Plasma and red blood cell concentrations of zinc, copper, selenium and magnesium in the first week of paediatric critical illness.

BACKGROUND & AIMS: Critically ill children are at risk of micronutrient deficiencies, which might lead to poor clinical outcomes. However, the interpretation of micronutrient concentrations in plasma is complicated due to age-dependent and critical illness-dependent changes. Certain red blood cell (RBC) concentrations might reflect the overall body status more reliably than plasma levels in the presence of systemic inflammatory response. This study longitudinally examined micronutrient concentrations in both plasma and RBC in critically ill children. METHODS: This secondary analysis of the PEPaNIC RCT investigated the impact of early versus late initiation of parenteral macronutrient supplementation in critically ill children. All children received micronutrients when EN was insufficient (<80 % energy requirements). Blood samples were obtained on days 1, 3, 5 and 7 of Paediatric Intensive Care Unit (PICU) admission. Inductively coupled plasma mass spectrometry was used to measure zinc, selenium, and copper in plasma and selenium, copper, and magnesium in RBCs. Plasma magnesium was measured with colorimetric detection. Micronutrient concentrations were compared with age-specific reference values in healthy children and expressed using Z-scores. Changes in micronutrient concentrations over time were examined using the Friedman and post hoc Wilcoxon signed-rank tests. RESULTS: For 67 critically ill children, median (Q1; Q3) age 9.5 (5.5; 13.2) years, PIM3 score -2.3 (-3.1; -0.8), samples were available at various time points during their PICU stay. For 22 patients, longitudinal samples were available. On day 1, the median plasma Z-score for zinc was -5.2 (-5.2; -2.9), copper -1.6 (-2.9; -0.2), selenium -2.6 (-3.8; -1.0), magnesium -0.2 (-1.6; 1.3), and median RBC Z-score for copper was 0.5 (-0.1; 1.3), selenium -0.3 (-1.1; 0.7), magnesium 0.2 (-0.4; 1.3). In the longitudinal analysis, plasma zinc was significantly higher on day 5 (Z-score -3.2 (-4.6; -1.4)) than on day 1 (Z-score -5.2 (-5.2; -3.0), p = 0.032), and plasma magnesium was significantly higher on day 3 (Z-score 1.1 (-0.7; 4.0)) than on day 1 (Z-score -0.3 (-1.6; 0.5), p = 0.018). Plasma copper and selenium remained stable, and the RBC concentrations of all micronutrients remained stable during the first five days. CONCLUSIONS: Most patients had low plasma zinc, copper and selenium concentrations in the first week of their PICU stay, whereas they had normal to high RBC concentrations. More research is needed to examine the relationships between micronutrients and clinical outcome.

Early hypophosphatemia in critically ill children and the effect of parenteral nutrition: A secondary analysis of the PEPaNIC RCT.

