Original Article
Factors and Outcomes of Persistent Pulmonary Hypertension of the Newborn Associated with Acute Kidney Injury in Thai Neonates Wuttichart Kamolvisit, MD1 Narongsak Nakwan, MD1
Sutthikiat Jaroensri, MD1
1 Department of Pediatrics, Hat Yai Medical Education Center,
Hat Yai, Songkhla, Thailand 2 Department of Health System Development, Hat Yai Hospital, Hat Yai, Songkhla, Thailand
Benthira Ratchatapantanakorn, PhD2
Address for correspondence Narongsak Nakwan, MD, Neonatal Intensive Care Unit, Department of Pediatrics, Hat Yai Medical Education Center, Hat Yai Hospital, Hat Yai, Songkhla 90110, Thailand (e-mail: [email protected]).
Abstract
Keywords
► persistent pulmonary hypertension of the newborn ► neonatal mortality ► acute kidney injury ► acute renal failure ► newborn infant
Objective This study aims to determine the risk factors and outcome of persistent pulmonary hypertension of the newborn (PPHN)-associated acute kidney injury (AKI). Study Design Infants diagnosed with PPHN at Hat Yai Hospital from January 2012 to December 2016 were retrospectively reviewed. Results Of the 109 included PPHN infants, 28.4% (31/109) died, and AKI was found in 28.4% following neonatal KDIGO classification. Of the 31, 19 who died (61.3%) reached stage 1, 3 (9.7%) reached stage 2, and 9 (29.0%) reached stage 3. AKI (all stages combined) was significantly associated with increased mortality with an odds ratio (OR) of 8.71 (95% confidence interval [CI], 3.37–22.49). Multivariate logistic regression analysis indicated that male gender (adjusted OR ¼ 8.56; 95% CI ¼ 0.84–85.09) and urine output of < 1 mL/kg/h in 12 hours of admission (adjusted OR ¼ 15.57; 95% CI ¼ 2.58–93.98) were the main factors associated with an increased risk for AKI, while birth by cesarean delivery was associated with reduced risk of AKI (adjusted OR ¼ 0.10; 95% CI ¼ 0.16–0.68). Conclusion The incidence of AKI in PPHN was high in this study, and this complication was also significantly associated with higher mortality. In PPHN neonates, AKI should be especially closely monitored in males and infants who have a urine output of < 1 mL/kg/h in the first 12 hours of admission.
Acute kidney injury (AKI) is a common complication of critically ill patients in the neonatal intensive care unit (NICU), leading to increased length of mechanical ventilation, hospital stay, morbidity, and mortality.1–4 The incidence of neonates in the NICU who develop an AKI ranges from 2.7 to 7.4%, depending on differing definitions of AKI.5–7 This number is much higher in some situations, for example, 19% in premature infants,1 64% in infants who have been treated with extracorporeal membrane oxygenation (ECMO), 8 or 15% in nearterm and term neonates with another illness.9 Before 2008, the
definition of AKI in neonates was based on a serum creatinine (Scr) level > 1.5 mg/mL, but this was an arbitrary assumption not based on clinical studies. In recent years, many investigators have attempted to determine a more objective definition of AKI, including in neonates, through such things as the Acute Kidney Injury Network (AKIN),10 the Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease (RIFLE) assessment tool,11 and the Kidney Disease: Improving Global Outcomes (KDIGO) organization.12 Many definitions for AKI have been offered by these groups for use in both adult and
received June 3, 2017 accepted after revision August 28, 2017
Copyright © by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI https://doi.org/ 10.1055/s-0037-1607213. ISSN 0735-1631.
Downloaded by: Scott Memorial Library, AISR. Copyrighted material.
Am J Perinatol
pediatric patients; however, to date, there is no widespread consensus on the definition of AKI in neonates. The most common cause of neonatal AKI is perinatal asphyxia, which causes blood to be shunted to vital organs thus depriving the kidneys of an adequate supply.1,5,13 Systemic hypotension, cardiac failure, or vasodilatation associated with sepsis have also been documented as causes of neonatal AKI.6,7 Also, a congenital genitorenal anomaly, resulting from things, such as cystic kidney disease, renal dysplasia, or obstructive uropathy (such as ureteropelvic junction obstruction or posterior urethral valve), is a less frequent of the cause of neonatal AKI.6,7 Our recent study found that one-fourth of persistent pulmonary hypertension of the newborn (PPHN) developed AKI, with a mortality risk hazard ratio of 2.9.14 Because of the higher incidence of AKI in the presence of these conditions, the relation of these factors to PPHN-associated AKI in the NICU setting needs to be clarified. To our knowledge, there are to date no published cohort studies specifically looking at PPHN with AKI in neonates. This study aimed to determine the risk factors and outcomes of PPHN-associated AKI in the major neonatal tertiary care unit in Southern Thailand.
