Hypotension Prediction Index guided Goal Directed therapy and the amount of Hypotension during Major Gynaecologic Oncologic Surgery: a Randomized Controlled clinical Trial.

Intraoperative hypotension (IOH) is associated with increased morbidity and mortality. Hypotension Prediction Index (HPI) is a machine learning derived algorithm that predicts IOH shortly before it occurs. We tested the hypothesis that the application of the HPI in combination with a pre-defined Goal Directed Therapy (GDT) hemodynamic protocol reduces IOH during major gynaecologic oncologic surgery. We enrolled women scheduled for major gynaecologic oncologic surgery under general anesthesia with invasive arterial pressure monitoring. Patients were randomized to a GDT protocol aimed at optimizing stroke volume index (SVI) or hemodynamic management based on HPI guidance in addition to GDT. The primary outcome was the amount of IOH, defined as the timeweighted average (TWA) mean arterial pressure (MAP) < 65 mmHg. Secondary outcome was the TWA-MAP < 65 mmHg during the first 20 min after induction of GA. After exclusion of 10 patients the final analysis included 60 patients (30 in each group). The median (25-75th IQR) TWA-MAP < 65 mmHg was 0.14 (0.04-0.66) mmHg in HPI group versus 0.77 (0.36-1.30) mmHg in Control group, P < 0.001. During the first 20 min after induction of GA, the median TWA-MAP < 65 mmHg was 0.53 (0.06-1.8) mmHg in the HPI group and 2.15 (0.65-4.2) mmHg in the Control group, P = 0.001. Compared to a GDT protocol aimed to SVI optimization, a machine learning-derived algorithm for prediction of IOH combined with a GDT hemodynamic protocol, reduced IOH and hypotension after induction of general anesthesia in patients undergoing major gynaecologic oncologic surgery.Trial registration number: NCT04547491. Date of registration: 10/09/2020.

Personalized Predictive Hemodynamic Management for Gynecologic Oncologic Surgery: Feasibility of Cost-Benefit Derivatives of Digital Medical Devices.

BACKGROUND: Intraoperative hypotension is associated with increased perioperative complications, hospital length of stay (LOS) and healthcare expenditure in gynecologic surgery. We tested the hypothesis that the adoption of a machine learning-based warning algorithm (hypotension prediction index-HPI) might yield an economic advantage, with a reduction in adverse outcomes that outweighs the costs for its implementation as a medical device. METHODS: A retrospective-matched cohort cost-benefit Italian study in gynecologic surgery was conducted. Sixty-six female patients treated with standard goal-directed therapy (GDT) were matched in a 2:1 ratio with thirty-three patients treated with HPI based on ASA status, diagnosis, procedure, surgical duration and age. RESULTS: The most relevant contributor to medical costs was operating room occupation (46%), followed by hospital stay (30%) and medical devices (15%). Patients in the HPI group had EURO 300 greater outlay for medical devices without major differences in total costs (GDT 5425 (3505, 8127), HPI 5227 (4201, 7023) p = 0.697). A pre-specified subgroup analysis of 50% of patients undergoing laparotomic surgery showed similar medical device costs and total costs, with a non-significant saving of EUR 1000 in the HPI group (GDT 8005 (5961, 9679), HPI 7023 (5227, 11,438), p = 0.945). The hospital LOS and intensive care unit stay were similar in the cohorts and subgroups. CONCLUSIONS: Implementation of HPI is associated with a scenario of cost neutrality, with possible economic advantage in high-risk settings.

A Case of Multidisciplinary Approach to Post-Radiotherapy Dilative Cardiomyopathy Undergoing Elective Cesarean Delivery: Anesthetic and Intensive Care Management.

