The lower limit of autoregulation (LLA) of cerebral blood flow (CBF) is the cerebral perfusion pressure (CPP) at which dynamic cerebrovascular resistance fails to preserve CBF in the face of arterial hypotension. As CPP decreases below the LLA, CBF becomes passive to changes in CPP. Autoregulation of CBF is therefore a protective mechanism against ischemia due to decrements in CPP. The elbow demarcating pressure-passive CBF from pressure-reactive CBF in the relationship of CBF to arterial blood pressure (ABP) was first described in humans by Lassen.1 This significant observation combined with the advent of intracranial pressure (ICP) monitoring2 has had profound influence on the conceptual model that drives current CPP-guided management of patients with traumatic brain injury (TBI).
Traditional teaching suggests that CPP is preserved by increases in ABP that are equal to the increase seen in ICP.3 However, restoring CPP after an acute increase in ICP by increasing ABP may not restore CBF to preinsult values. Studies have demonstrated multiple factors that can theoretically affect the LLA, both globally and regionally, including age, injury, inflammation, and pharmacology.4 Current CPP-based management guidelines for adults with TBI recognize our inability to delineate the LLA that is applicable to all patients, recommending a CPP >60 mm Hg.5
In our prior study of cerebrovascular autoregulation,6 an experiment was conducted to test the compliance dependence of an ICP-waveform-based monitor of autoregulation. That experiment required a determination of the LLA at two levels of ICP: naïve and 20 mm Hg. A steady-state ICP increase was created by ventricular infusion of artificial cerebrospinal fluid (aCSF) in piglets. A secondary outcome of that study was that, in piglets with an ICP of 20 mm Hg, the LLA appeared to occur at a higher CPP, when compared to the naïve group.6 This result was unexpected as the ICP increase was both atraumatic and noninflammatory, implicating a mechanical effect on the vascular dynamics responsible for autoregulation. We therefore hypothesized that the CPP at LLA (LLACPP) is increased by acute increases in ICP. To test this hypothesis in a more robust fashion in the present study, we determined the LLA in a group of piglets that had ICPs of 40 mm Hg and compared their LLACPP with piglets studied under otherwise similar conditions with ICPs that were at the naïve level or elevated to 20 mm Hg.
All procedures were approved by the Johns Hopkins Animal Care and Use Committee and conformed to the standards of animal experimentation of the National Institutes of Health. Three ICP groups of piglets were studied: naïve ICP (n = 10; weight, 2.30 ± 0.15 kg), moderately elevated ICP (n = 11; ICP, 20 mm Hg; weight, 2.35 ± 0.37 kg), and severely elevated ICP (n = 9; ICP, 40 mm Hg; weight, 2.93 ± 0.75 kg). Data from the naïve and elevated ICP groups have been published as part of a validation study of the pressure-reactivity index, a continuous metric of autoregulation.6
All 30 infant piglets (age, 5–10 days old; weight, 2.2–3.9 kg) were anesthetized by a previously described protocol that balances minimization of inhaled drug with narcotic to provide comfort while limiting impact on the autoregulation mechanism.7 Induction was by inhalation of 5% isoflurane, 50% N2O, and 50% O2. After tracheostomy and mechanical ventilation (goal pH, 7.35–7.45; Pao2, 200–300 mm Hg, Paco2, 35–45), maintenance anesthesia was provided using inhalation of 0.8% isoflurane vaporized with 50% N2O and 50% O2, combined with IV dosing of vecuronium (5 mg bolus and 2 mg/h infusion) and fentanyl (25 μg bolus and 25 μg/h infusion). Fentanyl was titrated between 10–50 μg/h (mean, 20 μg/h) to a target heart rate of <200 bpm before hemodynamic manipulation. During active decreasing of ABP, fentanyl infusion was kept constant and subsequent tachycardia was permitted. Warming pads were applied to maintain brain and rectal temperature at 38.5–39.5°C.
