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Resuscitation with centhaquin and 6% hydroxyethyl starch 130/0.4 improves survival in a swine model of hemorrhagic shock: a randomized experimental study

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Abstract

Purpose

To investigate the effects of the combination of centhaquin and 6% hydroxyethyl starch 130/0.4 (HES 130/0.4) in a swine model of hemorrhagic shock.

Methods

Twenty Landrace–Large White pigs were instrumented and subjected to hemorrhagic shock. The animals were randomly allocated in two experimental groups, the control (group CO, n = 10) and the centhaquin groups (0.015 mg/kg, n = 10, group CH). Acute hemorrhage was induced by stepwise blood withdrawal (18 mL/min) from the internal jugular vein until MAP decreased to 40–45 mmHg, whereas anesthesia remained constant. All animals received HES 130/0.4 solution in the resuscitation phase until their mean arterial pressure (MAP) reached 90% of the baseline. The animals were observed for 60 min, during which no further resuscitation was attempted.

Results

The total amount of blood and the bleeding time did not differ significantly between group CO and group CH (120 ± 13 vs. 120 ± 14 mL, p = 0.6; 20 ± 2 vs. 20 ± 1 min, p = 0.62, respectively). During the hemorrhagic phase, only a difference in heart rate (97.6 ± 4.4 vs. 128.4 ± 3.6 beats/min, p = 0.038) was observed between the two groups. The time required to reach the target MAP was significantly shorter in the centhaquin group compared to controls (13.7 ± 0.4 vs. 19.6 ± 0.84 min, p = 0.012). During the resuscitation phase, a statistical significant difference was observed in MAP (75.2 ± 1.6 vs. 89.8 ± 2.1 mmHg, p = 0.02) between group CO and group CH. During the observation phase, a statistical significant difference was observed in SVR (1109 ± 32.65 vs. 774.6 ± 21.82 dyn s/cm5, p = 0.039) and cardiac output (5.82 ± 0.31 vs. 6.9 ± 0.78 L/min, p = 0.027) between the two groups. Two animals of group CO and seven animals of group CH survived for 24 h (p = 0.008). We observed a marked increase in microvascular capillary permeability in group CO compared to group CH, with the wet/dry weight ratio being significantly higher in group CO compared to group CH (4.8 ± 1.6 vs. 3.08 ± 0.6, p < 0.001).

Conclusions

The combination of centhaquin 0.015 mg/kg and HES 130/0.4 resulted in shorter time to target MAP, lower wet-to-dry ratio, and better survival rates after resuscitation from hemorrhagic shock.

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References

  1. Mtaweh H, Trakas EV, Su E, Carcillo JA, Aneja RK. Advances in monitoring and management of shock. Pediatr Clin N Am. 2013;60:641–4.

    Google Scholar 

  2. Gutierrez G, Reines HD, Wulf-Gutierrez ME. Clinical review: hemorrhagic shock. Crit Care. 2004;8:373–81.

    PubMed  PubMed Central  Google Scholar 

  3. Santry HP, Alam HB. Fluid resuscitation: past, present, and the future. Shock. 2010;33:229–41.

    PubMed  PubMed Central  Google Scholar 

  4. Bunn F, Alderson P, Hawkin V. Colloid solution for fluid resuscitation. Cochrane database Syst Rev. 2000;2:CD001319.

    Google Scholar 

  5. Perel P, Roberts I. Colloids versus crystalloids for fluid resuscitation in critically ill patients. Cochrane Database Syst Rev. 2012;6:CD000567.

    Google Scholar 

  6. Naig CM, Win DK. Do colloids in comparison to crystalloids for fluid resuscitation improve mortality? Trans R Soc Trop Med Hyg. 2010;104:311–2.

    Google Scholar 

  7. Burns JW, Baer LA, Darlington DN, Dubick MA, Wade CE. Screening of potential small volume resuscitation products using a severe hemorrhage sedated swine model. Int J Burn Trauma. 2012;2:59–67.

    CAS  Google Scholar 

  8. Rizolli SB. Crystalloids and colloids in trauma resuscitation: a brief overview of the current debate. J Trauma. 2003;54:82–8.

    Google Scholar 

  9. Finfer S, Liu B, Taylor C, Bellomo R, Billot L, Cook D, et al. Resuscitation fluid use in critically ill adults: an international cross-sectional study in 391 intensive care units. Crit Care. 2010;14:R185.

    PubMed  PubMed Central  Google Scholar 

  10. Dubin A, Pozo MO, Casabella CA, Murias G, Pálizas F Jr, Moseinco MC, et al. Comparison of 6% hydroxyethyl starch 130/0.4 and saline solution for resuscitation of the microcirculation during the early goal-directed therapy of septic patients. J Crit Care. 2010;25:659.e1–8.

