Effects of moderate hypothermia on 0, consumption at various 0, deliveries in a sheep model J. M. SINARD, Department SINARD,J.M.,D. BARTLETT.Effects
D. VYAS, K. HULTQUIST,
VYAS, K. HULTQUIST,J. HARB,AND R.H.
moderate hypothermia on 0, consumption at various 0, deliveries in a sheep model. J. Appl. Physiol. 72(6): 2428-2434,1992.-The effects of modesthypothermia on oxyof
genconsumption (VO& were studied at various levelsof oxygen delivery (no,) in six sheep.Each animal wasplaced on cardiopulmonary bypassby extrathoracic cannulations. 00, wasvaried by changing blood flow through an extracorporeal circuit. Vo2 was measuredspirometrically across a membrane lung. VO, was initially measuredat various levels of 00, at normothermic temperatures (39°C). The animalswere then cooledto 33°C. 00, was varied, and the correspondingVO,‘s were determined. The data at both temperatures demonstratedthe biphasic relationship of VO, to various levels of DO,. A critical level of Do, u&crit) was defined to reflect the transition area between the dependent and independent portions of the consumption-delivery curve. The averagebaselineVO,‘s on the delivery independent portion of the curve were calculated to be 5.33 and 3.17 ml 0,. kg-‘. min-’ at 39 and 33”C, respectively (P < 0.001). The correspondingh~~~rit)swere 6.17 and 4.57 ml o2. kg-’ . min-’ (P < 0.05). The oxygen extraction ratios at Do 2critfor each of these temperatures did not differ significantly. We conclude that hypothermia, by lowering baseline VO,, reduces 00, crit. Hypothermia may therefore reduce or eliminate the anaerobic metabolism and subsequentacidosis that would otherwise occur during normothermia at low levels of Do,. metabolism;critical value of oxygen delivery; oxygen extraction ratio
SEVERAL STUDIES have investigated the dependence of whole-body oxygen consumption (VO,) over a wide range of oxygen deliveries (DO,) (1,2,4-7,12,13,16,21-23). A
biphasic relationship exists such that at deliveries greater than a critical value (00, &, vo2 is relatively constant. Deliveries less than 00, crit cause an apparently linear drop in the VO, (20). The ratio of DO, to VO, when delivery is near 00, crit is approximately 2:l. In a normal healthy resting state, the ratio is usually 4:l (Fig. 1). Several investigators have varied the individual components of 00, (hematocrit, hemoglobin saturation, and cardiac output) in acute animal preparations and have demonstrated that the rate of DO,, rather than the means by which it is delivered, remains the important variable (5, 21). The effect of hypothermic temperatures on vo2 has been extensively studied and is routinely utilized in cardiopulmonary bypass surgery (1). Hypothermia predictably lowers the basal metabolic rate and VO,, presumably by slowing, at the subcellular level, the enzymatic 2428
J. HARB,
AND
R. H. BARTLETT
of Surgery, University of Michigan Medical Center, Ann Arbor, Michigan 48109
0161-7567/92
$2.00 Copyright
reactions that regulate oxygen utilization and by inducing changes in tissue microcirculation. Defining the relationship between VO, and 00, during hypothermic perfusion remains controversial. Studies spanning three decades that used extracorporeal perfusion examined VO, as a function of flow, not DO,, and did not make comparisons with normothermic controls (2,7, 12,18,22). More recent studies have reassessed VO, as a function of 00, and have specifically focused on the changes in Ijozcrit as a function of temperature. The results have been contradictory. Cain and Bradley (6) found that in the hypothermic rat model the value of . Do 2crit did not change at lower temperatures. Willford et al. (23), using a pig model, demonstrated that 00, crit decreased during hypothermia. Gutierrez et al. (l3), studying dog metabolism, supported the findings of Wilford et al. No study to date has examined an individual animal’s response to several levels of 00, at normothermia and then again during hypothermia. This paper presents an experimental design that permits a more complete assessment of the evolving changes in VO, as DO, is changed at different temperatures. Modifications of this design have been used previously (7, 10). Achieving total cardiopulmonary bypass with an extracorporeal circuit enabled complete monitoring and control of cardiac output and subsequent DO,. Indirect spirometry across a membrane lung provided independent measurements of VO,. The extracorporeal circuit allowed for uniform and gradual cooling and provided the ability to maintain temperatures at relatively constant levels. Numerous data points could be collected on the six animals. Each animal was studied first at normothermic and then at hypothermic temperatures. After the hypothermic phase of the study, each sheep was rewarmed back to 39°C and similar measurements were repeated. Reproduction of the original consumption-delivery curve provided an internal control to ensure persistent viability of the animal. METHODS
Eight young female sheep, weighing 18-25 kg, were utilized for data collection. Pentobarbital sodium sedation (500-1,000 mg) provided sufficient anesthesia for endotracheal intubation and shearing. Atropine (1.0-1.5 mg) was administered to decrease secretions. A Bird Mark 7 respirator ventilated the animal until extracorporeal bypass was established. Anesthesia was administered intravenously with pentobarbital and ketamine (Ketalar, 5-10 mg/kg) throughout the experiment. Pancuronium bromide (Pavulon, 1.0 mg/kg) was given peri-
0 1992 the American
Physiological
Society
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EFFECTS
OF
HYPOTHERMIA
ON
ire,
AND
2429
i)oz
Transition point from the delivery dependent to independent portions of the curve (bo2:902 - 2:l) ne VO2 . ..... ..... ...... ...... ...... ...... ..... ...... . * . ... ... ... ... .. ... ... ... ... ... ... .
Resting state (bO2:VOZ * 4: 1) *
bO2 Crit
Oxygen FIG.
1. Graphic
depiction
of the relationship
between
Delivery oxygen
odically to prevent any increase in VO, from shivering during hypothermia. A cannula inserted in the femoral artery permitted continuous blood pressure monitoring (E. for M. Honeywell Transducing System) and initial blood gas sampling. All blood gases were analyzed for oxygen partial pressure ( Pao,), carbon dioxide partial pressure (Pacog), and pH (Radiometer ABL-30 Acid-Base analyzer), in addition to hemoglobin content and saturation (IL-282 CO-oximeter, Instrumentation Laboratories). A pulmonary arterial catheter containing a fiber-optic channel was inserted through the femoral vein into proper position. Mixed venous saturation was continuously displayed during the experiment (Oximetrix So&O computer), initially via the pulmonary artery catheter and later by a catheter within the bypass circuit. The right jugular vein and common carotid artery were also dissected for later cannulation. A small left thoracotomy provided access to the pulmonary artery. A circumferential tourniquet placed loosely about the main pulmonary artery enabled complete occlusion of this vessel to prevent pulmonary blood flow once total bypass was reached. An extracorporeal bypass circuit was constructed as described in Fig. 2. Polyvinylchloride tubing connected the various components of the circuit. Siphoned blood from the right atrium would first enter an expandable silicone rubber reservoir mounted on a bladder box. A microswitch in the bladder box controlled power to a double occlusion roller pump. If pump outflow exceeded venous drainage (i.e., pump inflow), the silicone rubber reservoir would collapse and temporarily interrupt power to the pump. Pump flow would resume once venous return replenished the volume in the reservoir. A fiber-optic catheter placed into the tubing lumen near the bladder continuously displayed mixed venous saturation of the blood during bypass. From the roller pump, the venous blood was directed into a membrane lung and a heat exchanger (Sci-Med Membrane Oxygenator with Integral Heat Exchanger, 3.5-4.5 m2), where gas exchange could occur. A blood warmer (Seabrook) connected to the heat exchanger permitted complete control of the animal’s temperature. The animal’s temperature was measured transvaginally with a thermistor probe connected to a
(i)O2) consumption
and oxygen
delivery.
