Secondary Logo

Journal Logo

Colloids and the Microcirculation

He, Huaiwu PhD*; Liu, Dawei PhD*; Ince, Can PhD†,‡

doi: 10.1213/ANE.0000000000002620
Basic Science
Continuing Medical Education

Colloid solutions have been advocated for use in treating hypovolemia due to their expected effect on improving intravascular retention compared with crystalloid solutions. Because the ultimate desired effect of fluid resuscitation is the improvement of microcirculatory perfusion and tissue oxygenation, it is of interest to study the effects of colloids and crystalloids at the level of microcirculation under conditions of shock and fluid resuscitation, and to explore the potential benefits of using colloids in terms of recruiting the microcirculation under conditions of hypovolemia. This article reviews the physiochemical properties of the various types of colloid solutions (eg, gelatin, dextrans, hydroxyethyl starches, and albumin) and the effects that they have under various conditions of hypovolemia in experimental and clinical scenarios.

From the *Department of Critical Care Medicine, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, China

Department of Translational Physiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands

Department of Intensive Care, Erasmus MC, University Hospital Rotterdam, Rotterdam, the Netherlands.

Published ahead of print November 1, 2017.

Accepted for publication September 27, 2017.

Funding: H. He received funding from the China Scholarship Council (No. 201608110082) and the Organization Department of Beijing Municipal Committee (No. 2015000020124G072). C. Ince has received honoraria and independent research grants from Fresenius-Kabi, Bad Homburg, Germany, and Baxter HealthCare, Deerfield, IL.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Can Ince, PhD, Department of Intensive Care, Erasmus Medical Center, s-Gravendijkwal 230, 3015 CE Rotterdam, the Netherlands. Address e-mail to

The composition and amount of fluid solutions used to treat hypovolemia in critical illness and anesthesia continue to be controversial, with debates continuing about various aspects of colloids versus crystalloids, balanced versus nonbalanced, and the use of different bicarbonate precursors (eg, lactate and acetate). In addition, flow-based intravenous management of fluid administration, also referred to as goal-directed administration of fluid resuscitation at the macrocirculation level, has been suggested as a standard of care for clinical practice.1,2 However, more and more evidence is emerging that fluid resuscitation, while being effective in improving the macrocirculation, does not always result in a parallel improvement in the perfusion of the microcirculation.3,4 Hence, the evaluation of global circulation on its own seems to be insufficient in guiding fluid resuscitation if the ultimate aim is, as is generally agreed on, to promote microcirculatory flow perfusion.5 That is why monitoring the microcirculation is relevant to guide fluid therapy, especially under conditions of circulatory shock.6,7

Investigation of the impact of colloid and crystalloids on tissue perfusion requires the study of the impact of the various types of the solution on microcirculatory hemodynamics under different conditions of shock and hypovolemia. The introduction of hand-held vital microscopy has allowed these issues to be investigated at the bedside by measuring the effect of such solutions on the microcirculation, measured mostly sublingually. Hand-held vital microscopy has been used to evaluate the microcirculatory response to many other interventions in critically ill patients, such as blood transfusions, vasoactive agents, and anti-inflammatory drugs. Moreover, the basic status of the microcirculation can also provide information about the potential response of microcirculation before the implementation of interventions, as well as allow evaluation of the efficacy of medical interventions.7

In this article, we review the literature on the use of colloids both experimentally and clinically in terms of their effects on microcirculatory hemodynamics, asking whether there is experimental evidence for the expected theoretical advantage of using colloids over crystalloids under conditions of hypovolemia and shock at the level of the microcirculation.

Back to Top | Article Outline


Colloid fluids are crystalloid electrolyte solutions containing a high molecular weight substance that retains the solution in the intravascular compartment due to colloid osmotic pressure. Crystalloids can freely pass through the vascular barrier either directly through the endothelial barrier and/or through the fenestration and pores comprising the intercellular junctions of the blood vessels in the microcirculation of the various organs. Colloids, however, would be expected to be better retained in the intravascular space. Indeed, many studies have shown that colloids have a stronger intravascular volume expansion effect and have a greater intravascular persistence when compared to crystalloids in fluid resuscitation and even under septic conditions when the vascular barrier is compromised.8–12 There are different types of colloid solutions; however, these may have different physiological properties due to their different physicochemical properties. Commonly, colloid solutions in clinical practice include gelatin, dextran, hydroxyethyl starch (HES), and human albumin.

Gelatins, which are derived mainly from bovine collagen, were the first fully artificial colloid solutions used for the treatment of shock in World War I.13 The advantages of gelatin include a significant oncotic effect, lower cost than albumin and other synthetic colloids, no limit of infusion, and rapid excretion by the kidney. The disadvantages of gelatins included anaphylactoid reactions and circulatory disturbance with increased plasma renin activity. Dextrans are derived from sucrose by Leuconostoc bacteria and have been used as a substitute for plasma for fluid resuscitation along with gelatin at the end of World War II.14 Currently, dextrans are rarely used for fluid resuscitation in clinical practice due to several adverse effects (eg, impairment of coagulation and renal function and anaphylactic reactions).15 However, dextrans continue to be used to improve local microcirculatory flow by decreasing blood viscosity and impeding erythrocyte aggregation and antiplatelet activity in microsurgery.16 HES is derived from the starch of either potatoes or maize. Sethi et al17 reported that both potato- and maize-derived HES had the same effect on blood coagulation and pulmonary, renal, and hepatic function when used to prime the cardiopulmonary bypass circuit in patients undergoing coronary artery bypass grafting. Tetrastarch, which was introduced as the third-generation production of HES to correct some of the side effects of previous-generation HES solutions, has a degree of substitution of 0.4 or 0.42 (HES 130/0.4 and 130/0.42) with fewer side effects, and is the most advanced HES solution to date and the most frequently used for perioperative settings.18 Recent studies, however, have suggested that HES may have deleterious effects on kidney function, requiring renal replacement therapy in critically ill patients.19–21 However, the methodological design of these trials and the conclusions drawn from the results have been questioned.22,23 Human serum albumin is derived by blood fractionation from human plasma and was used to resuscitate burn patients in the Pearl Harbor attack in 1941. A 4%–5% human albumin solution is dissolved in isotonic saline, and a 20%–25% solution is dissolved in hypotonic saline. Albumin replacement compared to crystalloid resuscitation did not improve the rate of survival at 28 and 90 days in the septic patients.24 Frenette et al25 found that albumin administration was associated with a dose-dependent risk of acute kidney injury in cardiac surgery. In this context, it should be underscored that all fluid solution, irrespective of composition, can harm the kidney if the fluid is not administered to a proper target chosen according to the pathophysiological principle. The characteristics of the different types of colloids solution and normal saline are summarized in the Table.



