Gregory Schmidt - Academia.edu (original) (raw)

Papers by Gregory Schmidt

The American journal of physiology

The roots of physiology lie in laboratory observation, and physiology courses continue to rely on... more The roots of physiology lie in laboratory observation, and physiology courses continue to rely on laboratory observation to provide students with practical information to correlate with their developing base of conceptual knowledge. To this end, animal laboratories provide a functioning example of interactions among organ systems and a source of data for student analysis. However, there are continuing objections to using animals for teaching, and animal labs are costly in time and effort. As an alternative laboratory tool, computer software can simulate the operation of multiple organ systems: responses to interventions illustrate intrinsic organ behavior and integrated systems physiology. Advantages of software over animal studies include alteration of variables that are not easily changed in vivo, repeated interventions, and cost-effective hands-on student access. Nevertheless, simulations miss intangible aspects of experimental physiology, and results depend critically on the assumptions of the model. We used both computer and animal demonstrations in teaching cardiovascular physiology to first-year medical students. The students rated both highly, but the computer-based session received a higher rating. We believe that both forms of teaching have educational merit. At the introductory level, the computer appears to provide an effective alternative.

CHEST Journal, 2015

Serum angiotensin converting enzyme (ACE) levels may be decreased by use of ACE inhibitor (ACEI) ... more Serum angiotensin converting enzyme (ACE) levels may be decreased by use of ACE inhibitor (ACEI) medication. In this study, we determined how often ACE levels were performed in patients receiving ACEI therapy. ACE levels analyzed over a 54 month "pre-intervention" time period at an academic medical center were reviewed retrospectively for tests performed during ACEI therapy. This data was compared with a large, de-identified dataset of ACE levels performed at a national reference laboratory, in vitro studies of ACEI inhibition, and liquid chromatography-time-of-flight mass spectrometry (LC-TOF-MS) detection of lisinopril in a subset of clinical specimens. Over a 54 month period, 1,292 patients had ACE levels performed, with 108 patients (8.4%) on ACEI therapy at time of testing. ACE levels performed for patients on ACEI therapy were substantially lower. In general, clinical teams did not recognize medication effect on ACE levels. Introduction of a warning prompt in the electronic health record reduced ordering of ACE levels in patients on ACEIs by more than 60% in a seventeen month "post-intervention" time period. The de-identified dataset of ACE levels at a reference laboratory showed a bimodal distribution, with a peak of very low ACE levels. Using LC-TOF-MS, the presence of lisinopril was confirmed in a subset of specimens with low ACE activity. In vitro studies of two different ACE assays showed significant inhibition of activity at clinically relevant concentrations. Assessment of ACE activity is often performed for patients on ACEIs, potentially leading to low ACE concentrations and inaccurate interpretations.

A24. MECHANISMS OF SEPSIS, 2009

Chest, 2015

In critically ill patients, the right ventricle is susceptible to dysfunction due to increased af... more In critically ill patients, the right ventricle is susceptible to dysfunction due to increased afterload, decreased contractility, or alterations in preload. With the increased use of point-of-care ultrasonography and a decline in the use of pulmonary artery catheters, echocardiography can be the ideal tool for evaluation and to guide hemodynamic and respiratory therapy. We review the epidemiology of right ventricular failure in critically ill patients; echocardiographic parameters for evaluating the right ventricle; and the impact of mechanical ventilation, fluid therapy, and vasoactive infusions on the right ventricle. Finally, we summarize the principles of management in the context of right ventricular dysfunction and provide recommendations for echocardiography-guided management.

