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					Scandinavian Journal of Surgery 94: 227–232, 2005


T. T. Niemi1, M. Silvanto2, P. H. Rosenberg1
1   Department of Anaesthesiology and Intensive Care Medicine, Helsinki University Central Hospital,
    Helsinki, Finland
2   Department of Anaesthesia, Orton Orthopaedic Hospital, Invalid Foundation, Helsinki, Finland


Background and Aims: Albumin may enhance and hydroxyethyl starch (HES) may im-
pair haemostasis. While the effects are also dependent on haemodilution we minimized
it by early structured transfusion therapy, and compared albumin and HES regarding
blood loss and coagulation parameters in hip arthroplasty patients.
   Material and Methods: 101 patients undergoing primary hip arthroplasty received in
random order 4 % albumin (n = 48) or HES (average Mw 120 kDa/molar substitution ra-
tio 0.7, n = 53). The administration of colloid, red blood cell (RBC), fresh frozen plasma
and platetet concentrates begun after a 6–8 %, 12–16 %, 60 % and 100 % blood loss of the
patient’s calculated blood volume respectively. Explanatory risk factors for blood loss
were modelled by regression analysis.
   Results and Conclusions: Administration of albumin or HES 1200 ml (500–2000 and
500–1800) [median (range) respectively] did not affect blood loss. The vWF antigen was
higher in the albumin group (p = 0.04) postoperatively. Haematocrit value, platelet count,
bleeding time, prothrombin time value, activated thromboplastin time, FV activity and
fibrinogen concentration were comparable between the groups. Long operation time was
associated with great blood loss (p < 0.001). In hip arthroplasty patients with near nor-
mal levels of haematocrit albumin enhanced coagulation without altering blood loss.
Key words: Albumin; HES; coagulation; blood loss

INTRODUCTION                                            these are mainly the results of haemodilution per se
                                                        or of an effect by the type of the infused solution used
The infusion of a crystalloid solution (1) or albumin   for the compensation of the surgical blood loss, e.g.,
(2, 3) may enhance coagulation while hydroxyethyl       the characteristics of the HES molecule (4), remains
starch (HES) solutions impair haemostasis both by       open.
dilution and a deterioration of coagulation factor         In our previous in vitro studies dilution of human
function in plasma of surgical patients (4). Whether    blood by 20 % with 4 % albumin clearly increased
                                                        and 6 % low-molecular weight HES decreased the
                                                        coagulation efficacy (5). To what extent these find-
  Tomi Niemi, M.D.
                                                        ings can be translated into clinical practice, e.g.,
  Department of Anaesthesiology and Intensive           whether perioperative haemorrhage and coagulation
  Care Medicine                                         are influenced by the solutions to a clinically signifi-
  Helsinki University Central Hospital                  cant extent, was investigated in patients undergoing
  PO Box 340, FIN - 00029 HUS, Finland                  hip arthroplasty. In order to minimize a dilutional
  Email:                              influence on coagulation function we applied an ac-
228                                                 T. T. Niemi, M. Silvanto, P. H. Rosenberg

