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.
Endotracheal suction; Premature infant; High-frequency ventilation; Electrical impedance tomography
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.
Endotracheal suctioning; preterm infants; developmental care
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).
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.
randomised controlled trial; opioids; preterm/term infants; hypotension; blood pressure variability
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.
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.
AIMS—To compare the
safety and effectiveness of morphine and diamorphine for the sedation
of ventilated preterm neonates in a double blind, randomised trial.
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.
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.
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.
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.
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.
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.
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
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.
Endotracheal tube; secretion removal; endotracheal tube suctioning; endotracheal tube occlusion; Mucus Shaver; mechanical ventilation; bacterial biofilm; ventilator associated pneumonia
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.
Elective endotracheal intubations are still commonly performed without premedication in many institutions. The hypothesis tested in this study was that morphine given prior to elective intubations in neonates would decrease fluctuations in vital signs, shorten the duration of intubation and reduce the number of attempts.
From December 1999 to September 2000, infants of all gestations admitted to a level III neonatal intensive care unit and requiring an elective endotracheal intubation were randomly assigned to receive morphine 0.2 mg/kg IV or placebo 5 minutes before intubation. Duration of severe hypoxemia (HR< 90/min and Sp02<85%), duration of procedure, duration of hypoxemia (Sp02<85%), number of attempts and change in mean blood pressure were compared between groups.
34 infants (median 989 g and 28 weeks gestation) were included. The duration of severe hypoxemia was similar between groups. Duration of procedure, duration of hypoxemia, number of attempts and increases in mean blood pressure were also similar between groups. 94% of infants experienced bradycardia during the procedure.
We failed to demonstrate the effectiveness of morphine in reducing the physiological instability or time needed to perform elective intubations. Alternatives, perhaps with more rapid onset of action, should be considered.
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.
Biofilm in endotracheal tubes (ETT) of ventilated patients has been suggested to play a role in the development of ventilator-associated pneumonia (VAP). Our purpose was to analyze the formation of ETT biofilm and its implication in the response and relapse of VAP.
We performed a prospective, observational study in a medical intensive care unit. Patients mechanically ventilated for more than 24 hours were consecutively included. We obtained surveillance endotracheal aspirates (ETA) twice weekly and, at extubation, ETTs were processed for microbiological assessment and scanning electron microscopy.
Eighty-seven percent of the patients were colonized based on ETA cultures. Biofilm was found in 95% of the ETTs. In 56% of the cases, the same microorganism grew in ETA and biofilm. In both samples the most frequent bacteria isolated were Acinetobacter baumannii and Pseudomonas aeruginosa. Nineteen percent of the patients developed VAP (N = 14), and etiology was predicted by ETA in 100% of the cases. Despite appropriate antibiotic treatment, bacteria involved in VAP were found in biofilm (50%). In this situation, microbial persistence and impaired response to treatment (treatment failure and relapse) were more frequent (100% vs 29%, P = 0.021; 57% vs 14%, P = 0.133).
Airway bacterial colonization and biofilm formation on ETTs are early and frequent events in ventilated patients. There is microbiological continuity between airway colonization, biofilm formation and VAP development. Biofilm stands as a pathogenic mechanism for microbial persistence, and impaired response to treatment in VAP.
An unbiased conditioned place preference paradigm was used to evaluate the effect of dextro-morphine on the morphine-produced reward in male CD rats. Morphine sulfate (1-10 mg/kg) given intraperitoneally dose-dependently produced the conditioned place preference. Pretreatment with dextro-morphine at a dose from 0.1 to 3 μg/kg given subcutaneously dose-dependently attenuated the morphine-produced conditioned place preference. However, dextro-morphine at a higher dose 100 μg/kg did not affect the morphine-produced conditioned place preference. Thus, dextro-morphine pretreatment induces an U-shaped dose-response curve for attenuating the morphine-produced conditioned place preference. The attenuation of the morphine-produced conditioned place preference was reversed by the pretreatment with the sigma1 receptor antagonist BD1047 (N-[2-(3,4-Dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine dihydrobromide. dextro-Morphine or BD1047 given alone did not affect the baseline place conditioning. It is concluded that dextro-morphine attenuated the morphine-produced conditioned place preference via the sigma1 receptor activation.
sigma receptors; addiction; opioid; morphine; rat
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.
