Hypertensive emergencies and hypertensive urgencies in children are uncommonly encountered in the pediatric emergency department and intensive care units, but the diseases are potentially a life-threatening medical emergency. In comparison with adults, hypertension in children is mostly asymptomatic and most have no history of hypertension. Additionally, measuring accurate blood pressure values in younger children is not easy. This article reviews current concepts in pediatric patients with severe hypertension.

Severe forms of hypertension are characterized by high blood pressure combined with end organ damage. Through the development and refinement of a transgenic rat model of malignant hypertension incorporating the mouse renin gene, we previously identified a quantitative trait locus on chromosome 10, which affects malignant hypertension severity and morbidity. We next generated an inducible malignant hypertensive model where the timing, severity, and duration of hypertension was placed under the control of the researcher, allowing development of and recovery from end organ damage to be investigated. We have now generated novel consomic Lewis and Fischer rat strains with inducible hypertension and additional strains that are reciprocally congenic for the refined chromosome 10 quantitative trait locus. We have captured a modifier of end organ damage within the congenic region and, using a range of bioinformatic, biochemical and molecular biological techniques, have identified angiotensin-converting enzyme as the modifier of hypertension-induced tissue microvascular injury. Reciprocal differences between angiotensin-converting enzyme and the anti-inflammatory tetrapeptide, N-acetyl-Ser-Asp-Lys-Pro in the kidney, a tissue susceptible to end organ damage, suggest a mechanism for the amelioration of hypertension-dependent damage.

Hypertension is a major risk factor for cardiovascular mortality and morbidity through its effects on target organs like the brain, heart, and kidney. Structural alterations in the microcirculation form a major link between hypertension and target organ damage. In this review, we describe damages related to hypertension in these target organs and the mechanisms involved in the pathogenesis of hypertension-induced cardiovascular diseases such as dementia, cardiac ischemia and remodeling, or nephropathy. We also focus on the therapeutical potential on the basis of such mechanisms. Several antihypertensive agents like diuretics, angiotensin converting enzyme (ACE) inhibitors, angiotensin II (Ang II) receptor antagonists, beta-blockers, or calcium channel blockers (CCBs) have been shown to reduce effectively hypertension associated cardiovascular events and to improve end organ damage. More recently, aldosterone antagonism has also shown beneficial effects. Part of the favorable effects of these agents is due to blood pressure lowering as such. Other mechanisms such as oxidative stress, inflammation, or endothelial dysfunction have appeared to play a key role in the pathogenesis of target organ damage and therefore represent another important pathway for therapy. In this review, we discuss the different therapeutic approaches aiming at reducing cardiovascular events and damages induced by hypertension.

The angiotensin-converting enzyme (ACE) gene has been implicated in the manifestation of the phenotype of malignant hypertension (MH). In 1990 the ACE gene polymorphism characterized by the insertion or deletion of a 287-base pair fragment in the 17q23 chromosome was identified. The DD genotype is associated with increased tissue and circulating ACE levels and elevated angiotensin II. ACE polymorphism was studied in 48 patients with MH, 25 patients with non-MH, and a control group of 78 normotensive individuals by real-time polymerase chain reaction using the LightCycler system (Roche Diagnostics Corporation, Indianapolis, IN). The DD genotype was found statistically more frequently in MH patients than controls (p=0.028; odds ratio, 2.5; confidence interval, 1.1-5.5). Presence of the DD genotype of the ACE gene is more frequent in MH patients than in controls, indicating that this genotype could be a significant risk factor and a predictor for the development of MH.

Genetic background has a major influence on the manifestation of multifactorial diseases such as hypertension in which severe complications may be caused through an interaction with additional factors, which may be genetically determined. We have previously described a genetic model of malignant hypertension (MH) in rats carrying the mouse Ren2 gene (TGRmRen2-27), in which the phenotype is dependent on the genetic background.

Using a single homozygous TGRmRen2-27 male as transgene donor, we produced two F1 populations with (a) 100% penetrance of MH in progeny heterozygous for the Fischer F344 genetic background and (b) 58.5% penetrance in progeny heterozygous for the Lewis genetic background. To identify the modifier loci affecting the phenotype, a cohort of 252 males was produced by breeding the same single male with Fischer-Lewis F1 females. The progeny were phenotyped for clinical and pathological features of MH.

Genome-wide screening and quantitative trait loci (QTL) analysis identified two loci, on chromosome 10 (LOD 4.4) and on chromosome 17 (LOD 3.9) close to the Ace and At1 genes, respectively, which contribute to the lethal MH phenotype. Their influence on mortality was consistent with a multiplicative effect of the two loci. In addition, we found higher plasma angiotensin-converting enzyme activity in progeny receiving the Fischer allele than in progeny receiving the Lewis allele (123.5 +/- 9.5 vs. 91.8 +/- 4.9 U/liter, P < 0.01), suggesting the association of angiotensin-converting enzyme and MH.

Our study demonstrates the application of a transgene as a "major gene" to facilitate the identification of modifier loci, which can affect the phenotype of MH, and reveals Ace and At1 as candidate genes involved in the manifestation of the MH phenotype.

A hypertensive crisis can be caused by many factors. Frequently, the mechanism involved is complex and highly variable among patients. Without drug therapy, this condition is associated with very high mortality and morbidity. There are a number of oral and intravenous hypotensive agents available, which can effectively control blood pressure in a hypertensive crisis. The relative advantages and disadvantages of each treatment option is discussed.

