Cerebral perfusion pressure, microdialysis biochemistry and clinical outcome in patients with traumatic brain injury
© Paraforou et al.; licensee BioMed Central Ltd. 2011
Received: 25 August 2011
Accepted: 14 December 2011
Published: 14 December 2011
Traumatic Brain Injury (TBI) is a major cause of death and disability. It has been postulated that brain metabolic status, intracranial pressure (ICP) and cerebral perfusion pressure (CPP) are related to patients' outcome. The aim of this study was to investigate the relationship between CPP, ICP and microdialysis parameters and clinical outcome in TBIs.
Thirty four individuals with severe brain injury hospitalized in an intensive care unit participated in this study. Microdialysis data were collected, along with ICP and CPP values. Glasgow Outcome Scale (GOS) was used to evaluate patient outcome at 6 months after injury. Fifteen patients with a CPP greater than 75 mmHg, L/P ratio lower than 37 and Glycerol concentration lower than 72 mmol/l had an excellent outcome (GOS 4 or 5), as opposed to the remaining 19 patients. No patient with a favorable outcome had a CPP lower than 75 mmHg or Glycerol concentration and L/P ratio greater than 72 mmol/l and 37 respectively. Data regarding L/P ratio and Glycerol concentration were statistically significant at p = 0.05 when patients with favorable and unfavorable outcome were compared. In a logistic regression model adjusted for age, sex and Glasgow Coma Scale on admission, a CPP greater than 75 mmHg was marginally statistically significantly related to outcome at 6 months after injury.
Patients with favorable outcome had certain common features in terms of microdialysis parameters and CPP values. An individualized approach regarding CPP levels and cut -off points for Glycerol concentration and L/P ratio are proposed.
KeywordsTraumatic brain injury Microdialysis Cerebral perfusion pressure Outcome Intensive care unit
Traumatic Brain Injury (TBI) is a major cause of death and disability . Beyond the primary injury, the secondary insults account for an unfavorable outcome . It is now feasible to monitor and record physiological variables with computerized multimodality monitoring systems in the neurointensive care unit patients. Monitoring assists the physician to implement the appropriate therapy and gives information about the expected outcome [3, 4]. It has been shown that poor outcome is related to high Intracranial Pressure (ICP), and low Cerebral Perfusion Pressure (CPP) [5–7]. Besides that, brain metabolic status, as it is expressed via glucose, glycerol and lactate-pyruvate (L/P) ratio has also been correlated to clinical outcome in various studies. High values of L/P ratio, Glycerol concentration and PbtO2, as well as low levels of Glucose have been related to poor outcome. However, data regarding certain cut-off points for the latter parameters are insufficient. Only broad value ranges for metabolic parameters are currently in use. The clinical use of CPP is based on theoretical suggestions that maintaining optimal cerebral blood flow is necessary to meet the metabolic needs of the injured brain . The goal is to preserve the ischemic penubra and avoid exacerbation of secondary insults. Based on international guidelines, a low threshold of CPP value is recommended , while there is a controversy regarding the upper limit of CPP values . It has been postulated that high values of CPP could be harmful, given that in many brain injuries brain auto-regulation is severely damaged. However, raised CPP values could be beneficial to many patients, even at relatively high ICP levels . The aim of this paper was to investigate the relation of CPP values and clinical outcome in patients with severe brain injuries as well as to assess the effectiveness of multimodal brain monitoring in relation to patients outcome.
Thirty - four patients (29 men and 5 women) participated in the study. They had suffered a traumatic brain injury and hospitalization in an intensive care unit was necessary (Glasgow Coma Scale ≤ 8). All patients received conservative treatment. Informed consent was obtained from the families of the patients. All patients were intubated, sedated and occasionally paralyzed. If an emergency operation was not required, cranial bolts for measurement of PbtO2, ICP and a brain MicroDialysis (MD) catheters were placed. Τhe three catheters were inserted into the brain through a triple lumen introducer kit (Integra, CMA 70 microdialysis bolt catheter) in the right frontal lobe, in the case of a diffuse damage, or in the ipsilateral frontal lobe in the case of a regional damage. A networked computerized multimodality monitoring system was used. Microdialysis data were collected every 2 hours and ICP and CPP were studied. Brain Glucose (Glu), Glycerol (Gly), Pyruvate, Lactate concentrations and PbtO2 were monitored. All patients were treated according to modern neurointensive care principles. The goal was to maintain a level of ICP < 20 mmHg, an acceptable PbtO2 ~ 20 mm, a Lactate/Pyruvate (L/P) ratio around 20-25, and definitely below 40. CPP values were appropriately adjusted, among other neuroprotective interventions, in order to achieve the aforementioned objective. The brain monitoring commenced within the first 24 hours of brain injury and continued until catheters were removed due to normalization of the monitored parameters without any neuroprotective intervention for 24 hours. For homogeneity reasons, in the case of prolonged monitoring, data from the first 10 days of hospitalization were evaluated. Glasgow Outcome Scale was used to evaluate patient outcome at 6 months after the injury. Ethical approval was given with the 158-22711 decision of the local ethical committee ("Koutlimpaneio & Triantafyllio Hospital" Scientific Committee).
