Neuroinflammation of the spinal cord and nerve roots in chronic radicular pain patients.

Numerous preclinical studies support the role of spinal neuroimmune activation in the pathogenesis of chronic pain, and targeting glia (eg, microglia/astrocyte)- or macrophage-mediated neuroinflammatory responses effectively prevents or reverses the establishment of persistent nocifensive behaviors in laboratory animals. However, thus far, the translation of those findings into novel treatments for clinical use has been hindered by the scarcity of data supporting the role of neuroinflammation in human pain. Here, we show that patients suffering from a common chronic pain disorder (lumbar radiculopathy), compared with healthy volunteers, exhibit elevated levels of the neuroinflammation marker 18 kDa translocator protein, in both the neuroforamina (containing dorsal root ganglion and nerve roots) and spinal cord. These elevations demonstrated a pattern of spatial specificity correlating with the patients' clinical presentation, as they were observed in the neuroforamen ipsilateral to the symptomatic leg (compared with both contralateral neuroforamen in the same patients as well as to healthy controls) and in the most caudal spinal cord segments, which are known to process sensory information from the lumbosacral nerve roots affected in these patients (compared with more superior segments). Furthermore, the neuroforaminal translocator protein signal was associated with responses to fluoroscopy-guided epidural steroid injections, supporting its role as an imaging marker of neuroinflammation, and highlighting the clinical significance of these observations. These results implicate immunoactivation at multiple levels of the nervous system as a potentially important and clinically relevant mechanism in human radicular pain, and suggest that therapies targeting immune cell activation may be beneficial for chronic pain patients.

Kinetics of plasma biomarkers of inflammation and lung injury in surgical patients with or without postoperative pulmonary complications.

BACKGROUND: Postoperative pulmonary complications (PPCs) are common after major abdominal surgery. The kinetics of plasma biomarkers could improve identification of patients developing PPCs, but the kinetics may depend on intraoperative ventilator settings. OBJECTIVE: To test whether the kinetics of plasma biomarkers are capable of identifying patients who will develop PPCs, and whether the kinetics depend on the intraoperative level of positive end-expiratory pressure (PEEP). DESIGN: A preplanned substudy of a randomised controlled trial. SETTING: Operation room of five centres. PATIENTS: Two hundred and forty-two adult patients scheduled for abdominal surgery at risk of developing PPCs. INTERVENTIONS: High (12 cmH2O) versus low (≤2 cmH2O) levels of PEEP. MAIN OUTCOME MEASURES: Individual PPCs were combined as a composite endpoint. Plasma samples were collected before surgery, directly after surgery and on the fifth postoperative day. The levels of the following were measured: tumour necrosis factor (TNF)-α, interleukin (IL)-6 and IL-8, the soluble form of the Receptor for Advanced Glycation End-products (sRAGE), Surfactant Protein (SP)-D, Clara Cell protein (CC)-16 and Krebs von den Lungen 6 (KL6). RESULTS: Blood sampling was complete in 242 patients: 120 patients in the high PEEP group and 122 patients in the low PEEP group. Increases in plasma levels of TNF- IL-6, IL-8 and CC-16, and a decrease in plasma levels of SP-D were greater in patients who developed PPCs; however, the area under the receiver operating characteristic curve was low for all biomarkers. CC-16 was the only biomarker whose level increased more in patients who had received high levels of PEEP. CONCLUSION: In patients undergoing abdominal surgery and at risk of developing PPCs, plasma levels of biomarkers for inflammation or lung injury showed distinct kinetics with development of PPCs, but none of the biomarkers showed sufficient prognostic value. The use of high levels of PEEP was associated with increased levels of CC-16, suggesting lung overdistension. TRIAL REGISTRATION: The PROVHILO trial, including this substudy, was registered at clinicaltrials.gov (NCT01441791).

Estimation of noise-free variance to measure heterogeneity.

