Abstract
This study investigates the association between timing of mechanical ventilation initiation and mortality in patients with refractory cardiogenic shock.
Acute myocardial infarction (MI) is complicated by cardiogenic shock (CS) in 4% to 10% of patients, and contemporary mortality rates range from 31% to 51%.1 A common sequela of CS is an elevated end-diastolic pressure leading to pulmonary congestion, and mechanical ventilatory (MV) support is required in up to 88% of patients.2 Positive end-expiratory pressure (PEEP) imparts favorable cardiovascular hemodynamic changes in patients with CS and reduced left ventricular (LV) function. Positive end expiratory pressure lowers pulmonary wedge pressure, LV afterload, myocardial oxygen demand, work of breathing, and improves cardiac index and oxygenation.3 Consequently, the timely initiation of MV in this population could theoretically attenuate physiologic deterioration or the ischemic cascade and improve outcomes; however, to our knowledge, the association between timing of MV initiation and mortality in patients with CS has not been described.
Methods
The Tilarginine Acetate Injection in a Randomized International Study in Unstable MI Patients With Cardiogenic Shock (TRIUMPH) trial randomized patients with an MI with refractory CS to a nitric oxide synthase inhibitor or placebo.2 The study defined refractory CS as a systolic pressure less than 100 mm Hg despite moderate inopressor doses and hypoperfusion for at least 1 hour after revascularization. We used the time-stamped onsets of CS and invasive MV initiation to explore the association between timing of MV initiation relative to CS onset and 30-day mortality. Given the trial’s refractory CS definition, the analysis examined the association in the 24-hour window before and after CS. The adjusted odds ratio (OR) for mortality was determined by adjusting for available CARDSHOCK score variables (age, prior coronary artery bypass grafting, MI, LV ejection fraction, and systolic blood pressure) and baseline patient differences (body mass index). Ethics committees at all sites approved the study and written consent was obtained for all patients.2 All statistical tests were 2-sided, and a P value of less than .05 was considered statistically significant.
Results
Among the 398 TRIUMPH trial participants, the study included 262 patients (65.8%) who received MV; 244 (93.1%) had MV initiated a median of 8.1 hours before the onset of refractory CS, and 18 (6.9%) had MV initiated a median of 17.8 hours after CS. Thirty-day mortality was 51.5%. Baseline differences were generally balanced (Table). Figure, A, shows each 1-hour delay in MV initiation was associated with higher 30-day morality (OR, 1.03; 95% CI, 1.00-1.06; P = .03), with a similar trend after multivariable adjustment (OR, 1.03; 95% CI, 1.00-1.06; P = .09). In a sensitivity analysis, each 1-hour delay in MV initiation from the time of MI onset (Figure, B) was independently associated with mortality (OR, 1.04; 95% CI, 1.01-1.06; P < .001).
Table. Baseline Characteristics of Patients’ Mechanical Ventilation Initiation 24 Hours Before and After the Onset of Cardiogenic Shock.
| Characteristic | All patients (n = 262) | Timing of mechanical ventilation initiation | P valuea | |
|---|---|---|---|---|
| Before shock (n = 244) | After shock (n = 18) | |||
| Age, median (25th-75th percentile), y | 66.5 (57.0-75.8) | 66.0 (55.6-75.1) | 76.8 (65.0-79.1) | .005 |
| Male, No. (%) | 186 (71.0) | 174 (71.3) | 12 (66.7) | .68 |
| BMI, median (25th-75th percentile) | 26.3 (24.5-30.0) | 26.6 (24.6-30.5) | 24.7 (24.0-26.8) | .02 |
| Medical history, No. (%) | ||||
| Hypertension | 161 (61.9) | 150 (62.0) | 11 (61.1) | .94 |
| Diabetes | 88 (33.7) | 82 (33.7) | 6 (33.3) | .97 |
| Current tobacco use | 81 (31.9) | 77 (32.6) | 4 (22.2) | .36 |
| Prior myocardial infarction | 74 (28.4) | 65 (26.7) | 9 (50.0) | .04 |
| Prior coronary artery bypass | 19 (7.3) | 18 (7.4) | 1 (5.6) | >.99 |
| Heart failure | 53 (20.4) | 47 (19.4) | 6 (33.3) | .22 |
| Cerebrovascular disease | 20 (7.7) | 19 (7.8) | 1 (5.6) | >.99 |
| COPD | 22 (8.5) | 22 (8.5) | 0 (0.0) | .38 |
| Baseline systolic BP (25th-75th percentile), mm Hg | 87 (80-93) | 87 (80-94) | 87 (81-91) | .92 |
| Baseline diastolic BP 25th-75th percentile), mm Hg | 53 (45-60) | 51 (43-60) | 47 (41-55) | .28 |
| Electrocardiogram findings, No. (%) | ||||
| ST elevation | 201 (76.7) | 190 (77.9) | 11 (61.1) | .14 |
| Angiographic findings, No. (%) | ||||
| Left main culprit lesion | 32 (12.2) | 29 (11.9) | 3(16.7) | .55 |
| Left anterior descending culprit lesion | 151 (57.6) | 146 (59.8) | 5 (27.8) | .008 |
