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Efficacy and safety of hypertonic saline solutions fluid resuscitation on hypovolemic shock: A systematic review and meta-analysis of randomized controlled trials

Kamil Safiejko1, Jacek Smereka23, Michal Pruc3, Jerzy R. Ladny34, Milosz J. Jaguszewski5, Krzysztof J. Filipiak6, Ruslan Yakubtsevich7, Lukasz Szarpak138
Pubmed: 33140397
Cardiol J 2022;29(6):966-977.

Abstract

Background: Fluid resuscitation is a fundamental intervention in patients with hypovolemic shock resulting from trauma. Appropriate fluid resuscitation in trauma patients could reduce organ failure, until blood components are available, and hemorrhage is controlled. We conducted a systematic review and meta-analysis assessing the effect of hypertonic saline/dextran or hypertonic saline for fluid resuscitation on patient outcomes restricted to adults with hypovolemic shock.
Methods: We conducted a search of electronic information sources, including PubMed, Embase, Web of Science, Cochrane library and bibliographic reference lists to identify all randomized controlled trials (RCTs) investigating outcomes of crystalloids versus colloids in patients with hypovolemic shock. We calculated the risk ratio (RR) or mean difference (MD) of groups using fixed or random-effect models.
Results: Fifteen studies including 3264 patients met our inclusion criteria. Survival to hospital discharge rate between research groups varied and amounted to 71.2% in hypertonic saline/dextran group vs. 68.4% for isotonic/normotonic fluid (normal saline) solutions (odds ratio [OR] = 1.19; 95% confidence interval [CI] 0.97–1.45; I2 = 48%; p = 0.09). 28- to 30-days survival rate for hypertonic fluid solutions was 72.8% survivable, while in the case of isotonic fluid (normal saline) — 71.4% (OR = 1.13; 95% CI 0.75–1.70; I2 = 43%; p = 0.56).
Conclusions: This systematic review and meta-analysis, which included only evidence from RCTs hypertonic saline/dextran or hypertonic saline compared with isotonic fluid did not result in superior 28- to 30-day survival as well as in survival to hospital discharge. However, patients with hypotension who received resuscitation with hypertonic saline/dextran had less overall mortality as patients who received conventional fluid.

11_CJ_2022_6_Safiejko_Efficacy

clinicAL CARDIOLOGY

original article

Cardiology Journal

2022, Vol. 29, No. 6, 966–977

DOI: 10.5603/CJ.a2020.0134

Copyright © 2022 Via Medica

ISSN 1897–5593

eISSN 1898–018X

Efficacy and safety of hypertonic saline solutions fluid resuscitation on hypovolemic shock: A systematic review and meta-analysis of randomized controlled trials

Kamil Safiejko1, Jacek Smereka2, 3, Michal Pruc3, Jerzy R. Ladny3, 4, Milosz J. Jaguszewski5, Krzysztof J. Filipiak6, Ruslan Yakubtsevich7, Lukasz Szarpak1, 3, 8

1Maria Sklodowska-Curie Bialystok Oncology Center, Bialystok, Poland 2Department of Emergency Medical Service, Wroclaw Medical University, Wroclaw, Poland 3Polish Society of Disaster Medicine, Warsaw, Poland 4Clinic of Emergency Medicine and Disaster, Medical University Bialystok, Poland 5First Department of Cardiology, Medical University of Gdansk, Poland 6First Chair and Department of Cardiology, Medical University of Warsaw, Poland 7Department of Anesthesiology and Intensive Care, Grodno State Medical University, Grodno, Belarus 8Maria Sklodowska-Curie Medical Academy, Warsaw, Poland

This paper was guest edited by Prof. Togay Evrin

Address for correspondence: Lukasz Szarpak, Assoc. Prof. PhD, MBA, Bialystok Oncology Center, ul. Ogrodowa 12, 15–027 Białystok, Poland, tel: +48 500186225, e-mail: lukasz.szarpak@gmail.com

Received: 28.08.2020 Accepted: 2.09.2020 Early publication date: 22.10.2020

This article is available in open access under Creative Common Attribution-Non-Commercial-No Derivatives 4.0 International (CC BY-NC-ND 4.0) license, allowing to download articles and share them with others as long as they credit the authors and the publisher, but without permission to change them in any way or use them commercially.

