Hypertonic Saline Resuscitation Research Articles

Hypertonic Saline Induces Host Protective Immune Responses against Brucella abortus Infection in Mice.

Hypertonic saline (HTS) resuscitation can enhance immune responses against various pathogens, however, the effect of HTS on brucellosis is yet to be defined. In this study, we found that HTS inhibited Brucella infection in mice by augmenting Th1 immunity. HTS treatment enhanced the serum cytokines production and the expression of nitric oxide synthase (NOS2) and nuclear factor kappa B (NF-ĸB) p50 and p65, crucial anti-Brucella effectors in splenocytes. In addition, HTS treatment also inhibited the phosphorylation of MAPK signaling, accompanied by the down-regulation of the autophagy marker LC3B-II. Due to directing an appropriate immune response, HTS treatment substantially decreased bacterial burden in spleen and liver tissues. In summary, corroborating previous studies showing the antimicrobial effects of HTS, our findings indicate that HTS treatment triggers a protective immune response against Brucella infection. Additionally, these results provide promising evidence of the immunomodulatory role of HTS in controlling bacterial infections.

Effect of 3% Hypertonic Saline Resuscitation on Lactate Clearance and Its Comparison With 0.9% Normal Saline in Traumatic Injury Patients: A Prospective Randomized Control Trial.

Fluid resuscitation with normal saline (NS) can aggravate lactate production. The objective of this study was to evaluate the efficacy of small-volume resuscitation using 3% hypertonic sodium chloride (HS) and its comparison with NS in trauma patients.The primary endpoint was an increase in lactate clearance after 1 hr of fluid resuscitation.The secondary endpoint was the incidence of hemodynamic stability, the volume of transfusion, correction of metabolic acidosis, and complications such as fluid overload and abnormal serum sodium levels. It was a prospective, randomized, single-blind study. The study was conducted on 60patients who arrived at the trauma center for emergency operative intervention. Inclusion criteria for patient selection were trauma victims of age more than 18 years and the requirement of emergency operative intervention for trauma except for traumatic brain injury. Patients were divided into two groups: Group HS (hypertonic saline) and Group NS (normal saline). Patients were resuscitated with either 3% HS (4ml/kg) or 0.9% NS (20ml/kg). The HS group had higher lactate clearance at 1 hour compared to the NS group, and this difference was statistically significant with a p-value of <0.001. When hemodynamic parameters were compared at 30 and 60 minutes after resuscitation, the HS group had a significantly lower heart rate (p<0.05 at 30 minutes and <0.001 at 60 minutes, respectively), a higher mean arterial pressure at 60 minutes (p<0.001), a higher pH at 60 minutes (p< 0.05), and a higher bicarbonate concentration at 60 minutes (p<0.05). The HS and NS groups had significant differences in serum sodium levels at 60 minutes (p<0.001). Resuscitation with 3% hypertonic saline improved lactate clearance. Lower volumes of fluid infusion for resuscitation achieved better hemodynamic stability and correction of metabolic acidosis in the hypertonic saline group. Our study shows that hypertonic saline can be a promising fluid for small-volume resuscitation in trauma patients with compensated mild to moderate shock.

Research progress of hypertonic saline in early resuscitation of acute pancreatitis

Local inflammatory reaction and microcirculation disturbance are the early manifestations of acute pancreatitis (AP). Studies have shown that early and reasonable fluid resuscitation of patients with AP can reduce related complications and prevent the deterioration to severe acute pancreatitis (SAP). Traditional isotonic crystalloid (such as Ringer solution) is considered to be a safe and reliable resuscitation solution, but too much and too fast infusion in the early stage of shock will increase the risk of complications such as tissue edema and abdominal compartment syndrome (ACS). Many scholars have found that hypertonic saline resuscitation solution has the advantages of reducing tissue and organ edema, rapidly restoring hemodynamics, inhibiting oxidative stress and inflammatory signal transduction, thereby improving the prognosis of AP patients and reducing the incidence of SAP and mortality. This article summarizes the mechanisms of hypertonic saline in the resuscitation treatment of AP patients in recent years, in order to provide reference for the clinical application and research of AP patients.

MULTIMODAL TREATMENT APPROACHES TO COMBINED TRAUMATIC BRAIN INJURY AND HEMORRHAGIC SHOCK ALTER POSTINJURY INFLAMMATORY RESPONSE.

