Volume therapy for cardiac arrest: a systematic review and meta-analysis

Abstract

Objective

To perform a systematic review and meta-analysis of intra-cardiac arrest and post-cardiac arrest intravascular volume therapy in adults and children.

Methods

Searches were performed in Ovid Medline, Ovid Embase, and the Cochrane Library on October 30, 2025. Randomized trials and non-randomized studies evaluating volume therapy during cardiac arrest and after return of spontaneous circulation were included. Two reviewers independently screened articles, extracted data, and assessed risk of bias. Meta-analyses were performed when appropriate. Certainty of evidence was assessed using GRADE methodology.

Results

Fifty-eight articles were included representing 14 trials enrolling 4815 patients and 44 observational studies including 710,118 patients. All randomized trials enrolled adult patients. Of the observational studies, two included paediatric patients and eight included mixed populations. For non-traumatic intra-cardiac arrest, trials of specific interventions, including hypertonic saline with hydroxyethyl starch (which is no longer used in clinical practice) and cold crystalloid infusion, showed no difference in outcomes. For traumatic intra-cardiac arrest, direct evidence was limited to a single trial subgroup analysis showing no difference between blood products and crystalloids. For post-cardiac arrest, trials of cold crystalloid infusion and balanced versus unbalanced crystalloids showed no differences in outcomes. Randomized trials were assessed to have some concern to high risk of bias. Observational studies were at serious or critical risk of bias with inconsistent results. The certainty of evidence was low to very low.

Conclusion

This systematic review found no trials directly comparing volume therapy to no volume therapy during cardiopulmonary resuscitation. The available trials, which compared different types of volume therapy strategies in adult patients, showed no significant difference in clinical outcomes across non-traumatic, traumatic, and post-cardiac arrest settings. Additional randomized trials are needed to establish the role of intra- and post-cardiac arrest volume therapy.

Introduction

Cardiac arrest is associated with high mortality and morbidity, even after successful resuscitation.1, 2 While intravascular volume therapy is recognised as a standard component of shock management,³ its role during and after cardiac arrest remains uncertain.

During cardiac arrest, volume therapy is only recommended in cases when hypovolaemia is evident or suspected.⁴ Identifying hypovolaemia during cardiac arrest is challenging, and fluids are sometimes administered empirically during resuscitation. Evidence to support routine volume therapy in patients in cardiac arrest is limited, and there are physiological concerns that volume therapy may increase right atrial pressure with venous congestion leading to impaired venous return and reduced coronary perfusion pressure.5, 6

Haemorrhage accounts for approximately half of traumatic cardiac arrests and volume therapy, specifically the administration of blood products, is recommended when hypovolaemia is suspected.7, 8 While rapid intravascular fluid administration may transiently restore preload and facilitate return of spontaneous circulation, fluid administration without definitive haemorrhage control may cause dilutional coagulopathy and exacerbate bleeding.⁹ Additionally, clinical trials of different types of volume therapies for trauma patients in haemorrhagic shock have reported mixed results.10, 11, 12

After successful resuscitation, many patients develop shock due to myocardial dysfunction, vasoplegia, and hypovolaemia.¹³ International guidelines recommend volume therapy in combination with vasoactive and inotropic drugs to maintain adequate perfusion.14, 15 However, the optimal volume type, dose, and timing for post-cardiac arrest care remain uncertain.

The last systematic review on this topic was conducted by the International Liaison Committee on Resuscitation (ILCOR) in 2010, which concluded that there was insufficient evidence to recommend for or against the routine use of intravenous fluids during cardiac arrest.¹⁶ With new evidence available, an updated systematic review is needed to inform the international guidelines.

The aim of this systematic review was to identify, assess, and synthesize the clinical evidence on intra- and post-cardiac arrest volume therapy for adults and children.

Methods

Protocol registration

The study protocol was submitted to the International Prospective Register of Systematic Reviews (PROSPERO) (CRD420251055283) on May 18, 2025. This systematic review was reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.¹⁷ The study protocol and PRISMA checklists are available in the Supplementary Material. The review was conducted on behalf of ILCOR.

