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didanawisgi · 7 years

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Pathophysiology and Pathogenesis Blood pressure is a product of cardiac output and peripheral vascular resistance (PVR). Cardiac output is a product of heart rate and stroke volume. In turn, stroke volume is determined by preload, contractility, and after-load/PVR [24]. Figure 1 outlines the various factors that determine the arterial blood pressure (adapted with permission from [25]).Any factor which enhances the heart rate and determinants of stroke volume would result in hypertension. The pathogenesis of hypertensive crisis is multifactorial and much of the supportive data is based on both animal and human adult studies. The factors that have been implicated in the pathogenesis include elevated blood pressure, fluid overload, sympathetic overactivity, renin-angiotensin-aldosterone system activation, oxidative stress, endothelial dysfunction, and inflammation. There is a complex interaction between all these factors and all or some factors occurring simultaneously may be involved in the pathogenesis of hypertensive crisis.

Figure 1:

Factors that determine the arterial blood pressure (adapted with permission from [25]).

2. Elevated Blood Pressure

Complex interactions between renal, humoral, neural, and cardiovascular systems are involved in the maintenance of normal perfusion pressures to target organs during fluctuations of blood pressures [24]. Any disturbance in the autoregulatory mechanisms results in mechanical stress resulting in vascular injury and endothelial damage. Endothelial damage thus initiates a cascade of proproliferative, prothrombotic, and proinflammatory reactions, in addition to release of vasoactive peptides. These cascades of events eventually result in fibrinoid necrosis and tissue ischemia. This culminates into a vicious cycle of tissue ischemia potentiating the blood pressure due to release of vasoactive peptides, sympathetic overactivity, and fluid retention leading to further endothelial damage and inflammation which in turn again worsen the tissue ischemia [26, 27].

3. Renin-Angiotensin-Aldosterone System (RAAS)

RAAS plays an important role in the regulation of blood pressure and during hypertensive crisis [28]. The enzyme renin acts on angiotensinogen (AGT) to generate angiotensin I (Ang I). Ang I is further converted to angiotensin II (Ang II) by angiotensin converting enzyme (ACE). Ang II exerts its effects by binding to two major types of receptors—AT1R and AT2R [29]. Functions like vasoconstriction, cellular proliferation, cellular hypertrophy, fibrosis, atherosclerosis, antinatriuresis, and release of aldosterone, endothelin, norepinephrine, and vasopressin are initiated by binding of Ang II to AT1R. In addition, Ang II induces mitochondrial dysfunction via a protein kinase C-dependent pathway by activating the endothelial cell NADPH oxidase and formation of peroxynitrite [30]. A recent study demonstrated that Ang II stimulates increased IL-6 production both in vivo and in vitro. In addition to its role in hypertension, increased IL-6 may play an important pathogenic role in CKD by Ang II-mediated induction of multiple fibrotic genes and ET-1 production leading to renal injury and fibrosis [31]. In addition, recent identification (Pro) Renin receptors and functionally active Ang II-derived peptides like Ang 1–7 have been shown to play pathological role in causing hypertension [32].

4. Inflammation

Various inflammatory cytokines and chemokines have been implicated in the pathogenesis of hypertension. Ang II has been shown to be proinflammatory and profibrotic by inducing and activating various inflammatory pathways and upregulating cytokines, chemokines, and NFKB. The pivotal role of various T-cell subsets and macrophages in the regulation of blood pressure and target organ damage has been demonstrated in recent studies [33–38]. Amelioration of the target organ damage by immune-suppressant treatment further confirms involvement of immune mediators in the pathogenesis of hypertension. Ang II also facilitates recruitment of leukocytes through the endothelium by induction of ICAM-1 and VCAM-1 [39, 40]. T lymphocytes CD4 (+) and, to a lesser extent, CD8 (+) have been demonstrated to mediate the accelerated microvascular thrombosis associated with Ang II-induced hypertension [41]. Although the exact mechanism is unclear, it is thought to be secondary to complex interaction between platelets and cytokines resulting in activation of coagulation cascade. In addition, the presence of NADPH oxidase-derived reactive oxygen species also facilitates prothrombotic action of Ang II [41]. Recent study also demonstrated immunosuppressive properties of regulatory T cells (Treg) when adaptive transfer of isolated Treg cells into Ang II–infused mice resulted in amelioration of cardiac damage [42].

