Alternative Methods of Drug Administration

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Chapter 26

Alternative Methods of Drug Administration

The rapid administration of lifesaving, pain-relieving, and sedative medications lies at the core of the practice of emergency medicine. The intravenous (IV) route is usually the delivery method of choice. However, there are circumstances in which vascular access is either not available or contraindicated. Thus, emergency providers need to have a working knowledge of alternative routes of drug administration. This chapter describes the endotracheal (ET), intranasal, and rectal routes. Intraosseous (IO) access is covered in Chapter 25.

ET Administration of Medication

Certain drugs can be delivered simply, rapidly, and effectively to the central circulation by way of the ET tube. This method is best reserved for situations in which a patient’s condition warrants immediate pharmacologic intervention but more conventional means of drug delivery, such as IV and IO, are not readily available. Such circumstances frequently arise in the prehospital or cardiac arrest scenario. Knowledge of the appropriate drugs and dosages that can be delivered effectively by this route may prove to be lifesaving.

Historical Perspective

ET drug administration dates back to 1857, when Bernard1 demonstrated that the lung could rapidly absorb a solution of curare. In this historical experiment he instilled a fatal solution into the upper respiratory tract of dogs by way of a tracheostomy. Over the following decades, other investigators expanded this work and demonstrated that solutions containing salicylates, atropine, potassium iodide, strychnine, and chloral hydrate were also rapidly absorbed from the lung and excreted in urine after injecting aqueous solutions into the tracheas of experimental animals.2 The use of intrapulmonary medication for the treatment of lung disease gained further acceptance when studies demonstrated that inhaling epinephrine mist dramatically relieved the symptoms of asthma.3

In the late 1930s and 1940s, several important observations were made concerning ET drug therapy: (1) penicillin delivered by the ET route demonstrated a depot effect, which resulted in therapeutic blood levels that lasted twice as long as those with intramuscular injection4; (2) various diluents mixed with penicillin affected both the rate and the degree of absorption from the lungs5; and (3) higher serum drug levels were attained with direct ET drug administration than with aerosolized administration.5 In the 1950s it was noted that drugs delivered endotracheally were absorbed much more rapidly than those applied to the posterior part of the pharynx. Drugs applied locally to the larynx and trachea were absorbed rapidly and even resulted in blood levels significant enough to cause adverse anesthetic reactions.6

In 1967, Redding and coworkers7 studied the use of ET administration as a route of drug delivery in a canine model of cardiopulmonary arrest. They administered epinephrine by the IV, intracardiac, and intratracheal routes to resuscitate dogs that had undergone both respiratory and circulatory arrest secondary to hypoxia. They then evaluated the effectiveness of the epinephrine after administration of the drug by all three of these routes. Their study revealed that all three routes of drug administration were equally effective in restoring the circulation of dogs in hypoxia-induced cardiac arrest, again demonstrating that the ET route of drug delivery provides effective access to the systemic circulation.

In the late 1970s, Roberts, Greenberg, and colleagues8–11 studied ET drug delivery in a series of laboratory experiments and clinical applications of ET epinephrine. Since that time, a number of important animal and human studies, as well as case reports, have been published in which the various aspects of ET drug administration were investigated. These studies have addressed (1) the appropriate dose of drug to administer; (2) the effect of the drug solution’s volume; (3) the effect of different diluent solutions; (4) the role of different ET drug delivery techniques; and (5) the effects of hypoxia, hypotension, shock, and cardiopulmonary arrest on the absorption, distribution, and efficacy of endotracheally administered drugs.

Recommendations For ET Drug Delivery

It is imperative to remember that ET drug delivery is not the delivery method of choice. The American Heart Association (AHA) recommends that if IV access is not available, IO access should be obtained.12 Although the AHA makes specific recommendations regarding the use of ET drug delivery for cardiac resuscitation (Table 26-1),1214 much of the existing literature is controversial and contradictory at times. It is therefore possible that some of these issues will continue to be the subject of future investigations.

