Abstract
OBJECTIVES:
To evaluate the effect of the intraoperative use of hydroxyethyl starch on the need for blood products in the perioperative period of oncologic surgery. The secondary end-points included the need for other blood products, the clotting profile, the intensive care unit mortality and length of stay.
METHODS:
Retrospective observational analysis in a tertiary oncologic ICU in Brazil including 894 patients submitted to oncologic surgery for a two-year period from September 2007. Patients were grouped according to whether hydroxyethyl starch was used during surgery (hydroxyethyl starch and No-hydroxyethyl starch groups) and compared using a propensity score analysis. A total of 385 propensity-matched patients remained in the analysis (97 in the No-hydroxyethyl starch group and 288 in the hydroxyethyl starch group).
RESULTS:
A higher percentage of patients in the hydroxyethyl starch group required red blood cell transfusion during surgery (26% vs. 14%; p = 0.016) and in the first 24 hours after surgery (5% vs. 0%; p = 0.015) but not in the 24- to 48-hour period after the procedure. There was no difference regarding the transfusion of other blood products, intensive care unit mortality or length of stay.
CONCLUSION:
Hydroxyethyl starch use in the intraoperative period of major oncologic surgery is associated with an increase in red blood cell transfusions. There are no differences in the need for other blood products, intensive care unit length of stay or mortality.
Tetrastarch; Adverse Events; Blood Transfusion; Surgical Blood Loss; Surgery; Cancer
INTRODUCTION
Fluid expansion is critical during surgery and in postoperative care. The ideal fluid type
(crystalloids or colloids) and the optimum dosage of fluids are much debated issues (11. Westphal M, James MF, Kozek-Langenecker S, Stocker R, Guidet B, Van Aken H.
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). Hydroxyethyl starches
(44. Gattas DJ, Dan A, Myburgh J, Billot L, Lo S, Finfer S, et al. Fluid resuscitation
with 6% hydroxyethyl starch (130/0.4) in acutely ill patients: an updated systematic review and
meta-analysis. Anesth Analg. 2012;114(1):159-69,
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) are widely used as fluid expanders in the perioperative
period and are the preferred colloids in many intensive care units (ICU) (55. Schortgen F, Deye N, Brochard LGroup CS. Preferred plasma volume expanders for
critically ill patients: results of an international survey. Intensive Care Med. 2004;30(12):2222-9,
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).
Hydroxyethyl starch (HES) may impair blood coagulation by reducing the levels of von Willebrand
factor and factor VIII and by decreasing the platelet count and function (77. Sossdorf M, Marx S, Schaarschmidt B, Otto GP, Claus RA, Reinhart K, et al. HES
130/0.4 impairs haemostasis and stimulates pro-inflammatory blood platelet function. Crit Care.
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SA. The effects of hydroxyethyl starches of varying molecular weights on platelet function. Anesth
Analg. 2001;92(6):1402-7, http://dx.doi.org/10.1097/00000539-200106000-00008.
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). It has been suggested that the new
generation HES (third generation, low molecular weight, low degree of substitution) is less prone to
cause blood coagulation disorders than the old compounds (1111. Langeron O, Doelberg M, Ang ET, Bonnet F, Capdevila X, Coriat P. Voluven, a
lower substituted novel hydroxyethyl starch (HES 130/0.4), causes fewer effects on coagulation in
major orthopedic surgery than HES 200/0.5. Anesth Analg. 2001;92(4):855-62,
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), but this issue remains controversial (77. Sossdorf M, Marx S, Schaarschmidt B, Otto GP, Claus RA, Reinhart K, et al. HES
130/0.4 impairs haemostasis and stimulates pro-inflammatory blood platelet function. Crit Care.
2009;13(6):R208, http://dx.doi.org/10.1186/cc8223.
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,1212. Kozek-Langenecker SA, Jungheinrich C, Sauermann W, Van der Linden P. The effects
of hydroxyethyl starch 130/0.4 (6%) on blood loss and use of blood products in major surgery: a
pooled analysis of randomized clinical trials. Anesth Analg. 2008;107(2):382-90,
http://dx.doi.org/10.1213/ane.0b013e31817e6eac.
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,1313. Hartog CS, Kohl M, Reinhart K. A systematic review of third-generation
hydroxyethyl starch (HES 130/0.4) in resuscitation: safety not adequately addressed. Anesth Analg.
2011;112(3):635-45, http://dx.doi.org/10.1213/ANE.0b013e31820ad607.
http://dx.doi.org/10.1213/ANE.0b013e3182...
) primarily because few
studies evaluated the issue (44. Gattas DJ, Dan A, Myburgh J, Billot L, Lo S, Finfer S, et al. Fluid resuscitation
with 6% hydroxyethyl starch (130/0.4) in acutely ill patients: an updated systematic review and
meta-analysis. Anesth Analg. 2012;114(1):159-69,
http://dx.doi.org/10.1213/ANE.0b013e318236b4d6.
http://dx.doi.org/10.1213/ANE.0b013e3182...
). In the perioperative period,
even the new generation starches inspire concerns about their safety, especially in terms of
coagulation disorders (11. Westphal M, James MF, Kozek-Langenecker S, Stocker R, Guidet B, Van Aken H.
Hydroxyethyl starches: different products-different effects. Anesthesiology. 2009;111(1):187-202,
http://dx.doi.org/10.1097/ALN.0b013e3181a7ec82.
http://dx.doi.org/10.1097/ALN.0b013e3181...
,77. Sossdorf M, Marx S, Schaarschmidt B, Otto GP, Claus RA, Reinhart K, et al. HES
130/0.4 impairs haemostasis and stimulates pro-inflammatory blood platelet function. Crit Care.