Patients and Methods This retrospective study included all infants diagnosed with PPHN between January 1, 2012 and December 30, 2016 in Hat Yai Hospital in Southern Thailand. The study was approved by the Hat Yai Hospital Ethics Committee. Infants diagnosed with PPHN with an additional major congenital anomaly (such as nervous system, musculoskeletal system, or gastrointestinal system), cyanotic heart disease, or chromosomal disorder, were excluded, with one exception— infants with PPHN due to congenital diaphragmatic hernia (CDH) or pulmonary hypoplasia were included in the study as these two conditions are important causes of PPHN. The diagnosis of PPHN was mainly based on presentation with refractory hypoxemia plus one or more of the three following conditions: (1) documented pulmonary hypertension, as defined by echocardiographic evidence of elevated pulmonary pressure (right to left or bidirectional shunt), (2) a pre- to postductal partial pressure of oxygen gradient 20 mm Hg (PaO2), and/or (3) a pulse oximetry oxygen satura-
Kamolvisit et al. tion (SpO2) gradient 10%. Definitive diagnosis of PPHN is only possible through echocardiography, but most of our diagnoses were made based on clinical examination with a hyperoxia-hyperventilation test to exclude cyanotic heart disease. AKI was defined using a Scr-based modification of the KDIGO criteria, the neonatal AKI KDIGO classification (►Table 1).15 Urine output following the modified KDIGO criteria was used to classify infants into one of three groups according to severity, as most of our patients were critically ill upon arrival at the NICU and had a urinary catheter inserted for continuous monitoring of urine output. The demographic characteristics of the neonates were recorded, including gestational age, birth weight, gender, mode of delivery, Apgar scores at 1 and 5 minutes, cause(s) of PPHN, and treatment modalities. The severity of illness was assessed by the Score for Neonatal Acute Physiology-Version II (SNAP-II) test within 12 hours of hospital admission.16 To determine the risk factors for AKI in PPHN, known potential and possible risk factors prior to AKI onset were recorded, including placement of central arterial and venous catheters, exposure to nephrotoxic drugs (such as gentamicin, amikacin, vancomycin, cephalosporins, amphotericin B, carbapenems, or nonsteroidal anti-inflammatory agents), maximum sodium and chloride values, the highest and lowest levels of hematocrit, platelet count, blood pressure, heart rate, and body temperature. Patient outcomes included mortality and morbidity in the form of the duration of mechanical ventilation and supplemental oxygen therapy, hospital length of stay, and requirement of renal replacement therapy.
Statistical Analysis Descriptive statistics are presented as mean (standard deviation) and median (interquartile range, IQR). Categorical data are presented as frequency and percentage. Comparisons of normally distributed continuous variables between the groups were analyzed using Student’s t-test. Nominal categorical data between the groups were compared using the chi-square test or Fisher’s exact test as appropriate. Nonnormal distribution continuous variables were compared using the Mann–Whitney U-test. Multiple logistic regression analysis was used to identify risk factors for AKI in PPHN and to assess the factors associated with AKI and the outcomes about time to hospital discharge or death. Odds ratio (OR)
Table 1 Neonatal AKI KDIGO classification Stage
Serum creatinine
Urine output
0
No change in Scr or rise < 0.3 mg/dL
0.5 mL/kg/h
1
Scr rise 0.3 mg/dL within 48 h or Scr rise 1.5–1.9 reference SCra within 7 d
< 0.5 mL/kg/h for 6–12 h
2
Scr rise 2.0–2.9 reference SCra
< 0.5 mL/kg/h for 12 h
3
a
Scr rise 3 reference SCr or Scr 2.5 mg/dLb or receipt of dialysis
< 0.3 mL/kg/h for 24 h or anuria for 12 h
Abbreviations: AKI, acute kidney injury; KDIGO, Kidney Disease: Improving Global Outcomes; Scr, serum creatinine. Note: Differences between the proposed neonatal AKI definition and KDIGO include the following: a Reference Scr will be defined as the lowest previous Scr value. b Scr value of 2.5 mg/dL represents < 10 mL/min/1.73 m2. American Journal of Perinatology
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Factors and Outcomes of PPHN-Associated AKI in Neonates
with 95% confidence interval (CI) were used to quantify the associations. A p value of < 0.05 was considered statistically significant. All statistical analyses were performed using SPSS 16.0 (SPSS Inc., Chicago, IL).
