KETOFOL USE IN THE ED By Carmen Lau Pharmacy Year 4 December 27th, 2013 Procedural sedation and analgesia (PSA) Definition: A technique of administering sedatives w/ or w/o analgesics to induce a state that allows for unpleasant procedures, also referred to as conscious sedation Procedures • Setting fractures • Draining abscesses • Reducing dislocations • Endoscopy • Cardioversion • TEE and other imaging Procedural sedation and analgesia (PSA) • The ideal drug • Easily titrated • Rapid onset • Brief duration of action • Provides adequate sedation and analgesia • Minimal respiratory and hemodynamic effects Propofol Class Short acting sedative hypnotic MOA Not well defined, potentiation of GABAA receptor activity→slowing channel closing time, also acts a sodium channel blocker PK Vd: 171-349L Metabolism: hepatic Excretion: 90% renal Onset: 10-50sec Duration after single dose: 3-10min Dosing Product: 1000mg in 100ml (10mg/ml) premixed in 10% fat Procedural dose: 1mg/kg IV followed by 0.5mg/kg q3-5min Monitoring ↓CO/Cl, ↓BP, ↓HR, ↓RR, SVR, PA, PCWP, CVP, UO ECG changes (PVC’s, PAC’s, S-T depression, bigeminy, VF, heart block) Adverse Effects • • • • • • Allergies Do not use in pts allergic to eggs or soybeans Hypotension, bradycardia, ECG changes Apnea, cough, hiccups Pain at injection site Myoclonic/clonic movement, hyperreflexia, twitching N/V/cramping HLD, pancreatitis Propofol use in PSA Pro’s • Rapid onset, short duration of action, antiemetic effects Con’s • Use limited to dose-dependent respiratory depression and hypotension • Lack of analgesic effect: often coadministered with opioids but the combination increases likelihood of adverse airway events Ketamine Class Dissociative sedative MOA • • • • • Noncompetitive NMDA receptor antagonist which interferes with pain transmission in spinal cord Inhibits nitric oxide synthase Binds to sigma and opioid receptors Blocks Ca and Na channels Acts a noradrenergic and serotonergic uptake inhibitor PK Metabolism: hepatic Excretion: renal Onset: 30-40sec Duration after single dose: 5-10min Dosing Product: 10mg/ml, 50mg/ml, 100mg/ml Procedural dose: 1-2mg/kg IV over 1-2min, then 0.25-0.5 mg/kg q5-10min Dose reduction: Caution in hepatic impairment→longer duration of action Monitoring ↑BP, ↑P, RR, pain score, sedative score Adverse Effects • • • • • Dysphoria, hallucinations, visual changes (increased color) Excessive sedation and salivation Increased muscle tone, muscle movement abnormalities HTN, N/V, ↑ICP Memory disruptions Ketamine in PSA Pro’s • Preservation of airway reflexes • CV and respiratory stimulation • Analgesia Con’s • Longer recovery time • Recovery agitation and vomiting Better together? Propofol Ketamine Does not have analgesic effects Analgesic effects even at subanesthetic concentrations Respiratory depression and ↓BP Sympathomimetic effects leads to respiratory stimulation and ↑BP Antiemetic and sedative Vomiting and hallucinations Physically compatible when mixed in a single polypropylene syringe and stable at room temperature with exposure to light The case 23yo 60kg F is brought to the ED with a dislocated left shoulder after a MVC. The physician decides to use ketofol for the procedure and asks you, the pharmacist, for help dosing the medication. How are you going to prepare this medication? Chem 7: Na 139, K 4.2, Cl 109, CO2 22, BUN 30, SCr 0.70, Glu 126 CBC: pending VS: HR 98, RR 22, Temp 37.6, BP 122/88 The 1st ketofol study (A prospective case series by Willman et al.) Objective Effectiveness and safety of IV ketofol for procedural sedation and analgesia in the ED Inclusion/ Exclusion Any patient treated with ketofol between July 2005- Feb 2006 at Lions Gate Hospital in Vancouver, BC Intervention Ketofol prepared at 1:1 mixture of ketamine 10mg/ml and propofol 10mg/ml in a 10 or 20ml syringe Results • • • • • 114 procedural sedation and analgesia events Median dose= 0.75mg/kg of each drug Median recovery time= 15min Procedural success w/o adjunctive sedatives: 110 (96.5%) 8 pts (7%) had minor adverse events (most common= 3 airway malalignments) • No cases of hypotension, vomiting, aspiration Conclusion Ketofol is effective and safe for PSA. Few adverse events occurred and recoveries were rapid. Other ED ketofol case series Sharieff, 2007 Andolfatto, 2010 Andolfatto, 2011 Patients 20 children for fracture