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Treatment of experimental hemorrhage with colloid-crystalloid mixtures
TREATMENT WITH S.
OF EXPERIMENTAL COLLOID-CRYSTALLOID
GOLLUB, AND
PH.D., CLARA
M.D., KIAT SCHAEFER,
HYPOVOLEMIA is currently treated with two types of blood substitutes-colloids and crystalloids. Colloids, such as the dextrans, hydroxyethyl starch, and gelatin, are retained completely in the vascular space. When administered in large amounts, they may induce complications [l-4], the most serious of which is a hemorrhagic diathesis [ 1, 51. Crystalloid solutions, which encompass a broad assortment of mono- or polyionic preparations, exhibit quite different properties. Only a minor fraction of the volume administered is retained in the vascular space and intravascular persistence is brief. Large-volume infusion is required to achieve blood volume restitution after hemorrhage. This may produce circulatory instability with complex fluid and electrolyte alterations [ 6, 71. The adverse effects of the two types of blood substitutes are dissimilar. In both cases, however, they accompany large-volume administration. Thus, it seemed possible to fashion a superior nonhemic resuscitating fluid by combining colloid and crystalloid solutions. Presumably, larger volumes could be administered without eliciting individual harmful efFrom the Department of Hematology, St. Barnabas Hospital, New York, N.Y. Supported by U.S. Army Surgical Research and Development Command Contracts DA-49-193-MD2566 and DA-49-193-MD-2655. Submitted for publication Sept. 3, 1968.
HEMORRHAGE MIXTURES KANGWALKLAI, B.S., A.S.C.P.
M.D.,
fects. Such a combination could distinctly facilitate the management of hemorrhage. This communication describes an investigation of blood replacement with prepared colloid-crystalloid mixtures in set proportions. Particular attention was given to the intravascular distribution and retention of administered volume, and to alterations in hemostasis. MATERIALS
AND
METHODS
Adult mongrel dogs of both sexes were anesthetized with barbiturates. Spontaneous, mechanically unassisted breathing was enabled through,an intratracheal tube. Splenectomy was performed. Arterial blood pressure was recorded continuously through a femoral indwelling catheter connected to a strain gauge. Blood samples were obtained from the companion vein. De contralateral femoral vessels were used for bleeding and for fluid administration. Injections of radioiodinated serum albumin for blood volume determinations were made through an exposed jugular vein. A total of 36 animals, divided into 6 groups, was used. In all of them, an amount of blood equal to 30% of the isotopically measured, uncorrected [8] blood volume was drained from the artery at 500 ml. per 20 to 30 minutes. 311
JOURNAL
OF SURGICAL
RESEARCH
VOL.
9 NO.
Thereafter a selected resuscitating fluid or mixture was infused at 500 ml. per 15 minutes. Hartmann’s (lactated Ringer’s) and 6% (75,000 mol. wt.) dextran solutions were administered (Table 1). Observations were made up to 3 hours and again at 24 hours.. The animals were then sacrificed and subjected to necropsy. Incisional rebleeding [l], a criterion of defective hemostasis was designated as follows: 0 = none; l+ = mild; 2+ = moderate; 3+ = marked; and 4+ = profuse. The condition of the dogs at 24 hours was graded under the general heading of “Morbidity”: 0 = none (excellent clinical condition); 1 = minimal (good clinical condition; ambulating); 2 = moderate (fair clinical condition; standing but not ambulating) ; 3 = marked (poor clinical condition; incapable of standing or ambulating) ; and 4 = extreme (moribund). The extent of tissue edema and of transudation into the pleural and peritoneal cavities was estimated by the following indices: 0 = none; l+ = minimal tissue bogginess; less than 100 ml. of fluid accumulation; 2+ = moderate tissue edema; 100 to 150 ml. of fluid collection; 3+ = severe congestion; 150 to 200 ml. of free fluid; and 4+ = anasarca. The expansion of intravascular volume by the infusion fluid employed was evaluated from a consideration of hematocrit changes and residual blood volume after bleeding. The residual blood volume after bleeding was calculated by subtracting the volume of shed Table 1.
