Heart transplantation (HTx) from brainstem dead (BSD) donors is the gold-standard therapy for sev... more Heart transplantation (HTx) from brainstem dead (BSD) donors is the gold-standard therapy for severe/end-stage cardiac disease, but is limited by a global donor heart shortage. Consequently, innovative solutions to increase donor heart availability and utilisation are rapidly expanding. Clinically relevant preclinical models are essential for evaluating interventions for human translation, yet few exist that accurately mimic all key HTx components, incorporating injuries beginning in the donor, through to the recipient. To enable future assessment of novel perfusion technologies in our research program, we thus aimed to develop a clinically relevant sheep model of HTx following 24 h of donor BSD. BSD donors (vs. sham neurological injury, 4/group) were hemodynamically supported and monitored for 24 h, followed by heart preservation with cold static storage. Bicaval orthotopic HTx was performed in matched recipients, who were weaned from cardiopulmonary bypass (CPB), and monitored for...
Novel 24-h ovine model of brain death to study the profile of the endothelin axis during cardiopu... more Novel 24-h ovine model of brain death to study the profile of the endothelin axis during cardiopulmonary injury
Introduction: Packed red blood cell (PRBC) transfusion in septic shock is generally reserved as a... more Introduction: Packed red blood cell (PRBC) transfusion in septic shock is generally reserved as a last resort hemodynamic resuscitative measure or for haemoglobin less than 7.0 g/dL. Ex-vivo preservation and storage predispose PRBCs to biochemical / mechanical changes whose impact in a septic host is unknown. This randomised pre-clinical trial specifically evaluates select markers of cardiovascular stress in an ovine model of endotoxemic shock receiving either fresh or stored blood. Methods: Twenty six anesthetised and mechanically ventilated merino ewes were randomly divided into endotoxemic shock (n = 16) or healthy (n = 10) groups. Endotoxemic shock was induced over 4 hours by infusing an escalating dose (total 11.25 mcg / kg) of lipopolysaccharide, LPS ( E.coli 055:B5 ). During the last hour of LPS infusion, 10 mls / kg of either fresh, ≤ 5 days (n = 8) or stored, ≥ 30 days (n = 8) ovine packed PRBCs were administered. Healthy ewes received either fresh, ≤ 5 days (n = 5) or stor...
Background / Purpose: Extracoproreal membrane oxygenation (ECMO) is a life saving supportive tool... more Background / Purpose: Extracoproreal membrane oxygenation (ECMO) is a life saving supportive tool for patients with severe cardiorespiratory failure. However ECMO has a significant impact on pharamcokinetics(PK) of vital drugs that are intended to reverse the pathology which will then result in liberation from ECMO. This mechanistic study aimed to relatively quantify the independent effects of the ECMO device on ciporfloxacin PK.Main conclusion: Critical illness has a major influence on ciprofloxacin PK during ECMO support and the independent effects of ECMO device may not be significant.; ;
BLOCKADE OF COMPLEMENT MEDIATED INFLAMMATION MAY IMPROVE LUNG TRANSPLANTATION OUTCOMES Introducti... more BLOCKADE OF COMPLEMENT MEDIATED INFLAMMATION MAY IMPROVE LUNG TRANSPLANTATION OUTCOMES Introduction: Brain death damages the Lungs more severely than any other organ. The lungs, which may have been perfect during life, may not be suitable following brain death. Previous work has shown that when donors are treated specially with a complement antagonist, it improves the donor lung function and results in better outcomes for the transplant recipient. Objectives: The aim of this study was to determine if complement factor 5a antagonist (C5a) also known as PMX53 can reduce inflammation in donor lungs and lung recipients, thereby improving lung transplants.
ABSTRACT Background / Purpose: Recent studies have highlighted the harmful effects of excessive f... more ABSTRACT Background / Purpose: Recent studies have highlighted the harmful effects of excessive fluid resuscitation and blood transfusion in patients with sepsis. However, the mechanisms behind this remains unclear.The aim of this study is to investigate the effects of fluid and blood (fresh vs stored) resuscitation on tissue blood flow (tflow), oxygen tension (tO 2 ) and metabolism during ovine endotoxaemia. Main conclusion: This validated ovine model provides preliminary insights into the tissue responses to endotoxaemia and resuscitation and can be an useful platform for sepsis research.
