Michael Broomé

A factor XIIa inhibitory antibody provides thromboprotection in extracorporeal circulation without increasing bleeding risk.

Blocking the enzyme that initiates the intrinsic coagulation pathway protects against thrombosis in bypass systems and does not cause excess bleeding in vivo. When Life-Saving Is Life-Threatening We all need a vacation sometimes. For the heart and lungs, that time can come during surgery (such as cardiopulmonary bypass procedures), in instances of organ failure (for example, in septic patients), or while awaiting a replacement organ for transplantation. When the heart and lungs take time off, oxygenation of the blood needs to occur outside of the body by circulation through a cardiopulmonary bypass system (also called a heart-lung machine). In order to prevent blood clot formation in the extracorporeal circuit, an anticoagulant is added to the system. Anticoagulants block thrombus formation that would occlude the circulation; however, the drugs also interfere with the body’s ability to stop bleeding at the site of injury. Thus, an ideal anticoagulant would only block blood clotting in thrombosis without causing excess bleeding. Now, Larsson et al. describe a new antibody that prevents thrombosis and facilitates blood flow in a specific heart-lung machine without causing bleeding in large animal models. The anticoagulant heparin is used most often during extracorporeal oxygenation and targets multiple components of the blood coagulation cascade that are necessary formation of fibrin—a clotting protein essential for stemming injury-related blood loss. The authors used phage display to identify an antibody that binds to and inhibits the protease activity of factor XIIa (FXIIa), a protein that controls fibrin formation in vitro but does not appear to be required for cessation of bleeding from injury sites. A fully humanized version of the antibody, called 3F7, protected against pathological thrombosis in the extracorporeal bypass system without increasing bleeding from injuries in rabbits. 3F7 had the added benefits of a broad therapeutic range and easy monitoring at the point of care. And because 3F7 doesn’t cause bleeding, it should not require neutralization after surgery and can simply be cleared from the patient’s circulation naturally. Even with optimal heparin treatment, bleeding remains the most common complication of anticoagulation therapy. Additional mechanistic and clinical studies will show whether 3F7—or an optimized version—will be able to give heparin a vacation from facilitating extracorporeal circulation and possibly other scenarios that require safe anticoagulation. Currently used anticoagulants prevent thrombosis but increase bleeding. We show an anticoagulation therapy without bleeding risk based on a plasma protease factor XII function-neutralizing antibody. We screened for antibodies against activated factor XII (FXIIa) using phage display and demonstrated that recombinant fully human antibody 3F7 binds into the FXIIa enzymatic pocket. 3F7 interfered with FXIIa-mediated coagulation, abolished thrombus formation under flow, and blocked experimental thrombosis in mice and rabbits. We adapted an extracorporeal membrane oxygenation (ECMO) cardiopulmonary bypass system used for infant therapy to analyze clinical applicability of 3F7 in rabbits. 3F7 provided thromboprotection as efficiently as heparin, and both drugs prevented fibrin deposition and thrombosis within the extracorporeal circuit. Unlike heparin, 3F7 treatment did not impair the hemostatic capacity and did not increase bleeding from wounds. These data establish that targeting of FXIIa is a safe mode of thromboprotection in bypass systems, and provide a clinically relevant anticoagulation strategy that is not complicated by excess bleeding.

Closed-loop real-time simulation model of hemodynamics and oxygen transport in the cardiovascular system

BackgroundComputer technology enables realistic simulation of cardiovascular physiology. The increasing number of clinical surgical and medical treatment options imposes a need for better understanding of patient-specific pathology and outcome prediction.MethodsA distributed lumped parameter real-time closed-loop model with 26 vascular segments, cardiac modelling with time-varying elastance functions and gradually opening and closing valves, the pericardium, intrathoracic pressure, the atrial and ventricular septum, various pathological states and including oxygen transport has been developed.ResultsModel output is pressure, volume, flow and oxygen saturation from every cardiac and vascular compartment. The model produces relevant clinical output and validation of quantitative data in normal physiology and qualitative directions in simulation of pathological states show good agreement with published data.ConclusionThe results show that it is possible to build a clinically relevant real-time computer simulation model of the normal adult cardiovascular system. It is suggested that understanding qualitative interaction between physiological parameters in health and disease may be improved by using the model, although further model development and validation is needed for quantitative patient-specific outcome prediction.

