7.3.3 Systemic Inflammatory Syndrome (SIRS)

Inflammation is a defence reaction of the body against an invader. It is a complex and redundant system, with many amplifying feedback loops, but also inhibitory circuits that limit its scope. If wounded, the skin or mucous membrane barrier is broken. The body must both protect itself from toxins and prevent blood loss. This is why the inflammatory reaction is closely linked to coagulation. Normally, blood is solely in contact with the vascular endothelium, with which it maintains a constant balance. When it encounters a non-endothelialized surface such as a lesion or foreign body, it triggers a whole cascade of protective phenomena. The inflammatory process is designed to remain localised, but sometimes the response is exaggerated or the aggression is systemic, as is the case when blood comes into contact with foreign surfaces like an ECC circuit. The body's defence reaction then becomes a Systemic Inflammatory Reaction Syndrome (SIRS).  

In cardiac surgery, SIRS is triggered by a range of phenomena: contact with the surfaces of the bypass circuit, contact with air in cardiotomy suctions, hypothermia, heparinisation and heparin-protamine complexes, ischaemia and reperfusion, or toxins released in the gastrointestinal tract. Approximately 20% of low-risk patients develop SIRS-related complications [19,25]: coagulopathy, interstitial fluid accumulation (cerebral oedema, gas exchange impairment), multi-organ dysfunction (neurological disorders, cardiac, renal and hepatic failure).

• Early phase; is initiated by contact of blood with a non-endothelialized surface such as the ECC (contact pathway), and consists of two interrelated components:

  • The humoral pathway, which includes 3 elements, coagulation, complement and cytokines;
  • The cellular pathway, consisting of the white blood cells and the endothelium.
• Late phase: is related to ischaemia and reperfusion injury and the release of endotoxins, mainly from the gastrointestinal tract.

Humoral pathway

Complement is the body's oldest means of defence, as prove sea urchins. It consists of a set of 35 molecules that assist the antigen-antibody reaction or anti-bacterial defence, and which converge on specially powerful proteins which can perforate cell membranes (MAC: membrane attack complex) [49]. Closely linked to the coagulation cascade, the complement chain includess 3 distinct pathways (classical, alternative and lectin) which converge towards the cleavage of factor C3 into C3a (anaphylatoxin I, histamine release) and C3b, which in turn cleaves factor C5 into C5a (anaphylatoxin II, leukocyte activator) and C5b which is the first component of the MAC complex (Figure 7.21).

Figure 7.21: Simplified diagram of complement activation. The complement chain includes 3 pathways that are initiated by distinct triggers: the classical pathway (antigen-antibody Ag-Ac reaction), the alternative pathway (direct activation by contact) and the lectin pathway (bacterial membrane site). Through various intermediate steps, they converge on the cleavage of factor C3 into C3a (anaphylatoxin I, histamine release) and C3b, which in turn cleaves factor C5 into C5a (anaphylatoxin II, leukocyte activator) and C5b, which is the first component of the MAC (membrane attack complex), a protein complex that attacks cell membranes and is the ultimate result of the complement pathways. The many intermediate steps are not illustrated here.

The kinin-kallikrein system includes a group of serum proteins involved in the regulation of vascular tone and permeability. They circulate as inactive kininogens, and are activated by kallikreins release in injured tissue. This reaction gives rise to bradykinin which is vasodilatory (secretion of NO and prostacyclin). There is a plasma kallikrein that circulates as inactive prekallikrein and is activated by coagulation factor XIIa (Hageman factor or contact factor). As the bradykinin formed is itself an activator of Factor XII, a self-amplifying system of the link to the coagulation cascade is formed here.

Cytokines are polypeptides that ensure communication between cells and trigger specific activities depending on their targets [48].

