Clinical Neurophysiology 116 (2005) 1028–1032 www.elsevier.com/locate/clinph
Acute isovolemic anemia impairs central processing as determined by P300 latency Richard B. Weiskopfa,*, Pearl Toyb, Harriet W. Hopfc, John Feinerd, Heather E. Finlayb, Michelle Takahashib, Alan Bostrome, Christopher Songsterf, Michael J. Aminoff f a
Departments of Anesthesia and Physiology, and Investigator, Cardiovascular Research Institute, University of California, San Francisco, 521 Parnassus Avenue, San Francisco, CA 94143-0648, USA b Department of Laboratory Medicine, University of California, San Francisco, CA 94143-0100, USA c Departments of Anesthesia and Surgery, University of California, San Francisco, CA 94143-0648, USA d Department of Anesthesia, University of California, San Francisco, CA 94143-0648, USA e Department of Epidemiology and Biostatistics, University of California, San Francisco, CA 94143-0840, USA f Department of Neurology, University of California, San Francisco, CA 94143-0114, USA Accepted 11 December 2004 Available online 25 January 2005
Abstract Objective: Acute anemia slows the responses to clinical tests of cognitive function. We tested the hypothesis that these slowed responses during acute severe isovolemic anemia in healthy unmedicated humans result from impaired central processing. Methods: A blinded operator measured the latency of the P300 peak in nine healthy volunteers at each volunteer’s baseline hemoglobin concentration (Hb), and again after isovolemic hemodilution to Hb 5 g/dL. At both Hb concentrations, the P300 latency was measured twice: with the blinded subject breathing air or 100% oxygen, administered in random order. Results: Anemia increased P300 latency significantly from baseline values (P!0.05). Breathing oxygen during induced anemia resulted in a P300 latency not different from that at baseline when breathing air (PZ0.5) or oxygen (PZ0.8). Conclusions: Impaired central processing is, at least in part, responsible for the slowed responses and deficits of cognitive function that occur during acute isovolemic anemia at Hb 5–6 g/dL. Significance: The P300 latency appears to be a potential measure of inadequate central oxygenation. In healthy young adults with acute anemia, erythrocytes should be transfused to produce HbO5–6 g/dL. As a temporizing measure, administration of oxygen can reverse the cognitive deficits and impaired central processing associated with acute anemia. q 2005 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Acute anemia; Hemodilution; P300; Transfusion; Critical hemoglobin concentration
1. Introduction Low hemoglobin concentration with attendant decreased oxygen carrying capacity and blood oxygen content is the most common reason given for erythrocyte transfusion. However, there are times when erythrocytes are not immediately available for transfusion. For example, in cases of autoimmune hemolytic anemia, all erythrocytes
* Corresponding author. Tel.: C415 476 2132; fax: C415 502 2132. E-mail address:
[email protected] (R.B. Weiskopf).
will be ‘incompatible’ until time consuming testing for alloantibodies is completed. In humans, with decline in hemoglobin concentration, systemic oxygen delivery is maintained unchanged initially by an increased heart rate and ventricular stroke volume (Weiskopf et al., 1998). Eventually, as hemoglobin concentration continues to decrease, compensation becomes incomplete, and oxygen delivery falls. The hemoglobin concentration at which this occurs (Hbi) is age and sex dependent (Weiskopf et al., 1998). For example, Hbi is 5.4 g/L for a 25-year-old woman and 7.5 g/L for a man of similar age. However, in healthy humans, even with
1388-2457/$30.00 q 2005 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2004.12.009
