Article 1
Angiotensin II for the treatment of refractory shock: a matched analysis. Smith LM, Mentz GB, Engoren MC. Critical Care Med. 2023 Dec 1;51(12):1674-1684.
Distributive shock, characterized by leaky capillaries, vasodilation, and inadequate tissue perfusion, is a common etiology of shock in the intensive care unit. Systemic vasodilation leads to decreased blood flow to the body’s vital organs. In this setting, Angiotensin II (AT2), has recently been used to increase blood pressure through direct renal vasoconstriction, and the promotion of fluid retention.
The study by Smith et al sought to determine if ATII is associated with improved clinical outcomes. The primary objective was to determine if the use of ATII was associated with a 30 and/or 90-day mortality benefit. Secondary outcomes included organ dysfunction like new onset renal replacement therapy and/or mechanical ventilation as well as any other adverse events. To accomplish this, the authors used University of Michigan’s DataDirect database for data extraction. Included in the study were adult patients who had received an IV infusion of norepinephrine, phenylephrine, vasopressin, dopamine or ATII. Both historical and ongoing cohorts were used as control arms. Various markers of clinical outcomes and organ dysfunction were abstract.
Over the study period, 271 qualified patients received ATII, while 542 patients were analyzed in the control arms. Patients receiving ATII were more likely to be diagnosed with septic shock had lower mean arterial pressure (MAP), higher SOFA scores, higher rates of chronic illness, higher lactic acid levels and were more likely to be mechanically ventilated and initiated on renal replacement therapy at enrollment. In matched cohorts, and adjustment for differences in baseline characteristics, mortality at 30 days (60% vs 56% p= 0.292) and 90 days (65% vs 63% p= 0.440) were similar in both groups. In patients with septic shock, ATII was not associated with any differences in mortality, renal replacement, or mechanical ventilation. Outcomes were more associated with pre-enrollment organ dysfunction.
These findings are similar to those from the ATHOS-3 trial in that the use of ATII was not found to have a mortality benefit in shock patients. Although, subgroup analyses in the ATHOS-3 did show improved mortality for patients receiving ATII if they received renal replacement therapy. As a caveat, the differences in study design, wherein ATII dosing was maintained while other pressors were weaned in ATHOS-3 compared to its use as salvage therapy in this study, may contribute to those outcomes. The limitations of this study include its retrospective, single institution design which limits its generalizability to other systems. Also, ATII was used as a salvage therapy, in refractory hypotension. This strategy of administration may limit its effects in providing any clinical benefits. As this paper states, future studies using ATII as first or second line therapy are needed.
Article 2
Sigh Ventilation in Patients With Trauma: The SiVent Randomized Clinical Trial. Albert RK, Jurkovich GJ, Connett J, et al. JAMA. 2023 Nov 28;330(20):1982-1990.
Mechanically ventilated patients in the intensive care unit on a volume or pressure-controlled mode typically receive a constant tidal volume with each delivered breath. Sigh breaths are theorized to have multiple functions including stimulating surfactant secretion and maintaining a healthy level of alveolar unit recruitment for gas exchange. Prior work has demonstrated that giving occasional maximal breaths on the ventilator – a sigh breath – could prevent alveolar collapse, maintain surfactant and, possibly, decrease overall ventilator induced lung injury.
This randomized control trial (RCT) utilized a pragmatic, parallel-group design to assign patients in a 1:1 ratio to a control group of usual intensivist care or an intervention group where a sigh breath producing a plateau pressure of 35 cm H2O (or 40 cm H2O for patients with a body mass index of greater than 35) was delivered once every 6 minutes. The primary outcome was ventilator-free days. The pre-specified secondary outcomes included 28-day mortality, the number of ICU-free days, complications, and discharge status.
