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Departments of *Anesthesiology and Intensive Care Medicine and
Cardiac Surgery, Klinikum Ludwigshafen, Ludwigshafen, Germany
Address correspondence and reprint requests to Stefan Suttner, MD, Department of Anesthesiology and Intensive Care Medicine, Klinikum Ludwigshafen, Bremserstr. 79, D-67063 Ludwigshafen, Germany. Address e-mail to suttner{at}gmx.de
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Abstract |
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IMPLICATIONS: We used systemic oxygen transport variables and skeletal muscle oxygen tension to assess the oxygenation status of moderately anemic, mechanically ventilated cardiac surgery patients in response to either allogeneic red blood cell transfusion or 100% oxygen ventilation. Transfusion of stored allogeneic blood was effective only in improving systemic oxygen delivery, whereas 100% oxygen ventilation improved systemic oxygenation and skeletal muscle oxygen tension.
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Introduction |
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Correcting or improving deficient oxygen delivery (DO2) by increasing the oxygen-carrying capacity of circulating blood is believed to be the major indication for allogeneic RBC transfusion (6). This approach assumes that an increase in hemoglobin (Hb) concentration with RBC transfusion will increase the oxygen content of blood and, thus, systemic DO2. Through this increase, regional DO2 should also increase, resulting in improved oxygen availability to tissues and organ function (6). However, the beneficial effects of RBC transfusion on tissue oxygenation have not been demonstrated convincingly (7–10). In fact, there is a growing body of evidence that RBCs stored for prolonged periods may not be effective oxygen carriers and may even compromise oxygenation of tissues and organ function (9,10).
Instead of RBC transfusion, ventilation with high inspiratory fractions of oxygen may increase the oxygen content of blood by increasing the amount of physically dissolved oxygen in the plasma compartment (11,12). This plasma-dissolved oxygen is highly diffusible and therefore preferentially used for tissue oxygenation (11,12). For this reason, 100% oxygen ventilation has emerged as a simple and effective intervention to increase oxygen tension in tissues and may be used to compensate for the decreased oxygen-carrying capacity during isovolemic anemia (11–13).
This study was designed to assess the oxygenation status of moderately anemic cardiac surgery patients after transfusion of 1 or 2 units of allogeneic RBCs by evaluating systemic oxygen transport variables and skeletal oxygen tension (PtiO2). We further tested the hypothesis that increasing oxygen-carrying capacity by 100% oxygen ventilation would be equally effective or even superior to RBC transfusion in improving tissue oxygenation in the immediate postoperative period.
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Methods |
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After cardiac surgery, mechanically ventilated and volume-resuscitated patients who had a nadir Hb concentration in the range from 7.5 to 8.5 g/dL within 3 h after arrival at the intensive care unit (ICU) were randomly assigned to 1 of 3 groups by using a closed envelope system. Patients in Group 1 (transfusion 1; n = 17) and 2 (transfusion 2; n = 17) received infusions of 1 and 2 units of allogeneic RBCs (each given over 30 min) and were mechanically ventilated with an inspired fraction of oxygen (FIO2) of 0.4, whereas Group 3 patients (100 oxygen; n = 17) received ventilation with 100% oxygen over 3 h and no allogeneic RBCs. In the case of hypovolemia with hemodynamic instability, patients in all groups were treated with additional intravascular volume (4% modified gelatin; GelafundinTM; B. Braun, Melsungen, Germany) to maintain pulmonary wedge pressure (PWP) between 10 and 14 mm Hg. Lactated Ringer’s solution (B. Braun) was administered to compensate for fluid loss by sweating, gastric tubes, and urine output or as a solvent for drugs (e.g., antibiotics) at 3–5 mL · kg–1 · h–1 in all patients. Inadequate cardiac output (cardiac index [CI] <2.0 L · min–1 · m–2 and mean arterial blood pressure [MAP] <60 mm Hg despite sufficient volume infusion) was treated with epinephrine. Norepinephrine was given when systemic vascular resistance was <700 dynes · s–1 · cm–5 and MAP was <60 mm Hg. If excessive acute blood loss occurred in any group (defined as chest tube drainage >200 mL/h for two consecutive hours) or Hb decreased to less than 7 g/dL, transfusion of 1 unit of allogeneic RBCs was mandated. Fresh frozen plasma and platelet concentrates were transfused for correction of microvascular bleeding in the presence of abnormal blood coagulation values (activated partial thromboplastin time >1.5 times normal, international normalized ratio >1.5, fibrinogen concentration <1 g/L, and platelet count <50 x 109/L). Patients received (leukocyte-depleted, buffy coat-free) saline-adenine-glucose-mannitol RBCs (German Red Cross Bloodbank, Hagen, Germany; 320 ± 20 mL/unit; hematocrit 60% ± 5%). RBC units were stored at 4°C for <14 days according to a standardized transfusion protocol of our hospital. After the study period, all patients received blood products according to the guidelines of the American Society of Anesthesiologists (6).
