Annuls of OioloKy. Rhiiioiofiy & tuiryngotogy 114(9):6'J9-7()4, 2(H)5 Annals Publishing Company. All rights reserved.

Platelet Gel for Endoseopic Sinus Surgery

Jonathan Pomerantz. MD: Jay M. Dutton. MD
Objectives: New techniques are being utilized to improve outcomes for endoseopic sinus surgery, including newer forms of packing. Platelet gel is an innovative technique that holds many advantages, including comfort, hemostasis. and growth factors that may improve wound healing. This report discusses the theoretical advantages of this packing material and describes the initial results in a cohort of patients who underwent endoseopic sinus surgery. Methods: A cohort of patients who underwent endoseopic sinus surgery were interviewed and evaluated after the placement of platelet gel. A quality of life study was also administered for further understanding. Results: None ofthe patients in the study had postoperative episiaxis that required additional packing, and there were tio instances of synechia formation or exuberant granulation tissue. Although not statistically significant because of a small population, the quality of life scores did show improvement over the control group. Conclusions: Platelet gel used as a packing material after endoseopic sinus surgery offers efficient hemostatic properties, as well as growth factors that can advance the healing process. The quality of life ofthe patient may be improved by the use of platelet gel packing. Key Words: autologous platelet gel. endoseopic sinus surgery, packing, paranasal sinus, platelet-poor plasma, plateletrich plasma, wound healing.

Sinus surgery has evolved in tnany ways over the past several decades. Many technological advances such as the nasal endoscope. computed tomographic scanning, computer-aided surgery, and microdebriders have helped to develop a more preci.se, more efficacious, and less Invasive form of sinus surgery. The packing utilized during such surgeries has also evolved. Becau.se earlier sinus procedures were often performed through external approaches and involved significant mucosal stripping, they required extensive gauze packing for hemostasis. Smaller sinus sponge packs have evolved, but still involve some discomfort upon removal and entail the risk of aspiration or toxic shock syndrome. Absorbable packs have been developed, but many involve their own risks. Fibrin glue has been available for approximately 30 years.' but utilizes pooled blood products and therefore risks transmission of communicable diseases. Products that utilize bovine collagen have also been developed, but are associated with a risk of allergic reaction. Moreover, studies have demonstrated that certain types of absorbable packing tnay actually impair wound healing and lead to increased scar tissue formation.--'' The ideal packing for sinus surgery would therefore exhibit several features.

1. Hemostasis. Perhaps the most important feature is to prevent hemorrhage. 2. Autogeny. The ideal packing material would not have a risk of transmissible disease or allergic reaction. 3. Comfort. Such a packing would be absorbable, so the patient would not have to endure a painful packing removal. 4. Wound healing properties. The ideal packing material would not only avoid retardation ofthe healing process; it would contain growth factors to actually improve wound healing. Platelet gel (PG) may bejust such a material. Platelet gel is a fibrin tissue adhesive produced from autologous platelet-rich plasma (PRP). It is a plateletbased wound sealant created from centrifugation of whole blood. The centrifuge separates the PRP from the red blood cell pack and platelet-poor plasma (PPP). Depending on the initial platelet counts, it is not uncommon to achieve platelet counts of 500,000 to 1 million microliters per 5 mL of PRP from this 3-component separation technique. Platelet gel differs from fibrin glue in that the former contains a higher concentration of platelets and a native concentration of fibrinogen. Platelet gel also contains many growth

From the Department (tf Otolaryngology and Bronchoesophagology. Rush University Medical Center. Chicago. Illinois. Presented al Ihe mcctinj; ofthe American Rhinologic Society. Orlando. Florida. September 20. 2003Correspondente: Jay M. Duiion, MD. 1725 W Harrison Si. Suite 340. Chicago. IL 6()(il2.
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700 The Intrinsic Pathway

Pomerantz & Diitton. Platelet Gel for Endoscopir Sinus Surgery The Extrinsic Pathway

Fig 1. Clolting cascade. HF Hageinan factor. (Information from Sherwood L. Human physiology. Pacific Grove. Calif: Brooks/Cole Publishing Co. 2001:383.)

