Cardiopulmonary Bypass: Pathophysiology and Management

Alterations of Arterial Pressure, Blood Flow Distribution, and Resistance

As long as blood flow and depth of anesthesia remain stable, mean arterial pressure (MAP) is dependent on systemic vascular resistance (SVR). There is considerable patient-to-patient variation in SVR during CPB. At the start of CPB, there is usually a fall in systemic blood pressure. This may be due to reduced intravascular blood volume or to a decrease in SVR from decreased blood viscosity secondary to hemodilution induced by the pump-priming fluid. In addition, decreased vascular tone occurs secondary to dilution of circulating catecholamines, temporary tissue ischemia, and altered calcium and magnesium levels in the priming fluid.

However, as CPB progresses, there is usually a steady increase in MAP due to increasing SVR if flow rates are kept constant. This is due to decreased vascular cross-sectional area from closure of portions of the microvasculature; vasoconstriction brought on by hypothermia, increasing levels of circulating catecholamines, arginine vasopressin (AVP), endothelin, and angiotensin II; and increases in blood viscosity secondary to hypothermia and rising hematocrit (due to urine output, translocation of fluid into the interstitial compartment, or hemoconcentrator use). This overall pattern of gradual increases in SVR may be transiently interrupted after infusion of cardioplegia solutions that can lead to transient decreases in SVR and MAP. A more consistent decrease in SVR and MAP usually occurs with release of the aortic cross-clamp and reperfusion of the heart. Despite cardioplegia and hypothermia, there is some degree of ongoing cardiac metabolic activity and utilization of myocardial energy stores during the ischemic period. This results in coronary vasodilation with a marked increase in coronary blood flow and decrease in arterial pressure. In addition, when the heart is reperfused, accumulated metabolites are washed out into the general circulation. Some of these metabolites, most notably adenosine, are potent vasodilators that decrease SVR.

The distribution of systemic flow is highly influenced by total flow. As total flow decreases, first flow to skin and muscle, then flow to splanchnic organs, renal flow, and finally (only at extremely low total flow) cerebral blood flow (CBF) is reduced.

One of the major physiologic derangements introduced by CPB is loss of pulsatile arterial blood flow , since most CPB circuits generate nonpulsatile flow. The benefits of pulsatile flow include transmission of more energy to the microcirculation, which improves tissue perfusion, lymphatic flow, and cellular metabolism, and reduction of adverse neuroendocrine responses (mainly vasoconstrictive that emanate from baroreceptors, the kidneys, and the endothelium). There are a number of ways of generating pulsatile flow, but these have significant limitations including the amount of pulsatile hydrodynamic energy that actually can be transmitted into the patient. Furthermore, there is considerable controversy about the merits of and need for pulsatile perfusion as compared to conventional nonpulsatile perfusion. ^, Data on the impact of nonpulsatile flow during CPB have been conflicting. An evidence-based review by Alghamdi and Latter in 2006 concluded that existing data were insufficient to support recommendations for or against pulsatile perfusion to reduce the incidence of complications following CPB. However, the recent European guidelines on CPB recommend its use in patients at high risk for adverse lung and renal outcomes.

Hematologic Changes

Exposure of blood to nonphysiologic surfaces and shear stresses causes alteration of proteins and formed elements of blood, activation of coagulation, and hemolysis. Changes in the coagulation cascade, platelets, and the fibrinolytic cascade are discussed in Chapter 13, Chapter 28 . Red blood cells (RBCs) become stiffer and less deformable during CPB, which may interfere with microcirculatory blood flow and increase susceptibility to hemolysis. The RBCs are exposed to foreign surfaces and shear stresses during CPB that may cause their destruction. The degree of hemolysis is increased by both higher flow rates and the accompanying increase in shear forces, and by gas-fluid interfaces in the extracorporeal circuit (ECC). As RBCs are lysed, the free hemoglobin produced binds to haptoglobin. When the amount of free hemoglobin generated exceeds the binding capacity of haptoglobin, serum-free hemoglobin concentrations increase and are filtered by the kidney, resulting in hemoglobinuria. Cardiotomy suction also contributes importantly to hemolysis during CPB.

CPB affects primarily neutrophils (polymorphonuclear leukocytes [PMNs]) and, to a lesser degree, monocytes. Shortly after the onset of CPB, circulating PMNs decrease markedly due to sequestration in various vascular beds. Blockage of vessels by PMN clumping or microcirculatory derangements induced by substances released from PMNs may contribute to organ dysfunction after CPB. Circulating PMN levels increase dramatically with rewarming. Neutrophils released from the pulmonary circulation and younger cells released from the bone marrow contribute to this neutrophilia. Effects of CPB on the host defense functions of PMNs remain controversial.

Exposure of proteins to gas-liquid interfaces causes denaturation . Protein denaturation leads to altered enzymatic function, altered solubility, lipid release into the blood stream, and RBC membrane alterations that promote capillary sludging and microcirculatory dysfunction. Hemodilution at the start of CPB causes plasma protein concentration and hence colloid osmotic pressure (COP) to fall, particularly if no colloids are added to the CPB circuit. There is controversy about the need and benefits of avoiding the fall in COP by using albumin or artificial colloids (eg, dextrans, starches) in the priming solution. Increased interstitial fluid in many tissues and organs is common during and following CPB. If extreme, this can cause pathologic capillary leak syndrome (eg, adult respiratory distress syndrome [ARDS], or cerebral edema).

Until recently, fluid fluxes at the microcirculatory level were attributed mainly to the factors described by Starling. These include the permeability of the membrane (“filtration coefficient”), the fluid pressure gradient across the membrane that are additive to the decrease in the oncotic pressure across the membrane, and clearance by the lymph flow. CPB shifts this balance toward accumulation of interstitial fluid by affecting several of these variables. Membrane permeability is increased by activation of a systemic inflammatory response (SIR) and intermittent ischemia/reperfusion potentially leading to organ injury. Plasma oncotic pressure falls due to the use of asanguinous priming fluids. Inadequate venous drainage may increase mean capillary hydrostatic pressure, whereas immobility, lack of pulsatile flow, and loss of negative intrathoracic pressure impede lymphatic flow. In addition the endothelial glycocalyx (EG) has been recognized as playing an important role in modifying the effect of these Starling factors. Shredding of the EG has been demonstrated during CPB, which likely increases capillary permeability and perhaps induces capillary leak syndrome.

Both ionized calcium and total and unfilterable fractions of magnesium commonly fall, whereas potassium levels may fluctuate widely, during CPB. The latter may be related to diuretics, catecholamines, β-blockers, potassium-containing cardioplegia, and renal dysfunction (RD). It is important to maintain normal levels of these ions to preserve normal muscle and cardiac function and prevent arrhythmias.

