![](media/image1.png)

*Proposed*

BioGlue^^ Surgical Adhesive

##### Instructions for Use

# Table of Contents

# DEVICE DESCRIPTION 2

# INDICATIONS FOR USE 2

# CONTRAINDICATIONS 2

# WARNINGS 3

# PRECAUTIONS 3

# ADVERSE EVENTS -- OBSERVED AND POTENTIAL INCIDENTS 4

## Observed Adverse Events 4

## Potential Adverse Events 5

# CLINICAL STUDIES 5

# HOW SUPPLIED 12

# PATIENT COUNSELING INFORMATION 12

# DIRECTIONS FOR USE 13

## Delivery Device Preparation 13

## Site Preparation and BioGlue Delivery Device Priming 13

## General Techniques for the Use of Adhesive in Surgery 14

# MAINTAINING DEVICE EFFECTIVENESS 15

## Precautions 15

## Cleaning 15

## Sterilization 16

# PRODUCT INFORMATION DISCLOSURE 16

# DISCLAIMER OF IMPLIED WARRANTIES 16 

![](media/image2.png)

BioGlue^^ Surgical Adhesive

**Instructions for Use**

**Caution:** Federal (U.S.A.) law restricts this device to sale by or on
the order of a physician.

Read Instructions for Use prior to using this product.

### [dEVICE Description]{.underline}

> BioGlue Surgical Adhesive (BioGlue), manufactured by CryoLife, Inc.,
> Kennesaw, GA, may be used prophylactically or after a leak is detected
> to seal and reinforce anastomoses in cardiac and vascular surgical
> repairs.
>
> BioGlue is a two-component surgical adhesive composed of purified
> bovine serum albumin (BSA) and glutaraldehyde. The BSA is derived from
> serum obtained from cattle exclusively from bovine spongiform
> encephalopathy (BSE) free countries and undergoes processing that
> removes/inactivates viruses. The solutions are dispensed by a
> controlled delivery system, composed of a reusable delivery device,
> applicator tips, and applicator tip extenders. Once dispensed, the
> adhesive solutions (in a predefined ratio) are thoroughly mixed *in
> vitro* through the tortuous path of the applicator tip where
> cross-linking starts to occur. The glutaraldehyde molecules covalently
> bond (cross-link) the BSA molecules to each other and, upon
> application, to the tissue proteins at the anastomotic repair site
> thereby creating a flexible mechanical seal, independent of the body's
> clotting mechanism. The device-mediated application is designed to
> provide reproducible mixing of the components *in vitro* and higher
> bonding strength than manual on-site (*in situ*) mixing and
> application. BioGlue begins to set up within 20 to 30 seconds and
> reaches its bonding strength within 2 minutes. BioGlue also adheres to
> synthetic graft materials via mechanical interlocks within the
> interstices of the graft matrix.

### [Indications For Use]{.underline}

> BioGlue^^ Surgical Adhesive is indicated for use as an adjunct to
> standard methods of cardiac and vascular repair such as sutures (or
> staples) to provide hemostasis.

### [Contraindications]{.underline}

-   Do not use in patients with known allergies to materials of bovine
    > origin.

-   Not for intravascular use.

-   Not for cerebrovascular repair.

### [Warnings]{.underline}

-   BioGlue Surgical Adhesive is not intended as a substitute for
    > sutures or staples.

-   Do not expose tissue to the device if it may be adversely affected
    > by contact with the device, e.g., aortic valve cusps and
    > intra-cardiac structures.

-   Do not allow device in either the uncured or polymerized form to
    > contact circulating blood flow.

-   Avoid exposing any nerves to surgical adhesive.

-   Avoid contact with skin or other tissue not intended for
    > application.

-   Glutaraldehyde treated tissue has an enhanced propensity for
    > mineralization. Laboratory experiments indicate that unreacted
    > glutaraldehyde may have mutagenic effects.

-   Unreacted glutaraldehyde may cause irritation to eye, nose, throat,
    > or skin; induce respiratory distress; and local tissue necrosis.
    > Prolonged exposure to unreacted glutaraldehyde may cause a central
    > nervous system or cardiac pathology. Operators using the device
    > should ensure that staff are adequately risk protected.

-   BioGlue should not be used in the presence of infection and should
    > be used with caution in contaminated areas of the body.

-   Exposure to bovine serum albumin may cause a reaction such as
    > swelling or edema at the application site.

-   BioGlue Surgical Adhesive contains a material of animal origin,
    > which therefore may be capable of transmitting infectious agents.

### [PRECAUTIONS]{.underline}

-   It is recommended that surgical gloves, sterile gauze pads/towels,
    > and surgical instruments be maintained moist to minimize the
    > potential for BioGlue inadvertently adhering to these surfaces.

-   Wear gloves, mask, protective clothing, and safety glasses. If
    > contact with solutions occurs, flush affected areas immediately
    > with water and seek medical attention.

-   BioGlue Surgical Adhesive solutions cartridges, applicator tips, and
    > applicator tip extenders are for single patient use only. Do not
    > re-sterilize.

-   Do not use if packages have been opened or damaged.

-   Do not prime delivery device until ready for immediate use.
    > Premature priming may cause the applicator tip to become
    > obstructed with polymerized adhesive.

-   Take care not to spill solutions out of the cartridge.

-   Do not compress the handle of the adhesive delivery device while
    > attaching the cartridge to the delivery device.

-   Attempting to apply the adhesive in a surgical field that is too wet
    > may result in poor adherence.

-   Ensure priming material does not come into contact with the surgical
    > site.

-   BioGlue Surgical Adhesive sets up immediately. Priming must occur
    > quickly, followed immediately by the application of adhesive.
    > Pausing between priming and application can cause set-up of
    > adhesive within the applicator tip.

