Effect of intravenous administration of lactated Ringer's solution or hetastarch for the treatment of isoflurane-induced hypotension in dogs

Turi K. Aarnes Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210.

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Richard M. Bednarski Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210.

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Phillip Lerche Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210.

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John A. E. Hubbell Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210.

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William W. Muir III Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210.

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Abstract

Objective—To determine the effect of IV administration of crystalloid (lactated Ringer's solution [LRS]) or colloid (hetastarch) fluid on isoflurane-induced hypotension in dogs.

Animals—6 healthy Beagles.

Procedures—On 3 occasions, each dog was anesthetized with propofol and isoflurane and instrumented with a thermodilution catheter (pulmonary artery). Following baseline assessments of hemodynamic variables, end-tidal isoflurane concentration was increased to achieve systolic arterial blood pressure (SABP) of 80 mm Hg. At that time (0 minutes), 1 of 3 IV treatments (no fluid, LRS [80 mL/kg/h], or hetastarch [80 mL/kg/h]) was initiated. Fluid administration continued until SABP was within 10% of baseline or to a maximum volume of 80 mL/kg (LRS) or 40 mL/kg (hetastarch). Hemodynamic variables were measured at intervals (0 through 120 minutes and additionally at 150 and 180 minutes in LRS- or hetastarch-treated dogs). Several clinicopathologic variables including total protein concentration, PCV, colloid osmotic pressure, and viscosity of blood were assessed at baseline and intervals thereafter (0 through 120 minutes).

Results—Administration of 80 mL of LRS/kg did not increase SABP in any dog, whereas administration of ≤ 40 mL of hetastarch/kg increased SABP in 4 of 6 dogs. Fluid administration increased cardiac index and decreased systemic vascular resistance. Compared with hetastarch treatment, administration of LRS decreased blood viscosity. Treatment with LRS decreased PCV and total protein concentration, whereas treatment with hetastarch increased colloid osmotic pressure.

Conclusions and Clinical Relevance—Results indicated that IV administration of hetastarch rather than LRS is recommended for the treatment of isoflurane-induced hypotension in dogs.

Abstract

Objective—To determine the effect of IV administration of crystalloid (lactated Ringer's solution [LRS]) or colloid (hetastarch) fluid on isoflurane-induced hypotension in dogs.

Animals—6 healthy Beagles.

Procedures—On 3 occasions, each dog was anesthetized with propofol and isoflurane and instrumented with a thermodilution catheter (pulmonary artery). Following baseline assessments of hemodynamic variables, end-tidal isoflurane concentration was increased to achieve systolic arterial blood pressure (SABP) of 80 mm Hg. At that time (0 minutes), 1 of 3 IV treatments (no fluid, LRS [80 mL/kg/h], or hetastarch [80 mL/kg/h]) was initiated. Fluid administration continued until SABP was within 10% of baseline or to a maximum volume of 80 mL/kg (LRS) or 40 mL/kg (hetastarch). Hemodynamic variables were measured at intervals (0 through 120 minutes and additionally at 150 and 180 minutes in LRS- or hetastarch-treated dogs). Several clinicopathologic variables including total protein concentration, PCV, colloid osmotic pressure, and viscosity of blood were assessed at baseline and intervals thereafter (0 through 120 minutes).

Results—Administration of 80 mL of LRS/kg did not increase SABP in any dog, whereas administration of ≤ 40 mL of hetastarch/kg increased SABP in 4 of 6 dogs. Fluid administration increased cardiac index and decreased systemic vascular resistance. Compared with hetastarch treatment, administration of LRS decreased blood viscosity. Treatment with LRS decreased PCV and total protein concentration, whereas treatment with hetastarch increased colloid osmotic pressure.

Conclusions and Clinical Relevance—Results indicated that IV administration of hetastarch rather than LRS is recommended for the treatment of isoflurane-induced hypotension in dogs.

Isoflurane is the most commonly used inhalation anesthetic in veterinary practice.1 Hypotension, an adverse effect of isoflurane anesthesia, increases the risk of morbidity and death as a result of diminished organ perfusion.1–3 Hypotension is defined as SABP < 80 mm Hg and is estimated to develop in 41% of anesthetized humans, in up to 32% of anesthetized dogs, and in up to 33% of anesthetized cats.1,4–6 Isoflurane increases blood flow to the brain, stomach, pancreas, and muscles and decreases blood flow to the kidneys and heart.3,7–9 Isoflurane also decreases myocardial oxygen consumption by decreasing cardiac afterload and myocardial contractility in dogs.10

Strategies for correction of isoflurane-induced hypotension include IV administration of fluids, reduction or termination of isoflurane delivery, administration of adjunct anesthetic and analgesic agents to reduce the inspired isoflurane concentration, and administration of inotropes and other vasoactive drugs.11–18 A reduction in the delivered anesthetic concentration can be effective, but may be impractical or inappropriate during surgery or diagnostic procedures because of the animal's return to consciousness. Coadministration of inhalation anesthetic–sparing drugs or adjunct anesthetic or analgesic agents (eg, ketamine hydrochloride, opioids, lidocaine hydrochloride, or α2-adrenergic receptor agonists) reduces the required inhalation anesthetic concentration and may restore normotension, but bradycardia and respiratory depression may develop and return to consciousness after anesthesia may be delayed.12–17 Inotropic drugs, such as dopamine or dobutamine, are advocated for treatment of anesthetic-induced hypotension in dogs, but increase myocardial oxygen demand and may induce cardiac arrhythmias.11,18

Intravenous administration of fluids is frequently proposed as the first option for correction of anesthetic-induced hypotension.1 Most crystalloid fluids are relatively inexpensive and readily available. Administration of balanced electrolyte solutions (eg, LRS) is recommended during anesthesia and surgery.19,20 Lactated Ringer's solution is an isotonic electrolyte solution that contains sodium chloride (6.0 g/L), sodium lactate (3.1 g/L), potassium chloride (0.3 g/L), and calcium chloride (0.2 g/L). It has the same osmolality as plasma; following administration, it rapidly but temporarily expands the extracellular fluid space and equilibrates in the larger interstitial fluid compartment.20 Administration of large volumes of crystalloids can result in hemodilution of blood constituents and development of pulmonary edema, respiratory distress, and heart failure.21–25 Hemodilution can impair hemostasis and decrease delivery of oxygen.26–28 Increased intracranial pressure, ascites, peripheral edema, hypoalbuminemia, and disseminated intravascular coagulation as a result of hemodilution have also been reported.24,25