Cooling and Warming

Hypothermia is a powerful stimulator of the stress and endocrine response to CPB. It also decreases oxygen consumption, and increases both blood viscosity and SVR. Thus, it may impair oxygen delivery and release to tissues partly depending on pH and Pa co ₂ management. In contemporary CPB practice, patients are typically hemodiluted to hematocrits of 20% to 30% during CPB due to asanguineous pump priming. Although oxygen-carrying capacity is decreased from hemodilution, oxygen delivery may paradoxically increase as a result of decreased viscosity and enhanced microcirculatory flow. In general, the viscosity remains stable if hematocrit (expressed as percentage) matches temperature (in degree Celsius) during hypothermia. The optimal degree of hemodilution during hypothermic CPB has not been determined. Recent studies have demonstrated an association between severe CPB hemodilution (hematocrits below 20%–24%) and morbidity and mortality. Clinicians should avoid both excessively high (increased blood viscosity and decreased microcirculatory flow) and low (inadequate oxygen content) hematocrits during CPB.

Hypothermia has a profound effect on biochemical reactions. The Q10 for chemical reactions is a measure of changes in rate of reaction for each 10°C increase in temperature. For human tissues, Q10 is approximately 2. As a result, for each 10°C decrease in body temperature, the rate of reaction (i.e., metabolic rate or oxygen consumption) is roughly halved. This also affects drug pharmacokinetics and dynamics. Hypothermia also changes the oxygen-hemoglobin dissociation curve. As temperature decreases, the affinity of oxygen for hemoglobin increases (i.e., the oxygen-hemoglobin dissociation curve shifts to the left). This is associated with a lower partial pressure of oxygen in the tissues, and consequently oxygen delivery to the tissues is limited. Furthermore, as temperature decreases, gases become more soluble in liquid. For a given partial pressure, more gas will be dissolved in the plasma. The higher solubility of oxygen partially offsets the left shift in the oxygen-hemoglobin dissociation curve. Neutral water is water in which the [H ⁺ ] is equal to the [OH ⁻ ]. At 37°C, the pH of neutral water is 6.8. At 25°C, the pH of neutral water is 7. The neutral pH of water increases linearly by 0.017 units for each degree Celsius decrease in temperature. This affects optimal management of pH and Pa co ₂ during CPB.

As the perfusate temperature is increased to rewarm the patient, variable circulatory responses are observed depending on the anesthetics used, patient hematocrit, underlying disease, and other factors. SVR and MAP increase frequently during initial rewarming from 25°C to 32°C, but then usually decrease as temperature increases above 32°C.

The Stress Response

CPB is associated with a marked exaggeration of the stress response associated with all types of surgery. This is manifested by large increases in circulating epinephrine, norepinephrine, AVP, adrenocorticotropic hormone, cortisol, growth hormone, and glucagon. Elevated catecholamines may adversely affect regional and organ blood flow patterns. Catecholamines also increase myocardial oxygen consumption, which may adversely affect the balance of myocardial oxygen supply and demand at the time of reperfusion. Other stress hormones also increase catabolic reactions that increase energy consumption and potentially cause tissue breakdown and impaired wound healing.

Hyperglycemia is invariably encountered during CPB, especially in patients with diabetes mellitus. Contributors to hyperglycemia include decreased insulin production, insulin resistance (enhanced by stress hormones and hypothermia), decreased consumption (related to insulin resistance and hypothermia), increased glycogenolysis and gluconeogenesis (related to stress hormones), increased reabsorption of glucose by the kidney, and administration of glucose in some intravenous and cardioplegia solutions. Observational studies have demonstrated an association between post-CPB hyperglycemia and increased morbidity and mortality. Although measurement and control of blood glucose values during and following CPB is strongly recommended, the optimal “target range” for serum glucose concentrations, and means of achieving this level remain controversial.

Renin, angiotensin II, and aldosterone levels all tend to rise during CPB. Some patients display the so-called sick-euthyroid syndrome with reduced triiodothyronine (T3), thyroxine (T4), and free thyroxin levels, but normal thyroid-stimulating hormone levels. The etiology of this phenomenon is unclear, but it provides the rationale for administration of thyroid hormone in some patients with a low cardiac output syndrome postoperatively.

Inflammation

All patients undergoing cardiac surgery will experience a systemic inflammatory response (SIR). Although the trauma of major surgery per se induces inflammation, the CPB circuit accentuates this response. SIR represents unphysiologic activation of the innate immune system resulting in a whole-body response resembling that associated with sepsis and trauma. There is a spectrum of responses ranging from near-universal evidence of very mild inflammation (fever, leukocytosis), to more significant clinical signs (tachycardia, increased cardiac output, decreased SVR, increased oxygen consumption, increased capillary permeability), to potentially frank organ dysfunction (cardiac, renal, pulmonary, gastrointestinal [GI], hepatic, central nervous system), and very rarely, to multiple organ dysfunction syndrome (MODS) and death.

Normal inflammation is a localized protective response composed of cellular and humoral components. When the localized inflammatory response becomes excessive, it may spill over to the rest of the body. The same response occurs when the injury is systemically widespread (e.g., CPB), in which case a generalized inflammatory response leads to diffuse end-organ damage. Nonspecific activators of the inflammatory response include surgical trauma and tissue injury, blood loss or transfusion, and hypothermia. However, CPB may independently activate the inflammatory response by several unique mechanisms. Contact activation occurs when blood interacts with foreign surfaces of the ECC. This activates the complement, coagulation, kallikrein-bradykinin, and fibrinolytic systems, as well as white blood cells and platelets. The use of cardiotomy suction contributes importantly to this response. Blood aspirated via cardiotomy suction becomes contaminated with tissue factor (TF), TF activator, and fibrin degradation products. Ischemia-reperfusion injury refers to damage to tissue caused when blood supply returns to the tissue after a period of ischemia. The absence of oxygen and nutrients from blood creates a condition in which the restoration of circulation results in inflammation and oxidative damage from the oxygen rather than reestablishment of normal function. The reintroduction of oxygen via restored blood flow promotes the formation of oxygen-free radicals, which damage cellular proteins, DNA, and plasma membranes. White blood cells (WBCs) carried to the area also release a host of inflammatory substances such as interleukins (ILs). As noted earlier, these activated leukocytes can build up in small capillaries to cause obstruction and more ischemia. Transient splanchnic hypoperfusion/ischemia during CPB damages GI mucosa to induce endotoxemia , which is a lipopolysaccharide in the cell wall of gram-negative bacteria. Endotoxin binds with lipopolysaccharide-binding protein to stimulate the release of tumor necrosis factor (TNF) from macrophages, thus potentially triggering SIR. Gaseous and particulate microemboli also induce an inflammatory response.

Once the inflammatory response is triggered, components of the immune and coagulation systems and various cells are activated which propagate the SIR. The complement system is activated by exposure of blood to foreign surfaces, endotoxin released from the GI tract, and heparin-protamine complexes. Its activation leads to the release of various substances (e.g., C3a, C3b, and C5a) that increase production of cytokines and leukotrienes, as well as capillary permeability and leukocyte-endothelial adhesion. Cytokines are released from activated monocytes, macrophages, lymphocytes, and the endothelium leading to both pro- and antiinflammatory effects. Nitric oxide (NO) production is upregulated, contributing to vasodilation, increased vascular permeability, and potential end-organ dysfunction. The release of leukotrienes are potent vasoconstrictors, and platelet-activating factor (PAF) contributes to activation of clotting, as well as inflammation. Tissue factor is expressed by many cells during CPB and initiates coagulation and release of cytokines. Activation of the Kallikrein-bradykinin system amplifies the inflammatory response and increases vascular permeability. Collagenases , gelatinases , and metalloproteases are released. Endothelins are released by endothelial cells and are potent vasoconstrictors.

