JOURNAL HOME CME HOME THIS MONTH PAST ISSUES ETOC COLLECTIONS
AUTHORS REVIEWERS EDITORIAL BOARD FEEDBACK RSS HELP
A&A International Anesthesia Research Society
QUICK SEARCH:   [advanced]


     

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (5)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Scharbert, G.
Right arrow Articles by Kozek-Langenecker, S. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Scharbert, G.
Right arrow Articles by Kozek-Langenecker, S. A.
Related Collections
Right arrow Blood
Right arrow Regional Anesthesia
Right arrow Pain

Anesth Analg 2004;99:823-827
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000131973.99804.61

PAIN MEDICINE

Inhibition of Platelet Function by Hydroxyethyl Starch Solutions in Chronic Pain Patients Undergoing Peridural Anesthesia

Gisela Scharbert, MD, Engelbert Deusch, MD, Hans Georg Kress, MD PhD, Manfred Greher, MD, Burkhard Gustorff, MD, and Sibylle A. Kozek-Langenecker, MD

Department of Anesthesiology and Intensive Care (B), University of Vienna, Austria

Address correspondence and reprint requests Sibylle A. Kozek-Langenecker, MD, Department of Anesthesiology and Intensive Care, University of Vienna, Währinger Gürtel 18–20, 1090-Vienna, Austria. Address e-mail to sibylle.kozek{at}univie.ac.at


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
The use of hydroxyethyl starch (HES) solutions as a fluid replacement before peridural blockade may compromise blood coagulation, thus increasing the risk of neuraxial bleeding. In this prospective, double-blind, placebo-controlled, crossover study, we compared the influence of HES 130 (molecular weight in kilodalton), HES 200, and lactated Ringer’s solution on platelet function and hemodynamics in chronic low back pain patients scheduled for peridural blockades. Patients received 3 test infusions of 10 mL/kg each administered IV for 30 min. Collagen/epinephrine and collagen/adenosine diphosphate were used as agonists for assessment of platelet function analyzer-closure times. Arterial blood pressure, heart rate, platelet counts, and hemoglobin levels were documented. Platelet function analyzer-closure times remained stable after lactated Ringer’s solution but were significantly prolonged after HES. The platelet-inhibiting effect of HES 200 was more than that of HES 130. Hemodynamic stability was sufficiently maintained by all test infusions. In contrast to previous observations, a relevant antiplatelet effect of both low and medium molecular weight HES solutions was found in this study in chronic pain patients undergoing peridural anesthesia. Because hemostasiological competence is a prerequisite for safe neuraxial blockade, the decision of HES for intravascular fluid administration before blockade should be critically made.

IMPLICATIONS: Crystalloids and hydroxyethyl starch (HES) solutions are widely used for fluid replacement in patients undergoing peridural anesthesia. We found a relevant antiplatelet effect of HES. Because hemostasiological competence is a prerequisite for safe neuraxial blockade, the decision of HES for fluid administration before blockade should be critically made.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Peridural anesthesia may induce systemic hypotension by sympathetic blockade. To maintain hemodynamic stability, crystalloids or colloidal solutions are routinely administered before the performance of a neuraxial blockade. Hydroxyethyl starch (HES) solutions are widely used for intravascular volume expansion but may compromise platelet function as measured by the platelet function analyzer (PFA) (1,2), platelet aggregometry (3,4), thromboelastography (5), and flow cytometry (1,2). Our previous studies have shown that the higher the molecular weight and the degree of substitution, the more a particular HES solution is likely to impair platelet function (2,5). The mechanism of HES-induced platelet inhibition involves a decrease in platelet-linking properties of von Willebrand factor (6,7), a decrease in fibrinogen levels (8) and thrombin generation (9), and a reduced availability of the functional receptor for fibrinogen on the platelet surface (glycoprotein IIb-IIIa) (1,2). Crystalloids are considered to not affect platelet function but to maintain hemodynamic stability less effectively than colloids.

