Effects of a nebulized NONOate, DPTA/NO, on group B streptococcus-induced pulmonary hypertension in newborn piglets

NONOates are chemical compounds that are stable as solids but generate nitric oxide (NO) in aqueous solutions. When nebulized or instilled intratracheally, NONOates can attenuate pulmonary hypertension in adult animals with lung injury. To assess the effect of a nebulized NONOate, DPTA/NO, on group B Streptococcus (GBS)-induced pulmonary hypertension in newborn piglets, we studied 20 anesthetized and mechanically ventilated piglets (4-10 d). They were randomly assigned to receive nebulized placebo solution or DPTA/NO (100 mg) 15 min after sustained pulmonary hypertension. Pulmonary artery and wedge, systemic, and right atrial pressures; cardiac output; and arterial blood gases were obtained at baseline and every 15 min during 120 min of continuous GBS infusion (6 x 10(8) CFU/min). Methemoglobin levels were measured at baseline and 60 min. A significant decrease in pulmonary artery pressure, pulmonary vascular resistance (PVR), systemic arterial pressure, and systemic vascular resistance (SVR) was observed after DPTA/NO nebulization (p <0.001). Whereas the increase in PVR/SVR observed after GBS infusion was sustained for 120 min in the placebo group, this ratio decreased after DPTA/NO nebulization and remained significantly lower throughout the study period (p <0.01). Cardiac output, arterial blood gases, and methemoglobin values did not differ between groups. These data demonstrate that the pulmonary hypertension induced by GBS infusion is markedly attenuated by DPTA/NO nebulization. The lower PVR/SVR observed in the treated group indicates that the vasodilatory effect of NONOate is more pronounced in the pulmonary than systemic vasculature. Therefore, NONOates may have clinical application in the management of pulmonary hypertension secondary to sepsis in neonates.     

雾化吸入NO供体对新生猪急性呼吸窘迫综合征炎症反应的干预作用

目的 探讨雾化吸入NO供体对急性呼吸窘迫综合征炎症反应的干预作用机制.方法 健康出生后3～5 d的新生绪45只随机分成5组,A组为对照组:气管插管,接呼吸机;B组为NS组:模型建立后,经呼吸机管道雾化吸入生理盐水30min;C组为模型建立后,经呼吸机管道雾化吸入Neb-SNP(1 mg/ml,0.9%NaCl配制)30 min;D组为模型建立后,经呼吸机管道雾化吸入Neb-SNP(5 mg/ml)30min;E组为模型建立后,,经呼吸机管道雾化吸入Neb-SNP(10mg/ml)30min.各组分30、60、120 min3个时间点各3只测定肺组织核因子(NF)-κB的表达及血清细胞因子TNF-α、IL-12、IL-10的浓度.结果 治疗组肺组织NF-κB表达显著降低(P＜0.05),血清TNF-α、IL-12浓度显著降低(P＜0.05),IL-10浓度明显增高(P＜0.05);Neb-SNP雾化浓度增加,NF-κB表达下降,炎症因子TNF-α、IL-12浓度下降,IL-10浓度升高[C组与D组差异有显著性(P＜0.05),D组与E组差异无显著性(P＞0.05)].结论 Neb-SNP通过下调NF-κB的活性,抑制炎症因子的表达从而减轻急性呼吸窘迫综合征的肺损伤.

Abstract：

Objective To investigate modulatory effects of Neb-SNP on inflammatory response and to explore the protection mechanisms of Neb-SNP in newborn piglets with ARDS. Methods Forty-five neonatal swines were randomly divided into five groups:group A (controlled group ,n = 9), group B (physiological saline group,n =9),group C (Neb-SNP 1 mg/ml,0. 9% NaCl, n = 9), group D (Neb-SNP 5 mg/ml,0. 9% NaCl, n = 9) and group E (Neb-SNP 10 mg/ml,0. 9% NaCl, n = 9). The pathological changes and activity of NF-κB in the lung tissue ,TNF-α ,IL-10 and IL-12 concentrations in serum at 30 minutes,60 minutes and 120 minutes after aerosol inhalation were observed. Results Activity of NF-κB and serum concentrations of TNF-α and IL-12 in the Neb-SNP treated group were lower than group B(P ＜0. 05) ,and serum IL-l0 concentration was obviously higher in the Neb-SNP group(P ＜0. 05). With an increase of Neb-SNP concentration,activity of NF-κB and serum concentrations of TNF-α and IL-12 were obviously increased, while serum concentrations of IL-10 was increased in group D and group E than that of group C (P ＜ 0. 05).Conclusion Inhalation of Neb-SNP reduced lung injury induced ARDS through lowering NF-κB activity and inhibiting expression of harmful inflammatory cytokines.     

