JOURNAL
OF SURGICAL
RESEARCH
Hemodynamic
19, 107-113 (1975)
Studies
in Conscious
Domestic
Ponies1
JAMES F. AMEND, PH.D., HAROLD E. GARNER, D.V.M., PH.D., JOHN P. ROSBOROUGH, D.V.M., PH.D., AND HEBBEL E. HOFF, M.D., PH.D. Department of Physiology, Baylor College of Medicine, Houston, Te.xas 77025 Submitted for publication October 16, 1974
Chronic studies in cardiovascular surgical research, in particular those studies involving mechanical circulatory assistance with implantation of various biomedical devices, require a large animal model which approximates the size of man, and presents physical, physiological, and behavioral attributes compatible with reasonably longterm laboratory use. In recent years, the calf has occupied a prominent position as a research model for circulatory assistance studies. Weber et al. [7] cited availability, docility, surgical suitability (vessel strength and accessibility), and similarity to man in thoracic and cardiovascular capacities as prime reasons for the popularity of the calf in this regard. Because of the extensive use of the calf, efforts have been made to document parameters of normal cardiovascular function in these animals. The above-cited report of Weber et al. represents perhaps the most effective of these studies, as they examined conscious, unrestrained calves. Other investigators also have evaluated hemodynamic function in calves, including Stowe and Good [5], and Kuida et al. [3]. These latter studies involved restrained or anesthetized animals, however. Perhaps the major difficulties arising in the application of the calf as a chronic research model for the study of implantable devices are, first, the immaturity of the animal during the period of its life in which it resembles man in size, and secondly, its rela‘This study was supported in part by grants from the U.S. Public Health Service (U.S.P.H.S. GM-44624, GM-38193, and HE-05125). and by research contracts from Chemagro Corporation (Kansas City, MO) and Hoffmann-La-Roche, Inc. (Nutley, NJ).
tively rapid rate of growth, which can complicate the long-term evaluation of an implanted device. A large animal model possessing the general suitability of the calf, yet showing similarity in size to man at maturity, could provide a solution to problems resulting from immaturity and growth. In this laboratory, the “grade,” or non-purebred domestic pony has been examined as a candidate for such a large animal surgical model. This report describes observed parameters of cardiovascular function in conscious, standing domestic ponies, and compares results obtained with reported measurements in calves. METHODS AND MATERIALS Table 1 describes the experimental population employed in this study. Fourteen domestic ponies were used (five males, seven females, and two geldings). Acquisition, preconditioning, housing, and laboratory restraint have been reported previously [ 1,2, 41. The ponies ranged in age from 0.8 to 3 yr (mean = 2.0 yr), and in body weight from 53.2 kg to 147.7 kg (mean = 97.1 kg). Body surface areas corresponding to the above body weights ranged from 1.43 to 2.80 m2 (mean = 2.10 m2). Ponies were maintained by the supplier for 2 wk prior to delivery, during which time they were kept in isolation. After delivery to the laboratory, each pony was allowed a 24-hr period for adaptation. After this period, anesthesia and surgery for implantation of chronic arterial and venous catheters was undertaken. Periods of surgery lasted for 1M hr on the average. Ponies were allowed 48 hr of recovery time before physiological studies
107 Copyright i) 1975 by Academic Press, Inc. All rights of reproduction in any form reserved.
108
JOURNAL
OF SURGICAL
RESEARCH,
VOL. 19, NO. 2, AUGUST
1975
TABLE 1 General Animal Data Body wt (kg)
Body surface area Cm*)
Heart wtlkg (g)
Heart wtlk (g)
Animal number
Age (YI)
3003 2099 4003 2096
2 1.5 3 3
M G M F
127.2 111.4 147.7 78.5
2.53 2.31 2.80 1.84
742 561 815 -
5.83 5.05 5.52 -
1002 4004 8002 1102
3 2 2 0.8
F F G F
118.2 90.9 86.4 53.2
2.41 2.03 1.96 1.43
610 580 513
5.16 6.38 6.63 -
1109 2097
0.8 3
M F
59.5 95.9
1.53 2.10
327
5.50 -
1027 1110 1001 3005 (n = 14) Mean SD
0.8 0.8 2 3
F F M M
64.0 57.7 147.7 120.9
1.60 1.49 2.80 2.45
325 250 869 686
5.08 4.33 5.88 5.80
97.1 32.5
2.10 0.47
572.8 214.5
5.55 0.65
2.0 0.9
Sex
5 hiale 7 Female 2 Gelding
were begun. The specifics of surgical preparation follow. Anesthesia. Each pony was premeditated prior to induction of anesthesia with either acetylpromazine (0.066 mg/kg) or xylazine (0.66 mg/kg). Anesthesia was induced with 2.2 cc/kg iv glyceryl guaiacolate and 0.2% thiamylal sodium in a liter of 5% dextrose in water. Halothane, nitrous oxide, and oxygen were used to maintain anesthesia. A 2: 1 ratio of oxygen and nitrous oxide was used to vaporize halothane in a Fluotec vaporizer. A total gas flow of l-I$$! liters per minute containing l-2% halothane provided a light and easily maintained plane of anesthesia (Stage III, plane 1 or 2). A circular rebreathing anesthetic machine, operated in a semiclosed fashion, was used to administer the gaseousagents. At the termination of the anesthetic period the pony was placed in a quiet, darkened box stall and allowed to recover spontaneously in isolation. In a few instances ropes were attached to tail and halter to assist the pony in rising to a standing position. All ponies were standing within 45 min after cessation of anesthesia.
