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Biomedical subjects

B P Kavanagh

Publications and source records attributed to B P Kavanagh.

At least 19 recordsLinked to original sources
PubMed2006

Hypercapnia: permissive and therapeutic.

Hypercapnia has traditionally been avoided in the quest to keep parameters normal. Recent understanding of the role of excessive tidal stretch has prompted clinicians to avoid high tidal volumes or plateau pressures, and the resulting permissive hypercapnia has been increasingly tolerated by clinicians. Newer data point to the potential for elevated CO2 to be protective, and in some experimental situations, to cause harm. The protective effects of so called therapeutic hypercapnia' remain experimental at present, but promising laboratory studies suggest potential roles for the eventual selective application at the bedside.

Animals↗
PubMed2000

Buffering hypercapnic acidosis worsens acute lung injury.

Hypoventilation, associated with hypercapnic acidosis (HCA), may improve outcome in acute lung injury (ALI). We have recently reported that HCA per se protects against ALI. The current study explored whether the mechanisms of protection with HCA were related to acidosis versus hypercapnia. Because CO(2) equilibrates rapidly across cell membranes, we hypothesized that (1) HCA would afford greater protection than metabolic acidosis. We further hypothesized that (2) buffering HCA would attenuate its protection. Forty isolated perfused rabbit lung preparations were randomized to: control (normal pH, PCO(2)); HCA; metabolic acidosis; or buffered hypercapnia. After ischemia-reperfusion (IR) injury wet:dry ratio was greatest with control and buffered hypercapnia, and rank order of capillary filtration coefficient was: control approximately buffered hypercapnia > metabolic acidosis > HCA. Isogravimetric pressure reduction was greatest with buffered hypercapnia. Despite comparable injury, pulmonary artery pressure elevation was less with buffered hypercapnia versus control. In vitro xanthine oxidase (XO) activity depended on pH, not PCO(2). We conclude that: (1) HCA and metabolic acidosis are protective, but HCA is the most protective; (2) buffering HCA attenuates its protection; (3) buffering HCA causes pulmonary vasodilation; (4) because metabolic acidosis and HCA similarly inhibit in vitro XO activity, the differential effects cannot be explained solely on the basis of extracellular XO activity.

Acidosis, Respiratory↗
PubMed2000

Adverse ventilatory strategy causes pulmonary-to-systemic translocation of endotoxin.

Accumulating evidence strongly suggests that ventilatory strategy has an important impact on development of lung injury and patient outcome. Adverse ventilatory strategies have been shown to cause release of pulmonary-derived cytokines and may permit bacterial translocation from the lung to the systemic circulation. Because endotoxin is a potent and clinically important stimulant of cytokine-mediated systemic inflammatory responses that can lead to multiorgan failure, we investigated the effects of ventilatory strategy on lung-to-systemic translocation of endotoxin. We studied the effects of protective (tidal volume [VT] 5 ml. kg(-)(1), positive end-expiratory pressure [PEEP] 10 to 12.5 cm H(2)O) versus nonprotective (VT 12 ml. kg(-)(1), PEEP zero) ventilatory strategy on translocation of endotracheally instilled endotoxin. Anesthetized New Zealand White rabbits were subjected to saline lung lavage, and 32 were randomized to one of four groups: PS (protective ventilation + instilled saline); PE (protective ventilation + instilled endotoxin); NS (nonprotective ventilation + instilled saline); NE (nonprotective ventilation + instilled endotoxin), and ventilated for 3 h. Plasma endotoxin levels increased significantly in the NE group, and remained low and unchanged in the other groups. Peak levels of plasma tumor necrosis factor-alpha (TNF-alpha) were higher in NE versus other groups. Pa(O(2)) and mean arterial pressure (Pa) were lowest, and requirement for pressor and bicarbonate support greatest, in the NE group. Finally, plasma endotoxin levels were significantly greater in eventual nonsurvivors than survivors. These data provide convincing evidence for pulmonary translocation of lung-derived endotoxin. This translocation depends on ventilatory strategy, and suggests a pathophysiologic link between ventilatory strategy and outcome.

Animals↗
PubMed2000

Injurious effects of hypocapnic alkalosis in the isolated lung.

