Comparison of 1-day versus 3-day intravenous terlipressin in cirrhosis patients with variceal bleeding: A pilot randomised controlled trial.

BACKGROUND: In cirrhosis patients with acute variceal bleeding (AVB), the optimal duration of vasoconstrictor therapy after endoscopic haemostasis is unclear. AIMS: We aimed to compare efficacy of 1-day versus 3-day terlipressin therapy in cirrhosis patients with AVB post-endoscopic intervention. The primary objective was to compare rebleeding at 5 days between the two arms. Secondary objectives included rebleeding and mortality rates at 6 weeks. METHODS: In this open-label, randomised controlled trial, cirrhosis patients with AVB were randomised to either 1-day or 3-day terlipressin therapy. RESULTS: A total of 150 cirrhosis patients with AVB were recruited to receive either 1 day (n = 75) or 3 days (n = 75) of terlipressin therapy. One patient from 1-day arm was excluded. Modified intention-to-treat analysis included 149 patients. Baseline characteristics were comparable between the two groups. Rebleeding at 5 days: 3 (4.1%; 95% confidence interval [CI]: 0.4-9.0) versus 4 (5.3%; 95% CI: 2.0-10.0), risk difference (RD) p = 0.726 and 5-day mortality rates: 1 (1.4%; 95% CI: 0-7.3) versus 1 (1.3%; 95% CI: 0.2-7.0), RD p = 0.960 were similar. Rebleeding at 42 days: 9 (12.2%; 95% CI: 7.0-20.0) versus 10 (13.3%; 95% CI: 7.0-20.0), RD p = 0.842 and mortality at 42 days: 5 (6.8%; 95% CI: 3.0-10.0) versus 4 (5.3%; 95% CI: 2.0-10.0), RD p = 0.704 were also similar. Patients in the 1-day terlipressin therapy arm experienced significantly fewer adverse effects compared with those receiving 3 days of terlipressin therapy: 28 (37.8%) versus 42 (56%), p = 0.026. CONCLUSIONS: Our results suggest that 1 day of terlipressin therapy is associated with similar 5-day and 42-day rebleeding rates, 42-day mortality and an overall superior safety profile compared with 3-day of terlipressin therapy. These findings require to be validated in double-blinded, larger, multiethnic and multicentre studies across the various stages of cirrhosis (CTRI/2019/10/021771).

Angiotensin-II Use for Refractory Hypotension in an Infant With Bilateral Renal Agenesis.

Infants with congenital bilateral renal agenesis are at significant risk for morbidity and mortality, despite substantial and continuing advances in fetal and neonatal therapeutics. Infants with bilateral renal agenesis may episodically develop severe hypotension that can be refractory to traditional vasopressors. Synthetic angiotensin-II has been successfully used in adult and a few pediatric patients with refractory hypotension but has not been extensively studied in infants. We describe the use of angiotensin-II in treating refractory hypotension in a premature infant with congenital bilateral renal agenesis admitted to the NICU. Within 48 hours, he no longer required other vasopressors. Subsequently, angiotensin-II was gradually weaned and discontinued over 10 days and the patient was ultimately discharged from the hospital. This case demonstrates that angiotensin-II may be a helpful agent to treat refractory hypotension in infants with bilateral renal agenesis.

A survey in the West Midlands of the United Kingdom of current practice in managing hypotension in lower segment caesarean section under spinal anaesthesia.

