Tolerance to Acute Isovolemic Hemodilution: Effect of Anesthetic Depth

Background: Acceptance of a lower transfusion trigger in the perioperative period requires study of the effects of anesthetic depth on the tolerance to acute isovolemic anemia. Anesthetic agents with negative effects on the cardiovascular system may exert proportionately greater depressant effects on cardiac output response than on tissue oxygen demand, reducing tolerance to acute isovolemic anemia.

Methods: In the first study, animals were anesthetized with halothane (n = 14; 23.8 +/- 4.8 kg, mean +/- SD). In a second study, animals were anesthetized with ketamine (n = 14; 24.3 +/- 4.7 kg). In each study, dogs were randomly allocated to receive either low or high concentrations of anesthetic. Oxygen delivery and oxygen consumption were determined from independent measurements during a stepwise isovolemic hemodilution protocol. In each dog, critical oxygen delivery was determined from a plot of oxygen consumption versus oxygen delivery using a least-sum-of-squares technique. Critical hemoglobin (hemoglobin) was determined from a plot of hemoglobin versus oxygen consumption using the same method.

Results: With both agents, the higher anesthetic concentration was associated with decreased oxygen consumption, resulting in a lower critical oxygen delivery. However, critical hemoglobin was significantly higher in the animals receiving the higher anesthetic dosage (1.5 vs. 1.0 minimum alveolar concentration of halothane: 4.1 +/- 1.3 vs. 2.3 +/- 0.5 g/dl, P < 0.05; high-vs. low-dose ketamine: 3.7 +/- 1.4 vs. 2.5 +/- 0.6 g/dl, P < 0.05). This was related to a marked blunting of the cardiac output response to hemodilution in the animals receiving the higher anesthetic dosage.     

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).     

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.     

Cardiovascular and metabolic response to acute normovolemic anemia. Effects of anesthesia

BACKGROUND: The maintenance of adequate tissue oxygenation during acute anemia depends on an increase in both cardiac output and tissue oxygen extraction. This study tested the hypothesis that anesthesia blunts the cardiac output response associated with acute normovolemic hemodilution. METHODS: Forty patients undergoing major abdominal surgery were prospectively randomized to undergo acute normovolemic hemodilution (ANH) either awake (awake group, n = 20) or with fentanyl-nitrous oxide-isoflurane anesthesia (anesthetized group, n = 20). Radial and pulmonary artery catheters were placed in all patients. After hemodynamic measurements were taken, patients in the two groups underwent hemodilution to decrease their hemoglobin concentration from 13 to 8 g/dl. A total of 1,875 +/- 222 ml (mean +/- SD) of blood was collected and simultaneously replaced by the same volume of medium molecular weight hydroxyethylstarch in both groups. RESULTS: In the awake group, ANH resulted in a significant increase in cardiac index (from 3.1 +/- 0.5 to 4.8 +/- 1.0 l. min-1. m-2) related to both an increase in heart rate and stroke index. Oxygen delivery remained unchanged, but oxygen consumption increased significantly, resulting in an increase in oxygen extraction ratio. In the anesthetized group, ANH resulted in a significantly smaller increase in cardiac index (from 2.3 +/- 0.5 to 3.1 +/- 0.7 l. min-1. m-2) related solely to an increase in stroke index. Oxygen delivery decreased but oxygen consumption was maintained as oxygen extraction increased. CONCLUSIONS: Anesthesia significantly reduces the cardiac output response associated with ANH. This could be related to the effects of the anesthetic drugs on the autonomic and the cardiovascular systems.     