tive transfusion strategy including early transfusion                        Blood Transfusion Service, Helsinki, Finland) or 6 % low
compartment therapy followed by administration of                            molecular weight HES (HES group n = 53) (average Mw 120
whole blood.                                                                 kDa/molar substitution ratio 0.7, Plasmafusin®, Medipolar,
                                                                             Oulu, Finland) for intravascular fluid replacement.
                                                                                The schematic presentation of transfusion management
                                                                             is shown in Table 1. The blood volume was estimated as
MATERIAL AND METHODS                                                         72 ml/kg for female and 77 ml/kg for male patients.
                                                                                Intraoperative blood loss was measured from the con-
After approval of the local Ethics committee and written                     tent of suction bottles and the increase in weight of surgi-
informed consent a total of 101 patients undergoing uni-                     cal swabs. In the recovery room and during the three post-
lateral primary noncemented total hip replacement (THR)                      operative days blood loss estimation was based on the vo-
were enrolled in the study. Patients having haemoglobin                      lume in the vacuum drainage bags. In addition, blood loss
concentration below 120 g/l, coagulation disorder or tak-                    was evaluated as a percent value of the patient’s calculat-
ing warfarin were excluded. Acetylsalicylic acid and dipy-                   ed blood volume. The units of transfused red blood cell
ridamol were not allowed within 7 days before surgery,                       concentrate (RBC, SAGM, Finnish Red Cross Blood Trans-
and nonsteroidal anti-inflammatory analgesic drugs                           fusion Service, Helsinki, Finland) and whole blood (WB,
(NSAIDs) within 2 days preoperatively. Low molecular                         CPD whole blood, Finnish Red Cross Blood Transfusion
weight heparin, enoxaparin 40 mg once a day, beginning                       Service, Helsinki, Finland) and their weight were also re-
11–16 h before anaesthesia, was given for thromboproph-                      gistered.
ANALGESIA                                                                    The colloid administration was begun after a 6–8 % blood
                                                                             loss of the patient’s calculated blood volume. Colloid (al-
The patients were premedicated with oral diazepam 10–                        bumin or HES) was given in a volume of 250 ml with one
20 mg 45–60 min before anesthesia. An epidural catheter                      RBC unit after every 450-ml blood loss.
was placed at the L1–L4 level. Thereafter spinal anaesthe-
sia was induced at the L2–4 level with plain bupivacaine 5
mg/ml 15–20 mg (Marcain spinal, Astra, Södertälje, Swe-                      RED BLOOD CELL CONCENTRATES AND WHOLE BLOOD
den). During surgery additional doses of bupivacaine 5
mg/ml were given epidurally as needed. The upper body                        RBC concentrates were given after 12–16 % blood loss. One
of the patients was covered by warm blankets to prevent                      RBC unit was given for a blood loss of 450 ml. After trans-
heat loss.                                                                   fusion of 4–6 RBC units (according to the weight 4 RBC
   The great majority of the operations (n = 86) were done                   units for 45–60 kg, 5 RBC units for 61–75 kg, 6 RBC units
by senior orthopaedic surgeons with all the patients in the                  for 76–90 kg) the blood loss was replaced by giving one
lateral decubitus position. A noncemented surgical tech-                     WB unit for a blood loss of 450 ml.
nique was used.
   The patients were given diclofenac 25 mg or 50 mg oral-                   RINGER’S AND 5 % GLUCOSE SOLUTION
ly three times a day beginning on the first postoperative
day. Additional postoperative pain management included                       After every 450-ml blood loss 250 ml of Ringer’s acetated
intramuscular oxycodone and epidural analgesia with                          solution (Ringersteril®, Medipolar, Oulu, Finland) was
bupivacaine 5 mg/l, as needed.                                               given with one RBC unit. Additionally, the patients were
                                                                             given 1000 ml of Ringer’s acetated solution and 2000 ml of
TRANSFUSION AND FLUID THERAPY DURING SURGERY                                 balanced 5 % glucose solution during the day of surgery.
AND IN THE RECOVERY ROOM                                                     The patients weighing over 60 kg were given additional
                                                                             250–500 ml of Ringer’s solution for every 10 kg increase of
The patients were randomized to receive either 4 % albu-                     weight. If there were signs of hypovolemia, 500–1000 ml
min (ALB group, n = 48) (Albumin 4 %®, Finnish Red Cross                     of Ringer’s solution was given.

                                                                     TABLE 1
   Schematic presentation of transfusion management. The arrows show the approximate start point of the administration of colloids (albumin or
 HES), red blood cell concentrates (RBC), whole blood (WB), fresh frozen plasma (FFP) and platelet concentrates (PC) according to the estimated
 blood loss of the patient’s calculated blood volume. Ringer’s solution and colloids were given 250 ml with each RBC unit. In addition the patients
                       were given 1000 ml of Ringer’s solution and 2000 ml of 5 % glucose solution during the day of surgery.