International Journal of Antimicrobial Agents, 2020
BACKGROUND Ventilator associated pneumonia occurs commonly and nebulized antibiotics are being us... more BACKGROUND Ventilator associated pneumonia occurs commonly and nebulized antibiotics are being used for its treatment. Although adequate pulmonary biodistribution is important for antibiotic effect, there is a lack of data for both intravenous (i.v.) or nebulized antibiotic administration during mechanical ventilation. OBJECTIVE To describe the comparative pulmonary regional distribution of i.v. and nebulized technetium-99m labelled tobramycin (99mTc-tobramycin) 400 mg in a mechanically ventilated ovine model. METHODS The study was performed in a mechanically ventilated ovine model. 99mTc-tobramycin 400 mg was obtained using a radiolabelling process. Computed tomography (CT) was performed. Five sheep each were given 99mTc-tobramycin 400 mg via i.v. or nebulized route. Planar images- dorsal, ventral and both lateral- were obtained using a gamma camera. Blood samples were obtained every 15 minutes for one hour (4 time points) and, lung, liver, both kidney, and urine samples were obtained post mortem. RESULTS Ten sheep were anesthetized and mechanically ventilated. Whole lung deposition of nebulized 99mTc-tobramycin 400 mg was significantly lower than with i.v. (8.8 vs 57.1%, p<0.001). For both administration routes, upper lung zones had a significantly lower deposition than the rest of the lungs. Dorsal deposition was significantly higher with nebulized 99mTc-tobramycin 400 mg compared to i.v. (68.9 vs 58.9%, p=0.003). The lung concentrations of 99mTc-tobramycin were higher with i.v. compared to nebulized. There were significantly higher concentrations of 99mTc-tobramycin in blood, liver and urine with i.v. administration compared to nebulized. CONCLUSIONS Nebulization resulted in lower whole and regional lung deposition of 99mTc-tobramycin and also appears associated with low blood and extra-pulmonary organ concentrations.
Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New... more Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Nebulized antibiotics may be used to treat ventilator-associated pneumonia. In previous pharmacokinetic studies, lung interstitial space fluid concentrations have never been reported. The aim of the study was to compare intravenous and nebulized tobramycin concentrations in the lung interstitial space fluid, epithelial lining fluid, and plasma in mechanically ventilated sheep with healthy lungs. Methods Ten anesthetized and mechanically ventilated healthy ewes underwent surgical insertion of microdialysis catheters in upper and lower lobes of both lungs and the jugular vein. Five ewes were given intravenous tobramycin 400 mg, and five were given nebulized tobramycin 400 mg. Microdialysis samples were collected every 20 min for 8 h. Bronchoalveolar lavage was performed at 1 and 6 h. Results The peak lung interstitial space fluid concentrations were lower with intravenous tobra...
Background: Sepsis is a multi-system syndrome that remains the leading cause of mortality and cri... more Background: Sepsis is a multi-system syndrome that remains the leading cause of mortality and critical illness worldwide, with hemodynamic support being one of the cornerstones of the acute management of sepsis. We used an ovine model of endotoxemic shock to determine if 0.9% saline resuscitation contributes to lung inflammation and injury in acute respiratory distress syndrome, which is a common complication of sepsis, and investigated the potential role of matrix metalloproteinases in this process. Methods: Endotoxemic shock was induced in sheep by administration of an escalating dose of lipopolysaccharide, after which they subsequently received either no fluid bolus resuscitation or a 0.9% saline bolus. Lung tissue, bronchoalveolar fluid (BAL) and plasma were analysed by real-time PCR, ELISA, flow cytometry and immunohistochemical staining to assess inflammatory cells, cytokines, hyaluronan and matrix metalloproteinases. Results: Endotoxemia was associated with decreased serum albumin and total protein levels, with activated neutrophils, while the glycocalyx glycosaminoglycan hyaluronan was significantly increased in BAL. Quantitative real-time PCR studies showed higher expression of IL-6 and IL-8 with saline resuscitation but no difference in matrix metalloproteinase expression. BAL and tissue homogenate levels of IL-6, IL-8 and IL-1β were elevated. Conclusions: This data shows that the inflammatory response is enhanced when a host with endotoxemia is resuscitated with saline, with a comparatively higher release of inflammatory cytokines and endothelial/glycocalyx damage, but no change in matrix metalloproteinase levels.