• TNF-alpha (Tumor necrosis factor); secreted by monocytes, mast cells and T-lymphocytes in response to bacterial endotoxins, it activates the inflammatory chain. In high concentrations, it causes septic shock symptomatology with cardiodepressor, vasodilator, thrombogen and capillary permeabilising effects.
• Pro-inflammatory interleukins (IL-1, IL-6, IL-8); secreted by leukocytes, they activate the production of C-reactive protein, fibrinogen and catecholamines; they cause hyperglycaemia, leukocytosis and fever.
• Anti-inflammatory interleukins (IL-10); they provide negative feedback that prevents these chain reactions from spiralling out of control.

The coagulation cascade (see Figure 7.20) is intimately connected to the inflammatory response. Thrombin, for example, potentiates several effects: activation of polymorphonuclear cells and platelets, secretion of IL-6 and IL-8, activation of C3. Platelets in turn stimulate leukocyte adhesion to the vascular wall. Despite heparinisation, thrombin production continues and maintains a consumption coagulopathy [25].

Cellular pathway

Polymorphonuclear neutrophils responsible for phagocytosis of pathogens contain granules that can release proteolytic enzymes, oxygen radicals and inflammatory mediators. When vascular injury occurs, they first roll onto the surface of the endothelium through the attachment of molecules called selectins,  then adhere to the injured endothelium through the anchoring of molecules called integrins (adhesion molecules). Thirdly, they migrate into the interstitial space by chemotaxis to release their bactericidal substances [45].

Basophils, activated by the complement pathway, mainly secrete histamine, which increases capillary permeability and eases the transfer of formed elements; it also causes vasodilation and bronchoconstriction. Mast cells look alike basophils but are confined to the perivascular space of organs and do not circulate; when stimulated by complement or thrombin, they secrete various inflammatory mediators including many interleukins. Finally, monocytes are macrophages that release a series of inflammatory factors (interleukins, TNF-alpha) and phagocyte foreign elements [48].

Endothelial cells are the natural regulators of coagulation and inflammation. They respond to the presence of thrombin, factor C5a, cytokines and interleukins by secreting selectins and integrins that immobilise macrophages. They manage vascular tone through the release of vasodilator substances such as NO, histamine and bradykinin or vasoconstrictor substances such as endothelin-1 or noradrenaline; in addition, NO inhibits platelet function.

In addition to leukocytes, ECC also activates thrombocytes, which will secrete coagulation factors, cytokines and wall adhesion molecules [25].

Late phase

The late phase has two components.

• Ischaemia and reperfusion injury. After being deprived of O₂ during ischaemia, the cell receives a large amount of O during reperfusion, which triggers a cascade of pathological events that are more severe than the damage caused by ischaemia through the massive formation of peroxides (free radicals, ROS reactive oxygen species) that contain an odd number of electrons in their outer orbital: peroxide (O₂^- ), H₂ O₂ , hydroxyl (^•OH) (see Chapter 24, Mechanisms). Peroxides released during leukocyte activation or during reperfusion after ischaemia trigger a major inflammatory reaction. Normally antagonized by natural antioxidants (superoxide dismutase, catalase, glutathione, vitamin E), they spill over into the extracellular fluid when produced en masse and attack membrane phospholipids, DNA and proteins [12,15].
• Endotoxins massively stimulate the production of complement, TNF-alpha and interleukins. Endotoxin release from Gram-negative bacteria present in the gastrointestinal tract is related to the decrease in splanchnic flow in bypass surgery and hypothermia; flow in the gastric mucosa, for example, is decreased by up to 60% through low flow and vasoconstriction [38].

The global inflammatory response leads to multiple organ dysfunctions: ARDS, renal or liver failure.

Special case: the ECC

ECC is the most emblematic case of contact stimulation. In the presence of negatively charged surfaces such as glass, metals or plastics, Factor XII cleaves to F XIIa (activated). This converts prekallikrein to kallikrein, kininogens to bradykinin and factor XI to F XIa; the latter process leads to the formation of thrombin via the intrinsic coagulation pathway. F XIIa also promotes the conversion of plasminogen to plasmin, resulting in fibrinolysis. Contact activates complement directly through the alternative pathway, and indirectly through F XIIa (classical pathway). Other phenomena in the ECC contribute to complement activation, such as the release of endotoxins and the formation of heparin-protamine complexes. The cellular pathway is also stimulated by contact, either via factor XIIa and kallikrein or directly by neutrophil activation. However, the extracorporeal circuit has no endothelium to limit these different reactions, which can therefore become excessive and dissiminated throughout the body (Figure 7.22).

