Authors: Ivan D Florez, Javier Sierra, Giordano Pérez-Gaxiola
Categories: Bicarbonates, Bicarbonates/therapeutic use, Child, Creatinine, Dehydration, Dehydration/etiology, Dehydration/therapy, Diarrhea, Diarrhea/therapy, Humans, Hypokalemia, Potassium, Potassium Chloride, Potassium Chloride/therapeutic use, Ringer's Lactate, Saline Solution, Sodium, Infectious disease, Diarrhoeal infections
Source: The Cochrane Database of Systematic Reviews
Although acute diarrhoea is a self‐limiting disease, dehydration may occur in some children. Dehydration is the consequence of an increased loss of water and electrolytes (sodium, chloride, potassium, and bicarbonate) in liquid stools. When these losses are high and not replaced adequately, severe dehydration appears. Severe dehydration is corrected with intravenous solutions. The most frequently used solution for this purpose is 0.9% saline. Balanced solutions (e.g. Ringer's lactate) are alternatives to 0.9% saline and have been associated with fewer days of hospitalization and better biochemical outcomes. Available guidelines provide conflicting recommendations. It is unclear whether 0.9% saline or balanced intravenous fluids are most effective for rehydrating children with severe dehydration due to diarrhoea.
To evaluate the benefits and harms of balanced solutions for the rapid rehydration of children with severe dehydration due to acute diarrhoea, in terms of time in hospital and mortality compared to 0.9% saline.
We used standard, extensive Cochrane search methods. The latest search date was 4 May 2022.
We included randomized controlled trials in children with severe dehydration due to acute diarrhoea comparing balanced solutions, such as Ringer's lactate or Plasma‐Lyte with 0.9% saline solution, for rapid rehydration.
We used standard Cochrane methods. Our primary outcomes were 1. time in hospital and 2. mortality. Our secondary outcomes were 3. need for additional fluids, 4. total amount of fluids received, 5. time to resolution of metabolic acidosis, 6. change in and the final values of biochemical measures (pH, bicarbonate, sodium, chloride, potassium, and creatinine), 7. incidence of acute kidney injury, and 8. adverse events. We used GRADE to assess the certainty of the evidence.
Characteristics of the included studies
We included five studies with 465 children. Data for meta‐analysis were available from 441 children. Four studies were conducted in low‐ and middle‐income countries and one study in two high‐income countries. Four studies evaluated Ringer's lactate, and one study evaluated Plasma‐Lyte. Two studies reported the time in hospital, and only one study reported mortality as an outcome. Four studies reported final pH and five studies reported bicarbonate levels. Adverse events reported were hyponatremia and hypokalaemia in two studies each.
Risk of bias
All studies had at least one domain at high or unclear risk of bias. The risk of bias assessment informed the GRADE assessments.
Primary outcomes
Compared to 0.9% saline, the balanced solutions likely result in a slight reduction of the time in hospital (mean difference (MD) −0.35 days, 95% confidence interval (CI) −0.60 to −0.10; 2 studies; moderate‐certainty evidence). However, the evidence is very uncertain about the effect of the balanced solutions on mortality during hospitalization in severely dehydrated children (risk ratio (RR) 0.33, 95% CI 0.02 to 7.39; 1 study, 22 children; very low‐certainty evidence).
Secondary outcomes
Balanced solutions probably produce a higher increase in blood pH (MD 0.06, 95% CI 0.03 to 0.09; 4 studies, 366 children; low‐certainty evidence) and bicarbonate levels (MD 2.44 mEq/L, 95% CI 0.92 to 3.97; 443 children, four studies; low‐certainty evidence). Furthermore, balanced solutions likely reduces the risk of hypokalaemia after the intravenous correction (RR 0.54, 95% CI 0.31 to 0.96; 2 studies, 147 children; moderate‐certainty evidence).
Nonetheless, the evidence suggests that balanced solutions may result in no difference in the need for additional intravenous fluids after the initial correction; in the amount of fluids administered; or in the mean change of sodium, chloride, potassium, and creatinine levels.
The evidence is very uncertain about the effect of balanced solutions on mortality during hospitalization in severely dehydrated children. However, balanced solutions likely result in a slight reduction of the time in the hospital compared to 0.9% saline. Also, balanced solutions likely reduce the risk of hypokalaemia after intravenous correction.
Furthermore, the evidence suggests that balanced solutions compared to 0.9% saline probably produce no changes in the need for additional intravenous fluids or in other biochemical measures such as sodium, chloride, potassium, and creatinine levels. Last, there may be no difference between balanced solutions and 0.9% saline in the incidence of hyponatraemia.
Keywords: Child, Humans, Bicarbonates, Bicarbonates/therapeutic use, Creatinine, Dehydration, Dehydration/etiology, Dehydration/therapy, Diarrhea, Diarrhea/therapy, Hypokalemia, Potassium, Potassium Chloride, Potassium Chloride/therapeutic use, Ringer's Lactate, Saline Solution, Sodium
The World Health Organization (WHO) defines acute diarrhoea as the passage of unusually loose or watery stools, usually at least three times in 24 hours, which lasts less than 14 days (WHO 2005). The American Academy of Pediatrics defines acute gastroenteritis as a diarrhoeal disease of rapid onset, with or without additional symptoms and signs such as nausea, vomiting, fever, or abdominal pain (American Academy of Pediatrics 1996). Both terms are commonly used to describe the gastrointestinal infection caused by specific micro‐organisms such as rotavirus, norovirus, Campylobacter, Escherichia coli, Salmonella, Shigella, and others (Guerrant 1990). We use the term 'acute diarrhoea' in this review to cover both acute diarrhoea and acute gastroenteritis.
Acute diarrhoea accounts for over 0.5 million deaths annually in children under five years old (Liu 2015). Although most cases of acute diarrhoea are self‐limiting, dehydration, the most common and dangerous complication, may occur in some children. During diarrhoea, there is an increased loss of water and electrolytes (sodium, chloride, potassium, and bicarbonate) in the liquid stools. Water and electrolytes are also lost through vomit, sweat, and urine. Dehydration occurs when these losses are not replaced adequately and a deficit of water and electrolytes develops (WHO 2005).