BACKGROUND: Spinal anaesthesia, the most common form of anaesthesia for caesarean section, leads to sympathetic blockade and profound maternal hypotension resulting in adverse maternal and neonatal outcomes. Hypotension, nausea and vomiting remain common but until the publication of the National Institute of Health and Care Excellence (NICE) 2021 guidance, no national guideline existed on how best to manage maternal hypotension following spinal anaesthesia for caesarean section. A 2017 international consensus statement recommended prophylactic vasopressor administration to maintain a systolic blood pressure of >90% of an accurate pre-spinal value, and to avoid a drop to <80% of this value. This survey aimed to assess regional adherence to these recommendations, the presence of local guidelines for management of hypotension during caesarean section under spinal anaesthesia, and the individual clinician's treatment thresholds for maternal hypotension and tachycardia. METHODS: The West Midlands Trainee-led Research in Anaesthesia and Intensive Care Network co-ordinated surveys of obstetric anaesthetic departments and consultant obstetric anaesthetists across 11 National Health Service Trusts in the Midlands, England. RESULTS: One-hundred-and-two consultant obstetric anaesthetists returned the survey and 73% of sites had a policy for vasopressor use; 91% used phenylephrine as the first-line drug but a wide range of recommended delivery methods was noted and target blood pressure was only listed in 50% of policies. Significant variation existed in both vasopressor delivery methods and target blood pressures. CONCLUSIONS: Although NICE has since recommended prophylactic phenylephrine infusion and a target blood pressure, the previous international consensus statement was not adhered to routinely.

Early Restrictive or Liberal Fluid Management for Sepsis-Induced Hypotension.

BACKGROUND: Intravenous fluids and vasopressor agents are commonly used in early resuscitation of patients with sepsis, but comparative data for prioritizing their delivery are limited. METHODS: In an unblinded superiority trial conducted at 60 U.S. centers, we randomly assigned patients to either a restrictive fluid strategy (prioritizing vasopressors and lower intravenous fluid volumes) or a liberal fluid strategy (prioritizing higher volumes of intravenous fluids before vasopressor use) for a 24-hour period. Randomization occurred within 4 hours after a patient met the criteria for sepsis-induced hypotension refractory to initial treatment with 1 to 3 liters of intravenous fluid. We hypothesized that all-cause mortality before discharge home by day 90 (primary outcome) would be lower with a restrictive fluid strategy than with a liberal fluid strategy. Safety was also assessed. RESULTS: A total of 1563 patients were enrolled, with 782 assigned to the restrictive fluid group and 781 to the liberal fluid group. Resuscitation therapies that were administered during the 24-hour protocol period differed between the two groups; less intravenous fluid was administered in the restrictive fluid group than in the liberal fluid group (difference of medians, -2134 ml; 95% confidence interval [CI], -2318 to -1949), whereas the restrictive fluid group had earlier, more prevalent, and longer duration of vasopressor use. Death from any cause before discharge home by day 90 occurred in 109 patients (14.0%) in the restrictive fluid group and in 116 patients (14.9%) in the liberal fluid group (estimated difference, -0.9 percentage points; 95% CI, -4.4 to 2.6; P = 0.61); 5 patients in the restrictive fluid group and 4 patients in the liberal fluid group had their data censored (lost to follow-up). The number of reported serious adverse events was similar in the two groups. CONCLUSIONS: Among patients with sepsis-induced hypotension, the restrictive fluid strategy that was used in this trial did not result in significantly lower (or higher) mortality before discharge home by day 90 than the liberal fluid strategy. (Funded by the National Heart, Lung, and Blood Institute; CLOVERS ClinicalTrials.gov number, NCT03434028.).

Intraoperative vasopressor use and early postoperative acute kidney injury in elderly patients undergoing elective noncardiac surgery.

