Neutrophil chemiluminescence and opsonic fibronectin levels following blunt trauma

Trauma is known to result in depression of opsonic fibronectin levels as well as abnormalities in neutrophil function. Neutrophil oxidative metabolism, important for bactericidal activity, has not been investigated following injury. Since fibronectin has been reported to increase neutrophil chemiluminescence (CL), we examined the relationship between neutrophil oxidative metabolism (as measured by chemiluminescence) and opsonic fibronectin levels following blunt trauma. Sera from 11 nonseptic and 9 eventually septic-trauma patients were studied. Normal neutrophils incubated in septic-trauma serum had decreased CL responses compared to incubation in nonseptic serum (P less than 0.0001). This difference was apparent immediately after injury, prior to the onset of sepsis. This depression was due to the presence of a serum suppressor of neutrophil chemiluminescence and not to the absence of a serum factor. This suppressor has been partially characterized as a protein of greater than 30,000 Da. Opsonic fibronectin levels were also depressed in septic-trauma sera compared to nonseptic-trauma sera (P less than 0.0001). However, no correlation could be demonstrated between the CL response and opsonic fibronectin levels. Addition of fibronectin to buffer increased the CL response, while addition of fibronectin to nonseptic-trauma serum had no effect. In contrast, addition of fibronectin to septic-trauma sera actually decreased the CL response (P less than 0.05), perhaps by forming complexes with abnormal proteins and interfering with membrane-particle interaction.     

Opsonic fibronectin deficiency in patients with intra-abdominal infection

The reticuloendothelial system provides host defense functions by the intravascular phagocytosis of bacteria and nonbacterial particulates. Fibronectin is opsonic for reticuloendothelial phagocytosis. Plasma fibronectin was measured before and after operation in patients with intra-abdominal infection. Preoperatively opsonic fibronectin was reduced by 39% of normal control levels in 16 patients with intra-abdominal infection. There was an even greater reduction of opsonic fibronectin after operation that was first observed in the recovery room. This deficiency persisted for the first 4 days with a tendency toward recovery of normal circulating levels by the fifth postoperative day. In contrast, patients who underwent elective major abdominal operation without infection manifested a transient opsonic fibronectin deficiency with recovery by the second and third postoperative days. Eight of 16 patients with intra-abdominal infection developed multiple organ failure. The opsonic fibronectin levels in those patients were lower than the levels in eight patients who did not develop multiple organ failure. Furthermore, there was no tendency toward recovery of normal circulating opsonic fibronectin in those patients. On all days when multiple organ failure occurred there was a marked deficiency of circulating opsonic fibronectin. We conclude that transient opsonic fibronectin deficiency occurs after major elective abdominal operation. Patients with intra-abdominal infection manifest opsonic fibronectin deficiency before operation, and further depletion of opsonic fibronectin occurs after operation. Postoperative multiple organ failure occurs only in association with severe opsonic fibronectin deficiency.     

Effect of fibronectin therapy and fibronectin deficiency on wound healing: a study in rats

Rats with standardized 3rd-degree burns of 1% body surface were treated intraperitoneally with different doses of human fibronectin or swine gelatin immediately after injury and on the following days. Controls received bovine albumin or no further treatment. Wound healing was assessed by planimetry (days 0, 2, and 7); additionally, plasma fibronectin was determined (days 3 and 7). On day 3 fibronectin levels were significantly elevated after albumin and the highest dosage of fibronectin (3 X 16 mg) and decreased after gelatin and the lowest dosage of fibronectin (3 X 4 mg). Wound healing was neither affected by albumin nor by human fibronectin, but it was significantly impaired by gelatin-induced lack of fibronectin. The data support the opinion that fibronectin is an essential factor for the post-traumatic clearance of gelatin-like tissue debris via the reticuloendothelial system (RES). Overload by gelatin results in fibronectin deficiency and RES dysfunction with risks of infection and poor wound healing.     

Purified fibronectin administration to patients with severe abdominal infections. A controlled clinical trial.

