Bloodstream Infections in Patients With Pulmonary Arterial Hypertension Treated With Intravenous Prostanoids: Insights From the REVEAL REGISTRY®

doi:10.1016/j.mayocp.2012.05.014

Mayo Clinic Proceedings

Volume 87, Issue 9, September 2012, Pages 825-834

https://doi.org/10.1016/j.mayocp.2012.05.014 Get rights and content

Abstract

Objective

To evaluate the rate of and potential risk factors for bloodstream infections (BSIs) using data from the REVEAL (Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension [PAH] Disease Management) REGISTRY^®, which provides current information about patients with PAH.

Patients and Methods

Patients were enrolled from March 30, 2006, through December 8, 2009, and data on reported BSIs were collected through the third quarter of 2010. Bloodstream infection rates were calculated per 1000 patient-days of risk.

Results

Of 3518 patients enrolled, 1146 patients received intravenous (IV) prostanoid therapy for more than 1 day (no BSI, n=1023; ≥1 BSI, n=123; total BSI episodes, n=166). Bloodstream infections rates were significantly increased in patients receiving IV treprostinil vs IV epoprostenol (0.36 vs 0.12 per 1000 treatment days; P<.001), primarily due to gram-negative organisms (0.20 vs 0.03 per 1000 treatment days; P<.001). Multivariate analysis adjusting for age, causes of PAH, and year of BSI found that treatment with IV treprostinil was associated with a 3.08-fold increase (95% confidence interval, 2.05-4.62; P<.001) in BSIs of any type and a 6.86-fold increase (95% confidence interval, 3.60-13.07; P<.001) in gram-negative BSIs compared with treatment with IV epoprostenol.

Conclusion

Compared with IV epoprostenol therapy, treatment with IV treprostinil is associated with a significantly higher rate of gram-negative BSIs; observed differences in BSI rate did not seem to be due to any other analyzed factors.

Trial Registration

clinicaltrials.gov Identifier: NCT00370214

Section snippets

Study Design

REVEAL is a 55-center, observational, US-based, longitudinal registry designed to provide current information on the demographic characteristics, course, and management of patients with PAH confirmed via RHC.12, 13 Between March 30, 2006, and December 8, 2009, 3518 consecutive patients with PAH meeting enrollment criteria were enrolled in REVEAL. All patients were followed up for at least 5 years from enrollment. The enrollment date was the date of obtaining informed consent, and time of

Enrollment Characteristics

Of the 1146 patients who had 1 or more patient-days at risk and were included in the analysis, 1023 did not have a BSI, and 123 patients had 1 or more BSIs during follow-up (Figure 1). Ninety-four of 123 patients with a BSI (76.4%) had only 1 BSI after enrollment in REVEAL, and 29 of 123 patients (23.6%) had 2 or more BSIs during follow-up. In total, 166 BSI episodes were reported. Coinfections with both gram-negative and gram-positive organisms were reported in 6 patients; these patients were

Discussion

In the present study, the overall BSI rate was 3.08-fold higher in patients with PAH receiving IV treprostinil compared with those receiving IV epoprostenol. The rates of gram-positive and gram-negative BSIs were also higher in patients receiving IV treprostinil when compared with IV epoprostenol (1.84-fold and 6.86-fold, respectively).

The Centers for Disease Control and Prevention conducted a retrospective pooled data analysis from 2003 to 2006 of patients with PAH treated with either IV

Conclusion

Overall BSI rates have decreased from previous reports. However, the present data suggest that the risk of a gram-negative BSI is greater with IV treprostinil therapy than with IV epoprostenol therapy. In addition, the data suggest that initial antibiotic therapy in a patient receiving IV treprostinil suspected of having a BSI should be initiated with a broad-spectrum antibiotic(s) with coverage for both gram-negative and gram-positive organisms, at least until speciation and sensitivities of

Acknowledgments

Manuscript preparation and editing support were provided by Mary Hines, BSc (Hons), Scarlett Geunes-Boyer, PhD, Latoya M. Mitchell, PhD, and Jennifer M. Kulak, PhD, of in Science Communications, Springer Healthcare. SAS programming support was provided by Ginny Lai, MPH, of ICON Late Phase & Outcomes Research.

Ms Kitterman thanks Dr Lynette Brown for her guidance and support of this project.

