Endocrine manifestations of critical illness in the child

The stress response in humans commonly includes elevations in plasma concentrations of glucocorticoids, catecholamines, glucagon, growth hormone, aldosterone, and renin, resulting in alterations in the metabolism of glucose and other energy substrates, and in increased sodium and water retention. In severe illness, triiodothyronine and sometimes thyroxine are decreased without evidence of clinical hypothyroidism. Antidiuretic hormone may be elevated in bacterial meningitis and other central nervous system disorders, as well as in acute asthma, chronic ventilator therapy, pneumothorax, atelectasis, and postoperatively. Increased ADH concentration can lead to significant hypoosmolality and hyponatremia with adverse effects on the patient. In the setting of severe intracerebral insults, ADH may be inappropriately low, resulting in diabetes insipidus. Insulin concentrations may be inappropriately low for serum glucose concentration, or insulin may have diminished receptor responsiveness in seriously stressed patients. Either situation leads to hyperglycemia. Disturbances in calcium, phosphorus, and magnesium homeostasis may occur relatively frequently in the critically ill patient in response to therapeutic interventions, or illness-induced altered metabolism. It is not always clear when an altered metabolic or hormonal state is an appropriate response to a stress, or represents decompensation of the body's mechanisms for coping with that stress. It is important, however to recognize the common responses of the organism to severe illness, and to monitor for treatable abnormalities which occur.     

Hormonal response to surgical stress in prepubertal children

The hormonal response to stress has not been previously studied in prepubertal children. We determined plasma cortisol, growth hormone (GH), prolactin, insulin, and glucose prior to anesthesia, 10 min after induction of anesthesia, 10 min after surgery began, and 60 min after anesthesia and surgery had ended, in 14 healthy children aged 5–9 years undergoing elective surgical procedures. Blood glucose rose significantly during surgery without a synchronous rise in insulin, which increased only in the immediate postoperative period. Prolactin values increased during anesthesia, remained high during surgery, and started to decline in the postoperative period. Cortisol also rose during anesthesia but remained at high levels throughout the study period. GH did not change during anesthesia; it increased during surgery and continued to rise during the postoperative period. In some children relatively high levels of cortisol or prolactin were detected preoperatively, possibly caused by psychological stress. The findings indicate that profound hormonal changes occur in prepubertal healthy children after even minor surgical procedures. This knowledge may lead to measures that could improve the outcome in sick or metabolically abnormal children undergoing surgical procedures. Offprint requests to: C. Dacou-Voutetakis     

Metabolic response to neonatal surgery.

The energy and protein metabolism of newborn infants differs from that of older individuals. Although energy expenditure and protein turnover are higher in newborn infants than in adults, the metabolic response to surgery in neonates has not been fully characterized. Preliminary studies indicate that metabolic response to operative stress is different in infants and adults: infants have an increased metabolic rate postoperatively for only 6 to 12 hours and do not have increased protein catabolism. More studies are needed in "stressed" newborn infants to further characterize substrate use and the metabolism of single organs.     

MDMA ('ecstasy') and other 'club drugs'. The new epidemic

Unfortunately, perceptions that the club drugs can be safe endure. Some groups, such as the Multidisciplinary Association for Psychedelic Study, continue to lobby for the legalization of MDMA for research purposes [76]. DanceSafe is an organization that seeks to educate the "nonaddicted" user to decrease the risks [82]. The DanceSafe Web site offers tips on the safe use of MDMA, such as attention to hydration status and ambient temperature. It also offers free testing of tablets submitted by mail and sells home testing kits to determine the content of pills sold as "ecstasy." Although much remains unknown about the long-term consequences of MDMA and the club drugs, there are clearly enough short-term dangers to prompt more aggressive education and surveillance for its use. Scare tactics and exaggerations often are ignored [53], while Web sites full of anecdotal or incomplete information may lead the unaware user to increased use [113]. Organizations such as DanceSafe imply that proper education decreases addiction and that only uneducated users or addicts suffer the life-altering consequences of drug use. The fallacy in the mission of educating "nonaddicted" users is evident. Peer-based education, with a focus on both he short-term dangers and long-term consequences, may be a more effective approach [9]. Both new and established drugs of abuse continue to plague teens and young adults. Pediatric, family practice, and Med-Peds physicians, and pediatric pharmacologists need to remain vigilant about patterns and trends of drug abuse. MDMA and the other "club drugs" are not benign. Their effects target the brain, alter neurochemistry, and possibly cause irreversible structural damage. What may seem like a harmless drug in a weekend dance club has the potential for major public health problems in years to come [109]. Effective education and timely intervention may prevent these addictive drugs from becoming a way of life, a lifestyle that may have a literal "dead end."     

