Serum inflammatory and brain injury biomarkers in COVID-19 patients admitted to intensive care unit: A pilot study.

Background: The aim of this study was to measure serum brain injury biomarkers in patients with COVID-19 admitted to intensive care unit (ICU), without evidence of brain impairment, and to determine potential correlations with systemic inflammatory markers, illness severity, and outcome. Methods: In patients admitted to the ICU with COVID-19, without clinical evidence of brain injury, blood S100 calcium-binding protein B (S100B), neuron-specific enolase (NSE) and interleukin-6 (IL-6) were measured on admission. Clinical, routine laboratory data and illness severity were recorded. Comparisons between 28-day survivors and non-survivors and correlations of neurological biomarkers to other laboratory data and illness severity, were analyzed. Results: We included 50 patients, median age 64 [IQR 58-78] years, 39 (78%) males, 39 (78%) mechanically ventilated and 11 (22%) under high flow nasal oxygen treatment. S100B and NSE were increased in 19 (38%) and 45 (90%) patients, respectively. S100B was significantly elevated in non-survivors compared to survivors: 0.15 [0.10-0.29] versus 0.11 [0.07-0.17] µg/L, respectively, (p = 0.03), and significantly correlated with age, IL-6, arterial lactate, noradrenaline dose, illness severity and lymphocyte count. IL-6 was significantly correlated with C-reactive protein, noradrenaline dose and organ failure severity. NSE was correlated only with lactate dehydrogenase. Conclusion: Brain injury biomarkers were frequently elevated in COVID-19 ICU patients, in the absence of clinical evidence of brain injury. S100B was significantly correlated with IL-6, low lymphocyte count, hypoperfusion indices, illness severity, and short-term outcome. These findings indicate a possible brain astrocytes and neurons involvement, also suggesting a broader role of S100B in systemic inflammatory response.

Methylmalonic acid and vitamin B12 in patients with heart failure.

OBJECTIVE: Vitamin B12 deficiency among patients with heart failure (HF) may have been underestimated. High serum levels of methylmalonic acid (MMA) have been identified in several studies as an early indicator of vitamin B12 deficiency. Furthermore, MMA seems to constitute a biomarker of oxidative stress and mitochondrial dysfunction. There are scarce data regarding vitamin B12 and MMA in patients with HF. The aim of this study was to investigate vitamin B12 and MMA serum levels in patients with HF. METHODS: One hundred five consecutive patients admitted to our hospital with symptoms and signs of acute decompensated HF were included in the study. Demographic and clinical characteristics as well as comorbidities and medical treatment before hospital admission were recorded. Transthoracic echocardiography was performed in all patients. Blood samples were collected during the first 24 hours of hospitalization and measured for complete blood count, biochemical profile, vitamin B12, N-terminal prohormone of brain natriuretic peptide, and MMA levels. Finally, 51 healthy individuals constituted the control group. RESULTS: A total of 43.8% of patients with HF had elevated MMA levels, but only 10.5% had overt vitamin B12 deficiency, defined as serum cobalamin levels below 189 pg/ml. Mean MMA level was higher in patients with HF than in controls (33.0 ± 9.6 vs. 19.3 ± 6.3 ng/ml; p < 0.001). This difference remained significant when adjusted for age, sex, vitamin B12, and folate serum levels and kidney function (B = 14.7 (9.6-19.7); p < 0.001). MMA levels were higher in patients with acutely decompensated chronic HF than in those with newly diagnosed acute HF (34.7 ± 10.5 vs. 30.7 ± 7.8 ng/ml; p = 0.036). Correlation analysis revealed significantly negative correlation between MMA and vitamin B12 levels only in patients without comorbidities. CONCLUSION: Patients with HF have elevated MMA levels, independent of age, gender, HF category, or comorbidities, possibly indicating subclinical vitamin B12 deficiency. Further research is needed to investigate subclinical vitamin B12 deficiency in patients with HF and/or to clarify whether MMA constitutes a biomarker of oxidative stress.

The Insertion of Electrodes in the Brain for Electrophysiological Recording or Chronic Stimulation Is Not Associated With Any Biochemically Detectable Neuronal Injury.