The coagulation-fibrinolysis cascade is closely intertwined with the inflammatory response and both are activated by cardiac surgery and CPB. These lead to both bleeding and thrombotic-embolic complications. The endothelium is an active participant in a variety of physiologic and pathologic processes. It plays a major role in regulating vascular tone, membrane permeability, coagulation and thrombosis, fibrinolysis, and inflammation. It attracts and directs the passage of leukocytes into areas of inflammation through the expression of adhesion molecules. CPB causes extensive activation and dysfunction of the endothelium due to ischemia/reperfusion, exposure to inflammatory mediators, surgical manipulation, and hemodynamic shear stresses. Expression of adhesion molecules mediates the binding of neutrophils to the endothelium and translocation into the interstitium. Resultant neutrophil degranulation attacks the endothelial barrier function to induce capillary leak and tissue edema. Interaction of activated endothelium and neutrophils with the endothelium leads to tissue damage and end-organ dysfunction via microvascular occlusion or release of toxic metabolites and enzymes. B and T lymphocytes decrease in number and function following CPB, which may cause immunosuppression and increase the risk for infections. Through the production and release of leukotrienes, serotonin, chemokines, Platelet factor 4 (PF4), and other substances, platelets contribute to the inflammatory response.

The inflammatory response to major surgery itself and to CPB likely contributes to multiple organ injuries, coagulopathy, disseminated intravascular coagulation (DIC), infection risk, and death. In most patients, the early SIR resolves without significant injury as a result of discontinuation of the stimulus, dissipation of mediators, or the action of naturally occurring antagonists (e.g., IL-10). The variability in the expression, consequences, and outcome of the inflammatory response to CPB is the subject of much speculation. Factors likely to influence this variability include the preoperative condition of the patient, type and complexity of the surgery, and, perhaps most importantly, underlying genetic polymorphism.

Although some studies have found that modifying the ECC and practice of CPB (e.g., surface heparin coating, minimizing circuit size, leukofiltration, eliminating or reducing cardiotomy suction, and shortening bypass duration) and even elimination of CPB (e.g., off-pump coronary artery bypass graft [OPCAB]) reduce inflammatory markers, they do not eliminate the SIR to cardiac surgery and may not improve clinical outcomes.

Changes in Microcirculation and Tissue/Organ Perfusion

During CPB, cardiac output and arterial pressure can be maintained at “normal” values. However, decreases in oxygen consumption and increases in serum lactate concentrations during CPB, as well as evidence of organ dysfunction post-CPB suggest that tissue perfusion may be impaired. Factors contributing to this may include constriction of precapillary arteriolar sphincters caused by catecholamines, angiotensin, vasopressin, thromboxane, endothelin, and decreased release of NO, increases in interstitial fluid volume (edema), decreased lymphatic drainage, loss of pulsatile flow, “sludging” in the capillaries due to hypothermia, altered deformability of RBCs, microaggregation and adhesion of WBCs, platelets, and fibrin onto the endothelium, and microemboli (gas, lipids, cellular aggregates), some related to the use of cardiotomy suction. Suggested ways to optimize microcirculatory function during CPB include administration of vasodilators, use of pulsatile perfusion techniques, hemodilution to a hematocrit between 20% and 30%, use of microfiltration, minimizing return of unprocessed cardiotomy suction blood directly into the CPB circuit, and other antiinflammatory strategies.

Altered Pharmacology of Anesthetic Agents During Bypass

The pharmacokinetics and pharmacodynamics of anesthetic drugs are altered significantly during CPB. The causes of these changes include hemodilution with subsequent reduced plasma protein concentrations, hypothermia, lung isolation resulting in drug sequestration, and other mechanisms listed in Table 25.1 . Cardiac anesthesiologists are required to have a good understanding of CPB-related alterations of the pharmacology of anesthetic drugs, in order to avoid under- or overdosing, particularly during initiation of CPB and rewarming. Barry et al. published a systematic review of the impact of CPB on the pharmacology of anesthetic agents.

CPB alters the pharmacology of intravenous anesthetics, opioids, and neuromuscular blocking agents. Hemodilution during CPB results in the reduction of intravenous anesthetic and opioid concentrations. However, serum protein concentrations such as albumin are also reduced due to hemodilution, resulting in higher fractions of unbound and pharmacodynamically active intravenous anesthetics and opioids. The lower serum protein concentration, therefore, offsets the effect of reduced intravenous anesthetic concentrations due to hemodilution. Hepatic metabolism and renal clearance of anesthetic drugs will be slowed during CPB, primarily due to hypothermia and diminished organ perfusion, which results in increased elimination half-lives and increased blood levels. Remifentanil is inactivated via temperature and pH dependence of Hofmann elimination; the lower the temperature, the slower the inactivation of the drug with a reduction of about 30% for each 5°C drop in temperature. If the patient is cooled to 32°C, there will be an initial hemodilution-induced reduction in plasma levels which is offset by the temperature-induced reduction in metabolism after about 20 to 30 minutes. During CPB, opioids and muscle relaxants are sequestered in the lungs. Therefore, during weaning from CPB and subsequent lung perfusion, plasma levels of these drugs will increase. Accidental awareness is higher in cardiac surgery when compared with noncardiac surgery. Furthermore, there is an association of accidental awareness with the use of muscle relaxants in cardiac anesthesia supporting the use of short-acting neuromuscular blocking agents and monitoring their effect throughout the case.

Results of a recent meta-analysis demonstrated that volatile anesthetics during CPB reduce mortality and the incidence of myocardial infarction. Furthermore, they resulted in a lower need for inotropic medications and a shorter time to extubation. A recent multicenter international survey demonstrated that 36% of anesthesiologists use volatile anesthetics routinely as the only maintenance during CPB. Volatile anesthetics can cross the microporous polypropylene hollow fiber membrane oxygenator and it has been demonstrated that the oxygenator exhaust line concentration of volatile anesthetics correlates well with the concentration in arterial blood of the patients. Volatile anesthetic agents do not pass through Poly (4-methyl-1-pentene) (PMP) plasma tight diffusion membrane oxygenators, and thus TIVA must be used if these oxygenators are used during CPB. Hemodilution decreases the blood/gas partition coefficient of volatile anesthetics (resulting in a rapid onset and offset of anesthetic action) and hypothermia increases it, resulting in neutralization of their opposite effects during most phases of CPB. During rewarming, the increase in temperature results in a faster onset/wash-in of volatile anesthetics. Requirements for volatile anesthetics are temperature dependent with less demand during hypothermia. This has been demonstrated by the usage of depth of anesthesia monitors.