尼莫地平对新生猪缺氧缺血性脑损伤的防治作用

为探讨莫尼地平对新生儿缺氧缺血性脑病的防治作用，将８６只新生猪分为正常对照组，缺氧缺血性脑损伤（ＨＩＥ）１小时（１ｈｒ）、２４ｈｒ、７２ｈｒ组，尼莫地平０．５μｇｋｇ－１ｍｉｎ－１治疗后１ｈｒ、２４ｈｒ、７２ｈｒ组，尼莫地平１μｇｋｇ－１ｍｉｎ－１治疗后１ｈｒ、２４ｈｒ、７２ｈｒ组。检测各组红细胞胞浆总钙（ＲＢＣＴＣａ）及游离钙（ＲＢＣＣａ２＋ｉ）的浓度变化。结果：ＨＩＥ１ｈｒ组ＲＢＣＴＣａ和Ｃａ２＋ｉ均明显高于正常组对照（Ｐ＜０．０１），随着缺氧缺血状态的改善，ＲＢＣＴＣａ和Ｃａ２＋ｉ含量逐渐下降，ＨＩＥ７２ｈｒ组接近正常对照组（Ｐ＞０．０５）。两种剂量尼莫地平各治疗组ＲＢＣＴＣａ和Ｃａ２＋ｉ均明显低于ＨＩＥ１ｈｒ和２４ｈｒ组（Ｐ＜０．０１），与正常对照组比较，差异无显著意义（Ｐ＞０．０５）。提示：窒息后细胞内钙的沉积与新生猪ＨＩＥ的发生有关，尼莫地平能阻止Ｃａ２＋内流，有效地保护神经细胞。     

肺动脉高压治疗的一种新途径--雾化吸入一氧化氮供体有效性的研究进展

一氧化氮(nitric oxide,N0)是血管内皮细胞释放的内皮依赖性的舒张因子(endothelium—derived relaxing factor EDRF)。NO具有极其广泛的生理作用,而它通过增加血管平滑肌细胞内eGMP的浓度扩张肺血管作用最为重要。这一研究的发现使得近十年来肺动脉高压(pulmonary hypertension,PH)的治疗领域取得了惊人的进步,即证实了     

雾化吸入硝酸甘油对高肺血流量大鼠肺动脉压力及肺动脉胶原代谢影响的研究

目的 探讨雾化吸入硝酸甘油对高肺血流大鼠肺动脉压力、肺动脉结构及肺动脉胶原代谢的影响。方法 24只健康雄性Wistar大鼠随机分为对照组(n＝11)、分流组(n＝6)和吸入组(n＝7)。对分流组和吸入组大鼠开腹行腹主动脉—下腔静脉分流术。12周后分流组和吸入组大鼠分别雾化吸入生理盐水和硝酸甘油3周。以右心导管测定肺动脉压，颈动脉插管测定体循环压，检测右心室肥厚，用图像分析与处理系统观测肺血管结构变化，用免疫组织化学法检测大鼠肺动脉平滑肌细胞胶原蛋白Ⅰ(collagen Ⅰ)及胶原蛋白Ⅲ(collagen Ⅲ)的表达。结果 分流组大鼠肺动脉平均压(PAMP)、右心室体重(RV/BW)和右心室／左心室 空间隔(RV／LV S)明显高于对照组(P＜0．01)，且分流组大鼠中、小型肺肌型动脉相对中膜面积及厚度增加，肺动脉平滑肌细胞collagen Ⅰ、Ⅲ蛋白表达增加。吸入组大鼠mSBP未受影响，PAMP明显低于分流组(P＜0.01)，RV/BW和RV／(LV S)与分流组比较无显著差异(P＞0．05)，吸入组大鼠肺血管重建缓解，collagenⅠ、Ⅲ蛋白表达成少。结论 长期雾化吸入硝酸甘油可缓解高肺血流量所致肺动脉高压和肺血管结构重建。     

