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Pediatric Nephrology

, Volume 34, Issue 10, pp 1671–1681 | Cite as

Evaluation and management of elevated blood pressures in hospitalized children

  • Abanti ChaudhuriEmail author
  • Scott M. Sutherland
Review

Abstract

Elevated blood pressures (BP) are common among hospitalized children and, if not recognized and treated promptly, can lead to potentially significant consequences. Even though we have normative BP data and well-developed guidelines for the diagnosis and management of hypertension (HTN) in the ambulatory setting, our understanding of elevated BPs and their relationship to HTN in hospitalized children is limited. Several issues have hampered our ability to diagnose and manage HTN in the inpatient setting including the common presence of physiologic conditions, which are associated with transient BP elevations (i.e., pain or anxiety), non-standard approaches to BP measurement, a lack of clarity regarding appropriate diagnostic and therapeutic thresholds, and marginal outcome data. The purpose of this review is to highlight the issues and challenges surrounding BP monitoring, assessment of elevated BPs, and the diagnosis of HTN in hospitalized children. Extrapolating from currently available clinical practice guidelines and utilizing the best data available, we aim to provide guidelines regarding evaluation and treatment of elevated BP in hospitalized children.

Keywords

Children Hypertension Management 

Introduction

Hypertension (HTN) is a significant problem in both adults and children. The most recent National Health and Nutrition Examination Survey (NHANES) data suggest that 45.6% of adults (> 18 years) have HTN [1]. The prevalence among healthy children is thought to be between 1.6 and 3.5%; an additional 2.2–9.4% have blood pressures (BP) considered to be elevated above normal [2, 3, 4, 5]. Though pediatric HTN has been well studied in the ambulatory setting, our understanding of elevated BP and its relationship to HTN in hospitalized children is less established. There are a number of issues that contribute to this, including non-standard approaches to BP measurement and inpatient-specific physiologic conditions that cause transient elevations in BP. Thus, while it is straightforward to characterize a BP as being “elevated” above a certain threshold, the significance of that elevation and the point at which “elevated BPs” evolve into true HTN is not entirely clear. Despite these challenges, the ability to more accurately identify and more effectively manage inpatient HTN is of paramount importance. Pediatric hospitalization-associated HTN has been on the rise over the last decade across all age groups; while it is challenging to know if these children are being admitted with HTN or developing it during their stay, there has been a significant increase in HTN-related healthcare costs according to data from the Healthcare Cost and Utilization Project (HCUP) Kids’ Inpatient Database [6]. Furthermore, severe HTN can result in significant complications if not recognized and treated promptly, underscoring the need for better diagnostic and management strategies. In this light, we discuss the best pediatric in-hospital data available and extrapolate from the most current clinical practice guidelines to provide concise recommendations regarding the diagnosis, evaluation, and management of elevated BPs in hospitalized children.

Epidemiology

Prevalence

Though limited, some data characterizing elevated BPs and HTN in hospitalized children do exist. For example, Alperstein et al. conducted a cross-sectional study using data from the 2012 HCUP database and found that the prevalence of HTN, based on International Classification of Diseases coding (ICD-9), was 1.02% in pediatric inpatients [7]. Another study using a nationally representative database of pediatric hospitalizations found that for approximately 1% of children, one of the discharge diagnoses were coded as HTN [6]. Both these studies relied upon billing code data which does not distinguish between disease present on admission and disease developed during admission; additionally, billing code data has historically been insensitive and associated with an underdiagnosis of HTN. For example, Hansen et al. found that among children with confirmed HTN based upon office BP data, only 26% carried an actual diagnosis code for the disease [4]. For comparative purposes, Sleeper et al. applied age-based normative data to admission BPs and found that 24% of these BPs were elevated (defined as an admission BP > 95th percentile) [8]. Notably, this study extrapolated a diagnosis of HTN from a single elevated measurement, which has traditionally overestimated the prevalence of HTN [2, 4, 5]. BP data from intensive care units (ICUs) seem to suggest that elevated BPs are more common in children receiving critical care. One study demonstrated that approximately 19% of pediatric ICU BP readings, by direct arterial, as well as indirect oscillometric, and manual measurements, were in the hypertensive range (defined as > 95th centile for age specific norms) [9]. Similarly, Ehrmann et al. performed a single-center retrospective study of 1215 critically ill children and found that 25% of the population had stage 2 HTN (3 systolic and/or diastolic readings > 99th percentile + 5 mmHg), based on arterial BP readings, and automated noninvasive oscillometric only if arterial readings were unavailable [10]. In summary, the best available data suggest that somewhere between 1 and 25% of hospitalized children experience elevated BPs during their stay. It is likely that children on acute care wards have incidences on the lower end of that spectrum and that the prevalence in pediatric ICUs is on the higher end.

