El uso de la presión positiva espiratoria final (PPEF) en el manejo de la insuficiencia respiratoria aguda / The use of final positive expiratory pressure (FPEP) in the management of acute respiratory failure / O uso da pressão positiva expiratória final (PEEP) no tratamento da insuficiência respiratória aguda

Resumen: Se analiza el efecto de la presión positiva espiratoria final (PPEF) en un grupo de pacientes con insuficiencia respiratoria aguda (IRA) de muy diversa etiología. Del mismo modo se analiza la evolución y otros aspectos del manejo ventilatorio de estos casos. La sola administración de la PPEF modificó en forma significativa y favorable varios de los parámetros respiratorios evaluados: aumento de la PaO2, disminución del índice FiO2/PaO2, disminución del Qs/Qt y del gradiente A-aDO2. No hubo alteración hemodinámica manifiesta a través de los parámetros clínicos: presión arterial, frecuencia cardiaca y diuresis, tampoco hubo alteraciones significativas del gradiente a-vDO2. Complicaciones atribuidas a la PPEF del tipo del «barotrauma¼ fueron encontrados en el 10.4% de los casos. El curso de la IRA fue hacia la mejoría en la mayoría de los pacientes al final de la evolución. La elevada tasa de mortalidad en este grupo de pacientes es atribuida a la presencia de sepsis no controlable y a la coexistencia de múltiples fallas orgánicas. En ninguno de los casos fue atribuida a hipoxemia aguda refractaria. La PPEF, una de las variedades de presión positiva continua, manejada en el concepto de «PPEF óptima¼, representa uno de los avances terapéuticos más importantes de la última década en el manejo de los pacientes con IRA.

Abstract: A group of 19 patients with acute respiratory failure (ARF) of diverse etiology received as a part of their treatment positive end expiratory pressure (PEEP). All of them were evaluated clinicaly and with several respiratory parameters. The response to treatment, complications and mortality rates are analyzed. The addition of PEEP in the management of this patients was accompanied by a significant increase of the PAO2 (p < 0.001) and a simultaneous decrease in the following parameters: FiO2/PaO2 index, Alveolo-arterial oxygen gradient (A-aDO2) and the pulmonary shunt (Qs/Qt). No hemodynamic deterioration was observed. None of the clinical parameters such as: blood pressure, heart rate and diuresis was significantly modified; neither a significant change in the arterious-venous oxygen gradient (a-vDO2) was detected. Pneumothorax as a complication of the use of PEEP was present in the 10.4% of the patients. The course of the ARF was toward the improvement in most of them at the end of the evolution. The high mortality rate in this study was considered to be secondary to uncontrolable sepsis and also to the presence of multiple organ failure. In none of the cases the poor outcome was secondary to refractory acute hypoxemia. PEEP which is one of the varieties of continuos positive pressure ventilation (CPPV) represents one of the most importants therapeutic advances in the last decade in the management of patients with acute respiratory failure.

Résumé: On analyse l'effet de la pression positive expiratoire finale (PPEF) dans un groupe de patients avec Insuf-misance respiratoire aiguë (IRA) d'une très diverse étiologie. De la même façon on analyse l'évolution et d'autres aspects du maniement ventriculaire de ces cas. La seule administration de la PPEF a modifié dans une forme significative et favorable plusieurs des paramètres respiratoires évalués: augmentation de la PaO2, diminution de I'ndice FiO2/PaO2, diminution du Qs/Qt et du gradient A-aDD2. Il n'y a pas eu d'altération hémodynamique manifeste à travers les paramètres cliniques: pression artérielle, fréquence cardiaque et diurèse, il n'y a pas eu non plus des altérations significatives du gradient a-vDO2. Des complications attribuées à la PPEF du type du «barotraume¼ ont été trouvées dans le 10.4% des cas. Le cours de l'IRA a tendu vers l'amélioration chez la plupart des patients à la fin de l'évolution. Le taux élevé de mortalité dans ce groupe de patients est attribué à la présense de sepsis non contrôlable et à la coexitance de multiples défauts organiques. Dans aucun des cas il a été attribué à hypoxémia aiguë réfractaire. La PPEF, une des variétés de pression positive continue, maniée dans le concept de «PPEF très bonne¼, représente l'un des avancements thérapeutiques les plus importants des dix dernières années dans le maniement des patients avec IRA.

Commercially available immunoglobulins contain virus neutralizing antibodies against all major genotypes of polyomavirus BK.

