Franz Meisner

Diaspirin crosslinked hemoglobin enables extreme hemodilution beyond the critical hematocrit

BackgroundNormovolemic hemodilution is an effective strategy to limit perioperative homologous blood transfusions. The reduction of hematocrit related to hemodilution results in reduced arterial oxygen content, which initially is compensated for by an increase in cardiac output and oxygen extraction ratio. To increase the efficacy of hemodilution, a low hematocrit should be aimed for; however, this implies the risk of myocardial ischemia and tissue hypoxia. ObjectiveTo assess whether hemodilution can be extended to lower hematocrit values by the use of a hemoglobin-based artificial oxygen carrier solution. DesignProspective, randomized, controlled. SettingAnimal laboratory of a university hospital. SubjectsTwelve anesthetized, mechanically ventilated pigs. InterventionsIsovolemic hemodilution was performed with either 10% diaspirin crosslinked hemoglobin (DCLHb Baxter Healthcare, Boulder, CO; n = 6) or 8% human albumin solution (HSA, oncotically matched to DCLHb, Baxter Healthcare; n = 6) to a hematocrit of 15%, 8%, 4%, 2%, and 1%. Measurements and Main Results In both groups, measurements were performed at baseline at the previously mentioned preset hematocrit values and at the onset of myocardial ischemia characterized by critical hematocrit (significant ST-segment depression >0.1 mV and/or arrhythmia). To determine peripheral tissue oxygenation and myocardial perfusion and function, the following variables were evaluated: total body oxygen transport variables, tissue oxygen partial pressure (tPo2, MDO-Electrode, Eschweiler Kiel, Germany) on the surface of the skeletal muscle, coronary perfusion pressure, left ventricular (LV) end-diastolic pressure, global and regional myocardial contractility (maximal change in pressure over time, LV segmental shortening, microsonometry method), LV myocardial blood flow (fluorescent microsphere technique), LV oxygen delivery, and the ratio between LV subendocardial and subepicardial myocardial perfusion. In the HSA group, critical hematocrit was found at 6.1 (1.8)% (hemoglobin, 2 g·dL−1), whereas all DCLHb-treated animals survived hemodilution until hematocrit 1.2 (0.2)% (hemoglobin, 4.7 g·dL−1) was achieved without signs of hemodynamic instability. Although arterial oxygen content was higher in the DCLHb group at 1.2% hematocrit than in the HSA group at critical hematocrit (i.e., hematocrit, 6.1%; hemoglobin, 2 g·dL−1) neither oxygen delivery and oxygen uptake nor median tPo2 and hypoxic tPo2 values on the skeletal muscle were different between groups. In contrast, subendocardial ischemia was absent in DCLHb-diluted animals until 1.2% hematocrit was achieved. This was attributable to a higher coronary perfusion pressure (65 (22) mm Hg vs. 19 (8) mm Hg;p < .05), higher subendocardial perfusion (4.1 (2.6) mL·min−1·g−1 vs. 1.2 (0.4) mL·min−1·g−1), and subendocardial oxygen delivery (5.7 (2) mL·min−1·g−1, p < .05) in DCLHb-diluted animals, resulting in superior myocardial contractility reflected by maximal change in pressure over time (3829 (1914) vs. 1678 (730);p < .05) and higher regional myocardial contractility (11 (8)% vs. 6 (2)%;p < .05). An increased LV end-diastolic pressure reflected LV myocardial pump failure in HSA-diluted animals but was unchanged in DCLHb-diluted animals. In the DCLHb group, systemic vascular resistance index remained at baseline values throughout the protocol, whereas coronary vascular resistance decreased. In contrast, both variables decreased in HSA-diluted animals. ConclusionDCLHb as a diluent allowed for hemodilution beyond the hematocrit value, determined “critical” after hemodilution with HSA (6.1% (1.8)%). Even at 1.2% hematocrit (hemoglobin, 4.7 g·dL−1) myocardial perfusion and function were maintained, although at the expense of peripheral tissue oxygenation. This discrepancy in regional oxygenation might be caused by a redistribution of blood flow favoring the heart, which is related to a disproportionate decrease of coronary vascular resistance index during hemodilution with DCLHb.