Serum bicarbonate is the only laboratory measurement that appears to be of some value for identifying dehydration in children with acute diarrhoea (Steiner 2004). However, it is not practical to obtain blood samples from every child with acute diarrhoea, and the most commonly used approach to assess the level of dehydration is clinical assessment. Dehydration is classified according to its degree, which reflects the magnitude of fluid loss. The gold standard for determining the degree of dehydration has been the child's weight loss (Pruvost 2013). There are three commonly used scales for the classification of dehydration in the Clinical Dehydration Scale (CDS) (Friedman 2004), Gorelick Scale (Gorelick 1997), and WHO scale (WHO 2005). The CDS classifies children to have 'no dehydration', 'some dehydration', or 'moderate dehydration' (Friedman 2004; Jauregui 2014). The Gorelick Scale classifies children to have 'no dehydration' or 'moderate to severe dehydration' (Gorelick 1997). The WHO's categories 'no dehydration', 'some dehydration', and 'severe dehydration' (WHO 2005). Although scales vary in their particular classifications, their value is to determine fluid management (Table 2).
Depending on which dehydration scale is used, it is estimated that children with 'no dehydration' have had no significant losses (depending on the dehydration scale used this means less than 3% or 5% of their bodyweight), children with 'some dehydration' have lost between 3% and 6% of their bodyweight, and those with 'severe dehydration' have lost more than 7% or more than 10% of their bodyweight (see Table 2 for more details on the dehydration classification according to the most commonly used dehydration scales). Since it is challenging, if not impossible, to know the precise weight of a child before the start of the diarrhoeal episode, the assessment of dehydration has traditionally relied on clinical evaluation of signs and symptoms (Falszewska 2018).
Appropriate classification of dehydration is crucial as it determines appropriate management. Children with 'no dehydration' may be managed at home, with increased fluid intake to prevent dehydration. Those with 'some dehydration' are managed by healthcare services and receive oral rehydration therapy, and children with severe dehydration require intravenous rehydration (WHO 2005). Rehydration of severely dehydrated children is achieved with rapid or slow rehydration therapy. Most of the management guidelines recommend a rapid rehydration therapy to treat children with severe dehydration due to diarrhoea (WHO 2005). In rapid therapy the fluid deficit is replaced over three to six hours, while in slow therapy, replacement occurs over more than six to eight hours (typically using one or two 10 mL/kg to 20 mL/kg boluses of 0.9% saline before the full replacement).
Although some micro‐organisms, such as rotavirus, have been associated with an increased risk of severe dehydration in high‐income countries (HIC) (Albano 2007), reports from low‐ and middle‐income countries (LMIC) have shown that micro‐organism identification does not predict the occurrence of severe dehydration (Andrews 2017). Severe dehydration may cause a significant loss of intravascular volume (hypovolaemia). When this loss is substantial, hypovolaemic shock, characterized by tachycardia and either prolonged capillary refill time or hypotension, may occur. Severe dehydration can also cause electrolyte disturbances and metabolic acidosis. Electrolyte disturbances may appear due to significant water, sodium, bicarbonate, and potassium losses. Large losses of bicarbonate in stools, hyperlactatemia caused by hypovolaemia, and long fasting periods causing hyperketonaemia explain metabolic acidosis in these children (Hirschhorn 1980; Levy 2013).
Last, deaths associated with severe dehydration may occur when a hypovolaemic shock is not appropriately managed and when it is associated with severe malnutrition and the coexistence of sepsis (Singh 2019). The mortality rate of children with severe dehydration may be as high as 13% (Akech 2018). Children with severe dehydration should receive intravenous rehydration therapy to restore volume and perfusion to vital organs, resolve metabolic acidosis, and replace the fluid deficit.
Crystalloids are aqueous solutions that contain ions at different concentrations. Crystalloids are widely recommended and used for volume replacement, fluid maintenance, and resuscitation in medicine in all care settings in adults and children (Holliday 2007; Long 2016; Myburgh 2013). Despite their ubiquitous use, the optimal concentration of electrolytes is currently unknown. Due to its low cost and widespread availability, 0.9% saline (also called sodium chloride) is the most widely used crystalloid (Santi 2015). The 0.9% saline solution contains 154 mmol/L each of sodium and chloride ions, with no additional electrolytes (Holliday 2007).
Balanced solutions (also called buffered solutions) are crystalloids that are an alternative to 0.9% saline but differ in several aspects. These solutions have lower concentrations of sodium and chloride; contain additional cations such as calcium, potassium, or magnesium; and contain anions such as lactate, acetate, or gluconate, which are metabolized to bicarbonate and may exert an additional buffering effect (Antequera Martin 2019; Santi 2015). These concentrations are more similar to the ones found in human plasma than 0.9% saline. The most common balanced solutions are Ringer's lactate (or Hartmann's solution) and Plasma‐Lyte 148 (or Plasma‐Lyte A).
There are two major approaches to the understanding of acid–base the standard base‐excess approach (Henderson 1913; Siggaard‐Andersen 1977), and the Stewart approach (Stewart 1978). Under the standard base‐excess approach, metabolic acidosis is mainly explained by an increase in total body acids or by bicarbonate losses, while, under the Stewart approach, acidosis is a consequence of alterations in the water dissociation of body fluids (Morgan 2009). Regardless of which acid–base approach is used, 0.9% saline solution has been shown to produce metabolic acidosis both in vitro and in vivo (Chowdhury 2012; Kellum 2006). Following the standard base‐excess approach, the infusion of 0.9% saline will produce an increase in the amount of body chloride (hyperchloraemia), which will result in a normal anion gap acidosis. The Stewart approach uses the calculation of the strong ion difference (SID) (i.e. the difference between strong cations and anion concentrations). For solutions where this difference is zero, such as 0.9% saline (because [Na^+^] – [Cl^‐^] = 154 mmol/L – 154 mmol/L = 0 mmol/L), the body's SID will be reduced, hence metabolic acidosis occurs (Stewart 1978).
In vitro and animal studies have shown several adverse effects of elevated extracellular chloride concentration on physiological variables. Hyperchloraemia has been associated with an increase in renal vascular resistance, and decreases in glomerular filtration rate (Quilley 1993; Wilcox 1987) and renin activity (Kotchen 1983). Hyperchloraemic acidosis has been shown to increase inflammatory molecules in rat models (Kellum 2006). Data demonstrated that washing red blood cells with 0.9% saline is associated with a near doubling of haemolysis during the first 24 hours after washing compared with Plasma‐Lyte A (Refaai 2018). One clinical study showed that an infusion of 0.9% saline induced hyperchloraemic acidosis at a higher rate than balanced solutions (Chowdhury 2012). Based on these characteristics, the use of balanced solutions is expected to produce a more physiological volume replacement and a faster improvement of metabolic acidosis than 0.9% saline in children with dehydration and hypovolaemia (Santi 2015).
