According to the April 2021 Extracorporeal Life Support Organization (ELSO, Ann Arbor, MI) Registry International Summary, patients over the last three decades undergoing extracorporeal life support (ECLS) have a survival to discharge rate of 54%.1 Extracorporeal life support involves extracorporeal circulation (ECC) of blood through an external membrane oxygenator and is vital in providing clinicians additional time to manage acute cardiac or respiratory failure patients. Fundamentally, ECC procedures temporarily replace the function of critical organs, namely the heart, lungs, or kidneys. Despite their extensive clinical utility, significant complications are known to develop, including thrombosis, thromboembolism, heparin-induced thrombocytopenia, cerebral hypoxia, pulmonary hemorrhage, and cerebrovascular compromise.2–5 To date, most research has focused on effects within the context of organ-scale physiology and the macrocirculation. This review explores the microvascular changes during and post ECC to establish potential mechanisms that explain end-stage organ failure in ECC.
This review first introduces several types of ECC, with a specific emphasis on their setup and hemodynamic impacts. Due to the wide range of conditions encompassed under ECC, medication regiments provided during these procedures are out of the scope for this review. To grasp the extent of the potential damage resulting from ECC procedures, this review then presents the various organ injuries observed and key causes that have been proposed and researched. Since ECC entails the circulation of blood ex vivo, the review examines the causes of excessive shear stress and pressure differentials while considering the implications of hemolysis in the microcirculation. Finally, this review outlines the current research on ECLS’s impact on the microcirculation and provide a call to action for microvascular ECLS research.
Hemodialysis and Hemofiltration
Dialysis, considered one of the earliest ECC procedures, is a form of renal replacement therapy (RRT) used in cases of chronic kidney disease, acute kidney injury (AKI), cardiorenal syndrome resistant to diuretic therapy, and end-stage renal failure secondary to glomerular disease in the absence of transplant.6 For patients with end-stage renal disease (ESRD), there are three primary conduits for hemodialysis: an arteriovenous fistula (AVF), a synthetic arteriovenous graft (AVG), or central venous access. The most ideal is an AVF, which shunts blood from an artery to a vein, bypassing the distal microcirculation, providing increased flow7 while reducing infection.8 When hemodialysis and hemofiltration are used in tandem, the procedure is termed hemodiafiltration. In this section, we aim to provide a brief discussion of hemodialysis, followed by hemofiltration, and a comparison of the two methods.
According to the United States Renal Data System (USRDS), as of 2017 over 60% of patients with ESRD underwent dialysis treatment, with an adjusted mortality rate of 167 per 1000 patient-years.9 Hemodialysis (Figure 1A) is a procedure to remove small metabolic waste products through diffusion and rectify electrolyte imbalance with a dialyzer. Blood is pulled from an artery and pumped into the lumen of a dialyzer’s semipermeable membrane, while dialysate solution is pumped outside. Countercurrent flow allows for efficient transport of small molecules and water across the membrane. Used dialysate is discarded, while the blood re-enters the venous circulation.10
;)
Figure 1.: Various types of extracorporeal circulation. A and B: Renal replacement therapies. C: The basic components of ECMO. A: Hemodialysis: Blood (red) flows within the dialyzer lumen, while dialysate (green) flows outside. This leverages diffusion, allowing for small molecules (blue) to pass across the membrane from high to low concentrations. B: Hemofiltration: Blood (red) flows within the dialyzer as a pressure differential is applied transverse across the membrane. This leverages convection, allowing for larger molecules (blue) to pass across the membrane from high to low pressure. Additional fluids are added to account for volume loss. C: ECMO basics: Venous blood feeds a pump (top) that pushes the fluid into the oxygenator (left). Sweep gas (white) flows within the lumen of the hollow fiber membrane, while blood flows outside, allowing for diffusion of CO2 and O2. Blood then passes through a heat exchanger (bottom) before reinfusion. ECMO, extracorporeal membrane oxygenation. 
On the other hand, hemofiltration (Figure 1B) involves removal of excess medium to large sized metabolic waste products while reducing hypervolemia. Blood is passed through a dialyzer in a manner similar to hemodialysis; however, dialysate is not passed outside the semipermeable membrane. By adjusting the dialyzer flow and transverse pressure gradient across the membrane, fluid and molecules are forced through the pores of the membrane, forming an effluent, which drains out medium and large sized metabolic waste.11 To maintain euvolemia, additional fluids are sometimes introduced before the reintroduction of blood back into the body.
