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Use of renal near-infrared spectroscopy measurements in congenital diaphragmatic hernia patients on ECMO
Journal of Pediatric Surgery 52 (2017) 689–692
Contents lists available at ScienceDirect
Journal of Pediatric Surgery journal homepage: www.elsevier.com/locate/jpedsurg
Use of renal near-infrared spectroscopy measurements in congenital diaphragmatic hernia patients on ECMO Patricio E. Lau a,b, Stephanie Cruz a,b, Joseph Garcia-Prats c, Milenka Cuevas c, Christopher Rhee c, Darrell L. Cass a,b,c,d, Sarah E. Horne b, Timothy C. Lee a,b, Stephen E. Welty a,c, Oluyinka O. Olutoye a,b,c,d,⁎ a
Texas Children's Fetal Center, Baylor College of Medicine, Houston, TX The Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX Department of Pediatrics, Baylor College of Medicine, Houston, TX d Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX b c
a r t i c l e
i n f o
Article history: Received 12 January 2017 Accepted 23 January 2017 Key words: CDH Near infrared spectroscopy ECMO NIRS
a b s t r a c t Introduction: This study tests the hypothesis that renal tissue oxygen saturation as measured by Near Infrared Spectroscopy (NIRS) would correlate with urine output in neonates with congenital diaphragmatic hernia (CDH) on extracorporeal membrane oxygenation (ECMO). Methods: Between 2012 and 2015, neonates with CDH were enrolled as part of a comprehensive study that provided renal/cerebral/abdominal NIRS monitoring for the duration of ECMO support. Continuous NIRS measurements, mean arterial pressure, and urine output were recorded. Periods of anuria (NU), adequate urine output N1 ml/kg/h (AU), and low urine output b 1 ml/kg/h (LU) were noted and analyzed. Results: Over 1500 h of continuous renal NIRS were obtained from six neonates. NIRS values were significantly different during periods of AU, LU, and anuria (84 ± 6%, 76 ± 3%, and 67 ± 6%, p b 0.01). ROC curves identified NIRS N76% as highly predictive of adequate urine output (AUC = 0.96). MAP was significantly lower only in anuric patients, 36.42 ± 10.26, compared to patients with AU and LU - 42.99 ± 5.25 and 42.85 ± 7.4, respectively (p b 0.001). Conclusion: Renal NIRS measurements correlate with urine production. Lower values are noted as urine output declines and precedes a decline in MAP. Renal NIRS may have promise as a non-invasive means of determining adequacy of renal perfusion and urine output in neonates with complex fluid shifts. Level of evidence: IIb. © 2017 Elsevier Inc. All rights reserved.
In recent years, near infrared spectroscopy (NIRS) has become a common modality in many centers for the monitoring of brain oxygenation delivery during cardiac surgery [1,2], with particular interest in monitoring patients undergoing pediatric cardiac surgery [3,4]. These observations have led to the implementation of NIRS for postoperative monitoring and management of children with cardiac disease in many cardiac intensive care units [5,6]. The use of findings on physical exam, pulse oximetry and blood pressure have been shown to be inadequate for the assessment of adequacy or inadequacy of the circulation in complex patients [7,8]. Therefore, of NIRS has increasingly been used as a means to accurately measure end organ perfusion. Recent studies have shown that other non-cardiac pediatric conditions such as congenital diaphragmatic hernia (CDH) and esophageal atresia might benefit from using NIRS to measure organ perfusion as part of the postnatal management [9–11]. With the implementation of Extracorporeal membrane oxygenation (ECMO), the survival of patients with severe CDH ⁎ Corresponding author at: Texas Children's Hospital, 6701 Fannin St., Suite 1210, Houston, TX 77030. Tel.: +1 832 822 3135; fax: +1 832 825 3141. E-mail address: [email protected] (O.O. Olutoye). http://dx.doi.org/10.1016/j.jpedsurg.2017.01.015 0022-3468/© 2017 Elsevier Inc. All rights reserved.
