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?COVID-19 Interim Practice Guidelines 4. 28.2020Steroids in cytokine storm in COVID19: Cytokine storm appears to be a major driver of mortality in COVID-19. A diagnosis of cytokine storm is based on the presence of severe respiratory failure plus abnormalities in ferritin, C-reactive protein, D-dimer, lactate dehydrogenase (LDH), and absolute lymphocyte count. Patients with COVID-19 and cytokine storm are at high risk of death without aggressive therapy; therefore, we recommend treating cytokine storm. Low-dose steroids are inadequate to quell inflammation in these patients.Recommendation is to use 60-125 mg IV methylprednisolone q6hr for up to 3 days for cytokine storm related to COVID-19, with tapering as soon as the C-reactive protein starts to fall. Steroids are not indicated for COVID-19 prior to cytokine storm. However, if a patient with COVID-19 has another indication for steroids such as an asthma or COPD exacerbation, it is appropriate to use steroids for another indication if necessary.Tube feed administration/nutrition on proned patients: There are some questions regarding whether to provide enteral nutrition (EN) to patients who are in a prone position. This is due to risk of gastrointestinal (GI) intolerance characterized by aspiration, vomiting, or increased volume of gastric residuals. There is limited evidence evaluating the safety and tolerability of enteral nutrition provided to patients in a prone position. Among the studies that have been published, results suggest that enteral nutrition provided to patients in a prone position did not increase the risk of GI intolerance compared to enteral nutrition provided to patients in a supine position. Furthermore, there are no significant differences in aspiration risk between patients who are fed via nasogastric tube versus post-pyloric tube during rotational therapy. Monitoring for signs/symptoms of feeding intolerance is key if planning to feed a patient in a prone position. Recommendation: There are no clinically relevant differences of gastric residual volume observed in prone and supine position; therefore, tube feeding should continue in patients who are mechanically ventilated and proned. The use of strategies to reduce enteral feeding intolerance such as prokinetic agents can be considered. The placement of post-pyloric feeding tubes should be done only as clinically indicated as the placement of post-pyloric tubes may increase potential virus exposure. TPN should be used only when clinically indicated with EN intolerance and should be maximally concentrated. The concern is increased volume input and the COVID population typically do better with an even or negative fluid balance. When EN is introduced during prone positioning, the recommendation is to keep the head of the bed elevated (reverse Trendelenburg) to at least 10-25 degrees to decrease risk of aspiration of gastric contents, facial edema and intra-abdominal hypertension. APRV mode of mechanical ventilation use in COVID-19 patients: A primary physiologic problem in COVID appears to be de-recruitment, which is well managed by APRV. The benefit of APRV is that it provides support and patient can be extubated successfully, while avoiding paralysis, proning, deep sedation, inhaled pulmonary vasodilators or ECMO. Experience from physicians in Italy and New York shows that patients are typically weaned from 100% FiO2 to 50% FiO2 on APRV within 6-12 hours as they slowly recruit. As such, APRV may be an economical mode which may reduce drug expenditures (e.g., cisatracurium) and limit the expenditure of PPE (e.g., proning a patient exposes many people repeatedly and consumes lots of PPE). Failure to respond to APRV within 12-24 hours of initiation (e PaO2/FiO2 < 150) would be a strong argument to move towards prone ventilation (discussed here). However, when started early APRV may be more likely to succeed – thereby avoiding the need for proning. Avoid in patient with severe obstructive disease as APRV can exacerbate auto-peeping. Recommendation: APRV is a safe mode that is best used on the initial onset of intubation. The mode is not as useful as a salvage mode as most patients are switching from a conventional