The WHO recommends the use of Ringer's lactate to rehydrate children with severe dehydration due to acute diarrhoea, and suggests the use of 0.9% saline when Ringer's lactate is not available (WHO 2005). The American Academy of Pediatrics recommends the use of either Ringer's lactate or 0.9% saline (American Academy of Pediatrics 1996). In contrast, the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN)/European Society for Pediatric Infectious Diseases (ESPID) guidelines recommend the use of 0.9% saline, and only recommend Ringer's lactate in severe cases of shock (Guarino 2014). The UK's National Institute for Health and Care Excellence (NICE) guidelines only recommend the use of 0.9% saline (NICE 2009). Additional solutions, such as Dhaka Solution, with different electrolyte compositions have been used in different contexts, and are recommended by some guidelines as alternatives to Ringer's lactate, if this is not available, before considering 0.9% saline (WHO 2005), although there is no evidence to support their use. Table 3 displays the electrolyte composition of some solutions that have been used for intravenous rehydration of children with acute diarrhoea. Moreover, a survey amongst paediatric emergency physicians in Canada showed that 0.9% saline is the preferred solution for intravenous rehydration (Freedman 2011). Thus, there are several alternative treatments and heterogeneity in the recommendations of the most important guidelines. This heterogeneity may be caused by the time of publication of the guidelines, but mostly reflects the lack of appropriate evidence.
One recent Cochrane Review found that critically ill children and adults treated with 0.9% saline for resuscitation had higher chloride levels, lower bicarbonate levels, and lower pH levels than children treated with balanced solutions, but failed to demonstrate differences in mortality (Antequera Martin 2019). The review's conclusions are not applicable to children with severe dehydration due to acute diarrhoea because authors aimed to determine the effect of the solutions on resuscitation of critically ill people regardless of their diagnoses. Although the Cochrane Review's authors considered subgroup analyses by age or disease, they could not perform them. Additionally, the review authors did not consider studies in children with severe dehydration unless they were considered to be critically ill, which potentially resulted in missing specific evidence for children with acute diarrhoea and dehydration.
Another Cochrane Review showed that balanced solutions reduce the incidence of hyperchloraemia and metabolic acidosis in elective surgery in adults, in comparison to treatment with 0.9% saline (Bampoe 2017). Similar to the Antequera Martin 2019 review, the authors did not find any difference in mortality between the groups. In addition, Bampoe 2017 addressed a population very different to children with severe dehydration due to acute diarrhoea.
In summary, some evidence from different conditions and patients (mostly from adults) has shown that the use of 0.9% saline may be associated with worse biochemical outcomes. Nevertheless, many guidelines still recommend this solution for replacing volume in children with severe dehydration due to acute diarrhoea, and to date there is no systematic review that has summarized the evidence. This review aims to synthesize all the available evidence on the efficacy and safety of balanced solutions in comparison to 0.9% saline to rehydrate children with severe dehydration due to acute diarrhoea. This evidence will be useful to inform future guidelines and updates on the management of children with acute diarrhoea and dehydration.
To evaluate the benefits and harms of balanced solutions for the rapid rehydration of children with severe dehydration due to acute diarrhoea, in terms of time in hospital and mortality compared to 0.9% saline.
We included randomized controlled trials (RCTs), irrespective of publication status and language.
We included children aged one month to 18 years old,
The interventions of interest were intravenous balanced crystalloid solutions, defined as any solution that contained lower sodium and chloride concentrations than 0.9% saline, maintained a difference between sodium and chloride levels of at least 20 mmol/L, and that contained bicarbonate or its precursors, such as acetate, lactate, or gluconate. Examples of balanced solutions included, but were not limited Ringer's lactate (also called 'Hartmann's solution') and multiple electrolytes' solution (Plasma‐Lyte 148 or Plasma‐Lyte A).
The control was 0.9% saline solution (also called 0.9% sodium chloride or 0.9% NaCl). We considered trials that gave oral rehydration salt (ORS) solution only when ORS was given to complement intravenous infusion in both trial groups.
We included RCTs regardless of language or publication status (published, unpublished, in press, and in progress).
We searched in the following databases from their
Search strategies are provided in Appendix 1. We conducted searches on 18 June 2020, with an update on 4 May 2022.
We searched ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/en/), both accessed on 4 May 2022. On the same date, we searched for abstracts from the most relevant meetings and conferences, such as those from the American Academy of Pediatrics; World Federation Pediatric Intensive and Critical Care Societies; North American and European Society of Pediatric Gastroenterology, Hepatology and Nutrition; and the International Pediatric Association. We did not limit these searches by date of publication. We contacted authors of included trials and experts in the field to ask for any ongoing, missed, or unreported studies. Finally, we checked reference lists of all studies identified by the above methods.
Two review authors (GPG and JMS) independently screened all relevant titles and abstracts to determine their eligibility. We retrieved the full‐text references of studies that at least one review author considered eligible. Subsequently, two review authors (GPG and JMS) independently assessed the eligibility of full‐text reports of potentially eligible studies to determine their inclusion. Review authors resolved disagreements through discussion or by consulting a third review author (IDF). We contacted the authors of one study to clarify its eligibility. We use the PRISMA flow diagram to describe the selection process (Moher 2009). We performed the screening of titles and abstract and full‐text selection of studies using Covidence.
Two review authors (GPS and JMS) independently extracted prespecified characteristics of each trial using a standardized, piloted data extraction form. We resolved any disagreements by discussion or by consulting a third review author (IDF). We extracted the following
Two review authors (GPG and JMS) independently assessed the risk of bias of the included studies using the Cochrane RoB 1 tool, which includes the following sequence generation; allocation concealment; blinding (masking) of participants, personnel, and outcome assessors; incomplete outcome data; selective outcome reporting; and other sources of bias (Higgins 2008). We judged each domain as low, unclear, or high risk of bias. We did not exclude trials on the basis of risk of bias, but conducted sensitivity analyses to explore the potential effects of high risk of bias in the meta‐analyses (see Sensitivity analysis). We considered industry funding as a potential source of bias (other bias) (Lundh 2017).