BACKGROUND & AIMS: Hypophosphatemia during critical illness has been associated with adverse outcome. The reintroduction of enteral or parenteral nutrition, leading to refeeding hypophosphatemia (RFH), has been presented as potential risk factor. We investigated the occurrence of early RFH, its association with clinical outcome, and the impact of early parenteral nutrition (PN) on the development of early RFH in pediatric critical illness. METHODS: This is a secondary analysis of the PEPaNIC randomized controlled trial (N = 1440), which showed that withholding supplemental parenteral nutrition (PN) for 1 week (late-PN) in the pediatric intensive care unit (PICU) accelerated recovery and reduced new infections compared to early-PN (<24 h). Patients with renal replacement therapy or unavailable phosphate concentrations were excluded from this analysis. Early RFH was defined as serum/plasma phosphate <0.65 mmol/L and a drop of >0.16 mmol/L within 3 days of admission to the PICU. The association between baseline characteristics and early RFH, and the association of early RFH with clinical outcome were investigated using logistic and linear regression models, both uncorrected and corrected for possible confounders. To examine the impact of nutritional intake on phosphate concentrations, structural nested mean models with propensity score and censoring models were used. RESULTS: A total of 1247 patients were eligible (618 early-PN, 629 late-PN). Early RFH occurred in 40 patients (3%) in total, significantly more in the early-PN group (n = 31, within-group occurrence 5%) than in the late-PN-group (n = 9, within-group occurrence 1%, p < 0.001). Patients who were older (OR 1.14 (95% CI 1.08; 1.21) per year added, p < 0.001) and who had a higher Pediatric Risk of Mortality (PIM3) score had a higher risk of developing early RFH (OR 1.36 (95% CI 1.15; 1.59) per unit added, p < 0.001), whereas patients in the late-PN group had a lower risk of early RFH (OR 0.24 (95% CI 0.10; 0.49), p < 0.001). Early RFH was significantly associated with a 56% longer PICU stay (p = 0.003) and 42% longer hospital stay (p = 0.007), but not with new infections (OR 2.01 (95% CI 0.90; 4.30), p = 0.08) or length of mechanical ventilatory support (OR 1.05 (95% CI -3.92; 6.03), p = 0.68), when adjusted for possible confounders. Increase of parenteral nutrition intake (in % kcal of predicted resting energy expenditure) decreased phosphate concentrations (c = -0.002 (95% CI -0.002; -0.001). CONCLUSIONS: Early RFH occurred in 3% of critically ill children. Patients randomized to late-PN had a lower chance of developing early RFH, which may be explained by the more gradual build-up of nutrition. As early RFH might impact recovery, it is important to closely monitor phosphate concentrations in patients, especially of those at risk for early RFH.

Glucose homeostasis, nutrition and infections during critical illness.

Critical illness is a complex life-threatening disease characterized by profound endocrine and metabolic alterations and by a dysregulated immune response, together contributing to the susceptibility for nosocomial infections and sepsis. Hitherto, two metabolic strategies have been shown to reduce nosocomial infections in the critically ill, namely tight blood glucose control and early macronutrient restriction. Hyperglycaemia, as part of the endocrine-metabolic responses to stress, is present in virtually all critically ill patients and is associated with poor outcome. Maintaining normoglycaemia with intensive insulin therapy has been shown to reduce morbidity and mortality, by prevention of vital organ dysfunction and prevention of new severe infections. The favourable effects of this intervention were attributed to the avoidance of glucose toxicity and mitochondrial damage in cells of vital organs and in immune cells. Hyperglycaemia was shown to impair macrophage phagocytosis and oxidative burst capacity, which could be restored by targeting normoglycaemia. An anti-inflammatory effect of insulin may have contributed to prevention of collateral damage to host tissues. Not using parenteral nutrition during the first week in intensive care units, and so accepting a large macronutrient deficit, also resulted in fewer secondary infections, less weakness and accelerated recovery. This was at least partially explained by a suppressive effect of early parenteral nutrition on autophagic processes, which may have jeopardized crucial antimicrobial defences and cell damage removal. The beneficial impact of these two metabolic strategies has opened a new field of research that will allow us to improve the understanding of the determinants of nosocomial infections, sepsis and organ failure in the critically ill.

Five-day pulsatile gonadotropin-releasing hormone administration unveils combined hypothalamic-pituitary-gonadal defects underlying profound hypoandrogenism in men with prolonged critical illness.