Group No. 1
2 3 5 D L 312
Type andFT;$me
Fluid Employed 1: Q-Dextran: Hartmann’s solution 2 : 8-Dextran : Harfmann’s solution 3 :‘I-Dextran: Hartmanbs solution 5:SDextran:Hartmann’s solution lOf& Dextran solution 100% Hartmann’s solution
of Resuscitating
5,
MAY
1969
blood from the RISA* blood volume. The alterations in large vessel hematocrit which would result from successive 50-ml. increments of volume expander to the postbleeding blood volume were calculated. These values were plotted as a continuous curve which served to gauge intravascular volume expansion by administered fluid. Extravascular fluid changes were assessed by means of a single calculation. The sum of the volumes of excreted urine and retained intravascular fluid was subtracted from the volume of infusion. The difference was considered to represent the vohrme of fluid in the extravascular compartments.
RESULTS The data are summarized in Figs. 1 through 7 and in Table 2. For purposes of comparison, values are expressed in percentages of prebleed values. Figure 1 shows changes in heart rate. At the completion of bleeding, a paradoxic bradycardia was observed. The large standard deviation of Group L after hemorrhage is attributable to the extreme values of one dog. This graph, as well as blood pressure alterations in Figs. 2 and 3, reff ect cardiovascular instability when resuscitation was with Hartmann’s solution only. In contrast, the pulse rate and blood pressure remained steady throughout when dextran was used. Intermediate gradaTable 2. Mortality and Morbidity from Treating Hemorrhage with Various Infusions
Volume Administered 3 x shed blood 3 x shed blood 3 x shed blood 3
x
shed blood
1 x shed blood 3 x shed blood
Group D 5 3 2 1 L
InciMorsional talRebleed’ ing (A%.) 4+ 4+ 1+ 0 8
0% 17% 17% 17% 33% 0%
‘Wadioiodinated serum albumin.
Mor-
Fluid Con-
bid-
gestion
* (%Zr.) 0 0 2+ 2+ 3+ 3+
rt;i 0 0 1+ ii 4+
GOLLUB
i
HEART RATE % CHANGE
!
22Y
n
ET
AL.:
COLLOW-CRYSTALLOW
MIXTURES
SYSTOLC BP. X CHANGE
lm-
-i
4
I
4Q4.
Bleed Resusc
’
’
Fig. 1. Effect on heart rate of treating hemorrhage with various infusions. The large standard deviation of the Hartmann’s solution group (L) after bleeding is attributable to extreme values from one dog. Tachycardia, reflecting cardiovascular instability, is noted in this group. The dextran group (D) is more stable. Variable responses are displayed by the remaining groups. tions of stability are discerned in the groups receiving mixtures of dextran and Hartmann’s solution. At 24 hours these parameters reached approximately the same levels for all groups. Figure 4 depicts the relative ability of different liquids to restore the circulating blood volume. Hartmann’s solution produced an expansion of approximately 1% times the amount of shed blood at the end of infusion. Since the quantity given was 3 times the blood loss, the net intravascular increment was only 5 of the original volume administered, Fluid retention was transient however. Within 1 hour the intravascular volume expansion fell to approximately 70%. As the proportion of dextran was increased in the infused medium, a consistent pattern of greater plasma expansion and more prolonged fluid retention emerged. As may be seen, there was a 120% expansion with dextran alone. This implies a migration of extravascular fluid into the intravascular compartment.
MD-
OP,C
Post Post Bleed Rerrc
I Hr.
3Hrs.
I 24 L
Fig. 2. Effect on systolic blood pressure of treating hemorrhage with various infusions. The pressure is sustained best with dextran (D) and is very unstable when Ha&mum’s solution is used exclusively (L) or in high proportion (1 and 2). gr
DIASTOLICBP. X CHANGE
Post Post Bleed Resux
I Hr. 3Hn.
t -42, in.
Fig. 3. Effect on diastolic blood pressure of treating hemorrha e with various infusions. Responses resemble ill ose with systolic pressure except that diastolic hypotension is evinced at 24 hours by all groups. 313
JOURNAL
II
OF SURGICAL
RESEARCH
VOL.
