A cerebral perfusion pressure (CPP) ≤ 60 mmHg correlated with favorable outcome in adult severe traumatic brain injury patients - a retrospective study

A cerebral perfusion pressure (CPP) ≤ 60 mmHg correlated with favorable outcome in adult severe traumatic brain injury patients - a retrospective study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article A cerebral perfusion pressure (CPP) ≤ 60 mmHg correlated with favorable outcome in adult severe traumatic brain injury patients - a retrospective study Linus Réen, Anna Radman, Edward Visse, David Cederberg, Niklas Marklund, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6079964/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Current guidelines for the treatment of severe TBI recommend maintaining a cerebral perfusion pressure (CPP) above 60 mmHg. However, the rationale for this target is not supported by high-level evidence demonstrating improved outcomes. In our institution, as well as others, an alternative algorithm—originally named the Lund concept—has been used. This approach employs metoprolol and clonidine to limit CPP, allowing levels below 60 mmHg, with the aim of reducing cerebral edema. Previous reports on this algorithm have suggested better outcomes compared to contemporary practices, but no population-based studies have been conducted to validate these findings. Research Question: Does allowing CPP levels lower than 60 mmHg improve outcome in severe TBI? Methods: The study included all adult patients (n=171) treated for severe traumatic brain injury (TBI) over a ten-year period in the southern Swedish healthcare region. Baseline data, intracranial pressure (ICP), CPP, treatment duration, surgical interventions, and administered drugs were correlated to the Glasgow Outcome Scale Extended (GOSE). Results: The 30-day and 6-month mortality rates were 16% and 20%, respectively. Good outcome (GOSE 7-8) was achieved in 29% of patients. Ordinal and linear regression analyses indicated that a CPP of 51-60 mmHg correlated with survival, while age and a CPP > 60 mmHg were associated with worse outcome. Conclusion: The application of CPP levels lower than those currently recommended appears to result in better outcomes compared to relevant population-based reports. However, it is possible that the use of metoprolol and clonidine may have additional effects beyond simply reducing CPP. Traumatic brain injury Intracranial pressure Cerebral perfusion pressure Lund Concept Neurointensive care Glasgow Outcome Scale – extended (GOS-E) Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Severe traumatic brain injury (TBI) remains one of the leading causes of morbidity and mortality in adults despite modern prevention 1 and advances in neurocritical care 2 – 4 . Worldwide, TBI is referred to as a silent epidemic with increasing incidence 5 – 7 . The surge of motor vehicles, and a lack of safety laws as well as insufficient preventive measures have led to a rise of TBI in low- and middle-income countries, whereas falls in elderly patients are becoming the predominant cause of injury in high-income countries 2 , 8 , 9 . Country-based estimates demonstrate great variations in fatal outcome after severe TBI. However, these numbers are uncertain as very few studies are population-based 10 – 13 and often mix moderate and severe TBIs 14 – 16 . At time of TBI, there is a primary brain injury that occurs as an immediate consequence of the trauma impact, while secondary brain injury is a process that occurs within hours to days thereafter. Secondary brain injury encompasses events such as vasogenic and cytotoxic edema, hypoxia, sterile inflammation, seizures, and excitotoxicity that ultimately lead to the loss of neuronal and glial cells. Brain edema commonly results in increased intracranial pressure (ICP) that is a critical cause of secondary brain injury following TBI 8 , 17 – 19 . Modern neurocritical care (NIC) is based on the assumption that prevention, monitoring and treatment of secondary injury factors improves outcome following TBI. The cornerstone of modern TBI treatment is primarily the monitoring of ICP and cerebral perfusion pressure (CPP), guiding interventions such as pharmacological therapy, surgical evacuation of expansive mass lesions including decompressive craniectomy 20 , 21 . The complexity and resource demands of this multimodality therapy requires specialized neurointensive care units (NICU:s) 8 , 22 Although there is relative general consensus of the basic principles of TBI management, various treatment protocols exist and so far, none of those have been proven to be superior to any other. Recent studies and guidelines recommend treatment of ICP > 20–25 mmHg 20 , 23 – 25 and maintaining a CPP between 60–70 mmHg 20 , 23 . However, these recommendations are based on moderate to low-quality evidence 20 , 23 . Particularly regarding CPP management, optimal thresholds are likely patient-specific and time-dependent 26 , 27 . The Lund concept (LC) 13 , 28 , 29 was originally presented in the 1990s as a method to reduce vasogenic oedema by controlling hydrostatic and osmotic forces in order to maintain fluid volume in the intravascular compartment and minimize transcapillary fluid transport. Specifically, in order to reduce cerebral edema, LC allowed CPP to be lower than in the contemporary protocols. To maintain a normovolemic fluid balance and a high hemoglobin concentration (110 g/l), liberal use of albumin (20% solution) and leukocyte-depleted blood transfusions were used. The rationale for using albumin as the main plasma volume expander and antihypertensive treatment was to reduce hydrostatic pressure and to restore the plasma oncotic pressure, thereby lowering ICP and minimizing transcapillary filtration. A key component of the protocol is the early introduction of clonidine and metoprolol, along with the avoidance of vasopressors, to reduce adrenergic stress and lower arterial pressure. The treatment protocol does not include wake-up calls and patients remain sedated with midazolam and fentanyl until ICP stabilization is achieved. In order to keep ICP 20 mmHg, management options include low-dose barbiturate administration, intraventricular drainage or, as a last resort, decompressive hemicraniectomy 30 (suppl. Figure 1). The treatment protocol has been much debated 31 but in recent years, guidelines for treatment of TBI and the Lund Concept have shown more similarities, particularly regarding CPP-targets and a more restricted use of vasopressors. Initial reports of outcome after treatment with LC showed reduced mortality and morbidity when compared to historical data from the same institutions, but these results may suffer from possible selection biases 29 , 32 , 33 . To date, no in-depth analysis of how different factors and components of the Lund concept correlate to outcome, and no systematic follow-up of the patients´ neurological and cognitive status as well as work capacity and quality of life has been presented in adults patients suffering severe TBI. Therefore, we hypothesized that the use of the specific algorithm encompassing early administration of clonidine and metoprolol with acceptance of CPP values < 60 mmHg would improve outcome compared to published population-based reports. Material and methods In the present study, we performed a retrospective analysis of adult patients (≥ 18 years old) with severe TBI, treated at the department of neurosurgery in Lund, Skane University Hospital 2007–2016. Skane University Hospital is the regional tertiary trauma center with exclusive responsibility for the management of severe TBI in the southern region of Sweden (referral population 2.0 million inhabitants). All severe TBI patients, except those where treatment is deemed futile based on clinical and radiological information, are transferred to the NICU at Skane University Hospital. Data was collected from medical record systems, including the monitoring system (Intellispace Critical Care and Anesthesia [ICCA] system; Philips, Eindhoven, Netherlands) at the NICU. Patients were identified by the International Classification of Diseases (ICD) 10 system (S061-S069) and keywords for TBI used by ICCA. Inclusion criteria were age ≥ 18 years at admission and severe TBI (GCS < 9 following trauma) or GCS ≥ 9 but rapidly deteriorating to GCS < 9 within 24 hours. Information regarding type of injury, operations, pharmacological treatment, and physiological variables were collected from medical charts. Radiological features, including Marshall classification 34 , were collected from the hospital´s radiology software (Sectra IDS7, Linköping, Sweden). From the 136 ICP-monitored patients with accurate data, a total of 24,683 ICP hourly values were collected. ICP was measured either by an intraventricular catheter, with the highest level of the subarachnoid space as reference point, or an intraparenchymal sensor (Codman®, Integra, Princeton, USA). Values were collected hourly until removal of ICP monitoring devices. Normal ICP values were defined as ICP < 20 mmHg and duration of time with ICP 30 mmHg were analyzed against outcome. A total of 22,772 CPP-values could be collected from 134 ICP-monitored patients. The cerebral perfusion pressure (CPP) was calculated using the mean arterial pressure (MAP), measured by an arterial line at the level of the right atrium and ICP recorded from an intraventricular or intraparenchymal catheter. Optimal CPP for adults with severe TBI is yet to be defined, however various thresholds and upper limits have been suggested 20 , 35 , 36 . In the present study, duration of time with CPP < 40 mmHg, 60 mmHg were analyzed against outcome. Absolute values of ICP and CPP were defined as the total number of values, whereas relative values were defined as the percentage of values above, below, or within a certain threshold (e.g., CPP > 60 mmHg or CPP 51–60 mmHg). We identified 171 patients, treated for severe TBI between 2007–2016 at the Neuro-ICU, Skane University Hospital, Lund, Sweden. Patient outcomes were estimated using the Glasgow Outcome Scale-Extended (GOSE) 37 -based questionnaires completed by patients and/or next of kin or via structured interviews conducted by study physicians using the same questionnaire. In cases were neither questionnaires were completed nor structured interviews were feasible, outcomes were estimated from medical records. Patient outcomes were obtained by questionnaires and/or structured interviews in 121 patients, and from medical charts in 34 patients. Outcome was defined as good recovery (GOSE 7–8), moderate disability (GOSE 5–6), severe disability (GOSE 3–4), vegetative (GOSE 2) and dead (GOSE 1). Median follow up time was 8 years post-injury (range 2–11 years). Patients lost to follow up were excluded from all calculations. Statistical analysis Chi square test was used for categorical data. For the analysis of the effect by different factors on GOSE the following dichotomies were assessed by binary linear regression ( glm in R); 8 versus 1–7, 7–8 versus 1–6, 5–8 versus 1–4 and 3–8 versus 1–2, 7–8 versus 5–6, 8 versus 5–7 and 2–8 versus 1. A p-value ≤ 0.05 was considered statistically significant. To assess whether statistics designated for ordinal stepwise data would give more information, an ordinal regression test, cumulative link models ( clm in R), was used and compared to glm of dichotomized GOSE outcomes. Statistically significant values from the ordinal regression test were also compared to the corresponding dichotomies in the glm analysis. Bonferroni correction was applied to account for multiple testing. Parametric data are presented as mean +- standard deviation (SD). Nonparametric data are presented as median and interquartile range (IQR). The odds ratio (OR) is presented with a 95% confidence interval (CI). All computations were run with the free statistical software R ( https://www.r-project.org ). Ethics Ethical approval was granted by local ethics committee (Regionala Etikprövningsnämnden Box 133/HS 12, 221 00 Lund). Reference number: 2017/469. The authors confirm that this study was conducted in accordance with the declaration of Helsinki. Results Patients and radiological appearance Patient characteristics are shown in Table 1. The initial CT scan was classified as Marshall 5 or 6 in the majority of patients (62%). There was a high male predominance (127 males vs 44 females; 74%). Median age was 48 (range 18–74) and median GCS was 6 (range 3–15). Pre-injury Co-morbidities were identified in ninety-two (54%) patients. The most prevalent were hypertension (13%), followed by alcohol abuse (10%), diabetes (8%) and depression (5%). Data on pupil reactivity was available in 154 patients (90%). Ninety-seven patients (57%) had fixed pupils, of whom 87 (51%) had unilateral and 10 (6%) bilateral pupillary abnormality. The predominant radiological diagnosis was cerebral contusions (65%), followed by subdural hematomas (51%). A majority (67%) of patients suffered from multiple intracranial injuries and 36 patients (21%) had various degrees of extracranial injuries. Sixteen patients (9%) were lost to follow up and were excluded in the analysis of mortality and GOSE. NICU treatment Both surgical evacuation and ICP-monitoring was performed in 114 patients (67%). Forty-one patients (24%) were managed with ICP-monitoring alone and decompressive craniectomy (DC) was performed in 19 patients (11%). Nine patients who underwent surgical evacuation of a hematoma were extubated in the immediate postoperative period, either due to a good neurological status on wake- up tests, or if further intervention was deemed futile, thus not receiving ICP-monitoring. Seven (4%) patients were treated without surgery and/or ICP-monitoring. ICP data was missing from 3 patients, and 136 ICP-monitored patients were included in the