Baseline characteristics, management, and predictors of early mortality in cardiogenic shock: insights from the FRENSHOCK registry

Introduction

Cardiogenic shock (CS) is a syndrome caused by a primary cardiovascular disorder in which inadequate cardiac output results in life-threatening tissue hypoperfusion associated with tissue oxygen metabolism impairment and hyperlactataemia which, depending on the severity, can result in multi-organ dysfunction and death.1 While in clinical practice there is a spectrum of presentations, clinical trials have used specific haemodynamic parameters to define CS. The common definition of CS in the SHOCK trial2 requires the presence of three major haemodynamic parameters: (i) persistent hypotension defined as systolic blood pressure (SBP) <90 mmHg (or mean arterial pressure 30 mmHg below the baseline), (ii) decreased cardiac index (<1.8 L/min/m2 without support or <2.2 L/min/m2 with support) with, (c) adequate or elevated filling pressure (left ventricular end-diastolic pressure >18 mmHg or right ventricular end-diastolic pressure >10 to 15 mmHg). These haemodynamic parameters, while necessary when enrolling patients in clinical trials, may not be universally applicable in clinical practice.

Inclusion criteria used to define CS in a study are not the only parameters of a study population to be considered. The study setting for prehospital, intensive cardiac care unit (ICCU) or general intensive care unit (ICU) provides patients with different characteristics and severity; hence the interest of studies on CS that recruit patients from different settings.

Ischaemic CS that complicates approximately 3–9% of the cases of acute myocardial infarction (AMI) was reported to be the most common cause of CS3-7 and confers a severe prognosis associated with a high hospital mortality rate of 24.6–51.0%.7-9 Data regarding non-ischaemic CS are limited9 probably in part because all the definitions of CS used are based only on AMI CS and the major studies have focused on ischaemic CS to evaluate management (myocardial revascularization, circulatory support and medications).2, 3 However, patients with non-ischaemic CS could represent more than 50% of all the cases of CS and may be associated with a better prognosis.10-14

The aim of this analysis is to report the baseline characteristics, management and independent correlates of 30 day mortality in patients with CS in routine clinical practice included in the FRENSHOCK multicentre registry, regardless of the aetiology and the initial place of admission.

Methods Patient population

FRENSHOCK is a prospective multicentre observational study conducted in metropolitan France during a 6 month period between April and October 2016 in ICU and ICCU (NCT02703038). The methods used for this registry have been previously described.15 Briefly, the primary objective was to evaluate the characteristics, management, and outcomes of CS patients, with a new modified definition of CS (Supporting information, Table S1) as seen in routine clinical practice, on a nation-wide scale.

All adult patients (≥18 years old) with CS were prospectively included in this registry if they met at least one criterion of each of the following three components: (i) haemodynamic criteria, defined as a low SBP <90 mmHg and/or the need for maintenance with vasopressors/inotropes and/or a low cardiac index <2.2 L/min/m2; (ii) left and/or right heart pressure elevation, defined by clinical signs, radiology, blood tests, echocardiography, or signs of invasive haemodynamic overload; and (iii) signs of organ malperfusion, which could be clinical and/or biological. Patients admitted after cardiopulmonary resuscitation were included if they fulfilled previously defined CS criteria. Patients could be included regardless of CS aetiology, and whether CS was primary or secondary. Exclusion criteria were refusal or the inability to consent and a diagnosis of CS refuted in favour of alternative diagnoses, such as septic shock, refractory cardiac arrest and post-cardiotomy CS.15

All institutions were invited to participate in the study, including university teaching hospitals, general and regional hospitals, public and private hospitals that manage CS patients (ICCUs, surgical ICUs, medical ICUs and general ICUs). The study was conducted in accordance with the guidelines for good clinical practice and French law. Written consent was obtained for all the patients. The data recorded and their handling and storage were reviewed and approved by the CCTIRS (French Health Research Data Processing Advisory Committee) (n° 15.897) and the CNIL (French Data Protection Agency) (n° DR-2016-109).

