Towards safer and efficient formulations: Machine learning approaches to predict drug-excipient compatibility.

Predicting drug-excipient compatibility is a critical aspect of pharmaceutical formulation design. In this study, we introduced an innovative approach that leverages machine learning techniques to improve the accuracy of drug-excipient compatibility predictions. Mol2vec and 2D molecular descriptors combined with the stacking technique were used to improve the performance of the model. This approach achieved a significant advancement in the predictive capacity as demonstrated by the accuracy, precision, recall, AUC, and MCC of 0.98, 0.87, 0.88, 0.93 and 0.86, respectively. Using the DE-INTERACT model as the benchmark, our stacking model could remarkably detect drug-excipient incompatibility in 10/12 tested cases, while DE-INTERACT managed to recognize only 3 out of 12 incompatibility cases in the validation experiments. To ensure user accessibility, the trained model was deployed to a user-friendly web platform (URL: https://decompatibility.streamlit.app/). This interactive interface accommodated inputs through various types, including names, PubChem CID, or SMILES strings. It promptly generated compatibility predictions alongside corresponding probability scores. However, the continual refinement of model performance is crucial before applying this model in practice.

Physical compatibility of sulbactam/durlobactam with select intravenous drugs during simulated Y-site administration.

PURPOSE: Sulbactam/durlobactam is a combination antibiotic designed to target Acinetobacter baumannii, including carbapenem-resistant and multidrug-resistant strains. The objective of this study was to determine the physical compatibility of sulbactam/durlobactam solution during simulated Y-site administration with 95 intravenous (IV) drugs. METHODS: Vials of sulbactam/durlobactam solution were diluted in 0.9% sodium chloride injection to a volume of 100 mL (the final concentration of both drugs was 15 mg/mL). All other IV drugs were reconstituted according to the manufacturer's recommendations and diluted with 0.9% sodium chloride injection to the upper range of concentrations used clinically or tested undiluted as intended for administration. Y-site conditions were simulated by mixing 5 mL of sulbactam/durlobactam with 5 mL of the tested drug solutions in a 1:1 ratio. Solutions were inspected for physical characteristics (clarity, color, and Tyndall effect), turbidity, and pH changes before admixture, immediately post admixture, and over 4 hours. Incompatibility was defined as any observed precipitation, significant color change, positive Tyndall test, or turbidity change of ≥0.5 nephelometric turbidity unit during the observation period. RESULTS: Sulbactam/durlobactam was physically compatible with 38 out of 42 antimicrobials tested (90.5%) and compatible overall with 86 of 95 drugs tested (90.5%). Incompatibility was observed with albumin, amiodarone hydrochloride, ceftaroline fosamil, ciprofloxacin, daptomycin, levofloxacin, phenytoin sodium, vecuronium, and propofol. CONCLUSION: The Y-site compatibility of sulbactam/durlobactam with 95 IV drugs was described. These compatibility data will assist pharmacists and nurses to safely coordinate administration of IV medications with sulbactam/durlobactam.

Definición y caracterización del fenómeno “Diagnóstico Lastre Generado por Medicamentos” / Definition and characterization of the phenomenon "Diagnosis of Drug-Generated Ballast"

Proponemos el presente estudio para la identifica-ción del fenómeno "Diagnóstico Lastre Generado por Medicamentos" (DLGM), que es la traducción farmacéutica de la interpretación médica de un problema de salud generado por medicamentos y atribuido a causas clínicas con la consiguiente pérdida de identidad que limita su identificación y manejo. No habrá mejoría de la enfermedad si no se corrige la causa del problema, por lo que cabe esperar un empeoramiento y persistencia de la enfermedad marcados por el fracaso farmacote-rapéutico, convirtiendo el problema de salud en un verdadero lastre para los pacientes a la espera de ser identificado.La propuesta de un algoritmo de caracterización del problema como herramienta de cribado se ha aplicado a 10 pacientes en el servicio de segui-miento farmacoterapéutico, confirmando la sospe-cha de DLGM, y demostrando que las reacciones adversas a medicamentos habían adquirido la identidad de una enfermedad. Un DLGM podría defi-nirse como la entidad que surge al diagnosticar una enfermedad sobre un resultado negativo asociado al uso del medicamento y que, por tanto, no recibe el tratamiento adecuado.La identificación del fenómeno DLGM permite detectar muchos resultados negativos asociados a la medicación (RNM) y contribuye a su adecuado tratamiento.No identificar un DLGM complica el estado clínico del paciente y limita su recuperación. (AU)

The present study was proposed for the identifica-tion the phenomenon "Diagnosis load Generated by Medications" (DLGM), which is the pharmaceutical translation to the medical interpretation of a health problem generated by medications and attributed to clinical causes with the consequent loss of iden-tity limiting its identification and handling. There will be no improvement of the desease if the cause of the problem is not corrected, so worsening and persistence of the disease marked by pharmaco-therapeutic failure is to be expected, making the health problem a real burden for patients to waiting to be identified.The proposal of an algorithm characterising the problem as a screening tool has been applied to 10 patients in the pharmacotherapeutic monitoring service, confirming the suspicion of DLGM, and demonstrating that adverse drugs reactions had acquired the identity of a disease. DLGM could be defined as the entity that arises from diagnosing a disease on a negative results associated to medici-ne use and that therefore does not receive adequa-te treatment.The identification of the DLGM phenomenon allows the detection of many Negative Outcomes Relea-ted to Mediccines (NOMs) and contributes to their adequate treatment.Not identifying DLGM complicates the clinical con-dition of the patient and his/her recovery. (AU)

Compatibility of calcium chloride with milrinone, epinephrine, vasopressin, and heparin via in vitro testing and simulated Y-site administration.