Mechanical ventilation can worsen morbidity and mortality by causing ventilator-associated lung injury, especially where adverse ventilatory strategies are employed. Adverse strategies commonly involve hyperventilation, which frequently results in hypocapnia. Although hypocapnia is associated with significant lung alterations (e.g., bronchospasm, airway edema), the effects on alveolar-capillary permeability are unknown. We investigated whether hypocapnia could cause lung injury independent of altering ventilatory strategy. We hypothesized that hypocapnia would cause lung injury during prolonged ventilation, and would worsen injury following ischemia-reperfusion. We utilized the isolated buffer-perfused rabbit lung model. Pilot studies assessed a range of levels of hypocapnic alkalosis. Experimental preparations were randomized to control groups (FI(CO(2)) = 0.06) or groups with hypocapnia (FI(CO(2)) = 0.01). Following prolonged ventilation, pulmonary artery pressure, airway pressure, and lung weight were unchanged in the control group but were elevated in the group with hypocapnia; elevation in microvascular permeability was greater in the hypocapnia versus control groups. Injury following ischemia-reperfusion was significantly worse in the hypocapnia versus control groups. In a preliminary series, degree of lung injury was proportional to the degree of hypocapnic alkalosis. We conclude that in the current model (1) hypocapnic alkalosis is directly injurious to the lung and (2) hypocapnic alkalosis potentiates ischemia-reperfusion-induced acute lung injury.

Alkalosis↗
PubMed2000

Therapeutic hypercapnia reduces pulmonary and systemic injury following in vivo lung reperfusion.

Permissive hypercapnia, involving tolerance to elevated Pa(CO(2)), is associated with reduced acute lung injury (ALI), thought to result from reduced mechanical stretch, and improved outcome in ARDS. However, deliberately elevating inspired CO(2) concentration alone (therapeutic hypercapnia, TH) protects against ALI in ex vivo models. We investigated whether TH would protect against ALI in an in vivo model of lung ischemia-reperfusion (IR). Anesthetized open chest rabbits were ventilated (standard eucapnic settings), and were randomized to TH (FI(CO(2)) 0.12) versus control (FI(CO(2)) 0.00). Pa(CO(2)) and arterial pH values achieved in the TH versus CON groups were 101 +/- 3 versus 44.4 +/- 4 mm Hg and 7.10 +/- 0.03 versus 7.37 +/- 0.03, respectively. Following left lung ischemia and reperfusion, TH versus control was associated with preservation of lung mechanics, attenuation of protein leakage, reduction in pulmonary edema, and improved oxygenation. Indices of systemic protection included improved acid-base and lactate profile, in the absence of systemic hypoxemia. In the TH group, mean BALF TNF-alpha levels were 3.5% of CON levels (p < 0.01), and mean 8-isoprostane levels were 30% of CON levels (p = 0.02). Western blot analysis demonstrated reduced lung tissue nitrotyrosine in TH, indicating attenuation of tissue nitration. Finally, preliminary data suggest that TH may attenuate apoptosis following lung IR. We conclude that in the current model TH is protective versus IR lung injury and mechanisms of protection include preservation of lung mechanics, attenuation of pulmonary inflammation, and reduction of free radical mediated injury. If these findings are confirmed in additional models, TH may become a candidate for clinical testing in critical care.

Animals↗
PubMed1999

Carbon dioxide and the critically ill--too little of a good thing?

Permissive hypercapnia (acceptance of raised concentrations of carbon dioxide in mechanically ventilated patients) may be associated with increased survival as a result of less ventilator-associated lung injury. Conversely, hypocapnia is associated with many acute illnesses (eg, asthma, systemic inflammatory response syndrome, pulmonary oedema), and is thought to reflect underlying hyperventilation. Accumulating clinical and basic scientific evidence points to an active role for carbon dioxide in organ injury, in which raised concentrations of carbon dioxide are protective, and low concentrations are injurious. We hypothesise that therapeutic hypercapnia might be tested in severely ill patients to see whether supplemental carbon dioxide could reduce the adverse effects of hypocapnia and promote the beneficial effects of hypercapnia. Such an approach could also expand our understanding of the pathogenesis of disorders in which hypocapnia is a constitutive element.

Acidosis↗
PubMed1999

Anemia, hypoxia and hypercapnia thresholds. Lessons from physiological limits in critically ill patients.

Physiological alterations occur in the critical care medicine and reflect illness. Rendering patients physiologic parameters in the range that is normal for the population is not necessarily good; it may be frankly harmful. We do not currently possess outcome-based tools that allow us to titrate physiological parameters and ensure improved outcome. It is highly unlikely that our practice will evolve to inducing anemia, hyperthermia, hypoxemia, hypercapnia and hypotension in our critically ill patients! However, evolving knowledge of the appropriate thresholds for these parameters in critically ill patients, in addition to greater understanding of the potential iatrogenic illness associated with parameter 'normalization', could lead to provision of enhanced patient care. In the coming years it is possible that we will redefine the 'normal' range for common clinical and laboratory values relating to the critically ill. We may switch to 'context sensitive' interpretation of parameters of illness, and manage critically ill patients accordingly.

