- Email: [email protected]
Cerebral perfusion pressure, microdialysis biochemistry, and clinical outcome in patients with spontaneous intracerebral hematomas
Journal of Critical Care (2012) 27, 83–88
Cerebral perfusion pressure, microdialysis biochemistry, and clinical outcome in patients with spontaneous intracerebral hematomas Irene Nikaina PhD a , Konstantinos Paterakis PhD b , Geogios Paraforos PhD a , Efthimios Dardiotis PhD c , Achilleas Chovas PhD a , Dimitrios Papadopoulos d , Alexandros Brotis PhD b , Apostolos Komnos PhD a,e,⁎ a
Intensive Care Unit, General Hospital of Larissa, Greece Neurosurgery Department, University Hospital of Larissa, Greece c Department of Neurology, University Hospital of Larissa, Greece d Intensive Care Unit, General Hospital of Larissa, Greece e Institute of Biomedical Research and Technology, CERETETH [CEnter for REsearch and TEchnology, THessaly], Larissa, Greece b
Keywords: Spontaneous intracerebral hematomas; CPP; Lactate; Pyruvate; Outcome; Glascow Coma Scale
Abstract Purpose: The aim of our study was to investigate the roles of cerebral perfusion pressure (CPP) and microdialysis marker values on the clinical outcome of patients with spontaneous intracerebral hematoma. Materials and Methods: Twenty-seven patients (18 men; mean ± SD age, 54.17 ± 10.05 years; 9 women, mean ± SD age, 65.00 ± 4.24 years) with a GCS of 8 or less upon admission were included in this study. After a 6-month follow-up period, a linear regression model was applied to evaluate the outcomes using the Glasgow Outcome Scale (GOS). Results: Of the 27 patients, 16 died within the first 6 months after discharge from the hospital. Six patients had a favorable prognosis after 6 months. In the patients who had a favorable outcome (GOS = 4 or GOS = 5), the CPP was above 75.46 mm Hg, and intracranial pressure was below 14.21 mm Hg. No patient with a favorable prognosis had a lactate-pyruvate (L/P) ratio greater than 37.40. An inverse linear relationship was found among the L/P ratio, the CPP, and patient outcome. Conclusion: The L/P ratio and CPP were found to be related to patient outcome. In addition, a CPP greater than 75.46 mm Hg and an L/P ratio lower than 37.40 mm Hg were related to a favorable outcome. © 2012 Elsevier Inc. All rights reserved.
1. Introduction Spontaneous intracerebral hematomas (SICHs) account for nearly 10% of the cerebral strokes in the Western world and ⁎ Corresponding author. Tel.: +30 2410 532787; fax: +30 2410 530648. E-mail address: [email protected] (A. Komnos). 0883-9441/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.jcrc.2011.04.004
15% of such strokes worldwide. The annual incidence of SICHs has been reported to be as high as 30 cases per 100,000 population, and the incidence is increasing. The overall mortality of patients with intracerebral hematomas (ICHs) has been estimated to be as high as 66%, with variations depending on the hemorrhage location. Complete recovery has been reported in approximately 20% of patients with ICH
84 [1-3]. Early detection and prompt treatment of secondary brain damage are critical for the management of this pathology. It is now possible to monitor and record a number of physiological variables in patients with ICH treated in neurointensive care units using computerized multimodality monitoring systems. This monitoring helps the physician implement the appropriate therapy and gives information about the expected outcome [4,5]. It has been shown that poor outcomes are related to high intracranial pressure (ICP) and low cerebral perfusion pressure (CPP) [6-8]. Brain metabolism, defined by the average concentration of glucose and glycerol and by the lactate-pyruvate (L/P) ratio, however, has prognostic value in terms of clinical outcomes. Nevertheless, the literature lacks specific cutoff values for these parameters to guide treatment and only provides broad ranges for the prognostic values of brain metabolic parameters. Similarly, the clinical use of CPP-targeted therapy is based on the theoretical suggestion that maintaining nearoptimal cerebral blood flow (CBF) is mandatory for meeting the metabolic needs of the injured brain [9]. According to international guidelines, a low CPP threshold (within a range of 50-70 mm Hg) is recommended [10]; however, the upper limit of the CPP is controversial [7]. Concurrently, a high CPP could be beneficial for many patients, particularly those with relatively high ICP levels [11]. Here, we investigated the association between CPP, microdialysis marker values, and clinical outcomes in patients with SICHs. This descriptive study presents CPP values and brain metabolic parameters and their relationships with long-term outcomes. We assessed the effectiveness of multimodal brain monitoring and its relationship with patient outcome. In addition, we aimed to determine the optimal cutoff value for the CPP and microdialysis markers to predict clinical outcomes 6 months after ictus.
2. Materials and methods 2.1. Study design To evaluate the roles of CPP and microdialysis parameters in decision making and outcome prognosis, we retrospectively studied the hospital records and clinical outcomes of 37 consecutive patients with severe ICH who were admitted to the intensive care unit (ICU) during a 3.5-year period. For the purpose of our study, we selected those who were conservatively treated in an ICU after suffering from ICH and a severe consciousness disturbance (GCS ≤8) and/or rapid clinical deterioration. Patients with impending death, serious comorbidity, an ICU hospitalization of less than 2 days duration, or a hospital discharge in less than 10 days were excluded from the study. These criteria were chosen to obtain adequate and reliable blood samples, to avoid severe comorbidity and to maximize homogeneity. Monitoring was terminated after 10 days for all of the patients, because the
I. Nikaina et al. economic cost of a longer duration was unfeasible. Ethical approval for conducting the study was obtained from the local ethics committee. The patient's closest relatives provided informed consent for the patient's treatment and inclusion in the study.
