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The Effects of 6% Hydroxyethyl Starch–Hypertonic Saline in Resuscitation of Dogs with Hemorrhagic Shock

Barros, João M. P. MD, PhD*; do Nascimento, Paulo Jr. MD, PhD*; Marinello, João Luiz P. MD*; Braz, Leandro G. MD, PhD*; Carvalho, Lídia R. PhD; Vane, Luiz A. MD, PhD*; Castiglia, Yara M. M. MD, PhD*; Braz, José R. C. MD, PhD*

doi: 10.1213/ANE.0b013e3181f2e9b2
Critical Care, Trauma, and Resuscitation: Research Reports
Chinese Language Editions

BACKGROUND: Hemodynamic and global oxygen transport variables have failed to reflect splanchnic hypoperfusion, resulting in a failure to recognize inadequately treated hemorrhagic shock. Volemic expansion after fluid resuscitation is essential to improve global and regional oxygen in hemorrhagic shock. We hypothesized that, in contrast to conventional plasma expanders, the smaller volemic expansion from 7.5 NaCl/6% hydroxyethyl starch (HHES) solution administration in hemorrhagic shock may provide lesser systemic oxygen delivery and gastric perfusion. We used hemorrhaged dogs to compare intravascular volume expansion and the early systemic oxygenation and gastric perfusion effects of fixed fluid bolus administration, which are usually used in clinical situations with severe hemorrhage, of HHES, lactated Ringer (LR), and 6% hydroxyethyl starch (HES) solutions.

METHODS: Thirty dogs were bled (30 mL · kg−1) to hold mean arterial blood pressure at 40 to 50 mm Hg over 45 minutes and were resuscitated in 3 groups: LR (n = 10) at 3:1 ratio to shed blood; HES (mean molecular weight 130 kDa, degree of substitution 0.4) (n = 10) at 1:1 to shed blood; and HHES (n = 10), 4 mL · kg−1. Intravascular volume expansion (Evans blue and hemoglobin dilution), hemodynamic, systemic oxygenation, venous-to-arterial CO2 gradient (Pv[Combining Macron]-aCO2), and gastric intramucosal-arterial PCO2 gradient (PCO2 gap) variables were measured at baseline, after 45 minutes of hemorrhage, and 5, 45, and 90 minutes after fluid resuscitation.

RESULTS: HHES increased blood volume because of the high volume expansion efficiency, but intravascular volume expansion with this solution was the smallest of the solutions (P < 0.05). All 3 solutions induced a similar hemodynamic performance but HHES showed lower mixed venous PO2 and higher systemic oxygenation extraction, Pv[Combining Macron]-aCO2, and PCO2 gap than LR and HES (P < 0.05).

CONCLUSIONS: In dogs submitted to pressure-guided hemorrhagic shock and fixed-volume resuscitation, the smaller intravascular volume expansion from HHES solutions provides worse recovery of systemic oxygenation and gastric perfusion compared with LR and HES solutions despite its high volume expansion efficiency, which was limited by low infused volume.

Published ahead of print September 14, 2010 Supplemental Digital Content is available in the text.

From the *Department of Anesthesiology, Botucatu Medical School, Universidade Estadual Paulista; and Department of Biostatistics, Institute of Biosciences, Universidade Estadual Paulista, Botucatu, Brazil.

Supported by scholarships from CAPES (to JMPB) and FAPESP (to JLPM) (2005/56112-5).

Disclosure: The authors report no conflicts of interest.

Address correspondence and reprint requests to José R. C. Braz, MD, PhD, Department of Anesthesiology, Botucatu Medical School, UNESP, District of Rubião Júnior, P.O. Box 530, 18618-970, Botucatu, SP, Brazil. Address e-mail to jbraz@fmb.unesp.br.

Accepted July 1, 2010

Published ahead of print September 14, 2010

Bleeding control and adequate intravascular volume replacement in patient shock continue to present a challenge in trauma management. The gastrointestinal tract is one of the earliest affected by hypoperfusion and may be a primary trigger in multiple organ system failure.1 Hemodynamic and global oxygen transport variables have failed to reflect splanchnic hypoperfusion resulting in a failure to recognize inadequately treated hemorrhagic shock.2,3An automatic technique using a gastric air tonometer for semicontinuous determination of intramucosal gastric CO2 (PgCO2) and to estimate gastric intramucosal pH (pHi) and intramucosal-arterial PCO2 gradient (PCO2 gap) was proposed as a routine tool to evaluate gastrointestinal perfusion.4

Recently, a new 6% hydroxyethyl starch (HES) was developed with an intermediate (130-kDa) molecular weight (MW) and very low (0.4) degree of substitution. Using hypertonic saline (HS) with HES (HHES), which is hypertonic and hyperoncotic, is a new perspective for intravascular volume replacement because it prolongs volume expansion through an endogenous fluid redistribution by osmotic-dependent absorption of interstitial fluid5 and proves more beneficial for hemodynamic and oxygen transport than 6% HES alone.6 The effects of this solution and its association with HS (HHES) on gastric perfusion after hemorrhagic shock are unknown. However, some studies have demonstrated that other HES solutions such as hetastarch and pentastarch improve gastrointestinal oxygenation after hemorrhagic shock in dogs7 or in patients undergoing surgery.8,9