Gaseous Microemboli

Gaseous microemboli (GME) are ubiquitous during CPB and have been suspected as a contributor to the inflammatory response and ischemic organ injury, especially to the brain. Their presence has been documented by ultrasound studies, and sources and methods of reducing their occurrence have been extensively studied. Kihar and Oihashi studied the complexity of determining air bubbles by echocardiography. Emboli are more common in open-chamber surgery and with unclamping of the aorta. GME have been associated with various maneuvers by perfusionists (e.g., injections into the circuit). However, the significance of GME (vs particulate emboli) is controversial.

Central Nervous System

Cerebral dysfunction, which ranges from subtle neurocognitive dysfunction to frank stroke or coma, is not infrequent following CPB. In the Multicenter Study of Perioperative Ischemia Research Group (McSPI) study of 2417 patients undergoing CABG between 1991 and 1993, 6.1% experienced adverse cerebral outcomes. These were classified into two groups: 3.1% were type I (stroke, transient ischemic attack [TIA], or persistent stupor or coma) and 3.0% were type II (deterioration in intellectual function, confusion, agitation, disorientation, memory deficits or seizures without evidence focal injury). The cause of these abnormalities is multifactorial and includes hypoperfusion, macroemboli, microemboli, and the inflammatory response to CPB. The causes of cerebral dysfunction and strategies to minimize adverse cerebral outcomes are discussed in detail in Chapter 31 .

Although postoperative delirium (POD) and postoperative cognitive dysfunction (POCD) are distinct disorders, similarities in their likely mechanisms, risk factors, and long-term sequelae suggest they may be part of an underlying neurobiologic “injury continuum.” Both delirium and POCD are referred to as types of “neurocognitive dysfunction.” The 2018 recommendations for the nomenclature of cognitive change associated with anesthesia and surgery recommend that preexisting cognitive impairment and POD, as well as early (first 30 days), intermediate (30 days–12 months), and late (beyond 12 months) POCD be included under the overarching term of “perioperative neurocognitive disorders.” They recommend the severity to be indicated as “mild” or “major” based on the Diagnostic and Statistical Manual for Mental Disorders , fifth edition, criteria. Abnormalities detected in the first 30 days are termed “delayed neurocognitive disorders” (“DNCDs”), those present between 30 days and 12 months are termed “postoperative NCDs” (“POCDs”), and those present beyond 12 months are termed “NCDs.” The general topic of perioperative neurocognitive disorder recently was addressed by an international workshop.

Kidney Injury

RD, or acute kidney injury (AKI) ranges from a rise in creatinine and release of renal tubular proteins to severe renal failure requiring renal replacement therapy (RRT), so-called “cardiac surgery-associated AKI or CSA-AKI.” It remains a persistent and prevalent problem following cardiac surgery (15%–30%) and is associated with increased morbidity and short- and long-term mortality. ^, Even mild elevations of serum creatinine are associated with increased morbidity and mortality, while need for postoperative RRT is associated with mortality as high as 60%. In a single-center study of patients who developed cardiac surgery related AKI, 84% regained baseline renal function, whereas 11% were dialysis dependent (see Chapter 37 ).

In a systematic review of 32 studies of patients having undergone cardiac surgery, the incidence of AKI was 22% (interquartile range [IQR]: 14%–34%), and RRT was 3.1% (IQR: 2%–5%). A more recent single-center study of 7633 patients undergoing cardiac surgery with CPB between 2008 and 2019 reported an incidence of AKI of 22.4% (17.5% in isolated CABG, 26.2% in valve, and 32.7% in CABG plus valve). In this latter study, the 30-day mortality in patients with AKI was 12.5% versus 0.9% in those without.

Features of cardiac surgery and CPB generally accepted to contribute to AKI include the inflammatory response; ischemia/reperfusion; embolization (both micro- and macroemboli of gas, and atheroma); hypotension; low cardiac output; elevated inferior vena cava pressure; damage-associated molecules (e.g., high mobility group proteins, hemoglobin, myoglobin, and uric acid); transfusion of blood products; and administration of nephrotoxic drugs (e.g., IV antibiotics). CPB per se is commonly considered as one of the contributors to CSA-AKI. However, a consensus conference concluded that off-pump CABG is associated with a decreased incidence of RD at 30 days, but no decrease in the need for RRT.

Identified risk factors for AKI include prior cardiac surgery, intra-aortic balloon pump (IABP) need, higher blood loss during surgery, older age, duration of surgery, diabetes mellitus, lower left ventricular ejection fraction (LVEF), lower baseline glomerular filtration rate (GFR), and intraoperative blood product transfusion. ^, In a study of AKI after heart transplant, Jocher et al. reported that CPB time > 170 minutes and use of vasopressors and inotropes post-transplant were risk factors. AKI has been associated with the severity of atherosclerosis of the ascending aorta, the magnitude and duration of MAP below the lower limit of autoregulation in the brain, and a critically low systemic oxygen delivery (<280 mL/min/m ² ) during CPB. ^, Intravascular hemolysis and hemoglobinuria can also cause acute tubular necrosis. One study found that increased duration of rewarming > 37°C on CPB was associated with a 51% increase of AKI, but that the duration of rewarming at lower temperatures was not. Preexisting renal failure has been demonstrated to be associated with higher hospital mortality compared with patients without preexisting renal failure (10.9% vs 1.4%). Page 9

Several approaches to predicting the occurrence of postoperative AKI have been described with variable success. Preoperative score cards that include age, gender, baseline GFR and LVEF, diabetes, and type of surgery have successfully predicted postoperative AKI. Another model including baseline GFR, change in GFR upon arrival in ICU, change in GFR in first 12 hours, preoperative hemoglobin, packed red blood cells (PRBC) given intraoperatively, and CPB time predicted 12 hours postoperative AKI. Others have found an association of low urinary oxygen partial pressure in the early postoperative period, intraoperative and postoperative urinary KIM1 and postoperative urinary IL-18 levels, circulating levels of endothelial microparticles at 12 hours postoperatively, Cardiac Surgery Urinary Neutrophil Gelatinase-Associated Lipocalin score, and serum-free hemoglobin with the development of AKI.

Vandenberghe et al. reviewed the diagnosis of CSA-AKI. They noted that even though it typically is diagnosed based on a rise in creatinine and reduced urine output (Kidney Disease Improving Global Outcomes [KDIGO] criteria), creatinine is slow to rise; therefore, various biomarkers that permit earlier recognition and therapeutic interventions are coming into practice. Prominent biomarkers include neutrophil gelatinase-associated lipocalin, tissue inhibitor of metalloproteinases-2 (TIMP-2), and insulin-like growth factor–binding protein 7 (IGFBP7). Meersch et al. observed that a urinary TIMP-2 ∗ IGFBP7 level of 0.3 ng/mL 4 hours post-CPB was predictive of CSA-AKI. McIIroy et al. found that the combination of elevated urinary biomarkers (cysteine-c, kidney injury molecule-1, chemokine ligand 2, or IL-18) and a rise in serum creatinine at 3 hours was superior in predicting hospital mortality or RRT.