Annals of the American Thoracic Society, 2014

Between 10% and 57% of lung transplant (LTx) recipients develop primary graft dysfunction (PGD) w... more Between 10% and 57% of lung transplant (LTx) recipients develop primary graft dysfunction (PGD) within 72 hours of LTx. PGD is clinically and histologically analogous to the acute respiratory distress syndrome. In patients at risk for or with acute respiratory distress syndrome, lung-protective ventilation strategies (low tidal volume and positive end-expiratory pressure) improve outcomes. There is, however, little information available on mechanical ventilation strategies after LTx. Our aim in this international survey was to describe the current practices of mechanical ventilation immediately after LTx. An electronic survey was sent to the medical and surgical directors of U.S. LTx programs (n = 111) and to members of the Pulmonary Council of the International Society for Heart and Lung Transplantation (n = 470). A total of 149 individuals from 18 countries responded to the questionnaire. The most common modes of ventilation were pressure assist/control (37%) and volume assist/control (35%). Tidal volumes were most often determined by recipient characteristics. Donor characteristics were rarely considered (35%) and were infrequently known by the team managing the ventilator (42%). When presented with a choice of ideal tidal volumes, a majority of respondents selected 6 ml/kg recipient predicted body weight (58%), fewer selected 10 ml/kg (21%), and none selected 15 ml/kg. A majority preferred limiting the fraction of inspired oxygen rather than positive end-expiratory pressure (PEEP) (69% versus 31%, P = 0.006). The median minimum PEEP was 5 cm H2O, and the median maximum PEEP was 11.5 cm H2O. The presence of PGD increased the perceived importance of monitoring plateau pressure to adjust tidal volumes. The median plateau pressure limit perceived as a threshold triggering reduction in tidal volume was 30 cm H2O. Most respondents reported using lung-protective approaches to mechanical ventilation after lung transplantation. Low tidal volumes based on recipient characteristics were frequently chosen. Donor characteristics often were not considered and frequently were not known by the team managing mechanical ventilation after LTx.

A24. MECHANISMS OF SEPSIS, 2009

Critical Care Medicine, 2008

To compare characteristics and outcomes of patients treated with drotrecogin alfa (activated) (Dr... more To compare characteristics and outcomes of patients treated with drotrecogin alfa (activated) (DrotAA) in clinical practice to those treated in a phase III randomized controlled trial (PROWESS). Observational data were collected retrospectively from patients who received DrotAA as part of physician-directed treatment. Intensive care units of five teaching institutions. Patients were > or = 18 yrs old, had severe sepsis (confirmed/suspected infection with one or more sepsis-induced organ dysfunctions), and received DrotAA. None. Baseline demographics, severity of illness, time from organ dysfunction onset to DrotAA treatment, daily assessment of organ dysfunction, serious bleeding events, and in-hospital mortality were reported. Timing from severe sepsis documentation to start of DrotAA infusion was categorized: day 0 (same calendar day); day 1 (next calendar day); and day > or = 2 (second calendar day or later). Clinical practice patients (n = 274) were younger, had more comorbidities, had higher severity of illness (as measured by organ dysfunction or greater vasopressor/ventilator use), and received DrotAA later than PROWESS patients (all p < .05). Overall hospital mortality for clinical practice patients was 42%, compared with 37% for DrotAA-treated PROWESS patients with Acute Physiology and Chronic Health Evaluation II score > or = 25. Mortality for day 0, day 1, and day > or = 2 groups was 33%, 40%, and 52%, respectively. In PROWESS, the vast majority were treated on day 0 or day 1. Serious bleeding events during infusion were noted in 4.0% of clinical practice patients compared with 2.2% of PROWESS DrotAA-treated patients with Acute Physiology and Chronic Health Evaluation II score > or = 25. Patients treated in clinical practice differed from those in PROWESS. Patients were younger, had more comorbidities, had greater severity of illness, and had longer mean time from severe sepsis onset to the start of DrotAA. Hospital mortality for patients treated within 1 day of severe sepsis onset was similar to DrotAA-treated PROWESS patients. While the low number of serious bleeding events precludes a definitive assessment, the observed incidence of serious bleeding events in clinical practice patients was numerically higher than in DrotAA-treated PROWESS patients.

Critical Care Medicine, 1992

Critical Care, 2010

Introduction: Microvascular dysregulation characterized by hyporesponsive vessels and heterogeneo... more Introduction: Microvascular dysregulation characterized by hyporesponsive vessels and heterogeneous bloodflow is implicated in the pathogenesis of organ failure in sepsis. The renin-angiotensin system (RAS) affects the microvasculature, yet the relationships between RAS and organ injury in clinical sepsis remain unclear. We tested our hypothesis that systemic RAS mediators are associated with dysregulation of the microvasculature and with organ failure in clinical severe sepsis. Methods: We studied 30 subjects with severe sepsis, and 10 healthy control subjects. Plasma was analyzed for plasma renin activity (PRA) and angiotensin II concentration (Ang II). Using near-infrared spectroscopy, we measured the rate of increase in the oxygen saturation of thenar microvascular hemoglobin after five minutes of induced forearm ischemia. In so doing, we assessed bulk microvascular hemoglobin influx to the tissue during reactive hyperemia. We studied all subjects 24 hours after the development of organ failure. We studied a subset of 12 subjects at an additional timepoint, eight hours after recognition of organ failure (early sepsis). Results: After 24 hours of resuscitation to clinically-defined endpoints of preload and arterial pressure, Ang II and PRA were elevated in septic subjects and the degree of elevation correlated negatively with the rate of microvascular reoxygenation during reactive hyperemia. Early RAS mediators correlated with microvascular dysfunction. Early Ang II also correlated with the extent of organ failure realized during the first day of sepsis. Conclusions: RAS is activated in clinical severe sepsis. Systemic RAS mediators correlate with measures of microvascular dysregulation and with organ failure.

