Various methods of CBF assessment have been used in animal models of cardiac arrest. A review of these methods is important to appreciate the benefits and additional information that can be acquired from research in animal models, as well as to aid in interpretation of blood flow data considering the limitations of each method. In animal models of cardiac arrest, available methods for the assessment of cerebral perfusion may be categorized regarding brain tissue penetration (invasive or non-invasive), and further categorized regarding the area assessed (regional vs. global), and time post-resuscitation (one time point vs. serially) (Table 1).

Limited evaluation of CBF has been performed in humans after CA, due to the availability of only a few non-invasive means and portable devices. For human use, an ideal tool for CBF assessment post-resuscitation should be employable early post-resuscitation and be portable, non-invasive, not interfere with clinical care, and allow for serial assessments. Post-resuscitation research is still in search of this tool, and this represents the largest knowledge gap and the greatest impediment to goal-directed cerebral resuscitation.

Cerebral perfusion can currently be assessed in children and adults after cardiac arrest using three techniques: TCD, ASL-MRI, or Xenon CT. Additionally, implantable CBF monitors such as thermal diffusion flowmetry are available invasive methods which have been used to assess perfusion in isolated case reports of cardiac arrest (11) and have been extensively used in patients with traumatic brain injury and subarachnoid hemorrhage (12, 13). In the past, valuable CBF data were obtained in adults using tracers (¹³³Xe) (14) or thermodilution methods (15); however, with the advent of the newer, less invasive technologies enumerated above, these two techniques have not been used recently.

In the immediate phase post-resuscitation, CBF disturbances have traditionally been characterized by hyperemia; however, recent studies show that the alterations are brain-region specific depend on three factors: age (pediatric vs. adult model), pathophysiological mechanism of cardiac arrest (VF vs. asphyxia), and insult duration (mild, moderate vs. severe insults).

In the adult experimental cardiac arrest, hyperemia is repeatedly noted in various models. Blomqvist and Wieloch (37) reported hyperemia of different intensities in 17 regions early after VF cardiac arrest in rats. Similarly, early hyperemia was also found in adult rats and dogs with longer duration (10–13 min) of VF cardiac arrest (38, 39). Hyperemia after asphyxial cardiac arrest was also described by Xu et al. in the thalamus and cortex (40). The regional distribution of hyperemia was also recognized in a dog model of VF cardiac arrest: the brain stem and basal ganglia had longer duration of hyperemia compared with the cortex (41). A comprehensive comparison of CBF in VF cardiac arrest vs. asphyxial cardiac arrest in adult rats revealed that after asphyxial cardiac arrest marked early hyperemia is observed in all regions, whereas after VF cardiac arrest early hyperemia was limited to the cortex, whereas subcortical regions had baseline levels of CBF (31). The influence of insult duration on CBF has not been completely characterized in adult models of cardiac arrest. To date, no studies provided a parallel assessment of regional CBF in insults of progressive durations in models of adult cardiac arrest.

In pediatric asphyxial cardiac arrest in rats, CBF is markedly dependent on the brain region (cortical vs. subcortical) and insult duration (moderate vs. severe insult) (Figure 1) (10). In contrast with earlier studies in adult animal models showing universal early hyperemia, in immature rats hyperemia is limited to the subcortical areas, whereas cortical areas have normal or even decreased CBF. Specifically, in insults of moderate duration (9-min asphyxia) subcortical areas are characterized by marked early hyperemia. However, after insults of prolonged duration (12 min) subcortical areas have baseline CBF levels without evidence of hyperemia (Figure 1) (10). Cortical CBF is markedly different than subcortical CBF. Cortical CBF returns to baseline level immediately after resuscitation in insults of moderate duration, whereas after cardiac arrest in insults of prolonged duration cortical hypoperfusion occurs immediately post-resuscitation (Figure 1) (10). Measurement of brain tissue oxygen level in these insults revealed that brain tissue oxygen mirrored the CBF changes: subcortical hyperoxia occurred in insults of moderate duration, while cortical hypoxia occurred in insults of severe duration (42). These studies in pediatric models of cardiac arrest showed that alterations in CBF are accompanied by alterations of tissue oxygenation post-resuscitation.

