ABSTRACT
Background
Vasoactive medications constitute an integral component of the hemodynamic support strategy in patients with cardiogenic shock (CS). However, there is an emerging signal of harm associated with the commonly used catecholamine, epinephrine (adrenaline), when used in the treatment of CS. The PAramedic randomized trial of Noradrenaline (norepinephrine) versus Adrenaline in the management of patients with cardiogenic shock (PANDA) was therefore designed to determine if the initial treatment with norepinephrine, compared with epinephrine, improves outcomes in patients with CS.
Methods and Design
The PANDA trial is a prehospital, open-label, single-blind, randomized controlled trial designed to assess the efficacy and safety of two commonly used catecholaminergic agents, norepinephrine and epinephrine, in the initial resuscitation of patients with suspected CS. Patients aged 18 years and older are eligible for recruitment by paramedics if there is clinical evidence of hypoperfusion, a measured systolic blood pressure of ≤90 mmHg despite adequate volume resuscitation with intravenous fluids, and the shock etiology is of a suspected cardiac cause (including cardiac arrest of an estimated duration of less than 30-minutes). Paramedics will randomize an anticipated 1,155 patients over an estimated 5-year period in a 1:1 ratio to receive an infusion of epinephrine or norepinephrine, which will be titrated to achieve a target systolic blood pressure of 100 mmHg. The primary efficacy outcome will be all-cause 28-day mortality. Recruitment commenced on February 28, 2024 and a total of 450 patients have been recruited thus far.
Implications
The PANDA trial will determine if norepinephrine, compared to epinephrine, for the initial hemodynamic support in CS improves outcomes. The results will help inform future treatment recommendations for the management of patients with CS.
Trial Registration
ACTRN12621000805875.
Rationale
Cardiogenic shock (CS) is a complex hemodynamic state, characterized by end-organ hypoperfusion due to cardiac dysfunction. ,, In addition to treating the underlying disease process, prompt hemodynamic support is essential to reduce the risk of developing multiple organ dysfunction syndrome (MODS) and restore cellular metabolism. Pharmacologic therapy with the use of vasopressors and inotropes is an essential element of this treatment strategy. In patients with a diagnosis of CS, 90% of those admitted to an intensive care unit (ICU) and 55% of patients treated in the prehospital setting receive at least one vasoactive medication. ,,, Despite the widespread use of this class of medications, there are limited randomized data to guide which agent should be used as the first-line medication to improve the prospects of a successful resuscitation, as well as reduce morbidity and mortality in this critically unwell patient population.
The initial study of vasoactive compounds and characterization of their pharmacology was first described in 1893 by the English physician George Oliver, who assessed the impact of glandular extracts from sheep on the vasoreactivity of his son’s radial artery. , Despite vast improvements in the sophistication of our understanding of these agents, there remains considerable uncertainty relating to their use in CS, which is largely driven by the historical challenges in conducting randomized controlled trials in this challenging patient population. This equipoise is reflected in the inconsistent recommendations for the first-line vasoactive medication to be used in patients with CS among various major cardiac societal guidelines, whereby clinician discretion or norepinephrine are typically recommended for CS with associated hypotension. ,,, This uncertainly is further highlighted through the variable practices observed among 25 emergency medical services (EMS) agencies (across Australasia, Europe and North America), with 52% of agencies using epinephrine as the first line agent, followed by 22% norepinephrine, and 18% dopamine in patients with suspected CS. However, despite the lack of consensus, there is an emerging body of data to support the use of the vasopressor norepinephrine in patients with CS and associated hypotension. ,,
The OPTIMA CC trial, a small double-blind, randomized controlled study assessed the safety and hemodynamic effects of norepinephrine and epinephrine in patients with acute myocardial infarction complicated by CS (AMI-CS) who had undergone percutaneous revascularization. Despite only recruiting 57 patients, OPTIMA CC, raised significant concerns about the safety and tolerability of epinephrine. Firstly, epinephrine was associated with worse acid-base status as evidenced by increased serum lactate; secondly, patients that received epinephrine had a significantly higher heart rate and a concomitant increase in the cardiac double product, a surrogate measurement for myocardial oxygen consumption; and finally, patients treated with epinephrine had increased rates of refractory CS (37% vs 7%, P =.008). Furthermore, a patient level meta-analysis that included 2,583 patients from 16 cohorts of patients with CS demonstrated that the risk of death was higher in epinephrine-treated CS patients, compared to treatment with other drug regimens (OR=3.3, 95% CI: 2.8-3.9). This concerning safety signal associated with epinephrine use, in combination with data to support norepinephrine use in CS, highlights the need for further randomized data assessing the safety and efficacy of epinephrine and norepinephrine in the management of CS.
