Hypertonic salt solution for peri‐operative fluid management
Abstract
Background
Fluid excess may place people undergoing surgery at risk for various complications. Hypertonic salt solution (HS) maintains intravascular volume with less intravenous fluid than isotonic salt (IS) solutions, but may increase serum sodium. This review was published in 2010 and updated in 2016.
Objectives
To determine the benefits and harms of HS versus IS solutions administered for fluid resuscitation to people undergoing surgery.
Search methods
In this updated review we have searched the Cochrane Central Register of Controlled Trials (CENTRAL; Issue 4, 2016); MEDLINE (January 1966 to April 2016); EMBASE (January 1980 to April 2016); LILACS (January 1982 to April 2016) and CINAHL (January 1982 to April 2016) without language restrictions. We conducted the original search on April 30th, 2007, and reran it on April 8th, 2016.
Selection criteria
We have included randomized clinical trials (RCTs) comparing HS to IS in people undergoing surgery, irrespective of blinding, language, and publication status.
Data collection and analysis
Two independent review authors read studies that met our selection criteria. We collected study information and data using a data collection sheet with predefined parameters. We have assessed the impact of HS administration on mortality, organ failure, fluid balance, serum sodium, serum osmolarity, diuresis and physiologic measures of cardiovascular function. We have pooled the data using the mean difference (MD) for continuous outcomes. We evaluated heterogeneity between studies by I² percentage. We consider studies with an I² of 0% to 30% to have no or little heterogeneity, 30% to 60% as having moderate heterogeneity, and more than 60% as having high heterogeneity. In studies with low heterogeneity we have used a fixed‐effect model, and a random‐effects model for studies with moderate to high heterogeneity.
Main results
We have included 18 studies with 1087 participants of whom 545 received HS compared to 542 who received IS. All participants were over 18 years of age and all trials excluded high‐risk patients (ASA IV). All trials assessed haematological parameters peri‐operatively and up to three days post‐operatively.
There were three (< 1%) deaths reported in the IS group and four (< 1%) in the HS group, as assessed at 90 days in one study. There were no reports of serious adverse events. Most participants were in a positive fluid balance postoperatively (4.4 L IS and 2.5 L HS), with the excess significantly less in HS participants (MD ‐1.92 L, 95% confidence interval (CI) ‐2.61 to ‐1.22 L; P < 0.00001). IS participants received a mean volume of 2.4 L and HS participants received 1.49 L, significantly less fluid than IS‐treated participants (MD ‐0.91 L, 95% CI ‐1.24 to ‐0.59 L; P < 0.00001). The maximum average serum sodium ranged between 138.5 and 159 in HS groups compared to between 136 and 143 meq/L in the IS groups. The maximum serum sodium was significantly higher in HS participants (MD 7.73, 95% CI 5.84 to 9.62; P < 0.00001), although the level remained within normal limits (136 to 146 meq/L).
A high degree of heterogeneity appeared to be related to considerable differences in the dose of HS between studies. The quality of the evidence for the outcomes reported ranged from high to very low. The risk of bias for many of the studies could not be determined for performance and detection bias, criteria that we assess as likely to impact the study outcomes.
Authors' conclusions
HS reduces the volume of intravenous fluid required to maintain people undergoing surgery but transiently increases serum sodium. It is not known if HS affects survival and morbidity, but this should be examined in randomized controlled trials that are designed and powered to test these outcomes.
PICOs
Plain language summary
Increased salt in solution to maintain fluid during surgery
Review question
Are solutions containing more salt than is normally used safe during surgery?
Background
People usually require fluids during surgery. Sometimes large volumes of fluid are given in order to maintain adequate blood volume, but these volumes may leave people with too much fluid. The fluids normally used during surgery have a salt balance similar to that found in blood, and are called isotonic. Hypertonic salt solutions (HS) have a higher sodium concentration than isotonic salt solutions (IS). HS might benefit people undergoing surgery by reducing the total volume of fluid required.
Search date
The evidence is up to date to April 8th, 2016.
Study characteristics
We included 18 trials that compared HS to IS in people undergoing surgery. The trials included 1087 participants. Five hundred and forty‐five (545) participants received HS and 542 received IS during their operations. The participants were randomly assigned to their groups. The studies took place in 11 countries. Study participants were over the age of 18. All studies excluded people with serious health risks from participating. All studies monitored fluid levels during the operation and up to three days after.
Key results
There were seven deaths in total, three (less than 1%) from the IS group and four (less than 1%) from the HS group. The risk of death was very low in these studies. The studies did not report the occurrence of serious adverse events.
Thirteen studies reported the amount of fluid given. The IS group received a mean of 2.4 L and the HS group received 0.91 L less (1.49 L). The highest amount of sodium in the blood over the course of the study was reported by 16 studies. The IS group had a median of 139 meq/L and the HS group was 7.73 meq/L higher. The normal acceptable range is 136 to 146 meq/L.
Quality of the evidence
For deaths and adverse events the trials lacked sufficient size and duration to adequately assess differences. We assessed the quality of evidence for deaths to be very low, and future studies are likely to change the result reported here.
The reporting of the highest amount of sodium is of moderate quality. The measuring of blood sodium during an operation is a common measurement that is unlikely to be misrepresented.
Authors' conclusions
Summary of findings
| Hypertonic salt compared to isotonic salt solution for peri‐operative resuscitation | ||||||
| Patient or population: any people undergoing surgery with fluid resuscitation | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| isotonic salt solution for peri‐operativeresuscitation | Hypertonic salt | |||||
| Mortality Follow‐up: range 1 to 90 days | Study population | ‐ | 1087 | ⊕⊝⊝⊝ | Any recorded death during the study period. The risk of bias impacting this outcome is considered to be low. Only one study had incidents of mortality | |
| ‐ | ‐ | |||||
| Serious adverse events Follow‐up: range 1 to 90 days | ‐ | ‐ | ‐ | 1087 (18 RCTs) | ⊕⊝⊝⊝ | Other adverse outcomes are collected as defined by each trial or if any of the following occurred: any organ failure, including renal, pulmonary, cardiac, or cerebral |
| Fluid balance (L) Follow‐up: range 1 to 3 days | The mean fluid balance (L) was 4.375 | The mean fluid balance (L) in the intervention group was 1.92 lower (2.61 lower to 1.22 lower) | ‐ | 737 | ⊕⊕⊝⊝ | The change in participant fluid volume at the end of fluid administration. A neutral fluid balance would be optimal |
| Total volume of crystalloid administered (L) Follow‐up: range 1 to 3 days | The mean total volume of crystalloid administered (L) was 2.43 | The mean total volume of crystalloid administered (L) in the intervention group was 0.91 lower (1.24 lower to 0.59 lower) | ‐ | 871 | ⊕⊕⊕⊝ | The total volume of fluid delivered intravenously over the study period. There are no defined minimum or maximum values for fluid delivery during surgery. Less resuscitating fluid is preferred |
| Peak serum sodium Follow‐up: range 1 to 3 days | The mean peak serum sodium (meq/L) was 139.1 | The mean peak serum sodium (meq/L) in the intervention group was 7.73 higher (5.84 higher to 9.62 higher) | ‐ | 780 | ⊕⊕⊕⊝ | The measurement of this variable is a common practice in operative procedures. Measured as the peak amount of sodium in the blood, given in milliequivelants per litre, over the study period. The normal acceptable range is 136 to 146 meq/L |
| Final serum sodium Follow‐up: range 1 to 3 days | The mean final serum sodium (meq/L) was 138.3 | The mean final serum sodium (meq/L) in the intervention group was 3.45 higher (2.46 higher to 4.44 higher) | ‐ | 640 | ⊕⊕⊕⊝ | The measurement of this variable is common practice in operative procedures. Measured as the final amount of sodium in the blood, given in milliequivelants per litre, at the end of the study. The normal acceptable range is 136 to 146 meq/L |
| Maximum intraoperative cardiac index Follow‐up: 1 to 3 days | The mean maximum intraoperative cardiac index (L/min/M²) was 2.9 | The mean maximum intraoperative cardiac index (L/min/m²) in the intervention group was 0.34 higher (0.19 higher to 0.49 higher) | ‐ | 418 | ⊕⊕⊕⊕ | The measurement of this variable is common practice in operative procedures. Measured by the volume of blood passing through one square meter each minute (L/min/M²). The normal range is 2.5 ‐ 4.0 L/min/M² |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Downgraded (2 levels) for indirectness: The majority of studies have an insufficient follow‐up period to adequately measure the outcome. | ||||||
Background
Description of the condition
Low‐volume resuscitation with hypertonic crystalloid solutions has been investigated for over 20 years (Shackford 1983). More recently, alterations in cellular immune function with hypertonic salt solution (HS) administration have been demonstrated in experimental and clinical studies (Kølsen‐Petersen 2004; Rizoli 2006). Several randomized controlled trials (RCTs) of HS resuscitation in critically ill participants have been performed. A systematic review of HS compared to isotonic salt solution (IS) in resuscitation following burns or trauma was unable to reach a conclusion regarding benefit or harm in the presence of wide confidence intervals (Bunn 2004). Trials of HS alone, or in combination with colloids, have also been performed in the trauma population. A meta‐analysis comparing 250 mL of HS (with or without dextran) with administration of 250 mL of isotonic crystalloid for the treatment of hypotension either in the field or at admission to the emergency department in 1233 trauma patients failed to demonstrate that HS with dextran confers a survival benefit (Wade 1997).
