Papers from 2015 that influenced my practice

Transcription

1 Papers from 2015 that influenced my practice Andis Graudins Clinical Toxicology Service at Monash Health And Monash Emergency Research Collaborative, Clinical School at Monash Health, Monash University, MELBOURNE, AUSTRALIA

2 Annals of Emergency Medicine, 2015;66(3): 230

3 Annals of Emergency Medicine, 2015;66(3): 230 Acute behavioural disturbance a common problem in EDs Multiple potential aetiologies Drug and alcohol intoxication Behavioural Organic delirium / dementia Varying recommendations for which agent(s) to use to parenterally sedate patients Many guidelines recommend multiple sedation agents Higher incidence of AEs with benzodiazepine sedation

4 Background 2010 double blinded RCT comparing IM droperidol (10mg) to droperidol (5mg) with midazolam (5mg) or midazolam (10mg) IMI droperidol alone provided good sedation with a single dose in ~75% of patients within 20 minutes 25% required a second dose Midazolam and midazolam with droperidol also resulted in sedation in a similar time frame Both associated with deeper unwanted levels of sedation and higher incidence of adverse events No evidence of QT prolongation with droperidol

5 Current study method Prospective observational study phase-4 safety and efficacy study in 6 EDs (August 2009 to April 2013). Adult patients requiring parenteral sedation for acute behavioral disturbance Patients received droperidol 10 mg IMI. If this did not sedate within 15 minutes further sedation was given A repeat dose of droperidol 10 mg was recommended as part of a sedation protocol

6 Outcomes Primary outcome: The proportion of patients with an abnormal QT interval after 10mg or more of droperidol, Defined by the at-risk line on the QT nomogram Secondary outcomes Effectiveness of droperidol as determined by: The time to sedation measured on the Sedation Assessment Tool Sedation Assessment Tool score decreased by 2 or returned to zero Use of additional sedation Adverse events Injury to staff or patients

7 Inclusion criteria Any adult patient with acute behavioral disturbance, at risk to themselves or others, Sedation Assessment Tool score of +2 to +3 Sample size Need 950 patients to be confident (97.5%CI) that an abnormal QT occurs in less than 0.5% of patients Incidence of QT prolongation and torsades de pointes is rare Assume QT prolongation occurs in no more than 0.5% of patients Aimed to recruit 1,000 patients, assuming that ECGs might not be conducted in 5% of them

8 Droperidol dosing protocol Based upon dose used in previous RCT Patient physically restrained Administered 10mg droperidol either IMI in the thigh or deltoid muscle or IV if a cannula had previously been inserted. If the patient did not settle within 15 minutes, an additional dose of droperidol 10 mg was administered Further sedation as per clinician s preference

9 Observations Cardiac monitoring, pulse oximetry, NIBP when settled. Sedation Assessment Tool scores and vital signs recorded every 5 minutes from the initial or subsequent doses of droperidol for 20 minutes and then half-hourly. Vital signs recorded on data collection form ECG was obtained as soon as practical and within 2 hours of droperidol dosing

10 Droperidol DORM 10mg in 2mL Phebra Pty Ltd Sydney, New South Wales, Australia

11 Recruited patients

12 Baseline characteristics

13 Droperidol dosing and effectiveness Median initial and total dose of droperidol 10mg Effective sedation with a single dose in 69% (968 pts) Additional sedation in 31% (435 pts) 299 received further droperidol only Others received midazolam, olanzapine, haloperidol, other drugs, combinations Median time to adequate sedation SAT score fall by 2 or more points or the score is 0 20min (IQR10-30min) (range 2-120min) 97% sedated within 120mins 49 patients failed sedation

14 Median (+IQR and 95% CI) time to sedation

15 ECG outcomes At least one documented ECG in 1009 patients There were no cases of TdP in any patient Median QT 360msec (95%CI ) 13 (1.3%) patients had an abnormal QT-HR pair 2 had preexisting abnormal QT 2 were receiving methadone 2 were receiving escitalopram 1 was receiving amiodarone 6 had unexplained QT prolongation