9 NO.
I.V. DISTRIBUTION -% OF BLOODLOSS
I
MAY
1969
jt
I.V. AS % INFUSED VOLUME
1
I
260-
5,
260240-
I
.b
220
0
I
OPre
I Post Post
I Hr. 3Hrs.
I 24 tin.
Fig. 4. Relative ability of various infusions to restore circulating blood volume after hemorrhage. Greater plasma expansion and more prolonged fluid retention is manifest with dextran solution (D) than with Hartmann’s solution (L) . The conspicuous expansion exhibited by dextran (D) is partly from mobilization of interstitial fluid to the intravascular compartment. Potentiation of the dextran effect occurs with mixtures containing larger amounts of colloid.
Figures 5, 6, and 7 show the distribution of the infused solutions in various body partitions. Figure 5 shows that in Group L-the group receiving Hartmann’s solution-slightly more than one-fifth of the volume administered was retained intravascularly by 3 hours. It is noteworthy that at 3 hours, urine volume (Fig. 6) approximated the volume of fluid that was retained in the intravascular compartment (20% ). Further, reference to Fig. 7 will show that the ratio of extravascular to intra314
Pra
Post post Bleed Resw
I Hr.
3Hrs.
24
I.
Fig. 5. Relative distribution of various infusions to the intravascular compartment. Distribution of Hartmann’s solution to the intravascular compartment is low immediately after infusion (50%) and rapidly decreases. Dextran appears to be completely distributed to the intravascular compartment-indeed, the colloid appears to mobilize additional fluid into the vascular space.
~ BS
Fig. 6.
URINE AS % INFUSEDVOLUM;
Bleed Resuse Relative urine output associated with
various infusions. Dextran (D) and combinations containing large amounts of it have a diuretic action.
GOLLUB
ET
AL. : COLLOID-CRYSTALLOID
MIXTURES
principal undesirable effect of this agent was a hemostatic disturbance manifested grossly as incisional rebleeding and prolonged ear bleeding times [l].
mn EXTRAVASCULAR DIST. AS % OF INFUSED VOLUME
BO60-
DISCUSSION
40?4 20B i 4 .P o8 ;-20. -4O-60 -6O-
L -O” Pro
Post PO61 I Hr. BloodRososc
3Hrs.
24 Hn
Fig. 7. Relative extravascular distribution of various infusions. The crystalloid solution and mixtures containing marked quantities of it are driven in large fraction to the extravascular compartment, whereas the colloid solution withdraws water from that compartment. vascular fluid at 3 hours was approximately 3:l (60%:20%). In marked contrast, the group of animals receiving dextran alone manifested a distribution ratio of extravascular to intravascular fluid of -1:+2 (-60%:+12070). Thus the volume expansion of the intravascular compartment with dextran took place at the expense of interstitial fluid volume in part. The data show that increasing ratios of dextran so modify the responses to Hartmann’s solution that proportionately less fluid is distributed to the extravascular compartment and intravascular retention is favored. One aspect of the data warrants emphasis: depletion of the extravascular space resulting from dextran alone was averted by incorporation of crystalloid fluid in the infusion. The morbidity patterns abstracted in the table indicate that the penalty of using a crystalloid solution exclusively or as a major fraction of the infusate is tissue edema of varying extent. While tissue edema was not seen with dextran alone, a
No single experimental model or design is satisfactory for investigating the complex mechanisms that are operative in hemorrhagic shock. In large part, conilicting opinions and conclusions stem from variations in experimental preparations and procedures. Some investigators [9, lo] assert that proper treatment of major blood loss or of hemorrhagic shock involves consideration of the fundamental role of sodium metabolism. Empiric formulations for blood volume replacement employed by others include large amounts of Hartmann’s solution alone-generally about three times the estimated blood loss [ll]Hartmann’s solution to supplement blood transfusion, in varying proportions [7,12], and colloid infusion alone, even for massive blood loss [13]. In this communication we have presented comparative data of the clinical, hemostatic, and pathophysiologic responses of splenectomized dogs subjected to an acute 30% volume blood loss and subsequently treated with colloid solution, crystalloid solution and various mixtures. The colloid solution employed elicits certain dose-dependent responses not seen with crystalloid solutions: mobilization of extravascular fluid to the intravascular space, and hemostatic alterations at high infusion volumes. Similarly, the crystalloid solution employed for volume expansion has certain characteristics which are absent in the colloid solution: transient retention intravascularly with major distribution to the extravascular compartments, resultant tissue bogginess and vascular instability. The individual effects of colloid solution and of crystalloid solution may be blended by using mixtures in certain proportions: the bleeding tendency observed with colloid infusion alone can be avoided and satisfactory intravascular volume restoration still be at-
JOURNAL
OF SURGICAL
RESEARCH
VOL. g
NO.