5. Oxidative Stress and Endothelial Dysfunction

Nitric oxide (NO) is synthesized by endothelial nitric oxide synthase (eNOS) in the vascular endothelium from its precursor molecule L-arginine. NO in the presence of soluble guanylate cyclase (sGC) results in increased intracellular levels of cyclic Guanosine monophosphate (cGMP). Elevated cGMP causes decrease in intracellular calcium ion levels leading to decreased vascular tone. Oxidative stress may play a causal role in the development of hypertension by altering the vascular tone either by oxidative modification of proteins and nucleic acids or by decreasing the bioavailability of nitric oxide. Superoxide anions generated by various enzymes such as NADPH oxidase, xanthine oxidase, and enzymes involved in mitochondrial respiratory chain may directly inactivate NO and inhibit sGC. Increased angiotensin II levels facilitate further generation of superoxide anions by stimulating these enzymes. In addition, superoxide anions lead to uncoupling of eNOS by oxidating the BH4 (tetrahydrobiopterin). BH4 is an essential cofactor necessary in generation of NO by eNOS enzyme. Uncoupling of eNOS also facilitates further generation of superoxide anions. These superoxide anions cause increased vascular cell proliferation and migration, apoptosis, inflammation, extracellular matrix alterations, and endothelial dysfunction [43–46].

6. Central Nervous System

The role of central nervous system in the regulation of blood pressure via modulation of sympathetic and parasympathetic nervous system is well known. However, recent studies suggest that increased sodium intake results in increase in endogenous ouabain (EO) levels in the paraventricular and supraoptic nuclei and at the circumventricular organs such as subfornical organ. This induces an acute but transient Ang-II- mediated increase in peripheral sympathetic nervous system resulting in elevation in blood pressures. Experiments conducted in rats reveal complex interactions involving sodium ions, epithelial sodium channels (ENaCs), RAAS, and EO in the brain which activate sympathetic nervous system. Thus, a brain Na+-ENaC-RAAS-EO pathway and a neuromodulatory pathway involving Aldosterone-EO-Ang II have been proposed in explaining the mechanism of action of hypertension. Further research and understanding of these novel mechanisms will help in newer antihypertensive therapies [47].

In addition, genetic mutations and polymorphisms [48], and insulin resistance [49], and abnormalities involving the sodium transport mechanisms like Na+/H+ exchanger, Na+/K+/2Cl-cotransporter, Na+Cl-cotransporter, Na+/K+ ATPase, and sodium-phosphate cotransporter [50, 51] have also been implicated in the pathogenesis of hypertension. A possible mechanism of hypertensive crisis is shown in Figure 2.

Figure 2:

Mechanism of hypertensive crisis.6.1. Clinical Features and Target-Organ Damage

Clinical presentation varies depending upon age, the target organ involved, and etiology. Neonates may present with apnea, cyanosis, irritability, and poor feeding [52].In addition, clinical features may reflect specific etiologies like endocrine diseases, autoimmune conditions, pregnancy, and drug abuse. Older children with long-term hypertension or acute exacerbation of chronic hypertension or sudden severe elevation of blood pressure may present with symptoms related to end organ abnormalities involving the heart, eye, kidney, and brain [53].

