JOURNAL OF SURGICAL RESEARCH 51,425-433 (1991)

Low Delivery Produced by Anemia, , and Low Cardiac Output

ROBERT E. CILLEY, M.D.,’ ANDREW M. SCHARENBERG, M.D., PHILLIP F. BONGIORNO, M.D., KENNETH E. GUIRE, M.S., AND ROBERT H. BARTLETT, M.D. Section of General Surgery, University of Michigan Medical Center, Ann Arbor, Michigan 48109-0331

Submitted for publication September 20, 1990

few studies have the variables DO, and VO, been mea- In pentobarbital-anesthetized dogs, oxygen delivery sured entirely independently [6, 7,8]. (DO,) was measured by thermodilution cardiac output In an earlier study, we controlled DO, and measured and cooximeter determined oxygen content, while oxy- VO, independently in anesthetized dogs [7]. In the gen consumption (VO,) was measured independently by current study, using a canine model, the components of . Oxygen delivery was decreased by isovole- oxygen delivery were manipulated independently to de- mic dilutional anemia, hypoxic gas mixtures, termine if DO,,, is dependent upon the component that or cardiac tamponade to reduce cardiac output. Base- is altered. In addition total body oxygen consumption line VO, (cc/hg/min) for the three groups was 5.9 f 0.7 was measured independently of oxygen delivery. Volu- (anemia), 5.4 + 0.4 (hypoxia), and 5.6 f 0.1 (low C.O.) metric spirometry was used to measure oxygen con- (NS). A critical level of oxygen delivery (DO,& was sumption while oxygen delivery was calculated from found at 9-10 cc/kg/min (anemia), lo-11 cc/kg/min thermodilution cardiac output and arterial oxygen con- (hypoxia), and 9-10 cc/hg/min (low C.O.) (NS.). Below tent. In order to analyze the data in a statistically valid this level, VO, fell (became supply dependent) and lac- fashion, a method of interpolation was applied to the tic acidosis occurred, regardless of the mechanism of data set. impaired oxygen delivery. 0 1991 Academic Press, Inc. The hypothesis of this experiment is that DOZctit is independent of the method by which DO, is reduced.

INTRODUCTION METHODS Mammalian studies have identified critically low lev- els of oxygen delivery (DO,) below which total body oxy- Experimental Design. gen consumption (VO,) is dependent upon oxygen deliv- (See Fig. 1) Mongrel dogs (15-20 kg) were fasted over ery and above which oxygen consumption is indepen- night, anesthetized with pentobarbital (15 mg/kg), and dent of oxygen delivery [l-5]. This critical level of ventilated with a volume ventilator to a pCOZ of 30-45 oxygen delivery (DO,,,,) is much lower than the normal mm Hg. FiO, was 0.3-0.5 except in the induced hypoxia DO, for any species and is associated with lactatemia, group. Supplemental pentobarbital was given through- acidosis, and hypotension. out the experiment to ablate the inner canthal reflex. In previous studies, the three components of oxygen Temperature was maintained at 37.5”C by external delivery (, arterial oxygen content, and car- warming. A right groin dissection was performed for in- diac output) have not been manipulated independently. troduction of an 8 French arterial catheter for arterial Also, in most studies, the same measured variable was blood sampling and systemic arterial blood pressure used to calculate both oxygen delivery and oxygen con- monitoring. An injectate catheter for cardiac output de- sumption. Either cardiac output and blood oxygen con- termination was positioned in the right atrium via the tent were measured and used to calculate oxygen con- right femoral vein. A balloon-tipped pulmonary artery sumption by the Fick relationship or oxygen consump- catheter with a thermistor was inserted through the tion was measured and used similarly to calculate right external jugular vein for measuring cardiac out- cardiac output in order to determine oxygen delivery. In puts. Position was confirmed by identifying the pulmo- nary artery pressure tracing that changed to a pulmo- 1To whom reprint requests should be addressed at Pediatric Sur- nary capillary wedge pressure tracing with 1 ml air in- gery, L2110 University of Michigan Medical Center, 1500 E Medical jected into the balloon. Additionally, the catheter was Center Drive, Ann Arbor, MI 48109-0245. palpated in the pulmonary artery at autopsy.