Etiology

HTN is a relatively uncommon primary admission diagnosis. Children tend to be admitted for exacerbations of pre-existing HTN, or with initial presentations of secondary forms of HTN. More commonly, BPs become elevated during the course of hospitalization. In some patients, the elevated BPs are due to their underlying disease (acute kidney injury, chronic kidney disease, obstructive uropathy or its resolution, renal mass effect, etc.) or to the treatments those diseases require (corticosteroids, sympathomimetics, intravenous fluids, vasoactive agents, etc.). In others, the cause may be related to pain or anxiety, postoperative salt and volume overload, a failure to administer the patient’s known antihypertensive medication, or an inability to give oral antihypertensive medication for a variety of reasons (poor family recall, patient is unable to take medications orally, or concerns for hypotension outweighs concern for hypertension). A list of the more common causes of elevated BP in hospitalized children is shown in Table 1.
Table 1

Etiology of acutely elevated blood pressures in hospitalized children

Renal

 Acute kidney injury

 Renovascular disease

 Glomerular disease

 Renal parenchymal disease

 Obstructive uropathy

 Polycystic kidney disease

 Renal tumors

Endocrine

 Pheochromocytoma

 Congenital adrenal hyperplasia

 Primary aldosteronism

 Cushing syndrome

 Hyperthyroidism

Neurologic

 Increased intracranial pressure (head trauma/brain tumor)

 Familial dysautonomia

 Guillain-Barre syndrome

 Cerebral hemorrhage or infarction

Cardiovascular

 Coarctation of the aorta

Drug induced/toxicology

 Sympathomimetics (e.g., cocaine, amphetamines, pseudoephedrine, PCP, ephedra-containing nutraceuticals, caffeine)

 Serotonin syndrome

 Anabolic steroids

 Corticosteroids

 Oral contraceptives

 Clonidine withdrawal

Miscellaneous

 Pain

 Anxiety

 Neuroleptic malignant syndrome

 Neurofibromatosis

 Hypercalcemia

Ambulatory diagnosis of hypertension

In 2017, the American Academy of Pediatrics (AAP) published revised guidelines for the evaluation and management of high BP based upon gender, age, and relative height percentile; these norms differed from those previously published primarily in their exclusion of BP data from overweight and obese children [3]. The AAP recommends that, the diagnosis of HTN in children less than 13 years of age is made when BPs on three separate visits are greater than the 95th percentile for age, gender, and height; in children greater than or equal to 13 years of age, the BPs are categorized as hypertensive if ≥ 130/80 mmHg (Table 2). The European Society of Hypertension (ESH) guidelines, which are based upon the normative auscultatory data from the US Task Force including obese/overweight children, are similar [11]. The main difference is that the age-related inflection point is 16; in children 16 years and older, the definition of HTN is based upon the absolute adult cutoff, which defines high-normal as 130–139/85–89 mmHg and HTN as ≥ 140/90 mmHg) [12]. Both sets of guidelines underscore the importance of choosing an appropriately sized cuff. If too small a cuff is used, the pressure generated by inflating the cuff may not be fully transmitted to the brachial artery. In this setting, the pressure in the cuff may be considerably higher than the intra-arterial pressure, leading to overestimation of the systolic pressure. On the other hand, too wide a cuff may produce lower readings than the actual intra-arterial pressure. Of note, all normative data was based upon auscultatory measurement and though it is reasonable to use oscillometry for screening, any elevated values should be confirmed by auscultation.
Table 2

Definition of hypertension based upon the American Academy of Pediatrics (AAP) 2017 pediatric hypertension guidelines and the 2016 European Society of Hypertension (ESH) guidelines

Category

AAP guidelines

ESH guidelines

 

Age 1–13 years

Age ≥ 13 years

Age 1–15 years

Age ≥ 16 years

Normal

< 90th percentile

< 120/80 mmHg

< 90th percentile

< 130/85 mmHg

Elevated BP/high-normal BP

≥ 90th percentile to < 95th percentile or 120/80 mmHg to < 95th percentile (whichever is lower)

120/<80 to 129/<80 mmHg

≥ 90th percentile to < 95th percentile or

130–139/85–89 mmHg

Hypertension

≥ 95th percentile

≥ 130/80

≥ 95th percentile

≥ 140/90

Stage 1 hypertension

95th percentile to 95th percentile + 12 mmHg OR 130–139/80–89 (whichever is lower)

130–139 / 80–89 mmHg

95th percentile to 99th percentile + 5 mmHg

140–159/90–99 mmHg

Stage 2 hypertension

≥ 95th percentile + 12 mmHg OR

≥140/90 mmHg

> 99th percentile + 5 mmHg

160–179/100–109 mmHg

Compiled from the most recent pediatric hypertension guidelines [3], this table summarizes the age specific definition of hypertension designed for children in the ambulatory setting. 2016 European Society of Hypertension guidelines that differ slightly in the age threshold for using the adult criteria [12]. BP blood pressure, OR odds ratio

Which blood pressure is “normal” for pediatric inpatients?

