Biomedical subjects

Sinno H P Simons

Publications and source records attributed to Sinno H P Simons.

7 recordsLinked to original sources

PubMed2006

Pain control: opioid dosing, population kinetics and side-effects.

Neonates undergoing invasive procedures, postoperative pain or ventilatory support commonly receive opioids for treating pain and stress. Randomized clinical trials have examined the benefits and adverse effects of morphine or fentanyl for ventilated neonates and other indications. This paper summarizes the current evidence for opioid dosing in newborns, reviews their side-effects and explains the use of population kinetics and non-linear mixed-effects modeling to analyze the data from clinical trials. Opioid use should be reserved for severe pain postoperatively or during intensive care in neonates, using continuous infusions rather than intermittent boluses. The safety and efficacy data from prolonged opioid use, particularly on the long-term outcomes of neonates, is still lacking. The pharmacodynamics and pharmacogenetics of opioid use in infancy needs further investigation, using non-linear mixed-effects models to drive individualized therapy. The current interest in opioid research will reap rich dividends in providing pain relief for neonates and avoiding dangerous side effects.

Analgesics, Opioid↗

PubMed2006

Pain perception development and maturation.

Newborn infants are not small adults. The pharmacokinetics and dynamics of analgesic drugs are immature at birth. Volumes of distribution, drug clearances, side-effects and drug efficacy all differ in newborns as compared to adults. Interestingly, these parameters develop before birth and during the postnatal period, reaching adult values after a period of months or years. This means that clinicians should anticipate on pharmacokinetic/pharmacodynamic (PK/PD) changes in newborns with increasing post-conceptual age. The ability to perceive pain might also be immature at birth. Lower pain thresholds due to the absence of inhibitory descending spinothalamic fibers and a not yet fully developed cortical pain memory system are points of interest for our understanding of differences in pain perception in the newborn infant. Although this is a relatively unexplored area of research in humans, we will discuss the maturation and development of neonatal pain experience and perception in this paper.

Analgesics↗

PubMed2006

Morphine metabolite pharmacokinetics during venoarterial extra corporeal membrane oxygenation in neonates.

OBJECTIVE: To examine morphine metabolite serum concentrations in neonates undergoing venoarterial extra corporeal membrane oxygenation (ECMO) and to quantify clearance differences between these neonates and those subjected to noncardiac major surgery. PATIENTS AND METHODS: This was an observational study in level III referral centre. Fourteen neonates (< 7 days old) undergoing ECMO were included. Morphine and concomitant medications were given by protocol, adapted to the clinical conditions of the neonates. Pharmacokinetic findings were compared with those from a previous study in infants after noncardiac major surgery. Nonlinear mixed-effect modelling was used. Parameter estimates were standardised to a 70 kg person using allometric modeling RESULTS: Morphine-3-glucuronide (M3G) was the predominant metabolite. Formation clearance to M3G at the start of ECMO on day 1 was lower than those in postoperative children, but matured more rapidly. After 10 days formation clearances of M3G in neonates on ECMO equalled those of postoperative children. Higher ECMO flows were associated with reduced formation clearances. Elimination clearances of M3G, but not morphine-6-glucuronide (M6G), were lower in the ECMO neonates; this was attributable to reduced renal clearance. These elimination clearances were correlated positively with ECMO flow and negatively with dopamine dose. Haemofiltration cleared M3G and M6G, but not morphine. CONCLUSION: Formation clearance to M3G, the predominant metabolite, is reduced during the first 10 days of ECMO. Elimination clearance of M3G and M6G is related to creatinine clearance. ECMO flow had a small effect on metabolite clearance. Higher flows were associated with decreased formation clearances, possibly reflecting illness severity. Dopamine dose reflected decreased renal clearance.

Adult↗

PubMed2005

Morphine pharmacokinetics during venoarterial extracorporeal membrane oxygenation in neonates.

OBJECTIVE: To study morphine pharmacokinetics in neonates undergoing venoarterial ECMO and to quantify differences between these neonates and neonates subjected to noncardiac major surgery. DESIGN AND SETTING: Observational study in a level III referral center. PATIENTS AND METHODS: Pharmacokinetic estimates from 14 neonates undergoing ECMO were compared with findings from a previous study in 0- to 3-year-olds after noncardiac major surgery using a nonlinear mixed effect model. A one-compartment linear disposition model with zero-order input (infusion) and first-order elimination was used to describe all data. RESULTS: Clearance in neonates (age <7 days) at the start of ECMO (2.2 l per hour per 70 kg) was lower than that in postoperative neonates (10.5 l per hour per 70 kg) but increased rapidly (maturation half-life 30 and 70 days, respectively) and equaled that of the postoperative group after 14 days. Clearance was affected by size and age only. Exchange transfusion, when used, contributed only 1.1% (CV 46%) of total clearance. Distribution volume increased with age and was 2.5 times (CV 102%) greater in ECMO children than in postoperative children. The between-subject variability values for volume of distribution and clearance were 49.4% and 38.7%. Weight and age information explained 83% of the overall clearance variability and 60% of overall distribution volume variability. CONCLUSIONS: Morphine clearance is reduced in infants requiring ECMO, possibly reflecting severity of illness. Clearance maturation on ECMO is rapid and normalizes within 2 weeks. Initial morphine dosing may be guided by age and weight, but clearance and distribution volume changes (and their variability) during prolonged ECMO suggests that morphine therapy should be subsequently guided by clinical monitoring.

Chi-Square Distribution↗

PubMed2003

Routine morphine infusion in preterm newborns who received ventilatory support: a randomized controlled trial.