Variance is a statistical parameter used to characterize heterogeneity or variability in data sets. However, measurements commonly include noise, as random errors superimposed to the actual value, which may substantially increase the variance compared to a noise-free data set. Our aim was to develop and validate a method to estimate noise-free spatial heterogeneity of pulmonary perfusion using dynamic positron emission tomography (PET) scans. On theoretical grounds, we demonstrate a linear relationship between the total variance of a data set derived from averages of n multiple measurements, and the reciprocal of n. Using multiple measurements with varying n yields estimates of the linear relationship including the noise-free variance as the constant parameter. In PET images, n is proportional to the number of registered decay events, and the variance of the image is typically normalized by the square of its mean value yielding a coefficient of variation squared (CV(2)). The method was evaluated with a Jaszczak phantom as reference spatial heterogeneity (CV(r)(2)) for comparison with our estimate of noise-free or 'true' heterogeneity (CV(t)(2)). We found that CV(t)(2) was only 5.4% higher than CV(r)2. Additional evaluations were conducted on 38 PET scans of pulmonary perfusion using (13)NN-saline injection. The mean CV(t)(2) was 0.10 (range: 0.03-0.30), while the mean CV(2) including noise was 0.24 (range: 0.10-0.59). CV(t)(2) was in average 41.5% of the CV(2) measured including noise (range: 17.8-71.2%). The reproducibility of CV(t)(2) was evaluated using three repeated PET scans from five subjects. Individual CV(t)(2) were within 16% of each subject's mean and paired t-tests revealed no difference among the results from the three consecutive PET scans. In conclusion, our method provides reliable noise-free estimates of CV(t)(2) in PET scans, and may be useful for similar statistical problems in experimental data.

The effect of omalizumab on ventilation and perfusion in adults with allergic asthma.

Omalizumab promotes clinical improvement in patients with allergic asthma, but its effect on pulmonary function is unclear. One possibility is that omalizumab improves asthma symptoms through effects on the regional distributions of ventilation, perfusion, and ventilation/perfusion matching, metrics which can be assessed with Nitrogen-13-saline Position Emission Tomography (PET). Four adults with moderate to severe uncontrolled allergic asthma underwent symptom assessment, spirometry and functional pulmonary imaging with Nitrogen-13-saline PET before and after 4-5 months of treatment with omalizumab. PET imaging was used to determine ventilation/perfusion ratios, the heterogeneity (coefficient of variation, COV) of ventilation and perfusion, and lung regions with ventilation defects. There were no significant changes in spirometry values after omalizumab treatment, but there was a trend towards an improvement in symptom scores. There was little change in the matching of ventilation and perfusion. The COV of perfusion was similar before and after omalizumab treatment. The COV of ventilation was also similar before (0.57 (0.28)) and after (0.66 (0.13)) treatment, and it was similar to previously published values for healthy subjects. There was a non-significant trend towards an increase in the extent of ventilation defects after omalizumab treatment, from 5 (15)% to 12.8 (14.7)%. Treatment of moderate to severe uncontrolled allergic asthma with omalizumab did not result in a significant improvement in ventilation and perfusion metrics assessed with functional PET imaging. The normal COV of ventilation which was unaffected by treatment supports the hypothesis that omalizumab exerts its clinical effect on lung function during allergen exposure rather than in between exacerbations.

Regional lung derecruitment and inflammation during 16 hours of mechanical ventilation in supine healthy sheep.

BACKGROUND: Lung derecruitment is common during general anesthesia. Mechanical ventilation with physiological tidal volumes could magnify derecruitment, and produce lung dysfunction and inflammation. The authors used positron emission tomography to study the process of derecruitment in normal lungs ventilated for 16 h and the corresponding changes in regional lung perfusion and inflammation. METHODS: Six anesthetized supine sheep were ventilated with VT=8 ml/kg and positive end-expiratory pressure=0. Transmission scans were performed at 2-h intervals to assess regional aeration. Emission scans were acquired at baseline and after 16 h for the following tracers: (1) F-fluorodeoxyglucose to evaluate lung inflammation and (2) NN to calculate regional perfusion and shunt fraction. RESULTS: Gas fraction decreased from baseline to 16 h in dorsal (0.31±0.13 to 0.14±0.12, P<0.01), but not in ventral regions (0.61±0.03 to 0.63±0.07, P=nonsignificant), with time constants of 1.5-44.6 h. Although the vertical distribution of relative perfusion did not change from baseline to 16 h, shunt increased in dorsal regions (0.34±0.23 to 0.63±0.35, P<0.01). The average pulmonary net F-fluorodeoxyglucose uptake rate in six regions of interest along the ventral-dorsal direction increased from 3.4±1.4 at baseline to 4.1±1.5 10(-3)/min after 16 h (P<0.01), and the corresponding average regions of interest F-fluorodeoxyglucose phosphorylation rate increased from 2.0±0.2 to 2.5±0.2 10(-2)/min (P<0.01). CONCLUSIONS: When normal lungs are mechanically ventilated without positive end-expiratory pressure, loss of aeration occurs continuously for several hours and is preferentially localized to dorsal regions. Progressive lung derecruitment was associated with increased regional shunt, implying an insufficient hypoxic pulmonary vasoconstriction. The increased pulmonary net uptake and phosphorylation rates of F-fluorodeoxyglucose suggest an incipient inflammation in these initially normal lungs.

