Guillaume Leurent
email: guillaume.leurent@chu-rennes.fr

Vincent Auffret

Camille Pichard

Marc Laine

Laurent Bonello

Keywords: balloon pump in cardiogenic shock management Intra-aortic balloon pump, Cardiogenic shock, Myocardial infarction, Left ventricular unloading

Is there still a role for the intra-aortic balloon pump in the management of cardiogenic shock following acute coronary syndrome?

Coronary flow

MOTS CLÉS

Ballon de contre pulsion intra-aortique ;

Presentation of the device

The intra-aortic balloon pump (IABP) was first described 50 years ago [START_REF] Kantrowitz | Initial clinical experience with intraaortic balloon pumping in cardiogenic shock[END_REF] in the management of cardiogenic shock (CS) [START_REF] Scheidt | Intra-aortic balloon counterpulsation in cardiogenic shock. Report of a co-operative clinical trial[END_REF]. The device is made of a balloon, which is inserted through the femoral artery [START_REF] Prondzinsky | Hemodynamic effects of intra-aortic balloon counterpulsation in patients with acute myocardial infarction complicated by cardiogenic shock: the prospective, randomized IABP shock trial[END_REF][START_REF] Reynolds | Cardiogenic shock: current concepts and improving outcomes[END_REF] French sheath) and placed in the descending aorta, between the subclavian artery and the renal arteries, under X-ray guidance. The balloon is linked to a mobile management console, which drives the helium inflation and deflation of the balloon in synchrony with the cardiac cycle, triggered by the electrocardiogram signal or the systemic arterial waveform. Although the "automatic" mode is widely used, several variables can be modified ("semiautomatic" or "manual" modes) -mostly the volume and duration of the inflation, and the trigger for the inflation of the balloon, according to the haemodynamic setting. Lastly, the balloon inflation/deflation rate can be settled (1 out of 1, 2 or 3 cardiac cycles). The main contraindications for the device are severe peripheral arterial disease precluding insertion of the balloon, more-than-moderate aortic regurgitation and severe dynamic left ventricular (LV) outflow tract obstruction.

Inflation occurs immediately after aortic valve closure at the onset of diastole. As a result of this diastolic inflation, the IABP increases the diastolic pressure upstream of the balloon, especially in the coronary arteries, to levels above that of systolic pressure (Fig. 1). In physiological conditions, autoregulation of the vasomotor tone in the coronary arteries and arterioles allows optimization of the coronary blood flow. Therefore, the coronary blood flow becomes directly dependent on perfusion pressure. However, in the setting of CS this autoregulation is ineffective, especially when the mean aortic pressure drops below 60 mmHg [START_REF] Silva | Coronary and microvascular physiology during intraaortic balloon counterpulsation[END_REF]. Moreover, coronary vascular tone autoregulation is also ineffective in the setting of myocardial infarction [START_REF] Pierrakos | Mechanical assistance by intra-aortic balloon pump counterpulsation during reperfusion increases coronary blood flow and mitigates the noreflow phenomenon: an experimental study[END_REF][START_REF] Van Nunen | Usefulness of Intra-aortic Balloon Pump Counterpulsation[END_REF]. As myocardial perfusion occurs during diastole, coronary artery blood flow is supposed to be improved by the IABP, which should be beneficial during CS secondary to an acute coronary syndrome. In addition to this first benefit of IABP, it is also associated with a reduction of LV afterload. As balloon deflation occurs immediately before aortic valve opening, at the onset of systole, it reduces aortic volume by 40-50 mL. Consequently, the device reduces LV systolic and end-diastolic pressures and volumes, central venous and pulmonary wedge pressures and myocardial oxygen consumption [START_REF] Schampaert | Intra-Aortic Balloon Pump Support in the Isolated Beating Porcine Heart in Nonischemic and Ischemic Pump Failure[END_REF]. Finally, the device increases cardiac output slightly, by approximately 0.5 L/min [START_REF] Scheidt | Intra-aortic balloon counterpulsation in cardiogenic shock. Report of a co-operative clinical trial[END_REF][START_REF] Prondzinsky | Hemodynamic effects of intra-aortic balloon counterpulsation in patients with acute myocardial infarction complicated by cardiogenic shock: the prospective, randomized IABP shock trial[END_REF]. Given these combined haemodynamic properties, IABP should, in theory, be beneficial in the management of CS.

Nonetheless, the physiopathology of CS is complex [START_REF] Reynolds | Cardiogenic shock: current concepts and improving outcomes[END_REF], with varying definitions according to different trials and registries [START_REF] Delmas | Cardiogenic shock management: Still a challenge and a need for large-registry data[END_REF]. Apart from the systemic inflammatory response syndrome, it combines systolic and diastolic dysfunctions, resulting in pulmonary congestion, a decrease in cardiac output and end-organ malperfusion. Because of the adaptive tachycardia, the myocardial oxygen demand increases, thus creating a vicious circle. The hypoxaemia and increased cardiac work worsen the ischaemic initial trigger in the setting of CS secondary to an acute coronary syndrome [START_REF] Topalian | Cardiogenic shock[END_REF]. Thus, the use of an IABP in this particular setting seemed attractive, to stop this vicious circle through its LV unloading/anti-ischaemic properties combined with a slight improvement in cardiac output. There was every reason to believe that this device would improve the poor prognosis of patients with CS. Despite animal experiments showing that IABP is effective at reducing the no-reflow phenomenon and improving myocardial salvage [START_REF] Pierrakos | Mechanical assistance by intra-aortic balloon pump counterpulsation during reperfusion increases coronary blood flow and mitigates the noreflow phenomenon: an experimental study[END_REF], the clinical benefits of the device in humans are still a matter of debate.