Anemia↗
PubMed1999

Gas exchange and hemodynamics in experimental pleural effusion.

OBJECTIVE: To investigate the cardiorespiratory effects of graded bilateral pleural effusions in the anesthetized pig. DESIGN: Prospective, randomized, controlled, laboratory study. SETTING: Animal laboratory. SUBJECTS: Eleven male Yorkshire pigs. INTERVENTIONS: Animals were anesthetized using inhaled isoflurane. Orotracheal intubation was followed by mechanical ventilation. Bilateral chest tubes were inserted, and graded increasing pleural effusions were created using saline of 0, 20, 40, and 80 mL/kg, divided equally between each side. At each pleural volume, intravascular volume was randomly altered (by phlebotomy or transfusion of colloid) to normal (unchanged), low (decreased by 10 mL/kg), or high (increased by 10 mL/kg). MEASUREMENTS AND MAIN RESULTS: Hemodynamic parameters, intrapleural pressures, hemoglobin, and blood gases were measured. At the lowest volume of pleural fluid, PaO2 was reduced by approximately 50% vs. baseline, whereas systemic hemodynamics were unchanged. PaO2 was reduced in a dose-dependent fashion as pleural volume increased but was not affected by alterations in intravascular volume. Intrapulmonary shunt was increased both by intrapleural volume in a dose-dependent fashion and by increases in intravascular volume at high levels of pleural volume. Cardiac output and systemic mean arterial pressure increased with elevated intravascular volume but were not influenced by lower levels of intrapleural volume. Mean pulmonary arterial pressure, central venous pressure, and pulmonary artery occlusion pressure were increased by elevations in both intrapleural volume and intravascular volume. Intrapleural pressure and pulmonary vascular resistance were related to intrapleural volume only. CONCLUSIONS: Hypoxemia occurs as an early event in acute bilateral pleural effusions and precedes hemodynamic decompensation. Oxygenation is independent of intravascular filling pressures, but hemodynamics are preserved with elevated filling pressures. Clinical studies should be undertaken to examine the risks/benefits of careful removal of pleural fluid in patients with pleural effusions, when oxygenation is impaired during mechanical ventilation.

Anesthesia, Inhalation↗
PubMed1999

A quantitative assessment of how Canadian intensivists believe they utilize oxygen in the intensive care unit.

OBJECTIVES: To investigate attitudes and practices regarding oxygen therapy in intensive care units (ICUs) and to devise quantitative descriptive indices. SETTING: Canadian university-affiliated adult ICUs. PARTICIPANTS: Fifty-two medical directors of ICUs in 48 institutions. INTERVENTION: Structured postal questionnaire returned by 48 participants. MEASUREMENTS AND MAIN RESULTS: Attitudes, beliefs, and stated practices relating to oxygen use in ICUs were determined. Novel descriptors S-50min (minutes of oxygen saturation [Sao2] acceptable to >50% of respondents), F-50max (maximum F(IO)2 above which <50% of respondents would increase F(IO)2), and F-50min (minimum F(IO)2 below which <50% of respondents would decrease F(IO)2) were determined. All respondents believed that oxygen toxicity was a concern. Twenty-nine percent of respondents indicated that they did not always assess tissue oxygenation in critical cases. A stepwise reduction in acceptance of progressive desaturation and increasing duration of hypoxemia was found. Presented with a stable patient with Sao2 of 98%, the maximum level of F(IO)2 above which respondents stated that they would not increase the F(IO)2 was 0.41+/-0.17 (mean +/- SD). For stable patients with Sao2 of 85%, the minimum F(IO)2 below which respondents would not reduce F(IO)2 was 0.59+/-0.23 (mean +/- SD). F-50max was 0.8 vs. 0.5 for Sao2 of 80%-85% vs. 85%-90%, respectively; F-50min was 0.6 vs. 0.21 for Sao2 of 90%-95% vs. 95%-100%, respectively. CONCLUSIONS: Considerable variation exists in the attitudes, beliefs, and stated practices relating to the management of oxygen therapy in the ICU. These data are amenable to quantitative description and illustrate the necessity for documentation of actual practice and development of support systems for decision-making in this and similar areas.

Adult↗
PubMed1999

Inhibition of endogenous nitric oxide synthesis potentiates the effects of sodium nitroprusside but not of adenosine in experimental pulmonary hypertension.

