Severe sepsis and septic shock in patients with pre-existing non-cardiac pulmonary hypertension: contemporary management and outcomes.

OBJECTIVE: To review treatment and outcomes of septic shock in patients with pulmonary hypertension (PH) managed at a tertiary care institution. DESIGN, SETTING AND PATIENTS: We identified consecutive patients with non-cardiac PH (non-Group 2 in the World Health Organization classification) who were treated for septic shock in four intensive care units at a tertiary care institution between July 2004 and July 2007. Patients with a left ventricular ejection fraction < 50%, diastolic dysfunction, pericardial effusion or significant valve disease were excluded. Descriptive statistics were used to analyse the data. MAIN OUTCOME MEASURES: Hospital mortality, duration of vasopressor and ventilatory support, length of hospital and ICU stay. RESULTS: The final group for analysis comprised 82 patients. The major causes of PH were chronic obstructive pulmonary disease, interstitial lung disease and portopulmonary hypertension. PH was mild in 46 patients (56%), moderate in 21 (26%) and severe in 15 (18%). Vasopressor treatment was initiated in 69 patients (84%) within the first 48 hours: noradrenaline was most commonly used (53 patients, 65%), and 51 patients (62%) were treated with more than one agent. Sixty-seven patients (82%) were mechanically ventilated, and 33 (40%) required renal replacement therapy. Fortythree patients (52%) survived to hospital discharge; 23 (28%) remained alive at 1 year. Hospital mortality increased with severity of PH: 28% in mild, 67% in moderate and 80% in severe PH. Nonsurvivors were more likely to have plateau pressures beyond 30 cm H(2)O while mechanically ventilated within the first 48 hours in the ICU (56% v 29%, P = 0.03), to develop atrial fibrillation (AF) (46% v 12%, P < 0.001), and to require longer vasopressor support (mean, 5.3 v 2.6 days, P = 0.003). In a multivariate logistic regression analysis, severity of PH (odds ratio [OR], 1.55; 95% CI, 1.04-2.46; P = 0.04), new-onset AF (OR, 6.51; 95% CI, 2.24-22.07; P < 0.001) and longer duration of vasopressor support (OR, 1.15; 95% CI, 1.03-1.34; P = 0.04) were associated with increased hospital mortality. CONCLUSIONS: The severity of PH, new-onset AF, and longer vasopressor support were associated with poor outcomes in patients with PH who developed severe sepsis and septic shock.

Measurement of urinary TGF-ß1 in patients with diabetes mellitus and normal controls.

OBJECTIVE: Increasing evidence links TGF-ß1 to progression of renal fibrosis including its association with diabetic nephropathy (DN). Current ELISA assays are not sensitive enough to measure TGF-ß1 in the urine of many clinically healthy individuals, even those with established renal disease. The objective of this study was to validate a sensitive urinary assay for TGF-ß1 and compare levels between healthy controls and patients with established DN. DESIGN AND METHODS: An ELISA method (R&D Systems) was utilized together with an amplification step to assay TGF-ß1 in urine samples from 190 patients with DN and 80 healthy controls. RESULTS: Using an ELAST (Perkin Elmer, Inc) amplification step, the ELISA for urinary TGF-ß1 had a limit of quantification of 15.6 pg/mL and limit of detection of 7 pg/mL. Preliminary studies demonstrated that TGF-ß1 was stable if urine was frozen promptly at -70°C without preservatives. Using this assay, 22/80 controls (27%) had detectable levels of urinary TGF-ß1 (range <7 to 40.9 pg/mL; mean±SD 6.4±11.1 pg/mL). This was significantly lower (p<0.0001) than in the DN group in whom 114/190 (60%) had detectable levels of urinary TGF-ß1 (range <7 to 526.4 pg/mL; mean±SD 20.4±45.8 pg/mL). Urinary protein and TGF-ß1 concentrations demonstrated modest correlation in patients with DN (r=0.47, P<0.001). TGF-ß1 measurement in patients with DN did not demonstrate significant association with progression of proteinuria or increase in serum creatinine during the next 12 months of follow-up. CONCLUSION: We have validated a sensitive ELISA assay for urinary TGF-ß1, and demonstrated correlations with the degree of proteinuria and higher levels in patients with DN compared to controls. Additional study will be necessary in order to determine if serial testing can predict renal prognosis independent of known prognostic factors for patients with DN.

