Simvastatin in the acute respiratory distress syndrome.

BACKGROUND: Studies in animals and in vitro and phase 2 studies in humans suggest that statins may be beneficial in the treatment of the acute respiratory distress syndrome (ARDS). This study tested the hypothesis that treatment with simvastatin would improve clinical outcomes in patients with ARDS. METHODS: In this multicenter, double-blind clinical trial, we randomly assigned (in a 1:1 ratio) patients with an onset of ARDS within the previous 48 hours to receive enteral simvastatin at a dose of 80 mg or placebo once daily for a maximum of 28 days. The primary outcome was the number of ventilator-free days to day 28. Secondary outcomes included the number of days free of nonpulmonary organ failure to day 28, mortality at 28 days, and safety. RESULTS: The study recruited 540 patients, with 259 patients assigned to simvastatin and 281 to placebo. The groups were well matched with respect to demographic and baseline physiological variables. There was no significant difference between the study groups in the mean (±SD) number of ventilator-free days (12.6±9.9 with simvastatin and 11.5±10.4 with placebo, P=0.21) or days free of nonpulmonary organ failure (19.4±11.1 and 17.8±11.7, respectively; P=0.11) or in mortality at 28 days (22.0% and 26.8%, respectively; P=0.23). There was no significant difference between the two groups in the incidence of serious adverse events related to the study drug. CONCLUSIONS: Simvastatin therapy, although safe and associated with minimal adverse effects, did not improve clinical outcomes in patients with ARDS. (Funded by the U.K. National Institute for Health Research Efficacy and Mechanism Evaluation Programme and others; HARP-2 Current Controlled Trials number, ISRCTN88244364.).

On the structure of prilocaine in aqueous and amphiphilic solutions.

The solvation of prilocaine has been investigated in pure water and in an amphiphilic methanol/water solution using a combination of neutron diffraction with isotopic substitution augmented by Empirical Potential Structure Refinement (EPSR) simulations. This combination of techniques allows for details of the solvation structure on the atomic scale to be unravelled. The hydration of prilocaine is significantly altered relative to when this molecule is in pure water (as a hydrochloride salt) or in an amphiphilic environment (as a freebase compound). Interestingly, there is not a significant change in hydration around the amine group on prilocaine hydrochloride compared with prilocaine as a freebase. Despite this group being an ammonium group in water and an amine group in methanol/water solutions, the hydration of this motif remains largely intact. The changes in hydration between prilocaine as a free base and prilocaine·HCl instead appears to arise from a change in hydration around the aromatic ring and the amide group in the prilocaine molecule.

Incidence and recognition of acute respiratory distress syndrome in a UK intensive care unit.

The reported incidence of ARDS is highly variable (2.5%-19% of intensive care unit (ICU) patients) and varies depending on study patient population used. We undertook a 6-month, prospective study to determine the incidence and outcome of ARDS in a UK adult University Hospital ICU. 344 patients were admitted during the study period, of these 43 (12.5%) were determined to have ARDS. Patients with ARDS had increased mortality at 28 days and 2 years post-diagnosis, and there was under-recognition of ARDS in both medical records and death certificattion. Our findings have implications for critical care resource planning.

On the positional and orientational order of water and methanol around indole: a study on the microscopic origin of solubility.

Although they are both highly polar liquids, there are a number of compounds, such as many pharmaceuticals, which show vastly different solubilities in methanol compared with water. From theories of the hydrophobic effect, it might be predicted that this enhanced solubility is due to association between drugs and the less polar -CH3 groups on methanol. In this work, detailed analysis on the atomic structural interactions between water, methanol and the small molecule indole - which is a precursor to many drugs and is sparingly soluble in water yet highly soluble in methanol - reveal that indole preferentially interacts with both water and methanol via electrostatic interactions rather than with direction interactions to the -CH3 groups. The presence of methanol hydrogen bonds with π electrons of the benzene ring of indole can explain the increase in solubility of indole in methanol relative to water. In addition, the excess entropy calculations performed here suggest that this solvation is enthalpically rather than entropically driven.

The solvation structure of alprazolam.