Neutralizing antibodies (NAbs) form the basis of immunotherapeutic strategies against many important human viral infections. Accordingly, we studied the prevalence, titer, genotype-specificity, and mechanism of action of anti-polyomavirus BK (BKV) NAbs in commercially available human immune globulin (IG) preparations designed for intravenous (IV) use. Pseudovirions (PsV) of genotypes Ia, Ib2, Ic, II, III, and IV were generated by co-transfecting a reporter plasmid encoding luciferase and expression plasmids containing synthetic codon-modified VP1, VP2, and VP3 capsid protein genes into 293TT cells. NAbs were measured using luminometry. All IG preparations neutralized all BKV genotypes, with mean EC50 titers as high as 254 899 for genotype Ia and 6,666 for genotype IV. Neutralizing titers against genotypes II and III were higher than expected, adding to growing evidence that infections with these genotypes are more common than currently appreciated. Batch to batch variation in different lots of IG was within the limits of experimental error. Antibody mediated virus neutralizing was dose dependent, modestly enhanced by complement, genotype-specific, and achieved without effect on viral aggregation, capsid morphology, elution, or host cell release. IG contains potent NAbs capable of neutralizing all major BKV genotypes. Clinical trials based on sound pharmacokinetic principles are needed to explore prophylactic and therapeutic applications of these anti-viral effects, until effective small molecule inhibitors of BKV replication can be developed.

Should HLA mismatch acceptability for sensitized transplant candidates be determined at the high-resolution rather than the antigen level?

Defining HLA mismatch acceptability of organ transplant donors for sensitized recipients has traditionally been based on serologically defined HLA antigens. Now, however, it is well accepted that HLA antibodies specifically recognize a wide range of epitopes present on HLA antigens and that molecularly defined high resolution alleles corresponding to the same low resolution antigen can possess different epitope repertoires. Hence, determination of HLA compatibility at the allele level represents a more accurate approach to identify suitable donors for sensitized patients. This approach would offer opportunities for increased transplant rates and improved long term graft survivals.

Rapamycin augments human DC IL-12p70 and IL-27 secretion to promote allogeneic Type 1 polarization modulated by NK cells.

Mammalian target of rapamycin kinase inhibitor (mTORi) rapamycin (RAPA) use in transplantation can lead to inflammatory complications in some patients. Our goal was to better understand how mTORi-exposed human monocyte-derived dendritic cells (DC) stimulated with pro-inflammatory cytokines shape T cell allo-immunity. RAPA-conditioned-DC (RAPA-DC) displayed a more immature phenotype than untreated, control (CTRL)-DC. However, subsequent exposure of RAPA-DC to an inflammatory cytokine cocktail (ICC) plus IFN-γ induced a mature Type-1 promoting phenotype, consisting of elevated HLA-DR and co-stimulatory molecules, augmented IL-12p70 and IL-27 production, but decreased IL-10 secretion compared to CTRL-DC. Co-culture of mature (m)RAPA-DC with allogeneic peripheral blood mononuclear cells resulted in significantly increased Type-1 (IFN-γ) responses by T cells. Moreover, NK cells acted as innate modulators that conveyed activating cell-to-cell contact signals in addition to helper (IFN-γ) and/or regulatory (IL-10) soluble cytokines. We conclude that production of IL12-p70, IL-27 and low IL-10 by RAPA-DC allowed us to elucidate how these cytokines as well as NK-DC interaction shapes T cell allo-immunity. Thus, lack of inhibitory NK cell function during allo-specific T cell activation by human ICC + IFN-γ-stimulated RAPA-DC may represent an unwanted effector mechanism that may underlie RAPA-induced inflammatory events in transplant patients undergoing microbial infection or allograft rejection.

FTY720 and everolimus in de novo renal transplant patients at risk for delayed graft function: results of an exploratory one-yr multicenter study.

This exploratory, multicenter, open-label study evaluated the efficacy and safety of FTY720, as a part of an immunosuppressive regimen, in combination with everolimus and steroids in de novo renal transplant recipients at increased risk of delayed graft function (DGF). Patients received FTY720 (5 mg) and everolimus (4 mg) 2-12 h pre-transplantation, followed by 2.5 mg/d FTY720 and concentration-controlled everolimus (4-8 ng/mL) post-transplant for 12 months. Induction therapy was prohibited. After enrollment of 56 of the planned 200 patients between 2000 and 2002, the recruitment was terminated. The primary endpoint, rate of graft loss, or death at three months was 15.4% and the biopsy-confirmed acute rejection was 42.3%. Death or graft loss at 12 months in the DGF and non-DGF arms was 36.0% and 25.9%, respectively. The mean estimated creatinine clearance at three months was 63 and 55 mL/min in the non-DGF and DGF groups, respectively, while at 12 months it was 56 mL/min in both the groups. Although there was no comparator arm, the results from this exploratory study (compared with data from other phases II and III trials) indicated no apparent benefits of FTY720-based regimens for prevention of acute rejection and preservation of renal function in renal transplant recipients at high risk of DGF.

