Naganobu, Kiyokazu BVSc; Hasebe, Yuzo DVM; Uchiyama, Yuka DVM; Hagio, Mitsuyoshi DVM; Ogawa, Hiroyuki DVM
Although epinephrine can be administered endobronchially or endotracheally during cardiopulmonary resuscitation (CPR) when venous access is delayed, its absorption after administration by these routes is sometimes insufficient (1–3). McCrirrick and Monk (3) showed that endotracheal doses of epinephrine of up to 10 μg/kg had no effect on arterial pressure or heart rate, whereas IV administration of 0.1 μg/kg epinephrine produced a mean increase in systolic pressure of 24 mm Hg in humans. Some technical factors, such as the type of diluent (4,5), volume of diluent (6,7), the site of administration (8,9), and use of positive pressure ventilation after drug administration (10) are considered to affect drug absorption.
Epinephrine is usually diluted with normal saline or distilled water for endobronchial or endotracheal administration because it is less effective when administered undiluted (4). However, it is still not clear which solution is most suitable as the diluent. When used for endotracheal administration, normal saline causes a smaller decrease in the arterial partial pressure of oxygen (Pao2) than distilled water (11). On the other hand, using a canine CPR model, Redding et al. (4) showed that, in comparison with saline, the resuscitation rate was higher when water was used as the diluent for the endotracheal administration of epinephrine. In many recent studies of both humans and animals, however, normal saline has been used as the diluent for the endotracheal administration of epinephrine (3,7,12,13).
Endobronchial drug administration is considered to be effective in animal CPR models (8,14,15). Mazkereth et al. (9) reported that absorption of epinephrine was greater when it was administered into the bronchus compared with administration into the trachea. However, there is little information about which diluent is most suitable for endobronchial epinephrine administration. In this study, we compared the effects of normal saline and distilled water as diluents of epinephrine for endobronchial administration in an anesthetized, non-CPR dog model.
This study was reviewed and approved by the Committee of the Ethics on Animal Experiment in Faculty of Agriculture, Miyazaki University, Japan, and carried out under the control of the Guidelines for Animal Experiment in Faculty of Agriculture, Miyazaki University, Japan, and the Law (No. 105) and Notification (No. 6) of the Government. A total of 14 healthy, adult mongrel dogs weighing between 7.4–18.3 kg were studied. The dogs were randomly assigned to two experimental groups. Six dogs received 2 mL of either normal saline or distilled water into the bronchus, and the other solution was administered by using the same procedure 1 wk later (Experiment 1). Eight dogs received epinephrine (0.02 mg/kg) diluted in either distilled water (E + water) or normal saline (E + saline) to a total volume of 2 mL into the bronchus, and the other solution was administered by using the same procedure 1 wk later (Experiment 2).
Each dog was anesthetized with 30 mg/kg IV pentobarbital sodium and placed in the supine position. After endotracheal intubation with a cuffed, low-pressure inflated endotracheal tube, controlled ventilation was started with air to maintain the end-tidal CO2 partial pressure around 35 mm Hg. Both femoral arteries were cannulated by using 20-gauge over-the-needle catheters under direct visualization for continuous arterial pressure measurement and blood sampling for epinephrine assay and blood gas analysis. The lead II electrocardiogram was monitored continuously and the dog’s rectal temperature was maintained at 37.0–38.5°C throughout the experiment. A second dose of pentobarbital sodium (10 mg/kg, IV) was injected and then, the animal’s condition was allowed to stabilize for 30 min.
Experiment 1: Endobronchial Administration of Normal Saline or Distilled Water
Either normal saline or distilled water was prepared and placed in an unmarked container. A 5F, 100-cm cardiovascular catheter and a syringe attached to the catheter were filled with the solution. The catheter was inserted into the distal bronchus through the endotracheal tube. Immediately after the bolus administration of 2 mL of the test solution, six forced manual ventilations with 20 cm H2O of airway pressure were provided. This was followed by controlled ventilation using the same conditions as before the administration. Arterial blood was collected for epinephrine assay and blood gas analysis (Gastat 3; Techno Medica, Tokyo, Japan) before and 0.5 (epinephrine assay only), 1, 2, 3, 5, 7, 10, 15, 30, and 60 min after the administration. Blood for the epinephrine assay was collected into prechilled test tubes containing EDTA-Na and centrifuged at 4,000 rpm for 10 min at 4°C. The plasma was stored at −80°C until assayed. The plasma epinephrine concentration was determined at a commercial laboratory (BML, Tokyo, Japan) by high-performance liquid chromatography (16). This method had a sensitivity limit of 0.01 ng/mL for epinephrine. After the measurement, the dogs received an analgesic dose of 0.2 mg/kg IM butorphanol.
