Cardiovascular Subphenotypes in Acute Respiratory Distress Syndrome.

OBJECTIVES: To use clustering methods on transthoracic echocardiography (TTE) findings and hemodynamic parameters to characterize circulatory failure subphenotypes and potentially elucidate underlying mechanisms in patients with acute respiratory distress syndrome (ARDS) and to describe their association with mortality compared with current definitions of right ventricular dysfunction (RVD). DESIGN: Retrospective, single-center cohort study. SETTING: University Hospital ICU, Birmingham, United Kingdom. PATIENTS: ICU patients that received TTE within 7 days of ARDS onset between April 2016 and December 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Latent class analysis (LCA) of TTE/hemodynamic parameters was performed in 801 patients, 62 years old (interquartile range, 50-72 yr old), 63% male, and 40% 90-day mortality rate. Four cardiovascular subphenotypes were identified: class 1 (43%; mostly normal left and right ventricular [LV/RV] function), class 2 (24%; mostly dilated RV with preserved systolic function), class 3 (13%, mostly dilated RV with impaired systolic function), and class 4 (21%; mostly high cardiac output, with hyperdynamic LV function). The four subphenotypes differed in their characteristics and outcomes, with 90-day mortality rates of 19%, 40%, 78%, and 59% in classes 1-4, respectively ( p < 0.0001). Following multivariable logistic regression analysis, class 3 had the highest odds ratio (OR) for mortality (OR, 6.9; 95% CI, 4.0-11.8) compared with other RVD definitions. Different three-variable models had high diagnostic accuracy in identifying each of these latent subphenotypes. CONCLUSIONS: LCA of TTE parameters identified four cardiovascular subphenotypes in ARDS that more closely aligned with circulatory failure mechanisms and mortality than current RVD definitions.

Hyperdynamic Left Ventricular Ejection Fraction in ICU Patients With Sepsis.

OBJECTIVES: To evaluate the cause and prognosis of hyperdynamic left ventricular ejection fraction in critically ill patients with sepsis. DESIGN: Retrospective, single-center cohort study. SETTING: University Hospital ICU, Birmingham, United Kingdom. PATIENTS: ICU patients who received a transthoracic echocardiogram within 7 days of sepsis between April 2016 and December 2019. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: The 90-day mortality rates of normal (55-70%), depressed (< 55%), and hyperdynamic left ventricular ejection fraction (> 70%) were compared. Multivariate logistic regression analysis was performed to determine the association of left ventricular ejection fraction phenotypes with mortality and the association of clinical variables with left ventricular ejection fraction phenotypes. One thousand fourteen patients met inclusion criteria and were 62 years old (interquartile range, 47-72), with mostly respiratory infections (n = 557; 54.9%). Ninety-day mortality was 32.1% (n = 325). Patients with hyperdynamic left ventricular ejection fraction had a higher mortality than depressed and normal left ventricular ejection fraction cohorts (58.9% [n = 103] vs 34.0% [n = 55] vs 24.7% [n = 167]; p < 0.0001, respectively). After multivariate logistic regression, hyperdynamic left ventricular ejection fraction was independently associated with mortality (odds ratio, 3.90 [2.09-7.40]), whereas depressed left ventricular ejection fraction did not (odds ratio, 0.62 [0.28-1.37]). Systemic vascular resistance was inversely associated with hyperdynamic left ventricular ejection fraction (odds ratio, 0.79 [0.58-0.95]), and age, frailty, and ischemic heart disease were associated with depressed left ventricular ejection fraction. CONCLUSIONS: Hyperdynamic left ventricular ejection fraction was associated with mortality in septic ICU patients and may reflect unmitigated vasoplegia from sepsis. Depressed left ventricular ejection fraction was not associated with mortality but was associated with cardiovascular disease.

Incidence of Gastrointestinal Bleeding After Transesophageal Echocardiography Use in Orthotopic Liver Transplantation.

