Inhaled nitric oxide for preterm infants--still an experimental therapy.
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Administration, Inhalation↗
Biomedical subjects
O D Saugstad
Publications and source records attributed to O D Saugstad.
Mutant transcripts of the LDL receptor gene: mRNA structure and quantity.
mRNA of the low-density lipoprotein receptor (LDLR) gene from 22 heterozygous familial hypercholesterolemic subjects possessing different mutations in this gene was analyzed by Northern blot analysis and reverse transcription-polymerase chain reaction (RT-PCR) in order to detect abnormally spliced transcripts. These analyses revealed abnormally spliced transcripts for the two splice-site mutations 1359-1G-->A and 1705 + 1G-->T. The abnormally spliced transcript for mutation 1359-1G-->A was caused by activation of a cryptic acceptor splice site in exon 10. As a result, seven nucleotides of exon 10 were deleted. For mutation 1705 + 1G-->T, two mutant transcripts were observed. In the first transcript, exon 10 was spliced to exon 13, and in the second transcript intron 11 was retained. The relative amount of mutant transcripts from 14 of the 22 subjects was determined by use of an RT-PCR-based method. Quantitation of the relative amounts of mutant transcripts for five missense mutations resulted in a mean value (+/-SD) of 52.8% (+/-4.55). In comparison, quantitation of the relative amounts of mutant transcripts for five nonsense mutations resulted in a mean value of 31.8% (+/-6.91). This value was significantly lower than the value of 54.2% (+/-2.38) obtained for nine healthy subjects (P < 0.0001). The relative amount of mutant transcripts for the 1705 + 1G-->T mutation was 36%. Thus, transcripts from alleles containing premature stop codons are present in reduced amounts, whereas transcripts from alleles containing missense mutations are present in normal amounts. These findings underscore the importance of determining how mutations affect mRNA structure and quantity in order to understand how mutations cause disease.
Alleles↗
Sodium nitroprusside prevents oxygen-free-radical-induced pulmonary vasoconstriction in newborn piglets.
The aim of the present study was to test whether hypoxanthine-xanthine oxidase (XO) induced a pulmonary vasoconstriction in newborn piglets, and whether this vasoconstriction could be attenuated or abolished by pretreatment of nitric oxide (NO) donor sodium nitroprusside (SNP). Twenty-five anesthetized newborn piglets (1-3 days old) were randomly assigned to the following four groups: the control group received saline intravenously only; the XO group received 0.1 mmol/kg of hypoxanthine subsequent with XO (1.5 U/kg); the SNP group received the same dosages of hypoxanthine/ XO together with SNP intravenously, allopurinol (ALP) group received ALP intravenously prior to hypoxanthine and XO injection. After giving XO, the pulmonary arterial pressure (PAP) and vascular resistance (PVR) increased, while the cardiac index decreased significantly in the XO group. By contrast, these variables were not significantly modified by XO injection in the SNP and ALP groups. The data suggest that oxygen free radicals induce a pulmonary vasoconstriction in newborn piglets, and this vasoconstriction can be prevented by infusion of the NO donor SNP.
Animals↗
Effects of hypoxia and reoxygenation with 21% and 100%-oxygen on cerebral nitric oxide concentration and microcirculation in newborn piglets.
Bioelectric sensors for continuous registration of nitric oxide (NO) concentrations in tissues provide a new tool for invasive measurement of this gaseous molecule. This study sought to validate cerebral NO measurements using an amperiometric sensor. A series of experiments in 1- to 3-day-old piglets was carried out to study the response of NO and microcirculation during hypoxia (F(i)O(2) 0.06) and reoxygenation with 100% and 21% oxygen. Two-channel laser Doppler flowmetry was performed in the forebrain cortex. Significant decreases of NO levels were observed immediately after induction of hypoxemia (p < 0.05). During reoxygenation with 21 or 100% O(2) for 30 min, NO increased significantly compared to the values at the end of hypoxia (p < 0.05). The increase of NO levels in the 100% oxygen group was greater than the increase in the 21% oxygen group (p < 0. 05). There were no significant differences between the two groups during the following 3.5 h of observation. A significant increase in CBF was found in the first 2 min of hypoxia (p < 0.05), it then continued to fall to values significantly lower than baseline values at the end of hypoxemia (p < 0.05). During reoxygenation CBF normalised and there were consistent but no significant differences between the two reoxygenation groups. We conclude that NO concentration decreased during the course of hypoxia. Hypoxia-induced cerebral hyperaemia occurred in spite of significantly lower NO concentrations. Reoxygenation with 21 or 100% O(2) restored CBF in both groups similarly, although values were higher after reoxygenation with 100% O(2) compared to air. In fact, reoxygenation with 100% O(2) led to supranormal levels of NO by contrast to 21% O(2).
