v v v 47 I u . 3'1‘13. .“f‘ 5“.’o o I v 5 r 1' :01 <\ .( 1 .1 . . no ~ . 1!1l‘. . all 1 1 .r. V: 1. .1 x n... 151511111 1! . . .1 ‘ 1 of on! u 1' .1.” o o ‘15.... .01....!¢111.J..1J.1lfi.1glls D I . 1 .1 1 I l lo‘d l. (i!\.l.. _ l 1. 1 . 1741‘. .1. 1 v 4 .- 0 I1 . .1 - 1 . .1 1 .. . ..1 .21. . 1. 1.. 1.. :1I ; r v 1 .10 l. Itasr1o|.. v a 11 11|1 1: .o 11 z .7... l .10 n. 51.1 .v 1 4o .11 11'; 1!. l 1 .. a. 1 .i1v'r..1.l 1.1.1 ....'~ol.~ 1‘1 .11 '- V I r a 1:1 1......1 . . o 1.1! (5.1.11 1 1 11. 1 .u; .11- 1 11:...) 1,111....11w14111111M 1911‘! 1 71.... 1. 1 o 1!». .u.-l1l|lr.o.l.ov,11U..n . o l. 1 1. 1 . .1?.‘I1!.lf!9.1«.h1k.ao...1.. at” ..|.\H§1)I.o1 Q‘v 1.1‘.-o.1r . - n c ' '1‘! 1 I . o .0” U1.oa> .fi!!! !.1U!1~;..\...l. . 1! 1". I‘o 1.. u l ! o 0"... VI . v1. 11 .. 1 1! _. 1 1 . I. . 11. 1 . 1, v . 1! - 111l1r1!l . 1H! I 1! 1.0!! 1.. . 1 - .-11u11ul.|||!1‘hv.!4“1 I 101‘?! .1 .1711 11". ‘1': a 1 . \ 11d. 0 ha I . . . 111 .1o.1.!.fl.olo {H.Nflmb. 1.. H1111“ ..«11.1h11.l1 .l . .41 .1 Tobi... 4§f.1!’ !l l II 1 .1 .!. I! “(‘10: I, 1 If!!!” .ffiruqfduflgfi f1. 1 IT a -1 lo, I [.13 . .1 OHIIII' 2| D1.ll!'1.h.lll"”l ! r'1'. {:40 Elk! .Iw $1. .!lr-Jol}"o 'w".l .1 o HR!JA.uIIVRo!l 1! J 1.! _ . 1 1 1.1 .l..u1q1.!..hl,.uuflflm.1. . ovll.n1 .\r.. !.. 1 all , ‘1!!! 8.1). l 1! 1 1 1o». 1 . .11 .111! I. :11! 1!. !..I11H1!o!1 for”... N1!!!) .1111! I.!o.\~1!lol.1..b.r\.!!o._!!.1. 11......1L111L1 1....1» .1: . o1 ’ 1.!.1I!.11! 1"» .JIHI!’ v! (Idirlf 1 <1 Lfl. .!I!C‘ [Alt v3.10! {1.14 13!..11J: .v u I II 'II loll 1 I . . b o . V! 1|. 1 181:!1110I11;ol. Rololnioollofiu lo éiool. _ rind P14911911“! lIF 3111 1 . r 93!- .11 If Rial} 19.1.IHIJW! {Uri-”11“}! II! 16") ‘1' ‘ cpl! ILIDOL. I‘ll: '1 1 ! 1 11 11-111! 1 1! l . mmflmflklo! .l!11.1.1!1..1..1 11 11 Nahum” 11.. . . , . 1 1 o, 3' 1 L .117 . '15.”, 111:] .1 Ito! . 1 yo 1 mm 1... . 1!!dR11:..1rF11fl111lo!11u.1u1u9u1 lbw!!!“ 111. .1111 !.Nuotrl.ol11!§.l!o OJ oi O‘III b o l v '3”. «I 0“ 11 1. 1, o unflofldrflflhu l1u1mufls1 ’ lo” I o ‘1! 1V.- . H1! - ”g1 Romafiorwol . 1 lynRerumflwx l.-l!111fi1fld!1M1K 1 1 - - flg1lxull1illflbdm! “Nico!!! (A Ell - v ,1! !1 L1! 1 . o 1 1dnlo %!Hol! -Ol !.1‘ll1 #(T‘. ‘ 1 l .0! ‘11} I I . . r I?!" 1H1!11H- !.I I. I l 1 1 o p . u 1 no. . N o a I . n 1 1 1o 1 I! C . I. 11 1 111.1 111 bu..- . c 14 1‘ 11!} . v. .111 1 1o 1. 711. v1 . 1 I 1 1 1 loan”. .1 1 . 1 . 1: . 1 . 1. 1. . ontll. ~o I A: .10 | l O! 1 I . k? l. . 1 . v 1 1 o o 1 g 5 1 '111 .1 .I .1 1. I. L. 1 1‘ l1 . fl... .1 1. . I 1. o .\ 1.1 a I l . a . .1 .. I I: ‘ I 1! l 1 1‘11. TIMUUI‘ 2.111 1J1- "obfuwuv 1. o 1. ll! "Ilh..f|.!o\olill'.l I‘RHN). IL? {In W l {no 1 n. rll o ... Iggth . “11 .r: u . . .. IhIIHth3hfir-1llll1lhd 1 1 N1! 11 I14. . I 4 .|o'n4‘!o‘}- t. .Iu.‘!|‘.l ”. .‘.ol..l’u” .‘ l . u. k . . ouflmgrldfl W111R 1.11J11umr11a..uo!k1¢ll!1.1111,1l 1 .. 1 1 n I «11 V on "I! '1 1‘. (IIJHVJIY1 1. v I n o l 1 111 Iowan. 11”"! .1! l !. I l . 1 I I. . ' o.fo"1fl.1\ .0 o l!- lvl..! 1 N I ‘ - '¥;l-‘:w!2~ lIBRARY Michigan State ¢ University This is to certify that the thesis entitled Evaluation Of Mixed Venous Oxygen Tension As An Estimate 0f Cardiac Output In Anesthetized Horses presented by Lois Ann Netmore has been accepted towards fulfillment of the requirements for Master of Science degreein Large Animal Clinical Sciences / Major professor Date August 4, 1987 0-7 639 ‘IVIESI—J RETURNING MATERIALS: Place in book drop to Lian/muss remove this checkout from —-c—. your record. FINES will be charged if book is returned after the date stamped below. EVALUATION OF MIXED VENOUS OXYGEN TENSION AS AN ESTIMATE OF CARDIAC OUTPUT IN ANESTHETIZED HORSES BY Lois Ann Wetmore A THESIS Submitted to Michigan State University in partial fulfillment of the requirements for the degree of MASTER OF SCIENCE Department of Large Animal Clinical Sciences 1987 ABSTRACT EVALUATION OF MIXED VENOUS OXYGEN TENSION AS AN ESTIMATE OF CARDIAC OUTPUT IN ANESTHETIZED HORSES BY Lois Ann Wetmore The relationship between mixed venous 02 tension and cardiac output was studied in six anesthetized horses breathing 100 percent 02. Cardiac output, 02 consumption, mean arterial pressure, heart rate, and arterial and venous blood gases were measured after administration of xylazine or dobutamine to horses in lateral, eternal and dorsal recumbencies. At the end of the approximately three-hour experimental period, Escherichia coli endotoxin was administered while horses were in dorsal recumbency, and all measurements were repeated. Relationships between cardiac index (CI) and P902, heart rate, mean arterial pressure, jugular PVOZ, and PVO2 of blood from a super- ficial limb vein were evaluated by linear regression analysis. Mean arterial pressure was significantly (P< 0.05) correlated with CI in horses in all positions and after endotoxin administration. However, data points were poorly grouped. Heart rate and CI were significantly Lois Ann Wetmore correlated in all horses in all positions but not after endotoxin administration. The correlations between jugular on2 and PVO2 of blood from a superficial limb vein were not significant in horses in sternal recumbency, and PVO of blood from a superficial limb vein was not significantly correlated with CI in horses in lateral recumbency. There was a significant and tight correlation between PVC and CI in horses in all positions and after endotoxin administra- tion. DEDICATION To my mother, Hanna Ivory Wetmore ii ACKNOWLEDGMENTS I wish to express my sincere gratitude to Dr. Frederik J. Derksen, my major advisor, for his guidance, enthusiasm and assistance in the preparation of this thesis. I am also indebted to Drs. Cheryl A. Blaze, George E. Eyster, and N. Edward Robinson, members of my graduate committee, for their assistance, counsel and constructive criticism. I am grateful to Roberta Milar and Cathy Berney, Pulmonary Lab Technicians, for their assistance. I wish to thank Margaret R. Hoffman, the graphic artist, for her expertise and patience in preparing the graphs. I also thank Kathryn Sayles Winsky, Antoinette Tenlen, Martha Devlin and Karen Schiffer for their clerical expertise in preparing the manuscript that is a portion of this thesis. Funding for this project was provided in part by a grant from the Jesse Smith Noyes Foundation. iii TABLE OF CONTENTS LIST OF TABLES .'. . . . . . . . . . . LIST OF FIGURES . . . . . . . . . . . INTRODUCTION . . . . . . . . . . . . . LITERATURE REVIEW . . . . . . . . . . 1. Cardiac Output Measurements in Horses . . . . . . . . . 2. Application of the Pick Principle for Estimation of Cardiac Output a. The Use of A-VOz Difference to Estimate CO . . . . . b. The Use of 8602 to Estimate c. The Use of PVOZ to Estimate MATERIALS AND METHODS . . . . . . . . Horses . . . . . . . . . . . . . . Measurement techniques . . . . . . Experimental design . . . . . . . . Statistical analysis . . . . . . . RESULTS . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . CONCLUSIONS . . . . . . . . . . . . . FOOTNOTES . . . . . . . . . . . . . . LIST OF REFERENCES . . . . . . . . . . iv CO . CO . page vi 19 24 24 24 28 30 32 47 52 54 LIST OF TABLES page Table 1. Cardiac Output Values in Standing Horses . . . . . . . . . . 4 Table 2. 3 x 3 latin square design describing random sequencing of recumbencies . . . . . . . . . . 29 Table 3. Cardiovascular measurements after xylazine (0.65 to 1 mg/kg) and after dobutamine administration (1 to 7 ug/kg/min) and 15 minutes after endotoxin administration (100 ug/kg) in six anesthetized horses . . . . . . . . . . . . . . 33 Table 4. The R values for linear regression analysis of CO or CI and cardio- vascular variables . . . . . . . . 45 Table 5. The R values for linear regression analysis of cardiac index and cardiovascular variables in each recumbency . . . . . . . . . . . . 