Introduction: The optimal management strategies for patients with polytraumatic injuries that include traumatic brain injury (TBI) are not well defined. Specific interventions including tranexamic acid (TXA), propranolol, and hypertonic saline (HTS) have each demonstrated benefits in patient mortality after TBI, but have not been applied to TBI patients with concomitant hemorrhage. The goals of our study were to determine the inflammatory effects of resuscitation strategy using HTS or shed whole blood (WB) and evaluate the cerebral and systemic inflammatory effects of adjunct treatment with TXA and propranolol after combined TBI + hemorrhagic shock. Methods: Mice underwent TBI via weight drop and were subsequently randomized into six experimental groups: three with HTS resuscitation and three with WB resuscitation. Mice were then subjected to controlled hemorrhagic shock for 1 h to a goal MAP of 25 mmHg. Mice were then treated with an i.p. dose of 4 mg/kg propranolol, 100 mg/kg TXA, or normal saline (NS) as a control. Mice were killed at 1, 6, or 24 h for serum and cerebral biomarker evaluation by multiplex ELISA and serum neuron-specific enolase, a biomarker of cerebral cellular injury. Results: Mice resuscitated with HTS had elevated serum proinflammatory cytokines compared with WB resuscitated groups at 6 and 24 h after injury, with no significant difference in cerebral cytokine levels. Within the TBI/shock + HTS groups, the addition of propranolol or TXA did not significantly alter serum cytokine concentration, but cerebral IL-2, IL-12, and macrophage inflammatory protein-1α (MIP-1α) decreased after propranolol administration. In the TBI/shock + WB cohorts, the addition of both propranolol and TXA increased systemic proinflammatory cytokine levels at 6 and 24 h after injury as demonstrated by serum IL-2, IL-12, MIP-1α, and IL-1β compared with NS control. By contrast, TBI/shock + WB mice demonstrated a significant reduction in cerebral IL-2, IL-12, and MIP-1α in propranolol treated mice 6 h after injury compared with NS group. While serum neuron-specific enolase was significantly increased 1 and 24 h after injury in TBI/shock + HTS + TXA cohorts compared with NS control, it was significantly reduced in the TBI/shock + WB + propranolol mice compared with NS control 24 h after injury. Conclusions: Whole blood resuscitation can reduce the acute postinjury neuroinflammatory response after combined TBI/shock compared with HTS. The addition of either propranolol or TXA may modulate the postinjury systemic and cerebral inflammatory response with more improvements noted after propranolol administration. Multimodal treatment with resuscitation and pharmacologic therapy after TBI and hemorrhagic shock may mitigate the inflammatory response to these injuries to improve recovery.

P076 Hypertonic saline resuscitation in acute intraoperative haemorrhage: case series presentation

P076 Hypertonic saline resuscitation in acute intraoperative haemorrhage: case series presentation

The impact of standardized protocol implementation for surgical damage control and temporary abdominal closure after emergent laparotomy.

To standardize care and promote early fascial closure among patients undergoing emergent laparotomy and temporary abdominal closure (TAC), we developed a protocol addressing patient selection, operative technique, resuscitation strategies, and critical care provisions. We hypothesized that primary fascial closure rates would increase following protocol implementation with no difference in complication rates. We performed a retrospective cohort analysis of 138 adult trauma and emergency general surgery patients who underwent emergent laparotomy and TAC, comparing protocol patients (n = 60) to recent historic controls (n = 78) who would have met protocol inclusion criteria. The protocol includes low-volume 3% hypertonic saline resuscitation, judicious wound vacuum fluid replacement, and early relaparotomy with sequential fascial closure. Demographics, baseline characteristics, illness severity, resuscitation course, operative management, and outcomes were compared. The primary outcome was fascial closure. Baseline characteristics, including age, American Society of Anesthesiologists class, and postoperative lactate levels, were similar between groups. Within 48 hours of initial laparotomy and TAC, protocol patients received significantly lower total intravenous fluid resuscitation volumes (9.7 vs. 11.4 L, p = 0.044) and exhibited higher serum osmolarity (303 vs. 293 mOsm/kg, p = 0.001). The interval between abdominal operations was significantly shorter following protocol implementation (28.2 vs. 32.2 hours, p = 0.027). The incidence of primary fascial closure was significantly higher in the protocol group (93% vs. 81%, p = 0.045, number needed to treat = 8.3). Complication rates were similar between groups. Protocol implementation was associated with lower crystalloid resuscitation volumes, a transient hyperosmolar state, shorter intervals between operations, and higher fascial closure rates with no difference in complications. Therapeutic study, level IV.