BACKGROUND: Intraoperative hypotension is a risk factor for postoperative acute kidney injury (AKI). Elderly patients are susceptible due to reduced responses to acute hemodynamic changes. AIMS: Determine the association between hypotension identified from anesthetic charts and postoperative AKI in elderly patients. METHODS: Retrospective cohort study of elective noncardiac surgery patients ≥65 years, at an Australian tertiary hospital (December 2019-March 2021), with the primary outcome of AKI ≤48 h of surgery. Factors of interest were intraoperative hypotension determined from anesthetic charts (mean arterial pressure <60 mmHg, systolic blood pressure <90 mmHg, recorded 5-min) and intraoperative vasopressor use. RESULTS: In 830 patients (mean age 75 years), systolic hypotension was more frequent than mean arterial hypotension (25.7% vs. 11.9%). Most hypotensive episodes were brief (7.2% of systolic and 4.2% of mean arterial hypotension lasted >10 min) but vasopressors were used in 84.7% of cases. The incidence of postoperative AKI was 13.9%. Systolic hypotension >20 min was associated with AKI (OR, 3.88; 95% CI: 1.38-10.9), which was not significant after adjusting for vasopressors, creatinine, American Society of Anesthesiologists class, and hemoglobin drop. The cumulative dose of any specific vasopressor >20 mg (or >10 mg epinephrine) was independently associated with AKI (adjusted OR, 2.47; 95% CI: 1.34-4.58). Every 5 mg increase in the total dose of all intraoperative vasopressors used during surgery was associated with 11% increased odds of AKI (95% CI: 3-19%). CONCLUSIONS: High vasopressor use was associated with postoperative AKI in elderly patients undergoing noncardiac surgery, independent of hypotension identified from anesthetic charts.

Simultaneous quantification of sumatriptan succinate and prochlorperazine maleate in orodispersible films using two validated UV-spectroscopic methods.

The study aimed at simultaneous quantification of sumatriptan succinate (SUM) and prochlorperazine maleate (PCP) in an orodispersible film using two validated spectroscopic methods viz. simultaneous equation (Method I) and the Q-absorption ratio (Method II). The Method I involved measurement of absorbances at λmax of both drugs while in Method II, absorbances were measured at isosbestic wavelength and λmax of one of the two components. Method validation were accomplished as per the ICH guidelines. A 1:1 mixture of the drugs and an orodispersible film (ODF) containing these drugs were assayed by both methods. The absorbance data of SUM and PCP in both methods were linear at respective wavelengths with correlation coefficient values >0.995. Both methods were precise as % RSD in repeatability, interday and intraday precision was less than 2. The estimation of SUM and PCP from the film dosage form by method I was104.74% and 98.34% and by method II was 103.45% and 98.85%, respectively, with a standard deviation <2. The study concluded that both the methods were simple, reliable and robust and can be applied successfully for the simultaneous quantification of SUM and PCP in mixture and orodispersible film dosage form.

Norepinephrine versus phenylephrine infusion for preventing postspinal hypotension during cesarean section for twin pregnancy: a double-blinded randomized controlled clinical trial.

BACKGROUND: Compared with singleton pregnancy, twin gestation is featured by a greater increase in cardiac output. Therefore, norepinephrine might be more suitable than phenylephrine for maintaining blood pressure during cesarean section for twins, as phenylephrine causes reflex bradycardia and a resultant decrease in cardiac output. This study was to determine whether norepinephrine was superior to phenylephrine in maintaining maternal hemodynamics during cesarean section for twins. METHODS: Informed consent was obtained from all the patients before enrollment. In this double-blinded, randomized clinical trial, 100 parturients with twin gestation undergoing cesarean section with spinal anesthesia were randomized to receive prophylactic norepinephrine (3.2 µg/min) or phenylephrine infusion (40 µg/min). The primary outcome was the change of heart rate and blood pressure during the study period. The secondary outcomes were to compare maternal complications, neonatal outcomes, Apgar scores and umbilical blood acid-base status between the two vasopressors. RESULTS: There was no significant difference observed for the change of heart rate between two vasopressors. The mean standardized area under the curve of heart rate was 78 ± 12 with norepinephrine vs. 74 ± 11 beats/min with phenylephrine (mean difference 4.4, 95%CI - 0.1 to 9.0; P = .0567). The mean standardized area under the curve of systolic blood pressure (SBP) was significantly lower in parturients with norepinephrine, as the mean of differences in standardized AUC of SBP was 6 mmHg, with a 95% CI from 2 to 9 mmHg (P = .0013). However, requirements of physician interventions for correcting maternal hemodynamical abnormalities (temporary cessation of vasopressor infusion for reactive hypertension, rescuing vasopressor bolus for hypotension and atropine for heart rate less < 50 beats/min) and neonatal outcomes were also not significantly different between two vasopressors. CONCLUSION: Infusion of norepinephrine was not associated with less overall decrease in heart rate during cesarean section for twins, compared with phenylephrine. TRIAL REGISTRATION: Chinese Clinical Trial Registry ( ChiCTR1900021281 ).