425 0022-4804/91 $1.50 Copyright 0 1991 by Academic Press, Inc. All rights of reproduction in any form reserved. 426 JOURNAL OF SURGICAL RESEARCH: VOL. 51, NO. 5, NOVEMBER 1991

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FIG. 1. Experimental diagram. Ventilator-respirometer measures VO,; cardiac instrumentation.

A right subcostal incision was then performed and the into the pericardial catheter to maintain cardiac output spleen was removed. Splenectomy was performed to pre- at baseline levels. Oxygen consumption was measured at vent splenic autotransfusion. A small area of pericar- progressively lower levels of oxygen delivery as the dogs dium was exposed through an incision in the right hemi- became more anemic. When very low levels of oxygen diaphragm and an 8 French catheter was secured inside delivery were reached, below the critical level of oxygen the pericardium by a purse string suture for the portion delivery, oxygen consumption fell and hemodynamic in- of the experiment requiring tamponade. stability occurred. To acquire more data points above The animal was then attached to the ventilator respi- and below the DO,,, , some dogs were resuscitated with rometer (see below, measurement of VO,) and sequen- whole blood to raise their oxygen delivery and return tial oxygen consumption measurements were performed their oxygen consumption to baseline. These animals over a 3-8 hr period during which oxygen delivery was were then bled further and data collection continued. As manipulated as described below. Dogs were assigned to cardiac output fell at very low levels of DO,, tamponade one of three experimental groups. In Group I seven dogs was released in an effort to keep the cardiac output at were made anemic with oxygenation and cardiac output baseline levels. All animals eventually died of heart fail- constant. In group II five dogs were made hypoxic at ure secondary to anemia and low DO,. constant hemoglobin and cardiac output. In Group III Hypoxia. Animals were made hypoxic by adding ni- four dogs underwent cardiac tamponade by injection of trogen to the ventilator-respirometer to decrease the isotonic saline into the pericardium to reduce cardiac FiO, in the apparatus. FiO, was changed in 2% incre- output at constant oxygenation and hemoglobin. ments until very low levels of DOz were reached. Ani- mals were returned to the original FiO, to confirm that Manipulation of Oxygen Delivery baseline VO, had not changed when DO, was above DOzctit. The lowest levels of oxygen delivery were inves- Anemia. Whole blood was removed from Group I tigated immediately prior to death from hypoxia. Car- animals in 200-ml aliquots followed by crystalloid re- diac tamponade was used to prevent the compensatory placement to return pulmonary capillary wedge pressure increase in cardiac output that occurs with hypoxia. As to the baseline level. As the dogs became anemic and DO, was lowered by hypoxia, marked respiratory muscu- began to develop tachycardia and increased cardiac out- lar activity was noted at very low DO, (

