Myocardial perfusion and oxidative stress after 21% vs. 100% oxygen ventilation and uninterrupted chest compressions in severely asphyxiated piglets.

AIM: Despite the minimal evidence, neonatal resuscitation guidelines recommend using 100% oxygen when chest compressions (CC) are needed. Uninterrupted CC in adult cardiopulmonary resuscitation (CPR) may improve CPR hemodynamics. We aimed to examine 21% oxygen (air) vs. 100% oxygen in 3:1 CC:ventilation (C:V) CPR or continuous CC with asynchronous ventilation (CCaV) in asphyxiated newborn piglets following cardiac arrest. METHODS: Piglets (1-3 days old) were progressively asphyxiated until cardiac arrest and randomized to 4 experimental groups (n=8 each): air and 3:1 C:V CPR, 100% oxygen and 3:1 C:V CPR, air and CCaV, or 100% oxygen and CCaV. Time to return of spontaneous circulation (ROSC), mortality, and clinical and biochemical parameters were compared between groups. We used echocardiography to measure left ventricular (LV) stroke volume at baseline, at 30min and 4h after ROSC. Left common carotid artery blood pressure was measured continuously. RESULTS: Time to ROSC (heart rate ≥100min(-1)) ranged from 75 to 592s and mortality 50-75%, with no differences between groups. Resuscitation with air was associated with higher LV stroke volume after ROSC and less myocardial oxidative stress compared to 100% oxygen groups. CCaV was associated with lower mean arterial blood pressure after ROSC and higher myocardial lactate than those of 3:1 C:V CPR. CONCLUSION: In neonatal asphyxia-induced cardiac arrest, using air during CC may reduce myocardial oxidative stress and improve cardiac function compared to 100% oxygen. Although overall recovery may be similar, CCaV may impair tissue perfusion compared to 3:1 C:V CPR.

The vascular effects of sodium tanshinone IIA sulphonate in rodent and human pregnancy.

Danshen, in particular its derivative tanshinone IIA (TS), is a promising compound in the treatment of cardiovascular diseases and has been used for many years in traditional Chinese medicine. Although many actions of TS have been researched, its vasodilator effects in pregnancy remain unknown. There have been a few studies that have shown the ability of TS to reduce blood pressure in women with hypertensive pregnancies; however, there are no studies which have examined the vascular effects of TS in the pregnant state in either normal or complicated pregnancies. Our aim was to determine the vasoactive role of TS in multiple arteries during pregnancy including: rat resistance (mesenteric and uterine) and conduit (carotid) arteries. Further, we aimed to assess the ability of TS to improve uterine blood flow in a rodent model of intrauterine growth restriction. Wire myography was used to assess vascular responses to the water-soluble derivative, sodium tanshinone IIA sulphonate (STS) or to the endothelium-dependent vasodilator, methylcholine. At mid-pregnancy, STS caused direct vasodilation of rat resistance (pEC50 mesenteric: 4.47±0.05 and uterine: 3.65±0.10) but not conduit (carotid) arteries. In late pregnancy, human myometrial arteries responded with a similar sensitivity to STS (pEC50 myometrial: 3.26±0.13). STS treatment for the last third of pregnancy in eNOS-/- mice increased uterine artery responses to methylcholine (Emax eNOS-/-: 55.2±9.2% vs. eNOS-/- treated: 75.7±8.9%, p<0.0001). The promising vascular effects, however, did not lead to improved uterine or umbilical blood flow in vivo, nor to improved fetal biometrics; body weight and crown-rump length. Further, STS treatment increased the uterine artery resistance index and decreased offspring body weight in control mice. Further research would be required to determine the safety and efficacy of use of STS in pregnancy.

Effect of sodium tanshinone IIA sulfonate treatment in a rat model of preeclampsia.

Preeclampsia is a disorder of pregnancy with a significant impact on maternal and fetal health. The complexity of this multifactorial condition has precluded development of effective therapies and, although many potential pathways have been investigated, the etiology still requires clarification. Our group has investigated the scavenger lectin-like oxidized LDL (LOX-1) receptor, which may respond to factors released from the distressed placenta that contribute to the vascular pathologies observed in preeclampsia. Given the known beneficial effects of sodium tanshinone IIA sulfonate (STS; a component of Salvia miltiorrhiza) on vasodilation, reduction of oxidative stress, and lipid profiles, we have investigated its role as a potential treatment strategy. We hypothesized that STS would improve vascular endothelial function and, combined with a reduction in oxidative stress, would improve pregnancy outcomes in a rat model of preeclampsia (reduced uteroplacental perfusion pressure, RUPP). We further hypothesized this may occur via the action of STS on the LOX-1 and/or platelet-activating factor (PAF) receptor axes. The RUPP model increased maternal blood pressure, vascular oxidative stress, and involvement of the vascular PAF receptor. Treatment with STS during pregnancy decreased both oxidative stress and involvement of the PAF receptor; however, it also increased involvement of the LOX-1 receptor, which is in line with the concept that scavenger receptors, such as LOX-1 and PAF, are upregulated in response to ligand binding and/or under pathological conditions. In this model of preeclampsia, however, the vascular actions of STS did not lead to improvements in pregnancy outcome such as fetal biometrics or maternal blood pressure.

