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Rationale: Although amphetamines are recognized as “likely” agents to cause drug- and toxin-associated pulmonary arterial hypertension (PAH), (meth)amphetamine-associated PAH (Meth-APAH) has not been well described. Objectives: To prospectively characterize the clinical presentation, histopathology, and outcomes of Meth-APAH compared with those of idiopathic PAH (iPAH). Methods: We performed a prospective cohort study of patients with Meth-APAH and iPAH presenting to the Stanford University Pulmonary Hypertension Program between 2003 and 2015. Clinical, pulmonary angiography, histopathology, and outcomes data were compared. We used data from the Healthcare Cost and Utilization Project to estimate the epidemiology of PAH in (meth)amphetamine users hospitalized in California. Measurements and Main Results: The study sample included 90 patients with Meth-APAH and 97 patients with iPAH. Patients with Meth-APAH were less likely to be female, but similar in age, body mass index, and 6-minute-walk distance to patients with iPAH. Patients with Meth-APAH reported more advanced heart failure symptoms, had significantly higher right atrial pressure (12.7 ± 6.8 vs. 9.8 ± 5.1 mm Hg; P = 0.001), and had lower stroke volume index (22.2 ± 7.1 vs. 25.5 ± 8.7 ml/m(2); P = 0.01). Event-free survival in Meth-APAH was 64.2%, 47.2%, and 25% at 2.5, 5, and 10 years, respectively, representing more than double the risk of clinical worsening or death compared with iPAH (hazard ratio, 2.04; 95% confidence interval, 1.28–3.25; P = 0.003) independent of confounders. California data demonstrated a 2.6-fold increase in risk of PAH diagnosis in hospitalized (meth)amphetamine users. Conclusions: Meth-APAH is a severe and progressive form of PAH with poor outcomes. Future studies should focus on mechanisms of disease and potential therapeutic considerations.

Background— Although much is known about the risk factors for poor outcome in patients hospitalized with acute heart failure and left ventricular dysfunction, much less is known about the syndrome of acute heart failure primarily affecting the right ventricle (acute right heart failure). Methods and Results— By using Stanford Hospital's pulmonary hypertension database, we identified consecutive acute right heart failure hospitalizations in patients with PAH. We used longitudinal regression analysis with the generalized estimating equations method to identify factors associated with an increased likelihood of 90-day mortality or urgent transplantation. From June 1999 to September 2009, 119 patients with PAH were hospitalized for acute right heart failure (207 episodes). Death or urgent transplantation occurred in 34 patients by 90 days of admission. Multivariable analysis identified a higher respiratory rate on admission (>20 breaths per minute; OR, 3.4; 95% CI, 1.5–7.8), renal dysfunction on admission (glomerular filtration rate 2 ; OR, 2.7; 95% CI, 1.2–6.3), hyponatremia (serum sodium ≤136 mEq/L; OR, 3.6; 95% CI, 1.7–7.9), and tricuspid regurgitation severity (OR, 2.5 per grade; 95% CI, 1.2–5.5) as independent factors associated with an increased likelihood of death or urgent transplantation. Conclusions— These results highlight the high mortality after hospitalizations for acute right heart failure in patients with PAH. Factors identifiable within hours of hospitalization may help predict the likelihood of death or the need for urgent transplantation in patients with PAH.

Background The assessment of pulmonary vascular resistance (PVR) plays an important role in the diagnosis and management of pulmonary arterial hypertension (PAH). The main objective of this study was to determine whether the noninvasive index of systolic pulmonary arterial pressure (SPAP) to heart rate (HR) times the right ventricular outflow tract time-velocity integral (TVI RVOT ) (SPAP/[HR × TVI RVOT ]) provides clinically useful estimations of PVR in PAH. Methods Doppler echocardiography and right-heart catheterization were performed in 51 consecutive patients with established PAH. The ratio of SPAP/(HR × TVI RVOT ) was then correlated with invasive indexed PVR (PVRI) using regression and Bland-Altman analysis. Using receiver operating characteristic curve analysis, a cutoff value for the Doppler equation was generated to identify patients with PVRI ≥ 15 Wood units (WU)/m 2 . Results The mean pulmonary arterial pressure was 52 ± 15 mm Hg, the mean cardiac index was 2.2 ± 0.6 L/min/m 2 , and the mean PVRI was 20.5 ± 9.6 WU/m 2 . The ratio of SPAP/(HR × TVI RVOT ) correlated very well with invasive PVRI measurements ( r = 0.860; 95% confidence interval, 0.759-0.920). A cutoff value of 0.076 provided well-balanced sensitivity (86%) and specificity (82%) to determine PVRI > 15 WU/m 2 . A cutoff value of 0.057 increased sensitivity to 97% and decreased specificity to 65%. Conclusion The novel index of SPAP/(HR × TVI RVOT ) provides useful estimations of PVRI in patients with PAH.

Purpose Sildenafil can cause transient, mild ERG changes in healthy individuals taking large single doses. Although the drug was originally intended for intermittent use in erectile dysfunction, it has now been approved for chronic use in subjects with pulmonary arterial hypertension (PAH). The purpose of our study is to investigate possible ERG changes in subjects using large doses of sildenafil on a chronic daily basis. Methods We examined five subjects with PAH taking sildenafil daily for 1–4 years. Full-field electroretinogram (ERG), multifocal ERG (mfERG), and color testing were performed. Three of the subjects returned on a later date for challenge off and on the medication. Results On chronic daily sildenafil, color vision testing was normal, and ERG and mfERG amplitudes were normal; however, cone implicit times on drug were modestly lengthened. There were no consistent full-field ERG changes when off the drug, but the mfERG showed a small amplitude increase and implicit time decrease, which returned 1 h after re-dosing. Conclusion There was a modest lengthening of cone implicit time on chronic daily doses of sildenafil and a hint that some of these changes may be reversible in the short term. It does not appear that chronic sildenafil usage at these dosage levels is seriously toxic or threatening to vision.