OBJECTIVE: The aim of this study was to evaluate the degree of brain tissue injury that could be potentially induced by the introduction of a) microrecording electrodes, b) macrostimulation electrodes, or c) chronic stimulation electrodes. We aimed to evaluate whether the use of five simultaneous microrecording tracks is associated with any brain injury not detectable by conventional imaging such as CT or MRI. MATERIALS AND METHODS: The study included 61 patients who underwent surgery for implantation of 121 DBS leads. In all cases, five simultaneous tracts were utilized for microelectrode recordings. All patients underwent measurements of serum S-100b at specific time points as follows: a) prior to the operation, and b) intraoperatively at specific stages of the procedure: 1) after opening the burr hole, 2) after the insertion of microrecording electrodes, 3) during macrostimulation, 4) at the end of the operation, and 5) on the first postoperative day. RESULTS: The levels of serum S-100B protein remained within the normal range during the entire period of investigation in all patients with the exception of two cases. In both patients, the procedure was complicated by intraparenchymal hemorrhage visible in neuro-imaging. The first patient developed a small intraparenchymal hemorrhage, visible on the postoperative MRI, with no neurological deficit. The second patient experienced a focal epileptic seizure after the insertion of the right DBS chronic lead and the postoperative CT scan revealed a right frontal lobe hemorrhage. CONCLUSION: These results strongly indicate that the insertion of either multiple recording electrodes or the implantation of chronic electrodes in DBS does not increase the risk of brain hemorrhage or of other intracranial complications, and furthermore it does not cause any biochemically detectable brain tissue damage.

Serum S100B protein is increased and correlates with interleukin 6, hypoperfusion indices, and outcome in patients admitted for surgical control of hemorrhage.

S100B protein, an acknowledged biomarker of brain injury, has been reported to be increased in hemorrhagic shock. Also, acute hemorrhage is associated with inflammatory response. The aim of this study was to investigate the concentrations of serum S100B and the potential relationships with interleukin 6 (IL-6), severity of tissue hypoperfusion, and prognosis in patients admitted for surgical control of severe hemorrhage. Patients undergoing elective abdominal aortic aneurysm surgery participated as control subjects. Serum samples were drawn before, at the end of surgery, and after 6 and 24 h. Sixty-four patients with severe hemorrhage (23 trauma and 41 nontrauma) and 17 control subjects were included. Increased preoperative concentrations of S100B protein (1.70 ± 2.13 and 0.81 ± 1.23 µg/L) and IL-6 (241 ± 291 and 226 ± 238 pg/mL) were found in patients with traumatic and nontraumatic reason, respectively, and remained elevated throughout 24 h. Compared with nontrauma, trauma patients exhibited higher preoperative S100B levels (P < 0.05). Overall mortality was 47%. In control subjects, preoperative S100B and IL-6 levels were within normal limits and increased at the end of surgery (P < 0.001 and P < 0.01, respectively). Preoperative S100B correlated with IL-6 (r = 0.78, P < 0.01), arterial lactate (r = 0.50, P < 0.01), pH (r = -0.45, P < 0.01), and bicarbonate (r = -0.40, P < 0.01). Multiple analysis revealed that preoperative S100B in trauma and lactate in nontrauma patients were independently associated with outcome. In predicting death, preoperative S100B yielded receiver operator characteristics curve areas of 0.75 for all patients and 0.86 for those with trauma. These results indicate that severe hemorrhage in patients without brain injury is associated with increased serum levels of S100B, which correlates with IL-6 and tissue hypoperfusion. Moreover, the predictive ability of S100B for mortality, suggests that it could be a marker of potential clinical value in identifying, among patients with severe hemorrhage, those at greater risk for adverse outcome.

Procollagen type III aminoterminal propeptide as biomarker of host response in severe sepsis.

PURPOSE: The purpose of this study is to test the hypothesis that procollagen type III aminoterminal propeptide (PIIINP) is early elevated in septic episodes and can indicate the acute organ dysfunction/failure characterizing severe sepsis. MATERIALS AND METHODS: This prospective study included 107 consecutive septic patients (44 with sepsis, 13 with severe sepsis, and 50 with septic shock) and 45 controls. After blood sampling (within 48 hours after onset of septic episodes), serum was assayed. Patients were followed up, and their disease severity was daily evaluated. RESULTS: Procollagen type III aminoterminal propeptide (median [range]) increased in patients with sepsis (9.4 [2.2-42.4] ng/mL) compared with controls (3.6 [1.9-4.9] ng/mL; P<.001), exhibiting further significant increase in patients with severe sepsis and septic shock (19.5 [6.0-52.4] and 20.2 [1.8-89.2] ng/mL, respectively; P<.01-.001 vs sepsis). Among biomarkers of host response severity, PIIINP was the sole that was independently associated with severe sepsis/septic shock (P=.01). The area under the receiver operating characteristic curve for PIIINP to predict which patients with sepsis would eventually develop severe sepsis/septic shock was 0.87; the cutoff of 12 ng/mL had sensitivity 82% and specificity 89%. CONCLUSIONS: Increased serum PIIINP can signify severe sepsis/septic shock and predict which patients with sepsis will eventually develop severe sepsis/septic shock, thus representing a biomarker of risk stratification of patients with sepsis.