digital display (Sorenson Research). The oxygenated blood was returned to the animal via the right common carotid artery. The circuit was first primed with normal saline and then with homologous sheep blood to avoid significant hemodilution. After the animal was systemically heparinized (200 U/kg), the neck vessels were cannulated with 2%32-Fr Argyl catheters for venous drainage and 18- to 20-Fr USC1 catheters for arterial reinfusion. A continuous heparin infusion, supplemented by periodic boluses, maintained the activated clotting time of the animal’s whole blood SO0 s. Once bypass was established, extracorporeal flow was gradually increased. Additional volume in the form of whole blood or crystaloid was provided as necessary to stabilize the animal’s perfusion pressure and permit adequate flows. Occlusion of the pulmonary artery with the previously placed tourniquet clamp ensured that all venous blood returning to the heart would be captured by the extracorporeal circuit. This occlusion permitted complete control of the animal’s effective cardiac output with the roller pump. Ventilation of the lungs was stopped and the endotracheal tube clamped once full bypass was reached, usually at blood flow rates approaching 100 ml kg-l min. Blood flow through the circuit was measured with an ultrasonic flowmeter (TlOl, Transonic Systems), which was connected to the circuit with a clamp-on probe to a short segment of G-in. polyv inylc hloride or si licone tubing. The accuracy of this flowmeter using blood at normothermia had been previously determined by this laboratory, with r = 0.99. The measured flow rates were continuously compared with the revolutions per minute of the roller pump to verify an expected linear relationship. VO, was measured spirometrically with a closed circuit as described in Fig. 3. The circuit contained, in series, the gas inlet and outlet ports of a membrane lung (Sci-Med), a tightly occluded roller pump, and a canister of soda lime crystals for CO, removal. The roller pump provided continuous flow of oxygen through the circuit. A volumetric spirometer, primed with 100% oxygen, was added to the circuit by a branched connector. A one-way valve was placed on the spirometer to prevent gas from entering. As oxygen was consumed across the membrane lung, CO, was released into the gaseous effluent. The soda lime l
l
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2430
EFFECTS
OF HYPOTHERMIA
ON ire, AND 00~
ExtraCorporeal Bypass Circuit
Pump
One-Way Valve
FIG. 2. Schematic depiction of extracorporeal bypass circuit. Arrows represent direction of blood flow, Spirometric circuit is connected by way of membrane lung. See text for details.
Data cdection. After full bypass was reached, 00, was varied by controlling bypass flows. Data collection at each delivery value included the animal’s temperature, mean blood pressure, the displayed mixed venous saturation, pre- and postoxygenator blood gases, hemoglobin concentration and saturation, blood flow and roller pump revolutions per minute, relative gas flow rate
crystals subsequently removed the CO,. The spirometer would then feed additional oxygen into the circuit to maintain a constant total partial pressure of all gasses present. All animals were cared for under the guidelines of the Unit of Laboratory Animal Medicine established by the University of Michigan.
Fluids
Hr-spafin ‘*\I
Blood Return
/
----
Right Atrium
--
,-,--IA * Loop Closed a imbfane Lung
I FIG.
details.
Bladder
1 0
0
1
pwomet
ric
Circuit
I
3. Schematic depiction of closed-loop spirometric circuit. Arrows represent direction of gas flow. See text for
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EFFECTS
OF HYPOTHERMIA
ON vo, AND Ijoz
2431
separate lines to each collection of the divided data. The through the membrane lung, ambient room temperature, barometric pressure, and the volume change within the total variance of the data about these two lines was calspirometric reservoir. When the data collection at a culated. The data groupings were then modified by segiven bypass flow rate was complete, the flow rate was quentially removing the VO, value that corresponded to the highest 00, value in the “dependent” group of data changed and the animal was monitored until a new apparand adding it to the group of data representing the “indeent baseline was reached. Typically 5-10 min were required for the animal to stabilize at each new OO,, as pendent” area. Two new lines were fitted to the these new groupings of data, and the variance of 60, about evidenced by plateauing of the mixed venous saturation. these lines was recalculated. Continuous analysis of the Occasionally, at very low flows (i.e., 5-20 ml kg-l min-I), a plateau was not reached, and data were collected after a data proceeded sequentially and systematically until all minimum of 5 min. Each spirometric measurement of reasonable combinations were considered. In most cases, the two equations having the minimal total error (i.e., VO, spanned 5 min. DO, values were alternated between minimal sum of the squares of the vertical distance behigh and low levels to permit resuscitation of the animal tween the fitted line and the measured VO, value) were and avoid progressive metabolic acidosis. Sodium bicarused to describe the two sets of data and define the indebonate was administered as required. Gas flow through the membrane lung was adjusted with each rate of bypass pendent and dependent portions of the relationship. In a few situations, the lines determined by the leastblood flow to avoid excessive CO, removal during lower squares method did not adequately represent the data. levels of blood flow. Pa,,, ‘s in blood typically ranged from 25 to 55 Torr. Each group of data was entered di- Too few points occasionally confounded the regression equations. Wilford et al. (23) likewise recognized the limirectly into a computer (Macintosh SE), which in turn tations imposed by least-squares analysis. When such generated a consumption-delivery graph. Blood flow rates were selected to represent the broadest range of situations were encountered, attention was given to both deliveries possible. When a sufficient, number of -data the slope of the line describing the independent region points had been collected at 39*C to demonstrate the and the y-intercept (VO, value) describing the dependent region. The data were then redivided into groups to minibiphasic relationship between Vo2 and OO,, the animal’s mize their total variance about the regression equation temperature was reduced to 33”Cover a period of 45-60 min. A temperature gradient between the thermistors in and also produce the independent region with the most the pulmonary artery and vagina did not exceed 1°C horizontal slope or dependent region that intersected the iTo axis closest to the origin. while the data were collected. Having two sets of equations to divide each data colData collection at 33OC proceeded, as described above, until sufficient points were collected to draw a new con- lection permitted the calculation of the baseline VO,'s and 00 2crit’s. The average of all the VO, values in the sumption-delivery curve. Each animal was then rewarmed back to 39”C, and the data collection process independent portion of the curves determined the basewas repeated for a final time. Typically, the animal was line V02. 002,rit described the transition between the two supported on bypass for 8-10 h and was subjected to curves. The intersection of the two regression equations for each data group defined its corresponding 00, crit* several intermittent episodes of low 00,. Theoretically, Paired Student’s t tests compared the corresponding valisolated organ damage could occur and be masked by the ues from each experimental animal. cardiopulmonary support provided. Reproduction of the original consumption-delivery curve after rewarming RESULTS served to demonstrate persistent, viability of the animal as measured by its baseline VO, and response to low levEight sheep were successfully cannulated for bypass, els of Doz. six of which provided data for subsequent analysis. ProData analysis. Ijo is calculated as the product of the gressive hemodynamic instability and loss of viability cardiac output (pump blood flow rate) and the arterial during the prolonged experiments caused two of the oxygen content (Ca,,), where Ca,, = 1.36 (Hb) (fracsheep to be unsuitable for analysis. Graphs of Vo2 vs. 00, tional %saturation of Hb) + 0.003 (Pa,,); 1.36 is oxygen for the remaining six animals are depicted in Figs. 4 and binding capacity of sheep Hb, 0.003 is solubility coeffi5. Each demonstrates an apparently biphasic relationcient of oxygen in plasma, and Pa,, is the po$oxygenator ship between 00, and VO,. The temperature of 39, and partial pressure of oxygen. The values for VO, were de- 39,“C refer, respectively, to the initial normothermic and termined by calculating the volume change within the rewarmed normothermic experimental conditions. spirometer, converting it to STP by making appropriate Table 1 summarizes the baseline VO,'s that were caladjustments for barometric pressure and room temperaculated from each of the sheep. The mean baseline VO, ture, and normalizing it to the weight of the animal. values at 39, and 39,“C were not significantly different Linear-regression analysis was used to determine the (P < 0.4). The average baseline VO, at 33°C was signifibaseline values for VO, and DO, trite The method used is a cantly lower than either value at 39’C (P < 0.001). variant of that described by Wilford et al. (23). The analyTable 2 summarizes the calculated values for DO, crit* sis relies pn the premise that the relationship between The corresponding average Do~&s at temperatures of VO, and DO, is biphasically linear. The data from each 39i, 33, and 39,“C were 6.17, 4.57, and 6.34 ml animal at a giyen temperature were ordered by increasq2 kg-’ min-‘, respectively. The difference between the ing values for DO, and then were divided into two groups, Do 2cri+,of 39i”C compared with DO, crit at 33OC was signifione of which clearly contained high delivery values and cant (P < 0.05), and that between the ~~~~~~~~~ at 39, and represented the points on the delivery independent por33OC approached significance (P < 0.059). No significant tion of the curve. Standard regression was used to fit two difference existed between the DO, crit’s at 39, and 39,“C. Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (163.015.154.053) on August 24, 2018. l
l
l
l
l
l
Copyright © 1992 American Physiological Society. All rights reserved.