Description of the intervention
Standard peri‐operative care includes IS administration to counter conditions which may cause transient intraoperative hypovolaemia including: fluid deprivation during preoperative fasting; vasodilatation due to epidural or general anaesthesia; third space sequestration of intravascular fluid; insensible fluid loss and intraoperative fluid or blood loss. These conditions are often reversed at the end of an operation. In fact, IS has been shown to increase the weight of people undergoing elective major surgery by an average of three to six kilograms (kg) (Grocott 2005). While most people tolerate the additional fluid well, postoperative improvement or reversal of the conditions outlined above may place those with compromised cardiovascular or renal function at increased risk for development of pulmonary oedema. People without cardiovascular or renal risk factors may also be adversely affected by peri‐operative fluid gain. A recent RCT demonstrated that peri‐operative fluid restriction resulted in fewer major or minor postoperative complications compared to traditional care in 172 adult participants undergoing elective colorectal surgery (Brandstrup 2003). Another study demonstrated that fluid overload delayed return of gastrointestinal function (Lobo 2002). Conversely, failure to maintain intravascular volume during surgery may place people at risk for cardiac or cerebral ischaemia. Indeed, supplemental peri‐operative fluid administration has been shown to improve tissue oxygenation (Arkiliç 2003).
How the intervention might work
HS has the potential to reduce the total volume of fluid administered during operative procedures by allowing people to draw fluid from the interstitium (and other body compartments) to counter peri‐operative hypotensive effects, and thereby provide Intravascular support without excess fluid administration. In situations where large volume resuscitation may be harmful, such as in brain trauma, a role for HS is emerging (Ogden 2005). Notwithstanding, several risks have been associated with HS, including potential hypernatraemia, metabolic acidosis and vasodilatation.
Why it is important to do this review
Several RCTs of prophylactic HS administration in the peri‐operative period have been published. In contrast to other trials where HS has been combined with colloid solutions to treat hypotension, these RCTs may provide a clinical picture of the effect of HS on peri‐operative fluid management.
Objectives
To determine the benefits and harms of HS versus IS solutions administered for fluid resuscitation to people undergoing surgery.
Methods
Criteria for considering studies for this review
Types of studies
We included RCTs comparing the administration of HS versus IS solution during non‐emergency operative procedures, regardless of language or publication status. RCTs are the gold standard for comparing the effect of one treatment versus another.
Types of participants
We included all participants undergoing any surgical procedures.
Types of interventions
We have included peri‐operative administration of either HS or IS solutions. We permitted concomitant measures so long as they applied to both arms of the study. We excluded studies that compared HS and a colloidal solution to IS alone. Additionally, we excluded studies that compared HS and IS solutions administered by inhalation or absorption from the nasal mucosa and involving non‐surgical patient populations (burns, trauma and head injury).
Types of outcome measures
Primary outcomes
1. Mortality
Defined as any deaths occurring during the study period. Where all participants are included in the results for other outcomes we have extrapolated that as indicating no deaths.
2. Serious adverse events
We collected other adverse outcomes as defined by each trial, or if any of the following occurred: any organ failure, any requirement for dialysis (renal failure) or prolonged ventilation (pulmonary failure); use of medical therapy for either pulmonary oedema or circulatory support (cardiac failure) or for confusion (cerebral failure).
Secondary outcomes
3. Fluid balance over the study period
We used authors' definitions where provided. For studies not clearly specifying the study period, we defined it to include the immediate preoperative (induction of anaesthesia), intraoperative and postoperative periods (up to 24 hours after surgery). Studies can report the fluid balance by reporting the difference in fluid given minus fluid excreted or by the change in weight of the participant. For studies that only reported weight change, we applied a conversion factor, wherein 1 kg = 1 L (litre), to calculate fluid balance. Fluid balance is expressed in litres.
4. Total volume of intravenous fluid delivered
A report of the volume of resuscitating fluid given to the participant intravenously during the peri‐operative and recovery period as reported by the studies. Fluid delivered is expressed in litres.
5. Peri‐operative diuresis
A measure of the urine output from the participant during the operative period. Diuresis is reported as litres.
6. Maximum serum sodium concentration
As measured from the participant's blood during the study and reported as milliequivalents per litre (meq/L).
7. Final serum sodium concentration
As measured in the participant's blood at the end of follow‐up, and reported as milliequivalents per litre (meq/L).
8. Duration of endotracheal intubation after operation
As reported by each study and converted to hours (h).
9. Duration of stay in intensive care after operation
As reported by each study and converted to hours (h).
10. Duration of stay in hospital after operation
As reported by each study and converted to days (d).
11. Other outcomes
We collected data regarding serum osmolarity, expressed as milliosmoles per kilogram of water (mOsm/kg H2O) and peri‐operative haemodynamic parameters: pulmonary artery wedge pressure, measured by mm of mercury (mm Hg); and cardiac index (CI), derived from cardiac output (CO = Heart rate/stroke volume/1000) and body surface area (BSA), CI = CO/BSA; it is a measure of the volume of blood passing through one square meter each minute (L/min/M²).
Search methods for identification of studies
Electronic searches
For this updated review we have searched the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 4, 2016); MEDLINE (January 1966 to April 2016); EMBASE (January 1980 to April 2016); LILACS (January 1982 to April 2016) and CINAHL (January 1982 to April 2016). We limited the publication types to clinical trials, controlled clinical trials, RCTs, multicentre studies and meta‐analyses, without language restrictions.
We originally used the search strategy described in the appendices (Appendix 1 MEDLINE; Appendix 2 EMBASE; Appendix 3 CINAHL; Appendix 4 LILACS; Appendix 5 CENTRAL) to search until August 2009. We have updated the search terms since the original search (see Appendix 6). In addition, we searched trial registries including clinicaltrials.gov/, www.controlled‐trials.com/ and www.ifpma.org/clinicaltrials.html for ongoing trials. We sought letter or email contact with principal investigators to inform them of the meta‐analysis and to ask for additional information.
The search was last run on April 8th, 2016.
Searching other resources
We handsearched the bibliographies of retrieved articles and the abstracts of conference proceedings published in Anaesthesia and Intensive Care; Anaesthesia and Analgesia; British Journal of Surgery; Critical Care Medicine; Journal of Vascular Surgery and Trauma; Injury; andInfection and Critical Care for the years 2000 to 2006.
Data collection and analysis
Selection of studies
Vivian McAlister (VM) with Brad Shrum (BS) scanned titles and abstracts identified by the initial search to exclude overlapped and irrelevant studies. Three authors (Tammy Znajda (TZ), Karen Burns (KB) and BS) identified trials that met our inclusion criteria. Brian Church (BC) resolved differences in data recorded and we resolved all differences of opinion through discussion.
Data extraction and management
At least two of the review authors abstracted data independently from the studies, using standardized forms developed for this review. We wrote to primary study authors for information regarding missing data or data that were not clearly stated. We resolved differences of opinion through discussion. We abstracted data pertaining to the included participants, interventions applied and outcomes reported for each trial. Where translation was needed we sought the help of native speakers of the language who had scientific training. The translator collected relevant information on the data collection forms provided.
We abstracted the following details from each of the included studies:
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Participants (inclusion and exclusion criteria; mean age; proportion of men; aetiology of disease; weight before and after surgery; serum electrolytes before, during and after surgery);
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Interventions (type of surgery; concentration and volume of hypertonic saline given; total volume of fluid administered and concomitant therapy);
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Trials (setting; methodological quality; publication status; duration of follow‐up and all outcomes).
Assessment of risk of bias in included studies
We based our assessment of 'Risk of bias' on the recommendations provided in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). The assessments were based on the allocation sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting, and other potential biases (Lundh 2012; Wood 2008).
Allocation sequence generation
Low risk of bias: sequence generation was achieved using computer random‐number generation or a random‐number table. Drawing lots, tossing a coin, shuffling cards, and throwing dice were adequate if performed by an independent person not otherwise involved in the trial.
Uncertain risk of bias: the method of sequence generation was not specified.
High risk of bias: the sequence generation method was not random.
Allocation concealment
Low risk of bias: the participant allocations could not have been foreseen in advance of, or during, enrolment. Allocation was controlled by a central and independent randomization unit. The allocation sequence was unknown to the investigators (for example, if the allocation sequence was hidden in sequentially‐numbered, opaque, and sealed envelopes).
Uncertain risk of bias: the method used to conceal the allocation was not described so that intervention allocations may have been foreseen in advance of, or during, enrolment.
High risk of bias: the allocation sequence was likely to be known to the investigators who assigned the participants.
