Circadian Rhythmicity of Vital Signs at Intensive Care Unit Discharge and Outcome of Traumatic Brain Injury.

BACKGROUND: Physiological functions with circadian rhythmicity are often disrupted during illness. OBJECTIVE: To assess the utility of circadian rhythmicity of vital signs in predicting outcome of traumatic brain injury (TBI). METHODS: A retrospective single-center cohort study of adult intensive care unit (ICU) patients with largely isolated TBI to explore the relationship between the circadian rhythmicity of vital signs during the last 24 hours before ICU discharge and clinical markers of TBI severity and score on the Glasgow Outcome Scale 6 months after injury (GOS-6). RESULTS: The 130 study participants had a median age of 39.0 years (IQR, 23.0-59.0 years), a median Glasgow Coma Scale score at the scene of 8.0 (IQR, 3.0-13.0), and a median Rotterdam score on computed tomography of the head of 3 (IQR, 3-3), with 105 patients (80.8%) surviving to hospital discharge. Rhythmicity was present for heart rate (30.8% of patients), systolic blood pressure (26.2%), diastolic blood pressure (20.0%), and body temperature (26.9%). Independent predictors of a dichotomized GOS-6 ≥4 were the Rotterdam score (odds ratio [OR], 0.38 [95% CI, 0.18-0.81]; P = .01), Glasgow Coma Scale score at the scene (OR, 1.22 [95% CI, 1.05-1.41]; P = .008), age (OR, 0.95 [95% CI, 0.92-0.98]; P = .003), oxygen saturation <90% in the first 24 hours (OR, 0.19 [95% CI, 0.05-0.73]; P = .02), serum sodium level <130 mmol/L (OR, 0.20 [95% CI, 0.05-0.70]; P = .01), and active intracranial pressure management (OR, 0.16 [95% CI, 0.04-0.62]; P = .008), but not rhythmicity of any vital sign. CONCLUSION: Circadian rhythmicity of vital signs at ICU discharge is not predictive of GOS-6 in patients with TBI.

Temperature Profile and Adverse Outcomes After Discharge From the Intensive Care Unit.

BACKGROUND: A predictive model that uses the rhythmicity of core body temperature (CBT) could be an easily accessible clinical tool to ultimately improve outcomes among critically ill patients. OBJECTIVES: To assess the relation between the 24-hour CBT profile (CBT-24) before intensive care unit (ICU) discharge and clinical events in the step-down unit within 7 days of ICU discharge. METHODS: This retrospective cohort study in a tertiary ICU at a single center included adult patients requiring acute invasive ventilation for more than 48 hours and assessed major clinical adverse events (MCAEs) and rapid response system activations (RRSAs) within 7 days of ICU discharge (MCAE-7 and RRSA-7, respectively). RESULTS: The 291 enrolled patients had a median mechanical ventilation duration of 139 hours (IQR, 50-862 hours) and at admission had a median Acute Physiology and Chronic Health Evaluation II score of 22 (IQR, 7-42). At least 1 MCAE or RRSA occurred in 64% and 22% of patients, respectively. Independent predictors of an MCAE-7 were absence of CBT-24 rhythmicity (odds ratio, 1.78 [95% CI, 1.07-2.98]; P = .03), Sequential Organ Failure Assessment score at ICU discharge (1.10 [1.00-1.21]; P = .05), male sex (1.72 [1.04-2.86]; P = .04), age (1.02 [1.00-1.04]; P = .02), and Charlson Comorbidity Index (0.87 [0.76-0.99]; P = .03). Age (1.03 [1.01-1.05]; P = .006), sepsis at ICU admission (2.02 [1.13-3.63]; P = .02), and Charlson Comorbidity Index (1.18 [1.02-1.36]; P = .02) were independent predictors of an RRSA-7. CONCLUSIONS: Use of CBT-24 rhythmicity can assist in stratifying a patient's risk of subsequent deterioration during general care within 7 days of ICU discharge.

Diagnostic Sensitivity of Plasma Endothelin-1 for Cerebral Vasospasm After Subarachnoid Hemorrhage, a Multicentre Double-Blind Study.