2.2. Intervention All of the patients included in the study were sedated, intubated, mechanically ventilated, and hemodynamically supported. For each patient, a multiparametric monitoring system was placed during the first 8 hours after his or her admission to the ICU department. Placement was performed using a 3-bolt kit (Licox bolt kit; Integra LifeSciences Corp., Plainsboro, NJ) through the same burr hole. Each patient was equipped with a catheter for continuous ICP monitoring (Goldman's intraparenchymal fiber optic), a catheter for continuous tissue oxygenation monitoring (Clark-Licoxtype), and a microdialysis catheter (CMA 70 Brain Microdialysis Catheter, 10-mm membrane length, 20-kd cutoff; CMA, Stockholm, Sweden) with a gold tip for computed tomography scanning. The catheters were placed into the intact parenchyma, ipsilateral to the damaged area. Right catheter placement was confirmed via a second computed tomography scan within 24 hours after admission. No complications were observed, with the exception of slight subdural hemorrhages in the catheter placement areas, which were not clinically relevant.
2.3. Input parameters The demographic features and medical histories of the patients were recorded, and thorough neurologic examinations were performed. The ICP was continuously recorded via the ICP monitoring catheter. Microdialysis data were obtained every 2 hours. The glucose and glycerol concentrations and the L/P ratios were the basic microdialysis parameters recorded. Due to the brain tissue microtrauma that occurred during catheter insertion, the initial microdialysis values might not have been reliable [12]. To avoid such false measurements, the first 2 samples were removed from the analysis. Brain monitoring continued for 10 days.
2.4. Outcome parameters and follow-up The patient outcomes were evaluated using the Glasgow Outcome Scale (GOS) 6 months after discharge, through either telephone contact or an outpatient examination whenever possible (with collaboration from the neurosurgeons in our hospital).
2.5. Statistical analysis Continuous parameters are expressed as mean ± SD. Normality was verified with the Shapiro-Wilk test. For every
Clinical outcome in patients with SICHS
85
patient, the biochemical values obtained during the entire study period (10 days) were averaged to calculate the overall personal mean value. Fischer exact test (2-tailed) was applied to the qualitative variables, and a t test was used for between-group comparisons when distribution was normal. Cutoff points were set for the microdialysis variables, with the cutoff point being the maximum values in the group of favorable outcome. Mann-Whitney U test for between-group comparisons when variables were not normally distributed was performed to test differences in GOS scale between the 2 groups with different CPP/LP values. A linear model for the outcome prognosis (with GOS as the dependent variable) was applied, and the CPP and L/P ratio was included. The model was age adjusted, and statistics were processed using the Statistical Package for Social Sciences (SPSS, Chicago, Ill), version 17.0.
3. Results
Table 2 Mean values of CPP and ICP depending on GOS evaluation at 6 months GOS after 6 mo 1 (n = 16) 2 (n = 2) 3 (n = 3) 4 (n = 4) 5 (n = 5)
Minimum Maximum Mean ± SD ICP CPP ICP CPP ICP CPP ICP CPP ICP CPP
4.64 70.24 9.69 70.57 7.98 70.46 8.14 75.46 9.88 76.42
22.70 109.16 13.53 73.53 20.23 83.05 12.20 98.48 14.21 84.77
13.14 ± 80.33 ± 11.61 ± 72.05 ± 13.31 ± 76.23 ± 10.82 ± 85.25 ± 12.05 ± 80.60 ±
5.25 9.86 2.72 2.09 6.28 6.36 1.85 10.01 3.06 5.90
in 16 of the patients, and 15 of the patients were nonsmokers (Table 1). In 19 patients, the hemorrhage was lobar, whereas the hemorrhage was located in the basal ganglia in 8 patients. The mean size of the hemorrhage was 44.1 ± 4.6 cm3.
3.2. Outcomes
3.1. Patient sample description A total of 27 patients (18 men; mean ± SD age, 54.17 ± 10.05 years; 9 women; mean ± SD age, 65.00 ± 4.24 years) with SICH were ultimately included in this study. The median GCS upon admission was 7. A sudden loss of consciousness was the most common clinical presentation, followed by headache and vomiting. Hypertension was present
Of the 27 patients, 16 died within the first 6 months after discharge from the hospital, and 6 had a favorable prognosis after 6 months. No statistically significant difference in the GCS upon admission was found between the patients with a favorable vs those with an unfavorable prognosis (7.83 ± 3.06 vs 6.57 ± 1.99, respectively).
3.3. Multimodal monitoring in patients with ICH Table 1 Demographic characteristics and clinical presentation of patients with spontaneous cerebral hemorrhage Age (y), mean ± SD Sex Men Women GCS on admission, median (25th-75th percentile) Personal medical history Hypertension Heart disease Diabetes mellitus Alcohol abuse Smoking habit Current smokers Ex-smokers Nonsmokers Clinical presentation Headache Vomit Seizures Aphasia Breathing disturbances Sudden loss of consciousness
18 9 7 (6-7)
16 7 5 6
54.17 ± 10.05 65.00 ± 4.24
A mean CPP above 75.46 mm Hg and a mean ICP below 14.21 mm Hg were found in patients who had a favorable outcome (GOS = 4 or GOS = 5; Table 2). No patient with a favorable prognosis had an L/P ratio greater than 37.4, which was a result that was marginally significant when comparing patients who had a favorable outcome with those who had an unfavorable outcome. Cerebral perfusion pressure alone could not be used to predict patient outcome (P = .07; Table 3). When the patients were divided into 2 subgroups
Table 3 CPP and L/P ratio in patients with favorable and unfavorable outcome Parameters
8 2 15 8 10 3 4 3 11
Outcome after 6 mo Unfavorable
CPP b75.46 9 CPP ≥75.46 12 Total 21 Fischer test, P = .071 L/P b36.05 10 L/P ≥36.05 11 Total 21 Fischer test, P = .054
Favorable
Total
0 6 6
9 18 27
6 0 6
16 11 27
86
I. Nikaina et al.
Table 4 Microdialysis parameters and PtiO2 values according to CPP cutoff values CPP
b
9 20.39 84.69 29.92 37.41 50.13 18 25.23 78.29 32.45 35.60 38.69 .64 b
9 9 40 19.00 32.00 34.00 18 14 40 19.75 22.00 28.25 .21 a
t test. Mann-Whitney U test.