Once the piglets were anesthetized, a central venous line and a 5 Fr esophageal balloon catheter (Cooper Surgical, Trundall, CT) were placed in the femoral veins. Gradual inflation of the balloon catheter at the level of the inferior vena cava was the mechanism of inducing hypotension in the piglets. The femoral artery was cannulated for placement of a pressure monitoring line. The ABP was continuously monitored after setting the transducer to zero at the level of the external auditory meatus, which was also at the level of the left atrium.
For piglets in the naïve ICP group, a single external ventricular drain catheter was placed 4 mm lateral and 4 mm rostral to the bregma at midline through a 2–3 mm craniotomy. Piglets in both elevated ICP groups required an additional contralateral 2–3 mm craniotomy for placement of a second external ventricular drain for aCSF infusion. Continuous ICP was monitored by transduction of the external ventricular drain in all animals with pressure lines set to zero at the external auditory meatus. CPP was calculated and recorded every 10 s as ABP-ICP. Craniotomy was also performed 4 mm lateral and 4 mm rostral to the first craniotomy in all piglets for placement of a laser-Doppler probe (Moor Instruments, Devon, UK). The probe was positioned against the surface of the frontoparietal cortex, and the position was adjusted to acquire a baseline value between 100 and 500 (arbitrary units). The laser-Doppler probe was then secured with rubber washers cemented to the skull. A brain temperature probe was placed epidurally in a final 1 mm craniotomy in the occipital skull lateral to the midline. Craniotomies were sealed with dental cement to re-establish a competent calvarium. The wound was sutured closed for heat retention.
Increasing the ICP
For piglets in the moderately elevated ICP group, aCSF (KCl 3.0 mmol/L, MgCl2 0.6 mmol/L, CaCl2 1.3 mmol/L, NaCl 131.8 mmol/L, NaHCO3 24.6 mmol/L, urea 6.7 mmol/L, glucose 3.6 mmol/L) was infused in the external ventricular drain at varying rates to achieve a steady-state ICP value of 20–25 mm Hg. Piglets with elevated ICP exhibited a spontaneous compensatory increase in ABP, which restored CPP to baseline values (60 mm Hg). Piglets in the severely elevated ICP group had a steady-state ICP value of 40–45 mm Hg. This group did not have a compensatory Cushing response to restore CPP to baseline, and instead showed a tendency for spontaneous hypotension. Hypotension and decreases in baseline laser-Doppler flux were prevented by IV infusion of phenylephrine (0.1–4 μg · kg−1 · min−1) until CPP was again restored to a minimum of 55 mm Hg.
Determining the LLA Using the Laser-Doppler
After CPP was restored to baseline values at the target ICP, the balloon catheter in the inferior vena cava was gradually inflated by infusion of saline from a syringe pump to slowly decrease CPP to approximately 10 mm Hg. Our goal was to reduce the ABP over 3 h to have a quasi-steady-state CPP with spontaneous slow fluctuations. ABP, ICP, and laser-Doppler flux were sampled at 60 Hz, using ICM+ software (Cambridge Neuroscience, Cambridge, UK). Durations of recording during ABP decreasing were 3.25 ± 1.25 h (±sd) and 3.17 ± 0.98 h for the naïve and moderately elevated ICP groups, respectively. The severely elevated ICP group had hemodynamic instability, and decreasing of the phenylephrine infusion was all that was required to produce sufficient decrement of CPP. In some cases, the CPP was ≥20 mm Hg after cessation of the phenylephrine, and the balloon was then inflated to finish the ABP reduction. A recording duration of 1.75 ± 0.76 h in the severely elevated ICP group was significantly lower than the other two groups.
A scatter plot of 60-s averaged values of laser-Doppler flux against CPP was made for each piglet, using SigmaStat software (Systat, San Jose, CA). The CPP that demarcated two sets of data on this plot with regression lines having the lowest combined residual squared error was determined, and the intersection of these two regression lines was solved to give the autoregulatory breakpoint. Similar methods have been described to determine the LLA.8
The average LLA for each group is presented with 95% confidence intervals. Statistical comparison of the LLA among groups was made using the Kruskal-Wallis one-way analysis of ranks because the variance was not homogeneous among groups. The measured ICP at the LLA for each animal was determined, and a scatter plot of LLACPP versus ICP at LLA was made. Spearman's rank coefficient was used to determine the linear correlation of CPP and ICP at LLA.
