Endotracheal drug administration in the critical care setting

TheJoumalofEmergency

MedIane, Vol 5, pp 407-414,1987

Printed tn the USA

??

CopyrIght ‘:I 1987 Pergarnon Journals Ltd

ENDOTRACHEAL DRUG ADMINISTRATION IN THE CRITICAL CARE SETTING Deborah Harper Brown, PharmD,* Akiko Kasuya, PharmD,* and Jerrold B. Leikin, MDt ‘Department of Pharmacy Practice, College of Pharmacy, Unlverslty of lll~no~sat Chlcago, TDepartment of Medicine, Abraham Lincoln College of Medicine, University of Illinois at Chicago Repnnt address, Deborah Harper Brown, PharmD, Department of Pharmacy Practice, College of Pharmacy, Unlverslty of lll~no~sat Chtcago, 833 South Wood Street, Room 244, Chlcago, IL 60612

U Abstract-Administration of drugs through an endotracbeal tube has been evaluated in a number of animal models. In addition, the technique has been utilized in humans as reported in several published cases. A review of endotracheal drug administration with emphasis on application to the critical care setting is presented. 0 Keywords- Endotracheal drug administration; critical care medicine

Introduction Rapid delivery of a drug to its site of action is especially important in the critical care setting. Although the intravenous route of administration is generally accepted as the method of choice in this context, certain conditions may hinder peripheral venous access. For example, elderly or obese patients, pediatric patients, or intravenous drug abusers may have blood vessels that are difficult to locate. In addition, peripheral vasoconstriction which can occur in traumatic shock,

RECEIVED: 23 September

circulatory collapse or cardiopulmonary arrest may also limit venous access. Alternative methods of rapid drug delivery such as intraosseous1-4 and intracardiac administration are invasive and may result in complications.5 Endotracheal drug administration has been investigated as an alternate method of rapid drug delivery. This article will review the development of endotracheal drug administration, highlight data on the technique in animals and humans, and discuss potential clinical applications of the method.

Physiology of Endotracheal Administration

Drug

The occurrence of systemic effects following inhalation of aerosolized agents including beta agonists, antibiotics, steroids, and antidysrhythmic drugs has been well documented.6 The concept of absorption of drugs in solution following administration directly to the lung has been attributed to the work of Claude Bernard.’

1986; ACCEPTED: 9 November 407

1986 0736-4679/87

$3.00-t

.OO

408

Bernard instilled a solution of curare into the respiratory tract of tracheostomized dogs. If the animals remained in the supine position, the effects of the drugs were not observed. However, when the animals were tilted to allow the drug to distribute into the lower respiratory tree, death from respiratory paralysis occurred within seven to eight minutes. From these findings, Bernard concluded that medication could be absorbed from the lung to result in pharmacologic effects. The endotracheal route of administration utilizes this absorptive capacity of the lung. The technique itself is relatively simple: a drug in solution is introduced into the distal end of the endotracheal tube, is allowed to filter into the lower respiratory tree with delivery to the site of absorption facilitated by insufflation of a manual ventilator or similar device (eg, Ambubag@ ). The proposed site of absorption following administration of drug into the lung is believed to be the alveolar capillary interface.* Once the drug reaches the level of the alveolus, diffusion is considered to be the major force for absorption. This process involves molecular movement of the drug substance from an area of high concentration, the alveolar space, to one of lower concentration, that is, the pulmonary capillary (Fig 1). Given the large surface area of the lung as well as the fact that virtually 100% of the cardiac output is delivered to the lung, rapid delivery to systemic circulation is anticipated. It is this aspect of endotracheal drug administration that is considered to be of theoretical advantage in instances of cardiopulmonary arrest. The drug is administered to the lung with subsequent transport directly to the cardiopulmonary circulation, bypassing the difficulties associated with absorption in the clinical setting of peripheral vasoconstriction. Thus with initial physiologic evidence to support systemic effects following drug administration to the lung, several investigators evaluated the safety, and efficacy of this method in various animal models.

D.H. Brown, A. Kasuya, J. B. Leikin

Figure 1. Schematic diagram of endotracheal drug administration. Drug in solution is administered into the proximal end of an endotracheal tube. Drug is forced into the lower respiratory tree to the level of the alveolar-capillary membrane where absorption into the systemic circulation occurs.