based on CPP with a cutoff of 75.46 mm Hg, no significant difference was detected in microdialysis values. The L/P ratio, however, was skewed toward 40 in the patients with a CPP less than 75.46 mm Hg and in the patients with a unfavorable prognosis (Tables 4 and 5). When the ageadjusted CPP and L/P ratio were included in a linear regression model for the outcome prognosis, a marginally significant inverse relationship was found between a combination of CPP and LP (CPP ≥75.46 mm Hg and LP b36.05) and the outcome (P = .047; Tables 6 and 7). The difference in outcome between the 2 groups is depicted in Graph 1. All microdialysis values correspond to a 10-day average for each patient and are expressed in millimoles per liter.
Table 5 Microdialysis parameters and PtiO2 values according to outcome GOS after 6 mo
Glucose Glycerol L/P ratio
Unfavorable n Valid 21 outcome Minimum 0.48 Maximum 2.19 Percentiles 25 0.74 50 1.05 75 1.23 Favorable n Valid 6 outcome Minimum 0.48 Maximum 1.39 Percentiles 25 0.51 50 0.63 75 0.86 P .11 a a b
GOS after 6 months and CPP/LP values n
Glucose Glycerol L/P ratio PtiO2
b75.46 n Valid 9 9 Minimum 0.51 21.14 Maximum 2.19 127.77 Percentiles 25 0.61 27.31 50 0.98 36.07 75 1.67 84.87 ≥75.46 n Valid 18 18 Minimum 0.48 13.72 Maximum 1.39 279.12 Percentiles 25 0.57 26.61 50 0.96 34.61 75 1.13 65.28 P .44 a .84 b a
Table 6
t test. Mann-Whitney U test.
21 13.72 279.12 28.07 34.49 67.95 6 22.11 69.76 22.23 50.23 60.50 .97 b
21 20.39 84.69 31.79 36.05 42.65 6 29.27 36.05 32.01 35.33 35.95 .41 b
PtiO2 21 9 40 19.50 24.00 32.50 6 18 33 20.25 25.50 31.50 .93 a
Mean z rank
P
GOS after 6 mo CPP ≥75.46 and 12 11.23 −2.28 .041 a LP b36.05 Other 15 17.46 a
Mann-Whitney U test.
4. Discussion According to the results of the present study, the CPP and L/P ratio have significant effects on the long-term outcome prognosis after a spontaneous cerebral hematoma. A CPP threshold that is higher than the currently recommended threshold appears to be critical for long-term outcome, and a cutoff for the L/P ratio also appears to be critical. The brain tissue of our patients was well oxygenated, and no statistically significant differences were detected between the patients who had a favorable prognosis and those who had an unfavorable prognosis; thus, we focused our interest on the L/P ratio. The L/P values were higher in the patients who had CPP values less than 75.6 mm Hg, although these differences did not reach statistical significance. A weak negative correlation between the L/P ratio and the CPP value was also found. A link between the CPP value and the L/P ratio may underlie a favorable metabolic profile and, ultimately, a favorable prognosis. Given that there is a lack of data regarding the CPP and microdialysis cutoff values for ICHs, the theoretical approach to this issue is primarily based on the traumatic brain injury literature. A controversy regarding the optimal CPP value still exists. For instance, values greater than 60 mm Hg have been tested with controversial results. It has been proposed that CPP values greater than 70 mm Hg or even 80 mm Hg may be beneficial in terms of outcome, whereas some studies have found no changes in outcome when the CPP was maintained above 50 mm Hg [13] or 60 mm Hg [14]. Other studies have warned about a higher risk of acute respiratory distress syndrome with a CPP above 70 mm Hg [13]. In an investigation of the mechanisms that account for a better prognosis at higher CPP levels, a positive effect on the PtiO2 has been reported as the CPP increased from 32 to 67 mm Hg. Although an additional
Table 7 CPP and L/P ratio as prognostic factors for SICH outcome (adjusted for age in a general linear model) Parameter
B
t
P
Constant Age CPP/LP (CPP ≥75.46 and LP b36.05 = 1, other = 2)
3.514 −0.023 1.20
0.746 −0.808 2.098
.463 .427 .047
R2 = 0.278.
Clinical outcome in patients with SICHS
87 those who manage to survive exhibit a favorable outcome. It seems that high CPP levels act as an acid test for determining the quality of life in the survivors. Intracellular pathways exhibit primary malfunction around brain-injured areas, with no obvious anatomical damage or substrate limitations, resulting in an elevated L/P ratio. Future studies should investigate the possible effect of CPP level on cellular integrity and CBF. The current study was a single-center study with a limited number of patients. The results draw attention to special subgroups of patients, with an emphasis on individualized CPP values and the L/P ratio as a guide. The results are suggestive and provide a foundation for further research.
