Optimised XUV holography using spatially shaped high harmonic beams.

We present a novel method for controlling the transverse positions and relative powers of multiple high-order harmonic beams. A phase-only spatial light modulator is used to produce multiple infrared foci, the positions and intensities of which can be controlled programmably, enabling the generation and control of multiple HHG beams. To demonstrate the utility of this method we perform Fourier transform holography with separate illumination of the object and reference pinhole by a pair of HHG beams, which makes optimal use of the available photon flux. The programmable control of the spatial distribution of HHG beams demonstrated here offers new opportunities for experiments at extreme ultraviolet (XUV) wavelengths, particularly for photon intensive applications such as imaging.

Spatially resolved common-path high-order harmonic interferometry.

Spatially resolved interference is observed between high-order harmonics generated in two longitudinally separated gas targets. High-contrast modulations in the intensity of each harmonic order up to the cutoff are observed on-axis in the far field of the source as the separation between the gas targets is increased. For low-order harmonics, additional off-axis modulations are observed, which are attributed to the interference between the contributions from the long quantum trajectories from each gas target. The inherent synchronization of this setup offers the prospect for high-stability metrology of quantum states with ultrafast temporal resolutions.

Expression of CD11c and EMR2 on neutrophils: potential diagnostic biomarkers for sepsis and systemic inflammation.

There is a need for cellular biomarkers to differentiate patients with sepsis from those with the non-infectious systemic inflammatory response syndrome (SIRS). In this double-blind study we determined whether the expression of known (CD11a/b/c, CD62L) and putative adhesion molecules [CD64, CD97 and epidermal growth factor (EGF)-like molecule containing mucin-like hormone receptor (EMR2)] on blood neutrophils could serve as useful biomarkers of infection and of non-infectious SIRS in critically ill patients. We studied 103 patients with SIRS, 83 of whom had sepsis, and 50 healthy normal subjects, using flow cytometry to characterize neutrophils phenotypically in whole blood samples. Patients with SIRS had an increased prevalence of neutrophils expressing CD11c, CD64 and EMR2 in comparison with healthy subjects (P < 0.001), but normal expression of CD11a, CD11b, CD62L and CD97. An increase in the percentage of neutrophils bearing CD11c was associated with sepsis, EMR2 with SIRS and CD64 with sepsis and SIRS. Neutrophils expressing CD11c had the highest sensitivity (81%) and specificity (80%) for the detection of sepsis, and there was an association between the percentage of neutrophils expressing EMR2 and the extent of organ failure (P < 0.05). Contrary to other reports, we did not observe an abnormal expression of CD11b or CD62L on neutrophils from patients with SIRS, and suggest that this discrepancy is due to differences in cell processing protocols. We propose that blood neutrophils expressing CD11c and EMR2 be considered as potential biomarkers for sepsis and SIRS, respectively.

Beyond the randomized clinical trial: citrate for continuous renal replacement therapy in clinical practice.

BACKGROUND: Premature circuit clotting is a major problem during continuous renal replacement therapy (CRRT). Six randomized controlled trials confirmed that regional anticoagulation with citrate is superior to heparin. Our objective was to compare circuit patency with citrate, heparin and epoprostenol in routine clinical practice. METHODS: We retrospectively analysed data on circuit patency of all circuits used in a single centre between September 2008 and August 2009. We differentiated between premature filter clotting, elective discontinuation and waste. RESULTS: 309 patients were treated with CRRT (n = 2,059 circuits). The mean age was 65.7; 63.8% were male. The methods to maintain circuit patency were unfractionated heparin (42.3%), epoprostenol (23.0%), citrate (14.7%), combinations of different anticoagulants (14.6%) and no anticoagulation (4.7%). Premature clotting was the most common reason for circuit discontinuation among circuits anticoagulated with heparin, epoprostenol or combinations of different anticoagulants (59-62%). Among circuits anticoagulated with citrate the main reason for discontinuation was elective (61%). Hazard regression analysis confirmed significantly better circuit survival with citrate. Changing from heparin to citrate decreased the risk of premature circuit clotting by 75.8%. CONCLUSION: In routine clinical practice, regional anticoagulation with citrate is associated with significantly better circuit patency than heparin or epoprostenol.

