Endotracheal drug therapy

RESEARCH SEMINARS

Endotracheal

J. Thomas Ward Jr,

Drug Therapy

MD

Introduction

Endotracheal drug administration has been present in the physician’s therapeutic armamentarium for over forty years. However, only recently has it become well appreciated that the endotracheal route of drug delivery may serve as a rapid and effective alternative means of drug administration in the absence of intravenous access.

Settings which mandate immediate therapeutic intervention in the form of drug therapy most frequently occur in emergency departments and critical care areas. When an intravenous route is not readily available, it becomes imperative that the specialists in these fields have knowledge of endotracheal drug administration.

History

The history of endotracheal drug administration is both interesting and informative. A number of important concepts were actually reported early in its devel- opment as a method of drug delivery, but the potential applications of these concepts have yet to be fully investigated. The renaissance of interest in this field compels us to review the history of this form of drug therapy and to note some of the important findings of the early, as well as recent, investigators.

From Piano General Hospital, Piano, Texas.

Address reprint requests to J. Thomas Ward Jr, MD, Emergency Dept, Plano General Hospital, 3901 West 15th Street, Piano, TX 750757799. Manuscript accepted January 3, 1983. Key Words: Atropine; dianepam; diluents; drug therapy, endotracheal; epinephrine; endotracheal drug therapy; lidocaine; naloxone; pharmacokinetics.

The concept of endotracheal drug therapy is hardly novel. Studies concerning this method of drug delivery date back to the mid-1800s. As early as 1857, Bernard demonstrated the absorptive capacity of the lungs when he instilled a solution of curare into the upper respiratory tracts of dogs by way of tracheostomy.’ After the dogs were tilted to an upright position, they died within seven to eight minutes, and Bernard concluded that the alveoli were far more permeable to curare than were the bronchi and bronchioles. In 1884 Peiper demonstrated that salicylates, in addition to curare, appeared in the urine after endotracheal administration.’ Later, in 1897, Washitzky made the observation that atropine, potassium iodide, strychnine, and chloral hydrate quickly appeared in the urine after injection of their aqueous solutions into the trachea.2 It was not until 1915, however, that Kline and Winternitz first suggested that direct medication of the lung might be an efficient therapeutic route. Their suggestion was based upon work they had performed in rabbits with pneumonia, which demonstrated that dye injected intrabronchially resulted in a dense impregna- tion of the exudate in the lung and contrasted sharply with the impaired circulation to the lung found in these later stages of pneumonia.3

Further research concerning endotracheal drug therapy came with the outbreak of World War I. The use of toxic gases by the military during this war stimu- lated research into the effects of noxious gases upon the respiratory tract as well as the potential modes of therapy for the treatment of such injuries. A book was published in 1920 concerning the pathology of war gas poisoning, a chapter of which was written by Major M.C. Winternitz. and dealt with “preliminary studies in intratracheal therapy.“4 Winternitz demonstrated that in dogs endotracheally administered solutions of phenolsulphonephthalein resulted in absorption and excretion of the drug more rapidly than when it was administered intramuscularly. He also showed that large amounts of saline were absorbed from the lungs after endotracheal administration in dogs. Based upon these studies, Winternitz again suggested the possibility of endotracheal therapy, as well as the concept of pulmonary irrigation.

Further groundwork drug therapy came with

for the use of endotracheal acceptance by physicians of a

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AMENCAN \OURNAL OF EMERGENCY MEDZCZNE . VOL 1 . IULY 1983

concept of “direct medication of the lungs.” In 1935,

Graeser and Rowe published a very important paper

titled “The Inhalation of Epinephrine for the Relief of Asthmatic Symptoms.“5 The use of epinephrine mist

for the treatment of asthma soon became the first widely accepted method of therapy that involved the “direct application of medication to the pulmonary epithelium.” The acceptance of this philosophy of drug therapy later contributed to the use of the endotracheal route as a means of drug delivery.

In the late 1930s and early 1940s the first anti- microbial agents for use in humans, sulfa drugs and

penicillin, were developed. These drugs were initially administered by the oral, intramuscular, and intra-

venous routes and brought dramatic clinical results in patients with bacterial infections by susceptible organ- isms.6c7 Experimental and clinical articles soon

appeared in great profusion in the literature. Observa- tions were soon made, however, that chronic suppurative disorders of the lung failed to respond to the rou- tine administration of these antibacterial agents, and the philosophy of “direct medication of the lung” then resulted in a number of studies involving the use of aerosolized solutions of both sulfa drugs and penicillin

for pulmonary infections.8-20 Early in the antibiotic

era, however, penicillin was in limited supply and Bea-

key, Gaensler, and Segal demonstrated that large amounts of antibiotics were lost to the environment

and apparatus when the method of aerosolization was used.” Also, some researchers believed that aerosolized drugs would not reach collapsed segments of the lung because of poor ventilation to those areas21 For these and other reasons, some researchers evaluated the use of endotracheally administered sulfa drugs and penicillin,20-23 and the era of endotracheal drug therapy began. In 1943, Norris reported the use of endo-

tracheally administered sulfathiazole suspension22 and in 1945 May and Floyer reported the use of endotra-