PURPOSE: The purpose of this study is to evaluate calcium chloride (CaCl) compatibility with commercially available and extemporaneously compounded milrinone, vasopressin, epinephrine, and heparin. This report describes 2 clinical scenarios in which patients experienced intravenous catheter precipitation when receiving multiple continuous infusions, including CaCl, and the results of an in vitro simulation of those scenarios. The hypothesis was that one or a combination of the medications would precipitate with CaCl. METHODS: CaCl compatibility was tested in 3 stages to simulate clinical situations where line precipitation occurred. Multiple tests were conducted in each stage to determine if precipitation had occurred, including visual assessment, absorbance measurement at 650 nm, and pH measurement. First, milrinone, vasopressin, epinephrine, and heparin were mixed pairwise with CaCl in a test tube. Second, the medications were mixed in different combinations deemed likely to precipitate. Finally, 5 medications were infused via simulated Y-site administration. Incompatibility was defined as observed crystals, haziness, or turbidity upon visual inspection or absorbance of greater than 0.01 absorbance unit (AU). All solutions were tested at time 0 and at 20, 60, 240, and 1,440 minutes. RESULTS: Across all tests, only a commercially available formulation of heparin 2 units/mL in 0.9% sodium chloride injection precipitated with CaCl, alone or in combination with other medications. Upon further review, it was found that this specific formulation of heparin contained a monohydrate and dibasic sodium phosphate buffer. CONCLUSION: CaCl only precipitated with a commercially available heparin formulation that contained a phosphate buffer. CaCl was deemed to be compatible with all other medications and formulations tested.

Physical compatibility of remimazolam with opioid analgesics, sedatives, and muscle relaxants during simulated Y-site administration.

PURPOSE: There is a lack of information on the compatibility of remimazolam with opioid analgesics, muscle relaxants, and other sedatives. This study aimed to evaluate the physical compatibility of remimazolam with these drug classes. METHODS: Remimazolam was combined with 1 or 2 target drugs (remifentanil, fentanyl, rocuronium, vecuronium, dexmedetomidine, and midazolam). Ten physical compatibility tests were conducted, including four 3-drug compatibility tests. Remimazolam was dissolved in 0.9% sodium chloride injection to a final concentration of 5 mg/mL. Other medications were diluted in 0.9% sodium chloride injection to obtain clinically relevant concentrations. Compatibility tests were conducted with 3 test solutions, wherein remimazolam and the target drugs were compounded at equal volume ratios (1:1 or 1:1:1). Visual appearance was assessed and testing of Tyndall effect, turbidity, and pH was performed immediately after mixing and then again 1 hour and 4 hours after mixing. Appearance and turbidity were evaluated by comparison with the control solution of each target drug diluted with 0.9% sodium chloride injection to the same concentration as the test solution. RESULTS: All drugs tested were determined to be compatible with remimazolam. The drug combination with the highest change of turbidity was remimazolam and vecuronium (a mean increase of 0.16 NTU relative to the remimazolam control solution), 4 hours after mixing. The combination with the highest pH was remimazolam, fentanyl, and vecuronium (mean [SD], 3.76 [0.01]), 4 hours after mixing. The combination of remimazolam and fentanyl showed a larger change in pH at 4 hours after mixing (a mean increase of 2.6%) than immediately after mixing. CONCLUSION: Remifentanil, fentanyl, rocuronium, vecuronium, dexmedetomidine, and midazolam are physically compatible with remimazolam during simulated Y-site administration.

Construção e validação de ferramenta preventiva sobre incompatibilidade medicamentosa em via Y / Construction and validation of a preventive tool on drug incompatibility in the Y-route / Construcción y validación de una herramienta preventiva de incompatibilidad de medicamentos en la ruta Y

Introdução: A terapia com medicamentos endovenosos é muito utilizada nas unidades hospitalares, porém, possui uma elevada chance de incidentes, principalmente quando os medicamentos são administrados simultaneamente em via Y. Essa prática pode resultar em incompatibilidades medicamentosas classificadas em reações físicas e químicas. Objetivo: Construir e validar uma ferramenta preventiva de incompatibilidade medicamentosa em via Y. Método: Estudo metodológico com abordagem quantitativa. Foi desenvolvido em três etapas: Levantamento bibliográfico, construção e diagramação do material e por fim, a validação da ferramenta preventiva. Para validação, a ferramenta preventiva foi submetida ao processo de validação de face e conteúdo por juízes com expertise na temática. Resultados: Construiu-se e validou-se uma ferramenta preventiva através da busca de dados na literatura com a participação de sete juízes especialistas na temática. Os itens avaliativos referentes a tabela de incompatibilidade medicamentosa quanto aos objetivos, estrutura, apresentação e relevância da ferramenta preventiva foi considerada válida, pois foram julgados como adequado pelos especialistas. Conclusão: A validação de conteúdo, foi considerada válida pelos juízes, portanto, espera-se que o material alcance o seu objetivo ao ser aplicado durante a prática clínica. Dessa forma, será disponibilizado à instituição para que seja utilizado, favorecendo a prevenção de danos e contribuindo para a segurança dos pacientes, bem como melhorando a qualidade da assistência e educação em saúde.

