Clinical course and challenging management of early COVID-19 infection after heart transplantation: case report of two patients.

BACKGROUND: There are limited data on Coronavirus disease 2019 (COVID-19) in solid organ transplant patients, especially in heart transplant recipients, with only a few case reports and case series described so far. Heart transplant recipients may be at particular high risk due to their comorbidities and immunosuppressed state. CASE PRESENTATION: This report describes the clinical course and the challenging management of early COVID-19 infection in two heart transplant recipients who tested positive for the SARS-CoV-2 virus in the perioperative period of the transplant procedure. The two patients developed a severe form of the disease and ultimately died despite the initiation of an antiviral monotherapy with hydroxychloroquine coupled with the interruption of mycophenolate mofetil. CONCLUSIONS: These two cases illustrate the severity and poor prognosis of COVID-19 in the perioperative period of a heart transplant. Thorough screening of donors and recipients is mandatory, and the issue of asymptomatic carriers needs to be addressed.

Extracorporeal CO2 removal and regional citrate anticoagulation in an experimental model of hypercapnic acidosis.

Low flow extracorporeal veno-venous CO2 removal (ECCO2 R) therapy is used to remove CO2 while reducing ventilation intensity. However, the use of this technique is limited because efficiency of CO2 removal and potential beneficial effects on pulmonary hemodynamics are not precisely established. Moreover, this technique requires anticoagulation that may induce severe complications in critically ill patients. Therefore, our study aimed at determining precise efficiency of CO2 extraction and its effects on right ventricular (RV) afterload, and comparing regional anticoagulation with citrate to systemic heparin anticoagulation during ECCO2 R. This study was performed in an experimental model of severe hypercapnic acidosis performed in two groups of three pigs. In the first group (heparin group), pigs were anticoagulated with a standard protocol of unfractionated heparin while citrate was used for ECCO2 R device anticoagulation in the second group (citrate group). After sedation, analgesia and endotracheal intubation, pigs were connected to a volume-cycled ventilator. Severe hypercapnic acidosis was obtained by reducing tidal volume by 60%. ECCO2 R was started in both groups when arterial pH was lower than 7.2. Pump Assisted Lung Protection (PALP, Maquet, Rastatt, Germany) system was used to remove CO2 . CO2 extraction, arterial pH, PaCO2 as well as systemic and pulmonary hemodynamic were continuously followed. Mean arterial pH was normalized to 7.37 ± 1.4 at an extracorporeal blood flow of 400 mL/min, coming from 7.11 ± 1.3. RV end-systolic pressure increased by over 30% during acute hypercapnic acidosis and was normalized in parallel with CO2 removal. CO2 extraction was not significantly increased in citrate group as compared to heparin group. Mean ionized calcium and MAP were significantly lower in the citrate group than in the heparin group during ECCO2 R (1.03 ± 0.20 vs. 1.33 ± 0.19 and 57 ± 14 vs. 68 ± 15 mm Hg, respectively). ECCO2 R was highly efficient to normalize pH and PaCO2 and to reduce RV afterload resulting from hypercapnic acidosis. Regional anticoagulation with citrate solution was as effective as standard heparin anticoagulation but did not improve CO2 removal and lead to more hypocalcemia and hypotension.

Prevention of ventilator-associated pneumonia and ventilator-associated conditions: a randomized controlled trial with subglottic secretion suctioning.