has improved [12]. Unfortunately, ECMO can be associated with complications and potential long term morbidity associated with aberrations in regional hemodynamics in this unique patient population; thus, suggesting that assessments of NIRS may be beneficial in this cohort. The current study focuses on the use of renal near infrared spectroscopy (rStO2) as a marker for renal tissue perfusion and compares it to urine output. We hypothesized that renal tissue oxygen saturation as measured by NIRS would correlate with urine output in neonates with congenital diaphragmatic hernia on extracorporeal membrane oxygenation (ECMO). 1. Patients and methods This study was part of a larger experimental study on the use of Near-infrared spectroscopy in CDH patients approved by Baylor College of Medicine Institutional Review Board (H-25598). All the patients were identified in the antenatal period in Texas Children's Fetal Center with the diagnosis of congenital diaphragmatic hernia. Consent for enrollment in the project was obtained from the patient's parents or guardian. As per study protocol, NIRS probes were placed on the patient's right
690
P.E. Lau et al. / Journal of Pediatric Surgery 52 (2017) 689–692
and left forehead, right lower abdominal quadrant and left flank within 24 h of birth. This was an observational study where clinicians were blinded to NIRS values, and no clinical decisions were based on the NIRS readings. Neonates born at less than 30 weeks of gestation and/or more than 24 h of life at enrollment were excluded from the study. 1.1. Data collection A near-infrared spectrometer (FORE-SIGHT, CASMED, Brandford, CT) was used to continuously measure cerebral, renal and splanchnic tissue oxygenation saturation. NIRS monitoring was initiated within 24 h of life and continued until 24 h after CDH repair or ECMO decannulation if ECMO was required. Renal tissue oxygen saturation values were collected on continuous 1 min intervals and time stamped in an encrypted file using LabVIEW™ (National Instruments, Austin, TX). Periods of time where no data was collected were excluded from analysis. Simultaneously, physiological data such as mean arterial blood pressure, arterial pH values, creatinine concentration, blood urea nitrogen concentration and urine output were collected. In addition, nursing staff was instructed to record with a time stamp any acute event, procedure, changes in position of the patient during the study period. 1.2. Data analysis For the purpose of this study, data from CDH patients who required ECMO support and had renal NIRS monitoring were analyzed. Periods of anuria (NU), adequate urine output N 1 ml/kg/h (AU) and low urine output b1 ml/kg/h (LU) while the patients were on ECMO were identified from the patients' chart. Anuria was defined by urine output of zero as recorded by the nursing staff over a period of at least 2 h. rStO2 values, mean arterial pressure, creatinine, BUN and pH were then assessed in these time periods of urine output. 1.3. Statistical analysis Statistical analysis was performed using IBM SPSS statistical software version 23 (IBM Corporation, Armonk, NY). Student's t-test and one-way ANOVA with Post Hoc analysis was used for continuous variables. Categorical data were analyzed with a chi-square test. A Receiver operating characteristic (ROC) curve analysis was also performed. A p-value of less than 0.05 was considered significant. 2. Results 2.1. Patient demographics During the study period, there were forty-two patients with CDH eligible for the study. Of these, twelve patients required ECMO. Six of the twelve patients requiring ECMO were excluded from the study due to long gaps in data collection and/or high signal-to-noise ratio.
The remaining six patients were used for the renal NIRS analyses. Collectively, over 1500 h of continuous NIRS were obtained from these neonates. The mean gestational age at birth in the cohort was 37 ± 3 weeks, their mean birth weight was 2.59 ± 0.1 kg and the mean ECMO run was 9.2 ± 4.1 days (Table 1). Five out of six patients were male with equal number of right and left CDH cases. Only 2 patients received veno-venous ECMO, while the remaining four received arteriovenous ECMO. The mean lung-to-head ratio for the cohort was 1.2 ± 0.37 and an expected-to-observed total fetal lung volume of 22.5 ± 9.3%. All of these patients had liver herniation, with a mean percent liver herniation of 38.5 ± 8.8%. The overall survival to discharge rate was 67% (4 of 6). 2.2. Urine output We observed a significant difference in the NIRS values among the three periods of anuria (NU), adequate urine output N1 ml/kg/h (AU) and low urine output b1 ml/kg/h (LU) (Table 2). Renal NIRS values among groups were 83.93 ± 6.26, 76.12 ± 2.98 and 67.18 ± 6.4 for AU, LU and NU respectively (Fig. 1). A ROC analysis showed a renal NIRS value of N76% was highly predictive of adequate urine output with a 90% sensitivity and 86% specificity and an area under the curve of 0.96 (Fig. 2). The mean arterial pressure was significantly lower among anuric patients, 36.42 ± 10.26, when compared to patients AU and LU patients, 42.99 ± 5.25 and 42.85 ± 7.4 respectively (p b 0.001). Blood urea nitrogen concentrations and pH showed no difference among the three groups (Table 2), There was a significant difference in creatinine values during AU compared to LU and NU (p = 0.007). Inversely, lactate levels were significantly higher at 3.77 ± 2.47 in patients with anuria (p b 0.001) (Table 2). 