cheally delivered penicillin.21 The use of aerosolized and endotracheally delivered

antibiotics continued for several years, but it was not until the latter half of the 1940s that researchers began

to investigate the absorptive capacity of the lungs. In 1946, Courtice and Phipps reported that both water and saline were rapidly absorbed when delivered into the lungs, but the water was absorbed much more rapidly than the saline.25 This later became an important concept when considering the use of diluents for endotracheal drug administration. In 1948 a number of important observations were made by Gaensler, Bea- key, and Segal. These investigators published a series

of excellent articles that dealt specifically with the pharmacodynamics of pulmonary absorption in

man.18-20 Their first paper compared the phar-

macokinetics of the intramuscular, endotracheal, and aerosolized administration of penicillin in normal male volunteers. l8 They found that endotracheally administered penicillin was rapidly absorbed into the bloodstream and resulted in therapeutic blood levels of

the drug at the time of the first blood sampling at one half hour. Of notable importance was their observa-

tion that therapeutic blood levels of penicillin after endotracheal administration were maintained for twice

as long when compared to the intramuscular injection of the drug. This was the first report that demonstrated that the lung may act as a “depot” from which

drugs may be slowly released after endotracheal adminstration. (Chapple and Lynch had reported a similar finding earlier with the use of aerosolized sulfonamide.)

The second paper by this trio of investigators again compared the three different modes of penicillin administration, but this time studied the effects of

“pharmacologically active diluents” which were used with the penicillin. I9 Diluents investigated were saline, neosynephrine, epinephrine, tri-ethylene glycol, chlorophyll, pantopaque, and human serum. Some very interesting results were noted. When 100,000 units of penicillin were diluted with 10 cc of 1:lOOO

neosynephrine and delivered endotracheally, the initial peak serum level of penicillin was threefold higher than that after the endotracheal administration of the penicillin in saline. In addition, when epinephrine l:lO,OOO was used as a diluent, higher initial blood

levels of penicillin were again obtained when compared to those obtained with saline as a diluent. This paper made the important observation that the rate

and degree of absorption of an endotracheally delivered

drug may be altered by the use of various diluents. This important concept still awaits further investigation into its potential applications today.

The final paper by Gaensler, Beakey, and Segal compared the three previously mentioned modes of penicillin administration in patients with chronic lung diseases2’ They found that although endotracheally administered penicillin was effective in the therapy of suppurative lung disease, it was not the preferred method of drug delivery because it was necessary to abolish the cough reflex with local anesthetics in order to deliver the drug. In patients with pulmonary infections, this was an unwanted and potentially detrimental procedure to perform. Thus, endotracheally

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RESEARCH SEMINARS l WARD l ENDOTRACHEAL DRUG THERAPY

administered penicillin soon fell into disuse by physicians, and an important period in the history of intra-

pulmonary drug delivery came to a close. With the era of endotracheal antibiotics now passed,

further research concerning endotracheal drug administration came from investigators attempting to eluci-

date the mechanism responsible for “anesthetic reactions.“26-30 These reactions were noted to occur in

patients undergoing topical anesthesia of the pharynx, larynx, and lower respiratory tract, and on occasion

resulted in the death of the patient. In 1952,

Steinhaus, one of the early investigators, studied the intrapulmonic instillation of tetracaine solution in rab-

bits.28 He reported that the “absorption of the local anesthetic agent, tetracaine, from the lungs is very

rapid and approximates intravenous injection.”

Further research concerning the intrapulmonary absorption of local anesthetics was conducted by Adri-

ani and Campbell in 1956 and 1958.29J30 The phar-

macological data they obtained indicated that “most toxic reactions from local anesthetics are associated

with high plasma levels from rapid absorption.“30 They had found that after endotracheal administration of tetracaine, peak serum drug levels occurred within four to six minutes, and these levels were at least one third of the peak serum level attained after intravenous adminstration of the drug.30 Thus, these

investigators of the “anesthetic reaction” demonstrated that the endotracheal adminstration of certain drugs resulted in rapid absorption into the bloodstream, at times approximating an intravenous injection of the

drug. These researchers also demonstrated the rate of absorption of drugs from the mucous membranes varied with the location of their application: absorp-

tion from the trachea was much more rapid than from the pharynx.3o

It was not until 1967, however, that this very important knowledge concerning endotracheal drug delivery was actually employed. Redding, Asuncion, and Pearson investigated the possibility of using the endotracheal route of drug delivery as a means of rapid systemic administration of a drug.31 They compared

the effectiveness of epinephrine adminstered by various routes in the resuscitation of dogs that had under- gone both a respiratory and circulatory arrest secon-

dary to hypoxia. Redding and his coworkers discerned that the intravenous, intracardiac, and intratracheal routes of drug administration were equally effective in restoring the circulation of dogs in cardiac arrest. These investigators also noted the advantage of epinephrine in water dilution (rather than in saline)

because of the shorter mean time from drug administration to return of circulation. Redding thus con-

cluded that “intratracheal (diluted), intravenous, and intracardiac routes are equally effective, and that whichever of these routes is most immediately avail-

able should be used.” This paper marked a change in the philosophy of endotracheal drug administration: no

longer would the endotracheal route be simply a means of topical drug therapy-it had now been shown to be

an effective window to the systemic circulation for the

rapid delivery of drugs. Surprisingly, a decade passed before further research

was published concerning the use of the endotracheal route of drug delivery as an alternate method of systemic drug administration. Roberts, Greenberg et al, revived the study of endotracheal drugs with a series

of papers dealing with both the experimental and clin-

ical adminstration of epinephrine endotracheally.32-36

Following this renewed interest in endotracheal drug

administration, a number of other papers were published concerning other drugs that proved to be effec-

tive when delivered by the endotracheal route. These reports included studies on the endotracheal administration of naloxone, diazepam, atropine, and lidocaine (Table 11.