Subnormal plasma fibronectin (Fn) levels are found in patients with severe abdominal infections (SAI). The repletion of Fn has been postulated to have therapeutic benefit by virtue of its opsonic, reticuloendothelial system (RES) stimulating effects. A controlled, prospective trial of Fn administration was performed in patients with SAI to assess its use as an adjunct to standard procedures of intensive care. Thirty-three SAI patients were given daily doses of 0.8 g of purified Fn on days 1-5 following admission to the ICU, whereas 34 control patients received no Fn. All patients received the clinical care, antibiotics, and pharmacologic agents appropriate to their individual needs. The admission status and laboratory profiles of the two patient groups (+ and -Fn) were comparable on admission to the study. No side effects of the Fn preparation were observed. As judged by subgroup averages, the Fn replacement regimen was effective in elevating Fn levels to within normal range from day 2 onwards, as measured by immunological and functional assays. The estimated intravascular recovery of Fn averaged 82% in those patients who survived, yet only 52% in the nonsurvivors. Ultimate hospital mortality was 9/33 (27.3%) in the +Fn group versus 13/34 (38.2%) in the -Fn group (p = 0.244, Fisher's exact test). Although ultimate mortality was not significantly changed by the administration of Fn, the Fn treated patients appeared to survive longer than did the control patients. This trend was confirmed through the analysis of expected survival curves (D = 3.12, 0.1 greater than p greater than 0.05). When compared to the survivors, the ultimate nonsurvivors entered the study with statistically higher group averages of bilirubin and creatinine concomitant with lower averages of Fn, antithrombin III, C4, C3, C3b-INH, and transferrin. These differences persisted throughout the 11-day monitoring period; differences between survivors and nonsurvivors with respect to platelets, plasminogen, B-1-H, alpha-2-macroglobulin, and prealbumin appeared during the same period. Dramatic differences between the +Fn and -Fn treatment groups were not seen. Other than Fn, the Fn recipients only developed higher levels of the acute phase reactants C4, C3b-INH, B-1-H and alpha-1-antitrypsin (p less than 0.05) than did their non-Fn treated counterparts. In the present study, we again found a highly significant pattern of correlations between the absolute levels as well as the changes of Fn and other plasma proteins.(ABSTRACT TRUNCATED AT 400 WORDS)     

Reversal of gelatin-impaired wound healing in rats by exogenous fibronectin.

Animal experiments have shown that administration of gelatin results in a deprivation of plasma fibronectin (FN) and impaired wound healing. For further elucidation of these findings a therapy study with purified human FN was performed in rats. Fifty animals received a standard burn injury of 1% body surface and were divided into five experimental groups. Positive controls given no further treatment or treated with solvent only served for estimation of normal healing. For a negative control, 10 animals received three intraperitoneal injections of gelatin (58 mg/kg body wt) on Days 0, 1, and 2 after injury. They exhibited a striking lack of plasma FN (Day 1) and a significant delay of wound contraction (Days 7 and 14). In the therapy groups each administration of gelatin was followed by an intraperitoneal or intracardiac injection of FN (58 mg/kg body wt) 1 hr later. In these animals the negative effect of gelatin upon plasma FN and wound contraction was prevented. According to this study wound healing is menaced by FN deficiency and can be optimized by substitution of exogenous FN.     

Reticuloendothelial failure in chronic intra-abdominal sepsis: the role of opsonic fibronectin

Severe sepsis leads to depression of the reticuloendothelial (RE) system with delayed bloodstream clearance of particulate matter and bacteria. Fibronectin may be an important opsonin of the RE system and low fibronectin levels often accompany severe sepsis in man. We have investigated the effect of prolonged intra-abdominal sepsis on plasma fibronectin concentrations and RE function. Serial plasma fibronectin concentrations were determined in rabbits for 2 weeks after either the induction of sepsis (appendix abscess) (n = 6) or laparotomy only (n = 6). RE function was measured at 2 weeks by determining the clearance kinetics and organ distribution of low dose technetium tin colloid (TTC). There was an early transient depression in plasma fibronectin values followed by elevated concentrations at 48-72 h which were more marked in the sepsis group. There was a delay in the blood clearance with reduced hepatic and increased bone uptake of TTC. We conclude that depletion of opsonic fibronectin is unlikely to be an important factor contributing to the impairment of RE function associated with intra-abdominal sepsis and that RE depression in septic animals is due to intrinsic Kupffer cell dysfunction.     

