Sepsis, October 14 edition

In this multicenter randomized trial of 584 adults with septic shock undergoing surgical source control, intraoperative dobutamine plus norepinephrine reduced new-onset or worsening acute kidney injury within 7 postoperative days from 34.7% to 22.8% compared with norepinephrine alone. Stage 2 and stage 3 acute kidney injury were also reduced, although tachycardia occurred more frequently with dobutamine.

Impact: This trial directly addresses a guideline-supported but weakly evidenced intervention in a high-risk septic shock population. The reduction in postoperative acute kidney injury provides clinically actionable evidence for perioperative hemodynamic management, while the multicenter randomized design strengthens causal interpretation.

Clinical Implications: For adults with septic shock undergoing surgical source control, intraoperative dobutamine added to norepinephrine may reduce postoperative acute kidney injury, particularly when persistent hypoperfusion or cardiac dysfunction is present. Clinicians should balance this potential renal benefit against the increased risk of tachycardia and await further studies addressing mortality and broader patient populations.

Future Directions: Future trials should evaluate whether the reduction in acute kidney injury translates into lower mortality, shorter hospitalization, or improved long-term kidney recovery. Studies should also identify the hemodynamic and echocardiographic phenotypes most likely to benefit and quantify the optimal dobutamine dose.

The VASSPR pragmatic cluster-crossover randomized trial included 3959 patients with septic shock across 13 hospitals and compared hospital strategies for initiating vasopressin at lower versus higher background vasopressor doses. Twenty-eight-day mortality was similar with lower-threshold and higher-threshold strategies, providing important negative evidence against routine early vasopressin initiation solely to improve survival.

Impact: This large pragmatic randomized trial addresses a common bedside decision for which practice variation is substantial. Its null mortality result is clinically valuable because it challenges assumptions that earlier addition of vasopressin necessarily improves outcomes and supports individualized rather than threshold-driven escalation.

Clinical Implications: Starting vasopressin at a lower norepinephrine-equivalent dose should not be expected to reduce 28-day mortality compared with later initiation. Vasopressin decisions should instead consider shock trajectory, vasopressor toxicity, cardiac function, regional perfusion, and treatment goals rather than a universal dose threshold.

Future Directions: Future research should identify patient subgroups that may benefit from vasopressin, including those with specific vasoplegic phenotypes or high catecholamine exposure. Comparative studies should also examine organ-specific outcomes, adverse events, cost, and long-term functional outcomes.

In a retrospective target-trial emulation of 5993 patients with sepsis and non-emergency ionized calcium levels of 0.90-1.10 mmol/L, calcium administration within 2 hours was associated with a higher standardized probability of being alive and vasopressor-free at 24 hours than deferral through 6 hours. The estimated risk difference was 8.69 percentage points, but early calcium increased hypercalcemia and did not establish benefit for mortality or severe arrhythmia.

Impact: This study applies modern causal-inference methods to a common but unresolved sepsis practice and explicitly emulates alternative treatment strategies rather than merely comparing treated and untreated patients. The findings generate a clinically testable hypothesis while appropriately emphasizing uncertainty and potential harm.

Clinical Implications: Early calcium administration may improve short-term hemodynamic recovery in vasopressor-treated patients with sepsis and mild ionized hypocalcemia, particularly at higher vasopressor doses, but it should not become routine solely on the basis of this observational analysis. Clinicians should monitor for hypercalcemia and await randomized confirmation before changing practice.

Future Directions: A multicenter randomized trial should test early calcium in predefined subgroups, particularly patients receiving substantial vasopressor support. Such trials should include mortality, organ failure, arrhythmia, renal outcomes, hypercalcemia, and patient-centered recovery as outcomes, with ionized calcium and calcium dose prespecified for effect-modification analyses.