Pheochromocytoma-Induced Inverted Takotsubo-Like Cardiomyopathy Leading to Cardiogenic Shock Successfully Treated With Extracorporeal Membrane Oxygenation

Pheochromocytoma classically displays a variety of rather benign symptoms, such as headache, palpitations, and sweating, although severe cardiac manifestations have been described. We report a case of pheochromocytoma-induced inverted takotsubo-like cardiomyopathy leading to shock and cardiac arrest successfully treated with extracorporeal membrane oxygenation (ECMO) as a bridge to pharmacological therapy and curative adrenalectomy. A previously healthy 46-year-old woman presented to the emergency department with abdominal pain, dyspnea, nausea, and vomiting. Clinical evaluation revealed cardiorespiratory failure with hypoxia and severe metabolic acidosis. Computed tomography (CT) scan showed pulmonary edema and a left adrenal mass. Transthoracic echocardiography (TTE) displayed severe left ventricular dysfunction with inverted takotsubo contractile pattern. Despite mechanical ventilation and inotropic and vasopressor support, asystolic cardiac arrest ensued. The patient was resuscitated using manual chest compressions followed by venoarterial ECMO. Repeated TTEs demonstrated resolution of the cardiomyopathy within a few days. Laboratory results indicated transient renal and hepatic dysfunction, and CT scan of the brain displayed occipital infarctions. Biochemical testing and radionuclide scintigraphy confirmed a pheochromocytoma. Pharmacological adrenergic blockade was instituted prior to delayed adrenalectomy after which the diagnosis was histopathologically verified. The patient recovered after rehabilitation. We conclude that pheochromocytoma should be considered in patients presenting with unexplained cardiovascular compromise, especially if they display (inverted) takotsubo contractile pattern. Timely, adequate management might involve ECMO as a bridge to pharmacological therapy and curative surgery.

Recirculation during veno-venous extra-corporeal membrane oxygenation – a simulation study

Purpose Veno-venous ECMO is indicated in reversible life-threatening respiratory failure without life-threatening circulatory failure. Recirculation of oxygenated blood in the ECMO circuit decreases efficiency of patient oxygen delivery but is difficult to measure. We seek to identify and quantify some of the factors responsible for recirculation in a simulation model and compare with clinical data. Methods A closed-loop real-time simulation model of the cardiovascular system has been developed. ECMO is simulated with a fixed flow pump 0 to 5 l/min with various cannulation sites – 1) right atrium to inferior vena cava, 2) inferior vena cava to right atrium, and 3) superior+inferior vena cava to right atrium. Simulations are compared to data from a retrospective cohort of 11 consecutive adult veno-venous ECMO patients in our department. Results Recirculation increases with increasing ECMO-flow, decreases with increasing cardiac output, and is highly dependent on choice of cannulation sites. A more peripheral drainage site decreases recirculation substantially. Conclusions Simulations suggest that recirculation is a significant clinical problem in veno-venous ECMO in agreement with clinical data. Due to the difficulties in measuring recirculation and interpretation of the venous oxygen saturation in the ECMO drainage blood, flow settings and cannula positioning should rather be optimized with help of arterial oxygenation parameters. Simulation may be useful in quantification and understanding of recirculation in VV-ECMO.

Experimental extracorporeal membrane oxygenation reduces central venous pressure: an adjunct to control of venous hemorrhage?

Background: Venoarterial ECMO has been utilized in trauma patients to improve oxygenation, particularly in the setting of pulmonary contusions and ARDS. We hypothesized that venoarterial ECMO could reduce the central venous pressure in the trauma scenario, thus, alleviating major venous hemorrhage. Methods: Ten swine were cannulated for venoarterial ECMO. Central venous pressure, mean arterial pressure, portal vein pressure and portal vein flow were recorded at three different flow rates in both a hemodynamic normal state and a setting of increased central venous pressure and right ventricular load, mimicking acute lung injury. Results: Venoarterial ECMO reduced the central venous pressure (CVP sup) from 9.4±0.8 to 7.3±0.7 mmHg (p<0.01) and increased the mean arterial pressure from 103±8 to 119±10 mmHg (p<0.01) in the normal hemodynamic state. In the state of increased right ventricular load, the CVPsup declined from 14.3±0.4 to 11.0±0.7mmHg (p<0.01) and the mean arterial pressure (MAP) increased from 66±6 to 113 ±5 mmHg (p<0.01). Conclusion: Venoarterial ECMO reduces systemic venous pressure while maintaining or improving systemic perfusion in both a normal circulatory state and in the setting of increased right ventricular load associated with acute lung injury. ECMO may be a useful tool in reducing blood loss during major venous hemorrhage in both trauma and selected elective surgery.

