Characterizing Fentanyl Variability Using Population Pharmacokinetics in Pediatric Burn Patients

Abstract Opioids are essential first line analgesics for pain management after burn injury. Opioid dosing remains challenging in burn patients, particularly in children, due to the immense variability in efficacy between patients. Opioid pharmacokinetics are altered in burned children, increasing variability and obviating dosing regimens extrapolated from adult-data. The present study aimed to characterize variability in fentanyl pharmacokinetics and identify significant contributors to variability in children with ≥10% total body surface area burn requiring fentanyl during routine wound care. We recorded patient demographics and clinical data. Blood samples were collected following fentanyl administration for pharmacokinetics at time 0, 30, 60, 120, and 240 minutes on day of admission and repeated on days 3 and 7. Serum fentanyl concentrations were quantified using tandem liquid chromatography mass spectrometry. Population analysis was used to estimate pharmacokinetics parameters. Fourteen patients, 1.2–17 years, with burns from 10–50.5% were included in analysis. A two-compartment model with body weight as a covariate best described fentanyl pharmacokinetics for the overall population. The population clearance and intercompartmental clearance were 7.19 and 2.16 L/hour, respectively, and the volume of distribution for the central and peripheral compartments was 4.01 and 25.1 L, respectively. Individual patient parameter estimates had extensive variability. This study confirmed the high variability in pediatric burn patient fentanyl pharmacokinetics and demonstrates similarities and differences to other populations reported in literature. Further research is needed with a larger number of patients to extensively investigate the impact of burns, genetic polymorphisms, and other factors on fentanyl efficacy and patient outcomes.

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11 Vitamin D Deficiency on Admission and the Association with Length of Stay in Patients with Thermal Injury: A Multi-center Analysis

Journal of Burn Care & Research ◽

10.1093/jbcr/irab032.016 ◽

2021 ◽

Vol 42 (Supplement_1) ◽

pp. S13-S14

Author(s):

Sarah Zavala ◽

Kate Pape ◽

Todd A Walroth ◽

Melissa A Reger ◽

Katelyn Garner ◽

...

Keyword(s):

Vitamin D ◽

Length Of Stay ◽

Vitamin D Deficiency ◽

Burn Injury ◽

Total Body Surface Area ◽

Inhalation Injury ◽

Hospital Length Of Stay ◽

Burn Patients ◽

Comfort Care ◽

The Impact

Abstract Introduction In burn patients, vitamin D deficiency has been associated with increased incidence of sepsis. The objective of this study was to assess the impact of vitamin D deficiency in adult burn patients on hospital length of stay (LOS). Methods This was a multi-center retrospective study of adult patients at 7 burn centers admitted between January 1, 2016 and July 25, 2019 who had a 25-hydroxyvitamin D (25OHD) concentration drawn within the first 7 days of injury. Patients were excluded if admitted for a non-burn injury, total body surface area (TBSA) burn less than 5%, pregnant, incarcerated, or made comfort care or expired within 48 hours of admission. The primary endpoint was to compare hospital LOS between burn patients with vitamin D deficiency (defined as 25OHD < 20 ng/mL) and sufficiency (25OHD ≥ 20 ng/mL). Secondary endpoints include in-hospital mortality, ventilator-free days of the first 28, renal replacement therapy (RRT), length of ICU stay, and days requiring vasopressors. Additional data collected included demographics, Charlson Comorbidity Index, injury characteristics, form of vitamin D received (ergocalciferol or cholecalciferol) and dosing during admission, timing of vitamin D initiation, and form of nutrition provided. Dichotomous variables were compared via Chi-square test. Continuous data were compared via student t-test or Mann-Whitney U test. Univariable linear regression was utilized to identify variables associated with LOS (p < 0.05) to analyze further. Cox Proportional Hazard Model was utilized to analyze association with LOS, while censoring for death, and controlling for TBSA, age, presence of inhalation injury, and potential for a center effect. Results Of 1,147 patients screened, 412 were included. Fifty-seven percent were vitamin D deficient. Patients with vitamin D deficiency had longer LOS (18.0 vs 12.0 days, p < 0.001), acute kidney injury (AKI) requiring RRT (7.3 vs 1.7%, p = 0.009), more days requiring vasopressors (mean 1.24 vs 0.58 days, p = 0.008), and fewer ventilator free days of the first 28 days (mean 22.9 vs 25.1, p < 0.001). Univariable analysis identified burn center, AKI, TBSA, inhalation injury, admission concentration, days until concentration drawn, days until initiating supplementation, and dose as significantly associated with LOS. After controlling for center, TBSA, age, and inhalation injury, the best fit model included only deficiency and days until vitamin D initiation. Conclusions Patients with thermal injuries and vitamin D deficiency on admission have increased length of stay and worsened clinical outcomes as compared to patients with sufficient vitamin D concentrations.

