Modelling intestinal glucose absorption in premature infants using continuous glucose monitoring data.

BACKGROUND: Model-based glycaemic control protocols have shown promise in neonatal intensive care units (NICUs) for reducing both hyperglycaemia and insulin-therapy driven hypoglycaemia. However, current models for the appearance of glucose from enteral feeding are based on values from adult intensive care cohorts. This study aims to determine enteral glucose appearance model parameters more reflective of premature infant physiology. METHODS: Peaks in CGM data associated with enteral milk feeds in preterm and term infants are used to fit a two compartment gut model. The first compartment describes glucose in the stomach, and the half life of gastric emptying is estimated as 20 min from literature. The second compartment describes glucose in the small intestine, and absorption of glucose into the blood is fit to CGM data. Two infant cohorts from two NICUs are used, and results are compared to appearances derived from data in highly controlled studies in literature. RESULTS: The average half life across all infants for glucose absorption from the gut to the blood was 50 min. This result was slightly slower than, but of similar magnitude to, results derived from literature. No trends were found with gestational or postnatal age. Breast milk fed infants were found to have a higher absorption constant than formula fed infants, a result which may reflect known differences in gastric emptying for different feed types. CONCLUSIONS: This paper presents a methodology for estimation of glucose appearance due to enteral feeding, and model parameters suitable for a NICU model-based glycaemic control context.

Executive summary and conclusions from the European Hydration Institute Expert Conference on human hydration, health, and performance.

On April 7-8, 2014, the European Hydration Institute hosted a small group of experts at Castle Combe Manor House, United Kingdom, to discuss a range of issues related to human hydration, health, and performance. The meeting included 18 recognized experts who brought a wealth of experience and knowledge to the topics under review. Eight selected topics were addressed, with the key issues being briefly presented before an in-depth discussion. Presented here is the executive summary and conclusions from this meeting.

Direct renovascular effect of somatostatin in the dog.

Recently, effects of somatostatin on the renal function have been described and the vasoactive properties of the peptide were proposed to contribute to this action. However, the available data on its effect in the renal vascular bed are very controversial. Therefore, we investigated the effect of local intaarterial somatostatin boluses in a wide range of doses (5 x 10(-11) - 5 x 10(-5) g) on the renal blood flow (RBF) in anesthetized dogs. RBF was measured by an electromagnetic flow probe. Somatostatin did not influence blood pressure or heart rate. RBF exhibited a significant, dose-dependent fall (ranging from 11.6 +/- 11.9% to 31.9 +/- 17.3%), with a threshold at a dose of 5 x 10(-10) g. These results offer conclusive evidence for the contribution of somatostatin-induced direct renal vasoconstriction to its renal effects, in addition to the demonstrated modulation of other vasoactive systems and tubular functions.

Role of bradykinin in the neonatal renal effects of angiotensin converting enzyme inhibition.

The vascular effects of angiotensin converting enzyme inhibitors are mediated by the inhibition of the dual action of angiotensin converting enzyme (ACE): production of angiotensin II and degradation of bradykinin. The deleterious effect of converting enzyme inhibitors (CEI) on neonatal renal function have been ascribed to the elevated activity of the renin-angiotensin system. In order to clarify the role of bradykinin in the CEI-induced renal dysfunction of the newborn, the effect of perindoprilat was investigated in anesthetized newborn rabbits with intact or inhibited bradykinin B2 receptors. Inulin and PAH clearances were used as indices of GFR and renal plasma flow, respectively. Perindoprilat (20 microg/kg i.v.) caused marked systemic and renal vasodilation, reflected by a fall in blood pressure and renal vascular resistance. GFR decreased, while urine flow rate did not change. Prior inhibition of the B2 receptors by Hoe 140 (300 microg/kg s.c.) did not prevent any of the hemodynamic changes caused by perindoprilat, indicating that bradykinin accumulation does not contribute to the CEI-induced neonatal renal effects. A control group receiving only Hoe 140 revealed that BK maintains postglomerular vasodilation via B2 receptors in basal conditions. Thus, the absence of functional B2 receptors in the newborn was not responsible for the failure of Hoe 140 to prevent the perindoprilat-induced changes. Species- and/or age-related differences in the kinin-metabolism could explain these results, suggesting that in the newborn rabbit other kininases than ACE are mainly responsible for the degradation of bradykinin.

Vasoactive compounds in the neonatal period.