The administration of colloidal solutions for the treatment of hypovolemia and hypotension is becoming increasingly popular in veterinary practice.20,29 Hetastarch, a colloid with a mean molecular weight of 450 kDa, is formulated as a 6% solution (in saline [0.9% NaCl] solution) that has a COP of 40 mm Hg. The administration of hetastarch usually results in a plasma volume expansion greater than the delivered volume.20 Hetastarch is degraded by amylase in the liver and has a duration of plasma volume expansion of 12 to 24 hours.20,30 Administration of large volumes of colloid fluids is associated with coagulopathies, renal failure, allergic reactions, and worsening of existing pulmonary edema.29,31,32

The efficacy of various fluid therapies for the treatment of isoflurane-induced hypotension has not been extensively investigated to our knowledge. The objective of the study of this report was to determine the effect of IV administration of a crystalloid (LRS) or colloid (hetastarch) fluid on isoflurane-induced hypotension in dogs. We hypothesized that IV fluid administration would correct isoflurane-induced hypotension, hetastarch administration would reverse isoflurane-induced hypotension more rapidly and effectively than LRS administration, and less volume of hetastarch would be required to treat hypotension.

Materials and Methods

Animals—Six purpose-bred Beagles (3 females and 3 males) were used in the study. Dogs were 1 to 2 years old and weighed 12 to 14 kg. Each dog was considered healthy on the basis of results of physical examination, fecal floatation, and a CBC. The study was approved by The Ohio State University's Institutional Animal Care and Use Committee.

Study design—The study was conducted in a random-order, 3-way crossover design. Food, but not water, was withheld for approximately 12 hours prior to each experiment. Isoflurane MAC was determined for each dog, as described previously.15 At least 1 week after MAC determination, all dogs underwent 3 experimental procedures at intervals of at least 7 days; during each procedure, dogs received 1 of 3 treatments: an infusion of hetastarcha (80 mL/kg/h), an infusion of LRSb (80 mL/kg/h), or NFT. Thus, each dog received each experimental treatment during the study.

Procedures—A 20-gauge IV catheter was inserted into the right cephalic vein of each dog prior to commencement of each experimental procedure. Anesthesia was induced in each dog by use of propofol (6 mg/kg, IV); following orotracheal intubation, the dog was mechanically ventilated by use of an ascending-bellows, volume-cycled, pressure-regulated ventilatorc that was connected to a circle rebreathing anesthetic circuit. The ventilator was set to deliver a tidal volume of 10 to 15 mL/kg at a rate of 8 to 12 breaths/min to maintain PaCO2 at 35 to 45 mm Hg. Isoflurane in 100% oxygen was delivered by use of an out-of-circuit precision isoflurane vaporizer.d The end-tidal isoflurane concentratione was initially maintained at 1.3 times the individual dog's predetermined MAC value. A warm water circulating blanketf and a warm air blanketg were used to maintain body temperature at 38 ± 1°C. A pulse oximetry probeh was attached to the tongue to determine hemoglobin oxygen saturation (%). A flow-directed 5-F, 80-cm thermodilution catheteri was introduced into the right jugular or left femoral vein through a 6-F catheter introducer by use of the Seldinger technique. The thermodilution catheter was advanced until the distal tip was positioned in the pulmonary artery, and its location was confirmed by detection of the characteristic pressure waveform. This catheter was used to measure core body temperature (°C), RAP (mm Hg), MPAP (mm Hg), and CO (L/min) via thermodilution.j The pulmonary artery port on the catheter was used for the collection of venous blood samples. A 20-gauge catheter was percutaneously inserted into a dorsal pedal artery or a surgically exposed femoral artery for continuous monitoring of arterial blood pressure variables and for anaerobic collection of arterial blood samples, which were stored on ice and analyzed within 5 minutes. A 16-gauge catheter was percutaneously introduced into the left jugular vein by use of the Seldinger technique for the continuous removal of blood for analysis of change in BV (%). The blood flowed through a sensork and was returned to the dog through a catheter that was inserted into the left cephalic vein.33 All instrumentation procedures were accomplished within 2 hours of induction of anesthesia, after which the dog was positioned in dorsal recumbency.

Experimental plan—Each dog was maintained at 1.3 times its individual isoflurane MAC for an additional 30 minutes following completion of instrumentation. Baseline data were collected and recorded. The isoflurane concentration was then increased to achieve and maintain an SABP of 80 mm Hg for 15 minutes (the end of the 15-minute period was designated as the 0-minute time point). The isoflurane concentration required to attain an SABP of 80 mm Hg was maintained for the duration of the experiment. For the hetastarch and LRS treatments, fluid administration began at 0 minutes (after measurements and blood sample collections were completed) at a rate of 80 mL/kg/h.l

Fluid administration was discontinued if SABP returned to a value that was within 10% of the baseline SABP. If SABP did not return to within 10% of its baseline value, fluid was administered to a predetermined maximum volume (equivalent to 40 mL of hetastarch/kg or 80 mL of LRS/kg). Therefore, the maximum duration of fluid administration was 0.5 hours for the hetastarch treatment and 1 hour for the LRS treatment. In the experiments involving hetastarch and LRS administrations, dogs were awakened from anesthesia after the 180-minute data collection time point, whereas in the experiments involving NFT, dogs were awakened from anesthesia after the 120-minute data collection time point. Catheters were removed after the final data collection time point. Signs of postanesthetic pain were clinically assessed on the basis of heart rate, respiratory rate, vocalization, and behavior. Dogs with elevated heart and respiratory rates (compared with preanesthetic values), excessive vocalization, and any obvious sign of pain were treated with parenterally administered hydromorphone and acepromazine.

