Simultaneous determination of remifentanil, etomidate, and rocuronium in serum microsamples from maternal or umbilical blood

Simultaneous determination of remifentanil, etomidate, and rocuronium in serum microsamples from maternal or umbilical blood | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Simultaneous determination of remifentanil, etomidate, and rocuronium in serum microsamples from maternal or umbilical blood Hao Liu, Meng Cai, Yong Peng, Jing-kun Miao, Jin Yu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4442620/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 16 Jul, 2025 Read the published version in Scientific Reports → Version 1 posted 12 You are reading this latest preprint version Abstract Purpose This study aimed to establish and validate an analytical method to accurately determine the anesthetics remifentanil, etomidate, and rocuronium simultaneously in extremely small volumes of serum from maternal or umbilical blood. Methods A microsample of serum (10 µl) was diluted up to 50 µl with pure water, then total protein was precipitated using acetonitrile, and the three anesthetics were determined using liquid chromatography-tandem mass spectrometry within 4 min. Mass spectrometry was performed with positive electrospray ionization in multiple reaction monitoring mode. The analytical method was characterized in terms of linearity, lower limit of quantification, accuracy, precision, and carry-over effects. The method was validated on samples from 20 pairs of newborns and their mothers. Results For all three anesthetics, the analytical method showed linearity (R² > 0.99), inter- and intra-day imprecision < 15% and carry-over < 5%. The lower limits of quantitation were 0.15 ± 0.02 ng/ml for remifentanil, 16.87 ± 0.51 ng/ml for etomidate, and 106.73 ± 8.63 ng/ml for rocuronium. Respective mean concentrations of each anesthetic in serum from maternal arteries, umbilical veins and umbilical arteries were as follows: remifentanil, 4.75 ± 0.19, 2.43 ± 0.13, and 1.33 ± 0.15 ng/ml; etomidate, 412.71 ± 35.29, 302.15 ± 29.03, and 166.24 ± 21.53 ng/ml; and rocuronium, 7.08 ± 0.48, 0.86 ± 0.16, and 0.44 ± 0.77 µg/ml. Respective rates of transport into placenta for the three anesthetics were 0.52 ± 0.02, 0.75 ± 0.04, and 0.13 ± 0.02 (all P < 0.001). Conclusion Our analytical method can accurately and reliably determine remifentanil, etomidate, and rocuronium simultaneously in microvolumes of maternal and umbilical serum, making it suitable for pharmacokinetic studies. Biological sciences/Drug discovery/Medicinal chemistry Biological sciences/Drug discovery/Pharmacology Biological sciences/Drug discovery Biological sciences/Biological techniques Biological sciences/Biological techniques/Analytical biochemistry Biological sciences/Biological techniques/Mass spectrometry Anesthetics caesarean section LC-MS/MS newborn Figures Figure 1 Introduction Recently, induction of anesthesia using propofol, rocuronium, and remifentanil are becoming popular [ 1 ] . Compared with propofol, etomidate has minimal impact to hemodynamics with low fluctuation of blood pressure and cardiac rhythm [ 2 ] . Therefore, the three anesthetics remifentanil, etomidate, and rocuronium are another choice for cesarean section, especially for pregnant women who have cardiovascular problems [ 3 – 5 ] .The three drugs operate through complementary mechanisms: remifentanil is an opioid analgesic; etomidate, a general anesthetic; and rocuronium, a muscle relaxant. Remifentanil is the preferred opioid analgesic for this situation: although it easily passes through the placental barrier, it is hydrolyzed in cord blood and rapidly metabolized in the fetus, and it is less likely to cause respiratory depression [ 6 ] . Etomidate and rocuronium are assumed to present minimal risk to fetal breathing because they are both administered at single dose [ 7 – 8 ] . However, the effect of the triple combination on fetal respiration has not been systematically analyzed, nor are the pharmacokinetics of the drugs in the mother and newborn well understood, which means their long-term safety is unclear. Pharmacokinetic and safety studies require appropriate analytical methods for determining all three anesthetics in blood, yet published methodsࣧwhether based on high-performance liquid chromatography or liquid chromatography-tandem mass spectrometryࣧrequire large sample volumes and time- or labor-intensive procedures and have been validated for only one or two of the three drugs [ 3 – 4 ] . Therefore we undertook the present study to develop and validate a single analytical method that could accurately determine all three anesthetics in extremely small volumes of serum from maternal and umbilical blood. Materials and methods Reagents HPLC-grade methanol and acetonitrile were purchased from Fisher Scientific (Geel, Belgium), and formic acid was purchased from Shanghai Aladdin Bio-Chem Technology (Shanghai, China). The following six narcotics were purchased from Toronto Research Chemicals (Toronto, Canada): remifentanil hydrochloride, sufentanil citrate, etomidate, metomidate hydrochloride, rocuronium bromide, and vecuronium bromide. Water in this study was purified using a Milli-Q apparatus (Millipore, Bedford, MA, USA). Calibration standards, internal standards, and quality control samples Stock solutions of remifentanil, etomidate, and rocuronium were prepared individually by dissolving solid compound into methanol to a concentration of 1 mg/ml, then vortexing at 1500 rpm for 5 min. The solutions were stored in brown vials at -80 ℃ and used within 12 months. These stock solutions were combined and suitably diluted into serum from pregnant women unexposed to the three anesthetics to yield final concentrations of 10 ng/ml remifentanil, 20000 ng/ml etomidate and 2000 ng/ml rocuronium. This working solution was stored in brown vials at -20 °C and used within one month. Stock solutions of the three internal standards sufentanil, metomidate and vecuronium were prepared individually by dissolving solid compound into acetonitrile to a concentration of 1 mg/ml, then vortexing at 1500 rpm for 5 min. These stock solutions were combined and suitably diluted into acetonitrile to yield final concentrations of 5 ng/ml sufentanil, 5 ng/ml metomidate, and 100 ng/ml vecuronium. This working solution was stored at -20 °C in brown vials and used within one month. Working solutions were diluted serially 1:2 in serum from pregnant women unexposed to the three anesthetics in order to determine calibration curves. Quality control samples were prepared by diluting working solutions into serum from unexposed pregnant women as follows: remifentanil, 0.5, 2.0 and 4.0 ng/ml; etomidate, 125.0, 500.0 and 1000.0 ng/ml; and rocuronium, 1000.00, 4000.00 and 8000.00 ng/ml. Sample collection and preparation With approval from the Ethics Committee of the Chongqing Health Center for Women and Children (2021-011) and informed consent from the women, we sampled maternal and umbilical blood from 20 women giving birth by cesarean section at our hospital. The blood from pregnant women who were not yet exposed to anesthetics was also abtained during establishing venous access. All women received anesthesia according to standard protocols at our hospital. Anesthesia was induced through target-controlled infusion of remifentanil at 5 ng/ml, inhalation of 5% sevoflurane, and intravenous injection of etomidate at 0.25 mg/kg. Sevoflurane was administered briefly and discontinued when the eyelash reflex disappeared. After umbilical cord ligation, rocuronium bromide was intravenously injected at 0.6 mg/kg. Anesthesia was maintained through target-controlled infusion of propofol at 3.5 µg/ml and of remifentanil at 5 ng/ml. All experiments were performed in accordance with relevant guidelines and regulations. Immediately after ligation of the umbilical cord, blood was collected from the left radial artery of the mother as well as from the umbilical vein and artery. The blood was centrifuged at 3000 rpm, and the serum was transferred to vials and stored at -80 °C until analysis. Frozen samples were thawed at room temperature for about 20 min, and 10-µl volumes of the thawed samples, quality control solutions and standards were placed into fresh microcentrifuge tubes, diluted up to 50 µl with pure water and vortexed at 1500 rpm for 3 min. Then 150 µl of acetonitrile containing internal standards was added to the vials, the solution was mixed and incubated at -20 °C for 20 min to precipitate proteins, and the solution was centrifuged at 13,000 g for 5 min at 4 °C. The supernatant (100 µl) was transferred into fresh microcentrifuge tubes. An aliquot of supernatant (10 µl) was diluted with water (90 µl) to ensure accurate determination, and an aliquot of the dilution (3 µl) was injected into the liquid chromatography system for analysis as described below. Liquid chromatography-tandem mass spectrometry Samples were analyzed on an ultra-high performance liquid chromatography-tandem mass spectrometry system (Xevo TQ-S, Waters Corporation, Milford, MA, USA) equipped with an electrospray ionization source operating in positive mode. Samples were fractionated on a reverse-phase Acquity BEH C18 column (50 × 2.1 mm, 1.7 µm; Waters Corporation) under the following gradient of 0.1% (v/v) formic acid in water (solution A) and a 1:1 (v/v) mixture of methanol and acetonitrile in solution A (solution B): 0 to 0.6 min, 10% B; 0.6–2.8 min, 10–90% B; 2.8–3.6 min, 90% B; and 3.6-4 min, 10% B. The flow rate was 0.4 ml/min and column temperature was 45 °C. Eluted compounds were analyzed in multiple reaction monitoring mode based on time-scheduled events with analyte-dependent parameters (Table 1 ) and the following additional parameters: ion source temperature, 150 °C; capillary voltage, 3.0 kV; desolvation temperature, 500 °C; gas flow rate for desolvation, 800 L/h; and gas flow rate in the cone, 150 L/h. Data were processed and quantified in MassLynx 4.2 software (Waters Corporation) based on the peak area and calibration with the internal standards. Amounts were quantified based on peak areas according to the internal standard method. Validation of the analytical method To assess linearity and the lower limit of quantitation (LLOQ), we prepared eight concentrations of each of the three anesthetics covering the following ranges: remifentanil, 0.08 to 10.00 ng/ml; etomidate, 15.63 to 2000 ng/ml; and rocuronium, 156.25 to 20000 ng/ml. The ratio of each analyte's peak area to the peak area of its corresponding internal standard was plotted against the nominal spiked concentration. A