The administration of IV halothane causes pulmonary dysfunction, acute respiratory distress syndrome, and death in both humans and animals. There are a number of case reports of self-administered or accidental administration of IV halothane that resulted in the production of an acute respiratory distress-like syndrome and often death [1-4]. In dogs, IV halothane administration (0.05-0.30 mL/kg) causes diffuse pulmonary edema and multiple hemorrhagic foci within 30 min . Despite these reports, volatile anesthetics may be administered via other routes when given in the appropriate delivery vehicle. Haynes and Kirkpatrick  injected a lecithin-coated methoxyflurane preparation into the tails of rats without the toxicity observed with the injection of liquid methoxyflurane. We report the pulmonary, anesthetic, and hemodynamic effects associated with the IV administration of 25-35 mL of halothane mixed with a lipid carrier.
After institutional approval, six adolescent Yorkshire swine (approximately 3-4 mo of age) were used to compare an IV halothane-lipid emulsion (HLE) with halothane administered by inhalation. The animals were fasted overnight, sedated with an IM injection of ketamine (500 mg), and anesthetized with halothane via a nose cone. After obtaining intravascular access, anesthesia was maintained with IV propofol. The animals were tracheally intubated, and ventilation was controlled to maintain the ETCO2 at 35-40 mm Hg. The total fresh gas flows (oxygen/air mixture) were maintained at 5 L/min with the inspired oxygen and nitrogen concentrations maintained at 25% and 75%. Inspired and expired oxygen, carbon dioxide, and halothane concentrations were continuously monitored by sampling respiratory gases from the elbow of a standard disposable circle system. Neuromuscular blocking drugs were not administered. An 8.5F sheath was inserted into the right external jugular vein to maintain volume infusion (lactated Ringer's solution, 4 mL [center dot] kg-1 [center dot] h (-1)) and placement of a continuous cardiac output pulmonary artery catheter to measure pulmonary artery pressure and to obtain cardiac output measurements. One femoral artery was isolated and cannulated with a 12F sheath for insertion of two 6F catheters. One catheter was positioned in the mid-aortic region to measure arterial pressure. The second was advanced into the left ventricle to measure left ventricular end-diastolic pressure (LVEDP) and automated calculation of dP/dt. A femoral vein was cannulated with an 8.5F introducer sheath for infusion of HLE. The electrocardiogram (leads II and V5) and invasive pressure waveforms were displayed on an 8-channel Hewlett-Packard Model 68 clinical monitor (Hewlett-Packard, Andover, MD) or a 12-channel Crystal Biotech CBI 8000 system (Crystal Biotech, Hopkinton, MA). Core body temperature was monitored via the pulmonary artery catheter and was maintained at 38.0 +/- 0.5[degree sign]C with heating lamps and a forced-air warming device.
Using aseptic technique, 25 mL of 20% intralipid (Liposyn III 20%; Abbott Laboratories, Chicago, IL) was removed from a 500-mL glass bottle and replaced with an equal volume of halothane (Abbott Laboratories). The bottle was placed on a slow speed orbital shaker for 12 h to ensure complete mixing. The mixture was visually inspected before administration to verify complete mixing.
The effects of halothane administered by inhalation of halothane vapor and by IV infusion as HLE were compared in all animals. The initial route of administration of halothane was determined by block randomization for the evaluation of: a) the acute pulmonary effects of 13.75 mL of halothane; b) the minimum alveolar anesthetic concentration (MAC) of halothane to ablate withdrawal to painful stimuli; c) the hemodynamic effects measured at 0.6%, 1.2%, and 1.8% end-tidal halothane (ET HAL). When these protocols were completed, the halothane was discontinued for 2 h, and anesthesia was maintained with IV propofol (100 [micro sign]g [center dot] kg-1 [center dot] min-1). The effects of the alternative halothane delivery method were then evaluated. In addition, oxygenation, ventilation, and total respiratory system compliance (tidal volume/[peak airway pressure-peak end-expiratory pressure]) were evaluated during both methods of halothane delivery and just before the pigs were killed. At the end of the experiment, pulmonary tissue was obtained for histopathologic analysis.
Protocol A: Determination of Acute Pulmonary Toxicity
The effects of HLE on pulmonary compliance, oxygenation, and ventilation were accomplished by administering 275 mL over 30 min (equivalent to 13.75 mL of liquid halothane). This was compared with administration of a similar volume of liquid halothane administered via a vaporizer. Halothane was administered at 2% via a calibrated vaporizer (Vapor 19.1; North American Drager, Telford, PA) and semiclosed circle system for 30 min using 5-L/min fresh gas flows. The volume of halothane gas delivered during the 30 min was calculated as 3000 mL. Using ambient temperature and barometric pressure, the volume of liquid halothane vaporized was calculated by the ideal gas Equation tobe approximately 13.75 mL. (Equation 1), (Equation 2) and (Equation 3) where M = mass, P = pressure, R = gas constant, T = temperature, and MW = molecular weight.