Data collection—In all experiments, heart rate, SABP, MABP, DABP, MPAP, RAP, CO, and percentage change in BV were measured and recorded at baseline (30 minutes after instrumentation), after SABP had been stabilized at 80 mm Hg for 15 minutes (0 minutes), and at 15, 30, 45, 60, 90, and 120 minutes. Additionally, these measurements were made at 150 and 180 minutes in dogs undergoing treatment with LRS or hetastarch. Cardiac output was normalized to body weight and reported as CI. Systemic vascular resistance was calculated by use of a standard formula.2

At baseline and at the 0-, 15-, 30-, 60-, and 120-minute time points, anaerobically collected samples of arterial and venous blood (3 mL each; 6 arterial and 6 venous blood samples/dog) were analyzed (within 5 minutes after collection) for PCV (%); COP (mm Hg)m; total protein (g/dL),n albumin (mg/dL),o sodium (mmol/L),p potassium (mmol/L),p chloride (mmol/L),p ionized calcium (mEq/L)p, lactate (mmol/ L),p and hemoglobin concentrations (g/dL)p; arterial oxygen saturation (%)p; pHp; PaO2p (mm Hg); and PaCO2p (mm Hg). Systemic DO2 was calculated by use of a standard formula.20

Whole blood viscosity was also assessed at baseline and at the 0-, 15-, 30-, 60-, and 120-minute time points, and an additional blood sample (3 mL) was obtained for determination of whole blood viscosity at the 180-minute time point in dogs that were receiving a fluid treatment. Whole blood viscosity (cP) was measured within 15 minutes of sample collection at 37°C by use of a viscometerq at a shear rate of 150 seconds−1.

A venous blood sample (6 mL) was collected from all dogs 24 hours after recovery from anesthesia for each of the 3 experimental procedures for assessment of PCV; total protein, albumin, and lactate concentrations; COP; and whole blood viscosity. In addition, a CBC and serum biochemical analyses were performed as part of an overall evaluation of health.

Statistical analysis—All data are reported as mean ± SD. A 2-way ANOVA with repeated measures was used to test for main effects of treatment and interaction of time. A Bonferroni posttest was performed to identify differences in the variables of interest within and between the 3 treatments. Values of P < 0.05 were considered significant.

Results

Among the 6 study dogs, isoflurane MAC ranged from 1.2% to 1.3%. End-tidal isoflurane concentrations at baseline or at 0 minutes were not different among dogs receiving any of the 3 treatments (Table 1).

Table 1—

Mean ± SD end-tidal isoflurane concentration (%) before and at intervals after induction of hypotension (SAPB, 80 mm Hg) via manipulation of isoflurane concentration in 6 dogs that were administered LRS or hetastarch IV at a rate of 80 mL/kg/h (maximum volume, 80 and 40 mL/kg, respectively) or NFT.

Time point (min)Treatment
HetastarchLRSNFT
Baseline1.9 ± 0.41.8 ± 0.21.9 ± 0.3
03.2 ± 0.6*3.2 ± 0.3*3.0 ± 0.4*
153.1 ± 0.63.2 ± 0.3*3.1 ± 0.4*
303.1 ± 0.63.2 ± 0.3*3.1 ± 0.4*
453.0 ± 0.5*3.2 ± 0.4*3.1 ± 0.4*
603.1 ± 0.5*3.2 ± 0.3*3.1 ± 0.4*
903.1 ± 0.6*3.3 ± 0.3*3.1 ± 0.4*
1203.1 ± 0.6*3.3 ± 0.3*3.2 ± 0.4*
1503.1 ± 0.53.4 ± 0.3*ND
1803.1 ± 0.53.4 ± 0.4*ND

For each treatment, baseline data were collected from each dog during anesthesia at 1.3 times its individual isoflurane MAC (prior to induction of hypotension). Isoflurane concentration was adjusted to achieve and maintain an SABP value of 80 mm Hg for 15 minutes prior to data collection (0-minute time point). Fluid administration was commenced after collection of data and blood samples at 0 minutes.

Within a treatment, value is significantly (P < 0.05) different from baseline value.

ND = Not determined.

Administration of 80 mL of LRS/kg did not result in an increase in SABP to within 10% of baseline value in any dog. However, administration of hetastarch increased SABP to within 10% of baseline value in 4 of 6 dogs. In those 4 dogs, the volume of hetastarch required to achieve that increase in SABP ranged from 4.3 to 40 mL/kg; the interval required to achieve that increase in SABP ranged from 5 to 46 minutes. In 1 dog, the SABP returned to within 10% of the baseline value 16 minutes after the maximum volume of hetastarch was administered.

Among the 3 treatments, there were no significant (P ≥ 0.05) differences in heart rate, SABP, DABP, MABP, MPAP, RAP, CI, and percentage change in BV at baseline or at 0 minutes (Table 2). At 0 minutes for each treatment, SABP, DABP, and MABP were decreased, compared with baseline values; although values of CI were less than the baseline values for all treatments at this time point, the difference was significant only in dogs receiving LRS or NFT. At 0 minutes, values of MPAP and RAP were typically greater than baseline values, but the differences were significant only for RAP in dogs receiving LRS or NFT. Compared with the 0-minute value, heart rate was increased at 45 through 180 minutes in dogs receiving hetastarch (P = 0.008 to 0.020). Systolic arterial blood pressure was significantly greater in dogs receiving hetastarch, compared with findings during LRS administration, at 15 through 180 minutes (P = 0.001 to 0.021). Systolic arterial blood pressure was similarly increased in hetastarch-treated dogs, compared with dogs receiving NFT, at 15 through 120 minutes (P = 0.004 to 0.039); at 120 minutes, the value in the hetastarch-treated dogs had returned to baseline value. There was no change in SABP from 0-minute values in dogs receiving LRS or NFT. Diastolic arterial blood pressure in dogs receiving NFT was not significantly different from values in dogs receiving hetastarch or LRS at any time point. Compared with the effect of LRS treatment, DABP was significantly greater as a result of hetastarch treatment at 45, 90, 120, and 180 minutes (P = 0.011 to 0.045). In dogs receiving LRS, DABP was significantly decreased from baseline at all time points (P = 0.001 to 0.018). Compared with the 0-minute value, MABP was significantly increased at all but 1 time points in dogs receiving hetastarch, but similar changes were not evident in dogs receiving LRS or NFT.