We performed all analyses according to the standards specified in the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2020). We calculated risk ratios (RR) for dichotomous outcomes and mean differences (MD) for continuous outcomes, both with their corresponding 95% confidence intervals (CIs).
We did not consider cross‐over or cluster‐RCTs due to the nature of the condition and the interventions under study. In cases of outcomes with repeated measurements, we planned to use a single time point (e.g. hyperkalaemia at six hours). In cases of studies with more than two groups, we considered only the data from the two groups of interest in the analyses and when more than two groups were eligible, we planned to include each balanced pair‐wise comparison separately, and divide the sample size of the 0.9% saline group amongst the comparisons. However, we did not identify any multiple‐group studies.
We attempted to contact trial authors to request any missing outcome data. If the trial authors did not respond within four to eight weeks, we considered alternatives. First, we imputed some data. Most of our outcomes were continuous, and it is common that authors provide central tendency and dispersion measures that are different from the ones we require (i.e. mean and SD). If, for these outcomes, authors provided medians with ranges or interquartile ranges, we applied the approach of Wan and colleagues to calculate the best estimation of mean and SD (Wan 2014). In cases in which authors provided the mean and no dispersion measure, we tried to impute the SD by borrowing the SD from one or more other studies, ideally from those with a similar sample size (Furukawa 2005). In those cases where we performed a transformation or imputation, we conducted sensitivity analyses to assess the robustness of the results (see Sensitivity analysis).
We assessed heterogeneity by considering clinical and methodological characteristics of studies, visual overlap of CIs in the forest plots, and statistical tests (Chi² and I² statistics) (Higgins 2003). We considered heterogeneity meaningful when the Chi² test had a P value of 0.10. Furthermore, we interpreted the I² value following Cochrane Handbook for Systematic Reviews of Interventions guidance, as 0% to 40%: might not be important; 30% to 60%: may represent moderate heterogeneity; 50% to 90%: may represent substantial heterogeneity; and 75% to 100%: considerable heterogeneity (Deeks 2020). We performed subgroup or sensitivity analyses to explore the potential reasons behind substantial or considerable heterogeneity.
We minimized reporting bias by including both published and unpublished studies (see Searching other resources). We visually assessed the likelihood of reporting bias per outcome, by creating a funnel plot and assessing its symmetry when there were 10 or more studies (Egger 1997).
We performed statistical analyses according to the recommendations of the Cochrane Handbook for Systematic Reviews of Interventions (Deeks 2020). We used a random‐effects model for statistical combination because we considered the intervention effects across studies were not identical. In this scenario, a random‐effects is preferable to a fixed‐effect model (Deeks 2020). We used Review Manager Web for data syntheses and analyses (RevMan Web 2023). When meta‐analysis was not appropriate, we provided a narrative description of the results.
We planned to perform subgroup analyses for the primary outcomes based
We planned to conduct sensitivity analyses for the primary outcomes to assess the robustness of the results. First, we planned to conduct analyses excluding studies that considered mixed populations (i.e. eligible and ineligible populations). We planned to exclude studies with high or unclear risk of bias in the domains of sequence generation and allocation concealment, and re‐run the analyses; however, given the scarcity of the data, we could to perform these analyses. We chose these domains because they address the bias arising from the randomization process (selection bias), which we considered key to define a rigorous RCT. Biases in this process will lead to unbalanced distribution of participants between the groups, a core element of the trials. Last, we planned to conduct analyses that excluded studies that required estimations and data extraction from figures, and studies in which we had to perform data transformation (i.e. estimating the best mean and SD) or imputation of SD. Nonetheless, we could not perform these analyses due to the scarcity of the studies in most of the outcomes.
We presented the certainty of the evidence using the GRADE approach (Guyatt 2011a). Two review authors (IF and JS) independently assessed the certainty of the evidence for each outcome. The assessment was performed for each outcome and started by assigning an evidence level according to the designs of the included studies. Evidence from RCTs is considered to be of high certainty. The body of evidence summarized was assessed against five study limitations (risk of bias), inconsistency, indirectness, imprecision, and publication bias (Guyatt 2011b). Since we only included RCTs, we started our assessment with high certainty, and assessed each criterion to consider whether we downgraded. We presented a summary of the evidence in the summary of findings table, which provides key information about the best estimate of the magnitude of the effect in relative terms, and absolute differences for each relevant comparison (Guyatt 2011b). In the summary of findings table, we provided information for the following time in hospital, mortality, time to resolution of metabolic acidosis, final pH after correction, final bicarbonate after correction, and adverse effects.
See Characteristics of included studies and Characteristics of excluded studies tables.
Our searches from electronic databases, trial registries, and handsearching identified 738 potentially relevant records. We screened 644 titles and abstracts after eliminating duplicates, and after removing 624 non‐relevant references, we identified 20 full‐text articles (Figure 1). We retrieved and reviewed these full texts against the inclusion criteria. We excluded 11 articles with reasons given in the Characteristics of excluded studies table, and we included five RCTs (nine articles). There are no studies awaiting classification or ongoing.
1 Study flow diagram.
All trials were published between 2012 and 2020. Four studies were conducted in LMICs (India and Pakistan) (Kartha 2017; Mahajan 2012; Naseem 2020; Rasheed 2020), and one recruited children from two HICs (the USA and Canada) (Allen 2016). In total, the five studies evaluated 465 children.
Studies included children aged one month to 18 years and all used the WHO definition of acute diarrhoea (WHO 2005). The mean age of the included children ranged from 15.5 months (Kartha 2017) to 65.5 months (Mahajan 2012). Three studies included children with severe dehydration using the WHO scale (Kartha 2017; Mahajan 2012; Naseem 2020), one study included children with moderate‐to‐severe dehydration using the Gorelick Scale (Allen 2016), and one study did not explicitly use a dehydration scale, but study authors created their own definition of severe dehydration (Rasheed 2020). None of the studies reported aetiology of the diarrhoea. The mean number of days with diarrhoea before the recruitment ranged from 1.5 days to 2.5 days.
