Acute Cyanide Toxicity and Emergency Management in a Goldsmith: A Case Report.

Acute cyanide toxicity is very rare but it is almost always associated with fatal outcomes. Here we describe the case of a 43-year-old healthy male who worked in a jewelry factory and presented with acute cyanide toxicity. He was successfully managed with all the supportive measures and an appropriate antidote kit containing amyl nitrite, sodium nitrite, and sodium thiosulfate. We also describe the relevant importance of knowing the history of easy access to cyanide as a part of the patient's profession, the critical nature of the patient at presentation, as well as the efforts needed to procure the antidote.

Infantile Hypertrophic Pyloric Stenosis Without Metabolic Alkalosis: A Report of Two Cases.

Infantile hypertrophic pyloric stenosis (IHPS) is a condition typically characterized by hypertrophy of the pylorus, leading to gastric outlet obstruction and forceful, nonbilious vomiting in young infants. This case series reports two infants with IHPS who exhibited metabolic acidosis, deviating from the classical biochemical presentation of hypochloremic, hypokalemic metabolic alkalosis. The unusual occurrence of metabolic acidosis in these cases suggests the possibility of alternative or additional pathophysiological mechanisms at play. Such deviations from the expected biochemical profile highlight the complexity of IHPS and the need for a broader diagnostic perspective.

Successfully managed alcoholic ketoacidosis with sepsis leading to multiple organ dysfunction syndrome: a case report.

We present the case of a 28-year-old male with a history of alcohol dependency and smoking, who presented with chest pain, shortness of breath, and altered sensorium. He exhibited severe metabolic acidosis, hypoglycemia, low platelet count, and acute kidney injury. Alcoholic ketoacidosis was suspected due to ketonuria, metabolic acidosis, and ketonemia, compounded by electrolyte abnormalities and radiographic findings of pneumonia.

An integrated multi-omics approach allowed ultra-rapid diagnosis of a deep intronic pathogenic variant in PDHX and precision treatment in a neonate critically ill with lactic acidosis.

The diagnosis of mitochondrial disorders is complex. Rapid whole genome sequencing is a first line test for critically ill neonates and infants allowing rapid diagnosis and treatment. Standard genomic technology and bioinformatic pipelines still have an incomplete diagnostic yield requiring complementary approaches. There are currently limited options for rapid additional tests to continue a diagnostic work-up after a negative rapid whole-genome sequencing result, reflecting a gap in clinical practice. Multi-modal integrative diagnostic approaches derived from systems biology including proteomics and transcriptomics show promise in suspected mitochondrial disorders. In this article, we report the case of a neonate who presented with severe lactic acidosis on the second day of life, for whom an initial report of ultra-rapid genome sequencing was negative. The patient was started on dichloroacetate as an emergency investigational new drug (eIND), with a sharp decline in lactic acid levels and clinical stabilization. A proteomics-based approach identified a complete absence of PDHX protein, leading to a re-review of the genome data for the PDHX gene in which a homozygous deep intronic pathogenic variant was identified. Subsequent testing in the following months confirmed the diagnosis with deficient pyruvate dehydrogenase enzyme activity, reduced protein levels of E3-binding protein, and confirmed by mRNA sequencing to lead to the inclusion of a cryptic exon and a premature stop codon. This case highlights the power of rapid proteomics in guiding genomic analysis. It also shows a promising role for dichloroacetate treatment in controlling lactic acidosis related to PDHX-related pyruvate dehydrogenase complex deficiency.

Family Occurrence of an m.3303C>T Point Mutation in the MT-TL1 Gene, Which Induces Cardiomyopathy Syndrome with/without Skeletal Muscle Myopathy.

This paper discusses the cases of siblings that were born healthy, then diagnosed in their neonatal periods with cardiomyopathy and/or severe metabolic acidosis, which ran progressive courses and contributed to death in infancy. Molecular testing of the children confirmed the presence of an m.3303C>T point mutation in the mitochondrial DNA in the MT-TL1 gene, which was also present in their oligosymptomatic mother and their mother's sister, an asymptomatic carrier.

Deferasirox-induced hyperammonemia and Fanconi syndrome: a case report.

