Secondary cerebral ischemia at traumatic brain injury is more closely related to cerebrovascular reactivity impairment than to intracranial hypertension

Summary.

The aim was to investigate the relationship between the development of secondary cerebral ischemia (SCI), intracranial pressure (ICP) and cerebrovascular reactivity (CVR) after traumatic brain injury (TBI).

Methods:

89 patients with severe TBI with ICP monitoring were studied retrospectively. The mean age was 36.3±4.8 years, 53 men, 36 women. The median GCS was 6.2±0.7. The median Injury Severity Score was 38.2±12.5. To specify the degree of impact of changes in ICP and CVR on the SCI progression in TBI patients, logistic regression was performed. Significant p-values were <0.05.

Results:

The deterioration of CVR in combination with the severity of ICP has a significant impact on the increase in the prevalence rate of SCI. The logistic regression analysis for a model of the SCI dependence on intracranial hypertension and the CVR was performed. The results of the analysis showed that the CVR was the most significant factor affecting the secondary cerebral ischemia development in TBI.

Conclusions.

The development of SCI in severe TBI is more dependent on the CVR impairment and to a lesser extent on the ICP level. The treatment for severe TBI patients with SCI progression should not be aimed only at intracranial hypertension correction but also at the CVR recovery.

Introduction

Increased intracranial pressure (ICP) is one of the main causes of the morbidity and mortality in a broad spectrum of pathologies, such as traumatic brain injury (TBI), non-traumatic intracerebral hemorrhage, hydrocephalus, brain tumors, etc. [1]. Current guidelines recommend maintaining intracranial pressure below 21 mmHg [2,3]. The oligemia is linked to hypoxic edema and cytotoxic cellular engorgement. The hyperemia is associated with high cerebral blood flow (CBF) and, when associated with vascular barrier impairment, may trigger interstitial edema. The development of intracranial hypertension may be linked to an excess or a lack of cerebral blood flow (CBF) and the formation of the ischemia or hyperemia. These conditions should be recognized to provide suitable treatment for ICP control [4].

Cerebral autoregulation (CA) is the mechanism responsible for maintaining a relatively constant CBF over a wide range of blood pressure which protects the brain from oligemia or hyperemia. [5]

Under certain conditions, the range of CA is severely compromised, increasing the risk of cerebral edema [6,7].

Many authors have tried to determine the relationship between CA and ICP in the development of poor outcomes, but the significance of the cerebral ischemia formation still poorly understood. [8,9,10,11].

It should be noted that compromised CA has been also shown in patients with normal ICP. It is believed that impaired CA and increased ICP can persist simultaneously and result from a breakthrough of the blood-brain barrier, disturbances of the vasomotion and subsequent brain swelling [12]. Thus, impaired CA may be a factor that triggers increases in ICP and vice versa. However, no consensus has been reached on the relationship between damaged CA and ICP in the development of secondary cerebral ischemia (SCI)

The aim of our study was the investigation of the relationship between intracranial hypertension and cerebrovascular reactivity (as quantified by PRx –pressure reactivity index) in the development of secondary cerebral ischemia after traumatic brain injury (TBI).

Material and Methods

This non-randomized single-center retrospective study complies with the Declaration of Helsinki, the protocol was approved by the local Ethics Committee. All the patients gave informed consent to participate in the study.

We included patients who had the following: severe TBI within 6h after a head injury with a GCS less 8; SCI at follow-up perfusion computed tomography (PCT), monitoring of ICP and mean arterial pressure (MAP) for at least 24 h; admission GCS, ISS data available.

Exclusion criteria were as follows: 1) younger than 16 years; 2) Glasgow Coma Score less than 4 and 3) Injury Severity Score more than 60.

The neuromonitoring of cerebral modalities was conducted as a part of standard patient care and archived in a database of neurophysiological monitoring. ICP more than 15 mm Hg was treated using head elevation (15⁰-25⁰), sedation, external ventricular drainage and mannitol. ICP was monitored continuously. Intraparenchymal (Codman MicroSensors ICP, Codman & Shurtleff, Raynham, MA, USA) or intraventricular probes (LiquoGuard, Möller Medical GmbH & Co. K) were inserted at the bedside in the ICU or in the operation room into the frontal or parietal lobe. The intraparenchymal probes were placed in white matter on the side of maximal lesions.

Physiological parameters were recorded continuously using a bedside monitor. In addition, these physiological variables, ICP and cerebral compliance were recorded every 5 seconds on the ICU flowsheet. Dynamic PRx was estimated from the measured parameters as the moving Pearson correlation of 30 consecutive MAP and ICP, updated every minute.

Each patient was managed according to a published TBI guideline. Ventilator management was tailored to maintain PaO₂ at more than 100 mm Hg and PaCO₂ between 30 and 35 mm Hg. Albumin and crystalloid boluses and norepinephrine were used to keep systolic blood pressure at more than 100 mm Hg and central venous pressure at approximately 80 mm H₂O.