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Fluconazole Pharmacokinetics in Burn Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.42.4.930 ◽

1998 ◽

Vol 42 (4) ◽

pp. 930-933 ◽

Cited By ~ 19

Author(s):

Bradley A. Boucher ◽

Stephen R. King ◽

Heidi L. Wandschneider ◽

William L. Hickerson ◽

Scott D. Hanes ◽

...

Keyword(s):

Surface Area ◽

Body Surface ◽

Half Life ◽

Total Body Surface Area ◽

Volume Of Distribution ◽

Parameter Estimates ◽

Burn Patients ◽

Significant Difference ◽

Total Body ◽

Over Time

ABSTRACT The pharmacokinetics of fluconazole in nine adult patients with severe (30 to 95% total body surface area) burns were studied. There was no significant difference in half-life (t 1/2), clearance (CL), or volume of distribution (V) over time in five patients on days 3 and 8 of the study (P > 0.05). Combined parameter estimates (means ± standard deviations) for all nine patients for the two study periods were as follows: t 1/2, 24.4 ± 5.8 h; CL, 0.36 ± 0.09 ml/min/kg; and V, 0.72 ± 0.12 liters/kg. These estimates oft 1/2 and CL in burn patients were approximately 13% shorter and 30% more rapid, respectively, than the most extreme estimates reported for other populations.

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Once-Daily Amikacin Dosing in Burn Patients Treated with Continuous Venovenous Hemofiltration

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00374-11 ◽

2011 ◽

Vol 55 (10) ◽

pp. 4639-4642 ◽

Cited By ~ 19

Author(s):

Kevin S. Akers ◽

Jason M. Cota ◽

Christopher R. Frei ◽

Kevin K. Chung ◽

Katrin Mende ◽

...

Keyword(s):

Burn Injury ◽

Continuous Venovenous Hemofiltration ◽

Burn Patients ◽

Small Reduction ◽

Target Attainment ◽

Clinical Pharmacokinetics ◽

Once Daily ◽

Renal Replacement Therapies ◽

Rapid Clearance ◽

The Impact

ABSTRACTAmikacin clearance can be increased in burn injury, which is often complicated by renal insufficiency. Little is known about the impact of renal replacement therapies, such as continuous venovenous hemofiltration (CVVH), on amikacin pharmacokinetics. We retrospectively examined the clinical pharmacokinetics, bacteriology, and clinical outcomes of 60 burn patients given 15 mg/kg of body weight of amikacin in single daily doses. Twelve were treated with concurrent CVVH therapy, and 48 were not. The pharmacodynamic target of ≥10 for the maximum concentration of drug in serum divided by the MIC (Cmax/MIC) was achieved in only 8.5% of patients, with a small reduction ofCmaxin patients receiving CVVH and no difference in amikacin clearance. Mortality and burn size were greater in patients who received CVVH. Overall, 172 Gram-negative isolates were recovered from the blood cultures of 39 patients, with amikacin MIC data available for 82 isolates from 24 patients. A 10,000-patient Monte Carlo simulation was conducted incorporating pharmacokinetic and MIC data from these patients. The cumulative fraction of response (CFR) was similar in CVVH and non-CVVH patients. The CFR rates were not significantly improved by a theoretical 20 mg/kg amikacin dose. Overall, CVVH did not appear to have a major impact on amikacin serum concentrations. The low pharmacodynamic target attainment appears to be primarily due to higher amikacin MICs rather than more rapid clearance of amikacin related to CVVH therapy.

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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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Population Pharmacokinetics of Fluconazole in Young Infants

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00569-08 ◽

2008 ◽

Vol 52 (11) ◽

pp. 4043-4049 ◽

Cited By ~ 120

Author(s):

K. C. Wade ◽

D. Wu ◽

D. A. Kaufman ◽

R. M. Ward ◽

D. K. Benjamin ◽

...

