Hemolysis during cardiac surgery is associated with increased intravascular nitric oxide consumption and perioperative kidney and intestinal tissue damage

Windsant, Iris C. Vermeulen; Wit, Norbert C.J. de; Sertório, Jonas T.; Bijnen, Annemarie A. van; Ganushchak, Yuri M.; Heijmans, John; Tanus‐Santos, José Eduardo; Jacobs, Michael J.; Maessen, Jos G.; Buurman, Wim A.

doi:10.3389/fphys.2014.00340

Cited by 113 publications

(97 citation statements)

References 38 publications

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“…Plasma hemoglobin and heme are also acutely elevated during and after extracorporeal circulation and during and after transfusion of SRBCs 25,34,35 . In the current study, we developed a murine model of hemorrhagic shock to mimic the common clinical condition of an initial injury due to prolonged hypotension followed by a second noxious event consisting of resuscitation with SRBCs.…”

Section: Discussionmentioning

confidence: 99%

Haptoglobin or Hemopexin Therapy Prevents Acute Adverse Effects of Resuscitation After Prolonged Storage of Red Cells

et al. 2016

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Background Extracellular hemoglobin and cell-free heme are toxic breakdown products of hemolyzed erythrocytes. Mammals synthesize the scavenger proteins haptoglobin and hemopexin, which bind extracellular hemoglobin and heme respectively. Transfusion of packed red blood cells (PRBCs) is a life-saving therapy for patients with hemorrhagic shock. Because erythrocytes undergo progressive deleterious morphological and biochemical changes during storage, transfusion of PRBCs that have been stored for prolonged intervals (SRBCs; stored for 35–40 days in humans or 14 days in mice) increases plasma levels of cell-free hemoglobin and heme. Therefore, in patients with hemorrhagic shock, perfusion-sensitive organs such as the kidneys are challenged not only by hypoperfusion, but also by the high concentrations of plasma hemoglobin and heme that are associated with the transfusion of SRBCs. Methods To test whether treatment with exogenous human haptoglobin or hemopexin can ameliorate adverse effects of resuscitation with SRBCs after two hours of hemorrhagic shock, mice receiving SRBCs were given a co-infusion of haptoglobin, hemopexin or albumin. Results Treatment with haptoglobin or hemopexin but not albumin improved the survival rate and attenuated SRBC-induced inflammation. Treatment with haptoglobin retained free hemoglobin in the plasma and prevented SRBC-induced hemoglobinuria and kidney injury. In mice resuscitated with fresh PRBCs, treatment with haptoglobin, hemopexin, or albumin did not cause harmful effects. Conclusions In mice the adverse effects of transfusion with SRBCs after hemorrhagic shock are ameliorated by treatment with either haptoglobin or hemopexin. Haptoglobin infusion prevents kidney injury associated with high plasma hemoglobin concentrations after resuscitation with SRBCs. Treatment with the naturally occurring human plasma proteins haptoglobin or hemopexin may have beneficial effects in conditions of severe hemolysis following prolonged hypotension.

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Section: Discussionmentioning

confidence: 99%

Haptoglobin or Hemopexin Therapy Prevents Acute Adverse Effects of Resuscitation After Prolonged Storage of Red Cells

et al. 2016

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“…However, in patients with hemolysis such as in sickle cell disease (SCD), during extracorporeal circulation, on transfusion of stored blood, or during malaria and sepsis, substantial quantities of cell-free Hb are occasionally released into plasma (3). In these conditions, cell-free Hb can promote disease complications (4)(5)(6)(7)(8)(9)(10)(11). Some of the most severe adverse effects associated with cell-free Hb exposure, including pulmonary and systemic hypertension, are caused by depletion of the vasodilator nitric oxide (NO) (12)(13)(14)(15)(16).…”

