Use of propofol for induction of anesthesia in dogs undergoing definitive radiation therapy: 31 cases (2006–2009)

Todd M. Erfourth Departments of Small Animal Clinical Sciences and Pathobiology and Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824.

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Elizabeth A. McNiel Departments of Small Animal Clinical Sciences and Pathobiology and Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824.

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Michael A. Scott Departments of Small Animal Clinical Sciences and Pathobiology and Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824.

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Deborah V. Wilson Departments of Small Animal Clinical Sciences and Pathobiology and Diagnostic Investigation, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824.

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Abstract

Objective—To evaluate changes in serial hemograms and serum biochemical profiles in tumor-bearing dogs undergoing daily anesthesia with propofol as an induction agent for radiation therapy.

Design—Retrospective case series.

Animals—31 dogs with cutaneous or subcutaneous malignancies over the trunk or limbs.

Procedures—Radiation therapy consisted of 18 daily treatments administered Monday through Friday over a period of 24 days. Propofol was administered IV to effect for induction of anesthesia. Complete blood count and serum biochemical data were generated at the beginning, middle, and end of radiation therapy and compared to identify changes over time via either a repeated-measures ANOVA or Friedman test.

Results—Leukocyte and platelet parameters did not differ significantly over time. Calculated Hct, erythrocyte count, hemoglobin concentration, and mean corpuscular hemoglobin concentration decreased overtime, whereas mean corpuscular volume increased overtime.

Conclusions and Clinical Relevance—Dogs receiving propofol for induction of anesthesia and radiation therapy had a decrease in RBC count, although these changes were not determined to be of clinical importance in this patient population. The cause of these alterations was not immediately apparent. Propofol appeared to be a safe choice for induction of anesthesia in dogs during daily radiation therapy.

Abstract

Objective—To evaluate changes in serial hemograms and serum biochemical profiles in tumor-bearing dogs undergoing daily anesthesia with propofol as an induction agent for radiation therapy.

Design—Retrospective case series.

Animals—31 dogs with cutaneous or subcutaneous malignancies over the trunk or limbs.

Procedures—Radiation therapy consisted of 18 daily treatments administered Monday through Friday over a period of 24 days. Propofol was administered IV to effect for induction of anesthesia. Complete blood count and serum biochemical data were generated at the beginning, middle, and end of radiation therapy and compared to identify changes over time via either a repeated-measures ANOVA or Friedman test.

Results—Leukocyte and platelet parameters did not differ significantly over time. Calculated Hct, erythrocyte count, hemoglobin concentration, and mean corpuscular hemoglobin concentration decreased overtime, whereas mean corpuscular volume increased overtime.

Conclusions and Clinical Relevance—Dogs receiving propofol for induction of anesthesia and radiation therapy had a decrease in RBC count, although these changes were not determined to be of clinical importance in this patient population. The cause of these alterations was not immediately apparent. Propofol appeared to be a safe choice for induction of anesthesia in dogs during daily radiation therapy.

Radiation therapy typically involves the delivery of the prescribed radiation dose in multiple treatments, called fractions, which are administered over a number of weeks. Whereas human patients are usually treated with 30 to 35 individual radiation fractions, veterinary patients receive far fewer. Coarse-fractionated protocols, which involve the administration of large individual doses, have been used in veterinary medicine for a variety of reasons, including the requirement for anesthesia during the irradiation of animals. General anesthesia is essential to permit personnel to leave the treatment vault during treatment as well as to allow accurate patient positioning.

In recent years, improvements in anesthesia, such as safe, short-acting drugs and monitoring tools, have facilitated the daily treatment of veterinary patients with radiation. One of the drugs commonly used for anesthetic induction is the commercially available phenolic anesthetic drug propofol (2,6 di-isopropylphenol). Propofol has a number of attractive properties, including a rapid onset of action, short duration of activity, and rapid recovery, compared with many agents including barbiturates.1 In children receiving radiation therapy, propofol provides reliable anesthesia generally without the development of tolerance necessitating increasing dosage.2–5 In cats, prolonged anesthesia with propofol has been associated with delayed recovery6 and repeated administration has been linked with oxidative injury to RBCs, characterized by Heinz body formation.7 Hemolysis can occur in feline RBCs secondary to oxidative damage, raising concerns for development of anemia. In contrast, recent studies8,9 have indicated no important adverse clinical or hematologic effects with repeated propofol anesthesia in cats, albeit at lower dosages than those used in previous studies. Previous studies8,10 of propofol administration to clinically normal dogs failed to identify RBC changes, although these animals were only given 3 doses, rather than more repetitive use.

If repeated dosing with propofol results in oxidative damage to RBCs, any resulting impact on erythroid mass via hemolysis may decrease the efficacy of radiation therapy, in addition to having a negative impact on overall patient health. It is widely accepted that hypoxic cells are more likely to survive and remain viable during radiation therapy and that hypoxia is a risk factor for poor locoregional tumor control and survival.11,12 Red blood cells are responsible for distributing oxygen to the tissues, and it is likely that anemia contributes to intratumoral hypoxia. Numerous studies13–16 have shown that human patients with decreased hemoglobin concentrations have poorer outcomes with radiation therapy. A recent study17 of dogs with tumors treated with radiation therapy showed a similar tendency for worse outcome in patients with hypoxia and decreased hemoglobin concentrations.

