Cefepime pharmacokinetics in adult extracorporeal membrane oxygenation patients.

BACKGROUND: The impact of extracorporeal membrane oxygenation (ECMO) on the pharmacokinetics/dynamics (PK/PD) of beta-lactam antibiotics have not been well studied in general, but cefepime specifically has the least amount of data. We aimed to investigate whether ECMO alters the PK of cefepime in adult intensive care unit (ICU) patients. METHODS: This single-center, retrospective case-control study evaluated cefepime therapeutic drug monitoring (TDM) results from ECMO patients that were matched 1:1 with TDM results in non-ECMO patients for drug regimen and renal function. The primary outcome was the difference in PK/PD of cefepime in ECMO compared with non-ECMO ICU patients. Secondary outcomes included hospital length of stay, treatment failure, superinfection, bacterial resistance, and survival to discharge. RESULTS: Eighty-two patients were included with 44 matched cefepime concentrations in each group. ECMO patients had higher free maximum concentrations (fCmax) (p = 0.003), lower free minimum concentration (fCmin)/1x minimum inhibitory concentration (MIC) ratios (p = 0.040), and lower attainment of free Cmin/4x MIC (p = 0.010). There were no differences between the groups for free Cmin, time above 1xMIC or 4x MIC, and pharmacokinetic parameters (ke, half-life, and Vd). Of those who survived to discharge, hospital length of stay was longer in the ECMO group (p < 0.001). Patients on ECMO were more likely to experience treatment failure (p = 0.036). The incidence of bacterial resistance, superinfection, or survival were similar among the groups. CONCLUSION: These data suggest that more aggressive empiric dosing may be warranted in patients on ECMO. Therapeutic drug monitoring and future prospective studies would provide more evidence to guide decision making regarding dose adjustments.

Advanced airway management and respiratory care in decompensated pulmonary hypertension.

Meticulous risk stratification is essential when considering intubation of a patient with decompensated pulmonary hypertension (dPH). It is paramount to understand both the pathophysiology of dPH (and associated right ventricular failure) and the complications related to a high-risk intubation before attempting the procedure. There are few recommendations in this area and the literature, guiding these recommendations, is limited to expert opinion and very few case reports/case series. This review will discuss the complex pathophysiology of dPH, the complications associated with intubation, the debates surrounding induction agents, and the available options for the intubation procedure, with specific emphasis on the emerging role for awake fiberoptic intubation. All patients should be evaluated for candidacy for veno-arterial extracorporeal membrane oxygen as a bridge to recovery, lung transplantation, or pulmonary endarterectomy prior to intubation. Only an experienced proceduralist who is both comfortable with high-risk intubations and the pathophysiology of dPH should perform these intubations.

Hyperammonemia After Lung Transplantation: Systematic Review and a Mini Case Series.

Background: Hyperammonemia after lung transplantation (HALT) is a rare but serious complication with high mortality. This systematic review delineates possible etiologies of HALT and highlights successful strategies used to manage this fatal complication. Methods: Seven biomedical databases and grey literature sources were searched using keywords relevant to hyperammonemia and lung transplantation for publications between 1995 and 2020. Additionally, we retrospectively analyzed HALT cases managed at our institution between January 2016 and August 2018. Results: The systematic review resulted in 18 studies with 40 individual cases. The mean peak ammonia level was 769 µmol/L at a mean of 14.1 days post-transplant. The mortality due to HALT was 57.5%. In our cohort of 120 lung transplants performed, four cases of HALT were identified. The mean peak ammonia level was 180.5 µmol/L at a mean of 11 days after transplantation. HALT in all four patients was successfully treated using a multimodal approach with an overall mortality of 25%. Conclusion: The incidence of HALT (3.3%) in our institution is comparable to prior reports. Nonetheless, ammonia levels in our cohort were not as high as previously reported and peaked earlier. We attributed these significant differences to early recognition and prompt institution of multimodal treatment approach.

Corrigendum: Hyperammonemia After Lung Transplantation: Systematic Review and a Mini Case Series.

[This corrects the article DOI: 10.3389/ti.2022.10433.].

Utility of the 4Ts score in excluding heparin-induced thrombocytopenia in lung transplant recipients.

