Study reference

Study characteristics

Patient characteristics

Intervention (I)

Comparison / control (C)

Follow-up

Outcome measures and effect size

Comments

Li, 2018

SR and meta-analysis of RCTs

Literature search up to January 16^th, 2018.

A: Benakatti, 2014

B: Maitlan, 2011

C: Santhanam, 2008

Study design:

A: prospective randomized trial

B: parallel-group randomized trial

C: parallel-group randomized trial

Setting and Country:

A: paediatric ICU, India

B: general paediatric wards at 6 clinical centres in Kenya, Tanzania and Uganda.

C: emergency department of a public hospital, India

Source of funding and conflicts of interest:

A: no information provided

B: funded by the Medical Research Council, UK

C: no information provided.

Inclusion criteria SR: RCTs, quasi RCTs and/or cluster RCTs studying adults and children with sepsis and septic shock comparing liberal versus. conservative fluid therapy.

Exclusion criteria SR: neonatal sepsis studies

3 paediatric studies included

Important patient characteristics at baseline:

Number of patients; characteristics important to the research question and/or for statistical adjustment (confounding in cohort studies); for example, age, sex, bmi, ...

N, mean age

A: 101 patients, 3 to 144 months

B: 3141, 60 days old to 12 years old, median age 23 months (IQR 14 to 37 months)

C: 160, 1 months to 12 years old

Sex:

A: not reported

B: n=1452 female; n=1689 male.

C: not reported.

Diagnosis:

A: children with septic shock

B: children with severe febrile illness and impaired perfusion

C: healthy children aged between 1 month and 12 years who were triaged as septic shock at the outpatient department

Inclusion criteria as reported per individual study:

A: not reported

B: Children between 60 days and 12 years of age, presenting with a severe febrile illness complicated by impaired consciousness (prostration or coma), respiratory distress (increased work of breathing), or both, and with impaired perfusion

C: “Healthy children aged between 1 month and 12 years triaged as septic shock at the outpatient department

Exclusion criteria as reported per individual study:

A: not reported

B: 1. Severe malnutrition 2. Gastroenteritis 3. Non-infectious causes of shock (e.g. trauma, surgery, burns) 4. Conditions for which volume expansion is contraindicated

C: “Age younger than 30 days, shock due to hypovolaemia, haemorrhage, anaphylaxis, envenomation, diabetic ketoacidosis, inborn errors, of metabolism, drug toxicity, trauma, burns, stridor, near fatal asthma, pre-hospital fluid resuscitation, grade 3 malnutrition, chronic systemic co-morbidities, genetic disorders, malignancies, immunocompromised conditions, human immunodeficiency virus, do not resuscitate orders, physician’s decision not to treat, and cardiopulmonary arrest before arrival or within the first hour of resuscitation”

Groups comparable at baseline? Unclear

A: conventional fluid regimen (mean 339 (SD 117) mL); n = not reported

B:
group 1: 20 mL of 5% albumin solution per kilogram of body weight; n = 1050

Group 2: 20 mL of 0.9% saline solution per kilogram of body weight; n = 1047

C: 40 mL/kg of fluid over 15 minutes followed by dopamine and further titration of therapy to achieve therapeutic goals (study protocol); n = 80

A: restrictive maintenance fluid regimen (mean 42.6 (SD 82.6) mL; n = not reported

B: no bolus (1.2 mL/kg), n=1044

C: 20 mL/kg over 20 minutes up to a maximum of 60 mL/kg over 1 hour followed by dopamine (control protocol) in septic shock; n = 80

End-point of follow-up:

A: not reported, duration was 12 months

B: not reported 24 weeks

C: not reported, 13 months

For how many participants were no complete outcome data available?

(intervention/control)

A: not stated

B: 69 withdrew from group A, 64 withdrew from group B, 44 from the control group.

C: 6 participants from intervention group, 7 from control group

All-cause mortality in hospital/ICU

Outcome was not further defined.