-   If the BioGlue Surgical Adhesive adheres to an undesired location,
    > allow the adhesive to polymerize and then attempt to gently
    > dissect the adhesive away from the affected area with forceps and
    > scissors. Do not attempt to peel away the BioGlue Surgical
    > Adhesive as this could result in tissue damage at the application
    > site.

### [Adverse Events -- Observed and potential]{.underline}

> **[Observed Adverse Events]{.underline}**
>
> In a prospective, multi-center, randomized controlled clinical trial,
> a total of 76 patients received standard surgical repair with BioGlue
> Surgical Adhesive and 75 received only standard surgical repair of
> cardiac and vascular anastomoses. Following is a complete list of
> adverse events that were observed in the BioGlue Surgical Adhesive
> group patients in the pivotal clinical trial.
>
> **Observed Adverse Events**

+-----------------------+---+------+-----+---+------+-----+---------+
| Adverse Event         | B |      |     | C |      |     | P-Value |
| Description           | i |      |     | o |      |     |         |
|                       | o |      |     | n |      |     |         |
|                       | G |      |     | t |      |     |         |
|                       | l |      |     | r |      |     |         |
|                       | u |      |     | o |      |     |         |
|                       | e |      |     | l |      |     |         |
|                       | G |      |     | G |      |     |         |
|                       | r |      |     | r |      |     |         |
|                       | o |      |     | o |      |     |         |
|                       | u |      |     | u |      |     |         |
|                       | p |      |     | p |      |     |         |
|                       |   |      |     |   |      |     |         |
|                       | N |      |     | N |      |     |         |
|                       | = |      |     | = |      |     |         |
|                       | 7 |      |     | 7 |      |     |         |
|                       | 7 |      |     | 4 |      |     |         |
|                       |   |      |     |   |      |     |         |
|                       | n |      |     | n |      |     |         |
|                       | % |      |     | % |      |     |         |
|                       | # |      |     | # |      |     |         |
|                       | e |      |     | e |      |     |         |
|                       | v |      |     | v |      |     |         |
|                       | e |      |     | e |      |     |         |
|                       | n |      |     | n |      |     |         |
|                       | t |      |     | t |      |     |         |
|                       | s |      |     | s |      |     |         |
+-----------------------+---+------+-----+---+------+-----+---------+
| Application of        | 1 | 1.3% | 1   | 0 | 0%   | 0   | 1.000   |
| Adhesive to           |   |      |     |   |      |     |         |
| Non-Targeted          |   |      |     |   |      |     |         |
| Tissue^1^             |   |      |     |   |      |     |         |
+-----------------------+---+------+-----+---+------+-----+---------+
| Death                 | 5 | 6.5% | 5   | 5 | 6.8% | 5   | 0.999   |
+-----------------------+---+------+-----+---+------+-----+---------+
| Failure of Products   | 1 | 1.3% | 1   | 0 | 0%   | 0   | 1.000   |
| to Adhere to          |   |      |     |   |      |     |         |
| Tissue^1^             |   |      |     |   |      |     |         |
+-----------------------+---+------+-----+---+------+-----+---------+
| Hemorrhage            | 3 | 3.9% | 3   | 3 | 4.1% | 3   | 1.000   |
+-----------------------+---+------+-----+---+------+-----+---------+
| Infection             | 1 | 1    | 15  | 1 | 1    | 13  | 0.653   |
|                       | 3 | 6.9% |     | 0 | 3.5% |     |         |
+-----------------------+---+------+-----+---+------+-----+---------+
| Inflammatory, Immune  | 2 | 2.6% | 2   | 0 | 0%   | 0   | 0.497   |
| Systemic Allergic     |   |      |     |   |      |     |         |
| Reaction^2^           |   |      |     |   |      |     |         |
+-----------------------+---+------+-----+---+------+-----+---------+
| Irreversible          | 0 | 0%   | 0   | 1 | 1.4% | 1   | 0.490   |
| Morbidity             |   |      |     |   |      |     |         |
+-----------------------+---+------+-----+---+------+-----+---------+
| Ischemia              | 3 | 3.9% | 3   | 2 | 2.7% | 2   | 1.000   |
+-----------------------+---+------+-----+---+------+-----+---------+
| Myocardial Infarction | 3 | 3.9% | 3   | 1 | 1.4% | 1   | 0.620   |
+-----------------------+---+------+-----+---+------+-----+---------+
| Neurological Deficits | 5 | 6.5% | 6   | 1 | 2    | 18  | 0.009   |
|                       |   |      |     | 6 | 1.6% |     |         |
+-----------------------+---+------+-----+---+------+-----+---------+
| Organ System          | 3 | 3.9% | 4   | 2 | 2.7% | 2   | 1.000   |
| Dysfunction/Failure   |   |      |     |   |      |     |         |
+-----------------------+---+------+-----+---+------+-----+---------+
| Paraplegia            | 1 | 1.3% | 3   | 2 | 2.7% | 3   | 0.615   |
+-----------------------+---+------+-----+---+------+-----+---------+
| Pleural Effusion      | 2 | 2    | 25  | 2 | 2    | 22  | 0.855   |
|                       | 0 | 6.0% |     | 1 | 8.4% |     |         |
+-----------------------+---+------+-----+---+------+-----+---------+
| Renal                 | 1 | 1    | 13  | 9 | 1    | 10  | 0.492   |
| Dysfunction/Failure   | 3 | 6.9% |     |   | 2.2% |     |         |
+-----------------------+---+------+-----+---+------+-----+---------+
| Respiratory           | 1 | 1    | 18  | 1 | 1    | 15  | 1.000   |
| Dysfunction/Failure   | 3 | 6.9% |     | 2 | 6.2% |     |         |
+-----------------------+---+------+-----+---+------+-----+---------+
| Stroke or Cerebral    | 1 | 1.3% | 1   | 3 | 4.1% | 5   | 0.360   |
| Infarction            |   |      |     |   |      |     |         |
+-----------------------+---+------+-----+---+------+-----+---------+
| Thromboembolism       | 1 | 1.3% | 1   | 1 | 1.4% | 4   | 1.000   |
+-----------------------+---+------+-----+---+------+-----+---------+
| Thrombosis            | 0 | 0%   | 0   | 1 | 1.4% | 1   | 0.490   |
+-----------------------+---+------+-----+---+------+-----+---------+
| Other^3,4^            | 4 | 5    | 108 | 4 | 5    | 100 | 0.514   |
|                       | 6 | 9.7% |     | 0 | 4.1% |     |         |
+-----------------------+---+------+-----+---+------+-----+---------+

