Emmanuel Carrera

Impact of tight glycemic control on cerebral glucose metabolism after severe brain injury: A microdialysis study*

Objectives:To analyze the effect of tight glycemic control with the use of intensive insulin therapy on cerebral glucose metabolism in patients with severe brain injury. Design:Retrospective analysis of a prospective observational cohort. Setting:University hospital neurologic intensive care unit. Patients:Twenty patients (median age 59 yrs) monitored with cerebral microdialysis as part of their clinical care. Interventions:Intensive insulin therapy (systemic glucose target: 4.4–6.7 mmol/L [80–120 mg/dL]). Measurements and Main Results:Brain tissue markers of glucose metabolism (cerebral microdialysis glucose and lactate/pyruvate ratio) and systemic glucose were collected hourly. Systemic glucose levels were categorized as within the target “tight” (4.4–6.7 mmol/L [80–120 mg/dL]) vs. “intermediate” (6.8–10.0 mmol/L [121–180 mg/dL]) range. Brain energy crisis was defined as a cerebral microdialysis glucose <0.7 mmol/L with a lactate/pyruvate ratio >40. We analyzed 2131 cerebral microdialysis samples: tight systemic glucose levels were associated with a greater prevalence of low cerebral microdialysis glucose (65% vs. 36%, p < 0.01) and brain energy crisis (25% vs.17%, p < 0.01) than intermediate levels. Using multivariable analysis, and adjusting for intracranial pressure and cerebral perfusion pressure, systemic glucose concentration (adjusted odds ratio 1.23, 95% confidence interval [CI] 1.10–1.37, for each 1 mmol/L decrease, p < 0.001) and insulin dose (adjusted odds ratio 1.10, 95% CI 1.04–1.17, for each 1 U/hr increase, p = 0.02) independently predicted brain energy crisis. Cerebral microdialysis glucose was lower in nonsurvivors than in survivors (0.46 ± 0.23 vs. 1.04 ± 0.56 mmol/L, p < 0.05). Brain energy crisis was associated with increased mortality at hospital discharge (adjusted odds ratio 7.36, 95% CI 1.37–39.51, p = 0.02). Conclusions:In patients with severe brain injury, tight systemic glucose control is associated with reduced cerebral extracellular glucose availability and increased prevalence of brain energy crisis, which in turn correlates with increased mortality. Intensive insulin therapy may impair cerebral glucose metabolism after severe brain injury.

Continuous electroencephalography in the medical intensive care unit.

Objectives:To examine predictors and the prognostic value of electrographic seizures (ESZs) and periodic epileptiform discharges (PEDs) in medical intensive care unit (MICU) patients without a primary acute neurologic condition. Design:Retrospective study. Setting:MICU in a university hospital. Patients:A total of 201 consecutive patients admitted to the MICU between July 2004 and January 2007 without known acute neurologic injury and who underwent continuous electroencephalography monitoring (cEEG) for investigation of possible seizures or changes in mental status. Intervention:None. Measurements and Main Results:Median time from intensive care unit (ICU) admission to cEEG was 1 day (interquartile range 1–4). The majority of patients (60%) had sepsis as the primary admission diagnosis and 48% were comatose at the time of cEEG. Ten percent (n = 21) of patients had ESZs, 17% (n = 34) had PEDs, 5% (n = 10) had both, and 22% (n = 45) had either ESZs or PEDs. Seizures during cEEG were purely electrographic (no detectable clinical correlate) in the majority (67%) of patients. Patients with sepsis had a higher rate of ESZs or PEDs than those without sepsis (32% vs. 9%, p < 0.001). On multivariable analysis, sepsis at ICU admission was the only significant predictor of ESZs or PEDs (odds ratio 4.6, 95% confidence interval 1.9–12.7, p = 0.002). After controlling for age, coma, and organ dysfunction, the presence of ESZs or PEDs was associated with death or severe disability at hospital discharge (89% with ESZs or PEDs, vs. 39% if not; odds ratio 19.1, 95% confidence interval 6.3–74.6, p < 0.001). Conclusion:In this retrospective study of MICU patients monitored with cEEG, ESZs and PEDs were frequent, predominantly in patients with sepsis. Seizures were mainly nonconvulsive. Both seizures and periodic discharges were associated with poor outcome. Prospective studies are warranted to determine more precisely the frequency and clinical impact of nonconvulsive seizures and periodic discharges, particularly in septic patients.

The thalamus and behavior: effects of anatomically distinct strokes.