Four studies evaluated Ringer's lactate (Kartha 2017; Mahajan 2012; Naseem 2020; Rasheed 2020), and one study evaluated Plasma‐Lyte (Allen 2016), both compared to 0.9% saline solution. In addition to the study fluids, two studies reported the administration of replacement fluids for ongoing gastrointestinal losses and maintenance, using oral rehydration solution or intravenous 0.45% saline in 5% dextrose (Kartha 2017; Mahajan 2012). Three studies supplemented children in both groups with zinc as per WHO guidance (Kartha 2017; Mahajan 2012; Naseem 2020). One study reported that other medications such as paracetamol, non‐steroidal anti‐inflammatory drugs, and narcotics were allowed orally or by intravenous infusion (or both) as cointerventions (Allen 2016). Only one study was a multicentric and set in eight paediatric emergency departments in North America (Allen 2016).
See Characteristics of included studies table.
We excluded 12 studies (Akech 2014; Allen 2014; Freedman 2013; Golshekan 2016; Houston 2019; Jucá 2005; Levy 2013; Mahalanabis 1972; Neville 2006; Rahman 1988; Sendarrubias 2018; Shaikh 2022). The exclusions were due to different populations (Akech 2018), different interventions (Golshekan 2016; Houston 2019; Jucá 2005; Levy 2013), different comparators (Freedman 2013; Mahalanabis 1972; Rahman 1988; Sendarrubias 2018), and one study in which we detected potential data fabrication (Shaikh 2022).
See Characteristics of excluded studies table.
We identified no studies awaiting classification.
We identified no ongoing studies.
See Characteristics of included studies table and Figure 2 for the risk of bias of the included studies.
2 Risk of bias review authors' judgements about each risk of bias criterion for each included study.
Four studies had an adequate description of the randomization process and were considered at low risk of bias for this domain (Kartha 2017; Mahajan 2012; Naseem 2020; Rasheed 2020), and one study did not detail the randomization procedure and, therefore, was at unclear risk of bias (Allen 2016).
Three studies adequately described allocation concealment, and were at low risk of bias (Allen 2016; Kartha 2017; Naseem 2020). Two studies did not provide information on the allocation concealment procedure and were at unclear risk of bias (Mahajan 2012; Rasheed 2020).
Three studies clearly reported the blinding of participants and personnel and were at low risk of bias (Allen 2016; Kartha 2017; Mahajan 2012). Two studies did not provide any information on blinding and were at unclear risk of bias (Naseem 2020; Rasheed 2020).
All included trials had appropriate follow‐up and analysed more than 90% of participants (Allen 2016; Kartha 2017; Mahajan 2012; Naseem 2020; Rasheed 2020). Thus, we considered all trials at low risk of attrition bias.
Two studies were at low risk of selective reporting bias as protocol were available or planned outcomes were the same reported (or both) (Kartha 2017; Mahajan 2012). Two studies did not provide registration numbers or access to the protocol to assess the prespecified outcomes and were at unclear risk of reporting bias (Naseem 2020; Rasheed 2020). The remaining study was at high risk of bias because the study authors reported "length of stay" as secondary outcome in the registered protocol but did not report this in the final publication (Allen 2016).
One study was at low risk of other bias (Naseem 2020). One study was at unclear risk of other bias because it did not provide information to verify the baseline balance between groups in the participants' characteristics or provide a funding statement (Rasheed 2020). Three studies were at high risk of other bias due to different reasons. One study had substantial imbalance between intervention and control groups in several variables (mean age, vomiting episodes, diarrhoea episodes, weight, and bicarbonate levels) (Allen 2016). One study was stopped (quote) "after an interim analysis by the independent data monitoring committee contended that it was futile to continue the study further" (Kartha 2017). One study had unbalanced groups at baseline (i.e. baseline mean pH value was lower in the 0.9% saline group) (Mahajan 2012).
See: Table 1
Two studies evaluating 90 children reported results on time in hospital or length of stay (Kartha 2017; Mahajan 2012). Balanced solutions likely results in a slight reduction of the time in hospital compared to 0.9% saline (MD −0.35 days, 95% CI −0.60 to −0.10; moderate‐certainty evidence; Analysis 1.1).
1.1 AnalysisComparison Balanced crystalloid solutions versus 0.9% saline, Outcome Time in hospital
We planned to conduct sensitivity analyses excluding studies with high or unclear risk of bias in the sequence generation or allocation concealment (selection bias) domains. Only one study was classified as such (Allen 2016). Its removal from the meta‐analysis did not yield any difference in comparison to the primary analysis (MD −0.33 days, 95% CI −0.59 to −0.07). We could not perform the planned subgroup analyses based on the type of balanced solution or the severity of the dehydration due to the low number of studies.
One study including 22 children reported results on mortality (Mahajan 2012). There was one death in the 0.9% saline group and none in the balanced solution group. The evidence is very uncertain about the effect of balanced solutions on mortality compared to 0.9% saline (RR 0.33, 95% CI 0.02 to 7.39; very low‐certainty evidence; Analysis 1.2).
1.2 AnalysisComparison Balanced crystalloid solutions versus 0.9% saline, Outcome Mortality (during hospitalization)
We could not perform the planned sensitivity analysis excluding studies of high or unclear risk of selection bias. There was only one study for this analysis, and we judged it an unclear risk of selection bias. Similarly, we could not perform the planned subgroup analyses based on the type of balanced solution or the severity of the dehydration due to the low number of studies.
One study including 22 children reported results on the need for additional fluids (Mahajan 2012). Four children required additional fluids after the initial fluid therapy with balanced solutions compared to six children in the 0.9% saline group. The evidence suggests that balanced solutions probably produce no changes in the need for additional fluids compared to 0.9% saline (RR 0.67, 95% CI 0.26 to 1.72; low‐certainty evidence; Analysis 1.3).
1.3 AnalysisComparison Balanced crystalloid solutions versus 0.9% saline, Outcome Need for additional fluids
Two studies including 138 children reported results on the total amounts of fluids received (Kartha 2017; Naseem 2020). The evidence suggests that balanced solutions do not reduce the total amount of fluids compared to 0.9% saline (MD −2.61 mL/kg, 95% CI −7.36 to 2.13; low‐certainty evidence; Analysis 1.4).
1.4 AnalysisComparison Balanced crystalloid solutions versus 0.9% saline, Outcome Total amount of fluids received
No studies reported the time for metabolic acidosis resolution.
Four studies including 366 children reported results as mean final pH after correction (Kartha 2017; Mahajan 2012; Naseem 2020; Rasheed 2020). Meta‐analysis showed that balanced solutions may result in a higher pH after correction compared to 0.9% saline (MD 0.06, 95% CI 0.03 to 0.09; low‐certainty evidence; Analysis 1.5).
