INTRODUCTION

During neonatal resuscitation, epinephrine is the most frequently used drug. It is administered either via an endotracheal tube (ETT) or intravenously.¹ Administration via the intravenous (i.v.) route is probably more effective, but is often delayed due to the time required to establish an i.v. access.^{1, 2, 3, 4, 5} Therefore, during neonatal resuscitation, administration via an ETT is generally the most rapidly accessible and practical route for epinephrine administration. However, the optimal delivery technique of epinephrine administration via an ETT is controversial.^{6, 7}

It has been argued that when administered directly into the ETT (D-ETT), a significant volume of the administered drug may collect in the connector or adhere to the ETT tube, and thus may not get delivered to the lungs.^{1, 8, 9} In order to ensure that the administered drug reaches the lungs, some healthcare providers prefer to inject the drug into a feeding catheter inserted into the ETT (C-ETT).^{1, 8, 9} Whether this method actually ensures more efficient delivery of the drug to the lungs compared to its administration via D-ETT, has not been convincingly demonstrated. Therefore, the purpose of this study was to compare the amount of epinephrine delivered by these two methods of administration, that is, D-ETT vs C-ETT during simulated resuscitation of infants in the birth weight range from 1 to 4 kg.

HYPOTHESIS

Based on the relatively smaller surface area of a standard feeding catheter (5F), compared to that of the ETTs (2.5 to 4.0 mm) (Table 1), we hypothesized that more epinephrine would be delivered when administered via C-ETT vs D-ETT.

Table 1 - Catheter and ETT Dimensions, Infant Weight, and Epinephrine Dose Used for Simulated Cardiorespiratory Resuscitation.

Full table

MATERIAL AND METHODS

Radiolabeled epinephrine (1-[7,8-³H] epinephrine) was obtained from Sigma, Inc., St. Louis, MO. Five-French polyvinyl chloride (PVC) feeding catheters (CR Bard Inc., Coulngton, GA), PVC ETTs (Hudson Respiratory Care Inc., Temecula, CA), and Self-Inflating Resuscitation Bags (Mercury Medical, Clearwater, FL) were used for the delivery of epinephrine during simulated cardiopulmonary resuscitation (CPR).

All experiments were conducted in vitro to simulate CPR conditions. Experiments were conducted to deliver epinephrine via the two methods (D-ETT and C-ETT), with the objectives to (1) measure the delivery of epinephrine to the distal end of the ETT; (2) compare the amounts of residual epinephrine in the ETT vs the feeding catheter when used for drug administration; (3) determine how much of the drug is retained in the ETT tube connector vs the body of the tube; and (4) compare the delivery of the drug with and without an air flush after administration via C-ETT.

Epinephrine Dosage

Epinephrine was diluted with normal saline to a final concentration of 1 Ci/ml. The epinephrine dose and size of the ETT used were chosen according to the Neonatal Resuscitation Program (American Academy of Pediatrics) guidelines for infants ranging in birth weights from 1 to 4 kg (Table 1) — 0.3 ml epinephrine and a 2.5 mm ETT for the simulated resuscitation of a 1 kg infant; 0.6 ml epinephrine and a 3.0 mm ETT for a 2 kg infant; 0.9 ml epinephrine and a 3.5 mm ETT for a 3 kg infant; and 1.2 ml epinephrine and a 4.0 mm ETT for a 4 kg infant.¹

Epinephrine Administration

C-ETT

A 5F PVC feeding catheter (length 38 cm) was inserted through an ETT, which was cut to 13 cm in length, with its tip extending just beyond the tip of the tube. Epinephrine was then administered via a 1 ml syringe for 0.3 and 0.6 ml doses and a 3 ml syringe for 0.9 and 1.2 ml doses. A 1 ml saline flush was then pushed through the catheter. In some experiments, 1 cm³ of air was used to flush the catheter after the saline flush.

D-ETT

The calculated epinephrine dose was administered using either a 1 ml (for 0.3 and 0.6 ml doses) or a 3 ml (for 0.9 and 1.2 ml doses) syringe into the connector of an ETT that had been cut to 13 cm in length. This was followed by one manual breath via a self-inflating bag attached to ETT.

