is limited, based on our analysis, we conclude that the trends indicate ketamine is ideally administered intravenously.     

Exploring the pharmacokinetics of oral ketamine in children undergoing burns procedures

Aims: The aim of this study was to describe ketamine pharmacokinetics when administered orally to children suffering from burn injury in >10% body surface area. Methods: Children (n = 20) were given ketamine 5 or 10 mg·kg^?1 orally 20 min prior to presentation for surgical procedures. Anesthesia during procedures was maintained with a volatile anesthetic agent. Additional intravenous ketamine was given as a bolus (0.5–1 mg·kg^?1) to nine children during the procedure while a further nine children were given an infusion (0.1 mg·kg^?1·h^?1) continued for 4–19 h after the procedure. Blood was assayed for ketamine and norketamine on six occasions over the study duration of 8–24 h. Data were pooled with those from an earlier analysis (621 observations from 70 subjects). An additional time–concentration profile from an adult given oral ketamine was gleaned from the literature (17 observations). A population analysis was undertaken using nonlinear mixed‐effects models. Results: The pooled analysis comprised 852 observations from 91 subjects. There were 20 children who presented for procedures related to burns management (age 3.5 sd 2.1 years, range 1–8 years; weight 14.7 sd 4.9 kg, range 7.9–25 kg), and these children contributed 214 ketamine and norketamine observations. A two‐compartment (central, peripheral) linear disposition model fitted data better than a one‐compartment model. Bioavailability of the oral formulation was 0.45 (90% CI 0.33, 0.58). Absorption half‐time was 59 (90% CI 29.4, 109.2) min and had high between‐subject variability (BSV 148%). Population parameter estimates, standardized to a 70‐kg person, were central volume 21.1 (BSV 47.1%) l·70 kg^?1, peripheral volume of distribution 109 (27.5%) l·70 kg^?1, clearance 81.3 (46.1%) l·h^?1·70 kg^?1, and inter‐compartment clearance 259 (50.1%) l·h^?1·70 kg^?1. Under the assumption that all ketamine was converted to norketamine, the volume of the metabolite was 151.9 (BSV 39.1%) l·70 kg^?1 with an elimination clearance of 64.4 (BSV 63.4%) l·h^?1·70 kg^?1 and a rate constant for intermediate compartments of 26.2 (BSV 52.1%) h^?1·70 kg^?1. Conclusions: The ketamine pharmacokinetics in children with minor burns are similar to those without burns. The peak ratio of norketamine/ketamine at 1 h is 2.8 after oral administration allowing an analgesic contribution from the metabolite at this time. There is low relative bioavailability (<0.5) and slow variable absorption. Dose simulation in a child (3.5 years, 15 kg) suggests a dose regimen of oral ketamine 10 mg·kg^?1 followed by intravenous ketamine 1 mg·kg^?1 i.v. with the advent of short‐duration surgical dressing change at 45 min.     

Procedural sedation for insertion of central venous catheters in children: comparison of midazolam/fentanyl with midazolam/ketamine

Background: There is a lack of studies evaluating procedural sedation for insertion of central venous catheters (CVC) in pediatric patients in emergency departments or pediatric intensive care units (PICU). This study was designed to evaluate whether there is a difference in the total sedation time for CVC insertion in nonintubated children receiving two sedation regimens. Methods: Patients were prospectively randomized to receive either midazolam/fentanyl (M/F) or midazolam/ketamine (M/K) i.v. The Children's Hospital of Wiscosin Sedation Scale was used to score the sedation level. Results: Fifty seven patients were studied (28 M/F and 29 M/K). Group M/F received midazolam (0.24 ± 0.11 mg·kg⁻¹) and fentanyl (1.68 ± 0.83 μg·kg⁻¹) and group M/K received midazolam (0.26 ± 0.09 mg·kg⁻¹) and ketamine (1.40 ± 0.72 mg·kg⁻¹). The groups were similar in age, weight, risk classification time and sedation level. Median total sedation times for M/F and M/K were 97 vs 105 min, respectively (P = 0.67). Minor complications occurred in 3.5% (M/F) vs 20.7% (M/K) (P = 0.03). M/F promoted a greater reduction in respiratory rate (P = 0.005). Conclusions: In this study of nonventilated children in PICU undergoing central line placement, M/F and M/K provided a clinically comparable total sedation time. However, the M/K sedation regimen was associated with a higher rate of minor complications. A longer period of study is required to assess the efficacy and safety of these sedative agents for PICU procedures in nonintubated children.     