The underlying physical mechanism by which hemodialysis and hemofiltration function accounts for many of their observed differences. Hemodialysis leverages diffusion, where concentration gradients between blood and dialysate across the membrane drive flux. On the other hand, hemofiltration leverages convective transport, in which the hydrostatic pressure differentials across the lumen of the membrane drives ultrafiltration.12 As a result, transport in hemofiltration is much faster, although less specific. From a chemical perspective, hemodialysis ensures that electrolytes (small molecules) are equalized between blood and dialysate, although larger molecules may not be. Alternatively, hemofiltration allows for excretion of metabolic waste of variable size but risks hypovolemia, often requiring volume resuscitation before reinfusion due to the lack of dialysate solution used.7
Cardiopulmonary Bypass
One of the most well-known types of ECC is cardiopulmonary bypass (CPB), which allows for a bloodless field during cardiac surgeries such as heart transplant13 or implantation of ventricular assist devices (VADs).14 In several surgical procedures, a cardioplegic solution is passed through the chambers of the heart to induce hypothermia and prevent death of myocardial tissue. A heart-lung machine takes over the primary function of the heart to pump oxygenated blood throughout the body. Blood is drained via cannulas into a reservoir, which feeds an oxygenator to allow for gas exchange. Temperature is controlled with a heat exchanger before being pumped back into the body through a cannula into the aorta. Auxiliary pieces of the circuit include cardiotomy suction, a cell saver for return of red blood cells (RBCs), and devices for left ventricular venting to prevent excessive distention due to low contractility and high afterload.15
Extracorporeal Membrane Oxygenation
Some patients fail to wean off CPB after open heart surgery, requiring initiation of extracorporeal membrane oxygenation (ECMO), otherwise known as ECLS. In general, use of ECMO (Figure 1C) is reserved for patients with severe acute respiratory failure, although general guidelines are provided in detail by the ELSO.15 Indications for ECMO include hypoxemic respiratory failure despite optimization of positive end-expiratory pressure and the inspiratory–to-expiratory ratio,16 acute lung injury that may progress to severe acute respiratory distress syndrome,17 hypercapnic respiratory failure (pH < 7.20),18 cardiac failure/arrest, and cardiogenic shock.19 There are two primary forms of ECMO, namely veno-arterial (VA-ECMO) and veno-venous (VV-ECMO). Importantly, VA-ECMO provides cardiac support, while VV-ECMO does not; several clinical situations merit the need of VA-ECMO versus VV-ECMO, although details are outside the scope of this review. For either technique, deoxygenated blood drains into a blood reservoir, which feeds a pump that imparts hydraulic energy to either supplement or take over cardiac function. Blood passes through an oxygenator to remove carbon dioxide (CO2) and load oxygen (O2) via gas diffusion across a semipermeable hollow fiber membrane. As with CPB, the heat exchanger controls temperature before reintroduction of newly oxygenated blood into the circulation. These components are connected by synthetic polymer tubing, usually comprised of silicone or PVC treated with DEHP, which can be connected to auxiliary elements such as bubble traps and filters to prevent emboli or coagulopathies.15
Several complications can result from ECMO, including bleeding, thromboembolism, neurologic compromise, vascular perforation, and heparin-induced thrombocytopenia. According to the ELSO International Summary for 2021, the survival rate over the past 30 years for VA-ECMO and VV-ECMO procedures is 65% and 77%, respectively.1 Some of the major complications for VA-ECMO are estimated at 55.6% AKI with 46% requiring RRT, 41.9% requiring a thoracotomy, 40.8% hemorrhage, and 30.4% infection.20 Despite ECMO’s lifesaving potential, complications are significant, and each clinical situation should be considered carefully before introducing ECMO treatment. Due to their similarities, ECMO and CPB will be the focus of this review moving forward.
Clinical Complications in Vital Organs
Organ failure after ECLS leads to high postoperative hospital mortality.21 The function of the disease is not well understood, although ECLS is known to induce a whole-body inflammatory reaction, postoperative complications, and complement activation. These symptoms are concurrent with conditions such as systemic inflammatory response syndrome and multiorgan dysfunction syndrome, which left untreated can be devastating to patient survival rate and recovery time.22 The following section highlights the impact of ECMO and CPB on various critical organs (Figure 2).
Figure 2.: Impact of ECMO and CPB on various organs. CPB, cardiopulmonary bypass; ECMO, extracorporeal membrane oxygenation. 
Heart
Impacts on cardiac function can vary depending on the modality used; research in VV-ECMO shows limited impact on systemic hemodynamics,23 while VA-ECMO and CPB have the potential to require left ventricular venting to preserve cardiac function. Due to high flow rates of blood returning from the circuit to the systemic circulation, supraphysiologic arterial pressures are often observed.19 Normally, the myocardial tissue would compensate by increasing contractility since rise in afterload increases myocardial stretch, which heightens myocardial length-dependent activation and contractility via the Frank–Starling mechanism.24 However, patients on VA-ECMO and CPB often have either acute fulminant or congestive heart failure, and both Frank–Starling and length-dependent activation at the sarcomere level are impaired. Some studies have suggested this is due to adrenergic downregulation, but the mechanisms remain unknown.25 Nonetheless, in most cases, patients on VA-ECMO or CPB are unable to compensate without inotropic stimulation, which is often associated with poor outcomes. Even with partial compensation, mechanisms to increase contractility jointly increases metabolic rate and demand, further worsening cardiac function.19 Furthermore, reduced right ventricular filling pressures with supraphysiologic arterial pressures in VA-ECMO or CPB can eventually result in decreased myocardial perfusion and ischemia.26 When this is compounded by lack of oxygenated blood, ischemia may progress to myocardial infarction. Importantly, the progression of ischemia is more dependent on elevations in left ventricular end diastolic pressure, which directly decreases myocardial perfusion pressure, and not lack of oxygenated blood; the latter only worsens the observed pathophysiology. Without adequate relief or with increased VA-ECMO circuit flow rate, elevated LV filling pressures induce a dilated LV with systolic dysfunction, leading to flow stasis and LV apical thromboembolism, or even accumulation of neutrophils and platelets.27 For these reasons, LV venting is preferred.
The main strategy to offload the heart is decompression, which can be achieved by venting or unloading.28 Venting passively diverts flow away without imparting energy to the fluid, either by atrial septostomy or fluid diversion by means of a split connector. In cases when venting on its own is not able to sufficiently depress ventricular filling pressures, one can unload the LV by means of a pump, which actively expends energy. Recent studies have shown that implantation of Impeller centrifugal pumps helps reduce myocardial infarction size by reducing metabolic demand and thus lowering the rate of LV remodeling.29 However, there is a tradeoff, since pumps increase the rate of hemolysis via shear, excess pressure, and in failure cases, excess air entrainment.30
Brain
The brain is the most important organ in the body—given the immeasurable assignment of conscious and unconscious control over body functions, memory, and a multitude of other imperative tasks. Depending on age, the brain can account for 20–50% of total resting oxygen consumption, making cerebral blood flow and oxygenation critical for patient recovery.31 Extracorporeal membrane oxygenation has been shown to induce neurologic injury beyond that secondary to cerebrovascular compromise and ischemic stroke, although the mechanism of acute neurologic injury remains unknown.32 Specifically, encephalopathy, anoxic brain injury, stroke (both hemorrhagic and ischemic), myoclonus, brain death, and coma of uncertain cause have all been observed.33 Importantly, the incidence of these is more associated with VA-ECMO. Risk factors for ECMO-induced neurologic injury include age, pre-existing coagulopathy, pre-existing cardiovascular disease, and pre-existing neurologic disease. With respect to age, the adult prevalence of ECMO induced neurologic injury is between 7% and 16%,34,35 while neonatal prevalence is as high as 50%.36 The pediatric population has recently been of clinical interest, as patients on ECMO have been observed to exhibit developmental deficiencies in adolescence in neuropsychologic areas such as visual-spatial memory and verbal skills later in life.37 Of all neurologic sequelae observed post-ECMO, the most common is stroke, with hemorrhagic and ischemic stroke showing relatively equal incidence. Risk factors include thrombocytopenia, low plasma fibrinogen levels (indicative of a consumptive coagulopathy, e.g., disseminated intravascular coagulation), and duration of ECMO.34 VA-ECMO is often associated with reduced internal carotid artery diameter, due to carotid remodeling post decannulation.36 Interestingly, peripheral cannulation is associated with lower middle cerebral artery velocity38 and increased risk of stroke postdecannulation, suggesting that the site of cannulation is of clinical importance.39 Furthermore, poor circulation leads to spikes in proinflammatory responses and metabolic shifts.40 Elevated creatinine levels from low clearance of metabolic byproducts,41 along with increased lactate and localized oxygen desaturation indicate the onset of cerebral hypoxia.36 Increased counts of B and T cells during ECMO indicate upregulation of the adaptive immune system,42 which persist post-ECMO, as reflected in elevated choline levels, although whether microglia are upregulated remains unknown, making the neurologic relevance questionable.41 Increased inflammation has also been associated with decreased autoregulation of cerebral flow,42 further increasing the risk of hypoperfusion and ischemic stroke.