The evolution of mean arterial pressure in critically ill patients on vasopressors before and during a trial comparing a specific mean arterial pressure target to usual care.

BACKGROUND: In randomized clinical controlled trials, the choice of usual care as the comparator may be associated with better clinician uptake of the study protocol and lead to more generalizable results. However, if care processes evolve to resemble the intervention during the course of a trial, differences between the intervention group and usual care control group may narrow. We evaluated the effect on mean arterial pressure of an unblinded trial comparing a lower mean arterial pressure target to reduce vasopressor exposure, vs. a clinician-selected mean arterial pressure target, in critically ill patients at least 65 years old. METHODS: For this multicenter observational study using data collected both prospectively and retrospectively, patients were recruited from five of the seven trial sites. We compared the mean arterial pressure of patients receiving vasopressors, who met or would have met trial eligibility criteria, from two periods: [1] at least 1 month before the trial started, and [2] during the trial period and randomized to usual care, or not enrolled in the trial. RESULTS: We included 200 patients treated before and 229 after trial initiation. There were no differences in age (mean 74.5 vs. 75.2 years; p = 0.28), baseline Acute Physiology and Chronic Health Evaluation II score (median 26 vs. 26; p = 0.47) or history of chronic hypertension (n = 126 [63.0%] vs. n = 153 [66.8%]; p = 0.41). Mean of the mean arterial pressure was similar between the two periods (72.5 vs. 72.4 mmHg; p = 0.76). CONCLUSIONS: The initiation of a trial of a prescribed lower mean arterial pressure target, compared to a usual clinician-selected target, was not associated with a change in mean arterial pressure, reflecting stability in the net effect of usual clinician practices over time. Comparing prior and concurrent control groups may alleviate concerns regarding drift in usual practices over the course of a trial or permit quantification of any change.

Development and Evaluation of an Integrated Outpatient Infusion Care Model for the Treatment of Pediatric Headache.

BACKGROUND: Care for pediatric patients with headache often occurs in high-cost settings such as emergency departments (EDs) and inpatient settings. Outpatient infusion centers have the potential to reduce care costs for pediatric headache management. METHODS: In this quality improvement study, we describe our experience in creating the capacity to support an integrated outpatient pediatric headache infusion care model through an infusion center. We compare costs of receiving headache treatment in this model with those in the emergency and inpatient settings. Because dihydroergotamine (DHE) is a costly infusion, encounters at which DHE was administered were analyzed separately. We track the number of ED visits and inpatient admissions for headache using run charts. As a balancing measure, we compare treatment efficacy between the infusion care model and the inpatient setting. RESULTS: The mean percentage increase in cost of receiving headache treatment in the inpatient setting with DHE was 61% (confidence interval [CI]: 30-99%), and that without DHE was 582% (CI: 299-1068%) compared with receiving equivalent treatments in the infusion center. The mean percentage increase in cost of receiving headache treatment in the ED was 30% (CI: -15 to 100%) compared with equivalent treatment in the infusion center. After the intervention, ED visits and inpatient admissions for headache decreased. The mean change in head pain was similar across care settings. CONCLUSIONS: Our findings demonstrate that developing an integrated ambulatory care model with infusion capacity for refractory pediatric headache is feasible, and our early outcomes suggest this may have a favorable impact on the overall value of care for this population.

Low-Concentration Norepinephrine Infusion for Major Surgery: A Safety and Feasibility Pilot Randomized Controlled Trial.

