Moderate exercise-induced dynamics on key sepsis-associated signaling pathways in the liver.

BACKGROUND: There is a clear relationship between quantitative measures of fitness (e.g., VO2 max) and outcomes after surgical procedures. Whether or not fitness is a modifiable risk factor and what underlying biological processes drive these changes are not known. The purpose of this study was to evaluate the moderate exercise training effect on sepsis outcomes (survival) as well as the hepatic biological response. We chose to study the liver because it plays a central role in the regulation of immune defense during systemic infection and receives blood flow directly from the origin of infection (gut) in the cecal ligation and puncture (CLP) model. METHODS: We randomized 50 male (♂) and female (♀) Sprague-Dawley rats (10 weeks, 340 g) to 3 weeks of treadmill exercise training, performed CLP to induce polymicrobial "sepsis," and monitored survival for five days (Part I). In parallel (Part II), we randomized 60 rats to control/sedentary (G1), exercise (G2), exercise + sham surgery (G3), CLP/sepsis (G4), exercise + CLP [12 h (G5) and 24 h (G6)], euthanized at 12 or 24 h, and explored molecular pathways related to exercise and sepsis survival in hepatic tissue and serum. RESULTS: Three weeks of exercise training significantly increased rat survival following CLP (polymicrobial sepsis). CLP increased inflammatory markers (e.g., TNF-a, IL-6), which were attenuated by exercise. Sepsis suppressed the SOD and Nrf2 expression, and exercise before sepsis restored SOD and Nrf2 levels near the baseline. CLP led to increased HIF1a expression and oxidative and nitrosative stress, the latter of which were attenuated by exercise. Haptoglobin expression levels were increased in CLP animals, which was significantly amplified in exercise + CLP (24 h) rats. CONCLUSIONS: Moderate exercise training (3 weeks) increased the survival in rats exposed to CLP, which was associated with less inflammation, less oxidative and nitrosative stress, and activation of antioxidant defense pathways.

Intraoperative administration of isoflurane improves survival in rats exposed to caecal ligation and puncture.

Background: Emerging data suggest that volatile anaesthetic agents may be protective during critical illness. Methods: Three-month-old Sprague Dawley rats were randomly allocated to one of four groups: isoflurane during surgery followed by 3 days of isoflurane 0.8% (and intralipid i.v.), propofol during surgery and 314 µg kg-1 h-1 propofol for 3 days, isoflurane during surgery and intralipid for 3 days, and propofol during surgery and intralipid for 3 days. After induction with propofol or isoflurane, rats breathed oxygen 100% spontaneously via a nose cone. Propofol or intralipid was administered through a 22-gauge jugular vein i.v. catheter. Caecal ligation and puncture was performed through a paramedian incision. The surgical concentration of isoflurane was kept at 2%, and propofol was maintained at 800 µg kg-1 h-1. After recovery and 3 days of exposure to intralipid or anaesthetic agents, the rats were allowed to roam free in an adequately vented, temperature- and humidity-controlled cage with food and water ad libitum. Results: Rats that received isoflurane for 3 days survived longer than the postoperative propofol group (P=0.0002, log-rank test). Among rats receiving no postoperative anaesthetic, those receiving isoflurane during surgery survived longer than those that received propofol during surgery group (P=0.0081). Conclusions: Exposure to isoflurane, as opposed to propofol, may improve survival in rats exposed to caecal ligation and puncture.

Non-contact thermography-based respiratory rate monitoring in a post-anesthetic care unit.

In patients at high risk of respiratory complications, pulse oximetry may not adequately detect hypoventilation events. Previous studies have proposed using thermography, which relies on infrared imaging, to measure respiratory rate (RR). These systems lack support from real-world feasibility testing for widespread acceptance. This study enrolled 101 spontaneously ventilating patients in a post-anesthesia recovery unit. Patients were placed in a 45° reclined position while undergoing pulse oximetry and bioimpedance-based RR monitoring. A thermography camera was placed approximately 1 m from the patient and pointed at the patient's face, recording continuously at 30 frames per second for 2 min. Simultaneously, RR was manually recorded. Offline imaging analysis identified the nares as a region of interest and then quantified nasal temperature changes frame by frame to estimate RR. The manually calculated RR was compared with both bioimpedance and thermographic estimates. The Pearson correlation coefficient between direct measurement and bioimpedance was 0.69 (R2 = 0.48), and that between direct measurement and thermography was 0.95 (R2 = 0.90). Limits of agreement analysis revealed a bias of 1.3 and limits of agreement of 10.8 (95% confidence interval 9.07 to 12.5) and - 8.13 (- 6.41 to - 9.84) between direct measurements and bioimpedance, and a bias of -0.139 and limits of agreement of 2.65 (2.14 to 3.15) and - 2.92 (- 2.41 to 3.42) between direct measurements and thermography. Thermography allowed tracking of the manually measured RR in the post-anesthesia recovery unit without requiring patient contact. Additional work is required for image acquisition automation and nostril identification.