The objective of the study reported here was to evaluate hematologic alterations, particularly RBC alterations, in tumor-bearing dogs receiving daily propofol for anesthetic induction during radiation therapy. In addition, serum biochemical data were examined to evaluate for other changes in overall health status during the course of treatment.

Materials and Methods

The radiation therapy database of the Michigan State University Center for Comparative Oncology was searched to identify dogs that underwent radiation therapy from 2006 through 2009. Dogs were included if they received definitive radiation therapy for a localized cutaneous or subcutaneous tumor involving the trunk or limbs. Dogs were excluded if they received concurrent chemotherapy or had concurrent systemic illness with the exception of hypothyroidism. Prior to the start of radiation therapy, all dogs had a complete physical examination, CBC, serum biochemical profile, urinalysis, and thoracic radiographs. When indicated, abdominal ultrasonography was also performed. Primary diagnosis was through histologic examination of tissue specimens in all cases.

All dogs were anesthetized with IV administration of propofol for induction and isoflurane in oxygen after endotracheal intubation for maintenance during delivery of radiation. Most patients received a premedicant prior to propofol administration, either hydromorphone or butorphanol. Intravenous fluids were administered during anesthesia via an 18- or 20-gauge cathetera at a rate of approximately 11 mL/kg/h (5 mg/lb/h). Intravenous catheters were removed during recovery from anesthesia and replaced daily. A dual-energy (6- and 10-MV photons) linear acceleratorb was used to deliver the irradiation.

Laboratory values from hemogramsc (including calculated Hct18 = [MCV × RBC count]/10, MCV, MCHC, mean corpuscular hemoglobin, RBC distribution width, hemoglobin distribution width, mean platelet volume, hemoglobin concentration, and RBC, WBC, neutrophil, and platelet counts) and serum biochemical profilesd (including anion gap; calculated osmolarity; concentrations of BUN, creatinine, sodium, potassium, chloride, total carbon dioxide, phosphorus, magnesium, total calcium, iron, total protein, albumin, globulin, glucose, cholesterol, total bilirubin, indirect bilirubin, and direct bilirubin; and activities of amylase, alkaline phosphatase, alanine transaminase, aspartate aminotransferase, and creatine kinase) were evaluated at 3 time points: within 3 weeks prior to the start of radiation therapy (T0), midway through the radiation protocol (T1; days 11 and 12), and at the end of radiation therapy (T2; days 23 and 24). Blood smears were reviewed for morphological abnormalities of all cell lines, and manual WBC differential counts replaced automated values when indicated. Samples were collected via jugular venipuncture with a 20-gauge needle and syringe and submitted for analysis within 1 hour to the in-house hospital laboratory. Samples at T1 and T2 were sometimes collected while the patients were recovering from anesthesia. Acute radiation morbidity to the skin was recorded at T1 and T2 and graded according to Veterinary Radiation Therapy Oncology Group standards, which define skin reaction as follows: grade 0 (no change over baseline), grade 1 (erythema, dry desquamation, and alopecia or epilation), grade 2 (patchy moist desquamation without edema), and grade 3 (confluent moist desquamation with edema or ulceration, necrosis, or hemorrhage).19

The null hypothesis for statistical purposes was that laboratory values for each dog would not differ with sampling time point. To test this hypothesis, repeated-measurement statistics,e,f which evaluate for changes for each patient over the 3 time points (T0, T1 and T2), were used.20 Parametric analysis with repeated-measures ANOVA was used when the sample size was ≥ 30 and normally distributed as determined by the Kolmogorov-Smirnov test. Nonparametric analysis with a Friedman test was used for a sample size < 30, regardless of distribution. Significance was set at P ≤ 0.05. Equivalent square field size, total volume irradiated, and thickness of the region irradiated were tested for normality with the Kolmogorov-Smirnov test. If the reported variable did not deviate significantly from a normal distribution, then it was described with mean ± SD. For variables that were not normally distributed, median and range were reported.

Results

Thirty-one cases met the study criteria. Patients ranged in age between 2.3 and 11 years, with a mean of 7.5 ± 2.0 years. The median patient body weight was 33 kg (71.8 lb), with a range of 8.1 to 59 kg (18.0 to 129 lb). There were 16 spayed female dogs, 14 castrated male dogs, and 1 sexually intact male dog. There were 12 mixed-breed dogs, 7 Golden Retrievers, 3 Labrador Retrievers, 2 Siberian Huskies, and 1 each of the following breeds: Pembroke Welsh Corgi, Maltese, German Shorthaired Pointer, Bernese Mountain Dog, Shetland Sheepdog, Cocker Spaniel, and Australian Cattle Dog. Tumor types included 17 STSs, 11 MCTs, and 3 infiltrative lipomas. The majority of tumors (n = 26 [84%]) were incompletely resected prior to the start of radiation therapy, with a median of 26.5 days (range, 8 to 155 days) between surgery and the start of radiation therapy. Five patients began radiation therapy with grossly detectable masses, including 3 MCTs and 2 infiltrative lipomas.

