952 SECTION VII Pediatric Critical Care Renal RAAS These patients may actually need judicious volume replen ishment while managing their HTN The child with altered mental status, anisocoric pupils, an[.]
952 S E C T I O N V I I Pediatric Critical Care: Renal A B C D • Fig 78.2 A 6-year-old female patient with sickle cell disease, acute chest syndrome complicated with acute kidney injury, and severe hypertension (A) Axial computed tomography (CT) image of the brain during the episode is normal (B–C) Axial fluid-attenuated inversion recovery (FLAIR) magnetic resonance images at the same level performed the same day as the CT scan show multiple supratentorial and left cerebellar lesions (D) Follow-up FLAIR image after the episode shows resolution of the lesions (From Onder AM, Lopez R, Teomete U, et al Posterior reversible encephalopathy syndrome in the pediatric renal population Pediatr Nephrol 2007;22:1921–1929.) RAAS These patients may actually need judicious volume replenishment while managing their HTN The child with altered mental status, anisocoric pupils, and systemic HTN needs agents directed at managing increased ICP, such as mannitol or hypertonic saline solution, along with careful rapid sequence intubation and controlled ventilation The goal here is to prevent cerebral herniation and not to directly lower BP too rapidly, which may be deleterious Finally, the strategic pharmacologic goal for a patient experiencing a hypertensive crisis is to aim for a controlled decrease in BP as opposed to a sudden rapid fall Lowering BP to the “normal range” too rapidly may produce a clinically significant decrease in cerebral blood flow, especially in patients with preexisting chronic HTN (see Fig 78.1) This can lead to cerebral ischemia One group reported the occurrence of permanent neurologic deficits in adults treated with bolus antihypertensive therapy resulting in rapid BP CHAPTER 78 Acute Severe Hypertension reduction59; similar catastrophes have occurred in children.60,61 Thus, we normally recommend that BP should be reduced by 25% of the planned BP reduction over first hours, a further 25% over the next to 12 hours, and the final 50% over the 24 hours after that.4 It can be challenging to follow such a gradual approach, and often antihypertensive medications may inadvertently produce greater than desired BP reductions.62,63 Therefore, it is important to closely monitor the patient, particularly the patient’s neurologic status, and to be prepared to back off treatment if the patient shows signs of neurologic deterioration The indications, pharmacology, and adverse effects of medications available for treatment of acute severe HTN are reviewed in the following section Dosing for recommended agents is summarized in Table 78.3 Some agents are included in the following section but not in the table; reasons for their exclusion will be evident from the discussion Finally, Fig 78.3 presents an algorithm for the pharmacologic management of pediatric patients with acute severe HTN Clonidine Clonidine is a centrally acting oral a2-adrenergic agonist that reduces BP by reducing cerebral sympathetic output Clonidine is a mixed agonist that stimulates both central a2-adrenergic and imidazoline receptors.64 The stimulation of a2-adrenergic receptors 953 Acute severe hypertension Life-threatening symptoms (seizures, CHF, etc.) Minor symptoms (nausea, headache, vomiting) Hypertensive emergency Hypertensive urgency Bolus dose of IV hydralazine or labetalol followed by nicardipine or labetalol infusion Able to tolerate PO medication: isradipine or clonidine Unable to tolerate PO medication: IV hydralazine or labetalol • Fig 78.3 Algorithm for initial management of children with acute severe hypertension CHF, Congestive heart failure; IV, intravenous; PO, oral TABLE Recommended Antihypertensive Agents for Acute Severe Hypertension 78.3 Drug Class Dose Route Comments Useful for Severely Hypertensive Patients With Life-Threatening Symptoms Esmolol b-Adrenergic blocker 100–500 mg/kg/min IV infusion Very short-acting—constant infusion needed May cause profound bradycardia Hydralazine Direct vasodilator 0.1–0.2 mg/kg/dose up to 0.4 mg/kg/ dose IV, IM Should be given q4h when given IV bolus Labetalol a- and b-adrenergic blocker Bolus: 0.20–1.0 mg/kg/dose, up to 40 mg/dose Infusion: 0.25–3.0 mg/kg/h IV bolus or infusion Asthma and overt heart failure are relative contraindications Nicardipine Calcium channel blocker Bolus: 30 mg/kg up to mg/dose Infusion: 0.5–4.0 mg/kg/min IV bolus or infusion May cause reflex tachycardia Increases cyclosporine and tacrolimus levels Sodium