Critical ICP thresholds in relation to outcome: Is 22 mmHg really the answer?

Monitoring the intracranial pressure (ICP) of unconscious patients after traumatic brain injury (TBI) to detect secondary injury and evaluate treatment is standard practice in neurointensive care [2, 12, 30, 40]. An elevated ICP, if untreated, is thought to worsen motor and cognitive deficits and may be associated with increased mortality [2, 14, 40]. Consequently, intensive care management among other things aims at avoiding exposure to high ICP [12, 22, 47]. Normal ICP values are usually below 16 mmHg [3, 29, 31], although higher values can occur without consequences in the brain of a fully awake and orientated patient [8]. Given the frequent use of ICP monitoring in neurointensive care and its known association with outcome, ICP has become an independent treatment parameter and therapeutic targets have developed organically, despite the absence of randomised trials [12, 21, 27].

Until 2016, the internationally recognised treatment strategy for patients admitted to a neurointensive care unit (neuro-ICU) was to aim for an ICP below 20 mmHg [6, 44]. However, in 2012 Sorrentino et al. reported that an ICP limit of 22 mmHg provided a more optimal distinction between survival vs. death as well as between favourable vs. unfavourable outcomes at 6 months after traumatic brain injury (TBI). This suggestion was based on a convenience cohort of 459 patients with traumatic brain injury undergoing continuous ICP measurement for at least 6 h. Repeated chi-square testing across different ICP thresholds (integers) was done against the resulting outcome distributions for ICP values above and below these limits. Finally, a limit of 22 mmHg was found to produce the highest chi-square value, which was interpreted as providing the best discrimination between outcomes. Subsequently, management recommendations published by the International Brain Trauma Foundation regarding intracranial pressure were modified and a new target of “ICP below 22 mmHg” was adopted in guidelines [6]. Thus, the third edition of the International Brain Trauma Foundation guidelines stated that “treatment should be initiated with ICP levels above 20 mmHg”[44] while the updated fourth edition stated that “treating ICP above 22 mmHg is recommended because values above this level are associated with increased mortality” [6].

The updated guidelines were criticised for several reasons [26, 30, 33]. First, the calculations by Sorrentino et al. used mean ICP values for the entire monitoring period rather than fluctuations or spikes, which may not be the most important ICP-derived variable for establishing a relationship to outcome [19, 39]. Second, a defined threshold might lead clinicians to focus solely on ICP measurements instead of the global clinical context [33]. Both arguments suggest that clinical management must consider a more complex reality than single ICP values, while reproducibility and traceability of the suggested threshold have never been addressed. The findings by Sorrentino et al. reflect a cohort of patients with severe TBI from their catchment area, who were managed with a 20 mmHg ICP threshold. It is increasingly recognised that single observational datasets may be impossible to reproduce [18]; hence, such findings should be externally validated in independent populations before they are used for guidelines [13, 32, 36]. Finally, the report from Sorrentino et al. was based on an observational study; the relationship between a higher ICP and a worse outcome could in theory be due to bias by indication, meaning that it was harder to reduce an increased ICP in patients with more serious injuries and a more serious diagnosis. Thus, a strong relationship between ICP higher than a given threshold and a poor outcome would not necessarily imply that reducing the ICP below the threshold would improve outcome.

In the present study, we replicated the approach by Sorrentino et al. [38] in order to validate their findings with regard to threshold ICP values and risk factors for mortality and functional outcome. For this purpose, we included a cohort of patients from Eastern Denmark who were admitted to the neuro-ICU with TBI. As the primary outcome, we studied ICP thresholds as uniform discriminators between favourable and unfavourable outcomes for the full population and across subgroups, as suggested by Sorrentino et al.

Of the 331 included patients, 88 (27%) were females and 243 (73%) were males. Median age was 57 [IQR: 37–69] and the median duration of ICP monitoring was 121.75 h [IQR 36.875–273, which corresponds to a median number of individual data points of 487 [IQR: 147.5–1092]. Six months after admission, 94 (28%) had died (GOSE 1), 216 (65%) had an unfavourable outcome (GOSE 1–5), and 115 (35%) had a favourable outcome (GOSE 6–8).

The results for the calculated thresholds with their respective chi-square value, p-value, sensitivity, and specificity are seen in Table 1. Figure 2 depicts all calculated chi-square values for ICP values vs. mortality and outcome, respectively, for the entire patient cohort. An ICP of 18 mmHg yielded the highest chi-square value for mortality and outcome for the entire cohort. Figure 3 shows the mean ICP with 95% confidence intervals for favourable and unfavourable outcomes (including death) at 6 months.

The ICP thresholds for survival and functional outcome in subgroups varied between 16 and 22 for the older, female, male, and low GCS, and between 19 and 30 for the young and high GCS (Table 1). No threshold achieved statistical significance for functional outcome in the subgroups for older, female, and high GCS. Generally, chi-square values were three to six times as high for survival compared to functional outcome. Furthermore, the sensitivity and specificity calculations showed a low sensitivity for all the results (10–45%), while the specificity was very high (99–100%).

