Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Hartling, 2011

PS: individual study characteristics and results are extracted from the SR (unless stated otherwise)

Cochrane SR and meta-analysis of RCTs

Literature search up to September 2010

Inpatients:

A: Abu-Shukair, 2001

B: Abul-Ainine, 2002

C: Bertrand, 2001

D: Bilan, 2007

E: John, 2006

F: Kadir, 2009

G: Patel, 2002

H: Sanchez, 1993

I: Wainwright, 2003

Outpatients:

J: Anil, 2010

K: Barlas, 1998

L: Beck, 2007

M: Khashabi, 2005

N: Kuyucu, 2004

O: Menon, 1995

P: Mull, 2004

Q: Okutan, 1998

R: Plint, 2009

S: Ralston, 2005

High income countries:

Australia: I

Canada: G, H, O, R

Chile: C

England: B

Israel: L

Turkey: J, K, N, Q

United States: P, S

Low income countries:

Jordan: A

Iran: D, M

India: E

Bangladesh: F

Source of funding and conflicts of interest:

ACP, HP, DWJ and TPK are authors and/or co-authors on trials included in this review. No other declarations of interest are noted.

Funding:

Internal sources

• Alberta Research Centre for Health Evidence (ARCHE), Canada.

External sources

• Canadian Institutes of Health Research, Canada.

• Programme for Advanced Medical Education (Fundação Calouste Gulbenkian, Fundação Champalimaud, Ministério da Saúde and

Fundação para a Ciência e Tecnologia), Portugal.

Ricardo M Fernandes (Fellowship)

Inclusion criteria SR:

• RCTs evaluating the efficacy of epinephrine versus placebo or another active intervention in the treatment of bronchiolitis were considered for inclusion.
• All studies of infants and young children up to 24 months of age.
• Only studies that defined bronchiolitis as a first episode of wheezing (with respiratory distress and clinical evidence of respiratory infection, for example, cough, coryza or fever).
• studies of inpatients or outpatients (ambulatory care or emergency department, or both).

Exclusion criteria SR: Studies in the intensive care setting or with intubated or ventilated

participants (or both).

19 studies included, with a total of 2256 participants

Important patient characteristics at baseline:

See the Cochrane review for all study details.

Groups comparable at baseline?

Yes, on relevant variables

Describe intervention:

In all 19 studies

epinephrine was administered via nebulization.

Racemic epinephrine (5 studies):

G, H, K, P, S

L-epinephrine 12 studies):

B, C, E, F, I, J, L, M, N, O, Q, R

Type of epinephrine unclear (2 studies):

A, D

Dexamethasone added to epinephrine (2 studies):

N, R (subgroup in these studies)

NB: we were not interested in this intervention.

Most trials reported administering epinephrine in multiple

doses (n = 12) with all others being delivered as a single dose (n

= seven).

Describe control:

Placebo (0.9% saline; 9 studies):

B, G, I, J, K, M, Q, R, S

Salbutamol/albuterol (15 studies):

A, C, D, E, G, H, J, K, L, M, N, O, P, Q, S

Steroid (prednisolone (n=15) or budesonide (n=15); dexamethasone (n=200)); 2 studies):

K, R

NB: We were not interested in this comparison.

Salbutamol and ipratropium bromide (1 study):

F

End-point of follow-up:

Not specifically mentioned per study. In general, children were monitored until hospital discharge and some examined admission and re-admission.

Incomplete outcome data

Incomplete outcome reporting was adequately addressed in 11 of 13 for the review primary outcomes; 13 of 18 for clinical severity score.

They combined results using random-effects models regardless of heterogeneity, due to expected differences in interventions,

outcomes and measurement instruments (for example, clinical scores measuring different clinical features or weighting these

differently).

Comparison 1. Epinephrine versus placebo

Nine studies compared epinephrine and placebo; these

comparisons involved a total of 1354 patients (677 epinephrine; 677 placebo).

Adverse events, narrative

Inpatients: One study (n=38) reported on adverse events and found no occurrences of vomiting, pallor, tremor or arrhythmias.

Outpatients: Three studies reported on adverse events (n = 944). One study observed pallor (11% epinephrine, 8% placebo), vomiting (2% epinephrine, 1.5% placebo), tremors (2% epinephrine, 1% placebo) and hypertension (0.5% epinephrine, 0% placebo). However, the occurrence was not significantly different between groups. The other study found no occurrences of tachycardia, withdrawal due to

worsening clinical status, or discontinuation of study medications due to adverse events.

Admissions at enrolment or < 24 hours

(outpatients only)

6 studies, n=995, RR 0.67 (95% CI 0.50 to 0.89)

Total events: 62 (Epinephrine), 93 (Placebo)

I²=0%

Test for overall effect: Z=2.72(P=0.01)

Admissions overall up to 7 days (outpatients

only)

3 studies, n=875, RR 0.81 (95% CI 0.63 to 1.03)

Total events: 88 (Epinephrine), 110 (Placebo)

I²=0%

Test for overall effect: Z=1.71(P=0.09)

Length of stay, days (inpatients only, Mean Difference (95% CI))

2 studies, n=292, -0.35 (-0.87 to 0.17)

Total: 149 (Epinephrine), 143 (Placebo)

I²=0%

Test for overall effect: Z=1.32(P=0.19)

Clinical score - all (outpatients)

At 60 minutes, Std. Mean Difference (95% CI)

6 studies, n=975, -0.40 (-0.58 to -0.23)

Total: 490 (Epinephrine), 485 (Placebo)

I²=27.91%

Test for overall effect: Z=4.5(P<0.0001)

At 120 minutes, Std. Mean Difference (95% CI)

2 studies, n=105, -0.73 (-1.13 to -0.33)

Total: 53 (Epinephrine), 52 (Placebo)

I²=0%

Test for overall effect: Z=3.61(P=0)

Clinical score – all (inpatients)

At 60 minutes, Std. Mean Difference (95% CI)

2 studies, n=232, -0.04 (-0.49 to 0.40)

Total: 118 (Epinephrine), 114 (Placebo)

 I²=45.84%

Test for overall effect: Z=0.2(P=0.84)

Comparison 2. Epinephrine versus salbutamol/albuterol

Fifteen studies compared epinephrine versus salbutamol/ albuterol; these comparisons involved 957 randomized participants (480 epinephrine; 477 salbutamol).

Adverse events

Inpatients: Two studies reported on adverse events. One study found no cases of pallor, vomiting or tremors (n = 46). The second study (n =30) reported no cases of tremor, increased blood pressure after

nebulization or tachycardia among the epinephrine group; the authors did not report on adverse events for the salbutamol group.

Outpatients: Three studies reported on adverse events. One study (n = 66) reported on pallor (one epinephrine, zero albuterol), vomiting (one epinephrine, five albuterol), and tremors (zero epinephrine, zero albuterol). The second study (n = 40) reported cases of tachycardia (zero epinephrine, two albuterol) but reported no cases of withdrawal due to worsening clinical status or discontinuation of study medications due to adverse events. The third study (n=186) reported no cases of tremor or increased heart rate in the epinephrine or albuterol groups.

Admissions at enrolment or < 24 hours

(outpatients only)

9 studies, n=444, 0.67 (0.41 to 1.09)

Total: 222 (Epinephrine), 222 (Salbutamol/Albuterol)

I²=30.88%

Test for overall effect: Z=1.6(P=0.11)

Admissions overall up to 7 days (outpatients

only)

3 studies, n=212, 1.05 (0.71 to 1.54)

Total: 109 (Epinephrine), 103 (Salbutamol/Albuterol)

I²=0%

Test for overall effect: Z=0.23(P=0.82)

Length of stay, days (inpatients only, Mean Difference (95% CI))

4 studies, n=261, -0.28 (-0.46 to -0.09)

Total: 131 (Epinephrine), 130 (Salbutamol/Albuterol)

I²=0%

Test for overall effect: Z=2.95(P=0)

Length of stay, days (outpatients only, Mean Difference (95% CI))

1 study, n=42, 0.46 (-0.27 to 1.20)

Total: 21 (Epinephrine), 21 (Salbutamol/Albuterol)

I²=not applicable

Test for overall effect: Z=1.23(P=0.22)

Clinical score - all (outpatients)

At 60 minutes, Std. Mean Difference (95% CI)

8 studies, n=397, -0.12 (-0.32 to 0.08)

Total: 199 (Epinephrine), 175 (Salbutamol/Albuterol)

I²=0%

Test for overall effect: Z=1.2(P=0.23)

At 120 minutes, Std. Mean Difference (95% CI)

7 studies, n=356, -0.10 (-0.31 to 0.11)

Total: 181 (Epinephrine), 130 (Salbutamol/Albuterol)

I²=0%

Test for overall effect: Z=0.93(P=0.35)

At 12 to 24 hours, Std. Mean Difference (95% CI)

2 studies, n=69, -0.21 (-0.86 to 0.44)

Total: 34 (Epinephrine), 35 (Salbutamol/Albuterol)

I²=41.27%

Test for overall effect: Z=0.64(P=0.52)

At 3 to 10 days, Std. Mean Difference (95% CI)

2 studies, n=69, -0.50 (-0.98 to -0.02)

Total: 34 (Epinephrine), 35 (Salbutamol/Albuterol)

I²=0%

Test for overall effect: Z=2.04(P=0.04)

Clinical score – all (inpatients)

At 60 minutes, Std. Mean Difference (95% CI)

4 studies, n=248, -0.79 (-1.45 to -0.13)

Total: 127 (Epinephrine), 121 (Salbutamol/Albuterol)

I²=79.23%

Test for overall effect: Z=2.36(P=0.02)

At 120 minutes, Std. Mean Difference (95% CI)

1 study, n=140, -0.52 (-0.86 to -0.18)

Total: 72 (Epinephrine), 68 (Salbutamol/Albuterol)

I²=not applicable

Test for overall effect: Z=3.02(P=0)

Comparison 3. Epinephrine versus salbutamol and ipratropium bromide

One study compared epinephrine versus salbutamol and ipratropium bromide among 60 inpatients.

