Download Retinal venous oxygen saturation and cardiac output during

J Appl Physiol 94: 891–896, 2003;
10.1152/japplphysiol.01197.2001.
Retinal venous oxygen saturation and cardiac output
during controlled hemorrhage and resuscitation
KURT R. DENNINGHOFF,1 MATTHEW H. SMITH,2
ART LOMPADO,2 AND LLOYD W. HILLMAN2
1
Department of Emergency Medicine, The University of Alabama at Birmingham,
Birmingham 35249; and 2Department of Physics, The University
of Alabama in Huntsville, Huntsville, Alabama 35899
Submitted 4 December 2001; accepted in final form 14 October 2002
SEVERAL KEY PARAMETERS ARE indicators of blood loss;
these include central venous oxygen saturation, cardiac output, serum lactate, and gastric pH (2, 32, 40,
53). Perhaps the most important of these in the situation of acute blood loss is cardiac output (8, 19, 32, 38).
However, cardiac output alone can be deceptive as is
demonstrated by increased cardiac output during septic and spinal shock (32). Indeed, when autoregulation
fails, cardiac output may increase as the patient’s condition worsens. However, in the situation of acute
blood loss, as normally seen in trauma, autoregulation
is maintained and cardiac output is a principal indicator of decreasing blood volume associated with blood
loss (32).
The clinician faced with a patient in shock or impending shock attempts to improve oxygen delivery,
especially to the central organs, by improving cardiac
output or blood oxygen-carrying capacity (40, 54). Several outcome studies have shown that central venous
oxygen saturation is a reliable index of oxygen delivery, facilitating these clinical decisions (1, 36, 39, 41,
50). Because obtaining mixed venous oxygen saturation (SvO2) requires invasive monitoring and has associated complications (7, 39, 40), a noninvasive, rapidly
applicable technique that provides a comparably reliable index of oxygen delivery from early blood loss to
profound shock would be a valuable adjunct to patient
management (1, 39, 41, 54).
The large vessels of the retina are a potential source
of noninvasive perfusion data and are relatively easily
observed (10, 11, 25). Previous attempts at retinal
vessel oximetry were able to detect changes in oxygen
saturation as small as ⫾4% (6, 10, 12, 26). These
devices were not used to monitor retinal saturation
changes during shock states and were not reduced to
clinical use. Studies of the retinal circulation have
shown a strong correlation between retinal perfusion
and regional cerebral blood flow (21, 30). The blood flow
to the central circulation including the retina (30) is
relatively preserved during shock states (40, 41), and
we have demonstrated that retinal venous oxygen saturation (SrvO2) is sensitive to early blood loss in anesthetized swine (14, 15).
Over the last seven years, we have developed an
experimental, noninvasive eye oximeter (EOX). The
device is used to noninvasively measure the optical
density of the large retinal vessels, arteries, and veins
(44) and uses a spectroscopic model to calculate their
oxygen saturation.
In a pilot test of the device in which swine were bled
at 0.4 ml 䡠 kg⫺1 䡠 min⫺1 to a total of 16 ml/kg, there was
a strong correlation between blood loss and SrvO2 (r ⫽
⫺0.93) (14). In another study, SrvO2 correlated with the
rate of blood loss during three intermediate rates of
early blood loss and subsequent reinfusion and was
Address for reprint requests and other correspondence: K. R.
Denninghoff, Dept. of Emergency Medicine, The Univ. of Alabama at
Birmingham, JTN 266, 619 South 20th St., Birmingham, AL 352337013 (E-mail: [email protected]).
