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      COVID-19: 10 things I wished I’d known some months ago

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          Abstract

          The COVID-19 pandemic is ongoing and spreading, affecting individuals in over 200 countries now. While COVID-19-related articles are being published every day, including guidelines of optimal clinical management [1], there are several practical issues that we wished we had known earlier. This viewpoint addresses 10 points that may be of interest both the logistics, as well as actual clinical care of critically ill COVID-19 patients. We stay away from items that are self-evident and will not address aspects of treatment that are explicitly described elsewhere [1]. Crisis management in the ICU and planning to surge capacity It cannot be stressed enough to prepare and anticipate [2–5]. Discuss logistics of upscaling the number of ICU beds and necessary resources (both equipment and personnel) required to treat these patients as early as possible, as both will become limited. There needs to be alignment with the hospital board of directors about allocation of resources, as shortage of ICU nurses means that healthcare providers working in the operation room and anesthesiology department are needed in the ICU, implying that other (non-urgent, elective) tasks need to be down-scaled or stopped. (Risk of) shortage of personal protective equipment imposes a huge psychological pressure on medical staff and updates should be communicated transparently. Personnel management Start training residents, non-ICU nurses in advance [2]. Apart from ICU-related matters that non-ICU personal need to become familiar with, adherence to infection control precautions is paramount. Also, a clear policy to allow/not allow healthcare providers with a medical history that may increase their vulnerability to COVID-19 to work in the COVID-unit should be communicated. Personnel will be confronted with moral dilemmas and may experience fear and anxiety that deserves attention. Peer-support and moral deliberation meetings help. Care-providers are extremely motivated and want to work hard, but, if feasible, try to facilitate days-off as well. Intensivists should act as leaders and therefore delegate as much as possible: ‘Everything someone else can do as well should not be done by you.’ For example, ask competent colleagues to take care of patient transport, vascular access, intubations [2–5]. In some settings, an ‘airway team’ or ‘vascular access team’ may tremendously facilitate intensivists. The value of conventional biomarkers Generally speaking, patients come in with a high CRP and low PCT. Over the days, typically CRP decreases, while short-lived increases in PCT may be observed that appear not to relate to bacterial infection [6]. There is highly fluctuating fever. Typically, patients that can be extubated ‘early’ (after approximately 10 days) show decreasing CRP and temperature kinetics. Presentation with a bacterial or opportunistic co-infection appears to be uncommon. However, if a co-infection is suspected, e.g., because of progressive shock or multiple organ failure, empirical therapy using antibiotics with activity against both typical and atypical respiratory pathogens should be considered. Cytokine elevation profiles appear reminiscent of secondary hemophagocytic lymphohistiocytosis (HLH), or macrophage activation syndrome (MAS). However, while ferritin values are clearly elevated, in the vast majority of patients, this is less than one would observe during MAS. D-dimer values may reach extremely high levels, and hypercoagulation is discussed in the next paragraph. The hidden problem: hypercoagulation and thrombosis There is a high incidence of thrombosis and pulmonary embolism [7–9]. In accordance, for patients on renal replacement therapy, the lifespan of filters appears to be much shorter compared to bacterial sepsis patients with AKI. There should be a low threshold to scan for pulmonary embolism, especially in patients that show a rapid and significant increase in their D-dimer level or a sudden increase in dead-space ventilation. Also, a spontaneous prolongation of the prothrombin or activated partial thromboplastin time appears to be a predictor of thrombotic complications [8]. Massive pulmonary embolism with acute circulatory arrest may be the first presentation of COVID-19. Some have advocated to use therapeutic anticoagulation in all patients, but this is clearly not without risks. Physicians should be vigilant as cerebral bleeding following anticoagulation may occur [10]. Doubling the thrombo-prophylactic dose in COVID-19 patients could be considered. Cardiac involvement Most COVID-19 patients display only mild hemodynamic instability. However, especially patients with preexistent cardiovascular disease are prone to hemodynamic decompensation. In addition to acute coronary syndrome, fulminant myocarditis may occur, with reduced systolic function, accounting for a large percentage of early deaths [11, 12]. Overall mortality is significantly higher in individuals with high TnT compared to those with normal TnT levels. However, severe pulmonary hypertension is not frequently present in the early phase of acute respiratory failure. Pharmacological treatment Antiviral, immunomodulating and other compounds with possible therapeutic efficacy are discussed elsewhere [1]. So far, no specific treatment has shown clinical benefit. Use of unproven