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1 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:

2 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

aggressive fluid resuscitation can lead to fluid overload and tissue edema.5%) have been investigated as resuscitation solutions in hemorrhagic shock with promising results. and urine . hence it can minimize prevent tissue edema and organ damage. 9-11 Therefore.8%–7. Hyperosmolar solutions of various concentrations (1.3 INTRODUCTION Reduction of intravascular volume due to blood loss and might be secondary capillary leakage is frequently occurred in patients with trauma.24.12-23 The beneficial effect of hypertonic saline has been shown related to its hypertonicity.18. improve microvascular flow with small volume infusion.1-2 Effective hemorrhage control and adequate intravenous fluid administration to restore intravascular volume and maintain the tissue perfusion is crucial for life saving. has been shown to improve cardiac output. It was demonstrated that hypertonic saline is able to restore hemodynamics. 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. oxygen delivery. containing a physiological concentration of potassium chloride and calcium chloride. a novel resuscitation strategy that overcomes those issues in the near future is still required. which in turn could result in hemodynamic decompensates and increased mortality.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. Severe intravascular volume deficits after trauma lead to the decrease of delivery oxygen and nutrients that necessary for normal tissue and cellular function.8 However.25 Small volume administration of a scientifically formulated and patent protected hyperosmolar sodium lactate solution (HSL).

and maintain stable hemodynamics better than isotonic crystalloid during volume deficits in post-cardiac surgery patients. hypertonicity related effects of HSL solution may offer volume efficiency of fluid infusion in hemorrhagic shock patients. this study is aimed to evaluate the efficacy and safety of the HSL as resuscitative fluid regimen in traumatic hemorrhagic shock patients. Therefore. there is no clinical study investigating the efficacy of hyperosmolar sodium lactate infusion in hemorrhagic shock.29 In addition. Bandung. Prior to the study.28.26.Ltd. controlled.27 However. Bandung. attenuate metabolic acidosis. METHODS Study Design This was a prospective. The composition of both solutions is detailed in Table 1. This study was conducted from July 2009 to January 2011 in Hasan Sadikin Hospital. . for resuscitating the patients with grade III hemorrhagic shock due to multiple injuries in comparison to commercially available Ringer Lactate solution (RL-Otsu). 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. Indonesia.4 output. Indonesia. 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. randomized. a written approval for the protocol has been obtained from the Ethics Committee of the Hasan Sadikin Hospital.

5 ml/kgBW/hour). For initial resuscitation during shock. decompensate heart failure. 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. i. 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. AIDS (CD4 <200/uL) or HIV serology positive with Highly-Active Anti-Retroviral Therapy (HAART). patients with cancer. heart rate >120 times/min. 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 ≥0.9368 GCS (Glasgow Coma Scale) + 0.2908 RR (Respiratory Rate). either Ringer’s Lactate (RL) group or hyperosmolar sodium lactate (HSL) group.5-2 L blood loss estimation. The exclusion criteria were coagulopathy.e. mean arterial pressure (MAP) <65 mmHg. HSL or control drug was administered concurrently to standard resuscitation fluid . 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. liver failure. pulse pressure <20 mmHg.5 Study Participants Screening and enrolment of eligible patients were done in the Emergency Unit. Grade III hemorrhagic shock was defined when patient fulfilled at least two of these following criteria: 1. patients with burn area >20%. pregnancy.7326 SBP (Systolic Blood Pressure) + 0. which was calculated with this formula: RTS = 0. HSL or RL was administered at similar dose. chronic renal failure. Glasgow Coma Score ≤ 13. During initial resuscitation.8408). respiratory rate 30-40 times/min or urinary output 5-15 ml/hour.

Comparison of each parameter at time point of measurement in each group was done by using ANOVA. Fifty three patients (24 in HSL group and 29 in RL group) were included for efficacy and safety analysis. having protocol violation (1 patient). Assessment of comparability between HSL group and RL group was done by unpaired student t-test and Chi-Square test (for categorical data). RESULTS Patient Characteristics Seventy one patients (36 patients in HSL group and 35 patients in RL group) were enrolled from July 2009 to January 2011.6 (0-2 L RL over 15 minutes. whereas 18 patients were excluded with these following reasons: not receiving proper dose of study drugs (5 patients). and having incomplete data (3 patients). depend on the volume of fluid received by patients before admission to the scene). Evolution of Hemodynamic Status . 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. developing grade IV hemorrhagic shock (9 patients). 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. Demographic and baseline data of both groups was depicted in Table 2. Two infusion lines in each patient were installed during the study.

