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1.  Effect of closed endotracheal suction in high-frequency ventilated premature infants measured with electrical impedance tomography 
Intensive Care Medicine  2009;35(12):2130-2134.
To determine the global and regional changes in lung volume during and after closed endotracheal tube (ETT) suction in high-frequency ventilated preterm infants with respiratory distress syndrome (RDS).
Prospective observational clinical study.
Neonatal intensive care unit.
Eleven non-muscle relaxed preterm infants with RDS ventilated with open lung high-frequency ventilation (HFV).
Closed ETT suction.
Measurements and results
Changes in global and regional lung volume were measured with electrical impedance tomography. ETT suction resulted in an acute loss of lung volume followed by spontaneous recovery with a median residual loss of 3.3% of the maximum volume loss. The median stabilization time was 8 s. At the regional level, the lung volume changes during and after ETT suction were heterogeneous in nature.
Closed ETT suction causes an acute, transient and heterogeneous loss of lung volume in premature infants with RDS treated with open lung HFV.
PMCID: PMC2779442  PMID: 19774364
Endotracheal suction; Premature infant; High-frequency ventilation; Electrical impedance tomography
2.  Neonatal Procedural Pain and Preterm Infant Cortisol Response to Novelty at 8 Months 
Pediatrics  2004;114(1):e77-e84.
Objectives. Stress systems may be altered in the long term in preterm infants for multiple reasons, including early exposure to procedural pain in neonatal intensive care. This question has received little attention beyond hospital discharge. Stress responses (cortisol) to visual novelty in preterm infants who were born at extremely low gestational age (ELGA; ≤28 weeks), very low gestational age (VLGA; 29–32 weeks), and term were compared at 8 months of age corrected for prematurity (corrected chronological age [CCA]). In addition, among the preterm infants, we evaluated whether cortisol levels at 8 months were related to neonatal exposure to procedural pain and morphine in the neonatal intensive care unit.
Methods. Seventy-six infants, 54 preterm (≤32 weeks' GA at birth) and 22 term-born infants who were seen at 8 months CCA composed the study sample, after excluding those with major sensory, motor, or cognitive impairment. Salivary cortisol was measured before (basal) and 20 minutes after introduction of novel toys (post 1) and after developmental assessment (post 2).
Results. Salivary cortisol was significantly higher in ELGA infants at 8 months, compared with the VLGA and term groups before and after introduction of visual novelty. Term-born and VLGA infants showed a slight decrease in cortisol when playing with novel toys, whereas the ELGA group showed higher basal and sustained levels of cortisol. After controlling for early illness severity and duration of supplemental oxygen, higher basal cortisol levels in preterm infants at 8 months' CCA were associated with higher number of neonatal skin-breaking procedures. In contrast, cortisol responses to novelty were predicted equally well by neonatal pain or GA at birth. No relationship between morphine dosing and cortisol response was demonstrated in these infants.
Conclusions. ELGA preterm infants show a different pattern of cortisol levels before and after positive stimulation of visual novelty than more maturely born, VLGA preterm and term-born infants. Exposure to high numbers of skin-breaking procedures may contribute to “resetting” basal arousal systems in preterm infants.
PMCID: PMC1351380  PMID: 15231977
3.  Pharmacokinetics of morphine infusion in premature neonates. 
Archives of Disease in Childhood  1993;69(1 Spec No):55-58.
Morphine pharmacokinetics were studied in 17 premature neonates (26-34 weeks' gestation) after intravenous infusion during the first 24 hours of life. Infants received either standard dose morphine that comprised of a 100 micrograms/kg/hour loading infusion for 2 hours followed by a maintenance infusion of 12.5 micrograms/kg/hour, or a high dose of 200 micrograms/kg/hour for 2 hours followed by 50 micrograms/kg/hour. Mean plasma concentrations of morphine (SD) after 2 and 24 hours were 99 (12.9) and 96.4 (3.2) ng/ml, and 184.2 (37.7) and 319 (71.2) ng/ml for the standard and high dose regimens, respectively. Morphine-3-glucuronide plasma concentrations achieved about 20% and 80% of morphine values at 2 and 24 hours respectively. Morphine-6-glucuronide could not be detected at 2 hours, but attained 20-25% of morphine plasma concentrations by 24 hours. The population mean morphine clearance was 2.4 ml/min/kg, the elimination half life was 8.75 hours and the volume of distribution was 1.82 1/kg. High plasma concentrations of morphine appeared to be well tolerated. Although mean arterial blood pressure decreased during the first six hours of treatment, this was not statistically significant; two infants experienced transient muscle rigidity, but no evidence of seizures was noted. There appears to be no clinical advantage in using the high dose regimen.
PMCID: PMC1029400  PMID: 8346956
4.  Randomised double blind trial of morphine versus diamorphine for sedation of preterm neonates 
AIMS—To compare the safety and effectiveness of morphine and diamorphine for the sedation of ventilated preterm neonates in a double blind, randomised trial.
METHODS—Eighty eight babies were allocated to receive either morphine (n = 44) or diamorphine (n = 44) by bolus infusion (200 or 120mcg/kg, respectively, over two hours), followed by maintenance infusion (25 or 15 mcg/kg/h, respectively) during the initial phase of their respiratory disease. Serial monitoring of physiological, behavioural, and biochemical variables over the first 24 hours of the infusions was performed. Longer term outcomes were also monitored.