statistical analyses (Fig. 1 ). Median NICU stay was 216 hours (range 18-1238 h). NICU drugs A majority of patients (85%) were initially sedated with propofol; however, midazolam was used in 67% of patients, either initially or later in course of the disease. Metoprolol and clonidine were administrated in 60% and 68% of patients, respectively. The use of pentothal was required in 32 patients (19%) (Table 2). ICP and CPP Only 1% of ICP values exceeded 30 mmHg while 70% were below 15 mmHg. CPP was kept > 50 mmHg 95% of time and < 1% of CPP values were < 40 mmHg (Table 3). Outcome Median GOSE was 5. The NICU mortality was 6%, the 30-day mortality was 16% and 6-month mortality 20% in patients that could be followed up after NICU discharge (n = 155) and including patients with mortality data but otherwise lost to follow up (n = 171) 15 and 18% respectively. There was a statistically significant correlation between high age and mortality (p < 0.05). Patients treated with clonidine did not differ significantly in GCS or Marshall Classification compared to those not receiving clonidine. However, they had a statistically significant lower mortality (p = 0.007). A favorable outcome, defined as GOSE 5–8, was achieved in 51% of patients and 49% had an unfavorable outcome (GOSE 1–4). Good outcome, defined as GOSE 7–8 was achieved in 29%, moderate outcome (GOSE 5–6) in 22% and severe outcome in 28% of patients. Among the patients not undergoing surgery or ICP monitoring, one was severely disabled (GOSE 3) while the remaining six had a favorable outcome (2 GOSE 6; 4 GOSE 7). Mortality in patients treated with surgical evacuation without ICP-monitoring (n = 9) was 44%, however surviving patients had a favorable outcome (2 GOSE 5; 1 GOSE 6; 2 GOSE 8). In the glm analysis, both absolute and relative ICP values of 15–20 mmHg were significantly correlated with survival when 6-month mortality was assessed. When analyzing 30-day mortality, absolute ICP values > 30 mmHg correlated significantly with mortality. However, this could not be confirmed after applying Bonferroni correction and no statistical significance could be found between ICP and outcome in the ordinal clm analysis. There was a significant correlation with unfavorable outcome and relative CPP values > 60 mmHg (Fig. 3 ). Both relative and absolute CPP values of 51–60 mmHg correlated significantly with survival in both ordinal clm (p = 0.04) and glm analyses (Fig. 4 ). After correcting for multiple testing, only a significant correlation between CPP values of 51–60 mmHg and 30-day mortality was found (OR = 0.95, 95% CI: 0.92–0.98, p = 0.006). Discussion The major findings of the present report, the largest patient’s series to date evaluating the Lund concept for the treatment of severe TBI, were that both 30-day and 6-month mortality were lower in patients with a high frequency of CPP values between 51–60 mmHg, whereas CPP values > 60mmHg were more common in patients with unfavorable outcome. We report a 6-month mortality of 20%, which is comparable to or lower than that reported in other recent outcome studies of severe TBI 38 – 44 . Twenty-nine percent of patients reached good outcome (GOSE 7–8) within 6 months which is perhaps more important as this is equivalent to cure in other diseases. In earlier studies evaluating the Lund concept, a mortality rate of 3–20% of adult patients with severe TBI was observed, as well as a favorable outcome of 52–82% 13 . However, it is difficult to compare these previous data with those from the present study, since important prognostic indicators, such as the Marshall classification and pupil status, were often missing 45 , 46 . Previous studies also involved smaller, selected, non-population-based cohorts of predominately younger patients 32 , 33 , 45 – 47 . As demonstrated by the present and previous studies, age is a significant negative predictor of outcome in severe TBI 3 , 48 , 49 , which may partially account for the notably low morbidity and mortality observed in prior studies evaluating the Lund concept 33 , 45 . Furthermore, outcome was assessed using the four level Glasgow Outcome Scale (GOS) 50 , in contrast to the GOSE utilized in the present study. It is widely agreed that the GOSE tends to classify fewer patients as having a “good recovery” but provides a more accurate reflection of social disability 37 . Our study is the largest case series of adult patients treated accorded the Lund Concept. We previously reported the long-term outcome in children < 18 years with severe TBI treated according to the Lund concept 51 . When compared to these results in the pediatric population, mortality is doubled, and favorable outcome is reduced from 75–51% in adult patients treated with the same algorithm. While these results emphasize that children < 18 year have a more favorable prognosis than adults after severe TBI, we cannot exclude that the efficacy of the Lund Concept is better in the pediatric population. Mortality and outcome in severe TBI are generally lower in randomized trials (RCT) than from population-based studies, which could be explained by selection bias in RCTs. The present mortality and outcome rates are similar or better than in recent RCTs, and in relevant population-based studies of severe TBI from countries with a high Human Development Index (HDI), where mortality ranges from 25–51% and 34–51% respectively have been reported 15 , 16 , 38 , 41 , 43 , 52 – 54 . In the present study all patients admitted to the tertiary NICU were included and thus the population also encompassed patients in GCS 3 and fixed dilated pupils which sometimes are excluded in RCTs. Also, when comparing outcome, it is important to note that different definitions of favorable outcome exist, and some studies include GOSE 4 43,55 , whereas in our study, as in many others, favorable outcome is defined as GOSE 5–8. A fundamental aspect of the Lund Concept involves the administration of metoprolol and clonidine to reduce the hydrostatic pressure with the intent of minimizing capillary fluid leakage through an impaired blood-brain barrier (BBB) 28 , 30 . However, the use of antihypertensive agents is sometimes discouraged due to the risk of unacceptably low CPP values (< 50 mmHg), which may partially explain why not all patients received metoprolol and clonidine (60% and 68% respectively) in this study. The patients receiving clonidine had a significantly lower mortality despite equal severity of injury. However, we cannot rule out that the choice of not using clonidine and/or metoprolol was influenced by other comorbid factors than avoidance of low blood pressure and thus low CPP values. Current TBI-guidelines 20 , 56 suggest that CPP should be kept at a minimum of 60–70 mmHg which is a lower goal than in previous guidelines. However, these recommendations were based merely on grade 2–3 evidence. Moreover, no specific upper CPP limit is suggested. The clinical benefit of the commonly used inotropic drugs in the management of severe TBI remains a subject of considerable debate 57 . However, liberal use of vasopressors aiming at increasing CPP has been associated with a five-fold increased risk of acute respiratory distress syndrome (ARDS) 58 . A basic assumption for the rationale of LC was that elevated CPP could exacerbate cerebral edema 28 , 30 , 45 . Based on current evidence 59 , 60 , this assumption is probably correct when there is a disruption of the BBB also resulting in impaired autoregulation 28 . Impaired autoregulation has been reported in 49–87% of patients with severe TBI 61 . The mechanisms underlying cerebral autoregulation are only partially understood 60 and the degree of impairment most likely varies significantly between patients with severe TBI 61 , 62 , adding to the complexity of defining thresholds for CPP. Since the introduction of the pressure reactivity index (PrX) 63 and optimal CPP (CPPopt) 64 there has been a growing interest in individualized CPP-management 65 – 68 . Even though this is theoretically appealing, to date there is still no gold standard for estimating cerebral autoregulation 69 , and there is conflicting evidence regarding the clinical benefits of CPPopt-guided treatment 67 , 70 , 71 . Moreover, CPPopt has only been prospectively evaluated by comparing CPPopt-guided treatment to treatment according to current guidelines (CPP 60–70 mmHg) 66 and not compared to lower CPP thresholds. The present study is cautiously supportive of CPP values between 51–60 mmHg and the avoidance of CPP values > 60 mmHg. Our findings closely align with those of a study by Elf et al. 36 , which similarly included patients in poor clinical condition, characterized by features such as dilated pupils and/or low GCS scores. This might suggest that the severely injured adult brain is highly sensitive to both low and high CPP values. Thus, a narrow target range, rather than a lower limit, is warranted. The absence of a correlation between low CPP values and outcome is most likely explained by the very high rate of CPP control achieved (95% of CPP > 50 mmHg). The effects of metoprolol and clonidine could also go beyond the mere reduction of CPP. Both metoprolol and clonidine have been proposed to reduce mortality and improve outcome in severe and moderate TBI by different suggested mechanisms as reduction of catecholamine outflow and immune modulation 72 – 74 The low percentage of elevated ICP in our study argues that the LC is effective in achieving ICP control in a majority of patients. The relatively low incidence of DC (11%) compared to other studies 43 may argue for a more pharmacological approach when managing moderately elevated ICP-values. We acknowledge that there are several limitations to the present study. As with all retrospective studies there are inherent uncertainties regarding data accuracy, various forms of bias and confounding factors. Data was collected over a relatively long time period, which may have affected the results. ICP and CPP were only recorded every hour, which in conjunction with the stringent control of CPP and ICP may explain the lack of correlation between high ICP/low CPP and outcome. High-frequency data sampling would have been desirable, as we believe this is crucial for determining optimal ICP and CPP thresholds in future studies. Moreover, the lower CPP values in patients with favorable outcome, as shown in the present study, must be interpreted with caution, as they may be influenced by confounding factors such as cardiovascular disease, age, secondary insults, autoregulatory status and other factors. As stated in the results, most of these correlations did not remain significant after applying Bonferroni correction, further emphasizing that although CPP < 60 mmHg was well tolerated in this cohort, this does not imply that CPP should be maintained < 60 mmHg in all adult severe TBI patients. Severe TBI encompasses a range of diagnoses and optimal CPP ranges in patients with predominantly contusions and TSAH most likely differ from those in patients with mass lesions and ICP liability. Although the low rate of elevated ICP may suggest that the Lund Concept is effective in achieving ICP control, it may also explain why CPP < 60 mmHg was well tolerated. This does not provide evidence that maintaining CPP < 60 mmHg is beneficial in clinical scenarios involving, for example, vasospasm and/or ICP instability. Another limitation of the present study is that head elevation, a common practice in the management of severe TBI, was not accounted for as the level of head elevation was not recorded in the medical charts. Theoretically, this could alter CPP values, leading to ambiguous results. The initial GCS assessment is often performed by less experienced physicians, which may lead to that some patients are assigned an erroneous GCS score, thereby skewing outcome data. Our NICU at Skane University Hospital is a referral center for the southern Swedish health region thus admitting all patients considered eligible for the treatment based on compound evaluation based on comorbidity, age, and severity of TBI. Although this ascertains a relatively constant selection over time, we cannot rule out bias due to varying preferences of admission by individual physicians on call. It is also worth noting that the Marshall Classification was used for radiological classification of TBI in the present study. Although several previous studies suggest that alternative radiological classifications may provide a more accurate description of injury severity and improved outcome prediction in severe TBI 75 – 77 , no universal gold standard currently exists. The Marshall Classification remains widely used in recent relevant studies 2 , 32 , 43 , 54 and was therefore used in the present study to facilitate comparison with previously published data. Conclusion Treatment of adults with severe TBI according to the Lund concept resulted in low morbidity and mortality. A CPP of 51–60 mmHg was well tolerated and correlated with favorable outcome. Declarations Acknowledgements The authors would like to extend their thanks to Susanne Månsson and Marit Bäckström for help with retrieving patient data from the neurointensive care unit, and for help with patient follow-up. Authorship confirmation/contribution statement LR, PS and AR drafted and designed the study. EV designed and executed the statistical analyses. LR, AR and PS collected data for the study. LR and AR wrote an initial manuscript draft. All authors commented on and approved the final manuscript. PS and NM supervised the project. Disclosure The authors declare no competing interests or other disclosures. Funding statement The study was supported by grants from Region Skåne and Lund University (ALF). Human Ethics and Consent to Participate Informed consent not applicable. 