Randomized clinical trials (RCTs) conducted during the past decade have shown that several therapies produce improvements in surrogate endpoints for patients with pulmonary arterial hypertension (PAH). Whether these therapies also influence clinical outcomes remains uncertain. These changes in the PAH landscape have raised several complex ethical issues regarding the conduct of RCTs in PAH, but to date, these issues have not been fully explored. In this article, we consider patients' potential motives for enrolling in PAH RCTs and identify those that are ethically acceptable. Second, we consider the efficiency of PAH RCTs-the ratio of the value of the information gained from RCTs to the risks and costs of obtaining it-and how this efficiency quotient contributes to a trial's ethics by enabling the fulfillment of patients' motives for participating. Third, we discuss the ethics of PAH RCTs using placebo control subjects versus those using active-treatment control subjects. Finally, we consider the ethical issues surrounding the roles of physician-investigators in PAH RCTs. We conclude with several recommendations, including (1) that investigators seek to ensure that patients enrolling in RCTs do so primarily to fulfill altruistic motives, (2) that research be conducted to determine the long-term risks associated with brief periods of withholding PAH therapies before further placebo-controlled trials without background therapies are conducted in PAH, and (3) that incentives for investigators to enroll more patients in PAH RCTs, such as enrollment-based authorship, be eliminated.

Background Idiopathic pulmonary arterial hypertension (IPAH) is a progressive disorder that usually culminates in right ventricular failure and death without treatment. Objective To assess mortality trends by race and gender for idiopathic pulmonary arterial hypertension in the United States from 1994-1998. Methods The U.S. National Center for Health Statistics data for the years 1994-1998 was reviewed for deaths in which the underlying cause was primary pulmonary hypertension (ICD-9 code 416.0), now known as IPAH. The age, gender, race and state of residence of the deceased were abstracted from the Centers for Disease Control Wonder System ( http://wonder.cdc.gov ). Average annual age-adjusted region-, raceand gender-specific rates were then calculated. Results African-American women demonstrated the highest mortality rates for IPAH across all age groups compared to other racial and gender groups. No geographical differences in mortality rates were noted. An increase in mortality rates with advancing age was observed in all racial and gender groups, with the highest mortality rates for IPAH noted in the elderly. Discussion African Americans with IPAH exhibit a substantially increased mortality compared with Caucasians, particularly African-American women.

Bacterial myocarditis (BM) is an uncommon cause of infectious myocarditis. BM is usually seen in the context of overwhelming sepsis or as part of a specific bacterial syndrome. The definitive diagnosis of bacterial myocarditis requires biopsy or morphologically proven active myocarditis with evidence of bacterial invasion or positive tissue cultures. The management of bacterial myocarditis consists of aggressive and early antibiotic or anti-toxin treatment, appropriate hemodynamic support, and treatment of arrhythmias or mechanical complications. We present a case of acute Listeria monocytogenes myocarditis in an immunocompetent patient and highlight the challenges in the diagnosis and treatment of bacterial myocarditis.

Pulmonary infection with Nocardia is an uncommon but serious infection found in immunocompromised patients. We describe a rapidly progressive pulmonary nocardiosis in a heart transplant patient. We then review the common clinical features of Nocardia infection in transplant recipients, outlining the challenges in its diagnosis and management. We also review the differences between Pneumocystis jiroveci prophylaxis regimens with respect to concomitant prophylaxis of Nocardia and other opportunistic infections.

Surgical and interventional therapies for pulmonary arterial hypertension (PAH) in appropriately selected patients have the potential to dramatically improve or, in some cases, cure PAH. These include atrial septostomy, a palliative procedure or bridge to transplantation in patients with refractory right heart failure, pulmonary thromboendarterectomy for pulmonary hypertension associated with chronic thromboembolic disease, and closure of congenital systemic-pulmonary shunts in patients with PAH but without significant pulmonary vascular disease. Lung transplantation should be considered for patients with all forms of PAH who demonstrate advanced or progressive disease.

Background Over the past 3 decades, the field of lung transplantation has been refined. However, many barriers exist that limit long-term success. The purpose of this study was to review a single institution's long-term experience with single and double lung transplantation and to assess the effect of different immunosuppressive therapies on outcomes. Methods Lung transplant recipients, both single and double, were reviewed, retrospectively. Patients were divided into five groups: group I, all lung transplants ( n = 127); group II, single lung transplants ( n = 73); group III, double lung transplants ( n = 54); group IV, OKT3 induction therapy recipients ( n = 27); and group V, RATG induction therapy recipients ( n = 100). Rates of survival, rejection, bronchiolitis obliterans syndrome (BOS) and infection were analyzed at 1, 3, and 5 years. Results There were no significant differences in survival, acute rejection rate, freedom from BOS, nor infection between single and double lung transplant recipients. Induction therapy with RATG (group V) was associated with significantly improved survival and freedom from acute rejection, BOS, and infection when compared to OKT3 induction therapy (group IV). Conclusions An earlier impression that RATG is superior to OKT3 induction therapy has borne true in terms of overall survival and incidence of BOS, acute rejection and infection rates. Lung transplantation, using RATG induction therapy, remains an important modality for end-stage pulmonary disease.

