Saab Dynamics is a division of Swedish company Saab AB, offering solutions, products, and services for military defence. Included in the Saab Dynamics portfolio is the Carl-Gustaf recoilless rifle; a man-portable, reusable, anti-tank weapon system. Another Saab produced system is the Trackfire Remote Weapon Station; a remotely operated weapon and sensor system, purposed for use on all types of military platforms. Armoured vehicles used by the Swedish Armed Forces are sometimes equipped with remote weapon stations that aim to provide the vehicle crew with protection, by allowing them to operate the weapons from inside the vehicle. These weapon stations can integrate a selection of different weapons, but there are currently no systems in operation that allow integration of the Carl-Gustaf system. This project was initiated based on a request from the Life Guards, for an integrating system between the Carl-Gustaf M4 and a remote weapon station. The project was conducted at Saab Dynamics, Karlskoga, in cooperation with Karlstad University, and aimed to generate suggestions of vehicle integration between the Carl-Gustaf M4 and a remote weapon station. The project was performed as a product development process, using a systematic method for construction and design to develop concept solutions of an integrating system between Carl-Gustaf M4 barrels, and the Trackfire RWS. The report includes a literature study, performed during a feasibility study, on the three systems: Carl-Gustaf weapon system, remote weapon stations, and wheeled armoured vehicles. Recoil principles and interior ballistics of recoilless rifles are further explained and applied to the study. The feasibility study resulted in a specification of requirements, which was used as a foundation for the concept development.  Concepts of solutions were generated and eliminated using a brainstorming session, a morphological matrix, elimination matrices, and decision matrices. One concept was chosen as the final concept solution; a concept comprised of a construction that enables integration of four Carl-Gustaf M4 barrels on the Trackfire RWS, while dampening the recoil that comes from firing a gun. The construction was modelled and analysed using 3D design and engineering platform 3DExperience. Analyses revealed a strong construction that withstands forces arising when a weapon is operated, yet further analyses on how the construction would manage subjection to long-term vehicle vibration and weapon operation are required. Construction dimension optimisations are encouraged, as well as further development of construction details. Recommendations and suggestions on how to proceed with the system integration are provided as a final part of the report. / Saab Dynamics är en division i svenska företaget Saab AB, som erbjuder lösningar, produkter och tjänster för militärt försvar. Inkluderat i Saab Dynamics porfolio finns granatgevär Carl-Gustaf; ett bärbart, återanvändbart pansarvärnsvapen. Ett annat Saab-producerat system är Trackfire Remote Weapon Station; ett fjärrstyrt vapen- och sensorsystem, ämnat för användning på alla typer av militärplattformar. Pansarfordon som används av Försvarsmakten är ibland utrustade med fjärrstyrda vapenstationer som skyddar fordonsbesättningen genom att låta dem manövrera vapnen inifrån fordonet. Dessa vapenstationer kan integrera ett urval av olika vapen, men för närvarande finns det inget system i drift som tillåter integrering av Carl-Gustaf systemet.  Detta projekt initierades baserat på en begäran från Livgardet, om ett integrerande system mellan Carl-Gustaf M4 och en fjärrstyrd vapenstation. Projektet utfördes på Saab Dynamics Karlskoga, i samarbete med Karlstads universitet, och syftade till att generera förslag på fordonsintegrering mellan Carl-Gustaf M4 och en fjärrstyrd vapenstation. Projektet utfördes som en produktutvecklingsprocess, och använde en systematisk metod för konstruktion och design för att utveckla konceptlösningar för ett integrerande system mellan Carl-Gustaf M4 eldrör och Trackfire RWS. Rapporten inkluderar en litteraturstudie, som utfördes under en förstudie, om de tre systemen: Carl-Gustaf granatgevär, fjärrstyrda vapenstationer och hjuldrivna pansarfordon. Rekylprinciper och inre ballistik hos granatgevär förklaras vidare och appliceras i studien. Förstudien resulterade i en kravspecifikation, som användes som grund för konceptutvecklingen. Konceptlösningar genererades och eliminerades genom användning av en brainstorming session, en morfologisk matris, elimineringsmatriser och beslutsmatriser. Ett koncept valdes ut som den slutliga lösningen; ett koncept bestående av en konstruktion som möjliggör integrering av fyra Carl-Gustaf M4 eldrör på Trackfire RWS, samtidigt som den dämpar rekylen som uppstår vid skjutning av ett eldrör. Konstruktionen modellerades och analyserades i 3D-design- och teknikplattformen 3DExperience. Analyser avslöjade en stark konstruktion som motstår de krafter som uppstår vid användning av ett granatgevär, dock är fortsatta analyser av hur konstruktionen skulle klara att utsättas för fordonsvibrationer och gevärsanvändning under en längre period nödvändiga. Optimering av konstruktionsdimensioner uppmuntras, så som fortsatt utveckling av konstruktionsdetaljer. Rekommendationer och förslag på hur arbetet med systemintegrationen kan fortsättas presenteras i slutet av rapporten.

