Bradykinin Receptor Antagonism During Cardiopulmonary Bypass
Condition: Cardiopulmonary Bypass; Inflammation; Fibrinolysis; Surgery
MeSH terms: Inflammation
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      Each year over a million patients worldwide undergo cardiac surgery requiring cardiopulmonary
      bypass (CPB). CPB is associated with significant morbidity including the transfusion of
      allogenic blood products, inflammation and hemodynamic instability. In fact, approximately
      20% of all blood products transfused are associated with coronary artery bypass grafting
      procedures. Transfusion of allogenic blood products is associated with well-documented
      morbidity and increased mortality after cardiac surgery. Enhanced fibrinolysis contributes to
      increased blood product transfusion in the perioperative period. The current proposal tests
      the central hypothesis that endogenous bradykinin contributes to the hemodynamic,
      fibrinolytic and inflammatory response to CPB and that bradykinin receptor antagonism will
      reduce hypotension, inflammation and transfusion requirements. In SPECIFIC AIM 1 we will test
      the hypothesis that the fibrinolytic and inflammatory response to CPB differ during ACE
      inhibition and angiotensin II type 1 receptor antagonism. In SPECIFIC AIM 2 we will test the
      hypothesis that bradykinin B2 receptor antagonism attenuates the hemodynamic, fibrinolytic,
      and inflammatory response to CPB. In SPECIFIC AIM 3 we will test the hypothesis that
      bradykinin B2 receptor antagonism reduces the risk of allogenic blood product transfusion in
      patients undergoing CPB. These studies promise to provide important information regarding the
      effects of drugs that interrupt the RAS and generate new strategies to reduce morbidity in
      patients undergoing CPB.
    

Detailed description: 
      Morbidity of cardiopulmonary bypass. Each year more than a million patients worldwide undergo
      cardiac surgery. Nearly all cardiac surgeries are performed on unbeating hearts supported by
      CPB. Although the use of off-pump coronary artery bypass surgery procedures are increasing,
      concerns regarding incomplete revascularization and reduced venous graft patency limit the
      use of this technique to specific patients. CPB activates various humoral cascades including
      the coagulation cascade, the KKS, the fibrinolytic cascade, and causes a systemic
      inflammatory response syndrome. Activation of these systems can lead to hypotension, fever,
      disseminated intravascular coagulation, diffuse tissue edema, or, in extreme cases, to
      multiple organ failure. Activation of the KKS contributes to the hemodynamic perturbations,
      fibrinolysis and inflammatory response observed in patients undergoing CPB. Aprotinin, a
      non-specific serine protease inhibitor, that works in part by decreasing bradykinin
      generation, decreases fibrinolysis, hypotension and the systemic inflammatory response
      associated with CPB. Aprotinin decreases blood loss and transfusion requirements, however,
      its use is mainly limited to redo-cardiac surgery because of cost. Other factors that may
      limit the widespread use of aprotinin include an increased risk for renal dysfunction,
      allergic reaction and non-specificity of the drug. Bradykinin mediates most of the effects of
      the KKS. Thus, bradykinin receptor antagonism has the potential to modulate the effects of
      KKS activation during CPB. The purpose of this proposal is to test the hypothesis that
      endogenous bradykinin contributes to the hemodynamic, fibrinolytic and inflammatory response
      to CPB and that bradykinin receptor antagonism will reduce hypotension, inflammation and
      transfusion requirements. The proposed studies promise to lead to novel therapies to reduce
      morbidity associated with CPB.

      Cardiopulmonary bypass activates the kallikrein-kinin system (KKS). Several groups, including
      ours, have reported that bradykinin concentrations increase during CPB. For example, Campbell
      et al demonstrated that bradykinin levels increase 10 to 20-fold during the first 10 minutes
      of CPB, returned to basal levels by 70 minutes of CPB and remained 1.7 to 5.2-fold elevated
      after CPB. Plasma and tissue kallikrein were reduced by 80 and 60% respectively, during the
      first minute of CPB. Similarly, we have demonstrated that bradykinin increases significantly
      during CPB and that ACE inhibition and smoking potentiate the kinin response during CPB.