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decreased oxygen deliveries of 10.7 mL O2/kg/min (Weiskopf et al., 1998) and 7.3 mL O2/kg/min (Lieberman et al., 2000), associated with a hemoglobin concentration of 5 g/ dL, there is an absence of systemic evidence of inadequate oxygenation (Lieberman et al., 2000; Weiskopf et al., 1998) or decreased peripheral subcutaneous PO2 (Hopf et al., 2000). Similarly, acute isovolemic anemia to a Hb of 8 g/dL in conscious and anesthetized humans does not produce systemic evidence of inadequate oxygenation (Ickx et al., 2000) Other clinical studies using various measures of function have similarly failed to identify the critical hemoglobin concentration or critical oxygen delivery (the value below which hemoglobin concentration or oxygen delivery is insufficient to satisfy oxygen requirements) (Carson et al., 1998; He´bert et al., 1999), and there is no relationship between maximal duration for which patients can exercise and their Hb (range 8–12 g/dL) 5 days after coronary artery bypass surgery (Johnson et al., 1992). In the absence of a clinically useful measure of inadequate systemic oxygen delivery of oxygen, clinicians use hemoglobin concentration as a guide for erythrocyte transfusion, although it is only one component of oxygen content and delivery. Systemic measures of inadequate oxygenation (oxygen consumption, blood lactate concentration, and blood basedeficit) may not be sufficiently sensitive to detect inadequate oxygenation of individual organs. We detected subtle deficits in cognitive function in healthy unmedicated humans at hemoglobin concentrations of 5 and 6 g/dL (Weiskopf et al., 2000) that were reversed with erythrocyte transfusion (Weiskopf et al., 2000) or oxygen administration (Weiskopf et al., 2002). Having established the human threshold (critical hemoglobin concentration) for central nervous system dysfunction, we have now tested the hypothesis that the slowed response during acute anemia relates to impaired central processing as opposed to a nonspecific effect on attention. Specifically, we recorded P300 potentials (auditory odd-ball task) and measured the response latencies before and after induction of acute isovolemic anemia. Measurement of P300 peak latency offered the possibility of both testing our hypothesis, and providing a clinically relevant measure that can be used to assess the need for augmented oxygen delivery (e.g. erythrocyte transfusion).
2. Methods After approval of our institutional review board and with informed consent of those participating, we studied nine paid adult volunteers who were without cardiovascular, pulmonary, neurologic, renal, or hepatic disease, did not smoke, were not taking any medications, and weighed less than 80 kg. The weight requirement was imposed to avoid excessively long experimental days, with potentially increased effects of time, owing to the need to remove
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large quantities of blood to achieve the desired hemoglobin concentration. To produce acute severe isovolemic anemia, a radial arterial and two peripheral venous cannulae were inserted in each subject after local anesthesia. Subjects then rested for 30 min before measurement of variables. The P300 recordings (see below) were performed with the subject in a semisitting position before removal of any blood, and twice after producing isovolemic anemia to a blood hemoglobin concentration of 5 g/dL by removal of aliquots of 450 mL blood into CPDA-1 collections bags (Baxter Healthcare Corp., Deerfield, IL). Removal of each 450 mL blood required approximately 10–15 min. Simultaneous with blood withdrawal, 5% human serum albumin (Baxter Healthcare, Glendale, CA) and the subject’s own plateletrich plasma (after separation from the erythrocytes of the removed blood) were infused intravenously in quantities 13%G3% (meanGSD) greater than that of the removed blood to maintain isovolemia (Weiskopf, 2001; Weiskopf et al., 1998) compensating for the extravascular distribution of albumin (Payen et al., 1997). Two tests were conducted at the baseline and nadir hemoglobin concentrations: with the volunteer breathing air or oxygen supplied in random order at 15 L/min via a tightfitting non-rebreathing face mask. A 5-min equilibration period was allowed while the subject breathed the test gas before the P300 was recorded. The P300 tests were conducted at the same time of day for all volunteers: Hb 12 at 9–10 am, and Hb 5 at 12–2 pm. Arterial blood gases and pH were measured during each test period. Following conclusion of the tests, all withdrawn erythrocytes were returned to each volunteer during the succeeding 12 h. P300 Measurements: Using an 8- or 16-channel evoked potential system (Viking IV and Bravo 16, Nicolet Biomedical, Madison, Wisconsin), evoked potentials were recorded, by an operator who was blinded to the randomized order of the gases, from gold-plated surface electrodes placed at FZ, CZ, and PZ, and referenced to linked mastoids. A left infraorbital electrode was placed to monitor eye movements and was also referenced to linked mastoids. Each volunteer was stimulated binaurally through headphones with a random sequence of 420 tones (75 dBHL, 40 ms duration, with a 5 ms rise and fall ramp) at a rate of 1 every 1.5 s. Two tones of different pitch were used. The frequent tones (1000 Hz frequency) accounted for 86% of all tones, whereas the rare tones (2000 Hz) accounted for 14% of all tones. Subjects were instructed to count the number of rare tones. The filters were set at 0.2–30 Hz. A minimum of two trials was performed with each gas at each hemoglobin concentration to ensure reproducibility of the waveforms (however, a third trial was never required). Measurements were made on the recording obtained at the CZ electrode. In three volunteers, the P300 response was divided into two subcomponents, P3a and P3b, rather than consisting of a fused potential. For these instances, the response was treated as a single peak for all measurements:
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a single latency measurement was taken of the entire complex by extrapolation of the up and down slopes, as recommended by others (Goodin, 1999). Data Analysis and Statistics: Prior to the initiation of this study there were no relevant data that could have been used for a power analysis to estimate the appropriate number of subjects to study. We had planned to conduct a power analysis after studying the first five subjects. However, data analysis at that time indicated that statistical significance had been achieved with respect to the effect of anemia on P300 peak latency. We elected to study an additional five volunteers. Following the conclusion of the study, data from one volunteer was found to be incomplete. Consequently, we report the results from the nine volunteers for whom we have complete data. Distributions of P300 latencies were examined using normal probability plots and Shapiro-Wilk tests. Paired comparisons were performed between baseline and hemoglobin 5 g/dL breathing air; and for baseline and hemoglobin 5 g/dL between breathing air and oxygen by Wilcoxon’s signed-rank test. Statistical significance was accepted at P%0.05 for all tests. Data are presented as meanGS.D. or median [quartiles].
3. Results The volunteers were aged 23G4 years (mean G SD), were 1.64G0.08 m tall, weighed 63G10 kg, and had an estimated body surface area of 1.69G0.17 m2. There were seven women and two men. Hemodilution reduced the hemoglobin concentration from 12.4G1.3 to 5.1G 0.2 g/dL. Breathing oxygen at Hb 12.4 g/dL increased Pa O2 from 101G8 to 445G21 mmHg (P!0.001), and at Hb 5.1 g/dL from 103G11 mmHg to 448G67 mmHg (P!0.001). The values for PaO2 at the two different hemoglobin concentrations when breathing equivalent oxygen concentrations did not differ (air, PO0.4; oxygen, PO0.9). Acute isovolemic anemia did not alter PaCO2: breathing air, it was 39.8G2.5 mmHg at baseline and 39.7G3.0 mmHg at Hb 5.1 g/dL (PO0.6). Isovolemic reduction of Hb from 12.4G1.3 to 5.1G 0.2 g/dL increased P300 latency from 296 [288, 304] ms to 316 [306, 344] ms (P!0.05; Fig. 1). When the volunteers breathed oxygen at the nadir hemoglobin concentration P300 latency was 304 [288, 339] ms, a value not different from that at the baseline hemoglobin concentration of 12.4 g/dL when breathing air (PO0.8) or oxygen (PO0.4; Fig. 1). The P300 latency at the baseline hemoglobin concentration, when the volunteers breathed oxygen (295 [288, 301]) did not differ from the P300 latency at that hemoglobin concentration when the volunteers breathed air (PO0.8; Fig. 1).
Fig. 1. Auditory P300 latencies in nine volunteers at hemoglobin concentration of 12.4 g/dL breathing air (Hb12-Air) or oxygen (Hb12-O2), and at hemoglobin concentration of 5.1 g/dL breathing air (Hb5-Air) or oxygen (Hb5-O2). Data are median and quartiles. *ZP!0.05 versus Hb12-Air.
