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CARDIOVASCULAR ANESTHESIA

Acute Intravascular Volume Expansion with Rapidly Administered Crystalloid or Colloid in the Setting of Moderate Hypovolemia

Department of Anesthesiology, University of Washington Medical Center, Seattle

Address correspondence and reprint requests to David McIlroy, Department of Anesthesia and Pain Management, Alfred Hospital, Commercial Rd., Melbourne 3004, Victoria, Australia. Address e-mail to d.mcilroy{at}alfred.org.au

	Abstract

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Although the distribution of various crystalloid and colloid solutions at equilibrium has been well established, the acute peak expansion of intravascular volume that can be achieved with the rapid administration of crystalloid or colloid is unknown. We studied eight healthy male subjects in a two-part crossover trial designed to assess the maximal increase in intravascular volume achieved with 1000 mL of lactated Ringer’s solution compared with the same volume of 6% Hetastarch. Subjects were made moderately hypovolemic by the withdrawal of 900 mL of blood, and then the crystalloid or colloid solution was rapidly infused over 5–7 min. Serial dilution of hematocrit was measured every 5 min for 30 min to determine changes in blood volume. Peak expansion of intravascular volume with lactated Ringer’s solution was 630 ± 127 mL, occurring immediately the rapid infusion was complete, whereas the peak expansion of intravascular volume with 6% Hetastarch was 1123 ± 116 mL and occurred 5 min after the completion of the fluid infusion. The results were significantly different (P < 0.001). These results would suggest that even for very short periods of time, rapid infusion of colloid significantly more effectively increases blood volume and, by inference, cardiac output than the same volume of crystalloid, even if the crystalloid is administered very rapidly.

IMPLICATIONS: Under conditions of moderate hypovolemia, the maximal acute intravascular volume expansion with the rapid infusion of 1000 mL of lactated Ringer’s solution is slightly more than half that achieved with the same volume of 6% Hetastarch.

	Introduction

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IV fluid resuscitation is an integral part of modern anesthesia practice. The goal is to increase intravascular volume as a means to augment cardiac output and organ perfusion. This may be attempted with a colloid or crystalloid solution. The benefits of each type of fluid have been widely debated for many years. Although the amount of each fluid that remains in the intravascular space at equilibrium has been well documented (1), the ability of a given fluid to acutely and temporarily expand the intravascular space when given rapidly to hypovolemic subjects has not been adequately investigated. Several complex and sophisticated mathematical models have predicted the rate of redistribution of these fluids and thus the increase in blood volume for differing rates and duration of crystalloid infusion (2). However, these models have used relatively slow fluid infusion rates (30 min) and rapidly administered fluid (>100 mL/min) does not fit the constructed pharmacokinetic model (3,4). Other recent studies from the same group show that a larger proportion of crystalloid than expected is retained in the intravascular space at equilibrium in subjects who are made hypovolemic immediately before the fluid challenge (5,6).

The aim of the present investigation was to compare the peak increase in intravascular volume achieved with crystalloid compared with colloid when administered IV rapidly to moderately hypovolemic subjects using a balanced crossover trial. The hypothesis was that equal volumes of crystalloid or colloid would provide the same initial increase in intravascular volume when administered rapidly to moderately hypovolemic subjects.

	Materials and Methods

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Eight healthy males 22–36 yr (mean, 29 yr) weighing 71–103 kg (84 ± 11 kg) were studied. We performed a prospective two-part crossover trial designed to assess the maximal increase in intravascular volume achieved with 1000 mL of lactated Ringer’s solution compared with 1000 mL of 6% Hetastarch. Each subject was studied on two separate occasions at least 6 days apart. Because of the long and slightly uncertain elimination half-life of 6% Hetastarch, (7) the order of fluids was not randomized, and each subject received the lactated Ringer’s solution on their first visit and then 6% Hetastarch at their second visit. The study was approved by the University of Washington’s IRB, and all volunteers gave written informed consent with the knowledge that they could withdraw from the trial at any time. The study was jointly funded by an intra-departmental research grant and a National Institute of Health grant to the University of Washington Clinical Research Center.

Subjects were admitted to the Clinical Research Center having been instructed to eat a light meal before their arrival. On arrival, their height and weight were checked and they were asked to void and then lay down in bed where baseline vital signs were obtained. A 14-gauge IV catheter was then placed in each antecubital fossa. Subjects were monitored with 3-lead electrocardiography, automated noninvasive blood pressure measurement, and pulse oximetry and remained supine throughout the procedure. An attending anesthesiologist was also present throughout the procedure with full resuscitation drugs and equipment available. A citrated blood collection bag was attached to one of the IV cannula, and 900 mL of venous blood was drained by gravity over 15 min. A rapid fluid infusing device (Level 1, Smiths Industries Medical System, Rockland, MA) was attached to the other IV cannula and was primed with either lactated Ringer’s solution (Baxter Healthcare Corporation, Deerfield, IL; electrolyte composition [mEq/L]: Na 130, K 4, Ca 2.7, Cl 109, and Lactate 28; 273 mOsm/L) or 6% Hetastarch (Abbott Laboratories, North Chicago, IL; electrolyte composition [mEq/L]: Na 154 and Cl 154; 308 mOsm/L).

