Development and validation of a nomogram to predict diabetes ketoacidosis resolution time in a tertiary care hospital in the United Arab Emirates.

AIM: This study aimed to develop and validate a nomogram to predict prolonged diabetes ketoacidosis (DKA) resolution time (DRT). METHODS: We retrospectively extracted sociodemographic, clinical, and laboratory data from the electronic medical records of 394 adult patients with DKA admitted to Tawam Hospital between January 2017 and October 2022. Logistic regression stepwise model was developed to predict DRT ≥ 24 h. Model discrimination was evaluated using C-index and calibration was determined using calibration plot and Brier score. RESULTS: The patients' average age was 34 years; 54 % were female. Using the stepwise model, the final variables including sex, diabetes mellitus type, loss of consciousness at presentation, presence of infection at presentation, body mass index, heart rate, and venous blood gas pH at presentation were used to generate a nomogram to predict DRT ≥ 24 h. The C-index was 0.76 in the stepwise model, indicating good discrimination. Despite the calibration curve of the stepwise model showing a slight overestimation of risk at higher predicted risk levels, the Brier score for the model was 0.17, indicating both good calibration and predictive accuracy. CONCLUSION: An effective nomogram was established for estimating the likelihood of DRT ≥ 24 h, facilitating better resource allocation and personalized treatment strategy.

Association between blood urea nitrogen to serum albumin ratio and in-hospital mortality in critical patients with diabetic ketoacidosis: a retrospective analysis of the eICU database.

Background: This study aimed to investigate the association between blood urea nitrogen to serum albumin ratio (BAR) and the risk of in-hospital mortality in patients with diabetic ketoacidosis. Methods: A total of 3,962 diabetic ketoacidosis patients from the eICU Collaborative Research Database were included in this analysis. The primary outcome was in-hospital death. Results: Over a median length of hospital stay of 3.1 days, 86 in-hospital deaths were identified. One unit increase in LnBAR was positively associated with the risk of in-hospital death (hazard ratio [HR], 1.82 [95% CI, 1.42-2.34]). Furthermore, a nonlinear, consistently increasing correlation between elevated BAR and in-hospital mortality was observed (P for trend =0.005 after multiple-adjusted). When BAR was categorized into quartiles, the higher risk of in-hospital death (multiple-adjusted HR, 1.99 [95% CI, (1.1-3.6)]) was found in participants in quartiles 3 to 4 (BAR≥6.28) compared with those in quartiles 1 to 2 (BAR<6.28). In the subgroup analysis, the LnBAR-hospital death association was significantly stronger in participants without kidney insufficiency (yes versus no, P-interaction=0.023). Conclusion: There was a significant and positive association between BAR and the risk of in-hospital death in patients with diabetic ketoacidosis. Notably, the strength of this association was intensified among those without kidney insufficiency.

Comparison of clinical characteristics and treatment outcomes between initially diagnosed type 1 and type 2 diabetes mellitus patients presenting with diabetic ketoacidosis.

OBJECTIVE: Patients with type 1 diabetes (T1DM) and type 2 diabetes (T2DM) can present with diabetic ketoacidosis (DKA) as the first manifestation. Differentiating types of newly diagnosed diabetes could provide appropriate long-term management. Therefore, we conducted this study to compare clinical characteristics and outcomes between initially diagnosed type 1 and type 2 diabetes mellitus patients presenting with DKA. MATERIALS AND METHODS: A retrospective study was conducted on adult patients who presented with DKA as the first diagnosis of diabetes in our tertiary hospital between January 2005 and December 2019. Demographic data, precipitating causes, laboratory investigations, treatment, and outcomes were obtained by chart review. The primary outcome was to compare the clinical characteristics of initially diagnosed patients with T1DM and T2DM who presented with DKA. RESULTS: A total of 100 initially diagnosed diabetic patients who presented with DKA were analyzed (85 T2DM patients and 15 T1DM patients). Patients with T1DM were younger than patients with T2DM (mean age 33 ± 16.2 vs. 51 ± 14.5 years, p value < 0.001). Patients with T2DM had a higher body mass index, family history of diabetes, precipitating factors, plasma glucose, and lower renal function than those with T1DM. There was no difference in resolution time or DKA management between T1DM and T2DM patients. The overall mortality rate of DKA was 4%. CONCLUSION: In this population, most adult patients who presented with DKA had T2DM. Older age, obesity, a family history of diabetes, and the presence of precipitating factors were strong predictors of T2DM. We can implement the same clinical management for DKA in both T1DM and T2DM patients. However, T2DM patients had longer hospitalization than T1DM patients. After DKA resolution for 12 months, more than half of patients with T2DM could discontinue insulin. Therefore, the accurate classification of the type of diabetes leads to appropriate treatment.