Background: Cardiovascular diseases are the most common non-obstetric cause of maternal death. These cases became more common thanks to the improvement in cardiovascular therapies. A multidisciplinary team is necessary to manage these pregnancies. Case Report: A 32 years old women at the 25th week of gestation for acute heart failure in pre-existing left ventricular dysfunction induced by radio-chemotherapy admitted to the Coronary Unit of IRCCS Policlinico Universitario Agostino Gemelli for worsening of dyspneic symptoms and anuria not responding to diuretic therapy. At the echocardiogram: ejection fraction 30%, enlarged left atrium, systolic pulmonary arterial pressure 38 mmHg, bilateral pleural effusion, bilateral diffused pulmonary B lines. A multidisciplinary team composed by cardiologists, gynecologists, anesthesiologists, cardiac surgeons, neonatologists and bioethicists decided for an elective cesarean delivery at the 27th week of gestation in the hybrid cardio-thoracic operating theater. Anesthesia was provided by combined spinal-epidural technique under invasive continuous hemodynamic monitoring with the Edwards Lifesciences HemoSphere with Hypotension Prediction Index (HPI) and ForeSight technology (Edwards Lifesciences, Irvine, USA) through catheterization of the left radial artery. The femoral arteries were left available for extracorporeal circulation. Continuous norepinephrine infusion was started once liquor was collected in the spinal needle at a 0.1 mcg/kg/minute through a central line and was continued until the end of surgery. Fluid management consisted of a total of 200 ml of crystalloids. HPI values never reached alarm values (maximum value =10). The patient was discharged home on the 5th day after delivery with good hemodynamic compensation. The baby was intubated at birth and then gradually weaned from mechanical ventilation, then discharged.

Impact of maternal lateral tilt on cardiac output during caesarean section under spinal anaesthesia: a prospective observational study.

BACKGROUND: Left uterine displacement (LUD) has been questioned as an effective strategy to prevent aortocaval compression after spinal anesthesia (SA) for cesarean delivery (CD). We tested if LUD has a significant impact on cardiac output (CO) in patients undergoing CD under SA during continuous non-invasive hemodynamic monitoring with Clearsight. METHODS: Forty-six patients were included in the final analysis. We considered 4 timepoints of 5 min each: T1 = baseline with LUD; T2 = baseline without LUD; T3 = after SA with LUD; T4 = after SA without LUD. LUD was then repositioned for CD. The primary outcome was to assess if CO decreased from T3 to T4 of at least 1.0 L/min. We also compared CO between T1 and T2 and other hemodynamic variables: mean, systolic and diastolic blood pressure (respectively MAP, SAP and DAP), heart rate (HR), stroke volume (SV), stroke volume variation (SVV), pulse pressure variation (PPV), contractility (dP/dt), dynamic arterial elastance (Eadyn) at the different timepoints. Data on fetal Apgar scores and umbilical arterial and venous pH were collected. RESULTS: CO did not vary from T3 to T4 (CO mean difference -0.02 L/min [95% CI -0.88 to 0.82; P = 1). No significant variation was registered for any variable at any timepoint. CONCLUSIONS: LUD did not show a significant impact on CO during continuous hemodynamic monitoring after SA for CD. TRIAL REGISTRATION: (retrospectively registered on 03/12/2021) NCT05143684 .

Performance of the Hypotension Prediction Index With Noninvasive Arterial Pressure Waveforms in Awake Cesarean Delivery Patients Under Spinal Anesthesia.