This thesis presents a procedure to collect, process, and analyse data for use in machine learning models within the rifle marksmanship domain. The machine learning model, features, and analysis presented in this thesis provide a first step towards models that can provide automated assistance for rifle marksmanship practice.A quasi-experiment is designed with eye movement and rifle handling as independent variables, and shooting result as dependent variable. The data is collected by letting 14 participants with different levels of marksmanship experience perform a rifle shooting exercise. Eye movement data is gathered using a Tobii Pro Glasses 3 eye tracker, and rifle handling data is gathered using an iCubeX Orient3D IMU. Analysis from the data shows a stratification of participant rifle marksmanship experience into five classes. The highest performing group, to a larger degree than the other groups, aimed with both eyes open, has a faster rifle acceleration, has a lower time between peak motion and shot, and are overall more consistent with their shots. A prototype random forest classification model trained to predict these classes shows a Cohen’s Kappa of 0.526, balanced accuracy of 0.599 and a one-vs-all AUC between 0.83 and 0.95 for the classes.

Acute Kidney Injury (AKI) is a prevalent systemic disorder that has an extremely high rate of mortality even after detection. Historically, the diagnosis and treatment of AKI was marred by the lack of universally accepted criteria defining AKI. Therefore, reports of incidence and mortality varied widely depending on location and the criteria used at the time, but all reports indicated a poor prognosis for the patient. Until recently, the only modes of detecting AKI were primarily through measurements of three clinical findings: serum creatinine concentration, blood urea nitrogen concentration, and urine output. While these measurements are still widely used as standard practice, they have limitations in their utility because their values can fluctuate depending on a person's age, gender, race, diet, and other comorbid conditions. Nevertheless, as these were the only universally accepted units of measurement for kidney function, the Acute Dialysis Quality Initiative (ADQI) used them to create the Risk, Injury, Failure, Loss, and End stage kidney disease (RIFLE) criteria to classify the severity of kidney injury across clinical settings. Eventually, modifications were made by the Acute Kidney Injury Network (AKIN) to increase the sensitivity of AKI diagnosis. It was not until the last decade that new biomarkers of kidney injury began to be researched that provided earlier detection of physical kidney injury before functional manifestations would present themselves. Some of these new biomarkers include cystatin C, kidney injury molecule-1 (KIM-1), and neutrophil gelatinase associated lipocalin (NGAL). This study will investigate how the properties of these new biomarkers are superior when compared to those of serum creatinine in early detection of AKI and specification as to the local site of injury within the nephron. The conclusion is that cystatin C has the potential to indicate damage to glomerular filtration while KIM-1 and NGAL have the ability to indicate damage to the proximal tubule. Along with the ability to provide information as to the specific site of renal injury, the levels of cystatin C, KIM-1, and NGAL increase much more rapidly and to a much higher value than serum creatinine once physical renal damage has occurred. These characteristics along with future research will allow for earlier detection of AKI, more personalized treatment plans, and an overall better prognosis for the patient.

There is a lack of data-driven training instructions for sports shooters, as instruction has commonly been based on subjective assessments. Many studies have correlated body posture and balance to shooting performance in rifle shooting tasks, but most of them have focused on single aspects of postural control. This thesis has focused on finding relevant rifle shooting factors by examining the entire body over sequences of time. We performed a data collection with 13 human participants who carried out live rifle shooting scenarios while being recorded with multiple biometric sensors, including several body trackers. An experiment was conducted to identify what aspects of rifle shooting could be predicted and explained using these data. We employed a pre-processing pipeline to produce a novel skeleton sequence representation, and used it to train a transformer model. The predictions from this model could be explained on a per sample basis using the attention mechanism, and visualised in an interactive format for humans to interpret. It was possible to separate the different phases of a shooting scenario from body posture with a high classification accuracy (81%). However, no correlation could be shown between shooting performance and body posture from our data. Future work could focus on novel feature engineering, and on examining alternative machine learning approaches. The dataset and pre-processing pipeline, as well as the techniques for generating explainable predictions presented in this thesis has laid the groundwork for future research in the sports shooting domain.

