By Dr. Phillip P. Chan

Heart disease shows no signs of slowing down as the leading cause of death worldwide, driven by the aging baby boomer generation, epidemics in obesity and diabetes, high blood pressure, smoking and unhealthy diets and lifestyles. Blocked coronary arteries, diseased heart valves, aortic aneurysms and dissections, and heart failure are just some of the reasons that 1.5 million people undergo open heart surgery each year, with a half million annually in the U.S. alone.

But the routineness of cardiac surgery belies its great technical complexity. To operate on the heart, the chest cavity is “cracked” open and the heart is then exposed and stopped. To keep the patient alive during surgery, the blood is diverted through a heart-lung machine that oxygenates and pumps blood to the rest of the body, in a process called cardiopulmonary bypass (CPB).



Then, over the course of many hours, cardiac surgeons often combine multiple surgical procedures such as valve replacement, coronary artery bypass grafting (CABG), aortic reconstruction and congenital defect repair to safely correct as many critical problems as they can in order to avoid future surgeries. Unfortunately, high-risk, complex cardiac surgery and long CPB times can generate a host of inflammatory toxins that can directly injure vital organs and contribute to serious postoperative complications such as acute kidney injury, failure to wean off of mechanical ventilation, circulatory collapse, risk of stroke and even death.

For example, patients undergoing aortic surgery have a 17 percent incidence of acute respiratory distress syndrome, one of the most severe forms of lung injury that can be fatal in up to 80 percent of cases following cardiac surgery. And up to 30 percent of cardiac surgery patients develop significant kidney injury, 1 to 2 percent of whom will require dialysis, increasing the risk of death eightfold. To avoid these dangerous complications, it is important to first understand how this inflammation occurs in cardiac surgery and what surgeons can do to prevent and treat it.

What happens during open-heart surgery?
Cardiac surgery generates significant inflammation that is directly proportional to the length and complexity of the procedure. For example, standard CABG does not involve cutting into the heart, has relatively short CPB times, and consequently, does not cause significant inflammation. However, more invasive procedures such as valve replacement and aortic reconstruction generate significant inflammation, putting patients at higher risk of latent organ failure and serious postoperative complications.

Of the various inflammatory mediators that are generated during cardiac surgery, plasma free hemoglobin is one of the primary offenders. Hemoglobin, the oxygen-carrying component of red blood cells, is generally non-toxic when contained inside the red blood cell. But when these cells get damaged and hemolyze, due to shear forces caused by high blood flow or suctioning of blood from the surgical field under vacuum, hemoglobin is released into the bloodstream where it can cause toxic oxygen radical damage as well as scavenge nitric oxide, the body’s most important vasodilator, from blood. This can lead to the damage and constriction of blood vessels throughout the body, leading to decreased blood flow and increased risk of ischemia to vital organs, increased resistance that the recovering heart must work hard to pump against, and a significantly increased risk of organ injury and organ failure.

Also complicating open heart surgery outcomes is the activation of complement, a family of immune system components that normally helps to fight infection, but when abnormally activated — as through blood contact with the foreign surfaces of the CPB circuit — it can cause widespread tissue and organ injury.

Cytokines round out the top three classes of inflammatory mediators. Secreted by immune cells in response to injury or infection, more than 100 different cytokines orchestrate the body’s immune response. Overproduction can lead to a “cytokine storm” that can cause widespread inflammation, capillary leak syndrome and direct tissue injury, resulting in organ failure in the postoperative period.

Battling inflammation
Uncontrolled inflammation and perioperative complications increase the risk of morbidity and mortality following cardiac surgery. Interventions that can control this inflammation that are administered before, during or after surgery may ultimately improve safety and long-term outcomes. The following represents some past, present and future strategies to achieve this goal. The use of anti-inflammatory or immunosuppressive drugs represents the first therapeutic category.

For example, corticosteroids such as methylprednisolone have been evaluated at high doses before and during heart surgery to reduce the risk of the inflammatory response. However, meta- analyses of published studies are mixed. Some show evidence that corticosteroids reduce the risk of death and reduce hospital stays, while others show no significant advantage of using corticosteroids for heart surgery.

Optimizing surgical conditions represents another viable strategy. For example, cardio-protective anesthetics such as desflurane, isoflurane and sevoflurane have been evaluated in the past as a means to protect the heart during and after surgery by a variety of mechanisms, including helping to reduce cardiac ischemia and reperfusion injury and to control inflammation.

An improved CPB design called minimized extracorporeal circulation (MECC) is another innovation in cardiac surgery. MECC combines shortened blood lines coated with heparin and other techniques designed to minimize blood contact with air and the blood circuit — known triggers for complement activation and cytokine release. MECC has been commercially available for nearly two decades and has been adopted by many centers. Although MECC has not demonstrated improved mortality compared to regular CPB, it has been associated in some studies with a reduction in adverse events such as stroke and the need for vasopressors as well as faster ventilator weaning and shorter ICU stays.

Another current and future strategy is the direct removal of free hemoglobin, cytokines, activated complement and other substances from whole blood during CPB. In the past, this was not technically possible, but led to the intraoperative use of leukoreduction filters that tried to indirectly lower cytokines by reducing circulating leukocytes that produced them.

A more advanced blood purification technology called CytoSorb, approved in the European Union, has been used to directly and safely reduce these inflammatory mediators in more than 4,000 open heart surgeries. CytoSorb is a hemoperfusion cartridge filled with hemocompatible, porous polymer beads the size of a grain of salt that rapidly reduce substances from blood using size exclusion, pore capture and adsorption. It is used during CPB and installs directly into a bypass circuit (post-pump to venous reservoir) at approximately a tenth of the blood flow of the main blood circuit. In small, randomized, controlled trials, CytoSorb has been used safely in mild to high-risk cardiac surgery patients, reducing cytokines, free hemoglobin and activated complement C3a and C5a, while leading to decreased sterna wound infections and reduced ICU times.

A large-scale U.S. randomized, controlled trial called REFRESH (REduction in FREe Hemoglobin) II, intended to support FDA approval of CytoSorb, will start later this year. This study will evaluate intraoperative CytoSorb use during elective, complex cardiac surgery, on clinical outcomes and reductions in adverse events. Complications from uncontrolled inflammation after surgery can be life-altering and even deadly.

For the large number of patients who undergo major cardiac surgery in the U.S. and around the world each year, better therapies are needed to lower the risk of serious postoperative complications. These various strategies, that use different methods to counter inflammation, are likely to act in synergy. This could pave the way for safer and more predictable clinical outcomes in complex cardiac surgery that is anything but routine.

About the author: Dr. Phillip P. Chan, M.D., Ph.D., is chief executive officer and president of CytoSorbents Corporation.