Study objectives: Patients with pulmonary arterial hypertension (PAH) often present with dyspnea and severe functional limitations, but their health-related quality of life (HRQOL) has not been studied extensively. This study describes HRQOL in a cohort of patients with PAH. Design: Cross-sectional study. Setting: A tertiary care, university hospital-based, pulmonary hypertension (PH) clinic. Participants: We studied HRQOL in 53 patients with PAH (mean age, 47 years; median duration of disease, 559 days). Eighty-three percent were women, 53% received epoprostenol, and 72% reported moderate-to-severe functional limitations with a New York Heart Association class 3 or 4 at enrollment. Measurements and results: We examined HRQOL by administering the Nottingham Health Profile, Congestive Heart Failure Questionnaire, and Hospital Anxiety and Depression Scale. We used the Visual Analog Scale and standard gamble (SG) techniques to measure preferences for current health (utilities). Compared with population norms, participants reported moderate-to-severe impairment in multiple domains of HRQOL, including physical mobility, emotional reaction, pain, energy, sleep, and social isolation. Mean SG utilities were 0.71, suggesting that, on average, participants were willing to accept a 29% risk of death in order to be cured of PH. Conclusions: PAH is a devastating condition that affects predominately young women in the prime of their life. Understanding HRQOL and preferences are important in the care and management of these patients. Compared with population norms, patients with PAH have substantial functional and emotional limitations that adversely affect their HRQOL.

Although idiopathic pulmonary arterial hypertension is perceived as a progressive disease with a uniformly poor outcome, the natural history of disease is heterogeneous, with some patients dying within months of diagnosis and others living for decades. The course of the disease has also been altered by advances in medical therapies. The outcome of patients with other types of pulmonary arterial hypertension (PAH) has been less well characterized. Assessment of prognosis of such patients is important, as it influences both medical therapy and referral for transplantation. This chapter will provide evidence based recommendations to assess the prognosis of patients with PAH.

While considerable advances have been achieved in the medical treatment of pulmonary arterial hypertension (PAH) over the past decade, surgical and interventional approaches continue to have important roles in those patients for whom medical therapy is unavailable or has been unsuccessful. These techniques include pulmonary thromboendarterectomy for chronic thromboembolic pulmonary hypertension, thoracic transplantation, and atrial septostomy. This chapter will provide evidence-based recommendations for the selection and timing of surgical and interventional treatments of PAH for physicians involved in the care of these complex patients.

Background Weight gain is frequently observed after lung transplantation, but the magnitude, predictors and implications of weight gain after lung transplant are unknown. Methods This retrospective cohort study included 826 lung transplant recipients randomly selected from 12 international transplant centers. We included adult patients with available weight data at baseline and 1 year post-transplant. We examined demographic and clinical predictors of first year weight gain using a multiple linear regression model (n = 579) with percent weight change as the dependent variable. To study the association between first year weight gain and subsequent survival, we performed a Cox proportional hazards analysis. p Results The median weight change was 10% (range −32% to 84%). On multi-variate analysis, increasing age and prolonged mechanical ventilation were inversely associated with weight gain; obstructive disease, interstitial disease and increasing ischemic time were positively associated with weight gain. Increasing baseline weight was negatively associated with weight gain in patients with obstructive and interstitial disease. The model accounted for 14% of the variance in weight gain. Patients with weight gain above the median had better subsequent survival (adjusted hazard ratio 0.61, 95% confidence interval 0.41 to 0.90). Infection was a more common cause of death in these patients, whereas malignant deaths were more frequent in patients with below-median weight gain. Conclusions Substantial weight gain occurs in the first year after lung transplantation. The predictors of weight gain may be used to target high-risk patients for early intervention. Higher weight gain is associated with better subsequent survival.

Study objectives An association between thyroid disease and pulmonary arterial hypertension (PAH) has been reported, yet the pathogenetic relationship between these conditions remains unclear. Because immune system dysfunction may underlie this association, we sought to determine the prevalence of autoimmune thyroid disease (AITD) in patients with PAH. Design and setting Prospective observational study at a single academic institution. Patients Sixty-three consecutive adults with PAH (ie, sustained pulmonary artery systolic pressure, > 25 mm Hg) were evaluated for clinical, biochemical, and serologic features of AITD. Measurements Thyroid gland dysfunction was determined by clinical examination for goiter, and by biochemical measurements of thyrotropin and free thyroxine. Immune system dysfunction was determined by serologic measurements of antibodies to thyroglobulin and thyroid peroxidase. First-degree family history of AITD also was ascertained in order to investigate for genetic clustering of autoimmunity. Results Thirty-one patients (49%; 95% confidence interval [CI], 37 to 62%) received diagnoses of AITD. Eighteen patients were newly diagnosed, and 9 patients required the initiation of pharmacologic treatment. There was no chronologic relationship between the diagnosis or treatment of PAH and that of AITD. Sixteen patients (25%; 95% CI, 15 to 36%) had 24 first-degree family members with AITD. Conclusions Approximately half of the patients with PAH have concomitant AITD. These two conditions may be linked by a common immunogenetic susceptibility, and the elucidation of this association may advance the understanding of the pathophysiology and treatment of PAH. Systematic surveillance for occult thyroid dysfunction in patients with PAH may prevent the hemodynamic exacerbation of right heart failure.