Anesthesia-Sepsis-Associated Alterations in Liver Gene Expression Profiles and Mitochondrial Oxidative Phosphorylation Complexes.

Background: Hepatic dysfunction plays a major role in adverse outcomes in sepsis. Volatile anesthetic agents may protect against organ dysfunction in the setting of critical illness and infection. The goal of this study was to study the impact of Sepsis-inflammation on hepatic subcellular energetics in animals anesthetized with both Propofol (intravenous anesthetic agent and GABA agonist) and Isoflurane (volatile anesthetic i.e., VAA). Methods: Sprague-Dawley rats were anesthetized with Propofol or isoflurane. Rats in each group were randomized to celiotomy and closure (control) or cecal ligation and puncture "CLP" (Sepsis-inflammation) for 8 h. Results: Inflammation led to upregulation in hepatic hypoxia-inducible factor-1 in both groups. Rats anesthetized with isoflurane also exhibited increases in bcl-2, inducible nitric oxide synthase, and heme oxygenase-1(HO-1) during inflammation, whereas rats anesthetized with Propofol did not. In rats anesthetized with isoflurane, decreased mRNA, protein (Complex II, IV, V), and activity levels (Complex II/III,IV,V) were identified for all components of the electron transport chain, leading to a decrease in mitochondrial ATP. In contrast, in rats anesthetized with Propofol, these changes were not identified after exposure to inflammation. RNA-Seq and real-time quantitative PCR (qPCR) expression analysis identified a substantial difference between groups (isoflurane vs. Propofol) in mitogen-activated protein kinase (MAPK) related gene expression following exposure to Sepsis-inflammation. Conclusions: Compared to rats anesthetized with Propofol, those anesthetized with isoflurane exhibit more oxidative stress, decreased oxidative phosphorylation protein expression, and electron transport chain activity and increased expression of organ-protective proteins.

Impact of inflammation on brain subcellular energetics in anesthetized rats.

BACKGROUND: Emerging data suggests that volatile anesthetic agents may have organ protection properties in the setting of critical illness. The purpose of this study was to better understand the effect of inflammation on cerebral subcellular energetics in animals exposed to two different anesthetic agents-a GABA agonist (propofol) and a volatile agent (isoflurane). RESULTS: Forty-eight Sprague-Dawley rats were anesthetized with isoflurane or propofol. In each group, rats were randomized to celiotomy and closure (sham) or cecal ligation and puncture (inflammation [sepsis model]) for 8 h. Brain tissue oxygen saturation and the oxidation state of cytochrome aa3 were measured. Brain tissue was extracted using the freeze-blow technique. All rats experienced progressive increases in tissue oxygenation and cytochrome aa3 reduction over time. Inflammation had no impact on cytochrome aa3, but isoflurane caused significant cytochrome aa3 reduction. During isoflurane (not propofol) anesthesia, inflammation led to an increase in lactate (+ 0.64 vs. - 0.80 mEq/L, p = 0.0061). There were no differences in ADP:ATP ratios between groups. In the isoflurane (not propofol) group, inflammation increased the expression of hypoxia-inducible factor-1α (62%, p = 0.0012), heme oxygenase-1 (67%, p = 0.0011), and inducible nitric oxide synthase (31%, p = 0.023) in the brain. Animals exposed to inflammation and isoflurane (but not propofol) exhibited increased expression of protein carbonyls (9.2 vs. 7.0 nM/mg protein, p = 0.0050) and S-nitrosylation (49%, p = 0.045) in the brain. RNA sequencing identified an increase in heat shock protein 90 and NF-κß inhibitor mRNA in the inflammation/isoflurane group. CONCLUSIONS: In the setting of inflammation, rats exposed to isoflurane show increased hypoxia-inducible factor-1α expression despite a lack of hypoxia, increased oxidative stress in the brain, and increased serum lactate, all of which suggest a relative increase in anaerobic metabolism compared to propofol. Differences in oxidative stress as well as heat shock protein 90 and NF-κß inhibitor may account for the differential expression of cerebral hypoxia-inducible factor-1α during inflammation.