Data collection

Data on baseline characteristics, including demographics (age, gender, body mass index, social status), risk factors (hypertension, diabetes, current smoking, hypercholesterolemia, family history of coronary artery disease), and medical history [cardiomyopathy, myocardial infraction (MI), stroke, peripheral artery disease (PAD), chronic kidney disease (CKD), active cancer, chronic obstructive lung disease], were collected as previously mentioned.15 Clinical, biological, and echocardiographic data within the first 24 h after admission were collected. Up to three CS triggers were determined for each patient by the local investigator, that is, ischaemic (Type 1 or Type 2 AMI according to European guidelines); ventricular and supraventricular arrhythmia; conduction disorder; infectious disease; non-compliance (poor compliance with medical treatment or hygiene and diet rules, for example, stopping or skipping an angiotensin-converting enzyme inhibitor or beta blocker treatment, deviation from a low sodium diet, etc.); or iatrogenesis. Investigators could also note other existing factors or aetiologies. Such triggering factors were indicated as ‘other’. Information regarding the use of cardiac procedures, that is, coronary angiography and/or percutaneous coronary intervention (PCI); right heart catheterization; the need for medications (inotropes, vasopressors, diuretics, and fibrinolysis) and organ replacement therapies such as mechanical ventilation (invasive or non-invasive); temporary mechanical circulatory support [intra-aortic balloon pump (IABP); extracorporeal membrane oxygenation or Impella® (Abiomed, Danvers, MA, USA)]; and renal replacement therapy (continuous or intermittent) were collected.

In-hospital complications, such as stroke, bleeding and transfusions, haemolysis, thrombocytopenia, nosocomial infections, vascular complications, and death, were noted. Information on mortality was obtained directly by the local investigators (cause and date).

Statistical analysis

Continuous variables are reported as means (SD) or medians and interquartile ranges when appropriate. Discrete variables are described in numbers and percentages. Groups (30 day survivors and non-survivors) were compared by analysis of variance for continuous variables and χ2 or Fisher's exact test for discrete variables. Odds ratios (ORs) are presented with their 95% confidence intervals (CIs).

To determine independent predictors of in-hospital all-cause mortality, binary logistic regression analyses were used, with a threshold <0.10 for variable elimination. Variables included in the final models were selected ad hoc based on their physiological relevance and potential to be associated with outcomes. Two multivariable analyses were conducted. The first included only variables available on admission: age, gender, type of institution, risk factors, comorbidities, and causes of CS. A sensitivity analysis was performed, and lactate peak was added to the covariates in the main analysis. The second model added in-hospital management variables (first place of admission; respiratory, circulatory, or renal support; use of inotropes, vasopressors, diuretics, and fibrinolysis in the first 24 h; and myocardial revascularization). This analysis was repeated on the subset of patients with ischaemic CS.

Analyses were repeated using forward stepwise analysis to assess the consistency of results. Collinearity was assessed by calculating variance inflation factors. Statistical analyses were performed using IBM SPSS 23.0 (IBM SPSS Inc.). For all analyses, two-sided P values <0.05 were considered significant.

Results Study population

A total of 772 CS patients were included in 49 centres. Clinical characteristics are presented in Table 1. CS criteria used to define CS are reported in Table S2. The main criteria were hypotension and/or echocardiographic parameters for the haemodynamic criteria, clinical parameters for the overload criteria, and biological parameters for the organ malperfusion criteria. Less than 8% of the patients were diagnosed based on invasive parameters of CS. Mean age of the population was 65.7 (±14.9) years with a predominance of men (71.5%). The rate of hypertension, dyslipidaemia, diabetes mellitus, and current smoking were high, respectively, 47.2%, 35.9%, 28.1%, and 26.7%. A history of cardiac disease was reported in 56.1% (29.8% coronary artery disease), previous PCI in 21.5%, previous stroke in 8.0%, PAD in 11.8%, and CKD in 21.2%.

