Complications of Medical Procedures

Massive transfusion, defined as the transfusion of total body blood volume (10 units of erythrocyte suspension or 8 units and above in some definitions) or more within 24 hours, remains one of the greatest challenges for the anesthetist. Despite all the medical advances, in cardiac surgery, obstetric surgery, trauma-orthopedic surgery, neurosurgery, major gastrointestinal-genitor-urinary system surgeries, which are among the major bleeding surgeries, massive hemorrhage continues to be an important mortality and morbidity factor. In addition to major surgeries with known expected bleeding, massive transfusion requirement may arise with any undesirable intraoperative event. While the process is easier to manage with proper preparation and an organized procedure in expected bleeding, a chaotic response may be encountered in unexpected situations. Special protocols for each division have been developed by clinicians to manage this critical process, and work continues on these protocols to improve the outcome. Massive bleeding management mainly focuses on transfusion and fluid resuscitation. Regardless of the situation requiring massive transfusion, the goals of treatment in massive bleeding are to maintain organ perfusion pressure and oxygen delivery, immediately stop bleeding and coagulopathy. While these goals can be achieved through resuscitation with blood products and surgical intervention, the triad of hypothermia, acidosis, and coagulopathy that occurs with the process contributes to increased morbidity and mortality in such scenarios. The literature on major bleeding from trauma has highlighted some issues contributed to improved clinical outcomes such as, damage-controlled resuscitation, including timely initiation of transfusion, early use of clotting factors, minimizing the use of crystalloids. The landmark PROPPR study found that in the resuscitation of trauma patients, a 1:1:1 ratio of FFP:platelet:ES transfusion during massive bleeding resulted in hemostasis in a greater number of patients (86% versus 78%) compared to a 1:1:2 ratio, additionally, they found fewer deaths from bleeding within 24 hours (14.6% versus 9.2%). However, no significant difference was found in 24-hour or 30-day overall mortality. In a systematic review evaluating retrospective data on transfusions for obstetric bleeding, it was shown that the amount of FFP administered was greater than the amount of ES. Since the mortality rate from massive obstetric hemorrhage is lower than that of traumatic hemorrhage, it is difficult to prospectively evaluate the effects of massive transfusion. This review recommends a FFP/ES ratio of ≥1, with the results of all retrospective studies described on transfusions for obstetric hemorrhage. Studies in cardiac surgery also suggest that higher rates of FFP/ES transfusion are associated with better outcomes in patients with massive bleeding. In general, the high ratio of transfused FFP to ES in bleeding surgeries requiring massive transfusion has been associated with positive results. FFP contains all coagulation factors and fibrinogen, as well as restoring the volume deficit that occurs with major bleeding, which reduces the crystalloid requirement and prevents extra dilution of coagulation factors. Fibrinogen is the clotting factor whose level drops the fastest during bleeding. Fibrinogen is a unique coagulation building block that plays a role in both primary and secondary hemostasis. Based on the results of the RETIC trial, the effectiveness of fibrinogen supplementation in limiting blood loss appears to be strongly dependent on timing of fibrinogen administration and increasing levels above 200 mg·dL-1. The 5th Edition of the European Guidelines for the Management of Major Posttraumatic Hemorrhage and Coagulopathy recommends early and repeated monitoring of fibrinogen concentrations and/or polymerization and rapid correction of deficiencies. Accordingly, 3-4 g of fibrinogen concentrate or 15-20 units of cryoprecipitate is recommended as an initial dose in massive bleeding. While RETIC stands out as a randomized controlled prospective study on the role of fibrinogen in massive transfusion in trauma patients, there are few cardiac and transplantation surgery studies in various types of research. Regardless of the cause, early restoration of fibrinogen levels in case of massive bleeding reduces transfusion requirement by preventing ongoing bleeding. In the FIBRES study, which evaluated the efficacy of fibrinogen concentrate in cardiac surgery patients with bleeding, it was emphasized that fibrinogen concentrate was not inferior to cryoprecipitate, easy