Comparison of Broadband and Discrete Wavelength Near-Infrared Spectroscopy Algorithms for the Detection of Cytochrome aa3 Reduction.

BACKGROUND: Cytochrome aa3, the terminal component of the electron transport chain, absorbs near-infrared radiation (NIR) differentially depending on its oxidation state (Cytox), which can in theory be measured using near-infrared spectroscopy (NIRS) by relating light absorption at specific wavelengths to chromophore concentrations. Some NIRS algorithms use discrete wavelengths, while others analyze a band of NIR (broadband NIRS). The purpose of this study was to test the ability of discrete wavelength and broadband algorithms to measure changes in Cytox (primary outcome), and to determine whether or not a discreet wavelength NIRS algorithm could perform similarly to a broadband NIRS algorithm for the measurement of Cytox in a staged hypoxia-cyanide model (hypoxia and cyanide have oppositional effects on tissue saturation, but both cause cytochrome reduction). METHODS: Twenty Sprague-Dawley rats were anesthetized with isoflurane, intubated, and instrumented. Blood pressure, end-tidal carbon dioxide, and arterial oxygen saturation were measured. A halogen light source transmitted NIR transcranially. NIR from the light source and the skull was transmitted to 2 cooled charge-coupled device spectrometers. Rats were subjected to anoxia (fraction of inspired oxygen, 0.0) until arterial oxygen saturation decreased to 70%. After recovery, 5 mg/kg sodium cyanide was injected intravenously. The cycle was repeated until cardiac arrest occurred. Relative concentrations of hemoglobin and cytochrome aa3 were calculated using discreet wavelength and broadband NIRS algorithms. RESULTS: Hypoxia led to an increase in calculated deoxyhemoglobin (0.20 arbitrary units [AUs]; 95% confidence interval [CI], 0.17-0.22; P < .0001), a decrease in calculated oxyhemoglobin (-0.16 AUs; 95% CI, -0.19 to -0.14; P < .0001), and a decrease in calculated Cytox (-0.057 AUs; 95% CI, -0.073 to 0.0040; P < .001). Cyanide led to a decrease in calculated deoxyhemoglobin (-0.037 AUs; 95% CI, 0.046 to -0.029; P < .001), an increase in calculated oxyhemoglobin (0.053 AUs; 95% CI, 0.040-0.065; P < .001), and a decrease in calculated Cytox (-0.056 AUs; 95% CI, -0.064 to -0.048; P < .001). The correlations between "discreet" wavelength algorithms (using 4, 6, 8, and 10 wavelengths) and the broadband algorithm for the measurement of calculated Cytox were 0.54 (95% CI, 0.52-0.56), 0.87 (0.87-0.88), 0.88 (0.88-0.89), and 0.95 (0.95-0.95), respectively. CONCLUSIONS: The broadband and 10 wavelength algorithm were able to accurately track changes in Cytox for all experiments.

A validation method for near-infrared spectroscopy based tissue oximeters for cerebral and somatic tissue oxygen saturation measurements.

We describe the validation methodology for the NIRS based FORE-SIGHT ELITE® (CAS Medical Systems, Inc., Branford, CT, USA) tissue oximeter for cerebral and somatic tissue oxygen saturation (StO2) measurements for adult subjects submitted to the United States Food and Drug Administration (FDA) to obtain clearance for clinical use. This validation methodology evolved from a history of NIRS validations in the literature and FDA recommended use of Deming regression and bootstrapping statistical validation methods. For cerebral validation, forehead cerebral StO2 measurements were compared to a weighted 70:30 reference (REF CXB) of co-oximeter internal jugular venous and arterial blood saturation of healthy adult subjects during a controlled hypoxia sequence, with a sensor placed on the forehead. For somatic validation, somatic StO2 measurements were compared to a weighted 70:30 reference (REF CXS) of co-oximetry central venous and arterial saturation values following a similar protocol, with sensors place on the flank, quadriceps muscle, and calf muscle. With informed consent, 25 subjects successfully completed the cerebral validation study. The bias and precision (1 SD) of cerebral StO2 compared to REF CXB was -0.14 ± 3.07%. With informed consent, 24 subjects successfully completed the somatic validation study. The bias and precision of somatic StO2 compared to REF CXS was 0.04 ± 4.22% from the average of flank, quadriceps, and calf StO2 measurements to best represent the global whole body REF CXS. The NIRS validation methods presented potentially provide a reliable means to test NIRS monitors and qualify them for clinical use.