The purpose of this study is to establish the diagnostic sensitivity of Endothelin-1 for risk stratification and screening of clinical vasospasm after subarachnoid hemorrhage.This is a multicentre, observational study, correlating daily blood Endothelin-1 with clinical variables. Binary logistic regression used to examine if Endothelin-1 levels could be used to predict clinical vasospasm. Bivariate modelling used to explore associations between patient characteristics and vasospasm. A Receiver Operating Curve used to explore cut-off values for Endothelin-1. Sensitivity and specificity was used to validate the cut-point found in the pilot study. A total of 96 patients were enrolled over two years. Median Endothelin-1 was higher for patients who experienced clinical vasospasm except for day-5, where median endothelin for patients without vasospasm was higher (3.6 IQR = 5.3), compared to patients with vasospasm (3.3 IQR = 8.5) although differences were not significant. The Receiver Operating Curve analysis confirmed that day-5 Endothelin-1 was not a good indicator of vasospasm, with an area under the curve of 0.506 (95% CI: 0.350-0.663, p = 0.938). The levels of Endothelin-1 in blood do not discriminate patients who may develop symptomatic vasospasm. The high variability in Endothelin-1 levels, aligns with the pathophysiological variability of most biomarkers, decreasing their ability to predict a clinical event.

Temperature rhythms and ICU sleep: the TRIS study.

BACKGROUND: Core body temperature (CBT) patterns associated with sleep have not been described in the critically ill. This study aimed to characterize night-time sleep and its relationship to CBT in ICU patients. METHODS: A prospective study was performed in a 27-bed tertiary adult intensive care unit of 20 mechanically ventilated patients in the weaning stage of their critical illness. The study assessed sleep by polysomnography (PSG) during the evening between 21:00-7:00 hours, nursing interventions using the Therapeutic Intervention Scoring System (TISS), illness severity using SOFA and APACHE II scores and CBT 24-hour pattern. RESULTS: Patients were awake for approximately half the study period (45.04%, IQR 13.81-77-17) with no REM (0%, IQR 0-0.04%) and median arousals of 19.5/hour (IQR 7.1-40.9). The 24-hour CBT had a rhythmic pattern in 13 (65%) patients with a highly variable phase of median peak time at 17:35 hours (IQR 12:40-19:39). No significant associations were found between CBT rhythmicity, sleep stages, sleep EEG frequency density, illness severity scores or TISS on the day of PSG. There was no relationship between time awake and CBT rhythmicity (P=0.48) or CBT peak time (P=0.82). The relationship between circadian rhythms and sleep patterns in the critically ill is complex. CONCLUSIONS: Patients recovering in ICU commonly have CBT loss of rhythmicity or a significant phase shift with loss of normal night-time patterns of sleep architecture. Appropriate care plans to promote sleep and circadian rhythm require further investigation of contributing factors such as environment, clinical care routines, illness type and severity.

Effect of Exogenous Melatonin Administration in Critically Ill Patients on Delirium and Sleep: A Randomized Controlled Trial.

INTRODUCTION: Sleep deprivation is a contributor for delirium in intensive care. Melatonin has been proposed as a pharmacological strategy to improve sleep, but studies have shown that the increase in plasma levels of melatonin do not correlate to a beneficial clinical effect; in addition, melatonin's short half-life may be a major limitation to achieving therapeutic levels. This study applies a previously published novel regimen of melatonin with proven sustained levels of melatonin during a 12 h period. In this study, the aim is to determine if such melatonin dosing positively influences on the sleep architecture and the incidence of delirium in intensive care. METHODS: Single center, randomized control trial with consecutive recruitment over 5 years. Medical and surgical patients were in a recovery phase, all weaning from mechanical ventilation. Randomized allocation to placebo or enteral melatonin, using a previously described regimen (loading dose of 3 mg at 21 h, followed by 0.5 mg hourly maintenance dose until 03am through a nasogastric tube). Sleep recordings were performed using polysomnogram at baseline (prior to intervention) and the third night on melatonin (postintervention recording). Delirium was assessed using the Richmond Agitation and the Confusion Assessment Method Scales. Environmental light and noise levels were recorded using a luxmeter and sound meter. RESULTS: 80 patients were screened, but 33 were recruited. Sleep studies showed no statistical differences on arousal index or length of sleep. Baseline delirium scores showed no difference between groups when compared to postintervention scores. RASS scores were 1 in both groups at baseline, compared to zero (drug group) and 0.5 (placebo group) posttreatment. CAM scores were zero (drug group) and 1 (placebo group) at baseline, compared to zero (in both groups) postintervention. CONCLUSION: High levels of plasma melatonin during the overnight period of intensive care cohort patients did not improve sleep nor decreased the prevalence of delirium. This trial is registered with Anzctr.org.au/ACTRN12620000661976.aspx.