Eligibility criteria and outcomes

Three distinct review questions were investigated and followed the PICO (Population, Intervention, Comparison, Outcome) framework. The questions differed by the clinical context including (1) non-traumatic intra-cardiac arrest, (2) traumatic intra-cardiac arrest, and (3) post-cardiac arrest care (Table 1 and study protocol).

Table 1.

PICO questions.

	Non-traumatic intra-cardiac arrest	Traumatic intra-cardiac arrest	Post-cardiac arrest
Population	Adults and children with non-traumatic cardiac arrest	Adults and children with traumatic cardiac arrest	Adults and children with cardiac arrest
Intervention	Intravascular volume therapy during cardiac arrest	Intravascular volume therapy during cardiac arrest	Intravascular volume therapy after cardiac arrest
Comparator	No intravascular volume therapy or a different intravascular volume therapy during cardiac arrest	No intravascular volume therapy or a different intravascular volume therapy during cardiac arrest	No intravascular volume therapy or a different intravascular volume therapy after cardiac arrest
Outcomes	Any clinical outcome	Any clinical outcome	Any clinical outcome

Volume therapy was defined as administration of intravascular crystalloids (balanced or unbalanced, with or without dextrose), colloids, blood products, or cold crystalloids to induce hypothermia.

Relevant outcomes were prioritized by the ILCOR Advanced Life Support Task Force based on the available outcomes reported in the literature. Outcomes included return of spontaneous circulation, survival, survival with a favourable neurological outcome, and health-related quality of life at any time point. For post-cardiac arrest studies, outcomes related to organ support, including need for vasopressors, mechanical ventilation, or renal replacement therapy, as well as intensive care unit or hospital length of stay were also considered. Studies assessing cost-effectiveness were included for a descriptive summary.

All original studies with a comparator group were considered, including randomized controlled trials and non-randomized studies (non-randomized controlled trials, cohort studies, and case-control studies). Animal studies, reviews, abstracts only, conference proceedings, letters, editorials, commentaries, unpublished trials, case reports, and case series were not included. Articles from all years and in all languages were considered if there was an English abstract or full text available.

Information sources and search strategy

We searched Ovid Medline, Ovid EMBASE, and the Cochrane Central Register of Controlled Trials from inception to October 30, 2025. The search strategies were developed by the author group and are provided in the study protocol. To identify additional eligible studies, we manually screened the bibliographies of all included full-text articles.

To identify ongoing trials, the International Clinical Trials Registry Platform (https://www.who.int/ictrp/) and ClinicalTrials.gov were searched.

Study selection

Two reviewers independently screened all titles and abstracts of retrieved articles and subsequently assessed full-text articles for eligibility. Any disagreements regarding inclusion or exclusion of articles at both stages were resolved via discussion between the respective reviewers or by involving a third reviewer when necessary. Screening and full-text review were conducted using Covidence systematic review software (Veritas Health Innovation, Melbourne, Australia).

Data collection and data items

Data were extracted by two reviewers using a standardized data extraction form. Any discrepancies were identified and resolved via discussion between the two reviewers or by involving a third reviewer. Missing relevant statistical parameters were calculated whenever possible.

Risk of bias in individual studies

Risk of bias was independently assessed by two reviewers for all included studies. For randomized studies, the revised Cochrane Risk of Bias (Rob 2) tool was used, and for non-randomized studies, the Risk of Bias in Non-Randomized Studies of Interventions (ROBINS-I) tool was used.18, 19 Risk of bias was assessed separately for each outcome when required. Disagreements about the risk of bias assessments were resolved via discussion. Details on rationales for risk of bias assessments are provided in the Supplementary Material.

Data synthesis

The included studies were assessed for clinical, methodological, and statistical heterogeneity. For clinical heterogeneity, the study population, intervention, comparator, and study outcomes were considered. Methodological heterogeneity was assessed by considering risk of bias and study design, while statistical heterogeneity was assessed based on forest plots, Chi-squared statistics, and I² statistics.

