Minimal Effects of Intravenous Administration of Xenogeneic Adipose Derived Stem Cells on Organ Function in a Porcine 40%TBSA Burn Model

Abstract Adipose stem cells (ASCs) have shown therapeutic promise for various conditions, including burn injury. While ASCs have immunomodulatory properties, concerns exist over pro-coagulant activity after intravenous (IV) administration. In the present study, we examined IV human ASC delivery in terms of coagulation, organ function, and inflammation in a 40% total body surface area (TBSA) swine burn model. Anesthetized female Yorkshire swine were burned and randomized to receive 15ml/kg Lactated Ringer’s containing: no ASCs; a low dose (5x10 5 ASCs/kg), or a high dose (5x10 6 ASCs/kg). For biochemical analysis, blood was collected at baseline (BL), 3, 6, 12, and 24 hours post-burn, while kidney and liver tissue was collected post-euthanasia. A significant, but transient, effect of ASCs was seen on prothrombin times and INR, wherein low doses revealed slight hypercoagulation. Burns increased partial thromboplastin time, fibrinogen, and d-dimer levels, which was unchanged with ASC administration. ASCs tended to exacerbate increases in bilirubin at 3 hours, but this didn’t reach statistical significance. A significant effect of ASCs on creatinine and BUN was seen, wherein low doses elevated levels at 24 hours (creatinine, p=0.0012; BUN, p=0.0195). Hepatic and renal TUNEL staining were similar for all groups. A dose-dependent decrease in IL-8 was observed, while low doses significantly increased IL-1RA at 3 (p=0.050), IL-12 at 12 (p=0.021) and IL-6 at 24 hours post-burn (p=0.035). IV administration of xenogeneic ASCs slightly increased coagulation, but effects on burn-induced renal and hepatic dysfunction effects were minimal. Despite some significant immunomodulation, organ dysfunction effects were modest. Collectively, this study provides evidence to be skeptical about xenogeneic ASC administration in regards to burn.

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125 Minimal Effects of Intravenous Administration of Xenogeneic Adipose Derived Stem Cells on Organ Function in a Porcine 40%TBSA Burn Model

Journal of Burn Care & Research ◽

10.1093/jbcr/irab032.129 ◽

2021 ◽

Vol 42 (Supplement_1) ◽

pp. S84-S85

Author(s):

Tiffany C Heard ◽

Belinda Gomez ◽

Jamila Duarte ◽

Michael A Dubick ◽

Robert J Christy ◽

...

Keyword(s):

Stem Cells ◽

Organ Dysfunction ◽

Low Dose ◽

Statistical Significance ◽

Total Body Surface Area ◽

Cumulative Effect ◽

High Dose ◽

Organ Function ◽

Human Ascs ◽

Coagulation Status

Abstract Introduction Adipose stem cells (ASCs) have shown therapeutic promise for inflammatory conditions that beget multi organ dysfunction, including burns. While ASCs have immunomodulatory properties, some studies have brought up safety concerns of increased pro-coagulant activity such as pulmonary microvascular thrombi formation after intravenous (IV) administration of ASCs. In the present study, the aims are two-fold: 1) to verify if IV administration of human ASCs promotes coagulation and 2) to determine if human ASCs affect organ function in a 40% total body surface area (TBSA) swine burn model. Methods Female Yorkshire swine (39.63 ± 8.26kg) were anesthetized and subjected to 40% TBSA full thickness contact burns according to a formerly established model. After recovery from anesthesia, animals were randomized to receive 15ml/kg Lactated Ringer’s Solution containing: 1- no ASCs; 2- a low dose (5x105 ASCs/kg), or 3- a high dose (5x106 ASCs/kg) over a 15-minute period as a bolus. Blood was collected at baseline (BL) and 3, 6, 12, and 24h post burn to determine the effect of ASCs on organ function and coagulation status. At 24h post-burn, animals were humanely euthanized, and kidney and liver tissue was collected for histological and Western blot analyses. Data is presented as mean ± SEM, and statistical significance was set at p< 0.05. Results The high dose of ASCs significantly increased the circulating number of monocytes starting at 12 hours. Two-way ANOVA revealed a significant effect of ASCs on both prothrombin times (PT) and international normalized ratio (INR) (1.03 ± 0.04, 0.93 ± 0.03, and 1.02 ± 0.04 for no, low and high ASC groups, respectively at 24 hours). There were no differences in partial thromboplastin time, fibrinogen, or d-dimer levels. Both doses of ASCs briefly exacerbated burn-induced increases in total bilirubin at 3 hours (0.062 ± 0.025mg/dL, 0.148 ± 0.060mg/dL, and 0.211 ± 0.086mg/dL in no, low, and high ASC groups, respectively). ASCs did not alter urine output; yet, there was a significant effect of ASCs on creatinine. Western blotting revealed a rise in caspase expression in the liver of animals receiving a low dose of ASCs, while there was no difference in caspase expression in kidneys. Conclusions We show that IV administration of xenogeneic ASCs produces minimal changes in coagulation status and renal and hepatic dysfunction. Modest changes in the extrinsic coagulation pathway were dose-dependent, while exacerbation of liver dysfunction was brief and normalized after administration of ASCs was completed. We cannot rule out that continuous infusion of ASCs would not have a cumulative effect on organ dysfunction.