mode with deep sedation levels and are already failing conventional mechanical ventilation. Therefore, the recommendation is to use APRV as an initial mode instead of a salvage mode in COVID-19 respiratory failure. Additionally, APRV allows for much lower doses of sedation. If a P:F ratio remains < 150 within 12-24h then proceed to prone ventilation.Zinc therapy in Covid: A 2010 study led by University of Leiden Medical researchers in the Netherlands sought to understand how zinc inhibited that replication. The team reported that zinc inhibits a cousin of SARS-CoV-2: SARS-CoV, the original SARS of the 2003 outbreak. Zn inhibits viral RNA dependent RNA polymerase (replicase). Of note, Zn is a ++ extracellular ion that requires active transport to pass across the cell membrane. It so happens that Chloroquine and hydroxychloroquine are zinc ionophores, thus provides zinc++ with a transport mechanism. Recommendation: Based on the codependence of Zinc and hydroxychloroquine, the recommendation is to co-administer Zinc 220mg BID with Hydroxychloroquine if Zinc is available. Acetazolamide therapy in Covid: There have been observations of deranged respiratory parameters in Covid-19 and high-altitude pulmonary edema (HAPE). Therefore, medications used in HAPE have been proposed as possible treatment in COVID-19. Furthermore, it is hypothesized that beginning early treatment with HAPE medications may prevent ARDS development. There is a paucity of high evidence level information regarding the use of acetazolamide in Covid-19 patients and its use has been anecdotal at best. Recommendation: It is reasonable to consider use of acetazolamide 250mg Q12h early in the course of Covid-19 when patients are managed with nasal canula or HFNC. If the patient progresses to endotracheal intubation, discontinue acetazolamide since its potential role is to prevent ARDS. It is appropriate to use acetazolamide for its usual indication of metabolic alkalosis with diuresis. It is recommended to monitor acid-base status with an ABG or VBG (if the patient is hemodynamically stable) for patients that are on acetazolamide.Hypercoagulability approach: COVID-19 disease has an associated hypercoaguable state with large vessel thrombosis such as DVT/PE, microvascular thrombosis and arterial events such as stroke. Approach to management is as follows:Recommendations: For algorithm, please see separate document for anticoagulation approach to COVID-19DVT ProphylaxisInitiate pharmacologic prophylactic anticoagulation therapy for all PUI patients unless otherwise contraindicatedIf CrCl > 30: Lovenox 40 mg SC dailyIf CrCl < 30 or AKI: Heparin 5000 units SC TIDHold if Platelets <30,000 or bleeding, start TEDs and SCDsTreatment of confirmed PE/DVTLMWH is preferred, to minimize blood draws and has superior efficiency in critical care population [10]. (See Dosing Guidelines for special populations and alternatives for renal failure) Patients who need to be on Unfractionated Heparin (instead of LMWH) should be monitored with antiXa levels** (as opposed to PTT given that the latter increases in severely ill COVID-19 patients and may render the PTT unreliable.) If the patient is on direct oral anticoagulants (DOACs) or Warfarin for VTE or Afib, switch to full dose anticoagulation (LMWH or UFH, as indicated based on renal function or clinical scenario).Concern for PE and DVTIf possible, obtain US and if + DVT, treat with full dose anticoagulation or if possible, obtain point of care ECHO and if evidence of acute, otherwise unexplained right heart strain, or intra-cardiac thrombus, treat with full dose anticoagulation. If patient unable to get US or ECHO due to concern of staff exposure to COVID-19 and clinical suspicion for PE remains high, we would suggest treating with full dose anticoagulation (unless contraindicated) over obtaining any diagnostics testingEmpiric treatment based on hematologic markersPreliminary data from Wuhan suggest that a higher intensity of LMWH or UFH above prophylactic doses may be of benefit in those patients with severe COVID-19 and D-dimer levels > 6 times the upper limit of normal (Tang et al, JTH, Mar 27, 2020). Many institutions (Duke, MGH,UNC) are choosing threshold values upon which to start systemic