Archives of Emergency Medicine and Critical Care

Fluid Resuscitation in Animal Models of Sepsis: A Comprehensive Review of the Current State of Knowledge

Review | Open Access | Volume 1 | Issue 1

  • 1. Department of Emergency Medicine, University of Mississippi Medical Center, USA
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Corresponding Authors
Alan E. Jones, Department of Emergency Medicine, University of Mississippi Medical Center, 2500 N State Street, Jackson

Sepsis, the systemic response to infection, is the leading cause of death in intensive care units, worldwide. Mortality rates of sepsis exceed 20%, highlighting the need for new approaches of therapy for this disease. Intravenous fluid resuscitation plays a crucial role in sepsis therapy. Most preclinical studies demonstrate an association between IV fluid therapy and improved outcomes in sepsis. The purpose of this review is to summarize the preclinical studies examining outcomes of sepsis associated with different resuscitation fluid types and volume in animal models, and to review studies that have investigated underlying mechanisms by which fluid resuscitation is thought to improve outcomes in sepsis. Data obtained from preclinical studies differ due to use of varied animal species and models of sepsis. The development of appropriate animal models of sepsis and design of experiments that closely mirror the clinical progression of this disease are paramount to enhance our knowledge and understanding of sepsis pathophysiology and develop effective therapies to improve outcomes associated with sepsis.


Cornelius DC, McCalmon M, Tharp J, Puskarich M, Jones AE (2016) Fluid Resuscitation in Animal Models of Sepsis: A Comprehensive Review of the Current State of Knowledge. Arch Emerg Med Crit Care 1(1): 1002.


Sepsis, Animal models, Fluid resuscitation


Severe sepsis, the documented or suspected presence of infection with manifestations of systemic response accompanied by organ dysfunction, affects about 33% of patients in intensive care units (ICUs) and is the leading cause of death in that population. Annual costs for treatment of sepsis in the United States exceed $20 billion annually, presenting a significant economic burden on health care [1]. Even with optimal treatment, mortality due to severe sepsis exceeds 20 to 40% in the case of septic shock [2], highlighting the need for development of new therapeutic strategies for management and treatment of this syndrome.

Animal models are routinely used to understand the biological cascades involved in disease processes and to help determine the viability of various treatment options for human disease. Intravenous (IV) fluid resuscitation is an important part of the optimal treatment protocol for patients with severe sepsis. Various animal models have been used to study the effect of IV fluids on clinical outcomes in sepsis. Moreover, the impact of different types of IV fluids has also been a topic of interest in sepsis research, with longstanding debates regarding the efficacy of colloid resuscitation [3-8] and recent data suggesting harm associated with the administration of large volumes of chloriderich solutions, such as 0.9% saline [9-12].

Fluids used for volume resuscitation can be divided into two broad categories: crystalloids and colloids. An extensive review of the different types of solutions and their specific characteristics and uses for treatment in severe sepsis / septic shock was recently published and is beyond the scope of the current review [13]. The purpose of this manuscript is to examine and summarize the preclinical studies that have assessed the effect of fluid type and volume on outcomes in severe sepsis and/or septic shock animal models. Furthermore, we will review data elucidating the underlying mechanisms by which fluid resuscitation is thought to improve outcomes in sepsis.

Role of intravenous fluid resuscitation in sepsis

Fluid resuscitation serves an important role in sepsis treatment because of the hypovolemia and resultant tissue hypoperfusion that occurs during the disease. The mechanisms of hypovolemia are multifactorial, but include decreased fluid intake, increased insensible fluid loss secondary to tachypnea, and fluid extravasation or “third-spacing” secondary to loss of the barrier function of the endothelium [14,15]. Severe or prolonged.

hypotension is associated with poor outcomes in patients with sepsis [16], while rapid restoration of organ perfusion appears to be associated with lower mortality [17]. Rapid or bolus intravenous fluid administration leads to short-term improvements in hemodynamics and tissue perfusion [18,19]. However, dysfunction of the vasculature leads to redistribution of this fluid into the interstitium resulting in tissue edema, an effect more pronounced with crystalloids than colloids. Nevertheless, given the vascular disruption observed in sepsis, even colloids can redistribute to the extravascular space, and due to their oncotic effects can further exacerbate tissue edema [20,21]. It has been hypothesized that this tissue edema may exacerbate preexisting organ dysfunction, particularly in the case of acute respiratory distress syndrome, and actually lead to worsened outcomes. Therefore, it is critical to understand the mechanisms related to and effects of differing types and volumes of fluid resuscitation during sepsis.

Effect of intravenous resuscitation fluid type on outcomes in sepsis animal models

Different animal models of sepsis have yielded differing conclusions as to which type of solution is better: crystalloid or colloid. A summary of these data are listed in Table 1.

Table 1: Articles examining effect of IV resuscitation fluid type on outcomes in sepsis animal models.

