Defective IL-2 production in patients with severe burns and sepsis.
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Burns↗
Biomedical subjects
J A Mannick
Publications and source records attributed to J A Mannick.
Reduction of polymorphonuclear leukocyte accumulations by inhibition of cyclooxygenase and thromboxane syntase in the rabbit.
Thromboxane (Tx) inhibition prevents pulmonary leukostasis after acid aspiration. This observation prompted study of polymorphonuclear leukocyte (PMN) accumulations and products of cyclooxygenase. Experiments were conducted with a skin abrasion preparation. Five groups of six rabbits were pretreated intravenously with: (1) placebo, (2) ibuprofen, (3) imidazole and two other Tx syntase inhibitors, (4) OKY 1555, or (5) OKY 046. Zymosan-activated serum (ZAS) and leukotriene B4 were used as chemotaxins and balanced salt solution as control. After pretreatment with placebo, PMN accumulation in leukotriene B4 sites was 2130 +/- 874 PMN/mm3 (mean +/- SD). Pretreatment with ibuprofen, imidazole, or OKY 046 decreased (p less than 0.05) accumulations to 205 +/- 139 PMN/mm3, 485 +/- 387 PMN/mm3, and 504 +/- 260 PMN/mm3, respectively. In ZAS sites, placebo pretreatment led to 2006 +/- 866 PMN/mm3, while the ibuprofen, imidazole, and OKY 046 groups had decreased (p less than 0.05) responses of 295 +/- 218 PMN/mm3, 444 +/- 477 PMN/mm3, and 386 +/- 151 PMN/mm3, respectively. Pretreatment with OKY 1555 did not produce significant reductions in response. Six animals in each group received intradermal injections of the two chemotaxins or Hank's balanced salt solution. Reduction in PMN accumulations after cyclooxygenase and Tx inhibition were similar to those observed in the skin abrasion preparation. Pretreatment with either ibuprofen, imidazole, or OKY 046 resulted in a decreased concentration of Tx in abrasion fluid exudate in response to leukotriene B4, 275 +/- 164 pg/ml, 460 +/- 144 pg/ml, and 440 +/- 260 pg/ml, respectively, as compared with 1168 +/- 380 pg/ml in the placebo group. The reduced responses were not the result of a decrease in regional perfusion as measured by 133Xe washout. The in vitro chemotactic response of PMN to leukotriene B4 and ZAS was unchanged after incubation in either ibuprofen, imidazole, OKY 1555, or OKY 046. These data show that cyclooxygenase and Tx syntase are integrally associated with PMN accumulations.
Animals↗
Edwards Foundation lecture. Femoropopliteal and infrapopliteal reconstruction: state of the art 1985.
A review of recent reports in the surgical literature and the author's recent experience suggest that autogenous vein grafts remain the best method for arterial reconstruction below the inguinal ligament. The in-situ vein graft appears superior to reversed grafts for femoro-infrapopliteal reconstruction. Bypass grafts of polytetrafluoroethylene or human umbilical vein have not achieved satisfactory long-term patency even in the femoropopliteal position and should probably be used sparingly.
Arterial Occlusive Diseases↗
Occluded infrainguinal reconstructions.
The causes of failure of infrainguinal arterial reconstruction vary with the method of reconstruction used. The commonest cause of autogenous vein-graft failure is myointimal hyperplasia of the graft itself. The commonest cause of polytetrafluoroethylene-graft failure, on the other hand, appears to be a myointimal hyperplastic lesion of the artery at, or just beyond, the distal anastomosis of the graft. Strategies for dealing with these two forms of graft failure, including the use of thrombolytic therapy, are discussed.
Blood Vessel Prosthesis↗
Femorofemoral bypass to relieve acute leg ischemia during intra-aortic balloon pump cardiac support.
This study reports our experience with 10 patients who underwent the emergent construction of a femorofemoral bypass graft to salvage an acutely ischemic lower extremity following the insertion of a transfemoral intra-aortic balloon pump catheter. All patients had excellent resolution of the ischemia and salvage of the extremity. Half of the procedures were done at the bedside with the remainder performed in the operating room. No long-term infections or ischemic sequelae resulted from the procedures in the nine patients available for long-term follow-up. The use of femorofemoral bypass grafting is, therefore, recommended in patients with severe ipsilateral limb ischemia who are dependent on an intra-aortic balloon pump to prevent extremity tissue loss as well as the systemic metabolic manifestations of ongoing tissue ischemia and necrosis. Patient selection, technical considerations, and postoperative management are discussed.
