The Impact of a Machine Learning Early Warning Score on Hospital Mortality: A Multicenter Clinical Intervention Trial.

OBJECTIVES: To determine the impact of a machine learning early warning risk score, electronic Cardiac Arrest Risk Triage (eCART), on mortality for elevated-risk adult inpatients. DESIGN: A pragmatic pre- and post-intervention study conducted over the same 10-month period in 2 consecutive years. SETTING: Four-hospital community-academic health system. PATIENTS: All adult patients admitted to a medical-surgical ward. INTERVENTIONS: During the baseline period, clinicians were blinded to eCART scores. During the intervention period, scores were presented to providers. Scores greater than or equal to 95th percentile were designated high risk prompting a physician assessment for ICU admission. Scores between the 89th and 95th percentiles were designated intermediate risk, triggering a nurse-directed workflow that included measuring vital signs every 2 hours and contacting a physician to review the treatment plan. MEASUREMENTS AND MAIN RESULTS: The primary outcome was all-cause inhospital mortality. Secondary measures included vital sign assessment within 2 hours, ICU transfer rate, and time to ICU transfer. A total of 60,261 patients were admitted during the study period, of which 6,681 (11.1%) met inclusion criteria (baseline period n = 3,191, intervention period n = 3,490). The intervention period was associated with a significant decrease in hospital mortality for the main cohort (8.8% vs 13.9%; p < 0.0001; adjusted odds ratio [OR], 0.60 [95% CI, 0.52-0.71]). A significant decrease in mortality was also seen for the average-risk cohort not subject to the intervention (0.49% vs 0.26%; p < 0.05; adjusted OR, 0.53 [95% CI, 0.41-0.74]). In subgroup analysis, the benefit was seen in both high- (17.9% vs 23.9%; p = 0.001) and intermediate-risk (2.0% vs 4.0 %; p = 0.005) patients. The intervention period was also associated with a significant increase in ICU transfers, decrease in time to ICU transfer, and increase in vital sign reassessment within 2 hours. CONCLUSIONS: Implementation of a machine learning early warning score-driven protocol was associated with reduced inhospital mortality, likely driven by earlier and more frequent ICU transfer.

PDGF-induced vascular smooth muscle cell proliferation is associated with dysregulation of insulin receptor substrates.

In vascular smooth muscle cells (VSMCs), platelet-derived growth factor (PDGF) plays a major role in inducing phenotypic switching from contractile to proliferative state. Importantly, VSMC phenotypic switching is also determined by the phosphorylation state/expression levels of insulin receptor substrate (IRS), an intermediary signaling component that is shared by insulin and IGF-I. To date, the roles of PDGF-induced key proliferative signaling components including Akt, p70S6kinase, and ERK1/2 on the serine phosphorylation/expression of IRS-1 and IRS-2 isoforms remain unclear in VSMCs. We hypothesize that PDGF-induced VSMC proliferation is associated with dysregulation of insulin receptor substrates. Using human aortic VSMCs, we demonstrate that prolonged PDGF treatment led to sustained increases in the phosphorylation of protein kinases such as Akt, p70S6kinase, and ERK1/2, which mediate VSMC proliferation. In addition, PDGF enhanced IRS-1/IRS-2 serine phosphorylation and downregulated IRS-2 expression in a time- and concentration-dependent manner. Notably, phosphoinositide 3-kinase (PI 3-kinase) inhibitor (PI-103) and mammalian target of rapamycin inhibitor (rapamycin), which abolished PDGF-induced Akt and p70S6kinase phosphorylation, respectively, blocked PDGF-induced IRS-1 serine phosphorylation and IRS-2 downregulation. In contrast, MEK1/ERK inhibitor (U0126) failed to block PDGF-induced IRS-1 serine phosphorylation and IRS-2 downregulation. PDGF-induced IRS-2 downregulation was prevented by lactacystin, an inhibitor of proteasomal degradation. Functionally, PDGF-mediated IRS-1/IRS-2 dysregulation resulted in the attenuation of insulin-induced IRS-1/IRS-2-associated PI 3-kinase activity. Pharmacological inhibition of PDGF receptor tyrosine kinase with imatinib prevented IRS-1/IRS-2 dysregulation and restored insulin receptor signaling. In conclusion, strategies to inhibit PDGF receptors would not only inhibit neointimal growth but may provide new therapeutic options to prevent dysregulated insulin receptor signaling in VSMCs in nondiabetic and diabetic states.

Clinical Analytics Prediction Engine (CAPE): Development, electronic health record integration and prospective validation of hospital mortality, 180-day mortality and 30-day readmission risk prediction models.