Data from registries and non-IABP-specific randomized trials

Despite the theoretical benefits, data from registries are inconsistent, with variable results according to the type of revascularization. Observational data from the fibrinolysis era strongly advocated for wide utilization of the IABP. Among 310 patients with CS included in the Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries (GUSTO-1) trial, the 1-year all-cause mortality was 57% in the IABP group versus 67% in the "no IABP" or "late IABP implantation" group (P = 0.04), despite a significantly higher haemorrhagic risk in the IABP group [START_REF] Anderson | Use of intraaortic balloon counterpulsation in patients presenting with cardiogenic shock: observations from the GUSTO-I Study. Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries[END_REF]. However, this study was observational, as the trial did not randomize patients between IABP and medical therapy. Similarly, in the SHould we emergently revascularize Occluded Coronaries for cardiogenic shocK? (SHOCK) registry, intrahospital mortality was significantly lower in IABP-treated patients (50% versus 72%; P < 0.0001), but this benefit was mainly the result of the revascularization of these patients [START_REF] Sanborn | Impact of thrombolysis, intra-aortic balloon pump counterpulsation, and their combination in cardiogenic shock complicating acute myocardial infarction: a report from the SHOCK Trial Registry. SHould we emergently revascularize Occluded Coronaries for cardiogenic shocK?[END_REF]. Last, an analysis from the National Registry of Myocardial Infarction (NRMI) of about 23,180 patients with ST-segment elevation myocardial infarction (STEMI)-related CS showed that an IABP was used in 31% of patients, and was associated with a mortality reduction in patients treated by fibrinolysis, but not in patients treated by primary angioplasty [START_REF] Barron | The use of intra-aortic balloon counterpulsation in patients with cardiogenic shock complicating acute myocardial infarction: data from the National Registry of Myocardial Infarction 2[END_REF].

More recent registries, with modern management of myocardial infarction, including systematic and prompt reperfusion by primary angioplasty, did not report any benefits of the IABP. Thus, in the Euro Heart Survey on percutaneous coronary intervention (PCI) [START_REF] Zeymer | Use and impact of intra-aortic balloon pump on mortality in patients with acute myocardial infarction complicated by cardiogenic shock: results of the Euro Heart Survey on PCI[END_REF], 25% of the 653 patients with CS were treated with an IABP. In-hospital mortality rates with and without an IABP were 56.9% and 36.1%, respectively, and the use of an IABP was not associated with improved survival (odds ratio 1.47, 95% confidence interval 0.97-2.21; P = 0.07) according to the multivariable analysis.

Data from randomized studies

For 40 years, the only trials assessing IABP on top of optimal management of ischaemic CS (including systematic reperfusion) randomized small populations and displayed divergent results [START_REF] Prondzinsky | Hemodynamic effects of intra-aortic balloon counterpulsation in patients with acute myocardial infarction complicated by cardiogenic shock: the prospective, randomized IABP shock trial[END_REF][START_REF] Gu | Intra-aortic balloon pump improves clinical prognosis and attenuates C-reactive protein level in acute STEMI complicated by cardiogenic shock[END_REF]. In 2012, the publication of the Intra-Aortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II) trial [START_REF] Thiele | Intraaortic Balloon Support for Myocardial Infarction with Cardiogenic Shock[END_REF] changed this situation significantly. In this multicentre trial, 600 patients with ischaemic CS (including 69% with STEMI) were randomized prospectively to receive or not to receive an IABP on top of optimal medical therapy, including reperfusion therapy. The definition of CS was the combination of systolic blood pressure ≤ 90 mmHg for > 30 minutes (or infusion of catecholamine needed to maintain systolic pressure > 90 mmHg) with clinical signs of pulmonary congestion and impairment of endorgan perfusion (altered mental status or cold clammy skin and extremities or oliguria or serum lactate > 2.0 mmol/L). The main exclusion criteria were resuscitation > 30 minutes, onset of CS > 12 hours before screening and mechanical causes of CS.

The trial was neutral for its primary endpoint (all-cause mortality at 30 days): 39.7% in the IABP group versus 41.3 % in the control group (P = 0.69). All secondary endpoints (e.g. in hospital reinfarction or stent thrombosis, serum lactate concentration, renal function or length of stay in the intensive care unit) were also similar between groups. However, the safety endpoints were reassuring, with no significant difference between the two groups with respect to the rates of stroke, bleeding, sepsis or peripheral ischaemic complications requiring intervention in the hospital. Meta-analysis of the published randomized trials assessing IABPs in ischaemic CS, albeit largely driven by IABP-SHOCK II, reached similar conclusions [START_REF] Ahmad | Intra-aortic Balloon Pump Therapy for Acute Myocardial Infarction: A Meta-analysis[END_REF][START_REF] Unverzagt | Intra-aortic balloon pump counterpulsation (IABP) for myocardial infarction complicated by cardiogenic shock[END_REF]. Moreover, these negative results were confirmed by the 1-year [START_REF] Thiele | Intra-aortic balloon counterpulsation in acute myocardial infarction complicated by cardiogenic shock (IABP-SHOCK II): final 12 month results of a randomised, open-label trial[END_REF] and long-term follow-up [START_REF] Thiele | Intraaortic Balloon Pump in Cardiogenic Shock Complicating Acute Myocardial Infarction: Long-Term 6-Year Outcome of the Randomized IABP-SHOCK II Trial[END_REF] of the IABP-SHOCK II trial: relative risk of mortality at 6.2 years was 66.3% in the IABP group versus 67.0% in the control group (P = 0.98), without any significant differences in recurrent myocardial infarction, stroke, repeat revascularization, rehospitalization for cardiac reasons or survivors' quality of life.

Because the IABP-SHOCK II trial is one of the most important in the field of CS, its main limitations should be underlined: [START_REF] Kantrowitz | Initial clinical experience with intraaortic balloon pumping in cardiogenic shock[END_REF] it was an open-label trial, with the usual bias of an unblinded study; (2) a substantial and asymmetrical number of crossovers were noted, as 30 patients (10%) from the control group subsequently underwent insertion of an IABP (even if the per protocol analysis was consistent with the intent-to-treat analysis, it is likely that the patients in whom crossover occurred were those in the worst condition, i.e. at highest risk of events); and (3) 270 patients (45%) had resuscitation before randomization, and 226 patients (37%) were treated by therapeutic hypothermia.