Table 1. Clinical characteristics at admission according to vital status at 30 days Overall population (n = 772) 30 day survivors (n = 571) 30 day non-survivors (n = 201) P value Age, mean ± SD, years 65.7 ± 14.9 64.0 ± 14.8 70.4 ± 14.3 <0.001 Male, n (%) 552 (71.5) 407 (71.3) 145 (72.1) 0.82 Body mass index, mean ± SD, kg/m2 25.8 ± 5.6 25.9 ± 5.5 25.6 ± 5.9 0.47 Employment status, n (%) Employed 128 (16.6) 108 (18.9) 20 (10) <0.001 Unemployed 25 (3.1) 21 (3.7) 4 (2.0) Househusband/wife 14 (1.8) 12 (2.1) 2 (1.0) Disability 56 (7.3) 35 (6.1) 21 (10.4) Retired 448 (58.0) 308 (53.9) 140 (69.7) Risk factors, n (%) Current smoker 206 (26.7) 159 (27.8) 47 (23.4) 0.22 Diabetes mellitus 217 (28.1) 166 (29.1) 51 (25.4) 0.41 Hypertension 364 (47.2) 263 (46.1) 101 (50.2) 0.51 Dyslipidaemia 277 (35.9) 205 (35.9) 72 (35.8) 0.84 Medical history, n (%) History of cardiac disease 433 (56.1) 312 (54.6) 121 (60.2) 0.34 Ischaemic 230 (29.8) 169 (29.6) 61 (30.3) 0.84 Hypertrophic 11 (1.4) 9 (1.6) 2 (1.0) 0.55 Toxic 34 (4.4) 28 (4.9) 6 (3.0) 0.17 Idiopathic 78 (10.1) 56 (9.8) 22 (10.9) 0.65 Multisite pacing 63 (8.2) 45 (7.9) 18 (9.0) 0.75 Defibrillator 127 (16.5) 96 (16.8) 31 (15.4) 0.75 Coronary artery bypass grafting 62 (8.0) 43 (7.5) 19 (9.5) 0.58 Percutaneous coronary intervention 166 (21.5) 123 (21.5) 43 (21.4) 0.84 Peripheral artery disease 91 (11.8) 72 (12.6) 19 (9.5) 0.41 Stroke 62 (8.0) 42 (7.4) 20 (10.0) 0.43 Chronic renal failure 164 (21.2) 104 (18.2) 60 (29.9) 0.002 Dialysis 11 (1.4) 8 (1.4) 3 (1.5) 0.84 Chronic obstructive pulmonary disease 50 (6.5) 33 (5.8) 17 (8.5) 0.35 Active cancer 51 (6.6) 36 (6.3) 15 (7.5) 0.72 Previous medications, n (%) Aspirin 288 (37.3) 210 (36.8) 78 (38.8) 0.63 P2Y12 inhibitors 126 (16.3) 96 (16.8) 30 (14.9) 0.57 Statins 286 (37.0) 210 (36.8) 76 (37.8) 0.69 Beta blockers 316 (41.0) 232 (40.6) 84 (41.8) 0.68 Vitamin K antagonist 165 (21.4) 108 (18.9) 57 (28.4) 0.01 Direct oral anticoagulant 56 (7.3) 48 (8.4) 8 (4.0) 0.08 ACE inhibitors or ARB 292 (37.8) 213 (37.3) 79 (39.3) 0.63 Sacubitril/valsartan 18 (2.3) 15 (2.6) 3 (1.5) 0.40 Loop diuretics 376 (48.7) 266 (46.6) 110 (54.7) 0.11 Aldosterone antagonist 108 (14.0) 82 (14.4) 26 (12.9) 0.60 Amiodarone 132 (17.6) 98 (17.5) 34 (17.7) 0.95 Proton pump inhibitor 276 (36.4) 206 (36.6) 70 (35.7) 0.83 ACE, angiotensin-converting enzyme; ARB, angiotensin-receptor blocker; SD, standard deviation.