Back to Top | Article Outline


Because the improvement of microcirculatory perfusion is the ultimate aim of fluid resuscitation,5 investigations directed at understanding microcirculatory hemodynamics are essential to understand the functional impact of colloid solutions on the microcirculation. Microcirculatory blood flow transport of oxygen (O2)-carrying red blood cells (RBCs) to the capillaries and the passive diffusion of O2 leaving the RBCs together determine the O2 extraction capacity of the tissue cells to meet the needs of the respiring mitochondria to achieve adenosine triphosphate production by oxidative phosphorylation. Essentially, there are 2 main determinants of O2 transport to tissue at the microcirculatory level: (1) convection, which is reflected by the blood flow transport of O2-carrying RBCs to the capillaries; and (2) diffusion, which is reflected by the density of capillaries filled with flowing O2-carrying RBCs.

We previously described how microcirculatory hemodynamic measurements can be used to guide and optimize fluid administration in terms of convection and diffusion.6 The beneficial effects of fluid infusion on microcirculatory hemodynamics include increased microcirculatory convection flow and expanded microvascular volume to recruit the microcirculation. In doing so, care must be taken to avoid the detrimental effect of fluid infusion on microcirculatory hemodynamics. These include impairment of microcirculatory diffusion due to hemodilution and tissue edema caused by capillary leakage from high capillary pressure, both of which can reduce the functional capillary density (FCD) of microcirculation. The potential benefit and detrimental effects of fluid resuscitation are summarized in the Figure.



The current conventionally applied emphasis when choosing targets for administering fluids is on increasing global blood flow with the presumed aim of improving microcirculatory flow. However, whether this actually occurs or not in clinical practice is unknown. Maintaining mainstream flow is certainly essential for the resuscitation of microcirculatory blood flow, but only if it results in increased FCD and microcirculatory RBC convection and O2 diffusion because these processes are key components for ensuring adequate O2 transport to tissue cells. However, too much fluid administration, as can occur during excessive hemodilution and tissue edema, can decrease FCD, making it more difficult for O2 to reach the cells by diffusion. Therefore, both microcirculatory convection and diffusion function should be considered to determine an optimal volume status in fluid resuscitation.6

Back to Top | Article Outline


Treating hypovolemia and avoiding excessive hemodilution and tissue edema characterize the hemodynamic challenge in the fluid resuscitation of hemorrhagic shock. That is why colloid solutions present several advantages concerning microcirculation recruitment during therapeutic fluid resuscitation for treatment of hemorrhagic shock. These include a better microvascular volume expansion with low capillary leakage combined with a higher viscosity, leading to a better recruitment of capillaries when compared to crystalloids. A number of animal studies have found that colloid solutions perform better in microcirculation recruitment (ie, increased FCD) when compared to crystalloids in hemorrhagic shock models. A recent systemic review summarized 71 studies of fluid resuscitation for microcirculation in a hemorrhagic shock animal model.26 The authors found that 14 of 19 studies supported the idea that a high osmotic/oncotic property of the fluid solution is an important factor in achieving and restoring the microcirculatory flow, and that 10 of 12 studies supported the fact that increased fluid viscosity was superior to normal or reduced fluid viscosity in the restoration of microcirculation.

In addition, experimental studies have demonstrated that resuscitation with a hypertonic/hyperoncotic solution (hypertonic saline + HES or human albumin) could lead to a rapid recovery of microcirculatory parameters and reduce lung tissue damage and pulmonary edema in hemorrhagic shock.27,28 Moreover, Vajda et al29 found that hypertonic/hyperoncotic solution (7.2% saline + 10% HES) induces a considerable improvement of the microcirculatory flow heterogeneity in the small intestine. Makiko et al30 showed that intravenous infusion of HES more effectively maintains the rabbit ear microcirculation, hemodynamics, and colloid osmotic pressure in a model of acute severe hemorrhagic than Ringer’s solution. Wu et al,31 however, recently found that intestinal microcirculation was restored only by a colloid solution (4% succinylated gelatin and 6% HES) when compared to normal saline in a rodent model of hemorrhagic shock.

Correction of blood viscosity is thought to play an important role in the restoration of the microcirculation in hemorrhagic shock. Studies have shown that blood viscosity is an independent regulator of microvascular blood flow.32–34 A low blood viscosity caused by severe hemodilution can result in microvascular flow maldistribution and impaired tissue O2 delivery.32 Experimental studies have supported the idea that using colloid solutions to increase blood viscosity is beneficial for correcting microvascular flow maldistribution and recruiting perfused capillaries.26 Moreover, clinical studies have also found that the use of viscous fluids such as blood or colloids is an effective method of recruiting previously unfilled capillaries and increasing the FCD.35 On the other hand, a too-high viscosity can also increase the resistance of blood flow and impair microcirculatory flow in nonhemodilution conditions based on the physiological concept. Zimmerman et al36 found that blood transfusion did not increase O2 delivery when hematocrit was >60% with a too-high blood viscosity. A study found that an acute hemodilution (hematocrit was diluted from 57% to 30%) did not improve the impairment of sublingual microcirculatory flow and decreased the O2 delivery in chronic polycythemia patients.37 Both positive and negative effects of blood viscosity on macrocirculation and microcirculation should be considered in clinical practice based on the patients’ pathophysiological conditions. Here, we underscore that a high-viscosity fluid solution has potential benefit for the recruitment of microcirculation during hemodilution.