BACKGROUND: Prevention of hypotension during the intra- and postoperative period is an important goal. Peripheral administration of low-concentration norepinephrine may be a safe and effective strategy to reduce the risk of hypotension. METHODS: We conducted a 2-center, randomized pilot feasibility trial, with a target of 60 adult patients undergoing major noncardiac surgery. We randomized patients to receive a peripheral low-concentration (10 µg/mL) norepinephrine or placebo (saline 0.9%) infusion. The study drug infusion was titrated to achieve a minimum systolic blood pressure target, preselected within 10% of baseline value and within the range limit 100 to 120 mm Hg during surgery and for up to 4 or 24 hours postoperatively. RESULTS: We achieved a high consent rate (84%), successful study drug administration throughout surgery (98% of patients) and absence of unblinding. There were no important study drug-related adverse events. The average intraoperative systolic blood pressure was 120 ± 12.6 mm Hg in the norepinephrine group and 115 ± 14.9 mm Hg in the placebo group. The mean difference between the intraoperative systolic blood pressure achieved less the preselected minimum systolic blood pressure target was 10.0 ± 12.7 mm Hg in the norepinephrine group and 2.9 ± 14.7 mm Hg in the placebo group; difference in means, 7.1 (95% confidence interval, 0.2-14.0) mm Hg. CONCLUSIONS: A future large trial evaluating the effectiveness and safety of peripheral administration of low-concentration norepinephrine during the perioperative period is feasible, and likely to achieve a minimum systolic blood pressure threshold.

Anaphylaxis: Emergency Department Treatment.

Anaphylaxis is a potentially life-threatening, multisystem allergic reaction that can cause airway, breathing, or circulatory compromise. Intramuscular epinephrine is the immediate treatment of all patients. Intravenous epinephrine should be used in patients in shock, either as a bolus or infusion, along with fluid resuscitation. Airway obstruction must be recognized, and early intubation may be necessary. For shock that is refractory to epinephrine, additional vasopressors may be needed. Disposition depends on patient presentation and response to treatment. Mandatory observation periods are not necessary, because biphasic reactions are difficult to predict and may occur outside of typical observation periods.

Comparison of push-dose phenylephrine and epinephrine in the emergency department.

BACKGROUND: There is limited evidence to support the efficacy and safety of push-dose vasopressor (PDP) use outside of the operating room (OR). Specifically, there are few head-to-head comparisons of different PDP in these settings. The purpose of this study was to compare the efficacy and safety of push-dose phenylephrine (PDP-PE) and epinephrine (PDP-E) in the Emergency Department (ED). METHODS: This retrospective, single-center study evaluated adults given PDP-PE or PDP-E in the ED from May 2017 to November 2020. The primary outcome was a change in heart rate (HR). Secondary outcomes included changes in blood pressure, adverse effects, dosing errors, fluid and vasopressor requirements, ICU and hospital lengths of stay (LOS), and in-hospital mortality. RESULTS: Ninety-six patients were included in the PDP-PE group and 39 patients in the PDP-E group. Median changes in HR were 0 [-7, 6] and - 2 [-15, 5] beats per minute (BPM) for PDP-PE and PDP-E, respectively (p = 0.138). PDP-E patients had a greater median increase in systolic blood pressure (SBP) (33 [24, 53] vs. 26 [8, 51] mmHg; p = 0.049). Dosing errors occurred more frequently in patients that received PDP-E (5/39 [12.8%] vs. 2/96 [2.1%]; p = 0.021). PDP-E patients more frequently received continuous epinephrine infusions before and after receiving PDP-E. There were no differences in adverse effects, fluid requirements, LOS, or mortality. CONCLUSION: PDP-E provided a greater increase in SBP compared to PDP-PE. However, dosing errors occurred more frequently in those receiving PDP-E. Larger head-to-head studies are necessary to further evaluate the efficacy and safety of PDP-E and PDP-PE.