CPP<75.46 & LP≥36.05
Other
5. Conclusions Graph 1 Glasgow Outcome Scale distribution depending on CPP/LP values.
increase in the CPP did not provide further improvement [15,16], others have observed that increasing the CPP to “supranormal values” is helpful for normalizing the PtiO2 in ischemic areas [17]. Brain metabolites and their relationship with CPP have also been examined. Using microdialysis, Zauner et al [18] showed that a CPP of 70 mm Hg was associated with an increase in brain tissue oxygenation, an increase in the brain glucose concentration, and a reduction in brain lactate levels. In another study, the concentrations of cerebral glucose, lactate, glycerol, glutamate, and pyruvate correlated with the CPP level, and an elevated critical CPP threshold (N70 mm Hg) was proposed for patients with head injuries and high ICP levels to prevent irreversible brain damage [19]. In contrast with the aforementioned evidence supporting CPP values greater than 70 mm Hg, some studies have reported lower thresholds. Chambers et al [20] reported a threshold value of 55 mm Hg for adults, suggesting that higher CPP values may be more important in adults with mass lesions, whereas evidence regarding cerebral compliance suggests optimal CPP to be between 60 and 80 mm Hg [21]. Steiner et al [22] also found the optimal CPP to be between 60 and 85 mm Hg. Substantial evidence seems to suggest that there is a critical CPP threshold around 60 mm Hg. Using cerebral oxygen extraction as an index of the adequacy of CBF, Stocchetti et al [23] showed that a CPP value lower than 60 mm Hg is associated with inadequate perfusion. Beyond these values, the life cost-benefit ratio is questionable. Given the controversy surrounding the definition of a CPP threshold and the differences observed across brain injury subgroups, an individualized approach to CPP that takes the injury type into account has been proposed. This study suggests an effect of CPP level on metabolic parameters, especially the L/P ratio, as a possible underlying mechanism linking a favorable outcome to CPP. Patients with high CPP levels appear to have a high mortality, but
Metabolic and brain pressure parameters appear to be related to SICH outcome. A relationship between the CPP value and L/P ratio is also possible and may affect long-term outcome prognosis. An individualized approach to CPP levels, without excluding “supranormal values,” is recommended.
Acknowledgments We would like to thank Dr Krommydas George for statistical advice and for editing the manuscript, Elfie Delios for linguistic advice, and GlaxoSmithKline Pharmaceuticals for financial support of this work. Part of the expendables was funded within the context of the European Program “Heraklitos.”
References [1] Anderson CS, Chakera TM, Stewart-Wynne EG, et al. Spectrum of primary intracerebral haemorrhage in Perth, Western Australia, 198990: incidence and outcome. J Neurol Neurosurg Psychiatry 1994;57: 936-40. [2] Broderick JP, Brott T, Tomsick T, et al. Intracerebral hemorrhage more than twice as common as subarachnoid hemorrhage. J Neurosurg 1993;78:188-91. [3] Panagos PD, Jauch EC, Broderick JP. Intracerebral hemorrhage. Emerg Med Clin North Am 2002;20:631-55. [4] Steiner LA, Andrews PJD. Monitoring the injured brain: ICP and CBF. Br J Anaesth 2006;97:26-38. [5] Sarrafzadeh AS, Sakowitz OW, Callsen TA, et al. Detection of secondary insults by brain tissue pO2 and bedside microdialysis in severe head injury. Acta Neurochir Suppl 2002;81:319-21. [6] Marmarou A, Anderson RL, Ward JD, et al. Impact of ICP instability and hypotension on outcome in patients with severe head trauma. J Neurosurg 1991;75:59-66. [7] Ling G, Neal C. Maintaining cerebral perfusion pressure is a worthy clinical goal. Neurocrit Care 2005;2:75-82. [8] Juul N, Morris GF, Marshall SB, et al. 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.
88 [9] Qureshi AI, Ali Z, Suri MF, et al. Extracellular glutamate and other amino acids in experimental intracerebral hemorrhage: an in vivo microdialysis study. Crit Care Med 2003;31:1482-9. [10] Brain Trauma Foundation: guidelines for the management of severe traumatic brain injury. 3rd ed. J Neurotrauma 24:1 106, 2007. [11] White H, Venkatesh B. Cerebral perfusion pressure in neurotrauma: a review. Anesth Analg 2008;107:979-88. [12] Diringer MN. Intracerebral hemorrhage: pathophysiology and management. Crit Care Med 1993;10:1591-603. [13] Robertson CS, Valadka AB, Hannay HJ, et al. Prevention of secondary ischemic insults after severe head injury. Crit Care Med 1999;27: 2086-95. [14] Juul N, Morris GF, Marshall SB, et al. Intracranial hypertension and cerebral perfusion pressure. Influence on neurological deterioration and outcome in severe head injury. The Executive Committee of the International Selfotel Trial. J Neurosurg 2000;92:1-6. [15] Kiening KL, Hartl R, Unterberg AW, et al. Brain tissue pO2monitoring in comatose patients: implications for therapy. Neurol Res 1997;19:233-40. [16] Sahuquillo J, Amoros S, Santos A, et al. Does an increase in cerebral perfusion pressure always mean a better oxygenated brain? A study in head-injured patients. Acta Neurochir Suppl 2000;76:457-62. [17] Marín-Caballos AJ, Murillo-Cabezas F, Cayuela-Domínguez A, et al. Cerebral perfusion pressure and risk of brain hypoxia in severe
I. Nikaina et al.
[18]
[19]
[20]
[21]
[22]
[23]
head injury: a prospective observational study. Crit Care 2005;9: R670-6. Zauner A, Doppenberg E, Woodward JJ, et al. Multiparametric continuous monitoring of brain metabolism and substrate delivery in neurosurgical patients. Neurol Res 1997;19:265-73. Poon WS, Ng SC, Chan MT, et al. Neurochemical changes in ventilated head-injured patients with cerebral perfusion pressure treatment failure. Acta Neurochir Suppl 2002;81:335-8. Chambers IR, Treadwell L, Mendelow AD. Determination of threshold levels of cerebral perfusion pressure and intracranial pressure in severe head injury by using receiver-operating characteristic curves: an observational study in 291 patients. J Neurosurg 2001;94: 412-6. Portella G, Cormio M, Citerio G, et al. Continuous cerebral compliance monitoring in severe head injury: its relation ship with intracranial pressure and cerebral perfusion pressure. Acta Neurochir (Wien) 2005;147:707-13. Steiner LA, Czosnyka M, Piechnik SK, et al. Continuous monitoring of cerebrovascular pressure reactivity allows determination of optimal cerebral perfusion pressure in patients with traumatic brain injury. Crit Care Med 2002;30:733-8. Stocchetti N, Barbagallo M, Bellini GC, et al. Arteriojugular difference of oxygen and intracranial pressure in comatose head injured patients. II. Clinical correlations. Minerva Anestesiol 1991;57:327-34.