16 ECG outcomes

17 Adverse events 71 events in 70/ 1403 patients Hypotension 28 O2 desaturation 22 Airway obstruction 8 Jaw thrust or nasopharygeal airway in 6 Repositioned 1 Intubated for acute TCA OD 1

18 Over-sedation SAT score = -3 Overall 109/1403 (7.8%) No specific intervention required for most cases 2 x more likely if: Additional sedation included a benzodiazepine or ketamine

19 Limitations Many ECGs not performed within the 2 hour timeframe Staff did not want to disturb patients Cannot rule out rare (<0.1%) adverse event such as TdP Although risk is <0.3% in this study Consecutive data collection only at one site Other sites missed about 213 patients enrolments Study performed in the ED setting Most patients were under 65 years Drug and alcohol intoxication most common May not be generalizable to other settings Hospital wards, pysch units, addiction units

20 Summary Droperidol Was safe and effective in sedation of patients with acute behavioural disturbance in the ED QT prolongation was uncommon Incidence of 1.3% similar to that seen in cohort of patients with non-cardiac drug poisoning No cases of TdP Significant adverse events were uncommon We have adopted a similar guideline for sedation in our ED network

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22 Background: ACE-I angioedema Estimated to occur in up to 0.68% of patients treated with an ACE-I Accounts for 1/3 of cases of angioedema treated in the ED Most commonly affects the upper airway, tongue, pharynx. Obstruction of the upper airway reported to occur in 10% of cases This is not a histamine-mediated reaction ACE-I inhibit breakdown of bradykinin Oedema thought to be related to bradykinin excess Response to standard treatments for anaphylaxis is poor Case reports of B-2 receptor antagonist icatabantreversing angioedema from ACE-I use Icatibant currently used for Rx of hereditary angioedema

23 Method Phase-2 placebo controlled double-dummy multi-centre RCT yo Taking an ACE-I Angioedema of face, lips, cheeks, tongue, soft palate or uvula, pharynx, and larynx Treatment initiated within 10 hours of symptom onset No previous angioedema prior to start of ACE-I therapy

24 Method Randomized to receive Icatibant 30 mg s/c + IV placebo OR IV Prednisolone 500mg and clemastine 2mg + S/C placebo Patients assessed for resolution of 6 symptoms 1,2,3,4,6,8,12,24,48hrs post-treatment Pain, SOB, dysphagia, change in voice, sensation of FB, feeling of pressure VAS 0-10 If no improvement by 6 hours Rescue medication with icatibant 30mg +prednisolone 500mg

25 End points Primary end point Time to complete resolution of oedema Investigator and patient symptom scores Secondary end points proportion of patients who required rescue therapy proportion of patients with complete resolution of oedema at 4 hours after treatment Incidence of and time to rescue therapy Any adverse events

26 Sample size 11 patients in each group 90% power to detect the expected between-group difference in distribution with respect to the time to complete resolution of edema Two-sided significance level of 5%, with the use of a Wilcoxon rank-sum test. Final sample of 15 patients in each treatment group was planned. Assuming a maximum dropout rate of 25% (to account for rescue intervention oedema progression

27 Results Icatibant (n=13) Standard Rx (n=14) Gender M 69% M 57% Age Previous ACE-I reaction 38% 36% Time to treatment 6.1hr 5.1hr Rescue treatment 0 3 patients Site of angioedema Tongue 62% 71% Larynx 46% 50% Floor of mouth 46% 64%

28 Results

29 Resolution of symptoms

30 Adverse events Icatibant Any AE 1/15 4/15 injection pain SOB Standard Rx COPD, incr BSL, flu-like illness, Drug related AEs 1/15 1/15 SOB Serious AEs 0 1/15 Trache Injection site AEs Redness 12/15 4/15 Swelling 8/15 3/15 Itch 4/15 1/15

31 Limitations Sample size too small to assess safety Did not assess effect of adrenaline for angioedema Did not assess cost effectiveness

32 Summary Icatibant may reduce Time to resolution of ACE-I induced angioedema Need for invasive airway interventions Need for intensive care unit admission