Safety and Efficacy of Microporous Polysaccharide ... and Efficacy of Microporous Polysaccharide Hemospheres in Neurosurgery BACKGROUND: Effective hemostasis is mandatory for brain

Safety and Efficacy of Microporous PolysaccharideHemospheres in Neurosurgery

BACKGROUND: Effective hemostasis is mandatory for brain tumor surgery. Microporouspolysaccharide hemosphere (MPH) powder, a white powder compounded from potatostarch, was recently introduced for surgical and emergency application.

OBJECTIVE: To evaluate the safety and efficacy of MPHs in brain tumor surgery.

METHODS: Thirty-three patients (mean age, 58 years; range, 22-84 years) underwentmicrosurgical brain tumor resection. Final hemostasis was performed by topical appli-cation of MPHs, video recorded, and subsequently analyzed. Blood samples were takenbefore surgery, before application of hemospheres, and postoperatively. Volumemeasurements of the tumor, resection cavity, and postoperative hematoma were doneon magnetic resonance imaging and computed tomography scans. Clinical examina-tions focused on neurological outcome, complications, and allergic reactions.

RESULTS: Effective hemostasis was achieved by exclusive use of MPHs in 32 patients. In 1patient, a single arterial bleeding underwent additional bipolar electrocauterization.Mean operative time was 156.8 minutes (range, 60-235 minutes). Hemostasis with MPHsrequired 57 seconds (mean; range, 8-202 seconds). Subjective neurosurgeons’ ranking ofthe hemostasis effect indicated excellent satisfaction. For the first 3 months, there wasno hemospheres-related postoperative neurological worsening, no signs of allergicreaction, and no embolic complications. Early postoperative and 3-month follow-upmagnetic resonance imaging and computed tomography scans excluded any expansivebleeding complication. As early as postoperative day 1, MPHs were no longer detected.There was no tumor mimicking contrast enhancement.

CONCLUSION: In neurosurgery, MPHs allow fast and effective minimally invasive he-mostasis. In this small case series, no adverse reactions were found.

KEY WORDS: Brain tumor, Microporous polysaccharide hemospheres, Topical hemostatic agent

Neurosurgery 69[ONS Suppl 1]:ons49–ons63, 2011 DOI: 10.1227/NEU.0b013e3182155a52

Microporous polysaccharide hemospheres(MPHs; Arista-AH, Medafor, Inc,Minneapolis, Minnesota) have been

shown to be a safe and effective topical hemostaticagent in clinical1-8 and experimental studies.9-16

MPHs are in trade as a medical device (Arista-AH) based on the MPH technology and intendedfor topical application to surgical wound sites as

an absorbable hemostatic agent. Microporouspolysaccharide hemospheres consist of particlesmanufactured from biologically inert plant poly-saccharides from potato starch. Hemostasis isachieved by immediate absorption of the fluidcomponents of blood and by concentration ofplatelets and clotting factors. After application,the blood cells and proteins form a gel matrix onthe surface of the particles (Figure 1). This resultsin accelerated blood clotting.Several experimental studies evaluated the

application of MPHs in reconstructive surgery,9

endovascular surgery,3 and renal trauma sur-gery.14-17 In these studies, MPHs caused rapid,effective, and durable hemostasis. No inhibitedbone healing was found in an experimental

Christoph A. Tschan, MD

Meike Nieß

Eike Schwandt, MD

Joachim Oertel, MD, PhD

Neurochirurgische Klinik, Universitaets-

medizin, Johannes Gutenberg-Universi-

taet, Mainz, Germany

Correspondence:

Prof Dr Joachim Oertel, MD, PhD,

Klinik fur Neurochirurgie,

Universitatsklinikum des Saarlandes,

Kirrberger Strabe,

D-66421 Homburg/Saar, Germany.

E-mail: [email protected]

Received, April 18, 2010.

Accepted, January 4, 2011.

Published Online, May 4, 2011.

Copyright ª 2011 by the

Congress of Neurological Surgeons

WHAT IS THIS BOX?

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with cameras, and

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ABBREVIATION: MPH, microporous polysaccha-

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NEUROSURGERY VOLUME 69 | OPERATIVE NEUROSURGERY 1 | SEPTEMBER 2011 | ons49

TUMOR Operative Technique

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rabbit model.10 In a rat abdominal infection model, rapid sub-strate degradation and a lower infection rate were observedcompared with gelatin matrix.12 Another experimental studyrevealed less peritoneal adhesion formation and less inflammationcompared with other topical hemostatic agents.13 In a rat neu-rosurgical model, MPHs were degraded more rapidly than Sur-gicel, Avitene, and FloSeal; there was no evidence of any foreignbody reaction.11

Clinically, several topical hemostatic agents are available and incommon use in surgical procedures.18-28 In cranial neurosurgery,a gelatin-thrombin matrix hemostatic sealant (FloSeal) has beenshown to be an effective topical hemostat.29,30 FloSeal alsoshowed good hemostatic results in ear-nose-throat surgery, vas-cular surgery, cardiac surgery, and liver surgery.26,31-35 On theother hand, the use of topical hemostatic agents can cause adversereactions. In orthopedic surgery, intrapedicular application ofhemostatic gelatin matrix during pedicle screw insertion causedneurological deficits.4 Application of FloSeal in the lumpectomycavity resulted in benign microcalcifications with a malignantappearance in mammographic studies.36 In an experimental studyfor renal surgery, FloSeal caused obstruction of the porcinecollecting system21; a rabbit model for ear-nose-throat surgeryrevealed increased reactive mucosal fibrosis.37 Use of gelatin-thrombin hemostatic agents seems to harbor the risk of foreign

body reaction, leading to giant-cell granuloma formation or aneosinophilic inflammatory response.38,39