RESULTS—Morphine, but not diamorphine, was associated with a mean (SEM) decrease in mean arterial blood pressure of 2.2 (1.0) mm Hg (p = 0.05) over the initial loading infusion. Physiological (blood pressure variability) and behavioural measures of sedation (clinical assessment and sedation scoring) indicated that the two drug regimens were equally effective after 24 hours, but the sedative effects of diamorphine were evident more quickly than those of morphine. Both regimens significantly reduced plasma adrenaline concentrations over the first 24 hours of the infusions. No significant differences in mortality, ventilator days, chronic lung disease or intracranial lesions were noted.
CONCLUSIONS—Both drug regimens reduce the stress response to ventilation in preterm neonates. However, diamorphine's more rapid onset of sedation and morphine's hypotensive tendency suggest that diamorphine is preferable for the sedation of mechanically ventilated preterm neonates.

PMCID: PMC1720807  PMID: 9797622
5.  Increased Clearance of Morphine in Sickle Cell Disease: Implications for Pain Management 
Acute vaso-occlusive painful episodes associated with sickle cell disease (SCD) are frequently treated with morphine. Many SCD individuals require relatively higher doses of morphine to achieve optimal analgesia. We studied pharmacokinetics of morphine in SCD to explore if altered disposition could be a factor for increased requirement of morphine in this population. The study subjects were in steady state of health to avoid the effect of hemodynamic changes associated with vaso-occlusion on morphine disposition. The plasma concentrations of morphine and its major metabolites were measured at timed intervals in 21 SCD subjects after they received a single 0.1 mg/ Kg infusion of morphine sulfate. USCPACK software was used to fit candidate pharmacokinetic models. Non-compartmental pharmacokinetic parameters for morphine were calculated. Morphine clearance was 2.4 – 3.6 L/h, half-life was 0.3 – 0.7 hours, AUC0−∞ was 27.7 – 42.5 ng*h/mL, and volume of distribution was 0.96 – 3.38 L/kg. Clearance of morphine in the study population was 3 – 10 folds higher than published estimates in the non-SCD population, with correspondingly lower AUC and half-life. Volume of distribution was similar. This observation suggests that due to increased clearance SCD individuals may require higher dose and frequency of morphine to achieve comparable plasma levels.
PMCID: PMC3086992  PMID: 21277838
Sickle cell disease; morphine; pharmacokinetics; clearance; pain management
6.  Long-term Effects of Neonatal Stress on Adult Conditioned Place Preference (CPP) and Hippocampal Neurogenesis 
Behavioural brain research  2011;227(1):7-11.
Critically ill preterm infants are often exposed to stressors that may affect neurodevelopment and behavior. We reported that exposure of neonatal mice to stressors or morphine produced impairment of adult morphine-rewarded conditioned place preference (CPP) and altered hippocampal gene expression. We now further this line of inquiry by examining both short- and long-term effects of neonatal stress and morphine treatment. Neonatal C57BL/6 mice were treated twice daily from postnatal day (P) 5 to P9 using different combinations of factors. Subsets received saline or morphine injections (2 mg/kg s.c.) or were exposed to our neonatal stress protocol (maternal separation 8 h/d ×5d + gavage feedings ± hypoxia/hyperoxia). Short-term measures examined on P9 were neuronal fluorojade B and bromodeoxyuridine staining, along with urine corticosterone concentrations. Long-term measures examined in adult mice (>P60) included CPP learning to cocaine reward (± the kappa opioid receptor (KOR) agonist U50,488 injection), and adult hippocampal neurogenesis (PCNA immunolabeling). Neonatal stress (but not morphine) decreased the cocaine-CPP response and this effect was reversed by KOR stimulation. Both neonatal stress or morphine treatment increased hippocampal neurogenesis in adult mice. We conclude that reduced learning and increased hippocampal neurogenesis are both indicators that neonatal stress desensitized mice and reduced their arousal and stress responsiveness during adult CPP testing. Reconciled with other findings, these data collectively support the stress inoculation hypothesis whereby early life stressors prepare animals to tolerate future stress.
PMCID: PMC3494415  PMID: 22061798
kappa opioid receptor; morphine; dynorphin; neonatal stress; stress inoculation hypothesis
7.  Neonatal procedural pain exposure predicts lower cortisol and behavioral reactivity in preterm infants in the NICU 
Pain  2005;113(3):293-300.
Data from animal models indicate that neonatal stress or pain can permanently alter subsequent behavioral and/or physiological reactivity to stressors. However, cumulative effects of pain related to acute procedures in the neonatal intensive care unit (NICU) on later stress and/or pain reactivity has received limited attention. The objective of this study is to examine relationships between prior neonatal pain exposure (number of skin breaking procedures), and subsequent stress and pain reactivity in preterm infants in the NICU. Eighty-seven preterm infants were studied at 32 (±1 weeks) postconceptional age (PCA). Infants who received analgesia or sedation in the 72 h prior to each study, or any postnatal dexamethasone, were excluded. Outcomes were infant responses to two different stressors studied on separate days in a repeated measures randomized crossover design: (1) plasma cortisol to stress of a fixed series of nursing procedures; (2) behavioral (Neonatal Facial Coding System; NFCS) and cardiac reactivity to pain of blood collection. Among infants born ≤ 28 weeks gestational age (GA), but not 29–32 weeks GA, higher cumulative neonatal procedural pain exposure was related to lower cortisol response to stress and to lower facial (but not autonomic) reactivity to pain, at 32 weeks PCA, independent of early illness severity and morphine exposure since birth. Repeated neonatal procedural pain exposure among neurodevelopmentally immature preterm infants was associated with down-regulation of the hypothalamic–pituitary–adrenal axis, which was not counteracted with morphine. Differential effects of early pain on development of behavioral, physiologic and hormonal systems warrant further investigation.