Introduction: Intravenous drug therapy is widely used in hospital units, however, it has a high chance of incidents, especially when drugs are administered simultaneously in a Y route. This practice can result in drug incompatibilities classified into physical and chemical reactions. Objective: To build and validate a preventive tool for drug incompatibility in the Y pathway. Method: Methodological study with a quantitative approach. It was developed in three stages: bibliographic survey, construction and layout of the material and finally, the validation of the preventive tool. For validation, the preventive tool was submitted to the face and content validation process by judges with expertise in the subject. Results: A preventive tool was built and validated through the search for data in the literature with the participation of seven expert judges on the subject. The evaluative items referring to the medication incompatibility table regarding the objectives, structure, presentation and relevance of the preventive tool were considered valid, as they were judged as adequate by the specialists. Conclusion: The content validation was considered valid by the judges, therefore, it is expected that the material reaches its objective when applied during clinical practice. In this way, it will be made available to the institution for use, favoring the prevention of damage and contributing to patient safety, as well as improving the quality of health care and education.

Introducción: La farmacoterapia intravenosa es ampliamente utilizada en las unidades hospitalarias, sin embargo, tiene una alta probabilidad de incidencias, especialmente cuando los fármacos se administran simultáneamente en una vía Y. Esta práctica puede dar lugar a incompatibilidades medicamentosas clasificadas en reacciones físicas y químicas. Objetivo: Construir y validar una herramienta preventiva de incompatibilidad de medicamentos en la vía Y. Método: Estudio metodológico con enfoque cuantitativo. Se desarrolló en tres etapas: relevamiento bibliográfico, construcción y diagramación del material y finalmente, la validación de la herramienta preventiva. Para la validación, la herramienta preventiva fue sometida al proceso de validación facial y de contenido por jueces expertos en el tema. Resultados: Se construyó y validó una herramienta preventiva a través de la búsqueda de datos en la literatura con la participación de siete jueces expertos en el tema. Los ítems evaluativos referentes a la tabla de incompatibilidad de medicamentos en relación a los objetivos, estructura, presentación y relevancia de la herramienta preventiva fueron considerados válidos, pues fueron juzgados como adecuados por los especialistas. Conclusiones: La validación del contenido fue considerada válida por los jueces, por lo tanto, se espera que el material alcance su objetivo al ser aplicado durante la práctica clínica. De esta forma, se pondrá a disposición de la institución para su uso, favoreciendo la prevención de daños y contribuyendo a la seguridad del paciente, además de mejorar la calidad de la atención y educación en salud.

Simultaneous infusion of two incompatible antibiotics: Impact of the choice of infusion device and concomitant simulated fluid volume support on the particulate load and the drug mass flow rates.

Vancomycin and piperacillin/tazobactam are known to be incompatible. The objectives of the present study were to evaluate the impact of their simultaneous infusion on mass flow rates and particulate load and identify preventive strategies. We assessed both static conditions and a reproduction of an infusion line used in a hospital's critical care unit. A high-performance liquid chromatography/UV diode array system and static and dynamic laser diffraction particle counters were used. The mass flow rates were primarily influenced by the choice of the infusion device and the presence of simulated fluid volume support. Drug incompatibility also appeared to affect vancomycin's mass flow rate, and the dynamic particulate load increased during flow rate changes - especially in the infusion set with a large common volume line and no concomitant simulated fluid volume support. Only discontinuation of the piperacillin/tazobactam infusion was associated with a higher particulate load in the infusion set with a large common volume line and no concomitant simulated fluid volume support. A low common volume line and the use of simulated fluid volume support were associated with smaller fluctuations in the mass flow rate. The clinical risk associated with a higher particulate load must now be assessed.

Frequently acquired drugs in neonatal intensive care and their physical compatibility.

AIM: Incompatibility of intravenous drugs is dangerous and therefore undesirable. The aim of this study was to identify the most commonly acquired intravenous drugs in five neonatal intensive care units and test these for compatibility. METHODS: The most frequently acquired drugs in five key hospitals in the South-Eastern district of Norway for 2019 and 2020 served as a proxy for the prevalence of use. Representatives were selected from the three most prevalent groups based on the Anatomical Therapeutic Chemical classification system. Co-administration of drug pairs was simulated using clinically relevant concentrations and infusion rates representing mixing ratios in the catheter. Particle formation was assessed by particle counting and size measurement, by visual examination using Tyndall beam, by turbidity and by measuring pH of mixed samples. RESULTS: The most frequently acquired drug groups were anti-infectives, neurological agents and cardiovascular drugs. Compatibility testing revealed that both ampicillin and benzylpenicillin were incompatible with morphine. Flecainide and fluconazole showed no signs of incompatibility with morphine. No information on these combinations in a neonatal-relevant setting is available. CONCLUSION: We recommend to abstain from co-administering ampicillin and benzylpenicillin with morphine in neonatal intensive settings. Morphine co-administered with flecainide and fluconazole in neonatal patients were evaluated as safe.

