Christopher J. Rhee

Renovascular reactivity measured by near-infrared spectroscopy

Hypotension and shock are risk factors for death, renal insufficiency, and stroke in preterm neonates. Goal-directed neonatal hemodynamic management lacks end-organ monitoring strategies to assess the adequacy of perfusion. Our aim is to develop a clinically viable, continuous metric of renovascular reactivity to gauge renal perfusion during shock. We present the renovascular reactivity index (RVx), which quantifies passivity of renal blood volume to spontaneous changes in arterial blood pressure. We tested the ability of the RVx to detect reductions in renal blood flow. Hemorrhagic shock was induced in 10 piglets. The RVx was monitored as a correlation between slow waves of arterial blood pressure and relative total hemoglobin (rTHb) obtained with reflectance near-infrared spectroscopy (NIRS) over the kidney. The RVx was compared with laser-Doppler measurements of red blood cell flux, and renal laser-Doppler measurements were compared with cerebral laser-Doppler measurements. Renal blood flow decreased to 75%, 50%, and 25% of baseline at perfusion pressures of 60, 45, and 40 mmHg, respectively, whereas in the brain these decrements occurred at pressures of 30, 25, and 15 mmHg, respectively. The RVx compared favorably to the renal laser-Doppler data. Areas under the receiver operator characteristic curves using renal blood flow thresholds of 50% and 25% of baseline were 0.85 (95% CI, 0.83-0.87) and 0.90 (95% CI, 0.88-0.92). Renovascular autoregulation can be monitored and is impaired in advance of cerebrovascular autoregulation during hemorrhagic shock.

The ontogeny of cerebrovascular pressure autoregulation in premature infants

Objective:To quantify cerebrovascular autoregulation as a function of gestational age (GA) and across the phases of the cardiac cycle.Study design:The present study is a hypothesis-generating re-analysis of previously published data. Premature infants (n=179) with a GA range of 23 to 33 weeks were monitored with umbilical artery catheters and transcranial Doppler insonation of the middle cerebral artery for 1-h sessions over the first week of life. Autoregulation was quantified by three methods, as a moving correlation coefficient between: (1) systolic arterial blood pressure (ABP) and systolic cerebral blood flow (CBF) velocity (Sx); (2) mean ABP and mean CBF velocity (Mx); and (3) diastolic ABP and diastolic CBF velocity (Dx). Comparisons of individual and cohort cerebrovascular pressure autoregulation were made across GA for each aspect of the cardiac cycle.Results:Systolic, mean and diastolic ABP increased with GA (r=0.3, 0.4 and 0.4; P<0.0001). Systolic CBF velocity was pressure-passive in infants with the lowest GA, and Sx decreased with advancing GA (r=−0.3; P<0.001), indicating increased capacity for cerebral autoregulation during systole during development. By contrast, Dx was elevated, indicating dysautoregulation, in all subjects and showed minimal change with advancing GA (r=−0.06; P=0.05). Multivariate analysis confirmed that both GA (P<0.001) and ‘effective cerebral perfusion pressure’ (ABP minus critical closing pressure (CrCP); P<0.01) were associated with Sx.Conclusion:Premature infants have low and usually pressure-passive diastolic CBF velocity. By contrast, the regulation of systolic CBF velocity by pressure autoregulation developed in this cohort between 23 and 33 weeks GA. Elevated effective cerebral perfusion pressure derived from the CrCP was associated with dysautoregulation.

The frequency response of cerebral autoregulation

The frequency-response of pressure autoregulation is not well delineated; therefore, the optimal frequency of arterial blood pressure (ABP) modulation for measuring autoregulation is unknown. We hypothesized that cerebrovascular autoregulation is band-limited and delineated by a cutoff frequency for which ABP variations induce cerebrovascular reactivity. Neonatal swine (n = 8) were anesthetized using constant minute ventilation while positive end-expiratory pressure (PEEP) was modulated between 6 and 0.75 cycles/min (min(-1)). The animals were hemorrhaged until ABP was below the lower limit of autoregulation (LLA), and PEEP modulations were repeated. Vascular reactivity was quantified at each frequency according to the phase lag between ABP and intracranial pressure (ICP) above and below the LLA. Phase differences between ABP and ICP were small for frequencies of >2 min(-1), with no ability to differentiate cerebrovascular reactivity between ABPs above or below the LLA. For frequencies of <2 min(-1), ABP and intracranial pressure (ICP) showed phase shift when measured above LLA and no phase shift when measured below LLA [above vs. below LLA at 1 min(-1): 156° (139-174°) vs. 30° (22-50°); P < 0.001 by two-way ANOVA for both frequency and state of autoregulation]. Data taken above LLA fit a Butterworth high-pass filter model with a cutoff frequency at 1.8 min(-1) (95% confidence interval: 1.5-2.2). Cerebrovascular reactivity occurs for sustained ABP changes lasting 30 s or longer. The ability to distinguish intact and impaired autoregulation was maximized by a 60-s wave (1 min(-1)), which was 100% sensitive and 100% specific in this model.

