Effects of Norepinephrine and Combined Norepinephrine and Fenoldopam Infusion on Systemic Hemodynamics and Indices of Renal Function in Normotensive Neonatal Foals
A.R. Hollis is with the New Bolton Center, Kennett Square, PA. K.T.T. Corley and J.O. Stephens are with the Anglesey Lodge Equine Hospital, The Curragh Co. Kildare, Ireland. This study was performed at the Equine Fertility Unit, Newmarket, UK, and the Royal Veterinary College, Hertfordshire, UK.
Corresponding author: Dr Kevin Corley, Anglesey Lodge Equine Hospital, The Curragh Co. Kildare, Ireland; e-mail: email@example.com.
Background: Norepinephrine increases arterial blood pressure but may have adverse effects on renal blood flow. Fenoldopam, a dopamine-1 receptor agonist, increases urine output in normotensive foals. The combination of norepinephrine and fenoldopam may lead to improved renal perfusion compared with an infusion of norepinephrine alone. The combined effects of these drugs have not been reported in the horse.
Hypothesis: Norepinephrine will alter the hemodynamic profile of foals without affecting renal function. Addition of fenoldopam will change the renal profile during the infusions without changing the hemodynamic profile.
Animals: Five conscious pony foals.
Methods: Each foal received norepinephrine (0.3 μg/kg/min), combined norepinephrine (0.3 μg/kg/min) and fenoldopam (0.04 μg/kg/min), and a control dose of saline in a masked, placebo-controlled study. Heart rate (HR), arterial blood pressure (direct), and cardiac output (lithium dilution) were measured, and systemic vascular resistance (SVR), stroke volume, cardiac index (CI), and stroke volume index were calculated. Urine output, creatinine clearance, and fractional excretion of electrolytes were measured.
Results: Norepinephrine and a combined norepinephrine and fenoldopam infusion increased arterial blood pressure, SVR, urine output, and creatinine clearance and decreased HR and CI compared with saline. The combination resulted in higher HR and lower arterial blood pressure than norepinephrine alone.
Conclusions and Clinical Importance: Norepinephrine might be useful for hypotensive foals, because in normal foals, this infusion rate increases SVR without negatively affecting renal function (creatinine clearance increased). Fenoldopam does not provide additional benefit to renal function. These findings warrant further investigation.
Norepinephrine is a potent vasopressor with α- and, to a lesser extent, β-1 receptor agonist activity.1 Norepinephrine primarily is used as a vasopressor in states of hyperdynamic shock, in which systemic vascular resistance (SVR) is decreased and mean arterial blood pressure is low.2 There are concerns about the possibility of norepinephrine adversely affecting renal hemodynamics, because it has been shown to decrease renal blood flow, urine output, or both in healthy humans3,4 and dogs.5 In normotensive sheep, however, norepinephrine increased urine output and renal blood flow,6,7 and at 0.1 μg/kg/min had no effect on urine output or creatinine clearance in normotensive foals, despite changing systemic hemodynamics.8 Norepinephrine-induced renal vasoconstriction appears to be less problematic in states of hyperdynamic shock, in which the addition of norepinephrine to the treatment protocol improved mean arterial blood pressure and urine output in septic humans,9–13 sheep,14 dogs,5 and foals.15
Fenoldopam is a dopamine-1 receptor agonist that, at a low dosage of 0.04 μg/kg/min, increased urine output without affecting systemic hemodynamics in the normotensive, neonatal foal.16 At a high dosage of 0.4 μg/kg/min, fenoldopam decreased arterial blood pressure and had no effect on urine output.16 The combination of norepinephrine and a low dose of fenoldopam may be preferable to an infusion of norepinephrine alone, because fenoldopam may dilate renal and splanchnic circulation, reducing the risk of excessive vasoconstriction after norepinephrine administration.
The hemodynamic effects of norepinephrine combined with fenoldopam have not been documented in the neonatal foal. The aim of this study was to investigate the hemodynamic effects of norepinephrine and a combined norepinephrine and fenoldopam infusion in the normotensive, neonatal foal. In addition, the effects of these infusions on renal function, measured by urine output, endogenous creatinine clearance and fractional excretion of electrolytes were investigated.
Materials and Methods
This protocol was approved by the Animal Welfare Committee of the study center (Equine Fertility Unit, Newmarket, and the Royal Veterinary College, Hertfordshire), and performed under Home Office Licence.