nitroprusside Direct vasodilator Starting: 0.3–0.5 to 10 mg/kg/min Maximum: 10 mg/kg/min IV infusion Monitor cyanide levels with prolonged (.72 h) use or in renal failure or coadminister with sodium thiosulfate Useful for Severely Hypertensive Patients With Less Significant Symptoms Clonidine Central a-agonist 2–5 mg/kg/dose, up to 10 mg/kg/ dose given q6–8h PO Side effects include dry mouth and drowsiness Fenoldopam Dopamine receptor agonist 0.2–0.5 mg/kg/min up to 0.8 mg/kg/ IV infusion Higher doses worsen tachycardia without further reducing BP Hydralazine Direct vasodilator 0.25 mg/kg/dose up to 25 mg/dose given q6–8h PO Half-life varies with genetically determined acetylation rates Isradipine Calcium channel blocker 0.05–0.1 mg/kg/dose up to mg/ dose given q6–8h PO Exaggerated fall in BP can be seen in patients receiving azole antifungals Minoxidil Direct vasodilator 0.1–0.2 mg/kg/dose up to 10 mg/ dose given q8–12h PO Most potent oral vasodilator; long acting ACE, Angiotensin-converting enzyme; BP, blood pressure; IM, intramuscular; IV, intravenous; PO, oral 954 S E C T I O N V I I Pediatric Critical Care: Renal in the CNS inhibits peripheral sympathetic activity that results in vasodilation Its effects are targeted primarily toward arterioles at lower doses.65 Clonidine is well known as an antihypertensive agent with a favorable hemodynamic profile, especially because of the infrequency of postural hypotension Compared with other centrally acting agents, clonidine has a relatively rapid onset of effect, approximately 15 to 30 minutes following oral administration,66 making it attractive for use in management of acute HTN It is metabolized by the liver into inactive forms and excreted unchanged in the urine with some gastrointestinal excretion because of enterohepatic recirculation Adverse effects of clonidine include bradycardia, dry mouth, and sedation.64 In addition, severe rebound HTN may occur in patients treated chronically with clonidine (including those treated with the transdermal preparation) if the drug is abruptly stopped This is not a danger if using intermittent doses of oral clonidine Esmolol Esmolol is an IV pure b1-adrenergic blocker that decreases BP by reducing CO In a study of 17 children (6 months to 14 years), esmolol was shown to lower BP along with cardiac index, shortening fraction and heart rate, while SVR remained unaffected.67 It has a rapid onset of action and short half-life (2–4 minutes), which makes it ideal for critically ill patients with labile HTN who require frequent titration for BP management.68 Because esmolol is rapidly hydrolyzed by esterases in the cytosol of red blood cells, its clearance is not dependent on organ blood flow or function.68 Like labetalol, esmolol has the advantage of not increasing ICP It should not be used in patients with asthma and should be used with caution if the patient has congestive heart failure It can cause profound bradycardia In addition, the use of b-blockers alone should be avoided in children with suspected neuroendocrine catecholamine-secreting tumors because the stimulation of a-receptors from these catecholamines without opposing b-stimulation can severely worsen BP A large multicenter, double-blind, randomized, dose ranging study of 116 pediatric patients (,6 years) with postoperative HTN after coarctation of the aorta repair studied one of doses of esmolol (125, 250, or 500 mg/kg per minute, after respective loading doses of 125, 250, and 500 mg/kg) The results showed a decrease in SBP in all three dose groups, but there was no statistically significant difference between groups in either the change from baseline or percent change from baseline.69 Despite the lack of dose-response in the clinical trial setting, it is likely that esmolol can be effectively titrated to achieve control of BP in children with severe HTN Hydralazine Hydralazine, available in both IV and oral preparations, is a direct vasodilator of arteriolar smooth muscle with an unclear mechanism of action, most likely an alteration of intracellular calcium metabolism, leading to interference with the calcium movements within the vascular smooth muscle that are responsible for initiating or maintaining the contractile state It does not affect coronary arteries or venous smooth muscle, but its effects on arteriolar smooth muscle stimulate the SNS, leading to tachycardia, increased renin activity, and sodium retention.70 The positive inotropic effects of hydralazine exhibit both cyclic adenylate monophosphate (cAMP)–dependent and independent mechanisms, yet the importance of each remains elusive.71 Nevertheless, it