Table 1. Partial list of drugs that have ken studied either clini-

cally or experimentally as to their effectiveness when given by

the endotracheal route.

Endotracheally Administered Drugs

Penicillin Lidocaine

Sulfonamides Epinephrine

Streptomycin Atropine

Naloxone Tetracaine

Pontocaine Diazepam

Endotracheal Drugs

At present, endotracheal drug therapy is used only in those settings in which immediate drug intervention is necessary but no intravenous access is readily avail-

able. Settings such as this are limited, and the number

of drugs useful in such settings are even more limited. However, it has been demonstrated that the endotra-

cheal route of drug delivery may prove to be life- saving,35-37 and thus knowledge of those drugs shown

to be effective by the endotracheal route becomes of paramount importance. To date, five drugs have been investigated as to their potential use as endotracheally administered drugs in emergent situations requiring immediate drug intervention. These drugs include

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lidocaine, epinephrine, atropine, naloxone, and

diazepam.

Lidocaine The pharmacokinetics of endotracheally admin-

istered lidocaine has been investigated by a number of researchers over the last 20 years. However, most of

these studies were performed in patients who received topical anesthesia prior to elective intubation before surgery. Thus, the results of these studies demonstrate well the kinetics of the drug after endotracheal admin-

istration in fairly normal subjects, but not in patients undergoing cardiopulmonary resuscitation, the setting

in which the drug is most likely to be given for sys-

temic effects when no intravenous access is available.

The amount by which the kinetics of the drug are altered (if at all) when the drug is delivered endotra-

cheally in a shock/CPR model is not known. This should be kept in mind when reviewing the existing data concerning endotracheal lidocaine (Table 2).

Since the initial study by Bromage and Robson in

1961,38 approximately 12 studies have appeared in the literature concerning the absorption of lidocaine after

endotracheal administration. 39-49 Among these studies,

however, there exists a rather large variation in the methods of investigation. Some authors have chosen to

investigate the use of lidocaine aerosol sprays,39142-44 others 2% to 10% solutions. 40,41,45-49 Some authors delivered the predetermined dose rapidly (less than one minute)40,43!45-49 while others chose to deliver it in a

stepwise manner over a period of 2 to 13 minutes.“’ 42,44 Lastly, studies have been performed in animal models,46 as well as human subjects.38‘4”~47~49 The data from the results of each of these studies must be interpreted in the light of their methods of investiga-

tion. It has been demonstrated that the manner by which

a drug is delivered intrapulmonically affects its rate and degree of absorption (see below). Thus, it would seem reasonable to scrutinize those studies in the

literature that utilized a manner of drug delivery similar to that used in the emergency administration of endotracheal drugs. In most emergent settings when a

drug is delivered endotracheally it is given in the form of a solution, rapidly injected into or through the endotracheal tube and followed by several insufflations with a mechanical ventilation device. 35-37 Of the literature

referred to above, only three articles have employed lidocaine solutions in the strengths of 4% to 10% and a method of rapid drug delivery on human subjects.47- 49 These studies include the paper by Telivuo in

74

1965,47 an article by Chu, et al in 1975,48 and a

recent publication by Boster, et al in 1982.49 The dis- cussion that follows is a reflection of the data from

these studies more so than the other cited references for the reasons previously mentioned.

Drug Dosage and Peak Serum Levels. Telivuo4’ used a standard dose of 200 mg of a 4% solution for all patients he studied, which translated to a dose of 2.4 to

3.2 mg/kg, depending on the patient’s weight. He found the mean peak serum level (+ SD) to be

6.6 (k6.0) pg/ml. Chu, et al also employed a standard dose of 200 mg of 4% lidocaine, which resulted

in doses of 2.4 to 3.8 mg/kg in their patients, with a mean dose of 3.3 mg/kg. The mean peak serum level

(* SD) attained in the patients in their series was

3.54(* 0.76) pg/ml. Finally, Boster, et al used a mean dose of 5.67 (+ 1.2) mg/kg of a 10% lidocaine hydro-

chloride solution and found that the mean peak serum level of patients studied was 3.16 (a 1.52) &ml. Thus, in these three studies dosages for the endotracheal administration of lidocaine ranged from 2.4 mg/kg to 7.74 mg/kg and resulted in peak serum lido- Caine levels that ranged from means of 6.6 (* 6.0) to

3.16 (+ 1.52) pg/ml. Serum levels were not propor- tional to dose and the results of these studies reflected

a large amount of individual variation. Despite the toxic mean peak level reported by Telivuo, no serious

side effects were noted in his patients. Thus, no patient suffered any adverse effects from doses of endotracheally administered lidocaine in the range of

2.4 mg/kg to 7.74 mg/kg. Onset of Therapeutic Serum Levels. Despite the

various dosages administered in the three studies, it

appears that most patients had reached a therapeutic serum lidocaine level (1.4 to 6.0 ~g/ml15’ by five minutes In Telivuo’s group the mean serum lidocaine

level was 3.5 (+ 3.2) pg/ml at five minutes, in Chu’s group 1.78 (* 0.35) pg/ml at five minutes, and in Boster’s group serum therapeutic levels of lidocaine were reached in a mean time of 5.1 (+ 3.2) minutes.

