Andrea Morelli, MD, from the Department of Anesthesiology and Intensive Care, University of Rome, “La Sapienza,” Italy, and colleagues conducted a randomized phase 2 trial at the University of Rome hospital intensive care unit between November 2010 and July 2012. The researchers randomly assigned 154 patients whose heartbeats exceeded 95 beats per minute (BPM) and who required high doses of norepinephrine to receive either continuous infusion of esmolol to maintain heart rate between 80 and 94 BPM (n = 77) or to receive standard treatment (n = 77) of norepinephrine during intensive care unit stays.
The target heartbeat rate was achieved in all patients in the esmolol group and was significantly lower than for patients in the control group. The median heart rate reduction came to −28 BPM for the esmolol group compared with −6 BPM for the control group (P < .001). The median continuously infused dose for esmolol was 100 mg/h (interquartile range [IQR], 50 – 300 mg/h).
The mortality rate for the esmolol group came to 49.4% for the esmolol group compared with 80.5% for the control group (P < .001). Stroke volume index was significantly higher in the esmolol group (P = .02), as was the left ventricular stroke work index (P = .03). Fluid requirements were reduced in the esmolol group compared with controls (P < .001), although no clinically relevant differences existed between groups for some other cardiopulmonary variables.
“Compared with standard treatment, esmolol also increased stroke volume, maintained [mean arterial pressure], and reduced norepinephrine requirements without increasing the need of inotropic support or causing adverse effects on organ function,” the researchers write.
Because esmolol is short-acting and has a half-life of about 2 minutes, it enables rapid resolution of any potential adverse effects. These new findings, the researchers write, suggest esmolol “allows better ventricular filling during diastole, hence, improving stroke volume and thereby improving the efficiency of myocardial work and oxygen consumption.”
Limitations of the study include selection of a predefined arbitrary heart rate threshold and the requirement that the study be nonblinded and not placebo-controlled. In addition, results might not be similar in a less at-risk population.
Paves the Way
“This is the unblindable trial. There’s no way to blind this trial. That will always be a limitation of whatever comes down the road,” R. Phillip Dellinger, MD, professor and head of critical care medicine at Cooper University Hospital in Camden, New Jersey, told Medscape Medical News. Dr. Dellinger is first author of a recent articleon treatment guidelines for sepsis.
The new study, Dr. Dellinger said, “clears the way for a larger phase 3 trial, and it offers support for moving the physiology in the direction that would, on the surface, look beneficial. It shows that it’s safe. The secondary outcomes all moved in a positive direction or didn’t move at all. So there are no signals here of potential problems with doing this; instead there is evidence that it helps cardiac function.”
Some aspects of this phase 2 trial differ from many phase 2 trials, he added. “This trial picked a population that would be predicted to more likely benefit from beta blockage, which is requiring very high doses of norepinephrine and being tachycardic.” Limiting the trial population may be better than including a large population in a study and dividing them up in subgroup analyses, he said, but the results might not be generalizable to a larger population.
In summary, Dr. Dellinger said, “Even though the trial was small, I think it was encouraging.”
This research was funded by the Department of Anesthesiology and Intensive Care of the University of Rome, “La Sapienza.” Dr. Morelli reports receiving honoraria for speaking at Baxter symposia. One coauthor reports serving as a consultant for and receiving honoraria from speaking at Baxter. The other authors and Dr. Dellinger have disclosed no relevant financial relationships.