46 Figure Figure Figure Figure Figure Figure LIST OF FIGURES Equipment used for measurement of oxygen consumption . The relationship between mixed venous 02 tension (PV02) and‘ cardiac index (CI). . . The relationship between jugular venous 02 tension (PVO JUG) and cardiac index (CI). . . The relationship between peripheral venous 02 tension (PV?2 PERI and cardiac index (CI The relationship between heart PH) rate (HR) and cardiac index (CI). The relationship between mean arterial blood pressure (MAP) and cardiac index (CI). vi page 26 35 37 39 41 43 INTRODUCTION A decrease in cardiac output is in part responsible for complications related to equine anesthesia including post- anesthetic recumbency myOpathy and increased alveolar- arterial oxygen tension differences. Horses that require emergency anesthesia for repair of acute gastrointestinal or reproductive disorders frequently have concurrent hemo- dynamic instability. In all these cases, intraoperative monitoring of cardiac output is desirable. Cardiac output in the horse has been measured directly and indirectly. Direct measurement of cardiac output is not clinically applicable. Indirect measurements of cardiac out- put have been made using indicator dilution methods and the Fick principle. Indicator dilution measurements of cardiac output are not routinely performed on anesthetized horses because these measurements require specialized equipment and technical familiarity with catheter placement and use of the equipment. Measurement of cardiac output (CO) using the Pick principle requires measurement of oxygen consumption (902) and the oxygen content of arterial and mixed venous blood. V02 CO = arterial 02 content - mixed venous 02 content 2 Where the content of oxygen (C02) in mixed venous or arterial blood is calculated from the following formula requiring hemo- globin content in gm/lOO ml blood (Hb), the 02 saturation of the hemoglobin ($02) and the oxygen tension in the blood (P02). C02 = (So2 x Hb x 1.34) + (PO2 x 0.003) Measurement and calculation of these variables is too cumber- some for routine clinical use. In a steady state a decrease in CO is accompanied by a decrease in SVO2 and PVO2 if oxygen consumption and arterial oxygen content remain constant. The purpose of the present study was to investigate the use of P602 in the estimation of CO in anesthetized normal horses and in horses given a bolus of Escherichia coli endo- toxin. In addition, I examined the variability of oxygen consumption in anesthetized horses because this variability might interfere with the use of on2 in the estimation of CO. LITERATURE REVIEW 1. Cardiac Output Measurements in Horses Cardiac output in the horse was first measured using the Pick principle (Zuntz and Hagemann, 1892). Blood was taken from an artery and from the right ventricle and blood gas analyses were performed. Oxygen consumption was deter- mined by examination of expired air. From these measurements a value of approximately 75 ml/kg/min was calculated. Cardiac output measurements in horses were not reported again until 1961 when Fisher and Dalton described results of a study using an indicator dilution method previously employed in other species. Dye (Evans blue 20 mg/ml) was injected into the jugular vein over four seconds at a dose of l ml/SO kg body weight. A series of arterial blood samples were then collected from the brachial artery. Analysis of the dye content in these samples was done and cardiac output was calculated. Using fourteen horses the mean cardiac output value was again 75 ml/kg/min. Over the following fifteen years dye dilution studies for determination of cardiac output in horses were repeated with variable results (Table 1). It wasn't until 1976 that a thermodilution method for cardiac output deter- mination was described in horses (Muir, Skarda, and Milne, 1976). Cardiac output was measured in each horse by both dye dilution and thermodilution techniques. Since there are 3 Table 1. Cardiac Output Values in Standing Horses Investigators Fick principle Zuntz and Hagemann (1892) Dye dilution technique Fisher and Dalton (1961) Eberly, Gillespie and Tyler (1964) Hall, Gillespie and Tyler (1968) Eberly, Gillespie, Tyler and Fowler (1968) Gillespie, Tyler and Hall (1969) Kubo, Senta and Sugimoto (1973) Bergsten (1974) Hillidge and Lees (1975) Muir, Skarda and Milne (1976) Thermodilution Technique Muir, Skarda and Milne (1976) 75.0 75.0 90.0 97.5 82.7 82.7 56.0 76.0 88.3 73.9 72.2 Cardiac output ml/kg/min (ponies) 5 many different types of thermodilution techniques and one had not been previously described for use in horses, five differ- ent volumes of injectate at two different temperatures were studied. Results obtained by injecting 40 ml of 0°C 5% dextrose in water into the right atrium were comparable to results obtained from the dye dilution studies (Table 1). Since the report of these results, other studies using the thermodilution technique for cardiac output determination have been done (Swanson, et al., 1985; Trim, et al., 1985). Today, only thermodilution and dye dilution methods are commonly used when measurement of cardiac output in horses is required. 2. Application of the Fick Principle for Estimation of Cardiac Output In 1870, Adolf Fick (Wilson and Gibson, 1978) related cardiac output (CO), tissue oxygen consumption (902), and arteriovenous oxygen content difference (A-VOZ) in a formula, today known as the Pick principle. co=—Y(-)3— A-VOZ The A-V02 will change inversely with CO when 902 remains constant. Unless a patient is hypermetabolic, febrile, or in shock, 902 will be approximately 145 i 15 mllmin/m2 (Wilson and Gibson, 1978). Therefore, A-VOZ and variables determining this difference, such as mixed venous oxygen saturation (5x702) and mixed venous oxygen tension (Pfioz) have been used to 6 estimate CO or changes in CO. In the next section of this literature review, I will discuss the use of A-VOZ, $902 and P§02 in the estimation of CO. a. The Use of A-VOziDifference to Estimate CO In a normal resting animal A-VOZ is 4-5 ml 02/100 ml blood. When CO does not meet the demand for 02, this dif- ference will increase to greater than 6 ml 02/100 ml blood. In 1978, Wilson et al reported results of a study that investigated the use of A-VOZ difference to provide an estimate of cardiac output in 200 critical patients. venous blood from the superior vena cava rather than true mixed venous blood from the pulmonary artery was used to measure the A-V02 difference. Cardiac output was measured using a dye dilution technique and was calculated using the measured A-VOZ difference and an average V02 of 135 ml/min/mz. Calculated and measured cardiac indices were compared and calculated values were found to be approximately 23% higher than measured values. Although thisdifference was signifi- cant, there was a significant (r2 = 0.49) correlation between the measured and calculated CI values. A-V02 dif- ference and measured CI values were compared although no statistical analysis was done. There was an inverse relationship between A-VOZ difference and CI. Patients with the lowest A-V02 differences had the highest CI values and patients with the highest A-V02 differences had the lowest CI values. 7 When measured CO and A-V02 difference were used to valculate V02 and when V02 was measured in 42 patients, the V02 values were found to be quite variable. Values ranged from 63 i 32 ml OZ/min/m2 in one group to 158 1 51 m1 OZ/min/m2 in another group. Results from this paper suggest that there is an inverse relationship between A-V02 and CO, but whether A-V02 can be used to estimate CO is questionable. For any A-VOZ there is a wide range of possible CO values associ- ated with it. Variation in V02 between patients contributes to the range of values. In patients such as these with cardiovascular instabilities and systemic disease, A-VOz cannot accurately and consistently reflect CO without simultaneous V02 measurement. b. The Use of SVOZ to Estimate CO Historically, as part of the method for Fick determina- tion of cardiac output, 8602 has been recorded and noted to change as a function of CO. In a study of 36 critical patients, Cournand et al, in 1943, showed that SV02 de- creased in proportion to the decrease in cardiac output. It wasn't until the late 1950 ' s that monitoring SVO2 was pro- posed asau1alternative method for CO measurement. Various investigators studied the relationship between $602 and C1 or perfusion index in healthy subjects (Barratt-Boyes and Wood, 1957) and patients undergoing heart-lung bypass for cardiac defect repair (Moffitt et a1, 1959, and Boyd et a1, 8 1959). Each investigator noted the importance of V02 and CaOz remaining constant or near constant in order for SVOZ to accurately reflect the CO. An important point to note is that both healthy subjects and surgical patients on heart lung bypass have fairly stable respiratory and metabolic functions. This accounts for the predictable relationship the authors noted between SVOZ and CO. Boyd et al actually separated his patients into two groups. Group 1 with cardiac index values above 2 L/min/m2 and SVO2 values above 50% , and group 2with CI and $902 below 2 L/min/m2 and 50%, respec- tively. There was a 66% mortality (10/15) in group 2 as compared to an 11% mortality (2/19) in group 1. This study (Boyd et a1, 1959) demonstrated the importance of monitor- ing either CO or $902 after Open heart surgery to prevent the persistent low outflow state that precedes cardiac arrest. As the use of $902 to reflect CO became more common, physicians began recognizing the limitation of this relation- shipixlcritical patients with inadequate myocardial function (Valentine et a1, 1966; Goldman et al, 1967; Goldman et a1, 1968). In a majority of patients SVOZ and CI were lowered but concurrent respiratory disease frequently interfered with the linear relationship between 8‘702 and CI that had previously been described in healthy patients. The monitoring of SVO2 did not lose its importance at this time; rather, it began to be considered an important early indicator of the deteri- oration in oxygen delivery (Cao2 and CO) to the tissues. The patient's clinical course correlated with 5602, and changes 9 in Sfioz were shown to be early indicators of changes in clinical status or response to therapy (Goldman et al, 1967; Goldman et a1, 1968; Kazarian and Del Guercio, 1980; de la Rocha et a1, 