OBJECTIVES: Ventilator-associated pneumonia diagnosis remains a debatable topic. New definitions of ventilator-associated conditions involving worsening oxygenation have been recently proposed to make surveillance of events possibly linked to ventilator-associated pneumonia as objective as possible. The objective of the study was to confirm the effect of subglottic secretion suctioning on ventilator-associated pneumonia prevalence and to assess its concomitant impact on ventilator-associated conditions and antibiotic use. DESIGN: Randomized controlled clinical trial conducted in five ICUs of the same hospital. PATIENTS: Three hundred fifty-two adult patients intubated with a tracheal tube allowing subglottic secretion suctioning were randomly assigned to undergo suctioning (n = 170, group 1) or not (n = 182, group 2). MAIN RESULTS: During ventilation, microbiologically confirmed ventilator-associated pneumonia occurred in 15 patients (8.8%) of group 1 and 32 patients (17.6%) of group 2 (p = 0.018). In terms of ventilatory days, ventilator-associated pneumonia rates were 9.6 of 1,000 ventilatory days and 19.8 of 1,000 ventilatory days, respectively (p = 0.0076). Ventilator-associated condition prevalence was 21.8% in group 1 and 22.5% in group 2 (p = 0.84). Among the 47 patients with ventilator-associated pneumonia, 25 (58.2%) experienced a ventilator-associated condition. Neither length of ICU stay nor mortality differed between groups; only ventilator-associated condition was associated with increased mortality. The total number of antibiotic days was 1,696 in group 1, representing 61.6% of the 2,754 ICU days, and 1,965 in group 2, representing 68.5% of the 2,868 ICU days (p < 0.0001). CONCLUSIONS: Subglottic secretion suctioning resulted in a significant reduction of ventilator-associated pneumonia prevalence associated with a significant decrease in antibiotic use. By contrast, ventilator-associated condition occurrence did not differ between groups and appeared more related to other medical features than ventilator-associated pneumonia.

Update on the role of extracorporeal CO2 removal as an adjunct to mechanical ventilation in ARDS.

This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2015 and co-published as a series in Critical Care. Other articles in the series can be found online at http://ccforum.com/series/annualupdate2015. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901.

Procalcitonin usefulness for the initiation of antibiotic treatment in intensive care unit patients.

OBJECTIVES: To test the usefulness of procalcitonin serum level for the reduction of antibiotic consumption in intensive care unit patients. DESIGN: Single-center, prospective, randomized controlled study. SETTING: Five intensive care units from a tertiary teaching hospital. PATIENTS: All consecutive adult patients hospitalized for >48 hrs in the intensive care unit during a 9-month period. INTERVENTIONS: Procalcitonin serum level was obtained for all consecutive patients suspected of developing infection either on admission or during intensive care unit stay. The use of antibiotics was more or less strongly discouraged or recommended according to the Muller classification. Patients were randomized into two groups: one using the procalcitonin results (procalcitonin group) and one being blinded to the procalcitonin results (control group). The primary end point was the reduction of antibiotic use expressed as a proportion of treatment days and of daily defined dose per 100 intensive care unit days using a procalcitonin-guided approach. Secondary end points included: a posteriori assessment of the accuracy of the infectious diagnosis when using procalcitonin in the intensive care unit and of the diagnostic concordance between the intensive care unit physician and the infectious-disease specialist. MEASUREMENTS AND MAIN RESULTS: There were 258 patients in the procalcitonin group and 251 patients in the control group. A significantly higher amount of withheld treatment was observed in the procalcitonin group of patients classified by the intensive care unit clinicians as having possible infection. This, however, did not result in a reduction of antibiotic consumption. The treatment days represented 62.6±34.4% and 57.7±34.4% of the intensive care unit stays in the procalcitonin and control groups, respectively (p=.11). According to the infectious-disease specialist, 33.8% of the cases in which no infection was confirmed, had a procalcitonin value>1µg/L and 14.9% of the cases with confirmed infection had procalcitonin levels<0.25 µg/L. The ability of procalcitonin to differentiate between certain or probable infection and possible or no infection, upon initiation of antibiotic treatment was low, as confirmed by the receiving operating curve analysis (area under the curve=0.69). Finally, procalcitonin did not help improve concordance between the diagnostic confidence of the infectious-disease specialist and the ICU physician. CONCLUSIONS: Procalcitonin measuring for the initiation of antimicrobials did not appear to be helpful in a strategy aiming at decreasing the antibiotic consumption in intensive care unit patients.

Arterial dP/dtmax accurately reflects left ventricular contractility during shock when adequate vascular filling is achieved.

