M. van Dijk

Randomised controlled trial evaluating effects of morphine on plasma adrenaline/noradrenaline concentrations in newborns

Objectives: To determine the effects of continuous morphine infusion in ventilated newborns on plasma concentrations of adrenaline (epinephrine) and noradrenaline (norepinephrine) and their relation to clinical outcome. Design: Blinded, randomised, placebo controlled trial. Setting: Level III neonatal intensive care units in two centres. Patients: A total of 126 ventilated neonates (inclusion criteria: postnatal age <3 days, duration of ventilation <8 hours, indwelling arterial catheter for clinical purposes; exclusion criteria: severe asphyxia, severe intraventricular haemorrhage, major congenital anomalies, neuromuscular blockers). Interventions: Plasma adrenaline and noradrenaline concentrations were determined in patients during blinded morphine (n  =  60) and placebo (n  =  66) infusion (100 μg/kg plus 10 μg/kg/h). Results: Plasma concentrations at baseline (nmol/l with interquartile range in parentheses) were comparable in infants treated with morphine (adrenaline, 0.22 (0.31); noradrenaline, 2.52 (2.99)) or placebo (adrenaline, 0.29 (0.46); noradrenaline, 2.44 (3.14)). During infusion, median adrenaline concentrations were 0.12 (0.28) and 0.18 (0.35) and median noradrenaline concentrations were 2.8 (3.7) and 3.8 (4.0) for the morphine and placebo treated infants respectively. Multivariate analyses showed that noradrenaline (p  =  0.029), but not adrenaline (p  =  0.18), concentrations were significantly lower in the morphine group than the placebo group. Furthermore, noradrenaline concentrations were related to the length of stay in the neonatal intensive care unit. Conclusions: Continuous morphine infusion significantly decreased plasma noradrenaline concentrations in ventilated newborns compared with placebo treatment. The results of this study support the idea that routine morphine administration decreases stress responses in ventilated neonates.

Morphine in ventilated neonates: Its effects on arterial blood pressure

Objective: To study the effects of continuous morphine infusion on arterial blood pressure in ventilated neonates. Design: Blinded randomised placebo controlled trial. Setting: Level III neonatal intensive care unit in two centres. Patients: A total of 144 ventilated neonates. Inclusion criteria were postnatal age <3 days, ventilation <8 hours, and indwelling arterial line. Exclusion criteria were severe asphyxia, severe intraventricular haemorrhage, major congenital anomalies, neuromuscular blockers. Intervention: Arterial blood pressure was measured before the start and during the first 48 hours of masked infusion of drug (morphine/placebo; 100 μg/kg + 10 μg/kg/h). Outcome measures: Arterial blood pressure and blood pressure variability. Results: There were no significant differences in overall mean arterial blood pressure between the morphine group (median (interquartile range) 36 mm Hg (6) and the placebo group (38 mm Hg (6)) (p  =  0.11). Although significantly more morphine treated patients (70%) showed hypotension than the placebo group (47%) (p  =  0.004), the use of volume expanders and vasopressor drugs was not significantly different (morphine group, 44%; placebo group, 48%; p  =  0.87), indicating the limited clinical significance of this side effect. Blood pressure variability was not influenced by routine morphine analgesia (p  =  0.81) or additional morphine (p  =  0.80). Patients with and without intraventricular haemorrhage showed no differences in blood pressure (Mann-Whitney U test 1953; p  =  0.14) or incidence of hypotension (χ2 test 1.16; df 1; p  =  0.28). Conclusions: Overall arterial blood pressure, use of inotropes, and blood pressure variability were not influenced by morphine infusion. Therefore the clinical impact of hypotension as a side effect of low dose morphine treatment in neonates is negligible.

Survival of patients with nonseminomatous germ cell cancer: a review of the IGCC classification by Cox regression and recursive partitioning.