Clinically, MPHs have provided excellent results in endoscopicnasal sinus surgery,1,2,7 dermatologic surgery,5,8 and laparoscopicsurgery.6 In these studies, rapid and effective hemostasis wasachieved. There were no severe adverse events or specific post-operative complications. At present, the main areas of applicationare in emergency medical services and the armed forces.The excellence results of MPHs in other surgical disciplines,

the advantages over other hemostatic agents in experimentalstudies, and the inexpensive price make the substance potentiallywell suited for neurosurgical use. No previous clinical experiencesin neurosurgery exist.

MATERIALS AND METHODS

Study Design

The aim of this clinical study was to evaluate MPHs to obtain he-mostasis in brain tumor surgery. To achieve this goal, hemostasis duringthe tumor procedure was achieved by standard electrocautery techniques.At the end of tumor resection, either after complete removal of the tumormass or after decompression of the tumor, which was considered the goalof surgery, MPHs were used for final hemostasis without additionaltopical agents or electrocautery. The procedures were done by 5 skilledmicrosurgical neurosurgeons to achieve an optimum of comparability foroperative technique and operating time. The operation and applicationresults were accurately documented and analyzed. Blood samples weretaken before, during (immediately before MPH application), and aftersurgery. Clinical history was taken; neurological examination and neu-roradiological imaging were performed preoperatively and post-operatively; and follow-up examination, including neuroimaging, wasdone 3 months after hospital discharge.

Description of the Absorbable Hemostat MPHs

Microporous polysaccharide hemospheres are intended for applicationto surgical wound sites as an absorbable hemostat. It is a 100% plant-based polysaccharide. The fine, dry, sterilized white powder contains noanimal or human components. The powder consists of hydrophilicmicroporous particles synthesized by cross-linking purified potato starchthrough a proprietary process. Microporous polysaccharide hemospheresare biocompatible, nonpyrogenic, and absorbed within 24 to 48 hours.The mechanism of action is like that of a hydrophilic molecular sieve(Figure 1): Fluid is absorbed, and platelets, red blood cells, and bloodproteins are concentrated on the particle surfaces to form a gelled matrix.This gel enhances normal clotting reactions and creates stable hemostaticplugs. This mechanism is almost independent of the patient’s co-agulation status.The medical device, MPH (Arista-AH, Medafor, Inc), has been

approved for use in human surgery by the regulatory authorities inGermany and in the United States since 2006. Although its applicationin neurosurgery and ophthalmology has been excluded in the UnitedStates, the device is permitted for neurosurgical use in Germany. InGermany, the device is not regarded as a medical drug but as a medicaldevice like an ultrasonic aspirator or a neuronavigational system. Becausethe Arista-AH device is permitted for neurosurgical application inGermany, no permission by the local ethical committee was acquired.The price for 1 g Arista-AH is around 60V in Germany.

FIGURE 1. Schematic drawing of microporous polysaccharide hemospheres(MPHs; Arista-AH) and their mechanism of hemostasis action. A, MPH particle(white ball) acts as a molecular sieve, absorbing the fluid (blue arrows) andconcentrating platelets, red blood cells, and blood proteins on the surface of theparticles. B, brain tumor resection cavity filled with MPH particles.

TSCHAN ET AL

ons50 | VOLUME 69 | OPERATIVE NEUROSURGERY 1 | SEPTEMBER 2011 www.neurosurgery-online.com



Surgical Application

Thirty-three patients suffering from glioma, meningioma, or brainmetastasis underwent microsurgical tumor resection. Microporouspolysaccharide hemospheres (Arista-AH; packages of 1 or 3 g) were appliedvia a sterile malleable and disposable applicator (FlexiTip, Medafor, Inc) tothe resection cavity to stop bleeding after complete or partial microsurgicaltumor resection (Figure 2A through 2C). The amount of the appliedMPHs was not predefined in the study design; it depended solely on theindividual preference of the performing surgeon. To evaluate the effect andthe optimum dose, the applied volume and the time duration for achievinghemostasis were documented and video recorded (Video 1, SupplementalDigital Content 1, http://links.lww.com/NEU/A395, which shows themicrosurgical resection in patient 14). In the microsurgical resection of anenlarged glioblastoma multiforme in patient 14, complete hemostasis wasachieved in 332 seconds by application of MPHs. No additional topicalhemostat or electric coagulation was used for the closing hemostasis.Postoperative cranial computed tomography (CT) imaging revealed nobleeding complication. Three distinct time intervals were predefined foranalysis: (1) application time of MPHs, the time needed to apply theMPHs from the beginning until the powder covered the complete re-section area; (2) time interval for complete hemostasis, the time intervaldefined from the beginning ofMPH application until complete hemostasiswas observed; and (3) the time interval from complete hemostasis untilcontinuation of the procedure. This time interval differed greatly betweensurgeons. Some continued immediately after complete hemostasis. Otherswaited (up to. 10 minutes) to ensure that hemostasis was sufficient by anadditional prolonged observation time. However, in no case were addi-tional maneuvers undertaken to secure hemostasis. No additional topicalagent or electrocautery was used to achieve primary hemostasis at the endof tumor resection (Figure 3).