3. Discussion The clinical monitoring and management of neonates with congenital diaphragmatic hernia is extremely challenging. Classical methods of monitoring such as heart rate, mean arterial pressure and clinical signs of end organ perfusion such as capillary return have been shown to be poor assessment tools of end organ perfusion in premature neonates that are ventilated [13]. In neonates with severe congenital diaphragmatic hernias the implementation of ECMO has impacted their survival [12,14]. Nevertheless, ECMO does not come without complications, among them is renal dysfunction among these patients. Many factors have been reported to cause acute kidney injury (AKI) during support on ECMO [15], and they have been characterized as inflammatory, hormonal and/or alterations in blood flow. Although in some cases, AKI might precede the use of ECMO, in this study patients were initiated on ECMO therapy within 24 h of life, and in most cases prior to the onset of renal dysfunction. Thus AKI seen in this patient population is more likely to be a sequela of ECMO rather than the hemodynamics before ECMO although this can be difficult to assess in this severely ill population. Among the factors identified for AKI, hemodynamic alterations are the most feasible for possible interventions. In order to prevent severe
Table 1 Patient's Demographics and Characteristics. Patient
Gender
Birth Weight (kg)
Gestational Age (weeks)
Side of CDH
In-Born
ECMO Duration (Days)
Major Anomalies
Survival To Discharge
Type of ECMO Cannula
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6
M M F M M M
2.27 2.16 2.78 3.08 2.95 2.30
38 38.14 39.28 39.42 37.86 32
Left Left Left Right Right Right
Yes Yes Yes Yes Yes Yes
13 7 4 11 14 6
Imperforate anus -
No No Yes Yes Yes Yes
V-A V-A V-V V-V V-A V-A
M: Male F: Female. V-A: Veno-arterial cannula. V-V: Veno-veno cannula.
P.E. Lau et al. / Journal of Pediatric Surgery 52 (2017) 689–692
691
Table 2 Urine output groups.
rStO2 (%) MAP (mmHg) BUN (mg/dl) Creatinine (mg/dl) pH (mmol) Lactate (mg/dl)
Appropriate Urine Output (AU)
Low Urine Output (LU)
No Urine Output (NU)
p-value
84 +/− 6 43.0+/−5.3 41.52+/−23.96 0.59+/−0.21
76 +/− 3 42.9+/−7.4 43.5+/−7.78 0.805+/−0.13
67 +/− 6 36.4+/−10.3 37.1 +/−23.32 0.86+/−0.28
b0.001 b0.001 0.864 0.007
7.30+/−0.09 1.74+/−0.93
7.28+/−0.07 1.28+/−0.56
7.29 +/−0.07 3.77+/−2.47
0.512 b0.001
hemodynamic changes that may injure the kidneys, better modalities for the assessment of their perfusion are necessary and it would be ideal if the assessments could be shown to be abnormal before overt signs of kidney injury are obvious. Since hemodynamic parameters such as blood pressure might not accurately reflect renal tissue perfusion there is a need for more accurate methods of monitoring renal blood flow/hemodynamics. This is where NIRS has its greatest potential. In recent years NIRS has gained distinction in the measurement of end organ perfusion, especially in sick pediatric patients. Although, the majority of the studies focus on its use during cardiac surgery, NIRS is starting to gain popularity for monitoring of patients with non-cardiac illnesses [10,16,17]. Animal studies have shown that renal NIRS changes in neonatal swine model of shock in advance to disturbances in cerebral flow and blood pressure [18]. In humans, renal NIRS was measured in patients who underwent laparoscopic surgery and showed no significant difference in perfusion during the creation of pneumoperitoneum [17]. In our study, we evaluated renal NIRS and correlated the measurement with urine production. We noted significant differences between the three groups categorized by urine output implying substantial physiologic changes occurring as urine output decreases. By performing a receiver operating characteristic (ROC) curve we found that a renal NIRS value of 76% was highly predictive of adequate urine output. This
Fig. 2. ROC Curve for renal NIRS versus urine output.
finding may potentially aid clinicians in the monitoring of these patients by intervening as the NIRS values drops to or below this threshold prior to the development of overt kidney injury. Concurrently, when we evaluated mean arterial pressure, we noted that the MAP was lower in the no urine output group but was not different in the low urine output group than in the adequate urine output even when the NIRS was lower in the low urine output group, suggesting that MAP is not an appropriate tool to address renal perfusion and that NIRS was a better instrument to assess renal perfusion compared to MAP. Our data do not show that renal NIRS was better than a fall in urine output to predict
Fig. 1. Renal NIRS compared to urine output. AU=Adequate urine output LU=Low urine output NU=No urine output ROC threshold at 76%.
