Critical hematocrit in intestinal tissue oxygenation during severe normovolemic hemodilution

BACKGROUND: A critical point in oxygen supply for microvascular oxygenation during normovolemic hemodilution has not been identified. The relation between organ microvascular oxygen partial pressure (microPO2) and organ oxygen consumption (VO2) during a decreasing oxygen delivery (DO2) is not well understood. The present study was designed to determine the systemic hematocrit and organ DO2 values below which organ microPO2 and VO2 cannot be preserved by regulatory mechanisms during normovolemic hemodilution. METHODS: Eighteen male Wistar rats were randomized between an experimental group (n = 12), in which normovolemic hemodilution was performed with pasteurized protein solution (PPS), and a control group (n = 6). Systemic hemodynamic and intestinal oxygenation parameters were monitored. Intestinal microPO2 was measured using the oxygen-dependent quenching of palladium-porphyrin phosphorescence. RESULTS: Baseline values in hemodilution and control group were similar. Hemodilution decreased hematocrit to 6.2 +/- 0.8% (mean +/- SD). Constant central venous pressure measurements suggested maintenance of isovolemia. Despite an increasing mesenteric blood flow, intestinal DO2 decreased immediately. Initially, microPO2 was preserved, whereas mesenteric venous PO2 (P(mv)O2) decreased; below a hematocrit of 15%, microPO2 decreased significantly below P(mv)O2. Critical DO2 was 1.5 +/- 0.5 ml x kg(-1) x min(-1) for VO2, and 1.6 +/- 0.5 ml x kg(-1) x min(-1) for microPO2. Critical hematocrit values for VO2 and microPO2 were 15.8 +/- 4.6% and 16.0 +/- 3.5%, respectively. CONCLUSIONS: Intestinal microPO2 and VO2 were limited by a critical decrease in DO2 and hematocrit at the same time. Beyond these critical points not only shunting of oxygen from the microcirculation could be demonstrated, but also a significant correlation between intestinal microPO2 and VO2.     

Mild hypothermia has minimal effects on the tolerance to severe progressive normovolemic anemia in Swine

BACKGROUND: The benefits of hypothermia during acute severe anemia are not entirely settled. The authors hypothesized that cooling would improve tolerance to anemia. METHODS: Eight normothermic (38.0 +/- 0.5 degrees C) and eight hypothermic (32.0 +/- 0.5 degrees C) pigs anesthetized with midazolam-fentanyl-vecuronium-isoflurane (0.5% inspired concentration) were subjected to stepwise normovolemic hemodilution (hematocrit, 15%, 10%, 7%, 5%, 3%). Critical hemoglobin concentration (Hgb(CRIT)) and critical oxygen delivery (DO(2CRIT)), i.e., the hemoglobin concentration (Hgb) and oxygen delivery (DO2) at which oxygen consumption (VO2, independently measured by indirect calorimetry) was no longer sustained, and Hgb at the moment of death, defined prospectively as the point when VO2, decreased below 40 ml/min, were used to assess the tolerance of the two groups to progressive isovolemic anemia. RESULTS: At hematocrits of 15% and 10% (Hgb, 47 and 31 g/l), VO2 was maintained in both groups by an increase (P < 0.001) in cardiac output (CO) and extraction ratio (ER; P< 0.001) with unchanged mean arterial lactate concentration (L(art)). At hematocrit of 7% (Hgb, 22 g/l), all normothermic but no hypothermic animals had DO2-dependent VO2. No normothermic and three hypothermic animals survived to 5% hematocrit (Hgb, 15 g/l), and none survived to 3%. Hgb(CRIT) was 23 +/- 2 g/l and 19 +/- 6 g/l (mean +/- SD) in normothermic and hypothermic animals, respectively (P = 0.053). Hgb at death was 19 +/- 3 g/l versus 14 +/- 4 g/l (P = 0.015), and DO(2CRIT) was 8.7 +/- 1.7 versus 4.6 +/- 0.8 ml x kg(-1) x min(-1) (P < 0.001). CONCLUSION: During progressive normovolemic hemodilution in pigs, hypothermia did not significantly change Hgb(CRIT), but it decreased the Hgb at death, i.e., short-term survival was prolonged.     

Intestinal and Cerebral Oxygenation during Severe Isovolemic Hemodilution and Subsequent Hyperoxic Ventilation in a Pig Model

Background: During severe isovolemic hemodilution, determination of critical hematocrit levels for the microvascular oxygenation of different organs might provide more insight into the effect of the redistribution of blood flow and oxygen delivery on the oxygenation of different organs. The effect of an increased amount of dissolved oxygen on tissue oxygenation during severely decreased hematocrit levels is not clear.