Immediately before MPH application, blood samples were taken forevaluation of differential blood count and various parameters of bloodclotting. Additionally, the amount of blood loss was documented beforeapplication of MPHs and immediately postoperatively. Attention waspaid to evaluate the blood loss accurately during surgery and to collect allfluid inflow and outflow. However, the blood loss could only be esti-mated. Thus, all blood loss measures in the Results section representestimated values.

Follow-up Examination

Directly postoperatively, at day 1 and before hospital discharge, thepatients were examined for signs of allergic reaction, embolic signs,infection, or neurological deficits. On postoperative day 1, bloodsamples were taken and compared with the preoperative and intra-operative results, including additional differential blood count, varioushemostasis parameters, and amylolytic enzymes. Within 72 hours,early postoperative neuroradiological imaging (gadolinium-enhancedmagnetic resonance imaging [MRI] scan or CT native and withcontrast) was performed (Figures 4 and 5). The follow-up examinationafter 3 months included neurological examination and neuroradio-logical imaging (MRI scan).

Data Analysis

The videos were analyzed by 2 research assistants for application timeand for time interval until complete hemostasis and up to dural closure.Additionally, a hemostasis-quality evaluation scale for subjective feasi-bility and effectiveness of MPHs was used. The optimum amount ofMPHs for effective and fast hemostasis was calculated and correlated tothe tumor size. The blood sample parameters were analyzed for signs of

FIGURE 2. Operative microsurgical application of microporous polysaccharide hemospheres (MPHs) to the tumor resection cavity. A and B, the 1-g Arista-AH blister. C, toapply MPH to deeper tumor resection cavities, a sterile, malleable, disposable, single-use applicator (FlexiTip) was used.

MICROPOROUS POLYSACCHARIDE HEMOSPHERES IN NEUROSURGERY




infection, blood loss, clotting function, and allergic reaction. Pre-operative, early postoperative, and follow-up neuroradiological imageswere analyzed for tumor recurrence and signs of infection. Volumemeasurements were performed by segmentation of the tumor resectioncavity and the intracavitary hematoma size (iPlanNet version 2.5, iPlan3.0 cranial software; BrainLab AG, Feldkirchen, Germany). All evalu-ations were performed by 2 authors (M.N. and E.S.) in a blinded manner(if appropriate).

RESULTS

Patient Population

Thirty-three patients (15 female, 18 male) underwent mi-crosurgical brain tumor resection (Figures 4A and 5A). Histo-pathologically, tumors consisted of 14 glioblastomas, 6metastases, 5 anaplastic astrocytomas, 4 meningiomas, and 4others (Table 1). Mean age at surgery was 58 years (range, 22-84years). Nine patients underwent surgery after long-time intake ofacetylsalicylic acid tablets or other anticoagulation drugs. Thismedication was paused 1 week before surgery. Preoperative bloodsamples revealed normal coagulation parameters and normalfunction of the liver and kidney. Preoperative clinical examina-tion showed various neurological deficits (Table 1).

Operative Results

Effective final hemostasis was achieved by use of MPHswithout additional bipolar electrocautery or other topical

hemostats in 32 patients (Figure 3 and Video 1). In 1 patient,a single bleeding artery from the falx cerebri underwent additionalbipolar coagulation (patient 28). All other bleedings from theremaining resection cavity were successfully treated with MPHs.Mean operative time was 156.8 minutes (range, 60-235 mi-nutes). There were no intraoperative complications. Particularly,no allergic reactions were recorded, and there were no decreases orincreases in blood pressure or heart rate. Blood transfusion of redblood cells was required in 5 patients (Table 2). Of these 5patients, 3 suffered from very large tumors, which might havecontributed to the cumulative blood loss. There was no intraduralblood loss after successful hemostasis was achieved with MPHapplication.

Analysis of the Procedure

Objective time measurements were performed by video anal-ysis by 2 independent investigators (Table 2). The mean appli-cation and hemostasis time of MPHs was 57 seconds (range, 8 to202 seconds). In general, more MPH agent was applied in largerresection areas to achieve hemostasis. Some neurosurgeonspaused the operation after hemostasis with MPHs for up to 900seconds until dural closure. A second hemostasis was not done inany case. The dura was immediately closed in all cases.

Early Postoperative Follow-up

Postoperative blood samples were compared with pre-operative and intraoperative (before MPH application) blood

FIGURE 3. Patient 20. Surgical hemostasis after tumor resection before dural closure performed exclusively with microporous polysaccharide hemospheres (MPHs). The whitepowder allows the location of recurrent or remnant bleeding. Complete hemostasis was achieved with MPH.

TSCHAN ET AL




samples (Table 3). No sign of infection or coagulopathy wasfound. Patients treated with dexamethasone showed a slightincrease in white blood cell count. There was no sign of allergicreaction; the eosinophilic leukocytes showed normal values in allpatients. The postoperative physical examination revealed nofever, no skin disturbances, and no other signs of infection orallergic reaction.