4. Discussion We found that a hemoglobin concentration of 5 g/dL in healthy unmedicated humans increases the P300 latency. Increased P300 latency is associated with impaired cognitive function. For example it is prolonged in demented patients with Alzheimer’s disease, toxic/metabolic disorders, vascular diseases, brain tumors, and multiple sclerosis, but not in non-demented patients with those disorders (Goodin, 1999; Goodin and Aminoff, 1986; Goodin and Aminoff, 1987). The P300 response reflects ‘how well the CNS can process and incorporate incoming information.’ (Polich, 2002; Polich and Herbst, 2000). Thus, our data can be taken as an indication that acute severe isovolemic anemia to a hemoglobin concentration of 5 g/dL impairs central processing. If cognitive changes were simply a reflection of an attention deficit, the P300 amplitude might have been attenuated or absent, but the latency would not have been affected. In an earlier study, we sought to determine the site of the previously observed deficits. Acute isovolemic anemia to similar hemoglobin concentrations in similar volunteers did not increase latencies of somatosensory evoked potentials (Weiskopf et al., 2003). Thus, the noted cognitive deficits do not appear to result from impaired afferent neural traffic. The experiment reported here points to central processing, at least in part, as the site of the impairment. In this study, we did not assess cognitive function, because limitations of time of keeping the volunteers at the nadir hemoglobin concentration did not allow for assessment of both P300 and neurocognitive function. However, we have repeatedly demonstrated subtle cognitive function deficits in similar volunteers with similar hemoglobin concentrations (Weiskopf et al., 2000; Weiskopf et al., 2002) Although the critical hemoglobin concentration and critical oxygen delivery have been defined in several species, few prospectively acquired data have been obtained in healthy humans. Systemic evidence of inadequate
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oxygenation was not found at a hemoglobin concentration of 5 g/dL with an oxygen delivery of 10.7 mL O2/kg/min (Weiskopf et al., 1998) or at the same hemoglobin concentration, but a lesser oxygen delivery of 7.3 mL O2/ kg/min (Lieberman et al., 2000). Similarly, subcutaneous PO2 does not decrease at Hb 5 g/dL owing to increased blood flow (Hopf et al., 2000). However, assessment of function of the central nervous system of humans appears to be a more sensitive measure of inadequate oxygenation than are measurements of blood base-deficit or lactate concentration, whole-body oxygen consumption, or subcutaneous PO2. In a study of cognitive function in humans subject to acute anemia, hemoglobin concentrations of 6 g/dL and 5 g/dL increased the time to perform addition and the digit-symbol substitution test, and immediate and delayed memory were degraded (Weiskopf et al., 2000). These deficits were reversed by transfusing erythrocytes to increase the hemoglobin concentration to 7 g/dL (Weiskopf et al., 2000), or by breathing oxygen (Weiskopf et al., 2002), which was physiologically equivalent to increasing the hemoglobin concentration by almost 3 g/dL (Weiskopf et al., 2002). Similarly, in the experiment reported here, we found that when the volunteers breathed oxygen during acute isovolemic anemia, the P300 latency was not different from baseline, confirming that breathing oxygen can serve as a temporizing measure until compatible erythrocytes are available for transfusion. There have been investigations regarding the effects of chronic anemia, and its reversal on the latency of the P300 peak, but the results have been inconsistent (Brown et al., 1991; Grimm et al., 1990; Kramer et al., 1996; Marsh et al., 1991; Triantafyllou et al., 1992), and are therefore difficult to interpret and to relate to our findings. Acute hypoxic hypoxia also prolongs P300 latency. Auditory P300 latency is prolonged by approximately 20 ms by reduction of arterial oxyhemoglobin saturation to 80–85% (Fowler and Prlic, 1995; Wesensten et al., 1993), and by approximately 30 ms at SpO2 of 65% (Fowler and Lindeis, 1992) or 75% (Fowler and Prlic, 1995). Although we reduced arterial oxygen content by approximately 60%, a value considerably greater than the reductions in the studies of acute hypoxic hypoxia, we found a prolongation of the auditory P300 (20 ms) that was similar to that noted with a reduction of arterial oxygen content of only 10–15% by hypoxic hypoxia, and less than that caused by a 30% reduction of arterial oxygen content by hypoxic hypoxia. Thus, hypoxic hypoxia appears to have a more profound effect on P300 than does an equivalent decrease in arterial oxygen content caused by acute anemia. Both hypoxic hypoxia and acute anemia increase cerebral blood flow, but the relative degrees to which that occurs in the structures responsible for generating the P300 is not known. It is possible that differences in cerebral blood flow might account for the differences in prolongation of the P300 during acute anemia versus acute hypoxic hypoxia. In addition, acute isovolemic anemia did not alter PaCO2. Our