Fentanyl analgesia increases the incidence of postoperative hypothermia in neonates

Postoperative hypothermia remains a clinical problem in neonates undergoing surgery. Intraoperative analgesia can blunt the metabolic and hormonal response to operative stress in neonates. However, its effects on heat production and thermoregulation are not known. The aim of this review was to characterise the effects of intraoperative analgesia on body temperature in neonates undergoing surgery. The case notes of 25 consecutive neonates who underwent major operations were retrospectively reviewed. Axillary temperature was measured before the operation, and postoperatively after returning to the neonatal intensive care unit (NICU). Patients were divided into groups based on the intraoperative analgesic used: (1) 9 neonates received fentanyl; (2) 5 received morphine; and (3) 11 received epidural bupivacaine. All groups were comparable in terms of conceptional age, postnatal age, body weight, duration of operation, and operative stress score. In all groups the body temperature was significantly lower at the time of returning to the NICU than preoperatively. Three patients (33%) who received fentanyl became hypothermic during the operation, whereas none of those who received either morphine or bupivacaine had hypothermia. The drop in temperature between preoperative and initial postoperative values was significantly greater in patients who received fentanyl intraoperatively (median drop 0.8 °C, range 0.6 – 2.4) when compared with patients who received morphine (P= 0.02) or epidural bupivacaine (P= 0.01). These data suggest that intraoperative fentanyl modulates the postoperative body temperature in neonates. We hypothesise that fentanyl blocks metabolic heat production, which results in a reduction in postoperative body temperature. Accepted: 12 September 1998     

The Role of Excercise in the Metabolic Control of Juvenile Diabetes

Exercise has a beneficial metabolic effect in diabetic children and adolescents only when they are in good metabolic control with optimal insulin administration. In insulin-deficient patients exercise may seriously aggravate the diabetic state. The physical working capacity of young diabetics is often lower than that of non-diabetic children. Their physical fitness can be improved by regular training programs. Exercise-induced hypoglycemia is due to suppression of hepatic glucose output in response to an abnormal insulinemia. It can as a rule be prevented by a liberal carbohydrate intake before and during the exercise period. On a long-term basis regular physical activity improves diabetic control in young diabetics, increases glucose tolerance and normalizes blood lipids. Regular physical activity increases diabetics' sense of well-being, gives self-confidence and makes feelings of being handicapped disappear. Exercise may contribute topreventing the development of long-term diabetic microangiopathy andneuropathy. However, when such complications once have become manifest, the value of exercise is less obvious. It may even be harmful and should therefore, in such situations, be undertaken with great caution and after careful medical evaluation.     

Longitudinal evaluation of glucose tolerance and insulin secretion in non-diabetic children and adolescents with cystic fibrosis: results of a two-year follow-up

Thirty-two patients with cystic fibrosis and repeatedly normal fasting blood glucose underwent oral glucose tests and islet-cell antibody assessments on two occasions approximately two years apart. Fourteen patients underwent two iv glucose tolerance tests also. Although in the group as a whole mean glucose areas in response to the oral test remained substantially unmodified over the two-year period, the prevalence of glucose tolerance abnormalities increased from 37.5 to 50%. Insulin output in response to both oral and iv tolerance tests decreased over time. Worsening of insulin secretion and/or of glucose tolerance was never accompanied by deteriorating clinical status. Islet-cell antibodies were detected in no patients, even in those who developed a diabetic glucose tolerance. These results support, on a longitudinal basis, the view of a progressive impairment of B-cell function in cystic fibrosis, which may precede the onset of metabolic abnormalities and is not triggered by autoimmunity.     