Follow-up Investigation

No secondary hemorrhage, infection, or allergic reaction wasrecorded during the follow-up period of 3 months. There wereno apparent hemosphere-related postoperative neurologicalcomplications. No signs of allergic reaction or embolic com-plication were seen (Table 1). In 8 patients, the ventricles were

opened during surgery. In those patients, follow-up examina-tion excluded any sign of hydrocephalus development. In 2patients, early tumor recurrence caused neurological worsening(patients 8 and 12).

Neuroimaging

Early postoperative MRI and CT scans and 3-month follow-upscans excluded any bleeding complications. Microporous poly-saccharide hemospheres were no longer detectable even as early aspostoperative day 1; there was no tumor mimicking contrastenhancement (Figures 4 and 5). The volume measurement(Table 4) revealed preoperative tumor volumes between 0.86 and150.55 cm3 (Figures 4A and 5A). The analysis of the postoperativehematoma in the resection cavity revealed up to 5.62 and 6.22 cm3

FIGURE 4. Preoperative T1-weighted gadolinium-enhanced MRI scan of patient 14. A, enlarged tumor. Histopathologicaldiagnosis revealed a glioblastoma multiforme. B, postoperative CT scan of the same patient. The contrast-enhanced CT showedcomplete resection of the enhancing part of the tumor. Minimal hematoma is found in the resection cavity. Microporouspolysaccharide hemospheres appear not to be visualized.





FIGURE 5. Neuroradiological imaging of patient 20. A, preoperative MRI scan revealed an enlarged frontal tumor(T1-weighted images with gadolinium enhancement). Histopathological examination confirmed the diagnosis ofglioblastoma multiforme. B, postoperative CT scan from the day of operation showed no bleeding complication. C,postoperative MRI scan (left, T1 without gadolinium enhancement; right, T2 without gadolinium enhancement)within 72 hours detected a small hematoma (4.6 cm3;) at the border of the resection cavity wall, possibly representingthe microporous polysaccharide hemosphere–related stable blood clot.

TSCHAN ET AL




in patients 3 and 27. Both patients suffered from enlarged tumors(patient 3, glioblastoma; patient 27, meningioma). However, therewas a very subtle layer of clotted blood within the cavity in the vastmajority of cases. In 13 of these cases, the postoperative hematomawas , 1 cm3 (Table 4 and Figure 5B and 5C).

Hemostasis Effect of MPHs

The subjective impression of the 5 neurosurgeons was thatMPHs caused very fast and sufficient hemostasis. Subjectiveranking of the handling and hemostasis effect showed excellentneurosurgeon satisfaction (Figure 6). To achieve full hemostasis,

TABLE 1. Patient Population Including Clinical Examination, Follow-up Examination, and Histopathological Diagnosisa