Xllla

Fibrin Polymer

Crossed Linked Fibrin Polymer

factors such as platelet-derived growth factor (PDGF) and transforming growth factor (TGF). Platelet gel has been used in many medical disciplines, such as plastic surgery, oral surgery, and orthopedic surgery, in which it has been shown to improve wound healing and postoperative results.'^-'' Although it would appear on the surface to be an ideal packing material, it has not yet been embraced in rhinology. in which it has received only a single description to date (M. Kerner. presentation to American Rhinologic Society. 2001). In this study, we present our initial experience with this relatively new and fascinating technology in a cohort of patients undergoing endoscopic sinus surgery (ESS). BASIC SCIENCE REVIEW Although many steps in the process of wound healing are yet to be clarified, an understanding of the basic process is necessary to understand the utility of PG. The process itself consists of 3 phases; the inflammatory phase, the proliferative phase, and the maturation and remodeling phase. A combination of cellular responses, including platelets, growth factors, and cytokines, is inherent to this process. The initial phase is the inflammatory phase, which consists of 2 components: inflammation and hemostasis. Collagen exposure acts as the signal to begin the event by interacting with kininogen and prekallikrein. or factor XII (Hageman factor). This then signals the activation of the intrinsic pathway. Factor XII activates factor XI, which then activates factor IX. Along with factor VIII and calcium, factor IX activates factor X. At the same time, thromboplas-

tin is being released because of the tissue injury. This compound, fonned from phospholipids and glycoproteins. activates factor VII as a part of the extrinsic pathway. The 2 pathways (extrinsic and intrinsic) meet as factor VII also activates factor X. This now combined pathway begins with factors X and V and calcium interacting to form thrombin from prothrombin. Thrombin acts to convert fibrinogen to fibrin monomers while at the same time activating factor XIII. Factor XIII can then polymerize the fibrin monomers by cross-linking them into an organized clot. This structural matrix allows monocytes. keratinocytes. and fibroblasts to adhere to the wound area-"^-^ (Fig I). The recruitment of these cells is enabled by platelets. These release epidermal growth factor (FGF), fibronectin. fibrinogen. histamine. PDGF. serotonin, and von Willebrand's factor. Clot formation can thus commence and further stabilize the wound. Hemostasis is thus activated. With the help of thromboxane and serotonin released by platelets, vasoconstriction is then also activated, which aids in hemo.stasis and prevents the dissipation of local tissue factors from the injury site."^ Other cells and factors are still allowed to enter the area because of a vascular permeability increase stimulated by histamine. The inflammatory phase continues with the migration of polymorphonuclear leukocytes, which function to scavenge debris and opsonized bacteria and destroy bacteria via superoxide and hydrogen peroxide formation. This process gives the wound the opportunity to continue the healing process in the elimination of infection. The secreted chemokines also attract macrophages

Pomerantz & Dutton, Platelet Gel for Endoseopic Sinus Surgery GROWTH FACTORS AND THEIR FUNCTIONS Cvtokine Platelet-derived growth factor Transforming growth factor a Transforming growth factor p Celh of Origin Platelets, macrophages. endothclial cells Macrophages, T lymphocytes, keratinocytes Platelets, T lymphocytes, macrophages, endothelial cells, keratinocytes Platelets, macrophages Macrophages, mast cells. T lymphocytes, endotheiial cells Fibroblasts Macrophages, mast cells. T lymphocytes Macrophages. mast cells, keratinocytes, lymphocytes Functions