At admission, mean SBP was 101 (±25) mmHg and mean heart rate was 96 (±30) bpm (Table 2). Clinical signs of left and right heart failure were frequent with 72.5% and 50% respectively. Mottling was reported in 37.5% of the cases.

Table 2. Clinical, echocardiographic and biological presentation according to vital status at 30 days Overall population (n = 772) 30 day survivors (n = 571) 30 day non-survivors (n = 201) P value Clinical presentation at admission Heart rate, mean ± SD, bpm 96 ± 30 95 ± 30 98 ± 27 0.19 SBP, mean ± SD, mmHg 101 ± 25 103 ± 25 96 ± 26 <0.001 DBP, mean ± SD, mmHg 63 ± 17 64 ± 17 59 ± 17 <0.001 Sinus rhythm, n (%) 399 (52.0) 308 (54.3) 91 (45.3) 0.03 Cardiac arrest, n (%) 79 (10.3) 54 (9.5) 25 (12.4) 0.12 Mottling, n (%) 248 (37.5) N = 660 169 (37.1) 79 (45.7) 0.045 Blood tests at admission, median (IQR) Sodium, mmol/L 135 (132–139) N = 760 136 (132–139) N = 559 135 (131–139) N = 201 0.15 eGFR, mL/min/1.73 m2 46 (28–67) N = 751 49 (32–70) N = 553 38 (23–54) N = 198 <0.001 Bilirubin, mg/L 16 (9–29) N = 544 16 (9.5–28) N = 395 17 (9–31) N = 149 0.17 Haemoglobin, g/dL 12.6 (11.0–14.0) N = 754 13.0 (11.0–14.0) N = 555 12.0 (11.0–14.0) N = 199 0.02 Arterial blood lactates, mmol/L 3.0 (2.0–4.75) N = 684 2.9 (2.0–4.2) N = 499 3 (2.0–5.0) N = 185 <0.001 ASAT, IU/L 90.0 (39.0–301.0) N = 547 80.50 (37.0–286.3) N = 396 121.00 (46.0–468.0) N = 151 0.92 ALAT, IU/L 59.0 (27.0–183.0) N = 459 58.0 (26.0–182.0) N = 407 62.0 (31.0–199.8) N = 152 0.81 Nt proBNP, pg/mL 9277 [4045; 23810] n = 224 7503 [3504; 16 845] n = 156 13 701 [5 386; 35 000] n = 68 <0.001 BNP, pg/mL 1150 [476; 2778] n = 264 1082 [441; 2561] n = 205 1670 [762; 3484] n = 59 0.04 CRP, mg/L 28 (9–69) N = 406 26 (9–62) N = 300 40 (9–96.5) N = 106 0.001 Baseline echocardiography LVEF, mean ± SD, % 26 ± 13 27 ± 13.5 24.5 ± 13 0.004 N = 763 N = 564 N = 199 TAPSE, mm; median (IQR) 13 [10–16] 13 [10–17] 12 [9–16] 0.6 N = 772 N = 195 N = 60 PSVtdi, cm/s; median (IQR) 8 [6–11] 8 [6–11] 9 [7–11] 0.23 N = 206 N = 155 N = 51 Severe mitral regurgitation, n (%) 107 (14.6) 79 (14.5) 28 (14.5) 0.96 Severe aortic stenosis, n (%) 36 (4.7) 22 (3.9) 14 (7.1) 0.03 Severe aortic regurgitation, n (%) 10 (1.3) 6 (1.1) 4 (2.1) 0.28 Unknown 117 (15.2) 36 (17.9) 81 (14.2) 0.24 ACE, angiotensin-converting enzyme; ALAT, alanine aminotransferase; ARB, angiotensin-receptor blocker; ASAT, aspartate aminotransferase; CRP, C-reactive protein; DBP, diastolic blood pressure; PSVtdi, peak systolic velocity tissue Doppler imaging; SBP, systolic blood pressure; SD, standard deviation; TAPSE, tricuspid annular plane systolic excursion.