Blinding of participants, personnel, and outcome assessors
Low risk of bias: blinding was performed adequately. Additionally, we defined lack of blinding (detection and performance bias) as not likely to affect the assessment of the outcome mortality.
Uncertain risk of bias: there was insufficient information to assess whether blinding was likely to introduce bias in the results.
High risk of bias: no blinding or incomplete blinding, and the assessment of outcomes were likely to be influenced by lack of blinding (all other outcomes than mortality and non‐subjective laboratory measures).
Incomplete outcome data
Low risk of bias: missing data were unlikely to make treatment effects depart from plausible values. Sufficient methods, such as multiple imputation, were employed to handle missing data.
Uncertain risk of bias: there was insufficient information to assess whether missing data in combination with the method used to handle missing data were likely to introduce bias in the results
High risk of bias: the results were likely to be biased due to missing data.
Selective outcome reporting
Low risk of bias: the trial reported clinically relevant outcomes, which we defined as mortality, hepatic encephalopathy, and serious adverse events. If we had access to the original trial protocol, the outcomes should be those specified in that protocol. If we obtained the protocol from a trial registry such as www.clinicaltrials.gov, we only used the information if the investigators registered the trial before inclusion of the first participant.
Unclear risk of bias: not all predefined criteria were reported fully, or it was unclear whether data on these outcomes were recorded or not.
High risk of bias: one or more predefined outcomes were not reported.
Other bias
Low risk of bias: the trial appeared to be free of other bias domains, including: medicinal dosing problems or follow‐up (as defined below).
Uncertain risk of bias: the trial may or may not have been free of other domains that could put it at risk of bias.
High risk of bias: there were other factors in the trial that could put it at risk of bias, such as the administration of inappropriate treatments being given to the controls (e.g. an inappropriate dose) or follow‐up (e.g. the trial included different follow‐up schedules for participants in the allocation groups being compared).
Evidence Quality
The control of bias in the included trials was part of the overall assessment of the quality of the body of evidence, which we classified as ‘High’, ‘Moderate’, ‘Low’, or ‘Very Low’. We based the assessment on the specific evidence grading system developed by the GRADE collaboration (GRADE 2004).
Measures of treatment effect
We performed the analyses in Review Manager 5 (RevMan 2014). We used the result value and number of participants in all intervention arms to calculate the mean difference (MD) for continuous outcomes, with 95% confidence intervals (CIs).
Unit of analysis issues
If the standard error of the mean was recorded in a study, we converted it to standard deviation following the Cochrane Handbook for Systematic Reviews of Interventions chapter 7.7.3.2. Briefly, SD = SE x Sqrt(n).
Dealing with missing data
We used the last observed response carried forward (LOCF) for participants with missing data.
Assessment of heterogeneity
We assessed heterogeneity visually through the use of funnel plots and further assessed it using the I² value. We explored sources of heterogeneity through sensitivity, subgroup, and meta‐regression analyses. The analyses included the extracted participant, intervention, and trial characteristics listed above as explanatory variables.
Assessment of reporting biases
We used funnel plot asymmetry to detect reporting biases where there were more than nine studies, to avoid false detections (Sterne 2001a; Sterne 2001b). Where funnel plots appeared to have asymmetry, we deployed the test by Matthias Egger (Egger 1997) as described by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011): linear regression of intervention effect estimate against its standard error, weighted by the inverse of the variance of the intervention effect estimate. We considered reporting biases to be evident where P < 0.05.
Data synthesis
We combined data in fixed‐effect meta‐analysis if the group I² was less than 30%. Where I² was 30% or greater, we used random‐effects meta‐analyses. We conducted intention‐to‐treat (ITT) analyses including all participants irrespective of compliance or follow‐up. In studies that had more than two treatment arms, we incorporated only two arms of the trial into the meta‐analysis: the arm using IS and the treatment arm evaluating HS solution. If there were two HS arms, we selected the one most different in concentration from IS for analysis. Where meta‐analysis was not possible due to a lack of events we used the Clopper‐Pearson method to estimate treatment group CIs (Clopper 1934).
Summary of findings table
We summarize the compiled data for this meta‐analysis in the summary of findings Table for the main comparison. Each outcome is shown with its anticipated incidence per 1000 people for each treatment group. The MD is shown with 95% CIs for continuous outcomes. The overall quality of the evidence for each outcome has been determined using the Guideline Development Tool from the GRADE working group criteria and that of Cochrane (GRADE 2004; Higgins 2011). We rated the quality of the evidence as high, moderate, low, or very low, and have shown it visually and textually. Where studies have been downgraded from high quality, we have used footnotes to indicate the reason. Notes are included for each outcome to briefly describe it, and if appropriate the method of measurement.
Subgroup analysis and investigation of heterogeneity
When appropriate after consideration of statistical and clinical heterogeneity, we performed subgroup analyses based on the following a priori criteria:
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Type of surgery
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Dose of HS: trials were stratified into three comparisons according to the dose of HS, calculated as the volume of 3% HS required to give the same amount of sodium: 7 mL/kg or less (comparison 01); 7.1 to 10 mL/kg (comparison 02); > 10 mL/kg (comparison 03). We specified these dose stratifications before the review was conducted on the basis of an anticipated range of HS doses
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Volume of crystalloid given to the control group: trials were stratified into three comparisons according to the total volume of fluid transfusion received by IS participants: < 2 L (comparison 01); 2 L to 5 L (comparison 02); > 5 L (comparison 03). We specified these volume stratifications in advance of the review on the basis of an anticipated range of peri‐operative fluid administration
We interpreted a lack of overlap between two CIs in the subgroup analyses as representing a statistically significant difference.
Sensitivity analysis
Where the data permitted we performed a sensitivity analysis using the following a priori criteria. We removed studies that were deemed to have a moderate or higher risk of bias based on the aforementioned criteria (see Assessment of reporting biases). Where potential for bias was uncertain the review authors considered the potential impact of each domain on the results. For the purposes of sensitivity analysis, unknown sequence randomization or allocation concealment did not increase the risk of bias in a study, but unknown or high risk in any other domains did increased the risk of bias.
Results
Description of studies
Results of the search
From 284 reports identified by the search strategy, 25 reports met the criteria for further assessment (Figure 1). Of these 25 references, we excluded seven studies after detailed review because they were not randomized (Auler 1987; Shao 2005), did not compare to an IS group (Li 2014; Li 2015), or did not report our desired primary or secondary outcomes (Auler 1992; Yang Z 2014; Yousefshahi F 2013) (see Characteristics of excluded studies). We found no recently completed studies in registries of clinical trials including clinicaltrials.gov/; www.controlled‐trials.com/; and www.ifpma.org/clinicaltrials.html.
Study flow diagram.
Included studies
Eighteen studies with 1087 participants were included (Baraka 1994; Bruegger 2005; Cross 1989; Durasnel 1999; Ishikawa 1996; Jarvela 2000; Jarvela 2001; Kato 1996; Kimura 1994; Kølsen‐Petersen 2004; Lavu 2014; Leverve 2008; Shackford 1983; Shackford 1987; Shao 2013; Veroli 1992; Wang 1997; Younes 1988) (see Characteristics of included studies). The included trials were performed in a wide variety of surgical situations: aortic surgery (four trials) (Bruegger 2005; Shackford 1983; Shackford 1987; Younes 1988); lower limb surgery (three trials) (Ishikawa 1996; Jarvela 2000; Veroli 1992); transurethral prostate resection (three trials) (Baraka 1994; Kato 1996; Kimura 1994); coronary artery bypass grafting (three trials) (Cross 1989; Jarvela 2001; Leverve 2008); hysterectomy (one trial) (Kølsen‐Petersen 2004); hernia repair (one trial) (Wang 1997); general surgery (one trial) (Durasnel 1999); pancreaticoduodenectomy (one trial) (Lavu 2014); and neurological surgery (one trial) (Shao 2013). Anaesthetic techniques included: general anaesthesia (ten trials) (Bruegger 2005; Cross 1989; Jarvela 2001; Kato 1996; Kølsen‐Petersen 2004; Lavu 2014; Shackford 1983; Shackford 1987; Shao 2013; Younes 1988) and spinal anaesthesia (seven trials) (Baraka 1994; Durasnel 1999; Ishikawa 1996; Jarvela 2000; Kimura 1994; Veroli 1992; Wang 1997).
Studies were performed in 11 countries, which include Brazil, China, Denmark, Finland, France, Germany, Indonesia, Japan, Lebanon, Niger, and USA. Four publications were written in languages other than English, including Japanese (two trials) (Ishikawa 1996; Kimura 1994); French (one trial) (Durasnel 1999); Portuguese (one trial) (Younes 1988). The majority of included studies had small sample sizes, enrolling between 20 and 72 participants. The largest study enrolled 259 participants (Lavu 2014). The interval between the first and last study was approximately 30 years (1983 to 2014). Only one of the studies was designed to determine differences in short‐term mortality (Lavu 2014), with the remaining studies focusing on fluid and haemodynamic measurement during the peri‐operative period. Follow‐up extended into the postoperative period in 10 trials (Bruegger 2005; Cross 1989; Jarvela 2000; Jarvela 2001; Kato 1996; Kølsen‐Petersen 2004; Lavu 2014; Leverve 2008; Shackford 1983; Shackford 1987), with durations ranging from the stay in the recovery unit to 90 days postoperative, while the other trials confined their observations to the period of anaesthesia. Two studies reported results with standard error which we converted to standard deviation by multiplication with the square root of the number in the group (Shackford 1983; Shackford 1987).