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Chin J Traumatol 26(6):357–362. 10.1016/j.cjtee.2023.04.002 Fletcher-Sandersjoo A, Tatter C, Yang L et al (2022) Stockholm score of lesion detection on computed tomography following mild traumatic brain injury (SELECT-TBI): study protocol for a multicentre, retrospective, observational cohort study. BMJ Open 12(9):e060679. 10.1136/bmjopen-2021-060679 Raj R, Siironen J, Skrifvars MB, Hernesniemi J, Kivisaari R (2014) Predicting outcome in traumatic brain injury: development of a novel computerized tomography classification system (Helsinki computerized tomography score). Neurosurgery 75(6):632–646 discussion 646-7. 10.1227/NEU.0000000000000533 Tables Table 1. Patient characteristics. Clinical and radiological features of all admitted patients presented as absolute values (n) and relative values (%). EDH – Epidural Hematoma, GCS – Glasgow Coma Scale, SDH – Subdural Hematoma, TSAH – Traumatic Subarachnoid Hemorrhage n % Patients 171 100 Age (median) 48 - Male 127 74 Female 44 26 GCS 3 20 12 GCS 4 16 9 GCS 5 20 12 GCS 6 29 17 GCS 7 5 3 GCS 8 32 19 GCS 9 14 8 GCS 12 9 5 GCS 13 12 7 GCS 14 4 2 GCS 15 10 6 Marshall 1 2 2 Marshall 2 50 29 Marshall 3 12 7 Marshall 5 105 61 Marshall 6 2 1 EDH 25 15 SDH 87 51 TSAH 60 35 Contusion 111 65 Fixed pupils 97 57 -bilateral 10 6 -unilateral 87 51 Comorbidities 92 54 -hypertension 23 13 -alcohol abuse 17 10 -diabetes 14 8 -depression 8 5 -other 30 18 Table 2. Summary of surgical and medical treatment. Absolute values (n) and relative values (%) are presented respectively. Medical treatment is shown as median values of total doses. DC – Decompressive Hemicraniectomy, ICP – Intracranial Pressure n % Conservative treatment 7 4 Hematoma evacuation without ICP-monitoring 9 5 Only ICP-monitor 41 24 Decompressive surgery and ICP-monitoring 114 67 DC 19 11 Propofol 146 85 - median dose (mg) 3120 - Midazolam 114 67 -median dose (mg) 2083 - Metoprolol 102 60 -median dose (mg) 126 - Clonidine 117 68 -median dose (ug) 2370 - Pentothal 32 19 -median dose (mg) 8163 - Table 3. A summary of all hourly collected ICP- and CPP values. Absolute (n) and relative (%) values for different cutoffs are shown. ICP – Intracranial Pressure, CPP – Cerebral Perfusion Pressure n % ICP (all values) 24683 100 30 mmHg 253 1 CPP (all values) 22772 100 < 40 mmHg 124 60 mmHg 17606 77 Table 4. Clinical parameters and ICP/CPP, stratified by outcome. Patients with favorable and unfavorable outcome are presented in 4a. Deceased and alive patients are presented in 4b. GCS – Glasgow Coma Scale, IQR – Interquartile Range, ICP – Intracranial Pressure, CPP – Cerebral Perfusion Pressure, OR – Odds Ratio, CI – Confidence Interval Table 4a Favorable Unfavorable OR (95 % CI) p-value Age (median (IQR)) 38(32.5) 57(27.2) 0.96 (0.95 - 0.98) 0.0002 GCS (median (IQR)) 8(3) 6(5) 1.057(0.965 - 1.1597) 0.239 Unilateral pupil dilatation (n (%)) a 14 (20%) 16 (24%) N/A 0.5728 Bilateral pupil dilatation (n (%)) 8 (11%) 5 (7%) N/A 0.5728 Unilateral pupil light respons (n (%)) 12 (17%) 13 (19%) N/A 0.8893 No pupil light respons (n (%)) 8 (11%) 8 (12%) N/A 0.8893 Marshall (median (IQR)) 5 (3) 5 (3) 1.03 (0.81 - 1.32) 0.8 Relative ICP > 20 mmHg (median (IQR)) 0.0099 (0.049) 0.0155 (0.086) 0.120 (0.0029 - 3.679) 0.236 Absolute ICP > 20 mmHg (median (IQR)) 3 (15.5) 3.5 (19.5) 1.003 (0.989 - 1.018) 0.657 Relative ICP < 15 mmHg (median (IQR)) 0.735 (0.588) 0.756 (0.506) 0.57 (0.23 -1.40) 0.2 Absolute ICP 60 mmHg (median (IQR)) 0.722 (0.429) 0.844 (0.271) 0.28 (0.09 - 0.78) 0.02 Absolute CPP > 60 mmHg (median (IQR)) 89 (124) 122 (124) 1.00(1.00 - 1.00) 0.8 Relative CPP 51-60 mmHg (median (IQR)) 0.111 (0.277) 0.098 (0.165) 1.75 (0.17-18.5) 0.64 Absolute CPP 51-60 mmHg (median (IQR)) 23.5 (41.5) 17 (29) 1.01 (0.997 - 1.02) 0.16 Relative CPP < 40 mmHg (median (IQR)) 0 (0) 0 (0.00283) < 0.0000001 (<0.001 - 7.8)* 0.3 Absolute CPP < 40 mmHg (median (IQR)) 0 (0) 0 (1) 0.93 (0.74 - 1.04) 0.38 Table 4b Deceased (6 months) Alive OR (95 % CI) p-value Age (median (IQR)) 61 (12.5) 42.5 (33.5) 1.05 (1.02 - 1.08) 0.0004 GCS (median (IQR)) 6 (8.5) 8 (4) 0.982(0.872 - 1.098) 0.756 Unilateral pupil dilatation (n (%)) 4 (13%) 26 (24%) N/A 0.4175 Bilateral pupil dilatation (n (%)) 0 (0%) 13 (12%) N/A 0.4175 Unilateral pupil light respons (n (%)) 3 (10%) 22 (20%) N/A 0.2623 No pupil light respons (n (%)) 2 (7%) 13 (12%) N/A 0.2623 Marshall (median (IQR)) 5 (2.5) 5 (3) 1.05 (0.8 - 1.4) 0.7 Relative ICP > 20 mmHg (median (IQR)) 0.0097 (0.044) 0.0135 (0.080) 1.199 (0.0112 - 59.4552) 0.932 Absolute ICP > 20 mmHg (median (IQR)) 3 (8.5) 3.5 (20.2) 0.978 (0.9412 - 1.0029) 0.172 Relative ICP < 15 mmHg (median (IQR)) 0.802 (0.587) 0.735 (0.537) 1.09 (0.36 - 3.57) 0.88 Absolut ICP 60 mmHg (median (IQR)) 0.853 (0.281) 0.769 (0.329) 1.41 (0.4 - 5.8) 0.6 Absolute CPP > 60 mmHg (median (IQR)) 68 (142) 119 (122) 1.0 (0.994 - 1.003) 0.6 Relative CPP 51-60 mmHg (median (IQR)) 0.073 (0.104) 0.111 (0.248) 0.03 (0.008 - 0.68) 0.04 Absolute CPP 51-60 mmHg (median (IQR)) 8 (14.5) 23 (38.8) 0.97 (0.94 - 0.99) 0.01 Relative CPP 10 000 (2.3 - >10 000)* 0.2 Absolute CPP < 40 mmHg (median (IQR)) 0 (0.5) 0 (0) 1.08 (0.99 - 1.28) 0.17 * Difficult to interpret data due to a very limited number of values a Information regarding pupillary status was missing in 18 patients (12%) Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6079964","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":442319242,"identity":"b301d14e-3c25-422f-9f4c-82b0d038482c","order_by":0,"name":"Linus Réen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2klEQVRIiWNgGAWjYBACPmY4k/kAAwMbgwxBLWwILWwJIC08hLUgmDwGRGph5z0m+YPhnhy/dM/XDR/KgBoPsD98gN9hfGnSPAzFxpJzzm67OeMcSAuPsQF+LTxm0gwMCYkbbuRuu83bBtbCJkFIC9BhCfX7b+Q8u/0XrIX9+Q9CWiR4GBISDCRy2G4zgrUwmOHTAdJibM1jkGA440aa2c2ecxI8kod5jPE6jJ//jOHNHxUJ8vwzkp/d+FFmI8d3vP3hB7zWgAEihIDmM+NROApGwSgYBaOAOAAA/4Y6gpzMagUAAAAASUVORK5CYII=","orcid":"","institution":"Lund University","correspondingAuthor":true,"prefix":"","firstName":"Linus","middleName":"","lastName":"Réen","suffix":""},{"id":442319243,"identity":"ba2c3a56-2a82-442e-8289-b5e1958fd382","order_by":1,"name":"Anna Radman","email":"","orcid":"","institution":"Skåne University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Anna","middleName":"","lastName":"Radman","suffix":""},{"id":442319244,"identity":"3e186ba7-086d-40ab-8697-d2758f189054","order_by":2,"name":"Edward Visse","email":"","orcid":"","institution":"Lund University","correspondingAuthor":false,"prefix":"","firstName":"Edward","middleName":"","lastName":"Visse","suffix":""},{"id":442319245,"identity":"dba6c5ec-dab3-4ee9-8ddc-a2e07f8337cd","order_by":3,"name":"David Cederberg","email":"","orcid":"","institution":"Lund University","correspondingAuthor":false,"prefix":"","firstName":"David","middleName":"","lastName":"Cederberg","suffix":""},{"id":442319246,"identity":"5221613e-43be-4f84-a425-86593c4b5565","order_by":4,"name":"Niklas Marklund","email":"","orcid":"","institution":"Lund University","correspondingAuthor":false,"prefix":"","firstName":"Niklas","middleName":"","lastName":"Marklund","suffix":""},{"id":442319247,"identity":"ffc9d901-da93-4eac-913c-ffedd528b7d9","order_by":5,"name":"Peter Siesjö","email":"","orcid":"","institution":"Lund University","correspondingAuthor":false,"prefix":"","firstName":"Peter","middleName":"","lastName":"Siesjö","suffix":""}],"badges":[],"createdAt":"2025-02-21 13:38:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6079964/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6079964/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":80633151,"identity":"16d21216-d3a6-4b2a-8944-cb70c232e756","added_by":"auto","created_at":"2025-04-15 11:56:09","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":270152,"visible":true,"origin":"","legend":"\u003cp\u003eFlowchart of all patients\u003c/p\u003e","description":"","filename":"Fig1FlowchartPEK2.png","url":"https://assets-eu.researchsquare.com/files/rs-6079964/v1/b6b6c8c7dc7ffaf7049249d6.png"},{"id":80635075,"identity":"b471d759-1911-4ed4-899f-71db94839a0a","added_by":"auto","created_at":"2025-04-15 12:20:09","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":265572,"visible":true,"origin":"","legend":"\u003cp\u003eOutcome and 6-month mortality shown as full 8 level GOSE scale (A), unfavorable/favorable (B). GOSE – Glasgow Outcome Scale Extended\u003c/p\u003e","description":"","filename":"Fig2.OveralloutcomeRev1LR.png","url":"https://assets-eu.researchsquare.com/files/rs-6079964/v1/b18b102c3b0929638d7a3e1d.png"},{"id":80634628,"identity":"a0fe093a-d68f-4682-adc0-7921c2ca178b","added_by":"auto","created_at":"2025-04-15 12:12:09","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":145851,"visible":true,"origin":"","legend":"\u003cp\u003eBoxplots illustrate relative times of CPP \u0026gt; 60 mmHg in patients with favorable (GOSE 5-8) and unfavorable outcome (GOSE 1-4). Dots represent individual patients. CPP – Cerebral Perfusion Pressure, GOSE Glasgow Outcome Scale Extended\u003c/p\u003e","description":"","filename":"Fig3CPPht60outcome.png","url":"https://assets-eu.researchsquare.com/files/rs-6079964/v1/fd8e854c4174eda55b12d5b5.png"},{"id":80633766,"identity":"cbb1e15f-8961-4a26-872f-19a0726f593e","added_by":"auto","created_at":"2025-04-15 12:04:09","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":1605308,"visible":true,"origin":"","legend":"\u003cp\u003eBoxplots illustrate relative times and absolute values of CPP 51-60 mmHg in alive and deceased patients. (A) and (B) compare 30-day mortality and (C) and (D) compare 6-month mortality. (A) and (C) display relative values (percentage of whole monitoring time) and (B) and (D) display absolute values (hours). After applying Bonferroni correction for multiple testing, only the correlation of CPP of 51-60 mmHg and 30-day mortality (B) remained significant. Dots represent individual patients. CPP – Cerebral Perfusion Pressure\u003c/p\u003e","description":"","filename":"Fig4CPP5160mortality.png","url":"https://assets-eu.researchsquare.com/files/rs-6079964/v1/8d3f2147744351ebf44c6cf7.png"},{"id":82003909,"identity":"cd76ae3d-a883-41f5-8ab0-b91c0faab7c6","added_by":"auto","created_at":"2025-05-05 20:46:35","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3786543,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6079964/v1/d0cb6543-7f83-44a2-ac4d-260c75d02fb2.pdf"},{"id":80633768,"identity":"9f551a68-cf79-4171-9071-c47af35c28bb","added_by":"auto","created_at":"2025-04-15 12:04:09","extension":"tiff","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":583860,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementaryfig1.LundConcept.tiff","url":"https://assets-eu.researchsquare.com/files/rs-6079964/v1/de60e263bd9395bf6188d8c4.tiff"}],"financialInterests":"No competing interests reported.","formattedTitle":"A cerebral perfusion pressure (CPP) ≤ 60 mmHg correlated with favorable outcome in adult severe traumatic brain injury patients - a retrospective study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSevere traumatic brain injury (TBI) remains one of the leading causes of morbidity and mortality in adults despite modern prevention \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e and advances in neurocritical care \u003csup\u003e\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Worldwide, TBI is referred to as a silent epidemic with increasing incidence \u003csup\u003e\u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. The surge of motor vehicles, and a lack of safety laws as well as insufficient preventive measures have led to a rise of TBI in low- and middle-income countries, whereas falls in elderly patients are becoming the predominant cause of injury in high-income countries \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. Country-based estimates demonstrate great variations in fatal outcome after severe TBI. However, these numbers are uncertain as very few studies are population-based \u003csup\u003e\u003cspan additionalcitationids=\"CR11 CR12\" citationid=\"CR75\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e and often mix moderate and severe TBIs \u003csup\u003e\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAt time of TBI, there is a primary brain injury that occurs as an immediate consequence of the trauma impact, while secondary brain injury is a process that occurs within hours to days thereafter. Secondary brain injury encompasses events such as vasogenic and cytotoxic edema, hypoxia, sterile inflammation, seizures, and excitotoxicity that ultimately lead to the loss of neuronal and glial cells. Brain edema commonly results in increased intracranial pressure (ICP) that is a critical cause of secondary brain injury following TBI \u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan additionalcitationids=\"CR18\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. Modern neurocritical care (NIC) is based on the assumption that prevention, monitoring and treatment of secondary injury factors improves outcome following TBI. The cornerstone of modern TBI treatment is primarily the monitoring of ICP and cerebral perfusion pressure (CPP), guiding interventions such as pharmacological therapy, surgical evacuation of expansive mass lesions including decompressive craniectomy \u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. The complexity and resource demands of this multimodality therapy requires specialized neurointensive care units (NICU:s) \u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e Although there is relative general consensus of the basic principles of TBI management, various treatment protocols exist and so far, none of those have been proven to be superior to any other. Recent studies and guidelines recommend treatment of ICP\u0026thinsp;\u0026gt;\u0026thinsp;20\u0026ndash;25 mmHg \u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan additionalcitationids=\"CR24\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e and maintaining a CPP between 60\u0026ndash;70 mmHg \u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. However, these recommendations are based on moderate to low-quality evidence \u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. Particularly regarding CPP management, optimal thresholds are likely patient-specific and time-dependent \u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e,\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. The Lund concept (LC) \u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e,\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e was originally presented in the 1990s as a method to reduce vasogenic oedema by controlling hydrostatic and osmotic forces in order to maintain fluid volume in the intravascular compartment and minimize transcapillary fluid transport. Specifically, in order to reduce cerebral edema, LC allowed CPP to be lower than in the contemporary protocols. To maintain a normovolemic fluid balance and a high hemoglobin concentration (110 g/l), liberal use of albumin (20% solution) and leukocyte-depleted blood transfusions were used. The rationale for using albumin as the main plasma volume expander and antihypertensive treatment was to reduce hydrostatic pressure and to restore the plasma oncotic pressure, thereby lowering ICP and minimizing transcapillary filtration. A key component of the protocol is the early introduction of clonidine and metoprolol, along with the avoidance of vasopressors, to reduce adrenergic stress and lower arterial pressure. The treatment protocol does not include wake-up calls and patients remain sedated with midazolam and fentanyl until ICP stabilization is achieved. In order to keep ICP\u0026thinsp;\u0026lt;\u0026thinsp;20mmHg, CPP levels as low as 50 mmHg can be tolerated. In cases of treatment-refractory ICP\u0026thinsp;\u0026gt;\u0026thinsp;20 mmHg, management options include low-dose barbiturate administration, intraventricular drainage or, as a last resort, decompressive hemicraniectomy \u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e (suppl. Figure\u0026nbsp;1). The treatment protocol has been much debated \u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e but in recent years, guidelines for treatment of TBI and the Lund Concept have shown more similarities, particularly regarding CPP-targets and a more restricted use of vasopressors. Initial reports of outcome after treatment with LC showed reduced mortality and morbidity when compared to historical data from the same institutions, but these results may suffer from possible selection biases \u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e,\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e,\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. To date, no in-depth analysis of how different factors and components of the Lund concept correlate to outcome, and no systematic follow-up of the patients\u0026acute; neurological and cognitive status as well as work capacity and quality of life has been presented in adults patients suffering severe TBI.\u003c/p\u003e \u003cp\u003eTherefore, we hypothesized that the use of the specific algorithm encompassing early administration of clonidine and metoprolol with acceptance of CPP values\u0026thinsp;\u0026lt;\u0026thinsp;60 mmHg would improve outcome compared to published population-based reports.\u003c/p\u003e"},{"header":"Material and methods","content":"\u003cp\u003eIn the present study, we performed a retrospective analysis of adult patients (\u0026ge;\u0026thinsp;18 years old) with severe TBI, treated at the department of neurosurgery in Lund, Skane University Hospital 2007\u0026ndash;2016. Skane University Hospital is the regional tertiary trauma center with exclusive responsibility for the management of severe TBI in the southern region of Sweden (referral population 2.0\u0026nbsp;million inhabitants). All severe TBI patients, except those where treatment is deemed futile based on clinical and radiological information, are transferred to the NICU at Skane University Hospital. Data was collected from medical record systems, including the monitoring system (Intellispace Critical Care and Anesthesia [ICCA] system; Philips, Eindhoven, Netherlands) at the NICU. Patients were identified by the International Classification of Diseases (ICD) 10 system (S061-S069) and keywords for TBI used by ICCA. Inclusion criteria were age\u0026thinsp;\u0026ge;\u0026thinsp;18 years at admission and severe TBI (GCS\u0026thinsp;\u0026lt;\u0026thinsp;9 following trauma) or GCS\u0026thinsp;\u0026ge;\u0026thinsp;9 but rapidly deteriorating to GCS\u0026thinsp;\u0026lt;\u0026thinsp;9 within 24 hours. Information regarding type of injury, operations, pharmacological treatment, and physiological variables were collected from medical charts. Radiological features, including Marshall classification \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e, were collected from the hospital\u0026acute;s radiology software (Sectra IDS7, Link\u0026ouml;ping, Sweden). From the 136 ICP-monitored patients with accurate data, a total of 24,683 ICP hourly values were collected. ICP was measured either by an intraventricular catheter, with the highest level of the subarachnoid space as reference point, or an intraparenchymal sensor (Codman\u0026reg;, Integra, Princeton, USA). Values were collected hourly until removal of ICP monitoring devices. Normal ICP values were defined as ICP\u0026thinsp;\u0026lt;\u0026thinsp;20 mmHg and duration of time with ICP\u0026thinsp;\u0026lt;\u0026thinsp;15 mmHg, 15\u0026ndash;20 mmHg, 21\u0026ndash;30 mmHg, and \u0026gt;\u0026thinsp;30 mmHg were analyzed against outcome. A total of 22,772 CPP-values could be collected from 134 ICP-monitored patients. The cerebral perfusion pressure (CPP) was calculated using the mean arterial pressure (MAP), measured by an arterial line at the level of the right atrium and ICP recorded from an intraventricular or intraparenchymal catheter. Optimal CPP for adults with severe TBI is yet to be defined, however various thresholds and upper limits have been suggested \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e. In the present study, duration of time with CPP\u0026thinsp;\u0026lt;\u0026thinsp;40 mmHg, \u0026lt; 50 mmHg, 50\u0026ndash;60 mmHg, and \u0026gt;\u0026thinsp;60 mmHg were analyzed against outcome. Absolute values of ICP and CPP were defined as the total number of values, whereas relative values were defined as the percentage of values above, below, or within a certain threshold (e.g., CPP\u0026thinsp;\u0026gt;\u0026thinsp;60 mmHg or CPP 51\u0026ndash;60 mmHg). We identified 171 patients, treated for severe TBI between 2007\u0026ndash;2016 at the Neuro-ICU, Skane University Hospital, Lund, Sweden. Patient outcomes were estimated using the Glasgow Outcome Scale-Extended (GOSE) \u003csup\u003e\u003cspan class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e-based questionnaires completed by patients and/or next of kin or via structured interviews conducted by study physicians using the same questionnaire. In cases were neither questionnaires were completed nor structured interviews were feasible, outcomes were estimated from medical records. Patient outcomes were obtained by questionnaires and/or structured interviews in 121 patients, and from medical charts in 34 patients. Outcome was defined as good recovery (GOSE 7\u0026ndash;8), moderate disability (GOSE 5\u0026ndash;6), severe disability (GOSE 3\u0026ndash;4), vegetative (GOSE 2) and dead (GOSE 1). Median follow up time was 8 years post-injury (range 2\u0026ndash;11 years). Patients lost to follow up were excluded from all calculations.\u003c/p\u003e\n\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n \u003ch2\u003eStatistical analysis\u003c/h2\u003e\n \u003cp\u003eChi square test was used for categorical data. For the analysis of the effect by different factors on GOSE the following dichotomies were assessed by binary linear regression (\u003cem\u003eglm\u003c/em\u003e in R); 8 versus 1\u0026ndash;7, 7\u0026ndash;8 versus 1\u0026ndash;6, 5\u0026ndash;8 versus 1\u0026ndash;4 and 3\u0026ndash;8 versus 1\u0026ndash;2, 7\u0026ndash;8 versus 5\u0026ndash;6, 8 versus 5\u0026ndash;7 and 2\u0026ndash;8 versus 1. A p-value\u0026thinsp;\u0026le;\u0026thinsp;0.05 was considered statistically significant. To assess whether statistics designated for ordinal stepwise data would give more information, an ordinal regression test, cumulative link models (\u003cem\u003eclm\u003c/em\u003e in R), was used and compared to \u003cem\u003eglm\u003c/em\u003e of dichotomized GOSE outcomes. Statistically significant values from the ordinal regression test were also compared to the corresponding dichotomies in the \u003cem\u003eglm\u003c/em\u003e analysis. Bonferroni correction was applied to account for multiple testing. Parametric data are presented as mean +- standard deviation (SD). Nonparametric data are presented as median and interquartile range (IQR). The odds ratio (OR) is presented with a 95% confidence interval (CI). All computations were run with the free statistical software R (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.r-project.org\u003c/span\u003e\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eEthics\u003c/h3\u003e\n\u003cp\u003eEthical approval was granted by local ethics committee (Regionala Etikpr\u0026ouml;vningsn\u0026auml;mnden Box 133/HS 12, 221 00 Lund). Reference number: 2017/469. The authors confirm that this study was conducted in accordance with the declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003ePatients and radiological appearance\u003c/h2\u003e \u003cp\u003ePatient characteristics are shown in Table\u0026nbsp;1. The initial CT scan was classified as Marshall 5 or 6 in the majority of patients (62%). There was a high male predominance (127 males vs 44 females; 74%). Median age was 48 (range 18\u0026ndash;74) and median GCS was 6 (range 3\u0026ndash;15). Pre-injury Co-morbidities were identified in ninety-two (54%) patients. The most prevalent were hypertension (13%), followed by alcohol abuse (10%), diabetes (8%) and depression (5%). Data on pupil reactivity was available in 154 patients (90%). Ninety-seven patients (57%) had fixed pupils, of whom 87 (51%) had unilateral and 10 (6%) bilateral pupillary abnormality. The predominant radiological diagnosis was cerebral contusions (65%), followed by subdural hematomas (51%). A majority (67%) of patients suffered from multiple intracranial injuries and 36 patients (21%) had various degrees of extracranial injuries. Sixteen patients (9%) were lost to follow up and were excluded in the analysis of mortality and GOSE.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eNICU treatment\u003c/h3\u003e\n\u003cp\u003eBoth surgical evacuation and ICP-monitoring was performed in 114 patients (67%). Forty-one patients (24%) were managed with ICP-monitoring alone and decompressive craniectomy (DC) was performed in 19 patients (11%). Nine patients who underwent surgical evacuation of a hematoma were extubated in the immediate postoperative period, either due to a good neurological status on wake- up tests, or if further intervention was deemed futile, thus not receiving ICP-monitoring. Seven (4%) patients were treated without surgery and/or ICP-monitoring. ICP data was missing from 3 patients, and 136 ICP-monitored patients were included in the statistical analyses (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Median NICU stay was 216 hours (range 18-1238 h).\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eNICU drugs\u003c/h2\u003e \u003cp\u003eA majority of patients (85%) were initially sedated with propofol; however, midazolam was used in 67% of patients, either initially or later in course of the disease. Metoprolol and clonidine were administrated in 60% and 68% of patients, respectively. The use of pentothal was required in 32 patients (19%) (Table\u0026nbsp;2).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eICP and CPP\u003c/h3\u003e\n\u003cp\u003eOnly 1% of ICP values exceeded 30 mmHg while 70% were below 15 mmHg. CPP was kept\u0026thinsp;\u0026gt;\u0026thinsp;50 mmHg 95% of time and \u0026lt;\u0026thinsp;1% of CPP values were \u0026lt;\u0026thinsp;40 mmHg (Table\u0026nbsp;3).\u003c/p\u003e\n\u003ch3\u003eOutcome\u003c/h3\u003e\n\u003cp\u003eMedian GOSE was 5. The NICU mortality was 6%, the 30-day mortality was 16% and 6-month mortality 20% in patients that could be followed up after NICU discharge (n\u0026thinsp;=\u0026thinsp;155) and including patients with mortality data but otherwise lost to follow up (n\u0026thinsp;=\u0026thinsp;171) 15 and 18% respectively. There was a statistically significant correlation between high age and mortality (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Patients treated with clonidine did not differ significantly in GCS or Marshall Classification compared to those not receiving clonidine. However, they had a statistically significant lower mortality (p\u0026thinsp;=\u0026thinsp;0.007). A favorable outcome, defined as GOSE 5\u0026ndash;8, was achieved in 51% of patients and 49% had an unfavorable outcome (GOSE 1\u0026ndash;4). Good outcome, defined as GOSE 7\u0026ndash;8 was achieved in 29%, moderate outcome (GOSE 5\u0026ndash;6) in 22% and severe outcome in 28% of patients. Among the patients not undergoing surgery or ICP monitoring, one was severely disabled (GOSE 3) while the remaining six had a favorable outcome (2 GOSE 6; 4 GOSE 7). Mortality in patients treated with surgical evacuation without ICP-monitoring (n\u0026thinsp;=\u0026thinsp;9) was 44%, however surviving patients had a favorable outcome (2 GOSE 5; 1 GOSE 6; 2 GOSE 8). In the glm analysis, both absolute and relative ICP values of 15\u0026ndash;20 mmHg were significantly correlated with survival when 6-month mortality was assessed. When analyzing 30-day mortality, absolute ICP values\u0026thinsp;\u0026gt;\u0026thinsp;30 mmHg correlated significantly with mortality. However, this could not be confirmed after applying Bonferroni correction and no statistical significance could be found between ICP and outcome in the ordinal clm analysis. There was a significant correlation with unfavorable outcome and relative CPP values\u0026thinsp;\u0026gt;\u0026thinsp;60 mmHg (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Both relative and absolute CPP values of 51\u0026ndash;60 mmHg correlated significantly with survival in both ordinal clm (p\u0026thinsp;=\u0026thinsp;0.04) and glm analyses (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). After correcting for multiple testing, only a significant correlation between CPP values of 51\u0026ndash;60 mmHg and 30-day mortality was found (OR\u0026thinsp;=\u0026thinsp;0.95, 95% CI: 0.92\u0026ndash;0.98, p\u0026thinsp;=\u0026thinsp;0.006).