A summary of physiologic variables measured during the experiments is shown in Table 1. None of the baseline variables were significantly different among groups (P > 0.05). Paco2 and other relevant variables are shown at both normal and low ABP to demonstrate that the animals were maintained within the same care variables as the ABP was decreased. A trend for decreasing hemoglobin was demonstrated over the course of the experiment, likely due to blood gas sampling and fluid administration, but this was not significant (P > 0.05).
Figure 1 shows autoregulation curves as averaged plots of laser-Doppler flux summarized from piglets in their respective ICP groups. Data are expressed as a percentage of baseline flux and as a function of CPP. The LLA was different among the three groups by a magnitude having clinical relevance. The average LLA for the naïve, moderately elevated, and severely elevated groups was 29.8 mm Hg (95% CI: 26.5–33.0 mm Hg), 37.6 mm Hg (95% CI: 32.0–43.2 mm Hg), and 51.4 mm Hg (95% CI: 41.2–61.7 mm Hg), respectively. Box-whisker plots of the LLA for the three groups are presented in Figure 2. Comparison of the LLA among groups was significant by the Kruskal Wallis test (P < 0.002).
Although animals in the same group shared a target ICP, the aCSF infusion method has some imprecision associated with it that creates a variance of 5–10 mm Hg among animals. Some variation was also seen within each animal as the constant rate aCSF infusion yields a quasi-steady-state ICP, in contrast to the hanging-bottle method, which adjusts infusion rates to keep ICP constant. Spontaneous slow waves of ICP were allowed to occur with the infusion method. We therefore determined the ICP at the LLA for each animal to show the relationship between the ICP and LLACPP. The regression line for the scatter plot of ICP versus LLACPP in Figure 3 has a slope of 0.6 and a Spearman's r of 0.67 (P < 0.0001).
The present study demonstrated that the CPP at which the LLA is determined increased when ICP was increased in a piglet model of acute hydrocephalus. This finding challenges the paradigm for CPP-oriented practice in patients with head trauma. Current practice assigns a fixed CPP goal to a patient regardless of level of ICP. According to this practice, ABP is increased by an amount equal to increases in ICP to produce a constant CPP. Our results suggest that the desired level of CPP to stay above the LLA may need to be increased as the level of ICP increases. The finding of this experiment raises a question about the clinical practice of keeping a constant level of CPP as ICP increases and adds to the difficulty of recommending CPP goals for patients who have ICP monitoring. Both optimal CPP and the LLA for patients with TBI are unknown. The present results suggest that the LLA and, presumably, optimal CPP are dynamic with increasing ICP.
Prior studies of the LLA have used models that decreased ABP, increased ICP or increased the jugular venous pressure, but not typically in combination.9–13 Several studies,11,12,14 but not all,10 have noted that decreases in ABP and increases in ICP yield a similar CPP at the LLA. However, most prior studies of the effect of ICP on autoregulation have used microsphere or tracer injections. Compared with continuous monitoring of laser-Doppler flux, these intermittent methods lack the temporal resolution required for precisely delineating the LLA in individual subjects and permitting statistical analysis of differences in LLA among groups.
One study compared the LLA at stratified ICP levels. Hauerburg and Juhler used a Xenon-133 tracer injection method to measure blood flow in adult rats at three levels of ICP: control, 30 mm Hg and 50 mm Hg. They reported with this intermittent CBF measurement method an inverse relationship to the one found in our study: the LLACPP appeared to decrease with increasing ICP. The authors postulate that a mechanism of enhanced arteriolar dilation is activated by intracranial hypertension, allowing autoregulation at CPP below the baseline LLA.15 We, in contrast, found animals with an ICP of 40 to have critically low and static CBF at a CPP of 30 mm Hg, which was the LLA for the naïve group. Speculation can be made about the myriad differences between the two studies. The age, species, anesthetics, rate of change of CPP, and method of CBF measurement likely have a role in the disparate findings. In addition, the method of calculating the LLA must be considered. Because of inter-subject variability in the degree of vasodilation at reduced CPP, Rosenblum16 has argued that forcing the CBF versus the CPP data to fit a horizontal plateau, as done by Hauerberg and Juhler, may not be the best fit of the physiologic response. Normal autoregulation can be associated with a slightly positive or negative slope and not necessarily with a horizontal plateau.17 Thus, we did not force one of the two regression lines that were used to determine the LLA by their intersection to have a slope of zero. This approach may give different estimates of the LLA when the autoregulatory relationship does not have a perfectly horizontal plateau. Nevertheless, inspection of the pooled data in Figure 1 suggests that forcing one of the regression lines to be horizontal still would have resulted in higher estimates of the LLA in our groups with elevated ICP.
