Pharmacokinetic and pharmacodynamic evaluation of various vasopressin doses and routes in a neonatal piglet model

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Schmölzer This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4637657/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 04 Oct, 2024 Read the published version in Scientific Reports → Version 1 posted 9 You are reading this latest preprint version Abstract Epinephrine is the only recommended vasopressor during neonatal cardiopulmonary resuscitation. However, there are concerns about the potential adverse effects of epinephrine, which might hamper efficacy during cardiopulmonary resuscitation. An alternative might be vasopressin, which has a preferable adverse effect profile, however, its optimal dose and route of administration is unknown. We aimed to compare the pharmacodynamics and pharmacokinetics of various vasopressin doses administered via intravenous (IV), intraosseous (IO), endotracheal (ETT), and intranasal (IN) routes in healthy neonatal piglets. Forty-four post-transitional piglets (1–3 days of age) were anesthetized, intubated via a tracheostomy, and randomized to receive vasopressin via intravenous (control), IO, ETT, or IN route. Heart rate (HR), arterial blood pressure, carotid blood flow, and cardiac function (e.g., stroke volume, ejection fraction) were continuously recorded throughout the experiment. Blood was collected prior to drug administration and throughout the observation period for pharmacodynamics and pharmacokinetic analysis. Significant changes in hemodynamic parameters were observed following IO administration of vasopressin while pharmacokinetic parameters were not different between IV and IO vasopressin. Administration of vasopressin via ETT or IN did not change hemodynamic parameters and had significantly lower maximum plasma concentrations and systemic absorption compared to piglets administered IV vasopressin ( p < 0.05). The IV and IO routes appear the most effective route for vasopressin administration in neonatal piglets, while ETT and IN routes appear not suitable for vasopressin administration. Health sciences/Medical research/Paediatric research Health sciences/Medical research/Pre clinical studies Infants Newborn Neonatal Resuscitation vasopressin pharmacokinetics PHARMACODYNAMICS Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Neonatal cardiac arrest is primarily caused by perinatal asphyxia, and ~ 0.1% of term and up to 15% of preterm infants at birth will require resuscitation with high-quality chest compressions and a vasopressor (i.e. epinephrine) for survival 1,2 . The current Neonatal Consensus of Science and Treatment Recommendation (CoSTR) recommends epinephrine at a dose of 0.01–0.03mg/kg, preferably given intravenous (IV) or intraosseous (IO) every 3–5 minutes during cardiopulmonary resuscitation (CPR) 3 . Epinephrine may also be given via an endotracheal tube (ETT) at a dose of 0.05–0.1mg/kg 3 . Epinephrine is currently the only recommended vasopressor during CPR, however, epinephrine increases myocardial oxygen demand, inhibits hemodynamic responses (e.g., aggravated arterial hypertension following return of spontaneous circulation (ROSC), reduced efficacy during respiratory and metabolic acidosis, and microcirculation impairment) 4–8 . Vasopressin, an antidiuretic hormone, might be an alternative to epinephrine, as its efficacy is not impaired during metabolic or respiratory acidosis 4,9,10 . Subgroup analysis of randomized trials of adults with out-of-hospital cardiac arrest reported that adults with asystolic arrest and treated with vasopressin had significantly higher rates of survival to hospital admission (29% vs. 20%, p = 0.02) and discharge (5% vs. 2%, p = 0.04) compared to receiving epinephrine 11 . Similarly, in a case series of four pediatric patients vasopressin at 0.4IU/kg/dose IV administered as rescue therapy, achieved ROSC in 3/4 children, 2/4 survived > 24 hours, and 1/4 survived to hospital discharge 12 . Furthermore Duncan et al reported that 5% of 1,293 pediatric patients received vasopressin during in-hospital cardiac arrest 13 , and although they had significantly longer duration of cardiac arrest (median 37 vs. 24 min, p = 0.004) and longer time to ROSC, their survival at 24 h or at discharge was not different to patients receiving epinephrine 13 . A recent feasibility study compared vasopressin (0.8 IU/kg) after an initial epinephrine dose in patients < 18 years of age ( n = 10) to ≥ 2 doses of epinephrine 14 . Patients who received vasopressin had increased 24 h survival (80% vs. 30%, odds ratio (OR) (95%CI) 9.3 (1.5–57.7)), with no difference in time to ROSC, survival to hospital discharge, and neurologic status at discharge. 14 Therefore vasopressin may be beneficial during neonatal CPR because in newborn infants 1) asphyxia results primarily in non-shockable rhythm, rather than ventricular fibrillation and 2) pulmonary vascular resistance is high at birth in newborns. There are no pharmacodynamics and pharmacokinetic data of vasopressin available for newborn infants. Therefore, we aimed to determine pharmacodynamics and pharmacokinetics of vasopressin administered either via IV, IO, ETT, or intranasal (IN) routes to assess the optimal dose for each route in a post-transitional piglet model. Methods This was a randomized controlled animal trial. 44 newborn mixed breed piglets were obtained on the day of experimentation from the University Swine Research Technology Centre located in Edmonton, Alberta, Canada. All experiments were conducted in accordance with the guidelines and approval of the Animal Care and Use Committee (Health Sciences), University of Alberta [AUP00004212], conducted and presented according to the ARRIVE guidelines 15 , conducted according to the Canadian Council of Animal Care guidelines, and registered at preclinicaltrials.eu (PCTE0000489). A graphical display of the study protocol is presented in Fig. 1 . Inclusion and exclusion criteria Mixed breed neonatal piglets with a current age of 1–3 days of age, weighing 2.0 kg (± 0.23kg) were included. There was no exclusion criterion. Sample size There was no formal sample size calculation as this study aimed to measure the pharmacodynamic, pharmacokinetic, and hemodynamic effects after epinephrine and vasopressin administration. We aimed for a sample size of 5 piglets per group. Randomization Piglets were randomly allocated to varying doses of vasopressin administered via IV, IO, ET, or IN. Allocation was block randomized with variable sized blocks using a computer-generated randomization program ( http://www.randomizer.org ). Sequentially numbered, sealed, brown envelopes containing the allocation were opened during the experiment (Fig. 1 ). Blinding One investigator (TFL) opened the randomization envelope and was solely responsible for drug preparation. The content of the drug syringe was only known to TFL to conceal group allocation. All remaining team members were blinded to group allocation. The statistical analysis was blinded to group allocation and only unblinded after the statistical analysis was completed. Animal preparation Piglets were instrumented as previously described with modifications 16–18 . Following the induction of anaesthesia using isoflurane, piglets were intubated via a tracheostomy, and pressure-controlled ventilation (Sechrist Infant Ventilator Model IV-100; Sechrist Industries, Anaheim, California) was commenced at a respiratory rate of 16–20 breaths/min and pressure of 20/5 cmH 2 O. Oxygen saturation was kept within 90–100%, glucose level and hydration was maintained with an intravenous infusion of 5% dextrose at 10 mL/kg/hr. During the experiment anaesthesia was maintained with intravenous propofol 5–10 mg/kg/hr and morphine 0.1 mg/kg/hr. Additional doses of propofol (1–2 mg/kg) and morphine (0.05–0.1 mg/kg) were also given as needed. The piglet’s body temperature was maintained within a normal porcine temperature range of 38.5–39.5°C using an overhead warmer and a heating pad. Hemodynamic parameters A 5-French Argyle® (Klein-Baker Medical Inc. San Antonio, TX) double-lumen catheter was inserted via the right femoral vein for administration of fluids and medications. A 5-French Argyle® single-lumen catheter was inserted above the right renal artery via the femoral artery for continuous arterial blood pressure monitoring in addition to arterial blood gas measurements. The right common carotid artery was also exposed and encircled with a real-time ultrasonic flow probe (2mm; Transonic Systems Inc., Ithica, NY) to measure cerebral blood flow 16–18 . A Millar® catheter (MPVS Ultra1, ADInstruments, Houston, TX) was inserted into the left ventricle via the left common carotid artery for continuous measurement of stroke volume, ejection fraction, end-diastolic and -systolic volumes, left ventricular pressure, and left ventricular contractile function (dp/dt max , dp/dt min ) 19,20 . Piglets were placed in supine position and allowed to recover from surgical instrumentation until baseline hemodynamic measures were stable (minimum of one hour). Ventilator rate was adjusted to keep the partial arterial CO 2 between 35–45 mmHg as determined by periodic arterial blood gas analysis. Mean systemic arterial pressure (MAP), systemic systolic arterial pressure, heart rate, and percutaneous oxygen saturation were continuously measured and recorded throughout the experiment with a Hewlett Packard 78833B monitor (Hewlett Packard Co., Palo Alto, CA) 16–18 . Experimental protocol Piglets were randomized into four routes and various vasopressin doses: 1) IV vasopressin (0.4IU/kg; n = 5, control), 2) IO vasopressin ( n = 5/dose; 0.2IU/kg, 0.4IU/kg, or 0.8IU/kg), 3) ETT vasopressin ( n = 5/dose; 4IU/kg, 8IU/kg, or 16IU/kg), 4) IN vasopressin ( n = 3/dose; 8IU/kg, 16IU/kg, or 32IU/kg). In all groups, a 3mL saline bolus was administered immediately after the vasopressin dose. 21,22 . IV vasopressin was used as a control as the IV route provides 100% drug bioavailability and immediate administration into systemic circulation. Preliminary tests on a few piglets were conducted to determine the optimal ETT vasopressin doses. IN vasopressin doses were based on a study administering ~ 2.1–3.1IU/kg IN vasopressin in macaques 23 , but doses were increased following a lack of hemodynamic response to 4IU/kg IN vasopressin. All piglets, regardless of randomization, underwent insertion of an intraosseous needle during surgical instrumentation to ensure each piglet underwent similar surgical procedures. Arterial blood was collected before vasopressin administration (baseline), 1, 2, 3, 4, 5, and 10 minutes after vasopressin administration. Following final collection of blood, piglets were euthanized with an intravenous overdose of sodium pentobarbital (100 mg/kg). Data collection and Statistical analysis Demographics of study piglets were recorded. Transonic flow probes, heart rate, and pressure transducer outputs, and Millar catheter were digitized and recorded with LabChart® programming software (ADInstruments, Houston, TX). Blood samples were collected and centrifuged at 11,000 rpm for five minutes, plasma was then separated and stored at -80°C. Concentrations of vasopressin were quantified using commercially