During this protocol, the minute ventilation was not altered, and cardiac output was maintained within 1.0 L/min of baseline by the infusion of dopamine or epinephrine.
Protocol B: Determination of MAC
At the end of Protocol A, halothane and inotropic infusions were discontinued, and withdrawal to painful stimuli was tested as previously described . In brief, a large hemostat was applied at frequent intervals to the coronary ligament between the second and third toe of the left lower extremity for 30 s. When withdrawal occurred, additional halothane was administered to increase the ET HAL concentration by 10%. After the ET HAL concentration was increased by 10% for 15 min, the 30-s coronary ligament clamping was repeated. Incremental increases in the ET HAL were continued until no withdrawal movement occurred.
Protocol C: Hemodynamic Responses and Halothane Blood Levels
After determination of individual MAC, the anesthetic was adjusted to evaluate the hemodynamic responses to 0.6%, 1.2%, and 1.8% ET HAL (0.5, 1.0, and 1.5 times the published inhalation MAC in swine). The desired end-tidal concentration was maintained for 15 min, hemodynamic variables were measured, and arterial blood samples were obtained for determination of blood halothane concentrations. Dopamine or epinephrine was not administered as a part of Protocol C.
Halothane blood concentrations were determined as previously described by Van Dyke and Wood . Using heptane extraction and a63 Ni electron-capture detector, gas chromatography was performed. Temperatures were 200[degree sign]C at the injector, 140[degree sign]C in the column, and 300[degree sign]C at the detector. Nitrogen was used as the carrier gas.
Over the time course of the experiments, serial blood gases were analyzed for arterial pH, carbon dioxide, and oxygen tensions. The total respiratory system compliance was calculated during the course of the experiment. The inspiratory to expiratory ratio (1:2.0) and inspiratory flow were the same for all animals. Immediately before death, a left subcostal incision was made, and the pleural cavity was entered through the diaphragm to examine the lungs. A biopsy of the left lower lobe was performed, and the tissue was placed into 10% buffered formalin. The animals were then killed with a saturated KCL solution. The time from administration of HLE to death ranged from approximately 4 to 8 h. The tissue was fixed in paraffin and stained with hematoxylin and eosin stain. Tissue samples were evaluated by a pathologist blinded to the treatment of the animals. These samples were compared with two additional lung samples obtained from swine not subjected to IV halothane or lipid administration.
All data are presented as means +/- SD in text and Tables. The means +/- SE are presented in the Figure. Group comparisons were performed by using two-way repeated measures analysis of variance. The two-way repeated-measures analysis of variance was combined with post hoc Tukey's honestly significant difference multiple range test to correct for multiple comparisons. Analysis of categorical variables was performed using chi squared analysis. Values were considered statistically different when P < 0.05 after correction for multiple comparisons.
The calculated total respiratory system compliance was not altered by either method of halothane administration (Table 1). Arterial oxygen and carbon dioxide tensions did not vary significantly during the study. Histopathologic examination of the lung tissue did not show edema or neutrophil infiltration. The control tissue samples were indistinguishable from the treatment tissue samples. The ET HAL concentration for ablation of withdrawal to the toe clamp during HLE administration was significantly different from the ET HAL for halothane administered via a vaporizer (0.78% +/- 0.08% vs 1.13% +/- 0.12%; P < 0.001).
There were no statistical differences in heart rate, cardiac index, stroke volume, central venous pressure, or LVEDP between the two methods of halothane delivery (Table 2). HLE caused a larger decrease in the mean arterial pressure at both 1.2% and 1.8% ET HAL (P < 0.05) and dP/dt at 1.8% ET HAL (P < 0.05).
During HLE administration, the blood halothane concentration was significantly (P < 0.05) higher than that for vaporized halothane at ET HAL concentration of 1.2% (0.82 vs 0.49 mg/mL) and 1.8% (1.29 vs 0.79 mg/mL) (Figure 1). The blood levels at ET HAL 0.6% were not statistically different. At the matched blood levels, the heart rates were similar, the LVEDP was lower, and the dp/dt and mean arterial pressure were higher when HLE was compared with halothane administered via a vaporizer (P < 0.05 Table 3).