2009;13(6):R208, http://dx.doi.org/10.1186/cc8223.
http://dx.doi.org/10.1186/cc8223...
,1313. Hartog CS, Kohl M, Reinhart K. A systematic review of third-generation
hydroxyethyl starch (HES 130/0.4) in resuscitation: safety not adequately addressed. Anesth Analg.
2011;112(3):635-45, http://dx.doi.org/10.1213/ANE.0b013e31820ad607.
http://dx.doi.org/10.1213/ANE.0b013e3182...
14. Schramko A, Suojaranta-Ylinen R, Kuitunen A, Raivio P, Kukkonen S, Niemi T.
Hydroxyethylstarch and gelatin solutions impair blood coagulation after cardiac surgery: a
prospective randomized trial. Br J Anaesth. 2010;104(6):691-7.-1515. Hartog CS, Reuter D, Loesche W, Hofmann M, Reinhart K. Influence of hydroxyethyl
starch (HES) 130/0.4 on hemostasis as measured by viscoelastic device analysis: a systematic review.
Intensive Care Med. 2011;37(11):1725-37,
http://dx.doi.org/10.1007/s00134-011-2385-z.
http://dx.doi.org/10.1007/s00134-011-238...
).
Patients submitted to oncologic surgery are subjected to long surgery procedures, with a great
need of fluid resuscitation and blood products transfusion. It has been suggested that surgical
cancer patients are more prone to being transfused with blood products than non-cancer patients
(1616. Amar D, Grant FM, Zhang H, Boland PJ, Leung DH, Healey JA. Antifibrinolytic
therapy and perioperative blood loss in cancer patients undergoing major orthopedic surgery.
Anesthesiology. 2003;98(2):337-42,
http://dx.doi.org/10.1097/00000542-200302000-00011.
http://dx.doi.org/10.1097/00000542-20030...
). No study has evaluated the effects of the
intraoperative use of a new generation HES on the intraoperative and postoperative red blood cells
and other blood products transfusion in patients submitted to elective major oncologic surgery.
We hypothesized that patients submitted to oncologic surgery that received a new generation HES during surgery would require more red blood cells transfusions during and after the surgery than patients that did not receive HES. To test our hypothesis, we evaluated whether a new generation HES led to more red blood cell transfusions during the first 48 hours after major elective oncologic surgery than patients that received only crystalloids using a propensity-matched approach. Secondary objectives included clotting profile, use of blood products other than red cells, ICU length of stay and mortality between the two groups.
PATIENTS AND METHODS
Study design: Retrospective analysis of medical records.
Patients: The Ethics Committee of the Hospital AC Camargo approved this study and waived patient consent due to its retrospective observational nature. From September 2007 to September 2009, all patients admitted to the hospital ICU (three units with a total of 33 beds) of our teaching hospital after an elective major oncologic surgery (head and neck, neurological, thoracic, abdominal and other sites) were included in the study.
Data collection: In the hospital, all data are recorded in a computerized physician order entry and an electronic medical record system. We collected the data recorded during the surgery and the following 48 hours. During the intraoperative period, we collected the number of packs of blood products transfused (red blood cells, fresh frozen plasma, platelets and cryoprecipitate), the surgery length and the volume of crystalloids and colloids infused. During ICU admission, we collected the simplified acute physiology score 3 (SAPS 3) and performed laboratory exams that included creatinine levels and clotting profile (composed of the platelets count and prothrombin time (PT). During the 48-hour period after the surgery, we collected the number of packages of blood products transfused and performed laboratory exams, including serum creatinine. We divided the 48-hour period after the surgery into two periods of 24 hours because the hypothetical HES side effect could be evanescent. The data were analyzed for three consecutive periods: the intraoperative period, the period from the end of the surgery to the first 24 hours after post-surgery (24-hour period) and the period between from 24 to 48 hours after the surgery (24- to 48-hour period). The patients were categorized in two groups according to the use of HES during the intraoperative period (HES and No-HES group). The patients in the HES group received at least 500 mL of new generation HES (Voluven¯ - 6% 130/0.4, Fresenius, Germany).
Perioperative transfusion policy: The hospital transfusion policy recommends that patients should
be admitted to the operating room with a hemoglobin level greater than 10 mg/dL and platelet count
above 50 × 103 units/mL. Coagulation disorders, as assessed by aPTT and PT, were treated
with preoperative fresh frozen plasma transfusion until both values were within the normal range
(international normalized ratio and aPTT ratio less or equal to 1.5). Other causes of coagulopathy,
such as vitamin K deficiency, were assessed as appropriate. Blood transfusion during surgery is left
to the discretion of the anesthesiologist and surgeon. All anesthesiologists in the hospital are
part of a small team that follows protocols for surgery resuscitation and blood transfusion. There
are five major surgical teams in the hospital (thoracic, abdominal, pelvic, neurological and soft
tissue) and each has a closed staff, i.e., surgery at each specific site is usually performed by a
very restricted number of surgeons. The ICU policy for transfusion suggests that red blood cell
packs should be transfused if the hemoglobin level is below 7 g/dL or below 8 g/dL with signs of
active bleeding and/or impaired tissue perfusion (delayed capillary refill time, elevated lactate
levels and nonchloremic metabolic acidosis) (1717. Drews RE. Critical issues in hematology: anemia, thrombocytopenia, coagulopathy,
and blood product transfusions in critically ill patients. Clin Chest Med. 2003;24(4):607-22,
http://dx.doi.org/10.1016/S0272-5231(03)00100-X.
http://dx.doi.org/10.1016/S0272-5231(03)...