CHEST Journal, 2013

Urate nephropathy is observed primarily in patients treated for malignancy, but several other pre... more Urate nephropathy is observed primarily in patients treated for malignancy, but several other predisposing conditions are recognized. We report a case in which urate nephropathy complicated status epilepticus and review the literature regarding previous similar cases. In addition, we discuss current views of the pathophysiology of acute kidney injury due to urate nephropathy. This case illustrates the value of carefully examining the urine of patients with acute kidney injury to identify causes that may have a specific treatment.

American Journal of Respiratory and Critical Care Medicine, 2010

Rationale: Many lines of evidence point toward the gastrointestinal (GI) tract in the pathophysio... more Rationale: Many lines of evidence point toward the gastrointestinal (GI) tract in the pathophysiology of organ dysfunction in sepsis. Splanchnic hypoperfusion during sepsis leads to enterocyte apoptosis, diminished barrier function, and release of bacterial products. Sepsis lowers levels of insulin-like growth factor (IGF)-1, a known antiapoptotic factor. We recently demonstrated that treatment with IGF-1 is protective in murine sepsis. Objectives: We hypothesize that decreased IGF-1 levels in sepsis contributes to the development of bacterial translocation. Methods: Sepsis was induced in C57BL/6 mice via intratracheal instillation of Pseudomonas aeruginosa. Human subjects with sepsis were enrolled if they had a documented positive blood culture with a nonenteric organism. Bacterial translocation was measured in serum by quantitative real-time polymerase chain reaction with primers specific for enteric bacteria. Serum IGF-1 was measured by ELISA. Apoptosis of the GI epithelium was assessed via immunohistochemistry. Measurements and Main Results: We found that mice with severe sepsis had evidence of bacterial translocation by 24 hours. Enteric bacterial load correlated inversely with levels of serum IGF-1. If we treated mice with IGF-1, bacterial translocation was significantly decreased. In addition, we found increased GI epithelial cell apoptosis after sepsis, which was significantly decreased after IGF-1 treatment. Human subjects with nonenteric sepsis developed progressive enteric bacteremia over 3 days. The degree of enteric bacteremia correlated inversely with serum IGF-1 levels. Conclusions: These data support the hypothesis that sepsis-induced reductions in IGF-1 levels contribute to the development of bacterial translocation in both a murine model and human subjects.

AJP: Heart and Circulatory Physiology, 2007

Severe sepsis is a systemic inflammatory response to infection resulting in acute organ dysfuncti... more Severe sepsis is a systemic inflammatory response to infection resulting in acute organ dysfunction. Vascular perfusion abnormalities are implicated in the pathology of organ failure, but studies of microvascular function in human sepsis are limited. We hypothesized that impaired microvascular responses to reactive hyperemia lead to impaired oxygen delivery relative to the needs of tissue, and that these impairments would be associated with organ failure in sepsis. We studied 24 severe sepsis subjects 24 hours after recognition of organ dysfunction; 15 healthy subjects served as controls. Near-InfraRed Spectroscopy (NIRS) was used to measure tissue:1) microvascular hemoglobin signal strength; and 2) oxygen saturation of microvascular hemoglobin (S t O 2 ).

Current Pulmonology Reports, 2015

Mechanical ventilation (MV) is an important aspect in the intraoperative and early postoperative ... more Mechanical ventilation (MV) is an important aspect in the intraoperative and early postoperative management of lung transplant (LTx)-recipients. There are no randomized-controlled trials of LTx-recipient MV strategies; however there are LTx center experiences and international survey studies reported. The main early complication of LTx is primary graft dysfunction (PGD), which is similar to the adult respiratory distress syndrome (ARDS). We aim to summarize information pertinent to LTx-MV, as well as PGD, ARDS, and intraoperative MV and to synthesize these available data into recommendations. Based on the available evidence, we recommend lung-protective MV with low-tidal-volumes (≤6 mL/kg predicted body weight [PBW]) and positive end-expiratory pressure for the LTx-recipient. In our opinion, the MV strategy should be based on donor characteristics (donor PBW as a parameter of actual allograft size), rather than based on recipient characteristics; however this donor-characteristics-based protective MV is based on indirect evidence and requires validation in prospective clinical studies.