Simulated Y-site compatibility of atosiban acetate with selected intravenous drugs.

OBJECTIVE: The physical compatibility of atosiban and selected drugs during simulated Y-site administration was evaluated. We also searched for any compatibility predictions regarding its physicochemical properties. STUDY DESIGN: Test admixtures were prepared by mixing 5 mL of each study drug solution with 5 mL of atosiban solution in a 1:1 ratio to simulate Y-site infusion. Assessments were made immediately after mixing (baseline), and at 0.5, 1, and 3 h. Visual incompatibility was defined as a presence of haze or any visible particulate matter, gas formation, or colour change. Turbidity and pH variation of the admixtures were also assessed using instrumental methods. RESULTS: None of the admixtures used with atosiban exhibited visual changes and no incompatibility regarding instrumental methods were observed, because no admixture had an increase of 0.5 nephelometric turbidity units, and no pH change was above one unit when compared to baseline. However, the pH of ampicillin and omeprazole admixtures fell outside of the atosiban stability range. CONCLUSIONS: Our study showed no physical incompatibility between atosiban and the test drugs in terms of visual changes or nephelometric and pH measurements. However, we recommend against atosiban and ampicillin or omeprazole coadministration until complementary compatibility studies are performed.

Utility of a Compatibility Chart for Continuous Infusions in the Intensive Care Unit.

BACKGROUND: In the intensive care unit (ICU), multiple intravenous drugs are often administered through the same catheter line, greatly increasing the risk of drug incompatibility. We previously developed a compatibility chart including 27 drugs and have used it to avoid drug incompatibilities in the ICU. This retrospective study evaluated the utility of this chart by analyzing prescriptions and incidents of incompatibilities in an ICU. METHODS: We analyzed 257 ICU prescriptions of two or more continuous infusions on the same day during the period between March 2016 and February 2017 and investigated the rate of compliance with the compatibility chart. Drug combinations were classified as "compatible," "tolerable compatible," "incompatible," and "no data." For all combinations, the compliance rate was defined as the ratio of compatible and tolerable compatible combinations. Additionally, using our hospital incident report database, we analyzed 27,117 injections administered in the ICU between March 2016 and February 2017 and investigated incidents related to incompatibility. RESULTS: Three hundred infusion combinations were identified in the prescriptions. The compliance rate was 97% (n = 293). Of the 113 combinations judged to be tolerable compatible, 98% (n = 111) consisted of three or more continuous medications injected through the same intravenous line. Of the two incidents related to incompatibility in the incident report database, the combination "nicardipine and furosemide" was defined as incompatible in the compatibility chart. CONCLUSIONS: The high rate of compliance with the compatibility chart suggested it was useful in preventing drug incompatibility.

Compatibility and Stability of Ten Commonly Used Clinical Drugs in Pediatric Electrolyte Supplements Injection.

Objective: Pediatric electrolyte supplements injection is mainly used to supplement heat and body fluid, and commonly used in pediatrics. Its compatibility and stability with common clinical drugs such as antibiotics was rarely reported to ensure the children's safety and the rational use of drugs. The aim of the present study was to investigate physical and chemical stability of pediatric electrolyte supplements injection mixed with ten commonly used clinical drugs. Methods: According to clinical drug concentration, we mix the pediatric electrolyte supplements injection mixed with ten drugs. The compatible solutions were withdrawn at certain time intervals (0, 0.5, 1, 2, 4, 6 hours) after mixing and tested by description, insoluble particles detection, pH determination and high performance liquid chromatography (HPLC) assay of active ingredient as measures of physicochemical compatibility. Results: No obvious appearance changes were observed when mixing. Furthermore, over the 6 hours post-preparation period the pH values were within the requirements of each drug quality standard and the number of insoluble particles (≥10 and ≥25µm) met requirements of Chinese Pharmacopeia (Edition 2020) except for mezlocillin sodium for injection. The percentages of the initial concentrations maintained at a minimum of 97% in the mixtures within 6 hours. Conclusions: Nine commonly used clinical drugs remained stable in the pediatric electrolyte supplements injection for 6 hours at 25°C and avoiding from light. Mezlocillin sodium for injection was not recommended to be combined with electrolyte supplement injection for children because its insoluble particles exceed the standard.

Stability of Aprepitant Injectable Emulsion in Alternate Infusion Bags, in Refrigerated Storage, and Admixed with Dexamethasone and Palonosetron.