BACKGROUND: Arterial hypotension is common after spinal anesthesia (SA) for cesarean delivery (CD), and to date, there is no definitive method to predict it. The hypotension prediction index (HPI) is an algorithm that uses the arterial waveform to predict early phases of intraoperative hypotension. The aims of this study were to assess the diagnostic ability of HPI working with arterial waveforms detected by ClearSight system in predicting impending hypotension in awake patients, and the agreement of pressure values recorded by ClearSight with conventional noninvasive blood pressure (NIBP) monitoring in patients undergoing CD under SA. METHODS: In this retrospective analysis of pregnant patients scheduled for elective CD under SA, continuous hemodynamic data measured with the ClearSight monitor until delivery were downloaded from an Edwards Lifesciences HemoSphere platform and analyzed. Receiver operating characteristic (ROC) curves were constructed to evaluate the performance of HPI algorithm working on the ClearSight pressure waveform in predicting hypotensive events, defined as mean arterial pressure (MAP) <65 mm Hg for >1 minute. The sensitivity, specificity, positive predictive value, and negative predictive value were computed at the optimal cutpoint, selected as the value that minimizes the difference between sensitivity and specificity. ClearSight MAP values were compared to NIBP MAP values by linear regression and Bland-Altman analysis corrected for repeated measurements. RESULTS: Fifty patients undergoing CD were included in the analysis. Hypotension occurred in 23 patients (48%). Among patients experiencing hypotension, the HPI disclosed 71 alerts. The HPI predicted hypotensive events with a sensitivity of 83% (95% confidence interval [CI], 69-97) and specificity of 83% (95% CI, 70-95) at 3 minutes before the event (area under the curve [AUC] 0.913 [95% CI, 0.837-0.99]); with a sensitivity of 97% (95% CI, 92-100) and specificity of 97% (95% CI, 92-100) at 2 minutes before the event (AUC 0.995 [95% CI, 0.979-1.0]); and with a sensitivity of 100% (95% CI, 100-100) and specificity 100% (95% CI, 100-100) 1 minute before the event (AUC 1.0 [95% CI, 1.0-1.0]). A total of 2280 paired NIBP MAP and ClearSight MAP values were assessed. The mean of the differences between the ClearSight and NIBP assessed using Bland-Altman analysis (±standard deviation [SD]; 95% limits of agreement with respective 95% CI) was -0.97 mm Hg (±4.8; -10.5 [-10.8 to -10.1] to 8.5 [8.1-8.8]). CONCLUSIONS: HPI provides an accurate real time and continuous prediction of impending intraoperative hypotension before its occurrence in awake patients under SA. We found acceptable agreement between ClearSight MAP and NIBP MAP.

Lung ultrasound to monitor the development of pulmonary atelectasis in gynecologic oncologic surgery.

BACKGROUND: Atelectasis formation is considered the major cause of hypoxemia during general anesthesia (GA). Gynecologic oncologic surgery (GOS) often requires pneumoperitoneum and steep bed angulation that further reduce lung compliance by shifting bowels and diaphragm. The aim of our study was to assess the impact of intraoperative variables on lung aeration using lung ultrasound (LUS) score and their correlation with postoperative oxygenation in women undergoing GOS. METHODS: In this prospective observational study 80 patients scheduled for GOS were enrolled. After three minutes pre-oxygenation, propofol-sufentanil-sevoflurane GA and standard mechanical ventilation (MV) were administered (tidal volume of 8 mL/kg of predicted body weight, FiO2 40%, I:E ratio of 1:2 and PEEP 5 cm H2O). A 0-36 LUS score was calculated considering 12 pulmonary areas, and arterial blood gas analysis were performed before GA (T1) and in recovery room (T2). RESULTS: LUS score increased significantly between T1 (1.79±2.39) and T2 (11.08±4.40, ΔLUS=9.29±4.10, P<0.05), mostly in basal and posterior areas. Changes in LUS score correlated significantly with time of MV (r=0.246, P<0.05), cumulative time in TR position (r=0.321, P<0.05) and worsening in oxygenation (ΔPaO2/FiO2, r=-0.260, P<0.05). ΔLUS score significantly correlated with colloid infusion. The linear regression analysis showed that TR time can predict ΔLUS score (F1,78=8.97, P=0.004). No correlation was found with pneumoperitoneum, apnea time at induction and TR angle. CONCLUSIONS: Aeration loss after GOS detected using LUS correlates with TR time, MV time, colloid infusion and worsening in oxygenation.

Lack of soluble circulating cardiodepressant factors in takotsubo cardiomyopathy.

Circulating cardiodepressant factors were found to mediate cardiac dysfunction in patients with sepsis and acute systolic heart failure. To investigate the presence of circulating cardiodepressant factors in patients with Takotsubo Cardiomyopathy (TC), plasma samples were collected from 4 patients with TC, 3 with septic shock, 5 with acute systolic heart failure and 4 healthy controls and injected intraperitoneally in mice. The cardiodepressant effects are measured with transthoracic echocardiography. Plasma injection from control and TC subjects had no effects on left ventricle ejection fraction (LVEF) whereas plasma from the other two groups induced a significant reduction in LVEF. At difference than sepsis and acute heart failure, TC is not characterized by the presence of soluble cardiodepressant factors. Myocardial dysfunction in TC may be mediated by a neurocardiogenic mechanism.

