Effects of an infusion of dopamine on the cardiopulmonary effects of Escherichia coli endotoxin in anaesthetised horses

Research in Veterinary Science 1991, 50, 54-63

Effects of an infusion of dopamine on the cardiopulmonary effects of Escherichia coli endotoxin in anaesthetised horses C. M. TRIM, J. N. MOORE, Departments of Large Animal Medicine and Physiology-Pharmacology, M. M. HARDEE*, Department of Large Animal Medicine, College of Veterinary Medicine, G. E. HARDEE*, Department of Pharmaceutics, College of Pharmacy, E. A. SLADEt,

University of Georgia, Athens, Georgia 30602, USA

Horses with colic may be endotoxaemic and subsequently develop hypotension during anaesthesia for surgical operation. The aim of this study was to evaluate the efficacy of dopamine as a means to improve cardiovascular function in anaesthetised endotoxaemic horses. Nine horses (five in group I and four in group 2) were anaesthetised with thiopentone and guaifenesin and anaesthesia was maintained with halothane. After approximately one hour, facial artery pressure, heart rate, pulmonary artery pressure, cardiac output, temperature, pHa, eaco2, Pao2, base excess, packed cell volume, plasma protein concentration and white cell count were measured (time 0). Escherichia coli endotoxin was infused intravenously over 15 minutes in both groups. Group 2 horses were given an intravenous infusion of dopamine (5 /zg kg-1 min-1) starting five minutes after the start of the endotoxin infusion and continuing for 60 minutes. Measurements were made at 15 minute intervals for 120 minutes. In group 1, one horse died during the endotoxin infusion and in two other horses mean facial artery pressures decreased to 50 mm Hg. Total pulmonary vascular resistance and packed cell volume were significantly increased. Cardiac output, cardiac index and change in mean arterial pressure were significantly greater in group 2 horses than in group 1 horses. Conversely, diastolic pulmonary artery pressure, total vascular resistance and total pulmonary resistance were significantly less in group 2 than in group 1. Pao2, base excess and white blood cell count were significantly decreased in both groups. It was concluded that dopamine improved cardiovascular function in the presence of endotoxaemia and attenuated the rate of haemoconcentration, but had no effect on the development of decreased Pao 2 or metabolic acidosis.

ENDOTOXAEMIA occurs in horses with naturally occurring (Meyers 1982, King and Gerring 1988, Fessler et al 1989) or experimentally induced (Moore et al 1981a) intestinal ischaemia. Horses with colic undergoing surgery may have decreased cardiovascular function as a result of endotoxaemia (Burrows 1970, Bottoms et al 1981) or anaesthesia (Steffey and Howland 1978). Furthermore, acute cardiovascular deterioration has occurred following manipulation of ischaemic intestine (Trim 1977, Trim et al 1989). Because hypoperfusion may have detrimental effects on organ function or patient survival, treatment to restore cardiovascular function may be necessary. Dopamine hydrochloride is a catechofamine that increases cardiac output in healthy halothane-anaesthetised horses (Trim et al 1985a, Swanson et al 1985) and is used to improve cardiovascular function in clinical patients (Harvey et al 1987, Trim et al 1989). The purpose of this investigation was to determine whether the administration of dopamine would alter the cardiopulmonary responses to endotoxaemia of halothane-anaesthetised horses. Materials and methods

Experiment 1 Four healthy quarterhorse crossbred geldings were studied to assess the effects of the proposed anaesthetic technique on the horse's cardiovascular system. The horses were two to four years old (mean 2-5 years) and between 305 and 448 kg hodyweight (mean 313 kg). The day before the experiment, the horses were removed from pasture and placed in individual indoor stalls. Food was withheld overnight but water was allowed. Anaesthesia was induced by an intravenous infusion of thiopentone sodium (4-4 mg kg J) and guaifenesin (110 mg kg -l) and maintained with halothane in oxygen (Dr~iger) with the horse lying on its left side. Ventilation was controlled at 10 breaths rain- l and a tidal volume of I 1 ml kg- 1. The first 60

*Present address: Upjohn Company, Kalamazoo, Michigan 49001, USA tPresent address: Dogwood Veterinary Hospital, Newnan, Georgia 30263, USA

54

Dopamine effects in anaesthetised endotoxaemic horses minutes following induction of anaesthesia was used for placement of catheters and to achieve a stable plane of anaesthesia. For the next 120 minutes, anaesthesia was maintained with a constant vaporiser setting of halothane and measurements ~vere recorded at 15 minute intervals. A 7 French thermodilution cardiac output catheter (Columbus Instruments) was inserted with an introducer into a jugular vein and advanced until the distal part was in the pulmonary artery. Polyethylene tubing was inserted through a 10 gauge catheter in the jugular vein until the tip was in the right atrium. Cardiac outputs were determined (Columbus Instruments) at end expiration by injection of 35 ml of ice-cold normal saline solution through the atrial catheter. The volume of the polyethylene tubing was determined so that it could be filled with ice-cold saline before each cardiac output determination, thus keeping injected fluids at 0°C. A 20 gauge catheter was inserted into the facial artery for measurement of arterial pressure. Pressures were measured with transducers previously calibrated with a mercury manometer and were recorded on a strip chart recorder (Hewlett-Packard). The zero reference point was at the level of the spinous processes of the thoracic vertebrae and the horse's head was positioned so that the facial artery catheter was level with this point. Measurements of heart rate, facial artery pressure, pulmonary artery pressure, and cardiac output commenced after the initial instrumentation period and continued at 15 minute intervals for 120 minutes. Temperature was recorded from the thermistor on the cardiac output catheter. At the same measurement times, arterial blood was collected anaerobically into heparinised glass syringes and analysed for pH and blood gases (Instrumentation Laboratories). Freeflowing blood was collected into capillary tubes for measurement of packed cell volume and plasma protein concentration. Blood was placed into tubes containing sodium EDTA for determination of the white blood cell count (Coulter Electronics). Arterial blood was also collected into tubes containing potassium oxalate/sodium fluoride and the plasma hal-vested for spectrophotometric determination of lactate and glucose concentrations (Gilford Instrument Laboratories). At the end of the measurement period, the horse was allowed to recover from anaesthesia.