Adult↗
Chemotactic activity of plasma and lung lymph in sheep with endotoxemia: effect of hydroxyl radical scavengers.
The formation and release of circulating chemoattractants has been considered to be responsible for the initial pulmonary leukostasis and subsequent pulmonary vascular injury seen with endotoxemia. Oxygen radicals released from granulocytes can produce these factors. Our purpose was (1) to determine whether chemotaxins are released with endotoxemia and whether the lung is the source of these factors and (2) if there is a cause and effect relationship between the release of chemoattractants and the lung injury. Lung lymph flow, QL, lymph protein clearance, and vascular pressures were used to monitor lung vascular integrity. Escherichia coli endotoxin was infused into 12 sheep. Six sheep were pretreated with dimethyl thiourea (DMTU), a scavenger of hydroxide ion radicals. Chemotactic activity (CA) of plasma and lung lymph was determined during baseline, the pulmonary hypertensive phase, and the permeability phase of the lung injury. It was found that endotoxemia was associated with generation of a granulocyte chemotactic factor in plasma but not in lung lymph. The peak increase in plasma CA occurred after the early pulmonary leukostasis. Pretreatment with DMTU eliminated the increased CA but had no effect on the initial leukopenia or the lung injury. It was concluded that (1) the lung is not the major source of increased CA after endotoxin and (2) increased plasma CA occurs but does not appear to be causative of the initial pulmonary leukostasis or the granulocyte-induced lung injury.
Animals↗
Coronary artery disease in patients requiring abdominal aortic aneurysm repair. Selective use of a combined operation.
The chief cause of operative mortality after abdominal aortic aneurysm (AAA) repair is myocardial infarction. For this reason, routine coronary angiography followed by prophylactic coronary artery bypass grafting (CABG) prior to AAA repair has been recommended by some surgeons. We report here the results of the selective use of a combined operation. Two hundred twenty-seven patients had elective or emergency repair of nonruptured AAA on our service from 1972 to 1983. Prior to surgery, all patients underwent careful clinical evaluation for the presence of coronary artery disease (CAD) and were classified into the following: group I (n = 121), no clinical evidence of CAD, 53%; group II (n = 96), clinical evidence of stable CAD, symptomatic or asymptomatic, 42%; group III (n = 10), unstable CAD, five per cent; Group IIIa (n = 4), asymptomatic AAA; and group IIIb (n = 6), symptomatic AAA. Seven patients ultimately assigned to group II underwent stress electrocardiogram (ECG) and eight group II patients had coronary angiography before surgery. All patients in groups I and II underwent elective or urgent repair of their AAA without CABG. Prior to surgery, these patients were managed with placement of a pulmonary artery catheter and incremental volume loading to construct a left ventricular performance curve as a guide to surgical fluid replacement. All were carefully monitored for at least 48 hours after surgery in an intensive care unit. Four patients (group IIIa) with unstable CAD and asymptomatic AAA underwent CABG followed by elective AAA repair within six months. Six patients (group IIIb) with unstable CAD and symptomatic AAA underwent combined open heart surgery (CABG and, in one patient, valve replacement) and AAA repair as a single operation. There was no operative mortality in group III patients. Thirty-day operative mortality for the entire group of 227 patients was 1.3% (three deaths), with only one death from a myocardial infarction (0.4%). While there is clearly a high incidence of CAD in patients with AAA, the present results indicate that these individuals can be managed with low risk by a selective approach based upon clinical assessment of their CAD. Our experience further demonstrates that patients with unstable CAD and symptomatic AAA may have both lesions safely repaired as a single operative procedure.
Adult↗
Changes in T lymphocyte subsets following injury. Assessment by flow cytometry and relationship to sepsis.