Circadian Hygiene in the ICU Environment (CHIE) study.

Objective: To investigate the environment and care in the intensive care unit (ICU) and its relationship to patient circadian temperature disruption. Design: 30-day, prospective period prevalence study. Setting: 27-bed tertiary ICU. Participants: Patients expected to remain in the ICU for at least 24 hours. Main outcome measures: Temperature, relative humidity, light and sound intensity in the ICU; nursing interventions (using the Therapeutic Intervention Scoring System-28); and core body temperature of ICU patients. Results: Of 28 patients surveyed, 20 (71%) were mechanically ventilated. Median (interquartile range [IQR]) light intensity peaked at 07:00 at 165 (12-1218) lux with a trough at 23:00 of 15 (12-51) lux and was consistently < 100 lux between 21:00 and 06:00. Peak median (IQR) sound intensity was at 07:00 (62.55 [57.87-68.03] dB) while 58.84 (54.81-64.71) dB at 02:00. Ambient temperature and humidity varied with median (IQR) peaks of 23.11°C (22.74-23.31°C) at 16:00 and 44.07% (32.76-51.08%) at 11:00 and median troughs of 22.37°C (21.79-22.88°C) at 05:00 and 39.95% (31.53-47.95%) at 14:00, respectively. Disturbances to sleep during the night occurred due to care activities including linen changes (15 patients, 54%) and bathing (13, 46%). On the day before and the day of the study, 13 patients (47%) and 10 patients (36%), respectively, had a circadian rhythm on core body temperature without an association with illness severity, nursing intervention or environmental measures. Conclusions: The ICU has low light intensity with relative humidity and ambient temperature not aligned to normal human circadian timing. Noise levels are commonly equivalent to conversational speech while patient care procedures interrupt overnight sleep. The contribution of these factors to disrupted CBT rhythmicity is unclear.

Clinical management practices of life-threatening asthma: an audit of practices in intensive care.

OBJECTIVE: Lack of management guidelines for lifethreatening asthma (LTA) risks practice variation. This study aims to elucidate management practices of LTA in the intensive care unit (ICU). DESIGN: A retrospective cohort study. SETTING: Thirteen participating ICUs in Australia between July 2010 and June 2013. PARTICIPANTS: Patients with the principal diagnosis of LTA. MAIN OUTCOME MEASURES: Clinical history, ICU management, patient outcomes, ward education and discharge plans. RESULTS: Of the 270 (267 patients) ICU admissions, 69% were female, with a median age of 39 years (interquartile range [IQR], 26-53 years); 119 (44%) were current smokers; 89 patients (33%) previously required ICU admission, of whom 23 (25%) were intubated. The median ICU stay was 2 days (IQR, 2-4 days). Three patients (1%) died. Seventy-nine patients (29%) received non-invasive ventilation, with 11 (14%) needing subsequent invasive ventilation. Sixty-eight patients (25%) were intubated, with the majority of patients receiving volume cycled synchronised intermittent mechanical ventilation (n = 63; 93%). Drugs used included ß2-agonist by intravenous infusion (n = 69; 26%), inhaled adrenaline (n = 15; 6%) or an adrenaline intravenous infusion (n = 23; 9%), inhaled anticholinergics (n = 238; 90%), systemic corticosteroids (n = 232; 88%), antibiotics (n = 126; 48%) and antivirals (n = 22; 8%). When suitable, 105 patients (n = 200; 53%) had an asthma management plan and 122 (n = 202; 60%) had asthma education upon hospital discharge. Myopathy was associated with hyperglycaemia requiring treatment (odds ratio [OR], 31.6; 95% CI, 2.1-474). Asthma education was more common under specialist thoracic medicine care (OR, 3.0; 95% CI, 1.61-5.54). CONCLUSION: In LTA, practice variation is common, with opportunities to improve discharge management plans and asthma education.