TABLE 1 changes in oxygen delivery in each group was analyzed. Coefficients of correlation between the changes in each Baseline Hemodynamic and Oxygenation Parameters in Anemic, Hypoxic, and Low C.O. Groups component of DO, and the changes in total DO, for each group are given in Table 2. Changes in DO, were due Group Anemia Hypoxia Low C.O. almost exclusively to the changes in SaO, in the “hyp- oxic group” (r = 0.91) and to CO in the “low cardiac 7 5 4 output group” (r = 0.98). Changes in DO, correlated : 04 16.6 + 1.2 18.2 -c 2.4 19.4 f 0.9 most highly with the changes in hemoglobin in the “ane- t (“C) 37.5 + 0.8 37.7 -c 0.6 37.6 -c 0.6 SBP (mm Hg) 186 -t 16 175 ? 32 173 * 45 mic group” (r = 0.78). DBP (mm Hg) 111 + 15 110 * 13 95 + 29 HR (min-‘) 169 + 24 183 ? 17 157 f 49 DO, and VO, Relationships PCWP (cmH,O) 10 * 3 9+3 6+3 TDCO (cc/kg/min) 172 k 38 156 + 38 141 r 65 The biphasic relationship between VO, and DO, is PH 7.38 k 0.05 7.33 * 0.05 7.34 k 0.05 illustrated for the anemic, hypoxic, and low cardiac out- PCO, 36 + 5 40 + 4 34 f 4 put group (Fig. 2). VO, values for every DO, interval PO, 163 + 118 122 + 50 166 + 125 were calculated using the method of interpolation. The Hb k/cU 13.7 + 2.7 17.5 + 3.1 14.5 + 4.1 VOz (cc/kg/min) 5.9 -t 0.7 5.4 + 0.7 5.6 + 0.05 statistical analysis used to determine the DO,,, for each Lactate (mmole/liter) 1.8 + 1.9 1.3 t 0.7 2.6 + 1.0 group is presented in Table 3. DO,,i, occurred in the 9-10 ml/kg/min interval for the anemic group, since Note. Differences are not significant. above this interval VO, does not differ significantly from the baseline; at and below 9-10 ml/kg/min, VO, values are significantly below baseline. The DO,,, for the hyp- interval when no data points were measured in that in- oxic group occurred in the lo-11 cc/kg/min interval, al- terval. Interpolated values were determined by compar- though two lower DO, values had VO, values which did ing the measured VO, values at the DO, interval higher not differ significantly from baseline because of the large and lower than the interval in question, and assigning standard deviation in these intervals and the degrees of the greater value of VO, to the interval. This method freedom imposed by the sample size. The DOZtit for the biases the interpolated values to not differ from baseline low cardiac output group occurred in the 9-10 cc/kg/min VO,. Group average values of VO, were determined for interval. each 1 cc/kg/min DO, interval using measured and in- The DO,/VO, relationships of the three groups are terpolated values. In each group a 1 tailed paired t test compared in Table 4. The differences between interval was used to compare the VO, of each interval to the VO, and baseline VO, were compared in each DO, inter- baseline VO,. The critical level of oxygen delivery was val. The analysis shows that the relationship between defined as the highest DO, interval at which a signifi- DO, and VO, is not statistically different between cant decrease from baseline was seen at the P < 0.05 groups at the interval of the DO,,, and all other DO, confidence level. The three groups were then compared intervals, except the anemic and low cardiac output using a one-tailed paired t test. The relationships be- groups in the DO, 12-13 cc/kg/min interval. tween serum lactate and DO,, and PvO, and DO,, were similarly analyzed. DO, and Serum Lactate Relationships All animals were cared for under guidelines estab- Serum lactate concentrations for the three groups are lished by the University of Michigan Unit for Labora- shown in Fig. 3. The biphasic relationships similar to tory Animal Medicine. that of VO, is readily apparent. The method of interpo- lation was applied to lactate levels at 1 cc/kg/min DO, RESULTS intervals to determine the DO, level at which lactate Comparison of Anemic, Hypoxic, and Low Cardiac Output Groups TABLE 2 The initial hemodynamic and oxygenation measure- ments prior to manipulation for each group are given in Correlation Coefficients between Percentage Change Table 1. No significant differences among the groups in DO, in Sequential Measurements and Percentage Change in Component of DO2 for Each Group of Experi- were present at baseline. In the anemic group, the lowest mental Animals level of hemoglobin obtained was 2.6 + 0.5 g/dl. The lowest p,O, achieved in the hypoxic group was 22 f 4 DO,:HB DO,:SaO, DO&O. mm Hg. Cardiac output was reduced to 34 f 11 cc/kg/ min in the low cardiac output group. To determine if the Anemic group 0.78 0.40 0.52 three groups were indeed separate, the influence of he- Hypoxic group -0.34 0.91 0.11 Low C.O. group -0.16 0.16 0.98 moglobin, arterial saturation, and cardiac output on the CILLEY ET AL.: CRITICAL DO,: ANEMIA, HYPOXIA AND LOW C.O. 429

