Maternal and neonatal demographics of macrosomic infants admitted to the neonatal intensive care unit.

OBJECTIVE: The objective of this study is to determine the incidence, significance, associated demographics and impact of macrosomic infants (⩾4 kg) admitted to the Neonatal Intensive Care Unit (NICU) on NICU census and resources. STUDY DESIGN: A retrospective cohort review was performed from 2010 to 2015. Descriptive statistical analyses were used. RESULTS: Of 19 308 deliveries, 1823 were infants ⩾4000 g and 213 were admitted to the NICU. Cesarean delivery occurred in 70% of the admitted infants, most (74.1%) were Grade 1 macrosomia and male (63%). Preterm birth occurred in 4%. The incidence of maternal diabetes was 25%. Primary admitting diagnoses were respiratory distress, suspected sepsis, hypoglycemia and perinatal depression. The average length of stay was 8±6 days for all macrosomic infants admitted, increased to 22±13 days for infants with Grade 3 macrosomia. CONCLUSION: Macrosomic infants are a growing population, who increase the demand on existing NICU resources. A larger multi-centered study is needed to determine the overall relevance of these findings in other populations.

Effect of spironolactone on diastolic function in hypertensive left ventricular hypertrophy.

We have previously shown rapid reversal of left ventricular hypertrophy (LVH) with 6 months of spironolactone therapy in patients with resistant hypertension (HTN), preserved left ventricular ejection fraction and no history of heart failure. In this substudy, we investigated the effect of mineralocorticoid receptor blockade with spironolactone on pre-clinical diastolic dysfunction. Thirty-four patients (19 with high and 15 with normal aldosterone levels) were treated with spironolactone and followed with cardiac magnetic resonance with tissue tagging at baseline, 3 and 6 months of treatment. Serum markers of collagen turnover (C-propeptide of type-I procollagen and carboxy-terminal telopeptide of type-I collagen) were measured at baseline and at 6 months. At baseline, patients demonstrated reduced E/A ratio (volumetric normalized peak early filling rate/late filling rate, normalized to left ventricular end-diastolic volume), lower peak early-diastolic mitral annular velocity and lower peak early-diastolic circumferential strain rates compared to the reference values obtained from 45 normal controls without HTN or cardiac disease (all comparisons, P<0.01). No significant change occurred in diastolic filling, relaxation parameters or collagen markers with spironolactone therapy at 6 months irrespective of aldosterone status despite significant reduction in left ventricular mass index in both high- and normal-aldosterone groups. In conclusion, resistant HTN patients with LVH demonstrate significant pre-clinical diastolic dysfunction. Short-term spironolactone therapy may not lead to improvement in diastolic function despite rapid reversal of LVH.

Apparent and true resistant hypertension: definition, prevalence and outcomes.

Resistant hypertension, defined as blood pressure (BP) remaining above goal despite the use of > or =3 antihypertensive medications at maximally tolerated doses (one ideally being a diuretic) or BP that requires > or =4 agents to achieve control, has received more attention with increased efforts to improve BP control rates and the emergence of device-based therapies for hypertension. This classically defined resistant group consists of patients with true resistant hypertension, controlled resistant hypertension and pseudo-resistant hypertension. In studies where pseudo-resistant hypertension cannot be excluded (for example, 24-h ambulatory BP not obtained), the term apparent resistant hypertension has been used to identify 'apparent' lack of control on > or =3 medications. Large, well-designed studies have recently reported the prevalence of resistant hypertension. Pooling prevalence data from these studies and others within North America and Europe with a combined sample size of >600,000 hypertensive participants, the prevalence of resistant hypertension is 14.8% of treated hypertensive patients and 12.5% of all hypertensives. However, the prevalence of true resistant hypertension, defined as uncontrolled both by office and 24-h ambulatory BP monitoring with confirmed medication adherence, may be more meaningful in terms of identifying risk and estimating benefit from newer therapies like renal denervation. Rates of cardiovascular events and mortality follow mean 24-h ambulatory BPs in patients with resistant hypertension, and true resistant hypertension represents the highest risk. The prevalence of true resistant hypertension has not been directly measured in large trials; however, combined data from smaller studies suggest that true resistant hypertension is present in half of the patients with resistant hypertension who are uncontrolled in the office. Our pooled analysis shows prevalence rates of 10.1% and 7.9% for uncontrolled resistant hypertension among individuals treated for hypertension and all hypertensive individuals, respectively.