calibration curve was generated using linear least-squares regression. The method was considered valid if the correlation coefficient (R 2 ) of the regression line exceeded 0.99. The LLOQ was defined as the lowest concentration at which the signal-to-noise ratio was at least 10 and the coefficient of variation was below 20%. Accuracy was assessed in terms of the relationship between measured concentrations and nominal spiked concentrations in quality control samples. Imprecision was expressed as the relative standard deviation (RSD%) for quality control samples at low, intermediate and high concentrations. Twenty replicates of each concentration were determined within a single day (intra-day imprecision) or once daily on five consecutive days (inter-day imprecision). The method was considered valid if accuracy was 85–115% overall and 80–120% at the LLOQ, and if inter- and intra-day imprecision was below 15% overall and below 20% at the LLOQ. Carry-over was assessed by analyzing three consecutive samples with high concentrations (H1, H2, H3) followed by three consecutive samples with low concentrations (L1, L2, L3). The carry-over rate was calculated as [ (L1 - L2) / (H3 - L3) ] × 100%. The method was considered valid if the carry-over rate was below 15% overall and below 20% at the LLOQ. Statistical analysis Data were reported as mean ± standard deviation, unless stated otherwise, as calculated in Microsoft Excel. Differences were assessed for significance using one-way ANOVA in SPSS 25 (IBM, Armonk, NY, USA). Results Column chromatography lasting 4 min was sufficient to cleanly separate the three anesthetics of interest from their respective internal standards (Fig. 1 ). Retention time did not vary significantly when samples were analyzed on different days (data not shown). The method showed good linear response for all three anesthetics (Table 2 ), and LLOQs were 0.08 ± 0.01 ng/ml for remifentanil, 18.69 ± 0.14 ng/ml for etomidate, and 106.73 ± 8.63 ng/ml for rocuronium (Table 3 ). For all three anesthetics, intra- and inter-day imprecision was below 15% (Table 4 ), recovery was 85–115% (Table 5 ), and carry-over was below 15% (Table 6 ). These results indicate that our analytical method is valid. Using this method, we determined levels of the three anesthetics in maternal arterial blood and in the blood from umbilical veins and arteries (Table 7 ). The mean concentration of remifentanil in maternal arterial blood was 4.75 ng/ml, in good agreement with the target-controlled infusion concentration of 5 ng/ml during anesthesia induction. The ratios of drug concentration in umbilical veins to the concentration in maternal arteries, which reflect rate of transport from mother to fetus, were 0.52 ± 0.02 for remifentanil, 0.75 ± 0.04 for etomidate, and 0.13 ± 0.02 for rocuronium. The corresponding ratios of drug concentration in umbilical arteries to the concentration in umbilical veins, which reflect rate of fetal consumption, were 0.53 ± 0.05, 0.57 ± 0.04 and 0.55 ± 0.04. Discussion Here we describe and validate an analytical method to simultaneously determine three anesthetics commonly given to pregnant women during cesarean section deliveries in maternal as well as umbilical blood. The method requires very small amounts of serum, which undergoes a straightforward protein precipitation procedure, followed by liquid chromatography and tandem mass spectrometry. The method shows satisfactory LLOQs, linearity, precision and accuracy for determining remifentanil, etomidate and rocuronium. Applying this method to a small sample of women giving birth by cesarean section at our hospital, we found respective mean concentrations of the anesthetics to be 4.75 ± 0.19 ng/ml, 412.71 ± 35.29 ng/ml and 7.08 ± 0.48 µg/ml in maternal arterial blood. The respective placental transfer rates were 0.52 ± 0.02, 0.75 ± 0.04 and 0.13 ± 0.02, with the three rates differing significantly from one another. The respective fetal utilization rates were 0.53 ± 0.05, 0.57 ± 0.04 and 0.55 ± 0.04, which did not differ significantly from one another. Our method should facilitate detailed studies of the pharmacokinetics of these drugs in the mother and newborn in order to verify their safety and identify any additive or antagonistic interactions among them. Our protein precipitation approach is similar to that reported in other methods designed to analyze individual anesthetics in our study, but not all of them together [ 9 – 10 ] . The protein precipitation procedure in our method provides good sensitivity, with LLOQs as low as 0.08 ng/ml, even though it uses only 10 µl of serum for analysis. This gives our relatively straightforward method a strong advantage over other approaches that require more complicated processing, such as solid-phase extraction or microextraction in a packed syringe [ 11 – 12 ] . Our LLOQ for remifentanil is higher than that of another method involving liquid-liquid extraction (0.08 vs. 0.05 ng/ml), yet that method requires approximately 500 µl of serum [ 13 ] . Rocuronium was nearly 4000 times more concentrated in maternal and umbilical serum than remifentanil or etomidate, which poses a challenge for their simultaneous determination. The success of our method depends on a suitably sensitive tandem mass spectrometry system that can accurately determine ions present at concentrations spanning five orders of magnitude [ 14 ] . We had to carefully optimize sample concentration and injection volume to prevent oversaturation by rocuronium. Rates of anesthetic transfer from mother to newborn varied widely: 13% for rocuronium, 52% for remifentanil and 75% for etomidate. These rates likely depend on several drug characteristics, such as size, lipophilicity, affinity for transporter proteins and extent of ionization [ 15 ] . The low transfer of rocuronium reflects its high water-solubility, which inhibits its passage through the placental barrier [ 16 ] . Remifentanil is known to be distributed and metabolized faster in the newborn than in the mother because of newborns' higher concentration of red blood cells in the circulation and their lower proportion of subcutaneous fat [ 17 ] . Whether the same is true for the other two anesthetics remains to be seen. In contrast to the different rates of transfer, rates of metabolism in the newborn were between 50 and 60% for all three anesthetics. Previous work reported a much higher rate of remifentanil transport from mother to newborn of 88% when the drug was used on its own, but only a slightly higher rate of 64% when it was used with propofol [ 18 – 19 ] . Combining remifentanil with propofol or etomidate may inhibit its transport from mother to newborn, which should be explored in future research. Declarations Funding This study was supported by the Natural Science Foundation of Chongqing, China (cstc2021jcyj-msxmX0763), an institutional research grant from the Chongqing Health Center for Women and Children (2021YJMS03) and the National Key Clinical Specialty Construction Project (Obstetrics and Gynecology). Author contributions H L, raw data processing, manuscript writing and execution. M C, sample and clinical information collection. Y P: statistical analysis. JK M, table and figure preparation. J Y, manuscript revision and study design. The authors has accepted responsibility for the entire content of this manuscript and approved its submission. Conflicts of interest None of the authors has any conflicts of interest to disclose. Ethics approval Blood sampling and analysis were approved by the Medical Ethics Committee of Chongqing Health Center for Women and Children (2021-011). The women provided informed consent for their blood and umbilical blood to be sampled and analyzed in this study. Consent to Participate declaration Every human provided informed consent to participate in this study. Data Availability declaration The data that support the findings of this study are available on request from the corresponding author. References Sumikura H, Niwa H, Sato M, Nakamoto T, Asai T, Hagihira S. Rethinking general anesthesia for cesarean section. J Anesth 2016; 30(2):268–73. https://doi.org/10.1007/s00540-015-2099-4 . Robertson S. Advantages of etomidate use as an anesthetic agent. Vet Clin North Am Small Anim Pract 1992; 22:277 – 80. https://doi.org/10.1016/s0195-5616(92)50609-x . Van de Velde M. The use of remifentanil during general anesthesia for caesarean section. Curr Opin Anaesthesiol 2016; 29:257–60. https://doi.org/10.1097/ACO.0000000000000334 . Eisa B, Amir A. K., Mehrnoosh T, Solmaz F. Anesthesia with etomidate and remifentanil for cesarean section in a patient with severe peripartum cardiomyopathy–a case report. Middle East J Anaesthesiol 2008; 19:1141–9 Demet C, Ahmet M, Sibel K, et al. Anaesthesia for caesarean section in the presence of multivalvular heart disease and severe pulmonary hypertension: a case report. Cases J. 2009; 2:9383. https://doi.org/10.1186/1757-1626-2-9383 . White LD, Hodsdon A, An GH, Thang C, Melhuish, TM, and Vlok, R.Induction opioids for caesarean section under general anaesthesia: A systematic review and meta-analysis of randomised controlled trials. Int. J. Obstet. 