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Nebulized racemic epinephrine for extubation of newborn infants

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Authors

Mark W Davies1, Peter G Davis2

Background - Methods - Results - Characteristics of Included Studies - References - Data Tables & Graphs


1Grantley Stable Neonatal Unit, Royal Brisbane and Women's Hospital, Department of Paediatrics & Child Health, The University of Queensland, Brisbane, Australia [top]
2Department of Newborn Research, The Royal Women's Hospital, Parkville, Australia [top]

Citation example: Davies MW, Davis PG. Nebulized racemic epinephrine for extubation of newborn infants. Cochrane Database of Systematic Reviews 2002, Issue 1. Art. No.: CD000506. DOI: 10.1002/14651858.CD000506.

Contact person

Mark W Davies

Grantley Stable Neonatal Unit, Royal Brisbane and Women's Hospital
Department of Paediatrics & Child Health, The University of Queensland
Butterfield St
Herston
Brisbane
Queensland
4029
Australia

E-mail: Mark_Davies@health.qld.gov.au

Dates

Assessed as Up-to-date: 15 March 2010
Date of Search: 17 December 2009
Next Stage Expected: 15 March 2012
Protocol First Published: Issue 4, 1997
Review First Published: Issue 3, 1998
Last Citation Issue: Issue 1, 2002

What's new

Date / Event Description
15 March 2010
Updated

This updates the review "Nebulized racemic epinephrine for extubation of newborn infants" published in the Cochrane Database of Systematic Reviews (Davies 2001).

Updated search in 2009 found no new trials.

No changes to conclusions.

History

Date / Event Description
24 March 2008
Amended

Converted to new review format.

30 September 2001
New citation: conclusions changed

Substantive amendment

Abstract

Background

Following a period of mechanical ventilation, post-extubation upper airway obstruction can occur in newborn infants, especially after prolonged, traumatic or multiple intubations. The subsequent increase in upper airway resistance may lead to respiratory insufficiency and failure of extubation. The vasoconstrictive properties of epinephrine, and its proven efficacy in the treatment of croup in infants, has led to the routine use of inhaled nebulized epinephrine immediately post-extubation in some neonatal units. It is also recommended for neonates with post-extubation tracheal obstruction and stridor in neonatal and respiratory textbooks and reviews.

Objectives

The primary objective was to assess whether nebulized epinephrine administered immediately after extubation in neonates weaned from IPPV decreases the need for subsequent additional respiratory support.

Search methods

Searches were of: MEDLINE from 1966 to September 2000; CINAHL from 1982 to September 2000; Current Contents from 1994 to September 2000; and the Cochrane Controlled Trials Register (Cochrane Library Issue 3, 2000). These searches were updated to September 2001 for this review update. Previous searches up to March 1999 included the Oxford Database of Perinatal Trials, expert informants and journal hand searching mainly in the English language, previous reviews including cross references, abstracts, and conference and symposia proceedings.
This search was updated in December 2009.

Selection criteria

All randomised and quasi-randomised control trials in which nebulized epinephrine was compared with placebo immediately post-extubation in newborn infants who have been weaned from IPPV and extubated, with regard to clinically important outcomes (i.e. need for additional respiratory support, increase in oxygen requirement, respiratory distress, stridor or the occurrence of side effects).

Data collection and analysis

No studies met our criteria for inclusion in this review.

Results

No studies were identified which looked at the effect of inhaled nebulized epinephrine on clinically important outcomes in infants being extubated.

Authors' conclusions

Implications for practice: There is no evidence either supporting or refuting the use of inhaled nebulized racemic 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 subglottic diameters (i.e. those infants with birth weights less than 1000 grams).

Plain language summary

Nebulized racemic epinephrine for extubation of newborn infants

The use of inhaled nebulized epinephrine after extubation in newborn infants is not supported or refuted by evidence from randomised controlled trials. 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.

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Background

Description of the condition

Assisted ventilation via an endotracheal tube (ETT) is a common therapy in neonates with respiratory insufficiency in the first few weeks of life. The presence of a foreign body in contact with mucosal surfaces of the larynx and sub-glottis may damage those upper airway surfaces (Phelan 1994). The delicate mucosal lining of the infant airway readily becomes edematous in response to irritation (O'Connor 1995). Prolonged intubation, traumatic intubations and multiple intubations have been associated with a greater risk of developing post-extubation upper respiratory tract inflammation (Fan 1983; Joshi 1972; da Silva 1999) and obstruction (Koka 1977). Direct visualisation using both flexible and rigid endoscopy has demonstrated laryngeal and sub-glottic swelling and erythema in neonates post-extubation (Fan 1982).