Hemostasiological competence is critical in patients undergoing neuraxial blockade because peridural or intrathecal bleeding may lead to rare, but disastrous, neurological complications. The impact of antiplatelet drugs on the safety of loco-regional anesthesia is an issue of debate (10), and guidelines for the management of neuraxial blockades in patients receiving antiplatelet drugs have recently been established (11). Ideally, fluid resuscitation before neuraxial blockade should maintain hemodynamic stability without affecting platelet function. The aim of the present prospective, double-blind, placebo-controlled, crossover study was to compare these two safety issues between a crystalloidal solution (lactated Ringer’s solution) and two colloidal solutions (low and medium molecular weight HES) in chronic low back pain patients scheduled for elective peridural blockade.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Forty adult patients with chronic low back pain scheduled for peridural blockades were included in a prospective, double-blind, placebo-controlled, crossover study. The study was approved by the IRB, and written informed consent was obtained from all participants.

Patients fasted for 10 h and received no premedication. All patients were using oral chronic pain medication consisting of opioids, antidepressants, or anticonvulsant drugs. All patients denied the use of any medication known to alter platelet function within the previous 14 days. Nonsteroidal antiinflammatory drugs were replaced by a selective cyclooxygenase-2 inhibitor (rofecoxib 25 mg once daily) 14 days before the study to exclude platelet inhibition by unselective cyclooxygenase-1 inhibitors (12).

Every patient received 3 test infusions of 10 mL/kg of lactated Ringer’s solution, HES 130/0.38–0.45 (molecular weight in kilodalton/degree of substitution (HES 130; Voluven® 6%; Fresenius Pharma Austria GmbH, Austria), and HES 200/0.6–0.66 (HES 200; Elohäst® 6%, Fresenius Pharma Austria GmbH) administered IV for 30 min. All HES preparations are approved and commercially available in Europe in a 6% solution diluted in 0.9% saline. The sequence of the IV test infusion was randomly assigned using computer-generated random tables. The study infusions were administered before the performance of the peridural anesthesia with 10 mL of ropivacaine 0.2% performed once a week. Although a solid foundation for the effectiveness is lacking (13,14), there is the tendency towards positive results favoring peridural injections in a meta-analysis (13). According to our university outpatient pain center’s standard protocol, we performed repeated peridural blockades once a week in patients with chronic lumbar disk syndrome (herniated disk) without an indication for surgery, failed back surgery syndrome, or lumbar bone abnormalities (spondylosis, spondylolisthesis, and spinal stenosis).

Before and after the infusion, blood was sampled into VacuetteTM tubes (Greiner, Kremsmünster, Austria) containing 3.8% trisodium citrate (9:1 vol/vol) from an antecubital vein by venipuncture without stasis using a 21-gauge butterfly needle. The first 3 mL were always discarded. Citrate was used as an anticoagulant because of its negligible intrinsic effects on platelets (15). All samples were processed within 3 min, and the following measurements were performed on duplicate samples. For assessment of PFA-closure times, 800 µL of blood was analyzed by using the PFA-100® (Dade, Miami, FL) with collagen/epinephrine and collagen/adenosine diphosphate (ADP) as agonists. The principle of the PFA-100® is very similar to that described by Kratzer and Born (16). The blood sample is aspirated through a capillary with a coated membrane and passes through an aperture. In response to the stimulation by collagen and epinephrine or ADP present in the coating and the shear stresses at the aperture, platelets adhere and aggregate on the collagen surface. The platelet plug ultimately occludes the aperture. The time required to obtain full occlusion of the aperture is defined as the PFA-closure time (normal range, epinephrine-induced PFA-closure times 85–165 s; ADP-induced PFA-closure times, 71–118 s).