Clinical score (inpatients)

At 6 to 12 hours, Std. Mean Difference (95% CI)

1 study, n=60, -0.60 (-1.12 to -0.09)

Total: 30 (Epinephrine), 30 (Salbutamol+IB)

I²=not applicable

Test for overall effect: Z=2.28(P=0.02)

Of the 19 included studies

• 42% (n = eight) had an overall risk of bias rating of 'Unclear': A, B, D, E, J, K, M, Q
• 32% (n = six) a rating of 'Low': G, L, O, P, R, S
• 26% (n = five) a rating of 'High': C, F, H, I, N,

Brief description of author’s conclusion:

This systematic review provides evidence that epinephrine is more effective than placebo for bronchiolitis in outpatients. Recent research suggests combined epinephrine and steroids may be effective for outpatients. There is no evidence to support the use of epinephrine for inpatients.

Sensitivity analyses (excluding low quality studies; relevant subgroup-analyses)

Epinephrine vs placebo

• Admissions at enrolment or <24 hours (outpatients only): 3 studies, n=842, RR 0.77 (95% CI 0.56, 1.07)
• LOS (inpatients only): 1 study, n=98, Mean Difference -0.15 (95%CI -1.05, 0.76)
• Clinical score at 60 minutes: 2 studies, n=796, Std. Mean Difference -0.32 (95% CI -0.46, -0.18)

When analyses for admission at Day 1 were restricted to trials with low risk of bias, results were no longer statistically significant.

There was no change in the results for LOS and clinical scores when only low risk of bias studies were included.

Epinephrine vs salbutamol/albuterol

• Admissions at enrolment or <24 hours (outpatients only): 3 studies, n=148, RR 0.66 (95% CI 0.28, 1.56)
• LOS (inpatients): 1 study, n=101, Mean Difference -0.07 (95% CI -1.01, 0.88)

Gadomski, 2014

PS: individual study characteristics and results are extracted from the SR (unless stated otherwise)

Cochrane SR and meta-analysis of RCTs

Literature search up to January 2014

Country:

See the Cochrane review; several countries worldwide.

Setting:

Outpatients / Emergency Department (ED):

1. Alario 1992
2. Anil 2010 (ED)
3. Can 1998 (ED)
4. Gadomski 1994a (ED)
5. Gadomski 1994b
6. Gupta 2008
7. Ipek 2011 (ED)
8. Klassen 1991 (ED)
9. Patel 2003 (ED)
10. Ralston 2005
11. Schuh 1990 (ED)
12. Schweich 1992 (ED)

Inpatients:

13. Chevallier 1995
14. Chowdhury 1995
15. Dobson 1998
16. Goh 1997
17. Gurkan 2004
18. Ho 1991
19. Karadag 2005
20. Karadag 2008 (same as Karadag 2005)
21. Levin 2008
22. Lines 1990
23. Lines 1992
24. Mallol 1987
25. Patel 2002
26. Scarlett 2012
27. Tal 1983
28. Tinsa 2009
29. Totapally 2002
30. Wang 1992

Source of funding and conflicts of interest:

Potential biases in the review process:

Gadomski is a trialist and a member of the American

Academy of Pediatrics Subcommittee on the Diagnosis and

Management of Bronchiolitis.

Internal sources of funding:

• National Prescribing Service Pty Ltd, Australia.

External sources

• No sources of support supplied

Inclusion criteria SR:

- Randomized, placebo-controlled trials of bronchodilators for

bronchiolitis.

- Infants and young children up to 24 months with bronchiolitis.

Bronchodilator therapy, including albuterol, salbutamol,

terbutaline, ipratropium bromide and adrenergic agents.

Exclusion criteria SR:

Studies of inhaled steroids were not included. Routes of administration

were: nebulized, oral and subcutaneous. Although included in the

original review, authors excluded studies of epinephrine in bronchiolitis

from the update.

30 studies included, with a total of 1922 participants

Important patient characteristics at baseline:

See the Cochrane review for all study details.

Fourteen studies included infants aged less than or equal to 12

months (Chevallier 1995; Chowdhury 1995; Gupta 2008; Henry

1983; Ho 1991; Karadag 2008; Levin 2008; Mallol 1987; Patel 2002;

Patel 2003; Scarlett 2012; Tal 1983; Tinsa 2009; Totapally 2002).

Groups comparable at baseline?

Yes, on relevant variables

Describe intervention:

Salbutamol/albuterol:

Outpatients:

Can 1998,

Gadomski 1994 – nebulization,

Klassen 1991, Ralston 2005, Schuh 1990, Schweich 1992

Inpatients:

Chevallier 1995, Dobson 1998, Gurkan 2004, Ho 1991, Karadag 2005 (SAL alone), Lines 1990,

Patel 2002, Scarlett 2012

Salbutamol and/or ipratropium bromide

Inpatients:

Chowdhury 1995, Goh 1997, Karadag 2005 (IPR alone), Lines 1992 (IPR only), Wang 1992

Salbutamol plus hypertonic saline or salbutamol plus normal saline

Outpatients:

Anil 2010, Ipek 2011

Other medications (not relevant to us):

Alario 1992, Gadomski 1994 – oral, Gupta 2008 – oral, Levin 2008 – population on mechanical ventilation, Mallol 1987, Patel 2003, Tal 1983, Tinsa 2009, Totapally 2002

Describe control:

Normal saline

End-point of follow-up:

Not specifically mentioned per study. In general, children were monitored until hospital discharge and some examined admission and re-admission.

Incomplete outcome data

In the outpatient studies, there tended to be more missing data for follow-up measurements beyond 60 minutes because many patients were discharged from these settings before 90 or 120- minute assessments could be done. Bronchodilators have short term

effects, therefore some outpatient trialists did not include

measurement of outcomes longer than 60 minutes post-treatment.

Therefore, the outpatient results are biased towards those data measured at a shorter interval from treatment administration, so

Sustained outcomes may have been missed.

Details regarding study attrition were often not well described in

the included studies. Drop out rates range from 0% to 13% (Gupta

2008; Patel 2003; Scarlett 2012). Few studies included study flow diagrams that could be used to assess differential drop out from the

study groups (Anil 2010 SAL 0.9%; Gupta 2008; Patel 2003; Ralston

2005). Few studies employed intention-to-treat (ITT) analysis when study participant attrition occurred (Patel 2002; Patel 2003). Possible attrition bias might be a factor in three studies that excluded participants from analysis because they were 'therapeutic

failures' (Tal 1983), or that withdrew participants for other reasons

(Dobson 1998; Goh 1997; Scarlett 2012).

Comparison: Salbutamol/albuterol (and/or ipratropium bromide) vs. normal saline

NB:

- For the inpatients analyses, the total /overall effect meta-analytic results in Gadomski include studies that are not relevant to our research question (i.e. studies with wrong drugs / methods or study design).

- Three trials employed cross-over designs (Alario 1992; Ho 1991; Totapally 2002).

- Ipratropium bromide studies are only inpatients studies.

- Two outpatient studies are included with hypertonic saline with salbutamol in experimental groups.

- Not all included studies reported on outcomes relevant to us.

Hospital admission after treatment (outpatients), OR, fixed, (95% CI)

7 studies

Total: 222 salbutamol/albuterol and 182 normal saline

Total events: 37 (Bronchodilator), 43 (Placebo)

0.77 (0.44 to 1.33)

I²=0%

Test for overall effect: Z=0.94(P=0.35)

Duration of hospitalization (inpatients), days, Std. Mean Difference, fixed, (95% CI)

5 studies

Total: 220 (Bronchodilator), 129 (Placebo)

0.06 (-0.27 to 0.39)

I²=0%

Test for overall effect: Z=0.38 (p=0.7)

Clinical Severity Score after treatment (outpatients), Std. Mean Difference, random, (95% CI)

7 studies

Total: 285 salbutamol/albuterol and 247 normal saline

-0.36 (-0.83 to0.11)

I²=85.08%

Test for overall effect: Z=1.49(P=0.13)

Clinical Severity Score after treatment (inpatients), Std. Mean Difference, random, (95% CI)

9 studies

Total: 249 (Bronchodilator), 167 (Placebo)

-0.14 (-0.41 to 0.12)

I²=35.96%

Test for overall effect: Z=1.06 (p=0.29)

Adverse effects (only narrative results)

Where adverse effects were reported, the authors note that these were exclusively found in the study groups receiving bronchodilators and they included: tachycardia (P value less than 0.05) (Klassen 1991; Lines 1990), decreased oxygen saturation (P value less than 0.05) (Ho 1991; Schweich 1992), flushing (four participants) (Gadomski 1994b - neb), hyperactivity (three participants) (Gadomski 1994b - neb), tachycardia and prolonged cough (two participants) (Henry 1983) and tremor (one participant) (Wang 1992).