This study examined the systemic and pulmonary vasodilator effects of sodium nitroprusside (SNP) and adenosine during experimental pulmonary hypertension with and without inhibition of endogenous NO synthesis. Male New Zealand White rabbits were anesthetized and mechanically ventilated. The NO synthesis inhibitor NG-nitro-L-arginine methyl ester (L-NAME) was administered to 15 of the 28 rabbits. Pulmonary hypertension was then produced in all rabbits by U46619, a thromboxane A2 mimetic. SNP was infused in 14 rabbits (7 L-NAME, 7 control) at doses of 0.5-20 microg/kg/min; adenosine was infused in the other 14 rabbits (8 L- NAME, 6 control) at doses of 12.5-300 microg/kg/min. The U46619 dose required to produce pulmonary hypertension was significantly lower in the L-NAME group. SNP dose-dependently decreased pulmonary (Ppa) and systemic (Psa) artery pressures and systemic vascular resistance (SVR). Both Ppa and Psa were decreased more with SNP in the L-NAME than in the no L-NAME group. The SNP ED50 for the decrease in PVR was almost threefold lower in the L-NAME group. Adenosine dose-dependently decreased Ppa, Psa, PVR and SVR. The adenosine ED50 for the decreases in PVR and SVR were similar in the L-NAME group and the control group. We conclude that inhibition of endogenous NO synthesis shifts the dose-response curves for both the pulmonary and systemic vasodilator effects to the left for the nitrovasodilator SNP but not for the non-nitrovasodilator adenosine.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1999

Inhaled nitric oxide potentiates actions of adenosine but not of sodium nitroprusside in experimental pulmonary hypertension.

Inhaled nitric oxide (NO), a selective pulmonary vasodilator, increases intracellular cyclic guanosine monophosphate. In contrast, adenosine, another selective pulmonary vasodilator, increases intracellular cyclic adenosine monophosphate. There has been only limited study on effects of inhaled NO combined with other pulmonary vasodilators. The current study examined the hypothesis that inhaled NO would potentiate in vivo pulmonary vasodilator effects of adenosine, but not those of sodium nitroprusside (SNP). Like inhaled NO, SNP acts via cyclic guanosine monophosphate. Rabbits were anesthetized and mechanically ventilated. The NO synthesis inhibitor NG-nitro-L-arginine methyl ester was administered. U46619, a thromboxane A2 mimetic, was infused to produce pulmonary hypertension. Rabbits then received either SNP at doses of 0.5, 1, 2, 4, 8, 16, and 32 microg/kg/min or adenosine at doses of 12.5, 25, 50, 100, 150, and 300 microg/kg/min. Hemodynamic measurements were obtained with or without inhaled NO (40 ppm) at each dose of SNP or adenosine. During U46619-induced pulmonary hypertension, inhaled NO decreased pulmonary artery pressure and pulmonary vascular resistance. Adenosine and SNP produced dose-related decreases in pulmonary artery pressure and pulmonary vascular resistance and increases in cardiac output. Inhaled NO decreased pulmonary artery pressure and pulmonary vascular resistance at all doses of adenosine, but had no significant pulmonary vasodilator effects at doses of SNP >0.5 microg/kg/min. We conclude that inhaled NO does not produce additional pulmonary vasodilation over that achieved at higher doses of SNP, but does produce additional vasodilation when combined with a vasodilator having different mechanisms of action. Since both inhaled NO and adenosine produce selective pulmonary vasodilation, such combination therapy may be effective in patients with pulmonary hypertension.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1998

Epidural bupivacaine-morphine analgesia versus patient-controlled analgesia following abdominal aortic surgery: analgesic, respiratory, and myocardial effects.

BACKGROUND: The efficacy and effects of epidural analgesia compared with patient-controlled analgesia (PCA) have not been reported in patients undergoing major vascular surgery. We compared the effects of epidural bupivacaine-morphine with those of intravenous PCA morphine after elective infrarenal aortic surgery. METHODS: Forty patients classified as American Society of Anesthesiologists physical status 2 or 3 received general anesthesia plus postoperative PCA using morphine sulfate (group PCA; n = 21) or general anesthesia plus perioperative epidural morphine-bupivacaine (group EPI; n = 19) during a period of 48 h. During operation, EPI patients received 0.05 mg/kg epidural morphine and 5 ml 0.25% bupivacaine followed by an infusion of 0.125% bupivacaine with 0.1% morphine (0.1 mg/ ml); group PCA received 0.1 mg/kg intravenous morphine sulfate. Continuous electrocardiographic monitoring (V4 and V5 leads) was performed from the night before surgery until 48 h afterward. Respiratory inductive plethysmographic data were recorded after tracheal extubation. Visual analog pain scores at rest and after movement were performed every 4 h after extubation. RESULTS: Nurse-administered intravenous morphine and time to tracheal extubation were less in group EPI, as were visual analog pain scores at rest and after movement from 20 to 48 h. Complications and the duration of intensive care unit and hospital stay were comparable. There was a similar, low incidence of postoperative apneas, slow respiratory rates, desaturation, and S-T segment depression. CONCLUSIONS: Epidural morphine-bupivacaine is associated with reduced early postoperative intravenous opioid requirements, more rapid tracheal extubation, and superior analgesia after abdominal aortic surgery, with comparable respiratory effects.

