Papers by Kristine Mulier
Artificial Organs, May 1, 2005
Shock, Sep 1, 1999
Adequate resuscitation of patients from shock states depends on restoration of oxygen delivery (D... more Adequate resuscitation of patients from shock states depends on restoration of oxygen delivery (DO2) to tissues. Direct measurement of systemic DO2 during shock states requires invasive techniques such as pulmonary artery catheterization. These experiments were performed to examine the ability of near-infrared spectroscopy (NIRS), to measure regional tissue oxygenation in a large-animal model of hemorrhagic shock, and to compare these measures to global measures of oxygen delivery. Splenectomized female pigs (n = 11) were anesthetized, instrumented, and monitored. NIRS probes were placed on the leg, in the stomach via nasogastric tube, and on the liver during laparotomy. Hemorrhagic shock was induced by phlebotomy of 28% of blood volume. After 1 hour, resuscitation was with shed blood and crystalloid until cardiac output plateaued. Measurements of physiologic parameters, blood gases, lactate, intramucosal pH, and NIRS values for regional tissue hemoglobin oxygen saturation (StO2), and cytochrome a,a3 redox state were recorded at intervals throughout the experiment. Tissue oxygenation as measured by oxyhemoglobin saturation and cytochrome a,a3 redox (NIRS) correlated with measures of systemic DO2 throughout the experiment. The liver probe demonstrated blunted changes in tissue oxygenation suggesting relatively protected circulation. Intramucosal pH did not correlate well with DO2. Regional tissue oxygenation as measured by NIRS shows excellent correlation with global oxygen delivery. NIRS may allow estimation of systemic oxygen delivery using rapid non-invasive techniques.
American Journal of Physiology-Lung Cellular and Molecular Physiology, 1997
Alveolar type II epithelial (ATII) cells repopulate the alveolus after acute lung injury. We hypo... more Alveolar type II epithelial (ATII) cells repopulate the alveolus after acute lung injury. We hypothesized that injury would initiate signals in nearby survivors. When rat ATII monolayers were wounded, elevations in intracellular free Ca2+concentration ([Ca2+]i) began at the edge of the wound and propagated outward as a wave for at least 300 μm. The [Ca2+]iwave was due to both influx of extracellular Ca2+and release of intracellular Ca2+stores. Reducing Ca2+influx with brief treatments of ethylene glycol-bis(β-aminoethyl ether)- N, N, N′, N′-tetraacetic acid or Gd3+reduced both the amplitude and the apparent speed. Draining intracellular Ca2+stores by pretreatment with cyclopiazonic acid eliminated the [Ca2+]iwave. Therefore, the [Ca2+]iwave depended critically on intracellular Ca2+stores. [Ca2+]ielevations propagated over a break in the monolayer, suggesting that extracellular pathways were involved. Furthermore, extracellular factors from injured cells elevated [Ca2+]iin uninjured ...
Methods of Tissue Engineering, 2002
Transplantation, 1995
Current bioartificial liver devices are based on the use of a large mass of hepatocytes exhibitin... more Current bioartificial liver devices are based on the use of a large mass of hepatocytes exhibiting differentiated metabolic function. The pig has become a source of interest for the acquisition of such cells-however, harvesting a large mass of highly viable cells has met with difficulty. This study describes a technique for harvesting large quantities of hepatocytes at viabilities greater than 90% and also describes several features documenting differentiated function. Pigs, 6 to 10 kg body weight, underwent in situ two-step whole liver perfusion (ethylene glycol tetraacetic acid and collagenase) and ex vivo cell harvest. Harvests yielded an average of 19.5 billion cells with an average viability of 94.6%. Hepatocytes were then entrapped in type I collagen (3 x 10(5) cells/well) and cultured in serum-free media for 5 days. Pig hepatocytes produced stable amounts of albumin and maintained cytochrome P-450 and glucuronidation activity over 5 days, as shown by the metabolism of lidocaine and 4-methylumbelliferone. These data indicate that pig hepatocytes can be harvested with high yields and can retain viability and differentiated function over at least 5 days of culture, and therefore should prove to be an excellent source of hepatocytes for bioartificial liver devices.
