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Critical Care and Resuscitation

Hypertonic Saline in Human Sepsis: A Systematic Review of Randomized Controlled Trials

Orbegozo, Diego MD; Vincent, Jean-Louis MD, PhD; Creteur, Jacques MD, PhD; Su, Fuhong MD, PhD

Author Information
doi: 10.1213/ANE.0000000000003955

Abstract

Sepsis and septic shock are common causes of hospital admission worldwide and are associated with high costs for society1,2 and considerable related morbidity and mortality.1–6 Sepsis is characterized by increased capillary permeability, which generates loss of protein and liquid into the interstitial space and a decrease in vascular tone. Both lead to a decrease in effective intravascular volume.7–9 Fluid requirements are, therefore, increased during sepsis, but excessive fluid administration can be harmful.10–13

The use of colloids to limit fluid overload while maintaining an adequate intravascular volume is controversial.14,15 Hypertonic saline solutions may represent a cheaper and potentially safer alternative. These fluids can promote a shift of water from the intracellular to the extracellular (interstitial and intravascular) compartment.16 Moreover, they may increase cardiac output,17 modulate the immune response,18 reduce the permeability of the vascular wall,19 reduce the volume of fluids needed to obtain the same hemodynamic targets as with crystalloid solutions,20 and promote the endogenous secretion of vasopressin.21 However, the high chloride content of hypertonic saline may have adverse effects, including acidosis, coagulopathy, and impaired renal function.22–25

Although preparation of hypertonic saline is simple and cheap and the fluid is available worldwide, it is not widely used, and clinical studies are limited. In view of its potential beneficial effects on a background of ongoing debate about optimal fluid choices, we reviewed the clinical experience with hypertonic saline in patients with sepsis by performing a systematic review of randomized controlled trials in which hypertonic saline infusion was compared to any isotonic fluid in patients of all ages with sepsis. We focused our review on the effects on hemodynamic status, electrolyte balance, acid-base status, renal function, coagulation, immune function, microcirculation, intensive care unit length of stay, and mortality.

METHODS

We adhered to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines.26 We searched PubMed and Embase from creation to January 31, 2018, looking for all original articles exploring the role of hypertonic saline solutions in patients with sepsis. The search was performed by a statistician to obtain sensitive queries for each database. MeSH and Emtree (for PubMed and Embase, respectively) were browsed to identify the most relevant and synonymous terms in each database. Selected queries were searched as MeSH and Emtree terms as well as free text within the titles, abstracts, and keywords of each article. The retained query for Embase was: ([“sepsis”/exp OR “sepsis”] OR [“septic shock”/exp OR “septic shock”]) AND ([“hypertonic solution”/exp OR “hypertonic solution”] OR [hypertonic AND {“saline”/exp OR saline}] OR [hypertonic AND {“sodium”/exp OR sodium}]), and for PubMed was (“hypertonic solutions” OR “hypertonic saline” OR “hypertonic sodium”) AND (“sepsis” OR “septic shock”). The search was not limited by date of publication, language, population age, or type of study.

Articles were retained for review if they were randomized controlled trials performed in patients with sepsis who received an infusion of hypertonic saline of any concentration. The included studies must have compared data from a cohort of patients receiving hypertonic saline alone and a cohort receiving an isotonic solution or a cohort receiving hypertonic saline in combination with a colloid if there was also a comparison cohort that received just a colloid. Given the limited data in this field, we included pediatric and adult studies. Two authors (D.O. and F.S.) independently reviewed the search results (initially titles and abstracts and then full texts of remaining articles) to retrieve the studies fulfilling the previous criteria, and any discrepancy was resolved by consensus. Data for any reported outcome were extracted to prespecified tables, but we focused on the following prespecified outcomes: administered volumes of liquids, effects on hemodynamic status, electrolyte concentrations, acid-base status, renal function, coagulation, immune function, microcirculation, intensive care unit length of stay, and mortality. The results were summarized and are presented as a systematic review. Risk of bias for each retrieved study was evaluated using the Cochrane Risk of Bias tool (RoB 2.0 tool).27 For assessment of the overall quality of evidence for each reported outcome, the Grading of Recommendations Assessment, Development, and Evaluation approach was used to create a summary of findings table with the GRADEpro Guideline Development Tool software (McMaster University, Evidence Prime, Inc, Hamilton, ON, Canada).