Sickle cell disease; morphine; pharmacokinetics; clearance; pain management
Mechanical ventilation is used for some infants in neonatal intensive care units (NICU) due to many physiological and clinical causes. Since these patients have endotracheal tubes, cleaning and keeping the airways open through suctioning should be done to increase oxygenation. This study aimed to evaluate effect of open and closed suctioning methods on respiratory parameters of infants undergoing mechanical ventilation.
Materials and Methods:
In this crossover clinical trial, 44 infants were selected among those undergone mechanical ventilation in NICU of Isfahan's Al-Zahra Hospital using convenience sampling method. The subjects were randomly divided into two groups. In the first group, open suctioning was carried out and after three hours of cleaning, closed suctioning was done. In the second group, closed suctioning was firstly done and following three hours of cleaning, open suctioning was implemented. Respiratory rate (RR) and percentage of arterial blood oxygen saturation was measured before, during and after each type of suctioning. Data were analyzed using repeated measures ANOVA and independent student's t-test.
There was a significant difference between mean respiratory rate and arterial blood oxygen saturation in infants before, during and after the closed and open suctioning. The percentage of arterial blood oxygen saturation had a significant reduction in open method compared to closed method during suctioning and immediately after it. RR three minutes after suctioning showed a significant reduction in both steps in open method compared to closed method.
Close method caused fewer changes in hemodynamic status of infants. Therefore, in order to prevent respiratory complications in infants, nurses are recommended to perform the endotracheal tube suctioning by closed method.
Respiratory rate; ventilation; neonate; suction
Aim. To describe the subsequent treatment of airway trauma sustained during laryngoscopy and endotracheal intubation.
Methods. A rare injury occurring during laryngoscopy and endotracheal intubation that resulted in perforation of the tongue by an endotracheal tube and the subsequent management of this unusual complication are discussed. A 65-year-old female with intraparenchymal brain hemorrhage with rapidly progressive neurologic deterioration had the airway secured prior to arrival at the referral institution. The endotracheal tube (ETT) was noted to have pierced through the base of the tongue and entered the trachea, and the patient underwent operative laryngoscopy to inspect the injury and the ETT was replaced by tracheostomy. Results. Laryngoscopy demonstrated the ETT to perforate the base of the tongue. The airway was secured with tracheostomy and the ETT was removed. Conclusions. A wide variety of complications resulting from direct and video-assisted laryngoscopy and tracheal intubation have been reported. Direct perforation of the tongue with an ETT and ability to ventilate and oxygenate subsequently is a rare injury.
Objective. Identification of the weight and postmenstrual age (PMA) at successful weaning of NCPAP in preterm neonates and the factors influencing the successful wean. Study Design. Retrospective review of 454 neonates ≤32 weeks of gestational age (GA) who were placed on NCPAP and successfully weaned to room air was performed. Results. Neonates had a mean birth weight (BW) of 1357 ± 392 grams with a mean GA of 29.3 ± 2.2 weeks. Neonates were weaned off NCPAP at mean weight of 1611 ± 432 grams and mean PMA of 32.9 ± 2.4 weeks. Univariate analysis showed that chorioamnionitis, intubation, surfactant use, PDA, sepsis/NEC, anemia, apnea, GER and IVH were significantly associated with the time to NCPAP wean. On multivariate analysis, among neonates that were intubated, BW was the only significant factor (P < 0.001) that was inversely related to time to successful NCPAP wean. Amongst non-intubated neonates, along with BW (P < 0.01), chorioamnionitis (P < 0.01), anemia (P < 0.0001), and GER (P < 0.02) played a significant role in weaning from NCPAP. Conclusion. Neonates were weaned off NCPAP at mean weight of 1611 ± 432 grams and mean PMA of 32.9 ± 2.4 weeks. BW significantly affects weaning among intubated and non-intubated neonates, though in neonates who were never intubated chorioamnionitis, anemia and GER also significantly affected the duration on NCPAP.
Morphine has been commonly used for postoperative pain control. We measured plasma concentrations of morphine and compared the efficacy and safety of continuous epidural analgesia (CEA) using morphine-bupivacaine with intravenous patient controlled analgesia (IV-PCA) with morphine for 48 hrs after the end of the operation.