The secondary sensitivity analysis with a monitoring period of minimum 75 min included 15 extra patients of which seven were dead at 6 months, three were alive with an unfavourable outcome, and six had a favourable outcome. It yielded a global threshold of 27 mmHg and show the ICP thresholds for survival and functional outcome in subgroups varied between 27 and 30 mmHg for the young, male, and high GCS, and between 15 and 18 mmHg for the older, female, and low GCS (Supplemental materials).

Tables 2 and 3 show the results of the multivariable logistic regression analysis. Age, GCS, and mean ICP were significant predictors for both mortality and outcome, while sex was not significantly related to either mortality or outcome.

In 2012, Sorrentino et al. reported that an ICP value of 22 mmHg represented a threshold regarding survival and functional outcome in a convenience cohort of 459 patients with severe TBI [38]. Although Sorrentino et al. interpreted their study to support the current guidelines at the time of publishing, and although the value was derived from an observational single-centre study, the report was cited as part of the basis for a subsequent level II B recommendation from the International Brain Trauma Foundation to treat ICP values above 22 mmHg [6]. The present study aimed to replicate this study but obtained a threshold of 18 mmHg. Our subgroup analyses suggested lower thresholds in the patients who were older, female, or had a low admission GCS, and higher values for young patients and males. In contrast to the original study, we found limited to no indication of a biological plausibility of an “optimal discriminator,” as there was virtually no progression in chi-square values around the “maximum value.” The incidental peaks of 18, 21, and 22 mmHg also appeared to be somewhat arbitrary (Fig. 2).

The findings regarding sensitivity and specificity are not in themselves problematic. Our analysis implied a low sensitivity for survival (29%), whereas specificity for survival was high (99%). Given the high specificity (meaning that few patients survived with a mean ICP above 18 mmHg), and in the absence of high-quality randomised trials, it would be intuitively attractive to set the threshold at this value. However, we strongly oppose the notion that the present data could be used to dictate a threshold above which ICP values should be viewed as invariably dangerous and should be treated at all costs. Firstly, this was an observational study, which were not based on randomised data. Thus, outcome differences could be driven by other factors than the differences in ICP. Secondly, even if the findings were assumed to represent a true causal relationship between ICP and outcome, other ICP metrics than the mean ICP would probably also be important for ensuring a good outcome. Thirdly, other aspects of supportive treatment such as targeted brain oxygen management and surgical procedures may change the relationship between ICP and outcome.

We performed a secondary sensitivity analysis with a monitoring period of minimum 75 min, which further emphasises how easily the threshold can be influenced. The new limit meant that 15 more people were added to the dataset. This changed the global threshold from 18 to 27 mmHg. Of the 15 patients who were eliminated by the 6-h minimum, seven (46%) were dead at the 6-month follow-up. They probably represented some of the most severe cases, who were potentially unresponsive to treatment or those who may have succumbed despite treatment.

In the validation approach, we elected to focus on ICP thresholds and not on CPP or pressure reactivity index (PRx) which were both analysed in the original study, because ICP remains the most frequently used invasive measure of intracranial homeostasis, with widely adopted targets and limits for treatment [2, 41, 48]. As in the original study, a retrospective cohort was included. However, our patient population was admitted from 2016 to 2022 (contrary to the original report, which studied patients admitted between 1992 and 2009); the lower age limit for inclusion was 18 years (contrary to the original age limit of 14 years). Furthermore, our approach differed with respect to the intervals for which ICP was averaged (15 min vs. 1 min in the original study). We used the extended 8-point version, GOSE, rather than the 5-point Glasgow Outcome Scale (GOS) for assessing functional outcome, as GOSE is recommended for research purposes for monitoring outcome after TBI [23, 25, 49]. It was developed from the GOS and translates to the original [50], which makes our dichotomised outcome comparable to the original study. Finally, the clinical management of our cohort differed from the original cohort with respect to the target range for PaCO₂ (4.5–5.5 vs. 4–4.5 in the original study) and the target SpO₂ (92% vs. 93%). As a result, our sample size was somewhat lower than the original sample size (331 vs. 459 patients); however, the number of patients older than 55 years was larger in our study (175 vs. 77), meaning that the lower sample size likely did not contribute to the fact that we could not identify statistically significant thresholds for the subgroups of older, females, and high GCS, or that the entire cohort retained the threshold of 18 mmHg that was identified in the female and low GCS. The overall heterogeneity of subgroup sizes mimics the subgroup sizes found in the Sorrentino study with fewer females than males and fewer patients with high compared to low initial GCS, except for a more equal distribution of age. Importantly, the cohort studied by Sorrentino et al. included patients before and after the 2007 recommendation by the Brain Trauma Foundation [5]. Thus, the authors describe that patients were managed slightly different over time, with a more CPP-centred algorithm before 2009 and a more ICP-centred approach after 2009. The implication of this is that the relationship between ICP and clinical outcome may also have shifted over time. By the same token, from 2018 some of the patients included in our study were managed according to both ICP and brain tissue oxygen tension.

