Crystalloid is as Effective as Blood in the Resuscitation of Hemorrhagic Shock

GURDEV SINGH, F.R.C.S.,* KHALIL 1. CHAUDRY,* and IRSHAD H. CHAUDRY, PH.D.*t

Recently there has been increasing concern over transfusionrelated diseases, especially acquired immune deficiency syndrome (AIDS). The authors therefore investigated the efficacy of lactated Ringer's solution (LRS) alone as compared with blood plus LRS resuscitation on body weight change and mortality rate after severe trauma-hemorrhagic shock. Rats, 250 to 310 g (n = 85), had a midline laparotomy performed (i.e., trauma induced), the incision was closed, and a carotid artery, jugular vein, and femoral artery were cannulated. The unrestrained, nonheparinized rats were allowed to recover from anesthesia and were bled within 10 minutes to a mean arterial pressure (MAP) of 40 mmHg. This MAP was maintained by removing more blood until the animal was unable to compensate (maximal bleedout; MB). The MAP was further maintained at 40 mmHg by returning fluid (LRS) until 50% of the MB volume (MBV) was returned. The rats were then resuscitated: group 1 with LRS 4 times the MBV; group 2 with 5 X LRS; group 3 with the shed blood returned + 2 X LRS. There was no difference between the groups in the initial weights, MAP, or hematocrit (Hct), percentage of blood volume removed, time to MB, or time to end of hemorrhage. The final Hct and MAP were higher in group 3 (p < 10-6) than in either of the other groups. Body weight gain was greater in group 2 compared with either of the other groups (p < 0.05) on day 1 after hemorrhage because of edema, but no differences were seen on subsequent days. There were no differences in the survival of animals in the different groups. These results suggest that there should perhaps be a higher threshold for blood transfusion in the management of severe trauma-hemorrhagic shock than is currently practiced.
From the Shock and Trauma Research Laboratories,

*Department of Surgery and tPhysiology, Michigan State

University, East Lansing, Michigan

T n RAUMA CONTINUES TO be a major problem and is the leading cause of death between the ages of 1 and 44 in the United States.' One halfof deaths occur from exsanguination or central nervous system trauma within 1 hour of injury, and within a further 1 to 2 hours another 30% of deaths occur.2 These are due to major internal injury.2 The cornerstone of management
Supported by NIH Grant 2 R01 GM 39519. Address reprint requests to Irshad H. Chaudry, Ph.D., Department of Surgery, Michigan State University, B424 Clinical Center, East Lansing, MI 48824. Accepted for publication November 4, 1991.

of hemorrhagic shock is identification of the source of bleeding and its control, and rapid fluid transfusion to maintain the circulating volume. Plasma and blood were the replacement fluids ofchoice until the early 1960s, when the classic work of Shires et al.3 demonstrated the superiority of a crystalloid solution combined with whole blood over whole blood alone or with the addition of plasma to the shed blood. During the Vietnam war, it was thought that infusions of colloid were necessary to prevent the adult respiratory distress syndrome,4 but it subsequently has been shown that posttraumatic pulmonary insufficiency is more correlated with sepsis than with the type of fluid used in resuscitation.5 Current practice in the United States involves transfusing crystalloid in the first instance' and using the "transfusion trigger" of a hematocrit (Hct) of 30%6 to decide when to give blood in addition. This figure of an Hct of 30% is arbitrary, however, and Hcts as low as 10% to 15% have been well tolerated.7 Also, there are several problems associated with blood transfusion, including hyperkalemia,8 acid-base imbalances,9 etc. The most emotionally charged concern is the transmission of the acquired immune deficiency syndrome (AIDS) virus.'0 In view of this, we investigated the efficacy of crystalloid alone as compared with a combination of whole blood and crystalloid resuscitation on body weight change and death after severe hemorrhagic shock.
Materials and Methods Hemorrhage Procedure Male Sprague-Dawley rats (Charles River, Wilmington, MA), 250 to 310 g (n = 85), were fasted overnight but allowed water ad libitum. They were lightly anesthetized