to apply, and a predictable robust effect. Further it is hypothesized that early replacement of fibrinogen in severely injured trauma patients may improve outcomes. However, there is little evidence to support this and, in addition, little evidence to support or refute the effects of cryoprecipitate or fibrinogen concentrate for fibrinogen replacement. Fibrinogen supplementation as cryoprecipitate within the first 90 minutes of major bleeding was considered feasable in a randomized controlled trial. As a matter of fact, in the E-FIT 1 study conducted with a very small number of patients, it was found that it is not effective to administer fibrinogen in the first 45 minutes. On the other hand, there is not only fibrinogen in the scene, results of the FIIRST 2 study comparing the use of combinations of fibrinogen concentrate and prothrombin complex concentrate (PCC) in hemorrhagic trauma patients are also eagerly awaited. Ideally, fibrinogen concentrate and/or cryoprecipitate are used in fibrinogen replacement, and FFP is used as a weaker fibrinogen source. During massive transfusion, repeated doses of FFP/cryoprecipitate/fibrinogen concentrate are used. All of these blood products have different amounts of fibrinogen content. In many previous studies, the formula for improving the results was investigated by looking at transfusion rates such as FFP/ES, ES/platelet, FFP/ES/Platelet. In the light of this information, our hypothesis is that mortality and morbidity can be reduced with a high rate of total fibrinogen from various sources. In order to combine the fibrinogen amounts from different sources under a single name, we determined an equalization according to the fibrinogen amounts they contain. In accordance with this formula, it was considered to investigate the effect of the overall ADEF/ES ratio on mortality and outcome in massive transfusion cases that fit the definitions. The primary aim of this study to determine the effect of the ratio of total fibrinogen to erythrocyte suspension (ADE Fibrinogen/ES) transfused at 24 hours on the composite outcome, which includes 30-day all-cause mortality, bleeding-specific mortality, and the Katz index of independence in activities of daily living (scored 0, 1, 2- i.e. extremely dependent to highly dependent). The secondary aim of this study to determine the relationship of ADEF/ES ratio with other parameters: * Postoperative 24-hour and 3-month all-cause and bleeding specific mortality * Morbidity(\>90 day) Morbidity defined as events continuing after 90 days (ICD code 9) * thrombotic event (DVT, Pulmonary Embolism, DIC) * respiratory event (ventilator-associated pneumonia, other surgery-related respiratory complications) * ischemic event (Myocardial infarction, TIA, Cerebrovascular accident) * infection (sepsis, surgical site infection, any drug-resistant infection) * permanent kidney damage * Mortality predictors Mortality predictors as defined ; * Age * Gender * ASA score * Glasgow coma scale * Charlson Comorbidity index * Euroscore II * TASH score * Shock index * ISTH (International Society on Thrombosis and Haemostasis) score * ISS score * AC SURGICAL RISK CALCULATOR * History of antiplatelet-anticoagulant and ACEI or ARBs drug use * Emergency surgery * Temperature * Surgery specific details (Type of surgery, Duration of surgery periods, cement use etc\] * Intraoperative Vasopressor-inotropic medicine Requirement * Laboratory data over time \- when statistic testing mortality the data will be adjusted for these predicting/contributing factors * Complications Complications as defined; \--- Cardiac complications * Arrest * New developed unstable Arrhythmia * MI * KKY * Aortic dissection \--- Kidney complications * AKI I/II/III/IV (defined by KDIGO Criteria) * CRRT (temporary) * Continuous dialysis/CRF \--- Lung complications * Pulmonary edema * Pneumothorax * Pleural effusion * ARDS/respiratory failure * Bronchospasm * Aspiration pneumonitis \--- Neurological complications * Ischemic cerebral events * Hemorrhagic cerebral events (non-traumatic) * Permanent sequelae * TIA * Seizure \--- Infective complications * Pneumonia * Mediastinitis * Meningitis * Urinary tract infection * Wound site infection (Surgical Site Infections) * Catheter location infection * Sepsis \--- Thrombotic complications * Deep vein thrombosis * Pulmonary embolism * Mesentery thromboembolism * Stroke * Other * MODS/SIRS * MT Complications * Hematological Complications * Hemolytic rxns (Acute/delayed) * Febrile non-hemolytic reactions * DIC * Allergic reactions * TRALI (transfusion related acute lung injury) * TRAHI (transfusion related acute hepatic injury) * TACO (transfusion