Heparin-induced thrombocytopenia (HIT) is a prothrombotic complication following heparin exposure. Data is limited on the incidence of HIT and validity of 4Ts score in the solid organ transplant population. This retrospective observational cohort included patients who underwent lung transplant between August 2015 and June 2018 and had a clinical suspicion of HIT with heparin-PF4 testing. The 4Ts score was correlated with the heparin-PF4 antibody and serotonin release assay (SRA) results, with positive SRA considered confirmed HIT. Of 146 patients evaluated, the overall incidence of HIT was low (2(1%)). Fifty-one patients had heparin-PF4 testing and were included in the cohort; 5 (10%) had positive heparin-PF4 and 1 (2%) had confirmed HIT. The median 4Ts score was 3 (3-4). Thirty (59%), 17 (33%), and 4 (8%) patients had low, intermediate, and high risk, respectively. The intermediate/high risk group compared to the low risk group had a higher use of alternative non-heparin anticoagulation [13 (62%) vs 7 (23%); p = 0.0086)] and a higher incidence of thrombosis [13 (62%) vs 1 (3%); p < 0.0001]. No patient with a low 4Ts score had confirmed HIT, supporting the utility of low 4Ts score to exclude HIT diagnosis in lung transplant recipients.

Dilution Factor of Quantitative Bacterial Cultures Obtained by Bronchoalveolar Lavage in Patients with Ventilator-Associated Bacterial Pneumonia.

Ventilator-associated bacterial pneumonia (VABP) is a difficult therapeutic problem. Considerable controversy exists regarding the optimal chemotherapy for this entity. The recent guidelines of the Infectious Diseases Society of America and the American Thoracic Society recommend a 7-day therapeutic course for VABP based on the balance of no negative impact on all-cause mortality, less resistance emergence, and fewer antibiotic treatment days, counterbalanced with a higher relapse rate for patients whose pathogen is a nonfermenter. The bacterial burden causing an infection has a substantial impact on treatment outcome and resistance selection. We describe the baseline bronchoalveolar lavage (BAL) fluid burden of organisms in suspected VABP patients screened for inclusion in a clinical trial. We measured the urea concentrations in plasma and BAL fluid to provide an index of the dilution of the bacterial and drug concentrations in the lung epithelial lining fluid introduced by the BAL procedure. We were then able to calculate the true bacterial burden as the diluted colony count times the dilution factor. The median dilution factor was 28.7, with the interquartile range (IQR) being 11.9 to 53.2. Median dilution factor-corrected colony counts were 6.18 log10(CFU/ml) [IQR, 5.43 to 6.46 log10(CFU/ml)]. In a subset of patients, repeat BAL on day 5 showed a good stability of the dilution factor. We previously showed that large bacterial burdens reduce or stop bacterial killing by granulocytes. (This study has been registered at ClinicalTrials.gov under registration no. NCT01570192.).

Does Admission to the ICU Prevent African American Disparities in Withdrawal of Life-Sustaining Treatment?

OBJECTIVE: We sought to determine whether black patients admitted to an ICU were less likely than white patients to withdraw life-sustaining treatments. DESIGN: We performed a retrospective cohort study of hospital discharges from October 20, 2015, to October 19, 2016, for inpatients 18 years old or older and recorded those patients, along with their respective races, who had an "Adult Comfort Care" order set placed prior to discharge. A two-sample test for equality of two proportions with continuity correction was performed to compare the proportions between blacks and whites. SETTING: University of Florida Health. PATIENTS: The study cohort included 29,590 inpatient discharges, with 21,212 Caucasians (71.69%), 5,825 African Americans (19.69%), and 2,546 non-Caucasians/non-African Americans (8.62%). INTERVENTIONS: Withdrawal of life-sustaining treatments. MEASUREMENTS AND MAIN RESULTS: Of the total discharges (n = 29,590), 525 (1.77%) had the Adult Comfort Care order set placed. Seventy-eight of 5,825 African American patients (1.34%) had the Adult Comfort Care order set placed, whereas 413 of 21,212 Caucasian patients (1.95%) had this order set placed (p = 0.00251; 95% CI, 0.00248-0.00968). Of the 29,590 patients evaluated, 6,324 patients (21.37%) spent at least one night in an ICU. Of these 6,324 patients, 4,821 (76.24%) were white and 1,056 (16.70%) were black. Three hundred fifty of 6,324 (5.53%) were discharged with an Adult Comfort Care order set. Two hundred seventy-one White patients (5.62%) with one night in an ICU were discharged with an Adult Comfort Care order set, whereas 54 Black patients (5.11%) with one night in an ICU had the order set (p = 0.516). CONCLUSIONS: This study suggests that Black patients may be less likely to withdraw life-supportive measures than whites, but that this disparity may be absent in patients who spend time in the ICU during their hospitalization.

Transitioning from parenteral to inhaled prostacyclin therapy in pulmonary arterial hypertension.