Five healthy, normotensive, neonatal pony foals were included in the study. There were 4 colts and 1 filly. They were 30–56 hours (mean, 43 hours) old and body weight was 32–42 kg (mean 37 kg). All were delivered spontaneously and at term. Postnatal hematology and baseline hemodynamics were measured, and only foals with normal values were included.17,18
Under sedation with 5–10 mg intravenous diazepama administered IV, foals were restrained in lateral recumbency on a foal mat and instrumented for the study. A 16 G 7.5 cm IV catheterb was aseptically placed in the jugular vein and secured with sutures and an elasticated bandage. An over-the-wire 20 G 3.81 cm IV catheterc was aseptically placed into the dorsal metatarsal artery, secured with superglue, and protected with a bandage. A 33-cm (fillies) or 55-cm (colts) 12 French Foley indwelling urinary catheterd was placed aseptically and connected to a closed collection system. The foals then were allowed to stand and nurse from the dam, and given a recovery period of at least 1 hour after administration of diazepam.
Hemodynamic and Other Measurements
Electrocardiogram (ECG) leads were placed on the foal in a base-apex configuration to allow monitoring of the animal's ECG.e Direct blood pressure was measured by connecting the dorsal metatarsal arterial catheter to an electronic pressure transducer,f which was placed and zeroed at the level of the right atrium. Cardiac output in L/min (CO) was determined by the lithium dilution method, as described.19 Briefly, a bolus of 0.45 mmol lithium chloride was injected into the jugular vein via the jugular catheter. At the same time, blood was withdrawn from the metatarsal artery via the arterial catheter. Blood was withdrawn through a lithium-specific electrode at a constant rate of 4 mL/min by means of a peristaltic pump. A lithium-time concentration curve was generated, and the CO was calculated from the area under the curve by a dedicated computer.g This method has been validated for use in the neonatal foal.19 Stroke volume in mL (SV) and SVR in dynes/s/cm5 were calculated by the LiDCO Plus computer according to standard formulas. The SVR was calculated, assuming a central venous pressure (CVP) of 7 mmHg, with the equation SVR = ([MAP − CVP] / CO × 79.9), where MAP is mean arterial pressure.
The cardiac index (CI) and stroke volume index (SVI) were calculated to normalize the data for body weight. In humans, CO and SV are indexed using calculated body surface area in m2,20 which generally is not used in horses.21 CI and SVI were calculated using the following equations:
During the study period, urine output was measured with a closed collection system attached to the indwelling urinary catheter. The urine collected was analyzed for specific gravity with a hand-held refractometer.h Serum samples also were collected at predetermined time points. Urine and serum samples were assayed for sodium, potassium, and chloride (with ion-selective electrodes) and creatinine (by end-point analysis colorimetric methodology) with the ILab 600.i
The creatinine clearance (CrCl) and fractional excretion of sodium, potassium, and chloride were calculated for each infusion in each foal using the following equations:
During the study period, the foals were restrained in lateral recumbency on a foal mat. They were administered 0.9% salinej IV at maintenance rate (4.17 mL/kg/h) during their period on the mat, which was delivered by a fluid pumpk throughout the drug infusion periods. During the 1st measuring period, baseline measurements of heart rate (HR), ECG, behavior, CO, direct blood pressure, SV, and SVR were recorded and baseline serum and urine samples were obtained.
After baseline measurements, the 1st infusion was started. Each foal received 1 dose of norepinephrine (0.3 μg/kg/min) (NE), 1 dose of norepinephrine (0.3 μg/kg/min) with fenoldopam (0.04 μg/kg/min) (NE+FEN), and 1dose of 0.9% saline as a placebo in a crossover, randomized, double blind manner. The drug solutions were made up in 20 mL of 0.9% saline, fresh for each foal. The solutions were randomized by a person not participating in the study using a table of random numbers, and stickers marked “A,”“B,” or “C” were applied to the otherwise identical syringes. The drug solutions were delivered by a Terumo syringe in a syringe driverl at a rate of 30 mL/h. The 0.9% saline infusion also was delivered at the same rate. Each infusion was maintained for 30 minutes. During the first 10 minutes (stabilization period), no measurements were recorded, but the foal was monitored closely. At 10 minutes, the measuring period commenced. The urine bag was emptied and the urine discarded, a serum sample was taken, and CO was determined. During the measuring period, the foal's HR, ECG, and direct blood pressure were displayed continuously by a critical care monitork and recorded every 2 minutes, and the foal's CO, SVR, and SV were measured and recorded every 10 minutes. The foal's behavior was recorded every 2 minutes. At the end of the 30-minute infusion period, the urine bag was emptied, urine volume measured, and serum and urine samples obtained. After the 1st infusion period, the foal was given a 40-minute drug wash-out and recovery period, when it was allowed to stand and nurse from the mare. The 2nd (B) and 3rd (C) infusions followed the same pattern, without the initial baseline measurements, with washout and recovery periods observed between each infusion. At the end of the experiment, all catheters and equipment were removed from the foal, and the foal was returned to the mare.