Sequential intrahepatic metabolic effects of enteric galactose alimentation in newborn rats

We determined metabolic responses after enteric galactose alimentation in 5- to 7-day-old newborn rats fasted for 24 h. The glycemic response was attenuated after enteric galactose feeding compared with the response after enteric glucose-fed rat pups. 14C radioactivity in blood from galactose-fed pups was reduced as counts in blood galactose were lower than counts in blood glucose in glucose-fed pups. Nonetheless within 15 min, [14C] from galactose appeared in blood glucose suggesting rapid conversion of galactose to glucose. The plasma insulin response was also attenuated after galactose feeding compared with the insulin response after enteric glucose. Hepatic glycogen content increased rapidly after enteric galactose feeding and was higher than after glucose feeding at 60, 120, and 180 min. Significant glycogen synthesis after oral glucose was delayed and occurred at 240 min. Carbon radioactivity in glycogen was higher in galactose fed pups between 15 and 360 min of the study. Serial determination of hepatic metabolites revealed an increase of galactose-1-phosphate levels after oral galactose at 240 and 300 min and a transient decline of ATP at 15 min. Other hepatic metabolites did not demonstrate significant differences between the two groups. These data suggest that hepatic glycogen synthesis is more rapid and occurs sooner after galactose than after glucose alimentation in previously fasted newborn rats. Galactose may enter a more direct pathway for neonatal hepatic glycogen synthesis. The relatively delayed entry of glucose label into hepatic glycogen and the delay of net glycogen synthesis after oral glucose suggest that glucose entry is not direct and may require further metabolism before incorporation into glycogen.(ABSTRACT TRUNCATED AT 250 WORDS)     

An inadequate glycaemic response to glucagon is linked to insulin resistance in preterm infants?

AIMS: To define clinical, metabolic, and hormonal characteristics of preterm infants relative to glucagon responsiveness. METHODS: Two phase study of 78 preterm infants (25-36 weeks gestation) on regular four hourly feeds anticipating discharge home at 36 weeks mean corrected gestation. In phase 1 infants were fasted until hypoglycaemic, or maximally for eight hours. Endocrine and metabolic profiles were obtained at completion. Phase 2 was performed the following day. A feed was omitted and replaced by a bolus dose of intravenous glucagon (100 micro g/kg). Main outcome measures were measurements of blood glucose and lactate concentrations, taken immediately pre-glucagon, and thereafter every 15 minutes for 60 minutes. A rise in glucose concentration of >1 mmol/l (55 infants) was defined as an adequate response to glucagon. An inadequate glycaemic response was <1 mmol/l (23 infants). RESULTS: Several differences in fasting blood glucose and hormone concentrations were identified in infants with an inadequate glycaemic response to glucagon compared to those with an adequate response: relative fasting hyperglycaemia (mean 3.7 v 3.3 mmol/l, p = 0.008); fasting hyperinsulinaemia (mean 4.3 v 2.6 mU/l, p = 0.014); an increased insulin:glucagon ratio (0.19 v 0.11, p = 0.014), and a lower insulin sensitivity QUICKI index (0.19 v 0.22, p = 0.04). There was no distinctive phenotype to reliably predict response to glucagon. CONCLUSION: Some preterm infants show an inadequate glycaemic response to glucagon and have features suggestive of insulin resistance. The potential long term implications of such insulin resistance may have appreciable public health consequences.     

Increased cerebral blood flow and plasma epinephrine in hypoglycemic, preterm neonates

Cerebral blood flow, plasma epinephrine, and plasma norepinephrine were measured in 25 spontaneously breathing, preterm neonates (mean gestational age 30.4 weeks) 2 hours after birth, during a routine screening for low blood glucose levels. Increased cerebral blood flow and plasma epinephrine values were observed when blood glucose levels were low, whereas plasma norepinephrine was constant throughout the blood glucose range. Hypoglycemia (defined as blood glucose concentration less than 30 mg/dL) was found in 13 neonates who were treated with intravenous glucose and milk enterally. Blood glucose levels were normal in the remaining 12 control neonates who received milk by a gastric line. Approximately 30 minutes after treatment with intravenous glucose and/or milk, cerebral blood flow had decreased by a mean of 11.3% in the 13 hypoglycemic neonates but was still 37.5% higher than cerebral blood flow in the control neonates despite normalization of plasma epinephrine concentration. Mean arterial blood pressure and blood gas values were identical between groups throughout the investigation. It is suggested that a normal coupling between cerebral metabolic demands and flow is present in very preterm neonates and that epinephrine may play a role in the cerebral hyperperfusion. Although none of the neonates had clinical signs of hypoglycemia, the data suggest that counterregulatory mechanisms are invoked when blood glucose values are less than 30 to 45 mg/dL.     

