Although the pathogenic and genetic basis of acute lung injury (ALI) remains incompletely understood, the identification of novel ALI biomarkers holds promise for unique insights. Expression profiling in animal models of ALI (canine and murine) and human ALI detected significant expression of pre-B-cell colony-enhancing factor (PBEF), a gene not previously associated with lung pathophysiology. These results were validated by real-time polymerase chain reaction and immunohistochemistry studies, with PBEF protein levels significantly increased in both bronchoalveolar lavage fluid and serum of ALI models and in cytokine- or cyclic stretch-activated lung microvascular endothelium. We genotyped two PBEF single-nucleotide polymorphisms (SNPs) in a well characterized sample of white patients with sepsis-associated ALI, patients with severe sepsis, and healthy subjects and observed that carriers of the haplotype GC from SNPs T-1001G and C-1543T had a 7.7-fold higher risk of ALI (95% confidence interval 3.01-19.75, p < 0.001). The T variant from the SNP C-1543T resulted in a significant decrease in the transcription rate (1.8-fold; p < 0.01) by the reporter gene assay. Together, these results strongly indicate that PBEF is a potential novel biomarker in ALI and demonstrate the successful application of robust genomic technologies in the identification of candidate genes in complex lung disease.

Background and Purpose-Assessment of autoregulation in the time domain is a promising monitoring method for actively optimizating cerebral perfusion pressure (CPP) in critically ill patients. The ability to detect loss of autoregulatory vasoreactivity to spontaneous fluctuations in CPP was tested with a new time-domain method that used near-infrared spectroscopic measurements of tissue oxyhemoglobin saturation in an infant animal model. Methods-Piglets were made progressively hypotensive over 4 to 5 hours by inflation of a balloon catheter in the inferior vena cava, and the breakpoint of autoregulation was determined using laser-Doppler flowmetry. The cerebral oximetry index (COx) was determined as a moving linear correlation coefficient between CPP and INVOS cerebral oximeter waveforms during 300-second periods. A laser-Doppler derived time-domain analysis of spontaneous autoregulation with the same parameters (LDx) was also determined. Results-An increase in the correlation coefficient between cerebral oximetry values and dynamic CPP fluctuations, indicative of a pressure-passive relationship, occurred when CPP was below the steady state autoregulatory breakpoint. This COx had 92% sensitivity (73% to 99%) and 63% specificity (48% to 76%) for detecting loss of autoregulation attributable to hypotension when COx was above a threshold of 0.36. The area under the receiver-operator characteristics curve for the COx was 0.89. COx correlated with LDx when values were sorted and averaged according to the CPP at which they were obtained (rϭ0.67). Conclusions-The COx is sensitive for loss of autoregulation attributable to hypotension and is a promising monitoring tool for determining optimal CPP for patients with acute brain injury.

Background and Purpose Individualizing mean arterial blood pressure (MAP) targets to a patient’s cerebral blood flow (CBF) autoregulatory range might prevent brain ischemia for patients undergoing cardiopulmonary bypass (CPB). This study compares the accuracy of real-time CBF autoregulation monitoring using near infra-red spectroscopy (NIRS) with that of transcranial Doppler (TCD). Methods Sixty adult patients undergoing CPB had TCD monitoring of middle cerebral artery blood flow velocity (MCA-FV) and NIRS monitoring. The mean velocity index (Mx) was calculated as a moving, linear correlation coefficient between slow waves of MCA-FV and MAP. The cerebral oximetry index (COx) was calculated as a similar coefficient between slow waves of cerebral oximetry and MAP. When CBF is autoregulated, Mx and COx vary around zero. Loss of autoregulation results in progressively more positive Mx and COx. Results Mx and COx showed significant correlation (r=0.55, P<0.0001) and good agreement (bias, 0.08 ± 0.18, 95% limits of agreement: −0.27 to 0.43) during CPB. Autoregulation was disturbed in this cohort during CPB (average Mx 0.38,95% CI 0.34 to 0.43). The lower CBF autoregulatory threshold (defined as incremental increase in Mx > 0.45) during CPB ranged from 45 to 80 mmHg. Conclusions CBF autoregulation can be monitored continuously with NIRS in adult patients undergoing CPB. Real-time autoregulation monitoring may have a role in preventing injurious hypotension during CPB.