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PEDIATRIC ANESTHESIA

The Physiologic Effects of Isoflurane Anesthesia in Neonatal Mice

Department of Anesthesia, Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine; Institute of Pediatric Anesthesia, Cincinnati Children’s Hospital Research Foundation, Cincinnati, Ohio

Address correspondence and reprint requests to Andreas Loepke, MD, PhD, Department of Anesthesia, Cincinnati Children’s Hospital Medical Center, ML2001, 3333 Burnet Avenue, Cincinnati, OH 45229. Address e-mail to andreas.loepke{at}cchmc.org.

	Abstract

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In neonatal rodents, isoflurane has been shown to confer neurological protection during hypoxia-ischemia and to precipitate neurodegeneration after prolonged exposure. Whether neuroprotection or neurotoxicity result from a direct effect of isoflurane on the brain or an indirect effect through hemodynamic or metabolic changes remains unknown. We recorded arterial blood pressure, heart rate, blood gases, and glucose in 10-day-old mice during 60 min of isoflurane anesthesia with spontaneous or mechanical ventilation, as well as during 60 min of hypoxia-ischemia with isoflurane anesthesia or without anesthesia. During isoflurane anesthesia, hypoglycemia and metabolic acidosis occurred with spontaneous and mechanical ventilation. During hypoxia-ischemia, isoflurane was fatal with spontaneous breathing but survivable with mechanical ventilation, with arterial blood pressure and heart rate being similar to that observed in unanesthetized animals. Minimum alveolar concentration (MAC) was 2.3% in 10-day-old mice. In summary, isoflurane anesthesia precipitated hypoglycemia, which may have contributed to the neurodegeneration observed in neonatal rodents. Use of 0.8 MAC isoflurane for evaluation of neuroprotection during hypoxia-ischemia requires mechanical ventilation and glucose supplementation in this model.

	Introduction

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Volatile anesthetics are widely used during surgery in human neonates and during neonatal animal research. In neonatal animals, volatile anesthetics have been shown to confer neurological protection against hypoxia-ischemia (H-I) (1) and to precipitate neuronal degeneration during prolonged exposure (2). At present, there are no drugs for use in clinical practice for neuroprotection in neonates. Although volatile anesthetics could be evaluated for this purpose, concerns about neurotoxicity require resolution before further neuroprotection studies are conducted.

Animal research to evaluate neuroprotection in neonates frequently uses the Rice-Vannucci model. Originally described in neonatal rats, the model employs permanent unilateral common carotid ligation under anesthesia, followed by a period of hypoxia after recovery from the anesthetic (3). Animals are then allowed to survive for varying lengths of time to evaluate histological or functional brain damage. This model has been extended to neonatal mice to investigate the genetic effects on brain ischemia (4). Many factors influence the severity of brain injury in this model, including duration of hypoxia, genetic strain, postnatal age, brain temperature, blood glucose, and carbon dioxide (5–8).

Isoflurane has been implicated to cause widespread neuronal degeneration in neonatal rat pups (2). Whether this is a direct effect of isoflurane on the brain or an indirect effect from hemodynamic or metabolic changes remains uncertain, as metabolic and physiologic variables were not monitored during isoflurane exposure. There are no data to describe the effects of isoflurane on arterial blood pressure (MAP), heart rate (HR), arterial blood gases, and glucose in neonatal rodents during normoxia or hypoxia. The present study characterized the physiological effects of isoflurane anesthesia during normoxia and during H-I in a neonatal mouse model.

	Methods

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After approval by the Institutional Animal Care And Use Committee, 42 10-day-old 129T2/SvEvMsJ x C57BL6/J F₁-hybrid mouse pups of both gender were studied as outlined in Figure 1. Animal care conformed to National Institutes of Health guidelines. Breeding pairs of female C57BL6/J and male 129T2/SvEvMsJ mice were housed with their offspring in a 12h-12h light-dark cycle at 25°C with free access to food and water. On postnatal day 10 (P10), mouse pups were anesthetized with isoflurane 3% in oxygen, the anterior neck was prepared, and the right common carotid artery was ligated through a 4–5 mm neck incision. Micro-Renathane tubing, outer diameter 0.635 mm (MRE 025, Braintree Scientific, Braintree, MA), was advanced 1–2 mm proximally into the right common carotid artery and MAP was transduced (Argon Medical Devices Inc., Athens, TX). The preparation for MAP recording took approximately 25 min. Electrocardiogram and MAP were recorded (BioPac MP-150 U, AcqKnowledge software version 3.7.3, Biopac Systems Inc., Goleta, CA). Rectal temperature was maintained at 37°C with a stage warmer (MidAtlantic Diagnostics Inc., Marlton, NJ).

