f

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

From the Shock and Trauma Research Laboratories,*Department of Surgery and tPhysiology, Michigan State

University, East Lansing, Michigan

Recently there has been increasing concern over transfusion-related diseases, especially acquired immune deficiency syndrome(AIDS). The authors therefore investigated the efficacy of lac-tated Ringer's solution (LRS) alone as compared with blood plusLRS resuscitation on body \\'eight change and mortality rateafter se,'ere 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, andfemoral artery were cannulated. The unrestrained, nonheparin-ized rats \\'ere allo\\'ed to recover from anesthesia and were bledwithin 10 minutes to a mea n arterial pressure (MAP) of 40mmHg. This MAP \\'as maintained by removing more blood untilthe animal was unable to compensate (maximal bleedout; MB).The MAP \\'as further maintained at 40 mmHg by returningfIuid (LRS) until 50% of the MB volume (MBV) was returned.The rats were then resuscitated: group 1 \\lth LRS 4 times theMBV; group 2 \\lth 5 X LRS; group 3 with the shed blood re-turned + 2 X LRS. There was no difference between the groupsin the initial \\'eights, MAP, or hematocrit (Hct), percentage ofblood volume remo,'ed, time to MB, or time to end ofhemorrhage.The final Hct and MAP \\'ere higher in group 3 (p < 10-6) thanin either of the other groups. Body weight gain was greater ingroup 2 compared \\lth either of the other groups (p < 0.05) ondar 1 after hemorrhage beca use of edema, but no differenceswere seen on subsequent days. There were no differences in thesurvival of animals in the different groups. These results suggestthat there should perhaps be a higher threshold for blood trans-fusion in the management of severe trauma-hemorrhagic shockthan is currently practiced.

of hemorrhagic shock is identification of the source ofbleeding and its control, and rapid fluid transfusion tomaintain the circulating volume.

Plasma and blood were the replacement fluids of choiceuntil the early 1960s, when the classic work of Shires etal.3 demonstrated the superiority of a crystalloid solutioncoro bined with whole blood ayer whole blood alone orwith the addition of plasma to the shed blood. Ouring theVietnam war, it was thought that infusions of colloid werenecessary to prevent the adult respiratory distress syn-drome,4 but it subsequently has been shown that post-traumatic pulmonary insufficiency is more correlated withsepsis iban with the type of fluid used in resuscitation.5Current practice in the United States involves transfusingcrystalloid in the first instancel and using the "transfusiontrigger" of a hematocrit (Hct) of 30%6 to decide when togive blood in addition.

This figure of an Hct of 30% is arbitrary, however, andHcts as low as 10% to 15% have been well tolerated! AIso,there are several problems associated with blood trans-fusion, including hyperkalemia,8 acid-base imbalances,9etc. The most emotionally charged concem is the trans-mission of the acquired immune deficiency syndrome(AIOS) virus. 10 In view ofthis, we investigated the efficacyof crystalloid alone as compared with a combination ofwhole blood and crystalloid resuscitation on body weightchange and death after severe hemorrhagic shock.

T RAUMA CONTINUES TO be a majar problem and

is the leading cause of death between the ages of

1 and 44 in the United States.] One halfofdeathsoccur from exsanguination or central nervous systemtrauma within 1 hour ofinjury, and within a further 1 to2 hours another 30% of deaths occur? These are due tomajar internal injury? The cornerstone of management

Materials and Methods

Hemorrhage Procedure -.

Male Sprague-Dawley rats (Charles River, Wilmington,MA), 250 to 310 g (n = 85), were fasted overnight butallowed water ad libitum. They were ligbtly anesthetized

Supported by NIH Grant 2 ROl 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.

