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Insulin-Like Growth Factor 1 (IGF-1) is a neurotrophic polypeptide with crucial roles to play in Central Nervous System (CNS) growth, development and maturation. Following interrogation of the neurobiology underlying several neurodevelopmental disorders and Autism Spectrum Disorders (ASD), both recombinant IGF-1 (mecasermin) and related derivatives, such as (1-3) IGF-1, have emerged as potential therapeutic approaches. Clinical pilot studies and early reports have supported the safety/preliminary efficacy of IGF-1 and related compounds in the treatment of Rett Syndrome, with evidence mounting for its use in Phelan McDermid Syndrome and Fragile X Syndrome. In broader ASD, clinical trials are ongoing. Here, we review the role of IGF-1 in the molecular etiologies of these conditions in addition to the accumulating evidence from early clinical studies highlighting the possibility of IGF-1 and related compounds as potential treatments for these childhood-onset neurodevelopmental disorders.
Atrial arrhythmias are common during episodes of acute respiratory failure in patients with chronic lung disease‐associated pulmonary hypertension. Expert opinion suggests that management of atrial arrhythmias in patients with pulmonary hypertension should aim to restore sinus rhythm. This is clinically challenging in pulmonary hypertension patients with coexisting chronic lung disease, as there is controversy on the use of rhythm control agents; generally, in regard to either their pulmonary toxicity profile or the lack of evidence supporting their use. Rate control methods are largely focused on the use of beta blockers and calcium channel blockers. Concerns regarding their use involve their negative inotropic properties in cor pulmonale, the risk of bronchospasm associated with beta blockers, and the potential for ventilation/perfusion mismatching associated with calcium channel blockers. While digoxin has been associated with promising outcomes during acute right ventricular failure, there is limited evidence to suggest its routine use. Electrical cardioversion is associated with a high failure rate and it frequently requires multiple attempts. Radiofrequency catheter ablation is a more definitive approach, but concerns surrounding mechanical ventilation and sedation limit its applicability in decompensated pulmonary hypertension. Individual approaches are needed to address atrial arrhythmia management during acute episodes of respiratory failure.
Pulmonary hypertension (PH), defined by a mean pulmonary artery pressure of >20 mm Hg, often presents with non-specific symptoms such as dyspnea and exercise intolerance, making it difficult to diagnose early before the onset of right heart dysfunction. Therefore, exercise testing can be of great utility for clinicians who are evaluating patients with an unclear etiology of exercise intolerance by helping identify the underlying mechanisms of their disease. The presence of PH is associated with adverse clinical outcomes, with distinct differences and patterns in the cardiovascular and ventilatory responses to exercise across various PH phenotypes. We discuss the role of exercise-invasive hemodynamic testing, cardiopulmonary exercise testing, and exercise stress echocardiography modalities across the spectrum of PH.
BACKGROUND: Pulmonary hypertension (PH) is a systemic illness with increasingly subtle disease manifestations including sleep disruption. Patients with PH are at increased risk for disturbances in circadian biology, although to date there is no data on "morningness" or "eveningness" in pulmonary vascular disease. RESEARCH QUESTIONS: Our group studied circadian rhythms in PH patients based upon chronotype analysis, to explore whether there is a link between circadian parameters and physiologic risk-stratifying factors to inform novel treatment strategies in patients with PH? STUDY DESIGN AND METHODS: We serially recruited participants from July 2022 to March 2024, administering in clinic the Munich Chronotype Questionnaire (MCTQ). We then compared free-day sleep measurements in PH and bed-partner controls (BPCs), investigating associations with survival predictors. In exploratory analysis we looked for associations between known single nucleotide polymorphism (SNP) variants of core clock genes and cardiopulmonary hemodynamics. Finally, we performed circadian analysis of time-stamped heart rate (HR) variation from a PH cohort compared to controls. RESULTS: In this pilot study, we recruited 103 patients with PH and 38 bed-partner controls (BPCs) aged 20 to 86 years. Compared to BPCs patients with PH had longer sleep duration and less social jet lag (SJL), with no clear difference in chronotype. Within the PH cohort, sleep duration was associated with worse functional class, while SJL was associated with a low risk for disease progression, and more severe signs of right ventricular dysfunction. However, a later chronotype was associated with a decrease in mean pulmonary artery pressure (mPAP). In an independent cohort of PH patients there was a relationship between functionally distinct core clock gene SNP variants and relevant hemodynamic parameters. PH patients exhibited a distinct delayed phase shift in circadian HR variation. INTERPRETATION: PH in adults is associated with significant changes in sleep duration and SJL, corroborated by both genomic and physiologic data. Dependence between circadian variables, SNP data and disease characteristics suggests that findings may directly relate to disease pathogenesis via derangement in the molecular core clock.