For randomized trials, meta-analyses were performed separately according to volume therapy strategy. Fixed-effects models were used when heterogeneity across studies was assessed to be minimal or when few trials were included. Random-effects models were used when there was evidence of substantial heterogeneity. Pre-specified subgroup analyses by initial rhythm and type of volume therapy were performed when permitted by the data.

Observational studies were summarized descriptively due to substantial heterogeneity in study populations, interventions, and comparators. Forest plots were generated to visualize the direction and magnitude of effect estimates across studies, but formal meta-analyses were not performed.

All analyses were conducted using R software, version 4.2.2 (R Foundation for Statistical Computing). Whenever available from original studies, categorical data are reported as counts (%) and continuous data are reported as means (±standard deviation) or medians (first quartile; third quartile). Results are reported as risk ratios (RR) with 95% confidence intervals (95% CI) for randomized trials and odds ratios (OR) with 95% CI for observational studies. Additional details are provided in the protocol.

Certainty of cumulative evidence

The certainty of the cumulative evidence was assessed using Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology.²⁰ The GRADEpro Guideline Development Tool (McMaster University and Evidence Prime, 2023) was used to develop GRADE tables.

Results

Overview

The systematic search identified 7932 unique records, of which 114 full-text studies were assessed for eligibility (Fig. 1). In total, 58 studies were identified, including 14 randomized trials and 44 non-randomized studies. No cost-effectiveness studies were identified. Three registered planned or ongoing randomized trials were identified (Table S1).

Fig. 1.

PRISMA diagram.

Diagram illustrating the flow of articles. Of 7932 titles and abstracts, 114 full-text articles were assessed for eligibility, and 58 studies were included in this systematic review, representing 14 randomized clinical trials and 44 non-randomized studies.

Randomized trials

Characteristics of the 14 randomized trials with reported adverse events are presented in Table 2, Table 3, Table 4 and the Supplementary Material. Risk of bias was assessed as some concern for 12 trials and high concern for two trials, mainly due to lack of blinding and concerns about selective reporting (Table S2).

Table 2.

Randomized trials on non-traumatic intra-cardiac arrest volume therapies.

Study	Cohort	N	Intervention	Control	Volumes	Main findings	Adverse events
Bender, 200721	OHCA	66	Prehospital bolus of hypertonic saline plus HES	Prehospital bolus of HES alone	2 mL/kg over 10 min	No differences in clinical outcomes	Not reported
Breil, 201222	OHCA	203	Prehospital bolus of hypertonic saline plus HES	Prehospital bolus of HES alone	2 mL/kg over 10 min	Signal towards improved neurological status (13% vs 4.9%)	Not reported
Debaty, 201423	OHCA	245	Prehospital rapid infusion of cold 0.9% saline solution	Standard care	Not reported	No differences in clinical outcomes	No difference in pulmonary oedema
Bernard, 201624	OHCA	1324	Prehospital rapid infusion of cold 0.9% saline solution	Standard care	1193 (±647) mL cold fluids, 1380 (±773) mL vs 1022 (±752) mL total amount of ambient and cold fluids	Decreased ROSC for shockable rhythms (41% vs 51%)	Higher pulmonary oedema rate (10% vs 4.5%)
Woo, 202325,a	OHCA, admitted	364	In-hospital use of Plasma Solution-A for 24 h	In-hospital use of 0.9% saline solution for 24 h	3918 (3640; 5420) mL vs 4029 (3562; 5650) mL	No differences in clinical outcomes	Not reported

Abbreviations: OHCA, out-of-hospital cardiac arrest; HES, hydroxyethyl starch; ROSC, return of spontaneous circulation; VF, ventricular fibrillation. Continuous data are reported as means (±standard deviation) or medians (first quartile; third quartile).

^aRandomization intra-cardiac arrest in 19% of cases in intervention group and 37% of cases in control group.

Table 3.

Randomized trials on traumatic intra-cardiac arrest volume therapies.