Formulation of drugs in a lipid emulsion or solvent is frequently done to decrease the local irritation associated with the delivery of drugs with limited aqueous solubility. However, emulsion formulations also influence the clinical characteristics by significantly altering pharmacodynamics and pharmacokinetics. For example, propofol, a highly lipid-soluble drug, is distributed in a 10% fat emulsion. Increasing the fat emulsion concentration decreases the free aqueous propofol concentration and significantly decreases the pain associated with injection [9,10]. In addition, the lipid emulsification of propofol decreases the volume of the central compartment 10-fold, decreases the total volume of distribution 3-fold, and improves safety compared with a lipid-free preparation [11,12]. This study is the first report of successful IV administration of liquid halothane using a lipid emulsion as a carrier agent. The data obtained in this study show that the IV delivery of halothane in a lipid emulsion limited the catastrophic pulmonary effects and death usually attributed to IV halothane [1-5,13]. The MAC for HLE was lower than that for inhaled halothane. The HLE had a more favorable hemodynamic profile compared with inhaled halothane at matched blood halothane concentrations.
In previously published case reports, <or=to9 mL of IV liquid halothane resulted in immediate tachycardia, apnea, and loss of consciousness. In addition, these patients experienced hypotension, right bundle branch block, pulmonary edema, cyanosis, hypoxia, and acidosis within 30 min of administration [1-4]. Animal studies performed by Kawamoto et al.  and Sandison et al.  showed similar physiologic effects of small volumes of IV halothane. In addition, Sandison et al.  reported the histopathologic evidence of peripleural and alveolar hemorrhage, edema, and leukocyte infiltration as early as 30 min after the injection of liquid halothane. We did not observe any of the reported deleterious physiologic or histopathologic effects after the administration of HLE. There were no changes in pulmonary compliance or arterial blood gases. Analysis of the pulmonary tissue 4-8 h after exposure to HLE did not show any evidence of hemorrhage, edema, or leukocyte infiltration. One explanation for the lack of HLE toxicity could be that the solubility of halothane in the lipid emulsion prevents a high free concentration of the drug with direct exposure of the pulmonary system.
We found the MAC for inhaled halothane to be 1.13% to a toe clamp in our 3- to 4-m-old pigs. This is similar to the findings of Weiskopf and Bogetz , who reported a MAC for halothane in 10-wk-old swine to be 1.25% to tail clamping. However, the MAC for HLE (0.78%) was lower than the MAC by inhalation. The pharmacokinetics of HLE are not known, and the blood halothane concentrations at MAC were not determined. It is possible that these differences merely reflect differences in alveolar and arterial concentration gradients inherent to the delivery methods, not a pharmacodynamic difference secondary to lipid emulsification. The similar blood halothane concentrations at 1.5 MAC equivalents defined by Protocol B (HLE 1.2%, inhaled halothane 1.8%) indicate that blood levels at equi-MAC concentrations may not be different. Although definitive evaluation of this MAC difference is needed, it does have clinical significance in assessing anesthetic depth.
The hemodynamic effects with both methods of administration were generally consistent for the cardiovascular profile associated with halothane. There was a dose-dependent decrease in the mean arterial pressure associated with decreases in the cardiac index and increases in LVEDP and central venous pressure. The heart rate decreased for both methods of administration at larger doses. This has been reported both by Lerman et al.  in newborn swine and McKinney et al.  in humans. However, there were some differences for mean arterial pressure and dP/dt between inhaled halothane and HLE at equivalent ET HAL concentrations. The animals had lower mean arterial pressures with HLE at end-tidal concentrations of 1.2% and 1.8%. The dP/dt was also lower with the HLE at 1.8% ET HAL concentration. However, there was no significant difference in the cardiac index. This could be explained both by the small population in our study and because the dP/dt is a more sensitive indicator of cardiac contractility than cardiac index. When the hemodynamic effects were compared at equivalent MAC and blood levels, HLE had a higher mean arterial pressure and dP/dt and a lower LVEDP than the inhaled halothane. These differences imply less cardiovascular depression. Because these observations occurred at equivalent blood concentrations, this pharmacodynamic difference requires further evaluation.
In summary, we successfully delivered a high volume of HLE without pulmonary damage and less cardiovascular depression than inhaled halothane. This work represents an initial description of an alternative form of total IV anesthesia. Future utility of this method of anesthesia could be realized from the use of small amounts of HLE in conjunction with a low-volume circle system, a carbon dioxide absorber, and an oxygen generator to simplify the logistics of anesthesia in austere locations. However, further work is necessary to evaluate the optimal carrier solution, shelf life, and the long-term safety associated with the use of HLE.
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