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. Aminofff
aDepartments of Anesthesia and Physiology, and Investigator, Cardiovascular Research Institute, University of California,
San Francisco, 521 Parnassus Avenue, San Francisco, CA 94143-0648, USA
bDepartment of Laboratory Medicine, University of California, San Francisco, CA 94143-0100, USA
cDepartments of Anesthesia and Surgery, University of California, San Francisco, CA 94143-0648, USA
dDepartment of Anesthesia, University of California, San Francisco, CA 94143-0648, USA
eDepartment of Epidemiology and Biostatistics, University of California, San Francisco, CA 94143-0840, USA
fDepartment of Neurology, University of California, San Francisco, CA 94143-0114, USA
Accepted 11 December 2004
Available online 25 January 2005
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
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
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
Clinical Neurophysiology 116 (2005) 1028–1032
1388-2457/$30.00 q 2005 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
* Corresponding author. Tel.: C415 476 2132; fax: C415 502 2132.
E-mail address: firstname.lastname@example.org (R.B. Weiskopf).
decreased oxygen deliveries of 10.7 mL O2/kg/min (Weis-
kopf 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 base-
deficit) 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 non-
specific 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).
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
large quantities of blood to achieve the desired hemoglobin
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 record-
ings (see below) were performed with the subject in a semi-
sitting 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 platelet-
rich 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 tight-
fitting 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 head-
phones 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:
R.B. Weiskopf et al. / Clinical Neurophysiology 116 (2005) 1028–10321029
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 hemo-
globin 5 g/dL breathing air; and for baseline and hemo-
globin 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].
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
Breathing oxygen at Hb 12.4 g/dL increased Pa O2from
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 PaO2at the two different hemoglobin concen-
trations 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).
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 dis-
orders, 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
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
R.B. Weiskopf et al. / Clinical Neurophysiology 116 (2005) 1028–10321030
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
PO2does 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 concen-
tration, 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 SpO2of 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
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
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 Anesthesiolo-
gists 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
The results from this study extend our earlier finding of
subtly degraded cognitive function at hemoglobin concen-
trations 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 proces-
sing associated with this level of severe anemia. Thus, when
compatible erythrocytes are not immediately available for
R.B. Weiskopf et al. / Clinical Neurophysiology 116 (2005) 1028–10321031
transfusion (for example, during acute autoimmune hemo- Download full-text
lytic 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
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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