~~'t";'l-

~~

~~~I;;

378 SINGH, CHAUDRY, AND CHAUDRY

with ether, and the ether Calle was removed while a 5-cmmidline laparotomy was performed using an electric cau-tery (i.e., trauma was induced). The organs then were in-spected visually to ensure the lack of damage by the cau-tery. After this, the abdominal incision was closed in layersand a carotid artery (for blood pressure monitoring), jug-ular vein (for fluid replacement), and femoral artery (forbleeding) were cannulated using PE 50 tubing (ClayAdams, Parsippany, NJ). The portion of the PE tubinginserted into the vessel was narrowed by extrusion to de-crease the internal diameter by approximately 50% toprevent clot formation in the tubing. The jugular andcarotid catheters were tunneled subcutaneously to thedorsal cervical region. The unrestrained, nonheparinizedrats then were allowed to recover from anesthesia, andblood pressure was monitored with a saline manometerthrough the carotid catheter.

Having recorded the initial mean arterial pressure(MAP) and the Hct, the animals were bled (by withdraw-ing the blood into a heparinized syringe to prevent clot-ting) ayer the course of 10 minutes to an MAP of 40mmHg. This pressure was maintained by removing moreblood in increments of 0.2 mL until the animal was nolonger able to maintain its blood pressure (maximal blee-dout; MB). The time taken to reach MB was recorded.At this point, the blood pressure was further maintainedat 40 mmHg by returning fluid in the forro of lactatedRinger's solution (LRS) in 0.2-mL increments until 50%ofthe shed blood volume was returned in that form (endofhemorrhage; EH). The time taken to EH was recorded.

Ann. Surg.. Aprill992

the shed blood volume as a percentage ofthe TCBV wascalculated. This was recorded as the percentage total bloodvolume removed (% TBVR). The animals were weigheddaily, and survival was noted each day.

Statistical Analysis

Statistical analyses were performed using one-wayanalysis of variance (ANOY A), Tukey's, and the chisquare test. The percentage data were subjected to arcsinetransformation before statistical analysis was performed.Differences were considered significant at p :5 0.05. Theresults are expressed as mean :t standard error of themean.

ResuIts

InitialParameters

There was no statistical difference between the groupsin the starting weights (282.8 :t 1.7 g), percentage ofbloodvolume removed (60.9 :t 0.2%), time to maximal bleedout(44.5 :t 0.2 minutes), time to end of hemorrhage (103.7:t 1.4 minutes), initial hematocrit (41.5:t 0.3%), orinitialMAP (118.9 :t 0.5 mmHg; one-way ANOV A; Table 1).This was true even if the animals were divided into sur-vivar and nonsurvivor subgroups and compared as suchwithin each group or between each group (Tables 2and 3).

Final Parameters

The final Hct (group l = 18.8 :t 0.2%; group 2 = 17.6:t 0.4%; group 3 = 39.3:t 0.7%) and the final MAP(group1 = 88.6 :t 2.1 rnrnHg; group 2 = 84.1 :t 1.5 rnrnHg;group 3 = 120.0 :t 2.1 rnrnHg) were significantly higher

in the blood-back group (group 3) than in either of the

TABLE l. Comparison oflhe Paramelers Measured in all Animals

Parameter Group Group 2 Group 3

Weight (g)% TBVRTMB (mio)TEH (mio)IHct (%)FHct (%)IMAP (mmHg)FMAP (mmHg)o

287.8:!: 1.961.1 :!:0.244.1 :!:0.2

107.9:!: 1.440.4 :!: 0.318.8 :!:0.2

117.8:!: 0.786.6:!: 2.1

37

282.8 :t 2.961.1 :t 0.344.0 :t 0.499.1 :t 1.940.9 :t 0.539.3:t 0.7*

118.2:t 1.0120.0:t 2.1*

21

Resuscitation Procedure

The rats then were divided into one of three groups:group 1 (n = 37) received LRS 3 times the shed bloodvolume over 45 minutes followed by a further 1 X over60 minutes (total of 4X resuscitation). Group 2 (n = 27)received 3X LRS over 45 minutes followed by a further2X 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 60minutes (blood-back resuscitation).

At the end of resuscitation, the final MAP and Hctwere recorded and the animals were lightly anesthetizedwith ether, decannulated, and the wounds were resutured.They were allowed to recover from the anesthetic andplaced in individual cages with free access to food andwater.