available ELISA kits (K049-H1, Arbor Assays, Ann Arbor, Michigan, USA). Analysis of pharmacokinetic parameters was performed with the Non-Compartmental Analysis program of the SimBiology Model Analyzer app within MATLAB (MATLAB ver. R2023b, MathWorks, Natick, MA, USA). The data was tested for normality (Shapiro-Wilk and Kolmogorov-Smirnov test) and compared using ANOVA for repeated measures using Tukey post-test for parametric and Dunn’s test for nonparametric comparisons of continuous variables, and Fisher’s exact test for categorical variables. The data are presented as mean (standard deviation - SD) for normally distributed continuous variables and median (interquartile range - IQR) when the distribution was skewed. P -values are 2-sided and p < 0.05 was considered statistically significant. Statistical analyses were performed with SigmaPlot (Systat Software Inc, San Jose, USA). Results 44 newborn mixed breed piglets (1–3 days of age, weighing 2.0kg (± 0.23kg)) were obtained on the day of experimentation. There were no differences in baseline parameters between IV and IO piglets (Table 1 ) or ETT and IN piglets within each route and vasopressin dose (Table 2 ). The sample size was reduced from five piglets per IN dose to three due the lack of hemodynamic response following drug administration. Table 1 Baseline characteristics of intravenous and intraosseous doses. IV IO p-value Vaso 0.4 ( n = 5) Vaso 0.2 ( n = 5) Vaso 0.4 ( n = 5) Vaso 0.8 ( n = 5) Age (days) 2 ( 2 – 3 ) 2 ( 2 – 3 ) 3 ( 3 – 3 ) 3 ( 3 – 3 ) 0.30 Weight (kg) 2.1 (1.9–2.2) 2.1 (1.7–2.1) 2.2 (2.2–2.4) 2.3 (2.2–2.3) 0.16 Sex (male/female) 3/2 ¼ 2/3 3/2 0.58 pH 7.44 (7.44–7.44) 7.46 (7.45–7.50) 7.44 (7.42–7.47) 7.46 (7.41–7.47) 0.96 paCO 2 (torr) 35.2 (34.3–39.7) 33.8 (32.4–36.3) 35.4 (32.6–35.5) 33.7 (33.3–33.9) 0.47 paO 2 (torr) 82.7 (65.9–83.5) 90 (82.4–91.7) 87.8 (84.2–88.2) 82.2 (64.7–87.1) 0.20 Base excess (mmol/L) 0.7 (-0.2 ~ 2.9) 1.2 (-1.1 ~ 1.8) -2.2 (-3 ~ 2.3) 0.6 (-3 ~ 2) 0.75 Lactate (mmol/L) 3.31 (3.14–3.33) 3.87 (3.77–4.32) 4.43 (4.3–5.21) 5.9 (4.77–7.13) 0.15 Hemoglobin (g/0.1L) 7.4 (7.1–9) 6.7 (6.4–6.9) 7.3 (6.6–9.2) 7.3 (6.8–7.7) 0.23 Heart rate (bpm) 160 (152–166) 188 (182–188) 189 (159–196) 195 (175–200) 0.15 Mean arterial pressure (mmHg) 61 (59–65) 63 (61–73) 63 (61–65) 63 (57–75) 0.36 Carotid blood flow (mL/kg/min) 89 (52–96) 86 (77–100) 78 (73–88) 96 (92–103) 0.82 Cardiac output (mL/kg/min) 431 (407.36–495) 535 (530–575) 327 (287–523) 478.5 (333.5–530.5) 0.68 Ejection fraction (%) 45.61 (39.93–47.55) 34 (34–43) 28.7 (22–35.1) 37 (26.5–41) 0.36 Stroke volume (mL/kg/min) 2.69 (2.68–2.75) 3.03 (2.84–3.12) 2.13 (1.58–2.19) 2.21 (1.56–2.51) 0.18 dp/dt max (mmHg) 2690 (2157–2890) 2998 (2635–3777) 3323 (2623–3615) 3451 (2877.5–4227.5) 0.48 dp/dt min (mmHg) -2776 (-3062~ -2022) -4172 (-4792~ -3502) -3608 (-4009~ -3171) -3858.5 (-4616.5~ -3192) 0.09 Data are presented as median (IQR); IV, intravenous; IO, intraosseous; Vaso, vasopressin. P-values are comparing all IO vasopressin doses to IV vasopressin. Table 2 Baseline characteristics of endotracheal and intranasal doses. ETT p-value IN p-value Vaso 4 ( n = 5) Vaso 8 ( n = 5) Vaso 16 ( n = 5) Vaso 8 ( n = 3) Vaso 16 ( n = 3) Vaso 32 ( n = 3) Age (days) 2 ( 1 – 2 ) 1 ( 1 – 2 ) 2 ( 1 – 2 ) 0.77 3 ( 2 – 3 ) 2 ( 1 – 2 ) 1 ( 1 – 3 ) 0.30 Weight (kg) 1.9 (1.8–1.9) 1.8 (1.8–2) 2 (1.8–2.1) 0.67 2.3 (2–2.3) 2.1 (1.8–2.2) 2 (1.9–2.1) 0.35 Sex (male/female) 2/2 4/1 4/1 0.59 2/1 3/0 2/1 0.63 pH 7.433 (7.427–7.448) 7.479 (7.449–7.492) 7.488 (7.429–7.5) 0.79 7.491 (7.411– 7.496) 7.531 (7.53–7.56) 7.484 (7.474–7.508) 0.06 paCO 2 (torr) 34.5 (32.7–36.7) 33.6 (31.4–35.3) 32.7 (31.9–34.9) 0.80 30.8 (30.3–37.5) 29 (28.1–30.5) 31.3 (30.9–39) 0.33 paO 2 (torr) 74.8 (69.2–79.1) 83.4 (77.6–86.1) 75.2 (71.1–79.9) 0.10 83.5 (70.1–92.9) 79.8 (73.3–90.4) 74.7 (61.4–83) 0.53 Base excess (mmol/L) -1 (-1.2~ -0.1) -0.1 (-0.6 ~ 2.6) 1.7 (-1.3 ~ 3.1) 0.80 0.2 (-0.8 ~ 0.3) 2.8 (0.8 ~ 3.8) 1.8 (-0.2 ~ 5) 0.23 Lactate (mmol/L) 4.25 (4.2–5.06) 3.81 (2.94–4.29) 4.57 (4.23–4.58) 0.78 4.25 (3.56–5.05) 4.26 (3.81–4.86) 4.31 (3.9–4.93) 0.98 Hemoglobin (g/0.1L) 7.9 ( 7 – 8 ) 8.2 (8–9.6) 7.9 (7.8–9.7) 0.80 8.4 (6.8–8.6) 8.2 (8.2–9.8) 6.8 (6.5–8.1) 0.19 Heart rate (bpm) 163 (158–175) 137 (122–138) 167 (122–192) 0.43 166 (129–180) 156 (155–166) 143 (134–150) 0.42 Mean arterial pressure (mmHg) 67 (64–68) 53 (48–58) 53 (51–58) 0.009 64 (61–66) 61 (58–65) 60 (53–61) 0.22 Carotid blood flow (mL/kg/min) 83 (76–87) 56 (53–64) 63 (58–68) 0.30 62 (49–74) 70 (63–71) 60 (53–72) 0.66 Cardiac output (mL/kg/min) 384 (380–384) 290 (222–322) 320 (311–326) 0.32 259.05 (219.3–298.8) 514.7 (465–564.4) 375.2 (300.3–495) 0.09 Ejection fraction (%) 36 (27–37) 41 (35–45) 29 (28–33) 0.14 40 (28.7–51.3) 37.1 (32.6–41.6) 28.1 (24.5–59.7) 0.98 Stroke volume (mL/kg/min) 2.51 (1.72–2.9) 2.04 (1.92–2.1) 2.24 (1.81–2.43) 0.65 1.75 (1.7–1.8) 3.2 (3–3.4) 2.8 (2.1–3.3) 0.07 dp/dt max (mmHg) 2943 (2611–3742) 2278 (2212–2671) 2262 (2248–3224) 0.37 2727 (2239–3215) 2670.5 (2634–2707) 2530 (220.1–2584) 0.68 dp/dt min (mmHg) -3526 (-4393~ -3380) -3230 (-3339~ -3077) -3275 (-3816~ -2587) 0.40 -3301 (-3684~ -2918) -3832 (-4182~ -3482) -3357 (-3540~ -3169) 0.40 Data are presented as median (IQR); ETT, endotracheal tube; IN, intranasal; Vaso, vasopressin. Intraosseous Route There were no significant changes in heart rate, dP/dT maximum or minimum in any vasopressin dose compared to baseline values or IV vasopressin (Fig. 2 a, g, h). MAP significantly increased for two minutes with 0.2IU/kg vasopressin, and five minutes with 0.4IU/kg, 0.8IU/kg, and IV vasopressin (Fig. 2 b). Carotid blood flow significantly decreased five-, 10- and 10-minutes post-drug administration with 0.4IU/kg, 0.8IU/kg, and IV vasopressin, respectively, while carotid blood flow was decreased two-minutes after 0.2IU/kg vasopressin administration, but had comparable values to baseline from three to 10 minutes (Fig. 2 c). Carotid blood flow was significantly higher after 0.2IU/kg vasopressin administration for four minutes compared to IV vasopressin (Fig. 2 c). Cardiac output was significantly decreased with 0.2 and 0.4IU/kg vasopressin one- and two-minutes after drug administration, respectively (Fig. 2 d). Compared to IV vasopressin, 0.4IU/kg vasopressin had significantly lower ejection fraction (8.4 (7.7–9.8)% vs. 23.3 (22.5–32.6)%, respectively, p = 0.042) and stroke volume (0.7 (0.63–0.91) mL/kg/min vs. 1.32 (1.31–2.63) mL/kg/min, respectively, p = 0.021) one minute after drug administration (Fig. 2 e & f). Endotracheal Route There were no changes from baseline in heart rate, carotid blood flow, cardiac output, ejection fraction, stroke volume, and dP/dT maximum or minimum with any vasopressin dose administered endotracheally (Fig. 3 a, d–h). Significant differences in MAP and carotid blood flow were observed between IV vasopressin and all ETT vasopressin doses (Fig. 3 b, c). Cardiac output was higher one minute after drug administration with 4IU/kg vasopressin compared to IV vasopressin (466 (394–558) mL/kg/min vs. 193.1 (170.3–365.8) mL/kg/min, respectively, p = 0.045) (Fig. 3 d). dP/dT minimum was significantly lower with 4 and 16IU/kg vasopressin compared to IV vasopressin (Fig. 3 h). Intranasal Route There were no changes in heart rate, carotid blood flow, cardiac output, ejection fraction, stroke volume, dP/dT maximum or minimum with any doses from baseline within the IN route (Fig. 4 a, c–h). 32IU/kg vasopressin had significantly higher MAP 10 minutes after IN drug administration compared to baseline (82 (72–96) vs. 60 (53–61)), respectively, p = 0.016) (Fig. 4 b). MAP and dP/dT minimum were significantly higher with IV vasopressin compared to all IN vasopressin doses, while carotid blood flow was higher with IN vasopressin doses compared to IV vasopressin (Fig. 4 b, h, c). Plasma Vasopressin Concentrations There were no differences in plasma vasopressin concentrations between any IO vasopressin dose (0.2, 0.4, or 0.8IU/kg) and IV vasopressin (Fig. 5 a). Compared to IV vasopressin, 4, 8, and 16IU/kg ETT vasopressin had significantly lower plasma vasopressin concentrations two-, three-, and five-minutes after drug administration, respectively (Fig. 5 b). 8 and 16IU/kg IN vasopressin had significantly lower plasma concentrations at all measured time points compared to IV vasopressin (Fig. 5 c). 32IU/kg IN vasopressin achieved comparable plasma concentrations to IV vasopressin 10-minutes after drug administration (Fig. 5 c). Pharmacokinetic Parameters All parameters were comparable after IV or any IO vasopressin doses (Fig. 6 I–V). C max values were significantly lower with 4IU/kg ETT vasopressin (958 (44) pg/mL, p < 0.0001), 8IU/kg IN (384 (126) pg/mL, p < 0.0001), and 16IU/kg IN vasopressin (399 (363) pg/mL, p < 0.0001) compared to IV vasopressin (2,253 (63)). Significantly lower AUC 0– t compared to IV vasopressin (1,6213 (680) pg⋅min/mL) was observed with 4IU/kg ETT (7,264 (1,576) pg/min/mL, p = 0.02), 8IU/kg IN (675 (681) pg/min/mL, p < 0.0001) and 16IU/kg IN vasopressin (2,012 (1,952) pg/min/mL, p < 0.0001). T max was significantly higher in all ETT vasopressin and 32IU/kg IN vasopressin piglets compared to IV vasopressin (Fig. 6III, p < 0.05). Elimination parameters of clearance and half-life could not be calculated for any ETT or IN doses as drug elimination had not yet begun. Discussion There is a need to find the optimal vasoactive drugs during neonatal CPR 3 . While several studies have compared epinephrine and vasopressin during CPR in animal models, this paper is the first study to systematically assess the pharmacokinetic and pharmacodynamics of vasopressin administered via different routes. In our current study, we compared 0.4IU/kg IV vasopressin to vasopressin administered via IO, ETT or IN. The results of our study can be summarized as follows: ( 1 ) IO vasopressin resulted in most significant changes in hemodynamic parameters (Fig. 2 ), ( 2 ) C max and T max were not different between IO or IV vasopressin doses (Fig. 6 ), and ( 3 ) ETT and IN routes resulted in poor drug absorption and hemodynamic response (Figs. 3 – 6 ). There were no differences in pharmacokinetics between IO and IV vasopressin, which indicates that IO administration is as effective as IV administration for vasopressin delivery and absorption. In a pediatric swine model of ventricular fibrillation, Wenzel et al compared 0.8IU/kg IV and IO vasopressin and reported similar plasma concentrations during CPR and the post–resuscitation period 24 . Similarly, Wimmer et al compared humeral IO and IV administration of vasopressin in a hypovolemic swine model and reported no differences between mean C max , T max , serum concentrations during CPR, rates of ROSC, or survival 25 . Although, 0.8IU/kg IO vasopressin produced comparable hemodynamic and pharmacokinetic changes compared to 0.4IU/kg IO or IV vasopressin, we previously reported that 0.8IU/kg IV vasopressin resulted in significantly higher base excess and lactate concentrations four hours after resuscitation compared to 0.4IU/kg IV vasopressin 26 . Therefore, it appears that 0.4IU/kg vasopressin might be the preferable dose during neonatal resuscitation. Significantly lower C max with 4IU/kg ETT vasopressin and higher T max in all ETT vasopressin doses compared to IV