B. Roth

Clinical experience with continuous intravenous sedation using midazolam and fentanyl in the paediatric intensive care unit

Twenty-four patients in a paediatric intensive care unit mostly undergoing cardiac surgery, received a midazolam dosage between 50–400 μg/kg per hour as a continuous intravenous infusion partly in combination with fentanyl [0,5–2,5 μg/kg per hour] for analgesia and sedation. The mean duration of midazolam infusion was 11.6 days (range 38h–40 days). Blood samples for the HPLC assay of serum midazolam concentration were taken and the clearance estimated. The efficiency of sedation in correlation to the midazolam concentration was evaluated by a clinical sedation score. Serum midazolam concentrations between 100–400 μg/l were sufficient for sedation. Dosage had to be increased during therapy according to an increased midazolam clearance. The evaluation of the sedation score showed that sedation of artifically ventilated infants and young children can be established by continuous intravenous infusion of midazolam.

Holocarboxylase synthetase deficiency: early diagnosis and management of a new case

We present a new case of holocarboxylase synthetase (HCS) deficiency, a rare autosomal recessive metabolic disorder, causing the “early-onset” form of multiple carboxylase deficiency. The patient was born at term of healthy consanguineous parents after an uncomplicated pregnancy. On the 2nd day of life she refused oral feeding, became tachydyspnoeic and showed excessive weight loss. Laboratory studies showed metabolic acidosis, marked lactic acidaemia, hyperammonaemia and increased urinary excretion of 3-hydroxyisovaleric acid, 3-methylcrotonyglycine, 3-hydroxypropionic acid and methylcritric acid. Peritoneal dialysis combined with oral supplementation of biotin (10 mg/day) started on the 3rd day of life resulted in rapid clinical recovery and normalisation of biochemical parameters. HCS deficiency was established in lymphocytes and skin fibroblasts. The activities of all biotin-dependent carboxylases were severely decreased in fibroblasts grown in medium with moderate biotin concentration (10−8 mol/l) but normal in a high biotin medium (10−5 mol/l). Mitochondrial carboxylase activities in lymphocytes were 23%–29% of mean normal during therapy with 20 mg of biotin/day, with the higher dose of 40 mg/day they were within (3-methylcrotoryl-CoA carboxylase, pyruvate carboxylase) or slightly below (propionyl-CoA carboxylase) the normal range. At the age of 3 years the patients physical and psychomotor development are normal. Early biotin supplementation should be considered in newborns with lactic acidosis and organoaciduria until a final diagnosis has been established. Furthermore, the required individual dose of biotin has to be carefully evaluated biochemically for the individual patient.

Glucocorticoid receptors in mononuclear blood cells and their correlation to endogenous and exogenous corticoids in healthy and asthmatic children

The number and affinity of glucocorticoid binding sites in peripheral mononuclear cells (MNC) of asthmatic and healthy children were determined by a whole cell (3H)dexamethasone binding assay at 37°C. Using HPLC determination, corresponding serum levels of non-protein-bound (free) cortisol, whole cortisol and cortisone as well as urine excretion of free cortisone and cortisol were assessed. The average number of binding sites (BS) per cell and the dissociation constant (KD) respectively, in atopic asthmatics (7768±666 BS/MNC resp. KD=17.2±2 nM) did not differ from the values measured in our control group (8333±691 BS/MNC resp. 25.4±4.8 nM). Within the age range 1 month-15.8 years neither age-dependent changes nor sex-related differences in the number of binding sites or the KD values could be detected. Active or currently inactive asthmatics, and patients under different antiasthmatic drug regimes, had similar binding sites on MNC. No differences in serum levels of cortisol, cortisone and free cortisol or in free cortisol and free cortisone of 24-h urine samples were found between healthy children and asthmatics. After a short course of prednisolone therapy for an acute severe asthmatic attack the number of glucocorticoid binding sites in peripheral MNC decreased to an average of 4632±421 BS/MNC, whereas the dissociation constant did not change significantly (14.5±3.6 nM). The corticod-hormone pattern in the serum, 24-h urine excretion, and the normal number and affinity of glucocorticoid receptors on peripheral MNC suggest that there is no primary, general impairment of glucocorticoid metabolism in asthmatic children. Short-term glucocorticoid administration resulted in suppression of endogenous corticoids to undetectable levels accompanied by down-regulation of glucocorticoid-receptor BS to about 55% of control levels.

Detoxification of cyanide in a new-born child.