Alprazolam is a benzodiazepine that is commonly prescribed for the treatment of anxiety and other related disorders. Like other benzodiazepines, it is thought to exert its effect through interaction with GABAA receptors. However, it has also been described as a potent and selective protein interaction inhibitor of bromodomain and extra-terminal (BET) proteins. Indeed, the only crystal structure of alprazolam bound to a protein is a complex between alprazolam and the BRD4 bromodomain. The structure shows that the complex also involves many water interactions that mediate contacts between the drug and the protein, a scenario that exists in many drug-protein complexes. How such waters relate to solvation patterns of small molecules may improve our understanding of what dictates their appearance or absence in bridging positions within complexes and thus will be important in terms of future rational drug-design. Here, we use neutron diffraction in conjunction with molecular dynamics simulations to provide a detailed analysis of how water molecules interact with alprazolam in methanol/water mixtures. The agreement between the neutron diffraction and the molecular dynamics is extremely good. We discuss the results in the context of drug design.

On the atomic structure of cocaine in solution.

Cocaine is an amphiphilic drug which has the ability to cross the blood-brain barrier (BBB). Here, a combination of neutron diffraction and computation has been used to investigate the atomic scale structure of cocaine in aqueous solutions. Both the observed conformation and hydration of cocaine appear to contribute to its ability to cross hydrophobic layers afforded by the BBB, as the average conformation yields a structure which might allow cocaine to shield its hydrophilic regions from a lipophilic environment. Specifically, the carbonyl oxygens and amine group on cocaine, on average, form ∼5 bonds with the water molecules in the surrounding solvent, and the top 30% of water molecules within 4 Šof cocaine are localized in the cavity formed by an internal hydrogen bond within the cocaine molecule. This water mediated internal hydrogen bonding suggests a mechanism of interaction between cocaine and the BBB that negates the need for deprotonation prior to interaction with the lipophilic portions of this barrier. This finding also has important implications for understanding how neurologically active molecules are able to interact with both the blood stream and BBB and emphasizes the use of structural measurements in solution in order to understand important biological function.

Does induced hypertension reduce cerebral ischaemia within the traumatized human brain?

Recent changes in published guidelines for the management of patients with severe head injury are based on data showing that aggressive maintenance of cerebral perfusion pressure (CPP) can worsen outcome due to extracranial complications of therapy. However, it remains unclear whether CPP augmentation could reduce cerebral ischaemia, a finding which might prompt the search for CPP augmentation protocols that avoid these extracranial complications. We studied 10 healthy volunteers and 20 patients within 6 days of closed head injury. All subjects underwent imaging of cerebral blood flow (CBF), blood volume (CBV), oxygen metabolism (CMRO2) and oxygen extraction fraction (OEF) using 15O PET. In addition, for patients, the EEG power ratio index (PRI), burst suppression ratio and somatosensory evoked potentials (SEP) were obtained and CPP was increased from 68 +/- 4 to 90 +/- 4 mmHg using an infusion of norepinephrine and measurements were repeated. Following elevation of CPP, CBF and CBV were increased and CMRO2 and OEF were reduced (P < 0.001 for all comparisons). Regions with a reduction in CMRO2 were associated with the greatest reduction in OEF (r2 = 0.3; P < 0.0001). Although CPP elevation produced a significant fall in the ischaemic brain volume (IBV) (from 15 +/- 16 to 5 +/- 4 ml; P < 0.01) and improved flow metabolism coupling, the IBV was small and clinically insignificant in the majority of these patients. However, the reduction in IBV was directly related to the baseline IBV (r2 = 0.97; P < 0.001) and patients with large baseline IBV showed substantial and clinically significant reductions. CPP augmentation increased the EEG PRI (5.0 +/- 1.5 versus 4.3 +/- 1.4, P < 0.01), implying an overall decrease in neural activity, but these changes did not correlate with the reduction in CMRO2 and there was no change in SEP cortical amplitude (N20-P27). These data provide support for recent changes in recommended CPP levels for head injury management across populations of patients with significant head injury. However, they do not provide guidance on whether the intervention may be more appropriate at earlier stages after injury, or in patients selected because of high baseline IBV. It also remains unclear whether CPP values below 65 mmHg can be safely used in this population. Clarification of the significance of a reduction in CMRO2 and neuronal electrical function will require further study.