1978). In contrast to these results, Muir et al in 1970 described results of a study also designed to assess the use of $702 as a measurement of CO in patients with varying degrees of acute myocardial infarction. Indicator dilution measurements of CO were made in 26 patients. Mixed venous blood gas samples were taken just prior to determination of CO. Mixed venous oxygen tension was measured directly and 5602 was derived from an oxyhemoglobin dissociation curve. There was a significant correlation (r = 0.74) between S§02 and CI. In individual (patients, changes in SVO2 appeared to correlate well with changes in CO. As was described in previous studies (Boyd et a1, 1959; Goldman et a1, 1968), 8602 also appeared to relate to the clinical status of the patient. In order to explain the direct relationship between Sfioz and CO, Muir et a1 assumed that V02 remained constant in patients with myocardial infarction even during low output states and that Saoz remained constant unless severe respiratory disease was present. These assumptions are acceptable in cases of uncom- plicated myocardial infarction or left ventricular failure unless backward failure results in pulmonary edema. In cases where respiratory disease is present or V02 is decreased as may occur in cases with backward failure and shock, other variables affecting 8902 must be evaluated before attributing 10 the decrease in $602 to inadequate CO alone (Hutter and Moss, 1970). The results of the study by Muir et al showed a large variation in the CI values for a given SVOZ so a single measure- ment of $602 was not shown to be useful in actual calculation of CO. As has been suggested by other investigators (Butter and Moss, 1970; Lee et a1, 1972), several measurements of SVOz would give a more accurate indication of changes in CO in response to therapeutic agents or due to depression of myocardial function, a decreased preload, or an increased afterload. In 1978, de la Rocha et al published results of a study done in children and infants to determine the relationship between $602 and cardiac index. Eleven patients undergoing surgery for congenital cardiac defects were monitored pre- operatively, intraoperatively and post0peratively. Variables monitored included 5902, cardiac index and various systemic, pulmonary and cardiac pressures. Linear regression analysis was done to evaluate the relationship between $902 and cardiac index. A significant correlation was found (r =0.78, p <.001) . All SVOZ values less than 65% corresponded to a cardiac index of less than 2.5 L/min/m2 except in one case. Patients with low cardiac output syndromes postoperatively (n=3) were treated with positive inotropes. This resulted in an increase in both 8902 and cardiac index (r'==0.86,p)<.05). Patients with uncom- plicated recoveries had 8602 values greater than 65% and normal cardiac index values. The one exception to this was a patient with a normal cardiac index with a Svoz lower than 65%. This 11 patient was also pyrexic. Oxygen consumption increases 10-13% for each degree Celsius elevation in body temperature above 37°C and may be responsible in this case for lowering SVOZ. This study confirmed a significant correlation between cardiac index and 8902. These results supported the results of studies by Moffitt et a1 and Boyd et al in 1959 showing that surgical patients appeared to be good cases to use SVOZ for evaluation of CO. Generally, their metabolic rate is stable which minimizes problems due to changing V02. This is in contrast to septic shock patients where higher metabolic rates and lower V02 occurs resulting in a decreased A-VOZ (Duff et a1, 1969). Despite the significant relationship between CI and $902, a specific $602 measurement had a range of CI values associated with it and an increase of $602 less than 10% did not associate well with a similar rise in CI (de la Rocha, 1978). The results Of this study suggest that an 8602 value less than 65% warrants further investigation and in surgical patients with no preexisting metabolic or respiratory disease emphasis can be placed on the patient's cardiovascular function. Investigations between 1959 and 1970 of the use of $602 as an indicator of cardiac output confronted the following problems which precluded its wide acceptance into postoper- ative and critical care. (1) Single 5602 measurements were difficult to interpret because of the large variability in cardiac index values for a specific 5602. (2) Changes in 12 cardiac output and SVO2 occurred rapidly, and single or inter- mittent measurements were not adequate for monitoring of unstable patients. (3) The number of samples taken could be influenced by patient blood volume and hemoglobin concentra- tion and (4) in vitro measurement of these samples was time consuming. The first report of continuous SVOZ measurement was made in 1962 by McArthur et al. This study described the use of a system whereby small amounts of mixed venous blood (18 ml blood/hour) were pumped continuously from the pulmonary artery to an anaerobic mixing cuvette equipped with an oxygen electrode for measurement of 8602. It wasn't until 1972 that a method for continuous in vivo measurement of $602 was described. This technique involved the use of a fiberOptic catheter oximeter which used alternating pulses of light at either 670 and 950 or 660 and 805 nm wavelengths. Reflected light was transmitted by a second set of fibers to a photo- electric device outside the patient. The ratio of intensities of the back scattered light of the two wavelengths was used to determine oxygen saturation. Investigators (Martin et a1, 1973) showed a significant correlation (r = 0.978) between simultaneously measured in vitro oximeter and fiberOptic oximeter 8902 values. In 1975 Krauss et al reported results of a study describing the use of this catheter to measure $902 in patients after cardiothoracic surgery. The intent of this project was to determine the predictive value of 8602 during 13 the postoperative period after thoracotomy. The value of 8602 as a predictor of cardiac output was also investigated. Fiberoptic catheters for continuous SVOZ measurement were placed in 19 patients either prior to (12) or after (7) surgery. Other variables monitored were cardiac index, arterial blood gases and pH, systemic and various cardiac pressures, and urine production. A correlation was found between cardiac index and S§02 (r = 0.78, n = 28, 0.64 < p <0.92) but only if 8902 were stable (change in $902 Of <3%) for at least five minutes before and after the measurement of CI. When CI was less than 2.0 L/min/mz, $902 was less than 60% in six out of eight patients. When CI was less than 2.5 L/min/mz, all but one patient had an SVO2 less than 65%. Urine production less than 20 ml/min, systemic blood pressure under 90/60 mmHg or other clinical signs of shock were pre- ceded by a fall in SVOZ of more than 5% or to values less than 60%. In patients that experienced respiratory distress, there was a simultaneous fall in 8602. The results of this study support the contention that a changing SVO2 reflects changes in variables determining this value, namely cardiac output, SaOz, hemoglobin and V02. Try- ing to evaluate Svo2 as an indicator of CO is impossible in patients with potential for respiratory dysfunction or meta- bolic instabilities. 8902 was shown in this study to change prior to obvious changes in other monitoring variables such as heart rate and blood pressure. Because of this, it may be useful as an early indicator of cardiovascular or 14 respiratory dysfunction. This study supported the use of continuous monitoring of SVOZ as a valuable monitoring tool in the care of critical postsurgical patients. These con- clusions were corroborated by results of similar studies by Martin et a1, 1973, and McArthur et a1, 1962. In 1978, a new system for reflection spectrOphotometry was developed using light pulses of three different wave- lengths between 600 and 1000 nm (Wilkinson et a1, 1979). Reflected light is transmitted to a photodetector to measure blood reflectance and to compute 8602 from the relative intensities corresponding to the three different wave lengths. A digital readout shows the average value for the preceding five seconds and is updated every second. Although it is more difficult to use (Schmidt and Staff, 1981), this catheter is more accurate than the older one because three different light wavelengths are used. In 1982, Jamieson et al used this fiberOptic catheter to compare hemodynamic parameters with 5902 in eighty-four patients at six predetermined periods between preparation for induction and recovery. Hemodynamic assessment included measurement Of heart rate, arterial blood gases, systemic blood pressure, right atrial (CVP), left atrial (LAP) and pulmonary capillary wedge (PCWP) pressures, temperature and cardiac output. Calculations of cardiac index, systemic (SVR) and pulmonary (PVR) vascular resistances and left ventricular stroke work index were then done. Observations were made in the postoperative period to assess effects of endotracheal 15 