Noninvasive monitoring of evolving urinary metabolic patterns in neonatal encephalopathy.

BACKGROUND: Infants with moderate and severe neonatal encephalopathy (NE) frequently suffer from long-term adverse outcomes. We hypothesize that the urinary metabolome of newborns with NE reflects the evolution of injury patterns observed with magnetic resonance imaging (MRI). METHODS: Eligible patients were newborn infants with perinatal asphyxia evolving to NE and qualifying for therapeutic hypothermia (TH) included in the HYPOTOP trial. MRI was employed for characterizing brain injury. Urine samples of 55 infants were collected before, during, and after TH. Metabolic profiles of samples were recorded employing three complementary mass spectrometry-based assays, and the alteration of detected metabolic features between groups was assessed. RESULTS: The longitudinal assessment revealed significant perturbations of the urinary metabolome. After 24 h of TH, a stable disease pattern evolved characterized by the alterations of 4-8% of metabolic features related to lipid metabolism, metabolism of cofactors and vitamins, glycan biosynthesis and metabolism, amino acid metabolism, and nucleotide metabolism. Characteristic metabolomic fingerprints were observed for different MRI injury patterns. CONCLUSIONS: This study shows the potential of urinary metabolic profiles for the noninvasive monitoring of brain injury of infants with NE during TH. IMPACT: A comprehensive approach for the study of the urinary metabolome was employed involving a semi-targeted capillary electrophoresis-time-of-flight mass spectrometry (TOFMS) assay, an untargeted ultra-performance liquid chromatography (UPLC)-quadrupole TOFMS assay, and a targeted UPLC-tandem MS-based method for the quantification of amino acids. The longitudinal study of the urinary metabolome identified dynamic metabolic changes between birth and until 96 h after the initiation of TH. The identification of altered metabolic pathways in newborns with pathologic MRI outcomes might offer the possibility of developing noninvasive monitoring approaches for personalized adjustment of the treatment and for supporting early outcome prediction.

[THE SEARCH AFTER PROGNOSTIC TESTS OF DEVELOPMENT OF UROLITHIASIS OF PATIENTS WITH VERTEBRO-CEREBROSPINAL TRAUMA].

The article presents analysis of alterations of biochemical indicators in blood serum and day urine of 22 patients in acute and early periods after vertebro-cerebrospinal trauma. Out of total number of patients in 10 (main group) in post-traumatic period urolithiasis developed In 12 patients no signs of urolithiasis were detected These examinedpatients were included into comparative group. The reference group was composed with 20 healthy individuals. The concentration of urea, creatinine, uric acid, calcium and inorganic phosphate in blood serum and day urine were detected In patients of main group statistically significant increasing of levels of urea and creatinine was detected in blood serum relative to patients of comparative group. In examined patients of main group clearance of urea was reliably lower than both values of comparative group (up to 2.55 times; p < 0.05) and indicators of reference group (up to 3.75 times; p < 0.05). In patients of this group, clearance of uric acid also had reliable differences from indicators both in comparative group and reference group. Therefore, in patients in acute and early periods of vertebro- cerebrospinal trauma expressed disorders of biochemical indicators of blood serum and urine that can be referred to predictors of risk of development of urolithiasis in the following. The most informative tests were increasing of concentration of urea in blood serum more than 5.30 mmol/l (ratio of likelihood ofpositive test--4.26) and decreasing of clearance of uric acid and urea.

A singular case of survival after acute methanol poisoning: toxicological and neuroimaging findings.

Acute methanol poisoning is a relatively uncommon and dangerous form of intoxication. It generally occurs after suicidal or accidental events and can be potentially fatal if not diagnosed and treated promptly. Here reported is the case of a 52-year-old Romanian man who survived acute methanol intoxication. Therefore, it was possible to monitor the clinical evolution, the arterial blood gas assay and toxicological research of methanol in blood and urine, as well as the brain damage by computed tomography and magnetic resonance imaging during a period of 20 days after the intake.

Multiple biomarkers and risk of clinical and subclinical vascular brain injury: the Framingham Offspring Study.