Venous Cannula Positioning in Arterial Deoxygenation During Veno-Arterial Extracorporeal Membrane Oxygenation-A Simulation Study and Case Report.

Abstract Venoarterial extracorporeal membrane oxygenation (VA‐ECMO) is indicated in reversible life‐threatening circulatory failure with or without respiratory failure. Arterial desaturation in the upper body is frequently seen in patients with peripheral arterial cannulation and severe respiratory failure. The importance of venous cannula positioning was explored in a computer simulation model and a clinical case was described. A closed‐loop real‐time simulation model has been developed including vascular segments, the heart with valves and pericardium. ECMO was simulated with a fixed flow pump and a selection of clinically relevant venous cannulation sites. A clinical case with no tidal volumes due to pneumonia and an arterial saturation of below 60% in the right hand despite VA‐ECMO flow of 4 L/min was described. The case was compared with simulation data. Changing the venous cannulation site from the inferior to the superior caval vein increased arterial saturation in the right arm from below 60% to above 80% in the patient and from 64 to 81% in the simulation model without changing ECMO flow. The patient survived, was extubated and showed no signs of hypoxic damage. We conclude that venous drainage from the superior caval vein improves upper body arterial saturation during veno‐arterial ECMO as compared with drainage solely from the inferior caval vein in patients with respiratory failure. The results from the simulation model are in agreement with the clinical scenario.

Individualized real-time clinical decision support to monitor cardiac loading during venoarterial ECMO

Veno-arterial extracoporeal membrane oxygenation (VA ECMO) is increasingly used for acute and refractory cardiogenic shock. Yet, in clinical practice, monitoring of cardiac loading conditions during VA ECMO can be cumbersome. To this end, we illustrate the validity and clinical applicability of a real-time cardiovascular computer simulation, which allows to integrate hemodynamics, cardiac dimensions and the corresponding degree of VA ECMO support and ventricular loading in individual patients over time.

Modelling the heart with the atrioventricular plane as a piston unit

Medical imaging and clinical studies have proven that the heart pumps by means of minor outer volume changes and back-and-forth longitudinal movements in the atrioventricular (AV) region. The magnitude of AV-plane displacement has also shown to be a reliable index for diagnosis of heart failure. Despite this, AV-plane displacement is usually omitted from cardiovascular modelling. We present a lumped-parameter cardiac model in which the heart is described as a displacement pump with the AV plane functioning as a piston unit (AV piston). This unit is constructed of different upper and lower areas analogous with the difference in the atrial and ventricular cross-sections. The model output reproduces normal physiology, with a left ventricular pressure in the range of 8-130 mmHg, an atrial pressure of approximatly 9 mmHg, and an arterial pressure change between 75 mmHg and 130 mmHg. In addition, the model reproduces the direction of the main systolic and diastolic movements of the AV piston with realistic velocity magnitude (∼10 cm/s). Moreover, changes in the simulated systolic ventricular-contraction force influence diastolic filling, emphasizing the coupling between cardiac systolic and diastolic functions. The agreement between the simulation and normal physiology highlights the importance of myocardial longitudinal movements and of atrioventricular interactions in cardiac pumping.

