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Published before final editing as: Ann Thorac Surg. 2026 May 26:S0003-4975(26)00479-0. doi: 10.1016/j.athoracsur.2026.05.014

Evaluating Antegrade Cerebral Perfusion Flow Rates for Neuroprotection During Hypothermic Circulatory Arrest

AlleaBelle Bradshaw 1,*, Jessica B Briscoe 1,*, Hawley Helmbrecht 2, Timothy Heck 2, Shivani Shirodkar 1, Andres Carvajal 1, Hilkiah Suga 1, Rachael Quinn 1, Bruno Henrique Gallo 3,4, Regina Fernandez Fernandez 3,4, Jace C Bradshaw 5, Michelle Carvajal Villalba 1, Joseph Scafidi 3,4, Lee Martin 6, Lauren Jantzie 2, Jennifer S Lawton 1
PMCID: PMC13360968  NIHMSID: NIHMS2193162  PMID: 42203134

Abstract

BACKGROUND:

Hypothermia is utilized to reduce metabolic demand and ischemic neurologic injury during cardiac surgery requiring circulatory arrest (HCA). However, adverse effects of hypothermia limit safe arrest times. Antegrade cerebral perfusion (ACP) may allow for longer arrest; however, randomized data are lacking to inform optimal operative strategies. We hypothesized that an ideal ACP flow rate could be determined that would provide neurocognitive protection during HCA.

METHODS:

Eighteen animals underwent HCA (90 min) and unilateral ACP via the carotid artery at 2.5, 5, or 10 mL/kg/min. Animals were compared to controls that received intravenous ketamine (potentially neuroprotective) but no ACP. Animals were survived and assessed for three days. Outcomes included behavior deficit scores, cognition (novel object recognition), neuropathologic injury, inflammatory response, neurologic injury biomarkers.

RESULTS:

No differences in postoperative behavioral deficit scores, cognition, or neuropathologic injury were observed among animals receiving ACP at any rate. ACP animals demonstrated improved behavioral scores vs. controls on postoperative days 1 and 2 (both p-values <0.05). Cognition was preserved in ACP-treated animals, with the 10 mL/kg/min group demonstrating postoperative preference for the novel object (p<0.05), consistent with intact cognition. Neuropathologic analysis demonstrated a trend toward lower global brain injury scores in ACP-treated animals compared with controls (p=0.06). Neurologic injury biomarkers and inflammatory markers were attenuated with high-flow ACP relative to lower flow groups (p<0.05).

CONCLUSIONS:

Our findings support the use of ACP as a neuroprotection strategy and suggest that increased flow rates within the studied range could be beneficial in patients undergoing HCA.

Keywords: Neuroprotection, hypothermia, circulatory arrest, aortic surgery

Graphical Abstract

graphic file with name nihms-2193162-f0001.jpg

Neurologic and cognitive injury after complex cardiac or aortic surgery is a significant contributor to patient morbidity and mortality.1,2 Hypothermic circulatory arrest (HCA) is commonly utilized to reduce metabolic demand and ischemic neurologic injury in patients undergoing aortic arch surgery.3,4 However, while reduced temperatures provide protection, the deleterious effects of hypothermia also limit the safe arrest time.5 Most surgeons now use antegrade or retrograde cerebral perfusion to supplement hypothermia for neuroprotection.

The goal of antegrade cerebral perfusion (ACP) is to maintain cerebral perfusion during HCA to mitigate ischemic injury, permit warmer temperatures, and extend the duration of safe circulatory arrest. Despite its widespread adoption, there is no consensus regarding optimal cerebral perfusion strategies, and ACP techniques vary substantially by surgeon and institution.6,7 Retrospective and registry studies have yielded mixed results regarding neurologic outcomes,8,9 and although several randomized trials have compared cerebral perfusion strategies, they have been underpowered to define best practices.10–13 A meta-analysis suggested that ACP is associated with lower mortality, but these findings are largely derived from non-randomized data and are susceptible to selection bias.14,15 While data supports the use of cerebral perfusion during HCA,15–17 optimal flow rates remain unknown, with limited and heterogenous data from both preclinical and clinical studies.18–20 Clinically significant neurocognitive injury continues to occur despite contemporary cerebral protection strategies, highlighting persistent uncertainty regarding how to optimize outcomes.21