vasopressin indicates that the ETT route is an inefficient route of vasopressin administration. The significantly lower C max and AUC with 8IU/kg and 16IU/kg IN compared to IV vasopressin indicates that IN administration of vasopressin is not an alternative for drug administration during neonatal CPR. ETT and IN administered vasopressors must be absorbed by epithelial cells and then transported into the systemic circulation, while IV and IO administered vasopressors are immediately deposited into circulation. This may account for the higher T max values of ETT and IN compared to IV and IO routes. The lack of significant changes in hemodynamic parameters following IN and ETT administration of vasopressin may be due to its poor absorption into systemic circulation. Poor absorption may result from the rapid metabolism of vasopressin by peptidases located throughout the respiratory tract; however, without radioimmunoassay analyses we can only speculate if vasopressin was metabolized 27,28 . A study examining plasma concentrations of IN-administered 1-deamino-8-D-arginine vasopressin (DDAVP, a vasopressin analogue) in healthy adult males reported a bioavailability of approximately 10%, and peak plasma concentrations were observed 1–2 hours after drug administration 29 . While elimination of vasopressin occurred within the IV and IO routes, there was no clearance after ETT or IN administration within 10 minutes, demonstrating delayed absorption. Therefore elimination parameters of clearance and half-life could be determined for IV and IO vasopressin doses, but not ET or IN doses (Fig. 6 IV–V), Limitations Based on the principle of reducing use in animal experiments, we discontinued the IN route after 12 piglets as we could not justify including further piglets without the prospect of achieving significant changes in hemodynamic parameters. Our neonatal model uses piglets that have already undergone the fetal to neonatal transition. Nevertheless, our findings are still clinically relevant as the distribution of cardiac output to vital organs (i.e. brain and heart) in the fetus and post-transitional neonate during asphyxia episodes are quantitatively similar 30,31 . Additionally, piglets were euthanized 10 minutes after drug administration; therefore, no comparisons could be made on potential long-term changes that may occur hours after drug administration. The only IN vasopressin dosage that produced any significant changes from baseline was 32IU/kg; however, tissue injury markers were not analyzed and requires further evaluation before clinical translation. Furthermore, our study examined various vasopressin doses in healthy post-transitional piglets, and will need to be replicated in a cardiac arrest model. Conclusion The IO route provides rapid vasopressin delivery and absorbance, and analysis of pharmacokinetic parameters demonstrates comparable results as IV-treated piglets. In our study IO vasopressin at 0.4IU/kg was most effective. Administration of vasopressin via ETT or IN resulted in unreliable absorption, no hemodynamics changes, and therefore might be unreliable during neonatal resuscitation. Declarations Competing interests: No, I declare that the authors have no competing interests as defined by Nature Research, or other interests that might be perceived to influence the results and/or discussion reported in this paper. Funding sources We would like to thank the public for donating money to our funding agencies: The study was support by a Grant-in-Aid from the Heart and Stroke Foundation Canada. MR is a recipient of the Canadian Institutes of Health Research Canada Graduate Scholarships-Master’s program, Walter H Johns Graduate Fellowship, Alberta Graduate Excellence Scholarship, and Medical Sciences Graduate Program Scholarship. Author Contribution Author’s contribution: Conception and design: GMS, MOR, MR, PYC, TFLCollection and assembly of data: GMS, MOR, MR, PYC, TFLAnalysis and interpretation of the data: GMS, MOR, MR, PYC, TFLDrafting of the 1st draft: MRCritical revision of the article for important intellectual content: GMS, MOR, MR, PYC, TFL Final approval of the article: GMS, MOR, MR, PYC, TFL Data Availability The datasets generated and analyzed for this study are available from the corresponding author (GMS), upon reasonable request The authors declare no conflict of interest. References Garcia-Hidalgo, C. & Schmölzer, G. M. Chest Compressions in the Delivery Room. Children (Basel) 6, 4 (2019). Halling, C. et al. Neonatal delivery room CPR: An analysis of the Get with the Guidelines®—Resuscitation Registry. Resuscitation 158, 236–242 (2021). Wyckoff, M. H. et al. Neonatal Life Support: 2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Circulation 142, S185–S221 (2020). Turner, D. W., Attridge, R. L. & Hughes, D. W. Vasopressin Associated With an Increase in Return of Spontaneous Circulation in Acidotic Cardiopulmonary Arrest Patients. Ann Pharmacother 48, 986–991 (2014). Papastylianou, A. & Mentzelopoulos, S. Current Pharmacological Advances in the Treatment of Cardiac Arrest. Emerg Med Int 2012, 815857 (2012). Schaer, H. Influence of respiratory and metabolic acidosis on epinephrine-inotropic effect in isolated guinea pig atria. Pflugers Arch. 347, 297–307 (1974). Fries, M., Tang, W., Chang, Y.-T., Castillo, C. & Weil, M. H. DETRIMENTAL EFFECTS OF EPINEPHRINE ON MICROCIRCULATORY BLOOD FLOW IN A PORCINE MODEL OF CARDIAC ARREST: 212. Critical Care Medicine 32, A56 (2004). Ristagno, G. et al. Epinephrine reduces cerebral perfusion during cardiopulmonary resuscitation*. Critical Care Medicine 37, 1408 (2009). Wyckoff, M. H. et al. Neonatal Life Support: 2020 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations. Circulation 142, S185–S221 (2020). Fox, A. W., May, R. E. & Mitch, W. E. Comparison of peptide and nonpeptide receptor-mediated responses in rat tail artery. J Cardiovasc Pharmacol 20, 282–289 (1992). Wenzel, V. et al. A Comparison of Vasopressin and Epinephrine for Out-of-Hospital Cardiopulmonary Resuscitation. N Engl J Med 350, 105–113 (2004). Mann, K., Berg, R. A. & Nadkarni, V. Beneficial effects of vasopressin in prolonged pediatric cardiac arrest: a case series. Resuscitation 52, 149–156 (2002). Duncan, J. M. et al. Vasopressin for in-hospital pediatric cardiac arrest: Results from the American Heart Association National Registry of Cardiopulmonary Resuscitation*. Pediatric Critical Care Medicine 10, 191–195 (2009). Carroll, T. G., Dimas, V. V. & Raymond, T. T. Vasopressin rescue for in-pediatric intensive care unit cardiopulmonary arrest refractory to initial epinephrine dosing: a prospective feasibility pilot trial. Pediatr Crit Care Med 13, 265–272 (2012). Percie du Sert, N. et al. The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research. BMC Veterinary Research 16, 242 (2020). Schmölzer, G. M. et al. Cardiopulmonary resuscitation with chest compressions during sustained inflations: a new technique of neonatal resuscitation that improves recovery and survival in a neonatal porcine model. Circulation 128, 2495–2503 (2013). Schmölzer, G. M. et al. 3:1 compression to ventilation ratio versus continuous chest compression with asynchronous ventilation in a porcine model of neonatal resuscitation. Resuscitation 85, 270–275 (2014). Cheung, P.-Y., Gill, R. S. & Bigam, D. L. A Swine Model of Neonatal Asphyxia. J Vis Exp 3166 (2011) doi: 10.3791/3166 . Wagner, M. et al. Effects of epinephrine on hemodynamic changes during cardiopulmonary resuscitation in a neonatal piglet model. Pediatr Res 83, 897–903 (2018). Shen, W., Xu, X., Lee, T.-F., Schmölzer, G. & Cheung, P.-Y. The Relationship Between Heart Rate and Left Ventricular Isovolumic Relaxation During Normoxia and Hypoxia-Asphyxia in Newborn Piglets. Front Physiol 10, 525 (2019). Sankaran, D. et al. Effect of a Larger Flush Volume on Bioavailability and Efficacy of Umbilical Venous Epinephrine during Neonatal Resuscitation in Ovine Asphyxial Arrest. Children (Basel) 8, 464 (2021). Sankaran, D. et al. Randomised trial of epinephrine dose and flush volume in term newborn lambs. Arch Dis Child Fetal Neonatal Ed 106, 578–583 (2021). Jiang, Y. & Platt, M. L. Oxytocin and vasopressin increase male-directed threats and vocalizations in female macaques. Sci Rep 8, 18011 (2018). Wenzel, V. et al. Intraosseous vasopressin improves coronary perfusion pressure rapidly during cardiopulmonary resuscitation in pigs. Critical Care Medicine 27, 1565–1569 (1999). Mark H. Wimmer, B. S. N. et al. The comparison of humeral intraosseous and intravenous administration of vasopressin on return of spontaneous circulation and pharmacokinetics in a hypovolemic cardiac arrest swine model. American Journal of Disaster Medicine 11, 237–242 (2016). Ramsie, M., Cheung, P.-Y., Lee, T.-F., O’Reilly, M. & Schmölzer, G. M. Comparison of various vasopressin doses to epinephrine during cardiopulmonary resuscitation in asphyxiated neonatal piglets. Pediatr Res 1–8 (2023) doi: 10.1038/s41390-023-02858-x . Patton, J. S. et al. The Particle has Landed—Characterizing the Fate of Inhaled Pharmaceuticals. Journal of Aerosol Medicine and Pulmonary Drug Delivery 23, S-71 (2010). Guo, Y. et al. Pharmaceutical strategies to extend pulmonary exposure of inhaled medicines. Acta Pharm Sin B 11, 2565–2584 (2021). Vilhardt, H. & Lundin, S. Biological effect and plasma concentrations of DDAVP after intranasal and peroral administration to humans. General Pharmacology: The Vascular System 17, 481–483 (1986). Cohn, H. E., Sacks, E. J., Heymann, M. A. & Rudolph, A. M. Cardiovascular responses to hypoxemia and acidemia in fetal lambs. American Journal of Obstetrics and Gynecology 120, 817–824 (1974). Rudolph, A. M. Distribution and regulation of blood flow in the fetal and neonatal lamb. Circ Res 57, 811–821 (1985). Additional Declarations No competing interests reported. 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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-4637657","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":328111976,"identity":"4808c127-7593-418d-aadc-141f9604079d","order_by":0,"name":"Ramsie M BSc","email":"","orcid":"","institution":"University of Alberta","correspondingAuthor":false,"prefix":"","firstName":"Ramsie","middleName":"M","lastName":"BSc","suffix":""},{"id":328111977,"identity":"20234f1e-a485-47d4-be5b-474934c30790","order_by":1,"name":"P-Y Cheung","email":"","orcid":"","institution":"University of Alberta","correspondingAuthor":false,"prefix":"","firstName":"P-Y","middleName":"","lastName":"Cheung","suffix":""},{"id":328111978,"identity":"fc65712e-3fac-4629-b04e-9c4ded9a4418","order_by":2,"name":"O’Reilly M PhD","email":"","orcid":"","institution":"University of Alberta","correspondingAuthor":false,"prefix":"","firstName":"O’Reilly","middleName":"","lastName":"M","suffix":"PhD"},{"id":328111979,"identity":"9f840234-22a9-4f89-a7fd-f84e56fe6614","order_by":3,"name":"Lee TF","email":"","orcid":"","institution":"University of Alberta","correspondingAuthor":false,"prefix":"","firstName":"Lee","middleName":"","lastName":"TF","suffix":""},{"id":328111980,"identity":"eb25b30e-9af2-416c-801d-3880f443df62","order_by":4,"name":"Georg M. Schmölzer","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8klEQVRIie2PsWrDMBCGT2g1ZCsqDegVzhgSCqFrX+NAoMmQ1ZMJBJolD1Dw0FfIFOgmI/DkOYsWZ8/gQgcNgTbuGLBCtg764G44/o+fA4hE/jM4rO4yk/sUuszj6m4FzY2kfF03X99QyvmDrTs6L5bZwRrwxX5USdtGVVOw6WelFVKin/dOE9u2blx5zzMuwBC6fCZIWJy5HDl7Cygfp0EpB2XuCX8wq5Z9UJEiyVgP/K8FiAziUw5BBROtOKBNd04rQUahcBrr0C9yYy3zRSnRqbrvzy84qdSx80WgxQDwBK+uZjQ/tKwAmA8lIpFIJPIL5/RVOvua/vAAAAAASUVORK5CYII=","orcid":"","institution":"University of Alberta","correspondingAuthor":true,"prefix":"","firstName":"Georg","middleName":"M.","lastName":"Schmölzer","suffix":""}],"badges":[],"createdAt":"2024-06-25 15:48:49","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4637657/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4637657/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41598-024-74188-9","type":"published","date":"2024-10-04T15:58:30+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":61192964,"identity":"0ca1c976-5273-47a0-b1bd-1129de0c543b","added_by":"auto","created_at":"2024-07-26 20:55:57","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":212011,"visible":true,"origin":"","legend":"\u003cp\u003eStudy flow chart.