820201.qxd

P R A C T I C A L P E D I AT R I C N E P H R O L O G Y R.D. Adelman · R. Coppo · M.J. Dillon
The emergency management of severe hypertension Received: 19 February 1998 / Revised: 16 August 1999 / Accepted: 17 August 1999 Abstract Severe hypertension in childhood is a life-
urgency describes blood pressure that is markedly in- threatening clinical problem that carries with it not only creased, but can be more gradually reduced within a few serious sequelae of inadequate treatment but equally se- days to avoid serious sequelae [1–5]. In the older termi- rious complications of over enthusiastic therapy. The nology a hypertensive emergency would equate with majority of cases have some form of underlying renal “malignant” or “accelerated” hypertension [1, 2, 6, 7], disease. Therapeutic success is achieved by slow and i.e., patients having bilateral retinal haemorrhages and safe reduction of blood pressure with the immediate tar- exudates with or without papilloedema [6], hypertensive get of avoiding hypertensive sequelae yet allowing pres- encephalopathy, hypertensive cardiac failure and evi- ervation of target organ function. Short-acting parenteral dence of other end organ damage such as hypertensive antihypertensives are recommended along with careful renal complications. Because there is considerable clini- blood pressure monitoring to prevent complications aris- cal and definitional overlap between what has been ing through loss of autoregulatory control.
called hypertensive urgency and hypertensive emergen-cy, it would seem simpler to refer to patients as having Key words Severe hypertension · Hypertensive
severe hypertension with or without end organ involve- emergency · Hypertensive crisis · Antihypertensive Similarly, there is no clear definition of what consti- tutes severe hypertension. It is, like beauty, often “in theeyes of the beholder.” The Second Task Force [8] de- fined severe hypertension as exceeding the 99th percen-tile for age. Others have suggested arbitrary absolute There is some controversy regarding terminology used to levels, such as a diastolic blood pressure in the adoles- describe the clinical syndrome of severe hypertension, cent, for example, in excess of 110 mmHg. In the final i.e., hypertension that represents a threat to life or to the analysis severe hypertension will be seen by the clini- function of vital organs. This has been called “hyperten- cian as that level at which the patient, at the time of pre- sive crisis” and has been subdivided, by some, into two sentation or in the very near future, will likely manifest categories, the “hypertensive emergency” and the “hy- serious clinical signs, symptoms and target organ seque- pertensive urgency” [1–5]. The hypertensive emergency describes hypertension of such a level that it requires ur-gent treatment to reduce it within minutes to hours toavoid life-threatening complications [1–5]. Hypertensive The aetiology of severe hypertension in childhood is, in Department of Pediatrics, Eastern Virginia Medical School, the majority of cases, some form of underlying renal disease [1, 9, 10]. The commonest causes are coarse re- nal scarring due to reflux nephropathy or obstructive Divisione di Nefrologia e Dialisi, Ospedale Regina Margherita, uropathy, various forms of glomerulopathy and reno- vascular disease [9]. Other aetiologies include end- stage renal failure and transplantation, inherited kidney Nephrourology Unit, Great Ormond Street Hospital for Children, disorders, haemolytic uraemic syndrome, coarctation of the aorta, phaeochromocytoma [1, 10] and occasionally e-mail: [email protected].: +44-20-79052651, Fax: +44-20-79160011 low renin hypertension, as seen in apparent mineralo- corticoid excess. The common aetiologies in the neo- latory mechanism that maintains adequate blood flow to nate include umbilical artery catheter-associated renal viscera across wide ranges of arterial pressures [16, 17].
artery and aortic thrombosis, chronic pulmonary dis- This is particularly relevant to the cerebral circulation. In ease and coarctation of the aorta. In the majority of patients with long-standing hypertension the range is re- these situations, other than in the neonate, the severely set upwards. Such individuals may be less able to com- increased blood pressure rose after a longish period of pensate for sudden falls of pressure which, at a level well sustained hypertension, as opposed to emerging acutely tolerated with normal autoregulation, might cause cere- in a newly acquired disease, such as acute glomerulone- bral infarction, transverse ischaemic myelopathy or blindness in the so-called watershed areas that becomecompromised with a drop in pressure [2, 11–13]. Moststudies regarding physical and functional features affect- ing autoregulation have involved the adult population;more pathophysiological studies in the paediatric popula- The clinical manifestations vary considerably but the tion on autoregulation of blood flow in different organs major complications in children involve the central ner- and at different ages are needed. A case in point is the vous system, the eyes, the heart and the kidneys. In a neonate that is at risk for intraventricular haemorrhages series of children recently reported, hypertensive reti- and other central nervous system sequelae related to nopathy occurred in 27%, hypertensive encephalopathy changes in blood pressure in the face of poor cerebral au- in 25%, convulsions in 25%, left ventricular hypertro- toregulation and highly vulnerable blood vessels in the phy in 13%, facial palsy in 12%, visual symptoms in subependymal germinal matrix of the central nervous 9% and hemiplegia in 8% [9]. The visual symptoms system [18, 19]. These factors are of importance when may be caused by retinopathy, cortical damage, vitre- blood pressure is treated and is the reason for slow and ous haemorrhage or anterior ischemic optic neuropathy controlled reduction. Complications are more likely to [9]. The latter is particularly a cause for concern and occur in long-standing hypertension as opposed to that may eventually lead to infarction of the optic nerves due to ciliary arterial hypertensive damage, especiallywhen blood pressure is reduced too quickly [11–13].