Authors did not report the cause of death in the trial, but cerebral damage is the main cause of death after cardiac arrest, without any potential benefit from an IABP in this setting. Moreover, it is known that haemodynamic compromise after cardiac arrest is mainly caused by functional hypovolaemia (because of a deep vasoplegia in the setting of systemic inflammatory response syndrome) [START_REF] Stub | Post cardiac arrest syndrome: a review of therapeutic strategies[END_REF].

Therefore, extensive filling is generally a more useful therapy than mechanical haemodynamic support in patients with CS after a cardiac arrest. Unfortunately, invasive monitoring was not requested in the trial, and data on filling pressure were not reported. This post cardiac arrest setting, present in a large proportion of patients who were randomized, may explain the neutral results of the IABP-SHOCK II trial.

Contemporary data

Following publication of the IABP-SHOCK II trial, guidelines downgraded IABP recommendation in the management of CS to Class 3, suggesting that its routine use may be harmful [START_REF] Bonello | Mechanical circulatory support in patients with cardiogenic shock in intensive care units: A position paper of the "Unite de Soins Intensifs de Cardiologie" group of the French Society of Cardiology, endorsed by the "Groupe Atherome et Cardiologie Interventionnelle" of the French Society of Cardiology[END_REF][START_REF] Ibanez | ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation[END_REF]. However, it is still widely implanted in the setting of CS. In 2015, in the multicentre prospective French CP-GARO registry, 62% out of 175 IABPs were implanted for CS [START_REF] Helleu | Current indications for the intra-aortic balloon pump: The CP-GARO registry[END_REF]. In the USA, the absolute number of IABPs implanted in patients with CS increased from 3149 in 2004 to 4225 in 2014, despite the guidelines and the fact that other mechanical supports were promoted [START_REF] Strom | National trends, predictors of use, and in-hospital outcomes in mechanical circulatory support for cardiogenic shock[END_REF].

The IABP-SHOCK II trial showed the futility of IABPs in the setting of ischaemic CS without mechanical complication. However, it seems that many cases of CS do not fit within this framework, depending on the inclusion criteria of the study: 27% of the 219 cases of CS included in the CARDSHOCK registry did not match the IABP-SHOCK II criteria [START_REF] Harjola | Clinical picture and risk prediction of short-term mortality in cardiogenic shock[END_REF]. Moreover, the recent FRENSHOCK registry prospectively included 772 patients with CS: only 36% of cases were ischaemic in nature, and 8% had mechanical complications. Thus, 516 patients (66% of the total population) would have been excluded from the trial [START_REF] Delmas | Design and preliminary results of FRENSHOCK 2016: A prospective nationwide multicentre registry on cardiogenic shock[END_REF]. As a matter of fact, the rate of ischaemic CS has decreased significantly over the last decade, from 65% in 2005 to 45% in 2014, according to the USA Nationwide Inpatient Sample databases [START_REF] Shah | Trends in mechanical circulatory support use and hospital mortality among patients with acute myocardial infarction and non-infarction related cardiogenic shock in the United States[END_REF].

Data on IABPs in non-ischaemic CS are scarce. An analysis of 489 consecutive patients treated with an IABP for CS showed that the CS aetiology had no effect on mortality [START_REF] Lauten | Intra-aortic counterpulsation for hemodynamic support in patients with acute ischemic versus non-ischemic heart failure[END_REF]. Also, another recent IABP registry of 193 patients (including 59 [30.6%] with non-ischaemic CS) reported no difference in the 30-day mortality rate between the ischaemic and non-ischaemic CS groups (34.3% vs 40.7%; P = 0.39) [START_REF] Gul | Usefulness of Intra-aortic Balloon Pump in Patients With Cardiogenic Shock[END_REF]. However, to date, there is no recommendation or robust data supporting the wide use of IABP in the setting of non-ischaemic CS.

Finally, analysis of IABP-related trials and registries is reassuring regarding the safety of the device: the rate of direct IABP-related complications (mostly peripheral ischaemia) was 4% in both the CP-GARO registry [START_REF] Helleu | Current indications for the intra-aortic balloon pump: The CP-GARO registry[END_REF] and the IABP-SHOCK II trial [START_REF] Thiele | Intraaortic Balloon Support for Myocardial Infarction with Cardiogenic Shock[END_REF], with a median duration of support of 41 hours and 3 days, respectively. Other potential complications of the balloon, such as renal impairment, are very difficult to assess, as they can also be caused by the CS itself. Accordingly, there were no differences in renal function, peripheral ischaemia, bleedings or ischaemic or haemorrhagic strokes between the two patient groups in the IABP-SHOCK II trial, demonstrating the safety of the device [START_REF] Thiele | Intraaortic Balloon Support for Myocardial Infarction with Cardiogenic Shock[END_REF].

Residual potential applications of the IABP

Mechanical complications

As mentioned above, patients with mechanical complications (mostly ventricular septal defect or papillary muscle rupture) were excluded from the IABP-SHOCK II trial. Moreover, the occurrence of mechanical complications after randomization was the only condition for crossover of patients from the control group to the IABP group [START_REF] Thiele | Intraaortic Balloon Support for Myocardial Infarction with Cardiogenic Shock[END_REF]. Mechanical complications have become rare since the STEMI systematic revascularization strategy era. However, they are still associated with high mortality rates, and only correction (surgical or percutaneous) allows survival. However, surgery may carry an extremely high risk, especially in the acute setting, because of the friable nature of the infarcted myocardium. Thus, postponing the surgical correction for a few days (or weeks) is sometimes proposed. The cornerstone of medical management of mechanical complications is afterload reduction, to increase effective LV stroke volume by reducing left-to-right shunting or mitral regurgitant volume. In this setting, an IABP may be considered routine care, even in patients who remain haemodynamically stable [START_REF] Jones | Ventricular septal rupture complicating acute myocardial infarction: a contemporary review[END_REF]. According to the European guidelines, an IABP should be considered in patients with CS arising from mechanical complications [START_REF] Ibanez | ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation[END_REF].