The BP readings used in the AAP and European guidelines were obtained in a highly controlled setting that differs dramatically from the inpatient environment. This raises the question of how applicable these guidelines are to inpatients—can they be accurately applied to hospitalized children? Inpatients are likely to have far greater stress and anxiety when compared with healthy ambulatory children. Additionally, hospitalized children may be in pain, and it is reasonable to question the significance of “spuriously” elevated readings. However, the challenge for the practitioner is to determine if the readings are due to a treatable underlying condition (pain, stress, fear) or if it is reflective of true HTN.

Though no definitive data exist, attempts have been made to define comparative inpatient values for various vital signs. For example, Bonafide et al. used vital sign data from 14,014 hospitalized children to develop heart rate (HR) and respiratory rate (RR) percentile curves for pediatric inpatients [13]. They found that up to 54% of HR and up to 40% of RR values fell outside standardized, textbook reference ranges. In general, their data-driven reference ranges were higher than the previously established ranges. Goel et al. performed a similar analysis using vital sign data from 9489 children admitted to acute care wards [14]. At every age, the locally derived vital sign ranges were higher than the established National Institute of Health (NIH) normative data. For example, the established NIH RR range for a 12-month old was 20–35 breaths per minute (bpm); the locally derived range (5th–95th centile) was 19–42 bpm [15]. Though no similar BP data exists for general pediatric inpatient populations, Eytan et al. generated age-based centile curves for BP in critically ill children; these curves were developed independent of admission or discharge diagnoses, procedures done during the hospitalization, ventilation status, sedation, or inotropic and vasopressor support [16]. Derived from over one billion data points, the centile curves are based upon intra-arterial (rather than oscillometric or auscultatory) BP measurements and include only critically ill children. Not surprisingly, the authors found that BPs tended to range higher in these critically ill children. While the 95th centile systolic BP for a 1-year-old boy might be as high as 105 mmHg based upon the ambulatory normative values, Eytan et al. found that the 95th centile for 1 year olds in the ICU was as high as 127 mmHg (Table 3). It is incredibly challenging to extrapolate from these data. Being hospitalized is not a “normal” condition and one cannot describe these inpatient-derived centile data as “normative.” However, it is clear that hospitalized children have higher respiratory rates, heart rates, and BPs at baseline than their ambulatory counterparts. More granularly, the data suggest that a 12-year-old girl admitted with cellulitis will have a higher average BP than an equivalent 12-year-old girl will in the outpatient setting, independent of all other clinical factors. This information may have an impact on the way we interpret BPs, elevated or not, in the inpatient setting.
Table 3

Comparison of 95th percentile blood pressure data in the ambulatory setting (manual BP readings) with critically ill children (intra-arterial BP readings)

 

2017 pediatric hypertension guidelines

Pediatric ICU population

1 year old

105/57

127/76

5 years old

112/71

133/80

10 years old

121/78

144/84

15 years old

135/85 (130/80)

155/85

To insure highest possible value, male gender and 95th percentile height were assumed. This table compares blood pressures in children of different ages in the ambulatory setting (compiled from data in 2017 pediatric hypertension guidelines [3]) with those who are critically ill (data obtained from the Supplementary tables in the manuscript “Heart Rate and Blood Pressure Centile Curves and Distributions by Age of Hospitalized Critically Ill Children” by Eytan et al. [16], where only the 95th percentile BP values for males and the average age of a given age range are chosen for comparison). This table demonstrates “normal” BPs are likely to be higher in inpatients than in ambulatory children. BP blood pressure, ICU Intensive Care Unit

Inpatient-specific challenges to measurement and diagnosis

More fundamentally, the most important aspect of diagnosing HTN is accurate BP measurement. Incorrect measurement techniques can lead to inappropriate diagnosis, unnecessary investigations and treatments, false negative findings, and non-treatment of patients with true HTN. In this section, we will highlight some measurement challenges that are particularly prevalent in the inpatient setting.

