[ ISSN : 2573-3680 ]
Pulmonary Hypertension; Congenital Heart Disease; Sildenafil
Pulmonary hypertension in children has many diverse etiologies. Although current treatment strategies lead to symptomatic improvement, the final outcome remains dismal. It is likely that increasingly sensitive screening biomarkers will allow for early clinical detection. Likewise, a greater understanding in molecular and biochemical mediating processes may lead to pathway specific therapeutic approaches. Hopefully, a breakthrough in treatment may not be too distant in the future.
Over the past two decades, Pulmonary Hypertension (PH) has evolved to become a subspecialty of its own. At the latest working group consensus in Dana point (2008), Panama (2011) and Nice (2013), its clinical classification had been further refined [1-3]. These classifications have grouped together etiologies with similar underlying pathology, hemodynamic and therapeutic approaches. For pediatric practice, the Panama classification is probably more applicable albeit more exhaustive in nature [Table 1]. These classifications may need further modifications when we are able to fully elucidate all the mechanisms involved in the various types of PH in children.
Incidence
The incidence of pediatric PH is still ill defined. Incidence of Idiopathic Pulmonary Arterial Hypertension (iPAH) in children is approximately 0.7 cases per million while there were 2.2 cases per million for Pulmonary Arterial Hypertension (PAH) with congenital heart disease [4].
Definitions
PH is defined as mean pulmonary artery pressure ≥25mmHg. Pulmonary Arterial Hypertension (PAH) is pre-capillary PH with end expiratory Pulmonary Artery Wedge Pressure (PAWP) ≥ 15mmHg and Pulmonary Vascular Resistance (PVR) >3 Wood units. IPAH is a diagnosis of exclusion where there is no known cause detected. Pulmonary hypertension secondary to left heart disease has PAWP of >15mmHg. The Panama classification has also included pulmonary hypertension in single ventricle which is define as PVR Index (PVRI) >3.0 WU m2 or a TransPulmonary Gradient (TPG) >6mmHg even when the pulmonary artery pressure is <25mmHg [3]. Occasionally complex congenital heart disease has a combination of etiologies leading to both a raised TPG and PAWP. PAWP may seem normal in left heart disease until a fluid challenge is provided to unmask the high left ventricular end diastolic pressure [5].
The major causes of pediatric PAH are those in association with newborn maladaptation of circulatory transition, associated with congenital heart disease, or are idiopathic in nature.
Pulmonary hypertension of the newborn
PH in the neonatal age group differs significantly from other groups in its presentation. The timing of presentation reflects the importance of the culpable chromosome; genetic influence; fetal growth; lung vasculature development or cardiopulmonary physiology adaptation during the perinatal transition period. Normal pulmonary pressure decreases after birth and continues to drop over the next 2 to 6 weeks. This may fail to occur in the presence of infection, meconium aspiration and perinatal asphyxia resulting in persistent pulmonary hypertension [6]. Under these conditions, pulmonary pressure remains high and, with patent ductus arteriosus, presents with significant differential oxygen saturations. Despite arduous treatment, most cases yield good clinical results. However it is likely that those with an underlying structural lung abnormality may persist with abnormal lung function and pulmonary pressure [7].
Table 1: Categories of Pediatric Pulmonary Hypertensive Vascular Disease from the Panama consensus.
Idiopathic pulmonary hypertension
Idiopathic pulmonary arterial hypertension has no known etiology. This is a poor prognostic group. Some may have incidental small left to right shunts which do not account for the degree of pulmonary hypertension. Many believe that an atrial septal defect could be an incidental finding in pulmonary hypertension [8].
Pulmonary hypertension associated with congenital heart disease
PAH in congenital heart disease results from a chronic and large left to right shunt under high pressure (e.g, ventricular septal defects and patent ductus arteriosus) leading to irreversible vascular remodeling. Early surgery has transformed the natural history of congenital heart disease and pulmonary hypertension now exists mainly in the un-operated adult congenital population. Many are at the severe spectrum of disease with reverse shunts known as Eisenmenger syndrome. Cyanotic heart disease with common mixing and unprotected pulmonary blood flow similarly results in pulmonary hypertension if surgery is not undertaken promptly.