Keyword(s):

Fixed Effects ◽

Compartment Model ◽

Volume Of Distribution ◽

Relative Standard Error ◽

Data Set ◽

Mixed Effect ◽

Young Infants ◽

Relative Standard ◽

Population Pk ◽

The Impact

ABSTRACT Fluconazole is being increasingly used to prevent and treat invasive candidiasis in neonates, yet dosing is largely empirical due to the lack of adequate pharmacokinetic (PK) data. We performed a multicenter population PK study of fluconazole in 23- to 40-week-gestation infants less than 120 days of age. We developed a population PK model using nonlinear mixed effect modeling (NONMEM) with the NONMEM algorithm. Covariate effects were predefined and evaluated based on estimation precision and clinical significance. We studied fluconazole PK in 55 infants who at enrollment had a median (range) weight of 1.02 (0.440 to 7.125) kg, a gestational age at birth (BGA) of 26 (23 to 40) weeks, and a postnatal age (PNA) of 2.3 (0.14 to 12.6) weeks. The final data set contained 357 samples; 217/357 (61%) were collected prospectively at prespecified time intervals, and 140/357 (39%) were scavenged from discarded clinical specimens. Fluconazole population PK was best described by a one-compartment model with covariates normalized to median values. The population mean clearance (CL) can be derived for this population by the equation CL (liter/h) equals 0.015 · (weight/1)0.75 · (BGA/26)1.739 · (PNA/2)0.237 · serum creatinine (SCRT)−4.896 (when SCRT is >1.0 mg/dl), and using a volume of distribution (V) (liter) of 1.024 · (weight/1). The relative standard error around the fixed effects point estimates ranged from 3 to 24%. CL doubles between birth and 28 days of age from 0.008 to 0.016 and from 0.010 to 0.022 liter/kg/h for typical 24- and 32-week-gestation infants, respectively. This population PK model of fluconazole discriminated the impact of BGA, PNA, and creatinine on drug CL. Our data suggest that dosing in young infants will require adjustment for BGA and PNA to achieve targeted systemic drug exposures.

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664 Risk Factors for the Development of Transaminitis in Pediatric Burn Patients Treated with Oxandrolone

Journal of Burn Care & Research ◽

10.1093/jbcr/iraa024.280 ◽

2020 ◽

Vol 41 (Supplement_1) ◽

pp. S177-S177

Author(s):

Kate Pape ◽

Sarah Zavala ◽

Rita Gayed ◽

Melissa Reger ◽

Kendrea Jones ◽

...

Keyword(s):

Risk Factors ◽

Length Of Stay ◽

Pediatric Patients ◽

Burn Injury ◽

Total Body Surface Area ◽

Future Research ◽

Burn Patients ◽

Thermal Burn ◽

Increased Risk ◽

Significant Difference

Abstract Introduction Oxandrolone is an anabolic steroid that is the standard of care for burn patients experiencing hypermetabolism. Previous studies have demonstrated the benefits of oxandrolone, including increased body mass and improved wound healing. One of the common side effects of oxandrolone is transaminitis, occurring in 5–15% of patients, but little is known about associated risk factors with the development of transaminitis. A recent multicenter study in adults found that younger age and those receiving concurrent intravenous vasopressors or amiodarone were more likely to develop transaminitis while on oxandrolone. The purpose of this study was to determine the incidence and identify risk factors for the development of transaminitis in pediatric burn patients receiving oxandrolone therapy. Methods This was a multicenter, retrospective risk factor analysis that included pediatric patients with thermal burn injury (total body surface area [TBSA] > 10%) who received oxandrolone over a 5-year time period. The primary outcome of the study was the development of transaminitis while on oxandrolone therapy, which was defined as aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >100 mg/dL. Secondary outcomes included mortality, length of stay, and change from baseline ALT/AST. Results A total of 55 pediatric patients from 5 burn centers met inclusion criteria. Of those, 13 (23.6%) developed transaminitis, and the mean time to development of transaminitis was 17 days. Patients who developed transaminitis were older (12 vs 6.4 years, p = 0.01) and had a larger mean %TBSA (45.9 vs 34.1, p = 0.03). The odds of developing transaminitis increased by 23% for each 1 year increase in age (OR 1.23, CI 1.06–1.44). The use of other concurrent medications was not associated with an increased risk of developing transaminitis. Renal function and hepatic function was not associated with the development of transaminitis. There was no significant difference in length of stay and mortality. Conclusions Transaminitis occurred in 23.6% of our study population and was associated with patients who were older and had a larger mean %TBSA burn. Older pediatric patients with larger burns who are receiving oxandrolone should be closely monitored for the development of transaminitis. Applicability of Research to Practice Future research is needed to identify appropriate monitoring and management of transaminitis in oxandrolone-treated pediatric burn patients.