The few studies evaluating the effects of hypertonic/hyperoncotic solutions on regional perfusion recovery are controversial.7,10,11 Sustained gastric mucosal acidosis was demonstrated during resuscitation with HS plus hyperoncotic dextran 70 (HSD) in dogs submitted to hemorrhagic shock,10,11 whereas another study, in a model of controlled hemorrhage in dogs, showed improved gastrointestinal perfusion with no significant differences in pHi after resuscitation with HS, HSD, HES (200/0.5), or lactated Ringer (LR) solutions.7

The advantage of using HHES and HS solutions is to give smaller volumes, which may have a less important circulatory effect in the initial phase of resuscitation from hemorrhagic shock than LR and HES solutions, but prevent the occurrence of side effects associated with resuscitation, such as acute pulmonary edema. Even though the infusion of HS in hemorrhaged animals quickly increases the plasmatic volume, the plasma volume (PV) remains less than the normal volume.12,13 Volemic expansion after fluid resuscitation is essential to improve global and regional oxygen in hemorrhagic shock.

We hypothesized that, in contrast with conventional plasma expanders, the smaller volemic expansion from HHES solution in hemorrhagic shock may provide lesser systemic oxygen delivery and gastric perfusion. The aim of this investigation was to compare intravascular volume expansion and the early systemic oxygenation and gastric perfusion effects of fixed bolus injections, which are usually used in clinical situations during severe hemorrhage, of HHES (HES 130/0.4 with 7.5% NaCl), LR, and HES (130/0.4) solutions in a pressure-adjusted hemorrhagic shock model in dogs.

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METHODS

This study was approved by the Ethics Committee for Animal Research at Botucatu School of Medicine, UNESP, in adherence to the Principles of Laboratory Animal Care, formulated by the National Society for Medical Research in the Guide for the Care and Use of Animals by National Health Institutes.

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Animal Preparation

Thirty mongrel dogs of both sexes, weighing from 12 to 26 kg, were used in the study. They were considered healthy after clinical examination and a normal erythrocyte count. The animals were fasted overnight but allowed water ad libitum.

A multiparametric data collection system (AS3; Datex-Engstrom Instrumentarium, Helsinki, Finland) was installed for monitoring and recording ventilation, anesthetic gas and oxygen concentrations, hemodynamic variables, automated air tonometry, and temperature. A 20-gauge peripheral IV line was inserted into the cephalic vein. Anesthesia was induced with propofol 6 mg · kg−1 IV and fentanyl 5 μg · kg−1 IV. Animals were then placed in dorsal recumbency on an operating table. After orotracheal intubation, their lungs were maintained on mechanical ventilation using a volume-controlled mode (210 SE Excel Anesthesia Machine; Ohmeda, Madison, WI) with a tidal volume of 20 mL · kg−1, 2 cm H2O of positive end-expiratory pressure, 0.50 inspired oxygen fraction, and a respiratory rate of 12 to 14 breaths · min−1 to initially maintain an end-tidal CO2 (PETCO2) concentration of 35 to 40 mm Hg. Inspired and expired gas samples were collected from the respiratory circuit to analyze PETCO2, oxygen, and isoflurane concentrations. Respiratory settings were kept constant during the experiment. Anesthesia was maintained during animal preparation at 2.0 minimum alveolar concentration (MAC) (2.8%) isoflurane, and then during the study at 1.0 MAC (1.4%) isoflurane, according to a previously published report.14 Neuromuscular blockade was provided by an initial IV dose of rocuronium bromide 0.6 mg · kg−1 and was maintained at 10 μg · kg−1 · min−1 with a 2-channel infusion pump (Anne; Abbott Laboratories, Abbott Park, IL). An esophageal thermometer was inserted. Animal temperature was maintained at 37°C to 38°C by a specific warming blanket (WarmTouch; Mallinckrodt, St. Louis, MO) at a temperature from 42°C to 46°C. A 3-lead electrocardiogram (lead DII) was installed, and a pulse oximetry sensor located on the animal's tongue. A urinary catheter was placed in the bladder.

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Surgical Technique

Both femoral arteries and veins and right external jugular vein were isolated by cut-down and cannulated with polyethylene catheters (P240). The left femoral artery was used to measure mean arterial blood pressure (MAP) and to sample blood. The right femoral artery was used for blood withdrawal. The right femoral vein was used for drug administration and blood sampling. The left femoral vein was used to administer fluids and resuscitation solutions. The right external jugular vein was used to inject dye. A thermistor-tip flow-directed catheter (7.5F; Baxter, Irvine, CA) was floated through the right external jugular vein into a pulmonary artery for mixed venous blood sampling and to measure central venous pressure, mean pulmonary artery pressure, pulmonary artery occlusion pressure, and cardiac output (CO). All pressure-measuring catheters were connected to transducers (Datex-Engstrom) and then to an AS3 biomonitor (Datex-Engstrom) for continuous recording of systemic and pulmonary artery pressures.

After a midline laparotomy, splenectomy was performed to prevent autotransfusion. A gastric air tonometer (Tonometrics catheter; Ohmeda, Worcester, MA) was placed in the stomach to determine mucosal gastric CO2 (PgCO2); its position was checked manually through palpation. We used continuous gastric suctioning but no H2 blockers were administered. After careful homeostasis, the abdomen was closed. To compensate for insensible water loss and fasting period, each animal was given LR solution at 6 mL · kg−1 · h−1 using a 2-channel infusion pump (Anne; Abbott Laboratories) during animal preparation and the stabilization period.