Data were analyzed by mixed and random regression models with foal as the random effect and repeated measures analysis. Hypothesis testing differences in the responses between drugs were examined using a P-value of .05 to separate chance from true differences, and Bonferroni's correction for multiple comparisons was applied. All data were analyzed by commercially available statistical software.m
As in previous experiments with the same experimental design,8,16 the techniques were well tolerated by the foals. Experimental periods immediately followed free-choice nursing from the mare, and the foals generally were somnolent or sleeping during the infusion periods. One foal had a brief period of restlessness that did not appear to affect its hemodynamics.
Baseline hemodynamic measurements were compared with those made during the infusion of saline, and no differences were observed (Table 1). No significant difference in USG between saline infusion and baseline was found (Table 2).
Table 1. The effects of norepinephrine, norepinephrine with fenoldopam, or saline infusion on hemodynamics in 5 healthy foals; data presented are the mean of all measurements taken over the 20 minute recording period ± standard deviation.
|Norepinephrine 0.3 μg/kg/min||89.3a,b± 8.97||172a,b± 26.6||80.0a,b± 10.9||108a,b± 10.9||7.32a± 1.48||199a± 31.6||1,150a± 209||83.8 ± 24.9||2.25 ± 0.50|
|Norepinephrine 0.3 μg/kg/min + fenoldopam 0.04 μg/kg/min||97.8a,b± 11.3||159a,b± 20.0||73.4a,b± 12.5||101a,b± 11.6||7.82a± 1.76||206a± 45.0||1,016a± 208||80.5 ± 12.4||2.16 ± 0.36|
|Saline||121 ± 11.7||136.9 ± 21.1||55.5 ± 7.49||81.1 ± 8.00||10.5 ± 2.46||282 ± 56.2||600 ± 139||85.5 ± 22.7||2.28 ± 0.49|
|Baseline||118 ± 10.3||137 ± 30.6||62.0 ± 6.75||86.6 ± 9.53||10.0 ± 1.42||271 ± 3.1||630 ± 54.7||85.1 ± 19.9||2.28 ± 0.23|
Table 2. The effects of norepinephrine, norepinephrine with fenoldopam, or saline infusion on renal function in 5 healthy foals.
|Norepinephrine 0.3 μg/kg/min||2.95a± 0.756||0.138 ± 0.248||0.211 ± 0.105||0.027 ± 0.028||283a± 102||1.0028 ± 0.00205|
|Norepinephrine 0.3 μg/kg/min + fenoldopam 0.04 μg/kg/min||2.73a± 0.445||0.027 ± 0.018||0.221 ± 0.081||0.067 ± 0.105||250a± 18||1.0024 ± 0.00207|
|Saline||1.82 ± 0.427||0.019 ± 0.014||0.253 ± 0.061||0.023 ± 0.022||128 ± 73||1.004 ± 0.00082|
|Baseline||—||—||—||—||—||1.0026 ± 0.00134|
Effects of Norepinephrine and Norepinephrine with Fenoldopam Infusions on Hemodynamics
Compared with saline, norepinephrine increased systolic arterial pressure (SAP) (P < .001), dystolic arterial pressure (DAP) (P < .001), MAP (P < .001), and SVR (P < .001), and decreased HR (P < .001), CO (P < .001), and CI (P < .001) (Table 1). No significant differences for SV or SVI were observed (Table 1).
Norepinephrine with fenoldopam resulted in increased SAP (P < .001), DAP (P < .001), MAP (P < .001) and SVR (P < .001), and decreased HR (P < .001), CO (P < .001), and CI (P < .001) compared with saline (Table 1). No significant differences for SV or SVI were observed.