Aged↗
PubMed1998

Hypercapnic acidosis may attenuate acute lung injury by inhibition of endogenous xanthine oxidase.

Relative hypoventilation, involving passively-or "permissively"-generated hypercapnic acidosis (HCA), may improve outcome by reducing ventilator-induced lung injury. However, the effects of HCA per se on pulmonary microvascular permeability (Kf,c) in noninjured or injured lungs are unknown. We investigated the effects of HCA in the isolated buffer-perfused rabbit lung, under conditions of: (1) no injury; (2) injury induced by warm ischemia-reperfusion; and (3) injury induced by addition of purine and xanthine oxidase. HCA (fraction of inspired carbon dioxide [FICO2] 12%, 25% versus 5%) had no adverse microvascular effects in uninjured lungs, and prevented (FICO2 25% versus 5%) the increase in Kf,c following warm ischemia-reperfusion. HCA (FICO2 25% versus 5%) reduced the elevation in Kf,c, capillary (Pcap), and pulmonary artery (Ppa) pressures in lung injury induced by exogenous purine/xanthine oxidase; inhibition of endogenous NO synthase in the presence of 25% FICO2 had no effect on Kf,c, but attenuated the reduction of Pcap and Ppa. HCA inhibited the in vitro generation of uric acid from addition of xanthine oxidase to purine. We conclude that in the current models, HCA is not harmful in uninjured lungs, and attenuates injury in free-radical-mediated lung injury, possibly via inhibition of endogenous xanthine oxidase.

Acidosis↗
PubMed1997

Comparison of lorazepam alone vs lorazepam, morphine, and perphenazine for cardiac premedication.

PURPOSE: To compare the effects of two premedication regimens on cardiorespiratory variables, sedation, and anxiety in patients scheduled for coronary artery bypass graft (CABG) surgery. METHODS: This was a prospective randomized, double-blind clinical trial. Sixty-eight patients were monitored for 1.5 hr before and 2.0 hr after premedication with lorazepam (0.03 mg.kg-1 sl), morphine (0.15 mg.kg-1 im), and perphenazine (0.05 mg.kg-1 im) [Group 1], or with lorazepam (0.03 mg.kg-1 sl) and saline (1.5 ml im) [Group 2]. All were continuously monitored with a 12-lead ECG ST monitors, respiratory inductive plethysmography (RIP), digital pulse oximetry, intra-arterial blood pressure, and arterial blood gas analysis. Sedation and anxiety scores were also recorded. RESULTS: The incidence and duration of myocardial ischaemia was low and similar in Groups 1 and 2. Patients in Group 1, but not in Group 2, had a greater number of events (P < 0.04) and duration (P < 0.02) of O2 desaturation; higher PaCO2 (P < 0.001), and more haemodynamic events (P < 0.006) after premedication when compared with baseline. There was no difference in RIP or ECG variables between the two groups. Following premedication, both groups reported reduced anxiety scores and elevated sedation scores (P < 0.01), with sedation greater in Group 1 than in Group 2 (P < 0.01). CONCLUSION: In CABG patients, premedication with lorazepam provides adequate anxiolysis and sedation, and the addition of morphine and perphenazine results in elevated PaCO2, arterial haemoglobin desaturation, and potentially adverse haemodynamic changes.

Aged↗
PubMed1997

Nitroglycerin does not alter pulmonary vascular permeability in isolated rabbit lungs.

Nitroglycerin (NTG) produces vasodilation by releasing nitric oxide (NO) at the cellular level. Other studies have suggested that NO may directly alter vascular permeability and may alter the development of tissue injury. We therefore examined the effects of NTG on vascular permeability in the buffer-perfused rabbit lung under normal conditions and during lung injury. Vascular permeability was assessed by measurement of the capillary filtration coefficient (Kf,c). In normal lungs, NTG did not alter Kf,c or the rate of weight gain. Oxidant lung injury was produced by the addition of purine and xanthine oxidase and resulted in increased Kf,c and increased weight gain. However, NTG did not alter these effects of oxidant lung injury. We conclude that NTG does not alter pulmonary vascular permeability in either normal or oxidant-injured lungs.

Animals↗