Patient Sex Age, y

Clinical Symptoms

Before Operation

Anticoagulation

Before Operation

Histopathological

Findings

Follow-up

Examinations

up to 3 mo, n

Signs of

Embolic/

Allergic

Reaction

1 F 61 Aphasia, spinocerebellar ataxia,

hemiplegia

No Glioblastoma WHO grade IV 3 No

2 M 73 GAIT ataxia, vertigo, dysarthria Acetylsalicylic acid

paused

Cerebellar metastasis 2 No

3 F 53 Hemianopsia No Glioblastoma WHO grade IV 3 No

4 M 72 Gait ataxia, urinary incontinence Acetylsalicylic acid

paused

Anaplastic oligoastrocytoma III 3 No

5 M 55 Aphasia Acetylsalicylic acid

paused

Glioblastoma WHO grade IV 3 No

6 M 84 Fine motor skills disorder, paresthesia Acetylsalicylic acid

paused


7 F 52 Vertigo, headache, gait ataxia Enoxaparin 40 mg/d Cerebellar metastasis 2 No

8 F 56 Facial nerve paresis, spastic

hemi-paresis, hyperesthesia, seizure

Acetylsalicylic acid

paused


9 F 59 Facial nerve palsy, hemiparesis No Glioblastoma WHO grade IV 2 No

10 M 47 Hemiparesis, vertigo No Glioblastoma WHO grade IV 2 No

11 F 55 Aphasia No Meningioma WHO grade III 3 No

12 M 65 Hemiparesis, vertigo, dysarthria No Glioblastoma WHO grade IV 4 No

13 M 47 Hemiparesis, vertigo, hemianopsia No Glioblastoma WHO grade IV 3 No

14 M 50 Headache, nausea, facial nerve palsy No Glioblastoma WHO grade IV 2 No

15 F 50 Seizure, headache No Oligoastrocytoma WHO grade III 2 No

16 F 70 Focal epilepsy Acetylsalicylic acid

paused

Cerebral metastasis 3 No

17 M 64 Headache, nausea, emesis No Ependymoma of the IVth

ventricle

2 No

18 M 65 Headache, nausea, personality changes No B-cell lymphoma 3 No

19 F 65 Headache, vertigo, hemianopsia,

memory disturbance

No Glioblastoma WHO grade IV 3 No

20 F 29 Headache, nausea No Glioblastoma WHO grade IV 1 No

21 M 76 Personality changes, disorientation No Astrocytoma WHO grade III 3 No

22 M 48 Depression No Astrocytoma WHO grade III 0 No

23 M 48 Aphasia No Oligoastrocytoma WHO grade III 2 No

24 M 63 Facial nerve palsy, cerebellar ataxia,

dysarthria

No Cerebellar metastasis 2 No

25 M 67 Seizure, headache Acetylsalicylic acid

paused

Low-grade glioma 3 No

26 M 44 Headache, disorientation No Glioblastoma WHO grade IV 0 No

27 F 75 Seizure, headache No Meningioma WHO grade I 3 No

28 F 81 Headache No Meningioma WHO grade I 0 No

29 F 22 Seizure, headache No Astrocytoma WHO grade II 0 No

30 M 68 Seizure, headache, aphasia Dalteparin paused Cerebral metastasis 3 No

31 F 60 Aphasia No Meningioma WHO grade I 3 No

32 F 41 Gait ataxia, imbalance No Cerebellar metastasis 3 No

33 M 50 Focal epilepsy No Glioblastoma WHO grade IV 3 No

aF, female; M, male; WHO, World Health Organization. Neurological follow-up examination was summarized by a point system: 0 = no neurological deficit; 1 = neurological

deficit; 2 = clinical improvement; 3 = stable disease; 4 = progression of deficit.





various doses of MPHs had to be applied. In 14 cases, the smallblister of 1 g was adequate to stop the bleeding (Figure 2). Forenlarged tumors, up to 3 g was applied (Table 2). After theapplication and contact period of MPHs, no additional hemo-stasis was performed (Figure 3 and Video 1). Before dural closure,the resection cavity was sometimes filled with isotonic salinesolution. In 18 cases, there was no additional fluid applied toavoid flushing of the MPH powder.

DISCUSSION

Bleeding complications after brain tumor resection are observedin 0.8% to 1.5% of all procedures, 60% occurring intracerebrally,

30% epidurally, and 10% subdurally.40 For malignant braintumors, the bleeding risk is even higher at 1% to 4%.41-44 Thesesecondary postoperative hemorrhages cause permanent morbidityin up to 33% of all patients with bleeding complications.43

Especially in brain tumor surgery, diffuse bleeding can bedifficult to manage and often prolongs the surgical time. Con-ventional hemostasis is normally done by electric tissue co-agulation. Because of thermal side effects and the difficulty ofcoagulating diffuse bleedings, several topical hemostatic agentsare in neurosurgical use. After brain tumor resection, these agentscan mimic tumor relapse or infection because of gadoliniumenhancement in the postoperative MRI. Additionally, granulomaformation, allergic reaction, or increased infection rates limit theapplication of topical hemostatic agents.

TABLE 2. Operative Results Including Video Analysisa

Patient

Operating

Time, min

Application

Time, s

Hemostasis

Time, s

Interruption

After

Complete

Hemostasis, s

Arista

Dose, g

Blood

Loss

Total, mL

Transfusion of Red

Blood

Cells, mL

1 225 25 25 608 1.0 400 0

2 186 170 170 250 1.0 70 0

3 208 202 202 272 2.0 1300 800

4 214 90 90 390 1.0 200 0

5 184 88 88 243 3.0 120 0

6 157 40 40 70 1.0 100 0

7 195 52 52 114 1.0 110 0

8 190 47 47 107 1.5 250 0

9 133 14 14 45 1.5 100 0

10 86 10 10 610 2.0 150 0

11 224 25 25 265 1.0 1400 1150

12 219 36 36 56 3.0 900 720

13 90 17 17 80 3.0 350 0

14 226 146 146 332 2.0 150 0

15 196 11 11 311 2.5 200 0

16 60 18 18 618 1.0 160 0

17 218 155 155 635 1.0 420 0

18 59 8 8 608 1.0 380 0

19 85 70 70 370 1.0 300 0

20 235 116 116 176 3.0 300 0

21 150 11 11 28 2.0 360 0

22 81 18 18 78 0.5 80 0

23 163 44 44 944 2.0 200 0

24 114 37 37 97 0.75 520 800

25 137 33 33 153 1.5 250 0

26 176 90 90 150 1.0 250 0

27 156 80 80 200 3.0 1750 540

28 139 48 48 140 3.0 170 0

29 122 49 49 77 1.0 350 0

30 111 24 24 92 1.0 300 0

31 110 30 30 750 3.0 200 0

32 169 40 40 45 1.0 170 0

33 108 32 32 52 3.0 180 0

aDisplayed are the measured time intervals of Arista application, the hemostasis time using only Arista for the final hemostasis procedure before dura closure, and the total time

of interruption of the procedure from the beginning of microporous polysaccharide hemosphere application until continuation, including a surgical pause for some individual

surgeons.