> ^1^ These adverse events were device related. Both complications were
> clearly warned against in the IFU.
>
> ^2^ These adverse events were not device related. One patient had an
> allergic reaction to a preoperative antibiotic and the other patient
> had an allergic reaction to Protamine.
>
> ^3^ Other adverse events observed in the BioGlue treated clinical
> trial patients were as follows: Acidosis (1%), Acute shortness of
> breath (1%), Altered mental status (3%), Anemia (5%), Atelectasis
> (8%), Cardiac arrhythmia (22%), Cerebral hemorrhage (1%), Colecystitis
> (1%), Coagulopathy (1%), Congestive Heart Failure (4%), Decreased
> femoral pulse (1%), Deep Vein Thrombosis (1%), Depression (4%),
> Diarrhea (3%), Dysphagia (5%), Edema (3%), Fever (3%), Heart
> enlargement (4%), Hematuria (1%), Hemoptysis (1%), Hernia (4%),
> Hoarseness (1%), Hypotension (1%), Ileus (4%), Incisional pain (3%),
> Lymphatic fistula (1%), Malnutrition (5%), Nausea (3%), Perforated
> viscus (1%), Pericardial effusion (1%), Pneumothorax (3%), Rectal
> bleeding (1%), Seizure (1%), Thigh and back pain (3%),
> Thrombocytopenia (1%), Urinary retention (4%), Vocal cord paralysis
> (3%).
>
> 4 Other adverse events observed in the Control Group clinical trial
> patients were as follows: Abdominal pain (1%), Abnormal lab value
> (5%), Acidosis (1%), Altered mental status (3%), Anemia (3%), Angina
> (1%), Aphasia (1%), Atelectasis (4%), Back pain (1%), Cardiac
> arrhythmia (19%), Cerebral hemorrhage (3%), Congestive heart failure
> (1%), Diarrhea (3%), Dizziness (1%), Duodenal ulcer (1%), Dysphagia
> (1%), Edema (1%), Emphysema (1%), Encephalopathy (1%), Failed
> extubation (1%), Fever (3%), Heart block (2%), Hematuria (1%),
> Hemothorax (1%), Hernia (1%), Hoarseness (4%), Hypotension (4%), Ileus
> (3%), Incisional pain (5%), Lower extremity weakness (1%), Nausea
> (4%), Near syncope (1%), Neck deformity (1%), Pericardial effusion
> (3%), Pneumothorax (3%), Post-kidney collection (3%), Reintubation
> (1%), Seizure (1%), Sexual dysfunction (1%), Shortness of breath (1%),
> Thrombocytopenia (4%), Thrombophlebitis (1%), Transfusion reaction
> (3%), Urinary retention (1%), Valve surgery (1%), Vocal cord paralysis
> (3%).
>
> > Adverse events were equal in severity in both the BioGlue group and
> > the standard surgical repair group. There were no unanticipated
> > device effects (UADE) in this investigation.
>
> **[Potential Adverse Events Related to Cardiac and Vascular
> Procedures]{.underline}**
>
> Adverse events associated with cardiac and vascular repair procedures
> may include but are not limited to:

+-----------------------------------+-----------------------------------+
| -   Cardiac tamponade             | -   Pulmonary emboli              |
+-----------------------------------+-----------------------------------+
| -   Infection                     | -   Renal dysfunction/failure     |
+-----------------------------------+-----------------------------------+
| -   Hemorrhage                    | -   Aortic insufficiency          |
+-----------------------------------+-----------------------------------+
| -   Paraplegia                    | -   Myocardial infarction         |
+-----------------------------------+-----------------------------------+
| -   Dissection                    | -   Neurological deficits         |
+-----------------------------------+-----------------------------------+
| -   Ischemia                      | -   Cerebral emboli               |
+-----------------------------------+-----------------------------------+
| -   Adhesions                     | -   Stroke or cerebral infarction |
+-----------------------------------+-----------------------------------+
| -   Injury to normal vessels or   | -   Anastomotic pseudoaneurysm    |
|     tissue                        |                                   |
+-----------------------------------+-----------------------------------+
| -   Thrombosis                    | -   Respiratory                   |
|                                   |     dysfunction/failure           |
+-----------------------------------+-----------------------------------+
| -   Vasospasm                     | -   Organ system                  |
|                                   |     dysfunction/failure           |
+-----------------------------------+-----------------------------------+
| -   Vessel rupture and hemorrhage | -   Death or irreversible         |
|                                   |     morbidity                     |
+-----------------------------------+-----------------------------------+
| -   Pleural effusion              |                                   |
+-----------------------------------+-----------------------------------+