Calculations and statistical analysis Heart rate was obtained from the arterial pressure recording. The systolic and diastolic vascular pressures were taken from the average of four consecutive beats to minimise the effects of controlled ventilation on blood pressure. Mean pressures were calculated as:

55

(Systolic - diastolic) + diastolic pressure 3 Cardiac index (c0 was calculated by the formula: Cardiac output (litre rain 1) Body surface area (BSA) where the 10" 5 x bodyweight (g)0.67 BSA =

10,000

(Altman and Dittmer 1964) Total vascular resistance (TVR) and total pulmonary r e s i s t a n c e (TPR) were calculated by the formula: (dyne sec cm -s) = or PAP/CI X 1332 X 60

TVR or TPR

MAP/CI

where MAP was mean arterial pressure and PAP was mean pulmonary artery pressure (Garman 1982). Left ventricular work index (LVWI) was calculated by the formula: LVWI (kg m min - l m -z) = CIXMAPX0"0136 Base excess was calculated from measurements of pHa and P a c o 2 using a Severinghaus blood gas calculator. Haemoglobin was estimated as 0 . 3 3 x packed cell volume. Pao2 was corrected for temperature and pH. The data were analysed using a one way analysis of variance and means were compared using Duncan's multiple range test. Data are expressed as the mean plus or minus the standard deviation ( ± SD). Significance was set at P < 0.05.

Experiment 2 Nine quarterhorse crossbred horses (eight geldings and one mare) were studied. They were two to six years old (mean 3.1 years) and between 265 and 556 kg bodyweight (mean 378 kg). Anaesthesia was induced in the same way as in experiment 1 except that, after the initial instrumentation period, the inspired halothane concentration was monitored (Engstr6m) and kept constant for the duration of anaesthesia (1 "0 + 0" 1 per cent). Instrumentation was the same as in experiment 1 except that a 14 gauge catheter was placed in the left femoral vein for infusion of endotoxin and a similar catheter was placed in the right jugular vein for infusion of dopamine or saline solution. Approximately one hour after induction of anaesthesia, two sets of measurements were recorded at a 15 minute interval (time - 15 and time 0). Escherichia coli O55:B5 endotoxin (Sigma) (1 /~g kg -l in saline) was then infused intravenously over 15 minutes (Lifecare pump; Abbott Laboratories). Five minutes

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after initiation of the infusion of endotoxin, an infusion of either saline (group 1; five horses) or dopamine hydrochloride (Intropin; American Critical Care) (group 2; four horses) was begun and maintained for 60 minutes. Dopamine was prepared as 400/zg ml-1 in saline and infused at 5 #g kgmin -~ (Ivac Corporation). Measurements were recorded at 15 minute intervals for 120 minutes from the beginning of the endotoxin infusion. Arterial blood from group 1 horses was collected into chilled tubes containing EDTA and sodium bisulphate. The blood was immediately centrifuged at 1000 g for three minutes, and the plasma harvested, frozen on dry ice, and stored ( - 7 0 ° C ) for later determination of catecholamine concentrations using a previously described technique (Hardee et al 1982). At the end of the 120 minute measurement period, the horses were allowed to recover from anaesthesia. Rectal temperature, heart rate, respiratory rate, packed cell volume, plasma protein concentration and behaviour were recorded at four and at eight hours after anaesthesia. Previous experience with similar dose rates of endotoxin in horses led us to expect that the horses would recover rapidly from the ill effects of endotoxin. Any horse exhibiting signs attributable to pain, or with observable evidence of dehydration or prolonged effects of endotoxaemia, was to receive an analgesic drug, fluid therapy or flunixin meglumine, respectively.

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Calculations were performed as for experiment 1. Time 0 was considered baseline value. Data from selected variables were expressed as per cent change from time 0 values (mean arterial pressure, cardiac output) or change from time 0 values (base excess). Bartletts test was applied to the variances of each variable. When the variances were equal, data were analysed using a two-way analysis of variance. Means were compared using Duncan's multiple range test. Kruskal-Wallis non-parametric test was applied when the variances were unequal (heart rate, systolic arterial pressure, mean arterial pressure, cardiac output, systolic pulmonary arterial pressure). Unless otherwise indicated, data are expressed as mean ± SD. Significance was set at P < 0" 05.