tained. With an appropriate combination of colloids and crystalloids, excess deposition of fluid in the extravascular compartment. can be reduced. For example, Hartmann’s solution, when used exclusively and administered in an amount threefold that of blood lost results in a partition ratio of 1:3 : : intravascular:extravascular. Conversely, dextran used exclusively in an amount equal to that of blood lost results in a partition ratio of +2: -1 : : intravascular:extravascular. That is, a depletion of extravascular fluid results. Such depletion of extravascular fluid when dextran alone is used would further aggravate the depletion accompanying trauma and hemorrhage [14, 151. However, employing a mixture of 20% dextran solution and 80% Hartmann’s solution in a volume three times the blood loss, the partition ratio is 1: 1, the blood volume is restored and maintained and hemostatic disturbance is not evidenced. This emphasizes the advantages to be gained by employing mixtures of crystalloid-colloid solutions. For as indicated by this study, inclusion of crystalloid solution is beneficial in that it reverses the dehydrating action and avoids the hemorrhagic complications of colloid alone. The authors do not suggest that the results obtained in this study are immediately applicable to any clinical situation. Nevertheless, the data do tend to clarify basic mechanisms and responses to replacement of blood loss by colloid and crystalloid solutions. It seems apparent, in general, that optimum results were associated with the preparations containing 20~~ or 30% of dextran solution (corresponding to an actual colloid concentration of 1.2% and 1.8%, respectively) used in a volume of three times the blood loss. However, even with the limited parameters of this study, ideal results were evidently not obtained in any case.
SUMMARY Thirty-six splenectomized dogs were subjected to acute loss of 30% blood volume and resuscitated with colloid solution alone, crystalloid solution alone, or mixtures of colloid and crystalloid solutions. 316
5,
MAY
1969
Certain dose-dependent disadvantageous effects associated with either type fluid alone were avoided by employing mixtures of solutions. Depletion of extravascular fluid, and the bleeding tendency associated with colloid use alone was not seen with appropriate mixtures. Excess water deposition in tissues and cardiovascular instability associated with crystalloid solution alone were absent. While ideal results were not obtained in any case, the optimal mixture in this study consisted of 1 part of 6% dextran solution and 4 parts of Hartmann’s (lactate Ringer’s) solution administered in a volume equal to three times the blood loss.
REFERENCES 1. Gollub, S., Schaefer, C., and Squitieri, A. The bleeding tendency associated with plasma expanders. Surg. Gytaec. O&et. 124:1203, 1987. 2. Ewald, It. A., Crosby, W. H., and Young, A. A. Particle formation in dextran solutions. M&t. Med. 129:952, 1964. 3. Bailey, G., Strub, It. L., Klein, R. C., and Salvaggio, J. Dextran-induced anaphylaxis. I.A.M.A. 200889, 1967. 4. Brisman, R., Parks, L. C., and Haller, J. A., Jr. Anaphylactoid reactions associated with the clinical use of dextran 70. J.A.M.A. 204:166, 1968. 5. Ganon, A. A., Cheng, C., Lemer, B., Lichtenstein, S., and Karlson, K. E. Hydroxyethyl starch ( HES ) and bleeding. J. Trauma 7:757, 1967. 6. Gollub, S., and Bailey, C. P. Management of major surgical blood loss without transfusion. J.A.M.A. 198:1170, 1966. 7. McClelland, R. N., Shires, 6. T., Baxter, C. R., Coin, C. D., and Carrico, J. Balanced salt solution in the treatment of hemorrhagic shock; studies in dogs. I.A.M.A. lQQ:l66, 196r. 8. Williams, J. A. Blood volume measurement. In Surgical Bleeding (A. W. Ulin and S. Gollub, Eds.), New York: McGraw-Hill Book Co., 1966. Pp. 347-354. 9, Dillon, J., Lynch, L. J., Jr., Myers, R., Butcher, H. R., Jr., and Moyer, C. A bioassay of treatment of hemorrhagic shock. Arch. Surg. (Chicago) 93:537, 1966. 10. Dillon, J. S. Importance of sodium-containing crystalloid solutions in hemorrhagic shock. Med. Ann. DC. 35:473, 1966. 11. Rush, B. F., and Morehouse, R. Volume re-