Complement 3 is involved with ventilator-induced lung injury.

Humoral molecules can trigger injury on mechanically stressed and damaged tissue. We have studied the role of complement 3 (C3) in a mouse model of ventilator-induced lung injury (VILI). Compared with sham-treated wild type (WT) mice, ventilated WT mice have reduced total bronchoalveolar lavage (BAL) cells; and elevated activities of thrombin and matrix metalloproteinases (MMPs), such as gelatinase/collagenase in the BAL fluid. In contrast, these parameters in ventilated C3 null mice are not significantly different from sham-treated WT and C3 null mice. In mechanically ventilated mice, thrombin activity and MMPs are lower in C3 null mice than in WT mice and are inversely correlated with total single BAL cells. C3 activation is associated with MMP activation in vitro. Pretreatment of WT mice with humanized cobra venom factor, which inactivates C3, reduces C3 deposition in the lung and increases total BAL cells in VILI. We propose that C3 is involved with VILI and inhibition of complement activation may be a potential therapeutic strategy.

Analysis of 2-[Fluorine-18]-Fluoro-2-deoxy-D-glucose uptake kinetics in PET studies of pulmonary inflammation.

Dynamic positron emission tomography (PET) imaging of the lung using the radiotracer 2-[fluorine-18]-fluoro-2-deoxy-D-glucose ((18)F-FDG) is an emerging method to assess noninvasively the metabolic activity of pulmonary inflammatory cells. Nevertheless, because of the distinct functional and structural characteristics of inflamed lung tissue standard methods of (18)F-FDG analysis can be substantially limited and there is no consensus about the best method for quantification of the (18)F-FDG signal for acute or chronic inflammatory lung diseases. This article gives an overview on recent advances in quantitative analysis of (18)F-FDG uptake kinetics in non-neoplastic inflamed lung tissue.

Assessment of lung inflammation with 18F-FDG PET during acute lung injury.

OBJECTIVE: The purpose of this review is to describe the current experimental and clinical data regarding the fundamentals and applications of (18)F-FDG PET during acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). CONCLUSION: Lung inflammation is a key feature of ALI. During ALI, FDG PET can be used to monitor lung neutrophils, which are essential cells in the pathophysiologic mechanisms of ALI. Pulmonary FDG kinetics are altered during experimental and human ALI and are associated with regional lung dysfunction, histologic abnormalities, and prognosis. FDG PET may be a valuable noninvasive method for gaining comprehensive understanding of the mechanisms of ALI/ARDS and for evaluating therapeutic interventions.

Measurement of regional specific lung volume change using respiratory-gated PET of inhaled 13N-nitrogen.

UNLABELLED: Regional specific lung volume change (sVol), defined as the regional tidal volume divided by the regional end-expiratory gas volume, is a key variable in lung mechanics and in the pathogenesis of ventilator-induced lung injury. Despite the usefulness of PET to study regional lung function, there is no established method to assess sVol with PET. We present a method to measure sVol from respiratory-gated PET images of inhaled (13)N-nitrogen ((13)NN), validate the method against regional specific ventilation (sV), and study the effect of region-of-interest (ROI) volume and orientation on the sVol-sV relationship. METHODS: Four supine sheep were mechanically ventilated (tidal volume V(T) = 8 mL/kg, respiratory rate adjusted to normocapnia) at low (n = 2, positive end-expiratory pressure = 0) and high (n = 2, positive end-expiratory pressure adjusted to achieve a plateau pressure of 30 cm H(2)O) lung volumes. Respiratory-gated PET scans were obtained after inhaled (13)NN equilibration both at baseline and after a period of mechanical ventilation. We calculated sVol from (13)NN-derived regional fractional gas content at end-inspiration (F(EI)) and end-expiration (F(EE)) using the formula sVol = (F(EI) - F(EE))/(F(EE)[1 - F(EI)]). sV was computed as the inverse of the subsequent (13)NN washout curve time constant. ROIs were defined by dividing the lung field with equally spaced coronal, sagittal, and transverse planes, perpendicular to the ventrodorsal, laterolateral, and cephalocaudal axes, respectively. RESULTS: sVol-sV linear regressions for ROIs based on the ventrodorsal axis yielded the highest R(2) (range, 0.71-0.92 for mean ROI volumes from 7 to 162 mL), the cephalocaudal axis the next highest (R(2) = 0.77-0.88 for mean ROI volumes from 38 to 162 mL), and the laterolateral axis the lowest (R(2) = 0.65-0.83 for mean ROI volumes from 8 to 162 mL). ROIs based on the ventrodorsal axis yielded lower standard errors of estimates of sVol from sV than those based on the laterolateral axis or the cephalocaudal axis. CONCLUSION: sVol can be computed with PET using the proposed method and is highly correlated with sV. Errors in sVol are smaller for larger ROIs and for orientations based on the ventrodorsal axis.