Surgery. Each pony was placed in right lateral recumbency for surgery. Using an electrocautery knife, an incision was made over and parallel to the jugular vein 3 in. craniad to the thoracic inlet. The vein was isolated, the craniad portion ligated, and the middle portion partially incised transversely, allowing caudal introduction of 3/16-in. i.d. polyvinylchloride catheter, which was advanced to the confluence of the jugular veins. Another skin incision was made 7 in. caudal to the left carotid bifurcation, and the left carotid artery was exposed. A pair of arterial catheters was marked with a ligature 37-42 cm (depending upon pony conformation) from the indwelling ends, and was passedinto the arterial system until the ligature rested at the arterial incision. The exact length introduced was based upon external estimation of the distance from the incision site to the aortic arch. After introduction, the arterial catheters were passed through the carotid and brachiocephalic arteries into the aorta. The ends were routinely placed 5-7 cm from the aortic valve, with the tips pointing downstream in the caudal (dorsal) aorta. The exterior por-
AMEND
ET AL.:
HEMODYNAMIC
tions of the catheters were then coiled and bandaged to the neck for maintenance and for access during physiological experiments. Catheter placement was examined at necropsy in all ponies, enabling more precise placement with each succeeding implantation. The venous implant served as an entry for repeated right-heart catheterizations for recording chamber and pulmonary arterial pressures, and injection of indocyanine green dye for cardiac output determinations. The aortic implants provided excellent systemic blood pressure recordings when connected to external transducers, and also provided a convenient route for introduction of a catheter-tip pressure device. The implants were routinely used for withdrawing arterial blood for cardiac output, pH,pC02, andp0, determinations. The implants were maintained for periods from 5-14 days. Electrocorticograms, electrocardiograms, and indirect blood pressures were recorded regularly during surgical procedures as indicators of physiological condition and level of anesthesia. Supportive fluid and antibiotic therapy were routinely employed postoperatively. Hemodynamic studies. Cardiac output was measured by indocyanine green dye di-
STUDIES
109
IN PONIES
lution. Dye was injected into the pulmonary artery via a 9 French Kifa catheter, passed previously through the jugular implant, and located in the pulmonary artery by visualization of pressure tracings. Arterial blood was withdrawn from one of the two implanted central arterial catheters, while the other was used to monitor simultaneous central arterial pressure. Arterial blood was passed through a Waters densitometer to record the dilution curve. The electrocardiogram was recorded, together with the pressure traces. From the above measurements, parameters of blood pressure, cardiac output, stroke volume, heart rate, and related normalized parameters were determined. The dilution curve was digitized for analysis using a Gerber digital data scanner; the digital data were processed by a suitably programmed IBM 7094 computer. Systolic time intervals. Systolic time intervals were measured from simultaneous traces of electrocardiogram, phonocardiogram, and arterial pressure pulse, recorded on occasions separate from the hemodynamic studies. Figure 1 illustrates the systolic time intervals and the manner in which they are measured. Heart rate (HR) was determined cycle by cycle from the formula 60/R-R interval (set) = HR; the R-R inter-
ELECTROCARDIOGRAM
PHONOCARDIOGRAM
I
I
PRESSURE
FIG. 1. Determination of systolic time intervals. R-R = preceding cardiac electrical measured cycle length; HR = cycle-by-cycle heart rate; Q-T = ventricular electrical tromechanical lag; Sl-S2 = mechanical systole; Q-S2 = electromechanical systole; PEP ICT = isovolumic contraction time; LVET = left ventricular ejection time; D = diastole. details of measurement and calculation.
cycle length; cycle; Q-S1 = preejection See text for
Q-Q = = elecperiod; specific
110
JOURNAL
OF SURGICAL
RESEARCH,
val immediately preceding each set of time intervals was measured from the electrocardiogram. Left ventricular ejection time (LVET) was measured from the onset of the sharp upstroke of the arterial pressure wave to the incisura of the wave. Electromechanical lag (Q-Sl) was measured from the Q-wave of the electrocardiogram to the first high-frequency component of the first heart sound. Electromechanical systole (Q-S2) was measured from the Q-wave of the electrocardiogram to the initial high-frequency component of the second heart sound. Ventricular electrical cycle was determined by measuring from the Q-wave to the end of the T wave of the electrocardiogram. Ejection time index (ETI) was calculated from the formula ET1 = LVET + 0.0039 HR. This equation was determined by linear regression analysis (See Table 4). Preejection period was calculated by taking the difference between durations of electromechanical systole (Q-S2) and left ventricular ejection time. Similarly, the externally obtained isovolumic contraction time (EICT) was calculated as the difference between left ventricular ejection time and mechanical systole (S I-S2). Specific techniques for these measurements and calculations are those described by Tavel [6] and by Weissler, Lewis, and Leighton [8]. Blood pressure measurements were taken directly from the previously calibrated pressure tracings, and represent average values over 10 cardiac cycles for both systolic and diastolic pressures. Measurements of systolic time intervals were obtained from graphic tracings (as in Fig. 1) recorded at 100 mm/set film speed, using a Honeywell Visicorder. A Gerber digital data scanner was used to measure intervals, and to transfer data to tabulator cards via an IBM 29 keypunch. The time resolution obtained by these methods was f 2 msec. Upon completion of the physiological studies, the pony was sacrificed and a necropsy performed. All internal organs were grossly examined, with particular at-
VOL.