Microvascular dysfunction progressing to pulmonary hypertension can be a primary cause of right ventricular failure or a secondary cause because of an underlying systemic illness. Little is known regarding the etiology and epidemiology of coronary microvascular dysfunction in pulmonary hypertension. Despite this limitation, its presence has been described in patients with pulmonary hypertension. This review focuses on the pathogenesis of cardiac and pulmonary microvascular dysfunction in pulmonary hypertension. Additionally, this review provides a contemporary assessment on the diagnosis and treatment of microvascular dysfunction in patients in pulmonary hypertension. This topic is important to raise awareness of microvascular dysfunction in the coronary and pulmonary circulation, so that future studies will investigate its impact on the pulmonary hypertension patient cohort.
Air emboli are rare and often difficult to diagnose. Transesophageal echocardiography remains the most definitive method of diagnosis, but this is not feasible in emergencies. We present a case of fatal air embolism in the setting of hemodialysis with recent evidence of pulmonary hypertension. The diagnosis was made by visualizing air in the right ventricle using bedside point of care ultrasound (POCUS). While POCUS is not routinely used for the diagnosis of air embolism, its accessibility makes it a powerful yet practical emerging tool for the diagnosis of respiratory and cardiovascular emergencies.
Belatacept is a novel T-cell costimulation blockade agent that has unresolved controversy in lung transplant recipients. Belatacept has been recognized as a calcineurin sparing agent for solid organ transplant recipients after reported success in renal transplant patients, despite limited evidence in other transplant recipients. We present the first case of a lung transplant recipient receiving Belatacept, in combination with low dose calcineurin inhibitor, who developed progressive multifocal leukoencephalopathy. While Belatacept without calcineurin inhibitor has been associated with increased risk of acute rejection in solid organ transplant recipients, its infectious risk profile in combination with calcineurin inhibitor remains unclear.
Interstitial Lung Disease [ILD] patients requiring Invasive Mechanical Ventilation [IMV] for Acute Respiratory Failure [ARF] are known to have a poor prognosis. Few studies have investigated determinants of outcomes and the utility of trialing Non-Invasive Positive Pressure Ventilation [NIPPV] prior to IMV to see if there are any effect[s] on mortality or morbidity.A retrospective study was designed using patients at four different intensive care units within one health care system. The primary objective was to determine if there are differences in outcomes for in-hospital and one-year mortality between patients who undergo NIPPV prior to IMV and those who receive only IMV. A secondary objective was to identify potential determinants of outcomes.Out of 54 ILD patients with ARF treated with IMV, 20 (37.0%) survived until hospital discharge and 10 (18.5%) were alive at one-year. There was no significant mortality difference between patients trialed on NIPPV prior to IMV and those receiving only IMV. Several key determinants of outcomes were identified with higher mortality, including higher ventilatory support, idiopathic pulmonary fibrosis (IPF) subtype, high dose steroids, use of vasopressors, supraventricular tachycardias (SVTs), and higher body mass index.Considering that patients trialed on NIPPV prior to IMV were associated with no mortality disadvantage to patients treated with only IMV, trialing patients on NIPPV may identify responders and avoid complications associated with IMV. Increased ventilator support, need of vasopressors, SVTs, and high dose steroids reflect higher mortality and palliative care involvement should be considered as early as possible if a lung transplant is not an option.