tube suctioning, positioning, shivering, and chest physio- therapy on the measured variables. During surgery a decreased SVO2 was treated with inotropic agents and vaso- pressors or vasodilators. Interpretation of therapeutic needs based on 8902 correlated well with other hemodynamic measurements. Changes in 8902 of more than 10% often pre- ceded changes in the hemodynamic status of the patient. When 8902 began to fall, the patient was evaluated for a decrease in preload (CVP, PCWP, LAP), contractility (LV stroke index) and an increase in afterload (SVR, PVR) and treated appropriately until SVO2 improved. Shivering, endotracheal tube suctioning, position changes and chest physiotherapy markedly decreased 5702' $902 improved when manipulation of the patient and/or shivering ceased. This study confirmed the importance of $602 as an early indicator of adequate tissue perfusion. In patients with stable V02, hemoglobin concentration and respiratory func- tion, SVOZ was also used to estimate cardiac output but 5702 and cardiac output had no "fixed" relationship. In 1982, two studies evaluating technical problems associated with placement of a new fiberOptic catheter were published. This catheter had both fiberOptic SVOZ measure- ment capabilities and the capacity for thermodilution cardiac output measurement. The study by Baele et al used critically ill adult patients requiring hemodynamic moni- toring. Waller et a1 placed these catheters in patients undergoing cardiac surgery. Measurements made included 16 in vivo fiberOptic measurement of $902, in vitro oximeter measurement of $602, and cardiac output. Patients in both studies were breathing an oxygen enriched gas. Baele et al found a significant correlation between in vitro and in vivo measurement of 5602 (r = 0.95). Waller et al found the correlation to be significant as well (r = 0.92, n = 99). This was true for a range of 8602 values from 60-95% measured with hemotocrits of 20-42%. Waller et al found a significant correlation between $902 and hemodynamic changes. An increase or decrease in Sfioz >5% correlated with a change in cardiac index (r = 0.69), stroke index (r = 0.67), and left ventricular stroke work index (r = 0.58). There were 39 instances when SVOZ values changed by 5% or more. Eighteen of 21 decreases in 8902 were accompanied by corresponding decreases in cardiac index and 14 of 18 8902 increases were accompanied by an increase in cardiac index. In vivo 8902 values did not correlate significantly with changes in mean arterial pressure, heart rate, pulmonary capillary wedge pressure or systemic vascular resistance. Baele et al showed by multivariant analysis that hemoglobin concentration, body temperature and cardiac index did not affect the accuracy of in vivo $602 measurement. Both of these studies support the hypothesis that SGOZ can be determined accurately in vivo by fiberOptic catheter measurement. 8‘702 correlated with CO but the relationship was not strong enough to define actual cardiac output values from SVOZ measurement. However, if 8602 did decrease by 5% 17 or more, Waller et al showed there was an 86% chance that cardiac index had also decreased. Because SVO2 is continu- ously measured and cardiac output is not, 8602 can serve as an early indicator of a diminished cardiac output. SVO2 also reflects changes in other important variables and may be more useful than any one of the other variables that determine $902 in critical patient care. A more recent study using the fiberOptic continuous $602 measurement was by Schmidt et a1, 1984. This study compared continuous SVO2 measurement with intermittently measured and calculated oxygen transport variables in the preoperative period of twenty adult cardiac surgery patients. All of these patients had impaired left ventricular function. Measurements made included continuous 8902, systemic blood pressure, cardiac filling pressures and heart rate. Inter- mittent arterial blood gases and cardiac output measurements were made. Calculations included A-VOz, oxygen delivery (D02 = C0 x Ca02), V02 and oxygen extraction ratio (OER = VOZIDOZ). There was a significant negative correlation (r = -0.84) between SVOz and percentage of 02 extracted from the blood (OER). No other oxygen transport variables includ- ing cardiac index showed significant correlation with SVOZ. Changes in $902 on occasion preceded changes in cardiac out- put but there was a large variation in the amount of change. At the onset of anesthesia, Sfioz actually increased 15% and cardiac output decreased. 18 As was described by Schmidt et al, the relationship of SVOZ to OER is more obvious if the equation OER = VOZ/Doz is simplified CO (Ca02 - €602) OER = C0 x CaO2 C902 OER = 1 - Caoz since the majority of the oxygen in whole blood is bound to hemoglobin Ca02 and C§02 can be simplified to Sa02 and $902. SaOz is usually about 100%, so OER = 1 - SVOZ Using $902 to estimate OER is less variable than using SVO to estimate CO and OER is more significant than CO in assess- ing tissue oxygenation. In a patient with normal V02 a decrease in CO can cause a decreased 8602. When V02 increases and CO remains constant, 5902 will also decrease. Schmidt et al claim that the cause of the decrease in SVOZ is not as important as the level to which it decreases. Arterial hyp- oxemia is just as significant a cause of tissue hypoxia as is a decreased CO. It is difficult to use 8502 as an estimate of CO since a multifactorial relationship exists. Other variables (V02 and SaOz) involved in this relationship may change at any time in critical care patients. Actual CO is not as relevant in patient care as is adequate tissue oxygen- ation. The reason emphasis is placed on maintaining or increasing CO is to assure tissues have enough oxygen to survive. The Pick Principle has been used widely in the past 19 to estimate cardiac output because CO has been so difficult to measure. Rapid changes in C0 are difficult to detect because indicator dilution measurement of CO has time and indicator volume limits. If 8902 were difficult to measure and CO was easy, CO measurement would likely be investigated as a way to estimate SVOZ. 3902 reflects significant changes in CO, V02 and arterial oxygenation and is an extremely use- ful monitoring variable in critical patient care. The purpose of S902 monitoring has evolved over the last 30 years. Initially it was monitored to reflect CO, a value rarely measured clinically because indicator dilution tech- niques were difficult to apply. Today 8902 is thought of as a variable which if monitored continuously will reflect early changes in a patient's tissue oxygenation which is a function of CO, systemic vascular resistance, pulmonary gas exchange and hemoglobin concentration. Svoz is believed to be more sensitive and a better prognostic indicator than any other single variable monitored in critical care patients (Schmidt et a1, 1984). $902 is also still useful in estimation of CO in patients with stable respiratory and metabolic functions (Sottile et a1, 1982; Magilligan et a1, 1983; Sheldon et al, 1983). c. The Use of P902 to Estimate CO One other way to evaluate CO is by P602 measurement. Pfioz is an indicator of tissue oxygenation and describes the 20 driving force moving oxygen from the blood to the tissues. Diffusion of oxygen is entirely dependent on P02 and not on the total amount of oxygen present. The speed and distance over which diffusion occurs depends on a partial pressure gradient. Oxygen dissociates from hemoglobin based on the binding affinity of hemoglobin for oxygen. This affinity is described by the oxyhemoglobin dissociation curve. Carbon dioxide tension, pH, temperature and concentration of 2,3 DPG inside the red blood cell determine the slope of this curve. At a P02 of 40 mmHg approximately 75% of the hemoglobin is bound. Between a P02 of 70 and 20 mmHg, there is a linear relationship between $02 and P02. Over this portion of the curve P02 determines $02. P902 is usually maintained between 36-40 mmHg. If this value decreases below 30 mmHg compen- satory mechanisms come into play. These mechanisms include a release of catecholamines which increase CO and P902. When P602 decreases it is because the circulatory system is failing to keep pace with the tissues' oxygen demands (Miller, 1982; Finch and Lenfant, 1972; Snyder and Carroll, 1982). The first investigators to propose that PVOZ was a use— ful indicator of the adequacy of tissue blood flow was Stanley and Isern-Amaral in 1974. Their conclusion was supported only by the fact that in patients where P992 was kept between 38-42 mmHg during bypass there was a signifi- cantly greater urine output and significantly lower bicarbonate requirements than in patients perfused at a 21 fixed rate of 40-60 ml/kg/min. Statistical evidence to support the use of P902 in estimation of CO was provided later by Parr et al in 1975 and Kohanna et al in 1981. In a study of 139 children less than two years of age and after cardiac surgery, Parr et al showed that there was a statis- tically significant correlation between CI