The Evaluation of
Pharmacologic Agents on Composite Graft Survival
Kenneth K. \s=b\ This study assessed the
Aden, MD, Merrill A. Biel, MD, PhD
efficacy of various pharmacologic
agents in improving composite graft viability in
60 New
Zealand white rabbits given bilateral auricular composite grafts. Treatments included methylprednisolone preoperatively and for 3 days postoperatively or for 7 days postop-
eratively only; chlorpromazine, dimethylsulfoxide, or superoxide dismutase preoperatively; or indomethacin preoperatively and for either 3 or 7 days postoperatively. Four treatment modalities yielded a statistically significant decrease in percentage of necrosis. Methylprednisolone, when given preoperatively and continued postoperatively, produced the greatest increase (77%) in composite graft tissue survival. Dimethylsulfoxide, chlorpromazine, and indomethacin for 3 days were also effective, but to a much lesser extent. It is speculated that these agents may help stabilize cell membranes during the anoxic phase of plasmic imbibition and minimize cellular edema until revascularization can occur. (Arch Otolaryngol Head Neck Surg. 1992;118:175-178)
composite free graft is composed of tissue from A germ layers that is completely severed from the donor site. The auricular of two
or more
has evaluated the pharmacologie manipulation of auricu¬ lar composite grafts. In this study methylprednisolone given preoperatively and for 4 days postoperatively improved tissue survival from 41% in control animals to 75% in experimental models. Pang et al4 evaluated a number of agents found to increase skin flap viability by increasing the blood flow to the tissue in the skin flap. Most recently a number of agents have been shown to "protect" tissue during time of ischemia and increase skin flap viability: methylprednisolone, Superoxide dismutase, dimethylsulfoxide, allopurinol, and chlorpro¬ mazine. Prostaglandins and their synthesis inhibitors, including ibuprofen and indomethacin, have also been shown to increase skin flap viability in animal models. The objective of this study was to evaluate a number of pharmacologie agents with regard to their ability to improve the viability of composite grafts. They include (1) methyl¬ prednisolone, which significantly improved tissue survival in earlier studies using the rabbit auricular composite graft model3; (2) the oxygen free radical scavengers chlorpro¬ mazine, dimethylsulfoxide, and Superoxide dismutase; and (3) indomethacin, a nonsteroidal anti-inflammatory agent.
composite graft composed
skin, cartilage, and skin is an excellent solution when skin
plus supporting cartilage is required for recon¬ struction. Use of an auricular composite graft was first re¬ ported by Konig in 1887, with a success rate of approxi¬ mately 53% in 37 cases. Since that time many other authors1 have reported the use of auricular composite grafts for reconstruction in the head and neck region. The sites commonly repaired using an auricular com¬ posite graft include the alar rim, lateral nasal wall, intranasal lining and support tissue, and columella. The com¬ posite graft has also' been used in reconstruction of the ear, trachea, and lip. However, the limitation of this type of graft is that only a small amount of tissue can be trans¬ planted successfully without a significant loss of the transplanted tissue. Converse2 reported that the most successful composite grafts were approximately 1 cm in width, although he noted exceptions to this standard size had been reported, with successful grafts up to 2.5 cm in width. However, Converse emphasized the rule of thumb for composite grafts: for a successful graft transplant, no area of the graft should be greater than 1 cm from the free margin of the graft. or mucosa
Various chemical agents have been examined to im¬ prove skin graft and flap viability. Only one study3 to date
MATERIALS AND METHODS New Zealand white rabbits weighing 3 to 5 kg were used. Each animal was anesthetized with 30 to 35 mg/kg of ketamine supple¬ mented with 5 mg/kg of xylazine. The neurovascular bundle at the base of each auricle was injected with 1.2 mL of 1% lidocaine for a local anesthetic effect. Two templates 2.0 cm in diameter were stabilized on opposite sides in the middle portion of each auricle, approximately 6.5 cm from the base of the skull. A small skin in¬ cision was made over the neurovascular bundle at the edge of the template, both distally and proximally, and the neurovascular bundle ligated with 6-0 silk to prevent excess bleeding during the time of resection. A through-and-through single incision was made to harvest the composite graft (Fig 1). The graft was then replaced into the original donor site and the skin and perichondrium on each side of the graft was closed with a single 6-0 Maxion running su¬ ture (Fig 2). Bacitracin ointment was applied to the graft and the procedure was repeated on the opposite ear. A total of 60 animals were surgically prepared, with four an¬ imals dying due to anesthetic complications prior to graft harvest. One hundred twelve grafts were evaluated from the re¬ maining 56 animals; however, the photographic documentation of one graft was unsuccessful, yielding 111 grafts (Table 1). The subjects were divided into the following eight groups. The control group (N 8) received 1.0 mL of normal saline in¬ tramuscularly 30 minutes prior to the surgical procedure. Two groups of animals received methylprednisolone. The first =
group (N 8) received methylprednisolone intramuscularly, 30 mg/kg, 4 hours after the initiation of surgery and for 3 days postoperatively. The second group (N 8) of animals received methylprednisolone intramuscularly, 30 mg/kg, 1 hour before surgery and then for 7 days postoperatively. Single agents that have been reported to act as oxygen radical scavengers were administered to three groups of animals preoper¬ atively: the first group (N 8) received 15 mg/kg of chlorpromazine =
Accepted From the
for publication August 2, 1991. Department of Otolaryngology, University of
sota, Minneapolis. Presented at the American
Minne-
Academy of Facial Plastic and ReconSurgery, Toronto, Ontario, June, 1989. Reprint requests to the Minneapolis Ear, Nose, and Throat Clinic, 2211 Park Ave S, Minneapolis, MN 55404 (Dr Biel). structive
=
=
Downloaded From: http://archotol.jamanetwork.com/ by a Penn State Milton S Hershey Med Ctr User on 05/26/2015
^. The composite tioned into defect.