Polymorphonuclear leukocyte function and serum opsonic activity in surgical patients

Thirty-six patients who underwent major surgery were studied in order to clarify the perioperative changes in polymorpho-nuclear leukocyte (PMNL) function and serum opsonic activity. In patients without postoperative infection, the PMNL phagocytic-bactericidal capacity and plasma elastase levels significantly increased, while the serum opsonic index remarkably decreased just after surgery, however, all returned to the preoperative levels within 1 or 2 weeks. Conversely, in patients with postoperative infection, the PMNL bactericidal capacity and plasma elastase levels remained at high levels even after 1 or 2 weeks, while the PMNL phagocytic capacity and serum opsonic index substantially decreased after 2 weeks compared with the patients without postoperative infection. Plasma leukotriene B₄, which is a potent chemo-attractant for PMNL, noticeably decreased in the patients with postoperative infection on the first postoperative day compared with that in the patients without postoperative infection. Our data suggests that the most important predisposing factors to postoperative infection may be a depressed PMNL phagocytic capacity and a lower serum opsonic activity after surgery, and that the increased PMNL bactericidal capacity and high plasma elastase levels during postoperative infection may contribute to the susceptibility to multiple organ failure.     

Antioxidant status in patients with osteoporosis: A controlled study

ObjectiveWe aimed to investigate serum antioxidant enzymes and nitric oxide (NO) levels in postmenopausal women with osteoporosis (OP) and in healthy controls; and to determine the relationship between these enzymes, NO and clinical parameters in this present study.MethodsForty-five postmenopausal women fulfilling OP diagnostic criteria of World Health Organization (WHO) and 42 postmenopausal healthy women without OP were enrolled. Patients in the study population were selected among individuals that were not pre-diagnosed or pre-treated for OP. Patients with metabolic bone diseases, fracture history, which were smokers, alcohol users and taking antioxidant drug treatment, were excluded from the study. Dual Energy X-ray Absorptiometry (DXA) results, body mass indices and demographic data were recorded. Erythrocyte catalases (CAT), glutathione reductase (GR) enzyme activities and erythrocyte glutathione (GSH) levels, plasma malondialdehyde (MDA) levels were measured by spectrophotometer whereas plasma nitrite+nitrate (NOx) levels were measured by ELISA microplate-reader.ResultsPatients had significantly lower GR (P < 0.01) enzyme activity and higher levels of MDA (P < 0.01) and NO (P < 0.01) than non osteoporotic healthy controls. There was no significant difference between both groups in erythrocyte GSH levels and CAT activities. Total femoral BMD measurements significantly correlated with MDA levels (P = 0.001). There was no significant relationship between other antioxidants and lumbar or femoral BMD.ConclusionOxidative stress may play an important role in postmenopausal bone loss and therefore it might be considered when pathogenesis of postmenopausal OP has been investigated.     

Autologous blood transfusion in revision hip arthroplasty. A prospective, controlled study of 30 patients.

In a prospective, randomized study of the efficacy and effects of autologous blood transfusion in revision hip arthroplasty, 30 patients were randomly allocated into two groups. The Control Group received homologous blood transfusion. The Study Group deposited 2-3 units of blood preoperatively, intraoperative blood salvage was used, and no homologous blood was transfused intraoperatively. There was a smaller postoperative blood loss in the Study Group. The preoperative hemoglobin values were lower in the Study Group, but one week postoperatively they were higher than in the Control Group. The decrease in the values of AT III and protein C was lower in the Study Group. The combination of preoperative blood donation and intraoperative blood salvage reduced blood loss and homologous blood transfusion in revision hip arthroplasty.     

Fibrinolytic defect in chronic back pain. A controlled study of plasminogen activator activity in 20 patients.