An implicit discontinuous Galerkin method for modeling acute edema and resuscitation in the small intestine.

Edema, also termed oedema, is a generalized medical condition associated with an abnormal aggregation of fluid in a tissue matrix. In the intestine, excessive edema can lead to serious health complications associated with reduced motility. A $7.5\%$ solution of hypertonic saline (HS) has been hypothesized as an effective means to reduce the effects of edema following surgery or injury. However, detailed clinical edema experiments can be difficult to implement, or costly, in practice. In this manuscript we introduce an implicit in time discontinuous Galerkin method with novel adaptations for modeling edema in the 3D layered physiology of the intestine. The model improves over early work via inclusion of the tissue intrinsic storage coefficient, and the effects of Starling overestimation for high venous pressures. Validation against a recent clinical experiment in HS resuscitation of acute edema is presented; the results support the clinical hypothesis that 7.5% HS solution may be effective in the resuscitation of acute edema formation. New results include an improved view into the effects of resuscitation on the hydrostatic pressure profile of edematous rats, effects on lumenal volume attenuation, relative fluid gain and an estimation of the impacts of both acute edema and resuscitation on intestinal motility.

Divergent Effects of Hypertonic Fluid Resuscitation on Renal Pathophysiological and Structural Parameters in Rat Model of Lower Body Ischemia/Reperfusion-Induced Sterile Inflammation.

The pathogenesis of acute kidney injury (AKI) is characterized by the deterioration of tissue perfusion and oxygenation and enhanced inflammation. The purpose of this study was to investigate whether or not the hemodynamic and inflammatory effects of hypertonic saline (HS) protect the kidney by promoting renal microcirculatory oxygenation and possible deleterious effects of HS due to its high sodium content on renal functional and structural injury following ischemia/reperfusion. Mechanically ventilated and anesthetized rats were randomly divided into four groups (n = 6 per group): a sham-operated control group; a group subjected to renal ischemia for 45 min by supra-aortic occlusion followed by 2 h of reperfusion (I/R); and I/R group treated with a continuous i.v. infusion (5 mL/kg/h) of either % 0.9 NaCl (IR+NS) or %10 NaCl (I/R+HS) after releasing the clamp. Systemic and renal hemodynamic, renal cortical (CμPO2), and medullar microcirculatory pO2 (MμPO2) are measured by the oxygen-dependent quenching of the phosphorescence lifetime technique. Renal functional, inflammatory, and tissues damage parameters were also assessed. HS, but not NS, treatment restored I/R-induced reduced mean arterial pressure, CμPO2, renal oxygen deliver (DO2ren), and consumption (VO2ren). HS caused a decrease in tubular sodium reabsorption (TNa) that correlated with an elevation of fractional sodium excretion (EFNa) and urine output. HS had an anti-inflammatory effect by reducing the levels TNF-α, IL-6, and hyaluronic acid in the renal tissue samples as compared with the I/R and I/R+NS groups (P < 0.05). HS treatment was also associated with mild acidosis and an increased renal tubular damage. Despite HS resuscitation improving the systemic hemodynamics, microcirculatory oxygenation, and renal oxygen consumption as well as inflammation, it should be limited or strictly controlled for long-term use because of provoking widespread renal structural damage.

Hypertonic saline resuscitation protects against kidney injury induced by severe burns in rats