Wafa 2014 Rat CASP IV Microcirculation: plasma extravasation and leukocyte adherence to endothelium HES = RL
Zhang 2003 Rat IV LPS IV Ventilator-induced ALI Albumin = RL
Zhou 2014 Rat CLP subcutaneous AKI and survival Plasma Lyte > 0.9% saline
Kellum 2014 Rat IV LPS IV Survival time and acid base balance Hextens > 0.9% saline or RL
Assaly 2004 Rat IV LPS and CLP IV Plasma extravasation PEG-albumin > albumin or 0.9% saline
Johannes 2009 Rat IV LPS IV Acute renal failure HES + low dose dexamethason > HES alone
Liu 2013 Rat IV LPS IV Lung function Saline+norepinephrine > saline alone
Kim 2012 Rat Intratracheal LPS IV Organ injury HES+PTX > HES, RL or RL+PTX
Santos 2011 Hamsters IV LPS IV Microcirculation and survival 0.9% saline > saline + dopamine
Cohen 1996 Dog IV LPS IV Cardiac function dextran = L-NAME
Qui 2007 Dog Intestinal puncture IV Capillary permeability, VEGF production, pulmonary edema HES > 0.9% or 7.5% saline
Su 2007 Sheep Feces spillage (abdominal peritonitis) IV Survival albumin or HES = RL
Abbreviations: CASP: Colon ascendens stent peritonitis; IV: Intravenous; LPS: Lipopolysaccharide; CLP: Cecal ligation punction; AKI : Acute kidney injury; ALI: Acute lung injury; VEGF: Vascular endothelial growth factor; HES: Hydroxyethyl starch: RL: Ringer’s Lactate; PEG: Polyethylene glycol; PTX : Pentoxifylline; L-NAME: L-NG-Nitroarginine methyl ester

The most widely used species to study fluid resuscitation in sepsis is a small animal model, the rat. In most of these studies, fluid resuscitation is accomplished through IV administration. These studies have provided conflicting data regarding the superiority of any particular type of fluid, but comparisons are limited by differing outcomes and methods of inducing the sepsis response, as well as volume of fluid administered among the studies. In regards to perfusion, studies in a colon ascendens stent peritonitis (CASP) rat model of sepsis determined that use of the colloid hydroxyethyl starch (HES) solutions provided no enhanced benefit on microcirculation when compared to crystalloid solutions [22]. Similarly in terms of organ failure, 5% and 25% albumin showed no superiority over Ringer’s Lactate in an endotoxic rat model of sepsis in its efficacy in reducing ventilator induced lung injury [23]. In contrast, a study of acute kidney injury (AKI) using a rat cecal-ligation and puncture (CLP) model of severe sepsis found that unbalanced crystalloid solution (0.9% NaCl) was inferior compared to a balanced crystalloid (Plasma-Lyte) on development of AKI and survival time [24]. A separate study in an endotoxic rat model reported increased survival time and less metabolic acidosis after resuscitation with the synthetic colloid solution Hextend, compared to saline or Ringer’s lactate (RL) [25].

In addition to comparing crystalloid and colloid solutions alone for fluid resuscitation in sepsis, studies assessing the effect of resuscitation fluids linked with other agents or associated with other drugs have also been conducted. A solution of albumin covalently liked to polyethylene glycol was developed as a resuscitative agent and infused into both the endotoxic and CLP rat models of septic shock. In both models, the conjugated solution decreased capillary leakage and albumin was retained.

in the vessels, thus decreasing the risk of edema injury from fluid resuscitation [26]. Additionally, HES resuscitation coupled with low dose dexamethasone was found to prevent septic acute renal failure in the endotoxic rat model [27]. Resuscitation with saline in conjunction with other drugs has also been tested in the endotoxic septic shock rat model. One study determined that early resuscitation with saline and norepinephrine, simultaneously, was protective against lung injury secondary to early aggressive fluid resuscitation alone [28]; and hypertonic saline combined with pentoxifylline (PTX) was superior in overall treatment of sepsis when compared with HES, RL alone or RL-PTX [29]. In contrast, it has been determined that dopamine is not beneficial in maintaining arteriolar blood flow or functional capillary density when used in conjugation with saline in the endotoxic hamster model. In fact, both doses of dopamine tested reduced tissue perfusion yielding reduced survival times and poorer outcomes compared to resuscitation with saline alone [30].

Though rodents are the most commonly used model of experimental sepsis and they conserve many of the biologic features that are common to mammals, there still remain distinct differences in their response to disease when compared to human responses. These differences may be less pronounced in larger animal models whose physiology is closer to that in humans. Furthermore, in large animals, it is possible to perform serial sampling of body fluids, and obtain detailed assessments of hemodynamic, cardiovascular and other end organ function over multiple time points, similar to what is obtained clinically [31,32]. Therefore, data obtained in larger animal models may be more translatable to treatment of human diseases. In contrast to the mixed findings in small animal models, sepsis studies in large animal models generally favor the use of colloid solution in sepsis. A study in IV LPS-induced endotoxic dogs found that resuscitation with dextran improved cardiac function to the same extent as a nitric oxide (NO) synthase inhibitor, without the risk of excessive vasoconstriction and ischemia [33]. Although this study compared a colloid solution with a diluted enzyme inhibitor, Qui, et al. examined the effect of fluid resuscitation, with crystalloid (0.9% NaCl and 7.5% NaCl) or colloid (HES) solutions, on capillary permeability, vascular endothelial growth factor (VEGF) levels, and development of pulmonary edema in an endotoxic dog model. The authors concluded that HES was superior to both crystalloid solutions in decreasing capillary permeability, VEGF tissue expression, and pulmonary edema [34]. In contrast, a study performed in a sheep model of peritonitis induced sepsis concluded that although the colloids albumin and HES improved cardiac output, oxygen delivery and lowered blood lactate levels, survival was no different than with the use of the crystalloid, RL [35].

