1. Severe Hypertension: Common, harmful & treatable Marwa Nabhan M.Sc. Pediatrics, Cairo University.

2. Severe Hypertension Severe hypertension is defined as a BP elevation that fulfills (and usually exceeds) the definition of stage 2 hypertension and that is accompanied by severe symptoms. Stage 2 hypertension: > 99th percentile plus 5 mmHg. (Flynn & Tullus, 2009)

3. Classification of normal and abnormal blood pressure in children and adolescents: Classification of BP SBP or DBP Normal < 90 th percentile. Prehypertension 90 th to < 95 th percentile, or if BP exceeds 120/80 in adolescents. Stage 1 hypertension 95 th to 99 th percentile plus 5mmHg. Stage 2 hypertension >99 th percentile plus 5 mmHg.

4. (Deal et al., 1992)

5. Presenting features in children with severe hypertension Incidental. Cardiac (congestive cardiac failure, palpitations, murmur). Headache ± vomiting ± lethargy. Visual disturbances. Acute hypertensive encephalopathy: seizures (early focal then generalized). Altered consciousness. Cerebrovascular accident. Facial palsy. Poor feeding and failure to thrive.

6. Severe Hypertension Severe hypertension has traditionally been divided into hypertensive emergencies and hypertensive urgencies. Hypertensive emergency is associated with life- threatening symptoms and/or target-organ injury. Hypertensive urgency is associated with less significant symptoms and no target-organ injury.

7. Hypertensive encephalopathy is a very severe complication seen in some children with severe hypertension. This condition is caused by a failure of the upper limit of the autoregulation of cerebral blood flow, which leads to cerebral hyperperfusion. Seizures can be presenting symptoms and also lethargy, confusion, headache, and visual disturbances, including blindness. (Vaughan & Delanty, 2000)

8. Altered cerebral autoregulation in chronic hypertension (Rose & Mayer, 2004)

9. PATHOLOGICAL LESIONS: Arteriolar damage & fibrinoid necrosis Ischaemia & microinfarcts Petecheal haemorrhages Cerebral oedema

10. Pathophysiology Pathophysiology of severe hypertension need to be put in mind while managing resistant hypertension as it will help us a lot in predicting why it is resistant to treatment.

11. Pathophysiology Renin-agiotensin system. Endothelial dysfunction. Fluid overload. Sympathetic stimulation. Medications and other substances.

12. Approach to management of severe hypertension The child with acute severe hypertension requires prompt evaluation and therapy in order to avoid the development of the complications discussed.

13. Management History: In most such children, the underlying diagnosis will be obvious from the medical history. In a child who is already hospitalized, sufficient information can usually be gleaned by review of the medical record.

14. History: For patients newly presenting with severe hypertension who have no prior history, then in addition to assessing symptom severity, questions will need to be asked regarding the onset of symptoms as well as recent and past medical history, focusing on eliciting clues to the conditions listed.

15. Examination: It is important to confirm that the BP has been accurately measured. The examination should then focus on an assessment of volume status, cardiac status, and neurologic status. Vital signs. Lower limb B.P.

16. Fundus examination (papilloedema, HTN retinopathy with hge & retinal exudates). Full neurological examination. Abdominal examination (Renal mass ?? tumour).

17. Management History. Examination. Investigations:  Initiation of treatment takes priority over definitive diagnosis  Knowing the exact cause will rarely seriously alter treatment. Treatment.

18. Treatment General supportive treatment. BP lowering treatment. Treatment of the causative disease.

19. General supportive treatment SETTING: Controlled & well monitored Quiet & minimal anxiety

20. General supportive treatment CARDIORESPIRATORY STATUS: Continuous monitoring of vital signs. BP monitoring: Non-invasive Arterial catheter Treatment of acute Lt ventricular failure. Respiratory support (pulmonary oedema or CNS failure).