Background: Cerebral regional microcirculation is altered following severe head injury. In additi... more Background: Cerebral regional microcirculation is altered following severe head injury. In addition to tissue disruption, partial pressure of tissue oxygenation is impaired due to an increase in the oxygen tissue gradient. The heterogenic distribution of cerebral microcirculation is multifactorial, and acute anemia challenges further the delivery of oxygen to tissues. Currently, a restrictive transfusion threshold is globally applied; however, it is unclear how anemia modifies regional cerebral microcirculation; hence, it is unclear if by aiming to a global endpoint, specific anatomical regions undergo ischemia. This study aims to quantify the temporal changes in cerebral microcirculation after severe head injury, under the effect of anemia and transfusion. It also aims to assess its effects specifically at the ischemic penumbra compared to contralateral regions and its interactions with axonal integrity in real time. Twelve ovine models were subjected to a severe contusion and acceleration-deceleration injury. Normovolemic anemia to a restrictive threshold was maintained after injury, followed by autologous transfusion. Direct quantification of cerebral microcirculation used cytometric count of color-coded microspheres. Axonal injury was assessed using amyloid precursor protein staining. Results: A mixed-effect regression model from pre-transfusion to post-transfusion times with a random intercept for each sheep was used. Cerebral microcirculation amongst subjects with normal intracranial pressure was maintained from baseline and increased further after transfusion. Subjects with high intracranial pressure had a consistent reduction of their microcirculation to ischemic thresholds (20-30 ml/100 g/min) without an improvement after transfusion. Cerebral PtiO 2 was reduced when exposed to anemia but increased in a 9.6-fold with transfusion 95% CI 5.6 to 13.6 (p value < 0.001). Conclusions: After severe head injury, the exposure to normovolemic anemia to a restrictive transfusion threshold, leads to a consistent reduction on cerebral microcirculation below ischemic thresholds, independent of cerebral perfusion pressure. Amongst subjects with raised intracranial pressure, microcirculation does not improve after transfusion. Cerebral oxymetry is impaired during anemia with a statistically significant increase after transfusion. Current transfusion practices in neurocritical care are based on a rigid hemoglobin threshold, a view that excludes cerebral metabolic demands and specific needs. An RCT exploring these concepts is warranted.
Intensive care medicine experimental, Jan 11, 2018
Nebulised antibiotics are frequently used for the prevention or treatment of ventilator-associate... more Nebulised antibiotics are frequently used for the prevention or treatment of ventilator-associated pneumonia. Many factors may influence pulmonary drug concentrations with inaccurate dosing schedules potentially leading to therapeutic failure and/or the emergence of antibiotic resistance. We describe a research pathway for studying the pharmacokinetics of a nebulised antibiotic during mechanical ventilation using in vitro methods and ovine models, using tobramycin as the study antibiotic. In vitro studies using a laser diffractometer and a bacterial-viral filter were used to measure the effect of the type and size of tracheal tubes and antibiotic concentration on the particle size distribution of the tobramycin 400 mg (4 ml; 100 mg/ml) and 160 mg (4 ml, 40 mg/ml) aerosol and nebulised mass delivered. To compare the regional drug distribution in the lung of two routes (intravenous and nebulised) of drug administration of tobramycin 400 mg, technetium-99m-labelled tobramycin 400 mg wi...