Such patients demonstrate loss of pupillary light reflex but retain a response to accommodation. Some patientspresent in cardiac failure and others in renal failure due The goal of treatment is to prevent hypertension-related to hypertensive renal damage. Significant proteinuria adverse effects by a controlled reduction of blood pres- and haematuria may, in these circumstances, be due to sure, allowing preservation of target organ function and the high blood pressure as opposed to a primary glo- minimizing complications of therapy, such as ischaemic merulopathy. In addition, some patients present with neuropathy of the optic nerve, transverse ischaemic my- gastrointestinal symptoms, including haemorrhage due elopathy and renal impairment [2, 11–13]. These occur to the microvascular damage caused by the high blood primarily because of loss of autoregulatory tone as an pressure, and some present with a microangiopathic haemolytic anaemia. In neonates, common clinical The therapeutic agents available for managing se- manifestations of hypertension include tachypnea, car- vere, potentially life-threatening hypertension are most diomegaly, congestive heart failure, lethargy, seizures, frequently administered intravenously and ideally have retinopathy and failure to thrive. Even in the presence short half-lives, allowing for careful but swift modifi- of very severe hypertension, some neonates remain cation of therapy according to response. Labetalol [1, 5, 9, 20–25], sodium nitroprusside [1, 5, 9, 23–27] andmore recently nicardipine [28–31] are frequently usedfor this purpose. In the management of severe hyperten- sion there can be no absolute recommendations regard-ing preferences of pharmacological agents. Each clini- It is not the purpose of this article to deal in detail with cian should use medications with which he or she is fa- the pathophysiology of severe or life-threatening hyper- miliar and comfortable. We would recommend sodium tension, but a few aspects need emphasizing since they nitroprusside, nicardipine and labetalol as effective, have relevance to the way affected children are managed.
safe parenteral agents that can be easily titrated in a The histological hallmark is fibrinoid arteriolar necrosis, clinical setting with little toxicity. Pulsed intravenous although this is not pathognomonic [2, 15]. Subintimal diazoxide [32–35] has received adverse publicity be- cellular proliferation is more commonly seen and can be cause of significant hypotensive complications; the sufficient to occlude the lumina, and has important im- agent has been used by slow intravenous infusion [1, plications in terms of the ischaemic complications that 36, 37], although paediatric experience is limited. Al- are seen in severely hypertensive situations when blood ternative agents that have been recommended include pressure is lowered too rapidly [2, 15]. Furthermore, hydralazine [1, 24, 25], clonidine [38], esmolol [5, 25] markedly increased blood pressure affects the autoregu- and enalaprilat [39]. Oral nifedipine [40–45] adminis- Table 1 Antihypertensive drug therapy for hypertensive emergencies (NO nitric oxide, IV intravenous, PO per os, NaHCO sodium
recommended for routine use butmay have role by infusion tered sublingually has also been recommended but the The usual approach would be for the child to be authors have concern about unpredictability in terms of carefully monitored when the blood pressure is being response. Sublingual absorption is negligible and it controlled. Usually this is an intensive care unit setting, seems likely that nifedipine is absorbed after swallow- or an emergency department with appropriate monitor- ing [46]. Because of concerns about the sequelae of ing, nursing and physician support. There are no uni- rapid and uncontrolled lowering of long-standing hy- versal recommendations concerning the optimal rate of pertension in which cerebral autoregulation may be im- reduction, but a rule of thumb that appears to work paired, we do not recommend oral agents, although ni- based upon clinical practice at Great Ormond Street fedipine continues to be widely used by colleagues in Hospital for Children is to reduce the blood pressure by nephrology according to a recent survey [47]. The sur- one-third of the amount to be reduced in the first 6 h, vey related primarily to acute severe hypertension in by a further third over the next 24–36 h and to take the asymptomatic individuals that suggests a population in pressure down to the proposed maintenance level over whom cerebral autoregulation may well be intact and a final 48–72 h. Careful attention to pupillary reactions, thus at lower risk for complications. Approximately vision, level of consciousness and neurological findings 10% of respondents identified serious adverse conse- is necessary, and an intravenous line should be avail- quences of oral nifedipine. Other oral agents that have able with saline or plasma on hand to increase the been used in severe hypertension include captopril blood pressure by volume expansion should sudden hy- [48–51] and minoxidil [23–25]. Table 1 shows the vari- ous agents available, the dosage regimens recommend- If sodium nitroprusside is utilized, monitoring of ed and the complications of usage. Agents recommend- blood cyanide or plasma cyanate levels is necessary ed by the authors are marked with asterisks.