Noninvasive arterial blood pressure and heart rate were documented in 1-min intervals. Platelet counts and hemoglobin concentration were determined before and after study infusion. Data were tested for normal distribution using the Kolmogorov-Smirnov test. The effect of IV study infusion on platelet function was analyzed by using analysis of variance for repeated measures. Post hoc comparisons were made by a paired t-test. The level of significance was adjusted according to Bonferroni correction. Data were expressed as mean ± SD if not otherwise indicated. P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Forty-three patients at the mean age of 50 ± 12 yr, with a mean weight of 77.7 ± 17.7 kg and a mean height of 169 ± 8 cm, were included. Three patients had to be excluded from the study because of study protocol violations (ingestion of nonselective cyclooxygenase inhibitors). All patients received a selective cyclooxygenase-2 inhibitor, rofecoxib, for chronic pain therapy in combination with either weak opioids (n = 8), potent opioids (n = 1), antidepressant drugs (n = 3), weak opioids and antidepressant drugs (n = 18), potent opioids and antidepressant drugs (n = 5), or opioids and anticonvulsant drugs (n = 5). The test infusion consisted of 10 mL/kg of each administered IV for 30 min. The degree of hemodilution was 5% and 7% after lactated Ringer’s solution, 11% and 12% after HES 130, and 12% and 10% after HES 200, as measured by the decrease in hemoglobin concentration and in platelet counts, respectively. Spread of the sensory blockade induced by peridural anesthesia with 10 mL of ropivacaine 0.2% was comparable after each test infusion (T8-12).

The effect of IV test infusion on PFA-closure times is shown in Figure 1. Baseline mean PFA-closure times were within the normal range before each test infusion. The IV infusion of lactated Ringer’s solution had no significant effect on PFA-closure times. Infusion of both HES 130 and HES 200 prolonged PFA-closure times when compared with preinfusion values (P < 0.05). The infusion of HES 200 prolonged both ADP- and epinephrine-induced PFA-closure times when compared with lactated Ringer’s solution and preinfusion values (P < 0.05) and prolonged ADP-induced PFA-closure times when compared with HES 130 (P < 0.05). Forty-five percent of samples exceeded the upper level of the normal range of epinephrine-induced PFA-closure times after the infusion of HES 200.



View larger version (28K):
[in this window]
[in a new window]
  		Figure 1. Effects of IV test infusion (10 mL/kg) of either lactated Ringer’s solution, hydroxyethyl starch (HES) 130 (mean molecular weight in kilodalton), or HES 200 on platelet function analyzed (PFA)-closure times using either epinephrine or adenosine diphosphate (ADP) as agonists. The IV infusion of lactated Ringer’s solution had no significant effect on PFA-closure times. The infusion of HES 130 prolonged PFA-closure times when compared with preinfusion value. The infusion of HES 200 prolonged both ADP- and epinephrine-induced PFA-closure times when compared with lactated Ringer’s solution and preinfusion values and prolonged ADP-induced PFA-closure times when compared with HES 130. Results are given as mean ± SD. P < 0.05 is significant versus *pre, **pre and Ringer, and #HES 130; lines = limits of normal range.

 
The effect of IV test infusion on arterial blood pressure is shown in Figure 2. Arterial blood pressure values were within the normal range throughout the entire study period. Systolic, mean, and diastolic blood pressure decreased significantly after all test infusions when compared with preinfusion values lasting for 30 min after peridural injection of ropivacaine. At the time points 20 and 45 min, the difference in systolic blood pressure between HES 130 and lactated Ringer’s solution was statistically significant (P < 0.05). At the time point 20 min, the difference in mean arterial blood pressure between HES 200 and the other groups was statistically significant (P < 0.05). There were no significant differences in diastolic blood pressure among the three crossover treatments.