Amphipathic solvation of indole: implications for the role of tryptophan in membrane proteins.

The microscopic structure of the tryptophan side chain, indole, in an amphiphilic environment has been investigated using a combination of neutron diffraction measurements and simulations in solution. The results show that indole is preferentially solvated by hydrogen bonding interactions between water and alcohol -OH groups rather than the interaction being dominated by indole-methyl interactions. This has implications for understanding how tryptophan interacts with the amphipathic membrane environment to anchor proteins into membranes, where the results here suggest that the benzene ring of tryptophan interacts directly with the interfacial water at the membrane surface rather than being buried into the hydrophobic regions of the membrane bilayer.

Assessment of cerebrovascular autoregulation in head-injured patients: a validation study.

BACKGROUND AND PURPOSE: Cerebrovascular autoregulation is frequently measured in head-injured patients. We attempted to validate 4 bedside methods used for assessment of autoregulation. METHODS: PET was performed at a cerebral perfusion pressure (CPP) of 70 and 90 mm Hg in 20 patients. Cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMRo2) were determined at each CPP level. Patients were sedated with propofol and fentanyl. Norepinephrine was used to control CPP. During PET scanning, transcranial Doppler (TCD) flow velocity in the middle cerebral artery was monitored, and the arterio-jugular oxygen content difference (AJDo2) was measured at each CPP. Autoregulation was determined as the static rate of autoregulation based on PET (SROR(PET)) and TCD (SROR(TCD)) data, based on changes in AJDo2, and with 2 indexes based on the relationship between slow waves of CPP and flow velocity (mean velocity index, Mx) and between arterial blood pressure and intracranial pressure (pressure reactivity index, PRx) RESULTS: We found significant correlations between SROR(PET) and SROR(TCD) (r2=0.32; P<0.01) and between SROR(PET) and PRx (r2=0.31; P<0.05). There were no significant associations between PET data and autoregulation as assessed by changes in AJDo2. Global CMRo2 was significantly lower at the higher CPP (P<0.01). CONCLUSIONS: Despite some variability, SROR(TCD) and PRx may provide useful approximations of autoregulation in head-injured patients. At least with our methods, CMRo2 changes with the increase in CPP; hence, flow-metabolism coupling may affect the results of autoregulation testing.

Responses of posttraumatic pericontusional cerebral blood flow and blood volume to an increase in cerebral perfusion pressure.

In and around traumatic contusions, cerebral blood flow (CBF) is often near or below the threshold for ischemia. Increasing cerebral perfusion pressure (CPP) in patients with head injuries may improve CBF in these regions. However, the pericontusional response to this intervention has not been studied. Using positron emission tomography (PET), we have quantified the response to an increase in CPP in and around contusions in 18 contusions in 18 patients. Regional CBF and cerebral blood volume (CBV) were measured with PET at CPPs of 70 and 90 mmHg using norepinephrine to control CPP. Based upon computed tomography, regions of interest (ROIs) were placed as two concentric ellipsoids, each of 1-cm width, around the core of the contusions. Measurements were compared with a control ROI in tissue with normal anatomic appearance. Baseline CBF and CBV increased significantly with increasing distance from the core of the lesion. The increase in CPP led to small increases in CBF in all ROIs except the core. The largest absolute CBF increase was found in the control ROI. Relative CBF increases did not differ between ROIs so that ischemic areas remained ischemic. Pericontusional oedema on computed tomography was associated with lower absolute values of CBF and CBV but did not differ from nonoedematous tissue in the relative response to CPP elevation.

Incidence and mechanisms of cerebral ischemia in early clinical head injury.