Broadband near-infrared spectroscopy can detect cyanide-induced cytochrome aa3 inhibition in rats: a proof of concept study.

PURPOSE: Clinically available near-infrared spectroscopy (NIRS) devices use two to five wavelengths of light to measure the relative amounts of oxyhemoglobin and deoxyhemoglobin in tissue to determine tissue hemoglobin oxygen saturation (StO2). In addition to StO2, broadband NIRS devices (using hundreds of wavelengths of light) may be able to measure the oxidation state of mitochondrial cytochrome aa3 (Cytox) which reflects the subcellular energetic state. We hypothesize that broadband NIRS devices can measure Cytox independent of changes in hemoglobin saturation. METHODS: In this prospective non-randomized study, 20 male Sprague-Dawley rats (300 g) were anesthetized with isoflurane, tracheally intubated, and ventilated with 100% O2 containing 2% isoflurane. They were subsequently instrumented with a broadband NIRS device that used a halogen light source coupled to an emitting fibreoptic cable. Three receiving fibreoptic cables were utilized; one analyzed the light source and the other two were directed at the base of the skull. Each receiving fibre was connected to a spectrometer to measure light intensity. Sodium cyanide (NaCN) 5 mg·kg-1 iv was injected in order to produce cytochrome aa3 reduction. Two to three minutes after injection, oxygen was eliminated and 100% nitrogen (i.e., anoxia) was used for ventilation in order to induce a reduction in both cytochrome aa3 and hemoglobin desaturation. Changes in the cytochrome oxidation state and hemoglobin oxygenation were calculated using a broadband algorithm and compared before and after both the NaCN and anoxia interventions. RESULTS: The NaCN injection resulted in a decrease in median [interquartile range (IQR)] deoxyhemoglobin (-0.014 [-0.29 to -0.005] arbitrary units [AU]; P < 0.001), an increase in oxyhemoglobin (0.013 [-0.011 to 0.031] AU; P < 0.001), and a reduction in cytochrome aa3 (-0.015 [-0.020 to -0.011] AU; P < 0.001). Anoxia resulted in an increase in median [IQR] deoxyhemoglobin (0.13 [0.11 to 0.18] AU; P < 0.001), a decrease in oxyhemoglobin (-0.17 [-0.22 to -0.15] AU; P < 0.001), and a reduction in cytochrome aa3 (-0.04 [-0.06 to -0.03] AU; P < 0.001). CONCLUSION: Broadband NIRS can effectively measure the directionality of changes in both Cytox and StO2 by uncoupling the cytochrome and hemoglobin signals through inhibition of the electron transport chain and anoxia.

Tissue Monitoring with Three-Wavelength Light Emitting Diode-Based Near-Infrared Spectroscopy.

Background Flap monitoring with near-infrared spectroscopy (NIRS) facilitates early detection of vascular compromise. However, standard NIRS devices that employ two wavelengths of light to assess tissue oxygenation (StO2) are susceptible to artifact from background noise and demonstrate significant variability in the clinical setting. As the number of wavelengths detected by a NIRS device is increased, the precision of StO2 measurements can be improved and additional chromophores other than oxyhemoglobin and deoxyhemoglobin can be measured. A three-wavelength light emitting diode NIRS device (Artinis, Zetten, the Netherlands) that also detects cytochrome aa3 , a measure of intracellular oxygen demand, was compared with the standard two-wavelength device commonly used for flap monitoring (ViOptix device, ViOptix Inc., Freemont, CA) to determine if there is an improvement in the precision of tissue oxygen measurements. Methods ViOptix and Artinis were applied to the forearms of human volunteers (n = 15) and a blood pressure cuff was placed around the upper arm to occlude arterial and venous flow. StO2 measurements were obtained from both devices. Artinis also yielded cytochrome aa3 oxidation state measurements. Results StO2 measurements from both devices were proportionate during ischemia (R2 = 0.79, p < 0.01). Monte Carlo stimulation showed Artinis outperformed ViOptix (p < 0.01) as a measure of change in StO2 during ischemia. Artinis did not detect a reduction in cytochrome aa3 associated with the decrease in StO2 during ischemia. Conclusion The addition of a third wavelength to NIRS monitoring may improve the precision of StO2 trend monitoring. However, the three-wavelength device lacked the sensitivity to reliably measure changes in cytochrome aa3 .