The increased susceptibility of severely injured patients to infection and death from sepsis has been attributed to abnormalities in cell-mediated immunity. The authors therefore assessed the relative number of peripheral blood T helper cells and T suppressor/cytotoxic cells and total T lymphocytes identified by the monoclonal antibodies (McA) OKT4, OKT8, and OKT3, respectively, in 25 patients with burns from 5 to 85% total body surface area (TBSA) (mean: 40%) and 21 patients with nonthermal injuries (mean Injury Severity Score (ISS): 21.4). Patients were compared to 21 healthy controls. Cells reacting with the McA were detected by flow cytometry, which enabled the examination of a population of cells the size of T lymphocytes, excluding larger contaminating cells that might bind the McA. Patients with burns of 30% TBSA or greater had a significant reduction (p less than or equal to 0.05) in OKT3+ cells up to 50 days post-burn. Both septic and nonseptic burn patients had reduced numbers of OKT3+ cells, as did patients after nonthermal injury, suggesting that this reduction was due to the injury itself. Patients with smaller burns (less than 30% TBSA) as a group did not have reduced OKT4+ cells, whereas those with larger burns showed significant reductions in OKT4+ cells (P less than or equal to 0.05) at 0 to 5, 6 to 10, 11 to 20, 21 to 30, and 41 to 50 days post-burn. Seven burn patients who became septic 10 days post-burn or later had significantly lower OKT4+ cells within 10 days of injury (mean: 33.75% +/- 7.4 SEM) than 10 patients who remained free of sepsis (mean: 42.2% +/- 5.4, p = 0.004). Patients with uncomplicated nonthermal injuries failed to show any significant reduction in OKT4+ cells. Following thermal injury, a reduction in OKT8+ cells was observed up to 10 days in patients with burns less than 30% TBSA, and up to 20 days in patients with larger burns. In both groups, at no time were increased OKT8+ cells found to correlate with clinical events. In patients with nonthermal injury, OKT8+ cells generally remained near the normal range.
Adolescent↗
Treatment of arterial occlusive disease of the lower extremities.
The surgical management of arterial occlusive disease of the lower extremities is reviewed, with emphasis on extra-anatomic and reoperative methods. Consideration is given to alternative interventional radiologic techniques, both as definitive therapy as well as in conjunction with conventional surgical reconstruction.
Angioplasty, Balloon↗
The iliac-origin arterial graft: a useful alternative for iliac occlusive disease.
The results of ilioiliac and iliofemoral bypass grafts were compared with those for aortic-origin grafts in 205 patients and 332 legs operated upon for aortoiliac occlusive disease since 1972. Poor-risk patients who had a patent distal aorta and at least one functionally patent proximal iliac artery were considered for reconstruction with the iliac artery used for the proximal anastomosis. The procedure, performed through a retroperitoneal approach, has several technical advantages and is especially satisfactory for patients who would otherwise have an axillofemoral graft. The data indicate that these iliac-origin reconstructions compare favorably in patency with aortic-origin reconstructions or with other "extra-anatomic" arterial reconstructions, enabling extremely low morbidity and mortality rates even in high-risk patients.
Aorta↗
Current treatment of metastatic renal cell carcinoma with xenogeneic immune ribonucleic acid.
In 1979 we reported a phase I trial involving 6 patients treated with immune ribonucleic acid for renal cell carcinoma. Since that report 27 patients with stage III or IV renal cell carcinoma have been assessed in a phase II trial. All patients have undergone excision of the primary tumor or superficial metastases, injection of tumor into guinea pigs and harvesting of immune ribonucleic acid. Autologous lymphocytes, obtained by plasmapheresis on an outpatient basis, have been incubated with immune ribonucleic acid and reinfused into the host. Results indicate complete response in 1 patient for more than 61 months, partial response in 5 patients for 6 to 10 months and stabilization in 10 patients for 2 to 8 months, all of whom had progressive disease before the institution of therapy. Six patients with continued progressive disease died at a median of 2 months after therapy. Of 5 patients treated in an adjuvant fashion only 1 has had a relapse from 9 to 18 months after therapy. Patients with pulmonary metastases seem to represent the most favorable group for this passive form of immunotherapy. This therapy would seem to offer reasonable alternatives in selected patients with advanced disease.
Adenocarcinoma↗
Femoral-tibial bypass. Introductory remarks.
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Aged↗
Determinants of cardiovascular stability during abdominal aortic aneurysmectomy (AAA).