CHEST Journal, 2014

We report the first case, to our knowledge, of amatoxin hepatotoxicity in Iowa and explore the et... more We report the first case, to our knowledge, of amatoxin hepatotoxicity in Iowa and explore the ethical and decisional challenges of offering an investigational treatment of a rare disease. Acute liver failure due to ingestion of amatoxin-containing mushrooms is a relatively rare entity. Once amatoxin poisoning is identified, there is no clearly effective treatment, leading to a broad range of theoretically beneficial, anecdotally successful, or investigational options. The evolution of hepatotoxicity led us to offer investigational treatment with silibinin, an extract of Mediterranean milk thistle. We explore the pitfalls in medical decision-making experienced by both the patient and the physician in the face of ambiguity. The patient did well following silibinin infusion, but we are left uncertain as to whether the patient truly responded to treatment or was simply destined to recover.

Critical Care Medicine, 2010

Physical and occupational therapy are possible immediately after intubation in mechanically venti... more Physical and occupational therapy are possible immediately after intubation in mechanically ventilated medical intensive care unit patients. The objective of this study was to describe a protocol of daily sedative interruption and early physical and occupational therapy and to specify details of intensive care unit-based therapy, including neurocognitive state, potential barriers, and adverse events related to this intervention. Detailed descriptive study of the intervention arm of a trial of mechanically ventilated patients receiving early physical and occupational therapy. Two tertiary care academic medical centers participating in a randomized controlled trial. Patients underwent daily sedative interruption followed by physical and occupational therapy every hospital day until achieving independent functional status. Therapy began with active range of motion and progressed to activities of daily living, sitting, standing, and walking as tolerated. Forty-nine mechanically ventilated patients received early physical and occupational therapy occurring a median of 1.5 days (range, 1.0-2.1 days) after intubation. Therapy was provided on 90% of MICU days during mechanical ventilation. While endotracheally intubated, subjects sat at the edge of the bed in 69% of all physical and occupational therapy sessions, transferred from bed to chair in 33%, stood in 33%, and ambulated during 15% (n = 26 of 168) of all physical and occupational therapy sessions (median distance of 15 feet; range, 15-20 feet). At least one potential barrier to mobilization during mechanical ventilation (acute lung injury, vasoactive medication administration, delirium, renal replacement therapy, or body mass index ≥ 30 kg/m) was present in 89% of patient encounters. Therapy was interrupted prematurely in 4% of all sessions, most commonly for patient-ventilator asynchrony and agitation. Early physical and occupational therapy is feasible from the onset of mechanical ventilation despite high illness acuity and presence of life support devices. Adverse events are uncommon, even in this high-risk group.

CHEST Journal, 2011

C ode status orders refer to decisions to perform or not perform CPR in the event of cardiopulmon... more C ode status orders refer to decisions to perform or not perform CPR in the event of cardiopulmonary arrest. In making decisions about code status orders it is essential that physicians and patients communicate effectively so that patients can receive informed, compassionate care that respects their treatment preferences. However, communication between physicians and patients (or their surrogates) about code status orders is diffi cult, 1 and misunderstandings about code status preferences may lead to unwanted medical interventions 2,3 or withholding of desired interventions. The need for effective and respectful communication about resuscitation preferences is heightened in the setting of the ICU where the pace of decision making is often rapid, the burdens of medical technology are typically signifi cant, diagnoses and prognoses may be uncertain, 4 surrogate decision making is common, 5 and the threat of death or disability understandably causes fear and anxiety.

Australian Occupational Therapy Journal, 2009

Intensive Care Medicine, 2014

Your article is protected by copyright and all rights are held exclusively by Springer-Verlag Ber... more Your article is protected by copyright and all rights are held exclusively by Springer-Verlag Berlin Heidelberg and ESICM. This e-offprint is for personal use only and shall not be selfarchived in electronic repositories. If you wish to self-archive your article, please use the accepted manuscript version for posting on your own website. You may further deposit the accepted manuscript version in any repository, provided it is only made publicly available 12 months after official publication or later and provided acknowledgement is given to the original source of publication and a link is inserted to the published article on Springer's website. The link must be accompanied by the following text: "The final publication is available at link.springer.com".