The subglottis 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-luminal 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 subglottic 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.

Description of the intervention

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).

How the intervention might work

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).

Why it is important to do this review

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.

Objectives

Primary Objective:

To assess whether nebulized epinephrine administered immediately after extubation in neonates weaned from IPPV decreases the incidence of the need for subsequent additional respiratory support.

Secondary objectives:

  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:

  1. preterm neonates;
  2. infants at high risk for developing post-extubation airway oedema.
  3. Infants at high risk include those intubated for seven days or more, those who had three or more intubations, and those who had a traumatic intubation or attempted intubation.

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Methods

Criteria for considering studies for this review

Types of studies

All randomised and quasi-randomised controlled trials in which nebulized epinephrine was compared with placebo immediately post-extubation.

Types of participants

Newborn infants who have been weaned from IPPV and extubated.

Types of interventions

nebulized epinephrine administered immediately post-extubation.

Types of outcome measures

  1. The need for additional respiratory support (i.e. tracheal intubation and ventilation or the commencement of NCPAP) by 24 hours and 7 days.
  2. An increase in oxygen (O2) requirement post-extubation.
  3. An increase in respiratory distress.
  4. The occurrence of stridor post-extubation.
  5. The occurrence of side effects, e.g. tachycardia, arrhythmias, hypertension, peripheral vasoconstriction, hyperglycaemia, hyperkalaemia, metabolic acidosis and leucocytosis with left shift.

Search methods for identification of studies

Searches were made using MeSH search terms 'epinephrine' and 'exp infant, newborn'. Databases searched included: MEDLINE and PREMEDLINE from 1966 to September 2001; CINAHL from 1982 to September 2001; and the Cochrane Controlled Trials Register, The Cochrane Library 2001 Issue 3. Previous searches up to March 1999 included the Oxford Database of Perinatal Trials, expert informants and journal hand searching mainly in the English language, previous reviews including cross references, abstracts, and conference and symposia proceedings.

In December 2009, we updated the search as follows: MEDLINE (search via PubMed), CINAHL, EMBASE and CENTRAL (The Cochrane Library) were searched from 2001 to December 2009. Search term: epinephrine. Limits: human, newborn infant and clinical trial. No language restrictions were applied.

Data collection and analysis

Criteria and methods used to assess the methodological quality of the trials: standard method of the Cochrane Collaboration and its Neonatal Review Group were used.

Selection of studies

All randomised and quasi-randomized controlled trials fulfilling the selection criteria described in the previous section were included. Both investigators reviewed the results of the search and separately selected the studies for inclusion.

Data extraction and management

If studies were identified for inclusion, we planned to independently extract the data. If needed, we planned on contacting study investigators for additional information or data.

Assessment of risk of bias in included studies

We planned to assess the methodological quality of the trials using the standard method of the Cochrane Collaboration and its Neonatal Review Group.

The two review authors worked independently to search for and assess trials for inclusion and methodological quality. If studies were identified for inclusion, we planned to assess the following key criteria: allocation concealment (blinding of randomisation), blinding of intervention, completeness of follow-up, and blinding of outcome measurement/assessment. For each criterion, assessment was yes, no, can't tell. Two review authors separately assessed each study. We planned to enter this information in the Characteristics of Included Studies Table.

If studies were identified at the time of the update (December 2009), we planned to evaluate the following issues and enter the data in the Risk of Bias Table:

  1. Sequence generation (checking for possible selection bias). Was the allocation sequence adequately generated?
    For each included study, we planned to categorize the method used to generate the allocation sequence as:
    • adequate (any truly random process e.g. random number table; computer random number generator);
    • inadequate (any non random process e.g. odd or even date of birth; hospital or clinic record number);
    • unclear.
  2. Allocation concealment (checking for possible selection bias). Was allocation adequately concealed?
    For each included study, we planned to categorize the method used to conceal the allocation sequence as:
    • adequate (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);
    • inadequate (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth);
    • unclear.
  3. Blinding (checking for possible performance bias). Was knowledge of the allocated intervention adequately prevented during the study? At study entry? At the time of outcome assessment?
    For each included study, we planned to categorize the methods used to blind study participants and personnel from knowledge of which intervention a participant received. Blinding was assessed separately for different outcomes or classes of outcomes. We planned to categorize the methods as:
    • adequate, inadequate or unclear for participants;
    • adequate, inadequate or unclear for personnel;
    • adequate, inadequate or unclear for outcome assessors.
    In some situations there may be partial blinding e.g. where outcomes are self-reported by unblinded participants but they are recorded by blinded personnel without knowledge of group assignment. If needed, we planned to add “partial” to the list of options for assessing quality of blinding.
  4. Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations). Were incomplete outcome data adequately addressed?
    For each included study and for each outcome, we planned to describe the completeness of data including attrition and exclusions from the analysis. We planned to note whether attrition and exclusions were reported, the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes.Where sufficient information was reported or supplied by the trial authors, we planned to re-include missing data in the analyses. We planned to categorize the methods as:
    • adequate (< 20% missing data);
    • inadequate (greater than/or equal to 20% missing data):
    • unclear.
  5. Selective reporting bias. Are reports of the study free of suggestion of selective outcome reporting?
    For each included study, we planned to describe how we investigated the possibility of selective outcome reporting bias and what we found. We assessed the methods as:
    • adequate (where it is clear that all of the study’s pre-specified outcomes and all expected outcomes of interest to the review have been reported);
    • inadequate (where not all the study’s pre-specified outcomes have been reported; one or more reported primary outcomes were not pre-specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);
    • unclear.
  6. Other sources of bias. Was the study apparently free of other problems that could put it at a high risk of bias?
    For each included study, we planned to describe any important concerns we had about other possible sources of bias (for example, whether there was a potential source of bias related to the specific study design or whether the trial was stopped early due to some data-dependent process). We planned to assess whether each study was free of other problems that could put it at risk of bias as:
    • yes;no;or unclear.

If needed, we planned to explore the impact of the level of bias through undertaking sensitivity analyses.

Measures of treatment effect

We planned to perform statistical analyses using Review Manager software. For individual trials, we planned to report mean differences (and 95% confidence intervals) for continuous variables such as duration of oxygen therapy. For categorical outcomes such as mortality, we planned to report the relative risk and risk difference (and 95% confidence intervals).

Assessment of heterogeneity

We planned to evaluate the heterogeneity between trials by inspecting the forest plots and quantifying the impact of heterogeneity using the I2statistic.

Data synthesis

If multiple trials were identified, we planned to perform meta-analysis using Review Manager software (RevMan 5) supplied by the Cochrane Collaboration. For estimates of typical relative risk and risk difference, we planned to use the Mantel-Haenszel method. For measured quantities, we planned to use the inverse variance method. All meta-analyses were planned to be done using the fixed effect model.

Subgroup analysis and investigation of heterogeneity

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 seven days or more, those who had three or more intubations, and those who had a traumatic intubation or attempted intubation.

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Results

Description of studies

No studies met our criteria for inclusion in this review.

Risk of bias in included studies

No studies met our criteria for inclusion in this review.

Effects of interventions

No randomised or quasi-randomised controlled trials have looked at the effect of inhaled nebulized epinephrine on clinical outcomes in newborn infants being extubated.

Discussion

As of September 2001 this review has found only two randomised controlled trials (Courtney 1987; Echevarria-Ybar 1986) in which inhaled nebulized racemic epinephrine was used immediately post-extubation in neonates.

Courtney et al (Courtney 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 (Echevarria-Ybar 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.

While 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 (i.e. those infants with birth weights less than 1000 grams).

Authors' conclusions

Implications for practice

There is no evidence either supporting or refuting the use of inhaled nebulized racemic 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 birth weights less than 1000 grams).

Acknowledgements

Professor David Henderson-Smart, NSW Centre for Perinatal Health Services Research, Sydney, Australia for his review of the protocol prior to submission.

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.

The Cochrane Neonatal Review Group has been funded in part with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN267200603418C.

Contributions of authors

Mark Davies (MD) and Peter Davis (PD) wrote the original review and updated the review in 1998.

The March 2010 update was conducted centrally by the Cochrane Neonatal Review Group staff (Yolanda Montagne, Diane Haughton, and Roger Soll). This update was reviewed and approved by MWD.

Additional tables

  • None noted.

Potential conflict of interest

  • None noted.