Exploratory, post hoc meta-analyses (in an attempt to generate hypotheses for future studies) were performed for outcomes reported in ≥6 of the studies, that is, for the amount of fluid administered and for mortality. The estimated effect of each study for these outcomes was calculated with 95% CIs, and the global effect was then assessed using a random effects model to address inherent differences among experimental protocols. Results are presented as forest plots with estimates of heterogeneity. For the amount of fluid administered, the global effect was reported as the standardized mean difference because infused volumes were not reported using the same units across the studies. If reported fluid volumes were assessed at different timepoints in a study, we selected the longest time period in an attempt to evaluate whether the effect was sustained over time. For mortality, the global effect was reported as the odds ratio for survival. Reported time periods for mortality assessment differed considerably among studies, but if >1 time period was reported, we selected the longest to determine whether the effect was sustained over time. Subgroup analyses considering only those studies comparing hypertonic saline with an isotonic crystalloid and only those studies comparing hypertonic saline + hydroxyethyl starch with hydroxyethyl starch alone were performed. Funnel plots, including imputed studies using Duval and Tweedie’s trim-and-fill methodology, were created to assess the risk of publication bias. All analyses were performed using Comprehensive Meta-Analysis V3 software (Englewood, CO).

RESULTS

A total of 483 articles were identified, but only 13 had been performed in patients with sepsis.28–40 Eight of the articles (including 381 patients who had received hypertonic saline) were randomized controlled trials29,30,32–35,39,40 and were retained for further analysis (Supplemental Digital Content, Figure S1, http://links.lww.com/AA/C670). Five articles were published in English and 3 in Chinese. The 5 single-cohort studies28,31,36–38 are shown in Supplemental Digital Content, Table S1, http://links.lww.com/AA/C670.

The study by Li et al30 had 4 cohorts. For our analyses, we compared the hypertonic saline versus normal saline groups separately from the hypertonic saline + hydroxyethyl starch versus hydroxyethyl starch alone groups.30 A study by Van Haren et al34 presented the same cohort of patients as in an article published in 2012 by the same author.35 However, because the presented outcomes were completely different, we kept it for descriptive purposes.

Five randomized controlled trials, 2 of which were in pediatric populations,33,39 compared hypertonic saline with an isotonic crystalloid (Table 1).29,30,33,39,40 Four randomized controlled trials compared hypertonic saline + hydroxyethyl starch with hydroxyethyl starch alone (Table 2).30,32,34,35 In general, the risk of bias was high; the results of each individual domain for each study are shown in Figure 1.

Table 1.
Table 1.:
Summary of Results From Randomized Controlled Trials Comparing Hypertonic Saline With an Isotonic Crystalloid
Table 2.
Table 2.:
Summary of Results From Randomized Controlled Trials Comparing Hypertonic Saline With a Colloid
Figure 1.
Figure 1.:
Estimated risk of bias for each included study.

The tonicity of the infused hypertonic saline solutions varied between 3%33 and 7.5%.32 The administered dose was either given according to body weight, between 432 and 15 mL/kg,33 or as a fixed dose between 250 mL34,35 and 500 mL.30

Effects on Amount of Fluid Administered

Table 3.
Table 3.:
Summary of Quality of the Evidence Using the GRADE Approach
Figure 2.
Figure 2.:
Forest plots of studies reporting administered fluid volumes. HES indicates hydroxyethyl starch; HS, hypertonic saline; NS, normal saline.

Six randomized controlled trials reported data on the amount of fluid administered. Five randomized controlled trials showed a significant decrease in the total volume of fluid administered when a hypertonic saline solution was infused regardless of whether the comparison was between hypertonic saline and isotonic crystalloid30,33,39 or between hypertonic saline + hydroxyethyl starch and hydroxyethyl starch alone.30,32,35 One randomized controlled trial reported no differences in the total volume of fluid administered during the first 72 hours when comparing hypertonic saline with an isotonic crystalloid.40 Meta-analysis of the 6 studies that reported this outcome found a significant reduction in the volume of fluids administered (standardized mean difference, −0.702; 95% CI, −1.066 to −0.337; P < .001; moderate-quality evidence [Table 3]) when hypertonic saline and hypertonic saline + hydroxyethyl starch were compared to an isotonic crystalloid and hydroxyethyl starch (Figure 2). However, there was a moderate degree of heterogeneity in this analysis (I2 = 72%). Subgroup analyses of studies that compared only hypertonic saline with an isotonic crystalloid or only hypertonic saline + hydroxyethyl starch with hydroxyethyl starch alone gave similar results (Supplemental Digital Content, Figure S2, http://links.lww.com/AA/C670). The Funnel plot showed minor publication bias not affecting the estimated global effect on the volume of fluids administered (Supplemental Digital Content, Figure S3, http://links.lww.com/AA/C670).