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FIG. 2. VO, vs DO, in anemic hypoxic and low C.O. groups; numbers correspond to individual animals. increased above baseline. Again the DO, levels at which DISCUSSION lactate rises significantly above baseline are 9-lO, lO-ll, and 9-10 cc/kg/min for anemic, hypoxic, and low car- The relationship between oxygen delivery and oxygen diac output groups, respectively. The levels do not differ consumption in mammalian models is bimodal. Oxygen significantly when the groups are compared. consumption is independent of delivery above a critical level of delivery, while below the critical level of oxygen DO, PvO, Relationships delivery, oxygen consumption becomes dependent upon delivery. Adams et al. observed a critical value of oxygen The partial pressure of oxygen in pulmonary arterial delivery in the rat of 23 cc/kg/min, with a baseline VO, blood for the three groups is shown in Fig. 4. Statistical of 17.9 cc/kg/min [2]. Below this value oxygen con- analysis employed after interpolation demonstrated no sumption was apparently linearly dependent upon oxy- difference between the anemic and low cardiac output gen delivery. Their methods involve the measurement group at any interval. The hypoxic group had a signifi- of oxygen consumption and the calculation of oxygen cantly lower PvO, at every DO, interval, including the delivery using the Fick relationship. The critical value D%rit . was well below the normal range of oxygen delivery in the rat. Thermodilution Cardiac Output us Fick Calculation of Critical levels of oxygen delivery have been deter- Cardiac Output from VO, mined in other animal models. Oxygen consumption fell and acidosis developed in fetal lambs below fetal oxygen The thermodilution cardiac output determination for delivery rates of 13.4 cc/kg/min in one study and 12-15 each data collection was compared to the cardiac output cc/kg/min in another with baseline VO, calculated by calculated from the oxygen consumption and arterial the Fick method at 7-8 cc/kg/min [4,5]. and venous oxygen contents (Fick method). Analysis of Using independently measured oxygen delivery (ther- variance revealed a correlation coefficient of .93. The modilution cardiac output, arterial oxygen content cal- thermodilution cardiac output averaged 19% higher culated from PO,, and hemoglobin) and VO, (mixed ex- than the Fick calculation. pired gas analysis), Pepe and Culver found DO,,, of 13.0 430 JOURNAL OF SURGICAL RESEARCH: VOL. 51, NO. 5, NOVEMBER 1991

TABLE 3 elusion drawn was that the ability of tissues to extract oxygen is dependent upon the absolute quantity of oxy- Determination of DOacrit: Comparison of VO, at Suc- cessive DO, Intervals with Baseline VO, for Anemic, gen delivered to the tissues and not on the p0, within the Hypoxic, and Low C.O. Animals tissue itself. At DO,,, anemic animals had significantly higher mixed venous oxygen tension than the hypoxic Mean difference between animals (45 vs 17 ml mm Hg, respectively). DO, interval interval and baseline VO, Significance Simmons et al. studied the blood lactate levels in dogs Anemia subjected to hypoxia and low cardiac output states [9]. 3-4 -2.2 f 1.00 P < 0.05 They failed to lower the oxygen delivery to the DO,,, 4-5 -2.1 -c 1.07 P < 0.05 level in their “reduced cardiac output” group. It is not 5-6 -1.9 k 0.91 P < 0.05 surprising that increased lactate was not found in this 6-7 -0.9 k 0.49 P < 0.05 group. In their hypoxic group in which the oxygen deliv- 7-8 -0.8 I!I 0.56 P < 0.05 8-9 -0.6 -+ 0.56 P < 0.05 ery did fall to the levels of DO,,,, elevated lactate was 9-10 -0.4 + 0.26 P < 0.05 found (DO, < 10 cc/kg/min). 10-11 -0.06 f 0.34 NS Lister has studied oxygen delivery and consumption 11-12 -0.04 k 0.34 NS 12-13 0.06 + 0.18 NS in conscious lambs at varying postnatal ages. In a study 13-14 -0.04 + 0.40 NS in which oxygen delivery was lowered by decreasing car- diac output, critical levels of oxygen delivery of 11.0 cc/ Hypoxia kg/min were found in lambs four weeks of age [lo]. Us- 4-5 -1.8 + 1.01 P < 0.05 ing a similar preparation oxygen delivery was decreased 5-6 -2.0 f 0.44 P < 0.05 by hypoxia in a group of chronically instrumented lambs 6-7 -0.9 * 0.94 NS 7-8 -0.7 f 0.73 NS 8-9 -0.3 k 0.26 P < 0.05 9-10 -0.3 f 0.26 P < 0.05 10-11 -0.2 f 0.19 P < 0.05 TABLE 4 11-12 -0.1 + 0.17 NS Comparison of DO,:VO, Relationship among Anemic, 12-13 -0.1 + 0.17 NS 13-14 -0.1 + 0.17 NS Hypoxic, and Low C.O. Groups

