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COVID-19
Sergio Caravita, MD, PhD
Department of Management, Information and Production Engineering, University of Bergamo
Cardiology Unit, IRCCS Istituto Auxologico Italiano San Luca Hospital, Milano
25/05/2020
https://twitter.com/i/status/1255719775918931968
Agenda
COVID and the heart
COVID and ARDS
COVID and the pulmonary circulation
Agenda
COVID and the heart
COVID and ARDS
COVID and the pulmonary circulation
Multiorgan SARS-CoV-2 Tropism
DOI: 10.1056/NEJMc2011400
Coronavirus 2 and ACE2 receptor
SARS-CoV-2 infection is caused by binding of the viral surface spike protein to the human angiotensin-converting enzyme 2 (ACE2) receptor after activation of the spike protein by transmembrane protease serine 2.
ACE2 is expressed in the lung (principally type II alveolar cells), in the heart, in the intestinal epithelium, vascular endothelium, and kidneys
https://doi.org/10.1161/CIRCULATIONAHA.120.046941
Coronavirus 2 and ACE2 receptor
ACE2 is highly expressed in the heart as well, counteracting the effects of angiotensin II in states with excessive activation of the renin-angiotensin system, such as hypertension, congestive heart failure, and atherosclerosis.
https://doi.org/10.1161/JAHA.120.016219
Myocardial injury, evidenced by elevated cardiac biomarkers, was recognized among early cases in China.
In a study of 138 hospitalized patients with COVID-19 in Wuhan, China, cardiac injury (elevated high-sensitivity cardiac troponin I [hs-cTnI] or new ECG or echocardiographic abnormalities) was present in 7.2% of patients overall and 22% of patients who required ICU care.
https://doi.org/10.1161/JAHA.120.016219
https://doi.org/10.1093/eurheartj/ehaa325
https://doi.org/10.1161/CIRCULATIONAHA.120.046941
Myocardial biopsy in a patient with COVID-19 and cardiogenic shock
https://doi.org/10.1002/ejhf.1828
Agenda
COVID and the heart
COVID and Acute Respiratory Distress Syndrome (ARDS)
COVID and the pulmonary circulation
COVID-19, interstital pneumonia and ARDS
Coronavirus-2 can cause an interstital pneumonia that, in up to 15% of cases, progresses towards Severe Acute Respiratory Syndrome (SARS-CoV-2), frequentlycomplicated by Acute Respiratory Distress Syndrome (ARDS).
Fifty years ago, Ashbaugh and colleagues described 12 patients with tachypnea, refractory hypoxemia, and diffuse opacities on chest radiographs after infection or trauma.
Prominent hyaline membranes were seen lining the alveolar spaces of the lungs in 6 of the 7 patients who died, findings previously thought to be specific for the respiratory distress syndrome of the newborn. Thus, the term adult (later changed to acute) respiratory distress syndrome (ARDS) was proposed.
DOI: 10.1056/NEJMra1608077
Etiology of ARDS
ARDS develops most commonly in the setting of:
- pneumonia (bacterial and viral; fungal is less common),
- nonpulmonary sepsis (with sources that include the peritoneum, urinary tract, soft tissue and skin),
- aspiration of gastric and/or oral and oesophageal contents (which may be complicated by subsequent infection) and
- major trauma (such as blunt or penetrating injuries or burns).
ARDS does not develop in the majority of patients with clinical risk factors for the disease (e.g., pneumonia, sepsis, or trauma), suggesting that other factors, including genetic susceptibility, play a key role in the pathogenesis of this disorder.
https://doi.org/10.1038/s41572-019-0069-0
DOI: 10.1056/NEJMra1608077
The histologic correlate of ARDS is widely considered to be “diffuse alveolar damage”.
In particular, a rapid development of capillary congestion, atelectasis, intraalveolarhemorrhage, and alveolar edema was described, followed days later by hyaline-membrane formation, epithelial-cell hyperplasia, and interstitial edema.