The American journal of physiology

The roots of physiology lie in laboratory observation, and physiology courses continue to rely on... more The roots of physiology lie in laboratory observation, and physiology courses continue to rely on laboratory observation to provide students with practical information to correlate with their developing base of conceptual knowledge. To this end, animal laboratories provide a functioning example of interactions among organ systems and a source of data for student analysis. However, there are continuing objections to using animals for teaching, and animal labs are costly in time and effort. As an alternative laboratory tool, computer software can simulate the operation of multiple organ systems: responses to interventions illustrate intrinsic organ behavior and integrated systems physiology. Advantages of software over animal studies include alteration of variables that are not easily changed in vivo, repeated interventions, and cost-effective hands-on student access. Nevertheless, simulations miss intangible aspects of experimental physiology, and results depend critically on the assumptions of the model. We used both computer and animal demonstrations in teaching cardiovascular physiology to first-year medical students. The students rated both highly, but the computer-based session received a higher rating. We believe that both forms of teaching have educational merit. At the introductory level, the computer appears to provide an effective alternative.

CHEST Journal, 2015

Serum angiotensin converting enzyme (ACE) levels may be decreased by use of ACE inhibitor (ACEI) ... more Serum angiotensin converting enzyme (ACE) levels may be decreased by use of ACE inhibitor (ACEI) medication. In this study, we determined how often ACE levels were performed in patients receiving ACEI therapy. ACE levels analyzed over a 54 month "pre-intervention" time period at an academic medical center were reviewed retrospectively for tests performed during ACEI therapy. This data was compared with a large, de-identified dataset of ACE levels performed at a national reference laboratory, in vitro studies of ACEI inhibition, and liquid chromatography-time-of-flight mass spectrometry (LC-TOF-MS) detection of lisinopril in a subset of clinical specimens. Over a 54 month period, 1,292 patients had ACE levels performed, with 108 patients (8.4%) on ACEI therapy at time of testing. ACE levels performed for patients on ACEI therapy were substantially lower. In general, clinical teams did not recognize medication effect on ACE levels. Introduction of a warning prompt in the electronic health record reduced ordering of ACE levels in patients on ACEIs by more than 60% in a seventeen month "post-intervention" time period. The de-identified dataset of ACE levels at a reference laboratory showed a bimodal distribution, with a peak of very low ACE levels. Using LC-TOF-MS, the presence of lisinopril was confirmed in a subset of specimens with low ACE activity. In vitro studies of two different ACE assays showed significant inhibition of activity at clinically relevant concentrations. Assessment of ACE activity is often performed for patients on ACEIs, potentially leading to low ACE concentrations and inaccurate interpretations.

A24. MECHANISMS OF SEPSIS, 2009

Chest, 2015

In critically ill patients, the right ventricle is susceptible to dysfunction due to increased af... more In critically ill patients, the right ventricle is susceptible to dysfunction due to increased afterload, decreased contractility, or alterations in preload. With the increased use of point-of-care ultrasonography and a decline in the use of pulmonary artery catheters, echocardiography can be the ideal tool for evaluation and to guide hemodynamic and respiratory therapy. We review the epidemiology of right ventricular failure in critically ill patients; echocardiographic parameters for evaluating the right ventricle; and the impact of mechanical ventilation, fluid therapy, and vasoactive infusions on the right ventricle. Finally, we summarize the principles of management in the context of right ventricular dysfunction and provide recommendations for echocardiography-guided management.