Shock, 1999
Adequate resuscitation of patients from shock states depends on restoration of oxygen delivery (D... more Adequate resuscitation of patients from shock states depends on restoration of oxygen delivery (DO2) to tissues. Direct measurement of systemic DO2 during shock states requires invasive techniques such as pulmonary artery catheterization. These experiments were performed to examine the ability of near-infrared spectroscopy (NIRS), to measure regional tissue oxygenation in a large-animal model of hemorrhagic shock, and to compare these measures to global measures of oxygen delivery. Splenectomized female pigs (n = 11) were anesthetized, instrumented, and monitored. NIRS probes were placed on the leg, in the stomach via nasogastric tube, and on the liver during laparotomy. Hemorrhagic shock was induced by phlebotomy of 28% of blood volume. After 1 hour, resuscitation was with shed blood and crystalloid until cardiac output plateaued. Measurements of physiologic parameters, blood gases, lactate, intramucosal pH, and NIRS values for regional tissue hemoglobin oxygen saturation (StO2), and cytochrome a,a3 redox state were recorded at intervals throughout the experiment. Tissue oxygenation as measured by oxyhemoglobin saturation and cytochrome a,a3 redox (NIRS) correlated with measures of systemic DO2 throughout the experiment. The liver probe demonstrated blunted changes in tissue oxygenation suggesting relatively protected circulation. Intramucosal pH did not correlate well with DO2. Regional tissue oxygenation as measured by NIRS shows excellent correlation with global oxygen delivery. NIRS may allow estimation of systemic oxygen delivery using rapid non-invasive techniques.
Critical Care Medicine, 2002
Surgical Infections, 2003
The reason for increased infectious complications after traumatic injury is complex and incomplet... more The reason for increased infectious complications after traumatic injury is complex and incompletely understood. We propose a relationship between the energetic state of circulating immune cells and immune cell function in traumatic injury. To examine this relationship, cellular adenosine triphosphate (ATP) concentration and cellular functions were measured in peripheral blood mononuclear cells from trauma patients and normal subjects. Mononuclear cells were isolated within 24 h of injury from trauma patients without (n = 12) or with (n = 10) hypotension (groups 1 and 2, respectively), and a group of normal control subjects (group 3, n = 13). Mononuclear cells were assayed for ATP levels using bioluminescence. Phagocytosis was quantified via flow cytometry after ingestion of fluorescent microspheres and phagocytic index (PI) was calculated (average number of particles ingested per monocyte). Protein synthesis was quantified using incorporation of (35)S-labeled methionine into cultured cells. Comparisons between groups were performed using one-way analysis of variance (ANOVA) with adjustment for multiple comparisons. All but one trauma patient suffered blunt injury. There were significantly more transfusions in group 2 (hypotensive) patients (p = 0.0005). Nosocomial infections, length of stay (LOS), and mortality did not differ between groups 1 and 2. Concentrations of ATP and PI in both groups of traum a patients did not significantly differ from controls. In hypotensive trauma patients, increased duration of hypotension was associated with increased mononuclear cell ATP levels (r(2) = 0.227). A negative correlation between PI and ATP levels in trauma patients was discovered. Incorporation of (35)S was significantly greater in normotensive trauma patients than controls. Mononuclear cell ATP levels and measured functions are preserved in early traumatic injury.
Public reporting burden for this collection of information is estimated to average 1 hour per res... more Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information Operations and Reports (0704-0188), 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number.
Journal of The American College of Surgeons, Sep 1, 2012
NTotal32024؍ Other government (N)8823؍ Medicaid (N)3108؍ Medicare (N)634,1؍ Uninsured (N... more NTotal32024؍ Other government (N)8823؍ Medicaid (N)3108؍ Medicare (N)634,1؍ Uninsured (N)83912؍ Private (Nϭ7978) 0.92 (0.71, 1.20) 0.66* (0.54, 0.82) 0.95 (0.73, 1.24) 1.93* (1.66, 2.24) Other government 0.72* (0.55, 0.96) 1.03 (0.73, 1.46) 2.10* (1.63, 2.70) Medicaid 1.43* (1.07, 1.91) 2.90* (2.30, 3.67) Medicare 2.03* (1.55, 2.67) Adjusted for age, sex, race, ISS, MOI, GCS-M, and presence of hypotension. *Statistically significant at pϽ0.05; ءءInterpretation: Row labels represent the reference group. Odds ratiosϭ{Odds of death | column type}/{Odds of death | row type}. Example-Odds ratio for death among "Other Government" versus "Private" ϭ 0.92.
