Hiram C. Polk

A randomized prospective clinical trial to determine the efficacy of interferon-γ in severely injured patients

Many aspects of the normal immune response are depressed after severe injury. Reduced monocyte human leukocyte antigen-DR (HLA-DR) levels have closely correlated with the development of major infection. After a pilot study with recombinant interferon-gamma (rIFN-gamma) showed restoration of depressed HLA-DR levels after major injury, a multicenter, prospective, randomized, double-blind trial was conducted. Two hundred thirteen trauma patients who were at high risk of infection received either placebo or rIFN-gamma (100 micrograms) subcutaneously each day for 10 days after admission. One hundred ninety-three patients were evaluable with respect to primary end points. Patients treated with rIFN-gamma were older (p = 0.10) and had more severe modes of injury (p = 0.02). By the third day, both monocyte HLA-DR antigen expression and outcome predictive score were significantly better in the rIFN-gamma-treated group than in the placebo group (p = 0.0001 and p = 0.0006, respectively). Nine deaths occurred in patients treated with rIFN-gamma compared with 12 deaths in the placebo group (p = 0.46). Major infections requiring surgical drainage or debridement occurred in 17 patients treated with rIFN-gamma compared with 22 treated with placebo. No difference between treatment arms was noted in overall major or minor infection rates, but there were fewer severe infections that required reoperation or computer tomographic-guided drainage in patients receiving IFN-gamma. While these results suggest that rIFN-gamma may be useful in some aspects of infection in the patient with severe trauma, a larger trial with longer treatment will be needed to prove the comprehensive value of rIFN-gamma.

Unifying concepts in treatment of esophageal leaks

Summary We treated 75 patients with esophageal trauma, perforation, or anastomotic leak. Several factors were shown to be associated with an increased mortality, including delayed treatment, presence of severe underlying esophageal disease, total parenteral nutrition catheter infection, the necessity for major extirpative procedures to treat the perforation, and the use of exclusion and diversion in the continuity procedure. The use of local muscle flaps to buttress suture line closure has led to excellent results in the 19 patients so treated. Delayed treatment of perforation or an anastomotic leak is a major problem, but the treatment protocol described herein has led to the survival of 12 of 16 patients treated. The use of primary muscle flap closure for extensive esophageal defects or delayed treatment of nonhealing leaks was evaluated in five patients. All five had healing of the defect, with one resultant esophageal stricture.

Multiple System Organ Failure

The current understanding of organ failures and their clinical presentation is reviewed. Some broad categories of the investigation of the pathophysiology of this failure are presented: blood-borne toxins, the microaggregate concept, host-defense dysfunction, and biochemical studies of altered metabolism in patients with sepsis.

Combined topical and systemic antibiotic prophylaxis in experimental wound infection

The effectiveness of a combined topical and systemic antibiotic regimen was studied in an animal model previously shown to simulate clinical surgical wound infection. At a high level of bacterial contamination, the combination regimen produced a lower infection rate than either a placebo (p less than 0.01), a topical antibiotic administered alone (p less than 0.01), or a systemic antibiotic administered alone. At a lower level of bacterial contamination, no additional reduction in infection rates was produced by the combination regimen when compared with systemic antibiotic administered alone. These experimental results suggest that when wound contamination is great, a combination of topical and systemic antibiotics is the more effective regimen. Where wound contamination is less severe, systemic antibiotic prophylaxis is all that is required; no further benefit is obtained by the additional administration of topical antibiotics. Clinical trials appear justified to confirm or refute this hypothesis.

Malignant tumors of the liver.

HCC occurs infrequently in Western countries, with recent increases being reported in California and parts of Europe. Southeast Asia, Japan, and South Africa continue to have a high incidence of this tumor with HBV, cirrhosis, and the ingestion of aflatoxins being identified as probable risk factors. Although the majority of patients present with abdominal pain or mass indicative of extensive tumor, asymptomatic, small HCCs are being detected with increasing frequency. Early detection in high-risk individuals is best accomplished by screening with serum AFP determinations and liver ultrasonography. CT and arteriography are valuable preoperatively in defining anatomy and determining resectability. Five-year survival following resection for cure of HCC ranges from 20 to 40 per cent, with improved survival reported for small asymptomatic tumors. Resection of metastatic liver tumors from colorectal primaries results in 48 per cent 2-year and 24 per cent 5-year survivals, with an additional 5 per cent dying of recurrent cancer after 5 years. Although patients with simultaneous and metachronous metastases do equally well after resection, the presence of four or more individual deposits adversely affects survival. Hepatic artery ligation or embolization can produce a significant palliative reduction in total tumor mass in patients with unresectable liver metastases. Regional chemotherapy using implantable hepatic artery drug infusion pumps is promising, with reports of prolonged survival compared with historical controls. Regional hyperthermia, laser vaporization of tumor, and cryosurgical techniques may prove to have useful roles in the selective treatment of liver cancer in the future. Orthotopic liver transplantation has been successful primarily in those in whom the malignancy is found incidentally in the chronically diseased liver.