Sufficient organ blood flow of healthy newborn babies is maintained by relatively low systemic blood pressure. Premature infants are at an increased risk of systemic hypotension, often but not obviously, resulting in hypoperfusion of the cerebral, renal and intestinal vascular beds. Maintaining a stable blood pressure in preterm babies is of high importance in order to prevent complications such as intraventricular hemorrhage, periventricular leucomalatia, necrotizing enterocolitis or renal failure. The regulation of systemic and local hemodynamics in newborns differs substantially from that of the adults. Developmental changes in catecholamine sensitivity, higher local vasodilator factor activity and structural differences of the immature myocardium should be taken into account when applying vasoactive agents in neonates. The effects of widely used catecholamines such as dopamine, epinephrine or dobutamine can not be directly adapted from adult therapeutics to neonatal care. Their administration should be supported by data on their effects on systemic and cerebral blood flow in addition to blood pressure changes. At the bedside, neonatologists should use new diagnostic tools to differentiate between neonatal hypotension and hypoperfusion, vasoconstriction and myocardial dysfunction in order to choose the appropriate medication. Newer vasoactive agents already used in adult or pediatric cardiovascular therapy such as milrinone, levosimendan or terlipressin need to be carefully evaluated before introducing them to the treatment of neonatal hypotensive states. Well-designed preclinical and human newborn studies also evaluating their local effects are warranted.

Endogenous bradykinin regulates renal function in the newborn rabbit.

The developmental changes in the activity of the renal kallikrein-kinin system (KKS) are related to the hemodynamic changes occurring in the neonatal kidney. In order to clarify the functional importance of the renal KKS in the developing kidney, the effect of the bradykinin B2 receptor antagonist HOE-140 was investigated in newborn rabbits. Effective blockade of bradykinin effect by HOE-140 was demonstrated in 10 rabbits. In 10 additional animals the subcutaneous injection of 300 micrograms/kg HOE-140 resulted in an increase in renal vascular resistance with a consequent decrease in renal blood flow. Glomerular filtration rate did not change significantly, while the filtration fraction rose, indicating preferential efferent arteriolar constriction. Urine flow rate increased as well as the fractional excretion of potassium. No change in sodium excretion was observed. The present data suggest a regulatory role for the renal KKS in the immature kidney under basal conditions. By inducing predominant efferent arteriolar vasodilation, the KKS appears to play a key role in regulating the neonatal glomerular microcirculation. This is in sharp contrast with the mature kidney, where the KKS predominantly acts on tubular function as a diuretic-natriuretic factor.

Chronic bradykinin receptor blockade modulates neonatal renal function.

Recent data indicate that bradykinin participates in the regulation of neonatal glomerular function and also acts as a growth regulator during renal development. The aim of the present study was to investigate the involvement of bradykinin in the maturation of renal function. Bradykinin beta2-receptors of newborn rabbits were inhibited for 4 days by Hoe 140. The animals were treated with 300 microg/kg s.c. Hoe 140 (group Hoe, n = 8) or 0.9% NaCl (group control, n = 8) twice daily. Clearance studies were performed in anesthetized rabbits at the age of 8-9 days. Bradykinin receptor blockade did not impair kidney growth, as demonstrated by similar kidney weights in the two groups, nor did it influence blood pressure. Renal blood flow was higher, while renal vascular resistance and filtration fraction were lower in Hoe 140-treated rabbits. No difference in glomerular filtration rate was observed. The unexpectedly higher renal perfusion observed in group Hoe cannot be explained by the blockade of the known vasodilator and trophic effect of bradykinin. Our results indicate that in intact kallikrein-kinin system is necessary for the normal functional development of the kidney.

The stressed neonatal kidney: from pathophysiology to clinical management of neonatal vasomotor nephropathy.

