Sarma, Dhruv

Abstract Background Greater vasopressor requirements predict higher mortality in patients with cardiogenic shock (CS).(1) The extent to which CS phenotype modifies the relationship between vasopressor dose and mortality risk is unknown. Purpose We investigated the association between in-hospital mortality and vasopressor dosing (expressed as norepinephrine equivalents [NEE]) during the first 24 hours of hospitalization across distinct CS phenotypes. Methods We included patients with CS admitted to our cardiac intensive care unit (CICU) between 2007 and 2015. Peak combined vasopressor doses during the first 24 hours of hospitalization were recorded as NEE. High dose vasopressor (HDV) use was defined as peak 24 hour NEE >0.3 mcg/kg/min. Unsupervised machine learning was used to assign patients to one of three phenotypes (non-congested, cardiorenal, and haemometabolic), as reported previously by our group and others.(2,3) The primary outcome was in-hospital mortality. Multivariable logistic regression was used to adjust for relevant covariates. Results A total of 1078 patients with CS (median age 69 years, 37% female, 59% with acute myocardial infarction) were admitted to our cardiac intensive care unit (CICU) between 2017 and 2015. The number of patients assigned to each CS phenotype were: haemometabolic (n=325, 30%), cardiorenal (n=314, 29%), non-congested (439, 41%). There was a strong incremental association between in-hospital mortality and NEE (Fig. 1, adjusted OR 1.104 per 0.1 mcg/kg/min, 95% CI 1.134–1.231, P<0.001), and patients receiving HDV (n=234, 22%) had significantly higher in-hospital mortality (57% vs 28%, p<0.001). Among patients who did not receive HDV, mortality was higher in haemometabolic CS (49%) compared to 24% in cardiorenal CS and 21% in non-congested CS (adjusted OR 3.58 relative to non-congested CS, 95% CI 2.46-5.23, p<0.001, Fig. 1). Among patients receiving HDV, hemometabolic CS was also associated with higher mortality (68%) than those with cardiorenal (46.2%) or non-congested CS (39.3%), (adjusted OR 3.26 relative to non-congested CS, 95% CI 1.75-6.18, P<0.001, Fig. 1). Conclusion Integration of CS phenotype with vasopressor requirements may provide incremental prognostic information in CS during the first 24 hours of admission, with haemometabolic CS portending a greater mortality risk even at lower NEE. Patients with HDV (particularly those requiring >=1 mcg/kg/min NEE) had high mortality irrespective of CS phenotype.Figure 1

Abstract Background Vasoactive medications and Mechanical Circulatory Support (MCS) are both central to the contemporary management of cardiogenic shock (CS). There are limited data on the interaction between vasoactive medication dosing and MCS in patients with CS. Purpose We investigated the association between in-hospital mortality and vasoactive medication dosing among patients with CS who did and did not receive MCS during hospitalization. Methods We included patients with CS admitted to our cardiac intensive care unit (CICU) between 2007 and 2015. The peak combined vasoactive medication dose during the first 24 hours of CICU admission was recorded and converted to norepinephrine equivalents (NEE)(references 1 & 2). The primary outcome was in-hospital mortality. Multivariable logistic regression was used to adjust for relevant variables and calculate adjusted odds ratios (OR). Results Of 1078 patients with CS (median age 69.0 years [Interquartile Range 59.1-77.3], 36.8% female, 59% with acute myocardial infarction), 721 (66.9%) received vasoactive medications in the first 24 hours and 510 (47.3%) received MCS (87% intra-aortic balloon pump). Among those receiving vasoactive medications during the first 24 hours, the median NEE was 0.16 (Interquartile Range 0.06-0.40) mcg/kg/min. In hospital mortality was 34.4% overall, and was lower among those who received MCS (26.1% versus 41.9%, p<0.001; adjusted OR 0.71 95% CI 0.50-0.99) and higher among those who received vasoactive medications (38.1% versus 26.9%, p<0.001). A gradient of mortality was observed according to the use of vasoactive medications and MCS (Fig. 1). We found a strong incremental association between in-hospital mortality and NEE (adjusted OR 1.11 per 0.1 mcg/kg/min, 95% CI 1.06–1.16, P<0.001; Fig. 2). Mortality was lower across the spectrum of NEE for patients who received MCS (Fig. 2). There was no statistically significant difference in the slope of the relationship between in-hospital mortality and NEE in patients who did and did not receive MCS (p = 0.86). Conclusion Increasing vasoactive medication requirement during the first 24 hours of CICU admission is incrementally associated with in-hospital mortality in CS, representing a simplified marker of shock severity. Patients who received MCS were at lower risk of mortality across the spectrum of vasopressor requirements, emphasizing the potential synergy between these two complementary approaches to hemodynamic support.Figure 1Figure 2

