Manuscript_HSL in Hemorrhagic Shock_250711

8/3/2019 Manuscript_HSL in Hemorrhagic Shock_250711

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Mini-Abstract

This prospective randomized controlled open-labeled study compared the efficacy and safety

between a patented hyperosmolar sodium lactate (HSL) with Ringer’s Lactate (RL) in

resuscitating hemorrhagic shock patients. HSL infusion was found to be effective for acute

resuscitation in hemorrhagic shock and could improve metabolic acidosis better than RL.

Abstract

Objective: To compare the efficacy and safety between a patented hyperosmolar sodium lactate

solution (HSL) with Ringer’s Lactate (RL) in resuscitating hemorrhagic shock patients.

Background: Effective and appropriate fluid resuscitation is crucial for life saving in

hemorrhagic shock. Promising effect of hyperosmolar solution as resuscitation fluid regimen in

hypovolemic patients has been reported; however, no study evaluated the effect of hyperosmolar

sodium lactate in this setting.

Methods: This prospective randomized controlled open-labeled study was performed in 71

grade III hemorrhagic shock patients. HSL or RL was administered on top standard fluid

resuscitation (up to 2 L isotonic crystalloid) at similar dose, loading infusion 5 mL/kgBW over

15 minutes followed by maintenance infusion of 2 mL/kgBW for the first 6 hours.

Results: Fifty three patients (24 in HSL group and 29 in RL group) were analyzed. The

evolutions of heart rate, blood pressure and mean arterial pressure were comparable between

both groups. Although the cumulative fluid intake was comparable between groups, the

cumulative urine output was significantly higher in HSL group than in RL group (p=0.0423).

Arterial blood gas analysis showed complete reversed metabolic acidosis in HSL group (pH:

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7.43; BE: 0.79), and partially compensated metabolic acidosis in RL group (pH: 7.37; BE:

-5.63). No side effect related to study treatment was observed.

Conclusion: Hyperosmolar sodium lactate infusion was effective for acute resuscitation in

hemorrhagic shock and improved metabolic acidosis better than RL.

Key words: hyperosmolar sodium lactate, hemorrhagic shock, acidosis

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INTRODUCTION

Reduction of intravascular volume due to blood loss and might be secondary capillary leakage is

frequently occurred in patients with trauma. Severe intravascular volume deficits after trauma

lead to the decrease of delivery oxygen and nutrients that necessary for normal tissue and cellular

function. Inadequate and inappropriate management of hemorrhagic shock may result in the

development of post-trauma multiple organ failure which increased the morbidity and mortality

of the patients.1-2 Effective hemorrhage control and adequate intravenous fluid administration to

restore intravascular volume and maintain the tissue perfusion is crucial for life saving.3-7

Concept of early aggressive large-volume resuscitation by administration of isotonic crystalloids

has been widely accepted and practiced for the treatment of trauma patients.8 However,

aggressive fluid resuscitation can lead to fluid overload and tissue edema, which in turn could

result in hemodynamic decompensates and increased mortality.9-11 Therefore, a novel

resuscitation strategy that overcomes those issues in the near future is still required.

Hyperosmolar solutions of various concentrations (1.8%–7.5%) have been investigated as

resuscitation solutions in hemorrhagic shock with promising results. It was demonstrated that

hypertonic saline is able to restore hemodynamics, improve microvascular flow with small

volume infusion, hence it can minimize prevent tissue edema and organ damage.12-23 The

beneficial effect of hypertonic saline has been shown related to its hypertonicity.18,24,25

Small volume administration of a scientifically formulated and patent protected hyperosmolar

sodium lactate solution (HSL), containing a physiological concentration of potassium chloride

and calcium chloride, has been shown to improve cardiac output, oxygen delivery, and urine

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output, attenuate metabolic acidosis, and maintain stable hemodynamics better than isotonic

crystalloid during volume deficits in post-cardiac surgery patients.26,27 However, there is no

clinical study investigating the efficacy of hyperosmolar sodium lactate infusion in hemorrhagic

shock. High lactate content in this solution might offer more benefit for patients as lactate has

been known to act as energy substrate in mitochondrion containing cells and can be easily

metabolized in hypoxia condition.28,29 In addition, hypertonicity related effects of HSL solution

may offer volume efficiency of fluid infusion in hemorrhagic shock patients. Therefore, this

study is aimed to evaluate the efficacy and safety of the HSL as resuscitative fluid regimen in

traumatic hemorrhagic shock patients.

