Mild induced hypothermia and coagulation and platelet function in patients with septic shock: Secondary outcome of a randomized trial.

Coagulation abnormalities and microthrombi contribute to septic shock, but the impact of body temperature regulation on coagulation in patients with sepsis is unknown. We tested the hypothesis that mild induced hypothermia reduces coagulation and platelet aggregation in patients with septic shock. Secondary analysis of randomized controlled trial. Adult patients with septic shock who required mechanical ventilation from eight intensive care units in Denmark were randomly assigned to mild induced hypothermia for 24 h or routine thermal management. Viscoelastography and platelet aggregation were assessed at trial inclusion, after 12 h of thermal management, and 24 h after inclusion. A total of 326 patients were randomized to mild induced hypothermia (n = 163) or routine thermal management (n = 163). Mild induced hypothermia slightly prolonged activated partial thromboplastin time and thrombus initiation time (R time 8.0 min [interquartile range, IQR 6.6-11.1] vs. 7.2 min [IQR 5.8-9.2]; p = .004) and marginally inhibited thrombus propagation (angle 68° [IQR 59-73] vs. 71° [IQR 63-75]; p = .014). The effect was also present after 24 h. Clot strength remained unaffected (MA 71 mm [IQR 66-76] with mild induced hypothermia vs. 72 mm (65-77) with routine thermal management, p = .9). The proportion of patients with hyperfibrinolysis was not affected (0.7% vs. 3.3%; p = .19), but the proportion of patients with no fibrinolysis was high in the mild hypothermia group (8.8% vs. 40.4%; p < .001). The mild induced hypothermia group had lower platelet aggregation: ASPI 85U (IQR 50-113) versus 109U (IQR 74-148, p < .001), ADP 61U (IQR 40-83) versus 79 U (IQR 54-101, p < .001), TRAP 108 (IQR 83-154) versus 119 (IQR 94-146, p = .042) and COL 50U (IQR 34-66) versus 67U (IQR 46-92, p < .001). In patients with septic shock, mild induced hypothermia slightly impaired clot initiation, but did not change clot strength. Platelet aggregation was slightly impaired. The effect of mild induced hypothermia on viscoelastography and platelet aggregation was however not in a range that would have clinical implications. We did observe a substantial reduction in fibrinolysis.

Long-term patient-important outcomes after septic shock: A protocol for 1-year follow-up of the CLASSIC trial.

BACKGROUND: In patients with septic shock, mortality is high, and survivors experience long-term physical, mental and social impairments. The ongoing Conservative vs Liberal Approach to fluid therapy of Septic Shock in Intensive Care (CLASSIC) trial assesses the benefits and harms of a restrictive vs standard-care intravenous (IV) fluid therapy. The hypothesis is that IV fluid restriction improves patient-important long-term outcomes. AIM: To assess the predefined patient-important long-term outcomes in patients randomised into the CLASSIC trial. METHODS: In this pre-planned follow-up study of the CLASSIC trial, we will assess all-cause mortality, health-related quality of life (HRQoL) and cognitive function 1 year after randomisation in the two intervention groups. The 1-year mortality will be collected from electronic patient records or central national registries in most participating countries. We will contact survivors and assess EuroQol 5-Dimension, -5-Level (EQ-5D-5L) and EuroQol-Visual Analogue Scale and Montreal Cognitive Assessment 5-minute protocol score. We will analyse mortality by logistic regression and use general linear models to assess HRQoL and cognitive function. DISCUSSION: With this pre-planned follow-up study of the CLASSIC trial, we will provide patient-important data on long-term survival, HRQoL and cognitive function of restrictive vs standard-care IV fluid therapy in patients with septic shock.

Induced hypothermia in patients with septic shock and respiratory failure (CASS): a randomised, controlled, open-label trial.

BACKGROUND: Animal models of serious infection suggest that 24 h of induced hypothermia improves circulatory and respiratory function and reduces mortality. We tested the hypothesis that a reduction of core temperature to 32-34°C attenuates organ dysfunction and reduces mortality in ventilator-dependent patients with septic shock. METHODS: In this randomised, controlled, open-label trial, we recruited patients from ten intensive care units (ICUs) in three countries in Europe and North America. Inclusion criteria for patients with severe sepsis or septic shock were a mean arterial pressure of less than 70 mm Hg, mechanical ventilation in an ICU, age at least 50 years, predicted length of stay in the ICU at least 24 h, and recruitment into the study within 6 h of fulfilling inclusion criteria. Exclusion criteria were uncontrolled bleeding, clinically important bleeding disorder, recent open surgery, pregnancy or breastfeeding, or involuntary psychiatric admission. We randomly allocated patients 1:1 (with variable block sizes ranging from four to eight; stratified by predictors of mortality, age, Acute Physiology and Chronic Health Evaluation II score, and study site) to routine thermal management or 24 h of induced hypothermia (target 32-34°C) followed by 48 h of normothermia (36-38°C). The primary endpoint was 30 day all-cause mortality in the modified intention-to-treat population (all randomly allocated patients except those for whom consent was withdrawn or who were discovered to meet an exclusion criterion after randomisation but before receiving the trial intervention). Patients and health-care professionals giving the intervention were not masked to treatment allocation, but assessors of the primary outcome were. This trial is registered with ClinicalTrials.gov, number NCT01455116. FINDINGS: Between Nov 1, 2011, and Nov 4, 2016, we screened 5695 patients. After recruitment of 436 of the planned 560 participants, the trial was terminated for futility (220 [50%] randomly allocated to hypothermia and 216 [50%] to routine thermal management). In the hypothermia group, 96 (44·2%) of 217 died within 30 days versus 77 (35·8%) of 215 in the routine thermal management group (difference 8·4% [95% CI -0·8 to 17·6]; relative risk 1·2 [1·0-1·6]; p=0·07]). INTERPRETATION: Among patients with septic shock and ventilator-dependent respiratory failure, induced hypothermia does not reduce mortality. Induced hypothermia should not be used in patients with septic shock. FUNDING: Trygfonden, Lundbeckfonden, and the Danish National Research Foundation.