In the STS database regarding surgical repair of ventricular septal defect after myocardial infarction, 65% of the 2876 patients were supported preoperatively with an IABP, and another 8% had a balloon placed during surgery [START_REF] Arnaoutakis | Surgical repair of ventricular septal defect after myocardial infarction: outcomes from the Society of Thoracic Surgeons National Database[END_REF]. In a retrospective single-centre registry regarding surgery for papillary muscle rupture after myocardial infarction, 21 of 48 patients (44%) received an IABP [START_REF] Bouma | Predictors of in-hospital mortality after mitral valve surgery for post-myocardial infarction papillary muscle rupture[END_REF]. In those two reports, preoperative IABP was significantly associated with higher intrahospital mortality, but it is likely that the most severe patients were preferably implanted, with an obvious selection bias.

In another retrospective analysis of 81 mechanical complications after myocardial infarction, IABP support reduced 30-day mortality in patients with CS (61% vs 100%; P = 0.04), but not in patients without CS (20% vs 27%; P = 0.7) [START_REF] Kettner | Utility of intra-aortic balloon pump support for ventricular septal rupture and acute mitral regurgitation complicating acute myocardial infarction[END_REF].

It must be acknowledged that data on the usefulness of IABP in mechanical complications are scarce and are mainly derived from retrospective studies. On the other hand, several appealing reports advocate for a strategy of full mechanical support (e.g. an Impella® device [Abiomed, Danvers, MA, USA] or extracorporeal membrane oxygenation [ECMO]) to allow for planned or delayed surgery.

In a single-centre retrospective analysis, venoarterial ECMO support in postinfarction ventricular septal rupture complicated by CS was feasible, and was associated with a lower rate of multiorgan failure. However, this approach was strongly limited by bleeding complications [START_REF] Rob | A rationale for early extracorporeal membrane oxygenation in patients with postinfarction ventricular septal rupture complicated by cardiogenic shock[END_REF].

LV unloading during ECMO

Over the last decade, the use of venoarterial ECMO for CS has increased significantly [START_REF] Strom | National trends, predictors of use, and in-hospital outcomes in mechanical circulatory support for cardiogenic shock[END_REF]. Despite the absence of randomized data on its benefits, many position papers or guidelines have selected this circulatory assistance as the cornerstone of management for the most severe patients [START_REF] Bonello | Mechanical circulatory support in patients with cardiogenic shock in intensive care units: A position paper of the "Unite de Soins Intensifs de Cardiologie" group of the French Society of Cardiology, endorsed by the "Groupe Atherome et Cardiologie Interventionnelle" of the French Society of Cardiology[END_REF][START_REF] Abrams | Position paper for the organization of ECMO programs for cardiac failure in adults[END_REF].

However, because of the retrograde flow in the aorta towards the left ventricle, ECMO greatly increases LV afterload and, subsequently, pulmonary wedge pressure, especially in low residual LV ejection fraction. In order to avoid pulmonary oedema, which is associated with the worst prognosis, several options are proposed for LV unloading [START_REF] Donker | Left ventricular unloading during venoarterial ECMO: a review of percutaneous and surgical unloading interventions[END_REF]: indirect venting through an IABP; or direct venting by central configuration of ECMO, an Impella® device or atrial septostomy. To date, there are no randomized data about the most efficient strategy for LV unloading. However, because of their ease of use, inexpensive nature and bedside availability, IABPs are widely used in this setting [START_REF] Meani | Modalities and Effects of Left Ventricle Unloading on Extracorporeal Life support: a Review of the Current Literature[END_REF][START_REF] Russo | Left Ventricular Unloading During Extracorporeal Membrane Oxygenation in Patients With Cardiogenic Shock[END_REF]. Furthermore, it has been suggested that the pseudopulsatile blood flow created by the balloon might improve regional microcirculation [START_REF] Jung | In vivo evaluation of tissue microflow under combined therapy with extracorporeal life support and intra-aortic balloon counterpulsation[END_REF]. A prospective single-centre observational study extensively analysed the haemodynamic effect of an IABP on top of venoarterial ECMO: while microcirculation variables were not affected by pumping, the balloon significantly decreased pulmonary wedge pressure and decreased LV end-systolic and end-diastolic diameters. Interestingly, the biggest benefit was reported in patients with an initial pulmonary wedge pressure > 15 mmHg [START_REF] Petroni | Intra-aortic balloon pump effects on macrocirculation and microcirculation in cardiogenic shock patients supported by venoarterial extracorporeal membrane oxygenation*[END_REF].

However, in a retrospective analysis of 799 patients, 302 of whom received combined ECMO and IABP treatment, and 227 of whom received ECMO support only, IABP implantation did not improve patient outcomes (14-day mortality rate: 47.7% vs 48.5% for patients treated by ECMO only), despite a significant increase in systolic blood pressure with IABP implantation (107.6 vs 99.5 mmHg) [START_REF] Lin | Effects of Additional Intra-aortic Balloon Counter-Pulsation Therapy to Cardiogenic Shock Patients Supported by Extra-corporeal Membranous Oxygenation[END_REF].

High-risk PCI

The use of mechanical circulatory support increases in the setting of high-risk PCI [START_REF] Atkinson | A Practical Approach to Mechanical Circulatory Support in Patients Undergoing Percutaneous Coronary Intervention: An Interventional Perspective[END_REF]. As its elective insertion was associated with a significant reduction in long-term mortality in a randomized trial [START_REF] Perera | Long-term mortality data from the balloon pumpassisted coronary intervention study (BCIS-1): a randomized, controlled trial of elective balloon counterpulsation during high-risk percutaneous coronary intervention[END_REF], IABP is sometimes used before complex PCI. However, given that it does not concern patients with CS, this topic will not be discussed further.