Participating Investigators: We thank the Principal Investigators and their Study Coordinators for their

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Sepsis and pulmonary arterial hypertension (PAH) may both present in a single patient in the intensive care unit. The impact of PAH on the sepsis process is not well understood. Here we assess the effect of PAH in patients with sepsis from multiple perspectives.
Patients with sepsis with or without PAH underwent propensity score matching according to age, sex and ethnicity. Clinical complications, hemodynamics, and laboratory examinations, including heart injury and inflammation, were compared between the 2 groups. We aimed to model the relationship between the severity of PAH and systemic inflammation levels using linear regression analysis. Factors associated with 28-day and one-year mortality in patients with sepsis with PAH were also analyzed using binary logistic regression.
A total of 285 pairs of patients with sepsis with or without PAH were included in the analysis. There were no significant differences in the C-reactive protein (CRP), white blood cell (WBC), or lactate levels or neutrophil percentage between the 2 groups, and the mean pulmonary arterial pressure and N-terminal pro b-type natriuretic peptide (NTproBNP) level did not correlate with CRP, WBC or lactate. The cardiac injury indexes were significantly higher in the PAH group. Lower mean arterial pressure was found in patients with PAH. Longer ventilation duration was a risk factor for, while obesity was protective against, both short- and long-term mortality in patients with sepsis with PAH.
PAH had little effect on the inflammation profile in sepsis, but it may worsen the sepsis outcome by impairing cardiac function and subsequent hemodynamic stability.
Complications associated with peripherally inserted central catheters and Hickman™ in patients with advanced pulmonary hypertension treated with intravenous prostanoids
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However, its short half-life makes necessary a continuous intravenous infusion through a central venous catheter connected to a perfusion pump. Complications associated with the infusion system are frequent, increasing the morbidity and mortality in this group of patients [5,6]. Choosing the right catheter depends on a wide range of elements, such as the treatment duration and the individual center's experience [7,8].
Epoprostenol requires continuous infusion and may lead to catheter-related complications. Evidence regarding the comparison between peripherally inserted central catheters (PICC) or tunneled central catheters in Pulmonary Hypertension (PH) is scarce. We sought to study the incidence of mechanical and infectious complications associated with PICC and Hickman catheters in patients with PH under epoprostenol treatment.
This is a single-center retrospective study of patients with PH who received continuous treatment with intravenous epoprostenol for at least 24 h between January 2010 and July 2020. Mechanical and infectious complications were analyzed according to the catheter type: PICC and Hickman. The incidence of catheter-related complications was calculated per 1000 exposure-days of risk.
175 catheters were implanted in 109 patients, of which 100 (57.1%) were Hickman and 75 (42.9%) were PICC. After a median follow-up of 334 [130–798] days, there were no differences in the rates of local (0.22 vs 0.21; p = 0.904) or blood-stream infections (0.13 vs 0.21; p = 0.405). Mechanical complications were more frequent in the PICC group (0.98 vs 0.23 p=<0.001), including venous thrombosis (0.16 vs 0.00 p = 0.003) and catheter occlusion (0.66 vs 0.04 p=<0.001). These complications were associated with a greater need for hospitalization (1.48 vs 0.50; p=<0.001), without differences in mortality during follow-up (0.33 vs 0.21; p = 0.288).
In patients with PH treated with intravenous epoprostenol, both Hickman and PICC catheters were associated with high rate of complications. Although there were no differences in the frequency of infectious-related complications, PICC was associated with a higher frequency of catheter occlusion and deep venous thrombosis.
Intravenous prostacyclin-analogue therapy in pulmonary arterial hypertension – A review of the past, present and future
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Therapy with intravenous prostacyclin analogues in patients with pulmonary arterial hypertension (PAH) has been established for decades and is an integral component of the current guidelines for the treatment of pulmonary hypertension.
Initially, these drugs were infused by external pump systems via tunnelled right atrial catheters with the need for cooling and frequent exchange of drug reservoirs. Associated complications included, among others, catheter-related infections.
More recently, fully implantable pump systems have been developed with drug reservoirs that are filled transcutaneously, allowing intervals between refills of several weeks. This technique results in a low rate of infections.
Epoprostenol, iloprost and treprostinil have all been used intravenously in PAH, but titration, dosing and dose escalation in long-term therapy are not standardized.
Intravenous prostacyclin analogues are still under-used, despite available data suggesting that early and broad application of these therapies as part of risk-oriented, guideline-directed combination therapy for patients with PAH may lead to a survival benefit.
This review provides a detailed overview of the drugs, infusion systems and dosing strategies used for intravenous therapy in patients with PAH.