Small firearms can create sound levels exceeding the safe threshold of human hearing with even one shot. Understanding how the sound propagates will lead to better range and military drill design. This thesis describes errors associated with different predictive interpolation models for the M16A4. Before directly discussing potential sources of error, the thesis first seeks to validate the data acquired. This is done through waveform inspection with a focus on shot-to-shot consistency. Finding the standard deviation in level between a 10-shot volley provides a good baseline with which other sources of error can be compared to. For both peak and 8-hour A-weighted equivalent levels, the deviation tended to be 1-1.2 dB. With this constraint in mind, the thesis then discussions potential error of measurements along the radial arc. By comparing nearest neighbor microphones with measured values, it was determined that a finer resolution behind the shooter is most relevant. Second, radial propagation was plotted to justify potential decay rates for further plotting. A model of spherical spreading is reasonable, but overestimates the level at farther distances e.g. 50 m. Lastly the thesis focuses on interpolation mapping to predict levels around the range. The baseline model was created using a Cartesian interpolation scheme that uses ghost points to help limit potential artifacts. Leave-one-out analysis highlighted a necessity of microphone placement behind the shooter and other less important microphones. Use of symmetry across the firing direction provides excellent results, generally below the 1 dB standard deviation. In the end, a best-practices guideline is given, which reduces number of required microphones by half. Through these analyses, future measurements will be more effective in microphone placement. With these level maps, one will also be able to better determine potential hearing risks associated with small firearm use and even avoid them through better drill.

“‘Law-Abiding Citizens’: How the National Rifle Association’s battle for gun rights shaped the New Right” explicates the development of the gun rights movement and its central role in the modern American Right. In recent decades scholars have explored the contributions of evangelical Christians, business leaders, white southerners, and women to the making of the modern conservative movement and the transformation of the Republican Party. This study establishes the central role of firearms owners and the NRA in the conservative ascendancy. Based on extensive research in congressional collections at the Dolph Briscoe Center, and the papers of Howard Metzenbaum, Roman Hruska, Birch Bayh, and Robert Dole, as well as the Nixon, Ford, and Reagan Presidential Libraries, the National Archives, and substantial research into NRA publications and related documents, the dissertation explores the evolving political strategy of the NRA and the broader gun community to halt gun control from the 1930s to the 1980s. During the 1960s, high-profile assassinations and rising crime rates put pressure on the Johnson, Nixon, and Ford administrations to “do something” about gun violence. The threat of strict federal gun control prompted the NRA and the broader gun rights community to mobilize grassroots action. Its failure to block the Gun Control Act of 1968 sparked a gradual shift within the association. As it moved rightward, its ability to mobilize its substantial membership and deliver votes made it an attractive political partner for the GOP. Long an association of hunters and shooting sportsmen devoted to firearms safety and military training in wartime, the struggle over gun control legislation divided and ultimately transformed the NRA. As it shifted its focus from hobby to lobby, the NRA became a foundational element of the New Right, playing a decisive role in the shaping of modern American conservatism. / 2025-06-16T00:00:00Z

The AK5C has reached the edge of life and is due for replacement. Studies have been investigating a new small arm but focus of these studies has been the army and its personnel. For flight maintenance personnel the AK5C was too heavy and when working on an aircraft the technicians had to lay the weapon aside. The question this study aims to answer is how the future small arms for flight maintenance personnel might look like. To illustrate when a flight technician might use their weapon three scenarios where created. The scenarios where all originated from reglemente flygbassystem and focused on the main tasks of flight maintenance personnel. In the study personnel with deep knowledge in the field of small arms from different branches of the Swedish Armed Forces were interviewed. The aim was to get an understanding of how the organization view the problem. A survey with flight maintenance personnel from Helicopter Squadron was also conducted and provided details of how the users views the problem. The main question that was asked both in the interviews and in the survey to the users was which attribute of a small arm are the most important for each of the scenarios. The primary difference between the interviewed and the survey was the understanding of penetration and range for different weapon types. The conclusion of the study was that a short barrelled automatic rifle could be a solution that could handle all the investigated scenarios. A recommendation is also made to strengthen the flight maintenance company with machineguns to increase the capacity when defending on longer ranges. / AK5C har nått tiden för sin slutanvändning. Vissa studier har genomförts kopplat till ett nytt eldhandvapen men de har främst varit fokuserade på Arméns behov. Det har visat sig att Flygunderhållspersonal har haft svårigheter att bära AK5C när de utför sin huvudtjänst flygunderhåll. Frågan denna studie ämnar besvara är hur den framtida beväpningen av flygunderhållspersonal kan tänkas se ut. För att skapa en bild av olika tillfällen en tekniker kan tänkas nyttja sitt vapen togs tre scenarier fram. Dessa scenarier är kopplade till reglemente flygbassystem och utgår från de uppgifter en flygtekniker kan tänkas få. I denna studie har personal med djup kunskap inom eldhandvapenområdet intervjuats, främst för att skapa en bild av hur organisationen ser på problemet. Utöver det har även en enkätundersökning med flygunderhållspersonal genomförts för att skapa en förståelse för hur brukarnas lösningar kan te sig. Frågorna som ställdes i både intervjuer och undersökningen med flygtekniker handlade främst om vilka egenskaper ett vapen bör ha kopplat till varje scenario. Det upptäcktes en viss skillnad i svaren mellan de intervjuade och flygteknikerna som deltog i undersökningen. Den största skillnaden var förståelse för vilken verkan olika typer av vapensystem besitter. Slutsatsen som drogs av det självständiga arbetet var att en kortpipig automatkarbin skulle vara en lösning vilket kunde passa alla scenarier. Dock föreslås det att flygunderhållskompanier får förstärkningsvapen i form av kulsprutor på en kompaninivå för att nå högre verkan vid främst försvar av egen gruppering då skjutavstånden överstiger 200 m.