). Transfusion
with hemoglobin levels above 9 g/dL was not encouraged and was performed only at the discretion of
the intensivist if massive blood lost was detected (high output in the drain with hemodynamic
instability). Platelets were transfused if the total count was less than 50 × 103
units/mL with active bleeding or after neurosurgery. Cryoprecipitate transfusion was indicated in
patients with fibrinogen levels less than 100 mg/dL. Fresh frozen plasma was administered if the
coagulation times were two-fold higher the normal value range in patients with active bleeding or
after neurosurgery.
Colloid use policy: At the time of the study, the only synthetic colloid available at our institution was a new generation 6% HES 130/0.4 (Voluven¯). HES was administered at the discretion of the anesthesiologist during surgery. HES use on the ICU postoperative period is not part of our postoperative resuscitation protocol and is discouraged. Albumin was not used during the postoperative period of elective oncologic surgery.
Statistical analysis: Categorical and continuous data are presented as percentages and the mean ± SD (or median and 25%-75% interquartile range [IQR]), respectively. Categorical variables were compared using the Chi-square or Fisher exact test, as appropriate. Quantitative continuous variables were compared using an unpaired t test or Mann-Whitney test for parametric or nonparametric variables, respectively.
Patients were clustered according to the administration of HES during surgery. Because the use of
colloids was not randomized, there were two unbalanced groups (Table 1). Because this was a retrospective analysis (patients were not randomized), the
creation of a propensity score is an effective method to reduce bias. Propensity-matched analyses
are increasingly being used in research due to its ability to improve the power of retrospective and
prospective non-randomized analysis (1818. Brookhart MA, Schneeweiss S, Rothman KJ, Glynn RJ, Avorn J, Sturmer T. Variable
selection for propensity score models. Am J Epidemiol.
2006;163(12):1149-56.,1919. Gayat E, Pirracchio R, Resche-Rigon M, Mebazaa A, Mary JY, Porcher R. Propensity
scores in intensive care and anaesthesiology literature: a systematic review. Intensive Care Med.
2010;36(12):1993-2003, http://dx.doi.org/10.1007/s00134-010-1991-5.
http://dx.doi.org/10.1007/s00134-010-199...
). Propensity score has been defined as the “condition probability of being
treated given the covariates” (2020. D'Agostino RB, Jr. Propensity score methods for bias reduction in the comparison
of a treatment to a non-randomized control group. Stat Med. 1998;17(19):2265-81,
http://dx.doi.org/10.1002/(SICI)1097-0258(19981015)17:19<2265::AID-SIM918>3.0.CO;2-B.
http://dx.doi.org/10.1002/(SICI)1097-025...
). Propensity-matched
analyses are able to take into account as many variables related to the outcome evaluated as needed,
which reduces bias (2020. D'Agostino RB, Jr. Propensity score methods for bias reduction in the comparison
of a treatment to a non-randomized control group. Stat Med. 1998;17(19):2265-81,
http://dx.doi.org/10.1002/(SICI)1097-0258(19981015)17:19<2265::AID-SIM918>3.0.CO;2-B.
http://dx.doi.org/10.1002/(SICI)1097-025...
).
To construct the propensity score, a logistic regression was fitted, and variables were chosen
for inclusion according to the methods of Brookhart et al. (1818. Brookhart MA, Schneeweiss S, Rothman KJ, Glynn RJ, Avorn J, Sturmer T. Variable
selection for propensity score models. Am J Epidemiol.
2006;163(12):1149-56.). We included variables that could be related to the study outcomes based on the
propensity score. To identify the variables potentially associated with the outcome, a univariate
analysis was performed to evaluate potential variables related to blood transfusion during the
entire perioperative period (from the surgical procedure to up to 48 hours after surgery). The
variables included on the propensity score were as follows: age, gender, body-mass index, metastatic
disease, surgery length, volume of crystalloid infused and surgical sites. Although age and body
mass index were not associated with the outcome, we believed that they were important variables that
could alter the fluid dynamics during the surgical procedures and included them in the model (2121. Hahn RG. Volume kinetics for infusion fluids. Anesthesiology.
2010;113(2):470-81, http://dx.doi.org/10.1097/ALN.0b013e3181dcd88f.
http://dx.doi.org/10.1097/ALN.0b013e3181...
). The best caliper was 0.05, which was obtained by the Austin
method (2222. Austin PC. An Introduction to Propensity Score Methods for Reducing the Effects
of Confounding in Observational Studies. Multivariate Behav Res. 2011;46(3):399-424,
http://dx.doi.org/10.1080/00273171.2011.568786.
http://dx.doi.org/10.1080/00273171.2011....
). After the propensity score was created, the
patients were matched according to their respective propensity scores. As reported in the current
literature, matching on the propensity score has now been clearly demonstrated to be the best method
to attempt to provide an unbiased estimation of the treatment effect (1919. Gayat E, Pirracchio R, Resche-Rigon M, Mebazaa A, Mary JY, Porcher R. Propensity
scores in intensive care and anaesthesiology literature: a systematic review. Intensive Care Med.
2010;36(12):1993-2003, http://dx.doi.org/10.1007/s00134-010-1991-5.
http://dx.doi.org/10.1007/s00134-010-199...
). First, based on the crude analysis, we pre-defined a match considering one
patient without HES use to a maximum of three patients with HES use. The match procedure was
performed with an optimal matching method, and to avoid overinflation, we did not permit replacement
of matched patients. The number of patients analyzed using the propensity score was smaller than the
total number of patients studied because matching was not possible for all patients. Our analysis
was performed with fewer patients than the original study population. Even with fewer patients, an
analysis using the propensity score is more reliable than traditional statistical methods because
imbalance between groups is reduced (1818. Brookhart MA, Schneeweiss S, Rothman KJ, Glynn RJ, Avorn J, Sturmer T. Variable
selection for propensity score models. Am J Epidemiol.