PlGF and sVEGFR-1 in chronic subdural hematoma: implications for hematoma development.

OBJECT: A considerable body of evidence indicates that inflammation and angiogenesis play a significant role in the development and progression of chronic subdural hematoma (CSDH). While various experimental and clinical studies have implicated placental growth factor (PlGF) in the processes that underpin pathological angiogenesis, no study has thus far investigated its expression in CSDH. The actions of PlGF and its related proangiogenic vascular endothelial growth factor (VEGF) are antagonized by a high-affinity soluble receptor, namely soluble VEGF receptor-1 (sVEGFR-1), and thus the ratio between sVEGFR-1 and angiogenic factors provides an index of angiogenic capacity. METHODS: In the present study, using an automated electrochemiluminescence assay, levels of PlGF and sVEGFR-1 were quantified in serum and hematoma fluid obtained in 16 patients with CSDH. RESULTS: Levels of PlGF and sVEGFR-1 were significantly higher in hematoma fluid than in serum (p < 0.0001). In serum, levels of sVEGFR-1 were higher than those of PlGF (p < 0.0001), whereas in hematoma fluid this difference was not apparent. Furthermore, the ratio of sVEGFR-1 to PlGF was significantly lower in hematoma fluid than in serum (p < 0.0001). CONCLUSIONS: Given previous evidence indicating a role for PlGF in promoting angiogenesis, inflammatory cell chemotaxis, and stimulation, as well as its ability to amplify VEGF-driven signaling under conditions favoring pathological angiogenesis, enhanced expression of PlGF in hematoma fluid suggests the involvement of this factor in the mechanisms of inflammation and angiogenesis in CSDH. Furthermore, a reduced ratio of sVEGFR-1 to PlGF in hematoma fluid is consistent with the proangiogenic capacity of CSDH. Future studies are warranted to clarify the precise role of PlGF and sVEGFR-1 in CSDH.

Serum S-100B protein monitoring in patients with severe traumatic brain injury.

OBJECTIVE: S-100B protein is a promising marker of injury severity and outcome after head injury. We examined the relationship between serum S-100B concentrations and injury severity, clinical course, survival, and treatment efficacy after severe traumatic brain injury (TBI). DESIGN AND SETTING: Prospective observational study in a neurosurgical intensive care unit. PATIENTS AND PARTICIPANTS: 102 adult patients with severe TBI, admitted between June 2001 and November 2003 (30 months). INTERVENTIONS: Serum S-100B levels were measured by immunoluminometric technique on admission and every 24 h thereafter for a maximum of 7 days. MEASUREMENTS AND RESULTS: Initial S-100B levels were significantly related to pupillary status, computed tomography severity 1, and 1-month survival. Cox's proportional hazard regression analysis showed that initial S-100B was an independent predictor of 1-month survival, in the presence of dilated pupils, and with increased age. Subjects with initial levels above 1 microg/l had a nearly threefold increased probability of death within 1 month. Serum S-100B alteration indicated neurological improvement or deterioration. Finally, surgical treatment reduced S-100B levels. CONCLUSIONS: Serum S-100B protein reflects injury severity and improves prediction of outcome after severe TBI. S-100B may also have a role in assessing the efficacy of treatment after severe TBI.

Slight and short-lasting increase of serum S-100B protein in extra-cranial trauma.

OBJECTIVE: Serum S-100B protein is an established biochemical marker of traumatic brain injury. At the same time, the question of extra-cranial S-100B release has been raised. This study evaluates the post-traumatic and post-operative release kinetics of S-100B in 45 trauma victims without head injury. METHOD: Serum S-100B protein was measured on admission and every 24 hours for 4 consecutive days. RESULTS: Initial S-100B was slightly increased (median: 0.54 microg L-1) and correlated with the severity of extra-cranial trauma (p = 0.0004, Mann-Whitney test). Both severely (abdominal or chest trauma with or without bone fractures) and mildly (long bone fractures) injured showed a rapid decline of S-100B (< 0.2 microg L-1) around 72 hours post-trauma. Extra-cranial surgery caused a secondary increase of S-100B, especially in the mildly injured group (p = 0.004, Wilcoxon signed rank test). CONCLUSIONS: Extra-cranial injury results in a mild elevation of serum S-100B protein that declines rapidly (1-3 days after injury).

Increased levels of serum S100B protein in critically ill patients without brain injury.