The use of mean ICP to calculate the thresholds received criticism [26, 30] as severe TBI tends to be associated with long durations of ICU and hospital stay [45, 51] and, by inference, durations of ICP monitoring. As ICP can vary substantially over time, the subsequent monitoring period might encompass a period with ICP values in the normal area and as a result, the mean ICP alone might reflect a tail of normalised ICP values. An additional point of controversy is how “elevated ICP” and “mean ICP” should be understood. Sorrentino et al. justified their use of mean ICP in their limitations, and referenced a study from their own group, that showed an association between protracted elevated ICP and outcome [7]. That study defined a protracted episode as 30–40 min with an ICP above 40 mmHg, and the authors argued that ICP elevations of shorter duration would not affect mean ICP and thereby fail to affect outcomes in the 2012 study. We cannot judge from available data whether the argument reflects empirical data or an element of circularity. In contrast to Sorrentino et al., Bennis et al. analysed ICP spikes over 30 mmHg for only 3 min which they considered signs of disturbed autoregulation that worsened outcome [4]. Currently, empirical justification for either view appears insufficient. These examples show the need for more empirical data on the association between outcome and an increased ICP over time, and it would seem reasonable to suggest looking into threshold values based on fluctuations of ICP, time of exposure to high ICP, and treatment interventions for ICP [16, 23].

The fact that it was not possible to reproduce the threshold found by Sorrentino et al. questions whether a definitive threshold or a “one-size-fits-all” approach to ICP management is feasible [23, 26, 41]. Besides the obvious problems of basing a threshold on an observational single-centre study, we suggest that the identification of an “optimal ICP threshold” [17] for clinical purposes by identifying the point of greatest discrimination between outcomes is fundamentally flawed. Single-target values or ranges for ICP may not reflect what is physiologically desirable at definite times after injury [6] and the value of “optimal” is not easily translated to patient benefit or absolute chance of survival [4, 11, 42]. The idea of a fixed ICP threshold, above which all patients should at all times and in the context of all possible treatments, undergo ICP-reducing therapy during their admission, ignores the heterogeneity of clinical presentations and mechanisms of TBIs, and coping mechanisms of the patients [10, 23, 41], and it is at best overly simple and at worst dangerous to patients. The risk of unintended severe ICP elevations with small changes in intracranial volume depends on the location on the intracranial volume-pressure curve. An ICP of 22 mmHg may in some patients be located on the steep part of the curve, where even small fluctuations in intracranial volume may lead to deleterious increases in ICP; this may render the clinical management of such a threshold unfeasible, if not impossible. It is also not obvious that a treatment target should aim at the steepest discriminating ICP rather than to a lower ICP, which may be even more beneficial after TBI. The threshold ICP at any given time should be considered in the context of the specific ICP-reducing therapy and its risk profile. Thus, ICP-reducing therapies that are associated with little or no risk of harm, such as elevating the head of the bed or keeping the head in a neutral position, are often administered to “all” patients, even those in whom ICP is low [1, 43, 46]. In contrast, if all non-invasive ICP-reducing therapies have been applied, and only decompressive craniectomy is left, the risk of harm associated with craniectomy means that the risk–benefit balance shifts toward a higher ICP [37]. Accordingly, the optimal ICP threshold depends on what treatment has been administered and which treatment is presently considered for that individual patient.

We could not reproduce the ICP threshold of 22 mmHg proposed by Sorrentino et al. Using a similar approach, we found ICP threshold values of 18 mmHg for survival and outcome for the entire cohort, as well as the female subgroup and the subgroup of patients with a low initial GCS ≤ 8. For the remaining subgroups, the ICP threshold for both mortality and favourable outcome was 16–30 mmHg. Age, initial GCS, and mean ICP, but not sex, were independent risk factors for functional outcome and survival.

The development of ICP thresholds as treatment indicators for mortality and outcome and creation of guidelines are interesting research fields, but as illustrated in this study contain many pitfalls, which require further examination with various analytical methods. In the light of our results, it does not seem reasonable to recommend ICP thresholds based on the present application of statistical analyses, and it would seem imprudent not to question the relevance of the change of an ICP threshold from 20 to 22 mmHg in the 2016 International Brain Trauma Foundation guidelines and the consequences it may have on the treatment and research of TBI patients. Moreover, our analyses reflect an underlying heterogeneity of the populations that casts a shadow of doubt on the project of defining treatment thresholds that should apply across large populations of intensive care patients.