Positive end-expiratory pressure oscillation facilitates brain vascular reactivity monitoring

The pressure reactivity index (PRx) identifies optimal cerebral perfusion pressure after traumatic brain injury. We describe a method to improve PRx precision by induced variations in arterial blood pressure (ABP) using positive end-expiratory pressure (PEEP) modulation (iPRx). Neonatal swine (n = 10) were ventilated with static PEEP and then with PEEP oscillated between 5 and 10 cmH(2)O at a frequency of 1/min. PRx was recorded as a moving correlation coefficient between ABP and intracranial pressure (ICP) from spontaneous ABP activity (0.05-0.003 Hz) during static PEEP. iPRx was similarly recorded with PEEP oscillation-induced ABP waves. The lower limit of autoregulation (LLA) was delineated with continuous cortical laser Doppler flux monitoring. PEEP oscillation increased autoregulation-monitoring precision. The ratios of median absolute deviations to range of possible values for the PRx and iPRx were 9.5% (8.3-13.7%) and 6.2% (4.2-8.7%), respectively (P = 0.006; median, interquartile range). The phase-angle difference between ABP and ICP above LLA was 161° (150°-166°) and below LLA, -31° (-42° to 12°, P < 0.0001). iPRx above LLA was -0.42 (-0.67 to -0.29) and below LLA, 0.32 (0.22-0.43, P = 0.0004). A positive iPRx was 97% specific and 91% sensitive for perfusion pressure below LLA. PEEP oscillation caused stable, low-frequency ABP oscillations that reduced noise in the PRx. Safe translation of these findings to clinical settings is expected to yield more accurate and rapid delineation of individualized optimal perfusion-pressure goals for patients.

The Upper Limit of Cerebral Blood Flow Autoregulation Is Decreased With Elevations in Intracranial Pressure

BACKGROUND The upper limit of cerebrovascular pressure autoregulation (ULA) is inadequately characterized. OBJECTIVE To delineate the ULA in an infant swine model. METHODS Neonatal piglets with sham surgery (n = 9), interventricular fluid infusion (INF) (n = 10), controlled cortical impact (CCI) (n = 10), or CCI + INF (n = 11) had intracranial pressure monitoring and bilateral cortical laser-Doppler flowmetry recordings during arterial hypertension to lethality using an aortic balloon catheter. An increase of red cell flux as a function of cerebral perfusion pressure was determined by piecewise linear regression, and static rates of autoregulation were determined above and below this inflection. The ULA was rendered as the first instance of an upward deflection of Doppler flux causing a static rate of autoregulation decrease greater than 0.5. RESULTS ULA was identified in 55% of piglets after sham surgery, 70% after INF, 70% after CCI, and 91% after CCI with INF (P = .36). When identified, the median (interquartile range) ULA was as follows: sham group, 102 mm Hg (97-109 mm Hg); INF group, 75 mm Hg (52-84 mm Hg); CCI group, 81 mm Hg (69-101 mm Hg); and CCI + INF group, 61 mm Hg (52-57 mm Hg) (P = .01). In post hoc analysis, both groups with interventricular INF had significantly lower ULA than that observed in the sham group. CONCLUSION Neonatal piglets without intracranial pathology tolerated acute hypertension with minimal perturbation of cerebral blood flow. Piglets with acutely increased intracranial pressure with or without trauma demonstrated loss of autoregulation when subjected to arterial hypertension.

Ontogeny of cerebrovascular critical closing pressure

Background:Premature infants are at risk of vascular neurologic insults. Hypotension and hypertension are considered injurious, but neither condition is defined with consensus. Cerebrovascular critical closing pressure (CrCP) is the arterial blood pressure (ABP) at which cerebral blood flow (CBF) ceases. CrCP may serve to define subject-specific low or high ABP. Our objective was to determine the ontogeny of CrCP.Methods:Premature infants (n = 179) with gestational age (GA) from 23–31 wk had recordings of ABP and middle cerebral artery flow velocity twice daily for 3 d and then daily for the duration of the first week of life. All infants received mechanical ventilation. CrCP was calculated using an impedance-model derivation with Doppler-based estimations of cerebrovascular resistance and compliance. The association between GA and CrCP was determined in a multivariate analysis.Results:The median (interquartile range) CrCP for the cohort was 22 mm Hg (19–25 mm Hg). CrCP increased significantly with GA (r = 0.6; slope = 1.4 mm Hg/wk gestation), an association that persisted with multivariate analysis (P < 0.0001).Conclusion:CrCP increased significantly from 23 to 31 wk gestation. The low CrCP observed in very premature infants may explain their ability to tolerate low ABP without global cerebral infarct or hemorrhage.