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Experiment l No significant change from time0 values occurred in any of the measured variables (Tables 1 and 2). The white cell count at time 0 was 8- 8 ± 4- 0 x 109 litre- 1; the wide standard deviation was due to one horse with a white cell count of 14.0 x 109 litre- I. The white cell

7.43±0.05 4.9 ± 0.5 50,7 ± 10.5" 0.5±1.5 36,5±0.7 0 - 3 3 ± O. 12 74 ± 2

0 7.44±0.04 4.9 ± 0-5 52-8 ± 8.9 ~ 0.8±0-8 36-4±0.8 0.32 ± 0.07 72 ± 4

15 7.43±0-05 5-0 ± 0-8 46"6±10.4" 0"5±0.7 36.4±0.7 0.32 ± 0.10 74 ± 2

30 7.43±0.04 5-1 ± 0 . 8 49.5 ± 12-5" 0.5±0.7 36-3±0-7 0.31 ± 0-09 75 ± 2

45 7.42±0.06 5.0 ± 0.9 47.7±7.7* 0.3±1-1 36,3 ± 0-7 0.32 ± 0.09 72 ± 8

Time (rain) 60

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Data expressed as mean ± SD n = 4 except where indicated, t n = 3 # Values signlficantly different from group 1 {P<: O" 05)

Heart rate (beats min 1) Systolic facial arterial pressure Imm Hg) Diastolic facial arterial pressure (ram Hg) Mean facial arterial pressure (mm Hg) Systolic pulmonary arterial pressure (mm Hg) Diastolic pulmonary arterial pressure (mm H9)

Variable 39 ± 36±3 96 ± 95±4 63 ± 57 ± 74 ± 69±7 32 ± 31 ± 23 ± 18 ± 5 3 4 3

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41 ± 9 43±11 103 ~ 35 93±7 75 ± 24 52 ± 8 84 ± 28 65±4 49 ± 14 37 ± 6 37 ± 8 22# ± 7

15 38 ± 6 40±3 97 ± 43 113±16 74 ± 30 69 ± 14 81 ± 35 83±14 44 ± 9 50 ± 14 33 ± 3 33 ± 7

30

60 40 ± 4 39±4 96 ± 36 118±19 60 ± 19 67 ± 13 72 ± 24 84±15 34 ± 7 34 ± 3 24 ± 7 26 ± 4

Time (min) 38 ± 6 38±4 102 ± 38 107±24 68 ± 27 61 ± 16 79 ± 30 76±17 37 ± 7 33 ± 3 26 ± 5 24 ± 4

45

75 7.42±0.07 5.1 ± 1 . 0 42.8±12-1" -0.2±0.6 36-3±0.8 0.30 ± 0.09 76 ± ' 4

TABLE 3: Cardiovascular values of anaesthetisad horses given endotoxin (group 1) or dopamine and endotoxin Igroup 2)

Data expressed as mean ± SD n = 4 except where indicated. * n - 3

pHa PaCO2 (kPa) Pa02 (kPa) Base excess (mmol litre -1 ) Temperature (°C) Packed cell volume (litres litre -1) Plasma protein (g litre -1)

Variable

38 ± 2 39±3? 92 ± 38 123±23 60 ± 22 76 ± 16 71 ± 27 92±18 33 ± 8 36 ± 2? 23 ± 8 25 ± 6?

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37 ± 1 39±3 88 ± 4 6 107±6 57 =~ 2 4 59 ± 8 67 ± 31 74±6 34 ± 8 36 ± ,6 24 ± 8 26 ± 7

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7.42±0.07 5 . 0 ± 1,1 43,0±12.8" -0.1±1-0 36.1 ±0.8 0 , 3 3 ± O. 11 75 ± 4

37 ± 2 37±1 89 ± 45 116±14 58 ± 25 67 ± 11 68 ± 31 83±11 34 ± 9 36 ± 9 24 ± 8 24 ± 6

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7.42±0.05 5.1 ± 1-1 44,6±9"3* 0.0±1.2 36-2±0.7 0 . 3 2 ± O- 12 76 ± 4

37 ± 2 38±2 91 ± 43 114±19 58 ± 24 71 ± 19 69 ± 30 85±19 34 ± 8 33 ± 6 23 ± 8 22 ± 4

7.43±0,05 5.0 ± 0.8 45.5±10-5" 0,I~0.7 36.3±0-8 0 - 3 2 ± O. 11 76 ± 3

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TABLE 2: No significant changes occurred in pHa, blood gases, packed cell volume, or plasma protein concentration during 120 minutes of anaesthesia in four horses

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FIG 1 : Per cent change in mean arterial pressure from time 0 in anaesthetised horses given endotoxin (group 1 ) and horses given dopamine and endotoxin (group 2). Mean ± SEM. tValues significantly different from group 1 (P
count at 60 minutes was 9.5 + 6 . 1 × 109 litre-~; at 120 minutes it was 9.9 ± 6.6 x 109 litre- 1. One horse had high blood lactate and glucose concentrations during anaesthesia. The blood lactate concentration at time 0 was 2.4 ~ 1.4 mmol litre-]; at 60 minutes it was 2-0 + 0-8 mmol litre -1 and at 120 minutes it was 1.9 + 0.6 mmol litre-l. The blood glucose at time 0 was 8.2 + 3.9 mmol litre- 1, at 60 minutes it was 6.4 ± 1" 9 mmol litre- 1and at 120 minutes it was 5.6 + 1.2 mmol litre-1. The horses recovered from anaesthesia without complications.

Time (min) FIG 2: Per cent change in cardiac output from time 0 in anaesthetised horses given endotoxin (group 1) and horses given dopamine and endotoxin (group 2). Mean ± SEM. *Values significantly different from time 0 (P
pHa and base excess decreased non-significantly from time 0 to 120 minutes, and Pacoa was unchanged (Table 5). When expressed as mmol litre -1 change from time 0 values, base excess decreased significantly at 30 to 120 minutes (P ---0.0001) (Fig 3). Paoa was significantly decreased at 60 to 120 minutes (P=0.0001) (Table 5). The lowest Pao 2 values recorded in individual horses were 10- 1 kPa, 12-6 kPa, 13.2 kPa, and 36.4 kPa.