Parameters Determined

In addition to the parameters mentioned above, thefollowing were noted: The total circulating blood volume(TCBV) was calculated, as previously described byHauptman et al.,ll to be 6.12% ofthe body weight, and

Comparison ofinitial body weight, percentage oftotal blood volumeremoved (% TBVR), time to maximum bleedout (TMB), time to endof hemorrhage (TEH), initial (IHct) and final (FHct) hematocrit, andinitial (IMAP) and final (FMAP) mean arterial pressure between group1 (resuscitation [Rx] with 4 times [X] shed blood volume in the forrn oflactated Ringer's solution [LRS]), group 2'(Rx with 5X LRS), and group3 (Rx with blood-back + 2X LRS).

Mean :t SEM..= p < 10-6 compared with the other two groups, ANOV A, Tukey's

test,

379RESUSCITATION IN TRAUMA-HEMORRHAGIC SHOCKVol.2IS.No.4

TABlE 2. Comparison ofthe Parameters Measured in Survivors

Group Group 2 Group 3Paramet~r 8

104x LRS

.5x LRS~ V Blood + 2x LRS288.9

61.044.3

109.440.418.9

117.688.9

,

275.5 :t 4.260.1 :t 0.445.2 :t 0.7

106.4 :t 4.443.80 :t 0.817.6 :t 0.6

120.1 :t 1.483.7 :t 2.3

282.1 :J: 4.060.9 :J: 0.444.2 :J: 0.5

101.2:J: 2.341.2:J: 0.539.1 :J: 1.0.

116.7:J: 0.9121.8:J: 2;4.

15

Weight (g)% TBVRTMB (min)TEH (min)IHct(%}FHct (%)IMAP (mmHg)FMAP (mmHg)n

6

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4

2

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14

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-8

Comparison ofinitial body weight, percentage oftotal blood volumeremoved (% TBVR), time to maximum bleedout (TMB), time to endof hemorrhage (TEH), initial (IHct) and final (FHct) hematocrit, andinitial (IMAP) and final (FMAP) mean arterial pressure between groupI (resuscitation [Rx] with 4 times [X] shed blood volume in the forrn oflactated Ringer's solution [LRS]), group 2 (Rx with 5X LRS), and group3 (Rx with blood-back + 2X LRS).

Mean :t SEM.* = P < 10-6 compared with the other two groups, ANOV A, Tukey's

-10o 1 2 3 4 5 6 7 8

Days post-hemorrhage

AG. l. Daily percentage weight change (mean :t SEM) after hemorrhageand resuscitation (see Materials and Methods for hemorrhage and re-suscitation 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. The changein weight on day 1 after hemorrhage in group 2 is significantly different(* = p < 0.05, arcsine transforrnation, followed by ANOV A) comparedwith either of the two other groups. The reason for the initial weightgain in group 2 is the edema due to fluid overload, which is cleared bythe second day after hemorrhage. No subsequent statistical differencesare seen.

test.

crystalloid resuscitation groups (ANOY A, Tukey's test; p< 10-6; Table 1). This same trend was seen in the survivorand nonsurvivor subgroups (Tables 2 and 3), but no sta-tistical differences were seen within the groups betweensurvivors and nonsurvivors.

Daily Body Weight and Mortality Rates

On day 1 after hemorrhage, the change in body weightin group 2 (+4.00 ::!: 1.27%) was significant1y higher (p< 0.05; arcsine transformation f0110wed by ANOV A; Fig.1) iban in either of the other two groups (group 1 = 1.17::!: 0.72%; Group 3 = -2.42 ::!: 0.46%). No statistica1 dif-ferences were seen in the percentage weight change eachsubsequent day after hemorrhage (maximum 10ss of7.93

:t 1.32% ofthe body weight on day 3) between the groupsor within the groups between survivors and nonsurvivors.

No statistical differences were seen in the percentagesurvival ofthe animals each day after hemorrhage betweenthe groups (group 1 = 67.6%, group 2 = 51.9%, group 3= 71.4% on day 7 after hemorrhage; arcsine transfor-mation followed by ANOV A, chi square test; Fig. 2).

TABLE 3. A Comparison ol/he Parameters Measured in Nonsurvivors

Group Group 2 Group 3Parameter

285.161.:44.:

104.l40.<18.l

118.:81.;

276.0 :!: 5.660.8 :!: 0.544.9 :!: 0.796.4 :!: 4.949.2:!: 0.717.7:!: 0.4

