Michael G. Franz

Guidelines for the treatment of diabetic ulcers

1. Chaired this panel2. University of Pittsburgh/UPMC, Pittsburgh, PA3. Georgetown University Hospital, Washington, DC4. Colaizzi Pedorthic Center, Pittsburgh, PA5. HCA Richmond Retreat Hospital, Richmond, VA6. University of Michigan Hospital, Ann Arbor, MI7. University of Texas Health Science Center, San Antonio, TX8. Covance, Princeton, NJ9. St Joseph’s Hospital, Belleville, IL10. University of South Florida, Tampa, FL11. Penn North Centers for Advanced Wound Care, Warren, PA12. Cabrini Medical Center, NY, NY13. Beth Israel Deaconess Medical Center, Boston, MA, and14. Barnes-Jewish Hospital at Washington University Medical Center, St Louis, MO

Tissue-Specific Cytokine Production During Experimental Acute Pancreatitis (A Probable Mechanism for Distant Organ Dysfunction)

Our purpose was to determine if cytokines are produced systemically during acute pancreatitis. Proinflammatory cytokines are elevated during acute pancreatitis and have been implicated in the progression of pancreatitis-associated multiple organ dysfunction. Whether these mediators are produced within all tissues or very few specific organs is not known. Edematous pancreatitis was induced in adult male mice by IP injection of cerulein. Necrotizing pancreatitis was induced in young female mice by feeding a choline-deficient, ethionine supplemented diet.Animals were sacrificed as pancreatitis worsened, with multiple organs prepared for tissue mRNA and protein analysis by RT-PCR and immunoblotting.Pancreatitis severity was established by histologic grading and serum amylase and lipase. There was no cytokine mRNA or protein detectable prior to the induction of pancreatitis. Tumor necrosis factor-α (TNF-α) and interleukin-1-β (IL-1β) mRNA and protein were detected within the pancreas early in the course of pancreatitis in both models,coinciding with the development of hyperamylasemia (both P < 0.001). Interleukin-6 was produced in the pancreas after pancreatitis was more fully developed (P< 0.001). IL-1β and TNF-α were subsequently produced in large amounts in lung, liver, and spleen but never within kidney, cardiac muscle, or skeletal muscle.A significant delay between pancreatic and distant organ cytokine production was always observed.It is concluded that proinflammatory cytokines are produced within the pancreas and within organs known to develop dysfunction during severe pancreatitis. Cytokine production is tissue specific,correlates with disease severity, and occurs within the pancreas first and subsequently within distant organs.

Interleukin-1 receptor antagonist decreases severity of experimental acute pancreatitis.

BACKGROUND Fulminant acute pancreatitis is a disease of complex origin that results in activation of several of the proinflammatory cytokines. Because interleukin-1 (IL-1) is an integral early component of the acute inflammatory process, the use of an IL-1 receptor antagonist (IL-1ra) was investigated in experimental acute pancreatitis to determine the therapeutic potential of proximal cytokine blockade and to further establish the role of inflammatory cytokines in the pathogenesis of acute pancreatitis. METHODS IL-1ra was administered in escalating doses either before or after acute edematous, necrotizing pancreatitis was induced in adult male mice by injection of cerulein. The severity of pancreatitis was quantified by serum amylase, lipase, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) levels, pancreatic wet weight, and blinded histologic grading. RESULTS Administration of medium (10 mg/kg) and high (100 mg/kg) doses of IL-1ra either before or after the induction of pancreatitis significantly decreased the expected rise in pancreatic wet weight, lipase, IL-6, and TNF-alpha (all, p < 0.01). Serum amylase was significantly reduced when IL-1ra was administered in either dosage before (p < 0.05), but not after, induction of pancreatitis. Pancreatic edema, necrosis, and inflammatory cell infiltrate were significantly diminished (p < 0.05) by histologic grading in all animals receiving medium or high doses of IL-1ra. Low doses of IL-1ra (1.0 mg/kg) had modest effects if given before, but no effect if given after, induction of pancreatitis. CONCLUSIONS The proinflammatory cytokines IL-6 and TNF-alpha are elevated during experimental acute pancreatitis and correlate well with the severity of local pancreatic destruction. Blockade of the cytokine cascade at the level of the IL-1 receptor before or soon after induction of pancreatitis significantly attenuates the rise in these cytokines and is associated with decreased severity of pancreatitis and reduced intrinsic pancreatic damage.