Kidney
ECMO and CPB have been known to lead to acute kidney injury (AKI), with a prevalence in adults around 60%43 and a prevalence in neonates and pediatrics ranging between 65% and 80%.44,45 Severe AKI is often treated with RRT, which is only effective about 50% of the time in these two most vulnerable populations. Mortality in neonates and pediatric patients are around 20% and 30%46 for those with less severe AKI, while those requiring RRT have an increased mortality of 40% and 60%,46 respectively.
Systemically, there are various changes that occur during and after ECMO and CPB. First, it is extremely common for cardiac output (CO) to drop immediately after weaning due to lower arterial pressures. This induces activation of the renin-angiotensin-aldosterone (RAAS) system and subsequent systemic vasoconstriction, particularly of renal afferent arterioles. As a result, renal perfusion pressure is low, which induces a so-called prerenal AKI (prerenal because the mechanism of AKI is not due to glomerular or tubular disease).47,48 The resulting oliguria along with reduced MAP have shown to be good predictors of mortality.47 Additionally, reduced CO can lead to fluid overload, which limits oxygen transport in critical tissues, reduces blood volume, and further contributes to oliguria, all consistent with a prerenal AKI.48 Various strategies to combat these issues have been used, including administration of inhaled nitric oxide (NO) before initiation of ECMO to help distribute blood flow.44 Another strategy used are loop diuretics, whose aim is to prevent hyperkalemia and to decrease hypervolemia secondary to cardiogenic shock or congestive heart failure.
Besides urine output, there are also several markers which have been associated with AKI. Serum creatine and blood urea nitrogen are indices of renal function, the former being a proxy for glomerular filtration rate. Indications for RRT include acidosis, abnormal electrolytes, specifically hyperkalemia to prevent peaked T waves and sudden cardiac death, intoxication (e.g., ethanol intoxication, ethylene glycol, or any compound that induces a high anion gap metabolic acidosis), fluid overload (e.g., secondary to CHF), and uremia, which is known to cause several clinical sequala, including uremic pericarditis.49 In neonates and pediatric patients, serum creatinine has been shown to double during CPB in 40% of patients,50 with levels above 1.5 mg/dl during ECMO displaying an elevated mortality risk.46 Additionally, elevated urinary neutrophil gelatinase-associated lipocalin (uNGAL) has been shown to be an early index of renal failure,49,50 which may have implications for patient selection for RRT. The changes in these markers are driven by hemolysis, as evident by increased plasma hemoglobin (pHb) levels.50 The downstream effects of increased pHb levels in the kidney are threefold. First, there are increased levels of neutrophils and platelets found in the kidney.27 Second, inflammatory markers such as neutrophil elastase, tumor necrosis factor alpha (TNF-α), IL-6, and reduced A1M levels in renal tubules are increased due to oxidative stress and upregulation of heme clearance.49 Last, tubular distension, epithelial cell detachment, and proximal tubular damage, all components of an ischemia mediated acute tubular necrosis have been observed.49
Intestines
Out of all the organs discussed regarding clinical sequala observed from ECMO or CPB, the least is known about the impact on the gastrointestinal tract, specifically the intestines. ECMO has been shown to induce leukocyte extravasation into the basal layer of the small intestine mucosa, microhemorrhages, and apical microvilli swelling.51 In addition, pHb increases spacing between epithelial cells, increasing epithelial layer permeability, as observed by migration of ileal lipid binding protein (FABP6)52 and intestinal fatty acid binding protein (FABP2).53 In cases of concordant infection, these changes allow for bacteria secreting proinflammatory pathogen associated molecular patterns, such as lipopolysaccharides, to pass into the bloodstream, inducing sepsis and a systemic inflammatory response. There are two primary mechanisms for this phenomenon. First, there is upregulation of the extrinsic apoptotic pathway by phosphorylation of p38 MAP kinase, which increases Fas ligand expression on small intestinal mast cells, leading to caspase 8 activation.53 Second, local inflammation induces intestinal mast cells to release large granule stores of TNF-α and IL-8 cytokines, as measured by elevation of plasma tryptase levels.51 High levels of inflammatory cytokines, such as TNF-α, have been shown to exacerbate permeability issues by leading to cytoskeleton contraction via increased MLC kinase activity.54 The addition of pHb from intravascular hemolysis results in NO scavenging and a subsequent decrease in NO levels, resulting in decreased intestinal microvascular perfusion, further compromising the barrier.52
Excessive Shear Stress From Pumps Induce Hemolysis in Extracorporeal Circulation
As discussed above, ECC can result in several complications in key organs, which affect patient outcomes, the most common of which include bleeding and thromboembolism. As with many extracardiac devices, excessive mechanical shear and pressure gradients mainly contribute to a so-called macroangiopathic intravascular hemolysis in ECC. To understand the mechanism of hemolysis in ECC, a basic understanding of the engineering of these devices is required. There are two types of pumps used, namely peristaltic and centrifugal. Peristaltic (rotary) pumps utilize rollers to pinch tubing located in the pump boot, trapping a section of fluid, and forcing the fluid from the inlet to the outlet as the pump head rotates. These are classified as positive displacement pumps since they typically deliver a constant volume at a fixed rotational speed independent of system pressure. While setup can vary by number of rollers, occlusion level, and tubing size, studies have shown that excess negative pressure,55 time with two consecutive rollers occluding the pump,56 and pressure pulsation frequency57 all increase the degree of hemolysis due to excess mechanical stress.
