Population Pharmacokinetic Modeling and Simulations of Imipenem in Burn Patients With and Without Continuous Venovenous Hemofiltration in the Military Health System.

Continuous venovenous hemofiltration (CVVH) is a life-sustaining procedure in patients with severe burns and acute kidney injury. Physiologic changes from burn injury and use of CVVH may alter imipenem pharmacokinetics (PK). We aimed to compare imipenem clearance (CL) in burn patients with and without CVVH, determine the effect of burn on imipenem volume of distribution (CVVH, n = 12; no CVVH, n = 11), in combination with previously published models. Model qualification was performed with standard diagnostics and comparing predicted PK parameters/time-concentration profiles with those in the existing literature. Monte Carlo simulations were conducted to evaluate the probability of target attainment. A 2-compartment model best described the data. Utilizing albumin as a covariate on volume parameters and leveraging the clearance model from prior literature, our model predicted imipenem central volume and CL within a 10% margin of error across healthy, renally impaired, and burn populations. We provide direct comparison of imipenem CL in burn patients with and without CVVH. Notably, there was no significant difference. Large imipenem Vd in patients with severe burns is likely explained by increased capillary permeability, for which serum albumin may be a reasonable surrogate. Dosing 500 mg every 6 hours is adequate for burn patients on renally dosed CVVH; however, suspicion of augmented renal clearance or patients placed on CVVH without renal impairment may necessitate dosing of 1000 mg every 6 hours.

Assessment of spontaneous breathing during pressure controlled ventilation with superimposed spontaneous breathing using respiratory flow signal analysis.

Integrating spontaneous breathing into mechanical ventilation (MV) can speed up liberation from it and reduce its invasiveness. On the other hand, inadequate and asynchronous spontaneous breathing has the potential to aggravate lung injury. During use of airway-pressure-release-ventilation (APRV), the assisted breaths are difficult to measure. We developed an algorithm to differentiate the breaths in a setting of lung injury in spontaneously breathing ewes. We hypothesized that differentiation of breaths into spontaneous, mechanical and assisted is feasible using a specially developed for this purpose algorithm. Ventilation parameters were recorded by software that integrated ventilator output variables. The flow signal, measured by the EVITA® XL (Lübeck, Germany), was measured every 2 ms by a custom Java-based computerized algorithm (Breath-Sep). By integrating the flow signal, tidal volume (VT) of each breath was calculated. By using the flow curve the algorithm separated the different breaths and numbered them for each time point. Breaths were separated into mechanical, assisted and spontaneous. Bland Altman analysis was used to compare parameters. Comparing the values calculated by Breath-Sep with the data from the EVITA® using Bland-Altman analyses showed a mean bias of - 2.85% and 95% limits of agreement from - 25.76 to 20.06% for MVtotal. For respiratory rate (RR) RRset a bias of 0.84% with a SD of 1.21% and 95% limits of agreement from - 1.53 to 3.21% were found. In the cluster analysis of the 25th highest breaths of each group RRtotal was higher using the EVITA®. In the mechanical subgroup the values for RRspont and MVspont the EVITA® showed higher values compared to Breath-Sep. We developed a computerized method for respiratory flow-curve based differentiation of breathing cycle components during mechanical ventilation with superimposed spontaneous breathing. Further studies in humans and optimizing of this technique is necessary to allow for real-time use at the bedside.

An Assessment of Research Priorities to Dampen the Pendulum Swing of Burn Resuscitation.

On June 17 to 18, 2019, the American Burn Association, in conjunction with Underwriters Laboratories, convened a group of experts on burn resuscitation in Washington, DC. The goal of the meeting was to identify and discuss novel research and strategies to optimize the process of burn resuscitation. Patients who sustain a large thermal injury (involving >20% of the total body surface area [TBSA]) face a sequence of challenges, beginning with burn shock. Over the last century, research has helped elucidate much of the underlying pathophysiology of burn shock, which places multiple organ systems at risk of damage or dysfunction. These studies advanced the understanding of the need for fluids for resuscitation. The resultant practice of judicious and timely infusion of crystalloids has improved mortality after major thermal injury. However, much remains unclear about how to further improve and customize resuscitation practice to limit the morbidities associated with edema and volume overload. Herein, we review the history and pathophysiology of shock following thermal injury, and propose some of the priorities for resuscitation research. Recommendations include: studying the utility of alternative endpoints to resuscitation, reexamining plasma as a primary or adjunctive resuscitation fluid, and applying information about inflammation and endotheliopathy to target the underlying causes of burn shock. Undoubtedly, these future research efforts will require a concerted effort from the burn and research communities.