BACKGROUND: Several biomarkers have been individually associated with vascular brain injury, but no prior study has explored the simultaneous association of a biologically plausible panel of biomarkers with the incidence of stroke/transient ischemic attack and the prevalence of subclinical brain injury. METHODS AND RESULTS: In 3127 stroke-free Framingham offspring (age, 59±10 years; 54% female), we related a panel of 8 biomarkers assessing inflammation (C-reactive protein), hemostasis (D-dimer and plasminogen activator inhibitor-1), neurohormonal activity (aldosterone-to-renin ratio, B-type natriuretic peptide, and N-terminal proatrial natriuretic peptides), and endothelial function (homocysteine and urinary albumin/creatinine ratio) measured at the sixth examination (1995-1998) to risk of incident stroke/transient ischemic attack. In a subset of 1901 participants with available brain magnetic resonance imaging (1999-2005), we further related these biomarkers to total cerebral brain volume, covert brain infarcts, and large white-matter hyperintensity volume. During a median follow-up of 9.2 years, 130 participants experienced incident stroke/transient ischemic attack. In multivariable analyses adjusted for stroke risk factors, the biomarker panel was associated with incident stroke/transient ischemic attack and with total cerebral brain volume (P<0.05 for both) but not with covert brain infarcts or white-matter hyperintensity volume (P>0.05). In backward elimination analyses, higher log-B-type natriuretic peptide (hazard ratio, 1.39 per 1-SD increment; P=0.002) and log-urinary albumin/creatinine ratio (hazard ratio, 1.31 per 1-SD increment; P=0.004) were associated with increased risk of stroke/transient ischemic attack and improved risk prediction compared with the Framingham Stroke Risk Profile alone; when the <5%, 5% to 15%, or >15% 10-year risk category was used, the net reclassification index was 0.109 (P=0.037). Higher C-reactive protein (ß=-0.21 per 1-SD increment; P=0.008), D-dimer (ß=-0.18 per 1-SD increment; P=0.041), total homocysteine (ß=-0.21 per 1-SD increment; P=0.005), and urinary albumin/creatinine ratio (ß=-0.15 per 1-SD increment; P=0.042) were associated with lower total cerebral brain volume. CONCLUSION: In a middle-aged community sample, we identified multiple biomarkers that were associated with clinical and subclinical vascular brain injury and could improve risk stratification.

Augmented creatinine clearance in traumatic brain injury.

BACKGROUND: Hypertonic saline and/or norepinephrine infusion are routinely used to achieve a desired cerebral perfusion pressure (CPP) in the management of traumatic brain injury (TBI). We hypothesized that creatinine clearances (CrCls) would be significantly augmented in this setting. METHODS: This was an observational cohort study in TBI patients older than 16 years with normal serum creatinine concentrations, requiring maintenance of CPP. Eight-hour urinary CrCl collections were performed while on and off active management. Demographic data, use of vasoactive medications, fluid balance, feeding regimen, and hemodynamic variables were recorded throughout the study period. Augmented CrCl was defined as >150 mL/min/1.73 m(2) in women and >160 mL/min/1.73 m(2) in men. RESULTS: Twenty patients were enrolled, and augmented clearances were demonstrated in 17 (85%). The mean maximum CrCl was 179 mL/min/1.73 m(2) while receiving CPP therapy (95% confidence interval [CI], 159-198), returning to a mean of 111 mL/min/1.73 m(2) (95% CI, 91-131; P < 0.001) when measured after discharge from the intensive care unit. The mean CrCl in the intensive care unit while not receiving CPP therapy was 150 mL/min/1.73 m(2) (95% CI, 134-167; P = 0.03). The mean time to reach peak CrCl while receiving active treatment was 4.7 days (95% CI, 3.0-6.4). In a multivariate analysis, norepinephrine use, saline loading, mean arterial blood pressure, and central venous pressure were associated with augmented CrCl on the day of measurement. CONCLUSIONS: Augmented CrCls are common in TBI patients receiving active management of CPP and persist even after discontinuation of such therapy. Further work is needed to clarify the impact of such clearances on renally excreted drugs in this setting.

Can admission S-100beta predict the extent of brain damage in head trauma patients?