Preshock

It is now admitted that, in clinical practice, there is a spectrum of presentation for CS, from preshock to refractory severe shock. The "refractory" shock (so-called "crash and burn") is the worst presentation.

However, a significant number of patients first present a state of "mild" or "pre" shock, i.e. arterial hypotension without tissue hypoperfusion [START_REF] Bellumkonda | Evolving Concepts in Diagnosis and Management of Cardiogenic Shock[END_REF]. In this situation, an IABP, with its limited yet beneficial haemodynamic properties, may have the potential to reduce clinical deterioration. However, this has not been investigated, as 89% of the IABP-SHOCK II patients received catecholamine at randomization, and the median serum lactate concentration was 4.1 mmol/L, underlying the severity of the CS of those patients. One wonders whether an IABP would be more clinically relevant as first-line haemodynamic support in patients in preshock, before catecholamine use. Indeed, these drugs, which increase myocardial oxygen consumption and have an arrhythmogenic effect, may actually worsen the prognosis of a patient with CS [START_REF] Schumann | Inotropic agents and vasodilator strategies for the treatment of cardiogenic shock or low cardiac output syndrome[END_REF].

A recent publication provided a risk score to accurately identify patients at highest risk of developing CS at the acute phase of STEMI [START_REF] Auffret | Predicting the development of in-hospital cardiogenic shock in patients with ST-segment elevation myocardial infarction treated by primary percutaneous coronary intervention: the ORBI risk score[END_REF]. Akin to patients with preshock, these patients may derive benefits from the increase in their myocardial blood supply, along with the slight haemodynamic improvement allowed by an IABP, rather than the real haemodynamic support provided by more elaborate devices, which have significant complication rates [START_REF] Nagpal | Temporary Mechanical Circulatory Support in Cardiac Critical Care: A State of the Art Review and Algorithm for Device Selection[END_REF]. The so-called "ORBI Risk Score" may help to include patients with preshock in prospective randomized trials, investigating the hypothesis that IABPs may prevent adverse outcomes.

Likewise, in the registry mentioned previously of 193 patients with CS treated by an IABP, 30-day mortality was 24% when the IABP was implanted within 1 hour of CS onset versus 49% when implanted at least 1 hour after recognition of CS (P = 0.001). Thus, time to IABP implantation predicted mortality, according to the multivariable analysis, suggesting that early use may be associated with a survival benefit [START_REF] Gul | Usefulness of Intra-aortic Balloon Pump in Patients With Cardiogenic Shock[END_REF].

Furthermore, the Counterpulsation Reduces Infarct Size Pre-PCI for Acute Myocardial Infarction (CRISP-AMI) trial failed to show any reduction in final infarct size in patients with anterior wall STEMI without CS [START_REF] Patel | Intra-aortic balloon counterpulsation and infarct size in patients with acute anterior myocardial infarction without shock: the CRISP AMI randomized trial[END_REF]. However, a small substudy of this trial focused on patients with "large" ischaemic area (summed ST deviation ≥ 15 mm) and poor ST deviation resolution despite optimal revascularization. In this subgroup (n = 36), the 6-month mortality rate was 24% in control group versus 0% in the IABP group (P = 0.046) [START_REF] Van Nunen | Intra-aortic balloon counterpulsation reduces mortality in large anterior myocardial infarction complicated by persistent ischaemia: a CRISP-AMI substudy[END_REF].

Regardless of the clinical setting, the respective place of the IABP in relation to new percutaneous circulatory supports, providing greater haemodynamic improvement, but associated with higher complication rates, should be addressed [START_REF] Bonello | Mechanical circulatory support in patients with cardiogenic shock in intensive care units: A position paper of the "Unite de Soins Intensifs de Cardiologie" group of the French Society of Cardiology, endorsed by the "Groupe Atherome et Cardiologie Interventionnelle" of the French Society of Cardiology[END_REF][START_REF] Schrage | Impella Support for Acute Myocardial Infarction Complicated by Cardiogenic Shock[END_REF].

Conclusions

Despite their theoretical benefits, data from randomized studies do not support the routine use of IABPs in the setting of CS. However, they are still widely used in clinical practice when no other haemodynamic support is available. Indeed, the clinical settings of many cases of CS were not investigated in clinical trials. Furthermore, potential IABP benefits in patients who are less severely haemodynamically compromised should be evaluated in randomized controlled trials.

Sources of funding

  Abbreviations: CS, cardiogenic shock; ECMO, extracorporeal membrane oxygenation; IABP, intra-aortic balloon pump; LV, left ventricular; PCI, percutaneous coronary intervention; STEMI, STsegment elevation myocardial infarction.

Figure 1 .

 1 Figure 1. Modification of arterial pressure by the intra-aortic balloon pump, settled on a 1/1 mode (panel A) or 1/2 mode (panel B). A. The diastolic inflation of the balloon increases the diastolic pressure; as a result, the assisted diastolic pressure (*) becomes greater than the assisted systolic pressure (arrow). B. Because of the reduction in left ventricular pressures, the assisted systolic pressure peak (**) is lower than the unassisted systolic pressure peak (*).

The other authors declare that they have no conflicts of interest concerning this article.