Annals of the American Thoracic Society, 2014

Between 10% and 57% of lung transplant (LTx) recipients develop primary graft dysfunction (PGD) w... more Between 10% and 57% of lung transplant (LTx) recipients develop primary graft dysfunction (PGD) within 72 hours of LTx. PGD is clinically and histologically analogous to the acute respiratory distress syndrome. In patients at risk for or with acute respiratory distress syndrome, lung-protective ventilation strategies (low tidal volume and positive end-expiratory pressure) improve outcomes. There is, however, little information available on mechanical ventilation strategies after LTx. Our aim in this international survey was to describe the current practices of mechanical ventilation immediately after LTx. An electronic survey was sent to the medical and surgical directors of U.S. LTx programs (n = 111) and to members of the Pulmonary Council of the International Society for Heart and Lung Transplantation (n = 470). A total of 149 individuals from 18 countries responded to the questionnaire. The most common modes of ventilation were pressure assist/control (37%) and volume assist/control (35%). Tidal volumes were most often determined by recipient characteristics. Donor characteristics were rarely considered (35%) and were infrequently known by the team managing the ventilator (42%). When presented with a choice of ideal tidal volumes, a majority of respondents selected 6 ml/kg recipient predicted body weight (58%), fewer selected 10 ml/kg (21%), and none selected 15 ml/kg. A majority preferred limiting the fraction of inspired oxygen rather than positive end-expiratory pressure (PEEP) (69% versus 31%, P = 0.006). The median minimum PEEP was 5 cm H2O, and the median maximum PEEP was 11.5 cm H2O. The presence of PGD increased the perceived importance of monitoring plateau pressure to adjust tidal volumes. The median plateau pressure limit perceived as a threshold triggering reduction in tidal volume was 30 cm H2O. Most respondents reported using lung-protective approaches to mechanical ventilation after lung transplantation. Low tidal volumes based on recipient characteristics were frequently chosen. Donor characteristics often were not considered and frequently were not known by the team managing mechanical ventilation after LTx.

A24. MECHANISMS OF SEPSIS, 2009

Critical Care Medicine, 2008

To compare characteristics and outcomes of patients treated with drotrecogin alfa (activated) (Dr... more To compare characteristics and outcomes of patients treated with drotrecogin alfa (activated) (DrotAA) in clinical practice to those treated in a phase III randomized controlled trial (PROWESS). Observational data were collected retrospectively from patients who received DrotAA as part of physician-directed treatment. Intensive care units of five teaching institutions. Patients were > or = 18 yrs old, had severe sepsis (confirmed/suspected infection with one or more sepsis-induced organ dysfunctions), and received DrotAA. None. Baseline demographics, severity of illness, time from organ dysfunction onset to DrotAA treatment, daily assessment of organ dysfunction, serious bleeding events, and in-hospital mortality were reported. Timing from severe sepsis documentation to start of DrotAA infusion was categorized: day 0 (same calendar day); day 1 (next calendar day); and day > or = 2 (second calendar day or later). Clinical practice patients (n = 274) were younger, had more comorbidities, had higher severity of illness (as measured by organ dysfunction or greater vasopressor/ventilator use), and received DrotAA later than PROWESS patients (all p < .05). Overall hospital mortality for clinical practice patients was 42%, compared with 37% for DrotAA-treated PROWESS patients with Acute Physiology and Chronic Health Evaluation II score > or = 25. Mortality for day 0, day 1, and day > or = 2 groups was 33%, 40%, and 52%, respectively. In PROWESS, the vast majority were treated on day 0 or day 1. Serious bleeding events during infusion were noted in 4.0% of clinical practice patients compared with 2.2% of PROWESS DrotAA-treated patients with Acute Physiology and Chronic Health Evaluation II score > or = 25. Patients treated in clinical practice differed from those in PROWESS. Patients were younger, had more comorbidities, had greater severity of illness, and had longer mean time from severe sepsis onset to the start of DrotAA. Hospital mortality for patients treated within 1 day of severe sepsis onset was similar to DrotAA-treated PROWESS patients. While the low number of serious bleeding events precludes a definitive assessment, the observed incidence of serious bleeding events in clinical practice patients was numerically higher than in DrotAA-treated PROWESS patients.

Critical Care Medicine, 1992

Critical Care, 2010

Introduction: Microvascular dysregulation characterized by hyporesponsive vessels and heterogeneo... more Introduction: Microvascular dysregulation characterized by hyporesponsive vessels and heterogeneous bloodflow is implicated in the pathogenesis of organ failure in sepsis. The renin-angiotensin system (RAS) affects the microvasculature, yet the relationships between RAS and organ injury in clinical sepsis remain unclear. We tested our hypothesis that systemic RAS mediators are associated with dysregulation of the microvasculature and with organ failure in clinical severe sepsis. Methods: We studied 30 subjects with severe sepsis, and 10 healthy control subjects. Plasma was analyzed for plasma renin activity (PRA) and angiotensin II concentration (Ang II). Using near-infrared spectroscopy, we measured the rate of increase in the oxygen saturation of thenar microvascular hemoglobin after five minutes of induced forearm ischemia. In so doing, we assessed bulk microvascular hemoglobin influx to the tissue during reactive hyperemia. We studied all subjects 24 hours after the development of organ failure. We studied a subset of 12 subjects at an additional timepoint, eight hours after recognition of organ failure (early sepsis). Results: After 24 hours of resuscitation to clinically-defined endpoints of preload and arterial pressure, Ang II and PRA were elevated in septic subjects and the degree of elevation correlated negatively with the rate of microvascular reoxygenation during reactive hyperemia. Early RAS mediators correlated with microvascular dysfunction. Early Ang II also correlated with the extent of organ failure realized during the first day of sepsis. Conclusions: RAS is activated in clinical severe sepsis. Systemic RAS mediators correlate with measures of microvascular dysregulation and with organ failure.