Antemortem demonstration of ischemia has proved elusive in head injury because regional CBF reductions may represent hypoperfusion appropriately coupled to hypometabolism. Fifteen patients underwent positron emission tomography within 24 hours of head injury to map cerebral blood flow (CBF), cerebral oxygen metabolism (CMRO2), and oxygen extraction fraction (OEF). We estimated the volume of ischemic brain (IBV) and used the standard deviation of the OEF distribution to estimate the efficiency of coupling between CBF and CMRO2. The IBV in patients was significantly higher than controls (67 +/- 69 vs. 2 +/- 3 mL; P < 0.01). The coexistence of relative ischemia and hyperemia in some patients implies mismatching of perfusion to oxygen use. Whereas the saturation of jugular bulb blood (SjO2) correlated with the IBV (r = 0.8, P < 0.01), SjO2 values of 50% were only achieved at an IBV of 170 +/- 63 mL (mean +/- 95% CI), which equates to 13 +/- 5% of the brain. Increases in IBV correlated with a poor Glasgow Outcome Score 6 months after injury (rho = -0.6, P < 0.05). These results suggest significant ischemia within the first day after head injury. The ischemic burden represented by this "traumatic penumbra" is poorly detected by bedside clinical monitors and has significant associations with outcome.

Pharmacokinetic optimisation of sustained-release bupropion for smoking cessation.

Sustained-release bupropion (bupropion SR) is a unique, non-nicotine smoking cessation aid that is hypothesised to act upon neurological pathways involved in nicotine dependence. Pharmacokinetic and metabolism studies reveal that bupropion SR is metabolised by multiple pathways with no single pathway predominating. When one pathway is inhibited, others are available to compensate. Therefore, only a few clinically relevant drug-drug interactions involving bupropion SR have been observed, although the potential for interactions exists, as with any extensively metabolised drug. Population pharmacokinetic/pharmacodynamic analyses of data from patients receiving daily oral doses of 100mg, 150mg, or 300mg reveal that the anti-smoking efficacy of bupropion SR is directly related to dose. The incidences of dry mouth and insomnia were directly related to bupropion plasma concentrations while the incidence of anxiety was inversely proportional to bupropion plasma concentrations. To maximise efficacy (with an acceptable safety profile), the optimal daily dose for the majority of patients is 300mg.

Extracellular Brain pH and Outcome following Severe Traumatic Brain Injury.

The ability to measure brain tissue chemistry has led to valuable information regarding pathophysiological changes in patients with traumatic brain injury (TBI). Over the last few years, the focus has been on monitoring changes in brain tissue oxygen to determine thresholds of ischemia that affect outcome. However, the variability of this measurement suggests that it may not be a robust method. We have therefore investigated the relationship of brain tissue pH (pH(b)) and outcome in patients with TBI. We retrospectively analyzed prospectively collected data of 38 patients admitted to the Neurosciences Critical Care Unit with TBI between 1998 and 2003, and who had a multiparameter tissue gas sensor inserted into the brain. All patients were managed using an evidence-based protocol targeting CPP > 70 mm Hg. Physiological variables were averaged over 4 min and analyzed using a generalized least squares random effects model to determine the temporal profile of pH(b) and its association with outcome. Median (IQR) minimum pH(b) was 7.00 (6.89, 7.08), median (IQR) maximum pH(b) was 7.25 (7.18, 7.33), and median (IQR) patient averaged pH(b) was 7.13 (7.07, 7.17). pH(b) was significantly lower in those who did not survive their hospital stay compared to those that survived. In addition, those with unfavorable neurological outcome had lower pH(b) values than those with favorable neurological outcome. pH(b) differentiated between survivors and non-survivors. Measurement of pH(b) may be a useful indicator of outcome in patients with TBI.

Effect of cerebral perfusion pressure augmentation with dopamine and norepinephrine on global and focal brain oxygenation after traumatic brain injury.

OBJECTIVE: To compare the effects of a cerebral perfusion pressure (CPP) intervention achieved with dopamine and norepinephrine after severe head injury. DESIGN: Prospective, controlled, trial. SETTING: Neurosciences critical care unit. PATIENTS: Eleven patients with a head injury, requiring dopamine or norepinephrine infusions to support CPP. INTERVENTION: Cerebral tissue gas measurements were recorded using a multimodal sensor, and regional chemistry was assessed using microdialysis. Patients received in, randomised order, either dopamine or norepinephrine to achieve and maintain a CPP of 65 mmHg, and then, following a 30-min period of stable haemodynamics, a CPP of 85 mmHg. Data were then acquired using the second agent. Haemodynamic measurements and measurements of cerebral physiology were made during each period. MEASUREMENTS AND RESULTS: The CPP augmentation with norepinephrine, but not with dopamine, resulted in a significant reduction in arterial-venous oxygen difference (37+/-11 vs 33+/-12 ml/l) and a significant increase in brain tissue oxygen (2.6+/-1.1 vs 3.0+/-1.1 kPa). The CPP intervention did not significantly affect intracranial pressure. There were no significant differences between norepinephrine and dopamine on cerebral oxygenation or metabolism either at baseline or following a CPP intervention; however, the response to a CPP intervention with dopamine seemed to be more variable than the response achieved with norepinephrine. CONCLUSIONS: If CPP is to be raised to a level higher than 65-70 mmHg, then it is important to recognise that the response to the intervention may be unpredictable and that the vasoactive agent used may be of importance.