Heart rate and heart rate variability in resistant versus controlled hypertension and in true versus white-coat resistance.

Sympathetic nervous system has an important role in resistant hypertension. Heart rate (HR) is a marker of sympathetic activity, but its association with resistant hypertension has not been assessed. We aimed to evaluate differences in HR values and variability between resistant and controlled patients and between true and white-coat resistant hypertensives (RHs). We compared office and ambulatory HR, nocturnal dip and s.d. in 14,627 RHs versus 11,951 controlled patients (on ⩽ 3 drugs) and in 8730 true (24 h blood pressure (BP) ⩾ 130 and/or 80 mm Hg) versus 4825 white-coat (24-h BP < 130/80 mm Hg) RHs. After adjusting for age, gender, body mass index, diabetes status and beta blocker use, HR values and variability were significantly elevated in resistant versus controlled patients and in true versus white-coat RHs. In logistic regression models, after adjustment for confounders, office HR (odds ratio for each increase in tertile: 1.337; 95% confidence interval: 1.287-1.388; P < 0.001), nocturnal dip (0.958; 0.918-0.999; P = 0.035) and night time s.d. (1.115; 1.057-1.177; P = 0.013) were all significantly associated with the presence of resistant hypertension. Moreover, night time HR (1.160; 1.065-1.265; P < 0.001), nocturnal dip (0.876; 0.830-0.925; P < 0.001) and 24-h s.d. (1.148; 1.092-1.207; P < 0.001) were all significantly associated with true resistant hypertension. In conclusion, both increased HR and variability are associated with resistant hypertension and with true resistance. These suggest the involvement of the sympathetic nervous system in the development of resistance to antihypertensive treatment.

Bartter syndrome: presentation in an extremely premature neonate.

Reports of Bartter syndrome in premature neonates are rare. We describe the presentation and clinical course of a neonate born at 25.6 weeks estimated gestational age with polyuria, hyponatremia, hypokalemia and hypercalciuria ,who was diagnosed with neonatal Bartter syndrome. The evaluation, diagnosis and management of neonatal Bartter syndrome in this premature neonate are discussed.

Resistant hypertension, obstructive sleep apnoea and aldosterone.

Obstructive sleep apnoea (OSA) and hypertension commonly coexist. Observational studies indicate that untreated OSA is strongly associated with an increased risk of prevalent hypertension, whereas prospective studies of normotensive cohorts suggest that OSA may increase the risk of incident hypertension. Randomized evaluations of continuous positive airway pressure (CPAP) indicate an overall modest effect on blood pressure (BP). Determining why OSA is so strongly linked to having hypertension in cross-sectional studies, but yet CPAP therapy has limited BP benefit needs further exploration. The CPAP studies do, however, indicate a wide variation in the BP effects of CPAP, with some patients manifesting a large antihypertensive benefit such that a meaningful BP effect can be anticipated in some individuals. OSA is particularly common in patients with resistant hypertension (RHTN). The reason for this high prevalence of OSA is not fully explained, but data suggest that it may be related to the high occurrence of hyperaldosteronism in patients with RHTN. In patients with RHTN, it has been shown that aldosterone levels correlate with severity of OSA and that blockade of aldosterone reduces the severity of OSA. Overall, these findings are consistent with aldosterone excess contributing to worsening of underlying OSA. We hypothesize that aldosterone excess worsens OSA by promoting accumulation of fluid within the neck, which then contributes to increased upper airway resistance.