The Mann-Whitney U-test was used to compare median values of variables that were not normally distributed (Normality control test: Shapiro-Wilk). GOS variable was dichotomized (binary distribution) according to favorable and unfavorable outcomes. Values greater than 3 (> 3) were considered as favorable outcome, while values ≤3 as an unfavorable one.
Mean CPP values were dichotomized at the level of 75 mmHg. The x2 test was used for comparisons of outcome rates, and Fisher's exact probability test was used, when the number of observations in a 2 × 2 contingency table was small enough. A logistic regression model was used for outcome prognosis. SPSS 17.0 was used for statistics.
Demographic characteristics of the sample, evaluation on admission and outcome
Mean Value/Median (25th-75th)
GCS score on admission
Favorable outcome at 6 months
Unfavorable outcome at 6 months
MD values in favorable and unfavorable outcome groups
CPP, L/P ratio and Glycerol concentration in patients with favorable and unfavorable outcome
CPP < 75 mmHg
CPP ≥ 75 mmHg
Fischer's test, p = 0.053
L/P > 37
L/P ≤ 37
Fischer's test, p = 0.024
Glycerol > 72 mmol/l
Glycerol ≤ 72 mmol/l
Fischer's test, p = 0.024
Logistic regression model for outcome prognosis adjusted for age and gender
95% C.I.for Exp(B)
CPP ≥ 75 mmHg
Glycerol > 72 μg/lt
Lp > 37
Gender (men = 1)
According to the findings of the present study, certain cut-off values in microdialysis parameters are helpful to determine patients' outcome. Favorable outcome was also related to CPP values beyond the consensus range of 60-70 mmHg.
There has been a controversy about CPP upper limits in patients with severe head injuries [6, 7, 10, 11]. A lower CPP goal of 60 mmHg has been endorsed by the American Association of Neurological Surgeons and recently the Brain Trauma Foundation suggested a general threshold in the realm of 50-70 mmHg . In this study, CPP regulation was guided by brain biochemistry and emphasis was placed on clinical outcome, provided that L/P ratio and PbtO2 remained at an acceptable level. The sum of patients with a favorable prognosis raised with an increased CPP beyond 70 mmHg. The 75 mmHg finally turned out to be the critical value. Patients who survived and exhibited CPP values over 75 mmHg exhibited an excellent outcome as well. The explanation possibly lies in PbtO2. Stocchetti et al. had found that cerebral perfusion pressure augmentation significantly increased levels of brain tissue oxygen and significantly reduced the regional oxygen extraction fraction. Patients with baseline PbtO2 values at low levels had demonstrated a greater increase in PbO2 in response to CPP augmentation . Values greater than 60 mmHg were also related to a more favorable PbtO2 in the study of Caballos et al. . Similar findings have been reported by Johnston et al.  and other researchers. Rosner and colleagues have studied the maintenance of a CPP greater than 70 mmHg in patients with severe TBI. Their results were excellent, with an overall mortality rate of 21%. Fifty-four percent of survivors had a good recovery or moderate disability . In their recent study, Nelson et al. demonstrated that patients with traumatic brain injury and a CPP in the realm of 70 mmHg exhibited better prognosis, although no significant relation was found between outcome and MD and MD values were poorly related to CPP .
Regarding L/P ratio and Glycerol, existing data also support our findings. Hutchinson et al. measured an L/P value of 26.38 ± 8.1 in patients with a traumatic brain injury, without signs of ischemia using PET (Positron Emission Tomography), with a normal Oxygen Extraction Fraction (OEF was approximately 0.4) . In a study including 21 patients who underwent surgery for a hematoma caused by spontaneous intracerebral hemorrhage, it was found that the zone surrounding the evacuated hematoma area exhibited a biochemical behavior similar to that of the zone surrounding the brain contusion, with an increase in the value of the lactic-pyruvate ratio of about 35 and an increase in glycerol concentration . That fact can be helpful in making a decision, whether the injury should be treated surgically or not.