METHODS

Study Design

This was a prospective, randomized, controlled, open-labeled trial to compare the efficacy and

safety of a scientifically formulated and patent protected hyperosmolar sodium lactate solution

(Totilac®), manufactured by Finusolprima Farma Indonesia for Innogene Kalbiotech Pte.Ltd, for

resuscitating the patients with grade III hemorrhagic shock due to multiple injuries in

comparison to commercially available Ringer Lactate solution (RL-Otsu). The composition of

both solutions is detailed in Table 1. This study was conducted from July 2009 to January 2011

in Hasan Sadikin Hospital, Bandung, Indonesia. Prior to the study, a written approval for the

protocol has been obtained from the Ethics Committee of the Hasan Sadikin Hospital, Bandung,

Indonesia.

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Study Participants

Screening and enrolment of eligible patients were done in the Emergency Unit. The inclusion

criteria for this trial were male or female patients aged 18-65 years with grade III hemorrhagic

shock due to multiple injuries and had survival probability >50% as predicted by Revised

Trauma Score (RTS) ≥4 (scale 0-7.8408), which was calculated with this formula: RTS = 0.9368

GCS (Glasgow Coma Scale) + 0.7326 SBP (Systolic Blood Pressure) + 0.2908 RR (Respiratory

Rate). Grade III hemorrhagic shock was defined when patient fulfilled at least two of these

following criteria: 1.5-2 L blood loss estimation, mean arterial pressure (MAP) <65 mmHg,

pulse pressure <20 mmHg, heart rate >120 times/min, respiratory rate 30-40 times/min or urinary

output 5-15 ml/hour. The exclusion criteria were coagulopathy, pregnancy, patients with burn

area >20%, Glasgow Coma Score ≤ 13, patients with cancer, chronic renal failure, liver failure,

decompensate heart failure, AIDS (CD4 <200/uL) or HIV serology positive with Highly-Active

Anti-Retroviral Therapy (HAART). Signed informed consent was obtained from all eligible

patients or the next of kin if the patient was not comprehend or unable to accept and sign

informed consent.

Randomization and Study Protocol

Eligible patients were randomly assigned by fixed block size of 6 into one of the two groups in a

1:1 ratio, either Ringer’s Lactate (RL) group or hyperosmolar sodium lactate (HSL) group. For

initial resuscitation during shock, HSL or RL was administered at similar dose, i.e. loading of 5

mL/kgBW/15 minutes followed by maintenance dose of 2 mL/kgBW/hour for the first 6 hours

after shock condition recovered (MAP ≥65 mmHg and UOP ≥0.5 ml/kgBW/hour). During initial

resuscitation, HSL or control drug was administered concurrently to standard resuscitation fluid

5



(0-2 L RL over 15 minutes, depend on the volume of fluid received by patients before admission

to the scene). Two infusion lines in each patient were installed during the study, one line was for

infusion of 0-2 L RL (as standard procedure of fluid resuscitation) and another line was for either

HSL or RL solution.

Statistical Analysis

The sample size of approximately 60 subjects (30 subjects in each group) was calculated based

on 80% power to detect a significant difference between treatment with HSL and RL at a 5%

significance level. Assessment of comparability between HSL group and RL group was done by

unpaired student t-test and Chi-Square test (for categorical data). Comparison of each parameter

at time point of measurement in each group was done by using ANOVA.

RESULTS

Patient Characteristics

Seventy one patients (36 patients in HSL group and 35 patients in RL group) were enrolled from

July 2009 to January 2011. Fifty three patients (24 in HSL group and 29 in RL group) were

included for efficacy and safety analysis, whereas 18 patients were excluded with these

following reasons: not receiving proper dose of study drugs (5 patients), developing grade IV

hemorrhagic shock (9 patients), having protocol violation (1 patient), and having incomplete data

(3 patients). Demographic and baseline data of both groups was depicted in Table 2.