Causes of metabolic acidosis in canine hemorrhagic shock: role of unmeasured ions

IntroductionMetabolic acidosis during hemorrhagic shock is common and conventionally considered to be due to hyperlactatemia. There is increasing awareness, however, that other nonlactate, unmeasured anions contribute to this type of acidosis.MethodsEleven anesthetized dogs were hemorrhaged to a mean arterial pressure of 45 mm Hg and were kept at this level until a metabolic oxygen debt of 120 mLO2/kg body weight had evolved. Blood pH, partial pressure of carbon dioxide, and concentrations of sodium, potassium, magnesium, calcium, chloride, lactate, albumin, and phosphate were measured at baseline, in shock, and during 3 hours post-therapy. Strong ion difference and the amount of weak plasma acid were calculated. To detect the presence of unmeasured anions, anion gap and strong ion gap were determined. Capillary electrophoresis was used to identify potential contributors to unmeasured anions.ResultsDuring induction of shock, pH decreased significantly from 7.41 to 7.19. The transient increase in lactate concentration from 1.5 to 5.5 mEq/L during shock was not sufficient to explain the transient increases in anion gap (+11.0 mEq/L) and strong ion gap (+7.1 mEq/L), suggesting that substantial amounts of unmeasured anions must have been generated. Capillary electrophoresis revealed increases in serum concentration of acetate (2.2 mEq/L), citrate (2.2 mEq/L), α-ketoglutarate (35.3 μEq/L), fumarate (6.2 μEq/L), sulfate (0.1 mEq/L), and urate (55.9 μEq/L) after shock induction.ConclusionLarge amounts of unmeasured anions were generated after hemorrhage in this highly standardized model of hemorrhagic shock. Capillary electrophoresis suggested that the hitherto unmeasured anions citrate and acetate, but not sulfate, contributed significantly to the changes in strong ion gap associated with induction of shock.

Hyperoxic ventilation at the critical hematocrit: Effects on myocardial perfusion and function

Background:  Hemodilution reduces hematocrit (Hct) and blood oxygen content. Tissue oxygenation is mainly preserved by increased cardiac output. As myocardial O2‐demands increase, coronary vasodilatation becomes necessary to increase myocardial blood flow. Myocardial ischemia occurs at a critical Hct‐value (Hctcrit), with accompanying exhaustion of coronary reserve. Hyperoxic ventilation is known to both reverse peripheral tissue hypoxia at Hctcrit and also to induce coronary vasoconstriction. This study aimed to determine whether hyperoxic ventilation at Hctcrit further exacerbates myocardial ischemia and dysfunction.

Diaspirin-crosslinked hemoglobin reduces mortality of severe hemorrhagic shock in pigs with critical coronary stenosis

Objective To evaluate the effects of resuscitation with a 10% diaspirin-crosslinked hemoglobin (DCLHb) solution on global hemodynamic variables, systemic and myocardial oxygen transport and tissue oxygenation, and contractile function of the left ventricle in an experimental model of severe hemorrhagic shock and critical stenosis of the left anterior descending coronary artery (LAD). Design Prospective, placebo-controlled, randomized study. Setting Experimental animal laboratory. Subjects A total of 20 anesthetized pigs. Interventions After implementation of a permanent critical LAD stenosis (ie, maintenance of basal blood flow but absence of reactive hyperemia after a 10-sec complete vessel occlusion), hemorrhagic shock (target mean aortic pressure, 45 mm Hg) was induced within 15 mins by programmed withdrawal of blood and maintained for 60 mins. Subsequently, the volume of plasma lost during hemorrhage was replaced by either a balanced electrolyte solution containing 10 g/dL DCLHb (DCLHb group; n = 10) or an 8 g/dL human albumin solution (HSA) oncotically matched to DCLHb (HSA group; n = 10). Data were collected immediately after the infusion of the different solutions and again after 60 mins had elapsed. Measurements and Main Results Although five of ten HSA-treated animals died of acute left ventricular failure within the first 20 mins after complete fluid resuscitation, all of the DCLHb-treated animals survived the 60-min observation period after resuscitation (p < .05). This significant difference in mortality is explained by higher coronary perfusion pressure in DCLHb-treated animals (75 ± 17 vs. 27 ± 17 torr DCLHb vs. HSA group;p < .05) and persistence of subendocardial ischemia and hypoxia (radioactive microspheres method) in HSA-treated animals on resus-citation particularly affecting the LAD-supported myocardium (subendocardial oxygen delivery: 20 ± 11 vs. 3 ± 1 mL oxygen·g−1·min−1, DCLHb vs. HSA group;p < .05). Except for enhanced myocardial contractility immediately on infusion of DCLHb (maximal left ventricular pressure increase: 2373 ± 782 vs. 1730 ± 543 torr·sec−1 DCLHb vs. HSA group;p < .05), no differences were detected between groups concerning the variables of systemic oxygen transport, tissue oxygenation, and regional contractile function of the myocardium (determined with microsonometry). Conclusions Fluid resuscitation with 10% DCLHb solution completely reverses hemorrhagic shock-induced subendocardial ischemia and hypoxia in the presence of compromised coronary circulation and thereby prevents early death after resuscitation.