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Long-Term Cryopreservation Does Not Affect Quality of Peripheral Blood Stem Cell Grafts: A Comparative Study of Native, Short-Term and Long-Term Cryopreserved Haematopoietic Stem Cells

Cell Transplantation ◽

10.1177/09636897211036004 ◽

2021 ◽

Vol 30 ◽

pp. 096368972110360

Author(s):

Daniel Lysak ◽

Michaela Brychtová ◽

Martin Leba ◽

Miroslava Čedíková ◽

Daniel Georgiev ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Statistical Significance ◽

Extended Period ◽

High Dose ◽

Atp Production ◽

Cd34 Cells ◽

Negative Effect

Cryopreserved haematopoietic progenitor cells are used to restore autologous haematopoiesis after high dose chemotherapy. Although the cells are routinely stored for a long period, concerns remain about the maximum storage time and the possible negative effect of storage on their potency. We evaluated the effect of cryopreservation on the quality of peripheral stem cell grafts stored for a short (3 months) and a long (10 years) period and we compared it to native products.The viability of CD34+ cells remained unaffected during storage, the apoptotic cells were represented up to 10% and did not differ between groups. The clonogenic activity measured by ATP production has decreased with the length of storage (ATP/cell 1.28 nM in native vs. 0.63 in long term stored products, P < 0.05). Only borderline changes without statistical significance were detected when examining mitochondrial and aldehyde dehydrogenase metabolic activity and intracellular pH, showing their good preservation during cell storage. Our experience demonstrates that cryostorage has no major negative effect on stem cell quality and potency, and therefore autologous stem cells can be stored safely for an extended period of at least 10 years. On the other hand, long term storage for 10 years and longer may lead to mild reduction of clonogenic capacity. When a sufficient dose of stem cells is infused, these changes will not have a clinical impact. However, in products stored beyond 10 years, especially when a low number of CD34+ cells is available, the quality of stem cell graft should be verified before infusion using the appropriate potency assays.

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Treatment of Anaemia in Patients with Acute Burn Injury: A Study of Blood Transfusion Practices

Journal of Clinical Medicine ◽

10.3390/jcm10030476 ◽

2021 ◽

Vol 10 (3) ◽

pp. 476

Author(s):

Ioana Tichil ◽

Samara Rosenblum ◽

Eldho Paul ◽

Heather Cleland

Keyword(s):

Blood Transfusion ◽

Surgical Management ◽

Burn Injury ◽

Total Body Surface Area ◽

Perioperative Period ◽

Hospital Length ◽

Hospital Length Of Stay ◽

Burn Care ◽

Transfusion Requirements ◽

Total Body

Objective: To determine blood transfusion practices, risk factors, and outcomes associated with the use of blood products in the setting of the acute management of burn patients at the Victorian Adult Burn Service. Background: Patients with burn injuries have variable transfusion requirements, based on a multitude of factors. We reviewed all acute admissions to the Victorian Adult Burns Service (VABS) between 2011 and 2017: 1636 patients in total, of whom 948 had surgery and were the focus of our analysis. Method and results: Patient demographics, surgical management, transfusion details, and outcome parameters were collected and analyzed. A total of 175 patients out of the 948 who had surgery also had a blood transfusion, while 52% of transfusions occurred in the perioperative period. The median trigger haemoglobin in perioperative was 80mg/dL (IQR = 76–84.9 mg/dL), and in the non-perioperative setting was 77 mg/dL (IQR = 71.61–80.84 mg/dL). Age, gender, % total body surface area (TBSA) burn, number of surgeries, and intensive care unit and hospital length of stay were associated with transfusion. Conclusions: The use of blood transfusions is an essential component of the surgical management of major burns. As observed in our study, half of these transfusions are related to surgical procedures and may be influenced by the employment of blood conserving strategies. Furthermore, transfusion trigger levels in stable patients may be amenable to review and reduction. Risk adjusted analysis can support the implementation of blood transfusion as a useful quality indicator in burn care.