Abstract

Background: Fluid resuscitation is a fundamental intervention in patients with hypovolemic shock resulting from trauma. Appropriate fluid resuscitation in trauma patients could reduce organ failure, until blood components are available, and hemorrhage is controlled. We conducted a systematic review and meta-analysis assessing the effect of hypertonic saline/dextran or hypertonic saline for fluid resuscitation on patient outcomes restricted to adults with hypovolemic shock.

Methods: We conducted a search of electronic information sources, including PubMed, Embase, Web of Science, Cochrane library and bibliographic reference lists to identify all randomized controlled trials (RCTs) investigating outcomes of crystalloids versus colloids in patients with hypovolemic shock. We calculated the risk ratio (RR) or mean difference (MD) of groups using fixed or random-effect models.

Results: Fifteen studies including 3264 patients met our inclusion criteria. Survival to hospital discharge rate between research groups varied and amounted to 71.2% in hypertonic saline/dextran group vs. 68.4% for isotonic/normotonic fluid (normal saline) solutions (odds ratio [OR] = 1.19; 95% confidence interval [CI] 0.97–1.45; I2 = 48%; p = 0.09). 28- to 30-days survival rate for hypertonic fluid solutions was 72.8% survivable, while in the case of isotonic fluid (normal saline) — 71.4% (OR = 1.13; 95% CI 0.75–1.70; I2 = 43%; p = 0.56).

Conclusions: This systematic review and meta-analysis, which included only evidence from RCTs hypertonic saline/dextran or hypertonic saline compared with isotonic fluid did not result in superior 28- to 30-day survival as well as in survival to hospital discharge. However, patients with hypotension who received resuscitation with hypertonic saline/dextran had less overall mortality as patients who received conventional fluid. (Cardiol J 2022; 29, 6: 966–977)

Key words: fluid resuscitation, hypovolemic shock, trauma, injury, hypertonic saline, normal saline, treatment, crystalloid, colloid fluid

Introduction

Fluid resuscitation is a fundamental intervention in patients with hypovolemic shock resulting from trauma. The main purpose of undertaking fluid therapy is to stabilize post-traumatic circulation disorders [1, 2]. Baroreceptor-mediated, catecholamine-induced venoconstriction acts on the venous capacitance system to increase venous return and maintain cardiac output, moreover the renin–angiotensin–aldosterone and adrenocortical systems produces an antidiuretic response to retain water [3]. The hypovolemic shock caused by acute hemorrhage occurs when intravascular volume loss exceeds the capacity of these compensatory mechanisms, resulting in the compromise of vital organ perfusion [4].

Advanced trauma life support recommends the prehospital assessment of a patient’s circulation status and to resuscitate with intravenous fluids in patients with obvious hemorrhage or systolic blood pressure (SBP) below 90 mmHg [5]. A particularly important problem of fluid therapy is observed in patients with multi-organ injuries, including those affecting the central nervous system, which is extremely susceptible to osmolality changes. For this reason, hypotonic solutions that increase intracerebral water and exacerbate post-traumatic brain edema are not recommended in patients treated for head injuries [6, 7]. As indicated by Reddy et al. [8] most infusion solutions exhibit hypoosmotic effects, since only some components of crystalline solutions are active in plasma and their osmotic coefficient is 0.92.

Crystalloid is a broad term that can encompass many different types of solutions from hypertonic normal saline (NS) to lactated Ringer’s solution to 5% dextrose and half NS. 0.9% sodium chloride (NS) is one of the most frequently administered solutions. It is also the basis for the preparation of many colloids, including hypertonic saline/dextran, human albumins or gelatins.

When infused, crystalloids with a sodium concentration close to that of intravascular fluid (140 mmol/L) produce a transient increase in intravascular volume before equilibrating with the extracellular fluid. Crystalloids can be used either as resuscitation fluids (to increase or maintain intravascular volume) or as maintenance fluids (to maintain hydration and basic electrolyte balance) in persons unable to tolerate enteral administration of fluid [9]. As indicated by the meta-analysis published by Safiejko et al. [10] hypotensive fluid resuscitation significantly reduced the mortality of traumatic hemorrhagic shock patients. Rapid administration of a large volume will cause hyperchloremic metabolic acidosis. This is because in the case of a standard 0.9% NaCl strong ion difference between 0.9% NaCl fluid solution and plasma (respectively 0 vs. 40 mEq/L). Therefore, it is important to know the effect of using both isotonic vs. hypertonic fluid solutions during fluid resuscitation of trauma patients.