PURPOSE: The stability of aprepitant injectable emulsion is evaluated in various admixture bags and solutions, under different storage conditions, and when combined with other antiemetics. METHODS: A volume of 18 mL aprepitant injectable emulsion was added to infusion bags (either non-di-(2-ethylhexyl) phthalate [DEHP], polyvinyl chloride [PVC]-containing bags or non-DEHP, non-PVC bags) containing 100, 130, or 250 mL of 0.9% normal saline solution (NSS) or 5% dextrose in water (D5W). Bags were stored at controlled room temperature (20-25°C) for up to 12 hours or refrigerated (2-8°C) for up to 72 hours. Compatibility/stability was also assessed in admixtures combined with either dexamethasone or palonosetron. At specified time points, bags were tested for appearance, pH, assay for aprepitant (ie, percent label claim of aprepitant) and aprepitant-related substances, Z-average particle size, globule size distribution, particulate matter, and DEHP content (PVC bags). In separate analyses to assess microbial burden, bags containing aprepitant were inoculated with seven different organisms and assessed for microbial growth. RESULTS: There was no detectable impact on the physicochemical properties or potential to promote microbial growth of aprepitant when diluted with various amounts of either NSS or D5W and when admixed with either dexamethasone or palonosetron at room temperature for at least 6 hours or during refrigeration for up to 72 hours in either PVC- or non-PVC-containing bags. CONCLUSION: Aprepitant-containing admixtures are stable under these conditions, a finding that may improve patient and provider convenience and reduce medication wastage.

Revisión de mezclas binarias, ternariasy cuaternarias para inducción y mantenimiento de anestesia libre de opiáceos / Review of binary, ternary and quaternary mixtures for induction and maintenance of opioid free anesthesia

Objetivo: Describir y estructurar la información actual disponible sobremezclas binarias, ternarias y/o cuaternarias empleadas en una “anestesialibre de opiáceos”, así como su estabilidad fisicoquímica, para facilitar sucorrecta administración, optimizar su uso y prevenir posibles problemasde efectividad o seguridad.Método: Revisión sistemática de la literatura sobre anestesia libre deopiáceos en PubMed/Medline, Trissel, Micromedex, Lexicomp, AHFS DrugInformation, Extended Stability for Parenteral Drugs y Stabilis Web. Artículos publicados en inglés o español hasta mayo de 2020 y con acceso atexto completo. Se emplearon los términos MeSH: “Drug Incompatibility”AND “Opioid Free Anesthesia” AND “Administration, Intravenous” AND“Dexmedetomidine” AND “Lidocaine” AND “Ketamine” AND “SulphateMagnesium” OR “Infusions, Intravenous”. Se realizó una primera búsquedaen PubMed/Medline incluyendo casos clínicos de anestesia general tipoanestesia libre de opiáceos. Los resultados obtenidos se estructuraron enuna base de datos. La segunda búsqueda fue sobre incompatibilidadesde las mezclas intravenosas. Se recogieron medicamentos compatibles/incompatibles; concentraciones de referencia; tiempo de estabilidad a temperatura ambiente (23 ± 2 °C) y en refrigeración (4 ± 2 °C); tipo de administración recomendada y resultados y conclusiones relevantes. Se crearon dos tablas bidimensionales de la compatibilidad de cada combinación defármacos para la administración en Y o en mezcla en una sola solución.Resultados: Se identificaron 780 artículos; se accedió al texto completo de 203. Se recogieron de forma cronológica los 4.762 casos tratados en 32 diferentes publicaciones con protocolos de anestesia librede opiáceos. El uso de dos fármacos fue la asociación más frecuente(42,4%). Los fármacos más empleados fueron dexmedetomidina (25 trabajos), clorhidrato de ketamina (25 trabajos) y lidocaína (14 trabajos). (AU)

Objective: To describe and organize the current information availableon binary, ternary and/or quaternary mixtures used in opioid-free anesthesia (OFA), as well as their physicochemical stability, in order to facilitate itscorrect administration, optimize its use, and prevent potential effectivenessand safety issues.Method: A systematic review of the literature on OFA was conductedin PubMed/Medline, Trissel, Micromedex, Lexicomp, www.ahfsdruginformation.com, ASHP’s Extended Stability for Parenteral Drugs, and www.stabilis.org. Only articles published in English or Spanish until May 2020and with access to full text were considered. MeSH terms used included:“drug incompatibility” AND “opioid-free anesthesia” AND “administration,intravenous” AND “dexmedetomidine” AND “lidocaine” AND “ketamine”AND “magnesium sulphate” OR “infusions, intravenous. A first search wascarried out in PubMed/Medline that included OFA clinical cases. Theresults obtained were collected in a database. A second search wascarried out on the incompatibilities of intravenous mixtures. Informationwas compiled on mutually-compatible/incompatible drugs, reference concentrations, stability time at room temperature (23 ± 2 °C) and under refrigeration (4 ± 2 ºC), type of administration recommended, and relevantresults and conclusions. Two two-dimensional tables on the compatibility of each drug combination were created for administration as Y-site infusionor as a mixture in a single solution. (AU)

Review of binary, ternary and quaternary mixtures for induction and maintenance of opioid free anesthesia.