assoc. circulatory overload) * Abdominal compartment syndrome \--- Ischemic hepatitis, shock liver * Length of stay in the ICU Length of stay in the hospital * Functional state at discharge (can perform daily activities, can perform daily activities with assistance, completely in need of help) * All cause and bleeding specific mortality- Surgery specific postoperative 24-hour, 30 day and 3-month * Katz index of independence in activities of daily living (0,1,2 bad and 5,6 good scores)- Surgery specific postoperative 24-hour, 30 day and 3-month * Tranexamic acid use and mortality relationship * Initial(admission) plasma fibrinogen level and amount of bleeding Initial(admission) plasma fibrinogen level and amount of ADEF

Study Objective This observational study aims to prospectively investigate to what extent tracheostomy-related complications in children are asymptomatic or associated with symptoms when detected through surveillance airway endoscopy. We also aim at investigating how reliable caregiver reports and investigations by pediatriscians are in identifying symptoms associated with severe tracheostomy-related airway complications. Background Children with airway obstruction due to congenital malformations, trauma, or chronic respiratory or neuromuscular conditions may require a tracheostomy. The Long-Term Intensive Care Unit (LIVA), part of the Pediatric Perioperative Medicine and Intensive Care (BPMI) at Karolinska University Hospital, has been providing specialized care for children with tracheostomies across Sweden since 1998. The care at LIVA involves assessements by a multidisciplinary team, including pediatricians, ENT specialists, pediatric anesthesiologists, nurses, physiotherapists, dietitians, speech therapists, counselors, and play therapists. Follow-up at LIVA includes regular multidisciplinary assessments and one to two surveillance airway endoscopies under anesthesia annually, aimed at early detection of airway complications related to the tracheostomy tube. Complications such as granulomas, infections, or bleeding are often asymptomatic but can be potentially life-threatening. There is currently no national or international consensus on the optimal frequency of surveillance endoscopies, and the potential for individualizing surveillance based on risk factors, including the presentation of symptoms, remains unexplored. Given the risks associated with anesthesia, minimizing unnecessary procedures is critical. Currently, a retrospective study is underway to examine the incidence of tracheostomy-related complications, their correlation with risk and demographic factors, and preoperative symptoms. Preliminary results indicate that 72% of patients experienced at least one tracheostomy-related complication, while only 19% exhibited symptoms prior to surveillance endoscopy according to patient records. Suprastomal granuloma was the most frequent complication observed. Interventions were required for all symptomatic patients and 71% of asymptomatic patients with identified complications. Patients using ventilators and/or cuffed cannulas had a higher incidence of complications compared to those without (88% vs. 61%, p\<0.05). Study Population The study population comprises children under 18 years of age undergoing follow-up at the Long-Term Intensive Care Unit (LIVA) at Karolinska University Hospital in Stockholm, Sweden. Research Questions 1. To what extent are tracheostomy-related complications in children asymptomatic when detected through surveillance airway endoscopy? 2. How reliable are caregiver reports in identifying symptoms associated with tracheostomy-related airway complications? Methods Children scheduled for surveillance airway endoscopy are admitted to LIVA. Upon admission, the caregiver is asked to complete a short questionnaire regarding symptoms that may indicate a tracheostomy-related complication. After the questionnaire has been completed, the child will be examined by the responsible paediatrician, with the aim of identifying any signs or symptoms that could indicate an airway complication. The examination includes physical examination and medical history conducted according to a predefined protocol. The airway endoscopy is performed by an ENT surgeon who has not examined the patient beforehand and is not informed of the caregiver's responses nor the result of the examination by the pediatrician. However, there is no strict protocol in place to blind the surgeon to any visibly apparent symptoms or to information that may be spontaneously reported by the caregiver or paediatrician. Ethical Approval Ethical approval for the study has been obtained (Ref. No: 2023-07493-01).