Appropriate Dose

All investigators agree that the ET dose of a medication should be at least equal to the IV dose of the same drug when given for the same indication, but most studies indicate that higher doses are needed when administering drugs endotracheally. For advanced cardiac life support (ACLS) medications in adults, the AHA recommends a dose that is 2.0 to 2.5 times the usual IV dose when administered endotracheally.12 This would be 2.0 to 2.5 mg (twice the standard IV dose of 1.0 mg). This recommendation is supported by the results of a study of epinephrine administered immediately after intubation in the out-of-hospital setting.15 Other studies of endotracheally administered lidocaine indicate that a 3-mg/kg dose (twice the standard IV dose of 1.5 mg/kg of lidocaine) was needed to obtain therapeutic serum levels.16,17

Some animal studies18 and case reports10 have reported conflicting results, with positive effects or recovery from cardiovascular collapse when epinephrine was used in doses equal to the recommended IV doses. In other animal19 and human20 studies, however, epinephrine administered endotracheally at doses of approximately 0.01 and 0.02 mg/kg, respectively, were shown to be unreliable in producing a physiologic response. In addition, studies using both normotensive and cardiac arrest canine models have shown that epinephrine doses of 0.01 mg/kg administered endotracheally produce serum levels approximately a 10th of that produced when the same dose is given intravenously.9,21,22 These studies recommend increasing the ET epinephrine dose to 0.1 mg/kg and are the basis for the 2010 AHA recommendation to use a 10-fold increased dose when administering ET epinephrine to pediatric patients.13 Some studies have shown that ET epinephrine at all doses causes a significant decrease in diastolic blood pressure immediately after instillation and that a dose of 0.3 mg/kg increases diastolic blood pressure after 1 minute. This may be due to β-adrenergic blockade at lower doses.23,24

ET drug delivery is associated with a depot effect, with ET drugs being “stored” and released slowly over time, similar to a continuous IV drip. This presumably occurs as a result of local vasoconstriction and lymphatic storage of the drug8 or pooling in lung tissue because of poor lung perfusion.25 With epinephrine use, the depot effect can produce postresuscitative dysrhythmias, hypertension, and tachycardia together with resultant increased myocardial oxygen demand. Given these conflicting data, it seems reasonable in adults to start with a dose 2.0 to 2.5 times the usual IV dose. If this is ineffective, higher doses may be used subsequently.

Volume for a Single Dose

For ET drugs, the AHA recommends a total volume of 10 mL in adults,12 5 mL in pediatric patients,13 and 1 mL in neonates.14 In studies involving dogs, Mace26 compared undiluted lidocaine with diluted lidocaine (volume ≈6.5 mL) and found significantly higher plasma lidocaine levels in the animals receiving diluted lidocaine. There were no changes in arterial blood gas values before or after ET drug administration. In another animal study, lidocaine diluted with normal saline to volumes of up to 25 mL produced no changes in arterial blood gases or the clinical condition and no change in the gross anatomy or histology of the lung.27 In contrast, a study comparing normal saline with distilled water revealed decreased arterial oxygen partial pressure (Pao2) with both solutions (water producing the greatest effect), but this study used large volumes (2 mL/kg) of solution.28

Studies of endotracheally administered lidocaine in human subjects reveal that dilution with distilled water to a total volume of 10 mL results in higher plasma lidocaine levels but also produces a decrease in Pao2 of approximately 40 mm Hg that persists for longer than 1 hour.29 A total volume of 5 mL yields lower plasma levels and a shorter period of hypoxemia. Data and volume recommendations in the setting of multiple doses of the drug are lacking.

It may be difficult or impossible to limit the total volume of the drug solution to 10 mL when using prefilled syringes. Prefilled syringes of epinephrine contain 1 mg in 10 mL (1 : 10,000). Giving 2.5 times the IV/IO dose requires the administration of 20 to 25 mL. It is possible to obtain epinephrine 1 : 1000 (1 mg/mL) and dilute it to a total volume of 5 to 10 mL, but the higher concentration of epinephrine may not be readily available during a cardiac arrest code. Likewise, prefilled syringes of atropine contain 1 mg in 10 mL (0.1 mg/mL). Prefilled syringes of lidocaine contain 20 mg/mL (100 mg/5 mL). A dose of 2 to 2.5 times the IV/IO dose could easily amount to 20 mL or more total volume in an obese patient.