Arm vs. leg blood pressures

In younger children in particular, measuring BPs in the leg is quite common; this is especially true as medical complexity increases. Often, bedside nurses prefer to avoid repeated occlusion of veins in extremities that have intravenous (IV) lines; many patients receiving critical care may have IV lines in both upper extremities, precluding BP monitoring in the arms. Lower extremity monitoring is problematic since calf/thigh BPs have been shown to be physiologically higher than arm BPs in adults [17]. It is important to note that while we believe the same to hold true for children, variable upper/lower extremity differences in systolic, diastolic, and mean arterial pressures have been found across different age groups [18, 19]. Though lower extremity BP readings are clearly relevant to evaluating for coarctation or peripheral vascular disease, they should not be used interchangeably with arm pressures for chronic measurement or compared to established norms.

Sitting vs. supine blood pressure measurements

When assessing BP in a hospitalized child, it is important to take the position of the patient into consideration. The BP (especially systolic) tends to drop in the standing position compared with the sitting and supine; systolic and diastolic BP is the highest in the supine position when compared to the other positions [20]. Most children who are hospitalized tend to have their BP taken while in the supine position, which may, in turn, result in values that are more elevated than the normative values obtained in the ambulatory setting, which are taken with children in the sitting position, with their feet on the ground. In addition, it is recommended that the cuff is horizontal at the level of the heart at the mid-sternal level as different cuff positions compared to the heart level have significant effects on BP readings [21]. Dependency of the arm below the heart level leads to an overestimation of systolic and diastolic BP and raising the arm above heart level leads to underestimation [22].

Arterial line vs. oscillometric vs. auscultatory blood pressure measurements

Even though practice varies across institutions, inpatient locations, ages, and severity of illness, mostly BPs in hospitalized patients will be obtained by oscillometry. It is recommended that BP values greater than the 90th percentile obtained by oscillometric methods are confirmed by auscultation since oscillometric measurements tend to be higher than those obtained by auscultation [23, 24]. In many critically ill children, however, real-time BP monitoring is required and measurements from arterial lines are common in the ICU; in fact, these continuous readings are considered standard of care for patients with hyper- or hypotensive crises [25]. Despite this, it is well recognized that over- and underdamping, calibration errors, and movement artifacts can lead to erroneous intra-arterial BP data and that noninvasive BP measurements may differ significantly from intra-arterial estimates [26, 27, 28, 29, 30, 31]. These differences are most relevant at BP extremes. For example, Lehman et al. examined 27,022 simultaneously measured invasive arterial/noninvasive BP pairs in adults receiving critical care [32]. They found that noninvasive determination overestimated systolic pressures when compared with invasive methods during periods of hypotension. Not only this, but hypotensive systolic noninvasive BP readings were associated with a greater acute kidney injury (AKI) and mortality risk than invasively obtained BP in the same range, suggesting that noninvasive systolic readings may fail to recognize end-organ hypoperfusion. Similar findings have been found in children outside the normotensive range as well. Holt et al. found automated readings to be higher during hypotension and lower during HTN when compared with intra-arterial measurements [9]. Thus, though frequent oscillometric measurements (confirmed by auscultation if necessary) are acceptable in hemodynamically stable patients, arterial BP remains the preferred method of BP monitoring in critically ill children.

Mean arterial pressure vs. systolic blood pressure

It has been shown that noninvasive and invasively obtained mean arterial pressures (MAP) show better agreement [32]. Lehman et al. demonstrated that the AKI prevalence and ICU mortality risk associated with hypotensive MAPs was similar regardless of measurement technique [32]. Thus, oscillometric measurement can be reliably used to assess MAP (as opposed to systolic or diastolic BP which can be inaccurate as they are calculated from MAP based on proprietary algorithms that vary from device to device) when intra-arterial monitoring is not available or is not feasible. However, there is no definitive normative MAP data in children. Haque et al. derived 5th centile estimates from task force data for children from 1 to 17 years of age and calculated normal MAP values using a standard mathematical formula [33]. These values are derived from healthy children and may need to be applied differently in critically ill children. It is to be noted that MAP values tend to vary across the height percentile within the same age group, just like systolic and diastolic BP and this variation may need to be considered when caring for a very short or tall child.