Background: The exact mechanism of hyperammonemia is thought to be multifactorial, but is not yet fully understood. No studies have yet reported hyperammonemia combined with Fanconi syndrome caused by deferasirox. Case presentation: A 10-year-old girl was admitted for vomiting and altered consciousness. Blood testing revealed hyperammonemia and normal liver and coagulation functions. During hospitalization, the patient also exhibited hyperchloremic metabolic acidosis, hypokalemia, hyponatremia, and hypophosphatemia. Additionally, urinalysis revealed glucose and protein levels clinically consistent with Fanconi syndrome. The patient had a history of severe beta-thalassemia and had received intermittent blood transfusions for approximately ten years. The patient had been administered oral deferasirox at a 400 mg/day dose at the age of four, which had been gradually increased to the current 750 mg/day dosage. Upon admission, deferasirox was discontinued and treatment including mechanical ventilation, continuous blood purification therapy for ammonia reduction and acidosis, and electrolyte imbalance corrections was administered. Subsequently, serological markers returned to normal, urine test findings improved. To the best of our knowledge, this is the first report of a case of hyperammonemia with Fanconi syndrome owing to deferasirox. Conclusions: For effective management and long-term follow-up of chronic diseases in children, pediatricians must master standardized treatments and the adverse reactions of various drugs. When symptoms are difficult to explain clinically, we must trace the source and adjust the treatment plan to maximize improving the patient's prognosis.

Trends in Antidiabetic Drug Use and Safety of Metformin in Diabetic Patients with Varying Degrees of Chronic Kidney Disease from 2010 to 2021 in Korea: Retrospective Cohort Study Using the Common Data Model.

BACKGROUND/OBJECTIVES: This study aimed to investigate trends in antidiabetic drug use and assess the risk of metformin-associated lactic acidosis (MALA) in patients with chronic kidney disease (CKD). METHODS: A retrospective observational analysis based on the common data model was conducted using electronic medical records from 2010 to 2021. The patients included were aged ≥18, diagnosed with CKD and type 2 diabetes, and had received antidiabetic medications for ≥30 days. MALA was defined as pH ≤ 7.35 and arterial lactate ≥4 mmol/L. RESULTS: A total of 8318 patients were included, with 6185 in CKD stages 1-2 and 2133 in stages 3a-5. Metformin monotherapy was the most prescribed regimen, except in stage 5 CKD. As CKD progressed, metformin use significantly declined; insulin and meglitinides were most frequently prescribed in end-stage renal disease. Over the study period, the use of SGLT2 inhibitors (13.3%) and DPP-4 inhibitors (24.5%) increased significantly, while sulfonylurea use decreased (p < 0.05). Metformin use remained stable in earlier CKD stages but significantly decreased in stage 3b or worse. The incidence rate (IR) of MALA was 1.22 per 1000 patient-years, with a significantly increased IR in stage 4 or worse CKD (p < 0.001). CONCLUSIONS: Metformin was the most prescribed antidiabetic drug in CKD patients in Korea with a low risk of MALA. Antidiabetic drug use patterns varied across CKD stages, with a notable decline in metformin use in advanced CKD and a rise in SGLT2 inhibitor prescriptions, underscoring the need for further optimized therapy.

Acute Renal Failure Secondary to Vibrio cholera Gastroenteritis in a United States Citizen, Corrected With Renal Replacement Therapy.

Cholera is an acute gastroenteritis that can lead to fatal dehydration and metabolic derangements. Cases of cholera in the United States are typically associated with international travel. Patients who are persistently dehydrated despite aggressive rehydration and antibiotic therapy may require hemodialysis until symptom resolution and stabilization of renal function. We present a case of a 47-year-old male who recently returned from a trip to Haiti and presented with intractable abdominal pain, nausea, vomiting, and watery diarrhea. He was found to be in acute renal failure with a high anion gap metabolic acidosis of an unclear etiology. Abdominal imaging was consistent with enterocolitis, and his stool culture grew Vibrio cholerae. In addition to aggressive fluid resuscitation, he underwent two intermittent hemodialysis sessions and received sodium bicarbonate and antibiotic therapy. Renal function normalized by hospital day 6. This is a novel case of severe renal failure and high anion gap metabolic acidosis in a US patient with cholera; our review of the literature did not find any case reports regarding cholera in the past decade involving a US citizen.

Health disparities in the risk of severe acidosis: real-world evidence from the All of Us cohort.