1.5 AnalysisComparison Balanced crystalloid solutions versus 0.9% saline, Outcome Final mean pH after correction
One study evaluating 70 children reported the change in the pH level (difference between mean final pH and mean pH at baseline per group) after correction (Naseem 2020). The study found that balanced solutions may result in a larger increase in mean pH after correction compared to 0.9% saline (MD 0.05, 95% CI 0.02 to 0.08).
Five studies including 443 children reported results as mean bicarbonate value after correction (Allen 2016; Kartha 2017; Mahajan 2012; Naseem 2020; Rasheed 2020). Meta‐analysis showed that balanced solutions may result in a larger bicarbonate level compared to 0.9% saline (MD 2.44 mEq/L, 95% CI 0.92 to 3.97; low‐certainty evidence; Analysis 1.6).
1.6 AnalysisComparison Balanced crystalloid solutions versus 0.9% saline, Outcome Final bicarbonate level after correction
One study including 70 children reported results as the change in bicarbonate level (mean final bicarbonate minus mean bicarbonate at baseline per group) after correction (Naseem 2020). The study found that balanced solutions may result in a larger increase of mean bicarbonate level after correction compared to 0.9% saline (MD 2.22 mEq/L, 95% CI 1.09 to 3.35).
One study including 70 children reported results as change in sodium level (difference between mean final sodium level after correction and mean sodium level at baseline, per group) (Naseem 2020). The study found that balanced solutions may result in no difference in mean change in sodium level after correction compared to 0.9% saline (MD −0.70 mEq/L, 95% CI −2.90 to 1.50; Analysis 1.7).
1.7 AnalysisComparison Balanced crystalloid solutions versus 0.9% saline, Outcome Change in sodium level after correction
No studies reported change in chloride level after correction (difference between mean final chloride level after correction and mean chloride level at baseline, per group)
One study including 70 children reported results as change in potassium level (difference between mean final potassium level after correction and mean potassium level at baseline, per group) (Naseem 2020). The study found that balanced solutions may result in no difference in mean change in the potassium level after correction compared to 0.9% saline (MD 0 mEq/L, 95% CI −0.21 to 0.21; Analysis 1.8).
1.8 AnalysisComparison Balanced crystalloid solutions versus 0.9% saline, Outcome Change in potassium level after correction
One study including 70 children reported results as change in creatinine level (difference between mean final creatinine level after correction and mean creatinine level at baseline, per group) (Naseem 2020). The study found that balanced solutions may result in no difference in mean change in the creatinine level after correction compared to 0.9% saline (MD 0.10 mg/dL, 95% CI −0.09 to 0.29; Analysis 1.9).
1.9 AnalysisComparison Balanced crystalloid solutions versus 0.9% saline, Outcome Change in creatinine level after correction
One study including 68 children reported results on the incidence of AKI (Kartha 2017). The study reported that seven children in the balanced solutions group had AKI in comparison to six children in the 0.9% saline group. The evidence suggests that balanced solutions may result in no difference in AKI compared to 0.9% saline (RR 1.17, 95% CI 0.44 to 3.11; Analysis 1.10).
1.10 AnalysisComparison Balanced crystalloid solutions versus 0.9% saline, Outcome Acute kidney injury at any time
Two studies including 147 children reported the number of cases of hyponatraemia after correction (Allen 2016; Naseem 2020). Meta‐analysis showed that balanced solutions may result in no difference in hyponatraemia compared to 0.9% saline (RR 1.41, 95% CI 0.96 to 2.07; low‐certainty evidence; Analysis 1.11).
1.11 AnalysisComparison Balanced crystalloid solutions versus 0.9% saline, Outcome Adverse events (hyponatraemia)
Two studies including 147 children reported the number of cases of hypokalaemia after correction (Allen 2016; Naseem 2020). Meta‐analysis showed that balanced solutions likely reduce the risk of hypokalaemia in comparison to 0.9% saline (RR 0.54, 95% CI 0.31 to 0.96; moderate‐certainty evidence; Analysis 1.12).
1.12 AnalysisComparison Balanced crystalloid solutions versus 0.9% saline, Outcome Adverse events (hypokalaemia)
In this systematic review, we included five studies that evaluated 465 children. The analyses from the primary outcomes showed that, in children with severe dehydration due to acute diarrhoea, balanced solutions likely results in a slight reduction of the time in the hospital compared to 0.9% saline, but we are uncertain whether there is an effect on mortality. The analyses from the secondary outcomes showed that balanced solutions may produce a higher increase in blood pH and bicarbonate levels after the intravenous correction.
However, the evidence suggests that balanced solutions result in no difference in the need for additional fluids; the total amount of fluids received; or in the change in sodium, potassium, chloride, and creatinine levels.
Last, in terms of adverse effects, in comparison to 0.9% saline, balanced solutions likely reduce the risk of hypokalaemia but may result in no difference in the incidence of hyponatraemia after intravenous correction.
The included studies were conducted primarily in LMIC. Three studies recruited children in India, one in Pakistan, and one in North America (the USA and Canada). Three studies included children with severe dehydration, and one included children with moderate‐to‐severe dehydration (one study did not explicitly use a dehydration scale). Therefore, these findings may be more applicable to LMIC than to HIC contexts. Furthermore, severe dehydration cases due to acute diarrhoea are much more common in LMIC, and these findings will definitely be of interest to clinicians and decision‐makers in these settings.
We have no information about the aetiology of the diarrhoeal episodes of the children included in the studies except for very few isolated cases reported in one study. Therefore, we cannot link these results to dehydration cases caused by specific micro‐organisms. Additionally, all studies excluded children with severe malnutrition; thus, this evidence may not apply to this population, which has had different recommendations for intravenous rehydration regimens (i.e. intravenous rehydration only in cases of hypovolaemic shock) (Ashworth 2004).
We evaluated 0.9% saline and balanced crystalloid solutions, as they are the most common solutions in clinical practice in children with severe dehydration. Nevertheless, some solutions may have been studied in this clinical scenario and did not meet our criteria to be considered in the 0.9% saline or the balanced solution groups. As a result, we did not consider trials using 0.45% saline or colloids, or comparing saline to dextrose in saline solutions. Likewise, out of five included trials, four evaluated Ringer's lactate solution and one evaluated Plasma‐Lyte. We found no evidence for other balanced crystalloids, such as Sterofundin/Ringerfundin, which has been used for resuscitation in paediatric sepsis (Trepatchayakorn 2021). Although balanced solutions may share the benefits as their compositions are similar, our results may only be applicable to the use of Ringer's lactate and Plasma‐Lyte.