Diagnosis of hypertension in hospitalized children

It is unlikely that BP values in the inpatient and ambulatory settings have identical thresholds and significance. The currently available inpatient data for other vital signs (HR and RR) ranges higher in hospitalized children and it is likely that BP data follows the same trend [13, 14, 15]. However, given the lack of inpatient data and the presence of robust ambulatory information, we recommend defining HTN in hospitalized children in concordance with the most recent clinical practice guidelines, i.e., when BPs are consistently ≥ 95th centile for the age, gender, and height of the patient (Table 3) [3, 12]. Care should be taken to measure BPs using an appropriately sized cuff on the arm whenever possible in calm, comfortable children. In critically ill children, as long as the arterial tracing is accurate, invasively measured BPs remain the standard of care. Practitioners should remember that while MAP data tends to correlate between invasive and noninvasive methods, oscillometric systolic values tend to be higher than invasively determined values, but MAP, as well as systolic and diastolic values, may vary by device and not all devices are validated in children.

Treatment

Who should be treated?

One of the more challenging aspects of managing elevated BP is the determination of treatment threshold. Though we recommend using the most recent data from clinical practice guidelines for inpatient HTN diagnosis, we do feel that treatment of inpatients diagnosed in this fashion will vary from that seen in the ambulatory setting. It is important to remember that treatment recommendations for ambulatory children are based upon the desire to prevent long-term systemic complications, which tend to develop over a period of many years. A child who has similar HTN transiently is unlikely to experience the same morbidity if the HTN resolves within days or weeks. In the inpatient setting, unless patients have longstanding HTN, which is unlikely to resolve, treatment decisions should revolve around the prevention of acute, symptomatic hypertensive complications. Ehrman et al. found that in children receiving intensive care, ≥ 5 readings over the 99th percentile plus 5 mmHg (stage 2 HTN) within a single day was associated with a significantly greater risk for AKI and prolonged length of stay [10]. This suggests that a full day of BPs above the stage 2 range may have clinical significance acutely in critically ill children. With lack of robust outcome data in hospitalized children, we propose that, even though patients with BPs ≥ 95th percentile are considered hypertensive, treatment be considered acutely in hospitalized patients who have sustained stage 2 HTN that persists for greater than a day. We would define stage 2 HTN as described above—a systolic, diastolic, greater than the 95th percentile plus 12 mmHg or the specific BP threshold for stage 2 HTN per the AAP or the ESH guidelines in older children (Table 2). In addition, treatment should be considered in children experiencing a sudden rise in BP, regardless of whether or not it meets the stage 2 threshold. Patients who have one or several BPs which greatly exceed the stage 2 threshold should be considered for therapy as well, regardless of the duration of the elevation. Any patient with hypertensive emergency or encephalopathy should obviously be treated immediately. Finally, the underlying risk for hypertensive complications should be considered. Children at greater risk for seizures or encephalopathy, as well as those who might be at greater risk for hypertensive complications (recent surgery, thrombocytopenia, etc.), should be treated at lower thresholds. On the other hand, children at greater risk for hypotensive complications (elevated ICP, etc.) might benefit from treatment at higher thresholds.

Treatment goals

The 2017 AAP pediatric HTN guidelines define “normal” BP in children to be < 90th percentile or < 120/80 for those ≥ 13 years [3, 12]. While an ideal treatment goal in outpatients will be to bring the BP to within the “normal” range, it may not be necessary or feasible in the inpatient setting. It may be sufficient targeting BPs < 95th percentile or < 130/80 in children ≥ 13 years as a baseline goal in inpatients; however, some children may benefit from stricter or more lenient management based on clinical circumstances. It is important to take the rapidity and duration of the elevated BPs into account when determining how quickly the goal BP should be reached. In children with chronic HTN, cerebral autoregulatory mechanisms adapt to protect the brain from ischemia. A rapid lowering of BP can lead to decreased cerebral perfusion and neurologic dysfunction, AKI, and transverse ischemic myelopathy [34]. It is recommended the BP is lowered gradually in a controlled fashion to reach the goal pressure. Per the Clinical Practice Guidelines, BP should be reduced by no more than 25% of the planned reduction over the first 8 h, with the remainder of the planned reduction over the next 12 to 24 h [3]. Children with a very rapid rise in BP from normal will not have adjusted to the higher BP range with minimal cerebral perfusion auto-regulation and are at high risk of posterior reversible encephalopathy syndrome; thus, they require aggressive and early antihypertensive therapy, which is usually well tolerated without evidence of organ ischemia. Many children found to have moderately severe elevations of BP can be managed on the general pediatric ward. Those children with hypertensive emergencies or with symptomatic BPs refractory to intermittently administered medications will often require ICU admission for continuous infusion of antihypertensive agents and close clinical monitoring.