The effects of normovolemic anemia and blood transfusion on cerebral microcirculation after severe head injury.

BACKGROUND: Cerebral regional microcirculation is altered following severe head injury. In addition to tissue disruption, partial pressure of tissue oxygenation is impaired due to an increase in the oxygen tissue gradient. The heterogenic distribution of cerebral microcirculation is multifactorial, and acute anemia challenges further the delivery of oxygen to tissues. Currently, a restrictive transfusion threshold is globally applied; however, it is unclear how anemia modifies regional cerebral microcirculation; hence, it is unclear if by aiming to a global endpoint, specific anatomical regions undergo ischemia. This study aims to quantify the temporal changes in cerebral microcirculation after severe head injury, under the effect of anemia and transfusion. It also aims to assess its effects specifically at the ischemic penumbra compared to contralateral regions and its interactions with axonal integrity in real time. Twelve ovine models were subjected to a severe contusion and acceleration-deceleration injury. Normovolemic anemia to a restrictive threshold was maintained after injury, followed by autologous transfusion. Direct quantification of cerebral microcirculation used cytometric count of color-coded microspheres. Axonal injury was assessed using amyloid precursor protein staining. RESULTS: A mixed-effect regression model from pre-transfusion to post-transfusion times with a random intercept for each sheep was used. Cerebral microcirculation amongst subjects with normal intracranial pressure was maintained from baseline and increased further after transfusion. Subjects with high intracranial pressure had a consistent reduction of their microcirculation to ischemic thresholds (20-30 ml/100 g/min) without an improvement after transfusion. Cerebral PtiO2 was reduced when exposed to anemia but increased in a 9.6-fold with transfusion 95% CI 5.6 to 13.6 (p value < 0.001). CONCLUSIONS: After severe head injury, the exposure to normovolemic anemia to a restrictive transfusion threshold, leads to a consistent reduction on cerebral microcirculation below ischemic thresholds, independent of cerebral perfusion pressure. Amongst subjects with raised intracranial pressure, microcirculation does not improve after transfusion. Cerebral oxymetry is impaired during anemia with a statistically significant increase after transfusion. Current transfusion practices in neurocritical care are based on a rigid hemoglobin threshold, a view that excludes cerebral metabolic demands and specific needs. An RCT exploring these concepts is warranted.

Cerebral Microcirculation and Histological Mapping After Severe Head Injury: A Contusion and Acceleration Experimental Model.

BACKGROUND: Cerebral microcirculation after severe head injury is heterogeneous and temporally variable. Microcirculation is dependent upon the severity of injury, and it is unclear how histology relates to cerebral regional blood flow. OBJECTIVE: This study assesses the changes of cerebral microcirculation blood flow over time after an experimental brain injury model in sheep and contrasts these findings with the histological analysis of the same regions with the aim of mapping cerebral flow and tissue changes after injury. METHODS: Microcirculation was quantified using flow cytometry of color microspheres injected under intracardiac ultrasound to ensure systemic and homogeneous distribution. Histological analysis used amyloid precursor protein staining as a marker of axonal injury. A mapping of microcirculation and axonal staining was performed using adjacent layers of tissue from the same anatomical area, allowing flow and tissue data to be available from the same anatomical region. A mixed effect regression model assessed microcirculation during 4 h after injury, and those results were then contrasted to the amyloid staining qualitative score. RESULTS: Microcirculation values for each subject and tissue region over time, including baseline, ranged between 20 and 80 ml/100 g/min with means that did not differ statistically from baseline flows. However, microcirculation values for each subject and tissue region were reduced from baseline, although their confidence intervals crossing the horizontal ratio of 1 indicated that such reduction was not statistically significant. Histological analysis demonstrated the presence of moderate and severe score on the amyloid staining throughout both hemispheres. CONCLUSION: Microcirculation at the ipsilateral and contralateral site of a contusion and the ipsilateral thalamus and medulla showed a consistent decline over time. Our data suggest that after severe head injury, microcirculation in predefined areas of the brain is reduced from baseline with amyloid staining in those areas reflecting the early establishment of axonal injury.

Cerebral microcirculation during mild head injury after a contusion and acceleration experimental model in sheep.