Experiments were also designed to compare the efficiency of epinephrine delivery following a saline flush alone vs a saline flush followed by an air flush, when administering via C-ETT.

Assessment of Epinephrine Delivery and Residue on the ETT and Catheter Wall

After epinephrine administration via D-ETT or C-ETT, the fluid coming out at the distal end of the ETT was collected in liquid scintillation vials to measure radioactivity in order to determine the efficiency of drug delivery by each method. The residual radioactivity in either the ETT or catheter was also measured. The radioactivity remaining in the ETT was separated into that remaining within the ETT connector and that retained within the body of the tube. The amount of radioactive epinephrine per sample was determined by liquid scintillation spectrometry. Each experiment was replicated at least 4 times, and each experimental sample was run in triplicate.

STATISTICAL ANALYSIS

Data were analyzed using ANOVA and a p-value of <0.05 was considered statistically significant.

RESULTS

All data are presented as meanSEM. Figure 1 shows the efficiency of epinephrine delivery after it was administered via D-ETT vs C-ETT methods using only saline flush. There was significantly more drug delivery via D-ETT vs C-ETT (p<0.05) administration for higher volumes (0.9 and 1.2 ml) of epinephrine administration. For these volumes, administration via D-ETT resulted in approximately 20% more drug delivery compared to administration via C-ETT without an air flush following the saline flush. However, when an air flush was used following a saline flush, there were no significant differences (p>0.05) in the epinephrine delivery between the two methods for all volumes of epinephrine administered (Figure 2). There was significantly (p<0.05) more retention in the catheter with higher volumes of epinephrine administration (0.9 and 1.2 ml vs 0.3 and 0.6 ml) during the C-ETT method when only a saline flush was used (Figure 3). However, an air-flush following the saline flush significantly (p<0.05) decreased drug retention in the catheter. Overall, there was no difference (p>0.05) in epinephrine retention as a % of the administered dose between D-ETT and C-ETT methods when both saline and air flushes were used during the C-ETT method (Figure 4). When we separated the drug retained in the ETT connector and the body during D-ETT method from the drug retained in the ETT, more than 50% was retained in the connector (Figure 5).

Figure 1.

The amount of epinephrine delivered when given directly into the endotracheal tube (D-ETT) vs via a feeding catheter inserted into the ETT (C-ETT), using only a saline flush is shown. Epinephrine delivery was significantly (^*p<0.05) greater via D-ETT vs C-ETT for higher volumes (0.9 and 1.2 ml) of epinephrine administered but not for lower volumes (0.3 and 0.6 ml). MeanSEM, n=4.

Full figure and legend (13K)

Figure 2.

The amount of epinephrine delivered when given directly into the endotracheal tube (D-ETT) vs via a feeding catheter inserted into ETT (C-ETT), using an air flush following the saline administration is shown. There were no differences (p>0.05) in epinephrine delivery for all volumes administered by the two methods. MeanSEM, n=4.

Full figure and legend (12K)

Figure 3.

The percentage of epinephrine retained in the catheter with and without an air flush following the saline flush with the feeding catheter inserted into the ETT method is shown. There was significantly (#p<0.05) greater retention in the catheter with higher volumes of epinephrine administration (0.9 and 1.2 ml vs 0.3 and 0.6 ml) when only the saline flush was used. This was significantly reduced (^*p<0.05) with an air flush following the saline flush. MeanSEM, n=4.

Full figure and legend (15K)

Figure 4.

The percentage of epinephrine retained in either ETT (D-ETT) or in the feeding catheter when an air flush following saline flush was used for the feeding catheter method is shown. There was no difference (p>0.05) in epinephrine retention between the two methods. MeanSEM, n=4.

Full figure and legend (11K)

Figure 5.

Relative amounts of epinephrine retained in ETT body vs connector when epinephrine is directly administered in ETT (D-ETT) are shown. Of the drug retained in the ETT, >50% was retained in the connector. MeanSEM, n=4.