19, NO. 2, AUGUST
1975
tention to heart and great vessels. Wet weight of the heart was determined after flushing of residual blood. Atria and ventricles were included in the weight determination. Location of the tips of the indwelling arterial catheters was noted to assist in later implantation technique. RESULTS Hemodynamic parameters obtained from conscious, standing, domestic ponies are presented in Table 2. Individual data sets are presented in order of increasing heart rate. Average heart rate for the group of 14 ponies at the time of cardiac output determination was 75.9 beats/min, with a range of 39-116 beat/min. When heart rates associated with systolic time interval determination are averaged, a value of 59.3 beats/min is observed. The difference in rates in the two circumstances may most reasonably be attributed to the additional manipulation associated with output determination (e.g., right-heart catheterization). In no case was the heart rate considered truly resting. Systemic arterial blood pressure averaged 139/99 mm Hg. The range of systolic pressures seen in the ponies was 115-155 mm Hg, while diastolic pressures ranged from 70-125 mm Hg. Cardiac output showed a mean of 8.9 liters/min; mean cardiac index was 4.46 liters/min/m2. Ranges for these parameters were 4.8-13.2 liters/min. and 3.37 to 6.35 liters/min/m2, respectively. Cardiac output normalized to body weight (CO/kg) ranged from 61-163 ml/min/kg, with a mean of 99 ml/min/kg. Stroke volume averaged 131 ml/stroke. Mean stroke index was 62.7 ml/stroke/m2, while mean stroke volume per kg body wt was 1.40 ml/stroke/kg. Stroke volume ranged from 45-305 ml/stroke, stroke index from 30-120 ml/stroke/m2, and stroke volume/kg body wt from 0.78-2.40 ml/ stroke/kg. Table 3 presents systolic time intervals obtained from 9 of the 14 ponies. These parameters were measured from tracings
AMEND
ET AL.:
HEMODYNAMIC
STUDIES
111
IN PONIES
TABLE 2 Hemodynamic Parameters’ Animal number
HR
ASP
ADP
CO
CI
CO/KG
3003 2099 4003 2096 1002 4004 8002 1102 1109 2097 1027 1110 (II = 12) Mean SD
39 54 64 65 71 72 72 72 93 96 97 116
130 155 115 130 150 150 155 120 150 115 150 15.5
100 120 90 80 100 110 90 80 110 70 125 120
11.9 7.8 13.2 4.8 10.4 7.5 11.8 5.8 9.7 11.7 7.6 5.2
4.70 3.37 4.71 2.61 4.31 3.70 6.03 4.04 6.35 5.57 4.74 3.47
93 70 89 61 88 82 136 109 163 88 119 90
8.9 2.9
4.46 1.12
75.9 21.1
139.6 16.3
99.6 17.9
99.0 28.6
SV
SI
W/KG
305 144 206 74 146 104 164 80 104 122 78 45
120 62 74 40 60 51 84 56 68 58 49 30
2.40 1.29 1.39 0.94 1.24 1.14 1.90 1.50 1.75 1.27 1.22 0.78
131.0 70.7
62.7 23.1
1.40 0.44
‘HR = heart rate in beats per minute; ASP = aortic systolic blood pressure in mm Hg; ADP = aortic diastolic pressure in mm Hg; CO = cardiac output in liters per minute; CI = cardiac index in liters per minute per square meter; CO/KG = cardiac output per kilogram body weight in liters per minute per kilogram; SV = stroke volume in ml. per stroke; SI = stroke index in ml. per stroke per square meter; SV/KG = stroke volume per kilogram body weight in ml. per stroke per kilogram; S.D. = standard deviation.