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Model of Hemorrhagic Shock

A 28 mL · kg−1 hemorrhage (38% of blood volume [BV]) was started from the right femoral artery catheter at 3 mL · kg−1 · min−1 for 15 minutes to keep MAP between 40 and 50 mm Hg, as reported in similar controlled hemorrhage models.7,12,15 These values were maintained for the next 45 minutes by additional bleeding if necessary.

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Groups and Fluid Resuscitation

Animals were randomly allocated, by opening a sealed envelope, to 1 of 3 groups (10 animals per group), according to the type of solution used for resuscitation: LR group—LR solution in a 3:1 ratio to shed BV; HES group—6% HES 130/0.4 (Voluven®; Fresenius Kabi, Campinas, Brazil) in a 1:1 ratio to shed BV; and HHES group—7.5% NaCl in 6% HES (130/0.4) solution (4 mL · kg−1). Fluid resuscitation was administered over 15 minutes.

Data were collected after a 30-minute stabilization period and once a steady state was achieved (baseline) at the end of the hemorrhagic shock period, and after 5, 45, and 90 minutes of fluid resuscitation. At these times, blood samples were collected to determine pH, blood gases, Na+, Cl, and lactate.

At the conclusion of the experiment, isoflurane was increased to 3.6% for 10 minutes and euthanasia was performed with an IV bolus injection of potassium chloride. The study design is shown in Figure 1.

Figure 1

Figure 1

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Determination of Blood and PV

In each experiment, during the stabilization period, an 18-mL blood sample was obtained to provide plasma for preparing the Evans blue standards and calibrating an absorption-versus-dye concentration calibration curve. Baseline PV (PV1) for each animal was measured at baseline by using Evans blue dilution.16 Exactly 2 mL of Evans blue dye (Vetec, Rio de Janeiro, Brazil) at a concentration of 5 mg · mL−1 was rapidly injected into the right external jugular vein. A stopwatch was started at the time of injection. The dye was thoroughly washed into the vein using 10 mL saline. Next, 6 samples of fresh circulating blood were withdrawn from the left femoral artery and timed so that the withdrawal midpoint was exactly 1, 2, 3, 4, 5, and 6 minutes after injection. The calculated plasma concentration of Evans blue at injection time was used to determine PV (mL), calculated as Evans blue dose (mg) divided by plasma concentration (mg · mL−1). Arterial hematocrit (Hct), hemoglobin (Hb), and PV1 were used to calculate baseline BV (BV1) and red blood cell volume (RBCV1). Dog BV at 45 minutes of hemorrhage (BV2) can be expressed as BV2 = (BV1 − SV) + BV1 [(Hb1 − Hb2) × Hb2−1], where SV is sample volume (blood sample for analysis plus shed blood). PV after hemorrhage can be expressed as PV2 = BV2 − [(RBCV1 − SV) × Hct2 × 100−1]. Subsequent BV (BV3, BV4, and BV5) and PV (PV3, PV4, and PV5) determinations were made from sequential iterations of these formulas after 5, 45, and 90 minutes of fluid resuscitation.

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Formulas Utilized

CO was measured in triplicate by thermodilution using 10 mL cold 5% dextrose solution. Cardiac index (CI = CO/body surface [BS] area) was calculated according to calculated BS area (BS = κ × BW2/3), where κ = 0.09 and BW is body weight.17 Arterial and mixed venous PO2, PCO2, and pH were measured with a blood gas analyzer (Chiron Diagnostics model 865; Halstead, Essex, UK). Hb, arterial oxygen saturation, and mixed venous oxygen saturation (Sv[Combining Macron]O2) were measured by a co-oximeter (Chiron Diagnostics model 865). An enzymatic electrode (Chiron Diagnostics model 865) was used to measure arterial lactate. Plasma Na+ and Cl were measured by an AVL Electrolyte Analyzer model 9180 (Roswell, GA). Arterial and mixed venous contents (CaO2 and Cv[Combining Macron]O2, respectively) were calculated as [CaO2 = (Hb × 1.34 × %HbO2) + (0.0031 × PaO2); Cv[Combining Macron]O2 = (Hb × 1.34 × %HbO2) + (0.0031 × Pv[Combining Macron]O2)]. System oxygen transport and uptake indexes (DO2I and VO2I, respectively) were calculated as DO2I = CI × CaO2 and VO2I = CI × (CaO2 − Cv[Combining Macron]O2). Systemic oxygen extraction ratio (O2ER) was calculated as O2ER = (CaO2 − Cv[Combining Macron]O2)/CaO2. Venous-to-arterial CO2 gradient (Pv[Combining Macron]-aCO2) was calculated as the difference between Pv[Combining Macron]CO2 and PaCO2, simultaneously and respectively obtained from central mixed venous blood and arterial blood samples. Stroke volume index was calculated with standard formula. The tonometer balloon was automatically filled with a 5-mL air sample and given 10 minutes to reach equilibrium with gastric lumen PCO2 and PgCO2; the gas was then automatically sampled and PgCO2 measured by infrared spectroscopy (Tonocap®; Datex, Helsinki, Finland). Arterial CO2 (PaCO2) was determined simultaneously with measurements of PgCO2 to calculate the gastric-to-arterial PCO2 gradient (PCO2 gap = PgCO2 − PaCO2).18 The change in BV divided by infused solution volume was calculated as an indicator of infused solution volume expansion efficiency (VEE).19 All volumes were expressed as milliliter · kilogram−1.