Acute respiratory distress syndrome has not been a described complication of hypothermia. Causes of hypothermia are commonly associated with alcohol abuse and infection, both of which could lead to acute respiratory distress syndrome. We present a case of severe hypothermia complicated by acute respiratory distress syndrome in a young immunocompetent male treated successfully with mechanical intubation and venovenous extracorpeal membrane oxygenation. Risk factors for known causes of acute respiratory distress syndrome included a witnessed aspiration event and RSV pneumonia. On review of the literature, severe hypothermia has been found to cause pulmonary edema in post-mortem studies, but acute respiratory distress syndrome has not yet been recognized as a known complication. Our case highlights that acute respiratory distress syndrome may be multifactorial in etiology and related to complications of severe hypothermia.
Proteus syndrome is a rare progressive multisystem disorder characterized by asymmetric, disproportionate overgrowth of bone, skin, and other tissue types. Molecular pathogenesis has been identified as somatic activating mutations of the AKT1 gene. The presentation of Proteus syndrome is exceptionally variable. Respiratory complications include emphysematous lung disease and predisposition to pulmonary emboli, the latter of which is a significant source of mortality. Pulmonary hypertension due to longstanding hypoxic lung disease as well as chronic thromboembolic events has been observed in this population. In contrast, precapillary pulmonary arterial hypertension in the absence of chronic pulmonary emboli and parenchymal lung disease has not been described in the literature on patients with Proteus syndrome. We report such a case in a young patient with Proteus syndrome, reviewing subsequent management and emphasizing the need for a detailed investigation of dyspnea.
Takayasu’s arteritis is a rare large vessel vasculitis which can involve the pulmonary arteries and progress to pulmonary artery (PA) stenosis with pulmonary hypertension. We present a case of Takayasu arteritis complicated by bilateral pulmonary stenosis and pulmonary hypertension that resolved after PA stenting and angioplasty. This case demonstrates the efficacy of endovascular intervention and sustained safety during 10 years of follow-up.
Abstract Background Interstitial lung disease (ILD) patients requiring invasive mechanical ventilation (IMV) for acute respiratory failure (ARF) are known to have a poor prognosis. Few studies have investigated determinants of outcomes and the utility of trialing non-invasive positive pressure ventilation (NIPPV) prior to IMV to see if there are any effect(s) on mortality or morbidity. Methods We designed a retrospective study using patients at four different intensive care units within one health care system. Our primary objective was to determine if there are differences in outcomes for in-hospital and one-year mortality between patients who undergo NIPPV prior to IMV and those who receive only IMV. A secondary objective was to identify potential determinants of outcomes. Results Of 54 ILD patients with ARF treated with IMV, 20 (37.0%) survived to hospital discharge and 10 (18.5%) were alive at one-year. There was no significant mortality difference between patients trialed on NIPPV prior to IMV and those receiving only IMV. Several key determinants of outcomes were identified with higher mortality, including: higher ventilatory support, idiopathic pulmonary fibrosis (IPF) subtype, high dose steroids, use of vasopressors, supraventricular tachycardias (SVTs), and higher body mass index. Conclusions Considering that patients trialed on NIPPV prior to IMV was associated with no mortality disadvantage to patients treated with only IMV, trialing patients on NIPPV may identify responders and avoid complications associated with IMV. Increased ventilator support, need of vasopressors, SVTs, and high dose steroids reflect higher mortality and palliative care involvement should be considered as early as possible if lung transplant is not an option.