BackgroundProper fluid resuscitation can relieve visceral damage and improve survival in severely burned patients. This study compared the effectiveness of resuscitation with 400mEq/L hypertonic saline (HS) and sodium lactate Ringer’s solution (LR) in rats with kidney injury caused by burn trauma. MethodsRats (Sprague-Dawley) underwent burn injury and were randomized into sham, LR, and HS groups. Samples from the kidney were assayed for water content ratio, histopathology, and oxidative stress (superoxide dismutase (SOD) and malondialdehyde (MDA)). Serum sodium, renal function (creatinine and cystatin (Cys)-C), and inflammatory response (tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and high mobility group protein box (HMGB)-1) were also examined as serum markers. ResultsHypertonic saline resuscitation reduced the renal water content ratio and improved renal histopathology caused by severe burns. This effect was accompanied by reductions in serum creatinine and Cys-C as well as TNF-α, IL-1β, and HMGB1. Serum sodium concentration and SOD activity were increased, whereas MDA content was decreased in the kidney tissue of the HS group. ConclusionsThe data indicate that 400mEq/L HS solution reduces hyponatremia and renal edema, inhibits the release of inflammatory mediators, and alleviates oxidative stress injury, thus protecting against kidney injury induced by severe burns.

Hypertonic saline resuscitation after emergent laparotomy and temporary abdominal closure.

Our objective was to establish the safety of 3% hypertonic saline (HTS) resuscitation for trauma and acute care surgery patients undergoing emergent laparotomy and temporary abdominal closure (TAC) with the hypothesis that HTS administration would be associated with hyperosmolar hypercholoremic acidosis, lower resuscitation volumes, and higher fascial closure rates, without adversely affecting renal function. We performed a retrospective cohort analysis of 189 trauma and acute care surgery patients who underwent emergent laparotomy and TAC, comparing patients with normal baseline renal function who received 3% HTS at 30 mL/h (n = 36) to patients with standard resuscitation (n = 153) by baseline characteristics, resuscitation parameters, and outcomes including primary fascial closure and Kidney Disease: Improving Global Outcomes stages of acute kidney injury. The HTS and standard resuscitation groups had similar baseline illness severity and organ dysfunction, though HTS patients had lower serum creatinine at initial laparotomy (1.2 mg/dL vs. 1.4 mg/dL; p = 0.078). Forty-eight hours after TAC, HTS patients had significantly higher serum sodium (145.8 mEq/L vs. 142.2 mEq/L, p < 0.001), chloride (111.8 mEq/L vs. 106.6 mEq/L, p < 0.001), and osmolarity (305.8 mOsm/kg vs. 299.4 mOsm/kg; p = 0.006), and significantly lower arterial pH (7.34 vs. 7.38; p = 0.011). The HTS patients had lower intravenous fluid (IVF) volumes within 48 hours of TAC (8.5 L vs. 11.8 L; p = 0.004). Serum creatinine, urine output, and kidney injury were similar between groups. Fascial closure was achieved for 92% of all HTS patients and 77% of all standard resuscitation patients (p = 0.063). Considering all 189 patients, higher IVF resuscitation volumes within 48 hours of TAC were associated with decreased odds of fascial closure (odds ratio, 0.90; 95% confidence interval, 0.83-0.97; p = 0.003). Hypertonic saline resuscitation was associated with the development of a hypernatremic, hyperchloremic, hyperosmolar acidosis, and lower total IVF resuscitation volumes, without adversely affecting renal function. These findings may not be generalizable to patients with baseline renal dysfunction and susceptibility to hyperchloremic acidosis-induced kidney injury. Prognostic study, level II.

200 mM hypertonic saline resuscitation attenuates intestinal injury and inhibits p38 signaling in rats after severe burn trauma

BackgroundAn overabundant discharge of inflammatory mediators plays a significant role in intestinal injury throughout the early stages of critical burns. The present study aims to explore the outcome of 200mM hypertonic saline (HS) resuscitation on the intestinal injury of critically burned rats. Materials and methodsFifty-six Sprague-Dawley rats were randomized into three groups: sham group (group A), burn plus lactated Ringer’s group (group B), and burn plus 200mM HS group (group C). Samples from the intestine were isolated and assayed for wet-weight-to-dry-weight (W/D) ratio, histopathology analyses, and p38 mitogen-activated protein kinase (MAPK) activity. Serum interleukin 1β (IL-1β) and high mobility group protein box 1 (HMGB1) concentrations were also examined. ResultsInitial resuscitation with 200mM Na+ HS significantly decreased the intestinal W/D ratio and improved intestinal histopathology caused by severe burn. HS resuscitation also inhibited the increase of serum IL-1β and HMGB1 concentrations, and p38 MAPK activity in the intestine of critically burned rats. ConclusionsThe overall findings of this study suggest that preliminary resuscitation with 200mM HS after severe thermal injury reduces intestinal edema, inhibits systemic inflammatory response, and attenuates intestinal p38 MAPK activation, thus reduces burns-induced intestinal injury.