A: Data from study A could not be used. Mortality rates in the PICU revealed no clear differences between compared groups (18.5% versus 23.4%; P = 0.54). However, because several participants were absent from each group, we were unable to extract usable data for analysis.

B: RR 1.45 (95%CI 1.13, 1.86)

C: RR 0.99 (95%CI 0.49, 1.98)

Pooled effect (random effects model): RR 1.38, 95% CI 1.07 to 1.77; NNTH = 34; favoring conservative fluid

Heterogeneity (I²): 3%

Sensitivity analysis for all-cause mortality in hospital/ICU:

Analyzed on the assumption for missing data (with ITT analysis), results showed no clear differences between liberal initial fluid therapy and conservative fluid therapy in risk of death (2 studies; N = 3301; RR 1.26, 95% CI 0.85 to 1.86). This indicated that missing data may have had some impact on study findings.

All-cause mortality at follow-up

Outcome was not further defined.

A: outcome not reported

B: mortality rate at 4 weeks follow-up was higher among participants receiving liberal fluid therapy compared to conservative therapy (RR 1.39, 95% CI 1.11 to 1.74; NNTH = 29)

I: 254/2097

C: 91/1044

C: outcome not reported

Pulmonary oedema at over 24 hours

Outcome was not further defined.

A: outcome not reported

B: no clear differences between liberal fluid and conservative fluid groups in the incidence of pulmonary oedema by 48 hours (RR 1.66, 95% CI 0.67 to 4.12)

C: outcome not reported

Adverse events: hepatomegaly

Outcome was not further defined.

A: outcome not reported

B: outcome not reported

C: no clear differences in the incidence of hepatomegaly between the two therapy groups by 60 minutes after infusion (RR 0.95, 95% CI 0.60 to 1.50)

Adverse events: need for ventilation

Outcome was not further defined.

A: outcome not reported

B: outcome not reported

C: no clear differences between the two therapy groups (RR 1.17, 95% CI 0.83 to 1.65)

Adverse events: other adverse events

Outcome was not further defined.

A: outcome not reported

B: by 48 hours after resuscitation, data showed no clear differences between liberal initial fluid and conservative fluid therapy in the incidence rate of adverse events, including:

- allergic reactions (N = 3141; RR 1.74, 95% CI 0.36 to 8.37)

- neurological sequelae (N =2983; RR 1.03, 95% CI0.61 to 1.75)

- increased intracranial pressure (N = 3141; RR 1.54, 95% CI 0.78 to 3.02)

- severe hypotension (N = 3141; RR 0.50, 95% CI 0.10 to 2.46

C: other adverse events at 60 minutes: no clear differences between the two therapy groups for occurrence of:

- desaturation (RR 1.81, 95% CI 0.97 to 3.38)

- tracheal intubation (RR 1.30, 95% CI 0.90 to 1.89).

Ventilator-free days in patients alive within 28 days

Outcome was not further defined.

A: Results show that liberal initial fluid therapy could lead to fewer ventilation-free days (mean ± SD: 6.3 ± 5.8 days) when compared with conservative fluid therapy (mean ±SD: 9.9± 5.2days; P =0.012). However, study authors did not report in this abstract the number of participants in each group and the data were skewed; we did not perform parameter testing.

B: outcome not reported

C: outcome not reported

NB: Li, 2018 studies liberal versus. conservative fluid regimen. To interpret data correctly according to the PICO of this chapter, results need to be inverted, as this concerns restrictive versus. liberal.

A: study data were not quantitatively extracted by authors as number of participants was unknown.

B: children with severe hypotension were not included in the analysis.

C:

Level of evidence: GRADE (per comparison and outcome measure) including reasons for down/upgrading

Sensitivity analyses (excluding small studies; excluding studies with short follow-up; excluding low quality studies; relevant subgroup-analyses); mention only analyses which are of potential importance to the research question

Heterogeneity: clinical and statistical heterogeneity; explained versus unexplained (subgroup analysis)

Study reference

Study characteristics

Patient characteristics ²

Intervention (I)

Comparison / control (C) ³

Follow-up

Outcome measures and effect size ⁴

Comments

Inwald, 2019

Type of study: pragmatic, open, multicentre pilot RCT.