Patel 2002 reported tachycardia, mild hypertension and slight tremor. One infant receiving albuterol was transferred to the intensive care unit for 48 hours but did not require mechanical ventilation.

Significant tachycardia (sustained heart rate over 200 beats per minute for more than 30 minutes) was reported in two infants receiving albuterol nebulization (Ralston 2005).

Scarlett 2012 reported a paradoxical response to albuterol in an infant whose phase angle increased after receiving albuterol (the expected response was a

decrease).

No side effects were reported by Karadag 2005 (IPR), Can 1998, Anil 2010.

Risk of bias of included and relevant studies:

Low: Anil 2010, Gadomski 1994, Karadag 2005, Klassen 1991, Levin 2008, Patel 2002, Ralston 2005, Scarlett 2012, Schuh 1990, Schweich 1992, Wang 1992

High: Can 1998, Goh 1997, Henry 1983

Unclear: Chowdhury 1995, Gurkan 2004, Ho 1991, Ipek 2011, Lines 1990

Problems in Gadomski 2014:

CSS/hospital admission after treatment: not specified how long after treatment.

Numbers per treatment arm are not specified.

Not specified which treatment arms were included (epinephrine arms were not included).

Treatment arms are not separately compared to one another or to placebo; results of all different treatment arms are combined and compared to placebo.

For some reason , for Karadag 2005 the results are split per treatment arm vs placebo.

Wang 1992; I checked the original study => number of patients (2 or 3 treatment arms taken together; the placebo group alone) do not match in any way with numbers in Gadomki 2014. Studies with treatment arms with oral medications are also included in their meta-analyses.

Sensitivity analyses (only low risk studies

CSS (RDAI)(outpatients)), Std. Mean Difference, random, (95% CI)

3 studies

Total: 137 salbutamol vs. 103 normal saline

-0.11(-0.48 to 0.25)

I²=46.79%

Test for overall effect: Z=0.62(P=0.54)

CSS (inpatients), Std. Mean Difference, random, (95% CI)

5 studies

Total: 125 salbutamol vs. 103 normal saline

0.01(-0.35 to 0.37)

I²=36.79%

Test for overall effect: Z=0.05 (P=0.96)

Brief description of author’s conclusion:

Given their high cost, adverse effects and lack of effect on oxygen saturation and other outcomes included in this meta-analysis, bronchodilators are not effective in the routine management of first-time wheezers who present with the clinical findings of bronchiolitis, in either inpatient or outpatient settings.

Zhang, 2017

PS: individual study characteristics and results are extracted from the SR (unless stated otherwise)

Cochrane SR and meta-analysis of RCTs

Literature search up to August 2017

Studies and Setting:

1. Al-Ansari 2010 (ED)
2. Angoulvant 2017 (ED)
3. Anil 2010 (ED)
4. Everard 2014 (inpatient)
5. Flores 2016 (inpatient)
6. Florin 2014 (ED)
7. Grewal 2009 (ED)
8. Ipek 2011 (ED)
9. Jacobs 2014 (ED)
10. Khanal 2015 (ED)
11. Köse 2016 (inpatient)
12. Kuzik 2007 (inpatient)
13. Li 2014 (outpatient)
14. Luo 2010 (inpatient)
15. Luo 2011 (inpatient)
16. Mahesh Kumar 2013 (inpatient)
17. Mandelberg 2003 (inpatient)
18. Miraglia Del Giudice 2012 (inpatient)
19. NCT01238848 (inpatient)
20. Ojha 2014 (inpatient)
21. Pandit 2013 (inpatient)
22. Ratajczyk-Pekrul 2016 (inpatient)
23. Sarrell 2002 (outpatient)
24. Sharma 2013 (inpatient)
25. Tal 2006 (inpatient)
26. Teunissen 2014 (inpatient)
27. Tinsa 2014 (inpatient)
28. Wu 2014 (ED)

Countries:

• Argentina: NCT01238848
• Canada: Grewal 2009
• China: Li 2014; Luo 2010; Luo 2011
• France: Angoulvant 2017
• India: Mahesh Kumar 2013; Pandit 2013;

Sharma 2013

• Israel: Mandelberg 2003; Sarrell 2002; Tal 2006
• Italy: Miraglia Del Giudice 2012
• Nepal: Khanal 2015;
• Ojha 2014
• Netherlands: Teunissen 2014
• Poland: Ratajczyk-
• Pekrul 2016
• Portugal: Flores 2016
• Qatar: Al-Ansari 2010
• Tunisia: Tinsa 2014
• Turkey: Anil 2010; Ipek 2011; Köse 2016
• UK: Everard 2014
• USA: Florin 2014; Jacobs 2014; Wu 2014
• The United Arab Emirates and Canada: Kuzik 2007

Source of funding and conflicts of interest:

Funding:

• Faculty of Medicine, Universidade Federal do Rio Grande, Brazil.

• National Council for Scientific and Technological Development (CNPq), Brazil. Fellowship of research productivity (PQ)

Authors declare no conflicts of interest except for Wainwright: She received travel grants from the North American Cystic Fibrosis Foundation and the European Cystic Fibrosis Society, travel and accommodation expenses from Novartis, Vertex and the University of Miami; has served as a consultant for/an advisory board member for Vertex; has previously and is currently receiving grants or grants pending from the National Health and Medical Research Council (Australia), and has previously and is currently receiving funds from Vertex, previously from Ablynx, and Novo Nordisk Phamaceuticals for site costs associated with clinical trial participation; her institution has previously received payment for her providing lectures from Novartis and Vertex Pharmaceuticals. None of the declared benefits were received in relation to this review or review topic or scope.

Inclusion criteria SR:

- randomized controlled trials and quasi-randomized controlled trials (in which there is alternate allocation to treatment and control groups)

- Children up to 24 months of age diagnosed with acute bronchiolitis.

Acute bronchiolitis was defined as the first episode of acute

wheezing associated with clinical evidence of a viral infection (cough, coryza, or fever). Confirmation of viral aetiology was not

necessary for study inclusion.

- studies of inpatients,

emergency department patients, or outpatients

- comparison of nebulized hypertonic (K 3%) saline solution with nebulized normal (0.9%) saline

Exclusion criteria SR:

- participants who had recurrent wheezing or who were intubated

and ventilated, and studies that assessed pulmonary function

alone

Included: 28 trials involving 4195 infants with acute bronchiolitis, of whom 2222 infants

received hypertonic saline

Important patient characteristics at baseline:

See the Cochrane review for all study details.

All 28 included studies were randomized, parallel-group, controlled trials. All but two trials were double-blinded (NCT01238848;

Everard 2014). Four studies were multicentre: a hospital in the United Arab Emirates and two hospitals in Canada in Kuzik 2007; 10 centres in the UK in Everard 2014; two centres in the USA in Wu 2014; and 24 centres in France in Angoulvant 2017.

Infants hospitalized with severe bronchiolitis (requiring mechanical ventilation or intensive care, or oxygen saturation <85% on room air) were excluded from all but two trials (Teunissen 2014; Wu 2014).

Groups comparable at baseline?

The baseline characteristics of participants were similar

between treatment groups in all 28 trials.

Describe intervention:

(1) Hypertonic Saline (HS)

• Angoulvant 2017 (ED) – 3%
• Florin 2014 (ED) - 3%
• Kuzik 2007 (inpatient) - 3%
• Li 2014 (outpatient) – 3% and 5% group (no results in Cochrane)
• Luo 2011 (inpatient) – 3%
• Ojha 2014 (inpatient) – 3%
• Wu 2014 (ED) – 3%

(2) HS + epinephrine / adrenaline

• Al-Ansari 2010 (ED) – 3% and 5% group together
• Grewal 2009 (ED) – 3%
• Jacobs 2014 (ED) – 7%
• Khanal 2015 (ED) – 3%
• Mandelberg 2003 (inpatient) – 3%
• Miraglia Del Giudice 2012 (inpatient) – 3%
• Pandit 2013 (inpatient) – 3%
• Tal 2006 (inpatient) – 3%
• Tinsa 2014 (inpatient) – 2x 5% +/- epinephrine (taken together) vs 1x NS

(3) HS + salbutamol / albuterol

• Flores 2016 (inpatient) – 3%
• Ipek 2011 (ED) – 2x 3% +/- salbutamol (taken together) vs 2x 0.9% +/- salbutamol (taken together)
• Köse 2016 (inpatient) – 3% and 7% group together
• Luo 2010 (inpatient) – 3%
• Mahesh Kumar 2013 (inpatient) – 3%
• NCT01238848 (inpatient) – 3%
• Ratajczyk-Pekrul 2016 (inpatient) – 3%
• Sharma 2013 (inpatient) – 3%
• Teunissen 2014 (inpatient) – 3% and 6% group together

(4) HS + salbutamol / albuterol and/or epi-nephrine/adrenaline

• Anil 2010 (ED) – 3%

Everard 2014 (inpatient) – open, wrong comparison

Intervention group:

3% + standard care

Control group: standard care

Sarrell 2002 (outpatient) – wrong drug

Intervention group: nebulized 3% + terbutaline

Control group: nebulized 0.9% + terbutaline

Describe control:

(1) Normal Saline (NS)

(2) NS + epinephrine / adrenaline

(3) NS + salbutamol / albuterol

(4) NS + salbutamol/albuterol and/or epinephrine/adrenaline

End-point of follow-up:

Not specifically mentioned per study. In general, children were monitored until hospital discharge and some examined admission and re-admission.