Patients undergoing abdominal aortic aneurysmectomy (AAA) develop depressed cardiac function during aortic clamping. The importance of volume status and thromboxane (Tx) mediated declines in cardiac contractility in determining this event was studied. In a blinded fashion, patients received the cyclo-oxygenase inhibitor ibuprofen 12 mg/kg by mouth (n = 11) or a placebo (n = 15), 1.5 hours prior to surgery. In the placebo group levels of 6-keto-PGF1 alpha, the hydrolysis product of prostacyclin (PGI2) rose from 20 +/- 10 to 1170 +/- 80 pg/ml (p less than 0.05) soon after incision. Concentrations of TxB2, the stable hydrolysis product of TxA2, were unchanged until 30 minutes after the aorta was clamped when arterial TxB2 concentrations rose from 90 +/- 20 to 230 +/- 30 pg/ml (mean +/- SEM) (p less than 0.05). A pulmonary source for PGI2 and TxA2 was indicated by the observation that arterial 6-keto-PGF1 alpha and TxB2 levels exceeded those in pulmonary arterial blood by 180 +/- 50 and 110 +/- 30 pg/ml, respectively (p less than 0.05). Levels of TxB2 in circulating platelets remained unchanged from baseline in the placebo group. During aortic clamping, cardiac index (CI) fell 0.7 +/- 0.2 1/min X m2 (p less than 0.05) in placebo treated patients, and there was a 6% decline in plasma contractility as bioassayed with a rat papillary muscle (p less than 0.05). Placebo patients entered surgery with a PAWP greater than or equal to 10 mmHg (mean 13 mm). Ibuprofen suppressed production of TxB2, such that 30 minutes after aortic clamping TxB2 was 70 +/- 30 pg/ml, a value lower than control patients (p less than 0.05). Further, plasma no longer depressed contractility of the papillary muscle. Five patients given ibuprofen had an initial pulmonary arterial wedge pressure (PAWP) of 10 mmHg or greater (mean 12 mmHg). During aortic clamping there was an insignificant decrease in CI of 0.2 +/- 0.1 1/min X m2. This was in contrast to the CI decrease in six other ibuprofen treated patients of 0.9 +/- 0.2 1/min X m2 whose PAWP at the start of surgery was less than 10 mmHg (mean 6 mmHg) (p less than 0.05), and to placebo patients whose initial PAWP was greater than or equal to 10 (p less than 0.05). Platelet counts fell from 185,000 to 121,000/mm3 in placebo patients (p less than 0.05), but did not fall when ibuprofen was given. Creatinine concentrations were unaffected by ibuprofen. Blood replacement in placebo and ibuprofen patients was similar, 1.90 +/- 0.20 and 0.65 +/- 0.15 1, respectively. Results indicate that CI will not decrease during AAA if sufficient volume is given before surgery to increase PAWP above 10 mmHg, and secondly, if TxB2 synthesis is inhibited.
Aged↗
Inadequate interleukin 2 production. A fundamental immunological deficiency in patients with major burns.
We studied the production of the two major mediators of cellular immune responses, Interleukin 1 (IL-1) and Interleukin 2 (IL-2), by the peripheral blood mononuclear cells of 23 burn patients (16 men, seven women, mean age 48.9 years) compared with 23 matched controls (16 men, seven women, mean age 46.7 years). Serial measurements were made of IL-1 production by adherent mononuclear cells after stimulation with lipopolysaccharide and of IL-2 production by lymphocytes after stimulation with phytohemagglutinin (PHA). Eighty determinations of IL-2 production by lymphocytes from 12 patients with greater than 30% body surface area burn revealed a mean IL-2 production of 0.71 u as compared with a mean of 1.23 u for patients with less than 30% burns (p = 0.04). Patients with greater than 30% body surface area burns had significantly reduced IL-2 production (p less than or equal to 0.05) until 60 days after injury, whereas those with smaller burns had reduced IL-2 production only at 20-29 and 30-39 days postburn. Nine burn patients with systemic sepsis showed significantly lower IL-2 production (p = 0.03) at 10-29 days postburn than nonseptic patients, and significantly less IL-2 production during septic episodes. Eight patients with greater than 50% suppression of lymphocyte response to PHA produced less IL-2 (0.4 u) than patients with less than 50% suppression, (1.07 u, p = 0.004). IL-1 production was significantly elevated as compared with controls (4.45 u vs. 3.6 u, p = 0.05) early after injury, but was subsequently within the normal range regardless of burn size. The percentage of circulating helper T-lymphocytes, the principal source of IL-2, was also reduced, although this did not always correlate with IL-2 production, which remained depressed after recovery of the helper T-cell population. These results indicate that failure to produce IL-2, a powerful mediator of cellular immune responses, is an important mechanism underlying the defective cell mediated immunity seen in burn patients.