Base teórica: O surgimento de bactérias multirresistentes levou a uma renovação no interesse de antigos antimicrobianos, como a polimixina B, medicamento que foi descartado no passado devido sua toxicidade. Nas últimas duas décadas, esse antimicrobiano tornou-se um dos mais importantes agentes terapêuticos para o tratamento de infecções causadas por bactérias multirresistentes; porém, ainda faltam estudos clínicos que avaliem a segurança da polimixina B, especialmente em altas doses. Objetivo: Avaliar eventos adversos graves relacionados à infusão e a falência renal nos pacientes que receberam altas doses de polimixina B intravenosa. Métodos: Realizamos um estudo de coorte retrospectivo, multicêntrico. Incluímos pacientes que receberam > 3mg/kg/ dia ou uma dose total ≥250mg/dia de polimixina B, no período de janeiro de 2013 a dezembro de 2015. Para a avaliação dos eventos relacionados a infusão, foram incluídos pacientes que receberam ≥ 1 dose de polimixina B e para avaliação de falência renal incluiu apenas os pacientes que receberam ≥ 48 horas de polimixina B. Os desfechos principais avaliados foram os eventos adversos graves relacionados à infusão de acordo com os Critérios de Terminologia Comuns para Eventos Adversos (CTCAE v4.0) e a falência renal, utilizamos os critérios RIFLE (Risk, Injury, Failure, Loss and End stage), para categorizar os diferentes graus de lesão renal aguda. As variáveis incluídas no estudo foram as variáveis demográficas (idade, sexo), as variáveis individuais (peso, comorbidades, escore de Charlson), os fatores de gravidade (internação em UTI, uso de vasopressor, uso de bloqueador neuromuscular), outras fármacos nefrotóxicas, dose de polimixina utilizada (total, média diária e em mg/kg/dia), associação com outros medicamentos, e características da infecção (sítio, isolamento microbiológico) foram avaliadas em análise bivariada. Variáveis com P≤0.2 foram incluídas uma a uma, em ordem crescente, em modelo de regressão de COX. Variáveis com P< 0.1 permaneceram no modelo final. Resultados: Foram incluídos 222 pacientes para análise de eventos graves relacionados à infusão. A dose média de polimixina B foi de 3.61± 0.97 mg/kg /dia (dose total media = 268 mg/kg). Ocorreram eventos adversos graves relacionados à infusão em dois pacientes, determinando uma incidência bruta de 0.9% (intervalo de confiança de 95%, 0.2-3.2): um 7 evento classificado como um risco ameaçador a vida (efeito adverso classe IV) ocorreu em um paciente, homem, de 40 anos, internado no Centro de Terapia Intensiva, com fibrose cística, que recebeu 3,3 mg / kg / dia de PMB e desenvolveu dor torácica súbita, dispnéia e hipoxemia, no quarto dia de tratamento e o outro evento adverso grave (classe III), ocorreu em um paciente, homem, 23 anos, internado na enfermaria, com linfoma, que recebeu 3,6 mg / kg / dia de PMB , que apresentou parestesia perioral, tonturas e dispnéia no primeiro dia de tratamento. A falência renal foi analisada em 115 pacientes que receberam ≥ 48 horas de polimixina B e que não estavam em diálise no início do tratamento com Polimixina B; Falência renal foi encontrada em 25 de 115 (21,7%) pacientes expostos as PMB. Nosso estudo identificou que 54 [47,0%] pacientes desenvolveram algum grau de lesão renal aguda, pelos critérios de RIFLE: risco, 15 (27,8%), injúria, 14 (25,9%) e falência, 25 (46,3%) dentro das categorias do RIFLE. Além disso, droga vasoativa, outros fármacos nefrotóxicos e clearance de creatinina foram fatores de risco independentes para falência renal. Nem a dose diária de polimixina B ajustada para o peso corporal, nem a dose diária total foram associadas a falência renal. A mortalidade intra-hospitalar foi de 60% (134 pacientes): 26% (57 pacientes) morreram durante o tratamento e nenhum óbito foi durante a infusão. Conclusão: Altas doses de polimixina B no tratamento de infecções por bactérias gramnegativo apresentaram incidência baixa de eventos adversos agudos no nosso estudo e incidência