Renal hemodynamics during and after cardiac surgery demonstrate strong evidence for renal medullary ischemia and hypoxia during CPB, and that monitoring for this and manipulating the conduct of CPB to minimize this effect could reduce the incidence of AKI. Evidence of renal ischemia during CPB was documented by Lannemyer et al., who observed an increase in renal vasoconstriction (∼20%), decrease in percent of systemic flow to the kidney (∼28%) and renal oxygen delivery (∼20%), an increase in renal oxygen extraction (∼40%), and the release of protein makers of tubular injury. After CPB, renal oxygenation was further impaired. Changes in management such as increasing arterial flow rates from 2.4 to 3.0 L/min/m ² progressively improved renal oxygenation in patients during CPB. The renal resistive index also may be elevated in patients with AKI, which may reflect an increase in intra-capsular pressure (i.e., injury-related “renal compartment syndrome”). The renal resistive index can be measured using transesophageal echocardiography (TEE) and has been found to be elevated early post-CPB in some patients; this could be an early predictor of AKI.

Urine output is a crude indicator of renal function, but there is no correlation between the amount of urine output during CPB and the incidence of postoperative renal failure. Urine output is greater when MAP is higher, when pulsatile perfusion is used, and when mannitol is added to pump-priming fluids.

Meersch et al. reviewed the prevention of AKI , while many studies have looked at various methods to reduce the incidence of CSA-AKI. Maintaining oxygen delivery during CPB ≥ 280 to 300 mL/min/m ² compared with conventional arbitrary flow reduced the incidence of stage 1, but not of stages 2 to 3 AKI. Numerous drugs including statins, levosimendan, dopamine, and dexmedetomidine have been studied to evaluate their effects on CSA-AKI, but none have been found to have a consistently significant positive effect. Techniques such as leukodepletion filters during elective valve surgery also have had minimal effects on the incidence of AKI.

In summary, although CPB per se may contribute to AKI, other preoperative and intraoperative surgical factors (e.g., low hematocrit and transfusion of RBCs) and postoperative course and care, also contribute to it ( Fig. 25.2 ). ^, Studies comparing off-pump with on-pump CABG have found less RD, but not less renal failure or RRT by avoiding use of CPB. Thus the development of renal failure appears to depend more on the preoperative renal function and postoperative hemodynamic status than on various manipulations during CPB, although maintaining adequate oxygen delivery is likely important.

Cardiac Injury

Some degree of myocardial injury and cell necrosis, as evidenced by release of troponin, occurs during CPB and may result in myocardial stunning and dysfunction. However, frank myocardial infarction is relatively uncommon; cardiac enzyme changes which identify myocardial infarction and particular myocardial injury after cardiac surgery have recently been described more in detail.

With the placement of the aortic cross-clamp after the start of CPB, myocardial tissue hypoxia develops resulting in acidosis, increased lactate as adenosine triphosphate (ATP) is consumed, and Ca ²⁺ accumulation. In severe ischemia the muscle cell membrane is disrupted and intracellular components leak into the extracellular compartment. Mitochondria supply ATP to cardiomyocytes, and they also have been associated with activation of cell death pathways, modulating the balance between death and survival. The mitochondrial permeability transition pore (mPTP) sits in the inner mitochondrial membrane as a nonselective channel. A closed mPTP protects the cardiomyocytes during acidosis. However, mPTP opening results in uncoupling or impairment of oxidative phosphorylation, which results in intracellular ATP depletion and cell death.

There are different kinds of myocardial dysfunction after ischemic reperfusion: stunning, no-flow phenomenon, reperfusion arrhythmias, and lethal reperfusion injury. Myocardial stunning is a mechanical dysfunction, which is reversible (see Chapter 6 ). No-reflow describes the situation that a previously ischemic region cannot be reperfused. Reperfusion arrhythmias are usually treatable, and lethal reperfusion injury is mediated by intracellular calcium overload, reactive oxygen species (ROS), and inflammation.

Myocardial protection has been based on the inhibition of the opening of the mPTP and also on activation of the opening of the ATP-dependent potassium (KATP) channel. It has been shown that myocardial ischemia can induce protection through G-protein–coupled cell surface receptors (reperfusion injury salvage kinase [RISK] pathway) and also via TNF-alpha receptors (survivor activating factor enhancement [SAFE] pathway). Beyond cardiomyocytes, other myocardial protection targets include the endothelium, platelets and leucocytes, autonomic myocardial innervation, and extracellular vesicles.

In order to protect the myocardium from ischemia and reperfusion injury, hypothermia and cardioplegia have been shown to be beneficial. Optimizing the metabolic state of the myocardium is fundamental to preserving its integrity. The major effects of temperature and functional activity (i.e., contractile and electrical work) on the metabolic rate of the myocardium have been well described. With the institution of CPB, the emptying of the heart significantly reduces contractile work and myocardial oxygen consumption (Mv o ₂ ). Nullifying this cardiac work reduces the Mv o ₂ by 30% to 60%. With subsequent reductions in temperature, the Mv o ₂ further decreases, and with induction of cardiac arrest and hypothermia, 90% of the metabolic requirements of the heart can be reduced ( Fig. 25.3 ).

The composition of the various cardioplegia solutions used during cardiac surgery varies as much between institutions as it does between individual surgeons. Cardioplegia can be classified into blood-containing and nonblood-containing (i.e., crystalloid) solutions. Crystalloid cardioplegia has fallen out of favor, and blood cardioplegia in various combinations of temperatures and routes of delivery is the most used solution. However, even within the category of blood cardioplegia, the individual chemical constituents of the solution vary considerably with respect to the addition of numerous additives. Table 25.2 outlines the various additives to cardioplegia solutions along with their corresponding rationale for use. Blood cardioplegia has the potential advantage of delivering sufficient oxygen to ischemic myocardium to sustain basal metabolism, or even augment high-energy phosphate stores, as well as possessing free radical scavenging properties. Although hypothermic cardioplegia is the most commonly used temperature, numerous investigations have examined tepid (27°C–30°C) and warm (37°C–38°C) temperature ranges for the administration of cardioplegia. Although hypothermia clearly offered some advantages to the myocardium in suppressing metabolism, it may have some detrimental effects.

Splanchnic, Gastrointestinal, and Hepatic Effects

GI complications are relatively uncommon (∼1.2%, range: 0.3%–6.1%) following cardiac surgery, but are associated with morbidity and high mortality (∼34%, range: 9%–87%). ^{, ,} These complications include GI bleeding (∼33% of GI complications and ∼0.4% of all cardiac surgery cases, respectively), mesenteric ischemia (13% and 0.16%), pancreatitis (3% and 0.13%), cholecystitis (9% and 0.11%), peptic ulcer (6% and 0.07%), diverticulitis (3% and 0.04%), liver failure (2% and 0.02%), and others (21%).

Multiple risk factors have been identified, but the most prominent preoperative factors include age > 70, low cardiac output, peripheral vascular disease, and chronic renal failure. The most prominent intraoperative factors include reoperative procedures, CABG plus valve procedures, duration of CPB, transfusion, and administration of vasopressors. A complicated postoperative course (e.g., sepsis, mediastinitis, bleeding, and prolonged mechanical ventilation > 24–48 h) is frequently associated with GI complications. The presumed cause of these complications is splanchnic ischemia that may be related to abnormal systemic hemodynamics (low flow, low MAP, lack of pulsatility), SIR, and microemboli.