CHEST Journal, 2013

Urate nephropathy is observed primarily in patients treated for malignancy, but several other pre... more Urate nephropathy is observed primarily in patients treated for malignancy, but several other predisposing conditions are recognized. We report a case in which urate nephropathy complicated status epilepticus and review the literature regarding previous similar cases. In addition, we discuss current views of the pathophysiology of acute kidney injury due to urate nephropathy. This case illustrates the value of carefully examining the urine of patients with acute kidney injury to identify causes that may have a specific treatment.

American Journal of Respiratory and Critical Care Medicine, 2010

Rationale: Many lines of evidence point toward the gastrointestinal (GI) tract in the pathophysio... more Rationale: Many lines of evidence point toward the gastrointestinal (GI) tract in the pathophysiology of organ dysfunction in sepsis. Splanchnic hypoperfusion during sepsis leads to enterocyte apoptosis, diminished barrier function, and release of bacterial products. Sepsis lowers levels of insulin-like growth factor (IGF)-1, a known antiapoptotic factor. We recently demonstrated that treatment with IGF-1 is protective in murine sepsis. Objectives: We hypothesize that decreased IGF-1 levels in sepsis contributes to the development of bacterial translocation. Methods: Sepsis was induced in C57BL/6 mice via intratracheal instillation of Pseudomonas aeruginosa. Human subjects with sepsis were enrolled if they had a documented positive blood culture with a nonenteric organism. Bacterial translocation was measured in serum by quantitative real-time polymerase chain reaction with primers specific for enteric bacteria. Serum IGF-1 was measured by ELISA. Apoptosis of the GI epithelium was assessed via immunohistochemistry. Measurements and Main Results: We found that mice with severe sepsis had evidence of bacterial translocation by 24 hours. Enteric bacterial load correlated inversely with levels of serum IGF-1. If we treated mice with IGF-1, bacterial translocation was significantly decreased. In addition, we found increased GI epithelial cell apoptosis after sepsis, which was significantly decreased after IGF-1 treatment. Human subjects with nonenteric sepsis developed progressive enteric bacteremia over 3 days. The degree of enteric bacteremia correlated inversely with serum IGF-1 levels. Conclusions: These data support the hypothesis that sepsis-induced reductions in IGF-1 levels contribute to the development of bacterial translocation in both a murine model and human subjects.

AJP: Heart and Circulatory Physiology, 2007

Severe sepsis is a systemic inflammatory response to infection resulting in acute organ dysfuncti... more Severe sepsis is a systemic inflammatory response to infection resulting in acute organ dysfunction. Vascular perfusion abnormalities are implicated in the pathology of organ failure, but studies of microvascular function in human sepsis are limited. We hypothesized that impaired microvascular responses to reactive hyperemia lead to impaired oxygen delivery relative to the needs of tissue, and that these impairments would be associated with organ failure in sepsis. We studied 24 severe sepsis subjects 24 hours after recognition of organ dysfunction; 15 healthy subjects served as controls. Near-InfraRed Spectroscopy (NIRS) was used to measure tissue:1) microvascular hemoglobin signal strength; and 2) oxygen saturation of microvascular hemoglobin (S t O 2 ).

Current Pulmonology Reports, 2015

Mechanical ventilation (MV) is an important aspect in the intraoperative and early postoperative ... more Mechanical ventilation (MV) is an important aspect in the intraoperative and early postoperative management of lung transplant (LTx)-recipients. There are no randomized-controlled trials of LTx-recipient MV strategies; however there are LTx center experiences and international survey studies reported. The main early complication of LTx is primary graft dysfunction (PGD), which is similar to the adult respiratory distress syndrome (ARDS). We aim to summarize information pertinent to LTx-MV, as well as PGD, ARDS, and intraoperative MV and to synthesize these available data into recommendations. Based on the available evidence, we recommend lung-protective MV with low-tidal-volumes (≤6 mL/kg predicted body weight [PBW]) and positive end-expiratory pressure for the LTx-recipient. In our opinion, the MV strategy should be based on donor characteristics (donor PBW as a parameter of actual allograft size), rather than based on recipient characteristics; however this donor-characteristics-based protective MV is based on indirect evidence and requires validation in prospective clinical studies.