[52, 53]. In reality, cyanate levels are rarely elevated unless nitroprusside is given over several days and/or dramatic increases in systolic and diastolic blood pres- in the presence of renal failure. Lactate/pyruvate ratios sure that are normal maturational events over the first have been advocated by some as a more-sensitive and few months of life can lead to both lack of recognition more easily measurable indication of toxicity [54].
of true severe hypertension and overdiagnosis and mis- Both the necessity for monitoring plasma cyanide lev- treatment of patients falsely labelled as hypertensive.
els and the cumbersome need to cover the medication There are few data in neonates on the level of hyperten- and infusion lines in patients receiving sodium nitro- sion at which therapy should be initiated, the conse- prusside is obviated by the use of intravenous nicardi- quences of non-treatment, the incidence of side effects pine or labetalol. Once blood pressure is stabilized then and the pharmacokinetics of antihypertensive agents the gradual introduction of oral antihypertensive agents [14]. Many infants, including some with very severe hy- is necessary, bearing in mind the perceived underlying pertension, may be asymptomatic. Our policy is to treat cause of the high blood pressure. Such agents as nifedi- all asymptomatic patients with severe hypertension as pine (ideally as a slow release combination), angioten- well as those with symptoms, which are usually cardio- sin converting enzyme (ACE) inhibitors and β-blockers respiratory and neurological. In the severely hyperten- are the usual oral agents that have been effective in our sive infant it is the authors’ policy to use parenteral experience. Sometimes more-powerful agents such as medications such as nitroprusside and nicardipine in a minoxidil, clonidine, prazosin and others are required careful titrated fashion to lower blood pressure prior to conversion to oral agents [60]. The newborn infant, es-pecially the premature infant, has a richly perfused frag-ile germinal matrix, and is at risk for intracranial haem- orrhages associated with hypertension, hypotension ormarked fluctuations in blood pressure; therefore, judi- Special situations arise that may require different ap- cious lowering of blood pressure is mandatory. Both ni- proaches in the immediate post acute management fedipine and captopril are very effective oral agents in phase. For example, children with phaeochromocytoma the subsequent management of the severely hyperten- may need phenoxybenzamine plus or minus a β-blocker sive neonate, although lower doses of captopril per kilo- [55]. Children with renin-dependent hypertension, such gram are needed in the neonate [61, 62] to avoid ad- as that associated with renovascular disease or renal pa- renchymal disease, may need ACE inhibitors, but cau-tion is necessary if main renal artery stenosis is consid-ered to be present [56]. Renal impairment with salt and water retention may well justify dialysis or diuretics,since hypervolaemia may blunt the response to antihy- Severe hypertension in childhood can be a life-threaten- pertensive medications. However, volume depletion is ing clinical problem that carries with it not only serious normally not required in the acute hypertensive emer- sequelae of inadequate treatment but equally serious gency, since most patients presenting in this way are salt complications if over enthusiastic therapy is introduced.
The key to success is slow and safe reduction of blood Patients with apparent mineralocorticoid excess or pressure with the immediate target of reducing the level Liddle syndrome, both examples of low renin hyperten- to a safe yet still hypertensive value, and then a slow fur- sion, can present with life-threatening severe hyperten- ther reduction to normal over several days. Short-acting sion and may not respond adequately to any therapy oth- parenteral therapy is recommended for successful and er than specific agents that act on the collecting tubules safe management, with careful bedside monitoring of such a triamterene or amiloride [57, 58]. This is the rare blood pressure to avoid complications arising through situation under which these medications may be used in the emergency setting. Patients with cerebrovascular dis-ease or increased intracranial pressure may need a sub- stantial blood pressure level to maintain cerebral perfu-sion. These individuals may not require the same ap- 1. Arbus GS, Farine M (1992). Management of hypertensive proach to blood pressure reduction as others. Indeed, emergencies in children. In: Loggie JMH (ed) Pediatric and ad- such an approach may be disastrous with major cerebral olescent hypertension. Blackwell Scientific, Oxford, pp 369– infarction ensuing as a result [59]. Antihypertensives such as labetalol may be safer in this setting than other 2. Isles CG (1994) Hypertensive emergencies: malignant hyperten- sion and hypertensive encephalopathy. In: Swales JD (ed) Text- agents that may increase cerebral blood flow and intra- book of hypertension. Blackwell Scientific, Oxford, pp 1233– In the treatment of the neonate [14] it is extremely 3. Abdelwahab W, Frishman W, Landau A (1995) Management of important to properly measure blood pressure with the hypertensive urgencies and emergencies. J Clin Pharmacol 35: appropriate size cuff in a resting state and compare sys- 4. Zampaglion B, Pascale C, Marchisio M, Cavallo Perin P tolic and diastolic pressure readings with norms for (1995) Hypertensive urgencies and emergencies. Prevalence birth weight and postnatal age. Failure to appreciate the and clinical presentation. Hypertension 27:144–147 5. Fivush B, Neu A, Furth S (1996) Acute hypertensive crisis in 32. McLaine PN, Drummond KN (1971) Intravenous diazoxide children: emergencies and urgencies. Curr Opin Pediatr 9: for severe hypertension in childhood. J Pediatr 79:829–832 33. Henrich WL, Cronin R, Miller PD, Anderson RJ (1977) 6. World Health Organization (1978) Arterial hypertension.