Table 2—

Mean ± SD physiologic and hemodynamic variables measured before and at intervals after induction of hypotension (SAPB, 80 mm Hg) via manipulation of isoflurane concentration in 6 dogs that were administered LRS or hetastarch IV at a rate of 80 mL/kg/h (maximum volume, 80 and 40 mL/kg, respectively) or NFT.

VariableTreatmentBaselineTime point (min)
01530456090120150180
Heart rate (beats/min)Hetastarch114 ± 26118 ± 19121 ± 14124 ± 13128 ± 20133 ± 19135 ± 18135 ± 17135 ± 17135 ± 15
LRS112 ± 17118 ± 12116 ± 10122 ± 9124 ± 10124 ± 11121 ± 14117 ± 13117 ± 14119 ± 12
NFT123 ± 19125 ± 10123 ± 10123 ± 12122 ± 12121 ± 12123 ± 10123 ± 10NDND
SABP (mm Hg)Hetastarch110 ± 980 ± 0*93 ± 10*†‡§92 ± 7*†‡§95 ± 7*†‡§99 ± 11†‡§97 ± 9*†‡§98 ± 13†‡§101 ± 16†§99 ± 16†§
LRS120 ± 2480 ± 0*79 ± 7*82 ± 6*79 ± 8*78 ± 8*75 ± 9*73 ± 6*†72 ± 8*71 ± 12*
NFT116 ± 1880 ± 1*77 ± 676 ± 477 ± 8*75 ± 8*73 ± 13*73 ± 11*NDND
DABP (mm Hg)Hetastarch65 ± 1143 ± 5*46 ± 7*45 ± 9*47 ± 749 ± 1147 ± 647 ± 948 ± 946 ± 9§
LRS65 ± 845 ± 9*40 ± 6*†39 ± 6*†38 ± 6*†38 ± 6*36 ± 6*†37 ± 5*†39 ± 8*36 ± 6*†
NFT69 ± 945 ± 6*44 ± 842 ± 742 ± 7*41 ± 6*40 ± 7*39 ± 6*NDND
MABP (mm Hg)Hetastarch78 ± 1254 ± 4*61 ± 5*†§60 ± 9*62 ± 6*†§65 ± 9†§63 ± 5*†§63 ± 9†§65 ± 10†§63 ± 9†§
LRS82 ± 1253 ± 4*53 ± 5*53 ± 7*52 ± 7*52 ± 8*50 ± 8*49 ± 7*50 ± 8*50 ± 8*
NFT84 ± 1257 ± 4*55 ± 753 ± 753 ± 752 ± 6*52 ± 7*51 ± 7*NDND
MPAP (mm Hg)Hetastarch16.7 ± 2.917.2 ± 2.721.1 ± 4.3*†23.8 ± 4.9*†‡24.9 ± 5.9*†‡24.3 ± 5.2*†‡22.7 ± 4.9*†22.0 ± 4.5*†22.0 ± 4.9*†21.8 ± 4.9*†
LRS17.3 ± 2.416.9 ± 2.821.7 ± 3.6*†‡24.3 ± 4.0*†‡25.3 ± 3.8*†‡25.4 ± 3.7*†‡21.6 ± 3.6*†19.3 ± 2.7*†19.8 ± 3.1*†20.9 ± 4.7*
NFT15.4 ± 4.015.7 ± 3.615.6 ± 2.915.8 ± 3.415.9 ± 3.215.8 ± 3.216.2 ± 4.316.6 ± 3.6NDND
RAP (mm Hg)Hetastarch4.2 ± 1.45.1 ± 2.07.2 ± 3.0*†9.3 ± 4.2*†9.6 ± 3.9*†8.7 ± 3.6*†7.9 ± 2.6*†‡7.3 ± 2.5*†6.9 ± 2.5*6.8 ± 2.4*
LRS2.8 ± 1.63.9 ± 1.5*6.2 ± 2.0*†7.4 ± 2.5*†8.6 ± 2.3*†‡9.0 ± 2.4*†‡7.3 ± 2.8*†6.4 ± 1.7*†5.9 ± 1.6*†5.5 ± 1.6*†
NFT3.0 ± 1.64.3 ± 1.5*4.3 ± 1.44.4 ± 1.44.2 ± 1.44.3 ± 1.44.0 ± 1.44.0 ± 1.4NDND
CI (mL/kg/min)Hetastarch147 ± 47106 ± 27158 ± 28†‡167 ± 54200 ± 84209 ± 95215 ± 91208 ± 96212 ± 99217 ± 102
LRS165 ± 27113 ± 16*152 ± 28196 ± 39†‡202 ± 46198 ± 53179 ± 55151 ± 39160 ± 55168 ± 53
NFT155 ± 28108 ± 24*110 ± 24117 ± 26119 ± 27124 ± 25129 ± 25125 ± 18NDND
SVR (dyne·s·cm−5)Hetastarch3,200 ± 7772,943 ± 9762,092 ± 4952,046 ± 9671,905 ± 9892,032 ± 12401,841 ± 9481,939 ± 9781,958 ± 9301,874 ± 962
LRS2,912 ± 5152,632 ± 5151,886 ± 3111,438 ± 277*†‡1,332 ± 305*†‡1,360 ± 341*†‡1,503 ± 363*†1,730 ± 363*†‡1,743 ± 438*†1,627 ± 278*
NFT3,175 ± 5553,028 ± 7902,856 ± 8362,598 ± 6642,556 ± 6402,380 ± 557*2,262 ± 480*2,268 ± 376*NDND
Change in BV (%)Hetastarch0.1 ± 4.90.1 ± 9.023.9 ± 16.3*†51.6 ± 27.8*†54.1 ± 27.4*†44.4 ± 26.2*†40.2 ± 23.2*†35.9 ± 21.1*†30.5 ± 21.1*†26.5 ± 20.0*†
LRS−0.7 ± 1.49.8 ± 21.335.4 ± 27.442.6 ± 22.3*†46.2 ± 19.0*†47.1 ± 17.2*†41.1 ± 16.0*†39.6 ± 12.7*†43.0 ± 24.8*†31.6 ± 34.0
NFT1.4 ± 1.419.0 ± 21.023.6 ± 24.625.8 ± 26.523.7 ± 19.328.4 ± 22.525.7 ± 34.036.1 ± 42.7NDND

Within a treatment, value is significantly (P < 0.05) different from the 0-minute value for this variable.