American journal of respiratory and critical care medicine, Jan 8, 2018
Fluid resuscitation is widely considered a life saving intervention in septic shock however recen... more Fluid resuscitation is widely considered a life saving intervention in septic shock however recent evidence has questioned both its safety and efficacy in sepsis. This study sought to compare fluid resuscitation with vasopressors with vasopressors alone in a hyperdynamic model of ovine endotoxemia. Endotoxemic shock was induced in sixteen sheep after which they received fluid resuscitation with 40mls/kg of 0.9% saline or commenced haemodynamic support with protocolized noradrenaline and vasopressin. Microdialysis catheters were inserted into the arterial circulation, heart, brain, kidney and liver to monitor local metabolism. Blood samples were recovered to measure serum inflammatory cytokines, creatinine, troponin, ANP, BNP and hyaluronan. All animals were monitored and supported for 12 hours after fluid resuscitation. After resuscitation animals receiving fluid resuscitation required significantly more noradrenaline to maintain the same mean arterial pressure in the subsequent 12 ...
Critical care and resuscitation : journal of the Australasian Academy of Critical Care Medicine, 2017
Significant interactions between drugs, extracorporeal membrane oxygenation (ECMO) circuits and c... more Significant interactions between drugs, extracorporeal membrane oxygenation (ECMO) circuits and critical illness may affect the pharmacokinetic properties of antibiotics in critically ill patients receiving ECMO. To describe the pharmacokinetic properties of ciprofloxacin during ECMO by integrating pre-clinical findings (ie, ex vivo and in vivo ovine models) to a critically ill patient. An ex vivo model of an ECMO circuit was used to describe ciprofloxacin concentration changes over 24 hours. An in vivo ovine model of ECMO was used to describe the population pharmacokinetic properties of ciprofloxacin in three different groups of sheep, and to investigate sources of pharmacokinetic variability. In the final phase, data from a 39-year-old critically ill man was used to validate the findings from the ovine pharmacokinetic model. In the ex vivo model of ECMO circuits, the median concentrations of ciprofloxacin at baseline and at 24 hours after ciprofloxacin infusion were similar. The t...
Heart transplantation (HTx) from brainstem dead (BSD) donors is the gold-standard therapy for sev... more Heart transplantation (HTx) from brainstem dead (BSD) donors is the gold-standard therapy for severe/end-stage cardiac disease, but is limited by a global donor heart shortage. Consequently, innovative solutions to increase donor heart availability and utilisation are rapidly expanding. Clinically relevant preclinical models are essential for evaluating interventions for human translation, yet few exist that accurately mimic all key HTx components, incorporating injuries beginning in the donor, through to the recipient. To enable future assessment of novel perfusion technologies in our research program, we thus aimed to develop a clinically relevant sheep model of HTx following 24 h of donor BSD. BSD donors (vs. sham neurological injury, 4/group) were hemodynamically supported and monitored for 24 h, followed by heart preservation with cold static storage. Bicaval orthotopic HTx was performed in matched recipients, who were weaned from cardiopulmonary bypass (CPB), and monitored for...
Novel 24-h ovine model of brain death to study the profile of the endothelin axis during cardiopu... more Novel 24-h ovine model of brain death to study the profile of the endothelin axis during cardiopulmonary injury
Introduction: Packed red blood cell (PRBC) transfusion in septic shock is generally reserved as a... more Introduction: Packed red blood cell (PRBC) transfusion in septic shock is generally reserved as a last resort hemodynamic resuscitative measure or for haemoglobin less than 7.0 g/dL. Ex-vivo preservation and storage predispose PRBCs to biochemical / mechanical changes whose impact in a septic host is unknown. This randomised pre-clinical trial specifically evaluates select markers of cardiovascular stress in an ovine model of endotoxemic shock receiving either fresh or stored blood. Methods: Twenty six anesthetised and mechanically ventilated merino ewes were randomly divided into endotoxemic shock (n = 16) or healthy (n = 10) groups. Endotoxemic shock was induced over 4 hours by infusing an escalating dose (total 11.25 mcg / kg) of lipopolysaccharide, LPS ( E.coli 055:B5 ). During the last hour of LPS infusion, 10 mls / kg of either fresh, ≤ 5 days (n = 8) or stored, ≥ 30 days (n = 8) ovine packed PRBCs were administered. Healthy ewes received either fresh, ≤ 5 days (n = 5) or stor...