    Google Scholar 

  11. Feldheiser A, Pavlova V, Bonomo T, Jones A, Fotopoulou C, Sehouli J, et al. Balanced crystalloid compared with balanced colloid solution using a goal-directed haemodynamic algorithm. Br J Anaesth. 2013;110:231–40.

    CAS  PubMed  Google Scholar 

  12. Srimal RC, Gulati K, Nityanand S, Dhawan BN. Pharmacological studies on 2-(2-(4-(3-methhylphenyl)-1-piperazinyl)ethyl) quinoline (centhaquin). I. Hypotensive activity. Pharmacol Res. 1990;22:319–29.

    CAS  PubMed  Google Scholar 

  13. Bhatnagar Z, Pande M, Dubey MP, Dhawan BN. Effect of centhaquin on spontaneous and evoked norepinephrine release from isolated perfused rabbit heart. Arzneimittelforschung. 1985;35:693–7.

    CAS  PubMed  Google Scholar 

  14. Lavhale MS, Havalad S, Gulati A. Resuscitative effect of centhaquin after hemorrhagic shock in rats. J Surg Res. 2013;179:115–24.

    CAS  PubMed  Google Scholar 

  15. Papapanagiotou P, Xanthos T, Gulati A, Chalkias A, Papalois A, Kontouli Z, et al. Centhaquin improves survival in a swine model of hemorrhagic shock. J Surg Res. 2016;200:227–35.

    CAS  PubMed  Google Scholar 

  16. Zornow MH, Prough DS. Fluid management in patients with traumatic brain injury. New Horiz. 1995;3:488–98.

    CAS  PubMed  Google Scholar 

  17. Xanthos TT, Balkamou XA, Stroumpoulis KI, Pantazopoulos IN, Rokas GI, Agrogiannis GD, et al. A model of hemorrhagic shock and acute lung injury in Landrace–Large White swine. Comp Med. 2011;61:158–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Xanthos T, Bassiakou E, Koudouna E, Rokas G, Goulas S, Dontas I, et al. Combination pharmacotherapy in the treatment of experimental cardiac arrest. Am J Emerg Med. 2009;27:651–9.

    PubMed  Google Scholar 

  19. Balkamou X, Xanthos T, Stroumpoulis K, Moutzouris DA, Rokas G, Agrogiannis G, et al. Hydroxyethyl starch 6% (130/0.4) ameliorates acute lung injury in swine hemorrhagic shock. Anesthesiology. 2010;113:1092–8.

    CAS  PubMed  Google Scholar 

  20. Shires GT, Cunningham JN, Backer CR, Reeder SF, Illner H, Wagner IY, et al. Alterations in cellular membrane function during hemorrhagic shock in primates. Ann Surg. 1972;176:288–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Chatrath V, Khetarpal R, Ahuja J. Fluid management in patients with trauma: restrictive versus liberal approach. J Anaesthesiol Clin Pharmacol. 2015;31:308–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Ross SW, Christmas AB, Fischer PE, Holway H, Walters AL, Seymour R, et al. Impact of common crystalloid solutions on resuscitation markers following class I hemorrhage: a randomized control trial. J Trauma Acute Care Surg. 2015;79:732–40.

    CAS  PubMed  Google Scholar 

  23. Mitra B, Gabbe BJ, Kaukonen KM, Olaussen A, Cooper DJ, Cameron PA. Long-term outcomes of patients receiving a massive transfusion after trauma. Shock. 2014;42:307–12.

    PubMed  Google Scholar 

  24. Delano MJ, Rizoli SB, Rhind SG, Cuschieri J, Junger W, Baker AJ, et al. Prehospital Resuscitation of Traumatic Hemorrhagic Shock with Hypertonic Solutions Worsens Hypocoagulation and Hyperfibrinolysis. Shock. 2015;44:25–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Perel P, Roberts I, Ker K. Colloids versus crystalloids for fluid resuscitation in critically ill patients. Cochrane Database Syst Rev. 2013;2:CD000567.

    Google Scholar 

  26. Annane D, Siami S, Jaber S, Martin C, Elatrous S, Declère AD, et al. CRISTAL Investigators. Effects of fluid resuscitation with colloids vs crystalloids on mortality in critically ill patients presenting with hypovolemic shock: the CRISTAL randomized trial. JAMA. 2013;310:1809–17.

    CAS  PubMed  Google Scholar 

  27. Vives M, Callejas R, Duque P, Echarri G, Wijeysundera DN, Hernandez A, et al. Modern hydroxyethyl starch and acute kidney injury after cardiac surgery: a prospective multicentre cohort. Br J Anaesth. 2016;117:458–63.