PMCID: PMC1447527  PMID: 15661436
Preterm infant; Pain; Morphine; Cortisol; Stress; Facial reactivity; Autonomic
8.  Intrathecal Morphine Plus General Anesthesia in Cardiac Surgery: Effects on Pulmonary Function, Postoperative Analgesia, and Plasma Morphine Concentration 
Clinics (Sao Paulo, Brazil)  2009;64(4):279-285.
To evaluate the effects of intrathecal morphine on pulmonary function, analgesia, and morphine plasma concentrations after cardiac surgery.
Lung dysfunction increases morbidity and mortality after cardiac surgery. Regional analgesia may improve pulmonary outcomes by reducing pain, but the occurrence of this benefit remains controversial.
Forty-two patients were randomized for general anesthesia (control group n=22) or 400 μg of intrathecal morphine followed by general anesthesia (morphine group n=20). Postoperative analgesia was accomplished with an intravenous, patient-controlled morphine pump. Blood gas measurements, forced vital capacity (FVC), forced expiratory volume (FEV), and FVC/FEV ratio were obtained preoperatively, as well as on the first and second postoperative days. Pain at rest, profound inspiration, amount of coughing, morphine solicitation, consumption, and plasma morphine concentration were evaluated for 36 hours postoperatively. Statistical analyses were performed using the repeated measures ANOVA or Mann-Whiney tests (*p<0.05).
Both groups experienced reduced FVC postoperatively (3.24 L to 1.38 L in control group; 2.72 L to 1.18 L in morphine FEV1 (p=0.085), group), with no significant decreases observed between groups. The two groups also exhibited similar results for FEV1/FVC (p=0.68) and PaO2/FiO2 ratio (p=0.08). The morphine group reported less pain intensity (evaluated using a visual numeric scale), especially when coughing (18 hours postoperatively: control group= 4.73 and morphine group= 1.80, p=0.001). Cumulative morphine consumption was reduced after 18 hours in the morphine group (control group= 20.14 and morphine group= 14.20 mg, p=0.037). The plasma morphine concentration was also reduced in the morphine group 24 hours after surgery (control group= 15.87 ng.mL−1 and morphine group= 4.08 ng.mL−1, p=0.029).
Intrathecal morphine administration did not significantly alter pulmonary function; however, it improved patient analgesia and reduced morphine consumption and morphine plasma concentration.
PMCID: PMC2694465  PMID: 19488583
Respiratory mechanics; Gas exchange; Cardiac surgery; Pain scores
9.  Opioids and clonidine modulate cytokine production and opioid receptor expression in neonatal immune cells 
Opioids and clonidine, used in for sedation, analgesia and control of opioid withdrawal in neonates, directly or indirectly activate opioid receptors expressed in immune cells. Therefore, our objective is to study how clinically relevant concentrations of different opioids and clonidine change cytokine levels in cultured whole blood from preterm and full-term infants.
Study design
Using blood from preterm (≤ 30 weeks gestational age, n=7) and full-term (≥37 weeks GA, n=19) infants, we investigated the changes in cytokine profile (IL-1β, IL-6, IL-8, IL-10, IL-12p70, and TNF-α), cyclic adenosine monophosphate (cAMP) levels and μ-, δ-, and κ- opioid receptor (OPR) gene and protein expression following in-vitro exposure to morphine, methadone, fentanyl, or clonidine at increasing concentrations ranging from 0 to 1 mM.
Following LPS activation, IL-10 levels were 146-fold greater in cultured blood from full-term than from preterm infants. Morphine and methadone, but not fentanyl, at >10-5M decreased all tested cytokines except IL-8. In contrast, clonidine at <10-9M increased IL-6, while at >10-5M increased IL-1β and decreased TNF-α levels. All cytokine changes followed the same patterns in preterm and full-term infant cultured blood and matched increases in cAMP levels. All three μ-, δ- and κ-OPR genes were expressed in mononuclear cells from preterm and full-term infants. Morphine, methadone and clonidine, but not fentanyl, at >10-5M decreased the expression of μ-OPR, but not δ- or κ-OPRs.
Generalized cytokine suppression along with downregulation of μ-OPR expression observed in neonatal mononuclear cells exposed to morphine and methadone at clinically relevant concentrations contrast with the modest effects observed with fentanyl and clonidine. Therefore, we speculate that fentanyl and clonidine may be safer therapeutic choices for sedation and control of opioid withdrawal and pain in neonates.
PMCID: PMC3640758  PMID: 23047422
morphine; methadone; fentanyl; clonidine; inflammation; preterm infant; full-term infant
Journal of Clinical Investigation  1974;54(6):1247-1258.