\u003c/p\u003e","description":"","filename":"VasoPKPDFig1.png","url":"https://assets-eu.researchsquare.com/files/rs-4637657/v1/0f0d89dfff062b712a476074.png"},{"id":61192967,"identity":"25f365c1-ed92-42a9-a475-0994dcee4494","added_by":"auto","created_at":"2024-07-26 20:56:02","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1823449,"visible":true,"origin":"","legend":"\u003cp\u003eChanges in hemodynamic and cardiac function parameters following intraosseous vasopressin administration. Data are presented as mean (SD). Changes in (a) heart rate, (b) mean arterial blood pressure (c) carotid blood flow (d) cardiac output (e) ejection fraction (f) stroke volume, (g) dP/dT\u003csub\u003emax\u003c/sub\u003e, and (h) dP/dT\u003csub\u003emin\u003c/sub\u003e. # Significantly different from baseline; * Significantly different from 0.4IU/kg IV vasopressin (\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.05).\u003c/p\u003e","description":"","filename":"VasoPKPDFig.2.png","url":"https://assets-eu.researchsquare.com/files/rs-4637657/v1/3df762d5c0e12f1c72e76db9.png"},{"id":61192968,"identity":"553d0a97-3815-4b71-a9b6-0dad2e133287","added_by":"auto","created_at":"2024-07-26 20:56:02","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":1611798,"visible":true,"origin":"","legend":"\u003cp\u003eChanges in hemodynamic and cardiac function parameters following endotracheal vasopressin administration. Data are presented as mean (SD). Changes in (a) heart rate, (b) mean arterial blood pressure, (c) carotid blood flow, (d) cardiac output, (e) ejection fraction, (f) stroke volume, (g) dP/dT\u003csub\u003emax\u003c/sub\u003e, and (h) dP/dT\u003csub\u003emin\u003c/sub\u003e. # Significantly different from baseline; * Significantly different from 0.4IU/kg IV vasopressin at the concurrent time point (\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.05).\u003c/p\u003e","description":"","filename":"VasoPKPDFig.3.png","url":"https://assets-eu.researchsquare.com/files/rs-4637657/v1/5df4bf99c319d022ac1636a3.png"},{"id":61192965,"identity":"5ea481fe-19c1-47a4-8cb0-c7a2bda33892","added_by":"auto","created_at":"2024-07-26 20:55:57","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1651855,"visible":true,"origin":"","legend":"\u003cp\u003eChanges in hemodynamic and cardiac function parameters following nasal vasopressin administration. Data are presented as mean (SD). Changes in (a) heart rate, (b) mean arterial blood pressure, (c) carotid blood flow, (d) cardiac output, (e) ejection fraction, (f) stroke volume, (g) dP/dT\u003csub\u003emax\u003c/sub\u003e, and (h) dP/dT\u003csub\u003emin\u003c/sub\u003e. # Significantly different from baseline; * Significantly different from 0.4IU/kg IV vasopressin at the concurrent time point (\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.05)\u003c/p\u003e","description":"","filename":"VasoPKPDFig.4.png","url":"https://assets-eu.researchsquare.com/files/rs-4637657/v1/ae6fc87c966e0436bf52c899.png"},{"id":61192963,"identity":"96f931f8-62d4-459e-a230-9c35861fe218","added_by":"auto","created_at":"2024-07-26 20:55:57","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":1471949,"visible":true,"origin":"","legend":"\u003cp\u003ePlasma vasopressin concentrations following drug administration. Data are presented as mean (SD). Plasma vasopressin concentration after administration via (a) intraosseous (IO), (b) endotracheal (ETT), and (c) intranasal (IN) routes. In the IO group piglets were administered vasopressin 0.2IU/kg (blue circle), 0.4IU/kg (green circle), and 0.8IU/kg (purple circle. In the ETT group piglets were administered vasopressin 4IU/kg (blue circle), 8IU/kg (green circle), and 16IU/kg (purple circle). In the IN group, piglets were administered vasopressin 8IU/kg (blue circle), 16IU/kg (green circle), and 32IU/kg (purple circle). All doses were compared to 0.4IU/kg IV vasopressin (red circle). * Significantly different from 0.4IU/kg IV vasopressin at the concurrent time point (\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.05).\u003c/p\u003e","description":"","filename":"VasoPKPDFig.5.png","url":"https://assets-eu.researchsquare.com/files/rs-4637657/v1/aadb0b6a811fe926f85186f9.png"},{"id":61192962,"identity":"01029c95-42bf-4c13-8c71-d4d131e90725","added_by":"auto","created_at":"2024-07-26 20:55:57","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":362225,"visible":true,"origin":"","legend":"\u003cp\u003e(I) Maximum vasopressin plasma concentration, (II) AUC (area under the curve) from baseline to 10 minutes, (III) time to maximum plasma concentration, (IV) clearance, and (V) half-life. Data are presented as mean (SD). IV, intravenous (red); IO, intraosseous (blue); ET, endotracheal (green); and IN, intranasal (grey). a, significantly different from the IV vasopressin group; b, significantly different from the 0.2IU/kg IO group; c, significantly different from the 0.8IU/kg IO group; d, significantly different from the 8IU/kg IN group; e, significantly different from the 16IU/kg IN group; f, significantly different from the 32IU/kg IN group (\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.05).\u003c/p\u003e","description":"","filename":"VasoPKPDFig.6.png","url":"https://assets-eu.researchsquare.com/files/rs-4637657/v1/a8245c2515ce4a6fc7a7bbcf.png"},{"id":66097823,"identity":"8dc01aa9-0cc2-4b48-93a6-d054fe5f6871","added_by":"auto","created_at":"2024-10-07 16:15:13","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":5621065,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4637657/v1/9fe8e9ac-3eab-4f2c-95c0-cc16286d91f3.pdf"},{"id":61193629,"identity":"be15a9ab-7841-4a98-baba-108204da0b35","added_by":"auto","created_at":"2024-07-26 21:03:57","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":284725,"visible":true,"origin":"","legend":"","description":"","filename":"AuthorChecklistFull.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4637657/v1/f5645fa0697276a7ecb099ae.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Pharmacokinetic and pharmacodynamic evaluation of various vasopressin doses and routes in a neonatal piglet model","fulltext":[{"header":"Introduction","content":"\u003cp\u003eNeonatal cardiac arrest is primarily caused by perinatal asphyxia, and ~\u0026thinsp;0.1% of term and up to 15% of preterm infants at birth will require resuscitation with high-quality chest compressions and a vasopressor (i.e. epinephrine) for survival\u003csup\u003e1,2\u003c/sup\u003e. The current Neonatal Consensus of Science and Treatment Recommendation (CoSTR) recommends epinephrine at a dose of 0.01\u0026ndash;0.03mg/kg, preferably given intravenous (IV) or intraosseous (IO) every 3\u0026ndash;5 minutes during cardiopulmonary resuscitation (CPR)\u003csup\u003e3\u003c/sup\u003e. Epinephrine may also be given via an endotracheal tube (ETT) at a dose of 0.05\u0026ndash;0.1mg/kg\u003csup\u003e3\u003c/sup\u003e. Epinephrine is currently the only recommended vasopressor during CPR, however, epinephrine increases myocardial oxygen demand, inhibits hemodynamic responses (e.g., aggravated arterial hypertension following return of spontaneous circulation (ROSC), reduced efficacy during respiratory and metabolic acidosis, and microcirculation impairment)\u003csup\u003e4\u0026ndash;8\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eVasopressin, an antidiuretic hormone, might be an alternative to epinephrine, as its efficacy is not impaired during metabolic or respiratory acidosis\u003csup\u003e4,9,10\u003c/sup\u003e. Subgroup analysis of randomized trials of adults with out-of-hospital cardiac arrest reported that adults with asystolic arrest and treated with vasopressin had significantly higher rates of survival to hospital admission (29% vs. 20%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.02) and discharge (5% vs. 2%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.04) compared to receiving epinephrine\u003csup\u003e11\u003c/sup\u003e. Similarly, in a case series of four pediatric patients vasopressin at 0.4IU/kg/dose IV administered as rescue therapy, achieved ROSC in 3/4 children, 2/4 survived\u0026thinsp;\u0026gt;\u0026thinsp;24 hours, and 1/4 survived to hospital discharge\u003csup\u003e12\u003c/sup\u003e. Furthermore Duncan \u003cem\u003eet al\u003c/em\u003e reported that 5% of 1,293 pediatric patients received vasopressin during in-hospital cardiac arrest\u003csup\u003e13\u003c/sup\u003e, and although they had significantly longer duration of cardiac arrest (median 37 vs. 24 min, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004) and longer time to ROSC, their survival at 24 h or at discharge was not different to patients receiving epinephrine\u003csup\u003e13\u003c/sup\u003e. A recent feasibility study compared vasopressin (0.8 IU/kg) after an initial epinephrine dose in patients\u0026thinsp;\u0026lt;\u0026thinsp;18 years of age (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;10) to \u0026ge;\u0026thinsp;2 doses of epinephrine\u003csup\u003e14\u003c/sup\u003e. Patients who received vasopressin had increased 24 h survival (80% vs. 30%, odds ratio (OR) (95%CI) 9.3 (1.5\u0026ndash;57.7)), with no difference in time to ROSC, survival to hospital discharge, and neurologic status at discharge.\u003csup\u003e14\u003c/sup\u003e Therefore vasopressin may be beneficial during neonatal CPR because in newborn infants 1) asphyxia results primarily in non-shockable rhythm, rather than ventricular fibrillation and 2) pulmonary vascular resistance is high at birth in newborns. There are no pharmacodynamics and pharmacokinetic data of vasopressin available for newborn infants. Therefore, we aimed to determine pharmacodynamics and pharmacokinetics of vasopressin administered either via IV, IO, ETT, or intranasal (IN) routes to assess the optimal dose for each route in a post-transitional piglet model.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis was a randomized controlled animal trial. 