Data on behavioral changes after thalamic lesion are sparse and largely based on isolated reports of patients with thalamic strokes. However, recent findings suggest that behavioral patterns can be delineated on the basis of the four main arterial thalamic territories. The anterior pattern consists mainly of perseverations and superimposition of unrelated information, apathy, and amnesia. After paramedian infarct, the most frequent features are disinhibition syndromes, with personality changes, loss of self-activation, amnesia, and, in the case of extensive lesions, thalamic “dementia”; this pattern may often be difficult to distinguish from primary psychiatric disorders, especially when neurologic dysfunction is lacking. After inferolateral lesion, executive dysfunction may develop but is often overlooked, although it may occasionally lead to severe long-term disability. After posterior lesion, whereas cognitive dysfunction with neglect and aphasia are well known, no specific behavioral syndrome has been reported. In the future, perfusion CT, functional MRI, and tractography using diffusion imaging in stroke patients may provide a better understanding of the role of the corticothalamic relationship in behavioral changes associated with thalamic stroke.

Early EEG correlates of neuronal injury after brain anoxia

Objectives: EEG and serum neuron-specific enolase (NSE) are used for outcome prognostication in patients with postanoxic coma; however, it is unclear if EEG abnormalities reflect transient neuronal dysfunction or neuronal death. To assess this question, EEG abnormalities were correlated with NSE. Moreover, NSE cutoff values and hypothermic EEG features related with poor outcome were explored. Methods: In a prospective cohort of 61 adults treated with therapeutic hypothermia (TH) after cardiac arrest (CA), multichannel EEG recorded during TH was assessed for background reactivity and continuity, presence of epileptiform transients, and correlated with serum NSE collected at 24–48 hours after CA. Demographic, clinical, and functional outcome data (at 3 months) were collected and integrated in the analyses. Results: In-hospital mortality was 41%, and 82% of survivors had good neurologic outcome at 3 months. Serum NSE and EEG findings were strongly correlated (Spearman rho = 0.45; p < 0.001). Median NSE peak values were higher in patients with unreactive EEG background (p < 0.001) and discontinuous patterns (p = 0.001). While all subjects with nonreactive EEG died, 5 survivors (3 with good outcome) had NSE levels >33 μg/L. Conclusion: The correlation between EEG during TH and serum NSE levels supports the hypothesis that early EEG alterations reflect permanent neuronal damage. Furthermore, this study confirms that absent EEG background reactivity and presence of epileptiform transients are robust predictors of poor outcome after CA, and that survival with good neurologic recovery is possible despite serum NSE levels> 33 μg/L. This underscores the importance of multimodal assessments in this setting.

Patent Foramen Ovale and Migraine A Cross-Sectional Study From the Northern Manhattan Study (NOMAS)

Background— A causal relationship between patent foramen ovale (PFO) and migraine has been hypothesized, and improvement of migraine frequency and severity after percutaneous PFO closure has been reported. Population-based data on the relationship between PFO and migraine are sparse, however. The objective of this study was to examine the association between PFO and migraine among stroke-free individuals in an urban, population-based, multiethnic cohort. Methods and Results— As a part of the ongoing Northern Manhattan Study (NOMAS), 1101 stroke-free subjects were assessed for self-reported history of migraine. The presence of PFO was assessed by transthoracic echocardiography. The mean age of the group was 69±10 years; 58% were women. Forty-eight percent were Caribbean Hispanic, 24% were white, 26% were black, and 2% were another race/ethnicity. The prevalence of self-reported migraine was 16% (13% migraine with aura). The prevalence of PFO was 15%. Migraine was significantly more frequent among younger subjects, women, and Hispanics. The prevalence of PFO was not significantly different between subjects who had migraine (26/178, or 14.6%) and those who did not (138/923, or 15.0%; P=0.9). In an adjusted multivariate logistic regression model, the presence of PFO was not associated with increased prevalence of migraine (odds ratio 1.01, 95% confidence interval 0.63 to 1.61). Increasing age was associated with lower prevalence of migraine in both subjects with a PFO (odds ratio 0.94, 95% confidence interval 0.90 to 0.99 per year) and those without PFO (odds ratio 0.97, 95% confidence interval 0.95 to 0.99 per year). The observed lack of association between PFO and migraine (with or without aura) was not modified by diabetes mellitus, hypertension, cigarette smoking, or dyslipidemia. Conclusions— In this multiethnic, elderly, population-based cohort, PFO detected with transthoracic echocardiography and agitated saline was not associated with self-reported migraine. The causal relationship between PFO and migraine remains uncertain, and the role of PFO closure among unselected patients with migraine remains questionable.

