Plasma therapies in thrombotic syndromes.

BACKGROUND: Plasma therapies are being applied to thombotic syndromes, but there are limited controlled studies. OBJECTIVE: To review the evidence and the current practices for plasma therapies in thrombotic syndromes. METHODS: Expert-enhanced evidence-based analysis. Evidence obtained as of Dec 31, 2002 using PubMed electronic reference library and expert-obtained library for a total of > 3,000 references obtained using the terms plasma therapy or plasma exchange or plasmapheresis or plasmafiltration or sorbents each combined with the words thrombotic syndrome or sepsis or septic shock. The authors screened the abstracts, reviewed the agreed set of papers, and compiled the recommendations. RESULTS: Plasma therapies, which alter the plasma components in patients, have been applied in thrombotic syndromes worldwide. In these patients, there is a biologic plausibility for plasma therapies since they have molecules that are prothrombotic and/or antifibrinolytic which would put them at risk for microvascular thrombosis and end-organ damage. There are respectively one randomized controlled trial (RCT) in primary thrombotic syndrome, and secondary thrombotic syndrome, which showed an improvement in mortality in applying plasma therapies (plasma exchange by centrifugation). However, there are numerous non-randomized and case series. Plasma exchange is accepted as the standard therapy for primary thrombotic syndrome as in thrombotic thrombocytopenic purpura (TTP). However, no consensus has been reached for plasma exchange in secondary thrombotic syndromes such as in sepsis, hemolytic uremic syndrome (HUS), thrombocytopenia associated multiple organ failure, TTP/HUS, s/p bone marrow or solid organ transplant, HELLP syndrome, immunologic disorders, drug exposure, or pancreatitis. CONCLUSIONS: As we understand more about the pathophysiology of thrombotic syndromes, specific plasma therapies can be applied for the specific need of a particular patient population. There are sufficient preliminary data to recommend a definitive RCT to evaluate the efficacy of the different types of plasma therapies in secondary thrombotic syndromes.

Significant expression of IGFBP2 in breast cancer compared with benign lesions.

BACKGROUND/AIM: Insulin-like growth factors (IGFs) and IGF binding proteins (IGFBPs) play a role in the normal development of breast tissue, and possibly in breast cancer aetiology. IGFBP2, one of six members of the IGFBP superfamily, acts as regulator of the IGFs and has pleiotropic effects in normal and neoplastic tissues. Because IGFs have mitogenic effects on mammary epithelia, this study investigated IGFBP2 expression in mammary tissues of different benign and malignant entities. METHODS: Immunohistochemistry was used to study correlations between the presence and intensity of IGFBP2 staining and tumour type and grade, in addition to steroid hormone receptor status, in 120 breast specimens. Expression was measured by quantitative colour video image analysis and semiquantitative evaluation, and the measurements correlated well (r = 0.92; p<0.05). RESULTS: Both methods found no significant expression of IGFBP2 in normal glandular cells and hyperplasia (group I). Atypical hyperplasia showed a slightly increased cytoplasmic expression of IGFBP2, and carcinoma in situ showed a distinctive, membrane associated and cytoplasmic expression (group II). Infiltrating carcinomas strongly expressed cytoplasmic IGFBP2 (group III). There were significant differences between group I and II, and between group II and III. There were no significant differences between invasive lobular and invasive ductal carcinoma, or between grades I, II, and III within these entities. There was no significant correlation between IGFBP2 immunostaining and oestrogen or progesterone receptor positivity within the malignant group. CONCLUSIONS: IGFBP2 mitogenic signals of autocrine/paracrine regulatory mechanisms may be responsible for the growth of breast carcinomas and IGFBP2 may be an independent indicator of malignancy.

A global measure of physical functioning: psychometric properties.