The present study is a systematic review and meta-analysis assessing the effect of hypertonic saline fluid resuscitation on patient outcomes restricted to adults with hypovolemic shock.

Methods

This review was conducted and presented according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement standards [11]. We did not publish a prior protocol for this review.

Literature searches

A computerized literature search was conducted from the PubMed, Embase, Web of Science, and the Cochrane library data bases from their inception to August 20th 2020. In addition to the reference lists of the selected articles they were hand-searched to identify additional relevant reports. Google Scholar and other Internet search engines were also used to search for additional information.

The search terms comprised the followings: (crystalloid* OR normal saline* OR saline OR Ringers OR Ringer’s OR Hartmanns OR Hartmann’s OR hypertonic OR 7.5% saline OR NaCl OR sodium chloride) AND (Emergency medicine OR Emergency treatment OR Emergency department OR Emergency room OR Emergency medical service OR EMS OR Hemorrhagic shock OR Hypovolemic shock OR trauma).

Selection and exclusion criteria

Two reviewers (K.S. and A.S.) independently screened the titles and abstracts of all citations retrieved during the literature search based on inclusion criteria. Disagreements were resolved through discussion until consensus was reached. Inclusive criteria: (a) Research types: randomized controlled trials (RCTs) and quasi-randomized trials; (b) Research subjects: human studies involved adult patients needing fluid resuscitation were involved in the meta-analysis. Also included were studies which were in preprint. Observational studies, case-control studies, non-trials conducted on simulated models, editorials, reviews, guidelines, meta-analysis, and theoretical models were excluded from the review. The search was limited to English language studies and adult patients needing fluid resuscitation. The data were recorded using Review Manager.

Data extraction

Two authors (K.S. and J.R.L.) independently reviewed all identified titles and abstracts against the prespecified eligibility criteria using a standardized form piloted before the study. The reviewers then independently evaluated the full texts of the selected articles, applied the selection criteria to them, and compared decisions for all the included and excluded studies. Disagreements were resolved by discussion with the other authors (J.S.). The duplicate publications of the same trial were excluded from the present study.

The clinical data were extracted as the following: the name of the first author, the year published, the country of the author, the types of study design, the number of patients, type of fluid infused, and follow-up time. The primary outcome herein, was survival to hospital discharge or at 28 to 30 days. Other mortality periods were also extracted as defined by the authors.

Outcome measures

The primary endpoint was short-term survival (hospital discharge or 28 to 30 days). Secondary outcomes included long-term mortality (≥ 3 months), 24-hour mortality, overall mortality, adverse outcome, length of stay in an intensive care unit and hospital, laboratory parameters at patient admission, the Glasgow Outcome Scale Extended score.

Risk of bias assessment

Two authors independently assessed the methodological quality and risk of bias of the included articles using the method outlined in the Cochrane Collaboration Handbook for Systematic Reviews of Interventions [12]. Risk of bias was assessed as high, low, and unclear for each of selection bias: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other biases. The review authors’ judgments about each risk of bias item are provided in Supplementary Digital File 1.

Statistical analysis

All analyses were performed by the Review Manager Version 5.4. (The Cochrane Collaboration, Oxford, Copenhagen, Denmark). Dichotomous data were presented as risk ratios using the Mantel–Haenszel method. Continuous data were presented as means with standard deviations and analyzed using the inverse variance. The random-effects model was used for I2 > 50%; otherwise, the fixed effects model was employed. When continuous data were presented as medians with ranges, the data were converted for inclusion into the meta-analysis using the method described by Hozo et al. [13]. Heterogeneity among the studies was assessed using the Cochran Q test (c2). Inconsistency was quantified by calculating I2 and was interpreted using the following guide: no heterogeneity, I2 = 0–25%; moderate heterogeneity, I2 = 25–50%; large heterogeneity, I2 = 50–75%; extreme heterogeneity, I2 = 75–100%. Where appropriate, subgroup analyses were performed based on the study design and methodological quality.