2432
EFFECTS
7
Hypothermia
OF HYPOTHERMIA
ON ire, AND Do,
3
#1
0
6
8 1
Hypothermia
#2
6-
0 #
xoOx w x0
41
0
I
E
2-
%
4
l
%
8
0
0 4
4
0
FIG. 4. Graphs of vo, vs. 00, in 6 sheep placed cardiopulmonary bypass. y-Axis represents VO, in 02. kg-’ . min-‘, and x-axis represents 00~ in 0,. kg-‘. min-‘. 0, Data points collected at 39i”C; points at 39,“C; +, points at 33OC.
4
4
4
4
4
o+
8
,
0 0
0;
w,.
0
I 2
1
4
,v
I
6
8
w
Hypothermia
61
4-
0 . 4
29
1
16
18
#3
4
4
4
4
4
4
4
4
4
l
%*
.
0
4
‘.
X,
4 4
1
w 14
4
0
.
-, 12
0%
39
1 -
,‘, 10
on ml ml
K 44
. 0
1 2
I
I 4
1
I 6
.
I 8
I 10
Table 3 contains the calculated oxygen extraction ratios (ER) at the critical DO, values based on the equation following: ER = Tjo, (at DO, crit) 1002 crit* The mean ER at 33OC did not differ significantly from either of the values calculated at either 39, or 39,“C (with the corresponding values of P < 0.23 and < 0.22, respectively.) DISCUSSION
The use of extracorporeal bypass and closed-loop spirometry permitted the calculation of individual baseline VO,‘S and DO, crit’ s for each animal investigated. These values could be compared with similar values from the same animal but obtained at different temperatures. The data could likewise be compared with similar values obtained from different sheep under the same study conditions. While on full bypass support, the sheep were completely paralyzed and fully sedated. Myocardial depression from excess anesthesia was not a consideration because cardiac function did not contribute to blood flow. Delivery values could be varied greatly. Alternating between high and low values permitted prolonged experimentation and the collection of numerous data points. Periodic resuscitation would not have been possible if myocardial function was the sole determinant of DO,. Our values for baseline VO, are consistent with those previously reported. The VO,% of our six sheep stabilized
I 12
I 14
on full bypass ranged from 4.36 to 6.62 ml. kg-l min-‘. Pepe and Culver (19) reported values of 5.5-8.8 ml kg-l min-l in anesthetized dogs; Hill et al. (16) reported values of 6.9-9 ml kg-l 6min-l in pigs; Cilley et al. (8) reported an average Oo, of 5.8 ml. kg-l min-’ in anesthetized dogs. The effects of heavy sedation and paralysis may have slightly lowered our VO, values compared with others. The extracorporeal circuit seemed to have negligible effects on metabolism, although any subtle effects at different animal temperatures were not tested for with this experimental design. The artificial surfaces of a bypass circuit may cause vascular dilation that does not respond to changes in body temperature. This vasodilitation could induce changes in the microcirculation during hypothermia, causing either shunting or overperfusion of certain organ systems. It is unlikely that these changes will produce a significant effect in whole body metabolism, but additional studies are needed to completely assess these potential microcirculatory effects. Three prior studies have contributed to our understanding of the relationship of OO,~, to temperature. Gutierrez et al. (13) compared two populations of dogs, each at temperatures of 37.7 and 30.5”C. VO, was calculated by the Fick equation. Dozcrit was determined through the use of a fourth-order polynomial equation that was fitted to the two collections of data. A single was value for 00, c*it at each of the two temperatures l
l
l
l
l
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EFFECTS Hypothermia
0 1
OF HYPOTHERMIA
#4
7
0
0
6
x0
5
Ox
0
6-
X
x
x
4
X
0
12
Hypothermia
.
0
0
O
w 0
2433
ON ire, AND Do,
16
20
24
#5
0
5-
0 x0 09(x
4-
On
=0x
O
xox
.
39
8"
.
=
4
FIG. 5. Graphs of vo, vs. Do, in 6 sheep placed cardiopulmonary bypass. y-Axis represents Vo2 in 0, kg-‘. min-l, and x-axis represents 00, in 0, kg-‘. min? 0, Data points collected at 39i”C; points at 39,“C; +, points at 33OC.
X
l 4
4
l
Ox
X
4 4
l
4
l
l
2-
4
.
on ml ml
4
X,
l*
6
Hypothermia
1 59
II . ,"o
4-
)b
#6 X
% O
X
0
0
0
ox
X
3-
x
O
.
l
2-
8
*
l
4
l *
l l
4
l
l
44
x*
l 4
1 1 o!
‘,‘,.
1.1’1.
0
2
4
6
I
8
10
12
.I’I
x
14
16
obtained. This method unfortunately did not permit any statistical comparisons of the values determined for DO 2 crit The calculated Do, crit value at 37.7OC of 8.5 ml kg-l rnin compared with a baseline VO, of 4.7 ml kg-’ min. The values at a temperature of 30.5OC fell to 6.2 and 3.2 ml kg-‘. min-‘, respectively. Cain and Bradley (6) compared three populations of rats each at study temperatures of 38,36, and 34OC. Spirometric measurements of Vo, were used to calculate the corresponding cardiac outputs. Temperature was varied by surface cooling, and the value for Ijo crit was obtained by determining the intersection of two fitted lines to the independent and dependent p,ortions of the curve. These investigators found that D02crit, which was -22 ml kg-l. min-l, did not appear to change over a temperature range of 34-38OC. l
l
l
l
l
l
l
TABLE 1. Baseline
vo, values
Sheep No.