GOLLUB
placement following acute bleeding compared to replacement after hemorrhagic shock: effectiveness of dextran and buffered saline. Surgery 62: 88-96, 1967. 12. Shires, T., Cohn, D., Carrico, J., and Lightfoot, S. Fluid therapy in hemorrhagic shock. Arch. Surg. (Chicago) 88:688, 1964. 13. Takaori, M., and Safar, P. Treatment of massive hemorrhage with colloid and crystalloid solu-
ET
AL.:
COLLOID-CRYSTALLOID
MIXTURES
tions, studies in dogs. J.A.M.A. 199:297, 1967. 14. Virtue, R. W., Levine, D. S., and Aikawa, J. K. Fluid shifts during the surgical period: RISA and Ssa determinations following glucose, saline or lactate infusion. Ann. Surg. 163:523, 1966. 15. Shires, T., Williams, J., and Brown, F. Acute change in extracellular fluids associated with major surgical procedures. Ann. Surg. 154:803, 1961.
317
OF EXPERIMENTAL COLLOID-CRYSTALLOID
GOLLUB, AND
PH.D., CLARA
M.D., KIAT SCHAEFER,
HYPOVOLEMIA is currently treated with two types of blood substitutes-colloids and crystalloids. Colloids, such as the dextrans, hydroxyethyl starch, and gelatin, are retained completely in the vascular space. When administered in large amounts, they may induce complications [l-4], the most serious of which is a hemorrhagic diathesis [ 1, 51. Crystalloid solutions, which encompass a broad assortment of mono- or polyionic preparations, exhibit quite different properties. Only a minor fraction of the volume administered is retained in the vascular space and intravascular persistence is brief. Large-volume infusion is required to achieve blood volume restitution after hemorrhage. This may produce circulatory instability with complex fluid and electrolyte alterations [ 6, 71. The adverse effects of the two types of blood substitutes are dissimilar. In both cases, however, they accompany large-volume administration. Thus, it seemed possible to fashion a superior nonhemic resuscitating fluid by combining colloid and crystalloid solutions. Presumably, larger volumes could be administered without eliciting individual harmful efFrom the Department of Hematology, St. Barnabas Hospital, New York, N.Y. Supported by U.S. Army Surgical Research and Development Command Contracts DA-49-193-MD2566 and DA-49-193-MD-2655. Submitted for publication Sept. 3, 1968.
HEMORRHAGE MIXTURES KANGWALKLAI, B.S., A.S.C.P.
M.D.,
fects. Such a combination could distinctly facilitate the management of hemorrhage. This communication describes an investigation of blood replacement with prepared colloid-crystalloid mixtures in set proportions. Particular attention was given to the intravascular distribution and retention of administered volume, and to alterations in hemostasis. MATERIALS
AND
METHODS
Adult mongrel dogs of both sexes were anesthetized with barbiturates. Spontaneous, mechanically unassisted breathing was enabled through,an intratracheal tube. Splenectomy was performed. Arterial blood pressure was recorded continuously through a femoral indwelling catheter connected to a strain gauge. Blood samples were obtained from the companion vein. De contralateral femoral vessels were used for bleeding and for fluid administration. Injections of radioiodinated serum albumin for blood volume determinations were made through an exposed jugular vein. A total of 36 animals, divided into 6 groups, was used. In all of them, an amount of blood equal to 30% of the isotopically measured, uncorrected [8] blood volume was drained from the artery at 500 ml. per 20 to 30 minutes. 311
JOURNAL
OF SURGICAL
RESEARCH
VOL.
