Response: Vasopressin and critically ill neonates: balancing treatment efficacy and 1 unintended hyponatremia 2 3

Peter Johnson ^* Jamie Miller Marjorie Makoni

• Oklahoma Children's Hospital, College of Medicine, University of Oklahoma, Oklahoma City, United States

"Vasopressin induced hyponatremia in infants <3 months of age om in the neonatal intensive 16 care unit". 2 We agree with several of the concerns that the authors have noted about the use of 17 vasopressin in neonates. However, we would like to take the opportunity to address several 18 concerns outlined in their letter.First, we have not noted any direct adverse clinical outcomes with hyponatremia due to 21 vasopressin in our study. Due to the retrospective nature of the study, we were limited in the 22 number of outcomes that we could assess. In addition, we were also limited in our and in the 23 ability to account for all confounding variables. Unfortunately, we did not collect information on 24 the presence of seizures in this study population since there as it was not our routine practice to 25 monitor seizures with electroencephalography (EEG) on every baby receiving vasopressin.26 Therefore, it is not possible to extrapolate definitive data on seizures. However, Tthis certainly is 27 a significant issue to address given the sequelae of hyponatremia and .However, it may be 28 prudent to obtain an EEG on neonates if seizures are considered as a differential diagnosis in the 29 case of refractory hypotension. Given the retrospective nature of this study, it is not possible to 30 extrapolate definitive data on seizures. This certainly is a significant issue to address given the 31 sequelae of hyponatremia.Second, the question was raised on how changes in practice may have impacted vasopressin- Since some the time-periods had a small number of patients, it would be difficult to make 43 significant conclusions, given the limited power and increased risk of a type II error. After 44 completion of this study, the neonatal hemodynamics consult service was established, and they 45 instituted targeted neonatal echocardiography, which allowed for personalized adjustments to 46 vasopressin. In addition, they provided guidance on enhancing fluid and electrolyte management.It is our belief that these measures significantly reduced the severity of hyponatremia, and it is 48 our hope to follow-up on this study and determine the impact of this intervention on the 49 incidence of hyponatremia with vasopressin.Next, the question was raised on if weabout assessment ofed the relationship between the 52 incidence of hyponatremia between the maximal and cumulative dose of vasopressin, sodium 53 intake, and urinary sodium losses. During the study period, providers did not routinely order 54 urinary sodium concentrations, so we are unable to comment further on this concern. In this 55 study, we did collect the initial, peak, and final vasopressin dose (milliunits/kg/min) (Table 2), 56 vasopressin duration (Table 2), and sodium intake from all sources (Table 4). 1 We also analyzed 57 the sodium intake 24 hours prior to nadir, day of nadir, and 24 hours of nadir and only found a 58 significant difference in the univariate analysis on the day of nadir and 24 hours after nadir.These changes were likely a reaction of providers to the development of hyponatremia and is not