Coagulopathy with the use of hetastarch in the treatment of vasospasm

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✓ The use of colloid agents to achieve hypervolemia in the prevention and treatment of postsubarachnoid hemorrhage (post-SAH) vasospasm is included in the standard of care at many institutions. Risk profiles are necessary to ensure appropriate use of these agents. In a series of 85 patients with recent aneurysmal SAH, 26 developed clinical symptoms of vasospasm. Fourteen of the 26 were treated with hetastarch for volume expansion while the other 12 received plasma protein fraction (PPF). Clinically significant bleeding pathologies were noted in six patients who received hetastarch as a continuous intravenous infusion. Hetastarch increased partial thromboplastin time from a mean of 23.9 seconds to a mean of 33.1 seconds (p < 0.001) in all patients who received infusions of this agent, while no effect was noted in the 12 patients who received PPF infusions. No other coagulation parameters were altered. This study shows an increase in coagulopathy with the use of hetastarch as compared with the use of PPF for the treatment of postaneurysmal vasospasm.

Volume expansion is one of the cornerstones in the prevention and treatment of postsubarachnoid hemorrhage (post-SAH) vasospasm. It has been shown to decrease ischemic infarct size and improve hemodynamic parameters.12,13,16,21,22 However, data concerning the risk profiles and efficacy of the various volume-expanding agents are scarce. Risk profiles are necessary to ensure appropriate use of these agents.

Hetastarch has been used at the Medical College of Virginia in postaneurysmal SAH patients with clinical signs of vasospasm. Multiple bleeding pathologies were noted in those patients who received hetastarch as a continuous intravenous infusion. Therefore, this study was undertaken to assess indices that may be of assistance in preventing further occurrences of bleeding pathologies and to assess the efficacy of hetastarch compared to plasma protein fraction (PPF), which was used concurrently in another group of patients.

Clinical Material and Methods

Between July, 1990, and November, 1992, all patients admitted to the hospital of the Medical College of Virginia with a recent (< 4 days of symptoms) SAH that required surgical clipping of an intracranial aneurysm underwent postoperative care in the neuroscience intensive care unit. Of these 85 patients, 26 developed clinically significant vasospasm, documented by a progressive postoperative neurological deficit that could not be explained on the basis of hydrocephalus, rebleeding, or other pathology. Beginning immediately upon admission, all patients received nimodipine for 21 days or until discharge. Hunt and Hess5 scores were also documented on admission. Hemodilution and hypervolemia were employed preventively in all patients, using a crystalloid solution. In those patients who developed clinical signs of vasospasm, hypervolemic therapy with a colloid solution and hypertensive therapy with phenylephrine were instituted. Either Hespan (6% hetastarch in 0.9% sodium chloride, with an average molecular weight of 480,000)* or Plasmanate (5% PPF, which is primarily albumin) were used as a colloid solution. Fourteen patients received hetastarch and 12 patients received PPF. Hetastarch was the preferred volume-expanding agent but PPF was frequently used for convenience because PPF was stocked in the intensive care unit whereas hetastarch was available only from the pharmacy. The choice of hetastarch versus PPF was therefore random but not blinded. There were no other differences in treatment protocol and all patients were managed under the supervision of the senior author (J.P.M.).

Both colloids were administered at a median intravenous rate of 50 cc/hour. Hematocrit was maintained between 30 and 35. Systolic blood pressure was maintained above 180 mm Hg. Pulmonary capillary wedge pressure was maintained at 12 ± 2 mm Hg. Prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen level, and platelet count were all measured prior to initiation of and after termination of therapy for symptomatic vasospasm. The total dose of hetastarch ranged from 5 L to 16 L. Most data, including demographic data, clinical condition, radiographic findings, surgical details, onset and duration of vasospasm, use of medications (including hetastarch and PPF), complications, and outcome, were collected prospectively. Patient charts were reviewed only for the calculation of the exact medication dose and to find the PTT, PT, fibrinogen, and platelet levels.

Results

At the beginning of therapy PT and PTT were in the normal range for all patients. A standard infusion rate of 50 cc/hour for either hetastarch or PPF was used in all but four patients. These four patients were given lower doses because of a history of congestive heart failure or pulmonary edema. The mean infusion rate for hetastarch was 0.67 cc/kg per hour and for PPF 0.69 cc/kg per hour. Posttreatment PT was slightly above pretreatment levels in both groups, whereas platelet and fibrinogen levels revealed no trend. The PTT was found to be significantly elevated (p < 0.001 by Wilcoxon's matched-pairs rank test) in all patients who received hetastarch (Fig. 1, Table 1), but was not significantly altered in patients who received PPF (Table 2). The difference in PTT changes between the hetastarch and PPF groups was significant (p < 0.001 by Wilcoxon's signed ranks test). The elevations in PTT were not related to dose or infusion rate of hetastarch.