OBJECTIVE: To examine the psychometric properties of a global physical functioning scale (GPFS) developed as a self-report measure and constructed to scale physical functioning from very poor (1) to excellent (100). DATA SOURCES: Data collection took place between January 1997 and September 1999. It consisted of self-ratings of surgical patients and the ratings of clinicians. The setting was the surgical department at a university hospital. STUDY DESIGN: Test-retest reliability and the convergence of the scores of patients and clinicians were examined in 106 patients before elective coronary or gastrointestinal surgery. Inter-rater reliability was tested in 36 hospitalized patients with cardiologic or vascular surgical diseases who were rated by random selection from a pool of 91 clinicians. The patients also rated their physical functioning. Discriminative validity, sensitivity to change, ceiling and floor effects, and influence of emotional state upon the scores were tested in 127 patients in six diagnostic groups who scored the GPFS before and subsequent to surgery. The concurrent validity was examined in 101 patients who scored the GPFS and the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) before elective coronary surgery. PRINCIPAL FINDINGS: The test-retest correlation (.90), correlation of the scores of the clinicians and patients (.87), and rater intraclass correlation coefficient (.82) were high. The GPFS discriminated among patients with different levels of physical functioning, and it was sensitive to change following coronary surgery. There were moderate ceiling and no floor effects. The correlation with the physical functioning scale of the SF-36 (PF-10) was .67. The GPFS differentiated patients with middle levels of physical functioning better than did the PF-10. CONCLUSIONS: The psychometric properties of the GPFS appeared adequate as a measure of general physical functioning. The scale is easy to use and also appears suitable for outcome studies following substantial changes in physical functioning as after coronary surgery.

Combined repair of adult coarctation of the aorta and aortic valvular stenosis.

A 57-year-old man with a high-grade aortic stenosis and aortic coarctation was treated with concomitant valve replacement and insertion of a conduit from the ascending aorta to the retrocardiac descending aorta via the left pleura. Because heart failure has been reported shortly after cardiopulmonary bypass using this technique, the conduit was initially clamped until the postrepair haemodynamics was stable. Computed tomography after 14 months verified patency of the shunt.

Predictors of satisfaction with surgical treatment.

OBJECTIVE: To investigate prospectively which medical, psychosocial or treatment-related factors predicted treatment satisfaction and to evaluate the adequacy of a preceding retrospective study which had examined the same factors. Furthermore, to examine the predictors and the stability of the major determinants of patient treatment satisfaction. DESIGN: Assessments made before admission, at discharge and 2 and 4 months after discharge were used to predict both the level and the rate of change in satisfaction with different aspects of treatment. SETTING: Three surgical departments at a University Hospital. STUDY PARTICIPANTS: Four-hundred and eighty-two patients electively admitted for several surgical conditions. RESULTS: The central treatment-related measures were the same in the retrospective and prospective studies: global satisfaction with treatment (GS), perceived quality of contact with the nursing (QCN) and medical staff (QCM) and provision of adequate treatment information (INF). More of the variance in GS was explained in the prospective study (48.7% versus 36.3%). GS was most influenced by treatment-related factors with QCN as the strongest predictor in both studies. Only a small portion of the variance in QCN and QCM could be accounted for by the characteristics of the patients. INF was predicted by characteristics of the patients, their illness and life situation and by treatment-related factors. QCN was the strongest predictor of INF. The relationships with the nursing and medical personnel appear to be the major determinants of both patient treatment satisfaction and patients' reception of adequate information about their condition and its treatment.

Resuscitation from accidental hypothermia of 13.7 degrees C with circulatory arrest.

In a victim of very deep accidental hypothermia, 9 h of resuscitation and stabilisation led to good physical and mental recovery. This potential outcome should be borne in mind for all such victims.

Effect of haemorrhagic shock and intraosseous resuscitation on plasma and urine catecholamine concentrations and urinary clearance in pigs.