At this time point, value is significantly (P < 0.05) different from the NFT value for this variable.

At this time point, value is significantly (P < 0.05) different from the LRS treatment value for this variable.

See Table 1 for remainder of key.

Overall, MPAP and RAP increased significantly in dogs receiving LRS or hetastarch, but not in dogs receiving NFT (Table 2). Cardiac index increased from the 0-minute value at 15 and 30 minutes as a result of hetastarch and LRS treatments, respectively, but did not increase at any time point in dogs receiving NFT. Systemic vascular resistance generally decreased with fluid administration (either hetastarch or LRS); SVR in dogs receiving NFT was significantly greater than the value in dogs receiving LRS at all time points from 15 through 120 minutes.

Among the 3 treatments, there were no significant differences in blood viscosity, PCV, total protein and albumin concentrations, and COP at baseline or at 0 minutes (Table 3). Blood viscosity decreased during fluid administration and was significantly less at 30, 60, and 180 minutes in dogs receiving LRS, compared with dogs receiving hetastarch (P = 0.009 to 0.024). In dogs receiving NFT, blood viscosity did not change from baseline value at the 0- through 120-minute time points; however, blood viscosity was increased at 24 hours, compared with the 0-minute value (P = 0.026). Also, in dogs receiving LRS, blood viscosity was increased at 24 hours, compared with baseline and 0-minute values. Packed cell volume decreased from baseline values for all treatments (although the difference was significant only for the LRS treatment at 15 and 60 minutes); values were significantly decreased from the 0-minute value at 30, 60, and 120 minutes in dogs administered LRS. For all treatments, PCV was significantly increased at 24 hours, compared with the 0-minute values.

At 15 through 120 minutes, total protein concentration in blood samples collected from dogs receiving LRS was significantly decreased, compared with values in samples collected from dogs receiving hetastarch or NFT (Table 3). Total protein concentration was significantly increased at 24 hours for all treatments, compared with findings at baseline and 0 minutes. Albumin concentration was significantly less in dogs receiving LRS, compared with dogs receiving NFT, at 15 through 120 minutes, and the value was significantly decreased from baseline at 0 through 120 minutes. Colloid osmotic pressure was significantly decreased from baseline value at the 0- through 120-minute time points in dogs receiving LRS; from 15 through 120 minutes, COP in dogs receiving LRS was significantly decreased, compared with findings in dogs receiving NFT. Colloid osmotic pressure was significantly increased in dogs that received hetastarch, compared with dogs that received LRS. After 24 hours, COP was significantly increased from baseline and 0-minute values in dogs that received hetastarch.

Table 3—

Mean ± SD hemorheologic variables measured before and at intervals after induction of hypotension (SAPB, 80 mm Hg) via manipulation of isoflurane concentration in 6 dogs that were administered LRS or hetastarch IV at a rate of 80 mL/kg/h (maximum volume, 80 and 40 mL/kg, respectively) or NFT.

VariableTreatmentBaselineTime point
0 minutes15 minutes30 minutes60 minutes 180 minutes24 hours
Viscosity (cP)Hetastarch4.7 ± 0.34.8 ± 0.34.3 ± 0.34.0 ± 0.2*†§3.9 ± 0.3*†§3.8 ± 0.2*†4.2 ± 0.2*†§5.6 ± 0.9
LRS4.2 ± 1.04.2 ± 0.43.4 ± 0.43.1 ± 0.2†‡2.9 ± 0.3*†‡3.4 ± 0.43.6 ± 0.2*†§5.7 ± 0.4*†
NFT4.5 ± 0.44.5 ± 0.14.3 ± 0.24.3 ± 0.24.5 ± 0.44.4 ± 0.6ND5.5 ± 0.2
PCV (%)Hetastarch39 ± 237 ± 230 ± 526 ± 728 ± 529 ± 5ND46 ± 2*†
LRS38 ± 337 ± 231 ± 3*28 ± 4†‡27 ± 3*†‡30 ± 2†‡ND47 ± 3
NFT37 ± 236 ± 135 ± 336 ± 236 ± 236 ± 2ND46 ± 4
Total protein concentration (g/dL)Hetastarch5.0 ± 0.44.9 ± 0.54.8 ± 0.3§4.5 ± 0.4§4.5 ± 0.5§4.4 ± 0.4§ND6.5 ± 0.7*†
LRS5.2 ± 0.45.0 ± 0.33.7 ± 0.6*†3.4 ± 0.5*†‡3.1 ± 0.5*†‡3.5 ± 0.2*†‡ND6.4 ± 0.5*†
NFT4.8 ± 0.24.9 ± 0.34.6 ± 0.34.7 ± 0.34.8 ± 0.24.8 ± 0.3ND6.3 ± 0.5*†
Albumin concentration (g/dL)Hetastarch3.2 ± 0.13.1 ± 0.12.2 ± 0.52.0 ± 0.62.1 ± 0.5*2.1 ± 0.6ND3.0 ± 0.4
LRS3.2 ± 0.13.1 ± 0.12.4 ± 0.2*†‡2.1 ± 0.2*†‡1.9 ± 0.2*†‡2.3 ± 0.1*†‡ND3.3 ± 0.2
NFT3.1 ± 0.13.0 ± 0.12.9 ± 0.1*2.9 ± 0.12.9 ± 0.22.9 ± 0.1ND3.3 ± 0.3
COP (mm Hg)Hetastarch17.3 ± 1.217.5 ± 1.822.2 ± 3.5‡§23.1 ± 4.2§20.3 ± 3.2§18.7 ± 3.0§ND23.6 ± 2.7*†
LRS18.4 ± 1.417.3 ± 1.0*11.6 ± 1.9*†‡10.0 ± 1.3*†‡8.0 ± 1.8*†‡10.8 ± 1.5*†‡ND20.4 ± 2.4
NFT17.1 ± 1.016.1 ± 1.015.9 ± 1.316.4 ± 1.215.8 ± 1.2*16.1 ± 1.6ND19.7 ± 2.9

See Tables 1 and 2 for key.