The main triggers of CS (not mutually exclusive) were ischaemic (36.3%), supra ventricular arrhythmias (13.3%), ventricular arrhythmias (12.6%), and infectious disease (11.9%) (Figure 1). Cardiac arrest occurred in 10.3% of patients.

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Cardiogenic shock trigger (in blue) and associated 30 day mortality (in red). For all patients who meet the FRENSHOCK criteria (n = 772), the cardiogenic shock trigger and the associated 30 day mortality are summarized. Up to three CS triggers (not mutually exclusive) were identified by the local investigator for each patient (i.e. ischaemic, ventricular, and supraventricular arrhythmia, conduction disorder, infectious disease, non-compliance or iatrogenesis).

Most patients had multiple organ failure as evidenced by kidney dysfunction, hepatic cytolysis and cholestasis, and lactate elevation.

Seven hundred and sixty patients (98.5%) had an echocardiography at admission. Left ventricular ejection fraction (LVEF) <40% was reported in 80.7% of the patients and <30% in 61.4%.

Vitals parameters at 24 h after admission are detailed in Table S3.

In-hospital management

In-hospital management is reported in Table 3. Most patients were directly admitted in ICCU (56.1%); 23.1% were admitted in ICU, and 13.3% were transferred from another centre (emergency or another department).

Table 3. In-hospital management according to vital status at 30 days Overall population (n = 772) 30 day survivors (n = 571) 30 day non-survivors (n = 201) P value Medications used, n (%) Diuretics 633 (82.0) 479 (83.9) 154 (76.6) 0.05 Volume expander 321 (41.6) 242 (42.4) 79 (39.3) 0.18 Dobutamine 632 (81.9) 460 (80.6) 172 (85.6) 0.11 Maximum dose: 5–10 μg/kg/min 405/632 (52.5) 322/460 (56.4) 83/172 (41.3) 10–15 μg/kg/min 136/632 (17.6) 76/460 (13.3) 60/172 (29.9) >15 μg/kg/min 47/632 (6.1) 29/460 (5.1) 18/172 (9.0) Unknown 184/632 (23.8) 144/460 (25.2) 40/172 (19.9) Norepinephrine 410 (53.1) 271 (47.5) 139 (69.2) <0.001 Epinephrine 95 (12.4) 58 (10.2) 37 (18.6) <0.001 Norepinephrine and dobutamine combination 352 (45.6%) 225 (39.4) 127 (63.2) <0.001 Levosimendan 57 (7.4) 42 (7.4) 15 (7.5) 0.55 Dopamine 2 (0.3) 0 (0) 2 (0.3) 0.03 Isoprenaline 32 (4.1) 27 (4.7) 5 (2.5) 0.22 Antiarrhythmic 298 (38.6) 217 (38.0) 81 (40.3) 0.45 Transfusion 128 (16.6) 87 (15.2) 41 (20.4) 0.05 Fibrinolysis 13 (1.7) 11 (1.9) 2 (1.0) 0.15 Organ replacement therapies, n (%) Respiratory support Invasive 291 (37.9) 199 (35.0) 92 (46.2) 0.005 Non-invasive 199 (25.9) 157 (27.6) 42 (21.1) 0.04 Mechanical circulatory support 143 (18.6) 96 (16.8) 47 (23.5) 0.04 IABP 48/143 (34.3) 30/96 (31.9) 18/47 (32.1) 0.22 Impella 26/143 (18.6) 17/96 (18.1) 9/47 (19.6) 0.99 ECLS 85/143 (60.7) 52/96 (55.3) 33/47 (71.7) 0.06 Renal replacement therapy 122 (15.8)

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