OBJECTIVE: To evaluate the plasma and urinary catecholamine concentrations after episodes of haemorrhagic shock treated by intraosseous infusion of a small volume of hyperosmotic fluid, followed by whole blood, in a standard porcine model. DESIGN: Randomised open study. SETTING: University hospital, Norway. MATERIAL: 18 piglets. INTERVENTIONS: All animals were bled to an arterial systolic pressure of 60 mm Hg. After 30 minutes 100 ml hyperosmotic (2.4 mol/l) fluid (glucose/sodium chloride) was given either intraosseously (n = 6) or intravenously (n = 6). Ninety minutes later the animals were again bled to a systolic pressure of 60 mm Hg, and after 30 minutes an autologous whole blood transfusion was given by either intraosseous or intravenous infusion. Six animals acted as untreated controls. MAIN OUTCOME MEASURES: Changes in haemodynamic variables and plasma and urinary catecholamine concentrations. RESULTS: Two pigs in the control group died. The hyperosmotic infusion improved the circulatory performance significantly (p < 0.05). Thirty minutes after both bleeds the plasma catecholamine concentrations were increased by 10-15 times, but returned to the reference range in all groups 90 minutes after the hyperosmotic infusion. Two hours after the whole blood infusion the catecholamine concentrations of the treated animals were at baseline values, significantly lower than those of the controls. The corresponding urinary catecholamine concentrations of the controls were significantly increased. There were no differences between the two treatment groups. CONCLUSION: The catecholamine measurements indicate that there may possibly be protective renal excretion of excess shock-induced plasma catecholamines after acute haemorrhage.

Fatal myocardial depression and circulatory collapse associated with complement activation induced by plasma infusion in severe porcine sepsis.

We have previously reported that fresh frozen plasma (FFP) may induce a rapid irreversible shock when repeatedly infused in pigs challenged with Gram-negative sepsis. The aims of the present study were to elucidate the cardiovascular nature of the shock and determine the aetiologic role of tumour necrosis factor (TNF), complement activation and halothane anaesthesia. Three groups of anaesthetized piglets were inoculated with a lethal dose of live E. coli bacteria. Groups I (n = 8) and III (n = 8) were anaesthetized with halothane and group II (n = 8) with ketamine. Animals in groups I and II received repeated infusions of FFP, whereas animals in group III received repeated infusions of 7% albumin. Six animals in group I and four animals in group II died during the first plasma infusion. Survival time was significantly longer in group II (P = 0.04) compared to group I. No animals in group III died during the albumin infusions, and no adverse effects were observed during the infusions. In group I the plasma induced shock was characterized by abruptly falling mean arterial pressure, cardiac index, systemic vascular resistance index and left ventricular contractility. Concomitant increases were recorded in left ventricular filling pressure and central venous pressure. Group II demonstrated a similar, but delayed response. Plasma infusion was associated with a significant increase in terminal complement complex (TCC) (P < 0.03 in group I, P < 0.05 in group II) and depletion of serum ionized calcium. We conclude that FFP may induce fatal myocardial depression and circulatory collapse in severe sepsis. Complement activation may be of aetiologic importance.

The effects of plasma and albumin infusion on organ function and sepsis markers in experimental gram-negative sepsis.

To study the effects of early plasma versus albumin infusion on vital organ function and the appearance of central sepsis mediators in septic shock, three groups of anesthetized piglets (n = 28) were inoculated with live Eschericia coli. Group I received fresh frozen plasma, group II received albumin, whereas group III served as nontreated septic controls. Plasma-treated animals exhibited improved survival (p < .02) compared with controls, and improved organ function compared with both controls and albumin-treated animals. Plasma infusion was associated with increased levels of endotoxin (p < .02) and terminal complement complex (TCC) (p < .03), and persisting high levels of tumor necrosis factor (TNF). Following albumin infusion TNF levels decreased to baseline values (p < .01), whereas endotoxin and TCC levels did not change significantly. Our study shows a beneficial effect of early plasma infusion on survival and vital organ function in septic animals. The effect of plasma infusion on circulating levels of endotoxin, TNF, and TCC may be potentially deleterious in uncompensated stages of septic shock.

Fatal course in severe meningococcemia: clinical predictors and effect of transfusion therapy.