Nineteen patients undergoing Mile's operation were assigned to receive a morphine loading dose of 5 mg followed by IV-PCA with 0.1% morphine (IV-PCA group, n = 9) or a morphine loading dose of 2 mg and 0.125% bupivacaine 10 ml, followed by CEA with 0.004% morphine and 0.075% bupivacaine at a rate of 5 ml/hr (CEA group, n = 10). The plasma concentrations of morphine were measured and visual analog scales (VAS) for pain were recorded at 1, 6, 12, 24, and 48 hr postoperatively and the effects on respiration and any other side effects were noted.
The mean maximal and minimal levels of plasma morphine were 40.2 ± 21.2 ng/ml and 23.4 ± 9.7 ng/ml for the IV-PCA group and 11.8 ± 3.5 ng/ml and 8.2 ± 1.9 ng/ml for the CEA group, respectively. Resting and dynamic pain scores were significantly lower in the CEA group than in the IV-PCA group. There were no significant differences for the effects on respiration and for any side effects between the two groups.
We evaluated plasma concentrations of morphine with CEA using morphine-bupivacaine and IV-PCA using morphine for the postoperative pain control. The CEA group had better postoperative analgesia than that of the IV-PCA group and the incidence of side effects were not significantly different between the two groups.
morphine; postoperative pain
Several transporters appear to be important in transporting various drugs. Many patients, who receive morphine as analgesic medication, also receive other medications with potency of changing morphine transport by affecting P-glycoprotein (P-GP) and oatp2 transport system. This could influence morphine pharmacokinetics and pharmacodynamics. The aim of present study was to elucidate the transport mechanisms involved in transporting morphine via MDCKII and MDCK-PGP cells. Morphine permeability was examined in the presence of various compounds with ability in inhibiting different transport systems including: digoxin, probenecid and d- glucose. The effect of morphine concentration changes on its transport was also examined. Morphine concentration was measured using HPLC with electrochemical detector. Morphine permeability via a MDCK II cells was greater than sucrose permeability, and reduced when a P-GP expressed cell line was used. Its permeability was increased significantly in the presence of a strong P-GP inhibitor. Morphine permeability decreased significantly in the presence of digoxin but not in the presence of d-glucose or probenecid. These results showed that morphine was a P-GP substrate, and digoxin related transporters such as oatp2 were involved in its transport. Morphine was not substrate for glucose or probenecid-sensitive transporters.
Morphine transport; P-glycoprotein; Probenecid-sensitive transport; Multidrug resistance related protein
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.
kappa opioid receptor; morphine; dynorphin; neonatal stress; stress inoculation hypothesis
A critical component of drug addiction research involves identifying novel biological mechanisms and environmental predictors of risk or resilience to drug addiction and associated relapse. Increasing evidence suggests microglia and astrocytes can profoundly affect the physiological and addictive properties of drugs of abuse, including morphine. We report that glia within the rat Nucleus Accumbens (NAcc) respond to morphine with an increase in cytokine/chemokine expression, which predicts future reinstatement of morphine conditioned place preference (CPP) following a priming dose of morphine. This glial response to morphine is influenced by early-life experience. A neonatal handling paradigm that increases the quantity and quality of maternal care significantly increases baseline expression of the anti-inflammatory cytokine IL-10 within the NAcc, attenuates morphine-induced glial activation, and prevents the subsequent reinstatement of morphine CPP in adulthood. IL-10 expression within the NAcc and reinstatement of CPP are negatively correlated, suggesting a protective role for this specific cytokine against morphine-induced glial reactivity and drug-induced reinstatement of morphine CPP. Neonatal handling programs the expression of IL-10 within the NAcc early in development, and this is maintained into adulthood via decreased methylation of the IL-10 gene specifically within microglia. The effect of neonatal handling is mimicked by pharmacological modulation of glia in adulthood with Ibudilast, which increases IL-10 expression, inhibits morphine-induced glial activation within the NAcc, and prevents reinstatement of morphine CPP. Taken together, we have identified a novel gene X early-life environment interaction on morphine-induced glial activation, and a specific role for glial activation in drug-induced reinstatement of drug-seeking behavior.