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with ether, and the ether cone was removed while a 5-cm midline laparotomy was performed using an electric cautery (i.e., trauma was induced). The organs then were inspected visually to ensure the lack of damage by the cautery. After this, the abdominal incision was closed in layers and a carotid artery (for blood pressure monitoring), jugular vein (for fluid replacement), and femoral artery (for bleeding) were cannulated using PE 50 tubing (Clay Adams, Parsippany, NJ). The portion of the PE tubing inserted into the vessel was narrowed by extrusion to decrease the internal diameter by approximately 50% to prevent clot formation in the tubing. The jugular and carotid catheters were tunneled subcutaneously to the dorsal cervical region. The unrestrained, nonheparinized rats then were allowed to recover from anesthesia, and blood pressure was monitored with a saline manometer through the carotid catheter. Having recorded the initial mean arterial pressure (MAP) and the Hct, the animals were bled (by withdrawing the blood into a heparinized syringe to prevent clotting) over the course of 10 minutes to an MAP of 40 mmHg. This pressure was maintained by removing more blood in increments of 0.2 mL until the animal was no longer able to maintain its blood pressure (maximal bleedout; MB). The time taken to reach MB was recorded. At this point, the blood pressure was further maintained at 40 mmHg by returning fluid in the form of lactated Ringer's solution (LRS) in 0.2-mL increments until 50% of the shed blood volume was returned in that form (end of hemorrhage; EH). The time taken to EH was recorded.
Resuscitation Procedure
The rats then were divided into one of three groups: group 1 (n = 37) received LRS 3 times the shed blood volume over 45 minutes followed by a further IX over 60 minutes (total of 4X resuscitation). Group 2 (n = 27) received 3X LRS over 45 minutes followed by a further 2X over 60 minutes (5X resuscitation). Group 3 (n = 21) received the shed blood (kept in the heparinized syringes) back over 45 minutes followed by a further 2X over 60 minutes (blood-back resuscitation). At the end of resuscitation, the final MAP and Hct were recorded and the animals were lightly anesthetized with ether, decannulated, and the wounds were resutured. They were allowed to recover from the anesthetic and placed in individual cages with free access to food and
water.

the shed blood volume as a percentage of the TCBV was calculated. This was recorded as the percentage total blood volume removed (%TBVR). The animals were weighed daily, and survival was noted each day. Statistical Analysis
Statistical analyses were performed using one-way analysis of variance (ANOVA), Tukey's, and the chi square test. The percentage data were subjected to arcsine transformation before statistical analysis was performed. Differences were considered significant at p < 0.05. The results are expressed as mean standard error of the
mean.

Results Initial Parameters There was no statistical difference between the groups in the starting weights (282.8 1.7 g), percentage of blood volume removed (60.9 0.2%), time to maximal bleedout (44.5 0.2 minutes), time to end of hemorrhage (103.7 1.4 minutes), initial hematocrit (41.5 0.3%), or initial MAP (1 18.9 0.5 mmHg; one-way ANOVA; Table 1). This was true even if the animals were divided into survivor and nonsurvivor subgroups and compared as such within each group or between each group (Tables 2 and 3). Final Parameters
The final Hct (group 1 = 18.8 0.2%; group 2 = 17.6 0.4%; group 3 = 39.3 0.7%) and the final MAP (group I = 88.6 2.1 mmHg; group 2 = 84.1 1.5 mmHg; group 3 = 120.0 2.1 mmHg) were significantly higher in the blood-back group (group 3) than in either of the
TABLE 1. Comparison of the Parameters Measured in all Animals Parameter

Group 1
287.8 1.9 61.1 0.2 44.1 0.2 107.9 1.4 40.4 0.3 18.8 0.2 117.8 0.7 86.6 2.1 37

Group 2
275.8 3.5 60.40.3 45.1 0.5 101.6 3.4 43.4 0.5 17.6 0.4 120.7 1.0 84.1 1.5 27

Group 3
282.8 2.9 61.1 0.3 44.0 0.4 99.1 1.9 40.9 0.5 39.3 0.7* 118.2 1.0 120.0 2.1* 21

Weight (g) %TBVR TMB (min) TEH (min) IHct (%) FHct (%)
IMAP(mmHg) FMAP (mmHg)
n

Parameters Determined In addition to the parameters mentioned above, the following were noted: The total circulating blood volume (TCBV) was calculated, as previously described by Hauptman et al.," to be 6.12% of the body weight, and

Comparison of initial body weight, percentage of total blood volume removed (% TBVR), time to maximum bleedout (TMB), time to end of hemorrhage (TEH), initial (IHct) and final (FHct) hematocrit, and initial (IMAP) and final (FMAP) mean arterial pressure between group 1 (resuscitation [Rx] with 4 times [X] shed blood volume in the form of lactated Ringer's solution [LRS]), group 2 (Rx with 5X LRS), and group 3 (Rx with blood-back + 2X LRS). Mean SEM. * = p < 10-6 compared with the other two groups, ANOVA, Tukey's
test.

