September 20, 2021

An article review from the ESICM Journal Review Club

Data from the CENTER-TBI study, regarding the management of PaCO2 in the first week after severe TBI


It is well known that changes in the arterial partial pressure of carbon dioxide (PaCO2) modulate cerebral blood flow (CBF) and cerebral blood volume (CBV) through changes in cerebrovascular tone. Hypercapnia causes cerebral vasodilation, with an increase in intracranial volume, which could raise intracranial pressure (ICP) in patients with poor intracranial compliance.

Hypocapnia, induced by hyperventilation (HV), causes vasoconstriction with reduction of CBV and ICP. However, hypocapnia can also reduce CBF – a risk factor for secondary ischaemic insults, leading to unfavourable long term outcomes. Although some concerns still exist, PaCO2 reduction is still widely used in the clinical setting for ICP control. The most common PaCO2 target declared by clinicians in the absence of intracranial hypertension (35–40 mmHg) is higher than in the case of raised ICP (30–35 mmHg).

The most recent evidence-based guidelines on traumatic brain injury (TBI) management do not provide definitive recommendations regarding target PaCO2 levels due to the low quality of evidence, and clinical practice remains highly variable. Therefore, the research group of the CENTER-TBI (The Collaborative European NeuroTrauma Effectiveness in Research in Traumatic Brain Injury) study collected data on the PaCO2 management in a large cohort of mechanically ventilated TBI patients and evaluated the association between the use of profound HV and long term clinical outcomes.

The objectives of the study were:

  1. to describe the PaCO2 values in the first week from ICU admission in mechanically ventilated TBI patients, and to evaluate practice variability across centres, particularly focusing on the lowest targets of PaCO2;
  2. to assess at a centre level the PaCO2 management in patients with/without ICP monitoring (ICPm) and with/without intracranial hypertension;
  3. To evaluate the association between patient outcomes and centre propensity to use profound HV.

HV was defined as moderate for PaCO2 between 30 and 35 mmHg and profound for PaCO2 < 30 mmHg. Intracranial hypertension was defined as ICP > 20 mmHg.

Mortality and functional outcome (measured as the Extended Glasgow Outcome Score, GOSE) were assessed at 6 months. An unfavourable outcome was defined as GOSE ≤ 4, which includes both poor functional outcomes and mortality.

Of the 4509 patients included in the CENTER-TBI dataset, 1100 were included in this analysis.

In the overall population, the mean PaCO2 at ICU admission was 39.1 (±6) mmHg, and the no-ICPm group had higher PaCO2 mean values compared to the ICPm patients (39.9 ± 6.8 vs 38.7 ± 5.6 mmHg, p < 0.002).

The overall mean lowest PaCO2 was 35.2 ± 5.4 mmHg with substantial heterogeneity between centres, whose means ranged from 32.3 (± 3.7) to 38.7 mmHg (±5.9). Mean minimum PaCO2 values were significantly lower in ICPm patients compared to no-ICPm (34.7 ± 4.9 mmHg vs 36.8 ± 5.7 mmHg, p < 0.001). In the subgroup of patients with ICP monitoring, the management strategies of different centres in response to episodes of intracranial hypertension was also investigated. Significant inter-centre differences were observed in the mean lowest PaCO2, both in the absence and presence of intracranial hypertension. The mean minimum PaCO2 was significantly lower in 398 patients with at least one episode of intracranial hypertension compared to the 240 who did not experience increased ICP (34.1 vs 35.6 mmHg, p < 0.001).

Of the 1100 patient cohort, 165 died before ICU discharge (15%). Of the 970 patients for whom 6-month outcomes were available, 246 (25.4%) died, and 529 (54.5%) experienced unfavourable functional outcomes. The 6 months mortality rate was 29% in patients who had at least one episode of profound HV and 23% in those who did not (p-value = 0.045), while the rates of unfavourable GOSE were 64% vs 49% in the two groups, respectively (p-value < 0.001). After adjusting for the dose of intracranial hypertension, no significant increase in mortality or unfavourable outcome was observed when profound HV was applied.

The results of this study suggest that moderate HV is widely used in severely brain-injured patients, especially when ICP is monitored and in case of elevated ICP.



• This study is representative of the current practices regarding PaCO2 management in TBI across Europe (1100 patients from 31 centres were included);
• It describes the discrepancies between recommendations regarding ventilation strategies in cases of TBI with or without raised ICP and real-life management of these patients.
• The analysis includes data on daily PaCO2, thus providing a longitudinal view of PaCO2 management over time.


• This is an analysis of data from a large study, which primarily addressed the epidemiology, clinical care and outcome of TBI. Therefore, more specific data on the ventilatory management of these patients are missing.
• 6 months GOSE and mortality are influenced by several other factors, such as systemic and ICU complications and post-ICU events. Therefore, it is speculative to draw a direct relationship between PaCO2 and outcome;
• The outcome was evaluated at 6 months, which can be considered as an early measurement of outcome after TBI.
• The temperature management of the patients, which can significantly affect PaCO2 values, was not taken into consideration.
• Only the daily lowest and highest PaCO2 values were collected in the available dataset, thus missing possible changes in PaCO2 and pulmonary function parameters that may occur suddenly and repeatedly during the day.


• Manipulation of PaCO2 is an easy method for temporary ICP control, although some consensus exists regarding HV-induced secondary ischaemic insults;
• There is substantial practice variation among countries and centres regarding PaCO2 levels adopted in TBI patients, with a large proportion of them being managed at PaCO2 levels below those suggested by expert consensus statements;
• No association between the risk of mortality or unfavourable functional outcome and more frequent use of profound hyperventilation was observed in this study;
• The available evidence still makes a case for caution in the use of HV, with careful consideration of risks and benefits on a case-by-case basis;
• We need randomised controlled trials and high-level evidence guidelines to support rational choices regarding optimal ventilation management and PaCO2 targets in patients with TBI.


This article review was prepared and submitted by Viktoria Ilieva, MD, PhD, Anesthesiologist and Intensive Care Physician at University Hospital “St. Ivan Rilski”, Sofia (Bulgaria), on behalf of ESICM Journal Review Club.


Citerio, G. et al. “Management of arterial partial pressure of carbon dioxide in the first week after traumatic brain injury: results from the CENTER-TBI study“. Intensive Care Med (2021), 47:961–973.

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