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P.E. Lau et al. / Journal of Pediatric Surgery 52 (2017) 689–692
kidney injury and determining that would take a systematic analysis of many more patients and assessing intra-individual assessments to try to determine whether changes in NIRS happened prior to a change in urine output. We interpret our findings as suggesting that MAP can be used to differentiate extreme changes in the tissue perfusion are present but not for more subtle changes in perfusion. On the other hand, NIRS might be a useful tool in order to detect these subtle changes in renal perfusion prior to significant damage and minimal interventions might be necessary to correct the perfusion deficit. Interestingly our data show that changes in serum biochemistry are not reasonable biomarkers for early kidney injury other than a change in serum creatinine concentrations. Other animal models have seen similar findings [18]. In the present study, Blood urea nitrogen (BUN) levels and pH were not different between the three groups of urine output. While creatinine levels were much lower among the patients with adequate urine output (p = 0.007). Lactate concentrations, on the other hand, showed a pattern similar to the one observed in MAP in that it was only elevated with frank anuria. It is likely that this pattern, like in the case of MAP, reflects the extreme hypoperfusion that was experienced by the kidneys with marked hypotension. This study was conducted on CDH patients that required ECMO. Although the data was prospectively acquired, it was analyzed retrospectively. Furthermore, due to the rarity of the condition and the need for ECMO, we have a limited sample size. An additional limitation was the presence of noise in the NIRS measurements or large gaps of data that were not interpretable due to the position of the probes during the project. Despite these limitations, the ability to record continuous renal NIRS values allowed us to acquire more than 1500 h of data on the 6 patients reported. This limitation can be addressed by studying many patients systematically preferably in a multi-institutional project where many centers use renal NIRS for the evaluation of tissue perfusion in their CDH ECMO patients. 4. Conclusion In conclusion, NIRS measurements of renal tissue oxygenation correlates with urine production. Lower NIRS values were noted as urine output declined and preceded a decline in mean arterial pressure. Renal NIRS may be a suitable non-invasive means of determining adequacy
of renal perfusion and attendant changes in urine output in neonates with complex fluid shifts and needs further study. Additional prospective studies will be necessary to determine a potential role for monitoring renal NIRS to prevent kidney injury. References [1] Edmonds Jr HL. Pro: all cardiac surgical patients should have intraoperative cerebral oxygenation monitoring. J Cardiothorac Vasc Anesth 2006;20(3):445–9. [2] Wahr JA, Tremper KK, Samra S, et al. Near-infrared spectroscopy: theory and applications. J Cardiothorac Vasc Anesth 1996;10(3):406–18. [3] Hirsch JC, Charpie JR, Ohye RG, et al. Near-infrared spectroscopy: what we know and what we need to know–a systematic review of the congenital heart disease literature. J Thorac Cardiovasc Surg 2009;137(1):154–9 [159e1-12]. [4] Andropoulos DB, Stayer SA, Diaz LK, et al. Neurological monitoring for congenital heart surgery. Anesth Analg 2004;99(5):1365–75 [table of contents]. [5] Mittnacht AJ. Near infrared spectroscopy in children at high risk of low perfusion. Curr Opin Anaesthesiol 2010;23(3):342–7. [6] Hyttel-Sorensen S, Pellicer A, Alderliesten T, et al. Cerebral near infrared spectroscopy oximetry in extremely preterm infants: phase II randomised clinical trial. BMJ 2015; 350:g7635. [7] Tibby SM, Hatherill M, Marsh MJ, et al. Clinicians' abilities to estimate cardiac index in ventilated children and infants. Arch Dis Child 1997;77(6):516–8. [8] Hoffman GM, Ghanayem NS, Tweddell JS. Noninvasive assessment of cardiac output. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2005:12–21. [9] Nielsen HB. Systematic review of near-infrared spectroscopy determined cerebral oxygenation during non-cardiac surgery. Front Physiol 2014;5:93. [10] Bishay M, Giacomello L, Retrosi G, et al. Decreased cerebral oxygen saturation during thoracoscopic repair of congenital diaphragmatic hernia and esophageal atresia in infants. J Pediatr Surg 2011;46(1):47–51. [11] Conforti A, Giliberti P, Landolfo F, et al. Effects of ventilation modalities on nearinfrared spectroscopy in surgically corrected CDH infants. J Pediatr Surg 2016; 51(3):349–53. [12] Heiss K, Manning P, Oldham KT, et al. Reversal of mortality for congenital diaphragmatic hernia with ECMO. Ann Surg 1989;209(2):225–30. [13] Kluckow M, Evans N. Relationship between blood pressure and cardiac output in preterm infants requiring mechanical ventilation. J Pediatr 1996;129(4):506–12. [14] Zalla JM, Stoddard GJ, Yoder BA. Improved mortality rate for congenital diaphragmatic hernia in the modern era of management: 15 year experience in a single institution. J Pediatr Surg 2015;50(4):524–7. [15] Villa G, Katz N, Ronco C. Extracorporeal membrane oxygenation and the kidney. Cardiorenal Med 2015;6(1):50–60. [16] Conforti A, Giliberti P, Mondi V, et al. Near infrared spectroscopy: experience on esophageal atresia infants. J Pediatr Surg 2014;49(7):1064–8. [17] Westgarth-Taylor C, de Lijster L, van Bogerijen G, et al. A prospective assessment of renal oxygenation in children undergoing laparoscopy using near-infrared spectroscopy. Surg Endosc 2013;27(10):3696–704. [18] Rhee CJ, Kibler KK, Easley RB, et al. Renovascular reactivity measured by near-infrared spectroscopy. J Appl Physiol (1985) 2012;113(2):307–14.
Contents lists available at ScienceDirect
Journal of Pediatric Surgery journal homepage: www.elsevier.com/locate/jpedsurg
Use of renal near-infrared spectroscopy measurements in congenital diaphragmatic hernia patients on ECMO Patricio E. Lau a,b, Stephanie Cruz a,b, Joseph Garcia-Prats c, Milenka Cuevas c, Christopher Rhee c, Darrell L. Cass a,b,c,d, Sarah E. Horne b, Timothy C. Lee a,b, Stephen E. Welty a,c, Oluyinka O. Olutoye a,b,c,d,⁎ a
Texas Children's Fetal Center, Baylor College of Medicine, Houston, TX The Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX Department of Pediatrics, Baylor College of Medicine, Houston, TX d Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX b c
a r t i c l e
i n f o
Article history: Received 12 January 2017 Accepted 23 January 2017 Key words: CDH Near infrared spectroscopy ECMO NIRS
a b s t r a c t Introduction: This study tests the hypothesis that renal tissue oxygen saturation as measured by Near Infrared Spectroscopy (NIRS) would correlate with urine output in neonates with congenital diaphragmatic hernia (CDH) on extracorporeal membrane oxygenation (ECMO). Methods: Between 2012 and 2015, neonates with CDH were enrolled as part of a comprehensive study that provided renal/cerebral/abdominal NIRS monitoring for the duration of ECMO support. Continuous NIRS measurements, mean arterial pressure, and urine output were recorded. Periods of anuria (NU), adequate urine output N1 ml/kg/h (AU), and low urine output b 1 ml/kg/h (LU) were noted and analyzed. Results: Over 1500 h of continuous renal NIRS were obtained from six neonates. NIRS values were significantly different during periods of AU, LU, and anuria (84 ± 6%, 76 ± 3%, and 67 ± 6%, p b 0.01). ROC curves identified NIRS N76% as highly predictive of adequate urine output (AUC = 0.96). MAP was significantly lower only in anuric patients, 36.42 ± 10.26, compared to patients with AU and LU - 42.99 ± 5.25 and 42.85 ± 7.4, respectively (p b 0.001). Conclusion: Renal NIRS measurements correlate with urine production. Lower values are noted as urine output declines and precedes a decline in MAP. Renal NIRS may have promise as a non-invasive means of determining adequacy of renal perfusion and urine output in neonates with complex fluid shifts. Level of evidence: IIb. © 2017 Elsevier Inc. All rights reserved.