Radiographic Heterogeneity in Patients with ARDS
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A variety of insults (such as acid, viruses, ventilator-associated lung injury, hyperoxia or bacteria) can injure the epithelium, either directly or by inducing inflammation, which in turn injures the epithelium. Direct injury is inevitably exacerbated by a secondary wave of inflammatory injury.
Fibroblasts secrete epithelial growth factors and deposit collagen, which, if excessive, can lead to fibrosis. Unfortunately, many endogenous reparative mechanisms are specifically inhibited during ARDS.
In addition, the many biological changes resulting from both endothelial and epithelial injury, and culminating in protein-rich oedematous fluid, contribute to surfactant dysfunction. Surfactant dysfunction can then increase atelectasis, which in turn can increase the risk of biophysical injury.
The normal alveolus The injured alveolus The repaired alveolus
https://doi.org/10.1038/s41572-019-0069-0
ARDS: the concept of «baby lung»
The ARDS lung is non-uniformly aerated, with nonaerated areas predominantly in gravity-dependent regions, owing to the superimposed weight of inflammatory pulmonary oedematous fluid.
Aerated lung volume is much smaller than normal, a phenomenon termed baby lung, identified and illustrated first with CT scans; this concept of the baby lung accounts for the low compliance of the respiratory system because it identifies the areas of the lung that are consolidated with oedema and inflammation and associated atelectasis
https://doi.org/10.1038/s41572-019-0069-0
ARDS and intrapulmonary shunt !Low VA/Q regions
DOI: 10.1183/09031936.00037014
ARDS and intrapulmonary shunt
A normal lung is imperfectly ventilated and perfused, and a small degree of intrapulmonary shunting (Qs/Qt = 4-10%) is normal. Anatomical shunting occurs when blood supply to the lungs via the bronchial arteries is returned via the pulmonary veins without passing through the pulmonary capillaries, thereby bypassing alveolar gas exchange.
Several studies have shown that arterial hypoxaemia in ARDS patients is mostly caused by shunt blood flow that might exceed 50% of cardiac output.
Low V′A/Q′ regions are either absent or a lesser cause of low PaO2
Impaired diffusion does not seem to contribute to arterial hypoxaemia
DOI: 10.1183/09031936.00037014
Qs=shunted bloodQt=total cardiac output
ARDS and «protective» mechanical ventilation
Historically, the focus of mechanical ventilation in acute respiratory failure has been to maintain adequate oxygenation and carbon dioxide elimination. Several preclinical studies indicated that the common clinical practice of using relatively high tidal volumes and elevated airway pressures for ARDS patients might exacerbate the degree of lung injury
in 2000, investigators supported by the US National Heart Lung and Blood Institute ARDS Network completed a randomized phase III clinical trial in which a tidal volume of 6 ml per kg PBW, compared with the more common higher tidal volume of 12 ml per kg PBW, improved survival, shortened duration of mechanical ventilation, attenuated systemic inflammation and accelerated recovery of extra-pulmonary organ failures, and the biologic findings were reported in other studies
Thus, with the discovery of the major role that mechanical forces play in the pathogenesis of lung injury, optimizing ventilator support to minimize VALI has become central to clinical management of ARDS, leading to the concept of lung-protective ventilation.
https://doi.org/10.1038/s41572-019-0069-0
Mechanical ventilation: tidal volume
The ARDS lung is non-uniformly aerated, with nonaerated areas predominantly in gravity-dependent regions, owing to the superimposed weight of inflammatory pulmonary oedematous fluid.
Aerated lung volume is much smaller than normal, a phenomenon termed baby lung, identified and illustrated first with CT scans; this concept of the baby lung accounts for the low compliance of the respiratory system because it identifies the areas of the lung that are consolidated with oedema and inflammation and associated atelectasis.
Thus, lower tidal volumes (e.g. 6 mL/Kg) are needed in ARDS to prevent regional overdistension.
https://doi.org/10.1038/s41572-019-0069-0
Mechanical ventilation: positive end-expiratory pressure (PEEP)
PEEP (5–20 cmH2O) is a key element of protective ventilation and is routinely applied in all patients with ARDS to facilitate adequate oxygenation and maintain alveolar recruitment.