Planning target volume included the tumor and surgical field and a 2- to 3-cm margin of normal tissue. For tumors located on extremities, treatment was calculated manually to deliver the prescribed dose to the midpoint of the PTV via parallel-opposed portals. For patients with a tumor located on the trunk, CT scans were performed, allowing for 3-D conformal computer-assisted treatment planning.g Tissue equivalent bolus material ranging from 1 to 1.5 cm in thickness was used to provide a superficial dose when appropriate. The prescribed dose for all patients was 54 Gy to the PTV delivered in 18 daily fractions (Monday through Friday) for a treatment duration of 24 days. Dose heterogeneity of ± 5% was permitted within the PTV. In determining radiation field size, 10 patients had CT scans available for computer-assisted planning. The radiation field was derived via hand calculations for the remaining 21 patients. Median equivalent square field size for all patients was 11 cm2 with a range of 4.5 to 21 cm2. Duration of exposure was approximately 30 to 60 seconds from each beam. Acute toxicosis of irradiated skin at T1 included 23 dogs with grade 0 reaction (no change over baseline), 6 with grade 1 (erythema, dry desquamation, and alopecia or epilation), 2 with grade 2 (patchy moist desquamation without edema), and 0 with grade 3 reaction (confluent moist desquamation with edema or ulceration, necrosis, or hemorrhage). At T2, no patients had grade 0 reaction, 13 had grade 1 reaction, 10 had grade 2 reaction, and 8 had grade 3 reaction.

Concurrent medications (those administered at least once during the course of radiation therapy) included tramadol (n = 23 dogs), NSAIDs (15), diphenhydramine (11), famotidine (9), gabapentin (6), metronidazole (5), cephalexin (4), prednisone (3), amoxicillin-clavulanate (2), metoclopramide (2), enrofloxacin (1), enalapril (1), sucralfate (1), and levothyroxine (1). For anesthetic induction, patients were premedicated with butorphanol, which was administered IV at a median dose of 0.20 mg/kg (0.09 mg/lb) with a range of 0.10 to 0.26 mg/kg (0.045 to 0.12 mg/lb). Two patients received hydromorphone instead of butorphanol at a dose of 0.04 mg/kg (0.018 mg/lb). In addition to butorphanol, 1 patient received acepromazine (0.03 mg/kg [0.014 mg/lb], IV) and 1 received midazolam (0.09 mg/kg [0.04 mg/lb], IV). Propofol was given to effect for induction of anesthesia; the median dosage of propofol administered was 3.6 mg/kg (1.6 mg/lb) with a range of 1.6 to 6.9 mg/kg (0.7 to 3.1 mg/lb). The median volume of propofol administered per dose was 0.4 mL/kg (0.018 mL/lb) with a range of 0.2 mL/kg (0.09 mL/lb) to 0.7 mL/kg (0.3 mL/lb), and the median total volume of propofol received was 6.5 mL/kg (3.0 mL/lb) with a range of 3.3 mL/kg (1.5 mL/lb) to 12.3 mL/kg (5.6 mL/lb). Propofol dose did not change significantly (P = 0.29) over time, with median doses at T0, T1, and T2 of 3.8 mg/kg (1.7 mg/lb) with a range from 2.5 to 6.5 mg/kg (1.1 to 3.0 mg/lb), 3.7 mg/kg (1.7 mg/lb) with a range from 1.8 to 6.9 mg/kg (0.8 to 3.1 mg/lb), and 3.7 mg/kg with a range from 1.8 to 6.9 mg/kg, respectively. Dogs were intubated and anesthesia was maintained with isoflurane at an inhaled percentage between 1% and 5% (median, 2.0%), with a median oxygen flow rate of 1.0 L/min (range, 0.5 to 2 L/min). Duration of anesthesia ranged from 5 to 90 minutes (median, 10 minutes). No serious adverse anesthetic events were reported.

The time between the initial blood draw (T0) and the start of radiation therapy varied, with a median of 3.5 days (range, 0 to 21 days). Significant decreases in RBC count, Hct, hemoglobin concentration, and MCHC were observed over time (Table 1). Mean corpuscular volume increased significantly (P < 0.005) over time. Mean values of only the RBC count and Hct were altered outside of reference intervals. These changes occurred predominantly between the samples collected at T0 and T1. Six of 31 dogs had a > 10% decrease in Hct. To better elucidate the mechanism of the RBC alterations, other laboratory parameters were analyzed. Among hematologic parameters, the only significant (P = 0.007) difference over time was a mild increase in neutrophil count. Other leukocyte parameters and the platelet count were not significantly changed. Most samples were free from hemolysis, with slight (1+) hemolysis being noted in 6 of the 93 (6%) samples. Slight (1+) polychromasia was noted in 11 of 93 (12%) samples (samples collected at T0 [n = 4 samples], T1 [4], and T2 [3]), and slight anisocytosis (1+) in 38 of 93 (41%) samples (T0, [17], T1 [9], and T2 [12]). Serum biochemical analyses demonstrated significant decreases in concentrations of albumin, total protein, total calcium, magnesium, creatinine, and iron. No significant changes in serum calculated osmolarity or sodium concentrations were noted.

Table 1—

Hematologic data at 3 collection times from 31 tumor-bearing dogs treated with definitive radiation therapy after induction of general anesthesia with propofol.

ParameterT0T1T2P valueReference interval
RBC count (× 106 RBCs/μL)6.86 ± 0.825.99 ± 0.866.04 ± 0.95< 0.0016.10–8.10
Hgb (g/dL)16.6 ± 1.714.4 ± 2.014.5 ± 2.1< 0.00114.0–19.3
Hct (%)46.0 ± 5.040.5 ± 5.440.9 ± 6.0< 0.00141.0–55.0
MCV (fL)67.2 ± 2.967.7 ± 2.967.9 ± 3.00.00562.0–71.0
MCH (pg)24.3 ± 1.224.1 ± 1.124.0 ± 1.10.2122.0–25.0
MCHC (g/dL)36.1 ± 1.335.6 ± 1.335.4 ± 1.30.00233.0–36.0
WBC count (× 103 WBCs/μL)9.26 ± 2.118.94 ± 5.5010.71 ± 4.430.165.90–11.60
Neutrophil count (× 103 neutrophils/μL)5.90 ± 1.615.55 ± 1.797.43 ± 3.510.0073.80–7.80
Platelet count (× 103 platelets/μL)330 ± 109305 ± 114333 ± 1180.32155–393
Total protein (g/dL)6.1 ± 0.45.9 ± 0.55.9 ± 0.60.0045.6–7.5
Albumin (g/dL)3.1 ± 0.22.9 ± 0.32.8 ± 0.2< 0.0012.8–4.0
Calcium (mg/dL)9.7 (9.2–10.9)9.6 (8.5–10.5)9.4 (8.8–10.4)< 0.0019.4–10.9
Magnesium (mg/dL)1.9 (1.6–2.4)1.8 (1.4–2.5)1.8 (1.3–2.2)< 0.0011.5–2.4
Creatinine (mg/dL)1.0 ± 0.30.9 ± 0.20.8 ± 0.2< 0.0010.7–2.0
Iron (μg/dL)148 (72.0–260)117 (63.0–235)94.0 (33.0–277)< 0.00161–226

Data are reported as mean ± SD for normally distributed data, which were evaluated via repeated-measures ANOVA to compare values across time. For other variables, data are reported as median (range) and the Friedman test was used for the comparison.

Hgb = Hemoglobin.

Variables were evaluated at 3 time points: within 3 weeks prior to the start of radiation therapy (T0), midway through the radiation protocol (T1; days 11 and 12), and at the end of radiation therapy (T2; days 23 and 24).

To evaluate whether the laboratory alterations were associated with tumor type, data from patients with MCT and STS were analyzed separately. This analysis showed that hematologic and laboratory alterations were similar (Tables 2 and 3). A few minor differences were noted between the groups. Serum iron and albumin concentrations significantly (P < 0.001 and P < 0.001, respectively) decreased in the STS group but not in the MCT group. Neutrophil count did not increase significantly in either group alone, in contrast with the patient population as a whole. A significant (P < 0.04) decrease in platelet concentration occurred in the STS group. Of the patients with a > 10% decrease in Hct, 1 had an infiltrative lipoma, 2 had MCTs, and 3 had STSs.

Table 2—

Hematologic data at 3 collection points from 11 dogs with MCT treated with definitive radiation therapy after induction of anesthesia with propofol.

ParameterT0T1T2P valueReference interval
RBC count (× 106 RBCs/μL)6.59 (5.19–7.65)5.52 (4.69–6.38)5.60 (4.31–7.08)< 0.0016.10–8.10
Hgb (g/dL)16.3 (13.8–19.1)13.8 (11.2–15.7)14.8 (10.8–17.8)0.00314.0–19.3
Hct (%)44.5 (34.8–53.1)39.4 (32.2–44.7)40.4 (30.5–49.3)< 0.00141.0–55.0
MCV (fL)68.2 (64.8–71.3)68.5 (67.1–72.0)69.3 (67.6–72.1)0.00162.0–71.0
MCHC (g/dL)36.6 (34.5–39.6)35.7 (34.6–36.7)35.4 (34.5–38.1)0.08633.0–36.0
WBC count (× 103 WBCs/μL)11.0 (7.39–13.2)8.89 (5.50–13.5)10.2 (6.46–24.2)0.355.90–11.60
Neutrophil count (× 103 neutrophils/μL)6.20 (4.42–8.55)6.17 (4.06–9.92)7.21 (4.15–19.7)0.443.80–7.80
Platelet count (× 103 platelets/μL)317 (210–660)317 (185–459)359 (174–544)0.35155–393
Total protein (g/dL)6.2 (5.2–6.7)5.9 (5.0–6.5)5.8 (4.9–6.4)0.0335.6–7.5
Albumin (g/dL)3.0 (2.6–3.3)2.8 (2.4–3.2)2.7 (2.5–3.1)0.072.8–4.0
Iron (μg/dL)134 (72.0–260)121 (63.0–224)111 (76.0–277)0.3561–226

Data are reported as median (range).

The Friedman test was used to compare values across time.

See Table 1 for remainder of key.

Table 3—

Hematologic data at 3 collection times from 17 dogs with STS treated with definitive radiation therapy after induction of anesthesia with propofol.

ParameterT0T1T2P valueReference interval
RBC count (× 106 RBCs/μL)7.02 (5.63–8.89)6.59 (4.24–7.97)6.28 (5.03–7.72)< 0.0016.10–8.10
Hgb (g/dL)16.6 (14.2–21.4)15.2 (9.90–19.6)14.6 (11.4–18.9)< 0.00114.0–19.3
Hct (%)46.1 (39.2–58.8)43.1 (28.0–53.3)42.5 (32.8–51.4)< 0.00141.0–55.0
MCV (fL)65.7 (60.5–69.7)66.6 (60.5–70.8)66.6 (60.2–70.8)0.5462.0–71.0
MCHC (g/dL)36.3 (34.0–37.3)35.6 (33.0–38.6)35.4 (33.1–37.5)0.6333.0–36.0
WBC count (× 103 WBCs/μL)8.77 (5.35–13.0)8.67 (2.43–13.0)9.60 (5.69–21.7)0.215.90–11.60
Neutrophil count (× 103 neutrophils/μL)5.64 (3.69–9.08)5.53 (1.64–9.73)6.67 (4.12–10.69)0.163.80–7.80
Platelet count (× 103 platelets/μL)337 (232–426)286 (220–702)286 (220–702)<0.04155–393
Total protein (g/dL)6.1 (5.4–6.9)5.9 (5.0–6.6)6.1 (4.7–7.1)0.0675.6–7.5
Albumin (g/dL)3.2 (2.8–3.6)3.0 (2.5–3.3)2.8 (2.2–3.2)< 0.0012.8–4.0
Iron (μg/dL)154 (77.0–214)115 (80–235)84.5 (33.0–157)< 0.00161–226

See Table 2 for key.

The data were also evaluated to determine the impact of NSAID administration on observed laboratory parameters. Fifteen patients received an NSAID at least once during the radiation protocol, compared with 16 patients that did not. A significant decrease in RBC count (P = 0.023), hemoglobin concentration (P = 0.008), and Hct (P = 0.018) was identified regardless of whether dogs had received NSAIDs (Tables 4 and 5). Dogs receiving NSAIDS had a decrease in total protein and albumin concentrations, whereas dogs not receiving NSAIDs had an increase in WBC and neutrophil counts. Only 1 of the 6 patients with a > 10% decrease in Hct received NSAIDs, suggesting that NSAID use was not the primary cause of changes observed.

Table 4—

Hematologic data at 3 collection times from 15 dogs not receiving NSAIDs treated with definitive radiation therapy after induction of anesthesia with propofol.

ParameterT0T1T2P valueReference interval
RBC count (× 106 RBCs/μL)6.72 (5.19–7.80)5.71 (4.69–7.21)4.67 (5.98–7.08)0.0026.10–8.10
Hgb (g/dL)16.6 (13.8–19.1)13.8 (11.2–16.7)14.3 (11.3–17.8)< 0.00114.0–19.3
Hct (%)47.2 (34.8–53.1)40.2 (32.2–46.8)39.6 (31.7–49.3)0.00541.0–55.0
MCV (fL)67.4 (60.5–74.1)68.2 (60.5–72.6)68.5 (60.2–73.5)0.8162.0–71.0
MCHC (g/dL)36.6 (33.3–39.6)35.5 (32.9–36.9)35.5 (32.7–38.1)0.1833.0–36.0
WBC count (× 103 WBCs/μL)8.58 (5.17–12.3)8.75 (5.50–34.9)11.2 (6.91–24.2)0.0175.90–11.60
Neutrophil count (× 103 neutrophils/μL)5.72 (3.71–8.05)5.12 (3.89–9.92)7.92 (5.38–19.7)0.0183.80–7.80
Platelet count (× 103 platelets/μL)396 (53.0–660)389 (174–702)389 (174–702)0.084155–393
Total protein (g/dL)6.2 (5.2–6.7)5.9 (5.0–6.4)6.0 (4.9–6.7)0.15.6–7.5
Albumin (g/dL)3.1 (2.6–3.6)3.0 (2.4–3.3)2.9 (2.5–3.2)0.0712.8–4.0
Iron (μg/dL)170 (100–260)120 (63.0–235)100 (49.0–277)0.01161–226

See Table 2 for key.

Table 5—

Hematogic data at 3 collection times from 16 dogs receiving NSAIDs treated with definitive radiation therapy after induction of anesthesia with propofol.

ParameterT0T1T2P valueReference interval
RBC count (× 106 RBCs/μL)6.97 (5.72–8.89)6.24 (4.24–7.97)6.26 (4.31–7.72)0.0236.10–8.10
Hgb (g/dL)16.5 (14.5–21.4)14.9 (9.90–19.6)15.1 (10.8–18.9)0.00814.0–19.3
Hct (%)45.8 (40.1–58.8)42.1 (28.0–53.3)42.7 (30.5–51.4)0.01841.0–55.0
MCV (fL)66.5 (62.1–70.1)67.1 (62.0–71.4)67.6 (62.9–71.5)0.7162.0–71.0
MCHC (g/dL)35.8 (34.5–37.3)35.7 (33.0–38.6)35.2 (33.2–37.5)0.3633.0–36.0
WBC count (× 103 WBCs/μL)9.57 (5.35–13.2)9.05 (2.43–13.0)9.16 (5.69–21.7)0.265.90–11.60
Neutrophil count (× 103 neutrophils/μL)6.14 (3.69–9.08)5.57 (1.64–9.73)4.97 (4.12–10.69)0.163.80–7.80
Platelet count (× 103 platelets/μL)292 (210–389)268 (193–674)261 (220–320)0.061155–393
Total protein (g/dL)6.1 (5.6–6.9)5.8 (5.0–6.6)5.9 (4.7–7.1)0.0265.6–7.5
Albumin (g/dL)3.1 (2.9–3.4)2.8 (2.5–3.3)2.7 (2.2–3.2)0.0012.8–4.0
Iron (μg/dL)142 (72.0–210)117 (80.0–150)88.5 (33.0–157)0.02161–226

See Table 2 for key.

Discussion

In the present study, although dogs with localized malignancies receiving full-course radiation therapy and daily induction of general anesthesia with propofol had significant decreases in RBC count, Hct, and hemoglobin concentration, the changes were mild in most cases. The mechanisms underlying the erythroid changes were not readily apparent and may be multifactorial. Evidence of regeneration, such as an increase in polychromasia and anisocytosis in later samples, was not observed. Hemolysis, either secondary to propofol or other factors, seemed to be unlikely, given that no Heinz bodies or other alterations such as elevation in BUN concentration were observed. As such, propofol appears to be a safe choice for daily induction of anesthesia during radiation therapy in dogs.

Inflammation occurring secondary to radiation therapy may have had an impact on our results. The significant increase in neutrophil count over time, although minute, may support an inflammatory process and was temporally consistent with acute effects of irradiation, given that it occurred from T1 to T2. In addition, a clear increase in the severity of skin toxicosis was observed between T1 and T2 for all patients. Interestingly, the increase in neutrophil count was not observed in dogs receiving NSAIDs, which could be a coincidence or consequence of anti-inflammatory properties. A consistent decrease in serum iron concentration was noted over time for all patient subsets, which could be secondary to iron loss or cytokine-mediated iron sequestration.

Another possible cause of anemia in cancer patients with a variety of tumor types is blood loss, either internal or external, although the source of hemorrhage may not be readily identifiable (eg, with gastrointestinal bleeding). Whereas the observed decrease in total protein concentration, RBC count, Hct, and hemoglobin concentration could have been secondary to external blood loss in the patients in this study, no source of blood loss was identified or expected in our patient population. A significant decrease in total protein and albumin concentrations was observed only for dogs having received NSAIDs; however, albumin concentration in the group that did not receive NSAIDs also decreased but not significantly (P = 0.071). Additionally, the decrease in RBC parameters was observed in both groups (with and without NSAIDs), indicating that these drugs were not likely responsible for the RBC changes. Furthermore, only 1 of the 6 dogs with a larger decrease in Hct (> 10%) received NSAIDs. An important influence from concurrent medications other than NSAIDs seems unlikely, considering their known adverse effects.

Additional causes of lowered erythroid values include factors such as splenic RBC sequestration, sampling differences, and hemodilution. The impact of these factors is difficult to assess retrospectively. A consistent and considerable change in patient hydration status during the course of treatment was unlikely, and hemodilution due to sampling from an IV catheter was avoided by direct venipuncture. However, some dogs had blood drawn during recovery from anesthesia at T1 or T2 but not at T0. These sampling differences with respect to anesthesia and fluid administration could account for at least some of the hemogram and protein changes observed between T0 and T1.

Although the mean decrease in Hct was minimal, there are circumstances that might merit caution. For example, a small decrease in RBC mass could be relevant to the well-being of patients with concurrent preexisting anemia. Anemia is common in patients with cancer, and some patients undergoing radiation therapy may be more sensitive than others to decreases in erythroid mass.21 Such decreases may also contribute to tumor hypoxia and impair the efficacy of radiation therapy. Furthermore, it is increasingly common to use multimodal treatment including radiation and chemotherapy for the treatment of aggressive malignancies. Chemotherapy administered either prior to or during radiation therapy would be expected to increase the magnitude of any existing anemia as a result of direct cytotoxicity to rapidly dividing hematopoietic precursors in the bone marrow. Clinically important anemia can be detected and limited by hematologic monitoring during prolonged irradiation protocols.

In addition to changes in erythroid parameters and iron, several other changes were noted in serum biochemical data in the patients in the present study, including significant decreases in albumin, total protein, total calcium, creatinine, and total magnesium concentrations. The causes of these changes may be attributable to the procedure, disease state, or other factors such as concurrent medications. The decrease in concentration of albumin (and consequently total protein) may have been secondary to blood loss. Radiation-induced inflammation may also have contributed because albumin is a negative acute-phase protein (concentration decreases in response to inflammation), but a concurrent increase in globulin concentration was not apparent. The decreased calcium and magnesium concentrations may have been secondary to decreased protein concentration and consequently fewer protein-bound cations. As with changes in erythroid parameters, the biochemical alterations noted were slight and deemed to be clinically unimportant. Therefore, the data are important in that they provide evidence for the safety of repetitive propofol usage for applications such as definitive radiation therapy requiring multiple anesthetic events, even in an elderly population of dogs.