In recent years, near infrared spectroscopy (NIRS) has become a common modality in many centers for the monitoring of brain oxygenation delivery during cardiac surgery [1,2], with particular interest in monitoring patients undergoing pediatric cardiac surgery [3,4]. These observations have led to the implementation of NIRS for postoperative monitoring and management of children with cardiac disease in many cardiac intensive care units [5,6]. The use of findings on physical exam, pulse oximetry and blood pressure have been shown to be inadequate for the assessment of adequacy or inadequacy of the circulation in complex patients [7,8]. Therefore, of NIRS has increasingly been used as a means to accurately measure end organ perfusion. Recent studies have shown that other non-cardiac pediatric conditions such as congenital diaphragmatic hernia (CDH) and esophageal atresia might benefit from using NIRS to measure organ perfusion as part of the postnatal management [9–11]. With the implementation of Extracorporeal membrane oxygenation (ECMO), the survival of patients with severe CDH ⁎ Corresponding author at: Texas Children's Hospital, 6701 Fannin St., Suite 1210, Houston, TX 77030. Tel.: +1 832 822 3135; fax: +1 832 825 3141. E-mail address: [email protected] (O.O. Olutoye). http://dx.doi.org/10.1016/j.jpedsurg.2017.01.015 0022-3468/© 2017 Elsevier Inc. All rights reserved.
has improved [12]. Unfortunately, ECMO can be associated with complications and potential long term morbidity associated with aberrations in regional hemodynamics in this unique patient population; thus, suggesting that assessments of NIRS may be beneficial in this cohort. The current study focuses on the use of renal near infrared spectroscopy (rStO2) as a marker for renal tissue perfusion and compares it to urine output. We hypothesized that renal tissue oxygen saturation as measured by NIRS would correlate with urine output in neonates with congenital diaphragmatic hernia on extracorporeal membrane oxygenation (ECMO). 1. Patients and methods This study was part of a larger experimental study on the use of Near-infrared spectroscopy in CDH patients approved by Baylor College of Medicine Institutional Review Board (H-25598). All the patients were identified in the antenatal period in Texas Children's Fetal Center with the diagnosis of congenital diaphragmatic hernia. Consent for enrollment in the project was obtained from the patient's parents or guardian. As per study protocol, NIRS probes were placed on the patient's right
690
P.E. Lau et al. / Journal of Pediatric Surgery 52 (2017) 689–692
and left forehead, right lower abdominal quadrant and left flank within 24 h of birth. This was an observational study where clinicians were blinded to NIRS values, and no clinical decisions were based on the NIRS readings. Neonates born at less than 30 weeks of gestation and/or more than 24 h of life at enrollment were excluded from the study. 1.1. Data collection A near-infrared spectrometer (FORE-SIGHT, CASMED, Brandford, CT) was used to continuously measure cerebral, renal and splanchnic tissue oxygenation saturation. NIRS monitoring was initiated within 24 h of life and continued until 24 h after CDH repair or ECMO decannulation if ECMO was required. Renal tissue oxygen saturation values were collected on continuous 1 min intervals and time stamped in an encrypted file using LabVIEW™ (National Instruments, Austin, TX). Periods of time where no data was collected were excluded from analysis. Simultaneously, physiological data such as mean arterial blood pressure, arterial pH values, creatinine concentration, blood urea nitrogen concentration and urine output were collected. In addition, nursing staff was instructed to record with a time stamp any acute event, procedure, changes in position of the patient during the study period. 1.2. Data analysis For the purpose of this study, data from CDH patients who required ECMO support and had renal NIRS monitoring were analyzed. Periods of anuria (NU), adequate urine output N 1 ml/kg/h (AU) and low urine output b1 ml/kg/h (LU) while the patients were on ECMO were identified from the patients' chart. Anuria was defined by urine output of zero as recorded by the nursing staff over a period of at least 2 h. rStO2 values, mean arterial pressure, creatinine, BUN and pH were then assessed in these time periods of urine output. 1.3. Statistical analysis Statistical analysis was performed using IBM SPSS statistical software version 23 (IBM Corporation, Armonk, NY). Student's t-test and one-way ANOVA with Post Hoc analysis was used for continuous variables. Categorical data were analyzed with a chi-square test. A Receiver operating characteristic (ROC) curve analysis was also performed. A p-value of less than 0.05 was considered significant. 2. Results 2.1. Patient demographics During the study period, there were forty-two patients with CDH eligible for the study. Of these, twelve patients required ECMO. Six of the twelve patients requiring ECMO were excluded from the study due to long gaps in data collection and/or high signal-to-noise ratio.