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Characteristics of studies

Characteristics of Included Studies

Characteristics of excluded studies

Courtney 1987

Reason for exclusion

No clinically important outcomes (the need for additional respiratory support, an increase in oxygen requirement/respiratory distress, the occurrence of stridor or side effects of epinephrine post-extubation) are given.

Echevarria-Ybar 1986

Reason for exclusion

Reporting of clinically relevant outcomes is incomplete.

Koren 1986

Reason for exclusion

Not a RCT.

Marshall 1984

Reason for exclusion

Not a RCT.

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References to studies

Included studies

  • None noted.

Excluded studies

Courtney 1987

Courtney SE, Wachtl JP, Hopson JF, Siervogel RM. Effect of racemic epinephrine on ventilatory function in the neonate postextubation. Pediatric Research 1987;21:381-5.

Echevarria-Ybar 1986

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;43:750-4.

Koren 1986

Koren G, Butt W, Whyte H. Racemic epinephrine in very low birth weight infants with post-intubation upper airway obstruction: a controlled prospective study. Journal of Perinatology 1986;6:24-6.

Marshall 1984

Marshall TA, Pai S. The effects of racemic epinephrine aerosol therapy after prolonged intubation in preterm infants. Respiratory Care 1984;29:138-43.

Studies awaiting classification

  • None noted.

Ongoing studies

  • None noted.

Other references

Additional references

Albert 1990

Albert DM, Mills RP, Fysh J, Gamsu H, Thomas JN. Endoscopic examination of the neonatal larynx at extubation: a prospective study of variables associated with laryngeal damage. International Journal of Pediatric Otorhinolaryngology 1990;20:203-12.

ASC of NYSSA 1972

Anesthesia Study Committee of the New York State Society of Anesthesiologists. Racemic epinephrine in postintubation laryngeal edema. New York State Journal of Medicine 1972;72:583-4.

Bancalari 1992

Bancalari E, Sinclair JC. Mechanical ventilation. In: Sinclair JC, Bracken MB, editor(s). Effective Care of the Newborn Infant. Oxford: Oxford University Press, 1992:200-20.

Corbet 1990

Corbet A. Respiratory disorders in the newborn. In: Kendig EL, Chernick V, editor(s). Disorders of the respiratory tract in children. 5th edition. Philadelphia: WB Saunders, 1990:268-99.

Corkey 1981

Corkey CW, Barker GA, Edmonds JF, Mok PM, Newth CJ. Radiographic tracheal diameter measurements in acute infectious croup: an objective scoring system. Critical Care Medicine 1981;9:587-90.

Couriel 1988

Couriel JM. Management of croup. Archives of Disease in Childhood 1988;63:1305-8.

da Silva 1999

da Silva O, Stevens D. Complications of airway management in very-low-birth-weight infants. Biology of the Neonate 1999;75:40-5.

Fan 1982

Fan LL, Flynn JW, Pathak DR, Madden WA. Predictive value of stridor in detecting laryngeal injury in extubated neonates. Critical Care Medicine 1982;10:453-5.

Fan 1983

Fan LL, Flynn JW, Pathak DR. Risk factors predicting laryngeal injury in intubated neonates. Critical Care Medicine 1983;11:431-3.

Fanconi 1990

Fanconi S, Burger R, Maurer H, Uehlinger J, Ghelfi D, Mühlemann C. Transcutaneous carbon dioxide pressure for monitoring patients with severe croup. Journal of Pediatrics 1990;117:701-5.

Greenough 1996

Greenough A. Respiratory support. In: Greenough A, Milner AD, Roberton NRC, editor(s). Neonatal respiratory disorders. London: Arnold, 1996:115-151.

Gwinnutt 1987

Gwinnutt CL, Lord WD. Nebulised adrenaline [letter]. Anaesthesia 1987;42:320-1.

Hoffman 1996

Hoffman BB, Lefkowitz RJ. Catecholamines, sympathomimetic drugs, and adrenergic receptor antagonists. In: Hardman JG, Limbird LE, editor(s). Goodman and Gilman’s, the pharmacological basis of therapeutics, 9th edition. New York: McGraw-Hill, 1996:199-248.

Jordan 1970

Jordan WS, Graves CL, Elwyn RA. New therapy for postintubation laryngeal edema and tracheitis in children. JAMA 1970;212:585-8.

Joshi 1972

Joshi VV, Mandavia SG, Stern L, Wiglesworth FW. Acute lesions induced by endotracheal intubation: occurrence in the upper respiratory tract of newborn infants with respiratory distress syndrome. American Journal of Diseases of Children 1972;124:646-9.