SummaryA well-developed male baby was given infusions of 2–5 µg/kg/min of sodium nitroprusside (SNP) in the first few days after birth on account of high arterial blood pressure. After 30 h of treatment, cyanide accumulation was found to have reached a life-threatening level. IV administration of 100 mg/kg of sodium thiosulphate promptly lowered the cyanide level. The mixed infusion of SNP together with thiosulphate, used in the subsequent course, was no longer toxic.ZusammenfassungEin reifer männlicher Säugling bekam wegen einer arteriellen Hypertonie in den ersten Lebenstagen 2–5 µg/kg/min Nitroprussid-Natrium (NPN) infundiert. Nach 30stündiger Therapie wurde eine lebensbedrohliche Zyanidkumulation festgestellt. Der Zyanidspiegel konnte mit 100 mg/kg Natriumthiosulfat i.v. prompt gesenkt werden. Die Mischinfusion von NNP zusammen mit Thiosulfat war im weiteren Verlauf nicht mehr toxisch.

Haemorrhagic shock-encephalopathy syndrome: plasmapheresis as a therapeutic approach

We present the case of a 4.5-week-old boy with acute encephalopathy, shock, intestinal bleeding and disseminated intravascular coagulation. The clinical course and typical laboratory parameters were compatible with a diagnosis of haemorrhagic shock-encephalopathy syndrome (HSE). Immediate shock treatment, repeated haemodialysis and plasmapheresis did not prevent a fatal outcome 4 days after the onset of clinical symptoms.

[Indocyanine green kinetics in newborns with non-hemolytic hyperbilirubinemia (author's transl)].

The kinetic parameters of indocyanine green elimination from blood were determined after an intravenous load of the dye in a dosage of 2-4 mg per kg body weight in 22 newborns with a non-hemolytic hyperbilirubinemia. Since the uptake of indocyanine green by liver is selectively carried out and the dye is not further metabolised, these kinetic parameters serve as measures for the performance of hepatocellular elimination. 11 of these newborns were treated 5 days previously with 7.5 mg phenobarbital per kg body weight. Compared to the untreated group, the serum bilirubin concentration significantly decreased after treatment with phenobarbital and the parameters of elimination of the dye from blood changed as described by saturation-kinetics. The maximal elimination-rate Vmax and the Michaelis-Menten-constant Km were significantly higher in newborns treated with phenobarbital (71.1 muMol/l-min and 356.4 muMol/l) than in the untreated ones (23.4 muMol/l-min and 100.0 mutmol/l). Kinetic data of indocyanine green elimination gathered in newborns treated with and without phenobarbital support the hypothesis that cytoplasmatic proteins oliver should facilitate the uptake of organic anions inclusively bilirubin into the liver cell. A defiency of such transport proteins may be one of the causes of non-hemolytic hyperbilirubinemia in newborns.SummaryThe kinetic parameters of indocyanine green elimimination from blood were determined after an intravenous load of the dye in a dosage of 2–4 mg per kg body weight in 22 newborns with a non-hemolytic hyperbilirubinemia. Since the uptake of indocyanine green by liver is selectively carried out and the dye is not further metabolised, these kinetic parameters serve as measures for the performance of hepatocellular elimination. 11 of these newborns were treated 5 days previously with 7.5 mg phenobarbital per kg body weight.Compared to the untreated group, the serum bilirubin concentration significantly decreased after treatment with phenobarbital and the parameters of elimination of the dye from blood changed as described by saturation-kinetics. The maximal elimination-rateVmax and the Michaelis-Menten-constantKm were significantly higher in newborns treated with phenobarbital (71.1 µMol/l·min and 356.4 µMol/l) than in the untreated ones (23.4 µMol/l·min and 100.0 µMol/l).Kinetic data of indocyanine green elimination gathered in newborns treated with and without phenobarbital support the hypothesis that cytoplasmatic proteins of liver should facilitate the uptake of organic anions inclusively bilirubin into the liver cell. A defiency of such transport proteins may be one of the causes of non-hemolytic hyperbilirubinemia in newborns.ZusammenfassungBei 22 Neugeborenen mit einer transitorischen Hyperbilirubinämie wurde eine intravenöse Belastung mit Indocyanin-Grün in einer Dosierung von 2 mg, 3 mg and 4 mg pro kg Körpergewicht durchgeführt und die kinetischen Parameter der Farbstoffelimination aus dem Blut bestimmt. Da Indocyanin-Grün selektiv von der Leber aufgenommen und nicht weiter metabolisiert wird, sind diese Parameter ein Maß für die Leistung hepatozellulärer Eliminationsmechanismen. 11 Neugeborene waren zuvor 5 Tage lang mit 7,5 mg Phenobarbital pro kg Körpergewicht zur Verhinderung einer transitorischen Hyperbilirubinämie behandelt worden.Im Vergleich zum unbehandelten Kollektiv war die Bilirubinkonzentration im Serum nach Phenobarbitalbehandlung signifikant erniedrigt und die Kenngrößen der Eliminations-Sättigungskinetik von Indocyanin-Grün aus dem Blut verändert. Die maximale EliminationsgeschwindigkeitVmax und die Michaelis-Menten-KonstanteKm waren bei den behandelten Säuglingen mit 71,1 µMol/l·min bzw. 356,4 µMol/l signifikant größer als bei den unbehandelten (23,4 µMol/l·min bzw. 100,0 µMol/l.Die kinetischen Daten der Indocyanin-Grün-Elimination, die bei Neugeborenen mit und ohne Phenobarbitalbehandlung bestimmt wurden, stützen die Vermutung, daß zytoplasmatische Transportproteine der Leber die Aufnahme organischer Anionen einschließlich des Bilirubins in die Zelle vermitteln. Ein Mangel dieser Proteine im Neugeborenenalter mag eine der Ursachen für die Entstehung der transitorischen Hyperbilirubinämie sein.