is known that intracellular calcium homeostasis is altered when hydralazine mediates its effects Hydralazine, when given orally, has low systemic bioavailability (16% in fast acetylators and 35% in slow acetylators) Consequently, the dose needed to achieve therapeutic levels is higher in fast acetylators because the acetylated form is inactive N-acetylation of hydralazine occurs in the bowel and/or liver The half-life is a function of genetically determined acetylation rates, but on average it is approximately 60 minutes It is cleared hepatically, and elimination is a function of hepatic blood flow The onset of action after IV administration is to 20 minutes, with a duration of to hours While hydralazine’s half-life is variable, its effect on BP generally persists for to hours.72 When administered orally, hydralazine has an onset of action of 30 minutes to hours and an unpredictable duration of action of to 12 hours Hydralazine also may be given intramuscularly; dosing is similar to IV administration Despite its long history of use in children,73 no prospective pediatric clinical trial of hydralazine has been conducted However, two recently published retrospective case series of hydralazine use in hospitalized children with acute HTN suggest that this agent can produce effective BP reduction after IV administration and that adverse effects are relatively infrequent.63,74 However, the BP response to IV hydralazine was erratic in both reports, likely reflecting the retrospective study designs There are no published pediatric data on the efficacy of oral hydralazine Adverse effects are related to the reflexive increase in sympathetic activity and include tachycardia, palpitations, flushing, headache, and dizziness Additionally, there appears to be an increased risk of excessive BP reduction following IV hydralazine administration in children.63 Thus, caution is advised when using this agent Isradipine Isradipine is an oral second-generation dihydropyridine calcium channel blocker (CCB) that is specific for the L-type calcium channel found in smooth muscle It lowers BP by relaxing arteriolar smooth muscle, leading to decreases in peripheral vascular resistance As a result, the CCBs elicit a sympathetic discharge that causes stimulation of the sinoatrial node and consequent tachycardia.75 It has a relatively rapid onset of action, with a peak effect that can last as long as hours Several retrospective case series of pediatric isradipine use have established its utility for both acute and chronic HTN.76–79 In a study of 282 hospitalized children with acute HTN treated with oral isradipine, BP reductions of 16.3% 11.6% (mean SD) for SBP and 24.2% 17.2% for DBP were observed.79 Another study examined chronic isradipine use in 80 children with secondary HTN over a 5-year period and found that isradipine monotherapy decreased SBP by a mean of 13 mm Hg and DBP by 10 mm Hg over a broad range of ages from week to 16.8 years of age.79 Similar responses to isradipine (a decrease in systolic pressure of 11.8% and diastolic pressure of 17.4%) were seen retrospectively in 53 children (ages day to 16 years) treated with an average dose of 0.4 mg/kg per day.76 Isradipine undergoes extensive first-pass metabolism in the liver by the cytochrome 450 isoenzyme CYP3A4.75 It is highly protein bound and is excreted essentially as inactive metabolites in the urine (two-thirds) and feces (one-third) Adverse events CHAPTER 78 Acute Severe Hypertension attributed to isradipine occurred in 9.5% of patients in one case series and included headache, dizziness, flushing, and tachycardia Of note, an exaggerated BP response to isradipine has been observed in patients receiving concomitant treatment with azole antifungal agents79; caution is advised when using isradipine in such patients In our experience, this has been an issue in children following stem-cell transplantation in particular, who may be receiving these medications for either prophylaxis or treatment of invasive fungal infection Labetalol Labetalol is a combined a- and b-adrenergic blocker that can be administered as a continuous IV infusion or as an IV bolus It lowers systemic vascular resistance with minimal effect on CO.80 It provides nonselective b-adrenergic blockade, which reduces reflex tachycardia and increased cardiac contractility that may be seen with vasodilators b2-adrenergic blockade would increase SVR, but this effect is counterbalanced by its a-adrenergic blockade, which is selective for the a1-receptor, resulting in vasodilation The a-to-b blocking ratio of the oral preparation is 1:3, whereas it is 1:7 for the