Blood gas analysis of mixed venous blood during normoxic acute isovolemic hemodilution in pigs

Mixed venous oxygen saturation of hemoglobin (SvO2) and mixed venous oxygen tension (PvO2) may reflect the overall balance between oxygen consumption and delivery. Because of the potential value of monitoring SvO2 and PvO2 as indications of the state of tissue oxygenation, the aim of this study was to determine, during normoxic acute isovolemic hemodilution in pigs, the critical PvO2, critical SvO2, and critical oxygen extraction ratio (ER) at which oxygen uptake starts to decline during further induced hemodilution. During stepwise induced isovolemic hemodilution, a gradual decline in SvO2 and PvO2 was observed in all animals. The mean +/- SD of the critical PvO2 of six animals was 32.3 +/- 3.1 mm Hg. The mean +/- SD of the critical SvO2 was 44.2% +/- 7.9%. The ER increased gradually. At an ER of 0.57 +/- 0.08, oxygen uptake started to decline. A significant correlation was found between changes in SvO2 and changes in ER. These degrees of hemodilution were accompanied by an increase in cardiac index, pulmonary wedge pressure, heart rate, and left ventricular stroke work index. Only a slight decrease in systemic vascular resistance was observed. We conclude that measurements of PvO2 and SvO2 can be used as indicators of the critical point of hemodilution and that the SvO2 during hemodilution reflects the overall balance between oxygen uptake and oxygen delivery, confirmed by the strong correlation found between SvO2 and oxygen extraction ratio.     

Splanchnic oxygen consumption is impaired during severe acute normovolemic anemia in anesthetized humans

BACKGROUND: In conscious humans, reduction in hemoglobin concentration to 5 g/dl did not produce inadequate systemic oxygenation. However, systemic measures of inadequate oxygenation may not be sufficiently sensitive to detect inadequate oxygenation in individual organs such as splanchnic organs. The authors tested the hypothesis that acute normovolemic anemia to hemoglobin less than 6.0 g/dl in anesthetized humans reduces splanchnic oxygen consumption because of diminished whole body oxygen delivery. METHODS: Elective spine (n = 12) and abdominal (n = 7) surgery patients underwent acute normovolemic anemia to decrease the hemoglobin concentration close to 6.0 g/dl. The authors assessed the development of supply-dependent conditions in systemic and regional vascular beds by two primary measures before and after acute normovolemic anemia: oxygen consumption and surrogate biochemical markers of anaerobic metabolism, including plasma lactate, regional lactate kinetics, and ketone body ratio. RESULTS: When hemoglobin was reduced from 13.6 +/- 1.2 to 5.9 +/- 0.3 g/dl, oxygen supply dependency occurred in the splanchnic and preportal tissues but not at the systemic level. Regional supply dependency was accompanied by biochemical markers of anaerobic metabolism. CONCLUSIONS: In anesthetized humans, a reduction in hemoglobin to 5.9 g/dl by acute normovolemic anemia diminished splanchnic and preportal whole body oxygen delivery and impaired splanchnic and preportal oxygen consumption. This was accompanied by increased plasma levels of regional lactate and an increased beta-hydroxybutyrate-to-acetoacetate ratio. These findings suggest that the risk to the gastrointestinal tract during acute normovolemic anemia may be underestimated.     

Cardiovascular and Metabolic Response to Acute Normovolemic Anemia: Effects of Anesthesia

Background: The maintenance of adequate tissue oxygenation during acute anemia depends on an increase in both cardiac output and tissue oxygen extraction. This study tested the hypothesis that anesthesia blunts the cardiac output response associated with acute normovolemic hemodilution.

Methods: Forty patients undergoing major abdominal surgery were prospectively randomized to undergo acute normovolemic hemodilution (ANH) either awake (awake group, n = 20) or with fentanyl-nitrous oxide-isoflurane anesthesia (anesthetized group, n = 20). Radial and pulmonary artery catheters were placed in all patients. After hemodynamic measurements were taken, patients in the two groups underwent hemodilution to decrease their hemoglobin concentration from 13 to 8 g/dl. A total of 1,875 +/- 222 ml (mean +/- SD) of blood was collected and simultaneously replaced by the same volume of medium molecular weight hydroxyethylstarch in both groups.