Effects of hypertonic sodium saline resuscitation on the liver damage of rats at early stage of severe scald

Objective: To explore the effects of hypertonic sodium saline (HSS) resuscitation on the liver damage of rats at early stage of severe scald. Methods: Fifty-six SD rats were divided into sham injury group (SI, n=8), lactated Ringer's solution group (LRS, n=24), and group HSS (n=24) according to the random number table. Rats in group SI were sham injured without resuscitation, while rats in the other two groups were reproduced deep partial-thickness to full-thickness scald model with 30% total body surface area on the back. Rats in group LRS were resuscitated with LRS, while rats in group HSS were resuscitated with 300 mmol/L sodium ion solution according to the Parkland formula. Blood of abdominal aorta and liver of 8 rats in group SI immediately post injury and in the other two groups at post injury hour (PIH) 2, 8, and 24 respectively were collected. Then liver water content was determined by dry-wet weight method. Serum content of alanine aminotransferase (ALT) and aspartate transaminase (AST) was detected by automatic biochemical analyzer. Serum content of tumor necrosis factor α (TNF-α), interleukin-1 (IL-1), and high mobility group box 1 (HMGB1) was determined by enzyme-linked immunosorbent assay. Liver content of malondialdehyde (MDA) and superoxide dismutase (SOD) was detected by ultraviolet spectrophotometer. Pathologic changes of liver were observed by HE staining. Data were processed with one-way analysis of variance and SNK test. Results: (1) At PIH 2, 8, and 24, liver water content of rats in group LRS was higher than that in group SI and group HSS (P<0.05 or P<0.01). (2) At PIH 2, serum ALT content of rats in the three groups was similar (with P values above 0.05). At PIH 8 and 24, serum ALT content of rats in group HSS and group LRS was higher than that in group SI (P<0.05 or P<0.01), and serum ALT content of rats in group HSS was lower than that in group LRS (with P values below 0.01). At PIH 2, 8, and 24, serum AST content of rats in group HSS and group LRS was higher than that in group SI (with P values below 0.01). At PIH 2 and 8, serum AST content of rats in group HSS was lower than that in group LRS (P<0.05 or P<0.01). (3) At PIH 2 and 8, serum TNF-α content of rats in group LRS was (123±39) and (153±38) pg/mL respectively, higher than that in group SI [(60±18) pg/mL] and group HSS [(85±10) and (94±16) pg/mL respectively, with P values below 0.01]. At PIH 8, serum TNF-α content of rats in group HSS was higher than that in group SI (P<0.05). At PIH 24, serum TNF-α content of rats in the three groups was similar (with P values above 0.05). At PIH 2, 8, and 24, serum IL-1 content of rats in group LRS was (122±35), (141±30), and (122±31) pg/mL respectively, and that in group HSS was (80±12), (93±15), and (80±11) pg/mL respectively, all higher than that in group SI [(40±17) pg/mL, with P values below 0.01]; serum IL-1 content of rats in group HSS was lower than that in group LRS (with P values below 0.01). At PIH 2, serum HMGB1 content of rats in the three groups was similar (with P values above 0.05). At PIH 8 and 24, serum HMGB1 content of rats in group LRS was (0.386±0.146) and (0.590±0.188) ng/mL respectively, higher than that in group SI [(0.050±0.027) ng/mL] and group HSS [(0.143±0.038) and (0.309±0.095) ng/mL respectively, with P values below 0.01]. At PIH 24, serum HMGB1 content of rats in group HSS was higher than that in group SI (P<0.01). (4) At PIH 2, 8, and 24, liver MDA content of rats in group HSS and group LRS was higher than that in group SI and their liver SOD content was lower than that in group SI (with P values below 0.01); liver MDA content of rats in group HSS was lower than that in group LRS and their liver SOD content was higher than that in group LRS (with P values below 0.01). (5) Compared with those of rats in group SI, liver cells of rats in group LRS showed massive steatosis at each time point, and liver cell-edema appeared at PIH 8 and 24; while liver cells of rats in group HSS showed little steatosis only at PIH 8 and 24, and the liver cell-edema never appeared. Conclusions: Compared with LRS, HSS resuscitation can alleviate liver injury of rats at the early stage of severe scald through relieving inflammatory mediators and reducing degree of oxidative stress, etc.