Hypoxic-ischaemic brain injury: imaging and neurophysiology abnormalities related to outcome.

BACKGROUND: The outcome for patients with hypoxic-ischaemic brain injury (HIBI) is often poor. It is important to establish an accurate prognosis as soon as possible after the insult to guide management. Clinical assessment is not reliable and ancillary investigations, particularly imaging and EEG, are needed to understand the severity of brain injury and the likely outcome. METHODS: We undertook a retrospective study of 39 patients on an intensive therapy unit (ITU) with HIBI who were referred for MRI. The patients were seen consecutively >57 months. HIBI was due to a variety of insults causing cardiac arrest, hypoperfusion or isolated hypoxia. RESULTS: The outcome was poor, 29 patients died, 7 were left severely disabled and only 3 made a good recovery. Characteristic imaging changes were seen on MRI. These included extensive changes in the cortex and the deep grey matter present on diffusion-weighted imaging (DWI) and T2-weighted imaging within 6 days of the insult. In other patients, different patterns of involvement of the cortex and basal ganglia occurred. There was no significant difference in the outcome or imaging appearances according to aetiology. A poor prognosis was consistently associated with a non- or poorly responsive EEG rhythm and the presence of periodic generalized phenomena with a very low-voltage background activity. CONCLUSION: In this retrospective study of patients with HIBI, MRI and EEG provided valuable information concerning prognosis.

Outcomes of critically ill patients with cirrhosis admitted to intensive care: an important perspective from the non-transplant setting.

BACKGROUND: Hospital admissions for cirrhosis have been increasing in the United Kingdom, leading to increased pressure on intensive care (ICU) services. Outcome data for patients admitted to ICU are currently limited to transplant centre reports, with mortality rates exceeding 70%. These tertiary reports could fuel a negative bias when patients with cirrhosis are reviewed for ICU admission in secondary care. AIMS: To determine whether disease severity and mortality rates in non-transplant general ICU are less severe than those reported by tertiary datasets. METHODS: A prospective dual-centre non-transplant ICU study. Admissions were screened for cirrhosis and physiological and biochemical data were collected. Disease-specific and critical illness scoring systems were evaluated. RESULTS: Cirrhosis was present in 137/4198 (3.3%) of ICU admissions. ICU and hospital mortality were 38% and 47%, respectively; median age 50 [43-59] years, 68% men, 72% alcoholic cirrhosis, median Child Pugh Score (CPS) 10 [8-11], Model for End-Stage Liver Disease (MELD) 18 [12-24], Acute Physiology and Chronic Health Evaluation II score (APACHE II) 16 [13-22]. CONCLUSIONS: Mortality rates and disease staging were notably lower than in the published literature, suggesting that patients have a more favourable outlook than previously considered. Transplant centre data should therefore be interpreted with caution when evaluating the merits of intensive care admission for patients in general secondary care ICUs.

Metabolic effects of intensive insulin therapy in critically ill patients.