6.2. Cardiovascular Manifestations

Depending on the duration and acuity of the symptoms, the cardiac involvement can be in the form of left ventricular hypertrophy (LVH), left ventricular failure, or left ventricular ischemia [54, 55]. Although left ventricular hypertrophy has traditionally been defined in pediatric population as left ventricular mass index (LVMI) greater than 38.6 g/m2.7 and has been recommended in the fourth report, a recent study has demonstrated that LVMI varies significantly in children particularly those <9 years of age. The study which was performed in 2,273 nonobese, healthy children demonstrated that in children aged >9 years the 50th percentile values of LVMI ranged from 27 g/m2.7(girls) to 32 g/m2.7(boys) and varied little with age. The 95th percentile values of LVMI in the >9 years age group ranged from 40 g/m2.7(girls) to 45 g/m2.7(boys). The authors concluded that values >40 g/m2.7 in girls and >45 g/m2.7 in boys should be considered abnormal. In contrast, the 50th percentile values of LVMI in children <9 years age group varied significantly from 56.44 g/m2.7(boys) and 55.38 g/m2.7(girls) in infants less than 6 months of age to 31.79 g/m2.7(boys) and 29.71 g/m2.7(girls) in children less than 8years of age. Similarly, the 95th percentile values of LVMI in the <9 years age group varied from 80.1 g/m2.7(boys) and 85.6 g/m2.7(girls) in infants less than 6 months of age to 44.6 g/m2.7(boys) and 43.5 g/m2.7(girls) in children less than 8 years of age (Table 3). This study provides normal percentile values for young children and emphasizes the need for age–appropriate LVMI cut points and use of appropriate percentile curves particularly in children <9 years of age [56]. The LVH is common in children with hypertension with an incidence of 41.1% particularly in children with high Body-Mass index (BMI) and in Hispanic population [57]. Left ventricular failure can lead to symptoms such as increased work of breathing, shortness of breath, chest pain, palpitations, decreased urine output, and poor appetite. Sudden acute increase in blood pressure may precipitate left ventricular failure in any pediatric age group but is more commonly reported in neonates [58–60]. Carotid intima media thickness (CIMT), measured by B-mode ultrasound at end diastole, has emerged as a surrogate marker of early atherosclerotic changes and is predictive of adult cardiovascular structural damage. Indeed, increasing number of studies in children with hypertension, dyslipidemia, diabetes, and obesity have shown an increased CIMT. However, a recent study showed that nonobese children with primary hypertension had increased CIMT compared with BMI-matched controls. Although obesity may play a significant role in vascular changes, this study provides strong and interesting evidence that CIMT may be increased in nonobese children with primary hypertension. The major drawback of this surrogate marker is that the reference values are not available for children younger than 10 years and further studies are needed to determine reference values of CIMT in this age group [61–63].

Table 3:

Age-specific reference values of the LVMI in boys and girls Adapted from [56].

6.3. Neurological Manifestations

Loss of cerebral autoregulation leading to disruption of the blood brain barrier and endothelial dysfunction results in imbalance in oxygen delivery, edema formation, and microhemorrhages [64]. These changes may lead to seizures, altered mental status, PRES, vomiting, signs of raised intracranial pressure, focal neurological deficits, and headache. Headache is the most common symptom [65–69]. In one study seizures occurred in 25% of children, encephalopathy in 25%, facial palsy in 12%, and hemiplegia in 8% [18]. Posterior reversible encephalopathy syndrome has been reported to predominantly affect the occipitoparietal white matter with occasional spread to basal ganglia, cerebellum, and brainstem. Various etiologies like post-chemotherapy, posttransplant, postinfectious, autoimmune conditions, and posthypertensive crisis have been known to cause PRES. Clinical features include headache, altered mental status, nausea, vomiting, seizures, cortical blindness, and focal neurological deficits. Magnetic Resonance Imaging shows bilateral, symmetrical, involvement of white matter in occipitoparietal regions which appear as hyperintense lesions on T2-weighted images and hypointense or isointense lesions on Diffusion-Weighted Images. PRES is a completely reversible condition with occasional reports of neurological deficits [70–72].

6.4. Renal Manifestations

Hematuria, flank pain, and oliguria would indicate renal involvement. The most common etiology leading to hypertension in children is renal disease but hypertension itself can result in renal injury and failure secondary to loss of autoregulation of renal blood flow. But the data exploring the impact of hypertension on the renal function and structural injury in pediatric population is limited. Histologically fibrinoid necrosis with thrombosis involving the intrarenal arteries has been demonstrated in adult studies which result in clinical presentation consistent with microangiopathic hemolytic anemia [73, 74]. A recent study, however, has demonstrated increased microalbuminuria and decreased glomerular filteration rate in prehypertensive children particularly with high blood pressure load [75]. In addition, another study demonstrated a reduction in microalbuminuria and LVH when hypertension was controlled with ACE inhibitors [76]. These findings suggest that renal dysfunction and structural injury may occur early even in pediatric population with hypertension and continue into adult life and studies are needed to further elucidate these findings.