IV form Therefore, labetalol is most useful in situations in which HTN is produced by excessive SNS activity Labetalol has an onset of action of to minutes, with a peak at to 15 minutes, and a bolus dose can last up to hours Its duration of action is longer than either nitroprusside or nicardipine and does not increase heart rate or CO, as does nitroprusside.81 It is metabolized in the liver through glucuronide conjugation and excreted in the urine, bile, and stool Published experience with IV labetalol in severely hypertensive children is limited to several small case series.14,16,82 In all of these reports, labetalol was felt to be an effective antihypertensive agent; in the most recent report, labetalol was felt to have a similar antihypertensive effect as nicardipine or nitroprusside Adverse effects include bradycardia and bronchospasm, although in one report a pediatric patient with a history of asthma experienced no respiratory difficulty when given labetalol for HTN.81 Unfortunately, no prospective pediatric trial of labetalol has been conducted Nicardipine Nicardipine is a second-generation IV dihydropyridine CCB that is specific for L-type calcium channels and is primarily an arteriolar vasodilator It is selective for L-type calcium channels in vascular smooth muscle as opposed to cardiac myocytes Moreover, nicardipine has profound coronary and cerebral vasodilatory activity Its potent BP actions are without negative inotropic effects or suppression of cardiac conduction; it has minimal effects on automaticity and causes no appreciable venodilation.75 Many pediatric case series of IV nicardipine use in infants and children with severe HTN have been published.15,83–86 In all of these, it has been reported to be effective and well tolerated The vasodilatory effects appear to be greater in patients with HTN than in patients with normal BP.87 In addition, it has gained a role in various cardiovascular, neurosurgical, and general surgery procedures as well as in the postoperative period.88 In head-to-head trials for treatment of severe HTN in adults, nicardipine was as effective as nitroprusside.13 Unlike nitroprusside, nicardipine does not pose the risk for cyanide or thiocyanate toxicity and can be used for a longer duration than nitroprusside It does have a slightly longer onset of action and a much longer 955 elimination half-life compared with nitroprusside.87 Plasma levels of nicardipine increase rapidly in the first few hours of a continuous infusion but then reach a steady state thereafter The elimination half-life is a few hours with normal renal function and prolonged with decreased clearance during renal failure Given its metabolism via the hepatic P450 enzyme system, there is the potential for clinically significant drug interactions.75 The most important of these include decreased clearance of cyclosporine, tacrolimus,89 and vecuronium Because nicardipine may cause thrombophlebitis when given through a peripheral IV line, either dilution to 0.1 mg/mL or central venous administration is recommended Like other arterial vasodilators, nicardipine has the potential to increase ICP Conversion of nicardipine infusions to oral dosing has been reported in adults,90 but no similar reports have been published for children Sodium Nitroprusside Sodium nitroprusside lowers SBP both as an arteriolar (peripheral resistance vessel) and venous (peripheral capacitance vessel) dilator Consequently, this effect often results in a reflex tachycardia because of the fall in arteriolar BP Nitroprusside lowers right atrial pressures through relaxation of venous capacitance vessels, thus increasing venous compliance In addition, nitroprusside reduces right ventricular afterload through its pulmonary arterial vasodilator activity.91 Its potent pulmonary vasodilation inhibits hypoxic-mediated pulmonary vasoconstriction.92 Generally, when used in acutely hypertensive patients with normal left ventricular function, nitroprusside reduces CO through its venous pooling (e.g., increased venous capacitance) effects On the other hand, nitroprusside improves CO in patients with poor left ventricular function and diastolic ventricular distension mainly by decreasing afterload by means of relaxing arteriolar resistance vessels.93 Nitroprusside has a prompt onset of action and a very short half-life, making it ideal for frequent titration It is an unstable compound that breaks down under alkaline conditions and when exposed to ambient light Immediately during infusion, nitroprusside interacts with oxyhemoglobin to yield methemoglobin, cyanide, and NO In contrast to the organic