9 NO.
Thereafter a selected resuscitating fluid or mixture was infused at 500 ml. per 15 minutes. Hartmann’s (lactated Ringer’s) and 6% (75,000 mol. wt.) dextran solutions were administered (Table 1). Observations were made up to 3 hours and again at 24 hours.. The animals were then sacrificed and subjected to necropsy. Incisional rebleeding [l], a criterion of defective hemostasis was designated as follows: 0 = none; l+ = mild; 2+ = moderate; 3+ = marked; and 4+ = profuse. The condition of the dogs at 24 hours was graded under the general heading of “Morbidity”: 0 = none (excellent clinical condition); 1 = minimal (good clinical condition; ambulating); 2 = moderate (fair clinical condition; standing but not ambulating) ; 3 = marked (poor clinical condition; incapable of standing or ambulating) ; and 4 = extreme (moribund). The extent of tissue edema and of transudation into the pleural and peritoneal cavities was estimated by the following indices: 0 = none; l+ = minimal tissue bogginess; less than 100 ml. of fluid accumulation; 2+ = moderate tissue edema; 100 to 150 ml. of fluid collection; 3+ = severe congestion; 150 to 200 ml. of free fluid; and 4+ = anasarca. The expansion of intravascular volume by the infusion fluid employed was evaluated from a consideration of hematocrit changes and residual blood volume after bleeding. The residual blood volume after bleeding was calculated by subtracting the volume of shed Table 1.
Group No. 1
2 3 5 D L 312
Type andFT;$me
Fluid Employed 1: Q-Dextran: Hartmann’s solution 2 : 8-Dextran : Harfmann’s solution 3 :‘I-Dextran: Hartmanbs solution 5:SDextran:Hartmann’s solution lOf& Dextran solution 100% Hartmann’s solution
of Resuscitating
5,
MAY
1969
blood from the RISA* blood volume. The alterations in large vessel hematocrit which would result from successive 50-ml. increments of volume expander to the postbleeding blood volume were calculated. These values were plotted as a continuous curve which served to gauge intravascular volume expansion by administered fluid. Extravascular fluid changes were assessed by means of a single calculation. The sum of the volumes of excreted urine and retained intravascular fluid was subtracted from the volume of infusion. The difference was considered to represent the vohrme of fluid in the extravascular compartments.
RESULTS The data are summarized in Figs. 1 through 7 and in Table 2. For purposes of comparison, values are expressed in percentages of prebleed values. Figure 1 shows changes in heart rate. At the completion of bleeding, a paradoxic bradycardia was observed. The large standard deviation of Group L after hemorrhage is attributable to the extreme values of one dog. This graph, as well as blood pressure alterations in Figs. 2 and 3, reff ect cardiovascular instability when resuscitation was with Hartmann’s solution only. In contrast, the pulse rate and blood pressure remained steady throughout when dextran was used. Intermediate gradaTable 2. Mortality and Morbidity from Treating Hemorrhage with Various Infusions
Volume Administered 3 x shed blood 3 x shed blood 3 x shed blood 3
x
shed blood
1 x shed blood 3 x shed blood
Group D 5 3 2 1 L
InciMorsional talRebleed’ ing (A%.) 4+ 4+ 1+ 0 8
0% 17% 17% 17% 33% 0%
‘Wadioiodinated serum albumin.
Mor-
Fluid Con-
bid-
gestion
* (%Zr.) 0 0 2+ 2+ 3+ 3+
rt;i 0 0 1+ ii 4+
GOLLUB
i
HEART RATE % CHANGE
!
22Y
n
ET
AL.:
COLLOW-CRYSTALLOW
MIXTURES
SYSTOLC BP. X CHANGE
lm-
-i
4
I
4Q4.
Bleed Resusc
’
’
Fig. 1. Effect on heart rate of treating hemorrhage with various infusions. The large standard deviation of the Hartmann’s solution group (L) after bleeding is attributable to extreme values from one dog. Tachycardia, reflecting cardiovascular instability, is noted in this group. The dextran group (D) is more stable. Variable responses are displayed by the remaining groups. tions of stability are discerned in the groups receiving mixtures of dextran and Hartmann’s solution. At 24 hours these parameters reached approximately the same levels for all groups. Figure 4 depicts the relative ability of different liquids to restore the circulating blood volume. Hartmann’s solution produced an expansion of approximately 1% times the amount of shed blood at the end of infusion. Since the quantity given was 3 times the blood loss, the net intravascular increment was only 5 of the original volume administered, Fluid retention was transient however. Within 1 hour the intravascular volume expansion fell to approximately 70%. As the proportion of dextran was increased in the infused medium, a consistent pattern of greater plasma expansion and more prolonged fluid retention emerged. As may be seen, there was a 120% expansion with dextran alone. This implies a migration of extravascular fluid into the intravascular compartment.