View larger version (34K): [in this window] [in a new window]   Figure 1. Timeline of the experiments. Time point 0 indicates separation from dam; fasting refers to housing in warmed environment without access to dam; ind refers to induction of anesthesia and exposure of right common carotid artery; prep refers to cannulation of right common carotid artery and preparation for arterial blood pressure and heart rate measurements; anesthesia refers to inhalation of 1.8% isoflurane during recording of arterial blood pressure and heart rate; H-I refers to hypoxia (10% inhaled oxygen concentration) and ischemia (right carotid artery ligation).

To assess the effects of ventilatory strategy during anesthesia and H-I, animals were assigned to spontaneous ventilation or mechanical ventilation groups. The mechanical ventilation group was orotracheally intubated with a 24-gauge catheter under direct vision of the trachea through a stereo microscope (Motic Instruments Inc., Richmond, B.C., Canada) and ventilated with a respiratory rate of 300 breaths/min and a tidal volume of 12 µL/g (MiniVent, Harvard Apparatus Inc., Holliston, MA). Animals in the spontaneous ventilation group breathed through a nose cone.

To study the influence of time on hemodynamics during anesthesia, MAP and HR were recorded for 1 h during spontaneous breathing (isoflurane-spontaneous ventilation group, n = 5) or mechanical ventilation (isoflurane-mechanical ventilation group, n = 4) with isoflurane 1.8% in oxygen. After the last MAP measurement, the arterial catheter was withdrawn and blood was aspirated anaerobically for arterial pH, blood gases, and glucose measurement (i-Stat Corp., East Windsor, NJ). To study the influence of isoflurane concentration on HR and MAP, inspired isoflurane was adjusted to 0.9%, 1.8%, and 3% inspired isoflurane in random sequence in 4 mechanically ventilated animals. The isoflurane concentration was kept constant at each condition for 10 min, after which MAP and HR were recorded for 2 min, followed by a change of the isoflurane concentration to the next condition.

Because the minimum alveolar concentration (MAC) of isoflurane in neonatal mice is not known, 10-day-old 129T2/SvEvMsJ x C57BL6/J F1-hybrid mice of both genders (n = 10) were anesthetized with isoflurane in oxygen. To achieve brain tissue and inspired gas equilibration, the isoflurane concentration (RGM 5250; Datex-Ohmeda Inc., Louisville, CO) was kept constant for 15 min, followed by clamping of the middle third of the tail with a hemostat clamp. Purposeful movement or phonation prompted a 10%–15% increase: lack of response led to a 10% decrease in isoflurane concentration. The new concentration was held constant for 15 min followed by repeat stimulation proximal to the previous test site. The number of stimulations was limited to 4, and blood glucose was verified in each animal at the end of the experiment to avoid the influence of hypoglycemia on the assessment of MAC. MAC was calculated in each animal as the mean of the isoflurane concentrations bracketing the response and lack of response and averaged for all 10 animals.

The influence of H-I on hemodynamics was studied in three other groups of animals. After preparation for HR and MAP monitoring, mice underwent 1 h of hypoxia (10% oxygen in nitrogen) and ischemia (carotid artery ligation for arterial cannulation). The isoflurane-H-I-mechanical ventilation group was orotracheally intubated and mechanically ventilated with isoflurane 1.8% at a respiratory rate of 350 breaths/min and a tidal volume of 20 µL/g (n = 5) and the isoflurane-H-I-spontaneous ventilation group was spontaneously breathing with isoflurane 1.8% (n = 5). An unanesthetized H-I-spontaneous ventilation group (n = 7) was also studied, in which isoflurane was discontinued after surgical preparation, immediately before initiation of H-I. MAP and HR were recorded and arterial pH, blood gases, and glucose were determined at the end of the H-I as described above.

A control group (n = 6) had arterial pH, blood gases, and glucose measured 5 min after induction of anesthesia. The blood was aspirated anaerobically from the exposed right carotid artery. By the time the blood was drawn, animals had been separated from the dam for 90 min to match the duration of fasting in the other groups at the time of their blood draw.