Incomplete outcome data

The number of withdrawals after randomization was small in all but two trials; the withdrawal rate was 18% in NCT01238848 and

Ojha 2014.

Seven trials reported using intention-to-treat analysis (Everard 2014; Florin 2014; Grewal 2009; Kuzik 2007; Mandelberg 2003; Sarrell 2002; Wu 2014).

- For outpatient or emergency department participants, rate of hospitalization was measured in Angoulvant 2017, Anil 2010, Florin 2014, Grewal 2009, Ipek 2011, Jacobs 2014, Sarrell 2002.

- All 17 inpatient trials except Tinsa 2014 used length of hospital stay as the primary outcome measure.

- All outpatient or emergency department trials measured clinical severity score.

- The same clinical severity score was used by 11 inpatient trials as a secondary outcome measure (Flores 2016; Köse 2016; Luo 2010; Luo 2011; Mahesh Kumar 2013; Mandelberg 2003; Miraglia

Del Giudice 2012; Ratajczyk-Pekrul 2016; Sharma 2013; Tal 2006; Tinsa 2014). This clinical score was initially described by Wang 1992. Other clinical scoring systems were used by two inpatient trials (Kuzik 2007; Ojha 2014).

- NB: in MA of Zhang 2017 Sarrell 2002 and Everard 2014 are included in out- and inpatients analyses (i.e. wrong drug and wrong control).

Rate of hospitalization (outpatients / ED), Risk Ratio (M-H, Random, 95% CI)

8 studies, n=1723

0.86 (0.76 to 0.98)

I²=7.01%

Test for overall effect: Z=2.28(P=0.02)

Length of Hospital Stay (days) (inpatients), Mean Difference (Random, 95% CI)

17 studies, n=1867

-0.41 (-0.75 to -0.07)

I²=79.07%

Test for overall effect: Z=2.36(P=0.02)

Clinical severity score (post-treatment) at day 1 / day 2 / day 3, Mean Difference (Random, 95% CI)

CSS at day 1:

Outpatients, 1 study, n=65, 33 HS and 32 NS

-1.28 (-1.92 to -0.64)

Test for overall effect: Z=3.9 (P<0.0001)

ED, 1 study, n= 171, 115 HS and 56 NS

-0.09(-0.51 to 0.33)

Test for overall effect: Z=0.42 (P=0.68)

Inpatients, 7 studies, n=576, 309 HS and 267 NS

-0.82 (-1.25 to -0.38)

I²=67.33%

Test for overall effect: Z=3.64 (P=0)

All patients, 9 studies, n=812

-0.77 (-1.18 to -0.36)

I²=74.44%

Test for overall effect: Z=3.67 (P=0)

CSS at day 2:

Outpatients, 1 study, n=65, 33 HS and 32 NS

-2(-2.93 to -1.07)

Test for overall effect: Z=4.21(P<0.0001)

ED, 1 study, n= 171, 115 HS and 56 NS

-0.27(-0.63 to 0.09)

Test for overall effect: Z=1.47(P=0.14)

Inpatients, 6 studies, n=467, 236 HS and 231 NS

-1.39(-1.95 to -0.84)

I²=75.53%

Test for overall effect: Z=4.92(P<0.0001)

All patients, 8 studies, n=703

-1.28(-1.91 to -0.65)

I²=87.72%

Test for overall effect: Z=3.99(P<0.0001)

CSS at day 3:

Outpatients, 1 study, n=65

-2.64(-3.85 to -1.43)

Test for overall effect: Z=4.28(P<0.0001)

Inpatients, 6 studies, n=434

-1.35(-1.72 to -0.98)

Test for overall effect: Z=7.13(P<0.0001)

I²=56.89%

All patients, 7 studies, n=499

-1.43(-1.82 to -1.04)

I²=60.53%

Test for overall effect: Z=7.17(P<0.0001)

Adverse events (narrative report only):

Twenty-four trials presented safety data: 13 trials (1363 infants, 703 treated with hypertonic saline) did not report any adverse events, and 11 trials (2360 infants, 1265 treated with hypertonic saline) reported at least one adverse event, most of which were mild and resolved spontaneously.

GRADE (according to Zhang 2017):

• Hospitalization rate: Moderate

=> downgraded for high clinical heterogeneity between studies.

• Lenght of hospital stay (days): Low

=> downgraded for inconsistent results between studies (high heterogeneity) and risk of bias.

• Clinical severity score (post-treatment), day 1-3: Low

=> downgraded for inconsistent results between studies (high heterogeneity) and risk of bias.

Problems with Zhang 2017:

- Takes results of different treatment arms together, for example Anil 2010, they take the epinephrine + HS together with the salbutamol + HS, just as the epi +NS with the sal +NS. Also Ipek 2011 salbutamol + HS and HS alone groups taken together, and salbutamol + NS and NS alone taken together.

- All outpatient or emergency department trials measured clinical severity score at 30 or 120 minutes, but post-treatment results are not reported. Variation in scoring methods and assessment time points made conducting meta-analyses inappropriate according to Zhang 2017. Only for Sarrell 2002 (outpatient) and Al-Ansari 2010 (ED) they are reported.

- The study of Li 2014 is missing in the analyses (only adverse events are reported).

Brief description of author’s conclusion:

Nebulized hypertonic saline may modestly reduce length of stay among infants hospitalized with acute bronchiolitis and improve clinical severity score. Treatment with nebulized hypertonic saline may also reduce the risk of hospitalization among outpatients and emergency department patients. However, authors assessed the quality of the evidence as low to moderate.

Hsieh, 2020

PS: individual study characteristics and results are extracted from the SR (unless stated otherwise)

SR and meta-analysis of RCTs

Literature search up to July 2019

Included studies:

1. Al-Ansari, 2010
2. Angoulvant, 2017
3. Anil, 2010
4. Everard, 2014
5. Flores, 2016
6. Florin, 2014
7. Grewal, 2009
8. Hou, 2016
9. Ipek, 2011
10. Islam, 2018
11. Kanjanapradap, 2018
12. Khanal, 2015
13. Kose, 2016
14. Kuzik, 2007
15. Kuzik, 2010
16. Li, 2014
17. Luo, 2010
18. Luo, 2011
19. Mahesh Kumar, 2013
20. Mandelberg, 2003
21. Miraglia, 2012
22. Morikawa, 2018
23. Ojha, 2014
24. Pandit, 2013
25. Ratajczyk-Pekrul, 2016
26. Sarrell, 2002
27. Sharma, 2013
28. Silver, 2015
29. Tal, 2006
30. Teunissen, 2014
31. Wang, 2014
32. Wu, 2014

Study design: RCT

Setting and Country:

20 (62.5%) were conducted in the Asian region, and six (18.8%) were conducted in the Americas or European countries. Regarding the research setting, 22 (68.8%) studies were conducted in hospital

wards with study targets being hospitalized children, and 10 studies (31.3%) were conducted in emergency wards of outpatient departments.

Source of funding and conflicts of interest:

Funding for this research was provided mainly by Taipei Medical University

(no. TMU106-AE1-B12, 109TMU-WFH-06) and Taiwan Ministry of Science and Technology (MOST 107–2320-B038–018-MY2).

The authors declare no conflicts of interests relevant to this article.

Inclusion criteria SR:

(1) population: children aged < 18 years with

bronchiolitis;

(2) intervention: hypertonic saline (3%); (3) control intervention: normal saline (0.9%);

(4) results: severity

of respiratory distress, length of hospital stay

(LOS), rate of hospitalization, rate of readmission, time

of sleeping, frequency of waking up in the night, drug side effects, etc.; (5) study design: RCTs.

Exclusion criteria SR:

Patients with other comorbidities such as

congenital respiratory tract disease, cardiac insufficiency and immunodeficiency.

32 RCTs included involving 4186 subjects with acute bronchiolitis, of which 2100 were treated with hypertonic saline (3%) abd 2086 were treated with normal saline.

Important patient characteristics at baseline:

The mean age of the two

population groups were 6.3 months vs. 6.5 months, the sex ratio were 58.3% males vs. 41.7% females, and there were no significant differences regarding the age or sex between these two groups (p > 0.05).

Studies included which add to Zhang 2017:

Islam 2018

Country: Bangladesh

Setting: Inpatients

Patients: n = 90,

age 1 ~ 24 months

Average Age (% male) 5.4 mon (56.6%)

Morikawa 2018

Country: Japan

Setting: inpatients

Patients, n=128

Age < 12 months,

Average age (% Male)

4.3 months (39.2%)

Groups comparable at baseline?