Investigating the pharmacodynamics of ketamine in children

BACKGROUND: The aim of this study was to describe ketamine pharmacodynamics (PD) in children. Adult ketamine concentrations during recovery are reported as 0.74 mg.l(-1) (sd 0.24 mg.l(-1)) with an EC(50) for anesthesia of 2 mg.l(-1) (sd 0.5 mg.l(-1)), but pediatric data are few. METHODS: Children presenting for painful procedures in an Emergency Department were given ketamine 1-1.5 mg.kg(-1) i.v. Blood was assayed for ketamine on three to six occasions (median 3) over the subsequent 14-152 min (median 28.5). Procedures were videotaped. Level of sedation (0-5; unresponsive - spontaneously awake without stimulus) and a test of memory were recorded. PD was investigated using a variable slope E(max) model (sedation) or logistic regression (arousal time, memory) with nonlinear mixed effects models. RESULTS: In total 60 children were enrolled. Pharmacokinetic data were collected in 54 of these children and there were 43 children available for PD study. The mean age was 8.15 years (sd 3.5 years) and weight was 34.9 kg (sd 15.8 kg). The half-time describing equilibration between the effect compartment and central compartment was 11 s (95% CI 0.07-20 s). The EC(50) for arousal was 0.52 (90% CI 0.22-1.17) mg.l(-1). The E(max) model with a baseline (E(0)) of five (spontaneously awake without stimulus) yielded a fractional E(max) 0.939 [coefficient of variability (CV) 24%], an EC(50) 0.56 (CV 136%) mg.l(-1) and a Hill coefficient 3.71. The EC(50) for recall memory was 0.44 (90% CI 0.09-1.70) mg.l(-1). The EC(50) for remembering was 0.38 (90% CI 0.12-1.75) mg.l(-1). CONCLUSIONS: Concentrations associated with arousal in children are analogous to adults. The ability to recall and remember occurs at similar concentrations to those associated with arousal. A concentration of 1 mg.l(-1) was associated with a sedation level of three or less (arouses to consciousness with moderate tactile or loud verbal stimulus) in 95% of children while 1.5 mg.l(-1) was associated with a sedation level of two or less (rouses slowly to consciousness with sustained painful stimulus) in 95% of children. These concentrations can be attained for 3-4 min after 1 mg.kg(-1) and 1.5 mg.kg(-1) ketamine IV bolus, respectively. The mean arousal time can be anticipated at approximately 10 min (1 mg.kg(-1)) and 15 min (1.5 mg.kg(-1)).     

Sedation with ketamine and low-dose midazolam for short-term procedures requiring pharyngeal manipulation in young children

BACKGROUND: Pediatric intestinal biopsy procedures including considerable transpharyngeal manipulation of a wire-guided metal capsule require adequate sedation or anesthesia. This retrospective cohort study was designed to evaluate intravenous sedation with ketamine and low-dose midazolam in young children undergoing these procedures before and also after discharge from the hospital. METHODS: A total of 244 biopsy procedures in 217 children under the age of 16 years were evaluated. All anesthesia records were reviewed according to a defined study protocol and in 145 cases the parents were also interviewed by telephone to obtain further information on possible adverse effects before and after discharge. RESULTS: Ketamine and low-dose midazolam were carefully titrated by an experienced anesthesia team at an approximate dose ratio of 40 : 1 (total doses 2.3 and 0.05 mg.kg(-1)) in continuously monitored spontaneously breathing children. Possibly associated problems before discharge were salivation (5.7%), vomiting (4.9%), oxygen desaturation (3.3%), laryngospasm (2.5%) and rash (1.2%) according to the patient records and blurred vision (27%), nausea and vomiting (19%), vertigo (13%) and hallucinations or nightmares (3.5%) according to telephone interviews. Few, mild and transient problems remained after discharge from the hospital. CONCLUSIONS: Careful titration of ketamine and low-dose midazolam provides adequate sedation for nonsurgical pediatric short-term procedures also requiring considerable pharyngeal manipulation, particularly considering the low number of serious airway problems such as laryngospasm. The high incidence of late postoperative problems suggests that prospective studies should be designed for long-term follow-up of young children subjected to sedation or anesthesia.     