44 newborn mixed breed piglets were obtained on the day of experimentation from the University Swine Research Technology Centre located in Edmonton, Alberta, Canada. All experiments were conducted in accordance with the guidelines and approval of the Animal Care and Use Committee (Health Sciences), University of Alberta [AUP00004212], conducted and presented according to the ARRIVE guidelines\u003csup\u003e15\u003c/sup\u003e, conducted according to the Canadian Council of Animal Care guidelines, and registered at preclinicaltrials.eu (PCTE0000489). A graphical display of the study protocol is presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eInclusion and exclusion criteria\u003c/h2\u003e \u003cp\u003eMixed breed neonatal piglets with a current age of 1\u0026ndash;3 days of age, weighing 2.0 kg (\u0026plusmn;\u0026thinsp;0.23kg) were included. There was no exclusion criterion.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eSample size\u003c/h2\u003e \u003cp\u003eThere was no formal sample size calculation as this study aimed to measure the pharmacodynamic, pharmacokinetic, and hemodynamic effects after epinephrine and vasopressin administration. We aimed for a sample size of 5 piglets per group.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eRandomization\u003c/h2\u003e \u003cp\u003ePiglets were randomly allocated to varying doses of vasopressin administered via IV, IO, ET, or IN. Allocation was block randomized with variable sized blocks using a computer-generated randomization program (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.randomizer.org\u003c/span\u003e\u003cspan address=\"http://www.randomizer.org\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). Sequentially numbered, sealed, brown envelopes containing the allocation were opened during the experiment (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eBlinding\u003c/h2\u003e \u003cp\u003eOne investigator (TFL) opened the randomization envelope and was solely responsible for drug preparation. The content of the drug syringe was only known to TFL to conceal group allocation. All remaining team members were blinded to group allocation. The statistical analysis was blinded to group allocation and only unblinded after the statistical analysis was completed.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eAnimal preparation\u003c/h2\u003e \u003cp\u003ePiglets were instrumented as previously described with modifications\u003csup\u003e16\u0026ndash;18\u003c/sup\u003e. Following the induction of anaesthesia using isoflurane, piglets were intubated via a tracheostomy, and pressure-controlled ventilation (Sechrist Infant Ventilator Model IV-100; Sechrist Industries, Anaheim, California) was commenced at a respiratory rate of 16\u0026ndash;20 breaths/min and pressure of 20/5 cmH\u003csub\u003e2\u003c/sub\u003eO. Oxygen saturation was kept within 90\u0026ndash;100%, glucose level and hydration was maintained with an intravenous infusion of 5% dextrose at 10 mL/kg/hr. During the experiment anaesthesia was maintained with intravenous propofol 5\u0026ndash;10 mg/kg/hr and morphine 0.1 mg/kg/hr. Additional doses of propofol (1\u0026ndash;2 mg/kg) and morphine (0.05\u0026ndash;0.1 mg/kg) were also given as needed. The piglet\u0026rsquo;s body temperature was maintained within a normal porcine temperature range of 38.5\u0026ndash;39.5\u0026deg;C using an overhead warmer and a heating pad.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eHemodynamic parameters\u003c/h2\u003e \u003cp\u003eA 5-French Argyle\u0026reg; (Klein-Baker Medical Inc. San Antonio, TX) double-lumen catheter was inserted via the right femoral vein for administration of fluids and medications. A 5-French Argyle\u0026reg; single-lumen catheter was inserted above the right renal artery via the femoral artery for continuous arterial blood pressure monitoring in addition to arterial blood gas measurements. The right common carotid artery was also exposed and encircled with a real-time ultrasonic flow probe (2mm; Transonic Systems Inc., Ithica, NY) to measure cerebral blood flow\u003csup\u003e16\u0026ndash;18\u003c/sup\u003e. A Millar\u0026reg; catheter (MPVS Ultra1, ADInstruments, Houston, TX) was inserted into the left ventricle via the left common carotid artery for continuous measurement of stroke volume, ejection fraction, end-diastolic and -systolic volumes, left ventricular pressure, and left ventricular contractile function (dp/dt\u003csub\u003emax\u003c/sub\u003e, dp/dt\u003csub\u003emin\u003c/sub\u003e)\u003csup\u003e19,20\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003ePiglets were placed in supine position and allowed to recover from surgical instrumentation until baseline hemodynamic measures were stable (minimum of one hour). Ventilator rate was adjusted to keep the partial arterial CO\u003csub\u003e2\u003c/sub\u003e between 35\u0026ndash;45 mmHg as determined by periodic arterial blood gas analysis. Mean systemic arterial pressure (MAP), systemic systolic arterial pressure, heart rate, and percutaneous oxygen saturation were continuously measured and recorded throughout the experiment with a Hewlett Packard 78833B monitor (Hewlett Packard Co., Palo Alto, CA)\u003csup\u003e16\u0026ndash;18\u003c/sup\u003e.\u003c/p\u003e \u003cdiv id=\"Sec9\" class=\"Section3\"\u003e \u003ch2\u003eExperimental protocol\u003c/h2\u003e \u003cp\u003ePiglets were randomized into four routes and various vasopressin doses: 1) IV vasopressin (0.4IU/kg; \u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5, control), 2) IO vasopressin (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5/dose; 0.2IU/kg, 0.4IU/kg, or 0.8IU/kg), 3) ETT vasopressin (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5/dose; 4IU/kg, 8IU/kg, or 16IU/kg), 4) IN vasopressin (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3/dose; 8IU/kg, 16IU/kg, or 32IU/kg). In all groups, a 3mL saline bolus was administered immediately after the vasopressin dose.\u003csup\u003e21,22\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIV vasopressin was used as a control as the IV route provides 100% drug bioavailability and immediate administration into systemic circulation. Preliminary tests on a few piglets were conducted to determine the optimal ETT vasopressin doses. IN vasopressin doses were based on a study administering\u0026thinsp;~\u0026thinsp;2.1\u0026ndash;3.1IU/kg IN vasopressin in macaques\u003csup\u003e23\u003c/sup\u003e, but doses were increased following a lack of hemodynamic response to 4IU/kg IN vasopressin. All piglets, regardless of randomization, underwent insertion of an intraosseous needle during surgical instrumentation to ensure each piglet underwent similar surgical procedures. Arterial blood was collected before vasopressin administration (baseline), 1, 2, 3, 4, 5, and 10 minutes after vasopressin administration. Following final collection of blood, piglets were euthanized with an intravenous overdose of sodium pentobarbital (100 mg/kg).\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eData collection and Statistical analysis\u003c/h2\u003e \u003cp\u003eDemographics of study piglets were recorded. Transonic flow probes, heart rate, and pressure transducer outputs, and Millar catheter were digitized and recorded with LabChart\u0026reg; programming software (ADInstruments, Houston, TX). Blood samples were collected and centrifuged at 11,000 rpm for five minutes, plasma was then separated and stored at -80\u0026deg;C. Concentrations of vasopressin were quantified using commercially available ELISA kits (K049-H1, Arbor Assays, Ann Arbor, Michigan, USA). Analysis of pharmacokinetic parameters was performed with the Non-Compartmental Analysis program of the SimBiology Model Analyzer app within MATLAB (MATLAB ver. R2023b, MathWorks, Natick, MA, USA).\u003c/p\u003e \u003cp\u003eThe data was tested for normality (Shapiro-Wilk and Kolmogorov-Smirnov test) and compared using ANOVA for repeated measures using Tukey post-test for parametric and Dunn\u0026rsquo;s test for nonparametric comparisons of continuous variables, and Fisher\u0026rsquo;s exact test for categorical variables. The data are presented as mean (standard deviation - SD) for normally distributed continuous variables and median (interquartile range - IQR) when the distribution was skewed. \u003cem\u003eP\u003c/em\u003e-values are 2-sided and p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. Statistical analyses were performed with SigmaPlot (Systat Software Inc, San Jose, USA).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e44 newborn mixed breed piglets (1\u0026ndash;3 days of age, weighing 2.0kg (\u0026plusmn;\u0026thinsp;0.23kg)) were obtained on the day of experimentation. There were no differences in baseline parameters between IV and IO piglets (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) or ETT and IN piglets within each route and vasopressin dose (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). The sample size was reduced from five piglets per IN dose to three due the lack of hemodynamic response following drug administration.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics of intravenous and intraosseous doses.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIV\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c5\" namest=\"c3\"\u003e \u003cp\u003eIO\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVaso 0.4 (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eVaso 0.2 (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eVaso 0.4 (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eVaso 0.8 (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3 (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.1 (1.9\u0026ndash;2.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.1 (1.7\u0026ndash;2.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.2 (2.2\u0026ndash;2.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.3 (2.2\u0026ndash;2.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex (male/female)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3/2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026frac14;\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2/3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3/2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.58\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.44 (7.44\u0026ndash;7.44)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.46 (7.45\u0026ndash;7.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.44 (7.42\u0026ndash;7.47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7.46 (7.41\u0026ndash;7.47)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.96\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epaCO\u003csub\u003e2\u003c/sub\u003e (torr)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e35.2 (34.3\u0026ndash;39.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33.8 (32.4\u0026ndash;36.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e35.4 (32.6\u0026ndash;35.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e33.7 (33.3\u0026ndash;33.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.47\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epaO\u003csub\u003e2\u003c/sub\u003e (torr)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e82.7 (65.9\u0026ndash;83.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e90 (82.4\u0026ndash;91.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e87.8 (84.2\u0026ndash;88.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e82.2 (64.7\u0026ndash;87.