October 2021

Synopsis: Cardiogenic shock is still associated with substantial morbidity and mortality. Pharmacologic support with inotropic medications is a mainstay of therapy, but little high quality evidence exists to guide selection of inotropic agents in clinical practice.

The Dobutamine Compared with Milrinone (DOREMI) trial, a randomized, double-blind clinical trial of milrinone as compared with dobutamine in patients with cardiogenic shock. Eligible patients were ≥18 years old, admitted to the cardiac intensive care unit (ICU), and had cardiogenic shock meeting the Society for Cardiovascular Angiography and Interventions (SCAI) definition of cardiogenic shock stage B, C, D, or E. Patients were randomized in a stratified fashion based upon the affected ventricle (left, right, or both).

The primary outcome was the composite of in-hospital death from any cause, resuscitated cardiac arrest, receipt of a cardiac transplant or mechanical circulatory support, nonfatal myocardial infarction, transient ischemic attack or stroke diagnosed by a neurologist, or initiation of renal replacement therapy.

A total of 192 patients were enrolled. Baseline characteristics were similar between the two groups. The median age was 70, 37% were female, median left ventricular ejection fraction was 25%, and median lactate was 2.9 mmol/L.

There was no difference in the risk of the primary outcome (relative risk (RR), 0.90; 95% CI 0.69-1.19; P=0.47). There were no significant differences between groups in any of the secondary outcomes, including in-hospital death (37% milrinone and 43% dobutamine; RR, 0.85; 95% CI, 0.60-1.21), resuscitated cardiac arrest (7% and 9%; hazard ratio (HR), 0.78; 95% CI, 0.29-2.07), receipt of mechanical circulatory support (12% and 15%; HR, 0.78; 95% CI, 0.36-1.71), or initiation of renal replacement therapy (22% and 17%; HR, 1.39; 95% CI, 0.73 to 2.67).

In addition, there were no significant differences with respect to secondary safety outcomes, including atrial or ventricular arrhythmias and sustained hypotension. This study was underpowered to detect smaller, potentially clinically meaningful differences in components of the primary outcome.

Take-Home Points:

This randomized trial found no significant difference in key outcomes between milrinone and dobutamine for patients with cardiogenic shock. In addition, these results challenge current dogma that milrinone is associated with greater hypotension and that dobutamine is associated with more dysrhythmia.

Synopsis: Fetal endoluminal tracheal occlusion (FETO) has emerged as a promising technique and surgical intervention for infants with pulmonary hypoplasia secondary to congenital diaphragmatic hernia. FETO, a highly specialized off-label use of an endovascular occlusion balloon, functions to temporarily occlude the trachea in neonates and stimulate fetal lung growth. Several small case studies and institutional trials have shown the efficacy of FETO, with substantial clear survival benefit, however, a randomized multicenter trial has not substantiated the data. In this context, these papers provide the first-ever multicenter randomized trials for FETO use in mothers with infants who have a severe or moderate left-sided diaphragmatic hernia. The inclusion criteria for eligible centers as well as eligible women was strict, and the trial was designed with planned five interim analyses to allow for early stopping in case of superiority.

Severe left-sided diaphragmatic hernia was defined as observed-to-expected lung-to-head ratio of less than 25%, irrespective of liver position. Fetoscopic balloon occlusion occurred at 27 to 29 weeks gestation with reversal scheduled at 34 weeks gestation. This trial was stopped early for efficacy after the third intern analysis with significance in the primary outcome: 40% of infants survived to discharge in the FETO group compared to 15% in the expectant management (control) group. This survival benefit was sustained at 6 months of age. However, the treatment is not without risk. The FETO group had 4.5x higher risk of preterm, prelabor rupture of membranes and 2.6x higher risk of preterm birth. Indeed, the median gestational age in the FETO group was 34.6 weeks compared to 38.4 weeks in the control group.

In the parallel study examining moderate left-sided diaphragmatic hernias, the inclusion criteria required an observed-to-expected lung-to-head ratio of 25-35% irrespective of liver position or a lung-to-head ratio of 35-45% with intrathoracic liver herniation. Balloon occlusion occurred slightly later at 30-31 weeks gestation, with reversal planned for 34 weeks, to minimize the risk of preterm labor and birth in infants with moderate disease and therefore considerably lower risk of death Survival to discharge and survival without oxygen supplementation at six months were examined and came just short of significance. Again demonstrated were higher risks of preterm rupture of membranes (3.8x) and preterm birth (2.9x). The delay in occlusion compared to the severe group (30-31 weeks vs 27-29 weeks) and the resultant shorter occlusion time may have contributed to the lack of significant therapeutic effect.