We hypothesized that an optimal ACP flow rate will maximize neuroprotection during HCA. Using a large-animal model, we evaluated neuroprotection with ACP delivered at three flow rates and compared outcomes with animals that received no ACP. End points included behavioral deficit scores, cognitive performance, neuropathologic injury, and serologic markers of neurologic injury and inflammation.

MATERIAL AND METHODS

This study was approved by the Animal Care and Use Committee at Johns Hopkins University (DO24M447, approved 1/10/2025). Animals were mixed-breed hound–type dogs of either sex, weighing 18–26 kg, aged 6 months to 1 year (Oak Hill Genetics, Ewing, IL). Animals were randomly assigned to one of three ACP flow rates (2.5, 5, or 10 mL/kg/min; n = 6 per group). A historical control cohort (n = 6) received ketamine without ACP and otherwise underwent identical procedures (Supplemental Text). In control animals, ketamine (2.85 mg/kg, intravenous (IV)) was divided into two doses and administered after HCA: immediately upon resumption of CPB and two hours later.

Surgical procedure

Animals were sedated with methohexital sodium (12 mg/kg, IV), in divided doses, intubated, and ventilated.22 Maintenance anesthesia was with isoflurane (0.5–2%). Normothermia was maintained at 37.5–38.5°C. An esophageal probe was used to monitor temperature. Lines were placed in the left femoral artery and vein. Intravenous heparin (300 U/kg) was given with additional doses as needed to reach an activated clotting time of > 400 seconds. Arterial blood gas (ABG) measurements (pH-stat) were taken every 15 to 30 min. Cannulas were placed in the right femoral artery (12 or 13 Fr), right femoral vein (15 or 17 Fr), and right external jugular vein (15 or 17 Fr). Animals were then placed on peripheral cardiopulmonary bypass (CPB). As soon as CPB was initiated, cooling to 18 °C was begun, and an ACP cannula (6 Fr) was placed in the right common carotid artery. Cooling was achieved via ice packs and a CPB gradient of 10°C. When the target temperature was reached, potassium chloride (40 mEq) was administered to achieve arrest. ACP was then initiated. After 90 minutes of HCA with ACP at the target temperature, ACP was discontinued, re-warming to normothermia begun, and sodium bicarbonate (50 mEq) and calcium gluconate (1 g) administered. Re-warming was achieved via warmed IV fluids, Bair hugger, warmed blankets, heating lamps, and a Hemotherm heater-cooler. Once the animal was warmed to 34°C, lidocaine (40–80 mg) and magnesium sulfate (500 mg) were given, and the animal was defibrillated (if indicated). Once the animal was in sinus rhythm, furosemide (10 mg) was given. Re-warming was continued until reaching normothermia, and the animal was weaned from CPB. Protamine sulfate was given, cannulas were removed, surgical sites closed, and the animal was extubated.

After testing on postoperative days (POD) 1, 2, and 3 was completed (described below), the animal was anesthetized, and intubated. Sternotomy was performed and the animal was centrally cannulated for bypass, exsanguinated, and infused with 24 L of crystalloid fluid for brain extraction.

Functional Neurological Injury and Behavioral Deficit Scoring

Behavior was evaluated using the Pittsburgh and Finnish scores on POD 1–3.23–27 Three separate scores were recorded by individuals blinded to treatment groups (two members of the surgical team and one member of the neuroscience team).