Purpose of review Cardiogenic shock (CS) results in persistently high short-term mortality and a lack of evidence-based therapies. Several trials of novel interventions have failed to show an improvement in clinical outcomes despite promising preclinical and physiologic principles. In this review, we highlight the challenges of CS trials and provide suggestions for the optimization and harmonization of their design. Recent findings CS clinical trials have been plagued by slow or incomplete enrolment, heterogeneous or nonrepresentative patient cohorts, and neutral results. To achieve meaningful, practice-changing results in CS clinical trials, an accurate CS definition, a pragmatic staging of its severity for appropriate patient selection, an improvement in informed consent process, and the use of patient-centered outcomes are required. Future optimizations include the use of predictive enrichment using host response biomarkers to unravel the biological heterogeneity of the CS syndrome and identify subphenotypes most likely to benefit from individualized treatment to allow a personalized medicine approach. Summary Accurate characterization of CS severity and its pathophysiology are crucial to unravel heterogeneity and identify the patients most likely to benefit from a tested treatment. Implementation of biomarker-stratified adaptive clinical trial designs (i.e., biomarker or subphenotype-based therapy) might provide important insights into treatment effects.

Background: Urine output (UO) measurement utility after out-of-hospital cardiac arrest (OHCA) survivors who undergo targeted temperature management (TTM) is not well understood. Methods: We included 247 comatose adult patients who underwent TTM after OHCA between 2007 and 2017 and excluded those on maintenance dialysis. Groups were defined based on mean hourly UO during the first 24 hours: Group 1 (<0.5 ml/kg/hr, n=73), Group 2 (0.5-1 ml/kg/hr, n=81) and Group 3 (>1 ml/kg/hr, n=93). Kidney Disease: Improving Global Outcomes (KDIGO) serum creatinine criteria were used to define and stage acute kidney injury (AKI). Multivariable analysis was used to evaluate in-hospital mortality. Results: In-hospital mortality decreased as 24-hour mean UO increased (56.2% [41/73] vs 29.6% [24/81] vs 18.3% [17/93] in Groups 1, 2 and 3, respectively; adjusted OR 0.93 per 0.1 ml/kg/h higher, 95% CI 0.87-0.99, p = 0.03), and UO < 0.5 ml/kg/hr was strongly associated with in-hospital mortality (adjusted OR 4.2 [1.6-10.8], p=0.003). In-hospital mortality varied by the KDIGO stage and UO group (Figure), lowest in KDIGO stage 0 and highest in KDIGO stage 3. Both UO (adjusted OR 0.92 per 0.1 ml/kg/h higher, p = 0.002) and KDIGO stage (adjusted OR 1.62 per each stage, p = 0.002) were associated with in-hospital mortality when included in the same model. Among patients with KDIGO stage 0, lower UO portended higher mortality (Figure). Likewise, among patients with low UO (group 1), a higher KDIGO stage predicted higher mortality. Conclusion: Amongst OHCA survivors undergoing TTM, higher UO is incrementally associated with lower in-hospital mortality. The lowest mortality was observed at UO >=1 ml/kg/h, suggesting this as a target for resuscitation in OHCA patients undergoing TTM. Low UO remains associated with in-hospital mortality even when accounting for AKI by creatinine criteria, suggesting that oliguria is a more sensitive prognostic marker in the early post-OHCA phase.

