Pathobiology of CPB

Placing patients on CPB elicits a rapid and profound inflammatory response. This response is highly complex and involves several interactive cellular and humoral pathways. The inflammatory response to CPB is not mechanistically dissimilar to that occurring after infection. Indeed, the spectrum and implications of the CPB-induced inflammatory response are similar to those observed in the infectious setting. The spectrum of this inflammatory response ranges from development of the less severe systemic inflammatory response syndrome (SIRS) to severe multiorgan dysfunction syndrome (MODS) ( Table 50-13 ). ^[211] Although SIRS represents the less severe end of the inflammatory response spectrum and is usually associated with short-term survival, it may be associated with or lead to a long-term increase in morbidity and mortality if the paradigm that is known to exist for sepsis^[212] also applies to patients undergoing cardiac surgery with CPB ( Fig. 50-34 ). In the clinical setting, a clear distinction between the host inflammatory response to CPB and that to sepsis is frequently not justified. Several host (e.g., diabetes), environmental (e.g., nosocomial infections), and intraoperative (e.g., gut translocation) factors, as well as CPB itself, may predispose the patient to infection.

A detailed description of the mechanisms underlying perioperative injury in cardiac surgery patients is beyond the scope of this chapter. The interested reader is referred to an extensive and exhaustive review by Laffey and colleagues ^[213] and to work by Gravlee and associates.^[214] Although several preoperative factors and patient-related conditions (e.g., active ischemia, impaired ventricular function, diabetes) may modulate the host inflammatory response, CPB itself evokes a profound multifaceted,

TABLE 50-13 -- Criteria for diagnosis of SIRS, sepsis, and MODS

SIRS: Diagnosis requires the presence of two or more of the following:

Temperature >38°C or <36°C

Heart rate >90 beats/min

Respiratory rate >20 breaths/min or PaCO2 <32 mm Hg

Leukocytes >12,000, <4,000/mm3 , or >10% immature (band) forms

Sepsis: SIRS with documented infection

Severe Sepsis: Sepsis associated with organ dysfunction, hypoperfusion, or hypotension

Septic Shock: Sepsis with hypotension despite adequate resuscitation, along with the presence of perfusion abnormalities

MODS: A state of altered organ function in an acutely ill patient such that homeostasis cannot be maintained without intervention

MODS, multiple organ dysfunction syndrome; SIRS, systemic inflammatory response syndrome.

From Laffey JG, Boylan JF, Cheng DC: The systemic inflammatory response to cardiac surgery: Implications for the anesthesiologist. Anesthesiology 97:215–252, 2002.

complex inflammatory host response. CPB and the host inflammatory response to CPB have clear, direct, and immediate implications but also indirectly alter outcome in that they can modulate (usually adversely) the patient's ability to respond to subsequent challenges such as infection. Hence, the term "multiple-hit syndrome" implies that the derangements that ensue after CPB involve multiple initiating and exacerbating events.

Several perioperative factors may initiate an inflammatory response, including factors that are not necessarily

Figure 50-34 Schematic diagram of the sequence of events by which cardiopulmonary bypass may lead to the development of systemic inflammatory response syndrome (SIRS).

1976

Mechanistically, the inflammatory response is mediated by multiple interactive pathways. The specific outcome in any individual patient depends on the pattern (magnitude, type, time-course) of the response and the interaction between the multiple pathways. The protean nature of the response likely reflects multiple variables, including underlying genetic polymorphism, differential preoperative health, and intraoperative factors such as the duration of CPB. The potential salutary influence of perioperative management (e.g., optimizing circulatory support, optimizing respiratory support) on the inflammatory response and thus on the propensity for the development of complications is probably important, although ideal studies that would definitively prove this are almost impossible to conduct.

Figure 50-35 Schematic diagram of the balance between the beneficial and adverse effects and the resultant clinical sequelae of the inflammatory response after cardiac surgery. CPB, cardiopulmonary bypass; SIRS, systemic inflammatory response syndrome.

The inflammatory response to CPB is initiated immediately when the patient's blood is exposed to the CPB tubing and oxygenator. However, ischemia-reperfusion injury during CPB (myocardial ischemia-reperfusion with aortic clamping and unclamping, noncardiac ischemia-reperfusion if organ hypoperfusion occurs during CPB) also contributes to the inflammatory response. The role of gut translocation as a contributor to CPB-associated injury remains unresolved, with the better-conducted studies failing to demonstrate an association between intramucosal pH and endotoxemia. Specific pathways involved in the response to CPB include the following:

1. Cellular immune activation with adhesion, margination, and translocation of granulocytes and macrophage activation. This cellular immune response is central to the inflammatory response associated with CPB.
2. The complement pathway, specifically, the alternative pathway thereof.
3. The cytokine system with both proinflammatory and anti-inflammatory cytokine activation resulting in immune modulation.
4. Coagulation and fibrinolytic system activation.
5. Upregulation of inducible NOS.
6. Activation of the oxidant-stress pathway resulting in the production of ROS, including superoxide and hydroxyl radicals and peroxynitrite.