Among the 3 treatments, there were no significant differences in blood pH; PaO2; PaCO2; lactate, potassium, sodium, ionized calcium, and chloride concentrations; and DO2 at baseline or at 0 minutes (Table 4). There was no significant change (from baseline) in blood pH over time for any treatment. Values of PaO2 did not differ significantly among the 3 treatments at any time point. Values of PaCO2 did not change significantly from baseline for any treatment and did not differ significantly among treatments at any time point. Blood lactate concentration decreased over time in dogs that did not receive fluids; concentrations changed from baseline value (albeit not significantly) in dogs that were administered fluids. For the 2 fluid treatments, DO2 was not significantly different at any time point.

Table 4—

Mean ± SD blood gas variables, electrolyte concentrations, and DO2 measured before and at intervals after induction of hypotension (SAPB, 80 mm Hg) via manipulation of isoflurane concentration in 6 dogs that were administered LRS or hetastarch IV at a rate of 80 mL/kg/h (maximum volume, 80 and 40 mL/kg, respectively) or NFT.

VariableTreatmentBaselineTime point (min)
0153060120
pHHetastarch7.328 ± 0.0477.313 ± 0.0307.294 ± 0.0357.315 ± 0.0397.323 ± 0.0277.330 ± 0.034
LRS7.344 ± 0.0187.316 ± 0.0327.305 ± 0.0487.321 ± 0.0357.359 ± 0.0367.356 ± 0.026
NFT7.328 ± 0.0237.330 ± 0.0177.333 ± 0.0227.320 ± 0.0257.313 ± 0.0367.313 ± 0.015
PaO2 (mm Hg)Hetastarch622 ± 13602 ± 14588 ± 38596 ± 20591 ± 30596 ± 14
LRS608 ± 51578 ± 41*566 ± 64565 ± 44571 ± 50582 ± 38
NFT599 ± 40586 ± 28584 ± 32582 ± 32552 ± 40540 ± 46
PaCO2 (mm Hg)Hetastarch40.8 ± 2.240.3 ± 3.642.3 ± 4.238.4 ± 3.139.3 ± 2.138.0 ± 3.0
LRS39.3 ± 2.040.9 ± 3.740.4 ± 4.040.2 ± 3.536.8 ± 2.938.2 ± 3.6
NFT39.3 ± 1.639.0 ± 2.237.7 ± 3.239.1 ± 2.738.6 ± 4.739.1 ± 3.3
Lactate∥ (mmol/L)Hetastarch2.5 ± 0.92.4 ± 0.71.8 ± 0.61.6 ± 0.41.8 ± 0.41.8 ± 0.5
LRS2.1 ± 0.42.3 ± 0.54.8 ± 2.54.7 ± 2.24.6 ± 1.92.2 ± 0.3
NFT2.3 ± 0.22.2 ± 0.22.0 ± 0.31.9 ± 0.11.8 ± 0.21.7 ± 0.2*†
Potassium (mmol/L)Hetastarch3.9 ± 0.24.9 ± 0.7*4.4 ± 0.74.5 ± 0.54.7 ± 0.64.8 ± 0.9
LRS3.9 ± 0.44.8 ± 0.9*4.4 ± 1.04.4 ± 0.94.5 ± 0.94.6 ± 0.8
NFT3.9 ± 0.44.7 ± 0.7*4.4 ± 0.84.6 ± 0.84.4 ± 0.65.0 ± 0.8
Sodium (mmol/L)Hetastarch144 ± 2143 ± 2143 ± 2143 ± 2141 ± 3141 ± 2
LRS144 ± 2143 ± 2*143 ± 3142 ± 2*140 ± 2*†139 ± 2*
NFT144 ± 3142 ± 3*143 ± 3142 ± 3*140 ± 4143 ± 4
Ionized calcium (mEq/L)Hetastarch2.65 ± 0.072.53 ± 0.08*2.42 ± 0.12*†2.34 ± 0.11*†2.36 ± 0.16*2.43 ± 0.12*
LRS2.67 ± 0.122.47 ± 0.19*2.36 ± 0.182.36 ± 0.212.38 ± 0.12*2.40 ± 0.15*
NFT2.60 ± 0.142.55 ± 0.132.46 ± 0.162.49 ± 0.132.25 ± 0.302.31 ± 0.35
Chloride (mmol/L)Hetastarch114 ± 2115 ± 4117 ± 4120 ± 5119 ± 7120 ± 6
LRS115 ± 3116 ± 3116 ± 3116 ± 2115 ± 2117 ± 7
NFT115 ± 4115 ± 3117 ± 7115 ± 4121 ± 9117 ± 3
DO2 (mL/min)Hetastarch403 ± 134284 ± 70371 ± 63342 ± 102416 ± 174430 ± 182
LRS449 ± 72294 ± 43*341 ± 62*411 ± 71394 ± 93325 ± 81
NFT409 ± 83278 ± 72*277 ± 73*294 ± 78295 ± 74*304 ± 67

Lactate concentrations in blood samples collected at 24 hours from dogs receiving hetastarch, LRS, or NFT were 1.9 ± 0.8 mmol/L, 1.5 ± 0.3 mmol/L, and 2.0 ± 0.4 mmol/L, respectively; these values did not differ significantly among the 3 treatments or from baseline or 0-minute values.

See Tables 1 and 2 for key.

Blood potassium concentration increased from baseline values during induction of hypotension in all experiments and returned to baseline values at 15 minutes (Table 4). For dogs receiving LRS, blood sodium concentration decreased over time and was significantly different from baseline value at 30 through 120 minutes. There was no significant difference in chloride concentration among treatments at any time point. In dogs receiving hetastarch or LRS, ionized calcium concentration was significantly decreased from baseline at 120 minutes.