Distribution and differentiation of myeloid-derived suppressor cells after fluid resuscitation in mice with hemorrhagic shock.

To investigate the distribution and differentiation of myeloid-derived suppressor cells (MDSCs) in hemorrhagic shock mice, which are resuscitated with normal saline (NS), hypertonic saline (HTS), and hydroxyethyl starch (HES). BALB/c mice were randomly divided into control, NS, HTS, and HES resuscitation groups. Three subgroups (n=8) in each resuscitation group were marked as 2, 24, and 72 h. Flow cytometry was used to detect the MDSCs, monocytic MDSCs (M-MDSCs), and granulocytic/neutrophilic MDSCs (G-MDSCs) in peripheral blood nucleated cells (PBNCs), spleen single-cell suspension, and bone marrow nucleated cells (BMNCs). The MDSCs in BMNCs among three resuscitation groups were lower 2 h after shock, in PBNCs of the HTS group were higher, and in spleen of the NS group were lower (all P<0.05 vs. control). The M-MDSC/G-MDSC ratios in PBNCs of the HTS and HES groups were lower (both P<0.05 vs. control). At 24 h, the MDSCs in PBNCs of the NS and HTS groups were higher, while the spleen MDSCs in the HTS group were higher (all P<0.05 vs. control). The M-MDSC/G-MDSC ratios were all less in PBNCs, spleen, and BMNCs of the NS and HTS groups, and were lower in BMNCs of the HES group (all P<0.05 vs. control). At 72 h, the elevated MDSCs in PBNCs were presented in the HTS and HES groups, and in spleen the augment turned up in three resuscitation groups (all P<0.05 vs. control). The inclined ratios to M-MDSC were exhibited in spleen of the NS and HTS groups, and in PBNCs of the NS group; the inclination to G-MDSC in BMNCs was shown in the HES group (all P<0.05 vs. control). HTS induces the earlier elevation of MDSCs in peripheral blood and spleen, and influences its distribution and differentiation, while HES has a less effect on the distribution but a stronger impact on the differentiation of MDSCs, especially in bone marrow.

Immunomodulatory effect of hypertonic saline in hemorrhagic shock

Multiple organ dysfunction syndrome (MODS) and nosocomial infection following trauma-hemorrhage are among the most important causes of mortality in hemorrhagic shock patients. Dysregulation of the immune system plays a central role in MODS and a fluid having an immunomodulatory effect could be advantageous in hemorrhagic shock resuscitation. Hypertonic saline (HS) is widely used as a resuscitation fluid in trauma-hemorrhagic patients. Besides having beneficial effects on the hemodynamic parameters, HS has modulatory effects on various functions of immune cells such as degranulation, adhesion molecules and cytokines expression, as well as reactive oxygen species production. This article reviews clinical evidence for decreased organ failure and mortality in hemorrhagic shock patients resuscitated with HS. Despite promising results in animal models, results from pre-hospital and emergency department administration in human studies did not show improvement in survival, organ failure, or a reduction in nosocomial infection by HS resuscitation. Further post hoc analysis showed some benefit from HS resuscitation for severely-injured patients, those who received more than ten units of blood by transfusion, patients who underwent surgery, and victims of traumatic brain injury. Several reasons are suggested to explain the differences between clinical and animal models.

Inhibition of Neutrophils by Hypertonic Saline Involves Pannexin-1, CD39, CD73, and Other Ectonucleotidases