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Pediatric burn resuscitation: past, present, and future

Burns & Trauma ◽

10.1186/s41038-017-0091-y ◽

2017 ◽

Vol 5 ◽

Cited By ~ 15

Author(s):

Kathleen S. Romanowski ◽

Tina L. Palmieri

Keyword(s):

Fluid Resuscitation ◽

Burn Injury ◽

Total Body Surface Area ◽

Burn Shock ◽

Basic Principles ◽

Future Directions ◽

Number Of Children ◽

History Of ◽

Adults And Children ◽

Total Body

Abstract Burn injury is a leading cause of unintentional death and injury in children, with the majority being minor (less than 10%). However, a significant number of children sustain burns greater than 15% total body surface area (TBSA), leading to the initiation of the systemic inflammatory response syndrome. These patients require IV fluid resuscitation to prevent burn shock and death. Prompt resuscitation is critical in pediatric patients due to their small circulating blood volumes. Delays in resuscitation can result in increased complications and increased mortality. The basic principles of resuscitation are the same in adults and children, with several key differences. The unique physiologic needs of children must be adequately addressed during resuscitation to optimize outcomes. In this review, we will discuss the history of fluid resuscitation, current resuscitation practices, and future directions of resuscitation for the pediatric burn population.

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Bone marrow mesenchymal stem cells promote remyelination in spinal cord by driving oligodendrocyte progenitor cell differentiation via TNFα/RelB-Hes1 pathway: a rat model study of 2,5-hexanedione-induced neurotoxicity

Stem Cell Research & Therapy ◽

10.1186/s13287-021-02518-z ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Shuangyue Li ◽

Huai Guan ◽

Yan Zhang ◽

Sheng Li ◽

Kaixin Li ◽

...

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Statistical Significance ◽

High Dose ◽

Sprague Dawley ◽

Oligodendrocyte Progenitor ◽

Hes1 Expression ◽

Marrow Mesenchymal Stem Cells

Abstract Background N-hexane, with its metabolite 2,5-hexanedine (HD), is an industrial hazardous material. Chronic hexane exposure causes segmental demyelination in the peripheral nerves, and high-dose intoxication may also affect central nervous system. Demyelinating conditions are difficult to treat and stem cell therapy using bone marrow mesenchymal stem cells (BMSCs) is a promising novel strategy. Our previous study found that BMSCs promoted motor function recovery in rats modeling hexane neurotoxicity. This work aimed to explore the underlying mechanisms and focused on the changes in spinal cord. Methods Sprague Dawley rats were intoxicated with HD (400 mg/kg/day, i.p, for 5 weeks). A bolus of BMSCs (5 × 107 cells/kg) was injected via tail vein. Demyelination and remyelination of the spinal cord before and after BMSC treatment were examined microscopically. Cultured oligodendrocyte progenitor cells (OPCs) were incubated with HD ± BMSC-derived conditional medium (BMSC-CM). OPC differentiation was studied by immunostaining and morphometric analysis. The expressional changes of Hes1, a transcription factor negatively regulating OPC-differentiation, were studied. The upstream Notch1 and TNFα/RelB pathways were studied, and some key signaling molecules were measured. The correlation between neurotrophin NGF and TNFα was also investigated. Statistical significance was evaluated using one-way ANOVA and performed using SPSS 13.0. Results The demyelinating damage by HD and remyelination by BMSCs were evidenced by electron microscopy, LFB staining and NG2/MBP immunohistochemistry. In vitro cultured OPCs showed more differentiation after incubation with BMSC-CM. Hes1 expression was found to be significantly increased by HD and decreased by BMSC or BMSC-CM. The change of Hes1 was found, however, independent of Notch1 activation, but dependent on TNFα/RelB signaling. HD was found to increase TNFα, RelB and Hes1 expression, and BMSCs were found to have the opposite effect. Addition of recombinant TNFα to OPCs or RelB overexpression similarly caused upregulation of Hes1 expression. The secretion of NGF by BMSC and activation of NGF receptor was found important for suppression of TNFα production in OPCs. Conclusions Our findings demonstrated that BMSCs promote remyelination in the spinal cord of HD-exposed rats via TNFα/RelB-Hes1 pathway, providing novel insights for evaluating and further exploring the therapeutical effect of BMSCs on demyelinating neurodegenerative disease.

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Restrictive Transfusion Strategy Is More Effective in Massive Burns: Results of the TRIBE Multicenter Prospective Randomized Trial

Military Medicine ◽

10.1093/milmed/usy279 ◽

2019 ◽

Vol 184 (Supplement_1) ◽

pp. 11-15 ◽

Cited By ~ 7

Author(s):

Tina L Palmieri ◽

James H Holmes ◽

Brett Arnoldo ◽

Michael Peck ◽

Amalia Cochran ◽

...