therapies requires informed consent and clearly also carries risks that should be discussed with the patient/family [13], while desperation may drive physicians to try therapies that are backed by little or no evidence. The difficult choice between this urge to treat (‘just-do-it option’) and the urgent need to generate knowledge on what actually works (‘must-learn-option’) is clear, but there are ways to blend these options [14]. The use of steroids during refractory shock is advocated [1], but this rarely occurs. Apart from this indication, later during the course some patients show a decrease in lung compliance in combination with high dead-space ventilation, suspect for development of fibrosis. As in other cases of ARDS, one may consider steroids in this subgroup of patients as well [15] Mechanical ventilation Endotracheal intubation is indicated for the usual thresholds. Both HFNO and NIV may be tried, but patients that are unable to decrease their respiratory drive as measured by esophageal pressure have a very high risk for failure [16]. Considering mechanical ventilation, one size does not fit all. COVID-19 patients may present with divergent pathological features ranging from the so-called L-type (low elastance, low driving pressure) to the H-type (high elastance, high driving pressure) [17]. Although the former appears to be more prevalent during the initial phase, this may change during the course of the disease [18]. Ultrasound could help at the bedside in identifying the different patterns [19]. The potential for recruitment for the L-type appears to be limited. Mechanical ventilation should be tailored to the mechanical lung properties. Lower PEEP and prolonged proning in case of severe hypoxia should be considered for L-type. The H-type may benefit from higher PEEP levels. Following the acute phase, pressure support mode is feasible in prone position. In our opinion this is safe, if an excessive respiratory drive is monitored by using P0.1, Pmus or transpulmonary pressure. Excessive respiratory drive may result in ‘patient-self-inflicted lung injury’ (P-SILI) and explain the transition from the L- to the H-type [17]. The thing nobody wants to think about It is extremely important that a triage decision system is agreed upon before an overwhelming number of critically ill patients flood ICU capacity and additional resources [20]. Deciding between two patients that under normal circumstances would both receive critical care treatment will pose an immense burden on those involved in decision making. We think that a triage decision team including intensivists, geriatricians, ethicists, nurses and lawyers should operationalize guidelines issued by a national Critical Care Society, achieve consensus with different medical specialists, nursing organizations and patient representatives and prepare the hospital for this worst-case scenario. Full immunity from prosecution and moral support for those involved are essential components of this process. Management of the tsunami of research ideas, email spamming and info-overload Clearly, intensive care physicians should be sure to keep informed of the evolving knowledge related to new insights into the new disease and its treatment [21], while at the same time, huge logistic challenges (that are extremely time-consuming) present themselves. National societies could play a role in providing cyclic updates in guidelines or establish a committee that selects clinically relevant papers and distribute these among their members. For research in this specific patient population, the risk of a situation like this is that too many sub-optimally designed, small (and therefore statistically underpowered) interventional studies are initiated and we may end with no clinically relevant answers. From the start of the outbreak, dozens of emails with suggestions for treatments were/will be sent to all of us. Central coordination and prioritizing is useful and will increase the chances of performing meaningful studies [22]. Post-intensive care follow-up Post-intensive care follow-up should be organized early. A large step-down facility is needed as the number of tracheostomized patients with severe muscular weakness will likely be immense. If ignored, discharge from the ICU will not be possible. We also need to organize nursing homes and rehabilitation centers that can facilitate, e.g., care for patients with a tracheal cannula. Psychological support should be offered early on because the lack of human contact caused by personal protection clothing and visitor limitations will likely result in a higher incidence of post-traumatic stress disorder, anxiety and depression in COVID-19 patients, as well as their families. Longer-term consequences are for now largely unknown but will present themselves in the near future. Concluding general remarks Current times in the ICU are unprecedented. During this pandemic, we are learning about a new disease and its treatment and optimal support, and knowledge is evolving by the day. Logistic challenges are immense and time-consuming, and information overload is a threat. We wished to provide a summary of our first experience with critically ill COVID-19 patients, 10 things that in our view were relatively underexposed in previous publications (Fig. 1). Fig. 1 Summary of previously underexposed issues related to COVID-19 Electronic supplementary material Below is the link to the electronic supplementary material. Supplementary material 1 (PPTX 49 kb)

