Pain and anxiety should be cautiously managed with the administration of morphine in selected patients with intense insisting pain not resolving with supportive treatment. Routine use of opiates is not recommended [4], as morphine has been associated with increased need for mechanical ventilation support, prolonged hospitalization and worse prognosis [76].

In the absence of signs of congestion and in patients with preload-dependent phenotypes, fluid resuscitation should be considered with boluses of normal saline or Ringer’s lactate, 250 mL over 15–30 min and under close monitoring with POCUS [1]. POCUS is a dynamic tool for the real-time and serial assessment of volume status and systematic congestion in order detect volume overload and to guide fluid administration. Valuable parameters for optimizing and monitoring fluid resuscitation include the IVC respiratory variation and collapsibility index, the presence of a B-line profile in the lungs, LV and RV diastolic diameters, LV filling pressure (e/e’) and RV filling pressure [1,43], as well as VExUS score [48]. Passive leg raising (PLR) could be reliably used in order to assess fluid responsiveness [77,78]. Fluid responsiveness is the increase in cardiac output of greater than 10% following a 500 mL fluid bolus [79]. PLR, acting as an endogenous fluid challenge, augments venous return, central venous pressure and biventricular preload, and the eventual rise in cardiac output indicates the need for volume expansion. Performance of the test in the ED setting could be aided by the use of echocardiography, estimating changes in the CO through the measurement of the left ventricular outflow tract velocity time integral (LVOT VTI) [80,81].

Currently, data on crystalloid type remain controversial for use in sepsis and shock. There is lack of robust data in the literature specifying the appropriate type of crystalloid fluid for CS patient resuscitation. There is a relative concern regarding the use of saline solutions, as they may cause hyperchloremic metabolic acidosis and acute kidney injury (AKI) [82], and since cardiorenal syndrome is a common complication of CS [83], selection of the least harmful fluid retains a significant importance. Studies on critically ill ICU patients have shown a favorable effect of balanced crystalloid (plasmalyte or Ringer’s lactate) versus saline administration with respect to the need for renal replacement therapy (RRT), AKI and mortality [84,85]. Hammond et al. showed in a metanalysis that administration of balanced crystalloids resulted in a relative reduction in the risk of death at 90 days, ranging from a 9% to 1% relative increase [86]. However, two other metanalyses concluded that there was no statistically significant difference between administration of balanced crystalloid solutions and saline in terms of mortality, incidence of AKI and RRT [87,88]. Given the rather contradictory results, and as critically ill ICU patients represent fairly heterogeneous populations, more studies are needed in order to elucidate which is the appropriate fluid therapy for such high-risk patients, especially those with CS.

The need for immediate intubation and mechanical ventilatory support must be addressed on arrival on a patient-to-patient basis [4]. Clinical presentation and point-of-care-acquired data will define the choice of noninvasive ventilatory support (NIV) versus invasive mechanical ventilatory support (IMV) [89]. The majority of patients with signs of congestion and without signs of acute RV failure will benefit from positive pressure ventilation both in respiratory and hemodynamic features, since the mechanical-ventilation-related decrease in left ventricular (LV) preload and afterload can reduce the workload of the failing LV [90,91]. Special caution must be taken with hemodynamically unstable patients who are not responding to initial therapy with vasopressors and inotropes and with those with signs of acute RV failure, where the reduction in the preload of the RV and increase in pulmonary vascular resistance caused by positive intrathoracic pressures may lead to further hemodynamic deterioration [8,91]. In this context, in most of the patients with CS, an early NIV trial of 30 min to 1 h will be beneficial, along with initial hemodynamic stabilization, and may help to avoid endotracheal-intubation-related risks such as airway complications, further destabilization due to anesthesia induction and the need for ongoing sedation [90]. Furthermore, IMV is associated with complications such as ventilator-acquired pneumonia, increased length of ICU stays, and increased in-hospital mortality [92]. Major contraindications to NIV are altered mental status on presentation, refractory hypotension, acute RV failure, facial deformities, secretions and vomiting, as well as an uncooperative patient [8,91,93]. The choice of NIV mode (C-PAP vs. Bi-PAP) depends mainly on the presence of hypercapnia, which outlines the need to support both oxygenation and ventilation [89]. Nevertheless, in patients scheduled for primary coronary intervention, the choice of IMV with early intubation and stabilization during the ED stay may be preferential, considering patient control, safety and positioning in the cath-lab. The indications and initial settings for both NIV and IMV are presented in Table 3.

Inotropes and vasopressors represent a necessary evil in the initial management of patients on the verge of circulatory compromise. They are indispensable and promptly available pharmacological agents, but they should be used at the lowest possible dose and for the lowest possible duration [94,95,96], since prolonged administration is associated with increased oxygen demand (further aggravating myocardial ischemia), increased afterload, impaired microcirculation, arrhythmogenesis [97] and mortality [98]. Their hemodynamic effects may vary, and selection of the appropriate agent should be based on CS etiology, hemodynamic profile and shock severity [22,97,99].

Use of vasopressors and inotropes should be individualized based on patient fluid status and CS etiology and should be adjusted based on clinical judgement. In fluid-responsive patients with signs of hypoperfusion (tachycardia and vasoconstriction) but without hypotension (compensated CS), inotropes (dobutamine or levosimendan) may be cautiously started after first the bolus of fluids has failed to restore peripheral organ perfusion. Attention is required in patients with RV dysfunction who may not tolerate fluid administration or in patients with signs of congestion. When hypotension is also present, concomitant administration of an inotropic agent and a vasopressor (preferably norepinephrine) should be initiated and titrated until perfusion is restored. In patients with refractory shock, escalation of therapy is required with the addition of a second vasopressor (vasopressin) or MCS [99].