BACKGROUND: As has been shown previously, S-100beta levels in serum can be a useful predictor of brain damage after head trauma. This pilot study was designed to investigate whether urine samples, which are much easier to obtain, could be used for the same purpose instead of serum samples. METHODS: Ninety-six consecutive patients admitted with head trauma were recruited in the study. After exclusion of 54 patients, mostly because of significant additional trauma, S-100beta levels were analyzed in serum and urine of 42 patients using a luminometric assay. A range for normal values was established based on samples from ten healthy volunteers. RESULTS: S-100beta serum levels increased proportional to the severity of the head trauma, as had been previously shown by several other groups. In many patients, initial increases in urine S-100beta levels were seen later than in serum, after which the kinetics of S-100beta levels in urine seemed to follow that established for serum levels. S-100beta values in urine were on average about 54% lower in urine than in serum. CONCLUSIONS: S-100beta levels in urine obtained on admission to the hospital are not a good indicator for the extent of brain damage. However, urine S-100beta levels obtained at later time points might be a useful indicator for the development of secondary brain injury.

Vasopressin serum levels and disorders of sodium and water balance in patients with severe brain injury.

BACKGROUND: Disorders of water and sodium balance are frequently seen in patients with severe brain injury (SBI), and may worsen their prognosis. PURPOSE: To evaluate vasopressin (AVP) serum levels and sodium and water balance disorders during the first week post-injury in patients with SBI. METHOD: Thirty-six adult patients with SBI (admission Glasgow Coma Scale score < or= 8) and an estimated time of injury

Basal ganglia lesions in a patient with 3-hydroxyisobutyric aciduria.

3-hydroxyisobutyric aciduria (3HiB-uria) is a very rare organic aciduria that involves valine metabolism. We report the case of a 7-year-old boy with 3HiB-uria who has suffered more than 20 ketoacidotic episodes since the age of 15 months. In the most recent ketoacidotic episode, which was particularly severe, he developed mild dystonia and choreoathetosis. Magnetic resonance imaging (MRI) revealed bilateral swelling and signal abnormalities of the putamina and heads of the caudate nuclei. The abnormal movements showed a gradual improvement over several months, in correlation with neuroradiological findings. 3HiB-uria should be recognized as one of the group of branched chain organic acidemias that can produce lesions in the basal ganglia.

Urinary S100B concentrations are increased after brain injury in children: A preliminary study.

OBJECTIVE: S100B is a renally excreted protein concentrated in glial cells of the nervous system. Increases in serum S100B concentrations reflect brain injury. However, increases in serum are rapid and transient and therefore may be of limited use in certain patients. Urinary S100B concentrations may be able to provide information about brain injury in this subgroup of patients. DESIGN: Prospective, descriptive study. SETTING: Level I trauma center. PATIENTS: Fifteen children with acute traumatic or hypoxemic brain injury (subjects) and 14 healthy controls. INTERVENTIONS: Urine and serum samples were collected from subjects and controls. Serial samples were collected in brain injury subjects up to every 12 hrs for 3 days. S100B concentrations were measured by enzyme-linked immunosorbent assay (Nanogen, San Diego CA). Outcome was assessed by Glasgow Outcome Scale score. MEASUREMENTS AND MAIN RESULTS: Urinary S100B concentrations were detectable in 80% of subjects with increased serum S100B concentrations and 0% of controls. Peak urinary S100B concentrations occurred significantly later than peak serum S100B concentrations: 55.3 (29.8) (mean [sd]) vs. 14.6 (11.8) hrs after injury (p = .002). All subjects with an undetectable urinary S100B had a good outcome vs. only 20% of subjects with a detectable urinary S100B. Subjects with increased serum S100B were more likely to have a poor outcome than those with normal S100B (p = .01). CONCLUSIONS: Increases in urinary S100B are found in the majority of children with acute brain injury and an increased serum S100B. Urinary S100B concentrations peak later than serum concentrations, suggesting that measurement of urinary S100B may be helpful in subjects in whom early serum S100B is unavailable. Urinary and/or serum S100B concentrations may be useful to assist in the prediction of outcome after pediatric brain injury.

Urinary Biomarkers of Brain Diseases.

Biomarkers are the measurable changes associated with a physiological or pathophysiological process. Unlike blood, urine is not subject to homeostatic mechanisms. Therefore, greater fluctuations could occur in urine than in blood, better reflecting the changes in human body. The roadmap of urine biomarker era was proposed. Although urine analysis has been attempted for clinical diagnosis, and urine has been monitored during the progression of many diseases, particularly urinary system diseases, whether urine can reflect brain disease status remains uncertain. As some biomarkers of brain diseases can be detected in the body fluids such as cerebrospinal fluid and blood, there is a possibility that urine also contain biomarkers of brain diseases. This review summarizes the clues of brain diseases reflected in the urine proteome and metabolome.