Norepinephrine with fenoldopam resulted in lower SAP (P < .001), DAP (P < .001), and MAP (P < .001), and higher HR (P < .001) than did norepinephrine alone (Table 1). There was no difference in CO, CI, SVR, SV, or SVI between the 2 infusions (Table 1).
Effects of Norepinephrine and Norepinephrine with Fenoldopam Infusions on Renal Function
Norepinephrine resulted in increased urine output (P= .001) and creatinine clearance (P < .001) compared with saline (Table 2). No differences in the fractional excretion of sodium, potassium, or chloride were observed (Table 2). The combined infusion of norepinephrine and fenoldopam increased urine output (P= .004) and creatinine clearance (P= .013) compared with saline (Table 2). No differences in the fractional excretion of sodium, potassium, or chloride were observed (Table 2).
There were no differences in urine output, creatinine clearance, or the fractional excretion of electrolytes between the infusions of norepinephrine and norepinephrine with fenoldopam (Table 2).
In this group of healthy equine neonates, norepinephrine caused an increase in SVR, MAP, SAP, and DAP, and a decrease in HR. These findings are in agreement with data from humans,3,4 conscious foals given norepinephrine at a lower dosage (0.1 μg/kg/min),8 and anesthetized foals given norepinephrine at a variety of dosages.22 These results are likely to be a consequence of the α-adrenergic activity of norepinephrine, which primarily causes vasoconstriction, measured as an increase in SVR. This increase in SVR leads to an increase in blood pressure. The decreased HR seen in normal foals is likely to be a reflex response mediated by increased blood pressure.8 However, in critically ill, hypotensive foals, norepinephrine increased MAP but had no effect on HR,15 which may reflect a difference in the cardiovascular status of normal versus critically ill foals. There are also species-specific differences in the hemodynamic response to norepinephrine. In normotensive dogs, a decrease in HR and increased blood pressure were observed at 10 μg/kg/min, but no change in HR was found at lower infusion rates, despite an increase in arterial blood pressure.23,24 In normotensive sheep, norepinephrine increased both HR and MAP,6,7 which may represent a response to the β-adrenergic effects of norepinephrine.
Norepinephrine caused a decrease in CO in the foals in this study. This confirms previous data obtained after norepinephrine administration in normal foals8 and in 1 study of anesthetized foals,22 but differs from data in other species and a study of hypotensive anesthetized foals, in which the administration of norepinephrine increased CO.6,7,24,25 The reasons for these differences are unclear. It has been hypothesized that norepinephrine has minimal β-effects in the normal neonatal foal,8 which is supported by data from 1 study of anesthetized foals22 but is not supported by data from anesthetized, hypotensive foals.25 Different effects of norepinephrine may predominate during times of physiologic stress, as seen in the hypotensive anesthetized foals, compared with normal animals or anesthetized foals that are not hypotensive. Additional investigation on the cardiovascular effects of norepinephrine in the foal is warranted.
Norepinephrine at 0.3 μg/kg/min had no effect on SV in these foals. This is in contrast to data from normal foals given norepinephrine at 0.1 μg/kg/min, where a decrease in SV was seen,8 but in agreement with 1 study of anesthetized foals given norepinephrine at 0.05–0.4 μg/kg/min.22 The reason for the difference in SV at different infusion rates is unclear. Norepinephrine may have a less-marked effect on cardiac afterload at a higher infusion rate in the normotensive conscious foal, which may be because of more β-2 adrenergic activity at this dosage. In other species and in anesthetized, hypotensive foals, norepinephrine at a variety of infusion rates increased SV.6,7,24 The observed differences in SV in foals during infusions of norepinephrine warrant further investigation.