Study	Cohort	N	Intervention	Control	Volumes	Main findings	Adverse events
Crombie, 202210,a	OHCA, haemorrhagic shock	41	Prehospital delivery of PRBCs with lyophilized plasma	Prehospital infusion of 0.9% saline solution	443 mL PRBCs and 266 mL plasma vs 638 mL 0.9% saline solution	No clinical differences	Signal towards higher ARDS rate (6% vs 2%) but no difference in transfusion-related complications

Abbreviations: OHCA, out-of-hospital cardiac arrest; PRBCs, Packed red blood cells; ARDS, Acute respiratory distress syndrome. Continuous data are reported as means.

^aSubgroup analysis of a larger trial cohort.

Table 4.

Randomized trials on post-cardiac arrest volume therapies.

Study	Cohort	N	Intervention	Control	Volumes	Main findings	Adverse events
Kim, 200726	OHCA	125	Prehospital rapid infusion of cold 0.9% saline solution	Standard care	Not reported	No clinical differences	No difference in pulmonary oedema or re-arrests
Kämäräinen, 200927	OHCA	37	Prehospital rapid infusion of cold Ringer’s solution	Standard care	Not reported	No clinical differences	No difference in pulmonary oedema or re-arrests
Bernard, 201029	OHCA, shockable	234	Prehospital rapid infusion of cold Ringer’s solution	In-hospital rapid infusion of cold Ringer’s solution	1900 (1000; 2000) mL cold fluids, 929 (±552) mL vs 1007 (±567) mL ambient fluids	No clinical differences	No difference in pulmonary oedema or re-arrests
Heradstveit, 201028	Witnessed OHCA, admitted	19	Use of hypertonic saline plus HES for 24 h	Use of 0.9% saline solution and Ringer’s solution for 24 h	4750 (3150; 9075) mL vs 8010 (5515; 12,908) mL	No clinical differences	Not reported
Bernard, 201230	OHCA, non-shockable	163	Prehospital rapid infusion of cold Ringer’s solution	In-hospital rapid infusion of cold Ringer’s solution	1500 (1000; 2000) mL cold fluids, 1000 (500; 1500) vs 1000 (500; 1500) mL ambient fluids	No clinical differences	No difference in pulmonary oedema or re-arrests
Kim, 201431	OHCA	1364	Prehospital rapid infusion of cold 0.9% saline solution	Standard care	Not reported	No clinical differences	Higher pulmonary oedema (41% vs 30%) and re-arrest (26% vs 21%) rates
Li, 201432	OHCA, admitted	45	In-hospital rapid infusion of cold 0.9% saline solution	No infusion of cold 0.9% saline solution	Not reported	Improved neurological status (57% vs 32%)	No difference in pulmonary oedema or re-arrests
Scales, 201733	OHCA	585	Prehospital rapid infusion of cold 0.9% saline solution	Standard care	640 (±470) vs 470 (±330) mL	No clinical differences	Lower pulmonary oedema rate (12% vs 18%) but no difference in re-arrests
Woo, 202325,a	OHCA, admitted	364	In-hospital use of Plasma Solution-A for 24 h	In-hospital use of 0.9% saline solutionfor 24 h	4029 (3562; 5650) mL vs 3918 (3640; 5420) mL	No clinical differences	No difference in acute kidney injury

Abbreviations: OHCA, out-of-hospital cardiac arrest; HES, hydroxyethyl starch. Continuous data are reported as means (± standard deviation) or medians (first quartile; third quartile).

^aRandomization post-cardiac arrest in 81% of cases in intervention group and 63% of cases in control group.

Non-traumatic intra-cardiac arrest

Five randomized trials investigated intra-cardiac arrest volume therapy for non-traumatic cardiac arrest, enrolling between 66 and 1324 patients (Table 2). Three trials were conducted in Europe, one in Asia, and one in Australia. All trials included adults with out-of-hospital cardiac arrest.21, 22, 23, 24, 25

Two trials, enrolling 263 patients, compared prehospital administration of 2 mL/kg over 10 min of hypertonic (7.2%) saline solution with 6% hydroxyethyl starch (200/0.5) to the same volume of 6% hydroxyethyl starch alone.21, 22 Meta-analyses showed no significant difference in survival to hospital admission (RR, 1.14; 95% CI, 0.89–1.46) (Fig. 2). One of the studies reported on survival to hospital discharge (RR, 0.99; 95% CI, 0.59–1.65) and favourable neurological outcome at hospital discharge (RR, 2.68; 95% CI, 0.99–7.24), showing no significant difference between groups.²²

Fig. 2.