CHEST Journal, 2014

We report the first case, to our knowledge, of amatoxin hepatotoxicity in Iowa and explore the et... more We report the first case, to our knowledge, of amatoxin hepatotoxicity in Iowa and explore the ethical and decisional challenges of offering an investigational treatment of a rare disease. Acute liver failure due to ingestion of amatoxin-containing mushrooms is a relatively rare entity. Once amatoxin poisoning is identified, there is no clearly effective treatment, leading to a broad range of theoretically beneficial, anecdotally successful, or investigational options. The evolution of hepatotoxicity led us to offer investigational treatment with silibinin, an extract of Mediterranean milk thistle. We explore the pitfalls in medical decision-making experienced by both the patient and the physician in the face of ambiguity. The patient did well following silibinin infusion, but we are left uncertain as to whether the patient truly responded to treatment or was simply destined to recover.

Critical Care Medicine, 2010

Physical and occupational therapy are possible immediately after intubation in mechanically venti... more Physical and occupational therapy are possible immediately after intubation in mechanically ventilated medical intensive care unit patients. The objective of this study was to describe a protocol of daily sedative interruption and early physical and occupational therapy and to specify details of intensive care unit-based therapy, including neurocognitive state, potential barriers, and adverse events related to this intervention. Detailed descriptive study of the intervention arm of a trial of mechanically ventilated patients receiving early physical and occupational therapy. Two tertiary care academic medical centers participating in a randomized controlled trial. Patients underwent daily sedative interruption followed by physical and occupational therapy every hospital day until achieving independent functional status. Therapy began with active range of motion and progressed to activities of daily living, sitting, standing, and walking as tolerated. Forty-nine mechanically ventilated patients received early physical and occupational therapy occurring a median of 1.5 days (range, 1.0-2.1 days) after intubation. Therapy was provided on 90% of MICU days during mechanical ventilation. While endotracheally intubated, subjects sat at the edge of the bed in 69% of all physical and occupational therapy sessions, transferred from bed to chair in 33%, stood in 33%, and ambulated during 15% (n = 26 of 168) of all physical and occupational therapy sessions (median distance of 15 feet; range, 15-20 feet). At least one potential barrier to mobilization during mechanical ventilation (acute lung injury, vasoactive medication administration, delirium, renal replacement therapy, or body mass index ≥ 30 kg/m) was present in 89% of patient encounters. Therapy was interrupted prematurely in 4% of all sessions, most commonly for patient-ventilator asynchrony and agitation. Early physical and occupational therapy is feasible from the onset of mechanical ventilation despite high illness acuity and presence of life support devices. Adverse events are uncommon, even in this high-risk group.

CHEST Journal, 2011

C ode status orders refer to decisions to perform or not perform CPR in the event of cardiopulmon... more C ode status orders refer to decisions to perform or not perform CPR in the event of cardiopulmonary arrest. In making decisions about code status orders it is essential that physicians and patients communicate effectively so that patients can receive informed, compassionate care that respects their treatment preferences. However, communication between physicians and patients (or their surrogates) about code status orders is diffi cult, 1 and misunderstandings about code status preferences may lead to unwanted medical interventions 2,3 or withholding of desired interventions. The need for effective and respectful communication about resuscitation preferences is heightened in the setting of the ICU where the pace of decision making is often rapid, the burdens of medical technology are typically signifi cant, diagnoses and prognoses may be uncertain, 4 surrogate decision making is common, 5 and the threat of death or disability understandably causes fear and anxiety.

Australian Occupational Therapy Journal, 2009

Intensive Care Medicine, 2014

Your article is protected by copyright and all rights are held exclusively by Springer-Verlag Ber... more Your article is protected by copyright and all rights are held exclusively by Springer-Verlag Berlin Heidelberg and ESICM. This e-offprint is for personal use only and shall not be selfarchived in electronic repositories. If you wish to self-archive your article, please use the accepted manuscript version for posting on your own website. You may further deposit the accepted manuscript version in any repository, provided it is only made publicly available 12 months after official publication or later and provided acknowledgement is given to the original source of publication and a link is inserted to the published article on Springer's website. The link must be accompanied by the following text: "The final publication is available at link.springer.com".