When the withdrawal of 900 mL of blood was complete, a 4-mL blood sample was obtained for baseline hematocrit measurement. We then began the rapid infusion of 1000 mL of fluid via the Level-1 device, which warms the fluid close to body temperature and delivers it under 300 mm Hg of pressure. Lactated Ringer’s solution 1000 mL was typically delivered in 4–5 min, whereas 1000 mL of 6% Hetastarch took 7–8 min to deliver.

The completion of the rapid infusion of fluid was designated time zero (0). A blood sample was obtained from the IV cannula not used for fluid infusion. The hematocrit of each 4-mL sample of blood was measured in duplicate (Cell Dyne 3500; Abott, Santa Clara, CA) by technicians blinded to which fluid had been given, and the mean was used for further calculations. Individual hematocrits are accurate to ±2 hematocrit percentage points. Sampling was repeated every 5 min for 30 min. At the time of each blood sample, an initial volume of 5 mL of venous blood was withdrawn to prevent any contamination of the sample with other fluid. This volume was subsequently returned to the patient. Previous studies indicate that the redistribution process of crystalloid is almost complete in euvolemic subjects 30 min after completion of the infusion (4,5).

After 30 min, the 900 mL of collected blood was returned to the subject over 90 min. Initial blood volume was calculated according to the formula of Nadler et al. (8):

We then subtracted 900 mL from this value as our postphlebotomy baseline blood volume, from which to calculate the increase in blood volume with fluid infusion.

Changes in blood volume were calculated from serial dilutional changes in hematocrit. Although traditional methods for measuring the amount of fluid remaining in the intravascular space involve indicator dye dilution or dilution of radiolabeled red blood cells, these methods are unsuitable for studies of nonsteady-state conditions because they require an unchanged blood volume for a period of 30–40 min to be accurate (4). Although most of the published work in this area has used hemoglobin dilution to indicate changes in blood volume (2,4,5,9), the precision of this technique has been questioned (10). It has been shown that the ratio of large-vessel:whole-body hematocrit does not remain constant in the setting of volume loading with colloid, and a more precise measure of blood volume change may be obtained with independent measures of erythrocyte volume and plasma volume, the sum of which provides blood volume. However, the calculation of plasma volume requires the injection of indocyanine green, which, because of its clearance, cannot be repeated more frequently than every 20 min. It was therefore deemed unsuitable for use in this setting, where the peak increase in intravascular volume was expected to occur within 5 min of completion of the fluid infusion, followed by a rapid decline in those subjects given crystalloid.

Corrections were not made for the blood samples removed (32 mL total) or the lactated Ringer’s solution used to flush the sampling line (24 mL total) because the small volumes were not felt to significantly affect the results.

There was no need to include a correction factor for the standard ratio between large-vessel and whole-body hematocrit because the initial blood volume calculation was not based on a large-vessel hematocrit measure. Previous studies (11) confirm that 6% Hetastarch does not significantly alter the rheological properties of blood independent of a simple dilutional effect.

The primary outcome measure was the difference in peak intravascular volume expansion between lactated Ringer’s solution and 6% Hetastarch after completion of the rapid infusion of fluid compared using Student’s t-test. The secondary outcome was time-specific differences in intravascular volume expansion between lactated Ringer’s solution and 6% Hetastarch determined using two-way repeated-measures analyses of variance.

	Results

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The withdrawal of 900 mL of blood from subjects was generally well tolerated. The mean reduction in systolic and diastolic blood pressure was 9 and 4 mm Hg, respectively. The mean change in heart rate was a reduction of 9 bpm (range, -29 to +17). One subject became symptomatically bradycardic at the completion of blood withdrawal with a sinus bradycardia at 28 bpm but responded to atropine 1 mg IV and was happy to continue the study. One other subject experienced some mild light headedness that settled with elevation of the legs. The rapid infusion of fluid via the Level 1 produced no symptoms.