Clinical and animal studies suggest that, although global splanchnic blood flow appears to be preserved during high-flow CPB, splanchnic flow will be compromised early in the hierarchy of regional blood flow whenever systemic flow is reduced. Administration of vasoconstrictors such as phenylephrine, norepinephrine, and vasopressin likely further reduces splanchnic blood flow. Furthermore, increased intestinal permeability, decreased gastric or intestinal mucosal pH and increased mucosal P co ₂ , decreased mucosal blood flow, and endotoxemia all suggest that mucosal ischemia can occur during CPB. Although SIR likely contributes to GI ischemia, conversely GI ischemia may play a primary role in the development of SIR syndrome and injury of other organs. Thus the GI tract is both the cause and a target of SIR in cardiac surgery.

Hyperbilirubinemia (>2.50–3.0 mg/dL) is encountered in approximately 25% (range: 9%–40%) of cardiac surgery patients, with an associated mortality of approximately 4%. In a recent systematic review and meta-analysis of 10 studies of 6100 patients, the incidence of hyperbilirubinemia (defined as >3 mg/dL in seven of the studies) was 23%. Preoperative risk factors included elevated right atrial (RA) pressure, bilirubin, and aspartate aminotransferase (AST), while intraoperative risk factors included CPB time, aortic cross-clamp time, and amount of blood transfused. Postoperative hyperbilirubinemia was associated with increased in-hospital mortality.

Liver failure occurs in 0.03% to 0.1% of cardiac surgery patients with an extremely high associated mortality of 56% to 78%. As with renal failure, hepatic dysfunction appears to be more dependent on hemodynamic status before and after CPB than on any direct effect of CPB. The risk of postoperative jaundice increases in the setting of high RA pressures, persistent hypotension after CPB, or significant transfusion.

Mesenteric ischemia is relatively rare (0.15%), but associated with a very high mortality (60%–90%). A retrospective cohort study compared 108 patients who developed mesenteric ischemia after cardiac surgery with 3:1 matched patients who did not. They observed that serum lactate concentrations > 3 mmol/L at the end of surgery, and lactate that remained >3 mmol/L at 24 hours postoperatively, were associated with a substantial increase in risk of mesenteric ischemia (four- to eightfold).

As with other adverse effects attributed to CPB following cardiac surgery, most studies have not found a reduced incidence of GI complications when CABG is done off-pump. Chapter 37

Pulmonary Injury

Pulmonary complications and acute lung injury are common after cardiac surgery. During CPB, the lungs are deprived of pulmonary blood flow, and receive reduced bronchial arterial flow. Thus the lungs become somewhat ischemic. Although less frequent than in the past, postoperative pulmonary complications remain a leading cause of morbidity and mortality. ^{, , ,} Manifestations range from the nearly ubiquitous decline in Pa o ₂ /Fi o ₂ ratio to ARDS (incidence: 0.4%–3%, mortality: 15%–70%). Other pulmonary complications include pulmonary effusions, pulmonary edema, transfusion-related acute lung injury (TRALI), pneumonia (incidence: 2%–10%, mortality: up to 43%), diaphragmatic dysfunction, and phrenic nerve paralysis.

Etiologies of these complications include an inflammatory response, activation of coagulation, pulmonary ischemia and reperfusion, left heart failure, atelectasis from absent ventilation during CPB, mechanical injury from entering the pleural cavities, blood transfusion, and perioperative lung management. Preoperative lung disease, poor left ventricular (LV) function, age and genetic makeup comprise other risk factors.

A single-center study of 4262 patients undergoing cardiac surgery between 2015 and 2017 reported an incidence of respiratory failure of 21%. The authors developed a risk score for respiratory failure that included body mass index (BMI) ≥ 30, diabetes, chronic lung disease, home oxygen, recent pneumonia, GFR < 60, previous cardiac intervention, NYHA classification ≥ 3, CPB duration, cardiogenic shock, mechanical support, total blood products, and American Society of Anesthesiologists (ASA) score ≥ 4. Liu et al. developed a nomogram to predict ARDS after cardiac surgery that included diabetes, preoperative albumin, CPB time, and APCHE II score after surgery, with an area under the curve (AUC) of 0.785.

Sanfilippo et al. reviewed the prevention and management of ARDS post-cardiac surgery; techniques to minimize lung injury associated with CPB remain controversial. Lung protective ventilation (low tidal volume, positive end-expiratory pressure [PEEP], recruitment maneuvers, and minimizing Fi o ₂ prior and following CPB) has been advocated. Typically, ventilation is interrupted, and the lungs are exposed to atmospheric pressure during CPB based on the assumption that ventilation is not required, as well as to facilitate surgical exposure. The possible benefits of applying continuous positive airway pressure (CPAP) or intermitted ventilation during CPB continue to be debated. Two meta-analyses of 17 and 15 RCTs involving 1169 and 748 patients, respectfully, recently were reported. ^, Both found that CPAP and/or ventilation during CPB temporarily may improve oxygenation, but there is little evidence that they have important clinical benefit beyond the immediate post-CPB period. A survey of practice of mechanical ventilation in 56 Italian cardiac surgery centers revealed significant heterogeneity. When not on CPB, 91% used a tidal volume of 6 to 8 mL/kg, 77% used PEEP of 3 cm H ₂ O, and 71% used an Fi o ₂ of 50% to 80%. While on CPB, 75% stopped ventilating, 16% applied PEEP, and 9% continued to ventilate.

Since some of the adverse effects of traditional CPB are attributed to lung ischemia due to interruption of pulmonary perfusion, some have advocated simultaneous lung perfusion and ventilation (autologous oxygenation) during cardiac surgery. However, a recent meta-analysis evaluating oxygenated blood perfusion of the lungs during CPB concluded that the benefits are uncertain and may be associated with increased mortality. Lung injury and its prevention and management are further discussed in Chapter 33 .

Systemic Blood Flow

The flow rate most commonly used during normothermic CPB is 2.2 to 2.8 L/min/m ² , which approximates the cardiac index of a normothermic anesthetized patient with a normal hematocrit. It is rational to use higher flows in the presence of reduced hematocrit and is common to accept lower flows during hypothermia, but there is little clinical evidence to guide optimal flow rates in these circumstances. In healthy animal models, even at flows of 2.4 L/min/m ² , muscle flow is significantly reduced during CPB, and as flow is progressively reduced, first splanchnic, then renal, and eventually (only at extremely low flows) cerebral flows are reduced.

The European guidelines suggest that pump flow be based on lean body mass in obese patients (BMI > 30). They also recommend that pump flow be guided by oxygenation, respiratory and metabolic parameters (e.g., Sv o ₂ and lactates), and flow rate should be adjusted according to the arterial oxygen content in order to maintain a minimal threshold of oxygen delivery (D o ₂ ) under moderate hypothermia.