Abstract Background Interstitial lung disease (ILD) patients requiring invasive mechanical ventilation (IMV) for acute respiratory failure (ARF) are known to have a poor prognosis. Few studies have investigated determinants of outcomes and the utility of trialing non-invasive positive pressure ventilation (NIPPV) prior to IMV to see if there are any effect(s) on mortality or morbidity.Methods We designed a retrospective study using patients at four different intensive care units within one health care system. Our primary objective was to determine if there are differences in outcomes for in-hospital and one-year mortality between patients who undergo NIPPV prior to IMV and those who receive only IMV. A secondary objective was to identify potential determinants of outcomes.Results Of 54 ILD patients with ARF treated with IMV, 20 (37.0%) survived to hospital discharge and 10 (18.5%) were alive at one-year. There was no significant mortality difference between patients trialed on NIPPV prior to IMV and those receiving only IMV. Several key determinants of outcomes were identified with higher mortality, including: higher ventilatory support, idiopathic pulmonary fibrosis (IPF) subtype, high dose steroids, use of vasopressors, supraventricular tachycardias (SVTs), and higher body mass index.Conclusions Considering that patients trialed on NIPPV prior to IMV was associated with no mortality disadvantage to patients treated with only IMV, trialing patients on NIPPV may identify responders and avoid complications associated with IMV. Increased ventilator support, need of vasopressors, SVTs, and high dose steroids reflect higher mortality and palliative care involvement should be considered as early as possible if lung transplant is not an option.
Introduction: Acute respiratory distress syndrome (ARDS) management in the intensive care unit (ICU) has attracted strong interest since the start of the COVID-19 pandemic. Our retrospective study aims to describe the outcomes and predictors of mortality of ARDS associated with COVID-19 within one university-based healthcare system. Methods: We identified 165 patients within our healthcare system during the months of April 2020 through July 2020, who were admitted to our medical ICUs and eligible for our study. Baseline patient characteristics, ICU and hospital course information, ICU interventions, ventilator settings, and hospital complications were collected and analyzed using descriptive statistical techniques. Results: Our cohort had an average age of 64. No significant difference in mortality was identified with male vs. female gender or BMI. Most of the patient cohort was identified as black (68.2%). The overall mortality of our cohort was 38.2%. Hyperlipidemia, coronary artery disease, and chronic obstructive pulmonary disease were all associated with higher mortality. There was a significant difference in mortality between those with higher observed ventilator plateau pressures at 24 hours and higher driving pressures at 24 hours. Conclusion: COVID-19-associated ARDS is associated with significant mortality. Physicians should be aware of pre-existing conditions potentially related to worse outcomes so that they receive an appropriate level of care in a timely manner. Ventilator management should focus on maintaining low intra-thoracic pressure changes. Prospective studies are needed to guide COVID-19-associated ARDS management.
Introduction: Acute respiratory distress syndrome (ARDS) management in the intensive care unit (ICU) has been debated since the start of the Covid-19 pandemic. Our study aims to describe the outcomes and predictors of mortality of ARDS associated with Covid-19 within one university-based healthcare system. Methods: This was a retrospective study performed within one university-based healthcare system. An electronic medical record was used to identify 166 patients admitted to the ICU for ARDS in the setting of SARS-CoV-2 infection at three different hospitals. Baseline patient characteristics, ICU and hospital course information, ICU interventions, ventilator settings, and hospital complications were collected and analyzed using descriptive statistical techniques. Results: The 166 patients meeting inclusion criteria had an average age of 64.1 (± 14.8). No significant difference in mortality was identified with male vs. female gender (57.9% vs. 42.1%, p=0.852) or BMI (8.4 ± 0.9 vs. 12.1 ± 1.5, p=0.727). The majority of the patient cohort was identified as black (68.2%). The overall mortality of our cohort was 38.2%. Hyperlipidemia (p=0.011), coronary artery disease (0.034), and chronic obstructive pulmonary disease (p=0.006) were all associated with higher mortality. Prone positioning was utilized in 42.8% of all patients, and ECMO in 6.0%. There was a significant difference of mortality between those with higher observed ventilator plateau pressures at 24 hours (25.7 vs. 23.1, p=0.010) and driving pressures at 24 hours (13.4 vs. 11.7, p=0.036). Conclusion: Covid-19 associated ARDS is associated with significant mortality. Physicians should be aware of pre-existing conditions that are potentially associated with worse outcomes so that they receive appropriate level of care in a timely manner. Lower plateau and driving pressures were associated with improved outcomes. Prospective studies are needed to guide Covid-19 associated ARDS management.