DO, Interval Anemia Hypoxia Significance Low C.O. 5-6 -2.2 f 0.95 P < 0.05 4-5 -2.1 f 1.14 -1.8 + 1.01 NS 6-7 -1.3 + 1.04 P < 0.05 5-6 -1.9 r 0.83 -2.0 + 0.19 NS 7-8 -0.9 + 0.62 P < 0.05 6-7 -1.0 + 0.24 -0.9 * 0.89 NS 8-9 -0.6 + 0.30 P < 0.05 7-8 -0.9 & 0.31 -0.7 + 0.53 NS 9-10 -0.6 IL 0.46 P < 0.05 8-9 -0.7 + 0.31 -0.3 f 0.67 NS 10-11 -0.3 + 0.30 NS 9-10 -0.4 + 0.66 -0.3 + 0.67 NS 11-12 -0.3 + 0.32 NS 10-11 -0.6 + 0.12 -0.2 * 0.04 NS 12-13 -0.2 + 0.29 NS 11-12 -0.4 f 0.12 -0.1 f 0.28 NS 13-14 0.00 f 0 NS 12-13 -0.6 k 0.33 -0.1 + 0.30 NS 13-14 -0.4 zk 0.16 -0.1 + 0.30 NS Hypoxia Low C.O. Significance cc/kg/min and VO, of 5.5-8.0 cc/kg/min in dogs [6]. When DO, was decreased by PEEP, by venous inflow 4-5 -1.8 f 1.01 -2.5 f 1.28 NS occlusion (both resulting in decreased cardiac output) or 5-6 -2.0 + 0.19 -2.2 f 0.91 NS by oleic acid injury (resulting in hypoxia) the DOzctiit 6-7 -0.9 k 0.89 -1.3 t 1.1 NS values were not significantly different. In our previous 7-8 -0.7 + 0.53 -0.9 + 0.39 NS 8-9 -0.3 k 0.67 -0.9 + 0.89 NS study using another technique of independent measure- 9-10 -0.3 IL 0.67 -0.6 + 0.21 NS ments of DO, and VO,, we found the DO,,, in anesthe- 10-11 -0.2 f 0.04 -0.3 + 0.87 NS tized dogs with a baseline VO, of 5.8 cc/kg/min to be 11-12 -0.1 k 0.03 -0.3 + 0.10 NS 8.0 [7]. 12-13 -0.1 t 0.03 -0.2 + 0.83 NS In studying low oxygen delivery states produced by Anemia Low C.O. Significance anemia and hypoxia, Cain used mixed expired gas analy- sis to measure VO, and calculated cardiac output from 4-5 -2.1 + 1.14 -2.5 f 1.28 NS the VO, and arterial-venous oxygen content difference 5-6 -1.9 + 0.83 -2.2 -c 0.9 NS 6-7 -1.0 k 0.24 -1.3 * 1.08 NS [ 11. He found the critical level of oxygen delivery to be 7-8 -0.9 iz 0.31 -0.9 f 0.39 NS 9.8 cc/kg/min in paralyzed, anesthetized dogs with a 8-9 -0.7 -c 0.31 -0.6 k 0.89 NS VO, of 6.2-6.4 cc/kg/min. DO,,, was determined by lin- 9-10 -0.4 + 0.66 -0.6 f 0.21 NS ear regression of VO, values which were pooled from 10-11 -0.6 + 0.12 -0.3 f 0.87 NS several experiments. There was no difference in the 11-12 -0.4 -t 0.12 -0.3 + 0.10 NS 12-13 0.6 k 0.03 -0.2 * 0.82 P < 0.05 DO,,,, found in the anemic or hypoxic group. The con- CILLEY ET AL.: CRITICAL DO,: ANEMIA, HYPOXIA AND LOW C.O. 431

ANEYIA

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0-t 1 I I I 0 10 20 30 40 DO2 (cc/kg/min)

FIG. 3. Lactate vs DO, in anemic hypoxic and low C.O. groups; numbers correspond to individual animals.