Back to Top | Article Outline


Microcirculatory alterations play an important role in the complicated pathophysiological procedure of sepsis, and the typical alterations of microcirculation include abnormal heterogeneity and microcirculatory shunting.38 The potential mechanisms of impaired microcirculatory perfusion include increased blood viscosity, impaired RBC deformability, endothelium dysfunction, capillary leakage, leukocyte adhesion, and activation of coagulation.38 The effect of fluid resuscitation on microcirculation has become a hotspot in sepsis.

There has been interest in the effects of colloids on microcirculation in models of sepsis. Klar et al39 found that the isovolumic hemodilution effect of dextran 60 can restore the number of perfusion capillaries of pancreatic microcirculation. Hotz et al40 found that using dextran could significantly increase capillary blood flow and perfused capillary percentage. Hoffmann et al41 reported that HES preserved the FCD in comparison with saline and no resuscitation in a normotensive endotoxemia model. The study by Dubin et al42 on septic sheep showed that HES could improve sublingual and serosal intestinal microcirculation but with persistent poor perfusion in intestinal mucosal villi.

However, the use of colloid solutions for fluid resuscitation in sepsis remains controversial. Wafa et al43 found that different HES solutions did not perform better when compared to crystalloids in the microcirculation of the mesentery of colon ascendens stent peritonitis-induced experimental sepsis in rats. A recent systemic review found that few animal model studies have investigated the microcirculatory effects of different types of fluid resuscitation for sepsis and septic shock.44 Sometimes, fluid resuscitation might not be effective in recruiting vulnerable microcirculatory beds because of impaired autoregulatory mechanisms in microcirculation, which may be different in hemorrhagic shock, in which there may be a relatively intact microcirculatory autoregulation function. Furthermore, there is a loss of hemodynamic coherence between macrocirculation and microcirculation in sepsis, and a single medical intervention (eg, fluid resuscitation/using pressor maintaining blood pressure) might be insufficient to recruit the microcirculation.45

Back to Top | Article Outline


Conventional goal-directed fluid resuscitation therapy focuses on the restoration of global systemic hemodynamic variables and can be considered superior to the traditional, generalized algorithm-based approach to fluid administration. Use of the generalized algorithm-based approach to guide fluid infusion does not consider individual requirement at the level of macrocirculation, which masks the potential advantages of using colloid solutions when compared to the crystalloid solutions for fluid resuscitation. Interestingly, the advantages of colloid solutions in microcirculation have been shown in goal-directed therapy and experimental and clinical studies.46–50

Hiltebrand et al46 found that goal-directed colloid administration (keeping the mixed venous O2 saturation at ≥60%) markedly increased microcirculatory blood flow in the small intestine and in intestinal tissue O2 tension after abdominal surgery. In contrast, goal-directed crystalloid and restricted crystalloid administration had no such effect. Kimberger et al47 reported that goal-directed colloid fluid therapy significantly increased microcirculatory blood flow and tissue O2 tension in the healthy and injured colon compared to goal-directed or restricted crystalloid fluid therapy.

Moreover, goal-directed therapy in clinical trials of the perioperative fluid therapy also demonstrated that the bolus colloids could efficiently increase microcirculatory perfusion in fluid-responsive patients and have an improved outcome.48–50 A recent international statement on perioperative fluid therapy recommends “the use of a goal-directed fluid regimen containing colloid and balanced-salt solutions in major surgery” and “colloid use may be considered an approach to limiting total volumes, which may contribute to better outcomes.”51 Dubin et al52 found that fluid resuscitation with 6% HES 130/0.4 had a higher capillary microvascular flow index, percentage of perfused capillaries, and perfused capillary than normal saline to improve sublingual microcirculation in the septic patients. The authors also found that the group using colloid solutions to restore the targets of early goal-directed therapy (central venous pressure 8–12 mm Hg, mean arterial pressure ≥65 mm Hg, central venous oxygen saturation ≥70%) needed less than half of the fluid volume when compared to using crystalloid solutions.

It could be argued that clinical trials have not been able to demonstrate that early goal-directed therapy improves the outcome in septic shock patients.53,54 However, we feel that it needs to be emphasized that using hemodynamics at the macrocirculation level to guide fluid resuscitation, although better than the use of the generalized algorithm-based approach, may not in itself improve perfusion at the level of the microcirculation.7 Xu et al55 found, with equal success in outcome, that microcirculatory-targeted fluid resuscitation required a substantially lower amount of fluids to reach microcirculatory targets than the amount of fluids needed for correcting blood pressure in the hemorrhagic shock pig model (blood pressure–guided group with 955 mL versus sublingual partial pressure of carbon dioxide–guided group with 170 mL). This study elegantly showed that using different targets to guide fluid therapy could cause a large variation in the amount of the fluid volume used while not affecting the outcome. From this consideration, it is clear that studies are needed to investigate the potential benefit of colloid fluids based on microcirculatory goal-directed administration.

Back to Top | Article Outline


The final aim of the amplification of microcirculatory perfusion is to improve tissue oxygenation, and the final aim of increasing tissue oxygenation is to improve cellular O2 utilization to correct the cellular hypoxia according to the pathophysiological consideration. Hence, the effect of fluid solutions on tissue oxygenation and cellular O2 utilization is attractive during fluid resuscitation.