Critical Care in the Military Health System: A 24-h Point Prevalence Study.

Background: Healthcare expenditures are a significant economic cost with critical care services constituting one of its largest components. The Military Health System (MHS) is the largest, global healthcare system of its kind. In this project, we sought to describe critical care services and the patients who receive them in the MHS. Methods: We surveyed 26 military treatment facilities (MTFs) representing 38 critical care services or intensive care units (ICUs). MTFs with multiple ICUs and critical care services responded to the survey as services (e.g., surgical or medical ICU service), whereas MTFs with only one ICU responded as a unit and gave information about all types of patients (i.e., medical and surgical). Our survey was divided into an administrative portion and a 24-h point prevalence survey of patients and patient care. The administrative portion is reported separately in this journal. The 24-h point prevalence survey collected information about all patients present in, admitted to, or discharged from participating services/units during the same 24-h period in December 2014. The survey was anonymous and protected health information was not collected. Findings: Sixteen MTFs (69%) and 27 ICU services/units (71%) returned the point prevalence survey. MTFs with >200 beds (n = 3, 22%) were categorized as "high capacity centers" (HCCs) whereas those with ≤200 beds (n = 13, 78%) were characterized as low capacity centers (LCCs). Two MTFs (one HCC and one LCC) returned only administrative data. The remaining 16 MTFs reported data about 151 patients. In all, 100 (67%) of the patients were at three HCCs during this study period. One HCC accounted for 39% (59 patients) of all patient care during this study. Most patients were cared for in mixed medical/surgical ICUs (34.4%), followed by medical (21.2%), surgical (18.5%), trauma (11.9%), cardiac (7.9%), and burn (6.0%) ICUs. The most common medical indication for admission was cardiac followed by general medical. The most common surgical indications for admission were trauma, other, and cardiothoracic surgery. The average APACHE II score of all patients across both LCCs and HCCs was 11 ± 8.1 (8 ± 7.8 vs. 13 ± 7.7 p = 0.008). The lower acuity of patients in this study is reflected in a high turnover rate, low rate of arterial and central line placements (33%), and low rates of life support (all types, 30%; mechanical ventilation only, 21.2%; noninvasive mechanic ventilation only, 7.9%; and vasoactive medications, 6.6%). Thirty-five (23.2%) patients within the study were affected by a total of 57 complications. The three most common complications experienced were acute kidney injury, bleeding, and sepsis. Discussion: This is the first detailed report about MHS critical care services and the patients receiving care. It describes a low acuity ICU patient population, concentrated at larger MTFs. This study highlights the need for the establishment of a system that allows for the continuous collection of high priority information about clinical care in the MHS in order to facilitate implementation of standardized protocols and process improvements.

Intravenous Antibiotic and Antifungal Agent Pharmacokinetic-Pharmacodynamic Dosing in Adults with Severe Burn Injury.