Two authors of included studies whom we contacted for further information responded. Dr. Lavu kindly provided mean and standard deviation values that were not available in the publication (Lavu 2014), and Dr. Jarvela provided additional methodological details regarding random sequence generation and allocation concealment for two studies (Jarvela 2000; Jarvela 2001). Dr. Shao was contacted regarding methodology but did not respond (Shao 2013).
Excluded studies
Seven studies were found but ultimately excluded from analysis; two due to a lack of randomization (Auler 1987; Shao 2005), two because there was no isotonic saline control group (Li 2014; Li 2015), and three due to an absence of primary or secondary outcomes (Auler 1992; Yang Z 2014; Yousefshahi F 2013). Dr. Yousefshahi was contacted for further information but did not respond (Yousefshahi F 2013).
Risk of bias in included studies
The overall risk of bias in the included studies is undetermined due to a large number of studies (72%) not fully reporting methodology (Characteristics of included studies). The domains with the largest potential for bias are for performance and detection bias. For performance and detection bias, eight studies did not provide sufficient information to determine the potential for bias (Baraka 1994; Bruegger 2005; Durasnel 1999; Jarvela 2000; Kimura 1994; Leverve 2008; Wang 1997; Younes 1988) and five studies did not protect their studies from performance or detection bias (Ishikawa 1996; Jarvela 2001; Shackford 1983; Shackford 1987; Shao 2013). Despite there being limited or unknown protection from performance bias it is unlikely that participants were informed of the fluid given to them for resuscitation. However, care givers and outcome assessors were either not blinded or insufficient information was given to determine the risk of bias, although this is unlikely to impact the majority of our measured outcomes, including mortality (Analysis 1.1), serious adverse events (Analysis 1.2), peak and final serum sodium (Analysis 1.6, Analysis 1.7), and maximum intraoperative serum osmolarity (Analysis 1.8), pulmonary artery wedge pressure (Analysis 1.9), and cardiac index (Analysis 1.10). Performance and detection bias could impact the results of fluid measurements, leaving the outcomes of fluid balance (Analysis 1.3), total volume of crystalloid administered (Analysis 1.4), and diuresis during study period (Analysis 1.5), at a greater risk of this source of bias and overall bias (Figure 2; Figure 3).
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each 'Risk of bias' item for each included study.
Allocation
Four trials described adequate random sequence generation (Cross 1989; Jarvela 2001; Kølsen‐Petersen 2004; Lavu 2014), using a table of random numbers or computer‐generated random numbers. The remaining 14 studies alluded to randomization but did not describe the method used (Baraka 1994; Bruegger 2005; Durasnel 1999; Ishikawa 1996; Jarvela 2000; Kato 1996; Kimura 1994; Leverve 2008; Shackford 1983; Shackford 1987; Shao 2013; Veroli 1992; Wang 1997; Younes 1988).
Adequate allocation concealment was reported in six trials, four in the publication (Cross 1989; Kølsen‐Petersen 2004; Lavu 2014; Shao 2013) and two through correspondence with the author (Jarvela 2000; Jarvela 2001).
From our assessment, four trials had a low risk of selection bias (Cross 1989; Jarvela 2001; Kølsen‐Petersen 2004; Lavu 2014) (Characteristics of included studies).
Blinding
Five studies reported adequate concealment of treatment from participants, personnel, and outcome assessors (Cross 1989; Kato 1996; Kølsen‐Petersen 2004; Lavu 2014; Veroli 1992); we have rated them as having a low risk of performance and detection bias (Characteristics of included studies).
Incomplete outcome data
We assessed 16 trials at a low risk of attrition bias (Baraka 1994; Bruegger 2005; Cross 1989; Jarvela 2000; Jarvela 2001;Kato 1996; Kimura 1994; Kølsen‐Petersen 2004; Lavu 2014; Leverve 2008; Shackford 1983; Shackford 1987; Shao 2013; Veroli 1992; Wang 1997; Younes 1988). Each of the 16 studies provided clear information about all participants including those with missing outcome data (Characteristics of included studies).
Of the 1121 enrolled participants, 1087 completed the protocol. Four participants in the HS group failed to complete the study, one because of consent withdrawal (Kølsen‐Petersen 2004); one for an anaphylactic reaction to another medication (Kølsen‐Petersen 2004); one because of operative complication which met a priori exclusion criteria (Lavu 2014); and one without a reason specified (Durasnel 1999). Seven participants in the IS group failed to complete the protocol, four because of operative complications which met a priori exclusion criteria (Lavu 2014), one because of an urgent return to the operating room for control of haemorrhage (Kølsen‐Petersen 2004); one because of a transfer to another hospital (Kølsen‐Petersen 2004) and one without a reason specified (Durasnel 1999). Twenty‐three participants failed to complete the protocol and were withdrawn from the studies without further information (Ishikawa 1996; Leverve 2008). One participant was withdrawn from Ishikawa 1996, while the other study had 22 people removed from the analysis due to major protocol violation or incomplete data collection, although they were still included in the safety profile (Leverve 2008).
Selective reporting
Seventeen of the studies reported all of the clinically relevant outcomes that were appropriate for their trial design (Baraka 1994; Cross 1989; Durasnel 1999; Ishikawa 1996; Jarvela 2000; Jarvela 2001; Kato 1996; Kimura 1994; Kølsen‐Petersen 2004; Lavu 2014; Leverve 2008; Shackford 1983; Shackford 1987; Shao 2013; Veroli 1992; Wang 1997; Younes 1988) (Figure 2; Figure 3). However, only one of the studies explicitly reported mortality (Lavu 2014). The remaining studies imply there were no deaths through their other outcome data and we have assessed them to be at an unclear risk of reporting bias (Figure 3). Additionally, the study by Bruegger 2005 reported a disproportionately low number of female participants and we have assessed this as an unclear risk of bias because it was not explained.
Other potential sources of bias
Baseline parameters were reported in each study and appeared to be similar in both study groups in all trials. We found no evidence for other sources of bias in any of the studies (Characteristics of included studies).
Effects of interventions
Primary outcomes
1. Mortality
One trial reported occurrences of deaths (Lavu 2014), four in the HS group and three in the IS group. From all of the studies there were 545 participants in the HS group and 542 in the IS group. Because only one study reported events an analysis to compare treatment groups could not be performed. Assessment of the HS group using the Clopper‐Person estimation shows that the upper bound for occurrences of events using a 95% CI is 0.019 (19/1000). Due to the paucity of events, neither a sensitivity nor subgroup analysis was feasible. We determine the quality of the evidence is very low (summary of findings Table for the main comparison).
2. Serious adverse events
There were no reports of serious adverse events such as organ failure, myocardial infarction, cerebrovascular accident or central pontine myelinolysis reported in the trials. The outcome was not explicitly measured and we have extrapolated the data. There were 1087 participants, 542 in the IS group and 545 in the HS group. Although an analysis comparing the treatment groups cannot be performed, assessment of the HS group utilizing the Clopper‐Pearson estimation shows that the upper bound for occurrences of events using a 95% CI is 0.007 (7/1000). We have graded the quality of the evidence for this outcome as very low (summary of findings Table for the main comparison).
Secondary outcomes
3. Fluid balance
Peri‐operative fluid balance was calculated in eight trials with 737 participants (51.1% HS, 48.9% IS) (Bruegger 2005; Cross 1989; Jarvela 2001;Lavu 2014; Leverve 2008; Shackford 1983; Shackford 1987; Shao 2013). Overall, the fluid balance was positive in both groups (summary of findings Table for the main comparison), the mean volume for the IS group being 4.4 L and 1.9 L lower for the HS group (MD ‐1.92, 95% CI ‐2.61 to ‐1.22; I² = 91%; P < 0.00001; Analysis 1.3). We rate the quality of this evidence as low (summary of findings Table for the main comparison).
We conducted a sensitivity analysis using only studies deemed to have a low risk of bias (Cross 1989; Lavu 2014). The fluid balance was again found to be statistically significantly lower for the HS group (MD ‐1.47, 95% CI ‐2.84 to ‐0.09; participants = 279; P = 0.04; I² = 60%; Analysis 2.1).
Subgroup analysis suggested no significant effect of the type of surgery (Analysis 3.1), dose of HS given (Analysis 3.2), or the total volume of fluid transfused (Analysis 3.3). There were too few studies to adequately investigate the high levels of heterogeneity.