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TABLE 2. Comparison of the Parameters Measured in Survivors

Parameter Weight (g) % TBVR TMB (min) TEH (min) IHct (%) FHct(%) IMAP(mmHg) FMAP (mmHg) n Group 1
288.9 2.6 61.0 0.2 44.3 0.2 109.4 1.5 40.4 0.3 18.9 0.2 117.6 0.8 88.9 2.5 25 Group 2 275.5 4.2 60.1 0.4 45.2 0.7 106.4 4.4 43.80 0.8 17.6 0.6 120.1 1.4 83.7 2.3 14 Group 3

10
8 6
o

282.1 4.0 60.9 0.4 44.2 0.5 101.2 2.3 41.2 0.5 39.1 1.0* 116.7 0.9 121.8 2.4* 15

2
o
a.)
*_4

Comparison of initial body weight, percentage of total blood volume removed (% TBVR), time to maximum bleedout (TMB), time to end of hemorrhage (TEH), initial (IHct) and final (FHct) hematocrit, and initial (IMAP) and final (FMAP) mean arterial pressure between group 1 (resuscitation [Rx] with 4 times [X] shed blood volume in the form of lactated Ringer's solution [LRS]), group 2 (Rx with 5X LRS), and group 3 (Rx with blood-back + 2X LRS). Mean SEM. * = p < 10-6 compared with the other two groups, ANOVA, Tukey's
test.

-2
-4

-6 -8
-10

Days post-hemorrhage

crystalloid resuscitation groups (ANOVA, Tukey's test; p < 10-6; Table 1). This same trend was seen in the survivor and nonsurvivor subgroups (Tables 2 and 3), but no statistical differences were seen within the groups between

survivors and nonsurvivors.

Daily Body Weight and Mortality Rates On day 1 after hemorrhage, the change in body weight in group 2 (+4.00 1.27%) was significantly higher (p < 0.05; arcsine transformation followed by ANOVA; Fig. 1) than in either of the other two groups (group 1 = 1.17 0.72%; Group 3 = -2.42 0.46%). No statistical differences were seen in the percentage weight change each subsequent day after hemorrhage (maximum loss of 7.93
TABLE 3. A Comparison ofthe Parameters Measured in Nonsurvivors

FIG. 1. Daily percentage weight change (mean SEM) after hemorrhage and resuscitation (see Materials and Methods for hemorrhage and resuscitation procedure). Group 1 = resuscitation (Rx) with 4 times (X) the shed blood volume with lactated Ringer's solution (LRS), group 2 = Rx with SX LRS, group 3 = shed blood-back + 2X LRS. The change in weight on day 1 after hemorrhage in group 2 is significantly different (* = p < 0.05, arcsine transformation, followed by ANOVA) compared with either of the two other groups. The reason for the initial weight gain in group 2 is the edema due to fluid overload, which is cleared by the second day after hemorrhage. No subsequent statistical differences
are seen.

Parameter

Group 1 285.7 2.5 61.3 0.5 44.3 0.3 104.6 2.7 40.4 0.5 18.6 0.4 118.3 1.2 81.7 3.5 12

Group 2 276.0 5.6 60.8 0.5 44.9 0.7 96.4 4.9 49.2 0.7 17.7 0.4 121.4 1.6 84.5 2.0 13

Group 3 284.7 61.5 43.3 93.7 40.3 39.7 122.2 115.7

1.32% of the body weight on day 3) between the groups or within the groups between survivors and nonsurvivors. No statistical differences were seen in the percentage survival ofthe animals each day after hemorrhage between the groups (group 1 = 67.6%, group 2 = 51.9%, group 3 = 71.4% on day 7 after hemorrhage; arcsine transformation followed by ANOVA, chi square test; Fig. 2).

Weight (g)
% TBVR TMB (min) TEH (min)

IHct (%)
FHct (%) IMAP (mmHg) FMAP (mmHg)
n

2.6 0.7 0.8 1.2 1.1

0.8*
1.7 3.5

Comparison of initial body weight, percentage of total blood volume removed (% TBVR), time to maximum bleedout (TMB), time to end of hemorrhage (TEH), initial (IHct) and final (FHct) hematocrit, and initial (IMAP) and final (FMAP) mean arterial pressure between group 1 (resuscitation [Rx] with 4 times [X] shed blood volume in the form of lactated Ringer's solution [LRS]), group 2 (Rx with SX LRS), and group 3 (Rx with blood-back + 2X LRS). Mean SEM. * = p < 10-6 compared with the other two groups, ANOVA, Tukey's
test.