Cumulative fluid balance was comparable between HSL and RL group (p=0. while hemoglobin. 1C). and 15 minutes (H. . 3 hours (H3) after study drugs administration. 1 hour (H1).0423) (Figure 1D). The increase of MAP and the decrease of heart rate and respiration rate over time was statistically significant in both groups (p<0. blood loss was not measured. cumulative urine output at the end of observation (H3) was significantly higher in HSL group than that in RL group (p=0. it was allowed to administer additional fluid infusion in case of recurrent shock. 2 hours (H2). The fluid balance was calculated by subtracting urine output from the total fluid infused. then after the first bolus (H. 1B). hematocrite. blood gas of each patient were evaluated and recorded at five time points including baseline (H0). Mean arterial pressure.5987). Cumulative fluid infusion was comparable between HSL and RL group (p=0.25). Glasgow Coma Scale. 2 hours (H2). body temperature.7 Hemodynamics monitoring was recorded at baseline. respiration rate. platelet count were measured at baseline (H0) and 3 hours after study drugs administration (H3). blood lactate.25).4215) (Fig. 1A. 3 hours (H3) of study drug infusion.5). Despite of similar cumulative fluid infusion in both groups. 1 hour (H1). Biological Parameters Serum electrolytes. 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. 30 minutes (H. heart rate (Fig.0001). In this study.

HCO 3 level in HSL group increased and reached normal level.0002) (Fig. 2B). The evolution of pCO2 and pO2 was comparable between HSL and RL group (data not shown). Hemoglobin. 2A) but it was still in normal range.0001) (Table 3).8 Serum sodium level significantly increased in HSL group whereas in RL group the sodium level decreased (p<0.0070). whereas in RL group it decreased continuously over time and the difference between both groups was significant (p<0.63) (p=0.0009) (Fig. (p>0. Oxygen saturation (SaO2) did not change and was comparable between both groups (data not shown). Safety Fisher exact test showed that mortality. and length of hospitalization were comparable between HSL and RL group.05) (Table 3). morbidity rates. Blood pH was almost unchanged in RL group. Serum potassium level was almost unchanged in HSL group. whereas in RL group it was almost unchanged from baseline (p=0.0018). 2C).0001). Blood lactate obviously increased after loading infusion and then decreased steadily close to baseline level during maintenance in HSL group. and platelet count decreased in both groups and the changes of hemoglobin level was comparable between HSL and RL group. Serum chloride level decreased in HSL group and almost unchanged in RL group (p=0.79). No complication and mortality occurred in both groups during the study were related to the study drugs. although the levels in both groups were still in normal range. hematocrite. Base excess continuously improved in HSL group and reached zero level at H2 and then increased to slightly positive (0.0104) (Fig. whereas in RL group it almost unchanged (5. whereas it significantly increased in HSL group (p=0. and slightly increased at H3 in RL group (p=0. .

the cumulative urine output in HSL group was significantly higher than that in RL group without any diuretics. However. fluid resuscitation is aimed to restore not only macro hemodynamics but also oxygenation up to cellular level. i. Therefore. We found here that HSL infusion had a comparable effect with RL on restoring and maintaining hemodynamic status in hemorrhagic shock patients. Basic .30 Although HSL is a hyperosmolar solution and is aimed for small volume fluid resuscitation. Hemorrhagic shock is defined as an inadequate tissue perfussion and oxygenation secondary to blood loss and associated with tissue acidosis and oxygen debt. This was an expected finding due to the hypertonicity of HSL solution.31-33 Therefore. the value ensuring a sufficient organ perfusion. despite the comparable cumulative fluid intake. This may be caused by the 2-liters of standard solution which was infused concurrently with the study drugs infusion. based on fluid volume received prior to the trial. in this study.e. loading dose of study drugs was given concurrently with standard resuscitation fluid. The infusion of 2 L standard solution has also a role in filling the intravascular volume. Control regimen (RL) and treatment procedure in this study was designed as close as the standard fluid management in hemorrhagic shock patients. the cumulative fluid intake in Totilac group did not differ significantly with that in RL group. up to 2 L RL. In this study it was allowed to give additional fluid in any recurrent shock until the MAP restored to ≥65mmHg.9 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.

