Appendix 1. Search methods for 2017 update

PubMed: ((infant, newborn[MeSH] OR newborn OR neonate OR neonatal OR premature OR low birth weight OR VLBW OR LBW or infan* or neonat*) AND (randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized [tiab] OR placebo [tiab] OR drug therapy [sh] OR randomly [tiab] OR trial [tiab] OR groups [tiab]) NOT (animals [mh] NOT humans [mh]))

Embase: (infant, newborn or newborn or neonate or neonatal or premature or very low birth weight or low birth weight or VLBW or LBW or Newborn or infan* or neonat*) AND (human not animal) AND (randomized controlled trial or controlled clinical trial or randomized or placebo or clinical trials as topic or randomly or trial or clinical trial)

CINAHL: (infant, newborn OR newborn OR neonate OR neonatal OR premature OR low birth weight OR VLBW OR LBW or Newborn or infan* or neonat*) AND (randomized controlled trial OR controlled clinical trial OR randomized OR placebo OR clinical trials as topic OR randomly OR trial OR PT clinical trial)

Cochrane Library: (infant or newborn or neonate or neonatal or premature or preterm or very low birth weight or low birth weight or VLBW or LBW)

Google Scholar: Reverse citaion on relavant articles

Appendix 2. Search methods for 2012 review

MeSH subject headings were infant, newborn, neonates, preterm infant, extravasation, saline, hyaluronidase, irrigation, therapeutic irrigation, and infiltration.

Summary of literature search details

MEDLINE‐ (searched from 1950 ‐ 24/06/2011) 28 references retrieved.

Embase‐ (searched from 1980 ‐ 24/06/2011) 26 references retrieved.

CINAHL‐ (searched from 1981 ‐ 28/06/2011) 38 references retrieved.

Cochrane Central Database of Clinical Trials (CENTRAL) ‐ (searched up to 28/06/2011) 26 references retrieved.

Web of Science‐ (searched from 1911 ‐ 11/07/2011) 1 reference retrieved.

Total references retrieved (after de‐duplication): 64

MEDLINE (Ovid) ‐ full search up to 24 June 2011

1 "Extravasation of Diagnostic and Therapeutic Materials"/pc, su, th (Prevention & Control, Surgery, Therapy)

2 Saline Solution, Hypertonic/or Saline.mp.

3 1 and 2

4 limit 3 to (English language and "newborn infant (birth to 1 month)")

5 "Extravasation of diagnostic and Therapeutic Materials"/

6 2 and 5

7 limit 6 to (English language and "newborn infant (birth to 1 month)")

8 from 4 keep 1‐3

9 extravasation.mp. or inflammation/

10 swelling.mp. or Edema/

11 Erythema/

12 9 or 10 or 11

13 catheterization, Peripheral/ or Infusions, Intravenous/

14 2 and 12 and 13

15 limit 14 to (English language and "newborn infant (birth to 1 month)")

16 neonate.mp

17 Infant, Newborn/or Infant, Premature/

18 16 or 17

19 14 and 18

20 3 and 18

21 13 and 18

22 2 and 21

23 5 and 18

24 limit 23 to English language

25 limit 24 to yr=Current

26 Therapeutic irrigation/ or irrigation.mp

27 hyaluronidase.mp. (mp=protocol supplementary concept, rare disease supplementary concept, title, original title, abstract, name of substance word, subject heading word, unique identifier)

28 5 and 26 and 27

29 5 and 27

30 18 and 29

Embase (Ovid) ‐ up to 27 June 2011

1 "Extravasation of Diagnostic and Therapeutic materials"/

2 extravasation.mp.

3 1 or 2

4 Infusions, Intravenous/

5 Catheterization, Peripheral/

6 4 or 5

7 Inflammation/

8 Erythema/

9 swelling.mp.

10 Edema/

11 7 or 8 or 9 or 10

12 6 and 11

13 3 or 12

14 Saline Solution, Hypertonic/ or Saline.mp.

15 hyaluronidase.mp. or hyaluronoglucosaminidase/

16 Therapeutic irrigation/ or Irrigation.mp.

17 13 and 14 and 15 and 16

18 13 and 14 and 15

19 limit 18 to English language (not limited to age)

20 limit 19 to "newborn infant (birth to 1 month)"(limit not valid in Embase; records were retained)

21 13 and 14 and 16

22 limit 21 to English language

23 13 and 14

24 limit 23 to English language

25 limit 20 to infant

26 2newborn"/

27 infant/

28 neonatal.mp.