Decreased mortality of severe acute pancreatitis after proximal cytokine blockade

ObjectiveThis study determined the ability of interleukin-1 receptor antagonist (IL-1ra) to decrease the mortality of experimental acute pancreatitis. The response of the inflammatory cytokine cascade and its subsequent effects on pancreatic morphology were measured to determine the role of these peptides in mediating pancreatic injury. Summary Background DataPrevious studes have shown that proinflammatory cytokines are produced in large amounts during acute pancreatitis and that blockade at the level of the IL-1 receptor significantly decreases intrinsic pancreatic damage. The subsequent effect on survival is not known. MethodsA lethal form of acute hemorrhagic necrotizing pancreatitis was induced in young female mice by feeding a choline-deficient, ethionine supplemented (CDE) diet for 72 hours. For determination of mortality, the animals were divided into 3 groups of 45 animals each: control subjects received 100/μ L normal saline intraperitoneally every 6 hours for 5 days; IL-1ra early mice received recombinant interleukin-1 receptor antagonist 15 mg/kg intraperitoneally every 6 hours for 5 days beginning at time 0; IL-1ra late mice received IL-1 ra 15 mg/kg intraperitoneally every 6 hours for 3.5 days beginning 1.5 days after introduction of the CDE diet. A parallel experiment was conducted simultaneously with a minimum of 29 animals per group, which were sacrificed daily for comparisons of serum amylase, lipase, IL-1, IL-6, tumor necrosis factor-α, IL-1ra, pancreatic wet weight, and blind histopathologic grading. ResultsThe 10-day mortality in the untreated control group was 73%. Early and late IL-1ra administration resulted in decreases of mortality to 44% and 51%, respectively (both p < 0.001). Interleukin-1 antagonism also was associated with a significant attenuation in the rise in pancreatic wet weight and serum amylase and lipase in both early and late IL-1ra groups (all < 0.05). All control animals developed a rapid elevation of the inflammatory cytokines, with maximal levels reached on day 3. The IL-1ra-treated animals, however, demonstrated a blunted rise of these mediators (all p < 0.05). Blind histologic grading revealed an overall decrease in the severity of pancreatitis in those animals receiving the antagonist. ConclusionsEarly or late blockade of the cytokine cascade at the level of the IL-1 receptor significantly decreases the mortality of severe acute pancreatitis. The mechanism by which this is

Timing of tumor necrosis factor antagonism is critical in determining outcome in murine lethal acute pancreatitis

BACKGROUND Tumor necrosis factor (TNF) is produced in large amounts within the pancreas, lungs, and liver during severe acute pancreatitis and is believed to mediate many of the detrimental consequences typical of this disease. Investigations into the benefit of TNF antagonism have suggested that TNF may also mediate processes that are protective to the host. METHODS With the hypothesis that timing plays a role in these dissenting views, TNF was antagonized either prophylactically or therapeutically with a recombinant form of the soluble type I TNF receptor (TNFbp) during a lethal model of necrotizing pancreatitis induced by feeding a choline-deficient diet. Mortality was determined for 10 days in 390 female mice divided into three groups: control, TNFbp early (time, 0 to 5 days), and TNFbp late (time, 1.5 to 5 days). Pancreatitis severity and cytokine production were assessed daily. RESULTS Animals in the control group had a 75% mortality rate that was significantly decreased by prophylactic TNF blockade (64%, p < 0.05). Delaying TNF antagonism until serum cytokines were elevated and pancreatitis was manifest decreased mortality to 42% (p < 0.001 versus control, p < 0.01 versus early). Early and late TNF blockade decreased pancreatic edema and serum amylase, lipase, interleukin-1, and interleukin-6 (all p < 0.05) but not TNF. Late antagonism typically resulted in the greatest attenuation of all these parameters. CONCLUSIONS Blockade of TNF by the administration of a soluble TNF receptor attenuates the severity of pancreatitis, decreases the production of associated inflammatory cytokines, and significantly improves survival. Delaying antagonism until pancreatitis is manifest and circulating cytokines are elevated but not yet maximal appears to be more protective than simple prophylactic TNF antagonism.

The Biology of Hernia Formation

Abdominal wall hernias occur when tissue structure and function are lost at the load-bearing muscle, tendon, and fascial layer. The fundamental biologic mechanisms are primary fascial pathology or surgical wound failure. In both cases, cellular and extracellular molecular matrix defects occur. Primary abdominal wall hernias have been associated with extracellular matrix diseases. Incisional hernias and recurrent inguinal hernias more often involve a combination of technical and biologic limitations. Defects in wound healing and extracellular matrix synthesis contribute to the high incidence of incisional hernia formation following laparotomy.

Sonography of Inguinal Region Hernias

OBJECTIVE The purpose of this article is to describe the anatomy of the inguinal region in a way that is useful for sonographic diagnosis of inguinal region hernias, and to illustrate the sonographic appearance of this anatomy. We show sonographic techniques for evaluating inguinal, femoral, and spigelian hernias and include surgically proven examples. CONCLUSION Understanding healthy inguinal anatomy is essential for diagnosing inguinal region hernias. Sonography can diagnose and differentiate between various inguinal region hernias.