In summary, the majority of rodent studies support the use of saline as the preferred resuscitative agent in treatment of severe sepsis and septic shock, though substantial variability in the method to induce sepsis, choice of study outcomes, and multiple concomitant treatment modalities significantly limits generalizations and may account for some of the variable findings among studies. There is a shortage of fluid resuscitation studies in larger vertebrate animals whose physiology and immune systems and response to sepsis may be more relevant to that of humans, though in contrast to rodent models the data that does exist seems to favor colloid resuscitation. However, this data is older and no clear conclusions can be determined from the data acquired from the few studies that have been performed in larger animals in recent years. This highlights a major gap in the area of basic mechanistic understanding of sepsis resuscitation research. Although guidelines are established for the types of fluid used for resuscitation in severe sepsis, research in animals testing these guidelines could provide insight in the mechanisms responsible for differential effects of intravenous fluids, and preclinical study of modifications to guideline recommendations could clarify which patients may benefit from certain types of resuscitation given the significant heterogeneity of the sepsis syndrome in human patients.

Effect of resuscitation fluid volume on outcomes in sepsis animal models

Not only is the type of fluid utilized for resuscitation during sepsis important, but also the volume infused. The goal of fluid resuscitation is to combat hypovolemia and restore blood pressure to maintain perfusion pressure so that adequate blood is received by the tissues [13]. In administering fluids, care must be taken to not overload the patient with fluids, as this can also be detrimental to septic patients and result in edema [36,37] as well as organ damage and dysfunction [36, 38-41]

The number of studies directly comparing fluid volumes is limited, though their results appear congruent (Table 2).

Table 2: Articles examining effect of resuscitation fluid volume on outcomes in sepsis animal models.

mouse CLP subcutaneous every 6 hours Low: 35 ml/kg- T0 
Intermediate: 35 ml/kg T0-T72 
High: 100ml/kg T0-T12; 35 ml/kg 
High volume > Low or 
Wu 2013 Pig IV LPS IV Low: 40 ml/kg;
Intermediate: 80 ml/kg;
High: 120 ml/kg
High volume > Low or 
Yu 1997 Pig IV E. coli IV Fluid administration until pulmonary 
artery occlusion pressure of 12 mmHg 
(high) or 8 mmHg (low)
Higher volume = lower 
Koci 2011 Pig IV E. coli IV 20 ml/kg/hr ~ 24 hrs Positive fluid balance does 
not harm celluar aerobic 
Abbreviations: CLP: Cecal ligation puncture; IV: Intravenous; LPS: Lipopolysaccharide; E. coli: Escheria coli

A mouse CLP model was used to compare the impact of varying subcutaneous fluid resuscitation regimens on cardiovascular performance and survival. In this study, the group receiving high volume (100ml/kg at T0, T6, T12; 35 ml/kg every 6 hours T18-T72) resuscitation with normal saline (5% dextrose) had the most improved CV function and higher survival compared to the low (35ml/kg at T0) and intermediate (35ml/kg at every 6 hours T0-T72) volume groups [42]. Other studies using the endotoxic pig model have drawn similar conclusions: a) higher volumes of fluid resuscitation in early stages of septic shock were superior at maintaining cardiovascular function without causing excessive lung water (pulmonary edema) [43, 44]; and b) a positive fluid balance from high volume resuscitation does not negatively impact cellular metabolism during endotoxic shock [45].

Based on this data, in comparison to fluid type, very few animal studies have focused on the impact of resuscitation volume on sepsis outcomes, and have focused primarily on the impact of aggressive or high volume fluid resuscitation during early sepsis, significantly limiting the generalization of these conclusions. In the clinical setting, patients do not always present during the early stages of sepsis and the impact of fluid volume in relation to timing is an area that requires further research, especially since clinical studies do not illustrate the same uniformly positive response to large volume resuscitation [46-50]. Studies examining the impact of high, intermediate, and low volume resuscitation regimens on cardiovascular performance, development of edema, capillary leakage, organ damage, and overall outcome at various time points during sepsis, both early and late, are needed to fill this knowledge gap. Furthermore, closer observation of the response to fluid resuscitation at various times points in the course of this disease may help to develop criteria for identifying the stage of sepsis in which a patient presents based on their response to

treatment. The ability to determine where a patient is on the disease spectrum may be of great benefit to clinicians in deciding on a course of treatment and may help to make treatment of septic patients more individualized and targeted.

Insights into the mechanisms underlying the outcomes associated with fluid resuscitation in sepsis

Insights into the mechanisms underlying the outcomes associated with fluid resuscitation in sepsis

Early studies in the endotoxic rat determined that circulating TNF-α levels were significantly reduced in resuscitated animals compared to non-resuscitated controls. The lowered TNFα was associated with decreased total peripheral resistance (TPR), higher cardiac index, and higher overall survival [51]. Additional studies using a rabbit model of sepsis highlighted the differences that exist in mechanical responses of different vessels in an organism to fluid resuscitation with saline: fluid resuscitation resulted in relaxation of arteriolar smooth muscle cells, and contraction of aortic smooth muscle cells [52]. We must, therefore, consider the regional and systemic responses to resuscitation treatment and tailor studies and treatments to account for such differences within the individual animal and patient.

Subsequent studies in the rat and hamster determined that NO has a pivotal role in the pathophysiology of sepsis as well as the response to resuscitation with fluids. The endothelium displays a vasodilatory response to fluid loading to accommodate the increase in flow and shear stress. Losser, et al. determined that in endotoxic rats, this endothelial response is impaired due to an alteration in the NO-dependent vasodilation [53]. Using the hamster as a model of LPS-induced sepsis, a recent study determined that increasing or restoring NO bioavailability during sepsis increased functional capillary density and arteriole dilation while decreasing leukocyte endothelial interactions and sequestration. This was associated with an overall increase in survival [54]. Importantly, other studies have determined that too much NO can result in excessive microvascular permeability leading to edema and increased morbidity in sepsis [55]. This highlights the importance of maintaining the delicate balance of NO and possibly other factors during treatment to optimize outcomes associated with fluid resuscitation.