It is of interest to note that in another group studied

by Telivuo, serum lidocaine levels were higher, earlier when epinephrine in the proportion of l:lOO,OOO was added to the 4% lidocaine adminstered endotracheally.

Time to Peak Serum Levels. With respect to time to peak serum levels of lidocaine after endotracheal administration there appears to be fairly good agree- ment. Telivuo reported peak levels at 20 minutes; Chu reported the same; and Boster reported that the time to maximum serum lidocaine level was 18.71(+ 8.7 1) minutes.

RESEARCH SEMINARS . WARD . ENDOTRACHEAL DRUG THERAPY

Table 2. Pharmacokinetics of lidocaine after endotracheal administration of its solution in human subjects.

Endotracheal Lidocaine

Doses studied Time to Time to Duration of Comments

therapeutic level peak serum level therapeutic levels

2.4 to 5 minutes 20 minutes 30 to 60 Data obtained from

7.7 mg/kg minutes human subjects in

non-shock/CPR setting

Table 3. Physiologic effects of epinephrine after endotracheal administration of its solution.

Endotracheal Eoineohrine

Manner of

investigation

Experimental

animal models

Doses studied

0.005 to

0.27 mg/kg

Time until

physiologic effects

Within 60 set

Duration

of effects

At least

25 to 30 min

Clinical

case reports

0.01 mg in infants,

1 mg in adults

Within 60 set Not reported

Duration of Serum Therapeutic Levels. The duration of serum therapeutic levels of lidocaine reported

in Boster’s study was a mean of 68.4 (* 29.7) minutes.

Chu reported serum therapeutic levels for a period of time that lasted between 30 and 60 minutes after drug

delivery. Although Telivuo did not sample blood in his group of patients beyond 40 minutes, the mean serum lidocaine level at that 40-minute sampling was

3.4 (I+ 1.6) pg/ml. Thus, there appears to be agree- ment among the data obtained by these three investigators that therapeutic serum lidocaine levels will be

maintained for a period of time between 30 and 60 minutes after an initial endotracheal dose of lidocaine

between 2.4 and 7.74 mg/kg.

Conclusion. There is no study in the literature that demonstrates the pharmacokinetics of endotracheal lidocaine in a shock/CPR model. All data concerning the endotracheal administration of the drug comes from studies involving fairly normal human subjects or animal models. There are three studies in the literature that approximate the manner in which endotra-

cheal lidocaine would be delivered in an emergency setting. Results from these studies show no serious side effects when lidocaine was administered endotracheally in a dose between 2.4 and 7.7 mg/kg, although

some patients were reported to have peak serum levels in the toxic range. Most patients given a dose of lido- Caine in the above mentioned range attained therapeutic serum lidocaine concentrations in approximately

five minutes and maintained these therapeutic levels for a period of time between 30 and 60 minutes. The

time required to reach peak levels of lidocaine was approximately 20 minutes.

Epinephrine Although epinephrine was used as a diluent in con-

junction with other drugs for endotracheal therapy as early as 1949, l8 it was not until 1967 that Redding, et al first showed that delivery of the drug via the endotracheal route was as effective as intravenous injection

in the resuscitation of animals undergoing CPR as a result of asphyxial arrest.31 This marked the first time

that the endotracheal route of drug delivery was used

as a systemic means of drug administration. Since that time, the pharmacokinetics of epinephrine after endo-

tracheal administration in animals has been elucidated by Roberts, Greenberg, et al. After their original article in 1978, they published a number of papers con-

cerning the endotracheal delivery of the drug in both experimental and clinical settings.33-36 (Table 3.)

In their first two papers Roberts, Greenberg, et al dealt with the physiological response and pharmacokinetics of epinephrine after endotracheal admini-

stration in animal models.32l33 They found that peak serum concentrations of epinephrine after endotracheal

delivery appeared at 15 seconds (first sampling], and physiologically the animals responded with a maximal increase in blood pressure within 60 seconds. With respect to duration of response, they found that at 30

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minutes after the endotracheal delivery of the drug, 80% of the initial blood level was still present in the peripheral circulation compared to only 10% present after intravenous adminstration. Likewise, significant

elevations of both blood pressure and heart rate above baseline values were noted for at least 30 minutes after

endotracheal administration. Thus, these investigators

found that epinephrine was rapidly absorbed and, like

lidocaine and penicillin, had a depot effect after endotracheal administration.