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe major findings of the present report, the largest patient\u0026rsquo;s series to date evaluating the Lund concept for the treatment of severe TBI, were that both 30-day and 6-month mortality were lower in patients with a high frequency of CPP values between 51\u0026ndash;60 mmHg, whereas CPP values\u0026thinsp;\u0026gt;\u0026thinsp;60mmHg were more common in patients with unfavorable outcome. We report a 6-month mortality of 20%, which is comparable to or lower than that reported in other recent outcome studies of severe TBI \u003csup\u003e\u003cspan additionalcitationids=\"CR39 CR40 CR41 CR42 CR43\" citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u003c/sup\u003e. Twenty-nine percent of patients reached good outcome (GOSE 7\u0026ndash;8) within 6 months which is perhaps more important as this is equivalent to cure in other diseases.\u003c/p\u003e \u003cp\u003eIn earlier studies evaluating the Lund concept, a mortality rate of 3\u0026ndash;20% of adult patients with severe TBI was observed, as well as a favorable outcome of 52\u0026ndash;82% \u003csup\u003e13\u003c/sup\u003e. However, it is difficult to compare these previous data with those from the present study, since important prognostic indicators, such as the Marshall classification and pupil status, were often missing \u003csup\u003e\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e45\u003c/span\u003e,\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u003c/sup\u003e. Previous studies also involved smaller, selected, non-population-based cohorts of predominately younger patients \u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e,\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e,\u003cspan additionalcitationids=\"CR46\" citationid=\"CR46\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e. As demonstrated by the present and previous studies, age is a significant negative predictor of outcome in severe TBI \u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e48\u003c/span\u003e,\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u003c/sup\u003e, which may partially account for the notably low morbidity and mortality observed in prior studies evaluating the Lund concept \u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e,\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e. Furthermore, outcome was assessed using the four level Glasgow Outcome Scale (GOS) \u003csup\u003e\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e50\u003c/span\u003e\u003c/sup\u003e, in contrast to the GOSE utilized in the present study. It is widely agreed that the GOSE tends to classify fewer patients as having a \u0026ldquo;good recovery\u0026rdquo; but provides a more accurate reflection of social disability \u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e. Our study is the largest case series of adult patients treated accorded the Lund Concept.\u003c/p\u003e \u003cp\u003eWe previously reported the long-term outcome in children\u0026thinsp;\u0026lt;\u0026thinsp;18 years with severe TBI treated according to the Lund concept \u003csup\u003e\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e51\u003c/span\u003e\u003c/sup\u003e. When compared to these results in the pediatric population, mortality is doubled, and favorable outcome is reduced from 75\u0026ndash;51% in adult patients treated with the same algorithm. While these results emphasize that children\u0026thinsp;\u0026lt;\u0026thinsp;18 year have a more favorable prognosis than adults after severe TBI, we cannot exclude that the efficacy of the Lund Concept is better in the pediatric population.\u003c/p\u003e \u003cp\u003eMortality and outcome in severe TBI are generally lower in randomized trials (RCT) than from population-based studies, which could be explained by selection bias in RCTs. The present mortality and outcome rates are similar or better than in recent RCTs, and in relevant population-based studies of severe TBI from countries with a high Human Development Index (HDI), where mortality ranges from 25\u0026ndash;51% and 34\u0026ndash;51% respectively have been reported \u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e,\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e,\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e,\u003cspan additionalcitationids=\"CR53\" citationid=\"CR53\" class=\"CitationRef\"\u003e52\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e54\u003c/span\u003e\u003c/sup\u003e. In the present study all patients admitted to the tertiary NICU were included and thus the population also encompassed patients in GCS 3 and fixed dilated pupils which sometimes are excluded in RCTs. Also, when comparing outcome, it is important to note that different definitions of favorable outcome exist, and some studies include GOSE 4 \u003csup\u003e43,55\u003c/sup\u003e, whereas in our study, as in many others, favorable outcome is defined as GOSE 5\u0026ndash;8.\u003c/p\u003e \u003cp\u003eA fundamental aspect of the Lund Concept involves the administration of metoprolol and clonidine to reduce the hydrostatic pressure with the intent of minimizing capillary fluid leakage through an impaired blood-brain barrier (BBB) \u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e,\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. However, the use of antihypertensive agents is sometimes discouraged due to the risk of unacceptably low CPP values (\u0026lt;\u0026thinsp;50 mmHg), which may partially explain why not all patients received metoprolol and clonidine (60% and 68% respectively) in this study. The patients receiving clonidine had a significantly lower mortality despite equal severity of injury. However, we cannot rule out that the choice of not using clonidine and/or metoprolol was influenced by other comorbid factors than avoidance of low blood pressure and thus low CPP values. Current TBI-guidelines \u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e56\u003c/span\u003e\u003c/sup\u003e suggest that CPP should be kept at a minimum of 60\u0026ndash;70 mmHg which is a lower goal than in previous guidelines. However, these recommendations were based merely on grade 2\u0026ndash;3 evidence. Moreover, no specific upper CPP limit is suggested. The clinical benefit of the commonly used inotropic drugs in the management of severe TBI remains a subject of considerable debate \u003csup\u003e\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e57\u003c/span\u003e\u003c/sup\u003e. However, liberal use of vasopressors aiming at increasing CPP has been associated with a five-fold increased risk of acute respiratory distress syndrome (ARDS) \u003csup\u003e\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e58\u003c/span\u003e\u003c/sup\u003e. A basic assumption for the rationale of LC was that elevated CPP could exacerbate cerebral edema \u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e,\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e,\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e. Based on current evidence \u003csup\u003e\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e59\u003c/span\u003e,\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e60\u003c/span\u003e\u003c/sup\u003e, this assumption is probably correct when there is a disruption of the BBB also resulting in impaired autoregulation \u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. Impaired autoregulation has been reported in 49\u0026ndash;87% of patients with severe TBI \u003csup\u003e\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e61\u003c/span\u003e\u003c/sup\u003e. The mechanisms underlying cerebral autoregulation are only partially understood \u003csup\u003e\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e60\u003c/span\u003e\u003c/sup\u003e and the degree of impairment most likely varies significantly between patients with severe TBI \u003csup\u003e\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e61\u003c/span\u003e,\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e62\u003c/span\u003e\u003c/sup\u003e, adding to the complexity of defining thresholds for CPP. Since the introduction of the pressure reactivity index (PrX) \u003csup\u003e\u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e63\u003c/span\u003e\u003c/sup\u003e and optimal CPP (CPPopt) \u003csup\u003e\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e64\u003c/span\u003e\u003c/sup\u003e there has been a growing interest in individualized CPP-management \u003csup\u003e\u003cspan additionalcitationids=\"CR66 CR67\" citationid=\"CR67\" class=\"CitationRef\"\u003e65\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR71\" class=\"CitationRef\"\u003e68\u003c/span\u003e\u003c/sup\u003e. Even though this is theoretically appealing, to date there is still no gold standard for estimating cerebral autoregulation \u003csup\u003e\u003cspan citationid=\"CR72\" class=\"CitationRef\"\u003e69\u003c/span\u003e\u003c/sup\u003e, and there is conflicting evidence regarding the clinical benefits of CPPopt-guided treatment \u003csup\u003e\u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e67\u003c/span\u003e,\u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e70\u003c/span\u003e,\u003cspan citationid=\"CR74\" class=\"CitationRef\"\u003e71\u003c/span\u003e\u003c/sup\u003e. Moreover, CPPopt has only been prospectively evaluated by comparing CPPopt-guided treatment to treatment according to current guidelines (CPP 60\u0026ndash;70 mmHg) \u003csup\u003e\u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e66\u003c/span\u003e\u003c/sup\u003e and not compared to lower CPP thresholds. The present study is cautiously supportive of CPP values between 51\u0026ndash;60 mmHg and the avoidance of CPP values\u0026thinsp;\u0026gt;\u0026thinsp;60 mmHg. Our findings closely align with those of a study by Elf et al. \u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e, which similarly included patients in poor clinical condition, characterized by features such as dilated pupils and/or low GCS scores. This might suggest that the severely injured adult brain is highly sensitive to both low and high CPP values. Thus, a narrow target range, rather than a lower limit, is warranted. The absence of a correlation between low CPP values and outcome is most likely explained by the very high rate of CPP control achieved (95% of CPP\u0026thinsp;\u0026gt;\u0026thinsp;50 mmHg).\u003c/p\u003e \u003cp\u003eThe effects of metoprolol and clonidine could also go beyond the mere reduction of CPP. Both metoprolol and clonidine have been proposed to reduce mortality and improve outcome in severe and moderate TBI by different suggested mechanisms as reduction of catecholamine outflow and immune modulation \u003csup\u003e\u003cspan additionalcitationids=\"CR73\" citationid=\"CR76\" class=\"CitationRef\"\u003e72\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR78\" class=\"CitationRef\"\u003e74\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe low percentage of elevated ICP in our study argues that the LC is effective in achieving ICP control in a majority of patients. The relatively low incidence of DC (11%) compared to other studies \u003csup\u003e\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e may argue for a more pharmacological approach when managing moderately elevated ICP-values.\u003c/p\u003e \u003cp\u003eWe acknowledge that there are several limitations to the present study. As with all retrospective studies there are inherent uncertainties regarding data accuracy, various forms of bias and confounding factors. Data was collected over a relatively long time period, which may have affected the results. ICP and CPP were only recorded every hour, which in conjunction with the stringent control of CPP and ICP may explain the lack of correlation between high ICP/low CPP and outcome. High-frequency data sampling would have been desirable, as we believe this is crucial for determining optimal ICP and CPP thresholds in future studies. Moreover, the lower CPP values in patients with favorable outcome, as shown in the present study, must be interpreted with caution, as they may be influenced by confounding factors such as cardiovascular disease, age, secondary insults, autoregulatory status and other factors. As stated in the results, most of these correlations did not remain significant after applying Bonferroni correction, further emphasizing that although CPP\u0026thinsp;\u0026lt;\u0026thinsp;60 mmHg was well tolerated in this cohort, this does not imply that CPP should be maintained\u0026thinsp;\u0026lt;\u0026thinsp;60 mmHg in all adult severe TBI patients. Severe TBI encompasses a range of diagnoses and optimal CPP ranges in patients with predominantly contusions and TSAH most likely differ from those in patients with mass lesions and ICP liability.