Giving a combination of vasopressin, steroids, and epinephrine (VSE) during cardiopulmonary resuscitation (CPR) and then treating survivors with daily steroids was associated with more than a doubling in the likelihood of being discharged with a neurologically favorable outcome vs standard care with epinephrine alone in a new study.The study, published in the July 17 issue of JAMA, was led by Spyros D. Mentzelopoulos, MD, Evaggelismos General Hospital, Athens, Greece.

“Our results are very promising,” he commented to Medscape Medical News. “I would say that they correspond to a level B recommendation, because there was a limited population and just one randomized trial. We will have to wait for the guidelines committees to decide if this treatment should be recommended for wider use, but I would definitely want it if it was me or one of my relatives as the patient.”Avoiding Secondary Neurologic Damage

The study evaluated the use of the 3 agents during CPR as well as continued treatment with intravenous steroids for up to a week in those surviving but hemodynamically unstable.

Dr. Mentzelopoulos believes both periods of treatment are important. “We need to improve resuscitation as much as possible assurvival rates after cardiac arrest are so low. We must focus on post-resuscitation care as well as that during CPR to get better outcomes. When spontaneous circulation comes back we need to avoid secondary neurological damage so we need to make sure the brain stays infused.”

In the JAMA paper, the researchers note that a previous study of a similar regimen has shown improved overall survival tohospital discharge, but this study did not reliably assess neurologically favorable survival. They add that this is a key outcome because among cardiac arrest survivors, the prevalence of severe cerebral disability or vegetative state ranges from 25% to 50%.

In the current study, 268 patients with in-hospital cardiac arrest requiring epinephrine according to resuscitation guidelines were randomly assigned to the combination treatment of vasopressin (20 IU/CPR cycle) plus epinephrine (VSE group) or saline placebo plus epinephrine (control group) for the first 5 CPR cycles after randomization.

In addition, during the first CPR cycle, patients in the VSE group received methylprednisolone (40 mg) and patients in the control group received saline placebo. And VSE patients who were successfully resuscitated but still hemodynamically unstable were treated with an intravenous infusion of hydrocortisone (300 mg daily for 7 days). Control patients were given saline placebo.

Results showed that patients in the VSE group had a higher probability of return of spontaneous circulation of 20 minutes or longer after CPR and a higher chance of survival to hospital discharge with a neurologically favorable outcome (CPC score of 1 or 2).

Table 1. Major Outcomes in Whole Study Population

Endpoints                               VSE (n = 130), n (%)         Control (n = 138), n (%)      Odds Ratio (95% Confidence Interval)     PValue
Return of spontaneous            109 (83.9)                                 91 (65.9)                                        2.98 (1.39-6.40)                              .005
Survival to hospital discharge   18 (13.9)                                  7 (5.1)                                            3.28 (1.17 = 9.20)                            .02
with favorable neurologic outcome

Among patients surviving after CPR but with post-resuscitation shock, those in the VSE group had a higher probability of survival to hospital discharge with CPC scores of 1 or 2.

Table 2. Patients Surviving After CPR But With Post-Resuscitation Shock

                    Endpoint                     VSE (n = 76), n (%)        Control (n = 73), n (%)      Odds Ratio (95% Confidence Interval)     PValue

Survival to hospital discharge           16 (21.1)                                    6 (8.2)                                         3.74 (1.20-11.62)                      .02
with favorable neurologic outcome

The VSE patients also had improved hemodynamics and central venous oxygen saturation, and less organ dysfunction.

Dr. Mentzelopoulos said, “We have more than doubled the number of patients with a successful outcome, although these patients still make up a very low percentage.”

He explained to Medscape Medical News that vasopressin is a vasoconstrictor-like epinephrine. “To maximize perfusion of vital organs, especially the brain, we thought combination of vasopressin and epinephrine would be optimal as they are both vasoconstrictors but stimulate different vascular receptors — epinephrine acts on the A1 adrenergic receptor while vasopressin acts on the B1 receptor, so they should give and additive vasoconstrictive action.”

He added that the rationale for steroid treatment after cardiac arrest is that the peripheral organs such as adrenal glands become ischemic after cardiac arrest so the steroid level would be low, especially in a stressful situation. “So we thought it would be meaningful to supplement with steroids. In addition, steroids potentiate the effects of the vasoconstrictors by facilitating signals through vasoconstrictor receptors.”

Dr. Mentzelopoulos said he could not precisely quantify the relative contribution to the final outcome of the VSE treatment given during resuscitation vs the hydrocortisone treatment given in the post-resuscitation period. “The VSE protocol was associated with a greater likelihood of successful resuscitation, but we don’t know how much this contributed to the end result. It appears that both protocols are contributing something.”

He noted that a limitation of the study was that because of small numbers a difference in survival at 1 year could not be reliably determined.

“Tremendous” Results

Commenting on the study for Medscape Medical News, Gordon Ewy, MD, University of Arizona, Tucson, said he thought the results were “tremendous.”

“There have been millions of dollars spent on randomized controlled trials which have failed to show benefits so it’s very exciting to finally see one with significant results,” he said. “This is the first randomized trial to have shown positive results in this population for decades.”

But he pointed out that the study was conducted in patients who had an in-hospital cardiac arrest, and the results could not be extrapolated to the out-of-hospital cardiac arrest scenario.

“In-hospital and out-of-hospital cardiac arrests are totally different situations with different etiologies. In-hospital arrests are usually in patients in intensive care who may have been deteriorating for a while, and help is normally on hand immediately. In contrast, out-of-hospital cardiac arrest in people over 40 years of age is almost always caused by an MI [myocardial infarction], and often help does not arrive for some time,” he pointed out.

“While we have made great strides in out-of-hospital cardiac arrest with chest compression-only CPR, there has been little progress in the treatment of in-hospital cardiac arrest, so it is terrific to see a positive study, even though it was relatively small.”


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