Methods: Fifteen anesthetized pigs were randomized between an experimental group (n = 10), in which severe isovolemic hemodilution was performed with 6% hydroxyethylstarch (1:1), and a time-matched control group (n = 5). Systemic, intestinal, and cerebral hemodynamic and oxygenation parameters were monitored. Microvascular oxygen partial pressure ([mu]Po2) was measured in the cerebral cortex and the intestinal serosa and mucosa, using the oxygen-dependent quenching of Pd-porphyrin phosphorescence. In the final phase of the experiment, fraction of inspired oxygen was increased to 1.0.

Results: Hemodilution decreased hematocrit from 25.3 +/- 3.0 to 7.6 +/- 1.2% (mean +/- SD). Systemic and intestinal oxygen delivery fell with the onset of hemodilution; intestinal oxygen consumption deceased at a hematocrit of 9.9%, whereas the systemic oxygen consumption decreased at a hematocrit of 7.6%. During hemodilution, the intestinal and cerebral oxygen extraction ratios increased from baseline with 130 and 52%, respectively. Based on the intersection of the two best-fit regression lines, determined by a least sum of squares technique, similar critical hematocrit levels were found for systemic oxygen consumption and the cerebral and intestinal mucosa [mu] Po2; the intestinal serosa [mu]Po2 decreased at an earlier stage (P < 0.05). Hyperoxic ventilation improved the [mu]Po2 values but not systemic or intestinal oxygen consumption.     

Mild Hypothermia Has Minimal Effects on the Tolerance to Severe Progressive Normovolemic Anemia in Swine

Background: The benefits of hypothermia during acute severe anemia are not entirely settled. The authors hypothesized that cooling would improve tolerance to anemia.

Methods: Eight normothermic (38.0 +/- 0.5[degrees]C) and eight hypothermic (32.0 +/- 0.5[degrees]C) pigs anesthetized with midazolam-fentanyl-vecuronium-isoflurane (0.5% inspired concentration) were subjected to stepwise normovolemic hemodilution (hematocrit, 15%, 10%, 7%, 5%, 3%). Critical hemoglobin concentration (HgbCRIT) and critical oxygen delivery (DO2CRIT), i.e., the hemoglobin concentration (Hgb) and oxygen delivery (DO2) at which oxygen consumption (VO2, independently measured by indirect calorimetry) was no longer sustained, and Hgb at the moment of death, defined prospectively as the point when VO2 decreased below 40 ml/min, were used to assess the tolerance of the two groups to progressive isovolemic anemia.

Results: At hematocrits of 15% and 10% (Hgb, 47 and 31 g/l), VO2 was maintained in both groups by an increase (P < 0.001) in cardiac output (CO) and extraction ratio (ER;P < 0.001) with unchanged mean arterial lactate concentration (Lart). At hematocrit of 7% (Hgb, 22 g/l), all normothermic but no hypothermic animals had DO2-dependent VO2. No normothermic and three hypothermic animals survived to 5% hematocrit (Hgb, 15 g/l), and none survived to 3%. HgbCRIT was 23 +/- 2 g/l and 19 +/- 6 g/l (mean +/- SD) in normothermic and hypothermic animals, respectively (P = 0.053). Hgb at death was 19 +/- 3 g/l versus 14 +/- 4 g/l (P = 0.015), and DO2CRIT was 8.7 +/- 1.7 versus 4.6 +/- 0.8 ml [middle dot] kg-1 [middle dot] min-1 (P < 0.001).     

Circulatory Effects of Hypoxia, Acute Normovolemic Hemodilution, and Their Combination in Anesthetized Pigs

Background: Because hemodilution decreases the oxygen-carrying capacity of blood, it was hypothesized that severe hemodilution would decrease the tolerance to alveolar hypoxia.

Methods: Hemodynamics, oxygen transport, and blood lactate concentrations were compared in ten pigs with normal hematocrit (33 +/-4%), and ten hemodiluted pigs (hematocrit 11+/-1%; mean+/-SD) anesthetized with ketamine-fentanyl-pancuronium during stepwise decreases in inspired oxygen fraction (FIO2; 1.0, 0.35, 0.21, 0.15, 0.10, 0.05).