Detection of neurologic injury using vascular reactivity monitoring and glial fibrillary acidic protein

New noninvasive methods for monitoring cerebrovascular pressure reactivity coupled with a blood-based assay for brain-specific injury in preterm infants could allow early diagnosis of brain injury and set the stage for improved timing and effectiveness of interventions. Using an adaptation of near-infrared spectroscopy, we report a case of a very low birth weight infant undergoing hemoglobin volume index monitoring as a measure of cerebrovascular pressure reactivity. During the monitoring period, this infant demonstrated significant disturbances in cerebrovascular pressure reactivity that coincided with elevation of serum glial fibrillary acidic protein and new findings of brain injury on head ultrasound. This case report demonstrates the potential of emerging noninvasive monitoring methods to assist in both detection and therapeutic management to improve neurologic outcomes of the very low birth weight neonate.

Use of Vasopressin in Neonatal Intensive Care Unit Patients With Hypotension

OBJECTIVE To evaluate the safety and efficacy of vasopressin for the treatment of hypotension in patients admitted to neonatal intensive care units (NICUs). METHODS Vasopressin use in 69 infants admitted to our NICU between 2011 and 2014 was examined. Data evaluated included demographics; serum creatinine, sodium, and lactate concentrations; urine output; and systolic, diastolic, and mean blood pressures (BPs). Parameters prior to vasopressin use were compared to those at maximum dose. RESULTS Vasopressin use was associated with increased urine output (p < 0.05), and increased systolic (p < 0.0005), diastolic (p < 0.01), and mean (p < 0.001) BP. There were no differences in sodium or lactate concentrations before vs during infusion; vasopressin use was not associated with hyponatremia (sodium < 130 mEq/L) at the maximum dose. CONCLUSIONS Vasopressin for the treatment of neonatal hypotension appears safe and was efficacious in raising BP. These data suggest that vasopressin could be considered a viable option in the treatment regimen in hypotensive infants in the NICU.

The Diastolic Closing Margin Is Associated with Intraventricular Hemorrhage in Premature Infants.

Premature infants are at an increased risk of intraventricular hemorrhage (IVH). The roles of hypotension and hyperemia are still debated. Critical closing pressure (CrCP) is the arterial blood pressure (ABP) at which cerebral blood flow (CBF) ceases. When diastolic ABP is equal to CrCP, CBF occurs only during systole. The difference between diastolic ABP and CrCP is the diastolic closing margin (DCM). We hypothesized that a low DCM was associated with IVH. One hundred eighty-six premature infants, with a gestational age (GA) range of 23-33 weeks, were monitored with umbilical artery catheters and transcranial Doppler insonation of middle cerebral artery flow velocity for 1-h sessions over the first week of life. CrCP was calculated linearly and using an impedance model. A multivariate generalized linear regression model was used to determine associations with severe IVH (grades 3-4). An elevated DCM by either method was associated with IVH (p < 0.0001 for the linear method; p < 0.001 for the impedance model). Lower 5-min Apgar scores, elevated mean CBF velocity, and lower mean ABP were also associated with IVH (p < 0.0001). Elevated DCM, not low DCM, was associated with severe IVH in this cohort.

Neonatal cerebrovascular autoregulation

Cerebrovascular pressure autoregulation is the physiologic mechanism that holds cerebral blood flow (CBF) relatively constant across changes in cerebral perfusion pressure (CPP). Cerebral vasoreactivity refers to the vasoconstriction and vasodilation that occur during fluctuations in arterial blood pressure (ABP) to maintain autoregulation. These are vital protective mechanisms of the brain. Impairments in pressure autoregulation increase the risk of brain injury and persistent neurologic disability. Autoregulation may be impaired during various neonatal disease states including prematurity, hypoxic–ischemic encephalopathy (HIE), intraventricular hemorrhage, congenital cardiac disease, and infants requiring extracorporeal membrane oxygenation (ECMO). Because infants are exquisitely sensitive to changes in cerebral blood flow (CBF), both hypoperfusion and hyperperfusion can cause significant neurologic injury. We will review neonatal pressure autoregulation and autoregulation monitoring techniques with a focus on brain protection. Current clinical therapies have failed to fully prevent permanent brain injuries in neonates. Adjuvant treatments that support and optimize autoregulation may improve neurologic outcomes.