\u003c/p\u003e \u003cp\u003eAlthough the low rate of elevated ICP may suggest that the Lund Concept is effective in achieving ICP control, it may also explain why CPP\u0026thinsp;\u0026lt;\u0026thinsp;60 mmHg was well tolerated. This does not provide evidence that maintaining CPP\u0026thinsp;\u0026lt;\u0026thinsp;60 mmHg is beneficial in clinical scenarios involving, for example, vasospasm and/or ICP instability. Another limitation of the present study is that head elevation, a common practice in the management of severe TBI, was not accounted for as the level of head elevation was not recorded in the medical charts. Theoretically, this could alter CPP values, leading to ambiguous results.\u003c/p\u003e \u003cp\u003eThe initial GCS assessment is often performed by less experienced physicians, which may lead to that some patients are assigned an erroneous GCS score, thereby skewing outcome data. Our NICU at Skane University Hospital is a referral center for the southern Swedish health region thus admitting all patients considered eligible for the treatment based on compound evaluation based on comorbidity, age, and severity of TBI. Although this ascertains a relatively constant selection over time, we cannot rule out bias due to varying preferences of admission by individual physicians on call.\u003c/p\u003e \u003cp\u003eIt is also worth noting that the Marshall Classification was used for radiological classification of TBI in the present study. Although several previous studies suggest that alternative radiological classifications may provide a more accurate description of injury severity and improved outcome prediction in severe TBI \u003csup\u003e\u003cspan additionalcitationids=\"CR76\" citationid=\"CR79\" class=\"CitationRef\"\u003e75\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR77\" class=\"CitationRef\"\u003e77\u003c/span\u003e\u003c/sup\u003e, no universal gold standard currently exists. The Marshall Classification remains widely used in recent relevant studies \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e,\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e,\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e54\u003c/span\u003e\u003c/sup\u003e and was therefore used in the present study to facilitate comparison with previously published data.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eTreatment of adults with severe TBI according to the Lund concept resulted in low morbidity and mortality. A CPP of 51\u0026ndash;60 mmHg was well tolerated and correlated with favorable outcome.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to extend their thanks to Susanne M\u0026aring;nsson and Marit B\u0026auml;ckstr\u0026ouml;m for help with retrieving patient data from the neurointensive care unit, and for help with patient follow-up.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthorship confirmation/contribution statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLR, PS and AR drafted and designed the study. EV designed and executed the statistical analyses. LR, AR and PS collected data for the study. LR and AR wrote an initial manuscript draft. All authors commented on and approved the final manuscript. PS and NM supervised the project.\u0026nbsp;\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eDisclosure\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests or other disclosures.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was supported by grants from Region Sk\u0026aring;ne and Lund University (ALF).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHuman Ethics and Consent to Participate\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent not applicable. The Swedish Ethical Review Authority has approved that NICU data from all patients treated at the departement of neurosurgery, Lund may be used in retrospective analyses (Reference number: 2017/469). All data has been de-identified and is presented only at the group level, not at the individual level.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eArtificial Intelligence\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe grammar and spelling of this study have, in part, been reviewed using ChatGPT ( https://openai.com/index/chatgpt/ChatGPT | OpenAI). The authors have processed the generated text and images and take full responsibility for the content.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMaas AIR, Menon DK, Manley GT et al (2022) Traumatic brain injury: progress and challenges in prevention, clinical care, and research. Lancet Neurol 21(11):1004\u0026ndash;1060. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/S1474-4422(22)00309-X\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\n\u003cli\u003eMaas AI, Stocchetti N, Bullock R (2008) Moderate and severe traumatic brain injury in adults. 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DOI: ARTN 92\u003c/li\u003e\n\u003cli\u003e1186/s40635-023-00579-3\u003c/li\u003e\n\u003cli\u003eAlshaya AI, Aldhaeefi M, Alodhaiyan N et al (2023) Clonidine safety and effectiveness in the management of suspected paroxysmal sympathetic hyperactivity post-traumatic brain injury: A retrospective cohort study. Sci Prog 106(4):00368504231201298. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1177/00368504231201298\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\n\u003cli\u003eLoftus TJ, Efron PA, Moldawer LL, Mohr AM (2016) \u0026amp;bgr-Blockade use for Traumatic Injuries and Immunomodulation. SHOCK 46(4):341\u0026ndash;351. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/shk.0000000000000636\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\n\u003cli\u003eZangbar B, Khalil M, Rhee P et al (2016) Metoprolol improves survival in severe traumatic brain injury independent of heart rate control. J Surg Res 200(2):586\u0026ndash;592. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.jss.2015.08.020\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\n\u003cli\u003eBiuki NM, Talari HR, Tabatabaei MH et al (2023) Comparison of the predictive value of the Helsinki, Rotterdam, and Stockholm CT scores in predicting 6-month outcomes in patients with blunt traumatic brain injuries. Chin J Traumatol 26(6):357\u0026ndash;362. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.cjtee.2023.04.002\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\n\u003cli\u003eFletcher-Sandersjoo A, Tatter C, Yang L et al (2022) Stockholm score of lesion detection on computed tomography following mild traumatic brain injury (SELECT-TBI): study protocol for a multicentre, retrospective, observational cohort study. BMJ Open 12(9):e060679. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1136/bmjopen-2021-060679\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\n\u003cli\u003eRaj R, Siironen J, Skrifvars MB, Hernesniemi J, Kivisaari R (2014) Predicting outcome in traumatic brain injury: development of a novel computerized tomography classification system (Helsinki computerized tomography score). Neurosurgery 75(6):632\u0026ndash;646 discussion 646-7. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1227/NEU.0000000000000533\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1.\u0026nbsp;\u003c/strong\u003ePatient characteristics. Clinical and radiological features of all admitted patients presented as absolute values (n) and relative values (%). \u0026nbsp;EDH \u0026ndash; Epidural Hematoma, GCS \u0026ndash; Glasgow Coma Scale, SDH \u0026ndash; Subdural Hematoma, TSAH \u0026ndash; Traumatic Subarachnoid Hemorrhage \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"442\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 70.5882%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 14.7059%;\"\u003en\u003c/td\u003e\n \u003ctd style=\"width: 14.7059%;\"\u003e%\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 70.5882%;\"\u003e\n \u003cp\u003ePatients\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e171\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 70.5882%;\"\u003e\n \u003cp\u003eAge (median)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e48\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 70.5882%;\"\u003e\n \u003cp\u003eMale\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e127\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e74\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 70.5882%;\"\u003e\n \u003cp\u003eFemale\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e44\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 70.5882%;\"\u003e\n \u003cp\u003eGCS 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 70.5882%;\"\u003e\n \u003cp\u003eGCS 4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 70.5882%;\"\u003e\n \u003cp\u003eGCS 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 70.5882%;\"\u003e\n \u003cp\u003eGCS 6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 70.5882%;\"\u003e\n \u003cp\u003eGCS 7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 70.5882%;\"\u003e\n \u003cp\u003eGCS 8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 70.5882%;\"\u003e\n \u003cp\u003eGCS 9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 70.5882%;\"\u003e\n \u003cp\u003eGCS 12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 70.5882%;\"\u003e\n \u003cp\u003eGCS 13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 70.5882%;\"\u003e\n \u003cp\u003eGCS 14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 70.5882%;\"\u003e\n \u003cp\u003eGCS 15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 70.5882%;\"\u003e\n \u003cp\u003eMarshall 1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 70.5882%;\"\u003e\n \u003cp\u003eMarshall 2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 70.5882%;\"\u003e\n \u003cp\u003eMarshall 3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 70.5882%;\"\u003e\n \u003cp\u003eMarshall 5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e105\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e61\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 70.5882%;\"\u003e\n \u003cp\u003eMarshall 6\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 70.5882%;\"\u003e\n \u003cp\u003eEDH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 70.5882%;\"\u003e\n \u003cp\u003eSDH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e51\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 70.5882%;\"\u003e\n \u003cp\u003eTSAH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e35\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 70.5882%;\"\u003e\n \u003cp\u003eContusion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e111\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e65\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 70.5882%;\"\u003e\n \u003cp\u003eFixed pupils\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e97\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e57\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 70.5882%;\"\u003e\n \u003cp\u003e-bilateral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 70.5882%;\"\u003e\n \u003cp\u003e-unilateral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e51\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 70.5882%;\"\u003e\n \u003cp\u003eComorbidities\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e54\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 70.5882%;\"\u003e\n \u003cp\u003e-hypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 70.5882%;\"\u003e\n \u003cp\u003e-alcohol abuse\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 70.5882%;\"\u003e\n \u003cp\u003e-diabetes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 70.5882%;\"\u003e\n \u003cp\u003e-depression\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 70.5882%;\"\u003e\n \u003cp\u003e-other\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.7059%;\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2.