Results: Median systemic oxygen delivery (DO2 SY) became critical (the DO2 SY value when arterial lactate exceeded 2.0 mmol *symbol* l sup -1) at 10.4 ml *symbol* kg sup -1 min sup -1 (range 6.9-16.1) in hemodiluted animals and at 11.8 ml *symbol* kg sup -1 *symbol* min sup -1 (5.9-32.2) in animals with normal hematocrits (NS). The relationship between mixed venous oxygen saturation and arterial lactate values was less consistent and median critical mixed venous oxygen saturation was higher (P < 0.05) in the hemodiluted group (35%, range 21-64), than in animals with normal hematocrits (21%, 7-68%). In animals with normal hematocrit, decreasing FIO2 from 1.0 to 0.10 resulted in a decrease in DO2 SY from 26.3+/-9.1 to 9.3 +/-3.9 ml *symbol* kg sup -1 *symbol* min sup -1 (P < 0.01). Cardiac output did not change, systemic oxygen extraction ratio increased from 0.23+/-0.08 to 0.68+/-0.13 (P < 0.01), and arterial lactate from 0.9+/-0.2 to 3.4+/-3.0 mmol *symbol* l sup -1 (P < 0.05). Cardiac venous blood flow, as measured by retrograde thermodilution, increased from 5.7+/-2.9 to 12.6+/-5.7 ml *symbol* kg sup -1 *symbol* min sup -1 (P < 0.01). When FIO2 was reduced to 0.05, three animals became hypotensive and died. In the second group, hemodilution increased cardiac output and systemic oxygen extraction ratio (P < 0.01). Cardiac venous blood flow increased from 4.1 +/-1.7 to 9.8+/-5.1 ml *symbol* kg sup -1 *symbol* min sup -1 (P < 0.01), and cardiac venous oxygen saturation from 22+/- 5 to 41+/-10% (P < 0.01). During the subsequent hypoxia, cardiac output and DO2 SY were maintained until FIO2 = 0.15 (DO2 SY = 10.1+/-3.3 ml *symbol* kg sup -1 *symbol* min sup -1). Cardiac venous blood flow was then 18.5+/-10.7 ml *symbol* kg sup -1 *symbol* min sup -1 (P < 0.01), but in spite of this, myocardial lactate production occurred. At FIO2 = 0.10 (DO2 SY = 7.7 +/-3.0 ml *symbol* kg sup -1 *symbol* min sup -1), arterial lactate concentration increased to 8.5+/-2.3 mmol *symbol* l sup -1 (P < 0.01), and most animals became hypotensive. All hemodiluted animals died when FIO2 was decreased to 0.05 (P < 0.01 when compared to animals with normal hematocrit).     

Critical Hematocrit in Intestinal Tissue Oxygenation during Severe Normovolemic Hemodilution

Background: A critical point in oxygen supply for microvascular oxygenation during normovolemic hemodilution has not been identified. The relation between organ microvascular oxygen partial pressure ([mu]Po2) and organ oxygen consumption ( o2) during a decreasing oxygen delivery (Do2) is not well understood. The present study was designed to determine the systemic hematocrit and organ Do2 values below which organ [mu]Po2 and o2 cannot be preserved by regulatory mechanisms during normovolemic hemodilution.

Methods: Eighteen male Wistar rats were randomized between an experimental group (n = 12), in which normovolemic hemodilution was performed with pasteurized protein solution (PPS), and a control group (n = 6). Systemic hemodynamic and intestinal oxygenation parameters were monitored. Intestinal [mu]Po2 was measured using the oxygen-dependent quenching of palladium-porphyrin phosphorescence.

Results: Baseline values in hemodilution and control group were similar. Hemodilution decreased hematocrit to 6.2 +/- 0.8% (mean +/- SD). Constant central venous pressure measurements suggested maintenance of isovolemia. Despite an increasing mesenteric blood flow, intestinal Do2 decreased immediately. Initially, [mu]Po2 was preserved, whereas mesenteric venous Po2 (Pmvo2) decreased; below a hematocrit of 15%, [mu]Po2 decreased significantly below Pmvo2. Critical Do2 was 1.5 +/- 0.5 ml[middle dot]kg-1[middle dot]min-1 for o2, and 1.6 +/- 0.5 ml[middle dot]kg-1[middle dot]min-1 for [mu]Po2. Critical hematocrit values for o2 and [mu]Po2 were 15.8 +/- 4.6% and 16.0 +/- 3.5%, respectively.     

The effects of hemodilution during pulmonary edema in dogs.

Because of their multiple medical problems, patients with the adult respiratory distress syndrome (ARDS) often develop anemia. In order to determine the effects of a low hemoglobin concentration on gas exchange in such patients, the authors studied the effects of isovolemic hemodilution in the dog oleic acid model of ARDS. Twelve splenectomized dogs with oleic acid-induced pulmonary edema and a consequent venous admixture of 31% +/- 5% (mean +/- SEM) (FIO2 = 0.21) underwent two-stage isovolemic hemodilution with Hetastarch followed by retransfusion of the withdrawn red cells. This resulted in hemoglobin levels at each stage of 12.7 +/- 0.7 g/100 ml, 9.1 +/- 0.6 g/100 ml, 6.5 +/- 0.5 g/100 ml, and 10.1 +/- 0.5 g/100 ml (mean +/- SEM). Oxygen transport fell from 363 +/- 25 ml/kg/min to 219 +/- 17 ml/kg/min (p less than 0.001) at maximum hemodilution during air ventilation and from 383 +/- 79 ml/kg/min to 292 +/- 91 ml/kg/min (p less than 0.001) during oxygen ventilation. Since oxygen consumption remained constant throughout the hemoglobin range studied, decreased hemoglobin resulted in declines in P-VO2. Hemodilution with Hetastarch did not affect intrapulmonary shunt or venous admixture despite the significant increase in cardiac output associated with hemodilution.     