OBJECTIVE: To assess the health disparities across social determinants of health (SDoH) domains for the risk of severe acidosis independent of demographical and clinical factors. MATERIALS AND METHODS: A retrospective case-control study (n = 13 310, 1:4 matching) is performed using electronic health records (EHRs), SDoH surveys, and genomics data from the All of Us participants. The propensity score matching controls confounding effects due to EHR data availability. Conditional logistic regressions are used to estimate odds ratios describing associations between SDoHs and the risk of acidosis events, adjusted for demographic features, and clinical conditions. RESULTS: Those with employer-provided insurance and those with Medicaid plans show dramatically different risks [adjusted odds ratio (AOR): 0.761 vs 1.41]. Low-income groups demonstrate higher risk (household income less than $25k, AOR: 1.3-1.57) than high-income groups ($100-$200k, AOR: 0.597-0.867). Other high-risk factors include impaired mobility (AOR: 1.32), unemployment (AOR: 1.32), renters (AOR: 1.41), other non-house-owners (AOR: 1.7), and house instability (AOR: 1.25). Education was negatively associated with acidosis risk. DISCUSSION: Our work provides real-world evidence of the comprehensive health disparities due to socioeconomic and behavioral contributors in a cohort enriched in minority groups or underrepresented populations. CONCLUSIONS: SDoHs are strongly associated with systematic health disparities in the risk of severe metabolic acidosis. Types of health insurance, household income levels, housing status and stability, employment status, educational level, and mobility disability play significant roles after being adjusted for demographic features and clinical conditions. Comprehensive solutions are needed to improve equity in healthcare and reduce the risk of severe acidosis.

Diffuse Large B-cell Lymphoma with Severe Lactic Acidosis and Liver Failure: A Case Report and Literature Review.

Among causes of liver failure, liver failure due to lymphocytic infiltration is rare. Unlike typical liver failure, some cases present with severe lactic acidosis and a poor prognosis. We herein report a case of diffuse large B-cell lymphoma with severe lactic acidosis and liver failure. We further discuss the characteristics of similar cases in the literature, suggesting that intrahepatic infiltration by hematological malignant cells should be considered as a differential diagnosis in the presence of severe lactic acidosis and liver failure. This study underscores the importance of early recognition and serves as a reference for future cases.

Neonatal Cardiac and Respiratory Arrest During Linezolid Therapy: A Case Report.

Lactic acidosis is one of the severe adverse reactions of linezolid. Its clinical manifestations are non-specific, primarily including abdominal discomfort, nausea, vomiting, diarrhea, weakness, lethargy, rapid breathing, and tachycardia, with no reports of cardiac and respiratory arrest. In this case report, we present a 13-day-old male infant with omphalitis caused by methicillin-resistant Staphylococcus aureus (MRSA) infection, who was treated with linezolid. He had lactic acidosis before treatment, which was not severe and was likely related to the infection. After linezolid therapy, he experienced cardiac and respiratory arrest, and re-measurement showed an increase in lactate levels. After resuscitation, linezolid withdrawal, and symptomatic treatment, lactate levels decreased. However, due to hypoxic-ischemic encephalopathy and uncorrectable ventricular arrhythmia caused by post-cardiopulmonary resuscitation myocardial damage, the infant died. A comprehensive autopsy and genetic testing were performed after death, and no congenital diseases or inherited metabolic diseases were found. Given that this case was a sudden infant death without typical symptoms of lactic acidosis and linezolid is often mistakenly considered safer than vancomycin in the treatment of special populations, this paper analyzes and discusses this to draw attention to clinical treatment. More research is needed in the future to fully demonstrate its causal relationship and mechanism of action.

Euglycemic Ketoacidosis Associated with SGLT-2 Inhibitors in Non-diabetic Patients-A Narrative Review.

Euglycemic ketoacidosis is an acute, life-threatening emergency that is characterized by euglycemia, metabolic acidosis, and ketonemia. It is a well-recognized adverse event in diabetic patients taking sodium-glucose cotransporter-2 inhibitor (SGLT-2 inhibitor). However, there is limited data on SGLT-2 inhibitor-related euglycemic ketoacidosis in non-diabetic patients. The mechanism behind SGLT-2 inhibitor-associated euglycemic ketoacidosis involves a general state of starvation or relative insulin deficiency, which exacerbates the mild baseline ketonemia caused by this class of medications while normoglycemia is maintained. The incidence of euglycemic ketoacidosis will likely increase with the increasing use of SGLT-2 inhibitors for various indications in addition to diabetes mellitus type 2, predominantly for congestive heart failure (CHF). Recognizing the signs and symptoms of this life-threatening condition is essential to treat it effectively. Our objective is to comprehensively revisit the pathophysiology of euglycemic ketoacidosis associated with SGLT-2 inhibitors and the risk factors for the condition, review the available data, and summarize the reported cases of euglycemic ketoacidosis in non-diabetic patients on SGLT-2 inhibitors. Our literature search identified five articles with six cases of euglycemic ketoacidosis in non-diabetic patients who were on SGLT-2 inhibitors for heart failure with reduced ejection fraction. The common risk factor in five out of the six cases was decreased oral intake due to acute illness, fasting, or a perioperative state.