BACKGROUND: Parenteral prostacyclin therapy for PAH has allowed for improvements in functional status, quality of life and mortality. Parenteral therapies however carry an increased risk of line-associated complications. Inhaled prostacyclins are an attractive alternative therapy; however, limited data exists supporting the safety and outcomes after transition. METHODS: We describe a retrospective observational analysis of adults with PAH who were transitioned from a parenteral prostacyclin to inhaled treprostinil at our institution. Endpoints include duration of transition, hospital length of stay, adverse effects during transition, and cardiopulmonary function post transition. RESULTS: Eight patients were included, all of which were on triple therapy. Seven patients receiving intravenous prostacyclin therapy were transitioned in an ICU setting, while one patient was transitioned from subcutaneous treprostinil as an outpatient. The average ICU and hospital length of stay was 4.1 ± 0.7 days. Patient preference was the most common reason for transition (n = 5), followed by line complication (n = 2), and intolerance to parenteral therapy (n = 1). One adverse event was observed while initiating inhaled treprostinil that only required slowing of the transition process. On follow-up (19.6 ± 11.1 months) functional class did not change, and non-parametric test showed no change in 6MWD after transition (p = 0.62). One patient failed inhaled therapy necessitating transition back to intravenous therapy. CONCLUSION: Transitioning patients from parenteral to inhaled prostacyclin therapy can be safely accomplished in specialized centers over a 48-72 h period. Patient preference was overwhelming the most prevalent reason for transition.

Severity of influenza A(H1N1) illness and emergence of D225G variant, 2013-14 influenza season, Florida, USA.

Despite a regional decline in influenza A(H1N1)pdm09 virus infections during 2013-14, cases at a Florida hospital were more severe than those during 2009-10. Examined strains had a hemagglutinin polymorphism associated with enhanced binding to lower respiratory tract receptors. Genetic changes in this virus must be monitored to predict the effect of future pandemic viruses.

Pulmonary hypertension in hereditary hemorrhagic telangiectasia: A clinical review.

Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant hereditary disorder characterized by recurrent spontaneous epistaxis, mucocutaneous telangiectasias, and solid organ arteriovenous malformations (AVMs). Pulmonary hypertension (PH) is an increasingly recognized complication in patients with HHT, most often precipitated by high-output heart failure in the presence of hepatic AVMs as well as pulmonary arterial hypertension in the form of a proliferative vasculopathy. The presence of PH in patients with HHT is associated with significant elevations in rates of morbidity and mortality. Additionally, there is growing recognition of a thromboembolic propensity in this population that increases the risk of chronic thromboembolic PH, posing unique clinical considerations regarding the use of anticoagulation. Patients with HHT are also at risk of PH due to disorders commonly seen in the general population, including left-sided heart and lung disease. The etiology of PH in HHT is multifaceted and complex; the diagnostic approach and treatment strategies must consider the underlying pathophysiology of HHT. This comprehensive review summarizes current knowledge of PH in HHT, detailing the pathogenesis of known etiologies, diagnostic evaluation, and suggested treatment modalities as well as emerging therapies that may be of future interest.

Hypoxia-induced endothelial CX3CL1 triggers lung smooth muscle cell phenotypic switching and proliferative expansion.

Distal arterioles with limited smooth muscles help maintain the high blood flow and low pressure in the lung circulation. Chronic hypoxia induces lung distal vessel muscularization. However, the molecular events that trigger alveolar hypoxia-induced peripheral endothelium modulation of vessel wall smooth muscle cell (SMC) proliferation and filling of nonmuscular areas are unclear. Here, we investigated the role of CX3CL1/CX3CR1 system in endothelial-SMC cross talk in response to hypoxia. Human lung microvascular endothelial cells responded to alveolar oxygen deficiency by overproduction of the chemokine CX3CL1. The CX3CL1 receptor CX3CR1 is expressed by SMCs that are adjacent to the distal endothelium. Hypoxic release of endothelial CX3CL1 induced SMC phenotypic switching from the contractile to the proliferative state. Inhibition of CX3CR1 prevented CX3CL1 stimulation of SMC proliferation and monolayer expansion. Furthermore, CX3CR1 deficiency attenuated spiral muscle expansion, distal vessel muscularization, and pressure elevation in response to hypoxia. Our findings indicate that the capillary endothelium relies on the CX3CL1-CX3CR1 axis to sense alveolar hypoxia and promote peripheral vessel muscularization. These results have clinical significance in the development of novel therapeutics that target mechanisms of distal arterial remodeling associated with pulmonary hypertension induced by oxygen deficiency that is present in people living at high altitudes and patients with obstructive lung diseases.

Value of impedance cardiography in patients studied for pulmonary hypertension.

