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Stephen J Lewis - One of the best experts on this subject based on the ideXlab platform.
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glutathione ethyl ester reverses the deleterious effects of fentanyl on ventilation and arterial blood gas chemistry while prolonging fentanyl induced analgesia
Scientific Reports, 2021Co-Authors: Michael W Jenkins, Faiza Khalid, Santhosh M Baby, Walter J May, Alex P Young, James N Bates, Feixiong Cheng, James M Seckler, Stephen J LewisAbstract:There is an urgent need to develop novel compounds that prevent the deleterious effects of opioids such as fentanyl on minute ventilation while, if possible, preserving the analgesic actions of the opioids. We report that L-glutathione ethyl ester (GSHee) may be such a novel compound. In this study, we measured tail flick latency (TFL), arterial blood gas (ABG) chemistry, Alveolar-Arterial Gradient, and ventilatory parameters by whole body plethysmography to determine the responses elicited by bolus injections of fentanyl (75 μg/kg, IV) in male adult Sprague-Dawley rats that had received a bolus injection of GSHee (100 μmol/kg, IV) 15 min previously. GSHee given alone had minimal effects on TFL, ABG chemistry and A-a Gradient whereas it elicited changes in some ventilatory parameters such as an increase in breathing frequency. In vehicle-treated rats, fentanyl elicited (1) an increase in TFL, (2) decreases in pH, pO2 and sO2 and increases in pCO2 (all indicative of ventilatory depression), (3) an increase in Alveolar-Arterial Gradient (indicative of a mismatch in ventilation-perfusion in the lungs), and (4) changes in ventilatory parameters such as a reduction in tidal volume, that were indicative of pronounced ventilatory depression. In GSHee-pretreated rats, fentanyl elicited a more prolonged analgesia, relatively minor changes in ABG chemistry and Alveolar-Arterial Gradient, and a substantially milder depression of ventilation. GSHee may represent an effective member of a novel class of thiolester drugs that are able to prevent the ventilatory depressant effects elicited by powerful opioids such as fentanyl and their deleterious effects on gas-exchange in the lungs without compromising opioid analgesia.
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Tempol Reverses the Negative Effects of Morphine on Arterial Blood-Gas Chemistry and Tissue Oxygen Saturation in Freely-Moving Rats
'Frontiers Media SA', 2021Co-Authors: Santhosh M Baby, Feixiong Cheng, Stephen J Lewis, Joseph F. Discala, Ryan Gruber, Paulina M. Getsy, Derek S. DamronAbstract:We have reported that pretreatment with the clinically approved superoxide dismutase mimetic, Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl), blunts the cardiorespiratory depressant responses elicited by a subsequent injection of fentanyl, in halothane-anesthetized rats. The objective of the present study was to determine whether Tempol is able to reverse the effects of morphine on arterial blood-gas (ABG) chemistry in freely-moving Sprague Dawley rats. The intravenous injection of morphine (10 mg/kg) elicited substantial decreases in pH, pO2 and sO2 that were accompanied by substantial increases in pCO2 and Alveolar-Arterial Gradient, which results in diminished gas-exchange within the lungs. Intravenous injection of a 60 mg/kg dose of Tempol 15 min after the injection of morphine caused minor improvements in pO2 and pCO2 but not in other ABG parameters. In contrast, the 100 mg/kg dose of Tempol caused an immediate and sustained reversal of the negative effects of morphine on arterial blood pH, pCO2, pO2, sO2 and Alveolar-Arterial Gradient. In other rats, we used pulse oximetry to determine that the 100 mg/kg dose of Tempol, but not the 60 mg/kg dose elicited a rapid and sustained reversal of the negative effects of morphine (10 mg/kg, IV) on tissue O2 saturation (SpO2). The injection of morphine caused a relatively minor fall in mean arterial blood pressure that was somewhat exacerbated by Tempol. These findings demonstrate that Tempol can reverse the negative effects of morphine on ABG chemistry in freely-moving rats paving the way of structure-activity and mechanisms of action studies with the host of Tempol analogues that are commercially available
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role of central and peripheral opiate receptors in the effects of fentanyl on analgesia ventilation and arterial blood gas chemistry in conscious rats