4. Total volume of crystalloid administered
The volume of intravenous fluid administered to participants was reported in 13 trials with 871 participants (51.3% HS, 48.7% IS) (Bruegger 2005; Cross 1989; Durasnel 1999; Ishikawa 1996; Jarvela 2000; Jarvela 2001; Kato 1996; Lavu 2014; Leverve 2008; Shackford 1983; Shackford 1987; Shao 2013; Younes 1988). IS participants received a mean volume of 2.4 L (summary of findings Table for the main comparison). Participants in the HS group received 1.49 L, considerably less fluid intravenously than those in the IS group (MD ‐0.91, 95% CI ‐1.24 to ‐0.59; I² = 99%; P < 0.00001; Analysis 1.4). We rate the quality of the evidence for this outcome as moderate (summary of findings Table for the main comparison).
We conducted a sensitivity analysis to include only studies deemed to be at low risk of bias (Cross 1989; Kato 1996; Lavu 2014). We found that the amount of fluid used in the HS group was still statistically significantly less than in the IS group (MD ‐1.08, 95% CI ‐1.92 to ‐0.24; I² = 75%; P = 0.01; Analysis 2.2).
A subgroup analysis according to type of surgery (Analysis 3.4) and the dose of HS (Analysis 3.5) did not reveal differences between the subgroups. The high degree of heterogeneity for this outcome was not explained by subgroup analysis according to type of surgery (Analysis 3.4) or the dose of HS (Analysis 3.5). Funnel plot analysis showed this outcome to cluster symmetrically (Figure 4), except for three outliers from studies that used considerably more HS than other trials (Lavu 2014; Shackford 1983; Shackford 1987). However, exclusion of these three trials from the analysis did not eliminate heterogeneity.
Funnel plot of comparison: 1 Hypertonic salt versus isotonic salt solution for peri‐operative resuscitation, outcome: 1.4 Total volume of crystalloid administered (L).
5. Diuresis during study period
Urine output during the trial was reported in nine trials including 777 participants (51.1% HS, 48.9% IS) (Bruegger 2005; Cross 1989; Jarvela 2000; Jarvela 2001; Lavu 2014; Leverve 2008; Shackford 1983; Shackford 1987; Shao 2013). There was no difference in peri‐operative urine output (L) between the two groups (MD 0.11, 95% CI ‐0.09 to 0.31; I² = 69%; P = 0.28; Analysis 1.5). We rate the quality of the evidence to be low for risk of bias (downgraded one level because the majority of the studies have not confirmed blinding of outcome assessors, and bias could seriously impact this result) and imprecision (downgraded one level: the volume of crystalloid solution delivered has a large range between studies).
A sensitivity analysis limited to studies with a low risk of bias (Cross 1989; Lavu 2014) did not change the findings of the outcome (MD 1.25, 95% CI ‐1.17 to 3.67; studies = 2; I² = 33%; Analysis 2.3).
Stratification by type of surgery (Analysis 3.6), dose of HS (Analysis 3.7), or the total volume of crystalloid use in the IS group (Analysis 3.8) did not alter the outcome or the degree of heterogeneity.
6. Peak serum sodium
The maximum serum sodium was measured in all but two trials (Durasnel 1999; Lavu 2014), and included 780 participants (50.6% HS, 49.4% IS) from 16 trials. Maximum serum sodium was higher in the HS group than the IS group, 147.4 versus 139.1 meq/L (MD 7.73, 95% CI 5.84 to 9.62; I² = 97%; P < 0.00001; Analysis 1.6). The maximum average serum sodium ranged between 138.5 and 159 in HS groups compared to between 136 and 143 meq/L in the IS groups. We rate the quality of the evidence as moderate for this outcome (summary of findings Table for the main comparison).
Sensitivity analysis restricted to studies with a low risk of bias did not change the outcome or the heterogeneity of the studies (Analysis 2.4).
Subgroup analysis by type of surgery (Analysis 3.9), the dose of crystalloid administered (Analysis 3.10), or by volume of HS (Analysis 3.11) did not alter the outcome or the heterogeneity between trials. Funnel plot analysis which showed peak serum sodium of each study clusters symmetrically around a positive MD. There is substantial overlap of MD from each study, regardless of the dose of HS given (Figure 5).
Funnel plot of comparison: 3 Subgroup analysis ‐ hypertonic salt versus isotonic salt solution for peri‐operative resuscitation, outcome: 3.10 Peak serum sodium (meq/L) by dose of HS.
7. Final serum sodium
Twelve studies with 640 participants (51.4% HS, 48.6% IS) reported final serum sodium (Bruegger 2005; Cross 1989; Jarvela 2000; Jarvela 2001; Kato 1996; Kølsen‐Petersen 2004; Leverve 2008; Shackford 1983; Shackford 1987; Shao 2013; Wang 1997; Younes 1988). By the end of the study period the serum sodium mean difference between the groups was considerably reduced from those reported at peak (MD 3.45, 95% CI 2.46 to 4.44; I² = 88%, P < 0.00001; Analysis 1.7) and the range for final average serum sodium was within normal limits: 136 to 146 meq/L and 136 to 140 meq/L in the HS and IS groups respectively. We assess the quality of this evidence as moderate (summary of findings Table for the main comparison).
A sensitivity analysis restricted to studies with a low risk of bias did not change the outcome or heterogeneity (Analysis 2.5).
Neither the result nor heterogeneity were altered in subgroup analysis by surgery type (Analysis 3.12), dose of HS (Analysis 3.13) or volume of crystalloid (Analysis 3.14).
8 ‐ 10. Duration of endotracheal intubation, intensive care stay and hospital stay
None of the trials reported the duration of mechanical ventilation and the length of stay in hospital. Only one trial (Cross 1989) reported the length of stay in intensive care, with mean stays (standard deviation) of 2.3 (0.2) versus 2.4 (0.6) days in the HS and IS groups respectively (P = 0.63).
11. Other outcomes of interest
Ten trials with 369 participants (50.9% HS, 49.1% IS) (Ishikawa 1996; Jarvela 2000; Jarvela 2001; Kato 1996; Kimura 1994; Kølsen‐Petersen 2004; Shackford 1983; Shackford 1987; Shao 2013; Younes 1988) reported maximum serum osmolarity (Analysis 1.8). We found that there was a statistically significant increase in serum osmolarity with HS, increased 5.3% from the median level of 289 mOsm/kg H20 in the IS group (MD 15.29 mOsm/kg H2O higher with HS, 95% CI 12.27 to 18.31; I² = 86%, P < 0.00001). We assess the quality of the evidence to be moderate. We downgraded the study quality because of a high degree of heterogeneity that probably derives from the wide range of crystalloid fluid given across the studies. Future high‐quality studies are likely to change this result.
Intraoperative pulmonary artery wedge pressure (Analysis 1.9) was reported in three studies with 150 participants (50.7% HS, 49.3% IS) (Jarvela 2001; Shackford 1983; Shackford 1987). There was no difference between the treatment groups (MD 0.16, 95% CI ‐1.69 to 2.02; I² = 0%; P = 0.86).
Maximum intraoperative cardiac index was reported in six studies with 418 participants (51.7% HS, 48.3% IS) (Cross 1989; Jarvela 2000; Jarvela 2001; Leverve 2008; Shackford 1983; Shackford 1987). We found that the maximum intraoperative cardiac index was elevated 11.7% in the HS group over the median level of 2.9 L/min/m² in the IS group (MD 0.34, 95% CI 0.19 to 0.49; I² = 40%; P = 0.0001; Analysis 1.10). We rate the quality of these data to be high (summary of findings Table for the main comparison).
Although only one of the trials (Lavu 2014) specifically reported adverse events, they have not met our criteria to be considered serious adverse events. Adverse events were reported over a 90‐day follow‐up period and the study found no difference between the HS and IS groups.
Discussion
Summary of main results
It was not possible to determine differences with respect to mortality or major morbidity between the treatment arms of this meta‐analysis. A preliminary survey carried out before designing the meta‐analysis suggested that trials of peri‐operative HS were usually designed to measure fluid volumes, haemodynamics and biochemistry rather than measure important clinical outcomes. Despite this, we chose mortality as the primary outcome for this review and we collected serious adverse event data because of their clinical importance.
Peri‐operative diuresis was similar in the HS and IS participants, suggesting that adequate intravascular volumes were maintained throughout surgery despite the fact that HS participants received significantly less intravenous fluid than IS participants (summary of findings Table for the main comparison). All of the participant groups completed surgery with a positive fluid balance (summary of findings Table for the main comparison). In some trials, the positive fluid balance was almost 10 L by the end of surgery. Pulmonary oedema was not recorded in the trials but it is reasonable to be concerned that excess fluid of this magnitude would result in pulmonary oedema in a population at risk of this complication. Use of HS significantly reduced the positive fluid balance experienced by all participants undergoing surgery. HS increased serum sodium and osmolarity (summary of findings Table for the main comparison). The doses of HS varied considerably between trials, but even in those who received very high doses of HS no adverse events related to hypernatraemia were encountered. Serum sodium returned to normal limits by the end of the study.
Overall completeness and applicability of evidence
Meta‐analysis of the outcomes measured by the trials provides a reasonably complete picture of the immediate impact of HS on peri‐operative fluid management. HS significantly reduces the positive fluid balance experienced by people undergoing surgery while maintaining a stable haemodynamic state. This observation was independent of the type of surgery or whether peri‐operative fluid protocol was restricted or unrestricted by volume. HS conserved fluid at lower doses as much as at higher doses. However the trials were not designed to look at the impact of the interventions on mortality or longer‐term morbidity.
To date, we have only found one trial where mortality and adverse events were explicitly measured over a period that extended beyond the original hospital stay (Lavu 2014). Mortality at 90 days did not differ between treatment groups of participants undergoing pancreaticoduodenectomy, but there is no evidence to suggest that this result would remain true at different centres or for different procedures. Until there are more, high‐power studies examining mortality in different surgical procedures at multiple centres, we cannot say with certainty that there is no effect of HS on mortality. This same study also measured postoperative complications (non‐serious adverse events). Although the result was not statistically significant, there were over 10% more postoperative complications in the IS group. Future trials will be necessary to test this finding.
This review showed that people receiving HS had a transient increase in serum sodium (summary of findings Table for the main comparison). Hypernatraemia has the potential to harm but this was not seen in the included studies. In hyponatraemic people, the risk of central pontine myelinolysis is thought to be related to underlying conditions more than the rate of electrolyte repletion, but increases in serum sodium of more than 10 meq/L per day should be avoided if possible (Kumar 2006). It is not known if people with normal serum sodium are at a similar risk of hyperosmotically induced demyelination. No episodes of central pontine myelinolysis were reported in these studies where the participants had normal serum sodium levels at baseline, and we did not find any case reports in the literature of central pontine myelinolysis in people who received HS.
Is there a potential therapeutic window for HS in people undergoing surgery, where peri‐operative weight gain can be minimized without a risk of significant hypernatraemia? Hypernatraemia is transient after administration of HS. However, it would seem prudent to avoid large increases in serum sodium. This is possible, with these studies suggesting that up to 10 ml/kg of 3% HS will reduce the positive fluid balance peri‐operatively by up to 1.5 L in the average adult without increasing serum sodium inappropriately. There is insufficient evidence to determine if such a reduction in peri‐operative fluid excess would improve clinically relevant outcomes but it provides the basis for an RCT.
The evidence is strong for a reduction in the volume of peri‐operative fluid required to maintain homeostasis with HS. There is no direct evidence that this results in better survival or quality of life. The principal barrier to meta‐analysis of some outcomes is a high degree of heterogeneity between the trials. Heterogeneity appears to be due to differences in the magnitude of the effect observed rather than differences in the effect itself. Subgroup analysis identified sources of heterogeneity in some instances. For example, there was considerable heterogeneity in peri‐operative diuresis even though there was no significant difference in diuresis between the test group, HS, and the control.
Overall there is a strong need for well‐controlled, high‐quality studies with adequate design to measure both short‐ and long‐term variables. The results of this systematic review and future studies could prove to be very important to patient care, particularly when low volumes of resuscitating fluid are needed. At this time the results show promise for HS as a safe choice for resuscitation during surgery where reduced volumes would be beneficial, but more evidence is needed.
Quality of the evidence
The quality of evidence across these trials ranged from high to very low. The majority of trials included in this study cover relatively few participants. The trials were conducted in several eras when other peri‐operative practices may have changed. There was also a large variation in the dose of HS given between studies which may have resulted in the high heterogeneity between them. Furthermore, many of the studies did not specify the methods of allocation concealment or randomization, which again probably reflects the era in which many of the studies were reported.
For determining mortality, the trials lacked sufficient size, duration and reporting to adequately assess important differences. Furthermore, only one study (Lavu 2014) explicitly reported the outcome, and we have extrapolated the data on the basis that other outcomes were reported by each study for all included participants. We have assessed the quality of evidence for mortality to be very low, and future studies are likely to change the result reported here (summary of findings Table for the main comparison).
We rate the quality of the evidence for fluid balance and diuresis to be low (summary of findings Table for the main comparison). There is a systemic lack of blinding of personnel across these studies, leaving these outcomes prone to bias. High‐quality study results are likely to change this outcome.
The reporting of peak and final serum sodium is of moderate quality (summary of findings Table for the main comparison). The level of blood sodium during surgery is a common hospital measurement that is unlikely to be biased. The difference in the number of samples collected by the different studies impacts the quality of this outcome. Future studies are likely to change this result.
We have rated the quality of the evidence for the maximum intraoperative cardiac index as high (summary of findings Table for the main comparison). The measurement during an operation is a common hospital procedure that is unlikely to be biased. The studies that report this outcome are well controlled, and the values reported are consistent across the studies. Future studies are unlikely to change this result.
Potential biases in the review process
Having searched the largest medical research data bases, without limit by language of publication, it is highly likely that we have found all published data that met our inclusion criteria.
The review authors tried to reduce the impact of personal bias in the presentation and analysis of the results. When assessing the degree that individual bias components would impact study results, we have undoubtedly relied on our own experiences. We have assumed, in cases where the information was not available, that the reports were conducted by compassionate physicians and dedicated researchers who have performed their work honestly and to the best of their abilities. Because of this, we have left our analysis open to being impacted by fraudulent reports.
Agreements and disagreements with other studies or reviews
This is the first systematic review of HS compared to IS for peri‐operative fluid management. This update confirms the findings of the first version (McAlister 2006). The findings are consistent with reviews of HS given for other indications such as fluid management in people with burns (Bunn 2004).
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each 'Risk of bias' item for each included study.
Funnel plot of comparison: 1 Hypertonic salt versus isotonic salt solution for peri‐operative resuscitation, outcome: 1.4 Total volume of crystalloid administered (L).
Funnel plot of comparison: 3 Subgroup analysis ‐ hypertonic salt versus isotonic salt solution for peri‐operative resuscitation, outcome: 3.10 Peak serum sodium (meq/L) by dose of HS.
Comparison 1 Hypertonic salt versus isotonic salt solution for peri‐operative resuscitation, Outcome 1 Mortality during the study period.
Comparison 1 Hypertonic salt versus isotonic salt solution for peri‐operative resuscitation, Outcome 2 Serious adverse events during the study period.
Comparison 1 Hypertonic salt versus isotonic salt solution for peri‐operative resuscitation, Outcome 3 Fluid balance (L) measured at the end of the recovery period.
Comparison 1 Hypertonic salt versus isotonic salt solution for peri‐operative resuscitation, Outcome 4 Total volume of crystalloid administered (L).
Comparison 1 Hypertonic salt versus isotonic salt solution for peri‐operative resuscitation, Outcome 5 Diuresis during study period (L).
Comparison 1 Hypertonic salt versus isotonic salt solution for peri‐operative resuscitation, Outcome 6 Peak serum sodium (meq/L).
Comparison 1 Hypertonic salt versus isotonic salt solution for peri‐operative resuscitation, Outcome 7 Final serum sodium (meq/L).
Comparison 1 Hypertonic salt versus isotonic salt solution for peri‐operative resuscitation, Outcome 8 Maximum intraoperative serum osmolarity (mOsm/kg H2O).
Comparison 1 Hypertonic salt versus isotonic salt solution for peri‐operative resuscitation, Outcome 9 Maximum intraoperative pulmonary artery wedge pressure (mm Hg).
Comparison 1 Hypertonic salt versus isotonic salt solution for peri‐operative resuscitation, Outcome 10 Maximum intraoperative cardiac index (L/min/M2).
Comparison 2 Sensitivity analysis ‐ hypertonic salt versus isotonic salt solution for peri‐operative resuscitation, Outcome 1 Fluid balance (L) measured during the study period: studies at low risk of bias.
Comparison 2 Sensitivity analysis ‐ hypertonic salt versus isotonic salt solution for peri‐operative resuscitation, Outcome 2 Total volume of crystalloid administered (L): studies at low risk of bias.
Comparison 2 Sensitivity analysis ‐ hypertonic salt versus isotonic salt solution for peri‐operative resuscitation, Outcome 3 Diuresis during study period (L): studies at low risk of bias.
Comparison 2 Sensitivity analysis ‐ hypertonic salt versus isotonic salt solution for peri‐operative resuscitation, Outcome 4 Peak serum sodium (meq/L): studies at low risk of bias.
Comparison 2 Sensitivity analysis ‐ hypertonic salt versus isotonic salt solution for peri‐operative resuscitation, Outcome 5 Final serum sodium (meq/L): studies at low risk of bias.
Comparison 2 Sensitivity analysis ‐ hypertonic salt versus isotonic salt solution for peri‐operative resuscitation, Outcome 6 Maximum intraoperative serum osmolarity (mOsm/kg H2O): studies at low risk of bias.
Comparison 3 Subgroup analysis ‐ hypertonic salt versus isotonic salt solution for peri‐operative resuscitation, Outcome 1 Fluid balance (L) by type of surgery.
Comparison 3 Subgroup analysis ‐ hypertonic salt versus isotonic salt solution for peri‐operative resuscitation, Outcome 2 Fluid balance (L) by dose of HS.