Clinical significance of acidic extracellular microenvironment modulated genes.

Background: The extracellular pH (pH e ) is known to be acidic. We investigated the effect of mild (pH e 6.8) and severe (pH e 5.9) acidosis on gene expression in mouse B16-BL6 melanoma cells using cDNA microarray analysis and compared them with the acidic pH e dependence of human tumors. Methods: B16-BL6 cells were treated with pH e 7.4 (control), pH e 6.8, and pH e 5.9. The mRNA expression was analyzed by using the cDNA microarray. Heat map, volcano plot, and gene ontology enrichment analysis were performed. The data were compared with the gene signatures of published data GSE52031 and GSE8401 and compared with the pathological staging by GEPIA2, and the prognostic signature of proteins was searched by the Human Protein Atlas database. If the acidic pH e -induced and -reduced genes were correlated with shortened and prolonged survival times, respectively, and also correlated with pathological staging, we defined it as "hit" and counted the sum of hit points of eight types of tumors such as breast, colorectal, prostate, gastric, liver, prostate, lung, and head and neck and melanoma. Results: Gene expression was differentially and commonly regulated by both pH e s. The number of genes upregulated fourfold or more at pH e 6.8 and 5.9 only for 25 and 131 genes, respectively, and 85 genes were common. The number of genes downregulated fourfold or less at pH e 6.8 and 5.9 only for 63 and 82 genes, respectively, and 118 genes were common. Compared with human mRNA expression data (GSE8401), there is no correlation with the overall pattern of the signature. In seven types of cancer (breast, colorectal, gastric, liver, prostate, lung, and head and neck) and melanoma, the relationship between acidic pH e -modulated gene expression and overall survival was evaluated. As a result, acidic pH e dependency contributing to prognosis was higher in colorectal, lung, and head and neck cancers and lower in prostate cancer. Conclusion: Tumor classification based on response to extracellular acidic pH e will provide new insights into chemotherapy strategy for patients with tumors.

Engineering of Kidney-Targeting Fluorophores with Tunable Emission from NIR-I to NIR-II for Early Diagnosis of Kidney Disease.

The development of rapidly distributed and retained probes within the kidneys is important for accurately diagnosing kidney diseases. Although molecular imaging shows the potential for non-intrusively interrogating kidney disease-related biomarkers, the limited kidney contrast of many fluorophores, owing to their relatively low distribution in the kidney, hinders their effectiveness for kidney disease detection. Herein, for the first time, an amino-functionalization strategy is proposed to construct a library of kidney-targeting fluorophores NHcy with tunable emissions from NIR-I to NIR-II. Among these, NHcy-8 is the first small-molecule NIR-II dye without a renal clearance moiety, designed specifically for kidney-targeting imaging. Building on this class of NIR-II fluorophore, the first NIR-II small-molecule kidney-targeting pH probe NIR-II-pH is developed, which exhibits a desirable kidney distribution after intravenous injection and is fluorescent only after activation by acidosis. NIR-II in vivo fluorescence/photoacoustic imaging of kidney disease models induced by cisplatin and renal I/R injury using NIR-II-pH reveals increasingly severe metabolic acidosis as the disease progressed, enabling sensitive detection of the onset of acidosis 36 h (cisplatin group) earlier than clinical methods. Thus, this study introduces a practical NIR-II kidney-targeting probe and provides a useful molecular blueprint for guiding kidney-targeting NIR-II fluorophores as diagnostic aids for kidney diseases.

Association between delta anion gap/delta bicarbonate and outcome of surgical patients admitted to intensive care unit.