Single ventricle with pulmonary hypertension
The Fontan circulation is the end result of single ventricle repair. This is a unique circulation where cardiac output and oxygenation hinges on low pulmonary pressure which is very different from the usual bi-ventricular circulation. As there is an absence of a subpulmonary ventricle, even the slightest increase in pulmonary pressure can lead to failure of the Fontan circulation. Consequently, the accepted pressure values of pulmonary hypertension in single ventricle are lower than the conventional values used in other causes of pulmonary hypertension. The Panama Task force has suggested a raised TPG or PVRI as a more accurate measurement [2].
Pulmonary hypertension due to lung disease
Pulmonary hypoplasia represents another important etiology of PH during the neonatal period. Congenital diaphragmatic hernia; severe eventration of diaphragm and prolonged rupture of membrane, especially during the second trimester in very premature babies, can result in pulmonary hypoplasia. Survivors in this group of patients often continue to have chronic respiratory issues with reduced lung capacity and recurrent chest infections, leading to impaired growth and increased long term morbidity. In some, pulmonary hypertension will persist. The PH secondary to chronic lung disease in extreme premature babies (bronchopulmonary dysplasia in older term) tends to improve as the lung grows, although the long term data remains ill defined.
Pulmonary hypertension in critical care setting
Pulmonary hypertension in the critical care setting is often a challenging acute clinical situation which can be life-threatening. Post cardiac surgery and severe lung diseases are often complicated by pulmonary hypertensive crises which can result in right ventricular failure. These crises sometimes present with respiratory difficulty leading to erroneous diagnosis and treatment.
The underlying pathogenesis leading to pulmonary hypertension was initially thought to be secondary to vasoconstriction and thrombosis. Recent findings suggest the role of inflammation and excessive vascular cell growth, with recruitment and infiltration of circulating cells [9]. At molecular level, a few mechanisms have also been described; involving growth factors, cytokines, metabolic signaling, elastases, and proteases [10].The final common pathway likely includes vasoconstriction, micro thrombosis and vascular remodeling.
Investigations
Investigations of pulmonary hypertension consist of screening and specific tests. Targeted screenings are performed on at risk patient groups which include those with congenital heart disease, chronic lung disease, liver diseases, connective tissue disease and HIV disease. Echocardiography is often used as a screening tool but is probably not sensitive enough to detect many asymptomatic children resulting in a delayed diagnosis. Direct parameters measured, including tricuspid and pulmonary regurgitation may be absent and this has limited the usefulness of echocardiography. Indirect measurements including RV hypertrophy and septal contour are less sensitive and more subjective in early phases of the disease. Tissue Doppler and speckle tracking hold some promise with better sensitivity [11]. Brain Natriuretic Peptide (BNP) is used to predict prognoses. However there are no individual markers useful enough for screening and this led to suggestions for a multi-biomarker. A proteomic approach may hold promise in discovering useful future biomarkers [12].
Specific investigations should be used to exclude some rare and treatable diseases instead of being labeled as iPH and subjected to exhaustive and escalating long term therapy. However, due to the diversity of etiologies, investigations in pediatric patients are often more suspicion directed and less comprehensive compared to adults. Furthermore, some investigations may not be relevant to children or impractical for babies. Blood tests for liver function, connective tissue disease and HIV are often performed as baseline. Although cardiac catheterization is invasive and has inherent risks, it is a diagnostic test for PH and acts as a guide for therapeutic strategies especially when vasoreactivity is present to suggest usefulness of the calcium channel blocker. Vasoreactivity is often only tested in iPAH as responders are very rare among other groups [5]. It is defined as a reduction of mean Pulmonary Artery Pressure (PAP) ≥10mmHg to reach an absolute value of mean PAP ≤40mmHg with an increased or unchanged cardiac output [2]. The lung function test is useful for older children and blood gases are helpful even in the very young. Nocturnal hypoventilation leading to obstructive sleep apnea may occur especially in children with adenotonsillar hypertrophy, craniofacial anomalies syndromic and also obese children [13]. Night time polysomnography can confirm this. Although thromboembolic diseases are uncommon in the young, this should still be considered and investigated if previous history suggests a prothrombotic tendency or an underlying sickle cell disease [14]. CT angiograms can exclude pulmonary venous stenosis and pulmonary capillary hemangiomatosis especially in premature infants.
Although the 6-minute walk test is sub maximal and interpretations may be quite subjective [15], it is useful in assessing the exercise tolerance and capacity especially for those patients who are unable to tolerate the cardiopulmonary exercise test. It also provides an objective measurement and helps set targets for treatment.