BACKGROUND: Numerous predictive models in the literature stratify patients by risk of mortality and readmission. Few prediction models have been developed to optimize impact while sustaining sufficient performance. OBJECTIVE: We aimed to derive models for hospital mortality, 180-day mortality and 30-day readmission, implement these models within our electronic health record and prospectively validate these models for use across an entire health system. MATERIALS & METHODS: We developed, integrated into our electronic health record and prospectively validated three predictive models using logistic regression from data collected from patients 18 to 99 years old who had an inpatient or observation admission at NorthShore University HealthSystem, a four-hospital integrated system in the United States, from January 2012 to September 2018. We analyzed the area under the receiver operating characteristic curve (AUC) for model performance. RESULTS: Models were derived and validated at three time points: retrospective, prospective at discharge, and prospective at 4 hours after presentation. AUCs of hospital mortality were 0.91, 0.89 and 0.77, respectively. AUCs for 30-day readmission were 0.71, 0.71 and 0.69, respectively. 180-day mortality models were only retrospectively validated with an AUC of 0.85. DISCUSSION: We were able to retain good model performance while optimizing potential model impact by also valuing model derivation efficiency, usability, sensitivity, generalizability and ability to prescribe timely interventions to reduce underlying risk. Measuring model impact by tying prediction models to interventions that are then rapidly tested will establish a path for meaningful clinical improvement and implementation.

Effect of hyperoxia and vitamin C on coronary blood flow in patients with ischemic heart disease.

Pathological formation of reactive oxygen species within the coronary circulation has been hypothesized to mediate some clinical manifestations of ischemic heart disease (IHD) by interfering with physiological regulation of coronary tone. To determine the degree to which coronary tone responds to acute changes in ambient levels of oxidants and antioxidants in vivo in a clinical setting, we measured the effect of an acute oxidative stress (breathing 100% oxygen) on coronary capacitance artery diameter (quantitative angiography) and blood flow velocity through the coronary microcirculation (intracoronary Doppler ultrasonography) before and after treatment with the antioxidant vitamin C (3-g intravenous infusion) in 12 IHD patients undergoing a clinical coronary interventional procedure. Relative to room air breathing, 100% oxygen breathing promptly reduced coronary blood flow velocity by 20% and increased coronary resistance by 23%, without significantly changing the diameter of capacitance arteries. Vitamin C administration promptly restored coronary flow velocity and resistance to a slightly suprabasal level, and it prevented the reinduction of coronary constriction with rechallenge with 100% oxygen. This suggests that acute oxidative stress produces prompt and substantial changes in coronary resistance and blood flow in a clinical setting in patients with IHD, and it suggests that these changes are mediated by vitamin C-quenchable substances acting on the coronary microcirculation. This observation may have relevance for clinical practice.

Usefulness of hyperglycemia in predicting renal and myocardial injury in patients with diabetes mellitus undergoing percutaneous coronary intervention.

A retrospective analysis of 165 patients who had diabetes mellitus and underwent percutaneous coronary intervention (PCI) between 1998 and 2003 demonstrated that those whose plasma glucose levels were >/=200 mg/dl before PCI exhibited greater creatine phosphokinase release and serum creatinine increases after PCI. These observations identified hyperglycemia as a potentially modifiable mediator of myocardial and renal injuries in patients who have diabetes and have undergone PCI.

Usefulness of temporary left ventricular pacing through the coronary sinus as an adjunct to transfemoral percutaneous coronary intervention.

In 10 patients who underwent percutaneous coronary intervention involving the right coronary artery, a new procedure for adjunctive temporary transfemoral pacing of the left ventricle through the coronary sinus was tested. The procedure was successful in 8 of 10 patients and could be performed in <5 minutes by experienced operators and supervised cardiology fellows.

Natural history of inadvertent aorta-saphenous vein-coronary vein bypass graft.

Inadvertent distal anastomosis of an aortocoronary bypass graft to a coronary vein is a rare but potentially serious complication of coronary artery bypass surgery. We describe a patient in whom such a conduit was discovered only incidentally 17 years after its creation. This case illustrates the pertinent features of this anomaly and demonstrates that it can have a benign natural history.

Diabetes mellitus and heart failure.