Cognitive Testing Using Novel Object Recognition Test

Prior to HCA, canines underwent a familiarization trial. Each canine was placed in the arena with two novel objects spaced approximately 40 cm apart for 5 min. Interaction time, defined as the nose within 2 cm of an object (sniffing, licking, biting), was recorded by a blinded observer. A minimum interaction threshold of 2 seconds with either object during familiarization was set a priori. On POD 1–3, canines were presented with one familiar object (from familiarization trial) and one novel object for 5 min. Interaction time with each object was recorded. Novel object placement was counterbalanced between the left and right sides of the arena to minimize bias.

Neuropathologic Assessments

The brain was harvested on POD 3. Half of the brain was placed in 10% neutral-buffered formalin for immersion fixation for at least two weeks. Hemispheres were randomized among right and left sides. For neuropathology, each hemisphere was uniformly cut into slabs (5 mm thick). From similar slabs from each hemisphere, representative regions of primary motor cortex, basal ganglia, hippocampus, and cerebellum were sampled and placed into plastic cassettes for paraffin processing. Paraffin-embedded brain tissue sections (8 μm thick) were stained with hematoxylin and eosin (H&E). Histopathologic injury scoring was assessed in six areas of the brain: dorsal hippocampus (CA1), dorsal dentate gyrus (DG), motor cortex (MC), basal ganglia/caudate nucleus (BG), cerebellar hemisphere (CbH), cerebellar vermis (CV) by one blinded neuropathologist unaware of canine treatment history. Regional and global neurologic injury (defined as the summed score from the regional assessment) were graded on a scale of 0 to 5, where grade 0 indicated no evidence of injury and grade 5 indicated severe injury (Supplemental Table 1).

Biomarkers

Cerebrospinal fluid (CSF) was obtained at four time points after sedation with methohexital sodium: Preoperatively (morning of surgery), POD 1 (24 h post-HCA), POD 2 (48 h post-HCA, and POD 3 (72 h post-HCA). Samples were analyzed for phosphorylated neurofilament protein (pNF) and neuron-specific enolase (NSE) using enzyme-linked immunosorbent assays (ELISA). (IL)-6, IL-8, tumor necrosis factor-α (TNF-α), and Monocyte Chemoattractant Protein-1 (MCP-1/CCL2) were also quantified.

Peripheral Immune Reactivity

On POD 2, blood was collected. PBMCs, defined as any blood cell with a round nucleus (i.e., lymphocyte, monocyte, or macrophage), were isolated as previously described.28–31 Equal amounts of peripheral blood were mixed with RPMI 1640 medium (Gibco, Waltham, MA), and gently placed over Ficoll Paque Plus (17-1440-02, GE, Chicago, IL). After centrifuging at 400g for 30 min at room temperature, PBMCs were harvested, resuspended and washed. Cells were counted using a Countess™ III Automated Cell Counter (Thermo Fisher Scientific). PBMCs were plated at a density of 1 × 106 cells/mL in RPMI medium with 10% FBS. Three replicates were plated for each sample on a 3.5 cm petri dish.

After plating, 10 ng/ml of lipopolysaccharide (LPS) or vehicle was added to each well and PBMCs were allowed to incubate for 4 or 24 h. After incubation, media were collected and centrifuged at 500g for 10 min. Cells and supernatant were subsequently stored at −80°C until biochemical analysis. IL-6, IL-8, TNF-α, and MCP-1/CCL2) in the secretome were quantified by ELISA.

Statistical Analysis

Continuous data are represented as mean ± standard deviation (SD) or mean and interquartile range (IQR). Behavior scores were compared using linear mixed-effects models with POD included as a repeated measure to evaluate whether different flow rates produced different recovery profiles. For NOR, a mixed model ANOVA (injury × treatment) and repeated measures (familiarization/recognition) with Bonferroni’s post hoc correction was performed. Neuropathologic injury scores were analyzed with the Kruskal-Wallis with Dunn’s multiple comparisons test. CSF and inflammatory biomarker levels were compared between groups using a mixed ANOVA. Boxplot graph boxes extend from the 25th to 75th percentiles, Tukey’s hinges show the IQR, whiskers extend to minimum and maximum observed values, and the line inside each box represents the median. Statistical analysis was conducted using R Studio (Version 4.2.2).

