Semi-elemental versus polymeric formula for enteral nutrition in brain-injured critically ill patients: a randomized trial.

BACKGROUND: The properties of semi-elemental enteral nutrition might theoretically improve gastrointestinal tolerance in brain-injured patients, known to suffer gastroparesis. The purpose of this study was to compare the efficacy and tolerance of a semi-elemental versus a polymeric formula for enteral nutrition (EN) in brain-injured critically ill patients. METHODS: Prospective, randomized study including brain-injured adult patients [Glasgow Coma Scale (GCS) ≤ 8] with an expected duration of mechanical ventilation > 48 h. INTERVENTION: an enteral semi-elemental (SE group) or polymeric (P group) formula. EN was started within 36 h after admission to the intensive care unit and was delivered according to a standardized nurse-driven protocol. The primary endpoint was the percentage of patients who received both 60% of the daily energy goal at 3 days and 100% of the daily energy goal at 5 days after inclusion. Tolerance of EN was assessed by the rate of gastroparesis, vomiting and diarrhea. RESULTS: Respectively, 100 and 95 patients were analyzed in the SE and P groups: Age (57[44-65] versus 55[40-65] years) and GCS (6[3-7] versus 5[3-7]) did not differ between groups. The percentage of patients achieving the primary endpoint was similar (46% and 48%, respectively; relative risk (RR) [95% confidence interval (CI)] = 1.05 (0.78-1.42); p = 0.73). The mean daily energy intake was, respectively, 20.2 ± 6.3 versus 21.0 ± 6.5 kcal/kg/day (p = 0.42). Protein intakes were 1.3 ± 0.4 versus 1.1 ± 0.3 g/kg/day (p < 0.0001). Respectively, 18% versus 12% patients presented gastroparesis (p = 0.21), and 16% versus 8% patients suffered from diarrhea (p = 0.11). No patient presented vomiting in either group. CONCLUSION: Semi-elemental compared to polymeric formula did not improve daily energy intake or gastrointestinal tolerance of enteral nutrition. TRIAL REGISTRATION: EudraCT/ID-RCB 2012-A00078-35 (registered January 17, 2012).

Hypertonic Lactate to Improve Cerebral Perfusion and Glucose Availability After Acute Brain Injury.

OBJECTIVES: Lactate promotes cerebral blood flow and is an efficient substrate for the brain, particularly at times of glucose shortage. Hypertonic lactate is neuroprotective after experimental brain injury; however, human data are limited. DESIGN: Prospective study (clinicaltrials.gov NCT01573507). SETTING: Academic ICU. PATIENTS: Twenty-three brain-injured subjects (13 traumatic brain injury/10 subarachnoid hemorrhage; median age, 59 yr [41-65 yr]; median Glasgow Coma Scale, 6 [3-7]). INTERVENTIONS: Three-hour IV infusion of hypertonic lactate (sodium lactate, 1,000 mmol/L; concentration, 30 µmol/kg/min) administered 39 hours (26-49 hr) from injury. MEASUREMENTS AND MAIN RESULTS: We examined the effect of hypertonic lactate on cerebral perfusion (using transcranial Doppler) and brain energy metabolism (using cerebral microdialysis). The majority of subjects (13/23 = 57%) had reduced brain glucose availability (baseline pretreatment cerebral microdialysis glucose, < 1 mmol/L) despite normal baseline intracranial pressure (10 [7-15] mm Hg). Hypertonic lactate was associated with increased cerebral microdialysis lactate (+55% [31-80%]) that was paralleled by an increase in middle cerebral artery mean cerebral blood flow velocities (+36% [21-66%]) and a decrease in pulsatility index (-21% [13-26%]; all p < 0.001). Cerebral microdialysis glucose increased above normal range during hypertonic lactate (+42% [30-78%]; p < 0.05); reduced brain glucose availability correlated with a greater improvement of cerebral microdialysis glucose (Spearman r = -0.53; p = 0.009). No significant changes in cerebral perfusion pressure, mean arterial pressure, systemic carbon dioxide, and blood glucose were observed during hypertonic lactate (all p > 0.1). CONCLUSIONS: This is the first clinical demonstration that hypertonic lactate resuscitation improves both cerebral perfusion and brain glucose availability after brain injury. These cerebral vascular and metabolic effects appeared related to brain lactate supplementation rather than to systemic effects.