Role of the funding source

There was no funding source for this study. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Results

Study selection

The comprehensive search yielded 1271 potentially relevant articles; after exclusion of duplicates and assessment of titles and/or abstracts, 43 articles were chosen for complete review. Finally, 15 studies including 3264 patients met our inclusion criteria, published between 1987 and 2011 [14–28]. Figure 1 shows the flow of studies through the review.

Figure 1. Flow diagram showing stages of database searching and study selection as per PRISMA guidelines.

Characteristics of included studies

The studies comprised a total of 3264 participants, of whom 54.9% were exposed to hypertonic saline solutions (Table 1).

Table 1. Characteristics of included studies.

Study

Country

Study design

Intervention

Hyper-saline group

Control group

N

Age

Males

N

Age

Males

Alpar et al. 2004

UK

RCT

Patients randomized to receive HSD or Hartmann’s. HSD infused at a dose of 4 mL/kg or maximum 250 mL, with further fluid resuscitation with Hartmann’s or blood transfusion. Average volume infused: HSD group: 4.5 L, Hartmann’s group: 6.5 L

90

34.3 ± 11.3

NS

90

33.5 ± 11

ns

Bulger et al. 2008

USA

Double-blind RCT

Prehospital resuscitation with 250 mL either HSD or Ringer’s lactate. Additional ongoing resuscitation with Ringer’s lactate only

110

41 ± 18

69 (62.7%)

99

38 ± 19

68 (68.7%)

Bulger et al. 2011

Multi-country

Multi- -center double-blind RCT

Patients randomized to receive a 250-mL bolus of either 7.5% HS, 7.5% HSD 70 or NS, in prehospital setting

476

37.2 ± 16.7

375 (78.8%)

376

36.2 ± 16.4

291 (77.4%)

Cooper et al. 2004

Australia

Double-blind RCT

Patients randomized to receive a 250 mL bolus of either 7.5% saline or Ringer’s lactate solution

114

38 ± 19

75 (65.8%)

115

37 ± 19

76 (66.1%)

Holcroft et al. 1987

USA

RCT

Patients randomized to receive a 3% NaCl (1028 mOsm/kg, 4 mL/kg) or lactated Ringer’s solution (12 mL/kg)

10

36 ± 13

9 (90.0%)

10

36 ± 21

9 (90.0%)

Holcroft et al. 1989

USA

RCT

Patients randomized to receive a 3% NaCl (1028 mOsm/kg, 4 mL/kg) or lactated Ringer’s solution (12 mL/kg)

29

38 ± 15.6

23 (79.3%)

31

38 ± 19

26 (83.9%)

Mattox et al. 1991

USA

Multi- -center double-blind RCT

Patients randomized to receive 250 mL either HSD or Ringer’s lactate as prehospital resuscitation

211

34 ± 12

184 (87.2%)

211

33 ± 12

175 (82.9%)

Morrison et al. 2011

Canada

Randomized controlled feasibility trial

250 mL of NS or 250 mL of HSD in a single dose. If the paramedics failed to obtain an intravenous access, the study’s solution could be started immediately at the arrival to the emergency department as long as this occurred within 4 h from the injury

50

46 ± 21

30 (60.0%)

57

43 ± 21

43 (75.4%)

Rizoli et al. 2006

Canada

Double-blind RCT

Patients randomized to receive a single 250-mL bolus of either HSD or normal saline. Mean (standard deviation) total volume in first 24 h; Control group: colloid 696 (773) mL, crystalloid 8080 (2736) mL; HSD group: colloid 361 (377) mL, crystalloid 7796 (3189) mL; p = 0.02 and p = 0.75 between groups for crystalloid and colloid respectively

10

49.3 ± 16.7

7 (70.0%)

14

47.5 ± 15.9

9 (64.3%)

Vassar et al. 1991

USA

Double-blind RCT

Trauma patient were given 250 mL of 7.5 HSD 70 or Ringer’s lactate as prehospital resuscitation

83

30.3 ± 6.1

NS

83

32.3 ± 6.1

ns

Vassar et al. 1993 (1)