Effects of Sodium Thiosulfate During Resuscitation From Trauma-and-Hemorrhage in Cystathionine Gamma Lyase (CSE) Knockout Mice.

BACKGROUND: Sodium thiosulfate (Na2S2O3) is a clinically established drug with antioxidant and sulphide-releasing properties. Na2S2O3 mediated neuro- and cardioprotective effects in ischemia/reperfusion models and anti-inflammatory effects in LPS-induced acute lung injury. Moreover, Na2S2O3 improved lung function during resuscitation from hemorrhagic shock in swine with pre-existing atherosclerosis, characterized by decreased expression of cystathionine γ-lyase (CSE), a major source of hydrogen sulfide (H2S) synthesis in the vasculature. Based on these findings, we investigated the effects of Na2S2O3 administration during resuscitation from trauma-and-hemorrhage in mice under conditions of whole body CSE deficit. METHODS: After blast wave-induced blunt chest trauma and surgical instrumentation, CSE knockout (CSE-/-) mice underwent 1 h of hemorrhagic shock (MAP 35 ±â€Š5 mm Hg). At the beginning of resuscitation comprising retransfusion, norepinephrine support and lung-protective mechanical ventilation, animals received either i.v. Na2S2O3 (0.45 mg g-1, n = 12) or vehicle (saline, n = 13). Hemodynamics, acid-base status, metabolism using stable isotopes, and visceral organ function were assessed. Blood and organs were collected for analysis of cytokines, mitochondrial respiratory capacity, and immunoblotting. RESULTS: Na2S2O3 treatment improved arterial paO2 (P = 0.03) coinciding with higher lung tissue glucocorticoid receptor expression. Norepinephrine requirements were lower in the Na2S2O3 group (P < 0.05), which was associated with lower endogenous glucose production and higher urine output. Na2S2O3 significantly increased renal tissue IκBα and heme oxygenase-1 expression, whereas it lowered kidney IL-6 and MCP-1 levels. CONCLUSION: Na2S2O3 exerted beneficial effects during resuscitation of murine trauma-and-hemorrhage in CSE-/- mice, confirming and extending the previously described organ-protective and anti-inflammatory properties of Na2S2O3. The findings make Na2S2O3 a potentially promising therapeutic option in the context of impaired CSE activity and/or reduced endogenous H2S availability.

Survey of Anesthesiologists on Topical Vasoconstrictors and Intravenous Tranexamic Acid for Endoscopic Sinus Surgery.

OBJECTIVES: Topical vasoconstrictors and intravenous tranexamic acid (IV TXA) are safe and efficacious to decrease bleeding and improve the surgical field during endoscopic sinus surgery (ESS). The purpose of this study was to investigate practice patterns, awareness of clinical evidence, and comfort levels among anesthesia providers regarding these hemostatic agents for ESS. METHODS: A total of 767 attending anesthesiologists, residents, and certified registered nurse anesthetists (CRNAs) at 5 United States academic centers were invited to participate in a survey regarding their experience with IV TXA and 3 topical vasoconstrictor medications (oxymetazoline, epinephrine, and cocaine) during ESS. RESULTS: 330 (47%) anesthesia providers responded to the electronic survey. 113 (97%) residents, 92 (83%) CRNAs, and 52 (68%) attendings managed 5 or fewer ESS cases per month. Two-thirds of providers had not reviewed efficacy or safety literature for these hemostatic agents. Oxymetazoline was perceived safest, followed by epinephrine, IV TXA, and cocaine. Respondents considered potential side effects over surgical field visibility when selecting agents. The majority of providers had no formal training on these agents for ESS, but indicated interest in educational opportunities. CONCLUSION: Many anesthesia providers are unfamiliar with safety and efficacy literature regarding agents used to improve hemostasis for ESS, highlighting a need for development of relevant educational resources. Rhinologic surgeons have an opportunity to communicate with anesthesia colleagues on the use of hemostatic agents to improve the surgical field during ESS.

