Expression of neutrophil collagenase (matrix metalloproteinase-8) in human atheroma: a novel collagenolytic pathway suggested by transcriptional profiling.

BACKGROUND: Loss of interstitial collagen, particularly type I collagen, the major load-bearing molecule of atherosclerotic plaques, renders atheroma prone to rupture. Initiation of collagen breakdown requires interstitial collagenases, a matrix metalloproteinase (MMP) subfamily consisting of MMP-1, MMP-8, and MMP-13. Previous work demonstrated the overexpression of MMP-1 and MMP-13 in human atheroma. However, no study has yet evaluated the expression of MMP-8, known as "neutrophil collagenase," the enzyme that preferentially degrades type I collagen, because granulocytes do not localize in plaques. METHODS AND RESULTS: Transcriptional profiling and reverse transcription-polymerase chain reaction analysis revealed inducible expression of MMP-8 transcripts in CD40 ligand-stimulated mononuclear phagocytes. Western blot analysis demonstrated that 3 atheroma-associated cell types, namely, endothelial cells, smooth muscle cells, and mononuclear phagocytes, expressed MMP-8 in vitro upon stimulation with proinflammatory cytokines such as interleukin-1beta, tumor necrosis factor-alpha, or CD40 ligand. MMP-8 protein elaborated from these atheroma-associated cell types migrated as 2 immunoreactive bands, corresponding to the molecular weights of the zymogen and the active molecule. Extracts from atherosclerotic, but not nondiseased arterial tissue, contained similar immunoreactive bands. Moreover, all 3 cell types expressed MMP-8 mRNA and protein in human atheroma in situ. Notably, MMP-8 colocalized with cleaved but not intact type I collagen within the shoulder region of the plaque, a frequent site of rupture. CONCLUSIONS: These data point to MMP-8 as a previously unsuspected participant in collagen breakdown, an important determinant of the vulnerability of human atheroma.

Transdermal fentanyl improves management of postoperative hemorrhoidectomy pain.

PURPOSE: Outpatient postoperative hemorrhoidectomy pain remains a difficult problem. The purpose of this study is to evaluate the use of transdermal fentanyl for analgesia following hemorrhoidectomy. METHODS: Patients were prospectively randomized in a double-blind fashion to one of two groups, placebo or transdermal fentanyl. Forty-two patients were eligible for the study (placebo, 21; fentanyl, 17; 4 were excluded). A visual analog scale was used to evaluate postoperative pain (0 = no pain; 10 = worst pain). RESULTS: Fewer patients in the fentanyl group (10/17) required postoperative parental narcotics than the placebo group (21/21) (P < 0.05 Fisher's exact test). The amount of narcotics consumed postoperatively was significantly less in the fentanyl group (97.05 mg of meperidine +/- 23.27) than in the placebo group (236.19 +/- 30.46) (P < .05 Student's t-test). Pain scores in the fentanyl group were significantly lower (less pain) than in the placebo group (P < 0.05 Kruskal-Wallis). CONCLUSION: Results indicate that use of transdermal fentanyl provides an effective analgesic alternative that improves the transition to noninvasive outpatient pain management in the hemorrhoidectomy patient.

Ketorolac and patient controlled analgesia in the treatment of postoperative pain.

Ketorolac tromethamine (Toradol [Syntex, Palo Alto]), a new commercially available nonsteroidal antiinflammatory drug (NSAID), has appropriate solubility and minimal tissue irritation, making it suitable for intramuscular injection. Previously, NSAID have only been available for oral use in the United States for the treatment of pain. Ketorolac, the most potent NSAID known, relieves pain through inhibition of arachidonic acid synthesis at the cyclooxygenase level and has no central opioid effects. The results of previous studies using parenteral ketorolac in combination with patient administered narcotics have shown a 40 percent reduction in narcotic requirements. However, ketorolac is presently only approved for intramuscular injection and oral use in the United States. In a prospective, randomized study, we compared intramuscular ketorolac in combination with patient controlled intravenous narcotic analgesia (morphine) (PCA-M) to PCA-M alone for the control of pain after extensive colonic resections. The combination of intramuscular ketorolac and PCA-M provided equal pain relief with no increased side effects when compared with narcotics alone. However, narcotic requirements of the patients were decreased by an average of 45 percent. Ketorolac and narcotics in combination provide effective postoperative pain relief and significantly decrease narcotic requirements. This combination may be particularly beneficial in the subpopulation of patients especially prone to narcotic related complications.