Yes on sex ratio and age, but the severity of respiratory syncytial virus (RSV) infection was inconsistent, and

this might have affected the effects of the interventions.

Describe intervention:

Hypertonic Saline 3%

Regarding required treatments according to different clinical symptoms, 22 studies (68.8%) combined treatment with epinephrine, bronchodilators, or steroids.

The nebulization treatment time lasted for 20 ~ 30 min, but the saline dosage used

for nebulizing ranged from 2 to 5 ml.

Studies included which add to Zhang 2017:

Islam 2018

Country: Bangladesh

4mL 3% HS

Morikawa 2018

Intervention: 2mL HS (n = 63) + 0.5% 0.1 mL

salbutamol

Describe control:

Normal saline 0.9%

Regarding required treatments according to different clinical symptoms, 22 studies (68.8%) combined treatment with epinephrine, bronchodilators, or steroids.

Islam 2018

4 mL NS (n = 45)

Morikawa 2018

2mL NS (n = 65) + 0.5% 0.1 mL

salbutamol

End-point of follow-up:

Not specifically mentioned per study. In general, children were monitored until hospital discharge and some examined admission and re-admission.

For how many participants were no complete outcome data available?

For bias due to missing outcome data, 20 studies (62.5%) conformed to the intention-to-treat principle, and

although there were certain data losses during the study

process, those did not affect the balance of the subjects’ basic characteristics, and these were determined to be

with low risk of bias; five studies (15.6%) had no information

on whether loss of data affected the results, and these were assessed to be with some concern of bias.

Summary SR results per outcome, mean difference or Risk Ratio, Random (95% CI)

CSS:

N=2010 (11 RCTs)

Risk with 0.9% Normal Saline:

The mean CSS was −3.57 to 8.8 point

Risk with 3% Hypertonic Saline:

MD 0.93 point lower (1.23 lower to 0.62 lower)

RDAI:

N=1369 (5 RCTs)

Risk with 0.9% Normal Saline:

The mean RDAI was −4.7 to 5.32 point

Risk with 3% Hypertonic Saline:

MD 0.6 point lower (0.95 lower to 0.26 lower)

LOS:

N=2055 (20 RCTs)

Risk with 0.9% Normal Saline:

The mean LOS was 1.4 to 7.49 days

Risk with 3% Hypertonic Saline:

MD 0.54 days lower (0.86 lower to 0.23 lower)

Rate of hospitalization:

N=1710 (8 RCTs)

Risk with 0.9% Normal Saline:

402 per 1000

Risk with 3% Hypertonic Saline:

342 per 1000 (298 to 394)

RR 0.85 (0.74 to 0.98)

Adverse events: narrative results only:

Twelve studies reported mild adverse events, including cough (6 studies), bronchospasm (2 studies), vomiting and diarrhea (2 studies), desaturation (1 study), agitation (2 studies), rhinorrhea (1 study), tachycardia (1 study), hoarse

voices (1 study), vigorous crying (1 study), vomiting and diarrhea (2 studies). One study reported adverse event (bradycardia and desaturation) in hypertonic saline group. However, these were mild and resolved naturally and all subjects completed the trial process.

Results of studies adding to Zhang 2017:

CSS > 3 days, mean (SD), mean difference, Random (95% CI)

Islam 2018, HS, n= 45, 1.64 (0.99); NS, n=45, 3 (1.48); -1.36 (-1.88, -0.84)

LOS, days, mean (SD), mean difference, Random (95% CI)

Islam 2018, HS, n=45, 2.42 (0.92); NS, n=45, 3.11 (1.13); -0.69 (-1.12,-0.26)

Morikawa 2018, HS, n=63, 4.81 (2.14); NS, n=65, 4.61 (2.18); 0.20 (-0.55, 0.95)

GRADE

CSS: LOW a,b

RDAI: MODERATE a

LOS: LOW a,b

Rate of hospitalization: MODERATE a

a. The overall of Risk of Bias was some concern

b. I2 > 75% (statistically significant)

Islam 2018: Some concerns for bias in measurement of the outcome. Other RoB low.

Morikawa 2018: Bias due to deviations from intended interventions, other RoB low.

Limitations of SR:

(1) inconsistent

disease severity in the included subjects;

(2) differences between studies with respect to dosage of hypertonic saline used for the intervention and the combined use of drugs such as bronchodilators; (3) evaluators of the

severity of respiratory distress were either medical personnel or research personnel who were not blinded.

Article conclusion:

Using hypertonic saline for nebulizing treatment in children with bronchiolitis can significantly improve the severity of respiratory distress, shorten the LOS, and increase the children’s night-time sleep quality. It is recommended

that a large-scale randomized clinical trial

with a standardized design be conducted in the future to investigate the effects of hypertonic saline in children with bronchiolitis.

Study reference

Study characteristics

Patient characteristics ²

Intervention (I)

Comparison / control (C) ³

Follow-up

Outcome measures and effect size ⁴

Comments

Modaressi, 2012

Type of study:

RCT

Setting and country:

- Inpatients

- Iran

Funding and conflicts of interest:

Conflict of Interest: The authors declare that they

have no competing interests.

No funding reported.

Inclusion criteria:

The target population included 1 month to 2 year old infants admitted to Amin and Al-Zahra hospitals and diagnosed as acute bronchiolitis by

the ICU or ward physicians.

Exclusion criteria:

Children with history of two or more

respiratory distresses, wheezing, family history of asthma, those who suffered from chronic pulmonary heart disease, suspected heart disease, bronchomalacia, previous use of bronchodilator and glucocorticoids, those treated with

monoamino oxydase inhibitors (MAOI), tachycardia >180/min, and respiratory rate >100/min,(4,10-16) were not included in the study.

N total at baseline:

- 40 were randomized

Intervention:

N = unknown

Control:

N = unknown

Important prognostic factors²:

age days, Mean (± SD):

I: 364±210.4 days

C: 409.6±207.6 days

Sex % M:

Overall: 20 (50%)

I: unknown

C: unknown

RDAI severity score, Mean (± SD):

I: 12.8 ± 2.4

C: 14.3 ± 1.8

Groups comparable at baseline?

yes

The first group

was given one dose of 0.1 ml/kg l-epinephrine in a

concentration of 1.10000.

Each volume was 3 cc, which was nebulized using

oxygen flow 8 liters per minute. Three doses of

each medication at intervals of 20 minutes were

prescribed; 10 minutes after the third dose, the

patient was rated again by Respiratory Distress

Assessment Instrument (RDAI)

During this medication, no other medications like antibiotics and steroids were prescribed for them.

The other group

received salbutamol 0.15 mg/kg at a minimum

volume of 1 mg mixed with normal saline.

Each volume was 3 cc, which was nebulized using

oxygen flow 8 liters per minute. Three doses of

each medication at intervals of 20 minutes were

prescribed; 10 minutes after the third dose, the

patient was rated again by Respiratory Distress

Assessment Instrument (RDAI)

During this medication, no other medications like antibiotics and steroids were prescribed for them.

Length of follow-up

No follow-up or incomplete data reported.

Patients were monitored until discharged from hospital (max 5 days).

LOS days, Mean ± SD

I - Epinephrine: 3±0.9

C - Salbutamol: 3.7±1.1

p=0.03

RDAI, Mean ± SD

After 10 minutes

I - Epinephrine: 10.6 ± 2.1

C - Salbutamol: 12.6 ± 1.4

After 180 minutes

I - Epinephrine: 8.2 ± 2.2

C - Salbutamol: 10 ± 1.5

After 1 day

I - Epinephrine: 4.5 ± 1.5

C - Salbutamol: 7.3 ± 2

After 2 days

I - Epinephrine: 3.1 ± 2.2

C - Salbutamol: 4.3 ± 2.6

After 3 days

I - Epinephrine: 1.8 ± 2.4

C - Salbutamol: 3 ± 2

After 4 days

I - Epinephrine: 0

C - Salbutamol: 1.3 ± 1.3

After 5 days

All zero

p=0.02

This was a triple-blind study, i.e. the patient, physician and statistical analyst were

unaware of the treatment.

N per group and most baseline characteristics are not mentioned.

Article conclusion: Regarding the effect of epinephrine on reduction of hospitalization duration and the RDAI index in patients with acute bronchiolitis, it seems that using epinephrine instead of salbutamol could be more

effective in the management of the disease.

Skjerven, 2013

Type of study:

RCT

Setting and country:

- Inpatients

- Norway

Funding and conflicts of interest:

Supported by Medicines for Children, a publicly funded body

administered by Haukeland University Hospital.

Disclosure forms provided by the authors are available with

the full text of this article at NEJM.org.

Inclusion criteria:

The inclusion criteria were clinical signs of bronchiolitis as defined by Court, Med J 1973;49:771-6, an

age of less than 12 months, and an overall clinical score of at least 4 on a scale of 0 to 10. The clinical score was the sum of points allotted, from 0 (indicating normal findings) to 2 (indicating severe illness), for each of the following: general condition, skin color, findings on auscultation,

respiratory rate, and retractions.