[Personalized glycemic management for patients with diabetic ketoacidosis based on machine learning].

OBJECTIVE: To explore the optimal blood glucose-lowering strategies for patients with diabetic ketoacidosis (DKA) to enhance personalized treatment effects using machine learning techniques based on the United States Critical Care Medical Information Mart for Intensive Care- IV (MIMIC- IV). METHODS: Utilizing the MIMIC- IV database, the case data of 2 096 patients with DKA admitted to the intensive care unit (ICU) at Beth Israel Deaconess Medical Center from 2008 to 2019 were analyzed. Machine learning models were developed, and receiver operator characteristic curve (ROC curve) and precision-recall curve (PR curve) were plotted to evaluate the model's effectiveness in predicting four common adverse outcomes: hypoglycemia, hypokalemia, reductions in Glasgow coma scale (GCS), and extended hospital stays. The risk of adverse outcomes was analyzed in relation to the rate of blood glucose decrease. Univariate and multivariate Logistic regression analyses were conducted to examine the relationship between relevant factors and the risk of hypokalemia. Personalized risk interpretation methods and predictive technologies were applied to individualize the analysis of optimal glucose control ranges for patients. RESULTS: The machine learning models demonstrated excellent performance in predicting adverse outcomes in patients with DKA, with areas under the ROC curve (AUROC) and 95% confidence interval (95%CI) for predicting hypoglycemia, hypokalemia, GCS score reduction, and extended hospital stays being 0.826 (0.803-0.849), 0.850 (0.828-0.870), 0.925 (0.903-0.946), and 0.901 (0.883-0.920), respectively. Analysis of the relationship between the rate of blood glucose reduction and the risk of four adverse outcomes showed that a maximum glucose reduction rate > 6.26 mmol×L-1×h-1 significantly increased the risk of hypoglycemia (P < 0.001); a rate > 2.72 mmol×L-1×h-1 significantly elevated the risk of hypokalemia (P < 0.001); a rate > 5.53 mmol×L-1×h-1 significantly reduced the risk of GCS score reduction (P < 0.001); and a rate > 8.03 mmol×L-1×h-1 significantly shortened the length of hospital stay (P < 0.001). Multivariate Logistic regression analysis indicated significant correlations between maximum bicarbonate levels, blood urea nitrogen levels, and total insulin doses with the risk of hypokalemia (all P < 0.01). In terms of establishing personalized optimal treatment thresholds, assuming optimal glucose reduction thresholds for hypoglycemia, hypokalemia, GCS score reduction, and extended hospital stay were x1, x2, x3, x4, respectively, the recommended glucose reduction rates to minimize the risks of hypokalemia and hypoglycemia should be ≤min{x1, x2}, while those to reduce GCS score decline and extended hospital stay should be ≥ max{x3, x4}. When these ranges overlap, i.e., max{x3, x4} ≤ min{x1, x2}, this interval was the recommended optimal glucose reduction range. If there was no overlap between these ranges, i.e., max{x3, x4} > min{x1, x2}, the treatment strategy should be dynamically adjusted considering individual differences in the risk of various adverse outcomes. CONCLUSIONS: The machine learning models shows good performance in predicting adverse outcomes in patients with DKA, assisting in personalized blood glucose management and holding important clinical application prospects.

Euglycemic Ketoacidosis in a Patient without Diabetes Taking Sodium-Glucose Cotransporter 2 Inhibitors for Heart Failure.