Animal Data Epinephrine is the agent that has been most extensively studied in animals following endotracheal administration. Initial investigations involved characterization of pharmacologic effects of the drug delivered by this technique. Redding et al9 first published investigations of intratracheally administered epinephrine. Cardiovascular collapse secondary to asphyxiation was induced in 80 dogs. Return of circulation was measured following administration of a 1 mg dose of epinephrine via the intratracheal, intravenous, intracardiac, sublingual, and intramuscular routes. When diluted in at least 10 ml water, intratracheal administration was as effective as the intravenous route of administration as determined by

Endotracheal

Drug Administration

the time elapsed before return of diastolic blood pressure. Epinephrine administered by the intramuscular, sublingual and undiluted intratracheal methods did not appear to be effective for resuscitation of the animals. Roberts et allo compared results of endotracheal and intravenous administration of various doses of epinephrine to seven anesthetized dogs. Their findings indicated that both routes of administration produced measurable effects on heart rate, systolic blood pressure, and respiratory rate. However, differences between the two routes were noted. Endotracheal epinephrine was reported to enhance respiratory rate and produce tachycardia immediately after administration. These effects were not reported with intravenous administration of the drug. In addition, formulation of a dose response curve indicated that increasing the dose of endotracheally administered drug above a certain level did not result in a corresponding increase in blood pressure. The authors suggested that this plateau effect may be the result of saturation of drug absorption sites in the lung. In another experiment, Roberts et al” utilized 3H-labelled epinephrine to characterize blood levels following endotracheal and intravenous administration. Seven anesthetized dogs were given doses of labelled drug ranging from 0.005 mg/kg to 0.09 mg/kg. Endotracheally administered epinephrine produced blood levels that were sustained over a longer period of time than intravenous administration. They speculated that the sustained blood levels were caused by a depot effect. Endotracheal drug administration is rapid, drug is deposited directly to the site of absorption, so the proposed rate limiting step is absorption. If a limited quantity of drug can diffuse across the alveolar capillary interface during a given time period, this step would result in a prolonged absorption phase. Simulating the clinical setting, Greenberg et a18induced anaphylactic shock in

409

eight dogs using intravenous histamine phosphate. Epinephrine was administered endotracheally and intravenously in doses of 0.05 mg/kg and 0.1 mg/kg. Endotracheal and intravenous routes of epinephrine were found to be equally effective in reversing the histamine-induced hypotension. Endotracheal administration of additional pharmacotherapeutic agents has been investigated in animal models. Elam et alI2 compared the effects of endotracheal and intravenous lidocaine, atropine, and epinephrine in dogs. Reversal of iatrogenically-induced ventricular dysrhythmias, bradycardia, and hypotension, respectively is documented. Barsan et a113 administered diazepam to five dogs via endotracheal tube and measured peak drug levels within two minutes. Blood levels of diazepam persist from 30 to 60 minutes. Immediately following drug administration, serial arterial blood gases were measured. Although the pC0, and arterial pH are unchanged from pre-administration values, there is a transient drop in PO,. The significance of this effect is unknown. None of the animals were reported to have a deterioration in cardiopulmonary status at any time during the experiment. Systemic absorption of naloxone has also been reported following endotracheal administration. Greenberg et alI4 induced respiratory depression in four rabbits using intravenous morphine. The mean minute ventilation of each rabbit after morphine administration was depressed to greater than half of resting baseline. Endotracheal naloxone administration is reported to increase minute ventilation 528% above baseline values. Administration of an equal amount of saline solution endotracheally did not result in increased minute ventilation. Following documentation of measurable blood levels and pharmacologic effects in animals, endotracheal drug administration has been utilized in several case reports in humans.

410

Use of Endotracheal Drug Administration in HumansCase Reports

Case Report 115 Epinephrine was endotracheally administered to a patient with cardiorespiratory collapse. The patient was intubated in the emergency department and had no venous access. One minute after 1 mg of epinephrine (10 ml of l:lO,OOO solution) was administered through the endotracheal tube a pulse was recorded with blood pressure of 230/130. In this case, a rapid onset of effect was observed and the patient recovered without adverse effects. Case Report 2’5 A 13-day-old infant male was brought to the emergency department with respiratory arrest. Venous access could not be obtained and the patient was intubated. Epinephrine 0.01 mg (0.01 ml of l:l,OOO solution) diluted in 1 ml of saline was endotracheally administered and manual ventilation was performed to distribute drug into the lower respiratory tree. Within 4.5 seconds of administration the pulse returned and sinus tachycardia (heart rate 160 beats per minute) was recorded by ECG. The patient was stabilized and admitted to an intensive care unit where he expired three days later secondary to an intraventricular hemorrhage. Case Report 376 Epinephrine was administered endotracheally to 10 premature infants. The infants were documented to have bradycardia unresponsive to 100% oxygen, external chest compressions, or sodium bicarbonate administration. A 1: 10,000 solution of epinephrine was administered, with dosage determined by the weight of the patient. All infants recovered with heart rates of 140 to 180 beats per minute.