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.20\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBase excess (mmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.7 (-0.2\u0026thinsp;~\u0026thinsp;2.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.2 (-1.1\u0026thinsp;~\u0026thinsp;1.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-2.2 (-3\u0026thinsp;~\u0026thinsp;2.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.6 (-3\u0026thinsp;~\u0026thinsp;2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.75\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLactate (mmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.31 (3.14\u0026ndash;3.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.87 (3.77\u0026ndash;4.32)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.43 (4.3\u0026ndash;5.21)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.9 (4.77\u0026ndash;7.13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHemoglobin (g/0.1L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.4 (7.1\u0026ndash;9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.7 (6.4\u0026ndash;6.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.3 (6.6\u0026ndash;9.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e7.3 (6.8\u0026ndash;7.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.23\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeart rate (bpm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e160 (152\u0026ndash;166)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e188 (182\u0026ndash;188)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e189 (159\u0026ndash;196)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e195 (175\u0026ndash;200)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean arterial pressure (mmHg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e61 (59\u0026ndash;65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e63 (61\u0026ndash;73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e63 (61\u0026ndash;65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e63 (57\u0026ndash;75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.36\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCarotid blood flow (mL/kg/min)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e89 (52\u0026ndash;96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e86 (77\u0026ndash;100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e78 (73\u0026ndash;88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e96 (92\u0026ndash;103)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.82\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCardiac output (mL/kg/min)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e431 (407.36\u0026ndash;495)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e535 (530\u0026ndash;575)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e327 (287\u0026ndash;523)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e478.5 (333.5\u0026ndash;530.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.68\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEjection fraction (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45.61 (39.93\u0026ndash;47.55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e34 (34\u0026ndash;43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e28.7 (22\u0026ndash;35.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e37 (26.5\u0026ndash;41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.36\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStroke volume (mL/kg/min)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.69 (2.68\u0026ndash;2.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.03 (2.84\u0026ndash;3.12)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.13 (1.58\u0026ndash;2.19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.21 (1.56\u0026ndash;2.51)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003edp/dt max (mmHg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2690 (2157\u0026ndash;2890)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2998 (2635\u0026ndash;3777)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3323 (2623\u0026ndash;3615)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3451 (2877.5\u0026ndash;4227.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.48\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003edp/dt min (mmHg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-2776 (-3062~ -2022)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-4172 (-4792~ -3502)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-3608 (-4009~ -3171)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-3858.5 (-4616.5~ -3192)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.09\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"6\"\u003eData are presented as median (IQR); IV, intravenous; IO, intraosseous; Vaso, vasopressin. P-values are comparing all IO vasopressin doses to IV vasopressin.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline characteristics of endotracheal and intranasal doses.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eETT\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c8\" namest=\"c6\"\u003e \u003cp\u003eIN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVaso 4\u003c/p\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eVaso 8\u003c/p\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eVaso 16\u003c/p\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eVaso 8\u003c/p\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eVaso 16\u003c/p\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003eVaso 32\u003c/p\u003e \u003cp\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge (days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e3 (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2 (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1 (\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.30\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight (kg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.9 (1.8\u0026ndash;1.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.8 (1.8\u0026ndash;2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (1.8\u0026ndash;2.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2.3 (2\u0026ndash;2.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.1 (1.8\u0026ndash;2.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2 (1.9\u0026ndash;2.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.35\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex (male/female)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2/2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4/1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4/1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2/1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3/0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2/1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.63\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.433 (7.427\u0026ndash;7.448)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.479 (7.449\u0026ndash;7.492)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.488 (7.429\u0026ndash;7.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7.491 (7.411\u0026ndash; 7.496)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e7.531 (7.53\u0026ndash;7.56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e7.484 (7.474\u0026ndash;7.508)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.06\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epaCO\u003csub\u003e2\u003c/sub\u003e (torr)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34.5 (32.7\u0026ndash;36.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33.6 (31.4\u0026ndash;35.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e32.7 (31.9\u0026ndash;34.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e30.8 (30.3\u0026ndash;37.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e29 (28.1\u0026ndash;30.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e31.3 (30.9\u0026ndash;39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epaO\u003csub\u003e2\u003c/sub\u003e (torr)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e74.8 (69.2\u0026ndash;79.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e83.4 (77.6\u0026ndash;86.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e75.2 (71.1\u0026ndash;79.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e83.5 (70.1\u0026ndash;92.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e79.8 (73.3\u0026ndash;90.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e74.7 (61.4\u0026ndash;83)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.53\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBase excess (mmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-1 (-1.2~ -0.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.1 (-0.6\u0026thinsp;~\u0026thinsp;2.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.7 (-1.3\u0026thinsp;~\u0026thinsp;3.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.2 (-0.8\u0026thinsp;~\u0026thinsp;0.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2.8 (0.8\u0026thinsp;~\u0026thinsp;3.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1.8 (-0.2\u0026thinsp;~\u0026thinsp;5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.23\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLactate (mmol/L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.25 (4.2\u0026ndash;5.06)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.81 (2.94\u0026ndash;4.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.57 (4.23\u0026ndash;4.58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4.25 (3.56\u0026ndash;5.05)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4.26 (3.81\u0026ndash;4.86)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e4.31 (3.9\u0026ndash;4.93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.98\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHemoglobin (g/0.1L)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.9 (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.2 (8\u0026ndash;9.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7.9 (7.8\u0026ndash;9.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e8.4 (6.8\u0026ndash;8.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e8.2 (8.2\u0026ndash;9.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e6.8 (6.5\u0026ndash;8.