Pulsatility

The importance of pulsatile flow remains controversial and unresolved. It is more commonly used in Europe than in the United States. ^{, ,} One major problem is the difficulty in transmitting significant pulsatile energy into the patient through the arterial cannula. A relatively simple means of generating pulsatile flow during CPB is with use on an IABP. The benefits of prophylactic IABP during cardiac surgery in high-risk patients remain controversial. ^, The success of long-term nonpulsatile flow as provided with current continuous flow left ventricular assist devices (LVADs) used for destination therapy, suggests that pulsatile flow is not critical to deliver end-organ perfusion (see Chapter 22 ).

Systemic Arterial Pressure

The acceptable or optimal range of MAP during CPB has been debated since the advent of CPB. ^, If pressure is too low, perfusion of critical vascular beds may be compromised, especially if vascular disease is present. Conversely, excessive arterial pressure increases noncoronary collateral flow to the heart during aortic cross-clamping (hence “washing out” myocardial protection with cardioplegia), bronchial flow to the lungs (increases blood return to the left heart), and places strain on arterial clamps and suture lines. Hemodilution itself will cause a decrease in MAP due to its effect on viscosity and SVR. Target pressures have been chosen empirically on the basis of physiologic principles, expert opinion, observational studies, and local practice. They often incorporate factors such as patient age, usual preoperative blood pressure, coexisting disease (e.g., renal, diabetes), and evidence of vascular disease. Many teams maintain MAP at 50 to 60 mm Hg during adult CPB, assuming the lower limit of autoregulation of the brain is 50 mm Hg; however, recent clinical data have observed that the lower limit of autoregulation of the brain during CPB in adults may vary between 43 and 90 mm Hg (see later). The review article on CBF and metabolism during CPB published by Schell et al. more than 25 years ago still is relevant.

Practice by experienced groups varies widely. A survey of 271 European centers in 2019 reported that 26% targeted 51 to 70 mm Hg, 17% targeted 71 to 90 mm Hg, 5% targeted 40 to 50 mm Hg, while 34% individualized the target. The scientific approach to the management of MAP during CPB was largely introduced by the landmark study by Govier et al. in 1984. They found, based on measurements of CBF during hypothermic CPB, no significant effect of variations of MAP between 35 and 85 mm Hg. However, in 1995 Gold et al. published an RCT of patients undergoing CPB that compared a high (80–100 mm Hg, actual average achieved about 70) versus a low (50–60 mm Hg, actual average achieved about 52) target during CPB. They found the incidence of the combined 6-month outcome of mortality and major cardiac or neurologic morbidity was lower in those managed with the higher MAP (4.8% vs 12.9%). However, the incidence of specific adverse outcomes was not different in the two groups.

In a more recent RCT, Siepe et al. compared the incidence of early (48 h) POD and POCD in 92 patients undergoing elective or urgent on-pump CABG managed with higher MAP (80–90 mm Hg, actual average: 84 ± 11 mm Hg) versus lower MAP (60–70 mm Hg, actual average: 65 ± 8 mm Hg) during CPB. The incidence of POD was much lower (0% vs 13%) and the drop in Mini-Mental State Examination scores were less (1.1 vs 3.9) in those managed with the higher pressure. Interestingly, the cerebral oxygen saturations measured using NIRS (i.e., cerebral oximetry) were nearly identical in the two groups. Studies such as these have led to the popular adoption of the use of higher perfusion pressures during CPB.

However, this debate was reenergized by a recent provocative study by Vedel et al. In their single-center RCT of 197 adult patients who underwent cardiac surgery during normothermic CPB, the authors compared patients managed with low MAP (40–50 mm Hg, mean: ∼45 ± 4) versus high MAP (70–80, mean: ∼67 ± 5). The latter was achieved by administering phenylephrine or norepinephrine. New evidence of cerebral injury on diffusion-weighted MRI was observed in 54% of all patients and was not different in the two groups. The volume of these new lesions also was similar, and the incidence of clinical evidence of stroke and new early and late postoperative cognitive decline also were not different in the two groups. The authors concluded that vasopressor-facilitated high-targeted MAP did not appear to be beneficial.

On the other hand, opposite findings were reported in a recent study by Sun et al. They reported on a retrospective analysis of prospectively collected continuous arterial blood pressure during cardiac surgery using CPB in 7457 patients. They found that the time MAP was 55 to 64 mm Hg and <55 mm Hg (compared with 65–74 mm Hg) during CPB was associated with an increased risk of stroke (2.1% and 3.8% vs 1.6%, respectively) and that each progressively longer 10 minutes that MAP was <55 mm Hg was an independent predictor of stroke. Other independent predictors of stroke risk included older age, history of hypertension, combined CABG/valve surgery, emergency surgical status, prolonged CPB duration, and postoperative new-onset atrial fibrillation.

It is difficult to reconcile the results of these studies. One was much larger in size, but retrospective and observational, while the other was smaller, but prospective and randomized. Differences in anesthetic technique and the conduct and management of CPB, which were not fully defined, and criteria for diagnosing stroke may explain some of these discrepant observations.

McEwen  et al recently published a systematic review of 8 randomized controlled trials (RCTs) comparing low  (50 to 70, average achieved 55 mm Hg) versus a high (> 60 to < 80 average achieved 74 mm Hg) targeted MAP during CPB involving 1116 patients. They found no difference in incidence of delirium, cognitive decline, stroke, ALI, or mortality in those managed with the low vs high MAP targets.

Rather than base the MAP target on an arbitrary level or on patient characteristics, it has been suggested that a more rational target would be the individual patient’s cerebral autoregulatory range. Over the past several years, the group at Johns Hopkins University has attempted to identify the cerebral autoregulatory range of MAP in patients during CPB. In 2012, they reported using transcranial Doppler (TCD) monitoring of the middle cerebral arteries and NIRS monitoring to identify the lower limit of cerebral autoregulation in patients undergoing CPB. They found the average lower limit of autoregulation was 66 mm Hg (95% prediction interval: 43–90 mm Hg) and notably that there was no relationship between preoperative MAP or a history of diabetes, hypertension, prior cerebrovascular accident and this lower limit of autoregulation. Their study demonstrated that real-time monitoring of autoregulation with cerebral oximetry index is possible, and may provide a more rational means for individualizing MAP during CPB. This group recently reported on a retrospective study of 614 patients who underwent cardiac surgery at three hospitals using TCD to identify the range of cerebral autoregulation. Monitoring could be used to identify the optimal MAP during CPB in 71% to 83% of patients. They found that optimal MAP during CPB was 78 ± 11 mm Hg and, as before, that optimal MAP was not influenced by age or history of hypertension or diabetes. Importantly, although the average optimal MAP during CPB was 78 ± 11 mm Hg, the lower limit of autoregulation in 17% of patients was above this range, which, if chosen, could lead to possible cerebral hypoperfusion. On the other hand, in 29% of patients, the upper limit of autoregulation was below this range, which, if chosen, could lead to possible cerebral hyperperfusion. Thus it is not possible to rely on the average optimal MAP for this population on all patients. This group also found that perfusion at a MAP below the lower limit of autoregulation could lead to increased morbidity (e.g., strokes) and mortality, whereas MAP above the upper limit of autoregulation may be associated with an increased incidence of POD. They have reported that keeping the MAP above the lower limit of autoregulation reduces the incidence of delirium, but did not reduce the incidence of a composite neurologic end-point or any of it components. They also reported that when patients had a MAP below the lower limit of autoregulation AKI was more common.