The risk of upper gastrointestinal bleeding (UGIB) after transesophageal echocardiography (TEE) in patients with high grade esophageal varices (EV) that are undergoing Orthotopic Liver transplantation (OLT) is poorly understood. This was a retrospective single-centre cohort study in all patients that underwent OLT at Queen Elizabeth Hospital Birmingham between September 2016 and September 2018. The primary outcome was to determine the incidence of UGIB in patients that have undergone OLT with EV that received TEE. 401 patients were included in the study, of which 320 (80%) received TEE. The incidence of post-operative UGIB in patients that received TEE was 1.6% (5/320) in the entire cohort: 2.7% (4/149) in patients with no evidence of EV and 0.6% (1/171) in patients with EV. UGIB occurred in 1 patient with grade 2 EV and did not occur in patients with grade 1 or 3 EV. The incidence of UGIB in patients that received TEE was not statistically different to patients that did not: 1.6% (5/320) vs. 3.7% (3/81) p = 0.218. In conclusion, in patients that underwent OLT, intra-operative TEE use was associated with low rates of UGIB, even in cohorts with high grade EV. This suggests that TEE is a relatively safe method of haemodynamic monitoring in patients undergoing OLT.

Right Ventricular Dysfunction and Its Association With Mortality in Coronavirus Disease 2019 Acute Respiratory Distress Syndrome.

OBJECTIVES: To assess whether right ventricular dilation or systolic impairment is associated with mortality and/or disease severity in invasively ventilated patients with coronavirus disease 2019 acute respiratory distress syndrome. DESIGN: Retrospective cohort study. SETTING: Single-center U.K. ICU. PATIENTS: Patients with coronavirus disease 2019 acute respiratory distress syndrome undergoing invasive mechanical ventilation that received a transthoracic echocardiogram between March and December 2020. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Right ventricular dilation was defined as right ventricular:left ventricular end-diastolic area greater than 0.6, right ventricular systolic impairment as fractional area change less than 35%, or tricuspid annular plane systolic excursion less than 17 mm. One hundred seventy-two patients were included, 59 years old (interquartile range, 49-67), with mostly moderate acute respiratory distress syndrome (n = 101; 59%). Ninety-day mortality was 41% (n = 70): 49% in patients with right ventricular dilation, 53% in right ventricular systolic impairment, and 72% in right ventricular dilation with systolic impairment. The right ventricular dilation with systolic impairment phenotype was independently associated with mortality (odds ratio, 3.11 [95% CI, 1.15-7.60]), but either disease state alone was not. Right ventricular fractional area change correlated with Pao2:Fio2 ratio, Paco2, chest radiograph opacification, and dynamic compliance, whereas right ventricular:left ventricle end-diastolic area correlated negatively with urine output. CONCLUSIONS: Right ventricular systolic impairment correlated with pulmonary pathophysiology, whereas right ventricular dilation correlated with renal dysfunction. Right ventricular dilation with systolic impairment was the only right ventricular phenotype that was independently associated with mortality.

Protection against ventricular fibrillation via cholinergic receptor stimulation and the generation of nitric oxide.