OBJECTIVE: To describe and organize the current information available on  binary, ternary and/or quaternary mixtures used in opioid-free anesthesia (OFA), as well as their physicochemical stability, in order to  facilitate its correct administration, optimize its use, and prevent potential  effectiveness and safety issues. METHOD: A systematic review of the literature on OFA was conducted in  PubMed/Medline, Trissel, Micromedex, Lexicomp,  ww.ahfsdruginformation.com, ASHP's Extended Stability for Parenteral Drugs, and www.stabilis.org. Only articles published in English or Spanish until May 2020 and with  access to full text were considered. MeSH terms used included: "drug  incompatibility" AND "opioid-free anesthesia" AND "administration, intravenous" AND "dexmedetomidine" AND "lidocaine"  AND "ketamine" AND "magnesium sulphate" OR "infusions, intravenous. A  first search was carried out in PubMed/Medline that included OFA clinical cases. The results obtained were collected in a database. A second search  was carried out on the incompatibilities of intravenous mixtures.  Information was compiled on mutually-compatible/incompatible drugs,  reference concentrations, stability time at room temperature (23 ± 2 °C)  and under refrigeration (4 ± 2 ºC), type of administration recommended,  and relevant results and conclusions. Two two-dimensional tables on the  compatibility of each drug combination were created for administration as  Y-site infusion or as a mixture in a single solution. RESULTS: Seven hundred and eighty articles were identified, with the full  text of 203 being accessed. A total of 4,762 cases treated with OFA  protocols were chronologically collected from 32 different publications. Administration of two concomitant drugs was the most usual  regimen (42.4%). The most frequently drugs were dexmedetomidine (25  studies), ketamine hydrochloride (25 studies) and lidocaine (14 studies).  Compatibility/incompatibility data was collected for 11 drugs, associated to  7 pharmacological groups; compatibility with Y-site administration was  found in 43 of 55 combinations (78.18%) and with integration into one  single solution in 13 of 55 drug combinations (23.63%). None of the  sources reviewed reported any adverse results related to potential  pharmacological incompatibilities. CONCLUSIONS: Despite the availability of multiple OFA protocols, few studies analyze the compatibility between binary drug mixtures. No  information exists as yet regarding compatibilities in the context of ternary and quaternary mixtures.  Despite the availability of multiple OFA  protocols, few studies analyze the compatibility between binary drug  mixtures. No information exists as yet regarding compatibilities in the  context of ternary and quaternary mixtures.

Objetivo: Describir y estructurar la información actual disponible sobre mezclas binarias, ternarias y/o cuaternarias empleadas en una  "anestesia libre de opiáceos", así como su estabilidad fisicoquímica, para  facilitar su correcta administración, optimizar su uso y prevenir posibles  problemas de efectividad o seguridad.Método: Revisión sistemática de la literatura sobre anestesia libre de opiáceos en PubMed/Medline, Trissel, Micromedex, Lexicomp, AHFS  Drug Information, Extended Stability for Parenteral Drugs y Stabilis Web.  Artículos publicados en inglés o español hasta mayo de 2020 y con acceso  a texto completo. Se emplearon los términos MeSH: "Drug Incompatibility" AND "Opioid Free Anesthesia" AND "Administration,  Intravenous" AND "Dexmedetomidine" AND "Lidocaine" AND "Ketamine"  AND "Sulphate Magnesium" OR "Infusions, Intravenous". Se realizó una  primera búsqueda en PubMed/Medline incluyendo casos clínicos de  anestesia general tipo anestesia libre de opiáceos. Los resultados  obtenidos se estructuraron en una base de datos. La segunda búsqueda  fue sobre incompatibilidades de las mezclas intravenosas. Se recogieron  medicamentos compatibles/ incompatibles; concentraciones de referencia; tiempo de estabilidad a temperatura ambiente (23 ± 2 °C) y en  refrigeración (4 ± 2 °C); tipo de administración recomendada y resultados  y conclusiones relevantes. Se crearon phardos tablas bidimensionales de la compatibilidad de cada combinación de fármacos para la administración en Y o en mezcla en una sola solución.Resultados: Se identificaron 780 artículos; se accedió al texto completo de 203. Se recogieron de forma cronológica los 4.762 casos  tratados en 32 diferentes publicaciones con protocolos de anestesia libre de opiáceos. El uso de dos fármacos fue la asociación más frecuente (42,4%). Los fármacos más empleados fueron dexmedetomidina (25 trabajos), clorhidrato de ketamina (25 trabajos) y lidocaína (14  trabajos). Se recopiló información de compatibilidad/incompatibilidad de  11 medicamentos, asociados a 7 grupos farmacológicos, encontrándose  compatibilidad en Y en 43 de 55 combinaciones (78,18%) y en mezcla en  una sola solución en 13 de 55 combinaciones de fármacos (23,63%). En  ningún trabajo publicado se expone algún tipo de evento adverso en  relación con una posible incompatibilidad farmacológica.Conclusiones: Existen múltiples protocolos de anestesia libre de  piáceos, pero los estudios de compatibilidad entre las diferentes mezclas  de fármacos empleadas son muy limitados cuando se trata de mezclas  binarias, y no existe información en el caso de mezclas ternarias y  cuaternarias.