Introduction: Peripheral artery disease (PAD) is a risk factor for adverse limb events (LE) and cardiovascular events (CVE) that often coexists with type 1 (T1) and type 2 (T2) diabetes mellitus (DM), which differ mechanistically. There is a paucity of data on comparative risk of LE and CVE in T1DM and T2DM patients with PAD. Methods: We queried our database of 40,144 patients ≥18y old who underwent ankle brachial index (ABI) measurement from 01/1996-02/2020. We isolated patients with T1DM or T2DM and with PAD diagnosed by ABI (low [<1.0] or elevated [>1.4]). We retrieved demographics including hemoglobin A1c (A1c). Primary outcomes were LE (critical limb ischemia or vascular amputation) and CVE (myocardial infarction or ischemic stroke). All-cause mortality was a secondary outcome. Multivariable Cox proportional regression yielded hazard ratios (HR) with 95% confidence intervals (CI) after adjusting for age, sex, A1c, hypertension, hyperlipidemia, coronary artery disease (CAD), chronic kidney disease (CKD), and tobacco use. Results: Our study found 9,271 patients with PAD and DM (36% T1DM, 64% T2DM) with median follow-up time 34 mo (interquartile range [IQR] 85 mo). T1DM patients were younger than T2DM (mean age 67 vs 70y), with higher median A1c (7.7 [IQR 1.9] vs 6.7% [IQR 1.6]), and higher prevalence of hypertension, hyperlipidemia, CAD, and CKD. Antiplatelet and statin use did not differ. Elevated ABI was more common in T1DM (47 vs 27%). LE occurred in 23% and CVE in 12% of patients. LE risk was higher in T1DM patients than T2DM (HR 1.59[95% CI 1.45,1.74], p<0.0001), but CVE and all-cause mortality did not differ significantly. Conclusions: PAD patients with T1DM had a higher LE risk than those with T2DM, even after adjustment for A1c and pertinent risk factors, but CVE risk and all-cause mortality were equivocal. These data suggest a potential role for more intensive LE risk modification in PAD patients with T1DM, but further investigation is needed to minimize limb morbidity.

Background Limited data exist regarding urine output (UO) as a prognostic marker in out-of-hospital-cardiac-arrest (OHCA) survivors undergoing targeted temperature management (TTM). Methods We included 247 comatose adult patients who underwent TTM after OHCA between 2007 and 2017, excluding patients with end-stage renal disease. Three groups were defined based on mean hourly UO during the first 24 h: Group 1 (<0.5 mL/kg/h, n = 73), Group 2 (0.5−1 mL/kg/h, n = 81) and Group 3 (>1 mL/kg/h, n = 93). Serum creatinine was used to classify acute kidney injury (AKI). The primary and secondary outcomes respectively were in-hospital mortality and favorable neurological outcome at hospital discharge (modified Rankin Scale [mRS]<3). Results In-hospital mortality decreased incrementally as UO increased (adjusted OR 0.9 per 0.1 mL/kg/h higher; p = 0.002). UO < 0.5 mL/kg/h was strongly associated with higher in-hospital mortality (adjusted OR 4.2 [1.6−10.8], p = 0.003) and less favorable neurological outcomes (adjusted OR 0.4 [0.2−0.8], p = 0.007). Even among patients without AKI, lower UO portended higher mortality (40% vs 15% vs 9% for UO groups 1, 2, and 3 respectively, p < 0.001). Conclusion Higher UO is incrementally associated with lower in-hospital mortality and better neurological outcomes. Oliguria may be a more sensitive early prognostic marker than creatinine-based AKI after OHCA.