Central hyposomatotropism and hypothyroidism have been inferred in long-stay intensive care patients. Pronounced hypoandrogenism presumably also contributes to the catabolic state of critical illness. Accordingly, the present study appraises the mechanism(s) of failure of the gonadotropic axis in prolonged critically ill men by assessing the effects of pulsatile GnRH treatment in this unique clinical context. To this end, 15 critically ill men (mean +/- SD age, 67 +/- 12 yr; intensive care unit stay, 25 +/- 9 days) participated, with baseline values compared with those of 50 age- and BMI-matched healthy men. Subjects were randomly allocated to 5 days of placebo or pulsatile iv GnRH administration (0.1 microg/kg every 90 min). LH, GH, and TSH secretion was quantified by deconvolution analysis of serum hormone concentration-time series obtained by sampling every 20 min from 2100-0600 h at baseline and on nights 1 and 5 of treatment. Serum concentrations of gonadal and adrenal steroids, T(4), T(3), insulin-like growth factor I (IGF), and IGF-binding proteins as well as circulating levels of cytokines and selected metabolic markers were measured. During prolonged critical illness, pulsatile LH secretion and mean LH concentrations (1.8 +/- 2.2 vs. 6.0 +/- 2.2 IU/L) were low in the face of extremely low circulating total testosterone (0.27 +/- 0.18 vs. 12.7 +/- 4.07 nmol/L; P < 0.0001) and relatively low estradiol (E(2); 58.3 +/- 51.9 vs. 85.7 +/- 18.6 pmol/L; P = 0.009) and sex hormone-binding globulin (39.1 +/- 11.7 vs. 48.6 +/- 27.8 nmol/L; P = 0.01). The molar ratio of E(2)/T was elevated 37-fold in ill men (P < 0.0001) and correlated negatively with the mean serum LH concentrations (r = -0.82; P = 0.0002). Pulsatile GH and TSH secretion were suppressed (P < or = 0.0004), as were mean serum IGF-I, IGF-binding protein-3, and acid-labile subunit concentrations; thyroid hormone levels; and dehydroepiandrosterone sulfate. Morning cortisol was within the normal range. Serum interleukin-1beta concentrations were normal, whereas interleukin-6 and tumor necrosis factor-alpha were elevated. Serum tumor necrosis factor-alpha was positively correlated with the molar E(2)/testosterone ratio and with type 1 procollagen; the latter was elevated, whereas osteocalcin was decreased. Ureagenesis and breakdown of bone were increased. C-Reactive protein and white blood cell counts were elevated; serum lactate levels were normal. Intermittent iv GnRH administration increased pulsatile LH secretion compared with placebo by an increment of +8.1 +/- 8.1 IU/L at 24 h (P = 0.001). This increase was only partially maintained after 5 days of treatment. GnRH pulses transiently increased serum testosterone by +174% on day 2 (P = 0.05), whereas all other endocrine parameters remained unaltered. GnRH tended to increase type 1 procollagen (P = 0.06), but did not change serum osteocalcin levels or bone breakdown. Ureagenesis was suppressed (P < 0.0001), and white blood cell count (P = 0.0001), C-reactive protein (P = 0.03), and lactate level (P = 0.01) were increased by GnRH compared with placebo infusions. In conclusion, hypogonadotropic hypogonadism in prolonged critically ill men is only partially overcome with exogenous iv GnRH pulses, pointing to combined hypothalamic-pituitary-gonadal origins of the profound hypoandrogenism evident in this context. In view of concomitant central hyposomatotropism and hypothyroidism, evaluating the effectiveness of pulsatile GnRH intervention together with GH and TSH secretagogues will be important.

Neuroendocrinology of prolonged critical illness: effects of exogenous thyrotropin-releasing hormone and its combination with growth hormone secretagogues.