Effect of cardiac index and hematocrit changes on oxygen consumption in resuscitated patients

Oxygen consumption (Vo2) has been found to depend on oxygen delivery (Do2) following resuscitation from hemorrhage in both humans and animals. The relative influence of blood flow and arterial oxygen (O2) content, the components of Do2, has not been separately assessed. To determine the relative contribution of content and flow, we determined Do2 and Vo2 while making systematic changes in cardiac index (CI) and hematocrit (HCT). Fourteen patients were studied within 36 hr of hypotension from which they were resuscitated to a HCT of 27.9 +/- 0.4% (mean +/- SEM). Following initial hemodynamic measurements, CI was manipulated by changing end expiratory pressure by increments of +/- 5 cm H2O and measurements were repeated. Patients were then transfused overnight to raise their HCT to 36.7 +/- 0.5% and measurements were repeated, varying CI in the same manner. The increase in HCT resulted in significant (P less than 0.05) increases in O2 delivery (+ 130 +/- 33 ml/min/m2), arterial O2 content (+ 3.9 +/- 0.3 vol%), and mixed venous O2 content (+ 3.7 +/- 0.4 vol%). O2 extraction decreased by 6 +/- 1% from 30 +/- 2%. The change in HCT did not alter Vo2 (143 +/- 7 ml/min/m2), CI (3.6 +/- 0.2 L/min/m2), or intrapulmonary shunt (18.1 +/- 1.7%). However, as CI was changed at both levels of HCT, there were changes in Vo2 directly dependent on Do2. We conclude that oxygen consumption in patients resuscitated from hemorrhage may be influenced by oxygen delivery and that this influence is related more to flow than to arterial content.     

Intestinal and cerebral oxygenation during severe isovolemic hemodilution and subsequent hyperoxic ventilation in a pig model

BACKGROUND: During severe isovolemic hemodilution, determination of critical hematocrit levels for the microvascular oxygenation of different organs might provide more insight into the effect of the redistribution of blood flow and oxygen delivery on the oxygenation of different organs. The effect of an increased amount of dissolved oxygen on tissue oxygenation during severely decreased hematocrit levels is not clear. METHODS: Fifteen anesthetized pigs were randomized between an experimental group (n = 10), in which severe isovolemic hemodilution was performed with 6% hydroxyethylstarch (1:1), and a time-matched control group (n = 5). Systemic, intestinal, and cerebral hemodynamic and oxygenation parameters were monitored. Microvascular oxygen partial pressure (muPo(2) ) was measured in the cerebral cortex and the intestinal serosa and mucosa, using the oxygen-dependent quenching of Pd-porphyrin phosphorescence. In the final phase of the experiment, fraction of inspired oxygen was increased to 1.0. RESULTS: Hemodilution decreased hematocrit from 25.3 +/- 3.0 to 7.6 +/- 1.2% (mean +/- SD). Systemic and intestinal oxygen delivery fell with the onset of hemodilution; intestinal oxygen consumption deceased at a hematocrit of 9.9%, whereas the systemic oxygen consumption decreased at a hematocrit of 7.6%. During hemodilution, the intestinal and cerebral oxygen extraction ratios increased from baseline with 130 and 52%, respectively. Based on the intersection of the two best-fit regression lines, determined by a least sum of squares technique, similar critical hematocrit levels were found for systemic oxygen consumption and the cerebral and intestinal mucosa muPo(2); the intestinal serosa muPo(2) decreased at an earlier stage (P < 0.05). Hyperoxic ventilation improved the muPo(2) values but not systemic or intestinal oxygen consumption. CONCLUSIONS: During isovolemic hemodilution, the diminished oxygen supply was redistributed in favor of organs with a lower capacity to increase oxygen extraction. It is hypothesized that redirection of the oxygen supply within the intestines resulted in the preservation of oxygen consumption and mucosal muPo(2) compared with serosal muPo(2).     