Outbreak of type A botulism and development of a botulism surveillance and antitoxin release system in Argentina.

CONTEXT: Botulism is an important public health problem in Argentina, but obtaining antitoxin rapidly has been difficult because global supplies are limited. In January 1998, a botulism outbreak occurred in Buenos Aires. OBJECTIVES: To determine the source of the outbreak, improve botulism surveillance, and establish an antitoxin supply and release system in Argentina. DESIGN, SETTING, AND PARTICIPANTS: Cohort study in January 1998 of 21 drivers of a specific bus route in urban Buenos Aires. MAIN OUTCOME MEASURE: Occurrence of botulism and implication of a particular food as the vehicle causing this outbreak. RESULTS: Nine (43%) of 21 bus drivers developed botulism, presenting with gastroenteritis, symptoms of acute cranial nerve dysfunction including ptosis, dysphagia, blurred vision, and motor weakness. One driver experienced respiratory failure. Type A toxin was detected from 3 of 9 patients' serum samples. All drivers received botulism antitoxin; there were no fatalities. Consumption of matambre (Argentine meat roll) was significantly associated with illness. Among 11 persons who ate matambre, 9 developed illness, compared with none of those who did not eat it (P<.001). The matambre had been cooked in water at 78 degrees C to 80 degrees C for 4 hours, sealed in heat-shrinked plastic wrap, and stored in refrigerators that did not cool adequately. Subsequently, a botulism surveillance and antitoxin release system was established. CONCLUSIONS: Insufficient cooking time and temperatures, storage in heat-shrinked plastic wrap, and inadequate refrigeration likely contributed to Clostridium botulinum spore survival, germination, and toxin production. A rapid-response botulism surveillance and antitoxin release system in Argentina should provide more timely distribution of antitoxin to patients and may serve as a model for other nations.

Improving results of pediatric renal transplantation.

BACKGROUND: Outcome after renal transplantation in children has been variable. We undertook a retrospective study of our experience over the past five years. STUDY DESIGN: From January 1, 1988, to October 15, 1992, 60 renal transplantations were performed upon 59 children at the Children's Hospital of Pittsburgh. Twenty-eight (47 percent) of the kidneys were from cadaveric donors, and 32 (53 percent) were from living donors. The recipients ranged in age from 0.8 to 17.4 years, with a mean of 9.8 +/- 4.8 years. Forty-six (77 percent) recipients were undergoing a first transplant, while 14 (23 percent) received a second or third transplant. Eight (13 percent) of the patients were sensitized, with a panel reactive antibody of more than 40 percent. Eleven of the 14 patients undergoing retransplantation and seven of the eight patients who were sensitized received kidneys from cadaveric donors. Thirty-three (55 percent) patients received cyclosporine-based immunosuppression, and 27 (45 percent) received FK506 as the primary immunosuppressive agent. RESULTS: The median follow-up period was 36 months, with a range of six to 63 months. The one- and four-year actuarial patient survival rate was 100 and 98 percent. The one- and four-year actuarial graft survival rate was 98 and 83 percent. For living donor recipients, the one- and four-year actuarial patient survival rate was 100 and 100 percent; for cadaveric recipients, it was 100 and 96 percent. Corresponding one- and four-year actuarial graft survival rates were 100 and 95 percent for the living donor recipients and 96 and 69 percent for the cadaveric recipients. Patients on cyclosporine had a one- and four-year patient survival rate of 100 and 97 percent, and patients on FK506 had a one- and three-year patient survival rate of 100 and 100 percent. Corresponding one- and four-year actuarial graft survival rates were 100 and 85 percent in the cyclosporine group, while one- and three-year actuarial graft survival rates were 96 and 84 percent in the FK506 group. The mean serum creatinine level was 1.24 +/- 0.64 mg per dL; the blood urea nitrogen level was 26 +/- 13 mg per dL. The incidence of rejection was 47 percent; 75 percent of the rejections were steroid-responsive. The incidence of cytomegalovirus was 10 percent. The incidence of post-transplant lymphoproliferative disorder was 8 percent. None of the patients on cyclosporine were able to be taken off prednisone; 56 percent of the patients receiving FK506 were taken off prednisone successfully. Early growth and development data suggest that the patients receiving FK506 off prednisone had significant gains in growth. CONCLUSIONS: These results support the idea that renal transplantation is a successful therapy for end-stage renal disease in children. They also illustrate the potential benefits of a new immunosuppressive agent, FK506.

Differential induction of nitric oxide synthase in hepatocytes during endotoxemia and the acute-phase response.