Ketamine disposition in children presenting for procedural sedation and analgesia in a children's emergency department

BACKGROUND: The aim of this study was to describe ketamine pharmacokinetics in children to simulate time-concentration profiles to predict duration of concentrations associated with anesthesia, arousal and analgesia. METHODS: Children presenting for painful procedures in the Emergency Dept were given ketamine 1-1.5 mgxkg(-1) i.v. Blood was assayed for ketamine on 3-6 occasions (median 3) over the subsequent 14-152 min (median 28.5). A population pharmacokinetic analysis was undertaken by using nonlinear mixed effects models (NONMEM). Simulation was used to predict time-concentration profiles in this cohort RESULTS: There were 188 observations from 54 children (age 8.3 sd 3.5 years, weight 32.5 sd 15.6 kg). A two-compartment (central, peripheral) linear disposition model fitted data better than a one-compartment model. Population parameter estimates and their between subject variability (BSV), standardized to a 70-kg person using allometric models, were central volume (V1) 38.7 (BSV 64%) l.70 kg(-1), peripheral volume of distribution (V2) 102 (51.7%) l.70 kg(-1), clearance (CL) 90 (38.1%) l.h(-1) 70 kg(-1) and intercompartment clearance (Q) 215 (19%) l.h(-1) 70 kg(-1). At 10 min half of the children given 1 mgxkg(-1) will have a serum concentration below 0.75 mgxl(-1). This is a concentration associated with 'awakening' in adults. However, almost all the children will still have a serum concentration above 0.1 mgxl(-1), a level associated with analgesia in adults. CONCLUSIONS: Ketamine 1 mgxkg(-1) i.v. provides satisfactory serum concentrations for children undergoing sedation for painful procedures of <5-min duration and produces concentrations associated with analgesic effect for more than 10 min. Clearance increases with decreasing age in children. The relationship between serum concentration and effect is poorly defined in children.     

Pretreatment with intravenous ketamine reduces propofol injection pain

BACKGROUND: Paediatric procedural sedation using propofol has been shown to be safe and effective and is widely used. Pain at the injection site is a frequent complaint and can be particularly distressing for children, especially for those undergoing repeated procedures. Ketamine has analgesic properties and can diminish the incidence of propofol infusion pain in adults. The aim of the study was to investigate whether pretreatment with ketamine would reduce infusion line pain in propofol sedation in children. METHODS: We performed a prospective, randomized, double-blind trial in a paediatric sedation unit of a tertiary referral teaching hospital. A total of 122 children admitted for gastroscopy were randomly allocated into two groups. Group 1 received atropine and ketamine before propofol infusion. Group 2 received atropine, normal saline solution, and a mixture of propofol with lidocaine. The main outcome measure evaluated was pain associated with the infusion and secondary outcome measures were mean medium arterial pressure decrease and desaturation. RESULTS: The incidence of pain of the infusion was significantly lower in patients pretreated with ketamine (8% vs 37%, P = 0.0001). CONCLUSIONS: Pretreatment with ketamine (0.5 mg.kg-1) is very effective in preventing propofol infusion pain.     

The evolution of ketamine applications in children

Ketamine has found many applications in pediatric anesthetic practice. Insights into the mechanism of action and the pharmacokinetics and pharmacodynamics of its isomers have led to a re‐evaluation of this drug, expanding the range of applications in children. Ketamine is a remarkably versatile drug that can be administered through almost any route. It can also be used for different purposes. The aim of this review is to look at the possible applications of this drug in children.     

Nasal midazolam and ketamine for paediatric sedation during computerised tomography

We have studied the sedation achieved with a mixture of midazolam (0.56 mg–kg^-1) and ketamine (5 mg kg^-1) administered nasally in 30 children weighing less than 16 kg undergoing computerised tomography. Assessment was two fold using a visual analogue scale; the radiologist/radiographer rated the exam from "failed examination" to "perfect working conditions" while the anesthetist's assessment ranged from "poor sedation" to "perfect sedation with clinical well being". This new method proved to be effective alone in 83% of the cases and there were no complications. The rapid onset obtained after intranasal midazolam and ketamine offers advantages over orally or rectally administered drugs. The absence of respiratory depression and oxygen desaturation suggests that this technique is safe and efficient in the CT room with its particular working conditions.     