Effects of tanshinone IIA, a major component of Salvia miltiorrhiza, on platelet aggregation in healthy newborn piglets.

ETHNOPHARMACOLOGICAL RELEVANCE: Tanshinone IIA (STS), an active ingredient of the Chinese herb Danshen (Salvia miltiorrhiza) for angina and stroke in adults, has been reported to inhibit platelet function. However, its effect on platelet and underlying mechanism remain largely unknown, particularly in neonates. MATERIALS AND METHODS: To investigate the effect of STS on the platelet aggregation and its interaction with various platelet activation pathways, platelet aggregatory function was studied in whole blood stimulated by collagen (2-10 µg/ml) ex vivo in newborn piglets receiving intravenous STS (0.1-10mg/kg, n=8) and in vitro in whole blood from newborn piglets (n=6) incubated with STS (0.1-100 µg/ml). The respective morphological changes of platelets were also examined by scanning electron microscopy. Plasma levels of nitrite/nitrate (NOx) and thromboxane B(2) (TxB(2)), matrix metalloproteinase (MMP)-2 and -9 activities were also examined. To further delineate the mechanistic pathway, the effect of STS on endothelial microparticles release from cultured human umbilical vein endothelial cells (HUVECs) was quantified by flow cytometry. RESULTS: STS impaired the ex vivo, but not in vitro, collagen-stimulated platelet aggregation. Infusion of STS elevated the plasma level of TxB(2) at 10mg/kg. However, STS had no effect on NOx level. Incubating cultured HUVECs with STS (1 and 10 µg/ml) caused a significant release of endothelial microparticles. Morphologically, STS elicited platelet activation in vivo, but not in vitro. CONCLUSIONS: STS impairs the ex vivo whole blood platelet aggregatory function by activating platelet in vivo in healthy newborn piglets. It implies that STS may elicit its effects by stimulating endothelial microparticles production and eicosanoid metabolism pathway.

Sodium tanshinone IIA sulfonate increased intestinal hemodynamics without systemic circulatory changes in healthy newborn piglets.

In traditional Chinese medicine, tanshinone IIA is a lipid-soluble component of Danshen that has been widely used for various cardiovascular and cerebrovascular disorders, including neonatal asphyxia. Despite promising effects, little is known regarding the hemodynamic effects of tanshinone IIA in newborn subjects. To examine the dose-response effects of sodium tanshinone IIA sulfonate (STS) on systemic and regional hemodynamics and oxygen transport, 12 newborn piglets were anesthetized and acutely instrumented for the placement of femoral arterial and venous, pulmonary arterial catheters to measure mean arterial, central venous, and pulmonary arterial pressures, respectively. The blood flow at the common carotid, renal, pulmonary, and superior mesenteric (SMA) arteries were continuously monitored after treating the piglets with either STS (0.1-30 mg/kg iv) or saline treatment (n = 6/group). To further delineate the underlying mechanisms for vasorelaxant effects of STS, in vitro vascular myography was carried out to compare its effect on rat mesenteric and carotid arteries (n = 4-5/group). STS dose-dependently increased the SMA blood flow and the corresponding oxygen delivery with no significant effect on systemic and pulmonary, carotid and renal hemodynamic parameters. In vitro studies also demonstrated that STS selectively dilated rat mesenteric but not carotid arteries. Vasodilation in mesenteric arteries was inhibited by apamin and TRAM-34 (calcium-activated potassium channel inhibitors) but not by meclofenamate (cyclooxygenase inhibitor) or N-nitro-l-arginine methyl ester hydrochloride (nitric oxide synthase inhibitor). In summary, without significant hemodynamic effects on newborn piglets, intravenous infusion of STS selectively increased mesenteric perfusion in a dose-dependent manner, possibly via an endothelium-derived hyperpolarizing factor vasodilating pathway.

Systemic and regional hemodynamic effects of high-dose epinephrine infusion in hypoxic piglets resuscitated with 100% oxygen.

