Cardiovascular death and progression to end-stage renal disease after major surgery in elderly patients.

BACKGROUND: Reliable estimates for risk of cardiovascular-specific mortality and progression to end-stage renal disease (ESRD) among elderly patients undergoing major surgery are not available. This study aimed to develop simple risk scores to predict these events. METHODS: In a single-centre cohort of elderly patients undergoing major surgery requiring hospital stay longer than 24 h, progression to ESRD and long-term cardiovascular-specific mortality were modelled using multivariable subdistribution hazard models, adjusting for co-morbidity, frailty and type of surgery. RESULTS: Before surgery, 2·9 and 11·9 per cent of 16 655 patients had ESRD and chronic kidney disease (CKD) respectively. During the hospital stay, 46·9 per cent of patients developed acute kidney injury (AKI). Patients with kidney disease had a significantly higher risk of cardiovascular-specific (CV) mortality compared with patients without kidney disease (adjusted hazard ratio (HR) for CKD without AKI 1·60, 95 per cent c.i. 1·25 to 2·01; AKI without CKD 1·70, 1·52 to 1·87; AKI with CKD 2·80, 2·50 to 3·20; ESRD 5·21, 4·32 to 6·27), as well as increased progression to ESRD (AKI without CKD 5·40, 3·44 to 8·35; CKD without AKI 8·80, 4·60 to 17·00; AKI with CKD 31·60, 19·90 to 49·90). CV Death and ESRD Risk scores were developed to predict CV mortality and progression to ESRD. Calculated CV Death and ESRD Risk scores performed well with c-statistics: 0·77 (95 per cent c.i. 0·76 to 0·78) and 0·82 (0·78 to 0·86) respectively at 1 year. CONCLUSION: Kidney disease in elderly patients undergoing major surgery is associated with a high risk of CV mortality and progression to ESRD. Risk scores can augment the shared decision-making process of informed consent and identify patients requiring postoperative renal-protective strategies.

ANTECEDENTES: No se dispone de estimaciones fiables acerca del riesgo de mortalidad cardiovascular y de progresión a insuficiencia renal terminal (end-stage renal disease, ESRD) en pacientes longevos a los que se realiza cirugía mayor. Este estudio tiene como objetivo desarrollar un sistema de puntuación simple de riesgos para predecir estos eventos. MÉTODOS: En una cohorte de un solo centro de 16.655 pacientes longevos a los que se realizó cirugía mayor con hospitalización de más de 24 horas, se estimó la progresión a ESRD y la mortalidad cardiovascular a largo plazo utilizando modelos multivariables de subdistribucion de riesgos ajustados por comorbilidades, fragilidad y tipo de cirugía. RESULTADOS: Antes de la cirugía, presentaron ESRD y enfermedad renal crónica (chronic kidney Disease, CKD) un 2,9% y un 12,3% de los pacientes, respectivamente. Durante la hospitalización, el 46,9% de los pacientes desarrollaron insuficiencia renal aguda (acute kidney injury, AKI). Los pacientes con enfermedad renal tenían un riesgo significativamente mayor de mortalidad cardiovascular (CV) en comparación con los pacientes sin enfermedad renal para presentar AKI (cociente de riesgos instantáneos, hazard ratio, HR ajustado) 1,6 (i.c. del 95% 1,3-2,0), AKI sin CKD 1,7 (1,5-1,9), AKI en presencia de CKD 2,8 (2,5-3,2) y ESRD 5,2 (4,3-6,3), así como una mayor progresión a ESRD (AKI sin CKD 5,4 (3,4-8,4), CKD sin AKI 8,8 (4,6-17), y AKI en presencia de CKD 31,6 (19,9-49,9)). Se desarrollaron las escalas CV Death y ESRD Risk para predecir la mortalidad cardiovascular y la progresión a ESRD. Ambas escalas funcionaron bien a 1 año con un coeficiente de concordancia de 0,77 (i.c. del 95% 0,76-0,78) y 0,82 (0,78-0,86) respectivamente. CONCLUSIÓN: La enfermedad renal en pacientes longevos tras cirugía mayor se asocia con un elevado riesgo de mortalidad cardiovascular y de progresión a ESRD. Las escalas de riesgo pueden facilitar la toma de decisiones en el momento del consentimiento informado e identificar los pacientes que requieren estrategias de protección renal postoperatorias.

Review: The Perioperative Use of Thromboelastography for Liver Transplant Patients.

Thromboelastography (TEG) is a viscoelastic test that allows rapid evaluation of clot formation and fibrinolysis from a sample of whole blood. TEG is increasingly utilized to guide blood product resuscitation in surgical patients and transfusions for liver transplant patients. Patients with severe liver failure have significant derangement of their clotting function due to impaired production of procoagulant and anticoagulant factors. Traditional coagulation studies are limited by the short time needed for the result and provide little information about the dynamics and strength of clot formation. In addition, traditional coagulation studies do not correlate well with bleeding episodes and may lead to over-transfusion of various blood products. Evidence is less robust regarding the use of TEG for transfusion management decisions in severe liver failure patients awaiting, undergoing, or immediately after liver transplant surgery. However, the available evidence suggests that systematic implementation of TEG rather than traditional coagulation studies results in the administration of fewer blood products without increased mortality or complications. The purpose of this study is to review the literature regarding the use of TEG in liver failure patients prior to liver transplant, intraoperatively, and postoperatively. Additional high-quality randomized controlled studies should be performed to evaluate the use of TEG to guide transfusion decisions, particularly in the postoperative period following liver transplantation.