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeart rate (bpm)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e163 (158\u0026ndash;175)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e137 (122\u0026ndash;138)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e167 (122\u0026ndash;192)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.43\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e166 (129\u0026ndash;180)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e156 (155\u0026ndash;166)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e143 (134\u0026ndash;150)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.42\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean arterial pressure (mmHg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e67 (64\u0026ndash;68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e53 (48\u0026ndash;58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e53 (51\u0026ndash;58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.009\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e64 (61\u0026ndash;66)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e61 (58\u0026ndash;65)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e60 (53\u0026ndash;61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.22\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCarotid blood flow (mL/kg/min)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e83 (76\u0026ndash;87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e56 (53\u0026ndash;64)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e63 (58\u0026ndash;68)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e62 (49\u0026ndash;74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e70 (63\u0026ndash;71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e60 (53\u0026ndash;72)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.66\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCardiac output (mL/kg/min)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e384 (380\u0026ndash;384)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e290 (222\u0026ndash;322)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e320 (311\u0026ndash;326)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e259.05 (219.3\u0026ndash;298.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e514.7 (465\u0026ndash;564.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e375.2 (300.3\u0026ndash;495)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.09\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEjection fraction (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36 (27\u0026ndash;37)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41 (35\u0026ndash;45)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29 (28\u0026ndash;33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e40 (28.7\u0026ndash;51.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e37.1 (32.6\u0026ndash;41.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e28.1 (24.5\u0026ndash;59.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.98\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStroke volume (mL/kg/min)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2.51 (1.72\u0026ndash;2.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.04 (1.92\u0026ndash;2.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.24 (1.81\u0026ndash;2.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.75 (1.7\u0026ndash;1.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.2 (3\u0026ndash;3.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2.8 (2.1\u0026ndash;3.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.07\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003edp/dt max (mmHg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2943 (2611\u0026ndash;3742)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2278 (2212\u0026ndash;2671)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2262 (2248\u0026ndash;3224)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2727 (2239\u0026ndash;3215)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2670.5 (2634\u0026ndash;2707)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2530 (220.1\u0026ndash;2584)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.68\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003edp/dt min (mmHg)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-3526 (-4393~ -3380)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-3230 (-3339~ -3077)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-3275 (-3816~ -2587)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-3301 (-3684~ -2918)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e-3832 (-4182~ -3482)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e-3357 (-3540~ -3169)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.40\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"9\"\u003eData are presented as median (IQR); ETT, endotracheal tube; IN, intranasal; Vaso, vasopressin.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIntraosseous Route\u003c/p\u003e \u003cp\u003eThere were no significant changes in heart rate, dP/dT maximum or minimum in any vasopressin dose compared to baseline values or IV vasopressin (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea, g, h). MAP significantly increased for two minutes with 0.2IU/kg vasopressin, and five minutes with 0.4IU/kg, 0.8IU/kg, and IV vasopressin (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb). Carotid blood flow significantly decreased five-, 10- and 10-minutes post-drug administration with 0.4IU/kg, 0.8IU/kg, and IV vasopressin, respectively, while carotid blood flow was decreased two-minutes after 0.2IU/kg vasopressin administration, but had comparable values to baseline from three to 10 minutes (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ec). Carotid blood flow was significantly higher after 0.2IU/kg vasopressin administration for four minutes compared to IV vasopressin (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ec). Cardiac output was significantly decreased with 0.2 and 0.4IU/kg vasopressin one- and two-minutes after drug administration, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ed). Compared to IV vasopressin, 0.4IU/kg vasopressin had significantly lower ejection fraction (8.4 (7.7\u0026ndash;9.8)% vs. 23.3 (22.5\u0026ndash;32.6)%, respectively, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.042) and stroke volume (0.7 (0.63\u0026ndash;0.91) mL/kg/min vs. 1.32 (1.31\u0026ndash;2.63) mL/kg/min, respectively, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.021) one minute after drug administration (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ee \u0026amp; f).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eEndotracheal Route\u003c/p\u003e \u003cp\u003eThere were no changes from baseline in heart rate, carotid blood flow, cardiac output, ejection fraction, stroke volume, and dP/dT maximum or minimum with any vasopressin dose administered endotracheally (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ea, d\u0026ndash;h). Significant differences in MAP and carotid blood flow were observed between IV vasopressin and all ETT vasopressin doses (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eb, c). Cardiac output was higher one minute after drug administration with 4IU/kg vasopressin compared to IV vasopressin (466 (394\u0026ndash;558) mL/kg/min vs. 193.1 (170.3\u0026ndash;365.8) mL/kg/min, respectively, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.045) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003ed). dP/dT minimum was significantly lower with 4 and 16IU/kg vasopressin compared to IV vasopressin (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eh).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIntranasal Route\u003c/p\u003e \u003cp\u003eThere were no changes in heart rate, carotid blood flow, cardiac output, ejection fraction, stroke volume, dP/dT maximum or minimum with any doses from baseline within the IN route (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003ea, c\u0026ndash;h). 32IU/kg vasopressin had significantly higher MAP 10 minutes after IN drug administration compared to baseline (82 (72\u0026ndash;96) vs. 60 (53\u0026ndash;61)), respectively, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.016) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eb). MAP and dP/dT minimum were significantly higher with IV vasopressin compared to all IN vasopressin doses, while carotid blood flow was higher with IN vasopressin doses compared to IV vasopressin (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eb, h, c).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003ePlasma Vasopressin Concentrations\u003c/h2\u003e \u003cp\u003eThere were no differences in plasma vasopressin concentrations between any IO vasopressin dose (0.2, 0.4, or 0.8IU/kg) and IV vasopressin (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003ea). Compared to IV vasopressin, 4, 8, and 16IU/kg ETT vasopressin had significantly lower plasma vasopressin concentrations two-, three-, and five-minutes after drug administration, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003eb). 8 and 16IU/kg IN vasopressin had significantly lower plasma concentrations at all measured time points compared to IV vasopressin (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003ec). 32IU/kg IN vasopressin achieved comparable plasma concentrations to IV vasopressin 10-minutes after drug administration (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003ec).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003ePharmacokinetic Parameters\u003c/h2\u003e \u003cp\u003eAll parameters were comparable after IV or any IO vasopressin doses (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eI\u0026ndash;V). \u003cem\u003eC\u003c/em\u003e\u003csub\u003e\u003cem\u003emax\u003c/em\u003e\u003c/sub\u003e values were significantly lower with 4IU/kg ETT vasopressin (958 (44) pg/mL, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), 8IU/kg IN (384 (126) pg/mL, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001), and 16IU/kg IN vasopressin (399 (363) pg/mL, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) compared to IV vasopressin (2,253 (63)). Significantly lower AUC\u003csub\u003e0\u0026ndash;\u003cem\u003et\u003c/em\u003e\u003c/sub\u003e compared to IV vasopressin (1,6213 (680) pg\u0026sdot;min/mL) was observed with 4IU/kg ETT (7,264 (1,576) pg/min/mL, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.02), 8IU/kg IN (675 (681) pg/min/mL, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) and 16IU/kg IN vasopressin (2,012 (1,952) pg/min/mL, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). \u003cem\u003eT\u003c/em\u003e\u003csub\u003e\u003cem\u003emax\u003c/em\u003e\u003c/sub\u003e was significantly higher in all ETT vasopressin and 32IU/kg IN vasopressin piglets compared to IV vasopressin (Fig.\u0026nbsp;6III, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Elimination parameters of clearance and half-life could not be calculated for any ETT or IN doses as drug elimination had not yet begun.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThere is a need to find the optimal vasoactive drugs during neonatal CPR\u003csup\u003e3\u003c/sup\u003e. While several studies have compared epinephrine and vasopressin during CPR in animal models, this paper is the first study to systematically assess the pharmacokinetic and pharmacodynamics of vasopressin administered via different routes. In our current study, we compared 0.4IU/kg IV vasopressin to vasopressin administered via IO, ETT or IN. The results of our study can be summarized as follows: (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) IO vasopressin resulted in most significant changes in hemodynamic parameters (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e), (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) \u003cem\u003eC\u003c/em\u003e\u003csub\u003e\u003cem\u003emax\u003c/em\u003e\u003c/sub\u003e and \u003cem\u003eT\u003c/em\u003e\u003csub\u003e\u003cem\u003emax\u003c/em\u003e\u003c/sub\u003e were not different between IO or IV vasopressin doses (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e), and (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) ETT and IN routes resulted in poor drug absorption and hemodynamic response (Figs.