Association between mean arterial pressure during the first 24 hours and hospital mortality in patients with cardiogenic shock

This study was approved by the Institutional Review Board of Mayo Clinic (IRB # 16-000722) as posing minimal risk to patients and was performed under a waiver of informed consent. We retrospectively analyzed a database containing data from the initial CICU admission for consecutive unique adult patients aged ≥ 18 years admitted to the CICU at Mayo Clinic Hospital St. Mary’s Campus between January 1, 2007, and December 31, 2015 [10‐12]. The Mayo Clinic CICU is a closed unit serving critically ill cardiac medical patients, but not postoperative cardiac surgery patients and patients receiving extracorporeal membrane oxygenation (ECMO) support. We included only those patients with an admission diagnosis of CS, defined as an International Classification of Diseases (ICD)-9 code of 785.51 documented within 1 day of CICU admission. We excluded all patients without an admission diagnosis of CS (including those without available admission diagnosis data), even if they had an ICD-9 code for CS documented at another time during hospitalization. Patients without available data on MAP were also excluded. Patients who declined Minnesota Research Authorization, according to Minnesota state law statute 144.295, were excluded from the study.

We recorded demographic, vital sign, laboratory, clinical, and outcome data, as well as procedures and therapies performed during the CICU and hospital stay, as previously described [10‐12]. All relevant data were extracted electronically from the medical record using the Mayo Clinic Multidisciplinary Epidemiology and Translational Research in Intensive Care Data Mart [13]. The admission value of all vital signs, clinical measurements, and laboratory values was defined as either the first value recorded after CICU admission or the value recorded closest to CICU admission. In addition, vital signs were recorded every 15 min, and the maximum, minimum, and mean values over the first 1, 6, and 24 h were recorded. Blood pressure was preferentially recorded from invasive measurements, when available, and otherwise was recorded from noninvasive measurements. Peak vasopressor and inotrope doses were used to calculate the Vasoactive-Inotropic Score [14]. Admission diagnoses included all ICD-9 diagnostic codes recorded on the day of CICU admission and the day before or after CICU admission; these admission diagnoses were not mutually exclusive, and the primary admission diagnosis could not be determined. Admission diagnoses of interest included CS, acute coronary syndrome (ACS), heart failure (HF), supraventricular tachycardia, atrial fibrillation, ventricular fibrillation, ventricular tachycardia, CA, respiratory failure, and sepsis. Discharge ICD-9 diagnostic codes were reviewed for a diagnosis of hypertension. Severe acute kidney injury (AKI) was defined as KDIGO stage 2 or 3 AKI during the CICU stay (i.e., doubling of serum creatinine or increase in serum creatinine to ≥ 4.0 mg/dl or new dialysis initiation in the CICU); mild AKI was defined as KDIGO stage 1 AKI (an increase in creatinine by ≥ 0.3 mg/dl or 50% from baseline) [11, 15]. Baseline creatinine was considered to be the latest creatinine within 1 year prior to the index hospital admission, and patients who had previously received dialysis were excluded from this AKI analysis. Non-cardiovascular organ failure was defined as a score ≥ 3 on any day 1 SOFA organ subscore [16].