mentioning

confidence: 99%

Haptoglobin Preserves Vascular Nitric Oxide Signaling during Hemolysis

Schaer¹,

Deuel²,

Schildknecht³

et al. 2016

Am J Respir Crit Care Med

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Rationale: Hemolysis occurs not only in conditions such as sickle cell disease and malaria but also during transfusion of stored blood, extracorporeal circulation, and sepsis. Cell-free Hb depletes nitric oxide (NO) in the vasculature, causing vasoconstriction and eventually cardiovascular complications. We hypothesize that Hb-binding proteins may preserve vascular NO signaling during hemolysis.Objectives: Characterization of an archetypical function by which Hb scavenger proteins could preserve NO signaling during hemolysis.Methods: We investigated NO reaction kinetics, effects on arterial NO signaling, and tissue distribution of cell-free Hb and its scavenger protein complexes.Measurements and Main Results: Extravascular translocation of cell-free Hb into interstitial spaces, including the vascular smooth muscle cell layer of rat and pig coronary arteries, promotes vascular NO resistance. This critical disease process is blocked by haptoglobin. Haptoglobin does not change NO dioxygenation rates of Hb; rather, the large size of the Hb:haptoglobin complex prevents Hb extravasation, which uncouples NO/Hb interaction and vasoconstriction. Size-selective compartmentalization of Hb functions as a substitute for red blood cells after hemolysis and preserves NO signaling in the vasculature. We found that evolutionarily and structurally unrelated Hb-binding proteins, such as PIT54 found in avian species, functionally converged with haptoglobin to protect NO signaling by sequestering cell-free Hb in large protein complexes.Conclusions: Sequential compartmentalization of Hb by erythrocytes and scavenger protein complexes is an archetypical mechanism, which may have supported coevolution of hemolysis and normal vascular function. Therapeutic supplementation of Hb scavengers may restore vascular NO signaling and attenuate disease complications in patients with hemolysis.

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“…This has been shown in several hemolysis-associated conditions (sickle cell disease and renal replacement therapy) [17, 21–23] and in studies involving animal models [24] and stored blood [25]. PHb was associated with NO consumption and biomarkers of renal and intestinal injury in adult CPB [26]. Children who received NO during CPB had shorter durations of mechanical ventilation and ICULOS [12].…”

Section: Discussionmentioning

confidence: 90%

“…In adult sickle cell patients, hemolysis is associated with progression of chronic kidney disease [33]. The production of PHb has been associated with renal injury in both adult [11, 26, 34] and pediatric [3] cardiac surgery.…”

Section: Discussionmentioning

confidence: 99%

Cell-Free Plasma Hemoglobin and Male Gender Are Risk Factors for Acute Kidney Injury in Low Risk Children Undergoing Cardiopulmonary Bypass

Kim‐Campbell

Gretchen

Callaway

et al. 2017

Critical Care Medicine

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Objective To determine the relationship between the production of cell-free plasma hemoglobin (PHb) and acute kidney injury (AKI) in infants and children undergoing cardiopulmonary bypass (CPB) for cardiac surgery. Design Prospective observational study Setting 12-bed cardiac ICU in a university-affiliated children’s hospital Patients Children were prospectively enrolled during their pre-operative outpatient appointment with the following criteria: >1month to <18 years old, procedures requiring CPB, no preexisting renal dysfunction. Interventions None Measurements and Main Results Plasma and urine were collected at baseline (in a subset), the beginning and end of CPB, and 2h and 24h after CPB in 60 subjects. Levels of PHb increased during CPB and were associated (p<0.01) with CPB duration (R2=0.22), depletion of Hp at end and 24h after CPB (R2=0.12 and 0.15, respectively), LDH levels at end CPB (R2=0.27), and change in creatinine (R2=0.12). 43% of patients developed AKI. There was an association between PHb level and change in creatinine that varied by age (overall [R2=0.12, p<0.01], in age >2yrs [R2=0.22, p<0.01], and in <2yrs [R2=0.03, p=0.42]). Change in PHb and male gender were found to be risk factors for AKI (OR 1.02 and OR 3.78, p<0.05). Conclusions Generation of PHb during CPB and male gender are associated with subsequent renal dysfunction in low risk pediatric patients, especially in those >2yrs of age. Further studies are needed to determine whether specific subgroups of pediatric patients undergoing CPB would benefit from potential treatments for hemolysis and PHb-associated renal dysfunction.

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Hemolysis during cardiac surgery is associated with increased intravascular nitric oxide consumption and perioperative kidney and intestinal tissue damage

Cited by 113 publications

References 38 publications

Haptoglobin or Hemopexin Therapy Prevents Acute Adverse Effects of Resuscitation After Prolonged Storage of Red Cells

Haptoglobin or Hemopexin Therapy Prevents Acute Adverse Effects of Resuscitation After Prolonged Storage of Red Cells

Haptoglobin Preserves Vascular Nitric Oxide Signaling during Hemolysis

Cell-Free Plasma Hemoglobin and Male Gender Are Risk Factors for Acute Kidney Injury in Low Risk Children Undergoing Cardiopulmonary Bypass

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