Results During the study period, a total of 3,584 infants were admitted to our NICU, of whom 125 (3.5%) were diagnosed with PPHN. Out of these 125 patients, 16 were excluded from the study due to congenital cyanotic heart disease (2 transposition of great vessels, 1 coarctation of the aorta, 1 total anomalous pulmonary venous return, 1 pulmonary atresia, and 4 complex heart disease), genetic abnormalities (1 Down’s syndrome, and 1 unspecified skeletal genetic disorder), or missing record data (5). The data from the remaining 109 infants were analyzed, with a mortality rate of 28.4% (31/109) from all causes. There were no significant differences in gestational age, birth weight, maternal age, level of resuscitation at delivery room, the cause of PPHN, treatment modalities, length of mechanical ventilation, and supplemental oxygen or hospital stay between the AKI group and the non-AKI group (►Table 2). Meconium aspiration syndrome was the most common etiology of PPHN in our study (67 of 109, 61.5%). PPHN infants with pulmonary hypoplasia (3) or CDH (6) had a higher risk of developing AKI than those without these diseases (16.1% versus 5.1%, retrospectively). Seven of these nine infants died, three due to severe PPHN, three from pulmonary hypoplasia, and one from CDH. Twenty-five infants (22.9%) were diagnosed with PPHN by echocardiography, and 84 (77.1%) were diagnosed by preand postductal SpO2 or PaO2 and/or the hyperoxia/hyperventilation test. For the treatment of PPHN with pulmonary vasodilators, of 109 infants, 61 (55.9%) were treated with inhaled nitric oxide (iNO), 7 were treated with only iNO, and 54 were treated with iNO combined with one or more pulmonary vasodilators such sildenafil, iloprost, or milrinone. In the non-iNO group, 32 (29.4%) infants were treated with sildenafil with or without one or more pulmonary vasodilators. Overall, 31 PPHN infants (28.4%) also had AKI according to the neonatal KDIGO classification. The median age of AKI onset was 24 (range: 24–48) hours. Of the 31 PPHN infants, 19 (61.3%) had stage 1 AKI, 3 had (9.7%) stage 2, and 9 had (29.0%) stage 3. When considering all PPHN neonates, the AKI group had a significantly higher mortality rate than the non-AKI group (19/31 (61.3%) versus 12/78 (15.4%), respectively, p < 0.01). In univariate analysis, AKI (all stages combined) was significantly associated with increased mortality with an OR of 8.71 (95% CI ¼ 3.37–22.49, p < 0.01). Stages 2 and 3 AKI combined (OR ¼ 18.10, 95% CI ¼ 3.68–89.02, p < 0.01) had greater mortality than stage 1 AKI (OR ¼ 0.36, 95% CI ¼ 0.13–0.99, p ¼ 0.04). PPHN male infants were significantly more likely to develop AKI. Also, significantly more non-AKI infants were born by cesarean delivery than AKI infants (52.6 vs. 29.0%, p ¼ 0.03). The AKI group had higher SNAP-II scores and lower Apgar scores at 1 and 5 minutes than the non-AKI group. Only two infants required peritoneal
Kamolvisit et al.
dialysis, both due to anuria and severe metabolic acidosis, one of whom died while the other fully recovered from the AKI. Possible risk factors in the 24 hours before AKI onset or the highest Scr in the study neonates with PPHN are shown in ►Table 3. The infants with AKI had lower mean arterial blood pressure, higher serum chloride (Schl), and higher Scr, than those without AKI (37.0 7.4 vs, 40.9 8.9 mm Hg, p ¼ 0.03, and 104.9 6.6 vs. 100.8 12.0 mEq/L, p ¼ 0.03, 1.2 0.7 vs. 0.8 0.3 mg/dL, p < 0.01, respectively). For individual SNAP-II parameters analysis, the lowest PaO2/FiO2 ratio of < 0.1, urine output of < 1.0 mL/kg/h, and the lowest pH of < 7.25 over the first 12 hours of NICU admission were found to be significant predictors of AKI in PPHN infants. In a univariate logistic regression analysis model performed to identify factors related to the development of AKI in the PPHN infants, several factors were determined to be significantly associated with AKI (►Table 4). Multivariate analysis indicated that male gender (adjusted OR ¼ 8.56; 95% CI ¼ 0.84–85.09), p ¼ 0.04, and urine output of < 1 mL/ kg/h in the first 12 hours of NICU admission (adjusted OR ¼ 15.57; 95% CI ¼ 2.58–93.98, p < 0.01) were the main factors associated with an increased risk for AKI, while infants with PPHN born by cesarean delivery had reduced risk of AKI (adjusted OR ¼ 0.10; 95% CI ¼ 0.16–0.68, p ¼ 0.02) (►Table 4).