The effect of methylprednisolone on hypoxic pulmonary vasoconstriction in the newborn late-gestation lamb

Methylprednisolone (30 mg/kg), which inhibits a number of mediators of hypoxic pulmonary vasoconstriction derived from arachidonic acid, has been found to alleviate hypoxic pulmonary vasoconstriction in adult humans and in the isolated rat lung preparation. We studied the effect of 30 mg/kg of methylprednisolone on the pulmonary vascular response to hypoxia in six late-gestation newborn lambs. During hypoxia, pulmonary vascular resistance nearly doubled compared with the baseline hyperoxic state. This was true both before and after administration of methylprednisolone. We conclude that methylprednisolone, when administered at the dosage used in previous studies of adult humans and animals, does not affect the response of the pulmonary vascular bed to hypoxia in newborn lambs.     

The effect of calcium antagonists on hypoxic pulmonary hypertension in the piglet

Cardiovascular responses to the calcium antagonists verapamil and nifedipine were evaluated in a piglet model of hypoxic pulmonary hypertension. All animals were mechanically ventilated and paralyzed. Cardiac output (CO), pulmonary artery (Ppa) and aortic blood pressure (AoP), pulmonary wedge pressure, right atrial pressure (Pra), and arterial blood gases were measured prior to and after pulmonary hypertension was induced by hypoxia and after administration of calcium-blocking agents. Results were compared to a control group of piglets subjected to a similar period of hypoxia. Verapamil infusion (0.15 mg/kg) resulted in a rapid decrease in Ppa, AoP and pulmonary vascular resistance (p less than 0.05) which returned to baseline values by 15 min. Nifedipine (100 micrograms/kg) resulted in a decrease in Ppa at 1 min (p less than 0.05) which remained significantly lower than controls throughout the study period. AoP declined precipitously during the same time period (p less than 0.01). No significant change in Ppa was noted when nifedipine was administered at a dose of 10 micrograms/kg. For the most part, these drugs have a transient vasodilatory action on pulmonary as well as systemic circulation in this animal model; however, they might in higher doses be associated with significant systemic hypotension. For this reason, the use of these drugs in the treatment of hypoxic pulmonary hypertension in the neonate should be approached with caution.     

Sildenafil reverses hypoxic pulmonary hypertension in highland and lowland newborn sheep

Perinatal exposure to chronic hypoxia induces sustained hypertension and structural and functional changes in the pulmonary vascular bed. We hypothesized that highland newborn lambs (HLNB, 3600 m) have a higher pulmonary arterial pressure (PAP) due in part to a higher activity/expression of phosphodiesterase 5 (PDE5). We administered sildenafil, a PDE5 inhibitor, during basal and hypoxic conditions in the pulmonary hypertensive HLNB and compared them to lowland newborn lambs (LLNB, 580 m). Additionally, we compared the vasodilator responses to sildenafil in isolated small pulmonary arteries and the PDE5 mRNA expression and evaluated the vascular remodeling by histomorphometric analysis in these newborn lambs. Under basal conditions, HLNB had a higher PAP and cardiac output compared with LLNB. Sildenafil decreased the PAP during basal conditions and completely prevented the PAP increase during hypoxia in both groups. HLNB showed a greater contractile capacity and a higher maximal dilation to sildenafil. PDE5 mRNA expression did not show significant differences between HLNB and LLNB. The distal pulmonary arteries showed an increased wall thickness in HLNB. Our results showed that HLNB are more sensitive to sildenafil and therefore could be useful for treatment of pulmonary hypertension in high-altitude neonates.     