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Statistical Analysis

The sample size of the groups was estimated as in the literature.10,11,20 Statistical analysis was performed using a Statistic Package for Social Sciences for Windows software (version 6.0; SPSS, Inc., Chicago, IL). Normal distribution of the data was confirmed using the Kolmogorov-Smirnov test. Morphometric variables and shed BV were compared among the 3 groups by analysis of variance. Gender was compared using Fisher exact test. Parametric continuous data were compared among the groups by analysis of variance for repeated measures, followed by Tukey's test to investigate differences at different times in each group. In this case, data are reported as means ± SD. Nonparametric continuous data were compared among the groups by the Kruskal-Wallis test for repeated measures, followed by Friedman's test to investigate differences at different times in each group. In this case, data are reported as median (25th–75th percentiles). Correlation between continuous variables was investigated by Pearson correlation coefficient. For all analyses, P < 0.05 was considered statistically significant.

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RESULTS

All animals survived to study end. We found no differences among groups according to morphometric variables or gender (Table 1).

Table 1

Table 1

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Hemodynamic Parameters

Target MAP was successfully achieved and maintained after 45 minutes of hemorrhage in all groups. Hypotension level was similar in all groups (Fig. 2). Average shed BV was 29.6 ± 6.3 mL · kg−1 in the LR group, 30.3 ± 4.7 mL · kg−1 in the HES group, and 30.0 ± 4.2 mL · kg−1 in the HHES group, corresponding approximately to 40% of the circulating BV (74 mL · kg−1). There were no significant differences among groups (P > 0.05). Hemorrhage caused marked effects on hemodynamics with no significant differences among groups (P > 0.05) (Fig. 3 and Table 2). After 5-minute fluid resuscitation, the majority of hemodynamic data were significantly lower in group HHES than groups LR and HES (P < 0.05). After 90-minute fluid resuscitation, the hemodynamic data were similar in all groups (P > 0.05), with the exception of heart rate, which in the HHES group was significantly higher than the LR group (P < 0.05) (Figs. 2 and 3 and Table 2).

Figure 2

Figure 2

Figure 3

Figure 3

Table 2

Table 2

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Systemic Oxygenation and Gastric Perfusion Variables

Hemorrhage also caused marked effects on systemic oxygenation variables with no significant differences among groups (P > 0.05) (Table 3). Signs of tissue hypoperfusion were evident. Thus, in all groups, there were significant increases of Pv[Combining Macron]-aCO2 (Table 3), PgCO2 (Table 4), and PCO2 gap (P < 0.05) (Fig. 4).

Figure 4

Figure 4

After fluid resuscitation, O2ER values were significantly higher and Sv[Combining Macron]O2 values were significantly lower in the HHES group than in the LR and HES groups (P < 0.05) (Table 3). Signs of tissue hypoperfusion were evident in the HHES group. After 90 minutes of fluid resuscitation, PgCO2, Pv[Combining Macron]-aCO2 (Table 3), and PCO2 gap values (Fig. 4) were significantly higher in this group than in the LR and HES groups (P < 0.05). Only HHES solution did not return PCO2 gap and Pv[Combining Macron]-aCO2 values to prehemorrhage levels (P < 0.05).

Table 3

Table 3

Table 4

Table 4

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Time Course of Blood and PV After Expansion

At all time points after the infusion period, LR solution increased BV by less than IV volume injected (Table 5) with a VEE of 0.38 at 5 minutes after infusion end; thereafter, it decreased to 0.11 after 90 minutes of resuscitation (Fig. 5). HES solution increased BV by a similar amount as IV volume injected at 5 and 45 minutes after infusion end (Table 5) with a VEE of 1.07 and 0.89, respectively (Fig. 5). BV expansion values peaked 5 minutes after LR and HES infusions. Thereafter, HES produced a more sustained volume expansion compared with LR (P < 0.05) (Fig. 6). HHES solution showed the highest VEE at all time points after the infusion period (P < 0.05) (Fig. 5) whereas BV expansion with HHES was the smallest (Fig. 6).

Table 5

Table 5

Figure 5

Figure 5

Figure 6

Figure 6

There was a significantly negative correlation between PCO2 gap and BV in HES (r = −0.40; P = 0.004) and HHES groups (r = −0.48; P = 0.0005) but not in the LR group (r = 0.078; P = 0.59).

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Acid-Base Status and Lactate

After exsanguinations, there were significant decreases in arterial pH and bicarbonate and increases in lactate values for all groups (P < 0.05). PaCO2 levels significantly increased after 5 minutes of fluid resuscitation in all groups (P < 0.05), but only the HHES group did not return to prehemorrhage levels after 90 minutes of fluid resuscitation (P < 0.05). Only HHES solution did not return arterial pH and bicarbonate values to baseline levels after 90 minutes of fluid resuscitation (P < 0.05). Arterial lactate increased more in group LR than in the other groups after 5 minutes of resuscitation (P < 0.05) but the values returned to prehemorrhage levels after 90 minutes of fluid resuscitation in all groups (P > 0.05) (Table 4).

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Hemodilution

Hb and Hct values were maintained lower than baseline levels after 90 minutes of fluid resuscitation in all groups (P < 0.05). However, the values in the HES group were significantly lower than in the LR and HHES groups after resuscitation (P < 0.05) (Table 5). Plasma Na+ and Cl levels were significantly higher after HHES resuscitation compared with the other solutions (P < 0.05) (Table 5).