Regarding Glycerol concentration, our data are in accordance with those of Peerderman et al., which measured glycerol levels in 15 patients with traumatic brain injury. Patients with an unfavorable prognosis had higher glycerol levels during the first 24 h of hospitalization. They also noticed that no patient with favorable prognosis had a glycerol concentration greater than 150 μmol/L, while 6 out of 10 patients with an unfavorable prognosis had one. . Clausen at al also observed significantly increased glycerol concentrations when PbtO2 was lower than 10 mm Hg or when cerebral perfusion pressure was lower than 70 mm Hg in TBI patients .
The low GCS on admission could account for the relatively high mortality in the present study. Depending on severity, TBI mortality rates within a 6 month period after the injury, ranged from 3% to 35% . The relationship between TBI severity at onset and mortality is well documented [21, 22]. It is noticed, however, that our data refer to adults below 65 years old, suffering from severe TBIs, who were administered conservative treatment only. A model including as many clinical and laboratory parameters as possible and a large number of patients with specific and homogenous brain damage features is necessary for definite conclusions to be drawn.
The findings of this study support the maintenance of high CPP levels guided by the metabolic status of the brain tissue and suggest certain cut-off values for microdialysis parameters. The findings support the latest BTF guidelines, which suggest a more individualized approach in CPP regulation. However, optimal CPP values may vary from patient to patient and over time, as the physiological environment of the injured brain changes. Neurointensivists should not be discouraged to maintain high CPP levels, if the brain metabolic state allows so. We suggest a broader monitoring including PbtO2, microdialysis, and local cerebral blood flow measure. Interventions should be guided by each patient's brain metabolic status, aiming for the best possible outcome.
Conflict of interest
The authors declare that they have no competing interests.
We would like to thank Dr. Krommidas George for statistical advice and editing and Milionis Ioannis, ACIL of IoL, TESOL, for linguistic review. We would also like to thank GlaxoSmithKline Pharmaceuticals for financial support of this work.
- Shackford SR, Mackersie RC, Davis JW, Hollingsworth-Fridlund P, Hoyt DB, Wolf PL: The epidemiology of traumatic death. a population based analysis. Arch Surg. 1993, 128: 571-575. 10.1001/archsurg.1993.01420170107016.PubMedView ArticleGoogle Scholar
- Chesnut RM, Marshall LF, Klauber MR, Blunt BA, Baldwin N, Eisenberg HM, Jane JA, Marmarou A, Foulkes MA: The role of secondary brain injury in determining outcome from severe head injury. J Trauma. 1993, 34: 216-222. 10.1097/00005373-199302000-00006.PubMedView ArticleGoogle Scholar
- Steiner LA, Andrews PJD: Monitoring the injured brain: ICP and CBF. British J Anaesth. 2006, 97: 26-38. 10.1093/bja/ael110.View ArticleGoogle Scholar
- Sarrafzasdeh AS, Sakowitz OW, Callsen TA, Lanksch WR, Unterberg AW: Detection of secondary insults by brain tissue pO2 and bedside microdialysis in severe head injury. Acta Neurochir suppl. 2002, 81: 319-321.Google Scholar
- Marmarou A, Anderson RL, Ward JD, Marshall L, Jane J: Impact of ICP instability and hypotension on outcome in patients with severe head trauma. J Neurosurg. 1991, 75: S59-S66.Google Scholar
- Ling G, Neal C: Maintaining cerebral perfusion pressure is a worthy clinical goal. Neurocrit Care. 2005, 2: 75-82. 10.1385/NCC:2:1:075.PubMedView ArticleGoogle Scholar
- Juul N, Morris GF, Marshall SB, Marshall LF: Intracranial hypertension and cerebral perfusion pressure:influence on neurological deterioration and outcome in severe head injury. The Executive Committee of the International Selfotel Trial. Neurosurg. 2000, 92: 1-6. 10.3171/jns.2000.92.1.0001.View ArticleGoogle Scholar
- Brain Trauma Foundation: Guidelines for the management of severe traumatic brain injury. J Neurotrauma. 2007, 24: S1 106-3Google Scholar