Our aim was to investigate the effects of glycemic control and insulin concentration on lipolysis, glucose, and protein metabolism in critically ill medical patients. For our methods, the patients were studied twice. In study 1, blood glucose (BG) concentrations were maintained between 7 and 9 mmol/l with intravenous insulin. After study 1, patients entered one of four protocols for 48 h until study 2: low-insulin high-glucose (LIHG; variable insulin, BG of 7-9 mmol/l), low-insulin low-glucose (LILG; variable insulin of BG 4-6 mmol/l), high-insulin high-glucose [HIHG; insulin (2.0 mU . kg(-1).min(-1) plus insulin requirement from study 1), BG of 7-9 mmol/l], or high-insulin low-glucose [HILG; insulin (2.0 mU.kg(-1).min(-1) plus insulin requirement from study 1), BG of 4-6 mmol/l]. Age-matched healthy control subjects received two-step euglycemic hyperinsulinemic clamps achieving insulin levels similar to the LI and HI groups. In our results, whole body proteolysis was higher in patients in study 1 (P < 0.006) compared with control subjects at comparable insulin concentrations and was reduced with LI (P < 0.01) and HI (P = 0.001) in control subjects but not in patients. Endogenous glucose production rate (R(a)), glucose disposal, and lipolysis were not different in all patients in study 1 compared with control subjects at comparable insulin concentrations. Glucose R(a) and lipolysis did not change in any of the study 2 patient groups. HI increased glucose disposal in the patients (HIHG, P = 0.001; HILG, P = 0.07 vs. study 1), but this was less than in controls receiving HI (P < 0.03). In conclusion, low-dose intravenous insulin administered to maintain BG between 7-9 mmol/l is sufficient to limit lipolysis and endogenous glucose R(a) and increase glucose R(d). Neither hyperinsulinemia nor normoglycemia had any protein-sparing effect.

Neutrophils in development of multiple organ failure in sepsis.

Multiple organ failure is a major threat to the survival of patients with sepsis and systemic inflammation. In the UK and in the USA, mortality rates are currently comparable with and projected to exceed those from myocardial infarction. The immune system combats microbial infections but, in severe sepsis, its untoward activity seems to contribute to organ dysfunction. In this Review we propose that an inappropriate activation and positioning of neutrophils within the microvasculature contributes to the pathological manifestations of multiple organ failure. We further suggest that targeting neutrophils and their interactions with blood vessel walls could be a worthwhile therapeutic strategy for sepsis.

Erythrocyte zinc in hospital patients.

BACKGROUND: Abnormal thyroid function tests (serum thyrotropin [TSH], free thyroxine [T(4)] and free triiodothyronine [T(3)]) are frequently seen in hospitalized patients. Assessment of thyroid function in these patients is difficult. It has been suggested that acutely ill patients may be hypothyroid at the tissue level. Erythrocyte zinc (EZn) has been shown to be increased in hypothyroidism. The aim of this study was to examine EZn as an index of thyroid status of hospital patients. METHODS: In order to assess the thyroid status at tissue level, we measured EZn in 26 healthy subjects, 39 critically ill patients and 19 hospitalized geriatric patients. EZn was measured in young cells, as the effect of illness is likely to be seen in the newly formed cells. RESULT: TSH and free T(3) were lower in critically ill patients and serum free T(3) was lower in geriatric patients. EZn in young cells was higher in both patient groups (by 13% and 23%, respectively). EZn in old cells was also higher in the geriatric group. CONCLUSION: We conclude that EZn is higher in hospitalized patients, suggesting that these patients may be hypothyroid at the tissue level.

Outcomes, cost and long term survival of patients referred to a regional weaning centre.

BACKGROUND: Regional weaning centres provide cost effective care for patients who have undergone prolonged mechanical ventilation. There are few published European data on outcomes in these patients. METHODS: Patients admitted for weaning to the Lane Fox Respiratory Unit (LFU) between January 1997 and December 2000 were identified. The proportion weaned from mechanical ventilation, in-hospital mortality, and subsequent survival after discharge were examined. RESULTS: A total of 153 patients had been ventilated for a median of 26 days before transfer. The daily cost per patient stay was 1350. Fifty eight patients (38%) were fully weaned, 42 (27%) died, and 53 (35%) required ventilatory support at discharge from hospital of whom 36 (24%) required only nocturnal ventilation. Univariate analysis showed increasing age (OR 1.06, p<0.001), length of ICU stay (OR 1.02, p = 0.001), APACHE II predicted risk of death score (OR 1.02, p = 0.05), and a surgical cause for admission (OR 4.04) were associated with mortality. Neuromuscular/chest wall conditions were associated with low mortality (OR 0.36) but low likelihood of weaning from ventilation (OR 0.28). Female sex (OR 2.13, p = 0.03) and COPD (OR 2.81) were associated with successful weaning. Overall survival at 3 years from admission was 47%. Long term survival was lowest in patients with COPD. CONCLUSIONS: Most patients survived to leave hospital, the majority having been liberated from ventilatory support. Survivors were younger and spent less time ventilated in the referring ICU. The underlying diagnosis determined success of weaning, hospital survival, and long term outcome.