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Propofol in combination with remifentanil for cesarean section: placental transfer and effect on mothers and newborns at different induction to delivery intervals. Taiwan J. Obstet. Gynecol 2017; 56 : 521–526. https://doi.org/10.1016/j.tjog.2016.09.010 . Tables Table 1. Chromatographic retention times and mass spectrometric parameters of analytes in this study Analyte Ion m/z Retention time (min) Cone energy (V) Collision energy (V) Precursor Product Anesthetics Remifentanil 377.0 113.2 1.85 6 30 317.4 6 16 Etomidate 244.9 95.2 2.33 4 24 141.2 4 8 Rocuronium 529.1 112.3 1.62 30 35 487.5 Internal standards Sufentanil 387.0 111.1 2.26 30 35 238.3 6 18 Metomidate 230.9 95.17 2.11 2 24 127.2 2 8 Vecuronium 557.8 100.5 1.78 30 35 356.3 30 35 Table 2. Linear regression of calibration curves for the three anesthetics. Analyte Regression equation R 2 Remifentanil Y = 0.997044 X + 0.0197252 0.994 Etomidate Y = 0.181642 X + 0.181636 0.997 Rocuronium Y = 0.00873526 X + 1.30879 0.992 Table 3. Lower limits of quantification (LLOQ) for the three anesthetics * Analyte LLOQ (ng/ml) Relative standard deviation (%) Signal/noise ratio Remifentanil 0.15 ± 0.02 16.08 ≥10 Etomidate 16.87 ± 0.51 3.01 ≥10 Rocuronium 106.73 ± 8.63 8.09 ≥10 Values are mean ± SD, unless otherwise noted. * From three replicates in one experiment. Table 4. Intra- and inter-day imprecision in determination of the three anesthetics Analyte Level Intra-day* Inter-day** Concentration (ng/ml) RSD (%) Concentration (ng/ml) RSD (%) Remifentanil Low 0.54 ± 0.08 15.41 0.52 ± 0.03 4.63 Interm 1.49 ± 0.19 12.77 2.14 ± 0.24 11.05 High 2.55 ± 0.31 12.30 4.11 ± 0.55 13.31 Etomidate Low 95.25 ± 8.86 9.30 110.12 ± 4.02 3.65 Interm 405.63 ± 46.03 11.35 520.48 ± 31.75 6.10 High 783.55 ± 75.60 9.65 969.65 ± 126.89 13.09 Rocuronium Low 1102.59 ± 134.60 12.21 1174.87 ± 122.67 10.44 Interm 2937.89 ± 332.78 11.33 4342.86 ± 473.68 10.91 High 4487.83 ± 450.81 10.05 8188.54 ± 408.94 4.99 Values are mean ± SD, unless otherwise noted. Interm, intermediate; RSD, relative standard deviation. * From 20 replicates of each concentration within the same day. **From five measurements made once daily on five consecutive days. Table 5. Accuracy of determination of the three anesthetics Analyte Level Concentration (ng/ml) RSD (%) Recovery (%) Nominal Measured* Re mifentanil Low 0.50 0.53 ± 0.04 7.55 106.00 Interm 2.00 2.27 ± 0.17 7.49 113.50 High 4.00 4.38 ± 0.47 10.73 109.50 Et omidate Low 125.00 127.45 ± 10.04 7.88 101.96 Interm 500.00 518.81 ± 28.94 5.58 103.76 High 1000.00 1143.26 ± 115.00 14.48 114.33 Ro curonium Low 1000.00 1096.43 ± 118.21 10.78 109.64 Interm 4000.00 4160.96 ± 261.63 6.29 104.02 High 8000.00 7430.55 ± 816.68 10.99 92.88 Values are mean ± SD, unless otherwise noted. Interm, intermediate * From five measurements made once daily on five consecutive days. Table 6. Carry-over during determination of the three anesthetics Analyte Sample (see Methods) Residual (%) High3 Low1 Low3 Re mifentanil 9.62 0.00 0.16 -1.66 Et omidate 1758.00 46.98 37.87 -0.53 Ro curonium 14731.36 627.60 611.86 -0.11 Values are concentrations in ng/ml, unless otherwise noted. Table 7. Concentrations of the three anesthetics in different sources of serum and their ratios * Serum source (1)Maternal artery (2)Umbilical vein (3)Umbilical artery Ratio (2)/(1) Ratio (3)/(2) Remifentanil (ng/ml) Mean ± SD 4.75±0.19 2.43±0.13 1.33±0.15 0.52±0.02 0.30～0.65 Range 2.77～5.79 1.32～3.39 0.31～2.44 0.53±0.05 0.16～0.88 Etomidate (ng/ml) Mean ± SD 412.71±35.29 302.15±29.03 166.24±21.53 0.75±0.04 0.57±0.04 Range 153.65～667.81 83.91～534.32 66.31～490.44 0.24～0.97 0.22～0.92 Rocuronium ( μ g/ml) Mean ± SD 7.08±0.48 0.86±0.16 0.44±0.77 0.13±0.02 0.55±0.04 Range 2.44～12.30 0.29～3.73 0.19～1.44 0.03～0.47 0.25～0.88 P ND ND ND < 0.001 0.855 * From 20 maternal-fetal pairs ND, not done. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 16 Jul, 2025 Read the published version in Scientific Reports → Version 1 posted Editorial decision: Revision requested 03 Jun, 2025 Reviews received at journal 22 Apr, 2025 Reviewers agreed at journal 11 Apr, 2025 Reviewers agreed at journal 05 Feb, 2025 Reviews received at journal 19 Jan, 2025 Reviewers agreed at journal 07 Jan, 2025 Reviewers agreed at journal 22 Sep, 2024 Reviewers invited by journal 17 Sep, 2024 Editor assigned by journal 02 Sep, 2024 Editor invited by journal 21 May, 2024 Submission checks completed at journal 21 May, 2024 First submitted to journal 18 May, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4442620","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":308919537,"identity":"ed49a49b-0120-4e69-95d6-acf4b09427cb","order_by":0,"name":"Hao Liu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAArUlEQVRIiWNgGAWjYBACNv7mAwc+GLDJEa+FT+JY4sMZFXzGxGuRY8gxNuY5I5fYQLzDGA6YSfO2maX3HU9g/PAxhxgtzA1pknPb0nJnnnnALDlzG3G2HJN423Ysd8ONBDZmXuK0JLZJ8Lb9TzcgQUsysyHPGbYEErRIHGMEBjKb4cwzD5uJ84t8f/8HUFTK8x1PPvjhIzFaEOAACVED05JAqo5RMApGwSgYKQAAz705m2M5KOQAAAAASUVORK5CYII=","orcid":"","institution":"Chongqing Health Center for Women and Children and Women and Children’s Hospital of Chongqing Medical University","correspondingAuthor":true,"prefix":"","firstName":"Hao","middleName":"","lastName":"Liu","suffix":""},{"id":308919538,"identity":"a0e209f1-a99d-4cbb-b8ee-0dfe9db7c7d6","order_by":1,"name":"Meng Cai","email":"","orcid":"","institution":"Chongqing Health Center for Women and Children and Women and Children’s Hospital of Chongqing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Meng","middleName":"","lastName":"Cai","suffix":""},{"id":308919540,"identity":"fdf16818-cf18-4dcc-99fc-899cf8e877b9","order_by":2,"name":"Yong Peng","email":"","orcid":"","institution":"Chongqing Health Center for Women and Children and Women and Children’s Hospital of Chongqing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yong","middleName":"","lastName":"Peng","suffix":""},{"id":308919542,"identity":"14e4115b-8657-472e-8b47-3f2c2a8a5798","order_by":3,"name":"Jing-kun Miao","email":"","orcid":"","institution":"Chongqing Health Center for Women and Children and Women and Children’s Hospital of Chongqing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jing-kun","middleName":"","lastName":"Miao","suffix":""},{"id":308919543,"identity":"e9eb1e9c-2f58-4e29-ac79-4b44919a1d3f","order_by":4,"name":"Jin Yu","email":"","orcid":"","institution":"Chongqing Health Center for Women and Children and Women and Children’s Hospital of Chongqing Medical University","correspondingAuthor":false,"prefix":"","firstName":"Jin","middleName":"","lastName":"Yu","suffix":""}],"badges":[],"createdAt":"2024-05-19 01:08:18","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4442620/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4442620/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-025-09454-5","type":"published","date":"2025-07-16T16:05:27+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":57616374,"identity":"3b8bb9a3-dc76-415c-9b0a-588d33b739e8","added_by":"auto","created_at":"2024-06-03 11:42:21","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":233322,"visible":true,"origin":"","legend":"\u003cp\u003eRepresentative total ion chromatograms (TICs) of \u003cstrong\u003e(A)\u003c/strong\u003e remifentanil and its internal standard sufentanil, \u003cstrong\u003e(B)\u003c/strong\u003e etomidate and its standard metomidate, or \u003cstrong\u003e(C)\u003c/strong\u003erocuronium and its standard vecuronium. In all chromatograms, the x-axis shows the retention time (min), while the y-axis shows relative ion intensity. The exact ion intensity is indicated at the upper right of each chromatogram.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-4442620/v1/76ea81961382c2fc29042073.png"},{"id":88506065,"identity":"73eda3e3-8b17-4e23-b4d8-d37ac41c4276","added_by":"auto","created_at":"2025-08-07 07:30:19","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1194119,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4442620/v1/cefe2bcf-58b3-435b-ab6b-3d8e9f043c10.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Simultaneous determination of remifentanil, etomidate, and rocuronium in serum microsamples from maternal or umbilical blood","fulltext":[{"header":"Introduction","content":"\u003cp\u003eRecently, induction of anesthesia using propofol, rocuronium, and remifentanil are becoming popular \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e. Compared with propofol, etomidate has minimal impact to hemodynamics with low fluctuation of blood pressure and cardiac rhythm \u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. Therefore, the three anesthetics remifentanil, etomidate, and rocuronium are another choice for cesarean section, especially for pregnant women who have cardiovascular problems \u003csup\u003e[\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e.The three drugs operate through complementary mechanisms: remifentanil is an opioid analgesic; etomidate, a general anesthetic; and rocuronium, a muscle relaxant. Remifentanil is the preferred opioid analgesic for this situation: although it easily passes through the placental barrier, it is hydrolyzed in cord blood and rapidly metabolized in the fetus, and it is less likely to cause respiratory depression \u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. Etomidate and rocuronium are assumed to present minimal risk to fetal breathing because they are both administered at single dose \u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. However, the effect of the triple combination on fetal respiration has not been systematically analyzed, nor are the pharmacokinetics of the drugs in the mother and newborn well understood, which means their long-term safety is unclear.\u003c/p\u003e \u003cp\u003ePharmacokinetic and safety studies require appropriate analytical methods for determining all three anesthetics in blood, yet published methodsࣧwhether based on high-performance liquid chromatography or liquid chromatography-tandem mass spectrometryࣧrequire large sample volumes and time- or labor-intensive procedures and have been validated for only one or two of the three drugs \u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. Therefore we undertook the present study to develop and validate a single analytical method that could accurately determine all three anesthetics in extremely small volumes of serum from maternal and umbilical blood.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eReagents\u003c/h2\u003e \u003cp\u003eHPLC-grade methanol and acetonitrile were purchased from Fisher Scientific (Geel, Belgium), and formic acid was purchased from Shanghai Aladdin Bio-Chem Technology (Shanghai, China). The following six narcotics were purchased from Toronto Research Chemicals (Toronto, Canada): remifentanil hydrochloride, sufentanil citrate, etomidate, metomidate hydrochloride, rocuronium bromide, and vecuronium bromide. Water in this study was purified using a Milli-Q apparatus (Millipore, Bedford, MA, USA).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eCalibration standards, internal standards, and quality control samples\u003c/h2\u003e \u003cp\u003eStock solutions of remifentanil, etomidate, and rocuronium were prepared individually by dissolving solid compound into methanol to a concentration of 1 mg/ml, then vortexing at 1500 rpm for 5 min. The solutions were stored in brown vials at -80 ℃ and used within 12 months. These stock solutions were combined and suitably diluted into serum from pregnant women unexposed to the three anesthetics to yield final concentrations of 10 ng/ml remifentanil, 20000 ng/ml etomidate and 2000 ng/ml rocuronium. This working solution was stored in brown vials at -20 \u0026deg;C and used within one month.\u003c/p\u003e \u003cp\u003eStock solutions of the three internal standards sufentanil, metomidate and vecuronium were prepared individually by dissolving solid compound into acetonitrile to a concentration of 1 mg/ml, then vortexing at 1500 rpm for 5 min. These stock solutions were combined and suitably diluted into acetonitrile to yield final concentrations of 5 ng/ml sufentanil, 5 ng/ml metomidate, and 100 ng/ml vecuronium. This working solution was stored at -20 \u0026deg;C in brown vials and used within one month.