Animals↗
Nebulization of sodium nitroprusside in lung-lavaged newborn piglets.
The aim of the present study was to test the hypothesis that nebulization of the nitric oxide donor sodium nitroprusside may selectively reduce pulmonary vascular resistance and improve oxygenation in lung-lavaged newborn piglets. Thirteen anesthetized piglets (1-3 d old) were subjected to repeated lung lavages and then randomly assigned to one of the following two groups: 1) an SNP group, which received SNP nebulization, and 2) a saline group, which received saline nebulization. Pulmonary arterial pressure and pulmonary vascular resistance increased significantly after lung lavage, whereas cardiac output decreased significantly in both groups. After SNP nebulization, pulmonary arterial pressure decreased from 32+/-1 to 17+/-1 mm Hg (p < 0.01) and PVR decreased from 255+/-20 to 172+/-15 mm Hg L(-1) min(-1) kg(-1) (p < 0.01). The arterial tension of oxygen concomitantly increased from 9.4+/-4.0 to 17.0+/-3.0 kPa (p < 0.01), and the arterial/alveolar ratio of oxygen tension increased from 0.11+/-0.01 to 0.22+/-0.03 (p < 0.01). Systemic hemodynamics were not modified significantly during nebulization of SNP. On the other hand, all variables were stable during nebulization of saline. These data suggest that SNP nebulization produces a selective pulmonary vasodilatation and improves oxygenation in lung-lavaged newborn piglets.
Acid-Base Equilibrium↗
Pulmonary hemodynamics in newborn piglets during hypoxemia and reoxygenation: blocking of the endothelin-1 receptors.
The effects of blocking endothelin (ET) receptors in pulmonary circulation during hypoxemia and reoxygenation were studied in five groups of piglets. Ten minutes before hypoxemia, the Hyp group (n = 10) was given saline and the 1-mg (n = 9) and 5-mg group (n = 9), respectively, were given 1 and 5 mg/kg i.v. SB 217242 (an ET receptor antagonist). Two groups served as normoxic controls. The piglets were ventilated with 8% O2 until base excess was <-20 mmol/L or mean arterial blood pressure was <20 mm Hg. Reoxygenation was performed with air. The increase of mean pulmonary artery pressure was significantly attenuated during hypoxemia and reoxygenation in the 1-mg group (p = 0.006). The pulmonary vascular resistance index increased significantly at the end of hypoxemia in the Hyp and 5-mg groups but was comparable to baseline in the 1-mg group. During the study period, the changes in pulmonary vascular resistance index were significantly attenuated in the 1-mg group compared with the 5-mg group. Stroke volume index was significantly attenuated compared with baseline in the 5-mg group during both hypoxemia and reoxygenation, whereas, in the Hyp and 1-mg group, stroke volume index was attenuated only at the end of hypoxemia. During hypoxemia, plasma ET-1 decreased from 1.9+/-0.2 to 1.3+/-0.3 ng/L (p = 0.008) in the Hyp group, remained unchanged in the 1-mg group, and increased from 1.6+/-0.2 to 6.6+/-1.6 ng/L (p = 0.008) in the 5-mg group. We conclude that blocking ET receptors attenuates pulmonary vasoconstriction during hypoxemia and reoxygenation in piglets.
Acid-Base Equilibrium↗
The amount of brainstem gliosis in sudden infant death syndrome (SIDS) victims correlates with maternal cigarette smoking during pregnancy.
Brainstem gliosis is elevated in some SIDS victims and has been associated with hypoxic-ischaemic events. Factors which increase the risk of SIDS include possible risk factors for hypoxic-ischaemic events during foetal and perinatal life. In this study a scoring system was developed whereby possible risk factors for hypoxic-ischaemic events during pregnancy, birth and in the perinatal period were correlated with the level of gliosis in the nucleus olivaris inferior in SIDS victims (n = 19). The mothers' antenatal care and obstetric records and the SIDS infants' perinatal hospital records were investigated, and each possible risk factor for hypoxic-ischaemic events was given one point. The points were summarized for each infant, and this sum was correlated with the level of gliosis in the infant's nucleus olivaris inferior. The number of cigarettes the mothers smoked during pregnancy was also compared with the level of gliosis. Our results show that in SIDS victims there is 41% probability that the more the mothers smoked during pregnancy, the more gliosis in the nucleus olivaris inferior is found in their infants (p < 0.01). Gliosis in the nucleus olivaris inferior also correlated with the possible risk factors for hypoxic-ischaemic events during pregnancy, birth and the perinatal period (r2 = 0.28, p < 0.05). However, if cigarette smoking was excluded as a possible hypoxic-ischaemic risk factor, no correlation was found.