Elevation of tumor necrosis factor in head injury.

Tumor necrosis factor (TNF) is a cytokine which mediates protein wasting in pathological states by promoting the catabolism of visceral tissues and skeletal muscle. The role that TNF plays in nitrogen wasting following head injury was studied by measuring TNF in the serum of 21 patients with severe head injury. Parallel measurements of TNF and urinary nitrogen excretion were performed on days 1, 3, and 5 after head injury. TNF values after head injury ranged from 65 pg/ml to 7500 pg/ml, with a mean of 1147 pg/ml, compared to control values of serum TNF of less than 38 pg/ml. The mean daily urinary nitrogen loss was 13 g/day with a range of 2.8 to 27.6 g/day, and the mean nitrogen balance was -5.8 g with a range of +4.6 to -19.1 g. While both serum TNF levels and nitrogen loss were increased after head injury, the elevation of TNF did not correlate strongly with nitrogen wasting.

Serum and urine nitrate and nitrite are not reliable indicators of intrathecal nitric oxide production in acute brain injury.

This study examined the correlation between nitric oxide (NO) metabolites in the three major body fluid compartments and assessed performance of newly described vanadium-based assay for simultaneous detection of nitrite and nitrate (NO(x)) in human samples. Vanadium reduces nitrate to nitrite, which can be measured after a colorimetric reaction with Griess reagents. Cisternal cerebro spinal fluid (CSF), serum and urine samples from 10 patients with acute brain injury (ABI) were compared to control subjects. Significantly higher CSF NO(x) levels were found in brain injury patients compared to control patients (19.7+/-13.7 vs. 6.5+/-2.3 microM; p=0.01), which persisted for 10-day period of observation. The serum and urine levels of NO(x) on admission were not statistically different (42.8+/-28.2 microM; 584.1+/-337.8 micromol/g Cr, respectively) from controls (36.8+/-14.8 microM; 819.7+/-356.0 micromol/g Cr), but tended to decrease during the disease course reaching the lowest level on day 6 (serum: 19.3+/-8.4 microM, urine: 300.4+/-111.9 micromol/g Cr). CSF levels of NO(x) correlated moderately with those in serum (p=0.001, R=0.5). Serum NO(x) concentrations correlated weakly with urine levels (p=0.04, R=0.3). There was no significant correlation between CSF NO(x) and urine NO(x) levels. In conclusion, patients suffering brain injury had increased NO(x) concentrations in CSF, which remained independent from other body fluid compartments. Serum and urinary NO(x) levels cannot be used as a reliable index to assess intrathecal NO production.

Lactosuria - a new metabolic feature of severe cerebrocranial trauma.

Under controlled dietary conditions the urinary excretion of lactose was studied in 15 healthy persons, 15 patients with cerebrocranial trauma and 15 patients with extracranial trauma. Urinary lactose levels were found to be markedly increased in patients with head injury and ranged from 10.3 to 147.7 mg/24 h with a mean 63.4 mg/24 h in contrast to patients with other injuries (3.1 to 17.0 mg/24 h, mean 9.4 mg/24 h; P less than 0.001), and healthy individuals (3.3 to 17.93 mg/24 h, mean 7.6 mg/24h; P less than 0.001). In the head injury group the lowest values were found in drowsy or disoriented patients with cerebral concussion and the highest in comatose subjects. The level of lactosuria decreases after approximately 12 to 16 days to normal levels even when the patient remains unconscious. An earlier return to normal excretion parallels or preceeds the reappearance of consciousness. Unlike alimentary lactosuria, caused by ingestion of milk or other dairy products in large quantities, the elevated lactose levels in head injury patients were not usually accompanied by a comparable rise in galactose excretion, mean 11.45 mg/24 h versus 9.17 mg/24 h in controls; P less than 0.2. The mechanism of enhanced lactose excretion in severe cerebrocranial trauma remains unknown. It is suggested that it may be associated with either an increased catabolism of brain gangliosides or a stimulated lactose synthesis in peripheral tissues probably due to the participation of the lactogenic hormone prolactin.

Determination of 3 methyl-L-histidine in human urine by ion exchange high performance liquid chromatography. Applications to patients in post-operative surgical care.