Type 2 diabetes mellitus substantially increases the lifetime risk of both developing and dying from heart failure. While this appears to be explained in part by the well-known association of diabetes with hypertension, dyslipidemia, and coronary atherosclerosis, additional pathophysiologic mechanisms linking type 2 diabetes and heart failure have recently been suggested. These include the potentially adverse effects of hyperglycemia on endothelial function and redox state, effects of excess circulating glucose and fatty acids on cardiomyocyte ultrastructure, intracellular signaling and gene expression, and the possibility that diabetes may impair recruitment of the myocardial insulin-responsive glucose transport system in response to ischemia. Because many of these putative pathophysiologic mechanisms should be amenable to normalization of the diabetic metabolic milieu, strategies designed to more carefully control circulating levels of glucose and fatty acids might conceivably delay or prevent the development of heart failure.

Anomalous great cardiac vein.

Anomalous coronary venous anatomy is a little studied and rarely reported subject that is of crucial importance in interventions that rely upon the assumption of normal coronary venous anatomy. In particular, the recognition of coronary vein anomalies that disconnect large segments of the left ventricular myocardium from the main coronary sinus is critical for cardiothoracic surgeons who perform interventions involving retrograde cardioplegia and other forms of coronary venous retroperfusion. We present a rare case of an anomalous great cardiac vein that bypassed the coronary sinus to drain directly into the superior vena cava, and suggest a possible role for antecedent imaging of the coronary venous system in patients who might be expected to undergo such interventions.

Measurement of thoracolumbar kyphosis after burst fracture: evaluation of intraobserver, interobserver, and variability of 4 measurement methods.

There are various methods for measuring kyphosis after thoracolumbar burst fracture. The reliability and reproducibility of these methods are not well defined. In the study reported here, we examined 4 commonly used measurement methods in order to determine intraobserver variability, interobserver variability, and variability between measurement methods. All 4 methods were found to be accurate and reproducible when used by 4 observers on 2 occasions. One method, in comparison with the others, tended to overestimate degree of kyphosis. Understanding the methods for measuring kyphotic deformity after thoracolumbar burst fracture is essential in making decisions about prognosis and treatment.

Nitrite consumption in ischemic rat heart catalyzed by distinct blood-borne and tissue factors.

Nitric oxide (NO) may limit myocardial ischemia-reperfusion injury by slowing the mitochondrial metabolism. We examined whether rat heart contains catalysts potentially capable of reducing nitrite to NO during an episode of regional myocardial ischemia produced by temporary coronary artery occlusion. In intact Sprague-Dawley rats, a 15-min coronary occlusion lowered the nitrite concentration of the myocardial regions exhibiting ischemic glucose metabolism to approximately 50% that of nonischemic regions (185 +/- 223 vs. 420 +/- 203 nmol/l). Nitrite was rapidly repleted during subsequent reperfusion. The heart tissue tested in vitro acquired a substantial ability to consume nitrite when made hypoxic at neutral pH, and this ability was slightly enhanced by simultaneously lowering the pH to 5.5. More than 70% of this activity could be abolished by flushing the coronary circulation with crystalloid to remove trapped erythrocytes. Correspondingly, erythrocytes demonstrated the ability to reduce exogenous nitrite to NO under hypoxic conditions in vitro. In erythrocyte-free heart tissue, the nitrite consumption increased fivefold when the pH was lowered to 5.5. Approximately 40% of this pH-sensitive increase in nitrite consumption could be blocked by the xanthine oxidoreductase inhibitor allopurinol, whereas lowering the Po(2) sufficiently to desaturate myoglobin accelerated it further. We conclude that rat heart contains several factors capable of catalyzing ischemic nitrite reduction; the most potent is contained within erythrocytes and activated by hypoxia, whereas the remainder includes xanthine oxidoreductase and other pH-sensitive factors endogenous to heart tissue, including deoxymyoglobin.

Effect of simulated postprandial hyperglycemia on coronary blood flow in cardiac transplant recipients.

Patients with diabetes mellitus exhibit postprandial hyperglycemia, systemic oxidative stress, impaired endothelium-dependent, nitric oxide (NO)-mediated coronary artery dilatation, and an increased incidence of coronary events. Whether hyperglycemia causally mediates these associations is unknown. To test the hypothesis that postprandial hyperglycemia acutely impairs coronary endothelial function in humans, we compared the ability of the endothelium-dependent vasodilator acetylcholine to increase conduit coronary diameter (the macrovascular response) and coronary blood flow velocity (the microvascular response) in 12 cardiac transplant recipients without diabetes before and after blood glucose was raised from 6.7 +/- 1.3 mmol/l (121 +/- 24 mg/dl) to 17.8 +/- 1.5 mmol/l (321 +/- 27 mg/dl) for 1 h. Hyperglycemia acutely doubled circulating levels of the oxidation product malondialdehyde, indicating systemic oxidative stress, but did not affect the ability of acetylcholine to dilate conduit coronary segments or accelerate coronary blood flow. We conclude that the oxidative stress associated with a single acute episode of hyperglycemia affects neither acetylcholine-mediated coronary endothelial NO release nor the subsequent bioavailability, metabolism, or action of NO within the coronary circulation of cardiac transplant recipients. These observations imply that the relationship among hyperglycemia, oxidative stress, and coronary endothelial dysfunction is presumably mediated by mechanisms operating over longer periods of time.