USA

Double-blind RCT

Trauma patients in prehospital transport were given 250 mL of: (1) normal saline; (2) 7.5% NaCl (HS); (3) 7.5% NaCl in 6% HSD 70

174

31.5 ± 14.5

NS

84

31 ± 12

ns

Vassar et al. 1993 (2)

USA

Double-blind RCT

Trauma patients were given 200 mL or more of: (1) Lactate Ringer’s solution, (2) 7.5% hypertonic saline solution, (3) 7.5% HS combined with 6% HSD 70, (4) 7.5 HS combined with 12% HSD 70

149

32 ± 13

NS

45

37 ± 18

ns

Wade et al. 2003

USA

Double-blind RCT

Trauma patients were given 250 mL of HSD (7.5% NaCl/6% HSD 70) or 250 mL of normal saline (0.9% NaCl)

120

32 ± 10.4

NS

110

32 ± 10.5

ns

Younes et al. 1992

Brazil

Double-blind RCT

Emergency unit patients received either an intravenous bolus infusion of 250 mL of hypertonic/ /hypertonic 7.5% NaCl + 6% HSD 70 or an isotonic 0.9% NaCl (NS) solution

70

NS

NS

35

NS

ns

Younes et al. 2002

Brazil

Double-blind RCT

Emergency unit patients received either an intravenous bolus infusion of 250 mL of hypertonic/ /hypertonic 7.5% NaCl + 6% HSD 70 or an isotonic 0.9% NaCl (IS) solution

101

39.8 ± 11.2

93 (92.1%)

111

40.8 ± 12.2

92 (82.9%)

HS — hypertonic saline; HSD — hypertonic saline/dextran; NS — normotonic/isotonic fluid; ns — not specified; RCT — randomized controlled trial

All studies were RCTs. Eight studies were conducted in the United States of America [15, 18–20, 24–26], two in Brazil [27, 28], two in Canada [21, 22], one in the United Kingdom [14], and one in Australia [17]. One study was multi-county [16]. In general, the studies were judged as being of good quality. Supplementary Digital File 1 presents inclusion and exclusion criteria, primary outcome as well as 28- to 30-day survival rate with an odds ratio (OR) (95% confidence interval [CI]).

Primary endpoint

In summary, 9 studies reported survival to hospital discharge including 2081 patients [16, 17, 21–27]. Survival to hospital discharge rate between research groups varied and amounted to 71.2% in hypertonic saline/dextran (HSD) group vs. 68.4% for isotonic fluid (NS) solutions (OR = 1.19; 95% CI 0.97–1.45; I2 = 48%; p = 0.09).

Subgroup analysis is shown in Figure 2. Eight studies reported a comparison between HSD and control group [16, 21–27]. The differences in terms of survival to hospital discharge were not significant and were respectively 72.8% vs. 72.3% (OR = 1.13; 95% CI 0.89–1.44; I2 = 36%; p = 0.30). In turn, 4 studies [16, 17, 25, 27] reported analyzed comparison between hypertonic saline and isotonic saline (68.8% vs. 68.1%, respectively; OR = 1.10; 95% CI 0.83–1.44; I2 = 0%; p = 0.51).

Figure 2. Forest plot of survival to hospital discharge rate while using hypertonic fluid solutions versus isotonic fluid solutions. The center of each square represents the weighted mean difference for individual trials, and the corresponding horizontal line stands for a 95% confidence interval (CI). The diamonds represent pooled results.

28- to 30-day survival rate was reported by 5 studies [15, 16, 19, 21, 28]. Pooled analysis showed that the use of hypertonic fluid solutions was 72.8% survivable, while in the case of isotonic fluid (NS) — 71.4% (OR = 1.13; 95% CI 0.75–1.70; I2 = 43%; p = 0.56).

As shown in Figure 3 in the HSD subgroup, 4 studies indicated that hypertonic/dextran solutions infusion [15, 16, 19, 21] was associated with a survival rate of 72.6% and NS with 72.8% (OR = = 1.06; 95% CI 0.64–1.77; I2 = 56%; p = 0.81). Analysis in the subgroup where the infusion of hypertonic saline vs. isotonic saline [16, 28] was used showed survival at the level of 73.1% vs. 71.9%, respectively (OR = 1.14; 95% CI 0.71–1.83; I2 = 49%; p = 0.59).