PURPOSE: Despite advances in the care of patients with severe burn injury, infection-related morbidity and mortality remain high and can potentially be reduced with antimicrobial dosing optimized for the infecting pathogen. However, anti-infective dose selection is difficult because of the highly abnormal physiologic features of burn patients, which can greatly affect the pharmacokinetic (PK) disposition of these agents. We review published PK data from burn patients and offer evidence-based dosing recommendations for antimicrobial agents in burn-injured patients. METHODS: Because most infections occur at least 48 hours after initial burn injury and anti-infective therapy often lasts ≥10 days, we reviewed published data informing PK-pharmacodynamic (PD) dosing of anti-infectives administered during the second, hypermetabolic stage of burn injury, in those with >20% total body surface area burns, and in those with normal or augmented renal clearance (estimated creatinine clearance ≥130 mL/min). Analyses were performed using 10,000-patient Monte Carlo simulations, which uses PK variability observed in burn patients and MIC data to determine the probability of reaching predefined PK-PD targets. The probability of target attainment, defined as the likelihood that an anti-infective dosing regimen would achieve a specific PK-PD target at the single highest susceptible MIC, and the cumulative fraction of response, defined as the population probability of target attainment given a specific dose and a distribution of MICs, were calculated for each recommended anti-infective dosing regimen. FINDINGS: Evidence-based doses were derived for burn-injured patients for 15 antibiotics and 2 antifungal agents. Published data were unavailable or insufficient for several agents important to the care of burn patients, including newer antifungal and antipseudomonal agents. Furthermore, available data suggest that antimicrobial PK properties in burned patients is highly variable. We recommend that, where possible, therapeutic drug monitoring be performed to optimize PK-PD parameter achievement in individual patients. IMPLICATIONS: Given the high variability in PK disposition observed in burn patients, doses recommended in the package insert may not achieve PK-PD parameters associated with optimal infectious outcomes. Our study is limited by the necessity for fixed assumptions in depicting this highly variable patient population. New rapid-turnaround analytical technology is needed to expand the menu of antimicrobial agents for which therapeutic drug monitoring is available to guide dose modification within a clinically actionable time frame.

Electron Microscopy as a Tool for Assessment of Anticoagulation Strategies During Extracorporeal Life Support: The Proof Is on the Membrane.

Extracorporeal life support (ECLS) is fast becoming more common place for use in adult patients failing mechanical ventilation. Management of coagulation and thrombosis has long been a major complication in the use of ECLS therapies. Scanning electron microscopy (SEM) of membrane oxygenators (MOs) after use in ECLS circuits can offer novel insight into any thrombotic material deposition on the MO. In this pilot study, we analyzed five explanted MOs immediately after use in a sheep model of different acute respiratory distress syndrome (ARDS). We describe our methods of MO dissection, sample preparation, image capture, and results. Of the five MOs analyzed, those that received continuous heparin infusion showed very little thrombosis formation or other clot material, whereas those that were used with only initial heparin bolus showed readily apparent thrombotic material.

Retrospective Analysis of Long-Term Outcomes After Combat Injury: A Hidden Cost of War.

BACKGROUND: During the conflicts in Iraq and Afghanistan, 52,087 service members have been wounded in combat. The long-term sequelae of these injuries have not been carefully examined. We sought to determine the relation between markers of injury severity and the subsequent development of hypertension, coronary artery disease, diabetes mellitus, and chronic kidney disease. METHODS AND RESULTS: Retrospective cohort study of critically injured US military personnel wounded in Iraq or Afghanistan from February 1, 2002 to February 1, 2011. Patients were then followed until January 18, 2013. Chronic disease outcomes were assessed by International Classification of Diseases, 9th edition codes and causes of death were confirmed by autopsy. From 6011 admissions, records were excluded because of missing data or if they were for an individual's second admission. Patients with a disease diagnosis of interest before the injury date were also excluded, yielding a cohort of 3846 subjects for analysis. After adjustment for other factors, each 5-point increment in the injury severity score was associated with a 6%, 13%, 13%, and 15% increase in incidence rates of hypertension, coronary artery disease, diabetes mellitus, and chronic kidney disease, respectively. Acute kidney injury was associated with a 66% increase in rates of hypertension and nearly 5-fold increase in rates of chronic kidney disease. CONCLUSIONS: In Iraq and Afghanistan veterans, the severity of combat injury was associated with the subsequent development of hypertension, coronary artery disease, diabetes mellitus, and chronic kidney disease.

Comparison of virtual bronchoscopy to fiber-optic bronchoscopy for assessment of inhalation injury severity.