Inflammatory markers in ST-elevation acute myocardial infarction.

After acute myocardial infarction, ventricular remodeling is characterized by changes at the molecular, structural, geometrical and functional level that determine progression to heart failure. Inflammation plays a key role in wound healing and scar formation, affecting ventricular remodeling. Several, rather different, components of the inflammatory response were studied as biomarkers in ST-elevation acute myocardial infarction. Widely available and inexpensive tests, such as leukocyte count at admission, as well as more sophisticated immunoassays provide powerful predictors of adverse outcome in patients with ST-elevation acute myocardial infarction. We review the value of inflammatory markers in ST-elevation acute myocardial infarction and their association with ventricular remodeling, heart failure and sudden death. In conclusion, the use of these biomarkers may identify subjects at greater risk of adverse events and perhaps provide an insight into the mechanisms of disease progression.

Cirrhotic cardiomyopathy in the pre- and post-liver transplantation phase.

Patients with advanced liver cirrhosis may develop a clinical syndrome characterized by a blunted contractile responsiveness to stress and/or altered diastolic relaxation, called "cirrhotic cardiomyopathy." This syndrome, which is initially asymptomatic, is often misdiagnosed due to the presence of symptoms that characterize other disorders present in patients with advanced liver cirrhosis, such as exercise intolerance, fatigue, and dyspnea. Stress and other conditions such as liver transplantation and transjugular intrahepatic portosystemic shunt (TIPS) may unmask this syndrome. Liver transplantation in this group of patients results in a clinical improvement and can be a cure for the cardiomyopathy. However, post-transplant prognosis depends on the identification of cirrhotics with cardiomyopathy in the pre-transplant phase; an early diagnosis of cirrhotic cardiomyopathy in the pre-transplant phase may avoid an acute onset or worsening of cardiac failure after liver transplantation. Since a preserved left ventricular ejection fraction may mask the presence of cirrhotic cardiomyopathy, the use of newer noninvasive diagnostic techniques (i.e. tissue Doppler, myocardial strain) is necessary to identify cirrhotics with this syndrome, in the pre-transplant phase. A pre-transplant treatment of heart failure in cirrhotics with cardiomyopathy improves the quality of life in this phase and reduces the complications during and immediately after liver transplantation. Since specific therapies for cirrhotic cardiomyopathy are lacking, due to the absence of a clear understanding of the pathophysiology of the cardiomyopathy, further research in this field is required.

Effects of Prolastin C (Plasma-Derived Alpha-1 Antitrypsin) on the acute inflammatory response in patients with ST-segment elevation myocardial infarction (from the VCU-alpha 1-RT pilot study).

Alpha-1 antitrypsin (AAT) has broad anti-inflammatory and immunomodulating properties in addition to inhibiting serine proteases. Administration of human plasma-derived AAT is protective in models of acute myocardial infarction in mice. The objective of this study was to determine the safety and tolerability of human plasma-derived AAT and its effects on the acute inflammatory response in non-AAT deficient patients with ST-segment elevation myocardial infarction (STEMI). Ten patients with acute STEMI were enrolled in an open-label, single-arm treatment study of AAT at 60 mg/kg infused intravenously within 12 hours of admission and following standard of care treatment. C-reactive protein (CRP) and plasma AAT levels were determined at admission, 72 hours, and 14 days, and patients were followed clinically for 12 weeks for the occurrence of new onset heart failure, recurrent myocardial infarction, or death. Twenty patients with STEMI enrolled in previous randomized trials with identical inclusion and/or exclusion criteria, but who received placebo, served as historical controls. Prolastin C was well tolerated and there were no in-hospital adverse events. Compared with historical controls, the area under the curve of CRP levels was significantly lower 14 days after admission in the Prolastin C group (75.9 [31.4 to 147.8] vs 205.6 [78.8 to 410.9] mg/l, p = 0.048), primarily due to a significant blunting of the increase occurring between admission and 72 hours (delta CRP +1.7 [0.2 to 9.4] vs +21.1 [3.1 to 38.0] mg/l, p = 0.007). Plasma AAT levels increased from admission (149 [116 to 189]) to 203 ([185 to 225] mg/dl) to 72 hours (p = 0.005). In conclusion, a single administration of Prolastin C in patients with STEMI is well tolerated and is associated with a blunted acute inflammatory response.

