Trends in prehospital pain management: two decades of point-of-injury care.

BACKGROUND: Pain control in trauma is an integral part of treatment in combat casualty care. More soldiers injured on the battlefield need analgesics for pain than life-saving interventions (LSIs). Early treatment of pain improves outcomes after injury, while inadequate treatment leads to higher rates of post-traumatic stress disorder (PTSD). OBJECTIVES: To describe the experience of the Israel Defense Forces (IDF) Medical Corps with prehospital use of analgesia. METHODS: All cases documented in the IDF-Trauma Registry between January 1997 and December 2019 were examined. Data collection included analgesia administered, mechanism of injury, wound distribution, and life-saving interventions performed. RESULTS: Of 16,117 patients, 1807 (11.2%) had at least one documented analgesia. Demographics included 91.2% male; median age 21 years. Leading mechanism of injury was penetrating (52.9%). Of injured body regions reported, 46.2% were lower extremity wounds. Most common types of analgesics were morphine (57.2%) and fentanyl (27%). Over the two decades of the study period, types of analgesics given by providers at point of injury (POI) had changed. Fentanyl was introduced in 2013, and by 2019 was given to 39% of patients. Another change was an increase of casualties receiving analgesia from 5-10% until 2010 to 34% by 2019. A total of 824 LSIs were performed on 556 patients (30.8%) receiving analgesia and no adverse events were found in any of the casualties. CONCLUSIONS: Most casualties at POI did not receive any analgesics. The most common analgesics administered were opioids. Over time analgesic administration has gained acceptance and become more commonplace on the battlefield.

Polyglutamate-based nanoconjugates for image-guided surgery and post-operative melanoma metastases prevention.

Rationale: Cutaneous melanoma is the most aggressive and deadliest of all skin malignancies. Complete primary tumor removal augmented by advanced imaging tools and effective post-operative treatment is critical in the prevention of tumor recurrence and future metastases formation. Methods: To meet this challenge, we designed novel polymeric imaging and therapeutic systems, implemented in a two-step theranostic approach. Both are composed of the biocompatible and biodegradable poly(α,L-glutamic acid) (PGA) nanocarrier that facilitates extravasation-dependent tumor targeting delivery. The first system is a novel, fluorescent, Turn-ON diagnostic probe evaluated for the precise excision of the primary tumor during image-guided surgery (IGS). The fluorescence activation of the probe occurs via PGA degradation by tumor-overexpressed cathepsins that leads to the separation of closely-packed, quenched FRET pair. This results in the emission of a strong fluorescence signal enabling the delineation of the tumor boundaries. Second, therapeutic step is aimed to prevent metastases formation with minimal side effects and maximal efficacy. To that end, a targeted treatment containing a BRAF (Dabrafenib - mDBF)/MEK (Selumetinib - SLM) inhibitors combined on one polymeric platform (PGA-SLM-mDBF) was evaluated for its anti-metastatic, preventive activity in combination with immune checkpoint inhibitors (ICPi) αPD1 and αCTLA4. Results: IGS in melanoma-bearing mice led to a high tumor-to-background ratio and reduced tumor recurrence in comparison with mice that underwent surgery under white light (23% versus 33%, respectively). Adjuvant therapy with PGA-SLM-mDBF combined with ICPi, was well-tolerated and resulted in prolonged survival and prevention of peritoneal and brain metastases formation in BRAF-mutated melanoma-bearing mice. Conclusions: The results reveal the great clinical potential of our PGA-based nanosystems as a tool for holistic melanoma treatment management.

The Influence of Gender Bias: Is Pain Management in the Field Affected by Health Care Provider's Gender?

INTRODUCTION: Appropriate pain management indicates the quality of casualty care in trauma. Gender bias in pain management focused so far on the patient. Studies regarding provider gender are scarce and have conflicting results, especially in the military and prehospital settings. STUDY OBJECTIVE: The purpose of this study is to investigate the effect of health care providers' gender on pain management approaches among prehospital trauma casualties treated by the Israel Defense Forces (IDF) medical teams. METHODS: This retrospective cohort study included all trauma casualties treated by IDF senior providers from 2015-2020. Casualties with a pain score of zero, age under 18 years, or treated with endotracheal intubation were excluded. Groups were divided according to the senior provider's gender: only females, males, or both female and male. A multivariate analysis was performed to assess the odds ratio of receiving an analgesic, depending on the presence of a female senior provider, adjusting for potential confounders. A subgroup analysis was performed for "delta-pain," defined as the difference in pain score during treatment. RESULTS: A total of 976 casualties were included, of whom 835 (85.6%) were male. Mean pain scores (SD) for the female only, male only, and both genders providers were 6.4 (SD = 2.9), 6.4 (SD = 3.0), and 6.9 (SD = 2.8), respectively (P = .257). There was no significant difference between females, males, or both female and male groups in analgesic treatment, overall and per specific agent. This remained true also in the multivariate model. Delta-pain difference between groups was also not significant. Less than two-thirds of casualties in this study were treated for pain among all study groups. CONCLUSION: This study found no association between IDF Medical Corps providers' gender and pain management in prehospital trauma patients. Further studies regarding disparities in acute pain treatment are advised.