Ventilator-associated pneumonia (VAP) is a serious and costly clinical problem. Specifically, receiving mechanical ventilation for over 24 hours increases the risk of VAP and is associated with high morbidity, mortality, and medical costs. Cost-effective endotracheal tubes (ETTs) that are resistant to bacterial infections could help prevent this problem. The objective of this study was to determine differences in the growth of Staphylococcus aureus on nanomodified and unmodified polyvinyl chloride (PVC) ETTs under dynamic airway conditions simulating a ventilated patient. PVC ETTs were modified to have nanometer surface features by soaking them in Rhizopus arrhisus, a fungal lipase. Twenty-four-hour experiments (supported by computational models) showed that airflow conditions within the ETT influenced both the location and the concentration of bacterial growth on the ETTs, especially within areas of tube curvature. More importantly, experiments revealed a 1.5 log reduction in the total number of S. aureus on the novel nanomodified ETTs compared with the conventional ETTs after 24 hours of airflow. This dynamic study showed that lipase etching can create nanorough surface features on PVC ETTs that suppress S. aureus growth, and thus may provide clinicians with an effective and inexpensive tool to combat VAP.
biofilm; laminar flow; ventilator-associated pneumonia; nanotechnology; endotracheal tubes; S. aureus
We have shown previously that withdrawal from morphine induces immunosuppression in mice. The present study reports the effects of morphine withdrawal on infection with Salmonella enterica serovar Typhimurium. Mice were made dependent on morphine by the implantation of a slow-release morphine pellet for 96 h. Controls received a placebo pellet. Withdrawal was induced by pellet removal. Mice were inoculated intraperitoneally with Salmonella 24 h postwithdrawal. Morphine withdrawal sensitized mice to Salmonella infection, as evidenced by increased mortality, shortened mean survival time, and increased bacterial load in the blood, spleen, and liver. Examination of the levels of a panel of proinflammatory cytokines in sera of infected, morphine-withdrawn mice showed that morphine withdrawal inhibited the elevation of interleukin-12p70 (IL-12p70). The production of IL-12p40 in morphine withdrawal mice was also suppressed. The administration of exogenous IL-12 significantly decreased the bacterial burden in morphine-withdrawn mice. These studies show a correlation between the suppression of IL-12 production and a heightened susceptibility to Salmonella infection in mice undergoing withdrawal from morphine.
Morphine is frequently used as an analgesic and sedative in preterm infants. Adult rats exposed to morphine have altered hippocampal neurochemical profile and decreased neurogenesis in the dentate gyrus of the hippocampus. To evaluate whether neonatal rats are similarly affected, rat pups were injected twice daily with 2 mg/kg of morphine or normal saline from postnatal days 3 to 7. On postnatal day 8, the hippocampal neurochemical profile was determined using in vivo 1H NMR spectroscopy. The mRNA and protein concentrations of specific analytes were measured in hippocampus, and cell division in dentate gyrus was assessed using bromodeoxyuridine. The concentrations of γ-aminobutyric acid (GABA), taurine and myo-insotol were decreased, while glutathione, phosphoethanolamine and choline-containing compounds concentrations were increased in morphine-exposed rats relative to control rats. Morphine decreased glutamic acid decarboxylase enzyme levels and myelin basic protein mRNA expression in the hippocampus. Bromodeoxyuridine labeling in the dentate gyrus was decreased by 60-70% in morphine-exposed rats. These results suggest that recurrent morphine administration during brain development alters hippocampal structure.
1H NMR spectroscopy; bromodeoxyuridine; γ-aminobutyric acid (GABA); hippocampus; morphine; taurine
We have examined sensitivity and specificity of pseudocontinuous arterial spin labeling (PCASL) to detect global and regional changes in cerebral blood flow (CBF) in response to two different psychoactive drugs. We tested alcohol and morphine in a placebo-controlled, double-blind randomized study in 12 healthy young men. Drugs were administered intravenously. Validated pharmacokinetic protocols achieved minimal intersubject and intrasubject variance in plasma drug concentration. Permutation-based statistical testing of a mixed effect repeated measures model revealed a widespread increase in absolute CBF because of both morphine and alcohol. Conjunction analysis revealed overlapping effects of morphine and alcohol on absolute CBF in the left anterior cingulate, right hippocampus, right insula, and left primary sensorimotor areas. Effects of morphine and alcohol on relative CBF (obtained from z-normalization of absolute CBF maps) were significantly different in the left putamen, left frontoparietal network, cerebellum, and the brainstem. Corroborating previous PET results, our findings suggest that PCASL is a promising tool for central nervous system drug research.
alcohol; cerebral blood flow; functional brain imaging; perfusion weighted MRI; pharma fMRI; morphine