by
Jean-Louis Vincent;
James A Russell;
Matthias Jacob;
Greg Martin;
Bertrand Guidet;
Jan Wernerman;
Ricard Ferrer Roca;
Stuart A McCluskey;
Luciano Gattinoni
Introduction: Patients with distributive shock who require high dose vasopressors have a high mortality. Angiotensin II (ATII) may prove useful in patients who remain hypotensive despite catecholamine and vasopressin therapy. The appropriate dose of parenteral angiotensin II for shock is unknown. Methods: In total, 20 patients with distributive shock and a cardiovascular Sequential Organ Failure Assessment score of 4 were randomized to either ATII infusion (N =10) or placebo (N =10) plus standard of care. ATII was started at a dose of 20 ng/kg/min, and titrated for a goal of maintaining a mean arterial pressure (MAP) of 65 mmHg. The infusion (either ATII or placebo) was continued for 6 hours then titrated off. The primary endpoint was the effect of ATII on the standing dose of norepinephrine required to maintain a MAP of 65 mmHg. Results: ATII resulted in marked reduction in norepinephrine dosing in all patients. The mean hour 1 norepinephrine dose for the placebo cohort was 27.6 ± 29.3 mcg/min versus 7.4 ± 12.4 mcg/min for the ATII cohort (P =0.06). The most common adverse event attributable to ATII was hypertension, which occurred in 20% of patients receiving ATII. 30-day mortality for the ATII cohort and the placebo cohort was similar (50% versus 60%, P =1.00). Conclusion: Angiotensin II is an effective rescue vasopressor agent in patients with distributive shock requiring multiple vasopressors. The initial dose range of ATII that appears to be appropriate for patients with distributive shock is 2 to 10 ng/kg/min. Trial registration: Clinicaltrials.gov NCT01393782. Registered 12 July 2011.
Intestinal barrier dysfunction is thought to contribute to the development of multiple organ dysfunction syndrome in sepsis. Although there are similarities in clinical course following sepsis, there are significant differences in the host response depending on the initiating organism and time course of the disease, and pathways of gut injury vary widely in different preclinical models of sepsis. The purpose of this study was to determine whether the timecourse and mechanisms of intestinal barrier dysfunction are similar in disparate mouse models of sepsis with similar mortalities. FVB/N mice were randomized to receive cecal ligation and puncture (CLP) or sham laparotomy, and permeability was measured to fluoresceinisothiocyanate conjugated-dextran (FD-4) six to 48 h later. Intestinal permeability was elevated following CLP at all timepoints measured, peaking at 6 to 12 h. Tight junction proteins claudin 1, 2, 3, 4, 5, 7, 8, 13, and 15, Junctional Adhesion Molecule-A (JAM-A), occludin, and ZO-1 were than assayed by Western blot, real-time polymerase chain reaction, and immunohistochemistry 12 h after CLP to determine potential mechanisms underlying increases in intestinal permeability. Claudin 2 and JAM-A were increased by sepsis, whereas claudin-5 and occludin were decreased by sepsis. All other tight junction proteins were unchanged. A further timecourse experiment demonstrated that alterations in claudin-2 and occludin were detectable as early as 1 h after the onset of sepsis. Similar experiments were then performed in a different group of mice subjected to Pseudomonas aeruginosa pneumonia. Mice with pneumonia had an increase in intestinal permeability similar in timecourse and magnitude to that seen in CLP. Similar changes in tight junction proteins were seen in both models of sepsis although mice subjected to pneumonia also had a marked decrease in ZO-1 not seen in CLP. These results indicate that two disparate, clinically relevant models of sepsis induce a significant increase in intestinal permeability mediated through a common pathway involving alterations in claudin 2, claudin 5, JAM-A, and occludin although model-specific differences in ZO-1 were also identified.
This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency Medicine 2018. Other selected articles can be found online at https://www.biomedcentral.com/collections/annualupdate2018. Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901.