OBJECTIVE: To investigate whether the administration of fresh-frozen plasma to patients with systemic meningococcal disease is associated with an increased mortality rate compared with the administration of plasma substitutes. DESIGN: Seventeen-year case-control study. SETTING: Intensive care units and departments of internal medicine and pediatrics of one university hospital and one local hospital. PATIENTS: A total of 336 patients with culture-proven meningococcemia or symptoms characteristic of meningococcemia who were admitted to two hospitals in northern Norway between 1974 and 1991. MEASUREMENTS AND MAIN RESULTS: High-risk patients were selected on the basis of two different scoring systems (Niklasson's score and clinical score) and classified according to the type of intravenous fluid regimen (fresh-frozen plasma, blood, or colloids). For comparison between groups, analysis of variance and chi-square tests were used. Assessments of adjusted effects on mortality rate were done by multiple logistic regression. Administration of blood or plasma was significantly associated with a fatal course, both in the total patient population (p < .01) and in the high-risk group (p = .02), while using colloids alone was negatively associated with death, although not reaching statistical significance. A significantly lower mortality rate was found in one of the hospitals where colloids were used instead of plasma or blood in the last part of the period studied (p < .05). CONCLUSION: The results support our hypothesis that the use of fresh-frozen plasma may negatively influence outcome in systemic meningococcal disease.

Repeated plasma therapy induces fatal shock in experimental septicemia.

Plasma therapy in severe septicemia, either as part of plasma exchange or alone, was evaluated in a model of lethal septic shock induced with live Escherichia coli in pigs. The following groups were studied: group I, septic animals treated with repeated plasma exchanges, n = 8; group II, nontreated septic controls, n = 8; group III, septic animals treated with repeated plasma infusions, n = 14; and group IV, nonseptic animals treated with repeated plasma infusions, n = 7. In the septic animals treated with plasma (groups I and III), a rapid fatal response was observed between 2 and 5 min after the start of plasma therapy, while the septic controls (group II) showed a progressively longer lasting septic shock. The nonseptic animals (group IV) were unaffected by the plasma infusions. Plasma levels of endotoxin above 2 ng/ml were associated with rapid death during plasma therapy. Ionized Ca2+ fell abruptly in this situation. This study indicates that commonly used plasma therapies (exchanges or transfusions) in septic animals may have acute deleterious effects. These effects may be explained by depletion of ionized calcium.

Resuscitation of pigs with haemorrhagic shock by an intraosseous hyperosmotic solution and transfusion of autologous whole blood.

OBJECTIVE: To evaluate resuscitation after episodes of haemorrhagic shock by the combination of intraosseous infusion of a small volume of hyperosmotic fluid, followed by whole blood, in a standard experiment in pigs. DESIGN: Randomised open study. MATERIAL: 18 piglets. INTERVENTIONS: After a 60 minute period of stabilization all animals were bled to an arterial systolic pressure of 60 mm Hg. After 30 minutes 100 ml hyperosmotic fluid was given over a seven minute period into the tibial bone marrow (n = 6) or into an ear vein (n = 6). Ninety minutes later the animals were again bled to a systolic pressure of 60 mm Hg and 30 minutes after this they were treated by autologous blood transfusion either by intraosseous or intravenous infusion. Six animals acted as untreated controls. MAIN OUTCOME MEASURES: Changes in haemodynamic, haematological and biochemical variables. RESULTS: Two pigs in the control group died. There was no difference between the intraosseous and intravenous routes for the infusion of small volumes of hyperosmotic fluid or whole blood. There was a significant improvement in haemodynamic variables after resuscitation with intraosseous infusion of small volumes of hyperosmotic fluid (p < 0.05). CONCLUSION: Intraosseous infusions were easy to establish, and may be a useful method of resuscitation from haemorrhagic shock, particularly in children.

Tumor necrosis factor and interleukin 1 appearance in experimental gram-negative septic shock. The effects of plasma exchange with albumin and plasma infusion.

To study the effect of plasma removal vs plasma administration on the appearance of tumor necrosis factor (TNF) and interleukin 1 in septic shock, 24 anesthetized piglets were inoculated with live Escherichia coli. Plasma exchange with albumin was performed in one group. Fresh-frozen plasma was administered to a second group. A third group served as nontreated controls. Following plasma exchange, a reduction in both TNF and interleukin 1 levels occurred, whereas plasma infusion was followed by a decrease in TNF levels only. No significant differences were observed between the two treated groups with respect to survival or cardiovascular performance, with both being significantly enhanced compared with the controls. High levels of TNF and interleukin 1 correlated with depressed cardiovascular performance in the early phase of the shock. Our results confirm the important role of TNF and interleukin 1 as early mediators of septic shock. However, the benefit of reducing cytokine activity in later stages of septicemia seems to be dubious.