Our study had several limitations, mainly attributable to its retrospective design. Definitive statements regarding the impact of propofol administration or irradiation themselves on the mild hematologic and biochemical alterations are limited by a lack of the following control populations: a group of dogs receiving the same radiation protocol without propofol for anesthesia and a group receiving the same repeated anesthesia without irradiation. Although evidence for clinically important Heinz body formation was not found, vital staining of RBCs with new methylene blue would have been more sensitive for detecting low numbers of Heinz bodies, and measurement of reticulocyte counts may have helped detect mild regenerative responses. Variability in concurrent medications administered during the study period could have influenced results; however, observed changes were independent of NSAID usage, and other medications were deemed unlikely to impact studied parameters. In addition, consistent sampling before induction of anesthesia at all 3 assessment times would have removed variables associated with fluid administration and effects of anesthesia on RBC distribution. It was not documented when samples were obtained, with some being drawn before and some after anesthetic induction. Finally, given the localized nature of the tumors in these patients and the mild alterations observed on laboratory testing, the reevaluation of laboratory tests was not performed at follow-up evaluations, which took place within 1 to 2 weeks after radiotherapy protocol completion. Thus, we were unable to evaluate for longer-term alterations.

Our primary goal was to determine whether clinically important anemia occurs in dogs with repeated propofol exposure, as has been suggested in cats.7 The erythrogram changes observed in this study cannot be linked directly with propofol and were of minimal clinical importance. In addition, tolerance to propofol necessitating an increasing dosage over time did not appear to develop. In general, propofol appears to be safe for daily induction of general anesthesia during radiation therapy in dogs.

ABBREVIATIONS

MCHC

Mean corpuscular hemoglobin concentration

MCT

Mast cell tumor

MCV

Mean corpuscular volume

PTV

Planning target volume

STS

Soft tissue sarcoma

a.

Insyte catheter, BD Medical, Sandy, Utah.

b.

Clinac 2100, Varian Medical Systems, Palo Alto, Calif.

c.

Advia 120 Analyzer, Siemens, New York, NY.

d.

Olympus AU640 Analyzer, Olympus America Inc, Mellville, NY.

e.

Prism, version 4.0, GraphPad Software Inc, San Diego, Calif.

f.

InStat, version 3.05, GraphPad Software Inc, San Diego, Calif.

g.

XiO, Elekta CMS Software, Maryland Heights, Mo.

References

  • 1 Tranquilli WJ, Thurmon JC, Grimm KA. Lumb & Jones' veterinary anesthesia and analgesia. 4th ed. Ames, Iowa: Blackwell, 2007.

  • 2 Buehrer S, Immoos S, Frei M, et al. Evaluation of propofol for repeated prolonged deep sedation in children undergoing proton radiation therapy. Br J Anaesth 2007; 99:556560.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3 Scheiber G, Ribeiro FC, Karpienski H, et al. Deep sedation with propofol in preschool children undergoing radiation therapy. Paediatr Anaesth 1996; 6:209213.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4 Keidan I, Perel A, Shabtai EL, et al. Children undergoing repeated exposures for radiation therapy do not develop tolerance to propofol: clinical and bispectral index data. Anesthesiology 2004; 100:251254.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5 Setlock MA, Palmisano WB, Berences JR, et al. Tolerance to propofol generally does not develop in pediatric patients undergoing radiation therapy. Anesthesiology 1996; 85:207209.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6 Pascoe PJ, Ilkiw JE, Frischmeyer KJ. The effect of the duration of propofol administration on recovery from anesthesia in cats. Vet Anesth Analg 2006; 33:27.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7 Andress JL, Day TK, Day DG. The effects of consecutive day propofol anesthesia on feline red blood cells. Vet Anesth 1995; 24:277282.

  • 8 Matthews NS, Brown RM, Barling KS, et al. Repetitive propofol administration in dogs and cats. J Am Anim Hosp Assoc 2004; 40:255260.

  • 9 Bley CR, Roos M, Price J, et al. Clinical assessment of repeated propofol-associated anesthesia in cats. J Am Vet Med Assoc 2007; 231:13471353.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10 Mohamadnia AR, Shahbazkia H, Akhlaghi M, et al. Clinical evaluation of repeated propofol total intravenous anesthesia in dog. Pak J Biol Sci 2008; 11:18201824.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11 Hall EJ, Giacci AJ. Oxygen effect and reoxygenation. In: Radiobiology for the radiologist. 6th ed. Philadelphia: Lippincott Williams & Wilkins, 2006;85105.

    • Search Google Scholar
    • Export Citation
  • 12 Synder SA, Dewhirst MW, Hauck ML. The role of hypoxia in canine cancer. Vet Comp Oncol 2008; 6:213223.

  • 13 Dietz A, Rudat V, Conradt C, et al. Prognostic value of hemoglobin level for primary radiochemotherapy of head-neck carcinomas [in German]. HNO 2000;48:655664.

    • Search Google Scholar
    • Export Citation
  • 14 Li L, Yu J, Xing L, et al. Serial hypoxia imaging with 99m Tc-HL91 SPECT to predict radiotherapy response in nonsmall cell lung cancer. Am J Clin Oncol 2006; 29:628633.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15 Bush RS. The significance of anemia in clinical radiation therapy. Int J Radiat Oncol Biol Phys 1986; 12:20472050.