reduction 219 children for mostly fracture reduction 728 adults for mostly fracture reduction Dose ketamine 0.5mg/kg + propofol 1.0mg/kg 0.8mg/kg of 1:1 mix in same syringe 0.7mg/kg of 1:1 mix in same syringe Success 95% 100% 98% Transient hypoxia 3/20 3/219 17/728 Median Recovery 38min 14min 14min The case cont. 23yo 60kg F is brought to the ED with a dislocated left shoulder. The physician decides to use ketofol for the procedure. Chem 7: Na 139, K 4.2, Cl 109, CO2 22, BUN 30, SCr 0.70, Glu 126 CBC: pending VS: HR 98, RR 22, Temp 37.6, BP 122/88 You start to prepare ketofol at a 1:1 mixture of ketamine 10mg/ml and propofol 10mg/ml in a 10ml syringe. How much are you going to draw up, and how is the physician supposed to administer it? Administration Approach 1 (Andolfatto et al.) • Initial dose= 0.375mg/kg of each ketamine and propofol administered during 15-30sec • Every minute thereafter, the physician assesses the pt’s level of sedation and administers 0.188mg/kg of each drug if needed until sedation Approach 2 • Administer 1-3ml aliquots of 1:1 ketamine 10mg/ml and propofol 10mg/ml at the physician’s discretion How to gauge sedation? • Physician assessment • Loss of lid reflexes, verbal response, tactile stimuli • Ramsay Sedation Scale <5 • Bispectral index (BIS) • Neurophysiological monitoring device that analyzes a pt’s electroencephalogram • Mostly used to assess deep anesthesia but is now studied in the ED The case cont. 23yo 60kg F is brought to the ED with a dislocated left shoulder. The physician decides to use ketofol for the procedure. Chem 7: Na 139, K 4.2, Cl 109, CO2 22, BUN 30, SCr 0.70, Glu 126 CBC: pending VS: HR 98, RR 22, Temp 37.6, BP 122/88 • You mix 30mg (3ml) of ketamine and 30mg (3ml) of propofol in a syringe • The physician gives 3ml of the mixture (0.25mg/kg of each drug) initially, followed in 1min by the remainder 3ml • Adequate sedation was not reaches, so more ketofol was prepared and the physician gives another 3ml The case cont. • A total of 9ml of the 1:1 mixture was administered • 9ml= 45mg of each drug • 45mg/60kg= 0.75mg/kg of each drug Remember that the median dose for the Willman et al. ketofol case series was 0.75mg/kg!!! The case cont. The shoulder reduction was successful and the physician thanks you for your help. BP only dropped to 114/80 during the procedure. The patient will be discharged in about 1 hour after she recovers. The physician really likes ketofol, but wonders how it compares to other PSA agents. You tell him that… Ketofol vs Propofol RCT Messenger, 2008 Patients 63 adults or teenagers for Fx reduction Ketofol arm Ketamine 0.3mg/kg followed 2min later by titrated propofol Propofol comparison Titrated propofol followed 2min later by fetanyl 1.5µg/kg Procedural success % Ketofol 97, propofol 100 Transiet hypoxia % Ketofol 38, propofol 77 Median recovery time Ketofol 28min, propofol 37min Primary outcome Fewer adverse events including hypoxia with ketofol Secondary outcomes • Similar satisfaction scores • More propofol required with ketofol Ketofol vs Propofol Case Series • Phillips et al. 2010 • Prospective randomized case series of 28 patients >21yo • Propofol 0.5-1.5mg/kg vs. ketofol 0.75mg/kg • Measured procedural success, BIS score, adverse effects, recovery time, and VS Results • Smaller % decline in SBP with ketofol (1.6% vs 12.5%) • Smaller difference between baseline and goal sedation BIS score with ketofol (18.78 vs 34.64) • Lower mean propofol dose with ketofol (92.5mg vs 177.27mg) • No respiratory depression in either group Ketofol vs Propofol RCT David, 2010 Patients 100 adults + 93 children for mostly Fx reduction Ketofol arm Ketamine 0.5mg/kg + propofol 1mg/kg, followed by propofol 0.5mg/kg prn Propofol comparison Propofol 1mg/kg, followed by propofol 0.5mg/kg prn Procedural success % Ketofol 100, propofol 100 Transiet hypoxia % Ketofol 7, propofol 12 Median recovery time N/A Primary outcome Similar incidence of respiratory depression Secondary outcomes • Ketofol had greater satisfaction scores • Less propofol administered with ketofol • More consistent sedation quality with ketofol based on the Colorado Behavioral Numerical Pain Scale Ketofol vs Propofol RCT Andolfatto, 2013 Patients 284 patients >14yo for mostly Fx reduction Ketofol arm • • Propofol comparison • • 0.375 mg/kg of each drug, every min