Meta-analyses of intra-cardiac arrest infusion of hypertonic saline plus HES.

Fixed-effects meta-analysis of prehospital intra-cardiac arrest bolus of hypertonic saline with hydroxyethyl starch (HES) compared to HES alone for survival to hospital admission. There was no statistically significant observed effect of the intervention.

Two trials, enrolling 1569 patients, compared prehospital rapid infusion of cold 0.9% saline solution or standard care for inducing therapeutic hypothermia.23, 24 Administered volumes were not reported for one trial²³, and were on average 1380 mL (±773) in the intervention group and 1022 mL (±752) in the control group of the second trial²⁴. Meta-analyses showed no significant difference in return of spontaneous circulation (RR, 0.89; 95% CI, 0.78–1.03), survival to hospital discharge (RR, 0.93; 95% CI, 0.68–1.27) or favourable neurological outcome at hospital discharge (RR, 0.98; 95% CI, 0.72–1.35). (Fig. 3). One study reported survival at one year (RR, 0.99; 95% CI, 0.29–3.34).²³ Subgroup analyses stratified by initial rhythm showed no significant difference in treatment effect (Fig. S1).23, 24

Fig. 3.

Meta-analyses of intra-cardiac arrest infusion of cold 0.9% saline solution.

Fixed-effects meta-analyses of prehospital intra-cardiac arrest rapid infusion of cold 0.9% saline solution compared to standard care. There were no statistically significant observed effects of the intervention for return of spontaneous circulation, survival to hospital discharge, and favorable neurological outcome at hospital discharge.

One trial, enrolling 364 patients, compared administration of a balanced crystalloid (plasma solution-A) to a 0.9% saline solution upon hospital admission. Median administered volumes were 3918 mL (3640; 5420) in the plasma solution A group and 4029 mL (3562; 5650) in the 0.9% saline solution group. Randomization occurred both during and after cardiac arrest. No differences in clinical outcomes were observed between groups.²⁵

The certainty of evidence was low to very low for all comparisons in non-traumatic intra-cardiac arrest, downgraded for risk of bias and imprecision, with additional downgrading for indirectness in trials of cold 0.9% saline solution designed to induce hypothermia (Tables S3 and S4).

Traumatic intra-cardiac arrest

One randomized trial investigated intra-cardiac arrest volume therapy for traumatic cardiac arrest (Table 3). This was a subgroup analysis of 41 patients with traumatic out-of-hospital cardiac arrest from a larger trial enrolling patients with trauma-related haemorrhagic shock.¹⁰

The trial compared prehospital administration of packed red blood cells and lyophilised plasma to 0.9% saline solution. On average, patients received 443 mL packed red blood cells with 266 mL lyophilised plasma or 638 mL 0.9% saline solution. In the cardiac arrest subgroup, 20 of 21 (95%) patients in the intervention group and 20 of 20 (100%) patients in the control group met the composite outcome of in-hospital mortality or impaired lactate clearance, with no significant difference between groups.¹⁰

The certainty of evidence was very low, downgraded for risk of bias and very serious imprecision due to the small sample size (Table S5).

Post-cardiac arrest

Nine randomized trials investigated post-cardiac arrest volume therapy, enrolling between 19 and 1364 patients (Table 4). Three trials were conducted in North America, two each in Europe, Asia, and Australia. Seven trials included adults with out-of-hospital cardiac arrest and two included mixed populations aged 14 years or older.25, 26, 27, 28, 29, 30, 31, 32, 33

Seven trials, enrolling 2556 patients, evaluated prehospital or in-hospital infusion of cold crystalloid solutions (0.9% saline or Ringer’s solution) for inducing therapeutic hypothermia.26, 27, 29, 30, 31, 32, 33 Administered volumes were reported in three of the trials, ranging from 640 to 1900 mL of cold crystalloid solutions with additional ambient fluids given during the peri-arrest phase (Table 4).29, 30, 33

Meta-analyses of six trials showed no significant difference in survival to hospital discharge (RR, 1.00; 95% CI, 0.90–1.11) or favourable neurological outcome at hospital discharge (RR, 0.98; 95% CI, 0.87–1.10) (Fig. 4). Subgroup analyses stratified by crystalloid type and by initial rhythm showed no significant differences in outcomes (Fig. 4 and Figs. S2, S3).26, 27, 29, 30, 31, 33

Fig. 4.