Effect of epidural analgesia on colorectal anastomotic healing and colonic motility.

BACKGROUND AND OBJECTIVES: To examine the effect of epidural local anesthetic and narcotic agents on colonic anastomotic healing. METHODS: A prospective randomized study was conducted in a porcine model. Twenty-one pigs undergoing colorectal resection and anastomosis were randomized to receive either bupivacaine (Group 1), morphine (Group 2), or normal saline (Group 3) by intraoperative and postoperative epidural infusion. Colonic blood flow was measured using laser doppler velocimetry and colonic motility assessed with radio-opaque markers and daily x-rays postoperatively. Seven days postoperatively, the anastomoses were resected and analysis of bursting pressure and hydroxyproline content performed. RESULTS: In this porcine model, epidural anesthesia accelerated colonic transit time. Group 1 and 2 animals had significantly faster colonic transit time (3.9 and 4 days, respectively) when compared with Group 3 animals (6 days; p less than 0.05, chi-square analysis). There was no statistically significant difference in blood flow, bursting pressure, and hydroxyproline content between the three groups, and no anastomotic complications occurred in any animal. CONCLUSIONS: These findings suggest in this model that postoperative epidural analgesia is a safe technique after colorectal resection and anastomosis.

Interleukin-6 response to laparoscopic and open colectomy.

PURPOSE: It has been postulated that cortisol and interleukin-6 play a significant role in the modulation of the early inflammatory response following surgical intervention. There are no available data on the normal responses of these mediators following major laparoscopic procedures. The purpose of this study was to assess changes in cortisol (by fluorescence polarization immunoassay), interleukin-6 (by enzyme-linked immunoassay), and interleukin-1 (by enzyme-linked immunoassay) after elective laparoscopic colon resections. METHODS: All patients undergoing colon resection between February 1, 1992 and April 30, 1992 were eligible for study. Selection of laparoscopic (N = 12) vs. open (N = 41) resection was determined by the attending surgeon. All patients received a standard general anesthetic with endotracheal intubation. Cortisol, interleukin-6, and interleukin-1 were measured at preinduction, 1 hour, 2 hours, 3 hours, 4 hours, and 5 hours after the induction. Interleukin-6 and interleukin-1 were additionally measured at 12 hours, 24 hours, and 72 hours after induction. Comparisons were made between the laparoscopic patients (N = 12) and age, sex, and operation-matched open patients (N = 12). RESULTS: Cortisol levels rose in the early postoperative period in both open and laparoscopic groups with no significant differences occurring between the cohorts at any of the measured time intervals. The interleukin-6 levels of the laparoscopic cohort (N = 12) were significantly lower than those of the open cohort (N = 12) between 3 and 24 hours postinduction (P < 0.05). Interleukin-1 levels remained undetectable in virtually all patients irrespective of operative technique or postoperative interval. There was no correlation between peak interleukin-6 levels and operative times (laparoscopic, r = 0.31; open, r = 0.36) or blood loss (laparoscopic, r = 0.10; open, r = 0.20). CONCLUSION: The results indicate that laparoscopic colon resections do not appear to alter cortisol or interleukin-1 responses when compared with open colon resection. There is, however, a significant blunting of the interleukin-6 response associated with the use of laparoscopic techniques for colectomy compared with standard laparotomy.

Epidural analgesia.