With respect to drug dosage, Roberts, Greenberg, et

al found that when similar doses of epinephrine were delivered by the intravenous and endotracheal routes, the maximum concentration attained after endotra-

cheal adminstration was only one tenth that found after intravenous adminstration. 33 In addition, it was

noted that to produce similar changes in blood pressure, the endotracheal dose had to be approximately

ten times the intravenous dose adminstered.32 Despite this, however, there was only a two- to threefold increase in parameters when equal doses were com-

pared. In addition, if epinephrine was delivered

beyond the tip of the endotracheal tube with a catheter, the magnitude of the physiologic response was almost identical with equally delivered doses via the endotracheal and intravenous routes.32

The third article published by Greenberg, Roberts, et al reported that endotracheal epinephrine in doses of 0.05 and 0.1 mg/kg effectively reversed histamine-

induced hypotension in dogs.M They found that after the above doses of epinephrine were administered

through a catheter that protruded past the tip of the

endotracheal tube, there was an immediate increase in the mean blood pressure in the animal. For the initial 90 to 120 seconds’ after administration of the drug by

the endotracheal route, the magnitude of the increase in the blood pressure was not as great as the response seen with intravenous administration. However, after that period of time, there was no significant difference in the blood pressure response.

Roberts, Greenberg, et al later reported two case reports concerning the endotracheal administration of

epinephrine in human subjects who were pulseless and apneic, and in whom an intravenous line was unable to be readily established.35t36 In both cases, the dosage of the drug delivered by the endotracheal route was the same as that used for intravenous administration in similar circumstances (10 cc of 1: 10,000 dilution of epinephrine in an adult and 0.01 cc of a 1: 1000 dilution of epinephrine in 1 cc of saline in an infant). In both instances this drug delivery appeared to be the

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cause for the successful resuscitation of each of the patients.

Conclusion. Endotracheally administered epinephrine has been demonstrated to produce significant physiological responses after very rapid absorption from

the lungs in both animals and human subjects. In addition, a depot effect of epinephrine has been demonstrated which has resulted in prolonged phy-

siologic responses for up to 30 minutes after endotracheal administration. The dosages used in the case

reports of endotracheal epinephrine delivered during CPR consisted of 10 cc of a 1: 10,000 dilution for an adult and 0.01 cc of a 1: 1000 dilution in 1 cc of normal saline for a 13-day-old child.

Atropine

The initial report of endotracheally administered atropine appears to have been in the year 1897.’ Since that time, however, little has been published in the

literature concerning its endotracheal use. In 1977, Elam studied the intrapulmonary delivery of atropine

to dogs that demonstrated a persistent bradycardia during resuscitation from cardiovascular collapse secondary to hypoxia.51 He found that intrapulmonary delivery produced a more rapid physiologic response (11 to 21 seconds) than intravenous delivery (47 to 65 seconds). In addition, Elam found that atropine exhi-

bited a depot effect when administered endotracheally, which led to a fourfold increase in the duration of EKG effects (sinus tachycardia) over that observed

when the same dose was administered intravenously.

The dose of atropine used by Elam was 2.0 mg diluted in 10 cc of distilled water.

The only other report of endotracheally delivered atropine in the literature is a case report by Greenberg

et al in 1982.37 In this paper a report is made of endotracheally administered atropine to an apneic, pulseless, hypotensive patient, who exhibited a nodal rhythm of 30 to 40 complexes per minute, and in whom no intravenous line could be immediately esta-

blished. An EKG response was noted in 30 seconds, and in addition, serum atropine levels were measured at 30 seconds (<3 ng/mll and 600 seconds (< 11 ng/ml) after drug delivery. Although the initial serum level of atropine at 30 seconds was less than 3 ng/ml, the patient appeared to have a physiologic response to the drug which proved to be advantageous. There has been no report in the literature that has successfully correlated serum atropine levels with magnitudes of physiologic responses, but there is definite data that physiologic responses to atropine do occur at levels of


Table 4. Physiologic response to the intrapulmonary delivery of atropine in solution.

Endotracheal Atropine

Manner of Doses studied Time until Duration Comments

investigation physiologic effects of effects

Experimental 2 mg 11 to 21 set 4 times longer Drug delivered

animal model than IV dose intrabronchially

Clinical 1 w Within 30 set Not reported Patient was apneic

case report and pulseless

less than 3 ng/m1.52 (Table 4.) The serum level of atropine at ten minutes after endotracheal administration of 1 mg was comparable to that after intravenous injection of the same 1 mg dose.53 It also is important to note that the patient was successfully resuscitated and later discharged from the hospital without any remarkable pulmonary or respiratory complications.37

Conclusion. Very little in the literature exists concerning the endotracheal administration of atropine.

One experimental study has shown the intrapulmonary delivery of 2 mg atropine in 10 cc of water to be both rapid and effective in the reversal of hypoxia induced

bradycardia. In addition, a four fold increase in the duration of action of drug was found after endotracheal administration. A single case report exists which has

shown the endotracheal administration of 1 mg of atropine to be effective in reversing bradycardia in a pulseless, apneic, hypotensive patient, who later developed

no respiratory complications.