### [Clinical Studies]{.underline}

> In June 1998, CryoLife, Inc. began a clinical trial investigating the
> use of BioGlue as an adjunct in the surgical repair of acute, Stanford
> Type A aortic dissections. CryoLife filed a Humanitarian Device
> Exemption (HDE) for the use of BioGlue in the surgical repair of acute
> thoracic aortic dissections, which was approved by FDA in December
> 1999 (H990007). The data is suggestive of a benefit in terms of 1)
> decreased rate of reoperation for bleeding and other bleeding
> complications without the need for other hemostatic devices and/or
> pharmacological agents, 2) fewer intraoperative blood transfusions,
> and 3) reinforcement of friable tissue of the dissected aorta without
> the need for pledgets. CryoLife gained approval in May 2000 to
> investigate the use of BioGlue for sealing anastomotic sites in
> cardiac and vascular repairs. Following is information from the
> cardiac and vascular repair investigation:

## Study Design

> > The "BioGlue Surgical Adhesive Effectiveness and Safety Trial as a
> > Surgical Adjunct in Cardiac and Vascular Surgical Repairs ("BEST"
> > Trial) was a prospective, multi-center, randomized controlled trial.
> > Randomized cardiac and vascular repairs include an adjunctive
> > BioGlue prophylactic treatment and a control group (standard
> > surgical repair). The overall objective was to collect clinical data
> > concerning the safety and effectiveness of BioGlue used as an
> > anastomotic sealant to provide hemostasis.
>
> > Cardiac and vascular repair procedures included but were not limited
> > to the surgical repair/reconstruction of the following clinical
> > conditions: ventricular aneurysm/rupture; aortic aneurysm/dilatation
> > (root, ascending arch, descending thoracic, thoracoabdominal,
> > abdominal, and aortoiliac); traumatic aortic transection;
> > annulo-aortic ectasia; and vascular bypass or repair.
>
> > Patients were randomized to receive standard surgical repair with
> > BioGlue applied to the anastomotic site (BioGlue group) or standard
> > surgical anastomotic repair alone (control group).

## Patient Assessment

> > [Effectiveness Evaluations]{.underline}
>
> > The BioGlue group and the standard surgical repair group were
> > compared to determine BioGlue's effectiveness for the following
> > endpoints:
>
> > **Primary Evaluation**
>
> > Anastomotic hemostasis (yes or no) of each of the repaired
> > anastomotic sites. Anastomotic hemostasis was defined as an
> > anastomosis that does not require additional agents (pledgets,
> > sutures, hemostatic devices, antifibrinolytic agents, thrombin
> > glues, fibrin glues) at the treated site(s) to control bleeding at
> > any point during the course of the original operation. Results were
> > also evaluated on a "per patient" basis. Patients with anastomotic
> > hemostatis at all anastomotic sites were considered successful.
>
> > **Secondary Evaluations**

-   Quantity, type, and number of donor exposures of blood replacement
    > products administered.

-   Type of additional agents used (pledgets, sutures, hemostatic
    > devices, antifibrinolytic agents, thrombin glues, fibrin glues)

-   Re-operation due to anastomotic site bleeding.

-   Major complications/adverse events through final follow-up.

-   Minor complications/adverse events through final follow-up.

-   Early hospital discharge mortality and mortality through last
    > follow-up.

> > **Cost Benefit Evaluations**

-   Total cardiopulmonary bypass time (when applicable).

-   Time required for aortic cross-clamp (when applicable).

-   Total operative time (skin incision to skin closure).

-   Total time in Intensive Care Unit.

-   Total hospitalization time.

> > **Safety Evaluations**
>
> > The criteria for evaluating safety in this patient population were:

-   Unanticipated Adverse Device Effects (UADE).

-   Device complications.

-   Surgical procedure complications.

## 

## 

## 

## 

## 

## 

## Demographic Data

> > A total of 151 patients were treated at 6 investigational sites in
> > the cardiac and vascular repair arm of the U.S. IDE clinical trial.
> > Pertinent information about the patient population is presented in
> > Tables 2 and 3. Surgical procedures performed are shown in Table 4.
>
> Table 2 -- Summary of Subjects

  ----------------- ----------------- ----------------- -----------------
                    **Treatment                         
                    Group**                             

  **Population**    **Surgical Repair **Conventional    **Total**
                    with BioGlue**    Surgical Repair** 

  All Randomized    76                75                151

  Cross Over        N/A               1                 1

  Intent-to-Treat   76                74                150

  Evaluable         76                74                149

  Safety            77                74                151
  ----------------- ----------------- ----------------- -----------------

> *Table 3 -- Demographic Characteristics (*All randomized patients)

  -------------------- -------------- ---------------- --------------- --------------
                       **Treatment                                     
                       Group**                                         

  **Characteristic**   **Surgical     **Conventional   **Crossover**   **Total**
                       Repair with    Surgical                         
                       BioGlue**      Repair**                         

  Age (years)                                                          

  N                    76             74               1               151

  Mean (SD)            63.4 (17.2)    66.3 (12.7)      73.8 (N/A)      64.8 (15.1)

  Min, Max             21, 87         25, 86           N/A             20, 87

                                                                       

  Gender                                                               

  Male                 49             48               0               97

  Female               27             26               1               54

  Total                76             74               1               151

  Race                                                                 

  African-American     6              6                0               12

  Asian                1              1                0               2

  Caucasian            67             66               1               133

  Hispanic             2              1                0               3

  Total                76             74               1               151
  -------------------- -------------- ---------------- --------------- --------------

> Table 4 -- Cardiac and Vascular Procedures Included

  -------------------- ------------- ---------------- --------------- ------------
                       **Treatment                                    
                       Group**                                        

  **System**           **Surgical    **Conventional   **Crossover**   **Total**
                       Repair with   Surgical                         
                       BioGlue**     Repair**                         

  Cardiac              24            25               0               49
  Procedures^\*\*^                                                    