The hemodynamic and metabolic effects of shivering during acute normovolemic hemodilution

To assess the hemodynamic and metabolic effects of shivering during extreme normovolemic hemodilution, we anesthetized 16 pigs with fentanyl-midazolam-pancuronium. Mild hypothermia (36.5 degrees +/- 0.1 degrees C) was induced by surface cooling, and the animals were randomized to either a control group (hemoglobin 118 +/- 3 g/L) or a hemodilution group (hemoglobin 52 +/- 2 g/L). In the latter group, blood was replaced with an isotonic Ringer's acetate/dextran 70 solution. Shivering was allowed to occur by a controlled decrease in the infusion rate of pancuronium. Shivering increased oxygen consumption (VO(2)) in both groups (P < 0.001). Initially, this was predominantly compensated for by an increased oxygen extraction ratio (ER), but when VO(2) was 2.3 +/- 0.2 times baseline, critical levels of mixed venous oxygenation (SVO(2) = 18% +/- 2%; PVO(2) = 22.5 +/- 1.5 mm Hg) and ER (82% +/- 3%) were recorded in anemic animals. Control animals did not reach critical levels until VO(2) was maximal (3.7 +/- 0.3 times baseline). Maximal attained VO(2) was less (2.9 +/- 0.1 times baseline) in the anemic animals (P = 0.01), and at this stage two of these pigs had myocardial lactate production, one of which died in ventricular fibrillation. Coronary perfusion pressure was significantly less (P < 0.001) in the anemic animals. We conclude that in this experimental model, maximal shivering as measured by VO(2) was limited in hemodiluted animals, and left ventricular oxygen balance was marginal, as evidenced by a decreased lactate uptake and extraction. IMPLICATIONS: The effect of acute increases in oxygen consumption (shivering) on severely anemic individuals has not been evaluated. In this experimental model, left ventricular oxygen balance was marginal, as evidenced by decreased lactate extraction.     

Glucagon potentiates intestinal reperfusion injury

Vasoactive agents, including glucagon, have been used in treatment of mesenteric ischemia. Such drugs change both intestinal blood flow and metabolism. Since reperfusion injury reflects the metabolic state of an organ as well as the duration and severity of ischemia, we investigated the effect of glucagon in a standard model of intestinal ischemia. Data were generated from denervated isoperfused rat small intestinal preparations (n = 39). Arterial and venous pressures, intestinal blood flow, and oxygen consumption were monitored. Animals were subjected to 15, 30, or 45 minutes of ischemia followed by 1 hour reperfusion. Experiments were performed without drug infusion or during intravenous glucagon administration (0.1, 0.2, or 0.4 micrograms/kg/min). After the rats were killed, histologic sections of intestine were graded 1 through 5 in a blinded fashion with 1 = normal villi and 5 = severe injury. Results (mean +/- SD) were analyzed by analysis of variance (*p less than 0.05). Glucagon at all concentrations increased intestinal blood flow and oxygen consumption before ischemia. For example, with 0.2 micrograms/kg/min glucagon, intestinal blood flow increased from 80.78 +/- 13.5 to 114.79 +/- 21.02 ml/min.100 gm* and oxygen consumption increased from 3.65 +/- 0.73 to 5.73 +/- 1.37 ml/min.100 gm.* Mucosal injury after ischemia reflected duration of ischemia and glucagon infusion rate. At all ischemic intervals, increased glucagon concentrations were associated with greater mucosal injury. In fact the histologic injury with 15 minutes of ischemia + 0.2 microgram/kg/min glucagon (3.04 +/- 0.49) exceeded that of 30 minutes of ischemia (2.87 +/- 0.06).(ABSTRACT TRUNCATED AT 250 WORDS)     

Electrical correlates of brain injury resulting from severe hypotension and hemodilution in monkeys

The effects of hypotension, hemodilution, and their combination on the relationship between concurrent brain electrical activity and resulting brain injury were studied in anesthetized monkeys. The authors compared changes in the electroencephalogram and somatosensory and auditory evoked potentials with eventual neuropathologic outcome. Our goals were: 1) to define the margin of safety for the monkey brain during hemodilution and hypotension under several simulated clinical conditions; and 2) to determine whether noninvasive measurements of brain electrical activity can predict ischemic brain cell damage. Forty-one monkeys were anesthetized with halothane (0.8 vol % inspired) and ventilated mechanically. Arterial hypotension was induced with trimethaphan (25 +/- 8 mmHg mean arterial blood pressure [MABP] for 30 min). Hemodilution was induced by replacing blood with lactated Ringer's solution (14 +/- 2% hematocrit for 1 h). Combined hemodilution and hypotension consisted of 30 min of hemodilution alone followed by superimposing hypotension for 30 min (16 +/- 3% hematocrit and 29 +/- 5 mmHg MABP). Ten monkeys died following severe hypotension alone or combined hemodilution and hypertension as a consequence of cardiac arrest or undetermined (possibly neurologic) causes. No histologic evidence of ischemic brain cell injury was found in surviving monkeys subjected to hemodilution or hypotension alone. Neuropathologic alterations in the cerebral cortex, cerebellum, hippocampus and globus pallidus as well as neurologic and behavioral deficits were found in seven of 16 surviving monkeys subjected to both hemodilution and hypotension. These findings resulted from combinations of hematocrit less than 20% and MABP below 40 mmHg.(ABSTRACT TRUNCATED AT 250 WORDS)     