Full figure and legend (19K)

DISCUSSION

Epinephrine is the most commonly used drug during neonatal resuscitation.^{1, 10} Although it is most often administered via the ETT route, the optimal technique of its administration through ETT is not clear. Based on differences in the surface areas of the standard ETTs and the 5F feeding catheter (Table 1), it has been recommended that in order to ensure more efficient drug delivery, it should be administered through a feeding catheter inserted into the ETT.^{1, 8, 9} Whether this method actually ensures more efficient drug delivery to the lungs via D-ETT has not been convincingly demonstrated. In fact, our data provide evidence that, for epinephrine doses recommended for 3 and 4 kg infants, significantly more (20%, p<0.05) drug is delivered when it is administered via D-ETT vs C-ETT method. The clinical implications of this finding are not clear, and it must be emphasized that this difference is observed only with relatively large doses of epinephrine used for the resuscitation of 3 and 4 kg infants. Further, with an air flush following the saline flush, there are no differences (p>0.05) in the efficiency of drug delivery between the two methods. The amount of drug residue in the ETT or the feeding catheter is <7.5% of the total administered dose if both a saline and an air flush are used with the C-ETT method. Of the drug residue in the ETT, >50% is retained in the connector of the ETT.

We hypothesized that a higher dosage of the drug will be delivered via C-ETT vs D-ETT method. However, our data did not support this hypothesis. Although the surface area (9.6 cm²) of the standard 5F feeding catheter (length 38 cm and internal diameter 0.075 cm) is smaller than the surface areas (10.21 to 16.33 cm²) of ETTs (2.5 to 4.0 mm internal diameters cut to 13 cm in length), the actual retention of the drug with both methods was similar, which was only a small fraction of the administered dose (<7.5%). The observed differences between the two methods were unlikely to be due to differences in the surface adsorption properties of ETTs and feeding catheter as both are made of the same material, PVC. Since the use of an air flush following the saline flush during C-ETT method eliminated excess drug retention with this method, it suggests that differences in aero/hydrodynamics of drug administration between the two methods are the most likely explanation for the observed data. It is possible that reduced epinephrine delivery via C-ETT method without an air flush is due to the drug retained in the tip of the feeding catheter because of the presence of side holes rather than an end hole in a standard feeding catheter. It is likely that the use of a catheter with an end hole, unlike side holes of a standard feeding catheter, may result in improved drug delivery. Although an air flush following the saline flush during C-ETT method improved drug delivery, this step has not been recommended,¹ and in actual practice probably not commonly practiced. Other techniques to improve epinephrine delivery via C-ETT method, for example, flushing the catheter with epinephrine prior to its actual administration, cutting the catheter to correspond to ETT length, and the use of multiple air flushes following epinephrine administration deserve consideration and may maximize drug delivery by this method. However, it has recently been shown that administration of epinephrine via C-ETT takes significantly more time and interrupts ventilation and chest compressions longer when compared to the administration of the drug directly into the ETT.⁶ Now our data suggest that to achieve drug delivery comparable to D-ETT method not only a saline but also an air flush needs to be given following its administration via C-ETT, making it even more cumbersome.

Although several investigators have described epinephrine absorption following endotracheal administration, most of the experimental data are based upon nonasphyxiated animal models with unaltered pulmonary blood flow and absent right to left shunting, a scenario that commonly occurs in asphyxiated newborns.^{11, 12} It has been repeatedly suggested that the actual epinephrine absorption following ETT administration during resuscitation, when cardiac output is compromised, may be very different than when it is studied during noncompromised situations.^{13, 14} In contrast, Lucas et al.¹⁵ have shown that transpulmonary absorption of epinephrine is not seriously affected even during the low pulmonary blood flow state associated with CPR in neonates. Our study was only designed to measure delivery of the administered drug and not its subsequent pharmacokinetics. However, our findings should be applicable equally to both the reduced and normal pulmonary blood flow situations.

CONCLUSION

Given that with the C-ETT method of epinephrine administration there is no improvement in drug delivery over the D-ETT method, we argue that there is no reason to continue using the C-ETT administration of epinephrine during neonatal resuscitation. Epinephrine administration directly into the body of ETT, thus by-passing the ETT connector should be the method of choice for its administration. Our results have potential implications for the guidelines for neonatal resuscitation.

References

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