Increased production of superoxide anion contributes to dysfunction of the arteriovenous fistula.

Vascular access dysfunction causes morbidity in hemodialysis patients. This study examined the generation and pathobiological significance of superoxide anion in a rat femoral arteriovenous fistula (AVF). One week after AVF creation, there was increased production of superoxide anion accompanied by decreased total superoxide dismutase (SOD) and Cu/Zn SOD activities and induction of the redox-sensitive gene heme oxygenase-1. Immunohistochemical studies of nitrotyrosine formation demonstrated that peroxynitrite, a product of superoxide anion and nitric oxide, was present in increased amounts in endothelial and smooth muscle cells in the AVF. Because uncoupled NOS isoforms generate superoxide anion, and NOS coupling requires tetrahydrobiopterin (BH(4)) as a cofactor, we assessed NOS uncoupling by determining the ratio of BH(4) to dihydrobiopterin (BH(2)); the BH(4)-to-BH(2) ratio was markedly attenuated in the AVF. Because Src is a vasculopathic signaling species upstream and downstream of superoxide anion, such expression was evaluated; expression of Src and phosphorylated Src was both markedly increased in the AVF. Expression of NADPH oxidase (NOX) 1, NOX2, NOX4, cyclooxygenase (COX) 1, COX2, p47(phox), and p67(phox) was all unchanged, as assessed by Western analyses, thereby suggesting that these proteins may not be involved in increased production of superoxide anion. Finally, administration of tempol, a superoxide anion scavenger, decreased neointima formation in the juxta-anastomotic venous segment and improved AVF blood flow. We conclude that the AVF exhibits increased superoxide anion generation that may reflect the combined effects of decreased scavenging by SOD and increased generation by uncoupled NOS, and that enhanced superoxide anion production promotes juxta-anastomotic stenosis and impairs AVF function.

Renal histological lesions and outcome in liver transplant recipients.

BACKGROUND: Chronic kidney disease in liver transplant (OLT) recipients is often attributed to calcineurin inhibitors (CNI) toxicity, but little is known about the spectrum of their renal histological lesions. METHODS: Between 1988 and 2008, 1698 OLTs were performed in our center. We retrospectively analyzed clinical and histological data on 23 recipients (1.4%) referred for kidney biopsy (KB). RESULTS: Median age at OLT was 50.2 yr, 65.2% were men, 30.4% had hepatitis C, and 95.7% were given CNI. KB was performed 6.9 yr (median) post-OLT. Median creatinine was 1 mg/dL pre-OLT and 2.2 mg/dL at KB. Main pathological diagnoses were focal segmental and global glomerulosclerosis (n = 8, 34.8%), glomerular diseases (7, 30.4%), CNI toxicity (2, 8.7%), and diabetic nephropathy (2, 8.7%). Moderate/severe interstitial fibrosis, tubular atrophy, arteriosclerosis, and hyalinosis were present in 47.8%, 43.5%, 60.9%, and 56.5%, respectively. Twelve patients (52.5%) reached end-stage renal disease (ESRD) and 17 (73.9%) died. Death was more common among those reaching ESRD, but the difference was not significant (83.3% vs. 63.6%, p = 0.37). CONCLUSION: Renal histology is variable and not limited to CNI toxicity in OLT recipients referred for KB. Whether management based on KB findings can directly improve outcomes remains unclear.

Mapping physicians' admission diagnoses to structured concepts towards fully automatic calculation of acute physiology and chronic health evaluation score.