All animals were euthanized with an intraperitoneal injection of ketamine, xylazine, and acepromazine after the last physiologic measurement.

Data are presented as mean ± sd. MAP and HR were compared within subjects and among groups using a general linear model of repeated measures and post hoc analysis for multiple comparisons. Blood gases, pH, and glucose data were compared with control or between ventilatory strategies using analysis of variance with post hoc analysis for multiple comparisons using Dunnett’s test or with Tukey’s test, respectively. Statistical calculations were performed using SPSS 11.0.2 for Macintosh OS X (SPSS Inc., Chicago, IL). Statistical significance was accepted at P < 0.05.

	Results

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All animals in the control group survived 5 min of isoflurane anesthesia, which was the time it took to expose the carotid artery to obtain the blood for analysis. All animals in the isoflurane-spontaneous ventilation and in the isoflurane-mechanical ventilation groups survived the 30-min preparation time plus 60 min of recording. All animals in the isoflurane-H-I-mechanical ventilation group survived the preparation time plus 60 min of recording during H-I. None of the isoflurane-H-I-spontaneous ventilation group survived. Animals in this group developed wide-complex cardiac arrhythmias and died from cardiovascular collapse within 10 to 15 min of initiation of H-I. In the unanesthetized H-I-spontaneous ventilation group, all animals survived the 30-min anesthesia induction and preparation time under isoflurane anesthesia and 86% of animals survived H-I. The 10-day-old mouse pups in the isoflurane-spontaneous ventilation group, isoflurane-mechanical ventilation group, H-I-spontaneous ventilation group, isoflurane-H-I-spontaneous ventilation group, isoflurane-H-I-mechanical ventilation group, control group, and MAC study group weighed 6.78 ± 0.36 g, 5.86 ± 0.57 g, 6.76 ± 0.74 g, 5.89 ± 0.53 g, 5.56 ± 0.17 g, and 5.31 ± 0.21 g, 5.19 ± 0.33 g, respectively.

The inspired MAC of isoflurane in 10-day-old mice was 2.26 ± 0.23%.

Table 1 displays the arterial pH, blood gases, and glucose in the anesthesia and H-I groups that survived the 60 min of experimental condition. Compared with the control group, blood glucose and base excess (BE) were significantly lower in all isoflurane-anesthetized groups. No physiologic differences were found between the isoflurane-spontaneous ventilation and isoflurane-mechanical ventilation groups. During H-I, pH, arterial Pco₂, Po₂, and BE were significantly lower in the isoflurane-H-I-mechanical ventilation and the unanesthetized H-I-spontaneous ventilation groups compared with the control group. Blood glucose was also significantly lower in the isoflurane-H-I-mechanical ventilation group compared with the control group. However, blood glucose was not statistically different in the unanesthetized H-I-spontaneous ventilation group compared with control. Animals in the isoflurane-H-I-mechanical ventilation group had lower pH and base deficits compared with the unanesthetized H-I-spontaneous ventilation group.

Figure 2 displays HR and MAP during isoflurane anesthesia in the isoflurane-spontaneous ventilation and the isoflurane-mechanical ventilation groups. MAP remained stable in both groups, whereas HR significantly increased over time in both groups (P < 0.0001).

View larger version (30K): [in this window] [in a new window]   Figure 2. Mean arterial blood pressure (MAP) and heart rate (HR) during 60 min of 1.8% isoflurane anesthesia in oxygen in spontaneously breathing 10-day-old mouse pups (n = 5, black boxes) and mechanically ventilated 10-day-old mouse pups (n = 4, gray circles). HR increased significantly with time in both groups (P < 0.0001). No difference was seen in HR or MAP between groups.

Figure 3 illustrates the MAP and HR during H-I in the isoflurane-H-I-mechanical ventilation and in the unanesthetized H-I-spontaneous ventilation groups. MAP during H-I significantly decreased with time in both groups (P < 0.0001). There were no differences in MAP or HR between the two groups.

View larger version (32K): [in this window] [in a new window]   Figure 3. Mean arterial blood pressure (MAP) and heart rate (HR) during 60 min of hypoxia-ischemia in spontaneously breathing, unanesthetized 10-day-old mouse pups (n = 6, black boxes) and in mechanically ventilated, isoflurane anesthetized 10-day-old mouse pups (n = 5, gray circles). MAP decreased significantly with time in both groups (P < 0.0001), without a difference between groups.