Treatment options

Once BP is found to be elevated, the first step is to eliminate iatrogenic causes if present and feasible. Pain and anxiety should be adequately managed and agitation should be reduced to the extent possible. Fluid overload, if present, should be treated with fluid restriction and/or diuretics if appropriate. If HTN persists, antihypertensive therapy should be considered. Despite the increase in published data over the last decade, pediatric safety and efficacy of oral antihypertensive agents remain limited, and technically, many agents are not cleared for use in children by the United States Food and Drug Administration. Current treatment relies on the experiences of individual providers, and an experienced clinician, such as a pediatric nephrologist or intensivist, should guide therapy of pediatric hypertensive emergencies.

If treatment is thought to be necessary after initial assessment, the provider should determine whether an oral or IV agent is appropriate initial therapy based on severity of symptoms, patient location within hospital, access available, and the ability to tolerate oral medications. Oral medications can be used for gradual BP reduction in patients with asymptomatic or mildly symptomatic HTN. In acute hypertensive urgency or situations where BP has changed rapidly, intermittent bolus dosing of short-acting IV antihypertensive agents which have a rapid onset of action can be used. In severe hypertensive crisis, a continuous IV infusion may be ideal since it allows rapid titration and is best suited to achieve gradual BP control. However, if patients are in hospital locations such as the emergency unit or the general pediatric floor where continuous infusion of antihypertensive medication cannot be performed, careful administration of an initial IV bolus therapy is recommended with frequent oscillometric BP monitoring until the patient can be transferred to an ICU. Once in the ICU, continuous infusion of IV antihypertensive agents is recommended with intra-arterial BP monitoring. Once symptoms are resolved and hypertensive crisis has been mitigated, patients can be transitioned to long acting oral medications. By this time, evaluation of HTN may have revealed an etiology, and when possible, the choice of agent should be dictated by this knowledge. The various antihypertensive agents that can be used are summarized in Table 4.
Table 4

Antihypertensive agents used in acute hypertension

Name

Mechanism of action

Onset of action

Route

Dose

Side effects

Comments

Hydralazine

Direct vasodilator

10–80 min

IV bolus or IM

0.2 to 0.6 mg/kg IV or IM, maximum single dose 20 mg, repeated every 4 h as required

Reflex tachycardia, headache, fluid retention

Duration of action 2–4 h

Labetalol

α and β adrenergic blocker

2–5 min

IV bolus or infusion

Bolus 0.2–1 mg/kg/dose, up to 40 mg/dose; infusion 0.25–3 mg/kg/h

Hypotension, dizziness, nausea, bradycardia, bronchospasm

Contraindicated in asthma, heart failure, and diabetics

Nicardipine

Calcium channel blocker

Few minutes

IV bolus or infusion

Bolus 30 μg/kg up to 2 mg/dose; infusion 0.5–4 μg/kg/min

Reflex tachycardia, peripheral edema

Risk of thrombophlebitis, central line preferred

Sodium nitroprusside

Vasodilator

< 2 min

IV infusion

0.5–10 μg/kg/min

Hypotension, palpitations, flushing

Monitor for cyanide and thiocyanate toxicity, measure cyanide levels with prolonged use (> 48 h) or in hepatic or renal failure, or co-administer with sodium thiosulfate

Esmolol

β-Blocker

< 1 min

IV infusion

100–500 μg/kg/min, up to 1000 μg/kg/min continuous IV infusion

Bradycardia, decreased cardiac output, bronchospasm

Contraindicated in asthma and heart failure. Very short-acting

Fenoldopam

Dopamine receptor agonist

10 min

IV infusion

0.2–0.8 μg/kg/min

Tachycardia, headache, nausea, flushing, hypotension, hypokalemia

Limited pediatric experience

Clevidipine

Calcium channel blocker

2 min

IV infusion

0.5–3.5 μg/kg/min (limited pediatric data on dosing)

Hypotension, tachycardia

Very short acting. Contraindicated in those with egg and soy allergy as well as lipid disorders

Enalaprilat

ACE inhibitor

≤ 15 min

IV bolus

5–10 μg/kg/dose up to 1.2 mg/dose

Acute kidney injury, hyperkalemia, hypotension

Neonates are at increased risk for prolonged hypotension and acute kidney injury

Phentolamine

α adrenergic antagonist

 