                                          6–8 %                 12–16 %              12–16 %              60 % blood loss       100 % blood loss
                                          blood loss            blood loss           blood loss

Colloid                                   →→→→                  →→→→                 →→→→→→→→             →→→→→→→→              →→→→→→→→

RBC one unit for a blood
loss of 450 ml                                                  ➡➡➡➡

WB one unit for a blood
loss of 450 ml                                                                       ➔➔➔➔➔➔➔              ➔➔➔➔➔➔➔               ➔➔➔➔➔➔➔

FFP                                                                                                       ➡➡➡➡➡➡➡➡              ➡➡➡➡➡➡➡➡

PC                                                                                                                              ➜➜➜➜➜➜➜
                                                     Albumin enhances coagulation                                            229

FRESH FROZEN PLASMA AND PLATELETS                                     terassay precision was 6.1 %. A frozen plasma pool of more
                                                                      than 50 normal donors was used as a standard in FV and
The indication for fresh frozen plasma (FFP) transfusion              vWF antigen assays. APTT was measured using standard
was a blood loss over 60 %. If the platelet count was be-             techniques and PT was measured by the P+P principle us-
low the level of 100 × 109/l or the blood loss was estimat-           ing commercial reagents. Anti-FXa-activity was deter-
ed to be over 100 % of the calculated blood volume, eight             mined by a commercial method (Kabi Coatest, Heparin).
units of platelets (Platelet concetrates, Finnish Red Cross           Bleeding time was measured on the volar surface of the
Blood Transfusion Service, Helsinki, Finland) average vol-            upper part ot the forearm with a transverse incision using
ume 85 ml/unit) were given. Transfusions and fluid ther-              the Simplate II R device (BioMeriéux, North Carolina,
apy on the 1st–3rd postoperative day were given using the             USA).
same principles.
                                                                      The patient number needeed was estimated to show a 25 %
Haemoglobin concentration (Hb, g/l), haematocrit value                difference in intraoperative blood loss. The number of
(Hct, %) and platelet count (PC, × 109/l) in whole blood              coagulation measurements was based on the data of vWF
were determined in all the study patients preoperatively,             antigen concentrations (30 % difference) shown in the pre-
in the recovery room, on the first, second and third post-            vious study (6). With a power of 80 % (α-error 5 %) the
operative day with a Coulter Counter T880 blood cell coun-            sample size was 40 for blood loss and 16 for coagulation
ter (Coulter Electronics Inc., Hialeah, Florida, USA).                measurements in both groups. The results were analyzed
   Coagulation determinations were done in random order               by the two-way analysis of variance (ANOVA) for repeat-
in 19 albumin treated and 21 HES treated patients. The de-            ed measurements. The Tukey multiple comparison test was
terminations included fibrinogen concentration (g/l), co-             used a posteriori to identify the differences between the
agulation factor V activity (FV, IU/ml), plasma von Wille-            groups. Patient characteristics, blood loss and transfusion
brand factor antigen (vWF, IU/ml), activated partial                  data were compared using the student t-test, the Mann-
thromboplastin time (APTT, s), prothrombin time value                 Whitney Rank Sum test, the χ2 -analysis or the Fisher Exact
(PT, %) and IVY bleeding time (BT, s). The venous blood               test as appropriate. The values are presented as means (SD)
samples were taken the day before surgery (fibrinogen, FV,            or medians (range). The possible variables affecting blood
vWF, APTT, PT, BT), before anaesthesia (fibrinogen, FV,               loss was modelled with multiple linear regression. The α
vWF), postoperatively in the recovery room (fibrinogen,               level was 0.05 for all statistical tests.
FV, vWF, APTT, PT, BT) and on the first postoperative day
(fibrinogen, FV, APTT, PT, BT). In addition, enoxaparin
concentrations were determined as anti-FXa-activity/ml
before anaesthesia.                                                   RESULTS
   For the coagulation measurements, 9 volumes of blood
was mixed with 1 volume of 0.129-M trisodium citrate. Af-             The patient groups had comparable demographic
ter centrifugation the plasma was aliquoted, snap-frozen              data (Table 2). The duration of surgery was longer
and stored at –70 ˚C until assayed. Levels of fibrinogen              in the ALB group (p = 0.004). The frequency of the
were measured using with ACL method (IL TestTM PT-                    preoperative use of NSAIDs did not differ between
Fibrinogen, Instrumentation Laboratory, Italy). A lot of IL           the groups (p = 0.065).
Test Calibration plasma was used as a standard. The inte-
rassay precision was 1.9 %. FV activity was measured us-
ing the one-stage method with rabbit brain thromboplas-               BLOOD LOSS AND TRANSFUSIONS
tin (Thromboplastin-IS, Baxter-dade, USA) with ACL co-
agulometer. The interassay precision was 3.5 %. Plasma                The perioperative blood loss, the amount of trans-
vWF antigen was assayed with an ELISA method. The in-                 fused RBC, WB and intravascular fluids were com-