BACKGROUND: Peak first derivative of femoral artery pressure (arterial dP/dtmax) derived from fluid-filled catheter remains questionable to assess left ventricular (LV) contractility during shock. The aim of this study was to test if arterial dP/dtmax is reliable for assessing LV contractility during various hemodynamic conditions such as endotoxin-induced shock and catecholamine infusion. METHODS: Ventricular pressure-volume data obtained with a conductance catheter and invasive arterial pressure obtained with a fluid-filled catheter were continuously recorded in 6 anaesthetized and mechanically ventilated pigs. After a stabilization period, endotoxin was infused to induce shock. Catecholamines were transiently administrated during shock. Arterial dP/dtmax was compared to end-systolic elastance (Ees), the gold standard method for assessing LV contractility. RESULTS: Endotoxin-induced shock and catecholamine infusion lead to significant variations in LV contractility. Overall, significant correlation (r=0.51; p<0.001) but low agreement between the two methods were observed. However, a far better correlation with a good agreement were observed when positive-pressure ventilation induced an arterial pulse pressure variation (PPV)≤11% (r=0.77; p<0.001). CONCLUSION: While arterial dP/dtmax and Ees were significantly correlated during various hemodynamic conditions, arterial dP/dtmax was more accurate for assessing LV contractility when adequate vascular filling, defined as PPV≤11%, was achieved.

Automatized lung disease quantification in patients with COVID-19 as a predictive tool to assess hospitalization severity.

The pandemic of COVID-19 led to a dramatic situation in hospitals, where staff had to deal with a huge number of patients in respiratory distress. To alleviate the workload of radiologists, we implemented an artificial intelligence (AI) - based analysis named CACOVID-CT, to automatically assess disease severity on chest CT scans obtained from those patients. We retrospectively studied CT scans obtained from 476 patients admitted at the University Hospital of Liege with a COVID-19 disease. We quantified the percentage of COVID-19 affected lung area (% AA) and the CT severity score (total CT-SS). These quantitative measurements were used to investigate the overall prognosis and patient outcome: hospital length of stay (LOS), ICU admission, ICU LOS, mechanical ventilation, and in-hospital death. Both CT-SS and % AA were highly correlated with the hospital LOS, the risk of ICU admission, the risk of mechanical ventilation and the risk of in-hospital death. Thus, CAD4COVID-CT analysis proved to be a useful tool in detecting patients with higher hospitalization severity risk. It will help for management of the patients flow. The software measured the extent of lung damage with great efficiency, thus relieving the workload of radiologists.

A preliminary cost-effectiveness analysis of lung protective ventilation with extra corporeal carbon dioxide removal (ECCO2R) in the management of acute respiratory distress syndrome (ARDS).

BACKGROUND: Mechanical ventilation (MV) is the cornerstone in the management of the acute respiratory distress syndrome (ARDS). Recent research suggests that decreasing the intensity of MV using lung protective ventilation (LPV) with lower tidal volume (Vt) and driving pressure (∆P) could improve survival. Extra-corporal CO2 removal (ECCO2R) precisely enables LPV by allowing lower Vt, ∆P and mechanical power while maintaining PaCO2 within a physiologic range. This study evaluates the potential cost-effectiveness of ECCO2R-enabled LPV in France. METHODS: We modelled the distribution over time of ventilated ARDS patients across 3 health-states (alive & ventilated, alive & weaned from ventilation, dead). We compared the outcomes of 3 strategies: MV (no ECCO2R), LPV (ECCO2R when PaCO2 > 55 mmHg) and Ultra-LPV (ECCO2R for all). Patients characteristics, ventilation settings, survival and lengths of stay were derived from a large ARDS epidemiology study. Survival benefits associated with lower ∆P were taken from the analysis of more than 3000 patients enrolled in 9 randomized trials. Health outcomes were expressed in quality-adjusted life years (QALYs). Incremental cost-effectiveness ratios (ICERs) were computed with both Day 60 cost and Lifetime cost. RESULTS: Both LPV and ULPV as enabled by ECCO2R provided favorable results at Day 60 as compared to MV. Survival rates were increased with the protective strategies, notably with ULPV that provided even more manifest benefits as compared to MV. LPV and ULPV produced +0.162 and + 0.627 incremental QALYs as compared to MV, respectively. LPV and ULPV costs were augmented because of their survival benefits. Nonetheless, ICERs of LPV and ULPV vs. MV were all well below the €50,000 threshold. ULPV also presented with favorable ICERs as compared to LPV (i.e. less than €25,000/QALY). CONCLUSIONS: ECCO2R-enabled LPV strategies might provide cost-effective survival benefit. Additional data from interventional and observational studies are needed to support this preliminary model-based analysis.