The autoregulation ability to maintain the tissue oxygenation differs in various tissue cells and organs during fluid therapy. A study reported that 3 different fluid volume regimens (low, medium, and high fluid volume groups) did not affect tissue O2 pressure in the jejunum and colon, but the high fluid volume group had a higher blood pressure, cardiac output, urine output, and subcutaneous tissue oxygenation in healthy pigs undergoing uncomplicated abdominal surgery.56 Moreover, the regulation of tissue oxygenation is also specific for different organ systems during progressive hemodilution, and the microvascular oxygenation pressure (µPo2) is always used to reflect the global and local redistribution of O2 delivery. Van Bommel et al57 reported that the renal µPo2 started to decrease at a hematocrit of 38.5%, but intestinal µPo2 decreased at a hematocrit of 17.4%, and a reduction of cardiac µPo2 was observed at a hematocrit of 8.7% in the rat model of hemodilution.

Studies have found that using crystalloid solutions for volume replacement could reduce tissue oxygenation, while using colloid solutions could keep tissue oxygenation within the acute normovolemic hemodilution.58,59 Funk and Baldinger58 found that volume replacement with artificial colloids yielded hemodynamic stability and adequate tissue O2 supply, whereas administration of crystalloids alone could impair skeletal muscle tissue perfusion (perfused capillary density decreased by 62%) and µPo2 (decreased from 19 to 8 mm Hg) in the awake hamster model of isovolumic hemodilution. Konrad et al59 reported that a hematocrit of 15% statistically significantly impaired renal µPo2 and renal function in the crystalloid group (using full electrolyte solution), while less tissue edema formation and an unimpaired renal µPo2 occurred in the colloid group (using HES 6% 130/0.4) in the pig model of acute normovolemic hemodilution.

Furthermore, colloid solutions have shown a better performance in several animals in restoring tissue oxygenation during fluid resuscitation for different types of circulatory shock.60–62 Knotzer et al60 found that gelatin infusion significantly improved mucosal tissue O2 tension of the porcine jejunum after severe hemorrhage when compared with lactated Ringer’s solution (mucosal µPo2 20 vs 13.8 mm Hg). Almac et al61 found that the HES 130/0.42 dissolved in acetate-balanced Ringer’s solution could restore renal blood flow back to 85% of the baseline level and most prominently improved renal microvascular oxygenation (from 24 to 50 mm Hg) when compared to normal saline and acetate-balanced Ringer’s solution in the rat model of hemorrhagic shock. Maier et al62 found that only an isotonic colloid solution (gelatin and HES) improved microvascular hemoglobin O2 saturation when compared to a hypertonic colloid solution (HES + 7.2% saline) during hemorrhagic shock. Moreover, Wettstein et al63 reported that using highly viscous and oncotic colloid solutions with fewer RBCs could restore the FCD and resulted in a more homogeneous distribution of tissue oxygenation in the hemorrhagic shock model. The authors concluded that using highly viscous and oncotic solutions for fluid resuscitation might reduce the transfusion trigger of hemoglobin concentrations during hemorrhagic shock.

With the development of the blood substitute, hemoglobin-based O2-carrying solutions and perfluorocarbon-based O2-carrying solutions were created to solve transfusional blood availability problems and shortages and with the aim of further enhancing O2 delivery. The viscosity and compatibility of other colloid solution play an important role in the microvascular oxygenation and perfusion when using O2-carrying solutions.64 Nolte et al65 reported that HES, gelatin, and human albumin are compatible with perflubron emulsion O2-carrying solution, but that dextran 60 was incompatible with perflubron emulsion and cause impaired capillary perfusion in the setting of acute normovolemic hemodilution.

The impairment of mitochondrial function has become a great challenge in the resuscitation of circulatory shock.66 The dysfunction of cellular O2 utilization always occurs together with impaired microvascular oxygenation, but sometimes cellular O2 utilization impairment could be independent of microcirculatory perfusion. Albuszies et al67 found that the restoration of macrocirculation allowed for the maintenance of gut and liver microvascular perfusion and increased capillary oxygenation after fluid resuscitation, but hepatic metabolic capacity was still impaired in a murine model of septic shock. Hence, impaired cellular O2 utilization could be present independently of the improvement in microcirculatory perfusion during fluid resuscitation. Johannes et al68 found that redistribution of renal µPo2 could be demonstrated when the renal blood flow and renal O2 delivery have been restored during fluid resuscitation, and HES 130/0.4 had no influence on the renal O2 consumption when compared to HES 200/0.5 or Ringer’s lactate. The response of cellular O2 utilization to various types of fluid solution is required to further investigate in different clinical conditions.

Back to Top | Article Outline


The uncontrolled inflammatory response involves the activation of cytokines, leukocytes, and cytokine storm, as well as the generation of reactive oxygen species (ROS), which together result in impairment of microcirculation. Moreover, ischemia reperfusion injury can further contribute to additional inflammation during fluid resuscitation.

Several studies have found that artifact colloid solutions might have specific anti-inflammatory properties in the context of fluid resuscitation after hemorrhagic shock by reducing leukocyte activation (stagnation, margination, and rolling) and leukocyte–endothelial interaction.69–72 Corso et al69 using intravital fluorescence microscopy found that dextran and hypertonic saline dextran attenuated leukocyte stagnation in liver sinusoids and leukocyte adherence in postsinusoidal venules when compared to Ringer’s solution after hemorrhagic shock. Maier et al72 found that using gelatin serum protein solutions as a resuscitative fluid could reduce leukocyte adhesion. Chen et al73 also reported that fluid resuscitation with HES 130/0.4 after hemorrhagic shock ameliorated oxidative stress and the inflammatory response (lower tumor necrosis factor-α and interleukin-6) in the liver, intestine, lungs, and brain compared with gelatins and HES 200/0.5. Moreover, Varga et al74 reported that HES provided a therapeutic advantage in this setting by exerting an inhibitory effect on the ischemia-reperfusion–induced local and systemic leukocyte reactions in postischemic periosteal microvascular dysfunction when compared with gelatin or dextran solutions.