The healthy term, and particularly the premature infant, is born with a very low glomerular filtration rate (GFR), controlled by a delicate balance of intrarenal vasoconstrictor and vasodilator forces. Vasoactive disturbances can easily further reduce the already low GFR. The newborn infant is thus prone to develop vasomotor nephropathy (VMNP) or acute renal failure (ARF). The main causes for ARF at this young age are prerenal mechanisms, and include hypotension, hypovolemia, hypoxemia perinatal asphyxia, and neonatal septicemia. Other causes include the administration of angiotensin converting enzyme inhibitors, indomethacin and tolazoline. The most-important factors governing the ultimate renal prognosis are the severity of the underlying disorder, the rapidity of an accurate diagnosis, prompt treatment, and avoidance of severe iatrogenic complications. The immediate treatment is of particular importance in VMNP, i.e., prerenal ischemic ARF, and consists of correcting abnormalities in fluid homeostasis and reduction of the complications of the acute azotemic state (uremia, hyperkalemia, acidosis, and hypertension). In severe and prolonged (established) ARF, temporary dialysis therapy may be indicated. Prerenal ARF with oliguria or anuria warrants immediate volume resuscitation. Special attention should be given to infants with congestive heart failure (CHF). The sick neonate with persistent oliguria and CHF should be treated with intravenous dopamine. Furosemide (FM) is the second line of therapy for babies with indomethacin-induced ARF. In most other conditions, the therapeutic effect of FM is limited to a transient increase in urine flow, without improving basic renal function. The special conditions of the maturing kidney have to be appreciated in order to protect babies from undue renal injury. With the increasing knowledge of the mechanisms governing the development of ARF, progress has been made in the development of new treatment modalities. For example theophylline, calcium antagonists, ATP-MgCl2, thyroxine, and a variety of cytokines may in the near future be used to prevent or ameliorate VMNP and/or recently established ARF. With a combination of time-honored and new therapeutic strategies, there may well be a brighter future for neonates with vasomotor, prerenal, ischemic ARF.

Bradykinin and hypoxemia-induced renal changes in the newborn rabbit.

Acute hypoxemia causes a decrease in glomerular filtration rate (GFR) and renal blood flow (RBF) in newborns. These changes are partly mediated by local-acting vasoactive factors. We have previously shown that bradykinin (BK) has a vasodilatory role in the basic regulation of neonatal hemodynamics. The purpose of the present study was to evaluate whether BK can modulate the severe renal vasoconstriction associated with hypoxemia in the newborn rabbit. The effect of systemic hypoxemia (PaO2 approximately 40 mmHg) on renal function was investigated in 9 newborn rabbits (controls) and in 8 animals in which BK-B2 receptors were blocked by Hoe 140 (300 microg/kg subcutaneously), given prior to the induction of hypoxemia. The studies were performed under pentobarbital anesthesia at the age of 5-9 days. In control animals, acute hypoxemia caused a significant decrease in GFR and RBF and an increase in renal vascular resistance. Similar glomerular hemodynamic changes were observed in BK-B2 receptor-blocked newborn rabbits. These results indicate that BK does not play a significant role in the renal vascular changes of the hypoxemic-stressed newborn.

The role of bradykinin in neonatal hemodynamic effects of ACE inhibition.

Angiotensin-converting enzyme (ACE) inhibitors exert their effects by inhibiting angiotensin II (AII) production, but also by inhibiting bradykinin (BK) degradation. In order to clarify whether BK is involved in the systemic effects of ACE inhibition in the newborn period, we investigated the effect of perindoprilat (20 microgram/kg i.v.) in newborn rabbits, with or without the blockade of BK beta(2)-receptors (Hoe 140, 300 microgram/kg s.c.). The bolus infusion of perindoprilat resulted in a marked fall in mean arterial blood pressure (MBP) and a slight decrease in heart rate. BK receptor blockade had no effect on the perindoprilat-induced hypotension but the negative chronotropic effect of ACE inhibition was partly prevented by pretreatment with Hoe 140. We therefore conclude that BK is not involved in neonatal blood pressure regulation but that the ACE inhibition-induced neonatal bradycardia is at least partly BK- mediated.

Association between G-308A polymorphism of the tumor necrosis factor-alpha gene and 24-hour ambulatory blood pressure values in type 1 diabetic adolescents.

Tumor necrosis factor-alpha (TNF-alpha) is an inflammatory cytokine, which also influences blood pressure (BP). The G-308A polymorphism of the TNF-alpha gene is associated with altered TNF-alpha production. The prevalence of the TNF-alpha-308A allele is reportedly higher among patients with type 1 diabetes mellitus (T1DM) than in the healthy population. In this study we investigated whether this genetic polymorphism might correlate with BP values in diabetic adolescents. Ambulatory BP monitoring (ABPM) was performed in 126 adolescents with T1DM (mean age: 14 +/- 2.4 years). The TNF-alpha G-308A genotype was determined by using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methodologies. ABPM results were related to healthy reference values and are given as standard deviation score (SDS). The prevalence of the -308A allele was higher in diabetic adolescents than the Hungarian reference population (0.26 vs 0.14, p < 0.01). TNF-alpha genotype was associated both with systolic and diastolic BP values (p < 0.01 and p < 0.01, respectively). In patients with TNF-alpha-308GG and -308GA/AA genotypes, the 24-h systolic BP average values were 0.37 +/- 1.33 and -0.38 +/- 1.28 SDS, while 24-h diastolic BP average values were 0.09 +/- 1.30 and -0.67 +/- 1.31 SDS. Hence, the TNF-alpha-308A allele carrier state appears to be associated with lower systolic and diastolic BP values.