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V. Baca · C. Lavalle · R. Garcia · T. Catalan · J.M. Sauceda
S.L. Watkins · R.J. Hogg · S. Mohan
G. Sanchez · I. Martinez · M.L. Ramirez · L.M. Marquez
J.C. Rojas
Effects of chronic renal failure and growth hormone on serum levels of insulin-like growth factor-binding protein- 4 in children with severe neuropsychiatric lupus a report of the Southwest Pediatric Nephrology Objective To evaluate the effect of intravenous methylpredniso-
J Clin Endocrinol Metab (1999) 84:596–601 lone (IVMP), and cyclophosphamide (IVCy) in children with se-vere neuropsychiatric (NP) systemic lupus erythematosus(NPSLE).
Children with chronic renal failure (CRF) have high serum levels We studied 7 consecutive pediatric patients with severe of insulin-like growth factor (IGF)-binding protein- 1 (IGFBP-1), NPSLE. All patients were treated initially with IVMP and IVCy -2, and -6. The excess IGFBP-2 and -1 may play a role in the followed by monthly IVCy for at least 3 months, and then every growth failure of CRF children by sequestering IGF peptides. In 2 and/or 3 months according to clinical response. Prednisone was contrast, IGFBP-3 levels rise with GH treatment of CRF children, given at 1-2 mg/kg during the first month. Laboratory studies in- suggesting a role for IGFBP-3 in their accelerated growth. The cluded routine laboratory tests, antinuclear antibodies, anli- present studies used sensitive and specific antisera to characterize dsDNA, antiphospholipid antibodies, and complement compo- levels and forms of IGFBP-4 and -5 in serum from CRF children.
nents C3 and C4. Neurodiagnostic studies included cerebrospinal By RIA, the mean baseline serum level of IGFBP-4 was high in fluid, magnetic resonance imaging, computed tomography scan- CRF children compared to that in normal children, but the IGFBP- ning, single photon emission computed tomography and electroen- 4 level in CRF serum did not correlate with height SD score; by immunoblot, high CRF levels were associated with increases in Results Three patients had organic brain syndrome with psycho-
both intact and fragmented IGFBP-4. Mean RIA levels of IGFBP- sis, 3 had seizures, 1 stroke, 1 cerebral vasculitis, 1 optic neuritis, 5 were comparable in sera from CRF and normal children. Treat- and 1 transverse myelitis. In 3 of these cases, nervous system in- ing CRF children with GH for 12 months increased serum IGFBP- volvement was the initial presentation of SLE. Five patients had 4 levels by 26% and IGFBP-5 levels by 49%, as determined by 2 or more NP manifestations. Most of them were accompanied by RIA; levels of IGFBP-5, but not IGFBP-4, correlated significantly general SLE activity. Anticardiolipin antibodies were positive in with serum levels of IGF-I, IGF-II, IGFBP-3, and acid-labile sub- 3 patients and none was anticoagulated. All patients improved, unit and with growth rate in these GH- treated children. In sum- 6 patients had a complete recovery and 1 patient recovered with mary, IGFBP-4 levels are high in serum of CRF children, and GH minor neurological deficit. All but one improved significantly increases serum levels of IGFBP-4 and IGFBP-5 in these children.
within the first week of combined IVMP and IVCy. The mean The data suggest a role for IGFBP-5 in the accelerated growth of time of follow-up was 37 months (range 8–55). IVCy was well GH-treated CRF children, perhaps as part of a ternary complex tolerated with minimal side effects.
with acid-labile subunit and IGFs. Additional studies on the rela- Conclusions Early aggressive treatment with combined IVMP and
tionship between intact IGFBP-4 levels and growth are needed to IVCy followed by monthly IVCy may be an effective therapy for determine what role IGFBP-4 plays in the linear growth process in

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