Independent roles of the priming and the triggering of the NLRP3 inflammasome in the heart.

AIMS: The NLRP3 inflammasome is activated in the ischaemic heart promoting caspase-1 activation, inflammation, and cell death. Ischaemic injury establishes both a priming signal (transcription of inflammasome components) and a trigger (NLRP3 activation). Whether NLRP3 activation, without priming, induces cardiac dysfunction and/or failure is unknown. The aim of this study was to assess the independent and complementary roles of the priming and the triggering signals in the heart, in the absence of ischaemia or myocardial injury. METHODS AND RESULTS: We used mice with mutant NLRP3 (constitutively active), NLRP3-A350V, under the control of tamoxifen-driven expression of the Cre recombinase (Nlrp3-A350V/CreT mice). The mice were treated for 10 days with tamoxifen before measuring the activity of caspase-1, the effector enzyme in the inflammasome. Tamoxifen treatment induced the inflammasome in the spleen but not in the heart, despite expression of the mutant NLRP3-A350V. The components of the inflammasome were significantly less expressed in the heart compared with the spleen. Subclinical low-dose lipopolysaccharide (LPS; 2 mg/kg) in Nlrp3-A350V/CreT mice induced the expression of the components of the inflammasome (priming), measured using real-time PCR and western blot, leading to the formation of an active inflammasome (caspase-1 activation) in the heart and LV systolic dysfunction while low-dose LPS was insufficient to induce LV systolic dysfunction in wild-type mice (all P < 0.01 for mutant vs. wild-type mice). CONCLUSION: The signalling pathway governing the inflammasome formation in the heart requires a priming signal in order for an active NLRP3 to induce caspase-1 activation and LV dysfunction.

Inflammation and C-reactive protein in atrial fibrillation: cause or effect?

Atrial fibrillation is associated with substantial morbidity and mortality rates. The incompletely understood pathogenesis of this cardiac dysrhythmia makes it difficult to improve approaches to primary and secondary prevention. Evidence has accumulated in regard to a relationship between inflammation and atrial fibrillation. Investigators have correlated the dysrhythmia with myocarditis, pericardiotomy, and C-reactive protein levels, suggesting that inflammation causes atrial fibrillation or participates in its onset and continuation. Conversely, other investigators suggest that atrial fibrillation induces an inflammatory response. In this review, we summarize and critically discuss the nature and clinical role of inflammation and C-reactive protein in atrial fibrillation.

Leukocyte activity in patients with ST-segment elevation acute myocardial infarction treated with anakinra.

Anakinra, the recombinant form of the human interleukin (IL)-1 receptor antagonist, blunts the acute systemic inflammatory response in patients with ST-segment elevation myocardial infarction (STEMI), by determining a fall in peripheral blood leukocyte and plasma C-reactive protein levels. The aim of the present study was to determine the effects of anakinra on the activity of leukocytes measured ex vivo. Blood was collected 72 h after admission in 17 patients enrolled in the Virginia Commonwealth University-Anakirna Remodeling Trial (2) (VCU-ART2) and randomly treated with anakinra (N=7) or placebo (N=10). Whole blood was cultured at 37°C for 24 h to measure spontaneous production of IL-6 or stimulated with Escherichia coli lipopolysaccharide (LPS) for toll-like receptor (TLR)-4 or heat-killed Staphylococcus epidermidis (SE) for TLR-2 activation. The cultures of anakinra-treated patients produced significantly less IL-6 spontaneously (71 pg/mL [27-114]) compared with placebo-treated patients (290 pg/mL [211-617], p=0.005). LPS- or SE-induced IL-6 production, on the other hand, was not statistically different between anakinra-versus placebo-treated patients (344 pg/mL [94-560] versus 370 pg/mL [306-991], p=0.32 for LPS, and 484 pg/mL [77-612] versus 615 pg/mL [413-871], p=0.31 for SE, respectively). IL-1 blockade with anakinra in STEMI patients results in reduced spontaneous leukocyte activity ex vivo without impairing the responsiveness to bacterial stimuli.

