An Update on the COGiTATE Phase II Study: Feasibility and Safety of Targeting an Optimal Cerebral Perfusion Pressure as a Patient-Tailored Therapy in Severe Traumatic Brain Injury.

INTRODUCTION: Monitoring of cerebral autoregulation (CA) in patients with a traumatic brain injury (TBI) can provide an individual 'optimal' cerebral perfusion pressure (CPP) target (CPPopt) at which CA is best preserved. This potentially offers an individualized precision medicine approach. Retrospective data suggest that deviation of CPP from CPPopt is associated with poor outcomes. We are prospectively assessing the feasibility and safety of this approach in the COGiTATE [CPPopt Guided Therapy: Assessment of Target Effectiveness] study. Its primary objective is to demonstrate the feasibility of individualizing CPP at CPPopt in TBI patients. The secondary objectives are to investigate the safety and physiological effects of this strategy. METHODS: The COGiTATE study has included patients in four European hospitals in Cambridge, Leuven, Nijmegen, and Maastricht (coordinating centre). Patients with severe TBI requiring intracranial pressure (ICP)-directed therapy are allocated into one of two groups. In the intervention group, CPPopt is calculated using a published (modified) algorithm. In the control group, the CPP target recommended in the Brain Trauma Foundation guidelines (CPP 60-70 mmHg) is used. RESULTS: Patient recruitment started in February 2018 and will continue until 60 patients have been studied. Fifty-one patients (85% of the intended total) have been recruited in October 2019. The first results are expected early 2021. CONCLUSION: This prospective evaluation of the feasibility, safety and physiological implications of autoregulation-guided CPP management is providing evidence that will be useful in the design of a future phase III study in severe TBI patients.

Continuous EEG Monitoring for Early Detection of Delayed Cerebral Ischemia in Subarachnoid Hemorrhage: A Pilot Study.

INTRODUCTION: Early identification of delayed cerebral ischemia (DCI) in patients with aneurysmal subarachnoid hemorrhage (aSAH) is a major challenge. The aim of this study was to investigate whether quantitative EEG (qEEG) features can detect DCI prior to clinical or radiographic findings. METHODS: A prospective cohort study was performed in aSAH patients in whom continuous EEG (cEEG) was recorded. We studied 12 qEEG features. We compared the time point at which qEEG changed with the time point that clinical deterioration occurred or new ischemia was noted on CT scan. RESULTS: Twenty aSAH patients were included of whom 11 developed DCI. The alpha/delta ratio (ADR) was the most promising feature that showed a significant difference in change over time in the DCI group (median -62% with IQR -87 to -39%) compared to the control group (median +27% with IQR -32 to +104%, p = 0.013). Based on the ROC curve, a threshold was chosen for a combined measure of ADR and alpha variability (AUC: 91.7, 95% CI 74.2-100). The median time that elapsed between change of qEEG and clinical DCI diagnosis was seven hours (IQR -11-25). Delay between qEEG and CT scan changes was 44 h (median, IQR 14-117). CONCLUSION: In this study, ADR and alpha variability could detect DCI development before ischemic changes on CT scan was apparent and before clinical deterioration was noted. Implementation of cEEG in aSAH patients can probably improve early detection of DCI.

Potential risk factors for developing heterotopic ossification in patients with severe traumatic brain injury.

BACKGROUND: Heterotopic ossification (HO) is a frequent complication after traumatic brain injury (TBI). The current preliminary study is intended to provide additional data on the potential roles that brain injury severity, concomitant orthopaedic trauma, and specific intensive care complicating events may play in the prediction of HO in patients who have sustained severe TBI. METHODS: A prospective cohort study in patients with severe TBI. RESULTS: Ninety-seven of the 176 patients were eligible for follow-up; 13 patients (13%) developed 19 clinically relevant HOs at 1 or more sites. Univariate analysis indicated that patients with HO remained in coma longer (P < .001) and were ventilated during a longer period (P = .002). Autonomic dysregulation (relative risk = 6.11, 95% confidence interval: 2.53-14.76) and surgically treated extremity fractures (relative risk = 5.02, 95% confidence interval: 1.68-15.04) also showed significant associations with the development of HO. CONCLUSION: Prolonged coma duration and mechanical ventilation, coexistent surgically treated bone fractures and clinical signs of autonomic dysregulation should be given further consideration as potential risk factors for developing clinically relevant HO. Larger-scale studies are needed to develop a valid risk profile that takes into account the interrelationships between variables.