In contrast, some studies have found that using artifact colloids solution could increase inflammatory response. Wu et al31 recently found that although intestinal microcirculation was restored by only colloid solutions (4% succinylated gelatin and 6% HES) when compared to normal saline in a rodent model of hemorrhagic shock, reperfusion-induced renal ROS formation was significantly higher when synthetic colloids were used. The authors inferred that increased reperfusion-induced renal ROS formation might contribute to acute kidney injury when using synthetic colloids for fluid resuscitation. It should be noted when evaluating the literature that there are considerable differential effects between the different HES formulations. In this context, Hüter et al75 reported that 10% HES 200/0.5 had more of a proinflammatory effect compared with 6% HES 130/0.42 and caused more pronounced tubular damage than did 6% HES 130/0.42 and Ringer’s lactate in an isolated porcine renal perfusion model. In summary, the published literature supports the idea that artifact colloid solutions might have a positive effect on inflammation in the context of hemorrhagic shock resuscitation, although care should be taken on its effects on renal function. Such effects on kidney function may be averted if a more physiologically based target, such as the restoration of microcirculatory function, is chosen as an end point.

In animal models of sepsis, however, there is more controversy surrounding the effects of HES on inflammation. Schick et al76 found that HES improved liver microcirculation but exhibited significantly increased proinflammatory cytokine levels in cecal ligation- and puncture-induced septic rodents. However, some other animal studies have found positive effects of HES on inflammatory processes in sepsis.77,78 On the other hand, it must be emphasized that all fluids probably cause inflammation. In fact, studies have also reported that Ringer’s lactate could activate neutrophils and cause an upregulation of inflammatory mediators in fluid resuscitation.79,80

Moreover, based on the idea that inflammatory activation of HES could be controlled by the coadministration of anti-inflammatory drugs, Ergin et al81 demonstrated in an endotoxin-induced septic model in the rat in which coadministration of N-acetylcysteine significantly improved renal oxygenation, O2 delivery, and O2 consumption and dampened the accumulation of neutrophil gelatinase-associated lipcalin or liver-type fatty acid-binding protein, hyaluronic acid, and nitric oxide in these septic kidneys. These studies suggest that future generations of fluids may benefit from the addition of anti-inflammatory compounds.

Back to Top | Article Outline


Recently, the potential benefit of albumin on inflammation and endothelial barrier function is attracting attention in fluid therapy literature. Albumin has several physiological advantages when used as a colloid during resuscitation, including antioxidant and anti-inflammatory properties, positive effects on vessel wall integrity, and ligand-biding abilities.82 Jacob et al83 found that albumin was more effective in preventing fluid extravasation in the isolated heart model than crystalloid or artificial colloid, and that this effect was partly independent of colloid osmotic pressure and could possibly be caused by an interaction of albumin with the endothelial glycocalyx. Studies have also shown that the leakage of HES into the interstitium is greater than that of albumin, and that starches might cause greater impairment to endothelial and epithelial barriers.84 The same team found that albumin supplementation abrogates the adverse effects of HES in the intestine, and that the underlying mechanism may occur via phosphorylation of Erk1/2 and Akt signal path. They inferred that albumin-containing HES solutions are superior to HES alone and may improve the suitability of HES in the clinic.85 Recently, Job et al86 demonstrated that albumin and HES induced markedly different effects on glycocalyx mechanics and had notably different effects after glycocalyx degradation by hyaluronidase. On the other hand, several studies have shown that HES can attenuate microvascular barrier dysfunction, leading to tissue edema in septic shock with high capillary leakage.87–89 From these considerations, it is clear that there is much-needed insight into the relationship among glycocalyx function, vascular barrier integrity, inflammation, and their response to fluid resuscitation of different compositions and hemodynamic targets.

Back to Top | Article Outline


This article has discussed how colloid solutions not only can have a better performance on the macrocirculation but also have potential advantages for recruitment of the microcirculation, especially under conditions of hypovolemia caused by hemorrhagic shock and when administered in a goal-directed manner. Further studies are required to identify which precise goal needs to be targeted where possible microcirculatory goal-directed therapy for fluid resuscitation could improve the outcome of patients. In addition, the concept of coadministrating other compounds such as anti-inflammatory drugs or even hemoglobin-based O2 carriers needs to be explored to develop a new generation of fluids to meet the challenges of perioperative and intensive care fluid management.

Back to Top | Article Outline


Name: Huaiwu He, PhD.

Contribution: This author helped review the related literature, draft the manuscript, and read and approve the final manuscript.

Name: Dawei Liu, PhD.

Contribution: This author helped revise the text, contribute to the critical review of the manuscript, and read and approve the final manuscript.

Name: Can Ince, PhD.

Contribution: This author helped review the related literature, revise the text, and read and approve the final manuscript.

This manuscript was handled by: Alexander Zarbock, MD.