The pulmonary physician in critical care * 2: oxygen delivery and consumption in the critically ill.

Early detection and correction of tissue hypoxia is essential if progressive organ dysfunction and death are to be avoided. However, hypoxia in individual tissues or organs caused by disordered regional distribution of oxygen delivery or disruption of the processes of cellular oxygen uptake and utilisation cannot be identified from global measurements. Regional oxygen transport and cellular utilisation have an important role in maintaining tissue function. When tissue hypoxia is recognised, treatment must be aimed at the primary cause. Supplemental oxygen may be life saving in some situations but cannot correct inadequate oxygen delivery caused by a low cardiac output or impaired ventilation. Recent innovations include artificial oxygen carrying proteins and "haemoglobin" molecules designed to improve tissue blood flow by reducing viscosity. Regulating cell metabolism using different substrates or drugs has so far been poorly explored but is an exciting area for further research. A minimum level of global oxygen delivery and perfusion pressure must be maintained in the critically ill patient with established "shock", but advances in the understanding and control of regional distribution and other "downstream" factors in the oxygen cascade are needed to improve outcome in these patients.

Increased distribution and expression of CD64 on blood polymorphonuclear cells from patients with the systemic inflammatory response syndrome (SIRS).

Evidence is growing to suggest that the multiple organ damage of the systemic inflammatory response syndrome (SIRS) arises from the untoward activity of blood polymorphonuclear cells (PMNs), which upon activation acquire the IgG high affinity receptor, CD64. In the current study, flow cytometry was used to assess the prevalence of CD64-bearing PMNs and the intensity of expression of CD64 in whole blood samples from 32 SIRS patients, 11 healthy normal subjects and from eight non-SIRS patients in the intensive care unit (ICU). The percentage of PMNs expressing CD64 was higher in SIRS patients (mean 65%) than in non-SIRS patients (mean 42%; P < 0.02) and in healthy controls (mean 19%; P < 0.001) and was particularly evident in patients with SIRS and sepsis (mean 71%; P < 0.02) as opposed to SIRS alone (mean 55%). There were more CD64 molecules expressed on PMNs from patients with SIRS (median 1331 molecules/cell) in comparison with PMNs from healthy subjects (median 678 molecules/cell; P < 0.01). The highest intensity of CD64 expression was associated with PMNs from patients with both SIRS and sepsis. Functional studies revealed that the supranormal binding of PMNs from patients with SIRS to endothelial monolayers treated with TNFalpha was impeded by anti-CD64 antibodies (mean 24% inhibition; P < 0.01). Monitoring the distribution of CD64+ PMNs and their level of CD64 expression could be of assistance in the rapid discrimination of patients with SIRS from other ICU patients and in the identification of PMNs which are likely to participate in the pathological manifestations of the disease.

The effects of leucodepletion in patients who develop the systemic inflammatory response syndrome following cardiopulmonary bypass.