obtained on occasions separate from hemodynamic determinations. Mean heart rate during these studies was 59.3 beats/ min. Left ventricular ejection time, electromechanical systole (Q-S2), and the Q-T interval were all found to bear significant inverse linear relationships to heart rate (Table 4). None of the remaining intervals
showed significant fits in regression analysis. Ejection time index, derived from the relationship between LVET and heart rate, averaged 603 in the pony group (The equation value was 608). Preejection period (PEP) ranged from 55-96 msec, with a mean of 73 msec. Externally obtained isovolumic contraction time (EICT) ranged from 17-50
TABLE 3 Systolic Time Intervals’ Animal number
Q-Q
4003 1001 8002 1002 3005 1102 1109 1110 2099 (I? = 9) Mean SD
1432 1219 1205 1167 1132 1012 964 797 645 1061 234
LVET
ET1
PEP
EICT
Q-S1
Q-S2
Q-T
42 49 50 51 53 59 62 75 93
453 421 396 343 421 393 389 295 237
617 612 591 542 628 623 631 587 600
64 96 76 73 62 74 55 86 68
19 50 36 22 21 18 17 47 34
45 46 40 51 41 56 38 39 34
517 517 472 416 483 467 444 381 305
466 460 419 377 445 413 417 339 287
59.3 15.7
372 69
603 28
73 12
29 12
43 6
444 68
402 58
HR
‘Time periods are expressed in milliseconds. Q-Q = cardiac electrical cycle length from EKG; HR = heart rate in beats per minute; LVET = left ventricular ejection time; ET1 = ejection time index; PEP = preejection period; EICT = externally obtained isovolumic contraction time; Q-S1 = electromechanical lag; Q-S2 = electromechanical systole; Q-T = ventricular electrical cycle; SD = standard deviation. These data were obtained on occasions separate from those related to the hemodynamic parameters.
112
JOURNAL
OF SURGICAL
RESEARCH,
VOL.
19, NO. 2, AUGUST
1975
TABLE 4 Linear Regression Equations for Systolic Time Intervals’ Parameter Left ventricular ejection time Electromechanical systole Ventricular electrical cycle Preejection period Isovolumic contraction time Electromechanical lag
Equation LVET Q-S2 Q-T PEP EICT Q-S1
= = = = = =
0.608-0.0039 0.682-0.0040 0.603Xi.0034 No significant No significant No significant
HR HR HR relationship relationship relationship
aThe linear regression equations present systolic time intervals efficient; SEE = standard error of the estimate.
msec. Mean EICT was 29 msec. Electromechanical lag (Q-Sl) ranged from 3456 msec., the mean was 43 msec. Necropsies revealed no gross lesions in any of the 14 ponies. No congenital or acquired anomalies of the heart or great vessels were observed. Mean heart weight (atria and ventricles) was 572.8 g (range 250-869 g). Normalization of heart weight to body weight yielded a mean of 5.55 g/kg (4.33-6.63 g/kg). The hearts averaged 0.55% of body wt (Table 1). DISCUSSION This study was intended to provide a general hemodynamic characterization of the “grade” or non-pure bred domestic pony. Data were obtained in the conscious, standing state, with no medication. While the animals were for the most part quiet and cooperative, the conditions may not be construed as genuinely resting. Size of the ponies was variable, with a maximum weight difference of 94.5 kg between largest and smallest ponies. The size difference, together with individual variation in responses to experimental manipulation, contributed to a rather broad range of values, particularly with regard to cardiac output. Nevertheless, a comparison with data presented in the literature for the calf [7] shows that significant differences are found only in parameters whose determination in part reflects the existing heart rate (Table 5). Mean heart rate for the pony group was 75.9 (at catheterization), as opposed to calves which showed a mean rate of 101 beats/min.
r
SEE
0.914 0.921 0.908
0.026 0.025 0.023
to heart rate to heart rate to heart rate
as a function
of heart rate. r = correlation
co-
Systolic and diastolic blood pressures, cardiac output and index, and the preejection period were not found to be significantly different in ponies and calves. Because the heart rates of the calves were significantly higher, however, all rate-dependent variables showed resultant differences. These are apparent in stroke volume and stroke index, in left ventricular ejection time, and electromechanical systole. Rate-related differences are illustrated by the ejection time index, which is significantly lower in the calf, as the higher rate yields a lesser y-intercept for the regression equation. The slope of the function is also reduced in the calves. Comparison of age, body weight, body surface area, and heart weight in ponies and calves shows that, although the ponies averaged eight times the age of the calves, there were no obvious differences in the physical measurements of weight, body surface, and heart weight. These results suggest that it is indeed possible to select domestic ponies, at maturity, within a size range which yields hemodynamic data similar to the calf, which has been shown by Weber et al. [7] to resemble man in hemodynamic function. These observations suggest that the domestic pony may be employed for hemodynamic studies in cardiovascular surgical research in those situations in which the calf has been considered the ideal large animal model, and that it can present a preparation in which maturity and stability of body size represent a major advantage over the rapidly growing calf.