Journal of The American College of Surgeons, Sep 1, 2006
Journal of The American College of Surgeons, Sep 1, 2007
creased aC3 positive cells at 24 h (5.5ϩ/Ϫ2.1 vs. 0.6ϩ/Ϫ0.03, pϽ.05) following kidney IRI, but no... more creased aC3 positive cells at 24 h (5.5ϩ/Ϫ2.1 vs. 0.6ϩ/Ϫ0.03, pϽ.05) following kidney IRI, but not BNx. TUNEL confirmed increased pulmonary apoptosis after kidney IRI, and co-localization with CD34 identified endothelial apoptosis. BAL protein (g/ml) increased following IRI in vehicle mice (540ϩ/Ϫ71 vs. 357ϩ/Ϫ35, pϽ.05), but not in Z-VAD-FMK mice (237ϩ/Ϫ57 vs. 223ϩ/Ϫ13). CONCLUSIONS: These data demonstrate activation of apoptosisrelated pathways in mouse lung after kidney IRI which contribute to AKI-associated lung microvascular injury and are caspasedependent.
Journal of Surgical Research, Feb 1, 2008
Internal carotid artery (ICA) injuries occur secondary to craniofacial trauma, however, diagnosis... more Internal carotid artery (ICA) injuries occur secondary to craniofacial trauma, however, diagnosis is often delayed and neurovascular sequelae can be devastating. The association between craniofacial fracture and ICA injury is poorly understood. This retrospective study examines the diagnosis, management, and outcomes of patients presenting with facial fractures found to have concomitant ICA lesions. Patterns of facial fractures associated with ICA injury are identified. Methods: 244 patients with ICA injury who presented to an urban trauma center between 1998-2006 were identified. 40 patients (17%) had concominant facial fractures. CT and/or MR angiography and facial, head, or neck CT with 3-D reconstruction were utilized to identify injuries. Patient records and radiographs were reviewed under an IRB approved protocol, and injuries were classified using the Biffl grading system. Results: The majority of the 40 patients studied were male (29), with an average age of 31 years (range 11-60). The mean injury severity score (ISS) was 35 (range 13-75). 80% (32) of injuries were associated with blunt trauma. Midface injuries alone or in combination with other facial fractures resulted in a higher grade of ICA injury (mean grade 2.9) than patients sustaining facial fractures to the mandible or upper face alone (mean grades 2.6 and 2.5, respectively). Increasing ICA injury grade generally corresponded with increased mortality; 91% of patients sustaining Grade IV-V injuries died. Facial fractures associated with skullbase fractures demonstrated a trend towards greater ICA injury grade (3.1 vs. 2.5, pϭ0.086) and a significant increase in the likelihood of death (63% vs. 25%, pϭ0.017) relative to patients without skull base injuries, despite similar ISS scores (mean 36 vs. 34). Presence of cervical spine fracture in association with facial fracture resulted in greater ICA injury grade (3.1 vs. 2.7), but the likelihood of death was lower (29% vs. 42%), despite similar ISS scores (36 vs. 35). Conclusion: Among patients diagnosed with facial fractures and carotid injuries, midface fractures were associated with a greater severity of ICA injury and likelihood of death than those with mandible or upper facial fractures. Skullbase injuries in association with facial fractures have a higher likelihood of mortality. Patients with facial fracture and concominant C-Spine injury tend to have lower mortality likely reflecting rotational dispersion of injury force. Consideration of ICA injuries in patients with facial fractures associated with skull base injuries may improve diagnosis and enable prompt therapeutic intervention.
Injury-international Journal of The Care of The Injured, Dec 1, 2018
Introduction: Age and sex affect outcomes from trauma. Older patients tend to be undertriaged, co... more Introduction: Age and sex affect outcomes from trauma. Older patients tend to be undertriaged, consume more healthcare resources, and experience worse outcomes relative to younger patients. Sex has also been associated with different outcomes, with women experiencing better
Shock, Aug 1, 2015
D-Q-hydroxybutyrate (BHB) and melatonin (M) treatment improves survival in animal models of hemor... more D-Q-hydroxybutyrate (BHB) and melatonin (M) treatment improves survival in animal models of hemorrhagic shock. Here, we evaluated the safety of BHB/M via 2 routes of administration in a porcine hemorrhagic shock/polytrauma model. Furthermore, we assessed BHB/M serum concentrations after intravenous and intraosseous infusion of different BHB/M doses in healthy pigs. Pigs underwent pulmonary contusion, liver injury, and hemorrhage. Injured animals were treated with an intravenous or intraosseous bolus of BHB/M or lactated Ringer's solution (LR), followed by 4 h of continuous infusion of the respective fluid (n = 12 per group). Pigs were resuscitated with LR (1 h) and then LR and shed blood (20 h). Physiological data and blood samples were analyzed throughout the experiment. In a second study, we infused healthy pigs intravenously or intraosseously with BHB/M at 3 different doses (n = 4 per group). There were no differences between groups in physiologic measurements (heart rate, mean arterial pressure, and cardiac output), organ function markers (alanine aminotransferase, aspartate aminotransferase, serum urea nitrogen, total creatinine kinase, and lactate dehydrogenase), or histopathology. The BHB/M-treated animals exhibited transient changes in blood Na + , K + , pH, and lactate. Differences in survival were not statistically significant. There was a trend toward decreased survival after intraosseous infusion, potentially related to lower circulating BHB and melatonin levels. Healthy pigs had higher drug serum concentrations after intravenous than after intraosseous infusion of BHB/M at the standard, but not the double dose. D-Q-hydroxybutyrate /M in doses previously shown to be associated with improved survival is safe in a porcine hemorrhagic shock/polytrauma model. Intravenous infusion is the preferred route of administration at standard doses.