RESULTS

Functional Neurological Injury and Behavioral Deficit Scoring

The three treated groups (ACP at 2.5, 5, or 10 mL/kg/min) showed no statistically significant differences from one another (Figure 2A, 2B). All treated groups demonstrated consistent neurological improvement from POD 1 to POD 3 (p<0.001 for all) (Figure 2A, 2B; Supplemental Figure 1A, 1B). The estimated means and confidence intervals overlapped at each timepoint, indicating similar recovery trajectories across flow rates. These patterns were consistent for both the Finnish and Pittsburgh scoring systems.

Figure 2.

Figure 2.

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Behavior scores in a model of hypothermic circulatory arrest with antegrade cerebral perfusion. Animals that underwent hypothermic circulatory arrest with antegrade cerebral perfusion (ACP) at 2.5, 5, or 10 mL/kg/min (n=6 each) were scored by Finnish (A) and Pittsburgh (B). Higher scores indicate better behavioral recovery on Finnish, while lower scores indicate better recovery on Pittsburgh. Animals in a control group treated with ketamine but no ACP (n=6) were also scored by Finnish (C) and Pittsburgh (D), and these animals were compared to all animals treated with ACP (n=18). ACP animals demonstrated improved Finnish scores vs. controls on POD 1 and 2 (both p-values <0.05) and improved Pittsburgh scores on POD 1 (p<0.001). Boxplot graph boxes extend from the 25th to 75th percentiles, whiskers extend to maximum and minimum observed values, and lines inside each box represent medians. Each animal is represented as a dot. POD, postoperative day. * = p<0.05; *** = p<0.001

Animals that underwent ACP scored significantly better than the historical controls (animals that received ketamine but no ACP) on both scoring systems. These differences were significant for both scores at POD 1 (p < 0.001 for both). On POD 2, ACP animals scored better on the Finnish test (p=0.012), while there was a trend to improvement in Pittsburgh (p=0.079). On POD 3, Pittsburgh and Finnish scores were not significantly different between comparing ACP to historical controls (p=0.442 and p=0.066, respectively) (Figure 2C, 2D; Supplemental Figure 1C, 1D).

Cognitive Testing Using Novel Object Recognition

By POD 2, canines in the 10 mL/kg/min ACP group and control group (ketamine only) demonstrated a preference for the novel object (p<0.05), indicating intact cognition and recognition memory. Animals that received ACP at 2.5 or 5 mL/kg/min did not have significant preference for the novel object on any postoperative day (Figure 3).

Figure 3.

Figure 3.

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Cognitive testing in a model of hypothermic circulatory arrest with antegrade cerebral perfusion. Animals underwent cognitive testing with novel object recognition testing on each postoperative day (POD). A preference for the novel object (longer interaction duration) compared to the familiar object indicates intact cognition. Animals that received ACP at 2.5, 5, or 10 mL/kg/min were compared to control animals treated with ketamine but no ACP (n=6). Animals were evaluated on POD 1 (A), POD 2 (B), and POD 3 (C). Animals in the 10 mL/kg/min group had a statistically significant preference for the novel object on POD 2 (p=0.05). *p=0.05. ACP, antegrade cerebral perfusion

Neuropathologic Assessments

Global histopathologic injury scores demonstrated a trend toward differences among groups (p=0.053), with lower median injury scores in all ACP groups compared with ketamine-only controls (Figure 4). Post-hoc pairwise comparisons did not reach statistical significance after adjustment for multiple testing. Similar trends were observed in the cerebellar vermis and dentate gyrus, while no differences were detected in other brain regions (Supplemental Table 2).

Figure 4.

Figure 4.