To evaluate the effects of morphine on the peripheral venous and arterial beds, 69 normal subjects were evaluated before and after the intravenous administration of 15 mg morphine. Venous tone was determined by three independent techniques in 22 subjects. The venous pressure measured in a hand vein during temporary circulatory arrest (isolated hand vein technique) fell from 20.2±1.4 to 13.4±0.9 mm Hg (P < 0.01) 10 min after morphine, indicating that a significant venodilation had occurred. With the acute occlusion technique, morphine induced a reduction in forearm venous tone from 12.8±1.1 to 7.9±2.3 mm Hg/ml/100 ml (P < 0.01). Although forearm venous volume at a pressure of 30 mm Hg (VV[30]) was increased from 2.26±0.17 to 2.55±0.26 ml/100 ml, measured by the equilibration technique, the change was not significant (P > 0.1). Of note is that the initial reaction to morphine was a pronounced venoconstriction, demonstrated during the first 1-2 min after the drug. (Isolated hand vein pressure increased to 37.2±5.4 mm Hg, P < 0.01). This rapidly subsided, and by 5 min a venodilation was evident. Morphine did not attenuate the venoconstrictor response to a single deep breath, mental arithmetic, or the application of ice to the forehead when measured by either the isolated hand vein technique or the equilibration technique.
To evaluate the effects of morphine on the peripheral resistance vessels in 47 normal subjects, forearm blood flow was measured plethysmographically before and 10-15 min after the intravenous administration of 15 mg of morphine. Although mean systemic arterial pressure was unchanged, forearm blood flow increased from 2.92±0.28 to 3.96±0.46 ml/min/100 ml (P < 0.01), and calculated vascular resistance fell from 42.4±5.2 to 31.6±3.2 mm Hg/ml/min/100 ml (P < 0.01). When subjects were tilted to the 45° head-up position, morphine did not block the increase in total peripheral vascular resistance that occurs; however, it did significantly attenuate the forearm arteriolar constrictor response (before morphine, + 25.7±5.4; after morphine, + 13.7±5.3 mm Hg/ml/min/100 ml, P < 0.05). However, morphine did not block the post-Valsalva overshoot of blood pressure, nor did it block the increase in forearm vascular resistance produced by the application of ice to the forehead. Similarly, morphine did not block the arteriolar or venoconstrictor effects of intra-arterially administered norepinephrine.
Morphine infused into the brachial artery in doses up to 200 μg/min produced no changes in ipsilateral forearm VV[30], forearm blood flow, or calculated forearm resistance. Intra-arterial promethazine, atropine, and propranolol did not block the forearm arteriolar dilator response to intravenous morphine; however, intra-arterial phentolamine abolished the response. These data suggest that in human subjects, morphine induces a peripheral venous and arteriolar dilation by a reflex reduction in sympathetic alpha adrenergic tone. Morphine does not appear to act as a peripheral alpha adrenergic blocking agent but seems to attenuate the sympathetic efferent discharge at a central nervous system level.
PMCID: PMC301677  PMID: 4612057
11.  Pre-Emptive Morphine Analgesia Attenuates the Long-Term Consequences of Neonatal Inflammation in Male and Female Rats 
Pediatric research  2008;64(6):625-630.
Despite mounting evidence on the importance of pain management in preterm infants, clinical use of analgesics in this population is limited. Our previous studies have shown that neonatal inflammation results in long-term alterations in adult somatosensory thresholds, characterized by decreased baseline nociceptive sensitivity, and enhanced hyperalgesia following a subsequent inflammatory insult. The present studies were conducted to determine if pre-emptive morphine attenuates these negative consequences. At P0, pups received an injection of morphine sulfate (MS) before an intraplantar injection of 1% carrageenan (CGN). Control pups received either saline (SAL) followed by intraplantar CGN, MS followed by intraplantar SAL, or SAL followed by intraplantar SAL. Pre-emptive morphine significantly attenuated neonatal injury-induced hypoalgesia in adolescence and adulthood. Similarly, morphine pre-treated animals displayed significantly less hyperalgesia and recovered faster from a subsequent inflammatory insult compared to controls. Neonatal morphine had no significant effect on morphine analgesia in adulthood. Interestingly, neonatally injured animals that did not receive morphine displayed a significant rightward shift in the morphine dose response curve in the absence of peripheral inflammation. Together, these results demonstrate that pre-emptive morphine significantly attenuates the long-term behavioral impact of neonatal inflammatory injury.
PMCID: PMC2638169  PMID: 18679159
morphine; pain; premature infant; opioid analgesia; neonate
12.  Characteristics of Distribution of Morphine and Metabolites in Cerebrospinal Fluid and Plasma with Chronic Intrathecal Morphine Infusion in Humans 
Anesthesia and analgesia  2012;115(4):797-804.
Despite widespread use of chronic intrathecal (IT) infusions of morphine, there is little systematic human work evaluating the steady-state morphine concentrations or cerebrospinal (CSF) chemistry after long-term IT morphine delivery. We sought to address these issues in patients receiving chronic IT morphine infusion.
Pain patients with implanted catheters and pumps (range: 127–2165 days), receiving a stable dosing (> 1 week) of IT morphine by infusion, were entered into the study. The following sequence was performed: 1) estimation of pain score; 2) radiograph localization of catheter tip; 3) Percutaneous sampling of lumbar CSF at the L4-5 or L5-S1 space. CSF/plasma samples were assayed for chemistry, and morphine and its 3/6 glucuronide metabolites (M3G, M6G) by liquid chromatography mass spectrometry.