The significance of early hyperemia is still being elucidated. Some studies suggest that hyperemia is an indication of coupling of CBF and metabolism, and thus is an indication of increased local metabolic rates. Others suggest that hyperemia is detrimental as it intensifies the reperfusion syndrome, and propose that a more gradual reperfusion might be beneficial. Thalamic areas, where early hyperemia is observed after pediatric cardiac arrest, is characterized by extensive degeneration of neurites and activation of microglia, suggesting an association between early hyperemia and neurodegeneration (43). Therapies targeting the early hyperemic phase to improve neurological outcome included antioxidants such as superoxide dismutase and polynitroxyl albumin, which decreased the early hyperemia of the subcortical areas and improved outcome (10, 44).

After the initial period post-resuscitation, CBF is generally characterized by a longer hypoperfusion stage, which appears to occur more uniformly across species, age groups, and models (34, 37–39, 41, 45–47). Hypoperfusion is observed anywhere from 15 to 60 min post-resuscitation and can persists for hours or even days.

In adult cardiac arrest models, both asphyxial and VF, hypoperfusion has been observed in all regions, cortical and subcortical (31). Gray matter appeared to be more vulnerable to hypoperfusion than the white matter (48).

In pediatric asphyxial cardiac arrest in immature rats the hypoperfusion is more evident in the cortex and is more pronounced in longer durations of cardiac arrest (10, 49). In the subcortical areas such as thalamus, hypoperfusion was seen only with prolonged durations of cardiac arrest (10) (Figure 1).

Cerebral blood flow and metabolism are likely uncoupled during the delayed hypoperfusion period, suggested by the cortical hypoxia observed after pediatric asphyxial cardiac arrest (42), and suggesting that the brain suffers a secondary ischemic event during this period. Multiple mechanisms are implicated in the development of delayed hypoperfusion, including damage at the level of the endothelial cells, unbalance of local vasodilator and vasoconstrictors, as well as impaired autoregulation in the setting of decreased blood pressure. Therapies targeting these mechanisms have been assessed in animal models (5, 30, 50–52).

Cerebral blood flow at greater than 12 h after experimental cardiac arrest has not been extensively studied. In severe cardiac arrest models, the animals need intensive care and might not survive if extubated and returned to their cages. CBF was assessed at 24 h after moderate durations of pediatric cardiac arrest (9 min, Figure 1). CBF returned to normal values in the delayed period in all regions except for the thalamus. Thalamic areas have increased CBF at 24 h after CA (53). The function of thalamic circuitry is impaired after pediatric cardiac arrest, as demonstrated by increased firing rates in thalamocortical neurons at 48–72 h after cardiac arrest and associated with histologic evidence of injury in the thalamic nuclei.

During the immediate and early periods after cardiac arrest there are microcirculatory disturbances, resulting in localized areas of no flow, interspersed with areas of low flow and increased flow. This phenomenon was initially described by Ames et al. in a model of global ischemia in rabbits in 1968 as incomplete filling of the cortical capillary bed upon perfusion with contrast agent and is known as the no-reflow phenomenon (54). The perfusion deficits increased with increased duration of ischemia and the no-reflow phenomenon has been observed in various models of cardiac arrest (55, 56).

Multiple mechanisms have been proposed to be responsible for the no-reflow phenomenon, including post-resuscitation hypotension, increase in blood viscosity, and fibrin clots (34, 57–59). Therapies targeting these mechanisms have shown beneficial effect in animal models. For example, blood flow promotion therapy with hypertension and hemodilution immediately after cardiac arrest has been shown to normalize the CBF pattern and improve outcome in dogs (46, 60). Thrombolytic therapies with plasminogen activator and heparin reduced no-reflow phenomenon seen after cardiac arrest and produced more homogeneous perfusion (61). The no-reflow phenomenon likely contributes to the hypoperfusion observed post-resuscitation and likely causes a secondary ischemic injury.

In summary, valuable data regarding alterations of CBF post-resuscitation is obtained from animal models of cardiac arrest. These models have the advantage of allowing serial, regional assessment of CBF, and comparison of CBF alterations in insults of progressive durations, simultaneous assessment of CBF, brain oxygenation, metabolism, and electrical activity (62), assessment of microvascular alterations, and development of novel CBF and neuronal targeted therapies.

Transcranial Doppler was used in several studies after cardiac arrest. These studies confirmed that cerebral hemodynamics are altered during the post-cardiac arrest syndrome and evolve during the first 24–72 h after cardiac arrest.

