title: Diaspirin crosslinked hemoglobin enables extreme hemodilution beyond the critical hematocrit.
abstract: BACKGROUND
  Normovolemic 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.
  
  
  OBJECTIVE
  To assess whether hemodilution can be extended to lower hematocrit values by the use of a hemoglobin-based artificial oxygen carrier solution.
  
  
  METHODS
  Prospective, randomized, controlled.
  
  
  METHODS
  Animal laboratory of a university hospital.
  
  
  METHODS
  Twelve anesthetized, mechanically ventilated pigs.
  
  
  METHODS
  Isovolemic 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%.
  
  
  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 x dL(-1)), whereas all DCLHb-treated animals survived hemodilution until hematocrit 1.2 (0.2)% (hemoglobin, 4.7 g x 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 x min(-1) x g(-1)), and subendocardial oxygen delivery (5.7 (2) mL x min(-1) x 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.
  
  
  CONCLUSIONS
  DCLHb 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 x 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.
authors.affiliation: Institute for Surgical Research, Klinikum Grobetahadern, Ludwig-Maximilians-University Munich, Germany.
authors.forename: F G
authors.initials: FG
authors.lastname: Meisner
authors.forename: G I
authors.initials: GI
authors.lastname: Kemming
authors.forename: O P
authors.initials: OP
authors.lastname: Habler
authors.forename: M S
authors.initials: MS
authors.lastname: Kleen
authors.forename: J H
authors.initials: JH
authors.lastname: Tillmanns
authors.forename: J W
authors.initials: JW
authors.lastname: Hutter
authors.forename: D A
authors.initials: DA
authors.lastname: Bottino
authors.forename: E
authors.initials: E
authors.lastname: Thein
authors.forename: J M
authors.initials: JM
authors.lastname: Meier
authors.forename: C J
authors.initials: CJ
authors.lastname: Wojtczyk
authors.forename: A
authors.initials: A
authors.lastname: Pape
authors.forename: K
authors.initials: K
authors.lastname: Messmer
mesh_terms: D000818:Animals; D001241:Aspirin / Q000031:analogs & derivatives / Q000494:pharmacology*; D001810:Blood Volume; D003326:Coronary Circulation / Q000187:drug effects; D006400:Hematocrit; D006438:Hemodilution; D006439:Hemodynamics / Q000187:drug effects; D006454:Hemoglobins / Q000494:pharmacology*; D006801:Humans; D009200:Myocardial Contraction / Q000187:drug effects; D010101:Oxygen Consumption; D012709:Serum Albumin / Q000494:pharmacology; D013552:Swine
chemical_list: D006454:Hemoglobins; D012709:Serum Albumin; C083478:diaspirin-cross-linked hemoglobin; D001241:Aspirin