Comparison of alfetanil and ketamine in combination with propofol for patient-controlled sedation during fiberoptic bronchoscopy

BACKGROUND: During fiberoptic bronchoscopy, propofol, ketamine, benzodiazepines, and opiates are most commonly used, alone or in combination for sedation. The aim of this study was to compare the clinical efficacy of propofol/ketamine with propofol/alfentanil for patient-controlled sedation (PCS) during fiberoptic bronchoscopy. METHOD: Patients undergoing fiberoptic bronchoscopy were randomly assigned to receive either propofol/alfentanil (PA group; n = 138) or propofol/ketamine (PK group; n = 138) via a patient-controlled analgesia (PCA) device for sedation and analgesia. Changes in blood pressure, heart rate (HR), and oxygen saturation were monitored. Degree of patient and bronchoscopist satisfaction was evaluated using a 10-cm visual analog scale (VAS) (0 = extremely uncomfortable to 10 = extremely comfortable). RESULTS: After sedation, systolic arterial pressure (SAP) decreased in the PA group, but SAP was stable in the PK group. Compared with values immediately before starting bronchoscopy, SAP and HR increased during the procedure in both groups (P < 0.05). Patients in the PK group showed more satisfaction [(9.5 (6-10) vs. 9.0 (6-10)), P < 0.05] and amnesia (82% vs. 61%, P < 0.01). Despite these differences, the majority (greater than 90%) of the patients in both groups stated that they were comfortable during the procedure. CONCLUSION: Our results show that although both techniques proved effective for sedation in patients undergoing fiberoptic bronchoscopy, ketamine is superior to alfentanil when used in combination with propofol because of the high patient satisfaction and amnesia.     

Comparison of propofol versus propofol‐ketamine combination for sedation during spinal anesthesia in children: randomized clinical trial of efficacy and safety

Objectives: This study was designed to compare the efficacy and safety of propofol vs propofol‐ketamine combination for sedation during pediatric spinal anesthesia. Methods: Forty children, aged 3–8 undergoing spinal anesthesia for lower abdominal surgeries were included. Participants were randomly assigned into two groups. Group 1 received propofol bolus of 2 mg·kg^?1 followed by an infusion of 4 mg·kg^?1·h^?1. Group 2 received a combination of 1.6 mg·kg^?1 propofol and 0.4 mg·kg^?1 ketamine followed by an infusion of 3.2 mg·kg^?1·h^?1 and 0.8 mg·kg^?1·h^?1, respectively. The infusion rate was titrated to keep the child sedated at University of Michigan Sedation Score of 3. The heart rate, blood pressure, respiratory rate and oxygen saturation were recorded every 5 min. The episodes of spontaneous body movements and requirement of supplemental sedation were recorded. The postoperative recovery was assessed by modified Aldrette score. Results: Seventeen patients in group 1 and four patients in group 2 (P < 0.001) required extra boluses of study drug to prevent movements during lumbar puncture. Four patients experienced respiratory depression and three airway obstruction in group 1 when compared to one patient each in group 2 (P < 0.05). The recovery time was similar in both groups. None of the patient had postoperative nausea/vomiting or psychomimetic reactions. Conclusions: Propofol‐ketamine combination provided better quality of sedation with lesser complications than propofol alone and thus can be a good option for sedation during spinal anesthesia in children.     

Experience with a propofol-ketamine mixture for sedation during pediatric orthopedic surgery