Appropriate Diluent

Both normal saline and distilled water may be used as diluents for ET drug administration, but it remains unclear which is preferred. In one study, intubated dogs were administered epinephrine via ET tube, and peak serum epinephrine levels were 13 times higher when distilled water was used as a diluent instead of normal saline.30 In addition, mean arterial blood pressure increased significantly only in dogs that were administered epinephrine diluted with distilled water. Greenberg and coworkers,28 however, reported that normal saline administered via the ET route produced fewer detrimental effects on arterial blood gases than distilled water did. Another study found no changes in pulmonary status (arterial blood gas, oxygen saturation, gross anatomy, or histology) in dogs given lidocaine diluted with normal saline in total volumes ranging between 6 and 25 mL.27 Still another study found no difference in arterial blood gases after the delivery of either diluent solution.31 Hence, the optimal diluent is controversial; saline may produce less pulmonary dysfunction, but distilled water appears to deliver a greater amount of drug.

Technique for ET Drug Delivery

Techniques for ET drug administration include direct instillation into the proximal end of the ET tube, administration via a catheter that extends just beyond the distal tip of the ET tube, deep endobronchial administration using a longer catheter, administration via ET tube monitoring ports, administration with equipment developed specifically for ET atomized drugs, and injection through the side of the ET tube with a needle. Several studies have indicated that the use of a catheter or feeding tube may not be needed to enhance the drug’s effectiveness. Greenberg and Spivey32 instilled radiopaque contrast material directly into the proximal end of the ET tube and compared its distribution with that of contrast material instilled via a catheter extending out the distal end of the tube. Both techniques were equally effective in distributing the contrast agent to the peripheral lung fields as long as five rapid manual ventilations followed the instillation. In addition, using a porcine cardiopulmonary arrest model, Jasani and colleagues33 showed no difference in resuscitation rates or physiologic responses between epinephrine administered by direct injection into the ET tube, via a catheter extending out the distal end of the ET tube, or via a monitoring lumen built into the side wall of the ET tube. Rehan and associates34 demonstrated that there was no difference in the amount of drug delivered via catheter versus direct instillation in neonates. In studies of patients with normal perfusion, some support “deep bronchial” ET drug administration, whereas others do not.3537

Some studies have suggested that drug absorption with direct instillation into the ET tube is inconsistent during cardiopulmonary arrest.17,20 To address one specific question, one study found no difference in plasma epinephrine levels when epinephrine was instilled during apnea versus instillation during the ventilator inspiratory cycle.38

Given these conflicting studies, use of a catheter to enhance deep pulmonary delivery seems reasonable. However, if a catheter is not readily available, direct injection into the ET tube appears to be justified.

Effects of Hypoxia, Hypotension, and Cardiopulmonary Arrest

Despite concerns that medications might not be absorbed in states of hypoxia or low blood flow, the data available reveal the opposite to be true. In a hemorrhagic shock model, Mace39 demonstrated that higher plasma lidocaine levels were obtained via the ET route during shock than during nonshock states. In a lamb model, when epinephrine was administered endotracheally, higher plasma epinephrine levels were achieved during hypoxia-induced low pulmonary blood flow than during baseline, normal pulmonary blood flow.40 Finally, plasma lidocaine levels rose earlier when lidocaine was administered endotracheally to dogs that were hypoxemic than to dogs that were not.41

Significant questions remain regarding the efficacy of endotracheally administered medications.17,19,20,4244 The 2010 guidelines for neonatal resuscitation14 discourage the routine use of ET epinephrine. More importantly, these studies serve to emphasize that ET drug administration should not be used in lieu of attempts to obtain definitive access to the systemic circulation. ET drug administration should not be performed when more direct means of accessing the central circulation are available.