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Multimodal Analgesia and Discharge Opioid Requirements in Burn Patients

Journal of Burn Care & Research ◽

10.1093/jbcr/iraa088 ◽

2020 ◽

Vol 41 (5) ◽

pp. 963-966

Author(s):

Michael Wright ◽

Jin A Lee

Keyword(s):

Surface Area ◽

Body Surface Area ◽

Body Surface ◽

Total Body Surface Area ◽

Multimodal Analgesia ◽

Burn Patients ◽

Area Burned ◽

Total Body ◽

The Impact

Abstract Analgesia in burn patients is challenging given the complexity of burn pain and prolonged need beyond hospital admission. Given the risks of opioids, the impact of multimodal analgesia postdischarge needs to be further elucidated in this population. This retrospective, single-center cohort study evaluated adult burn patients who were consecutively admitted to the burn service with at least 10% total body surface area burned and subsequently followed in the burn clinic between February 2015 and September 2018. Subjects were separated into two cohorts based on discharge pain regimens: multimodal and nonmultimodal. The primary outcome was the change in opioid requirements (measured in oral morphine equivalents) between discharge and first follow-up interval. Secondary outcomes included the classes of multimodal agents utilized and a comparison of opioid requirements between the last 24 hours of admission and discharge. A total of 152 patients were included for analysis, 76 in the multimodal cohort and 76 in the nonmultimodal cohort. The multimodal cohort was noted to have increased total body surface area burned and prolonged number of days spent in the intensive care unit at baseline; however, the multimodal cohort exhibited a more significant decrease in opioid requirements from discharge to first follow-up interval when compared with the nonmultimodal cohort (106.6 vs 75.4 mg, P = .039).

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Kinetics of dodecanedioic acid triglyceride in rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1999.276.3.e497 ◽

1999 ◽

Vol 276 (3) ◽

pp. E497-E502

Author(s):

A. de Gaetano ◽

G. Mingrone ◽

M. Castagneto ◽

G. Benedetti ◽

A. V. Greco ◽

...

Keyword(s):

High Performance ◽

Compartment Model ◽

High Performance Liquid Chromatographic ◽

Volume Of Distribution ◽

Peripheral Compartment ◽

Parameter Estimates ◽

Tissue Uptake ◽

Male Wistar Rats ◽

Dodecanedioic Acid ◽

Kinetics Of

The kinetics of the triglyceride of dodecanedioic acid (TGDA) has been investigated in 30 male Wistar rats after a rapid intravenous bolus injection. TGDA and its product of hydrolysis, nonesterified dodecanedioic acid (NEDA), were measured in plasma samples taken at different times using an improved high-performance liquid chromatographic method. The 24-h urinary excretion of TGDA was 1.54 ± 0.37 μmol, corresponding to ∼0.67% of the administered amount. Several kinetics models were considered, including central and peripheral compartments for the triglyceride and the free forms and expressing transports between compartments with combinations of linear, carrier-limited, or time-varying mechanisms. The parameter estimates of the kinetics of TGDA and of NEDA were finally obtained using a three-compartment model in which the transfer of TGDA to NEDA was assumed to be linear, through a peripheral compartment, and the tissue uptake of NEDA was assumed to be carrier limited. TGDA had a large volume of distribution (∼0.5 l/kg body wt) with a fast disappearance rate from plasma (0.42 min−1), whereas NEDA had a very small volume of distribution (∼0.04 l/kg body wt) and a tissue uptake with maximal transport rate of 0.636 mM/min. In conclusion, this first study on the triglyceride form of dodecanedioic acid indicates that it is rapidly hydrolyzed and that both triglyceride and nonesterified forms are excreted in the urine to a very low extent. The tissue uptake rate of NEDA is consistent with the possibility of achieving substantial energy delivery, should it be added to parenteral nutrition formulations. Furthermore, the amount of sodium administered with the triglyceride form is one-half of that necessary with the free diacid.

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726 The Use of Xeroform Dressings for Partial Thickness Scald Burn Injuries in a Verified Pediatric Burn Center

Journal of Burn Care & Research ◽

10.1093/jbcr/iraa024.310 ◽

2020 ◽

Vol 41 (Supplement_1) ◽

pp. S194-S195

Author(s):

Lisa C Vitale ◽

Jennifer Livingston ◽

Erica Curtis ◽

Katherine Oag ◽

Christina M Shanti ◽

...