Adjuvant pretreatment with alum protects neonatal mice in sepsis through myeloid cell activation.

The high mortality in neonatal sepsis has been related to both quantitative and qualitative differences in host protective immunity. Pretreatment strategies to prevent sepsis have received inadequate consideration, especially in the premature neonate, where outcomes from sepsis are so dismal. Aluminium salts-based adjuvants (alum) are used currently in many paediatric vaccines, but their use as an innate immune stimulant alone has not been well studied. We asked whether pretreatment with alum adjuvant alone could improve outcome and host innate immunity in neonatal mice given polymicrobial sepsis. Subcutaneous alum pretreatment improves survival to polymicrobial sepsis in both wild-type and T and B cell-deficient neonatal mice, but not in caspase-1/11 null mice. Moreover, alum increases peritoneal macrophage and neutrophil phagocytosis, and decreases bacterial colonization in the peritoneum. Bone marrow-derived neutrophils from alum-pretreated neonates produce more neutrophil extracellular traps (NETs) and exhibit increased expression of neutrophil elastase (NE) after in-vitro stimulation with phorbol esters. In addition, alum pretreatment increases bone marrow and splenic haematopoietic stem cell expansion following sepsis. Pretreatment of neonatal mice with an alum-based adjuvant can stimulate multiple innate immune cell functions and improve survival. These novel findings suggest a therapeutic pathway for the use of existing alum-based adjuvants for preventing sepsis in premature infants.

Soybean oil: a potentially new intravascular perfusate.

BACKGROUND: Given that micelles of lipids are colloids, the hypothesis was generated that the rapid administration of large volumes of soybean oil micelles would be an effective perfusion fluid. We also hypothesized that oxygen loading would be enhanced due to the greater solubility of oxygen in lipids compared to water. METHODS: A 100% lethal mouse model of blood loss was used to compare the ability of soybean oil micelles to that of Ringer's lactate, blood and other fluids, with respect to raising and maintaining the blood pressure for one hour. Oxygen on- and off-loading of various concentrations of soybean oil micelles was determined using mass spectroscopy. Nitric oxide uptake by micelles was also determined in a similar fashion. RESULTS: A 20% soybean oil emulsion was superior to Ringer's lactate in raising and maintaining blood pressure. A 20% soybean oil emulsion with 5% albumin added was superior to shed blood as well as solutions comprised of 5% albumin added to either normal saline or Ringer's lactate. There was a linear relationship between oxygen content and micelle concentration between 10% and 30%. Off-loading of oxygen from the micelles was nearly as fast as off-loading from water. Nitric oxide also loaded preferentially onto soybean oil micelles. CONCLUSIONS: (1) Soybean oil emulsions were superior to other fluids in restoring and maintaining the blood pressure; (2) oxygen-carrying ability of soybean oil micelles exceeds that of water and follows Henry's law between 10% and 30% w/v oil content; (3) nitric oxide was carried by the micelles; (4) animals receiving soybean oil micelles did not exhibit fat embolization; (5) colloids comprised of soybean oil-containing micelles may be used to replace blood loss and may be used to deliver oxygen and other potentially therapeutic gases such as nitric oxide to tissues.

Dose-dependent improvements in outcome with adenoviral expression of interleukin-10 in a murine model of multisystem organ failure.

Targeted expression of interleukin-10 (IL-10) has been proposed as a means to suppress acute and chronic inflammation. We explored the capacity of targeted adenoviral expression of human or viral IL-10 to improve outcome in a zymosan-induced model of acute lung injury and multisystem organ failure. Intratracheal administration of adenovirus expressing either human or viral IL-10 prior to zymosan administration significantly improved survival at a dose of 10(7) particles (P<0.01), whereas the same recombinant vectors were ineffective at 10(8) particles and increased mortality at 10(9) particles. Improved survival after administration of 10(7) particles of adenovirus expressing viral or human IL-10 was associated with local tissue expression of IL-10 (100-300 pg/g wet wt). In contrast, mortality after administration of 10(9) particles was associated with markedly elevated IL-10 expression, both in the lung (10000-70000 pg/g wet wt) and systemically (1000-3000 pg/ml plasma), with evidence of an exaggerated systemic inflammatory response (plasma IL-6 and TNFalpha). Targeted gene expression of IL-10 can be used to treat acute inflammatory processes, but increased doses resulting in its systemic release are not associated with improvements in outcome, and may actually exacerbate acute inflammatory processes.