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volunteers remained normocarbic, whereas acute hypoxic hypoxia induces hyperventilation and hypocapnia, with the latter reducing cerebral blood flow in comparison with normocarbic hypoxia (Cohen et al., 1967). Since each person in our study served as their own control, the order of breathing air or oxygen was randomized, and breathing oxygen reversed the effect of anemia, demographic factors cannot explain our findings. The changes we found in P300 latency are unlikely to have been due to a factor other than oxygen delivery, such as duration of each day’s experimentation, because the P300 latency was not prolonged when the subjects breathed oxygen when they were anemic, and repetitive measurements of P300 latency are stable within a day (Piperova-Dulbokova and Dincheva, 1980) and for at least two months in healthy people (Goodin et al., 1978) with no effect of diurnal variation (Piperova-Dulbokova and Dincheva, 1980). Similarly, it is unlikely that fatigue influenced our results. Breathing oxygen during severe isovolemic anemia reverses cognitive function deficits (Weiskopf et al., 2002), but not the subjective sense of fatigue (Toy et al., 2000). Our findings have clinical implications. Erythrocytes are transfused to prevent or treat inadequate oxygen delivery. The many published practice guidelines for erythrocyte transfusion, including those of the British Committee for Standards in Haematology (British Committee for Standards in Haematology, 2001) and the American Society of Anesthesiologists (American Society of Anesthesiologists Task Force on Blood Component Therapy, 1996) have been unable to provide a precise indication for erythrocyte transfusion for many reasons. These include the lack of knowledge of the critical hemoglobin concentration or critical oxygen delivery in healthy humans, the limited ability to determine the impact of patients’ disease processes on oxygen delivery and utilization, and the absence of an accurate, clinically available, rapid method for assessing tissue oxygenation of critical tissues or organs (Weiskopf, 1998). The results from this study extend our earlier finding of subtly degraded cognitive function at hemoglobin concentrations of 5–6 g/dL (Weiskopf et al., 2000; Weiskopf et al., 2002). Although these can be immediately reversed with transfusion of erythrocytes (Weiskopf et al., 2000) or breathing oxygen (Weiskopf et al., 2002) when the person has had the nadir hemoglobin concentration for a relatively brief period of time, it is not known whether these findings pertain for longer periods of equivalently severe isovolemic anemia. Our results, in healthy young adults, provide objective evidence that at Hb 5–6 g/dL oxygen delivery to the brain is inadequate, suggesting that at this level erythrocytes should be transfused. Furthermore, as a temporizing measure, administration of oxygen reverses the cognitive function deficits and impaired central processing associated with this level of severe anemia. Thus, when compatible erythrocytes are not immediately available for
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transfusion (for example, during acute autoimmune hemolytic anemia until time-consuming testing for alloantibodies is completed) breathing oxygen can be efficacious. These results and those of our previous studies (Weiskopf et al., 2000; Weiskopf et al., 2002) have additional importance. They provide a method by which a therapy, biologic, or pharmaceutical proposed to increase oxygen delivery (e.g. increase of blood flow, erythrocyte transfusion, or administration of an oxygen therapeutic) can be tested for efficacy. Indeed, as one of us has previously noted, until our earlier study (Weiskopf et al., 2000), the limitation of a practical human model has prevented the demonstration of efficacy of erythrocyte transfusion (Weiskopf, 1998).
Acknowledgements Supported, in part, by a Public Health Service Award from the National Heart, Lung and Blood Institute, National Institutes of Health, Grant no. 1 P50 HL54476. These studies were carried out, in part, in the General Clinical Research Center, University of California Medical Center, San Francisco, with funds provided by the National Center for Research Resources, 5 MO1 RR-00079.
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