Surgery was performed in a single surgical unit with a standard operative technique. Anesthesia was induced and maintained according to the patient’s need, by using weight-related dosages of midazolam (0.07 mg/kg), sufentanil (1.5 µg/kg), and pancuronium (0.1 mg/kg). After intubation of the trachea, the lungs were ventilated with 50% oxygen in air. Ventilation was controlled with a tidal volume of 8–10 mL/kg and a positive end-expiratory pressure of 5 mm Hg. The ventilatory rate was adjusted to maintain an arterial partial pressure of carbon dioxide (PaCO2) of 32 to 42 mm Hg and arterial pH between 7.35 and 7.45. CPB was performed with a Sarns 9000 CPB machine (Sarns Inc., Ann Arbor, MI) and a hollow-fiber membrane oxygenator (Cobe Optima XPTM; Cobe Laboratories, Planegg-Martinsried, Germany). In all patients, the circuit was primed with 1000 mL of lactated Ringer’s solution and 500 mL of gelatin (4% modified gelatin; Gelafundin). Temperature was kept at mild hypothermia (bladder temperature >33°C), and a CPB flow rate of 2.4 L · min–1 · m–2 was used. Packed RBCs (PRBCs) were added when the hematocrit was <20%. During weaning off bypass, as much pump blood as necessary to maintain PWP between 10 and 14 mm Hg was infused. The residual blood remaining in the CPB circuit was processed through a cell-saving device and retransfused after sternal closure. All patients were admitted to the ICU, and controlled mechanical ventilation was continued during the following 6 h at minimum. After the patients showed stable systemic hemodynamics (MAP >70 mm Hg, CI >2.0 L · min–1 · m–2, and PWP between 10 and 14 mm Hg) for 30 min, the study protocol was begun as previously described. In the ICU, mechanical ventilation was maintained with a tidal volume of 8–10 mL/kg, a respiratory frequency of 10–14 breaths/min, a positive end-expiratory pressure of 5 mm Hg, and the designated FIO2. After the study period, tracheal extubation was performed when systemic hemodynamics remained stable for 30 min, body temperature was >36°C, and the patients breathed spontaneously with adequate blood gas variables (PaCO2 <42 mm Hg and PaO2 >75 mm Hg at an FIO2 <0.35). Physicians directly caring for the patients were aware of the group allocation, but they took no part in subsequent data collection and analysis.