[ 111. The critical level of oxygen delivery at age 25-40 Further evidence that the DO,,, has the same physio- days was found to be 10.2 cc/kg/min. This further sup- logic implication in anemic, hypoxic, and low cardiac ports the finding that the limitation in tissue utilization output states comes from analysis of serum lactate con- of oxygen is dependent upon the total delivery of oxygen centrations. In these previously healthy animals, in- to the tissue and not upon the method in which delivery creased lactate production occurred concurrently with is limited. supply-dependent oxygen delivery. Lactate production The current study failed to demonstrate differences in increased at delivery levels lower than the DOzctiit and did the DOzcrit when the components of oxygen delivery were not differ significantly among the groups. This “anaero- independently varied. The implication of these findings bic threshold” or “shock state” is defined by the DO, is that the absolute level of whole body oxygen delivery is and not by an absolute level of hemoglobin, PO,, or car- of greater importance than the particular value of hemo- diac output. The implication in clinical physiology is globin, arterial PO,, or cardiac output in preventing de- that DOPcrit is a physiologic definition of nonseptic livery dependence and lactic acidosis (“shock”). The ex- shock. perimental animals developed lactic acidosis and hypo- In the current study whole body oxygen consumption, tension below the DO,,, regardless of how the low oxygen delivery, and lactate were measured. Reduction delivery state was achieved. There was no absolute hemo- in the components of oxygen delivery may have different globin value, p0, value, or level of cardiac output that effects on different organs. This does not imply that all was of itself detrimental. There are obvious practical tissues and organs respond identically to decreased total limits to these findings determined by rheology, the oxy- body oxygen delivery. The effect of manipulating the gen-carrying capacity of blood, and the limits of cardiac components of oxygen delivery on individual organ performance. (1) Hemoglobin cannot be increased indefi- blood flow and function requires further investigation. nitely to compensate for hypoxia and low cardiac output. (2) If hemoglobin is saturated with oxygen, dissolved ox- Methods ygen can only increase the arterial oxygen content slightly in anemia and low flow states. (3) Cardiac out- Closed circuit spirometry was used to directly measure put can only compensate to a point for hypoxia and whole body VO,, and thermal dilution cardiac output anemia. was used to calculate DO,. The technique of closed cir- 432 JOURNAL OF SURGICAL RESEARCH: VOL. 51, NO. 5, NOVEMBER 1991

ANEMIA b ments could be made, increasing the likelihood of error. The thermal dilution cardiac output determination is 6 , 1 5 subject to numerous errors [ 121. Standardization of tech- 2 nique will result in reproducible results. The possibility of systematic error with thermal dilution cardiac out- puts is real. The thermal dilution cardiac output

30. ’ 6 2 (TDCO) was consistently 19% higher than the Fick cal- Pv4 2 3 db? culated cardiac output without obvious explanation. . (mm Hg) ’ 5 42. The r value of 0.93 shows close correlation between the 20- “b?%l two, however. We have used TDCO to calculate DO, for methodologic reasons as noted above. It is clear that our 1 results would be similar if we had calculated DO, from the Fick VO, accepting the mathematical coupling in- volved. The only difference would be a lowering of the ‘II:0 10 20 30 40 50 DO, values. Ideally studies of VO, and DO, should avoid all phar- HYPOXIA macologic agents that affect these variables. Anesthetic 2 4 1 6 agents have been used in most previous studies reported. 3 The light pentobarbital anesthesia used in this experi- 1 3 ment may affect both cardiac output as well as whole 40. 3 6 body oxygen consumption. Pharmacologic paralysis was 2 2 ‘5 I, avoided as much as possible; however, strong reflexes 43 stimulating marked muscular activity at the lowest lev- els of DO, induced by hypoxia necessitated paralysis under these circumstances.

Were the Groups Really Separate? 10. Normal compensatory mechanisms respond to falling 0-l . , , . , . , . , levels of oxygen delivery. The most common is an in- 0 10 20 30 40 50 crease in cardiac output seen initially in response to ane- mia and hypoxia. The response may not be seen if ane- mia is accompanied by hypovolemia or if insufficient LOW CARDIAC OUTPUT cardiac reserve is present. At the extremes of hypoxia, cardiac output will also fall. Splenectomy was used to prevent reflex splenic autotransfusion that occurs in ca- nines. Cardiac tamponade was a simple method of re- stricting cardiac output when necessary. The analysis presented in Table 2 indicated that the desired result was largely achieved but it is clear that low cardiac out- put was partially responsible for the decrease in DO, in the “anemic” group.

Statistical Analysis Previous studies have determined DO,, by adapta- tions of curve-fitting techniques. These adaptations * I I. I I I have been as simple as the best visual guess [4]. Others 0 10 40 50 have used the intersection of regression lines below the Do:(cclk&i”) DO,,, with regression lines above the DO,, [l, 3,6,10, FIG. 4. PvO, vs DO2 in anemic hypoxia and low C.O. group; num- 111. Polynomial curve-fitting techniques using com- bers correspond to individual animals. puter analysis likewise generate numerical values for “inflection points” [ 131. Using the method of interpola- tion, the VO, for any given DO, interval is assigned a cuit spirometry is very accurate; however, it does depend value for each experimental animal. A mean and stan- upon a steady state VO, over the measurement interval. dard deviation are then calculated for that interval al- At the lowest levels of oxygen delivery animal deteriora- lowing a valid statistical comparison to other DO, inter- tion limited the time over which replicate VO, measure- vals. This method seeks an inflection point by asking the CILLEY ET AL.: CRITICAL DO,: ANEMIA, HYPOXIA AND LOW C.O. 433