The ideal PEEP might be sufficiently high to prevent cyclic opening and collapse of distal airspaces during tidal ventilation yet low enough to avoid tidal overdistension.
Recruitability is a term used to identify distal airspaces of the lung that may be collapsed or oedematous that could be inflated with higher levels of PEEP, therefore, participating in gas exchange.
https://doi.org/10.1038/s41572-019-0069-0
Hemodynamic effects of PEEP
DOI: 10.1016/j.jacc.2018.06.074
DOI: 10.1016/j.jacc.2018.06.074
DOI: 10.1016/j.jacc.2018.06.074
Mechanical ventilation: prone positioning
By modifying the regional distribution of transpulmonary pressure, prone positioning decreases regional heterogeneity of lung aeration, leading to an improvement of gas exchange and a decreased risk of mechanical lung injury
https://doi.org/10.1038/s41572-019-0069-0
Non-invasive ventilation
For patients with mild ARDS, avoiding invasive mechanical ventilation altogether may be beneficial. Invasive positive-pressure ventilation and the related co-interventions carry their own risks: sedative infusions that predispose to delirium, decreased mobility that predisposes to neuromuscular weakness and risk of ventilator-associated pneumonia, among other complications.
Noninvasive positive-pressure ventilation improves oxygenation and is used often in patients with mild ARDS but without a clear benefit on outcome; device interface may influence patient tolerance and efficacy.
https://doi.org/10.1038/s41572-019-0069-0
Rescue treatments: extracorporealmembrane oxygenation (ECMO)
Veno-venous extracorporeal membrane oxygenation (ECMO) is a treatment in which blood is circulated outside of the body for oxygenation on a gas-permeable membrane. ECMO has been proposed as a rescue therapy for patients with established very severe ARDS; for these trials, patients are typically those with severe ARDS in whom sufficient correction of gas exchange is inconsistent with lung-protective ventilation
The pulmonary circulation in «classical» ARDS
Hypoxic pulmonary vasoconstriction
Microthrombosis
Pulmonary vascular remodeling
The pulmonary circulation in ARDS
Mild to moderate elevations in mean pulmonary artery pressure (mPAP) are seen in most patients with ARDS
Pulmonary vascular resistance (PVR) is known to be elevated in patients with ARDS
Other factors potentially contributing to increase PAP are: microthrombosis and vascular remodeling
https://doi.org/10.1186/s13613-014-0028-6
Hypoxic pulmonary vasoconstriction
The mechanisms that underlie hypoxic pulmonary vasoconstriction (HPV) are complex and primarily relate to intracellular increases in calcium concentration and Rho kinase-mediated sensitisation in pulmonary arterial smooth muscle cells.
HPV in non-ventilated lung units contributes significantly to the increase in pulmonary vascular resistance in ARDS.
This reflex vascular modulation can reduce blood flow to atelectatic regions by 50%, with a significant improvement of ventilation/perfusion ratio and may limit the intrapulmonary shunt, whereby increasing right ventricular afterload.
In addition to the influence of HPV, disruption of the endothelium in ARDS results in an alteration in the normal balance of mediators of vasodilation (NO, prostacyclin) and vasoconstriction (thromboxane, leukotrienes, endothelin, serotonin, angiotensinII) favouring vasoconstriction.
https://doi.org/10.1186/s13613-014-0028-6
Hypoxic pulmonary vasoconstriction
DOI: 10.1183/09031936.00037014
Microvascular thrombosis
There is now ample evidence supporting the concept of lung injury causing local, as opposed to systemic, coagulation in ARDS
Tissue factor (TF) is released from endothelial cells that have been injured, in response to a variety of pro-inflammatory stimuli. TF is a strong activator of the extrinsic clotting cascade. Increased activation of pro-coagulant processes occurs in the lung in ARDS and does not result from the systemic activation of coagulation.