BACKGROUND: Cerebral microcirculation after head injury is heterogeneous and temporally variable. Regions at risk of infarction such as peri-contusional areas are vulnerable to anaemia. However, direct quantification of the cerebral microcirculation is clinically not feasible. This study describes a novel experimental head injury model correlating cerebral microcirculation with histopathology analysis. OBJECTIVE: To test the hypothesis that cerebral microcirculation at the ischaemic penumbrae is reduced over time when compared with non-injured regions. METHODS: Merino sheep were instrumented using a transeptal catheter to inject coded microspheres into the left cardiac atrium, ensuring systemic distribution. After a blunt impact over the left parietal region, cytometric analyses quantified cerebral microcirculation and amyloid precursor protein staining identified axonal injury in pre-defined anatomical regions. A mixed effect regression model assessed the hourly blood flow results during 4 hours after injury. RESULTS: Cerebral microcirculation showed temporal reductions with minimal amyloid staining except for the ipsilateral thalamus and medulla. CONCLUSION: The spatial heterogeneity and temporal reduction of cerebral microcirculation in ovine models occur early, even after mild head injury, independent of the intracranial pressure and the level of haemoglobin. Alternate approaches to ensure recovery of regions with reversible injury require a targeted assessment of cerebral microcirculation.

Is inhaled prophylactic heparin useful for prevention and Management of Pneumonia in ventilated ICU patients?: The IPHIVAP investigators of the Australian and New Zealand Intensive Care Society Clinical Trials Group.

PURPOSE: To determine whether prophylactic inhaled heparin is effective for the prevention and treatment of pneumonia patients receiving mechanical ventilation (MV) in the intensive care unit. METHODS: A phase 2, double blind randomized controlled trial stratified for study center and patient type (non-operative, post-operative) was conducted in three university-affiliated intensive care units. Patients aged ≥18years and requiring invasive MV for more than 48hours were randomized to usual care, nebulization of unfractionated sodium heparin (5000 units in 2mL) or placebo nebulization with 0.9% sodium chloride (2mL) four times daily with the main outcome measures of the development of ventilator associated pneumonia (VAP), ventilator associated complication (VAC) and sequential organ failure assessment scores in patients with pneumonia on admission or who developed VAP. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ACTRN12612000038897. RESULTS: Two hundred and fourteen patients were enrolled (72 usual care, 71 inhaled sodium heparin, 71 inhaled sodium chloride). There were no differences between treatment groups in terms of the development of VAP, using either Klompas criteria (6-7%, P=1.00) or clinical diagnosis (24-26%, P=0.85). There was no difference in the clinical consistency (P=0.70), number (P=0.28) or the total volume of secretions per day (P=.54). The presence of blood in secretions was significantly less in the usual care group (P=0.005). CONCLUSION: Nebulized heparin cannot be recommended for prophylaxis against VAP or to hasten recovery from pneumonia in patients receiving MV.

Variable use of amiodarone is associated with a greater risk of recurrence of atrial fibrillation in the critically ill.

BACKGROUND: Atrial fibrillation is a common rhythm disturbance in the general medical-surgical intensive care unit. Amiodarone is a popular drug in this setting but evidence to inform clinical practice remains scarce. We aimed to identify whether variation in the clinical use of amiodarone was associated with recurrent atrial fibrillation. METHODS: This was a retrospective audit of 177 critically ill patients who developed new-onset atrial fibrillation after admission to a tertiary level medical-surgical trauma intensive care unit. Patterns of amiodarone prescription (including dosage schedule and duration) were assessed in relation to recurrence of atrial fibrillation during the intensive care unit stay. Known recurrence risk factors, such as inotrope administration, cardiac disease indices, Charlson Comorbidity Index, magnesium concentrations, fluid balance, and potassium concentrations, were also included in adjusted analysis using forward stepwise logistic regression modelling. RESULTS: The cohort had a median (interquartile range) age of 69 years (60-75), Acute Physiology and Chronic Health Evalution II score of 22 (17-28) and Charlson Comorbidity Index of 2 (1-4). A bolus dose of amiodarone followed by infusion (P = 0.02), in addition to continuing amiodarone infusion through to discharge from the intensive care unit (P < 0.001), were associated with less recurrent dysrhythmia. Recurrence after successful treatment was associated with ceasing amiodarone while an inotrope infusion continued (P < 0.001), and was more common in patients with a prior history of congestive cardiac failure (P = 0.04), and a diagnosis of systemic inflammatory response syndrome (P = 0.02). CONCLUSIONS: Amiodarone should be administered as a bolus dose followed immediately with an infusion when treating atrial fibrillation in the medical-surgical intensive care unit. Consideration should be given to continuing amiodarone infusions in patients on inotropes until they are ceased.