In summary, the optimal MAP during CPB remains unclear. A reasonable hypothesis is that this should be best guided by maintaining the MAP within the autoregulatory range of CBF. However, studies have shown that this may vary considerably in individual patients from traditionally accepted values and is not predictable. Although prior studies have suggested an association between a MAP below or above the limit of autoregulation during CPB and harm, and although it is reasonable to suspect that maintaining patient MAP within the patient’s autoregulatory range would improve outcome, no prospective studies have documented such a benefit. Such studies are ongoing and will be required before this technique should be advocated for routine clinical care. The Johns Hopkins group has used analysis of NIRS instead of the more-difficult-to-obtain TCD to identify the autoregulatory range clinically. Furthermore, the best method of increasing arterial pressure (e.g., increasing flow, increasing hematocrit, or use of vasoactive medications) is undetermined. The decision as to the level of arterial pressure to maintain during CPB in any patient must be left to the clinical judgment of the team, based upon an assessment of the benefits and risks of higher or lower perfusion pressures for each patient. The 2019 European guidelines recommend maintaining MAP between 50 and 80 mm Hg by administration of vasopressors or vasodilators. The impact of MAP during CPB on the CNS is further discussed in Chapter 31 .

Central Venous Pressure

Organ perfusion pressure is the difference between MAP and venous pressure. Normally the latter is low and relatively insignificant, but due to problems with venous cannulation and drainage, it may become unacceptably high and compromise organ perfusion, especially when maintaining relatively low MAPs. Avoiding elevated pressure in the jugular veins (i.e., in the superior vena cava [SVC]) is particularly important for cerebral perfusion and demands accurate monitoring of the venous pressure cephalad to the end of the venous cannula.

Hematocrit/Hemoglobin

The optimal or lowest acceptable hematocrit during CPB remains unresolved. ^, A reduced hematocrit may improve microcirculation during hypothermia, but the current widespread use of tepid or normothermic CPB makes this unnecessary or even dangerous. Unfortunately, both severe anemia and red blood cell (PRBC) transfusion have been found to increase the risk of adverse postoperative outcomes. Observational studies in the last 14 years have suggested a critical hematocrit level of between 20% and 24% (hemoglobin of 7–8 g/dL) during CPB. This is likely influenced by the patient’s temperature, systemic blood flow, and vascular disease. Since administration of PRBCs has adverse consequences, efforts should be directed at minimizing the occurrence of a low hematocrit during CPB (instead of treating it with allogeneic RBC transfusion). This may be achieved by preventing and correcting preoperative anemia (use of preoperative anemia clinics), reducing prime volumes (employment of minimized circuits), use of retrograde or antegrade autologous priming, rigorous hemostasis, and retrieval of shed blood.

In a survey of 271 European centers in 2019, 37% reported that their transfusion trigger was hemoglobin ≤ 7g/dL, 22% used a trigger of < 8 g/dL, and 4% a trigger of < 9 g/dL, while 33% individualized the trigger for different patients. The European guidelines recommend that PRBCs be transfused during CPB if the hemoglobin value is <6.0 g/dL (Class I recommendation, level of evidence C); PRBCs should not be transfused during CPB if the hematocrit is >24%. They state that for hematocrit values between 18% and 24%, PRBCs may be transfused based on an assessment of the adequacy of tissue oxygenation (D o ₂ is maintained at >273 mL/min/m ² and cerebral oximetry is satisfied).

While these are not unreasonable suggestions, to make them recommendations seems problematic, especially the contraindication to giving PRBC if the hematocrit is >24%. The recent Society of Cardiovascular Anesthesiologists (SCA) Clinical Practice Improvement Advisory for Management of Perioperative Bleeding and Hemostasis in Cardiac Surgery Patients recommended that PRBCs be given when the hemoglobin is <7.5 g/dL, but not when the hemoglobin is more than 10 g/dL. Three recent studies found no benefit from a restrictive versus more liberal transfusion threshold in patients undergoing cardiac surgery. Encouraging teams to make decisions based on markers of inadequate oxygen delivery (e.g., hemodynamic instability, increased lactate levels, severe metabolic acidosis, or other signs of ischemia in various organs), rather than the hemoglobin concentration alone would seem more prudent. The most recently published multidisciplinary clinical practice guidelines for patient blood management from the STS/SCA/AmSECT/SABM task force identified 23 new or updated recommendations. Among them were several class I recommendations including preoperative identification of high-risk patients for transfusion, use of synthetic antifibrinolytic agents, retrograde autologous priming, reduced CPB circuit primes, and use of autotransfusion/cell salvage.

Temperature

Until recently, CPB was conducted utilizing moderate hypothermia (28°C–32°C) both to reduce oxygen demands on the oxygenator and the risk of neurologic injury. In recent years, “tepid” (34°C–36°C) or normothermic bypass is more commonly employed to both reduce time spent in cooling and warming and to minimize the risks associated with rewarming. Current clinical outcome evidence does not strongly support one method or another. Despite lack of good clinical evidence of neuroprotective effect of moderate hypothermia during CPB (excluding deep hypothermia with circulatory arrest [DHCA]), many groups continue to use mild-to-moderate hypothermia for protection against unexpected or accidental periods of hypoperfusion and to permit lower flow rates or arterial pressure. There remains some controversy regarding location to measure temperature, how pH and Pa co ₂ should be managed during hypothermia (pH stat or alpha-stat), and acceptable cooling and warming gradients. These issues have been addressed in the 2015 STS, SCA, and AmSECT Clinical Practice Guidelines for Temperature Management During CPB . Key recommendations include:

• Oxygenator arterial outlet temperature is the recommended surrogate for cerebral temperature (class I recommendation, level C evidence)

• Oxygenator arterial outlet temperature is assumed to underestimate cerebral temperature (class I, level C)

• Nasopharyngeal or pulmonary artery (PA) temperatures are reasonable estimates of core temperature after weaning from CPB (class IIa, level C)

• Arterial outlet temperature should be limited to <37°C during CPB to prevent cerebral hyperthermia (class I, level C)

• Peak cooling temperature gradient between the oxygenator arterial outlet and venous inlet should not exceed 10°C to prevent the generation of gaseous emboli (class I, level C)

• Peak warming temperature gradient between the oxygenator arterial outlet and venous inlet should not >10°C to prevent outgassing (class I, level C)

• During warming, when oxygenator arterial outlet temperature ≥ 30°C, warming gradient between the oxygenator arterial outlet and venous inlet should be ≤4°C and/or warming rate ≤ 0.5°C/min

PaO ₂

Because of the theoretic concerns with the danger of hyperoxia (production of toxic free radicals and aggravation of reperfusion injury), it is recommended to avoid high levels of PaO ₂ . However, acceptable levels have not been defined and clinical evidence supporting the advantage of avoiding hyperoxia is not available. Recent studies have offered conflicting conclusions. ^{, ,} The result of the Risk of Oxygen during Cardiac surgery (ROSC) prospective RCT may be helpful.