IV bolus

0.05–0.1 mg/kg/dose, up to 5 mg

Tachycardia

Useful in catecholamine and cocaine- or pseudoephedrine-induced hypertension

Isradipine

Calcium channel blocker

1 h

PO

0.05–0.1 mg/kg/dose up to 5 mg/dose

Headache, nausea, flushing, hypotension

Stable suspension can be compounded

Clonidine

Central α agonist

30–60 min

PO

0.05–0.1 mg/dose, may be repeated up to 0.8 mg total

Dry mouth and sedation

Risk of rebound hypertension if standing doses are withdrawn abruptly

Minoxidil

Direct vasodilator

30 min

PO

0.1–0.2 mg/kg per dose

Edema, and hypertrichosis with chronic use

Long duration of action

Nifedipine

Calcium channel blocker

1–5 min

PO

0.1–0.25 mg/kg per dose up to 10 mg per dose

Hypotension, flushing, tachycardia, syncope

Not recommended for pediatric use

Intermittent IV therapies

Two of the intermittent IV agents which are commonly used to treat children with acutely elevated BPs are hydralazine and labetolol. Single-center retrospective studies evaluating the efficacy and safety of IV hydralazine in hospitalized children have reported an average reduction in systolic and diastolic BP of 8–10% with a single dose, though larger decrements have been reported [35]. In our experience, tachyphylaxis to the antihypertensive effects of intravenous hydralazine may occur, making subsequent doses less effective after 48–72 h. Additionally, efficacy may be limited due to reflex tachycardia related to stimulation of the sympathetic nervous system. Alternatively, labetalol is effective in reducing BPs in the setting of acute elevations, though it has been associated with hypotension when used in infants and young children [36, 37]. Labetalol can also be used as a continuous infusion. Enalaprilat, the only FDA-approved angiotensin-converting enzyme inhibitor available in IV form, can also be effective [38, 39]. However, it can induce AKI as well as hyperkalemia, and must be used with great caution in neonates and patients with AKI, chronic kidney disease, and volume depletion [40].

IV continuous infusion

Nicardipine is commonly used as a continuous infusion in children with severe BP elevation. It is effective in reducing BP and is associated with minimal adverse effects across many disease states and age groups [41, 42, 43]. One issue which can be seen with nicardipine is thrombophlebitis and it is recommended that the medication be administered centrally if possible. Esmolol, although less pediatric data exists, is thought to be safe and effective particularly in hypertensive infants and young children following cardiac surgical repair [44, 45]. One benefit is that its metabolism is independent of hepatic and renal metabolism, making it suitable for patients with multiorgan failure [46]. Sodium nitroprusside is very effective in reducing BP and can be titrated rapidly. Though the incidence of complications is low, many practitioners avoid it due to the risk for cyanide and thiocyanate accumulation after extended use (24–48 h), particularly in children with concomitant renal or liver dysfunction [47]. It must be noted, however, that in a randomized, double-blind study, not a single patient demonstrated overt evidence of toxicity even in the setting of significantly elevated cyanide levels [48]. Newer IV agents like fenoldopam and clevidipine are promising based on adult trials, but pediatric experience is still limited [48, 49].

Oral agents

In hospitalized patients, calcium channel blockers are used with great frequency due to their efficacy and side effect profile. Options include isradipine, preferred for its rapid onset and short duration of action (half-life of 1.5 to 2 h), amlodipine, less preferred in the acute situation for its slow onset and longer duration of action (half-life of 30–50 h), hence, typically used if requiring isradipine frequently, and nifedipine (half-life of 2 h) [50, 51, 52]. Nifedipine, however, is no longer a preferred agent in children due to its association with large drops in BP in children and an increased risk for myocardial infarction, stroke, and death reported in the adult population [53, 54]. Notably, stable solutions of isradipine and amlodipine can be compounded, which is particularly advantageous in infants and young children. Clonidine, which is available in a transdermal form as well, is used frequently in patients with chronic HTN as well as in the ICU [55, 56]. It is particularly useful in the settings of catecholamine-induced HTN, HTN associated with withdrawal of sedatives, and in those with neurologically mediated HTN. Minoxidil is effective in severe childhood HTN; however, we tend to use it only in HTN refractory to other medications due to the risk for cardiac effusions [57, 58].

Transitions, discharge, and follow up

If the patient remains on oral antihypertensive therapy at the time of hospital discharge, families should go home with an FDA-cleared BP monitoring device complete with an appropriately sized cuff, which should be ideally correlated with the hospital device prior to discharge, or alternatively, caregivers should be taught how to measure BP manually. Patients and families should receive appropriate education regarding HTN, medication side effects, and a monitoring plan. Many patients will benefit from parameters below which the medication should be held (level varies with the physicians preference) as well as parameters for contacting the nephrology team (i.e., hypotension or persistent HTN). Follow up with a nephrologist or other specialists in the management of hypertension should be organized prior to discharge, and parents should be provided with BP logs and instructions to bring them to clinic.