The costs of publication of this article were defrayed in part by the
payment of page charges. The article must therefore be hereby
marked ‘‘advertisement’’ in accordance with 18 U.S.C. Section 1734
solely to indicate this fact.
retinal oximetry; noninvasive monitoring; swine; calibration
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8750-7587/03 $5.00 Copyright © 2003 the American Physiological Society
891
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Denninghoff, Kurt R., Matthew H. Smith, Art Lompado, and Lloyd W. Hillman. Retinal venous oxygen saturation and cardiac output during controlled hemorrhage
and resuscitation. J Appl Physiol 94: 891–896, 2003; 10.1152/
japplphysiol.01197.2001.—The objective was to test calibration of an eye oximeter (EOX) in a vitiligo swine eye and
correlate retinal venous oxygen saturation (SrvO2), mixed
venous oxygen saturation (SvO2), and cardiac output (CO)
during robust changes in blood volume. Ten anesthetized
adult Sinclair swine with retinal vitiligo were placed on
stepwise decreasing amounts of oxygen. At each oxygen level,
femoral artery oxygen saturation (SaO2) and retinal artery
oxygen saturation (SraO2) were obtained. After equilibration
on 100% O2, subjects were bled at 1.4 ml 䡠 kg⫺1 䡠 min⫺1 for 20
min. Subsequently, anticoagulated shed blood was reinfused
at the same rate. During graded hypoxia, exsanguination,
and reinfusion, SraO2 and SrvO2 were measured by using the
EOX, and CO and SvO2 were measured by using a pulmonary
artery catheter. During graded hypoxia, SraO2 correlated
with SaO2 (r ⫽ 0.92). SrvO2 correlated with SvO2 (r ⫽ 0.89)
during exsanguination and reinfusion. SvO2 and SrvO2 correlated with CO during blood removal and resuscitation (r ⫽
0.92). Use of vitiligo retinas improved the calibration of EOX
measurements. In this robust hemorrhage model, SrvO2 correlates with CO and SvO2 across the range of exsanguination
and resuscitation.
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RETINAL VENOUS OXYGEN SATURATION AND CARDIAC OUTPUT
MATERIALS AND METHODS
The EOX scans low-power lasers across the retinal vasculature. The light scattered and reflected back out of the eye is
collected and analyzed, and the optical density of the blood
within the vessels is determined from the collected signals.
These optical density measurements are made at multiple
wavelengths, and a spectroscopic model is used to calculate
the oxygen saturation of the blood within the vessels (6, 10,
26, 44, 52).
Through an eyepiece, the EOX provides an image of the
subject’s ocular fundus to the operator. The operator then
targets a retinal artery or vein and initiates the measurement procedure. A full data set is acquired within 0.1 s.
Typically, 8–16 data sets are averaged to comprise a single
saturation determination (44). A detailed description of the
device used for these experiments is provided elsewhere (45).
J Appl Physiol • VOL
This study adhered to National Institutes of Health guidelines for the use of laboratory animals and was approved by
the Institutional Animal Care and Use Committee.
Ten mature Sinclair swine (2–6 yr old) with retinal vitiligo, weighing 55–95 kg, were fasted overnight but allowed
water ad libitum. On the morning of the experiment, the
animals were given intramuscular preanesthetic ketamine
50 mg/kg and xylazine 2 mg/kg. The swine were placed in the
supine position, intubated endotracheally, and placed on a
ventilator. The swine were placed on 2–4% isoflurane during
the surgical procedures, and the depth of anesthesia was
monitored by using web space stimulation. An esophageal
temperature probe was used to monitor core body temperature, and continuous electrocardiographic monitoring was
utilized. The eyes were treated with two drops of 1% cyclopentolate hydrochloride. At the beginning of the surgical
preparation, the animal was given a bolus of 1,000 ml of
normal saline. A solution of 5% dextrose in half normal saline
with 10 milliequivalents of KCl per liter was infused at
80–110 ml/h. A celiotomy was performed by using an infraumbilical approach, the bladder was exposed, and a Foley
catheter was placed in the bladder via cystotomy. The abdominal wall was closed around the bladder catheter. A
femoral cut down was performed, a 7.0-Fr catheter was
placed in the femoral artery, and an 8.0-Fr introducer was
placed in the femoral vein. The femoral artery catheter was
connected to a Hewlett-Packard 78203 physiological pressure
monitoring system, and a 7.5-Fr Abbott continuous mixed
SvO2 monitoring catheter was placed in the central circulation via the introducer in the femoral vein. The distal port of
the central venous catheter was connected to a HewlettPackard 78203 physiological pressure monitoring system.