                                                               TABLE 2
                                Patient characteristics. Values are mean (SD) unless otherwise indicated.

                                                                               ALB n = 48                   HES n = 53

Age, years                                                                     53 (10)                      56 (8)
Sex F/M (number)                                                               19/29                        19/34
Weight, kg                                                                     73 (13)                      75 (12)
Height, cm                                                                     167 (10)                     167 (9)
ASA physical status [(median (range)]                                          I (I–II)                     I (I–III)
Calculated blood volume, ml                                                    5404 (1022)                  5561 (999)
Preoperative use of NSAID# (number)                                            22                           35
Arterial hypertension (number)                                                 6                            13
Ischaemic heart disease (number)                                               1                            2
Diabetes (number)                                                              3                            1
Intraoperative bupivacaine dose, mg [median(range)]                            20 (16–83)                   20 (17–145)
Duration of surgery min [median (range)]                                       119 (60–225)*                104 (52–281)*

* P = 0.004 between the groups (Mann-Whitney Rank Sum test).
# stopped two days before surgery, at the latest.
ASA American Society of Anesthesiologists physical status
NSAID Nonsteroidal anti-inflammatory drug
230                                                  T. T. Niemi, M. Silvanto, P. H. Rosenberg

                                                                      TABLE 3
             Blood loss. The values presented are milliliters as medians (range). There are no significant differences between the groups.

Group                              Intraoperative blood          Blood loss in the            Additional blood loss        Additional blood loss
                                   loss, ml                      recovery room, ml            until first postoperative    until first postoperative
                                                                                              morning, ml                  evening, ml

ALB n = 48                         1400 (400–3500)               1000 (200–2600)              300 (0–1100)                 100 (0–570)
HES n = 53                         1200 (400–8300)               1150 (300–3400)              300 (0–1000)                 150 (0–600)

                                                                      TABLE 4
 The amounts of transfused red blood cell concentrate (RBC), whole blood (WB) and colloid in the albumin group (ALB) and hydroxyethyl starch
                group (HES). The values presented are medians (range). There are no significant differences between the groups.

Group                  During surgery                                                     In the recovery room

                       RBC, g              WB, g               Colloid, ml                RBC, g              WB, g               Colloid, ml

ALB n = 48             1158 (0–1935)       0 (0–1800)          725 (400–1600)             400 (0–1905)        595 (0–4095)        475 (0–1100)
HES n = 53             1135 (0–2270)       0 (0–4775)          700 (450–1500)             595 (0–1840)        595 (0–4715)        450 (0–1100)