Discussion To our knowledge, this is the first cohort study to evaluate the outcomes and risk factors of PPHN-associated AKI. Almost one-third of our 109 PPHN infants developed AKI according to the KDIGO neonatal definition. Our study also found that PPHN-associated AKI also had a significantly increased risk of mortality. Male gender, the presence of oliguria in the first 12 hours of hospital admission, and delivery by cesarean delivery were also significantly associated with AKI, the first two with higher risk and the last with lower. The mortality outcomes of infants with PPHN vary depending on the etiology of the disease and the experience of the neonatal care team. In this current study, the mortality rate of PPHN was high (28.4%), although our hospital has many modern therapeutic options, such as high frequency oscillatory ventilation and iNO, along with other pulmonary vasodilators such as iloprost, sildenafil, or bosentan for adjuvant therapy. In previous studies, approximately 20 to 45% of PPHN infants who received iNO did not respond, while in this study, most of our patients received iNO combined with one or more pulmonary vasodilators.17,18 Unfortunately, ECMO is not available in our hospital due to its very high cost, although studies from developed countries have found that this treatment can significantly increase the survival rate of PPHN.19,20 Also, again due to financial restrictions, our hospital has and had at the time of the study only a limited number of neonatal nurses, with three to four critically ill infants usually being cared for by only one nurse. One of the notable causes of high mortality in our PPHN infants was CDH/pulmonary hypoplasia (seven of nine American Journal of Perinatology
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Factors and Outcomes of PPHN-Associated AKI in Neonates
Factors and Outcomes of PPHN-Associated AKI in Neonates
Kamolvisit et al.
Table 2 Demographic and clinical characteristic of infants with PPHN with and without AKI Characteristics
AKI (n ¼ 31)
No AKI (n ¼ 78)
p Value
Gestational age (wk), mean SD
38.3 2.7
38.8 1.9
0.31
Birth weight (g), mean SD
2,968 682
3,041 557
0.60
Male, n (%)
26 (83.9%)
49 (62.8%)
0.03
SNAP-II scores, mean SDa
41.8 17.3
24.8 12.1
< 0.01
Apgar score at 1 min, mean SD
5.6 2.7
6.8 2.5
0.04
Apgar score at 5 min, mean SD
6.8 2.5
8.1 2.8
< 0.01
Maternal age (y)b
27.6 7.1
27.6 6.8
0.97
Cesarean delivery
9 (29.0%)
41 (52.6%)
0.03
5 (16.1%)
11 (14.1%)
0.79
Perinatal history, n (%)
Oxygen inhalation only Endotracheal intubation and/or meconium suctioning
16 (51.6%)
29 (37.2%)
0.19
Positive pressure ventilation by mask with bag
5 (16.1%)
12 (15.4%)
0.92
Chest compression
1 (3.2%)
3 (3.8%)
0.89
Echocardiography
6 (19.4%)
19 (24.4%)
0.58
Pre- and postductal SpO2 or PaO2 difference and/or hyperoxia/hyperventilation test
25 (80.6%)
59 (75.6%)
Diagnostic methods of PPHN, n (%)
Causes of PPHN, n (%) Meconium aspiration syndrome
16 (51.6%)
51 (65.4%)
0.19
Pulmonary hypoplasia or congenital diaphragmatic hernia
5 (16.1%)
4 (5.1%)
0.60
Congenital pneumonia
6 (19.4%)
13 (16.7%)
0.78
Transient tachypnea of the newborn
0
2 (2.6%)
0.37
Idiopathic PPHN
1 (3.2%)
2 (2.6%)
0.85
Respiratory distress syndrome
2 (6.5%)
3 (3.8%)
0.56
Sepsis with shock
1 (3.2%)
3 (3.8%)
0.88
Treatment modalities, n (%) High frequency oscillatory ventilation
26 (83.9%)
54 (69.2%)
0.15
Intravenous iloprost
17 (54.8%)
46 (59.0%)
0.83
Intragastric sildenafil
23 (74.2%)
61 (78.2%)
0.80
Inhaled nitric oxide
15 (48.4%)
45 (57.7%)
0.40
Intravenous milrinone
9 (29.0%)
19 (24.4%)
0.63
Intragastric bosentan
0
3 (3.8%)
0.27
Stage 0
0
78 (100%)
NA
Stage 1
19 (61.3%)
0
Stage 2
3 (9.7%)
0
Stage 3
9 (29.0%)
0
AKI outcome Neonatal KDIGO classification, n (%)
Length of mechanical ventilation (d), median (IQR)
10.0 (3.0–17.0)
11.5 (7.0–17.3)
0.18
Length of supplemental oxygenation (d), median (IQR)
11.0 (3.0–22.0)
16.0 (10.0–25.0)
0.27
Length of stay (d), median (IQR)
11.0 (2.0–22.0)
18.5 (10.0–30.0)
0.06
Peritoneal dialysis, n (%)
2 (6.5%)
0
NA
In-hospital mortality, n (%)
19 (61.3%)
12 (15.4%)
Factors and Outcomes of Persistent Pulmonary Hypertension of the Newborn Associated with Acute Kidney Injury in Thai Neonates Wuttichart Kamolvisit, MD1 Narongsak Nakwan, MD1
Sutthikiat Jaroensri, MD1
1 Department of Pediatrics, Hat Yai Medical Education Center,
Hat Yai, Songkhla, Thailand 2 Department of Health System Development, Hat Yai Hospital, Hat Yai, Songkhla, Thailand
Benthira Ratchatapantanakorn, PhD2
Address for correspondence Narongsak Nakwan, MD, Neonatal Intensive Care Unit, Department of Pediatrics, Hat Yai Medical Education Center, Hat Yai Hospital, Hat Yai, Songkhla 90110, Thailand (e-mail: [email protected]).
