The main findings of the present study are that during acute normovolemic anemia, 1) the choice of the IV fluid has an impact on the maintenance of tissue oxygenation as reflected by variation in the extent of anemia tolerance; 2) anemia tolerance is higher when using colloids than when using crystalloids, and 3) among the colloids, tetrastarch (6% HES 130/0.4) provided higher anemia tolerance than did gelatin (3.5% urea-crosslinked polygeline) and hetastarch (6% HES 450/0.7). This was reflected by significantly lower values of Hbcrit and a higher allowable volume of blood exchanged for tetrastarch.
is the hemoglobin concentration associated with a critical limitation of O2
supply and hallmarks the ultimate tolerance limit of acute normovolemic anemia [10
]. In our previous experimental studies, hemodilution to Hbcrit
was associated with 100% mortality, if no further treatment (such as elevation of fraction of inspired O2
, transfusion of red blood cells, or infusion of artificial O2
carriers) was initiated after institution of critical normovolemic anemia [12
]. Several authors found Hbcrit
at values between 1.6 and 3.0 g/dL [10
]. In detail, Hbcrit
was reduced by 1) hypothermia (moderate reduction of body core temperature reduces total body O2
]); 2) hyperoxemia (bioavailability of physically dissolved O2
is excellent in profound anemia [12
]); 3) infusion of norepinephrine (stabilization of coronary perfusion pressure during hemodilution [19
]); 4) artificial O2
carriers (maintenance of arterial oxygen content despite reduced hematocrit [18
]), and 5) con-tinuous neuromuscular blockade (lowering skeletal muscular O2
While different infusion fluids were used for hemodilution in the aforementioned studies, their particular impact on the limit of anemia tolerance has not been fully elucidated. In a similar hemodilution study performed in anesthetized and splenectomised dogs, van der Linden and coworkers found no differences between pentastarch (6% HES 200/0.5) and a 3% gelatin preparation in relation to the value of Hbcrit
]. However, the typical increase of CI in compensation for dilutional anemia was absent in that study, which was explained by cardio-depressant effects of the anesthesia regimen employed [20
In the present study, gelatin provided more extensive anemia tolerance than did hetastarch. While the occasional use of hetastarch is predominantly reported by US physicians [24
], European physicians rather avoid this fluid due to its adverse effects on coagulation and renal function [25
]. Nevertheless, a recent clinical study found a reduction of mortality in trauma victims resuscitated with hetastarch in addition to the advanced trauma life support (ATLS)-standard of care treatment (that is, crystalloids along with blood products) [26
Hetastarch is a hyperoncotic infusion fluid with a high viscosity in vitro
(see Table ). However, the effects of these properties in vivo
are still not fully understood. While a decrease of plasma viscosity entails the increase of venous return, thereby enabling the hemodynamic compensation of acute anemia [27
], recent experimental data suggest that increased plasma viscosity prevents microvascular collapse (for example, after fluid resuscitation from hemorrhagic shock) [6
]. Furthermore, the effect of hetastarch on plasma viscosity is limited by its oncotic properties, as the reabsorption of interstitial fluid involves the dilution of viscogenic materials thereby lowering plasma viscosity in the long term [28
In the present study, animals hemodiluted with hetastarch featured a significantly higher O2-ER at Hbcrit when compared with animals of the TS- or GEL-group, indicating that macro- and microhemodynamic compensation of anemia was completely exhausted. In other words, hetastarch failed to prevent microcirculatory collapse at an earlier stage of hemodilution than did tetrastarch or gelatin. Although plasma viscosity was not assessed in the present study, it may be assumed that a dilution-related fading of viscogenic potential might have contributed to this result.
Whether fluid resuscitation should be performed with crystalloids or colloids, has been a matter of controversy for decades, and the discussion is still open [29
]. Although most crystalloid infusion fluids are plasma-isotonic, they cross the capillary membranes within 20 to 30 minutes of infusion, and most of the volume infused is shifted into the interstitium. To maintain normovolemia with crystalloids, it has been recom-mended to replace an acute blood loss in a ratio of at least 1:3 [30
]. However, the exclusive use of crystalloids for volume replacement results in edema formation and may thereby compromise tissue oxygenation [31
]. Actually, excessive tissue hydration due to pure crystalloid volume replacement in the perioperative phase was held responsible for many postoperative complications including increased incidence of anastomotic dehiscence in abdominal surgery, postoperative vomiting and orthostatic dysregulation [32
]. Moreover, an experimental study in pigs subjected to colon anastomosis surgery found that microcirculatory blood flow and oxygen tension in perianastomotic colon tissue were increased in animals infused with tetrastarch when compared with crystalloid fluid management [34
]. This finding was explained by homogenisation of mucosal microcirculatory blood flow after infusion of tetrastarch.