Overall, these studies are monumental in demonstrating the significant benefit of FETO as an intervention for infants with a severe left-sided congenital diaphragmatic hernia. Implicit in all fetal therapies is consideration of mom as an innocent bystander; in both studies there were no adverse maternal events. FETO offers a tangible surgical solution for mothers considering intervention and a cost-saving opportunity for hospital systems to address the costliest non-cardiac birth defect. Regardless of its innovation and clear survival benefit, FETO comes with significant barriers and risk: namely the level of specialization required of the procedure, requirements of relocation to specialized FETO centers globally, and the increased risk of threatened pregnancy for mothers already negotiating a high-risk pregnancy. Significant consideration and shared decision making should be undertaken prior to proceeding with this invasive procedure and it should be considered only for those fetuses with severe disease and at highest risk for perinatal mortality.

Synopsis: The rupture of abdominal aortic aneurysms (AAA) is a surgical emergency with high mortality, standing as the 15th leading cause of death in the United States (US). Therefore, the early detection of these patients is integral to identify the high risk subgroup who would benefit from preventative aneurysm repair to prevent mortality from rupture. Currently, the United States Preventive Task Force recommends a one-time screening ultrasound for men ages 65 to 75 with a history of smoking or family history of aneurysm; and the Centers for Medicare and Medicaid expands on that to cover women within the same age group with a family history. The current screening criteria have decreased the incidence of ruptured AAA; however there is concern that a significant proportion of ruptured AAAs (rAAAs) patients do not meet the screen criteria.

In “Epidemiology of Endovascular and Open Repair for Abdominal Aortic Aneurysms in the United States from 2004 to 2015 and Implications for Screening”, published in the Journal of Vascular Surgery in August 2021, Dansey et al examined the trends, treatment patterns and outcomes for intact and ruptured AAA repairs, and identified the patients who were not eligible for AAA screening. The study was a retrospective cohort analysis using data from the Nationwide Inpatient Sample (NIS), a database that looks at in-hospital diagnoses and procedures for 20% of all hospitalizations in the US. Due to limited data from the NIS (no information on smoking status or family history), the proportion of patients eligible for screening was estimated from epidemiologic data from the Vascular Quality Initiative (VQI) database and Medicare. Per VQI, 10% of patients undergoing AAA repair have a family history of aneurysm, and 87% of men undergoing AAA repair have a smoking history. Per Medicare, 17% of patients presenting with rAAA had previous diagnoses of AAA, which was assumed to be the result of a screening study. These proportions were extrapolated up to create the estimated screening-eligible cohort from the NIS sample.

From 2004 to 2015, the study identified 65,125 admissions for rAAAs and 461,191 repairs for intact AAAs. Using the methods described above, the study predicted that of the 65,125 patients admitted for rAAAs, 44,155 (68%) patients did not meet the criteria for screening. Of those who did not qualify, 61% were over the age of 75, 24% were under the age of 65, 9 % were women between ages 65 and 75 without a family history of AAA, and 6% were men aged 65 to 75 who did not smoke nor had a family history. Among patients admitted with rAAAs, those who were ineligible for screening had a higher in-hospital mortality compared with the screening-eligible patients (45% vs 34%, p<0.001). Furthermore., over the 11 year study period, there was a significant increase in the proportion of EVAR performed for rAAA (10% in 2004 to 55% in 2015, p<0.001) as well as a decrease in the overall mortality after rAAA repair (42% in 2004 to 28% in 2015, p<0.001). Women were noted to have significantly worse outcomes with an overall mortality of 41% after rAAA repair.

In this study, most patients with rAAAs did not qualify for screening, resulting in an increased overall mortality. Of those admitted with rAAAs, more than half were older than 75 and almost a quarter were younger than 65, with women constituting a significant portion, suggesting that screening guidelines should be expanded to include a larger subset of the population. The main limitation of this study however is that it was almost entirely predictive, as the database used did not include smoking data or family history and these rates were estimated based on prior VQI data. Further studies are needed to design a more sensitive screening algorithm, that includes other well established risk factors, to capture these high risk patients.

Synopsis: Instead of providing my own commentary, please see this excellent editorial regarding this paper as well as a podcast starring our very own Dr. Charles Vasquez discussing his work.

Editorial and Podcast (as Supplementary Data):
https://journal.chestnet.org/article/S0012-3692(21)01071-0/fulltext