Brain Stem↗
Practical aspects of resuscitating asphyxiated newborn infants.
Of all newborn infants, 5% require some degree of basic life support at birth. Newborn resuscitation therefore is one of the most frequent procedures carried out in medicine. It is therefore important that the routines in use are evidence based. Newborn resuscitation can be divided into ten steps: (1) initial stabilisation; (2) evaluation; (3) ventilation; (4) oxygen supplementation; (5) external heart massage; (6) medication; (7) response assessment; (8) withdrawal; (9) post resuscitation care; and (10) documentation. The procedures used in these steps are rarely based on scientific investigation and there is a need for more research in this field. Training programmes, identification of risk cases and preparation for resuscitation should be part of the routine in all delivery units. It is underlined that the need for oxygen, external heart massage or medication is rare. Most depressed newborn infants manage well with suctioning, gentle tactile stimulation or a few ventilations with a bag and mask.
Air↗
Oxygen delivery and consumption in surfactant-depleted newborn piglets.
OBJECTIVE: To study the relationship between oxygen (O2) delivery (DO2) and O2 consumption (VO2) in surfactant-depleted newborn piglets. DESIGN: Prospective animal study. SETTING: Hospital surgical research laboratory. SUBJECTS: Twenty-six anesthetized and ventilated newborn piglets. INTERVENTIONS: Twenty of the animals were subjected to repeated saline lung lavages, and then assigned to either the saline group or the L-NAME group. The other six animals without lavage were studied as the control group. Piglets in the L-NAME group and the control group received 3 mg/kg of N(omega)-nitro-L-arginine methyl ester (L-NAME, an inhibitor of NO synthase) i.v.; and those in the saline group received the same volume of saline i.v. MEASUREMENTS AND RESULTS: Cardiac output (CO) was measured and arterial and mixed venous blood gases were analyzed. DO2, O2 extraction ratio (O2ER) and VO2 were calculated. Plasma hypoxanthine was analyzed. In the lung lavaged groups, cardiac index, DO2 and VO2 decreased significantly after L-NAME i.v. but not after saline i.v. Further, the decrease in VO2 in the L-NAME group correlated with the decrease in DO2 (r = 0.83, p < 0.001). In the control group, cardiac index and DO2, but not VO2, decreased significantly after L-NAME i.v. Simultaneously, O2ER increased significantly. Plasma hypoxanthine was not modified by lung lavage but increased after L-NAME i.v. in both the L-NAME and control groups. CONCLUSION: These data suggest that O2 supply dependency is present in surfactant-depleted newborn piglets.
Animals↗
Diving seals, ischemia-reperfusion and oxygen radicals.
The cardiovascular adaptations of seals that contribute to their ability to tolerate long periods of diving asphyxial hypoxia result in episodic regional ischemia during diving and abrupt reperfusion upon termination of the dive. These conditions might be expected to result in production of oxygen-derived free radicals and other forms of highly reactive oxygen species. Seal organs vary during dives with respect to the degree and persistence of ischemia. Myocardial perfusion is reduced and intermittent; kidney circulation is vigorously vasoconstricted. Heart and kidney tissues from ringed seals (Phoca hispida) and domestic pigs (Sus scrofa) were compared in reactions to experimental ischemia. Resulting production of hypoxanthine, indicative of ATP degradation, was higher in pig than in seal tissues. Activity of superoxide dismutase (SOD), an oxygen radical scavenger, was higher in seal heart. We suggest that these results indicate enhanced protective cellular mechanisms in seals against the potential hazard of highly reactive oxygen forms. SOD activity was unexpectedly higher in pig kidney.
Animals↗
Fatty acid composition in maternal milk and plasma during supplementation with cod liver oil.
