Letters to the Editor

Firstly, the normative data of 78 preterm neonates also include neonates with vasopressor and umbilical arterial catheter (UAC). Furthermore, 26.5% of these neonates had patent ductus arteriosus (PDA) out of which 17.6% were indomethacin resistant. Vasopressors, UACs, and PDA are likely to affect Sto2 values. Indomethacin is known to decrease intestinal blood flow and hence can affect Sto2 values (2, 3). It is not clear how many of these PDAs were hemodynamically significant. It would be prudent to exclude these neonates while generating “normative data.” The histogram illustrating normative data in non-NEC preterm neonates (Fig. 2 in [1]) is left skewed with many values below 40% and has lot of outliers. Such low values could be due to the presence of above-said factors. Secondly, among 14 neonates with NEC, 50% were treated with indomethacin. The decreased Sto2 values in first week in NEC neonates could be confounded by indomethacin. The authors have not found any significant difference beyond first week between NEC and non-NEC neonates (at the time of development of NEC). It is also noteworthy that there was no difference in Sto2 values between NEC neonates who died versus those who survived. Lastly, multiple logistic regression was done to identify independent predictor for development of NEC. Seven putative risk factors were entered in the model for 14 events. The regression model in such low event rates is not stable to provide meaningful evaluation (4). Hence, more data are needed to conclude the independent association of Sto2 less than 56% and NEC. We believe that these comments would be helpful for better interpretation of the data. We hope that this wellconducted study will stimulate further research related to the role of near-infrared spectroscopy in early diagnosis of NEC. Dr. Saini is employed by the Post Graduate Institute of Medical Education and Research, Chandigarh, India. Dr. Mahajan is employed by the Government Medical College and Hospital, Chandigarh, India. Shiv Sajan Saini, DM, Neonatal Unit, Department of Pediatrics, Post Graduate Institute of Medical Education and Research, Chandigarh, India; Vidushi Mahajan, DNB, Department of Pediatrics, Government Medical College and Hospital, Chandigarh, India

REFERENCES

1. Patel AK, Lazar DA, Burrin DG, et al: Abdominal Near-Infrared Spectroscopy Measurements Are Lower in Preterm Infants at Risk for Necrotizing Enterocolitis. Pediatr Crit Care Med 2014; 15:735–741 2. Ohlsson A, Walia R, Shah SS: Ibuprofen for the treatment of patent ductus arteriosus in preterm and/or low birth weight infants. Cochrane Database Syst Rev 2013; 4:CD003481 3. Dyess DL, Peeples GL, Ardell JL, et al: Indomethacin-induced blood flow distribution in premature and full-term piglets. J Pediatr Surg 1993; 28:1396–1400 4. Lee J: An insight on the use of multiple logistic regression analysis to estimate association between risk factor and disease occurrence. Int J Epidemiol 1986; 15:22–29 DOI: 10.1097/PCC.0000000000000325

Pediatric Critical Care Medicine

The authors reply:

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e thank Saini and Mahajan (1) for the thoughtful comments on our work. The majority of their concerns are centered on the validity of normative Sto2 values in the presence of confounding factors, such as vasopressors, umbilical artery catheters (UACs), and patent ductus arteriosus (PDA). In our population, there was no difference in Sto2 values in the first week of life between those who received vasopressors and those who did not (77.0% ± 8.9% vs 74.2% ± 11.0%; p = 0.355). Patients who had UACs also did not have Sto2 values that were significantly different from their counterparts without UACs (76.7 ± 9.8 vs 79.6 ± 9.2; p = 0.200) in the first week of life. We did note, however, that patients who had a PDA had significantly lower Sto2 than those without a PDA (72.2% ± 10.0% vs 77.4% ± 8.8%; p = 0.023). Concomitantly, patients who received indomethacin had significantly lower Sto2 values than those who did not receive indomethacin therapy (68.5% ± 11.2% vs 77.9% ± 8.4%; p = 0.003). Of the 13 patients who were treated with indomethacin, the majority (n = 8) were treated in the first week of life when the continuous readings were obtained. Interestingly, four of the patients who were treated with indomethacin in the first week of life developed necrotising enterocolitis (NEC) and had lower Sto2 (59.9% ± 12.2%) than those who were treated with indomethacin in the same time frame but did not develop NEC (70.5 ± 7.27; p = 0.187). These findings suggest that treatment with indomethacin led to reduced intestinal tissue oxygen saturation. Given the fact that this study focuses on preterm neonates, we felt that the inclusion of patients on vasopressors with UACs and PDAs provided a more realistic depiction of this patient population and did not exclude patients with these potential confounders from our analysis. Rather, our findings seem to suggest that low intestinal tissue oxygen saturation, regardless of the etiology, may predispose these premature neonates to the development of NEC. We did not find a significant difference in Sto2 between NEC and non-NEC patients beyond the first week of life. As stated in our article, we did not monitor continuous Sto2 after the first week of life. We therefore did not capture the onset of NEC at which time significant differences in Sto2 may have been observed. We propose a “two-hit” hypothesis for the development of NEC: the first insult is a period of perinatal gut hypoxia that is noted in our study as the lower Sto2 values in patients who subsequently developed NEC; the second insult is related to stress to the already susceptible gastrointestinal tract from enteral feeds. The use of the Sto2 in the first week may therefore be useful in identifying the initial insult and predicting those at risk. As such, it is not surprising that we did not observe differences in intestinal tissue oxygenation between NEC survivors and nonsurvivors. Using a receiver operating characteristic curve, we found that Sto2 up to 56% identified infants who were likely to develop NEC. A multivariate regression analysis was then performed, and we found that Sto2 less than or equal to 56% was an independent predictor of the development of NEC. Based on our power analysis a priori, we were adequately powered to detect www.pccmjournal.org