Naloxone

A single study exists in the literature concerning the endotracheal administration of naloxone. It was

performed by Greenberg, Roberts, and Baskin in rabbits that were subjected to narcotic-induced respiratory depression.54 Rabbits were administered intravenous morphine sulfate until respiratory depression was pro-

duced as measured by a decrease in minute ventilation of at least 50%. The animals were then administered

1 cc of normal saline, followed five minutes later by 1 cc naloxone, followed five minutes later by 1 cc normal saline. Minute ventilation was measured for the

five-minute period after each administration. After the first 1 cc aliquot of normal saline, the minute ventilation increased to a level of 7% above the initial baseline. Then, after the administration of naloxone, minute ventilation increased to 528% above the baseline level.

It would appear that endotracheal naloxone is effective in the reversal of morphine-induced respiratory

depression in rabbits. However, no control group existed in this study, and the amount of increase in minute ventilation due to naloxone versus increasing amounts of endotracheally administered fluid is not

known. It seems probable, however, that naloxone was primarily responsible for the increase in minute ventilation since the first and second aliquots of nor-

mal saline did not produce as significant a rise in the minute ventilation as did the naloxone.

No data exists concerning the endotracheal administration of naloxone in humans.

Diazepam Diazepam is the most recent of drugs to be investi-

gated as to its potential for endotracheal use. In 1982

Barsan, Ward, and Otten studied the endotracheal adminstration of diazepam in dogs.55 The animals

were administered a dose of 0.5 mg/kg of diazepam

diluted to a volume of 5 cc with 95% ethanol (Table 5). The method of delivery was through a catheter

placed through the endotracheal tube so that its tip

protruded just past the tip of the endotracheal tube. The authors measured arterial serum levels of

diazepam at various time intervals. In addition, arterial blood gases were monitored to determine the short term effects of the drug delivery upon the phys-

iologic function of the lungs.

The authors found that endotracheal administration of diazepam in doses similar to those used clinically

(0.5 mg/kg) resulted in peak serum levels of the drug as rapidly as with intravenous adminstration. Thera-

peutic levels of the drug were maintained for 15 to 30 minutes, again similiar to that seen after intravenous

administration.56 Of interest, it was noted that the depot effect seen with certain other endotracheally administered drugs was not observed after endotracheally delivered diazepam. In addition, the results of the arterial blood gas analyses did not reflect any serious acute damage to the lung. Thus, diazepam was found to be as effectively delivered by the endotra-

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Table 5. Pharmacodynamics of endotracheally administered diazepam diluted in 95% ethanol.

~~

cheal route as by intravenous injection. Moreover, no depot effect was observed after endotracheally adminstered diazepam, and no serious acute pulmonary complications were found (Table 6). No data exists concerning the endotracheal use of diazepam in humans.

Areas for Research

The subject of endotracheal drug therapy will require much more investigation before it can be ade-

quately understood and applied to its fullest potential. A number of observations have been made in the last 40 years concerning endotracheal therapy, but many questions have yet to be answered. Most of the “un- knowns” of endotracheal drug therapy can be placed into one of three broad categories: 11 pharmacokinetics in a shock/CPR model, 2) factors affecting absorption, and 3) sequelae of endotracheal therapy.

Table 6. List of drugs demonstrated to exhibit a depot effect

after endotracheal adminstration of their solutions.

Drugs that Exhibit a Depot Effect

Atropine

Epinephrine

Lldocaine

Penicillin

Sulfonamides

Pharmacokinetics in a ShocWCPR Model Most studies in the literature concerning endotra-

cheal drug therapy have been performed in fairly healthy human subjects, or anesthetized animals: non-shock/CPR settings. However, those clinical settings which most frequently require endotracheal drug therapy are hypotension, shock, and cardiac or respiratory arrest.35d7 At present, it is not known how sustained hypotension or shock may affect the absorption of drugs delivered into the pulmonary tree. The manner in which CPR (the setting most frequently requiring endotracheal therapy) affects the absorption and elimination of drugs is not known. In addition, a number of factors such as congestive heart failure, pulmonary edema, severe acidosis, chronic obstructive pulmonary disease, and infectious lung disease, may

frequently precede cardiac or respiratory arrest, yet the manner in which these disorders affect the absorption of the drugs from the tracheobronchial tree is not known. Perhaps the dose of the drug should be increased in patients who arrest secondary to the hypoxemia of pulmonary edema because of the increased amount of transudate in the lungs, or

perhaps the transudate will help to facilitate distrib- ution and absorption of the delivered drug, so the dose

should be decreased. All of these disease processes which are frequently the setting in which endotracheal drug therapy is required need further elucidation as to

how they effect the pharmacokinetics of the endotracheally delivered drugs.

Case reports do exist in the literature, however, that report the delivery shock/CPR settings?5-37

of endotracheal drugs in The drugs administered have

been found to be absorbed and elicit their physiological response, but it remains to be determined how the setting of CPR affects the known kinetics of drug absorption and elimination.