There is increasing evidence that the release of S100B protein, which is an acknowledged marker of brain injury, is also induced by other causes including hemorrhagic shock. The aim of this study was to investigate the serum concentration of S100B in critically ill mechanically ventilated patients with various degrees of organ dysfunction but without evidence of brain injury or any other neurological disorder and its possible association with tissue perfusion indices. Forty-six critically ill mechanically ventilated patients were studied on intensive care unit admission and until 6 days later. Measurement of serum S100B protein was obtained daily at the time of laboratory sampling and blood gas and lactate analysis. All patients exhibited increased levels of serum S100B levels at least once (median, 0.31 microg/L; interquartile range 25%-75%, 0.17-0.68 microg/L; range 0.04-18 microg/L). There was a significant correlation between S100B and arterial lactate (r, 0.66; P < 0.001), mean arterial pressure (MAP) (r, -0.41; P < 0.001), and pH (r, -0.37; P < 0.001). Serum concentrations of S100B were significantly higher in the presence of hemoglobin (Hb) level of less than 7 mg/dL compared with those measured when Hb level was greater than 7 mg/dL (median, 1.61 mg/dL; interquartile range 25%-75%, 0.66-3.57, vs. median, 0.29; interquartile range 25%-75%, 0.15-0.56, respectively; P < 0.001). Multiple regression analysis with dependent variable S100B and independent variables lactate, Hb, pH, and MAP showed that the only independent variable was the lactate (r, 0.79; r2, 0.62; P < 0.001). Sequential organ failure assessment score was positively associated with S100B values (P < 0.05). In conclusion, serum levels of S100B protein are elevated in critically ill patients, in the absence of an apparent brain damage. Increased S100B values correlated positively with lactate levels and negatively with MAP and pH. Low Hb level is associated with increased S100B levels. These results indicate that serum S100B protein concentration may be related to tissue hypoperfusion.

Serum S-100B as an indicator of early postoperative deterioration after meningioma surgery.

BACKGROUND: S-100B protein is an established serum marker of primary and secondary brain damage in head injury and stroke. Despite major progress in neurophysiologic monitoring, there are still difficulties in the early identification and quantification of evolving edema or trauma after craniotomy for tumor. In this study we aimed to correlate serum S-100B values with early postoperative neurologic course as well as late outcome in meningioma surgery. METHODS: We enrolled 50 consecutive patients who underwent meningioma resection. Serum S-100B was measured preoperatively and postcraniotomy for 7 consecutive days. Twenty-five patients (50%) developed immediate postoperative neurologic deterioration, and 15 (30%) had unfavorable 6-month outcomes. We used the Mann-Whitney U-test to assess the association of S-100B with all variables of interest. We used multiple logistic regression to search for the most significant predictor of postoperative deterioration. RESULTS: Increased S-100B was highly correlated with larger tumors, intraoperative difficulties, postcraniotomy acute deterioration, and long-term poor outcome. In addition, multiple logistic regression showed that age, sex, site, preoperative edema, history of meningioma resection, extent of resection, and histologic type did not correlate with postoperative increases in S-100B. Furthermore, patients with postoperative S-100B values >0.4 microg/L had increased risk of deterioration (relative risk = 9.0; 95% confidence interval, 2.4-34; P <0.0001) and of poor ultimate outcome (relative risk = 11; 95% confidence interval, 1.6-77; P = 0.002). CONCLUSIONS: After meningioma excision, postcraniotomy increases in serum S-100B appear to be an early indicator of short-term postoperative neurologic deterioration and of a poor longer-term outcome.

Elevated serum S-100B protein as a predictor of failure to short-term return to work or activities after mild head injury.

Protein S-100B is an established serum marker of primary and secondary brain damage and stroke. A group of patients after mild head injury (MHI) develop post-concussion symptoms that interfere with the ability in the short-term to return to work or undertake certain activities. The aim of this study was to examine the correlation of serum S-100B with short-term outcome after MHI. We studied 100 subjects who were referred to the Emergency Department (ED) after a MHI. All subjects had a GCS of 15 either with or without loss of consciousness (LOC) and/or post-traumatic amnesia (PTA). Serum S-100B was collected within 3 h from the injury and a value of > or = 0.15 microg/L was considered as abnormal. Subjects with other injuries, including scalp or cervical spine, were excluded, as well as those with alcohol/narcotic drug consumption or history of serious physical/mental illness. An independent observer measured the return to work/activities within one week. Thirty-two (32%) subjects had elevated S-100B. The failure to return to work/activities was significantly correlated with elevated S-100B: subjects with increased S-100B had a failure rate of 37.5% versus 4.9% of those with normal values (p = 0.0001). In MHI, the elevated S-100B seemed to correlate with an unfavorable short-term outcome. This might be useful in (1) selecting patients who need closer observation, hospitalization, and further investigations (such as CT scan or MRI), and (2) the prognosis of genuine post-concussion symptoms, that interfere with return to work or activities, versus other causes such as premorbid personality, labyrinthine dysfunction, whiplash syndrome, postinjury stress, occupational injury, litigation, and malingering.