Hemodynamic Effects

Two randomized controlled trials reported no differences in cardiac filling pressures between hypertonic saline and an isotonic crystalloid or between hypertonic saline + hydroxyethyl starch and hydroxyethyl starch alone.30,35

An increase in arterial pressure during the first hours of resuscitation was reported in 2 randomized controlled trials when hypertonic saline + hydroxyethyl starch was compared with hydroxyethyl starch alone,30,32 but no such differences were reported in 4 other randomized controlled trials.29,33,35,39

Two randomized controlled trials evaluated cardiac function using echocardiography: 1 reported similar increases in cardiac output with hypertonic saline and an isotonic crystalloid,29 and the other reported higher stroke volume and tissue Doppler velocities with hypertonic saline + hydroxyethyl starch than with hydroxyethyl starch alone.35

Three randomized controlled trials reported equivalent vasopressor doses when hypertonic saline was compared with an isotonic crystalloid,30,33,40 and 1 randomized controlled trial reported a higher mean arterial pressure-to-norepinephrine dose ratio with the infusion of hypertonic saline + hydroxyethyl starch compared to hydroxyethyl starch alone.35 One randomized controlled trial reported equivalent cardiovascular sequential organ failure assessment scores during the first 7 days of intensive care unit stay when hypertonic saline was compared with an isotonic crystalloid.40

Electrolytes and Acid-Base Status

Five studies reported data on sodium and chloride levels. Four showed a transient increase in their concentrations,33,35,39,40 and 1 reported no difference 2 hours after the hypertonic saline infusion.29 One randomized controlled trial reported that safety limits (sodium >155 mEq/L or sodium change in 24 hours >12 mEq/L) were reached more frequently (39.3% vs 4.1%; P < .0001) when hypertonic saline was administered compared to an isotonic crystalloid.40 However, in this randomized controlled trial, repeated boluses were allowed during the first 3 days in the intensive care unit, leading to the infusion of a median (p25–p75) volume of 1.4 (0.6–2.0) L of 3% hypertonic saline in the intervention group.

Two studies reported no changes in blood pH after hypertonic saline infusion.29,35

Renal Function and Coagulation

One randomized controlled trial reported a higher urine output in patients receiving hypertonic saline + hydroxyethyl starch than in those receiving just hydroxyethyl starch.32 One randomized controlled trial reported no differences in the renal sequential organ failure assessment score and in the need for renal replacement therapy in patients after receiving hypertonic saline compared to an isotonic crystalloid.40

No study reported any data on coagulation parameters, bleeding, or transfusion.

Immune System

In 1 randomized controlled trial, the hypertonic saline + hydroxyethyl starch cohort had a lower gene expression for matrix metalloproteinase-9 and for l-selectin than the hydroxyethyl starch cohort but no changes in other inflammatory biomarkers (Table 2).34

Microcirculation and Gastric Tonometry

One randomized controlled trial reported no significant differences in the sublingual microcirculation (using side-stream dark field videomicroscopy) or gastric tonometry variables between hypertonic saline + hydroxyethyl starch and hydroxyethyl starch alone cohorts.35

Intensive Care Unit Length of Stay and Mortality

Two randomized controlled trials reported no significant differences in the intensive care unit length of stay between a hypertonic saline and an isotonic crystalloid cohort.33,40

Figure 3.
Figure 3.:
Forest plots of studies reporting mortality. HES indicates hydroxyethyl starch; HS, hypertonic saline; NS, normal saline.

Seven randomized controlled trials reported data on mortality (Tables 1 and 2).29,30,32,33,35,39,40 None of the studies reported a statistically significant difference in mortality rates between groups; however, the majority of studies were underpowered for this outcome. A meta-analysis of the 7 studies showed no differences in mortality rates between hypertonic saline and other fluids (odds ratio, 0.946; 95% CI, 0.688–1.301; P = .733; low-quality evidence; Figure 3). There was no significant heterogeneity in this analysis (I2 = 0%). Subgroup analyses of studies comparing only hypertonic saline with an isotonic crystalloid or only hypertonic saline + hydroxyethyl starch with hydroxyethyl starch alone also showed no significant differences (Supplemental Digital Content, Figure S4, http://links.lww.com/AA/C670). The Funnel plot showed some degree of publication bias but not affecting the estimated global effect on mortality (Supplemental Digital Content, Figure S5, http://links.lww.com/AA/C670).