AMEND
Comparison
ET AL.: HEMODYNAMIC
TABLE 5 of Data from Domestic Ponies and from Calves’
Parameter
Ponies
Calves
p value
Age 04 Weight (kg) Body surface area WI Heart wt (g) Heart rate (beats per minute) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Cardiac output (liters/min) Cardiac index (liters/min/ma) Stroke volume (ml/stroke) Stroke index (ml/stroke/m2) Ejection time index Electromechanical systole (set) Preejection period (set)
2.0 97.1
0.25 90-100.5
-
2.10 572.8
2.14 597
-
-
75.9
101
(0.01
139.6
134
>O.lO
99.6
94
>O.lO
8.9
8.4
>O.lO
4.46
3.9
>O.lO
84
OF SURGICAL
RESEARCH
Hemodynamic
19, 107-113 (1975)
Studies
in Conscious
Domestic
Ponies1
JAMES F. AMEND, PH.D., HAROLD E. GARNER, D.V.M., PH.D., JOHN P. ROSBOROUGH, D.V.M., PH.D., AND HEBBEL E. HOFF, M.D., PH.D. Department of Physiology, Baylor College of Medicine, Houston, Te.xas 77025 Submitted for publication October 16, 1974
Chronic studies in cardiovascular surgical research, in particular those studies involving mechanical circulatory assistance with implantation of various biomedical devices, require a large animal model which approximates the size of man, and presents physical, physiological, and behavioral attributes compatible with reasonably longterm laboratory use. In recent years, the calf has occupied a prominent position as a research model for circulatory assistance studies. Weber et al. [7] cited availability, docility, surgical suitability (vessel strength and accessibility), and similarity to man in thoracic and cardiovascular capacities as prime reasons for the popularity of the calf in this regard. Because of the extensive use of the calf, efforts have been made to document parameters of normal cardiovascular function in these animals. The above-cited report of Weber et al. represents perhaps the most effective of these studies, as they examined conscious, unrestrained calves. Other investigators also have evaluated hemodynamic function in calves, including Stowe and Good [5], and Kuida et al. [3]. These latter studies involved restrained or anesthetized animals, however. Perhaps the major difficulties arising in the application of the calf as a chronic research model for the study of implantable devices are, first, the immaturity of the animal during the period of its life in which it resembles man in size, and secondly, its rela‘This study was supported in part by grants from the U.S. Public Health Service (U.S.P.H.S. GM-44624, GM-38193, and HE-05125). and by research contracts from Chemagro Corporation (Kansas City, MO) and Hoffmann-La-Roche, Inc. (Nutley, NJ).
tively rapid rate of growth, which can complicate the long-term evaluation of an implanted device. A large animal model possessing the general suitability of the calf, yet showing similarity in size to man at maturity, could provide a solution to problems resulting from immaturity and growth. In this laboratory, the “grade,” or non-purebred domestic pony has been examined as a candidate for such a large animal surgical model. This report describes observed parameters of cardiovascular function in conscious, standing domestic ponies, and compares results obtained with reported measurements in calves. METHODS AND MATERIALS Table 1 describes the experimental population employed in this study. Fourteen domestic ponies were used (five males, seven females, and two geldings). Acquisition, preconditioning, housing, and laboratory restraint have been reported previously [ 1,2, 41. The ponies ranged in age from 0.8 to 3 yr (mean = 2.0 yr), and in body weight from 53.2 kg to 147.7 kg (mean = 97.1 kg). Body surface areas corresponding to the above body weights ranged from 1.43 to 2.80 m2 (mean = 2.10 m2). Ponies were maintained by the supplier for 2 wk prior to delivery, during which time they were kept in isolation. After delivery to the laboratory, each pony was allowed a 24-hr period for adaptation. After this period, anesthesia and surgery for implantation of chronic arterial and venous catheters was undertaken. Periods of surgery lasted for 1M hr on the average. Ponies were allowed 48 hr of recovery time before physiological studies
107 Copyright i) 1975 by Academic Press, Inc. All rights of reproduction in any form reserved.
108
JOURNAL
OF SURGICAL
RESEARCH,
VOL. 19, NO. 2, AUGUST
1975
TABLE 1 General Animal Data Body wt (kg)
Body surface area Cm*)
Heart wtlkg (g)
Heart wtlk (g)
Animal number
Age (YI)
3003 2099 4003 2096
2 1.5 3 3
M G M F
127.2 111.4 147.7 78.5
2.53 2.31 2.80 1.84
742 561 815 -
5.83 5.05 5.52 -
1002 4004 8002 1102
3 2 2 0.8
F F G F
118.2 90.9 86.4 53.2
2.41 2.03 1.96 1.43
610 580 513
5.16 6.38 6.63 -
1109 2097
0.8 3
M F
59.5 95.9
1.53 2.10
327
5.50 -
1027 1110 1001 3005 (n = 14) Mean SD
0.8 0.8 2 3
F F M M
64.0 57.7 147.7 120.9
1.60 1.49 2.80 2.45
325 250 869 686
5.08 4.33 5.88 5.80
97.1 32.5
2.10 0.47
572.8 214.5
5.55 0.65
2.0 0.9
Sex
5 hiale 7 Female 2 Gelding
were begun. The specifics of surgical preparation follow. Anesthesia. Each pony was premeditated prior to induction of anesthesia with either acetylpromazine (0.066 mg/kg) or xylazine (0.66 mg/kg). Anesthesia was induced with 2.2 cc/kg iv glyceryl guaiacolate and 0.2% thiamylal sodium in a liter of 5% dextrose in water. Halothane, nitrous oxide, and oxygen were used to maintain anesthesia. A 2: 1 ratio of oxygen and nitrous oxide was used to vaporize halothane in a Fluotec vaporizer. A total gas flow of l-I$$! liters per minute containing l-2% halothane provided a light and easily maintained plane of anesthesia (Stage III, plane 1 or 2). A circular rebreathing anesthetic machine, operated in a semiclosed fashion, was used to administer the gaseousagents. At the termination of the anesthetic period the pony was placed in a quiet, darkened box stall and allowed to recover spontaneously in isolation. In a few instances ropes were attached to tail and halter to assist the pony in rising to a standing position. All ponies were standing within 45 min after cessation of anesthesia.