Experiment 2 Group 1. One horse died during the endotoxin infusion; data from that horse were not included in the results. Among the survivors, heart rate was not significantly changed by the infusion of endotoxin (Table 3). There was wide variation in arterial pressure values between horses in this group (Table 3). Two horses maintained adequate arterial pressure for 120 minutes but mean arterial pressure of approximately 50 mm Hg or less was present in one horse at 30 to 120 minutes and in a second horse at 60 to 120 minutes. Mean arterial pressure in group 1 horses, expressed as per cent change from time 0 values, declined progressively (Fig 1). The changes in pulmonary artery pressures, cardiac output, cardiac index, left ventricular work index and total vascular resistance were not statistically significant (Tables 3 and 4, Fig 2). Total pulmonary resistance was significantly increased at 15 minutes (P = 0" 005) (Table 4).

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46 ± 8 38±6 2"93 ± 0.66 2.64±0.30 3 . 0 6 ~= 1 . 4 4 2.47±0.24 2012 ± 260 2127 ± 378

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746 ± 211 764 ± 282

45 ± 11 38±10 2.85 ± 0.83 2.61 ±0.61 3.15 ± 1 .70 2.49±0"40 2214 ± 434 2311 ± 750 1564" ± 818 806 ± 526

39 ± 14 47±21 2-46 ± 1 .06 3,27± 1.37 3.09 ± 2"25 2-89±1.14 2842 ± 457 1812# =E 691

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41 ± 7 58#±12 2 . 5 8 ~= 0 . 4 0 4.06# ±0.71 2 - 8 4 ± 1 -37 4.62±1,15 2586 ± 1169 1669 ± 360

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60 59 ± 2 65 ± 17 3.66±0-26 4"52±1"14 3 - 6 5 ± 1 "45 5.24±1.83 1552 ± 433 1532 ± 331 585±112 542 ± 223

772±190 559 ± 207

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50 ± 13 58 ± 14 3,13±0"70 4"03±0"90 3"23 ± 1.17 4-17±1"23 2192 ± 1207 1574 =1=486

Time 45

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692=1=151 630 ± 3 2 6 t

48 ± 5 62 ± 2 5 t 3-04±0-44 4.19±1,63t 3"02 ± 1.43 5.16±2'86t 1824 ± 497 1744 ± 4 0 2 t

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44 =E 8 52 ± 10 2"76±0"63 3"62±0'76 2"77 ± 1 '68 4.31±1"69 1948 ± 525 1905 ± 309

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42 -~ 10 51 ± 12 2'64±0"77 3.53±0"73 2 ' 6 2 ± 1 "76 4"02±1'14 2025 ± 732 1938 ± 417

120

875±159 703 ± 229

39 ± 9 48 ± 6 2.49±0"70 3.38±0-34 2 - 4 5 ± 1 "68 3.42±0-35 2097 ± 6 8 4 1788 ± 287

30 ± 3 36±4 7.7±0,6 7,1±0.5

7.7±0.8 6.5±1.4

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7.54±0.08 7"46±0"03 4.4±0.9 5-0±0.7 49-2± 3-6 48.1±3-1 5-5±2-2 3-2±1-9 37"0±0-5 36.9±0-7

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7.56±0-06 7"47# ±0"03 4.1 ±0.7 4.9±0.6 50.3±1.4 49.4±4-1 4.9±2-2 3.1±1-7 36-6±0"4 36-9±0-8

Data are expressed as mean ± SD n = 4 except where indicated, t n = 3 * Values significantly different from time 0 (P < 0 - 05) # Values significantly different f r o m g r o u p 1 ( P < 0 . 0 5 )

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31 ± 5 35±4 7-7±0.6 7.0±0.5

7.49±0.05 7.38# ±0'05 4,8±0.5 6-2#±0-7 59.5±4.6 48-8#±6.5 3.6±3.0 1.4±1-4 36'5±0"3 36,9±0.8

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2.3*±0.4 3.7*±2"3

34 ± 2 37=t=4 7,6±0.6 7.0±0.4

7.50±0.06 7 ' 4 0 # ~=0-05 4-4±0-7 5.6#±0-7 47,2±13.2 40.6±18.6 2-9±3.1 0-7±1-4 36-5±0"2 37,0±0-8

50

2.1"±0"4 2.3"±1.1

36 ± 4 39±3 7-8±0.5 7.0±0.5

7.49±0.08 7"38 ±0"04 4.5±0.7 5.6#±0.6 25.4"±12.9 32.3±13.9 2.2±3.3 -0-1"±1.4 36-5±0"3 37.0±0,9

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2.1"±0.5 1-8" ±0.5t

37* ± 4 39 ~: 3~ 8.0±0.4 7-3 ±0.4t

7.45±0.09 7"41 ± O . 0 4 t 4.7±0.9 5.3±0"6t 22.5"±14.6 25.0" ± 14.4t 0.9±3.5 0.5± 1.3t 36-4±0"3 37-1 ± 0 . 8

75

1.9"±0.3 1.8" ±0-8

37* ± 4 40±4 8.0±0-4 7-2±0.6

7.45±0-11 7"38±0"05 4,7±0-8 5.7±0"8 23.8"±14-3 21.1"±15.3 0.3±4.4 -0.1"±1.4 36"4±0"4 37.3±0.5

