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Abstract Analysis of peripheral venous pressure (PVP) waveforms is a novel method of monitoring intravascular volume. Two pediatric cohorts were studied to test the effect of anesthetic agents on the PVP waveform and cross-talk between peripheral veins and arteries: (1) dehydration setting in a pyloromyotomy using the infused anesthetic propofol and (2) hemorrhage setting during elective surgery for craniosynostosis with the inhaled anesthetic isoflurane. PVP waveforms were collected from 39 patients that received propofol and 9 that received isoflurane. A multiple analysis of variance test determined if anesthetics influence the PVP waveform. A prediction system was built using k-nearest neighbor (k-NN) to distinguish between: (1) PVP waveforms with and without propofol and (2) different minimum alveolar concentration (MAC) groups of isoflurane. 52 porcine, 5 propofol, and 7 isoflurane subjects were used to determine the cross-talk between veins and arteries at the heart and respiratory rate frequency during: (a) during and after bleeding with constant anesthesia, (b) before and after propofol, and (c) at each MAC value. PVP waveforms are influenced by anesthetics, determined by MANOVA: p value  < 0.01, η 2 = 0.478 for hypovolemic, and η 2 = 0.388 for euvolemic conditions. The k-NN prediction models had 82% and 77% accuracy for detecting propofol and MAC, respectively. The cross-talk relationship at each stage was: (a) ρ = 0.95, (b) ρ = 0.96, and (c) could not be evaluated using this cohort. Future research should consider anesthetic agents when analyzing PVP waveforms developing future clinical monitoring technology that uses PVP.