The International Germ Cell Consensus (IGCC) classification identifies good, intermediate and poor prognosis groups among patients with metastatic nonseminomatous germ cell tumours (NSGCT). It uses the risk factors primary site, presence of nonpulmonary visceral metastases and tumour markers alpha-fetoprotein (AFP), human chorionic gonadotrophin (HCG) and lactic dehydrogenase (LDH). The IGCC classification is easy to use and remember, but lacks flexibility. We aimed to examine the extent of any loss in discrimination within the IGCC classification in comparison with alternative modelling by formal weighing of the risk factors. We analysed survival of 3048 NSGCT patients with Cox regression and recursive partitioning for alternative classifications. Good, intermediate and poor prognosis groups were based on predicted 5-year survival. Classifications were further refined by subgrouping within the poor prognosis group. Performance was measured primarily by a bootstrap corrected c-statistic to indicate discriminative ability for future patients. The weights of the risk factors in the alternative classifications differed slightly from the implicit weights in the IGCC classification. Discriminative ability, however, did not increase clearly (IGCC classification, c=0.732; Cox classification, c=0.730; Recursive partitioning classification, c=0.709). Three subgroups could be identified within the poor prognosis groups, resulting in classifications with five prognostic groups and slightly better discriminative ability (c=0.740). In conclusion, the IGCC classification in three prognostic groups is largely supported by Cox regression and recursive partitioning. Cox regression was the most promising tool to define a more refined classification.

Thyroid function in short children born small-for-gestational age (SGA) before and during GH treatment

Context  Disturbances in thyroid function have been described in small‐for‐gestational age (SGA) children but the influence of prematurity is unclear. In addition, the effect of GH treatment on thyroid function has not been studied in short SGA children.

Morphine Pharmacodynamics in Mechanically Ventilated Preterm Neonates Undergoing Endotracheal Suctioning

To date, morphine pharmacokinetics (PKs) are well quantified in neonates, but results about its efficacy are ambiguous. This work presents an analysis of a previously published study on pain measurements in mechanically ventilated preterm neonates who received either morphine or placebo to improve comfort during invasive ventilation. The research question was whether morphine reduces the pain associated with endotracheal or nasal suctioning before, during, and after suctioning. Because these neonates cannot verbalize their pain levels, pain was assessed on the basis of several validated pain measurement instruments (i.e., COMFORT‐B, preterm infant pain profile [PIPP], Neonatal Infant Pain Scale (NIPS), and visual analogue scale (VAS)). The item response theory (IRT) was used to analyze the data in order for us to handle the data from multiple‐item pain scores. The analysis showed an intra‐individual relationship between morphine concentrations and pain reduction, as measured by COMFORT‐B and VAS. However, the small magnitude of the morphine effect was not considered clinically relevant for this intervention in preterm neonates.

A Comparative Analysis of Preemptive Versus Targeted Sedation on Cardiovascular Stability After High-Risk Cardiac Surgery in Infants.

Objective: To compare the effect of two sedation practices on cardiovascular stability during the early postoperative period in young infants following cardiac surgery: the routine early use of midazolam infusion (preemptive sedation) and the discretionary use of sedatives tailored to the patient’s clinical condition (targeted sedation). Design: Retrospective cohort study with matched controls. Setting: A 15-bedded pediatric cardiac ICU. Patients: Sedation strategies were compared by matching patients before and after the introduction of a targeted sedation guideline, replacing the existing practice of preemptive sedation. Inclusion criteria were age less than 6 months and cardiopulmonary bypass time greater than 150 minutes. Matching criteria were surgical procedure, age, and duration of cardiopulmonary bypass and cross-clamp. The main outcome was cardiovascular instability, defined by the presence of one of the following criteria in the first 12 hours after PICU admission: 1) simultaneous administration of greater than or equal to two inotropic or vasopressor drugs; 2) administration of greater than 60 mL/kg fluid boluses. Secondary outcomes were: 1) markers of cardiac output adequacy (heart rate, blood pressure, vasoactive inotropic score, urine output, volume of fluid boluses, central venous oxygen saturation, lactate); 2) occurrence of adverse events (cardiac arrest, extracorporeal membrane oxygenation, death); 3) sedatives administered and depth of sedation. Interventions: Introduction of a guideline of targeted sedation. Measurements and Main Results: Thirty-three patients with preemptive sedation were matched to 33 patients with targeted sedation. Targeted sedation resulted in less frequent oversedation, without compromising cardiovascular stability, as indicated by similar occurrence of cardiovascular instability (68.8% with preemptive sedation vs 62.5% with targeted sedation; p = 0.53) and adverse events, and similar markers of cardiac output adequacy. Although all preemptively sedated patients received an infusion of midazolam in the first 12 hours after surgery, only 19.4% of patients in the targeted sedation group received a sedative infusion (p < 0.001). Conclusions: Our data suggest that after high-risk cardiac surgery in young infants, routine sedation with midazolam may not prevent low cardiac output syndrome. When accompanied by a careful assessment of level of sedation, routine sedation of infants after high-risk cardiac surgery can be avoided without compromising hemodynamic stability or patient safety. The potential benefit of this approach is reduced exposure to sedative.