Multiparameter Predictor of Fluid Responsiveness in Cardiac Surgical Patients Receiving Tidal Volumes Less Than 10 mL/kg.

Introduction We hypothesize that respiratory variation in the pulmonary artery tracing predicts fluid responsiveness (primary hypothesis) and that inclusion of multiple physiologic waveforms as well as ventilator settings in a predictive model of fluid responsiveness would lead to improvements in the clinical utility of this class of metrics (secondary hypothesis). Methods Blood pressure tracings were prospectively recorded in 35 patients immediately following cardiac surgery. Fluid bolus administration data, ventilator settings, and cardiac output were recorded prospectively before and after fluid boluses given at the discretion of the treating physician. Results We observed statistically significant but limited relationships between pulmonic (r(2) = .26, P = .0052) and systemic (r(2) = .13, P = .011) pulse pressure variation and changes in cardiac index. A multiparameter estimate of fluid responsiveness, which included respiratory variation in central venous pressure and pulmonary artery pressure, indexed tidal volumes, positive end-expiratory pressure, and mean airway pressure, was also correlated with change in cardiac index (r(2) = .42, P = .0056). Using the area under the curve (AUC) technique to compare specificity and sensitivity, dynamic indicators (AUC = 0.74, 0.67, and 0.81 for systemic arterial respiratory [pulse pressure] variation, pulmonic arterial respiratory [pulse pressure] variation, and the multiparameter estimate, respectively) outperformed static estimates (0.49 and 0.48 for central venous pressure and pulmonary artery diastolic pressure, respectively). Conclusion While integration of multiple physiologic waveforms as well as ventilator parameters improves the predictability of fluid responsive metrics in the setting of lung-protective ventilation, the composite index may still be of limited predictive value.

The contribution of arterial blood gases in cerebral blood flow regulation and fuel utilization in man at high altitude.

The effects of partial acclimatization to high altitude (HA; 5,050 m) on cerebral metabolism and cerebrovascular function have not been characterized. We hypothesized (1) increased cerebrovascular reactivity (CVR) at HA; and (2) that CO2 would affect cerebral metabolism more than hypoxia. PaO2 and PaCO2 were manipulated at sea level (SL) to simulate HA exposure, and at HA, SL blood gases were simulated; CVR was assessed at both altitudes. Arterial-jugular venous differences were measured to calculate cerebral metabolic rates and cerebral blood flow (CBF). We observed that (1) partial acclimatization yields a steeper CO2-H(+) relation in both arterial and jugular venous blood; yet (2) CVR did not change, despite (3) mean arterial pressure (MAP)-CO2 reactivity being doubled at HA, thus indicating effective cerebral autoregulation. (4) At SL hypoxia increased CBF, and restoration of oxygen at HA reduced CBF, but neither had any effect on cerebral metabolism. Acclimatization resets the cerebrovasculature to chronic hypocapnia.

The accuracy of a near-infrared spectroscopy cerebral oximetry device and its potential value for estimating jugular venous oxygen saturation.