Centrifugal pumps are also used in both CPB and ECMO. These turbomachines impart energy to the fluid by transfer of kinetic energy generated by rotation of an impeller. A portion of the kinetic energy is then converted to pressure as the fluid passes through the volute. Design of these pumps are extremely complex, and the geometry of the pump is optimized to produce correct flow and pressure to meet system requirements. Computational fluid dynamic (CFD) analyses allow for optimal efficiency by adjusting key parameters, such as blade number and blade angle before impeller manufacture.58 Furthermore, these simulations need to predict excessive red cell lysis to prevent macroangiopathic hemolytic anemia, as discussed above. From CFD, hemolysis indices are calculated based on shear stress and residence time for comparisons.59 Verification using benchtop hydraulic testing with a blood-mimicking fluid such as glycerin and water solution60 and xenograft blood show that friction points, especially at rotor bearings61 create higher degrees of hemolysis. For this reason, it is more common for centrifugal blood pumps to have magnetically levitated rotors. Centrifugal pumps have also been used as VADs for heart failure patients, each with their own intended use and observed complications. For instance, pediatric heart transplant patients with an EXCOR implanted survived at a higher rate as compared with pediatric ECMO patients.62 However, hemorrhage and stroke remain a big concern with these patients, with 29% of patients experience at least one neurologic event while the EXCOR was implanted.63 Another device, the CentriMag, showed impact to leukocyte function,64 increased levels of nonphysiologic shear stress leading to increased platelet activation and receptor shedding,65 and decreases in von Willebrand factor collagen binding activity.66 Recent investigation into off-label use of the CentriMag for pediatric ECMO has revealed increased platelet activation as compared with on-label use for adult ECMO; interestingly, the PediVAS, a device intended for pediatric ECMO showed retrograde flow during CFD analysis, highlighting that operation of blood pumps should be performed at their design point.67 In summary, centrifugal pumps are generally regarded as producing more hemolysis as compared with roller pumps but require less circuit volume (and as a direct result, foreign surface area).15 Clinically, there is no consensus as to which pump minimizes bleeding and thromboembolism and improves outcomes, and the choice of pump varies by institution.15
Beyond macroangiopathic hemolytic anemia, erythrocyte injury has several downstream consequences, including formation of systemic thromboemboli and several other systemic consequences secondary to cell-free hemoglobin release into the plasma (pHb).68 Thrombus formation is driven primarily through activation of platelets, which is exacerbated from hemolysis via NO scavenging and ADP release from plasma free hemoglobin.69 The Platelet Activation State has been used as a relative measure of platelet activation in both in-vitro70 and computational settings.71 Initial protein adsorption onto circuit surfaces over time eventually gets replaced by higher-affinity proteins for the surface such as fibrinogen, which is known as the Vroman effect. On the other hand, while adhesion with fibrinogen increases over time, research has also shown that adhesion due to von Willebrand factor decreases over time partly due to platelet receptor shedding,65 which affects hemostasis. Bleeding is known to occur in between 30% and 50% of all patients who receive ECMO and is secondary to continuous anticoagulation and platelet dysfunction.72,73 Furthermore, formation of antiplatelet factor 4 (anti-PF4) antibodies can result in heparin-induced thrombocytopenia, which has been associated with patients on ECMO,5 the mechanism being unknown. Most commonly, systemic thromboemboli resulting from either direct formation within the ECMO circuit or secondary to the induced consumptive coagulopathy are known to occur. For this reason, new technologies are continuously developed to prevent serious complications and improve patient outcomes.
Extracorporeal Circulation and the Microcirculation
Hemolysis and the Microcirculation.
The effects of pHb have been well established and are particularly pronounced in the microcirculation. Once Hb is released from lysed RBCs, pHb scavenges NO produced by vascular endothelial cells (ECs) and limits NO availability for smooth muscles, resulting in vasoconstriction.74 NO oxidizes pHb into methemoglobin (metHb), which can dissociate and form hemin from heme.75 Hemin contributes to low-density lipoprotein oxidation, resulting in proinflammatory upregulation of hemeoxygenase 1 and ferritin within ECs.76 Heme itself causes a proinflammatory response by activating toll-like receptor 4 on the surface of macrophages, inducing release of TNF-α.74,77 In addition, the depletion of NO by pHb can decrease the cGMP levels by decreasing soluble guanylyl cyclase (sGC) activity, leading to increased platelet aggregation.78
Blood contains several mechanisms to control pHb and its byproducts. pHb binds to haptoglobin (Hp) in plasma to form a Hb-Hp complex, which binds to CD163 receptors on the surface of macrophages to be internalized and metabolized, releasing heme and iron. However, when pHb levels exceed the Hp binding capacity, pHb oxidizes, causing methemoglobinemia and Hb dissociation, releasing heme.79 Hemopexin (Hx) can bind heme, which then binds to CD91 receptors on hepatocytes, allowing for heme breakdown and clearance. Once oxidation occurs, Hx prevents excessive loss of iron and oxidative stress in critical tissues.75 Hp is considered an acute response protein due to its high binding affinity for Hb, while Hx demonstrates more benefit in chronic hemolytic conditions to mitigate oxidative stress. One advantage of Hx is that it can be recycled, while Hp is ultimately consumed and needs to be remanufactured.77 Innately, the levels of these molecules are miniscule when compared with concentrations of hemoglobin and can easily become overwhelmed in severe hemolytic conditions.80
As illustrated previously, ECC causes hemolysis of RBCs and thus increases pHb.30,50 The resulting vasoconstriction can reduce perfusion in the microcirculation, leading to a hypoxic and eventually ischemic condition.81 The generation of reactive oxygen species may contribute to endothelial dysfunction.82 This increase in vascular permeability coupled with redistributed intravascular pressure may affect filtration and reabsorption across the lumen of capillaries and overall microcirculatory dysfunction. Therefore, the introduction of pHb into the circulation can ultimately lead to damage within multiple organ systems.83
Current State
While the main goal of ECMO is to increase oxygen blood content, whether this translates to improved oxygen delivery in the microcirculation is unknown. To investigate the effects of ECMO on the microcirculation, several techniques exist, including Laser Doppler, Near Infrared Spectroscopy and Imaging (NIRS), laser speckle imaging, orthogonal polarization spectral (OPS), and dark field microscopy (both incident and sidestream),84 with the latter two used most commonly in ECMO research. Both OPS and dark field microscopy are relatively noninvasive imaging techniques, which allow for use in clinical settings. Additionally, dark field microscopy has become more popular due to better image quality and development of biomedical devices such as the CytoCAM devices (Braedius Medical).85 Nonetheless, there are several limitations. Since both these imaging techniques are at a wavelength specific to hemoglobin, the cell-free layer (CFL) cannot be imaged. Consequently, in small arterioles85 and hemodilution cases, where CFL thickness is increased relative to vessel size (Fahraues–Lindquvist effect86), vessel diameter measurements from these techniques may be underestimated. Further, both these imaging modalities require relatively translucent connective tissue for direct visualization.85 Additionally, most of the parameters obtained are semiquantitative counts of vessel perfusion87; however, both OPS and dark field microscopy cannot address the mechanisms of flow changes, which may be important in assessing microcirculatory disorders secondary to septic shock or multiorgan dysfunction.