and PVOZ. The results also showed that acute cardiac death was more reliably predicted using CI and PVOZ than either one alone. Kohanna et al also discussed results supporting a statistically significant correlation between PVC2 and CI. This was shown in a study of 25 patients after cardiac oper- ations. The thermodilution CO measurements were made and compared to PVOZ, P302: PVCOz' Pacoz, venous and arterial pH, packed red cell volume, temperature, left atrial preSe sure, central venous pressure, urine output, heart rate, and mean arterial pressure. Only P602, PVCOZ, PacoZ, venous and arterial pH, and temperature had significant r values (p < 0.01) and the highest r value was found with the cor- relation between CI and P902 (r = 0.49). The authors (Kohanna et al and Parr et a1) state that the correlation between PVC2 and CI were too low to be relied on clinically and that measurement of CO was the only accurate way to deter- mine adequate cardiac function. As an alternate use for P902 Kasnitz et al evaluated its use as a prognostic indi- cator for critically ill patients with circulatory and/or respiratory abnormalities. Results of the study showed that all of the nine patients with P902 values less than, 22 28 mmHg died, whereas only two of the eleven patients with P702 values greater than 28 mmHg died. They also showed that measurement (If Pfioz alone was a better prognostic indicator than measurement (If CO alone in critically ill patients. By 1978, continuous monitoring of 8602 had been reported and shown to be superior to intermittent Sfio2 monitoring. In an effort to apply this technique to P602 monitoring, Armstrong et al described the use of continuous P602 measure- ment in monitoring twenty-five patients with cardiorespi- ratory disorders. A double lumen catheter was used with a miniature polarographic electrode mounted on the end. During periods of cardiorespiratory stability, the mean PVC2 was 43,4 1 0.3 mmHg. Decreases in P602 below 40 mmHg occurred in patients experiencing a reduction in F102! acute respiratory failure, hypoventilation, hypovolemia and cardiac arrhythmias. In four of five cases, the decrease in PVOZ preceded clinical signs of deterioration. It is clear from the results discussed that P602 cannot be used for estimation of CO in patients with unstable respiratory or metabolic function. When respiratory and metabolic function are stable, then, as was demonstrated with 8902 (Scottile et a1, Magilligan et a1, Sheldon et a1, Boyd et a1), P602 is useful for estimation of CO. As pointed out earlier, a decrease in CO is a common cause of life threatening complications in horses. Because 23 metabolic and respiratory function are likely to be stable in anesthetized horses, I hypothesized that P602 is a useful indicator of CO in anesthetized horses. Further— more, in order to enhance the clinical applicability of this research, the relationship between onz and CO was studied with horses in dorsal, lateral, and sternal recumbencies and in horses with a metabolic disturbance induced by Escherichia coli endotoxin administration. MATERIALS AND METHODS Horses - Six healthy mixed breed horses (9.8 i 3.6 years of age, weighing 466.2 I 18.5 kg [2 1 SEM]) were used. Measurement techniques - For measurement of CO, a 110-cm 7-F balloon-tipped catheter with a thermistor near the tip3 was percutaneously placed in the pulmonary artery via the jugular vein. A polyethylene catheter (inside diameter 1.67 mm, outside diameter 2.42 mm)b was percutaneously placed in the right atrium also via the jugular vein. Catheters were attached to pressure transducers,°and an oscillosc0ped was used to verify placement by the presence of character- istic pressures and wave form. The zero pressure reference point was considered to be at the level of the sternum for horses in lateral recumbency and at the point of the shoulder for horses in sternal and dorsal recumbency. To measure CO, 40 ml of 0°C 5% dextrose in water was injected in <2 3 into the right atrium using a pressure injectore at 27.2 atmo- spheres. Falsely increased CO data were obtained when indicator solution was allowed to warm in the atrial catheter before making CO measurements. To prevent this, the atrial catheter was filled with cold 5% dextrose in water just before CO measurement. Injections of indicator solution were made during exhalation at the onset of a QRS 24 25 complex. Cardiac output was calculated using a CO computer.a Each data point was the mean of at least three CO deter- minations. Oxygen consumption was measured volumetrically (Brody, 1945). Briefly, at end exhalation, the endotracheal tubef was connected through a three-way valveg to a 120-L spirom- eterg containing a known volume of 100% 02 (Figure 1). The horse was allowed to breathe from the spirometer through a unidirectional Y piece for five minutes. Carbon dioxide was removed from the circle system using a C02 absorbant.h At the end of exhalation after approximately five minutes of breathing through the spirometer, the three-way valve was switched to allow the horse to breathe through the demand valve.1 The change in gas volume in the spirometer was measured, and a calculation of V02 was made. Values were corrected to STPD using standard equations. Blood samples were collected anaerobically from the facial artery, pulmonary artery, jugular vein, and a super- ficial limb vein (median or medial saphenous). Blood gas tensions were determined using a blood gas analyzer.J Mean arterial blood pressure was measured using a facial artery catheterk and pressure transducer connected to a multichannel physiograph. Heart rate was measured using a bipolar ECG lead system.d From these values we calculated stroke volume (SV), (SV = CO/HR) and peripheral vascular resistance (PVR) PVR = MAP/CO 26 Figure 1. Equipment used for measurement of oxygen consumption. 27 SPIROMETER 11m (UHF?! .. ..: coz ABSORBER \/p . DEMAND \UNIDIRECTIONAL Y 02 VALVE , PIECE 3WAY VALVE 28 where MAP is mean arterial blood pressure. Cardiac index was calculated using the equations (Henness et al, 1977) C1 = CO/body surface area where body surface area (m2) = (10.1 x W2/3)/104 and W is body weight in grams. Experimental design - Horses were fasted for 12 hours before anesthetic induction. After placement.of catheterS‘ in the pulmonary artery, right atrium and jugular vein, anesthesia was induced with 1 mg of xylazineI/kg of body weight IV and 2 mg of ketaminem/kg, IV. A surgical anes- thetic plane was maintained with a mixture of 10% guaifenesinn and 0.4% thiamylalo for 4.4 i 0.1 hours. Horses ventilated spontaneously through an endotracheal tube and a demand valve that delivered 100% 02. Horses were placed in lateral, sternal, or dorsal recumbency as predetermined by two 3 x 3 latin square designs (Table 2). To achieve a low CO, xylazine (0.65 to 1 mg/kg, IV) was administered. At least five minutes after xylazine adminis- tration, CO and then V02 were measured. During the V02 measurement, blood samples were taken for 02 and C02 tension measurements. Heart rate (HR) and MAP were also recorded during the V02 measurement period. Subsequently, to increase P CO, dobutamine in 5% dextrose and water was administered by an infusion pumpq at 1 to 7 ug/kg/min. In four instances during dobutamine administration, a persistent second degree atrio- ventricular (AV) block was observed. Because this arrhythmia 29 Table 2. 3 x 3 latin square design describing random sequencing of recumbencies. Recumbencies First Second Third Lateral Sternal Dorsal Lateral Dorsal Sternal Sternal Dorsal Lateral Sternal Lateral Dorsal Dorsal Lateral Sternal Dorsal Sternal Lateral 30 interferes with indicator dilution CO measurement, 3 to 5 mg of atropine sulfate was administered IV. After at least five minutes of dobutamine administration, all measurements were repeated in the sequence described. The horse was then moved to the next position, and the series of measurements was repeated as described. Steady state was determined through- out each measurement period by constant monitoring of MAP and HR. Repeated measurements of CO and.VOz were made periodically at the end of the measurement periods and were never significantly different from earlier CO and V02 measure- ments made during that period. To determine if the relationship between CO and P602 applied to horses with endotoxemia, horses were placed in dorsal recumbency after the last measurement period and n n o o r I o I Escherichia c011 endotox1n was administered. An endotox1n dose of 100 ng/kg was suspended in 60 ml of 0.9% NaCl and was administered IV over a period of five minutes. Fifteen minutes after endotoxin administration, measurements were repeated. Statistical analysis — The effect of position on all variables was analyzed using a two-way analysis of variance. If a significant F value were found, Tukey's w test was used to compare means. The effect of dobutamine and endotoxin administration was analyzed using paired t tests. Linear regression analysis was used to relate CI and P602, HR, MAP, jugular venous oxygen tension (on2 JUG) and