Assessment of the physical compatibility of injectable enrofloxacin with commonly used intravenous fluids and drugs during simulated Y-port administration.

OBJECTIVE: To evaluate physical compatibility of small animal (SAE) and large animal (LAE) injectable formulations of enrofloxacin with select IV fluids and drugs. SAMPLE: 162 admixtures containing SAE or LAE with saline (0.9% NaCl) solution, lactated Ringer solution (LRS), Plasma-Lyte A (PLA), 6% hydroxyethylstarch 130/0.4 (HES), metoclopramide, or ampicillin-sulbactam. PROCEDURES: In the first of 2 simultaneously conducted experiments, admixtures containing enrofloxacin (10 mg/kg) and a volume of IV fluid that would be administered over a 20-minute period when dosed at the maintenance infusion rate (40 mL/kg/d for saline solution, LRS, and PLA and 20 mL/kg/d for HES) were created. In the second experiment, enrofloxacin (10 mg/kg) was admixed with saline solution (40 mL/kg/d) and metoclopramide (2 mg/kg/d) or ampicillin-sulbactam (30 mg/kg). In both experiments, admixture components were infused into a flask over 20 minutes assuming patient weights of 5, 10, and 20 kg. Admixtures were created by use of undiluted SAE and SAE diluted 1:1 with saline solution and undiluted LAE and LAE diluted 1:1 and 1:10 with saline solution. Admixtures were assessed for physical incompatibility at 0, 15, 30, and 60 minutes after completion of mixing. Physical incompatibility was defined as gross precipitation, cloudiness, Tyndall effect, or change in turbidity. RESULTS: Admixtures containing undiluted SAE or LAE were physically incompatible with saline solution, PLA, LRS, and HES. Because saline solution was used to dilute SAE and LAE, all admixtures containing diluted SAE or LAE were also physically incompatible. Physical compatibility of enrofloxacin with metoclopramide or ampicillin-sulbactam could not be assessed because those admixtures also contained saline solution. CONCLUSIONS AND CLINICAL RELEVANCE: Enrofloxacin was physically incompatible with all tested solutions.

Análisis de incompatibilidades medicamentosas en una unidad cardiointensiva: estudio transversal / Analysis of drug incompatibilities in a cardiac intensive unit: a cross-sectional study / Análise das incompatibilidades medicamentosas em uma unidade cardiointensiva: estudo transversal

OBJETIVO: Evaluar las incompatibilidades de los medicamentos intravenosos en pacientes cardíacos ingresados en una unidad cardiointensiva, asociando posibles incompatibilidades con la gravedad y las características del evento adverso. MÉTODO: Estudio transversal, observacional y cuantitativo. Realizado en una Unidad Cardiointensiva de un Hospital Universitario en la ciudad de Rio de Janeiro. La recopilación de datos se realizó de marzo a junio de 2018. Para identificar y clasificar las incompatibilidades de medicamentos se utilizó Micromedex(R). RESULTADOS: Se analizaron 111 recetas, con un total de 1,497 medicamentos recetados, el número promedio de medicamentos recetados fue 13,49 (6 ± 24), 580 (38.74%) por vía intravenosa, de los cuales el 41.38% se administraron simultáneamente con otro medicamento. El estudio mostró 121 incompatibilidades y las clases de drogas que tuvieron el mayor número de incompatibilidades fueron diuréticos, hipnóticos y sedantes, estimulantes cardiovasculares (aminas vasoactivas), antibióticos para uso sistémico, corticosteroides para uso sistémico, vasodilatadores cardiovasculares y agentes antiarrítmicos. Destacando las incompatibilidades clasificadas como moderadas, furosemida con hidrocortisona y midazolam con omeprazol y fentanilo severo con amiodarona. CONCLUSIÓN: El estudio destaca la importancia de la programación y administración de medicamentos por parte del equipo de enfermería con base en el conocimiento farmacológico. Se espera que el cuadro de recomendaciones preparado en el estudio, con atención de enfermería relacionada con incompatibilidades con mayor potencial de gravedad y sus eventos, pueda contribuir a la seguridad de los medicamentos

OBJECTIVE: To evaluate the incompatibilities of intravenous medications in cardiac patients admitted to a cardiac intensive unit, associating possible incompatibilities with the severity and characteristics of the adverse event. METHOD: Cross-sectional, observational, and quantitative study, held in a Cardiac intensive Unit of a University Hospital in the city of Rio de Janeiro. Data collection took place from March to June 2018. Micromedex(R) identified and classified drug incompatibilities. RESULTS: We analyzed 111 prescriptions with a total of 1,497 prescription drugs, the average number of prescription drugs was 13.49 (6 ± 24), 580 (38.74%) intravenously in which 41.38% were administered simultaneously with another medicine. The study showed 121 incompatibilities and the drug classes that had the highest number of incompatibilities were diuretics, hypnotics and sedatives, cardiovascular stimulants (vasoactive amines), antibiotics for systemic use, corticosteroids for systemic use, cardiovascular vasodilators, and antiarrhythmic agents. We highlight the incompatibilities classified as moderate, furosemide with hydrocortisone, and midazolam with omeprazole, and severe fentanyl with amiodarone. CONCLUSION: The study highlights the importance of medication scheduling and administration by the nursing team based on pharmacological knowledge. We expect that the chart of recommendations prepared in the study with nursing care related to incompatibilities with greater potential for severity and its events can contribute to drug safety