Vasopressor Discontinuation Order in Septic Shock With Reduced Left Ventricular Function.

BACKGROUND: The optimal vasopressor management for septic patients with left ventricular (LV) dysfunction has not been well established, and current evidence is conflicting regarding the optimal vasopressor discontinuation order. OBJECTIVE: The objective was to evaluate the impact of LV dysfunction on the hemodynamic management of septic shock by assessing the incidence of clinically significant hypotension after vasopressor discontinuation. METHODS: In this single-center, retrospective cohort study, adult patients were included if they met the Sepsis-3 definition of septic shock, had LV dysfunction (defined as an ejection fraction ≤40%), and received norepinephrine and vasopressin as the last vasopressors discontinued. The primary outcome was the incidence of clinically significant hypotension following discontinuation of vasopressin or norepinephrine. Clinically significant hypotension was defined as a MAP less than 60 mmHg and the need for either: 1) the reinstitution of the previously discontinued agent at any dosage, 2) the receipt of at least 500 mL of a crystalloid at a rate of at least 500 mL/hour, 3) or the receipt of at least 25 grams of albumin 5% at a rate of at least 25 gram/hour. Secondary outcomes included intensive care unit (ICU) and hospital lengths of stay, and ICU and hospital mortality. RESULTS: A total of 78 patients met inclusion criteria, with 37 patients having vasopressin discontinued first and 41 having norepinephrine discontinued first. Clinically significant hypotension occurred in 28 patients (76%) following the discontinuation of vasopressin, compared to 28 patients (81%) following the discontinuation of norepinephrine (p = 0.61). ICU length of stay was 9 days in the vasopressin discontinued first cohort, compared to 15 days in the norepinephrine discontinued first cohort (p = 0.01). There was no statistically significant difference in mortality observed. CONCLUSION: The discontinuation order of norepinephrine and vasopressin did not impact the incidence of clinically significant hypotension in patients with septic shock and LV dysfunction, but may influence ICU length of stay, although other factors may have impacted this finding.

Urine Biomarkers for the Assessment of Acute Kidney Injury in Neonates with Hypoxic Ischemic Encephalopathy Receiving Therapeutic Hypothermia.

OBJECTIVE: To evaluate the predictive performance of urine biomarkers for acute kidney injury (AKI) in neonates with hypoxic ischemic encephalopathy (HIE) receiving therapeutic hypothermia. STUDY DESIGN: We performed a multicenter prospective observational study of 64 neonates. Urine specimens were obtained at 12, 24, 48, and 72 hours of life and evaluated for neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), cystatin C, interleukin-18 (IL-18), tissue inhibitor of metalloproteinases 2 (TIMP2), and insulin-like growth factor-binding protein 7 (IGFBP7). Logistic regression models with receiver operating characteristics for area under the curve (AUC) were used to assess associations with neonatal modified KDIGO (Kidney Disease: Improving Global Outcomes) AKI criteria. RESULTS: AKI occurred in 16 of 64 infants (25%). Neonates with AKI had more days of vasopressor drug use compared with those without AKI (median [IQR], 2 [0-5] days vs 0 [0-2] days; P = .026). Mortality was greater in neonates with AKI (25% vs 2%; P = .012). Although NGAL, KIM-1, and IL-18 were significantly associated with AKI, the AUCs yielded only a fair prediction. KIM-1 had the best predictive performance across time points, with an AUC (SE) of 0.79 (0.11) at 48 hours of life. NGAL and IL-18 had AUCs (SE) of 0.78 (0.09) and 0.73 (0.10), respectively, at 48 hours of life. CONCLUSIONS: Urine NGAL, KIM-1, and IL-18 levels were elevated in neonates with HIE receiving therapeutic hypothermia who developed AKI. However, wide variability and unclear cutoff levels make their clinical utility unclear.