Background: Acute lung failure requiring respiratory treatment is the most common cause of intensive care in Sweden and the condition has a high mortality rate; approximately 40%. To a large extent, the high mortality rate is due to the patient's underlying disease, e.g. sepsis or trauma but the respiratory treatment itself can also cause mechanical damage to the lungs with the risk of secondary development of acute lung failure and failure in other organ systems such as the liver, kidneys, heart and brain. In order to reduce the risk and damage of ventilator treatment, it is necessary to improve monitoring of lung function and to develop and evaluate methods for more gentle respiratory treatment. The studies aim to map the elastic properties of the lungs (pulmonary elastance and transpulmonary drive pressure) in different patient groups, lung healthy and patients with acute lung failure, using the non-invasive PEEP step method. Since the method is non-invasive and is based only on a change in the end expiratory pressure in the ventilator, it can be easily applied during clinical conditions, thus allowing a significant improvement in monitoring and setting of ventilator therapy in both patients under general anesthesia in "major surgery" and patients with acute pulmonary failure in intensive care units. During general anesthesia, patients lung elasticity will be measured immediately after starting the anesthesia and during surgery and before emergence. In intensive care, the measurement procedure will be applied immediately after the patient has been placed on a ventilator and then during respiratory care when normal intensive care measures take place, such as changing the ventilator setting in terms of breath volume, respiratory rate, end expiratory pressure (PEEP) and similar measures, as well as respiratory suction and inhalations to identify elastic properties within the range normally present in intensive care patients. Aim: The aim of the studies is to be able to evaluate lung function during intensive care with new noninvasive measurement methods such as measuring transpulmonary pressure and calculating lung drive pressure, to evaluate lung function during intensive care in order to try to find optimal methods for gentle but effective ventilation of critically ill patients. Studies have previously shown that more gentle respiratory treatment can reduce mortality in respiratory-treated intensive care patients. The development and adaptation of new methods for respiratory treatment and monitoring, can offer better decision support when adjusting airway pressure and volumes, which may ultimately lead to improvements in the form of shorter respiratory time and reduced mortality in respiratory patients. An additional aim is to map normal values of the elastance of the lung ("stiffness") on a population of normal lungs in lung-healthy patients who are sedated for planned surgery. Main issues: 1. Is the measurement with the PEEP step up and down procedure sufficient to accurately present the lung pressure/volume curve and the transpulmonary drive pressure in respiratory-treated patient populations in surgery and ICU? 2. Is it possible to collect data on a normal population of lung-healthy patients who are sedated for operative surgery as well as in intensive care patients with different degrees of lung failure with the intention of mapping pulmonary elastance/transpulmonary drive pressure and changes in these parameters at initiation of and during respiratory treatment? Methods: The PEEP-step method for determining lung elastane: The elastic properties of the lung are measured by increasing PEEP from the clinical baseline level and then lowering the measurement procedure by setting the breath volume to correspond to the lung volume increase that occurs during the PEEP increase. PEEP and tidal volume changes are very common routine measures in both general anesthesia and intensive care. So far, all analysis has been done through manual calculations off-line, but now the measurement procedure and calculations must be automated as far as possible and the transpulmonal drive pressure is presented breath by breath in order to be used for the individualization of the ventilator treatment bedside. This automation is performed in the form of software development. This work is ongoing and expected to be completed in August 2020. Then the PEEP-step method can be implemented and tested in the clinic. During ten years, in two doctoral theses and four validation studies and additional lung model studies, the