Objective Acute Physiology and Chronic Health Evaluation (APACHE) is most widely used as a mortality prediction score in US intensive care units (ICUs), but its calculation is onerous. The authors aimed to develop and validate automatic mapping of physicians' admission diagnoses to structured concepts for automated APACHE IV calculation. Methods This retrospective study was conducted in medical ICUs of a tertiary healthcare and academic centre. Boolean-logic text searches were used to map admission diagnoses, and these were compared with conventional APACHE database entry by bedside nurses and a gold-standard physician chart review. The primary outcome was APACHE IV predicted hospital mortality. The tool was developed in a larger cohort of ICU patients. Results In a derivation cohort of 192 consecutive critically ill patients, the diagnosis coefficient coded by three different methods had a positive correlation, highest between manual and gold standard (r(2)=0.95; mean square error (MSE)=0.040) and least between manual and automatic tool (r(2)=0.88; MSE=0.066). The automatic tool had an area under the curve (95% CI) value of 0.82 (0.74 to 0.90) which was similar to the physician gold standard, 0.83 (0.75 to 0.91) and standard manual entry, 0.81 (0.73 to 0.89). The Hosmer-Lemeshow goodness-of-fit test demonstrated good calibration of automatically calculated APACHE IV score (χ(2)=6.46; p=0.6). The automatic tool demonstrated excellent discrimination with an area under the curve value of 0.87 (95% CI 0.83 to 0.92) and good calibration (p=0.58) in the validation cohort of 593 patients. Conclusion A Boolean-logic text search is an efficient alternative to manual database entry for mapping of ICU admission diagnosis to structured APACHE IV concepts.

Limiting ventilator-induced lung injury through individual electronic medical record surveillance.

BACKGROUND: To improve the safety of ventilator care and decrease the risk of ventilator-induced lung injury, we designed and tested an electronic algorithm that incorporates patient characteristics and ventilator settings, allowing near-real-time notification of bedside providers about potentially injurious ventilator settings. METHODS: Electronic medical records of consecutive patients who received invasive ventilation were screened in three Mayo Clinic Rochester intensive care units. The computer system alerted bedside providers via the text paging notification about potentially injurious ventilator settings. Alert criteria included a Pao2/Fio2 ratio of <300 mm Hg, free text search for the words "edema" or "bilateral + infiltrates" on the chest radiograph report, a tidal volume of >8 mL/kg predicted body weight (based on patient gender and height), a plateau pressure of >30 cm H2O, and a peak airway pressure of >35 cm H2O. Respiratory therapists answered a brief online satisfaction survey. Ventilator-induced lung injury risk was compared before and after the introduction of ventilator-induced lung injury alert. FINDINGS: The prevalence of acute lung injury was 42% (n = 490) among 1,159 patients receiving >24 hrs of invasive ventilation. The system sent 111 alerts for 80 patients, with a positive predictive value of 59%. The exposure to potentially injurious ventilation decreased after the intervention from 40.6 ± 74.6 hrs to 26.9 ± 77.3 hrs (p = .004). INTERPRETATIONS: Electronic medical record surveillance of mechanically ventilated patients accurately detects potentially injurious ventilator settings and is able to influence bedside practice at moderate costs. Its implementation is associated with decreased patient exposure to potentially injurious mechanical ventilation settings.

Periodic fever syndrome with relapsing glomerulonephritis: a case report and teaching points.

We report a case of relapsing mesangial and endocapillary proliferative glomerulonephritis (GN) associated with a periodic fever syndrome. The patient presented 11 times in >4 years with acute febrile episode followed in 1-3 days by hematuria, thrombocytopenia and other symptoms of acute GN with variable severity of acute kidney injury. In three episodes, the patient required renal replacement therapy for 7, 10 and 2 treatments, respectively. Shortly after the acute symptoms of the febrile episode had resolved each time, the kidney function would recover and the serum creatinine would return to baseline. Two kidney biopsies obtained during separate episodes showed acute tubular injury along with morphological changes resembling post-infectious GN but with no clinical evidence to support an infectious etiology. Multiple treatment regimens were unable to control the disease. Symptoms were alleviated by rituximab but did not completely remit. Stable remission of the periodic fever and GN was finally achieved after anakinra therapy was initiated 18 months ago. Since then, the patient had several episodes of documented infection without high fever and nephritic kidney manifestations. His kidney function remained stable with normal serum creatinine.

Arterial pulmonary hypertension in noncardiac intensive care unit.