ET drug therapy is indicated when emergency pharmacologic intervention is needed and other access, either IV or IO, is not available. This most frequently occurs during cardiovascular collapse. Though intuitively and experimentally attractive, randomized, controlled trials of the efficacy of ET drug therapy are lacking.45 Niemann and colleagues, in a retrospective cohort study, examined the outcomes of 596 cardiac arrest patients who received IV or ET medications. There were no survivors to hospital discharge in the 101 patients who received ET medications versus a 5% survival rate in patients who received IV medications. However, more patients in the ET group were asystolic, a sign that these patients were already in much worse condition.45

Specific indications for the delivery of a drug endotracheally are the same as those for IV and IO administration. However, only a limited number of emergency drugs can be given safely by the ET route (Boxes 26-1 and 26-2). Medications that are appropriate for ET administration based on animal and human studies include epinephrine,8,10,47 atropine,4850 lidocaine,36,39,41,51 and naloxone.52,53 ET naloxone is not currently recommended in neonates.14

Diazepam has also been shown to be effective.54,55 However, in one animal model, diazepam produced pneumonitis when 0.5 mg/kg was administered via the ET route.46 Because diazepam is sparingly soluble in water, it is available only in a solution of propylene glycol, ethanol, and benzyl alcohol. It is unknown whether the reported pneumonitis was due to the direct effect of diazepam or the diluent. The AHA has removed diazepam from its list of medications that can be given safely via the ET route; other routes may be more appropriate for this drug.13,56,57

Experimental studies of vasopressin,58,59 midazolam,60 flumazenil,61 propranolol,48 and metaraminol62 in animal models suggest that these medications may also be effective when administered endotracheally, but no clinical studies in humans have been conducted to verify these findings. Efrati and coworkers’ study59 demonstrated that ET vasopressin had greater effects on diastolic blood pressure than did ET epinephrine with little effect on the heart rate, but no clinical trials have evaluated its efficacy. Based on a study by Wenzel and colleagues,58 the 2010 ACLS guidelines added vasopressin to the list of cardiac resuscitation drugs that can be administered via the ET route (in addition to lidocaine, epinephrine, atropine).12 It is interesting to note that in the study of midazolam, no pathologic changes were seen in lung sections after the administration of midazolam.60 In addition, midazolam is available commercially in aqueous solution and could therefore be diluted with normal saline or distilled water for ET administration. However, given that midazolam is approved for intramuscular use, it seems unlikely that ET administration would ever be necessary. Palmer and associates61 demonstrated that therapeutic blood levels of flumazenil were obtained within a minute after ET delivery of 1 mg of the drug diluted in 10 mL of saline. This is 10 times the recommended IV dose of 0.1- to 0.2-mg aliquots. The role of flumazenil by ET administration remains to be determined.


At present, the only true contraindication to the ET delivery of an appropriate drug is the presence of another form of access to the systemic circulation through which the needed drug can be delivered rapidly and effectively. A complete list of drugs that are contraindicated for ET delivery is not available, but specific medications that have been shown to be ineffective or unsafe when given via the ET route include sodium bicarbonate, amiodarone, isoproterenol, and bretylium. In dogs, sodium bicarbonate was shown to inactivate lung surfactant.63 Isoproterenol, even when given in doses 10 times the IV dose, failed to produce significant changes in arterial blood pressure or heart rate.49 Studies of bretylium also indicate low serum levels after ET administration, even when administered at doses of 20 mg/kg.64 Amiodarone induces pneumonitis and pulmonary fibrosis in animals and is therefore not recommended for ET administration.65


The patient must first be intubated endotracheally. It should be noted that in studies in which the recommended ET tube doses of medications were administered by Combitube (Kendall-Sheridan, Argyle, NY) or laryngeal mask airway (LMA North America, San Diego, CA), absorption of drugs was found to be subtherapeutic.66–68 A Combitube, when placed in the esophagus (requiring medications to travel out the side holes to reach the trachea), needs 10 times more epinephrine than that used with an ET tube to obtain the same serum concentration and hemodynamic effects.66 Presumably, a Combitube that enters the trachea directly would function equivalently to an ET tube, but no studies have been done to support this assumption.

The equipment listed here is that required to perform any of the four different techniques described. This equipment is suggested for the ideal situation; at no time should drug delivery be delayed while searching for the “perfect” piece of equipment.