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DISCUSSION

The principal finding of this study is that fixed-volume resuscitation with HHES provides smaller volemic expansion and a worse recovery of systemic oxygenation and regional perfusion variables than HES and LR solutions in dogs submitted to pressure-adjusted hemorrhagic shock.

Current anesthesia and surgical textbooks quoting a “3:1 rule” indicating that 3 mL of crystalloids is needed to replace 1 mL of blood loss implies that one-third of infused crystalloid remains intravascular, whereas colloids replace blood loss at close to a 1:1 ratio.20,21 Circulatory PV restoration is achieved with a small infused volume of hypertonic and hyperoncotic solution (4 mL · kg−1).12 However, clinical studies22,23 and an experimental study in normovolemic sheep19 measuring vascular volume expansion after crystalloid infusion showed VEE <0.2 soon after infusion. For this reason, a large volume of this solution is necessary for plasmatic volume expansion. However, volume expansion can be somewhat larger and more sustained in animals and humans under hypovolemia conditions19,22,24,25 in which a crystalloid VEE as high as 0.30 similar to our results was reported immediately after infusion. During hypovolemia, capillary pressure and lymphatic return are lower than normovolemia, tending to favor intravascular volume expansion and increase the effective volume of infused fluid.19 However, poor intravascular retention of balanced salt solutions transiently supports intravascular volume but can later cause tissue edema with impaired oxygen perfusion.26,27 As in our study, many early volume expansion studies have been made under hypovolemia and anesthesia.7,10,12,20 Anesthetics such as isoflurane are also credited with intraoperative changes in variables that directly or indirectly modify circulating BV.28,29 In our study, we used isoflurane as the anesthetic agent, according to a previously published report.30 In this study, the authors demonstrated that isoflurane resulted in less cardiovascular depression than sevoflurane and halothane at equipotent MAC in a model of volume-guided hemorrhage (32 mL · kg−1) in dogs.

VEE of HES after infusion end was similar to that reported after liver trauma in pigs31 and in clinical studies during hypovolemia.32 Different than what occurred with LR solution, VEE and volume expansion decrease were lower after HES infusion ended. Molecules from HES solution remain largely intravascular, augmenting PV and plasma oncotic pressure, thereby limiting transvascular fluid filtration.32 These effects may explain the hemodilution effect in the HES group. The volume expansion effects of starch preparations depend on the number of osmotically active particles retained within the circulation. The lower MW of HES 130/0.4 means that, when broken down, there is a sharp increase in the number of osmotically active particles within the plasma.33 This effect accounts for the PV expansion being greater than the volume infused, and probably accounts for the greater persistence of the volume effect of this starch because the metabolic process continuously produces increasing numbers of osmotically active particles.32

Even though HHES infusion increased BV, consequently this solution's VEE, the BV remained less than baseline and it was the smallest of all the solutions because of the low infused volume of this solution. The infused volume of HS and HHES solutions is limited because both solutions determine hypernatremia and hyperchloremia.12 An experimental study comparing expansion with a bolus infusion of HS only and hyperoncotic solution only showed that HS caused peak volume expansion immediately after infusion whereas hyperoncotic solution took 15 to 30 minutes after infusion to exert its maximal effect.34 When using HHES, a smaller volume load is needed because hypertonic crystalloid solution, as with HS, expands both the vascular and interstitial volume by borrowing fluid from the intracellular compartment.19 The addition of a colloid such as dextran or starch to HS slightly increases and substantially prolongs volume expansion.12

The short-term effects of fixed fluid bolus administration, which is usually used in clinical situations of a patient with severe hemorrhage, showed that LR and HES solutions, by different mechanisms, resulted in early and larger intravascular volume expansion, and consequently, better hemodynamic performance than HHES solution. This implies that solution-infused volume quantities were not equieffective. However, after 90 minutes of fluid resuscitation, all 3 solutions induced similar hemodynamic performance. Probably the higher heart rate in group HHES than in the other groups aided the maintenance of the CI and other hemodynamic variables at values similar to the other groups. However, at this time, HHES solution in relation to the other solutions studied showed a significant alteration of systemic oxygenation variables, as oxygen extraction and Sv[Combining Macron]O2, and a lower gastric perfusion, with higher PCO2 gap and Pv[Combining Macron]-aCO2 values. Pv[Combining Macron]-aCO2 is a systemic variable used as a reflection of inappropriate tissue perfusion.35

The smallest volemic state in the HHES group may explain the results obtained in relation to systemic oxygenation and tissue hypoperfusion, compared with the other groups. Tissue hypoxia by gastrointestinal vasoconstriction might have been the main mechanism responsible for intramucosal acidosis during hemorrhage.11 Under conditions of shock, the most vulnerable layer of the gastrointestinal tract is the mucosa.1,10 The villi have peculiar microvascular architecture, characterized by a countercurrent exchange of oxygen from arteriole to adjacent venule along its length, with a low effective Hct.10 Under normal conditions, this oxygen shunting is not harmful to the villi. However, under conditions in which blood flow to the gastrointestinal tract becomes curtailed, such as in our hemorrhage model, the oxygen deficit in the tips of the villi may become so severe that they can undergo ischemic death.36 Therefore, conditions of low oxygen delivery may induce both tissue hypoxia and hypercarbia by incrementing the countercurrent oxygen exchange between arteriole and venule, threatening cells at villi tips. These conditions jeopardize the integrity of gastrointestinal mucosal cells, predisposing the gut to increased permeability and translocation of bacteria and their toxins. Consequently, a systemic inflammatory response may be induced leading to multiple organ failure.11,36 A PCO2 gap value of 25 to 35 mm Hg is considered the cutoff point for anaerobic metabolism.37