Keyword(s):

Wound Healing ◽

Burn Injury ◽

Total Body Surface Area ◽

Inhalation Injury ◽

Transfusion Strategy ◽

Restrictive Transfusion ◽

Blood Utilization ◽

Outcome Differences ◽

Total Body ◽

Restrictive Transfusion Strategy

Abstract Objectives Studies suggest that a restrictive transfusion strategy is safe in burns, yet the efficacy of a restrictive transfusion policy in massive burn injury is uncertain. Our objective: compare outcomes between massive burn (≥60% total body surface area (TBSA) burn) and major (20–59% TBSA) burn using a restrictive or a liberal blood transfusion strategy. Methods Patients with burns ≥20% were block randomized by age and TBSA to a restrictive (transfuse hemoglobin <7 g/dL) or liberal (transfuse hemoglobin <10 g/dL) strategy throughout hospitalization. Data collected included demographics, infections, transfusions, and outcomes. Results Three hundred and forty-five patients received 7,054 units blood, 2,886 in massive and 4,168 in restrictive. Patients were similar in age, TBSA, and inhalation injury. The restrictive group received less blood (45.57 ± 47.63 vs. 77.16 ± 55.0, p < 0.03 massive; 11.0 ± 16.70 vs. 16.78 ± 17.39, p < 0.001) major). In massive burn, the restrictive group had fewer ventilator days (p < 0.05). Median ICU days and LOS were lower in the restrictive group; wound healing, mortality, and infection did not differ. No significant outcome differences occurred in the major (20–59%) group (p > 0.05). Conclusions: A restrictive transfusion strategy may be beneficial in massive burns in reducing ventilator days, ICU days and blood utilization, but does not decrease infection, mortality, hospital LOS or wound healing.

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A Comparative Study between C-Reactive Protein and Procalcitonin in Iraqi Burn Patients

Al-Mustansiriyah Journal of Science ◽

10.23851/mjs.v28i1.310 ◽

2017 ◽

Vol 28 (1) ◽

pp. 41

Author(s):

Alia E. Al-Ubadi

Keyword(s):

Burn Injury ◽

Total Body Surface Area ◽

Latex Agglutination ◽

Burn Patients ◽

C Reactive Protein ◽

Reactive Protein ◽

Survivor Group ◽

Significant Difference ◽

The Mean ◽

Total Body

Association between Procalcitonin (PCT) and C-reactive protein (CRP) and burn injury was evaluated in 80 burned patients from Al-Kindy and Imam Ali hospitals in Baghdad-Iraq. Patients were divided into two groups, survivor group 56 (70%) and non-survivor group 24 (30%). PCT was estimated using (Human Procalcitonin ELISA kit) provided by RayBio/USA while CRP was performed using a latex agglutination kit from Chromatest (Spain). Our results declared that the mean of Total Body Surface Area (TBSA %) affected were 63.5% range (36%–95%) in non-survivor patients, while 26.5% range (10%–70%) in survivor patients. There is a significant difference between the two groups (P = 0.00), the higher mean percentage of TBSA has a significant association with mortality. Serum PCT and CRP were measured at the three times of sampling (within the first 48hr following admission, after 5thdays and after 10th days). The mean of PCT serum concentrations in non-survivor group (2638 ± 3013pg/ml) were higher than that of survivor group (588 ± 364pg/ml). Significantly high levels of CRP were found between the survivor and non-survivor groups especially in the 10th day of admission P=0.000, present study show that significant differences is found within the non-survivor group through the three times P= 0.01, while results were near to significant differences within survivor group through the three times (P= 0.05).

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The predisposing factors of AKI for prophylactic strategies in burn care

PeerJ ◽

10.7717/peerj.9984 ◽

2020 ◽

Vol 8 ◽

pp. e9984

Author(s):

Shin-Yi Tsai ◽

Chon-Fu Lio ◽

Shou-Chuan Shih ◽

Cheng-Jui Lin ◽

Yu-Tien Chen ◽

...