nitrates (e.g., nitroglycerin) that require thiol-containing compounds to generate NO, nitroprusside spontaneously generates NO, thus functioning as a prodrug.94 Once generated, NO activates the enzyme guanylate cyclase found within vascular smooth muscle, resulting in increased levels of cGMP, which inhibits calcium entry into vascular smooth muscle cells, producing vasodilation Its onset of action is 30 seconds, it peaks at minutes, and it is eliminated minutes after cessation The cyanide that is produced is rapidly cleared by nonenzymatic means by reacting with sulfhydryl groups on proteins in surrounding tissue and in erythrocytes.92 In addition, the liver enzymatically metabolizes cyanide to thiocyanate by means of rhodanese Because the liver is the major source of rhodanese, in patients with liver failure, signs and symptoms of cyanide intoxication may develop upon nitroprusside administration Adverse effects from methemoglobinemia generated by nitroprusside metabolism are rare, even in patients with a congenital inability to convert methemoglobin to hemoglobin (i.e., methemoglobin reductase deficiency) In any event, any patient receiving nitroprusside in whom CNS dysfunction, cardiovascular instability, and/or increasing metabolic acidosis develops should be evaluated for 956 S E C T I O N V I I Pediatric Critical Care: Renal cyanide toxicity.92 If cyanide toxicity is suspected, nitroprusside infusion should be stopped, and therapies directed toward cyanide toxicity should be considered Because the rate-limiting step of cyanide detoxification to thiocyanate usually entails the need for a sulfur donor, coadministration of sodium thiosulfate as a sulfur donor increases the rate of reaction of rhodanese, removing cyanide from the circulation A solution of 0.1% nitroprusside and 1% sodium thiosulfate or a 1:10 ratio by weight in lightprotected tubing is administered according to the usual dosing guidelines for nitroprusside.95,96 Alternatively, hydroxocobalamin (vitamin B12a) can be used to trap the cyanide ion by exchanging the hydroxyl group for cyanide and forming cyanocobalamin, which is excreted unchanged in the urine.97 Cyanocobalamin is the synthetic form of vitamin B12 (cobalamin) that is used for food additives and is nontoxic Of note, IV methylene blue is contraindicated in treating methemoglobinemia attributable to cyanide toxicity because the conversion of methemoglobin to hemoglobin may liberate large amounts of cyanide.97 Thiocyanate is eliminated in the urine with an elimination half-life of days in patients with normal renal function Because thiocyanate accumulates in patients with renal failure and can result in renal toxicity, nitroprusside should usually be avoided in children with renal failure In fact, a significant proportion of children with completely normal renal function treated with nitroprusside may develop elevated cyanide levels98; thus, widespread use of nitroprusside in pediatric patients is probably not advisable Clinically, patients with thiocyanate toxicity exhibit anorexia, nausea, fatigue, disorientation, and psychosis Thiocyanate also inhibits iodine uptake by the thyroid and may produce hypothyroidism Thus, thiocyanate levels should be monitored with prolonged infusion (.24 hours) In one study evaluating the effectiveness of nitroprusside in children presenting with acute severe HTN of renal origin, target levels of BP were achieved within to 20 minutes in all patients In addition, symptoms of cardiac failure resolved in all patients and neurologic symptoms abated in 80% of children within 24 to 48 hours.99 In a more recent clinical trial in children requiring prolonged hypotension, nitroprusside was significantly more effective than placebo in maintaining BP control.98 The disadvantages of nitroprusside include not only the potential for cyanide and thiocyanate toxicity but also acute hypotension, rebound HTN, increasing cerebral blood flow/ICP, oxygen desaturations (via inhibition of hypoxic vasoconstriction), and, in time, tachyphylaxis Other Available Agents Clevidipine is a recently developed, ultra-short-acting, third-generation IV dihydropyridine CCB with high specificity for vascular smooth muscle Unlike oral dihydropyridine CCBs—such as amlodipine, which have relatively slow onset and long durations of action75—clevidipine administration lowers BP within minutes after initiation of a continuous infusion and has a rapid offset once the infusion is discontinued, with a half-life of just a few minutes.100 This makes its pharmacokinetics similar to those of nitroprusside Indeed, comparative studies of clevidipine