Group                  Intraoperatively and during the first postoperative day

                       RBC, g                  WB, g                   Colloid, ml

ALB n = 48             1848 (1420–2245)        1148 (0–5385)           1200 (500–2000)
HES n = 53             1810 (735–2955)         920 (0–5385)            1200 (500–1800)

parable between the groups (Table 3 and 4). The                              postoperatively in albumin treated patients, indicat-
average intraoperative administration of albumin 725                         ing an enhancement of coagulation, is in accordance
ml (400–1600) [median (range)] or HES 700 ml (450–                           with our in vitro results (5) and a recent in vivo pre-
1500) did not influence intraoperative blood loss and                        liminary study (3). Other coagulation parameters
the amount of transfused RBC and WB units. Long                              changed to a similar extent as in the HES group sug-
operation time, but not the patient preoperative char-                       gesting a dilutional effect.
acteristics, was associated with high blood loss as                             The type of replacement fluid used and the degree
shown by multiple linear regression analysis (p <                            of haemodilution seem to determine the efficacy of
0.001). All the patients received RBC transfusion by                         coagulation during haemodilution (7). Low haema-
the end of the recovery room period.                                         tocrit may compromise blood coagulation (8), and al-
                                                                             logeneic blood transfusions have been recommend-
LABORATORY FINDINGS                                                          ed for raising the haematocrit at least to 30 % just to
                                                                             optimize blood coagulation. Furthermore, during
The measured clotting variables decreased to a simi-                         massive transfusion correction of haematocrit is es-
lar extent in both groups as compared with preoper-                          sential for sustaining adequate hemostasis (9), and
ative values (Table 5). The vWF antigen concentra-                           patients with low haematocrit levels may bleed more
tion was higher in the ALB group postoperatively in                          than patients having haematocrit level above 33 %
the recovery room (p = 0.04, Tukey test) (Table 5).                          after cardiac surgery (10).
Before anaesthesia the anti-FXa-activity was 0.2 (0.06)                         In the current study the median intraoperative
U/ml [(mean, (SD)] in both groups (p = 0.88). The                            blood loss was relatively high, 1400 ml (ALB group)
Hb concentration (Fig. 1), Hct value and PC (data not                        and 1200 ml (HES group), and totally 2860 ml and
shown) decreased (p < 0.001) similarily in the study                         2950 ml, respectively, until the end of the first post-
groups.                                                                      operative day. There were however no clinical rele-
                                                                             vant abnormalities in the measured coagulation pa-
                                                                             rameters which could aggravate haemorrhage. Usu-
DISCUSSION                                                                   ally in orthopaedic surgery RBC transfusions with
                                                                             high blood loss are most common in patients with
This study demonstrates that the administration of                           reduced preoperative red blood cell reserve, female
4 % albumin and 6 % HES (Mw 120 kDa/ molar sub-                              gender, advancing age, small body size and frequent
stitution ratio 0.70) have comparable effects on blood                       comorbid diseases (11). However, we could not iden-
loss intra- and postoperatively in primary total hip                         tify those factors as risk for blood loss in the present
replacement patients with modest haemodilution.                              study which is in accordance with a recent study in
The finding of a higher vWF antigen concentration                            patients undergoing total hip arthroplasty (12).
                                                           Albumin enhances coagulation                                                                                  231

                                                                     TABLE 5
Mean (SD) clotting variables. The p-values indicate the significance level as compared to the preoperative value within both groups. The concentra-
 tion of vWF antigen was higher postoperatively in the ALB group (*P = 0.04 between the groups, Tukey test). Otherwise there are no significant
                                                          differences between the groups.