D.H. Brown, A. Kasuya, J. B. Letkin

Case Report 4” A 76-year-old woman, cared for in a longterm facility following a massive stroke, was noted by the staff to have continuous generalized tonic clonic seizures. Attempts at intravenous access failed and there was no response to 90 mg of phenobarbital given intramuscularly. The patient was given 5 mg diazepam through her tracheostomy and ventilated with positive pressure. Seizure activity was noted to terminate within two minutes.

Case Report 518 A patient admitted to the Cardiac Telemetry Unit was noted to have ventricular tachycardia. Following cardioversion and numerous pharmacologic interventions, the patient developed bradycardia. Shortly after the administration of an intravenous dose of atropine, access was lost. Atropine 0.6 mg was administered through the endotracheal tube. A rapid improvement in heart rate was recorded with estimated time of response of approximately ten seconds.

Case Report 6’9 A 74-year-old female was brought to the emergency department with no detectable blood pressure. The patient was intubated, but venous access was not available. An initial rhythm strip by ECG indicated heart rate of 30 to 40 beats per minute. Atropine 1 mg was administered through the endotracheal tube, and the heart rate 30 seconds after drug administration was reported to be 100 beats per minute. An intravenous access was obtained and blood levels were drawn. Levels reported were less than 3 ng/ml and 11 ng/ml at 30 and 600 seconds, respectively. The patient was stabilized, and eventually discharged without respiratory complications.

Endotracheal

Drug Adminlstration

Case Report 720 A 24-year-old male was brought to the emergency department by friends following presumed heroin overdose. The patient was comatose, cyanotic, and venous access was not obtained secondary to damage to peripheral veins. After intubation, 0.8 mg naloxone was administered through the endotracheal tube. Twenty seconds later, another dose of 0.8 mg naloxone was given. Sixty seconds following the initial dose, the patient was awake, alert, and had to be restrained. Blood levels were qualitatively positive for naloxone, and urine toxicology screen indicated presence of naloxone and morphine. The patient was discharged six hours after admission without complication. Following endotracheal drug administration in each case, patients exhibited pharmacologic responses consistent with known intravenous drug administration, specifically, increases in heart rate or blood pressure and termination of seizure activity. Adverse effects were not reported on either a short-or long-term basis. The last two cases are of interest for an additional finding. The patients’ clinical conditions were responsive to the pharmacologic agents administered, but blood levels also documented systemic absorption of these agents following endotracheal administration.

Clinical Considerations Before widespread use of the endotracheal route of administration is recommended, several aspects of its use must be taken into consideration.

411

the animals were tilted to allow the drug to filter into the lower respiratory tree pharmacologic effects were noted. Several techniques have been reported in the literature to assure proper distribution of drug following endotracheal administration in humans. One investigatorI utilized a catheter to allow medication to filter into the lungs, resulting in increased drug absorption in animals. Adequate ventilation may also play an important role in the distribution of drug into the respiratory tree following endotracheal drug administration. Although all case reports utilizing the technique in humans recommend this, methodology is not specified. Most reports suggest manual ventilation at least 5-10 times to assure maximal distribution. In addition, at least two investigatorsZ’,2Z report the use of special devices that allow drug to be administered endotracheally without interruption of ventilation.

Diluent The most suitable diluent for drug administration has not been delineated. In at least two animal studies911Z, a drug dissolved in water was found to have greater absorptive capacity than the same drug dissolved in normal saline. However, in a dog study by Greenberg et a123, administration of normal saline by the endotracheal route produces less detrimental effects on arterial blood gases than does endotracheal administration of distilled water. It is important to note that many of the drugs used in pharmacotherapy of cardiopulmonary arrest are dissolved in saline.

PH Importance

of Proper Technique

In initial experiments by curare, animals remaining position did not experience cular effects of the drug.