Respiratory Physiology & Neurobiology, 2014Co-Authors: Fraser Henderson, Santhosh M Baby, Walter J May, Alex P Young, Joseph F. Discala, Ryan B Gruber, Veljko Puskovic, Stephen J LewisAbstract:This study determined the effects of the peripherally restricted μ-opiate receptor (μ-OR) antagonist, naloxone methiodide (NLXmi) on fentanyl (25μg/kg, i.v.)-induced changes in (1) analgesia, (2) arterial blood gas chemistry (ABG) and Alveolar-Arterial Gradient (A-a Gradient), and (3) ventilatory parameters, in conscious rats. The fentanyl-induced increase in analgesia was minimally affected by a 1.5mg/kg of NLXmi but was attenuated by a 5.0mg/kg dose. Fentanyl decreased arterial blood pH, pO2 and sO2 and increased pCO2 and A-a Gradient. These responses were markedly diminished in NLXmi (1.5mg/kg)-pretreated rats. Fentanyl caused ventilatory depression (e.g., decreases in tidal volume and peak inspiratory flow). Pretreatment with NLXmi (1.5mg/kg, i.v.) antagonized the fentanyl decrease in tidal volume but minimally affected the other responses. These findings suggest that (1) the analgesia and ventilatory depression caused by fentanyl involve peripheral μ-ORs and (2) NLXmi prevents the fentanyl effects on ABG by blocking the negative actions of the opioid on tidal volume and A-a Gradient.
Michael B Fallon - One of the best experts on this subject based on the ideXlab platform.
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pulse oximetry is insensitive for detection of hepatopulmonary syndrome in patients evaluated for liver transplantation
Hepatology, 2019Co-Authors: Kimberly A Forde, Michael B Fallon, David S Goldberg, Michael J Krowka, Michael H Sprys, Karen L Krok, M Patel, Grace Lin, Carl Mottram, Paul D ScanlonAbstract:Screening for hepatopulmonary syndrome (HPS) using pulse oximetry is recommended in liver transplant (LT) candidates because mortality is increased, independently of the severity of the oxygenation defect. LT exception points may be afforded to those with HPS and severe hypoxemia. We assessed the screening characteristics of pulse oximetry for HPS. The Pulmonary Vascular Complications of Liver Disease 2 study is a multicenter, prospective cohort study of adults undergoing their first LT evaluation. Patients underwent protocolized assessment of oxygen saturation by pulse oximetry (SpO2 ), arterial blood gas, spirometry, and contrast-enhanced echocardiography (CE). HPS was defined as an Alveolar-Arterial Gradient ≥15 mm Hg (≥20 mm Hg if age >64 years), intrapulmonary vascular dilatation on CE, and absence of lung disease. The study sample included 363 patients. Of these, 75 (20.7%; 95% confidence interval [CI], 16.6%-25.2%) met the criteria for HPS. The area under the receiver operating characteristic curve (or c-statistic) for SpO2 in discriminating HPS was 0.59 (95% CI, 0.51-0.66). An SpO2 <96%, recommended by practice guidelines as a threshold to require further testing, had low sensitivity (28%; 95% CI, 18%-28%). The c-statistic of SpO2 in discriminating HPS with a partial pressure of oxygen (PaO2 ) <60 mm Hg (eligible for LT exception points) was 0.76 (95% CI, 0.46-1.00). An SpO2 cutoff of <96% had higher sensitivity for detecting HPS with PaO2 <60 mm Hg (71%; 95% CI, 38%-100%) but was still inadequate. Conclusion: Pulse oximetry is not sufficiently sensitive to screen for HPS in LT candidates. Arterial blood gas and CE are required in LT candidates for diagnosis of HPS.
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isolated intrapulmonary vascular dilatations and the risk of developing hepatopulmonary syndrome in liver transplant candidates
Annals of Hepatology, 2017Co-Authors: Manuel Mendizabal, David S Goldberg, Federico Pinero, Diego Arufe, Maria Jose De La Fuente, Pablo Testa, Matias Coronel, Sergio Baratta, Luis G Podesta, Michael B FallonAbstract:Abstract Background The natural history of intrapulmonary vascular dilations (IPVD) and their impact on patient outcomes in the setting of portal hypertension has only been described in small series. Aims To assess the development of hepatopulmonary syndrome (HPS) in patients with isolated IPVD and to evaluate outcomes of IPVD and HPS among patients evaluated for liver transplantation (LT). Material and methods Data from a prospective cohort of patients evaluated for LT with standardized screening for HPS were analyzed. IPVDs were defined as the presence of microbubbles in the left atrium > 3 cycles following right atrial opacification. HPS was defined as the presence of IPVD and hypoxemia (Alveolar-Arterial Gradient ≥ 15 mmHg) in the absence of concomitant cardiopulmonary disease. Results A total of 104 patients with negative contrast-enhanced echocardiogram (CE) were compared to 63 patients with IPVD and 63 patients with HPS. Only four patients were categorized as ‘severe’ HPS based on degree of hypoxemia (defined as PaO2 0.5). Conclusions Patients with IPVD appear to have a substantial risk of developing oxygenation impairment over time and progress to HPS. In our cohort, survival in patients with HPS and isolated IPVD is not different when compared to those without IPVDs.