新型气体信号分子硫化氢对低氧性肺动脉高压和肺血管结构重建的调节作用

慢性低氧性肺动脉高压(HPH)是临床上许多心肺疾病发生发展过程中伴随或最终的病理生理环节，但其发病机制还不清楚。近几年人们已发现一些小气体分子如一氧化氮(NO)、一氧化碳(CO)在调节HPH中具有重要作用。最近的研究发现，小气体分子H2S也具有与NO和CO相似的作用，但对HPH调节作用的机制不清。本实验通过大鼠低氧模型和其免疫组织化学方法，首次探讨H2S对肺动脉高压与肺血管结构重建的调节作用。     

硫酸镁治疗缺氧小猪肺动脉高压的实验研究

为探讨硫酸镁治疗新生儿持续肺动脉高压 (PPHN)的疗效 ,以12只实验小猪吸入低浓度氧气造成缺氧性肺动脉高压模型模拟PPHN。通过颈外静脉插入心导管 ,进入肺动脉检测肺动脉压力 (PAP)和心输出量等 ,通过股动脉插管检测体循环血压 ,同时检测心率、血氧饱和度 (SaO2)、血气分析和血镁浓度。结果显示 ,实验小猪缺氧10分钟后肺动脉收缩压 (SPAP)升高53.5%±25.4% (P<0.001) ,舒张压 (DPAP)和平均肺动脉压 (MPAP)分别升高57.1%±31.0%和50.6%±27.8% (P<0.001) ;静脉滴注硫酸镁后SPAS下降24.1 %±5.0 % (P<0.001) ,DPAP和MPAP分别下降22.7 %±7.2 %和19.8%±6.4% (P<0.001)。SaO2 和血氧分压均有升高。体循环血压也有下降 ,但下降幅度较小且与剂量有关。心率有轻度降低 ,心输出量无改变。血镁浓度明显升高 ,从0.79±0.14mmol/L升高至2.74±0.96mmol/L(P<0.001)。提示硫酸镁能显著降低肺动脉高压 ,改善血氧分压 ,对体循环血压、心率及心输出量影响较小 ,而且价格便宜 ,使用方便 ,值得在PPHN治疗中提倡。     

The role of endothelin converting enzyme inhibition during group B streptococcus-induced pulmonary hypertension in newborn piglets

An endothelin-converting enzyme mediates the conversion from low-potency pro-endothelin to potent endothelin-1 (ET-1). Increased ET-1 levels have been observed in pulmonary hypertension of various etiologies in infants. We hypothesized that increased ET-1 levels induce pulmonary hypertension during group B Streptococcus (GBS) infusion, and this can be attenuated by the administration of an endothelin-converting enzyme inhibitor (ECEI). Twenty-two unanesthetized, chronically instrumented newborn piglets received a continuous infusion of GBS (3.5 x 10(8) colony-forming units/kg/min) while exposed to 100% O2. They were randomly assigned to receive a placebo (PL) or an ECEI (phosphoramidon, 30 mg/kg i.v.) 15 min after sustained pulmonary hypertension. Comparison of hemodynamic measurements and arterial blood gases at baseline and over the first 210 min from the onset of pulmonary hypertension was performed between groups. GBS infusion caused significant increases in mean pulmonary artery pressure, pulmonary vascular resistance (PVR), systemic vascular resistance (SVR), and PVR/SVR, and significant decreases in cardiac output, pH, and base excess. After the administration of ECEI, a significant reduction in pulmonary artery pressure (p < 0.0001), PVR (p < 0.001), and PVR/SVR (p < 0.01) and an improvement in cardiac output (p < 0.01) were observed during GBS infusion. The decrease in pH (p < 0.001) and base excess (p < 0.001) during GBS infusion was less marked after the administration of ECEI compared with the PL. Plasma ET-1 levels were obtained in 20 additional piglets; levels were significantly lower in the ECEI compared with PL after 3 h of GBS infusion (p < 0.02). All animals in the ECEI group survived the study period as opposed to 25% survival in the PL group (p < 0.001). These data suggest that the increased circulating ET-1 levels mediate, in part, the GBS-induced pulmonary hypertension.     

Effect of pentoxifylline on cytokine- and eicosanoid-induced acute pulmonary hypertension in piglets.