The primary endpoint was all-cause hospital mortality; secondary endpoints included CICU mortality and post-discharge mortality up to 1 year among hospital survivors. Mortality and other outcome data were extracted from Mayo Clinic electronic databases, the state of Minnesota electronic death certificates, and the Rochester Epidemiology Project database [17]. Categorical variables are reported as number (percentage), and the Pearson chi-squared test was used to compare groups. Continuous variables are reported as mean (± standard deviation); the Wilcoxon rank-sum test was used to compare groups. The calculation of 24-h mean MAP (mMAP₂₄) was performed using invasive blood pressure measurements, if available; otherwise, mMAP₂₄ was calculated using noninvasive blood pressure values. Logistic regression was used to determine the association between mMAP₂₄ with hospital mortality before and after adjusting for age, gender, race, Charlson Comorbidity Index (CCI), and Acute Physiology and Chronic Health Evaluation IV (APACHE-IV) predicted mortality; admission diagnoses of CA, sepsis, HF, and ACS; peak 24-h VIS; and the use of intra-aortic balloon pump (IABP), dialysis, pulmonary artery catheter (PAC), coronary angiography, percutaneous coronary intervention (PCI), and mechanical ventilation. Subgroup analysis was performed by repeating multivariable logistic regression after excluding patients with SCAI shock stages A or B or sepsis; besides, logistic regression was repeated in the overall cohort after adjusting for SCAI shock stages. Discrimination was assessed using the area under the receiver-operator characteristic curve (AUC, c-statistic) value, and the optimal cutoff defined using Youden’s J index. Post-discharge survival among hospital survivors was evaluated using the Kaplan-Meier survival analysis and Cox proportional-hazards analysis. Two-tailed p values < 0.05 were considered statistically significant. Statistical analyses were performed using JMP Pro version 14.1.0 (SAS Institute, Cary, NC).

The database included 10,004 unique CICU patient admissions, of whom 1078 had an admission diagnosis CS and were potentially eligible for inclusion [10]. We excluded 76 of these patients due to lack of available data for MAP (Supplemental Figure 1). The final study population of 1002 unique patients had a mean age of 67.7 ± 13.7 years, including 36.4% females (Table 1). The mean CCI was 2.4 ± 2.5, and the mean APACHE-IV predicted hospital mortality was 38.4% ± 29.3 overall. Concomitant admission diagnoses included ACS in 599 (59.8%) patients, HF in 740 (73.9%), sepsis in 199 (19.9%), and CA in 379 (37.8%); 77 (7.7%) patients had neither ACS nor HF as an admission diagnosis. Non-cardiovascular organ failure developed on the first day in 690 (68.9%) patients; 630 (73.2%) patients developed AKI during the CICU stay, including 314 (36.5%) with severe AKI.

The mMAP₂₄ for the population was 73.4 ± 10.1 mmHg. A total of 186 (18.6%) patients had a mMAP₂₄ < 65 mmHg, and 390 (38.9%) patients had a mMAP₂₄ ≥ 75 mmHg. During the first 24 h of the CICU stay, 719 (71.8%) patients received vasoactive drugs, including vasopressors in 668 (66.7%), and inotropes in 282 (28.1%), with a mean peak 24-h VIS of 26.1 ± 54.3. IABP was used during the CICU admission in 389 (38.8%) of patients.

Patients with a mMAP₂₄ < 65 mmHg differed from patients with a mMAP₂₄ 65–75 mmHg or mMAP₂₄ ≥ 75 mmHg (Table 1), with greater severity of illness (APACHE-III score 100.8 ± 35.3 vs. 87.5 ± 32.0 vs. 77.9 ± 30.2, p < 0.001), more severe CS based on Society for Cardiovascular Angiography and Interventions (SCAI) staging, increased incidence of severe AKI (30.0% vs. 19.8% vs. 14.8%, p = 0.001, Fig. 1a), greater use of vasoactive infusions (85.5% vs. 78.9% vs. 54.4%, p < 0.001), and an increased number of non-cardiac organ injury (mean 1.4 vs. 1.1 vs. 0.9, < 0.001, Fig. 1b). Conversely, patients with mMAP₂₄ < 65 mmHg underwent fewer coronary angiograms (52.5% vs. 64.6% vs. 70.5%, p < 0.001) and were less often supported with an IABP or Impella device (Abiomed, Danvers, MA, USA) (30.1% vs. 50.5% vs. 46.4%, respectively, p < 0.001).