39i”C
33°C
1
5.38-t0.88 5.98t0.24 4.83kO.39 6.62t0.42 4.81t0.41 4.36-t0.25 5.33~10.84
3.41t0.32 4.05kO.27 3.11kO.37 3.33t0.21 2.61~10.16 2.53k0.26 3.17kO.56
2 3 4 5 6 Average
5.15t0.11 6.011kO.38 4.84kO.34 5.77t0.63 4.4oMI.35 4.82t0.36 5.17kO.61
Values are means ? SD in ml -02 4kg-’ min? VO,, O2 consumption; subscript i, initial normothermic; subscript r, rewarmed normothermic.
I.1
18
20
Willford et al. (23) studied two groups of pigs at temperatures of 29 and 37OC. An extracorporeal circuit was used to cool the animal. An electromagnetic flow probe on the aortic arch measured the cardiac output, and the Po2 was calculated by the Fick equation. Their method of Do 2 crit determination is similar to the one used by us. They found that ~Io,,~~~ decreased significantly from 7.9 ml kg-l min-l at 37OC to 5.2 ml* kg-‘. min-’ at 29°C (P < 0.005). They did not, however, demonstrate a significant difference in the baseline VO,‘s at these temperatures (4.96 ml. kg-’ min-’ at 37OC and 4.02 ml kg-l mine1 at 29OC with P < 0.1). Our results support the hypothesis that cooling, by lowering the metabolic rate, also lowers the value for 00, crita The difference between baseline Vo2's at 33 and 39OC was highly significant (P < 0.001). A statistically significant difference also existed between the DO2crit’S at 39, and 33OC (P < 0.05), whereas the difference between the l
l
l
l
l
Sheep No.
39i”C
33°C
39,“C
1 2 3 4 5 6
7.06 6.14 5.79 7.69 5.50 4.86
2.95 4.49 3.65 7.11 5.19 4.03
7.88 5.73 5.41 9.42 5.49 4.08
Average -t SD
6.17zk1.04
4.57t1.46
6.341~1.95
l
Values are expressed in ml 0, kg-l min? l
l
DO,,
0, delivery.
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2434
EFFECTS
3. Oxygen extraction
TABLE
OF
HYPOTHERMIA
ratios
Sheep No.
39i"C
33°C
39,"C
1 2 3 4 5 6
0.77 0.94 0.74 0.80 0.79 0.84
0.97 0.89 0.79 0.46 0.50 0.56
0.65 0.97 0.93 0.66 0.78 1.07
Average
+ SD
ON
0.8l-tO.07
0.7OkO.22
0.84kO.17
.
Do 2crit’~ at 33 and 39,“C approached significance (P < 0.059). Prolonged experimentation with frequent but intermittent low oxygen delivery states may have produced subtle organ damage that caused this change in OO,,,, upon rewarming. Although the baseline VO, at 39,“C was less than that at 39i”C, the decrease was not significant
3.
4.
5. 6.
7.
8.
9.
(P < 0.4).
Induced hypothermia has been routinely used for the past 30 years during surgery requiring cardiopulmonary bypass. Our results support the clinical findings developed through human cardiopulmonary bypass research and add practical application for the use of hypothermia. A biphasic relationship similar to that between VO, and 00, has been demonstrated between VO, and $ (bypass flow rate) in several human studies (2, 3, 7, 9, 12, 14, 15, 17). Some of these studies have defined a critical flow at which VO, becomes dependent on the flow rate. Unfortunately these critical flow values cannot be compared because the studies do not account for the subjects’ hematocrit and temperature. Cooling patients during cardiopulmonary bypass reduces not only myocardial but also whole body metabolism. Reduced levels of DO, are subsequently better tolerated, and lower bypass flow rates are permissible. Lower flow rates cause less hemolysis, permit a clearer surgical field, and decrease noncoronary collateral flow (6). As cooling progresses and metabolism falls, the value for Dozcrit will also decrease. Hypothermia theoretically could produce such a significant drop in VO, and Dozcrit that even low flow rates (and therefore low Do,'s) could be tolerated by select organ systems without invoking anaerobic metabolism to provide energy. This work was supported by National Institute of Child Health and Human Development Grant HD-15434. Address for reprint requests: R. H. Bartlett, Dept. of Surgery, University of Michigan Medical Center, Taubman Center 2920, Box 0331, 1500 E. Medical Center Dr., Ann Arbor, MI 48109. Received
4 March
1991; accepted
in final
form
21 November
10.
11. 12.
13.
14.
15.
16.
17.
18.
19.
20. 21.
1991.
REFERENCES 1. ADAMS, R. P., L. A. DIELEMAN, AND S. M. CAIN. A critical value for O2 transport in the rat. J. Appl. Physiol. 53: 660-664, 1982. 2. ALSTON, R. P., M. SINGH, AND A. D. MCLAREN. Systemic oxygen uptake during hypothermic cardiopulmonary bypass-effects of
22. 23.
Vo,
62
AND
Do,
,5
flow rate, flow character, and arterial pH. J. Thorac. Cardiouasc. Surg. 98: 757-768, 1989. ANDERSON, M. N., AND A. SENNING. Studies in oxygen consumption during extracorporeal circulation with a pump oxygenator. Ann. Surg. 148: 59-65, 1958. BIGELOW, W. G., W. K. LINDSAY, R. C. HARRISON, R. A. GORDON, AND W. F. GREENWOOD. Oxygen transport and utilization in dogs at low body temperatures. Am. J. Physiol. 160: 125-137, 1950. CAIN, S. M. Oxygen delivery and uptake in dogs during anemic and hypoxic hypoxia. J. Appl. Physiol. 42: 228-234, 1977. CAIN, S. M., AND W. E. BRADLEY. Critical O2 transport values at lowered body temperatures in rats. J. Appl. Physiol. 55: 1713-1717, 1983. CHENG, H. C., T. KUSANOKI, L. H. BOSHER, R. B. MCELVEIN, AND D. A. BLAKE. A study of oxygen consumption during extracorporeal circulation. Trans. ASAIO 5: 273-276c, 1959. CILLEY, R. E., T. 2. POLLEY, J. B. ZWISCHENBERGER, J. M. TooMASIAN, AND R. H. BARTLETT. Independent measurement of oxygen consumption and oxygen delivery. J. Surg. Res. 47: 242-247, 1989. CLOWES, G. H. A., W. E. NEVILLE, G. SABGAA, AND Y. SHIBOTA. The relationship of oxygen consumption, perfusion rate, and temperature to the acidosis associated with cardiopulmonary bypass. Surgery 44: 220-239, 1958. CORNISH, J. D., D. R. GERSTMANN, D. M. NULL, JR., M. D. SMITH, AND T. J. KUEHL. Oxygen delivery rate and sufficiency of oxygenation during ECMO in newborn baboons. J. Appl. Physiol. 66: 210216, 1989. FICK, A. Veber die Messung des Blutquantums in den Herzventrikeln. SB Phys. Med. July 9, 1870. Fox, L. S., E. H. BLACKSTONE, J. W. KIRKLIN, R. W. STEWART, AND P. N. SAMUELSON. Relationship of whole body oxygen consumption to perfusion flow rate during hypothermic cardiopulmonary bypass. J. Thorac. Cardiovasc. Surg. 83: 239-248, 1982. GUTIERREZ, G., A. R. WARLEY, AND D. R. DANTZKER. Oxygen delivery and utilization in hypothermic dogs. J. Appl. Physiol. 60: 751757, 1986. HARRIS, E. A., E. R. SEDYE, AND A. W. SQUIRE. Oxygen consumption during cardiopulmonary bypass with moderate hypothermia. Br. J. Anaesth. 