BACKGROUND: An intriguing potential clinical use of cerebral oximeter measurements (SctO2) is the ability to noninvasively estimate jugular bulb venous oxygen saturation (SjvO2). Our purpose in this study was to determine the accuracy of the FORE-SIGHT(®) (CAS Medical Systems, Branford, CT), which is calibrated to a weighted average of 70% (SjvO2) and 30% arterial saturation, for Food and Drug Administration pre-market approval 510(k) certification by adapting an industry standard protocol, ISO 9919:2005 (www.ISO.org) (used for pulse oximeters), and to evaluate the use of SctO2 and SpO2 measurements to noninvasively estimate jugular venous oxygen saturation (SnvO2). METHODS: Paired blood gas samples from the radial artery and the jugular venous bulb were collected from 20 healthy volunteers undergoing progressive oxygen desaturation from 100% to 70%. The blood sample pairs were analyzed via co-oximetry and used to calculate the approximate mixed vascular cerebral blood oxygen saturation, or reference SctO2 values (refSctO2), during increasing hypoxia. These reference values were compared to bilateral FORE-SIGHT SctO2 values recorded simultaneously with the blood gas draws to determine its accuracy. Bilateral SctO2 and SpO2 measurements were then used to calculate SnvO2 values which were compared to SjvO2. RESULTS: Two hundred forty-six arterial and 253 venous samples from 18 subjects were used in the analysis. The ipsilateral FORE-SIGHT SctO2 values showed a tolerance interval (TI) of [-10.72 to 10.90] and Lin concordance correlation coefficient (CCC) with standard error (SE) of 0.83 ± 0.073 with the refSctO2 values calculated using arterial and venous blood gases. The ipsilateral data had a CCC of 0.81 + 0.059 with TI of [-9.22 to 9.40] with overall bias of 0.09%, and amplitude of the root mean square of error after it was corrected with random effects analysis was 2.92%. The bias and variability values between the ipsilateral and the contralateral FORE-SIGHT SctO2 measurements varied from person to person. The SnvO2 calculated from the ipsilateral SctO2 and SpO2 data showed a CCC ± SE of 0.79 ± 0.088, TI = [-14.93 to 15.33], slope of 0.98, y-intercept of 1.14% with SjvO2 values with a bias of 0.20% and an Arms of 4.08%. The SnvO2 values calculated independently from contralateral forehead FORE-SIGHT SctO2 values were not as correlated with the SjvO2 values (contralateral side CCC + SE = 0.72 ± 0.118, TI = [-14.86 to 15.20], slope of 0.66, and y-intercept of 20.36%). CONCLUSIONS: The FORE-SIGHT cerebral oximeter was able to estimate oxygen saturation within the tissues of the frontal lobe under conditions of normocapnia and varying degrees of hypoxia (with 95% confidence interval of [-5.60 to 5.78] with ipsilateral blood sample data). These findings from healthy volunteers also suggest that the use of the calculated SnvO2 derived from SctO2 and SpO2 values may be a reasonable noninvasive method of estimating SjvO2 and therefore global cerebral oxygen consumption in the clinical setting. Further laboratory and clinical research is required to define the clinical utility of near-infrared spectroscopy determination of SctO2 and SnvO2 in the operating room setting.

Effects of elevated oxygen and carbon dioxide partial pressures on respiratory function and cognitive performance.

Hyperoxia during diving has been suggested to exacerbate hypercapnic narcosis and promote unconsciousness. We tested this hypothesis in male volunteers (12 at rest, 10 at 75 W cycle ergometer exercise) breathing each of four gases in a hyperbaric chamber. Inspired Po2 (PiO2 ) was 0.21 and 1.3 atmospheres (atm) without or with an individual subject's maximum tolerable inspired CO2 (PiO2 = 0.055-0.085 atm). Measurements included end-tidal CO2 partial pressure (PetCO2 ), rating of perceived discomfort (RPD), expired minute ventilation (V̇e), and cognitive function assessed by auditory n-back test. The most prominent finding was, irrespective of PetCO2 , that minute ventilation was 8-9 l/min greater for rest or exercise with a PiO2 of 1.3 atm compared with 0.21 atm (P < 0.0001). For hyperoxic gases, PetCO2 was consistently less than for normoxic gases (P < 0.01). For hyperoxic hypercapnic gases, n-back scores were higher than for normoxic gases (P < 0.01), and RPD was lower for exercise but not rest (P < 0.02). Subjects completed 66 hyperoxic hypercapnic trials without incident, but five stopped prematurely because of serious symptoms (tunnel vision, vision loss, dizziness, panic, exhaustion, or near syncope) during 69 normoxic hypercapnic trials (P = 0.0582). Serious symptoms during hypercapnic trials occurred only during normoxia. We conclude serious symptoms with hyperoxic hypercapnia were absent because of decreased PetCO2 consequent to increased ventilation.