The most frequently used postoperative analgesia techniques are intramuscular injection (IM) and patient controlled analgesia (PCA). Recently, the use of epidural catheter injection (EPI) has been done with success. This study was done to prospectively compare these three techniques for postoperative analgesia after extensive operations upon the colon and rectum. Patients were randomized to one of three analgesia groups--IM, intramuscular morphine sulfate; PCA, patient controlled morphine sulfate, and EPI, epidural morphine sulfate. Data collected included age, time to first bowel movement, amount of narcotic, number achieving 75 per cent of preoperative forced vital capacity, postoperative pruritus, headache, nausea and vomiting, respiratory depression, atelectasis or pneumonitis. A visual analog pain scale was used to evaluate postoperative pain severity (0, no; 1, partial; 2, marked, and 3, total relief). Sixty-eight patients were eligible for study (IM, 19; PCA, 22; EPI, 23, and excluded, four). The EPI group required significantly less daily narcotic compared with either the IM or PCA groups (17.0 +/- 6.12 milligrams; 67.8 +/- 26.8 milligrams; 40.5 +/- 20.6 milligrams, respectively, less than 0.05 ANOVA) and total narcotic (81.3 +/- 31.3 milligrams; 355.4 +/- 147.7 milligrams; 215.3 +/- 105.4 milligrams, respectively, p less than 0.05 ANOVA). EPI achieves excellent pain control in more patients with a significantly lower dose of narcotics and significantly fewer pulmonary complications. Therefore, epidural analgesia is the optimal method of postoperative analgesia after extensive abdominal operations.

Superior nitrogen balance after laparoscopic-assisted colectomy.

BACKGROUND: Although early resumption of enteral feeding after gastrointestinal surgery results in improved nitrogen balance and lower infectious complications, no postoperative nutritional data after laparoscopic-assisted colectomy exists. OBJECTIVE: The authors prospectively compared nitrogen balance after laparoscopic-assisted colectomy versus open colectomy. METHODS: This is a series of colon resections (open, N = 10; laparoscopic-assisted, N = 9) at the Ferguson-Blodgett Hospital, Grand Rapids, Michigan, between January and March 1993. Nitrogen intake and 24-hour urine collections were performed on postoperative days 1, 3, and 7 for the analysis of total urinary nitrogen and urinary 3 methylhistidine-(3mH). RESULTS: The time to passage of flatus (4.7 +/- 0.6; 2.0 +/- 0.2), resumption of oral intake (6.1 +/- 0.7; 1.4 +/- 0.2; p < 0.05, Student's test), first bowel movement (5.2 +/- 1.0; 3.0 +/- 0.3; p < 0.05, Student;s t test), and discharge (10.3 +/- 1.3; 4.1 +/- 1.8; p < 0.05, Student's t test) occurred significantly earlier in the laparoscopic-assisted colectomy group. Overall hospital charges were lower in the laparoscopic-assisted colectomy group ($11,572 +/- $823 vs. $13,961 +/- $1050). The operative time was higher in the laparoscopic-assisted colectomy group (176 +/- 12 hours vs. 105 +/- 17 hours, p < 0.05,Student's test). Blood loss was higher in the open group (805 +/- 264 mL vs 217 +/- 32 mL, p < 0.05, Student's test). Urinary nitrogen losses were similar between the two groups; however, significantly more patients in the laparoscopic-assisted colectomy group achieved net positive nitrogen on day 3 (6/9; 0/10; p < 0.05, Fisher's exact test), and day 7 (9/9; 4/10; p < 0.05, Fisher's exact test). Infectious complications occurred less frequently in the laparoscopic-assisted colectomy group (0/9 vs. 4/10; p < 0.05, Fisher's exact test). CONCLUSIONS: Patients undergoing laparoscopic-assisted colectomy can achieve early resumption of enteral nutrition with earlier return to positive nitrogen balance compared with open colectomy. This may offer benefits of fewer infectious complications and lower cost of care.