The remaining six patients were used for the renal NIRS analyses. Collectively, over 1500 h of continuous NIRS were obtained from these neonates. The mean gestational age at birth in the cohort was 37 ± 3 weeks, their mean birth weight was 2.59 ± 0.1 kg and the mean ECMO run was 9.2 ± 4.1 days (Table 1). Five out of six patients were male with equal number of right and left CDH cases. Only 2 patients received veno-venous ECMO, while the remaining four received arteriovenous ECMO. The mean lung-to-head ratio for the cohort was 1.2 ± 0.37 and an expected-to-observed total fetal lung volume of 22.5 ± 9.3%. All of these patients had liver herniation, with a mean percent liver herniation of 38.5 ± 8.8%. The overall survival to discharge rate was 67% (4 of 6). 2.2. Urine output We observed a significant difference in the NIRS values among the three periods of anuria (NU), adequate urine output N1 ml/kg/h (AU) and low urine output b1 ml/kg/h (LU) (Table 2). Renal NIRS values among groups were 83.93 ± 6.26, 76.12 ± 2.98 and 67.18 ± 6.4 for AU, LU and NU respectively (Fig. 1). A ROC analysis showed a renal NIRS value of N76% was highly predictive of adequate urine output with a 90% sensitivity and 86% specificity and an area under the curve of 0.96 (Fig. 2). The mean arterial pressure was significantly lower among anuric patients, 36.42 ± 10.26, when compared to patients AU and LU patients, 42.99 ± 5.25 and 42.85 ± 7.4 respectively (p b 0.001). Blood urea nitrogen concentrations and pH showed no difference among the three groups (Table 2), There was a significant difference in creatinine values during AU compared to LU and NU (p = 0.007). Inversely, lactate levels were significantly higher at 3.77 ± 2.47 in patients with anuria (p b 0.001) (Table 2). 3. Discussion The clinical monitoring and management of neonates with congenital diaphragmatic hernia is extremely challenging. Classical methods of monitoring such as heart rate, mean arterial pressure and clinical signs of end organ perfusion such as capillary return have been shown to be poor assessment tools of end organ perfusion in premature neonates that are ventilated [13]. In neonates with severe congenital diaphragmatic hernias the implementation of ECMO has impacted their survival [12,14]. Nevertheless, ECMO does not come without complications, among them is renal dysfunction among these patients. Many factors have been reported to cause acute kidney injury (AKI) during support on ECMO [15], and they have been characterized as inflammatory, hormonal and/or alterations in blood flow. Although in some cases, AKI might precede the use of ECMO, in this study patients were initiated on ECMO therapy within 24 h of life, and in most cases prior to the onset of renal dysfunction. Thus AKI seen in this patient population is more likely to be a sequela of ECMO rather than the hemodynamics before ECMO although this can be difficult to assess in this severely ill population. Among the factors identified for AKI, hemodynamic alterations are the most feasible for possible interventions. In order to prevent severe
Table 1 Patient's Demographics and Characteristics. Patient
Gender
Birth Weight (kg)
Gestational Age (weeks)
Side of CDH
In-Born
ECMO Duration (Days)
Major Anomalies
Survival To Discharge
Type of ECMO Cannula
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6
M M F M M M
2.27 2.16 2.78 3.08 2.95 2.30
38 38.14 39.28 39.42 37.86 32
Left Left Left Right Right Right
Yes Yes Yes Yes Yes Yes
13 7 4 11 14 6
Imperforate anus -
No No Yes Yes Yes Yes
V-A V-A V-V V-V V-A V-A
M: Male F: Female. V-A: Veno-arterial cannula. V-V: Veno-veno cannula.