Cerebral Microcirculation during Experimental Normovolaemic Anemia.

Anemia is accepted among critically ill patients as an alternative to elective blood transfusion. This practice has been extrapolated to head injury patients with only one study comparing the effects of mild anemia on neurological outcome. There are no studies quantifying microcirculation during anemia. Experimental studies suggest that anemia leads to cerebral hypoxia and increased rates of infarction, but the lack of clinical equipoise, when testing the cerebral effects of transfusion among critically injured patients, supports the need of experimental studies. The aim of this study was to quantify cerebral microcirculation and the potential presence of axonal damage in an experimental model exposed to normovolaemic anemia, with the intention of describing possible limitations within management practices in critically ill patients. Under non-recovered anesthesia, six Merino sheep were instrumented using an intracardiac transeptal catheter to inject coded microspheres into the left atrium to ensure systemic and non-chaotic distribution. Cytometric analyses quantified cerebral microcirculation at specific regions of the brain. Amyloid precursor protein staining was used as an indicator of axonal damage. Animals were exposed to normovolaemic anemia by blood extractions from the indwelling arterial catheter with simultaneous fluid replacement through a venous central catheter. Simultaneous data recording from cerebral tissue oxygenation, intracranial pressure, and cardiac output was monitored. A regression model was used to examine the effects of anemia on microcirculation with a mixed model to control for repeated measures. Homogeneous and normal cerebral microcirculation with no evidence of axonal damage was present in all cerebral regions, with no temporal variability, concluding that acute normovolaemic anemia does not result in short-term effects on cerebral microcirculation in the ovine brain.

Physiopathology of anemia and transfusion thresholds in isolated head injury.

BACKGROUND: Blood transfusion strategies among patients with critical illness use a restrictive hemoglobin threshold. However, among patients with head injury, no outcome differences have been shown between either liberal or restrictive strategies. Several studies and literature reviews suggest that anemia is associated with markers of tissue ischemia. The paucity of prospective data confuses the association between surrogates of tissue ischemia and neurological outcome. METHODS: A narrative review of transfusion practices among patients in the acute phase of head injury was performed using PubMed, MEDLINE, EMBASE, Cochrane, and WEB of Science databases. A total of 104 articles were reviewed. RESULTS: There are few data to guide clinical practice. Clinicians use blood hemoglobin concentrations to trigger transfusion. Markers of potential cerebral injury are not in regular use despite experimental and observational data rising from histologic examination, microdialysis, oximetry, and flow-based multimonitoring systems recommending their use to titrate blood transfusion in neurotrauma. CONCLUSION: The generalization of transfusion triggers is common practice. Evidence-based approaches to transfusions strategies in head injury are lacking and not based on an understanding of cerebral physiopathology.

The effect of ventricular assist devices on cerebral blood flow and blood pressure fractality.

Biological signals often exhibit self-similar or fractal scaling characteristics which may reflect intrinsic adaptability to their underlying physiological system. This study analysed fractal dynamics of cerebral blood flow in patients supported with ventricular assist devices (VAD) to ascertain if sustained modifications of blood pressure waveform affect cerebral blood flow fractality. Simultaneous recordings of arterial blood pressure and cerebral blood flow velocity using transcranial Doppler were obtained from five cardiogenic shock patients supported by VAD, five matched control patients and five healthy subjects. Computation of a fractal scaling exponent (α) at the low-frequency time scale by detrended fluctuation analysis showed that cerebral blood flow velocity exhibited 1/f fractal scaling in both patient groups (α = 0.95 ± 0.09 and 0.97 ± 0.12, respectively) as well as in the healthy subjects (α = 0.86 ± 0.07). In contrast, fluctuation in blood pressure was similar to non-fractal white noise in both patient groups (α = 0.53 ± 0.11 and 0.52 ± 0.09, respectively) but exhibited 1/f scaling in the healthy subjects (α = 0.87 ± 0.04, P < 0.05 compared with the patient groups). The preservation of fractality in cerebral blood flow of VAD patients suggests that normal cardiac pulsation and central perfusion pressure changes are not the integral sources of cerebral blood flow fractality and that intrinsic vascular properties such as cerebral autoregulation may be involved. However, there is a clear difference in the fractal scaling properties of arterial blood pressure between the cardiogenic shock patients and the healthy subjects.