Long-term effects of aldosterone blockade in resistant hypertension associated with chronic kidney disease.

Hypertension is a major risk factor for the development and progression of chronic kidney disease (CKD). Mineralocorticoid receptor antagonists (MRAs) are effective in the management of resistant hypertension but are not widely used in CKD because of the risk of hyperkalemia. We retrospectively evaluated the long-term effects and safety of MRAs added to a pre-existing antihypertensive regimen in subjects with resistant hypertension associated with stage 3 CKD. In all, 32 patients were treated with spironolactone and 4 with eplerenone for a median follow-up of 312 days. MRAs induced a significant decrease in systolic blood pressure from 162±22 to 138±14 mm Hg (P<0.0001) and in diastolic blood pressure from 87±17 to 74±12 mm Hg (P<0.0001). Serum potassium increased from 4.0±0.5 to 4.4±0.5 mEq l(-1) (P=0.0001), with the highest value being 5.8 mEq l(-1). The serum creatinine increased from 1.5±0.3 to 1.8±0.5 mg dl(-1) (P=0.0004) and the estimated glomerular filtration rate decreased from 48.6±8.7 to 41.2±11.5 ml min(-1) per 1.73 m(2) (P=0.0002). One case of acute renal failure and three cases of significant hyperkalemia occurred. MRAs significantly reduced blood pressure in subjects with resistant hypertension associated with stage 3 CKD, although close biochemical monitoring is recommended because of an increased risk of hyperkalemia and worsening of renal function.

Non-dipping pattern relates to endothelial dysfunction in patients with uncontrolled resistant hypertension.

Resistant hypertension (RHTN) includes both patients whose blood pressure (BP) is uncontrolled on three or more medications (uncontrolled RHTN (UCRH)) and patients whose BP is controlled with use of four or more drugs (controlled RHTN (CRH)). It is unknown whether endothelial function and nocturnal drop demonstrate a similar pattern in patients with CRH and UCRH. We examined circadian BP patterns and vascular function in these patients. In all, 40 CRH and 26 UCRH patients, and 25 normotensives underwent biochemical testing, ambulatory BP monitoring, determination of brachial artery responses to endothelial-dependent (flow-mediated; dilation (FMD)) and independent (nitroglycerin mediated) stimuli. The nighttime drop in systolic BP (SBP) and diastolic BP (DBP) was less pronounced in UCRH than in CRH (SBP, 1.9±1.6 versus 4.9±1.7%; DBP, 7.5±1.8 versus 10.9±1.8%, UCRH and CRH, respectively; P<0.05). FMD was greater in control group compared with RHTN patients. Patients with UCRH had significantly impaired FMD compared with CRH (5.9±2.3% versus 7.1±5.1%; P<0.0001). Therefore, UCRH patients have less nocturnal dipping and a more impaired endothelial response compared with CRH patients. These findings suggest that important differences among patients with RHTN may allow identify subgroups with increased cardiovascular risk.

24-Hour ambulatory blood pressure control with triple-therapy amlodipine, valsartan and hydrochlorothiazide in patients with moderate to severe hypertension.

