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

After prenatal diagnosis of fetal bilateral renal agenesis, a gravida 4, para 2 woman underwent serial amnioinfusions per the Renal Anhydramnios Fetal Therapy trial protocol (NCT 03101891).⁴  Eleven amnioinfusions were given between 22 and 31 weeks’ estimated gestational age (EGA). Fetal chromosomal microarray testing detected a paternally inherited interstitial deletion of 16p12.2, associated with autosomal recessive deafness. The mother had several multidisciplinary consultations that discussed the need for prolonged neonatal intensive care; she consistently expressed a desire to continue intensive care during subsequent periods of clinical instability. She experienced premature rupture of membranes at 31 1/7 weeks’ EGA, and a male infant was delivered by scheduled repeat cesarean section at 33 0/7 weeks’ EGA after completion of rescue betamethasone attended by a team skilled with complex neonatal resuscitation.

After admission, the infant required high-frequency oscillatory ventilation and nitric oxide administration for pulmonary hypoplasia, pulmonary hypertension, and respiratory distress syndrome. The clinical team initiated kidney replacement therapy using Aquadex (Nuwellis, Inc, Minnesota) on day 2. His initial cranial ultrasound showed a left grade III intraventricular hemorrhage with minimal ventriculomegaly. On day 10, he was extubated and subsequently weaned to room air but demonstrated intermittent need for supplemental oxygen. At birth, he had moderately depressed right ventricular function, which resolved by day 12. He also experienced episodes of hypotension during procedures, with infections, or at times of significant negative fluid balance. At these times, he regularly received dopamine and vasopressin infusions and occasionally midodrine. Postnatal genetic testing using a panel for detection of congenital anomalies of the kidney and urinary tract was nondiagnostic. He did have a heterozygous variant of uncertain significance in SOX17 on chromosome 8q11.23, which can be associated with autosomal dominant vesicoureteral reflux, in addition to the prenatally diagnosed 16p12.2 deletion.

At 3 months of age (48 4/7 weeks’ PMA), while still intermittently hypotensive on midodrine and daily Aquadex therapy, he developed worsening hypotension and focal seizures that progressed to status epilepticus within 24 hours despite treatment with phenobarbital, fosphenytoin, and levetiracetam. He was reintubated for stridor and retractions that raised concern about an upper airway obstruction and was started on a midazolam infusion. A workup for infectious etiologies, including cerebrospinal fluid analysis, was unrevealing. A cranial ultrasound, bedside computed tomography of the head, and later magnetic resonance imaging of the brain showed ex vacuo hydrocephalus without evidence of progressive hemorrhage or infarct. His previously intermittent hypotension became persistent with systolic blood pressures ranging between 40 and 50 mm Hg and mean arterial pressures (MAP) between 25 and 35 mm Hg. He received fluid resuscitation and reinitiation of hydrocortisone and infusions of dopamine, vasopressin, and epinephrine. His cerebral oxygen saturation levels were 30% to 50% (previously 50% to 70%) and somatic (flank) saturation levels were 80%, with a perfusion index (PI) that intermittently fell below 1%. Figure 1 demonstrates vital sign changes before and after initiation of vasopressors.

Because of refractory hypotension, on day 5 of illness, he was started on an angiotensin-II infusion at 1.25 ng/kg/min that was titrated up to 40 ng/kg/min over 4 days. His renin level before initiation was 8.6 pg/mL (reference range, 3.2–52.2 pg/mL). His blood pressure stabilized and all other vasopressors were discontinued within 26 hours. He briefly required vasopressin reinitiation for 25 hours for transient hypotension after receiving boluses of phenobarbital, fosphenytoin, and fentanyl. Angiotensin-II was slowly weaned and discontinued over the course of 10 days, with continued blood pressure stability by day 14 of illness (Fig 1). During angiotensin-II administration, he also received a continuous heparin infusion to prevent thrombosis. He did not develop bleeding and his platelets remained >100 000/µL throughout this acute illness. He developed mild transaminitis (peak aspartate aminotransferase 90 IU/L and peak alanine aminotransferase 118 IU/L), which normalized within 1 week of angiotensin-II discontinuation. He did not experience any arrhythmias. After ongoing clinical stability and growth, he was transitioned to peritoneal dialysis. He passed a hearing screen. At approximately 6 months of age, he was transferred to a hospital closer to his family’s home, subsequently discharged on peritoneal dialysis, and is currently undergoing evaluation for kidney transplantation.