43: 1114-1120, 1971. HICKEY, R. F., AND P. E. HOAR. Whole-body oxygen consumption during low-flow hypothermic cardiopulmonary bypass. J. Thorac. Cardiovasc. Surg. 83: 903-906, 1983. HILL, E. P., D. C. WILLFORD, W. Y. MOORES, R. BELLAMY, AND W. H. HEYDORN. Oxygen transport and oxygen consumption vs. cardiac output at different haematocrits. Perfusion 2: 39-50, 1987. MCGOON, D. C., E. A. MOFFIT, R. A. THEYE, AND J. W. KIRKLIN. Physiological studies during high flow, normothermic, whole body perfusion. J. Thorac. Cardiovasc. Surg. 39: 275-287, 1960. PANETH, M., R. SELLERS, V. L. GOTT, W. L. WEIRICH, P. ALLEN, R. C. READ, AND C. W. LILLEHEI. Physiological studies upon prolonged cardiopulmonary by-pass with the pump oxygenators with particular reference to (1) acid-base balance, (2) siphon caval drainage. J. Thorac. Surg. 34: 570-579, 1957. PEPE, P. E., AND B. H. CULVER. Independently measured oxygen consumption during reduction of oxygen delivery by positive endexpiratory pressure. Am. Rev. Respir. Dis. 132: 788-792, 1985. SCHUMACKER, P. T., AND S. M. CAIN. The concept of a critical oxygen delivery. Intensive Care Med. 13: 223-229, 1987. SCHWARTZ, S., R. A. FRANTZ, AND W. C. SCHOEMAKER. Sequential hemodynamic and oxygen transport responses in hypovolemia, anemia and hypoxia. Am. J. Physiol. 241 (Heart Circ. Physiol. 10): H864-H871, 1981. STARR, A. Oxygen consumption during cardiopulmonary bypass. J. Thorac. Cardiovasc. Surg. 38: 46-56, 1959. WILLFORD, D. C., E. P. HILL, F. C. WHITE, AND W. Y. MOORES. Decreased critical mixed venous oxygen tension and critical oxygen transport during induced hypothermia in pigs. J. Clin. Monit. 2: 155-168, 1986.
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D. VYAS, K. HULTQUIST,
VYAS, K. HULTQUIST,J. HARB,AND R.H.
moderate hypothermia on 0, consumption at various 0, deliveries in a sheep model. J. Appl. Physiol. 72(6): 2428-2434,1992.-The effects of modesthypothermia on oxyof
genconsumption (VO& were studied at various levelsof oxygen delivery (no,) in six sheep.Each animal wasplaced on cardiopulmonary bypassby extrathoracic cannulations. 00, wasvaried by changing blood flow through an extracorporeal circuit. Vo2 was measuredspirometrically across a membrane lung. VO, was initially measuredat various levels of 00, at normothermic temperatures (39°C). The animalswere then cooledto 33°C. 00, was varied, and the correspondingVO,‘s were determined. The data at both temperatures demonstratedthe biphasic relationship of VO, to various levels of DO,. A critical level of Do, u&crit) was defined to reflect the transition area between the dependent and independent portions of the consumption-delivery curve. The averagebaselineVO,‘s on the delivery independent portion of the curve were calculated to be 5.33 and 3.17 ml 0,. kg-‘. min-’ at 39 and 33”C, respectively (P < 0.001). The correspondingh~~~rit)swere 6.17 and 4.57 ml o2. kg-’ . min-’ (P < 0.05). The oxygen extraction ratios at Do 2critfor each of these temperatures did not differ significantly. We conclude that hypothermia, by lowering baseline VO,, reduces 00, crit. Hypothermia may therefore reduce or eliminate the anaerobic metabolism and subsequentacidosis that would otherwise occur during normothermia at low levels of Do,. metabolism;critical value of oxygen delivery; oxygen extraction ratio
SEVERAL STUDIES have investigated the dependence of whole-body oxygen consumption (VO,) over a wide range of oxygen deliveries (DO,) (1,2,4-7,12,13,16,21-23). A
biphasic relationship exists such that at deliveries greater than a critical value (00, &, vo2 is relatively constant. Deliveries less than 00, crit cause an apparently linear drop in the VO, (20). The ratio of DO, to VO, when delivery is near 00, crit is approximately 2:l. In a normal healthy resting state, the ratio is usually 4:l (Fig. 1). Several investigators have varied the individual components of 00, (hematocrit, hemoglobin saturation, and cardiac output) in acute animal preparations and have demonstrated that the rate of DO,, rather than the means by which it is delivered, remains the important variable (5, 21). The effect of hypothermic temperatures on vo2 has been extensively studied and is routinely utilized in cardiopulmonary bypass surgery (1). Hypothermia predictably lowers the basal metabolic rate and VO,, presumably by slowing, at the subcellular level, the enzymatic 2428
J. HARB,
AND
R. H. BARTLETT
of Surgery, University of Michigan Medical Center, Ann Arbor, Michigan 48109
0161-7567/92
$2.00 Copyright
reactions that regulate oxygen utilization and by inducing changes in tissue microcirculation. Defining the relationship between VO, and 00, during hypothermic perfusion remains controversial. Studies spanning three decades that used extracorporeal perfusion examined VO, as a function of flow, not DO,, and did not make comparisons with normothermic controls (2,7, 12,18,22). More recent studies have reassessed VO, as a function of 00, and have specifically focused on the changes in Ijozcrit as a function of temperature. The results have been contradictory. Cain and Bradley (6) found that in the hypothermic rat model the value of . Do 2crit did not change at lower temperatures. Willford et al. (23), using a pig model, demonstrated that 00, crit decreased during hypothermia. Gutierrez et al. (l3), studying dog metabolism, supported the findings of Wilford et al. No study to date has examined an individual animal’s response to several levels of 00, at normothermia and then again during hypothermia. This paper presents an experimental design that permits a more complete assessment of the evolving changes in VO, as DO, is changed at different temperatures. Modifications of this design have been used previously (7, 10). Achieving total cardiopulmonary bypass with an extracorporeal circuit enabled complete monitoring and control of cardiac output and subsequent DO,. Indirect spirometry across a membrane lung provided independent measurements of VO,. The extracorporeal circuit allowed for uniform and gradual cooling and provided the ability to maintain temperatures at relatively constant levels. Numerous data points could be collected on the six animals. Each animal was studied first at normothermic and then at hypothermic temperatures. After the hypothermic phase of the study, each sheep was rewarmed back to 39°C and similar measurements were repeated. Reproduction of the original consumption-delivery curve provided an internal control to ensure persistent viability of the animal. METHODS
Eight young female sheep, weighing 18-25 kg, were utilized for data collection. Pentobarbital sodium sedation (500-1,000 mg) provided sufficient anesthesia for endotracheal intubation and shearing. Atropine (1.0-1.5 mg) was administered to decrease secretions. A Bird Mark 7 respirator ventilated the animal until extracorporeal bypass was established. Anesthesia was administered intravenously with pentobarbital and ketamine (Ketalar, 5-10 mg/kg) throughout the experiment. Pancuronium bromide (Pavulon, 1.0 mg/kg) was given peri-
0 1992 the American
Physiological
Society
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EFFECTS
OF
HYPOTHERMIA
ON
ire,
AND
2429
i)oz
Transition point from the delivery dependent to independent portions of the curve (bo2:902 - 2:l) ne VO2 . ..... ..... ...... ...... ...... ...... ..... ...... . * . ... ... ... ... .. ... ... ... ... ... ... .