The effects of renal transplantation on circulating precursor dendritic cells.

BACKGROUND: Dendritic cells (DCs) are potent antigen-presenting cells that induce and regulate immune responses. Recent advances allow accurate quantification of peripheral blood (PB) myeloid and plasmacytoid DC populations (mDC and pDC, respectively), although the response to renal transplantation (RT) remains unknown. METHODS: Using flow cytometry, PBDC levels were quantified in patients with end-stage renal disease (ESRD) undergoing renal transplantation. RESULTS: PBDC levels were significantly reduced in ESRD patients pretransplantation compared to healthy controls, with further reduction noted immediately following a hemodialysis session. RT resulted in a dramatic decrease in both subsets, with a greater reduction of pDC levels. Both subset levels were significantly lower than in control patients undergoing abdominal surgery without RT. Subgroup analysis revealed significantly greater mDC reduction in RT recipients receiving antilymphocyte therapy, with preferential binding of antibody preparation to this subset. Samples from later time points revealed a gradual return of PBDC levels back to pretransplant values concurrent with overall reduction of immunosuppression. Finally, PBDC levels were significantly reduced in patients with BK virus nephropathy compared to recipients with stable graft function, despite lower overall immunosuppression. CONCLUSIONS: Our findings suggest that PBDC levels may reflect the degree of immunosuppression in renal allograft recipients. Furthermore, PBDC monitoring may represent a novel strategy to predict important outcomes such as acute rejection, long-term graft loss, and infectious complications.

Diabetes-impaired healing and reduced wound nitric oxide synthesis: a possible pathophysiologic correlation.

BACKGROUND: Nitric oxide (NO) is synthesized in wounds, but its role in the healing process is not fully understood. The inhibition of NO production during wound healing is accompanied by decreased wound reparative collagen deposition. To further define the role of NO in reparative collagen accumulation, we studied its production during diabetes-induced wound healing impairment. METHODS: Male Sprague-Dawley rats (290 to 310 gm) were rendered diabetic by intraperitoneal streptozotocin administration. Seven days after induction of diabetes (blood glucose greater than 300 mg/dl), the rats underwent dorsal skin incision and subcutaneous implantation of polyvinyl alcohol sponges. Beginning on the day of wounding, 21 diabetic animals were treated with 3 units/day insulin via intraperitoneally implanted miniosmotic pumps. Ten days after injury, wound breaking strength was determined, and wound collagen accumulation and types I and III collagen gene expression were measured in subcutaneously implanted polyvinyl alcohol sponges. NO-synthesis, as measured by nitrite/nitrate accumulation, was determined in wound fluid and in supernatants of wound cell cultures. RESULTS: Streptozotocin-induced diabetes markedly impaired wound breaking strength and collagen deposition. A parallel decrease occurred in wound NO synthesis as reflected by decreased nitrite/nitrate concentration in wound fluid and in diminished ex vivo NO production by wound cells. Insulin treatment partially but significantly improved wound mechanical strength (p < 0.01) and collagen accumulation (p < 0.001). Decreased wound NO accumulation and ex vivo NO production by wound cells were also partially restored by insulin treatment. CONCLUSIONS: Impaired diabetic wound healing is paralleled by decreased wound NO synthesis, supporting the hypothesis that NO plays a significant role in wound reparative collagen accumulation.

Nitric oxide, an autocrine regulator of wound fibroblast synthetic function.

Nitric oxide (NO) is synthesized in wounds, but its exact role and cellular source are not known. Wound fibroblasts (WF) are phenotypically characterized by increased collagen synthesis and contractility. We hypothesized that WF may be also phenotypically altered during wound healing to synthesize NO. WF were isolated from polyvinyl alcohol sponges implanted in male Lewis rats and harvested 10 days later. Proliferation in response to 10% fetal bovine serum was assessed by [3H]thymidine incorporation in a microculture system. A fibroblast-populated collagen lattice was used for assaying contractility. Collagen synthesis was determined by measuring the collagenase-sensitive fraction of protein-incorporated [3H]proline. Fibroblasts were incubated in the presence or the absence of 0.5 mM S-methyl-isothio-uronium or 0.5 mM N-monomethyl-L-arginine, both competitive inhibitors of NO synthase. WF spontaneously synthesize and release NO (4.60 +/- 0.29 nmol nitrite/microg DNA/48 h). Normal dermal fibroblasts do not synthesize NO. WF NO synthesis was limited to the first and second passages postharvest and was inhibitable by S-methyl-isothio-uronium (96%) and N-monomethyl-L-arginine (84%). In vivo iNOS expression by WF was confirmed by in situ hybridization and immunohistochemistry. Inhibition of endogenous NO synthesis had no effect on fibroblast proliferation. However, fibroblast-mediated collagen contraction was enhanced (p < 0.01), and collagen synthesis was significantly decreased (p < 0.05) by inhibiting NO synthase. The data show that WF are phenotypically altered during the healing process to synthesize NO, which, in turn, regulates their collagen synthetic and contractile activities.