The duration of bypass surgery, the depth of hypothermia, the degree of haemodilution and genetic factors have all been mentioned as aggravating factors, but they appear to have only a secondary role in the genesis of SIRS [22]. Mechanical damage due to pump, oxygenator and filters, contact of the blood with foreign surfaces (circuits) and with air (aspirations, venous reservoir) are the main triggers. More than 50% of neutrophils are sequestered in the lungs during rewarming; their degranulation contributes to lung cell damage. The SIRS is triggered in the first minutes of the bypass surgery and disappears by 4^ème - 5^ème postoperative day, followed by a period of relative immunosuppression [41]. The peak of inflammatory markers occurs at around the 5^th hour after bypass surgery [12].

During ECC, inflammatory stimulation thus leads to an unstable state characterised by a series of phenomena (Figure 7.23).

• Elevation of all inflammatory markers (TNF-alpha, interleukins, cytokines, C-reactive protein);
• Activation of complement and leukocytes;
• Production of thrombin and stimulation of the coagulation cascade;
• Production of plasmin and stimulation of fibrinolysis (elevation of D-dimer);
• Activation and consumption of platelets;
• Release of endotoxins and TNF-alpha;
• Release of free radicals and oxidants;
• Release of bradykinin, histamine and anaphylatoxins: increased capillary permeability, systemic vasodilation, pulmonary vasoconstriction;
• Alterations in cardiac, pulmonary, renal and cerebral function; the incidence of atrial fibrillation is proportional to the elevation of inflammatory markers [14].

Figure 7.22: Activation via the contact pathway. In a vessel layered with intact endothelium, the various factors circulate in inactive form. But in the presence of negatively charged surfaces such as glass, metals or plastics (ECC), Factor XII cleaves to F XIIa (activated). This converts prekallikrein to kallikrein, kininogens to bradykinin and factor XI to F XIa; the latter process leads to the formation of thrombin via the intrinsic coagulation pathway. F XIIa also promotes the conversion of plasminogen to plasmin, causing fibrinolysis. Contact activates complement directly through the alternative pathway, and indirectly through F XIIa (classical pathway). MAC (membrane attack complex): a protein complex that attacks cell membranes, the ultimate result of the complement pathways.

The question of how much the genesis of SIRS is due to bypass surgery versus cardiac surgery itself can be approached by looking at beating heart surgery. The latter is associated with a reduction, but not an elimination, of postoperative levels of inflammatory response markers such as C3a, C5a, TNF-alpha or interleukin-6 and -8 [8,9,18]. However, the significance of these variations is uncertain, as IL-8 and C3a are related to direct tissue trauma and IL-10 has anti-inflammatory properties [34]. The effects of ECC depend largely on the balance between the release of pro- and anti-inflammatory mediators [26]. Some populations show a dominant pro-inflammatory response, such as the elderly or those with left ventricular dysfunction [44]. They may particularly benefit from beating heart surgery. In low-risk groups, SIRS-related complication rates are identical between operations with and without bypass surgery [36,40]. The bypass circuit is therefore a major triggering factor, but not the only one responsible for the inflammatory response [52].

Figure 7.23: Schematic representation of the mechanisms involved in the genesis of systemic inflammatory syndrome [22,47].

Technical improvements

Apart from beating heart procedures, various technical means aim at reducing the inflammatory syndrome triggered by bypass surgery, but none of them can eliminate it. The clinical significance of these improvements is modest at most [30,55].

• Suction restriction; sucked blood contains air, cellular debris and activators of coagulation (TNF, thrombin, plasmin) or inflammation (interleukins, C3a, C5a). Suctions are the main source of embolism, haemolysis, thrombocytopenia, coagulopathy and SIRS stimulation [47]. Disruption of the coagulatory system is markedly reduced when sucked blood is not recycled or is filtered by a CellSaver™ system, alas these manoeuvres remove platelets, proteins and coagulation factors [53].
• Restriction of circuit size; miniaturisation of circuits and elimination of the cardiotomy reservoir (MECC: mini-extracorporeal circuit) minimises blood contact with foreign surfaces and eliminates contact with air, thus reducing the release of coagulation activators and inflammatory triggers (see Mini-ECC) [3,58].
• Biocompatibility of circuits; preheparinised circuits and circuits impregnated with polymers such as poly-2-methoxy-ethyl-acrylate inhibit the complement cascade and leukocyte activation, reduce platelet adhesiveness and coagulation factor adsorption [20]. Although they reduce pulmonary, renal and neurological complications, their clinical impact is not significant [32,50].
• Haemofiltration; reduces excess fluid specific to bypass surgery and removes water-soluble inflammatory triggers. It reduces postoperative interstitial oedema, transfusion requirements, systemic inflammatory syndrome and multi-organ failure [5,7,29,42].
• Leukocyte filters; reducing leukocyte levels is beneficial especially for gas exchange, since the lungs are the main site of leukocyte sequestration during bypass surgery. Unfortunately, these filters do not prevent postoperative respiratory failure [2].
• Normothermia; maintaining temperature ≥ 34°C avoids coagulation alterations and inflammatory flare-up triggered by rewarming, but the ideal temperature for bypass surgery has not yet been defined [37,43].

These improvements are likely to have an impact on postoperative complications in high-risk or complex procedures, but have little influence on standard procedures in low- to moderate-risk patients. Given the increased cost, these new technologies do not currently have a favourable cost/benefit ratio for routine use. Normothermia by itself costs nothing,

Steroids

Corticosteroids maintain the integrity of cell membranes, particularly in the heart and lungs, inhibit leukocyte adhesion and reduce complement and cytokine production [23,54,55]. Despite a clear attenuation of the inflammatory response and a clear decrease in inflammatory markers after ECC, they only prevent multi-organ dysfunction in hypocortic patients, and their clinical impact remains unclear. Various reviews and meta-analyses have summarised the results obtained so far with steroids [1,6,35,56].

• The reduction in the incidence of AF is significant, but this effect is clear in studies of small scale populations [11].
• ICU stay and hospital stay are reduced.
• Intraoperative haemodynamic stability is improved, the use of vasopressor is reduced.
• The reduction of bleeding is marginal.
• The duration of mechanical ventilation is somewhat shortened; some studies have shown an attenuation of respiratory complications, but other publications show a worsening of postoperative gas exchange and a delay in extubation.
• Waking up is improved: the rate of nausea, vomiting and shivering is reduced.
• The rate of wound infection is the same, and the rate of general infections is marginely modified.
• The rate of hyperglycaemic episodes is increased 1.5 times in one meta-analysis and the rate of GI bleeding is doubled in another.
• Mortality is not changed.

Although the protocols of the different studies vary greatly, it can be concluded that prophylactic steroid administration may reduce postoperative morbidity, provided that it does not itself cause increased infection and bleeding [1]. As the traditional dosages are quite high (methylprednisolone 30 mg/kg, dexamethasone 1 mg/kg), it is possible that lower doses may have a better benefit/complication ratio while maintaining satisfactory activity in reducing the inflammatory response [35].