Hypertonic saline (HS) resuscitation has been studied as a possible strategy to reduce polymorphonuclear neutrophil (PMN) activation and tissue damage in trauma patients. Hypertonic saline blocks PMNs by adenosine triphosphate (ATP) release and stimulation of A2a adenosine receptors. Here, we studied the underlying mechanisms in search of possible reasons for the inconsistent results of recent clinical trials with HS resuscitation. Purified human PMNs or PMNs in whole blood were treated with HS to simulate hypertonicity levels found after HS resuscitation (40 mmol/L beyond isotonic levels). Adenosine triphosphate release was measured with a luciferase assay. Polymorphonuclear neutrophil activation was assessed by measuring oxidative burst. The pannexin-1 (panx1) inhibitor panx1 and the gap junction inhibitor carbenoxolone (CBX) blocked ATP release from PMNs in purified and whole blood preparations, indicating that HS releases ATP via panx1 and gap junction channels. Hypertonic saline blocked N-formyl-Met-Leu-Phe-induced PMN activation by 40% in purified PMN preparations and by 60% in whole blood. These inhibitory effects were abolished by panx1 but only partially reduced by CBX, which indicates that panx1 has a central role in the immunomodulatory effects of HS. Inhibition of the ectonucleotidases CD39 and CD73 abolished the suppressive effect of HS on purified PMN cultures but only partially reduced the effect of HS in whole blood. These findings suggest redundant mechanisms in whole blood that may strengthen the immunomodulatory effect of HS in vivo. We conclude that HS resuscitation exerts anti-inflammatory effects that involve panx1, CD39, CD73, and other ectonucleotidases, which produce the adenosine that blocks PMNs by stimulating their A2a receptors. Our findings shed new light on the immunomodulatory mechanisms of HS and suggest possible new strategies to improve the clinical efficacy of hypertonic resuscitation.

Cardiovascular effects of shock and trauma in experimental models. A review

Experimental models of human pathology are useful guides to new approaches towards improving clinical and surgical treatments. A systematic search through PubMed using the syntax (shock) AND (trauma) AND (animal model) AND (cardiovascular) AND ("2010/01/01"[PDat]: "2015/12/31"[PDat]) found 88 articles, which were reduced by manual inspection to 43 entries. These were divided into themes and each theme is subsequently narrated and discussed conjointly. Taken together, these articles indicate that valuable information has been developed over the past 5 years concerning endothelial stability, mesenteric lymph, vascular reactivity, traumatic injuries, burn and sepsis. A surviving interest in hypertonic saline resuscitation still exists.

Prehospital Hypertonic Saline Resuscitation Attenuates the Activation and Promotes Apoptosis of Neutrophils in Patients With Severe Traumatic Brain Injury

Activation of polymorphonuclear neutrophils (PMNs) is thought to contribute to traumatic brain injury (TBI). Since hypertonic fluids can inhibit PMN activation, we studied whether hypertonic fluid resuscitation can reduce excessive PMN activation in TBI patients. Trauma patients with severe TBI were resuscitated with 250 mL of either 7.5% hypertonic saline (HS; n = 22), HS + 6% dextran-70 (HSD; n = 22), or 0.9% normal saline (NS; n = 39), and blood samples were collected on hospital admission and 12 and 24 h after resuscitation. Polymorphonuclear neutrophil activation (CD11b, CD62L, CD64) and degranulation (CD63, CD66b, CD35) markers and oxidative-burst activity, as well as spontaneous PMN apoptosis were measured by flow cytometry. Relative to healthy controls, TBI patients showed increased PMN activation and decreased apoptosis of PMNs. In the HS group, but not in the HSD group, markers of PMN adhesion (CD11b, CD64) and degranulation (CD35, CD66b) were significantly lower than those in the NS group. These effects were particularly pronounced 12 h after resuscitation. Treatment with HS and HSD inhibited PMN oxidative burst responses compared with NS-treated patients. Hypertonic saline alone partially restored delayed PMN apoptosis. Despite these differences, the groups did not differ in clinical outcome parameters such as mortality and Extended Glasgow Outcome Scale. This study demonstrates that prehospital resuscitation with HS can partially restore normal PMN activity and the apoptotic behavior of PMNs, whereas resuscitation with HSD was largely ineffective. Although the results are intriguing, additional research will be required to translate these effects of HS into treatment strategies that improve clinical outcome in TBI patients.