Bernard7 with in the upright the neuromusHowever, when

In addition to type of diluent, the optimal pH of drugs for endotracheal use has not been elucidated. Drugs which have been administered endotracheally have solutions with pH ranging from 2.5 to 7. In each of the case reports on this route of

412

D.H. Brown, A. Kasuya, J. B. Leikin

administration in humans, adverse effects have not been reported in association with drug use.

Volume

The optimal volume of fluid to insert into the lung through the endotracheal tube must also be established. Volumes reported in the literature range from 0.25 ml in a pediatric patient to 10 ml in adults. Adverse effects have not been reported from instillation of these volumes.

Dosage (Table 1)

All dosages of drugs administered endotracheally have been chosen somewhat arbitrarily. Most case reports utilize dosages similar to those which would be utilized intravenously although one report’* suggests that higher initial dosages may be required when administering the drug via the endotracheal tube. In addition, other investigators9J2 have suggested a prolonged or depot type of effect following this route of administration. If this effect does occur, this should alter dosing interval for repeated doses. With the exception of the case report by Tanberg et al*Ousing endotracheally administered naloxone, other reports have not given more than one dose of drug by this route.

Potential Risks of Endotracheal Administration

Drug

Epinephrine, atropine, and naloxone are reported to be effective when given endotracheally and do not appear to have associated adverse effects. There are, however, several drugs that have been reported in animals that should not be given by this

route. In unpublished data, Elam et all* reported that the volume of sodium bicarbonate required to provide adequate reversal of acidosis inactivates lung surfactant in dogs. Isoproterenol and calcium chloride are reported to result in tissue necrosis following endotracheal administration.6 In a study by Murphy et a12”, endotracheally administered bretylium is poorly absorbed and does not result in adequate blood levels.

Summary and Conclusions Endotracheal drug administration has been investigated as an alternate route of drug delivery when suitable venous access cannot be readily obtained. Clinical responses to several drugs administered by this route have been documented in animal studies and several human case reports. In addition to considerations discussed above regarding drug administration (ie, dose, diluent, volume, etc), other factors must be addressed. Additional considerations are indicated subsequent to reports of tissue necrosis from administration of isoproterenol and calcium chloride6, inadequate absorption of bretylium tosylate24, and inactivation of pulmonary surfactant by sodium bicarbonate.‘* Studies addressing difficulties of emergency vascular access in pediatric patients suggest an additional alternative. Intraosseous infusion has been used to obtain access to venous circulation.‘-3 In addition, Kanter et al4 suggest alternative methods of drug administration (intraosseous or intratracheal) may be useful procedures to facilitate subsequent venous access. Until further data is accumulated, endotracheal drug administration should be considered an investigational tool, which may become useful for the management of critically ill patients.

REFERENCES 1. McNamara RM, Spivey WH, Sussman C: Pediatric resuscitation without an intravenous line. Am JEmerg Med 1986; 4:3l-33.

2. Mayer TA: Emergency pediatric vascular access-old solutions to an old problem. Am J Emerg Med 1986; 4:98-10X

Endotracheal

413

Drug Administration

Table 1. Endotracheal

Drug Dosages in Humans

Epinephrine Adult

1 .O mg (10 cc of l:lO,OOO dilution)

15

0.1 mglml solution 0.25-i .O ml based on weight

16

Atropine

1 .O mg 0.6 mg

19 18

Naloxone

0.8 mg

20

Diazepam

5mg

17

Pediatric

Appendix Endotracheal Drug Epinephrine

References

Dosage

Drug

(ET) Drug Administration Model

1

in Animal Models Subjects

Doses

Results

References

Induced cardiac arrest

80 dogs

Induced cardiovascular collapse

8 dogs

2 mgll0 ml Saline ET vs 1.5 mg IV

ET administration found to have slightly slower onset but longer duration of action than IV

12

Induced anaphylactic shock

8 dogs

0.05 mg/kg 0.1 mg/kg ET. IV

Both ET and IV gave measurable effects on BP

8

Anesthetized non arrested

7 dogs

0.005 mglkg 0.03, 0.06, 0.09 mglkg IV, ET 0.27 mglkg ET

ET Epi rapidly absorbed, gives lower blood levels than IV. Both effect BP, HR, and RR.