Variable                                             ALB group                           P-value                 HES group                               P-value

Fibrinogen, g/l                                      n = 19                                                      n = 21
Day before surgery                                   3.6   (1.1)                                                 3.4   (0.6)
Before anaesthesia                                   3.3   (1.1)                           0.15                  3.2   (0.5)                               0.56
Recovery room                                        2.2   (0.5)                         < 0.001                 2.3   (0.3)                             < 0.001
First postoperative morning                          4.0   (0.7)                           0.003                 3.9   (0.5)                             < 0.001
Factor V, IU/ml                                      n = 19                                                      n=2
Day before surgery                                   114   (14)                                                  1115 (18)
Before anaesthesia                                   102   (16)                          < 0.001                 0107 (18)                               < 0.001
Recovery room                                        070   (16)                          < 0.001                 0067 (11)                               < 0.001
First postoperative morning                          083   (15)                          < 0.001                 0078 (11)                               < 0.001
PT, %                                                n = 48                                                      n = 48
Day before surgery                                   99 (25)                                                     102 (20)
Recovery room                                        65 (12)                             < 0.001                 060 (11)                                < 0.001
First postoperative morning                          65 (14)                             < 0.001                 059 (10)                                < 0.001
Day before surgery                                   28 (9) n = 48                                               260(2) n = 48
Recovery room                                        27 (3) n = 48                        0.41                   280(3) n = 53                                0.09
First postoperative morning                          28 (2) n = 48                        1.0                    290(5) n = 53                                0.004
vWF antigen, IU/ml                                   n = 19                                                      n = 21
Day before surgery                                   112 (33)                                                    124 (35)
Before anaesthesia                                   107 (30)                             0.85                   123 (35)                                     1.0
Recovery room                                        134 (53)*                            0.04                   109 (31)*                                    0.20
Bleeding time, min
Day before surgery                                   6.8 (1.9) n = 48                                            6.8 (1.9) n = 48
Recovery room                                        8.4 (2.8) n = 37                    < 0.001                 8.6 (2.9) n = 41                        < 0.001
First postoperative morning                          7.4 (2.3) n = 48                      0.26                  7.9 (2.3) n = 53                          0.005

   The findings concerning HES in the present study                         Hb (g/l)
are in accordance with a previous study in volunteers                         180
where a small dose of a low molecular weight HES
(125 kDa) with high substitution ratio (0.7) caused
no, or only minimal changes in blood coagulation                              160
                                                                                                                 *               *                 *             *
(13). However, had a larger dose of HES had been                                                        n=48
given, a decrease in coagulation factor levels might                          140
                                                                                                                     n=48            n=48              n=48
have been seen (14). The small postoperative de-                                                                                                                         n=48
creases in fibrinogen concentration, FV activity and                          120
PT value as well as the lenghtening of bleeding time                                                                      n=53              n=53
were similar in both groups and probably the result                                                                                                       n=53
of the modest dilution by the intravenous fluids.                             100

   The transfusion algorithm designed particularly
for the present study is certainly too liberal, and ex-                         80
pensive and we do not recommend it for routine cli-                                  0              1            2               3                 4                 5
nical practice. Guidelines for blood component thera-                                                            Sample number
py suggest to accept lower haemoglobin concentra-                                            ALB
tions, coagulation factor levels and platelet counts                                         HES
than traditionally have been considered safe (15).                         Fig. 1. Haemoglobin concentration (Hb) (mean, SD) in whole
Whole blood should be used only under special cir-                         blood. *P < 0.001 in comparison with preoperative value within
cumstances such as in pediatric cardiac or craniofa-                       both groups (Tukey test). The sample numbers are 1 = preopera-
cial surgery and possibly in war situations (16, 17).                      tively, 2 = in the recovery room, 3 = first postoperative morning,
                                                                           4 = second postoperative morning, 5 = third postoperative morn-
This is also partly supported by our findings in the                       ing.
current study where no clinical significant enhance-
ment in coagulation or reduced blood loss could be
demonstrated although relatively high red blood cell
mass was maintained. The findings in this study do                         fusion is indicated when patients with normal initial
not challenge the current recommendation for FFP                           level of coagulation factors have been transfused
administration either, which suggests that FFP trans-                      with more than one blood volume (15).
232                                             T. T. Niemi, M. Silvanto, P. H. Rosenberg

   In summary, the administration of albumin to pa-                   08. Turitto VT, Weiss HJ: Red blood cells: their dual role in throm-
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