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diagnostic utility of contrast echocardiography and lung perfusion scan in patients with hepatopulmonary syndrome
Gastroenterology, 1995Co-Authors: Gary A Abrams, Carl C Jaffe, Paul B Hoffer, Henry J Binder, Michael B FallonAbstract:Abstract Background & Aims: Two modalities, contrast echocardiography and lung perfusion scan, are used to identify intrapulmonary vascular dilatation and diagnose hepatopulmonary syndrome (HPS), but a comparison of these two procedures has not been performed. The aim of this study was to compare the use of these diagnostic modalities in detecting intrapulmonary vascular dilatation and diagnosing HPS. Methods: Forty consecutive outpatients with biopsy-proven cirrhosis had contrast echocardiography, a lung perfusion scan, and arterial blood gases analyzed. Results: Fifteen of 40 cirrhotics (38%) had positive contrast echocardiogram results. Seven patients with positive echocardiogram results had gas exchange abnormalities and could be considered to have HPS (7 of 40 [17.5%]). Three of these patients were hypoxemic and had no concurrent cardiopulmonary disease, and each had positive contrast echocardiogram and lung perfusion scan results and were readily diagnosed as having HPS. The other 4 patients (3 hypoxemic and 1 normoxemic with an elevated Alveolar-Arterial Gradient) had coexisting intrinsic lung disease and/or chest radiograph abnormalities complicating the diagnosis of HPS, and each had positive echocardiogram and negative lung scan results. The remaining 8 patients with positive echocardiogram results had normal lung scan and normal gas exchange results. No patient had positive lung scan and negative contrast echocardiogram results. Conclusions: Contrast echocardiography is the most useful screening test for intrapulmonary vasodilatation and may be positive more frequently than lung perfusion scans in patients with HPS.
Francois Peronnet - One of the best experts on this subject based on the ideXlab platform.
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detection of disturbances in pulmonary gas exchanges during exercise from arterialized earlobe po2
Respiratory Physiology & Neurobiology, 2011Co-Authors: Bernard Aguilaniu, Jocelyne Maitre, Samia Diab, Helene Perrault, Francois PeronnetAbstract:Blood sampling from the arterialized earlobe is widely used in clinical exercise testing but Fajac et al. (1998) (Eur. Respir. J. 11, 712-715) have shown that arterialized P(O2) Pc(CO2) is not a valid surrogate for Pa(O2). In the present study, in order to detect disturbances in pulmonary gas exchanges during clinical exercise testing from the Alveolar-Arterial Gradient of P(O2) (P[Ai-a](O2)), a correction factor for Pc(O2) was validated from data on a large cohort (107 patients at one or two levels of exercise: 172 pairs of samples). Pulmonary gas exchanges and pH, P(O2), P(CO2), PA(iO2) and P(Ai-a)(O2) from arterial and arterialized blood were measured or computed. Arterial and arterialized pH and P(CO2) (and thus PA(iO2)) were similar but P(CO2) was lower than arterial P(O2) (Pa(O2)). However, when corrected for the systematic bias between Pa(O2) and Pc(O2), which increased with Pc(O2), Pc(O2) adequately detected disturbances in pulmonary gas exchanges with a very high sensibility and specificity (predictive values of a negative or positive test ∼95%).
Jeffrey M Pearl - One of the best experts on this subject based on the ideXlab platform.
