The Latest in Critical Care, 7/10/23 (Issue #8)
Continuous meropenem infusion for critically ill patients with sepsis
Antibiotics have a time-dependent effect on bacteria; maintaining bacteriocidal concentrations of antibiotics should help subdue infections better than intermittent dosing. A 2018 meta-analysis reviewed here suggested that prolonged infusion of antipseudomonal beta-lactams reduced mortality by 30% compared with shorter infusions, and more observational data has accumulated since that time.
Many institutions have created protocols for extended infusions of beta lactam antibiotics, available online. However, the practice has not been supported by randomized trials.
In the MERCY trial, 607 critically ill patients with sepsis (most with septic shock) at 26 hospitals in Croatia, Italy, Kazakhstan, and Russia were randomized to receive meropenem by either continuous (3 g / 24 hours) or intermittent administration (1 g every 8 hours).
At 28 days, there were no observed differences in the primary outcome (an odd composite of mortality and emergence of antibiotic resistance), and no difference in survival at 90 days.
Mortality was about 30% in each group, and most patients had hospital-acquired sepsis.
The largest previous randomized trial, BLING II (n=432), likewise did not show any improvement in survival at 28 or 90 days, or any other outcome, with extended beta lactam infusions. A sequel to that trial, BLING III, is underway.
Continuous infusions impose some logistical barriers—restricting the patient’s free movement, requiring compatibility with other infusions or additional I.V. access, etc., detailed here.
Editorialists argued that “guidelines and clinical practice may continue to favor prolonged dosing of β-lactam antibiotics when circumstances allow given the ongoing possibility of benefit and absence of harm." Intermittent dosing remains just as appropriate, given the negative findings of two randomized trials and a third in process. Read in JAMA
When to start anticoagulation after ischemic stroke from atrial fibrillation
It’s been unclear when to start anticoagulation after an ischemic stroke presumed due to thromboembolism from atrial fibrillation. There’s a period of time after ischemic stroke when damaged cerebral blood vessels are susceptible to bleeding. Anticoagulation during this vulnerable period could result in so-called hemorrhagic transformation, worsening brain injury and complicating care.
Usually neurologists make the call on the timing of anticoagulation after ischemic stroke, but sometimes it’s a cardiologist. Delays before starting anticoagulation could vary from as little as 48 hours after small strokes, to two weeks for large ischemic strokes or in patients with severe hypertension or other risk factors. Aspirin is sometimes given during the waiting period. Heparin infusions are usually avoided.
In the ELAN trial, 2013 patients were randomized to undergo either “later” anticoagulation with a direct oral anticoagulant (DOAC)—generally following the above parameters, or “early” (day 6 or 7 after a large stroke, day 3 or 4 for moderate strokes).
Patients with petechial hemorrhage could be enrolled, but not those with “confluent parenchymal hematoma within infarcted brain tissue or intracranial hemorrhage remote from infarcted tissues.”
Significantly fewer patients receiving “early” DOACs had recurrent ischemic strokes at 30 and 90 days (or the primary composite outcome which also included major bleeding and death).
Almost a quarter of patients had large ischemic strokes, and the risk of hemorrhagic transformation did not appear higher in this subset. There were two intracranial hemorrhages in each group.
Based on this trial I would start a DOAC “early” rather than “late” in eligible patients, or collegially nudge the neurologist or cardiologist to do so. Read in NEJM
Should platelets be transfused in thrombocytopenic patients before central line placement?
Central venous catheterization (CVC or central lines), when placed with ultrasound guidance, have a low rate of severe bleeding complications, even in patients with significant thrombocytopenia. Nevertheless, platelets are frequently transfused prior to CVC placement in patients with platelet counts 20,000-50,000/mcL. Is this justified?
The PACER trial randomized 358 patients with platelet counts 10,000-50,000/mcL undergoing central line placement to receive one unit of platelet concentrate or not. They were not transfused to any specific target, but half the patients who were transfused reached platelets >54,000/mcL, and those who were not had a median 26,000/mcL.
There was significantly more severe bleeding in those not transfused platelets (5% vs. 2%), defined as requiring red cell transfusions or surgical interventions, sometimes with hemodynamic instability.
They incidentally reported there were higher up-front costs in the transfusion group, but higher overall costs in the not-transfused group, owing to later platelet transfusions and surgical interventions to stop bleeding.
The patient mix mattered greatly: most severe bleeding was in hematology patients, while ICU patients had significantly less, overall. According to the authors:
For patients in the ICU with lower platelet counts, we would consider a no-transfusion strategy with intensive monitoring and a low threshold for the therapeutic use of blood products. The patients in the ICU had a lower bleeding risk than those on the hematology ward, and the ICU setting allows for more intensive monitoring.
This paper modified my practice. I plan to follow the suggestions of the authors by
transfusing platelets on a case by case in the ICU in severely thrombocytopenic patients undergoing central venous catheter placement,
with frequent site exams for the next 24-48 hours,
where prophylactic transfusion is deferred, transfusing platelets at the first sign of any significant bleeding.
In The News
FDA approved the new intravenous antibiotic sulbactam-durlobactam (Xacduro) for healthcare-associated pneumonia caused by Acinetobacter baumannii-calcoaceticus complex (A. baumannii). Sulbactam is a beta-lactam and durlobactam a beta-lactamase inhibitor. Carbapenem-resistant Acinetobacter infections increased by almost 80% between 2019 and 2020, and Xacduro showed nominal superiority over colistin in subsets of randomized trials. Read at FDA
Paxlovid appears to improve outcomes from Covid-19 infection in younger patients with significant comorbidities, but not in healthy young adults. The drug was approved in older adults, but its use expanded off label to younger patients, most of whom will likely not benefit. Read in Read in Clinical Infectious Diseases