Another factor that has been identified as having an important role in the response to fluid resuscitation is the vasopressin 1 receptor (V1 R). Vasopressin is a neurohypophyseal protein that is essential for cardiovascular homeostasis and is increased in response to shock [56]. Batista, et al. determined that in the endotoxic rat, during periods of low vasopressin secretion, resuscitation with fluids can trigger the release of vasopressin to activate the V1 R which is required for the increased blood pressure response to fluids [57]. This same group later determined that the same pathway was active and responsible for responses to fluid resuscitation in the CLP rat model of severe sepsis [58]. Studies are needed to determine if the vasopressin pathway involvement is conserved in higher vertebrate models of sepsis. Confirmation of these studies may identify factors in the vasopressin pathway that may be targeted for treatment of sepsis.

Due to the small number of studies that have examined the underlying mechanisms mediating responses to fluid resuscitation (Figure 1), there remains a significant knowledge gap in this area, as well. Studies to determine the mechanisms that contribute to both positive and negative responses to fluid resuscitation can identify new therapeutic options for more targeted therapies for this disease. Furthermore, this could result in improvement in management of sepsis and a decrease in morbidity associated with fluid overload.

Mechanisms and outcomes associated with fluid resuscitation therapy in animal models of sepsis.

Figure 1: Mechanisms and outcomes associated with fluid resuscitation therapy in animal models of sepsis


Due to the small number of studies that have examined the underlying mechanisms mediating responses to fluid resuscitation (Figure 1), there remains a significant knowledge gap in this area, as well. Studies to determine the mechanisms that contribute to both positive and negative responses to fluid resuscitation can identify new therapeutic options for more targeted therapies for this disease. Furthermore, this could result in improvement in management of sepsis and a decrease in morbidity associated with fluid overload. 

differences within animal species, and differences in models used to induce sepsis. There remains a need for the development of more appropriate animal models of sepsis where induction of sepsis is more closely comparable to that of sepsis in humans. Furthermore, the course of the disease and responses to current therapy should also mimic those observed in patients. Only after these conditions are optimized can we move forward in identifying underlying mechanisms that contribute to the pathophysiology associated with sepsis progression and patient responses to treatment. Identification of these pathways could then be used as reliable therapeutic targets, both immunological and physiological, and better understanding of the natural history of this devastating disease.


Dr. Cornelius has received salary support through 16SDG27520000 from the American Heart Association. Dr. Puskarich has received salary support throughK23GM113041-01 from the National Institute of General Medical Sciences/National Institutes of Health.


1. Stevenson EK, Rubenstein AR, Radin GT, Wiener RS, Walkey AJ. Two decades of mortality trends among patients with severe sepsis: a comparative meta-analysis. Crit Care Med. 2014; 42: 625-631.

2. Kaukonen KM, Bailey M, Suzuki S, Pilcher D, Bellomo R. Mortality related to severe sepsis and septic shock among critically ill patients in Australia and New Zealand, 2000-2012. JAMA. 2014; 311: 1308- 1316.

3. Patel A, Laffan MA, Waheed U, Brett SJ. Randomised trials of human albumin for adults with sepsis: systematic review and meta-analysis with trial sequential analysis of all-cause mortality. BMJ. 2014; 349: 4561.

4. Farrugia A, Bansal M, Balboni S, Kimber MC, Martin GS, Cassar J. Choice of Fluids in Severe Septic Patients - A Cost-effectiveness Analysis Informed by Recent Clinical Trials. Rev Recent Clin Trials. 2014; 9: 21-30.

5. Perner A, Haase N, Wetterslev J, Aneman A, Tenhunen J, Guttormsen AB, et al. Comparing the effect of hydroxyethyl starch 130/0.4 with balanced crystalloid solution on mortality and kidney failure in patients with severe sepsis (6S--Scandinavian Starch for Severe Sepsis/Septic Shock trial): study protocol, design and rationale for a double-blinded, randomised clinical trial. Trials, 2011; 12: 24.

6. Ertmer C, Rehberg S, Van Aken H, Westphal M. Relevance of nonalbumin colloids in intensive care medicine. Best Pract Res Clin Anaesthesiol. 2009; 23: 193-212.

7. Fan E, Stewart TE. Albumin in critical care: SAFE, but worth its salt? Crit Care. 2004; 8: 297-299.

8. Velanovich V. Crystalloid versus colloid fluid resuscitation: a metaanalysis of mortality. Surgery. 1989; 105: 65-71.

9. VAN DE Louw A, Shaffer C, Schaefer E. Early intensive care unitacquired hypernatremia in severe sepsis patients receiving 0.9% saline fluid resuscitation. Acta Anaesthesiol Scand. 2014; 58:1007- 1114.

10. Besen BA, Gobatto AL, Melro LM, Maciel AT, Park M. Fluid and electrolyte overload in critically ill patients: An overview. World J Crit Care Med, 2015; 4:116-129.

11. Shaw AD, Raghunathan K, Peyerl FW, Munson SH, Paluszkiewicz SM, Schermer CR. Association between intravenous chloride load during resuscitation and in-hospital mortality among patients with SIRS. Intensive Care Med, 2014; 40:1897-1905.