DISCUSSION

Use of hypertonic saline in the treatment of sepsis and septic shock has been widely investigated in animal models,18–21,41–44 but data in humans remain limited. The majority of studies we identified had small patient cohorts, and relevant outcomes (renal function, coagulation, and other adverse events) were not always reported, limiting their potential conclusions. The main observation from our review is that lower volumes of hypertonic saline than other fluid types are required to obtain the desired hemodynamic goals. As expected, the studies we reviewed observed a transient increase in natremia and chloremia with hypertonic saline but no associated safety issues (notably on hemodynamics or renal function). In the few studies we identified, there were no significant mortality differences between hypertonic saline and other fluids.

About two-thirds of human body water is found in the intracellular compartment.45 When hypertonic saline is infused, it diffuses rapidly into the intravascular and interstitial spaces because electrolytes can freely cross the endothelial barrier. However, at the cellular membrane level, electrolytes are unable to proceed; thus, the tonicity of the extracellular compartment increases and water escapes from the intracellular compartment.45,46 Various animal studies in septic models confirm that less volume is needed to obtain similar hemodynamic goals when using hypertonic saline compared to an isotonic crystalloid,20,42 and human studies in healthy volunteers, which directly measured the blood volume, have shown that hypertonic saline is 4–5 times more efficient than a crystalloid solution in terms of volume expansion.16,47 In our review, we found a clear association between hypertonic saline infusion and reduction in the total volume of fluids needed to achieve the same hemodynamic effect.

Hypertonic saline can have a direct influence on endothelial permeability. Some animal data suggest that hypertonic saline can decrease the transcapillary flow of proteins in hemorrhagic or septic states.19 Evidence suggests that hypertonic saline can decrease sepsis-induced endothelial activation by reducing the expression of different chemotactic and proinflammatory molecules or by modulating the function of different immune cells.18,41,48,49 Ding et al36 suggested some modulation of the inflammatory response with infusion of hypertonic saline, but the lack of a control group limits the interpretation of their findings. Perhaps more relevant is the study by Van Haren et al,34 which showed that hypertonic saline could inhibit the gene expression of matrix metalloproteinase-9 and l-selectin. Importantly, patients with sepsis may have either a predominantly proinflammatory or an anti-inflammatory state, and data on the role of hypertonic saline for different phenotypes of sepsis do not exist.

Different animal studies have also suggested that hypertonic saline can preserve the microcirculation in shock states,50 decreasing the apoptosis and edema of endothelial cells,51 inducing selective arteriolar vasodilatation while improving tissue perfusion46 or interfering with the rheological behavior of red blood cells.52 Only 1 human study has evaluated the effects of hypertonic saline on the sublingual microcirculation, and it reported no significant differences compared to isotonic saline.35 However, the sample size of this study was small, and the patients studied had no significant alterations in capillary density at baseline, making it difficult to show improvement with fluid administration.

The infusion of hypertonic saline generates an important stimulus (via different osmoreceptors) to the posterior pituitary gland, leading to vasopressin secretion.21,53,54 Vasopressin decreases water loss by the kidneys through the V2 receptors and simultaneously increases vascular tone through the V1 receptors.55 The vascular effects of vasopressin may contribute substantially to the hemodynamic effects of hypertonic saline (mainly when shock is present), as suggested by the lack of increase in arterial pressure following a bolus of hypertonic saline after blockade of the V1 receptor in endotoxemic rats.21 In our review, we found no marked change in arterial pressure after a bolus of hypertonic saline, but none of the included randomized controlled trials evaluated a possible role of vasopressin in the obtained responses. It is interesting to note that in recent single-cohort studies in which plasma vasopressin concentrations were measured before and after a bolus of hypertonic saline, an abnormal response was detected in around half of the patients.31,37,38 In these studies, this alteration was evident from 24 hours after the diagnosis of sepsis38 and persisted for ≤5 days after discontinuation of vasopressors.37 In 1 study, patients with impaired osmoregulation had an increased intensive care unit length of stay and mortality.38