View larger version (20K):
[in this window]
[in a new window]
  		Figure 2. Effects of IV test infusion (10 mL/kg) of either lactated Ringer’s solution, hydroxyethyl starch (HES) 130 (mean molecular weight in kilodalton), or HES 200 on arterial blood pressure using an automated noninvasive monitoring. Systolic, mean, and diastolic blood pressures decreased significantly in all test infusion groups when compared with preinfusion values lasting for 30 min after the peridural injection of ropivacaine. At indicated time points, the difference in systolic blood pressure between HES 130 and lactated Ringer’s solution and the difference in mean arterial blood pressure between HES 200 and other groups were statistically significant. Pre = baseline values before test infusion; 0 min = immediately after test infusion; 5 to 120 min = minutes after performance of peridural blockade using 10 mL of ropivacaine 0.2%. Results are given as mean ± SEM. P < 0.05 at *Ringer versus HES 130 and #HES 200 versus other test infusions.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
In this study, the effect of various HES solutions and lactated Ringer’s solution on platelet reactivity was determined by assessing PFA-closure times as an on-site index of platelet function (17). Results presented in Figure 1 demonstrate that in contrast to lactated Ringer’s solution, medium and low molecular weight HES solutions at a clinically the relevant volume of 10 mL/kg prolonged both epinephrine- and ADP-induced PFA-closure times after IV infusion for 30 min in patients with chronic low back pain scheduled for an elective peridural blockade. In agreement with previous studies, the platelet inhibiting effect of HES 200 was more than that of HES 130 and the crystalloid solution (1,2,5). Whereas the percentage of prolongation (29%) in PFA-closure time after HES 200 was comparable to our previous findings, the magnitude of prolongation (21%) induced by HES 130 was clearly higher than previously observed in healthy male volunteers (2%) (1,2). Hüttner et al. (18) also found no significant increase in PFA-closure times after infusion of even larger amounts (2.1 L) of HES 130. The reason for the discrepancy is unclear but may be related to differences in the patient populations studied. In contrast to previous studies, we investigated the effect of HES in older chronic pain patients and of both sexes. Although the sample size of the present study is too small to reliably identify the effect of sex on platelet reactivity, we found a trend towards a more pronounced prolongation in PFA-closure times in female than in male patients. However, further studies are required to evaluate this hypothesis.

Although conventional, unselective nonsteroidal antiinflammatory drugs were replaced by a selective cyclooxygenase-2 inhibitor, rofecoxib, and all patients denied the use of any medication known to alter platelet function within 14 days before the study, unknown side effects of oral pain therapeutics and other drugs used by the patient according to the patient’s preexisting internal comorbidity may also have influenced platelet reactivity. Interestingly, although mean baseline PFA-closure time values were within the normal range, there was a large percentage of samples exceeding the upper level (Fig. 1), suggesting an overall impairment of platelet function before the first test infusion. Nevertheless, pronounced in vitro hemodilution significantly prolonged PFA-closure time indicating that administration of large doses of HES 130 may also trigger coagulation problems (2).

We did not observe any neuraxial bleeding complication, which is a very rare event after neuraxial blockade. However, impairment of platelet function, as seen with von Willebrand syndrome or various platelet-active drugs, is associated with increased risk of spontaneous and surgical bleeding (19). Although administration of HES was safe and did not increase bleeding in patients undergoing elective abdominal aortic aneurysm repair (20,21), there are several case reports documenting significant bleeding after administration of large quantities of middle and high molecular weight HES (8,22–24). Blood loss was larger in cardiac surgical patients receiving high versus middle molecular weight HES (3). The risk of neuraxial bleeding caused by HES-induced platelet dysfunction is unknown. However, neuraxial bleeding is potentially disastrous, and therefore, optimal hemostasis must be maintained. The present data show that platelet function occurs below potential critical limits after HES infusion in a large percentage of patients. When choosing a colloid for a specific purpose, its therapeutic value must be carefully weighed against its risk for adverse effects, such as impairment of cellular elements.