12. Shaw AD, Schermer CR, Lobo DN, Munson SH, Khangulov V, Hayashida DK, Kellum J et al. Impact of intravenous fluid composition on outcomes in patients with systemic inflammatory response syndrome. Crit Care. 2015; 19: 334. 

13. Corrêa TD, Rocha LL, Pessoa CM, Silva E, de Assuncao MS. Fluid therapy for septic shock resuscitation: which fluid should be used? Einstein (Sao Paulo). 2015; 13: 462-468.

14. Rivers EP, Jaehne AK, Eichhorn-Wharry L, Brown S, Amponsah D. Fluid therapy in septic shock. Curr Opin Crit Care. 2010; 16: 297-308. 15.Jones AE, Puskarich MA. Sepsis-induced tissue hypoperfusion. Crit Care Nurs Clin North Am. 2011; 23: 115-125. 16.Jones AE, Yiannibas V, Johnson C, Kline JA. Kline. Emergency department hypotension predicts sudden unexpected in-hospital mortality: a prospective cohort study. Chest. 2006; 130:941-946.

17. Jones AE, Brown MD, Trzeciak S, Shapiro NI, Garrett JS, Heffner AC, et al. Emergency Medicine Shock Research Network investigators. The effect of a quantitative resuscitation strategy on mortality in patients with sepsis: a meta-analysis. Crit Care Med. 2008; 36: 2734-2739.

18. Marik P, Bellomo R. A rational approach to fluid therapy in sepsis. Br J Anaesth. 2016; 116: 339-349.

19. Marik PE. Early management of severe sepsis: concepts and controversies. Chest. 2014; 145: 1407-1418.

20. Myburgh JA. Fluid resuscitation in acute medicine: what is the current situation? J Intern Med. 2015; 277: 58-68.

21. Karakala N, Raghunathan K, Shaw AD. Intravenous fluids in sepsis: what to use and what to avoid. Curr Opin Crit Care. 2013; 19: 537-543.

22. Wafa K, Herrmann A, Kuhnert T, Wegner A, Gründling M, Pavlovic D, et al, Short time impact of different hydroxyethyl starch solutions on the mesenteric microcirculation in experimental sepsis in rats. Microvasc Res. 2014; 95:88-93.

23. Zhang H, Voglis S, Kim CH, Slutsky AS. Effects of albumin and Ringer’s lactate on production of lung cytokines and hydrogen peroxide after resuscitated hemorrhage and endotoxemia in rats. Crit Care Med, 2003; 31:1515-1522

24. Zhou F, Peng ZY, Bishop JV, Cove ME, Singbartl K, Kellum JA, et al. Effects of fluid resuscitation with 0.9% saline versus a balanced electrolyte solution on acute kidney injury in a rat model of sepsis. Crit Care Med, 2014; 42: 270-278.

25. Kellum JA. Fluid resuscitation and hyperchloremic acidosis in experimental sepsis: improved short-term survival and acid-base balance with Hextend compared with saline. Crit Care Med. 2002; 30: 300-305.

26. Assaly RA, Azizi M, Kennedy DJ, Amauro C, Zaher A, Houts FW, et al. Plasma expansion by polyethylene-glycol-modified albumin. Clin Sci (Lond). 2004; 107: 263-272.

27. Johannes T, Mik EG, Klingel K, Dieterich HJ, Unertl KE, Ince C, et al. Low-dose dexamethasone-supplemented fluid resuscitation reverses endotoxin-induced acute renal failure and prevents cortical microvascular hypoxia. Shock, 2009; 31:521-528.

28. Liu W, Shan LP, Dong XS, Liu XW, Ma T, Liu Z. et al. Effect of early fluid resuscitation on the lung in a rat model of lipopolysaccharide-induced septic shock. Eur Rev Med Pharmacol Sci. 2013; 17:161-169.

29. Kim HJ, Lee KH. The effectiveness of hypertonic saline and pentoxifylline (HTS-PTX) resuscitation in haemorrhagic shock and sepsis tissue injury: comparison with LR, HES, and LR-PTX treatments. Injury, 2012; 43: 1271-1276.

30. Santos AO, Furtado ES, Villela NR, Bouskela E. Microcirculatory effects of fluid therapy and dopamine, associated or not to fluid therapy, in endotoxemic hamsters. Clin Hemorheol Microcirc. 2011; 47:1-13.

31. Zanotti-Cavazzoni SL, Goldfarb RD. Animal models of sepsis. Crit Care Clin. 2009; 25: 703-719.

32. Nemzek JA, Hugunin KM, Opp MR. Modeling sepsis in the laboratory: merging sound science with animal well-being. Comp Med. 2008; 58: 120-128.

33. Cohen RI, Huberfeld S, Genovese J, Steinberg HN, Scharf SM. A comparison between the acute effects of nitric oxide synthase inhibition and fluid resuscitation on myocardial function and metabolism in entotoxemic dogs. J Crit Care, 1996; 11: 27-36.

34. Qiu YZ, Sun H, Li F. [Effect of fluid resuscitation on capillary permeability and vascular endothelial growth factor in dogs with septic shock]. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. 2007; 19: 270- 273.

35. Su F, Wang Z, Cai Y, Rogiers P, Vincent JL. Fluid resuscitation in severe sepsis and septic shock: albumin, hydroxyethyl starch, gelatin or ringer’s lactate-does it really make a difference? Shock. 2007; 27: 520-526.