Experimental and clinical significance of endotoxin-dependent HLA-DR expression on monocytes

For much of the last decade, an increasing number of surgeons have been interested in objective assessment of cellular contributors to host defense function. In order to study many of these processes, it is apparently desirable that the cells be isolated to the extent feasible for the purpose of analyzing a more or less pure population of cellular elements. The purpose of this paper is to describe the physiologic activation of mononuclear cells that occurs as a result of the isolation process. Therefore, it follows logically that such cells are therein intrinsically less responsive to further physiologic manipulation in vitro. Analyses of such data without an awareness of this intrinsic aberration will undoubtedly lead to misinterpretation of the capacity of such cells for further modulation by immunostimulants or by the intrinsic processes related to injury, anesthesia, and operation. Furthermore, it may indicate that certain agents, e.g., cytokines, are unable to stimulate cellular function when, in fact, the defense function of the cell has been initially stimulated by the isolation procedure. Fractionation of human peripheral blood over Hypaque-Ficoll and subsequent purification of monocytes by adherence to plastic lead to an increase in the relative density of HLA-DR on monocytes. This increase occurred when carried out in endotoxin lipopolysaccharide (LPS)-contaminated or LPS-depleted reagents. LPS, added experimentally to whole blood, enhanced HLA-DR expression on monocytes without further manipulation. Monocyte HLA-DR expression measured in whole blood was reduced in patients with major sepsis (n = 19) compared to normal subjects (n = 10).(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of hydrocortisone on superoxide production by leukocytes

Abstract Corticosteroids have been shown to significantly depress intracellular bactericidal pathways. Formation of superoxide anion (O 2 − ) is thought to be an important intermediary in this process. We have demonstrated that actively phagocytizing PMNs generate significantly diminished levels of O 2 − in the presence of hydrocortisone sodium succinate.

Effects of interferon-γ treatment on surgically simulated wound infection in mice

Interferon-γ (IFN-γ) has been shown to have immunoregulatory properties and is able to modulate resistance to several microbial infections. This study was designed to determine the efficacy of IFN-γ treatment in a mouse model of infection that simulates many clinical conditions associated with surgical wound infection: viz, a bacteria laden suture and tissue injury. The test bacteria were Klebsiella pneumoniae. Groups of CBA/J mice received either IFN-γ or RPMI1640 medium (controls) subcutaneously. IFN-γ was administered daily at a dose of 7500 units for 5 days prior to bacterial challenge. Mice treated with IFN-γ survived significantly longer than controls. Systemic bacterial recovery was significantly reduced in the IFN-γ treated group but local bacterial recovery was unaffected.

Recurrent cancer of the colon.

To manage recurrent colorectal cancer effectively, the surgeon must be aware of the prognostic significance of the pathologic features of the primary disease, the adequacy of the original operation, the time since the initial treatment, and the various kinds of recurrence. Timely detection of recurrent disease is beneficial, but reresection is often palliative not curative.

Hyperthermic isolated limb perfusion increases circulating levels of inflammatory cytokines

Hyperthermic isolated limb perfusion is an established method of treatment for regionally advanced melanoma. Recent studies suggest that exogenously administered cytokines potentiate tumor response in patients with in-transit melanoma. We hypothesized that isolated limb perfusion induces an immunogenic response characterized by increased circulating levels of cytokines in the pump circuit, potentially contributing to the antitumor effect. We obtained blood samples from the perfusion circuit and systemic circulation at various intervals from patients undergoing isolated chemotherapeutic perfusion for melanoma. Samples were analyzed for serum cytokine profiles by enzyme-linked immunosorbent assay. When compared with baseline values, significant increases in serum levels of interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor (TNF) occurred within the perfusion circuit during isolated limb perfusion (P<0.05). In addition, there was a corresponding increase in IL-8 within the systemic circulation at the 60-min interval (P<0.05), suggesting some degree of leakage from the isolated circuit due to the extremely high levels of IL-8 in the perfusion circuit. A transient but insignificant decrease in circulating levels of neutrophils was also observed during the perfusion process, which may be attributed to margination. Increased levels of cytokines IL-6, IL-8, and TNF occurred within the isolated circuit during hyperthermic limb perfusion and may contribute to tumor response seen in patients treated with isolated limb perfusion.