in hour 1 the lactate level was already approaching the baseline level. assessment of tissue perfusion and oxygenation is critical to assess the effectiveness of fluid resuscitation properly.34 and serial BE evaluation can be used as an indicator of adequacy of resuscitation.37 Lactate level in HSL group was obviously higher than in RL group (p<0. indicating partial compensation of tissue acidosis. Tissue acidosis is one of the main variables evaluated for determining the tissue perfusion and oxygenation.31. In HSL group the acidosis was completely compensated after two hours of HSL infusion.36. in the presence of restored macro hemodynamics (cardiac output and MAP). the need for blood .38 It has also been demonstrated that BE value could significantly give the prognosis of hemodynamic stability. and the normal levels of pH and BE were maintained until the end of study.10 parameters. However. indicating that the exogenous lactate could be rapidly metabolized. Serial assessment of blood gas analysis showed a significant different evolution of acid base status between the two groups. and urine output.31.63) eventhough the pH was normal. tissue oxygenation could be still compromised. It has been suggested that BE provides an indirect estimation of tissue acidosis due to insufficient tissue perfusion. such as consciousness. heart rate. However.0001) due to higher exogenous lactate infusion.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. Baseline laboratory data showed metabolic acidosis in both groups due to inadequate tissue oxygenation which is commonly found in shock patients.31 Therefore. In contrast. Base excess (BE) and lactate level have also been suggested as endpoints of resuscitation. were generally used as endpoints of resuscitation.34. BE level in RL group was below normal until the end of study (BE: -5.34. blood pressure.

11 transfusions and fluid administration. It was reported that hyperosmolar sodium lactate infusion in hemorrhagic shock model increased cardiac function. morbidity and length of hospitalization of the patients because they were not different between both groups.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. in addition to normal acid base status. patients in RL group were actually still in compromised cellular oxygenation as indicating by their BE. As expected in HSL group. which in turn will result in an . RR). 36 Hence. MAP. despite the restored classical hemodynamic parameters (blood pressure. higher level of blood lactate in HSL group was unlikely to be associated with poor cellular perfusion since. lactate can enter the cells and then will be metabolized. Lactate paradigm has changed from lactate as the waste end product into lactate as energy substrate in many cells containing mitochondrion. and mortality. HR. which might also indicate inadequate resusctitation.27 Therefore.39 Hyperosmolar sodium lactate infusion during hypovolemia induced by cardiac surgery significantly improve cardiac function and tissue perfusion. although they were still in normal range. Whereas HSL administration improved macro hemodynamics and also reversed completely tissue acidosis which suggested an adequate resuscitation that restored tissue perfusion. sodium level was significantly higher and chloride level was significantly lower compared to RL group. Higher lactate level in HSL group also might not associate to increased mortality. After HSL infusion. Hyperlactatemia has been correlated with poor prognosis if it persists after 12 hours of ongoing resuscitation and coincides with acidosis. the urine output was also normal.

M.27 The levels of hemoglobin. and platelet counts in both groups decreased during the study. Similar MAP. The decrease of these hematology parameters could be due to blood loss and also hemodilution effect. and Vita Kurniati Lubis. 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. In conclusion. Pte. hematocrit.27 However further study is required to confirm this vasodilating effect in hemorrhagic shock patients. Acknowledgement This study was sponsored by Innogene Kalbiotech. Slight greater reduction of hemoglobin and hematocrit in HSL group than RL group could be due to larger intravascular filling effect of HSL solution. for the assistance in preparing this paper. Then excessive sodium will be balanced by efflux of chloride from intracellular to the extracellular compartment (electroneutrality balance). The authors would like to thank Christina Sitorus. M.D. Ltd. lower hemoglobin and hematocrit. This mechanism explains how the sodium level increased and chloride level decreased after hyperosmolar sodium lactate infusion.12 excess of sodium in extracellular compartment and lead to extracellular cation-anion imbalance.. Hyperosmolar sodium lactate composition is patented and registered as Totilac™.D. 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. Ph.D. The chloride efflux is accompanied by water leading to cell volume reduction. .

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9268. RL.05). diamond shape with continuous line: HSL. Square shape with dashed lines: RL. MAP: p=0. CFI: p=0. Panel C: Cumulative Fluid Intake (CFI) (mL). Square shape with dashed lines: RL. UOP: p=0. Hemodynamic effect and fluid management between HSL vs. Panel B: Heart Rate (beats/min). Figure 2. HR: p=0. Statistical comparison between HSL and RL group was carried out with unpaired tstudents’ test. Panel B: HCO3 level. HCO3 and BE were significantly different between HSL and RL group (p<0. Statistical comparison between HSL and RL group was carried out with unpaired t-students’ test. pH.0423. Panel A: Mean Arterial Pressure (MAP) (mm Hg).4215. Results are expressed as means±SEM. Panel D: Cumulative Urine Output (UOP) (mL). Panel A: pH. Results are expressed as means±SEM. diamond shape with continuous line: HSL. Blood gas analysis. . Comparison of each parameter at time point of measurement in each group was done by using ANOVA. Panel C: Base Excess (BE).1064.17 Figure Legends Figure 1. Comparison of each parameter at time point of measurement in each group was done by using ANOVA.