The methylxanthine derivative pentoxifylline (PTF) demonstrates vasodilatory properties in vivo. We tested the hypothesis that PTF infusion would blunt or inhibit tumor necrosis factor-alpha (TNF alpha)-induced and U46,619-induced increases in mean pulmonary artery pressure and pulmonary vascular resistance (PVR) in the neonatal piglet and would do so by altering production of eicosanoid vasoactive mediators. Anesthetized, paralyzed piglets (age 10-29 d) were randomized and treated with a 30-min infusion of TNF alpha alone (n = 13 animals), with a combination of TNF alpha plus pretreatment and continuous infusion with PTF (n = 6), or with a combination of U46,619 for 30 min plus pretreatment and continuous infusion of PTF (n = 5). There was no difference in pulmonary or systemic hemodynamic indices between the three groups at baseline. PVR was significantly elevated at 15 min and at 2 h in the TNF alpha-only group. The TNF alpha-induced rise in mean pulmonary artery pressure and PVR was inhibited by the PTF until 2 h, by which time PVR was elevated above baseline and was comparable to the value found in animals treated with only TNF alpha. PTF produced no inhibition in the U46,619-induced elevation of PVR during the 30-min simultaneous treatment. In the PTF + TNF alpha group, mean systemic blood pressure declined to 50% of baseline value (p less than 0.02) by 2 h of age. No significant decline was noted in mean systemic arterial pressure of the TNF alpha-only or the U46,619-treated group.(ABSTRACT TRUNCATED AT 250 WORDS)     

吸入一氧化氮逆转幼猪急性缺氧性肺动脉高压

目的 观察吸入不同浓度一氧化氮（ＮＯ）是否可逆转幼猪急性缺氧性肺动脉高压。方法 选用１０头上海种白猪。利用低氧建立急性缺氧性肺动脉高压模型。吸入不同浓度ＮＯ（０,１０,２０,４０,８０,１２０ｐｐｍ）。在各时相分别进行血液动力学指标、二氧化氮和高铁血红蛋白浓度监测。结果 吸入不同浓度ＮＯ可明显降低肺动脉平均压（ＭＰＡＰ）、肺循环阻力指数（ＰＶＲＩ）、跨肺压（ＴＰＧ）、体肺动脉压之比（Ｐｐ／Ｐｓ）、     

持续肺动脉高压新生猪肺组织血管活性因子的变化及硫酸镁对其的影响

胎粪吸入综合征 (ＭＡＳ)诱导的持续肺动脉高压 (ＰＰＨ)的机制复杂 ,目前仍未完全阐明 ,除缺氧酸中毒 ,还有众多因素参与。本研究通过重症ＭＡＳ模型探讨胎粪诱导的ＰＰＨ猪肺组织内皮素 1(ＥＴ 1)、血管紧张素转换酶 (ＡＣＥ)、诱生性一氧化氮合酶 (ｉＮＯＳ)的变化及硫酸镁 (ＭｇＳＯ4 )对其的影响。材料和方法1.实验动物 :将 1～ 6日龄的健康新生猪随机分成对照组 (ｎ =5 )、ＭＡＳ组 (ｎ =6)和ＭＡＳ +ＭｇＳＯ4 组 (ｎ =7) ,三组动物日龄、体重差异无显著性 (Ｐ >0 .0 5 )。2 .主要试剂 :抗人 /猪ＥＴ 1鼠单克隆抗体 ,抗猪ＡＣＥ鼠单…     

Prostaglandin E1 selectively reduces group B beta-hemolytic streptococci-induced pulmonary hypertension in newborn piglets

Group B beta-hemolytic streptococci (GBS)-induced pulmonary hypertension was generated in ten newborn piglets. Intravenous infusions of either prostaglandin E1 (PGE1) (n = 5) or placebo (n = 5) were begun after 60 minutes of stable pulmonary hypertension. The effects of these interventions on cardiopulmonary hemodynamics were studied. Pulmonary artery pressure (PAP) increased similarly in both groups during the first 60 minutes of GBS infusion. By two hours after intervention, PAP was significantly lower in the animals given PGE1 (20 +/- 4 vs 32 +/- 5 mm Hg for PGE1 vs placebo). The ratio of pulmonary to systemic vascular resistance followed a pattern analogous to PAP, increasing with the GBS infusion, indicating selective pulmonary vasoconstriction. The pulmonary vascular resistance/systemic vascular resistance ratio decreased after intervention in the group given PGE1 only (0.25 +/- 0.08 vs 0.50 +/- 0.12 for PGE1 vs placebo), indicating selective pulmonary vasodilation. Transient systemic hypotension was noted at one hour after initiation of PGE1 infusion. Prostaglandin E1 infusion selectively improved GBS-induced pulmonary hypertension and hypoxemia in newborn piglets with only transient systemic hypotension.     