2006;163(12):1149-56.,2323. Brookhart MA, Wang PS, Solomon DH, Schneeweiss S. Instrumental variable analysis
of secondary pharmacoepidemiologic data. Epidemiology. 2006;17(4):373-4,
http://dx.doi.org/10.1097/01.ede.0000222026.42077.ee.
http://dx.doi.org/10.1097/01.ede.0000222...
). The correct construction of the propensity score was performed with the
box-plot method. After the propensity score matches were performed, we performed a diagnostic to
ensure good balance in the matched population through the bias reduction method and the stabilized
standardized difference (because we were using 1:N matching instead of 1:1 matching) (1919. Gayat E, Pirracchio R, Resche-Rigon M, Mebazaa A, Mary JY, Porcher R. Propensity
scores in intensive care and anaesthesiology literature: a systematic review. Intensive Care Med.
2010;36(12):1993-2003, http://dx.doi.org/10.1007/s00134-010-1991-5.
http://dx.doi.org/10.1007/s00134-010-199...
,2222. Austin PC. An Introduction to Propensity Score Methods for Reducing the Effects
of Confounding in Observational Studies. Multivariate Behav Res. 2011;46(3):399-424,
http://dx.doi.org/10.1080/00273171.2011.568786.
http://dx.doi.org/10.1080/00273171.2011....
). After matching, the
groups were compared using conventional statistical tests.
We performed an additional analysis using “corrected total volume” (CTV) instead of crystalloid
volume as a variable in the propensity score (see Appendix). CTV was defined as total crystalloid
volume × 0.3 plus 1.4 × infused colloid volume (2121. Hahn RG. Volume kinetics for infusion fluids. Anesthesiology.
2010;113(2):470-81, http://dx.doi.org/10.1097/ALN.0b013e3181dcd88f.
http://dx.doi.org/10.1097/ALN.0b013e3181...
,2424. Perner A, Haase N, Guttormsen AB, Tenhunen J, Klemenzson G, Aneman A, et al.
Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis. N Engl J Med.
2012;367(2):124-34.,2525. Bellmann R, Feistritzer C, Wiedermann CJ. Effect of molecular weight and
substitution on tissue uptake of hydroxyethyl starch: a meta-analysis of clinical studies. Clin
Pharmacokinet. 2012;51(4):225-36,
http://dx.doi.org/10.2165/11594700-000000000-00000.
http://dx.doi.org/10.2165/11594700-00000...
). This alternative
analysis was conducted to balance the effective volume used for expansion in both groups (see
Appendix for details). All the statistical analysis were performed in SPSS 19.0, and a
p-value of 0.05 for was considered significant for all comparisons.
RESULTS
We included 894 patients; 614 received HES, and 280 received only crystalloids during surgery.
Before the use of the propensity score, the patients in the HES group had longer surgical times, had
received more crystalloids, were younger and were less likely to have any comorbidity compared with
the No-HES group (Table 1). There were also differences
regarding the surgery site between groups. After the creation of the matched groups, 385
propensity-matched patients (97 in the crystalloids group and 288 in the HES group) were analyzed.
Patients in the paired groups had similar baseline characteristics (Table 1). The median volume of infused HES was 1 L [0.5-1.0]. No patient received less
than 0.5 L. Creatinine values were similar for both groups in all the observation periods. The
incidence of acute kidney injury (AKI) (defined according to the RIFLE criteria of risk, i.e., an
increase of serum creatinine of 50% or more over the baseline) (2626. Abosaif NY, Tolba YA, Heap M, Russell J, El Nahas AM. The outcome of acute renal
failure in the intensive care unit according to RIFLE: model application, sensitivity, and
predictability. Am J Kidney Dis. 2005;46(6):1038-48,
http://dx.doi.org/10.1053/j.ajkd.2005.08.033.
http://dx.doi.org/10.1053/j.ajkd.2005.08...
,2727. Prowle JR, Liu YL, Licari E, Bagshaw SM, Egi M, Haase M, et al. Oliguria as
predictive biomarker of acute kidney injury in critically ill patients. Crit Care. 2011;15(4):R172,
http://dx.doi.org/10.1186/cc10318.
http://dx.doi.org/10.1186/cc10318...
) was similar between the groups (7% versus 7%,
p>0.99). More detailed results regarding the other propensity matched analysis (using CTV), standard
logistic regression and non-propensity matched results analysis can be found in the Appendix.
Red blood cells and other blood products transfusions: The variables related to transfusion of red blood cell pack transfusion for all the perioperative transfusions are shown in Table 2). Most patients in both groups did not require blood products transfusion. In the HES group, a higher percentage of patients received red blood cell transfusion in the intraoperative and 24-hour postoperative period, but the percentage was similar for the 24- to 48-hour postoperative period (Figure 1). For the patients in both groups that received red blood cell transfusions, the number of packs per patient was higher in the HES group during the intraoperative period (0.55 versus 0.39; p = 0.028). No patient in the No-HES group received a blood transfusion after surgery. There was no difference regarding the use of fresh frozen plasma, cryoprecipitate and platelets concentrate in any period.
The patients that received HES had a small but statistically significant lower hemoglobin level at ICU admission (11.2±1.9 versus 12.0±1.7; p<0.001) but not at the 24-hour (11.1±1.8 versus 11.3±1.6; p = 0.11) and 48-hour (10.2±1.7 versus 10.2±1.5; p = 0.20) postoperative periods.