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Cell chemotaxis, mitogenesis of fibroblasts, stimulation of angiogenesis. stimulation of wound contraction Mitogenesis of keratinocytes and fibroblasts, stimulation of keratinocyte migration Cell chemotaxis, stimulation of angiogenesis and fibroplasia Mitogenesis of keratinocytes and fibroblasts, stimulation of keratinocyte migration Chemotaxis and mitogenesis of fibroblasts and keratinocytes, stimulation of angiogenesis Stimulation of keratinocyte migration, differentiation, and proliferation Activation of macrophages, mitogenesis of fibroblasts, stimtjlation of angiogenesis IL-1: induction of fever and adrenocorticotropic hormone release, enhancement of tumor necrosis factor a and interferon-y. activation of granulocytes and endothelial cells, stimulation of hematopoiesis lL-2: activation of macrophages. T cells, natural killer cells, and lymphokine-aclivated killer cells; stimulation of differentiation of activated B cells; stimulation of proliferation of activated B and T cells; induction of fever IL-6: induction of fever, enhancement of release of acute-phase reactants by liver IL-8: enhancement of neutrophil adherence, chemotaxis. and granule release Activation of macrophages, inhibition of fibroblast proliferation Potent vasoconstriction

Epidermal growth factor Fibroblast growth factor Keratinocyte growth factor Tumor necrosis factor Interleukins 1, 2. 6. and 8

Interferons a, p, and A Thromboxane A2 Modified from Rosenberg.^

Lymphocytes, fibroblasts Destroyed wound cells

that secrete enzytnes and cytokines. Collagenases are included, which debride the wound. The tumor necrosis factor (TNF) and interleukins secreted stimulate fibroblasts that produce collagen and promote angiogenesis. Transforming growth factor stimulates keratinocytes and significantly increases and stimulates the deposition of an extracellular matrix.-^ The proliferative stage follows as the second stage of wound healing. With the aid of angiogenesis and the fibroblastic deposition of a new extracellular matrix, a new growth develops, consisting of mucopoly.saccharides, elastin. and collagen. Angiogenesis occurs by endothelial migration under the guidance of TNF-a. This forms new capillaries vital for nourishing the granulation tissue bed. The fibroblasts are afforded the opportunity to continue collagen deposition and use tbe assistance of growth factors such as PDGF. insulin-like growth factor (IGF), and FGF. During this time, epithelialization occurs as normal epithelial cells from the periphery migrate inward. If there is an intact basement membrane below tbe wound, epithelial cells migrate inward.'' The final phase of remodeling and maturation of the wound follows. The mature scar forms as a care-

ful balance between collagen lysis and collagen formation, with the realignment of collagen fibers for optimal strength.^ The Table^ reviews the various growth factors and cytokines. Within the paranasal sinuses, the wound healing process takes 12 to 18 weeks for normal mucosa to form. The healing process is divided into 4 phases: hemorrhagic crusting, obstructive lymphatic edema, mesenchymal tissue reaction, and scar formation.^ Blood crust formation over the whole wound occurs in the first 7 to 12days. By 2 to 4 weeks, granulation tissue is visible. An increasingly edematous .swelling then reaches its maximum by the 3rd to 5th weeks and decreases in the 7th to 12tb weeks.^ Wound healing in the sinuses follows a concentrically regenerating pattern.'" MATERIALS AND METHODS This was a retro.spective .study. Platelet gel was instituted for a 6-month period from October 2002 through March 2003. during which all patients (16) who underwent ESS received PG for their sinus packing. These patients were then matched to a cohort of the previous 16 patients who had undergone ESS with

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Pomerantz & DttUon. PlaieleJ Gel for Endoseopic Sinus Surgery-

Fig 4. Platelei gel lorni... ...,., .oiiibiriatioii of plateletrich plasma and thrombin-calcium. (Compliments of PPAI Medical. Fort Myers, Florida.) Fig 2. AulologoLS blood preparation just before centrifugation.