de nefrotoxicidade elevadas, mas semelhantes a alguns estudos prévios com doses usuais”. Portanto, doses elevadas podem ser testadas em ensaios clínicos, objetivando melhorar os desfechos dos pacientes gravemente doentes com infecções por bactérias multirresistentes e minimizar o surgimento da resistência a polimixina B. / Background: The emergence of multiresistant bacteria has led to a renewal in the interest of old antimicrobials, such as polymyxin B, a drug that has been discarded in the past due to its toxicity. However, at this time, this antimicrobial has become one of the most important therapeutic agents for the treatment of infections caused by multiresistant bacteria but there is still a lack of clinical studies that evaluate the safety of polymyxin B, especially in relation to the use of high doses. This strategy, high doses, may be necessary in the fight against Gramnegative bacteria with a high minimum inhibitory concentration. Patients and methods: A retrospective, multicenter cohort study; the period evaluated was from January 2013 to December 2015, included patients who received > 3mg/kg/day or a total dose of ≥250mg/day of polymyxin B. The study included the evaluation of infusion-related events, patients who received ≥ 1 dose of polymyxin B and patients who received ≥ 48 hours of PMB were included for evaluation of renal failure. Major outcomes were serious adverse events related to infusion according to the Common Terminology Criteria for Adverse Events (CTCAE v4.0) and categorized renal failure by the RIFLE criteria (Risk, Injury, Failure, Loss, End stage). Factors potentially related to nephrotoxicity or mortality in 30 days were: demographic variables (age, sex), individual variables (weight, comorbidities, Charlson score), severity factors (ICU admission, use of vasopressor, use of Neuromuscular blocker), nephrotoxicity (other nephrotoxic drugs), polymyxin dose (total, daily mean and mg / Kg / day), association of drugs and infection characteristics (site and microbiological isolate) were evaluated in bivariate analysis. Variables with P≤0.2 were included one by one, in ascending order, in a Cox regression model. Variables with P <0.1 remained in the final model. Results: Two of 222 patients presented a severe infusion-related adverse event during PMB infusion, resulting in a crude incidence of 0.9% (95% Confidence Interval [CI], 0.2-3.2); one was classified as life-threatening and one classified as severe (crude incidence of each adverse event, 0.45%; 95% CI, 0.08-2.5). The life-threatening adverse effect occurred in an ICU patient (crude incidence among ICU patients, 0.67%; 95% CI, 0.12-3.7), a 40-years old male with cystic fibrosis who used 3.3 mg/kg/day of PMB and developed sudden thoracic pain, dyspnea and hypoxemia, in the fourth day of treatment. The severe adverse effect occurred in a non-ICU patient (crude incidence among non-ICU patients, 1.3%; 95% CI, 0.2-7.2), a 23- years old male with lymphoma exposed to 3.6 mg/kg/day of PMB, who presented perioral 9 paresthesia, dizziness and dyspnea in the first day of treatment. Renal failure was analysed in 115 patients who received ≥48 hours of PMB and who were not previously in dialysis. A total of 54 [47.0%] patients developed any degree of AKI, categorised as Risk [27.8%]; Injury [25.9%] and Failure [46.3%]) and 25 of 115 (21.7%) patients presented renal failure Vasoactive drug, concomitant nephrotoxic drugs and baseline creatinine clearance were independent risk factors for renal failure. Neither PMB daily dose scaled by body weight nor total daily dose were associated with renal failure. In-hospital mortality was 60% (134 patients): 26% (57 patients) occurred during treatment and none during infusion. Conclusion: Results suggest that high dose regimens have similar safety profile of usual doses and could be further tested in clinical trials assessing strategies to improve patients’ outcomes and minimize the emergence of PMB resistance.