PURPOSE: Compare virtual bronchoscopy (VB) to fiberoptic bronchoscopy (FOB) for scoring smoke inhalation injury (SII). METHODS: Swine underwent computerized tomography (CT) with VB and FOB before (0) and 24 and 48 h after SII. VB and FOB images were scored by 5 providers off line. RESULTS: FOB and VB scores increased over time (p<0.001) with FOB scoring higher than VB at 0 (0.30±0.79 vs. 0.03±0.17), 24 h (4.21±1.68 vs. 2.47±1.50), and 48h (4.55±1.83 vs. 1.94±1.29). FOB and VB showed association with PaO2-to-FiO2 ratios (PFR) with areas under receiver operating characteristic curves (ROC): for PFR≤300, VB 0.830, FOB 0.863; for PFR≤200, VB 0.794, FOB 0.825; for PFR≤100, VB 0.747, FOB 0.777 (all p<0.001). FOB showed 80.3% specificity, 77% sensitivity, 88.8% negative-predictive value (NPV), and 62.3% positive-predictive value (PPV) for PFR≤300 and VB showed 67.2% specificity, 85.5% sensitivity, 91.3% NPV, and 53.4% PPV. CONCLUSIONS: VB provided similar injury severity scores to FOB, correlated with PFR, and reliably detected airway narrowing. VB performed during admission CT may be a useful screening tool specifically to demonstrate airway narrowing induced by SII.

Determination of resting energy expenditure after severe burn.

The purpose of this study was to evaluate the accuracy of nine predictive equations for calculating energy expenditure in severely burned adult subjects. The selected equations have been reported as commonly used or determined to be the most accurate. This prospective, observational study was conducted on adult subjects admitted between October 2007 and July 2010 with ≥ 20% TBSA full-thickness burns (excluding electrical burns or severe head injury). Indirect calorimetry measurements were conducted as a convenience sample during the first 30 days after injury. Demographic data were collected, and resting energy expenditure was calculated using the nine selected predictive equations and compared to measured energy expenditure (MEE) using descriptive and comparative statistics. Data were collected on 31 subjects with an average age of 46 ± 19 years and %TBSA burn of 48 ± 21%. For all equations, slopes and intercepts were significantly different from the line of identity when compared with MEE. A calorie-dependent bias was present for all equations, in that lower calorie range was overestimated and the higher calorie range was underestimated. Only the Carlson and Milner equations had results that were not significantly different from the MEE and mean differences that were not significant in all burn size ranges. None of the equations had a strong correlation with MEE. Of the equations available, the Milner and Carlson equations are the most satisfactory in predicting resting energy expenditure in severely burned adults when indirect calorimetry is unavailable.

Renal replacement therapy in support of combat operations.

BACKGROUND: Renal replacement therapy has been used by the U.S. Army at the combat support hospital echelon of care since the Korean conflict. Although there has been a general decline in the incidence of wartime acute kidney injury, the mortality associated with acute kidney injury and the use of renal replacement therapy remain unchanged, in the range of 60% to 80%. The U.S. Army official doctrine is that field dialysis is provided through a specialized Hospital Augmentation Team; however, this team has not been deployed to either Iraq or Afghanistan as a result of the ability to rapidly evacuate most cases requiring renal replacement therapy. The history of wartime renal replacement therapy is reviewed along with the general epidemiology of battlefield acute kidney injury and renal replacement therapy. DISCUSSION: Recent literature documents cases of renal replacement therapy performed in and out of theater in support of the current operations. In-theater renal replacement therapy has been provided through a variety of modalities, including conventional hemodialysis, peritoneal dialysis, and both continuous venovenous and continuous arteriovenous hemodialysis. Out of theater, casualties have received both intermittent and continuous hemodialysis at Landstuhl Regional Medical Center and Walter Reed Army Medical Center, whereas patients sustaining burns have undergone aggressive continuous venovenous hemofiltration or hemodiafiltration at Brooke Army Medical Center. SUMMARY: Acute kidney injury requiring renal replacement therapy in wartime casualties is an uncommon occurrence but one with extremely high mortality. Future doctrine should be prepared for contingencies in which the incidence may be increased as a result of mass crush injury casualties or prolonged evacuation times.