traditional packing for whom adequate follow-up data were available. The latter group had received conventional packing with Kennedy Merocel sponges after surgery (control group), and the "PG" group received PG packing. Each group completed 2 validated quality of life (QOL) surveys. One survey was filled out in reference to how the patient felt before surgery, and the second referred to how he or she felt after surgery. The QOL survey used was the SNOT16 (Sinonasal Outcome Test. 16 question). The survey includes questions on topics such as facial pain and pressure, sleeping issues, and postnasal drip, among others. The SNOT-16 is a validated survey and a popular assessment of QOL for sinus patients." After receiving the results of 12 patients (6 from each group), we scored the surveys and analyzed the data to assess any difference between the 2 groups. The patients who received PG represented 16 consecutive ESS patients from October 2002 through March 2003. In.stitutional review board approval was obtained for the use of this technology within the hospital. These patients were compared to the previous 16 patients who had undergone ESS with traditional nasal pack-

ing. All patients underwent ESS for chronic sinusitis: the majority had operations on the maxillary, ethmoid, sphenoid, and frontal sinuses. At the completion of surgery, each group received nasal packing. The control group received bilateral preformed Merocel packs. The study group received PG. For the latter group, before operation. 88 mL of whole blood was drawn and placed into a standard blood collection bag containing citrate-phosphate-dextrose anticoagulant (Fig 2). The blood was then centrifuged to separate the buffy coat suspended in the plasma from the red cell pack and the PPP fraction. Secquire (PPAI Medical, Fort Myers, Florida) and Magellan (Medtronic, Inc, Minneapolis, Minnesota) centrifuge systems were utilized; this equipment is specifically designed to prepare PG and may not yet be readily available at most hospitals. The concentrated buffy coat was then combined 10:1 with thrombin-calcium (Fig 3) to form a solution in which the platelets interdigitated with fibrin to create a gel (Fig 4). Typically, 8 mL of gel was injected into each sinus cavity at the completionof the surgery, for a total of 16 mL of gel per patient. The gel is soluble; thus, no packing removal is necessary, although it is typically removed during subsequent postoperative debridements. The preparation time for PG is roughly 30 minutes, although preparation can be performed by a perfusionist concurrent to the ESS so that it does not add to the overall operating room time. Platelet gel is viable for roughly 6 hours after harvest. Follow-up visits of these patients were recorded over at least 21 weeks (147 days). A QOL survey .study was then carried out as further assessment, de.scribed in the section below. This is to be considered as a "phase I" trial of our cohort. The SNOT-16 surveys were provided to 32 patients (16 from each group), I survey relating to preoperative symptom scores and 1 relating to postoperative scores. For each symptom in the survey, the patient selects a score of 0 to 3. A score of 3 indicates a severe problem, and 0 indicates no problems at all. A total score is then re-

Fig 3. Platelet-rich plasma combined 10:1 with Ihrombin-calcium.

Pomerantz & Dutton. Platelet Gel for Endoscopic Sinus Surgery

703

corded as a mean of all categories answered. Higher scores indicate a poorer QOL. Change scores, both relative and absolute, are then assessed by comparing pretreatment and posttreatment surveys. A higher absolute change score would indicate a more improved state, and a lower relative change score would also indicate a greater improvement. Five additional questions were added to the study asking about the difficulty of the surgery, whether the patient would recommend the surgery to others, the patient's preference for a type of packing, the level of nasal congestion immediately after the operation, and the amount of medication needed the first week after surgery. The answers to these questions were recorded and totaled. RESULTS Sixteen patients have undergone a trial of PG packing after ESS. All patients were seen every 1 to 2 weeks during the first 2 months after the operation, and they were carefully examined endoscopicaliy at each visit. None of these patients had postoperative epistaxis that required additional packing. There were no instances of synechia formation that required office correction, and there was no evidence of exuberant granulation tissue. The QOLsurveys (SNOT-16) were used to generate preoperative and postoperative scores. Twelve surveys 6 from each group were received, from 6 female patients and 6 male patients ranging in age from 16 to 71 years (mean. 43.7 years). The preoperative mean scores for the control group and the PG group were 1.52 and 1.91. respectively. The postoperative mean scores for the control group and the PG group were 0.802 and 0.583. respectively. An absolute change score was then calculated for each group. This is the difference between the preoperative and postoperative means. The control group scored 0.938. and the PG group had a score of 0.957. A relative change score was also calculated, which is the absolute change score divided by the preoperative mean. The control group result was 0.624. and the PG group result was 0.499. A higher absolute change score indicates a greater improvement from preoperative status to postoperative status. Our data showed the PG group to have the greater absolute change score (0.957. as opposed to 0.938). A lower relative change score indicates that the QOL has improved since the operation. Our data also supported this improvement, as the PG group had a lower relative change score (0.499. as opposed to 0.624). Although the trend was for more improved QOL scores in the PG group, the difference was not statistically significant because of the small population size. With the 5 additional questions included in the survey, more data were

