A prospective study on serum citrate levels and clinical correlations in patients receiving regional citrate anticoagulation.

Background: Current ways to diagnose citrate accumulation (CA) in patients receiving regional citrate anticoagulation (RCA) continuous renal replacement therapy (CRRT) are confounded by various clinical factors. Serum citrate measurement emerges as a more direct way to diagnose CA, but its clinical utility and optimal cut-off values remain undefined. This study examined serum citrate kinetics and its diagnostic performance for CA in patients receiving RCA CRRT. Methods: A multicentre prospective study was carried out in two tertiary referral centre intensive care units in Hong Kong with serum citrate levels measured at baseline and 2, 6, 12, 24, 36, 48 and 72 h after initiation of RCA CRRT and their relationships with the development of CA. Results: Among the 133 patients analysed, 18 patients (13.5%) developed CA. The serum citrate levels at baseline and 2, 6 and 12 h after initiation of RCA CRRT in patients who had CA were significantly higher than the non-CA group (P < .001 for all). The CA group also had higher serum citrate levels than the non-CA group {median 0.93 mmol/L [interquartile range (IQR) 0.81-1.16) versus 0.37 mmol/L (IQR 0.26-0.57), P < .001}. Using a cut-off of 0.85 mmol/L, the serum citrate level had a sensitivity of 0.77 and a specificity 0.96 for the diagnosis of CA [area under the receiver operating characteristics curve (AUROC) 0.90, P < .001]. The 2-h and 6-h serum citrate levels had good discriminatory abilities for predicting subsequent development of CA (AUROC 0.86 and 0.83 for 2-h and 6-h citrate levels using cut-off values of 0.34 and 0.63 mmol/L, respectively; P < .001). Conclusion: Serum citrate levels were significantly higher in patients with CA compared with patients without CA. Serum citrate levels showed good performance in diagnosing and predicting the development of CA.

Impact of neuraminidase inhibitors on influenza A(H1N1)pdm09-related pneumonia: an individual participant data meta-analysis.

BACKGROUND: The impact of neuraminidase inhibitors (NAIs) on influenza-related pneumonia (IRP) is not established. Our objective was to investigate the association between NAI treatment and IRP incidence and outcomes in patients hospitalised with A(H1N1)pdm09 virus infection. METHODS: A worldwide meta-analysis of individual participant data from 20 634 hospitalised patients with laboratory-confirmed A(H1N1)pdm09 (n = 20 021) or clinically diagnosed (n = 613) 'pandemic influenza'. The primary outcome was radiologically confirmed IRP. Odds ratios (OR) were estimated using generalised linear mixed modelling, adjusting for NAI treatment propensity, antibiotics and corticosteroids. RESULTS: Of 20 634 included participants, 5978 (29·0%) had IRP; conversely, 3349 (16·2%) had confirmed the absence of radiographic pneumonia (the comparator). Early NAI treatment (within 2 days of symptom onset) versus no NAI was not significantly associated with IRP [adj. OR 0·83 (95% CI 0·64-1·06; P = 0·136)]. Among the 5978 patients with IRP, early NAI treatment versus none did not impact on mortality [adj. OR = 0·72 (0·44-1·17; P = 0·180)] or likelihood of requiring ventilatory support [adj. OR = 1·17 (0·71-1·92; P = 0·537)], but early treatment versus later significantly reduced mortality [adj. OR = 0·70 (0·55-0·88; P = 0·003)] and likelihood of requiring ventilatory support [adj. OR = 0·68 (0·54-0·85; P = 0·001)]. CONCLUSIONS: Early NAI treatment of patients hospitalised with A(H1N1)pdm09 virus infection versus no treatment did not reduce the likelihood of IRP. However, in patients who developed IRP, early NAI treatment versus later reduced the likelihood of mortality and needing ventilatory support.

Dodecafluoropentane Emulsion Extends Window for tPA Therapy in a Rabbit Stroke Model.