  Aortic Procedures^†^ 57            47               1               105

  Peripheral Vascular  25            23               0               48
  Procedures^\*\*\*^                                                  

  Total                106           95               1               202
  -------------------- ------------- ---------------- --------------- ------------

> \*\**Cardiac repairs include: aortic root replacements (4),
> aortoplasty (1), aortic valve annuloplasty (5), aortic valve
> resuspension (1), aortic valve replacement (23), Bentall procedure
> (2), composite valved conduit procedures (8), mitral valve
> replacements (2), Ross procedure (2), coronary artery bypass grafting
> (1).*
>
> ^†^*Aortic aneurysm repairs include: abdominal aortic aneurysm (21),
> ascending aortic aneurysm (21), ascending/ transverse aortic arch
> aneurysm (9), ascending/ transverse arch/ descending aortic aneurysm
> (1), descending aortic aneurysm (8), thoracoabdominal aortic aneurysm
> (32), transverse aortic arch aneurysm (12), Type B aortic dissection
> (1)*
>
> *\*\*\*Peripheral vascular repairs include: aorto-femoral bypass (5),
> aorto-iliac bypass (2), aorto-innominate bypass (1), carotid bypass
> (1), carotid endarterectomy (19), femoral-distal bypass (3),
> femoral-femoral bypass (2), femoral-popliteal bypass (5),
> hepatic-renal bypass (1), popliteal-dorsalis pedis bypass (1),
> profunda endarterectomy (1), renal bypass (6), renal endarterectomy
> (1)*

## 

## Data Analysis and Results

> > The tables and figures in this section present information from the
> > cardiac and vascular repair arm of the U.S. IDE clinical trial.
>
> > [Efficacy Data]{.underline}
>
> > Table 5 presents the intra-operative hemostasis data for the
> > intent-to-treat patients on both a "per patient" and a "per
> > anastomotic repair site" basis. The proportion of both patients and
> > anastomotic repair sites achieving hemostasis based upon the
> > protocol definition was statistically greater in the BioGlue group
> > (Fisher's Exact Test, p \< 0.05).
>
> Table 5 -- Intra-operative Hemostasis --
>
> Intent-to-Treat Patients (Success/Total)

  --------------------- ---------------- ---------------- ----------------
                        Treatment Group                   

                        Surgical Repair  Conventional     P value
                        With BioGlue     Surgical Repair  

  Per patient^\*^       61% (46/76)      39% (29/74)      0.014

  Per Repair Site^\*\*^ 81% (164/202)    57% (105/184)    \<0.001
  --------------------- ---------------- ---------------- ----------------

> ^\*^ Hemostasis on a "per patient" basis was defined as hemostasis of
> 100% of the anastomotic repair sites.
>
> ^\*\*^ The average number of repair sites (anastomoses) per patient
> were 2.6 (range: 1 to 8).
>
> > Use of intra-operative blood products is outlined in Table 6. No
> > statistically significant differences were noted between the BioGlue
> > group and the control group based upon a one-sided 95% confidence
> > interval of the difference between the treatment means.
>
> *Table 6 --Intra-operative Blood Products and Donor Exposures*
> (Intent-to-Treat Patients)

  --------------------------- --------------------- ---------------------
                              Treatment Group       

                              Surgical Repair With  Conventional Surgical
                              BioGlue               Repair

  Red Blood Cells                                   

  N                           76                    74

  Mean (SD)                   2.3 (3.6)             1.9 (2.4)

  Min, Max                    0, 22                 0, 12

                                                    

  Platelets                                         

  N                           76                    74

  Mean (SD)                   5.1 (10.1)            5.2 (10.0)

  Min, Max                    0, 60                 0, 50

                                                    

  Fresh Frozen Plasma                               

  N                           75                    73

  Mean (SD)                   3.8 (6.6)             3.3 (5.0)

  Min, Max                    0, 30                 0, 19

                                                    

  Cryoprecipitate                                   

  N                           74                    72

  Mean (SD)                   4.3 (11.9)            2.0 (8.3)

  Min, Max                    0, 60                 0, 40

                                                    

  Total Number of Donor                             
  Exposures                                         

  N                           48                    51

  Mean (SD)                   20.6 (26.3)           14.2 (18.2)

  Min, Max                    0, 106                0, 89
  --------------------------- --------------------- ---------------------

> > Investigators in this trial documented their usage of pledgeted
> > sutures to reinforce their primary repair. Anastomotic sites treated
> > with BioGlue had a statistically lower incidence of pledget usage on
> > the primary repair when compared to the control group (Table 7).
>
> Table 7 -- Pledgets on Primary Repair - Intent-to-Treat Anastomotic
> Sites (Success/Total Number of Anastomotic Sites)

+----------------------------+--------------+-------------+-----------+
|                            | Treatment    |             |           |
|                            | Group        |             |           |
+----------------------------+--------------+-------------+-----------+
|                            | Surgical     | C           | P Value   |
|                            | Repair with  | onventional |           |
|                            | BioGlue      | Surgical    |           |
|                            |              | Repair      |           |
+----------------------------+--------------+-------------+-----------+
| Pledgets Used on Primary   | 26%          | 36%         | 0.047     |
| Repair                     |              |             |           |
|                            | (53/202)     | (66/184)    |           |
+----------------------------+--------------+-------------+-----------+

> > Any anastomotic repair site that was not immediately hemostatic was
> > evaluated to determine the additional methods used to obtain
> > hemostasis. There was no statistical difference noted in the
> > additional measures taken to obtain hemostasis, which indicates that
> > BioGlue did not inhibit the surgeons ability to obtain hemostasis
> > through use of conventional measures or additional BioGlue. These
> > results are summarized in Table 8 below:
>
> *Table 8 -- Measures Required to Obtain Hemostasis - Intent-to-Treat
> Bleeding Anastomotic Sites (Bleeding Anastomotic Sites Requiring
> Measure/Total Bleeding Sites)*