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          Incidence of thrombotic complications in critically ill ICU patients with COVID-19

          Introduction COVID-19 may predispose to both venous and arterial thromboembolism due to excessive inflammation, hypoxia, immobilisation and diffuse intravascular coagulation. Reports on the incidence of thrombotic complications are however not available. Methods We evaluated the incidence of the composite outcome of symptomatic acute pulmonary embolism (PE), deep-vein thrombosis, ischemic stroke, myocardial infarction or systemic arterial embolism in all COVID-19 patients admitted to the ICU of 2 Dutch university hospitals and 1 Dutch teaching hospital. Results We studied 184 ICU patients with proven COVID-19 pneumonia of whom 23 died (13%), 22 were discharged alive (12%) and 139 (76%) were still on the ICU on April 5th 2020. All patients received at least standard doses thromboprophylaxis. The cumulative incidence of the composite outcome was 31% (95%CI 20-41), of which CTPA and/or ultrasonography confirmed VTE in 27% (95%CI 17-37%) and arterial thrombotic events in 3.7% (95%CI 0-8.2%). PE was the most frequent thrombotic complication (n = 25, 81%). Age (adjusted hazard ratio (aHR) 1.05/per year, 95%CI 1.004-1.01) and coagulopathy, defined as spontaneous prolongation of the prothrombin time > 3 s or activated partial thromboplastin time > 5 s (aHR 4.1, 95%CI 1.9-9.1), were independent predictors of thrombotic complications. Conclusion The 31% incidence of thrombotic complications in ICU patients with COVID-19 infections is remarkably high. Our findings reinforce the recommendation to strictly apply pharmacological thrombosis prophylaxis in all COVID-19 patients admitted to the ICU, and are strongly suggestive of increasing the prophylaxis towards high-prophylactic doses, even in the absence of randomized evidence.
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            High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study

            Little evidence of increased thrombotic risk is available in COVID-19 patients. Our purpose was to assess thrombotic risk in severe forms of SARS-CoV-2 infection.
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              COVID-19 pneumonia: different respiratory treatments for different phenotypes?