One limitation of our study is that the degree of hemodilution after IV infusion of 10 mL/kg of lactated Ringer’s solution was approximately half of that of the HES test solutions. This study design, however, represents common clinical practice, where not more than 1 L of fluid is administered before peridural blockade. Whether more intense degrees of hemodilution using crystalloids significantly affect platelet reactivity needs to be defined.

HES solutions are widely used for hemodilution and plasma volume expansion. Our results confirm that HES solutions better maintain hemodynamic variables than equal amounts of crystalloids (Fig. 2). However, although statistically significant, the differences in the decrease in arterial blood pressure after sympathetic blockade induced by the peridural injection of the local anesthetic ropivacaine was probably not clinically important between the test solutions investigated. The power of the present study to detect excessive intravascular volume from fluid administration or hypotension despite fluid resuscitation was too small. Accordingly, before recommending replacing HES by crystalloid infusion in this clinical setting, further studies comparing the risk for hemodynamic instability and including a large number of patients are required.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Stögermüller B, Stark J, Willschke H, et al. The effects of hydroxyethyl starch 200 kd on platelet function. Anesth Analg 2000; 91: 823–7.[Abstract/Free Full Text]
  2. Franz A, Bräunlich P, Gamsjäger T, et al. The effects of hydroxyethyl starches of varying molecular weight on platelet function. Anesth Analg 2001; 92: 1402–7.[Abstract/Free Full Text]
  3. Boldt J, Knothe C, Zickmann B, et al. Influence of different intravascular volume therapies on platelet function in patients undergoing cardiopulmonary bypass. Anesth Analg 1993; 76: 1185–90.[Web of Science][Medline]
  4. Türkan H, Ural A, Beyan C, Yalcin A. Effects of hydroxyethyl starch on blood coagulation profile. Eur J Anaesthesiol 1999; 16: 156–9.[Web of Science][Medline]
  5. Felfernig M, Franz A, Braeunlich P, et al. The effects of hydroxyethyl starch solutions on thromboelastography. Acta Anaesthesiol Scand 2002; 47: 70–3.
  6. Conroy J, Fishman R, Reeves S, et al. The effects of desmopressin and 6% hydroxyethyl starch on factor VIII:C. Anesth Analg 1996; 83: 804–7.[Abstract]
  7. Kapiotis S, Quehenberger P, Eichler H, et al. Effect of hydroxyethyl starch on the activity of blood coagulation and fibrinolysis in healthy volunteers: comparison with albumin. Crit Care Med 1994; 22: 606–12.[Web of Science][Medline]
  8. Ruttmann T, James M, Aronson I. In vivo investigation into the effects of haemodilution with hydroxyethyl starch (200/0.5) and normal saline on coagulation. Br J Anaesth 1998; 80: 612–6.[Abstract/Free Full Text]
  9. Engelmann L, Pilz U, Gundelach K, et al. Akute elementare effekte der kolloidalen plasmaersatzmittel infukoll HES 10%, gelafusal-N und infukoll M40 (Dextran) bei patienten mit sepsis. J Anaesth Intensivmed 1997; 3: 39–46.
  10. Kozek-Langenecker S. Lokoregionalanästhesie und blutgerinnung: behandlung mit thrombozytenfunktionshemmern. Anaesthesist 2003; 52: 549–66.[Web of Science][Medline]
  11. Gogarten W, VanAken H, Büttner J, et al. Rückenmarksnahe regionalanästhesien und thromboembolieprophylaxe/antithrombotische medikation. Anästh Intensivmedizin 2003; 44: 218–30.
  12. Leese P, Recker D, Kent J. The COX-2 selective inhibitor, valdecoxib, does not impair platelet function in the elderly: results of a randomized controlled trial. J Clin Pharmacol 2003; 43: 504–13.[Abstract/Free Full Text]
  13. Nelemans P, deBie R, deVet H, Sturmans F. Injection therapy for subacute and chronic benign low back pain. Spine 2001; 26: 501–15.[Web of Science][Medline]
  14. Hildebrandt J. Relevanz von nervenblockaden bei der diagnose und therapie von rückenschmerzen. Schmerz 2001; 15: 474–83.[Web of Science][Medline]
  15. Golanski J, Pietrucha T, Baj Z, et al. Molecular insight into anticoagulant-induced spontaneous activation of platelets in whole blood: various anticoagulants are not equal. Thromb Res 1996; 83: 199–215.[Web of Science][Medline]
  16. Kratzer M, Born G. Simulation of primary haemostasis in vitro. Haemostasis 1985; 15: 357–62.[Web of Science][Medline]
  17. Kundu S, Heilmann E, Sio R, et al. Description of an in vitro platelet function analyzer - PFA-100. Semin Thromb Hemost 1995; 21: 106–12.[Web of Science][Medline]
  18. Hüttner J, Boldt J, Haisch G, et al. Influence of different colloids on molecular markers of haemostasis and platelet function in patients undergoing major abdominal surgery. Br J Anaesth 2000; 85: 417–23.[Abstract/Free Full Text]
  19. Kövesi T, Royston D. Is there a bleeding problem with platelet-active drugs? Br J Anaesth 2002; 88: 159–63.[Free Full Text]
  20. Gold M, Russo J, Tissot M, et al. Comparison of hetastarch to albumin for perioperative bleeding in patients undergoing abdominal aortic aneurysm surgery. Ann Surg 1990; 211: 482–5.[Web of Science][Medline]
  21. Marik P, Iglesias J, Maini B. Gastric intramucosal pH changes after volume replacement with hydroxyethyl starch or crystalliod in patients undergoing elective abdominal aortic aneurysm repair. J Crit Care 1997; 12: 51–5.[Web of Science][Medline]
  22. Damon L, Adams M, Stricker R. Intracranial bleeding during treatment with hydroxyethyl starch. N Engl J Med 1987; 317: 964–5.[Web of Science][Medline]
  23. Sanfelippo M, Suberviola P, Geimer N. Development of a von Willebrand-like syndrome after prolonged use of hydroxyethyl starch. Am J Clin Pathol 1987; 88: 653–5.[Web of Science][Medline]
  24. Lockwood D, Bullen C, Machin S. A severe coagulopathy following volume replacement with hydroxyethyl starch in a Jehova’s Witness. Anaesthesia 1988; 43: 391–3.[Web of Science][Medline]
Accepted for publication March 9, 2004.