Figure 3. Forest plot of 28- to 30-days survival rate while using hypertonic fluid solutions versus isotonic fluid solutions. The center of each square represents the weighted mean difference for individual trials, and the corresponding horizontal line stands for a 95% confidence interval (CI). The diamonds represent pooled results.

Secondary endpoints

The detailed results of the secondary endpoints are presented in Table 2. 24 h survival rate in case of hypertonic fluids was 88.6% and was higher than with isotonic fluids — 72.3% (OR = 2.99; 95% CI 2.04–4.39; I2 = 0%; p < 0.001). In the case of the 3-month survival rate, there was no significant statistical difference (55.3% vs. 48.2%; OR = 1.33; 95% CI 0.79–2.23; p = 0.29).

Table 2. Characteristics of outcomes: hypertonic fluid solutions versus isotonic fluid solutions.

Type of adverse event

Number of trials

Total numer of patients

Percentage of adverse event

Treatment effect (hypertonic vs. normotonic fluid solutions)

OR/MD (95% CI)

P value

I2, statistic, %

HSD or HS

NS

24-h survival

HSD

2

575

89.4%

73.8%

2.99 (1.88–4.75)

< 0.001

18%

NS

2

332

86.4%

68.6%

3.01 (1.54–5.89)

0.001

23%

Total

4

807

88.6%

72.3%

2.99 (2.04–4.39)

< 0.001

0%

28- to 30-day survival

HSD

4

972

72.6%

72.8%

1.06 (0.64–1.77)

0.81

56%

NS

2

844

73.1%

71.9%

1.14 (0.71–1.83)

0.59

49%

Total

5

1440

72.8%

71.4%

1.13 (0.75–1.70)

0.56

54%

Survival to discharge

HSD

8

1511

72.8%

72.3%

1.13 (0.89–1.44)

0.30

36%

NS

4

1026

68.8%

68.1%

1.10 (0.83–1.44)

0.51

0%

Total

9

2081

71.2%

69.4%

1.19 (0.97–1.45)

0.09

48%

Survival at 3 months

HSD

NS

1

228

55.3%

48.2%

1.33 (0.79–2.23)

0.29

Total

1

228

55.3%

48.2%

1.33 (0.79–2.23)

0.29

Length of hospital stay (days)

HSD

3

361

1.05 (–1.88–3.98)

0.48

0%

NS

1

222

1.50 (0.42–2.58)

0.007

Total

4

583

1.45 (0.43–2.46)

0.005

0%

ARDS-free survival rate to day 28

HSD

2

805

51.8%

54.9%

1.15 (0.84–1.57)

0.39

0%

NS

1

632

66.0%

65.4%

1.03 (0.73–1.43)

0.88

Total

2

1061

58.0%

54.9%

1.10 (0.85–1.44)

0.46

6%

Total fluids in first 24-h

HSD

4

1268

–1.14 (–2.15––0.13)

0.03

0%

NS

1

632

–0.70 (–2.47–1.07)

0.44

Total

4

1524

–1.07 (–2.03––0.12)

0.03

0%

Hypernatremia (Na > 160 mEq/L) requiring intervention

HSD

1

596

0.9%

1.3%

0.68 (0.13–3.54)

0.65

NS

1

632

1.9%

1.3%

1.48 (0.42–5.16)

0.54

Total

1

852

1.5%

1.3%

1.11 (0.35–3.52)

0.86

Overall mortality

HSD

6

1459

17.3%

23.3%

0.72 (0.55–0.94)

0.01

20%

NS

3

914

23.7%

25.9%

0.90 (0.66–1.23)

0.51

10%

Total

7

1962

19.7%

24.8%

0.76 (0.61–0.94)

0.01

33%

ARDS — acute respiratory distress syndrome; CI — confidence interval; HSD — hypertonic fluid solutions; MD — mean difference; NS — izotonic/norotonic fluid solutions; OR — odds ratio

Seven studies [14, 16, 20, 22, 26–28] reported overall mortality in the experimental group was 19.7% compared with NS group — 24.8% (OR = 0.76; 95% CI 0.61–0.94; I2 = 33%; p = 0.01). Subgroup analysis showed higher total mortality in the HSD group (23.3% for hypertonic vs. 17.3% for isotonic group; p = 0.01) as well as in the hypertonic saline group (25.9% vs. 23.7%, respectively; p = 0.51; Fig. 4).