Insulin responsiveness of neonatal pig myocardium

The transition from preferential use of carbohydrates to fatty acids for energy production by neonatal mammalian myocardium might be hormonally influenced. In neonatal pigs (between 1 and 4 days of age), plasma glucose, lactate, and glucagon concentrations remained constant at adult levels, while plasma triglycerides and insulin content remained stable at substantially lower levels. Insulin, whether administered in vivo or during perfusion, increased myocardial glucose utilization [GU] and lactate production [LP]. Stimulation of GU and LP by insulin exposure in vivo persisted for at least 1 h during perfusions after insulin was removed. Exogenous lactate (0.5 mM) diminished insulin-stimulated GU and LP; and was used as a substrate at 1.25 mM. Thus, insulin augmented glycolytic activity of neonatal piglet myocardium; however, exogenous lactate, within the physiological range, altered the nature of the myocardium's response by, as yet, undetermined mechanisms. Therefore, the transition from carbohydrate to fatty acid utilization for energy production by the neonatal myocardium does not appear to result from decreased carbohydrate metabolism or reduced myocardial responsiveness to insulin.     

Effects of early amino acid administration on leucine and glucose kinetics in premature infants

We previously showed that, in prematurely born infants, an anabolic state without metabolic acidosis can be achieved upon intravenous amino acid (AA) administration in the immediate postnatal phase, despite a low energy intake. We hypothesized that the anabolic state resulted from an increased protein synthesis and not a decreased proteolysis. Furthermore, we hypothesized that the energy needed for the higher protein synthesis rate would be derived from an increased glucose oxidation. To test our hypotheses, 32 ventilated premature infants (<1500 g) received intravenously either solely glucose or glucose and 2.4 g AA/kg/d immediately postnatally. On postnatal d 2, each group received primed continuous infusions of either [1-13C]leucine or [U-13C6]glucose. 13CO2 enrichments in expiratory air and plasma [1-13C]alpha-KICA (as an intracellular leucine precursor) and [U-13C6]glucose enrichments were measured by mass spectrometry techniques. The AA administration resulted in an increased incorporation of leucine into body protein and a higher leucine oxidation rate, whereas leucine release from proteolysis was not affected. Glucose oxidation rate did not increase upon AA administration. In conclusion, the anabolic state resulting from AA administration in the immediate postnatal period resulted from increased protein synthesis and not decreased proteolysis. The energy needed for the additional protein synthesis was not derived from an increased glucose oxidation.     

Inborn errors of amino acid and fatty acid metabolism with hypoglycemia as a major clinical manifestation

During the last decade it has become increasingly clear that severe hypoglycemia may be caused by specific enzymatic defects of amino acid and fatty acid metabolism. Several reports have presented hypoglycemic syndromes with reduced fatty acid transport or oxidation, decreased ketogenesis, or abnormalities of the Krebs cycle and electron transport chain. It is of particular interest that several enzymatic defects here discussed may present as Reye's syndrome. An intriguing fact is a highly variable clinical presentation, even in the presence of well-defined enzyme deficiencies. Some patients are desperately ill in the newborn period, whereas in other cases there are symptoms only during catabolic phases later in childhood. The presence of hypoglycemia may be related to low levels of acetyl CoA, with consequently reduced gluconeogenesis; alternatively the glucose-sparing effect of ketones is lost in states of reduced ketone body production. Treatment with pharmacological doses of vitamins may be attempted, depending upon the established or suspected diagnoses. With manifest hypoglycemia i.v. glucose infusion is the treatment of choice. By such means convulsions, and brain damage may be prevented.     