Signs of autonomic neuropathy in childhood uremia.

To evaluate the presence of autonomic neuropathy in childhood uremia, cardiovascular autonomic reflexes were examined in children with chronic renal failure. Cardiovascular autonomic reflexes of 10 uremic patients on chronic dialysis and 10 transplanted patients were compared to assess the effect of transplantation on autonomic neuropathy. Resting heart rate, heart rate changes induced by deep breathing, by Valsalva maneuver, and following standing up, and blood pressure change induced by handgrip test were examined. Of the 10 uremic children, 4 showed early involvement and 2 had definite involvement of autonomic neuropathy. Only 1 of the 10 transplanted patients showed early signs of autonomic neuropathy. Autonomic tests demonstrated predominantly parasympathetic dysfunction. In conclusion, cardiovascular autonomic neuropathy is not rare in children and adolescents and young adults with chronic renal failure. In contrast, the prevalence is very low in transplanted patients with similar uremic precedents. Efforts should be made to prevent or delay this uremia-related complication.

Variance of ACE and AT1 receptor gene does not influence the risk of neonatal acute renal failure.

High neonatal activity of the renin-angiotensin system (RAS) is crucial for the maintenance of glomerular filtration of the newborn. The aim of the present study was to investigate whether genetic polymorphisms leading to lower angiotensin converting enzyme activity (ACE) or impaired functionality of angiotensin II (AII) type 1 receptor (AT1R) might predispose very low birth weight newborns (VLBWs) to the development of acute renal failure (ARF). The medical records of 110 VLBW infants were analyzed. ARF developed in 42 of them during the first postnatal week, while 68 neonates exhibited normal renal function. The ACE I/D polymorphism and the A1166C variants of AT1R were determined from dried blood samples. The frequency of the ACE I allele did not differ in ARF and non-ARF groups (0.307 and 0.284); the frequency of the AT1R C1166 variant was also the same in ARF and non-ARF groups (0.250 and 0.227). Although low activity of RAS has been implicated in the development of neonatal ARF and data indicated that the functionality of RAS is influenced by the I/D variants of the ACE gene and the A1166C variant of the AT1R gene, we could not demonstrate any effect of these polymorphisms on the development of ARF in VLBW infants.

Monitoring cardiovascular changes during hemodialysis in children.

Hemodialysis (HD) causes rapid volume shifts and circulatory changes. In chronic renal failure (CRF) Na+/K+ATP-ase is depressed, whereas endogenous digoxin-like factor (EDLF) is elevated. Our aim was to characterize HD-induced cardiovascular adaptation and its possible links to Na+/K+ATP-ase and EDLF. Eleven children with CRF on HD (aged 14.7 +/- 3.7 years) and 11 healthy children were investigated for basic circulatory parameters. Thoracic impedance (Zo) and circulatory parameters were monitored by impedance cardiography (ICG) during HD. Erythrocyte Na+/K+ATP-ase and EDLF were measured before and after HD. Up to the loss of 6% of total body weight, Zo rose linearly with fluid removal, above this no further increase occurred. Heart rate and mean arterial pressure (MAP) were inversely related (r = -0.97); MAP rose in the first and decreased in the second part of HD. Systemic vascular resistance paralleled MAP, whereas stroke volume rapidly decreased, but stabilized in the second part of HD. The ratio of preejection period/ventricular ejection time (PEP/VET) correlated positively with HD duration (r = 0.92), suggesting diminished cardiac filling. Cardiac index (CI) remained stable. EDLF was high in uremia accompanied by depressed Na+/K+ATP-ase (P < 0.05 and P < 0.01, respectively). Following HD Na+/K+ATP-ase normalized. Correlation between Na+/K+ATP-ase activity and MAP was linear (r = 0.85). In conclusion, ICG during HD provides detailed information concerning circulatory adaptation resulting in stable CI, suggesting that the dialysis-induced hypovolemia is compensated by the centralization of the blood volume. Changes of Na+/K+ATP-ase indicate that dialyzable blood pressure-regulating substance(s) inhibit(s) the pump. However, lack of further correlation between Na+/K+ATP-ase, EDLF, and cardiovascular parameters indicates the complexity of the regulatory processes.