MD-
OP,C
Post Post Bleed Rerrc
I Hr.
3Hrs.
I 24 L
Fig. 2. Effect on systolic blood pressure of treating hemorrhage with various infusions. The pressure is sustained best with dextran (D) and is very unstable when Ha&mum’s solution is used exclusively (L) or in high proportion (1 and 2). gr
DIASTOLICBP. X CHANGE
Post Post Bleed Resux
I Hr. 3Hn.
t -42, in.
Fig. 3. Effect on diastolic blood pressure of treating hemorrha e with various infusions. Responses resemble ill ose with systolic pressure except that diastolic hypotension is evinced at 24 hours by all groups. 313
JOURNAL
II
OF SURGICAL
RESEARCH
VOL.
9 NO.
I.V. DISTRIBUTION -% OF BLOODLOSS
I
MAY
1969
jt
I.V. AS % INFUSED VOLUME
1
I
260-
5,
260240-
I
.b
220
0
I
OPre
I Post Post
I Hr. 3Hrs.
I 24 tin.
Fig. 4. Relative ability of various infusions to restore circulating blood volume after hemorrhage. Greater plasma expansion and more prolonged fluid retention is manifest with dextran solution (D) than with Hartmann’s solution (L) . The conspicuous expansion exhibited by dextran (D) is partly from mobilization of interstitial fluid to the intravascular compartment. Potentiation of the dextran effect occurs with mixtures containing larger amounts of colloid.
Figures 5, 6, and 7 show the distribution of the infused solutions in various body partitions. Figure 5 shows that in Group L-the group receiving Hartmann’s solution-slightly more than one-fifth of the volume administered was retained intravascularly by 3 hours. It is noteworthy that at 3 hours, urine volume (Fig. 6) approximated the volume of fluid that was retained in the intravascular compartment (20% ). Further, reference to Fig. 7 will show that the ratio of extravascular to intra314
Pra
Post post Bleed Resw
I Hr.
3Hrs.
24
I.
Fig. 5. Relative distribution of various infusions to the intravascular compartment. Distribution of Hartmann’s solution to the intravascular compartment is low immediately after infusion (50%) and rapidly decreases. Dextran appears to be completely distributed to the intravascular compartment-indeed, the colloid appears to mobilize additional fluid into the vascular space.
~ BS
Fig. 6.
URINE AS % INFUSEDVOLUM;
Bleed Resuse Relative urine output associated with
various infusions. Dextran (D) and combinations containing large amounts of it have a diuretic action.
GOLLUB
ET
AL. : COLLOID-CRYSTALLOID
MIXTURES
principal undesirable effect of this agent was a hemostatic disturbance manifested grossly as incisional rebleeding and prolonged ear bleeding times [l].
mn EXTRAVASCULAR DIST. AS % OF INFUSED VOLUME
BO60-
DISCUSSION
40?4 20B i 4 .P o8 ;-20. -4O-60 -6O-
L -O” Pro
Post PO61 I Hr. BloodRososc
3Hrs.