Interleukin-1ß blockade improves left ventricular systolic/diastolic function and restores contractility reserve in severe ischemic cardiomyopathy in the mouse.

BACKGROUND: Interleukin-1ß (IL-1ß) modulates the inflammatory response during acute myocardial infarction (AMI) and progression to ischemic cardiomyopathy. We investigated whether blockade of IL-1ß after the onset of the cardiac dysfunction prevented left ventricular (LV) adverse remodeling in a mouse model of anterior nonreperfused AMI. METHODS: Infarct size and LV systolic function were assessed by echocardiography 7 days after coronary artery ligation. Mice with large infarct size and LV ejection fraction (LVEF) <40% were randomly assigned to treatment with a monoclonal antibody directed toward IL-1ß antibody (10 mg/kg IL-1ß-AB) or with a cyclosporine directed antibody (10 mg/kg control-AB). Echocardiogram was repeated after 10 weeks, followed by assessment of contractile reserve using isoproterenol challenge and LV catheterization. RESULTS: After 10 weeks, control-AB-treated mice showed significantly increased LV end-diastolic diameter (+15%, P < 0.001) and decreased LVEF (-18%, P = 0.050). IL-1ß-AB had no significant effect on LV end-diastolic diameter (+10%, P = 0.25 vs. control-AB) but significantly prevented LVEF reduction (+7%, P = 0.031 vs. control-AB), enlargement of the right ventricle (P = 0.024), impairment in myocardial performance index (P = 0.028) and contractile reserve (P = 0.008), and increased LV end-diastolic pressure (P = 0.030). CONCLUSIONS: IL-1ß blockade using a monoclonal antibody in mice with severe LV dysfunction after AMI prevents further deterioration in LV systolic and diastolic function and restores contractile reserve.

Targeting inflammation: impact on atherothrombosis.

Atherothrombosis is a worldwide epidemic accounting for an unacceptable toll of deaths and disabilities. Its pathophysiology is complex and hardly referable to a specific mechanism; however, in the last 20 years, a growing amount of evidence has demonstrated that inflammatory processes play a major role from the very beginning to the ultimate complication of atherothrombosis. These evidences are addressing a growing interest toward anti-inflammatory agents as preventive or curative treatments of atherothrombosis. At present, accumulated data are not conclusive, but strong evidence exists in favor of an anti-inflammatory positive effect for several drugs as statins or renin-angiotensin inhibitors. More conclusive data are expected from ongoing trials directly exploring the role of specific cytokines antagonists.

Increasing specificity of high-sensitivity troponin: new approaches and perspectives in the diagnosis of acute coronary syndromes.

In the past years, new generations of assays to detect cardiac troponin (cTn), called sensitive or high sensitivity troponin (hs-Tn), have been introduced. Progressive improvement in the analytical sensitivity of cTn assays has led to a more rapid diagnosis of acute myocardial infarction (AMI) and improved risk stratification in patients with non ST-elevation acute coronary syndromes (NSTE-ACS) but, at the same time, has introduced the problem of a lower diagnostic specificity. As a matter of fact, hs-Tn assays are able to detect very small increases in the biomarker concentration and therefore result "positive" in a wide range of non-ischemic clinical conditions, acute and chronic, cardiac and extra-cardiac. The reduced specificity of hs-Tn versus the previous generation cTn assays may, therefore, lead to an increased number of inappropriate hospitalizations, i.e. patients with high cTn due to no-ACS conditions, and requires a more careful evaluation, not only on the clinical side, but also on the information that hs-Tn assessment may provide. Several approaches to increase this specificity have been used, but the most promising appear to be the "delta approach", which tries to quantify the relative or absolute change in cTn concentration, and the "age approach", which highlights the need for a different cutoff with a better diagnostic efficiency in the elderly population, often affected by other conditions, different from ACS, that can cause an increased level of cTn.