Figure 4. Forest plot of overall mortality rate while using hypertonic fluid solutions versus isotonic fluid solutions. The center of each square represents the weighted mean difference for individual trials, and the corresponding horizontal line stands for a 95% confidence interval (CI). The diamonds represent pooled results.

The use of hypertonic fluid was associated with a longer hospital stay than with isotonic fluid solutions (mean difference [MD] = 1.45; 95% CI 0.43–2.46; p = 0.005). Acute respiratory distress syndrome-free survival rate at 28 days was re- ported in 2 studies. The difference between hypersaline and normosaline groups was not statistically significant (OR = 1.10; 95% CI 0.85–1.44; p = 0.46).

The use of hypertonic fluid solutions was associated with higher SBP at hospital admission compared to isotonic fluids (MD = 6.71; 95% CI 1.75–11.67; I2 = 72%; p = 0.008; Suppl. Digital File 1).

Polled analyses illustrated selected laboratory parameters are presented in Supplementary Digital File 1.

Adverse events

Pooled analysis showed no statistically significant incidence of complications between hypertonic vs. isotonic fluids solutions. Detailed analysis of particular types of adverse events is presented in Table 3. The most frequently observed nosocomial infections were pneumonia, urinary tract infection, or bloodstream infection. For noninfectious complications: abdominal compartment syndrome, cerebral infarction, or deep vein thrombosis. A summary of the injuries related and the use of fluid types is presented in Supplementary Digital File 1.

Table 3. Characteristics of adverse events between hypertonic fluid solutions versus isotonic fluid solutions.

Type of adverse event

Number of trials

Total numer of patients

Percentage of adverse event

OR (95%CI)

P value

I2, statistic, %

HSD or HS

NS

Nosocomial inections

Pneumonia

4

1695

9.9%

9.8%

0.95 (0.68–1.31)

0.75

0%

ARDS

1

422

0.0%

0.9%

0.20 (0.01–4.15)

0.30

Blood stream infection

2

1061

7.2%

6.1%

1.18 (0.72–1.93)

0.51

0%

Urinary tract infection

2

1061

6.1%

7.6%

0.79 (0.49–1.28)

0.34

0%

Wound infection

2

1061

5.8%

4.0%

1.50 (0.84–2.67)

0.17

0%

Intra-abdominal abcess

2

631

1.6%

0.3%

3.49 (0.57–21.54)

0.18

11%

Sinustis

1

209

0.9%

0.0%

2.71 (0.11–67.69)

0.54

Pseudomembranous colitis

1

209

1.0%

0.0%

2.73 (0.11–67.69)

0.54

Line infection

1

209

1.0%

0.0%

2.73 (0.11–67.69)

0.54

Sepsis

1

422

0.0%

1.4%

0.14 (0.01–2.74)

0.20

Other

1

311

3.8%

0.0%

8.27 (0.47–144.75)

0.15

One or more nosocomial infections

2

1061

23.0%

21.9%

1.06 (0.79–1.42)

0.70

0%

Noninfectious complications

Acute renal failure

3

780

0.8%

1.6%

0.52 (0.14–1.95)

0.33

0%

Abdominal compartment syndrome

1

209

3.6%

8.1%

0.43 (0.13–1.47)

0.18

Cardiac arrest

2

568

1.0%

1.5%

0.71 (0.17–2.88)

0.63

Myocardial infarction

3

780

1.0%

2.1%

0.52 (0.16–1.67)

0.28

0%

Cerebral infarction

2

421

4.3%

2.8%

1.61 (0.58–4.53)

0.36

0%

Dead bowel

1

359

0.0%

0.6%

0.32 (0.01–7.79)

0.48

Deep vein thrombolysis

1

209

0.9%

7.0%

0.12 (0.01–1.00)

0.05

Pulmonary embolism

2

568

0.3%

1.1%

0.39 (0.06–2.70)

0.34

0%

Coagulopathy

1

359

0.9%

0.0%

2.73 (0.11–67.69)

0.54

ARDS — acute respiratory distress syndrome; CI — confidence interval; HS — hypertonic saline; HSD — hypertonic fluid solutions; NS — isotonic/norotonic fluid solutions; OR — odds ratio

Publication bias

The risk of bias of all the RCTs included in the meta-analysis is shown in Supplementary Digital File 1. Overall, the included RCTs suggested good quality in terms of risk of bias.

