8.6.6 Anti-inflammatory therapy

 The close link between coagulation and inflammatory response (see Inflammation and Complement) suggests that attenuation of the latter could improve bleeding or thrombotic risk. As the intensity of the Systemic Inflammatory Response Syndrome (SIRS) depends on a cascade of different elements, it is no surprise that multiple approaches are potentially useful in curbing it [4].

Steroids

Corticosteroids maintain the integrity of cell membranes, particularly in heart and lungs, inhibit leukocyte adhesion and reduce complement and cytokine production [5,15]. Despite a clear attenuation of inflammatory response and a clear decrease in inflammatory markers after ECC, they 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 [1,2,8,16].

  • Reduction in AF incidence is significant.
  • ICU stay and hospital stay are reduced.
  • Intraoperative haemodynamic stability is improved, vasopressor use is reduced.
  • Reduction in bleeding rate  is marginal.
  • 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: rate of nausea, vomiting and shivering is reduced.
  • Rate of wound infection is the same, and rate of general infections is marginaly changed.
  • Rate of hyperglycaemic episodes is increased 1.5 times in one meta-analysis and rate of GI bleeding is doubled in another.
  • Mortality is not changed.

Although  protocols of  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 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 inflammatory response [8].

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 [3]. 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  most (OR 0.77). Although these results are not overwhelming, this trial clearly demonstrated   treatment safety, which did not trigger any worsening of  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 [17]. Mortality was not significantly reduced (OR 0.87), rate of major complications was unchanged (OR 1.03) and rate of infection was unchanged, as was incidence of delirium. These two methodologically sound studies do not therefore support use of steroids as routine to reduce inflammatory response to ECC.

 Other pharmacological substances

In clinical trials, a variety of substances have been suggested as possible attenuators of inflammatory response, without any of them standing out as having a clear effect [4].

  • Aprotinin reduces intensity of systemic inflammatory response and production of C1, TNF and kallikrein [6]. Aminocaproic acid and tranexamic acid have less effect.
  • Statins have an anti-inflammatory effect and reduce mortality after coronary artery bypass grafting [13].
  • Methylene blue is an anti-NO and therefore has an anti-inflammatory effect, but its use is reserved for situations of refractory hypotension [7].
  • Insulin; hyperglycaemia is accompanied by hypersecretion of cytokines, and diabetics are known to have excessive production of superoxide by their mitochondria [7]. Therefore, maintaining normoglycaemia attenuates the inflammatory response, but the latter induces insulin resistance which may explain  difficulties encountered in managing intraoperative blood glucose levels [11].
  • N-acetyl-cysteine (Salmucol® ) or allopurinol (Xyloric® ) decrease inflammatory markers and block the toxic effect of free radicals, but their clinical use has been disappointing and does not provide any benefit in terms of mortality or morbidity [10].
  • Complement inhibitors: 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 demonstrated significant clinical effects [12].

Anaesthetic aspects

The anaesthetist can influence inflammatory response in several ways [4].

  • Ventilation: lowering the tidal volume to 4-8 mL/kg from 10-12 mL/kg and lowering the FiO2 to 0.6 limits mechanical and cellular damage and lowers  levels of cytokines released from lungs.
  • Haemodynamic stability: tissue hypoperfusion (hypotension and low flow) activates release of cytokines and endotoxins, particularly in gastrointestinal tract.
  • Preconditioning: Halogens have the property of reducing ischaemic injury impact  on myocardial cell, at least momentarily (see Chapter 5 Preconditioning) [9]. Remote preconditioning with short periods of muscular limb ischaemia has a protective effect on the myocardium and on clinical survival [14].

 

 Anti-inflammatory therapy 
 Steroids (methylprednisolone 500 mg or dexamethasone 1 mg/kg at induction): reduce systemic inflammatory response and associated markers. They reduce incidence of AF, nausea-vomiting, haemodynamic instability, respiratory failure, infections, intensive care unit stay. They do not modify mortality. However, they do not increase the risk of infection or bleeding.
 
A range of substances have been investigated for their anti-inflammatory potential. However, although they tend to lower inflammatory markers, none of them have shown a significant impact on overall morbidity and mortality after cardiac surgery.
 
In anaesthesia, protective low tidal volume ventilation and maintenance of adequate blood pressure and flow, including during ECC, improves postoperative clinical outcomes, in part by reducing SIRS. The use of halogen (preconditioning) reduces myocardial injury during coronary revascularisation.

 

© CHASSOT PG, MARCUCCI Carlo, last update November 2019.

 

References

 

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