Resting state (bO2:VOZ * 4: 1) *
bO2 Crit
Oxygen FIG.
1. Graphic
depiction
of the relationship
between
Delivery oxygen
odically to prevent any increase in VO, from shivering during hypothermia. A cannula inserted in the femoral artery permitted continuous blood pressure monitoring (E. for M. Honeywell Transducing System) and initial blood gas sampling. All blood gases were analyzed for oxygen partial pressure ( Pao,), carbon dioxide partial pressure (Pacog), and pH (Radiometer ABL-30 Acid-Base analyzer), in addition to hemoglobin content and saturation (IL-282 CO-oximeter, Instrumentation Laboratories). A pulmonary arterial catheter containing a fiber-optic channel was inserted through the femoral vein into proper position. Mixed venous saturation was continuously displayed during the experiment (Oximetrix So&O computer), initially via the pulmonary artery catheter and later by a catheter within the bypass circuit. The right jugular vein and common carotid artery were also dissected for later cannulation. A small left thoracotomy provided access to the pulmonary artery. A circumferential tourniquet placed loosely about the main pulmonary artery enabled complete occlusion of this vessel to prevent pulmonary blood flow once total bypass was reached. An extracorporeal bypass circuit was constructed as described in Fig. 2. Polyvinylchloride tubing connected the various components of the circuit. Siphoned blood from the right atrium would first enter an expandable silicone rubber reservoir mounted on a bladder box. A microswitch in the bladder box controlled power to a double occlusion roller pump. If pump outflow exceeded venous drainage (i.e., pump inflow), the silicone rubber reservoir would collapse and temporarily interrupt power to the pump. Pump flow would resume once venous return replenished the volume in the reservoir. A fiber-optic catheter placed into the tubing lumen near the bladder continuously displayed mixed venous saturation of the blood during bypass. From the roller pump, the venous blood was directed into a membrane lung and a heat exchanger (Sci-Med Membrane Oxygenator with Integral Heat Exchanger, 3.5-4.5 m2), where gas exchange could occur. A blood warmer (Seabrook) connected to the heat exchanger permitted complete control of the animal’s temperature. The animal’s temperature was measured transvaginally with a thermistor probe connected to a
(i)O2) consumption
and oxygen
delivery.
digital display (Sorenson Research). The oxygenated blood was returned to the animal via the right common carotid artery. The circuit was first primed with normal saline and then with homologous sheep blood to avoid significant hemodilution. After the animal was systemically heparinized (200 U/kg), the neck vessels were cannulated with 2%32-Fr Argyl catheters for venous drainage and 18- to 20-Fr USC1 catheters for arterial reinfusion. A continuous heparin infusion, supplemented by periodic boluses, maintained the activated clotting time of the animal’s whole blood SO0 s. Once bypass was established, extracorporeal flow was gradually increased. Additional volume in the form of whole blood or crystaloid was provided as necessary to stabilize the animal’s perfusion pressure and permit adequate flows. Occlusion of the pulmonary artery with the previously placed tourniquet clamp ensured that all venous blood returning to the heart would be captured by the extracorporeal circuit. This occlusion permitted complete control of the animal’s effective cardiac output with the roller pump. Ventilation of the lungs was stopped and the endotracheal tube clamped once full bypass was reached, usually at blood flow rates approaching 100 ml kg-l min. Blood flow through the circuit was measured with an ultrasonic flowmeter (TlOl, Transonic Systems), which was connected to the circuit with a clamp-on probe to a short segment of G-in. polyv inylc hloride or si licone tubing. The accuracy of this flowmeter using blood at normothermia had been previously determined by this laboratory, with r = 0.99. The measured flow rates were continuously compared with the revolutions per minute of the roller pump to verify an expected linear relationship. VO, was measured spirometrically with a closed circuit as described in Fig. 3. The circuit contained, in series, the gas inlet and outlet ports of a membrane lung (Sci-Med), a tightly occluded roller pump, and a canister of soda lime crystals for CO, removal. The roller pump provided continuous flow of oxygen through the circuit. A volumetric spirometer, primed with 100% oxygen, was added to the circuit by a branched connector. A one-way valve was placed on the spirometer to prevent gas from entering. As oxygen was consumed across the membrane lung, CO, was released into the gaseous effluent. The soda lime l
l
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2430
EFFECTS
OF HYPOTHERMIA
ON ire, AND 00~
ExtraCorporeal Bypass Circuit
Pump
One-Way Valve
FIG. 2. Schematic depiction of extracorporeal bypass circuit. Arrows represent direction of blood flow, Spirometric circuit is connected by way of membrane lung. See text for details.
Data cdection. After full bypass was reached, 00, was varied by controlling bypass flows. Data collection at each delivery value included the animal’s temperature, mean blood pressure, the displayed mixed venous saturation, pre- and postoxygenator blood gases, hemoglobin concentration and saturation, blood flow and roller pump revolutions per minute, relative gas flow rate
crystals subsequently removed the CO,. The spirometer would then feed additional oxygen into the circuit to maintain a constant total partial pressure of all gasses present. All animals were cared for under the guidelines of the Unit of Laboratory Animal Medicine established by the University of Michigan.
Fluids
Hr-spafin ‘*\I
Blood Return
/
----
Right Atrium
--
,-,--IA * Loop Closed a imbfane Lung
I FIG.
details.