In the early phase of recovery from anesthesia following LRS administration, 1 or more adverse effects were detected in 5 of 6 dogs; 3 dogs had fluid dripping from their noses, 5 dogs developed chemosis, and 3 dogs vomited. Chemosis resolved within 4 hours, and no further episodes of vomiting were observed. One dog had diarrhea 24 hours following hetastarch administration. No dog that received NFT appeared to have any long-term adverse effects as a result of undergoing 120 minutes of isoflurane-induced hypotension without IV fluid administration. For each dog, a CBC and serum biochemical analyses were performed 24 hours after recovery from anesthesia for each of the 3 experimental procedures, and all results were within reference values. In addition, no dog required sedation or analgesia during or following recovery from anesthesia for each of the 3 experimental procedures.

Discussion

The data obtained in the present study of dogs with isoflurane-induced hypotension indicated that IV administration of hetastarch increased SABP, IV administration of LRS did not change SABP and MABP and decreased DABP, either treatment increased CI (albeit not significantly), and reliance on the use of arterial blood pressure measurements to estimate overall cardiovascular function has limitations. On the basis of these findings, treatment of isoflurane-induced hypotension in dogs via IV administration of hetastarch appears to be more effective than IV administration of LRS or NFT.

The administration of hetastarch or LRS increased BV, compared with the value at 0 minutes, but hetastarch increased BV comparatively more quickly and for a longer period by use of a smaller administered volume. Fluid administration results in an increased release of atrial natriuretic peptide, which induces vasodilation in response to atrial distention.34 The volume and duration of administration of LRS were twice those of hetastarch in the dogs with isoflurane-induced hypotension in the present study. In addition, the large-volume administration of LRS resulted in marked hemodilution and decreased COP; this may have disrupted the endothelial glycocalyx and resulted in decreased flow resistance and loss of fluid into the interstitium.35,36 Blood volume in dogs receiving NFT was increased (compared with the 0-minute value) at all subsequent time points, but the change was not significant and was not apparent in every dog. Isoflurane-induced vasodilation in dogs receiving NFT most likely resulted in a decreased capillary hydrostatic pressure that caused a fluid shift from the interstitium into the vasculature.37 Autotransfusion of fluid from the interstitium to the vasculature would account for the apparent increase in BV.

Systolic arterial blood pressure, MABP, and DABP all increased from baseline or the 0-minute values following hetastarch administration only, but CI generally increased (although not significantly at most time points) following LRS or hetastarch administration. Systemic vascular resistance largely decreased from the baseline or 0-minute values following each of the 3 treatments, but the magnitude of change was least during NFT; thus, it is possible that isoflurane-induced vasodilation persisted during fluid administrations, but not during NFT. The change detected in the dogs receiving NFT could be indicative of a baroreceptor response to hypotension. However, that does not explain why heart rate did not increase during NFT. The baroreceptor reflex is blunted during inhalation anesthesia, and this could possibly explain the lack of heart rate increase in all dogs during isoflurane-induced hypotension.38

Blood pressure may not be the single best indicator of successful fluid resuscitation. In the present study, whereas hetastarch administration altered all 3 arterial blood pressure measurements, LRS administration did not increase SABP and MABP and NFT did not increase SAPB, DAPB, and MAPB; however, other indices of cardiovascular performance (eg, CI and DO2) did not differ among the 3 treatments overall. In previous studies39–41 in humans, LRS administration was ineffective in maintaining arterial blood pressure, yet CI increased. An increase in CI with little or no increase in SABP during LRS administration is likely attributable to factors that modulate SVR. In addition, results of a study42 in humans with sepsis suggest that CI and DO2 should be determined and used in conjunction with arterial blood pressure measurements as indices of successful fluid resuscitation.

Other factors including vessel diameter and length, organization of vascular beds, and the physical properties of blood (eg, density and viscosity) also influence resistance to blood flow and therefore tissue perfusion.43 A decrease in viscosity during hemodilution results in an increase in blood flow and CO without a concurrent increase in arterial blood pressure.35,44 This could, in part, explain the increase in CI detected in dogs with isoflurane-induced hypotension during LRS administration in the present study because that treatment was associated with increased BV and decreased blood viscosity, PCV, total protein and albumin concentrations, and COP. Blood flow increases with a decrease in vessel resistance, according to the Poiseuille-Hagen equation.38,45 This same equation also predicts that arterial blood pressure and blood viscosity are directly related and that arterial blood pressure decreases as blood viscosity decreases. The net result of these effects upon tissue blood flow may be an increase in tissue perfusion, if adequate tissue perfusion pressure can be maintained.

In the dogs with isoflurane-induced hypotension in the present study, a large volume of LRS was administered, which resulted in hemodilution and decreased blood viscosity, PCV, total protein and albumin concentrations, and COP. Hemodilution can impair autoregulation and decrease cerebral perfusion.46 Excessive fluid administration resulting in extreme hemodilution (ie, PCV reduced to 50% of the baseline value) decreases blood viscosity and vessel wall shear stress.38,47 Decreased blood (plasma) viscosity promotes blood flow and increases CO, but decreased plasma viscosity combined with hemodilution may decrease DO2 as a result of maldistribution of blood flow.47 Maintenance of plasma viscosity > 2.2 cP has been recommended to provide adequate vessel wall shear stress for nitric oxide production, vasodilation, and DO2.47 In the present study, viscosity reached a nadir of 2.9 cP at 60 minutes in the LRS-treated dogs, which was also the time point at which the maximum volume of LRS had been administered and fluid administration was discontinued. Viscosity returned to 3.4 cP within 1 hour of terminating LRS administration. The effects of LRS on blood viscosity in the present study were related to dose and duration of fluid administration and were short-lived, and there was no significant difference in DO2 between the hetastarch- and LRS-treated dogs. Viscosity also decreased during hetastarch administration, although not to the same extent as during LRS administration. From 15 through 120 minutes, COP was significantly higher in dogs receiving hetastarch, compared with dogs receiving LRS, but values were comparable at the 24-hour time point. In dogs receiving NFT, COP was decreased from baseline value at 60 minutes but returned to baseline value at 24 hours, as did COP in dogs receiving LRS. Viscosity in dogs receiving LRS, total protein concentration in dogs receiving either fluid treatment or NFT, and PCV in dogs receiving hetastarch were all significantly higher than baseline values at 24 hours; these findings may be indicative of increased urine production and decreased oral fluid intake during the 24 hours following the experiment because those aforementioned variables are indicators of hemoconcentration.