Exclusion criteria:

The exclusion criteria were the presence of any serious cardiac, immunologic, neurologic, or oncologic disease or any serious pulmonary disease other than bronchiolitis; more than one previous episode of obstructive airway disease; symptoms of disease of the lower airway (e.g., coughing) for more than 4 weeks; and receipt of any glucocorticoid therapy in the preceding 4 weeks.

N total at baseline: 404 Infants underwent randomization

Intervention:

- adrenaline on demand: 102

- adrenaline fixed schedule: 101

Control:

- NS on demand: 98

- NS fixed schedule: 103

Important prognostic factors²:

age days, Mean (SD):

Intervention:

- adrenaline on demand: 134.9±91.6

- adrenaline fixed schedule: 116.9±87.8

Control:

- NS on demand: 117.8±68.1

- NS fixed schedule: 136.0±97.0

Sex % M:

Intervention:

- adrenaline on demand: 63 (61.8)

- adrenaline fixed schedule: 60 (59.4)

Control:

- NS on demand: 54 (55.1)

- NS fixed schedule: 63 (61.2)

Groups comparable at baseline?

yes

10 ml of racemic adrenaline dissolved in

0.9% saline to form a solution of 20 mg per milliliter.

on demand or on a fixed schedule

The dose administered was based on the infant’s weight: 0.10 ml for infants weighing less

than 5 kg, 0.15 ml for those weighing 5 to 6.9 kg, 0.20 ml for those weighing 7 to 9.9 kg, and 0.25 ml for those weighing 10 kg or more. The medications were diluted in 2 ml of saline before

nebulization and were administered with a Respironics

Facemask.

No other inhaled medications, with the exception of 0.9% inhaled saline could be administered during the period when the infant was participating in the trial. Supportive

therapy and any other treatments were provided

in accordance with routine care.

0.9% saline alone.

The medications were diluted in 2 ml of saline before

nebulization and were administered with a Respironics

Facemask.

on demand or on a fixed schedule

No other inhaled medications, with the exception of 0.9% inhaled saline could be administered during the period when the infant was participating in the trial. Supportive

therapy and any other treatments were provided

in accordance with routine care.

Follow-up:

No Follow-up, only monitored children until discharge.

Incomplete data:

Intervention:

- adrenaline on demand

17 Discontinued study

11 Had treatment

failure

4 Were withdrawn by

parent

2 Were inappropriately

Withdrawn

- adrenaline fixed schedule

19 Discontinued study

12 Had treatment

failure

2 Had side effects

4 Were withdrawn by

parent

1 Was inappropriately

Withdrawn

167 Completed inhaled RA

Control:

- NS on demand

20 Discontinued study

15 Had treatment

failure

1 Had side effects

3 Were withdrawn by

parent

1 Was inappropriately

Withdrawn

- NS fixed schedule

27 Discontinued study

21 Had treatment

failure

5 Were withdrawn by

parent

1 Was inappropriately

Withdrawn

154 Completed inhaled saline

The study medication was discontinued

in 83 children (20.5%) for the reasons listed above.

321 Completed study

LOS in hours

The mean (±SD) length of stay for all infants was 80±67 hours

I: Inhaled Racemic Adrenaline (N=203), Mean (range)

63.6 (46.2 to 81.0)

C: Inhaled Saline (N=201), Mean (range)

68.1 (49.8 to 86.4)

Mean difference (95% CI): 4.5 (-6.5 to 15.5)

P=0.42

change in the clinical

score 30 minutes after the first inhalation

I: Inhaled Racemic Adrenaline (N=203), Mean (range)

-1.26 (-1.44 to -1.08)

C: Inhaled Saline (N=201), Mean (range)

-1.08 (-1.23 to -0.92)

Mean difference (95% CI): Not reported.

Ventilatory support

I : Inhaled Racemic Adrenaline (N=203), n/N (%)

15/203 (7.4)

C: Inhaled Saline (N=201), n/N (%)

15/201 (7.5)

Rate Ratio (95% CI): 0.99 (0.50 to 1.97)

The primary outcome, length of hospital stay, was defined as the time from the first study inhalation until discharge from the hospital.

No serious adverse events were reported. Three

children (including one who was receiving inhaled

saline) discontinued treatment because of moderate tachycardia, which may have been due to the study medication.

Article conclusion: There was no significant difference in length of hospital stay between children treated with inhaled racemic adrenaline and those treated with inhaled saline (P = 0.43). There were also no significant between-group differences in the use of nasogastric-tube feeding, supplemental oxygen, or ventilatory support; clinical scores before and after the first inhalation of the study medication; or the number of children in whom the study medication was discontinued.

Faten, 2014

Type of study:

RCT

Setting and country:

- Inpatients

- Tunis

Funding and conflicts of interest:

Not reported

Inclusion criteria:

Eligible infants included all previously well infants aged between one month old and 12 months old with a clinical diagnosis of first acute viral

bronchiolitis and who are hospitalized during the study period.

Exclusion criteria:

Children were excluded from the study if they had a gestational age at birth <34 weeks, or underlying chronic cardiac or pulmonary disease (eg, broncho-pulmonary dysplasia, cystic fibrosis), recurrent wheezing, severe respiratory distress, as evidence by apnea, heart rate> 200 beats per minute, respiratory rate >80 breath/minute, profound lethargy, duration of illness exceeding 15 days.

N total at baseline:

97 infants were randomized to the study protocol

94 patients achieved the study.

Intervention:

- Group 1: 31 patients received 5% hypertonic saline

- Group 2: 37 a mixed 5% hypertonic

saline and standard epinephrine

Control:

- 26 received normal saline (placebo)

Important prognostic factors²:

age ± SD:

I: Group 1: 3,76±2,8

 Group 2: 3,28±2,53

C: 3,06±2,47

Sex % M:

I: Group 1: 71%

 Group 2: 59%

C: 54%

Baseline Wang Severity score:

I: Group 1: 5,35±1,4

 Group 2: 5,76±1,84

C: 4,28±1,53

Groups comparable at baseline?

No

Group 1: nebulized 5% hypertonic saline

(4ml)

Group 2: mixed 5% hypertonic saline with standard epinephrine ( 2ml

standard epinephrine + 2 ml 5% hypersaline)

Control: normal saline placebo (4ml of normal saline)

Length of follow-up:

Infants were only monitored until hospital discharge; no follow-up.

Loss-to-follow-up / incomplete data:

Three patients were excluded from statistical analyses: Two patients were withdrawn by the pediatric inpatient team because of worsening clinical status during the first 24 hours. These patients had been

randomized to receive placebo. Another patient was withdrawn at

parents’ request because the parents refused the hospitalization.

NB: Only those who completed the study were included in the analyses.

Wang clinical severity score, 30, 60, and 120 minutes after start treatment, mean (SD)

T30

Intervention:

Group 1: 4,74±1,3

Group 2: 4,54±1,53

Control: 4,42±1,8

p=0,74

T60

Intervention:

Group 1: 4,42±1,4

Group 2: 4,3±1,45

Control: 4 ± 1,55

p=0,56

T120

Intervention:

Group 1: 4±1,48

Group 2: 3,68±1,25

Control: 3,76±1,56

p=0,63

The mean time for discharge (SD) days

Intervention:

Group 1: 3,6± 1,7

Group 2: 3,5±1,973

Control: 4,48±3,81

p=0,32

No patients in either treatment group experienced clinically significant adverse side effects (tachycardia, flushing, tremor or bronchospasm)

Criteria of discharge from the hospital included: no need for supplemental oxygen, Wang severity score less than 3 and adequate fluid intake.

NB:

Patients in control group were less often male and had a lower severity score at baseline than intervention groups.

Article conclusion: Nebulized 5% hypertonic saline or mixed 5% hypertonic

saline with epinephrine are safe but do not appear effective in treating moderately ill infants with the first acute bronchiolitis.

Flores-Gonzalez, 2015

Type of study:

RCT

Setting and country:

- Inpatients

- Spain

Funding and conflicts of interest:

Funding: This work was supported by grants from

the Spanish Ministry of Health, Social Politics and

Equality for the promotion of independent clinical

research of 2010 (EC10-180). The funder had no role

in study design, data collection and analysis, decision

to publish, or preparation of the manuscript.

Competing Interests: The authors have declared

that no competing interests exist.

Inclusion criteria:

Eligible patients included infants aged under 24 months admitted to Hospital with a clinical diagnosis of acute bronchiolitis classified as moderate in severity. The diagnosis was based on a first episode of respiratory distress with wheezing and/or crackles, preceded by an infection of the upper airways.

Exclusion criteria:

Infants were excluded

if they had any of the following risk factors: premature birth as defined by the World Health

Organization (< 37 weeks), in infants with an adjusted age of less than 6 weeks at the time of

enrollment, chronic respiratory disease, hemodynamically significant heart disease, immunodeficiency,

and neuromuscular disease. Infants with previous episodes of wheezing or a physician’s

diagnosis of asthma were also excluded. Finally, we also excluded patients receiving

other non-study treatments during hospitalization.