Evolution of Hemodynamic Status

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Hemodynamics monitoring was recorded at baseline, then after the first bolus (H.25), 30 minutes

(H.5), 1 hour (H1), 2 hours (H2), 3 hours (H3) of study drug infusion. The increase of MAP and

the decrease of heart rate and respiration rate over time was statistically significant in both groups

(p<0.0001). Mean arterial pressure, heart rate (Fig. 1A, 1B), respiration rate, body temperature,

Glasgow Coma Scale, and Revised Trauma Score (not shown) exhibited a similar evolution at the

measurement times and no significant difference was noted between the two groups

Fluid Balance

During initial resuscitation and maintenance phase, it was allowed to administer additional fluid

infusion in case of recurrent shock. Cumulative fluid infusion was comparable between HSL and

RL group (p=0.4215) (Fig. 1C). Despite of similar cumulative fluid infusion in both groups,

cumulative urine output at the end of observation (H3) was significantly higher in HSL group

than that in RL group (p=0.0423) (Figure 1D). In this study, blood loss was not measured. The

fluid balance was calculated by subtracting urine output from the total fluid infused. Cumulative

fluid balance was comparable between HSL and RL group (p=0.5987).

Biological Parameters

Serum electrolytes, blood lactate, blood gas of each patient were evaluated and recorded at five

time points including baseline (H0), and 15 minutes (H.25), 1 hour (H1), 2 hours (H2), 3 hours

(H3) after study drugs administration, while hemoglobin, hematocrite, platelet count were

measured at baseline (H0) and 3 hours after study drugs administration (H3).

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Serum sodium level significantly increased in HSL group whereas in RL group the sodium level

decreased (p<0.0001), although the levels in both groups were still in normal range. Serum

potassium level was almost unchanged in HSL group, and slightly increased at H3 in RL group

(p=0.0070). Serum chloride level decreased in HSL group and almost unchanged in RL group

(p=0.0018). Blood lactate obviously increased after loading infusion and then decreased steadily

close to baseline level during maintenance in HSL group, whereas in RL group it decreased

continuously over time and the difference between both groups was significant (p<0.0001)

(Table 3). Blood pH was almost unchanged in RL group, whereas it significantly increased in

HSL group (p=0.0104) (Fig. 2A) but it was still in normal range. The evolution of pCO2 and pO2

was comparable between HSL and RL group (data not shown). HCO 3 level in HSL group

increased and reached normal level, whereas in RL group it was almost unchanged from baseline

(p=0.0009) (Fig. 2B). Base excess continuously improved in HSL group and reached zero level

at H2 and then increased to slightly positive (0.79), whereas in RL group it almost unchanged (-

5.63) (p=0.0002) (Fig. 2C). Oxygen saturation (SaO2) did not change and was comparable

between both groups (data not shown). Hemoglobin, hematocrite, and platelet count decreased in

both groups and the changes of hemoglobin level was comparable between HSL and RL group.

(p>0.05) (Table 3).

Safety

Fisher exact test showed that mortality, morbidity rates, and length of hospitalization were

comparable between HSL and RL group. No complication and mortality occurred in both groups

during the study were related to the study drugs.

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DISCUSSION

This study is the first study evaluating the potential benefit of a solution containing hyperosmolar

sodium lactate for resuscitating patients with hemorrhagic shock in comparison to Ringer’s

Lactate solution. Control regimen (RL) and treatment procedure in this study was designed as

close as the standard fluid management in hemorrhagic shock patients. Therefore, loading dose

of study drugs was given concurrently with standard resuscitation fluid, i.e. up to 2 L RL, based

on fluid volume received prior to the trial.