We analyzed the fibrinolytic system in patients with chronic low back pain using a venous occlusion test to stimulate fibrinolysis, and we subsequently determined the levels of tissue plasminogen activator (TPA) and fast-acting inhibitor of TPA (PAI). There were 20 patients with a mean age of 50 years. Two thirds had radiographically spinal stenosis. Scar tissue around the spinal nerves was seen in 11 cases. Thirteen patients had undergone back surgery, whereas 21 healthy subjects served as controls. In the basal samples, TPA activity was decreased in the patients while TPA antigen level was increased compared with the controls. No clear explanation for this defective function of TPA in the patients was obtained, because no difference was seen in PAI level in basal samples. After the venous occlusion, no difference was observed in TPA activity between the two groups excluding the constitutionally defective fibrinolytic system in the patients. However, our results confirm low basal fibrinolytic activity in patients with chronic low back pain with manifest spinal pathology.     

Histopathological changes preceding spontaneous rupture of a tendon. A controlled study of 891 patients.

We evaluated specimens obtained from the biopsy of spontaneously ruptured tendons in 891 patients who were treated between 1968 and 1989. The specimens, which were removed at the time of repair, included 397 Achilles tendons, 302 biceps brachii tendons, forty extensor pollicis longus tendons, eighty-two quadriceps tendons and patellar ligaments, and seventy other tendons. Age and sex-matched control specimens, from 445 tendons taken at the time of death from the cadavera of previously healthy individuals who died accidentally, also were obtained and evaluated. The histopathological analyses of the specimens included light and polarized light microscopy and scanning and transmission electron microscopy. A healthy structure was not seen in any spontaneously ruptured tendon, but two-thirds of the control tendons were structurally healthy (p less than 0.001). There were characteristic histopathological patterns in the spontaneously ruptured tendons. Most (97 per cent) of the pathological changes were degenerative; they included hypoxic degenerative tendinopathy, mucoid degeneration, tendolipomatosis, and calcifying tendinopathy, either alone or in combination. These changes were also found in 34 per cent of the control tendons, but significantly less frequently (p less than 0.001). In the other twenty-six ruptured tendons (3 per cent), the pathological change was an intratendinous foreign body, rheumatoid tendinitis, a xanthoma, a tumor, or a tumor-like lesion such as an intratendinous ganglion. The findings clearly indicate that, at least in an urban population, degenerative changes are common in the tendons of people who are older than thirty-five years and that these changes are associated with spontaneous rupture.     

Maximum perineal stimulation. A controlled study

Previous workers have debated the value of maximal perineal stimulation (MPS) in the treatment of urinary incontinence in women. In order to assess the efficacy of this simple technique a prospective study was undertaken on 107 consecutive incontinent women. They included those with stress, urge and mixed patterns of leakage. Patients were placed at random into treatment and control groups. All underwent clinical assessment, urodynamic study and a single session of pelvic floor re-education with measurement of pelvic contraction and cystoscopy. Those in the treatment group were given MPS using monophasic square wave pulses while under anaesthesia. Independent follow-up assessment was performed 6 and 12 weeks after treatment. Of the 107 patients 94 completed the trial. Forty-five were treated and 49 acted as controls. Analysis of age, parity, duration and severity of incontinence showed that randomisation had produced comparable results between the treated and the control groups. Sixty per cent of the treatment group and 66% of the control group had significant symptomatic improvement. Pelvic floor function was re-assessed, using a perineometer, and found to be more efficient, having increased equally in both groups. Both groups of women improved irrespective of the pattern of incontinence. This suggests that MPS does not contribute to the management and that a single physiotherapy session with skillful counselling can produce beneficial results in women with all types of urinary incontinence.     

Cardiovascular hemodynamics after opsonic alpha-2-surface binding glycoprotein therapy in injured patients.