Patients were monitored in the ICU until the first postoperative day. Perioperative monitoring included pulse oximetry, continuous monitoring of leads II and V5 of the electrocardiogram, automated ST segment analysis, continuous invasive measurement of MAP, and central venous pressure. Body temperature was continuously monitored by the thermistor of a pulmonary artery catheter. Each cardiac output was determined at least in triplicate by the thermodilution technique by using 10 mL of cold saline (<10°C). Derived hemodynamic data (CI and systemic vascular resistance index) and oxygen transport data (DO2 index and oxygen consumption [
O2] index) were calculated with standard formulas (Appendix 1) (14). A Licox CMPTM system (Integra NeuroSciences Ltd., Andover Hampshire, UK), a digital bedside monitor that displays tissue oxygen tension values directly, together with a graphical trend, and flexible minimally invasive microsensoric catheters (RevoxodeTM; Integra NeuroSciences Ltd.) were used for continuous assessment of tissue oxygenation. The Revoxode consists of a closed polarographic cell that is precalibrated at the time of manufacture and supplied with individual calibration data electronically stored on a "smart card." The PtiO2 is determined at the tip of the probe in a cylindrical tissue layer located concentrically along the axis of the microcatheter. Revoxode probes average the heterogeneous local tissue oxygen tension values over their probe area of 14 mm2, which eliminates random positioning error of microprobe sensors. Oxygen diffuses from the tissue through the polyethylene wall of the catheter into its inner electrolyte chamber, where the Revoxode enables reversible electrolyte reactions to occur at the Clark electrode. This property of the Revoxode preserves sensitivity and offset within a narrow range (5%) over a 5-day period of operation (15). The PO2-sensitive area of the precalibrated catheter was inserted approximately 25 mm into the deltoid muscle via a 20-gauge guiding cannula (VasofixTM; B. Braun). To avoid tissue damage or compression of capillaries, which might influence the PtiO2 measurement, the guiding cannula was retracted by approximately 10 mm. For correction of the PtiO2 data, the temperature within the deltoid muscle was measured simultaneously with a second probe (CC-10; Integra NeuroSciences Ltd.) implanted alongside the tissue oxygen sensor. Both tissue oxygen and temperature sensors interface with a laptop computer, allowing data to be recorded on a continuous basis and stored electronically. This technique and equipment are well established for the measurement of tissue oxygen tensions (16,17). Arterial and mixed venous blood samples were analyzed in an automatic multiwavelength blood gas tension analyzer (RapidlabTM 860; Bayer HealthCare, Leverkusen, Germany) in 30-min intervals for Hb, arterial and mixed venous oxygen saturation, PaO2, venous partial pressure of oxygen (PvO2), PaCO2, pH, and lactate concentrations. Hemodynamics, PtiO2 values, systemic oxygen transport, and blood gas variables are reported at a nadir Hb in the range of 7.5 to 8.5 g/dL before any intervention (baseline) and at 30, 60, 90, 120, and 180 min after increasing the FIO2 to 1.0. In Group 1 and 2 patients, time points 30 and 60 min denote the completion of infusion of 1 and 2 units, respectively, of allogeneic RBCs. In addition, plasma concentrations of cardiac troponin T (by using a commercial monoclonal-monoclonal double antibody and one-step sandwich enzyme immunoassay; Boehringer Mannheim, Germany; normal value, <0.1 µg/L) were measured as a marker of myocyte necrosis at baseline and 60 and 180 min thereafter.
Primary outcome measures were PtiO2 and systemic oxygen transport variables in response to either RBC transfusion or 100% oxygen ventilation. The number of patients to be studied was determined with a power analysis according to data from a previous experimental study on the effects of 100% oxygen ventilation on tissue oxygenation (11). In this study, switching ventilation from 21% oxygen to 100% oxygen improved organ oxygen tensions and provided an amount of oxygen equivalent to augmenting Hb by approximately 1.5 g/dL, which is clinically significant because this corresponds to transfusion of 1 unit of PRBCs in a 70-kg patient (11). Using the SD of PtiO2 and assuming that the administration of oxygen is at least as effective as transfusion of erythrocytes in increasing tissue DO2, we calculated that 17 patients needed to be enrolled in each group to obtain an 80% chance of detecting such an effect at the P < 0.05 level of significance.
All data are presented as mean ± SD unless otherwise stated. The MedCalc 4.30 (MedCalc Software, Mariakerke, Belgium) software package was used for statistical analyses. The Kolmogorov-Smirnov test was used to check the normality assumption. Continuous variables with a normal distribution were compared by applying Student’s t-test, and if not normally distributed, they were compared by using a Wilcoxon test. One-way and two-way analysis of variance with repeated measures and post hoc Scheffé tests were used to determine the effects of group and time and group-time interactions. The 
2 analysis and Fisher’s exact test were used to compare proportions. Pearson’s correlation coefficients, simple linear regression analyses, and forward stepwise regression analyses were used to compare associations between continuous variables. Associations between continuous and categorical variables were examined with a Mann-Whitney ranked sum test. Accounting for the 6 time points, a Bonferroni-corrected value of P < 0.05/6 was used as the criterion for statistical significance.