Early prediction of coma recovery after cardiac arrest with blinded pupillometry.

OBJECTIVE: Prognostication studies on comatose cardiac arrest (CA) patients are limited by lack of blinding, potentially causing overestimation of outcome predictors and self-fulfilling prophecy. Using a blinded approach, we analyzed the value of quantitative automated pupillometry to predict neurological recovery after CA. METHODS: We examined a prospective cohort of 103 comatose adult patients who were unconscious 48 hours after CA and underwent repeated measurements of quantitative pupillary light reflex (PLR) using the Neurolight-Algiscan device. Clinical examination, electroencephalography (EEG), somatosensory evoked potentials (SSEP), and serum neuron-specific enolase were performed in parallel, as part of standard multimodal assessment. Automated pupillometry results were blinded to clinicians involved in patient care. Cerebral Performance Categories (CPC) at 1 year was the outcome endpoint. RESULTS: Survivors (n = 50 patients; 32 CPC 1, 16 CPC 2, 2 CPC 3) had higher quantitative PLR (median = 20 [range = 13-41] vs 11 [0-55] %, p < 0.0001) and constriction velocity (1.46 [0.85-4.63] vs 0.94 [0.16-4.97] mm/s, p < 0.0001) than nonsurvivors. At 48 hours, a quantitative PLR < 13% had 100% specificity and positive predictive value to predict poor recovery (0% false-positive rate), and provided equal performance to that of EEG and SSEP. Reduced quantitative PLR correlated with higher serum neuron-specific enolase (Spearman r = -0.52, p < 0.0001). INTERPRETATION: Reduced quantitative PLR correlates with postanoxic brain injury and, when compared to standard multimodal assessment, is highly accurate in predicting long-term prognosis after CA. This is the first prognostication study to show the value of automated pupillometry using a blinded approach to minimize self-fulfilling prophecy. Ann Neurol 2017;81:804-810.

Bedside cerebral microdialysis monitoring of delayed cerebral hypoperfusion in comatose patients with poor grade aneurysmal subarachnoid haemorrhage.

BACKGROUND: Delayed cerebral ischaemia (DCI) is frequent after poor grade aneurysmal subarachnoid haemorrhage (SAH). Owing to the limited accuracy of clinical examination, DCI diagnosis is often based on multimodal monitoring. We examined the value of cerebral microdialysis (CMD) in this setting. METHODS: 20 comatose SAH participants underwent CMD monitoring-for hourly sampling of cerebral extracellular lactate/pyruvate ratio (LPR) and glucose-and brain perfusion CT (PCT). Patients were categorised as DCI when PCT (8±3 days after SAH) showed cerebral hypoperfusion, defined as cerebral blood flow <32.5 mL/100 g/min with a mean transit time >5.7 s. Clinicians were blinded to CMD data; for the purpose of the study, only patients who developed cerebral hypoperfusion in anterior and/or middle cerebral arteries were analysed. RESULTS: DCI (n=9/20 patients) was associated with higher CMD LPR (51±36 vs 31±10 in patients without DCI, p=0.0007) and lower CMD glucose (0.64±0.34 vs 1.22±1.05, p=0.0005). In patients with DCI, CMD changes over the 18 hours preceding PCT diagnosis revealed a pattern of CMD LPR increase (coefficient +2.96 (95% CI 0.13 to 5.79), p=0.04) with simultaneous CMD glucose decrease (coefficient -0.06 (95% CI -0.08 to -0.01), p=0.03, mixed-effects multilevel regression model). No significant CMD changes were noted in patients without DCI. CONCLUSIONS: In comatose patients with SAH, delayed cerebral hypoperfusion correlates with a CMD pattern of lactate increase and simultaneous glucose decrease. CMD abnormalities became apparent in the hours preceding PCT, thereby suggesting that CMD monitoring may anticipate targeted therapeutic interventions.