Pulmonary artery pressure elevation complicates the course of many complex disorders treated in a noncardiac intensive care unit. Acute pulmonary hypertension, however, remains underdiagnosed and its treatment frequently begins only after serious complications have developed. Significant pathophysiologic differences between acute and chronic pulmonary hypertension make current classification and treatment recommendations for chronic pulmonary hypertension barely applicable to acute pulmonary hypertension. In order to clarify the terminology of acute pulmonary hypertension and distinguish it from chronic pulmonary hypertension, we provide a classification of acute pulmonary hypertension according to underlying pathophysiologic mechanisms, clinical features, natural history, and response to treatment. Based on available data, therapy of acute arterial pulmonary hypertension should generally be aimed at acutely relieving right ventricular (RV) pressure overload and preventing RV dysfunction. Cases of severe acute pulmonary hypertension complicated by RV failure and systemic arterial hypotension are real clinical challenges requiring tight hemodynamic monitoring and aggressive treatment including combinations of pulmonary vasodilators, inotropic agents and systemic arterial vasoconstrictors. The choice of vasopressor and inotropes in patients with acute pulmonary hypertension should take into consideration their effects on vascular resistance and cardiac output when used alone or in combinations with other agents, and must be individualized based on patient response.

Update on drug-eluting coronary stents.

The introduction of drug-eluting stents (DES) to interventional cardiology practice has resulted in a significant improvement in the long-term efficacy of percutaneous coronary interventions. DES successfully combine mechanical benefits of bare-metal stents and stabilizing the lumen, with direct delivery and the controlled elution of a pharmacologic agent to the injured vessel wall to suppress further neointimal proliferation. The dramatic reduction in restenosis has resulted in the implementation of DES in clinical practice, and has rapidly expanded the whole spectrum of successfully treatable coronary conditions, particularly in high-risk patients and complex lesions. In this review the authors present current data on DES. Currently, two types of DES are available in the USA: sirolimus-eluting stents (SES) CYPHER (Cordis Corp., FL, USA) and paclitaxel-eluting stents (PES) TAXUS (Boston Scientific, MA, USA), and many more are on the way to approval. In addition to sirolimus and paclitaxel, several other drugs have been successfully used in DES. Everolimus and ABT-578 are both analogs of sirolimus that also have immunosuppressive and antiproliferative properties. Another approach in the development of DES is to use drugs that can accelerate re-endothelialization and restore normal endothelial function following vascular injury. Recent advances in vascular gene transfer have also demonstrated potential new treatment modalities for cardiovascular disease, particularly in the treatment of vascular restenosis.

Antisense therapy for restenosis following percutaneous coronary intervention.

Recent advances in vascular gene transfer have shown potential new treatment modalities for cardiovascular disease, particularly in the treatment of vascular restenosis. The antisense approach to inhibiting gene expression involves introducing oligonucleotides complementary to mRNA into cells in order to block any one of the following processes: uncoiling of DNA, transcription of DNA, export of RNA, DNA splicing, RNA stability, or RNA translation involved in the synthesis of proteins in cellular proliferation. The approach includes the use of antisense oligonucleotides, antisense mRNA, autocatalytic ribozymes, and the insertion of a section of DNA to form a triple helix. Proof of principle has been established that inhibition of several cellular proto-oncogenes, including DNA binding protein c-myb, non-muscle myosin heavy chain, PCNA proliferating-cell nuclear antigen, platelet-derived growth factor, basic fibroblast growth factor and c-myc, inhibits smooth muscle cell proliferation in vitro and in several animal models. The first clinical study demonstrated the safety and feasibility of local delivery of antisense in the treatment and prevention of restenosis; another randomised clinical trial (AVAIL) with local delivery of c-myc morpholino compound in patients with coronary artery disease demonstrated its long-term effect on reducing neointimal formation, as well as its safety. These preliminary findings from the small cohort of patients require confirmation in a larger trial utilising more sophisticated drug-eluting technologies.

Role of the endothelium in modulating neointimal formation: vasculoprotective approaches to attenuate restenosis after percutaneous coronary interventions.