A total of 524 patients were randomized with 261 patients assigned to the sigh breath group and 263 patients to the usual care group. Patients were recruited across 15 academic trauma centers and were 18 years and older, mechanically ventilated for trauma for less than 24 hours, had at least one risk factor for ARDS, were expected to be ventilated for at least 24 hours and were expected to survive for at least 48 hours. Patients were adequately matched across a wide range of demographics, illness severity, ventilator modes, baseline CT chest scans and gas exchange statuses. There was no difference between the sigh intervention group and usual care for the primary end point of ventilator free days. While the sigh group had a median of 18.4 ventilator free days the usual care group had 16.1 ventilator free days (p=0.08). Of note, however, patients in the sigh group did have a shorter time to successful extubation. Additionally, among the secondary outcomes there was a difference in 28-day mortality favoring the sigh group – while 11.6% (30/259) of patients in the sigh group died within 28 days, 17.6% (46/261) of patients in the usual care group died within 28 days. There was no difference in other complications between the two groups.
This pragmatic study has several strengths including its randomized design and matching across a wide range of patient, illness and radiographic variables. Its weaknesses include the inability to adequately blind providers from the sigh intervention group or control the ventilatory strategies used by intensivists in the control group. Overall, this is the first study to investigate, with a rigorous RCT, the clinical significance of sigh breaths specifically in trauma patients. Of note it confirms findings from the PROTECTION study, which investigated the impact of sigh breaths in ARDS patients, that sigh breaths were not harmful. Given the lack of significant harm, further research is indicated to parse out the utility of integrating sigh breaths into the usual care of mechanically ventilated trauma patients.
Article 3
Timely Cessation of Protein Pump Inhibitors in Critically Ill Patients Impacts Morbidity and Mortality: A Propensity Score-Matched Cohort Study. Palmowski L, von Busch A, Unterberg M, et al. Critical Care Med. 2024 Feb 1;52(2):190-199.
Protein pump inhibitors (PPIs) are commonplace in treatment of critically ill patients in the intensive care unit (ICU), with a recommended duration of eight weeks. However, as is often seen in medications started in the hospital, PPIs are not often prescribed with a duration or end date. The lack of timely cessation proports both economic burden and side effect risk to patients, including greater risk of clostridium difficile infection, gastritis, pneumonia, cardiovascular events, chronic renal failure, greater frequency of various neoplasms, possibly malabsorption disorders evoking vitamin B12 deficiency, hypocalcemia, and hypomagnesemia. The objective of this study was to examine the impact of unnecessary long-term continuation of newly initiated stress ulcer prophylaxis in the ICU on morbidity and mortality after hospital discharge.
This is a nationwide retrospective cohort study of critically ill patients between 2017-2018 with two year follow up, using the health claims data from a large German health insurer. In a dataset of 591,207 adult hospitalized patients, the authors identified critically ill patients in need of complex multimodal intensive care and initiation of PPI therapy during the ICU stay; they then performed propensity score matching to compare outcomes between patients without PPI therapy and those who unnecessarily continued the therapy, followed by analyzing the prevalence of potential adverse effects within the first year of discharge.
Among the 591,207 patients in their single country healthcare insurer database, 11,576 ICU patients received PPI therapy for the first time during their index ICU stay without having an indication for its continuation. The proportion of patients with continued PPI therapy without an objectifiable indication was 41.7% (4,825 of 11,576 patients), nearly half of which were on permanent (> 1 year) therapy. These patients on unnecessary PPI had a 27% greater risk of pneumonia (odds ratio [OR] 1.27), 26% greater risk of developing chronic renal failure (OR 1.26), and a 17% greater risk of cardiovascular events (OR 1.17). Moreover, there was a 2.7 fold increased risk of esophageal (OR 2.74) and 2.4 fold increase risk of pancreatic cancer (OR 2.44). Additionally, unnecessary PPI continuation resulted in 1.3 fold increased risk of vitamin B12 deficiency, 2.1 fold increased risk of hypomagnesemia, and 1.6 fold increased risk of hypocalcemia. Lastly, continued PPI therapy was associated with a 34% greater risk of rehospitalization (OR 1.34) and a nearly 20% greater 2-year mortality risk (hazard ratio 1.17).
In summary, this retrospective review demonstrates an excessive overtreatment with PPI in prior critically ill ICU patients following 8 weeks after hospital discharge, with a lack of indication for PPI treatment in a large proportion of patients and subsequent clinical consequence. These data call into question the practice of ubiquitous PPI prescriptions without end dates and highlight the necessary vigilance of the ICU physician toward communication and interventions ensuring timely cessation of an only temporarily indicated PPI therapy.