To determine the effectiveness and safety of once-daily combination therapy with amlodipine, valsartan and hydrochlorothiazide for reducing ambulatory blood pressure (ABP) in patients with moderate to severe hypertension, a multicenter, double-blind study was performed (N=2271) that included ABP monitoring in a 283-patient subset. After a single-blind, placebo run-in period, patients were randomized to receive amlodipine/valsartan/hydrochlorothiazide (10/320/25 mg), valsartan/hydrochlorothiazide (320/25 mg), amlodipine/valsartan (10/320 mg) or amlodipine/hydrochlorothiazide (10/25 mg) each morning for 8 weeks. Efficacy assessments included change from baseline in 24-h, daytime and night time mean ambulatory systolic BP (SBP) and diastolic BP (DBP). Statistically significant and clinically relevant reductions from baseline in all these parameters occurred in all treatment groups (P<0.0001, all comparisons versus baseline). At week 8, least squares mean reductions from baseline in 24-h, daytime and night time mean ambulatory SBP/DBP were 30.3/19.7, 31.2/20.5 and 28.0/17.8 mm Hg, respectively, with amlodipine/valsartan/hydrochlorothiazide; corresponding reductions with dual therapies ranged from 18.8-24.1/11.7-15.5, 19.0-25.1/12.0-16.0 and 18.3-22.6/11.1-14.3 mm Hg (P≤0.01, all comparisons of triple versus dual therapy). Treatment with amlodipine/valsartan/hydrochlorothiazide maintained full 24-h effectiveness, including during the morning hours; all hourly mean ambulatory SBP and mean ambulatory DBP measurements were ≤130/85 mm Hg at end point. Amlodipine/valsartan/hydrochlorothiazide combination therapy was well tolerated. Once-daily treatment with amlodipine/valsartan/hydrochlorothiazide (10/320/25 mg) reduces ABP to a significantly greater extent than component-based dual therapy and maintains its effectiveness over the entire 24-h dosing period.

Characteristics of resistant hypertension: ageing, body mass index, hyperaldosteronism, cardiac hypertrophy and vascular stiffness.

Resistant hypertension (RHTN) includes patients whose blood pressure (BP) is controlled with the use of four or more antihypertensive medications, and is referred to as 'controlled resistant hypertension' (CRH). While specifically comparing patients with CRH and uncontrolled resistant hypertension (UCRH), we hoped to identify distinguishing characteristics that would provide insight into factors contributing to resistance to antihypertensive therapies. RHTN patients were identified as controlled (CRH, n=43) or uncontrolled (UCRH, n=47). No statistical differences were observed between the CRH and UCRH subgroups with respect to age and gender. The body mass index, aldosterone-renin ratio and pulse wave velocity (PWV) were significantly higher in UCRH patients. Although both subgroups showed increased cardiac mass, left ventricular mass index was significantly higher in UCRH compared with CRH patients. Multivariate linear regression analysis indicated that PWV was significantly dependent on age in both UCRH and CRH patients; however, the influence of ageing was more pronounced in the former subgroup. Older age, greater vascular stiffness, higher aldosterone levels and greater left ventricular hypertrophy were significantly associated with lack of BP control in patients with RHTN. These findings suggest important possibilities in terms of preventing and better treating RHTN.

Effectiveness of initiating treatment with valsartan/hydrochlorothiazide in patients with stage-1 or stage-2 hypertension.

This prospective, 6-week, multicenter, double-blind study examined the benefits of initiating treatment with combination valsartan/hydrochlorothiazide (HCTZ) compared with initial valsartan monotherapy for 648 patients with stage-1 or stage-2 hypertension (age=52.6+/-10 years; 54% male; baseline blood pressure (BP)=161/98 mm Hg, 32% stage 1). Patients were randomized to valsartan 80 mg (V-low), valsartan 160 mg (V-high) or valsartan/HCTZ 160/12.5 mg (V/HCTZ), and electively titrated after weeks 2 and 4 to the next dosage level (maximum dose valsartan/HCTZ 160/25 mg) if BP remained >140/90 mm Hg. At end of the study, patients initiated with V/HCTZ required less titration steps compared with the initial valsartan monotherapy groups (63 vs 86% required titration by study end, respectively) and reached the target BP goal of <140/90 mm Hg in a shorter period of time (2.8 weeks) (P<0.0001) vs V-low (4.3 weeks) and V-high (3.9 weeks). Initial combination therapy was also associated with higher BP control rates and greater reductions in both systolic and diastolic BP from baseline (63%, -27.7+/-13/-15.1+/-8 mm Hg) compared with V-low (46%, -21.2+/-13/-11.4+/-8 mm Hg, P<0.0001) or V-high (51%, -24.0+/-13/-12.0+/-10 mm Hg, P<0.01). Overall and drug-related AEs were mild to moderate and were similar between V/HCTZ (53.1 and 14.1%, respectively) and the two monotherapy groups, V-low (50.5 and 13.8%) and V-high (50.7 and 11.8%). In conclusion, initiating therapy with a combination of valsartan and low-dose HCTZ results in early, improved BP efficacy with similar tolerability as compared with starting treatment with a low or higher dose of valsartan for patients with stage-1 and stage-2 hypertension.