BACKGROUND Sodium-glucose cotransporter 2 (SGLT2) inhibitors are used to improve the prognosis of patients with diabetes, heart failure, or chronic kidney disease. The use of SGLT2 inhibitors in patients without diabetes is expected to increase. Diabetic ketoacidosis is a severe complication of SGLT2 inhibitors in patients with diabetes. People without diabetes are thought to be less likely to develop ketoacidosis, and reports of SGLT2 inhibitor-induced ketoacidosis are uncommon in people without diabetes. CASE REPORT Herein, we describe a case of ketoacidosis in an 83-year-old Japanese woman without diabetes who was administered SGLT2 inhibitors for heart failure (ejection fraction: approximately 30%). Two weeks prior to admission, she had suffered a vertebral fracture and rib fracture due to a fall, which was followed by anorexia, but she continued to take SGLT2 inhibitors. On admission, blood test results revealed a blood glucose level of 124 mg/dL, hemoglobin A1C level of 5.9%, pH of 7.329, HCO3⁻ concentration of 14.3 mmol/L, and a ß-hydroxybutyrate concentration of 5150 µmol/L, leading to a diagnosis of euglycemic ketoacidosis. The patient's C-peptide level was consistent with the blood glucose levels on admission, indicating that she had adequate insulin secretion. The patient was treated only with glucose administration without insulin and was discharged after discontinuation of the SGLT2 inhibitor. CONCLUSIONS This case illustrates that patients with or without diabetes may develop SGLT2 inhibitor-related ketoacidosis after several days of inadequate food intake; therefore, patients should be informed of this risk.

Risk of chronic kidney disease in patients with a hyperglycemic crisis as the initial presentation of type 2 diabetes.

Limited data exist on long-term renal outcomes in patients with hyperglycemic crisis (HC) as initial type 2 diabetes presentation. We evaluated the risk of chronic kidney disease (CKD) development in those with concurrent HC at diagnosis. Utilizing Taiwan's insurance claims from adults newly diagnosed with type 2 diabetes during 2006-2015, we created HC and matched non-HC cohorts. We assessed incident CKD/diabetic kidney disease (DKD) by 2018's end, calculating the hazard ratio (HR) with the Cox model. Each cohort comprised 13,242 patients. The combined CKD and DKD incidence was two-fold higher in the HC cohort than in the non-HC cohort (56.47 versus 28.49 per 1000 person-years) with an adjusted HR (aHR) of 2.00 (95% confidence interval [CI] 1.91-2.10]). Risk increased from diabetic ketoacidosis (DKA) (aHR:1.69 [95% CI 1.59-1.79]) to hyperglycemic hyperosmolar state (HHS) (aHR:2.47 [95% CI 2.33-2.63]) and further to combined DKA-HHS (aHR:2.60 [95% CI 2.29-2.95]). Subgroup analysis in individuals aged ≥ 40 years revealed a similar trend with slightly reduced incidences and HRs. Patients with HC as their initial type 2 diabetes presentation face a higher CKD risk than do those without HC. Enhanced medical attention and customized interventions are crucial to reduce this risk.

Case report: management of a young male patient with diabetic ketoacidosis and thyroid storm.

This report describes a case of concomitant diabetic ketoacidosis (DKA) and thyroid storm (TS) in a 20-year-old male patient that presented both diagnostic and management challenges owing to their intricate interrelationship in endocrine-metabolic disorders. The patient, previously diagnosed with type 1 diabetes mellitus (T1DM) and hyperthyroidism, was admitted to the emergency department with symptoms of DKA and progressive exacerbation of TS. Initial treatment focused on correcting DKA; as the disease progressed to TS, it was promptly recognized and treated. This case emphasizes the rarity of simultaneous occurrence of DKA and TS, as well as the challenges in clinical diagnosis posed by the interacting pathophysiological processes and overlapping clinical manifestations of DKA and TS. The patient's treatment process involved multiple disciplines, and after treatment, the patient's critical condition of both endocrine metabolic diseases was alleviated, after which he recovered and was eventually discharged from the hospital. This case report aims to emphasize the need for heightened awareness in patients with complex clinical presentations, stress the possibility of concurrent complications, and underscore the importance of prompt and collaborative treatment strategies.

Fluid resuscitation with balanced electrolyte solutions results in faster resolution of diabetic ketoacidosis than with 0.9% saline in adults - A systematic review and meta-analysis.