OBJECTIVE: We investigated how cod liver oil influences the amount of essential fatty acids in mothers' breast milk. DESIGN AND INTERVENTION: Lactating mothers (n =22) were randomized into four groups 3-8 weeks after parturition. They were supplemented for 14 days with 0, 2.5, 5 and 10 ml cod liver oil (7.7 g eicosapentaenoic acid (EPA, 20:5n-3), 10.2 g docosahexaenoic acid (DHA, 22:6n-3) and 22.9 g n-3 fatty acids in total per 100 ml). RESULTS: In maternal plasma phospholipids there was an increase in the content of EPA and DHA in the group supplemented with 10 ml cod liver oil daily (P < or = 0.05). DHA concentrations in breast milk pre-supplementation ranged from 0.15 to 1.56 wt% and increased in all supplemented groups (P< or =0.05). The concentration of EPA in breast milk increased in the groups supplemented with 5 or 10 ml cod liver oil (P< or =0.05), whereas the concentration of arachidonic acid (AA, 20:4n-6) did not change in any of the supplemented groups. Total intake of DHA adjusted to body mass index (BMI), correlated to DHA concentrations in plasma (r = 0.49, P = 0.02) and breast milk (r = 0.45, P = 0.04). The concentration of tocopherol did not change during the supplementation period, neither in plasma nor in breast milk. CONCLUSION: Dietary intake of DHA is reflected in the concentration of DHA in breast milk, without affecting the concentration of AA or tocopherol.
Adult↗
Acute effects on systemic circulation after intratracheal instillation of Curosurf or Survanta in surfactant-depleted newborn piglets.
Systemic vasodilatation in surfactant-depleted newborn piglets is induced by 200 mg/kg of modified porcine lung surfactant (Curosurf). The aim of this investigation was to study whether this effect is dependent on dose and could further be induced by instillation of a bovine surfactant preparation (Survanta). Twenty-two 3-5-d old piglets were subjected to repeated saline lung lavage and then randomized to one of three groups. Instillation of either Curosurf l00 mg/kg (n=8), Survanta l00 mg/kg (n=7) or Curosurf 200 mg/kg (n=7) was performed through the endotracheal tube. Systemic vascular resistance decreased 7 (+/-4)%, 15 (+/-12)% and 18 (+/-6)% in the three groups, respectively (p < 0.05 in all three groups). A significant difference between the high and low dose Curosurf groups was found (p < 0.05), whereas no significant difference was seen between the Curosurf 100 mg group and the Survanta group. The decrease in vascular resistance was compensated by an increase in cardiac output, resulting in a stable mean arterial blood pressure. In conclusion, both Curosurf and Survanta induce a significant decrease in systemic vascular resistance in surfactant-depleted newborn piglets. A more pronounced effect was observed after 200 mg/kg than after 100mg/kg of Curosurf.
Animals↗
Are elevated cerebrospinal fluid levels of IL-6 in sudden unexplained deaths, infectious deaths and deaths due to heart/lung disease in infants and children due to hypoxia?
Many SIDS cases probably die after periods of hypoxia and it has been shown that hypoxia may stimulate IL-6 production. The purpose of this paper was to examine if there were any correlations between hypoxanthine in vitreous humour and IL-6 in CSF. The concentration of IL-6, IL-1beta and TNFalpha in cerebrospinal fluid of 50 Sudden Infant Death syndrome (SIDS) cases, 9 borderline SIDS cases, 18 infectious deaths, 8 violent deaths and 22 cases with heart/lung disease were measured by ELISA. The hypoxanthine (Hx) vitreous humour concentrations in the same groups were determined by high performance liquid chromatography. The IL-6 levels in cases of infectious death, heart/lung disease and borderline cases were significantly higher than in the SIDS cases (p < 0.01). The Hx levels were in the same range in cases of SIDS, borderline SIDS and infectious death, and they were significantly higher than the levels in cases of violent death and heart/lung disease (p < 0.01). There was no correlation between hypoxanthine and IL-6 in any of the groups. In the cases studied IL-6 elevation is probably not induced by hypoxia, but is rather a result of immunological stimulation.
Biomarkers↗
Cerebral excitatory amino acids and Na+,K+-ATPase activity during resuscitation of severely hypoxic newborn piglets.