We found here that HSL infusion had a comparable effect with RL on restoring and maintaining

hemodynamic status in hemorrhagic shock patients. In this study it was allowed to give

additional fluid in any recurrent shock until the MAP restored to ≥65mmHg, the value ensuring a

sufficient organ perfusion.30 Although HSL is a hyperosmolar solution and is aimed for small

volume fluid resuscitation, in this study, the cumulative fluid intake in Totilac group did not

differ significantly with that in RL group. This may be caused by the 2-liters of standard solution

which was infused concurrently with the study drugs infusion. The infusion of 2 L standard

solution has also a role in filling the intravascular volume. However, despite the comparable

cumulative fluid intake, the cumulative urine output in HSL group was significantly higher than

that in RL group without any diuretics. This was an expected finding due to the hypertonicity of

HSL solution.

Hemorrhagic shock is defined as an inadequate tissue perfussion and oxygenation secondary to

blood loss and associated with tissue acidosis and oxygen debt.31-33 Therefore, fluid resuscitation

is aimed to restore not only macro hemodynamics but also oxygenation up to cellular level. Basic

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parameters, such as consciousness, blood pressure, heart rate, and urine output, were generally

used as endpoints of resuscitation. However, in the presence of restored macro hemodynamics

(cardiac output and MAP), tissue oxygenation could be still compromised.31,34,35 It was reported

that up to 85% of shock patients are under-resuscitated when blood pressure and urine output

was used as sole indicators to sufficient or complete resuscitation.31 Therefore, assessment of

tissue perfusion and oxygenation is critical to assess the effectiveness of fluid resuscitation

properly. Tissue acidosis is one of the main variables evaluated for determining the tissue

perfusion and oxygenation. Base excess (BE) and lactate level have also been suggested as

endpoints of resuscitation.

34,36,37

Lactate level in HSL group was obviously higher than in RL

group (p<0.0001) due to higher exogenous lactate infusion. However, in hour 1 the lactate level

was already approaching the baseline level, indicating that the exogenous lactate could be rapidly

metabolized.

Baseline laboratory data showed metabolic acidosis in both groups due to inadequate tissue

oxygenation which is commonly found in shock patients. Serial assessment of blood gas analysis

showed a significant different evolution of acid base status between the two groups. In HSL

group the acidosis was completely compensated after two hours of HSL infusion, and the normal

levels of pH and BE were maintained until the end of study. In contrast, BE level in RL group

was below normal until the end of study (BE: -5.63) eventhough the pH was normal, indicating

partial compensation of tissue acidosis. It has been suggested that BE provides an indirect

estimation of tissue acidosis due to insufficient tissue perfusion,31,34 and serial BE evaluation can

be used as an indicator of adequacy of resuscitation.38 It has also been demonstrated that BE

value could significantly give the prognosis of hemodynamic stability, the need for blood

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transfusions and fluid administration, and mortality.36 Hence, despite the restored classical

hemodynamic parameters (blood pressure, MAP, HR, RR), patients in RL group were actually

still in compromised cellular oxygenation as indicating by their BE, which might also indicate

inadequate resusctitation. Whereas HSL administration improved macro hemodynamics and also

reversed completely tissue acidosis which suggested an adequate resuscitation that restored

tissue perfusion.

Hyperlactatemia has been correlated with poor prognosis if it persists after 12 hours of ongoing

resuscitation and coincides with acidosis.

38

Recent studies showed that the increase of lactate

during hypoxia or ischemic condition is merely an adaptive response of our body to produce

readily used energy substarte. Lactate paradigm has changed from lactate as the waste end

product into lactate as energy substrate in many cells containing mitochondrion. It was reported

that hyperosmolar sodium lactate infusion in hemorrhagic shock model increased cardiac

function.39 Hyperosmolar sodium lactate infusion during hypovolemia induced by cardiac

surgery significantly improve cardiac function and tissue perfusion.27 Therefore, higher level of

blood lactate in HSL group was unlikely to be associated with poor cellular perfusion since, in

addition to normal acid base status, the urine output was also normal. Higher lactate level in HSL

group also might not associate to increased mortality, morbidity and length of hospitalization of

the patients because they were not different between both groups.