Treatment
Clinicians may have dilemmas in choosing the best therapy as there may be a combination of pathologies present, leading to difficulties in recognizing the dominant underlying etiology. Conventional treatment for PH includes oxygen and diuretics. Anticoagulation is indicated in thromboembolic causes but remains contentious in other groups.
Medications
Specific treatments of IPAH and PH associated with congenital heart disease have been widely investigated, with multiple published studies, ranging from conventional treatments to specific pulmonary vasodilators. Many of these medications were first studied in the adult population and proved efficacious. These medications mainly targeted the 3 main pathways: nitric oxide, endothelin and prostacyclin. Prostanoids (epoprostenol, treprostinil, iloprost, beraprost), endothelin receptor antagonists (bosentan, ambrisentan), and phosphodiesterase type 5 inhibitors (sildenafil, tadalafil) are used depending on local preference and availability. Therapeutic interventions with these medications have yielded successful results on both IPAH and PH with congenital heart disease. Novel compounds such as macitentan, riociguat and selexipag have had some preliminary results and may prove useful in the future [16]. The fact that these medications can be used for diverse aetiologies of PH suggests that there is a final common pathway which leads to pulmonary hypertension.
With the same rationale, these medications have been tried on other groups of pulmonary hypertension. Children with chronic lung disease have had similar results of improvement with pulmonary vasodilators despite oxygen therapy being the primary treatment. Favourable data of sildenafil is increasing but remains insufficient for other medications [17]. Pulmonary vasodilators are also increasingly used in patients with single ventricle.
Surgery
There are no definite criteria for operability in children with intracardiac shunt and rose pulmonary pressure. We often subject this group of patients to pulmonary vasodilator treatment and subsequently repeat studies of hemodynamic to demonstrate improvement of PVR to <6 wood units and increased left to right shunt with oxygen to indicate suitability for a full repair. However, there are risks to surgery as this may result in a physiology similar to idiopathic pulmonary arterial hypertension which has a much poorer prognosis. Careful consideration should include partially closing the VSD or leaving an atrial fenestration in this situation.
Ventilation
In a critical care setting where conventional ventilation strategies fail to maintain satisfactory gas exchange, other modes of ventilation including high frequency oscillatory ventilation with Inhaled Nitric Oxide(iNO), prostacyclin and phosphodiesterase 5 inhibitor (sildenafil) have been used with good results [18,19]. INO is the most widely used and has advantages particularly in situations where ventilation perfusion mismatch exists. ECMO is sometimes required especially when severe hypoxemia persists despite aggressive pulmonary vasodilators and ventilation support. Neonates with supra systemic Right Ventricular (RV) pressure may be stabilized with ductal patency; septostomy may be required to maintain cardiac output.
Ballon septostomy has been performed in patients with right ventricular failure or syncope. There is evidence that it alleviates symptoms and may improve survival. Although this is a high risk and technically challenging procedure, this risk may be lowered if it performed earlier. It improves LV filling and cardiac output at the expense of cyanosis. LA pressure of >20 is associated with increased mortality and may be an exclusion criteria. This procedure should be considered in settings where there is an inadequate response to drug therapy or bridging towards lung transplant [20,21].
Exercise
Exercise rehabilitation in PH is an intriguing subject. In normal population exercise leads to a mild increase in pulmonary pressure secondary to increased flow or elevation in left atrial pressure. In pulmonary hypertension, the increase may be highly exaggerated because of raised PVR. Exercise training and cardiopulmonary rehabilitation has been utilized in the adult population to improve pulmonary pressure, endurance and muscle strength as well as quality of life [22,23]. It is possible that the group with exercise increased PVR may deteriorate on exercise programs but identifying this group would be a challenge. This strategy may be useful for the older children for logistic reasons.Despite many anecdotal reports, evidence suggests that currently used drugs may be efficacious to different types of PH. However, usage in children with portopulmomary hypertension is still largely unknown. Newer therapy involving endothelial progenitor cells may induce neovascularisation, which is promising; although it’s therapeutic use remains controversial [24].
Outcome
Survival rate of pulmonary hypertensive children has improved over the years. IPAH survival at 1, 3 and 5 years stands at 89%, 84% and 75% respectively, compared to median survival of 4.1 years before specific therapy was available [25,26]. Although many specific therapies have been developed and proven successful in terms of symptom improvement and delayed mortality, none have proven capable in reversing disease progression. However, with early treatment targeted at specific individual pathways which mediate PH, this may prove a possibility.