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Global neuropathology injury scores in a model of hypothermic circulatory arrest with antegrade cerebral perfusion. After three postoperative days, the brain was removed and analyzed for evidence of neuropathologic injury. Animals that received ACP at 2.5, 5, or 10 mL/kg/min were compared to animals that received ketamine but no ACP. Boxplots show the distribution of global injury scores across animals receiving ketamine alone or antegrade cerebral perfusion (ACP) at 2.5, 5, or 10 mL/kg/min. Higher scores indicate worse injury. A trend toward group differences was observed (p=0.053). Boxes represent the interquartile range (IQR) with medians indicated by horizontal lines. Whiskers extend to 1.5× IQR. Individual data points are colored dots.

Biomarkers

For CSF pNF levels, no significant increases were observed across preoperative or postoperative time points. On POD 1, pNF levels were significantly lower in the 10 mL/kg/min group compared with the 2.5 mL/kg/min group (p=0.01) (Figure 5).

Figure 5.

Figure 5.

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Phosphorylated neurofilament in a model of hypothermic circulatory arrest with antegrade cerebral perfusion. Phosphorylated neurofilament levels in cerebrospinal fluid were compared between animals undergoing HCA for 90 minutes with ACP flow rate groups of 2.5, 5, or 10 mL/kg/min. pNF levels were lower (improved) in the 10 mL/kg/min group compared to the 2.5 group (p=0.01) on POD 1. *P<0.05.ACP, antegrade cerebral perfusion; pNF, phosphorylated neurofilament; POD, postoperative day

CSF NSE levels increased from preoperative baseline to POD 1 in the 2.5 mL/kg/min group (p=0.025), while no significant increases were observed in the 5 or 10 mL/kg/min groups. On POD 1, CSF NSE levels were significantly lower in the 10 mL/kg/min group compared with the 2.5 mL/kg/min group (p=0.049) (Figure 6).

Figure 6.

Figure 6.

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Neuron-specific enolase in model of hypothermic circulatory arrest with antegrade cerebral perfusion. Neuron specific enolase levels in cerebrospinal fluid were compared between animals undergoing HCA for 90 minutes with ACP flow rate groups of 2.5, 5, or 10 mL/kg/min. NSE levels increased from preoperative baseline to POD 1 in the 2.5 mL/kg/min group (p=0.025). On POD 1, NSE levels were lower in the 10 mL/kg/min group compared with the 2.5 mL/kg/min group (p=0.049). *P-value<0.05. ACP, antegrade cerebral perfusion; POD, postoperative day

Peripheral Blood Mononuclear Cells (PBMCs) Reactivity

TNF secretion increased in all flow rate groups with LPS stimulation, suggesting a robust immune response among all animals after HCA. PBMCs from animals with ACP at 5 mL/kg/min secreted significantly more TNF after 4 h compared to the 10 mL/kg/min group with LPS stimulation (p=0.017), suggesting lower immune response in the higher flow rate group. After 24 h, PMBCs from animals in the 2.5 mL/kg/min group secreted more MCP/CCL2 compared to the 5 mL/kg/min group (p=0.012) and 10 mL/kg/min group (p=0.011). There were no significant differences in secretion of IL-6 or IL-8 between groups at 4 h or 24 h time points. Taken together, these data reveal peripheral immune hyperreactivity after HCA and a protracted time course of cytokine secretion in stimulated PMBCs from HCA animals undergoing lower ACP flows (Figure 7).

Figure 7.

Figure 7.

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Inflammatory markers in a model of hypothermic circulatory arrest with antegrade cerebral perfusion. Cytokine and chemokine measurements at baseline (4 h) and after 24h in conditioned medium of PBMCs are shown. PBMCs from animals with ACP at 5 mL/kg/min secreted significantly more TNF compared to the 10 mL/kg/min group with LPS stimulation (p=0.017). PMBCs from animals in the 2.5 mL/kg/min group secreted more MCP/CCL2 compared to the 5 mL/kg/min group (p=0.012) and 10 mL/kg/min group (p=0.011). PBMCs, peripheral blood mononuclear cells. * = p<0.05; * = p<0.01; *** = p<0.001