内源性一氧化碳对缺氧性肺动脉高压与肺血管结构调节的研究

目的 研究内源性一氧化碳（CO）对缺氧性肺动脉高压（PH）和肺血管结构的调节作用。方法 将18只Wistar大鼠随机分为对照组、低氧组、低氧＋ZnPP组。均以右心导管法测定肺动脉压力；对肺组织进行弹力纤维染色，测定肌型动脉百分比，以及肺中、小动脉的相对中膜面积（RMA）、厚度（RMT）；采用免疫组织化学法检测Ⅰ、Ⅲ型胶原蛋白的表达，核酸原位杂交法检测肺动脉Ⅲ型前胶原[Pro－α1（Ⅲ）胶原]mRNA表达。结果 鼠肌型动脉百分比和肺中、小型动脉RNA及PTM均明显增高；ZnPP促使低氧上述肺血管结构重建指标增高更加显著（P均＜0．01）。低氧大鼠肺动脉Ⅰ、Ⅲ型胶原蛋白及Pro－α1（Ⅲ）胶原mRNA表达均显著增高，ZnPP促使低氧大鼠动脉Ⅰ、Ⅲ型胶原蛋白及Pro－α1（Ⅲ）胶原mRNA表达更加明显（P均＜0．01）。结论 内源性CO在缺氧性PH和肺血管结构重建形成中发挥着重要的保护作用，其机制至少部分与CO对低氧大鼠肺动脉胶原蛋白合成的调节有关。     

长期雾化吸入硝酸甘油对高肺血流大鼠肺动脉压力及肺血管结构重建的影响

目的探讨长期雾化吸入硝酸甘油对高肺血流大鼠肺动脉压力、肺血管结构的作用及其机制。方法24只健康雄性Wistar大鼠随机分为对照组、分流组和吸入组。对分流组和吸入组大鼠开腹行腹主动脉-下腔静脉分流术,12周后两组大鼠分别雾化吸入生理盐水和硝酸甘油3周。以右心导管法测定肺动脉压,颈动脉插管测定体循环压,检测右心室肥厚,观测肺血管显微及超微结构变化,用免疫组织化学法检测大鼠肺动脉人类尾加压素Ⅱ(hUⅡ)的表达。结果分流组大鼠肺动脉平均压(PAMP)和右心室/左心室 室间隔重量比值(RV/LV S)明显高于对照组(P<0.01),且分流组大鼠肺小血管肌化程度明显增强(P<0.01),中、小型肺肌型动脉相对厚度(RMT)增加,肺动脉内皮细胞和平滑肌细胞hUⅡ表达明显增强。吸入组大鼠mSBP未受影响,PAMP明显低于分流组(P<0.01),RV/(LV S)高于对照组(P<0.01),但与分流组比较差异无显著性(P>0.01),吸入组大鼠肺小血管肌化程度明显改善,小型肺肌型动脉RMT及小型肺动脉内皮细胞和平滑肌细胞hUⅡ减少。结论长期雾化吸入硝酸甘油可缓解高肺血流量所致肺动脉高压和肺血管结构的重建,其对肺动脉内皮细胞和平滑肌细胞hUⅡ表达的抑制作用,可能参与高肺血流量所致肺血管结构重建和肺动脉高压的调节。     

Usefulness of a new Doppler index for assessing both ventricular functions and pulmonary circulation in newborn piglet with hypoxic pulmonary hypertension