Abstract
Keywords
► persistent pulmonary hypertension of the newborn ► neonatal mortality ► acute kidney injury ► acute renal failure ► newborn infant
Objective This study aims to determine the risk factors and outcome of persistent pulmonary hypertension of the newborn (PPHN)-associated acute kidney injury (AKI). Study Design Infants diagnosed with PPHN at Hat Yai Hospital from January 2012 to December 2016 were retrospectively reviewed. Results Of the 109 included PPHN infants, 28.4% (31/109) died, and AKI was found in 28.4% following neonatal KDIGO classification. Of the 31, 19 who died (61.3%) reached stage 1, 3 (9.7%) reached stage 2, and 9 (29.0%) reached stage 3. AKI (all stages combined) was significantly associated with increased mortality with an odds ratio (OR) of 8.71 (95% confidence interval [CI], 3.37–22.49). Multivariate logistic regression analysis indicated that male gender (adjusted OR ¼ 8.56; 95% CI ¼ 0.84–85.09) and urine output of < 1 mL/kg/h in 12 hours of admission (adjusted OR ¼ 15.57; 95% CI ¼ 2.58–93.98) were the main factors associated with an increased risk for AKI, while birth by cesarean delivery was associated with reduced risk of AKI (adjusted OR ¼ 0.10; 95% CI ¼ 0.16–0.68). Conclusion The incidence of AKI in PPHN was high in this study, and this complication was also significantly associated with higher mortality. In PPHN neonates, AKI should be especially closely monitored in males and infants who have a urine output of < 1 mL/kg/h in the first 12 hours of admission.
Acute kidney injury (AKI) is a common complication of critically ill patients in the neonatal intensive care unit (NICU), leading to increased length of mechanical ventilation, hospital stay, morbidity, and mortality.1–4 The incidence of neonates in the NICU who develop an AKI ranges from 2.7 to 7.4%, depending on differing definitions of AKI.5–7 This number is much higher in some situations, for example, 19% in premature infants,1 64% in infants who have been treated with extracorporeal membrane oxygenation (ECMO), 8 or 15% in nearterm and term neonates with another illness.9 Before 2008, the
definition of AKI in neonates was based on a serum creatinine (Scr) level > 1.5 mg/mL, but this was an arbitrary assumption not based on clinical studies. In recent years, many investigators have attempted to determine a more objective definition of AKI, including in neonates, through such things as the Acute Kidney Injury Network (AKIN),10 the Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease (RIFLE) assessment tool,11 and the Kidney Disease: Improving Global Outcomes (KDIGO) organization.12 Many definitions for AKI have been offered by these groups for use in both adult and
received June 3, 2017 accepted after revision August 28, 2017
Copyright © by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.
DOI https://doi.org/ 10.1055/s-0037-1607213. ISSN 0735-1631.
Downloaded by: Scott Memorial Library, AISR. Copyrighted material.
Am J Perinatol
pediatric patients; however, to date, there is no widespread consensus on the definition of AKI in neonates. The most common cause of neonatal AKI is perinatal asphyxia, which causes blood to be shunted to vital organs thus depriving the kidneys of an adequate supply.1,5,13 Systemic hypotension, cardiac failure, or vasodilatation associated with sepsis have also been documented as causes of neonatal AKI.6,7 Also, a congenital genitorenal anomaly, resulting from things, such as cystic kidney disease, renal dysplasia, or obstructive uropathy (such as ureteropelvic junction obstruction or posterior urethral valve), is a less frequent of the cause of neonatal AKI.6,7 Our recent study found that one-fourth of persistent pulmonary hypertension of the newborn (PPHN) developed AKI, with a mortality risk hazard ratio of 2.9.14 Because of the higher incidence of AKI in the presence of these conditions, the relation of these factors to PPHN-associated AKI in the NICU setting needs to be clarified. To our knowledge, there are to date no published cohort studies specifically looking at PPHN with AKI in neonates. This study aimed to determine the risk factors and outcomes of PPHN-associated AKI in the major neonatal tertiary care unit in Southern Thailand.