By conducting the PAramedic randomized trial of Noradrenaline versus Adrenaline in the management of patients with cardiogenic shock (PANDA) study, we aim to establish if a treatment strategy with the vasopressor norepinephrine improves clinical outcomes, compared to the inotrope epinephrine, in the initial resuscitation of patients with suspected CS. The trial will recruit patients during the prehospital treatment phase, allowing randomization and trial agent commencement prior to exposure to alternate pharmacotherapy and in-hospital therapies including percutaneous revascularization and mechanical circulatory support. The results generated from this study will be generalizable to a range of clinical settings and serve to inform future EMS, cardiac and intensive care guideline recommendations for the management of patients with CS.
Methods
Study design and methodology
The PANDA study is a phase III, prehospital, open-label, single blind, population-based randomized controlled, superiority trial. Randomization will occur in the prehospital setting and be conducted by Ambulance Victoria in the state of Victoria, Australia. Ambulance Victoria is the sole provider of EMS in Victoria and has significant experience in prehospital enrollment and the conduct of critical care randomized controlled trials. , The EMS system provides a 2-tiered response to medical emergencies in the community, consisting of 4,500 advanced life support (ALS) paramedics and approximately 500 mobile intensive care ambulance (MICA) paramedics capable of advanced airway management and administration of a wider scope of medications (including intravenous vasoactive infusions and thrombolytics). Study participation will be limited to MICA paramedics only. Recruitment commenced on February 28, 2024 and a total of 450 patients have been recruited thus far ( Figure 1 ).
Study design for PANDA trial.
Patient population
The inclusion and exclusion criteria are presented in Table 1 . Patients will be screened by paramedics. Eligible individuals will be aged 18 years and older, have clinical evidence of hypoperfusion as defined by Ambulance Victoria’s Clinical Practice Guideline (CPG) (and can include any of the following examination findings: peripheral features, cool, pale, clammy; altered hemodynamic parameters, tachycardia (HR >100 beats per minute) or hypotension (systolic blood pressure <90 mmHg); altered mentation), a systolic blood pressure of 90 mmHg or less despite adequate fluid resuscitation, and an etiology of shock suspected by paramedics to be cardiac in origin. Fluid resuscitation will be in accordance with Ambulance Victoria’s CS CPG, an intravenous bolus of 0 to 500 mL Normal Saline is administered in patients with hypoperfusion (in cases where the patient has clinical evidence of pulmonary oedema, the trial agent will be commenced without administration of intravenous fluids). Suspected cardiac etiology is defined as a suspected prehospital primary diagnosis of acute coronary syndrome, resuscitated cardiac arrest, tachy or brady arrhythmia, or decompensated acute or chronic heart failure. Key exclusion criteria are suspected traumatic, anaphylactic, or asthmatic shock etiology, a recorded heart rate less than 50 beats per minute, cardiac arrest of duration greater than or equal to 30-minutes prior to return of spontaneous circulation (ROSC), interhospital transfer, and the administration of a vasoactive medication infusion prior to randomization. Patients who are suspected of being pregnant will also be excluded given the higher likelihood of a noncardiac cause of their shock. The trial adopts a broad eligibility criteria, allowing for patient recruitment in the field by paramedics prior to exposure to other therapeutic interventions and to enhance generalizability of our findings.