The gut has long been hypothesized to be the 'motor' of multiple organ dysfunction syndrome. This review serves as an update on new data elucidating the role of the gut as the propagator of organ failure in critical illness. Recent findings Under basal conditions, the gut absorbs nutrients and serves as a barrier that prevents approximately 40 trillion intraluminal microbes and their products from causing host injury. However, in critical illness, gut integrity is disrupted with hyperpermeability and increased epithelial apoptosis, allowing contamination of extraluminal sites that are ordinarily sterile. These alterations in gut integrity are further exacerbated in the setting of preexisting comorbidities. The normally commensal microflora is also altered in critical illness, with increases i n microbial virulence and decreases in diversity, which leads to further pathologic responses within the host. Summary All components of the gut are adversely impacted by critical illness. Gut injury can not only propagate local damage, but can also cause distant injury and organ failure. Understanding how the multifaceted components of the gut interact and how these are perturbed in critical illness may play an important role in turning off the 'motor' of multiple organ dysfunction syndrome in the future.
We sought to examine trends in the race-specific incidence of acute respiratory failure in the United States. Design: Retrospective cohort study. Setting: We used the National Hospital Discharge Survey database (1992-2007), an annual survey of approximately 500 hospitals weighted to provide national hospitalization estimates. Patients: All incident cases of noncardiogenic acute respiratory failure hospitalized in the United States. INTERVENTIONS:: None. Measurements and Main Results: We identified noncardiogenic acute respiratory failure by the presence of International Classification of Diseases, Ninth Revision, codes for respiratory failure or pulmonary edema (518.4, 518.5, 518.81, and 518.82) and mechanical ventilation (96.7×), excluding congestive heart failure. Incidence rates were calculated using yearly census estimates standardized to the age and sex distribution of the 2000 census population. Annual cases of noncardiogenic acute respiratory failure increased from 86,755 in 1992 to 323,474 in 2007. Noncardiogenic acute respiratory failure among black Americans increased from 56.4 (95% confidence interval 39.7-73.1) to 143.8 (95% confidence interval 123.8-163.8) cases per 100,000 in 1992 and 2007, respectively. Among white Americans, the incidence of noncardiogenic acute respiratory failure increased from 31.2 (95% confidence interval 26.2-36.5) to 94.0 (95% confidence interval 86.7-101.2) cases per 100,000 in 1992 and 2007, respectively. The average annual incidence of noncardiogenic acute respiratory failure over the entire study period was 95.1 (95% confidence interval 93.9-96.4) cases per 100,000 for black Americans compared to 66.5 (95% confidence interval 65.8-67.2) cases per 100,000 for white Americans (rate ratio 1.43, 95% confidence interval 1.42-1.44). Overall in-hospital mortality was greater for other-race Americans, but only among patients with two or more organ failures (57% [95% confidence interval 56%-59%] for other race, 51% [95% confidence interval 50%-52%] for white, 50% [95% confidence interval 49%-51%] for black). Conclusions: The incidence of noncardiogenic acute respiratory failure in the United States increased between 1992 and 2007. Black and other-race Americans are at greater risk of developing noncardiogenic acute respiratory failure compared to white Americans.
Background: We hypothesized that maternal alcohol use occurs in pregnancies that end prematurely and that in utero alcohol exposure is associated with an increased risk of morbidities of premature newborns.
Methods: In an observational study of mothers who delivered very low birth weight newborns (VLBW) ≤1,500 g, maternal alcohol use was determined via a standardized administered questionnaire. We compared the effect of maternal drinking on the odds of developing late-onset sepsis (LOS), bronchopulmonary dysplasia (BPD), death, BPD or Death days on oxygen or any morbidity (either LOS, BPD or death). The effect of drinking amounts (light versus heavy) was also evaluated.
Results: A total of 129 subjects who delivered 143 VLBW newborns were enrolled. Approximately 1 in 3 (34%) subjects reported drinking alcohol during the first trimester ("exposed"). Within the exposed group, 15% reported drinking ≥7. drinks/week ("heavy") and 85% of the subjects reported drinking < 7. drinks/week ("light"). When controlling for maternal age, drug or tobacco use during pregnancy and neonatal gestational age, any drinking increased the odds of BPD or Death and any morbidity. Furthermore, light or heavy drinking increased the odds of BPD or Death and any morbidity, whereas heavy drinking increased the odds of LOS.
Conclusions: In utero alcohol exposure during the first trimester occurred in 34% of VLBW newborns. Maternal drinking in the first trimester was associated with significantly increased odds of neonatal morbidity. Further studies are warranted to determine the full effect of . in utero alcohol exposure on the adverse outcomes of VLBW premature newborns.