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calpain inhibition decreases endothelin 1 levels and pulmonary hypertension after cardiopulmonary bypass with deep hypothermic circulatory arrest
Critical Care Medicine, 2005Co-Authors: Jodie Y Duffy, Steven M Schwartz, Jefferson M Lyons, Jason H Bell, Connie J Wagner, Basilia Zingarelli, Jeffrey M PearlAbstract:OBJECTIVE Cardiopulmonary bypass in infants and children can result in cardiopulmonary dysfunction through ischemia and reperfusion injury. Pulmonary hypertension and injury are particularly common and morbid complications of neonatal cardiac surgery. Inhibition of calpain, a cysteine protease, has been shown to inhibit reperfusion injury in adult organ systems. The hypothesis is that calpain inhibition can alleviate the cardiopulmonary dysfunction seen in immature animals following ischemia and reperfusion with cardiopulmonary bypass. DESIGN Animal case study. SETTING Medical laboratory. SUBJECTS Crossbred piglets (5-7 kg). INTERVENTIONS Piglets were cooled with cardiopulmonary bypass to 18 degrees C followed by deep hypothermic circulatory arrest for 120 mins. Animals were rewarmed to 38 degrees C on cardiopulmonary bypass and maintained for 120 mins. Six animals were administered calpain inhibitor (Z-Leu-Leu-Tyr-fluoromethyl ketone; 1 mg/kg, intravenously) 60 mins before cardiopulmonary bypass. Nine animals were administered saline as a control. Plasma endothelin-1, pulmonary and hemodynamic function, and markers of leukocyte activity and injury were measured. MEASUREMENTS AND MAIN RESULTS Calpain inhibition prevented the increased pulmonary vascular resistance seen in control animals (95.7 +/- 39.4 vs. 325.3 +/- 83.6 dyne.sec/cm, respectively, 120 mins after cardiopulmonary bypass and deep hypothermic circulatory arrest, p = .05). The attenuation in pulmonary vascular resistance was associated with a blunted plasma endothelin-1 response (4.91 +/- 1.72 pg/mL with calpain inhibition vs. 10.66 +/- 6.21 pg/mL in controls, p < .05). Pulmonary function after cardiopulmonary bypass was better maintained after calpain inhibition compared with controls: Po2/Fio2 ratio (507.2 +/- 46.5 vs. 344.7 +/- 140.5, respectively, p < .05) and Alveolar-Arterial Gradient (40.0 +/- 17.2 vs. 128.1 +/- 85.2 mm Hg, respectively, p < .05). Systemic oxygen delivery was higher after calpain inhibition compared with controls (759 +/- 171 vs. 277 +/- 46 mL/min, respectively, p < .001). In addition, endothelial nitric oxide synthase activity in lung tissue was maintained with calpain inhibition. CONCLUSIONS The reduction in plasma endothelin-1 and maintenance of lung endothelial nitric oxide levels after cardiopulmonary bypass and deep hypothermic circulatory arrest with calpain inhibition were associated with reduced pulmonary vascular resistance. Improved gas exchange and higher systemic oxygen delivery suggest that calpain inhibition may be advantageous for reducing postoperative cardiopulmonary dysfunction commonly associated with pediatric heart surgery and cardiopulmonary bypass.
Santhosh M Baby - One of the best experts on this subject based on the ideXlab platform.
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glutathione ethyl ester reverses the deleterious effects of fentanyl on ventilation and arterial blood gas chemistry while prolonging fentanyl induced analgesia
Scientific Reports, 2021Co-Authors: Michael W Jenkins, Faiza Khalid, Santhosh M Baby, Walter J May, Alex P Young, James N Bates, Feixiong Cheng, James M Seckler, Stephen J LewisAbstract:There is an urgent need to develop novel compounds that prevent the deleterious effects of opioids such as fentanyl on minute ventilation while, if possible, preserving the analgesic actions of the opioids. We report that L-glutathione ethyl ester (GSHee) may be such a novel compound. In this study, we measured tail flick latency (TFL), arterial blood gas (ABG) chemistry, Alveolar-Arterial Gradient, and ventilatory parameters by whole body plethysmography to determine the responses elicited by bolus injections of fentanyl (75 μg/kg, IV) in male adult Sprague-Dawley rats that had received a bolus injection of GSHee (100 μmol/kg, IV) 15 min previously. GSHee given alone had minimal effects on TFL, ABG chemistry and A-a Gradient whereas it elicited changes in some ventilatory parameters such as an increase in breathing frequency. In vehicle-treated rats, fentanyl elicited (1) an increase in TFL, (2) decreases in pH, pO2 and sO2 and increases in pCO2 (all indicative of ventilatory depression), (3) an increase in Alveolar-Arterial Gradient (indicative of a mismatch in ventilation-perfusion in the lungs), and (4) changes in ventilatory parameters such as a reduction in tidal volume, that were indicative of pronounced ventilatory depression. In GSHee-pretreated rats, fentanyl elicited a more prolonged analgesia, relatively minor changes in ABG chemistry and Alveolar-Arterial Gradient, and a substantially milder depression of ventilation. GSHee may represent an effective member of a novel class of thiolester drugs that are able to prevent the ventilatory depressant effects elicited by powerful opioids such as fentanyl and their deleterious effects on gas-exchange in the lungs without compromising opioid analgesia.