This article has been cited by other articles:


Home page
 Anesth. Analg.Home page
J. Boldt
Modern Rapidly Degradable Hydroxyethyl Starches: Current Concepts
Anesth. Analg., May 1, 2009; 108(5): 1574 - 1582.
[Abstract] [Full Text] [PDF]

Home page
 Br J AnaesthHome page
J. Boldt, S. Suttner, C. Brosch, A. Lehmann, and A. Mengistu
Influence on coagulation of a potato-derived hydroxethylstarch (HES 130/0.42) and a maize-derived hydroxethylstarch (HES 130/0.4) in patients undergoing cardiac surgery
Br. J. Anaesth., February 1, 2009; 102(2): 191 - 197.
[Abstract] [Full Text] [PDF]

Home page
 Anesth. Analg.Home page
J. Boldt, T. Scholhorn, J. Mayer, S. Piper, and S. Suttner
The value of an albumin-based intravascular volume replacement strategy in elderly patients undergoing major abdominal surgery.
Anesth. Analg., July 1, 2006; 103(1): 191 - 199.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a colleague
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowRequest Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (5)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Scharbert, G.
Right arrow Articles by Kozek-Langenecker, S. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Scharbert, G.
Right arrow Articles by Kozek-Langenecker, S. A.
Related Collections
Right arrow Blood
Right arrow Regional Anesthesia
Right arrow Pain

Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2004 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press