90

1.9"±0-5 1.5"±0"5

38* ± 4 40±2 8.0±0.4 7.3 ±0.7t

7.43±0"09 7-37±0"05 4-7±0.7 5-6±0.4 26.0"±13.1 22.3"±12.6 0'4=L4"5 1,2"±1-6 36'4±0"4 3 7 . 3 =E0 . 6

105

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39* ± 5 42±2 8.1 ±0.4 7.4±0.6

7.42±0-09 7-37±0.03 4.6±0.7 5.7#±0-5 28.8"=t=12,0 23.0"±11-5 --1"3±4"5 -1.0"±1.4 36"3±0-5 37.3±0.7

120

TABLE 5: pH, blood gases, packed cell volume, plasma protein and white cell count in anaesthetised horses given endotoxin (group 1) or dopamine and endotoxin (group 2)

Data expressed as mean ± SD n - 4 except where indicated, t n = 3 * Values significantly different from time 0 (P< 0 • 05) # Velues significantly different f r o m g r o u p 1 ( P < O - 0 5 )

Cardiac output (mlkg 1 min-1) Cardiac index ( l i t r e m - 2 m i n -1) Leftventricularworkindex ( k g m m i n l m 2) Total vascular resistance (dynes s 1 c m - 5 ) Total pulmonary resistance (dynes s - 1 c m - 5 )

Variable

TABLE 4: Cardiovascular values of anaesthetised horses given endotoxin (group 1) or dopamine and endotoxin (group 2)

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Packed cell volume was significantlyincreased at 75 to 120 minutes (P < 0-01) whereas the plasma protein concentration remained unchanged (Table 5). The white cell count was Significantly decreased at 15 to 120 minutes (P = 0.0001) (Table 5). Plasma concentrations of lactate and glucose were determined for two horses. Plasma lactate concentrations in these horses at time 0 were 1.2 and 1.3 mmol litre- t and increased to 2- 1 and 2- 6 mmol litre- l at 120 minutes. Blood glucose concentrations at time 0 were 4.4 and 5.8 mmol litre -~ and at 120 minutes were 2.9 and 4.2 mmol litre- 1. Plasma noradrenaline concentration increased non-significantly from 284 -4- 163 pg m1-1 at time 0 to 508 .4- 278 pg m l - 1at 60 minutes and 418 .4- 383 pg ml-~ at 120 minutes. Plasma adrenaline concentration was 79 -4- 73 pg m l - t at time O, 236 .4- 125 pg ml-~ at 60 minutes and 110 .4- 12 pg ml-~ at 120 minutes. Plasma dopamine concentration at time 0 was 145 .4- 94 pg m1-1 and remained unchanged for 120 minutes.

Group 2. Heart rate was unchanged for 120 minutes (Table 3). Systolic and diastolic facial arterial pressures were not significantlyincreased from time 0 (Table 3). Mean arterial pressure, expressed as per cent change of time 0 value, was greater than in group 1 at 60 minutes (P = 0- 052), 75 minutes (P < 0.05), 90 minutes (P=0.057) and 105 minutes ( P < 0 . 0 5 ) (Fig 1). Increases in systolic and diastolic pulmonary arterial pressures were not statistically significant (Table 3), and diastolic pulmonary arterial pressure was significantly less than in group 1 at 15 minutes ( P < 0 . 0 5 ) (Table 3). Cardiac output and cardiac index were significantly increased from group 1 at 30 minutes (P < 0.05) (Table 4). When expressed as per cent change from time 0, cardiac output was increased at 30 to 90 minutes and was significantly increased from group 1 at 30 and 120 minutes (P < 0.05) (Fig 2). Changes in left ventricular work index, total vascular resistance and total pulmonary resistance were not statistically significant (Table 4). Total vascular resistance was significantly less than in group 1 at 15 minutes (P<0-05) and total pulmonary resistance was significantly less than in group 1 at 30 minutes (P < 0.005) (Table 4). pHa was significantly lower than in group 1 from time 0 to 45 minutes, due in part to a higher Paco 2 (P<0-05) (Table 5). Base excess was significantly decreased from time 0 at 60 minutes and 90 to 120 minutes (P<0.01), but values were not different from group 1. The mmol litre- ~change in base excess from time 0 was significant from 30 to 120 minutes (P < 0.05) (Fig 3). Pao 2 was significantly decreased from time 0 at 75 to 120 minutes (P < 0.01) and from group 1 value at 30 minutes (P<0"05). The lowest