Hospital mortality was 33.7%, including 23.4% of patients who died in the CICU. Patients who died in the hospital had lower mMAP₂₄ (70.8 vs. 74.7 mmHg, p < 0.001). Crude hospital mortality was higher in patients with mMAP₂₄ < 65 mmHg compared with patients with mMAP₂₄ 65–75 mmHg or mMAP₂₄ ≥ 75 mmHg (57.0% vs. 29.8% vs. 26.9%, p < 0.001 for mMAP₂₄ < 65 mmHg vs. other groups and p = 0.36 between other groups). The mMAP₂₄ was inversely associated with hospital mortality (unadjusted OR 0.82 per 5 mmHg higher mMAP₂₄, 95% CI 0.76–0.88, p < 0.001; optimal cutoff 64.6 mmHg; Fig. 2). Similar findings were observed in patients with ACS or HF (Supplemental Figures 2A and 2B), patients with CA (Supplemental Figures 3A and 3B), patients with a pre-admission diagnosis of hypertension (Supplemental Figures 4A and 4B), and patients aged 65 years and older (Supplemental Figure 5). Mean values of systolic, diastolic, and mean BP were significantly lower for inpatient deaths at all time points (1, 6, and 24 h), although the magnitude of these differences was relatively modest (Supplemental Figure 6). The association between mMAP₂₄ and mortality remained after excluding patients with SCAI stages A and B of CS (adjusted OR 0.850 per 5 mmHg higher, 95% CI 0.755–0.957, p = 0.007), as well as in the overall cohort after adjusting for SCAI CS stage (adjusted OR 0.913 per 5 mmHg, 95% CI 0.838–0.994, p = 0.035). The association between mMAP₂₄ and hospital mortality persisted after excluding patients with an admission diagnosis of sepsis (adjusted OR 0.873, 95% CI 0.794–0.960, p = 0.0052). The association between mMAP₂₄ and hospital mortality was present in patients without sepsis (adjusted OR 0.873, 95% CI 0.794–0.960, p = 0.0052). The optimal mMAP₂₄ cutoff for predicting hospital mortality was 65.2 mmHg in patients with ACS and 70.0 mmHg in patients with HF. Hospital mortality varied as a function of mMAP₂₄ and the maximum number of vasopressors during the first 24 h and the peak VIS during the first 24 h (Fig. 3). In subgroups of patients with and without a diagnosis of hypertension, there was no association between mMAP₂₄ and the incidence of severe AKI (p = 0.83) (Supplemental Figures 4A and 4B).

After multivariable adjustment, mMAP₂₄ remained inversely associated with hospital mortality (adjusted OR 0.89 per 5 mmHg higher mMAP₂₄, 95% CI 0.82–0.97, p = 0.01, Table 2). Patients with a mMAP₂₄ < 65 mmHg were at higher risk of hospital mortality (adjusted OR 2.05, 95% CI 1.38–3.02, p < 0.001), with no difference between patients with mMAP₂₄ 65–75 mmHg and mMAP₂₄ ≥ 75 mmHg (p = 0.77).

This retrospective cohort study has a number of inherent limitations, including the potential for unmeasured confounders and missing data to have influenced the results. This single-center cohort may not fully represent the general patient population with CS. The mMAP₂₄ values included both invasive and noninvasive MAP measurements, but we could not determine which MAP measurements were made using each method, and mMAP₂₄ potentially included a mixture of both. Admission diagnoses are based on ICD-9 coding and may underrepresent the number of patients with CS and associated comorbidities. The inclusion of a mixed CICU population without available hemodynamic or echocardiographic data implies that some patients may have had non-cardiogenic or mixed cardiogenic-septic shock states. MAP data is limited to the first 24 h of CICU admission, so this study cannot evaluate the association between patient outcomes and MAP beyond 24 h. For this reason, we specifically focused on organ failure occurring during the first 24 h of CICU admission and cannot comment on later development of organ failure. Detailed data regarding vasopressor doses over time could potentially provide additional indication of illness severity in the context of mMAP₂₄; unfortunately, these data were not available. Patients with mMAP₂₄ < 65 mmHg were less likely to undergo PCI; the reasons for this are likely multifactorial and largely dependent on clinical factors and contraindications (e.g., severe shock, renal injury, or concern for cerebral anoxia). Unfortunately, our retrospective dataset cannot account for these clinical decisions. In addition, we could not determine the incidence of relevant cardiovascular adverse events attributable to vasopressor and inotrope therapy. Due to lack of data availability, we could not account for patient-level variables before CICU admission, including specific diagnostic or therapeutic interventions which took place before CICU admission.