superficial limb 31 vein 02 tension (PVO2 PERIPH). Significance was determined by calculation of a t value for the regression coefficient (b). Significance was set at P < 0.05. RESULTS Positioning had an effect on C0, CI, SV, PVR, MAP, and Pa02 (Table 3). When compared with values in horses in lateral recumbency, after xylazine administration, CO, CI and SV were lower in horses in sternal recumbency whereas PVR was higher in horses in sternal recumbency. In horses in dorsal recum- bency, after xylazine administration, MAP, PVR and Pa02 were significantly lower and CO and CI were significantly higher than those in horses in sternal recumbency but not those in horses in lateral recumbency. In horses in all positions, dobutamine increased CO, CI, HR, MAP, Pfioz, on2 JUG, and PV02 PERIPH (Table 3) but the increase in HR was not significant in horses in lateral recumbency. Dobutamine also increased V02 but the increase was only significant in horses in sternal recumbency. In horses in sternal recumbency, dobutamine increased SV and decreased PVR. In horses in dorsal recumbency, dobutamine significantly increased PaOZ. In horses in lateral recum- bency, dobutamine significantly increased PaCOZ- When compared with data obtained after xylazine adminis- tration with horses in dorsal recumbency, endotoxin administra- tion increased HR and decreased SV and PVO2 PERIPH. Other variables were not changed significantly. 32 .cova-Luu.cvsco oc.~¢.»x sou»: mucoosauou pam.ov sou» Amo.o v av acotoeevu x—Acourcwcowm . A .coAuALuA_c.sua ocvnapxx Lune. successunt potoum— sot» Amo.o v av acoLoAAAv xpucuuAAAcOAm A A .33 2:22.. .8: Gas v 3 “carat... 2:81:83 . . .cOAAcAA ~o a:0co> Lopsoan - gnu ~o>a icoAAcAA No maoco> BEA. po.u.Atoa:A A :QHaua ~o>a acovmcou ~ou FAALAAL- u ~ou-a “co.AcAu ~o mango» vex_s . ~ooa acoAAcou ~c FAALAALA A ~o~g aco_uasamcou No . Nos "Aug-AAAAAL sa—auuo> putosnvtoa - ¢>n "usaunoua vac—a pAALoALA can: a a oxoguu - >m "nova. uupcgou u —u uuaauao OAADLAO A 09 14 DJ A.v A m.om Ao.~ A ~.so n.n A a.nm ov.- A m.o- a.» A o.om co.o A ~.o~ c.n A o.~n “a: .0 say and ~o>a c—.m A o.mn on.- A «.00 o.m A n.om co.m— A o.e- ~.~ A o.mm ou.o~ A a.onn a.m~ A n.~c— an: .0 sew xa_¢ua ~o>a oé A m.~m m.~ A «.3 «J A ado vim A win ué A adv. c~.— A v.3 A; A n.3,. 3: Co 55 ~83 o.~ A o.nv o~.n A o.oo ~.~ A n.mv Ao.n~ A o.su n.~ A 9.»: c~.¢ A o.oo ~.~ A u.mv “a: A0 gas ~ooa To... A m6: on;— A m.~n~ flow A 9.02 0.: A 9.3 +0.3 A .63 ~6~ A n63 can A mdow 3: Ac 55 3:. o~.o A mo.~ -.o A c~.~ -.o A oo._ c-.o A un.~ o~.o A Aw.~ c~.c A ——.~ n~.o A as._ Ac_s\ug\—Ev ~oo 36 A 3..” 9A.... A 86 on... A 3.... .8... A 3.. t8.— A a; on... A 3." 36 A 3.... €2.33: .0 :5 a: n.o_ A n.om cm.—~ A n.o~— o.s A o.- oo.n A n.om~ Aw.s A n.c- on.- A o.cn~ m.» A ~.~c Au: co gr; EA: Ao.c A 5.5m on.“ A m.om n.n A c.»« co.» A u.nm —.~ A s.nn v.- A n.oo o.~ A ~.~n Acwsxmuooav a: Ao.mm A ~.mwe «.sou A n.-o n.~a A m.~v~ o~.¢o A o.¢oo Ao.ms A ~.ovm A.~o A _.omm ~.c- A o.oMm Ape. >m oo.o A am.v Aco.o A -.n mc.o A co.v coo.~ A oo.n ++cc.o A oo.n ovm.c A on.“ An.o A om.c A~E\cws\4. .u n.~ A m.om A~.~. A v.co o.m A m.oo An.n~ A o.~o ++~.m A ~.on Am.- A o.m¢ n.e A o.vo AcAE\m4\_EV ou cAAvoucu oc_eAuanoo Acm~APMM‘ ocssmuaooo ocANApaA AcAEaAaoom acu~a+mx acmeotamcmx pomtoo postman putmuoa .Aomgog uo~_uozumoco x,» c_ on\a: ooflv co_bmtum,cAEum cwonoucu LAAAA Auuacvs ma uco Acts\mx\o: A cu ~V cowuutumchEUA ocAEAASBou Levee vca onxus g o» mo.ov ocvumpxx touts mucocmtamome topaumququLuu .n spank 34 Correlations between CI and HR, MAP, PVOZ , PVC2 JUG, and PV02 PERIPH were statistically significant (Figures 2-6, Tables 4 and 5). There was a significant relationship between CI and either P902 or MAP in all positions and after endotoxin administration. In horses in sternal recumbency, on2 JUG and PVOZ PERIPH did not significantly correlate with C1. In horses in lateral recumbency, the correlation between PVO2 PERIPH and CI was also not sig- nificant. There was a significant correlation between HR and CI in horses in all positions, but not after endo- toxin administration (Table 5). 35 Figure 2. The relationship between mixed venous 02 tension (PV02) and cardiac index (CI). Measurements made in six horses in lateral, sternal, and dorsal recumbencies and in dorsal recumbency after endotoxin admin- istration are shown on upper panels; cumulative data are shown in lower panel. Regression coefficient (b) t SE of the regression coefficient. All b and R values are significant. ( A = xylazine, O = dobutamine, [] = endotoxin.) 36 LATERAL [501: STERNléL IOO~ IOO‘F 0 o o 75 ~ 0 75 ~ O 50- 50~ A A AA A 25 - b=4.99+0.98 25 » b=946+238 *R = 0.85 *R=0.78 I I I l l l 2 6 I0 2 6 I0 RSA R 0 loop 00 L 'OOI' DO SALAN ENDOTDXIN A a; 25 - b: 5.832.096 25 b= 5.742090 :1: «R4139 *R=O.85 E l l l I l I v 2 6 IO 2 6 IO N ISO r- .9 ° . 0. I25 ~ IOO - 75 L 50 - b=6.47.t HS 0 o *R= 0.66 25 ~ 0 1 l I 1 I 2.0 40 6.0 8.0 I00 Cardiac Index (llmin/m2) 37 Figure 3. The relationship between jugular venous 02 tension (PVO2 JUG) and cardiac index (CI). Measurements made in Six horses in lateral, sternal, and dorsal recumbencies and in dorsal recumbency after endotoxin admin- istration are shown on upper panels; cumulative data are shown in lower panel. Regression coefficient (b) t SE of the regression coefficient. Significant b and R values are indicated (*). ( A = xylazine, O = dobutamine, E) = endotoxin.) PV02 Jugular (mmHg) 38 LATERAL 200 _ O STERNAL> 0 HQ; I00 — I00 ‘- o 75" 75 _. A O 50 ~ 50 ~ A A o A b=6.26::l.34 b=9.89 14.6l 25 » *R=O.63 25 ~ R=O.57 4 I l J L I 2 6 IO 2 6 l0 0 XINO '00 _ loo _ DORSAL mg ENDOTO O 75 — 75 - 50 50 - b=7.732.l96 ‘3 b=7.73il.66 25 _ *R-OJe 25 - 'R=0.76 I I I l 1 1 2 6 IO 2 6 I0 250 - 200 - O O ISOr O O I OO~ _ 0 ca, b=742 L l.83 50 ° *R=.O.54 O O l I I l l 2.0 4.0 6.0 8.0 I0.0 Cardiac Index (I/min/mz) 39 Figure 4. The relationship between peripheral venous Oz tension (PV02 PERIPH) and cardiac index (CI). Measurements in six horses in lateral, sternal, and dorsal recumbencies and in dorsal recumbency after endotoxin administration are shown on upper panels; cumulative data are shown in lower panel. Regression coefficient (b) t SE of the regression coefficient. Significant b and R values are indicated (*). ( A = xylazine, O = dobutamine, C] = endotoxin.) 40 LATERAL STERNAL O A 200 ' 200 r '50 ” I50 r :9 O '00 '- I00 I- A O A E A 50* b=I3.I3:6.I2 50 AB A b=9.2O:42I R=O.46 R=O.57 l 1 l 1 J l 2 6 IO 2 6 l0 200 — OORSAL 200 - DORSAL AND ENDOTOXIN I50 ~ I50 - O O A '00 " '00" :‘n” A E 50 ~ 50 — A E flII=95311253 A fl6:951: 2.I2 V J R=077 D R=0.75 " TL___.L __.5___.I% J g 2 6 IO 6 l0 5 .- 2 250 o I— O 0' O 8‘ > 200 - n. O 0 I50 r o I00 F oO o b= l0.90*.3.0I *R=O.5O O 50 I. C!) O O O 1 1 _l 1 L 20 40 6.0 8.0 IOO Cardiac Index (I/min/mz) 41 Figure 5. The relationship between heart rate (HR) and cardiac index (CI). Measurements in six horses in lateral, sternal, and dorsal recumbencies and in dorsal recumbency after endotoxin administration are shown on upper panels; cumulative data are shown in lower panel. Regression coefficient (b) 1 SE of the regression coefficient. Significant b and R values are indicated (*). ( A = xylazine, O = dobutamine, D = endotoxin, bpm = beats per minute.) 42 T '00” LATERAL o '00 _ S ERNAL O 60 I" 60'- b=8 481l9| b=4.6610.97 20 - “2:031 20 - *R=O.84 J l l l l l 2 6 IO 2 6 IO DORSAL DORSAL AND ENDOTOXIN IOO " IOO _ O O 60 E b=4.9l'_£l80 A0 A b=3.5ItI.69 a 20 __ *R=0.66 20 " [2:045 ‘9 4 J l J 1 I 33 2 6 IO 2 6 IO 2 .. IZO I L. (U m I IOO )- O 80 - 60 ~ 40» 0° D: 5.20 1 0.90 20 * *R=O.66 0 I I I I I 2.0 4.0 60 8.0 I00 Cardiac Index (Ilmin/mz) 43 Figure 6. The relationship between mean arterial blood pressure (MAP) and cardiac index (CI). Measurements in six horses in lateral, sternal, and dorsal recumbencies and in dorsal recumbency after endotoxin administration are shown on upper panels; cumulative data are shown in lower ipanel. Regression coefficient (b) 1 SE of the regression coefficient. All b and R values are significant. ( A = xylazine, O = dobutamine, E] = endotoxin. ) Mean Arterial Pressure (mmHg) 200 l20 40 200 l20 40 200 I60 l20 80 40 44 LATERAL O 200 _ STE RNAL I20 b=I332 :3I9 b=6.0612.40 b ”Fir-080 40 L *R= 0.62 l l l l I 41 2 6 IO 2 6 Io _ DORSAL 200 .. DORSAL AND ENDOTOXIN I20 — b=l4.l8 :t 294 ,_ 40 _ b=l38| $3.0l *R=0.84 II R= 075 J I I L_.|_____|.___|__ 2 6 IO 2 6 l0 0 o O 0 o O b=9.391' 2.I2 o o *R=O.57 I— o O Q) o o o 0 J I l I 4 20 4.0 6.0 8.0 I00 Cardiac Index (I/min/m2) 45 Table 4. The R values for linear regression analysis of CO or CI and cardiovascular variables. Variable CO (ml/kg/min) CI (L/min/mz) PVOZ 0.66 0.66 HR 0.69 0.68 MAP 0.57 0.57 va2 JUG 0.53 0.54 PVOZ PERIPH 0.49 0.50 CO = cardiac output, CI = cardiac index, P002 = mixed venous 02 tension, HR = heart rate, MAP = mean arterial blood pressure, on2 vein and PVO2 PERIPH = 02 tension of blood from JUG = 02 tension of blood from the jugular a superficial limb vein. All R values statistically significant. 