Cerebral perfusion pressure, microdialysis biochemistry, and clinical outcome in patients with spontaneous intracerebral hematomas Irene Nikaina PhD a , Konstantinos Paterakis PhD b , Geogios Paraforos PhD a , Efthimios Dardiotis PhD c , Achilleas Chovas PhD a , Dimitrios Papadopoulos d , Alexandros Brotis PhD b , Apostolos Komnos PhD a,e,⁎ a
Intensive Care Unit, General Hospital of Larissa, Greece Neurosurgery Department, University Hospital of Larissa, Greece c Department of Neurology, University Hospital of Larissa, Greece d Intensive Care Unit, General Hospital of Larissa, Greece e Institute of Biomedical Research and Technology, CERETETH [CEnter for REsearch and TEchnology, THessaly], Larissa, Greece b
Keywords: Spontaneous intracerebral hematomas; CPP; Lactate; Pyruvate; Outcome; Glascow Coma Scale
Abstract Purpose: The aim of our study was to investigate the roles of cerebral perfusion pressure (CPP) and microdialysis marker values on the clinical outcome of patients with spontaneous intracerebral hematoma. Materials and Methods: Twenty-seven patients (18 men; mean ± SD age, 54.17 ± 10.05 years; 9 women, mean ± SD age, 65.00 ± 4.24 years) with a GCS of 8 or less upon admission were included in this study. After a 6-month follow-up period, a linear regression model was applied to evaluate the outcomes using the Glasgow Outcome Scale (GOS). Results: Of the 27 patients, 16 died within the first 6 months after discharge from the hospital. Six patients had a favorable prognosis after 6 months. In the patients who had a favorable outcome (GOS = 4 or GOS = 5), the CPP was above 75.46 mm Hg, and intracranial pressure was below 14.21 mm Hg. No patient with a favorable prognosis had a lactate-pyruvate (L/P) ratio greater than 37.40. An inverse linear relationship was found among the L/P ratio, the CPP, and patient outcome. Conclusion: The L/P ratio and CPP were found to be related to patient outcome. In addition, a CPP greater than 75.46 mm Hg and an L/P ratio lower than 37.40 mm Hg were related to a favorable outcome. © 2012 Elsevier Inc. All rights reserved.
1. Introduction Spontaneous intracerebral hematomas (SICHs) account for nearly 10% of the cerebral strokes in the Western world and ⁎ Corresponding author. Tel.: +30 2410 532787; fax: +30 2410 530648. E-mail address: [email protected] (A. Komnos). 0883-9441/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.jcrc.2011.04.004
15% of such strokes worldwide. The annual incidence of SICHs has been reported to be as high as 30 cases per 100,000 population, and the incidence is increasing. The overall mortality of patients with intracerebral hematomas (ICHs) has been estimated to be as high as 66%, with variations depending on the hemorrhage location. Complete recovery has been reported in approximately 20% of patients with ICH
84 [1-3]. Early detection and prompt treatment of secondary brain damage are critical for the management of this pathology. It is now possible to monitor and record a number of physiological variables in patients with ICH treated in neurointensive care units using computerized multimodality monitoring systems. This monitoring helps the physician implement the appropriate therapy and gives information about the expected outcome [4,5]. It has been shown that poor outcomes are related to high intracranial pressure (ICP) and low cerebral perfusion pressure (CPP) [6-8]. Brain metabolism, defined by the average concentration of glucose and glycerol and by the lactate-pyruvate (L/P) ratio, however, has prognostic value in terms of clinical outcomes. Nevertheless, the literature lacks specific cutoff values for these parameters to guide treatment and only provides broad ranges for the prognostic values of brain metabolic parameters. Similarly, the clinical use of CPP-targeted therapy is based on the theoretical suggestion that maintaining nearoptimal cerebral blood flow (CBF) is mandatory for meeting the metabolic needs of the injured brain [9]. According to international guidelines, a low CPP threshold (within a range of 50-70 mm Hg) is recommended [10]; however, the upper limit of the CPP is controversial [7]. Concurrently, a high CPP could be beneficial for many patients, particularly those with relatively high ICP levels [11]. Here, we investigated the association between CPP, microdialysis marker values, and clinical outcomes in patients with SICHs. This descriptive study presents CPP values and brain metabolic parameters and their relationships with long-term outcomes. We assessed the effectiveness of multimodal brain monitoring and its relationship with patient outcome. In addition, we aimed to determine the optimal cutoff value for the CPP and microdialysis markers to predict clinical outcomes 6 months after ictus.
2. Materials and methods 2.1. Study design To evaluate the roles of CPP and microdialysis parameters in decision making and outcome prognosis, we retrospectively studied the hospital records and clinical outcomes of 37 consecutive patients with severe ICH who were admitted to the intensive care unit (ICU) during a 3.5-year period. For the purpose of our study, we selected those who were conservatively treated in an ICU after suffering from ICH and a severe consciousness disturbance (GCS ≤8) and/or rapid clinical deterioration. Patients with impending death, serious comorbidity, an ICU hospitalization of less than 2 days duration, or a hospital discharge in less than 10 days were excluded from the study. These criteria were chosen to obtain adequate and reliable blood samples, to avoid severe comorbidity and to maximize homogeneity. Monitoring was terminated after 10 days for all of the patients, because the
I. Nikaina et al. economic cost of a longer duration was unfeasible. Ethical approval for conducting the study was obtained from the local ethics committee. The patient's closest relatives provided informed consent for the patient's treatment and inclusion in the study.