121.4:!: 1.684.5 :!: 2.0

13

284.7 :t 2.661.5:tO.743.3 :t 0.893.7:t 1.24O.3:t 1.139.7 :t 0.8-

122.2:t 1.7115.7:t3.5

6

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

Discussion

Latta, in 1832,12 was the first to demonstrate the useofintravenous saline solution to treat hypovolemic shock.In 1899, Crilel3 showed that the maintenance of an ad-equate circulating volume and central venous pressurewith an intravenous infusion of warm saline resulted inreduced mortality rate in experimental hemorrhagicshock. Despite this, the treatment of hypovolemic shockduring World War I remained seating the patient uprightand bleeding him until he was unconscious because shockwas thought to be due to a circulating toxin.14 In 1930,the demonstration by Blalockl5 that the cause oftraumaticshock was hypovolemia, and the experience gained in themanagement of casualties in World War 11, finally dis-pelled the toxemia theory of shock. Since then there have

Comparison ofinitial body weight, percentage oftotal b]ood volumeremoved (% TBVR), time to maximum bleedout (TMB), time to endof hemorrhage (TEH), initial (IHct) and final (FHct) hematocrit, andinitial (IMAP) and final (FMAP) mean arterial pressure between groupI (resuscitation [Rx) with 4 times [X) shed blood volume in the forro oflactated Ringer's solution [LRS)), group 2 (Rx with 5X LRS), and group3 (Rx with blood-back + 2X LRS).

Mean :!: SEM..= p < 10-6 compared with the other two groups, ANOV A, Tukey's

test.

':1:1:1:

+'-,:1:,:1:1:1:

+1-1:1:

15

2.60.2

0.21.50.30.2

0.82.5

':1:1:1:1:1:i:1:1:1:i:1:1:1:':1:

12

2.50.50.32.70.50.41.23.5

SINGH. CHAUDRY. AND CHAUDRY380 Ann. Su~. ApriJ 1992

I ,r'I'!" I

90

80 ~-o ~".. 'v-- -'._'.~..""---

""" o--Ó=:Ó:==Ó:=670'iO>">1..;jUJ

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60 ...

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50

40

30 o.'i7

20

4x LRS

5x LRS

Blood + 2x LRS10

o ' 11 I ': 1 1 ..-

012345678

Days post-hemorrhage

FIG. 2. No differences in the daily percentage ofanimals stillliving afterhemorrhage and resuscitation were seen between any ofthe groups (seeMaterials and Methods for hemorrhage and resuscitation procedure).Group I = resuscitation (Rx) with 4 times (X) the shed blood volumewith lactated Ringer's solution (LRS), group 2 = Rx with 5X LRS, group3 = shed blood-back + 2X LRS.

..

comparing crystalloid alone with a combination ofbloodand crystalloid.

In ibis study, we used a model of surgical trauma; inother words, a 5-cm laparotomy incision. This is a sig-nificant trauma. Livingston and Malangoni2O have shownthat even al-cm skin incision before or after hemorrhageincreases infection in the rato Stephan et al.21 al so haveshown that laparotomy alone produces a marked depres-sion in cell-mediated immunity. Studies in OUT laboratoryhave demonstrated that whereas the mortality rate wasonly 10% after hemorrhage and resuscitation in the ab-sence of such trauma, it was 60% if laparotomy was per-formed before hemorrhage.22 Thus the model used in thisstudy involved not only hemorrhage, but also significanttissue trauma (5 cm laparotomy), which plays a majarTole in the outcome of the animals after hemorrhage.

The present study demonstrates that there is no differ-ence in the survival ofrats after trauma (laparotomy) andsevere hemorrhage when they are resuscitated with LRSalone or with a combination of blood and LRS (Fig. 2).Furthermore, there was no difference in the change indaily body weights at day 1 after hemorrhage (Fig. 1). Thereason for the weight gain in group 2 on the first day afterhemorrhage was edema due to fluid overload. This wascleared by the second post-hemorrhage day.