Cytomegalovirus (CMV) disease was previously shown to be unaltered by a 28-day course of ganciclovir compared with placebo in seronegative recipients of hearts from seropositive donors (D+/R-). This study tests the hypothesis that a combination of ganciclovir plus CMV hyperimmune globulin (CMVIG) is more effective than ganciclovir alone for preventing acute CMV illness and its long-term sequelae.The study population receiving CMVIG (n=80) included 27 heart transplant recipients (D+/R-) and 53 heart-lung and lung transplant recipients (R+ and/or D+). Each group was matched with historical controls who underwent transplantation within the preceding 2-3 years. Outcome measures compared were as follows: 3-year incidence of CMV disease; fungal infection; acute rejection; survival; rates and severity of transplant coronary artery disease (in heart patients) defined by intimal thickness (ultrasound) and coronary artery stenosis (angiographic); and incidence and death from obliterative bronchiolitis defined by pathological criteria on endobronchial biopsy specimens (in heart-lung/lung patients).Patients treated with CMVIG had a higher disease-free incidence of CMV, lower rejection incidence, and higher survival rate compared with the patients treated with ganciclovir alone. The coronary artery intimal thickness and the prevalence of intimal thickening were lower in the patients receiving CMVIG. Heart-lung and lung transplant patients treated with CMVIG had lower incidences of obliterative bronchiolitis and death from obliterative bronchiolitis and longer survival compared with the patients treated with ganciclovir alone.CMVIG plus ganciclovir seems to be more effective that ganciclovir alone for preventing the sequelae of CMV infection. A prospective randomized study is required to confirm these observations.

Background RAD is a novel macrolide with potent immunosuppressive and antiproliferative activities. This study characterizes the safety, tolerability, and pharmacokinetics of two different single oral doses of RAD in stable lung and heart/lung transplant recipients with and without cystic fibrosis (CF). Methods This was a Phase I, multicenter, randomized, double-blind, two-period, two-sequence, crossover study. Single doses of RAD capsules at doses of 0.035 mg/kg (2.5 mg maximum) or 0.10 mg/kg (7.5 mg maximum) were administered with cyclosporine (Neoral [cyclosporine, USP] modified), steroids, and azathioprine on Day 1. The alternate dose was administered on Day 16. Laboratory assessments, vital signs, and adverse events were recorded throughout the study. RAD pharmacokinetic profiles were assessed over a 7-day period following each dose. Steady-state cyclosporine (CsA) profiles were assessed at baseline and with each RAD dose; RAD and CsA trough concentrations were obtained throughout the study period. Results Of the 20 patients randomized, 8 had CF and 12 did not. Single doses of RAD were safe and well tolerated. Headache was the most common side effect. RAD produced a mild, dose-dependent, reversible decrease in platelet and leukocyte counts. Cholesterol and triglycerides were minimally affected. At both doses, CF patients had significantly lower peak concentrations of RAD than did non-CF patients (p = 0.03); however, overall exposure (area under the curve/dose) was not different between the groups (p = 0.63). At the higher dose, there was a clinically minor under-proportionality in AUC, averaging −11%. Steady-state pharmacokinetics of CsA were not affected by RAD co-administration. Conclusions RAD was safe and well tolerated by stable lung and heart/lung transplant recipients with and without CF. The presence of CF did not influence the extent of RAD exposure. Single doses of RAD did not affect the pharmacokinetics of CsA. Ongoing studies are assessing the long-term safety and efficacy of RAD in lung and heart/lung transplantation.

Background Differentiating between acute rejection and cytomegalovirus (CMV) infection is one of the major challenges of lung transplantation. The aims of this study were to: (1) quantify the transcription of the cytotoxic T lymphocyte (CTL) effector molecules in the bronchoalveolar lavage (BAL) of lung transplant recipients and (2) evaluate the clinical usefulness of this technique. Methods Sixty-six single-lung, double-lung, or heart-lung transplant patients were prospectively enrolled in the study. BAL was performed either for routine surveillance or for acute graft dysfunction. RNA was extracted from BAL cell pellets and underwent competitive reverse transcription-assisted polymerase chain reaction (RT-PCR) for perforin, granzyme B, granulysin, and Fas ligand. Gene transcript analysis was compared to clinical diagnosis established by conventional methods [BAL microbiological and transbronchial biopsy (TBB) analyses]. Results After exclusion of several BAL according to the study criteria, 62 BAL were submitted for data analysis. Significantly higher expression of all the analyzed transcripts was found during CMV infection, compared with each of the other defined diagnostic categories, namely nonsignificant pathology, acute rejection, and nonviral pulmonary infection. Conclusion Quantification by competitive RT-PCR of the CTL effector molecule transcripts (perforin, granzyme B, granulysin, and Fas ligand) could represent a valuable tool for the differential diagnosis of graft dysfunction in lung transplantation.

Anthrax, a disease of great historical interest, is once again making headlines as an agent of biological warfare. Bacillus anthracis, a rod-shaped, spore-forming bacterium, primarily infects herbivores. Humans can acquire anthrax by agricultural or industrial exposure to infected animals or animal products. More recently, the potential for intentional release of anthrax spores in the environment has caused much concern. The common clinical manifestations of anthrax are cutaneous disease, pulmonary disease from inhalation of anthrax spores, and GI disease. The course of inhalational anthrax is dramatic, from the insidious onset of nonspecific influenza-like symptoms to severe dyspnea, hypotension, and hemorrhage within days of exposure. A rapid decline, culminating in septic shock, respiratory distress, and death within 24 h is not uncommon. The high mortality seen in inhalational anthrax is in part due to delays in diagnosis. Classic findings on the chest radiograph include widening of the mediastinum as well as pleural effusions. Pneumonia is less common; key pathologic manifestations include severe hemorrhagic mediastinitis, diffuse hemorrhagic lymphadenitis, and edema. Diagnosis requires a high index of suspicion. Treatment involves supportive care in an intensive care facility and high doses of penicillin. Resistance to third-generation cephalosporins has been noted. Vaccines are currently available and have been shown to be effective against aerosolized exposure in animal studies.