Patients and Methods This retrospective study included all infants diagnosed with PPHN between January 1, 2012 and December 30, 2016 in Hat Yai Hospital in Southern Thailand. The study was approved by the Hat Yai Hospital Ethics Committee. Infants diagnosed with PPHN with an additional major congenital anomaly (such as nervous system, musculoskeletal system, or gastrointestinal system), cyanotic heart disease, or chromosomal disorder, were excluded, with one exception— infants with PPHN due to congenital diaphragmatic hernia (CDH) or pulmonary hypoplasia were included in the study as these two conditions are important causes of PPHN. The diagnosis of PPHN was mainly based on presentation with refractory hypoxemia plus one or more of the three following conditions: (1) documented pulmonary hypertension, as defined by echocardiographic evidence of elevated pulmonary pressure (right to left or bidirectional shunt), (2) a pre- to postductal partial pressure of oxygen gradient 20 mm Hg (PaO2), and/or (3) a pulse oximetry oxygen satura-
Kamolvisit et al. tion (SpO2) gradient 10%. Definitive diagnosis of PPHN is only possible through echocardiography, but most of our diagnoses were made based on clinical examination with a hyperoxia-hyperventilation test to exclude cyanotic heart disease. AKI was defined using a Scr-based modification of the KDIGO criteria, the neonatal AKI KDIGO classification (►Table 1).15 Urine output following the modified KDIGO criteria was used to classify infants into one of three groups according to severity, as most of our patients were critically ill upon arrival at the NICU and had a urinary catheter inserted for continuous monitoring of urine output. The demographic characteristics of the neonates were recorded, including gestational age, birth weight, gender, mode of delivery, Apgar scores at 1 and 5 minutes, cause(s) of PPHN, and treatment modalities. The severity of illness was assessed by the Score for Neonatal Acute Physiology-Version II (SNAP-II) test within 12 hours of hospital admission.16 To determine the risk factors for AKI in PPHN, known potential and possible risk factors prior to AKI onset were recorded, including placement of central arterial and venous catheters, exposure to nephrotoxic drugs (such as gentamicin, amikacin, vancomycin, cephalosporins, amphotericin B, carbapenems, or nonsteroidal anti-inflammatory agents), maximum sodium and chloride values, the highest and lowest levels of hematocrit, platelet count, blood pressure, heart rate, and body temperature. Patient outcomes included mortality and morbidity in the form of the duration of mechanical ventilation and supplemental oxygen therapy, hospital length of stay, and requirement of renal replacement therapy.
Statistical Analysis Descriptive statistics are presented as mean (standard deviation) and median (interquartile range, IQR). Categorical data are presented as frequency and percentage. Comparisons of normally distributed continuous variables between the groups were analyzed using Student’s t-test. Nominal categorical data between the groups were compared using the chi-square test or Fisher’s exact test as appropriate. Nonnormal distribution continuous variables were compared using the Mann–Whitney U-test. Multiple logistic regression analysis was used to identify risk factors for AKI in PPHN and to assess the factors associated with AKI and the outcomes about time to hospital discharge or death. Odds ratio (OR)
Table 1 Neonatal AKI KDIGO classification Stage
Serum creatinine
Urine output
0
No change in Scr or rise < 0.3 mg/dL
0.5 mL/kg/h
1
Scr rise 0.3 mg/dL within 48 h or Scr rise 1.5–1.9 reference SCra within 7 d
< 0.5 mL/kg/h for 6–12 h
2
Scr rise 2.0–2.9 reference SCra
< 0.5 mL/kg/h for 12 h
3
a
Scr rise 3 reference SCr or Scr 2.5 mg/dLb or receipt of dialysis
< 0.3 mL/kg/h for 24 h or anuria for 12 h
Abbreviations: AKI, acute kidney injury; KDIGO, Kidney Disease: Improving Global Outcomes; Scr, serum creatinine. Note: Differences between the proposed neonatal AKI definition and KDIGO include the following: a Reference Scr will be defined as the lowest previous Scr value. b Scr value of 2.5 mg/dL represents < 10 mL/min/1.73 m2. American Journal of Perinatology
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Factors and Outcomes of PPHN-Associated AKI in Neonates
with 95% confidence interval (CI) were used to quantify the associations. A p value of < 0.05 was considered statistically significant. All statistical analyses were performed using SPSS 16.0 (SPSS Inc., Chicago, IL).