Placement of the central venous catheter was verified by
waveform. The catheter oximeter calibration was verified by
using mixed venous blood obtained from the distal port. All
blood gas analysis was performed by use of an IL 482 COoximeter system. The eyelids were sutured open, and sutures
were placed in the conjunctiva to hold the eye in place. A
catheter, attached to a 60-ml syringe filled with buffered
0.9% saline (pH ⫽ 7.0), was sutured to the periocular skin
and used to bathe the eye every 30–45 s to maintain corneal
hydration throughout the experimental protocol. When the
surgical preparation was completed, the isoflurane was decreased to 1.0–1.5% as needed to maintain anesthesia. The
respiratory rate was adjusted such that arterial CO2 tension
was between 36 and 44 Torr and the blood pH was between
7.35 and 7.45. The end-tidal CO2 was measured continuously
by using a Datex 254 airway gas monitor. The central venous
catheter placed in the pulmonary artery was used to record
continuous mixed SvO2, and the thermodilution technique
was used to measure cardiac output at 2-min intervals during exsanguination and reinfusion. The EOX was aimed at a
large artery near the optic disk, and the swine were placed on
stepwise decreasing amounts of oxygen. At each level of
oxygen, femoral artery oxygen saturation and retinal artery
oxygen saturation were obtained. After the arterial study
was complete, the animals were placed on 100% oxygen and
allowed to equilibrate for 20 min. The EOX was then aimed
at a large vein near the optic disk, and the SrvO2 was measured every minute for 5 min to obtain baseline data. After
the baseline data were acquired, each animal was exsanguinated at 1.4 ml 䡠 kg⫺1 䡠 min⫺1 until a total of 28 ml/kg had
been removed. Shed blood was anticoagulated by using anticoagulant citrate phosphate dextrose (ACD) solution. When
the exsanguination was complete, the animal was resuscitated by reinfusing the anticoagulated shed blood at 1.4
ml 䡠 kg⫺1 䡠 min⫺1.
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more sensitive to blood loss than vital sign measurements in the same animals (15).
Published studies using an EOX to measure SrvO2
during exsanguination used a mild amount of blood
removal (20% of total blood volume) and did not demonstrate calibration of measurements (14, 15, 44, 45).
We believe that calibration of data is desirable because
it may allow for a single measurement to be used when
making decisions about resuscitation or triage. Trending data can be used to monitor patients, but this
requires repeated measures over time in the initial
period of resuscitation when decisions must be made
rapidly if a patient is to survive (2, 54). After an
extensive review of the literature, we are unable to find
any reports comparing SrvO2 to cardiac output, SvO2, or
blood volume across the range of profound blood removal and subsequent reinfusion. It is unknown what
changes will occur in SrvO2 measurements during more
life threatening blood removal and during resuscitation from blood removal.
Studies using a model eye and the human eye have
demonstrated that the highly absorbing fundus and
pigment variation in the retina make calibration of
oximetry measurements difficult (3, 17, 46). We have
performed experiments using a model eye with a
highly reflective background that allowed for calibration in this model (13). We have also performed experiments in a model eye and in the human eye that
utilized a detection pathway filter to correct for fundus
pigmentation (17, 46). However, in this study, we used
a device without a detection pathway filter to study
swine from Sinclair Research that spontaneously develop melanoma and then reject the tumor during
adolescence. These swine sometimes develop vitiligo of
the retina, making them an ideal test subject because
increasing fundus reflectivity increases the effective
light pathlength and simplifies our data reduction (33).
We hypothesized that utilizing an animal model that
had retinal vitiligo would increase retinal reflectivity
similar to our model eye (i.e., have a highly reflective
background) and consequently improve the calibration
of our data. We also hypothesized that SrvO2 changes
would correlate with cardiac output and SvO2 during
profound exsanguination (40% of total blood volume)
and subsequent resuscitation.