investigators have developed an alternative method for measuring the transpulmonary drive pressure, which does not require oesophageal pressure measurement, but only to make a change in the end expiratory pressure (PEEP) in the ventilator and determine the resulting lung volume increase (DEELV) using the ventilator's volume measurement. The elastic properties of the lung (lung elastane, EL) are calculated as DPEEP/DEELV and then the transpulmonary drive pressure is calculated as the volume of breath of the lung elastance, EL x VT. The above additional measurement methods have been evaluated during the last 15 years. Measurement methods collects data from standard monitoring equipment used in clinical anesthesiological practice since the 1980s. Protocol: The study is a longitudinal observational study. Measurements will be performed before, during and after respiratory treatment in patients in intensive care units and in surgical units. The measurements take place during the respiratory care period with focus on variations in lung mechanics before and after the procedures included in the clinical routine regarding respiratory settings and other care. Noninvasive measurement methods will be used (see above) of which no one has a negative impact on the patient. Physiological data will be collected from blood gas analyses and monitoring equipment. The monitoring equipment will be connected to a laptop with software that collects continuous clinical data for analysis. Informed consent: 1) Adult patients who are about to undergo surgery will be consulted at the preoperative assessment approximately 1-2 weeks before surgery about their participation. 2) In adult intensive care patients treated with respiratory therapy, surrogate consent will be prompted. Since it is not previously predicted which patients will be treated on a ventilator in the intensive care unit, the patient's relatives will be asked for informed consent. For key-references, se References

A three-arm randomized clinical study will be conducted: * Group 1 (study group): Ridge preservation with "Pontic-shield" technique. * Group 2 (positive control): Ridge preservation with deproteinized bovine bone and porcine collagen membrane after tooth extraction. * Group 3 (negative control): Tooth extraction only (fresh socket). A cone-beam computed tomography will be performed prior to tooth extraction and 4 months postoperative. Radiographic changes between before and after intervention will be evaluated to asses the effectiveness of "Pontic-shield" technique.

To understand the impact of thumb-tack needle therapy on postoperative sleep and recovery in patients who have undergone general anesthesia, and to explore the clinical significance of thumb-tack needle therapy in improving postoperative sleep quality, preventing postoperative sleep disorders, and promoting postoperative recovery

Multi-center, prospective, single-blind, randomized and parallel controlled trials are used to evaluate the role and impact of "digital chronic pain treatment system equipment" based on MR mixed reality technology in the clinical basic treatment of patients clinically diagnosed with chronic pain.

The aim of the study is to check whether vagus nerve stimulation (VNS) combined with manual therapy (TM), given its neuroanatomical relationship with the structures involved in pain in the TMJ, is more effective in reducing pain, increasing joint range and increasing the quality ofthe patient lives than TM alone. The research team is made up of three physiotherapists. It has been decided to distribute the tasks as follows: * Physiotherapist 1 will be in charge of the treatment of all patients. * Physiotherapist 2 will be responsible for screening the sample and evaluating the study. * Physiotherapist 3 will be in charge of analyzing the results and statistics. This component of the team, being blinded and not knowing the group of origin of the patient, will be able to interpret the results without any type of convenience bias, showing absolutely transparency in the elaboration of the conclusions. Once the screening will be completed, the patients will be divided into two groups: an experimental group (TM + ENV) and a control group (TM + ENV placebo).The randomization will be carried out through the statistical program Epidat 4,237 9 obtaining two homogeneous groups. Each patient will be assigned a code with the aim that the physiotherapist who is in charge of the statistical analysis is not able to establish links between the data and the subjects to which it refers.