Shock and poor regional perfusion are common in asphyxiated neonates. We compared the systemic and regional hemodynamic effects of high-dose epinephrine (E) with those of dopamine combined with low-dose epinephrine (DE) infusions in a neonatal model of hypoxia-reoxygenation. Neonatal piglets (1-3 days, 1.5-2.5 kg) were acutely instrumented to continuously monitor systemic arterial pressure (SAP), pulmonary artery pressure, cardiac index (CI), and blood flows at the left common carotid, superior mesenteric, and renal arteries. Either epinephrine (1 microg.kg(-1).min(-1)) or dopamine (10 microg.kg(-1).min(-1)) and epinephrine (0.2 microg.kg(-1).min(-1)) were given for 2 h in hypoxic piglets resuscitated with 100% oxygen (n = 8 per group) in a randomized blinded fashion. Control piglets received hypoxia and reoxygenation but no catecholamine infusion (n = 7). Alveolar hypoxia (PaO2, 33-37 mmHg) caused reduced CI (89-92 vs. 171-186 mL.kg(-1).min(-1) of baseline, P < 0.05), hypotension (SAP, 28-32 mmHg) with pH 7.05 to 7.10, and decreased regional flows. Upon reoxygenation, CI and SAP improved but gradually deteriorated to 131 to 136 mL.kg(-1).min(-1) and 41 to 49 mmHg at 2 h of reoxygenation, respectively. E and DE administration similarly improved CI (167 +/- 60 and 166 +/- 55 vs. 121 +/- 35 mL.kg(-1).min(-1) of controls) and SAP (53 +/- 7 and 56 +/- 10 vs. 39 +/- 8 mmHg of controls), respectively, and the pulmonary vascular resistance (vs. controls, all P < 0.05). Heart rate and pulmonary artery pressure were not different between groups. Systemic oxygen delivery and consumption were increased in E- and DE-treated groups with no difference in extraction ratio between groups. There were no differences in regional blood flows and oxygen delivery between groups. After hyperlactatemia with hypoxia, plasma lactate levels decreased with no difference between groups. Epinephrine given as the sole agent is as effective as dopamine and low-dose epinephrine combined in treating shock and hypotension that follow the resuscitation of hypoxic neonatal piglets, with no reduction in regional perfusion.

Ototoxic drugs and sensorineural hearing loss following severe neonatal respiratory failure.

AIM: To determine relationships between ototoxic drugs and 4-y sensorineural hearing loss (SNHL) in near-term and term survivors of severe neonatal respiratory failure. METHODS: All 81 survivors of the Canadian arm of the Neonatal Inhaled Nitric Oxide Study (mortality 32, loss to follow-up 9) received loop diuretics, aminoglycosides, and neuromuscular blockers (NMB), and 50 received vancomycin as neonates. Prospective, longitudinal secondary outcome using audiological tests diagnosed late-onset, progressive SNHL in 43 (53%); not flat (sloping) in 29, flat (severe to profound) in 14. Risk for SNHL was determined. RESULTS: A combination of duration of diuretic use of >14 d and average NMB dose of >0.96 mg/kg/d contributed to SNHL among survivors (odds ratio 5.2; 95% CI 1.6, 16.7). Markers of illness severity did not contribute. Dosage or duration of aminoglycosides use did not relate to SNHL. Cumulative dosages and duration of use of diuretics; NMB; use of vancomycin; and overlap of diuretics with NMB, aminoglycosides, and vancomycin individually linked to SNHL (p<0.001). CONCLUSION: Overuse of loop diuretics and/or NMB contributes to SNHL after neonatal respiratory failure; markers of illness severity or the appropriate administration of aminoglycosides do not.

A dose-response study of graded reoxygenation on the carotid haemodynamics, matrix metalloproteinase-2 activities and amino acid concentrations in the brain of asphyxiated newborn piglets.

PURPOSE: It is controversial to choose an appropriate oxygen concentration to resuscitate asphyxiated newborns regarding the clinical and biochemical oxidative effects. We examined the vasomotor response to reoxygenation with graded reoxygenation and the effects on matrix metalloproteinases and amino acids of the immature brain. METHODS: Thirty-two piglets (1-3 days, 1.5-2.1 kg) were instrumented for continuous monitoring of left common carotid and pulmonary arterial flows (Transonic). Piglets were randomized to a sham-operated control group (without hypoxia/reoxygenation) or 2 h hypoxia induced by decreasing the inspired oxygen concentration to 10-15%, followed by reoxygenation with 21, 50 or 100% oxygen for 1 h and then 21% oxygen for 3 h (n=8 each). The brains were then flash frozen and analyzed for matrix metalloproteinases and amino acid levels by zymography and HPLC, respectively. RESULTS: After 2 h oxygen deprivation, the absolute carotid flow remained similar but accounted for 38% of cardiac output (increased from 17% at baseline, p=0.001). During early reoxygenation, the flow rose in the piglets resuscitated with air (p<0.05), but not in those with supplemental oxygen. Carotid vascular resistance correlated significantly with the arterial partial pressure of oxygen (r=0.7). There was an oxygen-dependent increase in global cerebral activity of matrix metalloproteinase-2 with specific increases in the basal ganglia of all hypoxic-reoxygenated brains. There were no significant differences in glutamate and other amino acids in any brain regions. CONCLUSIONS: Although using high oxygen concentration to resuscitate asphyxiated newborn piglets increased carotid vascular resistance and cerebral matrix metalloproteinase-2 activity, there is no detrimental effect observed in this acute model of hypoxia-reoxygenation.