              The Surviving Sepsis Campaign panel recently recommended that “mechanically ventilated patients with COVID-19 should be managed similarly to other patients with acute respiratory failure in the ICU [1].” Yet, COVID-19 pneumonia [2], despite falling in most of the circumstances under the Berlin definition of ARDS [3], is a specific disease, whose distinctive features are severe hypoxemia often associated with near normal respiratory system compliance (more than 50% of the 150 patients measured by the authors and further confirmed by several colleagues in Northern Italy). This remarkable combination is almost never seen in severe ARDS. These severely hypoxemic patients despite sharing a single etiology (SARS-CoV-2) may present quite differently from one another: normally breathing (“silent” hypoxemia) or remarkably dyspneic; quite responsive to nitric oxide or not; deeply hypocapnic or normo/hypercapnic; and either responsive to prone position or not. Therefore, the same disease actually presents itself with impressive non-uniformity. Based on detailed observation of several cases and discussions with colleagues treating these patients, we hypothesize that the different COVID-19 patterns found at presentation in the emergency department depend on the interaction between three factors: (1) the severity of the infection, the host response, physiological reserve and comorbidities; (2) the ventilatory responsiveness of the patient to hypoxemia; (3) the time elapsed between the onset of the disease and the observation in the hospital. The interaction between these factors leads to the development of a time-related disease spectrum within two primary “phenotypes”: Type L, characterized by Low elastance (i.e., high compliance), Low ventilation-to-perfusion ratio, Low lung weight and Low recruitability and Type H, characterized by High elastance, High right-to-left shunt, High lung weight and High recruitability. COVID-19 pneumonia, Type L At the beginning, COVID-19 pneumonia presents with the following characteristics: Low elastance. The nearly normal compliance indicates that the amount of gas in the lung is nearly normal [4]. Low ventilation-to-perfusion (VA/Q) ratio. Since the gas volume is nearly normal, hypoxemia may be best explained by the loss of regulation of perfusion and by loss of hypoxic vasoconstriction. Accordingly, at this stage, the pulmonary artery pressure should be near normal. 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 [5]. To conceptualize these phenomena, we hypothesize the following sequence of events: the 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 [6]. Vasoplegia accounts for severe hypoxemia. The normal response to hypoxemia is to increase minute ventilation, primarily by increasing the tidal volume [7] (up to 15–20 ml/kg), which is associated with a more negative intrathoracic inspiratory pressure. Undetermined factors other than hypoxemia markedly stimulate, in these patients, the respiratory drive. The near normal compliance, however, explains why some of the patients present without dyspnea as the patient inhales the volume he expects. This increase in minute ventilation leads to a decrease in PaCO2. 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, initially described by Barach in [8] and Mascheroni in [9] both in an experimental setting, has been recently recognized as the leading cause of patient self-inflicted lung injury (P-SILI) [10]. 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 [11]. At this stage, dyspnea develops, which in turn leads to worsening P-SILI. The transition from Type L to Type H may be due to the evolution of the COVID-19 pneumonia on one hand and the injury attributable to high-stress ventilation on the other. COVID-19 pneumonia, Type H The Type H patient: 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 [12]. High lung recruitability. The increased amount of non-aerated tissue is associated, as in severe ARDS, with increased recruitability [5]. The Type H pattern, 20–30% of patients in our series, fully fits the severe ARDS criteria: hypoxemia, bilateral infiltrates, decreased the respiratory system compliance, increased lung weight and potential for recruitment. Figure 1 summarizes the time course we described. In panel a, we show the CT in spontaneous breathing of a Type L patient at admission, and in panel b, its transition in Type H after 7 days of noninvasive support. As shown, a similar degree of hypoxemia was associated with different patterns in lung imaging. Fig. 1 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 Respiratory treatment Given this conceptual model, it follows that the respiratory treatment offered to Type L and Type H patients must be different. The proposed treatment is consistent with what observed in COVID-19, even though the overwhelming number of patients seen in this pandemic may limit its wide applicability. The first step to reverse hypoxemia is through an increase in FiO2 to which the Type L patient responds well, 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 noninvasive ventilation (NIV). At this stage, the measurement (or the estimation) of the inspiratory esophageal pressure swings is crucial [13]. In the absence of the esophageal manometry, surrogate measures of work of breathing, such as the swings of central venous pressure [14] or clinical detection of excessive inspiratory effort, should be assessed. In intubated patients, the P0.1 and P occlusion should also be determined. High 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. The magnitude of inspiratory pleural pressures swings may determine the transition from the Type L to the Type H phenotype. As esophageal pressure swings increase from 5 to 10 cmH2O—which are generally well tolerated—to above 15 cmH2O, the risk of lung injury increases and therefore intubation should be performed as soon as possible. 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. Prone positioning should be used only as a rescue maneuver, as the lung conditions are “too good” for the prone position effectiveness, which is based on improved stress and strain redistribution. 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. In conclusion, Type L and Type H patients are best identified by CT scan and are affected by different pathophysiological mechanisms. If not available, signs which are implicit in Type L and Type H definition could be used as surrogates: respiratory system elastance and recruitability. Understanding the correct pathophysiology is crucial to establishing the basis for appropriate treatment.
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                Author and article information

                Contributors
                peter.pickkers@radboudumc.nl
                Journal
                Intensive Care Med
                Intensive Care Med
                Intensive Care Medicine
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0342-4642
                1432-1238
                3 June 2020
                3 June 2020
                : 1-4
                Affiliations
                [1 ]GRID grid.10417.33, ISNI 0000 0004 0444 9382, Department of Intensive Care Medicine, , Radboud University Medical Center, ; Internal Mail 710, PO Box 9101, 6500HB Nijmegen, The Netherlands
                [2 ]GRID grid.10417.33, ISNI 0000 0004 0444 9382, Radboud Center for Infectious Diseases, , Radboud University Medical Center, ; Internal Mail 710, PO Box 9101, 6500HB Nijmegen, The Netherlands
                [3 ]GRID grid.7563.7, ISNI 0000 0001 2174 1754, School of Medicine and Surgery, , University of Milano - Bicocca, ; Milan, Italy
                Author information
                http://orcid.org/0000-0002-1104-4303
                Article
                6098
                10.1007/s00134-020-06098-z
                7268592
                515038dd-770b-445e-abad-62112af107d6
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.

                History
                : 21 April 2020
                : 8 May 2020
                Categories
                What's New in Intensive Care

                Emergency medicine & Trauma
                Emergency medicine & Trauma

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