In relation to gastric perfusion, HES and LR solutions gave the best results, the former aided by its effect on BV expansion. In addition, HES 130/0.4 seems to provide larger and faster increases in tissue oxygenation than HES with high MW38 and LR solution; this is probably caused by decreased microvascular endothelium cell swelling and a restoring of shock-induced microcirculatory disturbances.25 However, starch solutions have been associated with side effects such as impaired renal and hemostatic function.33,39 However, the rapidly degradable HES 130/0.4 and starch associated with HS solutions seem to have a minimal influence on hemostasis.33,40

The most widespread use of hypertonic and hyperoncotic solutions has been for the initial treatment of posttraumatic hypotension. The effects of these solutions on gastric tonometry have not been extensively investigated. In a model in dogs of pressure-adjusted hemorrhagic shock and resuscitation with a fixed-volume of LR, HES 200/0.5, HS, and HSD solutions, pHi was not significantly different among groups; however, LR and HES, but not HS and HSD, returned pHi to prehemorrhage values.7 In another study of hemorrhagic shock in dogs, resuscitation with 3% NaCl/10% dextran 40 in a volume equivalent to 25% of total shed blood gave sustained elevated PCO2 gap despite rapid hemodynamic restoration with this solution.10 In a model of uncontrolled hemorrhage from a vascular injury in swine and limited resuscitation with HSD, LR, or HS acetate with 6% dextran 75 (HAD) solutions, pHi was not significantly different among groups, with the gut becoming acidic in all limited resuscitation groups, although alkalosis was seen in systemic arterial blood samples from the HAD group.11 In pigs submitted to 2 hours of occlusion of the mesenteric artery and resuscitation with sodium chloride (SC group) or HS associated with 10% HES 200/0.5 (HHES group) solutions, pHi was significantly different between groups. In the SC group, gastric pHi decreased even further, whereas the HHES group showed a normalization of pHi and serum lactate within 30 minutes.41

A high PCO2 gap may be superior in predicting morbidity and mortality in multiple organ failure to global hemodynamics and metabolic variables, including lactate concentration and acid-base variables of critically ill patients.42 In this study, the changes in PCO2 gap were recorded after resuscitation, not to predict outcome but to evaluate the effectiveness of early resuscitation.

Use of the chloride anion in HHES solution resulted in hyperchloremia and maintained the metabolic acidosis that may have affected gut mucosal acidosis by increasing plasma chloride concentration relative to plasma sodium concentration.43 The result is a reduction in strong ion difference, the difference between positively and negatively charged electrolytes, which in turn produces an increase in free hydrogen ions to preserve electrical neutrality. This is measured as a decrease in pH.

However, LR solution aided by its buffering effect on arterial pH corrected arterial pH and gastric mucosal acidosis. Lactate is rapidly converted to bicarbonate and acts as a buffer that may alleviate the preexisting metabolic acidosis of hemorrhagic shock.42 In our study, the absence of a significant correlation between PCO2 gap and BV in the LR group strengthens the importance of the buffering effect on gastric mucosal acidosis of the LR solution.

Some further limitations of this study need to be discussed. As with any animal model, data cannot be directly transposed to humans. The principal advantage of an animal model is that it ensures identical standardized treatment and permits measurements at defined time points. A 30 mL · kg−1 hemorrhage was produced. This is a significant amount of blood, approximately 40% of total BV, limiting the analysis to a severe hemorrhagic shock, especially in relation to a low infused volume of HHES. Another limitation was that we did not investigate solutions with equivalent numbers of osmotically active particles. Only the immediate response to a single fixed bolus injection of different solutions was investigated. The medium- or long-term response might have been different. Crystalloid solutions must be administered after the initial bolus of HHES to sustain the hemodynamic benefits as well as splanchnic perfusion. Fluid-saving properties after hypertonic solution infusion may also avoid crystalloid-induced excessive intravascular volume.

We conclude that in dogs submitted to pressure-adjusted hemorrhagic shock and fixed-volume resuscitation, the smaller volemic expansion from HHES solution provides worse recovery of systemic oxygenation and gastric perfusion than LR and HES solutions despite its high volume expansion efficiency, which was limited by low infused volume.

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AUTHOR CONTRIBUTIONS

JMPB helped with study design, conduct of study, and manuscript preparation; PdN helped with study design; JLPM and LGB helped with conduct of study; LRC helped with data analyses; LAV and YMMC helped with study design and manuscript preparation; and JRCB helped with study design, data analyses, and manuscript preparation.