\u003c/p\u003e \u003cp\u003eWorking solutions were diluted serially 1:2 in serum from pregnant women unexposed to the three anesthetics in order to determine calibration curves. Quality control samples were prepared by diluting working solutions into serum from unexposed pregnant women as follows: remifentanil, 0.5, 2.0 and 4.0 ng/ml; etomidate, 125.0, 500.0 and 1000.0 ng/ml; and rocuronium, 1000.00, 4000.00 and 8000.00 ng/ml.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eSample collection and preparation\u003c/h2\u003e \u003cp\u003e With approval from the Ethics Committee of the Chongqing Health Center for Women and Children (2021-011) and informed consent from the women, we sampled maternal and umbilical blood from 20 women giving birth by cesarean section at our hospital. The blood from pregnant women who were not yet exposed to anesthetics was also abtained during establishing venous access. All women received anesthesia according to standard protocols at our hospital. Anesthesia was induced through target-controlled infusion of remifentanil at 5 ng/ml, inhalation of 5% sevoflurane, and intravenous injection of etomidate at 0.25 mg/kg. Sevoflurane was administered briefly and discontinued when the eyelash reflex disappeared. After umbilical cord ligation, rocuronium bromide was intravenously injected at 0.6 mg/kg. Anesthesia was maintained through target-controlled infusion of propofol at 3.5 \u0026micro;g/ml and of remifentanil at 5 ng/ml. All experiments were performed in accordance with relevant guidelines and regulations.\u003c/p\u003e \u003cp\u003eImmediately after ligation of the umbilical cord, blood was collected from the left radial artery of the mother as well as from the umbilical vein and artery. The blood was centrifuged at 3000 rpm, and the serum was transferred to vials and stored at -80 \u0026deg;C until analysis. Frozen samples were thawed at room temperature for about 20 min, and 10-\u0026micro;l volumes of the thawed samples, quality control solutions and standards were placed into fresh microcentrifuge tubes, diluted up to 50 \u0026micro;l with pure water and vortexed at 1500 rpm for 3 min. Then 150 \u0026micro;l of acetonitrile containing internal standards was added to the vials, the solution was mixed and incubated at -20 \u0026deg;C for 20 min to precipitate proteins, and the solution was centrifuged at 13,000 \u003cem\u003eg\u003c/em\u003e for 5 min at 4 \u0026deg;C. The supernatant (100 \u0026micro;l) was transferred into fresh microcentrifuge tubes.\u003c/p\u003e \u003cp\u003eAn aliquot of supernatant (10 \u0026micro;l) was diluted with water (90 \u0026micro;l) to ensure accurate determination, and an aliquot of the dilution (3 \u0026micro;l) was injected into the liquid chromatography system for analysis as described below.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eLiquid chromatography-tandem mass spectrometry\u003c/h2\u003e \u003cp\u003eSamples were analyzed on an ultra-high performance liquid chromatography-tandem mass spectrometry system (Xevo TQ-S, Waters Corporation, Milford, MA, USA) equipped with an electrospray ionization source operating in positive mode. Samples were fractionated on a reverse-phase Acquity BEH C18 column (50 \u0026times; 2.1 mm, 1.7 \u0026micro;m; Waters Corporation) under the following gradient of 0.1% (v/v) formic acid in water (solution A) and a 1:1 (v/v) mixture of methanol and acetonitrile in solution A (solution B): 0 to 0.6 min, 10% B; 0.6\u0026ndash;2.8 min, 10\u0026ndash;90% B; 2.8\u0026ndash;3.6 min, 90% B; and 3.6-4 min, 10% B. The flow rate was 0.4 ml/min and column temperature was 45 \u0026deg;C.\u003c/p\u003e \u003cp\u003eEluted compounds were analyzed in multiple reaction monitoring mode based on time-scheduled events with analyte-dependent parameters (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) and the following additional parameters: ion source temperature, 150 \u0026deg;C; capillary voltage, 3.0 kV; desolvation temperature, 500 \u0026deg;C; gas flow rate for desolvation, 800 L/h; and gas flow rate in the cone, 150 L/h. Data were processed and quantified in MassLynx 4.2 software (Waters Corporation) based on the peak area and calibration with the internal standards. Amounts were quantified based on peak areas according to the internal standard method.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eValidation of the analytical method\u003c/h2\u003e \u003cp\u003eTo assess linearity and the lower limit of quantitation (LLOQ), we prepared eight concentrations of each of the three anesthetics covering the following ranges: remifentanil, 0.08 to 10.00 ng/ml; etomidate, 15.63 to 2000 ng/ml; and rocuronium, 156.25 to 20000 ng/ml. The ratio of each analyte's peak area to the peak area of its corresponding internal standard was plotted against the nominal spiked concentration. A calibration curve was generated using linear least-squares regression. The method was considered valid if the correlation coefficient (R\u003csup\u003e2\u003c/sup\u003e) of the regression line exceeded 0.99.\u003c/p\u003e \u003cp\u003eThe LLOQ was defined as the lowest concentration at which the signal-to-noise ratio was at least 10 and the coefficient of variation was below 20%. Accuracy was assessed in terms of the relationship between measured concentrations and nominal spiked concentrations in quality control samples. Imprecision was expressed as the relative standard deviation (RSD%) for quality control samples at low, intermediate and high concentrations. Twenty replicates of each concentration were determined within a single day (intra-day imprecision) or once daily on five consecutive days (inter-day imprecision). The method was considered valid if accuracy was 85\u0026ndash;115% overall and 80\u0026ndash;120% at the LLOQ, and if inter- and intra-day imprecision was below 15% overall and below 20% at the LLOQ.\u003c/p\u003e \u003cp\u003e Carry-over was assessed by analyzing three consecutive samples with high concentrations (H1, H2, H3) followed by three consecutive samples with low concentrations (L1, L2, L3). The carry-over rate was calculated as [ (L1 - L2) / (H3 - L3) ] \u0026times; 100%. The method was considered valid if the carry-over rate was below 15% overall and below 20% at the LLOQ.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eData were reported as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation, unless stated otherwise, as calculated in Microsoft Excel. Differences were assessed for significance using one-way ANOVA in SPSS 25 (IBM, Armonk, NY, USA).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eColumn chromatography lasting 4 min was sufficient to cleanly separate the three anesthetics of interest from their respective internal standards (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Retention time did not vary significantly when samples were analyzed on different days (data not shown). The method showed good linear response for all three anesthetics (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e), and LLOQs were 0.08\u0026thinsp;\u0026plusmn;\u0026thinsp;0.01 ng/ml for remifentanil, 18.69\u0026thinsp;\u0026plusmn;\u0026thinsp;0.14 ng/ml for etomidate, and 106.73\u0026thinsp;\u0026plusmn;\u0026thinsp;8.63 ng/ml for rocuronium (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). For all three anesthetics, intra- and inter-day imprecision was below 15% (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e), recovery was 85\u0026ndash;115% (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e), and carry-over was below 15% (Table\u0026nbsp;\u003cspan refid=\"Tab6\" class=\"InternalRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThese results indicate that our analytical method is valid. Using this method, we determined levels of the three anesthetics in maternal arterial blood and in the blood from umbilical veins and arteries (Table\u0026nbsp;\u003cspan refid=\"Tab7\" class=\"InternalRef\"\u003e7\u003c/span\u003e). The mean concentration of remifentanil in maternal arterial blood was 4.75 ng/ml, in good agreement with the target-controlled infusion concentration of 5 ng/ml during anesthesia induction. The ratios of drug concentration in umbilical veins to the concentration in maternal arteries, which reflect rate of transport from mother to fetus, were 0.52\u0026thinsp;\u0026plusmn;\u0026thinsp;0.02 for remifentanil, 0.75\u0026thinsp;\u0026plusmn;\u0026thinsp;0.04 for etomidate, and 0.13\u0026thinsp;\u0026plusmn;\u0026thinsp;0.02 for rocuronium. The corresponding ratios of drug concentration in umbilical arteries to the concentration in umbilical veins, which reflect rate of fetal consumption, were 0.53\u0026thinsp;\u0026plusmn;\u0026thinsp;0.05, 0.57\u0026thinsp;\u0026plusmn;\u0026thinsp;0.04 and 0.55\u0026thinsp;\u0026plusmn;\u0026thinsp;0.04.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eHere we describe and validate an analytical method to simultaneously determine three anesthetics commonly given to pregnant women during cesarean section deliveries in maternal as well as umbilical blood. The method requires very small amounts of serum, which undergoes a straightforward protein precipitation procedure, followed by liquid chromatography and tandem mass spectrometry. The method shows satisfactory LLOQs, linearity, precision and accuracy for determining remifentanil, etomidate and rocuronium. Applying this method to a small sample of women giving birth by cesarean section at our hospital, we found respective mean concentrations of the anesthetics to be 4.75\u0026thinsp;\u0026plusmn;\u0026thinsp;0.19 ng/ml, 412.71\u0026thinsp;\u0026plusmn;\u0026thinsp;35.29 ng/ml and 7.08\u0026thinsp;\u0026plusmn;\u0026thinsp;0.48 \u0026micro;g/ml in maternal arterial blood. The respective placental transfer rates were 0.52\u0026thinsp;\u0026plusmn;\u0026thinsp;0.02, 0.75\u0026thinsp;\u0026plusmn;\u0026thinsp;0.04 and 0.13\u0026thinsp;\u0026plusmn;\u0026thinsp;0.02, with the three rates differing significantly from one another. The respective fetal utilization rates were 0.53\u0026thinsp;\u0026plusmn;\u0026thinsp;0.05, 0.57\u0026thinsp;\u0026plusmn;\u0026thinsp;0.04 and 0.55\u0026thinsp;\u0026plusmn;\u0026thinsp;0.04, which did not differ significantly from one another. Our method should facilitate detailed studies of the pharmacokinetics of these drugs in the mother and newborn in order to verify their safety and identify any additive or antagonistic interactions among them.