6.5. Ophthalmological Manifestations

Retinal bleeds, papilledema, loss of visual acuity, acute ischemic optic neuropathy, and cortical blindness have been reported secondary to hypertensive crisis [77]. Loss of vision can be serious and permanent. Traditionally hypertensive retinopathy assessed by direct fundoscopy has been described based on Keith-Wagner-Barkar’s classification (1939) which was subsequently modified by Scheie (1953) [78, 79]. The major drawback of these classifications is that direct fundoscopic examination is limited by physician’s experience and high inter- and intraobserver variability. More recently Wong and Mitchell (2004) (Table 4) proposed a new classification which stratified cardiovascular risks associated with different grades of hypertensive retinopathy in adults [80]. The data regarding the prevalence of hypertensive retinopathy in general pediatric population is largely unknown. However, in two studies the prevalence of hypertensive retinopathy in children with hypertension varied from 8.9% (assessed by direct fundoscopy) to 50% (assessed by retinal photographs) [13, 81]. Majority of the children in both studies had mild retinopathy and none had higher-grade retinopathy. In addition, evidence of grade III and grade IV hypertensive retinopathy was lacking in 32% of adults with hypertensive encephalopathy [82]. Although many studies involving the risk stratification and prognostic importance based on the retinopathy grades are available in adults, no such data exists in pediatric population. In general, moderate-to-severe grades of retinopathy are relatively rare in children and further studies are needed to elucidate the importance of mild retinopathy and long-term prognosis. But newer techniques like digital imaging and computer analysis of the early retinal changes and newer grading systems will further help in risk stratification and disease progression [83].

Table 4:

Wong and Mitchell’s classification (adapted from [80]).

7. Clinical Assessment

Clinical assessment begins with obtaining relevant present, past medical history. Potential risk factors include history of low birth weight, intrauterine growth retardation, prematurity, oligo or polyhydramnios, umbilical artery catheterization, recurrent urinary tract infections, weak stream of the urine in male child, hematuria, flank pain, polyuria, failure to thrive, joint pains, skin rashes, headaches, visual disturbances, chest pain, palpitations, and poly or oliguria. Family history of diabetes, hypertension, obesity, hypercholesteremia, early strokes, coronary artery diseases, sudden cardiac deaths, malignancies, autoimmune conditions, or hereditary conditions involving the kidneys, liver, and brain should be assessed. A detailed endocrine-related history should also be obtained. Medication history involving steroids, antihypertensives, tacrolimus, cyclosporine, oral contraceptives, and dietary and life-style history regarding smoking, alcohol, and drug abuse should be elucidated. In addition in teenage adolescent girls, pregnancy-related symptoms should be elicited. In obese children, history of sleep apnea and daytime somnolence should be obtained.

Physical examination should involve general examination to look for edema, skin rashes, neurocutaneous markers, cyanosis, elfin facies, webbing of neck, hirsutism, cushingoid features, thyroid enlargement, proptosis, and so forth. Heart rate, respiratory rate, and four-extremity blood pressure preferably both in lying and sitting position, peripheral pulses, height, weight, and BMI should be recorded. A detailed cardiovascular, respiratory, abdominal, and neurological examination should be performed to look for any evidence of coarctation, LVH, pulmonary edema, pleural, and pericardial effusions. In addition, examine for hepatosplenomegaly, intra-abdominal masses, ascites, and genitourinary abnormalities. Look for any evidence of spina bifida, hydrocephalus, signs of raised ICP, papilledema, focal neurological deficits, and cranial nerve palsies particularly 3rd and 7th cranial nerves.

#emergency medicine #pediatrics #family medicine #pathophysiology #Hypertension #medical physiology

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