Treatment limitations in the era of ECMO

Once relegated to the fringes of medicine, the use of extracorporeal membrane oxygenation (ECMO) in adults with severe respiratory or cardiac failure is now increasing at an extraordinary pace. ECMO is perceived by many as life-saving, and this growth is continuing despite a paucity of widely accepted evidence demon strating benefit. Without such evidence, our obligation to carefully assess the place of this technology in patient care is heightened. In this rapidly evolving area, how do we decide when to offer such high-risk, resource-intensive interventions, and when to withhold or withdraw them? When making complex medical decisions, we should first decide what our interventions might offer in terms of survival and quality of life. We should then engage with our patients and their surrogates, providing them options within a clinical context while, in turn, they provide us with guidance on their values and goals. Together, we decide which life-sustaining options have the potential to achieve these goals. Importantly, clinicians should not abrogate their responsibility to serve as a guide in this process, imparting judgments that are both medically sound and palatable to the patient. Clinicians should avoid the temptation to offer a menu of specific therapeutic options to patients and surrogates, forcing them to make difficult medical decisions without adequate guidance, and opening the door to potentially contradictory and inappropriate treatments. One of the challenges that our health-care systems will face with the increasing use of ECMO will be the inclination to broaden our current code status orders to incorporate ECMO. Many institutions offer orders, such as “do not resuscitate (DNR) and do not intubate (DNI)” as well as “DNR, intubation ok”. What are the implications of including ECMO explicitly in these discussions? When the prognosis is uncertain, is it possible to limit treatment, yet proceed with ECMO? Could a patient have a DNR order but accept ECMO? Although this would seem inconsistent, and in many scenarios be inappropriate, the division of life-sustaining treatments into those we will provide and those we will not, is not without precedent. We might choose to withhold cardiopulmonary resuscitation (CPR), yet initiate other life-sustaining measures such as invasive mechanical ventilation. Clearly, such a decision to proceed with ECMO would have to be made with very specific, potentially achievable goals in mind. On the other hand, CPR could be considered in some patients in whom ECMO would not. The clearest example is the use of ECMO to support the circulation during cardiac arrest, so-called extracorporeal CPR. Circulatory arrest— and therefore circulatory death—might be suspended by the initiation of extracorporeal CPR in an attempt to buy time to reverse the culpable pathology. The provision of conventional CPR, and withholding of extracorporeal CPR, in centres that offer it, is a reasonable approach. Could a patient have a DNI order but accept extracorporeal CO2 removal? A scenario we are very likely to confront—one that has already played out in medical literature—is the use of extracorporeal CO2 removal in patients with acute respiratory failure, in lieu of invasive mechanical ventilation, precisely because the patient has chosen to forgo invasive mechanical ventilation. The promise of extracorporeal CO2 removal is that it is potentially less invasive and lower risk than ECMO. Yet it is not without risks. So long as the patient or surrogate decision makers are well informed of the risks, the degree of invasiveness that they choose to tolerate is a personal decision. However, we might find ourselves wrestling with additional issues if we choose this route. When a patient with an acute exacerbation of advanced chronic obstructive pulmonary disease, who is failing to respond to non-invasive ventilation, simultaneously chooses extracorporeal CO2 removal along with a DNI order, what happens if she becomes stable and comfortable on extracorporeal CO2 removal but cannot be weaned from it? Different from invasive mechanical ventilation, dependence on extracorporeal CO2 removal currently confines the patient to an intensive care unit (ICU). What options exist at that point? Continuation of extracorporeal CO2 removal until it fails to support life could be the default for many. Invasive mechanical ventilation and tracheostomy would allow continued survival outside the ICU, but might not be consistent with the patient’s wishes. Finally, withdrawal of support or transitioning to comfort care measures might be preferable. This potential unintended consequence, and the patient’s preferences for how to approach the situation, should ideally be discussed before extracorporeal CO2 removal is underway. More provocative still is the notion that ECMO is now a special class of device requiring us to delineate when we would and would not initiate it when discussing goals †Participants listed in the appendix

Contribution of the Arterial System and the Heart to Blood Pressure during Normal Aging – A Simulation Study

During aging, systolic blood pressure continuously increases over time, whereas diastolic pressure first increases and then slightly decreases after middle age. These pressure changes are usually explained by changes of the arterial system alone (increase in arterial stiffness and vascular resistance). However, we hypothesise that the heart contributes to the age-related blood pressure progression as well. In the present study we quantified the blood pressure changes in normal aging by using a Windkessel model for the arterial system and the time-varying elastance model for the heart, and compared the simulation results with data from the Framingham Heart Study. Parameters representing arterial changes (resistance and stiffness) during aging were based on literature values, whereas parameters representing cardiac changes were computed through physiological rules (compensated hypertrophy and preservation of end-diastolic volume). When taking into account arterial changes only, the systolic and diastolic pressure did not agree well with the population data. Between 20 and 80 years, systolic pressure increased from 100 to 122 mmHg, and diastolic pressure decreased from 76 to 55 mmHg. When taking cardiac adaptations into account as well, systolic and diastolic pressure increased from 100 to 151 mmHg and decreased from 76 to 69 mmHg, respectively. Our results show that not only the arterial system, but also the heart, contributes to the changes in blood pressure during aging. The changes in arterial properties initiate a systolic pressure increase, which in turn initiates a cardiac remodelling process that further augments systolic pressure and mitigates the decrease in diastolic pressure.