As expected in HSL group, sodium level was significantly higher and chloride level was

significantly lower compared to RL group, although they were still in normal range. After HSL

infusion, lactate can enter the cells and then will be metabolized, which in turn will result in an

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excess of sodium in extracellular compartment and lead to extracellular cation-anion imbalance.

Then excessive sodium will be balanced by efflux of chloride from intracellular to the

extracellular compartment (electroneutrality balance). The chloride efflux is accompanied by

water leading to cell volume reduction. This mechanism explains how the sodium level increased

and chloride level decreased after hyperosmolar sodium lactate infusion.27

The levels of hemoglobin, hematocrit, and platelet counts in both groups decreased during the

study. The decrease of these hematology parameters could be due to blood loss and also

hemodilution effect. Slight greater reduction of hemoglobin and hematocrit in HSL group than

RL group could be due to larger intravascular filling effect of HSL solution. Similar MAP, lower

hemoglobin and hematocrit, and higher urine output in HSL group compared to RL group

suggested a vasodilating effect of hyperosmolar sodium lactate solution since previous study

showed that hyperosmolar sodium lactate infusion decreases vascular resistance.27 However

further study is required to confirm this vasodilating effect in hemorrhagic shock patients.

In conclusion, infusion of hyperosmolar sodium lactate solution for resuscitation of grade III

hemorhhagic shock could restore and maintain stable hemodynamic status and also reverse the

existing metabolic acidosis.

Acknowledgement

This study was sponsored by Innogene Kalbiotech, Pte. Ltd. Hyperosmolar sodium lactate

composition is patented and registered as Totilac™. The authors would like to thank Christina

Sitorus, M.D. and Vita Kurniati Lubis, M.D., Ph.D. for the assistance in preparing this paper.

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Figure Legends

Figure 1. Hemodynamic effect and fluid management between HSL vs. RL. Square shape with

dashed lines: RL, diamond shape with continuous line: HSL. Panel A: Mean Arterial Pressure

(MAP) (mm Hg); Panel B: Heart Rate (beats/min); Panel C: Cumulative Fluid Intake (CFI)

(mL); Panel D: Cumulative Urine Output (UOP) (mL); Results are expressed as means±SEM.

Comparison of each parameter at time point of measurement in each group was done by using

ANOVA. Statistical comparison between HSL and RL group was carried out with unpaired t-

students’ test. MAP: p=0.9268; HR: p=0.1064; CFI: p=0.4215; UOP: p=0.0423.

Figure 2. Blood gas analysis. Square shape with dashed lines: RL, diamond shape with

continuous line: HSL. Panel A: pH; Panel B: HCO3 level; Panel C: Base Excess (BE). Results

are expressed as means±SEM. Comparison of each parameter at time point of measurement in

each group was done by using ANOVA. Statistical comparison between HSL and RL group was

carried out with unpaired t-students’ test. pH, HCO3 and BE were significantly different between

HSL and RL group (p<0.05).

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Table 1. Composition of the HSL and RL.

CompositionHyperosmolar

sodium lactate (HSL)

Ringer Lactate

(RL) Na+ (mmol/L)/(g/L) 504.15/11.5 130.5/2.98K + (mmol/L)/(g/L) 4.02/0.16 4.02/0.16

Ca2+(mmol/L)/(g/L) 1.36/0.050 0.67/0.024

Cl- (mmol/L)/(g/L) 6.74/0.24 109.9/3.90

Lactate (mmol/L)/(g/L) 504.15/44.92 28.0/2.49Calculated total osmolarity (mosm/L) 1020.42 273

Total inorganic osmolarity (mosm/L) 516.27 245

Calculated total osmolarity is the sum of all cations and anions; total inorganic osmolarity is the

sum of inorganic ions (i.e. subtracted lactate anions) and represents the tonicity.

Table 2 . Demographic and baseline characteristics of patients.