During the first 12 h after cardiac arrest several small studies in adults demonstrate the presence of hypoperfusion and high vascular resistance, evidenced by low mean flow velocity and high PI (68–70). This diffuse hypodynamic TCD pattern suggests microangiopathy secondary to vasoconstriction and no-reflow in the microcirculation, and is associated with poor neurological outcome (18).

After 24 h post- resuscitation, a diffuse hyperdynamic pattern is observed, evidenced by high mean flow velocity and low PI, suggesting hyperemia or vasospasm (68–70). This pattern was also associated with poor prognosis, progression to brain death, and increased ICP (18). These changes were associated with increased endothelin levels, decreased nitric oxide levels, and increased cGMP levels, suggesting that an imbalance between local vasodilators and vasoconstrictors plays a role in the cerebral vasoconstriction and hypoperfusion phase (70).

Underscoring the importance of serial assessment of CBF post-cardiac arrest, one study showed that the initial hypodynamic pattern observed during the first 12 h after resuscitation was followed by normalization of mean flow velocity and PI for 24 h, and then by increased mean flow velocity and low PI for 48–72 h (69). Therefore, a single measurement cannot be used for prognostication without taking into account the CBF trajectory for the respective patient. Possibly related to the time of measurement of CBF post-resuscitation, a recent study failed to show a correlation between TCD parameters and outcome. In this particular study, the first CBF measurement was obtained within 48 h after cardiac arrest, and subsequent measurements were obtained at days 3–5 and 7–10 post-resuscitation (71).

Transcranial Doppler was successfully assessed in 17 children after cardiac arrest at three points: during the pre-hypothermia, hypothermia, and rewarming phases. All patients with undetectable flow during any phase died. Patients with normal mean flow velocity during the rewarming phase had better prognosis vs. patients with low mean flow velocity. Patients with normal pulsatility indices during the hypothermia and rewarming phases had better outcomes compared with the ones with high pulsatility indices (72).

MRI assessment of CBF early after cardiac arrest is difficult to perform, due to the patients’ clinical instability. In a prospective observational study, pediatric patients underwent MRI to assess CBF and ADC maps after cardiac arrest (21). This study was the first pilot study in the pediatric patients to assess CBF after cardiac arrest and identified both the opportunities and current challenges of ASL-MRI after cardiac arrest. The patients were transported to the MRI suite when the clinical team was comfortable that the patient was stable for transport and seizure-free. The brain MRI was performed at 6 ± 4 days after cardiac arrest (IQR 2.7–8.7 days).

Cerebral blood flow was 76.8 + 32.5 vs. 91.6 + 38.9 ml/100 g/min for patients with favorable vs. unfavorable outcome, with no significant difference between patients with favorable vs. unfavorable outcomes. Importantly, children with unfavorable outcome had decreased apparent diffusion coefficient compared with children with favorable outcome, suggesting cytotoxic edema. Brain regions with abnormalities in diffusion consistent with cerebral edema had also increased CBF. The assessment of CBF at only one time point after cardiac arrest and the necessity to analyze data after cardiac arrest among patients of different ages could have contributed to the limited conclusions that could be drawn regarding CBF from this study. Another study of 14 adults and 2 children that underwent ASL-MRI at a range of 1 and 13 days after cardiac arrest showed a universal global hyperperfusion pattern. A majority of patients in this latter study died (10/14 adults, and 2/2 children) (73).

Before the advent of MRI, CBF was measured in human subjects for decades using the Xe¹³³ washout technique. Xe¹³³ was administered by inhalation, and CBF was calculated using a compartment method (74). With this technique, human CBF and metabolism were assessed in eight adult patients post-resuscitation with inhalation of Xe¹³³ and concomitant measurement of CMRO₂ using the jugular venous oxygen tension measurement technique. From 2 to 6 h post-cardiac arrest, CBF was decreased to 50% along with a decrease in oxygen metabolism. After 6 h, CBF was increased toward baseline, while the metabolism also started recovering, albeit disproportionately in comparison to CBF, such that a relative hyperemia developed. This “luxury perfusion” was also seen at 24–60 h after cardiac arrest. This study suggested that CBF at delayed time points after cardiac arrest is uncoupled from metabolism (75).

Similarly, in 13 patients resuscitated from cardiac arrest, CBF was assessed using Xe inhalation. Seven (54%) patients who regained consciousness had normal CBF values, while six (46%) patients who did not regained consciousness had increased CBF between 18 and 36 h. In these comatose patients, decreased CBF after the period of hyperemia was associated with isoelectric encephalogram and death (76). In another similar study, a majority of patients had relative hyperemia; however, CBF showed great variability between patients (77).