Nineteen patients were enrolled. CSF samples were obtained from 16 subjects. Three patients were not included in the primary analysis because one catheter was epidural, one catheter was fractured and one had a granuloma at the catheter tip. Of the 13 sampled patients, the range of daily doses, rates and concentrations were 1.6–25 mg/d and 0.1–1 ml/d, 5–50 mg/mL, respectively. The principal observations were: i) morphine, M3G and M6G were present in the CSF and plasma and showed a significant regression slope when plotted versus daily dose; ii) in contrast, the regression slope of the group ratio Morphine: M3G: M6G plotted versus daily dose in CSF or plasma was not different from zero; iii) plotting “normalized” CSF analyte concentration (e.g., concentration at site/daily IT morphine dose) against the segmental distance of the sampling site from the catheter tip revealed a significant decline in concentration of morphine, but not of conjugates as a function of distance from the catheter tip; iv) plotting CSF protein, glucose, red and white cell counts versus daily morphine dose or morphine concentration at the sampling site revealed no significant regression; and v) patients with a catheter failure or a granuloma showed reduced concentrations of morphine in their CSF.
Chronic infusion of morphine shows high concentrations which correlate with the infusion dose and the proximity of the sampling site to the infusion site with no effects on CSF chemistry.
PMCID: PMC3456964  PMID: 22822192
13.  Morphine in ventilated neonates: its effects on arterial blood pressure 
To study the effects of continuous morphine infusion on arterial blood pressure in ventilated neonates.
Blinded randomised placebo controlled trial.
Level III neonatal intensive care unit in two centres.
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.
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.
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).
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.
PMCID: PMC2672650  PMID: 16131531
randomised controlled trial; opioids; preterm/term infants; hypotension; blood pressure variability
14.  Endotracheal Suctioning in Preterm Infants Using Four-Handed versus Routine Care 
To evaluate the effect of four-handed care on preterm infants’ physiologic and behavioral responses to and recovery from endotracheal suctioning versus routine endotracheal (ETT) suctioning.
Randomized crossover design with infants as their own controls.
Single-family-room newborn intensive care unit in an academic health center.
Ten intubated infants on conventional ventilation with inline suctioning who were fewer than 37 weeks gestation at birth, and less than one week of age.
Each infant was observed twice on a single day. One observation involved routine ETT suctioning and one involved four-handed care. Physiologic and behavioral response data were collected.
No differences were noted when comparing baseline heart rate (HR) or oxygen saturation (SpO2) data to those obtained during and after suctioning while in the routine care condition. In the four-handed care condition, mean SpO2 increased from preobservation 95.49 to during observation saturation 97.75 (p = .001). Salivary cortisol levels did not differ between groups at baseline or postsuctioning. No significant difference in behavior state was observed between the two conditions. More stress and defense behaviors occurred postsuctioning when infants received routine care as opposed to four-handed care (p = .001) and more self-regulatory behaviors were exhibited by infants during (p = .019) and after suctioning (p = .016) when receiving four-handed care. No statistical difference was found in the number of monitor call-backs postsuctioning.
Four-handed care during suctioning was associated with a decrease in stress and defense behaviors and an increase in self-regulatory behaviors.
PMCID: PMC3565562  PMID: 23316894
Endotracheal suctioning; preterm infants; developmental care
15.  Pharmacokinetics of single dose intravenous propacetamol in neonates: effect of gestational age 
Aim: To investigate the pharmacokinetics and pharmacodynamics of single dose propacetamol in preterm and term infants on the first day of life.
Methods: Neonates were stratified by gestational age. Preterm (< 37 weeks) and term (37–41 weeks) infants received a single dose of propacetamol in the first 24 hours of life when they had minor, painful procedures or as additional treatment in infants receiving opioids. Blood samples were taken from an arterial line, and pain was evaluated by a multidimensional pain scale. Results were reported as mean (SD). Student's t and Wilcoxon tests were used to compare the groups.
Results: Thirty neonates were included, 10 of which were term infants. Serum half life was 277 (143) minutes in the preterm infants and 172 (59) minutes in the term infants (p < 0.05). Clearance was 0.116 (0.08) litre/kg/h in the preterm infants and 0.170 (0.06) litre/kg/h in the term infants (p < 0.05). Gestational age correlated with serum half life (r = -0.46). No effect of sex or administration of prenatal steroids was found on the pharmacokinetics of paracetamol. In neonates who only received propacetamol (n = 15), the level of analgesia seemed to be associated with the therapeutic (> 5 mg/l) level.
Conclusions: A correlation was found between gestational age and the serum half life of propacetamol. The maturational trend of clearance and half life in preterm and term neonates is in line with data on the pharmacokinetics of propacetamol beyond the newborn period.
PMCID: PMC1721651  PMID: 14711849
16.  A clinical assessment of the Mucus Shaver, a device to keep the endotracheal tube free from secretions 
Critical Care Medicine  2012;40(1):119-124.
We evaluated a new device designed to clean the endotracheal tube (ETT) in mechanically ventilated patients: the Mucus Shaver.
Prospective, randomized trial.