Ticks are capable of transmitting viruses, bacteria, protozoa, and rickettsiae to man. Several of these tick-borne pathogens can lead to pulmonary disease. Characteristic clinical features, such as erythema migrans in Lyme disease, or spotted rash in a spotted fever group disease, may serve as important diagnostic clues. Successful management of tick-borne diseases depends on a high index of suspicion and recognition of their clinical features. Patients at risk for tick bites may be coinfected with two or more tick-borne pathogens. A Lyme vaccine has recently become available for use in the United States. Disease prevention depends on the avoidance of tick bites. When patients present with respiratory symptoms and a history of a recent tick bite or a characteristic skin rash, a differential diagnosis of a tick-borne pulmonary disease should be considered. Early diagnosis and appropriate antibiotic therapy for these disorders lead to greatly improved outcomes.

Introduction In the setting of organ transplantation, prior to prophylaxis, Pneumocystis carinii pneumonia (PCP) had been a common clinical problem, particularly in heart-lung and lung recipients who receive long-term immunosuppressive therapy to prevent allograft rejection. Continuous oral trimethoprim-sulfamethoxazole (TMP-SMX) has been highly effective in preventing PCP in these patients. Report In this paper we report a case of recurrent Pneumocystis carinii infection in a chronic (> 15 years) heart-lung allograft recipient on long-term TMP-SMX prophylaxis. Twice, in 1995 and again in 1998, Pneumocystis carinii infection was diagnosed by bronchoalveolar lavage (BAL), in the same patient, despite continued oral TMP-SMX (960 mg TMP/4800 mg SMX per week) prophylaxis. The subject was not lymphopenic (his CD4 count was 569/mm 3 ) and there was no associated deterioration in pulmonary function, nor evidence of hypoxemia. Conclusion This case demonstrates that asymptomatic Pneumocystis carinii lung infections may recur in chronic heart-lung transplant recipients who take standard oral PCP prophylaxis.

A recent North-American-European Consensus Conference proposed new, uniform criteria for the definition of acute lung injury, in part to facilitate earlier identification of patients for clinical trials. However, these criteria have not been evaluated prospectively. We designed a prospective cohort study of 123 consecutive patients with acute lung injury prospectively identified on admission to the adult intensive care units of a tertiary care university hospital. The objectives were to determine if selection of patients using the new criteria for acute lung injury results in a significant change in the clinical characteristics, risk factors, or predictors of mortality when compared with prior studies of patients with adult respiratory distress syndrome (ARDS); and to determine if a quantitative index of the severity of acute lung injury has prognostic value in identifying nonsurvivors of acute lung injury. We used three methods: (1) prospective identification of patients with acute lung injury using a PaO2/FIO2 ratio < 300 and bilateral infiltrates on chest radiograph in the absence of left heart failure; (2) evaluation of the severity of lung injury using a four-point scoring system; and (3) stepwise logistic regression analysis to identify variables significantly associated with hospital mortality. Overall hospital mortality was 58%. Sepsis was the most common clinical disorder (50/123 or 41%) associated with the development of acute lung injury. Using the new definition for acute lung injury, 66 of the 123 patients were enrolled with a PaO2/FIO2 ratio between 150 and 299; 57 of the 123 patients had a PaO2/FIO2 < 150 at the time of entry into the study.(ABSTRACT TRUNCATED AT 250 WORDS)

Background Though much is known about the prognostic influence of acute kidney injury (AKI) in left-side heart failure, much less is known about AKI in patients with pulmonary arterial hypertension (PAH). Methods and Results We identified consecutive patients with PAH who were hospitalized at Stanford Hospital for acute right-side heart failure. AKI was diagnosed according to the criteria of the Acute Kidney Injury Network. From June 1999 to June 2009, 105 patients with PAH were hospitalized for acute right-side heart failure (184 hospitalizations). AKI occurred in 43 hospitalizations (23%) in 34 patients (32%). The odds of developing AKI were higher among patients with chronic kidney disease (odds ratio [OR] 3.9, 95% confidence interval [CI] 1.8–8.5), high central venous pressure (OR 1.8, 95% CI 1.1–2.4, per 5 mm Hg), and tachycardia on admission (OR 4.3, 95% CI 2.1–8.8). AKI was strongly associated with 30-day mortality after acute right-side heart failure hospitalization (OR 5.3, 95% CI 2.2–13.2). Conclusions AKI is relatively common in patients with PAH and associated with a short-term risk of death.

Although obesity, dyslipidemia and insulin resistance (IR) are well known risk factors for systemic cardiovascular disease, their impact on pulmonary arterial hypertension (PAH) is unknown. The present authors' previous studies indicate that IR may be a risk factor for PAH. The current study has investigated the prevalence of IR in PAH and explored its relationship with disease severity. Clinical data and fasting blood samples were evaluated in 81 nondiabetic PAH females. In total, 967 National Health and Nutrition Examination Surveys (NHANES) females served as controls. The fasting triglyceride to high-density lipoprotein cholesterol ratio was used as a surrogate of insulin sensitivity. While body mass index was similar in NHANES versus PAH females (28.6 versus 28.7 kg.m(-2)), PAH females were more likely to have IR (45.7 versus 21.5%) and less likely to be insulin sensitive (IS; 43.2 versus 57.8%). PAH females mostly (82.7%) had New York Heart Association (NYHA) class II and III symptoms. Aetiology, NYHA class, 6-min walk-distance and haemodynamics did not differ between IR and IS PAH groups. However, the presence of IR and a higher NYHA class was associated with poorer 6-months event-free survival (58 versus 79%). Insulin resistance appears to be more common in pulmonary arterial hypertension females than in the general population, and may be a novel risk factor or disease modifier that might impact on survival.