Hypoxemia and acute mountain sickness: which comes first?

Hypoxemia is usually associated with acute mountain sickness (AMS), but most studies have varied in time and magnitude of altitude exposure, exercise, diet, environmental conditions, and severity of pulmonary edema. We wished to determine whether hypoxemia occurred early in subjects who developed subsequent AMS while resting at a simulated altitude of 426 mmHg (approximately 16,000 ft or 4880 m). Exposures of 51 men and women were carried out for 8 to 12 h. AMS was determined by Lake Louise (LL) and AMS-C scores near the end of exposure, with spirometry and gas exchange measured the day before (C) and after 1 (A1), 6 (A6), and last (A12) h at simulated altitude and arterial blood at C, A1, and A12. Responses of 16 subjects having the lowest AMS scores (nonAMS: mean LL=1.0, range=0-2.5) were compared with the 16 having the highest scores (+AMS: mean LL=7.4, range=5-11). Total and alveolar ventilation responses to altitude were not different between groups. +AMS had significantly lower PaO2 (4.6 mmHg) and SaO2 (4.8%) at A1 and 3.3 mmHg and 3.1% at A12. Spirometry changes were similar at A1, but at A6 and A12 reduced vital capacity (VC) and increased breathing frequency suggested interstitial pulmonary edema in +AMS. The early hypoxemia in +AMS appears to be the result of diffusion impairment or venous admixture, perhaps due to a unique autonomic response affecting pulmonary perfusion. Early hypoxemia may be useful to predict AMS susceptibility.

Perioperative echocardiographic examination for ventricular assist device implantation.

Ventricular assist devices (VADs) are systems for mechanical circulatory support of the patient with severe heart failure. Perioperative transesophageal echocardiography is a major component of patient management, and important for surgical and anesthetic decision making. In this review we present the rationale and available data for a comprehensive echocardiographic assessment of patients receiving a VAD. In addition to the standard examination, device-specific pre-, intra-, and postoperative considerations are essential to the echocardiographic evaluation. These include: (a) the pre-VAD insertion examination of the heart and large vessels to exclude significant aortic regurgitation, tricuspid regurgitation, mitral stenosis, patent foramen ovale, or other cardiac abnormality that could lead to right-to-left shunt after left VAD placement, intracardiac thrombi, ventricular scars, pulmonic regurgitation, pulmonary hypertension, pulmonary embolism, and atherosclerotic disease in the ascending aorta; and to assess right ventricular function; and (b) the post-VAD insertion examination of the device and reassessment of the heart and large vessels. The examination of the device aims to confirm completeness of device and heart deairing, cannulas alignment and patency, and competency of device valves using two-dimensional, and color, continuous and pulsed wave Doppler modalities. The goal for the heart examination after implantation should be to exclude aortic regurgitation, or an uncovered right-to-left shunt; and to assess right ventricular function, left ventricular unloading, and the effect of device settings on global heart function. The variety of VAD models with different basic and operation principles requires specific echocardiographic assessment targeted to the characteristics of the implanted device.

Regional gas exchange and cellular metabolic activity in ventilator-induced lung injury.

BACKGROUND: Alveolar overdistension and repetitive derecruitment-recruitment contribute to ventilator-induced lung injury (VILI). The authors investigated (1) whether inflammatory cell activation due to VILI was assessable by positron emission tomography and (2) whether cell activation due to dynamic overdistension alone was detectable when other manifestations of VILI were not yet evident. METHODS: The authors assessed cellular metabolic activity with [(18)F]fluorodeoxyglucose and regional gas exchange with [(13)N]nitrogen. In 12 sheep, the left ("test") lung was overdistended with end-inspiratory pressure of 50 cm H(2)O for 90 min, while end-expiratory derecruitment of this lung was either promoted with end-expiratory pressure of -10 cm H(2)O in 6 of these sheep (negative end-expiratory pressure [NEEP] group) or prevented with +10 cm H(2)O in the other 6 (positive end-expiratory pressure [PEEP] group) to isolate the effect of overdistension. The right ("control") lung was protected from VILI. RESULTS: Aeration decreased and shunt fraction increased in the test lung of the NEEP group. [(18)F]fluorodeoxyglucose uptake of this lung was higher than that of the control lung and of the test lung of the PEEP group, and correlated with neutrophil count. When normalized by tissue fraction to account for increased aeration of the test lung in the PEEP group, [(18)F]fluorodeoxyglucose uptake was elevated also in this group, despite the fact that gas exchange had not yet deteriorated after 90 min of overdistension alone. CONCLUSION: The authors could detect regional neutrophil activation in VILI even when end-expiratory derecruitment was prevented and impairment of gas exchange was not evident. Concomitant end-expiratory derecruitment converted this activation into profound inflammation with decreased aeration and regional shunting.