question, “Does the VO, value for this interval differ 2. Adams, R. P., Dieleman, L. A., and Cain, S. M. A critical value significantly from the VO, value assigned as the base- for 0, transport in the rat. J. Appl. Physiol.: Respir. Environ. line?” The method assumes that the baseline VO, is de- Exercises Physiol. 53(3): 660, 1982. livery independent. The DO,,, generated by this 3. Shibutani, K., Komatsu, T., Kubal, K., et al. Critical level of oxygen delivery in anesthetized man. Crit. Care Med. 11(8):640, method can be compared in a valid statistical fashion 1983. with one another. The results are likewise dependent 4. Wilkening, R. B., and Meschia, G. Fetal oxygen uptake, oxygen- upon the size of the DO, interval. In this case the inter- ation, and acid-base balance as a function of uterine blood flow. val of 1 cc/kg/min was chosen because smaller intervals Am. J. Physiol. 244 (Heart Circ. Physiol. 13) H749, 1983. did not change the results. It is of note that when curve- 5. Itskovitz, J., LaGamma, E. F., and Rudolph, A. The effect of fitting techniques are applied to the pooled data from all reducing umbilical blood flow on fetal oxygenation. Am. J. Ob- experiments the conclusions would be unchanged as can stet. Gynecol. 146: 813, 1983. be seen from Figure 2. The method of interpolation al- 6. Pepe, P. E., and Culver, B. H. Independently measured oxygen lows these conclusions to be reached in a more statisti- consumption during reduction of oxygen delivery by positive end-expiratory pressure. Am. Rev. Respir. Dis. 132: 788, 1985. cally valid fashion. 7. Cilley, R. E., Polley, T. Z., Zwischenberger, J. B., Toomasian, J. M., and Bartlett, R. H. Independent measurement of oxygen CONCLUSIONS consumption and oxygen delivery. J. Surg. Res. 47: 242,1989. 8. Annat, G., Viale, J. P., Percival, C., Froment, M., and Moting, J. In anesthetized dogs, oxygen delivery (DO,) and oxy- Oxygen delivery and uptake in the adult respiratory distress syn- gen consumption (VO,) was measured by independent drome. Am. Rev. Respir. Dis. 133: 999, 1986. methods. The resting VO, was 5.4-5.9 cc/kg/min. When 9. Simmons, D. H., Alpas, A. P., Tashkin, D. P., et al. Hyperlactate- mia due to arterial hypoxemia or reduced cardiac output, or both. oxygen delivery was decreased by anemia, hypoxia, or J. Appl. Physiol.: Respir. Environ Exercise Physiol. 45(2): 195, cardiac tamponade, a critical level of oxygen delivery 1978. (DO,,,,) was found at approximately 10 cc/kg/min in all 10. Fahey, J. T., and Lister, G. Postnatal changes in critical cardiac three groups. Lactic acidosis, and decreased (supply de- output and oxygen transport in conscious lambs. Am. J. Physiol. pendent) VO, occurred when the DO,, baseline VO, ra- 253 (Heart Circ. Physiol. 22): HlOO, 1984. tio was below 1.8:1, regardless of the mechanism of im- 11. Moss, M., Moreau, G., and Lister, G. Oxygen transport and me- paired oxygen delivery. tabolism in the conscious lamb: The effects of hypoxemia. Pe- diatr. Res. 22: 177, 1987. 12. Levett, J. M., and Replogle, R. L. Thermodilution cardiac out- REFERENCES put: a critical analysis and review of the literature. J. Surg. Res. 27: 392, 1979. 1. Cain, S. M. Oxygen delivery and uptake in dogs during anemic 13. Gutierrez, G., Warley, A., and Dantzker, D. R. Oxygen delivery and hypoxic hypoxia. J. Appl. Physiol. Respir. Environ. Exercise and utilization in hypothermic dogs. J. Appl. Physiol. 60: 751, Physiol. 42(2): 228, 1977. 1986.