21. General supportive treatment FLUID STATUS Monitoring Electrolytes Current fluid status Acid-base status Intake and losses Urine output Weight. Management Na intake Fluid intake Diuretics Dialysis

22. General supportive treatment OTHER SYSTEMS CNS: irritability, seizures, treat pain adequately. Renal: uraemia. Haematological: severe anaemia, bleeding, anticoagulation/ bleeding tendency. Infection.

23. Children presenting with severe symptoms need to be treated promptly. However, it may be risky to lower the BP too rapidly, especially in those whose hypertension has been long-standing. In such patients, a shift in cerebral autoregulation occurs, which in the hypertensive state protects the brain from excessive perfusion. (Rose & Mayer, 2004) BP lowering treatment.

24. A too rapid lowering of the BP in patients with such alterations of cerebral flow might lead to ischemic stroke from underperfusion of the brain. BP should be reduced by 25% of the planned BP reduction over first 8–12 h, a further 25% over the next 8–12 h, and the final 50% over the 24 h after that. (Flynn & Tullus, 2009)

25. Availability of drugs with established efficacy in children Therapeutic options for pediatric patients requiring treatment for severe hypertension are significantly limited: only half of the intravenous antihypertensive medications currently marketed in the USA have pediatric labeling approved by the Food and Drug Administration (FDA).

26. Of those agents with approved pediatric labeling, one is no longer in routine use (diazoxide), and another was demonstrated to have limited efficacy in children compared to adults (fenoldopam). Because of this, practitioners who care for children with severe hypertension have had to use unapproved medications on an off- label basis. (Flynn & Tullus, 2009)

27. Intravenous agents currently used in children with severe hypertension A variety of intravenous antihypertensive agents are currently in widespread use for emergency reduction of acute hypertension in children, including sodium nitroprusside, labetalol, nicardipine, hydralazine and esmolol. Enalaprilat, the intravenous formulation of the ACE inhibitor enalapril, has been utilized to a more limited degree in this setting as well.

28. Pediatric labeling status of intravenous antihypertensives

30. Proposed algorithm for initial management of children with severe hypertension. (Flynn & Tullus, 2009)

31. Sodium nitroprusside Sodium nitroprusside is a direct vasodilator of both arteriolar and venous smooth muscle cells. It is metabolized to nitric oxide, which dilates both arterioles and venules, resulting in both a reduced total peripheral resistance and reduced venous return, thus decreasing both preload and afterload. For this reason, this agent can be used in severe congestive heart failure as well as in patients with severe hypertension.

32. Nitroprusside has a rapid onset of action, 1–2 min, and a plasma half-life of <10 min, enabling it to achieve rapid changes in blood pressure. The metabolism of nitroprusside accounts for its primary toxicity, cyanide accumulation, which results from the conversion of nitroprusside to cyanide and thiocyanate. The risk of toxicity increases after 24–48 h or in patients with renal insufficiency.

33. Labetalol Labetalol is a combined α 1 and β -adrenergic blocking agent that can be administered either orally or intravenously. Due to its capacity to block α 1 receptors, it produces vasodilatation; hemodynamic studies have demonstrated that labetalol lowers peripheral resistance with little or no effect on cardiac output.

34. Labetalol Administered intravenously, it is this vasodilatation which accounts for labetalol’s efficacy in the treatment of severe hypertension. The hypotensive effects of a single dose of intravenous labetalol appear within 2–5 min after administration, peak at 5–15 min, and last up to 2–4 h.

35. Intravenously administered labetalol has been extensively studied in adults with severe hypertension, and case series of successful use in children with severe hypertension have been published.

36. Nicardipine Nicardipine is a second-generation dihydropyridine calcium channel blocker that has been shown to be an effective antihypertensive agent in numerous studies in adults, comparing favorably to nitroprusside in terms of overall efficacy. (Flynn et al., 2000)

37. Nicardipine It has high vascular selectivity and strong cerebral and coronary vasodilatory activity; the latter property probably accounts for its favorable effects on myocardial oxygen balance. The initial onset of nicardipine given intravenously occurs within 1 min, and the duration of action after a single intravenous dose is approximately 3 h.