The development of the systemic inflammatory response syndrome (SIRS) is associated with increased morbidity and mortality. Numerous anticytokine trials have failed to demonstrate any outcome benefit and there has been little evidence of improvement in the prognosis of this condition over the past 20 years. This study examines the effect of using a white cell filter designed to remove polymorphonuclear cells (PMNs) in patients who developed SIRS 36 h after cardiopulmonary bypass (CPB). Twenty-four patients were randomized to receive either leucofiltration (LF) or control therapy (CT). The two groups were well matched at study entry in terms of age, severity of illness and length of time on CPB. LF patients received 60 min filtration periods using a venovenous extracorporeal circuit at a flow rate of 200 ml/min with the cycle repeated every 12 h while SIRS and other entry criteria were met. CT patients received standard therapy. LF patients received an average of 4.2 cycles (range 1-8) and, after 15 min filtration, the total leucocyte count had fallen from 16.2 +/- 5.3 to 10.4 +/- 3.3 x 10(9)/l and PMN from 14.4 +/- 5.2 to 8.3 +/- 4.2 x 10(9)/l. The mean platelet count changed from 127 +/- 87 to 117 +/- 82 x 10(9)/l. No adverse effects related to leucodepletion were observed. There was no difference between the groups in either mortality or length of stay at the intensive care unit or at hospital discharge. Organ function was assessed regularly during the study period and significant changes occurred only in respiratory and renal function. In the LF patients, respiratory function assessed by change in hypoxaemia index from baseline and renal function assessed by serum creatinine showed significant treatment effects compared to CT patients (p < 0.01, < 0.01 respectively); three CT patients, but no LF patients, received haemofiltration during the study period. Leucofiltration safely and effectively removes circulating PMNs from patients with SIRS following CPB. This may result in improved pulmonary and renal function in these patients. Further studies are required of the kinetics and phenotypic characteristics of PMN removal by leucofiltration and a larger multicentre study will be necessary to determine whether this novel therapy has a significant outcome benefit in critically ill patients with SIRS.

Leucodepletion and the interaction of polymorphonuclear cells with endothelium in systemic inflammatory response syndrome.

The abnormal interaction of polymorphonuclear cells (PMNs) with blood vessel walls is considered to underlie the multiple organ failure of systemic inflammatory response syndrome (SIRS). This consideration is supported by the present finding that PMNs from patients with SIRS are activated, as assessed by an increased distribution of cells bearing CD64, enhanced expression of CD11b and decreased expression of CD62L, and are highly adhesive to endothelial monolayers. Passage of SIRS blood through leucodepletion filters in a laboratory-designed extracorporeal circuit resulted in a marked depletion of PMNs. Of the PMNs that remained in the blood, far fewer cells bound to cultured endothelial cells in comparison with PMNs prior to leucofiltration. We propose that leucofiltration of SIRS blood will limit the number of PMNs available for binding to blood vessel walls and, hence, reduce the pathological manifestations associated with this disorder.

Effects of glutamine supplementation, GH, and IGF-I on glutamine metabolism in critically ill patients.

During critical illness glutamine deficiency may develop. Glutamine supplementation can restore plasma concentration to normal, but the effect on glutamine metabolism is unknown. The use of growth hormone (GH) and insulin-like growth factor I (IGF-I) to prevent protein catabolism in these patients may exacerbate the glutamine deficiency. We have investigated, in critically ill patients, the effects of 72 h of treatment with standard parenteral nutrition (TPN; n = 6), TPN supplemented with glutamine (TPNGLN; 0.4 g x kg(-1) x day(-1), n = 6), or TPNGLN with combined GH (0.2 IU. kg(-1). day(-1)) and IGF-I (160 microg x kg (-1) x day(-1)) (TPNGLN+GH/IGF-I; n = 5) on glutamine metabolism using [2-(15)N]glutamine. In patients receiving TPNGLN and TPNGLN+GH/IGF-I, plasma glutamine concentration was increased (338 +/- 22 vs. 461 +/- 24 micromol/l, P < 0.001, and 307 +/- 65 vs. 524 +/- 71 micromol/l, P < 0.05, respectively) and glutamine uptake was increased (5.2 +/- 0.5 vs. 7.4 +/- 0.7 micromol x kg(-1) x min(-1), P < 0.05 and 5.2 +/- 1.1 vs. 7.6 +/- 0.8 micromol x kg(-1) x min(-1), P < 0.05). Glutamine production and metabolic clearance rates were not altered by the three treatments. These results suggest that there is an increased requirement for glutamine in critically ill patients. Combined GH/IGF-I treatment with TPNGLN did not have adverse effects on glutamine metabolism.