Trends in prehospital pain management following the introduction of new clinical practice guidelines.

BACKGROUND: Early pain treatment following injury has been shown to improve long-term outcomes, while untreated pain can facilitate higher posttraumatic stress disorder rates and worsen outcomes. Nonetheless, trauma casualties frequently receive inadequate analgesia. In June 2013, a new clinical practice guideline (CPG) regarding pain management was introduced in the Israel Defense Forces (IDF) Medical Corps, recommending oral transmucosal fentanyl citrate (OTFC) and low-dose intravenous (IV)/intramuscular ketamine. The purpose of this study was to examine trends in prehospital pain management in the IDF. METHODS: All cases documented in the IDF trauma registry between 2008 and 2020 were examined. This study compared casualty parameters before and after the introduction of analgesia CPG in 2013. Parameters compared included demographics, injury parameters, treatment modalities, and types of analgesia provided. RESULT: Overall, 5,653 casualties were included in our study. During the 6 years before the introduction of the CPG, 289 (26.7%) of 1,084 casualties received an analgesic treatment, compared with 1,578 (34.5%) of 4,569 casualties during the 7 years following (p < 0.001). Since its introduction, OTFC was administered to 41.8% of all casualties who received analgesia and became the most used analgesic drug in 2020 (61.1% of casualties receiving analgesia). The rate of IV morphine significantly decreased after 2013 (22.6-16%, p < 0.001). CONCLUSION: Pain management has become more common in trauma patients' prehospital care in the IDF in recent years. There has been a significant increase in analgesia administration, with the increased use of OTFC, along with a significant reduction in the use of IV morphine. These results may be attributed to introducing a pain management CPG and implementing OTFC among medical teams. The perception of OTFC as a safe user-friendly analgesic may have contributed to its use by medical providers, increasing analgesia rates overall. LEVEL OF EVIDENCE: Therapeutic/care management, level III.

Clinical Course and Outcomes of Severe Covid-19: A National Scale Study.

Knowledge of the outcomes of critically ill patients is crucial for health and government officials who are planning how to address local outbreaks. The factors associated with outcomes of critically ill patients with coronavirus disease 2019 (Covid-19) who required treatment in an intensive care unit (ICU) are yet to be determined. METHODS: This was a retrospective registry-based case series of patients with laboratory-confirmed SARS-CoV-2 who were referred for ICU admission and treated in the ICUs of the 13 participating centers in Israel between 5 March and 27 April 2020. Demographic and clinical data including clinical management were collected and subjected to a multivariable analysis; primary outcome was mortality. RESULTS: This study included 156 patients (median age = 72 years (range = 22-97 years)); 69% (108 of 156) were male. Eighty-nine percent (139 of 156) of patients had at least one comorbidity. One hundred three patients (66%) required invasive mechanical ventilation. As of 8 May 2020, the median length of stay in the ICU was 10 days (range = 0-37 days). The overall mortality rate was 56%; a multivariable regression model revealed that increasing age (OR = 1.08 for each year of age, 95%CI = 1.03-1.13), the presence of sepsis (OR = 1.08 for each year of age, 95%CI = 1.03-1.13), and a shorter ICU stay(OR = 0.90 for each day, 95% CI = 0.84-0.96) were independent prognostic factors. CONCLUSIONS: In our case series, we found lower mortality rates than those in exhausted health systems. The results of our multivariable model suggest that further evaluation is needed of antiviral and antibacterial agents in the treatment of sepsis and secondary infection.

Rational Design of Polyglutamic Acid Delivering an Optimized Combination of Drugs Targeting Mutated BRAF and MEK in Melanoma.

Targeted therapies against cancer can relieve symptoms and induce remission, however, they often present limited duration of disease control, cause side effects and often induce acquired resistance. Therefore, there is a great motivation to develop a unique delivery system, targeted to the tumor, in which we can combine several active entities, increase the therapeutic index by reducing systemic exposure, and enhance their synergistic activity. To meet these goals, we chose the biocompatible and biodegradable poly(α,L-glutamic acid) (PGA) as a nanocarrier that facilitates extravasation-dependent tumor targeting delivery. The RAS/RAF/MEK/ERK pathway when aberrantly activated in melanoma, can lead to uncontrolled cell proliferation, induced invasion, and reduced apoptosis. Here, we selected two drugs targeting this pathway; a MEK1/2 inhibitor (selumetinib; SLM) and a modified BRAF inhibitor (modified dabrafenib; mDBF), that exhibited synergism in vitro. We synthesized and characterized our nanomedicine of PGA conjugated to SLM and mDBF (PGA-SLM-mDBF). PGA-SLM-mDBF inhibited the proliferation of melanoma cells and decreased their migratory and sprouting abilities without inducing a hemolytic effect. Moreover, the polymer-2-drugs conjugate exhibited superior anti-tumor activity in comparison with the two separate polymer-drug conjugates in vitro and with free drugs in a mouse model of primary melanoma and prolonged survival at a lower dose.