The reason for the lack ofbenefit ofblood resuscitationmay lie in the viscosity of the circulating blood. Crowellet al!3 found that increasing the hematocrit above 35%by re-transfusion ofblood decreased survival in dogs afterhemorrhagic shock, and suggested that the reason for ibismay be increased blood viscosity. After hemorrhage andresuscitation, we found that there was no significant dif-ference between the final Hcts of the 4X (18.8 :t 0.2%)LRS and 5X (17.6:t 0.4%) LRS-resuscitated groups, butthat of the blood + 2X LRS (39.3 :t 0.7%) resuscitatedgroup was significantly higher (p < 10-6). Thus, althoughthere was increased oxygen-carrying capacity in the blood-back group, the benefits appear to have been outweighedby the increase in blood viscosity.

Crowell and Read24 have demonstrated that there ishypercoagulability after resuscitation of animals with shedblood. They suggested that this may be due to release ofmicrothrombi into the circulation. This also may affectthe supply of nutrients to the tissues and the removal ofthe products of metabolism, leading to increased mortalityTale in the blood-back group.

We found that the final MAP was significantly higher(p < 10-6) in the group of animals resuscitated with bloodand LRS (120.0 :t 2.1 mmHg) iban in either the 4X (86.6:t 2.1 mmHg) or the 5X (84.1 :t 1-:5 mmHg) LRS-resus-citated groups. This is not surprising because it is knownthat LRS rapidly enters the extravascular space, and ibisis one of the reasons Shires et al.3 recommended its usein the resuscitation of hypovolemic shock. Despite ibis,

been vagues and controversies as to the type offluid thatshould be used for resuscitation.4.16

A combination of plasma and blood was the replace-ment regimen of choice until the early 1960s, when Shireset al.3 clearly demonstrated the need to replace the extra-cellular fluid deficit with crystalloid solutions as well asthe intravascular fluid losses. Also, Wolfmann et al.l?showed that survival was markedly improved after he m-orrhagic shock if dogs were resuscitated with LRS anddonar blood rather than shed blood alone. Jenkins et al.,18in 1950, suggested that it was the excessive infusion ofsalt solutions that was the cause of congestive atelectasisseen frequently after severe hemorrhagic shock. The highincidence of pulmonary insufficiency seen in the severelyinjured in the Vietnam war led many investigators to be-lieve that infusions of colloid were necessary to preventthe adult respiratory di stress syndrome.19 It subsequentlyhas been shown that post-traumatic pulmonary insuffi-ciency is more correlated with sepsis than with the typeof fluid used in resuscitation.5 Current practice in theUnited States is to resuscitate with LRS followed by bloodas necessary. I

There are, however, several problems with the use ofblood and blood products, and these are currently causefor concern, especially with the problems associated withtransfusion-transmitted AIOS. For this reason, we decidedto investigate resuscitation after severe hemorrhagic shock

RESUSCITATION IN TRAUMA;.HEMORRHAGIC SHOCK 381

Storage of blood increases the 2,3-DPG level of erythro-cytes and this decreases the affinity of hemoglobin foroxygen, thereby decreasing the delivery of oxygen to tis-sues.34 Hypothermia is a complication of the massivetransfusion of refrigerated blood, leading to several clinicalproblems.3S Stored blood develops particulate debris con-sisting of microaggregates of platelets, leukocytes, and fi-brin, some ofwhich are too small to be removed by stan-dard 170-}Lm blood infusion filters and may result in pul-monary insufficiency.36 Antibodies present in therecipient's plasma and directed against foreign transfusedred cell antigens can cause serious problems and evendeath.37

Probably the most emotionally charged complicationof transfusion of blood and blood products presentIr isthe possibility of transfusion-transmitted diseases. Themost serious problem in terms of frequency and compli-cations is non-A, non-B hepatitis. Evidence for the infec-tion can be found in as many as 7% of transfusion recip-ients within 6 months of the transfusion, and chronichepatitis develops in as many as 50% of the affected in-dividuals.38 The most serious problem in terms ofpublicconcem is the possible transmission ofthe AJOS virus.IOIn 1987, 886 cases of transfusion-associated AJOS hadbeen reported,39 but to put this in perspective, more than10 million transfusions are given yearly.6