Factors Affecting Absorption Besides the status of the cardiopulmonary system, as

mentioned above, there are several other factors that may affect the absorption of drugs after endotracheal

delivery. Method of delivery. The optimal means of endotra-

cheal drug delivery remains unknown. A number of

factors associated with drug delivery could potentially affect the rate and degree of drug absorption, but the magnitude of these effects is unknown. Presently, in

most clinical settings, an endotracheally delivered drug is simply injected in solution down the endotracheal tube and followed with several insufflations of a

mechanical ventilation device in order to promote more distal drug delivery.35-37 Some authors feel that if the subject is placed in an inclined position such that gravity helps in the delivery of the drug to the

distal segments of the lung, then absorption will be more rapid.ltM No controlled study has been performed, however, to validate this assumption. Some authors have found a greater physiologic response is

78


obtained if the drug is delivered past the tip of the endotracheal tube via a catheter placed through the endotracheal tube.33 In addition, some feel the drug should be delivered through a catheter passed though the endotracheal tube and “wedged” into a segment of

the lung, thus insuring very distal delivery of the

drug.51 Again, no comparative study has been performed with this latter method to validate its merit.

A controlled comparison of drug delivery by aerosol versus solution should also be conducted. Aerosolized

sprays are felt to be delivered more distally with positive pressure ventilation thus promoting more rapid absorption than with drugs delivered in solution.

There appears to be some suggestion that this concept

is true. Several authors have reported significantly

earlier peak levels of both lidocaine and penicillin when delivered by the aerosol method rather than in solution 18,19,39,43

One final point should be made concerning the method of drug delivery. Some authors have studied the endotracheal delivery of drugs to patients who are spontaneously breathing and to others who were subjected to positive pressure breathing.43f47 The peak serum levels of various drugs were significantly higher

in the group of patients under positive pressure ventilation compared to patients who were spontaneously breathing. This underscores the importance of deliver-

ing the four to five insufflations with a mechanical ventilation device after the endotracheal delivery of a drug.

Diluents. It has already been demonstrated that various diluents can affect the rate of absorption of a drug, the peak serum level attained by a drug and the

duration of therapeutic levels of that drug.1914’ The potential exists for the use of various diluents to mani-

pulate the pharmocokinetics of a drug to fit the needed effects in a given clinical setting. Further investigation

is needed to elucidate which properties of diluents affect the manner in which a drug is absorbed after its

endotracheal administration. The osmolality of a diluent solution may be one of

those properties that affects the rate of absoption of a drug. As early as 1946, Courtice and Phipps showed that water was much more rapidly absorbed than saline after endotracheal administration in rabbits.25

In addition, Redding showed that the time from drug administration to return of circulation was longer in those dogs given epinephrine diluted in saline endotracheally than in the group of animals treated with epinephrine in water. It would appear that this difference in absorption is related to the osmolality of the

solution, with hypo-osmolar solutions being absorbed

more rapidly than iso-osmolar solutions. Of interest,

however, is the finding by Barsan, Ward, and Otten who reported that diazepam is rapidly absorbed from the lungs of dogs after endotracheal administration.55

The diluent used in their study was 95% ethanol (diazepam is not soluble in saline or water), and the osmolality of the resulting solution was much greater than that of serum. However, ethanol itself may exert an effect upon absorption that is separate from the

effect of its osmolality in 95% solution. Thus, the role that the osmolality of a solution plays in its absorption

after endotracheal administration requires clarification.

Another property of diluents that may affect the rate of drug absorption is the inherent “pharmacological activity” of the diluent. The fact that cer-

tain drugs in solution affect the manner in which a primary drug is absorbed after endotracheal administration was first observed by Beakey, Gaensler, and Segal in 1948. I9 At that time they found that if 100,000 units of penicillin was diluted with either 1: 1000 neosynephrine or 1: 10,000 epinephrine, then

the time to peak serum levels of penicillin occurred earlier and the peak serum levels attained were higher than when the penicillin was delivered in normal

saline. (It is unfortunate they did not compare with

penicillin diluted in water also.) A similar finding was observed by Telivuo, who noted that serum lidocaine

levels were higher and earlier when epinephrine in the proportion of 1: 100,000 was added to the 4% solution of lidocaine adminstered endotracheally to his patients.47 As mentioned previously, the role that ethanol played in the rapid absorption of diazepam in

Barsan, Ward, and Otten’s study has yet to be deter-

mined. Thus, a large amount of investigation is needed to determine whether certain diluents possess

“pharmacologic activity” that affects the absorption of

the primary drug they are combined with.

Other properties of diluent solutions may exist that affect the manner in which they are absorbed from the tracheobronchial tree and include such factors as pH, degree of ionization, and solubility.

Volume. Redding, Asuncion, and Pearson noted in 1967 that the endotracheal administration of 1 mg of epinephrine diluted to a volume of 10 cc with water was as effective as intravenous or intracardiac injection

of 1 rng of epinephrine in the resuscitation of animals

that had sustained a cardiopulmonary arrest secondary

to hypoxia.31 However, when this same 1 mg dose of epinephrine was diluted to a volume of only 1 cc and delivered endotracheally, it was no more effective in