gathered. When asked whether they would prefer having PG instead of conventional packing, 5 of the 6 patients (83%) from the PG group responded yes and 4 of the 6 patients (67%) from the control group responded yes. for a total of 9 of 12 (75%). Five of the 6 patients (83%) of the PG group would recommend ESS to others, versus 4 of the 6 patients (67%) in the control group. Three of the PG patients (50%) stated that their surgery was less difficult than expected, and 2 of the 6 (33%) thought it was as difficult as expected. On the other hand, only I of the 6 control group patients (0.17%) found the surgery to be less difficult than expected, and 3 of the 6 (50%) felt that it was more difficult than expected. Because of the low return rate of surveys, no statistical significance can be drawn from these data, and it is estimated that at least 40 total surveys would need to be returned to achieve statistical significance. DISCUSSION There appears to have been a gradual evolution in packing materials for ESS. from extensive gauze packing to more concentrated sponges and now to various absorbable materials. Because patients consider packing removal to be the most unpleasant aspect of ESS.'-the use of absorbable packing becomes more and more enticing. Moreover, absorbable packing prevents the risks of aspiration, toxic shock syndrome, and foreign body giant cell reactions that are all inherent to permanent packing.'^ However, there is a relative paucity of data regarding patient outcomes with these various types of absorbable packing. Platelet gel is an autologous source of concentrated PDGF and TNF-p that is used to accelerate the rate and degree of surgical wound repair while greatly minimizing the risk of postoperative complications. It functions to reduce infection, swelling, pain, and bruising. It also hastens wound closure and provides hemostasis. The physiologic components of PRP include PDGF, TGF-a. TGF-P. EGF, fibroblast growth factor (FGF). IGF. platelet-derived angiogenesis factor, white blood cells, phagocytic cells, native fibrinogen concentration, vasoactive and chemotactic agents, and a high concentration of platelets. Platelet a granules present are proteins that initiate wound healing by attracting and activating fibroblasts, endothelial cells, macrophages. and other cells to promote rapid wound repair. The growth factors mentioned above function to signal coordination of cellular proliferation. These factors consist mostly of larger peptides and glycoproteins released from macrophages. neutrophils. lymphocytes, platelets, and fibroblasts. They bind by specific cell-surface receptors, and activate

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Pomerantz & Dutton, Platelet Gel for Endoscopic Sinus Surgery-