Bladder
1 0
0
1
pwomet
ric
Circuit
I
3. Schematic depiction of closed-loop spirometric circuit. Arrows represent direction of gas flow. See text for
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EFFECTS
OF HYPOTHERMIA
ON vo, AND Ijoz
2431
separate lines to each collection of the divided data. The through the membrane lung, ambient room temperature, barometric pressure, and the volume change within the total variance of the data about these two lines was calspirometric reservoir. When the data collection at a culated. The data groupings were then modified by segiven bypass flow rate was complete, the flow rate was quentially removing the VO, value that corresponded to the highest 00, value in the “dependent” group of data changed and the animal was monitored until a new apparand adding it to the group of data representing the “indeent baseline was reached. Typically 5-10 min were required for the animal to stabilize at each new OO,, as pendent” area. Two new lines were fitted to the these new groupings of data, and the variance of 60, about evidenced by plateauing of the mixed venous saturation. these lines was recalculated. Continuous analysis of the Occasionally, at very low flows (i.e., 5-20 ml kg-l min-I), a plateau was not reached, and data were collected after a data proceeded sequentially and systematically until all minimum of 5 min. Each spirometric measurement of reasonable combinations were considered. In most cases, the two equations having the minimal total error (i.e., VO, spanned 5 min. DO, values were alternated between minimal sum of the squares of the vertical distance behigh and low levels to permit resuscitation of the animal tween the fitted line and the measured VO, value) were and avoid progressive metabolic acidosis. Sodium bicarused to describe the two sets of data and define the indebonate was administered as required. Gas flow through the membrane lung was adjusted with each rate of bypass pendent and dependent portions of the relationship. In a few situations, the lines determined by the leastblood flow to avoid excessive CO, removal during lower squares method did not adequately represent the data. levels of blood flow. Pa,,, ‘s in blood typically ranged from 25 to 55 Torr. Each group of data was entered di- Too few points occasionally confounded the regression equations. Wilford et al. (23) likewise recognized the limirectly into a computer (Macintosh SE), which in turn tations imposed by least-squares analysis. When such generated a consumption-delivery graph. Blood flow rates were selected to represent the broadest range of situations were encountered, attention was given to both deliveries possible. When a sufficient, number of -data the slope of the line describing the independent region points had been collected at 39*C to demonstrate the and the y-intercept (VO, value) describing the dependent region. The data were then redivided into groups to minibiphasic relationship between Vo2 and OO,, the animal’s mize their total variance about the regression equation temperature was reduced to 33”Cover a period of 45-60 min. A temperature gradient between the thermistors in and also produce the independent region with the most the pulmonary artery and vagina did not exceed 1°C horizontal slope or dependent region that intersected the iTo axis closest to the origin. while the data were collected. Having two sets of equations to divide each data colData collection at 33OC proceeded, as described above, until sufficient points were collected to draw a new con- lection permitted the calculation of the baseline VO,'s and 00 2crit’s. The average of all the VO, values in the sumption-delivery curve. Each animal was then rewarmed back to 39”C, and the data collection process independent portion of the curves determined the basewas repeated for a final time. Typically, the animal was line V02. 002,rit described the transition between the two supported on bypass for 8-10 h and was subjected to curves. The intersection of the two regression equations for each data group defined its corresponding 00, crit* several intermittent episodes of low 00,. Theoretically, Paired Student’s t tests compared the corresponding valisolated organ damage could occur and be masked by the ues from each experimental animal. cardiopulmonary support provided. Reproduction of the original consumption-delivery curve after rewarming RESULTS served to demonstrate persistent, viability of the animal as measured by its baseline VO, and response to low levEight sheep were successfully cannulated for bypass, els of Doz. six of which provided data for subsequent analysis. ProData analysis. Ijo is calculated as the product of the gressive hemodynamic instability and loss of viability cardiac output (pump blood flow rate) and the arterial during the prolonged experiments caused two of the oxygen content (Ca,,), where Ca,, = 1.36 (Hb) (fracsheep to be unsuitable for analysis. Graphs of Vo2 vs. 00, tional %saturation of Hb) + 0.003 (Pa,,); 1.36 is oxygen for the remaining six animals are depicted in Figs. 4 and binding capacity of sheep Hb, 0.003 is solubility coeffi5. Each demonstrates an apparently biphasic relationcient of oxygen in plasma, and Pa,, is the po$oxygenator ship between 00, and VO,. The temperature of 39, and partial pressure of oxygen. The values for VO, were de- 39,“C refer, respectively, to the initial normothermic and termined by calculating the volume change within the rewarmed normothermic experimental conditions. spirometer, converting it to STP by making appropriate Table 1 summarizes the baseline VO,'s that were caladjustments for barometric pressure and room temperaculated from each of the sheep. The mean baseline VO, ture, and normalizing it to the weight of the animal. values at 39, and 39,“C were not significantly different Linear-regression analysis was used to determine the (P < 0.4). The average baseline VO, at 33°C was signifibaseline values for VO, and DO, trite The method used is a cantly lower than either value at 39’C (P < 0.001). variant of that described by Wilford et al. (23). The analyTable 2 summarizes the calculated values for DO, crit* sis relies pn the premise that the relationship between The corresponding average Do~&s at temperatures of VO, and DO, is biphasically linear. The data from each 39i, 33, and 39,“C were 6.17, 4.57, and 6.34 ml animal at a giyen temperature were ordered by increasq2 kg-’ min-‘, respectively. The difference between the ing values for DO, and then were divided into two groups, Do 2cri+,of 39i”C compared with DO, crit at 33OC was signifione of which clearly contained high delivery values and cant (P < 0.05), and that between the ~~~~~~~~~ at 39, and represented the points on the delivery independent por33OC approached significance (P < 0.059). No significant tion of the curve. Standard regression was used to fit two difference existed between the DO, crit’s at 39, and 39,“C. Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (163.015.154.053) on August 24, 2018. l
l
l
l
l
l
Copyright © 1992 American Physiological Society. All rights reserved.
2432
EFFECTS
7
Hypothermia
OF HYPOTHERMIA
ON ire, AND Do,
3
#1
0
6
8 1
Hypothermia
#2
6-
0 #
xoOx w x0
41
0
I
E
2-
%
4
l
%
8
0
0 4
4
0
FIG. 4. Graphs of vo, vs. 00, in 6 sheep placed cardiopulmonary bypass. y-Axis represents VO, in 02. kg-’ . min-‘, and x-axis represents 00~ in 0,. kg-‘. min-‘. 0, Data points collected at 39i”C; points at 39,“C; +, points at 33OC.
4
4
4
4
4
o+
8
,
0 0
0;
w,.
0
I 2
1
4
,v
I
6
8
w
Hypothermia
61
4-
0 . 4
29
1
16
18
#3
4
4
4
4
4
4
4
4
4
l
%*
.
0
4
‘.
X,
4 4
1
w 14
4
0
.
-, 12
0%
39
1 -
,‘, 10
on ml ml
K 44
. 0
1 2
I
I 4
1
I 6
.
I 8
I 10
Table 3 contains the calculated oxygen extraction ratios (ER) at the critical DO, values based on the equation following: ER = Tjo, (at DO, crit) 1002 crit* The mean ER at 33OC did not differ significantly from either of the values calculated at either 39, or 39,“C (with the corresponding values of P < 0.23 and < 0.22, respectively.) DISCUSSION
The use of extracorporeal bypass and closed-loop spirometry permitted the calculation of individual baseline VO,‘S and DO, crit’ s for each animal investigated. These values could be compared with similar values from the same animal but obtained at different temperatures. The data could likewise be compared with similar values obtained from different sheep under the same study conditions. While on full bypass support, the sheep were completely paralyzed and fully sedated. Myocardial depression from excess anesthesia was not a consideration because cardiac function did not contribute to blood flow. Delivery values could be varied greatly. Alternating between high and low values permitted prolonged experimentation and the collection of numerous data points. Periodic resuscitation would not have been possible if myocardial function was the sole determinant of DO,. Our values for baseline VO, are consistent with those previously reported. The VO,% of our six sheep stabilized
I 12
I 14
on full bypass ranged from 4.36 to 6.62 ml. kg-l min-‘. Pepe and Culver (19) reported values of 5.5-8.8 ml kg-l min-l in anesthetized dogs; Hill et al. (16) reported values of 6.9-9 ml kg-l 6min-l in pigs; Cilley et al. (8) reported an average Oo, of 5.8 ml. kg-l min-’ in anesthetized dogs. The effects of heavy sedation and paralysis may have slightly lowered our VO, values compared with others. The extracorporeal circuit seemed to have negligible effects on metabolism, although any subtle effects at different animal temperatures were not tested for with this experimental design. The artificial surfaces of a bypass circuit may cause vascular dilation that does not respond to changes in body temperature. This vasodilitation could induce changes in the microcirculation during hypothermia, causing either shunting or overperfusion of certain organ systems. It is unlikely that these changes will produce a significant effect in whole body metabolism, but additional studies are needed to completely assess these potential microcirculatory effects. Three prior studies have contributed to our understanding of the relationship of OO,~, to temperature. Gutierrez et al. (13) compared two populations of dogs, each at temperatures of 37.7 and 30.5”C. VO, was calculated by the Fick equation. Dozcrit was determined through the use of a fourth-order polynomial equation that was fitted to the two collections of data. A single was value for 00, c*it at each of the two temperatures l
l
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l
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Downloaded from www.physiology.org/journal/jappl by ${individualUser.givenNames} ${individualUser.surname} (163.015.154.053) on August 24, 2018. Copyright © 1992 American Physiological Society. All rights reserved.