    CAS  PubMed  Google Scholar 

  28. Schindler AW, Marx G. Evidence-based fluid management in the ICU. Curr Opin Anaesthesiol. 2016;29:158–65.

    PubMed  Google Scholar 

  29. Kheirabadi BS, Miranda N, Terrazas IB, Gonzales MD, Grimm RC, Dubick MA. Does small-volume resuscitation with crystalloids or colloids influence hemostasis and survival of rabbits subjected to lethal uncontrolled hemorrhage? J Trauma Acute Care Surg. 2017;82:156–64.

    CAS  PubMed  Google Scholar 

  30. Roger C, Muller L, Deras P, Louart G, Nouvellon E, Molinari N, et al. Does the type of fluid affect rapidity of shock reversal in an anaesthetized-piglet model of near-fatal controlled haemorrhage? A randomized study. Br J Anaesth. 2014;112:1015–23.

    CAS  PubMed  Google Scholar 

  31. Garnacho-Montero J, Fernández-Mondéjar E, Ferrer-Roca R, Herrera-Gutiérrez ME, Lorente JA, Ruiz-Santana S, et al. Crystalloids and colloids in critical patient resuscitation. Med Intensiva. 2015;39:303–15.

    CAS  PubMed  Google Scholar 

  32. Gulati A, Hussain G, Srimal RC. Effect of repeated administration of centhaquin, a centrally acting hypotensive drug, on adrenergic, cholinergic (muscarinic), dopaminergic, and serotonergic receptors in brain-regions of rat. Drug Dev Res. 1991;23:307–23.

    CAS  Google Scholar 

  33. Gulati A, Hussain G, Srimal RC. Effect of repeated administration of clonidine on adrenergic, cholinergic (muscarinic), dopaminergic, and serotonergic receptors in brain-regions of rat. Drug Dev Res. 1991;22:141–52.

    CAS  Google Scholar 

  34. Lavhale MS, Briyal S, Parikh N, Gulati A. Endothelin modulates the cardiovascular effects of clonidine in the rat. Pharm Res. 2010;62:489–99.

    CAS  Google Scholar 

  35. Gulati A, Srimal RC. Endothelin antagonizes the hypotension and potentiates the hypertension induced by clonidine. Eur J Pharmacol. 1993;230:293–300.

    CAS  PubMed  Google Scholar 

  36. Gondos T, Marjanek Z, Ulakcsai Z, Szabó Z, Bogár L, Károlyi M, et al. Short-term effectiveness of different volume replacement therapies in postoperative hypovolaemic patients. Eur J Anaesthesiol. 2010;27:794–800.

    PubMed  Google Scholar 

  37. Rooke GA, Schwid HA, Shapira Y. The effect of graded hemorrhage and intravascular volume replacement on systolic pressure variation in humans during mechanical and spontaneous ventilation. Anesth Analg. 1995;80:925–32.

    CAS  PubMed  Google Scholar 

  38. Funk DJ, Jacobsohn E, Kumar A. Role of the venous return in critical illness and shock: part II-shock and mechanical ventilation. Crit Care Med. 2013;41:573–9.

    PubMed  Google Scholar 

  39. Shen T, Baker K. Venous return and clinical hemodynamics: how the body works during acute hemorrhage. Adv Physiol Educ. 2015;39:267–71.

    PubMed  Google Scholar 

  40. Wang P, Li Y, Li J. Hydroxyethyl starch 130/0.4 prevents the early pulmonary inflammatory response and oxidative stress after hemorrhagic shock and resuscitation in rats. Int Immunopharmacol. 2009;9:347–53.

    CAS  PubMed  Google Scholar 

  41. Michelet P, Lambert D, Papazian L, Auffray JP, Carpentier JP. Comparison of lung injury after normal or small volume optimized resuscitation in a model of hemorrhagic shock. Intensive Care Med. 2007;33:1645–54.

    PubMed  Google Scholar 

  42. Feng X, Yan W, Liu X, Duan M, Zhang X, Xu J. Effects of hydroxyethyl starch 130/0.4 on pulmonary capillary leakage and cytokines production and NF-κB activation in CLP-induced sepsis in rats. J Surg Res. 2006;135:129–36.

    CAS  PubMed  Google Scholar 

  43. Lv R, Zhou W, Chu C, Xu J. Mechanism of the effect of hydroxyethyl starch on reducing pulmonary capillary permeability in a rat model of sepsis. Ann Clin Lab Sci. 2005;35:174–83.

    CAS  PubMed  Google Scholar 

  44. Tian J, Lin X, Guan R, Xu JG. The effects of hydroxyethyl starch on lung capillary permeability in endotoxic rats and possible mechanisms. Anesth Analg. 2004;98:768–74.