The transfusion rate was similar between the groups when we employed the propensity analysis that included CTV (Additional Table 2). The results of the non-propensity analysis (see Appendix, Additional Table 3 and 4) showed that red blood cell transfusion was more frequent in the HES patients. The multivariate analysis showed that the factors associated with red blood cell transfusion in the perioperative period included age, metastatic disease, total operative time, crystalloid volume used and colloid use (any dose). Thoracic and head and neck surgery were protective factors against transfusion (see Additional Table 5).
Secondary objectives: Patients in the HES group showed lower levels of platelets at ICU admission compared to the No-HES group (Table 3). The international normalized ratio (INR) was also higher in the HES patients at ICU admission and in the first 24 hours after surgery (Table 3). Table 4 shows the coagulation values for transfused and non-transfused patients in both groups (No-HES and HES). The INR was higher in transfused No-HES patients than in non-transfused No-HES patients. The INR was also higher in the transfused HES patients than the non-transfused HES patients at ICU admission. There were no differences between transfused patients in the HES and No-HES groups regarding platelet count or INR at any period studied. Non-transfused HES patients also had a higher INR than non-transfused No-HES patients.
ICU mortality and length of stay were similar between HES and No-HES groups (Table 3).
DISCUSSION
In this retrospective analysis using a propensity-matched cohort of surgical patients, HES use was associated with more frequent red blood cells transfusions during major oncologic surgery and in the first 24 hours after the procedure. ICU length of stay and mortality were the same for both groups.
There is an intense debate involving HES use in critically ill patients. HES are considered more
efficient volume expanders than crystalloids; i.e., less volume is needed to obtain the same
hemodynamic effect (2828. Verheij J, van Lingen A, Beishuizen A, Christiaans HM, de Jong JR, Girbes AR, et
al. Cardiac response is greater for colloid than saline fluid loading after cardiac or vascular
surgery. Intensive Care Med. 2006;32(7):1030-8,
http://dx.doi.org/10.1007/s00134-006-0195-5.
http://dx.doi.org/10.1007/s00134-006-019...
,2929. Trof RJ, Sukul SP, Twisk JW, Girbes AR, Groeneveld AB. Greater cardiac response
of colloid than saline fluid loading in septic and non-septic critically ill patients with clinical
hypovolaemia. Intensive Care Med. 2010;36(4):697-701,
http://dx.doi.org/10.1007/s00134-010-1776-x.
http://dx.doi.org/10.1007/s00134-010-177...
). A recent randomized controlled trial suggested that patients with penetrating trauma
required less total volume when resuscitated by HES compared with saline; there was no difference,
however, in patients with blunt trauma (3030. James MF, Michell WL, Joubert IA, Nicol AJ, Navsaria PH, Gillespie RS.
Resuscitation with hydroxyethyl starch improves renal function and lactate clearance in penetrating
trauma in a randomized controlled study: the FIRST trial (Fluids in Resuscitation of Severe Trauma).
Br J Anaesth. 2011;107(5):693-702.). A recently
published trial in septic patients suggested that less fluid was needed to reach hemodynamic
stability in patients resuscitated with HES (3131. Guidet B, Martinet O, Boulain T, Philippart F, Poussel JF, Maizel J, et al.
Assessment of hemodynamic efficacy and safety of 6% hydroxyethylstarch 130/0.4 vs. 0.9% NaCl fluid
replacement in patients with severe sepsis: The CRYSTMAS study. Crit Care. 2012
24;16(3):R94.). A larger
multicenter randomized trial has shown no difference regarding the total fluid need in septic
patients (2424. Perner A, Haase N, Guttormsen AB, Tenhunen J, Klemenzson G, Aneman A, et al.
Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis. N Engl J Med.
2012;367(2):124-34.). The need for less fluid to obtain the same
hemodynamic effect would be particularly interesting during the intraoperative period, when
hemodynamic optimization associated with less total fluid volume may be beneficial (3232. Lobo SM, Ronchi LS, Oliveira NE, Brandao PG, Froes A, Cunrath GS, et al.
Restrictive strategy of intraoperative fluid maintenance during optimization of oxygen delivery
decreases major complications after high-risk surgery. Crit Care. 2011;15(5):R226,
http://dx.doi.org/10.1186/cc10466.
http://dx.doi.org/10.1186/cc10466...
).
HES and other colloids are not related to any robust positive clinical outcome, such as mortality
or reduced ICU length of stay (3333. Perel P, Roberts I. Colloids versus crystalloids for fluid resuscitation in
critically ill patients. Cochrane Database Syst Rev. 2011(3):CD000567.). In the recently published
6S Trial, septic patients that were randomized to fluid resuscitation with HES had higher mortality,
suggesting that at least in this specific population, HES use should be strongly discouraged (2424. Perner A, Haase N, Guttormsen AB, Tenhunen J, Klemenzson G, Aneman A, et al.
Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis. N Engl J Med.
2012;367(2):124-34.). The doubtful greater efficiency of HES may be counteracted by
significant side effects, including coagulation abnormalities and AKI (1313. Hartog CS, Kohl M, Reinhart K. A systematic review of third-generation
hydroxyethyl starch (HES 130/0.4) in resuscitation: safety not adequately addressed. Anesth Analg.
2011;112(3):635-45, http://dx.doi.org/10.1213/ANE.0b013e31820ad607.
http://dx.doi.org/10.1213/ANE.0b013e3182...
). The impact of these side effects on outcome, especially for HES 6% 130/0.4, is
largely unknown (44. Gattas DJ, Dan A, Myburgh J, Billot L, Lo S, Finfer S, et al. Fluid resuscitation
with 6% hydroxyethyl starch (130/0.4) in acutely ill patients: an updated systematic review and
meta-analysis. Anesth Analg. 2012;114(1):159-69,
http://dx.doi.org/10.1213/ANE.0b013e318236b4d6.
http://dx.doi.org/10.1213/ANE.0b013e3182...