46 Table 5. The R values for linear regression analysis of cardiac index and cardiovascular variables in each recumbency. Dorsal and Variable Lateral Sternal Dorsal Endotoxin on2 0.85* 0.78* 0.89* 0.85* PV02 JUG 0.83* 0.57 0.78* 0.76* PVOz PERIPH 0.46 0.57 0.77* 0.75* HR 0.81* 0.84* 0.663 0.46 MAP 0.80* 0.62* 0.84* 0.75* onz = mixed venous oxygen tension, on2 JUG = jugular venous oxygen tension, PVO2 PERIPH = Superficial limb vein oxygen tension, HR = heart rate, and MAP = mean arterial blood pressure in different recumbencies and in dorsal recumbency after endotoxin administration. * Significant R values. DISCUSSION The present study demonstrates that P602 was signifi— cantly correlated with C1 in anesthetized horses. Moffitt et al describes a significant correlation between mixed venous oxygen saturation (8902) and perfusion index (L/min/mz) in human patients on a cardiopulmonary bypass machine. The correlation between SVO2 or P902 and CI have been confirmed in a variety Of clinical settings. (Stanley and Isern-Amaral, Armstrong et al, Parr et a1, Kohanna et a1, Dyson et a1, de la Rocha et al, Muir AL et al, and Kasnitz et a1). When SVO2 decreases to <60% or if Pfioz is decreased to 30 mmHg, the occurrence of death because of acute cardiac failure increases significantly (Armstrong et a1; Kasnitz et al). In most studies, these values of SVOZ and PVC2 correlate with a CI of 2 L/min/m2 (Parr et al; Kasnitz et al). In the present study, a P902 of 40 mmHg correlated with a mean CI of 2 L/min/mz. Xylazine and dobutamine were administered to give a wide range of CI values over which to test the correlation between CI and PVOZ. Xylazine was used to decrease CI where— as dobutamine increased CI. Administration of xylazine IV induces transient second degree AV blocks and depresses HR (Kerr et a1). Systemic arterial blood pressure rises initially, then gradually decreases to less than base line 47 fl . 48 values (Kerr et a1). Peripheral vascular resistance increases twenty minutes after IM injection Of xylazine at 2 mg/kg (McCashin and Gabel). In the present study, CI decreased five to ten minutes after IV xylazine administra- tion compared with the CI values calculated after dobutamine administration. Second degree AV blocks did not occur immediately after xylazine administration. Dobutamine increases CI and may also increase systemic arterial blood pressure and the rate of develOpment of left ventricular pressure (dp/dt); there is no change in total peripheral vascular resistance (Swanson et al). Effects on HR are variable depending on the horse and the dose administered (Swanson et a1). Sinus bradycardia occurs frequently with infusion rates of 3 to 5 ug of dobutamine/ kg/min and a second degree AV block has been reported in one horse (Swanson et al). In the present study, dobutamine consistently increased CI as compared with CI values calcu- lated after xylazine administration. Second degree AV blocks occurred in four horses during dobutamine adminis- tration. Previous xylazine administration may have been partially responsible for the high occurrence of this arrhythmia (Kerr et al). In critical equine colic patients, endotoxemia is frequently present. After administration of anesthetic agents, CO may be further depressed (McDonell). In the present study, endotoxin was administered and the 49 relationship between P902 and CI was evaluated. Endotoxin administration (200 ug/kg) results in an increased HR and MAP and a decreased CO fifteen minutes after administration (Bottoms et al; Burrows). In the present study, endotoxin increases HR, but did not change CO or MAP. This differ- ence is likely related to the lower dose of endotoxin. There is a significant correlation between HR and CO in resting and exercising horses (r = 0.91) (Bergsten). In the present study, the correlation between HR and CI was significant (r = 0.68) and HR of twenty-five beats per minute correlated with a CI of 2 L/min/mz; however, endotoxin administration significantly increased HR with— out changing CI, resulting in an insignificant correla- tion between HR and CI. This finding may have clinical importance because many horses with severe gastrointes— tinal disease, which are anesthetized, have endotoxemia (Moore). The P602 was significantly correlated with CI in our anesthetized horses regardless of positioning. In addi- tion, the correlation between P902 and CI was unaltered by endotoxin administration. Whereas, HR and P902 are significantly correlated with CI in the healthy anesthe- tized horse, only P602 correlates with CI in anesthetized horses after endotoxin administration. THE MAP was also significantly correlated with CI but the data points were poorly grouped, making it 50 difficult to derive a specific CI value for a measured MAP. Therefore, MAP was not as good an estimate of CI in anes- thetized horses as was P602. Because a catheter must be placed in the pulmonary artery to collect mixed venous blood, we also evaluated the correlation between PV02 in the jugular blood or blood obtained from superficial limb veins and CI. In horses in lateral and sternal recumbency, on2 PERIPH did not correlate with C1, whereas in horses in sternal recum- bency, PVO2 JUG and CI did not correlate. Therefore, PVO2 PERIPH and PV02 JUG were poor indicators of C0 in anesthetized horses. Cardiovascular changes resulting from sternal recum- bency were noticed. The decreased SV and CO may be attributed to mechanical interference with venous return or CO. Sympathetic response to the decreased CO would account for the increased PVR, although an increased HR would also be expected. This was not observed. The V02 in our anesthetized horses ranged from 1.78 1 0.13 to 1.89 1 0.17 ml/kg/min and was unaffected by positioning. These values are slightly lower than those predicted for conscious horses (Brody). This slight difference may be explained by the effects of general anesthesia (Mikat et a1). Present C0 values ranged from 39.1 1 5.1 to 64.0 1 4.3 ml/kg/min. These values are comparable with results of 51 studies (Hillidge and Lees) in which CO in halothane- anesthetized ponies ranged from 51.7 1 8.7 to 68.9 1 6.1 ml/kg/min and CO in anesthetized horses was 46.3 m1/kg/min (Gillespie et al). In anesthetized horses, CO is frequently depressed because of the myocardial depressant effects of anesthetic agents or because of decreased venous return caused by positive pressure ventilation (Lumb and Jones). A low C0 contributes to the severity of alveolar-arterial 02 tension gradients in horses with intrapulmonary shunts (Gillespie et a1; Kelman et a1) and may have a role in the pathogenesis of postanesthetic recumbency myOpathy (Lindsay et al). To prevent these complications, monitor- ing of C0 and parameters that reflect CO is useful because it allows for early detection and treatment of low output states. In clinical practice, measurement of C0 is difficult; therefore, measurement of P902, which reflects C0, may be a useful adjunct to the management of anesthe- tized horses. CONCLUSIONS From results presented in this thesis the following conclusions can be made: 1) 2) 3) A significant statistical correlation can be made between 8902 (PV02 or A-VOZ) and C0 because of the relationship described in the Pick Principle. This relationship does not allow accurate calcu- lation of C0 without measurement of all variables included in this principle. An estimation of CO from SVOZ, P902 and A-VOz can be made in patients that are known to have stable metabolic and respiratory function. Continuous monitoring is more useful than inter- mittent monitoring of SVO2 and P602 because it allows these measurements to be used as early indicators of changes in cardiorespiratory function. A decrease in onz or SVO2 indicates the need for further diagnostics. There is a statistically significant relationship between P902 and CI in anesthetized horses regard— less of position of the horse or the presence of endotoxin. 