Dodecafluoropentane emulsion (DDFPe) nanodroplets are exceptional oxygen transporters and can protect ischemic brain in stroke models 24 h without reperfusion. Current stroke therapy usually fails to reach patients because of delays following stroke onset. We tested using DDFPe to extend the time window for tissue plasminogen activator (tPA). Longer treatment windows will allow more patients more complete stroke recovery. We test DDFPe to safely extend the time window for tPA thrombolysis to 9 h after stroke. With IACUC approval, randomized New Zealand white rabbits (3.4-4.7 kg, n = 30) received angiography and 4-mm blood clot in the internal carotid artery for flow-directed middle cerebral artery occlusion. Seven failed and were discarded. Groups were IV tPA (n = 11), DDFPe + tPA (n = 7), and no therapy controls (n = 5). DDFPe (0.3 ml/kg, 2 % emulsion) IV dosing began at 1 h and continued at 90 min intervals for 6 doses in one test group; the other received saline injections. Both got standard IV tPA (0.9 mg/kg) therapy starting 9 h post stroke. At 24 h, neurological assessment scores (NAS, 0-18) were determined. Following brain removal percent stroke volume (%SV) was measured. Outcomes were compared with Kruskal-Wallis analysis. For NAS, DDFPe + tPA was improved overall, p = 0.0015, and vs. tPA alone, p = 0.0052. For %SV, DDFPe + tPA was improved overall, p = 0.0003 and vs. tPA alone, p = 0.0018. NAS controls and tPA alone were not different but %SV was, p = 0.0078. With delayed reperfusion, DDFPe + tPA was more effective than tPA alone in preserving functioning brain after stroke. DDFPe significantly extends the time window for tPA therapy.

Dodecafluoropentane emulsion delays and reduces MRI markers of infarction in a rat stroke model: a preliminary report.

BACKGROUND: Dodecafluoropentane emulsion (DDFPe), an oxygen transport agent, has been shown to reduce infarct volume in animal models of acute ischemic stroke (AIS). Our study assesses the effect of DDFPe on MRI markers of infarct evolution in the early hours after vascular occlusion in a rat AIS model. We hypothesized that DDFPe will delay the development of MRI markers of AIS and/or reduce the extent of infarction. METHODS: Permanent, unilateral surgical occlusion of the middle cerebral and common carotid arteries was performed in control (n=4) and treatment (n = 10) rats. The treatment group received 1 IV dose of 2% w/v DDFPe at 0.6 mL/kg at 1 hour post-occlusion versus none. Diffusion-weighted (DWI) and inversion recovery (IR) MRI sequences were obtained over the 4 hours following occlusion. Infarct extent was quantified by number of abnormal MRI slices per sequence for each group and time point. Student's T-test was applied. RESULTS: DDFPe-treated rats demonstrated reduced infarct extent versus controls over combined time points on IR at 5.43 ± 0.40 (mean ± standard error) abnormal slices vs. 7.38 ± 0.58 (P = 0.01) and on DWI at 5.21 ± 0.54 vs. 9.00 ± 0.95 (P < 0.01). Development of abnormal MRI signal was delayed in the treatment group. CONCLUSIONS: DDFPe delays and reduces MRI markers of AIS in the early hours following vascular occlusion in a rat stroke model. Further investigation of DDFPe as a neuroprotectant is warranted.

Effectiveness of neuraminidase inhibitors in reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual participant data.