Back to Top | Article Outline


1. Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Crit Care Med. 2017;45:486–552.
2. Cecconi M, Hofer C, Teboul JL, et al.; FENICE Investigators; ESICM Trial Group. Fluid challenges in intensive care: the FENICE study: a global inception cohort study. Intensive Care Med. 2015;41:1529–1537.
3. Pottecher J, Deruddre S, Teboul JL, et al. Both passive leg raising and intravascular volume expansion improve sublingual microcirculatory perfusion in severe sepsis and septic shock patients. Intensive Care Med. 2010;36:1867–1874.
4. Ospina-Tascon G, Neves AP, Occhipinti G, et al. Effects of fluids on microvascular perfusion in patients with severe sepsis. Intensive Care Med. 2010;36:949–955.
5. Vincent JL, De Backer D. Circulatory shock. N Engl J Med. 2013;369:1726–1734.
6. Ince C. The rationale for microcirculatory guided fluid therapy. Curr Opin Crit Care. 2014;20:301–308.
7. Pranskunas A, Koopmans M, Koetsier PM, Pilvinis V, Boerma EC. Microcirculatory blood flow as a tool to select ICU patients eligible for fluid therapy. Intensive Care Med. 2013;39:612–619.
8. Lobo DN, Stanga Z, Aloysius MM, et al. Effect of volume loading with 1 liter intravenous infusions of 0.9% saline, 4% succinylated gelatine (Gelofusine) and 6% hydroxyethyl starch (Voluven) on blood volume and endocrine responses: a randomized, three-way crossover study in healthy volunteers. Crit Care Med. 2010;38:464–470.
9. McIlroy DR, Kharasch ED. Acute intravascular volume expansion with rapidly administered crystalloid or colloid in the setting of moderate hypovolemia. Anesth Analg. 2003;96:1572–1577.
10. Gondos T, Marjanek Z, Ulakcsai Z, et al. Short-term effectiveness of different volume replacement therapies in postoperative hypovolaemic patients. Eur J Anaesthesiol. 2010;27:794–800.
11. Verheij J, van Lingen A, Beishuizen A, et al. Cardiac response is greater for colloid than saline fluid loading after cardiac or vascular surgery. Intensive Care Med. 2006;32:1030–1038.
12. Kuitunen A, Suojaranta-Ylinen R, Kukkonen S, Niemi T. A comparison of the haemodynamic effects of 4% succinylated gelatin, 6% hydroxyethyl starch (200/0.5) and 4% human albumin after cardiac surgery. Scand J Surg. 2007;96:72–78.
13. Hogan JJ. The intravenous use of colloidal (gelatin) solutions in shock. J Am Med Assoc. 1915;LXIV:721–726.
14. Bowman HW. Clinical evaluation of dextran as a plasma volume expander. JAMA.1953;153:24–26.
15. Drumi W, Polzleitner D, Laggner AN, et al. Dextran-40, acute renal failure and elevated plasma oncotic pressure. N Engl J Med. 1988;318:252–254.
16. Ljungström KG. Dextran 40 therapy made safer by pretreatment with dextran 1. Plast Reconstr Surg. 2007;120:337–340.
17. Sethi BS, Chauhan S, Bisoi AK, et al. Comparison of a waxy maize and a potato starch-based balanced hydroxyethyl starch for priming in patients undergoing coronary artery bypass grafting. J Cardiothorac Vasc Anesth. 2014;28:690–697.
18. Toyoda D, Shinoda S, Kotake Y. Pros and cons of tetrastarch solution for critically ill patients. J Intensive Care. 2014;2:23.
19. Brunkhorst FM, Engel C, Bloos F, et al.; German Competence Network Sepsis (SepNet). Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med. 2008;358:125–139.
20. Myburgh JA, Finfer S, Bellomo R, et al.; CHEST Investigators; Australian and New Zealand Intensive Care Society Clinical Trials Group. Hydroxyethyl starch or saline for fluid resuscitation in intensive care. N Engl J Med. 2012;367:1901–1911.
21. Perner A, Haase N, Guttormsen AB, et al.; 6S Trial Group; Scandinavian Critical Care Trials Group. Hydroxyethyl starch 130/0.42 versus Ringer’s acetate in severe sepsis. N Engl J Med. 2012;367:124–134.
22. Meybohm P, Van Aken H, De Gasperi A, et al. Re-evaluating currently available data and suggestions for planning randomised controlled studies regarding the use of hydroxyethyl starch in critically ill patients—a multidisciplinary statement. Crit Care. 2013;17:R166.
23. Doshi P. Data too important to share: do those who control the data control the message? BMJ. 2016;2:352.
24. Caironi P, Tognoni G, Masson S, et al.; ALBIOS Study Investigators. Albumin replacement in patients with severe sepsis or septic shock. N Engl J Med. 2014;370:1412–1421.
25. Frenette AJ, Bouchard J, Bernier P, et al. Albumin administration is associated with acute kidney injury in cardiac surgery: a propensity score analysis. Crit Care. 2014;18:602.
26. Naumann DN, Beaven A, Dretzke J, Hutchings S, Midwinter MJ. Searching for the optimal fluid to restore microcirculatory flow dynamics after haemorrhagic shock: a systematic review of preclinical studies. Shock. 2016;46:609–622.
27. Wettstein R, Erni D, Intaglietta M, Tsai AG. Rapid restoration of microcirculatory blood flow with hyperviscous and hyperoncotic solutions lowers the transfusion trigger in resuscitation from hemorrhagic shock. Shock. 2006;25:641–646.
28. Gao J, Zhao WX, Xue FS, Zhou LJ, Yu YH, Zhou HB. Effects of different resuscitation fluids on acute lung injury in a rat model of uncontrolled hemorrhagic shock and infection. J Trauma. 2009;67:1213–1219.
29. Vajda K, Szabó A, Boros M. Heterogeneous microcirculation in the rat small intestine during hemorrhagic shock: quantification of the effects of hypertonic-hyperoncotic resuscitation. Eur Surg Res. 2004;36:338–344.
30. Komori M, Takada K, Tomizawa Y, Uezono S, Nishiyama K, Ozaki M. Effects of colloid resuscitation on peripheral microcirculation, hemodynamics, and colloidal osmotic pressure during acute severe hemorrhage in rabbits. Shock. 2005;23:377–382.