  ----------------------- ---------------- ---------------- -------------
                          Treatment Group                   

                          Surgical Repair  Conventional     P value
                          With BioGlue     Surgical Repair  

  Make-up Stitches        82% (31/38)      81% (64/79)      1.00

  Hemostatic Device^\*^   8% (3/38)        10% (8/79)       1.00

  Additional BioGlue      55% (21/38)      N/A              N/A

  Other^†^                8% (3/38)        19% (15/79)      0.17
  ----------------------- ---------------- ---------------- -------------

> > ^\*^ *Hemostatic Devices included Surgicel^®^, Avitene^®^,
> > Gelfoam^®^, Fibrin Glue, Thrombin Glue.*
>
> > ^†^ *Other includes: Additional pledgets (16), FloSeal (1), Teflon
> > felt ring (1)*
>
> > The study protocol allowed investigators to "cross-over" and use
> > BioGlue for control patients who suffered uncontrollable bleeding.
> > Only one patient was noted to have uncontrollable bleeding. The
> > investigator was able to obtain hemostasis at all anastomotic sites
> > after using BioGlue for this patient.
>
> > Incidence of re-operation for anastomotic site bleeding is presented
> > in Table 9. Only one patient had a re-operation due to anastomotic
> > site bleeding.
>
> Table 9 -- Re-operation Due to Anastomotic Site Bleeding

+-----------------------+----------------+----------------+------------+
|                       | Treatment      |                |            |
|                       | Group          |                |            |
+-----------------------+----------------+----------------+------------+
|                       | Surgical       | Conventional   | One-Sided  |
|                       | Repair With    | Surgical       | 95%        |
|                       | BioGlue        | Repair         | Confidence |
|                       |                |                | Interval   |
|                       | N (%)          | N (%)          |            |
+-----------------------+----------------+----------------+------------+
| Re-operation          | 0 (0.0%)       | 1 (1.4%)       | \[\--,     |
|                       |                |                | 0.9\]      |
+-----------------------+----------------+----------------+------------+

> > Table 10 shows a summary of intra-operative times, days spent in the
> > ICU, and total hospitalization time. The differences between the
> > BioGlue group and the control group were not statistically
> > significant.
>
> Table 10 -- Procedure, ICU, and Hospitalization Times
>
> (Intent-to-Treat)

+-------------------------------+------------------+------------------+
|                               | Treatment Group  |                  |
+-------------------------------+------------------+------------------+
|                               | Surgical Repair  | Conventional     |
|                               | With BioGlue     | Surgical Repair  |
+-------------------------------+------------------+------------------+
| **Procedure Times**           |                  |                  |
+-------------------------------+------------------+------------------+
| Cardiopulmonary Bypass Time\* |                  |                  |
|                               |                  |                  |
| (minutes)                     |                  |                  |
+-------------------------------+------------------+------------------+
| N                             | 34               | 35               |
+-------------------------------+------------------+------------------+
| Mean (SD)                     | 168.1 (67.4)     | 144.2 (60.6)     |
+-------------------------------+------------------+------------------+
| Min, Max                      | 54, 358          | 54, 387          |
+-------------------------------+------------------+------------------+
|                               |                  |                  |
+-------------------------------+------------------+------------------+
| Cross-Clamp Time\* (minutes)  |                  |                  |
+-------------------------------+------------------+------------------+
| N                             | 54               | 55               |
+-------------------------------+------------------+------------------+
| Mean (SD)                     | 74.0 (46.1)      | 69.1 (41.3)      |
+-------------------------------+------------------+------------------+
| Min, Max                      | 10, 196          | 19, 196          |
+-------------------------------+------------------+------------------+
|                               |                  |                  |
+-------------------------------+------------------+------------------+
| Total Operative Time          |                  |                  |
| (minutes)                     |                  |                  |
+-------------------------------+------------------+------------------+
| N                             | 75               | 73               |
+-------------------------------+------------------+------------------+
| Mean (SD)                     | 237.7 (125.1)    | 228.7 (100.8)    |
+-------------------------------+------------------+------------------+
| Min, Max                      | 85, 650          | 60, 515          |
+-------------------------------+------------------+------------------+
|                               |                  |                  |
+-------------------------------+------------------+------------------+
| **ICU Time**                  |                  |                  |
+-------------------------------+------------------+------------------+
| Days in ICU\*                 |                  |                  |
+-------------------------------+------------------+------------------+
| N                             | 70               | 72               |
+-------------------------------+------------------+------------------+
| Mean (SD)                     | 3.9 (5.6)        | 4.8 (7.1)        |
+-------------------------------+------------------+------------------+
| Min, Max                      | 0, 32            | 0, 36            |
+-------------------------------+------------------+------------------+
|                               |                  |                  |
+-------------------------------+------------------+------------------+
| **Hospitalization Time**      |                  |                  |
+-------------------------------+------------------+------------------+
| Days in Hospital              |                  |                  |
+-------------------------------+------------------+------------------+
| N                             | 72               | 73               |
+-------------------------------+------------------+------------------+
| Mean (SD)                     | 9.5 (10.6)       | 10.9 (9.7)       |
+-------------------------------+------------------+------------------+
| Min, Max                      | 1, 81            | 1, 55            |
+-------------------------------+------------------+------------------+

> > *\* Where applicable.*
>
> > [Safety Data]{.underline}
>
> > Mortality rates for intent-to-treat in this trial are presented in
> > Table 11. No differences were observed in either early (through
> > hospital discharge) mortality or late (through final follow-up)
> > mortality.
>
> *Table 11 -- Mortality Rates -- Intent-to-Treat Patients
> (Event/Total)*

