The effect of maternal and fetal β2-adrenoceptor and nitric oxide synthase genotype on vasopressor requirement and fetal acid-base status during spinal anesthesia for cesarean delivery.
The effect of maternal and fetal β2-adrenoceptor and nitric oxide synthase genotype on vasopressor requirement and fetal acid-base status during spinal anesthesia for cesarean delivery.
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DOI：
10.1213/ane.0b013e3182179424
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发表时间：
2011-06
影响因子：
5.7
通讯作者：
Ngan Kee WD
中科院分区：
文献类型：
--
作者：
Landau R;Liu SK;Blouin JL;Smiley RM;Ngan Kee WD
以前的研究表明，母体β2-肾上腺素受体基因（ADRB 2）的单倍型影响剖宫产时麻黄碱的需求。与纯α-肾上腺素能激动剂（如苯肾上腺素）相比，麻黄碱的使用与脐动脉（UA）pH值降低相关，被认为继发于胎儿代谢增加。尚无数据评价胎儿/新生儿基因型对母体给予血管加压药的代谢反应的影响。我们推测新生儿ADRB 2基因型会影响新生儿酸血症的程度。我们还研究了母体ADRB 2和内皮型一氧化氮合酶基因（NOS 3）对治疗母体低血压的麻黄碱和苯丙氨酸需求的影响。该研究对104名计划在脊髓麻醉下进行剖宫产的中国妇女进行，这些妇女参加了一项双盲随机临床试验，评价麻黄碱与苯丙氨酸输注对母体和新生儿的影响。分别从UA、脐静脉和母体桡动脉采血，测定血气值、乳酸、麻黄碱和苯丙氨酸浓度，并测定母体和新生儿ADRB 2基因第16（rs 1042713）和第27（rs 1042714）位非同义单核苷酸多态性和NOS基因第298（rs 1799983）位非同义单核苷酸多态性的基因型。比较不同基因型间的临床变量（UA pH、UA乳酸和血管加压药剂量），并建立回归模型以评估基因型对血管加压药剂量和胎儿酸碱状态的影响。母体ADRB 2基因型不影响麻黄碱剂量。新生儿16号密码子基因型影响胎儿酸碱状态。Arg 16纯合子新生儿的UA pH值较高p.16Arg/Arg为7.31 ± 0.03，p.16Arg/Gly和p.16Gly/Gly为7.25 ± 0.11; P < 0.001，95%C.I差异0.03 ~ 0.09），UA乳酸降低（p.16 Arg/Arg为2.67 mmol/L ± 0.99，p.16 Arg/Gly和p.16 Gly/Gly为4.28 mmol/L ± 2.79; p < 0.001，差异的95% C.I为−2.40 ~ −0.82）。在接受麻黄碱的母亲所生的新生儿中，基因型之间的差异程度甚至更大p.16Arg/Arg的pH7.30 ± 0.02，p.16Arg/Gly和p.16Gly/Gly的pH7.19 ± 0.10; P < 0.001，95%C.I差异0.07 ~ 0.14）和UA乳酸降低（p.16 Arg/Arg为3.66 mmol/L ± 1.30，p.16 Arg/Gly和p.16 Gly/Gly为5.79 mmol/L ± 2.88; p = 0.003，差异的95% C.I为−3.48 ~ −0.80）。在多元线性回归模型中（R2 = 63.6%; P = 0.03），新生儿ADRB 2基因型（p.16Arg/Arg和p.27Gln/Glu）和较低的新生儿出生体重预测较低的UA乳酸浓度。苯巴比妥剂量不受母体ADRB 2或NOS 3基因型的影响，新生儿NOS 3基因型不影响UA pH或UA乳酸。与之前在北美队列中的发现相反，在中国队列中，母体ADRB 2基因型并不影响择期剖宫产期间的麻黄碱需求。然而，我们的研究结果表明，新生儿ADRB 2 p.Arg16纯合性赋予发展中的精氨酸诱导的胎儿酸血症的保护作用。
Previous work demonstrated that maternal haplotypes of the β2-adrenoceptor gene (ADRB2) influence ephedrine requirements during cesarean delivery. The use of ephedrine versus a pure α-adrenergic agonist such as phenylephrine has been associated with lower umbilical artery (UA) pH, thought to be secondary to increased fetal metabolism. There are no data evaluating the effect of fetal/neonatal genotypes on the metabolic response to maternally administered vasopressors. We hypothesized that neonatal ADRB2 genotype would affect the extent of neonatal acidemia. We also examined the effect of maternal ADRB2 and the endothelial nitric oxide synthase gene (NOS3) on ephedrine and phenylephrine requirements for treatment of maternal hypotension. The study was performed on 104 Chinese women scheduled for cesarean delivery under spinal anesthesia who were participating in a double-blinded randomized clinical trial evaluating the maternal and neonatal effects of ephedrine versus phenylephrine infusions. Blood samples were drawn from the UA, umbilical vein and maternal radial artery to measure blood gas values, lactate, ephedrine and phenylephrine concentrations, and determine maternal and neonatal genotype at non-synonymous single nucleotide polymorphisms at codons 16 (rs1042713) and 27 (rs1042714) of ADRB2 and codon 298 (rs1799983) of NOS. Clinical variables (UA pH, UA lactate and dose of vasopressors) among genotypes were compared, and regression models were created to assess the effect of genotype on vasopressor dose and fetal acid-base status. Maternal ADRB2 genotype did not affect the ephedrine dose. Neonatal genotype at codon 16 influenced fetal acid-base status. UA pH was higher in Arg16 homozygous neonates (7.31 ± 0.03 in p.16Arg/Arg vs 7.25 ± 0.11 in p.16 Arg/Gly and p.16 Gly/Gly; p < 0.001, 95% C.I of difference 0.03 ~ 0.09) and UA lactate was lower (2.67 mmol/L ± 0.99 in p.16Arg/Arg vs 4.28 mmol/L ± 2.79 in p.16 Arg/Gly and p.16 Gly/Gly; p < 0.001, 95% C.I of difference −2.40 ~ −0.82). In neonates born to mothers receiving ephedrine, the magnitude of the difference among genotypes was even greater (pH 7.30 ± 0.02 in p.16Arg/Arg vs 7.19 ± 0.10 in p.16 Arg/Gly and p.16 Gly/Gly; p < 0.001, 95% C.I of difference 0.07 ~ 0.14) and UA lactate was lower (3.66 mmol/L ± 1.30 in p.16Arg/Arg vs 5.79 mmol/L ± 2.88 in p.16 Arg/Gly and p.16 Gly/Gly; p = 0.003, 95% C.I of difference −3.48 ~ −0.80). In a multiple linear regression model (R2 = 63.6%; P = 0.03), neonatal ADRB2 genotypes (p.16Arg/Arg and p.27Gln/Glu) and lower neonatal birth weight predicted lower UA lactate concentrations. Phenylephrine dose was not affected by maternal ADRB2 or NOS3 genotypes, and neonatal NOS3 genotype did not affect UA pH or UA lactate. In contrast to previous findings in a North American cohort, maternal ADRB2 genotype did not affect ephedrine requirements during elective cesarean delivery in a Chinese cohort. However, our findings suggest that neonatal ADRB2 p.Arg16 homozygosity confers a protective effect against developing ephedrine-induced fetal acidemia.