Comparison 3 Subgroup analysis ‐ hypertonic salt versus isotonic salt solution for peri‐operative resuscitation, Outcome 3 Fluid balance (L) by volume given to control group.
Comparison 3 Subgroup analysis ‐ hypertonic salt versus isotonic salt solution for peri‐operative resuscitation, Outcome 4 Total volume of crystalloid administered (L) by type of surgery.
Comparison 3 Subgroup analysis ‐ hypertonic salt versus isotonic salt solution for peri‐operative resuscitation, Outcome 5 Total volume of crystalloid administered (L) by dose of HS.
Comparison 3 Subgroup analysis ‐ hypertonic salt versus isotonic salt solution for peri‐operative resuscitation, Outcome 6 Diuresis during study period (L) by type of surgery.
Comparison 3 Subgroup analysis ‐ hypertonic salt versus isotonic salt solution for peri‐operative resuscitation, Outcome 7 Diuresis during study period (L) by dose of HS.
Comparison 3 Subgroup analysis ‐ hypertonic salt versus isotonic salt solution for peri‐operative resuscitation, Outcome 8 Diuresis during study period (L) by volume given to control group.
Comparison 3 Subgroup analysis ‐ hypertonic salt versus isotonic salt solution for peri‐operative resuscitation, Outcome 9 Peak serum sodium (meq/L) by type of surgery.
Comparison 3 Subgroup analysis ‐ hypertonic salt versus isotonic salt solution for peri‐operative resuscitation, Outcome 10 Peak serum sodium (meq/L) by dose of HS.
Comparison 3 Subgroup analysis ‐ hypertonic salt versus isotonic salt solution for peri‐operative resuscitation, Outcome 11 Peak serum sodium (meq/L) by volume given to control group.
Comparison 3 Subgroup analysis ‐ hypertonic salt versus isotonic salt solution for peri‐operative resuscitation, Outcome 12 Final serum sodium (meq/L) by type of surgery.
Comparison 3 Subgroup analysis ‐ hypertonic salt versus isotonic salt solution for peri‐operative resuscitation, Outcome 13 Final serum sodium (meq/L) by dose of HS.
Comparison 3 Subgroup analysis ‐ hypertonic salt versus isotonic salt solution for peri‐operative resuscitation, Outcome 14 Final serum sodium (meq/L) by volume given to control group.
| Hypertonic salt compared to isotonic salt solution for peri‐operative resuscitation | ||||||
| Patient or population: any people undergoing surgery with fluid resuscitation | ||||||
| Outcomes | Illustrative comparative risks* (95% CI) | Relative effect | No of Participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| isotonic salt solution for peri‐operativeresuscitation | Hypertonic salt | |||||
| Mortality Follow‐up: range 1 to 90 days | Study population | ‐ | 1087 | ⊕⊝⊝⊝ | Any recorded death during the study period. The risk of bias impacting this outcome is considered to be low. Only one study had incidents of mortality | |
| ‐ | ‐ | |||||
| Serious adverse events Follow‐up: range 1 to 90 days | ‐ | ‐ | ‐ | 1087 (18 RCTs) | ⊕⊝⊝⊝ | Other adverse outcomes are collected as defined by each trial or if any of the following occurred: any organ failure, including renal, pulmonary, cardiac, or cerebral |
| Fluid balance (L) Follow‐up: range 1 to 3 days | The mean fluid balance (L) was 4.375 | The mean fluid balance (L) in the intervention group was 1.92 lower (2.61 lower to 1.22 lower) | ‐ | 737 | ⊕⊕⊝⊝ | The change in participant fluid volume at the end of fluid administration. A neutral fluid balance would be optimal |
| Total volume of crystalloid administered (L) Follow‐up: range 1 to 3 days | The mean total volume of crystalloid administered (L) was 2.43 | The mean total volume of crystalloid administered (L) in the intervention group was 0.91 lower (1.24 lower to 0.59 lower) | ‐ | 871 | ⊕⊕⊕⊝ | The total volume of fluid delivered intravenously over the study period. There are no defined minimum or maximum values for fluid delivery during surgery. Less resuscitating fluid is preferred |
| Peak serum sodium Follow‐up: range 1 to 3 days | The mean peak serum sodium (meq/L) was 139.1 | The mean peak serum sodium (meq/L) in the intervention group was 7.73 higher (5.84 higher to 9.62 higher) | ‐ | 780 | ⊕⊕⊕⊝ | The measurement of this variable is a common practice in operative procedures. Measured as the peak amount of sodium in the blood, given in milliequivelants per litre, over the study period. The normal acceptable range is 136 to 146 meq/L |
| Final serum sodium Follow‐up: range 1 to 3 days | The mean final serum sodium (meq/L) was 138.3 | The mean final serum sodium (meq/L) in the intervention group was 3.45 higher (2.46 higher to 4.44 higher) | ‐ | 640 | ⊕⊕⊕⊝ | The measurement of this variable is common practice in operative procedures. Measured as the final amount of sodium in the blood, given in milliequivelants per litre, at the end of the study. The normal acceptable range is 136 to 146 meq/L |
| Maximum intraoperative cardiac index Follow‐up: 1 to 3 days | The mean maximum intraoperative cardiac index (L/min/M²) was 2.9 | The mean maximum intraoperative cardiac index (L/min/m²) in the intervention group was 0.34 higher (0.19 higher to 0.49 higher) | ‐ | 418 | ⊕⊕⊕⊕ | The measurement of this variable is common practice in operative procedures. Measured by the volume of blood passing through one square meter each minute (L/min/M²). The normal range is 2.5 ‐ 4.0 L/min/M² |
| *The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Downgraded (2 levels) for indirectness: The majority of studies have an insufficient follow‐up period to adequately measure the outcome. | ||||||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Mortality during the study period Show forest plot | 18 | 1087 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 2 Serious adverse events during the study period Show forest plot | 18 | 1087 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 3 Fluid balance (L) measured at the end of the recovery period Show forest plot | 8 | 737 | Mean Difference (IV, Random, 95% CI) | ‐1.92 [‐2.61, ‐1.22] |
| 4 Total volume of crystalloid administered (L) Show forest plot | 13 | 871 | Mean Difference (IV, Random, 95% CI) | ‐0.91 [‐1.24, ‐0.59] |
| 5 Diuresis during study period (L) Show forest plot | 9 | 777 | Mean Difference (IV, Random, 95% CI) | 0.11 [‐0.09, 0.31] |
| 6 Peak serum sodium (meq/L) Show forest plot | 16 | 780 | Mean Difference (IV, Random, 95% CI) | 7.73 [5.84, 9.62] |
| 7 Final serum sodium (meq/L) Show forest plot | 12 | 640 | Mean Difference (IV, Random, 95% CI) | 3.45 [2.46, 4.44] |
| 8 Maximum intraoperative serum osmolarity (mOsm/kg H2O) Show forest plot | 10 | 369 | Mean Difference (IV, Random, 95% CI) | 15.29 [12.27, 18.31] |
| 9 Maximum intraoperative pulmonary artery wedge pressure (mm Hg) Show forest plot | 3 | 150 | Mean Difference (IV, Fixed, 95% CI) | 0.16 [‐1.69, 2.02] |
| 10 Maximum intraoperative cardiac index (L/min/M2) Show forest plot | 6 | 418 | Mean Difference (IV, Random, 95% CI) | 0.34 [0.19, 0.49] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Fluid balance (L) measured during the study period: studies at low risk of bias Show forest plot | 2 | 279 | Mean Difference (IV, Random, 95% CI) | ‐1.47 [‐2.84, ‐0.09] |