Feasibility of extracorporeal membrane oxygenation cardiopulmonary resuscitation by low volume centers in Belgium.

OBJECTIVE: To assess the feasibility of delivering extracorporeal cardiopulmonary resuscitation (ECPR) in refractory out-of-hospital cardiac arrests (OHCA) by low volume extracorporeal membrane oxygenation (ECMO) centers and to explore pre-ECPR predictors of survival. METHODS: Between 2016 and 2020, we studied 21 ECPR patients admitted in 2 tertiary ECMO centers in Liège, Belgium. Our ECPR protocol was based on 6 prehospital criteria (no flow < 3 minutes, low flow < 60 minutes, initial shockable rhythm, end-tidal CO2 > 15 mmHg, age < 65 years, and absence of comorbidities). A dedicated training, prehospital checklist and call number for 24/7 ECMO team assistance were implemented. Hemodynamics and blood gases on admission also were assessed. RESULTS: Twenty-one (28%) out of 75 refractory OHCA patients referred were treated by ECPR, with a hospital survival rate of 43% (n = 9/21), comparable to ECPR results from the international extracorporeal life support organization registry. Transient return of spontaneous circulation before ECPR (89% in survivors vs 17% in non-survivors, P = 0.002) and higher initial serum bicarbonate (med [P25-P75] 14.0 [10.6-15.2] vs 7.5 [3.7-10.5] mmol/L, P = 0.019) or lower initial base deficit (14.9 [11.9-18.2] vs 21.6 [17.9-28.9] mmol/L, P = 0.039) were associated with a more favorable outcome. CONCLUSION: In low volume ECMO centers, the implementation of a specific ECPR protocol for refractory OHCA patients is feasible and provides potential clinical benefit. Highly selective inclusion criteria seem essential to select candidates for ECPR. Initial serum bicarbonate and base deficit integrating cumulative cell failure may be relevant pre-ECMO prognostic factors and require larger-scale evaluation.

Model-Based Weaning Tests for VA-ECLS Therapy.

Venoarterial extracorporeal life support (VA-ECLS) is used in ICUs (intensive care units) for the most extreme presentations of acute and severe cardiogenic shock, and one of the main issues the clinicians have to deal with is the weaning from VA-ECLS. In this study, a patient-specific model of the cardiovascular system connected to a VA-ECLS is built to improve the understanding of this complex system. Pig experiments are performed to validate the model, and the results are quite promising since the mean difference between experimental data and simulation is smaller than 5% for all the hemodynamic quantities. It is also a major objective of this paper to provide a proof-of-concept analysis that model-based approaches could improve the weaning strategy for VA-ECLS therapy.

STAR-Liège Clinical Trial Interim Results: Safe and Effective Glycemic Control for All.

While the benefits of glycemic control for critically ill patients are increasingly demonstrated, the ability to deliver safe, effective control to intermediate target ranges is widely debated due to the increased risk of hypoglycemia. This study analyzes interim clinical trial results of the fully computerized model-based Stochastic TARgeted (STAR) glycemic control framework at the University Hospital of Liège, Belgium. Patients with dysglycemia were randomly assigned to the full version of STAR, modulating both insulin and nutrition inputs, or STAR-IO, an insulin only version of STAR. Both arms target the normoglycemic 80-145 mg/dL (4.4-8.0 mmol/L) band. Results are further compared to retrospective data from 20 patients under the standard unit protocol targeting a higher 100-150 mg/dL (5.6-8.3 mmol/L) band. Much higher time in target band is provided under the full version of STAR, with similar safety and significantly lower incidence of mild hyperglycemia (blood glucose > 145 mg/dL or 8.0 mmol/L) and severe hyperglycemia (blood glucose > 180 mg/dL or 10.0 mmol/L). As a result, lower median blood glucose levels are safely and consistently achieved with lower glycemic variability, suggesting STAR's potential to improve clinical outcomes. These interim results show the possibility to achieve safe, effective control for all patients using STAR, and suggest glycemic control to lower targets could be beneficial.