\u0026nbsp;\u003c/strong\u003eSummary of surgical and medical treatment. Absolute values (n) and relative values (%) are presented respectively. Medical treatment is shown as median values of total doses. DC \u0026ndash; Decompressive Hemicraniectomy, ICP \u0026ndash; Intracranial Pressure\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"426\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 69.4836%;\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15.2582%;\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15.2582%;\"\u003e\n \u003cp\u003e%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 69.4836%;\"\u003e\n \u003cp\u003eConservative treatment\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15.2582%;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15.2582%;\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 69.4836%;\"\u003e\n \u003cp\u003eHematoma evacuation without ICP-monitoring\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15.2582%;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15.2582%;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 69.4836%;\"\u003e\n \u003cp\u003eOnly ICP-monitor\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15.2582%;\"\u003e\n \u003cp\u003e41\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15.2582%;\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 69.4836%;\"\u003e\n \u003cp\u003eDecompressive surgery and ICP-monitoring\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15.2582%;\"\u003e\n \u003cp\u003e114\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15.2582%;\"\u003e\n \u003cp\u003e67\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 69.4836%;\"\u003e\n \u003cp\u003eDC\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15.2582%;\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15.2582%;\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 69.4836%;\"\u003e\n \u003cp\u003ePropofol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15.2582%;\"\u003e\n \u003cp\u003e146\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15.2582%;\"\u003e\n \u003cp\u003e85\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 69.4836%;\"\u003e\n \u003cp\u003e- median dose (mg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15.2582%;\"\u003e\n \u003cp\u003e3120\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15.2582%;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 69.4836%;\"\u003e\n \u003cp\u003eMidazolam\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15.2582%;\"\u003e\n \u003cp\u003e114\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15.2582%;\"\u003e\n \u003cp\u003e67\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 69.4836%;\"\u003e\n \u003cp\u003e-median dose (mg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15.2582%;\"\u003e\n \u003cp\u003e2083\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15.2582%;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 69.4836%;\"\u003e\n \u003cp\u003eMetoprolol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15.2582%;\"\u003e\n \u003cp\u003e102\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15.2582%;\"\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 69.4836%;\"\u003e\n \u003cp\u003e-median dose (mg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15.2582%;\"\u003e\n \u003cp\u003e126\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15.2582%;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 69.4836%;\"\u003e\n \u003cp\u003eClonidine\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15.2582%;\"\u003e\n \u003cp\u003e117\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15.2582%;\"\u003e\n \u003cp\u003e68\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 69.4836%;\"\u003e\n \u003cp\u003e-median dose (ug)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15.2582%;\"\u003e\n \u003cp\u003e2370\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15.2582%;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 69.4836%;\"\u003e\n \u003cp\u003ePentothal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15.2582%;\"\u003e\n \u003cp\u003e32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15.2582%;\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 69.4836%;\"\u003e\n \u003cp\u003e-median dose (mg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15.2582%;\"\u003e\n \u003cp\u003e8163\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 15.2582%;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3. \u0026nbsp;\u003c/strong\u003eA summary of all hourly collected ICP- and CPP values. Absolute (n) and relative (%) values for different cutoffs are shown. \u0026nbsp;ICP \u0026ndash; Intracranial Pressure, CPP \u0026ndash; Cerebral Perfusion Pressure\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"430\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 44.6429%;\"\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 27.6786%;\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 27.6786%;\"\u003e\n \u003cp\u003e%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 44.6429%;\"\u003e\n \u003cp\u003eICP (all values)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 27.6786%;\"\u003e\n \u003cp\u003e24683\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 27.6786%;\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 44.6429%;\"\u003e\n \u003cp\u003e\u0026lt; 15 mmHg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 27.6786%;\"\u003e\n \u003cp\u003e17301\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 27.6786%;\"\u003e\n \u003cp\u003e70\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 44.6429%;\"\u003e\n \u003cp\u003e15-20 mmHg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 27.6786%;\"\u003e\n \u003cp\u003e5375\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 27.6786%;\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 44.6429%;\"\u003e\n \u003cp\u003e21-30 mmHg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 27.6786%;\"\u003e\n \u003cp\u003e1754\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 27.6786%;\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 44.6429%;\"\u003e\n \u003cp\u003e\u0026gt; 30 mmHg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 27.6786%;\"\u003e\n \u003cp\u003e253\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 27.6786%;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 44.6429%;\"\u003e\n \u003cp\u003eCPP (all values)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 27.6786%;\"\u003e\n \u003cp\u003e22772\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 27.6786%;\"\u003e\n \u003cp\u003e100\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 44.6429%;\"\u003e\n \u003cp\u003e\u0026lt; 40 mmHg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 27.6786%;\"\u003e\n \u003cp\u003e124\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 27.6786%;\"\u003e\n \u003cp\u003e\u0026lt; 1\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 44.6429%;\"\u003e\n \u003cp\u003e40-50 mmHg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 27.6786%;\"\u003e\n \u003cp\u003e1069\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 27.6786%;\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 44.6429%;\"\u003e\n \u003cp\u003e51-60 mmHg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 27.6786%;\"\u003e\n \u003cp\u003e3973\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 27.6786%;\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 44.6429%;\"\u003e\n \u003cp\u003e\u0026gt; 60 mmHg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 27.6786%;\"\u003e\n \u003cp\u003e17606\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 27.6786%;\"\u003e\n \u003cp\u003e77\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4.\u0026nbsp;\u003c/strong\u003eClinical parameters and ICP/CPP, stratified by outcome. Patients with favorable and unfavorable outcome are presented in 4a. Deceased and alive patients are presented in 4b. GCS \u0026ndash; Glasgow Coma Scale, IQR \u0026ndash; Interquartile Range, ICP \u0026ndash; Intracranial Pressure, CPP \u0026ndash; Cerebral Perfusion Pressure, OR \u0026ndash; Odds Ratio, CI \u0026ndash; Confidence Interval\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4a\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"779\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 37.3556%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.5802%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFavorable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 13.2221%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eUnfavorable\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 27.2144%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOR (95 % CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.62773%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 37.3556%;\"\u003e\n \u003cp\u003eAge (median (IQR))\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.5802%;\"\u003e\n \u003cp\u003e38(32.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 13.2221%;\"\u003e\n \u003cp\u003e57(27.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 27.2144%;\"\u003e\n \u003cp\u003e0.96 (0.95 - 0.98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.62773%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.0002\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 37.3556%;\"\u003e\n \u003cp\u003eGCS (median (IQR))\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.5802%;\"\u003e\n \u003cp\u003e8(3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 13.2221%;\"\u003e\n \u003cp\u003e6(5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 27.2144%;\"\u003e\n \u003cp\u003e1.057(0.965 - 1.1597)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.62773%;\"\u003e\n \u003cp\u003e0.239\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 37.3556%;\"\u003e\n \u003cp\u003eUnilateral pupil dilatation (n (%))\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.5802%;\"\u003e\n \u003cp\u003e14 (20%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 13.2221%;\"\u003e\n \u003cp\u003e16 (24%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 27.2144%;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.62773%;\"\u003e\n \u003cp\u003e0.5728\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 37.3556%;\"\u003e\n \u003cp\u003eBilateral pupil dilatation (n (%))\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.5802%;\"\u003e\n \u003cp\u003e8 (11%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 13.2221%;\"\u003e\n \u003cp\u003e5 (7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 27.2144%;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.62773%;\"\u003e\n \u003cp\u003e0.5728\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 37.3556%;\"\u003e\n \u003cp\u003eUnilateral pupil light respons (n (%))\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.5802%;\"\u003e\n \u003cp\u003e12 (17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 13.2221%;\"\u003e\n \u003cp\u003e13 (19%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 27.2144%;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.62773%;\"\u003e\n \u003cp\u003e0.8893\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 37.3556%;\"\u003e\n \u003cp\u003eNo pupil light respons (n (%))\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.5802%;\"\u003e\n \u003cp\u003e8 (11%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 13.2221%;\"\u003e\n \u003cp\u003e8 (12%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 27.2144%;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.62773%;\"\u003e\n \u003cp\u003e0.8893\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 37.3556%;\"\u003e\n \u003cp\u003eMarshall (median (IQR))\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.5802%;\"\u003e\n \u003cp\u003e5 (3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 13.2221%;\"\u003e\n \u003cp\u003e5 (3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 27.2144%;\"\u003e\n \u003cp\u003e1.03 (0.81 - 1.32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.62773%;\"\u003e\n \u003cp\u003e0.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 37.3556%;\"\u003e\n \u003cp\u003eRelative ICP \u0026gt; 20 mmHg (median (IQR))\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.5802%;\"\u003e\n \u003cp\u003e0.0099 (0.049)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 13.2221%;\"\u003e\n \u003cp\u003e0.0155 (0.086)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 27.2144%;\"\u003e\n \u003cp\u003e0.120 (0.0029 - 3.679)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.62773%;\"\u003e\n \u003cp\u003e0.236\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 37.3556%;\"\u003e\n \u003cp\u003eAbsolute ICP \u0026gt; 20 mmHg (median (IQR))\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.5802%;\"\u003e\n \u003cp\u003e3 (15.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 13.2221%;\"\u003e\n \u003cp\u003e3.5 (19.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 27.2144%;\"\u003e\n \u003cp\u003e1.003 (0.989 - 1.018)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.62773%;\"\u003e\n \u003cp\u003e0.657\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 37.3556%;\"\u003e\n \u003cp\u003eRelative ICP \u0026lt; 15 mmHg (median (IQR))\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.5802%;\"\u003e\n \u003cp\u003e0.735 (0.588)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 13.2221%;\"\u003e\n \u003cp\u003e0.756 (0.506)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 27.2144%;\"\u003e\n \u003cp\u003e0.57 (0.23 -1.40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.62773%;\"\u003e\n \u003cp\u003e0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 37.3556%;\"\u003e\n \u003cp\u003eAbsolute ICP \u0026lt; 15 mmHg \u0026nbsp;(median (IQR))\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.5802%;\"\u003e\n \u003cp\u003e110 (83)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 13.2221%;\"\u003e\n \u003cp\u003e105 (108)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 27.2144%;\"\u003e\n \u003cp\u003e1.0 (0.996 - 1.003)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.62773%;\"\u003e\n \u003cp\u003e0.65\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 37.3556%;\"\u003e\n \u003cp\u003eRelative CPP \u0026gt; 60 mmHg \u0026nbsp;(median (IQR))\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.5802%;\"\u003e\n \u003cp\u003e0.722 (0.429)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 13.2221%;\"\u003e\n \u003cp\u003e0.844 (0.271)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 27.2144%;\"\u003e\n \u003cp\u003e0.28 (0.09 - 0.78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.62773%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.02\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 37.3556%;\"\u003e\n \u003cp\u003eAbsolute CPP \u0026gt; 60 mmHg \u0026nbsp;(median (IQR))\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.5802%;\"\u003e\n \u003cp\u003e89 (124)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 13.2221%;\"\u003e\n \u003cp\u003e122 (124)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 27.2144%;\"\u003e\n \u003cp\u003e1.00(1.00 - 1.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.62773%;\"\u003e\n \u003cp\u003e0.8\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 37.3556%;\"\u003e\n \u003cp\u003eRelative CPP 51-60 mmHg \u0026nbsp;(median (IQR))\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.5802%;\"\u003e\n \u003cp\u003e0.111 (0.277)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 13.2221%;\"\u003e\n \u003cp\u003e0.098 (0.165)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 27.2144%;\"\u003e\n \u003cp\u003e1.75 (0.17-18.