Antipyretics in children

Fever is an important symptom of underlying disease condition and in general is considered harmful in pediatric age group as it may lead to febrile seizures, stupor, dehydration increase work of breathing, discomfort and tachycardia. The increase metabolic demands stress the patient with marginal cardiac and cerebral vascular supply. The hypothalamus controls the body temperature. The fever results due to resetting of the hypothalamus that occur from the prostaglandins produced by the pyrogens. Fever is treated variedly by the pediatricians. The physical therapy offers a simple and cost effective way of lowering the body temperature. The drugs as paracetamol, nimesulide and ibuprofen lower the temperature by inhibiting the prostaglandin synthesis. Paracetamol is considered the safest of all the antipyretic drugs. It is recommended that a combination of physical therapy such as tepid sponging and paracetamol is best way of controlling temperature.     

Influence of Donor Blood Temperature on Metabolic and Hormonal Changes During Exchange Transfusion

Measurements of plasma glucose, free fatty acid, glycerol, insulin, growth hormone, and glucagon were made during exchange transfusions performed with blood heated to 36·5 to 38·5 °C or cooled to 10 to 13 °C. Term, normally grown infants suffering from rhesus incompatibility were studied. 10 received warm transfusions and 9 cold transfusions. Cold transfusions caused a progressive fall in rectal, umbilical vein, and skin temperature, whereas warm transfusions caused little change in body temperature. Infants receiving cold transfusions had a greater net positive balance of glucose and a smaller net negative balance of free fatty acids than those receiving warm transfusions. Other metabolic and hormonal responses to exchange transfusion were similar in the two groups.It was concluded that while exchange transfusion performed with cold blood did cause thermal stress to the infant, the metabolic consequences were slight and were mitigated by the glucose in the donor blood. There was no evidence that insulin, growth hormone, or glucagon played a part in the response of the newborn infant to cold.     

Role of nutrients in the regulation of in vivo protein metabolism in humans

Nutrients regulate protein metabolism both in an acute fashion and on a long-term basis. The ingestion of meals is associated with a dramatic switch from an overall catabolic state to a state of net protein anabolism. The acute response of protein metabolism to meal ingestion is mediated, in part, by an increase in insulin secretion, itself a consequence of glucose absorption. Whereas insulin may primarily suppress rates of proteolysis, amino acids are responsible for the stimulation of protein synthesis that follows food intake. In the long run, the effects of nutrition on protein metabolism depend on the energy supply, the source of the energy (carbohydrate versus fat) and dietary protein intake. Finally, specific amino acids, such as glutamine, may play an additional role as protein anabolic agents.     

Role of nutrients in the regulation of in vivo protein metabolism in humans

Nutrients regulate protein metabolism both in an acute fashion and on a long-term basis. The ingestion of meals is associated with a dramatic switch from an overall catabolic state to a state of net protein anabolism. The acute response of protein metabolism to meal ingestion is mediated, in part, by an increase in insulin secretion, itself a consequence of glucose absorption. Whereas insulin may primarily suppress rates of proteolysis, amino acids are responsible for the stimulation of protein synthesis that follows food intake. In the long run, the effects of nutrition on protein metabolism depend on the energy supply, the source of the energy (carbohydrate versus fat) and dietary protein intake. Finally, specific amino acids, such as glutamine, may play an additional role as protein anabolic agents.     

Nonalcoholic fatty liver disease and carotid atherosclerosis in children

Nonalcoholic fatty liver disease (NAFLD) is closely associated with several metabolic syndrome features, including obesity, dyslipidemia, insulin resistance, and increased cardiovascular risk. The present study was undertaken to assess whether NAFLD in children is associated with increased carotid artery intima-media thickness (IMT), a marker of early-generalized atherosclerosis. We analyzed carotid IMT along with serum triglycerides, total, low-density lipoprotein and high-density lipoprotein cholesterol, glucose, insulin, insulin resistance index (as homeostasis model assessment of insulin resistance), aminotransferases, leptin, and adiponectin in 29 obese children with NAFLD, 33 obese children without liver involvement, and 30 control children. The diagnosis and severity of NAFLD was based on ultrasound scan, after exclusion of infectious and metabolic disorders. Obese children with NAFLD had significantly increased carotid IMT [mean 0.58 (95% confidence intervals 0.54-0.62 mm)] than obese children without liver involvement [0.49 (0.46-0.52) mm; p = 0.001] and control children [0.40 (0.36-0.43) mm; p < 0.0005]. In a stepwise multiple regression model, after adjusting for age, gender, Tanner stage, and cardiovascular risk factors, the severity of fatty liver was significantly associated with maximum IMT (b = 0.08; p < 0.0005). Our results suggest that NAFLD is strongly associated with carotid atherosclerosis even in childhood.     

