Background - Methods - Results - References
A new search for studies was performed on 30/09/2001 and no new studies were found to include in this review.
Following mechanical ventilation, airway swelling and obstruction can occur in newborn infants (especially after prolonged, traumatic or multiple intubations). This may compromise breathing and cause failure of extubation. Because epinephrine can decrease swelling and its effect has been proven in the treatment of croup in infants, it has been used immediately after extubation to prevent breathing problems. The reviewers did not identify any studies that examined clinically relevant outcomes following the use of nebulized epinephrine in newborn infants. They concluded that there is no evidence either supporting or refuting the use of inhaled nebulized epinephrine in newborn infants.
Implications for research: randomised controlled trials are needed comparing inhaled nebulized racemic epinephrine with placebo in neonates post-extubation. This should be looked at both as a routine treatment post-extubation and as specific treatment for post-extubation upper airway obstruction. Study populations should include the group of infants at highest risk for upper airway obstruction from mucosal swelling because of their small glottic and sub-glottic diameters (ie those infants with birthweights less than 1000 grams).
The sub-glottis is the narrowest portion of the upper airway in infants (O'Connor 1995, Willging 1995). In neonates the upper airways contribute more to total airway resistance than peripheral airways (Wohl 1990). Whilst the specific contribution of the glottis and sub-glottis to total airway resistance is largely unknown, it is thought to be substantial (Wohl 1990). The most important determinant of resistance in airways (particularly in the small calibre upper airways in neonates) is the radius of the airway lumen (O'Brodovich 1990). Even mild oedema in these narrowest portions of the upper respiratory tract will reduce the intra-lumenal cross-sectional area by more than 50% (O'Connor 1995) and result in a significant increase in airway resistance (O'Brodovich 1990). Increased airway resistance after the infant is extubated may lead to respiratory insufficiency and failure of extubation.
Four prospective series have looked at post-extubation stridor in neonates. Laing 1986 found an incidence of post-extubation stridor in neonates of 14%. The study population included all ventilated neonates in a neonatal intensive care nursery from 1978 to the mid 1980's, intubated with Cole type, 'shouldered' ETTs. The incidence of stridor post-extubation leading to reintubation was 2% - none of the infants in this series had permanent sub-glottic stenosis. Albert (Albert 1990) studied 30 consecutive infants who had been ventilated for >24 hours, intubated with Cole type ETTs, and found an incidence of stridor post-extubation of 30%. Fan (Fan 1982) described an incidence of stridor post-extubation of 16% in 73 consecutive neonates who required intubation. These infants were intubated with McGill ETTs (i.e. with a constant external diameter). The most recent study (da Silva 1999) of ETT complications in very low birthweight infants gives an incidence of post-extubation stridor of 4.8% (11/227). Infants in this study had all been intubated with ETTs with a constant external diameter. It is also noted that some of the 227 infants had been pretreated with systemic corticosteroids.
Epinephrine stimulates both alpha and beta adrenergic receptors and is a potent inotrope and chronotrope. It acts on vascular smooth muscle to produce vasoconstriction which markedly decreases blood flow to capillary beds, especially in the skin and mucosal surfaces. The decrease in blood flow to the surfaces of the upper respiratory tract shrinks the mucosa and reduces oedema (Hoffman 1996, Remington 1986).
When epinephrine is nebulized and inhaled the actions of the drug are largely restricted to the respiratory tract, however, systemic reactions can occur (Hoffman 1996). Side effects of epinephrine include tachycardia, arrhythmias, hypertension, peripheral vasoconstriction, hyperglycaemia, hyperkalaemia, metabolic acidosis and leucocytosis with left shift (Hoffman 1996, Solomon 1984).
Inhaled nebulized epinephrine is widely used in the treatment of infective croup in children (Couriel 1988, Skolnik 1989) and its efficacy has been well demonstrated in randomised control trials (Kuusela 1988, Kristjánsson 1994, Fanconi 1990, Corkey 1981). There is also anecdotal evidence that nebulized epinephrine can alleviate obstruction caused by laryngeal or tracheal oedema from other causes in infants (Gwinnutt 1987) and children (ASC of NYSSA 1972, Jordan 1970).