Background / Purpose: Extracoproreal membrane oxygenation (ECMO) is a life saving supportive tool... more Background / Purpose: Extracoproreal membrane oxygenation (ECMO) is a life saving supportive tool for patients with severe cardiorespiratory failure. However ECMO has a significant impact on pharamcokinetics(PK) of vital drugs that are intended to reverse the pathology which will then result in liberation from ECMO. This mechanistic study aimed to relatively quantify the independent effects of the ECMO device on ciporfloxacin PK.Main conclusion: Critical illness has a major influence on ciprofloxacin PK during ECMO support and the independent effects of ECMO device may not be significant.; ;
BLOCKADE OF COMPLEMENT MEDIATED INFLAMMATION MAY IMPROVE LUNG TRANSPLANTATION OUTCOMES Introducti... more BLOCKADE OF COMPLEMENT MEDIATED INFLAMMATION MAY IMPROVE LUNG TRANSPLANTATION OUTCOMES Introduction: Brain death damages the Lungs more severely than any other organ. The lungs, which may have been perfect during life, may not be suitable following brain death. Previous work has shown that when donors are treated specially with a complement antagonist, it improves the donor lung function and results in better outcomes for the transplant recipient. Objectives: The aim of this study was to determine if complement factor 5a antagonist (C5a) also known as PMX53 can reduce inflammation in donor lungs and lung recipients, thereby improving lung transplants.
ABSTRACT Background / Purpose: Recent studies have highlighted the harmful effects of excessive f... more ABSTRACT Background / Purpose: Recent studies have highlighted the harmful effects of excessive fluid resuscitation and blood transfusion in patients with sepsis. However, the mechanisms behind this remains unclear.The aim of this study is to investigate the effects of fluid and blood (fresh vs stored) resuscitation on tissue blood flow (tflow), oxygen tension (tO 2 ) and metabolism during ovine endotoxaemia. Main conclusion: This validated ovine model provides preliminary insights into the tissue responses to endotoxaemia and resuscitation and can be an useful platform for sepsis research.
International Journal of Antimicrobial Agents, 2020
BACKGROUND Ventilator associated pneumonia occurs commonly and nebulized antibiotics are being us... more BACKGROUND Ventilator associated pneumonia occurs commonly and nebulized antibiotics are being used for its treatment. Although adequate pulmonary biodistribution is important for antibiotic effect, there is a lack of data for both intravenous (i.v.) or nebulized antibiotic administration during mechanical ventilation. OBJECTIVE To describe the comparative pulmonary regional distribution of i.v. and nebulized technetium-99m labelled tobramycin (99mTc-tobramycin) 400 mg in a mechanically ventilated ovine model. METHODS The study was performed in a mechanically ventilated ovine model. 99mTc-tobramycin 400 mg was obtained using a radiolabelling process. Computed tomography (CT) was performed. Five sheep each were given 99mTc-tobramycin 400 mg via i.v. or nebulized route. Planar images- dorsal, ventral and both lateral- were obtained using a gamma camera. Blood samples were obtained every 15 minutes for one hour (4 time points) and, lung, liver, both kidney, and urine samples were obtained post mortem. RESULTS Ten sheep were anesthetized and mechanically ventilated. Whole lung deposition of nebulized 99mTc-tobramycin 400 mg was significantly lower than with i.v. (8.8 vs 57.1%, p<0.001). For both administration routes, upper lung zones had a significantly lower deposition than the rest of the lungs. Dorsal deposition was significantly higher with nebulized 99mTc-tobramycin 400 mg compared to i.v. (68.9 vs 58.9%, p=0.003). The lung concentrations of 99mTc-tobramycin were higher with i.v. compared to nebulized. There were significantly higher concentrations of 99mTc-tobramycin in blood, liver and urine with i.v. administration compared to nebulized. CONCLUSIONS Nebulization resulted in lower whole and regional lung deposition of 99mTc-tobramycin and also appears associated with low blood and extra-pulmonary organ concentrations.
Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New... more Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New Background Nebulized antibiotics may be used to treat ventilator-associated pneumonia. In previous pharmacokinetic studies, lung interstitial space fluid concentrations have never been reported. The aim of the study was to compare intravenous and nebulized tobramycin concentrations in the lung interstitial space fluid, epithelial lining fluid, and plasma in mechanically ventilated sheep with healthy lungs. Methods Ten anesthetized and mechanically ventilated healthy ewes underwent surgical insertion of microdialysis catheters in upper and lower lobes of both lungs and the jugular vein. Five ewes were given intravenous tobramycin 400 mg, and five were given nebulized tobramycin 400 mg. Microdialysis samples were collected every 20 min for 8 h. Bronchoalveolar lavage was performed at 1 and 6 h. Results The peak lung interstitial space fluid concentrations were lower with intravenous tobra...
Background: Sepsis is a multi-system syndrome that remains the leading cause of mortality and cri... more Background: Sepsis is a multi-system syndrome that remains the leading cause of mortality and critical illness worldwide, with hemodynamic support being one of the cornerstones of the acute management of sepsis. We used an ovine model of endotoxemic shock to determine if 0.9% saline resuscitation contributes to lung inflammation and injury in acute respiratory distress syndrome, which is a common complication of sepsis, and investigated the potential role of matrix metalloproteinases in this process. Methods: Endotoxemic shock was induced in sheep by administration of an escalating dose of lipopolysaccharide, after which they subsequently received either no fluid bolus resuscitation or a 0.9% saline bolus. Lung tissue, bronchoalveolar fluid (BAL) and plasma were analysed by real-time PCR, ELISA, flow cytometry and immunohistochemical staining to assess inflammatory cells, cytokines, hyaluronan and matrix metalloproteinases. Results: Endotoxemia was associated with decreased serum albumin and total protein levels, with activated neutrophils, while the glycocalyx glycosaminoglycan hyaluronan was significantly increased in BAL. Quantitative real-time PCR studies showed higher expression of IL-6 and IL-8 with saline resuscitation but no difference in matrix metalloproteinase expression. BAL and tissue homogenate levels of IL-6, IL-8 and IL-1β were elevated. Conclusions: This data shows that the inflammatory response is enhanced when a host with endotoxemia is resuscitated with saline, with a comparatively higher release of inflammatory cytokines and endothelial/glycocalyx damage, but no change in matrix metalloproteinase levels.
Background: Cerebral regional microcirculation is altered following severe head injury. In additi... more Background: Cerebral regional microcirculation is altered following severe head injury. In addition to tissue disruption, partial pressure of tissue oxygenation is impaired due to an increase in the oxygen tissue gradient. The heterogenic distribution of cerebral microcirculation is multifactorial, and acute anemia challenges further the delivery of oxygen to tissues. Currently, a restrictive transfusion threshold is globally applied; however, it is unclear how anemia modifies regional cerebral microcirculation; hence, it is unclear if by aiming to a global endpoint, specific anatomical regions undergo ischemia. This study aims to quantify the temporal changes in cerebral microcirculation after severe head injury, under the effect of anemia and transfusion. It also aims to assess its effects specifically at the ischemic penumbra compared to contralateral regions and its interactions with axonal integrity in real time. Twelve ovine models were subjected to a severe contusion and acceleration-deceleration injury. Normovolemic anemia to a restrictive threshold was maintained after injury, followed by autologous transfusion. Direct quantification of cerebral microcirculation used cytometric count of color-coded microspheres. Axonal injury was assessed using amyloid precursor protein staining. Results: A mixed-effect regression model from pre-transfusion to post-transfusion times with a random intercept for each sheep was used. Cerebral microcirculation amongst subjects with normal intracranial pressure was maintained from baseline and increased further after transfusion. Subjects with high intracranial pressure had a consistent reduction of their microcirculation to ischemic thresholds (20-30 ml/100 g/min) without an improvement after transfusion. Cerebral PtiO 2 was reduced when exposed to anemia but increased in a 9.6-fold with transfusion 95% CI 5.6 to 13.6 (p value < 0.001). Conclusions: After severe head injury, the exposure to normovolemic anemia to a restrictive transfusion threshold, leads to a consistent reduction on cerebral microcirculation below ischemic thresholds, independent of cerebral perfusion pressure. Amongst subjects with raised intracranial pressure, microcirculation does not improve after transfusion. Cerebral oxymetry is impaired during anemia with a statistically significant increase after transfusion. Current transfusion practices in neurocritical care are based on a rigid hemoglobin threshold, a view that excludes cerebral metabolic demands and specific needs. An RCT exploring these concepts is warranted.