Advances in our understanding of the basic pathophysiology of pulmonary arterial hypertension (PAH) has led to an expanding number of therapeutic options. The ultimate goals of therapy are to lengthen survival while improving symptoms and quality of life. A wealth of research in other conditions has established health-related quality of life (HRQoL) to be an important clinical endpoint. Until recently, however, little was known about HRQoL in PAH, and how best to measure it. Over the past few years, several studies have begun contributing to this growing area of research. Instruments used to assess HRQoL have varied between studies. The extent to which these instruments are valid in PAH depend on their specific measurement properties. In this article, we provide an overview of the different types of patient-reported outcomes (PROs) used in PAH, focusing in particular on the measurement of HRQoL. In the process, we review the current literature on HRQoL in PAH, summarize the available data from randomized controlled trials, and discuss the implications of these findings on future research. Despite significant progress, the study of HRQoL in PAH remains a nascent field relative to other conditions. As the use of PROs continues to increase, additional work will be needed to begin standardizing the reporting and interpretation of such outcomes in future clinical trials.

Right ventricular (RV) function may be impaired in pulmonary hypertension (PH), congenital heart disease (CHD), and coronary artery disease and in patients with left-sided heart failure (HF) or valvular heart disease. In recent years, many studies have demonstrated the prognostic value of RV function in cardiovascular disease. In the past, however, the importance of RV function has been underestimated. This perception originated from studies on open-pericardium dog models and from the observation that patients may survive without a functional subpulmonary RV (Fontan procedure). In the 1940s, studies using open-pericardium dog models showed that cauterization of the RV lateral wall did not result in a decrease in cardiac output or an increase in systemic venous pressure.1–3 As was later demonstrated, the open-pericardium model did not take into account the complex nature of ventricular interaction. In 1982, Goldstein and colleagues2 showed that RV myocardial infarction (RVMI) in a closed-chest dog model led to significant hemodynamic compromise. These findings were further supported by clinical studies demonstrating an increased risk of death, arrhythmia, and shock in patients with RVMI.4 The study of the RV is a relatively young field. In 2006, the National Heart, Lung, and Blood Institute identified RV physiology as a priority in cardiovascular research.5 The goal of this review is to present a clinical perspective on RV physiology and pathobiology. In the first article of the series, the anatomy, physiology, embryology, and assessment of the RV were discussed. In this second part, we discuss the pathophysiology, clinical importance, and management of RV failure. RV failure is a complex clinical syndrome that can result from any structural or functional cardiovascular disorder that impairs the ability of the RV to fill or to eject blood. The cardinal clinical manifestations of RV failure are (1) fluid retention, which may lead …

Pulmonary hypertension may be encountered in the intensive care unit in patients with critical illnesses such as acute respiratory distress syndrome, left ventricular dysfunction, and pulmonary embolism, as well as after cardiothoracic surgery. Pulmonary hypertension also may be encountered in patients with preexisting pulmonary vascular, lung, liver, or cardiac diseases. The intensive care unit management of patients can prove extremely challenging, particularly when they become hemodynamically unstable. The objective of this review is to discuss the pathogenesis and physiology of pulmonary hypertension and the utility of various diagnostic tools, and to provide recommendations regarding the use of vasopressors and pulmonary vasodilators in intensive care.We undertook a comprehensive review of the literature regarding the management of pulmonary hypertension in the setting of critical illness. We performed a MEDLINE search of articles published from January 1970 to March 2007. Medical subject headings and keywords searched and cross-referenced with each other were: pulmonary hypertension, vasopressor agents, therapeutics, critical illness, intensive care, right ventricular failure, mitral stenosis, prostacyclin, nitric oxide, sildenafil, dopamine, dobutamine, phenylephrine, isoproterenol, and vasopressin. Both human and animal studies related to pulmonary hypertension were reviewed.Pulmonary hypertension presents a particular challenge in critically ill patients, because typical therapies such as volume resuscitation and mechanical ventilation may worsen hemodynamics in patients with pulmonary hypertension and right ventricular failure. Patients with decompensated pulmonary hypertension, including those with pulmonary hypertension associated with cardiothoracic surgery, require therapy for right ventricular failure. Very few human studies have addressed the use of vasopressors and pulmonary vasodilators in these patients, but the use of dobutamine, milrinone, inhaled nitric oxide, and intravenous prostacyclin have the greatest support in the literature. Treatment of pulmonary hypertension resulting from critical illness or chronic lung diseases should address the primary cause of hemodynamic deterioration, and pulmonary vasodilators usually are not necessary.

Pulmonary arterial hypertension (PAH) is a progressive disease of the pulmonary vasculature, characterized by relentless deterioration and death. Patients with PAH are known to be at increased risk for anesthetic complications and surgical morbidity and mortality. However, outcomes in patients have improved with the recent development of new drug therapies. The 3 major drug classes for treatment of PAH are prostanoids, endothelin-receptor antagonists, and phosphodiesterase-5 inhibitors. In this review, the authors provide an overview of each drug class, its mechanism of action, indications, and current supportive literature. Surgical and interventional treatments of PAH, including atrial septostomy, pulmonary thromboendarterectomy, and transplantation, are briefly reviewed, and the rationale, indications, and selection criteria for each are discussed. Although available medical and surgical therapies for PAH have improved patient outcomes, acute decompensated right heart failure (RHF) remains a common and challenging complication of PAH. The authors review this topic and provide an outline of the general pathophysiology of RHF and an approach to its management.