KEY POINTS: Animal studies suggest an anti-fibrillatory action of the vagus nerve on the ventricle, although the exact mechanism is controversial. Using a Langendorff perfused rat heart, we show that the acetylcholine analogue carbamylcholine raises ventricular fibrillation threshold (VFT) and flattens the electrical restitution curve. The anti-fibrillatory action of carbamylcholine was prevented by the nicotinic receptor antagonist mecamylamine, inhibitors of neuronal nitric oxide synthase (nNOS) and soluble guanylyl cyclase (sGC), and can be mimicked by the nitric oxide (NO) donor sodium nitroprusside. Carbamylcholine increased NO metabolite content in the coronary effluent and this was prevented by mecamylamine. The anti-fibrillatory action of both carbamylcholine and sodium nitroprusside was ultimately dependent on muscarinic receptor stimulation as all effects were blocked by atropine. These data demonstrate a protective effect of carbamylcholine on VFT that depends upon both muscarinic and nicotinic receptor stimulation, where the generation of NO is likely to be via a neuronal nNOS-sGC dependent pathway. ABSTRACT: Implantable cardiac vagal nerve stimulators are a promising treatment for ventricular arrhythmia in patients with heart failure. Animal studies suggest the anti-fibrillatory effect may be nitric oxide (NO) dependent, although the exact site of action is controversial. We investigated whether a stable analogue of acetylcholine could raise ventricular fibrillation threshold (VFT), and whether this was dependent on NO generation and/or muscarinic/nicotinic receptor stimulation. VFT was determined in Langendorff perfused rat hearts by burst pacing until sustained VF was induced. Carbamylcholine (CCh, 200 nmol l(-1) , n = 9) significantly (P < 0.05) reduced heart rate from 292 ± 8 to 224 ± 6 b.p.m. Independent of this heart rate change, CCh caused a significant increase in VFT (control 1.5 ± 0.3 mA, CCh 2.4 ± 0.4 mA, wash 1.1 ± 0.2 mA) and flattened the restitution curve (n = 6) derived from optically mapped action potentials. The effect of CCh on VFT was abolished by a muscarinic (atropine, 0.1 µmol l(-1) , n = 6) or a nicotinic receptor antagonist (mecamylamine, 10 µmol l(-1) , n = 6). CCh significantly increased NOx content in coronary effluent (n = 8), but not in the presence of mecamylamine (n = 8). The neuronal nitric oxide synthase inhibitor AAAN (N-(4S)-4-amino-5-[aminoethyl]aminopentyl-N'-nitroguanidine; 10 µmol l(-1) , n = 6) or soluble guanylate cyclase (sGC) inhibitor ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one; 10 µmol l(-1) , n = 6) prevented the rise in VFT with CCh. The NO donor sodium nitrprusside (10 µmol l(-1) , n = 8) mimicked the action of CCh on VFT, an effect that was also blocked by atropine (n = 10). These data demonstrate a protective effect of CCh on VFT that depends upon both muscarinic and nicotinic receptor stimulation, where the generation of NO is likely to be via a neuronal nNOS/sGC-dependent pathway.

Cardiovascular Subphenotypes in ARDS: Diagnostic and Therapeutic Implications and Overlap with Other ARDS Subphenotypes.

Acute respiratory distress syndrome (ARDS) is a highly heterogeneous clinical condition. Shock is a poor prognostic sign in ARDS, and heterogeneity in its pathophysiology may be a barrier to its effective treatment. Although right ventricular dysfunction is commonly implicated, there is no consensus definition for its diagnosis, and left ventricular function is neglected. There is a need to identify the homogenous subgroups within ARDS, that have a similar pathobiology, which can then be treated with targeted therapies. Haemodynamic clustering analyses in patients with ARDS have identified two subphenotypes of increasingly severe right ventricular injury, and a further subphenotype of hyperdynamic left ventricular function. In this review, we discuss how phenotyping the cardiovascular system in ARDS may align with haemodynamic pathophysiology, can aid in optimally defining right ventricular dysfunction and can identify tailored therapeutic targets for shock in ARDS. Additionally, clustering analyses of inflammatory, clinical and radiographic data describe other subphenotypes in ARDS. We detail the potential overlap between these and the cardiovascular phenotypes.

The utility of arterial blood gas parameters and chest radiography in predicting appropriate intubations in burn patients with suspected inhalation injury-A retrospective cohort study.

BACKGROUND: This study evaluates the utility of arterial blood gas (ABG) parameters and chest radiography in predicting intubation need in patients with burn injuries with suspected inhalation injury. METHODS: Patients with suspected inhalation injury admitted to a single centre, Burn Intensive Care Unit, between April 4th 2016 and July 5th 2019, were included. Admission ABG parameters and chest radiograph opacification were compared with whether the patient received an appropriate intubation: defined as intubation for a duration of over 48 h. Area under the receiver operator characteristic curve was calculated (AUROC). RESULTS: Eighty-nine patients were included. The majority (84%; n = 75) were intubated, of which 81% (n = 61) received appropriate intubations. pH had an AUROC of 0.88 and a pH of <7.30 had an 80% sensitivity and specificity for detecting appropriate intubation. P/F ratio had an AUROC of 0.81 and a P/F ratio of <40 had a 70% sensitivity and specificity for appropriate intubation. Chest radiograph opacification had poor utility in this regard (AUROC = 0.69). Adding pH and P/F ratio to the ABA criteria improved their sensitivity in detecting appropriate intubations (sensitivity: ABA + pH + P/F = 0.97 vs ABA = 0.86; p = 0.013), without altering their specificity. CONCLUSIONS: In patients suspected inhalation injury, pH and P/F ratio were good predictors for appropriate intubations. Incorporating the parameters into the ABA criteria improved their clinical utility.