Background: Various combinations of propofol and ketofol have been described for the provision of procedural sedation in both adults and children. Utilization of ‘ketofol’ for deep sedation during prolonged pediatric orthopedic procedures has not previously been described. Methods: During an orthopedic aid trip, a 1:1 mixture of propofol and ketamine (200 mg of each drawn up to 22 ml) was utilized to provide deep sedation or general anesthesia as an adjunct to regional analgesia for lower limb surgery. Details for 18 patients having a total of 19 procedures were recorded with a record of intraoperative and postoperative parameters including initial bolus doses and infusion rates of ketofol required to produce deep sedation. Results: Mean operating time was 153.7 min (range 64–241 min). The mean initial bolus dose of ketofol was 0.19 ml·kg^?1 (range 0.1–0.5 ml·kg^?1) or 1.7 mg·kg^?1 each of propofol and ketamine (range 0.9–4.5 mg·kg^?1). The mean upper limit of the infusion rate required to maintain deep sedation was 0.19 ml·kg^?1·h^?1 (range 0.07–0.26 ml·kg^?1·h^?1) or 1.7 mg·kg^?1·h^?1 (range 0.6–2.4 mg·kg^?1·h^?1) and the mean lower limit of the infusion rate was 0.08 ml·kg^?1·h^?1 (range 0.02–0.13 ml·kg^?1·h^?1) or 0.7 mg·kg^?1·h^?1 (range 0.2–1.2 mg·kg^?1·h^?1). The mean initial bolus dose of ketofol was 0.19 ml·kg^?1 (range 0.1–0.5 ml·kg^?1). There were no episodes of hypo‐ or hypertension or of desaturation. Mean time to eye opening after infusion cessation was 5.1 min (median 2 min; range 0–17 min). Conclusion: Ketofol successfully produced deep sedation for prolonged pediatric orthopedic procedures in conjunction with regional analgesia. Further research to confirm its safety and applicability to a wider range of settings is required.     

Safe pediatric procedural sedation and analgesia by anesthesiologists for elective procedures: A clinical practice statement from the European Society for Paediatric Anaesthesiology

The growing number of medical procedures performed in children that require cooperation of patients, lack of movement, anxiolysis or/and analgesia triggers the increased need for procedural sedation. This document presents the consensus statement of the European Society for Paediatric Anaesthesiology about the principles connected with the safe management of procedural sedation and analgesia (PSA) by anaesthesiologists for elective procedures in children. It does not aim to provide a legal statement on how and by whom PSA should be performed. The document highlights that any staff taking part in sedation of children must be appropriately trained with the required competencies and must be able to demonstrate regularly that they have maintained their knowledge, skills and clinical experience. The main goal of creating this document was to reflect the opinions of the community of the paediatric anaesthesiologists in Europe regarding how PSA for paediatric patients should be organized to make it safe.     

盐酸氯胺酮与异丙酚复合应用的研究进展

介绍氯胺酮与异丙酚复合应用于镇静、麻醉诱导与维持,对血液动力学、脑血流以及对缺氧性肺血管收缩的影响。     

Intravenous regional anaesthesia with ketamine

Ketamine, 40 ml 0.5% solution, was used in the technique of intravenous regional anaesthesia in 14 patients undergoing upper limb surgery. Satisfactory analgesia was obtained in 12 of the patients. The method is limited by the fact that all patients became unconscious within a few minutes of tourniquet release, and that this could not be prevented by naloxone.     

Propofol-ketamine vs propofol-fentanyl for sedation during pediatric upper gastrointestinal endoscopy

BACKGROUND: The aim of this study was to compare the clinical efficacy and safety of propofol-ketamine with propofol-fentanyl in pediatric patients undergoing diagnostic upper gastrointestinal endoscopy (UGIE). METHODS: This was a prospective, randomized, double blinded comparison of propofol-ketamine with propofol-fentanyl for sedation in patients undergoing elective UGIE. Ninety ASA I-II, aged 1 to 16-year-old patients were included in the study. Heart rate (HR), systolic arterial pressure, peripheral oxygen saturation, respiratory rate (RR) and Ramsey sedation scores of all patients were recorded perioperatively. Patients were randomly assigned to receive either propofol-ketamine (PK; n = 46) or propofol-fentanyl (PF; n = 44). PK group received 1 mg x kg(-1) ketamine + 1.2 mg x kg(-1) propofol, and PF group received 1 microg x kg(-1) fentanyl + 1.2 mg x kg(-1) propofol for sedation induction. Additional propofol (0.5-1 mg x kg(-1)) was administered when a patient showed discomfort in either group. RESULTS: The number of patients who needed additional propofol in the first minute after sedation induction was eight in Group PK (17%), and 22 in Group PF (50%) (P < 0.01) and those who did not need additional propofol throughout the endoscopy were 14 in Group PK (30%) and three in Group PF (7%) (P < 0.01). HR and RR values after induction in Group PF were significantly lower than Group PK (P < 0.01). CONCLUSIONS: Both PK and PF combinations provided effective sedation in pediatric patients undergoing UGIE, but the PK combination resulted in stable hemodynamics and deeper sedation though more side effects.