Fig
graft
harvested from auricle to be
reposi¬
Fig 2. —Composite graft sutured back
into
original site.
—
(N 8) received 40 mg/kg of The third group (N 6) re¬ intramuscularly. dimethylsulfoxide ceived 20000 U/kg of Superoxide dismutase intravenously.
intramuscularly.
The second group
=
Table 1.—Percent Necrosis per
=
Two groups of animals received indomethacin. The first group (N 5) received 3 mg/kg of indomethacin intramuscularly pre¬ operatively, and for 3 days postoperatively. The second group (N 5) received the same dosage preoperatively and for 7 days =
=
postoperatively. The composite graft was evaluated by photographs at days 7,14, and 21 with
a
90-mm
macro
lens
on a
35-mm
camera
to obtain
a
photograph-to-tissue relationship. The photographs then enlarged approximately five times. The area of necrosis vs the area of the original graft was measured using an analysis system (Zeiss Intra-active Digital Analysis System) to yield the rel¬ ative percentage of necrosis (Fig 3). The average percent necrosis from each composite group was then analyzed using a data program (Stat View 12, Macintosh Microsoftwear, Apple Com¬ puter Ine, Cupertino, Calif) to obtain the SD and SE for each group. Each group was then compared with the control group using Stu¬ dent's f test; an analysis of variance was also performed. one-to-one were
RESULTS The results from each group, including mean percentage of necrosis, SD, and SE, are shown in Table 1. An overall re¬ view of the mean percentage of necrosis along with the and F values for each group are given in Table 2. A comparative histogram showing the individual mean percentage of ne¬ crosis per group and the associated value is seen in Fig 3. The group that received methylprednisolone preoperatively had the smallest percentage of necrosis when compared with the other study groups (P
Pharmacologic Agents on Composite Graft Survival
Kenneth K. \s=b\ This study assessed the
Aden, MD, Merrill A. Biel, MD, PhD
efficacy of various pharmacologic
agents in improving composite graft viability in
60 New
Zealand white rabbits given bilateral auricular composite grafts. Treatments included methylprednisolone preoperatively and for 3 days postoperatively or for 7 days postop-
eratively only; chlorpromazine, dimethylsulfoxide, or superoxide dismutase preoperatively; or indomethacin preoperatively and for either 3 or 7 days postoperatively. Four treatment modalities yielded a statistically significant decrease in percentage of necrosis. Methylprednisolone, when given preoperatively and continued postoperatively, produced the greatest increase (77%) in composite graft tissue survival. Dimethylsulfoxide, chlorpromazine, and indomethacin for 3 days were also effective, but to a much lesser extent. It is speculated that these agents may help stabilize cell membranes during the anoxic phase of plasmic imbibition and minimize cellular edema until revascularization can occur. (Arch Otolaryngol Head Neck Surg. 1992;118:175-178)
composite free graft is composed of tissue from A germ layers that is completely severed from the donor site. The auricular of two
or more
has evaluated the pharmacologie manipulation of auricu¬ lar composite grafts. In this study methylprednisolone given preoperatively and for 4 days postoperatively improved tissue survival from 41% in control animals to 75% in experimental models. Pang et al4 evaluated a number of agents found to increase skin flap viability by increasing the blood flow to the tissue in the skin flap. Most recently a number of agents have been shown to "protect" tissue during time of ischemia and increase skin flap viability: methylprednisolone, Superoxide dismutase, dimethylsulfoxide, allopurinol, and chlorpro¬ mazine. Prostaglandins and their synthesis inhibitors, including ibuprofen and indomethacin, have also been shown to increase skin flap viability in animal models. The objective of this study was to evaluate a number of pharmacologie agents with regard to their ability to improve the viability of composite grafts. They include (1) methyl¬ prednisolone, which significantly improved tissue survival in earlier studies using the rabbit auricular composite graft model3; (2) the oxygen free radical scavengers chlorpro¬ mazine, dimethylsulfoxide, and Superoxide dismutase; and (3) indomethacin, a nonsteroidal anti-inflammatory agent.