).
Oncologic patients may have coagulation abnormalities related to their illness and chemotherapy
side effects (3434. Kvolik S, Jukic M, Matijevic M, Marjanovic K, Glavas-Obrovac L. An overview of
coagulation disorders in cancer patients. Surg Oncol. 2010;19(1):e33-46,
http://dx.doi.org/10.1016/j.suronc.2009.03.008.
http://dx.doi.org/10.1016/j.suronc.2009....
). We aimed to evaluate the effects of HES on
the perioperative need for blood transfusion in this specific population. This outcome is important
because blood transfusion may be associated with worse outcome after oncologic surgery, including
long-term survival (3535. Perisanidis C, Dettke M, Papadogeorgakis N, Schoppmann A, Mittlbock M, Kyzas PA,
et al. Transfusion of allogenic leukocyte-depleted packed red blood cells is associated with
postoperative morbidity in patients undergoing oral and oropharyngeal cancer surgery. Oral Oncol.
2012;48(4):372-8, http://dx.doi.org/10.1016/j.oraloncology.2011.11.020.
http://dx.doi.org/10.1016/j.oraloncology...
36. Komatsu Y, Orita H, Sakurada M, Maekawa H, Hoppo T, Sato K. Intraoperative blood
transfusion contributes to decreased long-term survival of patients with esophageal cancer.
World J Surg. 2012;36(4):844-50.
37. Ng T, Ryder BA, Chern H, Sellke FW, Machan JT, Harrington DT, et al.
Leukocyte-depleted blood transfusion is associated with decreased survival in resected early-stage
lung cancer. J Thorac Cardiovasc Surg. 2012;143(4):815-9,
http://dx.doi.org/10.1016/j.jtcvs.2011.12.031.
http://dx.doi.org/10.1016/j.jtcvs.2011.1...
-3838. Rzyman W, Dziadziuszko R, Skokowski J, Wilimski R, Raiter A, Szymanowska A, et
al. The influence of blood transfusion on survival in operated non-small cell lung cancer patients.
J Thorac Cardiovasc Surg. 2003;126(3):755-60,
http://dx.doi.org/10.1016/S0022-5223(03)00217-4.
http://dx.doi.org/10.1016/S0022-5223(03)...
). Blood transfusion is not harmless and has been associated with several clinical side
effects, including transfusion related acute lung injury and fluid overload (3939. Hayden SJ, Albert TJ, Watkins TR, Swenson ER. Anemia in Critical Illness:
Insights into Etiology, Consequences and Management. Am J Respir Crit Care Med.
2012;185(10):1049-57, http://dx.doi.org/10.1164/rccm.201110-1915CI.
http://dx.doi.org/10.1164/rccm.201110-19...
). In critically ill patients, blood transfusion is associated with poorer
outcomes (3939. Hayden SJ, Albert TJ, Watkins TR, Swenson ER. Anemia in Critical Illness:
Insights into Etiology, Consequences and Management. Am J Respir Crit Care Med.
2012;185(10):1049-57, http://dx.doi.org/10.1164/rccm.201110-1915CI.
http://dx.doi.org/10.1164/rccm.201110-19...
).
Our propensity-matched data showed that HES use is independently related to a greater need for red blood cell transfusion in the perioperative period. As previously reported, even low doses of HES could result in coagulation abnormalities (1414. Schramko A, Suojaranta-Ylinen R, Kuitunen A, Raivio P, Kukkonen S, Niemi T. Hydroxyethylstarch and gelatin solutions impair blood coagulation after cardiac surgery: a prospective randomized trial. Br J Anaesth. 2010;104(6):691-7.). In addition to requiring more red blood cell transfusions, HES patients also had lower hemoglobin levels at ICU admission, suggesting that the difference was not only due to over transfusion of the HES group. Corroborating with our results, other studies have shown a higher need for blood products in critically ill patients who received HES (2424. Perner A, Haase N, Guttormsen AB, Tenhunen J, Klemenzson G, Aneman A, et al. Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis. N Engl J Med. 2012;367(2):124-34.,4040. Brunkhorst FM, Engel C, Bloos F, Meier-Hellmann A, Ragaller M, Weiler N, et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med. 2008;358(2):125-39.). Patients with blunt trauma resuscitated with HES required more blood transfusions than patients who received saline, although this conclusion is likely confounded by a higher injury severity in the HES-resuscitated patients (3030. James MF, Michell WL, Joubert IA, Nicol AJ, Navsaria PH, Gillespie RS. Resuscitation with hydroxyethyl starch improves renal function and lactate clearance in penetrating trauma in a randomized controlled study: the FIRST trial (Fluids in Resuscitation of Severe Trauma). Br J Anaesth. 2011;107(5):693-702.). Our standard multivariate analysis showed that colloid use was a risk factor for the perioperative need for red blood cell transfusion. When we performed the CTV analysis, both groups had similar transfusion rates. Nevertheless, because this analysis included fewer patients (with only 41 patients in the No-HES group - see Appendix), it is possible that the smaller sample reduced the power of the study to detect any difference.
It can be argued that because the use of HES is associated with a greater degree of plasma volume
expansion, and considering that the two groups were paired to the crystalloid volume infused, our
findings may be related only to the increased hemodilution caused by HES use (4141. Dubniks M, Persson J, Grande PO. Plasma volume expansion of 5% albumin, 4%
gelatin, 6% HES 130/0.4, and normal saline under increased microvascular permeability in the rat.
Intensive Care Med. 2007;33(2):293-9, http://dx.doi.org/10.1007/s00134-006-0454-5.
http://dx.doi.org/10.1007/s00134-006-045...