EFFECTS Hypothermia
0 1
OF HYPOTHERMIA
#4
7
0
0
6
x0
5
Ox
0
6-
X
x
x
4
X
0
12
Hypothermia
.
0
0
O
w 0
2433
ON ire, AND Do,
16
20
24
#5
0
5-
0 x0 09(x
4-
On
=0x
O
xox
.
39
8"
.
=
4
FIG. 5. Graphs of vo, vs. Do, in 6 sheep placed cardiopulmonary bypass. y-Axis represents Vo2 in 0, kg-‘. min-l, and x-axis represents 00, in 0, kg-‘. min? 0, Data points collected at 39i”C; points at 39,“C; +, points at 33OC.
X
l 4
4
l
Ox
X
4 4
l
4
l
l
2-
4
.
on ml ml
4
X,
l*
6
Hypothermia
1 59
II . ,"o
4-
)b
#6 X
% O
X
0
0
0
ox
X
3-
x
O
.
l
2-
8
*
l
4
l *
l l
4
l
l
44
x*
l 4
1 1 o!
‘,‘,.
1.1’1.
0
2
4
6
I
8
10
12
.I’I
x
14
16
obtained. This method unfortunately did not permit any statistical comparisons of the values determined for DO 2 crit The calculated Do, crit value at 37.7OC of 8.5 ml kg-l rnin compared with a baseline VO, of 4.7 ml kg-’ min. The values at a temperature of 30.5OC fell to 6.2 and 3.2 ml kg-‘. min-‘, respectively. Cain and Bradley (6) compared three populations of rats each at study temperatures of 38,36, and 34OC. Spirometric measurements of Vo, were used to calculate the corresponding cardiac outputs. Temperature was varied by surface cooling, and the value for Ijo crit was obtained by determining the intersection of two fitted lines to the independent and dependent p,ortions of the curve. These investigators found that D02crit, which was -22 ml kg-l. min-l, did not appear to change over a temperature range of 34-38OC. l
l
l
l
l
l
l
TABLE 1. Baseline
vo, values
Sheep No.
39i”C
33°C
1
5.38-t0.88 5.98t0.24 4.83kO.39 6.62t0.42 4.81t0.41 4.36-t0.25 5.33~10.84
3.41t0.32 4.05kO.27 3.11kO.37 3.33t0.21 2.61~10.16 2.53k0.26 3.17kO.56
2 3 4 5 6 Average
5.15t0.11 6.011kO.38 4.84kO.34 5.77t0.63 4.4oMI.35 4.82t0.36 5.17kO.61
Values are means ? SD in ml -02 4kg-’ min? VO,, O2 consumption; subscript i, initial normothermic; subscript r, rewarmed normothermic.
I.1
18
20
Willford et al. (23) studied two groups of pigs at temperatures of 29 and 37OC. An extracorporeal circuit was used to cool the animal. An electromagnetic flow probe on the aortic arch measured the cardiac output, and the Po2 was calculated by the Fick equation. Their method of Do 2 crit determination is similar to the one used by us. They found that ~Io,,~~~ decreased significantly from 7.9 ml kg-l min-l at 37OC to 5.2 ml* kg-‘. min-’ at 29°C (P < 0.005). They did not, however, demonstrate a significant difference in the baseline VO,‘s at these temperatures (4.96 ml. kg-’ min-’ at 37OC and 4.02 ml kg-l mine1 at 29OC with P < 0.1). Our results support the hypothesis that cooling, by lowering the metabolic rate, also lowers the value for 00, crita The difference between baseline Vo2's at 33 and 39OC was highly significant (P < 0.001). A statistically significant difference also existed between the DO2crit’S at 39, and 33OC (P < 0.05), whereas the difference between the l
l
l
l
l
Sheep No.
39i”C
33°C
39,“C
1 2 3 4 5 6
7.06 6.14 5.79 7.69 5.50 4.86
2.95 4.49 3.65 7.11 5.19 4.03
7.88 5.73 5.41 9.42 5.49 4.08
Average -t SD
6.17zk1.04
4.57t1.46
6.341~1.95
l
Values are expressed in ml 0, kg-l min? l
l
DO,,
0, delivery.
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2434
EFFECTS
3. Oxygen extraction
TABLE
OF
HYPOTHERMIA
ratios
Sheep No.
39i"C
33°C
39,"C
1 2 3 4 5 6
0.77 0.94 0.74 0.80 0.79 0.84
0.97 0.89 0.79 0.46 0.50 0.56
0.65 0.97 0.93 0.66 0.78 1.07
Average
+ SD
ON
0.8l-tO.07
0.7OkO.22
0.84kO.17
.
Do 2crit’~ at 33 and 39,“C approached significance (P < 0.059). Prolonged experimentation with frequent but intermittent low oxygen delivery states may have produced subtle organ damage that caused this change in OO,,,, upon rewarming. Although the baseline VO, at 39,“C was less than that at 39i”C, the decrease was not significant
3.
4.
5. 6.
7.
8.
9.
(P < 0.4).
Induced hypothermia has been routinely used for the past 30 years during surgery requiring cardiopulmonary bypass. Our results support the clinical findings developed through human cardiopulmonary bypass research and add practical application for the use of hypothermia. A biphasic relationship similar to that between VO, and 00, has been demonstrated between VO, and $ (bypass flow rate) in several human studies (2, 3, 7, 9, 12, 14, 15, 17). Some of these studies have defined a critical flow at which VO, becomes dependent on the flow rate. Unfortunately these critical flow values cannot be compared because the studies do not account for the subjects’ hematocrit and temperature. Cooling patients during cardiopulmonary bypass reduces not only myocardial but also whole body metabolism. Reduced levels of DO, are subsequently better tolerated, and lower bypass flow rates are permissible. Lower flow rates cause less hemolysis, permit a clearer surgical field, and decrease noncoronary collateral flow (6). As cooling progresses and metabolism falls, the value for Dozcrit will also decrease. Hypothermia theoretically could produce such a significant drop in VO, and Dozcrit that even low flow rates (and therefore low Do,'s) could be tolerated by select organ systems without invoking anaerobic metabolism to provide energy. This work was supported by National Institute of Child Health and Human Development Grant HD-15434. Address for reprint requests: R. H. Bartlett, Dept. of Surgery, University of Michigan Medical Center, Taubman Center 2920, Box 0331, 1500 E. Medical Center Dr., Ann Arbor, MI 48109. Received
4 March
1991; accepted
in final
form
21 November
10.
11. 12.
13.
14.
15.
16.
17.
18.
19.
20. 21.
1991.
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22. 23.
Vo,
62
AND
Do,
,5
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