Julien Nael

Mathilde Ruggiu

Clotilde Bailleul

Sofia Ortuno

Jean-Luc Diehl

Damien Vimpère

Jean-Loup Augy

Emmanuel Guerot

Nicolas Danchin

Etienne Puymirat

Nadia Aissaoui
email: nadia.aissaoui@aphp.fr

Impact of hyperoxia on patients hospitalized in an intensive care unit for acute heart failure

Keywords: AHF, acute heart failure, BNP, B-type natriuretic peptide, CI, confidence interval, ICU, intensive care unit, PaO2, partial pressure of oxygen, SOFA, sequential organ failure assessment, SpO2, saturation of peripheral oxygen

niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Méthodes. -Il s'agissait d'une étude observationnelle, rétrospective et monocentrique conduite entre janvier 2015 et décembre 2016. Les patients présentant un OAP grave étaient inclus. Le groupe hyperoxie (H) était défini par une PaO2 strictement supérieure à 100 mmHg au gaz du sang artériel au cours des premières 24 heures d'hospitalisation alors que le groupe contrôle (C) définissait les autres patients. Le critère de jugement principal était la mortalité à 30 jours. Les critères de jugement secondaire étaient la réadmission hospitalière à 30 jours, la survenue d'infections en cours d'hospitalisation et les durées de séjours en réanimation et hospitalières.

Résultats. -75 patients avec un âge médian de 76 ans (68-83) ont été inclus. Quarante-trois (57,3 %) patients ont présenté une hyperoxie (H) alors que C comprenait 32 patients (4,7 %). Le critère de jugement principal composite n'était pas significativement différent entre les deux groupes (14,0 % vs 18,8 % ; P = 0,85). Les critères de jugement secondaires ne différaient également pas entre les deux groupes. En analyse multivariable, l'hyperoxie n'était ni délétère ni protectrice à 30 jours (OR 0,77, IC95 % 0,24-2,41).

Conclusion. -Chez les patients hospitalisés pour OAP graves, il n'existait pas de différence de morbimortalité en fonction de la présence de phases d'hyperoxie.

KEYWORDS

Réhospitalisation

Introduction

Acute heart failure (AHF) is the most frequent cause of unscheduled hospital admissions, with over 150,000 hospitalizations in France each year [START_REF] Chouihed | Management of suspected acute heart failure dyspnea in the emergency department: results from the French prospective multicenter DeFSSICA survey[END_REF][START_REF] Ponikowski | ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC[END_REF]. Among the various clinical phenotypes of AHF, acute pulmonary oedema represents between 16% and 38% of cases [START_REF] Chouihed | Management of suspected acute heart failure dyspnea in the emergency department: results from the French prospective multicenter DeFSSICA survey[END_REF][START_REF] Asfar | Hyperoxia and hypertonic saline in patients with septic shock (HYPERS2S): a two-by-two factorial, multicentre, randomised, clinical trial[END_REF][START_REF] Chu | Mortality and morbidity in acutely ill adults treated with liberal versus conservative oxygen therapy (IOTA): a systematic review and meta-analysis[END_REF][START_REF] Ruggiu | Hyperoxia effects on intensive care unit mortality: a retrospective pragmatic cohort study[END_REF].

Acute pulmonary oedema is the most important indication for oxygen therapy and mechanical ventilation in patients with AHF. Expert guidelines recommend that supplemental oxygen therapy should be considered for patients with saturation of peripheral oxygen (SpO2) < 90% or partial pressure of oxygen (PaO2) < 60 mmHg, to correct hypoxaemia and/or to relieve symptoms related to hypoxaemia [START_REF] Ponikowski | ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC[END_REF].

Standard clinician behaviour promotes prompt uncontrolled administration of high-flow highconcentration oxygen therapy to critically ill patients with AHF with acute respiratory distress, with supranormal values of PaO2 frequently being achieved [START_REF] Chouihed | Management of suspected acute heart failure dyspnea in the emergency department: results from the French prospective multicenter DeFSSICA survey[END_REF]. Hyperoxia occurs when the partial pressure of intra-alveolar oxygen exceeds normal breathing conditions, thus leading to hyperoxaemia [START_REF] Asfar | Hyperoxia and hypertonic saline in patients with septic shock (HYPERS2S): a two-by-two factorial, multicentre, randomised, clinical trial[END_REF].

Although oxygen is essential for cell metabolism and organ function, it can trigger free radical formation and cause potential iatrogenic harm to innate immunity and the functioning of the heart and lungs [START_REF] Asfar | Hyperoxia and hypertonic saline in patients with septic shock (HYPERS2S): a two-by-two factorial, multicentre, randomised, clinical trial[END_REF]. Noxious effects of hyperoxia have been reported in critically ill patients with septic shock, cardiac arrest and acute myocardial infarction [START_REF] Asfar | Hyperoxia and hypertonic saline in patients with septic shock (HYPERS2S): a two-by-two factorial, multicentre, randomised, clinical trial[END_REF][START_REF] Chu | Mortality and morbidity in acutely ill adults treated with liberal versus conservative oxygen therapy (IOTA): a systematic review and meta-analysis[END_REF][START_REF] Hofmann | Oxygen Therapy in Suspected Acute Myocardial Infarction[END_REF][START_REF] Roberts | Association Between Early Hyperoxia Exposure After Resuscitation From Cardiac Arrest and Neurological Disability: Prospective Multicenter Protocol-Directed Cohort Study[END_REF][START_REF] Stub | Air Versus Oxygen in ST-Segment-Elevation Myocardial Infarction[END_REF]. In a single-centre, open-label, randomized trial, the authors aimed to assess whether a conservative protocol for oxygen supplementation could improve outcomes in 434 critically ill patients. Compared with standard management (SpO2 values between 97% and 100%), conservative oxygen therapy maintaining SpO2 between 94% and 98% (or PaO2 between 70 and 100 mmHg) reduced intensive care unit (ICU) death (absolute risk reduction 8.6%, 95% confidence interval [CI] 1.7-15%; P = 0.01) and episodes of shock, liver failure and bacteraemia [START_REF] Girardis | Effect of Conservative vs Conventional Oxygen Therapy on Mortality Among Patients in an Intensive Care Unit: The Oxygen-ICU Randomized Clinical Trial[END_REF]. Interestingly, the subgroup analysis among patients presenting with respiratory failure at admission (n = 250) showed an absolute risk reduction in ICU death of 12.8% (95% CI 2.3-23.0). Cardiovascular hyperoxia consequences have been evaluated in small groups of healthy individuals and patients with chronic heart failure. Hyperoxia induced vasoconstriction, reduced cardiac output by decreasing systolic ejection volume, increased peripheral vascular resistance and increased filling pressure [START_REF] Daly | Effects of oxygen breathing on the heart rate, blood pressure, and cardiac index of normal men--resting, with reactive hyperemia, and after atropine[END_REF][11][START_REF] Haque | Hemodynamic effects of supplemental oxygen administration in congestive heart failure[END_REF][START_REF] Mak | Effect of hyperoxia on left ventricular function and filling pressures in patients with and without congestive heart failure[END_REF][START_REF] Park | Potentially detrimental cardiovascular effects of oxygen in patients with chronic left ventricular systolic dysfunction[END_REF][START_REF] Sepehrvand | Oxygen Therapy in Patients With Acute Heart Failure: Friend or Foe?[END_REF].