29 neonate.mp.(mp=title,abstract,subject heading, heading word, drug trade name, original title, device manufacturer, drug manufacturer,device trade name, keyword)

30 26 or 27 or 28 or 29

24 and 30

Web of Science ‐ up to 11/07/2011

#1 Topic = (extravasation)

#2 Title = Extravasation

#3 #1 AND #2

#4 Topic = Saline

#5 Topic = hyaluronidase

#6 Topic = therapeutic irrigation

#8 #7 or #6

#9 #8 AND #5 AND #4 AND #3

#10 #5 AND #4 AND #3

#11 #8 AND #4 AND #3

#12 #4 AND #3

#13 #4 AND #3 limited to2007 ‐ 2010

#14 #4 AND #3 limited to 2007 ‐ 2010 and Neonat #10

#15 #4 AND #3 limited to 2011

CINAHL (EBSCO) ‐ up to 28 June 2011

S21 S3 or S11

Limiters ‐ English language; published date from 20000101‐20111231; age groups: infant, newborn: birth, 1 month, infant 1‐23 months

Expanders ‐ also search within the full text of articles

Search modes ‐ Boolean/phrase

S20 S3 or S11

Limiters ‐ English language; age groups: infant, newborn: birth, 1 month, infant 1‐23 months

Expanders ‐ also search within the full text of articles

Search modes ‐ Boolean/phrase

S19 S12 and S13

Limiters ‐ age groups: infant, newborn: birth, 1 month, infant 1‐23 months

Expanders ‐ also search within the full text of articles

Search modes ‐ Boolean/phrase

S18 S12 and S13

Expanders ‐ also search within the full text of articles

Search modes ‐ Boolean/phrase

S17 S12 and S13 and S14

Expanders ‐ also search within the full text of articles

Search modes ‐ Boolean/phrase

S16 S12 and S13 and S14 and S15

Expanders ‐ also search within the full text of articles

Search modes ‐ Boolean/phrase

S15 (MH " Feeding Tube irrigation") OR (MH " Catheter irrigation, Vascular") OR (MH " Irrigation")

Expanders ‐ also search within the full text of articles

Search modes ‐ Boolean/phrase

S14 ( MH " HYaluronidase")

Expanders ‐ also search within the full text of articles

Search modes ‐ Boolean/phrase

S13 ( MH "Saline Solution, Hypertonic") OR " Saline"

Expanders ‐ also search within the full text of articles

Search modes ‐ Boolean/phrase

S12 S3 or S11

Expanders ‐ also search within the full text of articles

Search modes ‐ Boolean/phrase

S11 S6 and S10

Expanders ‐ also search within the full text of articles

Search modes ‐ Boolean/phrase

S10 S7 or S8 or S9

Expanders ‐ also search within the full text of articles

Search modes ‐ Boolean/phrase

S9 (MH " Erythema")

Expanders ‐ also search within the full text of articles

Search modes ‐ Boolean/phrase

S8 (MH "inflammation") OR "Inflammation"

Expanders ‐ also search within the full text of articles

Search modes ‐ Boolean/phrase

S7 "swelling" OR (MH "Edema")

Expanders ‐ also search within the full text of articles

Search modes ‐ Boolean/phrase

S6 S4 OR S5

Expanders ‐ also search within the full text of articles

Search modes ‐ Boolean/phrase

S5 (MH " Catheterization, Peripheral" ) OR (MH " Catheterization, Peripheral Central venous")

Expanders ‐ also search within the full text of articles

Search modes ‐ Boolean/phrase

S4 (MH "intravenous therapy") OR (MH " Fluid Resuscitation")

Expanders ‐ also search within the full text of articles

Search modes ‐ Boolean/phrase

S3 S1 or S2

Expanders ‐ also search within the full text of articles

Search modes ‐ Boolean/phrase

S2 "extravasation"

Expanders ‐ also search within the full text of articles

Search modes ‐ Boolean/phrase

S1 (MH "Extravasation of Diagnostic and Therapeutic Materials")

Expanders ‐ also search within the full text of articles

Search modes ‐ Boolean/phrase

The Cochrane Central Register of Controlled trials (CENTRAL) (2011, Issue 2) in the Cochrane Library ‐ 28 June 2011

#1 MeSH descriptor Extravasation of Diagnostic and Therapeutic Materials explode all trees

#2 extravasation

#3 (#1 OR #2)

#4 MeSH descriptor Infusions, Intravenous explode all trees

#5 MeSH descriptor Catheterization, Peripheral explode all trees

#6 (#4 OR #5)

#7 MeSH descriptor inflammation, this term only

#8 MeSH descriptorErythema explode all trees

#9 swelling

#10 edema

#11 (#7 OR #8 OR #9 OR10)