Effects of supplemental oxygen administration on coronary blood flow in patients undergoing cardiac catheterization.

Patients with heart disease are frequently treated with supplemental oxygen. Although oxygen can exhibit vasoactive properties in many vascular beds, its effects on the coronary circulation have not been fully characterized. To examine whether supplemental oxygen administration affects coronary blood flow (CBF) in a clinical setting, we measured in 18 patients with stable coronary heart disease the effects of breathing 100% oxygen by face mask for 15 min on CBF (via coronary Doppler flow wire), conduit coronary diameter, CBF response to intracoronary infusion of the endothelium-dependent dilator ACh and to the endothelium-independent dilator adenosine, as well as arterial and coronary venous concentrations of the nitric oxide (NO) metabolites nitrotyrosine, NO(2)(-), and NO(3)(-). Relative to breathing room air, breathing of 100% oxygen increased coronary resistance by approximately 40%, decreased CBF by approximately 30%, increased the appearance of nitrotyrosine in coronary venous plasma, and significantly blunted the CBF response to ACh. Oxygen breathing elicited these changes without affecting the diameter of large-conduit coronary arteries, coronary venous concentrations of NO(2)(-) and NO(3)(-), or the coronary vasodilator response to adenosine. Administering supplemental oxygen to patients undergoing cardiac catheterization substantially increases coronary vascular resistance by a mechanism that may involve oxidative quenching of NO within the coronary microcirculation.

Glucose and insulin management in the post-MI setting.

Despite dramatic advances in the treatment of acute myocardial infarction (AMI) in recent years, patients with diabetes mellitus continue to experience disproportionately high morbidity and mortality. A substantial body of experimental and clinical data suggest that the ability of the heart to augment its energetic metabolism of glucose in the acute setting is critical to survival and functional recovery after AMI. Emerging evidence also suggests that chronic hyperglycemia may predispose to post-AMI ischemia and heart failure via adverse effects on coronary endothelial function and myocardial ultrastructure, energy metabolism, and gene transcription. A strong case can be made for intensive insulin-based control of glycemic level in the AMI patient with diabetes mellitus.

Cardiac catheterization in morbidly obese patients.

The safety and findings of cardiac catheterization and coronary angiography in morbidly obese patients with suspected coronary heart disease (CHD) have not been fully examined in the modern era. From a database of 4,978 patients undergoing diagnostic cardiac catheterization, we identified 110 with morbid obesity (body mass > or = 145 kg and body mass index > or = 40 kg/m(2)). Relative to all the other patients in this database, morbidly obese patients had a lower prevalence of CHD (45% vs. 72%; P < 0.05), reflecting a higher prevalence of false positive noninvasive tests. Overall, noninvasive tests were only 75% sensitive and 39% specific for CHD in this group. Use of radial access (66%) and femoral closure devices (24%) was much more frequent in the morbidly obese cohort. Complications were no more frequent in the morbidly obese group, with major (0 vs. 0.9%) and minor (4.7% vs. 3.5%) adverse outcomes being similar to the rest of the database. We conclude that cardiac catheterization using the radial artery or a femoral closure device is a safe and effective method of evaluating CHD in morbidly obese patients. In contrast, noninvasive testing is frequently not definitive and may be misleading.

Sterile inflammation associated with transradial catheterization and hydrophilic sheaths.

In 1999, we noted the development of inflammation and/or abscesses at the site of radial access in a group of patients. Over a 3-year period, we noted this inflammation in 33 patients out of 2,038 (1.6%) who had catheterization via the radial approach. The radial abscesses occurred in 30 patients out of 1,063 (2.8%) in whom we could confirm the use of a hydrophilic-coated sheath, but in no patient for whom we can document that an uncoated sheath was used. No infectious agent could be implicated, and the time course for the development of the abscess, typically 2 to 3 weeks, seemed long for a bacterial infection. Later patients had biopsies, and granulomatous reactions were seen in most. Additionally, a few of the biopsies showed an amorphous extravascular substance consistent with the catheter coating. All patients had good long-term outcomes.