Setting and country: four regional hospitals with 2 PICUs and nine district general hospitals with an emergency department, UK.

Funding and conflicts of interest: This study was funded by the NIHR HTA programme (13/04/105). The authors declare there are no competing interests.

Inclusion criteria: age older than 37 weeks (corrected gestational age) and younger than 16 years; clinical suspicion of infection; and signs of shock—defined as age-adjusted hypotension (less than fifth centile systolic blood pressure (BP) for age or capillary refill time (CRT) greater than or equal to 3 s)—after receipt of 20 mL/kg of bolus fluid. Fifth centile systolic BP was provided to sites in age bands on wallet-sized cards for quick reference (<1 week: <60 mm Hg; 1 week to <1 year: <70 mm Hg; 1 to <2 years: <75 mm Hg; 2 to <5 years: <80 mm Hg; 5 to <12 years: <85 mm Hg; and ≥12 years: <90 mm Hg)

Exclusion criteria: prior receipt of more than 20 mL/kg of bolus fluid; conditions in which bolus fluid resuscitation should be curtailed; or full active resuscitation not within the current goals of care.

N total at baseline:

Intervention: 39

Control: 34

Important prognostic factors²:

For example

Median age (IQR)

I: 11 (1-35) months

C: 2 (1-17) months

Sex:

I: 61.5% M

C: 52.9% M

Groups comparable at baseline? Baseline characteristics were well matched, although there was some imbalance in age and consequently in weight

10 mL/kg boluses over a 4-hour resuscitation period

The resuscitation period was divided into 15 min cycles, with one bolus of either 10 mL/kg to be delivered in each cycle. The maximum amount of fluid that could be given per bolus was either 500 mL (for those allocated to 10 mL/ kg boluses). Fluid type and other interventions were left to the discretion of the treating clinician. At the end of each cycle, if age-adjusted signs of shock persisted, then another bolus of the same size was given within the next 15 min cycle. In participants whose shock resolved or who showed signs of fluid overload, delivery of further fluid boluses was withheld. If, within the 4-hour resuscitation period, fluid boluses were indicated, that is, signs of shock were present in the absence of signs of fluid overload, cycles were recommenced with allocated boluses until the end of the 4-hour intervention period. After this period, any further treatment was at the discretion of the treating clinician. The maximum amount of fluid that could be given within the pilot trial protocol, regardless of allocation, was 120 mL/kg (excluding the 20 mL/kg bolus prerandomisation)

20 mL/kg boluses over a 4-hour resuscitation period

The resuscitation period was divided into 15 min cycles, with one bolus of 20 mL/kg to be delivered in each cycle. The maximum amount of fluid that could be given per bolus was 1000 mL (for those allocated to 20 mL/kg boluses). Fluid type and other interventions were left to the discretion of the treating clinician. At the end of each cycle, if age-adjusted signs of shock persisted, then another bolus of the same size was given within the next 15 min cycle. In participants whose shock resolved or who showed signs of fluid overload delivery of further fluid boluses was withheld. If, within the 4-hour resuscitation period, fluid boluses were indicated, that is, signs of shock were present in the absence of signs of fluid overload, cycles were recommenced with allocated boluses until the end of the 4-hour intervention period. After this period, any further treatment was at the discretion of the treating clinician. The maximum amount of fluid that could be given within the pilot trial protocol, regardless of allocation, was 120 mL/kg (excluding the 20 mL/kg bolus prerandomisation)

Length of follow-up: from July 2016 to April 2017, with follow-up completed on 31 May 2017, mean not reported.