A new chromatographic procedure is proposed for measuring 3 methyl-L-histidine (3 MH) in human urine. The sample was purified on a cation-exchange resin (AGR 50W-X4) and analysed by ion exchange high performance liquid chromatography on a PARTISIL 10 SCX Whatman column in UV light at 210 nm within 16 min. This procedure gave similar outputs of 3 MH to those described in human normal urine (mean +/- SEM = 213 +/- 15 mumol X 24 h-1, n = 19). It was used to measure the urinary outputs of 3 MH of five patients admitted to an intensive surgical care unit, for 48, 28, 25, 15 and 10 days, respectively. The urinary outputs of 3 MH were normal or lower than normal. The 10(3) urinary 3 MH/creatinine molar ratios were also calculated; this new 3 MH analysis could help the reanimator to prescribe an adequate nutritional assessment.

Serum and urine zinc response in head-injured patients.

A prospective longitudinal evaluation of serum zinc concentrations was performed in 26 head-trauma patients, and 24-hour urine zinc excretion was determined in 15 of these subjects. Patients had markedly depressed admission serum zinc concentrations (mean +/- standard error of the mean: 40.2 +/- 3.2 micrograms/dl; normal values: 70 to 120 micrograms/dl), which gradually increased during the 16-day study period. All subjects demonstrated increased urinary zinc losses throughout the study period. Urinary zinc excretion was greater in patients with more severe head injuries. Indeed, patients with more severe head trauma had mean peak urinary zinc losses of greater than 7000 micrograms/day (normal less than 500 (micrograms/day). The implications of this altered zinc metabolism for protein metabolism, wound healing, and immune function, and the specific role of zinc in brain function and recovery from injury are discussed.

Steroid administration and nitrogen excretion in the head-injured patient.

The effect of steroid administration on metabolic rate and nitrogen excretion was examined in 20 head-injured patients alternately assigned to receive either methylprednisolone for 14 days or no steroid treatment. Although metabolic rate, caloric intake, and nitrogen intake were not different between the two groups, the patients who received steroids had a 30% higher excretion of nitrogen during the first 6 days after injury than did the patients not receiving steroids. All patients had an increase in nitrogen excretion through the 2nd week, peaking on Day 11. By Day 21 after injury, the patients had an average cumulative nitrogen loss of 162 gm and had lost an average of 5 kg body weight regardless of whether they had received steroids. Serum albumin levels decreased in the steroid-treated patients but returned to nearly normal by Day 21 in the untreated group. Immunosuppression, evidenced by a lower initial total lymphocyte count and a higher incidence of infections, was present in the steroid group; hyperglycemia requiring insulin treatment was more common in those patients.

The acute-phase response of the brain-injured patient.

The acute response to injury and infection is manifested by increased synthesis of acute-phase proteins by the liver, an increased white blood cell count, fever, a negative nitrogen balance, and altered serum mineral levels (zinc, iron, and copper). This response is thought to be partially mediated by cytokines such as interleukin-1, but has not been well studied in head-injured patients. In this study, 25 patients were studied for evidence of the acute-phase response extending from hospital admission up to 21 days postinjury. The patients were divided into two groups to determine if severity of injury influenced the response. Group 1 consisted of nine patients with admission peak 24-hour Glasgow Coma Scale (GCS) scores of 4 or less; Group 2 consisted of 16 patients with admission peak 24-hour GCS scores of 8 or greater. All patients demonstrated some evidence of the acute-phase response. Serum alpha-1 acid glycoprotein, ceruloplasmin, and C-reactive protein levels were elevated on admission and throughout the study. Serum albumin and zinc levels were depressed on admission; zinc levels gradually normalized by Day 21 in both groups, but hypoalbuminemia was observed throughout the study period. Serum copper levels were normal on admission but increased to above normal in both groups by Day 11 postinjury. Urinary urea nitrogen excretion was elevated in both groups and peaked on Day 7 for Group 1 and Day 11 for Group 2 patients. The patients with admission GCS scores equal to or less than 4 had overall higher temperatures than were seen in those with GCS scores greater than or equal to 8 (p = 0.009). All patients but one had an elevated white blood cell count on admission. It is concluded that brain-injured patients with admission GCS scores of 3 to 4 and 8 to 14 demonstrate an acute-phase response which lasts for at least 3 weeks postinjury. It is speculated that this response is at least partially mediated by increased intraventricular interleukin-1 activity.