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the difference that was noted. However, one cannot underestimate the value of larger studies to validate our findings. Finally, as stated in our article and also highlighted by Schneider et al (2), there is significant variance in near-infrared spectroscopy (NIRS) technologies such that NIRS values do not correlate from one device to another. This should be taken into consideration when similar studies are performed with other devices. Again, we thank you for your comments and for the opportunity to clarify our results. Drs. Akinkuotu, Cruz, and Olutoye have disclosed that equipment was provided by Hutchinson Technology, Hutchinson, MN (near-infrared spectroscopy probes and monitors provided by the maker). They received support for article research from the United States Department of Agriculture (grant number 6250-51000-046-01A). Their institutions received grant support from Hutchinson Technology, Hutchinson, MN (research grant for investigator-initiated study). Adesola C. Akinkuotu, MD, Stephanie M. Cruz, MD, Oluyinka O. Olutoye, MD, PhD, Texas Children's Hospital and the Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX

REFERENCES

1. Saini SS, Mahajan V: Abdominal Regional Oxygen Saturations Using Near-Infrared Spectroscopy in Preterm Neonates. Pediatr Crit Care Med 2015; 16:200–201 2. Schneider A, Minnich B, Hofstätter E, et al: Comparison of four nearinfrared spectroscopy devices shows that they are only suitable for monitoring cerebral oxygenation trends in preterm infants. Acta Paediatr 2014; 103:934–938 DOI: 10.1097/PCC.0000000000000335

Dysnatremia After Neurosurgery: Which Is the Main Marker? To the Editor:

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hanges in sodium concentration are a concernment in PICU, especially considering patients after neurosurgery. In a recent issue of Pediatric Critical Care Medicine, we read the very interesting article published by Topjian et al (1) describing fluctuations in serum sodium levels associated with increased mortality in children with externalized ventriculostomy drains (EVDs). The manipulation of the CNS increases the risks for dysnatremia (2–4). EVDs are frequently used in the pediatric population; however, there have been few studies reporting their indications and the prevalence of related complications. Hyponatremia is a potential complication of EVD drainage (5). Indeed, it is documented as a complication of EVDs in patients with hydrocephalus, likely secondary to ongoing cerebrospinal fluid drainage (5). Topjian et al (1) described dysnatremias among patients with EVDs, and risk factors for this kind of sodium fluctuations included patients receiving total parenteral nutrition, patients

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receiving IV quarter/half normal saline or 3% saline, and those who had clinical seizures. An independent association of increase in in-hospital mortality with fluctuations of serum sodium but not with hyponatremia alone was observed by the author. Previous studies also showed a higher risk of mortality related with wide range of sodium fluctuations (6), which could lead to clinical outcomes, such as unwanted seizures (7). The article under discussion stated “hyponatremia was not associated with seizures or hospital mortality.” As opposed from that the literature states that hyponatremia may be associated with an increase in mortality. Funk et al (8) suggest in a study that involved adult ICU patients that hyponatremia itself carries a risk of increased mortality and demonstrated that even small decreases in serum sodium were independently associated with adverse outcomes in critically ill patients (8). Williams et al (3) described a sample of children who underwent neurosurgical procedure for intracranial tumor and found that hyponatremia was associated with more complicated and significantly worse neurological outcomes. Topjian et al (1) also suggest that the EVDs may have been protective perhaps by decreasing the risk of cerebral edema but being a retrospective observational study, where the number of patients was not calculated, the power to determine causality is limited, particularly when talking about hyponatremia. They found a small number of patients with severe hyponatremia, and it was described in the Materials and Methods section what was considered severe (Na < 125 meq/L), moderate (125–130 meq/L), and mild hyponatremia (131–134 meq/L), but in the analysis, the authors added severe and moderate hyponatremia and calculated their outcomes as one. Besides that, systematic continuous electroencephalography monitoring was not performed during the study, and some subclinical seizures could have occurred. This could have an effect on the results and should be taken in consideration. From this discussion, the following question may arise: Which disturbance could be the most important in determining mortality, fluctuations on the natremia, or hyponatremia per se? Future researches are needed to answer this pending demand. Having that in mind, precautions should be taken to avoid hyponatremia. The authors have disclosed that they do not have any potential conflicts of interest. Alice L. Fante, MD, Josiane C. S. Maia, MD, Werther Brunow de Carvalho, MD, PhD, Artur F. Delgado, MD, PhD, Intstituto da Criança da Faculdade de Medicina, University of São Paulo, São Paulo, Brazil

REFERENCES

1. Topjian AA, Stuart A, Pabalan AA, et al: Greater Fluctuations in Serum Sodium Levels Are Associated With Increased Mortality in Children With Externalized Ventriculostomy Drains in a PICU. Pediatr Crit Care Med 2014; 15:846–855 2. Mekitarian Filho E, Carvalho WB, Cavalheiro S: Perioperative patient management in pediatric neurosurgery. Rev Assoc Med Bras 2012; 58:388–396 3. Williams CN, Belzer JS, Riva-Cambrin J, et al: The incidence of postoperative hyponatremia and associated neurological sequelae in children with intracranial neoplasms. J Neurosurg Pediatr 2014; 13:283–290 February 2015 • Volume 16 • Number 2

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