Only one study was funded a pharmaceutical industry (Allen 2016). Specifically, this study was funded by the manufacturer of Plasma‐Lyte. Moreover, two of this study's authors were employees of the manufacturer. The other studies had no direct funding or were funded by a not‐for‐profit organization (hospital or university).
We consider our results may be useful to inform practice guidelines. As previously described, some guidelines either suggest the use of 0.9% saline in preference to Ringer's lactate (Guarino 2014; NICE 2009), or do not recommend one over the other (American Academy of Pediatrics 1996). Therefore, our results may inform revisions of the recommendations. In contrast, WHO guidelines have explicitly recommended Ringer's lactate over 0.9% saline for rehydrating severely dehydrated children with acute diarrhoea and only recommend 0.9% saline when the Ringer's lactate is unavailable (WHO 2005). Our results may be used to support the WHO recommendation on Ringer's lactate over 0.9% saline. However, additional factors, such as costs and availability of solutions need to be considered to support future recommendations
The certainty of the evidence ranged between very low and moderate. The results for the primary outcomes were judged as moderate certainty (time in hospital) and low certainty (mortality) (Table 1). The reasons for downgrading the certainty were mainly due to study limitations (risk of bias of individual studies) and imprecision, and in one case, due to inconsistency. The study limitations for time in hospital were due to other biases and unclear allocation concealment.
All the trials, except Naseem 2020 were judged at high or unclear risk of other bias due to early stopping of the study, manufacturer funding, or unbalanced groups at baseline. We downgraded due to imprecision in the mortality, need for additional fluids, the total amount of fluids received, and adverse effects (hyponatraemia). We downgraded for inconsistency for the final bicarbonate after correction outcome.
Even though we applied a comprehensive search strategy without language restrictions, we may have missed relevant studies from other databases. Moreover, we could not graphically explore the risk of publication bias due to the low number of studies. In addition, some data were missing. For instance, in Allen 2016, we could not obtain the SD for the total amount of fluids received per group, from the published paper, and we received no response after contacting the authors by email. Therefore, we excluded this study from this outcome analysis. In addition, we excluded one study due to potential fabricated data (Shaikh 2022), because it had identical results in many outcomes to another study already included (Mahajan 2012).
One study presented outcome data as medians and ranges (Kartha 2017). We transformed these data to the best mean and SD, according to the approach by Wan 2014. This approach could have had an impact on the results. Moreover, we planned sensitivity analyses based on the outcomes that had some data transformation. However, there was not enough information for the primary outcomes.
Some outcomes from the trials did not contribute to the meta‐analyses because they were reported in a different form than that defined by our protocol. For instance, some outcomes were presented as final values, and we were interested in evaluating the change between final and baseline values (e.g. change in sodium, potassium, chloride, and creatinine). As a result, we did not use the information for these outcomes.
To our knowledge, this is the first systematic review that summarizes the evidence comparing 0.9% saline with balanced solutions in children with severe dehydration due to acute diarrhoea. Nonetheless, the effectiveness and safety of balanced crystalloid solutions compared to 0.9% saline have been extensively studied in different clinical scenarios, and several systematic reviews have summarized the evidence.
One Cochrane Review found that critically ill children and adults treated with balanced solutions had lower chloride levels, and higher pH and bicarbonate levels (Antequera Martin 2019). Another Cochrane Review focusing on perioperative care found that compared to 0.9% saline, balanced solutions reduced the incidence of hyperchloraemia and metabolic acidosis in elective surgery in adults (Bampoe 2017).
Non‐Cochrane reviews have also evaluated balanced solutions against 0.9% saline for critically ill people. One recent comparing balanced and saline solutions in critically ill people found that balanced solutions were similar to the saline solution for mortality, major kidney adverse events, length of intensive care unit stay, and level of creatinine (Zhu 2021). Similarly, another recent review focusing on critically ill children found that a balanced solution improved serum bicarbonate and blood pH values compared with the unbalanced fluid, but found no differences in AKI or mortality (Lehr 2022).
In summary, previous Cochrane and non‐Cochrane reviews have found some benefits in biochemical outcomes, such as improvement in pH and bicarbonate, and lower chloride levels, which are similar to our findings. However, only one review has focused on children, which found that balanced solutions improve serum bicarbonate and blood pH values compared with the unbalanced fluids, but found no differences in AKI or mortality in critically ill children (Lehr 2022). Our review found that 0.9% saline was associated with significantly more hypokalaemia, which may be relevant for clinicians who need to choose between interventions to rehydrate dehydrated children due to acute diarrhoea.
Protocol first Issue 6, 2020
We thank Vittoria Lutje, Cochrane Infectious Diseases Group (CIDG) Information Specialist, for her invaluable support with the design of the search strategy and for conducting the searches.
The CIDG editorial base is funded by UK aid from the UK Government for the benefit of low‐ and middle‐income countries (project number 300342‐104). The views expressed do not necessarily reflect the UK Government's official policies.
The following people conducted the editorial process for this article.
<1946 to 3 May 2022>
exp Diarrhea/
diarrh$.mp.
exp Gastroenteritis/
gastroenteritis.mp.
gastrointestinal infection$.mp.
enteritis.mp.
exp Rotavirus Infection/
rotavir$.mp.
dysenter$.mp.
or/1‐9
dehydration.tw. or exp DEHYDRATION/
rehydration.tw. or Fluid Therapy/
hydration.tw.
hypovolemia.tw. or hypovolaemia.tw. or exp Shock/ or exp HYPOVOLEMIA/
(intraven* or IV or parenteral).tw.
or/11‐15
10 and 16
exp isotonic solutions/
exp hypotonic solutions/
exp REHYDRATION SOLUTIONS/
rehydration solution$.tw.
exp electrolytes/
balanced fluid$.mp.
unbalanced fluid$.mp.
buffer.mp.
exp sodium chloride/
(nacl adj "0.9").mp.
("0.9" adj3 (saline or sodium chloride or solution or Nacl)).tw.
saline solution.tw.
(normal adj2 saline).tw.
(physiological adj2 (saline or solution$)).tw.
(isotonic adj2 (saline or solution$)).tw.