    CAS  PubMed  Google Scholar 

  45. Di Filippo A, Ciapetti M, Prencipe D, Tini L, Casucci A, Ciuti R, et al. Experimentally-induced lung injury: the protective effect of hydroxyethyl starch. Ann Clin Lab Sci. 2006;36:345–52.

    PubMed  Google Scholar 

  46. Feng X, Yan W, Wang Z, Liu J, Yu M, Zhu S, et al. Hydroxyethyl starch, but not modified fluid gelatin, affects inflammatory response in a rat model of polymicrobial sepsis with capillary leakage. Anesth Analg. 2007;104:624–30.

    CAS  PubMed  Google Scholar 

  47. Chen G, You G, Wang Y, Lu M, Cheng W, Yang J, et al. Effects of synthetic colloids on oxidative stress and inflammatory response in hemorrhagic shock: comparison of hydroxyethyl starch 130/0.4, hydroxyethyl starch 200/0.5, and succinylated gelatin. Crit Care. 2013;17:R141.

    PubMed  PubMed Central  Google Scholar 

  48. Silva PL, Güldner A, Uhlig C, Carvalho N, Beda A, Rentzsch I, et al. Effects of intravascular volume replacement on lung and kidney function and damage in nonseptic experimental lung injury. Anesthesiology. 2013;118:395–408.

    PubMed  Google Scholar 

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Acknowledgements

This study was supported by the Experimental-Research Center ELPEN Pharmaceuticals (E.R.C.E), Athens, Greece by providing the research facilities for this project. We would like to thank, A. Zacharioudaki, E. Karampela, K. Tsarea, M. Karamperi, N. Psychalakis, A. Karaiskos, S. Gerakis and E. Gerakis, staff members of the E.R.C.E., for their assistance during the experiments.

Author information

Author notes

  1. Zinais Kontouli and Chryssoula Staikou equally contributed to the study.

Authors and Affiliations

  1. Postgraduate Study Program (MSc) “Cardiopulmonary Resuscitation”, Medical School, National and Kapodistrian University of Athens, Athens, Greece

    Zinais Kontouli, Nicoletta Iacovidou & Evaggelia Kouskouni

  2. Department of Anesthesiology, Medical School, Aretaieio Hospital, National and Kapodistrian University of Athens, Athens, Greece

    Chryssoula Staikou

  3. Department of Neonatology, Medical School, Aretaieio Hospital, National and Kapodistrian University of Athens, Athens, Greece

    Nicoletta Iacovidou

  4. Hellenic Society of Cardiopulmonary Resuscitation, Athens, Greece

    Nicoletta Iacovidou, Panagiotis Papapanagiotou & Athanasios Chalkias

  5. Department of Hygiene, Epidemiology and Medical Statistics, Medical School, National and Kapodistrian University of Athens, Athens, Greece

    Ioannis Mamais

  6. Department of Health Sciences, European University Cyprus, Nicosia, Cyprus

    Ioannis Mamais

  7. Department of Life Sciences, European University Cyprus, Nicosia, Cyprus

    Ioannis Mamais

  8. Department of Biopathology, Medical School, Aretaieio Hospital, National and Kapodistrian University of Athens, Athens, Greece

    Evaggelia Kouskouni

  9. Experimental-Research Centre ELPEN, Athens, Greece

    Apostolos Papalois

  10. Department of Pharmaceutical Sciences, Chicago College of Pharmacy, Midwestern University, Downers Grove, IL, USA

    Anil Gulati

  11. Department of Anesthesiology and Perioperative Medicine, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larisa, Greece

    Athanasios Chalkias

  12. School of Medicine, European University Cyprus, Nicosia, Cyprus

    Theodoros Xanthos

  13. Larisa, Greece

    Athanasios Chalkias

Authors
  1. Zinais Kontouli
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  2. Chryssoula Staikou
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  5. Evaggelia Kouskouni
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  6. Apostolos Papalois
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  7. Panagiotis Papapanagiotou
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  8. Anil Gulati
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  9. Athanasios Chalkias
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  10. Theodoros Xanthos
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Corresponding author

Correspondence to Athanasios Chalkias.

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Conflict of interest

Zinais Kontouli, Chryssoula Staikou, Nicoletta Iacovidou, Ioannis Mamais, Evaggelia Kouskouni, Apostolos Papalois, Panagiotis Papapanagiotou, Anil Gulati, Athanasios Chalkias, and Theodoros Xanthos declare that they have no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Informed consent

Non-applicable. We did not include patients in this study.

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Kontouli, Z., Staikou, C., Iacovidou, N. et al. Resuscitation with centhaquin and 6% hydroxyethyl starch 130/0.4 improves survival in a swine model of hemorrhagic shock: a randomized experimental study. Eur J Trauma Emerg Surg 45, 1077–1085 (2019). https://doi.org/10.1007/s00068-018-0980-1

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