Effect of mannitol and hypertonic saline on cerebral oxygenation in patients with severe traumatic brain injury and refractory intracranial hypertension

Background: The impact of osmotic therapies on brain oxygen has not been extensively studied in humans. We examined the effects on brain tissue oxygen tension (PbtO2) of mannitol and hypertonic saline (HTS) in patients with severe traumatic brain injury (TBI) and refractory intracranial hypertension. Methods: 12 consecutive patients with severe TBI who underwent intracranial pressure (ICP) and PbtO2 monitoring were studied. Patients were treated with mannitol (25%, 0.75 g/kg) for episodes of elevated ICP (>20 mm Hg) or HTS (7.5%, 250 ml) if ICP was not controlled with mannitol. PbtO2, ICP, mean arterial pressure, cerebral perfusion pressure (CPP), central venous pressure and cardiac output were monitored continuously. Results: 42 episodes of intracranial hypertension, treated with mannitol (n = 28 boluses) or HTS (n = 14 boluses), were analysed. HTS treatment was associated with an increase in PbtO2 (from baseline 28.3 (13.8) mm Hg to 34.9 (18.2) mm Hg at 30 min, 37.0 (17.6) mm Hg at 60 min and 41.4 (17.7) mm Hg at 120 min; all p<0.01) while mannitol did not affect PbtO2 (baseline 30.4 (11.4) vs 28.7 (13.5) vs 28.4 (10.6) vs 27.5 (9.9) mm Hg; all p>0.1). Compared with mannitol, HTS was associated with lower ICP and higher CPP and cardiac output. Conclusions: In patients with severe TBI and elevated ICP refractory to previous mannitol treatment, 7.5% hypertonic saline administered as second tier therapy is associated with a significant increase in brain oxygenation, and improved cerebral and systemic haemodynamics.

Transcranial Doppler for predicting delayed cerebral ischemia after subarachnoid hemorrhage.

OBJECTIVETranscranial Doppler (TCD) is widely used to monitor the temporal course of vasospasm after subarachnoid hemorrhage (SAH), but its ability to predict clinical deterioration or infarction from delayed cerebral ischemia (DCI) remains controversial. We sought to determine the prognostic utility of serial TCD examination after SAH. METHODSWe analyzed 1877 TCD examinations in 441 aneurysmal SAH patients within 14 days of onset. The highest mean blood flow velocity (mBFV) value in any vessel before DCI onset was recorded. DCI was defined as clinical deterioration or computed tomographic evidence of infarction caused by vasospasm, with adjudication by consensus of the study team. Logistic regression was used to calculate adjusted odds ratios for DCI risk after controlling for other risk factors. RESULTSDCI occurred in 21% of patients (n = 92). Multivariate predictors of DCI included modified Fisher computed tomographic score (P = 0.001), poor clinical grade (P = 0.04), and female sex (P = 0.008). After controlling for these variables, all TCD mBFV thresholds between 120 and 180 cm/s added a modest degree of incremental predictive value for DCI at nearly all time points, with maximal sensitivity by SAH day 8. However, the sensitivity of any mBFV more than 120 cm/s for subsequent DCI was only 63%, with a positive predictive value of 22% among patients with Hunt and Hess grades I to III and 36% in patients with Hunt and Hess grades IV and V. Positive predictive value was only slightly higher if mBFV exceeded 180 cm/s. CONCLUSIONIncreased TCD flow velocities imply only a mild incremental risk of DCI after SAH, with maximal sensitivity by day 8. Nearly 40% of patients with DCI never attained an mBFV more than 120 cm/s during the course of monitoring. Given the poor overall sensitivity of TCD, improved methods for identifying patients at high risk for DCI after SAH are needed.

Anteromedian, Central, and Posterolateral Infarcts of the Thalamus Three Variant Types