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AMERZCAN lOURNAL OF EMERGENCY MEDZCINE 0 VOL 1 . WLY 1983

restoring circulation than when no drug was used. The authors presumed that an appreciable amount of the drug remained in the endotracheal tube when the undiluted dose was used for administration. Thus, the importance of adequate volume for endotracheal drug

delivery becomes obvious. The most appropriate volume for drug delivery

endotracheally has not yet been determined. If an insufficient volume is used, drug delivery may be

inadequate and the desired systemic effects may not be obtained. On the other hand, the possibility of hypoxia or respiratory acidosis with too large a volume of solution must be considered.57-59 This especially becomes a concern if more than one dose of an endotracheal drug is required. When endotracheal drug therapy was first begun, antibiotics were delivered in solutions that ranged from a volume of 3 to 2O cc 18-21,24,60 Most of these patients had infectious

pulmonary diseases with poor respiratory reserve, and yet they appeared to tolerate the endotracheal delivery of these solutions fairly well. Today, most drugs that

are emergently delivered by the endotracheal route are administered in a volume of 5 to 10 cc, probably due

moreso to the prefill syringes that are so readily available than to any other reason. In the case reports available this volume appears to be adequate for drug delivery, in that the systemic effects desired were obtained, and no serious sequelae were noted.37 Obvi- ously, however, further investigation is required to

more accurately determine the most appropriate volumes of diluents for endotracheal drug delivery.

Another area of concern in endotracheal therapy is the question of the maximum number of doses of

drugs that can be delivered by the endotracheal route.

Obviously, the answer to this question will vary for each clinical setting and type of diluent used. While no guidelines exist concerning the number of doses

[total volume) that may be used in a patient requiring endotracheal drug delivery, a number of interesting observations have been made. In the antibiotic era of endotracheal therapy some patients with bronchiectasis were delivered doses of penicillin in a volume of 20 cc of normal saline twice daily for several days without deterioration of their pulmonary status.” Also, two dog studies have shown that a dose as large as 2 cc/kg of normal saline delivered endotracheally did not result

in significant changes in arterial pH or pCO,, and the decrease in the mean arterial p0, was only to a level of around 80% of control values.57f61 (Nevertheless, any decrease in arterial p0, in a critically ill patient may be very significant.) However, the same was not

80

true for a dose of 2 cc/kg of distilled water. Dogs administered this dose of distilled water developed CO, retention and consequent respiratory acidosis. Also, the decrease in mean arterial p0, was significantly greater than that observed for the normal saline. This demon-

strates that the maximum amount of solution that can be safely delivered endotracheally depends in part upon

the nature of the solution used. Guidelines for the total amount of a solution that can be delivered endotracheally without causing a detrimental change in

the status of a given patient must await further investigation.

Sequelae of Endotracheal Therapy Little information exists in the literature concerning

the short or long term effects of endotracheal drug delivery upon pulmonary function in humans. In the antibiotic era of endotracheal therapy, only gross obser-

vations were made concerning the pulmonary status of the patients treated with endotracheal drugs, and most of these patients improved after therapy. As men-

tioned previously, the possibility of hypoxia induced by endotracheally administered solutions in a patient with little respiratory reserve secondary to active pulmonary

infection is an obvious concern. However, there

appear to be no reports of this having been a serious problem. Today, with endotracheal drug therapy reserved primarily for emergency settings, it becomes difficult to assess a patient’s respiratory status before and after drug delivery without having a number of

other variables affect the data. Thus, the small

amount of information available concerning the effects endotracheally administered solutions have upon the

respiratory system comes from the study of animal models. Many studies report the effect of large vol-

umes 12 cc/kg or more) of saline or water upon the

lungs, 57-59~61 but there is only one paper that deals

with the effects of small volumes (5 to 10 ccl of solution upon the lungs after endotracheal administration. This study, by Barsan, Ward, and Otten, monitored serial arterial blood gases in order to determine the effects endotracheally administered diazepam had upon the lungs of dogs. Diazepam was delivered in a dose of 0.5 mg/kg diluted to a volume of 5 cc in 95%

ethanol. The results of their study showed that the mean arterial pH and pC0, did not change significantly from the control values, and the mean arterial p0, showed a transient drop during the first 60 minutes, but returned towards the control values at the end of 90 minutes. The largest change in mean arterial 0, saturation occurred at 60 minutes, at which


time the change from the mean control value was 12.2

torr. These investigators concluded that the values did not reflect any serious acute damage to the lungs.

While other studies concerning the effect of small volumes (5 to 10 ccl of diluents upon the lungs after endotracheal administration are lacking, one other

study concerning endotracheal therapy should be mentioned. In 1982 Greenberg, Baskin, et al published a

paper on the effects of endotracheally administered

normal saline and distilled water upon arterial blood gases of dogs.57 The administration of normal saline

solution to dogs resulted in a less detrimental effect on arterial oxygen levels than that of endotracheally administered distilled water. However, the dose of solution used in these experiments was 2 cc/kg of

body weight, approximately 15 to 30 times the rou- tinely used single dose volume of drug solution administered in endotracheal therapy in human subjects. Thus, it becomes difficult to apply these results directly to the clinical setting where much smaller vol-

umes of diluents are utilized. In the much larger experimental doses used by Greenberg et al however, it would appear that normal saline is less acutely toxic

to the lungs than distilled water. As with many of the other areas concerning endo-

tracheal drug administration, further investigation is

needed to more adequately assess the short and long term sequelae of endotracheal therapy.

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Endotracheal drug therapy