Pulmonary hypertension therapy has improved with better understanding of the disease process. With current treatment strategies the progression of disease is delayed, but cannot be arrested or reversed. The challenge lies in developing a sensitive screening test and elucidating the specific etiological/molecular pathways that mediate the progression of such a disease, thereby allowing the process to be reverse or modified at an earlier stage. New studies on therapies targeting inflammation and circulating cells are now under way; however, it may take a while before clinical efficacy is established, especially in the pediatric age group.
Tan SC and Lim ZS. Pulmonary Hypertension: A Pediatric Perspective. SM J Clin Med. 2016; 2(2): 1016.
The purpose of this statement is none other than to highlight the importance of ethical standards and quality required in basic and applied research currently being done so we can subsequently inform health care professionals of new developments that are taking place in this area.
Ma. Esperanza Rodríguez-van Lier*
Chemotherapy is commonly used in cancer treatment. So far, chemotherapy agents can be categorized into three types: classical chemotherapeutic drugs, molecular target agents and cellular machineries target drugs.
Ziyou Wang1,2 and Zunnan Huang1,2*
Blood transfusion can cause some transfusion adverse reactions. In order to understand the incidence of adverse transfusion reactions, we performed a meta-analysis in Chinese hospitals. Of 809 literatures, seven studies involving a total of 211, 050 patients with blood transfusion treatment were included in this meta-analysis. Meta-analysis showed that the total incidence of adverse reactions was 0.4% [95% CI (0.2, 0.9), P < 0.0001]. Further subgroup analysis showed that the incidence of febrile and allergic reactions was 0.2% [95% CI (0.1, 0.5), P < 0.0001] and 0.2% [95% CI (0.1, 0.3), P < 0.0001], respectively. The common blood components caused adverse reactions were red blood cell, plasama, and platelet in clinical practice.
Yulu Gao1 , Qinyun Li2 , Zongshuai Gao2 , Yunxia Zhu4 , Yanqiu Liao5 , Changtai Zhu2 *# , Yongning Sun3 *#
Background: CT scanning remains one of the most routinely used diagnostic tools in a setting of Interstitial Lung Disease (ILD). New and improved technologies, such as High Resolution Computer Tomography (HRCT) have revolutionized the quality of imaging, leading to a prominent increase in number of incidental findings that may or may not be of any clinical significance. The aim of this study was to evaluate the prevalence of incidental findings on thoracic CT and their clinical significance.
Methods: Retrospective analysis was conducted on a cohort of 84 patients referred to our academic center as cases of ILD. Patients were referred for further evaluation between January 2000 and January 2014 and were followed over the disease course. CT scans were done annually as part of clinical management and patients were screened for any incidental findings. All incidental findings were reviewed, recorded in a clinical database and followed up on subsequent visits.
Results: 25 (30%) patients were found to have incidental findings. Liver abnormalities were found in 12 (14.29 %) patients. 11(13.10 %) patients were reported to have coronary artery calcifications. 5 (5.95 %) and 3 (3.57%) patients had thyroid abnormalities and renal cysts, respectively. A malignant lesion was found in 1 patient each in liver and thyroid abnormality subgroup.
Conclusion: Incidental findings are common on thoracic CT scans providing valuable and unexpected findings which warrant investigation by health care providers to exclude malignant processes.
Sonu Sahni1,2*, Sameer Verma1,2, Reeju S Thomas1 , Barbara Capozzi3 and Arunabh Talwar1,2
Hepatitis C Virus infection (HCV) is an increasing public health concern with an estimated 184 million people infected worldwide and approximately 350.000 yearly deaths from HCV-related complications.
Nesrine Gamal and Pietro Andreone*
We report a case of large cell undifferentiated lung carcinoma in a middle aged patient with previously treated tuberculosis and scarring. 20 pack years of smoking history was noted. He presented with metastasis at multiple sites including trochanter, liver and acute bilateral lateral rectus palsy. Chest radiography showed fibrosis of right upper zone with homogenous opacity. Sputum examination for AFB was negative. Computerized tomography of the thorax showed an irregular heterogeneously enhancing mass involving right upper lobe with cavitation, necrosis along with lymph node involvement and the erosion of the 4th rib with liver metastasis. Radiography of hip joint was suggestive of lesser trochanteric metastasis. MRI brain was suggestive of mass at base of brain in parasellar area. Fine needle aspiration cytology and CT guided biopsy confirmed undifferentiated large cell carcinoma of lung. Tuberculosis and smoking may increase the risk of lung scarring and malignancy and pulmonary scarring may be associated with increased lung carcinoma in ipsilateral lung. Clinician needs to be more sensitive to look for malignancy association particularly in patient with or previously treated for tuberculosis and even more emphasis to be laid if scarring of lung is observed.