Stability of cerebral metabolism and substrate availability in humans during hypoxia and hyperoxia.

Characterization of the influence of oxygen availability on brain metabolism is an essential step toward a better understanding of brain energy homoeostasis and has obvious clinical implications. However, how brain metabolism depends on oxygen availability has not been clearly examined in humans. We therefore assessed the influence of oxygen on CBF (cerebral blood flow) and CMRO2 (cerebral metabolic rates for oxygen) and carbohydrates. PaO2 (arterial partial pressure of oxygen) was decreased for 15 min to ~60, ~44 and ~35 mmHg [to target a SaO2 (arterial oxygen saturation) of 90, 80 and 70% respectively], and elevated to ~320 and ~430 mmHg. Isocapnia was maintained during each trial. At the end of each stage, arterial-jugular venous differences and volumetric CBF were measured to directly calculate cerebral metabolic rates. During progressive hypoxaemia, elevations in CBF were correlated with the reductions in both SaO2 (R2=0.54, P<0.05) and CaO2 (arterial oxygen content) (R2=0.57, P<0.05). Despite markedly reduced CaO2, cerebral oxygen delivery was maintained by increased CBF. Cerebral metabolic rates for oxygen, glucose and lactate remained unaltered during progressive hypoxia. Consequently, cerebral glucose delivery was in excess of that required, and net lactate efflux increased slightly in severe hypoxia, as reflected by a small increase in jugular venous lactate. Progressive hyperoxia did not alter CBF, CaO2, substrate delivery or cerebral metabolism. In conclusion, marked elevations in CBF with progressive hypoxaemia and related reductions in CaO2 resulted in a well-maintained cerebral oxygen delivery. As such, cerebral metabolism is still supported almost exclusively by carbohydrate oxidation during severe levels of hypoxaemia.

Real-time Doppler-based arterial vascular impedance and peripheral pressure-flow loops: a pilot study.

OBJECTIVE: Arterial pressure-flow loops and vascular impedance provide additional data that could be used to assess the hemodynamic effects of therapeutic interventions in anesthetized patients. To evaluate the utility of such an approach, the authors sought to design a device that combines flow waveforms from an esophageal Doppler probe and pressure waveforms from a peripheral artery to produce real-time pressure-flow loops and estimates of arterial vascular impedance. DESIGN: Prospective, cohort study. SETTING: Single center, university-based teaching hospital. PARTICIPANTS: Patients undergoing surgery in whom the attending anesthesiologist had opted to place an esophageal Doppler probe and a peripheral arterial catheter for hemodynamic monitoring. INTERVENTIONS: This was a non-interventional study designed to record pressure-flow loops and arterial vascular impedance intraoperatively using a novel, noninvasive device. MEASUREMENTS AND MAIN RESULTS: Pressure-flow loops and arterial vascular impedance were measured noninvasively using radial artery pressure and descending thoracic aorta flow waveforms in real time. CONCLUSIONS: Real-time arterial vascular impedance and peripheral pressure-volume loops can be determined using available monitoring devices. Technical feasibility of this technology in patients is a crucial first step to permit meaningful evaluation of the clinical value of this approach for accurate determination of complex hemodynamic indices and, eventually, improvement of outcomes.

Inhaled fentanyl aerosol in healthy volunteers: pharmacokinetics and pharmacodynamics.

BACKGROUND: Rapid delivery of potent opioid to the systemic circulation is an important feature for the effective treatment of acute and acute-on-chronic breakthrough pain. The delivery of different opioids by the pulmonary route has been inconsistent, usually resulting in low bioavailability of the drug. Staccato® Fentanyl for Inhalation is a handheld inhaler producing a single metered dose of aerosolized fentanyl during a single inspiration. The aerosol is of high purity (≥98%) at a particle size (1 to 3.5 microns) shown to be best for pulmonary absorption. METHODS: We conducted the study in healthy volunteers in 2 stages. In the crossover stage, 10 subjects received IV fentanyl 25 µg and inhaled fentanyl 25 µg on separate occasions. The dose escalation stage was a multidose, randomized, double-blind, placebo-controlled, single-period dose escalation study of inhaled fentanyl (50 to 300 µg). Serial blood sampling was performed over an 8-hour period after drug administration to determine the pharmacokinetic profile, and serial pupillometry was performed as a measure of pharmacodynamic effect. RESULTS: In the crossover stage the pharmacokinetic profiles of the inhaled and IV fentanyl showed similar peak arterial concentrations and areas under the curve. The time to maximum concentration was slightly shorter for the inhaled than IV fentanyl, 20.5 and 31.5 seconds, respectively. In the dose escalation stage the administration of repeated doses resulted in predictable, dose-dependent serum concentrations. CONCLUSIONS: This study has demonstrated that the pharmacokinetic profile of single doses of inhaled fentanyl is comparable to IV administration.