- White H, Venkatesh B: Cerebral perfusion pressure in neurotrauma: a review. Anesth Analg. 2008, 107: 979-888. 10.1213/ane.0b013e31817e7b1a.PubMedView ArticleGoogle Scholar
- Brain Trauma Foundation, American Association of Neurological Surgeons: The joint section on Neurotrauma and Critical Care. Guidelines for cerebral perfussion pressure. J Neurotrauma. 2000, 17: 507-551.View ArticleGoogle Scholar
- Balestreri M, Czossnyka M, Hutchinson P, Hiler M, Smielewski P, Pickard JD: Impact of intracranial pressure and cerebral perfusion pressure on severe disability and mortality after head injury. Neurocrit Care. 2006, 4: 8-13. 10.1385/NCC:4:1:008.PubMedView ArticleGoogle Scholar
- Stochetti N, Chieregato A, De Marchi M, Croci M, Benti R, Grimoldi N: High cerebral perfusion pressure improves low values of local brain tissue O2 tension (PtiO2) in focal lesions. Acta Neurochir Suppl. 1998, 71: 162-165.Google Scholar
- Marín-Caballos AJ, Murillo-Cabezas F, Cayuela-Domínguez A, Domínguez-Roldán JM, Rincón-Ferrari MD, Valencia-Anguita J, Flores-Cordero JM, Muñoz-Sánchez MA: Cerebral perfusion pressure and risk of brain hypoxia in severe head injury: a prospective observational study. Crit Care. 2005, 9: R670-676. 10.1186/cc3822.PubMedPubMed CentralView ArticleGoogle Scholar
- Johnston AJ, Steiner L, Coles J, Chatfield DA, Fryer TD, Smielewski P, Hutchinson PJ, O'Connell MT, Al-Rawi PG, Aigbirihio FI, Clark JC, Pickard JD, Gupta AK, Menon DK: Effect of cerebral perfusion pressure augmentation on regional oxygenation and metabolism after head injury. Crit Care Med. 2005, 33: 189-195. 10.1097/01.CCM.0000149837.09225.BD.PubMedView ArticleGoogle Scholar
- Rosner MJ, Rosner SD, Johnson AH: Cerebral perfusion pressure: management protocol and clinical results. J Neurosurg. 1995, 83: 949-962. 10.3171/jns.1995.83.6.0949.PubMedView ArticleGoogle Scholar
- Nelson DW, Thornquist B, MacCallum RM, Nyström H, Holst A, Rudehill A, Wanecek M, Bellander BM, Weitzberg E: Analyses of cerebral microdialysis in patients with traumatic brain injury: relations to intracranial pressure, cerebral perfusion pressure and catheter placement. BMC Med. 2011, 9: 21-10.1186/1741-7015-9-21.PubMedPubMed CentralView ArticleGoogle Scholar
- Hutchinson PJ, Gupta AK, Fryer TF, Al-Rawi PG, Al-Rawi PG, Chatfield DA, Coles JP, O'Connell MT, Kett-White R, Minhas PS, Aigbirhio FI, Clark JC, Kirkpatrick PJ, Menon DK, Pickard JD: Correlation between cerebral blood flow, substrate delivery, and metabolism in head injury: a combined microdialysis and triple oxygen positron emission tomography study. J Cereb Blood Flow Metab. 2002, 22: 735-745.PubMedView ArticleGoogle Scholar
- Peerdeman SM, Girbes AR, Polderman KH, Vandertop WP: Changes in cerebral interstitial glycerol concentration in head-injured patients; correlation with secondary events. Intensive Care Med. 2003, 29: 1825-1828. 10.1007/s00134-003-1850-8.PubMedView ArticleGoogle Scholar
- Clausen T, Alves OL, Reinert M, Doppenberg E, Zauner A, Bullock R: Association between elevated brain tissue glycerol levels and poor outcome following severe traumatic brain injury. J Neurosurg. 2005, 103: 233-238. 10.3171/jns.2005.103.2.0233.PubMedView ArticleGoogle Scholar
- Foulkes MA, Eisenberg HM, Jane JA, Marmarou A, Marshall LF, the Traumatic Coma Data Bank Research Group: The Traumatic Coma Data Bank: design, methods, and baseline characteristics. J Neurosurg. 1991, 75: S8-S13. 10.3171/jns.1991.75.1.0008.View ArticleGoogle Scholar
- Hiler M, Czosnyka M, Hutchinson P, Balestreri M, Smielewski P, Matta B, Pickard JD: Predictive value of initial computerized tomography scan, intracranial pressure, and state of autoregulation in patients with traumatic brain injury. J Neurosurg. 2006, 104: 731-737. 10.3171/jns.2006.104.5.731.PubMedView ArticleGoogle Scholar
- Brown AW, Leibson CL, Malec JF, Perkins PK, Diehl NN, Larson DR: Long term survival after traumatic brain injury:a population based analysis. Neurorehabilitation. 2004, 19: 37-43.PubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.