\u003c/p\u003e \u003cp\u003eOur protein precipitation approach is similar to that reported in other methods designed to analyze individual anesthetics in our study, but not all of them together \u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. The protein precipitation procedure in our method provides good sensitivity, with LLOQs as low as 0.08 ng/ml, even though it uses only 10 \u0026micro;l of serum for analysis. This gives our relatively straightforward method a strong advantage over other approaches that require more complicated processing, such as solid-phase extraction or microextraction in a packed syringe \u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. Our LLOQ for remifentanil is higher than that of another method involving liquid-liquid extraction (0.08 vs. 0.05 ng/ml), yet that method requires approximately 500 \u0026micro;l of serum \u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eRocuronium was nearly 4000 times more concentrated in maternal and umbilical serum than remifentanil or etomidate, which poses a challenge for their simultaneous determination. The success of our method depends on a suitably sensitive tandem mass spectrometry system that can accurately determine ions present at concentrations spanning five orders of magnitude \u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e. We had to carefully optimize sample concentration and injection volume to prevent oversaturation by rocuronium.\u003c/p\u003e \u003cp\u003eRates of anesthetic transfer from mother to newborn varied widely: 13% for rocuronium, 52% for remifentanil and 75% for etomidate. These rates likely depend on several drug characteristics, such as size, lipophilicity, affinity for transporter proteins and extent of ionization \u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. The low transfer of rocuronium reflects its high water-solubility, which inhibits its passage through the placental barrier \u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e. Remifentanil is known to be distributed and metabolized faster in the newborn than in the mother because of newborns' higher concentration of red blood cells in the circulation and their lower proportion of subcutaneous fat \u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. Whether the same is true for the other two anesthetics remains to be seen. In contrast to the different rates of transfer, rates of metabolism in the newborn were between 50 and 60% for all three anesthetics. Previous work reported a much higher rate of remifentanil transport from mother to newborn of 88% when the drug was used on its own, but only a slightly higher rate of 64% when it was used with propofol \u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e. Combining remifentanil with propofol or etomidate may inhibit its transport from mother to newborn, which should be explored in future research.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by the Natural Science Foundation of Chongqing, China (cstc2021jcyj-msxmX0763), an institutional research grant from the Chongqing Health Center for Women and Children (2021YJMS03) and the National Key Clinical Specialty Construction Project (Obstetrics and Gynecology).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eH L, raw data processing, manuscript writing and execution. M C, sample and clinical information collection. Y P: statistical analysis. JK M, table and figure preparation. J Y, manuscript revision and study design. The authors has accepted responsibility for the entire content of this manuscript and approved its submission.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone of the authors has any conflicts of interest to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBlood sampling and analysis were\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003eapproved by the Medical Ethics Committee of Chongqing Health Center for Women and Children (2021-011). The women provided informed consent for their blood and umbilical blood to be sampled and analyzed in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Participate declaration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEvery human provided informed consent to participate in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Availability declaration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available on request from the corresponding author.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSumikura H, Niwa H, Sato M, Nakamoto T, Asai T, Hagihira S. Rethinking general anesthesia for cesarean section. J Anesth 2016; 30(2):268\u0026ndash;73. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s00540-015-2099-4\u003c/span\u003e\u003cspan address=\"10.1007/s00540-015-2099-4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRobertson S. Advantages of etomidate use as an anesthetic agent. Vet Clin North Am Small Anim Pract 1992; 22:277\u0026thinsp;\u0026ndash;\u0026thinsp;80. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/s0195-5616(92)50609-x\u003c/span\u003e\u003cspan address=\"10.1016/s0195-5616(92)50609-x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVan de Velde M. The use of remifentanil during general anesthesia for caesarean section. 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Gynecol 2017; 56 : 521\u0026ndash;526. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.tjog.2016.09.010\u003c/span\u003e\u003cspan address=\"10.1016/j.tjog.2016.09.010\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1.\u0026nbsp;\u003c/strong\u003eChromatographic retention times and mass spectrometric parameters of analytes in this study\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"605\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.666666666666668%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eAnalyte\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eIon \u003cem\u003em/z\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eRetention time (min)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eCone energy (V)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eCollision energy (V)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\"\u003e\n \u003cp\u003e\u003cstrong\u003ePrecursor\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\"\u003e\n \u003cp\u003e\u003cstrong\u003eProduct\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eAnesthetics\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.666666666666668%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eRemifentanil\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e377.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e113.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e1.85\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\"\u003e\n \u003cp\u003e317.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003eEtomidate\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e244.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e95.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e2.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e141.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003eRocuronium\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e529.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e112.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e1.62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e35\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e487.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" colspan=\"2\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eInternal standards\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.666666666666668%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eSufentanil\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e387.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e111.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e2.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e35\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e238.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.666666666666668%\" rowspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eMetomidate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" rowspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003e230.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e95.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" rowspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003e2.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e127.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"16.666666666666668%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eVecuronium\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e557.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e100.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e1.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.666666666666668%\" valign=\"top\"\u003e\n \u003cp\u003e35\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e356.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"33.333333333333336%\" valign=\"top\"\u003e\n \u003cp\u003e35\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\u003cbr\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2.\u0026nbsp;\u003c/strong\u003eLinear regression of calibration curves for the three anesthetics.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"454\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.13907284768212%\"\u003e\n \u003cp\u003e\u003cstrong\u003eAnalyte\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50.11037527593819%\"\u003e\n \u003cp\u003e\u003cstrong\u003eRegression equation\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.750551876379692%\"\u003e\n \u003cp\u003e\u003cstrong\u003eR\u003csup\u003e2\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.13907284768212%\"\u003e\n \u003cp\u003eRemifentanil\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50.11037527593819%\"\u003e\n \u003cp\u003e\u003cem\u003eY\u003c/em\u003e = 0.997044\u003cem\u003eX\u003c/em\u003e + 0.0197252\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.750551876379692%\"\u003e\n \u003cp\u003e0.994\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.13907284768212%\"\u003e\n \u003cp\u003eEtomidate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50.11037527593819%\"\u003e\n \u003cp\u003e\u003cem\u003eY\u003c/em\u003e = 0.181642\u003cem\u003eX\u003c/em\u003e + 0.181636\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.750551876379692%\"\u003e\n \u003cp\u003e0.997\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.13907284768212%\"\u003e\n \u003cp\u003eRocuronium\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50.11037527593819%\"\u003e\n \u003cp\u003e\u003cem\u003eY\u003c/em\u003e = 0.00873526\u003cem\u003eX\u003c/em\u003e + 1.30879\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"20.750551876379692%\"\u003e\n \u003cp\u003e0.992\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\u003cbr\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3.