Surgery. Each pony was placed in right lateral recumbency for surgery. Using an electrocautery knife, an incision was made over and parallel to the jugular vein 3 in. craniad to the thoracic inlet. The vein was isolated, the craniad portion ligated, and the middle portion partially incised transversely, allowing caudal introduction of 3/16-in. i.d. polyvinylchloride catheter, which was advanced to the confluence of the jugular veins. Another skin incision was made 7 in. caudal to the left carotid bifurcation, and the left carotid artery was exposed. A pair of arterial catheters was marked with a ligature 37-42 cm (depending upon pony conformation) from the indwelling ends, and was passedinto the arterial system until the ligature rested at the arterial incision. The exact length introduced was based upon external estimation of the distance from the incision site to the aortic arch. After introduction, the arterial catheters were passed through the carotid and brachiocephalic arteries into the aorta. The ends were routinely placed 5-7 cm from the aortic valve, with the tips pointing downstream in the caudal (dorsal) aorta. The exterior por-
AMEND
ET AL.:
HEMODYNAMIC
tions of the catheters were then coiled and bandaged to the neck for maintenance and for access during physiological experiments. Catheter placement was examined at necropsy in all ponies, enabling more precise placement with each succeeding implantation. The venous implant served as an entry for repeated right-heart catheterizations for recording chamber and pulmonary arterial pressures, and injection of indocyanine green dye for cardiac output determinations. The aortic implants provided excellent systemic blood pressure recordings when connected to external transducers, and also provided a convenient route for introduction of a catheter-tip pressure device. The implants were routinely used for withdrawing arterial blood for cardiac output, pH,pC02, andp0, determinations. The implants were maintained for periods from 5-14 days. Electrocorticograms, electrocardiograms, and indirect blood pressures were recorded regularly during surgical procedures as indicators of physiological condition and level of anesthesia. Supportive fluid and antibiotic therapy were routinely employed postoperatively. Hemodynamic studies. Cardiac output was measured by indocyanine green dye di-
STUDIES
109
IN PONIES
lution. Dye was injected into the pulmonary artery via a 9 French Kifa catheter, passed previously through the jugular implant, and located in the pulmonary artery by visualization of pressure tracings. Arterial blood was withdrawn from one of the two implanted central arterial catheters, while the other was used to monitor simultaneous central arterial pressure. Arterial blood was passed through a Waters densitometer to record the dilution curve. The electrocardiogram was recorded, together with the pressure traces. From the above measurements, parameters of blood pressure, cardiac output, stroke volume, heart rate, and related normalized parameters were determined. The dilution curve was digitized for analysis using a Gerber digital data scanner; the digital data were processed by a suitably programmed IBM 7094 computer. Systolic time intervals. Systolic time intervals were measured from simultaneous traces of electrocardiogram, phonocardiogram, and arterial pressure pulse, recorded on occasions separate from the hemodynamic studies. Figure 1 illustrates the systolic time intervals and the manner in which they are measured. Heart rate (HR) was determined cycle by cycle from the formula 60/R-R interval (set) = HR; the R-R inter-
ELECTROCARDIOGRAM
PHONOCARDIOGRAM
I
I
PRESSURE
FIG. 1. Determination of systolic time intervals. R-R = preceding cardiac electrical measured cycle length; HR = cycle-by-cycle heart rate; Q-T = ventricular electrical tromechanical lag; Sl-S2 = mechanical systole; Q-S2 = electromechanical systole; PEP ICT = isovolumic contraction time; LVET = left ventricular ejection time; D = diastole. details of measurement and calculation.
cycle length; cycle; Q-S1 = preejection See text for
Q-Q = = elecperiod; specific
110
JOURNAL
OF SURGICAL
RESEARCH,
val immediately preceding each set of time intervals was measured from the electrocardiogram. Left ventricular ejection time (LVET) was measured from the onset of the sharp upstroke of the arterial pressure wave to the incisura of the wave. Electromechanical lag (Q-Sl) was measured from the Q-wave of the electrocardiogram to the first high-frequency component of the first heart sound. Electromechanical systole (Q-S2) was measured from the Q-wave of the electrocardiogram to the initial high-frequency component of the second heart sound. Ventricular electrical cycle was determined by measuring from the Q-wave to the end of the T wave of the electrocardiogram. Ejection time index (ETI) was calculated from the formula ET1 = LVET + 0.0039 HR. This equation was determined by linear regression analysis (See Table 4). Preejection period was calculated by taking the difference between durations of electromechanical systole (Q-S2) and left ventricular ejection time. Similarly, the externally obtained isovolumic contraction time (EICT) was calculated as the difference between left ventricular ejection time and mechanical systole (S I-S2). Specific techniques for these measurements and calculations are those described by Tavel [6] and by Weissler, Lewis, and Leighton [8]. Blood pressure measurements were taken directly from the previously calibrated pressure tracings, and represent average values over 10 cardiac cycles for both systolic and diastolic pressures. Measurements of systolic time intervals were obtained from graphic tracings (as in Fig. 1) recorded at 100 mm/set film speed, using a Honeywell Visicorder. A Gerber digital data scanner was used to measure intervals, and to transfer data to tabulator cards via an IBM 29 keypunch. The time resolution obtained by these methods was f 2 msec. Upon completion of the physiological studies, the pony was sacrificed and a necropsy performed. All internal organs were grossly examined, with particular at-
VOL.