Results During the study period, a total of 3,584 infants were admitted to our NICU, of whom 125 (3.5%) were diagnosed with PPHN. Out of these 125 patients, 16 were excluded from the study due to congenital cyanotic heart disease (2 transposition of great vessels, 1 coarctation of the aorta, 1 total anomalous pulmonary venous return, 1 pulmonary atresia, and 4 complex heart disease), genetic abnormalities (1 Down’s syndrome, and 1 unspecified skeletal genetic disorder), or missing record data (5). The data from the remaining 109 infants were analyzed, with a mortality rate of 28.4% (31/109) from all causes. There were no significant differences in gestational age, birth weight, maternal age, level of resuscitation at delivery room, the cause of PPHN, treatment modalities, length of mechanical ventilation, and supplemental oxygen or hospital stay between the AKI group and the non-AKI group (►Table 2). Meconium aspiration syndrome was the most common etiology of PPHN in our study (67 of 109, 61.5%). PPHN infants with pulmonary hypoplasia (3) or CDH (6) had a higher risk of developing AKI than those without these diseases (16.1% versus 5.1%, retrospectively). Seven of these nine infants died, three due to severe PPHN, three from pulmonary hypoplasia, and one from CDH. Twenty-five infants (22.9%) were diagnosed with PPHN by echocardiography, and 84 (77.1%) were diagnosed by preand postductal SpO2 or PaO2 and/or the hyperoxia/hyperventilation test. For the treatment of PPHN with pulmonary vasodilators, of 109 infants, 61 (55.9%) were treated with inhaled nitric oxide (iNO), 7 were treated with only iNO, and 54 were treated with iNO combined with one or more pulmonary vasodilators such sildenafil, iloprost, or milrinone. In the non-iNO group, 32 (29.4%) infants were treated with sildenafil with or without one or more pulmonary vasodilators. Overall, 31 PPHN infants (28.4%) also had AKI according to the neonatal KDIGO classification. The median age of AKI onset was 24 (range: 24–48) hours. Of the 31 PPHN infants, 19 (61.3%) had stage 1 AKI, 3 had (9.7%) stage 2, and 9 had (29.0%) stage 3. When considering all PPHN neonates, the AKI group had a significantly higher mortality rate than the non-AKI group (19/31 (61.3%) versus 12/78 (15.4%), respectively, p < 0.01). In univariate analysis, AKI (all stages combined) was significantly associated with increased mortality with an OR of 8.71 (95% CI ¼ 3.37–22.49, p < 0.01). Stages 2 and 3 AKI combined (OR ¼ 18.10, 95% CI ¼ 3.68–89.02, p < 0.01) had greater mortality than stage 1 AKI (OR ¼ 0.36, 95% CI ¼ 0.13–0.99, p ¼ 0.04). PPHN male infants were significantly more likely to develop AKI. Also, significantly more non-AKI infants were born by cesarean delivery than AKI infants (52.6 vs. 29.0%, p ¼ 0.03). The AKI group had higher SNAP-II scores and lower Apgar scores at 1 and 5 minutes than the non-AKI group. Only two infants required peritoneal
Kamolvisit et al.
dialysis, both due to anuria and severe metabolic acidosis, one of whom died while the other fully recovered from the AKI. Possible risk factors in the 24 hours before AKI onset or the highest Scr in the study neonates with PPHN are shown in ►Table 3. The infants with AKI had lower mean arterial blood pressure, higher serum chloride (Schl), and higher Scr, than those without AKI (37.0 7.4 vs, 40.9 8.9 mm Hg, p ¼ 0.03, and 104.9 6.6 vs. 100.8 12.0 mEq/L, p ¼ 0.03, 1.2 0.7 vs. 0.8 0.3 mg/dL, p < 0.01, respectively). For individual SNAP-II parameters analysis, the lowest PaO2/FiO2 ratio of < 0.1, urine output of < 1.0 mL/kg/h, and the lowest pH of < 7.25 over the first 12 hours of NICU admission were found to be significant predictors of AKI in PPHN infants. In a univariate logistic regression analysis model performed to identify factors related to the development of AKI in the PPHN infants, several factors were determined to be significantly associated with AKI (►Table 4). Multivariate analysis indicated that male gender (adjusted OR ¼ 8.56; 95% CI ¼ 0.84–85.09), p ¼ 0.04, and urine output of < 1 mL/ kg/h in the first 12 hours of NICU admission (adjusted OR ¼ 15.57; 95% CI ¼ 2.58–93.98, p < 0.01) were the main factors associated with an increased risk for AKI, while infants with PPHN born by cesarean delivery had reduced risk of AKI (adjusted OR ¼ 0.10; 95% CI ¼ 0.16–0.68, p ¼ 0.02) (►Table 4).