Het meten van pijn bij kinderen: dagelijkse routine of voer voor onderzoekers?

SummaryPain assessment in children may be achieved by self report, behavioural observations or physiological responses. Self report is usually considered useful from the age of four years onward. Crying, facial expression and body movement are the most used behavioural indicators in pain instruments. The quality of a pain instrument should be tested for its reliability, validity and usefulness in clinical practice. Pain instruments for older children are applied to express the pain intensity in a simple way. Many pain instruments have been developed for neonates, infants, and toddlers, although they are rather similar. Up to now, pain instruments have been used for research purposes only. Now it is time to implement pain assessment in daily care, which will require time, money, manpower, and good communication.SamenvattingHet meten van pijn bij kinderen omvat zelfrapportage, gedragsobservaties, en fysiologische reacties. Zelfrapportage wordt over het algemeen vanaf de leeftijd van vier jaar toegepast. Huilen, gezichtsuitdrukking en lichaamsbeweging zijn de meest gebruikte indicatoren in pijnmeetinstrumenten. De kwaliteit van een pijnmeetinstrument wordt getoetst op de mate van betrouwbaarheid, validiteit en toepasbaarheid in de klinische praktijk. Pijnmeetinstrumenten bij oudere kinderen zijn vaak hulpmiddelen om op eenvoudige wijze de ernst van de pijn aan te geven. Voor zuigelingen en jonge kinderen zijn meerdere pijnmeetinstrumenten ontwikkeld, die overigens vrij veel op elkaar lijken. Pijnmeetinstrumenten zijn tot nu toe alleen gebruikt voor onderzoeksdoeleinden. Het is nu tijd om pijnmeting in de dagelijkse praktijk te implementeren, maar dit vereist tijd, geld, mankracht en goede communicatie

Enhancement of the Cobra Venom Direct Lytic Factor by Prostaglandins and Related Synergistic Phenomena on Pulmonary Microvascular Events

The synergism of phospholipase A with the direct lytic factor (DLF), the most basic small molecular-weight protein isolated from Elapid venoms, has initially been studied in the hemolysis of washed erythrocytes (Condrea et al., 1964a). It is now accepted that the presence of both DLF and phosphohpase A is responsible for the hemolytic effect of cobra venoms. Furthermore it has been shown that DLF is the only component of Naja naja venom which has the ability to produce the type of microvascular lesion which can readily be observed after topical application of the full venom on the pulmonary pleural surface of dogs (Bonta et al., 1969; 1972b). This type of microvascular damage was initially described as a local hemorrhage (Bonta et al., 1970; 1973) though recent and as yet uncompleted microscopical studies point in the direction of vascular congestion accompanied by permeabihty changes (G. M. Bohm, personal conmiunication). In view of the continuing uncertainty as to the exact ultrastructural character of the pulmonary microcirculatory lesion by cobra venom, it will be mentioned throughout the present paper as microvascular lesion or damage. Phospholipase A does not share this property of DLF, to induce the vascular event mentioned above, but the enzyme can reinforce the vascular damaging effect of the lytic protein (Bonta et al., 1972b; 1973).

Neugeborene: Langzeitnebenwirkungen nach Morphin?

Bei Fruh- und Neugeborenen wiesen Daten aus Tierversuchen auf mogliche negative Folgen einer fruhen und chronischen Exposition mit Morphin hin. Vor diesem Hintergrund wurde von 2000–2002 eine Studie durchgefuhrt, die 150 Sauglinge und Fruhgeborene aufnahm, die in den ersten Lebenswochen auf einer Intensivstation kunstlich beatmet wurden und entweder eine Morphindauerinfusion oder eine Placeboinfusion erhielten. In der vorliegenden Arbeit werden Langzeitdaten der mittlerweile 8–9 Jahre alten Kinder veroffentlicht, die jetzt auch eine quantitative sensorische Testung beinhalten.