Continuous infusion of clonidine in ventilated newborns and infants: a randomized controlled trial.

OBJECTIVES: To assess the influence of an infusion of clonidine 1 µg/kg/hr on fentanyl and midazolam requirement in ventilated newborns and infants. DESIGN: Prospective, double-blind, randomized controlled multicenter trial. Controlled trials.com/ISRCTN77772144. SETTING: Twenty-eight level 3 German PICUs/neonatal ICUs. PATIENTS: Ventilated newborns and infants: stratum I (1-28 d), stratum II, (29-120 d), and stratum III (121 d to 2 yr). INTERVENTIONS: Patients received clonidine 1 µg/kg/hr or placebo on day 4 after intubation. Fentanyl and midazolam were adjusted to achieve a defined level of analgesia and sedation according to Hartwig score. MEASUREMENTS AND MAIN RESULTS: Two hundred nineteen infants were randomized; 212 received study medication, 69.7% were ventilated in the postoperative care and 30.3% for other reasons. Primary endpoint: consumption of fentanyl and midazolam in the 72 hours following the onset of study medication (main observation period) in the overall study population. The confirmatory analysis of the overall population showed no difference in the consumption of fentanyl and midazolam. Explorative age-stratified analysis demonstrated that in stratum I (n = 112) the clonidine group had a significantly lower consumption of fentanyl (clonidine: 2.1 ± 1.8 µg/kg/hr, placebo: 3.2 ± 3.1 µg/kg/hr; p = 0.032) and midazolam (clonidine: 113.0 ± 100.1 µg/kg/hr, placebo: 180.2 ± 204.0 µg/kg/hr; p = 0.030). Strata II (n = 43) and III (n = 46) showed no statistical difference. Sedation and withdrawal-scores were significantly lower in the clonidine group of stratum I (p < 0.001). Frequency of severe adverse events did not differ between groups. CONCLUSIONS: Clonidine 1 µg/kg/hr in ventilated newborns reduced fentanyl and midazolam demand with deeper levels of analgesia and sedation without substantial side effects. This was not demonstrated in older infants, possibly due to lower clonidine serum levels.

Remifentanil-induced tolerance, withdrawal or hyperalgesia in infants: a randomized controlled trial. RAPIP trial: remifentanil-based analgesia and sedation of paediatric intensive care patients.

BACKGROUND: Short-acting opioids like remifentanil are suspected of an increased risk for tolerance, withdrawal and opioid-induced hyperalgesia (OIH). These potential adverse effects have never been investigated in neonates. OBJECTIVES: To compare remifentanil and fentanyl concerning the incidence of tolerance, withdrawal and OIH. METHODS: 23 mechanically ventilated infants received up to 96 h either a remifentanil- or fentanyl-based analgesia and sedation regimen with low-dose midazolam. We compared the required opioid doses and the number of opioid dose adjustments. Following extubation, withdrawal symptoms were assessed by a modification of the Finnegan score. OIH was evaluated by the CHIPPS scale and by testing the threshold of the flexion withdrawal reflex with calibrated von Frey filaments. RESULTS: Remifentanil had to be increased by 24% and fentanyl by 47% to keep the infants adequately sedated during mechanical ventilation. Following extubation, infants revealed no pronounced opioid withdrawal and low average Finnegan scores in both groups. Only 1 infant of the fentanyl group and 1 infant of the remifentanil group required methadone for treatment of withdrawal symptoms. Infants also revealed no signs of OIH and low CHIPPS scores in both groups. The median threshold of the flexion withdrawal reflex was 4.5 g (IQR = 2.3) in the fentanyl group and 2.7 g (IQR = 3.3) in the remifentanil group (p = 0.312), which is within the physiologic range of healthy infants. CONCLUSIONS: Remifentanil does not seem to be associated with an increased risk for tolerance, withdrawal or OIH.

Remifentanil/midazolam versus fentanyl/midazolam for analgesia and sedation of mechanically ventilated neonates and young infants: a randomized controlled trial.

PURPOSE: Common opioids for analgesia and sedation of mechanically ventilated infants may tend to accumulate and cause prolonged sedation with an unpredictable extubation time. Remifentanil is a promising option due to its unique pharmacokinetic properties, which seem to be valid in adults as well as in infants. METHODS: In this double-blind, randomized, controlled trial mechanically ventilated neonates and young infants (<60 days) received either a remifentanil or fentanyl-based analgesia and sedation regimen with low dose midazolam. The primary endpoint of the trial was the extubation time following discontinuation of the opioid infusion. Secondary endpoints included efficacy and safety aspects. RESULTS: Between November 2006 and March 2010, we screened 431 mechanically ventilated infants for eligibility. The intention to treat group included 23 infants who were assigned to receive either remifentanil (n = 11) or fentanyl (n = 12). Although this was designed as a pilot study, median extubation time was significantly shorter in the remifentanil group (80.0 min, IQR = 15.0-165.0) compared to the fentanyl group (782.5 min, IQR = 250.8-1,875.0) (p = 0.005). Remifentanil and fentanyl provided comparable efficacy with more than two-thirds of the measurements indicating optimal analgesia and sedation (66.4 and 70.2 %, respectively; p = 0.743). Overall, both groups had good hemodynamic stability and a comparably low incidence of adverse events. CONCLUSIONS: As neonates and young infants have a decreased metabolism of common opioids like fentanyl and are more prone to respiratory depression, remifentanil could be the ideal opioid for analgesia and sedation of mechanically ventilated infants.

Voriconazole serum concentrations in prophylactically treated acute myelogenous leukaemia patients.