Discussion To our knowledge, this is the first cohort study to evaluate the outcomes and risk factors of PPHN-associated AKI. Almost one-third of our 109 PPHN infants developed AKI according to the KDIGO neonatal definition. Our study also found that PPHN-associated AKI also had a significantly increased risk of mortality. Male gender, the presence of oliguria in the first 12 hours of hospital admission, and delivery by cesarean delivery were also significantly associated with AKI, the first two with higher risk and the last with lower. The mortality outcomes of infants with PPHN vary depending on the etiology of the disease and the experience of the neonatal care team. In this current study, the mortality rate of PPHN was high (28.4%), although our hospital has many modern therapeutic options, such as high frequency oscillatory ventilation and iNO, along with other pulmonary vasodilators such as iloprost, sildenafil, or bosentan for adjuvant therapy. In previous studies, approximately 20 to 45% of PPHN infants who received iNO did not respond, while in this study, most of our patients received iNO combined with one or more pulmonary vasodilators.17,18 Unfortunately, ECMO is not available in our hospital due to its very high cost, although studies from developed countries have found that this treatment can significantly increase the survival rate of PPHN.19,20 Also, again due to financial restrictions, our hospital has and had at the time of the study only a limited number of neonatal nurses, with three to four critically ill infants usually being cared for by only one nurse. One of the notable causes of high mortality in our PPHN infants was CDH/pulmonary hypoplasia (seven of nine American Journal of Perinatology
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Factors and Outcomes of PPHN-Associated AKI in Neonates
Factors and Outcomes of PPHN-Associated AKI in Neonates
Kamolvisit et al.
Table 2 Demographic and clinical characteristic of infants with PPHN with and without AKI Characteristics
AKI (n ¼ 31)
No AKI (n ¼ 78)
p Value
Gestational age (wk), mean SD
38.3 2.7
38.8 1.9
0.31
Birth weight (g), mean SD
2,968 682
3,041 557
0.60
Male, n (%)
26 (83.9%)
49 (62.8%)
0.03
SNAP-II scores, mean SDa
41.8 17.3
24.8 12.1
< 0.01
Apgar score at 1 min, mean SD
5.6 2.7
6.8 2.5
0.04
Apgar score at 5 min, mean SD
6.8 2.5
8.1 2.8
< 0.01
Maternal age (y)b
27.6 7.1
27.6 6.8
0.97
Cesarean delivery
9 (29.0%)
41 (52.6%)
0.03
5 (16.1%)
11 (14.1%)
0.79
Perinatal history, n (%)
Oxygen inhalation only Endotracheal intubation and/or meconium suctioning
16 (51.6%)
29 (37.2%)
0.19
Positive pressure ventilation by mask with bag
5 (16.1%)
12 (15.4%)
0.92
Chest compression
1 (3.2%)
3 (3.8%)
0.89
Echocardiography
6 (19.4%)
19 (24.4%)
0.58
Pre- and postductal SpO2 or PaO2 difference and/or hyperoxia/hyperventilation test
25 (80.6%)
59 (75.6%)
Diagnostic methods of PPHN, n (%)
Causes of PPHN, n (%) Meconium aspiration syndrome
16 (51.6%)
51 (65.4%)
0.19
Pulmonary hypoplasia or congenital diaphragmatic hernia
5 (16.1%)
4 (5.1%)
0.60
Congenital pneumonia
6 (19.4%)
13 (16.7%)
0.78
Transient tachypnea of the newborn
0
2 (2.6%)
0.37
Idiopathic PPHN
1 (3.2%)
2 (2.6%)
0.85
Respiratory distress syndrome
2 (6.5%)
3 (3.8%)
0.56
Sepsis with shock
1 (3.2%)
3 (3.8%)
0.88
Treatment modalities, n (%) High frequency oscillatory ventilation
26 (83.9%)
54 (69.2%)
0.15
Intravenous iloprost
17 (54.8%)
46 (59.0%)
0.83
Intragastric sildenafil
23 (74.2%)
61 (78.2%)
0.80
Inhaled nitric oxide
15 (48.4%)
45 (57.7%)
0.40
Intravenous milrinone
9 (29.0%)
19 (24.4%)
0.63
Intragastric bosentan
0
3 (3.8%)
0.27
Stage 0
0
78 (100%)
NA
Stage 1
19 (61.3%)
0
Stage 2
3 (9.7%)
0
Stage 3
9 (29.0%)
0
AKI outcome Neonatal KDIGO classification, n (%)
Length of mechanical ventilation (d), median (IQR)
10.0 (3.0–17.0)
11.5 (7.0–17.3)
0.18
Length of supplemental oxygenation (d), median (IQR)
11.0 (3.0–22.0)
16.0 (10.0–25.0)
0.27
Length of stay (d), median (IQR)
11.0 (2.0–22.0)
18.5 (10.0–30.0)
0.06
Peritoneal dialysis, n (%)
2 (6.5%)
0
NA
In-hospital mortality, n (%)
19 (61.3%)
12 (15.4%)