A combined infusion of norepinephrine and fenoldopam decreased HR and CO and increased SVR, SAP, DAP, and MAP. These changes are similar to those seen with an infusion of norepinephrine alone and are likely to have been mediated by the effects of norepinephrine on hemodynamics. To the authors' knowledge, a combined infusion of norepinephrine and fenoldopam has not been investigated in any normotensive species. Fenoldopam has been given at the same time as infusions of norepinephrine with dobutamine in septic human patients, in whom the addition of fenoldopam had no effect on systemic hemodynamics.26 Fenoldopam at 0.04 μg/kg/min had no effect on the hemodynamics of normotensive foals,16 and it would be expected that the addition of fenoldopam at this dosage to an infusion of norepinephrine would have no effect on the hemodynamic profile compared with that seen with norepinephrine alone. Compared with an infusion of norepinephrine, the combination of norepinephrine and fenoldopam resulted in lower SAP, DAP, and MAP and a higher HR. The lower blood pressure seen with the combination infusion may be a result of dopamine-1 receptor-mediated vasodilatation by the fenoldopam, blunting the hemodynamic effects of norepinephrine in these animals. This vasodilatation may be more marked in some vascular beds than others. Because the low HR seen during an infusion of norepinephrine is likely to be mediated by a reflex in response to increased blood pressure, the higher HR seen with the combination infusion is the expected response.
In this group of healthy foals, norepinephrine at 0.3 μg/kg/min increased urine output and creatinine clearance. This finding is in contrast to that observed in foals receiving a lower dosage rate of norepinephrine (0.1 μg/kg/min), where no change in urine output or creatinine clearance was seen.8 The reason for this difference is unclear. The higher dosage of norepinephrine may have improved renal perfusion as a result of increased arterial blood pressure, therefore increasing urine output and creatinine clearance. The different renal response of the normal foal to different dosages of norepinephrine warrants further investigation. However, the increase in urine output and creatinine clearance seen at this dosage in the normotensive foal is not unique to this species. Norepinephrine increased urine output and creatinine clearance in normotensive sheep at 0.4 μg/kg/min.6,7 In addition, norepinephrine increased urine output in septic foals when given at infusion rates of 0.1–1.5 μg/kg/min.15 Norepinephrine may have beneficial effects on renal function in the foal.
Compared with saline, an infusion of norepinephrine plus fenoldopam increased creatinine clearance and urine output. There was no difference in urine output and creatinine clearance between norepinephrine alone and norepinephrine plus fenoldopam. In normotensive foals, fenoldopam at 0.04 μg/kg/min increased urine output without affecting systemic hemodynamics.16 Therefore, the addition of fenoldopam to another infusion may be expected to increase urine output. Norepinephrine may increase renal perfusion by increasing arterial blood pressure, leading to an increase in urine output. The addition of fenoldopam to norepinephrine decreased arterial blood pressure compared with norepinephrine alone, and therefore no further increase in urine output was seen.
The 40-minute washout period was based on previously conducted experiments with norepinephrine8 and fenoldopam16 in the neonatal foal and on the half life of fenoldopam (10 minutes)27 and norepinephrine (2–2.5 minutes) in humans. This approach could have led to very low drug concentrations after the norepinephrine or norepinephrine plus fenoldopam infusions. Although study design controlled for this eventuality, differences in all parameters may have been blunted among the 3 infusions. Although persistence of effects was not specifically evaluated, this was not noted by the investigators in this or the previous, similarly designed experiments. It may have been beneficial to record baseline measurements at the beginning of each infusion period to rule out the persistent effects of the drugs, but this was not done. In addition, there were no notable changes in the recorded parameters over the measurement period, but this was not specifically analyzed. The 10-minute stabilization period was carried out to try and eliminate this possibility.
In this group of healthy foals, norepinephrine and a combined infusion of norepinephrine and fenoldopam increased arterial blood pressure, SVR, urine output, and creatinine clearance, and decreased HR and CO. The combination resulted in lower arterial blood pressure and higher HR than norepinephrine alone. These findings warrant further investigation.
aDiazemuls, Dumex, Barnstable, UK
bMila, Mila International Inc, Erlanger, KY
cRA-04220, Arrow International, PA
dCook Veterinary Products, Brisbane, Queensland, Australia
eDynascope 5300W, Fukuda Denshi, Tokyo, Japan
fUtah Medical Products Ltd Co, Westmeath, Ireland
gLiDCO plus, LiDCO Ltd, London, UK
hArnolds Veterinary Products, Shropshire, UK
iInstrumentation Laboratory, Milan, Italy
jVetIvex 1, Larne, UK
kFlo-gard 6300, Baxter Healthcare Corporation, Deerfield, IL
lIVAC P6000, Alaris Medical Systems, Hants, UK
mStata 9.2 for Windows, StataCorp LP, College Station, TX
This work was supported by funding from the Thoroughbred Breeder's Association, Rossdale and Partners and the Royal Veterinary College.