      Fibrinolytic response to cardiopulmonary bypass. CPB increases t-PA antigen and activity in a
      time-dependent manner. The fibrinolytic response during CPB is heterogeneous, with t-PA
      levels varying as much as 250-fold. The mechanism of t-PA release during CPB is likely
      multifactorial. As outlined above, we and others have shown that CPB increases bradykinin, a
      potent stimulus to t-PA release. In addition, thrombin or complement generated during CPB may
      stimulate the release of t-PA from endothelium. In addition to the changes in t-PA
      concentrations during CPB, PAI-1 activity falls because of hemodilution and the rise in t-PA
      release which consumes active PAI-1. Plasmin generation increases over 100-fold while D-dimer
      generation increases 200-fold within 5 minutes of CPB initiation. For the remainder of the
      CPB, average plasmin and D-dimer levels remain 20-fold to 30-fold above baseline levels. The
      postoperative period is marked by a systemic inflammatory response caused by a combination of
      CPB and surgery producing an acute -phase response that results in increased PAI-1
      production. PAI-1 levels begin to rise about 2 hours after surgery. Once CPB is over, PAI-1
      levels continue to rise and peak during the first 12-36 hours postoperatively and return to
      normal by the second postoperative day. Thus, the fibrinolytic response to CPB is
      characterized by an initial hyperfibrinolytic phase that begins with a rapid rise in t-PA,
      plasmin, and D-dimer concentrations followed by a postoperative hypofibrinolytic phase
      associated with a rise in PAI-1 secretion and a fall in t-PA concentrations.

      Interaction between the renin-angiotensin system (RAS), the KKS and fibrinolytic system.
      There is evidence that fibrinolytic balance is regulated by the RAS and the KKS. ACE is
      strategically poised to control fibrinolytic balance by promoting the breakdown of bradykinin
      and the conversion of Ang I to Ang II. Ang II causes the release of PAI-1 thus inhibiting
      fibrinolysis. Bradykinin stimulates t-PA release through its B2 receptor. ACE inhibition
      decreases PAI-1 antigen levels and increases endothelial t-PA release through endogenous
      bradykinin. In addition, ACE inhibition enhances exogenous bradykinin-mediated vasodilation
      and t-PA release. The augmentation of bradykinin-induced vasodilation, the increase in t-PA
      and the decrease in PAI-1 described with ACE inhibition in patients with ischemic heart
      disease may contribute to the primary mechanism of the anti-ischemic effects associated with
      chronic ACE inhibitor therapy. We have demonstrated that inpatients undergoing coronary
      artery bypass grafting (CABG) requiring CPB, not only did ACE inhibition increase
      fibrinolytic activity by decreasing PAI-1 antigen and increasing t-PA activity, but also
      enhanced the kinin response. Increased PAI-1 concentrations in the perioperative period are
      associated with acute vein graft thrombosis. Thus, ACE inhibitors have a potential to reduce
      the risk of acute graft thrombosis through their effects on Ang II generation by attenuating
      the PAI-1 response after CABG. As opposed to the beneficial effects of ACE inhibition on
      PAI-1, the augmentation of the kinin response during CPB may have detrimental effects
      including increased fibrinolysis with consequent bleeding and hypotension. The effect of
      angiotensin II type 1 (AT1) receptor antagonist on the fibrinolytic response to CPB is not
      known. Inpatients with essential hypertension AT1 receptor antagonist decreases PAI-1 antigen
      in some but not other studies. In Specific Aim 1 we will test the hypothesis that
      angiotensin-converting enzyme inhibitors and AT1 receptor antagonist modulate the
      fibrinolytic and inflammatory response to CPB differently.