Base teórica: O surgimento de bactérias multirresistentes levou a uma renovação no interesse de antigos antimicrobianos, como a polimixina B, medicamento que foi descartado no passado devido sua toxicidade. Nas últimas duas décadas, esse antimicrobiano tornou-se um dos mais importantes agentes terapêuticos para o tratamento de infecções causadas por bactérias multirresistentes; porém, ainda faltam estudos clínicos que avaliem a segurança da polimixina B, especialmente em altas doses. Objetivo: Avaliar eventos adversos graves relacionados à infusão e a falência renal nos pacientes que receberam altas doses de polimixina B intravenosa. Métodos: Realizamos um estudo de coorte retrospectivo, multicêntrico. Incluímos pacientes que receberam > 3mg/kg/ dia ou uma dose total ≥250mg/dia de polimixina B, no período de janeiro de 2013 a dezembro de 2015. Para a avaliação dos eventos relacionados a infusão, foram incluídos pacientes que receberam ≥ 1 dose de polimixina B e para avaliação de falência renal incluiu apenas os pacientes que receberam ≥ 48 horas de polimixina B. Os desfechos principais avaliados foram os eventos adversos graves relacionados à infusão de acordo com os Critérios de Terminologia Comuns para Eventos Adversos (CTCAE v4.0) e a falência renal, utilizamos os critérios RIFLE (Risk, Injury, Failure, Loss and End stage), para categorizar os diferentes graus de lesão renal aguda. As variáveis incluídas no estudo foram as variáveis demográficas (idade, sexo), as variáveis individuais (peso, comorbidades, escore de Charlson), os fatores de gravidade (internação em UTI, uso de vasopressor, uso de bloqueador neuromuscular), outras fármacos nefrotóxicas, dose de polimixina utilizada (total, média diária e em mg/kg/dia), associação com outros medicamentos, e características da infecção (sítio, isolamento microbiológico) foram avaliadas em análise bivariada. Variáveis com P≤0.2 foram incluídas uma a uma, em ordem crescente, em modelo de regressão de COX. Variáveis com P< 0.1 permaneceram no modelo final. Resultados: Foram incluídos 222 pacientes para análise de eventos graves relacionados à infusão. A dose média de polimixina B foi de 3.61± 0.97 mg/kg /dia (dose total media = 268 mg/kg). Ocorreram eventos adversos graves relacionados à infusão em dois pacientes, determinando uma incidência bruta de 0.9% (intervalo de confiança de 95%, 0.2-3.2): um 7 evento classificado como um risco ameaçador a vida (efeito adverso classe IV) ocorreu em um paciente, homem, de 40 anos, internado no Centro de Terapia Intensiva, com fibrose cística, que recebeu 3,3 mg / kg / dia de PMB e desenvolveu dor torácica súbita, dispnéia e hipoxemia, no quarto dia de tratamento e o outro evento adverso grave (classe III), ocorreu em um paciente, homem, 23 anos, internado na enfermaria, com linfoma, que recebeu 3,6 mg / kg / dia de PMB , que apresentou parestesia perioral, tonturas e dispnéia no primeiro dia de tratamento. A falência renal foi analisada em 115 pacientes que receberam ≥ 48 horas de polimixina B e que não estavam em diálise no início do tratamento com Polimixina B; Falência renal foi encontrada em 25 de 115 (21,7%) pacientes expostos as PMB. Nosso estudo identificou que 54 [47,0%] pacientes desenvolveram algum grau de lesão renal aguda, pelos critérios de RIFLE: risco, 15 (27,8%), injúria, 14 (25,9%) e falência, 25 (46,3%) dentro das categorias do RIFLE. Além disso, droga vasoativa, outros fármacos nefrotóxicos e clearance de creatinina foram fatores de risco independentes para falência renal. Nem a dose diária de polimixina B ajustada para o peso corporal, nem a dose diária total foram associadas a falência renal. A mortalidade intra-hospitalar foi de 60% (134 pacientes): 26% (57 pacientes) morreram durante o tratamento e nenhum óbito foi durante a infusão. Conclusão: Altas doses de polimixina B no tratamento de infecções por bactérias gramnegativo apresentaram incidência baixa de eventos adversos agudos no nosso estudo e incidência de nefrotoxicidade elevadas, mas semelhantes a alguns estudos prévios com doses usuais”. Portanto, doses elevadas podem ser testadas em ensaios clínicos, objetivando melhorar os desfechos dos pacientes gravemente doentes com infecções por bactérias multirresistentes e minimizar o surgimento da resistência a polimixina B. / Background: The emergence of multiresistant bacteria has led to a renewal in the interest of old antimicrobials, such as polymyxin B, a drug that has been discarded in the past due to its toxicity. However, at this time, this antimicrobial has become one of the most important therapeutic agents for the treatment of infections caused by multiresistant bacteria but there is still a lack of clinical studies that evaluate the safety of polymyxin B, especially in relation to the use of high doses. This strategy, high doses, may be necessary in the fight against Gramnegative bacteria with a high minimum inhibitory concentration. Patients and methods: A retrospective, multicenter cohort study; the period evaluated was from January 2013 to December 2015, included patients who received > 3mg/kg/day or a total dose of ≥250mg/day of polymyxin B. The study included the evaluation of infusion-related events, patients who received ≥ 1 dose of polymyxin B and patients who received ≥ 48 hours of PMB were