BACKGROUND: Patients undergoing high-risk surgeries with acid-based disorders are associated with poor outcomes. The screening of mixed acid-based metabolic disorders by calculating delta anion gap (AG)/delta bicarbonate (Bic) has a clinically relevant role in patients with high AG metabolic acidosis (MA), however its utility in individuals facing high-risk surgical procedures remains unclear. OBJECTIVE: Characterize metabolic acidosis using delta-AG/delta-Bic and its associations in patients undergoing high-risk surgeries with possible outcome-related complications. DESIGN: Prospective observational multicentric study. SETTING: Three tertiary hospitals in Brazil. PATIENTS: Patients undergoing high-risk surgeries, aged 18 years or older, requiring postoperative critical care. MAIN OUTCOME MEASURES: Patients undergoing high-risk surgeries monitored during the postoperative phase across three distinct intensive care units (ICUs), with assessment encompassing laboratory analyses upon admission and 24 h thereafter. Patients with MA and with elevated AG within 24 h were separated into 3 subgroups: [G1 - delta-AG/delta-Bic < 1.0] MA associated with hyperchloremia; [G2 - delta-AG/delta-Bic between 1.0 and 1.6] MA and no mixed disorders; and [G3 - delta-AG/delta-Bic > 1.6] MA associated with alkalosis. Primary endpoint was 30-day mortality. The secondary endpoints were cardiovascular, respiratory, renal, neurological, coagulation and infective complications. RESULTS: From the 621 surgical patients admitted to ICU, 421 (51.7%) had any type of acidosis. After 24 h, 140 patients remained with MA with elevated AG (G1: 101, G2: 18, and G3: 21). When compared to patients from subgroups 1 and 3, the subgroup with no mixed disorders 2 showed higher 30-day mortality (adjusted HR = 3.72; 95% CI 1.11-12.89, p = 0.001), cardiovascular complications (p = 0.001), ICU mortality (p = 0.03) and sum of all complications during the ICU period (p = 0.021). CONCLUSION: In the postoperative time, patients with metabolic acidosis and no mixed disorders present higher ICU-Mortality and higher cardiovascular postoperative complications when compared with patients with combined hyperchloremia or alkalosis. Delta-AG/delta-Bic can be a useful tool to evaluate major clinical outcomes in this population.

Hyperchloremic metabolic acidosis potentially benefiting sodium bicarbonate therapy: A multi-center cohort study.

BACKGROUND: The use of sodium bicarbonate for metabolic acidosis has been a topic of debate, primarily due to the lack of clinical efficacy evidence. This study aims to identify which types of patients with various acid-base balance parameters can benefit from sodium bicarbonate therapy. METHODS: Patients diagnosed with metabolic acidosis were screened from a large multi-center critical care database to form a retrospective cohort. Mortality curves, logistic regression analysis, simulation methods, and propensity scores were used to compare data between sodium bicarbonate (SOB group) and non-treated (Non-SOB group) patients. RESULTS: There was an interaction between baseline chloride, anion gap levels and sodium bicarbonate therapy on patients' in-hospital death. As chloride levels increased, the in-hospital mortality curves of the SOB group and Non-SOB group gradually converged, with the difference narrowing from approximately 20 % to 10 %, and then gradually widened with the increase of the anion gap. Furthermore, when patients had high chloride levels (≥112 mmol/L), those in the SOB group exhibited a higher incidence of hypernatremia, hypokalemia, and hypocalcemia at 24 h, and a lower incidence of hyperchloremia. Patients in SOB group also had a lower simulated mortality. Among patients treated with sodium bicarbonate, those with low chloride had more difficulty in normalizing pH compared to those with high chloride. CONCLUSIONS: This study identified an interaction between baseline chloride and sodium bicarbonate therapy on patient survival. Hyperchloremic metabolic acidosis may potentially benefit from sodium bicarbonate therapy. Further prospective randomized controlled studies are warranted.

Effects of single-dose ruminal infusions of high or low short-chain fatty acid concentrations and high or low pH on apparent total tract digestibility and hindgut fermentation of pre-weaned dairy calves.