Discussion Latta, in 1832,12 was the first to demonstrate the use of intravenous saline solution to treat hypovolemic shock. In 1899, Crile'3 showed that the maintenance of an adequate circulating volume and central venous pressure with an intravenous infusion of warm saline resulted in reduced mortality rate in experimental hemorrhagic shock. Despite this, the treatment of hypovolemic shock during World War I remained seating the patient upright and bleeding him until he was unconscious because shock was thought to be due to a circulating toxin.'4 In 1930, the demonstration by Blalock'5 that the cause oftraumatic shock was hypovolemia, and the experience gained in the management of casualties in World War II, finally dispelled the toxemia theory of shock. Since then there have

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SINGH, CHAUDRY, AND CHAUDRY

1001

Ann. Surg. * April 1992

90

80 70
--I

V.....~ ~~7.........

........1 ........1

co
-I

60 50 40 30 20
10

.-4 0 U) 0

4x LRS 5x ~~~~~0LRS V7 Blood + 2x LRS

n v
0
1

Days post-hemorrhage
FIG. 2. No differences in the daily percentage of animals still living after hemorrhage and resuscitation were seen between any of the groups (see Materials and Methods for hemorrhage and resuscitation procedure). Group 1 = resuscitation (Rx) with 4 times (X) the shed blood volume with lactated Ringer's solution (LRS), group 2 = Rx with 5X LRS, group 3 = shed blood-back + 2X LRS.

been vogues and controversies as to the type of fluid that should be used for resuscitation.4"6 A combination of plasma and blood was the replacement regimen ofchoice until the early 1960s, when Shires et al.3 clearly demonstrated the need to replace the extracellular fluid deficit with crystalloid solutions as well as the intravascular fluid losses. Also, Wolfmann et al.'7 showed that survival was markedly improved after hemorrhagic shock if dogs were resuscitated with LRS and donor blood rather than shed blood alone. Jenkins et al.,'8 in 1950, suggested that it was the excessive infusion of salt solutions that was the cause of congestive atelectasis seen frequently after severe hemorrhagic shock. The high incidence of pulmonary insufficiency seen in the severely injured in the Vietnam war led many investigators to believe that infusions of colloid were necessary to prevent the adult respiratory distress syndrome.'9 It subsequently has been shown that post-traumatic pulmonary insufficiency is more correlated with sepsis than with the type of fluid used in resuscitation.5 Current practice in the United States is to resuscitate with LRS followed by blood several problems with the use of blood and blood products, and these are currently cause for concern, especially with the problems associated with transfusion-transmitted AIDS. For this reason, we decided to investigate resuscitation after severe hemorrhagic shock
as necessary.' There are, however,

comparing crystalloid alone with a combination of blood and crystalloid. In this study, we used a model of surgical trauma; in other words, a 5-cm laparotomy incision. This is a significant trauma. Livingston and Malangoni20 have shown that even a 1-cm skin incision before or after hemorrhage increases infection in the rat. Stephan et al.2' also have shown that laparotomy alone produces a marked depression in cell-mediated immunity. Studies in our laboratory have demonstrated that whereas the mortality rate was only 10% after hemorrhage and resuscitation in the absence of such trauma, it was 60% if laparotomy was performed before hemorrhage.22 Thus the model used in this study involved not only hemorrhage, but also significant tissue trauma (5 cm laparotomy), which plays a major role in the outcome of the animals after hemorrhage. The present study demonstrates that there is no difference in the survival of rats after trauma (laparotomy) and severe hemorrhage when they are resuscitated with LRS alone or with a combination of blood and LRS (Fig. 2). Furthermore, there was no difference in the change in daily body weights at day 1 after hemorrhage (Fig. 1). The reason for the weight gain in group 2 on the first day after hemorrhage was edema due to fluid overload. This was cleared by the second post-hemorrhage day. The reason for the lack ofbenefit ofblood resuscitation may lie in the viscosity of the circulating blood. Crowell et al.23 found that increasing the hematocrit above 35% by re-transfusion ofblood decreased survival in dogs after hemorrhagic shock, and suggested that the reason for this may be increased blood viscosity. After hemorrhage and resuscitation, we found that there was no significant difference between the final Hcts of the 4X (18.8 0.2%) LRS and 5X (17.6 0.4%) LRS-resuscitated groups, but that of the blood + 2X LRS (39.3 0.7%) resuscitated group was significantly higher (p < 10-6). Thus, although there was increased oxygen-carrying capacity in the bloodback group, the benefits appear to have been outweighed by the increase in blood viscosity. Crowell and Read24 have demonstrated that there is hypercoagulability after resuscitation of animals with shed blood. They suggested that this may be due to release of microthrombi into the circulation. This also may affect the supply of nutrients to the tissues and the removal of the products of metabolism, leading to increased mortality rate in the blood-back group. We found that the final MAP was significantly higher (p < 10-6) in the group of animals resuscitated with blood and LRS (120.0 2.1 mmHg) than in either the 4X (86.6 2.1 mmHg) or the 5X (84.1 1.5 mmHg) LRS-resuscitated groups. This is not surprising because it is known that LRS rapidly enters the extravascular space, and this is one of the reasons Shires et al.3 recommended its use in the resuscitation of hypovolemic shock. Despite this,