The age-dependence of intestinal absorption using d-xylose as an example

In 40 infants the serum concentrations of d-xylose were measured from capillary blood samples up to 300 min after an oral dosage of 0.5 g of d-xylose per kg body weight. The parameters of the absorption kinetics, which are calculated by a digital computer program, showed an age-dependent behavior. Infants up to the age of 2 months have lower maximal serum concentrations compared to older ones because of a larger volume of distribution. The rate constant of invasion k1, which serves as a measure for the rate of intestinal absorption and the rate constant of elimination k2 were significantly lower in infants up to the age of 2 months compared to older ones. The quotient of k1∶k2 was independent of age. The time it took to reach maximal serum concentration was significantly longer in young infants.By adding metoclopramide simultanously to the oral d-xylose doses it could be demonstrated that the slower motility of the gastrointestinal tract in newborns and young infants is not exclusively responsible for the slower rate of absorption of d-xylose. Comparing the absorption rates in 26 infants after different d-xylose dosages a saturation kinetics may be supposed.ZusammenfassungBei 40 Säuglingen wurde eine D-Xylose-Belastung mit 0.5 g pro kg Körpergewicht durchgeführt und die Serumkonzentrationen bis zu 300 min nach oraler Verabreichung aus Kapillarblut bestimmt. Die aus der Konzentrationskurve mit Hilfe eines elektronischen Rechenprogramms ermittelten kinetischen Daten verhalten sich altersabhängig. Jüngere Säuglinge bis zum 2. Lebensmonat zeigen infolge des großen Verteilungsvolumens wesentlich niedrigere maximale Serumkonzentrationen als ältere Kinder. Die Größe der Invasioskonstanten k1 als Maß für die Resorptionsgeschwindigkeit von D-Xylose aus dem Dünndarm ist ebenso wie die der Eliminations-konstanten k2 bei jungen Säuglingen signifikant kleiner gegenüber älteren, das Verhältnis von k1∶k2 jedoch altersunabhängig. Der Zeitpunkt des Erreichens der maximalen Serumkonzentration ist bei jungen Säuglingen signifikant verlängert im Vergleich zu älteren.Durch gleichzeitige Gabe von Metoclopramid zur D-Xylose bei 11 Säuglingen wurde nachgewiesen, daß die verringerte Magen-Darm-Motilität im frühen Säuglingsalter nicht allein für die verminderte Resorptionsgeschwindigkeit verantwortlich gemacht werden kann. Die bei 26 Säuglingen zusätzlich durchgeführten oralen D-Xylose-Belastungen mit 0,3 g pro kg Körpergewicht ergaben Hinweise dafür, daß die D-Xylose-Resorption aus dem Dünndarm einer Sättigungskinetik folgt.

Immunocytological studies in a case of Bruton's disease

Immunopathological findings in a case with infantile X-linked agamma globulinemia (Brutons disease) are reported and compared to similar data from two cousins of the patient. Besides a severe decrease in B-lymphocytes in blood and lymph node, residual B-cells showed an almost total defect in Ig surface receptor expression. In addition, there was an unusual lymphocyte population which apparently exhibited E-rosette formation (i.e. T-cell characteristics) and phagocytosis. The data suggest that in Brutons disease there may be a disturbance of the T-cell system besides the well known B-cell deficiency.