(Ringer lactate).tw.
Hartman$ solution.tw.
hartman$.tw.
ringer$ acetate.mp.
(plasma?lyte or sterofundin or inosteril or iso?lyte).mp.
(poly?electrolyte or multi?electrolyte).mp.
(solution or non?buffer or electrolyte or acetated)).tw.
or/18‐39
17 and 40
((randomised controlled trial or controlled clinical trial).pt. or randomized.ab. or placebo.ab. or clinical trials as topic.sh. or randomly.ab. or trial.ti.) not (animals not (humans and animals)).sh.
(Infan or new‐born or neonat or babies or toddler or boy or boys or boyhood or girl or children or schoolchild).mp. or schoolchild.tw. or schoolchild.mp. or juvenil.mp. or teenage.mp. or exp Pediatrics/ or pediatric.mp. or peadiatric.tw. or prematur.mp.
41 and 42 and 43
<1974 to 2022 Week 17>
1 exp Diarrhea/
2 diarrh$.mp.
3 exp Gastroenteritis/
4 gastroenteritis.mp.
5 gastrointestinal infection$.mp.
6 enteritis.mp.
7 exp Rotavirus Infection/
8 rotavir$.mp.
9 dysenter$.mp.
10 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9
11 dehydration.tw. or exp DEHYDRATION/
12 rehydration.tw. or Fluid Therapy/
13 hydration.tw.
14 (hypovolemia or hypovolaemia).tw. or exp Shock/ or exp HYPOVOLEMIA/
15 (intraven* or IV or parenteral).tw.
16 11 or 12 or 13 or 14 or 15
17 10 and 16
18 exp isotonic solutions/
19 exp hypotonic solutions/
20 exp REHYDRATION SOLUTIONS/
21 rehydration solution$.tw.
22 exp electrolytes/
23 balanced fluid$.mp.
24 unbalanced fluid$.mp.
25 buffer.mp.
26 exp sodium chloride/
27 (nacl adj "0.9").mp.
28 ("0.9" adj3 (saline or sodium chloride or solution or Nacl)).tw.
29 saline solution.tw.
30 (normal adj2 saline).tw.
31 (physiological adj2 (saline or solution$)).tw.
32 (isotonic adj2 (saline or solution$)).tw.
33 (Ringer lactate).tw.
34 Hartman$ solution.tw.
35 hartman$.tw.
36 ringer$ acetate.mp.
37 (plasma?lyte or sterofundin or inosteril or iso?lyte).mp.
38 (poly?electrolyte or multi?electrolyte).mp.
39 (solution or non?buffer or electrolyte or acetated)).tw.
40 18 or 19 or 20 or 21 or 22 or 23 or 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39
41 17 and 40
42 (Infan or new‐born or neonat or babies or toddler or boy or boys or boyhood or girl or children or schoolchild).mp. or schoolchild.tw. or schoolchild.mp. or juvenil.mp. or teenage.mp. or exp Pediatrics/ or pediatric.mp. or peadiatric.tw. or prematur.mp.
43 41 and 42
44 crossover procedure/ or double blind procedure/ or single blind procedure/
45 (random* or factorial* or placebo* or assign* or allocat* or crossover*).tw.
46 randomized controlled trial.mp. or randomized controlled trial/
47 ((blind* or mask*) and (single or double or triple or treble)).tw.
48 44 or 45 or 46 or 47
49 43 and 48
Issue 4, 2022
#73 MeSH [Diarrhea] explode all trees
#74 diarrh*
#75 MeSH [Gastroenteritis] explode all trees
#76 gastroenteritis
#77 gastrointestinal infections
#78 enteritis
#79 MeSH [Rotavirus Infections] explode all trees
#80 rotavir*
#81 dysenter*
#82 #73 or #74 or #75 or #76 or #77 or #78 or #79 or #80 or #81
#83 dehydration
#84 rehydration
#85 MeSH [Fluid Therapy] explode all trees
#86 hydration
#87 hypovolemia or hypovolaemia or Shock
#88 (intraven* or IV or parenteral)
#89 #83 or #84 or #85 or #86 or #87 or #88
#90 #82 and #89
#91 isotonic solution*
#92 hypotonic solution*
#93 rehydration solution*
#94 electrolytes
#95 balanced fluid*
#96 unbalanced fluid*
#97 buffered fluid*
#98 sodium chloride
#99 nacl and "0.9"
#100 "0.9" and (saline or sodium chloride or solution or Nacl)
#101 saline solution
#102 normal saline
#103 "physiological saline" or "physiological solution"
#104 "isotonic saline" or "isotonic solution"
#105 "Ringer's solution"
#106 "Ringer's lactate"
#107 "Hartman's solution"
#108 Hartman
#109 "Ringer's acetate"
#110 plasmalyte or sterofundin or inosteril or isolyte
#111 polyelectrolyte or multielectrolyte
#112 solution* and (physiological or buffer* or nonbuffer* or balanced or unbalanced or isotonic or hypotonic or sodium chloride or NaCL or bicarbonate or electrolyte or acetated)
#113 #91 or #92 or #93 or #94 or #95 or #96 or #97 or #98 or #99 or #100 or #101 or #102 or #103 or #104 or #105 or #106 or #107 or #108 or #109 or #110 or #111 or #112
#114 #90 and #113
#115 Infan or new‐born or neonat or babies or toddler or boy or boys or boyhood or girl or children or schoolchild
#116 #114 and #115
diarrhea or gastroenteritis or rotavirus or dysentery [Words] and and isotonic or ipotonic or rehydration or fluid$ or sodium or electrolytes [Words] and randomized OR randomised OR controlled trial OR clinical trial OR random OR randomly [Words]
fluid therapy | Diarrhea | Child
(diarrhea or gastroenteritis ) and (fluid therapy or rehydration)
We did not conduct the following analyses specified in the protocol (Florez 2020b), due to a low number of included
Conceiving and designing the IDF
Writing the protocol and providing intellectual IDF, JMS, GPG
Screening and reviewing the GPG, JMS
Extracting the data and assessing the risk of bias of the included JMS, GPG, IDF
Entering data into Review Manager Web and conducting the IDF
Interpreting the IDF, JMS, GPG
Writing the first draft of the IDF
Critically reviewing of the manuscript for important intellectual content; JMS, GPG
All review authors read and approved the final review version.
IDF: none.
JMS: none.
GPG: none.
New