CONTEXT: Newborns admitted to neonatal intensive care units (NICUs) undergo a variety of painful procedures and stressful events. Because the effect of continuous morphine infusion in preterm neonates has not been investigated systematically, there is confusion regarding whether morphine should be used routinely in this setting. OBJECTIVE: To evaluate the effects of continuous intravenous morphine infusion on pain responses, incidence of intraventricular hemorrhage (IVH), and poor neurologic outcome (severe IVH, periventricular leukomalacia, or death). DESIGN, SETTING, AND PATIENTS: A randomized, double-blind, placebo-controlled trial conducted between December 2000 and October 2002 in 2 level III NICUs in the Netherlands of 150 newborns who had received ventilatory support (inclusion criteria: postnatal age younger than 3 days and ventilation for less than 8 hours; exclusion criteria: severe asphyxia, severe IVH, major congenital malformations, and administration of neuromuscular blockers). INTERVENTIONS: Intravenous morphine (100 microg/kg and 10 microg/kg per hour) or placebo infusion was given for 7 days (or less because of clinical necessity in several cases). MAIN OUTCOME MEASURES: The analgesic effect of morphine, as assessed using validated scales; the effect of morphine on the incidence of IVH; and poor neurologic outcome. RESULTS: The analgesic effect did not differ between the morphine and placebo groups, judging from the following median (interquartile range) pain scores: Premature Infant Pain Profile, 10.1 (8.2-11.6) vs 10.0 (8.2-12.0) (P =.94); Neonatal Infant Pain Scale, 4.8 (3.7-6.0) vs 4.8 (3.2-6.0) (P =.58); and visual analog scale, 2.8 (2.0-3.9) vs 2.6 (1.8-4.3) (P =.14), respectively. Routine morphine infusion decreased the incidence of IVH (23% vs 40%, P =.04) but did not influence poor neurologic outcome (10% vs 16%, P =.66). In addition, analyses were adjusted for the use of additional open-label morphine (27% of morphine group vs 40% of placebo group, P =.10). CONCLUSIONS: Lack of a measurable analgesic effect and absence of a beneficial effect on poor neurologic outcome do not support the routine use of morphine infusions as a standard of care in preterm newborns who have received ventilatory support. Follow-up is needed to evaluate the long-term effects of morphine infusions on the neurobehavioral outcomes of prematurity.

Analgesics, Opioid↗

PubMed2003

Do we still hurt newborn babies? A prospective study of procedural pain and analgesia in neonates.

BACKGROUND: Despite an increasing awareness regarding pain management in neonates and the availability of published guidelines for the treatment of procedural pain, preterm neonates experience pain leading to short- and long-term detrimental effects. OBJECTIVE: To assess the frequency of use of analgesics in invasive procedures in neonates and the associated pain burden in this population. METHODS: For 151 neonates, we prospectively recorded all painful procedures, including the number of attempts required, and analgesic therapy used during the first 14 days of neonatal intensive care unit admission. These data were linked to estimates of the pain of each procedure, obtained from the opinions of experienced clinicians. RESULTS: On average, each neonate was subjected to a mean +/- SD of 14 +/- 4 procedures per day. The highest exposure to painful procedures occurred during the first day of admission, and most procedures (63.6%) consisted of suctioning. Many procedures (26 of 31 listed on a questionnaire) were estimated to be painful (pain scores >4 on a 10-point scale). Preemptive analgesic therapy was provided to fewer than 35% of neonates per study day, while 39.7% of the neonates did not receive any analgesic therapy in the neonatal intensive care unit. CONCLUSIONS: Clinicians estimated that most neonatal intensive care unit procedures are painful, but only a third of the neonates received appropriate analgesic therapy. Despite the accumulating evidence that neonatal procedural pain is harmful, analgesic treatment for painful procedures is limited. Systematic approaches are required to reduce the occurrence of pain and to improve the analgesic treatment of repetitive pain in neonates.

Analgesics↗

PubMed2002

The effects of analgesia in the vulnerable infant during the perinatal period.

Although our knowledge of pain and its management in the perinatal period has increased, little is known about the first hours and days of life when major physiologic transition events occur. Prematurity and critical illnesses further complicate analgesic use during this time. Increased morbidity and mortality have been shown in infants receiving placebo infusions after surgery compared with infants with analgesia, highlighting the negative consequences of pain in infants. Opioids can help promote hemodynamic stability, promote respirator synchrony, and decrease the incidence of grade III & IV intraventricular hemorrhage in ventilated preterm neonates. Long-term follow-up studies suggest improved behavioral and cognitive outcomes in children given morphine infusions during NICU confinement. The necessity of fetal analgesia is dictated by the ability of the fetus to feel pain and by the adverse effects of noxious stimuli on future sensory development. Effects of drugs given to the pregnant woman on the (preterm) newborn might be influenced by decreased or absent transplacental transport, compression of the umbilical cord during delivery, or diminished blood flow in the placenta in pre-eclamptic women, resulting in higher serum concentrations. Pharmacokinetics and drug metabolism change in the last trimester, and pain sensitivity may be altered after 32 weeks of gestation. Consequently, dose and dose interval may vary considerably between neonates and within an individual during the first days of life. This subpopulation is not homogenous, and drug doses in a term neonate with a postnatal age of 2 weeks may be quite different from those at birth and are certainly different from those in a premature neonate. Size must be disentangled from age-related factors when examining developmental pharmacokinetic parameters. There are no longitudinal studies published investigating the pharmacokinetic properties of any analgesic more than once per infant. Polymorphisms of the genes encoding for the enzymes involved in the metabolism of analgesics or in genes involved in receptor expression may contribute to the large interindividual pharmacokinetic parameter variability. Polymorphism of the human mu opioid receptor has not yet satisfactorily explained pharmacodynamic variability.

Analgesia↗