The catabolic state of prolonged critical illness is associated with a low activity of the thyrotropic and the somatotropic axes. The neuroendocrine component in the pathogenesis of these low activity states was assessed by investigating the effects of continuous intravenous infusions of TRH, GH-releasing peptide-2 (GHRP-2), and GHRH. Twenty adult patients, critically ill for several weeks, were studied during two consecutive nights. They had been randomly allocated to one of three combinations of peptide infusions, each administered in random order: TRH (one night) and placebo (other night), TRH + GHRP-2 (one night) and GHRP-2 (other night), or TRH + GHRH + GHRP-2 (one night) and GHRH + GHRP-2 (other night). The peptide infusions were started after a 1-microgram/kg bolus and infused (1 microgram/kg per h) until 0600 h. Blood sampling was performed every 20 min, and pituitary hormone secretion was quantified by deconvolution analysis. Reduced pulsatile fraction of TSH, GH, and PRL secretion and low serum concentrations of T4, T3, insulin growth factor-I (IGF-I), IGF-binding protein-3 (IGFBP-3), and the acid-labile subunit (ALS) were documented in the untreated state. Infusion of TRH alone or in combination with GH secretagogues augmented nonpulsatile TSH release 2- to 5-fold; only TRH + GHRP-2 increased pulsatile TSH secretion (4-fold). Average rises in T4 (40-54%) and in T3 (52-116%) were obtained with all three combinations, whereas reverse T3 levels did not increase, except when TRH was infused alone. Pulsatile GH secretion was amplified > 6- and > 10-fold, respectively, by GHRP-2 and GHRH + GHRP-2 infusions, generating mean increases of serum IGF-I (66% and 106%), IGFBP-3 (50% and 56%), and ALS (65% and 97%) within 45 h. The addition of TRH did not alter the GH secretory patterns. TRH infusion increased PRL release only when combined with GH secretagogues. No effects on serum cortisol were detected. In conclusion, the pathogenesis of the low activity state of the thyrotropic and somatotropic axes in prolonged critical illness appears to have a neuroendocrine component, because these axes are both readily activated by coinfusion of TRH and GH secretagogues.

Pituitary responsiveness to GH-releasing hormone, GH-releasing peptide-2 and thyrotrophin-releasing hormone in critical illness.

OBJECTIVE: Protein hypercatabolism and preservation of fat depots are hallmarks of critical illness, which is associated with blunted pulsatile GH secretion and low circulating IGF-I, TSH, T4 and T3. Repetitive TRH administration is known to reactivate the pituitary-thyroid axis and to evoke paradoxical GH release in critical illness. We further explored the hypothalamic-pituitary function in critical illness by examining the effects of GH-releasing hormone (GHRH) and/or GH-releasing peptide-2 (GHRP-2) and TRH administration. PATIENTS AND DESIGN: Critically ill adults (n = 40; mean age 55 years) received two i.v. boluses with a 6-hour interval (0900 and 1500 h) within a cross-over design. Patients were randomized to receive consecutively placebo and GHRP-2 (n = 10), GHRH and GHRP-2 (n = 10), GHRP-2 and GHRH+GHRP-2 (n = 10), GHRH+GHRP-2 and GHRH+GHRP-2 + TRH (n = 10). The GHRH and GHRP-2 doses were 1 microgram/kg and the TRH dose was 200 micrograms. Blood samples were obtained before and 20, 40, 60 and 120 minutes after each injection. MEASUREMENTS: Serum concentrations of GH, T4, T3, rT3, thyroid hormone binding globulin (TBG), IGF-I, insulin and cortisol were measured by RIA; PRL and TSH concentrations were determined by IRMA. RESULTS: Critically ill patients presented a striking GH response to GHRP-2 (mean +/- SEM peak GH 51 +/- 9 micrograms/l in older patients and 102 +/- 26 micrograms/l in younger patients; P = 0.005 vs placebo). The mean GH response to GHRP-2 was more than fourfold higher than to GHRH (P = 0.007). In turn, the mean GH response to GHRH+GHRP-2 was 2.5-fold higher than to GHRP-2 alone (P = 0.01), indicating synergism. Adding TRH to the GHRH+GHRP-2 combination slightly blunted this mean response by 18% (P = 0.01). GHRP-2 had no effect on serum TSH concentrations whereas both GHRH and GHRH+GHRP-2 evoked an increase in peak TSH levels of 53 and 32% respectively. The addition of TRH further increased this TSH response > ninefold (P = 0.005), elicited a 60% rise in serum T3 (P = 0.01) and an 18% increase in T4 (P = 0.005) levels, without altering rT3 or TBG levels. GHRH and/or GHRP-2 induced a small increase in serum PRL levels. The addition of TRH magnified the PRL response 2.4-fold (P = 0.007). GHRP-2 increased basal serum cortisol levels (531 +/- 29 nmol/l) by 35% (P = 0.02); GHRH provoked no additional response, but adding TRH further increased the cortisol response by 20% (P = 0.05). CONCLUSIONS: The specific character of hypothalamic-pituitary function in critical illness is herewith extended to the responsiveness to GHRH and/or GHRP-2 and TRH. The observation of striking bursts of GH secretion elicited by GHRP-2 and particularly by GHRH+GHRP-2 in patients with low spontaneous GH peaks opens the possibility of therapeutic perspectives for GH secretagogues in critical care medicine.