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REFERENCES

1. Reilly PM, Wilkins KB, Fuh KC, Haglund U, Bulkley GB. The mesenteric hemodynamic response to circulatory shock: an overview. Shock 2001;15:329–43
2. Ince C, Sinaasappel M. Microcirculatory oxygenation and shunting in sepsis and shock. Crit Care Med 1999;27:1369–77
3. Chiara O, Pelosi P, Segala M, Turconi MG, Brazzi L, Bottino N, Taccone P, Zambelli M, Tiberio G, Boswell S, Scalea TM. Mesenteric and renal oxygen transport during hemorrhage and reperfusion: evaluation of optimal goals for resuscitation. J Trauma 2001;51:356–62
4. Creteur J, De Backer D, Vincent JL. Monitoring gastric mucosal carbon dioxide pressure using gas tonometry: in vitro and in vivo validation studies. Anesthesiology 1997;87:504–10
5. Ragaller M, Muller M, Bleyl JU, Strecker A, Segiet TW, Ellinger K, Albrecht DM. Hemodynamic effects of hypertonic hydroxyethyl starch 6% solution and isotonic hydroxyethyl starch 6% solution after declamping during abdominal aortic aneurysm repair. Shock 2000;13:367–73
6. Sirieix D, Hongnat JM, Delayance S, D'Attellis N, Vicaut E, Bérrébi A, Paris M, Fabiani JN, Carpentier A, Baron JF. Comparison of the acute hemodynamic effects of hypertonic or colloid infusions immediately after mitral valve repair. Crit Care Med 1999;27:2159–65
7. Braz JRC, do Nascimento P Jr, Paiva Filho O, Braz LG, Vane LA, Vianna PTG, Rodrigues GR Jr. The early systemic and gastrointestinal oxygenation effects of hemorrhagic shock resuscitation with hypertonic saline and hypertonic saline 6% dextran-70: a comparative study in dogs. Anesth Analg 2004;99:536–46
8. Marik PE, Iglesias J, Maini B. Gastric intramucosal pH changes after volume replacement with hydroxyethyl starch or crystalloid in patients undergoing elective abdominal aortic aneurysm repair. J Crit Care 1997;12:51–5
9. Wilkes NJ, Woolf R, Mutch M, Mallett SV, Peachey T, Stephens R, Mythen MG. The effects of balanced versus saline-based hetastarch and crystalloid solutions on acid-base and electrolyte status and gastric mucosal perfusion in elderly surgical patients. Anesth Analg 2001;93:811–6
10. Poli de Figueiredo LF, Cruz RJ Jr, Silva E, Yada-Langui MM, Rocha e Silva M. Sustained gastric mucosal acidosis after hemorrhage in spite of rapid hemodynamic restoration with blood or hypertonic/hyperoncotic solution. J Invest Surg 2005;18:257–64
11. Doucet JJ, Hall RI. Limited resuscitation with hypertonic saline, hypertonic sodium acetate, and lactated Ringer's solutions in a model of uncontrolled hemorrhage from a vascular injury. J Trauma 1999;47:956–63
12. Velasco IT, Rocha e Silva M, Oliveira MA, Oliveira MA, Silva RI. Hypertonic and hyperoncotic resuscitation from severe hemorrhagic shock in dogs: a comparative study. Crit Care Med 1989;17:261–4
13. Smith GJ, Kramer GC, Perron P, Nakayama S, Gunther RA, Holcroft JW. A comparison of several hypertonic solutions for resuscitation of bled sheep. J Surg Res 1985;39:517–28
14. Kazama T, Ikeda K. Comparison of MAC and the rate of rise of alveolar concentration of sevoflurane with halothane and isoflurane in the dog. Anesthesiology 1988;68:435–7
15. Dubin A, Estenssoro E, Murias G, Canales H, Sottile P, Badie J, Barán M, Pálizas F, Laporte M, Rivas Díaz M. Effects of hemorrhage on gastrointestinal oxygenation. Intensive Care Med 2001;27:1931–6
16. Foldager N, Blomqvist CG. Repeated plasma volume determination with the Evans Blue dye dilution technique: the method and a computer program. Comput Biol Med 1991;21:35–41
17. Guyton AC, Jones CE, Coleman TG. Normal cardiac output and its variation. In: Guyton AC, Joes CE, Coleman TG, eds. Cardiac Output and Its Regulation. 2nd ed. Philadelphia: WB Saunders Company, 1973:3–29
18. Lebuffe G, Decoene C, Pol A, Prat A, Vallet B. Regional capnometry with air-automated tonometry detects circulatory failure earlier than conventional hemodynamics after cardiac surgery. Anesth Analg 1999;89:1084–90
19. Tollofsrud S, Elgjo GI, Prough DS, Williams CA, Traber DL, Kramer G. The dynamics of vascular volume and fluid shifts of lactated Ringer's solution and hypertonic-saline-dextran solutions infused in normovolemic sheep. Anesth Analg 2001;93:823–31
20. Otsuki DA, Fantoni DT, Margarido CB, Marumo CK, Intelizano T, Pasqualucci CA, Costa Auler JO Jr. Hydroxyethyl starch is superior to lactated Ringer as a replacement fluid in a pig model of acute normovolemic haemodilution. Br J Anaesth 2007;98:29–37
21. Ganter MT, Hofer CK, Pittet JF. Postoperative intravascular fluid therapy. In: Miller RD, ed. Miller's Anesthesia. 7th ed. Philadelphia: Churchill Livingstone & Elsevier, 2010:2783–803
22. Lamke LO, Liljedahl SO. Plasma volume changes after infusion of various plasma expanders. Resuscitation 1976;5:93–102