Increased cortical capillary transit time heterogeneity in Alzheimer's disease: a DSC-MRI perfusion study.

Alzheimer's disease (AD) is characterized by the accumulation of hyperphosphorylated tau and neurotoxic Aß in the brain parenchyma. Hypoxia caused by microvascular changes and disturbed capillary flows could stimulate this build-up of AD-specific proteins in the brain. In this study, we compared cerebral microcirculation in a cohort of AD and mild cognitive impairment (MCI) patients with that of age-matched controls, all without a history of diabetes or of hypertension for more than 2 years, using dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI). Vascular flow disturbances were quantified using a parametric model and mapped to the mid-cortical surface for group-wise statistical analysis. We found widespread hypoperfusion in patients compared with controls and identified areas of increased relative capillary transit time heterogeneity (RTH), consistent with low tissue oxygen tension. Notably, RTH was positively correlated with white matter hyperintensities and positively correlated with symptom severity in the patient cohort. These correlations extended over large parts of the temporal, parietal, and frontal cortices. The results support the hypothesis of disturbed capillary flow patterns in AD and suggest that DSC-MRI may provide imaging biomarkers of impaired cerebral microcirculation in AD.

[Cerebral manifestations of influenza A (H1N1)v]. / Cerebrale manifestationer ved influenza A (H1N1)v.

We describe two patients with cerebral manifestations of influenza A (H1N1)v. A 13-year-old boy developed severe cerebral oedema and increased intracranial pressure despite medical treatment and external drainage of cerebrospinal fluid. He was treated with bifrontal decompressive craniectomy with good result. A 25-year-old man with a previous kidney transplant developed encephalopathy and convulsions. Magnetic resonance imaging showed encephalitis. The patient fully recovered. The cases demonstrate that influenza A (H1N1)v can cause seriously and potentially life-threatening neurological complications.

Bayesian estimation of cerebral perfusion using a physiological model of microvasculature.

Perfusion weighted MRI has proven very useful for deriving hemodynamic parameters such as CBF, CBV and MTT. These quantities are important diagnostically, e.g. in acute stroke, where they are used to delineate ischemic regions. Yet the standard method for estimating CBF based on singular value decomposition (SVD) has been demonstrated to underestimate (especially high) flow components and to be sensitive to delays in the arterial input function (AIF). Furthermore, the estimated residue functions often oscillate. This compromises their physiological interpretation/basis and makes estimation of related measures such as flow heterogeneity difficult. In this study, we estimate perfusion parameters based on a vascular model (VM) which represents heterogeneous capillary flow and explicitly leads to monotonically decreasing residue functions. We use a fully Bayesian approach to obtain posterior probability distributions for all parameters. In simulation studies, we show that the VM method has less bias in CBF estimates than the SVD based method for realistic SNRs. This also applies to cases where the AIF is delayed. We employ our method to estimate perfusion maps using data from (i) a healthy volunteer and (ii) from a stroke patient.

Automatic selection of arterial input function using cluster analysis.

Quantification of cerebral blood flow (CBF) using dynamic susceptibility contrast MRI requires determination of the arterial input function (AIF) representing the delivery of intravascular tracer to tissue. This is typically accomplished manually by inspection of concentration time curves (CTCs) in regions containing the ICA, VA, and MCA. This is, however, a time consuming and operator dependent procedure. We suggest a completely automatic procedure for establishing the AIF based on a cluster analysis algorithm. In 20 normal subjects CBF maps calculated in 2 slices by the automatic procedure were compared to maps obtained with AIFs selected individually by 7 experienced operators. The average manual to automatic CBF ratio was 1.03+/-0.15 in the lower slice and 1.05+/-0.12 in the upper slice, demonstrating excellent agreement between the manual and automatic method. The algorithm provides means for objectively assessing AIF candidates in local AIF search algorithms designed to reduce bias due to delay and dispersion. Given the reproducibility and speed (10 s) of the automatic method, we speculate that it will greatly improve the accuracy of perfusion images and facilitate their use in clinical diagnosis and decision-making, particularly in acute stroke but also in cerebrovascular disease in general.