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however, there was no difference in the survival of the animals in the three groups. Thus, it appears that blood transfusion is not always necessary in the management of hemorrhagic shock, and this is in agreement with the suggestions of other investigators.6'25 There has been concern expressed about erythrocyte replacement because transfusion ofcrystalloids alone will diminish the oxygen-carrying capacity of blood after significant blood loss. Recent studies in this laboratory have indicated that 50% acute hemodilution with LRS in shamoperated animals did not significantly affect cardiac output.26 Similar observations concerning cardiac output and hemodilution have been reported by others.27'28 Furthermore, Pelton et al.,7 in graded hemodilution studies, have shown that Hcts of 10% to 15% in animals subjected to acute hemodilution were well tolerated. Moreover, Mesh and Gewertz,29 in an intestinal ischemia model, have demonstrated that hemodilution has no adverse effects on oxygen consumption during hypotension and hypoperfusion. Indeed, they suggest that hemodilution may even be beneficial during reperfusion after ischemia.29 It should be pointed out that we are not advocating that blood never be used in the resuscitation of hypovolemic shock, but suggesting that the threshold for its use may perhaps be higher than at present. The commonly used "transfusion trigger" Hct of 30%6 is arbitrary and, as pointed out previously, Hcts as low as 10% to 15% have been well tolerated.7 This is in agreement with our findings that a hematocrit of 15% to 20% was no more detrimental to the survival of animals subjected to severe traumahemorrhagic shock than that ofanimals with Hcts of 35% to 40%. The results of the study presented here are of significance especially in the present climate of attempting to avoid the transfusion of blood and blood products. There are several potential problems associated with the use of blood and blood products, even if they were not so expensive and in relative short supply. Platelet and coagulation factor deficiencies are seen in some patients after a massive blood transfusion and may lead to a bleeding diathesis. This is commonly known as "dilutional coagulopathy," but dilution is only a small part of the problem.30 3' There is an excess of citrate in stored blood to completely bind calcium and prevent clotting and, under normal circumstances, this is rapidly metabolized in the liver. We have recently shown, however, that hepatocellular dysfunction occurs early after hemorrhage and persists despite fluid resuscitation.32 This may be part of the explanation for the hypocalcemia seen after blood transfusion.33 The concentration of potassium in the plasma of stored blood increases with time, and hyperkalemia may occur during the rapid phase of transfusion.8 Banked blood is acidic because of the citrate anticoagulant and becomes more acidic with storage as lactic acid accumulates. This may lead to acid-base imbalances.9

Storage of blood increases the 2,3-DPG level of erythrocytes and this decreases the affinity of hemoglobin for oxygen, thereby decreasing the delivery of oxygen to tissues.34 Hypothermia is a complication of the massive transfusion of refrigerated blood, leading to several clinical problems.35 Stored blood develops particulate debris consisting of microaggregates of platelets, leukocytes, and fibrin, some of which are too small to be removed by standard 1 70-,um blood infusion filters and may result in pulmonary insufficiency.36 Antibodies present in the recipient's plasma and directed against foreign transfused red cell antigens can cause serious problems and even death.37 Probably the most emotionally charged complication of transfusion of blood and blood products presently is the possibility of transfusion-transmitted diseases. The most serious problem in terms of frequency and complications is non-A, non-B hepatitis. Evidence for the infection can be found in as many as 7% of transfusion recipients within 6 months of the transfusion, and chronic hepatitis develops in as many as 50% of the affected individuals.38 The most serious problem in terms of public concern is the possible transmission of the AIDS virus.' 0 In 1987, 886 cases of transfusion-associated AIDS had been reported,39 but to put this in perspective, more than 10 million transfusions are given yearly.6 In summary, therefore, we compared the weight changes and mortality rates in rats subjected to trauma and severe hemorrhagic shock and resuscitated with either LRS alone or with blood plus LRS. We found that there was no statistical difference in the mortality rate and no differences in weight change at day 2 after hemorrhage between these different resuscitation regimens. These results suggest that the "hematocrit trigger" for transfusion should perhaps be lowered to 20%.
Acknowledgments
The authors wish to thank Ms Renee Ziobron for her skill and patience in the editorial stages of this manuscript.

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