Effect of 200 mEq/L Na+ hypertonic saline resuscitation on systemic inflammatory response and oxidative stress in severely burned rats

BackgroundExcessive release of inflammatory mediators and oxidative stress play important roles in the increased vascular permeability and systemic edema during the early stage of severe burn. This study investigates the effect of 200 mEq/L Na+ hypertonic saline (HS) on systemic inflammatory response and oxidative stress in severely burned rats. Materials and methodsSprague-Dawley rats were divided into three groups: sham group, burn plus lactated Ringer's group, and burn plus HS group. Lung edema was assessed in terms of wet-weight-to-dry-weight ratio. Tumor necrosis factor α and interleukin 6 concentrations in serum were examined by enzyme-linked immunosorbent assay. Peripheral blood mononuclear cells were isolated and the expression of p38 mitogen-activated protein kinase was determined by Western blot analysis. The lung and intestinal concentrations of malondialdehyde, an indicator of oxidative stress, were also measured. ResultsResuscitation with 200 mEq/L Na+ HS significantly decreased the lung wet-weight-to-dry-weight ratio and abolished hyponatremia induced by burn injury. HS treatment also prevented the increases of myeloperoxidase activity and malondialdehyde content in the lung and intestine of severely burned rats. However, there were no significant differences, either in serum tumor necrosis factor α and interleukin 6 concentrations or with respect to the p38 mitogen-activated protein kinase expression in peripheral blood mononuclear cells, between the burn plus lactated Ringer's group and burn plus HS group (P > 0.05). ConclusionsInitial resuscitation with 200 mEq/L Na+ HS after severe burn injury decreases pulmonary edema, prevents hyponatremia, and attenuates oxidative stress, but is not capable of inhibiting the systemic inflammatory response.

ROC trials update on prehospital hypertonic saline resuscitation in the aftermath of the US-Canadian trials

The objectives of this review are to assess the current state of hypertonic saline as a prehospital resuscitation fluid in hypotensive trauma patients, particularly after the 3 major Resuscitation Outcomes Consortium trauma trials in the US and Canada were halted due to futility. Hemorrhage and traumatic brain injury are the leading causes of death in both military and civilian populations. Prehospital fluid resuscitation remains controversial in civilian trauma, but small-volume resuscitation with hypertonic fluids is of utility in military scenarios with prolonged or delayed evacuation times. A large body of pre-clinical and clinical literature has accumulated over the past 30 years on the hemodynamic and, most recently, the anti-inflammatory properties of hypertonic saline, alone or with dextran-70. This review assesses the current state of hypertonic fluid resuscitation in the aftermath of the failed Resuscitation Outcomes Consortium trials.

Hypertonic saline resuscitation contributes to early accumulation of circulating myeloid-derived suppressor cells in a rat model of hemorrhagic shock

Background Hemorrhagic shock is usually associated with complicated immune and inflammatory responses, which are sometimes crucial for the prognosis. As regulators of the immune and inflammatory system; proliferation, migration, distribution and activation of myeloid-derived suppressor cells (MDSCs) are intimately linked to the inflammation cascade. Methods In a model of severe hemorrhagic shock, thirty-five rats were randomly divided into control, sham, normal saline resuscitation (NS), hypertonic saline resuscitation (HTS), and hydroxyethyl starch resuscitation (HES), with seven in each group. MDSCs were analyzed by flow cytometric staining of CD11b/c+Gra+ in peripheral blood mononuclear cells (PBMC), spleen cell suspensions, and bone marrow nucleated cells (BMNC). Simultaneously, the expressions of arginase-1 (ARG-1) and inducible nitric oxide synthase (iNOS) mRNA in MDSCs were evaluated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). Results In the early stage after hemorrhagic shock, fluid resuscitation and emergency treatment, the MDSCs in the PBMC of NS, HTS and HES groups markedly increased, and MDSCs in BMNC of these groups decreased accordingly, significantly different to the control group. In hemorrhagic shock rats infused with HTS at the early resuscitation stage, MDSCs in PBMC increased about 2 and 4 folds, and MDSCs in BMNC decreased about 1.3 and 1.6 folds, as compared to the sham group respectively, with statistically significant difference. Furthermore, compared to the NS and HES groups, the MDSCs in PBMC of HTS group increased 1.6 and 1.8 folds with statistically significant differences; the MDSCs decrease in BMNC was not significant. However, there was no statistically significant difference in MDSCs of spleen among the five groups. In addition, compared to the control, sham, NS and HES groups, the ARG-1 and iNOS mRNA of MDSCs in PBMC, spleen and BMNC in the HTS group had the highest level of expression, but no statistically significant differences were noted. Conclusions In this model of rat with severe and controlled hemorrhagic shock, small volume resuscitation with HTS contributes to dramatically early migration and redistribution of MDSCs from bone marrow to peripheral circulation, compared to resuscitation with NS or HES.