Cerebral autoregulation (CA) is the mechanism that maintains adequate cerebral blood flow (CBF) based on cerebral metabolism independent of fluctuations in systemic arterial blood pressure (ABP). This process is controlled by three main mechanisms: myogenic, metabolic, and neurogenic [
Some factors linked to hyperaemia have been found to trigger ICH because impaired pressure reactivity in cerebral microvessels is associated with higher capillary permeability, resulting in interstitial swelling [
However, no strong evidence is available in the literature regarding the influence of ICH on CA. The objective of this study was to analyse CA during induced ICH in a nontraumatic experimental model and to determine how ICH treatment affects CA.
The protocol was approved by the “Research Ethical Committee” at Sao Paulo University Medical School. Two-month-old crossbred Landrace and Duroc piglets weighing approximately 18-20 kg were anaesthetized with propofol 5-10 mg/kg/h (1% Provine®), and fentanyl was used for analgesia (Fentanest®, Cristália) at an initial dose of 5
Two 3-mm holes were made 1 cm lateral to the metopic suture: one for a multiparameter cerebral catheter to measure intracranial pressure, temperature, and tissue oxygen (microsensor-type microchip, Neurovent-PTiO®; Raumedic), which was placed in a hole anterior to the coronal suture and inserted 1.5 cm deep into the frontal lobe, and the other for a paediatric 8-French bladder catheter, which was placed in a hole 1 cm posterior to the coronal suture and inserted 2 cm deep into the parietal lobe. A third small hole was made in the middle anterior fossa to be used as a window for the duplex ultrasound probe (transducer 4-8 Mhz, MicroMaxx® model, SonoSite®, Bothel, WA) [
(a) Ultrasound transducer under the lateral hole, a multiparametric catheter in the anterior hole, and a bladder catheter in the posterior hole. (b and c) B-mode ultrasound duplex demonstrating the inflated balloon. Doppler mode was used to obtain CBFV before (d) and after balloon inflation (e).
In this nontraumatic model, after each animal was prepared, the paediatric catheter balloon was progressively inflated with 0.9% saline solution over 15 min using continuous pump infusion until 4 ml or 7 ml was infused to trigger either mild ICH or severe ICH, respectively. The 4-ml volume corresponds to an expansive lesion of 72.7 ml in human adults, and the 7-ml volume corresponds to a lesion of 127.3 ml [
The cerebral static autoregulation (sCA) index was evaluated using CBF velocities (CBFV) obtained using ultrasound Doppler (MicroMaxx® model, SonoSite®, Bothell, WA, USA). The ultrasound operator was blinded to the ICP and balloon volume. The sCA index was tested before and after each of the following experimental steps: ICH induction, 3% saline infusion, and balloon deflation. The MABP was elevated (20 mmHg) by phenylephrine, and the upper limit of the MABP was 120 mmHg. The initial and final MABPs and CBFVs were recorded to calculate cerebral vascular resistance (CVR) as follows: CVR=MABP/CBFV. The static rate of regulation (sROR) or sCA index was calculated as follows: sROR=100(%ΔCVR/%ΔMABP), where ΔCVR is the change in CVR and ΔMABP is the change in MABP [
A two-way repeated-measures ANOVA was performed to analyse differences in the effects of the intervention (intracranial hypertension, saline solution, and surgery) on selected variables (ICP, CBFV, MABP, sCA, and EtCO2) between the two groups (mild and severe ICH). All the statistical analyses were performed using SPSS (version 12.0; SPSS Inc., Chicago, IL). Significance was set a priori at p<0.05. When significant interactions were identified, we applied Scheffé post hoc tests. Pearson’s correlation coefficient analysis was performed for continuous variables.
A total of 28 piglets were studied. Of these, all the data were collected for the 16 piglets that completed the protocol, while 12 piglets were excluded because they experienced circulatory arrest after the balloon was inflated. The demographic and clinical characteristics of the piglets are summarized in Table
Demographic and clinical characteristics of the piglets (SD); ICH (intracranial hypertension), ETCO2 (end tidal CO2), CBFv (cerebral blood flow velocity), MABP (mean arterial blood pressure), and ICP (intracranial pressure).