Gastrointestinal decontamination for acute poisoning.

Acute poisoning remains a common cause of morbidity and even mortality in children and adults. The goal of gastrointestinal decontamination is to eliminate or to reduce the potentially life-threatening effects of the ingested poison. Methods of gastrointestinal detoxication in case of acute poisoning, such as induced emesis, gastric lavage, administration of activated charcoal and intestinal cleansing are discussed. As far as induced emesis is still concerned, only the administration of Ipecac-syrup can be retained. The controversy between emesis and gastric lavage still remains. For those toxins well adsorbed by activated charcoal, the administration of activated charcoal, followed or not by gastric lavage, is the treatment of choice. Single doses of activated charcoal can be insufficient. In certain kinds of poisoning, repeated doses of activated charcoal are advisable because of the interruption of the entero-hepatic and entero-enteric circulation. The benefit and the indications for intestinal cleansing in case of acute poisoning seem to be very limited.

Changes in myocardial metabolism during therapy in patients with chronic stable angina: a comparison of long-term dosing with propranolol and nicardipine.

The long-term effects of antianginal therapy on coronary blood flow and myocardial metabolism were studied in 35 patients with chronic stable angina. Arterial and coronary sinus blood samples and coronary blood flow measurements were obtained before and after 1 month of oral administration of propranolol or of the calcium antagonist nicardipine. When the data obtained at a fixed heart rate (10% to 15% above the pretreatment sinus rhythm) were compared, no significant differences were evidenced between the propranolol and the nicardipine groups. Coronary blood flow and myocardial oxygen uptake were unchanged with both drugs. Myocardial lactate uptake increased in 11 patients of the propranolol group (from -2 +/- 42 to 66 +/- 47 mumol/min, p less than .001) and in 11 patients of the nicardipine group (from 0 +/- 36 to 31 +/- 29 mumol/min, p less than .001). In these 22 patients, the increase in lactate uptake was accompanied by reductions in uptake of free fatty acids and by a decrease in the coronary sinus concentration of thromboxane B2 from 131 +/- 87 to 61 +/- 32 pg/ml (p less than .01), whereas the transcardiac release of prostacyclin increased. None of these changes in free fatty acids or in prostanoid handling were observed in the nine patients (five in the propranolol and four in the nicardipine group) in whom lactate uptake was not augmented. During pacing-induced tachycardia, the metabolic effects of the two drugs appeared different. Myocardial lactate uptake decreased more in the patients receiving propranolol than in those receiving nicardipine and the combined productions of alanine and glutamine rose by 3.2 +/- 5.8 mumol/min in the propranolol group while it decreased by 3.1 +/- 8.2 mumol/min in the nicardipine group (p less than .025 propranolol vs nicardipine). In conclusion, long-term antianginal therapy with propranolol or nicardipine improved several markers of myocardial ischemia in approximately two-thirds of the patients. Although the changes observed at low heart rates were similar with the two drugs, the data also suggest that better metabolic protection is provided by the calcium antagonist during pacing-induced tachycardia.