). The increase in the frequency of red blood cell pack transfusions in the HES
group in the main propensity analysis might to some degree be related to the expansion effect of HES
and not to its impact on blood coagulation. The lack of difference in the CTV analysis corroborates
this hypothesis. It should be stated that the effectiveness of HES as a dilutional agent appears to
be reduced after major injury (4242. Persson J, Grande PO. Plasma volume expansion and transcapillary fluid exchange
in skeletal muscle of albumin, dextran, gelatin, hydroxyethyl starch, and saline after trauma in the
cat. Crit Care Med. 2006;34(9):2456-62,
http://dx.doi.org/10.1097/01.CCM.0000233876.87978.AB.
http://dx.doi.org/10.1097/01.CCM.0000233...
) and that our patients also
used a small volume of starch that was below the suggested maximum daily dose of 50 mL/kg.
There were small differences in the coagulation profile between the HES and No-HES groups. Those differences are likely without clinical significance because the values were very similar between the groups (Table 3). There were no differences in the coagulation profile (including the INR and platelet count) between the transfused patients in both groups (Table 4). The higher need for transfusions cannot be explained by the differences in coagulation features after surgery.
In our multivariate analysis, thoracic surgery was a protector factor against transfusion. It may be speculated that because restrictive fluid therapy is frequently used in thoracic surgery (4343. Doherty M, Buggy DJ. Intraoperative fluids: how much is too much? Br J Anaesth. 2012;109(1):69-79.), patients received less fluid, with less hemodilution and bleeding related to dilutional coagulopathy, and therefore required less red blood cell transfusion.
The ICU length of stay and mortality were similar between groups, but our analysis was likely underpowered to detect a significant difference in a population with low mortality (below 2%) and short ICU length of stay (one day of median ICU stay). In the univariate analysis, ICU length of stay was higher in the HES group than in the No-HES group (Additional Table 6).
There are several limitations in our analysis. First, this study has a single-center retrospective analysis design. Second, the propensity score analysis was unable to match for unmeasured variables. Third, due to its retrospective nature, we were unable to control for personal preferences variables regarding red blood cell transfusion and specific tumor staging (which could be related to technical difficulties during the surgical procedure), although we included metastatic disease in the propensity score. Fourth, although our hospital has strict policies for transfusion and perioperative fluid therapy, we cannot guarantee that these protocols were followed in all of the patients analyzed. Triggers for transfusion were also unavailable for analysis. Fifth, our study was underpowered to evaluate the ICU length of stay and mortality.
Our finding that HES use is associated with a greater need for blood transfusion is biologically
plausible and has been reported in other clinical scenarios (2424. Perner A, Haase N, Guttormsen AB, Tenhunen J, Klemenzson G, Aneman A, et al.
Hydroxyethyl starch 130/0.42 versus Ringer's acetate in severe sepsis. N Engl J Med.
2012;367(2):124-34.,4040. Brunkhorst FM, Engel C, Bloos F, Meier-Hellmann A, Ragaller M, Weiler N, et al.
Intensive insulin therapy and pentastarch resuscitation in severe sepsis.
N Engl J Med. 2008;358(2):125-39.). If these findings are confirmed in large,
prospective studies, HES use should be questioned in the subjects undergoing elective oncologic
surgery due to its unproven clinically efficacy over crystalloids (44. Gattas DJ, Dan A, Myburgh J, Billot L, Lo S, Finfer S, et al. Fluid resuscitation
with 6% hydroxyethyl starch (130/0.4) in acutely ill patients: an updated systematic review and
meta-analysis. Anesth Analg. 2012;114(1):159-69,
http://dx.doi.org/10.1213/ANE.0b013e318236b4d6.
http://dx.doi.org/10.1213/ANE.0b013e3182...
,1313. Hartog CS, Kohl M, Reinhart K. A systematic review of third-generation
hydroxyethyl starch (HES 130/0.4) in resuscitation: safety not adequately addressed. Anesth Analg.
2011;112(3):635-45, http://dx.doi.org/10.1213/ANE.0b013e31820ad607.
http://dx.doi.org/10.1213/ANE.0b013e3182...
). The surgical procedures on oncologic patients
have specific aspects that need further study.
The intraoperative use of HES 6% 130/0.4 during major elective oncologic surgery is associated with an increase in red blood cell transfusions in the perioperative period of major oncologic surgery. There were no differences in ICU length of stay and mortality. Further randomized clinical trials in this specific population are urgently needed.
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31Guidet B, Martinet O, Boulain T, Philippart F, Poussel JF, Maizel J, et al. Assessment of hemodynamic efficacy and safety of 6% hydroxyethylstarch 130/0.4 vs. 0.9% NaCl fluid replacement in patients with severe sepsis: The CRYSTMAS study. Crit Care. 2012 24;16(3):R94.
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32Lobo SM, Ronchi LS, Oliveira NE, Brandao PG, Froes A, Cunrath GS, et al. Restrictive strategy of intraoperative fluid maintenance during optimization of oxygen delivery decreases major complications after high-risk surgery. Crit Care. 2011;15(5):R226, http://dx.doi.org/10.1186/cc10466.
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35Perisanidis C, Dettke M, Papadogeorgakis N, Schoppmann A, Mittlbock M, Kyzas PA, et al. Transfusion of allogenic leukocyte-depleted packed red blood cells is associated with postoperative morbidity in patients undergoing oral and oropharyngeal cancer surgery. Oral Oncol. 2012;48(4):372-8, http://dx.doi.org/10.1016/j.oraloncology.2011.11.020.