and nitroprusside in adults following coronary artery bypass have confirmed similar clinical efficacy of these two agents.101 Clevidipine may be superior to both nitroprusside and IV nicardipine owing to its decreased tendency to produce tachycardia compared with nitroprusside and its more rapid offset of action compared with nicardipine Although originally developed for control of BP during surgical procedures, clevidipine has also found a role in the management of postoperative severe HTN in adults following cardiac surgery.102 Pediatric use of clevidipine has been reported in several clinical situations, primarily in patients requiring intraoperative BP reduction.103 In a recently published open-label trial, clevidipine was administered to 30 children undergoing spinal fusion in whom controlled hypotension was needed All patients achieved the desired reduction in MAP without significant adverse effects, such as tachycardia.104 Enalaprilat is an IV form of the ACE inhibitor enalapril ACE inhibition blocks the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor Thus, ACE inhibition leads to vasodilation because of decreased levels of angiotensin II.19 Interestingly, ACE also metabolizes bradykinin Hence, bradykinins increase during ACE inhibition, and this effect may contribute to vasodilation as well.105 In any event, ACE inhibitors such as enalaprilat decrease SVR and thus afterload and systolic wall stress Consequently, CO and stroke volume improve All ACE inhibitors are cleared predominantly by the kidneys Therefore, doses of these agents need to be reduced in patients with renal insufficiency ACE inhibitors are most potent in patients with high renin levels; significant decreases in BP can occur in this population Enalaprilat should not be used in patients with myocardial infarction, bilateral renal artery stenosis, pregnancy, or preeclampsia/eclampsia There is no established pediatric dose for enalaprilat A dose range of to 10 mg/kg per dose IV every to 24 hours was reported as effective in one small case series of hypertensive neonates.106 However, no further pediatric reports of this agent have been published Therefore, it is probably best avoided in severely hypertensive children, many of whom will have renovascular forms of HTN, for whom use of an ACE inhibitor is not recommended in the acute setting.9 Fenoldopam is the first available peripheral dopamine1 receptor (DA1) agonist, the newest class of antihypertensive agents available to treat acute severe HTN Stimulation of the DA1 receptor causes vasodilation of peripheral arteries as well as the mesenteric and renal vasculature, with less effect in the cerebral and coronary circulations Thus, it lowers BP and peripheral vascular resistance while maintaining renal blood flow.107 DA1 receptor stimulation leads to vasodilation by increasing cAMP, which promotes smooth muscle relaxation cAMP also inhibits the sodium-hydrogen exchanger and the sodium/potassium-adenosine triphosphatase pump in the renal tubule.19 This feature gives fenoldopam the advantage of maintaining or increasing renal perfusion; its use is associated with short-term increases in urine output, sodium excretion, and creatinine clearance Fenoldopam has an onset and duration of action similar to that of IV nicardipine and has a half-life ranging from to 10 minutes.107 It has been shown to be generally equivalent to nitroprusside in the management of acute severe HTN in adults.107,108 Pediatric experience with this agent for severe HTN is limited to a few case reports.109,110 However, it has found use in children requiring perioperative BP control In a blinded, randomized, prospective study of children ranging from weeks to 12 years of age who were scheduled for surgery with a planned induction of hypotension, fenoldopam rapidly lowered MAP compared with placebo.111 A retrospective analysis of 13 patients aged months to 18 years with primarily cardiac lesions demonstrated increased urine output with fenoldopam without the need ... patients with thiocyanate toxicity exhibit anorexia, nausea, fatigue, disorientation, and psychosis Thiocyanate also inhibits iodine uptake by the thyroid and may produce hypothyroidism Thus, thiocyanate... require thiol-containing compounds to generate NO, nitroprusside spontaneously generates NO, thus functioning as a prodrug.94 Once generated, NO activates the enzyme guanylate cyclase found within... Because the rate-limiting step of cyanide detoxification to thiocyanate usually entails the need for a sulfur donor, coadministration of sodium thiosulfate as a sulfur donor increases the rate of reaction