Discussion

This systematic review and meta-analysis evaluated data from RCTs of hypertonic fluid solutions (HSD or hypertonic saline) and isotonic fluid solutions (0.9% NaCl or lactated Ringer’s solution) for fluid resuscitation in fluid with traumatic hypovolemic shock, encompassing 15 studies and approximately 3264 adult trauma patients. At primary timepoints assessed (including at 28- to 30-days survival rate or survival to hospital discharge), treatment with hypertonic fluid solutions was associated with a higher rate than treatment with isotonic fluid solutions). However, in the case of 24-survival rate treatment with hypertonic fluid solutions was related to a significantly higher survival rate, as well as significantly lower overall mortality.

0.9% sodium chloride solution is a basic crystalline fluid used in both pre-hospital and hospital care [29]. Due to high chlorine levels in the isotonic salt, there is a potential risk of metabolic hyperchloremic acidosis [30]. An alternative to 0.9% NaCl is Ringer’s lactate, also called Hartman’s solution, where the sodium and calcium concentration corresponds to the plasma concentration of these ions. However, it is important to note that the calcium contained in Ringer’s lactate can bind to and interfere with some drugs. Indeed, Ringer’s lactate is not free of disadvantages. Its main disadvantage is that it binds calcium to citrate anticoagulants in blood products, which can lead to clots in the bloodstream. Due to the above, Ringer’s lactate is contraindicated as a diluent for blood transfusions [31, 32]. Hypertonic solutions, on the other hand, result in a slight improvement in volume and a rapid restoration of hemodynamics. The present analysis looked at hemodynamic parameters, such as SBP, and indicated that the use of hypertonic fluid solutions was associated with a statistically significant higher SBP than that of isotonic solutions (p = 0.008).

According to laboratory studies, hypertonic solutions especially improve the hemodynamics of microcirculation. This is due to the recruitment of intra-tissue volume by these fluids, which increases the volume of circulating blood and at the same time increases blood pressure. According to numerous studies, a 7.5% NaCl solution should be administered at 250 mL or 4 mL/kg body weight [33]. The same volume of hypertonic fluid administered compared to the isotonic solution causes a greater increase in the volume of fluid in the vascular bed, as this difference comes from the intracellular fluid, which penetrates from the cells into the extracellular space. Therefore, the use of hypertonic solutions should be reflected in the treatment of trauma patients as they allow to restore intravascular volume without increasing intravascular space [34]. Moreover, the present results showed no significant differences in adverse events between the treatment of hypertonic fluid solutions compared with isotonic solutions. However, it should be noted that many studies have not reported adverse events, which is a potential source of bias.

Limitations of the study

There are potential limitations in this systematic review and meta-analysis. One limitation is to include only studies on the use of fluid therapy in patients with hypovolemic shock resulting from the injury. However, this was deliberate because it is a specific group of patients who require different treatment from patients with no hypovolemic shock due to the bleeding. The second limitation of the study is the fact that over the last years no randomized study has been published in the scope discussed in the article. With the development of medical technology and the creation of new guidelines of conduct, the authors believe that a multi-center study should be carried out, involving a large number of patients, which would verify the data from previous articles.

Conclusions

This systematic review and meta-analysis, which included only evidence from RCTs hypertonic saline/dextran or hypertonic saline compared with isotonic fluid did not result in superior 28- to 30-day survival as well as in survival to hospital discharge. However, patients with hypotension who received resuscitation with HSD had less overall mortality than patients who received conventional fluid. These findings highlight an urgent need for further research and guidance for physicians regarding when to administer fluid solutions to ensure optimal fluid therapy for the resuscitation of hypovolemic shock caused by acute hemorrhage.

Acknowledgments

The study was supported by the ERC Research Net and by the Polish Society of Disaster Medicine.

Conflict of interest: None declared

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