Abstract
Anesthetics can affect biochemical parameters, complicating the interpretation of laboratory results and perhaps leading to erroneous diagnoses. The present study was performed to characterize variations in selected rabbit biochemical parameters after inhalant anesthetics. Twenty New Zealand White rabbits were allocated to 2 treatment groups (n = 10 animals each), which received either halothane or isoflurane. Anesthesia was induced by using a face-mask, and rabbits were intubated for maintenance of anesthesia for 30 min. Blood samples were obtained before induction and at 1, 10, 30, 60, and 120 min and 24, 48, and 72 h after intubation. Serum cholesterol, triglycerides, albumin, total proteins, total bilirubin, sodium, potassium, chloride, calcium, and phosphorus concentrations were measured by using an autoanalyzer. Administration of halothane significantly increased serum triglyceride levels and decreased serum cholesterol, albumin, total protein, and potassium levels. Isoflurane administration increased serum triglyceride, phosphorus, and chloride concentrations and decreased serum calcium and potassium levels. Caution is required in interpreting data on serum biochemical parameters from rabbits anesthetized with halothane or isoflurane.
The possibility has been suggested 13 that some anesthetics can influence blood biochemistry values in rabbits, complicating the interpretation of laboratory results, and perhaps leading to erroneous diagnoses. Whether inhalant anesthetics, like intravenous agents,14 alter biochemical parameters in rabbits is unclear. In the present study, we evaluated the effect of 2 inhalant anesthetics, halothane and isoflurane, on selected biochemical parameters.
Halothane and isoflurane are potent inhalant anesthetics. Halothane has a depressant effect on the cardiovascular system and can produce arrhythmias and moderate hypotension at surgical levels of anesthesia. Isoflurane produces slightly more severe respiratory depression than halothane but slightly less depression of the cardiovascular system.9 The main objective of the present study was to determine which of these agents would be the most suitable in studies involving measurements of biochemical parameters in rabbits.
Materials and Methods
The 20 female New Zealand White rabbits (age, approximately 1 y; weight, 3.5 to 4.5 kg; Granja San Bernardo, Navarra, Spain) used in this study were housed in individual wire-rod-floored stainless-steel cages each measuring 48 × 61 × 46 cm, with a collection pan beneath each cage and in a room with controlled environmental conditions (20 to 22 °C; 50% to 55% relative humidity; 10 to 15 air changes per hour; and a 12:12-h light:dark cycle). The rabbits were quarantined 15 d prior to use to permit adaptation to environmental conditions, food, and water and to enable daily evaluation of health status. All the rabbits were clinically healthy prior to the study. Animals were free of recognized pathogens (Pasteurella multocida, Bordetella bronchoseptica, Trychophyton microsporum, Escherichia coli, coccidia, ectoparasites, and endoparasites). The rabbits were fed a standard rabbit diet (150 g daily; Purina Lab Rabbit Chow, Purina, Barcelona, Spain), and fresh water purified by reverse osmosis was provided ad libitum. All experimental manipulations were performed between 09:15 and 12:45. The experimental protocols were approved by the Institutional Animal Care and Use Committee of the Veterinary Faculty of Madrid at Universidad Complutense (Madrid, Spain). All procedures were completed in accordance with the Guide for the Care and Use of Laboratory Animals18 and conformed with the relevant European Union Directive.5
The anesthetic circuit was flushed for 2 min with oxygen at a flow of 4 L/min to ensure that no residual anesthetic agent remained in the system. Oxygen then was delivered at a flow rate of 4 L/min for 2 min, with the face mask held in position manually. Animals were randomly allocated into 2 treatment groups (n = 10 animals each) to receive either halothane (Fluothane, Zéneca Farma, Pontevedra, Spain) or isoflurane (Isoflurano, Laboratorios Inibsa, Barcelona, Spain). A control group was not included because due to the lack of groups induction and associated handling, control and treated groups would not be comparable.
Anesthesia was induced by using a face mask attached to an Ayre T-piece (with Jackson–Rees modification) breathing system. Conscious rabbits were placed into restraining cages for blood collection, whereas during induction of anesthesia, animals were restrained manually; anesthetized rabbits did not require additional restraint for these procedures. To provide firm restraint in the event of pronounced struggling, the operator leaned over each rabbit, positioning 1 arm on either side of the rabbit's body, with the lower back of the animal in apposition to the operator's body. Halothane and isoflurane were delivered in by increasing the anesthetic concentration by 0.5% (according to the vaporizer) every 30 s, to measured, delivered concentrations of 3.5% halothane and 4.5% isoflurane with a dedicated vaporizer for each anesthetic. Both anesthetics were supplied in a fresh gas flow rate of 4 L/min oxygen. The anesthetic gas concentration was maintained at this maximal level until induction was complete based on loss of righting, pedal withdrawal, and auricular reflexes. The vaporizer percentages for both anesthetic agents during the induction and maintenance of the anesthesia were based on preliminary studies and a review of previous anesthetic studies involving laboratory rabbits.9
The trachea was intubated by using a cuffed endotracheal tube (inner diameter, 3 mm), and anesthetic gases (1.5% halothane and 2.5% isoflurane) were supplied in oxygen at 2 L/min. Anesthesia was maintained for 30 min, after which the vaporizer was switched off. The depth of anesthesia was monitored by using the pedal withdrawal, ear pinch, palpebral, corneal, and righting reflexes. Heart rate was calculated from the electrocardiogram (Bexgraph, Bexen-Osatu, Vizcaya, Spain), and respiratory rate was assessed visually by counting respirations. Rectal temperature was measured by a rectal thermometer. Samples (2 mL each) of blood were taken from the central ear artery just before induction and 1, 10, 30, 60, 120 min and 24, 48 and 72 h after intubation by using 21-gauge needles; EMLA (eutectic mixture of local anesthetics) cream (Astra Läkemedel, Södertälje, Sweden) was applied over the central ear artery 45 to 60 min before blood collection. Ears were alternated for consecutive blood collections. Blood samples were maintained in collection tubes with no additives for 2 h at 20 to 22 °C and then centrifuged (Minifuge RF, Heraeus, Hannover, Germany) at 1200 × g and 4 °C for 20 min. Serum was separated and stored frozen at –30 °C until assayed. Serum cholesterol, triglyceride, albumin, total protein, total bilirubin, and electrolyte (sodium, potassium, chloride, calcium, and phosphorus) concentrations were measured by using an autoanalyzer (Hitachi 747, Boehringer Mannheim, Madrid, Spain).
The Kolmogorov–Smirnov test was performed to determine whether data showed normal distribution. Data for serum cholesterol, triglyceride, albumin, total protein, total bilirubin, and electrolyte concentrations and heart and respiratory rates are presented as mean ± SEM. Within each treatment group, data were analyzed by 1-way ANOVA followed by the Duncan post hoc test when a significant difference (that is, P < 0.05). Statistical calculations were performed by using SAS software (SAS Institute, Cary, NC).
Results
Heart and respiratory rates.
Compared with the baseline value (303 ± 9 bpm), heart rate was decreased (P < 0.001) in the halothane group at 1, 10, and 30 min after intubation (211 ± 15 bpm at 30 min), whereas heart rate was unchanged in isoflurane-treated rabbits. Respiratory rate was decreased (P < 0.001) at 1 min after intubation in the halothane (109 ± 7 to 50 ± 2 breaths per minute) and isoflurane (99 ± 6 to 48 ± 6 breaths per minute) groups. Respiratory rate continued to be less (P > 0.05) than baseline values throughout anesthesia. During the recovery period, these values returned to the baseline levels.
Reflexes monitored.
Loss of the righting reflex occurred at 312 ± 56 s during induction of anesthesia with halothane and at 255 ± 48 s in the isoflurane group. Loss of the pedal withdrawal and auricular reflexes occurred at 402 ± 78 and 396 ± 78 s, respectively, in the halothane-treated rabbits and at 360 ± 64 s and 328 ± 68 s, respectively, in those given isoflurane. After the vaporizer was switched off, the time required for return of the pedal withdrawal and auricular reflexes was 176 ± 48 s and 174 ± 52 s, respectively, in the halothane group and 140 ± 36 s and 132 ± 36 s in the isoflurane group. The time required for the return of the righting reflex was 252 ± 58 s in the halothane group and 202 ± 42 s in the isoflurane group.
Temperature.
Mean rectal temperature (38.5 ± 0.6 °C) did not change significantly in either group during anesthesia.
Serum cholesterol, triglycerides, albumin, total protein, and total bilirubin
(Table 1). Compared with baseline values, serum cholesterol levels were decreased (P < 0.05) at 1 and 30 min and 24 h after intubation in halothane-anesthetized rabbits. Serum triglyceride levels were increased (P < 0.05) at 48 h in the halothane group and at 10 and 60 min and 24 h in the isoflurane group. Moreover, serum total proteins were decreased (P < 0.05) at 1 min and at 24 and 72 h whereas serum albumin concentrations decreased 72 h after intubation in the halothane group; isoflurane-treated rabbits did not show any change in serum cholesterol, albumin, and total proteins. No changes in serum total bilirubin (P > 0.05) were found in either anesthetized group.
Table 1.
Serum concentrations of cholesterol (mg/dL), triglycerides (mg/dL), albumin (g/dL), total protein (g/dL), and total bilirubin (mg/dL) at various times after intubation of rabbits (n = 10 per group) anesthetized with halothane or isoflurane
| Time point | Treatment group | Cholesterol (10–80 mg/dL) | Triglycerides (7–205 mg/dL) | Albumin (2.42–4.05 g/dL) | Total protein (5–8.3 g/dL) | Total bilirubin (0–0.74 mg/dL) |
| 0 min | ||||||
| Halothane | 66.9 ± 5.78 | 88.94 ± 13.78 | 3.88 ± 0.13 | 5.96 ± 0.12 | 0.26 ± 0.03 | |
| Isoflurane | 68.0 ± 4.88 | 72.29 ± 7.83 | 3.66 ± 0.12 | 5.68 ± 0.22 | 0.25 ± 0.02 | |
| 1 min | ||||||
| Halothane | 48.6 ± 5.52a | 97.14 ± 8.95 | 3.60 ± 0.12 | 5.41 ± 0.18a | 0.24 ± 0.01 | |
| Isoflurane | 75.4 ± 9.51 | 87.47 ± 8.13 | 3.82 ± 0.13 | 5.80 ± 0.26 | 0.26 ± 0.02 | |
| 10 min | ||||||
| Halothane | 52.1 ± 5.87 | 105.85 ± 14.39 | 3.79 ± 0.10 | 5.74 ± 0.19 | 0.27 ± 0.02 | |
| Isoflurane | 71.7 ± 8.06 | 94.20 ± 6.48a | 3.72 ± 0.13 | 5.57 ± 0.24 | 0.28 ± 0.02 | |
| 30 min | ||||||
| Halothane | 49.7 ± 5.29a | 95.12 ± 12.18 | 3.67 ± 0.12 | 5.58 ± 0.17 | 0.22 ± 0.02 | |
| Isoflurane | 68.6 ± 11.36 | 97.79 ± 13.83 | 3.58 ± 0.14 | 5.39 ± 0.34 | 0.21 ± 0.03 | |
| 60 min | ||||||
| Halothane | 54.2 ± 6.46 | 118.26 ± 19.83 | 3.74 ± 0.18 | 5.73 ± 0.37 | 0.28 ± 0.03 | |
| Isoflurane | 78.4 ± 1.28 | 133.56 ± 17.52a | 3.66 ± 0.17 | 5.51 ± 0.43 | 0.21 ± 0.02 | |
| 120 min | ||||||
| Halothane | 49.6 ± 6.71 | 82.32 ± 10.57 | 3.64 ± 0.12 | 5.56 ± 0.32 | 0.29 ± 0.03 | |
| Isoflurane | 69.6 ± 8.91 | 88.36 ± 10.46 | 3.60 ± 0.10 | 5.52 ± 0.44 | 0.23 ± 0.03 | |
| 24 h | ||||||
| Halothane | 40.4 ± 6.61a | 100.28 ± 15.87 | 3.54 ± 0.09 | 5.46 ± 0.19a | 0.22 ± 0.01 | |
| Isoflurane | 74.2 ± 9.58 | 112.48 ± 16.42a | 3.56 ± 0.09 | 5.40 ± 0.18 | 0.25 ± 0.02 | |
| 48 h | ||||||
| Halothane | 45.0 ± 11.15 | 162.13 ± 14.07a | 3.70 ± 0.12 | 6.01 ± 0.38 | 0.19 ± 0.02 | |
| Isoflurane | 79.6 ± 10.58 | 94.80 ± 14.23 | 3.84 ± 0.15 | 6.27 ± 0.30 | 0.24 ± 0.02 | |
| 72 h | ||||||
| Halothane | 46.67 ± 6.38 | 126.63 ± 14.03 | 3.20 ± 0.15a | 4.98 ± 0.17b | 0.20 ± 0.03 | |
| Isoflurane | 79.20 ± 13.39 | 77.10 ± 16.36 | 3.90 ± 0.10 | 6.06 ± 0.39 | 0.25 ± 0.02 | |
All values are expressed as mean ± SEM. Samples were obtained from anesthetized animals at 1, 10, and 30 min and from conscious animals for the others time points. Normal references values3,21 are given under the names of the parameter.
Significantly different (P < 0.05) from the baseline (0 min) value.
Significantly different (P < 0.01) from the baseline (0 min) value.