Oxygent as a top load to colloid and hyperoxia is more effective in resuscitation from hemorrhagic shock than colloid and hyperoxia alone.

Perfluorocarbon (PFC) emulsions are intravascular oxygen therapeutics that temporarily enhance tissue oxygenation in dilutional anemia. However, PFC emulsions are not resuscitation fluids because PFCs only work optimally in the presence of high O2 partial pressure (hyperoxia); moreover, because they have no oncotic potential, dosing limitations prevent their use to permanently replace large hemorrhage volumes. Our objective was to clarify whether in the presence of hyperoxia a conventional colloid therapy supplemented by PFC is more efficacious than colloid alone. To answer this question, 22 anesthetized, ventilated dogs were hemorrhaged to a mean arterial pressure of 45 mmHg and were kept at this level until a metabolic O2 debt of 120 mL kg−1 body weight had evolved. Hyperoxia was established and dogs were randomly allocated to receive colloid (6% HES, Hydroxy Ethyl Starch shed blood volume) or colloid together with Oxygent™ (perflubron emulsion, 60%, w/v; Alliance Pharmaceutical Corp., San Diego, CA; single dose, 4.5 mL kg−1; i.e., 2.7 g PFC kg−1 body weight) in a blinded fashion. Hemodynamic and O2 transport parameters, intestinal mucosal blood flow (microspheres), and O2 partial pressure (MDO-Electrode; Eschweiler, Kiel, Germany) were measured at baseline, in shock, and during 3 h post-therapy. In the presence of hyperoxia, Oxygent™ improved the amount of physically dissolved O2 in plasma and increased the contribution of physically dissolved O2 to global O2 delivery (P < 0.05) and thus whole body O2 consumption when compared with colloid alone (P < 0.05). As a result, Oxygent™ reduced intestinal mucosal hypoxia and global O2 debt within the first hour post-therapy (P < 0.05). We conclude that under hyperoxic conditions, fluid resuscitation supplemented by Oxygent™ was more efficacious than colloid and hyperoxia alone. PFC temporarily enhanced intestinal mucosal tissue oxygenation during resuscitation.

Improved Ventricular Function during Inhalation of PGI 2 Aerosol Partly Relies on Enhanced Myocardial Contractility

Inhaled prostacyclin (PGI₂) aerosol induces selective pulmonary vasodilation. Further, it improves right ventricular (RV) function, which may largely rely on pulmonary vasodilation, but also on enhanced myocardial contractility. We investigated the effects of the inhaled PGI₂ analogs epoprostenol (EPO) and iloprost (ILO) on RV function and myocardial contractility in 9 anesthetized pigs receiving aerosolized EPO (25 and 50 ng·kg^–1·min^–1) and, consecutively, ILO (60 ng·kg^–1·min^–1) for 20 min each. We measured pulmonary artery pressure (PAP), RV ejection fraction (RVEF) and RV end-diastolic-volume (RV-EDV), and left ventricular end-systolic pressure-volume-relation (end-systolic elastance, E_es). EPO and ILO reduced PAP, increased RVEF and reduced RVEDV. E_es was enhanced during all doses tested, which reached statistical significance during EPO_25ng and ILO, but not during EPO_50ng. PGI₂ aerosol enhances myocardial contractility in healthy pigs, contributing to improve RV function.

Fluid resuscitation from severe hemorrhagic shock using diaspirin cross-linked hemoglobin fails to improve pancreatic and renal perfusion

Background:  Fluid resuscitation from hemorrhagic shock is intended to abolish microcirculatory disorders and to restore adequate tissue oxygenation. Diaspirin cross‐linked hemoglobin (DCLHb) is a hemoglobin‐based oxygen carrier (HBOC) with vasoconstrictive properties. Therefore, fluid resuscitation from severe hemorrhagic shock using DCLHb was expected to improve perfusion pressure and tissue perfusion of kidneys and pancreas.