1. Manual bag ventilation device capable of delivering a fraction of inspiratory oxygen (Fio2) of at least 50%. When ET drug delivery is indicated, the patient’s condition almost always warrants supplemental oxygen. Although the technique may not result in any significant deterioration in respiratory function, it is still advisable to administer additional oxygen after drug delivery. Use the bag ventilation device to also deliver several rapid insufflations immediately after drug delivery to assist in delivery of the drug distally, where it may be absorbed more rapidly and effectively.32 It should be noted, however, that the priorities of drug administration via the ET route must be balanced against the potential deleterious effects that such rapid insufflation might have on hemodynamics and cerebral perfusion. Excessive hyperventilation of victims of out-of-hospital cardiac arrest is common and associated with poor outcomes.69

2. A fine-bore catheter or special ET tube designed to deliver the drug at or beyond the distal end of the ET tube. For adults, select a catheter that is at least 8 Fr in size and 35 cm (14 inches) in length. It should be long enough to protrude past the distal end of the ET tube. The diameter of the catheter should be large enough to allow rapid delivery of 10 mL of solution. Several different types of tubes and catheters commonly available in the emergency department (ED) can be used for this purpose:

Alternatively, some ET tubes are made with built-in ports that allow the instillation of drugs without removing the bag ventilation device.

3. An IV adapter lock. This can be placed as needed onto the proximal end of the irrigation lumen of the Hi-Lo Jet Tracheal Tube or on the catheters described previously to convert them for use with prefilled syringes. This adapter is generally unnecessary if a standard syringe is used.

4. A 10- to 20-mL syringe, preferably a Luer-Lok type, large enough to deliver the desired volume of drug solution plus an additional 5 mL of air. Most of the medications now prescribed for emergency situations come in prefilled syringes. This type of apparatus does not usually allow one to draw up diluent or an additional volume of air to empty the syringe of solution. In addition, depending on the manufacturer and model, some prefilled syringes have either needles or a needleless system that may require an IV adapter lock to use them for ET injection.

5. Diluent solution. Keep an adequate volume of diluent available, such as normal saline or distilled water.

6. Medications to be instilled (see Box 26-1).

7. An 18- or 19-gauge needle to draw up the medication and inject it. Use an 18-gauge, 8.9-cm (3.5-inch) spinal needle for direct instillation of medications into the proximal end of the ET tube.

8. Alcohol wipes to clean the vials and injection ports.

9. Gloves, mask, and eye protection. After instillation, the solution often refluxes out of the ET tube, which makes blood and body fluid precautions critical.


The procedure of choice is one that will deliver the medication to the patient in the least amount of time. Secure the ET tube before instilling medications endotracheally to prevent the tube from being expelled if the patient coughs. Inflate the cuff of the tube, if present.

Direct Instillation into the ET Tube

While the patient is being ventilated, draw up the desired drug into a syringe (or use a prefilled syringe) (Fig. 26-1, step 1). Dilute the drug to a final volume of 10 mL (adults), 5 mL (children), or 1 mL (neonates) with normal saline or distilled water. Attach an 18- or 19-gauge needle. Some authors recommend using an 8.9-cm (3.5-inch) spinal needle. If using a prefilled syringe, draw up an appropriate volume of diluent in a second syringe so that the total instillation volume (drug plus diluent) equals 10 mL (adults), 5 mL (children), or 1 mL (neonates). Attach an 18- or 19-gauge needle, which will be used to flush the ET tube after instillation of the drug.

Interrupt the connection between the proximal end of the ET tube and the bag ventilation device. Insert the needle of the syringe into the proximal opening of the ET tube (see Fig. 26-1, step 2). Hold the proximal end of the needle with one hand to prevent loss of the needle into the tube. Inject the drug solution rapidly and forcefully. If using a prefilled syringe, flush the tube immediately with the diluent in a second syringe. If the patient makes an effort to cough, place a thumb over the opening of the ET tube to prevent expulsion of the solution. Reattach the bag ventilation device and deliver five rapid insufflations.