2.2. Intervention All of the patients included in the study were sedated, intubated, mechanically ventilated, and hemodynamically supported. For each patient, a multiparametric monitoring system was placed during the first 8 hours after his or her admission to the ICU department. Placement was performed using a 3-bolt kit (Licox bolt kit; Integra LifeSciences Corp., Plainsboro, NJ) through the same burr hole. Each patient was equipped with a catheter for continuous ICP monitoring (Goldman's intraparenchymal fiber optic), a catheter for continuous tissue oxygenation monitoring (Clark-Licoxtype), and a microdialysis catheter (CMA 70 Brain Microdialysis Catheter, 10-mm membrane length, 20-kd cutoff; CMA, Stockholm, Sweden) with a gold tip for computed tomography scanning. The catheters were placed into the intact parenchyma, ipsilateral to the damaged area. Right catheter placement was confirmed via a second computed tomography scan within 24 hours after admission. No complications were observed, with the exception of slight subdural hemorrhages in the catheter placement areas, which were not clinically relevant.
2.3. Input parameters The demographic features and medical histories of the patients were recorded, and thorough neurologic examinations were performed. The ICP was continuously recorded via the ICP monitoring catheter. Microdialysis data were obtained every 2 hours. The glucose and glycerol concentrations and the L/P ratios were the basic microdialysis parameters recorded. Due to the brain tissue microtrauma that occurred during catheter insertion, the initial microdialysis values might not have been reliable [12]. To avoid such false measurements, the first 2 samples were removed from the analysis. Brain monitoring continued for 10 days.
2.4. Outcome parameters and follow-up The patient outcomes were evaluated using the Glasgow Outcome Scale (GOS) 6 months after discharge, through either telephone contact or an outpatient examination whenever possible (with collaboration from the neurosurgeons in our hospital).
2.5. Statistical analysis Continuous parameters are expressed as mean ± SD. Normality was verified with the Shapiro-Wilk test. For every
Clinical outcome in patients with SICHS
85
patient, the biochemical values obtained during the entire study period (10 days) were averaged to calculate the overall personal mean value. Fischer exact test (2-tailed) was applied to the qualitative variables, and a t test was used for between-group comparisons when distribution was normal. Cutoff points were set for the microdialysis variables, with the cutoff point being the maximum values in the group of favorable outcome. Mann-Whitney U test for between-group comparisons when variables were not normally distributed was performed to test differences in GOS scale between the 2 groups with different CPP/LP values. A linear model for the outcome prognosis (with GOS as the dependent variable) was applied, and the CPP and L/P ratio was included. The model was age adjusted, and statistics were processed using the Statistical Package for Social Sciences (SPSS, Chicago, Ill), version 17.0.
3. Results
Table 2 Mean values of CPP and ICP depending on GOS evaluation at 6 months GOS after 6 mo 1 (n = 16) 2 (n = 2) 3 (n = 3) 4 (n = 4) 5 (n = 5)
Minimum Maximum Mean ± SD ICP CPP ICP CPP ICP CPP ICP CPP ICP CPP
4.64 70.24 9.69 70.57 7.98 70.46 8.14 75.46 9.88 76.42
22.70 109.16 13.53 73.53 20.23 83.05 12.20 98.48 14.21 84.77
13.14 ± 80.33 ± 11.61 ± 72.05 ± 13.31 ± 76.23 ± 10.82 ± 85.25 ± 12.05 ± 80.60 ±
5.25 9.86 2.72 2.09 6.28 6.36 1.85 10.01 3.06 5.90
in 16 of the patients, and 15 of the patients were nonsmokers (Table 1). In 19 patients, the hemorrhage was lobar, whereas the hemorrhage was located in the basal ganglia in 8 patients. The mean size of the hemorrhage was 44.1 ± 4.6 cm3.
3.2. Outcomes
3.1. Patient sample description A total of 27 patients (18 men; mean ± SD age, 54.17 ± 10.05 years; 9 women; mean ± SD age, 65.00 ± 4.24 years) with SICH were ultimately included in this study. The median GCS upon admission was 7. A sudden loss of consciousness was the most common clinical presentation, followed by headache and vomiting. Hypertension was present
Of the 27 patients, 16 died within the first 6 months after discharge from the hospital, and 6 had a favorable prognosis after 6 months. No statistically significant difference in the GCS upon admission was found between the patients with a favorable vs those with an unfavorable prognosis (7.83 ± 3.06 vs 6.57 ± 1.99, respectively).
3.3. Multimodal monitoring in patients with ICH Table 1 Demographic characteristics and clinical presentation of patients with spontaneous cerebral hemorrhage Age (y), mean ± SD Sex Men Women GCS on admission, median (25th-75th percentile) Personal medical history Hypertension Heart disease Diabetes mellitus Alcohol abuse Smoking habit Current smokers Ex-smokers Nonsmokers Clinical presentation Headache Vomit Seizures Aphasia Breathing disturbances Sudden loss of consciousness
18 9 7 (6-7)
16 7 5 6
54.17 ± 10.05 65.00 ± 4.24
A mean CPP above 75.46 mm Hg and a mean ICP below 14.21 mm Hg were found in patients who had a favorable outcome (GOS = 4 or GOS = 5; Table 2). No patient with a favorable prognosis had an L/P ratio greater than 37.4, which was a result that was marginally significant when comparing patients who had a favorable outcome with those who had an unfavorable outcome. Cerebral perfusion pressure alone could not be used to predict patient outcome (P = .07; Table 3). When the patients were divided into 2 subgroups
Table 3 CPP and L/P ratio in patients with favorable and unfavorable outcome Parameters
8 2 15 8 10 3 4 3 11
Outcome after 6 mo Unfavorable
CPP b75.46 9 CPP ≥75.46 12 Total 21 Fischer test, P = .071 L/P b36.05 10 L/P ≥36.05 11 Total 21 Fischer test, P = .054
Favorable
Total
0 6 6
9 18 27
6 0 6
16 11 27
86
I. Nikaina et al.
Table 4 Microdialysis parameters and PtiO2 values according to CPP cutoff values CPP
b
9 20.39 84.69 29.92 37.41 50.13 18 25.23 78.29 32.45 35.60 38.69 .64 b
9 9 40 19.00 32.00 34.00 18 14 40 19.75 22.00 28.25 .21 a
t test. Mann-Whitney U test.
based on CPP with a cutoff of 75.46 mm Hg, no significant difference was detected in microdialysis values. The L/P ratio, however, was skewed toward 40 in the patients with a CPP less than 75.46 mm Hg and in the patients with a unfavorable prognosis (Tables 4 and 5). When the ageadjusted CPP and L/P ratio were included in a linear regression model for the outcome prognosis, a marginally significant inverse relationship was found between a combination of CPP and LP (CPP ≥75.46 mm Hg and LP b36.05) and the outcome (P = .047; Tables 6 and 7). The difference in outcome between the 2 groups is depicted in Graph 1. All microdialysis values correspond to a 10-day average for each patient and are expressed in millimoles per liter.