The effect of Ventricular Assist Devices on cerebral autoregulation: A preliminary study.

BACKGROUND: The insertion of Ventricular Assist Devices is a common strategy for cardiovascular support in patients with refractory cardiogenic shock. This study sought to determine the impact of ventricular assist devices on the dynamic relationship between arterial blood pressure and cerebral blood flow velocity. METHODS: A sample of 5 patients supported with a pulsatile ventricular assist device was compared with 5 control patients. Controls were matched for age, co-morbidities, current diagnosis and cardiac output state, to cases. Beat-to-beat recordings of mean arterial pressure and cerebral blood flow velocity, using transcranial Doppler were obtained. Transfer function analysis was performed on the lowpass filtered pressure and flow signals, to assess gain, phase and coherence of the relationship between mean arterial blood pressure and cerebral blood flow velocity. These parameters were derived from the very low frequency (0.02-0.07 Hz), low frequency (0.07-0.2 Hz) and high frequency (0.2-0.35 Hz). RESULTS: No significant difference was found in gain and phase values between the two groups, but the low frequency coherence was significantly higher in cases compared with controls (mean ± SD: 0.65 ± 0.16 vs 0.38 ± 0.19, P = 0.04). The two cases with highest coherence (~0.8) also had much higher spectral power in mean arterial blood pressure. CONCLUSIONS: Pulsatile ventricular assist devices affect the coherence but not the gain or phase of the cerebral pressure-flow relationship in the low frequency range; thus whether there was any significant disruption of cerebral autoregulation mechanism was not exactly clear. The augmentation of input pressure fluctuations might contribute in part to the higher coherence observed.

Intraaortic Balloon Pump Counterpulsation and Cerebral Autoregulation: an observational study.

BACKGROUND: The use of Intra-aortic counterpulsation is a well established supportive therapy for patients in cardiac failure or after cardiac surgery. Blood pressure variations induced by counterpulsation are transmitted to the cerebral arteries, challenging cerebral autoregulatory mechanisms in order to maintain a stable cerebral blood flow. This study aims to assess the effects on cerebral autoregulation and variability of cerebral blood flow due to intra-aortic balloon pump and inflation ratio weaning. METHODS: Cerebral blood flow was measured using transcranial Doppler, in a convenience sample of twenty patients requiring balloon counterpulsation for refractory cardiogenic shock (N = 7) or a single inotrope to maintain mean arterial pressure following an elective placement of an intra-aortic balloon pump for cardiac surgery (N = 13). Simultaneous blood pressure at the aortic root was recorded via the intra-aortic balloon pump. Cerebral blood flow velocities were recorded for six minute intervals at a 1:1 balloon inflation-ratio (augmentation of all cardiac beats) and during progressive reductions of the inflation-ratio to 1:3 (augmentation of one every third cardiac beat). Real time comparisons of peak cerebral blood flow velocities with systolic blood pressure were performed using cross-correlation analysis. The primary endpoint was assessment of cerebral autoregulation using the time delay between the peak signals for cerebral blood flow velocity and systolic blood pressure, according to established criteria. The variability of cerebral blood flow was also assessed using non-linear statistics. RESULTS: During the 1:1 inflation-ratio, the mean time delay between aortic blood pressure and cerebral blood flow was -0.016 seconds (95% CI: -0.023,-0.011); during 1:3 inflation-ratio mean time delay was significantly longer at -0.010 seconds (95% CI: -0.016, -0.004, P < 0.0001). Finally, upon return to a 1:1 inflation-ratio, time delays recovered to those measured at baseline. During inflation-ratio reduction, cerebral blood flow irregularities reduced over time, whilst cerebral blood flow variability at end-diastole decreased in patients with cardiogenic shock. CONCLUSIONS: Weaning counterpulsation from 1:1 to 1:3 inflation ratio leads to a progressive reduction in time delays between systolic blood pressure and peak cerebral blood flow velocities suggesting that although preserved, there is a significant delay in the establishment of cerebral autoregulatory mechanisms. In addition, cerebral blood flow irregularities (i.e. surrogate of flow adaptability) decrease and a loss of cerebral blood flow chaotic pattern occurs during the end-diastolic phase of each beat in patients with cardiogenic shock.