36. Larsen TR, Singh G, Velocci V, Nasser M, Mc Cullough PA. Mc Cullough, et al. Frequency of fluid overload and usefulness of bioimpedance in patients requiring intensive care for sepsis syndromes. Proc (Bayl Univ Med Cent), 2016; 29:12-15.

37. Fishel RS, Are C, Barbul A. Vessel injury and capillary leak. Crit Care Med. 2003; 31: S502-511.

38. Murphy CV, Schramm GE, Doherty JA, Reichley RM, Gajic O, Afessa B, et al. The importance of fluid management in acute lung injury secondary to septic shock. Chest. 2009; 136: 102-109.

39. Arikan AA, Zappitelli M, Goldstein SL, Naipaul A, Jefferson LS, Loftis LL, et al. Fluid overload is associated with impaired oxygenation and morbidity in critically ill children. Pediatr Crit Care Med. 2012; 13: 253-258.

40. Van Biesen W, Yegenaga I, Vanholder R, Verbeke F, Hoste E, Colardyn F, et al, Relationship between fluid status and its management on acute renal failure (ARF) in intensive care unit (ICU) patients with sepsis: a prospective analysis. J Nephrol, 2005; 18: 54-60.

41. National Heart, Lung, and Blood Institute Acute Respiratory Distress Syndrome (ARDS) Clinical Trials Network, Wiedemann HP, Wheeler AP, Bernard GR, Thompson BT, Hayden D, et al. Comparison of two fluid-management strategies in acute lung injury. N Engl J Med, 2006; 354: 2564-2575.

42. Zanotti-Cavazzoni SL, Guglielmi M, Parrillo JE, Walker T, Dellinger RP, Hollenberg SM, et al. Fluid resuscitation influences cardiovascular performance and mortality in a murine model of sepsis. Intensive Care Med. 2009; 35: 748-754.

43. Wu F, Lu GP, Lu ZJ, Wu JL, Li Z, Hong JG, et al. [Changes of the hemodynamics and extravascular lung water after different-volume fluid resuscitation in a piglet model of endotoxic shock]. Zhonghua Er Ke Za Zhi, 2013; 51:649-653.

44. Yu M, Hasaniya NW, Takanishi DM, Caldeira A, Caldeira CC, Char E, et al. High-volume vs standard fluid therapy in a septic pig model. Impact on pulmonary function. Arch Surg. 1997; 132: 1111-1115.

45. Koci J, Oberreiter M, Hyspler R, Ticha A, Valis M, Lochman P, et al. A positive fluid balance does not deteriorate tissue metabolism during fluid resuscitation of sepsis. Neuro Endocrinol Lett, 2011; 32: p. 345- 348.

46. Skellett S, Mayer A, Durward A, Tibby SM, Murdoch IA. Chasing the base deficit: hyperchloraemic acidosis following 0.9% saline fluid resuscitation. Arch Dis Child. 2000; 83: 514-516.

47. Noritomi DT, Soriano FG, Kellum JA, Cappi SB, Biselli PJ, Libório AB, et al. Metabolic acidosis in patients with severe sepsis and septic shock: a longitudinal quantitative study. Crit Care Med. 2009; 37: 2733-2739. 

48. O’Dell E, Tibby SM, Durward A, Murdoch IA. Murdoch, Hyperchloremia is the dominant cause of metabolic acidosis in the postresuscitation phase of pediatric meningococcal sepsis. Crit Care Med, 2007; 35: 2390-2394.

49. Chang DW, Huynh R, Sandoval E, Han N, Coil CJ, Spellberg BJ, et al. Volume of fluids administered during resuscitation for severe sepsis and septic shock and the development of the acute respiratory distress syndrome. J Crit Care. 2014; 29:1011-1015.

50. Smorenberg A, Ince C, Groeneveld AJ. Dose and type of crystalloid fluid therapy in adult hospitalized patients. Perioper Med (Lond). 2013; 2: 17.

51. Smith EF 3rd, Slivjak MJ, Egan JW, Gagnon R, Arleth AJ, Esser KM, et al. Fluid resuscitation improves survival of endotoxemic or septicemic rats: possible contribution of tumor necrosis factor. Pharmacology. 1993; 46: 254-267.

52. Cholley BP, Lang RM, Berger DS, Korcarz C, Payen D, Shroff SG. Alterations in systemic arterial mechanical properties during septic shock: role of fluid resuscitation. Am J Physiol. 1995; 269: 375-384.

53. Losser MR, Forget AP, Payen D. Nitric oxide involvement in the hemodynamic response to fluid resuscitation in endotoxic shock in rats. Crit Care Med. 2006; 34: 2426-2431.

54. Villela NR, dos Santos AO, de Miranda ML, Bouskela E. Fluid resuscitation therapy in endotoxemic hamsters improves survival and attenuates capillary perfusion deficits and inflammatory responses by a mechanism related to nitric oxide. J Transl Med. 2014; 12: 232.

55. Singh S, Anning PB, Winlove CP, Evans TW. Regional transcapillary albumin exchange in rodent endotoxaemia: effects of fluid resuscitation and inhibition of nitric oxide synthase. Clin Sci (Lond), 2001; 100: 81-89.

56. Holmes CL, Landry DW, Granton JT. Science review: Vasopressin and the cardiovascular system part 1--receptor physiology. Crit Care. 2003; 7: 427-434.