We tested the hypothesis that early brain recovery in hypoxic newborn piglets is improved by resuscitating with an O2 supply close to the minimum level required by the newborn piglet brain. Severely hypoxic 2-5-d-old anaesthetized piglets were randomly divided into three resuscitation groups: hypoxaemic (n = 8), 21% O2 (n = 8), and 100% O2 groups (n = 8). The hypoxaemic group was mechanically ventilated with 12-18% O2 adjusted to achieve a cerebral venous O2 saturation of 17-23% (baseline; 45 +/- 1%, mean +/- SEM). During the 2h resuscitation period, extracellular aspartate and glutamate concentrations in the cerebral striatum were higher during hypoxaemic resuscitation (p = 0.044 and p = 0.055, respectively) than during resuscitation with 21% O2 or 100% O2, suggesting an unfavourable accumulation of potent excitotoxins during hypoxaemic resuscitation. The cell membrane Na+,K+-ATPase activity of cerebral cortical tissue after 2 h resuscitation was similar in the three groups (p = 0.30). In conclusion, hypoxaemic resuscitation did not normalize early cerebral metabolic recovery as efficiently as resuscitation with 21% O2 or 100% O2. Resuscitation with 21% O2 was as efficient as resuscitation with 100% O2 in this newborn piglet hypoxia model.
Analysis of Variance↗
Ochratoxin A: a naturally occurring mycotoxin found in human milk samples from Norway.
The presence of ochratoxin A (OA) in human milk samples from different regions in Norway was investigated to determine the level of infant exposure to OA from human milk. OA was found in 38 (33%) of 115 human milk samples (range 10-130 ng l(-1)). It was found that 2-26% of the samples contained more than 40 ng l(-1) OA, which will cause a daily intake of OA from human milk exceeding the suggested tolerable dose of 5 ng kg(-1) body weight. Significant regional differences were found.
Female↗
Early cerebral metabolic and electrophysiological recovery during controlled hypoxemic resuscitation in piglets.
We tested the hypothesis that controlled hypoxemic resuscitation improves early cerebral metabolic and electrophysiological recovery in hypoxic newborn piglets. Severely hypoxic anesthetized piglets were randomly divided into three resuscitation groups: hypoxemic, 21% O2, and 100% O2 groups (8 in each group). The hypoxemic group was mechanically ventilated with 12-18% O2 adjusted to achieve a cerebral venous O2 saturation of 17-23% (baseline; 45 +/- 1%). Base excess (BE) reached -22 +/- 1 mM at the end of hypoxia. During a 2-h resuscitation period, no significant differences in time to recovery of electroencephalography (EEG), quality of EEG at recovery, or extracellular hypoxanthine concentrations in the cerebral cortex and striatum were found among the groups. BE and plasma hypoxanthine, however, normalized significantly more slowly during controlled hypoxemic resuscitation than during resuscitation with 21 or 100% O2. We conclude that early brain recovery during controlled hypoxemic resuscitation was as efficient as, but not superior to, recovery during resuscitation with 21 or 100% O2. The systemic metabolic recovery from hypoxia, however, was delayed during controlled hypoxemic resuscitation.
Animals↗
Chronic lung disease: the role of oxidative stress.
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Animals↗
Hypoxemic resuscitation in newborn piglets: recovery of somatosensory evoked potentials, hypoxanthine, and acid-base balance.
We tested the hypothesis that hypoxic newborn piglets can be successfully resuscitated with lower O2 concentrations than 21%. Severely hypoxic, 2-4-d-old, anesthetized piglets were randomly divided into five resuscitation groups: 21% O2 (n = 10), 18% O2 (n = 9), 15% O2 (n = 9), 12% O2 (n = 8), all normoventilated, and a hypoventilated 21% O2 group (PaCO2; 7.0-8.0 kPa, n = 9). Base excess (BE) reached -20 +/- 1 mmol/L at the end of hypoxia. After 3 h of resuscitation, BE had risen to -4 +/- 1 mmol/L in the 21% O2, 18% O2, and hypoventilated groups, but was -10 +/- 2 mmol/L in the 15% O2 group (p < 0.05 versus 21% O2 group) and -22 +/- 2 mmol/L in the 12% O2 group (p < 0.05 versus 21% O2 group). Four animals died during resuscitation, all allocated to the 12% O2 group (p < 0.05 versus 21% O2 group). Somatosensory evoked potentials (SEPs) recovered in 39 of 45 piglets, and remained present during resuscitation in all except the 12% O2 group. SEP recovered initially even in six of eight animals in the 12% O2 group, but disappeared again in all later during resuscitation. The SEP amplitude recovered to levels not significantly different from the 21% O2 group in all groups except the 12% O2 group. Plasma hypoxanthine concentrations and extracellular hypoxanthine concentrations in the striatum decreased during resuscitation to levels not significantly different from the 21% O2 group in all but the 12% O2 group (p < 0.05 versus 21% O2 group). In conclusion, severely hypoxic newborn piglets were resuscitated as efficiently with both hypoventilation and 18% O2 as with 21% O2.
Acid-Base Equilibrium↗