The Predictive Applicability of Liberal vs Restrictive Intubation Criteria in Adult Patients With Suspected Inhalation Injury-A Retrospective Cohort Study.

This study compares the ability of liberal vs restrictive intubation criteria to detect prolonged intubation and inhalation injury in burn patients with suspected inhalation injury. Emerging evidence suggests that using liberal criteria may lead to unnecessary intubation in some patients. A single-center retrospective cohort study was conducted in adult patients with suspected inhalation injury admitted to intensive care at Queen Elizabeth Hospital, Birmingham between April 2016 and July 2019. Liberal intubation criteria, as reflected in local guidelines, were compared to restrictive intubation criteria, as outlined in the American Burn Association guidelines. The number of patients displaying positive characteristics from either guideline was compared to the number of patients who had prolonged intubation (more than 48 hours) and inhalation injury. In detecting a need for prolonged intubation (n = 85), the liberal criteria had greater sensitivity (liberal = 0.98 [0.94-1.00] vs restrictive = 0.84 [0.75-0.93]; P = .013). However, the restrictive criteria had greater specificity (restrictive = 0.96 [0.89-1.00] vs liberal = 0.48 [0.29-0.67]; P < .001). In detecting inhalation injury (n = 72), the restrictive criteria were equally sensitive (restrictive = 0.94 [0.87-1.00] vs liberal = 0.98 [0.84-1.00]; P = .48) and had greater specificity (restrictive = 0.86 [0.72-1.00] vs liberal = 0.04 [0.00-0.13]; P < .001). In patients who met liberal but not restrictive criteria, 65% were extubated within 48 hours and 90% did not have inhalation injury. Liberal intubation criteria were more sensitive at detecting a need for prolonged intubation, while restrictive criteria were more specific. Most patients intubated based on liberal criteria alone were extubated within 48 hours. Restrictive criteria were highly sensitive and specific at detecting inhalation injury.

Characterisation and outcomes of ARDS secondary to pneumonia in patients with and without SARS-CoV-2: a single-centre experience.

INTRODUCTION: Acute respiratory distress syndrome (ARDS) is the major cause of mortality in patients with SARS-CoV-2 pneumonia. It appears that development of 'cytokine storm' in patients with SARS-CoV-2 pneumonia precipitates progression to ARDS. However, severity scores on admission do not predict severity or mortality in patients with SARS-CoV-2 pneumonia. Our objective was to determine whether patients with SARS-CoV-2 ARDS are clinically distinct, therefore requiring alternative management strategies, compared with other patients with ARDS. We report a single-centre retrospective study comparing the characteristics and outcomes of patients with ARDS with and without SARS-CoV-2. METHODS: Two intensive care unit (ICU) cohorts of patients at the Queen Elizabeth Hospital Birmingham were analysed: SARS-CoV-2 patients admitted between 11 March and 21 April 2020 and all patients with community-acquired pneumonia (CAP) from bacterial or viral infection who developed ARDS between 1 January 2017 and 1 November 2019. All data were routinely collected on the hospital's electronic patient records. RESULTS: A greater proportion of SARS-CoV-2 patients were from an Asian ethnic group (p=0.002). SARS-CoV-2 patients had lower circulating leucocytes, neutrophils and monocytes (p<0.0001), but higher CRP (p=0.016) on ICU admission. SARS-CoV-2 patients required a longer duration of mechanical ventilation (p=0.01), but had lower vasopressor requirements (p=0.016). DISCUSSION: The clinical syndromes and respiratory mechanics of SARS-CoV-2 and CAP-ARDS are broadly similar. However, SARS-CoV-2 patients initially have a lower requirement for vasopressor support, fewer circulating leukocytes and require prolonged ventilation support. Further studies are required to determine whether the dysregulated inflammation observed in SARS-CoV-2 ARDS may contribute to the increased duration of respiratory failure.