31. Wu CY, Chan KC, Cheng YJ, Yeh YC, Chien CT; NTUH Center of Microcirculation Medical Research. Effects of different types of fluid resuscitation for hemorrhagic shock on splanchnic organ microcirculation and renal reactive oxygen species formation. Crit Care. 2015;19:434.
32. Tsai AG, Friesenecker B, McCarthy M, Sakai H, Intaglietta M. Plasma viscosity regulates capillary perfusion during extreme hemodilution in hamster skinfold model. Am J Physiol. 1998;275:H2170–H2180.
33. Tomiyama Y, Brian JE Jr, Todd MM. Plasma viscosity and cerebral blood flow. Am J Physiol Heart Circ Physiol. 2000;279:H1949–H1954.
34. Tomiyama Y, Jansen K, Brian JE Jr, Todd MM. Hemodilution, cerebral O2 delivery, and cerebral blood flow: a study using hyperbaric oxygenation. Am J Physiol. 1999;276:H1190–H1196.
35. Yuruk K, Almac E, Bezemer R, Goedhart P, de Mol B, Ince C. Blood transfusions recruit the microcirculation during cardiac surgery. Transfusion. 2011;51:961–967.
36. Zimmerman R, Tsai AG, Salazar Vázquez BY, et al. Posttransfusion increase of hematocrit per se does not improve circulatory oxygen delivery due to increased blood viscosity. Anesth Analg. 2017;124:1547–1554.
37. van Bommel J, Trouwborst A, Smeets JW, Henny CP. Acute hemodilution in a chronic polycythemic patient may be deleterious. Anesthesiology. 2001;95:1291–1293.
38. Ince C. The microcirculation is the motor of sepsis. Crit Care. 2005;9suppl 4S13–S19.
39. Klar E, Herfarth C, Messmer K. Therapeutic effect of isovolemic hemodilution with dextran 60 on the impairment of pancreatic microcirculation in acute biliary pancreatitis. Ann Surg. 1990;211:346–353.
40. Hotz HG, Schmidt J, Ryschich EW, et al. Isovolemic hemodilution with dextran prevents contrast medium induced impairment of pancreatic microcirculation in necrotizing pancreatitis of the rat. Am J Surg. 1995;169:161–166.
41. Hoffmann JN, Vollmar B, Laschke MW, Inthorn D, Schildberg FW, Menger MD. Hydroxyethyl starch (130 kD), but not crystalloid volume support, improves microcirculation during normotensive endotoxemia. Anesthesiology. 2002;97:460–470.
42. Dubin A, Edul VS, Pozo MO, et al. Persistent villi hypoperfusion explains intramucosal acidosis in sheep endotoxemia. Crit Care Med. 2008;36:535–542.
43. Wafa K, Herrmann A, Kuhnert T, 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.
44. Obonyo NG, Fanning JP, Ng AS, et al. Effects of volume resuscitation on the microcirculation in animal models of lipopolysaccharide sepsis: a systematic review. Intensive Care Med Exp. 2016;4:38.
45. Ince C. Hemodynamic coherence and the rationale for monitoring the microcirculation. Crit Care. 2015;19suppl 3S8.
46. Hiltebrand LB, Kimberger O, Arnberger M, Brandt S, Kurz A, Sigurdsson GH. Crystalloids versus colloids for goal-directed fluid therapy in major surgery. Crit Care. 2009;13:R40.
47. Kimberger O, Arnberger M, Brandt S, et al. Goal-directed colloid administration improves the microcirculation of healthy and perianastomotic colon. Anesthesiology. 2009;110:496–504.
48. Sinclair S, James S, Singer M. Intraoperative intravascular volume optimisation and length of hospital stay after repair of proximal femoral fracture: randomised controlled trial. BMJ. 1997;315:909–912.
49. Kita T, Mammoto T, Kishi Y. Fluid management and postoperative respiratory disturbances in patients with transthoracic esophagectomy for carcinoma. J Clin Anesth. 2002;14:252–256.
50. Conway DH, Mayall R, Abdul-Latif MS, Gilligan S, Tackaberry C. Randomised controlled trial investigating the influence of intravenous fluid titration using oesophageal Doppler monitoring during bowel surgery. Anaesthesia. 2002;57:845–849.
51. Navarro LH, Bloomstone JA, Auler JO Jr, et al. Perioperative fluid therapy: a statement from the international Fluid Optimization Group. Perioper Med (Lond). 2015;4:3.
52. Dubin A, Pozo MO, Casabella CA, 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.e1–659.e8.
53. Yealy DM, Kellum JA, Huang DT, et al.; ProCESS Investigators.A randomized trial of protocol-based care for early septic shock. N Engl J Med. 2014;370:1683–1693.
54. Peake SL, Delaney A, Bailey M, et al.; ARISE Investigators, ANZICS Clinical Trials Group. Goal directed resuscitation for patients with early septic shock. N Engl J Med. 2014;371:1496–1506.
55. Xu J, Ma L, Sun S, et al. Fluid resuscitation guided by sublingual partial pressure of carbon dioxide during hemorrhagic shock in a porcine model. Shock. 2013;39:361–365.
56. Hiltebrand LB, Pestel G, Hager H, Ratnaraj J, Sigurdsson GH, Kurz A. Perioperative fluid management: comparison of high, medium and low fluid volume on tissue oxygen pressure in the small bowel and colon. Eur J Anaesthesiol. 2007;24:927–933.
57. van Bommel J, Siegemund M, Henny ChP, Ince C. Heart, kidney, and intestine have different tolerances for anemia. Transl Res. 2008;151:110–117.
58. Funk W, Baldinger V. Microcirculatory perfusion during volume therapy. A comparative study using crystalloid or colloid in awake animals. Anesthesiology. 1995;82:975–982.
59. Konrad FM, Mik EG, Bodmer SI, et al. Acute normovolemic hemodilution in the pig is associated with renal tissue edema, impaired renal microvascular oxygenation, and functional loss. Anesthesiology. 2013;119:256–269.
60. Knotzer H, Pajk W, Maier S, et al. Comparison of lactated Ringer’s, gelatine and blood resuscitation on intestinal oxygen supply and mucosal tissue oxygen tension in haemorrhagic shock. Br J Anaesth. 2006;97:509–516.
61. Almac E, Aksu U, Bezemer R, et al. The acute effects of acetate-balanced colloid and crystalloid resuscitation on renal oxygenation in a rat model of hemorrhagic shock. Resuscitation. 2012;83:1166–1172.