BACKGROUND: Neuraminidase inhibitors were widely used during the 2009-10 influenza A H1N1 pandemic, but evidence for their effectiveness in reducing mortality is uncertain. We did a meta-analysis of individual participant data to investigate the association between use of neuraminidase inhibitors and mortality in patients admitted to hospital with pandemic influenza A H1N1pdm09 virus infection. METHODS: We assembled data for patients (all ages) admitted to hospital worldwide with laboratory confirmed or clinically diagnosed pandemic influenza A H1N1pdm09 virus infection. We identified potential data contributors from an earlier systematic review of reported studies addressing the same research question. In our systematic review, eligible studies were done between March 1, 2009 (Mexico), or April 1, 2009 (rest of the world), until the WHO declaration of the end of the pandemic (Aug 10, 2010); however, we continued to receive data up to March 14, 2011, from ongoing studies. We did a meta-analysis of individual participant data to assess the association between neuraminidase inhibitor treatment and mortality (primary outcome), adjusting for both treatment propensity and potential confounders, using generalised linear mixed modelling. We assessed the association with time to treatment using time-dependent Cox regression shared frailty modelling. FINDINGS: We included data for 29,234 patients from 78 studies of patients admitted to hospital between Jan 2, 2009, and March 14, 2011. Compared with no treatment, neuraminidase inhibitor treatment (irrespective of timing) was associated with a reduction in mortality risk (adjusted odds ratio [OR] 0·81; 95% CI 0·70-0·93; p=0·0024). Compared with later treatment, early treatment (within 2 days of symptom onset) was associated with a reduction in mortality risk (adjusted OR 0·48; 95% CI 0·41-0·56; p<0·0001). Early treatment versus no treatment was also associated with a reduction in mortality (adjusted OR 0·50; 95% CI 0·37-0·67; p<0·0001). These associations with reduced mortality risk were less pronounced and not significant in children. There was an increase in the mortality hazard rate with each day's delay in initiation of treatment up to day 5 as compared with treatment initiated within 2 days of symptom onset (adjusted hazard ratio [HR 1·23] [95% CI 1·18-1·28]; p<0·0001 for the increasing HR with each day's delay). INTERPRETATION: We advocate early instigation of neuraminidase inhibitor treatment in adults admitted to hospital with suspected or proven influenza infection. FUNDING: F Hoffmann-La Roche.

Dodecafluoropentane Emulsion (DDFPe) Decreases Stroke Size and Improves Neurological Scores in a Permanent Occlusion Rat Stroke Model.

BACKGROUND: Dodecafluoropentane emulsion (DDFPe), given IV one hour after stroke, has been shown to greatly reduce the percent stroke volume (%SV) in rabbits. With repeated doses its effect continued for 24 hours. PURPOSE: Test DDFPe as neuroprotective agent in permanent occlusion rat stroke models in Sprague Dawley (SD) and Spontaneously Hypertensive Rats (SHR) measuring both %SV and neurological assessment scores (NAS). METHODS: The male rats received either saline (control), or one or four doses (1x or 4x) of DDFPe (0.6ml/kg IV) one hour post stroke. Treatment groups were SD (n=26) (control, 1x and 4x; n=12, 7 and 7) and SHR (n=14) (control, 1x and 4x; n=7, 3 and 4). The 4x doses were given at 1.5 hour intervals. At six hours post stroke, the rats received a NAS using standard tests for balance, reflexes, and motor performance. Then rats were euthanized and brains removed for TTC evaluation of %SV. RESULTS: For %SV analysis strain differences were not significant therefore strains were combined. DDFPe significantly decreased %SV in 1x and 4xDDFPe groups compared to control groups (2.59±1.81 and 0.98±0.88 vs. 9.24±6.06, p≤0.001 each; p≤0.0001 for the overall test for treatment effect). The 1x versus 4xDDFPe groups were not significantly different (p=0.40). In NAS analysis both strains showed significant improvement with 4xDDFPe therapy vs. controls, (SD: 5.00+2.45 vs. 9.36+3.56, p=0.01; SHR: 7.75+4.43 vs. 12.14+3.08, p=0.05). Differences between the 1x DDFPe group and controls were not significant (SD: 8.43+3.69; SHR: 9. 33+3.51). CONCLUSION: DDFPe treatment provides significant neuroprotection when assessed six hours post stroke.