Serum sodium, potassium, chloride, calcium, and phosphorus
(Table 2). In the isoflurane group, serum sodium at 1 min after intubation was significantly increased (P < 0.05) compared with baseline. Compared with baseline levels, serum potassium was decreased (P < 0.001) at 1 through 60 min and 24 through 72 h after intubation in the halothane group and from 1 through 120 min in the isoflurane group. In addition, serum chloride was increased (P < 0.05) 1 min after intubation, serum calcium levels were decreased (P < 0.05) at 60 min and 48 and 72 h, and serum phosphorus concentrations were increased (P < 0.01) at 60 and 120 min and at 72 h in the isoflurane group. Serum sodium, chloride, calcium, and phosphorus did not change throughout or after anesthesia in the halothane-treated rabbits.
Table 2.
Serum concentrations of sodium (mmol/L), potassium (mmol/L), chloride (mmol/L), calcium (mg/dL), and phosphorus (mg/dL) at various times after intubation of rabbits (n = 10 per group) anesthetized with halothane or isoflurane
| Time point | Treatment group | Sodium (114–156 mmol/L) | Potassium (3.7–7.4 mmol/L) | Chloride (89–120 mmol/L) | Calcium (5.6–15 mg/dL) | Phosphorus (2.3–6.9 mg/dL) |
| 0 min | ||||||
| Halothane | 141.09 ± 2.06 | 5.29 ± 0.13 | 106.48 ± 1.50 | 13.14 ± 0.54 | 4.19 ± 0.45 | |
| Isoflurane | 143.58 ± 1.85 | 5.51 ± 0.25 | 105.32 ± 1.33 | 12.64 ± 0.30 | 4.69 ± 0.23 | |
| 1 min | ||||||
| Halothane | 143.09 ± 2.25 | 4.64 ± 0.18b | 108.18 ± 2.73 | 13.23 ± 0.45 | 4.43 ± 0.30 | |
| Isoflurane | 149.18 ± 1.98a | 4.69 ± 0.23a | 110.26 ± 1.03a | 13.60 ± 0.54 | 6.21 ± 0.54 | |
| 10 min | ||||||
| Halothane | 145.90 ± 2.82 | 4.46 ± 0.15c | 108.11 ± 2.75 | 13.71 ± 0.46 | 4.52 ± 0.31 | |
| Isoflurane | 147.87 ± 3.72 | 4.46 ± 0.24b | 107.26 ± 2.33 | 12.54 ± 0.81 | 6.46 ± 0.61 | |
| 30 min | ||||||
| Halothane | 144.86 ± 2.74 | 4.59 ± 0.214a | 108.80 ± 2.03 | 13.12 ± 0.46 | 4.69 ± 0.47 | |
| Isoflurane | 147.01 ± 2.41 | 4.34 ± 0.24b | 105.33 ± 1.17 | 11.61 ± 0.86 | 5.98 ± 0.68 | |
| 60 min | ||||||
| Halothane | 141.74 ± 3.77 | 4.49 ± 0.32a | 104.75 ± 3.21 | 13.52 ± 0.81 | 4.63 ± 0.37 | |
| Isoflurane | 144.42 ± 3.77 | 3.94 ± 0.24b | 104.14 ± 2.85 | 10.88 ± 0.83a | 7.12 ± 0.61a | |
| 120 min | ||||||
| Halothane | 140.18 ± 4.38 | 5.34 ± 0.31 | 106.60 ± 3.88 | 13.78 ± 0.92 | 4.51 ± 0.25 | |
| Isoflurane | 144.42 ± 2.36 | 4.08 ± 0.32b | 107.70 ± 2.39 | 11.66 ± 0.71 | 7.62 ± 0.82b | |
| 24 h | ||||||
| Halothane | 140.74 ± 2.31 | 4.39 ± 0.22b | 109.65 ± 1.87 | 12.70 ± 0.87 | 3.95 ± 0.49 | |
| Isoflurane | 140.60 ± 2.15 | 5.55 ± 0.24 | 105.02 ± 1.75 | 13.88 ± 0.87 | 5.17 ± 0.63 | |
| 48 h | ||||||
| Halothane | 146.90 ± 2.99 | 4.71 ± 0.08a | 108.77 ± 1.97 | 13.70 ± 0.31 | 4.24 ± 0.45 | |
| Isoflurane | 147.68 ± 3.11 | 5.03 ± 0.26 | 107.78 ± 3.10 | 14.24 ± 0.51a | 6.11 ± 0.67 | |
| 72 h | ||||||
| Halothane | 139.50 ± 2.23 | 4.24 ± 0.30b | 103.90 ± 1.99 | 12.30 ± 0.61 | 3.80 ± 0.49 | |
| Isoflurane | 148.24 ± 2.73 | 5.06 ± 0.31 | 109.64 ± 2.49 | 14.72 ± 0.89a | 6.29 ± 0.32a | |
All values are expressed as mean ± SEM. Samples were obtained from anesthetized animals at 1, 10, and 30 min and from conscious animals for the others time points. Normal references values3,21 are given under the names of the parameter.