Cerebral Lactate Metabolism After Traumatic Brain Injury.

Cerebral energy dysfunction has emerged as an important determinant of prognosis following traumatic brain injury (TBI). A number of studies using cerebral microdialysis, positron emission tomography, and jugular bulb oximetry to explore cerebral metabolism in patients with TBI have demonstrated a critical decrease in the availability of the main energy substrate of brain cells (i.e., glucose). Energy dysfunction induces adaptations of cerebral metabolism that include the utilization of alternative energy resources that the brain constitutively has, such as lactate. Two decades of experimental and human investigations have convincingly shown that lactate stands as a major actor of cerebral metabolism. Glutamate-induced activation of glycolysis stimulates lactate production from glucose in astrocytes, with subsequent lactate transfer to neurons (astrocyte-neuron lactate shuttle). Lactate is not only used as an extra energy substrate but also acts as a signaling molecule and regulator of systemic and brain glucose use in the cerebral circulation. In animal models of brain injury (e.g., TBI, stroke), supplementation with exogenous lactate exerts significant neuroprotection. Here, we summarize the main clinical studies showing the pivotal role of lactate and cerebral lactate metabolism after TBI. We also review pilot interventional studies that examined exogenous lactate supplementation in patients with TBI and found hypertonic lactate infusions had several beneficial properties on the injured brain, including decrease of brain edema, improvement of neuroenergetics via a "cerebral glucose-sparing effect," and increase of cerebral blood flow. Hypertonic lactate represents a promising area of therapeutic investigation; however, larger studies are needed to further examine mechanisms of action and impact on outcome.

Modulation of cerebral ketone metabolism following traumatic brain injury in humans.

Adaptive metabolic response to injury includes the utilization of alternative energy substrates - such as ketone bodies (KB) - to protect the brain against further damage. Here, we examined cerebral ketone metabolism in patients with traumatic brain injury (TBI; n = 34 subjects) monitored with cerebral microdialysis to measure total brain interstitial tissue KB levels (acetoacetate and ß-hydroxybutyrate). Nutrition - from fasting vs. stable nutrition state - was associated with a significant decrease of brain KB (34.7 [10th-90th percentiles 10.7-189] µmol/L vs. 13.1 [6.5-64.3] µmol/L, p < 0.001) and blood KB (668 [168.4-3824.9] vs. 129.4 [82.6-1033.8] µmol/L, p < 0.01). Blood KB correlated with brain KB (Spearman's rho 0.56, p = 0.0013). Continuous feeding with medium-chain triglycerides-enriched enteral nutrition did not increase blood KB, and provided a modest increase in blood and brain free medium chain fatty acids. Higher brain KB at the acute TBI phase correlated with age and brain lactate, pyruvate and glutamate, but not brain glucose. These novel findings suggest that nutritional ketosis was the main determinant of cerebral KB metabolism following TBI. Age and cerebral metabolic distress contributed to brain KB supporting the hypothesis that ketones might act as alternative energy substrates to glucose. Further studies testing KB supplementation after TBI are warranted.

How to manage blood pressure after brain injury?

Manipulation of blood pressure (BP) is a mainstay of therapy in patients with acute brain injury (ABI). In the early emergent phase (first hours from injury), depending on intracranial pathology, BP manipulation aims to: 1) limit the progression of parenchymal hematomas or hemorrhagic transformation (in patients with ischemic/hemorrhagic stroke and aneurysmal subarachnoid hemorrhage [SAH]), and 2) attenuate hypoperfusion and secondary cerebral ischemic insults (in patients with traumatic brain injury [TBI]). During the intensive care unit (ICU) phase, BP management is primarily focused at identifying the so-called "optimal" BP/cerebral perfusion pressure (CPP), i.e. the threshold of mean arterial pressure (MAP)/CPP to prevent secondary cerebral ischemia. BP augmentation is also an essential component of the medical management of delayed cerebral ischemia following SAH. Increasing clinical data support the use of surrogate monitoring modalities of cerebral perfusion (including trans-cranial Doppler and brain tissue oximetry) to indentify BP/CPP targets in ABI patients. We reviewed herein the actual evidence regarding BP control in the early phase after ABI and recent clinical investigations using multimodal monitoring to optimize CPP and BP in severe ABI patients. The main purpose of this review is to provide a pragmatic approach of BP management, taking into account the timing of injury and differences in brain pathologies.