Pao 2 values recorded in individual horses were 12.4 kPa, 12-8 kPa, 14-0 kPa and 30.3 kPa. Packed cell volume increased non-significantlyand plasma protein concentration was unchanged (Table 5). The white cell count was significantly decreased from time 0 at 45 to 120 minutes (P < 0.05) (Table 5). Plasma lactate progressively increased from a time 0 concentration of 1.1 ± 0"2 mmol litre-~ to 1" 6 ± 0" 2 mmol litre-~ at 60 minutes and to 2-3 .4- 0.4 mmol litre -~ at 120 minutes. Lactate was significantly increased from time 0 at 75 to 120 minutes (P<0.005). Blood glucose was 4-9 .4- 0.1 mmol litre- ~at time 0, 7.4 .4- 2.5 mmol litre- ~at 60 minutes and 6-9 .4- 3.6 mmol litre-~ at 120 minutes. The horses in both groups recovered from anaesthesia normally and without difficulty; one horse was slightly lame in the right hindlimb. At four hours after anaesthesia, all horses were alert and eating hay. Rectal temperatures and respiratory rates were mildly or moderately increased, and heart rates were normal or moderately increased. All packed cell volumes were less than 0.40 litres litre-1 and plasma protein concentrations were similar to values recorded before anaesthesia. At eight hours, temperatures, heart rates and respiratory rates had decreased, except in one horse that maintained an increased temperature and heart rate and a second horse that had a mildly increased heart rate. Flunixin meglumine was administered to the latter two horses (group 1 horses) after the eight hour values were recorded. The horses did not appear to be distressed in the period after anaesthesia, except for increased respiratory rates. Further medical treatment was judged to be unnecessary. Discussion Horses with colic that are anaesthetised for surgical intervention frequently develop hypotension and other evidence of inadequate cardiovascular function (Harvey et al 1987, Trim et al 1989). Although a variety of factors may contribute to this malfunction, endotoxaemia is prevalent in horses with colic (King and Gerring 1988, Fessler et al 1989) and may be in part responsible for these haemodynamic alterations. Endotoxaemia may also develop in some horses during anaesthesia subsequent to manipulation of ischaemic intestine (Moore et al 1981a). Using an intravenous infusion of endotoxin, the present authors attempted to mimic the clinical situation involving surgery on an anaesthetised horse with colic and specifically during surgical manipulation of ischaemic intestine. The delay of five minutes before the start of a dopamine infusion was intended to mimic the time required to recognise the need for cardiovascular support and to prepare a dopamine solution.

Dopamine effects in anaesthetised endotoxaemic horses Four horses were anaesthetised without receiving either endotoxin or dopamine treatments and were monitored for 120 minutes of anaesthesia. Although the depth of anaesthesia was not determined by measurement of the end-tidal halothane concentration, no changes occurred in the cardiopulmonary or haematological values measured. Consequently, the same anaesthetic technique was used for the remainder of the study. The inspired halothane concentration was measured and kept constant in the horses given dopamine and, or, endotoxin. Because inspired and not end-expired halothane concentration was measured, it is likely that the depth of anaesthesia may have increased slightly during the 120 minute measurement period. Values recorded at time - 1 5 and at time 0 were similar, which would be expected with a stable anaesthetic plane. Controlled ventilation was used in this study because hypercapnia may have a significant effect on the haemodynamic responses to endotoxin (Larsson and Ekstr6m-Jodal 1986). Pulmonary arterial hypertension, lactic acidosis, haemoconcentration and neutropenia developed in the endotoxaemic horses in this investigation. These changes are characteristic of endotoxaemia in horses and ponies (Burrows 1979, Moore et al 1980, 1981b, Bottoms et al 1982, Fessler et al 1982, Frauenfelder et al 1982, Ewert et al 1985). The initial increase at 15 minutes in total vascular and pulmonary resistances observed in the horses given endotoxin might be explained by an abrupt increase in the synthesis of thromboxane A 2, as the plasma concentration of thromboxane B2 peaks in approximately 30 minutes (Moore et al 1986, Templeton et al 1987). After the initial vasoconstrictive response to endotoxaemia, there is an enhanced synthesis of the vasodilatory prostaglandin 12. In previous studies in horses, peak plasma concentrations of 6-keto prostaglandin F ~ , the stable metabolite of prostaglandin 12, occurred 60 to 90 minutes after administration of endotoxin (Moore et al 1986, Templeton et al 1987). This may account for the decrease in total vascular resistance observed in our horses at 60 minutes. The increase in cardiac output occurring at 60 minutes after administration of endotoxin may have been secondary to vasodilation caused by the increased synthesis of prostaglandin 12 (Trim et al 1985b). The contribution of circulating catecholamines to the increase in cardiac output is unclear. In the experiments reported here, small increases in plasma concentrations of adrenaline and noradrenaline developed at 60 minutes. However, there was considerable variation between horses. This is in contrast to the increases in plasma concentrations of catecholamines that have been measured after endotoxin administration in other species (Ekstrfm-Jodal et al 1982). Presumably these differences and the wide variability in the response of our individual horses

61

were due to the low dose of endotoxin used in the present study when compared to thelarger doses used in other species. None of the horses given an infusion of dopamine developed hypotension in response to endotoxin administration. Furthermore, cardiac output values were higher in horses given dopamine and endotoxin compared with those administered endotoxin alone. Increased cardiac output during infusion of dopamine has been reported previously in healthy anaesthetised horses (Swanson et al 1985, Trim et al 1985a). These results lend credence to the intraoperative use of dopamine in hypotensive horses anaesthetised for surgical treatment of intestinal ischaemia. In other species, infusion of dopamine has had beneficial effects during endotoxaemia or septic shock by reversing cardiac depression and hypotension and increasing survival rate (Somani and Saini 1981, Lobe et al 1987). An interesting consequence of endotoxin administration in the present horses was the late development of low Pao2. Transient hypoxaemia occurred in conscious ponies immediately after a bolus injection of endotoxin (Moore et al 1980, 1981b) but was not observed in anaesthetised ponies (Olson 1985, Olson et al 1985). Increased venous admixture due to physiological shunting in the pulmonary circulation has been suggested as the cause for hypoxaemia in septic shock. This shunting may be the result of closure of alveoli and an abnormal pattern of blood flow distribution due to interstitial oedema or microembolism (Hess et al 1981). Inhibition of hypoxic pulmonary vasoconstriction by endotoxin (Hutchison et al 1985) may contribute to the increased PAo2-Pao2 difference. Considerable damage to the endothelium of pulmonary blood vessels has been seen after the administration of endotoxin in ponies (Moore et al 1981c, Turek et al 1985). Evidence in other species indicates that neutrophils are marginated in the pulmonary microcirculation and release proteolytic enzymes that destroy fibronectin which joins adjacent endothelial cells, thereby increasing vascular permeability (Traber 1985). Release of other products, such as leucotrienes, has also been implicated. This damage may result in impaired oxygen uptake from the alveoli or the development of pulmonary oedema. Although increased lung water is a feature of endotoxaemia in sheep (Demling et al 1981, Traber et al 1987), no evidence of increased lung water was identified in anaesthetised p o n i e s after endotoxin infusion (Olson 1985). Infusion o f prostaglandin 12 to anaesthetised horses resulted in a similar decrease in Pao2 in conjunction with decreased arterial blood pressure and decreased total pulmonary vascular resistance (Trim et al 1985b). Clearly these effects of endotoxaemia are mediated by inflammatory substances in addition to prostaglandin 12, as total