Analysis of SARS-CoV infection in laboratory models has shown that the delicate balance between coagulation and fibrinolysis is shifted towards fibrin deposition during infection leading to ARDS
Therefore, ARDS represents a procoagulant, anti-fibrinolytic phenotype and results in the local formation of microthrombi, which may, in turn, act to increase the pulmonary vascular resistance by the mechanical obstruction of blood flow.
Activation of coagulation pathways is particularly marked in severe COVID manifestations.
https://doi.org/10.1016/S2213-2600(20)30216-2
Pulmonary microthrombosis / pulmonaryembolism and dead space ventilation
DOI: 10.1183/09031936.00037014
Fibrosis, destruction of the capillary bed and vascular remodeling
Fibroproliferation is a characteristic of the late stage of ARDS, and is present in approximately 55% of patients who die of this condition. It is associated with increased mortality, and the presence of fibrosis on thin cut CT scan has been used to predict outcome in ARDS
There is increasing destruction of the capillary bed as ARDS progresses, which may contribute to elevations in the PVR.
Extensive vascular remodelling may occur in severe in ARDS, with fibrocellularobliteration of the arteries, veins and even lymphatic vessels. In the late stage, vascular remodelling is associated with distorted, tortuous arteries and veins, concentrated in regions of dense or irregular fibrosis. The number of capillaries is reduced, and they are often dilated. Muscularisation of the arteries can be very marked in the late phase. This mechanical disruption of the course of blood vessels is likely to contribute to the sustained elevation in PVR seen in non-survivors.
https://doi.org/10.1186/s13613-014-0028-6
Agenda
COVID and the heart
COVID and ARDS
COVID and the pulmonary circulation
pulmonary embolism
microthrombi
intrapulmonary shunt
COVID and pulmonary embolism
About 20-25% of COVID patients may present with pulmonary embolism despiteprophylactic anticoagulation with low molecular weight heparin in hospitalizedpatients.
Acute pulmonary embolism can affect segmental / subsegmental pulmonary arteriesor main pulmonary arteries
Acute pulmonary emblism can be asymptomatic or rapidly deteriorate the clinicalpicture (acute cor pulmonale)
DOI: 10.1183/13993003.01365-2020https://doi.org/10.1161/CIRCULATIONAHA.120.047430
DOI: 10.1056/NEJMc2010459
COVID and microthrombi
Microthrombi in the Interalveolar Septa of a Lung from a Patient Who Died from Covid-19
DOI: 10.1056/NEJMoa2015432
COVID and intrapulmonary shunt
“As shown in our first 16 patients, a respiratory system compliance of 50 ± 14 ml/cm H2O is associated with a shunt fraction of 0.50 ± 0.11. Such a wide discrepancy is virtually never seen in most forms of ARDS.
Relatively high compliance indicates a well-preserved lung gas volume in this patient cohort, in sharp contrast to expectations for severe ARDS.”
https://doi.org/10.1164/rccm.202003-0817LE
L phenotype vs H phenotype
a CT scan acquired during spontaneous breathing. The cumulative distribution of the CT number is shifted to the left (well-aerated compartments), being the 0 to − 100 HU compartment, the non-aerated tissue virtually 0. Indeed, the total lung tissue weight was 1108 g, 7.8% of which was not aerated and the gas volume was 4228 ml. Patient receiving oxygen with venturi mask inspired oxygen fraction of 0.8. b CT acquired during mechanical ventilation at end-expiratory pressure at 5 cmH2O of PEEP. The cumulative distribution of the CT scan is shifted to the right (non-aerated compartments), while the left compartments are greatly reduced. Indeed, the total lung tissue weight was 2744 g, 54% of which was not aerated and the gas volume was 1360 ml. The patient was ventilated in volume controlled mode, 7.8 ml/kg of tidal volume, respiratory rate of 20 breaths per minute, inspired oxygen fraction of 0.7.