Fig. 1.
Fig. 1.

Bar graph illustrating mean changes in partial thromboplastin time (PTT) in patients receiving either hetastarch or plasma protein fraction (PPF) for treatment of vasospasm. Vertical bars = standard error of the mean; ** = p < 0.001 compared to post-PPF measurements.

TABLE 1

Hemorheological parameters at the beginning and end of treatment in patients receiving hetastarch*

Case No.Hetastarch Dose (cc/kg/hr)PT (sec)PTT (sec)PLT (× 109/liter blood)FIB (mg/dl)
StartEndStartEndStartEndStartEnd  
10.661313243316992262204
180.571215214638121150025
240.7513132634229247321214
360.7011122032320318501284
490.5414132833253190482313
530.9113132938140318201286
610.7513122537156137203219
631.161216233515178228306
650.5912132234263355273229
670.5713162231184183349393
680.671328263627883268109
760.5513142141268172288194
770.2512132125426311730389
780.7613132639181137272395

Abbreviations: PT = prothrombin time; PTT = partial thromboplastin time; PLT = platelet count; FIB = fibrinogen level.

Weight estimated at 55 kg; other weights documented in patient chart.

TABLE 2

Hemorheological parameters at the beginning and end of treatment in patients receiving PPF*

Case No.PPF Dose (cc/kg/hr)PT (sec)PTT (sec)PLT (× 109/liter blood)FIB (mg/dl)
20.7612122121282 376518404
50.7713132022 380159262
70.5812132327124 270470281
210.5912122423274 360274228
260.8213142731252 569359546
410.7213132635201 486294226
440.6312132425244 384706
580.761212242384 279394440
700.7013122322273 376341645
790.6513122524306 285730501
820.4812142223206 143569354
830.8514122827351 401194300

Abbreviations: PPF = plasma protein fraction; PT = prothrombin time; PTT = partial thromboplastin time; PLT = platelet count; FIB = fibrinogen level.

Not tested.

The elevation in PTT was evidenced clinically by an increase in occult blood loss in the hetastarch-treated patients, requiring transfusion in four patients. One patient receiving hetastarch (Case 67) required reexploration 5 days after surgery for subgaleal arterial bleeding from the operative site. Another patient (Case 18), while receiving hetastarch, developed a delayed postoperative epidural hematoma that required evacuation. In none of these patients was outcome believed to be negatively influenced by the aforementioned complications.

Discussion

Hetastarch is an appealing alternative to PPF in the treatment of cerebral vasospasm because it has an extended shelf life, is not subject to shortages that may affect the blood supply, may be given to patients who would refuse blood products on religious grounds, and carries no risk of transmitting blood-borne diseases.10,15 The risk of anaphylactic reactions is also very small, at approximately 0.0005%.15 Dextran has been used in the past for similar reasons but concern about coagulopathy has limited its use.15 No risk profile has been documented with the prolonged infusion of hetastarch for the treatment of intracranial vasospasm, although this agent continues to be used for such treatment at many centers. In a nicardipine trial 10 of 40 centers used hetastarch and in an ongoing tirilazad trial 11 of 46 centers are using it in the treatment of patients with SAH (NF Kassell, personal communication, 1994).

Much of the literature concerning the use of moderate intravenous doses of hetastarch has focused on the repletion of intravascular volume secondary to trauma or surgery.17 Fluid resuscitation using hetastarch occurs over a shorter period of time than the treatment of vasospasm necessitates, but the volume of hetastarch administered on a daily basis is comparable to the doses used in this study.18 Hetastarch serves as a potent volume expander, with the initial intravascular component comparable to the infused volume.3,4 This agent has been shown to decrease serum albumin and globulin in a dilutional manner.11 However, a dose of up to 1 gm of hetastarch per kilogram of patient weight has not been associated with coagulopathy if use is limited to a single infusion lasting less than 24 hours.4