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.62773%;\"\u003e\n \u003cp\u003e0.64\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 37.3556%;\"\u003e\n \u003cp\u003eAbsolute CPP 51-60 mmHg \u0026nbsp;(median (IQR))\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.5802%;\"\u003e\n \u003cp\u003e23.5 (41.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 13.2221%;\"\u003e\n \u003cp\u003e17 (29)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 27.2144%;\"\u003e\n \u003cp\u003e1.01 (0.997 - 1.02)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.62773%;\"\u003e\n \u003cp\u003e0.16\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 37.3556%;\"\u003e\n \u003cp\u003eRelative CPP \u0026lt; 40 mmHg \u0026nbsp;(median (IQR))\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.5802%;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 13.2221%;\"\u003e\n \u003cp\u003e0 (0.00283)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 27.2144%;\"\u003e\n \u003cp\u003e\u0026lt; 0.0000001 (\u0026lt;0.001 - 7.8)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.62773%;\"\u003e\n \u003cp\u003e0.3\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 37.3556%;\"\u003e\n \u003cp\u003eAbsolute CPP \u0026lt; 40 mmHg \u0026nbsp;(median (IQR))\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12.5802%;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 13.2221%;\"\u003e\n \u003cp\u003e0 (1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 27.2144%;\"\u003e\n \u003cp\u003e0.93 (0.74 - 1.04)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.62773%;\"\u003e\n \u003cp\u003e0.38\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4b\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"788\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 35.4061%;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.4315%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDeceased (6 months)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.3401%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAlive\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.1777%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOR (95 % CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.64467%;\"\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 35.4061%;\"\u003e\n \u003cp\u003eAge (median (IQR))\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.4315%;\"\u003e\n \u003cp\u003e61 (12.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.3401%;\"\u003e\n \u003cp\u003e42.5 (33.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.1777%;\"\u003e\n \u003cp\u003e1.05 (1.02 - 1.08)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.64467%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.0004\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 35.4061%;\"\u003e\n \u003cp\u003eGCS (median (IQR))\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.4315%;\"\u003e\n \u003cp\u003e6 (8.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.3401%;\"\u003e\n \u003cp\u003e8 (4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.1777%;\"\u003e\n \u003cp\u003e0.982(0.872 - 1.098)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.64467%;\"\u003e\n \u003cp\u003e0.756\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 35.4061%;\"\u003e\n \u003cp\u003eUnilateral pupil dilatation (n (%))\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.4315%;\"\u003e\n \u003cp\u003e4 (13%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.3401%;\"\u003e\n \u003cp\u003e26 (24%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.1777%;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.64467%;\"\u003e\n \u003cp\u003e0.4175\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 35.4061%;\"\u003e\n \u003cp\u003eBilateral pupil dilatation \u0026nbsp;(n (%))\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.4315%;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.3401%;\"\u003e\n \u003cp\u003e13 (12%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.1777%;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.64467%;\"\u003e\n \u003cp\u003e0.4175\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 35.4061%;\"\u003e\n \u003cp\u003eUnilateral pupil light respons (n (%))\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.4315%;\"\u003e\n \u003cp\u003e3 (10%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.3401%;\"\u003e\n \u003cp\u003e22 (20%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.1777%;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.64467%;\"\u003e\n \u003cp\u003e0.2623\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 35.4061%;\"\u003e\n \u003cp\u003eNo pupil light respons (n (%))\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.4315%;\"\u003e\n \u003cp\u003e2 (7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.3401%;\"\u003e\n \u003cp\u003e13 (12%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.1777%;\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.64467%;\"\u003e\n \u003cp\u003e0.2623\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 35.4061%;\"\u003e\n \u003cp\u003eMarshall (median (IQR))\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.4315%;\"\u003e\n \u003cp\u003e5 (2.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.3401%;\"\u003e\n \u003cp\u003e5 (3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.1777%;\"\u003e\n \u003cp\u003e1.05 (0.8 - 1.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.64467%;\"\u003e\n \u003cp\u003e0.7\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 35.4061%;\"\u003e\n \u003cp\u003eRelative ICP \u0026gt; 20 mmHg (median (IQR))\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.4315%;\"\u003e\n \u003cp\u003e0.0097 (0.044)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.3401%;\"\u003e\n \u003cp\u003e0.0135 (0.080)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.1777%;\"\u003e\n \u003cp\u003e1.199 (0.0112 - 59.4552)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.64467%;\"\u003e\n \u003cp\u003e0.932\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 35.4061%;\"\u003e\n \u003cp\u003eAbsolute ICP \u0026gt; 20 mmHg (median (IQR))\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.4315%;\"\u003e\n \u003cp\u003e3 (8.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.3401%;\"\u003e\n \u003cp\u003e3.5 (20.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.1777%;\"\u003e\n \u003cp\u003e0.978 (0.9412 - 1.0029)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.64467%;\"\u003e\n \u003cp\u003e0.172\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 35.4061%;\"\u003e\n \u003cp\u003eRelative ICP \u0026lt; 15 mmHg (median (IQR))\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.4315%;\"\u003e\n \u003cp\u003e0.802 (0.587)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.3401%;\"\u003e\n \u003cp\u003e0.735 (0.537)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.1777%;\"\u003e\n \u003cp\u003e1.09 (0.36 - 3.57)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.64467%;\"\u003e\n \u003cp\u003e0.88\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 35.4061%;\"\u003e\n \u003cp\u003eAbsolut ICP \u0026lt; 15 mmHg \u0026nbsp;(median (IQR))\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.4315%;\"\u003e\n \u003cp\u003e81 (115)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.3401%;\"\u003e\n \u003cp\u003e110 (88.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.1777%;\"\u003e\n \u003cp\u003e1 (0.995 - 1.004)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.64467%;\"\u003e\n \u003cp\u003e0.94\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 35.4061%;\"\u003e\n \u003cp\u003eRelative CPP \u0026gt; 60 mmHg \u0026nbsp;(median (IQR))\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.4315%;\"\u003e\n \u003cp\u003e0.853 (0.281)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.3401%;\"\u003e\n \u003cp\u003e0.769 (0.329)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.1777%;\"\u003e\n \u003cp\u003e1.41 (0.4 - 5.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.64467%;\"\u003e\n \u003cp\u003e0.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 35.4061%;\"\u003e\n \u003cp\u003eAbsolute CPP \u0026gt; 60 mmHg \u0026nbsp;(median (IQR))\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.4315%;\"\u003e\n \u003cp\u003e68 (142)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.3401%;\"\u003e\n \u003cp\u003e119 (122)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.1777%;\"\u003e\n \u003cp\u003e1.0 (0.994 - 1.003)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.64467%;\"\u003e\n \u003cp\u003e0.6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 35.4061%;\"\u003e\n \u003cp\u003eRelative CPP 51-60 mmHg \u0026nbsp;(median (IQR))\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.4315%;\"\u003e\n \u003cp\u003e0.073 (0.104)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.3401%;\"\u003e\n \u003cp\u003e0.111 (0.248)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.1777%;\"\u003e\n \u003cp\u003e0.03 (0.008 - 0.68)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.64467%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.04\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 35.4061%;\"\u003e\n \u003cp\u003eAbsolute CPP 51-60 mmHg \u0026nbsp;(median (IQR))\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.4315%;\"\u003e\n \u003cp\u003e8 (14.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.3401%;\"\u003e\n \u003cp\u003e23 (38.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.1777%;\"\u003e\n \u003cp\u003e0.97 (0.94 - 0.99)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.64467%;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.01\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 35.4061%;\"\u003e\n \u003cp\u003eRelative CPP \u0026lt; 40 mmHg \u0026nbsp;(median (IQR))\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.4315%;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.3401%;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.1777%;\"\u003e\n \u003cp\u003e\u0026gt; 10 000 (2.3 - \u0026gt;10 000)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.64467%;\"\u003e\n \u003cp\u003e0.2\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 35.4061%;\"\u003e\n \u003cp\u003eAbsolute CPP \u0026lt; 40 mmHg \u0026nbsp;(median (IQR))\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.4315%;\"\u003e\n \u003cp\u003e0 (0.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 14.3401%;\"\u003e\n \u003cp\u003e0 (0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 20.1777%;\"\u003e\n \u003cp\u003e1.08 (0.99 - 1.28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9.64467%;\"\u003e\n \u003cp\u003e0.17\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e* Difficult to interpret data due to a very limited number of values\u003c/p\u003e\n\u003cp\u003e\u003csup\u003ea\u003c/sup\u003e\u0026nbsp; Information regarding pupillary status was missing in 18 patients (12%)\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Traumatic brain injury, Intracranial pressure, Cerebral perfusion pressure, Lund Concept, Neurointensive care, Glasgow Outcome Scale – extended (GOS-E)","lastPublishedDoi":"10.21203/rs.3.rs-6079964/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6079964/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e Current guidelines for the treatment of severe TBI recommend maintaining a cerebral perfusion pressure (CPP) above 60 mmHg. However, the rationale for this target is not supported by high-level evidence demonstrating improved outcomes. In our institution, as well as others, an alternative algorithm—originally named the Lund concept—has been used. This approach employs metoprolol and clonidine to limit CPP, allowing levels below 60 mmHg, with the aim of reducing cerebral edema. Previous reports on this algorithm have suggested better outcomes compared to contemporary practices, but no population-based studies have been conducted to validate these findings.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResearch Question:\u003c/strong\u003e Does allowing CPP levels lower than 60 mmHg improve outcome in severe TBI?\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e The study included all adult patients (n=171) treated for severe traumatic brain injury (TBI) over a ten-year period in the southern Swedish healthcare region. Baseline data, intracranial pressure (ICP), CPP, treatment duration, surgical interventions, and administered drugs were correlated to the Glasgow Outcome Scale Extended (GOSE).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e The 30-day and 6-month mortality rates were 16% and 20%, respectively. Good outcome (GOSE 7-8) was achieved in 29% of patients. Ordinal and linear regression analyses indicated that a CPP of 51-60 mmHg correlated with survival, while age and a CPP \u0026gt; 60 mmHg were associated with worse outcome.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e The application of CPP levels lower than those currently recommended appears to result in better outcomes compared to relevant population-based reports. However, it is possible that the use of metoprolol and clonidine may have additional effects beyond simply reducing CPP.\u003c/p\u003e","manuscriptTitle":"A cerebral perfusion pressure (CPP) ≤ 60 mmHg correlated with favorable outcome in adult severe traumatic brain injury patients - a retrospective study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-15 11:56:04","doi":"10.21203/rs.3.rs-6079964/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"31c62f8d-ffa1-406f-bc1a-7cf3f99ee3c1","owner":[],"postedDate":"April 15th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-05-05T20:38:25+00:00","versionOfRecord":[],"versionCreatedAt":"2025-04-15 11:56:04","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6079964","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6079964","identity":"rs-6079964","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}