Following the approval for the research by the Ethics Committee (Clinical Hospital Center, Zagreb, Croatia), a total of ninety (90) patients will be included in the research. Forty five (45) patients will be assigned to the study group (SG) and forty five (45) patients to the control group (CG). Research Goals: Primary goals 1. Observe and compare circulatory and respiratory stability in patients undergoing procedural sedation with either remimazolam besylate or propofol during colonoscopic polypectomies 2. Define and compare the incidence of hypotension between the study grou and the control group. 3. Define and compare the incidence of respiratory depression between the study group and the control group. Secondary goals 1. Define and compare the success of remimazolam besylate sedation compared with propofol. 2. Define and compare the time required to achieve adequate sedation between the two observed groups. 3. Define and compare the time to achieve full consciousness between the two observed groups. 4. Define and compare the time to complete recovery between the two groups. Patients from both groups, upon arrival to the gastroenterology ward will have a peripheral venous line installed by puncturing one of the veins on the dorsum of the hand or forearm. The veins of choice include the rete venosum dorsale manus, vena cephalica and vena basilica, and an 18 G or 20 G intravenous cannula will be placed. After confirming the functionality of the venous line, the intravenous administration of Fifty will follow. The infusion rate will depend on the patient's BMI and circulatory status. Study Group (SG): A total of 45 patients are included in this group. After non-invasive monitoring, positioning the patient in the left lateral position and placing a nasal catheter with a continuous oxygen flow of 3 l/min, the patient will receive the intravenous opioid analgesic Sufentanyl 0.2 mcg/kg over a period of 30 seconds. After 1 to 2 minutes the patient will receive remimazolam besylate intravenously in a dose of 5.0 mg over a period of 1 minute. After two minutes, a maintenance dose of 2.5 mg will be administered using the titration method over a period of 15 seconds until the desired sedation effect is achieved.The maximum intravenous dose of administered remimazolam besylate will be 33 mg.BIS monitoring and a modified MOAA/S (Modified Observers Assessment of Alertness and Sedation Scale) scale will be used to assess the depth of sedation. The first measurement of the depth of sedation will be initially following the complete administration of the sedative remimazolam besylate and will serve as the initial/starting point. Afterwards, a measurement of the MOAA/S scale will be performed every 30 seconds for a total of 3 minutes. The most desirable level of sedation for the planned procedure is defined as a MOAA/S measurement of \<3. Control group (CG) A total of 45 patients will be included in this group. Firstly, non-invasive monitoring will be applied to the patient, then they will be placed in the left lateral position and through a nasal catheter a continuous oxygen flow of 3l/min will be administered. The patient will be given intravenous opioid analgesia Sufentanyl 0.2 mg/kg. within 30 seconds. After approximately 1-2 minutes the patient will receive the titrated anesthetic propofol intravenously at a dose of 1.5 to 2.5 mg/kg, (20.0 to 30.0 mg propofol every 10 seconds). In elderly patients and patients with ASA grade III, the total dose of propofol will be at least 1 mg/kg with an administration rate of 10.0 to 20.0 mg every 10 seconds. Sedation will be maintained using propofol in a continuous intravenous infusion. The maintenance dose given will be 0.5 to 1.0 mg propofol/kg/hour. BIS monitoring and a modified MOAA/S (Modified Observers Assessment of Alertness and Sedation Scale) scale will be used to assess the depth of sedation. The first measurement of the MOAA/S score will be conducted after the total intravenous propofol dose was administered and this first measurement will be considered the starting/zero measurement. MOAA/S scale point will be measured every 30 seconds for a total of 3 minutes. A measurement of \<3 points will be considered the most desirable level of sedation for the planned procedure. In both study groups the following parameters will continuously be measured: 1. Pulse oxymetry (SpO2), respiratory rate (RR), EKG, heart rate (HR) and rhythm, systolic, diastolic and mean arterial pressure. 2. Circulatory parameters including systolic, diastolic and mean arterial pressure will be measured: Primary measurement: Upon patients' arrival to the pre-op room (first measurement) and 5 minutes before proceeding to the operating theater. During the procedure: Before administering the sedative remimazolam besylate or propofol and at 3, 5, 10, and 15 minutes. (every 5 minutes during the procedure) until the patient is consciousness, followed by the first of five sets of MOAAS/S measurements upon completion of the procedure or when the last dose of medication is given. Frequency of hypotension in both groups of patients and comparing the results between the SG and CG. Hypotension during the procedure using sedation or propofol is defined as: a decrease in systolic systemic pressure of 20% or more compared with the first measurement before the administration of remimazolam besylata or propofol. A mean arterial pressure of ≤60 mmHg during while the patient is under sedation. 4\. Sinus bradycardia is defined as a decreased cardiac rate. 5. The frequency of respiratory depression compared between the two groups, SG and CG. Respiratory depression during sedation is defined as: Respiratory rate of \<8 breaths per minute and/or a peripheral blood oxygen percentage of (SpO2) \<90. 6\. BIS monitoring. 7. The success of procedural sedation using remimazolam besylate and sedation using propofol: Will be shown as the percentage of successfully sedated patients defined as: The completion of endoscopic polypectomy, without the need for rapid/fast acting emergency sedation or a maximum number of 5 additional doses given withing 15 minutes of the first dose to maintain adequate sedation. 8\. The time to achieve adequate sedation is defined as the time from administering the first dose of medication until achieving \<3 points on the MOAA/S scale and/ora BIS. 9\. The time to achieve full consciousness is defined as the time since the administration of the last dose of medication until the patient is fully aware, or until the patients has 5 points on the MOAA/S scale. 10\. The time needed for the patient to fully recover after the procedure in both groups is defined by the criteria for patient dismissal using the - Modified Aldrete score scale. The total volume of the given crystalloid solution (Plasma-lyte) will be measured in both groups.