In summary, therefore, we compared the weightchanges and mortality rates in rats subjected to traumaand severe hemorrhagic shock and resuscitated with eitherLRS alone or with blood plus LRS. We found that therewas no statistical difference in the mortality rate and nodifferences in weight change at dar 2 after hemorrhagebetween these different resuscitation regimens. These re-sults suggest that the "hematocrit trigger" for transfusionshould perhaps be lowered to 20%.

Vol.2ISoNo.4

however, there was no difference in the survival of theanimals in the three groups. Thus, it appears that bloodtransfusion is not always necessary in the managementof hemorrhagic shock, and this is in agreement with thesuggestions of other investigators.6.25

There has been concern expressed about erythrocytereplacement beca use transfusion of crystalloids alone willdiminish the oxygen-carrying capacity of blood after sig-nificant blood loss. Recent studies in this laboratory haveindicated that 50% acute hemodilution with LRS in sham-operated animals did not significantly affect cardiac out-put.26 Similar observations concerning cardiac output andhemodilution have been reported by others.27.28 Further-more, Pelton et al.,7 in graded hemodilution studies, haveshown that Hcts of 10% to 15% in animals subjected toacute hemodilution were well tolerated. Moreover, Meshand Gewertz,29 in an intestinal ischemia model, havedemonstrated that hemodilution has no adverse effectson oxygen consumption during hypotension and hypo-perfusion. Indeed, they suggest that hemodilution mayeven be beneficial during reperfusion after ischemia!9

It should be pointed out that we are not advocatingthat blood never be used in the resuscitation of hypovo-lemic shock, but suggesting that the threshold for its usemay perhaps be higher than at presento The commonlyused "transfusion trigger" Hct of 30%6 is arbitrary and,as pointed out previously, Hcts as low as 10% to 15% havebeen well tolerated! This is in agreement with our findingsthat a hematocrit of 15% to 20% was no more detrimentalto the survival of animals subjected to severe trauma-hemorrhagic shock than that of animals with Hcts of 35%to 40%. The results of the study presented here are ofsignificance especially in the present climate of attemptingto avoid the transfusion of blood and blood products.There are several potential problems associated with theuse of blood and blood products, even if they were notso expensive and in relative short supply.

Platelet and coagulation factor deficiencies are seen insome patients after a massive blood transfusion and maylead to a bleeding diathesis. This is commonly known as"dilutional coagulopathy," but dilution is only a smallpart of the problem.30.31 There is an excess of citrate instored blood to completely bind calcium and preventclotting and, under normal circumstances, this is rapidlymetabolized in the liver. We have recently shown, how-ever, that hepatocellular dysfunction occurs early afterhemorrhage and persists despite fluid resuscitation.32 Thismay be part ofthe explanation for the hypocalcemia seenafter blood transfusion.33 The concentration of potassiumin the plasma of stored blood increases with time, andhyperkalemia may occur during the rapid phase oftrans-fusion.8 Banked blood is acidic beca use ofthe citrate an-ticoagulant and becomes more acidic with storage as lacticacid accumulates. This may lead to acid-base imbalances.9

Acknowledgments

The autho~ wish to thank Ms Renee Ziobron for her skill and patiencein the editorial stages ofthis manuscript.

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382 SINGH, CHAUDRY, AND CHAUDRY Ann. Sur¡. o April 1992

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