Experiment 2: Endobronchial Administration of Epinephrine Diluted with Normal Saline or Distilled Water
Epinephrine (1:1000) was diluted with either normal saline (E + saline) or distilled water (E + water) and placed in an unmarked container. Two milliliters of the solution, containing 0.02 mg/kg epinephrine, was administered into the bronchus by the procedure used in Experiment 1. Monitoring and measurements were the same as for Experiment 1. After the measurement, the dogs received an analgesic dose of 0.2 mg/kg IM butorphanol.
Data are expressed as the mean ± sd. The plasma epinephrine concentrations, mean arterial pressure (MAP), and Pao2 were compared over time within each study group by analysis of variance for repeated measures with Scheffé’s multiple comparison test. The plasma epinephrine concentrations, MAP, Pao2, and pharmacokinetic data were compared between two study groups by one-way analysis of variance with Scheffé’s multiple comparison test. A P < 0.05 was considered significant.
Endobronchial administration of normal saline or distilled water without epinephrine did not significantly affect the plasma epinephrine concentration, the MAPs, and the Pao2 (Fig. 1). The plasma epinephrine concentration increased significantly above the baseline level after the administration of either E + water or E + saline, and was significantly larger after E + water administration than after E + saline administration (Fig. 2). The mean peak plasma epinephrine concentration was significantly larger after treatment with E + water (26.5 ± 7.9 ng/mL; range, 13.7–36.3) than after E + saline (2.1 ± 0.7 ng/mL; range, 0.9–3.0) (Table 1). The area under the curve (AUC) of the plasma epinephrine concentration from 0 to 60 min after epinephrine administration was used to estimate the extent of epinephrine absorption. AUC was significantly higher after E + water administration than after E + saline administration (Table 1).
There was no significant difference between the baseline MAP data recorded before the two treatments (Fig. 2). When epinephrine was diluted with distilled water, MAP was significantly higher than the baseline value. The maximal increase in MAP was 91 ± 24 mm Hg (range, 54–121 mm Hg), which was observed 2.0 ± 0.5 min after administration. This represents a 74 ± 25% (range, 39% to 104%) increase from the baseline value. By contrast, epinephrine diluted in normal saline did not significantly affect MAP. Compared with E + saline, E + water caused significantly higher MAPs.
There was no significant difference between the baseline Pao2 value recorded before the two treatments (Fig. 2). Pao2 was below the baseline value 60 min after endobronchial administration of E + saline. E + water did not significantly affect Pao2. However, the maximal decrease in Pao2 after E + water (14 ± 5 mm Hg; range, 7–24 mm Hg), which was observed 20 ± 27 min after the administration, was significantly greater than after E + saline (7 ± 2 mm Hg; range, 3–10 mm Hg), which was observed 46 ± 25 min after the administration. The maximal decrease in Pao2 after E + water and after E + saline was 13 ± 5% (range, 7% to 24%) and 6 ± 2% (range, 3% to 9%) below the baseline value, respectively.
The main findings of this study are: 1) increases in both the plasma concentration of epinephrine and MAP were greater when epinephrine (0.02 mg/kg) was administered with distilled water than with normal saline, each at a total volume of 2 mL, and 2) the endobronchial administration of 2 mL of distilled water or normal saline alone did not depress Pao2.
In previous studies of dogs (7,9), endotracheal or endobronchial administration of 0.02 mg/kg epinephrine diluted with normal saline increased the plasma epinephrine concentration but did not increase the arterial pressure. In the current study, 0.02 mg/kg endobronchial epinephrine diluted with normal saline increased the plasma epinephrine concentration but did not increase MAP (Fig. 2), which is consistent with previous studies. However, when we diluted the epinephrine with distilled water, there were significant increases in both the arterial pressure and the plasma epinephrine concentration. The peak plasma epinephrine concentration after epinephrine administration was approximately 13 times larger when the diluent was distilled water than when it was normal saline, and the AUC was approximately 3 times higher when the diluent was distilled water, than when it was normal saline. The time course of change in MAP after epinephrine administration with distilled water was similar to that of the plasma epinephrine concentration. Given that the administration of distilled water per se did not increase the plasma epinephrine concentration or MAP, it was considered that the increase in arterial pressure after epinephrine administration with distilled water was caused by absorbed epinephrine.
Water is absorbed more rapidly by the lung than is saline (17,18). Water is hypotonic, whereas normal saline is isotonic, which may be why water moves more quickly from the alveoli into the intravascular space (18). In humans, better absorption of endobronchially administered lidocaine has also been demonstrated when it is diluted with distilled water, rather than with normal saline (5). Therefore, we considered that absorption of epinephrine into the systemic circulation would be greater for water-diluted than for saline-diluted epinephrine, and that water-diluted epinephrine would markedly increase the plasma epinephrine concentration and arterial pressure.