57. Batista MB, Bravin AC, Lopes LM, Gerenuti E, Elias LL, AntunesRodrigues J, et al. Pressor response to fluid resuscitation in endotoxic shock: involvement of vasopressin. Crit Care Med, 2009; 37: 2968- 2972.

58. Santiago MB, Vieira AA, Elias LL, Rodrigues JA, Giusti-Paiva A. Neurohypophyseal response to fluid resuscitation with hypertonic saline during septic shock in rats. Exp Physiol. 2013; 98: 556-563.

Cornelius DC, McCalmon M, Tharp J, Puskarich M, Jones AE (2016) Fluid Resuscitation in Animal Models of Sepsis: A Comprehensive Review of the Current State of Knowledge. Arch Emerg Med Crit Care 1(1): 1002.

Received : 28 Mar 2016
Accepted : 20 May 2016
Published : 21 May 2016
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ISSN : 2573-1165
Launched : 2016
JSM Nutritional Disorders
ISSN : 2578-3203
Launched : 2017
Annals of Neurodegenerative Disorders
ISSN : 2476-2032
Launched : 2016
Journal of Fever
ISSN : 2641-7782
Launched : 2017
JSM Bone Marrow Research
ISSN : 2578-3351
Launched : 2016
JSM Mathematics and Statistics
ISSN : 2578-3173
Launched : 2014
Journal of Autoimmunity and Research
ISSN : 2573-1173
Launched : 2014
JSM Arthritis
ISSN : 2475-9155
Launched : 2016
JSM Head and Neck Cancer-Cases and Reviews
ISSN : 2573-1610
Launched : 2016
JSM General Surgery Cases and Images
ISSN : 2573-1564
Launched : 2016
JSM Anatomy and Physiology
ISSN : 2573-1262
Launched : 2016
JSM Dental Surgery
ISSN : 2573-1548
Launched : 2016
Annals of Emergency Surgery
ISSN : 2573-1017
Launched : 2016
Annals of Mens Health and Wellness
ISSN : 2641-7707
Launched : 2017
Journal of Preventive Medicine and Health Care
ISSN : 2576-0084
Launched : 2018
Journal of Chronic Diseases and Management
ISSN : 2573-1300
Launched : 2016
Annals of Vaccines and Immunization
ISSN : 2378-9379
Launched : 2014
JSM Heart Surgery Cases and Images
ISSN : 2578-3157
Launched : 2016
Annals of Reproductive Medicine and Treatment
ISSN : 2573-1092
Launched : 2016
JSM Brain Science
ISSN : 2573-1289
Launched : 2016
JSM Biomarkers
ISSN : 2578-3815
Launched : 2014
JSM Biology
ISSN : 2475-9392
Launched : 2016
Archives of Stem Cell and Research
ISSN : 2578-3580
Launched : 2014
Annals of Clinical and Medical Microbiology
ISSN : 2578-3629
Launched : 2014
JSM Pediatric Surgery
ISSN : 2578-3149
Launched : 2017
Journal of Memory Disorder and Rehabilitation
ISSN : 2578-319X
Launched : 2016
JSM Tropical Medicine and Research
ISSN : 2578-3165
Launched : 2016
JSM Head and Face Medicine
ISSN : 2578-3793
Launched : 2016
JSM Cardiothoracic Surgery
ISSN : 2573-1297
Launched : 2016
JSM Bone and Joint Diseases
ISSN : 2578-3351
Launched : 2017
JSM Bioavailability and Bioequivalence
ISSN : 2641-7812
Launched : 2017
JSM Atherosclerosis
ISSN : 2573-1270
Launched : 2016
Journal of Genitourinary Disorders
ISSN : 2641-7790
Launched : 2017
Journal of Fractures and Sprains
ISSN : 2578-3831
Launched : 2016
Journal of Autism and Epilepsy
ISSN : 2641-7774
Launched : 2016
Annals of Marine Biology and Research
ISSN : 2573-105X
Launched : 2014
JSM Health Education & Primary Health Care
ISSN : 2578-3777
Launched : 2016
JSM Communication Disorders
ISSN : 2578-3807
Launched : 2016
Annals of Musculoskeletal Disorders
ISSN : 2578-3599
Launched : 2016
Annals of Virology and Research
ISSN : 2573-1122
Launched : 2014
JSM Renal Medicine
ISSN : 2573-1637
Launched : 2016
Journal of Muscle Health
ISSN : 2578-3823
Launched : 2016
JSM Genetics and Genomics
ISSN : 2334-1823
Launched : 2013
JSM Anxiety and Depression
ISSN : 2475-9139
Launched : 2016
Clinical Journal of Heart Diseases
ISSN : 2641-7766
Launched : 2016
Annals of Medicinal Chemistry and Research
ISSN : 2378-9336
Launched : 2014
JSM Pain and Management
ISSN : 2578-3378
Launched : 2016
JSM Women's Health
ISSN : 2578-3696
Launched : 2016
Clinical Research in HIV or AIDS
ISSN : 2374-0094
Launched : 2013
Journal of Endocrinology, Diabetes and Obesity
ISSN : 2333-6692
Launched : 2013
Journal of Substance Abuse and Alcoholism
ISSN : 2373-9363
Launched : 2013
JSM Neurosurgery and Spine
ISSN : 2373-9479
Launched : 2013
Journal of Liver and Clinical Research
ISSN : 2379-0830
Launched : 2014
Journal of Drug Design and Research
ISSN : 2379-089X
Launched : 2014
JSM Clinical Oncology and Research
ISSN : 2373-938X
Launched : 2013