Acanthamoeba species are known to cause 2 well-described entities: (1) granulomatous amoebic encephalitis (GAE), which usually affects immunocompromised hosts, and (2) keratitis, which typically follows trauma associated with contamination of water or contact lenses. Less common manifestations include pneumonitis and a subacute granulomatous dermatitis. We describe a case of granulomatous dermatitis secondary to Acanthamoeba infection in a lung transplant recipient and a successful outcome following treatment with lipid formulation of amphotericin B and voriconazole. We believe this is the second case report describing disseminated Acanthamoeba infection in a lung transplant recipient. We also describe successful outcome with a combination of lipid formulation of amphotericin B and voriconazole, drugs that have not been previously reported to treat Acanthamoeba.

Although idiopathic pulmonary arterial hypertension is perceived as a progressive disease with a uniformly poor outcome, the natural history of disease is heterogeneous, with some patients dying within months of diagnosis and others living for decades. The course of the disease has also been altered by advances in medical therapies. The outcome of patients with other types of pulmonary arterial hypertension (PAH) has been less well characterized. Assessment of prognosis of such patients is important, as it influences both medical therapy and referral for transplantation. This chapter will provide evidence based recommendations to assess the prognosis of patients with PAH.

While considerable advances have been achieved in the medical treatment of pulmonary arterial hypertension (PAH) over the past decade, surgical and interventional approaches continue to have important roles in those patients for whom medical therapy is unavailable or has been unsuccessful. These techniques include pulmonary thromboendarterectomy for chronic thromboembolic pulmonary hypertension, thoracic transplantation, and atrial septostomy. This chapter will provide evidence-based recommendations for the selection and timing of surgical and interventional treatments of PAH for physicians involved in the care of these complex patients.

Increased microvascular permeability and extravasation of inflammatory cells are key events of lung ischemia-reperfusion (IR) injury. The purpose of this study was to investigate the role of matrix metalloproteinases (MMP) in IR-induced alveolar capillary membrane disruption after experimental lung transplantation. We used a rat model of lung orthotopic transplantation (n = 86) with a prolonged cold ischemic phase. MMP2 and MMP9 were elevated 4 h after the onset of ischemia and further increased during reperfusion. Compared to sham values, the alveolar-capillary membrane permeability increased by 105% and 82.6% after 4 h of ischemia and 2 h or 24 h of reperfusion, respectively. A 4- and 5-fold increase of the infiltration of ischemic tissue by neutrophils was also observed after 2 h and 24 h of reperfusion. The PO2/FIO2 ratio dropped significantly from 244 to 76.6 after 2 h of reperfusion and from 296.4 to 127.6 after 24 h of reperfusion. A nonselective inhibitor of MMP, administered to the rats and added to the preservation solution, reduced significantly the alveolar-capillary leakage, the transmigration of neutrophils and improved gas exchanges in animals submitted to 4 h of ischemia combined with 2 h or 24 h of reperfusion. We conclude that inhibition of MMP attenuates IR injury after experimental lung transplantation.

The current treatment of obliterative bronchiolitis in lung transplant recipients is sub-optimal. Triptolide is a novel immunosuppressant that has a mechanism of action distinct from currently available immunosuppressants, including induction of T-cell apoptosis, blockade of fibroblast proliferation/maturation and inhibition of transforming growth factor-beta (TGF-beta) mRNA production. We hypothesized that triptolide may be helpful in blocking obliterative airway disease in lung transplant recipients. We investigated the effect of PG490-88, a water-soluble derivative of triptolide, in a mouse heterotopic tracheal allograft model of obliterative airway disease. We show that PG490-88 attenuates airway obliteration in this model and inhibits accumulation of inflammatory cells, and therefore may have preventive or therapeutic benefits for patients with obliterative airway disease (OAD) following lung transplantation.

Background. Recent animal data suggest that inducible nitric oxide synthase (iNOS) mRNA expression in the bronchoalveolar lavage (BAL) may be useful for the diagnosis of lung rejection. The aim of this study was to evaluate iNOS mRNA transcription in the BAL fluid of human lung allografts. Methods, iNOS mRNA transcription was quantified by competitive reverse transcription-polymerase chain reaction in 51 BAL cell pellets of lung transplant patients. According to bacteriological and histological results, BAL samples were divided into three groups: normal (n=21), acute rejection (AR, n=15), and infection (INF, n=15). Results. Compared with the control group, iNOS transcription increased significantly with INF (P=0.0005) but only slightly with AR (P>0.05). INF values were significantly higher than AR values (P=0.0029). Conclusion. BAL iNOS mRNA transcript determination by competitive reverse transcription-polymerase chain reaction may be useful in differentiating infected from normal and/or acutely rejecting allografts.