The use of plasma-expanding agents for the treatment of vasospasm requires a different treatment regimen than fluid resuscitation. The literature supports the use of various plasma substitutes for optimum hemodynamic and hemorheological effects in the cerebral circulation.9 Previous studies have shown a reduction in cerebral infarct size with the use of these agents.8,16 In addition, cerebral blood flow has been shown to improve in ischemic as well as normal brain.6,22 The etiology of this improvement is unclear, but suggested theories have included hemodilution, decreased plasma viscosity, increased cardiac output, or mild elevation of clotting time.8,12,14,16,19,21,22 The mild elevation of clotting time has been ascribed to precipitation by hetastarch of factor VIII.1,7,20 Studies in humans have used doses lower than those necessary for the treatment of vasospasm and have used normal volunteers.8,20 We have found that 500 cc/day of hetastarch is inadequate to maintain pulmonary capillary wedge pressure and hemodilution at levels that, in our opinion, are optimum for patients experiencing vasospasm. More than 1 L/day is usually necessary, and this dose has been maintained as long as there is clinical concern about symptomatic vasospasm. Even these higher doses are less than the previously recommended maximum dose of 20 ml of hetastarch per kilogram of body weight for 24 hours.4

An additional concern about hetastarch is its extended half-life. The high-molecular-weight hetastarch used in this study has a half-life of approximately 36 hours, making it useful for maintaining intravascular volume but difficult to clear should an unexpected side effect occur.15 Hetastarch is also a very heterogeneous product, raising concern that its half-life may be extended further by its higher molecular weight components. Most hetastarch is cleared by the kidney after enzymatic degradation by amylase.15 Both PPF and dextran have a half-life of less than 24 hours and therefore can be more quickly cleared should an unexpected complication arise.15 There have been two previous reports of hetastarch-associated coagulopathy occurring postoperatively.2,10 One occurred in a child who received 2000 ml of hetastarch after a posterior spinal fusion and who was found to have a PTT of 90 postoperatively. The other occurred in a patient undergoing a craniotomy, who received 2000 ml of hetastarch intraoperatively and was found to have a PTT of 46 postoperatively, with a hematoma in the operative bed. Human volunteer studies using a 1-L intravenous bolus have revealed prolonged PTT and decreased factor VIII activity in vivo but not in vitro.20

This study shows that high doses are not necessary to see an alarming trend toward coagulopathy in patients receiving hetastarch infusions for cerebral vasospasm. The significant rise in PTT seen in this study in patients who received moderate-dose infusions of hetastarch for treatment of symptomatic vasospasm reveals the need to monitor daily coagulation screens in all patients given hetastarch infusions. Additionally, the risk of postoperative bleeding is elevated and an evaluation for potential intracranial hemorrhage must be performed in patients who receive hetastarch infusions and then show a decline in mental status.

Conclusions

The advantages of hetastarch use must be weighed against the disadvantages. The present study serves to point out one potentially serious disadvantage of this agent, specifically, coagulopathy beyond that accounted for on the basis of dilutional effects alone. Such coagulopathy is not seen in patients receiving similar doses of PPF. On the basis of this hetastarch-associated coagulopathy and recent experimental data showing that PPF may well be the most effective agent to increase cerebral blood flow and prevent infarction,12,13 we have discontinued the use of hetastarch in the neuroscience intensive care unit and now use PPF exclusively.

References

  • 1.

    Alexander B: Effects of plasma expanders on coagulation and hemostasis: dextran, hydroxyethyl starch, and other macromolecules revisited. Prog Clin Biol Res 19:2933301978Prog Clin Biol Res 19:

  • 2.

    Cully MDLarson CP JrSilverberg GD: Hetastarch coagulopathy in a neurosurgical patient. Anesthesiology 66:7067071987 (Letter)Anesthesiology 66:

  • 3.

    Dodge CGlass DD: Crystalloid and colloid therapy. Semin Anesth 1:2933001982Semin Anesth 1:

  • 4.

    Gold MSRusso JTissot Met al: Comparison of hetastarch to albumin for perioperative bleeding in patients undergoing abdominal aortic aneurysm surgery. A prospective, randomized study. Ann Surg 211:4824851990Ann Surg 211:

  • 5.

    Hunt WEHess RM: Surgical risk as related to time of intervention in the repair of intracranial aneurysms. J Neurosurg 28:14201968J Neurosurg 28:

  • 6.

    Korosue KIshida KMatsuoka Het al: Clinical, hemodynamic, and hemorheological effects of isovolemic hemodilution in acute cerebral infarction. Neurosurgery 23:1481531988Neurosurgery 23:

  • 7.

    Korttila KGröhn PGordin Aet al: Effect of hydroxyethyl starch and dextran on plasma volume and blood hemostasis and coagulation. J Clin Pharmacol 24:2732821984J Clin Pharmacol 24:

  • 8.