Influenza virus and factors that are associated with ICU admission, pulmonary co-infections and ICU mortality.

PURPOSE: While most influenza patients have a self-limited respiratory illness, 5-10% of hospitalized patients develop severe disease requiring ICU admission. The aim of this study was to identify influenza-specific factors associated with ICU admission and mortality. Furthermore, influenza-specific pulmonary bacterial, fungal and viral co-infections were investigated. METHODS: 199 influenza patients, admitted to two academic hospitals in the Netherlands between 01-10-2015 and 01-04-2016 were investigated of which 45/199 were admitted to the ICU. RESULTS: A history of Obstructive/Central Sleep Apnea Syndrome, myocardial infarction, dyspnea, influenza type A, BMI > 30, the development of renal failure and bacterial and fungal co-infections, were observed more frequently in patients who were admitted to the ICU, compared with patients at the normal ward. Co-infections were evident in 55.6% of ICU-admitted patients, compared with 20.1% of patients at the normal ward, mainly caused by Staphylococcus aureus, Streptococcus pneumoniae, and Aspergillus fumigatus. Non-survivors suffered from diabetes mellitus and (pre-existent) renal failure more often. CONCLUSIONS: The current study indicates that a history of OSAS/CSAS, myocardial infarction and BMI > 30 might be related to ICU admission in influenza patients. Second, ICU patients develop more pulmonary co-infections. Last, (pre-existent) renal failure and diabetes mellitus are more often observed in non-survivors.

Cerebral Perfusion and Cerebral Autoregulation after Cardiac Arrest.

Out of hospital cardiac arrest is the leading cause of death in industrialized countries. Recovery of hemodynamics does not necessarily lead to recovery of cerebral perfusion. The neurological injury induced by a circulatory arrest mainly determines the prognosis of patients after cardiac arrest and rates of survival with a favourable neurological outcome are low. This review focuses on the temporal course of cerebral perfusion and changes in cerebral autoregulation after out of hospital cardiac arrest. In the early phase after cardiac arrest, patients have a low cerebral blood flow that gradually restores towards normal values during the first 72 hours after cardiac arrest. Whether modification of the cerebral blood flow after return of spontaneous circulation impacts patient outcome remains to be determined.

Brain imaging in comatose survivors of cardiac arrest: Pathophysiological correlates and prognostic properties.

INTRODUCTION: Hypoxic-ischemic brain injury is the main cause of death and disability of comatose patients after cardiac arrest. Early and reliable prognostication is challenging. Common prognostic tools include clinical neurological examination and electrophysiological measures. Brain imaging is well established for diagnosis of focal cerebral ischemia but has so far not found worldwide application in this patient group. OBJECTIVE: To review the value of Computed Tomography (CT), Magnetic Resonance Imaging (MRI), and Positron Emission Tomography (PET) for early prediction of neurological outcome of comatose survivors of cardiac arrest. METHODS: A literature search was performed to identify publications on CT, MRI or PET in comatose patients after cardiac arrest. RESULTS: We included evidence from 51 articles, 21 on CT, 27 on MRI, 1 on CT and MRI, and 2 on PET imaging. Studies varied regarding timing of measurements, choice of determinants, and cut-off values predicting poor outcome. Most studies were small (n = 6-398) and retrospective (60%). In general, cytotoxic oedema, defined by a grey-white matter ratio <1.10, derived from CT, or MRI-diffusion weighted imaging <650 × 10-6 mm2/s in >10% of the brain could differentiate between patients with favourable and unfavourable outcomes on a group level within 1-3 days after cardiac arrest. Advanced imaging techniques such as functional MRI or diffusion tensor imaging show promising results, but need further evaluation. CONCLUSION: CT derived grey-white matter ratio and MRI based measures of diffusivity and connectivity hold promise to improve outcome prediction after cardiac arrest. Prospective validation studies in a multivariable approach are needed to determine the additional value for the individual patient.

Influence of Induced Blood Pressure Variability on the Assessment of Cerebral Autoregulation in Patients after Cardiac Arrest.