While the importance of pH and short-chain fatty acids (SCFA) on rumen development are well-known, their impact on the small and large intestine are unclear. This study investigated how single-dose ruminal infusions with high or low short-chain fatty acid concentrations and high or low pH affect calves' productivity as well as physiological parameters associated with hindgut acidosis at 3-time points in 49 d. Holstein bull calves (n = 32) were individually housed and fed milk replacer (900 g/d) twice daily and calf starter and water ad libitum. At d 10 ± 3 of life, the rumens were fistulated and cannulated. At d 14 of life, calves were grouped by body weight and assigned in a 2 × 2 factorial arrangement of treatments: high or low SCFA concentration (285 vs. 10 mM) and high or low pH (6.2 vs. 5.2), creating 4 treatment groups: high SCFA concentration, high pH (HS-HP); high SCFA concentration, low pH (HS-LP); low SCFA concentration, high pH (LS-HP); and low SCFA concentration, low pH (LS-LP). On d 21, 35, 49, feces were sampled to calculate apparent total-tract digestibility, determinate organic acid concentrations (i.e., SCFA, BCFA and lactic acid), and pH. Afterward, the rumen was evacuated and underwent a single-dose infusion for 4 h with one of 4 treatment buffers. After completion of rumen infusion on d 49, calves were harvested, and the tissue weight and length, and digesta pH of the rumen, cecum, colon, and rectum were recorded along with the digesta pH of duodenum, jejunum, and ileum only at d 49 after dissection. Data were analyzed with main factors as fixed effects and repeated measures for weekly measurements. Treatments did not affect performance parameters such as feed intake, ADG, apparent total-tract digestibility and gut measurements. In the duodenum, jejunum, and ileum, HS-HP had a greater digesta pH than LS-HP, while the hindgut digesta pH was only affected by the SCFA concentration. High SCFA concentration increased the concentration of colonic isovaleric acid and fecal BCFA, while only colonic acetic acid and fecal lactic acid concentrations were affected by treatment. Fecal SCFA and BCFA concentrations increased mainly on d 35. In summary, 4 h of physiological buffer infusion in the rumen does not change apparent total-tract digestibility and gut measurements but does affect hindgut fermentation parameters (i.e., organic acid concentrations and digesta pH). In addition, calves can experience increased risks of hindgut acidosis around 35 d of life.

High altitude impact on serum bicarbonate in healthy Mexican children: concerning the overdiagnosis of renal tubular acidosis.

BACKGROUND: Altitude influences bicarbonate levels, it is a variable that is hardly considered in diagnosing Renal Tubular Acidosis (RTA), so it should be a factor to consider when diagnosing this pathology, especially at 2250 mts over the sea level as it is the case of Mexico City. RTA is most often misdiagnosed. Regarding of this, the present study established reference limits for bicarbonate levels in healthy children without pathologies associated with alterations in the acid-base balance in Mexico City and it´s metropolitan area. METHODS: A total of 267 healthy pediatric patients were included, within normal estimated glomerular filtration rate (eGFR), and without any associated pathology of any alteration in the acid-base balance. RESULTS: Compared to older children, children younger than two years of age showed statistically higher levels of calcemia and cystatin C. On the other hand, this same group showed lower values of creatininemia, pCO2, and HCO3-. Percentile 50 of bicarbonate in children under two years of age were 19.9 mEq/L and 21.9 mEq/L in those over that age. A correlation was identified between HCO3- levels and pCO2 (r = 0.68; p < 0.001). CONCLUSIONS: In the study population, an effect of altitude on blood levels of pCO2 and HCO3- was observed.

Synergistic effects of rivaroxaban and hypothermia or acidosis on coagulation initiation measured with ROTEM®: a prospective observational study.

BACKGROUND: Hypothermia and acidosis individually inhibit haemostasis. We designed this study with the aim to investigate whether rivaroxaban combined with hypothermia or acidosis exhibit synergistic inhibitory effects on haemostasis using ROTEM®. METHODS: Patients with a clinical indication to start rivaroxaban treatment were prospectively included. Blood samples were collected before initiation of treatment and the day after. All blood samples were in vitro modified with respect to temperature (incubated and analysed at 28, 33, 37 and 40 degrees Celsius (°C)) and pH (6.8, 7.0, 7.2 and 7.4). The temperature and acidosis effects on the ROTEM EXTEM variables clotting time (CT), clot formation time (CFT) and alpha-angle (AA) were measured along with the individual effect of rivaroxaban on the same variables. The additive effect was calculated. The observed (potential synergistic) effects for the temperature and pH modified rivaroxaban samples on the same ROTEM variables, were registered. Differences between the additive and observed (potential synergistic) effects were analysed using matched non-parametric hypothesis testing. RESULTS: In total, 13 patients were included. Hypothermia and rivaroxaban exhibited a synergistic effect on CT at 28 °C (p = 0.0002) and at 33 °C (p = 0.0007). The same applied for acidosis at pH 6.8 (p = 0.003) and pH 7.0 (p = 0.003). There were no signs of synergistic effects of rivaroxaban and temperature or acidosis on CFT. In AA there were signs of synergism at 28 °C (p = 0,001), but not at other tested temperatures or pH levels. CONCLUSIONS: The combination rivaroxaban together with hypothermia or acidosis demonstrated inhibitory synergistic effects on haemostasis. TRIAL REGISTRATION: The study was retrospectively registered 2023-03-01 at ClinTrials.gov with NCT05669313.