10

Anesthetized non arrested

7 dogs

0.005 mglkg 0.003,0.06, 0.09 mglkg ET. IV

Epi and metabolites assayed; ET had longer duration of action

11

Atropine

Induced bradycardia

8 dogs

2mgET 1.2-l .6 mg IV

ET Atropine had slightly longer duration of action than IV

12

Bretylium

Anesthetized non arrested

5 mglkg ET 10 mg-20 mglkg IV

Blood levels of ET Bretylium low

24

11 dogs

1 mglml ET ET administration 1 mgll0 ml in H,O comparable to IV IV -

9

(continued)

D.H. Brown, A. Kasuya,

414

Appendix

J. B. Lerkin

1

Continued Drug

Model

Diazepam

Anesthetized non arrested

Lidocaine

Induced Ventricular dia Ventricular

Naloxone

Subjects

Doses

Results

References

5 dogs

0.5 mglkg ET

ET administered Diazepam gave rapid peak concentrations

13

8 dogs

20 mg ET

ET Lidocaine

12

20 mg IV

has slightly slower onset but longer duration than IV

0.4 mg ET

ET Naloxone reversal of respiratory depression

TachycarFibrillation

Morphine induced respiratory depression

4 rabbits

3. Glaeser PW, Losek JD: Emergency intravenous infusions in children. Am J Emerg Med 1986; 4: 34-36. 4. Kanter RK, Zimmerman JJ, Strauss RH, et al: Pediatric emergency intravenous access. Am J Dis Chitd 1986; 140:132-134. 5. Standards and Guidelines for Cardiopulmonary Resuscitation (CPR) and Emergency Cardiac Care (ECC). JAMA 1986; 255:485. 6. Greenberg MI, Roberts JR, Baskin SI, et al: The use of endotracheal medication for cardiac arrest. Topics in Emerg Med 1979; 1:29-40. capacity of the airways 7. Dal Santo G: Absorption and lungs. Int Anesthesiol Clin 1977; 5:61-90. 8. Greenberg MI, Roberts JR, Krusz JC, et al: Endotracheal epinephrine in a canine anaphylactic shock model. JACEP 1979; 8:500-503. 9. Redding JS, Asuncion JS, Pearson JW: Effective routes of drug administration during cardiac arrest. Anesth Analg 1967; 46~253. 10. Roberts JR, Greenberg MI, Knaub M, et al: Comparison of the pharmacological effects of epinephrine administered by the intravenous and endotracheal routes. JACEP 1978; 7:260-264. 11. Roberts JR, Greenberg MI, Knaub M, et al: Blood levels following intravenous and endotracheal epinephrine administration. JACEP 1979; 8153-56. 12. Elam J: The intrapulmonary route for CPR drugs. In Safar P ted]: Advances in Cardiopulmonary Resuscitation. New York, SpringerVerlag, 1977; pp 132-140. 13. Barsan WC, Ward JT, Ohen EJ: Blood levels of diazepam after endotracheal administration in dogs. Ann Emerg Med 1982; 111242-246.

14

14. Greenberg MI, Roberts JR, Baskin SI: Endotracheal naloxone reversal of morphine-induced respiratory depression in rabbits. Ann Emerg Med 1980; 9:289-292. 15. Roberts JR, Greenberg MI, Baskin SI: Endotracheal epinephrine in cardiorespiratory collapse. JACEP 1979; 8:515-519. 16. Lindemann R: Resuscitation of the newbornendotracheal administration of epinephrine. Acta Paediatr Stand 1984; 73:210. 17. Pasternak SJ, Heller MB: Endotracheal diazepam in status epilepticus. Ann Emerg Med 1985; 14:485. 18. Welik R, LaGana GM: Successful ET administration of atropine. (Let) Ann Emerg Med 1983; 12:516. 19. Greenberg MI: Endotracheal administration of atropine sulfate. Ann Emerg Med 1982; 11:546548. 20. Tanberg D, Abercrombie D: Treatment of heroin overdose with endotracheal naloxone. Ann EmergMed 1982; 1 l:443-445. 21. Ferferman I, Leblanc L: A simple method for administering endotracheal medication. (Let) Ann EmergMed 1983; 12:196. 22. Simon JS: Device for endotracheal route medication. Ann EmergMed 1981; 10:341. 23. Greenberg MI, Baskin SI, Kaplan AM, et al: Effects of endotracheally administered distilled water and normal saline on the arterial blood gases of dogs. Ann Emerg Med 1982; 11:600604. 24. Murphy KM: Endotracheal bretylium tosylate in a canine model. Ann Emerg Med 1984; 13:87.