Sustained moderate reductions in arterial CO2 after brain trauma time-course of cerebral blood flow velocity and intracranial pressure.

OBJECTIVE: In healthy volunteers cerebral blood flow starts to recover towards baseline within a few minutes of continued hyperventilation due to normalisation of perivascular pH. We investigated the time-course of changes in middle cerebral artery mean flow velocity (FVm) and intracranial pressure (ICP) in head-injured patients during sustained moderate reductions in arterial partial pressure of CO(2) (PaCO(2)). DESIGN: Observational study. PATIENTS: Twenty-seven sedated, mechanically ventilated patients with severe head injury. INTERVENTIONS: Measurements were made during and after routine determination of CO(2)-reactivity: an acute 20% increase in respiratory minute volume was followed by a 10-min stabilisation period and 50 min of continued moderate hyperventilation at a constant PaCO(2) (>3.5 kPa). MEASUREMENTS AND RESULTS: FVm was monitored with transcranial Doppler, ICP was monitored with intraparenchymal probes. During the 50-min period with stable PaCO(2) FVm increased in 36% of patients. All other patients showed a decline in FVm over the same time period. Overall FVm recovery was -0.03+/-0.14%.min(-1). The time-course of ICP changes was significantly different from that of FVm, with ICP reaching its lowest value earlier than FVm (23+/-12 vs 37+/-20 min; P = 0.001) and returning more rapidly towards baseline than FVm (0.23+/-0.23 vs -0.03+/-0.14%.min(-1); P< 0.0001). CONCLUSIONS: Head-injured patients may adapt differently to hyperventilation than healthy volunteers. Potentially harmful reductions in cerebral blood flow may persist beyond the duration of useful ICP reduction.

Pharmacokinetics and pharmacodynamics of dopamine and norepinephrine in critically ill head-injured patients.

OBJECTIVE: To explore the pharmacokinetics and pharmacodynamics of dopamine and norepinephrine. DESIGN: Prospective, controlled, trial. SETTING: Neurosciences critical care unit. PATIENTS: Eight patients with a head injury, requiring dopamine or norepinephrine infusions to support cerebral perfusion pressure (CPP). INTERVENTION: Patients received in randomised order, either dopamine or norepinephrine to achieve and maintain a CPP of 70 mmHg, and then, following a 30-min period of stable haemodynamics, a CPP of 90 mmHg. Data were then acquired using the second agent. Haemodynamic measurements were made during each period and a blood sample was obtained at the end of each study period for analysis of plasma catecholamine concentrations MEASUREMENTS AND RESULTS: Plasma levels of norepinephrine and dopamine were significantly related to infusion rates but did not have a simple linear relationship to haemodynamic parameters. However, there was a significant quadratic relationship between the infusion rate of dopamine and cardiac index (r2=0.431), and systemic vascular resistance index (r2=0.605), with a breakpoint (at which cardiac index reduced and SVRI increased) at a dopamine plasma level of approximately 50 nM/l (corresponding to an infusion rate of approximately 15 microg.kg(-1).min(-1)). CONCLUSIONS: Norepinephrine and dopamine have predictable pharmacokinetics; however, those of dopamine do not fit a simple first-order kinetic model. The pharmacodynamic effects of dopamine and norepinephrine show much inter-individual variability and unpredictability. Plasma levels of dopamine appear to relate to variations in adrenergic receptor effects with break points that reflect expectations from infusion-rate related pharmacodynamics.

The effect of peripherally inserted central catheter (PICC) valve technology on catheter occlusion rates--the 'ELeCTRiC' study.