Adult↗
Depression of cellular immunity after multiple trauma in the absence of sepsis.
We have previously reported that severe burn injury was regularly accompanied by impaired lymphocyte responses to T cell mitogens, circulating suppressor lymphocytes, and serum factors suppressive of lymphocyte activation. However, in burned patients it was difficult to determine whether these manifestations of suppressed immunity were predictive of, or the result of, sepsis which was ubiquitous in this population. In an attempt to clarify this issue, we have studied 31 patients with multiple trauma (without burns) mean age, 31 years; average injury severity score, 22; range, 9-56; in whom sepsis was less common. Patients were tested for lymphocyte response to the T cell mitogens PHA and Con A, the percentage of circulating putative suppressor (OKT8) and helper (OKT4) T cells using monoclonal antibodies, circulating suppressor cell activity as revealed by functional assays, and serum suppression of lymphocyte activation. Patients were compared with ten normal volunteers (mean age, 32) studied simultaneously. Significant suppression (greater than 50% compared with controls) in lymphocyte responses to mitogens 1 to 5 days after injury was seen in 12 patients, was accompanied by a shift in the ratio of helper (OKT4) to suppressor (OKT8) T cells (patients, 0.96:1; normals, 1.82:1; p less than 0.01), and was followed by the appearance of significant (greater than 50%) serum suppressive activity in six of the 12 patients. Circulating suppressor cell activity as revealed by functional assays was also seen early after injury in three of 12 patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Circulating T6 antigen positive cells.
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Adult↗
The effect of short term postoperative intravenous feeding upon cell-mediated immunity and serum suppressive activity in well nourished patients.
Thirty-four patients undergoing elective abdominal aortic aneurysmectomy were studied, and they were randomly allocated to a "fed group receiving amino acid dextrose solutions intravenously and fat emulsions or an "unfed" group receiving standard postoperative care. Cell-mediated immunity was measured by lymphocyte count, the in vitro response to the T-cell mitogen PHA and determination of T-cell subsets using monoclonal antibodies. Serum suppressive activity was measured by the ability of the sera of the patient to suppress the response of normal lymphocytes to PHA. Feeding was continued for three to five days postoperatively until satisfactory oral intake was achieved. There was no significant improvement in lymphocyte count or blastogenesis postoperatively in the "fed" group, and operation did not lead to any alteration in the ratio of T-cell subsets, although there was a fall in T-cell count (OKT3 positive cells). We conclude that short term parenteral nutrition in well nourished patients, postoperatively, does not abrogate the depression of cell-mediated immunity which occurs after extensive operative procedures.
Aged↗
Effect of aspirin and dipyridamole on the patency of lower extremity bypass grafts.
Recent clinical studies indicate that the use of aspirin and dipyridamole improves graft patency rates in patients with infrainguinal polytetrafluoroethylene (PTFE) grafts and aortocoronary vein grafts. We undertook a prospective, double-blind, randomized study to determine whether these drugs administered postoperatively to patients with PTFE or autologous vein infrainguinal bypasses would improve graft patency during the first 24 months after operation. Patients received either aspirin 325 mg and dipyridamole 75 mg or identical placebo tablets three times a day, taken orally. Patency rates were compared by computing standard life tables and comparing cumulative patency rates. One hundred patients with 102 grafts were studied. The cumulative patency rate at 24 months was not significantly different for the treatment (57%) versus control (67%) groups or for any subgroup. We conclude that aspirin and dipyridamole administered postoperatively in the doses used in this study do not improve the overall patency rates of vein or PTFE infrainguinal bypass grafts.
Aged↗