Lastly, a recent systematic review and meta-analysis showed that too much supplemental oxygen increased mortality for medical patients in hospital [START_REF] Chu | Mortality and morbidity in acutely ill adults treated with liberal versus conservative oxygen therapy (IOTA): a systematic review and meta-analysis[END_REF], but no study has evaluated the effect of hyperoxia on the outcome of patients presenting with pulmonary congestion caused by AHF. The main objective of our study was to evaluate the impact of early hyperoxia exposure on patients with AHF hospitalized for pulmonary congestion.

Methods

Study design

This was a retrospective, single-centre, observational study conducted in the ICU of the Hôpital Européen Georges Pompidou, in Paris, over a 2-year period (2015-2016). Data collection and analyses were conducted in accordance with the French national guidelines. All patients (or proxies) admitted to the ICU were informed that medical data might be used for research; no opposition to using data for research was expressed by the patients (or proxies).

Patients

All adult patients admitted to the ICU at the Hôpital Européen Georges Pompidou between 1 January 2015 and 31 December 2016 for acute respiratory distress caused by AHF were assessed. Patients presenting with pulmonary congestion caused by AHF (defined by clinical presentation of AHF with acute pulmonary oedema and at least one of these objective findings of AHF: B-type natriuretic peptide [BNP] > 400 pg/mL or N-terminal prohormone of BNP > 1200 pg/mL or pulmonary echography or chest X-ray showing pulmonary vascular congestion signs or echocardiography showing structural and/or functional alterations of the heart) were included.

Patients who presented with an out-of-hospital cardiac arrest, severe chronic obstructive pulmonary disease or long-term oxygen therapy, and those who had received oxygen therapy in the previous month or who died in the first 24 hours following admission were not included.

All arterial blood gases collected in the ICU during the first day were analysed. Venous blood gases were not taken into account.

Data on baseline characteristics, patient medications, oxygen therapy with the fraction of inspired oxygen (FiO2), use of mechanical ventilation (invasive and non-invasive), occurrence of infection during ICU stay, ICU length of stay, hospital length of stay, alive/dead status at discharge and at 30 days and unplanned hospital readmission at 30 days were collected.

Endpoints

The primary endpoint was all-cause death at 30 days. The 30-day time frame was chosen as a shorter time frame would not catch recurrence and morbidity, and a longer time frame would catch events more likely linked to chronic morbidity than to the AHF syndrome [START_REF] Cluzol | Prehospital and in-hospital course of care for patients with acute heart failure: Features and impact on prognosis in "real life[END_REF][START_REF] Nieminen | EuroHeart Failure Survey II (EHFS II): a survey on hospitalized acute heart failure patients: description of population[END_REF].

The secondary endpoints were prevalence of hyperoxia (defined as at least one arterial blood gas with a PaO2 > 100 mmHg), unplanned hospital readmission within the first 30 days, occurrence of pneumonia and bacteraemia, hypoxic events, ICU length of stay and total length of stay. Hypoxic events were defined as SpO2 ≤ 88% for longer than 2 minutes and requiring therapeutic action.

Patient groups

Patients with AHF were divided into two groups: the hyperoxia group, including patients with at least one arterial blood gas with a PaO2 > 100 mmHg in the first 24 hours; and the control group, including patients in whom the PaO2 was ≤ 100 mmHg for all arterial blood gases. Hyperoxia was defined as a PaO2 strictly > 100 mmHg in an arterial blood gas.

Statistical analyses

The results are presented as medians (interquartile ranges) for quantitative variables, and as numbers (proportions) for qualitative variables. Baseline characteristics and outcomes were compared between the two groups of patients (the hyperoxia group and the control group). Non-parametric tests were used. Binary logistic regression multivariable analysis was performed to determine if hyperoxia was an independent risk factor for 30-day outcome. The covariables used in the model were age, male sex and sequential organ failure assessment (SOFA) score [START_REF] Vincent | The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine[END_REF].

All statistical tests were two-tailed, with a significance threshold of 0.05. Analyses were performed with R (version 3.2.4).

Results

Patient characteristics

From 1 January 2015 to 31 December 2016, 96 patients were admitted to the ICU for acute pulmonary oedema; 75 met the inclusion criteria and were included in the analysis.

The main characteristics of the population are reported in Table 1. The median age was 76 (68-83) years, and there were 38 men (51%). The median SOFA score was 5 (4-6). Among the 40 patients requiring mechanical ventilation, 28 (37%) were treated by non-invasive ventilation and 12 (16%) needed orotracheal intubation. Eleven patients (15%) received catecholamines, 59 (79%) received diuretics and 26 (35%) received vasodilator agents.