A greater decrease in Pao2 follows the endotracheal administration of distilled water compared with normal saline, which is a disadvantage of using distilled water as the diluent (11,19). Greenberg et al. (11) showed that when 2 mL/kg of normal saline or distilled water is administered endotracheally to dogs, Pao2 decreases to 61% of the baseline value after distilled water administration, whereas Pao2 decreases to 74.73% of the baseline value after normal saline administration. In many recent studies of both humans and animals, normal saline was used as the diluent for the endotracheal administration of epinephrine (3,7,12,13).
Surprisingly Pao2 did not decrease after the endobronchial administration of 2 mL of either normal saline or distilled water (without epinephrine). This was in contrast to the study by Greenberg et al. (11). However, it has been reported that, in humans, a larger volume of distilled water used as the diluent for endobronchial lidocaine administration decreases Pao2 to a significantly greater extent than a smaller volume (6). Thus, we considered that using a small volume of distilled water as the diluent can minimize the decrease in Pao2 after endobronchial drug administration. The maximal decrease in Pao2 observed after E + water was, however, greater than after E + saline. Because the absorption of epinephrine was greater after E + water, the decrease in Pao2 may be related to the effects of the absorbed epinephrine. Thrush et al. (20) reported that epinephrine increases the intrapulmonary shunt and reduces arterial oxygen saturation during experimental ventricular fibrillation and CPR. This mechanism may be related to the decrease in Pao2 observed in our study after the endobronchial administration of epinephrine.
The maximal decrease in Pao2 in our dogs, 14 mm Hg, occurred when epinephrine was administered with distilled water. For adult human patients, dilution to 10 mL is recommended for endotracheal drug administration (19). When lidocaine was diluted with normal saline or distilled water to 10 mL and administered endobronchially to anesthetized adult humans, Pao2 decreased to approximately 40–60 mm Hg; from 157 to 115 mm Hg for distilled water and from 157 to 95 mm Hg for normal saline (5). In another study of anesthetized adult humans, endotracheal and endobronchial administration of lidocaine diluted with normal saline to 10 mL decreased Pao2 to 75% of the baseline value (21). It is difficult to compare the results from humans with those from animals. However, Pao2 is usually increased during CPR by oxygen administration. In one human study, Pao2 during CPR was 303 ± 141 mm Hg and 219 ± 169 mm Hg in patients with and without return of spontaneous circulation, respectively (22). Thus, the decrease in Pao2 to 14 mm Hg below the baseline value (a 13% decrease) seen in our dogs appears to be a minor decrease, especially if ventilation is performed with pure oxygen. If we take the advantages of distilled water dilution into consideration, such as a larger plasma epinephrine concentration and higher arterial pressure, using a small volume of distilled water as the diluent appears to be more beneficial for endobronchial epinephrine administration than using normal saline.
However, some limitations in our study must be considered. We used an anesthetized, non-CPR animal model. During closed-chest CPR, cardiac output decreases and circulation time is slowed compared with normal circulation states (23). In an animal study, it has been shown that mean pulmonary arterial flow during closed-chest CPR decreases to 11% to 13% of the precardiac arrest level (24). Thus, absorption of epinephrine from the lung would be reduced during CPR compared with an anesthetized, non-CPR state. A larger dosage of epinephrine may be needed during CPR to ensure the pharmacological effects of endobronchial epinephrine. In addition, the ratios of the administration volume (2 mL) to body weight in our 7.4–18.3 kg dogs were 0.27–0.11 mL/kg. Although these values are comparable to those in humans weighing 37–91 kg receiving 10 mL, the influence of 2 mL of distilled water on Pao2 in dogs may be different from that of 10 mL in humans. Thus, the volume of distilled water that could be used without serious adverse effects on Pao2 in humans needs to be determined.
In conclusion, using distilled water as the diluent for endobronchial epinephrine administration to a total volume of 2 mL significantly increased both epinephrine absorption and the arterial pressure, without seriously reducing Pao2, compared with using normal saline as a diluent in an anesthetized, non-CPR dog model. Therefore, we recommend using distilled water as the diluent for endobronchial epinephrine administration. Further studies are needed to optimize the dose of epinephrine and the volume of distilled water for endobronchial administration during CPR. In addition, because it is uncertain whether our data from dogs are applicable to humans, the effects of the endobronchial administration of epinephrine diluted with distilled water should be determined for humans.
We gratefully acknowledge Drs. Mayumi Takasaki of the Miyazaki Medical College, Ryohei Nishimura of the University of Tokyo, and Masahiko Hirata of the Miyazaki University for their advice.
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