| | |
---|---|---|
gender [%] | F 3 [37.8] | F 5 [62.5] |
weight kg | 19.12 (0.7) | 19.31 (1.0) |
ETCO2 mmHg | 41 (5.8) | 41.62 (4.4) |
CBFv cm/s.1 | 44.8 (22.8) | 25.0 (7.5) |
MABP mmHg | 77 (12.5) | 91.6 (7.6) |
ICP pre insufflation | 4.88 (4.6) | 8.87 (3.4) |
In response to changes in ICP, ANOVA revealed significant interactions between the groups and between interventions (p=0.01 and p=0.002, respectively). In both groups, balloon inflation resulted in a higher ICP than that recorded at baseline. Moreover, the ICP gradually decreased during the interventions. ICP variations were significant only in the severe ICH group (p=0.007 between baseline and balloon inflation, p=0.04 between baseline and saline solution infusion, and p=0.02 between saline solution infusion and surgery). In the severe ICH group, no significant difference was observed between balloon inflation and saline solution infusion ICP (p=0.87) or between baseline and surgery ICP (p=0.88). ICP was higher in the severe ICH group after balloon inflation and during saline solution injection (p=0.01 for both) (Figure
Main findings in the different steps of the experiment (SD);
| | |||||||
---|---|---|---|---|---|---|---|---|
| | | | | | | | |
| 78.32 (33.88) | 66.73 (96.23) | 35.85 (46.59) | 12.60 (30.96) | 74.75 (39.96) | 10.56 (15.05) | 57 (49.53) | 41.21 (48.36) |
| 4.88 (4.6) | 12.02 (6.64) | 9.88 (6.32) | 2.7 (2.53) | 8.87 (3.45) | 48.26 (19.05) | 41.23 (26.73) | 9.78 (5.67) |
| 44.80 (22.8) | 41.03 (20) | 53.83 (27.14) | 48.98 (27.36) | 25.06 (7.55) | 23.21 (7.71) | 36.16 (21.52) | 29.18 (11.01) |
| 28 (20) | 9 (34)Ω | 16 (35) | -5 (21) | 18 (10)# | -12 (21) | 20 (36) | 10 (42) |
| 77.71 (12.54) | 78 (17.26) | 80.14 (13.78) | 76.71 (10.06) | 91.62 (7.68) | 88.5 (12.48) | 89.12 (18.37) | 81.37 (18.81) |
ICP before and after ICH induction and treatment in the mild and severe ICH groups (
ANOVA showed that sCA was significantly different between the interventions (p=0.001). Although an increase in ICP led to impaired sCA in both groups, the difference reached statistical significance only in the severe ICH group (p=0.001). In the severe ICH group, an increase in the sCA index was observed after saline was injected (p=0.02) and after surgery (p=0.04) (Figure
sCA and MABP before and after ICH induction and treatment in the mild and severe ICH groups (#p=0.03 for differences between the groups and
CBFV was higher in the mild ICH group than that in the severe ICH group (p<0.002). In the severe ICH group, CBFV was higher after saline infusion than that at baseline or after balloon inflation (p=0.04). Additionally, in the severe ICH group, a nonsignificant tendency towards a higher ABP was observed (Figure
CBFV and CVRi in the mild and severe ICH groups during the experiment; CBFV (
Statistically significant differences were observed in both groups for CVR after balloon inflation (p=0.04 in the mild ICH group and p<0.02 in the severe ICH group) (Figure
Pearson’s analysis disclosed an inverse correlation between ICP and the sCA index, showing that a higher ICP was associated with impaired CA (
Pearson’s correlation analysis of ICP and sCA and of CPP and sCA; ICP (intracranial pressure), CPP (cerebral perfusion pressure), and sCA (static cerebral autoregulation).
Concerning systemic pH and ETCO2 levels, significant differences were observed between the results at the beginning of the experiment and those obtained at the moment that the balloon was deflated (7.4 and 7.3, respectively (p=0.005), and 37.5 and 38.3 mmHg, respectively (p=0.037)).
The results of the present study clearly indicate CA impairment during ICH and low CPP (Figures
Some experimental studies have demonstrated that CVR during severe ICH was reduced, possibly to compensate for a decrease in CPP [
Determining the CBFV of larger intracranial arteries by Doppler was a useful method for estimating CBF in the animals in this study. CBFV was significantly decreased during severe ICH despite increased systemic blood pressure and a subsequent CVR reduction to compensate for the decrease in CPP (Figures
During ICH treatment, osmotic agents can improve regional CBF, increase CPP, and decrease ICP [
After the balloon was deflated, an abrupt reduction in ICP was observed (Figure
The main limitation of our research was the instability of the subjects. Systemic acidosis and higher ETCO2 levels after balloon deflation were observed and likely affected the sCA index in both the mild ICH and severe ICH groups. This result was particularly true in the mild ICH group in which CA was completely impaired by the end of the experiment and after infusion of saline solution. The study was performed in immature animals, and the results could potentially be different in adult subjects. Other limitations prevented us from performing a dynamic CA technique, and despite the strength of the correlation between the static and dynamic CA, dynamic data would add important information to our findings.
The results of the present study indicate that ICH triggers CA impairment, and saline solution and surgery used to relieve high ICP can improve CA in association with ICP reduction.
The data used to support the findings of this study are available from the corresponding author upon request.
The authors have no conflicts of interest to declare.