19, NO. 2, AUGUST
1975
tention to heart and great vessels. Wet weight of the heart was determined after flushing of residual blood. Atria and ventricles were included in the weight determination. Location of the tips of the indwelling arterial catheters was noted to assist in later implantation technique. RESULTS Hemodynamic parameters obtained from conscious, standing, domestic ponies are presented in Table 2. Individual data sets are presented in order of increasing heart rate. Average heart rate for the group of 14 ponies at the time of cardiac output determination was 75.9 beats/min, with a range of 39-116 beat/min. When heart rates associated with systolic time interval determination are averaged, a value of 59.3 beats/min is observed. The difference in rates in the two circumstances may most reasonably be attributed to the additional manipulation associated with output determination (e.g., right-heart catheterization). In no case was the heart rate considered truly resting. Systemic arterial blood pressure averaged 139/99 mm Hg. The range of systolic pressures seen in the ponies was 115-155 mm Hg, while diastolic pressures ranged from 70-125 mm Hg. Cardiac output showed a mean of 8.9 liters/min; mean cardiac index was 4.46 liters/min/m2. Ranges for these parameters were 4.8-13.2 liters/min. and 3.37 to 6.35 liters/min/m2, respectively. Cardiac output normalized to body weight (CO/kg) ranged from 61-163 ml/min/kg, with a mean of 99 ml/min/kg. Stroke volume averaged 131 ml/stroke. Mean stroke index was 62.7 ml/stroke/m2, while mean stroke volume per kg body wt was 1.40 ml/stroke/kg. Stroke volume ranged from 45-305 ml/stroke, stroke index from 30-120 ml/stroke/m2, and stroke volume/kg body wt from 0.78-2.40 ml/ stroke/kg. Table 3 presents systolic time intervals obtained from 9 of the 14 ponies. These parameters were measured from tracings
AMEND
ET AL.:
HEMODYNAMIC
STUDIES
111
IN PONIES
TABLE 2 Hemodynamic Parameters’ Animal number
HR
ASP
ADP
CO
CI
CO/KG
3003 2099 4003 2096 1002 4004 8002 1102 1109 2097 1027 1110 (II = 12) Mean SD
39 54 64 65 71 72 72 72 93 96 97 116
130 155 115 130 150 150 155 120 150 115 150 15.5
100 120 90 80 100 110 90 80 110 70 125 120
11.9 7.8 13.2 4.8 10.4 7.5 11.8 5.8 9.7 11.7 7.6 5.2
4.70 3.37 4.71 2.61 4.31 3.70 6.03 4.04 6.35 5.57 4.74 3.47
93 70 89 61 88 82 136 109 163 88 119 90
8.9 2.9
4.46 1.12
75.9 21.1
139.6 16.3
99.6 17.9
99.0 28.6
SV
SI
W/KG
305 144 206 74 146 104 164 80 104 122 78 45
120 62 74 40 60 51 84 56 68 58 49 30
2.40 1.29 1.39 0.94 1.24 1.14 1.90 1.50 1.75 1.27 1.22 0.78
131.0 70.7
62.7 23.1
1.40 0.44
‘HR = heart rate in beats per minute; ASP = aortic systolic blood pressure in mm Hg; ADP = aortic diastolic pressure in mm Hg; CO = cardiac output in liters per minute; CI = cardiac index in liters per minute per square meter; CO/KG = cardiac output per kilogram body weight in liters per minute per kilogram; SV = stroke volume in ml. per stroke; SI = stroke index in ml. per stroke per square meter; SV/KG = stroke volume per kilogram body weight in ml. per stroke per kilogram; S.D. = standard deviation.