Loss-to-follow-up:

Intervention:

N (%) 1/40

Reasons (describe): not approached for consent (n=1)

Control:

N (%) 1/35

Reasons (describe): not approached for consent (n=1)

Incomplete outcome data:

Intervention:

N (%): 3

Reasons (describe): not described

Control:

N (%): 2

Reasons (describe) not described

Outcome measures and effect size (include 95%CI and p-value if available):

Hospital mortality:

Outcome was not defined.

I: 0/39

C: 0/34

Mortality at 30 days post randomisation:

Outcome was not defined.

I: 0/39

C: 0/34

Length of hospital stay:

Outcome was not defined.

I: median 4 days (IQR 3-7)

C: median 5 days (IQR 4-8)

Difference: -1 (-2.5 to 0.5)

Length of PICU stay:

I: 45 hours (IQR 18-143); n=10

C: 119 hours (IQR 52-228); n=11

Difference: −65 (−171 to 41)

Receipt of mechanical ventilation:

I: 4/36

C: 8/32

Difference: −13.9 (−32.1 to 4.3)

Duration of mechanical ventilation:

I: median 6 days (IQR 4-8)

C: median 5.5 (IQR 4-8,5)

Difference: 0 (−5.9 to 5.9)

Notes:

37 (78.7%) of 47 boluses were delivered at the correct volume and within 15 min in the 10 mL/kg group, whereas 24 (54.5%) of 44 boluses were delivered at the correct volume and within 15 min in the 20 mL/kg group

No power calculation was used to determine sample size as there was no primary outcome defined in this small pilot RCT.

Study

First author, year

Appropriate and clearly focused question?¹

Yes/no/unclear

Comprehensive and systematic literature search?²

Yes/no/unclear

Description of included and excluded studies?³

Yes/no/unclear

Description of relevant characteristics of included studies?⁴

Yes/no/unclear

Appropriate adjustment for potential confounders in observational studies?⁵

Yes/no/unclear/notapplicable

Assessment of scientific quality of included studies?⁶

Yes/no/unclear

Enough similarities between studies to make combining them reasonable?⁷

Yes/no/unclear

Potential risk of publication bias taken into account?⁸

Yes/no/unclear

Potential conflicts of interest reported?⁹

Yes/no/unclear

Li, 2018

Yes

Yes

Yes

Yes

Not applicable

Yes

No, studies compared different boluses but data were pooled in one meta-analysis.

No, because <10 studies were included publication bias was not studied by the author.

Unclear, in two of the included studies conflict of interest was not reported.

Study reference

Describe method of randomisation¹

Bias due to inadequate concealment of allocation?²

(unlikely/likely/unclear)

Bias due to inadequate blinding of participants to treatment allocation?³

(unlikely/likely/unclear)

Bias due to inadequate blinding of care providers to treatment allocation?³

(unlikely/likely/unclear)

Bias due to inadequate blinding of outcome assessors to treatment allocation?³

(unlikely/likely/unclear)

Bias due to selective outcome reporting on basis of the results?⁴

(unlikely/likely/unclear)

Bias due to loss to follow-up?⁵

(unlikely/likely/unclear)

Bias due to violation of

intention to treat analysis?⁶

(unlikely/likely/unclear)

Inwald, 2019

Extracted from study protocol via: https://www. journalslibrary. nihr. ac. uk/ programmes/ hta/ 1304105/#/.

“Eligible patients will be randomised on a 1:1 basis to bolus fluid resuscitation with either 20 ml/kg or 10 ml/kg boluses using sealed opaque envelopes available at each site”

“…allocation will be by randomised permuted blocks (with variable block lengths), stratified by recruiting site only. Patient randomisation must be performed prior to commencement of any study intervention”

Unclear, patients were unaware of allocation because they were informed until after the intervention about the study. Randomisation was stratified per site, so presumably all staff was aware of treatment allocation.

Unlikely, patients were not aware they participated in the trial until after the intervention.

Unclear, as randomisation was stratified per site, presumably all staff was aware of treatment allocation.

Unclear, not reported.

Unlikely

Unlikely

Unlikely, all patients were studied as intention to treat.