The median length of stay in hospital was 15 [START_REF] Haque | Hemodynamic effects of supplemental oxygen administration in congestive heart failure[END_REF][START_REF] Mak | Effect of hyperoxia on left ventricular function and filling pressures in patients with and without congestive heart failure[END_REF][START_REF] Park | Potentially detrimental cardiovascular effects of oxygen in patients with chronic left ventricular systolic dysfunction[END_REF][START_REF] Sepehrvand | Oxygen Therapy in Patients With Acute Heart Failure: Friend or Foe?[END_REF][START_REF] Cluzol | Prehospital and in-hospital course of care for patients with acute heart failure: Features and impact on prognosis in "real life[END_REF][START_REF] Nieminen | EuroHeart Failure Survey II (EHFS II): a survey on hospitalized acute heart failure patients: description of population[END_REF][START_REF] Vincent | The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine[END_REF] days and the median length of stay in the ICU was 5 (4-6) days.

Prevalence of hyperoxia

During the first 24 hours, 43 patients (57.3%) presented at least one arterial blood gas with a PaO2 > 100 mmHg, whereas 32 patients (42.7%) did not. Of note, hyperoxia was already present at admission in 17 patients (23%) (Table 2).

The admission clinical and biological data for the two groups are described in Table 1.

Primary and secondary endpoints

At 30 days, the mortality rate did not differ between the two groups: six patients died in the hyperoxia group (14.0%) compared with six in the control group (18.8%) (P = 0.85) (Table 3 and Fig. 1).

The 30-day hospital readmission rate did not differ between groups (14.0% in the hyperoxia group compared with 9.3% in the control group; P = 0.21) (Table 3 and Fig. 1).

The ICU lengths of stay, hospital lengths of stay and rates of infection were not significantly different between the two groups. The incidence of hypoxic events was higher in the control group compared with in the hyperoxia group (34.9% vs 68.8%; P < 0.001) (Table 3).

Factors associated with 30-day mortality

After adjustment for age and other confounders, hyperoxia was not associated with death at 30 days (odds ratio 0.77, 95% CI 0.24-2.41).

Discussion

To our knowledge, this is the first study assessing the prevalence and potential effects of hyperoxia in patients admitted to an ICU for acute pulmonary oedema resulting from AHF. Our first finding was that at least some periods of hyperoxia are frequent in patients with AHF managed in the ICU. In addition, hyperoxia was not associated with increased 30-day death. Of note, the 30-day hospital readmission rate did not differ between groups.

In our study, only a few patients presented with hyperoxia at the time of admission to the ICU. However, once admitted, the majority of patients experienced hyperoxia, underlying the crucial role of physicians in generating phases of hyperoxia, and thus the possibility to avoid them. This point raises the question of the benefit/risk balance in the administration of high amounts of oxygen to critically ill patients, considering the risk of harmful effects of hyperoxia, as the endothelial production of free radicals induces cerebral, systemic, coronary vasoconstriction and deleterious haemodynamic effects, as described previously.

Our results did not confirm those of studies published recently. Indeed, these studies demonstrated harmful effects of hyperoxia in patients with different acute diseases, such as cardiac arrest or myocardial infarction [START_REF] Asfar | Hyperoxia and hypertonic saline in patients with septic shock (HYPERS2S): a two-by-two factorial, multicentre, randomised, clinical trial[END_REF][START_REF] Hofmann | Oxygen Therapy in Suspected Acute Myocardial Infarction[END_REF][START_REF] Roberts | Association Between Early Hyperoxia Exposure After Resuscitation From Cardiac Arrest and Neurological Disability: Prospective Multicenter Protocol-Directed Cohort Study[END_REF].

The 30-day death rate in our study was higher than in previous studies assessing patients with AHF [START_REF] Cluzol | Prehospital and in-hospital course of care for patients with acute heart failure: Features and impact on prognosis in "real life[END_REF][START_REF] Nieminen | EuroHeart Failure Survey II (EHFS II): a survey on hospitalized acute heart failure patients: description of population[END_REF][START_REF] Follath | Clinical presentation, management and outcomes in the Acute Heart Failure Global Survey of Standard Treatment (ALARM-HF)[END_REF], which reported 30-day mortality rates of around 6-8%. Compared with previous studies conducted in cardiac ICUs, ours was conducted in a general ICU admitting more severe patients. During their hospitalization, almost half of the patients (53.3%) needed mechanical ventilation, a high number had an endotracheal intubation and 15% had inotropic drugs. In the French OFICA study, assessing 631 patients with AHF with pulmonary oedema, and in the 581 patients from the EuroHeart Failure Survey II, 15.4% and 31.5% of patients, respectively, required non-invasive ventilation [START_REF] Nieminen | EuroHeart Failure Survey II (EHFS II): a survey on hospitalized acute heart failure patients: description of population[END_REF][START_REF] Follath | Clinical presentation, management and outcomes in the Acute Heart Failure Global Survey of Standard Treatment (ALARM-HF)[END_REF]. Also, our population included many patients with co-morbidities, with one-third having kidney failure.

Study limitations

Because of the low number of patients included, our study suffered from a lack of power to draw definite conclusions about the consequences of hyperoxia. Moreover, the study was carried out in a single centre, and was observational and retrospective, which applies additional limitations to its findings. Of note, we assessed neither the duration nor the level of hyperoxia. There were selection biases because of the heterogeneity and severity of our population, making it hard to prove the harmful effect of hyperoxia on patient outcome. We are currently designing a multicentre randomized controlled clinical trial to compare a conservative oxygen therapy strategy with a liberal oxygen therapy strategy, to provide a definitive answer about the consequences of hyperoxia in a larger population of patients with acute pulmonary oedema.

Conclusion

In this preliminary study assessing patients referred to an ICU for acute pulmonary oedema, we did not identify any difference in outcomes between patients with phases of hyperoxia and patients without hyperoxia.

Sources of funding

None.

Figure 1 .

 1 Figure 1. Outcomes, according to oxygenation group.

Table 3

 3 Outcomes, according to oxygenation group. Data are expressed as number (%) or median (interquartile range). ICU: intensive care unit.

	Hyperoxia group	Control group	P
	(n = 43)	(n = 32)

Data

Clinical and biological data were collected prospectively in the computer database routinely used for clinical purposes.

Disclosure of interest

The authors declare that they have no conflicts of interest concerning this article.