\u0026nbsp;\u003c/strong\u003eLower limits of quantification (LLOQ) for the three anesthetics *\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"482\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.70954356846473%\"\u003e\n \u003cp\u003e\u003cstrong\u003eAnalyte\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.38589211618257%\"\u003e\n \u003cp\u003e\u003cstrong\u003eLLOQ (ng/ml)\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.327800829875518%\"\u003e\n \u003cp\u003e\u003cstrong\u003eRelative standard deviation (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.57676348547718%\"\u003e\n \u003cp\u003e\u003cstrong\u003eSignal/noise ratio\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.70954356846473%\"\u003e\n \u003cp\u003eRemifentanil\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.38589211618257%\"\u003e\n \u003cp\u003e0.15\u0026nbsp;\u0026plusmn; 0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.327800829875518%\"\u003e\n \u003cp\u003e16.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.57676348547718%\"\u003e\n \u003cp\u003e\u0026ge;10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.70954356846473%\"\u003e\n \u003cp\u003eEtomidate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.38589211618257%\"\u003e\n \u003cp\u003e16.87\u0026nbsp;\u0026plusmn; 0.51\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.327800829875518%\"\u003e\n \u003cp\u003e3.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.57676348547718%\"\u003e\n \u003cp\u003e\u0026ge;10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"19.70954356846473%\"\u003e\n \u003cp\u003eRocuronium\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"27.38589211618257%\"\u003e\n \u003cp\u003e106.73\u0026nbsp;\u0026plusmn; 8.63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.327800829875518%\"\u003e\n \u003cp\u003e8.09\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.57676348547718%\"\u003e\n \u003cp\u003e\u0026ge;10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\u003cbr\u003e\n\u003cp\u003eValues are mean \u0026plusmn; SD, unless otherwise noted.\u003c/p\u003e\n\u003cp\u003e* From three replicates in one experiment.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4.\u0026nbsp;\u003c/strong\u003eIntra- and inter-day imprecision in determination of the three anesthetics\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"633\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.428120063191153%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eAnalyte\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.004739336492891%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eLevel\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.652448657187996%\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eIntra-day*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"37.91469194312796%\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eInter-day**\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"32.72357723577236%\"\u003e\n \u003cp\u003e\u003cstrong\u003eConcentration (ng/ml)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.495934959349594%\"\u003e\n \u003cp\u003e\u003cstrong\u003eRSD\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.504065040650406%\"\u003e\n \u003cp\u003e\u003cstrong\u003eConcentration (ng/ml)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.276422764227643%\"\u003e\n \u003cp\u003e\u003cstrong\u003eRSD\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.406940063091483%\" rowspan=\"3\"\u003e\n \u003cp\u003eRemifentanil\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.990536277602523%\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.394321766561514%\"\u003e\n \u003cp\u003e0.54\u0026nbsp;\u0026plusmn; 0.08\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.353312302839116%\"\u003e\n \u003cp\u003e15.41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.44794952681388%\"\u003e\n \u003cp\u003e0.52\u0026nbsp;\u0026plusmn; 0.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.406940063091483%\"\u003e\n \u003cp\u003e4.63\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.382513661202186%\"\u003e\n \u003cp\u003eInterm\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.326047358834245%\"\u003e\n \u003cp\u003e1.49\u0026nbsp;\u0026plusmn; 0.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.57559198542805%\"\u003e\n \u003cp\u003e12.77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.233151183970858%\"\u003e\n \u003cp\u003e2.14\u0026nbsp;\u0026plusmn; 0.24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.482695810564662%\"\u003e\n \u003cp\u003e11.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.382513661202186%\"\u003e\n \u003cp\u003eHigh\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.326047358834245%\"\u003e\n \u003cp\u003e2.55\u0026nbsp;\u0026plusmn; 0.31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.57559198542805%\"\u003e\n \u003cp\u003e12.30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.233151183970858%\"\u003e\n \u003cp\u003e4.11\u0026nbsp;\u0026plusmn; 0.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.482695810564662%\"\u003e\n \u003cp\u003e13.31\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.406940063091483%\" rowspan=\"3\"\u003e\n \u003cp\u003eEtomidate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.990536277602523%\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.394321766561514%\"\u003e\n \u003cp\u003e95.25\u0026nbsp;\u0026plusmn; 8.86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.353312302839116%\"\u003e\n \u003cp\u003e9.30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.44794952681388%\"\u003e\n \u003cp\u003e110.12\u0026nbsp;\u0026plusmn; 4.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.406940063091483%\"\u003e\n \u003cp\u003e3.65\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.382513661202186%\"\u003e\n \u003cp\u003eInterm\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.326047358834245%\"\u003e\n \u003cp\u003e405.63\u0026nbsp;\u0026plusmn; 46.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.57559198542805%\"\u003e\n \u003cp\u003e11.35\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.233151183970858%\"\u003e\n \u003cp\u003e520.48\u0026nbsp;\u0026plusmn; 31.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.482695810564662%\"\u003e\n \u003cp\u003e6.10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.382513661202186%\"\u003e\n \u003cp\u003eHigh\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.326047358834245%\"\u003e\n \u003cp\u003e783.55\u0026nbsp;\u0026plusmn; 75.60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.57559198542805%\"\u003e\n \u003cp\u003e9.65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.233151183970858%\"\u003e\n \u003cp\u003e969.65\u0026nbsp;\u0026plusmn; 126.89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.482695810564662%\"\u003e\n \u003cp\u003e13.09\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.406940063091483%\" rowspan=\"3\"\u003e\n \u003cp\u003eRocuronium\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.990536277602523%\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.394321766561514%\"\u003e\n \u003cp\u003e1102.59\u0026nbsp;\u0026plusmn; 134.60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.353312302839116%\"\u003e\n \u003cp\u003e12.21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.44794952681388%\"\u003e\n \u003cp\u003e1174.87\u0026nbsp;\u0026plusmn; 122.67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.406940063091483%\"\u003e\n \u003cp\u003e10.44\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.382513661202186%\"\u003e\n \u003cp\u003eInterm\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.326047358834245%\"\u003e\n \u003cp\u003e2937.89\u0026nbsp;\u0026plusmn; 332.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.57559198542805%\"\u003e\n \u003cp\u003e11.33\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.233151183970858%\"\u003e\n \u003cp\u003e4342.86\u0026nbsp;\u0026plusmn; 473.68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.482695810564662%\"\u003e\n \u003cp\u003e10.91\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"10.382513661202186%\"\u003e\n \u003cp\u003eHigh\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.326047358834245%\"\u003e\n \u003cp\u003e4487.83\u0026nbsp;\u0026plusmn; 450.81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.57559198542805%\"\u003e\n \u003cp\u003e10.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"28.233151183970858%\"\u003e\n \u003cp\u003e8188.54\u0026nbsp;\u0026plusmn; 408.94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.482695810564662%\"\u003e\n \u003cp\u003e4.99\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\u003cbr\u003e\n\u003cp\u003eValues are mean \u0026plusmn; SD, unless otherwise noted. Interm, intermediate; RSD, relative standard deviation.\u003c/p\u003e\n\u003cp\u003e* From 20 replicates of each concentration within the same day.\u003c/p\u003e\n\u003cp\u003e**From five measurements made once daily on five consecutive days.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 5.\u0026nbsp;\u003c/strong\u003eAccuracy of determination of the three anesthetics\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"557\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.647482014388489%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eAnalyte\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.151079136690647%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eLevel\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"43.34532374100719%\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eConcentration (ng/ml)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.690647482014388%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eRSD\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.165467625899282%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eRecovery\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"49.586776859504134%\"\u003e\n \u003cp\u003e\u003cstrong\u003eNominal\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50.413223140495866%\"\u003e\n \u003cp\u003e\u003cstrong\u003eMeasured*\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.61938958707361%\" rowspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eRe\u003c/strong\u003emifentanil\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.131059245960502%\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.54398563734291%\"\u003e\n \u003cp\u003e0.50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.903052064631957%\"\u003e\n \u003cp\u003e0.53\u0026nbsp;\u0026plusmn; 0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.669658886894075%\"\u003e\n \u003cp\u003e7.55\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.132854578096946%\"\u003e\n \u003cp\u003e106.