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Results |
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O2 index remained unchanged (Fig. 2). Oxygen 100% ventilation increased PtiO2 significantly (from 24.0 ± 5.1 mm Hg to 34.2 ± 6.2 mm Hg). No significant change in PtiO2 was found after transfusion of allogeneic blood (transfusion 1: from 25.2 ± 5.2 mm Hg to 24.4 ± 3.9 mm Hg; transfusion 2: from 22.7 ± 6.1 mm Hg to 26.3 ± 6.5 mm Hg) (Fig. 2). Routine chest radiographs after exposure to 100% oxygen did not show any evidence of clinically relevant pulmonary atelectasis or injury. No significant correlations were found between systemic and regional oxygen kinetics and transfusion-related variables.
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Discussion |
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O2 was due to physically dissolved oxygen. Similar results were reported by Habler et al. (11), who evaluated systemic oxygenation status in anesthetized dogs undergoing normovolemic hemodilution while breathing 100% oxygen. They found that at an Hb concentration of 7.0 g/dL, almost 15% of DO2 and 47% of O2 was due to physically dissolved oxygen. Circulatory adaptations to dilutional anemia, such as a compensatory increase of cardiac output, might further explain the increase in systemic DO2 that was observed in our patients who received 100% oxygen ventilation. The increase in cardiac output might be related to a reduction in blood viscosity resulting in increased venous return and decreased ventricular afterload, as well as an increased sympathetic stimulation of the heart (18–20).
The significantly larger amount of intravascular volume (colloids and crystalloids) received during the first 12 hours after surgery might be another contributing factor for the higher cardiac output observed in those patients placed on 100% oxygen. It should be noted, however, that the physiologic adjustments to a decrease in blood oxygen-carrying capacity are influenced by several factors, such as comorbidity, the use of anesthetics or medications with cardiac or peripheral vascular effects, and, most important, the patient’s intravascular volume status (18–20). For this reason, a strict anesthesia and volume-replacement scheme with predefined hemodynamic goals was followed in all patients during the entire study period to allow for full exploitation of the compensatory mechanisms to dilutional anemia. Previous studies have not consistently demonstrated that increasing DO2 by RBC transfusion was followed by a parallel increase in O2 or improved tissue oxygenation (7–10). In this study, O2 and PtiO2 remained unchanged in patients who received blood transfusions. Augmentation of blood oxygen content by 100% oxygen ventilation also failed to increase O2 but was followed by an immediate increase in PtiO2. There are several reasons that may explain the absence of a beneficial effect of RBC transfusion and 100% oxygen ventilation on systemic O2.
First, systemic O2 was not dependent on oxygen supply before a blood transfusion or 100% oxygen ventilation, which might be attributed to the absence of a true oxygen deficit in these patients. It should be noted, however, that an almost 70% reduction of Hb concentration from baseline is necessary to induce oxygen supply dependency in experimental animals (9). Thus, it is not surprising that there is no pathologic oxygen supply dependency in most clinically resuscitated patients with an Hb concentration more than 7–8 g/dL (21). Moreover, anemic patients usually do not exhibit signs of tissue hypoxia or anaerobic metabolism before transfusion unless they also have acute circulatory failure (22). Indeed, all patients in this study had normal pretransfusion lactate levels and exhibited no signs of myocardial ischemia. Because there is no consensus regarding the degree of tolerable anemia in cardiac surgical patients, we chose a transfusion trigger that would not expose our patients unduly to complications caused by a critically decreased hematocrit. Second, long-term blood storage decreases RBC concentrations of adenosine triphosphate and 2,3-diphosphoglycerate, resulting in decreased erythrocyte membrane deformability and an increased affinity of Hb for oxygen (23,24). These storage effects may interfere with the ability of RBCs to transport and unload oxygen at the capillary level (9,10). Third, transfusion of RBCs is associated with an increase in hematocrit and a concomitant increase in blood viscosity, a major determinant of capil- lary blood rheology. Consequently, any increase in blood viscosity by increases in RBC mass may alter capillary RBC flux, and this may decrease tissue DO2. Thus, a lower hematocrit, as during moderate isovolemic anemia, may actually be more beneficial to microcirculatory blood flow and tissue oxygenation (25).