#12 (#6 AND #11)

#13 (#3 OR #12)

#14 MeSH descriptor Saline Solution, hypertonic explode all trees

#15 saline

#17 hyaluronidase

#18 MeSH descriptor Hyaluronoglucosaminidase explode all trees

#19 (#17 OR #18)

#20 MeSH descriptor Therapeutic Irrigation, this term only

#21 irrigation

#22 (#20 OR #21)

#23 (#13 AND #16 AND #19 AND #22)

#24 (#13 AND #16 AND #19)

#25 (#13 AND #16)

#26 ( #13 AND #16)

#27 neonat*

#28 MeSH descriptor Infant, Newborn explode all trees

#29 infant

#30 ( #27 Or #28 Or #29)

#31 (#25 AND #30)

#32 (#13 AND #30)

#33 (#32 AND NOT #25)

#34 (#33 AND NOT #31)

Appendix 3. Risk of bias tool

We used the standard methods of the Cochrane Collaboration and the Cochrane Neonatal Review Group to assess the methodological quality (to meet the validity criteria) of trials. For each trial, we sought information regarding the method of randomisation and blinding and reporting of all outcomes for all infants enrolled in the trial. We assessed each criterion as low, high, or unclear risk. Two review authors separately assessed each study. We resolved disagreements by discussion. We added this information to the Characteristics of included studies table. We evaluated the following issues and entered the findings into the risk of bias table.

1. Sequence generation (checking for possible selection bias). Was the allocation sequence adequately generated?

For each included study, we categorised the method used to generate the allocation sequence as:

a. Low risk (any truly random process, e.g. random number table; computer random number generator);

b. High risk (any non‐random process, e.g. odd or even date of birth; hospital or clinic record number); or

c. Unclear risk.

2. Allocation concealment (checking for possible selection bias). Was allocation adequately concealed?

For each included study, we categorised the method used to conceal the allocation sequence as:

a. Low risk (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);

b. High risk (open random allocation; unsealed or non‐opaque envelopes, alternation; date of birth); or

c. Unclear risk.

3. Blinding of participants and personnel (checking for possible performance bias). Was knowledge of the allocated intervention adequately prevented during the study?

For each included study, we categorised 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 categorised the methods as:

a. Low risk, high risk, or unclear risk for participants; and

b. Low risk, high risk, or unclear risk for personnel.

4. Blinding of outcome assessment (checking for possible detection bias). Was knowledge of the allocated intervention adequately prevented at the time of outcome assessment?

For each included study, we categorised the methods used to blind outcome assessment. Blinding was assessed separately for different outcomes or classes of outcomes. We categorised the methods as:

a. Low risk for outcome assessors;

b. High risk for outcome assessors; or

c. Unclear risk for outcome assessors.

5. 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 described completeness of data including attrition and exclusions from the analysis. We noted 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 when reported, and whether missing data were balanced across groups or were related to outcomes. When sufficient information was reported or supplied by trial authors, we re‐included missing data in the analyses. We categorised the methods as:

a. Low risk (< 20% missing data);

b. High risk (≥ 20% missing data); or

c. Unclear risk.

6. Selective reporting bias. Are reports of the study free of the suggestion of selective outcome reporting?

For each included study, we described how we investigated the possibility of selective outcome reporting bias and what we found. We assessed the methods as:

a. Low risk (when it is clear that all of the study's prespecified outcomes and all expected outcomes of interest to the review have been reported);

b. High risk (when not all of the study's prespecified outcomes have been reported; when one or more reported primary outcomes were not prespecified outcomes of interest and are reported incompletely and so cannot be used; when study fails to include results of a key outcome that would have been expected to have been reported); or

c. Unclear risk.

7. Other sources of bias. Was the study apparently free of other problems that could put it at high risk of bias?

For each included study, we described any important concerns that we had about other possible sources of bias (e.g. whether a potential source of bias was related to the specific study design, whether the trial was stopped early owing to some data‐dependent process). We assessed whether each study was free of other problems that could put it at risk of bias as:

a. Low risk;

b. High risk; or

c. Unclear risk.

If needed, we explored the impact of the level of bias by undertaking sensitivity analyses.

Appendix 4. Reason for increased duration of this update from the original review published in February 2012

A prospective surveillance on literature by the review authors yielded no relevant RCTs or quasi‐RCTs and even cohort studies. Hence the review authors decided to defer updating this review until 2017.

Appendix 5. Next update of this review

The review authors propose to update this review with an enhanced duration of four years by 2021, with the hope that more relevant studies will be published in the literature by that time.