Background and Purpose— Thalamic infarcts have traditionally been classified into 4 territories: anterior, paramedian, inferolateral, and posterior. The purpose of this study was to review this classical versus variant distribution in patients with thalamic stroke. Methods— We reviewed all patients with a first clinical stroke included in the Lausanne Stroke Registry between 1990 and 2002. Among 71 patients with an acute stroke isolated to the thalamus confirmed by MRI, we selected all patients with lesions outside the classical territories and studied their clinical, etiological, and radiological features. Results— A total of 21 patients (30% of all thalamic stroke patients) showed infarction outside the classical territories, allowing us to delineate 3 variant distributions: (1) Anteromedian territory (9 patients [13%]) involving anterior and paramedian territories, with predominantly cognitive impairment, including executive dysfunction, anterograde amnesia, and aphasia in left-sided or bilateral lesions. The most frequent stroke mechanism was cardiac embolism. (2) Central territory (4 patients [6%]), with lesions on the central part of the thalamus, resulting in a variety of neurological and neuropsychological signs, reflecting the involvement of several adjacent structures. Microangiopathy was the most frequent etiology. (3) Posterolateral territory (8 patients [11%]), involving inferolateral and posterior territories, with hemihypesthesia as the most frequent manifestation, followed by hemiataxia, executive dysfunction, and aphasia in left-sided lesions. Artery-to-artery embolism and microangiopathy were the main stroke mechanisms. Conclusions— We describe 3 variant topographic patterns of thalamic infarction with distinct manifestations and etiologies. We postulate that these infarcts are the result of a variation in thalamic arterial supply or reflect borderzone ischemia.

Continuous Electroencephalographic Monitoring in Critically Ill Patients With Central Nervous System Infections

OBJECTIVES To determine the prevalence, predictors, and clinical significance of electrographic seizures (ESz) and other continuous electroencephalographic monitoring findings in critically ill patients with central nervous system infections. DESIGN Retrospective cohort study. SETTING Eighteen-bed neurocritical care unit. PATIENTS We identified 42 consecutive patients with primary central nervous system infection (viral, 27 patients [64%]; bacterial, 8 patients [18%]; and fungal or parasitic, 7 patients [17%]) who underwent continuous electroencephalographic monitoring between January 1, 1996, and February 28, 2007. MAIN OUTCOME MEASURES Presence of ESz or periodic epileptiform discharges (PEDs). RESULTS Electrographic seizures were recorded in 14 patients (33%), and PEDs were recorded in 17 patients (40%). Twenty patients (48%) had either PEDs or ESz. Of the 14 patients with ESz, only 5 (36%) had a clinical correlate. Periodic epileptiform discharges (odds ratio=13.4; P=.001) and viral cause (odds ratio=13.0; P=.02) were independently associated with ESz. Both ESz (odds ratio=5.9; P=.02) and PEDs (odds ratio=6.1; P=.01) were independently associated with poor outcome at discharge (severe disability, vegetative state, or death). CONCLUSIONS In patients with central nervous system infections undergoing continuous electroencephalographic monitoring, ESz and/or PEDs were frequent, occurring in 48% of our cohort. More than half of the ESz had no clinical correlate. Both ESz and PEDs were independently associated with poor outcome. Additional studies are needed to determine whether prevention or treatment of these electrographic findings improves outcome.

Brain Lactate Metabolism in Humans With Subarachnoid Hemorrhage

Background and Purpose— Lactate is central for the regulation of brain metabolism and is an alternative substrate to glucose after injury. Brain lactate metabolism in patients with subarachnoid hemorrhage has not been fully elucidated. Methods— Thirty-one subarachnoid hemorrhage patients monitored with cerebral microdialysis (CMD) and brain oxygen (PbtO2) were studied. Samples with elevated CMD lactate (>4 mmol/L) were matched to PbtO2 and CMD pyruvate and categorized as hypoxic (PbtO2 <20 mm Hg) versus nonhypoxic and hyperglycolytic (CMD pyruvate >119 &mgr;mol/L) versus nonhyperglycolytic. Results— Median per patient samples with elevated CMD lactate was 54% (interquartile range, 11%–80%). Lactate elevations were more often attributable to cerebral hyperglycolysis (78%; interquartile range, 5%–98%) than brain hypoxia (11%; interquartile range, 4%–75%). Mortality was associated with increased percentage of samples with elevated lactate and brain hypoxia (28% [interquartile range 9%–95%] in nonsurvivors versus 9% [interquartile range 3%–17%] in survivors; P=0.02) and lower percentage of elevated lactate and cerebral hyperglycolysis (13% [interquartile range, 1%–87%] versus 88% [interquartile range, 27%–99%]; P=0.07). Cerebral hyperglycolytic lactate production predicted good 6-month outcome (odds ratio for modified Rankin Scale score, 0–3 1.49; CI, 1.08–2.05; P=0.016), whereas increased lactate with brain hypoxia was associated with a reduced likelihood of good outcome (OR, 0.78; CI, 0.59–1.03; P=0.08). Conclusions— Brain lactate is frequently elevated in subarachnoid hemorrhage patients, predominantly because of hyperglycolysis rather than hypoxia. A pattern of increased cerebral hyperglycolytic lactate was associated with good long-term recovery. Our data suggest that lactate may be used as an aerobic substrate by the injured human brain.