University hospital intensive care unit.
We enrolled 24 patients, expected to remain ventilated for more than 72 hours.
The Mucus Shaver is a concentric, inflatable catheter for the removal of mucus and secretions from the interior surface of the ETT. The Mucus Shaver is advanced to the distal ETT tip, inflated and subsequently withdrawn over a period of 3–5 seconds. Patients were prospectively randomized, within 2 hours of intubation, to receive standard ETT suctioning treatment or standard suctioning plus Mucus Shaver use, until extubation.
Measurements and Main Results
During the study period, demographic data, recent medical history, adverse events and staff evaluation of the Mucus Shaver were recorded. At extubation, each ETT was removed, cultured and analyzed by Scanning Electron Microscopy (SEM). 12 patients were assigned to the study group and 12 to the control group. No adverse events related to the use of the Mucus Shaver were observed. At extubation, only 1 ETT from the Mucus Shaver group was colonized, while in the control group, 10 ETTs were colonized (8% vs. 83%; p<0.001). SEM showed little secretions on the ETTs from the study group, while thick bacterial deposits were present on all the ETTs from the control group (p<0.001 by Fisher’s exact test, using a maximum biofilm thickness of 30 µm as cut-off). The nursing staff was satisfied by the overall safety, feasibility, and efficacy of the Mucus Shaver.
The Mucus Shaver is a safe, feasible and efficient device for ETT cleaning in the clinical setting. The Mucus Shaver is helpful in preventing ETT colonization by potentially harmful microorganisms.
PMCID: PMC3405906  PMID: 21926595
Endotracheal tube; secretion removal; endotracheal tube suctioning; endotracheal tube occlusion; Mucus Shaver; mechanical ventilation; bacterial biofilm; ventilator associated pneumonia
17.  Cyclosporine-inhibitable Blood-Brain Barrier Drug Transport Influences Clinical Morphine Pharmacodynamics 
Anesthesiology  2013;119(4):10.1097/ALN.0b013e3182a05bd3.
The blood-brain barrier is richly populated by active influx and efflux transporters influencing brain drug concentrations. Morphine, a drug with delayed clinical onset, is a substrate for the efflux transporter P-glycoprotein in vitro and in animals. This investigation tested whether morphine is a transporter substrate in humans.
Fourteen healthy volunteers received morphine (0.1 mg/kg, 1 h intravenous infusion) in a crossover study after nothing (control) or the validated P-glycoprotein inhibitor cyclosporine (5 mg/kg, 2 h infusion). Plasma and urine morphine and morphine glucuronide metabolite concentrations were measured by mass spectrometry. Morphine effects were measured by miosis and analgesia.
Cyclosporine minimally altered morphine disposition, increasing the area under the plasma morphine concentration versus time curve to 100 ± 21 versus 85 ± 24 ng/ml•hr (p < 0.05) without changing maximum plasma concentration. Cyclosporine enhanced (3.2 ± 0.9 vs. 2.5 ± 1.0 mm peak) and prolonged miosis, and increased the area under the miosis-time curve (18 ± 9 vs. 11 ± 5 mm-hr), plasma-effect site transfer rate constant (ke0, median 0.27 vs. 0.17 hr−1), and maximum calculated effect site morphine concentration (11.5 ± 3.7 vs. 7.6 ± 2.9 ng/ml) (all p < 0.05). Analgesia testing was confounded by cyclosporine-related pain.
Morphine is a transporter substrate at the human blood-brain barrier. Results suggest a role for P-glycoprotein or other efflux transporters in brain morphine access, although the magnitude of the effect is small, and unlikely to be a major determinant of morphine clinical effects. Efflux may explain some variability in clinical morphine effects.
PMCID: PMC3823830  PMID: 23851346
18.  Effects of neonatal stress and morphine on murine hippocampal gene expression 
Pediatric research  2011;69(4):285-292.
Critically ill preterm infants experience multiple stressors while hospitalized. Morphine is commonly prescribed to ameliorate their pain and stress. We hypothesized that neonatal stress will have a dose-dependent effect on hippocampal gene expression, and these effects will be altered by morphine treatment. Male C57BL/6 mice were exposed to 5 treatment conditions between postnatal day 5 and 9: 1) Control, 2) mild stress + saline, 3) mild stress + morphine, 4) severe stress + saline and 5) severe stress + morphine. Hippocampal RNA was extracted and analyzed using Affymetrix Mouse Gene 1.0 ST Arrays. Single gene analysis and gene set analysis were used to compare groups with validation by qPCR. Stress resulted in enrichment of genes sets related to fear response, oxygen carrying capacity and NMDA receptor synthesis. Morphine downregulated gene sets related to immune function. Stress plus morphine resulted in enrichment of mitochondrial electron transport gene sets, and down-regulation of gene sets related to brain development and growth. We conclude that neonatal stress alone influences hippocampal gene expression, morphine alters a subset of stress-related changes in gene expression and influences other gene sets. Stress plus morphine show interaction effects not present with either stimulus alone. These changes may alter neurodevelopment.
PMCID: PMC3085998  PMID: 21178816
19.  Outcome at 5-6 years of prematurely born children who received morphine as neonates 
AIM—To assess outcome at 5-6 years in a cohort of very preterm infants (<34 weeks of gestation) who had been randomly allocated within a controlled clinical trial to receive morphine or non-morphine treatment in the neonatal period.