Restenosis at the site of an endoluminal procedure remains a significant problem in the practice of interventional cardiology. We present current data on intimal hyperplasia, which identify the major role of endothelial cells (ECs) in the development of restenosis. Considering endothelial denudation as one of the most important mechanisms contributing to restenosis, we focus more attention on methods of accelerating restoration of endothelial continuity. Prevention of restenosis may be achieved by promoting endothelial regeneration through the use of growth factors, EC seeding, vessel reconstruction with autologous EC/fibrin matrix, and the use of estrogen-loaded stents and stents designed to capture progenitor ECs.

Advanced c-myc antisense (AVI-4126)-eluting phosphorylcholine-coated stent implantation is associated with complete vascular healing and reduced neointimal formation in the porcine coronary restenosis model.

An advanced six-ring morpholino backbone c-myc antisense (AVI-4126) was shown to inhibit c-myc expression and intimal hyperplasia after local catheter delivery in a porcine balloon injury model. The purpose of this study was to investigate the effects of an AVI-4126-eluting phosphorylcholine-coated (PC) stent on c-myc expression restenosis and vascular healing after stent implantation in porcine coronary arteries. PC stents were loaded with AVI-4126 using soak trap. Nine pigs underwent AVI-4126 PC coronary stent implantation (two stents/animal). Two to six hours postprocedure, three pigs were sacrificed and stented segments were analyzed by Western blot for c-myc expression. In chronic experiments, six pigs (12 stent sites) were sacrificed at 28 days following intervention and vessels were perfusion-fixed. High-performance liquid chromatography analysis of plasma samples showed minimal presence of the antisense. Western blot analysis of the stented vessels demonstrated inhibition of c-myc expression at 2 and 6 hr after procedure. Quantitative histologic morphometry showed that the neointimal area was significantly reduced (by 40%) in the antisense-coated group compared with control (2.3 +/- 0.7 vs. 3.9 +/- 0.8 mm(2), respectively; P = 0.0077). Immunostaining and electron microscopy demonstrated complete endothelialization, without fibrin deposition, thrombosis, or necrosis in all implanted stents. In the porcine coronary model, an advanced c-myc-eluting PC stent blocked c-myc expression and significantly inhibited myointimal hyperplasia and allowed complete reendothelialization and healing response.

Update on sirolimus drug-eluting stents.

Percutaneous transluminal coronary angioplasty (PTCA) has become the main method of coronary revascularization. However, despite technical advancement, restenosis with incidence rate of 30 to 50% remains a major limitation to the long-term success of PTCA. The introduction of stents has significantly improved capability of interventional cardiology in treatment and prevention of restenosis. Recent experimental studies in animals, clinical studies in humans and multi-center randomized clinical trials with Sirolimus-eluting stents, have demonstrated a significant reduction in vasculoproliferative response with no intimal tissue growth. Moreover, no significant adverse clinical events have been reported at long-term follow-up and first studies that explored the potential of this technology for the treatment of in-stent restenosis demonstrated safety and efficacy. Although the first clinical experiences with drug-eluting stents have produced stunning results, there are a number of theoretical limitations to these devices, including: 1) limitations of drug loading capacity and 2) ability to control drug elution that could result in unfavorable pharmacokinetics. There are also questions about the durability of the polymer coatings (deformation under mechanical stress, gaps between metal and arterial wall, etc). The thickness of some coatings makes them unsuitable for very small vessels. Finally most biodegradable coatings are prone to chronic inflammation. Since only a polymer-coated bare metal stent remains following the drug's release, the potential for long term polymer biocompatibility problems remains a concern. The potential for some drugs to produce radiation-like effects such as "black holes", malapposed and naked struts and wall thinning are potentially the dark side of this technology and may contribute to late thrombosis, aneurysms or delayed restenosis. Long term clinical follow-up is necessary to assess the long term safety of this technology. There is a legitimate question as to whether drug-eluting stents will produce similar results across all patient subsets encountered in "real-life" interventional practice (e.g. long lesions, small diameter vessels, vein grafts, chronic total occlusions, bifurcated and ostial lesions). Cost-benefit issues also need to be addressed, especially because multivessel stenting and multistent usage is likely to increase.