Sreenivasa Rao Sudulagunta1 *, Shyamala Krishnaswamy Kothandapani2 , Mahesh Babu Sodalagunta3 , Hadi Khorram2 , Mona Sepehrar4 and Zahra Noroozpour1
Systemic Sclerosis (SSc) is a connective tissue disease characterized by fibrosis of the skin and internal organs, pronounced alterations in the microvasculature and frequent cellular and humoral immunity abnormalities. The rheumatic involvement of SSc is polymorphic and can reveal the disease or may appear during the course of its progression. Musculoskeletal involvement is dominated by non specific arthralgia, polyarthritis, and bony resorption especially acro-osteolysis. The diagnosis of these rheumatic manifestations is generally based on x rays examination. Musculoskeletal involvement in SSc is generally relieved with Non Steroidal Anti-Inflammatory Drugs (NSAID) or low dose of corticotherapy. The immunosuppressive therapy is used in corticoid-resistant or corticoid-dependent forms such us méthotrexate. The aim of our review is to presents an overview of the different osteoarticular and muscular involvement in SSc, their diagnosis and management.
Nessrine Akasbi*, Fatima Ezzahra Abourazzak and Taoufik Harzy
Sedigheh Mirhashemi1 , Mohammad Hosein Kalantar Motamedi1 *, Amir Hossein Mirhashemi2 and Hamid Reza Rasouli1
We encountered two autopsy cases of huge cardiomegaly with over 1000g in weight. Histochemical characteristics were examined using conventional staining including HE and Azan stains and immunohistochemical staining using antibodies against Complement Component 9 (CC9), RNA Binding Protein Motif 3(RBM3), Endothelial Type NO Synthase (eNOS) and Hypoxic Inducible Factor1α (HIF1). The reactive area with anti CC9 antibody, which presumed to be a marker of hypoxic change of myocardium, overlapped with eosinophilic area by HE and basophilic one by Azan. Although the reactive area with anti CC9 antibody showed relatively weak in the cytoplasm by anti eNOS antibody and no in the nucleus of cardiocytes with anti RBM3 antibody, outside of the reactive area with anti CC9 antibody there were intensive reactivity with anti eNOS antibody in cytoplasm and in a nucleus with anti RBM3 antibody. Anti HIF1 antibody showed weak reactivity with cytoplasm of endocardial cardiocytes and no with cytoplasm of cardiocytes in another area. The results obtained from the present cases revealed that the hypoxic change was equivalent even though the cause of cardiomegaly was deferred between two cases, and conventional staining such as HE and Azan utilized to detect hypoxic change in the heart and immunohistochemical studies seemed to be a useful tool for clarifying the cascade of hypoxic changes in the myocardium.
Satoshi Furukawa1,2*, Mayumi Kataoka1 , Satomu Morita1,2, Akari Uno2 , Masahito Hitosugi2 , Hiroshi Matsumoto1,3 and Katsuji Nishi1,2
A 45-year-old woman with multiple sclerosis was admitted to our hospital after out of hospital cardio-pulmonary resuscitation. The first ECG showed ventricular fibrillation. Following direct current defibrillation and mechanical reanimation, spontaneous circulation was restored and the ECG unremarkable without any signs of ischemia. Coronary angiography showed unobstructed coronary arteries Figure 1, (Panel A). Left ventriculography revealed apical wall obstruction, suggestive of apical aneurysm (Panel B, supplementary videos). Transthoracic echocardiography and Cardiac Magnetic Resonance Imaging (CMR) eventually lead to the diagnosis of a rare case of Apical Hypertrophic Cardiomyopathy (AHC) with ace of spades-form (Panel C,D). The patient underwent Cardioverter-Defibrillator Implantation (ICD) and amiodarone medical therapy for secondary prophylaxis. Patient’s family history and screening for HCM were unsuspicious.
Wiedemann S# *, Heidrich FM# , Speiser U and Strasser RH