Meta-analyses of post-cardiac arrest infusion of cold crystalloids stratified by intervention.

Random-effects meta-analyses of prehospital post-cardiac arrest rapid infusion of cold 0.9% saline solution or Ringer’s solution stratified according to intervention type. There were no statistically significant observed effects of the interventions for survival to hospital discharge and favorable neurological outcome. The test for subgroup differences was non-significant.

One small trial, enrolling 19 patients, compared in-hospital use of hypertonic (7.2%) saline with 6% hydroxyethyl starch (200/0.5) to a combined use of Ringer’s and 0.9% saline solution for 24 h post-cardiac arrest with patients receiving a median volume of 4750 mL (3150; 9075) and 8010 mL (5515; 12,908), respectively. The trial found no difference in survival at one year between groups (RR, 1.03; 95% CI, 0.64–1.64).²⁸

One trial, enrolling 364 patients, compared in-hospital use of a balanced crystalloid (plasma solution-A) to a 0.9% saline solution for 24 h after hospital admission. The median administered volumes were 3918 mL (3640; 5420) in the plasma solution A group and 4029 mL (3562; 5650) in the 0.9% saline solution group. The trial found no differences in survival to hospital discharge (RR, 1.05; 95% CI, 0.64–1.71), favourable neurological outcome at hospital discharge (RR, 1.01; 95% CI, 0.60–1.71), survival at six months (RR, 0.83; 95% CI, 0.50–1.39), or favourable neurological outcome at six months (RR, 0.93; 95% CI, 0.54–1.59).²⁵

The certainty of evidence was low to very low for all comparisons in post-cardiac arrest, downgraded for risk of bias, indirectness, and imprecision (Tables S6–S8).

Non-randomized studies

Characteristics of the 44 non-randomized studies are presented in Tables S9–S13 and the Supplementary Material. Risk of bias was assessed as serious or critical, mainly due to confounding and selection bias (Table S14).

Non-traumatic intra-cardiac arrest

Six studies investigated intra-cardiac arrest volume therapy for non-traumatic cardiac arrest, analysing a total of 566,642 patients (Table S9).34, 35, 36, 37, 38, 39 Three studies were conducted in Asia, two in North America, and one in Europe. All studies included out-of-hospital cardiac arrests. Two studies included both children and adults.

Two studies compared cold 0.9% saline solution to standard care,34, 38 two studies compared crystalloids to no fluid administration,35, 37 one assessed transfusion of blood products in the emergency department,³⁹ and one study assessed prehospital hypertonic saline with hydroxyethyl starch.³⁶ Results were inconsistent, with individual studies suggesting benefit, harm, or no difference (Fig. S4).

Traumatic intra-cardiac arrest

Fourteen studies investigated intra-cardiac arrest volume therapy for traumatic cardiac arrest, analysing a total of 97,348 patients (Table S10).40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53 Seven studies were conducted in Europe, six in Asia, and one in North America. One study included both in-hospital and out-of-hospital cardiac arrests. Six studies included both adults and children.

Ten studies assessed crystalloids or colloids41, 42, 44, 45, 46, 48, 49, 50, 51, 53 and five assessed blood products.40, 43, 44, 47, 52 Studies of crystalloid or colloid therapy compared to no volume therapy generally reported benefit or no significant association with survival (Fig. S5). Studies of blood products reported inconsistent results (Fig. S6).