23. Tollofsrud S, Bjerkelund CE, Kongsgaard U, Hall C, Noddeland H. Cold and warm infusion of Ringer's acetate in healthy volunteers: the effects on hemodynamic parameters, transcapillary fluid balance, diuresis and atrial peptides. Acta Anaesthesiol Scand 1993;37:768–73
24. Norberg A, Brauer KI, Prough DS, Gabrielsson J, Hahn RG, Uchida T, Traber DL, Svensén CH. Volume turnover kinetics of fluid shifts after hemorrhage, fluid infusion, and the combination of hemorrhage and fluid infusion in sheep. Anesthesiology 2005;102:985–94
25. Tollofsrud S, Tonnessen T, Skraastad O, Noddeland H. Hypertonic saline and dextran in normovolemic and hypovolemic healthy volunteers increases interstitial and intravascular fluid volumes. Acta Anaesthesiol Scand 1998;42:145–53
26. Lang K, Boldt J, Suttner S, Haisch G. Colloids versus crystalloids and tissue oxygen tension in patients undergoing major abdominal surgery. Anesth Analg 2001;93:405–9
27. Kimberger O, Arnberger M, Brandt S, Plock J, Sigurdsson GH, Kurz A, Hiltebrand L. Goal-directed colloid administration improves the microcirculation of healthy and perianastomotic colon. Anesthesiology 2009;110:496–504
28. Connolly CM, Kramer GC, Hahn RG, Chaisson NF, Svensén CH, Kirschner RA, Hastings DA, Chinkes DL, Prough DS. Isoflurane but not mechanical ventilation promotes extravascular fluid accumulation during crystalloid volume loading. Anesthesiology 2003;98:670–81
29. Brauer KI, Svensen C, Hahn RG, Traber LD, Prough DS. Volume kinetic analysis of the distribution of 0.9% saline in conscious versus isoflurane-anesthetized sheep. Anesthesiology 2001;96:442–9
30. Teixeira Neto FJ, Luna SP, Cruz ML, Braz JR, Massone F, Nogueira CS. A study of the effect of hemorrhage on the cardiorespiratory actions of halothane, isoflurane and sevoflurane in the dog. Vet Anaesth Analg 2007;34:107–16
31. Zaar M, Lauritzen B, Secher NH, Krantz T, Nielsen HB, Madsen PL, Johansson PI. Initial administration of hydroxyethyl starch vs lactated Ringer after liver trauma in the pig. Br J Anaesth 2009;102:221–6
32. James MF, Latoo MY, Mythen MG, Mutch M, Michaelis C, Roche AM, Burdett E. Plasma volume changes associated with two hydroxyethyl starch colloids following acute hypovolaemia in volunteers. Anaesthesia 2004;59:738–42
33. Jungheinrich C, Sauermann W, Bepperling F, Vogt NH. Volume efficacy and reduced influence on measures of coagulation using hydroxyethyl starch 130/0.4 (6%) with an optimised in vivo molecular weight in orthopaedic surgery: a randomised, double-blind study. Drugs RD 2004;5:1–9
34. Dubick MA, Davis JM, Myers T, Wade CE, Kramer GC. Dose response effects of hypertonic saline and dextran on cardiovascular responses and plasma volume expansion in sheep. Shock 1995;3:137–44
35. Vallée F, Vallet B, Mathe O, Parraguette J, Mari A, Silva S, Samii K, Fourcade O, Genestal O. Central-venous-to-arterial carbon dioxide difference: an additional target for goal-directed therapy in septic shock? Intensive Care Med 2008;34:2218–25
36. Neviere R, Chagnon JL, Teboul JL, Vallet B, Wattel F. Small intestine intramucosal PCO2 and microvascular blood flow during hypoxic and ischemic hypoxia. Crit Care Med 2002;30:379–84
37. Schlichtig R, Mehta N, Gayowski TJ. Tissue-arterial PCO2 difference is a better marker of ischemia than intramural pH (pHi) or arterial pH-pHi difference. J Crit Care 1996;11:51–6
38. Standl T, Burmeister MA, Schroeder F, Currlin E, Schulte am Esch J, Freitag M, Schulte am Esch J. Hydroxyethyl starch (HES) 130/0.4 provides larger and faster increases in tissue oxygen tension in comparison with prehemodilution values than HES 70/0.5 or HES 200/0.5 in volunteers undergoing acute normovolemic hemodilution. Anesth Analg 2003;96: 936–43
39. Davidson IJ. Renal impact of fluid management with colloids: a comparative review. Eur J Anaesthesiol 2006;23:721–38
40. Haas T, Fries D, Holz C, Innerhofer P, Streif W, Klingler A, Hanke A, Velik-Salchner C. Less impairment of hemostasis and reduced blood loss in pigs after resuscitation from hemorrhagic shock using the small-volume concept with hypertonic saline/ hydroxyethyl starch as compared to administration of 4% gelatin or 6% hydroxyethyl starch solution. Anesth Analg 2008; 106:1078–86
41. Jonas J, Heimann A, Strecker U, Kempski O. Hypertonic/ hyperoncotic resuscitation after intestinal superior mesenteric artery occlusion: early effects on circulation and intestinal reperfusion. Shock 2000;14:24–9
42. Poeze M, Solberg BC, Greve JW, Ramsay G. Monitoring global volume-related hemodynamic or regional variables after initial resuscitation: what is a better predictor of outcome in critically ill septic patients? Crit Care Med 2005;33:2494–500
43. Prough DS, White RT. Acidosis associated with perioperative saline administration: dilution or delusion? Anesthesiology 2000;93:1167–9
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