Depression of reticuloendothelial (RE) phagocytic function has been clearly documented following trauma and operation. This phagocytic failure is mediated in part by depletion of an opsonic glycoprotein. Depletion of this opsonic protein may result in prolonged blood retention of potentially harmful particulates that may interfere with the microcirculation and may possibly result in altered organ function. Isolation and identification of this opsonic protein has led to the finding of the identity between opsonic glycoprotein and cold insoluble globulin (CIg) or so-called plasma fibronectin. Since CIg is concentrated in cryoprecipitate, this blood component was used as a readily available source of opsonic protein for replacement studies. Nine patients were studied following a 1-hour infusion of cryoprecipitate obtained from 10 units of plasma and suspended in a volume of 250 ml. Both the pulmonary shunt fraction and the fraction of dead space ventilation decreased significantly (P = 0.02) after cryoprecipitate administration. Limb blood flow (P = 0.001), limb oxygen consumption (P = 0.001), and reactive hyperemia of the limb (P = 0.05) increased significantly following cryoprecipitate infusion. Cardiac output, total oxygen consumption did not change consistently. The data demonstrate that the infusion of cryoprecipitate resulted in improved pulmonary and microcirculatory function--possibly due to opsonic glycoprotein replacement.     

Postoperative chest wound infections in patients requiring coronary bypass. A controlled study evaluating prophylactic antibiotics.

A controlled study investigating clean chest wound infections in 904 patients undergoing myocardial revascularization was performed. Four hundred fifty-one patients received systemic antibiotics before and after the operation, and 453 patients received no prophylactic systemic antibiotics. The infection rate was 1.10 per cent and 1.76 per cent, respectively, indicating no statistical difference between the two groups. Preoperative skin preparation and subsequent local antibiotic wound irrigation may be the most important factors in preventing clean wound infection.     

Reversal of direct oral anticoagulants in adult hip fracture patients. A systematic review and meta-analysis

BackgroundIncreasing numbers of patients are taking Direct Oral Anticoagulants at the time of hip fracture. Evidence is limited on how and if the effects of DOAC's should be reversed before surgical fixation. Wide variations in practice exist. We conducted a systematic review to investigate outcomes for three reversal strategies. These were: “watch and wait” (also referred to as “time-reversal”), plasma product reversal and reversal with specific antidotes.MethodsA systematic search was conducted using multiple databases. Results were obtained for studies directly comparing different DOAC reversal strategies in hip fracture patients and for studies comparing DOAC-taking hip fracture patients (including patients “reversed” using any method and “non-reversed” patients) against matched controls taking either a vitamin-K antagonist or not receiving anticoagulation therapy. This allowed construction of a network meta-analysis to indirectly compare outcomes between “reversed” and “non-reversed” DOAC patients. With respect to “watch and wait”/“time-reversal”, a cut-off time to surgery of 36 hours was used to distinguish between “time-reversed” and “non time-reversed” DOAC patients. The primary outcome was early/inpatient mortality, reported as Odds Ratios (OR).ResultsNo studies investigating plasma products or reversal agents specifically in hip fracture patients were obtained. Fourteen studies were suitable for analysis of “watch and wait”/“time- reversal”. Two studies directly compared “time-reversed” and “non time-reversed” DOAC-taking hip fracture patients (58 “time-reversed”, 62 “non time-reversed”). From 12 other studies we used indirect comparisons between “time-reversed” and “non time-reversed” DOAC patients (total, 357 “time-reversed”, 282 “non time-reversed”). We found no statistically significant differences in mortality outcomes between “time-reversal” and “non time-reversal” (OR 1.48 [95%CI: 0.29-7.53]). We also did not find a statistically significant difference between “time reversal” and “non time-reversal” in terms of blood transfusion requirements (OR 1.16 [95% CI 0.42-3.23]). However, several authors described that surgical delay is associated with worse outcomes related to prolonged hospitalisation, and that operating within 36 hours is safe.ConclusionsWe suggested against “watch and wait” to reverse the DOAC effect in hip fractures. Further work is required to assess the optimal timing for surgery as well as the use of plasma products or specific antidotes in DOAC-taking hip fracture patients.     