Post-cardiac arrest

Seventeen studies investigated post-cardiac arrest volume therapy, analysing a total of 9602 patients (Table S11).54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70 Eight studies were conducted in Europe, six in North America, and three in Asia. All studies included adult patients, predominantly with out-of-hospital cardiac arrest.

Interventions were heterogeneous, including cold crystalloid infusions, liberal vs restrictive fluid strategies, fluid balance assessments, blood product transfusions, balanced vs unbalanced crystalloids, and post-resuscitation care bundles. Results generally showed no consistent association between volume therapy and outcomes (Figs. S7, S8).

Additional studies

Five studies addressed multiple PICO questions and analysed 34,259 patients combined (Table S12).71, 72, 73, 74, 75 Two studies assessed fluid balance or albumin administration in patients receiving extracorporeal cardiopulmonary resuscitation.72, 75 Three studies compared prehospital fluid administration to no fluid administration but did not specify the timing of volume therapy relative to return of spontaneous circulation.71, 73, 74

Two studies addressed volume therapy in paediatric cardiac arrest, analysing 2267 patients (Table S13).76, 77 One investigated intra-cardiac arrest fluid administration during delivery room resuscitation in neonates,⁷⁶ and one assessed prehospital fluid administration in children with non-traumatic out-of-hospital cardiac arrest.⁷⁷

Results of individual studies showed no consistent association between volume therapy and outcomes (Figs. S9, S10).

Discussion

This systematic review identified 14 randomized trials and 44 observational studies evaluating volume therapy across non-traumatic intra-cardiac arrest, traumatic intra-cardiac arrest, and post-cardiac arrest settings. The available trials, which compared different types of volume therapy strategies in adult patients, showed no significant difference in clinical outcomes. Observational studies were limited by serious or critical risk of bias and reported inconsistent results. The certainty of evidence was low to very low for all comparisons, primarily due to risk of bias, indirectness, and imprecision.

The physiological effects of intra-cardiac arrest volume therapy remain unclear. Volume therapy may compensate for vasoplegia in the absence of vasopressor administration and intravascular volume depletion, potentially increasing preload and cardiac output from chest compressions. There are also concerns that fluid administration may increase right atrial pressure, impair venous return, and consequently reduce coronary perfusion pressure.5, 6 Despite this uncertainty, no trials have directly compared volume therapy to no volume therapy during cardiopulmonary resuscitation.

For non-traumatic cardiac arrest, the identified trials evaluated specific interventions, such as hypertonic saline with hydroxyethyl starch21, 22 or cold crystalloid infusion for inducing therapeutic hypothermia.23, 24 The cold crystalloid infusion trials are difficult to interpret as the control groups often received ambient temperature fluids, resulting in comparisons of cold versus ambient crystalloids with similar volumes, rather than volume therapy versus no volume therapy.²⁴ Trials of hypertonic saline with hydroxyethyl starch showed no difference in outcomes.21, 22 However, hydroxyethyl starch solutions have been withdrawn or heavily restricted in most countries because of increased risk of coagulopathy, acute kidney injury, and mortality in large, randomized trials of critically ill patients.⁷⁸ These established harms are directly applicable to the intra- and post-cardiac arrest population and the respective cardiac arrest trials identified in this review are therefore of limited relevance.21, 22, 28

For traumatic cardiac arrest, direct evidence was limited to a subgroup analysis within a larger trial of patients with haemorrhagic shock.¹⁰ Most evidence regarding volume therapy in trauma is derived from studies of patients with haemorrhagic shock who did not have cardiac arrest, but those studies were outside the scope of the current review. Given the limited direct evidence and the distinct pathophysiology of traumatic cardiac arrest, the optimal volume therapy strategy remains uncertain.