P.E. Lau et al. / Journal of Pediatric Surgery 52 (2017) 689–692
691
Table 2 Urine output groups.
rStO2 (%) MAP (mmHg) BUN (mg/dl) Creatinine (mg/dl) pH (mmol) Lactate (mg/dl)
Appropriate Urine Output (AU)
Low Urine Output (LU)
No Urine Output (NU)
p-value
84 +/− 6 43.0+/−5.3 41.52+/−23.96 0.59+/−0.21
76 +/− 3 42.9+/−7.4 43.5+/−7.78 0.805+/−0.13
67 +/− 6 36.4+/−10.3 37.1 +/−23.32 0.86+/−0.28
b0.001 b0.001 0.864 0.007
7.30+/−0.09 1.74+/−0.93
7.28+/−0.07 1.28+/−0.56
7.29 +/−0.07 3.77+/−2.47
0.512 b0.001
hemodynamic changes that may injure the kidneys, better modalities for the assessment of their perfusion are necessary and it would be ideal if the assessments could be shown to be abnormal before overt signs of kidney injury are obvious. Since hemodynamic parameters such as blood pressure might not accurately reflect renal tissue perfusion there is a need for more accurate methods of monitoring renal blood flow/hemodynamics. This is where NIRS has its greatest potential. In recent years NIRS has gained distinction in the measurement of end organ perfusion, especially in sick pediatric patients. Although, the majority of the studies focus on its use during cardiac surgery, NIRS is starting to gain popularity for monitoring of patients with non-cardiac illnesses [10,16,17]. Animal studies have shown that renal NIRS changes in neonatal swine model of shock in advance to disturbances in cerebral flow and blood pressure [18]. In humans, renal NIRS was measured in patients who underwent laparoscopic surgery and showed no significant difference in perfusion during the creation of pneumoperitoneum [17]. In our study, we evaluated renal NIRS and correlated the measurement with urine production. We noted significant differences between the three groups categorized by urine output implying substantial physiologic changes occurring as urine output decreases. By performing a receiver operating characteristic (ROC) curve we found that a renal NIRS value of 76% was highly predictive of adequate urine output. This
Fig. 2. ROC Curve for renal NIRS versus urine output.
finding may potentially aid clinicians in the monitoring of these patients by intervening as the NIRS values drops to or below this threshold prior to the development of overt kidney injury. Concurrently, when we evaluated mean arterial pressure, we noted that the MAP was lower in the no urine output group but was not different in the low urine output group than in the adequate urine output even when the NIRS was lower in the low urine output group, suggesting that MAP is not an appropriate tool to address renal perfusion and that NIRS was a better instrument to assess renal perfusion compared to MAP. Our data do not show that renal NIRS was better than a fall in urine output to predict
Fig. 1. Renal NIRS compared to urine output. AU=Adequate urine output LU=Low urine output NU=No urine output ROC threshold at 76%.
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kidney injury and determining that would take a systematic analysis of many more patients and assessing intra-individual assessments to try to determine whether changes in NIRS happened prior to a change in urine output. We interpret our findings as suggesting that MAP can be used to differentiate extreme changes in the tissue perfusion are present but not for more subtle changes in perfusion. On the other hand, NIRS might be a useful tool in order to detect these subtle changes in renal perfusion prior to significant damage and minimal interventions might be necessary to correct the perfusion deficit. Interestingly our data show that changes in serum biochemistry are not reasonable biomarkers for early kidney injury other than a change in serum creatinine concentrations. Other animal models have seen similar findings [18]. In the present study, Blood urea nitrogen (BUN) levels and pH were not different between the three groups of urine output. While creatinine levels were much lower among the patients with adequate urine output (p = 0.007). Lactate concentrations, on the other hand, showed a pattern similar to the one observed in MAP in that it was only elevated with frank anuria. It is likely that this pattern, like in the case of MAP, reflects the extreme hypoperfusion that was experienced by the kidneys with marked hypotension. This study was conducted on CDH patients that required ECMO. Although the data was prospectively acquired, it was analyzed retrospectively. Furthermore, due to the rarity of the condition and the need for ECMO, we have a limited sample size. An additional limitation was the presence of noise in the NIRS measurements or large gaps of data that were not interpretable due to the position of the probes during the project. Despite these limitations, the ability to record continuous renal NIRS values allowed us to acquire more than 1500 h of data on the 6 patients reported. This limitation can be addressed by studying many patients systematically preferably in a multi-institutional project where many centers use renal NIRS for the evaluation of tissue perfusion in their CDH ECMO patients. 4. Conclusion In conclusion, NIRS measurements of renal tissue oxygenation correlates with urine production. Lower NIRS values were noted as urine output declined and preceded a decline in mean arterial pressure. Renal NIRS may be a suitable non-invasive means of determining adequacy
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