Rapid infusion of lactated Ringer’s solution produced no significant change in mean heart rate or mean value of systolic blood pressure. However, the mean pulse pressure did increase from 51 ± 12 mm Hg to 58 ± 16 mm Hg. By contrast, the rapid infusion of 6% Hetastarch was associated with an increase in mean heart rate from 69 ± 21 bpm to 79 ± 17 bpm. There was also an increase in the mean value of systolic blood pressure from 115 ± 24 mm Hg to 128 ± 19 mm Hg along with an increase in the mean value of pulse pressure from 51 ± 12 mm Hg to 59 ± 12 mm Hg (Fig. 1 and 2).

View larger version (16K): [in this window] [in a new window]   Figure 1. Heart rate (bpm) at admission, after 900 mL of venesection, and every 5 min for 30 min after the rapid infusion of either lactated Ringer’s solution or 6% Hetastarch 1000 mL. Time 0 represents immediately when the fluid infusion was complete.

View larger version (16K): [in this window] [in a new window]   Figure 2. Pulse pressure (mm Hg) at admission, after 900 mL of venesection, and every 5 min for 30 min after the rapid infusion of either lactated Ringer’s solution or 6% Hetastarch 1000 mL. Time 0 represents immediately when the fluid infusion was complete.

View larger version (18K): [in this window] [in a new window]   Figure 3. Increase in intravascular volume (mean ± SD) determined by hemodilution after the rapid infusion of 1000 mL of lactated Ringer’s solution or 6% Hetastarch. Time 0 represents the completion of the rapid infusion of fluid.

View larger version (22K): [in this window] [in a new window]   Figure 4. Peak increase in intravascular volume after rapid infusion of 1000 mL of lactated Ringer’s solution or 6% Hetastarch. Lines show the results for individual subjects. Also shown are mean ± SD. For lactated Ringer’s solution, the peak increase occurred immediately after completion of the fluid infusion. For 6% Hetastarch, the peak volume expansion occurred 5 min after completion of the infusion.

The intravascular volume expanding effect of the 6% Hetastarch was well maintained throughout the study period. There was no statistically significant reduction in the volume expansion until time = 30 min, where the reduction in mean volume expansion was a little over 100 mL compared with the volume expansion at time = 5–10 min.

Not surprisingly, the intravascular volume expanding effect of lactated Ringer’s solution declined rapidly after its initial peak at time = 0. By 15 min after completion of the infusion, the mean increase in intravascular volume was only 403 ± 88 mL. Beyond 15 min, there was no further significant decline in intravascular volume.

	Discussion

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The expansion of intravascular volume by crystalloid and colloid after the process of redistribution has occurred is well documented in physiology texts (1). However, complete redistribution to equilibrium takes significant time, and more recent work has focused on the distribution of these fluids during and shortly after their infusion (2–5,9). In fact, by examining the early distribution of these fluids, complex and sophisticated mathematical models have been developed that are able to predict the expansion in intravascular volume for a given volume of crystalloid infused over a set period of time. From these models, and the studies on which they are based, it has become apparent that IV infused crystalloid is distributed in an expandable space that is significantly smaller than the traditional extracellular volume (20% lean body mass), (2) particularly in the first 30 minutes after completion of the infusion.

Hypovolemia also increases the amount of crystalloid retained in the intravascular space (5,9). Typically, with moderate hypovolemia, blood volume increases by approximately 50% of the administered volume of crystalloid. Increased volume expansion, at least temporarily, is also achieved with more rapid infusions (3,12).

Most of the previous studies have infused the crystalloid into subjects over a period of 30 minutes. In the one study, in which normovolemic volunteers received 1500 mL of lactated Ringer’s solution over 15 minutes, the increase in intravascular volume did not fit the mathematical models (3). However, the reality of anesthesia is that moderate or severe hypovolemia occurs often and when blood is not instantly available, and much faster rates of crystalloid or colloid resuscitation must be used to temporize the situation. In such a situation, does it matter whether you infuse a colloid or a crystalloid to these patients while waiting for blood to arrive, so long as you do it quickly?

We have demonstrated a significant difference in the ability of 6% Hetastarch and lactated Ringer’s solution to acutely expand the intravascular volume in moderately hypovolemic subjects in the period immediately after rapid infusion. Despite the moderate hypovolemia and infusing the fluid rapidly, 1000 mL of the lactated Ringer’s solution could only expand the intravascular volume by 630 ± 127 mL compared with the 1123 mL ± 116-mL expansion achieved by 6% Hetastarch under the same conditions. These results would suggest that for acute resuscitation, 6% Hetastarch is significantly more able to expand the intravascular volume and, by inference, the cardiac output than is the same volume of lactated Ringer’s solution, even in the initial 5–10 minutes.