Figure 4 displays the influence of isoflurane concentration on MAP and HR in mechanically ventilated mice. MAP significantly decreased as isoflurane concentration increased (P < 0.001), whereas HR did not change significantly with isoflurane concentration.

View larger version (23K): [in this window] [in a new window]   Figure 4. Arterial blood pressure (MAP) and heart rate (HR) during 0.9% (n = 4), 1.8% (n = 8), and 3% (n = 4) of isoflurane in oxygen in mechanically ventilated 10-day-old mouse pups. MAP decreased significantly with increasing isoflurane concentration (P < 0.001).

	Discussion

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In neonatal rodents, isoflurane has been shown to confer neurological protection during brain H-I (1) and to precipitate neurodegeneration after prolonged exposure (2). Whether the neuroprotection or neurotoxicity result from a direct effect of the drug on the brain or an indirect effect through changes in cerebral oxygen and/or glucose delivery remains unknown. In the present study, we found that hypoglycemia and metabolic acidosis occurred with isoflurane anesthesia, that survival during H-I with isoflurane required mechanical ventilation, and that MAP decreased during H-I similarly in isoflurane-anesthetized and in unanesthetized animals.

Growth and development of the central nervous and cardiovascular systems occurs at different rates among different mammalian species in accordance with their lifespan and ontogeny. In humans, brain growth and structural maturation occurs most rapidly during the third trimester of gestation and the first year of life. Brain weight triples reflecting an increase in cellular and noncellular components, as well as an increase in myelination and synaptic arborization. In mice, by comparison, such brain growth and structural maturation occurs most rapidly during the first 2 weeks after birth. Mice and rats are very similar in this regard. The brain structural maturity of 4-day-old, 7-day-old, and 10-day-old mice or rats corresponds to that of 26-week, 36-week, and 40-week human gestation, respectively (9). Therefore, the 10-day-old mice used in the present study equate to human term neonates in relation to brain maturation state. The cardiovascular system develops at a different rate than the brain, albeit at a faster rate in small rodents compared with humans in keeping with their respective lifespans (10). Closure of the ductus arteriosus occurs within 2–5 hours after birth in mice, compared with 15 hours in humans. The heart grows as a result of increases in both cardiac myocyte number and cellular volume. Myocyte proliferation occurs most rapidly during the first 4 months of life in humans and during the first 3–6 days of life in mice and rats. Myocytes reach their adult volume at approximately 3 months of age in mice and 15 years of age in humans. In humans and rats, systolic arterial blood pressure increases rapidly after birth, reaching adult levels after 10 years of age and 10 weeks of age, respectively. HR initially increases after birth in humans, mice, and rats but reaches adult levels within weeks in small rodents, whereas adult levels are not reached until 12 years of age in humans. Thus, the cardiovascular system of the mouse at 10 days of age is closer to the adult state than the central nervous system.

The definition of hypoglycemia in human neonates varies somewhat among clinicians. Hypoglycemia has been defined as blood glucose less than 40 mg/dL, (11) 45 mg/dL, (12) and 60 mg/dL (13). Using these definitions, none of our control animals were hypoglycemic. However, hypoglycemia occurred, respectively, in 50%, 50%, and 67% of the isoflurane-spontaneous ventilation animals and 75%, 75%, and 75% of the isoflurane-mechanical ventilation animals. During H-I, using the same criteria, hypoglycemia occurred in 0%, 0%, and 25% of unanesthetized H-I-spontaneous ventilation animals, and 80%, 80%, and 100% of the isoflurane-H-I-mechanical ventilation animals, respectively.

Hypoglycemia during inhaled anesthesia in neonatal mice has not been reported previously. In several of our animals, the hypoglycemia was profound, as glucose decreased to less than 20 mg/dL, the lowest level measurable by the equipment. This decrease in blood glucose was caused by isoflurane, regardless of ventilatory strategy, but not by H-I or by fasting for comparable lengths of time. In our study, the duration of fasting was defined as the time of removal of the pups from the dam to the time of the blood analysis. Because pups suckle constantly while with the dam, fasting started on separation of the pup from the dam. In the experimental groups, anesthesia was induced for 5 minutes, followed by surgical instrumentation for 25 minutes and recording for another 60 minutes before blood sampling. The control group was removed from the dam, placed in a warm environment for 85 minutes, and then anesthetized for 5 minutes before blood sampling. Thus, the duration of fasting in all groups was 90 minutes. Because blood was obtained at the end of the experimental protocol and only one blood sample could be obtained (because the blood volume of a neonatal mouse is close to the sample requirement), it remains unknown how quickly hypoglycemia occurred after exposure to isoflurane. Furthermore, it is uncertain if hypoglycemia continues for a longer anesthesia exposure and whether blood glucose recovers after the discontinuation of isoflurane. Interestingly, our results in neonatal mice are in contrast to an increase in blood glucose observed in adult rats (14).