Cerebral Microdialysis Monitoring to Improve Individualized Neurointensive Care Therapy: An Update of Recent Clinical Data.

Cerebral microdialysis (CMD) allows bedside semicontinuous monitoring of patient brain extracellular fluid. Clinical indications of CMD monitoring are focused on the management of secondary cerebral and systemic insults in acute brain injury (ABI) patients [mainly, traumatic brain injury (TBI), subarachnoid hemorrhage, and intracerebral hemorrhage (ICH)], specifically to tailor several routine interventions-such as optimization of cerebral perfusion pressure, blood transfusion, glycemic control and oxygen therapy-in the individual patient. Using CMD as clinical research tool has greatly contributed to identify and better understand important post-injury mechanisms-such as energy dysfunction, posttraumatic glycolysis, post-aneurysmal early brain injury, cortical spreading depressions, and subclinical seizures. Main CMD metabolites (namely, lactate/pyruvate ratio, and glucose) can be used to monitor the brain response to specific interventions, to assess the extent of injury, and to inform about prognosis. Recent consensus statements have provided guidelines and recommendations for CMD monitoring in neurocritical care. Here, we summarize recent clinical investigation conducted in ABI patients, specifically focusing on the role of CMD to guide individualized intensive care therapy and to improve our understanding of the complex disease mechanisms occurring in the immediate phase following ABI. Promising brain biomarkers will also be described.

Non-Ischemic Cerebral Energy Dysfunction at the Early Brain Injury Phase following Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: The pathophysiology of early brain injury following aneurysmal subarachnoid hemorrhage (SAH) is still not completely understood. OBJECTIVE: Using brain perfusion CT (PCT) and cerebral microdialysis (CMD), we examined whether non-ischemic cerebral energy dysfunction may be a pathogenic determinant of EBI. METHODS: A total of 21 PCTs were performed (a median of 41 h from ictus onset) among a cohort of 18 comatose mechanically ventilated SAH patients (mean age 58 years, median admission WFNS score 4) who underwent CMD and brain tissue PO2 (PbtO2) monitoring. Cerebral energy dysfunction was defined as CMD episodes with lactate/pyruvate ratio (LPR) >40 and/or lactate >4 mmol/L. PCT-derived global CBF was categorized as oligemic (CBF < 28 mL/100 g/min), normal (CBF 28-65 mL/100 g/min), or hyperemic (CBF 69-85 mL/100 g/min), and was matched to CMD/PbtO2 data. RESULTS: Global CBF (57 ± 14 mL/100 g/min) and PbtO2 (25 ± 9 mm Hg) were within normal ranges. Episodes with cerebral energy dysfunction (n = 103 h of CMD samples, average duration 7.4 h) were frequent (66% of CMD samples) and were associated with normal or hyperemic CBF. CMD abnormalities were more pronounced in conditions of hyperemic vs. normal CBF (LPR 54 ± 12 vs. 42 ± 7, glycerol 157 ± 76 vs. 95 ± 41 µmol/L; both p < 0.01). Elevated brain LPR correlated with higher CBF (r = 0.47, p < 0.0001). CONCLUSION: Cerebral energy dysfunction is frequent at the early phase following poor-grade SAH and is associated with normal or hyperemic brain perfusion. Our data support the notion that mechanisms alternative to ischemia/hypoxia are implicated in the pathogenesis of early brain injury after SAH.