OBJECTIVE: Nitric oxide (NO) is a potent biologic mediator produced by hepatocytes following exposure to cytokines and lipopolysaccharide (LPS). These cytokines are also known to regulate induction of the hepatic acute-phase response. The objective of this study was to determine whether inducible nitric oxide synthase (iNOS), the enzyme that produces NO, is expressed as part of the hepatic acute-phase response. DESIGN: The gene expression for inducible NOS (iNOS) as well as alpha 1-acid glycoprotein (AGP), an established acute-phase reactant, was measured by Northern blot analysis in rat hepatocytes in vivo during endotoxemia (LPS injection) and during the acute-phase response produced by hindlimb turpentine injection. Hepatocyte iNOS messenger RNA (mRNA) levels were correlated with iNOS activity and circulating plasma nitrite and nitrate levels. In vitro, iNOS and AGP mRNA levels were determined in cultured hepatocytes stimulated with interleukin 6 (IL-6), interleukin 1 beta (IL-1 beta), tumor necrosis factor alpha (TNF-alpha), or dexamethasone. RESULTS: The AGP mRNA levels were increased in vivo following both LPS and turpentine injection, while iNOS expression was induced only by LPS injection. Hepatocyte iNOS activity and plasma nitrite and nitrate levels also increased after LPS treatment. In vitro, the cytokine combination IL-6, IL-1 beta, and TNF-alpha induced hepatocyte iNOS expression but had minimal effects on AGP in the absence of dexamethasone. Addition of dexamethasone alone markedly increased AGP mRNA levels, with further increases seen with TNF-alpha or IL-1 beta addition. In contrast, dexamethasone decreased iNOS expression. CONCLUSION: The results show that hepatocyte iNOS expression is not part of the acute-phase response induced by remote inflammation and indicates that iNOS is differentially regulated from the acute-phase reactant, AGP.

Recent developments in renal transplantation - FK506 and bone marrow augmentation.

In the past 40 years, clinical renal transplantation has evolved from a risky, highly speculative endeavor to a fairly mature, well-established service. There are hundreds of programs around the world, transplanting thousands of patients annually, and reasonably good suecess rates have been achieved. Current expectations are of one year patient survival of 90 - 98%, and one year graft survival of 75 - 90%. In addition, patients who have been successfully transplanted have a markedly improved quality oflife compared with patients on dialysis. However, in spite of these encouraging results, there remain significant problems. Among them are acute rejection, which still occurs in 40 - 75% of cases, and graft loss secondary to rejection, acute or chronic, which limits the half-life of cadaveric kidneys to 8 years. As part of an effort to address these issues, there have been a number of new immunosuppressive agents and therapeutic modalities that have been investigated over the past several years. This chapter will focus on 2 areas of ongoing research in our institution, the use of FK506 in renal transplant patients, and the program of combined kidney/bone marrow transplantation.

Initial studies with FK506 in renal transplantation.

FK506 is a novel immunosuppressive agent which is approximately 100 times as potent as cyclosporine in vitro. In this initial trial, 65 renal transplant patients of high complexity received primary FK506 immunosuppression. Overall, graft and patient survival rates are 80% and 98.5%, respectively. A major advantage of FK506 is its potency with relatively few side effects, which has permitted elimination of steroids in 31 (60%) of these patients. Because of these encouraging results, a randomized trial comparing the therapeutic efficacy and toxicity of FK506 and cyclosporine is currently underway at our institution.

Immunodepletion in xenotransplantation.

Xenograft transplantation is perhaps the most immunologically difficult problem in transplantation today. An overwhelming hyperacute rejection reaction (HAR) occurs within minutes of organ implantation. Preformed antibodies are thought to initiate this process. We used a pig-to-dog renal xenograft transplant model and investigated methods of decreasing the severity of hyperacute rejection. Female pigs weighing 15-20 kg were used as donors. Recipients were mongrel dogs weighing 15-25 kg. Experimental dogs were all given a number of treatments of IgG depletion using an antibody removal system (Dupont-Excorim). This machine immunoadsorbs plasma against a column containing immobilized staphylococcal protein A, which is known to bind the IgG Fc receptor. An 84% reduction in the IgG levels and a 71% reduction in IgM levels was achieved. Postoperative assessment was made of urine output, time to onset of HAR, and histopathological examination of the rejected kidneys. Although cross-matches between donor lymphocytes and recipient sera remained strongly positive in the treated dogs, there was a two- to fourfold reduction in the titers. The time to onset of HAR was prolonged in the experimental group, and the urine output was increased slightly. The histopathologic changes in the experimental group generally showed signs of HAR, but of less intensity than in the nonimmunodepleted control group.