Comparison of functional residual capacity and static compliance of the respiratory system during a positive end-expiratory pressure (PEEP) ramp procedure in an experimental model of acute respiratory distress syndrome.

INTRODUCTION: Functional residual capacity (FRC) measurement is now available on new ventilators as an automated procedure. We compared FRC, static thoracopulmonary compliance (Crs) and PaO2 evolution in an experimental model of acute respiratory distress syndrome (ARDS) during a reversed, sequential ramp procedure of positive end-expiratory pressure (PEEP) changes to investigate the potential interest of combined FRC and Crs measurement in such a pathologic state. METHODS: ARDS was induced by oleic acid injection in six anesthetised pigs. FRC and Crs were measured, and arterial blood samples were taken after induction of ARDS during a sequential ramp change of PEEP from 20 cm H2O to 0 cm H2O by steps of 5 cm H2O. RESULTS: ARDS was responsible for significant decreases in FRC, Crs and PaO2 values. During ARDS, 20 cm H2O of PEEP was associated with FRC values that increased from 6.2 +/- 1.3 to 19.7 +/- 2.9 ml/kg and a significant improvement in PaO2. The maximal value of Crs was reached at a PEEP of 15 cm H2O, and the maximal value of FRC at a PEEP of 20 cm H2O. From a PEEP value of 15 to 0 cm H2O, FRC and Crs decreased progressively. CONCLUSION: Our results indicate that combined FRC and Crs measurements may help to identify the optimal level of PEEP. Indeed, by taking into account the value of both parameters during a sequential ramp change of PEEP from 20 cm H2O to 0 cm H2O by steps of 5 cm H2O, the end of overdistension may be identified by an increase in Crs and the start of derecruitment by an abrupt decrease in FRC.

Mathematical modeling of extracorporeal CO2 removal therapy : A validation carried out on ten pigs.

The extracorporeal CO2 removal device (ECCO2RD) is used in clinics to treat patients suffering from respiratory failures like acute respiratory distress syndrome (ARDS) or chronic obstructive pulmonary disease (COPD). The aim of this device is to decarboxylate blood externally with low blood flow. A mathematical model is proposed to describe protective ventilation, ARDS, and an extracorporeal CO2 removal therapy (ECCO2RT). The simulations are compared with experimental data carried out on ten pigs. The results show a good agreement between the mathematical simulations and the experimental data, which provides a nice validation of the model. This model is thus able to predict the decrease of PCO2 during ECCO2RT for different blood flows across the extracorporeal lung support.

Ejection Fraction May Not Reflect Contractility: Example in Veno-Arterial Extracorporeal Membrane Oxygenation for Heart Failure.

Precise assessment of left ventricular (LV) contractility during veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support is crucial. However, changes in loading conditions may mask changes in LV function when assessed with load-dependent parameters. We compared end-systolic elastance (Ees, mm Hg/ml), the reference load-independent parameter of LV contractility, with LV ejection fraction (LVEF) in two patients. The first patient was a 54-year-old patient supported with femoro-femoral VA-ECMO for a cardiogenic shock. Afterload was calculated by using arterial elastance (Ea, mm Hg/ml). Although Ees near doubled from day 0 to day 3, no significant change was observed in LVEF. The second patient was a 61-year-old patient supported with femoro-femoral VA-ECMO for severe heart failure complicated with sepsis. We retrospectively showed that discrepancy between LVEF and Ees resulted from changes in LV-arterial coupling. We concluded that LVEF may be misleading in the assessment of LV function during VA-ECMO for heart failure.

Pre-ejection period, the reason why the electrocardiogram Q-wave is an unreliable indicator of pulse wave initialization.