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.191489361702128%\"\u003e\n \u003cp\u003eInterm\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.53191489361702%\"\u003e\n \u003cp\u003e2.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.95744680851064%\"\u003e\n \u003cp\u003e2.27\u0026nbsp;\u0026plusmn; 0.17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.829787234042554%\"\u003e\n \u003cp\u003e7.49\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.48936170212766%\"\u003e\n \u003cp\u003e113.50\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.191489361702128%\"\u003e\n \u003cp\u003eHigh\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.53191489361702%\"\u003e\n \u003cp\u003e4.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.95744680851064%\"\u003e\n \u003cp\u003e4.38\u0026nbsp;\u0026plusmn; 0.47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.829787234042554%\"\u003e\n \u003cp\u003e10.73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.48936170212766%\"\u003e\n \u003cp\u003e109.50\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.61938958707361%\" rowspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eEt\u003c/strong\u003eomidate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.131059245960502%\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.54398563734291%\"\u003e\n \u003cp\u003e125.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.903052064631957%\"\u003e\n \u003cp\u003e127.45\u0026nbsp;\u0026plusmn; 10.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.669658886894075%\"\u003e\n \u003cp\u003e7.88\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.132854578096946%\"\u003e\n \u003cp\u003e101.96\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.191489361702128%\"\u003e\n \u003cp\u003eInterm\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.53191489361702%\"\u003e\n \u003cp\u003e500.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.95744680851064%\"\u003e\n \u003cp\u003e518.81\u0026nbsp;\u0026plusmn; 28.94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.829787234042554%\"\u003e\n \u003cp\u003e5.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.48936170212766%\"\u003e\n \u003cp\u003e103.76\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.191489361702128%\"\u003e\n \u003cp\u003eHigh\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.53191489361702%\"\u003e\n \u003cp\u003e1000.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.95744680851064%\"\u003e\n \u003cp\u003e1143.26\u0026nbsp;\u0026plusmn; 115.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.829787234042554%\"\u003e\n \u003cp\u003e14.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.48936170212766%\"\u003e\n \u003cp\u003e114.33\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.61938958707361%\" rowspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eRo\u003c/strong\u003ecuronium\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.131059245960502%\"\u003e\n \u003cp\u003eLow\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.54398563734291%\"\u003e\n \u003cp\u003e1000.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.903052064631957%\"\u003e\n \u003cp\u003e1096.43\u0026nbsp;\u0026plusmn; 118.21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.669658886894075%\"\u003e\n \u003cp\u003e10.78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.132854578096946%\"\u003e\n \u003cp\u003e109.64\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.191489361702128%\"\u003e\n \u003cp\u003eInterm\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.53191489361702%\"\u003e\n \u003cp\u003e4000.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.95744680851064%\"\u003e\n \u003cp\u003e4160.96\u0026nbsp;\u0026plusmn; 261.63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.829787234042554%\"\u003e\n \u003cp\u003e6.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.48936170212766%\"\u003e\n \u003cp\u003e104.02\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.191489361702128%\"\u003e\n \u003cp\u003eHigh\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.53191489361702%\"\u003e\n \u003cp\u003e8000.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.95744680851064%\"\u003e\n \u003cp\u003e7430.55\u0026nbsp;\u0026plusmn; 816.68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.829787234042554%\"\u003e\n \u003cp\u003e10.99\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.48936170212766%\"\u003e\n \u003cp\u003e92.88\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\u003cbr\u003e\n\u003cp\u003eValues are mean \u0026plusmn; SD, unless otherwise noted. Interm, intermediate\u003c/p\u003e\n\u003cp\u003e* From five measurements made once daily on five consecutive days.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 6.\u0026nbsp;\u003c/strong\u003eCarry-over during determination of the three anesthetics\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"554\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"15.342960288808664%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eAnalyte\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"65.70397111913357%\" colspan=\"4\"\u003e\n \u003cp\u003e\u003cstrong\u003eSample (see Methods)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.95306859205776%\" rowspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eResidual (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"39.010989010989015%\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eHigh3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.659340659340659%\"\u003e\n \u003cp\u003e\u003cstrong\u003eLow1\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"45.32967032967033%\"\u003e\n \u003cp\u003e\u003cstrong\u003eLow3\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.14801444043321%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eRe\u003c/strong\u003e\u003cstrong\u003emifentanil\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.826714801444044%\"\u003e\n \u003cp\u003e9.62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.288808664259928%\"\u003e\n \u003cp\u003e0.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.783393501805055%\"\u003e\n \u003cp\u003e0.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.95306859205776%\"\u003e\n \u003cp\u003e-1.66\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.14801444043321%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eEt\u003c/strong\u003e\u003cstrong\u003eomidate\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.826714801444044%\"\u003e\n \u003cp\u003e1758.00\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.288808664259928%\"\u003e\n \u003cp\u003e46.98\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.783393501805055%\"\u003e\n \u003cp\u003e37.87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.95306859205776%\"\u003e\n \u003cp\u003e-0.53\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.14801444043321%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eRo\u003c/strong\u003e\u003cstrong\u003ecuronium\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.826714801444044%\"\u003e\n \u003cp\u003e14731.36\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.288808664259928%\"\u003e\n \u003cp\u003e627.60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.783393501805055%\"\u003e\n \u003cp\u003e611.86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.95306859205776%\"\u003e\n \u003cp\u003e-0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\u003cbr\u003e\n\u003cp\u003eValues are concentrations in ng/ml, unless otherwise noted.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 7.\u0026nbsp;\u003c/strong\u003eConcentrations of the three anesthetics in different sources of serum and their ratios *\u003c/p\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"642\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.08398133748056%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSerum source\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.174183514774494%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e(1)Maternal artery\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.774494556765163%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e(2)Umbilical vein\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.573872472783826%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e(3)Umbilical artery\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.774494556765163%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eRatio (2)/(1)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.618973561430794%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eRatio (3)/(2)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.08398133748056%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eRemifentanil (ng/ml)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.174183514774494%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.774494556765163%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.573872472783826%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.774494556765163%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.618973561430794%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.08398133748056%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean \u0026plusmn; SD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.174183514774494%\" valign=\"top\"\u003e\n \u003cp\u003e4.75\u0026plusmn;0.19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.774494556765163%\" valign=\"top\"\u003e\n \u003cp\u003e2.43\u0026plusmn;0.13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.573872472783826%\" valign=\"top\"\u003e\n \u003cp\u003e1.33\u0026plusmn;0.15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.774494556765163%\" valign=\"top\"\u003e\n \u003cp\u003e0.52\u0026plusmn;0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.618973561430794%\" valign=\"top\"\u003e\n \u003cp\u003e0.30～0.65\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.08398133748056%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eRange\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.174183514774494%\" valign=\"top\"\u003e\n \u003cp\u003e2.77～5.79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.774494556765163%\" valign=\"top\"\u003e\n \u003cp\u003e1.32～3.39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.573872472783826%\" valign=\"top\"\u003e\n \u003cp\u003e0.31～2.