Recent research efforts to quantify changes in the microcirculation with ECC, specifically ECMO, have expanded. Studies have shown that administration of VA-ECMO in patients with severe respiratory failure improved functional capillary density (FCD) in the buccal mucosa (i.e., cheek lining) as compared to patients on ventilation. However, FCD tends to be lower in VA-ECMO patients with respiratory disease, independent of blood pressure and heart rate.88,89 Therefore, changes in the systemic circulation do not necessarily translate to the microcirculation, highlighting the relevance of microvascular perfusion. Furthermore, studies regarding type of ECMO support have shown little difference in the microcirculation, while patient age has been associated with changes in microcirculatory hemodynamics.90 Microvascular measurements can also be used as predictive markers for cardiogenic (and septic) shock in patients,84,89,91 especially in refractory cases.92
Mammalian models have been utilized to understand the effects of ECC on the microcirculation, which comes with advantages and disadvantages of its own. Animal research allows control over more variables (e.g., priming fluids, pathophysiology of the animal, etc.), but it reduces translatability due to differences in underlying physiology as compared to humans. Some of the earliest models used were pigs, sheep, and dogs; these models were used in conjunction with OPS and other techniques such as microsphere deposition. Recently, researchers have combined conventional microcirculation techniques in small mammals (e.g., cremaster, omentum, and dorsal skinfold preparations) with scaled down or simplified ECC circuits to allow for more precise assessments of the microhemodynamics. For instance, Kamler et al.93 have done significant work regarding the inflammatory response in the microcirculation as a result of ECC in Golden Syrian hamsters. These techniques should be utilized more often and expanded upon to elucidate more of the underlying causes of microvascular dysfunction due to ECC.
CONCLUSIONS AND FUTURE WORK
The primary goal of ECC is to allow physicians time to treat underlying disease in patients with acute organ failure. ECC circuits can vary in their role, setup, and components. Due to the need to drive blood flow ex vivo, pumps are often used to impart energy to the fluid; however, this can induce macroangiopathic hemolytic anemia as well as downstream pHb release. Subsequent systemic vasoconstriction, organ dysfunction, and systemic immune system activation are observed, although not completely understood.
Importantly, however, the redistribution of flow in the microcirculation partly explains microvascular complications secondary to ECC. Thus, understanding the implications of ECC on microvascular hemodynamics is vital. Subsequent disruption of metabolic waste exchange and nutrient/metabolite delivery can lead to ischemia–reperfusion injury, shock, and end-organ hypoperfusion, ultimately leading to organ failure. We therefore propose a call to action for research in ECMO microvascular hemodynamics and ECC in general to improve survival to discharge rates in an extremely vulnerable patient population.
ACKNOWLEDGMENT
We would like to acknowledge that some statistics are provided with reports from data gathered by the ELSO. Additionally, some of the data reported here have been supplied by the USRDS. The interpretation and reporting of these data are the responsibility of the author(s) and in no way should be seen as an official policy or interpretation of the US Government.
REFERENCES
1. International Summary of the ECMO Registry of the Extracorporeal Life Support Organization (ELSO), Ann Arbor, Michigan, April, 2021. Available at:
https://www.elso.org/Registry/Statistics/InternationalSummary.aspx.
2. Olson SR, Murphree CR, Zonies D, et al.: Thrombosis and bleeding in extracorporeal membrane oxygenation (ECMO) without anticoagulation: A Systematic Review. ASAIO J. 67: 290–296, 2021.
3. Fernandez AG, Snell K, Gajkowski E, Mehta Y. Diffuse alveolar hemorrhage and extracorporeal membrane oxygenation (ECMO): A bloody conundrum. Chest. 156:A1911–A1912, 2019
4. Xie A, Jayewardene ID, Dinale A, Macdonald P, Pye R, Dhital K. Cerebral hypoxia during venoarterial extracorporeal membrane oxygenation: An in-vitro study. J Heart Lung Transplantation. 34:S196–S197, 2015
5. Natt B, Hypes C, Basken R, Malo J, Kazui T, Mosier J: Suspected heparin-induced thrombocytopenia in patients receiving extracorporeal membrane oxygenation. J Extra Corpor Technol. 49: 54–58, 2017.
6. Murdeshwar HN, Anjum F. Hemodialysis. StatPearls Publishing; 2020. Accessed May 20, 2021.
https://www.ncbi.nlm.nih.gov/books/NBK563296/
7. Maher JF. Replacement of Renal Function by Dialysis: A Textbook of Dialysis. Springer Netherlands; 1989. Accessed February 7, 2021.
https://doi.org/10.1007/978-94-009-1087-4
8. Churchill DN, Taylor DW, Cook RJ, et al.: Canadian hemodialysis morbidity study. Am J Kidney Dis. 19: 214–234, 1992.
9. US Renal Data System 2019 Annual Data Report: Epidemiology of kidney disease in the United States. Am J Kidney Dis. 75:S1–S64, 2020.