Spironolactone reduces severity of obstructive sleep apnoea in patients with resistant hypertension: a preliminary report.

Obstructive sleep apnoea (OSA) and hyperaldosteronism are very common in subjects with resistant hypertension. We hypothesized that aldosterone-mediated chronic fluid retention may influence OSA severity in patients with resistant hypertension. We tested this in an open-label evaluation by assessing the changes in the severity of OSA in patients with resistant hypertension after treatment with spironolactone. Subjects with resistant hypertension (clinical blood pressure (BP) >or=140/90 mm Hg on >or=3 antihypertensive medications, including a thiazide diuretic and OSA (defined as an apnoea-hypopnoea index (AHI) >or=15) had full diagnostic, polysomnography before and 8 weeks after spironolactone (25-50 mg a day) was added to their ongoing antihypertensive therapy. In all, 12 patients (mean age 56 years and body mass index 36.8 kg m(-2)) were evaluated. After treatment with spironolactone, the AHI (39.8+/-19.5 vs 22.0+/-6.8 events/h; P<0.05) and hypoxic index (13.6+/-10.8 vs 6.7+/-6.6 events/h; P<0.05), weight and clinic and ambulatory BP were significantly reduced. Plasma renin activity (PRA) and serum creatinine were significantly higher. This study provides preliminary evidence that treatment with a mineralocorticoid receptor antagonist substantially reduces the severity of OSA. If confirmed in a randomized assessment, it will support aldosterone-mediated chronic fluid retention as an important mediator of OSA severity in patients with resistant hypertension.

Treatment of resistant hypertension.

AIM: Resistant hypertension (RH) is a common clinical problem. Patients with RH have increased cardiovascular risk. These patients also have high risk for having reversible causes of hypertension and may potentially benefit from special diagnostic or therapeutic considerations. The purpose of this review was to discuss RH, its definition, recognition, evaluation and treatment. METHODS: Authors define RH and the implications of this definition. They present latest data on its prevalence, prognostic implications, genetics, and patient characteristics. Elements of pseudoresistance and possible etiologies of treatment resistance are also identified. Lastly, diagnostic and therapeutic approaches to RH are discussed, focusing on antihypertensive medication classes that have proven benefit in patients with RH, and also on novel therapeutic approaches in these patients. CONCLUSION: RH is a common clinical problem and carries an increased risk for cardiovascular morbidity and mortality, as well as target organ damage. Patients with RH are aat high risk for reversible causes of hypertension and may benefit from special diagnostic or therapeutic considerations. Elements of pseudoresistance, intake of interfering substances and secondary causes of hypertension should be searched for and corrected, if possible. Therapeutic lifestyle modifications should be emphasized. Medical therapy includes optimizing diuretic use and considering the use of mineralocorticoid antagonists as add on antihypertensive agents. Novel approaches include surgical and transcatheter techniques, chronotherapy, and new classes of antihypertensive agents.

Efficacy and safety of initial combination therapy with amlodipine/valsartan compared with amlodipine monotherapy in black patients with stage 2 hypertension: the EX-STAND study.