e.024 109.67%) 77.27 Ringer Lactate (RL) 130.80 (15.60) 50.67%) 8 (33.5 4.88 (0.14) 115.74%) 3.46 (2.96%) 10 (37.06) 36.71 (24.18 Table 1.6241 0.4362 0.(mmol/L)/(g/L) Lactate (mmol/L)/(g/L) Calculated total osmolarity (mosm/L) Total inorganic osmolarity (mosm/L) Hyperosmolar sodium lactate (HSL) 504.26%) 5 (21.3898 0.43 (2.83) 55.76%) 70.1188 0.24%) 24 (82.16 0.0/2.86%) 7 (24.92 1020.14%) 162.49) 9 (37.63 (9.41 (0.21 (18.53) 2 (8.6647 0. Composition of the HSL and RL.4533 0.83) 22 (75. Parameters Age* (years) Sex† Male Female Height‡ (cm) Weight‡ (kg) Response† Rapid Transient Onset of Trauma‡ (hours) GCS§ 14 15 Systolic BP‡ (mmHg) Diastolic BP‡ (mmHg) MAP‡ (mmHg) Heart rate‡ (beat/min) Respiratory rate‡ (X/min) Temperature‡ (oC) Revised Trauma Score‡ Fluid infusion prior trial† Yes Totilac Group (n = 24) 35. Demographic and baseline characteristics of patients.42 516.1835 0.75 (15.5029 0.70 (12. Composition Na+ (mmol/L)/(g/L) K+ (mmol/L)/(g/L) Ca2+(mmol/L)/(g/L) Cl.84) 6. subtracted lactate anions) and represents the tonicity.43 (0.3142 .66) 30.82) 6.49 273 245 Calculated total osmolarity is the sum of all cations and anions.68) 36.5%) RL Group (n = 29) 32.02/0.05 (12.7339 0.1236 0. total inorganic osmolarity is the sum of inorganic ions (i.7188 0.73) 41.16 1.33%) 22 (91.30) 18 (78.050 6.61 (0.17%) p-value 0.9/3.25 (9.92 (9.74) 30.74/0.93) 5 (17.64) 16 (55.00 (17.36) 57.15/11.36/0.31) 17 (62.08 (9.9522 0.85) 53.10) 16 (66.31) 122.3716 0.3860 0. Table 2.02/0.67/0.90 28.66) 42.5/2.41 (6.33%) 162.24 504.76 (9.04%) 4.98 4.08 (20.36 (6.96 (5.15/44.

45±2.48±2. † Chi-square test.76 102.47 105.48±2.67 Platelet RL 10.89 2.69 101.48 3.45 3.04±3.57±2. .99±1.38 105. Biochemical parameters.48±2.27 140.48 102. Statistical comparison between HSL and RL group was carried out with unpaired t-students’ test.0001 <0.05±4.55±0.44 (814.05).0018 0.03±1.63 (mmol/L) RL HSL 103.61±2. Table 3.48±2.78%) 13 (81.52 (mmol/L) RL HSL 137.22 Na+ 137.25±2.88 3.44 K+ 3.98 5.11) 1144.25 H1 H2 H3 p-value <0.62±3.32±3.57±0.79±3.03 139.89±0.59 Lactate4.2937 categorical variables.46 3.24 136.96 3.75%) 1162.34 136.22 101.0001 0. * Independent t-test.09 104.24) 761.67 Hb (g/L) RL 10.83%) 1.68±2.82±3.95±2.47±4.000 0.65 NM NM NM 7.21 HSL 10.65 NM NM NM 7.94±0.43±3.69 NM NM NM 8.39) continuous variables and count (%) for the No significant difference was observed between baseline characteristics of HSL and RL group (p >0.61±2.22 136. H0 H.31±2.61±2.40 139.48±2.22%) 3 (18.37 2. The data are means±SEM.96±4.25%) 2 (22.11) 806.35±0.0070 0.3049 0.21 HSL 10.86±2.67 Ht (%) RL 10. ‡ Mann-Whitney test.63±1.13±2.48±2.03±2.69 NM NM NM 8.5%) 13 (44.84 3.65 NM NM NM 7.16±0.27 136.25 (548.69 NM NM NM 8.17±2. § Fisher’s exact test.44 5.62 (mmol/L) RL HSL 10.08 6.80±0.21 105.52±2.70±1.50±0.95±0.54 (489. 7 (77.63±1.88±3.48±3.5728 point of HSL 5.41±2.06 139.31±3.15 (mmol/L) RL HSL 3.79 3.47 3.95±2.35 2.95±2.32 Cl105.50 (826.21 NM: not measured.47±0.2187 0.61 4.3049 0.05±2.08 9. Comparison of each parameter at time measurement in each group was done by using ANOVA.19 No Type of pre-trial infusion§ RL Other Pre-trial infusion – RL‡ (mL) Pre-trial infusion – all‡ (mL) Values are means (SD) for the 15 (62.39±3.

Figure 2.20 Figure 1. HSL RL . .