Enhanced central organ oxygenation after application of bovine cell-free hemoglobin HBOC-201

PURPOSE: While the effects of dilutional anemia or isovolemic hemodilution (IHD) on the oxygen extraction and tissue oxygenation in peripheral organs after application of hemoglobin-based oxygen carriers like HBOC-201 have been studied intensively, little is known about tissue oxygenation properties of hemoglobin solutions in central organs like the liver. METHODS: Twelve Foxhounds were anesthetized and then randomized to either a control group without hemodilution (Group 1) or underwent first step isovolemic hemodilution (pulmonary artery occlusion pressure constant) with Ringer's solution (Group 2) to a hematocrit of 25% with second step infusion of HBOC-201 until a hemoglobin concentration of +0.6 g.dL(-1) was reached. Tissue oxygen tensions (tpO2) were measured in the gastrocnemius muscle using a polarographic needle probe, and in the liver using a flexible polarographic electrode. RESULTS: While arterial oxygen content and oxygen delivery decreased with hemodilution in Group 2, global liver and muscle oxygen extraction ratio increased after hemodilution and additional application of HBOC-201. Hemodilution and application of HBOC-201 provided augmentation of the mean liver tpO2 (baseline: 48 +/- 9, 20 min: 53 +/- 10, 60 min: 67 +/- 11*, 100 min: 68 +/- 7*; *P < 0.05 vs baseline and Group 1), while oxygen tensions in Group 1 remained unchanged. Oxygen tension in the skeletal muscle increased after hemodilution and additionally after application of HBOC-201 in comparison to baseline and to the control group (P < 0.05). CONCLUSION: In the present animal model, IHD with Ringer's solution and additional application of HBOC-201 increased oxygen extraction and tpO(2) in the liver and skeletal muscle, in parallel and in comparison with baseline values and a control group.     

Effects of hemodilution and phenylephrine on cerebral blood flow and metabolism during cardiopulmonary bypass

OBJECTIVE: Hypotension resulting from hemodilution on cardiopulmonary bypass is often treated by pressor (eg, phenylephrine) infusion. The effect of phenylephrine on cerebral blood flow (CBF) in this setting is not clear. It was hypothesized that phenylephrine might decrease CBF. MEASUREMENTS and MAIN RESULTS: Six different radioactively labeled microspheres (15 microm) were used to measure CBF at 6 time points (T) in 9 pigs (mean body weight 11.3 +/- 1.2 kg): T1 baseline before bypass (mean arterial pressure [MAP] 76 +/- 5 mmHg), T2 on mildly hypothermic CPB (34 degrees C, pump flow 100 mL/kg/min, hematocrit 30%, MAP 79 +/- 7 mmHg), T3 after moderate hemodilution with crystalloid (hematocrit 20%, resulting MAP 62 +/- 6 mmHg), T4 after phenylephrine administration to increase MAP to baseline values (hematocrit 20%), T5 after severe hemodilution (hematocrit 10%, resulting MAP 41 +/- 4 mmHg), and T6 after phenylephrine administration to normalize MAP (hematocrit 10%). In addition, blood flow to liver, small bowel and skeletal muscle, and pH of jugular venous blood were measured at each time point. After institution of CPB, the CBF (mL/min/100 g tissue) increased significantly to 53 +/- 9 (baseline levels 44 +/- 8, T1 v T2, p = 0.03). Hemodilution resulted in significant increases in CBF on CPB to 65 +/- 9 and 90 +/- 9 at hematocrit 20% and hematocrit 10%, respectively (T2 v T3, p = 0.03; T3 v T5, p = 0.01) and a progressive fall in jugular venous pH. At each level of hemodilution, phenylephrine resulted in an additional increase in CBF (T4, 74 +/- 8; T6, 108 +/- 12; T3 v T4, p = 0.04; T5 v T6, p = 0.01) but did not improve jugular venous pH. Changes in liver blood flow after hemodilution and vasopressor injection showed a similar pattern to CBF. However, the blood flow to small bowel and skeletal muscle increased with hemodilution but decreased significantly with phenylephrine administration. CONCLUSIONS: Phenylephrine redirects blood flow from the bowel and muscle to the brain and liver. Hemodilution increases CBF and pressor administration further increases CBF by elevating perfusion pressure. Maintenance of a higher hematocrit on CPB increases MAP and should decrease the need for vasopressor administration.     