METHODS—Assessments were made on 87 children at 5-6 years who had been recruited in the neonatal period to two sequential controlled studies (1989-92). Infants requiring mechanical ventilation had been randomly allocated to receive either morphine (n=62) or other (n=33) solutions starting on the first day of life. Each child was seen by a single experienced observer and assessed at 5-6 years using the WPPSI-R, Movement ABC, and the Child Behaviour Checklist. The performance of children exposed to morphine was compared with that of those in the non-morphine group. Blood samples for thyroid stimulating hormone (TSH) measurement were obtained from children whose parents gave consent.
RESULTS—There was no significant difference in any of the three test scales between infants in the two groups, but there was a trend towards better performance in all three tests in the morphine group. Assessment of TSH values in a subgroup of the survivors showed no difference in thyroid function between the two groups.
CONCLUSION—Exposure to morphine in the neonatal period to facilitate mechanical ventilation does not seem to have any adverse effects on intelligence, motor function, or behaviour when these children are assessed at 5-6 years of age.

PMCID: PMC1720823  PMID: 9797623
20.  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.
PMCID: PMC1721820  PMID: 15613571
21.  Neonatal Pain-Related Stress Predicts Cortical Thickness at Age 7 Years in Children Born Very Preterm 
PLoS ONE  2013;8(10):e76702.
Altered brain development is evident in children born very preterm (24–32 weeks gestational age), including reduction in gray and white matter volumes, and thinner cortex, from infancy to adolescence compared to term-born peers. However, many questions remain regarding the etiology. Infants born very preterm are exposed to repeated procedural pain-related stress during a period of very rapid brain development. In this vulnerable population, we have previously found that neonatal pain-related stress is associated with atypical brain development from birth to term-equivalent age. Our present aim was to evaluate whether neonatal pain-related stress (adjusted for clinical confounders of prematurity) is associated with altered cortical thickness in very preterm children at school age.
42 right-handed children born very preterm (24–32 weeks gestational age) followed longitudinally from birth underwent 3-D T1 MRI neuroimaging at mean age 7.9 yrs. Children with severe brain injury and major motor/sensory/cognitive impairment were excluded. Regional cortical thickness was calculated using custom developed software utilizing FreeSurfer segmentation data. The association between neonatal pain-related stress (defined as the number of skin-breaking procedures) accounting for clinical confounders (gestational age, illness severity, infection, mechanical ventilation, surgeries, and morphine exposure), was examined in relation to cortical thickness using constrained principal component analysis followed by generalized linear modeling.
After correcting for multiple comparisons and adjusting for neonatal clinical factors, greater neonatal pain-related stress was associated with significantly thinner cortex in 21/66 cerebral regions (p-values ranged from 0.00001 to 0.014), predominately in the frontal and parietal lobes.
In very preterm children without major sensory, motor or cognitive impairments, neonatal pain-related stress appears to be associated with thinner cortex in multiple regions at school age, independent of other neonatal risk factors.
PMCID: PMC3800011  PMID: 24204657
22.  Repeated Cannabinoid Injections into the Rat Periaqueductal Gray Enhances Subsequent Morphine Antinociception 
Neuropharmacology  2008;55(7):1219-1225.
Cannabinoids and opiates inhibit pain, in part, by activating the periaqueductal gray (PAG). Evidence suggests this activation occurs through distinct mechanisms. If the antinociceptive mechanisms are distinct, then cross-tolerance between opioids and cannabinoids should not develop. This hypothesis was tested by measuring the antinociceptive effect of microinjecting morphine into the ventrolateral PAG of rats pretreated with the cannabinoid HU-210 for two days. Male Spraque-Dawley rats were injected twice a day for two days with vehicle (0.4 µL), morphine (5µg/0.4 µL), HU-210 (5µg/0.4 µL), or morphine combined with HU-210 into the ventrolateral PAG. Repeated injections of morphine caused a rightward shift in the morphine dose response curve on Day 3 (i.e., tolerance developed). No tolerance was evident in rats pretreated with morphine combined with HU-210. In rats pretreated with HU-210 alone, morphine antinociception was enhanced. This enhancement was blocked by pretreating rats with the cannabinoid receptor antagonist AM-251, and it also disappeared when rats were tested one week later. Acute microinjection of HU-210 into the PAG antagonized morphine antinociception, suggesting that HU-210-induced enhancement of morphine antinociception is a compensatory response. As hypothesized, there was no evidence of cross-tolerance between morphine and HU-210. In fact, cannabinoid pretreatment enhanced the antinociceptive effect of microinjecting morphine into the ventrolateral PAG. These findings suggest that alternating opioid and cannabinoid treatment could be therapeutically advantageous by preventing the development of tolerance and enhancing morphine antinociception.
PMCID: PMC2743428  PMID: 18723035
pain; analgesia; tolerance; cross-tolerance; opioid; opiate
23.  Neonatal pain, parenting stress and interaction, in relation to cognitive and motor development at 8 and 18 months in preterm infants 
Pain  2009;143(1-2):138-146.