      Bradykinin receptor antagonism could reduce the hypotensive response to CPB. Low systemic
      vascular resistance (SVR) commonly occurs during and early after CPB. It is usually transient
      and easy to treat. Occasionally, patients have a more severe and persistent fall in SVR,
      referred to postoperative vasodilatory shock. Risk factors for vasodilatory shock includes
      the preoperative use of ACE inhibitors, low left ventricular ejection fraction and heart
      failure syndrome. Treatment is frequently required to maintain adequate perfusion pressure
      during CPB and to establish satisfactory hemodynamics when ready to separate the patient from
      bypass. This usually entails counteracting the effect of the vasodilatory mediators by
      administration of drugs such as norepinephrine or phenylephrine. Although usually effective
      and safe, these drugs can redistribute blood flow in such a way as to compromise the
      splanchnic and renal circulation. Several mediators are thought to be responsible for
      producing postoperative shock, including bradykinin. For example, there is an inverse
      correlation between bradykinin concentrations and mean arterial pressure during CPB,
      suggesting that bradykinin is an important mediator in the decrease in SVR. We and others
      have shown that bradykinin induces vasodilation through its B2 receptor. In contract, B1
      receptor stimulation does not cause vasodilation. As outlined under PRELIMINARY STUDIES, we
      have demonstrated that endogenous bradykinin contributes to protamine-related hypotension
      following CPB and that bradykinin receptor antagonism administered just prior to protamine
      attenuates this hypotensive response. In Specific Aim 2 we will test the hypothesis that
      bradykinin receptor antagonism modulate the hemodynamic changes observed during CPB.

      Bradykinin receptor antagonism could reduce hyperfibrinolysis and CPB-associated blood loss.
      Inhibiting hyperfibrinolysis during CPB reduces blood loss and blood product requirements. On
      the other hand, modulating the hypofibrinolytic phase after CPB has the potential to reduce
      thrombotic complications. We and others have shown that bradykinin stimulates t-PA release
      from human forearm vasculature and the coronary circulation through a NO
      synthase-independent, and cyclooxygenase-independent pathway. As with vasodilation,
      bradykinin-stimulated t-PA release is mediated via the B2 receptor. Several groups have
      reported that bradykinin concentrations increase during CPB. We demonstrated a direct
      correlation between bradykinin and t-PA concentrations during CPB suggesting that bradykinin
      plays an important role in activating the fibrinolytic response during CPB. As outlined under
      PRELIMINARY STUDIES we have shown that HOE 140 (a B2 receptor antagonist) administered prior
      to CPB blunts the increase in D-dimer similar to e-aminocaproic acid. Thus, B2 receptor
      antagonism has the potential to reduce bradykinin-mediated fibrinolysis during CPB. In
      Specific Aim 2 we will test the hypothesis that bradykinin receptor antagonism modulate the
      fibrinolytic response observed during CPB.

      Bradykinin receptor antagonism could reduce the inflammatory response to CPB. During CPB,
      exposure of blood to bioincompatible surfaces of the extracorporeal circuit, as well as
      tissue ischemia and reperfusion associated with the procedure, induce the activation of
      several major humoral pathways of inflammation. Bradykinin produces many of the
      characteristics of the inflammatory state, such as changes in local blood pressure, edema,
      and pain, resulting in vasodilation and increased microvessel permeability. Bradykinin
      activates NF-kB and upregulates interleukin(IL)-1b and TNFa-stimulated IL-8 production
      through the B2 receptor. In addition, bradykinin stimulates the release of IL-6 from a
      variety of cells. The growing knowledge of the biological role of kinins, in particular in
      inflammation, has fueled the development of potent and selective kinin receptor antagonist as
      potential therapeutics. For example, the bradykinin antagonist, deltibant (CP-0127) showed a
      significant improvement in the 28-day risk-adjusted survival of patients with gram-negative
      sepsis. In an animal model of intestinal ischemia-reperfusion injury, B2 receptor antagonism
      inhibited reperfusion induced increases in vascular permeability, neutrophil recruitment and
      expression of B1 receptor mRNA. The role of B2 receptor antagonist in myocardial
      ischemia-reperfusion injury is more controversial. Kumari et al demonstrated a protective
      effect of HOE 140 during in vivo ischemia-reperfusion injury, whereas in isolated rabbit
      heart studies, CP-0127 impaired recovery from acute coronary ischemia. This contradictory
      results may be the result of different antagonist used, differences in species sensitivity or
      different experimental protocols. The role of B1 receptor antagonist in inflammation is
      unclear. In contrast to the constitutively expressed bradykinin B2 receptor, bradykinin B1
      receptor expression is upregulated following an inflammatory insult or ischemia-reperfusion
      injury. It appears that each kinin receptor subtype mediates different aspects of the
      inflammatory response. However, B1 receptor antagonism administered prior to CPB may be
      detrimental. For example, Siebeck et al demonstrated that B2 receptor blockade attenuates
      endotoxin-induced mortality in pigs, whereas additional B1 receptor blockade seemed to
      reverse these beneficial effects. Taken together, B2 receptor antagonism may decrease the
      acute inflammatory response whereas additional B1 receptor blockade may be harmful. These
      studies, and also the fact that aprotinin exerts part of its beneficial effects through a
      reduction in bradykinin concentrations, suggest the hypothesis that pharmacological
      strategies to block the bradykinin B2 receptor may be superior to reducing bradykinin
      concentrations in modulating the inflammatory response to CPB.