Significantly different (P < 0.05) from the baseline (0 min) value.
Significantly different (P < 0.01) from the baseline (0 min) value.
Significantly different (P < 0.001) from the baseline (0 min) value.
Discussion
Our study shows the response of selected biochemical parameters after administration of halothane or isoflurane to laboratory rabbits. Although small but significant variations were noted in several serum chemistry parameters during or after 30 min of anesthesia with halothane or isoflurane in female New Zealand White rabbits, most changes were not biologically significant. Minimizing potential interactions between the anesthetic regimen used and a particular experimental protocol can be important. In these circumstances, avoid the use of several anesthetics agents and inducing anesthesia solely with a volatile agent may be advantageous.10
Halothane produces free radicals during hepatic biotransformation in rats, and these free radicals occasionally cause hepatic injury, especially in cases of multiple halothane exposures over short periods.19 The decreases in serum cholesterol concentrations after administration of halothane to rabbits may result from similar production of free radicals as has been described for rats;24 serum cholesterol levels decreased after halothane administration to rats.19, 20, 24 Isoflurane had no effect on cholesterol levels in rabbits, although one study reported a decrease in flying foxes.16 In contrast, serum triglycerides increased after halothane and isoflurane administration. Both anesthetics increase serum glucocorticoids in rabbits;12 lypolysis increases under the influence of catecholamines, and corticosteroids contribute to fat mobilization.2 Some authors have observed an increase in serum triglycerides after halothane administration to rats,19 whereas others have reported decreases after halothane20 or no increases after isoflurane in rats.6 All values for cholesterol and triglycerides in the current study were within reference ranges.3,21
Inhalant anesthetic agents may alter protein concentrations.25 In our study, serum albumin and total proteins were decreased 72 h after halothane administration. Halothane exerts differential inhibitory effects on the synthesis of albumin and total proteins in rats: at early time points, relative rates of albumin synthesis are unaffected by halothane, but as anesthetic exposure is prolonged, the production of albumin and total proteins decreases.8 Some studies report decreases in total proteins after halothane in humans and rats,4,11, 19 but others observed no change in total protein concentration in rats.24 In our rabbits, total protein and albumin levels remained constant after isoflurane; some studies report decreases in serum albumin in humans and flying foxes exposed to isoflurane.4,16
Halothane did not change serum total bilirubin in rabbits, as was the case for horses and rats.7, 19 Isoflurane similarly had no effect on total bilirubin in rabbits.
Serum sodium levels did not change after halothane or isoflurane anesthesia of rabbits, as reported previously in rats.24 However, serum potassium concentrations were decreased in both groups of rabbits. Similar changes occurred in isoflurane-anesthetized nonhuman primates,17 but halothane anesthesia had no effect on serum potassium in rats.24 Hypokalemia during anesthesia may be a consequence of stress-induced adrenaline secretion.23 All serum sodium and potassium concentrations were within normal reference ranges for rabbits.
Serum calcium decreased and phosphate levels increased in rabbits after isoflurane administration, as previously described in flying foxes and nonhuman primates.16, 17 Glomerular and tubular functions can be affected transiently after isoflurane,15 and phosphorus increases during renal failure.2 Mice did not demonstrate significant alterations in serum calcium concentrations.22
In rabbits, serum chloride levels were increased at 1 min after intubation in the isoflurane group. The kidney is the main site of chloride excretion, so a brief reduction in renal function immediately after isoflurane anesthesia may increase serum chloride levels transiently. Isoflurane induces increases in serum chloride in the flying fox.16 Halothane administration did not alter chloride concentrations in rabbits or humans.1 All serum chloride values we recorded were within the normal reference range for rabbits.
These results indicate that halothane and isoflurane induce minor but statistically significant variations in several serum chemistry parameters during and soon after administration of anesthetic, although most of the changes noted were not biologically significant. Changes in serum biochemical parameters should be taken into account during the evaluation of experimental results from rabbits treated with halothane or isoflurane, because the effects of the anesthetic agent may confound interpretation of the results and lead to erroneous conclusions.
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