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C. M. Trim, J. N. Moore, M. M. Hardee, G. E. Hardee, E. A. Slade

pulmonary vascular resistance was not decreased in the horses given endotoxin. Dopamine administration had no beneficial effect in preventing low Pao2. Similarly, no improvement in arterial oxygenation was obtained in hypoxic normal dogs after infusion of dopamine, and this was attributed to a dopamineinduced increase in oxygen consumption (Lejeune et al 1987). Metabolic acidosis is a characteristic feature of endotoxaemia in horses and ponies and, in this investigation, a significant base deficit occurred despite maintenance of adequate arterial pressure and cardiac output with dopamine. Although peripheral perfusion may be influenced by haemoconcentration and decreased plasma volume (Spurlock et al 1985), there is evidence that lactic acid is produced during endotoxaemia despite adequate oxygen delivery, and that oxygen extraction by tissues is impaired (Nelson et al 1988, Samsel et al 1988). Plasma glucose may change in a biphasic pattern after endotoxin administration. Measurements in ponies have identified significant increases in plasma glucose at 60 minutes, followed by a maintained increase or return to baseline at 120 minutes and subsequent significant decreases (Fessler et al 1982, Ewert et al 1985). The initial increase in plasma glucose has been attributed to an increase in hepatic production of glucose and the hypoglycaemia attributed to a return of the hepatic synthesis of glucose to a normal level, coupled with increased glucose utilisation by peripheral tissues (Naylor and Kronfeld 1985). Plasma glucose concentrations did not decrease in our horses given dopamine and endotoxin compared with two horses given endotoxin alone. This difference was probably an effect of dopamine administration, although the effect of dopamine on plasma glucose concentrations in healthy horses was not significant (Trim et al 1985a, Robertson et al 1988). The present authors concluded that dopamine infusion modified the cardiovascular responses of anaesthetised horses to endotoxin and prevented hypotension. Dopamine had no effect on the development of decreased Pao2 and metabolic acidosis. The effectiveness of dopamine in preventing hypotension from a larger dose of endotoxin remains to be determined.

Acknowledgements This work was presented in part at the American College of Veterinary Anesthesiologist's Annual Meeting, Atlanta, Georgia, October 1983 and at the Second Equine Colic Research Symposium, Athens, Georgia, September 1985. This work was supported by the University of Georgia, Veterinary Medical Experiment Station Animal Disease Grant number

29-26-GR207-002, Projects 81-112 and 83-112, and by the Bolshoi Equine Colic Research Fund. The authors wish to thank American Critical Care, Division of American Hospital Supply Corporation, for supplying the dopamine, Cindy Jo Brown for technical assistance, and Dr E. Susan Clark, Department of Large Animal Medicine, for assistance with the statistical analyses.