Future studies and work

Despite well-established ambulatory guidelines, elevated BPs often go unrecognized in hospitalized pediatric patients, potentially putting them at risk for the sequelae of untreated HTN. In a retrospective study of 1143 hospitalized children, a concern for HTN was documented for only 26% of subjects admitted with stage 2 HTN (admission BP > 99th percentile + 5 mmHg) [8]. Thus, it is clear that we need additional strategies to improve the recognition of HTN. In children, BP reference tables are complex and require the use of multiple variables, including sex, age, and height, which makes determining BP percentiles challenging; we believe that addressing this issue is likely to have a significant impact on HTN identification. At a minimum, the BP interpretation tables based on age, sex, and height percentile need to be readily available in the hospital setting. However, better recognition rates have been observed with simplified abnormal BP screening tables which is a reasonable alternative [59]. Another option is to use the electronic medical record (EMR) to our advantage. The EMR contains all BP data as well as the information needed to determine percentiles. Simple approaches such as flagging BPs that meet a certain threshold (i.e., > 95th percentile + 12 mmHg) are likely to be quite beneficial. Additional options include EMR-based tools such as real-time alerts or applications capable of calculating BP percentiles automatically; studies investigating these tools confirm they show promise in improving elevated BP recognition [60, 61]. In our center, we have a web-based, EMR-integrated, pediatric HTN diagnosis and treatment decision support tool (https://hyperisk.stanfordchildrens.org/about/). This tool passes Health Insurance Portability and Accountability Act (HIPAA) compliant data from the EMR to a web-based platform, which then provides percentile information, diagnosis, and treatment recommendations (Fig. 1). There is clearly a need for the development of similar tools suitable for widespread use that would improve our ability to diagnose and manage HTN. Development of inpatient BP data across all age groups of hospitalized children based on epidemiologic outcome measures as opposed to statistical population norms will be an important development in the future as well; this will be important to help us determine the optimal treatment thresholds and goals. Finally, pediatric randomized controlled trials are required to assess treatment efficacy, safety, and outcomes for the different antihypertensive agents to allow more informed management decisions.
Fig. 1

Web-based hypertension (HTN) diagnostic platform. This figure is an example of the information provided for by Hyperisk, a web-based, electronic medical record (EMR)-integrated, pediatric HTN diagnosis and treatment decision support tool (https://hyperisk.stanfordchildrens.org/about/). Linkage with the EMR allows Health Insurance Portability and Accountability Act (HIPAA) compliant data do be passed directly to the web-based platform which then calculates blood pressure percentiles, a diagnosis based upon the readings available, and treatment recommendations. In this case, the 3-year 7-month-old male has more than 3 values which are between the 95th percentile and 99th percentile + 5 mmHg, which is consistent with stage 1 HTN. Treatment recommendations are customized because the patient is located in an inpatient setting; ambulatory recommendations are taken directly from the most recent pediatric HTN guidelines

Summary

Elevated BP is common among hospitalized children and the prevalence seems to be on the rise; currently we estimate that between 1 and 25% of pediatric inpatients experience elevated BP, with higher rates in those receiving critical care. In hospitalized children, there are a number of inpatient-specific issues that plague our ability to obtain accurate, reliable BP measurements, and it is important for the clinician to understand these challenges and the manner in which they affect BP measurements. One of the biggest challenges facing us is determination of which patients and which BP values require therapeutic intervention. While data suggest that BPs, on average, range higher in the hospital than they do in the ambulatory setting, we believe the exceptional ambulatory normative data for children is the best data to use in the inpatient setting as well. Thus, HTN should be diagnosed at similar threshold in both locations. However, given the different risks patients have in the two settings, we recommend initiating treatment at a higher threshold (stage 2 HTN or 95th percentile + 12 mmHg) and targeting somewhat less aggressive control when appropriate. Obviously, the ultimate decision is patient specific and some patients may benefit from higher or lower treatment thresholds and therapeutic targets; it is clear that many of these decisions will need to be individualized. Once the decision is made to begin therapy, a variety of agents are available in oral and intravenous forms; the choice of agent will depend on clinical circumstances, underlying disease, etiology, severity of HTN, and rapidity with which the elevation occurred. Future directions should include the development of stronger EMR-based diagnostic tools and prospective studies to help us better understand therapy-related outcomes in these children.

Notes

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

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Copyright information

© IPNA 2018

Authors and Affiliations

  1. 1.Division of Nephrology, Department of PediatricsStanford UniversityCaliforniaUSA

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