      The RAS, KKS and inflammation. Activation of the RAS exerts proinflammatory effects. For
      example, Ang II activates the transcription factor nuclear factor (NF)-kB, which in turn
      regulates genes involved in cellular recruitment and the inflammatory cytokine cascade. Ang
      II induces the synthesis and secretion of the inflammatory interleukin (IL)-6. As mentioned
      above, bradykinin produces many of the characteristics of the inflammatory state and
      upregulates IL-1b and TNFa-stimulated IL-8 and stimulates the release of IL-6. Thus, both Ang
      II and bradykinin stimulates the release of IL-6. ACE inhibitor treatment is associated with
      a reduction in IL-6 response to CPB. In a randomized non-blinded study, Trevelyan and
      colleagues20 demonstrated that ACE inhibition produced a highly significant decrease of 51%
      in the release of IL-6 in patients identified as high producers of IL-6 by the -174 G/C
      polymorphism, whereas losartan had a similar but less marked effect. Potential mechanisms for
      this variation in IL-6 response between ACE inhibitors and angiotensin receptor blocker may
      be due to their differential effect on Ang II formation and bradykinin degradation.
      Furthermore, bradykinin-induced increases in IL-6 protein and total mRNA are inhibited by the
      selective B2 receptor antagonist HOE-140 but not by a selective B1 receptor antagonist. In
      Specific Aim 1 we will test the hypothesis that angiotensin-converting enzyme inhibitors and
      angiotensin II type 1 (AT1) receptor antagonist modulate the fibrinolytic and inflammatory
      response to CPB differently.
    

Intervention name(s): HOE 140; Aminocaproic Acid; Placebo
Intervention type(s): Drug; Drug; Drug
Intervention description(s): HOE 140 (a bradykinin B2 receptor antagonist) was started in the operating room after induction of anesthesia and before heparinization, continued throughout the bypass period, and discontinued at the end of surgery. HOE 140 was given as an intravenous bolus of 22 µg/kg over one-half hour followed by an infusion of 18 µg/kg/hr.; Aminocaproic acid (an antifibrinolytic drug) was started in the operating room after induction of anesthesia and before heparinization, continued throughout the bypass period, and discontinued at the end of surgery. Aminocaproic acid was given as an intravenous bolus of 100 mg/kg over one-half hour followed by an infusion of 30 mg/kg/hr.; Normal saline (placebo) was started in the operating room after induction of anesthesia and before heparinization, continued throughout the bypass period, and discontinued at the end of surgery.
Other intervention name(s): Icatibant; Amicar; EACA; Placebo/Normal Saline
Intervention MeSH terms: Icatibant; Aminocaproic Acid
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Prevention
Keywords: Coronary Artery Bypass; Blood Transfusion; Bradykinin Receptor Antagonism; Anti-Inflammatory Agents; Antifibrinolytic Agents