RETINAL VENOUS OXYGEN SATURATION AND CARDIAC OUTPUT
893
After the exsanguination and reinfusion, the retina was
examined for laser damage by using direct ophthalmoscopy.
At the conclusion of the experimental protocol, the anesthetized swine were euthanized by using supersaturated potassium chloride.
RESULTS
Fig. 1. Correlation plot of femoral arterial saturation and retinal
arterial saturation demonstrates the calibration possible in animals
with high fundus reflectivity. Each individual arterial calibration
line was used to calculate retinal venous saturation for that subject.
J Appl Physiol • VOL
Fig. 2. Changes in retinal venous oxygen saturation (SrvO2) and
normalized cardiac output during blood removal and resuscitation
with anticoagulated blood demonstrate the tight correlation between
these 2 variables in this model. Average values (Ave) ⫾ SD are
shown.
DISCUSSION
We performed model eye experiments by using a
highly reflective background that demonstrated improved calibration in our instrument. On the basis of
these results, we expected improved calibration in this
in vivo retinal vitiligo model. The need for calibration
to a range of 3 to 4% is evident from our exsanguination and reinfusion experiments in which a change of
10% oxygen saturation correlated with a 5% change in
blood volume (15). The hypothesis that retinal vitiligo
would improve calibration of our measurements is supported by our data. In previous studies using Yorkshire
swine with normal retinal pigmentation, we had significant variations in slopes and intercepts of our calibration plots (14), and the overall correlation coefficient when all data from all swine were plotted
Fig. 3. For comparison purposes, this figure shows the same plot as
seen in Fig. 2 except that mixed venous oxygen saturation (SvO2) is
shown rather than SrvO2. Average values ⫾ SD are shown.
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Retinal artery oxygen saturation (SraO2) correlated
with femoral artery oxygen saturation during graded
hypoxia (r ⫽ 0.92). SrvO2 correlated with SvO2 (r ⫽
0.89), blood volume (r ⫽ 0.9), and cardiac output (r ⫽
0.92) during the baseline blood loss and resuscitation
periods of the experiment. Figure 1 shows how SraO2
correlated with femoral artery oxygen saturation during graded hypoxia. The linear best fit for the conglomerate data from all the swine tested for arterial calibration is shown as the heavy line on the figure (r ⫽
0.92, slope ⫽ 0.93, intercept ⫽ 0.03). The data set from
each individual swine is shown by using a different
symbol, and the linear best fit for each animal is shown
as a fine line. The average residual retinal artery
saturation for this calibration plot was 1.5 ⫾ 8.9%.
Figure 2 shows the tight correlation of SrvO2 and normalized cardiac output (the cardiac output at the beginning of the baseline period divided into each subsequent measurement in that swine) measured during
blood removal and resuscitation. For comparison purposes, Fig. 3 shows SvO2 and normalized cardiac output. Figure 4 shows the correlation plot of SrvO2 with
normalized cardiac output during exsanguination and
reinfusion; the data shown are extracted from Fig. 2
and are the average cardiac output and SrvO2 measured concurrently with the cardiac output during exsanguination and resuscitation. Figure 5 shows the
correlation between average SrvO2 and SvO2 during
exsanguination (r ⫽ 0.97) and resuscitation (r ⫽ 0.82).
All error bars shown and reported ranges are the
standard deviation from the mean.
894
RETINAL VENOUS OXYGEN SATURATION AND CARDIAC OUTPUT
together was significantly inferior to our results here
(with the Yorkshire swine r ⫽ 0.646, slope ⫽ 0.57,
intercept ⫽ 0.235). However, the average residuals
from our calibration experiment had an error of ⫾8.9%
saturation; thus we were still unable to achieve our
goal of 3 or 4% error in calibration. As noted in the
introduction, our laboratory utilized detection pathway
filters and scanning systems (46) to address this concern (17).