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37Ng T, Ryder BA, Chern H, Sellke FW, Machan JT, Harrington DT, et al. Leukocyte-depleted blood transfusion is associated with decreased survival in resected early-stage lung cancer. J Thorac Cardiovasc Surg. 2012;143(4):815-9, http://dx.doi.org/10.1016/j.jtcvs.2011.12.031.
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40Brunkhorst FM, Engel C, Bloos F, Meier-Hellmann A, Ragaller M, Weiler N, et al. Intensive insulin therapy and pentastarch resuscitation in severe sepsis. N Engl J Med. 2008;358(2):125-39.
-
41Dubniks M, Persson J, Grande PO. Plasma volume expansion of 5% albumin, 4% gelatin, 6% HES 130/0.4, and normal saline under increased microvascular permeability in the rat. Intensive Care Med. 2007;33(2):293-9, http://dx.doi.org/10.1007/s00134-006-0454-5.
» http://dx.doi.org/10.1007/s00134-006-0454-5 -
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APPENDIX
Results of propensity score using corrected total volume and the results of standard multivariate analysisImpact of intraoperative HES 6% 130/0.4 on the need for blood transfusion after major oncologic surgery: A propensity-matched analysis
Corrected total volume (CTV) analysis
Our propensity score analysis using CTV instead of infused crystalloid volume resulted in 97
patients in the No-HES group and 162 patients in the HES group. The major difference between this
analysis and the previous analysis was the use of the corrected total volume (CTV) as a variable
instead of the volume of infused crystalloid. We sought to minimize the role of hemodilution as a
trigger to transfusion; i.e., the propensity-matched patients in this analysis would have received
the same amount of plasma expansion. Because the expansion effects of colloids are different from
crystalloids, we created a variable that would account for the corrected amount of fluid expansion
received (CTV). We defined the CTV in patients in the No-HES group as equivalent to the crystalloid
volume infused multiplied by 0.3 11. Westphal M, James MF, Kozek-Langenecker S, Stocker R, Guidet B, Van Aken H.
Hydroxyethyl starches: different products-different effects. Anesthesiology. 2009;111(1):187-202,
http://dx.doi.org/10.1097/ALN.0b013e3181a7ec82.
http://dx.doi.org/10.1097/ALN.0b013e3181...
. The CTV in the HES group
was defined as the sum of the crystalloid volume multiplied by 0.3 plus the volume of HES multiplied
by 1.4 (CTV = [crystalloid volume × 0.3] + [1.4 × colloid
volume]). The use of the 1.4 ratio aimed at accounting for the theoretical greater expansion effects
of the colloids 23. Corcoran T, Emma Joy Rhodes J, Clarke S, Myles PS, Ho KM. Perioperative fluid
management strategies in major surgery: a stratified meta-analysis. Anesth Analg.
2012;114(3):640-51, http://dx.doi.org/10.1213/ANE.0b013e318240d6eb.
http://dx.doi.org/10.1213/ANE.0b013e3182...
,33. Corcoran T, Emma Joy Rhodes J, Clarke S, Myles PS, Ho KM. Perioperative fluid
management strategies in major surgery: a stratified meta-analysis. Anesth Analg.
2012;114(3):640-51, http://dx.doi.org/10.1213/ANE.0b013e318240d6eb.
http://dx.doi.org/10.1213/ANE.0b013e3182...
.
This alternative propensity analysis included 41 patients in the No-HES group and 118 patients in the HES group (Additional Table 1). There was no difference in the need for red blood cell transfusion between the groups when this analysis was performed (Additional Table 2). The international normalized ration (INR) was higher at ICU admission in the HES group, but the other coagulation variables were similar (Additional Table 3).
Study results of standard analysis
The second approach was a standard multivariate logistic regression. The stepwise backward method was used to determine the factors associated with red blood cell transfusion in the perioperative time. The initial model consisted of all of the independent variables that had a p value of less than 0.25 in the bivariate analysis associated with red cell blood transfusion or between the HES and non-HES groups in the 894 patients (the Hosmer-Lemeshow logistic regression). The variables were removed one at a time if they did not contribute to the model assessed according to a likelihood ratio test (p < 0.050). The continuous variables were checked for the assumption of linearity in the logit. Single colinearity was evaluated with Pearson's correlation between the independent variables, and multi-colinearity was evaluated with the variance inflation factor. The odds-ratios and corresponding 95% confidence intervals for each variable were computed. The discriminative ability of the model to predict the outcome of patients was assessed by the area under the receiver operating characteristic (AUC) curve. The calibration ability for the model was evaluated with Hosmer-Lemeshow goodness-of-fit statistics.
The major outcomes regarding the need for blood transfusion on crude analysis are displayed in Additional Table 4. The major difference between propensity-matched versus standard analysis was that before matching, the need for blood products other than red blood cell packs was more common in the HES patients. The HES patients in the unmatched analysis received fresh frozen plasma during surgery more frequently than the No-HES patients. The need for cryoprecipitate was also more frequent in the HES patients in the first 24 hours after the procedure.
A multivariate analysis was performed to evaluate the risk factors for red blood cell transfusion from the intraoperative period up to 48 hours after the procedure (Additional Table 5). The factors associated with the red blood cell transfusions included age, metastatic disease, volume of crystalloid used, total operative time and use of any dose of HES. These factors may only highlight that patients that received blood transfusion were subject to more aggressive and/or technically difficult surgeries. Head and neck and thoracic surgery were protectors against transfusion.
The ICU length of stay was higher in the HES group (Additional Table 6).
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No potential conflict of interest was reported.
Publication Dates
-
Publication in this collection
Apr 2013
History
-
Received
14 Oct 2012 -
Reviewed
12 Nov 2012 -
Accepted
21 Dec 2012