Several limitations of the present study should be considered. First, because these data were obtained in immature piglets, the result may not extrapolate to the adult population. Neonatal baseline ABP and consequent myogenic tone are less than that in mature cerebral arteries, and these differences might influence autoregulation to combined intracranial hypertension and arterial hypotension. Second, measurement of CBF at a single discrete location in cortex can confound calculation of the LLA if regional differences in basal oxidative metabolism affect CBF. Cytochrome oxidase staining, which is a marker of oxidative metabolism, is highly heterogeneous for areas of primary sensorimotor and associative cerebral cortex at this stage of development, but we have found this location to give consistent autoregulation curves in animals with normal ICP.7 Third, we assume that elevated ICP did not decrease oxidative metabolism because laser-Doppler flux was unchanged as the ICP was increased. However, we cannot exclude the fact that the elevated ICP groups had localized reductions in metabolism that could have influenced autoregulation. Finally, laser-Doppler flowmetry uses an algorithm of local red blood cell velocity and red cell volume to calculate red cell flux in small vessels. Bulk arterial blood flow and microcirculatory red cell flux may not change by exactly the same proportion when CPP is reduced. Increases in ICP will increase microcirculatory blood volume10 by compressing downstream veins.18 The increase in microcirculatory blood volume could potentially influence the signals used to derive red cell flux.
The dynamic and nonlinear ICP-LLA relationships that we observed could explain the finding by Cremer et al. of an increase in the LLA of patients with head trauma who had elevated ICP.19 Middle cerebral artery blood flow velocity and the static rate of autoregulation were calculated in 3 sessions each for 13 patients, as CPP was pharmacologically manipulated from a mean of >100 mm Hg to a mean of 50 mm Hg. The authors observed that, when patients had an ICP of <20 mm Hg, the decrease in CPP was tolerated with intact autoregulation, whereas patients with ICP of >20 mm Hg lost autoregulation when CPP was <77 mm Hg. The authors concluded that the LLA was increased by increasing ICP, an inference that is congruent with the result of the study presented here. Inspection of Figure 3 shows that increasing ICP did not affect the LLA until an ICP of 20 mm Hg was exceeded.
The relevance of a dynamic LLA has been stated. Population norms of optimal CPP have not been adequately defined in patients with TBI. The current guideline from the Brain Trauma Foundation suggests a minimum CPP of 60 mm Hg for adults and cites a role for ancillary monitoring to determine individually optimized CPP goals.5 Increasing CPP above 70 mm Hg carries a risk of respiratory compromise, but that risk would have to be compared to a potential benefit from a higher level of CPP if the LLA is elevated.20 Knowing the CPP at the LLA for an individual patient would be helpful in determining a CPP goal, but isolated determinations of the autoregulation curve are inadequate if the LLA is a moving target. Continuous monitoring of autoregulation may be a useful tool both to provide these data for patient populations in research protocols and to clinically determine optimal CPP in patients with elevated ICP.
In summary, the data from this elevated ICP model in piglets show that the LLA is increased when the ICP is increased, especially when the ICP is increased above 20 mm Hg. These findings suggest that CPP-guided therapy by itself is inadequate to assure sufficient cerebral perfusion in patients with elevated ICP. We suggest that continuous autoregulation monitoring may complement ICP monitoring to clarify CPP targets.
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