Fluid resuscitation during diabetic ketoacidosis (DKA) is most frequently performed with 0.9% saline despite its high chloride and sodium concentration. Balanced Electrolyte Solutions (BES) may prove a more physiological alternative, but convincing evidence is missing. We aimed to compare the efficacy of 0.9% saline to BES in DKA management. MEDLINE, Cochrane Library, and Embase databases were searched for relevant studies using predefined keywords (from inception to 27 November 2021). Relevant studies were those in which 0.9% saline (Saline-group) was compared to BES (BES-group) in adults admitted with DKA. Two reviewers independently extracted data and assessed the risk of bias. The primary outcome was time to DKA resolution (defined by each study individually), while the main secondary outcomes were changes in laboratory values, duration of insulin infusion, and mortality. We included seven randomized controlled trials and three observational studies with 1006 participants. The primary outcome was reported for 316 patients, and we found that BES resolves DKA faster than 0.9% saline with a mean difference (MD) of -5.36 [95% CI: -10.46, -0.26] hours. Post-resuscitation chloride (MD: -4.26 [-6.97, -1.54] mmoL/L) and sodium (MD: -1.38 [-2.14, -0.62] mmoL/L) levels were significantly lower. In contrast, levels of post-resuscitation bicarbonate (MD: 1.82 [0.75, 2.89] mmoL/L) were significantly elevated in the BES-group compared to the Saline-group. There was no statistically significant difference between the groups regarding the duration of parenteral insulin administration (MD: 0.16 [-3.03, 3.35] hours) or mortality (OR: -0.67 [0.12, 3.68]). Studies showed some concern or a high risk of bias, and the level of evidence for most outcomes was low. This meta-analysis indicates that the use of BES resolves DKA faster than 0.9% saline. Therefore, DKA guidelines should consider BES instead of 0.9% saline as the first choice during fluid resuscitation.

Factors influencing mortality in COVID-19-associated mucormycosis: The international ID-IRI study.

The emergence of COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), triggered a global pandemic. Concurrently, reports of mucormycosis cases surged, particularly during the second wave in India. This study aims to investigate mortality factors in COVID-19-associated mucormycosis (CAM) cases, exploring clinical, demographic, and therapeutic variables across mostly Asian and partly African countries. A retrospective, cross-sectional analysis of CAM patients from 22 medical centers across eight countries was conducted, focusing on the first 3 months post-COVID-19 diagnosis. Data collected through the ID-IRI included demographics, comorbidities, treatments, and outcomes. A total of 162 CAM patients were included. The mean age was 54.29 ± 13.04 years, with 54% male. Diabetes mellitus (85%) was prevalent, and 91% had rhino-orbital-cerebral mucormycosis. Surgical debridement was performed in 84% of the cases. Mortality was 39%, with advanced age (hazard ratio [HR] = 1.06, [P < .001]), rituximab use (HR = 21.2, P = .05), and diabetic ketoacidosis (HR = 3.58, P = .009) identified as risk factors. The mortality risk increases by approximately 5.6% for each additional year of age. Surgical debridement based on organ involvement correlated with higher survival (HR = 8.81, P < .001). The utilization of rituximab and diabetic ketoacidosis, along with advancing age, has been associated with an increased risk of mortality in CAM patients. A combination of antifungal treatment and surgical intervention has demonstrated a substantial improvement in survival outcomes.

Over a third of patients who developed mucormycosis after COVID-19 died. Older people, those on specific immunosuppressive treatments, and those with diabetic ketoacidosis had a higher risk of death. However, undergoing surgery as part of treatment significantly improved survival.

Risk of perioperative discontinuation of SGLT2 inhibitors.

When sodium-glucose cotransporter-2 (SGLT2) inhibitors were primarily prescribed for treatment of diabetes mellitus, guidelines recommended withholding SGLT2 inhibitors before surgery to mitigate the associated risk of ketoacidosis. However, currently, SGLT2 inhibitors are an established therapy for patients with heart failure, and there is evidence that withholding SGLT2 inhibitors can worsen these patients' cardiovascular risk profile. We present an updated risk-benefit analysis of withholding SGLT2 inhibitors before surgery, focusing on patients with heart failure and addressing the risk of ketoacidosis and its treatment in these patients. Clinicians should consider perioperative continuation of SGLT2 inhibitors when prescribed for treatment of heart failure.

Clinical and Prognostic Features of Diabetic Ketoacidosis According to the Trigger of the Syndrome.