The clinical significance of retained needle fragments remains unknown. Needle retentions can be asymptomatic, cause local symptoms, and can sometimes even lead to dangerous complications such as needle emboli to the heart or lungs. The most common injection sites are likely the peripheral veins of the arms. However, continuous IVD use leads to vein sclerosis, and patients with long-term use may therefore also use peripheral veins of their lower limbs and even the central veins of the groin or neck. Subcutaneously retained needles can pose a risk of needlestick injury to medical staff during clinical examination and treatment procedures. Unrecognized retained needles can also cause hazards during magnetic resonance imaging. The study protocol received a positive review from the Tampere University Hospital Ethics Committee (study code: R22037). The researchers subsequently received the organizational permissions necessary to conduct the study. PWIDs will be asked to give written informed consent prior to any study procedures. Participants will be asked to fill in a questionnaire about their basic information, drug use history, previous injection sites, and whether they have had any local complications due to injecting drugs. After the completion of the questionnaire, participants will undergo targeted X-ray imaging of the injection sites. As metallic objects, needle fragments can be visualized with standard X-ray imaging. Female participants of childbearing potential (\< 50 years) will undergo urine sample pregnancy testing prior to X-ray imaging. A pilot study with 20 participants will be conducted first. Experiences from the pilot will be used to refine the study protocol if needed. If modifications are made, they will be subjected to ethics review and will be provided on ClinicalTrials.gov. After the pilot study, the researchers aim to recruit an additional 80 patients (totaling up to 100 participants). Our research questions are 1) What is the prevalence of radiologically confirmed needle retention among PWIDs\*? The secondary research questions are 1. Do patient-reported symptoms and the suspicion of a retained needle fragments correspond to radiologically confirmed needle retention? 2. What are the predisposing factors to needle fragmentation? 3. Have PWIDs sought medical attention prior to the study for possible symptoms in the injection sites? 4. How frequently are verified needle fragments surgically removed within five years after their detection, and are verified needle fragments a proxy or a risk factor for mortality? \*As only patients in outpatient care will be recruited, the sample is not entirely representative of all PWIDs in the study area (e.g., people who are hospitalized or imprisoned are not recruited).

The study will be divided into three parts: Part A: Single Ascending Dose - healthy participants cohorts with up to 5 dose levels. Part B: Multiple Ascending Doses - healthy participants cohorts with up to 3 dose levels. Part C: Surgical patients cohorts with up to 3 dose levels. The primary Objective is to investigate the safety and tolerability of TT5 in single and multiple ascending intravenous doses in healthy participants and in surgical patients. The Secondary Objectives are To investigate the pharmacokinetics (PK) of TT5 after single and multiple ascending intravenous doses in healthy participants and after intravenous doses in surgical patients. * To investigate the acute and chronic psychological subjective response of the healthy participants and surgical patients to TT5 * To assess the pharmacodynamics (PD) of TT5 after intravenous doses in surgical patients. Exploratory Objectives areto explore potential fluid biomarkers for TT5