Section 6: Pharmacology II: Agents to Optimize Cardiac Output and Blood Pressure

Epinephrine Epinephrine hydrochloride produces beneficial effects in patients during cardiac arrest, primarily because of its a-adrenergic receptor–stimulating properties.1 The adrenergic effects of epinephrine increase myocardial and cerebral blood flow during CPR.2 The value and safety of the b-adrenergic effects of epinephrine are controversial because they may increase myocardial work and reduce subendocardial perfusion.3 Although epinephrine has been used universally in resuscitation, there is a paucity of evidence to show that it improves outcome in humans. For a number of years researchers and clinicians have also questioned the optimal dose of epinephrine. The “standard” dose of epinephrine (1.0 mg) is not based on body weight. Historically a standard dose of 1 mg epinephrine was used in surgical operating rooms for intracardiac injections.4–6 Surgeons observed that 1 to 3 mg of intracardiac epinephrine was effective in restarting the arrested heart.6,7 When these and other experts first produced resuscitation guidelines in the 1970s, they assumed that 1 mg of IV epinephrine would work in a similar manner as 1 mg of intracardiac epinephrine. Adult patients vary greatly in weight, yet clinicians continue to inject the same 1-mg dose of epinephrine for all body weights. The dose-response curve of epinephrine was investigated in a series of animal experiments during the 1980s. This work showed that epinephrine produced its optimal response in the range of 0.045 to 0.20 mg/kg.8–11 From these studies it seemed that higher doses of epinephrine were necessary to improve hemodynamics and achieve successful resuscitation, particularly as the interval from cardiac arrest increased. This work led many clinicians to use higher doses of epinephrine in humans, and optimistic case series and retrospective studies were published in the late 1980s and early 1990s.12–14 Results from 4 clinical trials then compared high-dose epinephrine with standard-dose epinephrine.8,15–17 Overall the rate of return of spontaneous circulation (ROSC) was increased with higher doses of epinephrine (0.07 to 0.20 mg/kg); however, no statistically significant improvement in the rate of survival to hospital discharge occurred. On the positive side, these trials failed to detect any significant harm from administration of higher doses of epinephrine. On the basis of this information, in 1992 the guidelines recommended that the first epinephrine dose continue to be 1 mg IV. The 1992 guidelines also recommended that the interval between subsequent doses of epinephrine be every 3 to 5 minutes rather than every 5 minutes. If the 1 mg epinephrine every 3 to 5 minutes seemed to be ineffective, the 1992 guidelines accepted the use of higher doses of epinephrine in either escalating doses (1, 3, 5 mg), intermediate doses (5 mg per dose rather than 1 mg), or high doses based on body weight (0.1 mg/kg). Both beneficial and toxic physiological effects of epinephrine administration during CPR have been shown in animal and human studies.18–26 Initial or escalating high-dose epinephrine has occasionally improved initial ROSC and early survival. But 8 randomized clinical studies involving more than 9000 cardiac arrest patients have found no improvement in survival to hospital discharge or neurological outcome, even in subgroups with initial high-dose epinephrine, compared with standard doses.15–17,27–31 These trials largely addressed initial use of high-dose epinephrine and not escalating doses after an initial failure of a 1-mg dose. In these studies there was no evidence of a worse outcome with high-dose epinephrine. Retrospective studies, however, have suggested that high cumulative epinephrine dosage is associated with worse hemodynamic and neurological outcome, but they do not prove causal effect.26,32 Careful laboratory studies corroborate both beneficial and harmful physiological effects and outcomes. High-dose epinephrine may improve coronary perfusion and increase vascular resistance to promote initial ROSC during CPR, but these same effects may lead to increased myocardial dysfunction and occasionally a severe toxic hyperadrenergic state in the postresuscitation period.18,21,23,25 Target populations with increased risk and potential increased benefit (catecholaminerefractory conditions) need to be identified. In summary, initial high-intravenous-dose epinephrine in cardiac arrest may increase coronary perfusion pressure and improve ROSC, but it may exacerbate postresuscitation myocardial dysfunction. Higher doses of epinephrine have not improved long-term survival and neurological outcome