Cerebral blood flow autoregulation is a physiological phenomenon that maintains a relatively constant CBF for blood pressures in the range of 50–150 mmHg, through vasodilatory and vasoconstrictor mechanisms.

After cardiac arrest, CBF autoregulation was found to be compromised in 13 of 18 adult patients in the first 24 h after resuscitation. For assessment of autoregulation, the blood pressure was increased with 30 mmHg using intravenous infusion of norepinephrine. The autoregulation was absent in some patients, while the lower limit of autoregulation was shifted toward a higher pressure in others. Five patients (28%) had normal autoregulation, eight patients (45%) had loss of autoregulation, and another five patients (28%) had preserved but right-shifted autoregulation, with the lower limit of autoregulation increased to a median of 114 mmHg (range 80–120), a derivation from a median of 76 mmHg (range 41–105) in the healthy individuals studied (78). Cerebral autoregulation was also found to be impaired in eight adult patients that were comatose 3 days after cardiac arrest. The patients had internal jugular vein cannulation, and CBF index was indirectly calculated using the arterial-jugular bulb venous oxygen content difference (79).

More recently, NIRS was validated as a tool for measuring cerebrovascular autoregulation (80). Correlating changes in oxygen saturation with fluctuations of arterial blood pressure over time can detect an impairment in the CBF autoregulation. Several studies correlated impaired autoregulation with worse neurological outcome after cardiac arrest. In a study in adults a combined measure of tissue oxygenation and blood pressure was performed daily for the first 3 days after CA. Impaired autoregulation on days 1–3 after cardiac arrest was associated with increased mortality at 3 months (81). In another study, impaired autoregulation was found in 35% patients during the first 24 h after cardiac arrest and was correlated with worse outcomes (82). Since hypotension after cardiac arrest was shown to be deleterious and higher blood pressure after cardiac arrest were associated with favorable outcomes (83, 84), it is important to maintain the blood pressure in an optimum range for cerebral perfusion. Important studies by Lee et al. generated an index of vasomotor reactivity by correlating relative tissue hemoglobin with mean arterial pressure (MAP), and based on this index, the optimal MAP range with most robust autoregulation can be identified (28, 85). In a landmark pilot study in 35 pediatric patients monitored with NIRS after cardiac arrest, patients who spent more time with MAP below the optimal autoregulatory range during the first 48 h after cardiac arrest had worse outcomes (27). Thus, combining real-time NIRS with continuous blood pressure monitoring might not only be used as a tool for prognostication early after cardiac arrest, and may serve as a measure of goal-directed blood pressure management after cardiac arrest.

The cerebrovascular reactivity to changes in arterial carbon dioxide tension (CO₂ reactivity), accountable for a 3% decrease in CBF in response to a 1 mmHg decrease in pCO₂ (86), appears to be maintained after cardiac arrest (70). Thus, hyperventilation after cardiac arrest might induce cerebral vasoconstriction and a secondary ischemic insult and should, therefore, be avoided.

In summary, there are relatively few studies assessing CBF post-resuscitation in adults, and even fewer studies in children. CBF varies greatly from infancy to adolescence, and thus pediatric studies of CBF should group data for each age group (neonate, infant, toddler, school age, and adolescent) to allow for meaningful interpretation of results. The limiting factor for assessing CBF after cardiac arrest is a reliable non-invasive device that can be used at the bedside and allow for serial measurements of cerebral perfusion. TCD could offer non-invasive repeated measures of cerebral perfusion, and is largely underutilized after cardiac arrest. There are good data to support that decreases in CBF correlate with decreases in cerebral oxygenation (1, 42) and thus NIRS could provide some guidance post-resuscitation especially to guide maintenance of blood pressure within the range with most robust autoregulation (27).

In conclusion, we reviewed here CBF changes in animal models and in adult and pediatric patients after cardiac arrest. There are many challenges to the assessment of perfusion after cardiac arrest. Multidisciplinary and multi-institutional collaborations are necessary to fully evaluate CBF dysregulation in pediatrics, as CBF varies vastly in an age-dependent manner. Understanding cerebral perfusion after cardiac arrest would be beneficial in guiding current therapies, assessing novel vasoactive therapies, and prognostication.