OBJETIVO: Avaliar as incompatibilidades de medicações intravenosas em pacientes cardiopatas internados em uma unidade cardiointensiva, associando as possíveis incompatibilidades com a gravidade e característica do evento adverso. MÉTODO: Estudo transversal, observacional e quantitativo. Realizado em uma Unidade Cardiointensiva de um Hospital Universitário do município do Rio de Janeiro. A coleta de dados ocorreu de março a junho de 2018. Para a identificação e classificação das incompatibilidades medicamentosas, foi utilizado o Micromedex(R). RESULTADOS: Foram analisadas 111 prescrições, com um total de 1.497 medicamentos prescritos, a média de medicamentos por prescrição foi 13,49 (6 ±24), sendo 580 (38,74%) por via intravenosa, destes, 41,38% foram administrados simultaneamente com outro medicamento. O estudo apresentou 121 incompatibilidades e as classes medicamentosas que apresentaram maior número de incompatibilidades foram diuréticos, hipnóticos e Sedativos, estimulantes cardiovasculares (aminas vasoativas), antibióticos de uso sistêmico, corticoides de uso sistêmico, vasodilatadores cardiovasculares e antiarrítmicos. Destacando-se as incompatibilidades classificadas como moderadas, a furosemida com hidrocortisona e o midazolam com omeprazol e grave o fentanil com amiodarona. CONCLUSÃO: O estudo destaca a importância do aprazamento e administração de medicamentos pela equipe de enfermagem com base em conhecimentos farmacológicos. Espera-se que o quadro de recomendações elaborado no estudo, com os cuidados de enfermagem relacionados as incompatibilidades com maior potencial de gravidade e seus eventos, possa contribuir para segurança medicamentosa

Strategies to prevent drug incompatibility during simultaneous multi-drug infusion in intensive care units: a literature review.

PURPOSE: Drug protocols in intensive care units may require the concomitant administration of many drugs as patients' venous accesses are often limited. A major challenge for clinicians is to limit the risk of simultaneously infusing incompatible drugs. Incompatibilities can lead to the formation of particles and inactivation of drugs, whose consequences on the body have already been indicated. Our objective was to assess current strategies to counter the risk of incompatible infusions and control the resulting clinical consequences. METHODS: This review was independently conducted by three investigators in respect of the PRISMA statement. Three online databases were consulted. Full-text articles, notes, or letters written in English or French, published or in press between the 1990s and the end of February 2020, with clinical study design, were eligible. Parameters of interest were mainly number and size of particles, and a number of observed/avoided incompatibilities. RESULTS: All in all, 382 articles were screened, 17 meeting all the acceptance criteria. The strategies outlined and assessed were filtration, the use of multi-lumen devices, the purging of infusion lines, incompatibility tables and databases, and the use of standard operating procedures. CONCLUSION: Although many strategies have been developed in recent years to address drug incompatibility risks, clinical data is still lacking. All studies with in vitro design were excluded although some current innovative strategies, like niosomes, should be considered and studied by means of clinical data in the future.

Physical Compatibility of Nafamostat with Analgesics, Sedatives, and Muscle Relaxants for Treatment of Coronavirus Disease 2019.

BACKGROUND: Severe coronavirus disease 2019 (COVID-19) may require continuous administration of analgesics, sedatives, and muscle relaxants. Nafamostat has recently been reported as a therapeutic agent for COVID-19. However, there is a lack of information on the compatibility of nafamostat with the aforementioned drug classes. This study evaluated the physical compatibility of nafamostat with these drug classes. METHODS: Nafamostat was combined with 1-3 target drugs (fentanyl, morphine, midazolam, dexmedetomidine, and rocuronium). Fifteen physical compatibility tests were conducted. Nafamostat was dissolved in 5% glucose solution; the final concentration was 10 mg/mL. All other medications were diluted in 0.9% sodium chloride to obtain clinically relevant concentrations. The power of hydrogen (pH) of all medications was measured during each test. Compatibility tests were conducted with 4 test solutions in which nafamostat and the target drugs were compounded at equal volume ratios (1:1, 1:1:1, or 1:1:1:1). Visual appearance, turbidity, and pH were evaluated immediately after mixing and at 1 and 3 hours. Physical incompatibilities were defined as gross precipitation, cloudiness, appearance of the Tyndall effect, or a turbidity change of ≥0.5 nephelometric turbidity units (NTU) based on nafamostat. RESULTS: The mean pH of nafamostat was 3.13 ± 0.03. The combination of nafamostat, fentanyl, and dexmedetomidine had the highest pH (3.39 ± 0.01; 3 hours after mixing). All drugs were compatible with nafamostat until 3 hours after admixture, with a mean turbidity value of ≤0.03 NTU. CONCLUSIONS: Infusions combining nafamostat with the tested sedatives, analgesics, and muscle relaxants could be safely administered.