For post-cardiac arrest care, randomized trials evaluating cold crystalloid infusion had similar limitations to those in the intra-cardiac arrest setting, as they were designed to induce therapeutic hypothermia rather than volume resuscitation.26, 27, 29, 30, 31, 32, 33 A single small trial compared balanced crystalloids to 0.9% saline solution and found no difference in clinical outcomes, although the trial was underpowered to detect clinically meaningful differences.²⁵ Regarding the choice of crystalloid, 0.9% saline solution can cause hyperchloraemic acidosis and may be associated with increased risk of acute kidney injury in critically ill patients compared to balanced crystalloids. However, this evidence is not specific to cardiac arrest and concerns have been raised about the lower tonicity of balanced fluids potentially worsening cerebral oedema.79, 80

Across all settings, the observational studies were assessed as having a serious or critical risk of bias, primarily due to confounding and selection bias. For intra-cardiac arrest studies, comparisons of volume therapy to no volume therapy are particularly susceptible to resuscitation time bias, as patients with longer resuscitation attempts are more likely to receive fluids and more likely to have poor outcomes.⁸¹ None of the observational studies was designed to account for resuscitation time bias and most studies did not adequately control for potential confounders, which likely explains the inconsistent results, with individual studies suggesting benefit, harm, or no association.

The previous 2010 ILCOR review concluded that there was insufficient evidence to recommend for or against routine intravenous fluids during cardiac arrest.¹⁶ Despite additional evidence since 2010, the certainty in evidence remains low to very low for all comparisons. A recent systematic review concluded similarly that there is a paucity of clinical evidence on this topic, with theoretical hemodynamic and neuroprotective benefits observed in preclinical studies that have not translated into improved clinical outcomes in human studies.⁸²

Limitations

This systematic review should be interpreted in the context of some limitations. First, despite comprehensive searches across several databases, there is a possibility that some relevant studies were missed. Second, the review was limited to studies with an English abstract or full text available, which may have excluded relevant non-English articles. Third, bias assessments are inherently subjective, and other reviewers might have made different risk of bias assessments. Fourth, the findings of this review apply to undifferentiated cardiac arrests and did not address the use of small fluid volumes for medication delivery during cardiopulmonary resuscitation. Lastly, direct paediatric evidence was limited to two observational studies. The findings of this review are therefore primarily applicable to adult populations.

Conclusion

This systematic review found no trials directly comparing volume therapy to no volume therapy during cardiopulmonary resuscitation. The available trials, which compared different types of volume therapy strategies in adult patients, showed no significant difference in clinical outcomes across non-traumatic intra-cardiac arrest, traumatic intra-cardiac arrest, and post-cardiac arrest settings. Observational studies were limited by at least serious risk of bias with inconsistent results. The certainty of evidence was low to very low for all comparisons. Additional randomized trials are needed to establish the role of intra- and post-cardiac arrest volume therapy.

CRediT authorship contribution statement

Johannes Wittig: Writing – original draft, Visualization, Methodology, Investigation, Formal analysis, Conceptualization. Shinichiro Ohshimo: Writing – review & editing, Methodology, Investigation, Conceptualization. Anders Aneman: Writing – review & editing, Methodology, Investigation, Conceptualization. Carrie Kah-Lai Leong: Writing – review & editing, Methodology, Investigation, Conceptualization. Brian J. O’Neil: Writing – review & editing, Methodology, Investigation, Conceptualization. Yew Woon Chia: Writing – review & editing, Methodology, Investigation, Conceptualization. Jacqueline Eleonora Ek: Writing – review & editing, Methodology, Investigation, Conceptualization. Peter Paal: Writing – review & editing, Methodology, Investigation, Conceptualization. Lars W. Andersen: Writing – review & editing, Methodology, Investigation, Conceptualization. Marie K. Jessen: Writing – review & editing, Methodology, Investigation, Conceptualization. Asger Granfeldt: Writing – review & editing, Methodology, Investigation, Conceptualization. Mathias J. Holmberg: Writing – review & editing, Visualization, Supervision, Methodology, Investigation, Formal analysis, Conceptualization.

Funding

This systematic review was commissioned by the International Liaison Committee on Resuscitation (ILCOR). The work of ILCOR is underpinned by contributions from its member councils. None of the authors received payment from this funding source to complete this systematic review.

Declaration of competing interest

Lars W. Andersen and Asger Granfeldt are part of the Editorial Board at Resuscitation Plus. None of the remaining authors have any conflicts of interest to report.

Appendix A. Supplementary material

The following are the Supplementary material to this article: