Sebastiaan Paul Blank

Implements Sequential Doubly Robust (SDR) and infinite-dimensional Targeted Maximum Likelihood (iTMLE) estimators for longitudinal modified treatment policies in settings with transitioning states, such as ICU, ward, or emergency department care episodes. Treatment is permitted in active states and becomes structurally inapplicable after a state transition (e.g. discharge or death). Supports asymmetric g- and Q-model regularisation, k-fold cross-fitting, and pluggable SuperLearner ensembles. Includes specialised SuperLearner wrappers (SL.tgt.* and SL.tmle_* families) for the iTMLE targeting step, which pass the logit offset as a covariate column to preserve correct subsetting during SuperLearner cross-validation. Methods based on Diaz et al. (2021) and Luedtke et al. (2017) .

Introduction: Diabetic ketoacidosis (DKA) is a common complication of diabetes mellitus characterized by metabolic acidosis, ketogenesis, hypovolemia, hyperglycemia, and electrolyte depletion. During treatment of DKA with intravenous fluids and insulin, some electrolyte disturbances can worsen. Hypophosphatemia is one such electrolyte disturbance that has not been well characterized in patients with severe DKA requiring Intensive Care Unit (ICU) admissions. This study sought to evaluate the incidence, severity, associations, and outcomes of hypophosphatemia in DKA. Methods: This retrospective multicenter study was conducted across DKA admissions to Queensland ICUs from 2016 to 2021. Adult patients (>18 years) requiring ICU admission for management of DKA were included in this study. Patients with DKA were stratified by lowest recorded phosphate level as: normal ≥ 0.80 mmol/L, mild 0.50–0.79 mmol/L, moderate 0.30–0.49 mmol/L and severe < 0.3 mmol/L. Patient demographics, comorbidities, ICU-related supports, and medications (including fluid, insulin administration, phosphate, and other electrolyte replacement) were collected. Univariate analysis was performed between hypophosphatemia severity and normophosphatemia subgroups to determine risk factors, outcomes, replacement, and progression of hypophosphatemia in the ICU. Phosphate replacement and administered insulin was compared to nadir serum phosphate level. Multivariate analysis and linear regression were performed to identify risk factors for the development of hypophosphatemia. Results: A total of 842 admissions of 669 unique patients due to DKA were included; 436 of 842 (51.8%) admissions maintained normophosphatemia in the ICU, while 220 (26.1%, n = 220/842) had mild hypophosphatemia, 124 (14.7%, n = 124/842) had moderate hypophosphatemia and 62 (7.4%, n = 62/842) had severe hypophosphatemia. Patients with higher BMI, higher APACHE II/III score, cerebrovascular disease and all blood gas parameters (excluding PaO₂) were found to have more severe hypophosphatemia. Lower serum phosphate was associated with greater replacement and greater insulin administration per kilogram body weight. ICU length of stay, hospital length of stay and mortality were not affected by degree of hypophosphatemia (p > 0.05). Linear regression revealed that standard base excess was strongly associated with the development of hypophosphatemia (β = 0.02, 95% CI 0.01–0.02, p < 0.001). Conclusions: Increasing severity of hypophosphatemia was associated with increasing severity of DKA. Increased ICU length of stay was related to increased severity of hypophosphatemia.

Background: Pulmonary embolism may cause hemodynamic instability requiring vasoactive support, but evidence on guiding agent selection is very limited. Methods: A retrospective cohort study of adult admissions to 12 Intensive Care Units in Queensland, Australia between 2015–2021. Clinical and outcome data was obtained through statewide hospital databases. Results: Of 89,123 admissions, 460 (0.6%) patients had a primary diagnosis of pulmonary embolism. Vasoactive infusions were administered within the first 24 h of ICU admission to 182/460 patients (39.6%) and 209/460 (45.4%) patients at any time during ICU admission. Norepinephrine was the most common (175/209; 83.7%), followed by epinephrine (37/209; 17.7%). The cohort had a median ICU length of stay of 3 days (IQR; 2-5), and a 30-day mortality rate of 11.3% (52/460). Higher vasoactive requirement on day-1 was associated with significantly higher 30-day mortality (odds ratio per 1-unit increase in vasoactive-inotrope score of 3.72, 95% confidence interval 1.80-8.75, P < .001). Conclusion: Primary diagnosis of PE is uncommon among ICU presentations but 45% of patients require vasoactive support. Norepinephrine was the most used vasoactive agent. Higher vasoactive requirements reflected greater illness severity and were associated with higher 30-day mortality.

Accurate assessment of severity in diabetic ketoacidosis (DKA) can optimise early management and facilitate prioritisation for high acuity care. The primary aim was to evaluate the relationship between severity of acidosis (considering pH, bicarbonate, and anion gap) and hyperosmolarity with hospital mortality. Secondary outcomes included intensive care mortality, mechanical ventilation, vasopressor/inotrope use, and dialysis. A retrospective cohort study was conducted of adults (≥ 16 yr) with DKA admitted to US intensive care units. Data were extracted from the Medical Information Mart for Intensive Care (MIMIC)-IV dataset and eICU Collaborative Research Database. Univariable and multivariable logistic regression analyses were used to evaluate biochemistry obtained within 4 h of admission and the primary and secondary outcomes. We identified 4071 eligible admissions. There was no clear relationship between serum bicarbonate or anion gap and any outcome. Almost half the population did not have blood gas analysis within 4 h of admission; for 2292 patients with blood gases available, pH < 7 and inappropriately high PCO₂ were associated with significant increases in mortality and all secondary outcomes. Osmolarity ≥ 320mosm/L was associated with fourfold increased mortality and higher rates of mechanical ventilation, use of vasopressors/inotropes, and dialysis. Failure of adaptive mechanisms (thirst and hyperventilation) indicating physiological decompensation may be more important for risk stratification in DKA than the degree of acidosis, which was only associated with outcome when severely abnormal. Blood gas analysis is essential to adequately assess disease severity as bicarbonate and anion gap were not predictive of outcome.

OBJECTIVES: Echocardiography is commonly used for hemodynamic assessment in sepsis, but data regarding its association with outcome are conflicting. The aim of this study was to evaluate the association between echocardiography and outcomes in patients with septic shock using the Medical Information Mart for Intensive Care IV database. DESIGN: Retrospective cohort study comparing patients who did or did not undergo transthoracic echocardiography within the first 5 days of admission for the primary outcome of 28-day mortality. SETTING: Admissions to the Beth Israel Deaconess Medical Center intensive care from 2008 to 2019. PATIENTS: Adults 16 years old or older with septic shock requiring vasopressor support within 48 hours of admission. Readmissions and patients admitted to the coronary care unit or cardiovascular intensive care were excluded, as well as patients with ST-elevation myocardial infarction or cardiac arrest. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Echocardiography was performed in 1,515 (27%) of 5,697 eligible admissions. The primary outcome was analyzed using a marginal structural model and rolling entry matching to adjust for baseline and time-varying confounders. Patients who underwent echocardiography showed no significant difference in 28-day mortality (adjusted hazard ratio 1.09; 95% CI, 0.95–1.25; p = 0.24). This was consistent across multiple sensitivity analyses. Secondary outcomes were changes in management instituted within 4 hours of imaging. Treatment changes occurred in 493 patients (33%) compared with 431 matched controls (29%), with the most common intervention being the administration of a fluid bolus. CONCLUSIONS: Echocardiography in sepsis was not associated with a reduction in 28-day mortality based on observational data. These findings do not negate the utility of echo in cases of diagnostic uncertainty or inadequate response to initial treatment.

Introduction Small case series have reported that diabetic ketoacidosis is associated with an elevated osmolar gap, while no previous studies have assessed the accuracy of calculated osmolarity in the hyperosmolar hyperglycemic state. The aim of this study was to characterize the magnitude of the osmolar gap in these conditions and assess whether this changes over time. Methods In this retrospective cohort study, two publicly available intensive care datasets were used: Medical Information Mart of Intensive Care IV and the eICU Collaborative Research Database. We identified adult admissions with diabetic ketoacidosis and the hyperosmolar hyperglycemic state who had measured osmolality results available contemporaneously with sodium, urea and glucose values. Calculated osmolarity was derived using the formula 2Na + glucose + urea (all values in mmol/L). Results We identified 995 paired values for measured and calculated osmolarity from 547 admissions (321 diabetic ketoacidosis, 103 hyperosmolar hyperglycemic states and 123 mixed presentations). A wide variation in the osmolar gap was seen, including substantial elevations and low and negative values. There was a greater frequency of raised osmolar gaps at the start of the admission, which tends to normalize by around 12–24 h. Similar results were seen regardless of the admission diagnosis. Conclusions The osmolar gap varies widely in diabetic ketoacidosis and the hyperosmolar hyperglycemic state and may be highly elevated, especially at admission. Clinicians should be aware that measured and calculated osmolarity values are not interchangeable in this population. These findings should be confirmed in a prospective study.

Aim: Diabetic ketoacidosis is a hyperglycaemic emergency that is often treated in intensive care units (ICUs) despite having a low mortality and good prognosis. Current risk stratification is based primarily on acidosis, but it has been suggested that hyperosmolarity may also be an important marker of increased severity. Our aim was to evaluate the relationship between raised serum osmolarity and adverse clinical outcomes in ICU admissions for ketoacidosis.Methods: Retrospective review of prospectively collected data for adult admissions with ketoacidosis in the Australian and New Zealand Intensive Care Society Adult Patient Database over a 15‐year period (2004–2018). Exclusions were readmissions and records with critical missing data. Serum hyperosmolarity was defined as > 320 mosm/l. The primary outcome was hospital mortality; secondary outcomes were ICU mortality and other adverse clinical events.Results: Some 17 379 admissions were included in the study population. People with hyperosmolarity had fourfold increased mortality, a higher incidence of renal failure and need for mechanical ventilation, and prolonged ICU and hospital length of stay. The relationship with mortality remained highly significant even after adjusting for severity of acidosis, hospital type, year of admission, time to ICU, and a modified Australia and New Zealand Risk of Death propensity score.Conclusions: Although adults with ketoacidosis have a good prognosis overall, hyperosmolarity was independently associated with a significantly higher incidence of multiple adverse outcomes including mortality. Whether or not this is directly causal, it may have practical applications to improve risk stratification and identify individuals at risk of adverse outcomes.