Koka 1977

Koka BV, Jeon IS, Andre JM, MacKay I, Smith RM. Postintubation croup in children. Anesthesia and Analgesia 1977;56:501-5.

Kristjánsson 1994

Kristjánsson S, Berg-Kelly K, Winsö E. Inhalation of racemic adrenaline in the treatment of mild and moderately severe croup. Clinical symptom score and oxygen saturation measurements for evaluation of treatment effects. Acta Pædiatrica 1994;83:1156-60.

Kuusela 1988

Kuusela A, Vesikari T. A randomized double-blind, placebo-controlled trial of dexamethasone and racemic epinephrine in the treatment of croup. Acta Pædiatrica Scandinavica 1988;77:99-104.

Laing 1986

Laing IA, Cowan DL, Ballantine GM, Hume R. Prevention of subglottic stenosis in neonatal ventilation. International Journal of Pediatric Otorhinolaryngology 1986;11:61-6.

O'Brodovich 1990

O’Brodovich HM, Haddad GG. The functional basis of respiratory pathology. In: Kendig EL, Chernick V, editor(s). Disorders of the respiratory tract in children. 5th edition. Philadelphia: WB Saunders, 1990:3-47.

O'Connor 1995

O’Connor DM. Developmental anatomy of the larynx and trachea. In: Myer CM, Cotton RT, Shott SR, editor(s). The pediatric airway. Philadelphia: JB Lippincott Co., 1995:1-14.

Phelan 1994

Phelan PD, Olinsky A, Robertson CF, editors. Neonatal respiratory disorders. In: Respiratory illness in children. 4th edition. Oxford: Blackwell Scientific Publications, 1994:8-26.

Pransky 1989

Pransky SM. Evaluation of the compromised neonatal airway. Pediatrics Clinics of North America 1989;36:1571-82.

Remington 1986

Remington S, Meakin G. Nebulised adrenaline 1:1000 in the treatment of croup. Anaesthesia 1986;41:923-6.

Skolnik 1989

Skolnik SN. Treatment of croup. A critical review. American Journal of Diseases of Children 1989;143:1045-9.

Solomon 1984

Solomon SL, Wallace EM, Ford-Jones EL, Baker WM, Martone WJ, Kopin IJ, et al. Medication errors with inhalant epinephrine mimicking an epidemic of neonatal sepsis. New England Journal of Medicine 1984;310:166-70.

Willging 1995

Willging JP, Cotton RT. Subglottic stenosis in the pediatric patient, editors. In: Myer CM, Cotton RT, Shott SR, editor(s). The pediatric airway. Philadelphia: JB Lippincott Company, 1995:111-132.

Wohl 1990

Wohl MEB, Mead J. Age as a factor in respiratory disease. In: Kendig EL, Chernick V, editor(s). Disorders of the respiratory tract in children. 5th edition. Philadelphia: WB Saunders, 1990:175-182.

Other published versions of this review

Davies 1998

Davies MW, Davis PG. Nebulized racemic epinephrine for extubatin of newborn infants. Cochrane Database of Systematic Reviews 1998, Issue 3. Art. No.: CD000506. DOI: 10.1002/14651858.CD000506.

Davies 1999

Davies MW, Davis PG. Nebulized racemic epinephrine for extubation of newborn infants. Cochrane Database of Systematic Reviews 1999, Issue 3. Art. No.: CD000506. DOI: 10.1002/14651858.CD000506.

Davies 2001

Davies MW, Davis PG. Nebulized racemic epinephrine for extubation of newborn infants. Cochrane Database of Systematic Reviews 2001, Issue 1. Art. No.: CD000506. DOI: 10.1002/14651858.CD000506.

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Data and analyses

  • None noted.

Sources of support

Internal sources

  • Royal Women's Hospital, Melbourne, Australia, Australia
  • University of Melbourne, Melbourne, Australia, Australia
  • Grantley Stable Neonatal Unit, Royal Women's Hospital, Brisbane, Australia
  • Dept of Paediatrics and Child Health, University of Queensland, Brisbane, Australia
  • Cochrane Perinatal Team, Brisbane, Australia

External sources

  • No sources of support provided.

This review is published as a Cochrane review in The Cochrane Library, Issue 5, 2010 (see http://www.thecochranelibrary.com External Web Site Policy for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent recent version of the review.