  ----------------------- ---------------- ---------------- -------------
                          Treatment Group                   

                          Surgical Repair  Conventional     One-Sided 95%
                          With BioGlue     Surgical Repair  Confidence
                                                            Interval

  Early/Hospital          3.9% (3/76)      2.7% (2/74)      \[\--, 6.1\]
  Discharge (\<30 days)                                     

  Post-operative          1.3% (1/76)      4.1% (3/74)      \[\--, 3.9\]
  Follow-up (3 months)                                      
  ----------------------- ---------------- ---------------- -------------

> > Adverse events were equal in severity in both the BioGlue group and
> > the standard surgical repair group. There were no unanticipated
> > device effects (UADE) in this investigation.
>
> **Conclusion**
>
> BioGlue was noted to have a statistically higher rate of
> intra-operative hemostasis when compared to the control group on both
> a "per patient" and a "per anastomotic site" basis. BioGlue-treated
> patients demonstrated a lower incidence of adjunctive pledgets use on
> their primary repairs to achieve hemostasis. There were no statistical
> differences in other endpoints, such as blood products or operative
> times, between study and control patients.

### [How Supplied]{.underline}

The adhesive solutions cartridge, applicator tips, and twist rings are
supplied sterile for single-patient use only. Discard unused material
from opened or damaged product.

The adhesive solutions are contained within a capped, double-chambered
cartridge. The cured adhesive is non-pyrogenic. Store below 25°C, but do
not freeze.

The Delivery Device is supplied sterile. It may be resterilized and
reused nine times. Refer to section "Reusable Delivery Device Product
Reuse Instructions" of this package insert for detailed cleaning and
resterilization instructions. Retain these Instructions for Use for
future reference.

**[PATIENT COUNSELING INFORMATION]{.underline}**

Exposure to bovine serum albumin may cause a reaction such as swelling
or edema at the application site.

BioGlue Surgical Adhesive contains a material of animal origin, which
therefore may be capable of transmitting infectious agents.

### [Directions for Use]{.underline}

> **[Delivery Device Preparation]{.underline}**

1.  Remove a sterile solutions cartridge from its package. Firmly grasp
    the cartridge with the nose facing upward. Turn the twist-off cap
    90° counterclockwise and gently remove from the solutions cartridge
    by rocking it side to side.

> **CAUTION:** Take care not to spill solutions out of cartridge during
> assembly.

2.  Remove a sterile applicator tip from package.

3.  While holding the cartridge with one hand, place the applicator tip
    on the cartridge. Take care to align notches on the collar of the
    applicator tip with the notches of the cartridge nose.

4.  If using a twist ring tool, remove it from its packaging, place it
    over the applicator tip and slide it firmly onto the applicator
    tip's rotating collar. Holding the twist ring tool or applicator tip
    collar, push the applicator tip down firmly onto the cartridge and
    then rotate the collar 90° clockwise to lock tip in place.

5.  If used, remove the twist ring tool and keep it for tip removal or
    any additional applicator tip exchanges that may take place during
    the procedure.

6.  Remove the adhesive delivery device trigger assembly (handle) and
    dual head plunger (plunger) from package. Lift the large latch
    (cartridge retainer latch) on top of the handle. While pushing
    upward on the small latch (plunger latch) located on the back of the
    handle, insert the plunger (with the ribbed surface facing downward)
    into the slit located at the front of the device. Still holding the
    plunger latch upward, push the plunger back completely. Align the
    small and large barrels of the solutions cartridge above the
    corresponding small and large plunger heads. Slide the solutions
    cartridge down into position and push cartridge retainer latch down
    to lock.

> **CAUTION:** Do not compress the handle of the adhesive delivery
> device while attaching the cartridge to the delivery device.

7.  Gently slide the plunger forward into position until resistance is
    felt. The assembled adhesive delivery device is now ready for
    priming and immediate use.

8.  If using an applicator tip with flexible extension, a desired angle
    may be created by bending the tip at the appropriate location and
    holding for 3-5 seconds. The angle created should hold for 5
    minutes.

9.  To remove the solutions cartridge, push and hold plunger latch
    upward while completely drawing back the plunger. Lift the cartridge
    retainer latch and slide the solutions cartridge out.

10. To remove occluded applicator tips, hold the applicator tip collar,
    rotate 90° counter-clockwise, and gently lift the applicator tip off
    of the solutions cartridge by rocking it side to side. The twist
    ring tool may be used to aid in turning the applicator tip collar.

> **[Site Preparation and BioGlue Delivery Device Priming]{.underline}**

1.  Completely prepare the surgical site for adhesive application prior
    to priming or dispensing of the adhesive. A dry field will maximize
    adhesive contact with tissue. An optimal dry field can be described
    as a surgical site that does not restain with blood within 4-5
    seconds after drying.

> **CAUTION:** Attempting to apply the adhesive in a surgical field that
> is too wet may result in poor attachment.

2.  Prime immediately prior to application by compressing the device
    trigger, expelling a narrow ribbon of adhesive approximately 3 cm
    long onto a disposable surface (i.e., gauze, towel, or sample cup).

> **CAUTION:** Ensure priming material does not come into contact with
> the surgical site.

3.  If the primed material looks colorless or contains bubbles, it could
    indicate that the first compression of the device trigger resulted
    in inadequate mixing. Repeat the prime until the mixture is a
    homogeneous light yellow to amber colored liquid. A properly primed
    device will deliver a uniform liquid with no bubbles.