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La evidencia creciente muestra que las complicaciones no asociadas a la esclerosis sistémica (ES) son una causa cada vez más frecuente de hospitalización y mortalidad, dentro de las cuales las infecciones se encuentran entre las primeras cinco causas. Los pacientes con ES presentan un riesgo elevado de infección asociado con las opciones terapéuticas y con la enfermedad misma. Por ejemplo, el compromiso pulmonar se asocia con una mayor frecuencia de infecciones respiratorias, mientras que la presencia de úlceras digitales o calcinosis pueden resultar en infecciones de piel y tejidos blandos, incluso en osteomielitis. Por otro lado, la tendencia creciente hacia la inmunomodulación y la inmunosupresión, como tratamiento de las enfermedades autoinmunes, pondrá a estos pacientes en un mayor riesgo de infecciones, incluidas las infecciones oportunistas. Son necesarios un umbral bajo de sospecha y un alto nivel de alerta entre las especialidades tratantes, particularmente los reumatólogos, para la prevención, el diagnóstico temprano y el manejo de las complicaciones infecciosas. Sin embargo, la información respecto a estrategias de gestión de riesgo en ES, como la vacunación o la profilaxis antibiótica, es escasa. Se realizó una revisión narrativa no sistemática que presenta una actualización sobre las complicaciones infecciosas en pacientes con ES.
Mounting evidence has shown non-systemic sclerosis (SSc) related complications as a rising cause of hospital admission and mortality, out of which infections are among the top-five causes. Patients with SSc are at an increased risk of infection due to several features of the treatment options and the disease itself. For instance, lung involvement is associated with a higher frequency of respiratory infections, whereas the presence of digital ulcers or calcinosis may result in skin and soft tissue infections, and even osteomyelitis. On the other hand, the growing trend towards immunomodulation and immunosuppression in patients with autoimmune diseases will place SSc patients at a higher risk of infectious complications, including opportunistic infections. A low suspicion threshold and an increasing awareness among treating specialists, particularly rheumatologists, are warranted for prevention, early diagnosis and management of infectious complications. Nonetheless, data on risk management strategies in SSc, such as vaccination and antimicrobial prophylaxis, are scarce. A narrative non-systematic review was performed to provide an update of infectious complications in patients with SSc.
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Epoprostenol is supplied as a sterile powder, must be reconstituted in diluent every one or two days by the patient, and loaded into the pump, all while maintaining sterility. Severe adverse effects are associated with the drug delivery system, including thrombosis, infection, pump malfunction, and interruption of the infusion.57,58 Treprostinil is an analogue of epoprostenol with the advantage of a longer half-life of 4.5 hours, allowing subcutaneous or intravenous administration.
Pulmonary arterial hypertension (PAH) is often a progressive and ultimately fatal disease. It is characterized by an elevated mean pulmonary arterial pressure because of disease of the small pulmonary arterioles. PAH leads to a constellation of symptoms, including dyspnea, fatigue, syncope, chest discomfort, and peripheral edema. Disease-targeted therapies for PAH produce symptomatic and functional improvement, but long-term survival remains uncommon without lung transplantation. Palliative care is appropriate to support patients with advanced PAH who typically have a high symptom burden. However, palliative care has historically focused on supporting patients with malignant disease, rather than progressive chronic disease such as PAH. Our aim is to provide palliative care clinicians with a background in the classification, pathophysiology, and modern treatment of PAH. This review describes disease-targeted therapies and their effects on symptoms, physical functioning, and health-related quality of life. We also review the unique physiology of PAH and its implication for palliative interventions. Pharmacological interactions with, and precautions related to commonly used palliative care medications, are discussed.
Long-term safety and outcome of intravenous treprostinil via an implanted pump in pulmonary hypertension
2018, Journal of Heart and Lung Transplantation
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In all comparisons, p < 0.05 was considered statistically significant. Rates of SAEs and complications related to the pump, catheter, pump pocket, and infection were calculated by dividing the number of events by the total number of exposure days and expressed per 1,000 treatment-days.19 In a sub-set of patients with hemodynamic data collected ≤ 3 months before pump implantation, Cox proportional hazards regression models were used to identify predictors of transplant-free survival.
We examined safety and long-term outcomes of intravenous treprostinil administered via the implantable LENUS Pro pump in patients with severe pulmonary hypertension (PH).
Patients with PH undergoing pump implantation between December 2009 and October 2016 in German referral centers were retrospectively analyzed (end of follow-up: May 2017). The primary objective was to determine long-term safety of the implantable pump. Secondary end points were 3-year survival and prognostic relevance of pre-implantation hemodynamics.
We monitored 129 patients (120 with pulmonary arterial hypertension, 1 with PH due to lung diseases, and 8 with inoperable chronic thromboembolic PH) for 260 patient-years (median follow-up, 19 months; interquartile range, 11–34 months). There were 82 complications/peri-procedural events in 60 patients; of these, 57 were serious adverse events (0.60 per 1,000 treatment-days), including 2 periprocedural deaths due to right heart failure. The incidence of complications related to the pump, catheter, infection, and pump pocket per 1,000 treatment-days was 0.074, 0.264, 0.032 (3 local infections; no bloodstream infections), and 0.380, respectively. Three-year overall and transplant-free survival were 66.5% and 55.7%, respectively (39 patients died; 16 underwent lung transplantation). Baseline cardiac index independently predicted transplant-free survival (multivariate hazard ratio, 1.90; 95% confidence interval, 1.11–3.28; p = 0.019; n = 95).
Our data suggest that intravenous treprostinil via the LENUS Pro pump in advanced PH is associated with a very low risk of bloodstream infections, but other serious adverse events may occur. Therefore, this therapy needs standardization and should be offered in specialized PH centers only. Further technical advances of the pump system and prospective studies are needed.