The strategy of initiating hypertension treatment with combination versus single-drug therapy was formally tested in a prospective, double-blind, parallel-group trial in blacks with stage 2 hypertension (mean sitting systolic BP (MSSBP) >or=160 and <200 mm Hg). Participants were randomized equally to amlodipine/valsartan (A/V) (n=286) or amlodipine (A) monotherapy (n=286). After 2 weeks, there was forced titration of A/V 5/160 mg to A/V 10/160 mg and of A 5 to A 10 mg followed by 10 additional weeks of treatment. If SBP was >or=130 mm Hg at week 4, the protocol allowed optional titration of A/V to the 10/320 mg dose and, at week 8, hydrochlorothiazide 12.5 mg was optionally added to both A/V and A if SBP >or=130 mm Hg. Amlodipine/valsartan at week 8 lowered MSSBP last observation carried forward significantly>A (33.3 vs 26.6 mm Hg, P<0.0001). Lowering of MSSBP with A/V significantly exceeded that of A in several specified subgroups-the elderly (>or=65 years), isolated systolic hypertension, and those with body mass index (BMI) >or=30 kg/m(2). More patients treated with A/V than A achieved BP control (<140/90 mm Hg) both at weeks 8 (49.8 vs 30.2%; P<0.0001) and 12 (57.2 vs 35.9%; P<0.0001). Both treatment regimens were well tolerated. In conclusion, the strategy of initiating combination antihypertensive drug therapy in blacks with stage 2 hypertension with amlodipine /valsartan achieves greater and quicker reductions in BP as well as significantly higher BP control rates than starting treatment with amlodipine monotherapy.

Enteral administration of hematopoietic growth factors in the neonatal intensive care unit.

UNLABELLED: By 20 wk of gestation, the human fetal gastrointestinal (GI) tract morphologically resembles that of the term infant, but functional development is limited before 26 wk. By 30 wk of gestation, the fetus has the capacity for limited digestion and enteral absorption. GI growth and development continue postnatally. Trophic factors, including nutrients, peptides, hormones and growth factors, are recognized as having important influences on the morphology and histology of the developing GI tract. Other trophic factors are important in adaptation and repair following injury. Many such factors are provided in utero via amniotic fluid swallowing and later by human colostrum and milk. CONCLUSION: This review discusses cytokines with known GI trophic effects, either in vitro or in vivo, and focuses on those cytokines that have been used in the neonatal intensive care unit.

Immune-mediated neutropenia in the neonate.

Alloimmune neonatal neutropenia, neonatal autoimmune neutropenia and autoimmune neutropenia of infancy have remained nebulous entities with difficulties in both clinical and laboratory identification. These disorders are reviewed in this article.

Hyperactive ENaC identifies hypertensive individuals amenable to amiloride therapy.

Pathophysiological features of both primary aldosteronism and pseudohyperaldosteronism are hyperactive amiloride-sensitive epithelial Na(+) channels (ENaC) and refractory hypertension. Peripheral blood lymphocytes express ENaC, which functions and is regulated similarly to ENaC expressed by renal principal cells. Thus it was hypothesized that individuals with either of these hypertensive etiologies could be identified by assessment of the function and regulation of peripheral blood lymphocyte ENaC, by whole cell patch clamp. We also tested the hypothesis that specific inhibition of hyperactive ENaC with amiloride could ameliorate the hypertension. To test these hypotheses, we solicited blood samples from normotensive, controlled hypertensive, and refractory hypertensive individuals. Lymphocytes were examined electrophysiologically to determine whether ENaC was hyperactive. All positive findings were from refractory hypertensive individuals. Nine refractory hypertensive patients had amiloride added to their hypertensive therapy. Amiloride normalized the blood pressure of four subjects. These individuals all had hyperactive ENaC. Amiloride had no effect on individuals with normal ENaC. These findings suggest that whole-cell patch clamp of peripheral blood lymphocytes can be used to identify accurately and rapidly hypertensive individuals who will respond to amiloride therapy.