  • 16 Haydaroğlu A, Yürüt V, Arican A, et al. The impact of the haemoglobin level on the response to radiotherapy. J BUON 2002; 7:3134.

  • 17 Rohrer BC, Ohlerth S, Roos M. Influence of pretreatment polarographically measured oxygenation levels in spontaneous canine tumors treated with radiation therapy. Strahlenther Onkol 2006; 182:518524.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18 Stockham SL, Scott MA. Fundamentals of veterinary clinical pathology. 2nd ed. Ames, Iowa: Blackwell, 2008.

  • 19 LaDue T, Klein MK. Toxicity criteria of the veterinary radiation therapy oncology group. Vet Radiol Ultrasound 2001; 42:475476.

  • 20 Norman GR, Streiner DL. Biostatistics: the bare essentials. 3rd ed. Hamilton, ON, Canada: BC Decker Inc, 2008.

  • 21 Madewell BR, Feldman BF. Characterization of anemias associated with neoplasia in small animals. J Am Vet Med Assoc 1980; 176:419425.

    • Search Google Scholar
    • Export Citation
  • 1 Tranquilli WJ, Thurmon JC, Grimm KA. Lumb & Jones' veterinary anesthesia and analgesia. 4th ed. Ames, Iowa: Blackwell, 2007.

  • 2 Buehrer S, Immoos S, Frei M, et al. Evaluation of propofol for repeated prolonged deep sedation in children undergoing proton radiation therapy. Br J Anaesth 2007; 99:556560.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3 Scheiber G, Ribeiro FC, Karpienski H, et al. Deep sedation with propofol in preschool children undergoing radiation therapy. Paediatr Anaesth 1996; 6:209213.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4 Keidan I, Perel A, Shabtai EL, et al. Children undergoing repeated exposures for radiation therapy do not develop tolerance to propofol: clinical and bispectral index data. Anesthesiology 2004; 100:251254.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5 Setlock MA, Palmisano WB, Berences JR, et al. Tolerance to propofol generally does not develop in pediatric patients undergoing radiation therapy. Anesthesiology 1996; 85:207209.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6 Pascoe PJ, Ilkiw JE, Frischmeyer KJ. The effect of the duration of propofol administration on recovery from anesthesia in cats. Vet Anesth Analg 2006; 33:27.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7 Andress JL, Day TK, Day DG. The effects of consecutive day propofol anesthesia on feline red blood cells. Vet Anesth 1995; 24:277282.

  • 8 Matthews NS, Brown RM, Barling KS, et al. Repetitive propofol administration in dogs and cats. J Am Anim Hosp Assoc 2004; 40:255260.

  • 9 Bley CR, Roos M, Price J, et al. Clinical assessment of repeated propofol-associated anesthesia in cats. J Am Vet Med Assoc 2007; 231:13471353.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10 Mohamadnia AR, Shahbazkia H, Akhlaghi M, et al. Clinical evaluation of repeated propofol total intravenous anesthesia in dog. Pak J Biol Sci 2008; 11:18201824.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11 Hall EJ, Giacci AJ. Oxygen effect and reoxygenation. In: Radiobiology for the radiologist. 6th ed. Philadelphia: Lippincott Williams & Wilkins, 2006;85105.

    • Search Google Scholar
    • Export Citation
  • 12 Synder SA, Dewhirst MW, Hauck ML. The role of hypoxia in canine cancer. Vet Comp Oncol 2008; 6:213223.

  • 13 Dietz A, Rudat V, Conradt C, et al. Prognostic value of hemoglobin level for primary radiochemotherapy of head-neck carcinomas [in German]. HNO 2000;48:655664.

    • Search Google Scholar
    • Export Citation
  • 14 Li L, Yu J, Xing L, et al. Serial hypoxia imaging with 99m Tc-HL91 SPECT to predict radiotherapy response in nonsmall cell lung cancer. Am J Clin Oncol 2006; 29:628633.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15 Bush RS. The significance of anemia in clinical radiation therapy. Int J Radiat Oncol Biol Phys 1986; 12:20472050.

  • 16 Haydaroğlu A, Yürüt V, Arican A, et al. The impact of the haemoglobin level on the response to radiotherapy. J BUON 2002; 7:3134.

  • 17 Rohrer BC, Ohlerth S, Roos M. Influence of pretreatment polarographically measured oxygenation levels in spontaneous canine tumors treated with radiation therapy. Strahlenther Onkol 2006; 182:518524.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18 Stockham SL, Scott MA. Fundamentals of veterinary clinical pathology. 2nd ed. Ames, Iowa: Blackwell, 2008.

  • 19 LaDue T, Klein MK. Toxicity criteria of the veterinary radiation therapy oncology group. Vet Radiol Ultrasound 2001; 42:475476.

  • 20 Norman GR, Streiner DL. Biostatistics: the bare essentials. 3rd ed. Hamilton, ON, Canada: BC Decker Inc, 2008.

  • 21 Madewell BR, Feldman BF. Characterization of anemias associated with neoplasia in small animals. J Am Vet Med Assoc 1980; 176:419425.

    • Search Google Scholar
    • Export Citation

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