Regional pulmonary perfusion, inflation, and ventilation defects in bronchoconstricted patients with asthma.

RATIONALE: Bronchoconstriction in asthma leads to heterogeneous ventilation and the formation of large and contiguous ventilation defects in the lungs. However, the regional adaptations of pulmonary perfusion (Q) to such ventilation defects have not been well studied. METHODS: We used positron emission tomography to assess the intrapulmonary kinetics of intravenously infused tracer nitrogen-13 ((13)NN), and measured the regional distributions of ventilation and perfusion in 11 patients with mild asthma. For each subject, the regional washout kinetics of (13)NN before and during methacholine-induced bronchoconstriction were analyzed. Two regions of interest (ROIs) were defined: one over a spatially contiguous area of high tracer retention (TR) during bronchoconstriction and a second one covering an area of similar size, showing minimal tracer retention (NR). RESULTS: Both ROIs demonstrated heterogeneous washout kinetics, which could be described by a two-compartment model with fast and slow washout rates. We found a systematic reduction in regional Q to the TR ROI during bronchoconstriction and a variable and nonsignificant change in relative Q for NR regions. The reduction in regional Q was associated with an increase in regional gas content of the TR ROI, but its magnitude was greater than that anticipated solely by the change in regional lung inflation. CONCLUSION: During methacholine-induced bronchoconstriction, perfusion to ventilation defects are systematically reduced by a relative increase in regional pulmonary vascular resistance.

The distribution of ventilation during bronchoconstriction is patchy and bimodal: a PET imaging study.

Recent PET imaging data from bronchoconstricted sheep (Vidal Melo et al., 2005) showed that V /Q distributions were bimodal and topographically patchy, but including a substantial heterogeneity at scales <2.2 ml. In this paper, we reanalyze the experimental data to establish the contribution of ventilation (V (r)) heterogeneity to the bimodality in V /Q . This analysis demonstrates that the distribution of V (r) during bronchoconstriction was bimodal with large patches of severe hypoventilation occupying an average of 41% of the imaged lung. The degree of hypoventilation to these regions was highly correlated with the degree of oxygenation impairment, but was quite variable amongst animals in spite of consistent degrees of mechanical obstruction. Remarkably, those regions were found to be hyperventilated before methacholine and their degree of hyperventilation was correlated with their degree of hypoventilation during bronchoconstriction. These data suggest that improving the uniformity of ventilation at baseline may be a desirable therapeutic target if the risk of severe hypoxemia during asthma attacks is to be minimized and/or the distribution of inhaled pharmaceuticals is to be optimized.

Topographic basis of bimodal ventilation-perfusion distributions during bronchoconstriction in sheep.

The distribution of ventilation-perfusion (VA/Q) ratios during bronchoconstriction measured with the multiple inert gases elimination technique is frequently bimodal. However, the topographic basis and the cause of that bimodality remain unknown. In this article, regional VA/Q is quantified by three-dimensional positron emission tomography (PET) imaging of methacholine-induced bronchoconstriction in sheep. Regional VA/Q ratios were calculated from the imaged kinetics of intravenously injected 13NN-saline bolus, assembled into global VA/Q distributions, and used to estimate gas exchange. During bronchoconstriction, large regions with impaired tracer washout were observed adjacent to regions of normal ventilation. PET-derived VA/Q distributions during bronchoconstriction were consistently bimodal, with areas of low VA/Q receiving a large fraction of Q. The standard deviation of the VA/Q distribution was 38% lower if small-scale (subresolution) heterogeneity (< 2.2 cm3) was ignored. Arterial blood gases predicted from PET data correlated well with measured values for Pa(O2) (r2= 0.91, p < 0.01) and Pa(CO2) (r2= 0.90, p < 0.01). We conclude that the bimodality of VA/Q distributions in bronchoconstriction reflects the involvement of large contiguous regions of hypoventilation with substantial subresolution intraregional VA/Q heterogeneity. Assessment of the subresolution VA/Q heterogeneity is therefore essential to accurately quantify global gas exchange impairment during bronchoconstriction.