Table 5 Microdialysis parameters and PtiO2 values according to outcome GOS after 6 mo
Glucose Glycerol L/P ratio
Unfavorable n Valid 21 outcome Minimum 0.48 Maximum 2.19 Percentiles 25 0.74 50 1.05 75 1.23 Favorable n Valid 6 outcome Minimum 0.48 Maximum 1.39 Percentiles 25 0.51 50 0.63 75 0.86 P .11 a a b
GOS after 6 months and CPP/LP values n
Glucose Glycerol L/P ratio PtiO2
b75.46 n Valid 9 9 Minimum 0.51 21.14 Maximum 2.19 127.77 Percentiles 25 0.61 27.31 50 0.98 36.07 75 1.67 84.87 ≥75.46 n Valid 18 18 Minimum 0.48 13.72 Maximum 1.39 279.12 Percentiles 25 0.57 26.61 50 0.96 34.61 75 1.13 65.28 P .44 a .84 b a
Table 6
t test. Mann-Whitney U test.
21 13.72 279.12 28.07 34.49 67.95 6 22.11 69.76 22.23 50.23 60.50 .97 b
21 20.39 84.69 31.79 36.05 42.65 6 29.27 36.05 32.01 35.33 35.95 .41 b
PtiO2 21 9 40 19.50 24.00 32.50 6 18 33 20.25 25.50 31.50 .93 a
Mean z rank
P
GOS after 6 mo CPP ≥75.46 and 12 11.23 −2.28 .041 a LP b36.05 Other 15 17.46 a
Mann-Whitney U test.
4. Discussion According to the results of the present study, the CPP and L/P ratio have significant effects on the long-term outcome prognosis after a spontaneous cerebral hematoma. A CPP threshold that is higher than the currently recommended threshold appears to be critical for long-term outcome, and a cutoff for the L/P ratio also appears to be critical. The brain tissue of our patients was well oxygenated, and no statistically significant differences were detected between the patients who had a favorable prognosis and those who had an unfavorable prognosis; thus, we focused our interest on the L/P ratio. The L/P values were higher in the patients who had CPP values less than 75.6 mm Hg, although these differences did not reach statistical significance. A weak negative correlation between the L/P ratio and the CPP value was also found. A link between the CPP value and the L/P ratio may underlie a favorable metabolic profile and, ultimately, a favorable prognosis. Given that there is a lack of data regarding the CPP and microdialysis cutoff values for ICHs, the theoretical approach to this issue is primarily based on the traumatic brain injury literature. A controversy regarding the optimal CPP value still exists. For instance, values greater than 60 mm Hg have been tested with controversial results. It has been proposed that CPP values greater than 70 mm Hg or even 80 mm Hg may be beneficial in terms of outcome, whereas some studies have found no changes in outcome when the CPP was maintained above 50 mm Hg [13] or 60 mm Hg [14]. Other studies have warned about a higher risk of acute respiratory distress syndrome with a CPP above 70 mm Hg [13]. In an investigation of the mechanisms that account for a better prognosis at higher CPP levels, a positive effect on the PtiO2 has been reported as the CPP increased from 32 to 67 mm Hg. Although an additional
Table 7 CPP and L/P ratio as prognostic factors for SICH outcome (adjusted for age in a general linear model) Parameter
B
t
P
Constant Age CPP/LP (CPP ≥75.46 and LP b36.05 = 1, other = 2)
3.514 −0.023 1.20
0.746 −0.808 2.098
.463 .427 .047
R2 = 0.278.
Clinical outcome in patients with SICHS
87 those who manage to survive exhibit a favorable outcome. It seems that high CPP levels act as an acid test for determining the quality of life in the survivors. Intracellular pathways exhibit primary malfunction around brain-injured areas, with no obvious anatomical damage or substrate limitations, resulting in an elevated L/P ratio. Future studies should investigate the possible effect of CPP level on cellular integrity and CBF. The current study was a single-center study with a limited number of patients. The results draw attention to special subgroups of patients, with an emphasis on individualized CPP values and the L/P ratio as a guide. The results are suggestive and provide a foundation for further research.