Diastolic blood pressure of 120 mm Hg or more is often cited as identifying a hypertensive crisis. However, the absolute level of blood pressure may not be as important as the rate of increase. One important feature that distinguishes hypertensive emergency from hypertensive "urgency" is the ongoing vascular damage that occurs with hypertensive emergency. When this is present, therapy should be initiated as soon as possible. The initial goal is to reduce mean arterial pressure about 15% to 25% within the first 48 hours. Overzealous or uncontrolled reduction in blood pressure may result in coma, stroke, myocardial infarction, acute renal failure, or death. Thus, a drug with titratable dosing (eg, intravenous nitroprusside sodium [Nipride, Nitropress]) is preferred in most situations. Patients with hypertensive urgency do not have evidence of vascular damage. Usually, they are asymptomatic, have no retinal lesions, and have a marked elevation in diastolic blood pressure. Hypertensive urgency does not require immediate normalization of blood pressure, but initiation of therapy and careful follow-up are critical.

Antihypertensive treatment reduces the risk of ischemic strokes and cerebral hemorrhage as complications of excessive or long-standing hypertension. However, neurologic dysfunction and brain damage may also accompany short-term, and under certain conditions, even long-term antihypertensive treatment. Therefore, treatment should be instituted restrictively and cautiously. Special regard should be given to the action of antihypertensive drugs on cerebral perfusion in patients with an increased risk for the development of treatment-induced cerebral ischemic complications, such as patients with hypertensive encephalopathy or autonomic dysfunction, and elderly patients with suspected sclerotic stenosis of cerebral or neck arteries. The structural and functional lesions of cerebral vessels observed in acute and chronic hypertension are reviewed, as are the effects of antihypertensive drugs on cerebral blood flow. Calcium channel blockers and angiotensin-converting enzyme inhibitors may have advantages as first-line drugs in the treatment of patients with an elevated risk of cerebral hypoperfusion, because of the selective action of these agents on vasoconstricted vessels and their differential effects in varying regional vascular beds. The excellent efficacy of these drugs in the short- and long-term treatment of hypertension may lead to changes in the traditional management of hypertensive emergencies as well as in management strategies for other patients at risk for treatment-induced complications.

A hypertensive urgency should be distinguished from a hypertensive emergency. Although the distinction may not always be obvious, certain guidelines may help the clinician determine which therapeutic approaches are most appropriate for each patient. Hypertensive emergencies include those conditions in which new or progressive severe end-organ damage is present and a delay in appropriate therapy might result in permanent damage, progression of complications, and a poor prognosis. Hypertensive urgencies include those conditions with minimal to no obvious end-organ damage in which blood pressure should be lowered expeditiously. The risk of immediate complications or organ damage is less likely to occur, and thus the immediate prognosis is better, although the ultimate prognosis, if untreated, is poor. There is a marked individual, racial, sexual, and age difference in the ability to tolerate high intraarterial pressure, as evidenced by patients' symptoms and signs of end-organ damage. Patients may have no symptoms of elevated blood pressure until significant intraarterial levels are reached. If symptoms are present, they may include headache, dizziness, blurred vision, shortness of breath (especially with exertion), chest pain, rapid pulse, palpitations, malaise and fatigue, nocturia, or pedal edema. Signs of hypertensive disease vary and depend not only on the level of blood pressure but also include funduscopic changes with arteriolar narrowing, atrioventricular nicking, hemorrhages, exudates or papilledema, central nervous system changes and neurologic abnormalities, cardiac changes with gallop rhythm, cardiomegaly, tachycardia, ectopic ventricular beats, left ventricular hypertrophy or signs of congestive heart failure, pulmonary edema, and signs of renal insufficiency.(ABSTRACT TRUNCATED AT 250 WORDS)

The term "hypertensive crisis" refers to a group of acute hypertensive disorders that have, in common, evidence of end-organ dysfunction. From a pathophysiological viewpoint, these disorders may be classified into two major categories. In primary hypertensive disorders, the predominant pathophysiological events and subsequent end-organ failure are directly attributable to the uncontrolled hypertension. Secondary hypertensive crises have many similar features; however, the ultimate progression from onset of hypertension to end-organ failure tends to be modified by concurrent target-organ disease. The chain of events leading to the progression from benign to malignant hypertension centers around two general theories--the pressure hypothesis and the humoral hypothesis--both of which suggest that when a critical imbalance of pressure and/or humoral factors occurs, depending variously on etiological factors, rapidity, and degree and duration of blood pressure elevation, a series of pathological events ensue leading to myointimal proliferation and fibrinoid necrosis. The primary target-organ effects of severe hypertension generally affect the central nervous, renal, and cardiovascular systems and occur when the normal compensatory mechanisms are exceeded either by a breakthrough in autoregulation, as in the central nervous system, or by an imbalance in myocardial supply and demand. To a certain extent the pathophysiological events and target-organ susceptibility will determine the manner in which the hypertensive event presents. Although effective therapy is optimally tailored to the specific underlying disease process, in the acute setting, where important clinical data may be lacking, an appreciation of these underlying mechanisms will aid in the selection of a regimen that is both safe and effective.