The question of whether routine steroid prophylaxis is advisable has been answered rather negatively by two randomised controlled trials. The first is a Dutch study (DECS, DExamethasone for Cardiac Surgery) of 4,494 patients randomised to dexamethasone 1 mg/kg or placebo, administered at induction of anaesthesia [10]. Mortality and major complications (MI, stroke, renal failure) were marginally lower in the steroid group (OR 0.83), while other morbidities were significantly reduced: infections (OR 0.64), delirium (OR 0.79), respiratory failure (OR 0.69). High-risk patients (EuroSCORE > 5) benefit the most (OR 0.77). Although these results are not overwhelming, this trial clearly demonstrated the safety of the treatment, which did not trigger any worsening of the bleeding or infectious risk. The second trial was a multicentre study (SIRS, Steroids In caRdiac Surgery) of 7,507 patients assigned to receive 500 mg methylprednisolone or placebo [57]. Mortality was not significantly reduced (OR 0.87), the rate of major complications was unchanged (OR 1.03) and the rate of infection was unchanged, as was the incidence of delirium. These two studies, which are methodologically indisputable, do not therefore encourage the use of steroids as a routine to reduce the rate of complications related to the inflammatory reaction of the ECC.

Other substances

Antifibrinolytics bind to the lysine of plasminogen and block the activation of plasmin, thus fibrinolysis. In clinical practice, they reduce blood loss by 30% overall. Three substances are used for this purpose (see Antifibrinolytics).

• Aprotinin is a non-specific inhibitor of many proteases that directly blocks plasmin; it inhibits complement, TNF and kallikrein production [26]. It was withdrawn from the market in November 2007 due to excess renal failure, cardiac complications and mortality, although it was more effective than the other two substances in reducing bleeding risk and transfusion rates [13,31].
• Tranexamic acid does not trigger allergic reactions or renal dysfunction, but high doses increase the risk of postoperative seizures [24,33]. Although it effectively reduces the risk of bleeding, it has little anti-inflammatory effect.
• e -aminocaproic acid is slightly less effective [24].

A wide range of pharmacological substances are potentially useful in alleviating the inflammatory syndrome, although it cannot be demonstrated that their clinical impact is significant.

• Complement inhibition: pexelizumab and TP10, which inhibit the complement chain at C5a, reduce morbidity and mortality after cardiac surgery in selected groups of patients, but have not yet shown significant clinical effects [49].
• Antioxidants: N-acetylcysteine may improve postoperative lung function [16]; ascorbic acid, alpha-tocoferol and allopurinol detoxify free radicals, but clinical studies have not found significant benefit [17].
• Pentoxifyline (theophylline analogue): inhibits mediators and the complement cascade, and appears to improve postoperative ventilation [4].
• Statins have an anti-inflammatory effect and reduce mortality after coronary artery bypass surgery [59].
• Methylene blue is an anti-NO and therefore has an anti-inflammatory effect, but its use is limited to situations of refractory hypotension [27].
• Insulin; hyperglycaemia is accompanied by hypersecretion of cytokines, and diabetics are known to produce excessive superoxide from their mitochondria. Therefore, maintaining normoglycaemia attenuates the inflammatory response, but the latter induces insulin resistance which may explain the challenge of managing intraoperative blood glucose [46].
• Various agents have some anti-inflammatory effect: milrinone, nitroprusside, morphine, heparin, ACE inhibitors [55].

Anaesthetic aspects

The anaesthetist can influence the inflammatory response in several ways [21].

• Ventilation: lowering the tidal volume to 4-8 mL/kg instead of 10-12 mL/kg, limiting the Pplateau to < 30 cm H₂ O, lowering the FiO₂ to 0.3-0.6, and performing recruitment manoeuvres every 30 minutes limit mechanical and cellular damage, and lower the levels of cytokines released from the lungs [28].
• Haemodynamic stability: tissue hypoperfusion (hypotension and low flow) activates the release of cytokines and endotoxins, particularly in the gastrointestinal tract.
• Preconditioning: Halogens have the property of reducing the impact of ischaemic injury on the myocardial cell, at least momentarily (see Chapter 5 Conditioning) [39]. Remote preconditioning with short periods of muscular ischaemia of a limb has a protective effect on the myocardium and clinical survival [51].

  © CHASSOT PG, GRONCHI F, April 2008, last update December 2019

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