TSCHAN ET AL




TABLE 3. Evaluated Blood Parametersa

Patient

Time of

Examination

Hb

(12-16 g/d)

Hct

(39%-44%)

Erythrocytes

(3.7-4.8/pL)

Leukocytes

(3.5-10/nL)

Eosinophils

(# 7%)

1 Preoperative 13.3 39.2 4.32 7.69 0.3

Intraoperative 10.6 30.6 3.40 5.94 0.3

Postoperative 10 31.1 3.18 4.24 1.4

2 Preoperative 16.8 48.8 5.52 11.8 ND

Intraoperative 11.0 33.9 4.53 11.8 0.7

Postoperative 14.7 45.1 4.60 25.6 1.0

3 Preoperative 11.4 35.6 4.38 10.1 ND

Intraoperative 8.6 26.7 3.20 9.8 1.2

Postoperative 8.1 24.2 2.99 4.5 0.9

4 Preoperative 13.7 42.8 4.82 7.83 ND

Intraoperative 11.2 35.6 2.99 8.46 0.1

Postoperative 12.5 37.4 4.26 19.0 0.1

5 Preoperative 16.0 47.0 5.38 15.3 ND

Intraoperative 13.1 38.1 4.38 10.5 0.3

Postoperative 13.7 42.2 4.77 23.4 0.3

6 Preoperative 14.9 44.0 5.13 14.3 ND

Intraoperative 12.8 37.8 4.40 11.9 0.1

Postoperative 15.5 45.3 5.32 24.4 0.1

7 Preoperative 14.0 41.7 4.65 12.6 ND

Intraoperative 10.1 30.5 3.42 11.8 0.1

Postoperative 11.6 33.2 3.78 21.2 0.0

8 Preoperative 12.4 33.6 4.7 9.6 ND

Intraoperative 9.1 26.7 3.08 5.14 0.9

Postoperative 11.2 32.4 3.80 12.8 0.4

9 Preoperative 12.9 38.4 4.44 9.46 ND

Intraoperative 10.0 29.8 3.48 6.93 0.0

Postoperative 11.3 33.9 3.98 12.2 0.0

10 Preoperative 16.9 50.0 5.62 11.8 ND

Intraoperative 13.2 39.9 4.37 6.96 1.6

Postoperative 15.2 45.2 5.05 15.0 0.0

11 Preoperative 13.1 39.7 4.27 16.0 ND

Intraoperative 8.4 23.9 2.84 10.9 0.1

Postoperative 9.6 27.7 3.27 20.5 0.1

12 Preoperative 10.8 34.1 3.67 5.26 ND

Intraoperative 10.5 32.4 ND ND ND

Postoperative 10.4 30.8 3.44 11.2 ND

13 Preoperative 16.0 45.6 5.20 14.5 ND

Intraoperative 12.6 37.5 4.18 9.53 0.7

Postoperative 14.9 44.4 4.97 18.6 0.5

14 Preoperative 17.5 47.9 5.28 10.3 ND

Intraoperative 14.8 42.3 4.61 9.96 0.1

Postoperative 15.4 43.6 4.71 19.3 0.1

15 Preoperative 14.3 42.8 4.79 5.99 ND

Intraoperative 10.2 29.9 3.39 6.78 0.3

Postoperative 9.3 27.7 3.08 11.2 0.1

16 Preoperative 12.6 36.4 4.18 9.7 ND



17 Preoperative 14.1 41.9 4.44 6.07 ND

Intraoperative 10.9 32.6 3.50 9.57 0.1

Postoperative 12.3 35.9 3.89 17.0 0.1

18 Preoperative 14.0 41.9 4.52 8.23 ND

Intraoperative 12.8 38.3 4.15 7.34 1.1

Postoperative 12.2 35.7 3.90 19.1 0.1

19 Preoperative 13.6 41.8 4.93 11.4 ND

(Continues)





TABLE 3. Continued

Patient

Time of

Examination

Hb

(12-16 g/d)

Hct

(39%-44%)

Erythrocytes

(3.7-4.8/pL)

Leukocytes

(3.5-10/nL)

Eosinophils

(# 7%)



20 Preoperative 14.4 42.7 4.86 14.2 ND

Intraoperative 10.7 30.2 3.54 7.49 0.3

Postoperative 10.3 29.7 3.50 16.2 0.2

21 Preoperative 13.2 38.5 4.71 12.5 ND

Intraoperative 13.7 40.7 4.89 9.12 0.4

Postoperative 13.4 39.8 4.78 14.1 0.3

22 Preoperative 14.2 41.6 4.84 7.99 ND

Intraoperative 11.5 34.5 4.09 6.1 5.1

Postoperative 13.1 39.1 4.65 19.7 0.1

23 Preoperative 14.1 40.6 4.54 8.40 ND

Intraoperative 12.0 33.1 3.72 15.9 0.0

Postoperative 12.1 36.5 3.97 12.4 0.1

24 Preoperative 11.4 35.2 3.77 14.0 ND

Intraoperative 10.0 29.9 3.37 10.6 0.5

Postoperative 12.7 38.4 4.40 23.1 1.4

25 Preoperative 13.7 37.9 4.48 7.20 ND

Intraoperative 11.7 35.2 3.96 8.18 0.5

Postoperative 12.1 35.5 4.10 12.8 0.2

26 Preoperative 14.7 44.4 5.32 16.60 ND

Intraoperative 12.7 37.2 4.68 12.50 0.2

Postoperative 14.6 44.2 5.33 14.8 0.4

27 Preoperative 13.1 38.7 4.51 9.98 ND

Intraoperative 7.6 22.9 2.70 3.91 ND


28 Preoperative 11.4 33.8 4.32 7.2 ND



29 Preoperative 11.8 34.4 4.05 9.83 ND



30 Preoperative 13.3 40.8 4.42 14.50 ND



31 Preoperative 13.9 41.1 4.73 7.94 ND

Intraoperative 10.2 29.8 3.47 5.29 1.1

Postoperative 10.6 31.8 3.59 8.03 0.6

32 Preoperative 13.7 39.1 4.81 9.11 ND

Intraoperative 12.5 36.8 4.44 6.70 0.1

Postoperative 13.1 36.9 4.58 10.9 0.2

33 Preoperative 13.7 40.4 4.50 10.1 ND

Intraoperative 11.7 33.6 3.83 6.73 0.2

Postoperative 13.0 39.2 4.29 7.72 0.3

Patient Thrombocytes (150-360/nL) Quick (70%-120%) INR APTT (26-36 s) Blood Transfusion, mL