thereafter if Ramsay Sedation Score <5 give another 0.188mg/kg Total dose= 0.7mg/kg of each Propofol 0.75mg/kg, every min thereafter if Ramsay Sedation Score <5 give another 0.375mg/kg Total dose= 1.5mg/kg Procedural success % Ketofol 100, propofol 100 Adverse respiratory event based on Quebec Criteria Ketofol 43 (30%), propofol 46 (32%) Median recovery time Ketofol 8min, propofol 6min Primary outcome Similar incidence of respiratory depression Secondary outcomes • • Sedation depth based on Ramsay Sedation Score appeared to be more consistent with ketofol (46% ketofol vs 65% propofol) Other secondary outcomes and satisfaction scores are similar Ketofol vs Propofol Recap • SBP • Less SBP % decrease with ketofol • Respiratory Depression • Similar if not fewer incidence of adverse respiratory events with ketofol • Sedation depth • Greater consistency based on Ramsay Scale and Colorado Behavioral Numerical Pain Scale with ketofol • Satisfaction score • Similar if not higher with ketofol • Mean propofol dose • Conflicting data, with most studies indicating less propofol required with ketofol Ketofol vs Ketamine RCT Shah, 2011 Patients 131 children for Fx reduction Ketofol arm Ketamine + propofol each 0.5mg/kg, followed by propofol 0.5mg/kg prn Ketamine comparison Ketamine 1mg/kg, followed by 0.25mg/kg prn Procedural success % Ketofol 96, ketamine 100 Transiet hypoxia % Ketofol 5, ketamine 3 Median recovery time Ketofol 10, ketamine 12 Primary outcome Sedation time was 3min shorter with ketofol Secondary outcomes • Similar efficacy and respiratory adverse events • Ketofol had less vomiting • Ketofol had greater provider and pt satisfaction Ketofol vs Midazolam/Fentanyl RCT Amir, 2011 Patients 62 patients >18yo for lacerations and Fx reduction Ketofol arm 0.75mg/kg of each drug, then more prn Midaz/fent comparison 0.04mg/kg midazolam and 2 µg/kg fetanyl Procedural success % Ketofol 96, ketamine 100 Transiet hypoxia % Ketofol 5, ketamine 3 Median recovery time Ketofol 10, ketamine 12 Primary outcome • No difference in sedation time • No difference in physician satisfaction • Pain as measured by the Visual Analog Scale was significantly lower with ketofol Secondary outcomes • VS differences mostly not statistically sig. • One pt from each group required bag-mask Are the benefits clinically relevant? • Safe sedation can be achieved with just propofol • Induced hypotension is usually transient and self limiting • Using “extra” propofol doesn’t necessarily mean lengthened recovery time • No compelling evidence showing that ketofol greatly reduces respiratory depression compared to propofol • Ketamine works well alone if dissociative sedation is desired • Added complexity of administering 2 drugs and having to anticipate the side effects of both • It does not make sense pharmacokinetically to mix an ultrashort acting medication with another that isn’t Conclusion • Ketofol provides adequate procedural sedation and analgesia • Ketofol is safe and effective: recovery times are short and adverse events are limited • Compared to other PSA agents, ketofol may have ↓ hypotension, ↓ respiratory depression, ↑ sedation quality, and ↑ patient satisfaction • It is still not certain whether ketofol offers clinically relevant benefits over either agent alone Questions? Unrelated fun fact: Photofrin is a drug that requires lasers!!! References Baker SN and Weant KA. Procedural Sedation and Analgesia in the Emergency Department. J Pharm Pract. 2011; 24(2): 189-195. Green SM, Andolfatto G, Krauss B. Ketofol for Procedural Sedation? Pro and Con. Ann Emerg Med. 2011; 57(5): 444-448. Willman EV, Andolfatto G. A Prospective Evaluation of “Ketofol” (Ketamine/Propofol Combination) for Procedural Sedation and Analgesia in the Emergency Department. Ann Emerg Med. 2007; 49(1): 23-30. Andolfatto G, Willman E. A Prospective Case Series of Single-syringe Ketamine-Propofol (Ketofol) for Emergency Department Procedural Sedation and Analgesia in Adults. Acad Emerg Med. 2011; 18: 237-245. Phillips W, Anderson A, Rosengreen M, et al. Propofol Versus Propofol/Ketamine for Brief Painful Procedures in the Emergency Department: Clinical and Bispectral Index Scale Comparison. J Pain Palliat Care Pharmacother. 2010; 24: 349-355. Andolfatto G, Abu-Laban RB, Zed PJ, et al. 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