Norepinephrine is recommended as a first-line vasopressor (Class IIb/B recommendation) [4] to restore end-organ perfusion and maintain systolic blood pressure [1,97]. Additionally, through cardiac β1 adrenergic stimulation, it enhances cardiac contractility and ventricular–arterial coupling [100]. The exact target of SBP is not fully clarified, but an initial goal of SBP > 90 mmHg and/or MAP of 55–75 mmHg in conjunction with other clinical markers of end-organ perfusion is advised [54]. Compared to epinephrine, norepinephrine had similar hemodynamic effects on mean arterial pressure (MAP) and CI, but epinephrine was associated with higher rates of refractory shock, tachycardia, lactic acidosis [101] and mortality [102,103]. Moreover, compared to dopamine, norepinephrine had a safer profile in patients with CS, due to a lower trend for arrhythmic events and mortality [104]. Vasopressin lacks inotropic properties and may be used as a second-line vasoactive agent, concomitantly to norepinephrine, if hemodynamic status does not improve with single use of norepinephrine [1,99,105]. Its administration may be appealing in special circumstances, like in patients with right ventricular failure, as it does not affect pulmonary arterial pressure [93,97,106], or in combination with milrinone in order to counteract its vasodilatory effect [1], but evidence is lacking [93].

Inotropes may be considered in addition to vasopressors in order to augment cardiac output and end-organ perfusion (Class IIb/C recommendation) [4]. Dobutamine is recommended over other inotropic agents if signs of hypoperfusion persist despite first-line vasopressor therapy [1]. However, a systematic review failed to show any benefit of dobutamine over levosimendan for short- and long-term survival [107]. Levosimendan and milrinone may be preferable over dobutamine in special cases such as long b-blockade, right ventricular dysfunction, pulmonary hypertension, or Takotsubo cardiomyopathy [1,4,108].

In CS patients with refractory hypotension, vasopressin may aid in preserving arterial blood pressure, as a third vasoactive agent, in conjunction with norepinephrine and dobutamine [99].

Patients who present with deteriorating or extremis CS, or those who fail to stabilize hemodynamically with two vasoactive agents may benefit from devices for temporary MCS in an individualized manner (Class IIa/C recommendation) [4,22]. Early initiation of MCS may provide univentricular or biventricular support by improving cardiac contractility, reducing left/right ventricular end-diastolic pressures, enhancing coronary perfusion and decreasing myocardial oxygen demand [109,110], resulting in effective weaning from cardiotoxic vasoactive agents [111]. However, controversial results with respect to mortality [112,113,114,115] incite the consideration of challenging issues regarding their application in practice, such as patient selection, type of device, appropriate timing, and prognostic impact. A characteristic recent example is the ECMO-CS randomized controlled trial where patients with deteriorating CS were randomized to immediate ECMO or early conservative therapy (with the ECMO kept as a bailout option at a later stage). The study did not show a benefit for the early ECMO approach. Despite having several limitations (i.e., relatively small sample size, mixed cohort of AMI- and non-AMI-related CS, and significant crossover rate (39% crossover to VA-ECMO in early conservative arm)), the study provides important data for the CS population.

Available choices for left ventricular assistance include the intra-aortic balloon pump (IABP), microaxial flow pumps (Impella CP, Impella 5), or the left-atrium-to-femoral-artery system device (Tandem Heart), while right ventricular assistance may be supported by the Impella RP, Tandem Heart RA-PA and Protek Duo devices. Venous–arterial extracorporeal membrane oxygenation (VA-ECMO) may reinforce biventricular performance and improve oxygenation [1,55,110]. Regarding the down-side of advanced percutaneous left ventricular devices, IABP use has subsided, taking into account no proven survival benefit for patients with AMI-CS [112], and currently its implementation may be considered for patients with refractory CS of non-AMI etiology (class IIb/C recommendation) [4] or for AMI-CS patients with mechanical complications as a bridge to more advanced MCS devices (class IIa/C recommendation) [42]. Even if Impella devices seem like promising approaches, data regarding their beneficial effect on mortality are scarce [113,114,116]. Although ECMO may ensure hemodynamic stabilization in cardiopulmonary resuscitation [117], it may also increase LV afterload, making its use reasonable with concomitant LV unloading (IABP, Impella, septostomy and hybrid circuit configuration) [1,110,118]. It must be emphasized that devices like Impella and ECMO necessitate the insertion of large-bore cannulas into major vessels and carry a high risk of complications, including vascular and bleeding complications. Characteristically, for Impella used in AMI-related CS, the rate of severe bleeding reported in the literature ranged from 8.5% to 31% [119,120]. Thus, to improve the efficacy of advanced MCS devices and increase the chances of positive studies in the CS field, specific measures should be taken to reduce complications. Such measures include comprehensive training in device insertion and maintenance, formation of dedicated teams (e.g., ECMO team including perfusionists), ultrasound guided vascular access, use of vascular closure systems, etc.

The uniqueness of each device, indicated by distinct hemodynamic effects, favorable profiles, contraindications and complications, limits their use to selected patients and under the supervision of expert teams [121]. The comprehensive approach by multidisciplinary teams in the context of a shock network emerges as an ultimate but not impossible goal to improve survival. Interestingly, recent data support that early initiation of MCS in the initial stages of CS, even before the administration of inotropes or the PCI strategy, is significantly associated with increased survival rates in patients presenting with AMI-CS [122], supporting the need to achieve shorter “door to support” intervals, so as to anticipate the deleterious effects of the fatal spiral of cardiac compromise [123].