A new paradigm for treating infections: "go hard and go home".

There is now significant evidence that initial use of the correct antibiotic saves more lives than virtually all other intensive care therapy. This means covering all possible causative organisms with the initial empirical choice. For nosocomial sepsis, broad-spectrum antibiotics must be started as soon as the relevant samples have been taken for culture, with de-escalation of therapy targeted to the causative organisms when results and susceptibilities are available. There is an international trend to use shorter antibiotic courses. Pseudomonas pneumonia probably needs a 7-10 day course. In our ICU, provided the infection source is controlled, we seldom use antibiotic courses longer than 7 days. Evaluation of the kill characteristics of antibiotics in experimental models suggests that different classes of antibiotics should have different dosing regimens. For Beta- lactam antibiotics, the kill characteristic is almost entirely related to the time that tissue and plasma levels exceed a certain threshold, with no significant post-antibiotic effect, particularly against gram-negative organisms. Kill characteristics of other antibiotics, such as aminoglycosides, relate to adequate peak concentrations and a significant post-antibiotic effect. Clinically, these kill characteristics translate into the need for appropriate doses of the various antibiotics in patients with sepsis. We have shown that some patients with normal serum creatinine levels have very high creatinine clearance rates; in ICU patients with sepsis, blood pressure and tissue perfusion are maintained with large fluid loads and inotropic agents, thereby raising creatinine clearance. High clearances produce low trough concentrations of antibiotic, with important implications for underdosing and the development of antibiotic resistance. The new paradigm for treating sepsis, particularly nosocomial sepsis, is: get it right the first time, hit hard up front, and use large doses of broad-spectrum antibiotics for a short period.

Is continuous infusion ceftriaxone better than once-a-day dosing in intensive care? A randomized controlled pilot study.

OBJECTIVES: To compare the clinical and bacteriological outcome of critically ill patients with sepsis treated by ceftriaxone administered as a once-a-day intermittent bolus dose or by 24 h continuous infusion. PATIENTS AND METHODS: We conducted an open-label, randomized controlled pilot study in 57 patients clinically diagnosed with sepsis (suspected/proven infection and systemic inflammatory response syndrome) in a tertiary level intensive care unit. Patients were randomized to receive 2 g of ceftriaxone administered by once-daily intermittent bolus dosing or by 24 h continuous infusion. Clinical and bacteriological outcomes were assessed by blinded clinicians. RESULTS: Fifty-seven patients were enrolled in the study, 50 of whom fulfilled the a priori definition of treatment for 4 or more days. The infusion (n = 29) and bolus groups (n = 28) were similar in terms of demographics, although the median age of those receiving the infusion was younger. Intention-to-treat analysis found no statistically significant differences in the primary outcomes for clinical response (P = 0.17), clinical cure [infusion n = 13/29 versus bolus n = 5/28; adjusted odds ratio (AOR) = 3.74; 95% confidence interval (95% CI) = 1.11-12.57; P = 0.06], bacteriological response (P = 0.41) and bacteriological cure (infusion n = 18/29 versus bolus 14/28; AOR = 1.64; 95% CI = 0.57-4.70; P = 0.52). However, logistic regression in patients that complied with the a priori definitions who received ceftriaxone by continuous infusion (AOR = 22.8; 95% CI = 2.24-232.3; P = 0.008) or patients with a low Acute Physiology and Chronic Health Evaluation (APACHE) II score (AOR = 0.70; 95% CI = 0.54-0.91; P = 0.008) were associated with an improved clinical outcome when age and Sepsis Organ Failure Assessment (SOFA) score at time of study entry were controlled for. CONCLUSIONS: This pilot study suggests clinical and bacteriological advantages of continuous infusion of ceftriaxone over bolus administration in critically ill patients in patients requiring 4 or more days of treatment. This sets the scene for a large multicentre double-blind randomized controlled trial to confirm these findings.