Antigen presentation by lung macrophages/dendritic cells (DC) is thought to be important in obliterative bronchiolitis/bronchiolitis obliterans syndrome (OB/BOS), which severely limits survival post-lung transplantation. However, a recent study found minimal numbers of DC in lung allografts. We looked at numbers and phenotype of macrophages/DC in lung allografts using endobronchial biopsy (EBB) and transbronchial biopsy (TBB) from 22 lung transplant patients. Biopsies were stained with monoclonal markers of DC (CD1a, RFD1, and major histocompatibility complex [MHC] Class II), and "suppressor macrophages" (RFD1 and RFD7). Dendritic cells were also stained for the costimulatory molecules CD80 and CD86. Significantly greater numbers of DC/high-power field (HPF) were seen in biopsies when we defined DC using dendritic morphology and Class II MHC expression instead of CD1a expression. Dendritic cell numbers were significantly higher in eight patients with OB/BOS compared with 14 stable patients. Fifty percent of DC expressed CD86 and 20% expressed CD80. There was no difference in CD80 or CD86 expression between OB/BOS patients and stable patients. There was no correlation between DC numbers and presence or absence of acute rejection (AR), and/or cytomegalovirus (CMV) pneumonitis on current or prior biopsies. There were significantly more MHC Class II DC in EBB compared with TBB. We found minimal staining for lung macrophages capable of suppressing T-cell inflammation. We conclude that studies of lung allografts may underestimate DC numbers if relying on CD1a as the sole marker of DC. DC are increased in patients with OB/BOS compared with stable patients. EBB may be more important than TBB in looking for inflammatory changes of OB. DC expressing costimulatory molecules are present in lung allografts, and costimulatory pathway blockade may be useful in human lung allografts. Also, the absence of "suppressor" macrophages may increase susceptibility of human lung allografts to the rejection process.

Preoperative pulmonary evaluation and preparation involve first identifying patients at risk for complications and then attempting to modify that risk. For most patients without underlying lung disease, a thorough history and physical examination and preoperative instruction in the use of incentive spirometry is sufficient. In patients with known or suspected lung disease, preoperative pulmonary function tests, while unproven as prognostic tools, may reduce risk by aiding in medical management, and in the case of the lung resection candidate, by helping determine very directly his or her viability for the procedure.

Lyme disease is a tick-borne spirochaete infection which, in a proportion of patients, can lead to neuropathy. This article describes a case of diaphragmatic paralysis due to Lyme disease. A 39-yr-old male presented to the hospital because of an acute left facial palsy. Six weeks prior to admission he had developed a circular rash on his left flank during a camping holiday. He also complained of shortness of breath and arthralgia for 1 week. His chest radiograph demonstrated a raised right hemi-diaphragm. Diaphragmatic paralysis was confirmed by fluoroscopy (a positive sniff test). Serology revealed evidence of recent infection by Borrelia burgdorferi. On the basis of the patient's clinical presentation, a recent history of erythema migrans, and positive Lyme serology, a diagnosis of neuroborreliosis was made. He received oral doxycycline therapy (200 mg x day(-1)) for three weeks. Facial and diaphragmatic palsies resolved within eight weeks. On the basis of this case, a diagnosis of Lyme disease should be considered in patients from endemic regions with otherwise unexplained phrenic nerve palsy.

Tropical pulmonary eosinophilia (TPE) usually affects people living in the tropics, especially those in Southeast Asia, India, and certain parts of China and Africa. However, owing to the rising frequency of world-wide travel and the migration between continents, this disease is increasingly seen in the West, where the diagnosis can be easily missed since it is rarely encountered and can mimic many other conditions. Cases of TPE have typically been reported to masquerade as acute or refractory bronchial asthma. TPE results from a hypersensitivity reaction to lymphatic filarial parasites found in endemic regions. There is evidence that it is more likely to occur in nonimmune individuals, ie, visitors to endemic regions, than in individuals of endemic populations who have developed immunity to filarial infections. Clinical features include paroxysmal cough, wheezing and dyspnea, and systemic manifestations such as fever and weight loss. A history of residence in a filarial endemic region and a finding of peripheral eosinophilia >3,000/mm3 should initiate a consideration of this disease. Other criteria for the diagnosis of TPE include absence of microfilariae in the blood, high titers of antifilarial antibodies, raised serum total IgE >1,000 U/mL, and a favorable response to the antifilarial, diethylcarbamazine, which is the recommended treatment. This disease, if left untreated or treated late, may lead to long-term sequelae of pulmonary fibrosis or chronic bronchitis with chronic respiratory failure. Herein lies the importance of early diagnosis and treatment of TPE.

Study objective To assess the potential utility of specific airway conductance (sGaw) in detecting small airways dysfunction, the postlung-transplant bronchiolitis obliterans syndrome (BOS) was used as a model of small airways dysfunction. BOS is defined as an otherwise unexplained 20% reduction in FEV 1 . We hypothesized that if sGaw is sensitive to small airways dysfunction, it should decrease before the decline in FEV 1 Design/methods The pulmonary function test and sGaw measurements of patients who underwent heart-lung or bilateral lung transplantation between May 1981 and January 1993 were reviewed. Patients with and without BOS were identified. A significant decrease in sGaw was defined as a 20% fall from baseline. Results Twenty-six BOS and 15 non-BOS patients had at least three sGaw measurements such that trends could be examined. Eleven of the 26 BOS patients (42%) had a significant decrease in sGaw before a 20% decrease in FEV 1 , as compared to 2 of the 15 non-BOS patients (13%) (p=0.08). In comparison, 12 of the 26 BOS patients (46%) and 4 of the 15 non-BOS patients (27%) had a significant decrease in forced expiratory flow at 25 to 75% of the forced lung volume (FEF25-75) (p=0.32), an accepted test of small airways dysfunction. Conclusion sGaw tended to decrease before FEV 1 in BOS. The trend in sGaw was similar to the trend in FEF25-75. We conclude that (1) small airways may contribute more to airway conductance than previously thought, and (2) further prospective studies are warranted to better define the relative contribution of small and large airways to sGaw.