BACKGROUND: Diabetic ketoacidosis (DKA) is an acute metabolic, life-threatening complication of diabetes mellitus with a mortality rate that now stand at less than 1%. Although mortality is coupled with the etiology of DKA, literature on the influence of DKA etiology on patient outcome is scarce. OBJECTIVES: To study different triggers for DKA and their effect on outcomes. METHODS: We conducted a retrospective study that include 385 DKA patients from 2004 to 2017. The study compared demographics, clinical presentation, and mortality rates by different precipitating factors. RESULTS: Patients with DKA due to infections had a higher risk to develop in-hospital mortality after controlling for age and sex (odds ratio 4.40, 95% confidence interval 1.35-14.30), had a higher Charlson Comorbidity Index score, a higher risk of being mechanical ventilated (14% vs. 3%, P < 0.01), and a longer duration of hospitalization (5 days vs. 3 days, P < 0.001). CONCLUSIONS: It is crucial to find the triggers that precipitate DKA and start the treatment as early as possible in addition to the metabolic aspect of the treatment especially when the trigger is an infectious disease.

A Rare Case of Hyperglycemia, Ketoacidosis, and Central Facial Paralysis in a Newly-Diagnosed Diabetic Woman.

BACKGROUND Diabetes mellitus is a chronic disease that occurs when the pancreas does not produce enough insulin or when the body is unable to effectively use the insulin it produces. Uncontrolled diabetes mellitus is usually associated with neurological manifestations, such as hemichorea, focal epileptic seizures, peripheral neuropathy, and peripheral facial paralysis. This report describes a 59-year-old woman presenting with hyperglycemia and ketoacidosis due to newly diagnosed diabetes mellitus, as well as a temporary episode of central facial paralysis, which regressed within a few days after medical treatment and metabolic correction. CASE REPORT A 59-year-old patient with hypertension and a family history of diabetes mellitus presented with polyuro-polydipsic syndrome and signs of metabolic ketoacidosis, with an elevated anion gap, compatible with newly discovered type 1 diabetes mellitus. Six hours after admission, we noted the abrupt onset of left central facial paralysis, with no brain damage shown on magnetic resonance imaging. Initially, the diagnosis was transient ischemic attack. After a second, normal cerebral magnetic resonance image on the fourth day, and clinical improvement on the fifth day after metabolic correction by insulin therapy and rehydration, the diagnosis of a regressive central facial paralysis was retained. CONCLUSIONS Central facial paralysis in diabetic ketoacidosis is a rare neuroendocrine entity. The pathophysiological mechanisms that can explain the occurrence of central facial paralysis are not yet described and require further investigation. This report highlights the importance of diagnosis, early management of hyperglycemia and diabetic ketoacidosis, and reversibility of central facial paralysis after treatment.

Multicentre, retrospective cohort study protocol to identify racial and ethnic differences in acute kidney injuries in children and adolescents with diabetic ketoacidosis.

INTRODUCTION: Approximately 40% of children with diabetic ketoacidosis (DKA) develop acute kidney injury (AKI), which increases the risk of chronic kidney damage. At present, there is limited knowledge of racial or ethnic differences in diabetes-related kidney injury in children with diabetes. Understanding whether such differences exist will provide a foundation for addressing disparities in diabetes care that may continue into adulthood. Further, it is currently unclear which children are at risk to develop worsening or sustained DKA-related AKI. The primary aim is to determine whether race and ethnicity are associated with DKA-related AKI. The secondary aim is to determine factors associated with sustained AKI in children with DKA. METHODS AND ANALYSIS: This retrospective, multicentre, cross-sectional study of children with type 1 or type 2 diabetes with DKA will be conducted through the Paediatric Emergency Medicine Collaborative Research Committee. Children aged 2-18 years who were treated in a participating emergency department between 1 January 2020 and 31 December 2023 will be included. Children with non-ketotic hyperglycaemic-hyperosmolar state or who were transferred from an outside facility will be excluded. The relevant predictor is race and ethnicity. The primary outcome is the presence of AKI, defined by Kidney Disease: Improving Global Outcomes criteria. The secondary outcome is 'sustained' AKI, defined as having AKI ≥48 hours, unresolved AKI at last creatinine measurement or need for renal replacement therapy. Statistical inference of the associations between predictors (ie, race and ethnicity) and outcomes (ie, AKI and sustained AKI) will use random effects regression models, accounting for hospital variation and clustering. ETHICS AND DISSEMINATION: The Institutional Review Board of Children's Minnesota approved this study. 12 additional sites have obtained institutional review board approval, and all sites will obtain local approval prior to participation. Results will be presented at local or national conferences and for publication in peer-reviewed journals.