Results: In the awake group, ANH resulted in a significant increase in cardiac index (from 3.1 +/- 0.5 to 4.8 +/- 1.0 l [middle dot] min-1 [middle dot] m-2) related to both an increase in heart rate and stroke index. Oxygen delivery remained unchanged, but oxygen consumption increased significantly, resulting in an increase in oxygen extraction ratio. In the anesthetized group, ANH resulted in a significantly smaller increase in cardiac index (from 2.3 +/- 0.5 to 3.1 +/- 0.7 l [middle dot] min-1 [middle dot] m-2) related solely to an increase in stroke index. Oxygen delivery decreased but oxygen consumption was maintained as oxygen extraction increased.     

Oxygen transport dynamics of acellular hemoglobin solutions in an isovolemic hemodilution model in swine.

BACKGROUND: One of the perceived advantages of a hemoglobin-based blood substitute is the provision of oxygen-carrying capacity. Although the hemodynamic response to the infusion of acellular hemoglobin solutions has been extensively studied, less is known about the oxygen transport dynamics of such solutions. We hypothesized that acellular hemoglobin solutions are useful oxygen carriers in anemic states and that higher P50 solutions transport O2 more efficiently than low P50 solutions. We sought to quantify O2 transport dynamics of hemoglobin solutions in an isovolemic hemodilution model in swine. METHODS: Eighteen swine were anesthetized, ventilated, and instrumented for hemodynamic measurements and for withdrawal of arterial and mixed venous blood. The swine were randomized into three groups and progressively bled from an initial hematocrit (Hct) of 30% to Hcts of 19%, 13%, and 8% using isovolemic exchange with pyridoxalated hemoglobin polyoxyethylene conjugate (PHP, n = 6); an identical hemoglobin solution without the pyridoxalation, resulting in a low P50 solution (POE-Hb, n = 6); or an osmotically similar control solution of pentastarch (PS, n = 6). Hemodynamic measurements, arterial and mixed venous O2 content, and O2 extraction ratio (ER), were determined in whole blood (WB), the red blood cell (RBC) phase, and the plasma phase utilizing a compartmentalized approach. RESULTS: Mean pulmonary arterial pressure was higher with hemodilution in the PHP and POE-Hb groups than in the PS group (p < 0.05). Cardiac index increased with hemodilution in all groups, but was significantly less than the cardiac index in the PS group at Hcts = 19% and 13%. Oxygen delivery and consumption were maintained at all hematocrits at baseline levels in the PHP and POE-Hb groups, but O2 delivery was significantly decreased in the PS group at Hct = 8% (p < 0.05 for PS vs. baseline and p < 0.05 for PHP and POE-Hb vs. PS). Oxygen extraction ratio increased with progressive hemodilution in both the RBC hemoglobin and plasma phases to a maximum of 39% for PHP and 36% for POE-Hb at Hct = 8%. The percent contribution from the plasma phase to total oxygen delivery and consumption likewise increased with hemodilution to maximum values of 52.7% (PHP) and 68.2% (POE-Hb) for delivery and 40.9% (PHP) and 39.3% (POE-Hb) for consumption. CONCLUSION: Acellular hemoglobin solutions provide a significant contribution to O2 delivery and consumption, particularly in severe anemia, in this model of isovolemic exchange. The differences in the P50 of the two hemoglobin solutions do not appear to significantly influence oxygen dynamics over the range of hematocrits studied.     

Systemic responses to hemodilution after transfusion with stored blood and with a hemoglobin-based oxygen carrier