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Tempol Reverses the Negative Effects of Morphine on Arterial Blood-Gas Chemistry and Tissue Oxygen Saturation in Freely-Moving Rats
'Frontiers Media SA', 2021Co-Authors: Santhosh M Baby, Feixiong Cheng, Stephen J Lewis, Joseph F. Discala, Ryan Gruber, Paulina M. Getsy, Derek S. DamronAbstract:We have reported that pretreatment with the clinically approved superoxide dismutase mimetic, Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl), blunts the cardiorespiratory depressant responses elicited by a subsequent injection of fentanyl, in halothane-anesthetized rats. The objective of the present study was to determine whether Tempol is able to reverse the effects of morphine on arterial blood-gas (ABG) chemistry in freely-moving Sprague Dawley rats. The intravenous injection of morphine (10 mg/kg) elicited substantial decreases in pH, pO2 and sO2 that were accompanied by substantial increases in pCO2 and Alveolar-Arterial Gradient, which results in diminished gas-exchange within the lungs. Intravenous injection of a 60 mg/kg dose of Tempol 15 min after the injection of morphine caused minor improvements in pO2 and pCO2 but not in other ABG parameters. In contrast, the 100 mg/kg dose of Tempol caused an immediate and sustained reversal of the negative effects of morphine on arterial blood pH, pCO2, pO2, sO2 and Alveolar-Arterial Gradient. In other rats, we used pulse oximetry to determine that the 100 mg/kg dose of Tempol, but not the 60 mg/kg dose elicited a rapid and sustained reversal of the negative effects of morphine (10 mg/kg, IV) on tissue O2 saturation (SpO2). The injection of morphine caused a relatively minor fall in mean arterial blood pressure that was somewhat exacerbated by Tempol. These findings demonstrate that Tempol can reverse the negative effects of morphine on ABG chemistry in freely-moving rats paving the way of structure-activity and mechanisms of action studies with the host of Tempol analogues that are commercially available
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role of central and peripheral opiate receptors in the effects of fentanyl on analgesia ventilation and arterial blood gas chemistry in conscious rats
Respiratory Physiology & Neurobiology, 2014Co-Authors: Fraser Henderson, Santhosh M Baby, Walter J May, Alex P Young, Joseph F. Discala, Ryan B Gruber, Veljko Puskovic, Stephen J LewisAbstract:This study determined the effects of the peripherally restricted μ-opiate receptor (μ-OR) antagonist, naloxone methiodide (NLXmi) on fentanyl (25μg/kg, i.v.)-induced changes in (1) analgesia, (2) arterial blood gas chemistry (ABG) and Alveolar-Arterial Gradient (A-a Gradient), and (3) ventilatory parameters, in conscious rats. The fentanyl-induced increase in analgesia was minimally affected by a 1.5mg/kg of NLXmi but was attenuated by a 5.0mg/kg dose. Fentanyl decreased arterial blood pH, pO2 and sO2 and increased pCO2 and A-a Gradient. These responses were markedly diminished in NLXmi (1.5mg/kg)-pretreated rats. Fentanyl caused ventilatory depression (e.g., decreases in tidal volume and peak inspiratory flow). Pretreatment with NLXmi (1.5mg/kg, i.v.) antagonized the fentanyl decrease in tidal volume but minimally affected the other responses. These findings suggest that (1) the analgesia and ventilatory depression caused by fentanyl involve peripheral μ-ORs and (2) NLXmi prevents the fentanyl effects on ABG by blocking the negative actions of the opioid on tidal volume and A-a Gradient.