Procedural pain in the neonatal intensive care unit triggers a cascade of physiological, behavioral and hormonal disruptions which may contribute to altered neurodevelopment in infants born very preterm, who undergo prolonged hospitalization at a time of physiological immaturity and rapid brain development. The aim of this study was to examine relationships between cumulative procedural pain (number of skin-breaking procedures from birth to term, adjusted for early illness severity and overall intravenous morphine exposure), and later cognitive, motor abilities and behavior in very preterm infants at 8 and 18 months corrected chronological age (CCA), and further, to evaluate the extent to which parenting factors modulate these relationships over time. Participants were N = 211 infants (n = 137 born preterm ≤32 weeks gestational age [GA] and n = 74 full-term controls) followed prospectively since birth. Infants with significant neonatal brain injury (periventricular leucomalacia, grade 3 or 4 intraventricular hemorrhage) and/or major sensori-neural impairments, were excluded. Poorer cognition and motor function were associated with higher number of skin-breaking procedures, independent of early illness severity, overall intravenous morphine, and exposure to postnatal steroids. The number of skin-breaking procedures as a marker of neonatal pain was closely related to days on mechanical ventilation. In general, greater overall exposure to intravenous morphine was associated with poorer motor development at 8 months, but not at 18 months CCA, however, specific protocols for morphine administration were not evaluated. Lower parenting stress modulated effects of neonatal pain, only on cognitive outcome at 18 months.
PMCID: PMC2836793  PMID: 19307058
Pain; Premature infants; Neonatal; Stress; Neurodevelopment; Parent
24.  Is ethnicity associated with morphine's side effects in children? morphine pharmacokinetics, analgesic response and side effects in children having tonsillectomy 
Paediatric Anaesthesia  2012;22(7):669-675.
To examine whether morphine pharmacokinetics (PK) and/or genetic polymorphisms in opioid-related genes, underlie differences in analgesic response and side effects to morphine in Latino (L) vs non-Latino Caucasian (NL) children.
Morphine has high interindividual variability in its analgesic response and side effects profile. Earlier studies suggest that morphine response may vary by race and ethnicity.
Prospective cohort study in L and NL children, 3–17 years of age comparing pain scores, occurrence of side effects, plasma morphine, morphine-6-and morphine-3-glucuronide concentrations measured after a single morphine IV bolus administration. Non-compartmental pharmacokinetic analysis and genotyping for 28 polymorphisms in 8 genes (UGT1A8, UGT2B7, ABCB1, COMT, STAT6, MC1R, OPRM1, and ARRB2) were done.
We enrolled 68 children (33 L, 35 NL). There were no differences in pain scores or need for rescue analgesia. Statistically significant differences in the occurrence of side effects were documented: While 58% of L children experienced at least one side effect only 20% of NL did (p=0.001). Pruritus was 4 times (p=0.006) and emesis 7 times (p=0.025) more frequent in L compared to NL. PK parameters were similar between groups. None of the assessed polymorphisms mediated the association between ethnicity and side effects.
We found statistically significant differences in occurrence of side effects after morphine administration between L and NL children. Neither differences in morphine or metabolite concentrations, nor the genetic polymorphisms examined, explain these findings. Studies are needed to further investigate reasons for the increase in morphine side effects by Latino ethnicity.
PMCID: PMC3366036  PMID: 22486937
25.  Novel device (AirWave) to assess endotracheal tube migration: A pilot study☆,☆☆ 
Journal of critical care  2013;28(4):535.e1-535.e8.
Little is known about endotracheal tube (ETT) migration during routine care among critically ill patients. AirWave is a novel device that uses sonar waves to measure ETT migration and obstructions in real time. The aim of the present study is to assess the accuracy of the AirWave to evaluate ETT migration. In addition, we determined the degree of variation in ETT position and tested whether more pronounced migration occurs in specific clinical scenarios.
After institutional review board approval, we included mechanically ventilated patients from February 2012 to May 2012. A chest radiography (CXR) was obtained at baseline and 24 hours when clinically indicated. The ETT distance at the lips was recorded at baseline and every 4 hours. The AirWave system continuously recorded ETT position changes from baseline, and luminal obstructions.
A total of 42 patients (age: 61 [SD ± 13] years, men: 52%) were recruited. A total of 19 patients had measurements of ETT migration at 24 hours by the 3 methodologies used in this study. The mean (SD) of the ETT migration at 24 hours was +0.04 (1.2), −0.42 (0.7) and +0.34 (1.81) cm when measured by portable CXR, ETT distance at the teeth and AirWave device, respectively. Bland-Altman analysis of tube migration at 24 hours comparing the AirWave with CXR readings showed a bias of 0.1 cm with 95% limit of agreement of −3.8 and +4.3 cm. Comparison of tube migration at 24 hours determined by AirWave with ETT distance at the lips revealed a bias of −0.4 with 95% limit of agreement −3.7 to +3 cm, similar to the values observed between CXR and ETT distance at the lips (bias of −0.3 cm, 95% limit of agreement of −3.4 to +2.8 cm). Factors associated with ETT migration at 24 hours were ETT size and initial measurement from ETT tip to carina by portable CXR. AirWave detected in eight patients some degree of ETT obstruction (30% ± 9.6%) that resolved with prompt ETT catheter suction.
The AirWave may provide useful information regarding ETT migration and obstruction in real time.
PMCID: PMC3713168  PMID: 23391719
AirWave; Endotracheal tube; Migration; Obstruction

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