obtained on occasions separate from hemodynamic determinations. Mean heart rate during these studies was 59.3 beats/ min. Left ventricular ejection time, electromechanical systole (Q-S2), and the Q-T interval were all found to bear significant inverse linear relationships to heart rate (Table 4). None of the remaining intervals
showed significant fits in regression analysis. Ejection time index, derived from the relationship between LVET and heart rate, averaged 603 in the pony group (The equation value was 608). Preejection period (PEP) ranged from 55-96 msec, with a mean of 73 msec. Externally obtained isovolumic contraction time (EICT) ranged from 17-50
TABLE 3 Systolic Time Intervals’ Animal number
Q-Q
4003 1001 8002 1002 3005 1102 1109 1110 2099 (I? = 9) Mean SD
1432 1219 1205 1167 1132 1012 964 797 645 1061 234
LVET
ET1
PEP
EICT
Q-S1
Q-S2
Q-T
42 49 50 51 53 59 62 75 93
453 421 396 343 421 393 389 295 237
617 612 591 542 628 623 631 587 600
64 96 76 73 62 74 55 86 68
19 50 36 22 21 18 17 47 34
45 46 40 51 41 56 38 39 34
517 517 472 416 483 467 444 381 305
466 460 419 377 445 413 417 339 287
59.3 15.7
372 69
603 28
73 12
29 12
43 6
444 68
402 58
HR
‘Time periods are expressed in milliseconds. Q-Q = cardiac electrical cycle length from EKG; HR = heart rate in beats per minute; LVET = left ventricular ejection time; ET1 = ejection time index; PEP = preejection period; EICT = externally obtained isovolumic contraction time; Q-S1 = electromechanical lag; Q-S2 = electromechanical systole; Q-T = ventricular electrical cycle; SD = standard deviation. These data were obtained on occasions separate from those related to the hemodynamic parameters.
112
JOURNAL
OF SURGICAL
RESEARCH,
VOL.
19, NO. 2, AUGUST
1975
TABLE 4 Linear Regression Equations for Systolic Time Intervals’ Parameter Left ventricular ejection time Electromechanical systole Ventricular electrical cycle Preejection period Isovolumic contraction time Electromechanical lag
Equation LVET Q-S2 Q-T PEP EICT Q-S1
= = = = = =
0.608-0.0039 0.682-0.0040 0.603Xi.0034 No significant No significant No significant
HR HR HR relationship relationship relationship
aThe linear regression equations present systolic time intervals efficient; SEE = standard error of the estimate.
msec. Mean EICT was 29 msec. Electromechanical lag (Q-Sl) ranged from 3456 msec., the mean was 43 msec. Necropsies revealed no gross lesions in any of the 14 ponies. No congenital or acquired anomalies of the heart or great vessels were observed. Mean heart weight (atria and ventricles) was 572.8 g (range 250-869 g). Normalization of heart weight to body weight yielded a mean of 5.55 g/kg (4.33-6.63 g/kg). The hearts averaged 0.55% of body wt (Table 1). DISCUSSION This study was intended to provide a general hemodynamic characterization of the “grade” or non-pure bred domestic pony. Data were obtained in the conscious, standing state, with no medication. While the animals were for the most part quiet and cooperative, the conditions may not be construed as genuinely resting. Size of the ponies was variable, with a maximum weight difference of 94.5 kg between largest and smallest ponies. The size difference, together with individual variation in responses to experimental manipulation, contributed to a rather broad range of values, particularly with regard to cardiac output. Nevertheless, a comparison with data presented in the literature for the calf [7] shows that significant differences are found only in parameters whose determination in part reflects the existing heart rate (Table 5). Mean heart rate for the pony group was 75.9 (at catheterization), as opposed to calves which showed a mean rate of 101 beats/min.
r
SEE
0.914 0.921 0.908
0.026 0.025 0.023
to heart rate to heart rate to heart rate
as a function
of heart rate. r = correlation
co-
Systolic and diastolic blood pressures, cardiac output and index, and the preejection period were not found to be significantly different in ponies and calves. Because the heart rates of the calves were significantly higher, however, all rate-dependent variables showed resultant differences. These are apparent in stroke volume and stroke index, in left ventricular ejection time, and electromechanical systole. Rate-related differences are illustrated by the ejection time index, which is significantly lower in the calf, as the higher rate yields a lesser y-intercept for the regression equation. The slope of the function is also reduced in the calves. Comparison of age, body weight, body surface area, and heart weight in ponies and calves shows that, although the ponies averaged eight times the age of the calves, there were no obvious differences in the physical measurements of weight, body surface, and heart weight. These results suggest that it is indeed possible to select domestic ponies, at maturity, within a size range which yields hemodynamic data similar to the calf, which has been shown by Weber et al. [7] to resemble man in hemodynamic function. These observations suggest that the domestic pony may be employed for hemodynamic studies in cardiovascular surgical research in those situations in which the calf has been considered the ideal large animal model, and that it can present a preparation in which maturity and stability of body size represent a major advantage over the rapidly growing calf.
AMEND
Comparison
ET AL.: HEMODYNAMIC
TABLE 5 of Data from Domestic Ponies and from Calves’
Parameter
Ponies
Calves
p value
Age 04 Weight (kg) Body surface area WI Heart wt (g) Heart rate (beats per minute) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Cardiac output (liters/min) Cardiac index (liters/min/ma) Stroke volume (ml/stroke) Stroke index (ml/stroke/m2) Ejection time index Electromechanical systole (set) Preejection period (set)
2.0 97.1
0.25 90-100.5
-
2.10 572.8
2.14 597
-
-
75.9
101
(0.01
139.6
134
>O.lO
99.6
94
>O.lO
8.9
8.4
>O.lO
4.46
3.9
>O.lO
84