Intensive care medicine experimental, Jan 11, 2018
Nebulised antibiotics are frequently used for the prevention or treatment of ventilator-associate... more Nebulised antibiotics are frequently used for the prevention or treatment of ventilator-associated pneumonia. Many factors may influence pulmonary drug concentrations with inaccurate dosing schedules potentially leading to therapeutic failure and/or the emergence of antibiotic resistance. We describe a research pathway for studying the pharmacokinetics of a nebulised antibiotic during mechanical ventilation using in vitro methods and ovine models, using tobramycin as the study antibiotic. In vitro studies using a laser diffractometer and a bacterial-viral filter were used to measure the effect of the type and size of tracheal tubes and antibiotic concentration on the particle size distribution of the tobramycin 400 mg (4 ml; 100 mg/ml) and 160 mg (4 ml, 40 mg/ml) aerosol and nebulised mass delivered. To compare the regional drug distribution in the lung of two routes (intravenous and nebulised) of drug administration of tobramycin 400 mg, technetium-99m-labelled tobramycin 400 mg wi...
American journal of respiratory and critical care medicine, Jan 8, 2018
Fluid resuscitation is widely considered a life saving intervention in septic shock however recen... more Fluid resuscitation is widely considered a life saving intervention in septic shock however recent evidence has questioned both its safety and efficacy in sepsis. This study sought to compare fluid resuscitation with vasopressors with vasopressors alone in a hyperdynamic model of ovine endotoxemia. Endotoxemic shock was induced in sixteen sheep after which they received fluid resuscitation with 40mls/kg of 0.9% saline or commenced haemodynamic support with protocolized noradrenaline and vasopressin. Microdialysis catheters were inserted into the arterial circulation, heart, brain, kidney and liver to monitor local metabolism. Blood samples were recovered to measure serum inflammatory cytokines, creatinine, troponin, ANP, BNP and hyaluronan. All animals were monitored and supported for 12 hours after fluid resuscitation. After resuscitation animals receiving fluid resuscitation required significantly more noradrenaline to maintain the same mean arterial pressure in the subsequent 12 ...
Critical care and resuscitation : journal of the Australasian Academy of Critical Care Medicine, 2017
Significant interactions between drugs, extracorporeal membrane oxygenation (ECMO) circuits and c... more Significant interactions between drugs, extracorporeal membrane oxygenation (ECMO) circuits and critical illness may affect the pharmacokinetic properties of antibiotics in critically ill patients receiving ECMO. To describe the pharmacokinetic properties of ciprofloxacin during ECMO by integrating pre-clinical findings (ie, ex vivo and in vivo ovine models) to a critically ill patient. An ex vivo model of an ECMO circuit was used to describe ciprofloxacin concentration changes over 24 hours. An in vivo ovine model of ECMO was used to describe the population pharmacokinetic properties of ciprofloxacin in three different groups of sheep, and to investigate sources of pharmacokinetic variability. In the final phase, data from a 39-year-old critically ill man was used to validate the findings from the ovine pharmacokinetic model. In the ex vivo model of ECMO circuits, the median concentrations of ciprofloxacin at baseline and at 24 hours after ciprofloxacin infusion were similar. The t...
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