https://doi.org/10.1007/s00134-020-06033-2
Type L COVID-19 pneumonia
• Low elastance: nearly normal compliance with nearly normal amoun of gas in the lung
• Low VA/Q ratio: loss of regulation of perfusion and by loss of hypoxic vasoconstriction
• Low lung weight. Only ground-glass densities are present on CT scan, primarily located subpleurally and along the lung fissures. Consequently, lung weight is only moderately increased
• Low lung recruitability. The amount of non-aerated tissue is very low; consequently, the recruitability is low
Viral infection leads to a modest local subpleural interstitial edema (ground-glass lesions) particularly located at the interfaces between lung structures with different elastic properties, where stress and strain are concentrated. Vasoplegia accounts for severe hypoxemia. The normal response to hypoxemia is to increase minute ventilation, primarily by increasing the tidal volume (up to 15–20 ml/kg), which is associated with a more negative intrathoracic inspiratory pressure.
https://doi.org/10.1007/s00134-020-06033-2
The evolution of the disease: transitioning between phenotypes
The Type L patients may remain unchanging for a period and then improve or worsen.
The possible key feature which determines the evolution of the disease, other than the severity of the disease itself, is the depth of the negative intrathoracic pressure associated with the increased tidal volume in spontaneous breathing.
Indeed, the combination of a negative inspiratory intrathoracic pressure and increased lung permeability due to inflammation results in interstitial lung edema. This phenomenon has been recently recognized as the leading cause of patient self-inflicted lung injury (P-SILI).
Over time, the increased edema increases lung weight, superimposed pressure and dependent atelectasis.
When lung edema reaches a certain magnitude, the gas volume in the lung decreases, and the tidal volumes generated for a given inspiratory pressure decrease
https://doi.org/10.1007/s00134-020-06033-2
Type H COVID-19 pneumonia
High elastance. The decrease in gas volume due to increased edema accounts for the increased lung elastance.
High right-to-left shunt. This is due to the fraction of cardiac output perfusing the non-aerated tissue which develops in the dependent lung regions due to the increased edema and superimposed pressure.
High lung weight. Quantitative analysis of the CT scan shows a remarkable increase in lung weight (> 1.5 kg), on the order of magnitude of severe ARDS.
High lung recruitability. The increased amount of non-aerated tissue is associated, as in severe ARDS, with increased recruitability
https://doi.org/10.1007/s00134-020-06033-2
Therapeutic implications
Type L patient responds well to an increase in FiO2 , particularly if not yet breathless
In Type L patients with dyspnea, several noninvasive options are available: high-flow nasal cannula (HFNC), continuous positive airway pressure (CPAP) or noninvasiveventilation (NIV). High Positive End-Expiratory Pressure (PEEP), in some patients, may decrease the pleural pressure swings and stop the vicious cycle that exacerbates lung injury. However, high PEEP in patients with normal compliance may have detrimental effects on hemodynamics. In any case, noninvasive options are questionable, as they may be associated with high failure rates and delayed intubation, in a disease which typically lasts several weeks.
Once intubated and deeply sedated, the Type L patients, if hypercapnic, can be ventilated with volumes greater than 6 ml/kg (up to 8–9 ml/kg), as the high compliance results in tolerable strain without the risk of VILI.
The PEEP should be reduced to 8–10 cmH2O, given that the recruitability is low and the risk of hemodynamic failure increases at higher levels. An early intubation may avert the transition to Type H phenotype.
Type H patients should be treated as severe ARDS, including higher PEEP, if compatible with hemodynamics, prone positioning and extracorporeal support
https://doi.org/10.1007/s00134-020-06033-2
COVID and oxygen sensing
the presentation of COVID-19 patients is atypical of ARDS in that the hypoxemia is often profound without appropriate dyspnea (“happy hypoxemia”).
These traits suggest a failure of the body’s homeostatic O2-sensing system(HOSS), which includes the pulmonary circulation, carotid body, adrenomedullarycells, and neuroepithelial bodies.