10. Elliott DA: Hemodialysis. Clin Tech Small Anim Pract. 15: 136–148, 2000.
11. Finkel KW: Waguespack DR. 32 - Renal replacement therapies. In: Finkel KW, Perazella MA, Cohen EP, eds. Onco-Nephrology. Elsevier; 2020:290–298.e3.
12. Jörres A: Hemofiltration or hemodialysis for acute kidney injury? Crit Care. 16: 147, 2012.
13. Shanewise J: Cardiac transplantation. Anesthesiol Clin North Am. 22: 753–765, 2004.
14. Cohn WE: New tools and techniques to facilitate off-pump left ventricular assist device implantation. Tex Heart Inst J. 37: 559–561, 2010.
15. Brogan TV, Lequier L, Lorusso R, MacLaren G, Peek G, Extracorporeal Life Support Organization. Extracorporeal Life Support: The ELSO Red Book; 2017.
16. Patel B, Chatterjee S, Davignon S, Herlihy JP: Extracorporeal membrane oxygenation as rescue therapy for severe hypoxemic respiratory failure. J Thorac Dis. 11(Suppl 14): S1688–S1697, 2019.
17. Combes A, Peek GJ, Hajage D, et al.: ECMO for severe ARDS: Systematic review and individual patient data meta-analysis. Intensive Care Med. 46:2048–2057, 2020.
18. Muellenbach RM, Kilgenstein C, Kranke P, et al.: Effects of venovenous extracorporeal membrane oxygenation on cerebral oxygenation in hypercapnic ARDS. Perfusion. 29: 139–141, 2014.
19. Rao P, Khalpey Z, Smith R, Burkhoff D, Kociol RD: Venoarterial extracorporeal membrane oxygenation for cardiogenic shock and cardiac arrest. Circ Heart Fail. 11: e004905, 2018.
20. Cheng R, Hachamovitch R, Kittleson M, et al.: Complications of extracorporeal membrane oxygenation for treatment of cardiogenic shock and cardiac arrest: A meta-analysis of 1,866 adult patients. Ann Thorac Surg. 97: 610–616, 2014.
21. Peek GJ, Killer HM, Sosnowski MA, Firmin RK: Modular extracorporeal life support for multiorgan failure patients. Liver. 22 (Suppl 2): 69–71, 2002.
22. Al-Fares A, Pettenuzzo T, Del Sorbo L: Extracorporeal life support and systemic inflammation. Intensive Care Med Exp. 7(Suppl 1): 46, 2019.
23. Shen J, Yu W, Shi J
et al: Effect of venovenous extracorporeal membrane oxygenation on the heart in a healthy piglet model. J Cardiothorac Surg. 8: 163, 2013.
24. Knowlton FP, Starling EH: The influence of variations in temperature and blood-pressure on the performance of the isolated mammalian heart. J Physiol. 44: 206–219, 1912.
25. Lymperopoulos A, Rengo G, Koch WJ: Adrenergic nervous system in heart failure: pathophysiology and therapy. Circ Res. 113: 739–753, 2013.
26. Choi MS, Sung K, Cho YH: Clinical pearls of venoarterial extracorporeal membrane oxygenation for cardiogenic shock. Korean Circ J. 49: 657–677, 2019.
27. Brix-Christensen V, Tønnesen E, Hjortdal VE, et al.: Neutrophils and platelets accumulate in the heart, lungs, and kidneys after cardiopulmonary bypass in neonatal pigs. Crit Care Med. 30: 670–676, 2002.
28. Lim HS: The physiologic basis and clinical outcomes of combined impella and veno-arterial extracorporeal membrane oxygenation support in cardiogenic shock. Cardiol Ther. 9: 245–255, 2020.
29. Schrage B, Becher PM, Bernhardt A, et al. Left ventricular unloading is associated with lower mortality in patients with cardiogenic shock treated with venoarterial extracorporeal membrane oxygenation. Circulation. 142:2095–2106, 2020.
30. Vercaemst L: Hemolysis in cardiac surgery patients undergoing cardiopulmonary bypass: A review in search of a treatment algorithm. J Extra Corpor Technol. 40: 257–267, 2008.
31. Clarke DD, Sokoloff L. Regulation of cerebral metabolic rate. Basic neurochemistry: Molecular, cellular and medical aspects 6th edition. 1999. Accessed April 16, 2021.
https://www.ncbi.nlm.nih.gov/books/NBK28194/
32. Bowling SM, Gomes J, Firstenberg MS. Neurologic Issues in Patients Receiving Extracorporeal Membrane Oxygenation Support. IntechOpen; 2016.
33. Nguyen DN, Huyghens L, Wellens F, Schiettecatte J, Smitz J, Vincent JL: Serum S100B protein could help to detect cerebral complications associated with extracorporeal membrane oxygenation (ECMO). Neurocrit Care. 20: 367–374, 2014.
34. Le Guennec L, Cholet C, Huang F, et al.: Ischemic and hemorrhagic brain injury during venoarterial-extracorporeal membrane oxygenation. Ann Intensive Care. 8: 129, 2018.
35. Lockie CJA, Gillon SA, Barrett NA, et al.: Severe respiratory failure, extracorporeal membrane oxygenation, and intracranial hemorrhage. Crit Care Med. 45: 1642–1649, 2017.
36. Wien MA, Whitehead MT, Bulas D, et al.: Patterns of brain injury in newborns treated with extracorporeal membrane oxygenation. AJNR Am J Neuroradiol. 38: 820–826, 2017.
37. Madderom MJ, Schiller RM, Gischler SJ, et al.: Growing up after critical illness: Verbal, visual-spatial, and working memory problems in neonatal extracorporeal membrane oxygenation survivors. Crit Care Med. 44: 1182–1190, 2016.
38. O’Brien NF, Buttram SDW, Maa T, Lovett ME, Reuter-Rice K, LaRovere KL; Pediatric Neurocritical Care Research Group (PNCRG): Cerebrovascular physiology during pediatric extracorporeal membrane oxygenation: A multicenter study using transcranial doppler ultrasonography. Pediatr Crit Care Med. 20: 178–186, 2019.