CPP<75.46 & LP≥36.05
Other
5. Conclusions Graph 1 Glasgow Outcome Scale distribution depending on CPP/LP values.
increase in the CPP did not provide further improvement [15,16], others have observed that increasing the CPP to “supranormal values” is helpful for normalizing the PtiO2 in ischemic areas [17]. Brain metabolites and their relationship with CPP have also been examined. Using microdialysis, Zauner et al [18] showed that a CPP of 70 mm Hg was associated with an increase in brain tissue oxygenation, an increase in the brain glucose concentration, and a reduction in brain lactate levels. In another study, the concentrations of cerebral glucose, lactate, glycerol, glutamate, and pyruvate correlated with the CPP level, and an elevated critical CPP threshold (N70 mm Hg) was proposed for patients with head injuries and high ICP levels to prevent irreversible brain damage [19]. In contrast with the aforementioned evidence supporting CPP values greater than 70 mm Hg, some studies have reported lower thresholds. Chambers et al [20] reported a threshold value of 55 mm Hg for adults, suggesting that higher CPP values may be more important in adults with mass lesions, whereas evidence regarding cerebral compliance suggests optimal CPP to be between 60 and 80 mm Hg [21]. Steiner et al [22] also found the optimal CPP to be between 60 and 85 mm Hg. Substantial evidence seems to suggest that there is a critical CPP threshold around 60 mm Hg. Using cerebral oxygen extraction as an index of the adequacy of CBF, Stocchetti et al [23] showed that a CPP value lower than 60 mm Hg is associated with inadequate perfusion. Beyond these values, the life cost-benefit ratio is questionable. Given the controversy surrounding the definition of a CPP threshold and the differences observed across brain injury subgroups, an individualized approach to CPP that takes the injury type into account has been proposed. This study suggests an effect of CPP level on metabolic parameters, especially the L/P ratio, as a possible underlying mechanism linking a favorable outcome to CPP. Patients with high CPP levels appear to have a high mortality, but
Metabolic and brain pressure parameters appear to be related to SICH outcome. A relationship between the CPP value and L/P ratio is also possible and may affect long-term outcome prognosis. An individualized approach to CPP levels, without excluding “supranormal values,” is recommended.
Acknowledgments We would like to thank Dr Krommydas George for statistical advice and for editing the manuscript, Elfie Delios for linguistic advice, and GlaxoSmithKline Pharmaceuticals for financial support of this work. Part of the expendables was funded within the context of the European Program “Heraklitos.”
References [1] Anderson CS, Chakera TM, Stewart-Wynne EG, et al. Spectrum of primary intracerebral haemorrhage in Perth, Western Australia, 198990: incidence and outcome. J Neurol Neurosurg Psychiatry 1994;57: 936-40. [2] Broderick JP, Brott T, Tomsick T, et al. Intracerebral hemorrhage more than twice as common as subarachnoid hemorrhage. J Neurosurg 1993;78:188-91. [3] Panagos PD, Jauch EC, Broderick JP. Intracerebral hemorrhage. Emerg Med Clin North Am 2002;20:631-55. [4] Steiner LA, Andrews PJD. Monitoring the injured brain: ICP and CBF. Br J Anaesth 2006;97:26-38. [5] Sarrafzadeh AS, Sakowitz OW, Callsen TA, et al. Detection of secondary insults by brain tissue pO2 and bedside microdialysis in severe head injury. Acta Neurochir Suppl 2002;81:319-21. [6] Marmarou A, Anderson RL, Ward JD, et al. Impact of ICP instability and hypotension on outcome in patients with severe head trauma. J Neurosurg 1991;75:59-66. [7] Ling G, Neal C. Maintaining cerebral perfusion pressure is a worthy clinical goal. Neurocrit Care 2005;2:75-82. [8] Juul N, Morris GF, Marshall SB, et al. 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.
88 [9] Qureshi AI, Ali Z, Suri MF, et al. Extracellular glutamate and other amino acids in experimental intracerebral hemorrhage: an in vivo microdialysis study. Crit Care Med 2003;31:1482-9. [10] Brain Trauma Foundation: guidelines for the management of severe traumatic brain injury. 3rd ed. J Neurotrauma 24:1 106, 2007. [11] White H, Venkatesh B. Cerebral perfusion pressure in neurotrauma: a review. Anesth Analg 2008;107:979-88. [12] Diringer MN. Intracerebral hemorrhage: pathophysiology and management. Crit Care Med 1993;10:1591-603. [13] Robertson CS, Valadka AB, Hannay HJ, et al. Prevention of secondary ischemic insults after severe head injury. Crit Care Med 1999;27: 2086-95. [14] Juul N, Morris GF, Marshall SB, et al. Intracranial hypertension and cerebral perfusion pressure. Influence on neurological deterioration and outcome in severe head injury. The Executive Committee of the International Selfotel Trial. J Neurosurg 2000;92:1-6. [15] Kiening KL, Hartl R, Unterberg AW, et al. Brain tissue pO2monitoring in comatose patients: implications for therapy. Neurol Res 1997;19:233-40. [16] Sahuquillo J, Amoros S, Santos A, et al. Does an increase in cerebral perfusion pressure always mean a better oxygenated brain? A study in head-injured patients. Acta Neurochir Suppl 2000;76:457-62. [17] Marín-Caballos AJ, Murillo-Cabezas F, Cayuela-Domínguez A, et al. Cerebral perfusion pressure and risk of brain hypoxia in severe
I. Nikaina et al.
[18]
[19]
[20]
[21]
[22]
[23]
head injury: a prospective observational study. Crit Care 2005;9: R670-6. Zauner A, Doppenberg E, Woodward JJ, et al. Multiparametric continuous monitoring of brain metabolism and substrate delivery in neurosurgical patients. Neurol Res 1997;19:265-73. Poon WS, Ng SC, Chan MT, et al. Neurochemical changes in ventilated head-injured patients with cerebral perfusion pressure treatment failure. Acta Neurochir Suppl 2002;81:335-8. Chambers IR, Treadwell L, Mendelow AD. Determination of threshold levels of cerebral perfusion pressure and intracranial pressure in severe head injury by using receiver-operating characteristic curves: an observational study in 291 patients. J Neurosurg 2001;94: 412-6. Portella G, Cormio M, Citerio G, et al. Continuous cerebral compliance monitoring in severe head injury: its relation ship with intracranial pressure and cerebral perfusion pressure. Acta Neurochir (Wien) 2005;147:707-13. Steiner LA, Czosnyka M, Piechnik SK, et al. Continuous monitoring of cerebrovascular pressure reactivity allows determination of optimal cerebral perfusion pressure in patients with traumatic brain injury. Crit Care Med 2002;30:733-8. Stocchetti N, Barbagallo M, Bellini GC, et al. Arteriojugular difference of oxygen and intracranial pressure in comatose head injured patients. II. Clinical correlations. Minerva Anestesiol 1991;57:327-34.