Keyword(s):

Burn Injury ◽

Laboratory Data ◽

Total Body Surface Area ◽

Kidney Injury ◽

Inhalation Injury ◽

Predisposing Factors ◽

Dust Explosion ◽

Burn Care ◽

Hospital Patients ◽

Total Body

Background Acute kidney injury (AKI) is one of the most severe complications of burn injury. AKI with severe burn injury causes high mortality. This study aims to investigate the incidence of and predisposing factors for AKI in burn patients. Methods This is a single-center, retrospective, descriptive criterion standard study conducted from June 27, 2015, to March 8, 2016. We used Kidney Disease Improving Global Outcomes criteria to define and select patients with AKI. The study was conducted by recruiting in hospital patients who suffered from the flammable cornstarch-based powder explosion and were treated under primary care procedures. A total of 49 patients who suffered from flammable dust explosion-related burn injury were enrolled and admitted on June 27, 2015. The patients with more than 20% total body surface area of burn were transferred to the intensive care unit. Patients received fluid resuscitation in the first 24 hours based on the Parkland formula. The primary measurements were the incidence of and predisposing factors for AKI in these patients. Demographic characteristics, laboratory data, and inpatient outcomes were also evaluated. The incidence of AKI in this cohort was 61.2% (n = 30). The mortality rate was 2.0% (n = 1) during a 59-day follow-up period. The multivariate analysis revealed inhalation injury (adjusted OR = 22.0; 95% CI [1.4–358.2]) and meeting ≥3 American Burn Association (ABA) sepsis criteria (adjusted OR = 13.7; 95% CI [1.7–110.5]) as independent risk factors for early advanced AKI. Conclusions The incidence rate of AKI was higher in this cohort than in previous studies, possibly due to the flammable dust explosion-related burn injury. However, the mortality was lower than that expected. In clinical practice, indicators of inflammation, including ABA sepsis criteria may help in predicting the risk of AKI in patients with burn injury.

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521 Incidence of Bone Fracture Rate Post-Burn and Trauma in Role 2 and 3 Treatment Centers

Journal of Burn Care & Research ◽

10.1093/jbcr/irab032.172 ◽

2021 ◽

Vol 42 (Supplement_1) ◽

pp. S107-S108

Author(s):

Linda E Sousse ◽

Amanda Staudt ◽

Christopher VanFosson

Keyword(s):

Bone Fracture ◽

Injury Severity ◽

Burn Injury ◽

Bone Fractures ◽

Total Body Surface Area ◽

Anatomical Location ◽

Fracture Rate ◽

Initial Correlation ◽

Total Body ◽

Markers Of Bone Resorption

Abstract Introduction One of the hallmarks of critical illness and trauma is that it triggers resorptive bone loss, as well as an increase in bone fractures and a reduction in bone density. Sustained markers of bone resorption, bone formation, and regulators of bone signaling pathways are linked to prolonged inflammatory activities and the prolonged deterioration of bone microstructure. The objective of this study is to evaluate the bone fracture rate of the U.S Military, non-U.S. Military, North Atlantic Treaty Organization (NATO) Military, local civilian, and Coalition Forces population in Operation Enduring Freedom and Operation Freedom’s Sentinel with burns from 2005 to 2018 using the Department of Defense Trauma Registry (DoDTR; n=28,707). Our hypothesis is that there is a direct relationship between burn injury severity and bone fracture rates. Methods Pearson’s correlation coefficient and scatterplots were used in this retrospective, observational study to demonstrate the correlation between total body surface area (TBSA) burn and number of fractures by anatomical location. Results Approximately 15,195 patients (age: 26 ± 10 years) in Role 2 and Role 3 treatment centers reported fractures. Of those patients, 351 suffered from burns with 632 anatomical fracture locations. Facial fractures were most prominent (16%), followed by foot (12%), skull (12%), tibia/fibula (11%), hand (11%), and ulna/radius (10%). There was no initial correlation between n increasing severity of TBSA burn and count of fracture locations (ρ=-0.03, p=0.8572). Conclusions There was no acute correlation between burn severity and bone fracture rates; however, further analyses are required to assess chronic post-burn fracture rates.

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Burns and Electrical Injuries

Mayo Clinic Critical and Neurocritical Care Board Review ◽

10.1093/med/9780190862923.003.0065 ◽

2019 ◽

pp. 409-414

Author(s):

Brandon T. Nokes ◽

Ayan Sen

Keyword(s):

Critical Care ◽

Surface Area ◽

Body Surface ◽

Burn Injury ◽

Total Body Surface Area ◽

Burn Injuries ◽

Burn Severity ◽

Thermal Burn ◽

Total Body ◽

Electrical Injuries

Burn injuries may cause morbidity and death, and patients may have widely variable presentations and outcomes. This chapter focuses on the critical care aspects of burn injury and management issues of burn and electrical injuries. Burns are classified according to the amount of total body surface area (TBSA) affected, the depth of burn, and the type of exposure associated with the burn. More specifically, burns can be chemical, electrical, or thermal. Burn severity is determined by the depth of involvement.

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