N total at baseline:

- 208 were randomized

- 185 in analyses

Intervention:

104 randomized, 94 in analyses

Control:

104 randomized, 91 in analyses

Important prognostic factors²:

age Mean months (SD):

I: 2.10±2.37

C: 2.12±2.08

Sex % M:

I: 46 (48.9)

C: 46 (50.5)

Wood-Downes Scale modified by Ferres (WDF) severity score, N (%)

I: 5.36±0.98

C: 5.24±1.17

Groups comparable at baseline?

yes

Patients received nebulized epinephrine (3 ml of a 1:1000 solution), in

3% hypertonic saline (7 mL).

The nebulized solution was administered by means of a mask

using an ultrasonic hospital nebulizer (Shinmed model Sw918) with a frequency of 1.7 MHz and a mist particle size of 1 to 5 μm.

The solutions were administered initially every

4 hours.

Infants received the same standard support (elevation

of the head of bed, supplemental oxygen when oxygen saturation dropped below 94%,

acetaminophen if fever, and a nasal lavage with sterile saline before and after the administration

of the nebulized solution).

Patients received nebulized 3% hypertonic

saline (7 mL) plus 3 mL placebo (sterile water).

The nebulized solution was administered by means of a mask

using an ultrasonic hospital nebulizer (Shinmed model Sw918) with a frequency of 1.7 MHz and a mist particle size of 1 to 5 μm.

The solutions were administered initially every

4 hours.

Infants received the same standard support (elevation

of the head of bed, supplemental oxygen when oxygen saturation dropped below 94%,

acetaminophen if fever, and a nasal lavage with sterile saline before and after the administration

of the nebulized solution).

Follow-up:

Patients were monitored only until hospital discharge.

Lost in follow-up:

I: 10/104 lost

- 6 were admitted to intensive care

- 2 were withdrawn by the pediatrician

- 1 was withdrawn by parent

- 1 failed to fulfil inclusion criteria

C: 13/104 lost

- 6 were admitted to intensive care

- 2 were withdrawn by pediatrician

- 3 were withdrawn by parent

- 2 failed to fulfil inclusion criteria

NB: Only those who completed the study were included in the analyses.

I: 94

C: 91

LOS days, mean (SD)

I: 3.94±1.37

C: 4.82±2.3

P = 0.011

Required more than 4 days of hospitalization, n (%)

I: 13 (13.8)

C: 28 (30.8)

P = 0.006

RR: 0.45, 95% CI: 0.25 to 0.81

Comparison of survival curves

showed significant differences in the LOS from day 4 onwards (P = 0.001)

WDF severity score at day 3, mean (95% CI)

I: 3.93 (3.68 to 4.17)

C: 4.31 (4.01 to 4.59)

 p = 0.029

WDF severity score at day 5

I: 3.37 (3.02 to 4.72)

C: 4.03 (3.67 to 4.40)

p = 0.036

The primary efficacy outcome was length of hospital stay (LOS), defined as the number of days from admission to the time at which the patient fulfilled the study discharge criteria: aWDF score of 3 or less, an oxygen saturation of 97% or more without supplemental oxygen, adequate oral tolerance, and no further need for nebulized therapy.

Authors report no adverse

events (i.e. tachycardia, sweating, pallor, trembling, or hypertension), during hospitalization.

NB: However, patients with such severe adverse events that PICU admission was necessary (6 in each group), were excluded from analyses.

Group n confusing: figure group data are swapped.

Article conclusion:

Nebulized epinephrine in 3% saline significantly shortens the length of hospital stay of infants with acute moderate bronchiolitis in our setting, where it normally exceeds 4 days, and reduces the risk of a prolonged stay, without any increase in the occurrence of adverse events, when compared with placebo in 3% saline.

Uysalol, 2017

Type of study:

RCT

Setting and country:

- Emergency Department (ED)

- Turkey

Funding and conflicts of interest:

Not reported

Inclusion criteria:

Children with acute bronchiolitis, aged between 2-24 months with a score as moderate (4-8) in the bronchiolitis clinical score (BCS) system were included.

Exclusion criteria:

Exclusion criteria were being younger than 2 months old, prematurity (less than 36th gestational week), low birth weight (less than 2,500 g), history of admission in neonatal intensive care unit due to respiratory distress, history of intubation in the intensive care unit, congenital heart/lung/neurologic or immunologic disease, history of atopic disease or recurrent wheezing, clinical or radiologic findings of bacterial infections, atelectasis or consolidations on X-ray and refusal to consent by parents.

N total at baseline:

- 386 patients were randomized.

- 378 patients were able to complete the trial and only these were included in statistical analyses.

Intervention:

Group 1 (HS): 77

Group 2 (ADR): 75

Group 3 (ADR+HS): 75

Group 4 (Salbutamol): 72

Control:

Group control (NS): 79

Important prognostic factors²:

age months, Median (IQR):

I: 7 (4-10) months (all groups the same)

C: 7 (4-10) months

Sex % M:

Intervention:

Group 1 (HS): 55.8%

Group 2 (ADR): 54.7%

Group 3 (ADR+HS): 54.7%

Group 4 (Salbutamol): 54.2%

Control:

Group control (NS): 54.4%

Groups comparable at baseline?

Yes

Drugs were administered by means of standard hospital nebulizers through a firmly applied face mask with an oxygen flow of 6 liters per minute within 6-8 minutes.

Administration at at 0, 30, and 60 minutes, and every 4 hours thereafter if needed to a maximum of 24 h.

Group 1: 3% hypertonic saline (HS); Group HS was given 4 ml HS

Group 2: nebulized adrenaline (ADR); group ADR received 4 ml NS with ADR 0.1 mg/kg

Group 3: nebulized adrenaline mixed with 3% hypertonic saline (ADR+HS); group ADR+HS received 4 ml HS with 0.1 mg/kg/dose ADR

Group 4: nebulized salbutamol; group Salbutamol had nebulized salbutamol 0.15 mg/kg with 4 ml NS

Control Group: normal saline (0.9% NaCl) (NS); group NS was administered 5 ml NS

Administration at at 0, 30, and 60 minutes, and every 4 hours thereafter if needed to a maximum of 24 h.

Length of follow-up:

Readmission to the hospital within first 15 days was recorded.

Loss-to-follow-up / incomplete data:

During the study, infants whose BCS had deteriorated worse than 9 were excluded from the study (2 in HS group, 1 in ADR group, 2 in salbutamol group and 3 in NS group). At the end, 378 patients were able to complete the trial

NB: Only those who completed the study were included in the analyses.

Comparison of Discharge Rates at 4 Hours of Treatment Options (Reference Group: Normal saline)

Odds Ratio (OR), 95%CI

Group 1 (HS): 1.595 (0.841 to 3.024)

p=0.153

Group 2 (ADR): 2.194 (1.150 to 4.186)

p=0.017

Group 3 (ADR+HS): 3.898 (1.993 to 7.625)

p<0.001

Group 4 (Salbut): 1.034 (0.534 to 2.004)

p=0.920

Discharge rate at 4 hrs, n (%)

Intervention:

Group 1 (HS): 37/77 (48.1%)

Group 2 (ADR): 42/75 (56%)

Group 3 (ADR+HS): 52/75 (69.3%)

Group 4 (Salbut): 27/72 (37.5%)

Control:

Group control (NS): 29/79 (36.7%)

p=0.001

Discharge rate at 24 hrs, n (%)

Intervention:

Group 1 (HS): 69 (77%)

Group 2 (ADR): 66 (88%)

Group 3 (ADR+HS): 71 (94.7%)

Group 4 (Salbut): 63 (87.5%)

Control:

Group control (NS): 66 (83.5%)

p=0.294

Length of Stay (LOS) (hours), median (IQR)

Intervention:

Group 1 (HS): 8 (12)

Group 2 (ADR): 4 (12)

Group 3 (ADR+HS): 4 (8)

Group 4 (Salbut): 16 (20)

Control:

Group control (NS): 16 (20)

p=0.039

Adverse events (tachycardia, pallor, tremor, nausea, vomiting), n (%)

Intervention:

Group 1 (HS): 0 (0%)

Group 2 (ADR): 7 (9.3%)

Group 3 (ADR+HS): 5 (6.7%)

Group 4 (Salbut): 7 (9.7%)

Control:

Group control (NS): 2 (2.5%)

p=0.079

Primary outcomes: LOS and Discharge rate.

The study was not powered to detect differences in secondary outcome measures.

Only those who completed the study were included in the analyses.

Criteria for discharge:

Infants were evaluated using BCS at 4-hour intervals and a score less than 3 were considered for discharge decision.

Article conclusion: Nebulized adrenaline mixed with 3% hypertonic saline, as compared with other options, were associated with a significantly higher discharge rate at 4th hours (p<0.001) and shorter length of hospital stay (p=0.039). However, there was no significant difference between options with regard to adverse events, discharge rates at 24th hours, and readmission rates within the first fifteen days.

Bashir, 2018

Type of study:

RCT

Setting and country:

- Inpatients, tertiary care hospital

- India

Funding and conflicts of interest:

None

Inclusion criteria:

Previously healthy infants and children of two months to 18 months of age, getting admitted with first episode of respiratory tract infection with wheeze, starting as a viral upper respiratory infection (coryza, cough, or fever), and a clinical score between 4 and 8 were included in the study.