The protocols used to infuse hypertonic saline in our included randomized controlled trials, and the doses administered were heterogeneous. For a hypothetical adult patient of 70 kg, the proposed quantity of chloride or sodium to be infused during each bolus of hypertonic saline (that will preferentially remain in the extracellular compartment) would vary between 20929 and 539 mEq.33 This electrolyte load is quite considerable when considering that, for such a subject, the estimated chloride content in the extracellular space is already around 1750 mEq, with only 230 mEq in the intracellular space. While most of the studies used only 1 fluid bolus of hypertonic saline, the large randomized controlled trial by Asfar et al40 exposed the interventional group to repeated boluses of hypertonic saline during the first 3 days in the intensive care unit. Unfortunately, this strategy led to the experimental protocol being stopped in 39% of the patients because the sodium concentration was >155 mEq/L or increased by >12 mEq/L in 24 hours. Any solution is potentially harmful if given in excess or if administered to high-risk populations. Animal and human studies have shown that a bolus of hypertonic saline causes minor alterations in the acid-base status when renal function is normal,56,57 but the presence of hyperchloremia added to renal failure, and the related metabolic acidosis may be problematic.58–60 Nevertheless, administration of hypertonic saline was generally well tolerated in our studies, with a transient increase in the sodium and chloride concentration levels and no major changes in the acid-base balance.

Hypertonic saline was associated with renal vasoconstriction in a canine denervated and auto-transplanted kidney model.22 We recently infused equivalent isosmotic doses of normal or hypertonic saline in an animal model of peritonitis. Renal function did not deteriorate despite the development of hyperchloremia, and survival time was prolonged in animals that received hypertonic saline.61 In their large randomized controlled trial, Asfar et al40 did not report any increase in the rate of renal adverse events or a decrease in kidney function despite administration of large doses of hypertonic saline. Future studies in this field should routinely report effects on renal function.

Hyperchloremic acidosis can also alter the coagulation system. Animal studies suggest that, compared to Ringer’s lactate, normal saline can induce a coagulopathic state.24 A recent meta-analysis in humans (mainly including patients in the operating room) found an increase in the estimated blood loss or the need for red blood cell transfusion in patients who received normal saline, especially in high-risk populations.25 No studies in our analysis reported on coagulation system outcomes, highlighting the need for future trials on the effects of hypertonic saline on coagulation.

The available data in our review show no statistically significant differences in clinically important outcomes, such as mortality, but the studies were generally small and underpowered for this outcome, so an effect on mortality cannot be ruled out. Unfortunately, identifying clinical signals in heterogeneous groups of critically ill patients can be extremely challenging because some patients may benefit from the intervention while others are harmed.62 Studies that have evaluated the role of hypertonic saline in resuscitation from hemorrhagic shock have reported no beneficial effect on survival in the whole population,63–65 although some post hoc analyses have suggested that patients with hypotension may have benefited, and those not needing blood transfusions in the first 24 hours may have been harmed by the hypertonic saline infusion.65–67 Future research is needed to identify and target those patients most likely to benefit from hypertonic saline.

Our study has several limitations. First, the included studies were considerably heterogeneous in design. Although we used a conservative approach in our forest plots by using random effects models and calculated the degree of heterogeneity for each analysis, all the studies had important differences in their protocols (infused solutions, observation periods, studied outcomes, etc). Second, we combined data from adult and pediatric randomized controlled trials in our forest plots, although they represent different populations. Nevertheless, the individual studies all showed similar trends in fluid balance and mortality independent of population age. Finally, in general, the risk of bias in the included studies was high. However, this finding is the result of our extensive literature search (including studies in foreign languages) retrieving several studies that did not clearly describe the methodology. It is also important to recognize that completely blinding the medical staff to the type of fluid in these studies is difficult because close observation of chloride levels will unmask the intervention cohort.

CONCLUSIONS

Hypertonic saline infusion in patients with sepsis is associated with the need for reduced fluid volumes compared to other solutions to achieve the same hemodynamic goals. Hypertonic saline administration seems to be safe. More research is needed to determine whether specific subpopulations of patients with sepsis are more likely to benefit from hypertonic saline administration than others.

DISCLOSURES

Name: Diego Orbegozo, MD.

Contribution: This author helped design the study, helped perform the literature search and extract the data, wrote the first draft of the manuscript, and read and approved the final version.

Name: Jean-Louis Vincent, MD, PhD.

Contribution: This author helped design the study, critically reviewed the manuscript for intellectual content, and read and approved the final version.

Name: Jacques Creteur, MD, PhD.

Contribution: This author helped design the study, critically reviewed the manuscript for intellectual content, and read and approved the final version.

Name: Fuhong Su, MD, PhD.

Contribution: This author helped design the study, helped perform the literature search and extract the data, critically reviewed the manuscript for intellectual content, and read and approved the final version.

This manuscript was handled by: Avery Tung, MD, FCCM.

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