Blood Loss

Total, mL

1 346 94 1.0 31.2

271 109 0.9 27.3

204 87 1.1 120 0 400

2 296 97 1.0 25.7

275 75 1.2 26.2

241 114 0.9 23 0 70

3 306 104 1.0 25.3

(Continues)

TSCHAN ET AL




TABLE 3. Continued


Blood Loss

Total, mL

224 69 1.2 27.8

199 54 1.4 103 800 1300

4 221 113 0.9 26

208 102 1.0 27.8

163 93 1.0 31.2 0 200

5 350 101 1.0 24.0

307 91 1.1 24.2

308 108 1.0 23.6 0 120

6 311 94 1.0 23.4

246 81 1.1 24.7

270 94 1.0 25.3 0 100

7 284 104 1.0 29.0

229 96 1.0 32.8

251 103 1.0 27.8 0 150

8 195 92.0 1.1 29.2

140 84 1.1 31.4

207 104 1.0 24.7 0 250

9 257 87 1.1 25.4

213 75 1.2 27.8

256 88 1.1 24.7 0 100

10 280 110 0.9 26.8

218 106 1.0 31.4

231 122 0.9 28.2 0 150.0

11 562 101 1.0 20.0

178 63 1.2 35.4

214 74 1.1 31.1 1150 1400

12 151 78 1.1 34.8

ND ND ND ND

116 81 1.1 35.2 720 900

13 196 110 0.9 26.0

158 ND ND ND

263 120 0.9 24.1 0 350

14 213 97 1.0 26.2

185 ND ND ND

207 102 1.0 28.1 0 150

15 280 107 1.0 26.0

194 84 1.1 24.9

183 87 1.1 31.1 0 200

16 383 114 0.9 29.3

ND ND ND ND

304 101 1.0 31.1 0 160

17 255 103 1.0 31.6

197 95 1.0 35.6

222 111 0.9 29.9 0 420

18 288 113 0.9 27.9

298 109 0.9 27.3

237 95 1.0 28.1 0 380

19 364 105 1.0 24.8

ND ND ND ND

438 92 1.1 25.5 0 300

20 353 105 1.0 28.7

251 69 1.2 31.7

210 94 1.0 31.9 0 300

21 188 95 1.0 25.4

152 80 1.1 22.5

(Continues)





In the present study, full hemostasis was achieved aftera mean period of 57 seconds (range, 8-202 seconds). The op-erative blood loss after application of MPHs was very low. Inmost cases, the diffuse bleeding from the resection cavitystopped immediately. For additional safety, some surgeonswaited up to 15 minutes. The topical agent was rated highlyeffective and feasible by the performing neurosurgeons. No sideeffects were observed. Thus, on the basis of the very limited dataof this series, the topical application of MPHs seems to befeasible for sufficient hemostasis in neurosurgical procedures.The avoidance of any diathermia application makes final he-mostasis with this device potentially less invasive. Additionally,

MPHs can be applied safely and easily in conjunction withbipolar electrocautery and other hemostatic agents. MPHs caneasily be sucked away, and the procedure can be continued.Before definite conclusions can be drawn, some peculiaritieshave to be discussed, and more data should be obtained.In 1 of 33 cases, arterial bleeding from the falx required the

additional use of bipolar electrocautery. This failure might berelated to the location of the bleeding vessel because the positionand surface of the falx might make the adhesion of the MPHpowder to the orthogonal surface difficult. However, this is justa hypothetic explanation. More data are required before anyconclusions can be made.

TABLE 3. Continued


Blood Loss

Total, mL

141 72 1.2 30.0 0 360

22 457 124 0.9 26.7

360 104 1.0 31.3

400 124 0.9 26.6 0 80

23 359 110 1.0 31.1

432 105 1.0 31.5

335 111 0.9 30.1 0 200

24 111 116 0.9 26.4

97 98 1.0 32.0

122 126 0.9 25.6 800 520

25 354 95 1.0 34.5

241 87 1.1 35.8

215 89 1.1 37.6 0 250

26 320 91 1.1 25.8

293 78 1.1 27.4

372 113 0.9 24.2 0 250

27 277 95 1.0 28.2

119 60 1.3 48.0

156 97 1.0 30.5 540 1750

28 112 114 1.0 31.6

97 104 1.0 32.1

99 105 1.0 33.2 0 170

29 373 108 1.0 25.6264 99 1.0 30.7

243 102 1.0 28.3 0 350

30 278 101 1.0 30.6

204 ND ND ND

215 81 1.1 50.9 0 300

31 290 112 0.9 27.4

202 76 1.2 34.2

222 108 0.9 35.6 0 200

32 236 85 1.1 21.9

173 72 1.2 22.5

149 82 1.1 24.5 0 170

33 341 115 0.9 25.5

202 106 1.0 30.3

244 120 0.9 26.1 0 180

aAPTT, activated partial thromboplastin time; Hb, hemoglobin; Hct, hematocrit; INR, international normalized ratio; ND, not determined.