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: Grant Support: This work and the REVEAL REGISTRY® were supported by Actelion Pharmaceutical US, Inc.

: Potential Competing Interests: Ms Kitterman has served on the advisory boards of Actelion, United Therapeutics, and Gilead; has participated in the Simply Speaking PAH program through Rush University; and has received honoraria for speaker's bureau participation from Actelion, Gilead, and United Therapeutics.

: Ms Poms serves as a consultant for clinical research studies and advisory boards for Actelion, Gilead, United Therapeutics, and GlaxoSmithKline; has received honoraria for speaker's bureau participation from Actelion, Gilead, and United Therapeutics; and has received grants from United Therapeutics and GlaxoSmithKline.

: Mr Miller is employed by ICON Late Phase & Outcomes Research, a company that receives support from Actelion and other pharmaceutical companies.

: Ms Lombardi has served on the advisory boards of Actelion, United Therapeutics, and Gilead, and has received honoraria for speaker's bureau participation from Actelion, United Therapeutics, and Gilead.

: Dr Farber serves as a consultant for Actelion, Gilead, Novartis, Bayer, and United Therapeutics; is on the speaker's bureau for Actelion and Gilead; has received a research grant from United Therapeutics; and has received honoraria for his service on the REVEAL Steering Committee, which is supported by Actelion.

: Dr Barst serves as a consultant for and has received honoraria from Actelion, Bayer, Corridor Pharmaceuticals, Eli Lilly & Company, GlaxoSmithKline, Gilead, Ikaria, Merck, Novartis, Pfizer, and VentriPoint; has provided expert testimony on diet pill litigation for the plaintiffs; has received grants from Actelion, Eli Lilly, Gilead, National Heart, Lung, and Blood Institute (National Institutes of Health), Novartis, Pfizer, and United Therapeutics; and has received honoraria for her service on the REVEAL Steering Committee, which is supported by Actelion.

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Original articleBloodstream Infections in Patients With Pulmonary Arterial Hypertension Treated With Intravenous Prostanoids: Insights From the REVEAL REGISTRY®

Abstract

Objective

Patients and Methods

Results

Conclusion

Trial Registration

Section snippets

Study Design

Enrollment Characteristics

Discussion

Conclusion

Acknowledgments

Mayo Clin Proc

J Am Coll Cardiol

J Am Coll Cardiol

Chest

Chest

Mayo Clin Proc

Chest

Circulation

Eur Heart J

Original article
Bloodstream Infections in Patients With Pulmonary Arterial Hypertension Treated With Intravenous Prostanoids: Insights From the REVEAL REGISTRY^®