A method to estimate urinary electrolyte excretion in patients at risk for developing cerebral salt wasting.

OBJECT: Two major criteria are necessary to diagnose cerebral salt wasting (CSW): a cerebral lesion and a large urinary excretion of Na+ and Cl- at a time when the extracellular fluid (ECF) volume is contracted. Nevertheless, it is difficult for the physician to confirm from bedside observation that a patient has a contracted ECF volume. Hyponatremia, although frequently present, should not be a criterion for a diagnosis of salt wasting. A contracted ECF volume is unlikely if there are positive balances of Na+ and Cl-. The goal of this study was to assess the accuracy of calculating balances for Na+ plus K+ and of Cl- over 1 to 10 days in an intensive care unit (ICU) setting. METHODS: A prospective comparison of measured and estimated quantities of Na+ plus K+ and of Cl- excreted over 1 to 10 days in 10 children and 12 adults who had recently received a traumatic brain injury or undergone recent neurosurgery. Plasma concentrations of electrolytes were recorded at the beginning and end of the study period. The total volumes infused and excreted and the concentrations of Na+, K+, and Cl- in the infusate were obtained from each patient's ICU chart. The electrolytes in the patients' urine were measured and calculated. Correlations between measured and calculated values for excretions of Cl- and of Na+ plus K+ were excellent. CONCLUSIONS: Mass balances for Na+ plus K+ and for Cl- can be accurately estimated. These data provide information to support or refute a clinical diagnosis of CSW. The danger of relying on balances for these electrolytes measured within a single day to diagnose CSW is illustrated.

Modified injury severity scale and concurrent steroid therapy: independent correlates of negative nitrogen balance in pediatric trauma.

Twelve well-nourished children with multiple trauma were separately grouped by the presence or absence of a head injury and associated steroid treatment. They were studied to determine the impact of the severity of overall injury (measured by MISS), neurologic injury (measured by GCS), and steroid administration on total urinary nitrogen excretion. All six children with significant head injury received steroids. Nitrogen loss was higher in more severely injured patients. Severity of overall injury was similar in the steroid and nonsteroid treated groups. The nitrogen loss in head-injured patients treated with steroids was significantly greater (P less than 0.001) than in the nonsteroid-treated patients.

[CSF enzyme activities in patients with head injury--especially on GOT, GPT, LDH, and CPK (AUTHOR'S TRANSL)].

In our studies on patients with head injury, it was noted that there are some correlations between their clinical courses and the urinary excretion of creatine (cr), creatinine (Crn), 17-ketosteroid and 17-hydroxycorticosteroid. We observed the high urinary excretion of Cr in patients with severe head injury while almost negative in a mild case. We reported those facts in 1974. Also noted in patients with head injury is the relationship between the enzyme-activities (GOT, GPT, LDH and CPK) in the cerebrospinal fluid and their clinical courses. In this paper, we reported 34 cases of head injured patients (simple type: 2, concussion: 9, contusion: 8, acute intracranial hematoma: 7 and chronic intra-cranial hematoma: 8). The control values of CSF enzyme-activities were determined in these 14 cases (simple head injury, whip-lash injury and osteoma of the skull) as GOT less that 15, GPT less than 7, LDH less than 12 and CPK less than 8 units. In the moderate cases, a slight increase in activities of 4 enzymes in CSF were observed, while in severe or comatose cases, the enzyme-activities (especially LDH and CPK) were greater than in the controls. In the dead cases these values were five times as high as the normal case. In the patients recovering from a serious stage, these activities decreased to normal. High CSF enzyme-levels tend to indicate a poor prognosis and low levels a favorable progrosis. In the patients with a significant elevation of CSF enzymes, a high urinary excretion of Cr [normal range: 0-150 (ca. 50)mg/day] was often observed. There was no apparent correlation between the enzyme level in CSF and that in serum and the increase or decrease of these 4 enzymes are not always proprotionate with each other. As reported by Green (1958) and Lending (1961), cerebral cell necrosis and increased permeability of BLB, BBB or cerebral cell membrane can be related to the increase of enzymeactivities. With these observations, it can be considered that severe head injury gives influence on metabolic function in the hypothalamus and may cause in the levels of CSF enzymes and/or the urinary excretions of Cr, Crn and corticosteroids. And the examinations of enzyme activities in the patients with head injury may become a useful aid to make an outlook of their clinical coure and prognosis.