Endogenous angiotensin-II is released when angiotensin-converting enzyme acts on angiotensin-I. Angiotensin-II has vasoconstrictive effects and elevates MAP (Fig 2). It is metabolized by nonspecific esterases in the plasma and major organs and has a very short half-life (<1 minute).¹⁰ 

Synthetic angiotensin-II is Food and Drug Administration-approved for treatment of septic or distributive shock in adults. The trial “Angiotensin-II for the treatment of high-output shock” first demonstrated its effectiveness as a rescue agent for distributive shock.¹¹  In a large study of adults with vasodilatory shock, nearly 70% patients were able to achieve a MAP >75 mm Hg within 3 hours of treatment with angiotensin-II compared with 23% of patients receiving placebo, and the treatment group reported fewer serious adverse events.¹²  In a multicenter retrospective study of adults with shock, angiotensin-II infusion was associated with hemodynamic improvement in two-thirds of patients and with lower mortality.¹³  The most common adverse events were transaminitis (24%), as seen in our patient, thrombocytopenia (24%), and arrhythmia (10%).¹³  Angiotensin-II was also effective in treating adults with severe distributive shock from SARS-CoV-2 infection, possibly by degrading angiotensin-converting enzyme-2 receptors, thereby preventing SARS-CoV-2 from entering cells.^14,15 

Two case reports have described use of angiotensin-II in children. In these cases, vasopressin and norepinephrine were discontinued within 90 and 120 minutes, respectively, of starting angiotensin-II.^8,9  Our institution uses angiotensin-II during pheochromocytoma resections, described in adult case reports.^16,17  This patient was the first in our NICU, and the first with bilateral renal agenesis, to receive this therapy. Previous reports have suggested starting with a continuous infusion of 1.25 ng/kg/min with increases by as much as 15 ng/kg/min every 5 minutes up to a maximum dose of 40 ng/kg/min through a central line.¹²  Angiotensin-II is compatible with other vasopressors, normal saline, and dextrose-containing fluids. Potential adverse effects include thrombosis (13%) and thrombocytopenia (10%).¹⁰ 

It is plausible that infants with bilateral renal agenesis have altered vascular tone and decreased angiotensin-II levels. Serial monitoring of renin-angiotensin-aldosterone system hormones would be beneficial in this population. Studies performed in older children and adults suggest that anephric patients have lower, or even undetectable, renin levels, with normal to low angiotensin-I and angiotensin-II levels,^18,19  although this test is not routinely performed in children. A recent study with advanced measurement techniques suggests that surgically anephric patients have no detectable circulating angiotensins.²⁰  Our patient’s renin level before angiotensin-II infusion was within the lower range of normal. Renin is initially synthesized by renal and nonrenal tissues as prorenin. Prorenin is converted to active renin solely in the juxtaglomerular cells of the kidney under physiologic conditions. Prorenin may be converted to renin during blood drawing and storage,²¹  which may explain the presence of a low renin level in our anephric patient. Interpretation of the renin level is also challenging given his prematurity and corrected term age at the time of acute illness. One study demonstrated higher prorenin levels in premature versus term infants, with resolution of differences by 4 weeks.²² 

Methods to monitor tissue perfusion closely may also be useful during administration of vasoactive therapies. Near-infrared spectroscopy (NIRS) and PI monitoring are potential bedside techniques to assess changes in regional tissue oxygenation and perfusion. NIRS is increasingly used in infants at risk for impaired perfusion because tissue oxygenation may not correlate well with blood pressure.^23,24  The PI, measured by a pulse oximeter, has limited utility in the neonatal population because of its significant variability, but values <0.7% have been associated with underperfusion and impaired cardiac output.²⁵  In our patient, acute hypotension was also reflected by low NIRS and PI measures and may have been triggered by fluid shifts during aquapheresis, by antiepileptics, and by central nervous system instability. His propensity for seizures was further exacerbated by his impaired cerebral autoregulation, manifested by decreases in cerebral oxygenation and perfusion observed after prolonged hypotension. Our patient’s NIRS improved after stabilization of blood pressure (Fig 1), which then facilitated weaning of pressor support.

It remains unclear when angiotensin-II may benefit infants with bilateral renal agenesis with refractory hypotension. Patients may regulate vascular tone when in a steady state but require angiotensin-II replacement under conditions of stress. Synergy with specific drugs such as vasopressin or hydrocortisone, optimal timing of angiotensin-II initiation, methods of monitoring treatment effectiveness, and recommendations for discontinuation all require additional investigation. Future research could explore how various genetic profiles may mediate the drug’s effect.

Angiotensin-II improved refractory hypotension in a critically ill infant with bilateral renal agenesis and vasoplegia. Further research is needed to determine optimal use, timing, and efficacy in this population.

The authors thank Drs Janene Fuerch and Shabnam Gaskari for their support and advocacy to facilitate patient treatment with Angiotensin-II in the NICU.

EGA

estimated gestational age

MAP

mean arterial pressure

NIRS

near-infrared spectroscopy

PI

perfusion index