JSM Bioinformatics, Genomics and Proteomics
ISSN : 2576-1102
Launched : 2014
JSM Chemistry
ISSN : 2334-1831
Launched : 2013
Journal of Trauma and Care
ISSN : 2573-1246
Launched : 2014
JSM Surgical Oncology and Research
ISSN : 2578-3688
Launched : 2016
Annals of Food Processing and Preservation
ISSN : 2573-1033
Launched : 2016
Journal of Radiology and Radiation Therapy
ISSN : 2333-7095
Launched : 2013
JSM Physical Medicine and Rehabilitation
ISSN : 2578-3572
Launched : 2016
Annals of Clinical Pathology
ISSN : 2373-9282
Launched : 2013
Annals of Cardiovascular Diseases
ISSN : 2641-7731
Launched : 2016
Journal of Behavior
ISSN : 2576-0076
Launched : 2016
Annals of Clinical and Experimental Metabolism
ISSN : 2572-2492
Launched : 2016
Clinical Research in Infectious Diseases
ISSN : 2379-0636
Launched : 2013
JSM Microbiology
ISSN : 2333-6455
Launched : 2013
Journal of Urology and Research
ISSN : 2379-951X
Launched : 2014
Journal of Family Medicine and Community Health
ISSN : 2379-0547
Launched : 2013
Annals of Pregnancy and Care
ISSN : 2578-336X
Launched : 2017
JSM Cell and Developmental Biology
ISSN : 2379-061X
Launched : 2013
Annals of Aquaculture and Research
ISSN : 2379-0881
Launched : 2014
Clinical Research in Pulmonology
ISSN : 2333-6625
Launched : 2013
Journal of Immunology and Clinical Research
ISSN : 2333-6714
Launched : 2013
Annals of Forensic Research and Analysis
ISSN : 2378-9476
Launched : 2014
JSM Biochemistry and Molecular Biology
ISSN : 2333-7109
Launched : 2013
Annals of Breast Cancer Research
ISSN : 2641-7685
Launched : 2016
Annals of Gerontology and Geriatric Research
ISSN : 2378-9409
Launched : 2014
Journal of Sleep Medicine and Disorders
ISSN : 2379-0822
Launched : 2014
JSM Burns and Trauma
ISSN : 2475-9406
Launched : 2016
Chemical Engineering and Process Techniques
ISSN : 2333-6633
Launched : 2013
Annals of Clinical Cytology and Pathology
ISSN : 2475-9430
Launched : 2014
JSM Allergy and Asthma
ISSN : 2573-1254
Launched : 2016
Journal of Neurological Disorders and Stroke
ISSN : 2334-2307
Launched : 2013
Annals of Sports Medicine and Research
ISSN : 2379-0571
Launched : 2014
JSM Sexual Medicine
ISSN : 2578-3718
Launched : 2016
Annals of Vascular Medicine and Research
ISSN : 2378-9344
Launched : 2014
JSM Biotechnology and Biomedical Engineering
ISSN : 2333-7117
Launched : 2013
Journal of Hematology and Transfusion
ISSN : 2333-6684
Launched : 2013
JSM Environmental Science and Ecology
ISSN : 2333-7141
Launched : 2013
Journal of Cardiology and Clinical Research
ISSN : 2333-6676
Launched : 2013
JSM Nanotechnology and Nanomedicine
ISSN : 2334-1815
Launched : 2013
Journal of Ear, Nose and Throat Disorders
ISSN : 2475-9473
Launched : 2016
JSM Ophthalmology
ISSN : 2333-6447
Launched : 2013
Journal of Pharmacology and Clinical Toxicology
ISSN : 2333-7079
Launched : 2013
Annals of Psychiatry and Mental Health
ISSN : 2374-0124
Launched : 2013
Medical Journal of Obstetrics and Gynecology
ISSN : 2333-6439
Launched : 2013
Annals of Pediatrics and Child Health
ISSN : 2373-9312
Launched : 2013
JSM Clinical Pharmaceutics
ISSN : 2379-9498
Launched : 2014
JSM Foot and Ankle
ISSN : 2475-9112
Launched : 2016
JSM Alzheimer's Disease and Related Dementia
ISSN : 2378-9565
Launched : 2014
Journal of Addiction Medicine and Therapy
ISSN : 2333-665X
Launched : 2013
Journal of Veterinary Medicine and Research
ISSN : 2378-931X
Launched : 2013
Annals of Public Health and Research
ISSN : 2378-9328
Launched : 2014
Annals of Orthopedics and Rheumatology
ISSN : 2373-9290
Launched : 2013
Journal of Clinical Nephrology and Research
ISSN : 2379-0652
Launched : 2014
Annals of Community Medicine and Practice
ISSN : 2475-9465
Launched : 2014
Annals of Biometrics and Biostatistics
ISSN : 2374-0116
Launched : 2013
JSM Clinical Case Reports
ISSN : 2373-9819
Launched : 2013
Journal of Cancer Biology and Research
ISSN : 2373-9436
Launched : 2013
Journal of Surgery and Transplantation Science
ISSN : 2379-0911
Launched : 2013
Journal of Dermatology and Clinical Research
ISSN : 2373-9371
Launched : 2013
JSM Gastroenterology and Hepatology
ISSN : 2373-9487
Launched : 2013
Annals of Nursing and Practice
ISSN : 2379-9501
Launched : 2014
JSM Dentistry
ISSN : 2333-7133
Launched : 2013
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