    Kroemer HHaass AMuller Ket al: Haemodilution therapy in ischaemic stroke: plasma concentrations and plasma viscosity during long-term infusion of dextran 40 or hydroxyethyl starch 200/0.5. Eur J Clin Pharmacol 31:7057101987Eur J Clin Pharmacol 31:

  • 9.

    Levy MLGiannotta SL: Cardiac performance indices during hypervolemic therapy for cerebral vasospasm. J Neurosurg 75:27311991J Neurosurg 75:

  • 10.

    Lockwood DNJBullen CMachin SJ: A severe coagulopathy following volume replacement with hydroxyethyl starch in a Jehovah's witness. Anaesthesia 43:3913931988Anaesthesia 43:

  • 11.

    Lucas CEDenis RLedgerwood AMet al: The effects of Hespan on serum and lymphatic albumin, globulin, and coagulant protein. Ann Surg 207:4164201988Ann Surg 207:

  • 12.

    Matsui TAsano T: The hemodynamic effects of prolonged albumin administration in beagle dogs exposed to experimental subarachnoid hemorrhage. Neurosurgery 32:79841993Neurosurgery 32:

  • 13.

    Matsui TSinyama HAsano T: Beneficial effect of prolonged administration of albumin on ischemic cerebral edema and infarction after occlusion of middle cerebral artery in rats. Neurosurgery 33:2933001993Neurosurgery 33:

  • 14.

    Muizelaar JP: The hemodynamic effects of prolonged Albumin administration in beagle dogs exposed to experimental subarachnoid hemorrhage. Neurosurgery 32:841993 (Editorial)Muizelaar JP: The hemodynamic effects of prolonged Albumin administration in beagle dogs exposed to experimental subarachnoid hemorrhage. Neurosurgery 32:

  • 15.

    Nearman HSHerman ML: Toxic effects of colloids in the intensive care unit. Crit Care Clin 7:7137231991Crit Care Clin 7:

  • 16.

    Perez-Trepichio ADFurlan AJLittle JRet al: Hydroxyethyl starch 200/0.5 reduces infarct volume after embolic stroke in rats. Stroke 23:178217901992Stroke 23:

  • 17.

    Rackow ECFalk JLFein IAet al: Fluid resuscitation in circulatory shock: a comparison of the cardiorespiratory effects of albumin, hetastarch, and saline solutions in patients with hypovolemic and septic shock. Crit Care Med 11:8398501983Crit Care Med 11:

  • 18.

    Shatney CHDeepika KMilitello PRet al: Efficacy of hetastarch in the resuscitation of patients with multisystem trauma and shock. Arch Surg 118:8048091983Arch Surg 118:

  • 19.

    Strauss RG: Review of the effects of hydroxyethyl starch on the blood coagulation system. Transfusion 21:2993021981Strauss RG: Review of the effects of hydroxyethyl starch on the blood coagulation system. Transfusion 21:

  • 20.

    Stump DCStrauss RGHenriksen RAet al: Effects of hydroxyethyl starch on blood coagulation, particularly factor VIII. Transfusion 25:3493541985Transfusion 25:

  • 21.

    Tu YKHeros RCCandia Get al: Isovolemic hemodilution in experimental focal cerebral ischemia. Part 1: Effects on hemodynamics, hemorheology, and intracranial pressure. J Neurosurg 69:72811988J Neurosurg 69:

  • 22.

    Vorstup SAndersen AJuhler Met al: Hemodilution increases cerebral blood flow in acute ischemic stroke. Stroke 20:8848891989Stroke 20:

Hespan prescribing information pamphlet (1989, p 5) supplied by Du Pont Pharmaceuticals, Wilmington, Delaware.

This study was supported in part by the Lind Lawrence Fund.

The data in this paper were presented at the Fifth International Symposium on Cerebral Vasospasm in Edmonton, Alberta, Canada, in May, 1993.

Article Information

Address reprint requests to: J. Paul Muizelaar, M.D., Ph.D., Wayne State University, 4201 St. Antoine, 6E, Detroit, Michigan 48201.

© AANS, except where prohibited by US copyright law."

Headings

Figures

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    Bar graph illustrating mean changes in partial thromboplastin time (PTT) in patients receiving either hetastarch or plasma protein fraction (PPF) for treatment of vasospasm. Vertical bars = standard error of the mean; ** = p < 0.001 compared to post-PPF measurements.

References

1.

Alexander B: Effects of plasma expanders on coagulation and hemostasis: dextran, hydroxyethyl starch, and other macromolecules revisited. Prog Clin Biol Res 19:2933301978Prog Clin Biol Res 19:

2.