| Left main or left anterior descending culprit lesion | 183 (69.8) | 175 (71.7) | 8(44.4) | .02 |
| 2- or 3-Vessel diseaseb | 36 (14.6) | 33 (14.3) | 3 (18.8) | .63 |
| LVEF, median (25th-75th percentile), % | 28 (20-34) | 27 (20-33) | 30 (22-35) | .55 |
| Laboratory values, median (25th-75th percentile) | ||||
| Hemoglobin, g/dL | 13.9 (12.4-15.95) | 14.0 (12.3-16.0) | 13.8 (12.0-15.4) | >.99 |
| Creatinine, mg/dL | 1.5 (1.0-1.8) | 1.4 (1.1-1.8) | 1.58 (1.23-2.1) | .19 |
| Baseline CK, IU/L | 1228 (133-4576) | 1414 (140-4699) | 715 (132-1132) | .12 |
| Baseline CK-MB, IU/L | 119.0 (17.4-382.1) | 130.2 (16.9-411.5) | 77.0 (23.4-143.0) | .24 |
| Time interval, median (25th-75th percentile), h | ||||
| Myocardial infarction to PCI | 5.3 (2.8-11.5) | 5.3 (2.8-11.4) | 4.7 (3.4-13.4) | .88 |
| Myocardial infarction to shock | 4.0 (1.4-9.4) | 3.9 (1.2-9.3) | 4.6 (2.0-10.0) | .48 |
| Medication use randomization to 24 h, No. (%) | ||||
| Aspirin | 188 (71.8) | 175 (71.7) | 13 (72.2) | .96 |
| Thienopyridine | 207 (79.0) | 191 (91.0) | 16 (88.9) | .38 |
| Heparin | 236 (90.1) | 222 (91.0) | 14 (77.8) | .09 |
| Glycoprotein IIb/IIIa inhibitor | 120 (45.8) | 112 (45.9) | 8 (44.4) | .91 |
| β-Blockers | 22 (8.4) | 20 (8.2) | 2 (11.1) | .65 |
| ACE or ARB | 11 (4.2) | 10 (4.1) | 1 (5.6) | .55 |
| Diuretics | 153 (58.4) | 139 (57.0) | 14 (77.8) | .08 |
| Statin | 111 (42.4) | 105 (43.0) | 6 (33.3) | .42 |
| Antiarrhythmic | 111 (42.2) | 105 (43.0) | 6 (33.3) | .42 |
| Baseline inotropes, No. (%) | 184 (70.2) | 169 (69.3) | 15 (83.3) | .21 |
| Baseline vasopressors, No. (%) | 259 (98.9) | 241 (98.8) | 18 (100.0) | .64 |
| Intra-aortic balloon pump, No. (%) | 232 (88.5) | 217 (88.9) | 15 (83.3) | .44 |
| Coronary artery bypass grafting, No. (%) | 7 (2.7) | 7 (2.9) | 0 | .47 |
| Left ventricular assist device, No. (%) | 14 (5.3) | 14 (5.7) | 0 | .30 |
| Hospital location, No. (%) | ||||
| North America | 85 (32.4) | 82 (33.6) | 3 (16.7) | .14 |
| Europe | 177 (67.6) | 162 (66.4) | 15 (83.3) | NA |
Abbreviations: ACE, angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers; BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); CK, creatine kinase; CK-MB, creatine kinase–MB fraction; COPD, chronic obstructive pulmonary disease; LVEF, left ventricular ejection fraction; PCI, percutaneous coronary intervention.
SI conversion factor: To convert creatine kinase to microkatals per liter, multiply by 0.0167; creatine kinase–MB fraction to micrograms per liter, multiply by 1; creatinine to micromoles per liter, multiply by 88.4; hemoglobin to grams per liter, multiply by 10.
P value for comparison between mechanical ventilation before and after shock onset.
Defined as at least 50% stenosis in either left anterior descending, right coronary, or left circumflex artery.
Figure. Mortality and Timing of Mechanical Ventilation Initiation Relative to the Onset of Refractory Cardiogenic Shock (A) and Myocardial Infarction (B).
Each 1-hour delay in mechanical ventilation initiation is associated with an increased risk of 30-day mortality.
Discussion
Little is known about the optimal timing, modes, or ventilatory strategies in patients with CS, and this has been identified as a research need.1,3 When pulmonary edema is associated with reduced LV systolic function, PEEP has a number of theoretical cardiovascular benefits. Positive end-expiratory pressure can improve congestion by reducing venous return, increasing transmural pressure, and decreasing LV afterload; all of which can improve oxygenation, hypercapnia, and acidosis.3,4,5 Moreover, MV can reduce work of breathing and improve tissue perfusion, which, in conjunction with PEEP, can reduce myocardial oxygen consumption. We hypothesize these mechanisms may mediate the observed association with reduced mortality in patients with CS, and these physiological benefits could be augmented in an MI with CS prior to revascularization. We acknowledge the potential for confounding, the modest size, lack of hemodynamics, cardiac arrest, lactate, neurologic variables, or ventilation data in the study and that mechanical circulatory support with isolated LV dysfunction may obviate these benefits. Nevertheless, in a cohort of patients with refractory CS despite revascularization, we observed modest associations between mortality and delays in MV initiation from CS onset and from the time of MI. The potential physiologic and hemodynamic benefits of MV in patients with reduced LV systolic function and CS highlight the need for larger randomized studies into the optimal use of MV in this high-risk population.
References
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