Superior ophthalmic vein thrombosis in unique double origin: a case report.

Superior ophthalmic vein thrombosis (SOVT) is a rare orbital pathology. It can cause serious complications if it isn´t diagnosed appropriately. It can be secondary to many etiologies, septic or aseptic ones. Diabetic ketoacidosis (DKA) may disturb the vascular endothelium and promote a prothrombotic state. The presence of which is related to a significantly increased risk of morbidity and mortality. We report the case of a 45-year-old woman who presented a SOVT revealing DKA. Orbit magnetic resonance imaging (MRI) showed thrombosis of the right superior ophthalmic vein. A treatment based on thrombolytic treatment, associated with antibiotic coverage and a glycemic balance was initiated. This case highlights the importance of considering both infection and diabetes as an important part of the diagnosis and management of SOVT.

Comparison of balanced crystalloids versus normal saline in patients with diabetic ketoacidosis: a meta-analysis of randomized controlled trials.

Purpose: The optimal resuscitative fluid for patients with diabetic ketoacidosis (DKA) remains controversial. Therefore, our objective was to assess the effect of balanced crystalloids in contrast to normal saline on clinical outcomes among patients with DKA. Methods: We searched electronic databases for randomized controlled trials comparing balanced crystalloids versus normal saline in patients with DKA, the search period was from inception through October 20th, 2023. The outcomes were the time to resolution of DKA, major adverse kidney events, post-resuscitation chloride, and incidence of hypokalemia. Results: Our meta-analysis encompassed 11 trials, incorporating a total of 753 patients with DKA. There was no significant difference between balanced crystalloids and normal saline group for the time to resolution of DKA (MD -1.49, 95%CI -4.29 to 1.31, P=0.30, I2 = 65%), major adverse kidney events (RR 0.88, 95%CI 0.58 to 1.34, P=0.56, I2 = 0%), and incidence of hypokalemia (RR 0.80, 95%CI 0.43 to 1.46, P=0.46, I2 = 56%). However, there was a significant reduction in the post-resuscitation chloride (MD -3.16, 95%CI -5.82 to -0.49, P=0.02, I2 = 73%) among patients received balanced crystalloids. Conclusion: Among patients with DKA, the use of balanced crystalloids as compared to normal saline has no effect on the time to resolution of DKA, major adverse kidney events, and incidence of hypokalemia. However, the use of balanced crystalloids could reduce the post-resuscitation chloride. Systematic review registration: https://osf.io, identifier c8f3d.

Prolonged Diabetic Ketoacidosis Associated With Sodium-Glucose Cotransporter-2 Inhibitors: A Review of Postmarketing Cases.

OBJECTIVE: To describe reported cases of prolonged or relapsed ketoacidosis (KA) in adults with type 2 diabetes receiving treatment with sodium-glucose cotransporter-2 (SGLT2) inhibitors. METHODS: We performed a search of the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System and medical literature, to identify our case series and to characterize cases of prolonged KA, relapsed KA, or persistent ketonemia, persistent ketonuria and/or persistent glucosuria in adults receiving SGLT2 inhibitors. RESULTS: The FDA identified 29 unique cases of prolonged or relapsed KA, as well as related terms persistent ketonemia, persistent ketonuria, and persistent glucosuria, in patients receiving SGLT2 inhibitors through July 26, 2022. The patients ranged in age from 26 to 85 years. Treatment duration of KA ranged from 3 to 20 days. There were 7 cases of relapsed KA when insulin was reduced or transitioned to subcutaneous route. Arterial pH value was 7.0 or below in 4 patients, and the median pH was 7.1. Associated factors for prolonged or relapsed KA included surgery, decreased caloric intake, and ketogenic/carbohydrate restricted diet. A total of 62% of the patients were taking 3 or more glycemic control medications including the SGLT2 inhibitor. All patients with sufficient follow-up information recovered. CONCLUSION: Although KA is a well-known risk associated with SGLT2 inhibitors, this case series demonstrated the potential for prolonged or recurrent KA events with serious outcomes. These cases informed updates to FDA's prescribing information to inform prescribers of this risk.