There have been several devices advocated as noninvasive systems for the direction of trauma resuscitation. Previously, noninvasive blood oxygenation measurements have been attempted (29, 35). Various
limitations exist with these approaches. Near infrared
spectroscopy is potentially erroneous because differences in skull and scalp thickness alter pathlength
(29). Pulse oximetry is sometimes inaccurate as a result of optical shunting (presence of light that alters
the true reading) (28, 48) and is sometimes associated
with thermal injury (34, 43, 47). The device measures
peripheral arterial oxygenation only (42) and is of
limited efficacy in patients with anemia or hypoxia (27,
42). More recently, gastric tonometry, retinal oximetry,
and sublingual capnometry have been tested in animal
and human models (17, 35a, 45, 53).
In this swine model, we have demonstrated a strong
correlation between cardiac output and SrvO2 across
the spectrum of survivable blood loss and resuscitation
(40% of total blood volume). This is important because
vital signs may be maintained until large amounts of
blood have been lost. To be used for clinical care, a
monitoring tool must be superior to present technology
and must change predictably across the breadth of the
clinical spectrum to allow the clinician to make accurate decisions about care. Also, calibration is important
because a single measurement, in conjunction with
vital signs and clinical assessment, may be all that is
available for critical decision making during time-sensitive trauma resuscitation (2).
J Appl Physiol • VOL
Fig. 5. Correlation between SrvO2 and SvO2 throughout the study
period.
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Fig. 4. Correlation plot of SrvO2 and normalized cardiac output
during the baseline, exsanguination, and resuscitation periods of the
experiments.
The change in SrvO2 and central venous oxygen saturation seen during resuscitation demonstrates the
monitoring capacity of these tools (see Figs. 2 and 3).
Both indicated a rapid response to initial reinfusion
and a marked flattening of this response after ⬃5–6%
of total blood volume had been infused. The nonlinear
response to the reinfusion of autologous blood seen in
this model has been described in a study using autologous blood transfusions in swine (20) and is similar to
changes that we have seen during resuscitation from
mild blood loss (14, 15). During resuscitation, SrvO2
increased more dramatically than SvO2 and behaved
more like cardiac output than SvO2. In Fig. 5, where
SrvO2 and SvO2 are correlated, the bimodal grouping of
data is evident as SrvO2 and SvO2 remain correlated but
the slope changes during resuscitation. This is probably a result of total body autoregulation shunting flow
to the central organs and may represent an advantage
in monitoring SrvO2 because the resuscitation of
trauma victims before definitive repair using traditional end points can lead to overresuscitation and
increased mortality in swine and humans (4, 9).
In conclusion, we have demonstrated improved calibration of a spectroscopic EOX achieved by use of an in
vivo model of increased retinal reflectivity by using
swine with retinal vitiligo. We have also demonstrated
the use of an experimental EOX during profound blood
loss and resuscitation in a specialized anesthetized
swine model. Changes in SrvO2 correlated with blood
volume, SvO2, and cardiac output during profound
blood removal and subsequent resuscitation. The response to changes in blood volume was nearly linear
during exsanguination. There was a nonlinear response to the reinfusion of autologous blood seen in
this model. This nonlinear response has been described
elsewhere and is probably a physiological response to
autologous blood transfusions and physiological hysteresis in swine (20). Use of a calibrated EOX to noninvasively monitor trauma patients for unrecognized
RETINAL VENOUS OXYGEN SATURATION AND CARDIAC OUTPUT
blood loss and during resuscitation from exsanguinating hemorrhage warrants further study.
We thank The University of Alabama at Birmingham Injury
Control Research Center for support. We also thank Sharon Tyra,
Senior Research Associate, UAB Department of Surgery, for technical support.
This work was supported by Department of the Army Grant
DAMD 17-98-1-8007 and Office of Naval Research Grant ONR
N00014-99-1-0226 and by the Centers for Disease Control Grant
R49/CCR403641.
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