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.774494556765163%\" valign=\"top\"\u003e\n \u003cp\u003e0.53\u0026plusmn;0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.618973561430794%\" valign=\"top\"\u003e\n \u003cp\u003e0.16～0.88\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.08398133748056%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eEtomidate (ng/ml)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.174183514774494%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.774494556765163%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.573872472783826%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.774494556765163%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.618973561430794%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.08398133748056%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean \u0026plusmn; SD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.174183514774494%\" valign=\"top\"\u003e\n \u003cp\u003e412.71\u0026plusmn;35.29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.774494556765163%\" valign=\"top\"\u003e\n \u003cp\u003e302.15\u0026plusmn;29.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.573872472783826%\" valign=\"top\"\u003e\n \u003cp\u003e166.24\u0026plusmn;21.53\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.774494556765163%\" valign=\"top\"\u003e\n \u003cp\u003e0.75\u0026plusmn;0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.618973561430794%\" valign=\"top\"\u003e\n \u003cp\u003e0.57\u0026plusmn;0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.08398133748056%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eRange\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.174183514774494%\" valign=\"top\"\u003e\n \u003cp\u003e153.65～667.81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.774494556765163%\" valign=\"top\"\u003e\n \u003cp\u003e83.91～534.32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.573872472783826%\" valign=\"top\"\u003e\n \u003cp\u003e66.31～490.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.774494556765163%\"\u003e\n \u003cp\u003e0.24～0.97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.618973561430794%\" valign=\"top\"\u003e\n \u003cp\u003e0.22～0.92\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.08398133748056%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eRocuronium (\u003c/strong\u003e\u003cstrong\u003e\u0026mu;\u003c/strong\u003e\u003cstrong\u003eg/ml)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.174183514774494%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.774494556765163%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.573872472783826%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.774494556765163%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.618973561430794%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.08398133748056%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean \u0026plusmn; SD\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.174183514774494%\" valign=\"top\"\u003e\n \u003cp\u003e7.08\u0026plusmn;0.48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.774494556765163%\" valign=\"top\"\u003e\n \u003cp\u003e0.86\u0026plusmn;0.16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.573872472783826%\" valign=\"top\"\u003e\n \u003cp\u003e0.44\u0026plusmn;0.77\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.774494556765163%\" valign=\"top\"\u003e\n \u003cp\u003e0.13\u0026plusmn;0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.618973561430794%\" valign=\"top\"\u003e\n \u003cp\u003e0.55\u0026plusmn;0.04\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.08398133748056%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eRange\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.174183514774494%\" valign=\"top\"\u003e\n \u003cp\u003e2.44～12.30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.774494556765163%\" valign=\"top\"\u003e\n \u003cp\u003e0.29～3.73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.573872472783826%\" valign=\"top\"\u003e\n \u003cp\u003e0.19～1.44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.774494556765163%\" valign=\"top\"\u003e\n \u003cp\u003e0.03～0.47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.618973561430794%\" valign=\"top\"\u003e\n \u003cp\u003e0.25～0.88\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22.08398133748056%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"16.174183514774494%\" valign=\"top\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.774494556765163%\" valign=\"top\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.573872472783826%\" valign=\"top\"\u003e\n \u003cp\u003eND\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.774494556765163%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.618973561430794%\" valign=\"top\"\u003e\n \u003cp\u003e0.855\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003cp\u003e* From 20 maternal-fetal pairs\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eND, not done.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Anesthetics, caesarean section, LC-MS/MS, newborn","lastPublishedDoi":"10.21203/rs.3.rs-4442620/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4442620/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eThis study aimed to establish and validate an analytical method to accurately determine the anesthetics remifentanil, etomidate, and rocuronium simultaneously in extremely small volumes of serum from maternal or umbilical blood.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA microsample of serum (10 \u0026micro;l) was diluted up to 50 \u0026micro;l with pure water, then total protein was precipitated using acetonitrile, and the three anesthetics were determined using liquid chromatography-tandem mass spectrometry within 4 min. Mass spectrometry was performed with positive electrospray ionization in multiple reaction monitoring mode. The analytical method was characterized in terms of linearity, lower limit of quantification, accuracy, precision, and carry-over effects. The method was validated on samples from 20 pairs of newborns and their mothers.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eFor all three anesthetics, the analytical method showed linearity (R\u0026sup2; \u0026gt; 0.99), inter- and intra-day imprecision\u0026thinsp;\u0026lt;\u0026thinsp;15% and carry-over \u0026lt;\u0026thinsp;5%. The lower limits of quantitation were 0.15\u0026thinsp;\u0026plusmn;\u0026thinsp;0.02 ng/ml for remifentanil, 16.87\u0026thinsp;\u0026plusmn;\u0026thinsp;0.51 ng/ml for etomidate, and 106.73\u0026thinsp;\u0026plusmn;\u0026thinsp;8.63 ng/ml for rocuronium. Respective mean concentrations of each anesthetic in serum from maternal arteries, umbilical veins and umbilical arteries were as follows: remifentanil, 4.75\u0026thinsp;\u0026plusmn;\u0026thinsp;0.19, 2.43\u0026thinsp;\u0026plusmn;\u0026thinsp;0.13, and 1.33\u0026thinsp;\u0026plusmn;\u0026thinsp;0.15 ng/ml; etomidate, 412.71\u0026thinsp;\u0026plusmn;\u0026thinsp;35.29, 302.15\u0026thinsp;\u0026plusmn;\u0026thinsp;29.03, and 166.24\u0026thinsp;\u0026plusmn;\u0026thinsp;21.53 ng/ml; and rocuronium, 7.08\u0026thinsp;\u0026plusmn;\u0026thinsp;0.48, 0.86\u0026thinsp;\u0026plusmn;\u0026thinsp;0.16, and 0.44\u0026thinsp;\u0026plusmn;\u0026thinsp;0.77 \u0026micro;g/ml. Respective rates of transport into placenta for the three anesthetics were 0.52\u0026thinsp;\u0026plusmn;\u0026thinsp;0.02, 0.75\u0026thinsp;\u0026plusmn;\u0026thinsp;0.04, and 0.13\u0026thinsp;\u0026plusmn;\u0026thinsp;0.02 (all \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eOur analytical method can accurately and reliably determine remifentanil, etomidate, and rocuronium simultaneously in microvolumes of maternal and umbilical serum, making it suitable for pharmacokinetic studies.\u003c/p\u003e","manuscriptTitle":"Simultaneous determination of remifentanil, etomidate, and rocuronium in serum microsamples from maternal or umbilical blood","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-03 11:42:16","doi":"10.21203/rs.3.rs-4442620/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-06-03T11:34:58+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-04-22T23:32:55+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"266512212824640555895833090743638201277","date":"2025-04-11T09:12:23+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"224067548249882333248024194027176246511","date":"2025-02-05T11:23:20+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-01-19T16:28:50+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"254296097731331340809391508714039243757","date":"2025-01-07T16:04:27+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"139312484737434932800217205106124084132","date":"2024-09-22T13:44:16+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-09-17T06:54:39+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-09-02T15:42:09+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-05-22T01:38:18+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-05-22T01:22:15+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-05-19T00:58:29+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0fea8fc6-46dc-48a8-a3ac-63fdaa9b270a","owner":[],"postedDate":"June 3rd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":32638987,"name":"Biological sciences/Drug discovery/Medicinal chemistry"},{"id":32638988,"name":"Biological sciences/Drug discovery/Pharmacology"},{"id":32638989,"name":"Biological sciences/Drug discovery"},{"id":32638990,"name":"Biological sciences/Biological techniques"},{"id":32638991,"name":"Biological sciences/Biological techniques/Analytical biochemistry"},{"id":32638992,"name":"Biological sciences/Biological techniques/Mass spectrometry"}],"tags":[],"updatedAt":"2025-08-07T07:12:04+00:00","versionOfRecord":{"articleIdentity":"rs-4442620","link":"https://doi.org/10.1038/s41598-025-09454-5","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2025-07-16 16:05:27","publishedOnDateReadable":"July 16th, 2025"},"versionCreatedAt":"2024-06-03 11:42:16","video":"","vorDoi":"10.1038/s41598-025-09454-5","vorDoiUrl":"https://doi.org/10.1038/s41598-025-09454-5","workflowStages":[]},"version":"v1","identity":"rs-4442620","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4442620","identity":"rs-4442620","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}