anticoagulation around a D-dimer >1,500 ng/mL(1.5ug/ml)- 2,500 ng/mL (2.5 mcg/mL) and fibrinogen >800 mg/mL. Please see the anticoagulation document for frther details.Post-discharge anticoagulation: There is a possible benefit of continuing some level of anticoagulation upon discharge for patients that are at higher risk of thrombosis. Patients who were admitted for COVID-19: Apixiban 2.5mg bid or Xarelto 10mg once daily for 30 days or until patient is mobilePatients who were admitted for issue unrelated to COVID-19 but found to have a positive test: consider Apixiban 2.5mg bid or Xarelto 10mg once daily especially if at higher risk for VTE including age >75, hospital admission >2 days, In ICU, have cancer diagnosis, h/o previous VTE or have D-Dimer >2X normal before dc home.**There is no nursing driven protocol for Xa levels and UFH; if your patient is on UFH gtt and you are monitoring Xa levels, you will need to follow and order hep gtt changes. ReferencesBlaser AR, Starkopf J, Alhazzani W et al. Early enteral nutrition in critically ill patients: ESICM clinical practice guidelines. Intensive Care Med. 2017;43:380-398.McClave SM, Taylor B, Martindale R, et al. Guidelines for the provision and assessment of nutrition support therapy in the adult critically ill patient: Society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (ASPEN). JPEN J Parenter Enteral Nutr. 2016;40(2):159-211.Linn DD, Beckett RD, Foellinger K. Administration of enteral nutrition to adult patients in the prone position. Intensive and Crit Care Nurs. 2015;31(1):38-43.Saez de la Fuente I, Saez de la Fuente J, Estelles MDQ et al. Enteral nutrition in patients receiving mechanical ventilation in a prone position. JPEN J Parenter Enteral Nutr.2016;40(2):250-255.Reignier J, Dimet J, Martin-Lefevre L, et al.Before-after study of a standardized ICU protocol for early enteral feeding in patients turned in the prone position. Clin Nutr.2010;29(2):210-216.Sams VG, Lawson CM, Humphrey CL et al. Effects of rotational therapy on aspiration risk of enteral feeds. Nutr Clin Pract. 2012;27(6):808-811. Cortegiani A, Ingoglia G, Ippolito M, Giarratano A, Einav S. A systematic review on the efficacy and safety of chloroquine for the treatment of COVID-19. J Crit Care. 2020 Mar 10. pii: S0883-9441(20)30390-7. doi: 10.1016/j.jcrc.2020.03.005. [Epub ahead of print]Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends. 2020 Mar 16;14(1):72-73. doi: 10.5582/bst.2020.01047. Epub 2020 Feb 19.Dong L, Hu S, Gao J. Discovering drugs to treat coronavirus disease 2019 (COVID-19). Drug Discov Ther. 2020;14(1):58-60. doi: 10.5582/ddt.2020.01012.Kruse RL. Therapeutic strategies in an outbreak scenario to treat the novel coronavirus originating in Wuhan, China. F1000Res. 2020 Jan 31;9:72. doi: 10.12688/f1000research.22211.2. eCollection 2020. Review.Song P, Karako T. COVID-19: Real-time dissemination of scientific information to fight a public health emergency of international concern. Biosci Trends. 2020 Mar 16;14(1):1-2. doi: 10.5582/bst.2020.01056. Epub 2020 Feb 25.Lake MA. What we know so far: COVID-19 current clinical knowledge and research. Clin Med (Lond). 2020 Mar;20(2):124-127. doi: 10.7861/clinmed.2019-coron. Epub 2020 Mar 5. Review.Cunningham AC, Goh HP, Koh D. Treatment of COVID-19: old tricks for new challenges. Crit Care. 2020 Mar 16;24(1):91. doi: 10.1186/s13054-020-2818-6.Pathological findings of COVID-19 associated with acute respiratory distress syndrome. (Epub ahead of print) Xu Z, Shi L, Wang Y, et al. Lancet Respir Med. 2020Solaimanzadeh I. Acetazolamide, Nifedipine and Phosphodiesterase Inhibitors: Rationale for Their Utilization as Adjunctive Countermeasures in the Treatment of Coronavirus Disease 2019 (COVID-19). Cureus. 2020;12(3):e7343. Published 2020 Mar 20. doi:10.7759/cureus.7343 Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, et al China Medical Treatment Expert Group for Covid-19. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020 Feb 28. doi: 10.1056/NEJMoa2002032. Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020 epublished Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395: 497-506. 4. Fei Zhou, Ting Yu, Ronghui Du et al. ................
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