Glucose homeostasis is tightly regulated by the islets of Langerhans as well as the hypothalamus and brainstem and involves a complex interaction between adenosine triphosphate-sensitive potassium (K_ATP) channels, glucokinase, and glucose transporter proteins in these cells (15,16) A decrease in blood glucose levels activates K_ATP channels in glucose-responsive neurons and in pancreatic islet cells, which, in turn, increases blood glucose through several intermediary steps (17). Isoflurane has been shown to activate K_ATP channels in some studies (18). However, if isoflurane activates K_ATP channels, it would increase blood glucose rather than decrease it. Thus, the mechanism by which isoflurane leads to hypoglycemia remains unclear.

Jevtovic-Todorovic et al. (2) reported widespread neurodegeneration in numerous brain regions after a 6-hour isoflurane anesthetic in neonatal rats. They also documented neurobehavioral disabilities in juvenile rats that had been exposed to isoflurane as neonates. However, glucose was not measured in their study. Severe hypoglycemia has been shown to cause neuronal apoptosis and necrosis in many animal models (19,20). In human neonates, mild hypoglycemia has been related to diminished motor function and mental development later in life (21). In neonatal mice, hypoglycemia has been shown to cause widespread neuronal cell death in hippocampus, cerebellum, hypothalamus, and amygdala (22). It is, therefore, possible that the neurodegeneration and neurobehavioral abnormalities after a 6-hour isoflurane anesthetic could be related to isoflurane-induced hypoglycemia rather than a toxic effect of the drug on neurons, as the authors proposed.

Volatile anesthetics have been shown to confer neuroprotection in several neonatal animal models of H-I (23–25); however, they have not been evaluated for neuroprotection in the Rice-Vannucci model. In this model, hypocapnia accompanies the H-I, a compensatory response to hypoxia and metabolic acidosis. We also observed hypocapnia with H-I in our unanesthetized mice. In the isoflurane-H-I-mechanical ventilation group, we attempted to match the hypocapnia during H-I through controlled ventilation. Interestingly, isoflurane administration during H-I was fatal in spontaneously breathing animals. Isoflurane blunts the ventilatory response to hypoxia and hypercarbia. The lack of hyperventilatory compensation in the isoflurane-H-I-spontaneous ventilation group may have contributed to the fatalities with isoflurane during H-I.

MAC decreases with age in humans and rodents. Because there are no published data of the MAC of isoflurane in neonatal mice, we measured MAC in 10-day-old neonatal mice using the tail clamp technique. As expected, the MAC value of 2.26% in our study was significantly higher than the 1.3% or 1.4% reported in adult C57BL6/J or 129/SvJ mice, respectively (26). However, our results closely resemble the isoflurane MAC in Wistar rats, which was measured as 2.34% in 9-day-old animals (27). The isoflurane concentration of 1.8% used in the current study therefore equates to 0.8 MAC in 10-day-old mice.

Hemodynamic effects of anesthetics are important considerations in their applicability to surgery and neuroprotection in neonates. MAP has not been described in unanesthetized or in isoflurane-anesthetized neonatal mice. In the present study, MAP measured 50 mm Hg and HR approximated 600 bpm during 0.8 MAC of isoflurane. MAP did not change during a 1-hour anesthetic, but HR increased, irrespective of ventilatory modality. Ishii et al. (28) reported that in halothane-anesthetized, neonatal mice, MAP and HR measured 40 mm Hg and 400 bpm, respectively. The slower HR and decreased MAP in their study could be explained by the stronger negative chronotropic properties of halothane compared with isoflurane. The stable MAP and HR during isoflurane anesthesia in our study suggest that it would be a good anesthetic for surgical procedures in neonatal mice, if arterial pH and glucose are monitored and controlled. Further, its hemodynamic stability during H-I, relative to the unanesthetized state, suggests that isoflurane would be a good drug to explore for neuroprotection in this model using mechanical ventilation.

	Footnotes

 
Accepted for publication July 26, 2005.

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999