We assessed the systemic effects of exchanges with blood or hemoglobin (Hb) raffimer under conditions of critical oxygen delivery (Do(2)crit). We compared Do(2)crit in animals receiving Hb-based oxygen carrier (HBOC; Hemolink), fresh blood (collected <24 h), or stored blood (10 days) before hemodilution. Rats were randomized to control, blood, or HBOC isovolemic exchange. Oxygen consumption was measured by using expired gas (o(2)a) and blood (o(2)b) samples, whereas whole-body oxygen delivery (Do(2)) was calculated from cardiac output and arterial oxygen content. After exchange, rats were subjected to stepwise isovolemic hemodilution. Blood pressure, gases, acid-base status, glucose, Hb oxygen saturation, heart rate, and total peripheral resistance were also measured. We found that 1) HBOC-treated rats showed an increased mean arterial blood pressure and total peripheral resistance throughout the hemodilution, 2) Do(2)crit calculated with o(2)a or o(2)b gave identical results, 3) Do(2)crit was not different between animals receiving blood and those receiving HBOC, 4) the terminal Hb concentration (1.8 +/- 0.1 g/dL) and Do(2) (5 +/- 1 mL . min(-1) . kg(-1)) were similar for all animals, and 5) most oxygen transport and biochemical variables changed similarly during hemodilution. The data suggest that tolerance to Do(2)crit is not altered by 50% replacement of native Hb by stored blood or Hb raffimer.     

Oxygen reverses deficits of cognitive function and memory and increased heart rate induced by acute severe isovolemic anemia

BACKGROUND: Erythrocytes are transfused to improve oxygen delivery and prevent or treat inadequate oxygenation of tissues. Acute isovolemic anemia subtly slows human data processing and degrades memory, increases heart rate, and decreases self-assessed energy level. Erythrocyte transfusion is efficacious in reversing these effects of acute anemia. We tested the hypothesis that increasing arterial oxygen pressure (Pao2) to 350 mmHg or greater would supply sufficient oxygen to be equivalent to augmenting hemoglobin concentration by 2-3 g/dl and thus reverse the effects of acute anemia. METHODS: Thirty-one healthy volunteers, aged 28 +/- 4 yr (mean +/- SD), were tested with verbal memory and standard, computerized neuropsychologic tests before and twice after acute isovolemic reduction of their hemoglobin concentration to 5.7 +/- 0.3 g/dl. Two sets of tests were performed in randomized order at the lower hemoglobin concentration: with the volunteer breathing room air or oxygen. The subject and those administering the tests and recording the results were unaware which gas was administered. As an additional control for duration of the experiment, 10 of these volunteers also completed the same tests on a separate day, without alteration of hemoglobin concentration, at times of the day similar to those on the experimental day. Heart rate, mean arterial blood pressure, and self-assessed sense of energy were recorded at the time of each test. RESULTS: Reaction time for digit-symbol substitution test increased, delayed memory was degraded, mean arterial pressure and energy level decreased, and heart rate increased at a hemoglobin concentration of 5.7 g/dl (all P < 0.05). Increasing Pao2 to 406 +/- 47 mmHg reversed the digit-symbol substitution test result and the delayed memory changes to values not different from those at the baseline hemoglobin concentration of 12.7 +/- 1.0 g/dl, and decreased heart rate (P < 0.05). However, mean arterial pressure and energy level changes were not altered with increased Pao2 during acute anemia. CONCLUSION: The authors confirmed that acute isovolemic anemia subtly slows human reaction time, degrades memory, increases heart rate, and decreases energy level. The findings of this study support the hypothesis that increasing Pao2 to 350 mmHg or greater by breathing oxygen reverses all of these effects of acute anemia except for decreased energy.     

Splanchnic Oxygen Consumption Is Impaired during Severe Acute Normovolemic Anemia in Anesthetized Humans

Background: In conscious humans, reduction in hemoglobin concentration to 5 g/dl did not produce inadequate systemic oxygenation. However, systemic measures of inadequate oxygenation may not be sufficiently sensitive to detect inadequate oxygenation in individual organs such as splanchnic organs. The authors tested the hypothesis that acute normovolemic anemia to hemoglobin less than 6.0 g/dl in anesthetized humans reduces splanchnic oxygen consumption because of diminished whole body oxygen delivery.

Methods: Elective spine (n = 12) and abdominal (n = 7) surgery patients underwent acute normovolemic anemia to decrease the hemoglobin concentration close to 6.0 g/dl. The authors assessed the development of supply-dependent conditions in systemic and regional vascular beds by two primary measures before and after acute normovolemic anemia: oxygen consumption and surrogate biochemical markers of anaerobic metabolism, including plasma lactate, regional lactate kinetics, and ketone body ratio.