Development and validation of a cerebral oximeter capable of absolute accuracy.

OBJECTIVE: Cerebral oximetry may be a valuable monitor, but few validation data are available, and most report the change from baseline rather than absolute accuracy, which may be affected by individuals whose oximetric values are outside the expected range. The authors sought to develop and validate a cerebral oximeter capable of absolute accuracy. DESIGN: An in vivo research study. SETTING: A university human physiology laboratory. PARTICIPANTS: Healthy human volunteers were enrolled in calibration and validation studies of 2 cerebral oximetric sensors, the Nonin 8000CA and 8004CA. The 8000CA validation study identified 5 individuals with atypical cerebral oxygenation values; their data were used to design the 8004CA sensor, which subsequently underwent calibration and validation. INTERVENTIONS: Volunteers were taken through a stepwise hypoxia protocol to a minimum saturation of peripheral oxygen. Arteriovenous saturation (70% jugular bulb venous saturation and 30% arterial saturation) at 6 hypoxic plateaus was used as the reference value for the cerebral oximeter. Absolute accuracy was defined using a combination of the bias and precision of the paired saturations (A(RMS)). MEASUREMENTS AND MAIN RESULTS: In the validation study for the 8000CA sensor (n = 9, 106 plateaus), relative accuracy was an A(RMS) of 2.7, with an absolute accuracy of 8.1, meeting the criteria for a relative (trend) monitor, but not an absolute monitor. In the validation study for the 8004CA sensor (n = 11, 119 plateaus), the A(RMS) of the 8004CA was 4.1, meeting the prespecified success criterion of <5.0. CONCLUSIONS: The Nonin cerebral oximeter using the 8004CA sensor can provide absolute data on regional cerebral saturation compared with arteriovenous saturation, even in subjects previously shown to have values outside the normal population distribution curves.

Consensus statements regarding the multidisciplinary care of limb amputation patients in disasters or humanitarian emergencies: report of the 2011 Humanitarian Action Summit Surgical Working Group on amputations following disasters or conflict.

Limb amputations are frequently performed as a result of trauma inflicted during conflict or disasters. As demonstrated during the 2010 earthquake in Haiti, coordinating care of these patients in austere settings is complex. During the 2011 Humanitarian Action Summit, consensus statements were developed for international organizations providing care to limb amputation patients during disasters or humanitarian emergencies. Expanded planning is needed for a multidisciplinary surgical care team, inclusive of surgeons, anesthesiologists, rehabilitation specialists and mental health professionals. Surgical providers should approach amputation using an operative technique that optimizes limb length and prosthetic fitting. Appropriate anesthesia care involves both peri-operative and long-term pain control. Rehabilitation specialists must be involved early in treatment, ideally before amputation, and should educate the surgical team in prosthetic considerations. Mental health specialists must be included to help the patient with community reintegration. A key step in developing local health systems the establishment of surgical outcomes monitoring. Such monitoring can optimizepatient follow-up and foster professional accountability for the treatment of amputation patients in disaster settings and humanitarian emergencies.

Best practice guidelines on surgical response in disasters and humanitarian emergencies: report of the 2011 Humanitarian Action Summit Working Group on Surgical Issues within the Humanitarian Space.

The provision of surgery within humanitarian crises is complex, requiring coordination and cooperation among all stakeholders. During the 2011 Humanitarian Action Summit best practice guidelines were proposed to provide greater accountability and standardization in surgical humanitarian relief efforts. Surgical humanitarian relief planning should occur early and include team selection and preparation, appropriate disaster-specific anticipatory planning, needs assessment, and an awareness of local resources and limitations of cross-cultural project management. Accurate medical record keeping and timely follow-up is important for a transient surgical population. Integration with local health systems is essential and will help facilitate longer term surgical health system strengthening.