Regulation of intestinal blood flow with increased intraluminal pressure

To better characterize the mechanisms which regulate intestinal blood flow (IBF), we studied the effects of gradual and rapid increases in intraluminal pressure (LP) in anesthetized canines. Polarographic measurements of hydrogen washout allowed repeated assessment of IBF (ml/min X g) in control (CL) and distended (DL) autoperfused small intestinal loops. In group I (n = 7) graded increases in LP (mm Hg) were produced by saline inflation. In group II (n = 4), IBF was measured before and after intraarterial aminophylline (adenosine blockade); LP was then rapidly raised to 24 mm Hg. IBF was unchanged by time (CL 0.64 +/- 0.24) or gradual distension (DL 0.65 +/- 0.28 at mean maximal LP = 26). Aminophylline did not change IBF at LP = 0. Rapid distension after adenosine blockade was accompanied by immediate increases in IBF (0.96 +/- 0.41, P less than 0.05) and decreased resistance (50 +/- 25% control). IBF is maintained despite gradual increases in luminal pressure. Blockade of adenosine, an intestinal vasodilator, does not inhibit this response; hyperemia associated with rapid distension is not impaired. We conclude that autoregulation of IBF during distension is not accomplished by an adenosine mediated metabolic mechanism.     

Influence of hematocrit on cardiopulmonary function after acute hemorrhage

The 'optimal' hematocrit to which patients should be resuscitated after shock and trauma is controversial. To test the hypothesis that sufficient oxygen delivery can be provided at a lower hematocrit without impairing oxygen consumption or hemodynamic function, 25 patients were prospectively studied immediately following injury and/or acute hemorrhage. Patients were randomized to have their hematocrits (HCT) maintained near 30% (29.7 +/- 0.4% (M +/- SEM); n = 12) or 40% (38.4 +/- 0.6%, n = 13). Cardiopulmonary parameters were measured twice a day for 3 days. Statistical analysis used a repeated measures analysis of variance with patient age, and ventilator parameters (FIO2, PEEP, and ventilator mode) as covariates. Arterial and venous O2 saturations were not significantly different at different hematocrits, although arterial and venous O2 contents were lower at 30% HCT (a = 14.1 +/- 0.2 m10(2)/dl, v = 10.1 +/- 0.3 m10(2)/dl; vs. a = 17.4 +/- 0.4 m10(2)/dl, v = 13.6 +/- 0.6 m10(2)/dl; p less than 0.05). This resulted in a lower oxygen delivery at the lower HCT. Between the two groups, there also was no significant difference in cardiac index (overall mean, 3.64 +/- 0.16 ml/min/m2), heart rate (99 +/- 4 bpm), systemic vascular resistance (1,058 +/- 55 dyne-sec/cm5), or left ventricular stroke work index (4.3 +/- 0.3 X 10(6) dyne-cm/m2). Intrapulmonary shunt was higher with higher hematocrit (22.6 +/- 2.4% at 40% HCT vs. 14.6 +/- 1.6% at 30% HCT; p less than 0.05) with no difference in end-expiratory pressure.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of pre-oxygenation on hemodynamics and oxygen consumption

Pre-oxygenation is routinely used prior to anesthesia and intubation. In awake, premedicated patients scheduled for major aortic surgery we assessed the effects of breathing oxygen for 10 min via a loosely fitting face mask on hemodynamics and oxygen consumption (VO2). RESULTS. O2-breathing increased arterial PO2 to 51 +/- 13 kPa and decreased VO2 from 109 +/- 18 to 92 +/- 24 ml.min-1.m-2 (P less than 0.001 for both variables). This reduction of VO2 resulted from both a fall in cardiac index from 3.22 +/- 0.67 to 3.04 +/- 0.75 1.min-1/m-2 (P less than 0.05) and a decrease in arterio-venous oxygen content difference from 3.45 +/- 0.60 to 3.03 +/- 0.57 ml/dl (P less than 0.001). Systemic peripheral vascular resistance increased slightly from 1453 +/- 359 to 1538 +/- 383 dyne.s.cm-5.m-2 (P less than 0.05). CONCLUSIONS. These results indicate that an increase in F1O2 in patients without severe limitations of oxygen uptake by the lungs or oxygen transport to the tissues does not improve tissue oxygenation. We speculate that increased peripheral shunting acts to protect tissue PO2 during high arterial PO2 levels.     

Experimental Subarachnoid Hemorrhage in Rats: Effect of Intravenous alpha-alpha Diaspirin Crosslinked Hemoglobin on Hypoperfusion and Neuronal Death

Background: Hemodilution with diaspirin crosslinked hemoglobin (DCLHb) ameliorates occlusive cerebral ischemia. However, subarachnoid hemoglobin has been implicated as a cause of cerebral hypoperfusion. The effect of intravenous DCLHb on cerebral perfusion and neuronal death after experimental subarachnoid hemorrhage was evaluated.