During hetastarch administration, total protein and albumin concentrations and PCV decreased in dogs with isoflurane-induced hypotension, but the changes were not significantly different from baseline values. Hetastarch administration affects total protein concentration values determined via refractometry; as the volume of hetastarch administered increases, the total protein concentration becomes approximately 4.5 g/dL, the refractometer reading for hetastarch itself.48

There were no unexpected or clinically relevant changes in pH, PaCO2, PaO2, and sodium, calcium, or chloride concentration in dogs receiving any of the 3 treatments. Hyperchloremic acidosis did not develop during hetastarch administration most likely because of the small volume of hetastarch administered (up to 40 mL/kg). In dogs with isoflurane-induced hypotension, blood potassium concentration increased slightly for a short time during all 3 treatments. Potassium may have been released from cells during the initial period of hypotension, but was either eliminated by the kidneys or returned to cells when intravascular volume was increased, either via fluid administration or fluid redistribution from the interstitium.36

During treatment with LRS, 5 of 6 dogs developed ≥ 1 clinical sign associated with fluid overload, including serous nasal discharge, chemosis, and vomiting.49 None of the adverse effects were considered serious, and all resolved within 24 hours. Fluid retention becomes more pronounced during isoflurane anesthesia as a result of reduced clearance and slower distribution into the interstitium.50 Large-volume colloid administration is associated with coagulopathies via an unknown mechanism, whereas large-volume crystalloid administration can result in hemodilution-induced coagulopathy.29,31 There were no clinical signs in any of the dogs that indicated development of a coagulopathy, despite the facts that the dose of hetastarch was twice the recommended daily dose of 20 mL/kg and that hemodilution resulted from LRS administration.20 However, no objective tests of coagulation pathways were performed. The hetastarch dose used in the present study was based on pilot data obtained from anesthetized dogs that were treated with 40 mL of hetastarch/kg and developed no observable adverse effects.

The isoflurane concentration was not reduced after induction of hypotension in the study dogs. Common clinical practice during hypotension in anesthetized dogs is to administer fluids and decrease the isoflurane concentration. However, the goal of the present study was to determine the effects of fluid administration on blood pressure during isoflurane-induced hypotension. Urine output and urine specific gravity were not measured and might have provided additional information regarding renal perfusion and function during isoflurane-induced hypotension and fluid administration. Reduced perfusion as a result of hypotension and fluid overload can lead to renal failure.36 Hetastarch and LRS were chosen for administration because they are commonly available fluids in most veterinary clinics. The electrolyte and ionic composition of the 2 fluids is different—the carrier for hetastarch is saline solution, whereas LRS is a balanced electrolyte solution that contains other ions in addition to sodium and chloride. Although there were no changes in measured electrolyte concentrations among the 3 treatments, the differences in electrolyte composition, presence of lactate in LRS, and differences in pH of the fluids may have influenced our results.

The ideal resuscitation fluid for isoflurane-induced hypotension should address the condition of the patient, reason for anesthesia, and sensible and insensible fluid losses.36 In nonanesthetized patients, the choice of crystalloid or colloid fluid administration depends on the cause of the hypotension. A crystalloid fluid is more appropriate for treatment of interstitial fluid loss, such as that associated with dehydration. A colloid fluid is more effective for replacement of intravascular volume loss, such as that associated with acute hemorrhage. The appropriate fluid choice for isoflurane-induced hypotension in dogs is unclear. If the end point of resuscitation is a relatively rapid return to baseline arterial blood pressure values, then results of the present study indicated that hetastarch is the better fluid choice. If improvement in CI and DO2 is the desired outcome, then results of the present study indicated that administration of either hetastarch or LRS is effective. However, hetastarch but not LRS improved SABP, CI, and DO2. No dog that received NFT appeared to have any long-term adverse effects as a result of undergoing 120 minutes of isoflurane-induced hypotension. Results of the present study have supported the use of hetastarch rather than LRS for the treatment of isoflurane-induced hypotension in healthy dogs.

ABBREVIATIONS

BV

Blood volume

CI

Cardiac index

CO

Cardiac output

COP

Colloid osmotic pressure

cP

Centipoise

DABP

Diastolic arterial blood pressure

DO2

Oxygen delivery

LRS

Lactated Ringer's solution

MABP

Mean arterial blood pressure

MAC

Minimum alveolar concentration

MPAP

Mean pulmonary artery pressure

NFT

No fluid treatment

RAP

Right atrial pressure

SABP

Systolic arterial blood pressure

SVR

Systemic vascular resistance

a.

Hetastarch 6%, Hospira Inc, Lake Forest, Ill.

b.

Baxter Healthcare Corp, Deerfield, Ill.

c.

Hallowell EMC 2KIE ventilator, Hallowell EMC, Pittsfield, Mass.

d.

Ohmeda Isotec 3, Madison, Wis.

e.

Gas module SE, Datascope, Montvale, NJ.

f.

T/Pump heat therapy pump, model TP-500, Gaymar Industries Inc, Orchard Park, NY.

g.

Thermacare convective warming unit TC3000, Gaymar Industries Inc, Orchard Park, NY.

h.

Passport 2, Datascope, Montvale, NJ.

i.

Thermodilution balloon catheter, Arrow International Inc, Reading, Pa.

j.

9520A cardiac output computer, American Edwards Laboratories, Irvine, Calif.

k.

Crit-Line IIR Hct monitor, HemaMetrics, Kaysville, Utah.

l.

Heska Vet IV2.2, Sensor Devices Inc, Waukesha, Wis.

m.

Colloid osmometer, model 4420, Wescor, Logan, Utah.

n.

Clinical refractometer J-351, Jorgensen Laboratories Inc, Loveland, Colo.

o.

Roche Hitachi 911, Indianapolis, Ind.

p.

ABL 725 Radiometer America, Westlake, Ohio.

q.

Brookfield Engineering Laboratories, Middleboro, Mass.

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