included for evaluation of renal failure. Major outcomes were serious adverse events related to infusion according to the Common Terminology Criteria for Adverse Events (CTCAE v4.0) and categorized renal failure by the RIFLE criteria (Risk, Injury, Failure, Loss, End stage). Factors potentially related to nephrotoxicity or mortality in 30 days were: demographic variables (age, sex), individual variables (weight, comorbidities, Charlson score), severity factors (ICU admission, use of vasopressor, use of Neuromuscular blocker), nephrotoxicity (other nephrotoxic drugs), polymyxin dose (total, daily mean and mg / Kg / day), association of drugs and infection characteristics (site and microbiological isolate) were evaluated in bivariate analysis. Variables with P≤0.2 were included one by one, in ascending order, in a Cox regression model. Variables with P <0.1 remained in the final model. Results: Two of 222 patients presented a severe infusion-related adverse event during PMB infusion, resulting in a crude incidence of 0.9% (95% Confidence Interval [CI], 0.2-3.2); one was classified as life-threatening and one classified as severe (crude incidence of each adverse event, 0.45%; 95% CI, 0.08-2.5). The life-threatening adverse effect occurred in an ICU patient (crude incidence among ICU patients, 0.67%; 95% CI, 0.12-3.7), a 40-years old male with cystic fibrosis who used 3.3 mg/kg/day of PMB and developed sudden thoracic pain, dyspnea and hypoxemia, in the fourth day of treatment. The severe adverse effect occurred in a non-ICU patient (crude incidence among non-ICU patients, 1.3%; 95% CI, 0.2-7.2), a 23- years old male with lymphoma exposed to 3.6 mg/kg/day of PMB, who presented perioral 9 paresthesia, dizziness and dyspnea in the first day of treatment. Renal failure was analysed in 115 patients who received ≥48 hours of PMB and who were not previously in dialysis. A total of 54 [47.0%] patients developed any degree of AKI, categorised as Risk [27.8%]; Injury [25.9%] and Failure [46.3%]) and 25 of 115 (21.7%) patients presented renal failure Vasoactive drug, concomitant nephrotoxic drugs and baseline creatinine clearance were independent risk factors for renal failure. Neither PMB daily dose scaled by body weight nor total daily dose were associated with renal failure. In-hospital mortality was 60% (134 patients): 26% (57 patients) occurred during treatment and none during infusion. Conclusion: Results suggest that high dose regimens have similar safety profile of usual doses and could be further tested in clinical trials assessing strategies to improve patients’ outcomes and minimize the emergence of PMB resistance.

Base teórica: O surgimento de bactérias multirresistentes levou a uma renovação no interesse de antigos antimicrobianos, como a polimixina B, medicamento que foi descartado no passado devido sua toxicidade. Nas últimas duas décadas, esse antimicrobiano tornou-se um dos mais importantes agentes terapêuticos para o tratamento de infecções causadas por bactérias multirresistentes; porém, ainda faltam estudos clínicos que avaliem a segurança da polimixina B, especialmente em altas doses. Objetivo: Avaliar eventos adversos graves relacionados à infusão e a falência renal nos pacientes que receberam altas doses de polimixina B intravenosa. Métodos: Realizamos um estudo de coorte retrospectivo, multicêntrico. Incluímos pacientes que receberam > 3mg/kg/ dia ou uma dose total ≥250mg/dia de polimixina B, no período de janeiro de 2013 a dezembro de 2015. Para a avaliação dos eventos relacionados a infusão, foram incluídos pacientes que receberam ≥ 1 dose de polimixina B e para avaliação de falência renal incluiu apenas os pacientes que receberam ≥ 48 horas de polimixina B. Os desfechos principais avaliados foram os eventos adversos graves relacionados à infusão de acordo com os Critérios de Terminologia Comuns para Eventos Adversos (CTCAE v4.0) e a falência renal, utilizamos os critérios RIFLE (Risk, Injury, Failure, Loss and End stage), para categorizar os diferentes graus de lesão renal aguda. As variáveis incluídas no estudo foram as variáveis demográficas (idade, sexo), as variáveis individuais (peso, comorbidades, escore de Charlson), os fatores de gravidade (internação em UTI, uso de vasopressor, uso de bloqueador neuromuscular), outras fármacos nefrotóxicas, dose de polimixina utilizada (total, média diária e em mg/kg/dia), associação com outros medicamentos, e características da infecção (sítio, isolamento microbiológico) foram avaliadas em análise bivariada. Variáveis com P≤0.2 foram incluídas uma a uma, em ordem crescente, em modelo de regressão de COX. Variáveis com P< 0.1 permaneceram no modelo final. Resultados: Foram incluídos 222 pacientes para análise de eventos graves relacionados à infusão. A dose média de polimixina B foi de 3.61± 0.97 mg/kg /dia (dose total media = 268 mg/kg). Ocorreram eventos adversos graves relacionados à infusão em dois pacientes, determinando uma incidência bruta de 0.9% (intervalo de confiança de 95%, 0.2-3.2): um 7 evento classificado como um risco ameaçador a vida (efeito adverso classe IV) ocorreu em um paciente, homem, de 40 anos, internado no Centro de Terapia Intensiva, com fibrose cística, que recebeu 3,3 mg / kg / dia de PMB e desenvolveu dor torácica súbita, dispnéia e