Convective transport of oxygen in the plasma phase should become important in enhancing tissue DO2 with the higher oxygen solubility produced by 100% oxygen ventilation (11). In the presence of a high PaO2, the PO2 gradient between arterial blood (500–600 mm Hg) and the peripheral tissues (15–40 mm Hg) is increased, and more of the oxygen transported in the blood is available for consumption in tissues. This increase in partial pressure difference should provide an additional driving gradient for diffusion of dissolved oxygen into the tissues and provide more oxygen for local mitochondrial metabolism (26). Increases in PaO2, PvO2, plasma oxygen content, and total arterial oxygen content in the current patients who received 100% oxygen ventilation imply an increase in oxygenation at the peripheral capillary beds and, therefore, an overall higher driving pressure for diffusion of oxygen from the capillaries into the tissues. The end result was an increase in PtiO2 and, thereby, an improvement in tissue oxygenation, which has been shown to be associated with important clinical outcomes, such as a decreased incidence of surgical wound infections or the delay of blood transfusions (16,27). The latter might be of particular importance for cardiac surgical patients during rewarming in the first few postoperative hours. Hemodilution often occurs at that time because of the administration of crystalloids and colloid solutions, causing a hematocrit nadir at which transfusion decisions are usually made (5). In the hours that follow the surgical procedure, diuresis and fluid mobilization result in hemoconcentration and an increase in hematocrit. Thus, cardiac surgical patients may benefit from pure oxygen ventilation as a temporary "oxygen transport bridge" until hemoconcentration occurs.
There are several limitations to this study. First, our study group was restricted to hemodynamically stable, low-risk patients without excessive bleeding. Therefore, the results of this study may not be extended to patients who exhibit a pathologic oxygen supply dependency or have perfusion failure (i.e., circulatory shock). Second, 100% oxygen ventilation is not completely risk free. Potential harmful effects of a high FIO2 would be injury to various organs because of the direct interaction of reactive species of oxygen with proteins, lipids, and nucleic acid (28). Furthermore, the administration of 100% oxygen has been shown to induce absorptive atelectasis in the immediate postoperative period, although the extent to which this atelectasis impairs pulmonary function and gas exchange is controversial (28–31). The exposure to 100% oxygen in our study was only of short duration, and routine chest radiographs after the procedure did not show any evidence of clinically relevant pulmonary atelectasis or injury. However, it might be argued that ordinary chest radiography is a rather insensitive tool for detecting and quantifying postoperative atelectasis formation. Third, the clinical usefulness of 100% oxygen ventilation as a temporary oxygen transport bridge might be limited by the fact that a spontaneous increase of hematocrit after cardiac surgery may take 12–24 hours or even longer. This would require prolonged intubation and ventilation with 100% oxygen or the administration of a high FIO2 by the use of a tight-fitting mask to take advantage of the increased oxygen-carrying capacity provided by plasma-dissolved oxygen. This in turn may increase the risk for adverse pulmonary effects, although the toxic FIO2 threshold—length of exposure and level—is still under debate. Fourth, tissue oxygenation was measured in only a single organ (skeletal muscle) and at only one specific area of muscle; therefore, other tissues or organs might get oxygenated differently than the site we measured. Another major problem with monitoring tissue gas tensions in clinical practice is that normal and critically abnormal values have not been established. In previous clinical studies, "normal" values for PtiO2 have been reported to be 14 to 25 mm Hg in patients undergoing CABG with use of CPB (32), 28 mm Hg in ICU patients with limited infection, 48 mm Hg in critically ill patients with severe sepsis, and 22 mm Hg in patients with cardiogenic shock (30). However, there is heterogeneity in microvascular blood flow and oxygenation between organs and at the level of each organ (33). This heterogeneity increases further during shock, sepsis, or other states of critical illness. Consequently, a common dysoxic threshold for skeletal muscle or any given tissue remains undefined.
In summary, we found that transfusion of stored allogeneic RBCs was effective only in improving systemic DO2, whereas 100% oxygen ventilation improved systemic oxygenation and PtiO2 in volume-resuscitated, moderately anemic cardiac surgery patients. This improved oxygenation status seems to be most likely due to an increase in convective oxygen transport with an increased driving gradient for diffusion of plasma-dissolved oxygen into the tissues.
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Appendix 1 |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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References |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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