composite graft composed
skin, cartilage, and skin is an excellent solution when skin
plus supporting cartilage is required for recon¬ struction. Use of an auricular composite graft was first re¬ ported by Konig in 1887, with a success rate of approxi¬ mately 53% in 37 cases. Since that time many other authors1 have reported the use of auricular composite grafts for reconstruction in the head and neck region. The sites commonly repaired using an auricular com¬ posite graft include the alar rim, lateral nasal wall, intranasal lining and support tissue, and columella. The com¬ posite graft has also' been used in reconstruction of the ear, trachea, and lip. However, the limitation of this type of graft is that only a small amount of tissue can be trans¬ planted successfully without a significant loss of the transplanted tissue. Converse2 reported that the most successful composite grafts were approximately 1 cm in width, although he noted exceptions to this standard size had been reported, with successful grafts up to 2.5 cm in width. However, Converse emphasized the rule of thumb for composite grafts: for a successful graft transplant, no area of the graft should be greater than 1 cm from the free margin of the graft. or mucosa
Various chemical agents have been examined to im¬ prove skin graft and flap viability. Only one study3 to date
MATERIALS AND METHODS New Zealand white rabbits weighing 3 to 5 kg were used. Each animal was anesthetized with 30 to 35 mg/kg of ketamine supple¬ mented with 5 mg/kg of xylazine. The neurovascular bundle at the base of each auricle was injected with 1.2 mL of 1% lidocaine for a local anesthetic effect. Two templates 2.0 cm in diameter were stabilized on opposite sides in the middle portion of each auricle, approximately 6.5 cm from the base of the skull. A small skin in¬ cision was made over the neurovascular bundle at the edge of the template, both distally and proximally, and the neurovascular bundle ligated with 6-0 silk to prevent excess bleeding during the time of resection. A through-and-through single incision was made to harvest the composite graft (Fig 1). The graft was then replaced into the original donor site and the skin and perichondrium on each side of the graft was closed with a single 6-0 Maxion running su¬ ture (Fig 2). Bacitracin ointment was applied to the graft and the procedure was repeated on the opposite ear. A total of 60 animals were surgically prepared, with four an¬ imals dying due to anesthetic complications prior to graft harvest. One hundred twelve grafts were evaluated from the re¬ maining 56 animals; however, the photographic documentation of one graft was unsuccessful, yielding 111 grafts (Table 1). The subjects were divided into the following eight groups. The control group (N 8) received 1.0 mL of normal saline in¬ tramuscularly 30 minutes prior to the surgical procedure. Two groups of animals received methylprednisolone. The first =
group (N 8) received methylprednisolone intramuscularly, 30 mg/kg, 4 hours after the initiation of surgery and for 3 days postoperatively. The second group (N 8) of animals received methylprednisolone intramuscularly, 30 mg/kg, 1 hour before surgery and then for 7 days postoperatively. Single agents that have been reported to act as oxygen radical scavengers were administered to three groups of animals preoper¬ atively: the first group (N 8) received 15 mg/kg of chlorpromazine =
Accepted From the
for publication August 2, 1991. Department of Otolaryngology, University of
sota, Minneapolis. Presented at the American
Minne-
Academy of Facial Plastic and ReconSurgery, Toronto, Ontario, June, 1989. Reprint requests to the Minneapolis Ear, Nose, and Throat Clinic, 2211 Park Ave S, Minneapolis, MN 55404 (Dr Biel). structive
=
=
Downloaded From: http://archotol.jamanetwork.com/ by a Penn State Milton S Hershey Med Ctr User on 05/26/2015
^. The composite tioned into defect.
Fig
graft
harvested from auricle to be
reposi¬
Fig 2. —Composite graft sutured back
into
original site.
—
(N 8) received 40 mg/kg of The third group (N 6) re¬ intramuscularly. dimethylsulfoxide ceived 20000 U/kg of Superoxide dismutase intravenously.
intramuscularly.
The second group
=
Table 1.—Percent Necrosis per
=
Two groups of animals received indomethacin. The first group (N 5) received 3 mg/kg of indomethacin intramuscularly pre¬ operatively, and for 3 days postoperatively. The second group (N 5) received the same dosage preoperatively and for 7 days =
=
postoperatively. The composite graft was evaluated by photographs at days 7,14, and 21 with
a
90-mm
macro
lens
on a
35-mm
camera
to obtain
a
photograph-to-tissue relationship. The photographs then enlarged approximately five times. The area of necrosis vs the area of the original graft was measured using an analysis system (Zeiss Intra-active Digital Analysis System) to yield the rel¬ ative percentage of necrosis (Fig 3). The average percent necrosis from each composite group was then analyzed using a data program (Stat View 12, Macintosh Microsoftwear, Apple Com¬ puter Ine, Cupertino, Calif) to obtain the SD and SE for each group. Each group was then compared with the control group using Stu¬ dent's f test; an analysis of variance was also performed. one-to-one were
RESULTS The results from each group, including mean percentage of necrosis, SD, and SE, are shown in Table 1. An overall re¬ view of the mean percentage of necrosis along with the and F values for each group are given in Table 2. A comparative histogram showing the individual mean percentage of ne¬ crosis per group and the associated value is seen in Fig 3. The group that received methylprednisolone preoperatively had the smallest percentage of necrosis when compared with the other study groups (P