Incisional herniation induces decreased abdominal wall compliance via oblique muscle atrophy and fibrosis.

Objective:The purpose of this study is to measure abdominal wall myopathic histologic and mechanical changes during incisional herniation and its effect on incisional hernia repairs. Summary Background Data:Unloaded skeletal muscles undergo characteristic atrophic changes, including change in fiber type composition, decreased cross-sectional area, and pathologic fibrosis. We hypothesize that these atrophic changes decrease muscle elastic properties and may contribute to the high laparotomy wound failure rate observed following incisional hernia repair. Methods:A rat model of chronic incisional hernia formation was used. Failing midline laparotomy incisions developed into incisional hernias. Controls were uninjured and sham laparotomy (healed) groups. Internal oblique muscles were harvested for fiber typing, measurement of cross-sectional area, collagen deposition, and mechanical analysis. Mesh hernia repairs were performed on a second group of rats with chronic incisional hernias or acute anterior abdominal wall myofascial defects. Results:The hernia group developed lateral abdominal wall shortening and oblique muscle atrophy. This was associated with a change in the distribution of oblique muscle fiber types, decreased cross-sectional area, and pathologic fibrosis consistent with myopathic disuse atrophy. These muscles exhibited significant decreased extensibility and increased stiffness. The healed (sham) laparotomy group expressed an intermediate phenotype between the uninjured and hernia groups. Recurrent hernia formation was most frequent in the chronic hernia model, and hernia repairs mechanically disrupted at a lower force compared with nonherniated abdominal walls. Conclusions:The internal oblique muscles of the abdominal wall express a pattern of changes consistent with those seen in chronically unloaded skeletal muscles. The internal oblique muscles become fibrotic during herniation, reducing abdominal wall compliance and increasing the transfer of load forces to the midline wound at the time of hernia repair.

Guidelines to aid healing of acute wounds by decreasing impediments of healing

1. Co-chaired this panel, 2. Department of Surgery, University of Michigan, Ann Arbor, Michigan, 3. Department of Surgery, University of South Florida, Tampa, Florida, 4. Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, 5. Department of Surgery, Sinai Hospital/Johns Hopkins University, Baltimore, Maryland, 6. Department of Surgery, NYU School of Medicine, New York, New York, 7. PolyRemedy Inc., Mountain View, California, 8. Department of Wound Healing, Cardiff University, Cardiff, Wales, United Kingdom, 9. Department of Surgery, Johns Hopkins University, Baltimore, Maryland, 10. Institute for Tissue Regeneration, Repair, and Rehabilitation, Bay Pines VA Healthcare System, Bay Pines, Florida, 11. Division of Plastic Surgery, University of South Florida, Tampa, Florida, 12. Department of Surgery, University of Arizona, Tucson, Arizona, and 13. Barnes Jewish Hospital, Washington University, St. Louis, Missouri

The prevention of incisional hernia formation using a delayed-release polymer of basic fibroblast growth factor.

Objective:We sought to reduce the high incidence of abdominal wall incisional hernias using sustained release growth factor therapy. Summary Background Data:Incisional hernias complicate 11% of abdominal wall closures, resulting in 200,000 incisional hernia repairs in the United States each year. Mechanical improvements alone in mesh, suture material, and surgical technique have failed to reduce the high rate of fascial wound failure. Methods:Sprague-Dawley rats underwent midline celiotomies that were closed with fast-absorbing suture to induce early biomechanical wound failure and incisional hernia formation. In primary wounds, fascial incisions were closed adjacent to a continuous release polygalactone polymer rod containing basic fibroblast growth factor (bFGF), no growth factor (control-rod), or without rods. In a second group, incisional hernias were repaired with either bFGF or control-rod therapy. Breaking strength was measured on postoperative day (POD) 7, and the incidence of incisional hernia formation was determined on POD 28. Results:Treatment with bFGF rods significantly increased fascial wound breaking strength. In the “hernia-prevention” experiments, incisional hernias developed in 90% of untreated incisions, 60% of control-rod incisions, and only 30% of bFGF-rod incisions (P < 0.05). In the “hernia-treatment” experiments, recurrent incisional hernias developed in 86% of control-rod incisions compared with only 23% of bFGF-rod treated incisions (P < 0.05). Immunohistochemistry demonstrated increased angiogenesis and collagen protein production in bFGF treated incisions. Conclusion:The treatment of abdominal fascial incisions with a sustained-release bFGF polymer significantly lowered the incidence of incisional hernias and the recurrence rate after repair.