38. Nicardipine Upon termination of infusions of nicardipine, plasma concentrations rapidly decline, with at least a 50% decrease during the first 2 h. The conversion of nicardipine infusions to oral dosing has been reported in adults, but no such data exist for children. (Wallin et al., 1990)

39. Hydralazine Hydralazine is a direct vasodilator of arteriolar smooth muscle with an unclear mechanism of action. Its effects on arteriolar smooth muscle stimulates the sympathetic nervous system, leading to tachycardia, increased renin activity, and sodium retention. (Hoffman, 2006)

40. Hydralazine The average maximal decrease in blood pressure usually occurs 10–80 min after intravenous administration. An advantage of hydralazine compared to other agents discussed herein is that it can be administered intramuscularly, which can be useful in situations when there is an immediate need to lower blood pressure but the patient does not yet have intravenous access established.

41. Hydralazine Patients treated with intravenous hydralazine can be easily converted to oral dosing; additionally, oral hydralazine may be useful in patients with less severe hypertension who are able to tolerate oral drugs.

42. Dose adjustment in renal failure: CrCL(ml/min) Interval 10-50 q8hr <10 q8-16hr

43. Diazoxide Diazoxide is another direct vasodilator. Diazoxide has a long history of use for the treatment of hypertensive emergencies in adults and has been utilized in children with severe hypertension for many years as well.

44. Diazoxide Diazoxide is rapidly and extensively protein bound, so rapid injection is necessary. However, the rapid injection of large bolus doses of diazoxide can produce significant hypotension, so a “mini-bolus” dosing regimen (doses of 1–3 mg/kg repeated at intervals of 5–15 min) is currently recommended.

45. Esmolol Esmolol is an ultra-short acting, cardioselective β -1 adrenergic blocker that is particularly well-suited for the management of intra-operative hypertension due to its rapid onset of action (approx. 60 s) and relatively short duration of action (10–20 min).

46. Esmolol Its rapid metabolism by an intracytoplasmic red blood cell esterase is independent of both renal and hepatic metabolism, making it potentially well-suited for critically ill patients with multiorgan failure. It is typically administered by continuous infusion after an initial loading bolus dose.

47. Enalaprilat The final intravenous agent that has found use in hypertensive children is enalaprilat, the only available intravenous ACE inhibitor. With the exception of patients with volume depletion, enalaprilat is reported to rapidly lower BP without causing severe hypotension, and it is felt to be especially effective in patients with renin-dependent forms of hypertension. (Grossman et al., 1998)

48. Dose adjustment in renal failure: CrCL(ml/min) Dose 10-50 0-25% reduction <10 50% reduction Use not recommended in infants and children < 16 yrs with GFR < 30 ml/min/1.73 m.

49. Oral agents of potential use in children with severe hypertension Clonidine is a centrally-acting α 2 adrenergic agonist that reduces BP by reducing cerebral sympathetic output. Compared to other centrally acting agents, it has a relatively rapid onset of effect, approximately 15–30 min following oral administration.

50. Clonidine is extremely useful in the acute setting, particularly in hemodialysis patients, perhaps due to the fact that it is minimally removed by hemodialysis and does not require dose adjustment in renal failure. ( Sica, 2007)

51. Isradipine is a second-generation dihydropyridine calcium channel blocker. It has a rapid onset of action, usually reducing BP within 1 h of administration, with its peak effect occurring in 2–3 h. One study in adults demonstrated that isradipine is effective in the acute treatment of severe hypertension; while no data for pediatric patients describing such use are available.

54. Contributors to iatrogenic hypertension in the ICU Anxiety Poorly controlled pain Early hypoxia Asynchrony with the ventilator Vasopressors Corticosteroids Catheters near the origin of the renal arteries

55. Conclusion oAcute severe hypertension is common in our practice in pediatric nephrology. oTherapeutic options for pediatric patients requiring treatment for severe hypertension are significantly limited. oWe need clinical trials for the use of these drugs in children to widen our choices.