39. Pinto VL, Pruthi S, Westrick AC, Shannon CN, Bridges BC, Le TM: Brain magnetic resonance imaging findings in pediatric patients post extracorporeal membrane oxygenation. ASAIO J. 63: 810–814, 2017.
40. Chen Q, Yu W, Shi J, et al.: The effect of venovenous extra-corporeal membrane oxygenation (ECMO) therapy on immune inflammatory response of cerebral tissues in porcine model. J Cardiothorac Surg. 8: 186, 2013.
41. Reitman AJ, Chapman R, Stein JE, et al.: The impact of venoarterial and venovenous extracorporeal membrane oxygenation on cerebral metabolism in the newborn brain. PLoS One. 11: e0168578, 2016.
42. Ortega SB, Pandiyan P, Windsor J, et al.: A pilot study identifying brain-targeting adaptive immunity in pediatric extracorporeal membrane oxygenation patients with acquired brain injury. Crit Care Med. 47: e206–e213, 2019.
43. Thongprayoon C, Cheungpasitporn W, Lertjitbanjong P, et al.: Incidence and impact of acute kidney injury in patients receiving extracorporeal membrane oxygenation: A meta-analysis. J Clin Med. 8: E981, 2019.
44. Zwiers AJ, de Wildt SN, Hop WC, et al.: Acute kidney injury is a frequent complication in critically ill neonates receiving extracorporeal membrane oxygenation: a 14-year cohort study. Crit Care. 17: R151, 2013.
45. Fleming GM, Sahay R, Zappitelli M, et al.: The incidence of acute kidney injury and its effect on neonatal and pediatric extracorporeal membrane oxygenation outcomes: A multicenter report from the kidney intervention during extracorporeal membrane oxygenation study group. Pediatr Crit Care Med. 17: 1157–1169, 2016.
46. Askenazi DJ, Ambalavanan N, Hamilton K, et al.: Acute kidney injury and renal replacement therapy independently predict mortality in neonatal and pediatric noncardiac patients on extracorporeal membrane oxygenation. Pediatr Crit Care Med. 12: e1–e6, 2011.
47. Chang WW, Tsai FC, Tsai TY, et al.: Predictors of mortality in patients successfully weaned from extracorporeal membrane oxygenation. PLoS One. 7: e42687, 2012.
48. Chen YC, Tsai FC, Fang JT, Yang CW: Acute kidney injury in adults receiving extracorporeal membrane oxygenation. J Formos Med Assoc. 113: 778–785, 2014.
49. Natanov R, Gueler F, Falk CS, et al.: Blood cytokine expression correlates with early multi-organ damage in a mouse model of moderate hypothermia with circulatory arrest using cardiopulmonary bypass. PLoS One. 13: e0205437, 2018.
50. Mamikonian LS, Mamo LB, Smith PB, Koo J, Lodge AJ, Turi JL: Cardiopulmonary bypass is associated with hemolysis and acute kidney injury in neonates, infants, and children*. Pediatr Crit Care Med. 15: e111–e119, 2014.
51. McILwain RB, Timpa JG, Kurundkar AR, et al.: Plasma concentrations of inflammatory cytokines rise rapidly during ECMO-related SIRS due to the release of preformed stores in the intestine. Lab Invest. 90: 128–139, 2010.
52. Hanssen SJ, Lubbers T, Hodin CM, Prinzen FW, Buurman WA, Jacobs MJ: Hemolysis results in impaired intestinal microcirculation and intestinal epithelial cell injury. World J Gastroenterol. 17: 213–218, 2011.
53. MohanKumar K, Killingsworth CR, McIlwain RB, et al.: Intestinal epithelial apoptosis initiates gut mucosal injury during extracorporeal membrane oxygenation in the newborn piglet. Lab Invest. 94: 150–160, 2014.
54. Kurundkar AR, Killingsworth CR, McIlwain RB, et al.: Extracorporeal membrane oxygenation causes loss of intestinal epithelial barrier in the newborn piglet. Pediatr Res. 68: 128–133, 2010.
55. Mulholland JW, Massey W, Shelton JC: Investigation and quantification of the blood trauma caused by the combined dynamic forces experienced during cardiopulmonary bypass. Perfusion. 15: 485–494, 2000.
56. Mulholland JW, Shelton JC, Luo XY. Blood flow and damage by the roller pumps during cardiopulmonary bypass. J Fluids Structures. 20:129–140, 2005.
57. Moscato F, Colacino FM, Arabia M, Danieli GA: Pressure pulsation in roller pumps: A validated lumped parameter model. Med Eng Phys. 30: 1149–1158, 2008.
58. Mozafari S, Rezaienia MA, Paul GM, Rothman MT, Wen P, Korakianitis T: The effect of geometry on the efficiency and hemolysis of centrifugal implantable blood pumps. ASAIO J. 63: 53–59, 2017.
59. Faghih MM, Keith Sharp M. Extending the power-law hemolysis model to complex flows. J Biomech Eng. 138: 124504, 2016.
60. Thamsen B, BlĂ¼mel B, Schaller J, et al.: Numerical analysis of blood damage potential of the HeartMate II and HeartWare HVAD rotary blood pumps. Artif Organs. 39: 651–659, 2015.
61. Bottrell S, Bennett M, Augustin S, et al.: A comparison study of haemolysis production in three contemporary centrifugal pumps. Perfusion. 29: 411–416, 2014.
62. Fraser CD Jr, Jaquiss RD, Rosenthal DN, et al.; Berlin Heart Study Investigators: Prospective trial of a pediatric ventricular assist device. N Engl J Med. 367: 532–541, 2012.
63. Jordan LC, Ichord RN, Reinhartz O, et al.: Neurological complications and outcomes in the Berlin Heart EXCOR® pediatric investigational device exemption trial. J Am Heart Assoc. 4: e001429, 2015.
64. Sun W, Zhang J, Shah A, et al. Neutrophil dysfunction due to continuous mechanical shear exposure in mechanically assisted circulation in vitro.[published online ahead of print September 13, 2021]. Artif Organs. doi: 10.1111/aor.14068.