52 4) 5) 6) 7) 53 In anesthetized horses V02 does not vary enough to interfere with the significant correlation between onz and CI. Oxygen tension of blood from the jugular vein or from a superficial limb vein does not consistently correlate with CI so is not useful in estimation of CI. Heart rate does not reflect the CO in anesthetized horses given a bolus of endotoxin. Mean arterial blood pressure cannot accurately be used in estimation of CI because of the wide scatter of data points around a particular CI value. FOOTNOTES aEdwards Laboratories, Santa Ana, Calif. bPE240, Intramedic, Clay Adams, Parsippany, NJ. cP23 series, Gould Inc. Oxnard, Calif. dSeries 702, Spacelabs Inc. Chatsworth, Calif. eCordis Corp, Miami, Fla. f . . Aire-Cuf, Bivona Inc, Gary, Ind. 8Warren E. Collins Inc, Braintree, Mass. hSodasorb, W.R. Grace and Co, Lexington, Mass. 1Hudson, Temecula, Calif. jABLl, Radiometer, COpenhagen NV, Denmark. kCathlon IV, Critkon, Tampa, Fla. 1Rompun, Haver Lockhart, Shawnee Mission, Kan. mVetalar, Parke-Davis, Morris Plains, NJ. nAceto Chemical Co, Inc, Flushing, NY. °Bio-tal, Bio-Cutic, St. Joseph, Mo. pDobutrex, Eli Lilly, Indianapolis, Ind. q5000b, Valley Labs, Boulder, Co. rSigma Chemical Co, St. Louis, Mo. 54 LI ST OF REFERENCES LI ST OF REFERENCES Armstrong RF, St Andrew D, Cohen SL, et al. Continuous monitoring of mixed venous oxygen tension (onz) in cardiorespiratory disorders. Lancet 1978;1:632-634. Baele PL, McMichan JC, Marsh HM, et a1. Continuous monitor- ing of mixed venous oxygen saturation in critically ill patients. Anesth Analg 1982;61:513-517. Barratt-Boyes BG, Wood EH. The oxygen saturation of blood in the vanae cavae, right-heart chambers, and pulmonary vessels of healthy subjects. J Lab Clin Med 1957;50: 93-106. Bergsten G. Blood pressure, cardiac output, and blood- gas tension in the horse at rest and during exercise. Acta Vet Scand [Suppl] 1974;48:1-88. Bottoms GD, Fessler JF, Roesel 0F, et a1. Endotoxin- induced hemodynamic changes in ponies: Effects of flunixin meglumine. Am J Vet Res 1981;42:1514-1518. Boyd AD, Tremblay RE, Spencer FC, et al. Estimation of cardiac output soon after intracardiac surgery with cardiOpulmonary bypass. Ann Surg 1959;150:613—626. Brody S. Bioenergetics and growth. New Yorszafner Publishing Co Inc, 1945;313-319. Burrows GE. Hemodynamic alterations in the anesthetized pony produced by slow intravenous administration of Escherichia coli endotoxin. AmJVet Res 1970;31:1975-1932. Cournand A, Riley RL, Bradley SE, et a1. Studies of the circulation in clinical shock. Surgery 1943;13:964- 995. de la Rocha AG, Edmonds JF, William WG, et a1. Importance of mixed venous oxygen saturation in the care of critically ill patients. Can J Surg 1978;21:227-229. Duff JH, Groves AC, McLean APH, et a1. Defective oxygen consumption in septic shock. Surg Gynecol Obstet 1969;128:1051-1060. 55 56 Dyson DH, Allen DG, McDonell WN. Comparison of three methods for cardiac output determination in cats. Am J Vet Res 1985;46:2546-2552. Eberly VE, Gillespie, JR, Tyler WS. Cardiovascular param- eters in the thoroughbred horse. Am J Vet Res 1964; 25:1712-1715. Eberly VE, Gillespie JR, Tyler WS, et a1. Cardiovascular values in the horse during halothane anesthesia. Am J Vet Res 1968;29:305-314. Fegler G. Measurement of cardiac output in anesthetized animals by a thermodilution method. QfJ Exp Physiol 1954;39:153-164. Finch CA, Lenfant C. Oxygen transport in man. N Engl J Med 1972;286:407-415. Fisher EW, Dalton RG. Determination of the cardiac output of cattle and horses by the injection method. Br Vet J 1961;118:143-151. Gillespie JR, Tyler WS, Hall LW. Cardi0pulmonary dysfunction in anesthetized, laterally recumbent horses. Am J Vet Res 1969;30:61-72. Goldman RH, Braniff BA, Harrison DC, et a1. Early detec- tion of heart failure by central venous oxygen saturation monitoring. J Am Cardiol (Abst) 1967;21:100. Goldman RH, Klughaupt M, Metcalf T, et al. Measurement of central venous oxygen saturation in patients with myocardial infarction. Circulation 1968;38:941-946. Hall LW, Gillespie JR, Tyler WS. Alveolar-arterial oxygen tension differences in anaesthetized horses. Br J Anaesth 1968;40:560-567. Henness AM, Theilen GH, Madewell BR, et al. Use of drugs based on square meters of body surface area. J Am Vet Med Assoc 1977;171:1076-1077. Hillidge CJ, Lees P. Cardiac output in the conscious and anaesthetized horse. Equine Vet J 1975;7:16-21. Hodges M, Downs JB, Mitchell LA. Thermodilution and Pick cardiac index determination following cardiac surgery. Crit Care Med 1975;3:182-184. 57 Hutter AM, Moss AJ. Central venous oxygen saturations: Value of serial determinations in patients with acute myocardial infarction. JAMA 1970;212:299-303. Jamieson WRE, Turnbull KW, Larrieu AJ, et a1. Continuous monitoring of mixed venous oxygen saturation in cardiac surgery. Can J Surg 1982;25:538-543. Kasnitz P, Druger GL, Yorra F, et al. Mixed venous oxygen tension and hyperlactatemia: Survival in severe cardiopulmonary disease. JAMA 1976;236:570—574. Kazarian KK, Del Guercio LRM. The use of mixed venous blood gas determinations in traumatic shock. Ann Emerg Med 1980;9z179-182. Kelman GR, Nunn JF, Prys-Roberts C, et al. The influence of cardiac output on arterial oxygenation: A theoretical study. Br J Anaesth 1967;39:450-458. Kerr DD, Jones EW, Huggins K, et al. Sedative and other effects of xylazine given intravenously to horses. Am J Vet Res 1972;33:525-532. Kohanna FH, Cunningham JN, Catinella FP, et a1. Cardiac output determination after cardiac operation: Lack of correlation between direct measurements and indirect estimates. J Thorac Cardiovasc Surg 1981;82:904-908. Krauss XH, Verdouw PD, Hugenholtz PG, et al. On-line monitoring of mixed venous oxygen saturation after cardiothoracic surgery. Thorax 1975;30:636-643. Kubo K, Senta T, Sugimoto 0. Cardiac output in the Thoroughbred horse. Exp Rep Equine Health Lab 1973; 10:84-89. Lee J, Wright F, Barber R, et a1. Central venous oxygen saturation in shock: A study in man. Anesthesiology 1972;36:472-478. Lindsay WA, McDonell W, Bignell W. Equine postanesthetic forelimb lameness: Intracompartmental muscle pressure changes and biochemical patterns. Am J Vet Res 1980; 41:1919-1924. Lumb WV, Jones EW. Veterinary anesthesia. 2nd ed. PhiladelphiazLea and Febiger, 1984;95-99, 147-153, 510-512. 58 Magilligan DJ, Eisiminger R, Fried M. Use of inline venous oxygen saturation to predict post bypass cardiac output. Circulation (Abst) 1983;68:111-152 (608). Manley SV. Monitoring the anesthetized horse. Vet Clin North Am [Large Anim Pract] 1981;3:111-133. Martin WE, Cheung PW, Johnson CC, et a1. Continuous monitoring of mixed venous oxygen saturation in man. Anesth Analg 1973;52:784-793. McArthur KT, Clark LC, Lyons C, et a1. Continuous record- ing of blood oxygen saturation in open-heart operations. Surgery 1962;51:121-126. McCashin FB, Gabel AA. Evaluation of xylazine as a seda- tive and preanesthetic agent in horses. Am J Vet Res 1974;36:1421-1429. McDonell WN. General anesthesia for equine gastrointestinal and obstetric procedures. Vet Clin North Am [Large Anim Pract] 1981;3:163-194. Mikat M, Peters J, Zinder M, et al. Whole body oxygen consumption in awake, sleeping, and anesthetized dogs. Anesthesioloqy 1984;60:220-227. Miller MJ. Tissue oxygenation in clinical medicine: An historical review. Anesth Analg 1982;61:527-535. Moffitt EA, Patrick RT, Swan HJC, et al. A study of blood flow, venous blood oxygen saturation, blood pressure and peripheral resistance during total body perfusion. Anesthesiology 1959;20:18-26. Moore JN. Management of pain and shock in equine colic. Compend Contin Educ Prac Vet 1985;7:5169-Sl77. Muir AL, Kirby BJ, King AJ, et al. Mixed venous oxygen saturation in relation to cardiac output in myocardial infarction. Br Med J l970;4:276-278. Muir WW, Skarda RT, Milne DW. Estimation of cardiac out- put in the horse by thermodilution techniques. Am J Vet Res 1976;37:697-700. Nunn JF. Applied respiratory physiology. 2nd ed. London: Butterworth and Co Ltd, 1981;388-395. Parr GVS, Blackstone EH, Kirklin JW. Cardiac performance and mortality early after intracardiac surgery in infants and young children. Circulation 1975;51:867-874. 59 Schmidt CR, Frank LP, Forsythe SB, et al. Continuous 3V0 measurement and oxygen transport patterns in caréiac surgery patients. Crit Care Med 1984;12: 523-527. Schmidt CR, Starr NJ. Evaluation of a continuous SVO2 monitoring system. Anesthesiology 1981;55:A125. Sheldon CA, Cerra FB, Bohnhoff N, et al. Peripheral post- capillary venous pressure: A new, more sensitive monitor of effective blood volume during hemorrhagic shock and resuscitation. Surgery 1983;94:399-406. Snyder JV, Carroll GC. Tissue oxygenation: A physiologic approach to a clinical problem. Curr Prob Surg 1982; 19:650-719. Sottile FD, Durbin CG, Hoyt JW, et al. Evaluation of pulmonary artery oximetry as a predictor of cardiac output. Anesthesiology 1982;57:A127. Stanley TH, Isern-Amaral J. Periodic analysis of mixed venous oxygen tension to monitor the adequacy of perfusion during and after cardiOpulmonary bypass. Can Anaesth Soc J 1974;21:454-460. Stowe CM, Good AL. Estimation of cardiac output by the direct Fick technique in domestic animals, with obser- vations on a case of traumatic pericarditis. Am J Vet Res 1961;22:1093-1096. Swanson CR, Muir WW, Bednarski RM, et a1. Hemodynamic responses in halothane-anesthetized horses given infusions of dopamine or dobutamine. Am J Vet Res 1985;46:365-370. Trim CM, Moore JN, White NA. CardioPUlmonary effects of dompamine hydrochloride in an anesthetized horse. Equine Vet J 1985;17:41-44. Valentine PA, Fluck DC, Mounsey JPD, et a1. Blood-gas changes after acute myocardial infarction. Lancet 1966;2z837-841. Waller JL, Kaplan JA, Bauman DI, et al. Clinical evalua- tion of a new fiberOptic catheter oximeter during cardiac surgery. Anesth Analg 1982;61:676-679. Wilkinson AR, Phibbs RH, Gregory GA. Continuous in vivo oxygen saturation in newborn infants with pulmonary disease. Crit Care Med l979;7:232-236. 60 Wilson RF, Gibson D. The use of arterial-central venous oxygen differences to calculate cardiac output and oxygen consumption in critically ill surgical patients. Surgery 1978;84:362-369. Zuntz N. Die ernahrung des herzens und ihre beziehung zu seiner arbeitsleistung. Dtsch Med Wochenschr 1892;18:109-111.