Results: When hemoglobin was reduced from 13.6 +/- 1.2 to 5.9 +/- 0.3 g/dl, oxygen supply dependency occurred in the splanchnic and preportal tissues but not at the systemic level. Regional supply dependency was accompanied by biochemical markers of anaerobic metabolism.     

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.     

Oxygen Reverses Deficits of Cognitive Function and Memory and Increased Heart Rate Induced by Acute Severe Isovolemic Anemia

Background: Erythrocytes are transfused to improve oxygen delivery and prevent or treat inadequate oxygenation of tissues. Acute isovolemic anemia subtly slows human data processing and degrades memory, increases heart rate, and decreases self-assessed energy level. Erythrocyte transfusion is efficacious in reversing these effects of acute anemia. We tested the hypothesis that increasing arterial oxygen pressure (Pao2) to 350 mmHg or greater would supply sufficient oxygen to be equivalent to augmenting hemoglobin concentration by 2-3 g/dl and thus reverse the effects of acute anemia.

Methods: Thirty-one healthy volunteers, aged 28 +/- 4 yr (mean +/- SD), were tested with verbal memory and standard, computerized neuropsychologic tests before and twice after acute isovolemic reduction of their hemoglobin concentration to 5.7 +/- 0.3 g/dl. Two sets of tests were performed in randomized order at the lower hemoglobin concentration: with the volunteer breathing room air or oxygen. The subject and those administering the tests and recording the results were unaware which gas was administered. As an additional control for duration of the experiment, 10 of these volunteers also completed the same tests on a separate day, without alteration of hemoglobin concentration, at times of the day similar to those on the experimental day. Heart rate, mean arterial blood pressure, and self-assessed sense of energy were recorded at the time of each test.

Results: Reaction time for digit-symbol substitution test increased, delayed memory was degraded, mean arterial pressure and energy level decreased, and heart rate increased at a hemoglobin concentration of 5.7 g/dl (all P < 0.05). Increasing Pao2 to 406 +/- 47 mmHg reversed the digit-symbol substitution test result and the delayed memory changes to values not different from those at the baseline hemoglobin concentration of 12.7 +/- 1.0 g/dl, and decreased heart rate (P < 0.05). However, mean arterial pressure and energy level changes were not altered with increased Pao2 during acute anemia.     

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 effect of hemodilution on blood flow regulation in normal and postischemic intestine

We investigated the effect of hemodilution on intestinal blood flow and oxygen consumption (VO2) in denervated rat small intestinal preparations. In one series of experiments, intestinal blood flow (IBF) and intestinal oxygen extraction (A-VO2) were measured during graded decreases in perfusion pressure. Control animals underwent consecutive studies without hemodilution; experimental animals were studied before and after isovolemic hemodilution. In a second series of experiments, normovolemic hemodilution was performed in experimental animals NH while hematocrit was maintained in controls, C. Preparations were then subjected to 30 min of complete ischemia followed by 30 min of reperfusion. Hemodilution (40.5 +/- 0.8% to 17.2 +/- 2.5%) decreased A-VO2 (3.9 +/- 0.5 to 2.1 +/- 0.4 ml/dl; P less than 0.05) but increased IBF (77.5 +/- 9.8 to 132.1 +/- 15.0 ml/min/100 gm; P less than 0.01). IBF was maintained to the limit of pressure:flow autoregulation (69 mmHg). Below this point, decreases in IBF were accompanied by increases in A-VO2 thus maintaining VO2. At a much lower "critical pressure" (42 mmHg) maximal oxygen extraction was reached and VO2 decreased with IBF. In the second series of experiments, hemodiluted animals (hematocrit 25 +/- 1%) studied during the reperfusion period maintained higher O2 consumption [30 min values (ml/min/100 gm): 4.8 +/- 0.9 NH vs 1.6 +/- 0.2 C, P less than 0.01] and A-VO2 difference [30 min values (vol%): 3.9 +/- 0.4 NH vs 2.1 +/- 0.4 C, P less than 0.005] than control animals (hct 33 +/- 2%). Hemodilution does not impair the intestine's ability to maintain O2 consumption during hypotension and hypoperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Aging: impact upon local cerebral oxygenation and blood flow with acute isovolemic hemodilution