ParametersTotilac Group

(n = 24)

RL Group

(n = 29) p-value

Age* (years) 35.05 (12.10) 32.25 (9.83) 0.3716

Sex†

0.6647Male 16 (66.67%) 22 (75.86%)

Female 8 (33.33%) 7 (24.14%)Height‡ (cm) 162.96 (5.83) 162.36 (6.36) 0.7339

Weight‡ (kg) 55.92 (9.30) 57.76 (9.31) 0.3898

Response†

0.3860Rapid 18 (78.26%) 17 (62.96%)

Transient 5 (21.74%) 10 (37.04%)

Onset of Trauma‡ (hours) 3.43 (2.53) 4.46 (2.93) 0.1188GCS§

0.436214 2 (8.33%) 5 (17.24%)

15 22 (91.67%) 24 (82.76%)Systolic BP‡ (mmHg) 77.08 (9.66) 70.00 (17.73) 0.1236

Diastolic BP

‡

(mmHg) 42.08 (20.85) 41.21 (18.60) 0.6241MAP‡ (mmHg) 53.75 (15.31) 50.80 (15.14) 0.4533Heart rate‡ (beat/min) 122.70 (12.74) 115.71 (24.66) 0.5029

Respiratory rate‡ (X/min) 30.63 (9.06) 30.41 (6.68) 0.7188

Temperature‡ (oC) 36.43 (0.82) 36.41 (0.84) 0.9522

Revised Trauma Score‡ 6.88 (0.49) 6.61 (0.64) 0.1835Fluid infusion prior trial†

0.3142Yes 9 (37.5%) 16 (55.17%)

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No 15 (62.5%) 13 (44.83%)

Type of pre-trial infusion§

1.000RL 7 (77.78%) 13 (81.25%)Other 2 (22.22%) 3 (18.75%)

Pre-trial infusion – RL‡ (mL) 1162.50 (826.24) 761.54 (489.11) 0.2187

Pre-trial infusion – all‡

(mL) 1144.44 (814.11) 806.25 (548.39) 0.2937Values are means (SD) for the continuous variables and count (%) for the categorical variables.

No significant difference was observed between baseline characteristics of HSL and RL group (p

>0.05).

* Independent t -test; † Chi-square test; ‡ Mann-Whitney test; § Fisher’s exact test.

Table 3. Biochemical parameters.

H0 H.25 H1 H2 H3 p-value

Lactate-

(mmol/L)

HSL 5.05±4.08 9.47±4.44 5.86±2.08 6.05±2.98 5.41±2.59

<0.0001RL 4.03±1.88 3.63±1.89 2.99±1.37 2.63±1.35 2.70±1.52

Na+

(mmol/L)

HSL 137.04±3.06 139.68±2.40 139.13±2.03 139.57±2.27 140.45±2.22<0.0001

RL 137.03±2.34 136.52±2.24 136.31±2.22 136.17±2.27 136.25±2.15

K +

(mmol/L)

HSL 3.57±0.48 3.35±0.46 3.50±0.47 3.47±0.45 3.55±0.440.0070

RL 3.94±0.96 3.80±0.84 3.89±0.79 3.95±0.61 4.16±0.63

Cl-

(mmol/L)

HSL 103.96±4.22 101.32±3.48 102.88±3.76 102.39±3.69 101.82±3.320.0018

RL 105.31±3.38 105.48±3.47 105.62±3.09 104.79±3.21 105.43±3.62

Hb (g/L)HSL 10.61±2.65 NM NM NM 7.95±2.67

0.3049RL 10.48±2.69 NM NM NM 8.48±2.21

Ht (%)HSL 10.61±2.65 NM NM NM 7.95±2.67

0.3049RL 10.48±2.69 NM NM NM 8.48±2.21

PlateletHSL 10.61±2.65 NM NM NM 7.95±2.67

0.5728RL 10.48±2.69 NM NM NM 8.48±2.21

NM: not measured. The data are means±SEM. Comparison of each parameter at time point of

measurement in each group was done by using ANOVA. Statistical comparison between HSL

and RL group was carried out with unpaired t-students’ test.

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Figure 1.

.

Figure 2.

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HSL

RL

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Manuscript_HSL in Hemorrhagic Shock_250711