| 2 Total volume of crystalloid administered (L): studies at low risk of bias Show forest plot | 3 | 319 | Mean Difference (IV, Random, 95% CI) | ‐1.08 [‐1.92, ‐0.24] |
| 3 Diuresis during study period (L): studies at low risk of bias Show forest plot | 2 | 279 | Mean Difference (IV, Random, 95% CI) | 1.25 [‐1.17, 3.67] |
| 4 Peak serum sodium (meq/L): studies at low risk of bias Show forest plot | 4 | 129 | Mean Difference (IV, Random, 95% CI) | 6.03 [3.96, 8.09] |
| 5 Final serum sodium (meq/L): studies at low risk of bias Show forest plot | 3 | 99 | Mean Difference (IV, Random, 95% CI) | 2.48 [0.33, 4.62] |
| 6 Maximum intraoperative serum osmolarity (mOsm/kg H2O): studies at low risk of bias Show forest plot | 2 | 79 | Mean Difference (IV, Random, 95% CI) | 15.81 [12.86, 18.77] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Fluid balance (L) by type of surgery Show forest plot | 8 | 737 | Mean Difference (IV, Random, 95% CI) | ‐1.92 [‐2.61, ‐1.22] |
| 1.1 Aortic surgery | 3 | 138 | Mean Difference (IV, Random, 95% CI) | ‐3.84 [‐6.45, ‐1.23] |
| 1.2 Neurosurgery | 1 | 40 | Mean Difference (IV, Random, 95% CI) | ‐1.20 [‐1.59, ‐0.81] |
| 1.3 Hepatobiliary surgery | 1 | 259 | Mean Difference (IV, Random, 95% CI) | ‐0.53 [‐2.20, 1.14] |
| 1.4 Coronary artery bypass surgery | 3 | 300 | Mean Difference (IV, Random, 95% CI) | ‐1.24 [‐1.92, ‐0.57] |
| 2 Fluid balance (L) by dose of HS Show forest plot | 8 | 737 | Mean Difference (IV, Random, 95% CI) | ‐1.91 [‐2.61, ‐1.22] |
| 2.1 < 7.1 mL 3% HS/kg | 1 | 40 | Mean Difference (IV, Random, 95% CI) | ‐1.20 [‐1.59, ‐0.81] |
| 2.2 7.1 ‐ 10 mL 3% HS/kg | 3 | 308 | Mean Difference (IV, Random, 95% CI) | ‐0.92 [‐1.22, ‐0.62] |
| 2.3 > 10 mL 3% HS/kg | 4 | 389 | Mean Difference (IV, Random, 95% CI) | ‐3.08 [‐5.23, ‐0.94] |
| 3 Fluid balance (L) by volume given to control group Show forest plot | 8 | 737 | Mean Difference (IV, Random, 95% CI) | ‐1.91 [‐2.61, ‐1.22] |
| 3.1 < 2000 mL | 0 | 0 | Mean Difference (IV, Random, 95% CI) | 0.0 [0.0, 0.0] |
| 3.2 2000 ‐ 5000 mL | 4 | 328 | Mean Difference (IV, Random, 95% CI) | ‐1.31 [‐1.92, ‐0.70] |
| 3.3 > 5000 mL | 4 | 409 | Mean Difference (IV, Random, 95% CI) | ‐2.87 [‐5.29, ‐0.44] |
| 4 Total volume of crystalloid administered (L) by type of surgery Show forest plot | 13 | 871 | Mean Difference (IV, Random, 95% CI) | ‐0.91 [‐1.24, ‐0.59] |
| 4.1 Cardiovascular surgery | 7 | 429 | Mean Difference (IV, Random, 95% CI) | ‐1.14 [‐1.71, ‐0.57] |
| 4.2 Non‐cardiovascular surgery | 6 | 442 | Mean Difference (IV, Random, 95% CI) | ‐0.78 [‐1.05, ‐0.50] |
| 5 Total volume of crystalloid administered (L) by dose of HS Show forest plot | 13 | 871 | Mean Difference (IV, Random, 95% CI) | ‐0.91 [‐1.24, ‐0.59] |
| 5.1 < 7.1 mL 3% HS/kg | 4 | 143 | Mean Difference (IV, Random, 95% CI) | ‐0.77 [‐1.19, ‐0.35] |
| 5.2 7.1 ‐ 10 mL 3% HS/kg | 5 | 339 | Mean Difference (IV, Random, 95% CI) | ‐0.76 [‐1.25, ‐0.27] |
| 5.3 > 10 mL 3% HS/kg | 4 | 389 | Mean Difference (IV, Random, 95% CI) | ‐2.50 [‐4.99, ‐0.02] |
| 6 Diuresis during study period (L) by type of surgery Show forest plot | 9 | 777 | Mean Difference (IV, Random, 95% CI) | 0.11 [‐0.10, 0.31] |
| 6.1 Cardiovascular surgery | 6 | 438 | Mean Difference (IV, Random, 95% CI) | 0.15 [‐0.22, 0.52] |
| 6.2 Non‐cardiovascular surgery | 3 | 339 | Mean Difference (IV, Random, 95% CI) | 0.00 [‐0.30, 0.30] |
| 7 Diuresis during study period (L) by dose of HS Show forest plot | 9 | 777 | Mean Difference (IV, Random, 95% CI) | 0.10 [‐0.10, 0.30] |
| 7.1 < 7.1 mL 3% HS/kg | 1 | 40 | Mean Difference (IV, Random, 95% CI) | ‐0.16 [‐0.54, 0.22] |
| 7.2 7.1 ‐ 10 mL 3% HS/kg | 4 | 348 | Mean Difference (IV, Random, 95% CI) | 0.00 [‐0.12, 0.13] |
| 7.3 > 10 mL 3% HS/kg | 4 | 389 | Mean Difference (IV, Random, 95% CI) | 0.31 [‐0.50, 1.11] |
| 8 Diuresis during study period (L) by volume given to control group Show forest plot | 9 | 777 | Mean Difference (IV, Random, 95% CI) | 0.09 [‐0.11, 0.30] |
| 8.1 < 2000 mL | 2 | 68 | Mean Difference (IV, Random, 95% CI) | 0.00 [‐0.16, 0.17] |
| 8.2 2000 ‐ 5000 mL | 3 | 300 | Mean Difference (IV, Random, 95% CI) | 0.33 [‐0.19, 0.85] |
| 8.3 > 5000 mL | 4 | 409 | Mean Difference (IV, Random, 95% CI) | ‐0.16 [‐0.48, 0.17] |
| 9 Peak serum sodium (meq/L) by type of surgery Show forest plot | 16 | 780 | Mean Difference (IV, Random, 95% CI) | 7.73 [5.84, 9.62] |
| 9.1 Cardiovascular surgery | 7 | 469 | Mean Difference (IV, Random, 95% CI) | 10.61 [6.91, 14.31] |
| 9.2 Transurethral resection of the prostate | 3 | 87 | Mean Difference (IV, Random, 95% CI) | 4.01 [1.86, 6.16] |
| 9.3 Other surgery | 6 | 224 | Mean Difference (IV, Random, 95% CI) | 6.52 [3.64, 9.40] |
| 10 Peak serum sodium (meq/L) by dose of HS Show forest plot | 16 | 780 | Mean Difference (IV, Random, 95% CI) | 7.73 [5.84, 9.62] |
| 10.1 < 7.1 mL 3% HS/kg | 6 | 218 | Mean Difference (IV, Random, 95% CI) | 5.31 [2.00, 8.63] |
| 10.2 7.1 ‐ 10 mL 3% HS/kg | 6 | 418 | Mean Difference (IV, Random, 95% CI) | 8.93 [5.16, 12.70] |
| 10.3 > 10 mL 3% HS/kg | 4 | 144 | Mean Difference (IV, Random, 95% CI) | 9.75 [5.50, 13.99] |
| 11 Peak serum sodium (meq/L) by volume given to control group Show forest plot | 11 | 619 | Mean Difference (IV, Random, 95% CI) | 9.10 [6.66, 11.53] |
| 11.1 < 2000 mL/kg | 4 | 141 | Mean Difference (IV, Random, 95% CI) | 4.94 [3.53, 6.34] |
| 11.2 2000 ‐ 5000 mL | 4 | 328 | Mean Difference (IV, Random, 95% CI) | 9.05 [4.54, 13.56] |
| 11.3 > 5000 mL | 3 | 150 | Mean Difference (IV, Random, 95% CI) | 13.93 [11.44, 16.42] |
| 12 Final serum sodium (meq/L) by type of surgery Show forest plot | 12 | 640 | Mean Difference (IV, Random, 95% CI) | 3.45 [2.46, 4.44] |
| 12.1 Cardiovascular surgery | 6 | 390 | Mean Difference (IV, Random, 95% CI) | 3.91 [2.55, 5.28] |
| 12.2 Transurethral resection of prostate | 1 | 40 | Mean Difference (IV, Random, 95% CI) | 2.0 [0.45, 3.55] |
| 12.3 Other surgery | 5 | 210 | Mean Difference (IV, Random, 95% CI) | 3.05 [0.77, 5.32] |
| 13 Final serum sodium (meq/L) by dose of HS Show forest plot | 12 | 640 | Mean Difference (IV, Random, 95% CI) | 3.45 [2.46, 4.44] |
| 13.1 < 7.1 mL 3% HS/kg | 3 | 140 | Mean Difference (IV, Random, 95% CI) | 3.69 [1.70, 5.68] |
| 13.2 7.1 ‐ 10 mL 3% HS/kg | 6 | 370 | Mean Difference (IV, Random, 95% CI) | 2.63 [1.17, 4.10] |
| 13.3 > 10 mL 3% HS/kg | 3 | 130 | Mean Difference (IV, Random, 95% CI) | 5.56 [3.16, 7.96] |
| 14 Final serum sodium (meq/L) by volume given to control group Show forest plot | 9 | 333 | Mean Difference (IV, Random, 95% CI) | 3.73 [2.29, 5.17] |
| 14.1 < 2000 mL | 3 | 111 | Mean Difference (IV, Random, 95% CI) | 2.32 [‐0.74, 5.39] |
| 14.2 2000 ‐ 5000 mL | 3 | 72 | Mean Difference (IV, Random, 95% CI) | 3.14 [1.02, 5.27] |
| 14.3 > 5000 mL | 3 | 150 | Mean Difference (IV, Random, 95% CI) | 5.70 [3.98, 7.43] |