Ataxia‐telangiectasia: A review of clinical features and molecular pathology

Ataxia‐telangiectasia (A‐T) is an autosomal recessive primary immunodeficiency (PID) disease that is caused by mutations in ataxia‐telangiectasia mutated (ATM) gene encoding a serine/threonine protein kinase. A‐T patients represent a broad range of clinical manifestations including progressive cerebellar ataxia, oculocutaneous telangiectasia, variable immunodeficiency, radiosensitivity, susceptibility to malignancies, and increased metabolic diseases. This congenital disorder has phenotypic heterogeneity, and the severity of symptoms varies in different patients based on severity of mutations and disease progression. The principal role of nuclear ATM is the coordination of cellular signaling pathways in response to DNA double‐strand breaks, oxidative stress, and cell cycle checkpoint. The pathogenesis of A‐T is not limited to the role of ATM in the DNA damage response (DDR) pathway, and it has other functions mainly in the hematopoietic cells and neurons. ATM adjusts the functions of organelles such as mitochondria and peroxisomes and also regulates angiogenesis and glucose metabolisms. However, ATM has other functions in the cells (especially cell viability) that need further investigations. In this review, we described functions of ATM in the nucleus and cytoplasm, and also its association with some disorder formation such as neurologic, immunologic, vascular, pulmonary, metabolic, and dermatologic complications.     

Insulin-like growth factor binding protein-1 and interleukin-6 are markers of fetal stress during parturition at term gestation

OBJECTIVE: Maintaining an adequate blood glucose level is essential for neuron integrity. The increased energy demand imposed on the fetus by the birth process in combination with a limited glucose production capacity therefore threatens brain function. It is logical to presume that mechanisms increasing glucose mobilization as well as decreasing peripheral glucose utilization has evolved to preserve brain function, even after complicated deliveries. DESIGN: We studied umbilical cord levels of hormones involved in acute glucose regulation as well as insulin-like growth factor-I (IGF-I), modulating factors insulin-like growth factor binding protein (IGFBP)-1 and -3 as well as interleukin-6 (IL-6) in 149 infants born after different degrees of birth stress. We measured glucose, insulin, IGF-I, IGFBP-1, IGFBP-3, glucagon, growth hormone (GH), prolactin, adrenocorticotropin (ACTH), cortisol and IL-6 in umbilical cord blood of infants born at term gestation after: A) elective Cesarean-section (n = 37), B) normal delivery (n = 87) or C) complicated delivery (n = 25). All infants were of normal birth weight for gestational age. Arterial pH and lactate as well as S-100B, a marker of neuronal damage, were used as stress variables. RESULTS: With increasing fetal stress, we found significant and generally progressive elevations in glucose, IGFBP-1, IL-6, ACTH, cortisol, glucagon, GH, prolactin and lactate. This was accompanied by significant decreases of IGF-I, insulin and arterial pH. S-100B and IGFBP-3 levels did not differ between groups. IGFBP-1 showed a significant positive correlation to IL-6 and lactate and a significant negative correlation to both IGF-I and arterial pH. CONCLUSIONS: Increasing stress and energy demands during birth are accompanied by increasing fetal levels of glucose-mobilizing hormones in combination with depressed levels of insulin and IGF-I, despite increasing blood glucose. Furthermore, IGFBP-1 and IL-6 increase steeply, presumably aimed at diminishing insulin-like activity of IGF-I, thereby reducing peripheral glucose utilization. We believe that IGFBP-1 and IL-6 deserve evaluation as potential intrapartum indicators of fetuses at risk for asphyxia.