Computed Tomography

All patients were subjected to dynamic perfusion computed tomography by tomograph Philips Ingenuity CT (Philips Medical Systems, Cleveland, USA). PCT was performed 1–2 days after TBI. We acquired non-contrast CT and post-contrast series in axial mode from the skull base to the vertex (16 cm z-axis coverage) using the following imaging parameters: 120 kV peak tube voltage, 320 mA tube current, slice thickness 5 mm, 32 cm scan field of view, 256 × 256 matrix. We acquired CTP images at the level of the basal ganglia and the third ventricle above the orbits. PCT data were transferred to a workstation Philips Core (Philips Medical Systems, Cleveland, USA) and analyzed by a standardized method to create perfusion maps of mean transit time (MTT), cerebral blood flow (CBF), and cerebral blood volume (CBV). We used deconvolution software. SCI core and penumbra were established using the appropriate MTT and CBV thresholds, which are MTT > 145% of the contralateral side values and CBV > 2.0 mL/100 g for the penumbra volume and MTT > 145% of the contralateral side values and CBV < 2.0 mL/ 100 g for the SCI core volume [13].

Statistical Analysis

Data are expressed as the mean ± standard deviation. To specify the degree of impact of changes in ICP and CVR on the SCI progression in TBI patients logistic regression was performed. Significant p-values were <0.05. All analyses were performed using the software package Statistica 7.0 (Statsoft, Inc., USA).

Results

Totally, eighty-nine patients with severe TBI admitted to the Nizhniy Novgorod Regional Hospital with ICP monitoring were studied. The mean age was 36.3±4.8 years (range 19–45 years). There were 77 men, 12 women. The mean age was 36.3±4.8 years, 53 men, 36 women. The median GCS was 6.2±0.7. The median ISS score at admission was 38.2±12.5.

During the described period, the mean CPP was 81.5 ± 12.5 mmHg. The mean ICP was 19.98 ± 5.3 mm Hg (min 11.7; max 51.7). The mean dynamic PRx was 0.23 ± 0.14.

The deterioration of CVR in combination with the severity of ICP has a significant impact on the increase in the prevalence rate of SCI. The post hoc comparison of the prevalence rate of SCI to different degrees of ICP and changes in CVR revealed significant differences. Thus, the increasing prevalence of SCI occurs because of both intracranial hypertension and the impairment of CVR. The logistic regression analysis for a model of the SCI dependence on intracranial hypertension and the CVR was performed. The results are shown in Table 1 and Figure 1.

Table 1.

The logistic regression model for predicting SCI in 89 patients with severe TBI

	Const B0	iPRx	ICP
Estimate	−6,390327	14,23774	0,07451441
Standart Error	2,021378	4,434144	0,06425401
t	−3,161371	3,210933	1,159685
p-level	0,00235866	0,00203311	0,2502931
−95%CL	−10,42501	5,387152	−0,053737
+95%CL	−2,355639	23,08833	0,202765
Wald χ2	9,994267	10,31009	1,34486
p-level	0,00157174	0,00132435	0,246185
odds ratio (unit ch)	0,001677	1525358	1,07736
−95%CL	0,00002968	21,858	0,947681
+95%CL	0,0948329	1,064469	1,224786
odds ratio (range)		126,5745	5,15165
−95%CL		6,244066	0,306598
+95%CL		256,5813	86,56113

Figure 1.

Results of logistic regression analysis: probability surface of SCI development

The results of logistic regression analysis showed that the CVR was the most significant factor affecting the secondary cerebral ischemia development in TBI. In particular, the probability of SCI development exceeded 50% even with the ICP level of 5 mm Hg at impaired CVR. Moreover, at the upper normal values of ICP (21 mmHg) and CVR (iPRx 0.3), the probability of the development of SCI in TBI reached 75%.

Discussion

Despite numerous research, the role of autoregulation and, intracranial hypertension in the development of cerebral ischemia at TBI remains unclear.

S. Klein and B. Depreitere found a correlation between impaired autoregulation and episodes of elevated ICP; the correlation was not ideal, suggesting that autoregulation was not impaired in all episodes of elevated ICP [14]. However, in regression analysis, they have shown that autoregulation disorders equally correlated only with outcomes but not SCI development.

At the normal state of CA and increased ICP, a tendency toward decreased CBF was described only in one study [11]. Meanwhile, the reverse situation is described in a large number of works [15, 16, 17, 18, 19].

It is assumed that one of the reasons for the development of SCI at the impairment of CA may be the uncoupling of cerebral metabolism and cerebral microcirculation [20].

It has been shown that cerebral metabolic crises can play a key role in CA damage and SCI development, causing cerebral hyperemia leading to the development of interstitial edema and intracranial hypertension [17]. According to studies, a persistent metabolic crisis is associated with a high lactate/pyruvate ratio, with high glutamate and low glucose levels, which was accompanied by a disruption of CA and intracranial hypertension, sometimes even despite decompressive craniectomy [21].

According to Ho et al. in all patients with signs of cerebral metabolic crisis and poor prognosis, PtbO₂ levels remained normal, which excluded hypoxia as the cause of malignant intracranial hypertension and increased the mitochondrial dysfunction. [22].

Metabolic crisis and inflammation in brain injury are also associated with a violation of CA, regardless of the level of ICP, which confirms our data [4]. On the other hand, a decrease in cerebrovascular reactivity associated with a continuing metabolic crisis may be a factor causing intracranial hypertension. However, some authors argue that intracranial hypertension itself is an independent cause of the impairment of CA [23]. Further studies are needed to clarify the proposed mechanisms of the development of SCI. The small size of studied patients was a limitation of our work.

Conclusions

The development of SCI in severe TBI is more dependent on the CVR impairment and to a lesser extent on the ICP level. The treatment for severe TBI patients with SCI progression should not be aimed only at intracranial hypertension correction but also at the CVR recovery. The finding of this study should be validated in larger cohorts.