Persistent pulmonary hypertension of the newborn is a clinical syndrome associated with a variety of cardiopulmonary diseases. Serial evaluation of pulmonary circulation and cardiac function is important, but available imaging techniques have been limited. A new Doppler index combining systolic and diastolic time intervals (the Tei index, which is a simple and noninvasive measurement) has been reported to be useful for the assessment of global cardiac function in adults and children. The purpose of this study was to test the effectiveness of the Tei index in prospectively assessing ventricular function and pulmonary circulation in a newborn piglet model with hypoxic pulmonary hypertension. One-day-old piglets (1.1-1.6 kg) were intubated and prepared for the experiments under room air and hypoxia. A complete two-dimensional Doppler echocardiographic examination was performed. Common hemodynamic variables were measured continuously throughout the study. The right ventricle (RV) Tei index under hypoxia (fraction of inspired oxygen = 0.10) was significantly higher than the value under air ventilation (medians, 0.38 versus 0.56; p < 0.05). Moreover, there was a significant correlation between RV Tei index and mean pulmonary artery pressure and positive linear correlation between individual changes in RV Tei index and changes in mPAP (r2 = 0.799, p < 0.05). We conclude that the Tei index is useful for assessing the function of the RV and the left ventricle and pulmonary circulation in a newborn piglet model with hypoxic pulmonary hypertension. These results suggest that the Tei index will become an objective method of assessing patients with persistent pulmonary hypertension of the newborn.     

Resuscitation of hypoxic newborn piglets with oxygen induces a dose-dependent increase in markers of oxidation

Newborn resuscitation with pure oxygen may be associated with long-term detrimental effects. Due to the change in attitude toward use of less oxygen upon resuscitation, there is a need to study effects of intermediate hyperoxia. The aim was to study dose-response correlation between inspiratory fraction of oxygen used for resuscitation and urinary markers of oxidative damage to DNA and amino acids. Hypoxemia was induced in newborn piglets following a standardized model; they were resuscitated for 15 min with either 21%, 40%, 60% or 100% oxygen and observed for 1 h. Urine samples were collected. Urinary elimination of 8-hydroxy-2'-deoxyguanosine (8-oxo-dG), 2'deoxyguanosine (2dG), ortho-tyrosine (o-Tyr) and phenylalanine (Phe) were determined by HPLC and tandem mass spectrometry (HPLC-MS/MS). Quotient of 8-oxo-dG/2dG and o-Tyr/Phe ratios were significantly and dose-dependant higher in piglets resuscitated with supplementary oxygen. 8-oxodG/dG: Mean (SD) 5.76 (1.81) versus 22.44 (12.55) p < 0.01 and o-Tyr/Phe: 19.07 (10.7) versus 148.7 (59.8)for 21% versus 100%, p < 0.001. Hypoxia and subsequent resuscitation for 15 min with graded inspiratory fraction of oxygen causes increased oxidative stress and a dose-dependant oxidation of DNA and Phenylalanine. The increase in the hydroxyl attack may lead to a pro-oxidative status and risk for genetic instability.     

Effects of magnesium sulphate and nitric oxide in pulmonary hypertension induced by hypoxia in newborn piglets.

AIM--To examine the haemodynamic effects of intravenous magnesium sulphate on an animal model of neonatal pulmonary hypertension induced by hypoxia. METHODS--The cardiac index (Q), pulmonary arterial pressure (PAP), systemic arterial pressure (SAP), and pulmonary (PVRI) and systemic (SVRI) vascular resistance indices were measured in nine newborn piglets (including three controls). Pulmonary hypertension was induced by lowering the FIO2 to 0.12-0.14, after which there was a significant increase in PAP and PVRI (37% and 142%, respectively; p < 0.01) and a significant fall in SAP and Q (30% and 33%, respectively; p < 0.01). RESULTS--Magnesium sulphate was infused intravenously as four doses of 25 mg/kg, 15 minutes apart, which resulted in a significant mean (SD) increase in serum magnesium (0.83 (0.07) mmol/l to 1.82 (0.19) mmol/l; p < 0.01). After the initial dose SAP, SVRI, PAP and PVRI decreased, but not significantly. Each subsequent dose of (50, 75, 100 mg/kg) was accompanied by further significant reductions in these variables from control baseline (p < 0.05). The PVRI:SVRI ratio remained unchanged throughout. Inhaled nitric oxide (NO) 40 ppm was administered after the last dose of magnesium sulphate. The PVRI:SVRI significantly decreased (p < 0.05), indicating that reversible pulmonary hypertension remained after a maximum dose of magnesium sulphate. CONCLUSIONS--Unlike NO, magnesium sulphate is not a selective pulmonary vasodilator and may lead to deleterious effects on systemic pressures in critically ill newborns.