and then induce cell migration, division, proliferation, and chemoattraction of other wound healing factors for rapid wound repair. Transforming growth factor p, specifically, has been shown to increase collagen synthesis and decrease dermal scarring. Platelet concentrate serves to increase proliferative activity, matrix formation, and mineral deposition of osteoblastic-like cells, which are sensitive to PDGF. IGF-1. IGF-2. TGF-P. EGF, and FGF.i In this study. QOL outcomes were compared in groups that received Merocel packing and PG packing after ESS. Although not supported by statistically significant evidence because of our small sample size, the raw data did provide support to the hypothesis that patients who received PG packing had a better QOL outcome after ESS. Their SNOT-16 scores were improved to a greater degree than those of the control group. Also, more PG patients stated that recovery from surgery was less difficult than expected. In both groups, the majority of patients stated that they would prefer having PG packing as opposed to conventional gauze packing. Although packing for ESS may contribute to hemostasis, another option is to avoid nasal packing entirely.'* This practice would avoid the discomfort, risk, and cost of packing, although it would lack the hemostatic properties and growth factors that promote healing that are inherent in PG. Similar to the option of "no nasal packing at all." PG is absorbable
1. Mausner P. Summary of presentations. Fibrin sealants in thoracic, heart, and vessel surgery. www.Medscape.com. Accessed August 21. 2003. 2. Chandra RK. Conlcy DB. Kern RC. The effect of FloSeal on mucosal healing after endoscopic sinus surgery: a comparison with thrombin-soaked gelatin foam. Am J Rhinol 2003; 17: 51-5. 3. Maccabee MS.Trune DR. Hwang PH. Effects of topically applied biomaterials on paranasal sinus mucosal healing. Am J Rhinol 2003:17:203-7. 4. Whitman DH. Berry RL. Green DM. Platelet gel: an autologous alternative to fibrin glue with applications in oral and maxillofacial surgery. J Oral Maxillofac Surg 1997;55:1294-9. 5. Bhanot S. Alex JC. Current applications of platelet gels in facial plastic surgery. Facial Plast Surg 2002; 18:27-33. 6. Townsend CM. Sabision textbook of surgery. 16th ed. Philadelphia. Pa: WB Saunders. 2001:78-82. 7. Rosenberg L. Wound healing, growth factors, www. Emedicine.com. Accessed May 2002. 8. Hosemann W. Dunker 1, Gode U. Wigand ME. Experimental studies of wound healing in the paranasal sinuses. III.

and does not require the removal and discomfort of gauze packing, although obviously at a higher monetary cost. In this study, we have found that patients prefer PG and that PG results in a better QOL after surgery. We are presently pursuing follow-up prospective studies to further test our hypothesis. An additional benefit of PG is its by-product. PPP. This routine by-product of the centrifugation process can be combined with thrombin to make an extremely resilient and "sticky" packing very similar to fibrin glue, but without the risk of transmissible diseases inherent to pooled blood products. Platelet-poor plasma does not contain the growth factors present in PRP. so for routine use after ESS it is less than ideal. However, this material would be readily available to use during ESS in the event of an iatrogenic cerebrospinal fluid leak. A major criticism of PG would be the added cost. The PG centrifuge systems are not readily available yet at most hospitals, and the co.sts of new systems can vary from $2,500 to $12.000. The typical perfusionist fee in our community was roughly $450 per case, including the disposable equipment. This is much more costly than the options of no packing at all, traditional gauze-type packing, and even newer absorbable packing materials. For this reason, in our practice PG is now used for cases in which there is felt to be a greater need for hemostasis and/or wound healing than in the typical ESS case.

REFERENCES
Endoscopy and histology of the surgical area after endonasal ethmoidectomy |in German). HNO 1991 ;39:111-5. 9. Weber R. Keerl R, Huppmann A. Schick B. Draf W. Effects of postoperative care on wound healing after endonasal paranasal sinus surgery |in German|. Laryngorhinootologie 1996;75:208-14. 10. Hosemann W. Wigand ME. Gode U. Langer F. Dunker I. Normal wound healing of the paranasal sinuses: clinical and experimental investigations. Eur Arch Otorhinolaryngol 1991248:390-4. 11. AndersonER. Murphy MR WcymulierEAJr. Clinimetric evaluation of the Sinonasal Oulcome Test-16. Otolaryngoi Head Neck Surg l999;l21:702-7. 12. von Schoenberg M. Robinson P, Ryan R. Nasal packing after routine nasal surgery is it justified? J Laryngol Oiol 1993;107:902-5. 13. Weber R. Keerl R. Hochapfel F. Draf W. Toffel PH. Packing in endonasal surgery. Am J Otolaryngol 2001:22:306-20. 14. Orlandi RR. Lanza DC. Is nasal packing necessary following endoscopic sinus surgery? Laryngoscope 2004:114: 1541-4.