Because of the problem of post-extubation upper airway obstruction and the vasoconstrictive properties of epinephrine, inhaled nebulized epinephrine administered immediately post-extubation is used routinely in some neonatal units (Bancalari 1992). Its effects have been studied in neonates in small, uncontrolled studies (Koren 1986, Marshall 1984). It is recommended for neonates with post-extubation tracheal obstruction and stridor in neonatal and respiratory textbooks (Phelan 1994, Greenough 1996, Corbet 1990) and reviews (Pransky 1989).
This review aimed to examine the evidence for the use of inhaled nebulized epinephrine in the prophylaxis and treatment of post-extubation upper airway obstruction in neonates.
This review updates the existing review of "nebulized racemic epinephrine for extubation of newborn infants" which was published in the Cochrane Library, Issue 1, 2001 (Davies 2001).
Secondary objectives included:
1. To asses whether nebulized epinephrine administered immediately
after extubation decreases other post-extubation morbidity. Morbidity was
considered in terms of increasing oxygen requirement or respiratory distress,
or stridor.
2. To assess whether nebulized epinephrine is associated with significant
side effects.
Subgroup analyses were planned to determine whether the results differ for: i. preterm neonates, ii. infants at high risk for developing post-extubation airway oedema. Infants at high risk include those intubated for 7 days or more, those who had 3 or more intubations, and those who had a traumatic intubation or attempted intubation.
Courtney et al (1987) compared nebulized racemic epinephrine with warm humidified gases in infants immediately after extubation. The primary study outcome was ventilatory function in the first hour post-extubation. The method of randomisation was not stated. 45 infants were randomised. Neither the investigators nor attending medical and nursing staff were blinded to the treatment.
Outcomes measured in this study were ventilatory function (pulmonary mechanics) measured up to one hour post-extubation, continuous respiratory and heart rate monitoring and continuous Holter monitoring of heart rate for arrhythmias (duration not stated).
There was a statistically significant - and clinically significant - difference in mean ±SD weight at extubation between the treatment and control groups (treatment 1.43 kg ± 0.36 versus control 1.81 ± 0.69).
The authors found that, whilst there was a statistically significant difference in airway resistance between the groups in males, this difference was not of any physiological significance as all measurements were still within normal range for a preterm population. This difference was not shown in the females. The authors felt that there was no consistent pattern of overall treatment effect and concluded that racemic epinephrine is not indicated as a routine in the infant post-extubation.
Whilst an attempt was made to monitor for arrhythmias with Holter monitoring, this was only possible in 16 out of 44 infants. Six infants experienced abnormalities of brief duration (2 treatment and 4 control) and no conclusions could be drawn regarding the impact of epinephrine on this side effect.
One infant who had been randomised to the control group experienced respiratory distress and stridor immediately post-extubation. The infant was withdrawn from the study, racemic epinephrine was given and no further respiratory support was required. The authors state in their discussion that no other infants developed symptoms post-extubation within 24 hours of extubation. It is unclear whether or not these symptoms were being looked for prospectively and, if so, how monitoring was performed.
This study was excluded because it did not address clinically important outcomes: the need for additional respiratory support up to a week post-extubation, an increase in oxygen requirement, or the development of stridor or respiratory distress post-extubation. In addition there was no systematic evaluation of infants for possible adverse effects of racemic epinephrine. We wrote to the first author (SEC) to see if there were any unpublished data relevant to clinically important outcome measures (as stated in our selection criteria - 'types of outcome measures'). Unfortunately there were no additional data available.
Echevarria-Ybarguengoitia et al (1986) aimed to evaluate the effect of nebulized racemic epinephrine on the incidence of post-extubation atelectasis in infants weaned from ventilation and extubated. Because this study randomised infants to nebulized epinephrine at the time of extubation, we considered it for inclusion in our review despite the fact that its aim was specifically to study other outcomes.
43 infants (32 preterm, 11 term) were randomised to a treatment group or a control group. The treatment group received nebulized racemic epinephrine twice pre-extubation and six times post-extubation at intervals of four hours. There was no placebo used in the control group. All patients were "monitored electronically for vital signs, looking for tachycardia".
Only two of the reported outcomes were relevant to our review. Tachycardia was looked for in all patients and in the results section the authors state that "none of the 20 neonates in the treatment group presented with any clinical signs of intoxication due to racemic epinephrine".
