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Timing of drug delivery (epinephrine)

Question Type:
Intervention
Full Question:
Among adults who are in cardiac arrest in any setting (P), does does early epinephrine delivery by IV or IO route (eg, less than 10 minutes after the beginning of resuscitation)  (I), compared with compared with delayed timing of epinephrine delivery (eg, more than 10 minutes after the beginning of resuscitation)  (C), change Survival with Favorable neurological/functional outcome at discharge, 30 days, 60 days, 180 days AND/OR 1 year, Survival only at discharge, 30 days, 60 days, 180 days AND/OR 1 year, ROSC (O)?
Consensus on Science:
In-Hospital Cardiac Arrest
For IHCA, for the critical outcome of survival to hospital discharge, there was 1 observational study(Donnino 2014, g3028) of low quality (downgraded for serious risk of bias and upgraded for dose-response effect) in 25 095 IHCA patients with a nonshockable rhythm that showed an improved outcome with early administration of adrenaline: compared with reference interval of 1 to 3 minutes, adjusted OR for survival to discharge was 0.91 (95% CI, 0.82–1.00) when epinephrine was given after 4 to 6 minutes, 0.74 (95% CI, 0.63–0.88) when given after 7 to 9 minutes, and 0.63 (95% CI, 0.52–0.76) when given at more than 9 minutes after onset of arrest.
For IHCA, for the critical outcome of neurologically favorable survival at hospital discharge (assessed with CPC 1 or 2), there was 1 observational study(Donnino 2014, g3028) of low quality (downgraded for serious risk of bias and upgraded for dose-response effect) in 25 095 patients with IHCA with a nonshockable rhythm that showed an improved outcome from early administration of adrenaline: compared with reference interval of 1 to 3 minutes, adjusted OR was 0.93 (95% CI, 0.82–1.06) with epinephrine given after 4 to 7 minutes, 0.77 (95% CI, 0.62–0.95) when given after 7 to 9 minutes, and 0.68 (95% CI, 0.53–0.86) when given at more than 9 minutes after onset of arrest.
For IHCA, for the important outcome of ROSC, there was 1 observational study(Donnino 2014, g3028) of low quality (downgraded for serious risk of bias and upgraded for dose-response effect) in 25 095 patients with IHCA with a nonshockable rhythm that showed an improved outcome from early administration of adrenaline: adjusted OR compared with reference interval of 1 to 3 minutes of 0.90 (95% CI, 0.85–0.94) when given after 4 to 7 minutes, 0.81 (95% CI, 0.74–0.89) when given after 7 to 9 minutes, and 0.70 (95% CI, 0.61–0.75) when given after 9 minutes.
No studies were identified that looked specifically at the effect of timing on administration of epinephrine after IHCA with an initial shockable rhythm.
Out-of-Hospital Cardiac Arrest
For the critical outcome of neurologically favorable survival at hospital discharge (assessed with CPC 1 or 2), there was very-low-quality evidence (downgraded for risk of bias, inconsistency, indirectness, and imprecision) from 4 observational studies(Hayashi 2012, 1639; Nakahara 2012, 782; Goto 2013, R188; Dumas 2014, 2360) involving more than 262 556 OHCAs, showing variable benefit from early administration of early epinephrine. One study of 1556 OHCAs who had achieved ROSC(Dumas 2014, 2360) demonstrated an association between the administration of epinephrine and worse CPC, but shorter times of administration were associated with less negative effects: adjusted OR of 0.54 (95% CI, 0.32–0.91) for good CPC with epinephrine at less than 9 minutes versus no prehospital epinephrine, and adjusted OR of 0.17 (95% CI, 0.09–0.34) for epinephrine at more than 22 minutes.
Another study enrolling 209 577 OHCAs(Goto 2013, R188) did not show any significant difference in 1-month CPC 1 or 2 with epinephrine given in less than 9 minutes compared with no epinephrine (OR, 0.71; 95% CI, 0.54–0.92 and OR, 0.95; 95% CI, 0.62–1.37).