Preliminary UK experience of dexmedetomidine, a novel agent for postoperative sedation in the intensive care unit.

Dexmedetomidine, a highly selective and potent alpha2-adrenergic agonist, has a potentially useful role as a sedative agent in patients requiring intensive care. As part of a larger European multicentre trial, a total of 119 postoperative cardiac and general surgical patients requiring ventilation and sedation in an intensive care unit were enrolled in four centres in the United Kingdom. One hundred and five patients were randomly allocated to receive either dexmedetomidine or placebo with rescue sedation and analgesia provided by midazolam and morphine, respectively. Compared with the control group, intubated patients receiving dexmedetomidine required 80% less midazolam [mean 4.9 (5.8) microg.kg-1.h-1 vs. 23.7 (27.5) microg.kg-1.h-1, p < 0.0001], and 50% less morphine [11.2 (13.4) microg.kg-1.h-1 vs. 21.5 (19.4) microg.kg-1.h-1,p = 0.0006]. Cardiovascular effects and adverse events could be predicted from the known properties of alpha-2 agonists. In conclusion, dexmedetomidine is a useful agent for the provision of postoperative analgesia and sedation.

A 25-year study of nosocomial bacteremia in an adult intensive care unit.

OBJECTIVE: To identify the organisms, their antibiotic susceptibility, and the associated focus on infection causing nosocomial bacteremia in patients in an adult intensive care unit (ICU) between 1971 and 1995. DESIGN: Prospective observational study. SETTING: A 12-bed general adult ICU in a 1,000-bed tertiary referral teaching hospital. PATIENTS: Four hundred eighty-six episodes of bacteremia involving 570 organisms in 425 patients. MEASUREMENTS AND MAIN RESULTS: Blood cultures taken from patients with suspected nosocomial infection were analyzed. Isolated organisms were identified, and their susceptibility to commonly used antibiotics was determined. Clinical details, including antibiotic treatment, were recorded for all patients. From 1986 to 1995, culture results of samples obtained from other sites were used to help identify the focus of infection causing bacteremia. All results were collected prospectively by clinical microbiologists. Between 1971 and 1990, the number of bacteremias and the relative frequency of isolation of individual organisms changed little, with Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, and Klebsiella species predominating. During 1991 to 1995, the number of bacteremias increased two-fold, largely attributable to increased isolation of Enterococcus species, coagulase-negative staphylococci, intrinsically antibiotic-resistant gram-negative organisms (particularly P. aeruginosa), and Candida species. The most commonly used antibiotics for the treatment of bacteremic patients throughout the 1970s were amoxicillin and gentamicin. After the introduction of cephalosporins in the early 1980s, their use increased progressively to equal that of gentamicin in the 1990s, whereas amoxicillin use decreased. Since the introduction of cephalosporins, increases in the antibiotic resistance of gram-negative organisms have been largely confined to an outbreak of gentamicin- and ceftazidime-resistant organisms caused by contaminated arterial pressure monitors during 1992 and 1993 and a two-fold increase in ceftazidime resistance of the Pseudomonas species. Gentamicin resistance of gram-negative aerobes remained unchanged (excluding the arterial pressure monitor outbreak), despite gentamicin being one of the most frequently prescribed antibiotics throughout the 25-yr period. Between 1986 and 1995, two thirds of all bacteremic organisms were cultured from intravascular catheters, which were designated as the focus of infection, 7% were secondary to gastrointestinal pathology, but only approximately 3% were secondary to wound, respiratory tract, or urinary tract infections. CONCLUSIONS: Bacteremias have become more frequent in the ICU, probably because of the increased use of intravascular catheters, which are the most frequent foci for bacteremic infection. The spectrum of organisms has changed, and this can be temporally related to the changes in the antibiotics prescribed. Gentamicin resistance of gram-negative organisms has not increased during a 25-yr period, despite being one of the most frequently prescribed antibiotics in the ICU.