Antifungal prophylaxis during first remission induction chemotherapy for acute myelogenous leukaemia requires broad spectrum azoles. In a clinical trial, therapeutic drug monitoring (TDM) of antifungal prophylaxis with voriconazole 200 mg bid was evaluated in a population of six patients. High pressure liquid chromatography was applied. Trough levels were obtained 24 h after the last voriconazole dose. Median time of voriconazole exposure prior to sample acquisition was 16 days (range 9-21). The mean voriconazole concentration was 486 µg l(-1) and ranged from 136 µg l(-1) to 1257 µg l(-1). Among possible or probable treatment-related adverse events, elevated liver function tests were the most frequent. Five of six patients developed fever during neutropenia, but none of them developed pulmonary infiltrates or other signs of invasive fungal infection while on voriconazole prophylaxis. Future investigations might aim at identifying drug level thresholds that allow for minimum toxicity and optimum efficacy of antifungal prophylaxis.

A double-blind trial on prophylactic voriconazole (VRC) or placebo during induction chemotherapy for acute myelogenous leukaemia (AML).

OBJECTIVES: Invasive fungal infections remain a frequent cause of morbidity and mortality in long-term neutropenic patients. The availability of tolerable broad-spectrum antifungals like voriconazole stimulated the discussion about optimal timing of antifungal therapy. We conducted a trial to analyze the efficacy and safety of voriconazole in the prevention of lung infiltrates during induction chemotherapy for acute myelogenous leukaemia (AML). METHODS: This was a prospective, randomised, double-blind, placebo-controlled phase III trial in AML patients undergoing remission induction chemotherapy. Oral voriconazole 200 mg twice daily or placebo was administered until detection of a lung infiltrate or end of neutropenia. Primary efficacy parameter was the incidence of lung infiltrates until day 21 after initiation of chemotherapy. Secondary objectives were incidence of infections, length of stay in hospital, time to antifungal treatment, time to first fever, and drug safety. RESULTS: A total of 25 patients were randomly assigned to receive voriconazole (N=10) or placebo (N=15). Incidence of lung infiltrates until day 21 was 0 (0%) in the voriconazole and 5 (33%) in the placebo group (P=0.06). Average length of stay in hospital was shorter in the voriconazole group (mean 31.9 days) than in the placebo group (mean 37.3 days, P=0.09). Four patients were diagnosed with hepatosplenic candidiasis until a 4 week follow-up, all in the placebo group (P=0.11). Adverse events and toxicity did not differ between the two treatment groups. The trial was stopped prematurely when another trial demonstrated reduced mortality by antifungal prophylaxis with posaconazole, thus rendering further randomisation against placebo unethical. CONCLUSION: In AML patients undergoing induction chemotherapy, prophylactic oral voriconazole 200 mg twice daily resulted in trends towards reduced incidences of lung infiltrates and hepatosplenic candidiasis. Voriconazole was safe and well tolerated.

Topotecan, cyclophosphamide, and etoposide (TCE) in the treatment of high-risk neuroblastoma. Results of a phase-II trial.

PURPOSE: Relapsed high-risk neuroblastoma patients still have a poor prognosis. This phase-II trial assessed a new topotecan containing chemotherapy approach in patients with active disease. METHODS: Chemotherapy consisted of topotecan (1.0 mg/m(2)/day 168-h continuous infusion), cyclophosphamide (100 mg/m(2)/day 1-h-infusion days 1-7 starting 6 h prior to topotecan), and etoposide (100 mg/m(2)/day 1-h-infusion days 8-10). Patients with relapsed neuroblastoma were scheduled for six cycles, untreated patients for two cycles followed by standard high-risk treatment. RESULTS: Main toxicity observed during 153 cycles were grade 3-4 leukopenia (97% of cycles), thrombocytopenia (92%), neutropenic fever (52%), and mucositis (10%). No treatment related fatal toxicity occurred. Complete or partial response was achieved in 19 of 31 (61%) evaluable relapsed patients and 8 of 11 (72%) untreated patients. CONCLUSIONS: The combination of topotecan, cyclophosphamide, and etoposide is tolerable and effective in relapsed and untreated neuroblastoma. Myelotoxicity is the main side effect but seems justified in view of the encouraging response rates. A randomized phase-III trial in primary disease has been commenced.

Consequences of Directive 2001/20/EC for investigator-initiated trials in the paediatric population--a field report.

On 4 April 2001, the European Parliament and Council enacted Directive 2001/20/EC, which had to be implemented in the national law of the European Union member states by May 2004. Its aim was to improve the quality of clinical trials and to assure the safety and well-being of trial subjects. We recently initiated the first paediatric investigator-initiated trial (IIT) at the University Hospital of Cologne according to Directive 2001/20/EC. This field report demonstrates the consequences and implications of the directive for paediatric IITs. Based on our experience, we agree that Directive 2001/20/EC improves the quality of clinical trials and assures the safety and well-being of trial subjects. However, at the same time, performing an IIT according to the new requirements is nearly impossible for clinicians and academic researchers without cooperating with expensive specialised experts, such as project managers, statisticians, data managers, pharmacists and monitors. Therefore, it is absolutely mandatory that financial support for paediatric IITs be adapted and increased in order to be able to meet the new requirements and obligations. Regulation (EC) No 141/2000 on orphan medicinal products and the recently adopted regulation on medicinal products for paediatric use (Paediatric Regulation) are important steps in improving clinical research in children. However, both regulations mainly encourage clinical research carried out by the pharmaceutical industry, whereas paediatric IITs are not in the scope of this legislation. We need to develop new concepts for funding to ensure future paediatric IITs, for example through specific grants from the European Union or member states.