Exclusion criteria:

Includes a history of any of the following: previous episode of wheezing, chronic cardiopul monary disease or immunodeficiency; critical illness at presentation requiring admission to intensive care; the use of nebulized HS within the previous 12 hours; or premature birth (gestational age 34 weeks).

N total at baseline: 189

Intervention: 96

Control: 93

Important prognostic factors²:

age median months (IQR):

I: 4.0 (2.63-8.0)

C: 4.0 (2.0-7.0)

Sex % M:

I: 64.6%

C: 69.9%

Groups comparable at baseline?

yes

Treatment with 4 mL of nebulized study solution containing 3% HS.

Every two hourly for three doses, followed by every four hourly for six doses, followed by every six hourly until discharge.

Treatment with 4 mL of nebulized study solution containing 0.9% NS.

Every two hourly for three doses, followed by every four hourly for six doses, followed by every six hourly until discharge.

Length of follow-up:

Until hospital discharge.

Loss-to-follow-up / incomplete data:

Five infants (one from the HS group and four from the NS group) were withdrawn before study completion but were included in the final intention to treat analysis and were counted as treatment failures.

Discharge within 1 day, n (%), RR (95%CI)

I: 55 (57.3%)

C: 4 (4.3%)

13.32 (5.03 to 35.28), p<.0001

Discharge within 2 days, n (%), RR (95%CI)

I: 94 (97.92%)

C: 59 (63.44%)

1.54 (1.32 to 1.81), p<.0001

Discharge within 3 days, n (%), RR (95%CI)

I: 96 (100%)

C: 90 (96.77%)

1.03 (0.996 to 1.072), p=0.083

100% Discharge within 4 days for all.

LOS mean days (SD)

I: 1.45 (0.54)

C: 2.35 (0.62)

p<.001

Reduction in Wang clinical severity score within 48 hours, mean (SD)

I: 2.26 (0.68)

C: 1.23 (0.49)

p<0.001 favouring 3% HS group

Children showing worsening of clinical scores and general condition during the course of the stay were excluded from the study and treated as the condition necessitates. However, these patients were included in the final analysis and were counted as treatment failures.

Criteria for discharge: patients were discharged once they were off oxygen support, maintaining saturations without any respiratory distress and accepting feeds well.

There were no adverse events noted in either of the groups in present study.

Article conclusion: This study demonstrates that 3% HS nebulization is safe and effective treatment for infants up to the age of 18 months hospitalized with acute bronchiolitis and decreases hospital stay by about one day.

Jaquet-Pilloud, 2020

Type of study:

RCT

Setting and country:

- Inpatients

- Switzerland

Funding and conflicts of interest:

Funding: The authors have not declared a specific grant for this research from any

funding agency in the public, commercial or not-for-profit sectors.

Competing interests: None declared.

Inclusion criteria:

Eligible patients included children aged from 6 weeks up to 24

months coming to the emergency department (ED) with a first

episode of acute bronchiolitis, defined as symptoms of upper

respiratory tract infection in addition to tachypnoea, wheezing

and widespread crackles at auscultation. Further inclusion

criteria were a Wang Score of 5–12 (moderate to severe) on

arrival.

Exclusion criteria:

Exclusion criteria were children with mild bronchiolitis (Wang

Score <5), previous episodes of wheezing, cardiac or chronic

respiratory disease, immunocompromised children, gestational

age <34 weeks and children with critical illness requiring

immediate admission to intensive care unit (ICU). Children

who received RSV immunoglobulin therapy, corticotherapy in

any form in the preceding 2 weeks or bronchodilators within

24 hours prior to presentation, were also excluded.

N total at baseline:

- 122 were randomized

- 120 in analyses

Intervention:

61 randomized, 60 in analyses

Control:

61 randomized, 60 in analyses

Important prognostic factors²:

age Mean months (95% CI):

I: 7.7 (6.4; 9.1)

C: 7.5 (6.2; 8.9)

Sex % M:

I: 39 (64%)

C: 37 (63%)

Wang severity score, N (%)

I: 15 (24%)

C: 14 (23%)

Wang severity score, N (%)

I: 46 (76%)

C: 45 (77%)

Groups comparable at baseline?

yes

HS 3% Group received 4 mL of NaCl 3% (MucoClear 3%) every 6 hours until discharge in addition to standard care.

Standard therapy

includes suctioning nasal secretions, water-electrolyte balance

maintenance and oxygen supplementation when needed.

If any child showed signs of respiratory failure including

either persistent major respiratory distress, signs of exhaustion

with a partial pressure of carbon dioxide above >50 mm Hg on the capillary blood gas, a nebulization of 4 mg of epinephrine

was given.

Nebulized epinephrine could be administered up to three

times within the hour. If respiratory failure continued despite a total of three nebulizations

of epinephrine / in the absence of response, the patient was

admitted to ICU.

Standard Care group with no inhalation.

Standard therapy

includes suctioning nasal secretions, water-electrolyte balance

maintenance and oxygen supplementation when needed.

If any child showed signs of respiratory failure including

either persistent major respiratory distress, signs of exhaustion

with a partial pressure of carbon dioxide above >50 mm Hg on the capillary blood gas, a nebulization of 4 mg of epinephrine

was given.

Nebulized epinephrine could be administered up to three

times within the hour. If respiratory failure continued despite a total of three nebulizations

of epinephrine / in the absence of response, the patient was

admitted to ICU.

Length of follow-up:

Readmission rate in the next 7 days following

discharge from hospital was studied.

Loss-to-follow-up:

None

Incomplete data:

HS was discontinued in 10 patients at parents’ request (sleep preservation (n=5), agitation with the inhalation facemask

(n=5).

Two patients were excluded after randomization, one for misdiagnosis (pneumonia) and the other for decompensation of

an unknown neurological disease and excluded from the intention to treat analyses.

Hospital LOS (hours), Mean (95% CI)

I: 47 (39 to 56)

C: 50.4 (39 to 61)

Difference -2.8 (-11 to 16)

p=0.33

Duration oxygen therapy (hours), mean (95% CI)

I: 29.5 (22 to 36)

C: 31.1 (22 to 39)

Difference -1.5 (-9.6 to 12)

p=0.6

Transfers to PICU, N (%)

I: 0 (0%)

C: 3 (5%)

RR: 0.138 (95%CI 0.007 to 2.620)

p=0.187

Racemic epinephrine nebulization rescue therapy, N (%)

I: 5 (8.2)

C (9 (15%)

RR: 0.537 (95%CI 0.191 to 1.510)

p=0.239

No serious adverse events were observed (bronchospasm, excessive

couching, infection, apnea and cyanosis) during the study.

Authors report: Sixty-one patients were allocated to the intervention group

(HS) and 61 were allocated to the control group (standard care alone). One hundred and twenty patients completed the whole study.

However, all Tables in article state that the HS group analyses were with n=61 and the standard care group with n=59 => included N is unclear.

Article conclusion: There were no differences in oxygen therapy duration, transfer to ICU, readmission rate or adverse events. Study does not support the use of

HS nebulization in children with moderate to severe

bronchiolitis.

Author and year

Reason for exclusion

Guo, 2018

Meta-analysis with all relevant studies already covered by the 3 Cochrane reviews.

House, 2020

No relevant outcome measures.

Simsek-Kiper, 2011

RCT that added to Hartling 2011 adrenaline, or so I thought, but did not present relevant outcome data.

Flores-Gonzalez, 2016

Adds to Hartling 2011 adrenaline, but seems to be the same study as Flores-Gonzalez 2015, but with older/incomplete data of the same trial - data until 2014

Morikawa, 2018

Adds to Zhang 2017, but already in Hsieh 2020 => data taken from there

Saseen, 2004

Is a summary of Hartling 2003

Bourke, 2011

SR excluded because everything in Hartling 2011, Gadomski 2014, or Zhang 2017

Chen, 2014

SR of which all relevant studies included in Zhang 2017

Castro-Rodriguez, 2015

Doesn't add any relevant information; just gives a summary of results of different SRs we already have

Everard, 2015

SR of which all relevant studies included in Zhang 2017

Maguire, 2015

SR of which all relevant studies included in Zhang 2017

Zhang, 2015

SR of which all studies included in Zhang 2017

Brooks, 2016

SR of which all studies included in Zhang 2017

Heikkilä, 2018

SR of which all relevant studies included in Zhang 2017

Zhang, 2018

SR of which all studies included in Zhang 2017

Wang, 2019

SR of which all studies included in Zhang 2017

Hartling, 2003

See Hartling 2011 for new Cochrane

Absar, 2008

Short communications, not all data present. Prospective Cohort.

Baron, 2016

Review is not systematic; not all necessary data

Unknown, 2010

Is a summary of Grewal 2009

Yasin, 2020

No RCT: quasi-randomized unblinded trial; allocation not blinded; prospective

Hartling, 2011

SR excluded because everything in Hartling 2011, Gadomski 2014, or Zhang 2017

Khanal, 2015

RCT included in Zhang 2017

King, 2004

SR of which all studies included in Hartling 2011

Ralston, 2014

No relevant data provided

Seiden, 2009

Narrative review

Wright, 2011

Narrative review

Panitch, 2003

Narrative review