The aim of this study was to evaluate the accuracy and precision of impedance cardiography as a method for noninvasive hemodynamic evaluation of patients with pulmonary hypertension (PH). We performed a prospective and blinded study of patients who underwent right heart catheterization (RHC) for evaluation of known or presumed PH at the University of Florida from August 2009 to March 2010. The cohort consisted of a total of 39 patients (age = 57 ± 14 years, 87% women) with presumed (23%) or confirmed PH (77%) of different etiologies. Patients underwent RHC and impedance cardiography using the PhysioFlow PF-05. The PhysioFlow PF-05 measures cardiac output (CO) and LV end-diastolic volume (LVEDV), among other parameters. The median pulmonary artery pressure was 36 (IQR 26-56) mmHg. The CO (mean ± SD) by thermodilution (CO-T) and by impedance cardiography (CO-IC) was 5.9 ± 2.2 and 5.6 ± 1.5 L/min, respectively. Bland-Altman analysis of CO-T versus CO-IC revealed a mean of 0.3 L/min (95% LoA: -2.2 to +2.8). In patients with PH, the correlation of CO-T and CO-IC had a mean of 0.4 L/min (95% LoA: 2.9 and -2.2). Pulmonary artery occlusion pressure (PAOP) correlated with LVEDV (R (2) = 0.2, p = 0.005). By ROC analysis, EDV ≥ 200 ml had a sensitivity of 53% and a specificity of 86% for PAOP > 15 mmHg (AUC = 0.78). In patients with PH, impedance cardiography had good accuracy and fair precision for CO determination when compared with thermodilution. Impedance cardiography may provide information about the preload status and has the potential to become a cost-effective and noninvasive method for the follow-up of patients with PH.

Pulmonary hypertension in eosinophilic versus noneosinophilic COPD.

BACKGROUND: The eosinophilic COPD phenotype is associated with greater airway remodelling, exacerbation risk and steroid responsiveness. However, little is known about the prevalence and characteristics of pulmonary hypertension (PH) in this patient population. METHODS: We retrospectively evaluated a cohort of COPD patients with right heart catheterisation (RHC) data at a university hospital between January 2011 and May 2019 and compared the pulmonary vascular profile and prevalence of PH between eosinophilic and noneosinophilic patients using a definition of eosinophilic COPD as at least three blood eosinophil values ≥300 cells·µL-1. We used multivariable logistic regression analyses to examine the association between eosinophilic COPD and various PH categories adjusting for age, sex, body mass index, forced expiratory volume in 1 s (%), smoking status and use of supplemental oxygen. RESULTS: Among 106 COPD patients with RHC data and at least three blood eosinophil values, 25% met the definition of eosinophilic COPD. Fewer patients among the eosinophilic group required long-term oxygen therapy (69% versus 93%, p=0.001) and total lung capacity was significantly lower in the eosinophilic group (p=0.006). This group had higher mean pulmonary arterial pressure (mPAP) (median (interquartile range) 30 (27-41) mmHg versus 25 (22-30) mmHg, p=0.001) and pulmonary vascular resistance (PVR) (4 (2.8-5.1) Wood units versus 2.9 (2.1-4.1) Wood units, p=0.018). On multivariable logistic regression analyses, eosinophilic phenotype was associated with PH (adjusted (a)OR 6.5, 95% CI 1.4-30.7; p=0.018) and pre-capillary PH (aOR 3.2, 95% CI 1.1-9; p=0.027), but not severe PH (aOR 2.1, 95% CI 0.6-7.2; p=0.219). CONCLUSION: Eosinophilic COPD was associated with higher mPAP and PVR and increased likelihood of PH. More studies are needed to further explore this finding.

A multicenter retrospective study of patients with pulmonary hypertension transitioned from inhaled to oral treprostinil.

Oral treprostinil has recently been shown to delay disease progression in patients with pulmonary arterial hypertension in a long-term outcomes study. The potential advantages of an oral formulation have resulted in patients transitioning from inhaled to oral treprostinil. The current study reports a retrospective analysis of patients who transitioned from treatment with inhaled to oral treprostinil. A multicenter retrospective chart review was conducted for 29 patients with pulmonary hypertension that transitioned from inhaled to oral treprostinil. Data were collected from inhaled treprostinil initiation and patients were followed until discontinuation of oral treprostinil or the end of the observation period. Persistence was calculated using Kaplan-Meier estimates. Prior to transition to oral treprostinil, patients had received inhaled treprostinil for a median of 643 (IQR: 322-991) days and 52% of patients were New York Heart Association/World Health Organization Functional Class III. For patients that cross-titrated between formulations, the median time to complete the cross titration was 24 (IQR: 1-57) days. At 16- and 24-weeks post-transition, oral treprostinil persistence was 86 and 76%, respectively. Persistence was 59% at 52 weeks post-transition. Clinical stability for the majority of patients at first follow-up post-transition was suggested based on available New York Heart Association/World Health Organization Functional Classification. Transitions from inhaled to oral treprostinil appeared safe and tolerable in the short-term. Additional prospective studies are needed to fully evaluate the safety and efficacy of transitions from inhaled to oral treprostinil.