hipoxemia, no quarto dia de tratamento e o outro evento adverso grave (classe III), ocorreu em um paciente, homem, 23 anos, internado na enfermaria, com linfoma, que recebeu 3,6 mg / kg / dia de PMB , que apresentou parestesia perioral, tonturas e dispnéia no primeiro dia de tratamento. A falência renal foi analisada em 115 pacientes que receberam ≥ 48 horas de polimixina B e que não estavam em diálise no início do tratamento com Polimixina B; Falência renal foi encontrada em 25 de 115 (21,7%) pacientes expostos as PMB. Nosso estudo identificou que 54 [47,0%] pacientes desenvolveram algum grau de lesão renal aguda, pelos critérios de RIFLE: risco, 15 (27,8%), injúria, 14 (25,9%) e falência, 25 (46,3%) dentro das categorias do RIFLE. Além disso, droga vasoativa, outros fármacos nefrotóxicos e clearance de creatinina foram fatores de risco independentes para falência renal. Nem a dose diária de polimixina B ajustada para o peso corporal, nem a dose diária total foram associadas a falência renal. A mortalidade intra-hospitalar foi de 60% (134 pacientes): 26% (57 pacientes) morreram durante o tratamento e nenhum óbito foi durante a infusão. Conclusão: Altas doses de polimixina B no tratamento de infecções por bactérias gramnegativo apresentaram incidência baixa de eventos adversos agudos no nosso estudo e incidência de nefrotoxicidade elevadas, mas semelhantes a alguns estudos prévios com doses usuais”. Portanto, doses elevadas podem ser testadas em ensaios clínicos, objetivando melhorar os desfechos dos pacientes gravemente doentes com infecções por bactérias multirresistentes e minimizar o surgimento da resistência a polimixina B. / Background: The emergence of multiresistant bacteria has led to a renewal in the interest of old antimicrobials, such as polymyxin B, a drug that has been discarded in the past due to its toxicity. However, at this time, this antimicrobial has become one of the most important therapeutic agents for the treatment of infections caused by multiresistant bacteria but there is still a lack of clinical studies that evaluate the safety of polymyxin B, especially in relation to the use of high doses. This strategy, high doses, may be necessary in the fight against Gramnegative bacteria with a high minimum inhibitory concentration. Patients and methods: A retrospective, multicenter cohort study; the period evaluated was from January 2013 to December 2015, included patients who received > 3mg/kg/day or a total dose of ≥250mg/day of polymyxin B. The study included the evaluation of infusion-related events, patients who received ≥ 1 dose of polymyxin B and patients who received ≥ 48 hours of PMB were included for evaluation of renal failure. Major outcomes were serious adverse events related to infusion according to the Common Terminology Criteria for Adverse Events (CTCAE v4.0) and categorized renal failure by the RIFLE criteria (Risk, Injury, Failure, Loss, End stage). Factors potentially related to nephrotoxicity or mortality in 30 days were: demographic variables (age, sex), individual variables (weight, comorbidities, Charlson score), severity factors (ICU admission, use of vasopressor, use of Neuromuscular blocker), nephrotoxicity (other nephrotoxic drugs), polymyxin dose (total, daily mean and mg / Kg / day), association of drugs and infection characteristics (site and microbiological isolate) were evaluated in bivariate analysis. Variables with P≤0.2 were included one by one, in ascending order, in a Cox regression model. Variables with P <0.1 remained in the final model. Results: Two of 222 patients presented a severe infusion-related adverse event during PMB infusion, resulting in a crude incidence of 0.9% (95% Confidence Interval [CI], 0.2-3.2); one was classified as life-threatening and one classified as severe (crude incidence of each adverse event, 0.45%; 95% CI, 0.08-2.5). The life-threatening adverse effect occurred in an ICU patient (crude incidence among ICU patients, 0.67%; 95% CI, 0.12-3.7), a 40-years old male with cystic fibrosis who used 3.3 mg/kg/day of PMB and developed sudden thoracic pain, dyspnea and hypoxemia, in the fourth day of treatment. The severe adverse effect occurred in a non-ICU patient (crude incidence among non-ICU patients, 1.3%; 95% CI, 0.2-7.2), a 23- years old male with lymphoma exposed to 3.6 mg/kg/day of PMB, who presented perioral 9 paresthesia, dizziness and dyspnea in the first day of treatment. Renal failure was analysed in 115 patients who received ≥48 hours of PMB and who were not previously in dialysis. A total of 54 [47.0%] patients developed any degree of AKI, categorised as Risk [27.8%]; Injury [25.9%] and Failure [46.3%]) and 25 of 115 (21.7%) patients presented renal failure Vasoactive drug, concomitant nephrotoxic drugs and baseline creatinine clearance were independent risk factors for renal failure. Neither PMB daily dose scaled by body weight nor total daily dose were associated with renal failure. In-hospital mortality was 60% (134 patients): 26% (57 patients) occurred during treatment and none during infusion. Conclusion: Results suggest that high dose regimens have similar safety profile of usual doses and could be further tested in clinical trials assessing strategies to improve patients’ outcomes and minimize the emergence of PMB resistance.