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThere were no differences in pharmacokinetics between IO and IV vasopressin, which indicates that IO administration is as effective as IV administration for vasopressin delivery and absorption. In a pediatric swine model of ventricular fibrillation, Wenzel \u003cem\u003eet al\u003c/em\u003e compared 0.8IU/kg IV and IO vasopressin and reported similar plasma concentrations during CPR and the post\u0026ndash;resuscitation period\u003csup\u003e24\u003c/sup\u003e. Similarly, Wimmer \u003cem\u003eet al\u003c/em\u003e compared humeral IO and IV administration of vasopressin in a hypovolemic swine model and reported no differences between mean \u003cem\u003eC\u003c/em\u003e\u003csub\u003e\u003cem\u003emax\u003c/em\u003e\u003c/sub\u003e, \u003cem\u003eT\u003c/em\u003e\u003csub\u003e\u003cem\u003emax\u003c/em\u003e\u003c/sub\u003e, serum concentrations during CPR, rates of ROSC, or survival\u003csup\u003e25\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAlthough, 0.8IU/kg IO vasopressin produced comparable hemodynamic and pharmacokinetic changes compared to 0.4IU/kg IO or IV vasopressin, we previously reported that 0.8IU/kg IV vasopressin resulted in significantly higher base excess and lactate concentrations four hours after resuscitation compared to 0.4IU/kg IV vasopressin\u003csup\u003e26\u003c/sup\u003e. Therefore, it appears that 0.4IU/kg vasopressin might be the preferable dose during neonatal resuscitation.\u003c/p\u003e \u003cp\u003eSignificantly lower \u003cem\u003eC\u003c/em\u003e\u003csub\u003e\u003cem\u003emax\u003c/em\u003e\u003c/sub\u003e with 4IU/kg ETT vasopressin and higher \u003cem\u003eT\u003c/em\u003e\u003csub\u003e\u003cem\u003emax\u003c/em\u003e\u003c/sub\u003e in all ETT vasopressin doses compared to IV vasopressin indicates that the ETT route is an inefficient route of vasopressin administration. The significantly lower \u003cem\u003eC\u003c/em\u003e\u003csub\u003e\u003cem\u003emax\u003c/em\u003e\u003c/sub\u003e and AUC with 8IU/kg and 16IU/kg IN compared to IV vasopressin indicates that IN administration of vasopressin is not an alternative for drug administration during neonatal CPR. ETT and IN administered vasopressors must be absorbed by epithelial cells and then transported into the systemic circulation, while IV and IO administered vasopressors are immediately deposited into circulation. This may account for the higher \u003cem\u003eT\u003c/em\u003e\u003csub\u003e\u003cem\u003emax\u003c/em\u003e\u003c/sub\u003e values of ETT and IN compared to IV and IO routes. The lack of significant changes in hemodynamic parameters following IN and ETT administration of vasopressin may be due to its poor absorption into systemic circulation. Poor absorption may result from the rapid metabolism of vasopressin by peptidases located throughout the respiratory tract; however, without radioimmunoassay analyses we can only speculate if vasopressin was metabolized\u003csup\u003e27,28\u003c/sup\u003e. A study examining plasma concentrations of IN-administered 1-deamino-8-D-arginine vasopressin (DDAVP, a vasopressin analogue) in healthy adult males reported a bioavailability of approximately 10%, and peak plasma concentrations were observed 1\u0026ndash;2 hours after drug administration\u003csup\u003e29\u003c/sup\u003e. While elimination of vasopressin occurred within the IV and IO routes, there was no clearance after ETT or IN administration within 10 minutes, demonstrating delayed absorption. Therefore elimination parameters of clearance and half-life could be determined for IV and IO vasopressin doses, but not ET or IN doses (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e IV\u0026ndash;V),\u003c/p\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eLimitations\u003c/h2\u003e \u003cp\u003eBased on the principle of reducing use in animal experiments, we discontinued the IN route after 12 piglets as we could not justify including further piglets without the prospect of achieving significant changes in hemodynamic parameters. Our neonatal model uses piglets that have already undergone the fetal to neonatal transition. Nevertheless, our findings are still clinically relevant as the distribution of cardiac output to vital organs (i.e. brain and heart) in the fetus and post-transitional neonate during asphyxia episodes are quantitatively similar\u003csup\u003e30,31\u003c/sup\u003e. Additionally, piglets were euthanized 10 minutes after drug administration; therefore, no comparisons could be made on potential long-term changes that may occur hours after drug administration. The only IN vasopressin dosage that produced any significant changes from baseline was 32IU/kg; however, tissue injury markers were not analyzed and requires further evaluation before clinical translation. Furthermore, our study examined various vasopressin doses in healthy post-transitional piglets, and will need to be replicated in a cardiac arrest model.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe IO route provides rapid vasopressin delivery and absorbance, and analysis of pharmacokinetic parameters demonstrates comparable results as IV-treated piglets. In our study IO vasopressin at 0.4IU/kg was most effective. Administration of vasopressin via ETT or IN resulted in unreliable absorption, no hemodynamics changes, and therefore might be unreliable during neonatal resuscitation.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eCompeting interests:\u003c/h2\u003e \u003cp\u003eNo, I declare that the authors have no competing interests as defined by Nature Research, or other interests that might be perceived to influence the results and/or discussion reported in this paper.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding sources\u003c/h2\u003e \u003cp\u003eWe would like to thank the public for donating money to our funding agencies: The study was support by a Grant-in-Aid from the Heart and Stroke Foundation Canada. MR is a recipient of the Canadian Institutes of Health Research Canada Graduate Scholarships-Master\u0026rsquo;s program, Walter H Johns Graduate Fellowship, Alberta Graduate Excellence Scholarship, and Medical Sciences Graduate Program Scholarship.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAuthor\u0026rsquo;s contribution: Conception and design: GMS, MOR, MR, PYC, TFLCollection and assembly of data: GMS, MOR, MR, PYC, TFLAnalysis and interpretation of the data: GMS, MOR, MR, PYC, TFLDrafting of the 1st draft: MRCritical revision of the article for important intellectual content: GMS, MOR, MR, PYC, TFL Final approval of the article: GMS, MOR, MR, PYC, TFL\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThe datasets generated and analyzed for this study are available from the corresponding author (GMS), upon reasonable request\u003c/p\u003e\u003cp\u003eThe authors declare no conflict of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eGarcia-Hidalgo, C. \u0026amp; Schm\u0026ouml;lzer, G. 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Circ Res 57, 811\u0026ndash;821 (1985).\u003c/span\u003e\u003c/li\u003e\u003c/ol\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":"Infants, Newborn, Neonatal Resuscitation, vasopressin, pharmacokinetics, PHARMACODYNAMICS","lastPublishedDoi":"10.21203/rs.3.rs-4637657/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4637657/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eEpinephrine is the only recommended vasopressor during neonatal cardiopulmonary resuscitation. However, there are concerns about the potential adverse effects of epinephrine, which might hamper efficacy during cardiopulmonary resuscitation. An alternative might be vasopressin, which has a preferable adverse effect profile, however, its optimal dose and route of administration is unknown. We aimed to compare the pharmacodynamics and pharmacokinetics of various vasopressin doses administered via intravenous (IV), intraosseous (IO), endotracheal (ETT), and intranasal (IN) routes in healthy neonatal piglets. Forty-four post-transitional piglets (1\u0026ndash;3 days of age) were anesthetized, intubated via a tracheostomy, and randomized to receive vasopressin via intravenous (control), IO, ETT, or IN route. Heart rate (HR), arterial blood pressure, carotid blood flow, and cardiac function (e.g., stroke volume, ejection fraction) were continuously recorded throughout the experiment. Blood was collected prior to drug administration and throughout the observation period for pharmacodynamics and pharmacokinetic analysis. Significant changes in hemodynamic parameters were observed following IO administration of vasopressin while pharmacokinetic parameters were not different between IV and IO vasopressin. Administration of vasopressin via ETT or IN did not change hemodynamic parameters and had significantly lower maximum plasma concentrations and systemic absorption compared to piglets administered IV vasopressin (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). The IV and IO routes appear the most effective route for vasopressin administration in neonatal piglets, while ETT and IN routes appear not suitable for vasopressin administration.\u003c/p\u003e","manuscriptTitle":"Pharmacokinetic and pharmacodynamic evaluation of various vasopressin doses and routes in a neonatal piglet model","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-26 20:55:43","doi":"10.21203/rs.3.rs-4637657/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-09-10T09:04:04+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-08-13T11:36:39+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"17607055955497613811478857543747187809","date":"2024-07-17T09:12:06+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"170233355679752637528505876376432124866","date":"2024-07-15T07:29:37+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-07-04T05:16:32+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-07-04T04:33:43+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-07-04T03:24:24+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-07-03T07:17:13+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-06-25T15:47:30+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":"2945a419-05a5-404f-8cf4-d671f5fe4dcb","owner":[],"postedDate":"July 26th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":34726185,"name":"Health sciences/Medical research/Paediatric research"},{"id":34726186,"name":"Health sciences/Medical research/Pre clinical studies"}],"tags":[],"updatedAt":"2024-10-07T16:12:50+00:00","versionOfRecord":{"articleIdentity":"rs-4637657","link":"https://doi.org/10.1038/s41598-024-74188-9","journal":{"identity":"scientific-reports","isVorOnly":false,"title":"Scientific Reports"},"publishedOn":"2024-10-04 15:58:30","publishedOnDateReadable":"October 4th, 2024"},"versionCreatedAt":"2024-07-26 20:55:43","video":"","vorDoi":"10.1038/s41598-024-74188-9","vorDoiUrl":"https://doi.org/10.1038/s41598-024-74188-9","workflowStages":[]},"version":"v1","identity":"rs-4637657","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4637657","identity":"rs-4637657","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}