PURPOSE: Peripherally Inserted Central Catheters (PICCs) are increasingly being used to provide short to medium-term central venous access. The current study was designed to test the hypothesis that PICC valve technology does not influence PICC occlusion rates. METHODS: Intensive care unit (ICU) patients who required a PICC were randomized to one of three types of dual lumen PICC (open ended non-valved, Groshong valve, PASV valve). PICC occlusions were recorded and managed with a protocol that used urokinase. RESULTS: A total of 102 patients were recruited to the study. The overall risk of occlusion per catheter was 35% (95% CI 26% to 44%). The overall rate of occlusion was 76 occlusions per 1000 catheter days (95% CI 61 to 95). Presence or type of valve did not significantly influence this rate (open-ended non-valved PICC 38% of catheters, 79 occlusions per 1000 catheter days; Groshong 38% of catheters, 60 occlusions per 1000 catheter days; PASV 27% of catheters, 99 occlusions per 1000 catheter days). The dose of urokinase required to treat PICC occlusions did not significantly differ between PICC types. CONCLUSIONS: Valved PICCs do not appear to influence PICC occlusion rates.

Effect of cerebral perfusion pressure augmentation on regional oxygenation and metabolism after head injury.

OBJECTIVE: In this study we have used O positron emission tomography, brain tissue oxygen monitoring, and cerebral microdialysis to assess the effects of cerebral perfusion pressure augmentation on regional physiology and metabolism in the setting of traumatic brain injury. DESIGN: Prospective interventional study. SETTING: Neurosciences critical care unit of a university hospital. PATIENTS: Eleven acutely head-injured patients requiring norepinephrine to maintain cerebral perfusion pressure. INTERVENTIONS: Using positron emission tomography, we have quantified the response to an increase in cerebral perfusion pressure in a region of interest around a brain tissue oxygen sensor (Neurotrend) and microdialysis catheter. Oxygen extraction fraction and cerebral blood flow were measured with positron emission tomography at a cerebral perfusion pressure of approximately 70 mm Hg and approximately 90 mm Hg using norepinephrine to control cerebral perfusion pressure. All other aspects of physiology were kept stable. MEASUREMENTS AND MAIN RESULTS: Cerebral perfusion pressure augmentation resulted in a significant increase in brain tissue oxygen (17 +/- 8 vs. 22 +/- 8 mm Hg; 2.2 +/- 1.0 vs. 2.9 +/- 1.0 kPa, p < .001) and cerebral blood flow (27.5 +/- 5.1 vs. 29.7 +/- 6.0 mL/100 mL/min, p < .05) and a significant decrease in oxygen extraction fraction (33.4 +/- 5.9 vs. 30.3 +/- 4.6 %, p < .05). There were no significant changes in any of the microdialysis variables (glucose, lactate, pyruvate, lactate/pyruvate ratio, glycerol). There was a significant linear relationship between brain tissue oxygen and oxygen extraction fraction (r = .21, p < .05); the brain tissue oxygen value associated with an oxygen extraction fraction of 40% (the mean value for oxygen extraction fraction in normal controls) was 14 mm Hg (1.8 kPa). The cerebral perfusion pressure intervention resulted in a greater percentage increase in brain tissue oxygen than the percentage decrease in oxygen extraction fraction; this suggests that the oxygen gradients between the vascular and tissue compartments were reduced by the cerebral perfusion pressure intervention. CONCLUSIONS: Cerebral perfusion pressure augmentation significantly increased levels of brain tissue oxygen and significantly reduced regional oxygen extraction fraction. However, these changes did not translate into predictable changes in regional chemistry. Our results suggest that the ischemic level of brain tissue oxygen may lie at a level below 14 mm Hg (1.8 kPa); however, the data do not allow us to be more specific.

Advanced monitoring in the neurology intensive care unit: microdialysis.

Cerebral microdialysis is a relatively new technique for measuring the levels of brain extracellular chemicals, which to date has predominantly been used as a research tool. This review considers the technical aspects of microdialysis, the importance of the commonly measured chemicals, and the use of microdialysis to monitor patients with ischemic stroke, head injury, and subarachnoid hemorrhage. The advantages and disadvantages of microdialysis are discussed, as is its future potential.