Cully MDLarson CP JrSilverberg GD: Hetastarch coagulopathy in a neurosurgical patient. Anesthesiology 66:7067071987 (Letter)Anesthesiology 66:

3.

Dodge CGlass DD: Crystalloid and colloid therapy. Semin Anesth 1:2933001982Semin Anesth 1:

4.

Gold MSRusso JTissot Met al: Comparison of hetastarch to albumin for perioperative bleeding in patients undergoing abdominal aortic aneurysm surgery. A prospective, randomized study. Ann Surg 211:4824851990Ann Surg 211:

5.

Hunt WEHess RM: Surgical risk as related to time of intervention in the repair of intracranial aneurysms. J Neurosurg 28:14201968J Neurosurg 28:

6.

Korosue KIshida KMatsuoka Het al: Clinical, hemodynamic, and hemorheological effects of isovolemic hemodilution in acute cerebral infarction. Neurosurgery 23:1481531988Neurosurgery 23:

7.

Korttila KGröhn PGordin Aet al: Effect of hydroxyethyl starch and dextran on plasma volume and blood hemostasis and coagulation. J Clin Pharmacol 24:2732821984J Clin Pharmacol 24:

8.

Kroemer HHaass AMuller Ket al: Haemodilution therapy in ischaemic stroke: plasma concentrations and plasma viscosity during long-term infusion of dextran 40 or hydroxyethyl starch 200/0.5. Eur J Clin Pharmacol 31:7057101987Eur J Clin Pharmacol 31:

9.

Levy MLGiannotta SL: Cardiac performance indices during hypervolemic therapy for cerebral vasospasm. J Neurosurg 75:27311991J Neurosurg 75:

10.

Lockwood DNJBullen CMachin SJ: A severe coagulopathy following volume replacement with hydroxyethyl starch in a Jehovah's witness. Anaesthesia 43:3913931988Anaesthesia 43:

11.

Lucas CEDenis RLedgerwood AMet al: The effects of Hespan on serum and lymphatic albumin, globulin, and coagulant protein. Ann Surg 207:4164201988Ann Surg 207:

12.

Matsui TAsano T: The hemodynamic effects of prolonged albumin administration in beagle dogs exposed to experimental subarachnoid hemorrhage. Neurosurgery 32:79841993Neurosurgery 32:

13.

Matsui TSinyama HAsano T: Beneficial effect of prolonged administration of albumin on ischemic cerebral edema and infarction after occlusion of middle cerebral artery in rats. Neurosurgery 33:2933001993Neurosurgery 33:

14.

Muizelaar JP: The hemodynamic effects of prolonged Albumin administration in beagle dogs exposed to experimental subarachnoid hemorrhage. Neurosurgery 32:841993 (Editorial)Muizelaar JP: The hemodynamic effects of prolonged Albumin administration in beagle dogs exposed to experimental subarachnoid hemorrhage. Neurosurgery 32:

15.

Nearman HSHerman ML: Toxic effects of colloids in the intensive care unit. Crit Care Clin 7:7137231991Crit Care Clin 7:

16.

Perez-Trepichio ADFurlan AJLittle JRet al: Hydroxyethyl starch 200/0.5 reduces infarct volume after embolic stroke in rats. Stroke 23:178217901992Stroke 23:

17.

Rackow ECFalk JLFein IAet al: Fluid resuscitation in circulatory shock: a comparison of the cardiorespiratory effects of albumin, hetastarch, and saline solutions in patients with hypovolemic and septic shock. Crit Care Med 11:8398501983Crit Care Med 11:

18.

Shatney CHDeepika KMilitello PRet al: Efficacy of hetastarch in the resuscitation of patients with multisystem trauma and shock. Arch Surg 118:8048091983Arch Surg 118:

19.

Strauss RG: Review of the effects of hydroxyethyl starch on the blood coagulation system. Transfusion 21:2993021981Strauss RG: Review of the effects of hydroxyethyl starch on the blood coagulation system. Transfusion 21:

20.

Stump DCStrauss RGHenriksen RAet al: Effects of hydroxyethyl starch on blood coagulation, particularly factor VIII. Transfusion 25:3493541985Transfusion 25:

21.

Tu YKHeros RCCandia Get al: Isovolemic hemodilution in experimental focal cerebral ischemia. Part 1: Effects on hemodynamics, hemorheology, and intracranial pressure. J Neurosurg 69:72811988J Neurosurg 69:

22.

Vorstup SAndersen AJuhler Met al: Hemodilution increases cerebral blood flow in acute ischemic stroke. Stroke 20:8848891989Stroke 20:

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