OBJECTIVE: To determine if increasing variability of blood pressure influences determination of cerebral autoregulation. METHODS: A prospective observational study was performed at the ICU of a university hospital in the Netherlands. 13 comatose patients after cardiac arrest underwent baseline and intervention (tilting of bed) measurements. Mean flow velocity (MFV) in the middle cerebral artery and mean arterial pressure (MAP) were measured. Coefficient of variation (CV) was used as a standardized measure of dispersion in the time domain. In the frequency domain, coherence, gain, and phase were calculated in the very low and low frequency bands. RESULTS: The CV of MAP was significantly higher during intervention compared to baseline. On individual level, coherence in the VLF band changed in 5 of 21 measurements from unreliable to reliable and in 6 of 21 measurements from reliable to unreliable. In the LF band 1 of 21 measurements changed from unreliable to reliable and 3 of 21 measurements from reliable to unreliable. Gain in the VLF and LF band was lower during intervention compared to baseline. CONCLUSIONS: For the ICU setting, more attention should be paid to the exact experimental protocol, since changes in experimental settings strongly influence results of estimation of cerebral autoregulation.

Low spontaneous variability in cerebral blood flow velocity in non-survivors after cardiac arrest.

OBJECTIVE: To investigate spontaneous variability in the time and frequency domain in mean flow velocity (MFV) and mean arterial pressure (MAP) in comatose patients after cardiac arrest, and determine possible differences between survivors and non-survivors. METHODS: A prospective observational study was performed at the ICU of a tertiary care university hospital in the Netherlands. We studied 11 comatose patients and 10 controls. MFV in the middle cerebral artery was measured with simultaneously recording of MAP. Coefficient of variation (CV) was used as a standardized measure of dispersion in the time domain. In the frequency domain, the average spectral power of MAP and MFV were calculated in the very low, low and high frequency bands. RESULTS: In survivors CV of MFV increased from 4.66 [3.92-6.28] to 7.52 [5.52-15.23] % at T=72h. In non-survivors CV of MFV decreased from 9.02 [1.70-9.36] to 1.97 [1.97-1.97] %. CV of MAP was low immediately after admission (1.46 [1.09-2.25] %) and remained low at 72h (3.05 [1.87-3.63] %) (p=0.13). There were no differences in CV of MAP between survivors and non-survivors (p=0.30). We noticed significant differences between survivors and non-survivors in the VLF band for average spectral power of MAP (p=0.03) and MFV (p=0.003), whereby the power of both MAP and MFV increased in survivors during admission, while remaining low in non-survivors. CONCLUSIONS: Cerebral blood flow is altered after cardiac arrest, with decreased spontaneous fluctuations in non-survivors. Most likely, these changes are the consequence of impaired intrinsic myogenic vascular function and autonomic dysregulation.

Prognostication of neurologic outcome in cardiac arrest patients after mild therapeutic hypothermia: a meta-analysis of the current literature.

PURPOSE: To assess the sensitivity and false positive rate (FPR) of neurological examination and somatosensory evoked potentials (SSEPs) to predict poor outcome in adult patients treated with therapeutic hypothermia after cardiopulmonary resuscitation (CPR). METHODS: MEDLINE and EMBASE were searched for cohort studies describing the association of clinical neurological examination or SSEPs after return of spontaneous circulation with neurological outcome. Poor outcome was defined as severe disability, vegetative state and death. Sensitivity and FPR were determined. RESULTS: A total of 1,153 patients from ten studies were included. The FPR of a bilaterally absent cortical N20 response of the SSEP could be calculated from nine studies including 492 patients. The SSEP had an FPR of 0.007 (confidence interval, CI, 0.001-0.047) to predict poor outcome. The Glasgow coma score (GCS) motor response was assessed in 811 patients from nine studies. A GCS motor score of 1-2 at 72 h had a high FPR of 0.21 (CI 0.08-0.43). Corneal reflex and pupillary reactivity at 72 h after the arrest were available in 429 and 566 patients, respectively. Bilaterally absent corneal reflexes had an FPR of 0.02 (CI 0.002-0.13). Bilaterally absent pupillary reflexes had an FPR of 0.004 (CI 0.001-0.03). CONCLUSIONS: At 72 h after the arrest the motor response to painful stimuli and the corneal reflexes are not a reliable tool for the early prediction of poor outcome in patients treated with hypothermia. The reliability of the pupillary response to light and the SSEP is comparable to that in patients not treated with hypothermia.