COMMENT

In a translational model of prolonged HCA, unilateral ACP was associated with improved neurologic outcomes compared with ketamine alone, and increasing ACP flow was associated with trends toward incremental improvement in outcomes. Animals receiving ACP demonstrated significantly better postoperative behavioral recovery vs controls, with consistent improvement over postoperative days and similar recovery trajectories across flow rates. While behavioral deficit scores did not differ among ACP groups, higher ACP flow was associated with improved performance on cognitive testing, attenuated responses in inflammatory markers (PMBCs), and decreased CSF neurologic injury biomarkers levels. Histopathologic injury scores showed a trend favoring ACP, though this did not reach statistical significance.

Prior experimental and clinical literature support the use of ACP as an adjunct to hypothermia for cerebral protection, though there are limited data examining neurological outcomes with different flow rates. Preclinical porcine studies demonstrated that ACP preserves cerebral metabolism and oxygenation across a range of flow rates, with diminishing returns beyond a minimum effective threshold.18,19 Clinical observational studies suggest that ACP is superior to no cerebral perfusion, though consensus regarding optimal flow rates is lacking.20 Our data reinforce that cerebral perfusion is neuroprotective, and raise the possibility that higher flow rates have incremental benefits. Improved cognitive performance and dampened inflammatory response observed at higher flow rates suggest that subtle neurocognitive or immunologic benefits may not be captured by traditional clinical endpoints alone, underscoring the value of multimodal neurologic assessment in translational models of HCA.

Limitations include: Sample sizes were small for ethical reasons.32 Lack of long-term follow-up precludes insight into long-term implications of ACP, particularly in terms of behavior and cognition. The duration of HCA (90 min) is longer than the typical duration utilized in humans. This duration was chosen to extend injury to allow comparisons between interventions.26 In addition, histologic analysis was limited to morphology using by H&E staining, which may miss nuanced cellular changes33, behavioral assessments lack sensitivity to detect subtle cognitive changes, and it is possible that the optimal flow rate is outside of the range tested.20

These findings suggest that cerebral perfusion during HCA confers measurable neuroprotection.

Supplementary Material

1
2

Figure 1.

Figure 1.

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Hypothermic circulatory arrest protocol. Canines were peripherally cannulated for cardiopulmonary bypass, cooled to 18°C, cannulated for unilateral ACP and underwent 90 min of hypothermic circulatory arrest. Animals were studied for three postoperative days. Eighteen animals were randomized to three ACP flow rates: 2.5, 5, or 10 mL/kg/min. These were compared to controls that received the same surgical interventions plus intravenous ketamine and no ACP. Outcomes included behavior and cognition scores, neurologic injury and inflammatory markers, and neuropathology. ACP, antegrade cerebral perfusion; CSF, cerebrospinal fluid; HCA, hypothermic circulatory arrest

Acknowledgements

Janelle Sangalang, Rachel Pan, Caroline Tran, Vishnu Dontu, Samrawit De La Cruz, Nivi Kumar, Joshua Fine, Joshua Carneglia, Chad Wierschke, Dr. Jie Wang, Dr. Jeffrey Dodd-O, and Dr. Ima Chinedozi

FUNDING:

NIH: #RO1 HL091541-24A1 (JSL), T32HL125239 (TH); AHA: 24POST1200461 (JBB), 25POST1356885 (AB)

ABBREVIATIONS

ABG

Arterial blood gas

ACP

Antegrade cerebral perfusion

CCL2

C-C motif ligand 2

CPB

Cardiopulmonary bypass

CSF

Cerebrospinal fluid

ELISA

Enzyme-linked immunosorbent assay

H&E

Hematoxylin and eosin

HCA

Hypothermic circulatory arrest

IQR

Interquartile range

IV

Intravenous

MCP-1

Monocyte chemoattractant protein-1

PBMC

Peripheral blood mononuclear cell

POD

Postoperative day

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Presented at the Society of Thoracic Surgeons annual meeting, 2/1/26

Declaration of interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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