Metabolomics, Jun 30, 2012
Resuscitation, Feb 1, 2012
Introduction: The neuroprotective ketone -hydroxybutyrate (BHB) and the antioxidant melatonin ha... more Introduction: The neuroprotective ketone -hydroxybutyrate (BHB) and the antioxidant melatonin have been found at elevated levels in hibernating mammals. Previous studies in rat models of hemorrhagic shock have suggested a benefit. We compared infusion of 4 M BHB and 43 mM melatonin (BHB/M) to 4 M sodium chloride and 20% DMSO (control solution) to evaluate for potential benefits in porcine hemorrhagic shock. Methods: Hemorrhagic shock was induced to obtain systolic blood pressures <50 mmHg for 60 min. Pigs were treated with a bolus of either BHB/M (n = 9) or control solution (n = 8) followed by 4-h infusion of the either BHB/M or control solution. All animals were then resuscitated for 20 h after shock. Physiological data were continually recorded, and blood samples were taken at intervals throughout the experiment. Serum samples were analyzed via high resolution NMR for metabolomic response. Results: BHB/M treatment significantly increased 24-h survival time when compared to treatment with control solution (100% versus 62%; p = 0.050), with a trend toward decreased volume of resuscitative fluid administered to animals receiving BHB/M. BHB/M-treated animals had lower base deficit and higher oxygen consumption when compared to animals receiving control solution. Serum metabolite profiles revealed increases in -hydroxybutyrate (BHB), succinate, 2-oxovalerate and adipate with BHB/M treatment as compared with animals treated with control infusion. Conclusion: Infusion of BHB/M conferred a survival benefit over infusion of control solution in hemorrhagic shock. BHB and its products of metabolism are identified in serum of animals subjected to shock and treated with BHB/M. Further preclinical studies are needed to clarify the mechanisms of action of this promising treatment strategy.
BMC Research Notes, Nov 29, 2017
Objective: Treatment with a combination of d-β-hydroxybutyrate (BHB) and melatonin (M) improves s... more Objective: Treatment with a combination of d-β-hydroxybutyrate (BHB) and melatonin (M) improves survival in hemorrhagic shock models. Our objective was to find the most effective melatonin concentration in combination with 4 molar BHB (4 M BHB). Survival and markers of organ injury were analyzed in pigs exposed to pulmonary contusion, liver crush injury, and hemorrhagic shock and treated with lactated Ringer's solution; 4 M BHB/43 mM M; 4 M BHB/20 mM M; 4 M BHB/10 mM M; 4 M BHB/4.3 mM M; or 4 M BHB/0.43 mM M. This work is an extension of a previously published research study. Results: Survival was highest in pigs receiving 4 M BHB/43 mM M (13/14), followed by lactated Ringer's solution (11/16) and BHB/M with decreased melatonin concentrations (4 M BHB/20 mM M 3/6, 4 M BHB/10 mM M 2/6, 4 M BHB/4.3 mM M 3/6, 4 M BHB/0.43 mM M 1/6, p = 0.011). High mortality was associated with increases in serum lactate, higher liver and muscle injury markers and decreases in PaO 2 :FiO 2 ratios. Our study indicates that treatment with 4 M BHB and melatonin concentrations below 43 mM lack the survival benefit observed from 4 M BHB/43 mM melatonin in pigs experiencing hemorrhagic shock and polytrauma.
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Papers by Kristine Mulier