References ALTMAN, P. L. & DITTMER, D. S. (1964) Biology Data Book. Washington DC, Federation of American Societies for Experimental Biology. p 121 BOTTOMS, G. D., FESSLER, J. F., ROESEL, O. F., MOORE, A. B., FRAUENFELDER, H. C. & BOON, G. D. (1981) Endotoxin-induced hemodynamic changes in ponies: Effects of flunixin meglumine~ American Journal of Veterinary Research 42, 1514-1518 BOTTOMS, G. D., TEMPLETON, C. B., FESSLER, J. F., JOHNSON, M. A., ROESEL, O. F., EWERT, K. M. &ADAMS, S. B. (1982) Thromboxane, prostaglandin 12 (epoprOstenol), and the hemodynamic changes in equine endotoxic shock. American Journal of Veterinary Research 43,999-1002 BURROWS, G. E. (1970) Hemodynamic alterations in the anestethized pony produced by slow intravenous administration of Escherichia coli endotoxin. American Journal of Veterinary Research 31, 1975-1982 BURROWS, G. E. (1979) Equine Escherichia coli endotoxemia: Comparison of intravenous and intraperitoneal endotoxin administration. American Journal of Veterinary Research 40, 991-998 DEMLING, R. H., SMITH, M., GUNTHER, R., FLYNN, J. T. & GEE, M. H. (1981) Pulmonary injury and prostaglandin production during endotoxemia in conscious sheep. American Journal of Physiology 240, H348-H353 EKSTROM-JODAL, B., H.~.GGENDAL, J., LARSSON, L. E. & WESTERLIND, A. (1982) Cerebral hemodynamics, oxyen uptake and cerebral arteriovenous differences of catecholamines following E coli endotoxin in dogs. Acta Anaesthesiologica Scandinavica 26, 446-452 EWERT, K. M., FESSLER, J. F., TEMPLETON, C. B., BOTTOMS, G. D., LATSHAW, H. S. & JOHNSON, M. A. (1985) Endotoxin-induced hematologic and blood chemical changes in ponies: Effects of flunixin meglumine, dexamethasone, and prednisolone. American Journal of Veterinary Research 46, 24-30 FESSLER, J. F., BOTTOMS, G. D., ROESEL, O. F., MOORE, A. B., FRAUENFELDER, H. C. & BOON, G. D. (1982) Endotoxin-induced change in hemograms, plasma enzymes, and blood chemical values in anesthetized ponies: Effects of flunixin meglumine. American Journal of Veterinary Research 43, 140-144 FESSLER, J. F., BOTTOMS, G. D., COPPOC, G. L., GIMARC, S., LATSHAW, H. S. & NOBLE, J. K. (1989) Plasma endotoxin concentrations in experimental and clinical equine subjects. Equine Veterinary Journal Supplement 7, 24-28 FRAUENFELDER, H. C., FESSLER, J. F., MOORE, A. B., BOTTOMS, G. D. & BOON, G. D. (1982) Effects of dexamethasone on endotoxic shock in the anesthetized pony: Hematologic, blood gas, and coagulation changes. American Journal of Veterinary Research 43,405-411 GARMAN, J. K. (1982) Clinical use of pulmonary artery catheters~ Proceedings of the International Anesthesia Research Society's 56th Congress. Cleveland, Ohio, International Anesthesia Research Society. pp 46-51 HARDEE, G. E., LAI, J. W., SEMRAD, S. D. & TRIM, C. M. (1982) Catecholamines in equine and bovine plasmas. Journal of Veterinary Pharmacology and Therapeutics 5, 279-284

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of flunixin meglumine on cardiopulmonary responses to endotoxin in ponies. Journal of Applied Physiology 59, 1464-1471 ROBERTSON, S. A., MALARK, J. & STEELE, C. (1988) Metabolic and hormonal changes during dopamine infusion in horses. 3rd Equine Colic Research Symposium Abstracts. Athens, University of Georgia, 42 SAMSEL, R. W., NELSON, D. P . SANDERS, W. M., WOOD, L. D. H. & SCHUMACKER, P. T. (1988) Effect of endotoxin on systemic and skeletal muscle 02 extraction. Journal of Applied Physiology 65, 1377-1382 SOMANI, P. & SAINI, R. K. (1981) A comparison of the cardiovascular, renal, and coronary effects of dopamine and monensin in endotoxic shock. Circulatory Shock 8, 451-464 SPURLOCK, G. H., LANDRY, S. L., SAMS, R., McGUIRK, S. & MUIR, W. W. (1985) Effect of endotoxin administration on body fluid compartments in the horse. American Journal of Veterinary Research 46, 1117-1120 STEFFEY, E. P. & HOWLAND, D. (1978) Cardiovascular effects of halothane in the horse. American Journal of Veterinary Research 39, 611-615 SWANSON, C. R., MUIR, W. W., BEDNARSKI, R. M., SKARDA, R. T. & HUBBELL, J. A. E. (1985) Hemodynamic responses in halothane-anesthetized horses given infusions of dopamine or dobutamine. American Journal of Veterinary Research 46, 365-370 TEMPLETON, C. B., BOTTOMS, G. D., FESSLER, J. F., EWERT, K. M., ROESEL, O. F., JOHNSON, M. A. & LATSHAW, H. S. (1987) Endotoxin-induced hemodynamic and prostaglandin changes in ponies: Effects of flunixin meglumine, dexamethasone, and prednisolone. Circulatory Shock 23, 231-240 TRABER, D. L. (1985) Pulmonary microvascular dysfunction during shock. Eds H. F. Janssen and C. D. Barnes. Circulatory Shock: Basic and Clinical Implications. New York, Academic Press. pp 23-46 TRABER, D. L., SCHLAG, G., REDL, H., STROHMAIR, W. & TRABER, L. D. (1987) Pulmonary microvascular changes during hyperdynamic sepsis in an ovine model. Circulatory Shock 22, 185-193 TRIM, C. M. (1977) Anaesthetic management of the horse with acute intestinal obstruction. Proceedings, Association of Veterinary Anaesthetists of Great Britain and Ireland 7, 28-41 TRIM, C. M., ADAMS, J. G., COWGILL, L. M. & WARD, S. L. (1989) A retrospective survey of anaesthesia in horses with colic. Equine Veterinary Journal Supplement 7, 84-90 TRIM, C. M., MOORE, J. N., HARDEE, M. M., HARDEE, G. E. & GRAHAM, D. A. M. (1985b) Cardiopulmonary effects of prostacyclin infusion in anesthetized horses. American Journal of Veterinary Research 46, 928-931 TRIM, C. M., MOORE, J. N. & WHITE, N. A. (1985a) Cardiopulmonary effects of dopamine hydrochloride in anaesthetised horses. Equine Veterinary Journal 17, 41-44 TUREK, J. J., TEMPLETON, C. B., BOTTOMS, G. D. & FESSLER, 3. F. (1985) Flunixin meglumine attenuation of endotoxin-induced damage to the cardiopulmonary vascular endothelium of the pony. American Journal of Veterinary Research 46, 591-596

Received February 6, 1990 Accepted July 27, 1990