Data from the neurosurgical critical care arena demonstrate a correlation between cerebral oxygenation, survival, and cognitive function. Transfusion may increase and hemodilution decrease cerebral oxygenation. Both acute and chronic anemia have been associated with cognitive dysfunction. Aggressive blood conservation protocols have been instituted across all age groups without conclusive evidence for their impact upon outcome. Aged subjects are at the greatest risk of cognitive sequelae after major surgery associated with significant blood loss. We hypothesize that cerebral physiologic changes associated with "normal" aging may compromise cerebral oxygenation in the presence of severe anemia.Fischer 344 rats, the NIH National Institute of Aging normal aging rat model, underwent a stepwise isovolemic hemodilution protocol. Age groups (Age Grp) studied were as follows: Age Grp-A (3 months), n=14; Age Grp-B (9 to 12 months), n=14; and Age Grp-C (24 months), n=14. Brain oxygen tension (PBrO2), laser Doppler flow, and mean arterial pressure were measured. Final hemoglobin averaged 6.1+/-0.9 g/dL. PBrO2 levels decreased from a baseline of 18.1+/-4.1 to 17.5+/-6.8 mm Hg (P=0.49), and laser Doppler flow increased by 18+/-20% (P<0.0001) after hemodilution. Employing repeated measures multiple regression, Age Grp (P=0.30) was not a significant controlling covariate of PBrO2 in response to isovolemic hemodilution. PBrO2 levels were actually higher in Age Grp-C animals at all time points of the hemodilution protocol, although this was not statistically significant. Aged animals were also fully capable of mounting a robust local cerebral hyperemic response to the anemic challenge that was not separable from the response of younger animals.     

Comparison of halothane, isoflurane, alfentanil, and ketamine in experimental septic shock

The effects of four commonly used anesthetic agents, halothane, isoflurane, alfentanil, and ketamine, on cardiovascular function and oxygen balance were studied in a dog model of septic shock. After initial pentobarbital administration, the dogs were given Escherichia coli endotoxin (3 mg/kg) and, after 30 min, fluids to restore cardiac filling pressures to baseline levels. This resulted in a low resistance shock in all animals. Dogs were then given for 2 h either halothane (n = 9, 0.5 MAC), isoflurane (n = 9, 0.5 MAC), or alfentanil (n = 9, 150 micrograms/kg IV plus 2 micrograms.kg-1.min-1) or ketamine (n = 9, 2 mg/kg IV plus 0.2 mg.kg-1.min-1) or no anesthetic (control: n = 9). Mean arterial pressure increased in the control group (+11 +/- 18 mm Hg) and with ketamine (+10 +/- 20 mm Hg), remained unchanged with isoflurane (-2 +/- 11 mm Hg), and decreased with halothane (-22 +/- 23 mm Hg) and alfentanil (-9 +/- 23 mm Hg). Heart rate tended to increase in the control group but decreased with the four anesthetic agents, especially with alfentanil and halothane. Cardiac index and left ventricular stroke work index increased in the control group and in each anesthetic group except the halothane group. Systemic vascular resistance decreased in all groups except in the ketamine group. In the control group, the increase in cardiac index was associated with significant increases in oxygen delivery and consumption, and with a significant decrease in blood lactate levels. There was a dramatic decrease in oxygen consumption in all anesthetic groups, whereas oxygen delivery failed to increase only with halothane. Blood lactate increased significantly with halothane (5.0 +/- 1.5 to 6.3 +/- 1.4 mM/L) and isoflurane (4.8 +/- 1.1 to 5.3 +/- 1.2 mM/L), remained unchanged with alfentanil (4.5 +/- 1.5 and 4.6 +/- 0.8 mM/L), and tended to decrease with ketamine (4.9 +/- 1.4 to 4.5 +/- 1.4 mM/L). In conclusion, among the four anesthetic agents tested, halothane had the least desirable effects. Ketamine best preserved cardiovascular function and appeared to have the least deleterious effects on the hypoxic tissues. Thus, ketamine could be the anesthetic agent of choice in septic shock.     