Methods: Rats (n = 48) were anesthetized with isoflurane and subarachnoid hemorrhage was induced by injecting 0.3 ml of autologous blood into the cistema magna. Each animal received one of the following regimens: Control, no hematocrit manipulation; DCLHb, hematocrit concentration decreased to 30% with DCLHb; or Alb, hematocrit concentration decreased to 30% with human serum albumin. The experiments had two parts, A and B. In part A, after 20 min, cerebral blood flow (CBF) was assessed with14 C-iodoantipyrine autoradiography. In part B, after 96 h, in separate animals, the number of dead neurons was determined in predetermined coronal sections by hematoxylin and eosin staining.

Results: Cerebral blood flow was greater for the DCLHb group than for the control group; and CBF was greater for the Alb group than the other two groups (P < 0.05). In one section, CBF was 45.5 +/- 10.9 ml [center dot] 100 g sup -1 [center dot] min sup -1 (mean +/- SD) for the control group, 95.3 +/- 16.6 ml [center dot] 100 g sup -1 [center dot] min sup -1 for the DCLHb group, and 138.1 +/- 18.7 ml [center dot] 100 g sup -1 [center dot] min sup -1 for the Alb group. The number of dead neurons was less in the Alb group (611 +/- 84) than in the control group (1,097 +/- 211), and was less in the DCLHb group (305 +/- 38) than in the other two groups (P < 0.05).     

Isoflurane causes only minimal increases in coronary blood flow independent of oxygen demand

Studies on the coronary circulation during halothane or isoflurane anesthesia are conflicting. Also, little attention has been paid to the time course of the effect of these agents on the coronary circulation. Therefore, we investigated the direct and temporal effects of halothane and isoflurane on coronary hemodynamics in chronically instrumented dogs, in the presence and absence of autonomic nervous system blockade. On different days anesthesia was induced via inhalation with 5% halothane or isoflurane in 100% oxygen. After tracheal intubation, anesthesia was maintained at 1.0 MAC for 30 min. Hemodynamics were recorded continuously. Myocardial oxygen consumption was estimated from the pressure-work index. A total of 36 experiments (four sets of experiments) were completed using nine chronically instrumented dogs. Induction of anesthesia with halothane caused a significant (P less than 0.05) increase in coronary blood flow (from 40 +/- 6 to 68 +/- 11 ml/min), which reached a peak at 1.4 +/- 0.3 min. These changes were secondary to increases in heart rate, arterial pressure, and pressure-work index (10.2 +/- 1.4 to 15.9 +/- 0.8 ml O2.min-1.100g-1). With autonomic nervous reflexes eliminated, halothane caused no change in coronary blood flow. Inhalation of isoflurane caused a greater (P less than 0.05) increase in coronary blood flow (from 39 +/- 6 to 85 +/- 14 ml/min) than did halothane; flow reached a peak at 1.8 +/- 0.6 min. With autonomic reflexes eliminated, isoflurane continued to produce an increase (P less than 0.05) in coronary blood flow (from 39 +/- 4 to 53 +/- 5 ml/min), which reached a peak at 2.1 +/- 0.4 min.(ABSTRACT TRUNCATED AT 250 WORDS)     

Myocardial blood flow and oxygen consumption during isovolemic hemodilution alone and in combination with adenosine-induced controlled hypotension

Recent reports have proposed combining isovolemic hemodilution and controlled hypotension to limit blood loss during surgery. Before such a technique can be considered for clinical use, it must be demonstrated that it does not endanger maintenance of adequate myocardial oxygenation. Accordingly, measurements of left ventricular myocardial blood flow and oxygen consumption were obtained during isovolemic hemodilution alone and in combination with adenosine-induced controlled hypotension in ten pentobarbital-anesthetized, open chest dogs with normal coronary circulation. Hemodilution to a hematocrit of 21.7% was produced by isovolemic exchange of whole blood for 5% dextran. In the presence of hemodilution, adenosine was infused intravenously at a rate sufficient to decrease mean aortic pressure to 51 mm Hg. Myocardial blood flow was measured with radioactive microspheres and used to calculate global left ventricular myocardial oxygen consumption and oxygen supply. Hemodilution alone increased aortic blood flow (+43%) but had no effect on aortic pressure, left atrial pressure, heart rate, or left ventricular dP/dtmax; an increase in myocardial blood flow (+130%) maintained oxygen supply and consumption at the baseline level. Adenosine-induced hypotension during hemodilution decreased heart rate (-35%), left ventricular dP/dt max (-28%), and aortic blood flow (-14%). These systemic responses were accompanied by reduced myocardial oxygen consumption (-29%) and increased myocardial blood flow (+54%) and myocardial oxygen supply (+72%). These latter effects resulted in reduction in the coronary arteriovenous oxygen content difference and in an attendant rise in coronary sinus Po2 (+66%), which are signs of luxuriant myocardial perfusion.(ABSTRACT TRUNCATED AT 250 WORDS)