The intravascular volume expansion created by the crystalloid is only slightly larger than that achieved in a previous study where 900 mL of lactated Ringer’s solution was infused over 30 minutes to moderately hypovolemic volunteers or yet another study where 25 mL/kg of crystalloid was administered to normovolemic subjects over various time periods ranging from 15 minutes to 45 minutes. This result is consistent with the theory that at rapid infusion rates, the compliance of the vasculature rapidly becomes less than the compliance of a portion of the interstitial space and so no further increase in intravascular volume occurs.

The only two subjects who experienced symptomatic hypotension with the blood withdrawal had the largest increase in intravascular volume with the lactated Ringer’s solution (744 mL and 798 mL). This may represent increased amounts of autotransfusion in these subjects. Autotransfusion is a powerful homeostatic mechanism. Several studies have addressed this topic and found varying results (5,9,13). Some have suggested increases in intravascular volume of up to 500 mL over 10 minutes because of autotransfusion, whereas others have documented much smaller volumes. Given that part of the mechanism of autotransfusion is believed to be a reduced capillary hydrostatic pressure operating as part of Starling’s forces, it seems logical that the two patients who started to decompensate from their hypovolemia may also have had the greatest degree of autotransfusion. It may also suggest that at even more profound levels of hypovolemia, the compliance of the vasculature may be such that larger amounts of crystalloid can be retained within the intravascular space.

Our observation that the peak expansion of intravascular volume with 6% Hetastarch was more than the infused volume (1123 mL) and occurred 5 minutes after the completion of the infusion is not a new finding (14). The delayed peak may simply represent imprecision of the measurement technique because between 0 and 25 minutes after completion of the infusion, there is no statistically significant difference between the increased intravascular volume measurements. However, the 6% Hetastarch solution is slightly hypertonic with respect to plasma (308 mOsm/L), and it may be that this is having a continuing effect of increasing intravascular volume in the time immediately after completion of the infusion.

The finding of a peak volume expansion that is larger than the volume administered may be explained by measurement error, but given that it was consistently present throughout all but one of the subjects, it more likely represents an effect of autotransfusion. However, given the rapidity with which autotransfusion can occur, it might be expected that it would be able to reverse just as quickly with appropriate restoration of intravascular volume. The increased intravascular volume in our subjects receiving colloid remained more than the 1000 mL infused throughout the entire 30-minute measurement period, possibly suggesting that it was caused by the hypertonicity of the fluid in addition to a component of autotransfusion. It may also represent an over estimation of the volume effect caused by an alteration of the large-vessel:whole-body hematocrit ratio.

Our study may be criticized for having used the hemoglobin dilution method because of the inconstancy of the large-vessel:whole-body ratio for hematocrit. Because of the time required for indocyanine green clearance (15,16), and the rapid redistribution of lactated Ringer’s solution after the initial peak increase in intravascular volume, the double label measurements of both plasma volume and erythrocyte volume (10) were not suitable for our study. However, the magnitude of the change in large-vessel:whole-body hematocrit ratio with a colloid volume load similar to ours has been demonstrated to be approximately 10%. This is unlikely to have had a significant impact on our primary outcome.

We may also be criticized for comparing two fluids of differing tonicity, but we believe that any confounding effect on the results is likely to have been small. Ideally, we would have used 6% Hextend as our colloid solution, but it is not available in our institution. Hextend is a hydroxyethyl starch colloid in an electrolyte solution very similar to Ringer’s solution rather than normal saline. We used healthy awake volunteers whose cardiovascular homeostatic defense mechanisms can be assumed to function optimally. The results of this controlled situation of moderate acute hypovolemia may, therefore, not be applicable to an anesthetized surgical population with more severe hypovolemia and shock superimposed on preexisting comorbidities.

Our measurements did not allow us to calculate the magnitude of any autotransfusion. Whereas this may potentially have affected our raw data for increase in intravascular volume, it will have operated equally across both colloid and crystalloid arms of the trial and is unlikely to have significantly affected the calculated difference between the two solutions in their ability to increase the intravascular volume under the conditions studied.

In conclusion, we have demonstrated that under controlled conditions of moderate hypovolemia, the rapid infusion of lactated Ringer’s solution 1000 mL over four to five minutes can acutely expand the intravascular volume by approximately 600 mL. By contrast, the same volume of 6% Hetastarch can expand intravascular volume by more than 1100 mL. Within the limitations discussed, these results would suggest that even for very short periods of time, rapid infusion of colloid is significantly more able to increase blood volume and, by inference, cardiac output than is the same volume of crystalloid even when the crystalloid is given very rapidly.

	Acknowledgments

 
Supported, in part, by the Department of Anesthesiology and NIH grant M01-RR-00037 of the University of Washington Clinical Research Center.

The authors would like to acknowledge the efforts of Ms Christine Hoffer in the recruitment of subjects for this study.

	References

Top Abstract Introduction Materials and Methods Results Discussion References

 

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999