Electrocardiographic ST-segment changes during acute, severe isovolemic hemodilution in humans

BACKGROUND: Controversy exists regarding the lowest blood hemoglobin concentration that can be safely tolerated. The authors studied healthy resting humans to test the hypothesis that acute isovolemic reduction of blood hemoglobin concentration to 5 g/dl would produce an imbalance in myocardial oxygen supply and demand, resulting in myocardial ischemia. METHODS: Fifty-five conscious healthy human volunteers were studied. Isovolemic removal of aliquots of blood reduced blood hemoglobin concentration from 12.8 +/- 1.2 to 5.2 +/- 0.5 g/dl (mean +/- SD). Removed blood was replaced simultaneously with intravenous fluids to maintain constant isovolemia. Hemodynamics and arterial oxygen content (Cao2) were measured before and after removal of each aliquot of blood. Electrocardiographic (ECG) changes were monitored continuously using a Holter ECG recorder for detection of myocardial ischemia. RESULTS: During hemodilution, transient, reversible ST-segment depression developed in three subjects as seen on the electrocardiogram during hemodilution. These changes occurred at hemoglobin concentrations of 5-7 g/dl while the subjects were asymptomatic. Two of three subjects with ECG changes had significantly higher heart rates than those without ECG changes at the same hemoglobin concentrations. When evaluating the entire study period, the subjects who had ECG ST-segment changes had significantly higher maximum heart rates than those without ECG changes, despite having similar baseline values. CONCLUSION: With acute reduction of hemoglobin concentration to 5 g/dl, ECG ST-segment changes developed in 3 of 55 healthy conscious adults and were suggestive of, but not conclusive for, myocardial ischemia. The higher heart rates that developed during hemodilution may have contributed to the development of an imbalance between myocardial supply and demand resulting in ECG evidence of myocardial ischemia. However, these ECG changes appear to be benign because they were reversible and not accompanied by symptoms.     

Acute Isovolemic Anemia Does Not Impair Peripheral or Central Nerve Conduction

Background: Previous studies have found subtle slowing of responses in tests of addition and digit-symbol substitution during acute severe isovolemic anemia to a hemoglobin concentration of 5 g/dl in healthy unmedicated humans. In this study, the authors tested the hypothesis that such changes relate to the slowing of afferent neural traffic.

Methods: The median nerve was stimulated at the wrist in seven healthy unmedicated volunteers before and after induction of acute isovolemic anemia to a nadir hemoglobin concentration of 5.1 +/- 0.3 g/dl (mean +/- SD). Times for neural impulses to travel from the stimulus site to the brachial plexus, cervical spinal cord, and cerebral cortex were measured using somatosensory evoked potentials. Tests were repeated during acute anemia with the subject breathing oxygen. As a control for time and intrasubject variation, the testing was repeated on a separate day when anemia was not produced at times equivalent to those on the experimental day.

Results: Induced acute severe isovolemic anemia decreased nerve conduction latencies from the wrist to the contralateral cerebral cortex (i.e., to the N20 peak) by 2.3 +/- 1.6% compared with values at a mean hemoglobin concentration of 12.7 g/dl (P < 0.01). These decreased latencies were due solely to an increased peripheral conduction velocity, from the wrist to the brachial plexus (P < 0.05), and were not altered when subjects breathed oxygen (P > 0.05). Conduction velocity from the brachial plexus or cervical spinal cord to the cerebral cortex did not change with acute anemia (P > 0.05). Latencies did not differ on the control day among the times of testing (all P > 0.05), nor did they differ at baseline between the control and experimental days (all P > 0.05).