TSCHAN ET AL




In 8 patients (25%), the ventricles were opened, and MPHscame in contact with the cerebrospinal fluid. No development ofpostoperative hydrocephalus was evident. Thus, the agent mightalso be suited for application within the cerebrospinal fluid or atthe skull base. Again, more data are required before any con-clusions can be drawn and definite statements can be made.

No adverse reactions such as inflammatory disease or allergicreaction have been reported for other surgical disciplines. This isfurther supported by the results of the present study. Thepostoperative MRI and CT findings revealed neither granulomaformation nor tumor or inflammation mimicking contrastenhancement caused by MPHs. Microporous polysaccharidehemospheres were not detectable in the MRI and CT scans;a rapid enzymatic absorption by the amylolytic enzyme also seems

to be possible in human brain tissue. Although the risk ofgranuloma formation or infection has to be considered very lowwith other hemostatic agents, the rapid degradation of MPHscould potentially represent another advantage compared withother topical hemostats. One of the major strengths of MPH isthat it is not derived from humans or animals. Thus, the riskswith animal-derived products such as hypersensitivity reactionsand infectious disease transmission are avoided.Another issue with intraoperative application of any agents is

their expansion in the limited intracranial space. In the presentseries, we have not observed any significant swelling or expansionof MPHs in any patient. However, this might still be an issuewith MPH application and has to be addressed in future studies.MPHs are inexpensive compared with other topical hemostats,

particularly those of human or animal origin. With the reducedsurgical time and low price, the use of MPHs could possibly bemore cost-effective, although no conclusions on this issue can bedrawn from the present data.On the basis of the limited data of the present series, the

primary benefits of MPH application could be a shortening ofhemostasis time, a reduction of blood loss, and potentiallya reduction of secondary bleeding complications after partial ortotal tumor resection. However, there was no head-to-headcomparison with anything else. The reduction of secondarybleeding complications cannot be addressed without a propercontrol group. Thus, any conclusions have to be drawncarefully.The best results might be achieved in diffuse moderate bleeding

from the resection cavity walls. The white powder also allows fastvisualization of remnant or recurrent bleeding. Another advantageof the technique is that no thermal side effects to healthy brain

TABLE 4. Volumetric Analysis of the Preoperative and

Postoperative Magnetic Resonance Imaging and Computed

Tomography Scans Done by Segmentation for Tumor Size,

Resection Cavity, and Postoperative Hematoma

Patient

Tumor

Volume, cm3Resection

Cavity, cm3Postoperative

Hematoma, cm3

1 8.00 66.30 1.31

2 18.26 21.63 2.20

3 150.55 145.41 5.62

4 66.03 67.21 0.87

5 0.86 0.91 0.45

6 24.20 24.53 0.57

7 11.23 11.32 1.53

8 48.00 22.62 3.87

9 45.04 45.15 2.08

10 55.13 61.25 1.30

11 132.11 142.06 1.33

12 100.05 99.12 5.10

13 85.03 85.55 0.96

14 54.82 55.75 0.61

15 11.09 27.96 1.36

16 6.65 5.90 0.16

17 34.36 22.67 2.85

18 21.34 24.07 1.00

19 8.86 11.81 0.26

20 123.60 128.56 4.60

21 46.38 51.47 2.56

22 18.61 25.16 1.89

23 41.31 46.47 0.80

24 2.41 2.89 0.42

25 17.81 22.84 3.53

26 23.76 22.53 0.70

27 56.04 38.34 6.22

28 40.46 43.81 1.88

29 11.99 14.67 2.32

30 53.83 26.61 1.38

31 15.64 14.89 0.59

32 22.94 23.01 0.98

33 29.30 29.85 0.86

FIGURE 6. Bar graphs of subjective ratings performed by the 5 neurosurgeonsinvolved in this study (mean and standard deviation). The subjective rating is forhandling of the microporous polysaccharide hemospheres and the applicator,impression of the hemostatic effect, and general satisfaction with the new method.0 = useless; 1 = equivocal; 2 = useful; 3 = excellent.





tissue occur. This is especially interesting for tumor resection ineloquent areas such as the central region or speech area.

CONCLUSION

This is the first study of MPH application to human braintissue. Microporous polysaccharide hemospheres allow very fastand effective hemostasis in brain tumor procedures. In mostcases, a single application is sufficient for full and long-lastinghemostasis. No adverse reactions have been evident so far in thissmall series. This study should be followed by a larger pro-spective randomized trial to further evaluate the potential of thisagent.

Disclosure

This study was supported by a grant from Friedhelm-Frees Stiftung,Wiesbaden, Germany. The authors have no personal financial or institutionalinterest in any of the drugs, materials, or devices described in this article.

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Acknowledgment

The authors gratefully acknowledge S. Kindel, MSc, for excellent support withthe artwork.





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