Keyword(s):

Burn Injury ◽

Wound Care ◽

Total Body Surface Area ◽

Burn Injuries ◽

Wound Complications ◽

Burn Wound ◽

Burn Center ◽

Partial Thickness ◽

Partial Thickness Burn ◽

At Home

Abstract Introduction For children who have suffered a burn injury one of the greatest challenges is managing pain with an adequate yet practical burn wound dressing that will ultimately be managed at home. Medical product companies have created a variety of wound care products available on the market. These products are advertised to be more superior over one another in categories such as decrease in wound infections, minimization of pain, ease of dressing application, increased dressing wear time, and better wound healing. With all the options for burn wound care there are many factors to consider when choosing a burn dressing such as cost, ease of dressing for families at home, comfort, and efficacy. At our ten year verified pediatric burn center we have tried many different burn wound care products, however we have found Xeroform and bacitracin to be the most practical and easy to use for our patient population. Methods A retrospective chart review was performed from 2016–2018 of all cascading scald injuries to children 0–5 years of age treated at our verified pediatric burn center. 179 patients were included in this review. Of those patients a total of 52 patients were excluded, 28 patients had no follow up, 21 patients received alternate dressings, and 3 patients had full thickness injuries requiring a split thickness skin graft (STSG). Charts were reviewed for total body surface area (TBSA), length of stay (LOS), discharge dressing type, complications, and time to healing. All patients included routinely received consistent application of the Xeroform and bacitracin. Results 127 patients discharged with Xeroform dressings were included in this study with an average age of 1.4 years old (range 0–5 years) and average TBSA of 2.5% (range 0.25–13%). The average LOS was 1.6 days (range 1–10 days). In this sample 32 (25%) patients were healed within 7 days. 77 (61%) patients were healed within 7–14 days. 11 (9%) patients were healed within 14–21 days. 7 (5%) patients were healed in greater than 21 days. There were no wound complications identified within this study group. Conclusions Using Xeroform as our standard of practice has streamlined the care provided to our patients. We have demonstrated consistent effective re-epithelization, protection from infection, and ease of dressings for families and burn providers. In our experience Xeroform has provided a versatile way to care for partial thickness burn injuries. Applicability of Research to Practice We suggest Xeroform and bacitracin dressings be used for partial thickness burn injuries in patients under 5 years of age. This dressing may be superior to other products because it allows for bathing while providing good wound epithelization and is easy to use.

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Presentation and Management of Staphylococcal Scalded Skin Syndrome in a Child After a Burn Injury: A Case Report

Journal of Burn Care & Research ◽

10.1093/jbcr/irz035 ◽

2019 ◽

Author(s):

Thomas Edward Pidgeon ◽

Federica D’Asta ◽

Malobi Ogboli ◽

Yvonne Wilson

Keyword(s):

Case Report ◽

Burn Injury ◽

Wound Care ◽

Total Body Surface Area ◽

Granular Cell ◽

Burn Wound ◽

Staphylococcal Scalded Skin Syndrome ◽

The Face ◽

Total Body ◽

Learning Points

Abstract This case report describes the clinical course of a child who developed staphylococcal scalded skin syndrome (SSSS) after a burn injury. The intent is to aid other units in recognizing the presentation of SSSS after a pediatric burn and to optimize subsequent management. The main clinical finding was of rapid, progressive, superficial epidermal loss at sites separate from the original burn, involving 55% of the total body surface area, 13 days after a 6% scald burn to the face, neck, and chest. Diagnosis was confirmed by multidisciplinary team clinical assessment and histopathology of an intraoperative skin biopsy. This confirmed epidermal cleavage at the granular cell layer. These findings were later supported by Staphylococcus aureus cultured from the burn wound, and a positive epidermolytic toxin A assay. Management was with general medical supportive care, clindamycin and flucloxacillin intravenous antibiotic therapy, and cleansing and dressing of the areas of epidermal loss. Key learning points from this case were that SSSS presented after a burn injury and that 13 days elapsed between the burn and SSSS. Factors differentiating it from toxic epidermal necrolysis are described, including the value of histopathology in confirming the diagnosis. The prompt use of antibiotics and attentive wound care are advocated as an effective management strategy.

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