62. Maier S, Holz-Hölzl C, Pajk W, et al. Microcirculatory parameters after isotonic and hypertonic colloidal fluid resuscitation in acute hemorrhagic shock. J Trauma. 2009;66:337–345.
63. Wettstein R, Tsai AG, Erni D, Lukyanov AN, Torchilin VP, Intaglietta M. Improving microcirculation is more effective than substitution of red blood cells to correct metabolic disorder in experimental hemorrhagic shock. Shock. 2004;21:235–240.
64. Cabrales P, Intaglietta M, Tsai AG. Transfusion restores blood viscosity and reinstates microvascular conditions from hemorrhagic shock independent of oxygen carrying capacity. Resuscitation. 2007;75:124–134.
65. Nolte D, Pickelmann S, Lang M, Keipert P, Messmer K. Compatibility of different colloid plasma expanders with perflubron emulsion: an intravital microscopic study in the hamster. Anesthesiology. 2000;93:1261–1270.
66. Ince C, Mik EG. Microcirculatory and mitochondrial hypoxia in sepsis, shock, and resuscitation. J Appl Physiol (1985). 2016;120:226–235.
67. Albuszies G, Radermacher P, Vogt J, et al. Effect of increased cardiac output on hepatic and intestinal microcirculatory blood flow, oxygenation, and metabolism in hyperdynamic murine septic shock. Crit Care Med. 2005;33:2332–2338.
68. Johannes T, Mik EG, Nohé B, Raat NJ, Unertl KE, Ince C. Influence of fluid resuscitation on renal microvascular PO2 in a normotensive rat model of endotoxemia. Crit Care. 2006;10:R88.
69. Corso CO, Okamoto S, Rüttinger D, Messmer K. Hypertonic saline dextran attenuates leukocyte accumulation in the liver after hemorrhagic shock and resuscitation. J Trauma. 1999;46:417–423.
70. Bauer M, Feucht K, Ziegenfuss T, Marzi I. Attenuation of shock-induced hepatic microcirculatory disturbances by the use of a starch-deferoxamine conjugate for resuscitation. Crit Care Med. 1995;23:316–322.
71. Pascual JL, Ferri LE, Seely AJ, et al. Hypertonic saline resuscitation of hemorrhagic shock diminishes neutrophil rolling and adherence to endothelium and reduces in vivo vascular leakage. [Erratum appears in Ann Surg. 2003 Jan;237(1):148]. Ann Surg. 2002;236:634–642.
72. Maier M, Wackerle M, Herzog C, Marzi I. Supplementary administration of serum protein solution during shock resuscitation in the rat. Eur J Trauma. 2004;30:289–295.
73. Chen G, You G, Wang Y, 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.
74. Varga R, Török L, Szabó A, et al. Effects of colloid solutions on ischemia-reperfusion-induced periosteal microcirculatory and inflammatory reactions: comparison of dextran, gelatin, and hydroxyethyl starch. Crit Care Med. 2008;36:2828–2837.
75. Hüter L, Simon TP, Weinmann L, et al. Hydroxyethylstarch impairs renal function and induces interstitial proliferation, macrophage infiltration and tubular damage in an isolated renal perfusion model. Crit Care. 2009;13:R23.
76. Schick MA, Isbary JT, Stueber T, et al. Effects of crystalloids and colloids on liver and intestine microcirculation and function in cecal ligation and puncture induced septic rodents. BMC Gastroenterol. 2012;12:179.
77. Feng X, Liu J, Yu M, Zhu S, Xu J. Protective roles of hydroxyethyl starch 130/0.4 in intestinal inflammatory response and survival in rats challenged with polymicrobial sepsis. Clin Chim Acta. 2007;376:60–67.
78. Lu WH, Jin XJ, Jiang XG, Wang Z, Wu JY, Shen GG. Resuscitation with hydroxyethyl starch 130/0.4 attenuates intestinal injury in a rabbit model of sepsis. Indian J Pharmacol. 2015;47:49–54.
79. Moore FA. The use of lactated Ringer’s in shock resuscitation: the good, the bad and the ugly. J Trauma. 2011;70:S15–S16.
80. Chen H, Koustova E, Shults C, Sailhamer EA, Alam HB. Differential effect of resuscitation on Toll-like receptors in a model of hemorrhagic shock without a septic challenge. Resuscitation. 2007;74:526–537.
81. Ergin B, Guerci P, Zafrani L, et al. Effects of N-acetylcysteine (NAC) supplementation in resuscitation fluids on renal microcirculatory oxygenation, inflammation, and function in a rat model of endotoxemia. Intensive Care Med Exp. 2016;4:29.
82. Vincent JL, De Backer D, Wiedermann CJ. Fluid management in sepsis: the potential beneficial effects of albumin. J Crit Care. 2016;35:161–167.
83. Jacob M, Bruegger D, Rehm M, Welsch U, Conzen P, Becker BF. Contrasting effects of colloid and crystalloid resuscitation fluids on cardiac vascular permeability. Anesthesiology. 2006;104:1223–1231.
84. Wong YL, Lautenschläger I, Dombrowsky H, et al. Hydroxyethyl starch (HES130/0.4) impairs intestinal barrier integrity and metabolic function: findings from a mouse model of the isolated perfused small intestine. PLoS One. 2015;10:e0121497.28.
85. Wong YL, Lautenschläger I, Zitta K, et al. Adverse effects of hydroxyethyl starch (HES 130/0.4) on intestinal barrier integrity and metabolic function are abrogated by supplementation with albumin. J Transl Med. 2016;14:60.
86. Job KM, O’Callaghan R, Hlady V, Barabanova A, Dull RO. The biomechanical effects of resuscitation colloids on the compromised lung endothelial glycocalyx. Anesth Analg. 2016;123:382–393.
87. Marx G, Cobas Meyer M, Schuerholz T, et al. Hydroxyethyl starch and modified fluid gelatin maintain plasma volume in a porcine model of septic shock with capillary leakage. Intensive Care Med. 2002;28:629–635.
88. Marx G, Pedder S, Smith L, et al. Attenuation of capillary leakage by hydroxyethyl starch (130/0.42) in a porcine model of septic shock. Crit Care Med. 2006;34:3005–3010.
89. Marx G, Pedder S, Smith L, et al. Resuscitation from septic shock with capillary leakage: hydroxyethyl starch (130 kd), but not Ringer’s solution maintains plasma volume and systemic oxygenation. Shock. 2004;21:336–341.
Copyright © 2017 International Anesthesia Research Society