Reversal of idiopathic hypogonadotropic hypogonadism: a cohort study in Chinese patients

Although idiopathic hypogonadotropic hypogonadism (IHH) has traditionally been viewed as a life-long disease caused by a deficiency of gonadotropin-releasing hormone neurons, a portion of patients may gradually regain normal reproductive axis function during hormonal replacement therapy. The predictive factors for potential IHH reversal are largely unknown. The aim of our study was to investigate the incidence and clinical features of IHH male patients who had reversed reproductive axis function. In this retrospective cohort study, male IHH patients were classified into a reversal group (n = 18) and a nonreversal group (n = 336). Concentration of gonadotropins and testosterone, as well as testicle sizes and sperm counts, were determined. Of 354 IHH patients, 18 (5.1%) acquired normal reproductive function during treatment. The median age for reversal was 24 years old (range 21–34 years). Compared with the nonreversal group, the reversible group had higher basal luteinizing hormone (LH) (1.0 ± 0.7 IU l^-1 vs 0.4 ± 0.4 IU l⁻¹, P < 0.05) and stimulated LH (28.3 ± 22.6 IU l⁻¹ vs 1.9 ± 1.1 IU l⁻¹, P < 0.01) levels, as well as larger testicle size (5.1 ± 2.6 ml vs 1.5 ± 0.3 ml, P < 0.01), at the initial visit. In summary, larger testicle size and higher stimulated LH concentrations are favorite parameters for reversal. Our finding suggests that reversible patients may retain partially active reproductive axis function at initial diagnosis.     

Plasma fibronectin in surgical patients

Plasma fibronectin (PFN) was measured to clarify the role in patients who underwent major surgery. There was no statistical difference between male and female, benign and malignant disease, or more than 60 years old and less. Compared to the preoperative values of PFN, the postoperative ones showed significant decrease immediately after operation, this decrease was attributed to massive bleeding and prolonged surgical procedure. In contrast to the previous papers reporting as an opsonin, no such results were obtained. However, there was close relationship between PFN and antithrombin III, alpha 2-plasmin inhibitor, factor XIII, retinol binding protein and transferrin, which represent hemostasis, fibrinolytic system and nutritional status, respectively. To determine whether PFN acts as an opsonin, heparin (opsonin cofactor) was given to Wistar rats in various conditions. There was no significant difference between PFN in those rats and in controls. These results indicate that postoperative PFN is a good parameter of glycoprotein in hemostasis, fibrinolytic system, and rapid turnover protein, not of an opsonin.     

Lung vascular permeability after reversal of fibronectin deficiency in septic sheep. Correlation with patient studies.

Plasma fibronectin deficiency and opsonic dysfunction exist in critically ill septic surgical, trauma, and burn patients with multiple organ failure. Fibronectin deficiency can be reversed by infusion of fresh plasma cryoprecipitate. The influence of therapy with human cryoprecipitate on lung vascular permeability in septic sheep with plasma fibronectin deficiency following surgery was evaluated. Additionally, selected studies on pulmonary function in septic surgical and trauma patients after infusion of plasma cryoprecipitate were completed. In patients, ventilation-perfusion balance appeared to improve as measured by the multiple inert gas elimination technique. With the lung lymph fistula preparation in fibronectin deficient sheep, infusion of human plasma cryoprecipitate (10 units; 250 ml) delayed the onset and minimized the increase in lung vascular permeability during postoperative Pseudomonas sepsis (5 X 10(9) bacteria, I.V.; 5 X 10(10) bacteria, I.P.). For example, in a first group of sheep, the transvascular protein clearance (TPC) at 2 hrs in septic sheep (n = 4) treated with only saline (volume control) was 20.1 +/- 3.1 ml/hr, compared to 11.23 +/- 0.83 ml/hr in the sheep (n =a 4) treated with fibronectin-rich cryoprecipitate (p less than 0.05). In a second group of sheep, cryoprecipitate depleted of fibronectin by affinity chromatography was used as the control solution. It also did not manifest this protective effect with respect to lung vascular permeability. Thus, at 2 hrs the lymph flow (Qlym) was 30.2 ml/hr and the transvascular protein clearance (TPC) was 18.0 ml/hr in septic sheep given fibronectin-deficient cryoprecipitate. In contrast, in the fibronectin-rich cryoprecipitate treated sheep, the Qlym was 14.8 ml/hr and the TPC was 8.12 ml/hr. It is suggested that fibronectin may influence lung vascular integrity during sepsis following surgery and trauma.