The HOSS optimizes oxygen uptake and systemic oxygen delivery. Hypoxicpulmonary vasoconstriction (HPV) is the pulmonary circulation’s homeostaticresponse to airway hypoxia in lung diseases, such as pneumonia. HPV constrictspulmonary arteries (PA) serving hypoxic lung segments, diverting blood to betterventilated alveoli, optimizing ventilation/perfusion (V/Q) matching. The carotidbody senses hypoxemia, increasing respiratory drive.
https://doi.org/10.1161/CIRCULATIONAHA.120.047915
COVID and oxygen sensing
SARS-CoV-2 infection of human cells changes expression of many proteins. Interestingly, 36% of all upregulated proteins and 19% of all downregulated proteins in SARS-CoV-2-infected cells are mitochondrial proteins2
These include apoptosis mediators (apoptosisinducing factor and cytochrome C) and proteinsinvolved in aerobic metabolism (relevant to the mechanism of O2-sensing). These findings are associations, not proofs; however, they offer biologicplausibility that SARS-CoV-2 may interfere with mitochondrial O2-sensing and cause mitochondrial-induced injury.
In severe COVID-19 pneumonia there are features of ARDS, but the consequences are exacerbated by loss of HPV, whether because of the viruses’ effects on mitochondria or the ability of endotoxin and inflammatory stimuli to obliterate HPV.
https://doi.org/10.1161/CIRCULATIONAHA.120.047915
Lung perfusion abnormalities in COVID
https://doi.org/10.1016/S1473-3099(20)30367-4
Intussusceptive angiogenesis in the lungof COVID patients
Panels A and B show scanning electron micrographs of microvascular corrosion casts from the thin-walled alveolar plexus of a healthy lung (Panel A) and the substantial architectural distortion seen in lungs injured by Covid-19 (Panel B). The loss of a clearly visible vessel hierarchy in the alveolar plexus is the result of new blood-vessel formation by intussusceptive angiogenesis. Panel C shows the intussusceptive pillar localizations (arrowheads) at higher magnification. Panel D is a transmission electron micrograph showing ultrastructural features of endothelial cell destruction and SARS-CoV-2 visible within the cell membrane (arrowheads) (the scale bar corresponds to 5 μm). RC denotes red cell.
DOI: 10.1056/NEJMoa2015432
Intussusceptive angiogenesis in COVID
DOI: 10.1056/NEJMoa2015432
Sprouting vs intussusceptive angiogenesis
https://doi.org/10.1159/000338278
https://doi.org/10.1002/dvdy.20184
Intussusceptive microvascular growth circumscribes the process of initiation of pillar formation and their subsequent expansion with the result that the capillary sur-face area is greatly enhanced.
DOI: 10.1007/s10456-009-9129-5
Pulmonary hemodynamics in COVID
Twenty-one mechanically-ventilated COVID-19 patients with ARDS (median age 67 [60-70], 86% men)
Left ventricular wall thickness was higher (interventricular septum: 12 [11-13] vs 11 [10-12] mm, p=0.024), and concentric remodeling was more frequent (77% vs 24%; p<0.001) in COVID-19 patients than in controls.
In COVID-19 patients, the cardiac index was higher than in control subjects (3.8 [2.7-4.5] vs 2.4 [2.1-2.8] L/min/m2, p<0.001). Also Qs/Qt was higher in COVID-19 patients than in controls (0.35 [0.28-0.45] vs 0.13 [0.06-0.17], p<0.001), and inversely related to lung compliance (r=-0.57, p=0.011).
Caravita S et al, submitted
Pulmonary hemodynamics in COVID
Although COVID-19 patients had severely reduced lung compliance (31 [24-42] mL/cmH2O) and severe respiratory failure, their pulmonary vascular resistance was normal and similar to that of control subjects (1.6 [1.1-2.5] vs 1.6 [0.9-2.0] WU, p=0.343).
Pulmonary hypertension was present in 76% of COVID-19 and in 19% of control subjects (p<0.001), and it was always post-capillary. Pulmonary artery wedge pressure was inversely related to lung compliance (r=-0.46, p=0.038).
Caravita S et al, submitted
COVID-19 and ARDS: a vicious circle between the lung and the heart ?
Caravita S et al, submitted