OBJECTIVE: Pulse wave velocity measurements are an indicator of arterial stiffness and possible cardiovascular dysfunction. It is usually calculated by measuring the pulse transit time (PTT) over a known distance through the arteries. In animal studies, reliable PTT measures can be obtained using two pressure catheters. However, such direct, invasive methods are undesirable in clinical settings. A less invasive alternative measure of PTT is pulse arrival time (PAT), the time between the Q-wave of an electrocardiogram (ECG) and the arrival of the foot of the beats pressure waveform at one pressure catheter. Since the Q-wave signifies the start of ventricular contraction, PAT includes the pre-ejection period (PEP), a time where no blood is ejected. Thus, inter- or intra- subject variation in PEP could result in poor correlation between pulse arrival time (PAT) and the desired pulse transit time (PTT). APPROACH: This study looks at the relationship between PAT and PTT, over a range of common critical care therapies and determines the effect of PEP on PAT as a possible surrogate of PTT in a critical care environment. The analysis uses data from five porcine experiments, where ECG, aortic arch and abdominal aortic pressure were measured simultaneously, over a range of induced hemodynamic conditions. RESULTS: The resulting correlations of PAT verse PTT varied within pigs and across interventions (r 2 = 0.32-0.69), and across pigs (r 2 = 0.05-0.60). Variability was due to three main causes. First, the interventions themselves effect PEP and PTT differently, second, pig specific response to the interventions, and third, inter- and intra- pig variability in PEP, independent of PTT. SIGNIFICANCE: The overall analysis shows PAT is an unreliable measure of PTT and a poor surrogate under clinical interventions common in a critical care setting, due to intra- and inter- subject variability in PEP.

Minimally invasive estimation of ventricular dead space volume through use of Frank-Starling curves.

This paper develops a means of more easily and less invasively estimating ventricular dead space volume (Vd), an important, but difficult to measure physiological parameter. Vd represents a subject and condition dependent portion of measured ventricular volume that is not actively participating in ventricular function. It is employed in models based on the time varying elastance concept, which see widespread use in haemodynamic studies, and may have direct diagnostic use. The proposed method involves linear extrapolation of a Frank-Starling curve (stroke volume vs end-diastolic volume) and its end-systolic equivalent (stroke volume vs end-systolic volume), developed across normal clinical procedures such as recruitment manoeuvres, to their point of intersection with the y-axis (where stroke volume is 0) to determine Vd. To demonstrate the broad applicability of the method, it was validated across a cohort of six sedated and anaesthetised male Pietrain pigs, encompassing a variety of cardiac states from healthy baseline behaviour to circulatory failure due to septic shock induced by endotoxin infusion. Linear extrapolation of the curves was supported by strong linear correlation coefficients of R = 0.78 and R = 0.80 average for pre- and post- endotoxin infusion respectively, as well as good agreement between the two linearly extrapolated y-intercepts (Vd) for each subject (no more than 7.8% variation). Method validity was further supported by the physiologically reasonable Vd values produced, equivalent to 44.3-53.1% and 49.3-82.6% of baseline end-systolic volume before and after endotoxin infusion respectively. This method has the potential to allow Vd to be estimated without a particularly demanding, specialised protocol in an experimental environment. Further, due to the common use of both mechanical ventilation and recruitment manoeuvres in intensive care, this method, subject to the availability of multi-beat echocardiography, has the potential to allow for estimation of Vd in a clinical environment.

Effects of BM-573, a thromboxane A2 modulator on systemic hemodynamics perturbations induced by U-46619 in the pig.

The aim of our study was to evaluate the effects of thromboxane A2 (TXA2) agonist, U-46619, on systemic circulatory parameters in the pigs before and after administration of a novel TXA2 receptor antagonist and synthase inhibitor (BM-573). Twelve anesthetized pigs were randomly assigned in two groups: in Ago group (n=6), the animals received six consecutive injections of U-46619 at 30 min interval, while in Anta group (n=6) they received an increasing dosage regimen of BM-573 10 min before each U-46619 injection. The effects of each dose of BM-573 on ex vivo platelet aggregation induced by arachidonic acid, collagen or ADP were also evaluated. Vascular properties such as characteristic impedance, peripheral resistance, compliance, arterial elastance were estimated using a windkessel model. Intravenous injections of 0.500 mg/ml of BM-573 and higher doses resulted in a complete inhibition of platelet aggregation induced by arachidonic acid. In the same conditions, BM-573 completely blocked the increase of arterial elastance, and stabilized both mean aortic blood pressure and mean systemic blood flow. In conclusion, BM-573 could therefore be a promising therapeutic approach in pathophysiological states where TXA2 plays a main role in the increase of vascular resistance like in pathologies such as systemic hypertension.