Another study enrolling 3161 subjects(Hayashi 2012, 1639) showed an association with improved 1-month neurologic outcome in VF/VT OHCA with early epinephrine (at 10 minutes or less from EMS call to administration) compared with no epinephrine (OR, 6.34; 95% CI, 1.49–27.02). A fourth study enrolling more than 49 000 cases(Nakahara 2012, 782) demonstrated a nonsignificant association with improved neurologic survival with early epinephrine (less than 10 minutes from EMS-initiated CPR): OR of 1.39 (95% CI, 1.08–1.78) versus OR of 2.01 (95% CI, 0.96–4.22).
For the critical outcome of survival to hospital discharge after OHCA, there was very-low-quality evidence (downgraded for risk of bias, inconsistency, indirectness, and imprecision), from 4 observational studies(Stiell 1992, 1045; Nakahara 2012, 782; Goto 2013, R188; Koscik 2013, 915) enrolling more than 420 000 OHCAs that showed variable effect from early administration of adrenaline. Goto(Goto 2013, R188) showed no significant difference in 1-month survival for shockable rhythms, but improved 1-month survival for shockable rhythms with epinephrine at less than 9 minutes (OR, 0.95; 95% CI, 0.77–1.16 and OR, 1.78; 95% CI, 1.5–2.1). Another study(Nakahara 2012, 782) showed an association with improved survival with early epinephrine (less than 10 minutes from EMS CPR): for arrests of cardiac origin: OR, 1.73 (95% CI, 1.46–2.04); for noncardiac origin: OR, 1.89 (95% CI, 1.37–2.61). A third study(Koscik 2013, 915) did not show any overall survival benefit for early epinephrine compared with late (epinephrine at more or less than 10 minutes): OR, 0.91 (95% CI, 0.35–2.37).
For the important outcome of ROSC, there was very-low-quality evidence (downgraded for risk of bias, indirectness, and imprecision) from 4 observational studies(Stiell 1992, 1045; Cantrell CL Jr 2013, 15; Goto 2013, R188; Koscik 2013, 915) of more than 210 000 OHCAs showing an association with improved outcome and early administration of adrenaline. One study(Cantrell CL Jr 2013, 15) showed increased ROSC for patients receiving the first vasopressor dose early (less than 10 versus more than 10 minutes after EMS call): OR, 1.91 (95% CI, 1.01–3.63).
Another study(Goto 2013, R188) showed an association with improved ROSC for epinephrine given at less than 9 minutes after arrest versus none (for nonshockable rhythms: OR, 8.83; 95% CI, 8.01–9.73; for shockable rhythms: OR, 1.45; 95% CI, 1.20–1.75). A third study(Koscik 2013, 915) showed an association with improved ROSC for early epinephrine versus late (more or less than 10 minutes after EMS call): OR, 1.78 (95% CI, 1.15–2.74).
The design flaws for most of the observational OHCA studies included the use of a “no epinephrine” control group as the comparator, thus not allowing for actual estimates of the effect of timing, and the lack of known timing of epinephrine administration upon arrival in the ED. The relationship of timing of defibrillation to timing of epinephrine is unknown for studies including shockable rhythms. These design issues make the question of timing of epinephrine difficult to interpret in the OHCA setting despite attempts to control for other confounders.
Treatment Recommendation:
For cardiac arrest with an initial nonshockable rhythm, we suggest that if epinephrine is to be administered, it is given as soon as feasible after the onset of the arrest (weak recommendation, low-quality evidence).
For cardiac arrest with an initial shockable rhythm, we found insufficient evidence to make a treatment suggestion regarding the timing of administration of epinephrine, particularly in relation to defibrillation, and the optimal timing may vary for different groups of patients and different circumstances.
Values, Preferences, and Task Force Insights
In making the recommendation for nonshockable rhythms, we place a higher value on being able to modify a current (standard) treatment at minimal cost.
For shockable rhythms, we place a higher value on early defibrillation than on administration of epinephrine but did not think there is sufficient evidence to make a treatment recommendation. Although we acknowledge that the pathophysiology of IHCA and OHCA is likely to be different, we were confident that the same recommendations could apply to both settings.
CoSTR Attachments:
Bias Assessments for IHCA.xlsx    
CoStar Statement For Timing of Administration of Epinephrine.docx    
Final Summary of Bias Assessments for Timing of Epinephrine in Cardiac Arrest.xlsx    
Grade Pro table for OHCA, Timing of Adminstration of Epinephrine Feb 2015.docx    
Time to Epi. GRADE and study overview IHCA.pdf    

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