24 Hn
Fig. 7. Relative extravascular distribution of various infusions. The crystalloid solution and mixtures containing marked quantities of it are driven in large fraction to the extravascular compartment, whereas the colloid solution withdraws water from that compartment. vascular fluid at 3 hours was approximately 3:l (60%:20%). In marked contrast, the group of animals receiving dextran alone manifested a distribution ratio of extravascular to intravascular fluid of -1:+2 (-60%:+12070). Thus the volume expansion of the intravascular compartment with dextran took place at the expense of interstitial fluid volume in part. The data show that increasing ratios of dextran so modify the responses to Hartmann’s solution that proportionately less fluid is distributed to the extravascular compartment and intravascular retention is favored. One aspect of the data warrants emphasis: depletion of the extravascular space resulting from dextran alone was averted by incorporation of crystalloid fluid in the infusion. The morbidity patterns abstracted in the table indicate that the penalty of using a crystalloid solution exclusively or as a major fraction of the infusate is tissue edema of varying extent. While tissue edema was not seen with dextran alone, a
No single experimental model or design is satisfactory for investigating the complex mechanisms that are operative in hemorrhagic shock. In large part, conilicting opinions and conclusions stem from variations in experimental preparations and procedures. Some investigators [9, lo] assert that proper treatment of major blood loss or of hemorrhagic shock involves consideration of the fundamental role of sodium metabolism. Empiric formulations for blood volume replacement employed by others include large amounts of Hartmann’s solution alone-generally about three times the estimated blood loss [ll]Hartmann’s solution to supplement blood transfusion, in varying proportions [7,12], and colloid infusion alone, even for massive blood loss [13]. In this communication we have presented comparative data of the clinical, hemostatic, and pathophysiologic responses of splenectomized dogs subjected to an acute 30% volume blood loss and subsequently treated with colloid solution, crystalloid solution and various mixtures. The colloid solution employed elicits certain dose-dependent responses not seen with crystalloid solutions: mobilization of extravascular fluid to the intravascular space, and hemostatic alterations at high infusion volumes. Similarly, the crystalloid solution employed for volume expansion has certain characteristics which are absent in the colloid solution: transient retention intravascularly with major distribution to the extravascular compartments, resultant tissue bogginess and vascular instability. The individual effects of colloid solution and of crystalloid solution may be blended by using mixtures in certain proportions: the bleeding tendency observed with colloid infusion alone can be avoided and satisfactory intravascular volume restoration still be at-
JOURNAL
OF SURGICAL
RESEARCH
VOL. g
NO.
tained. With an appropriate combination of colloids and crystalloids, excess deposition of fluid in the extravascular compartment. can be reduced. For example, Hartmann’s solution, when used exclusively and administered in an amount threefold that of blood lost results in a partition ratio of 1:3 : : intravascular:extravascular. Conversely, dextran used exclusively in an amount equal to that of blood lost results in a partition ratio of +2: -1 : : intravascular:extravascular. That is, a depletion of extravascular fluid results. Such depletion of extravascular fluid when dextran alone is used would further aggravate the depletion accompanying trauma and hemorrhage [14, 151. However, employing a mixture of 20% dextran solution and 80% Hartmann’s solution in a volume three times the blood loss, the partition ratio is 1: 1, the blood volume is restored and maintained and hemostatic disturbance is not evidenced. This emphasizes the advantages to be gained by employing mixtures of crystalloid-colloid solutions. For as indicated by this study, inclusion of crystalloid solution is beneficial in that it reverses the dehydrating action and avoids the hemorrhagic complications of colloid alone. The authors do not suggest that the results obtained in this study are immediately applicable to any clinical situation. Nevertheless, the data do tend to clarify basic mechanisms and responses to replacement of blood loss by colloid and crystalloid solutions. It seems apparent, in general, that optimum results were associated with the preparations containing 20~~ or 30% of dextran solution (corresponding to an actual colloid concentration of 1.2% and 1.8%, respectively) used in a volume of three times the blood loss. However, even with the limited parameters of this study, ideal results were evidently not obtained in any case.
SUMMARY Thirty-six splenectomized dogs were subjected to acute loss of 30% blood volume and resuscitated with colloid solution alone, crystalloid solution alone, or mixtures of colloid and crystalloid solutions. 316
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1969
Certain dose-dependent disadvantageous effects associated with either type fluid alone were avoided by employing mixtures of solutions. Depletion of extravascular fluid, and the bleeding tendency associated with colloid use alone was not seen with appropriate mixtures. Excess water deposition in tissues and cardiovascular instability associated with crystalloid solution alone were absent. While ideal results were not obtained in any case, the optimal mixture in this study consisted of 1 part of 6% dextran solution and 4 parts of Hartmann’s (lactate Ringer’s) solution administered in a volume equal to three times the blood loss.
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