65. Doyle AJ, Hunt BJ: Current understanding of how extracorporeal membrane oxygenators activate haemostasis and other blood components. Front Med (Lausanne). 5: 352, 2018.
66. Coghill PA, Kanchi S, Azartash-Namin ZJ, Long JW, Snyder TA: Benchtop von Willebrand factor testing: Comparison of commercially available ventricular assist devices and evaluation of variables for a standardized test method. ASAIO J. 65: 481–488, 2019.
67. Fiusco F, Broman LM, Prahl Wittberg L. Blood pumps for extracorporeal membrane oxygenation: platelet activation during different operating conditions. ASAIO J. 68: 79–86, 2022.
68. Valladolid C, Yee A, Cruz MA: von Willebrand Factor, free hemoglobin and thrombosis in ECMO. Front Med (Lausanne). 5: 228, 2018.
69. Helms CC, Marvel M, Zhao W, et al.: Mechanisms of hemolysis-associated platelet activation. J Thromb Haemost. 11: 2148–2154, 2013.
70. Jesty J, Bluestein D: Acetylated prothrombin as a substrate in the measurement of the procoagulant activity of platelets: Elimination of the feedback activation of platelets by thrombin. Anal Biochem. 272: 64–70, 1999.
71. Pelosi A, Sheriff J, Stevanella M, Fiore GB, Bluestein D, Redaelli A: Computational evaluation of the thrombogenic potential of a hollow-fiber oxygenator with integrated heat exchanger during extracorporeal circulation. Biomech Model Mechanobiol. 13: 349–361, 2014.
72. Mazzeffi M, Greenwood J, Tanaka K, et al.: Bleeding, transfusion, and mortality on extracorporeal life support: ECLS Working Group on Thrombosis and Hemostasis. Ann Thorac Surg. 101: 682–689, 2016.
73. Sklar MC, Sy E, Lequier L, Fan E, Kanji HD: Anticoagulation practices during venovenous extracorporeal membrane oxygenation for respiratory failure. A systematic review. Ann Am Thorac Soc. 13: 2242–2250, 2016.
74. Rother RP, Bell L, Hillmen P, Gladwin MT: The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: A novel mechanism of human disease. JAMA. 293: 1653–1662, 2005.
75. Balla G, Jacob HS, Eaton JW, Belcher JD, Vercellotti GM: Hemin: A possible physiological mediator of low density lipoprotein oxidation and endothelial injury. Arterioscler Thromb. 11: 1700–1711, 1991.
76. Jeney V, Balla J, Yachie A, et al.: Pro-oxidant and cytotoxic effects of circulating heme. Blood. 100: 879–887, 2002.
77. Schaer DJ, Buehler PW, Alayash AI, Belcher JD, Vercellotti GM: Hemolysis and free hemoglobin revisited: Exploring hemoglobin and hemin scavengers as a novel class of therapeutic proteins. Blood. 121: 1276–1284, 2013.
78. Gkaliagkousi E, Ritter J, Ferro A: Platelet-derived nitric oxide signaling and regulation. Circ Res. 101: 654–662, 2007.
79. Jeney V, Eaton JW, Balla G, Balla J: Natural history of the bruise: Formation, elimination, and biological effects of oxidized hemoglobin. Oxid Med Cell Longev. 2013: 703571, 2013.
80. Smith A, McCulloh RJ: Hemopexin and haptoglobin: Allies against heme toxicity from hemoglobin not contenders. Front Physiol. 6: 187, 2015.
81. Sambuceti G, Marzilli M, Marraccini P, et al.: Coronary vasoconstriction during myocardial ischemia induced by rises in metabolic demand in patients with coronary artery disease. Circulation. 95: 2652–2659, 1997.
82. Incalza MA, D’Oria R, Natalicchio A, Perrini S, Laviola L, Giorgino F: Oxidative stress and reactive oxygen species in endothelial dysfunction associated with cardiovascular and metabolic diseases. Vascul Pharmacol. 100: 1–19, 2018.
83. Pires IS, Govender K, Munoz CJ, et al.: Purification and analysis of a protein cocktail capable of scavenging cell-free hemoglobin, heme, and iron. Transfusion. 61: 1894–1907, 2021.
84. Yeh Y-C, Chiu C-T. Association and dissociation of microcirculation and macrocirculation in critically ill patients with shock. J Emerg Crit Care Med. 3:60–60, 2019.
85. Groner W, Winkelman JW, Harris AG, et al.: Orthogonal polarization spectral imaging: A new method for study of the microcirculation. Nat Med. 5: 1209–1212, 1999.
86. FĂ¥hræus R, Lindqvist T. The viscosity of the blood in narrow capillary tubes. Am J Physiol Legacy Content. 96:562–568, 1931.
87. De Backer D, Hollenberg S, Boerma C, et al.: How to evaluate the microcirculation: Report of a round table conference. Crit Care. 11: R101, 2007.
88. Top AP, Ince C, van Dijk M, Tibboel D: Changes in buccal microcirculation following extracorporeal membrane oxygenation in term neonates with severe respiratory failure. Crit Care Med. 37: 1121–1124, 2009.
89. Kara A, Akin S, Dos Reis Miranda D, et al.: Microcirculatory assessment of patients under VA-ECMO. Crit Care. 20: 344, 2016.
90. Erdem Ö, Kuiper JW, van Rosmalen J, et al.: The sublingual microcirculation throughout neonatal and pediatric extracorporeal membrane oxygenation treatment: Is it altered by systemic extracorporeal support? Front Pediatr. 7: 272, 2019.
91. Montero S, Chommeloux J, Franchineau G, Combes A, Schmidt M: Microcirculation in cardiogenic shock supported with extracorporeal membrane oxygenation: The need for a homogeneous population and strict evolution assessment. Crit Care. 22: 281, 2018.
92. Chommeloux J, Montero S, Franchineau G, et al.: Microcirculation evolution in patients on venoarterial extracorporeal membrane oxygenation for refractory cardiogenic shock. Crit Care Med. 48: e9–e17, 2020.
93. Kamler M, Jakob H, Lehr HA, Gebhard MM, Hagl S: Direct visualization of leukocyte/endothelial cell interaction during extracorporeal circulation (ECC) in a new animal model. Eur J Cardiothorac Surg. 11: 973–980, 1997.