Table 1
PANDA trial enrolment inclusion and exclusion criteria.
| Inclusion criteria (all must be present) | Exclusion criteria (none must be present) |
|---|---|
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Randomization
Randomization will be performed by MICA paramedics. Each MICA unit will be assigned a trial pack, which contains the treatment allocation and instructions pertaining to the administration of the trial agents. The patients are randomized in a 1:1 fashion by a computer-generated code utilizing block randomization in block sizes of 6, with the treatment allocation and administration instructions contained in an opaque, externally numbered envelope. All participating MICA units will have their envelopes restocked at the earliest convenient time with the remaining envelopes held at the ambulance station. The randomization schedule will be produced and managed by an independent, blinded biostatistician. In previous trials conducted by the investigators, paramedic randomization using opaque envelopes has proved both feasible and practicable for allocation concealment. ,,,,,,
Consent and ethics
All eligible patients will be critically unwell with evidence of hypoperfusion. As randomization and commencement of the study protocol must occur in an emergent fashion, to avoid delays in treating life threatening hypoperfusion, it is not possible to obtain informed consent from the patient or next of kin prior to enrolment.
The issue of nonconsent in the setting of randomization for clinical trials is addressed in the state of Victoria under section 53 of the Medical Treatment Planning and Decision Act (2016). This section of legislation recognizes the administration of a medical research treatment to a person without consent, if the medical research treatment is deemed necessary as a matter of urgency to “prevent the person from suffering or continuing to suffer significant pain or distress.” Given that this research project is addressing hypoperfusion in patients with CS, immediate treatment is required to prevent suffering and adverse clinical outcomes. Accordingly, the investigators have been granted approval to enroll and randomize patients to receive either trial agent without obtaining informed consent. However, following randomization patients retain the right to withdraw from the study. This process is consistent with previous prehospital trials performed by the investigators in the cardiac emergency setting. , Overarching approval for this trial has been granted by The Alfred Hospital Human Research Ethics Committee (HREC/73653/Alfred-2021), Monash University Human Research Ethics Committee (Project 36199) and the Ambulance Victoria Research Governance Committee (Project R21-019). The Trial has also been prospectively registered with the Australian New Zealand Clinical Trials Registry (ACTRN12621000805875).
Study intervention
All patients will receive standard management in accordance with Ambulance Victoria CPGs. Study agents will be delivered via peripheral venous access. While trial agents are being prepared, patients may receive 0.5 to 1 mg intravenous metaraminol boluses every 1 to 2 minutes to support blood pressure. In patients allocated to receive an epinephrine infusion, 3 mg of epinephrine will be added to 50 mL of 5% dextrose or normal saline and commenced at a rate of 5 mcg/min. For patients assigned to a norepinephrine infusion, 3 mg of norepinephrine will be added to 50 mL of 5% dextrose or normal saline and commenced at a rate of 5 mcg/min. Both agents will be titrated in 5 to 10 mcg/min increments to a maximum dose of 250 mcg/min to achieve a systolic blood pressure of 100 mmHg or greater determined by noninvasive blood pressure assessment (EMS do not routinely obtain invasive blood pressure measurements). In the event of persistent hypotension, cross-over is not permitted.
After randomization, epinephrine may only be administered to patients assigned to receive norepinephrine in the following circumstances: 1) during recurrent cardiac arrest resuscitation, which occurs following randomization, in accordance with the Australian Resuscitation Council guidelines ; 2) in the setting of unstable bradycardia following inadequate response to atropine as described in Ambulance Victoria’s CPG.
Emergency Department (ED) and Intensive Care Units will be requested, but not mandated, to follow treatment allocation for patients enrolled in the trial.
Outcomes
The primary endpoint assessed is all-cause 28-day mortality. The primary and secondary end-points are presented in Table 2 . A blinded, independent clinical event adjudication committee will review all cases to determine shock etiology. Additional secondary end points stratified by the adjudicated etiology are displayed in Table 3 . Table 4 presents the prespecified subgroup analyses of the primary end point.
Table 2
Primary and secondary end points.
| Primary end point |
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| Safety end point |
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| Secondary end points |
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