Figures are also quoted for the number of patients re-intubated due to post-extubation atelectasis: 6/23 in the control group and 5/20 in the treatment group. It is specifically stated in both the text and the tables that the infants were re-intubated due to post-extubation atelectasis. It is not clear whether there were any other infants who were re-intubated (or required any other form of respiratory support) for other reasons.
Because the exact number of infants needing to be re-intubated is unknown and no other relevant outcomes were given we have excluded this study from our review. We have written to the authors to see if there were any unpublished data relevant to clinically important outcome measures, but we have not received a reply.
Both the above studies failed to meet our inclusion criteria mainly because no clinically important outcome measures were looked for or completely reported. No unpublished data is available from either study. Therefore, neither study can help the clinician decide whether using inhaled nebulized racemic epinephrine, as routine treatment for infants being extubated, is an efficacious treatment in preventing morbidity post-extubation.
Whilst inhaled nebulized racemic epinephrine has a theoretical basis for decreasing any laryngeal and sub-glottic swelling present post-extubation, this does not translate to proven efficacy in neonatal intensive care. Two important questions remain unanswered. Firstly, does the routine use of inhaled nebulized racemic epinephrine post-extubation prevent failure of extubation? Secondly, does inhaled nebulized racemic epinephrine successfully treat post-extubation upper airway obstruction? In addition, if the answer to these questions is yes, then do the benefits outweigh any risks of administration?
Failure of extubation may result from a number of factors including alveolar atelectasis, decreased respiratory drive associated with prematurity, or inadequate pulmonary mechanics associated with a compliant chest wall. A further factor is the increased airway resistance associated with laryngeal and sub-glottic oedema. The increased airway resistance alone may be enough to cause failure of extubation (this may be obvious in an infant with post-extubation respiratory distress and stridor) or may act in addition to other factors. The use of inhaled nebulized racemic epinephrine in the infant without any overt symptoms of upper airway obstruction may therefore decrease airway resistance sufficiently to allow successful extubation. This may be particularly important in the in VLBW infant where a very small decrease in internal diameter of the upper airway can result in large increases in resistance.
The use of inhaled nebulized racemic epinephrine is of proven efficacy in infective croup in older children. However, it remains unstudied in neonates with upper airway obstruction post-extubation.
Given the theoretical basis for using inhaled nebulized racemic epinephrine as routine treatment in neonates post-extubation and the fact that it is currently used routinely in some neonatal units, the next step should be a randomised controlled trial comparing inhaled nebulized racemic epinephrine with placebo. This should be looked at both as a routine treatment post-extubation and as specific treatment for post-extubation upper airway obstruction. Study populations should include the group of infants at highest risk for upper airway obstruction from mucosal swelling because of their small glottic and sub-glottic diameters (ie those infants with birthweights less than 1000 grams).
Dr Paz Lazoiga, Paediatric Registrar, Logan Hospital, Loganholme, Queensland, Australia for her translation of a Spanish language journal article.
Dr Jose Diaz Rossello, Latin American Centre for Perinatology and Human Development, Montevideo, Uruguay, for his assistance with translating a Spanish language journal article.
| Study | Reason for exclusion |
| Courtney 1987 | No clinically important outcomes (the need for additional respiratory support, an increase in oxygen requirement/respiratory distress, the occurence of stridor or side effects of epinephrine post-extubation) are given. |
| Echevarria-Ybar 1986 | Reporting of clinically relevant outcomes is incomplete. |
| Koren 1986 | Not a RCT. |
| Marshall 1984 | Not a RCT. |
Courtney SE, Wachtl JP, Hopson JF, Siervogel RM. Effect of racemic epinephrine on ventilatory function in the neonate postextubation. Pediatr Res 1987;21:381-385.
Echevarria-Ybar 1986 {published data only}
Echevarria-Ybarguengoitia JL, Olivarez-Embriz GR, Jasso-Gutierrez L. Does racemic epinephrine prevent post-extubation atelectasis? [Spanish]. Boletin Medico del Hospital Infantil de Mexico 1986;43:750-754.
Koren 1986 {published data only}
Koren G, Butt W, Whyte H. Racemic epinephrine in very low birth weight infants with post-intubation upper airway obstruction: a controlled prospective study. J Perinatol 1986;6:24-26.
Marshall 1984 {published data only}
Marshall TA, Pai S. The effects of racemic epinephrine aerosol therapy after prolonged intubation in preterm infants. Respir Care 1984;29:138-143.
* indicates the primary reference for the study
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