4.  Quickly proceed to application.

> **CAUTION:** BioGlue Surgical Adhesive sets up immediately. Priming
> must occur quickly, followed immediately by the application of
> adhesive. Pausing between priming and application can cause set-up of
> adhesive within the applicator tip.
>
> **[General Techniques for the Use of Adhesive in
> Surgery]{.underline}**
>
> Before using the BioGlue Surgical Adhesive, surgeons should become
> familiar by appropriate training with the surgical techniques and
> variations. The use of BioGlue Surgical Adhesive should be practiced
> prior to initial use in the surgical suite.

1.  The patient should be prepared and draped according to the site's
    standard procedures. Procedures such as entry of the chest,
    cardiopulmonary bypass, clamping, and myocardial protection should
    follow the surgeon's standard techniques.

2.  Maintain a dry surgical field during the application of the
    adhesive. An optimal dry field could be described as a surgical site
    that does not restain with blood within 4-5 seconds after removal.

3.  The tissue surrounding the surgical site can be protected from the
    undesired application of BioGlue Surgical Adhesive by placing moist
    sterile gauze pads in these areas. Directly after application,
    remove gauze before adhesive polymerizes.

4.  If BioGlue Surgical Adhesive does adhere in an undesired location,
    allow the adhesive to polymerize and then attempt to gently dissect
    the adhesive away from the affected area with forceps and scissors.

> **CAUTION:** Do not attempt to peel away the BioGlue Surgical Adhesive
> as this could result in tissue damage at the application site.

5.  Apply an even adhesive coating 1.2 - 3.0 mm thick for anastomosis of
    vessels with greater than 2.5 cm diameter or tissue reinforcement;
    apply an even adhesive coating 0.5 - 1.0 mm for vessels with less
    than 2.5 cm diameter.

6.  Do not compress the area of application or subject it to extra
    pressure. Allow the adhesive to polymerize for at least 2 minutes.
    Once the adhesive has polymerized (wait at least 2 minutes), remove
    the sponges or balloon catheter from within the lumen and secure
    sutures as necessary.

7.  After adhesive hardens, trim away excess or irregular adhesive edges
    with scissors and pickups.

> **CAUTION:** If the BioGlue Surgical Adhesive adheres to an undesired
> location, allow the adhesive to polymerize and then attempt to gently
> dissect the adhesive away from the affected area with forceps and
> scissors. Do not attempt to peel away the BioGlue Surgical Adhesive as
> this could result in tissue damage at the application site.

8.  If a portion of the dissected/repaired vessel or tissue is replaced
    with a graft, potential bleeding sites at the anastomosis between
    the graft and the native tissue can be sealed with BioGlue Surgical
    Adhesive. The field must be dry and free of blood.

### [Maintaining Device Effectiveness]{.underline}

> **[Precautions]{.underline}**

1.  Do not use glutaraldehyde based cleaners or other cleaners corrosive
    to metal parts as these may corrode parts of the delivery device and
    impede its function.

2.  Do not use ultrasonic cleaning methods as these may lead to material
    fatigue and to failure of the device.

3.  Do not use dry heat cleaning methods as this device is not designed
    to withstand these high temperatures.

4.  Do not clean with enzyme-based detergents since these may reduce the
    number of times the delivery device may be reused.

> **[Cleaning]{.underline}**
>
> Inspect the adhesive delivery device for signs of deterioration or
> damage such as cracking, blistering, or pitting. Discard if
> deterioration or damage is observed. Remove the plunger from the
> handle by lifting the plunger latch upward and drawing forward the
> plunger. CryoLife has determined that the adhesive delivery device may
> be satisfactorily cleaned by thoroughly washing with a mild detergent
> such as Alconox^®^. The effectiveness of other cleaning solutions has
> not been determined.
>
> NOTE: Use of the Alconox^®^ trademark in this document does not
> constitute an endorsement by CryoLife, Inc. Alconox^®^ is listed only
> as an example.
>
> **[Sterilization]{.underline}**
>
> Sterilize by autoclaving. The BioGlue Delivery Device should first be
> cleaned and placed in appropriate packing materials. The following
> autoclave settings have been tested to ensure sterility and product
> functionality:

  ----------------- ----------------- ------------------- -----------------
  **Cycle           **Cycle           **Cycle Time**      **Cycle Type**
  Temperature (C)** Temperature (F)**                     

  121 -- 131°C      250 -- 268°F      30 minutes          Pre-vacuum

  132°C             270°F             4 - 30 minutes      Pre-vacuum

  134°C             273°F             3 - 18 minutes      Pre-vacuum

  132°C             270°F             10 minutes          Gravity
  ----------------- ----------------- ------------------- -----------------

> Exposures outside of these settings have not been evaluated. The
> BioGlue Delivery Device can be resterilized up to 9 times under normal
> use.
>
> NOTE: The user should verify that the BioGlue Delivery Device is still
> functional after each cleaning and sterilization. This is easily
> accomplished by assembling the BioGlue Delivery Device (described
> above) and observing that the plunger moves forward with each
> depression of the lever.

### [PRODUCT INFORMATION DISCLOSURE]{.underline}

Handling and storage of this device by the user as well as factors
related to the patient, the patient's diagnosis, treatment, surgical
procedures, and other matters beyond manufacturer\'s control may
directly or indirectly affect this device and the results obtained from
its use. This device should not be used except on the order of a
physician.

### [DISCLAIMER OF IMPLIED WARRANTIES]{.underline}

CryoLife, Inc. disclaims all implied warranties with respect to this
surgical adhesive, including but not limited to, the implied warranty of
merchantability and any warranty of fitness for a particular purpose.
Prices, specifications, and availability are subject to change without
notice.

> ![](media/image3.wmf){width="2.3222222222222224in"
> height="0.6465277777777778in"}

1655 Roberts Blvd., NW\
Kennesaw, Georgia 30144 USA

770-419-3355 or 800-438-8285\
Fax 770-590-3749