In the present study, with Ringer's solution, the exchange of blood was associated with increased pulmonary edema formation (elevated EVLWI) and an impairment of pulmonary gas exchange (decreased paO2). This phenomenon was not observed in animals hemodiluted with gelatin, hetastarch or tetrastarch. Although EVLWI merely reflects the degree of tissue hydration at the site of pulmonary circulation, it may be supposed that a relevant edema formation also occurred in peripheral O2-consuming tissues: while O2 extraction increased consistently in animals hemodiluted with any of these colloids, O2 extraction was not increased when animals of the RS-group met their individual Hbcrit. As this finding may reflect a microcirculatory disorder related to excessive tissue hydration, we conclude that the comparatively early VO2-decrease in the RS-group might, in addition to the anemia-related restriction of the O2 transport capacity, also be attributable to an edema-related impairment of O2 uptake at the site of pulmonary and peripheral microcirculation.
A certain transcapillary filtration rate is also characteristic for gelatin preparations [35
]. Their low molecular weight (30 to 40 kDa) entails a rapid passage into the interstitial space and a rapid clearance by glomerular filtration, finally reducing volume efficacy to 80% (that is, 20% extravasation rate). Consistently, EVLWI increased much later in the GEL-group than in the RS-group. Moreover, when hemodilution was continued below Hb 3.7 g/dL, O2
extraction could be augmented, reflecting that microcirculatory function might have been maintained more adequately than in the RS-group.
The strict maintenance of normovolemia is essential for adequate hemodynamic compensation of acute anemia, that is, for the increase in cardiac output. However, one weakness of the present protocol is the verification of normovolemia at time points characterized by extreme anemia. During extreme hemodilution, the kinetic of ICG elimination is significantly altered by dilution of albumin and increased cardiac output. Therefore, a measurement of circulating blood volume at this point would yield results not comparable with the baseline measurement [7
], so normovolemia was deduced from clinically assessable parameters, for example, ITBVI and SVV.
While ITBVI represents LV preload, decreases in SVV reflect adequate volume responsiveness. After hemodilution with either fluid, ITBVI increased above the baseline level, indicating that volume replacement was adequate to achieve macro-hemodynamic compensation of acute anemia (increase of venous return to the heart, augmentation of LV preload). However, the increase of ITBVI was more pronounced in the TS- and HS-groups. In the course of hemodilution, SVV decreased in the TS-, GEL-, and HS-groups. In the RS-group, SVV remained unchanged and at Hbcrit, it was significantly lower than in the HS-group. Both findings reflect that volume responsiveness was most strongly expressed in the starch groups. In the RS-group, however, volume responsiveness and volume efficacy were limited by partial extravasation despite infusion of 3 mL RS per mL blood withdrawn.
Although this procedure provided adequate LV preload for hemodynamic compensation of acute anemia, it may be argued that the infusion of higher volumes of RS (4 or 5 mL per mL blood withdrawn) might have elevated intravascular volume and might have improved volume responsiveness. On the other hand, extravasation and tissue hydration would have exacerbated and might have further impaired O2 uptake and tissue oxygenation.
Likewise, the volume effect of gelatin appeared to be limited by its short intravascular half-life and its extravasation tendency. No differences between the colloid groups were observed in LV preload or volume responsiveness until hemodilution to Hb 3.0 g/dL. However, after continuation of hemodilution to 2.7 g/dL, ITBVI tended to decrease and SVV to increase in the GEL-group, and both parameters differed significantly from the TS-group. Nevertheless, animals of the GEL-group still featured sufficient hemodynamic compensation of acute anemia (CI, SVI and ITBVI remained increased vs. baseline), which precludes that they were actually hypovolemic.
These findings indicate that 1) the infusion of 1.2 mL gelatin per mL blood withdrawn was adequate to maintain LV preload and volume responsiveness over a wide range of the hemodilution protocol; 2) in spite of this, the volume effect of gelatin could not be sustained until the end of the protocol, and 3) that extravasation and fading volume responsiveness might have compromised microvascular perfusion, which finally caused animals of the GEL-group to earlier achieve Hbcrit than the TS-group.
We chose Hbcrit
as the primary endpoint of the hemodilution protocol. In our previous studies, lactate concentrations began to increase 60 to 90 minutes after institution of Hbcrit
]. Of note, we employed the identical hemodilution protocol in the present study but animals were killed immediately after achievement of Hbcrit
, so that elevated lactate concentrations could not yet be expected.
In the present experimental model, the effects of the investigated infusion fluids became apparent when the O2 transport capacity was driven to its critical limit. Whether differences between the groups existed already at less severe degrees of anemia, is difficult to conclude.
However, a clinical investigation in healthy volunteers undergoing moderate hemodilution with different HES preparations (HES 130/0.4, HES 70/0.5 or HES 200/0.5) demonstrated that tetrastarch provided the most sustained increase of tissue O2
partial pressure (tpO2
In summary, our data suggest that the choice of the IV infusion fluid used for acellular volume replacement has an impact on the maintenance of O2 supply. Among the fluids investigated in the present study, tetrastarch (HES 130/0.4) provided the most extensive anemia tolerance when compared with gelatin, hetastarch or Ringer's solution. While the exact underlying mechanism remains to be elucidated, extravasation and formation of interstitial edema were associated with decreased anemia tolerance, indicating that the microcirculatory effects of the fluids investigated had a major impact on tissue oxygenation.