April 30, 2020: Care of the Critically Ill Pregnant Woman with COVID-19
Contributors: Kathleen Zacherl, MD
Physiologic Changes in Pregnancy
- Increase by 48% at term
- Increase in Tidal Volume
- Due to increase in minute ventilation by 20-40%.
- Increase O2 Consumption by 20%
- FEV1 unchanged
- Functional Residual Capacity decrease by 18% - most trouble in 3rd trimester
- ** This causes Respiratory Failure faster than nonpregnant.
- RR>24 can indicate need for respiratory support in pregnancy.
- Decrease Pulmonary Vascular Resistance by 34%
- Decrease Colloid Osmotic Pressure by 14% (but up to 50% in preeclampsia)
- Compensated Respiratory Alkalosis
- Hypoxia can cause uterine contractions
Respiratory Distress in Pregnancy
- PAO2/FiO2 <300: Acute Respiratory Failure.
- SpO2< 95% concerning in Pregnancy.
- RR≥30 concerning in pregnancy.
- Intubate Early - AW difficult in pregnancy due to swelling
- Use smaller ET tube.
- 8x increased risk of failure to intubate in pregnancy.
- Video laryngoscope may be necessary, esp if obese.
- Caution if full stomach - increased risk aspiration in pregnancy.
- Peak Pressures
- Can be falsely elevated due to enlarged breasts in pregnancy—can reposition patient to help improve.
- O2 sat goal ≥ 92-95% in pregnancy
- CO2 goal
- Too much permissive hypercapnia could affect the fetus (balance with benefit to pregnant patient). Joint decision with ICU/OB teams.
- Can be used in pregnancy.
- Favorable outcomes in pregnancy in case report.
Viral Pneumonia in Pregnancy
- H1N1: 4x more likely to be admitted.
- SARS: Maternal death rate 25% in some countries.
- Case reports on severe ARDS in pregnancy.
- Overall, data suggests respiratory complications appear similar to general population.
Delivery Considerations and Fetal Monitoring
- No data delivery improves maternal outcomes in ARDS. Decrease in O2 requirements, but no change in lung compliance. 
- Physiologic changes of labor, delivery, and postpartum can cause higher potential for endothelial dysfunction, pulmonary edema, myocardial edema, and cardiac dysfunction. 
- Consider if >34 weeks and expect prolonged illness. 
- Need to be prepared for urgent delivery via C-section in ICU if maternal decompensation. OB team has crash/perimortem C/S cart available.
- Will attempt delivery in Main OR if patient able to be transferred. Make contingency plans for locations of delivery upon admission to ICU.
- Will be determined by joint decisions with OB, MFM, ICU teams.
- May need continuous fetal monitoring in ICU. Only do continuous monitoring if plan to intervene for decelerations or nonreassuring tracing. Can consider intermittent monitoring.  Decide in corroboration with MFM team.
- See attached chart.
- High doses - 12mg IM q24h x 2 used to help decrease neonatal complications in pregnant women with high risk of delivering prematurely.
- Would reconsider if patient is higher risk for steroids, such as on vent for >14d.
- Single Course only, do not give >34 weeks.
- Joint decision between ICU and OB teams.
- Magnesium Sulfate
- Used in preterm pregnant mothers at high risk of preterm delivery to improve fetal neurological outcomes or in preeclampsia for seizure prevention.
- Use if benefits outweigh risk of pulmonary edema and respiratory suppression.
- Can improve bronchospasm associated with intubation.
- Joint decision between ICU and OB teams.
- Tocolysis (preterm labor medications)
- Nifedipine preferred med in COVID-19 pregnant patients: caution if pt is hypotensive.
- Indomethacin: case by case, weighed against potential risk of NSAIDS in COVID-19.
- Not contraindicated in pregnancy.
- Expect to cause changes in fetal heart rate: lower baseline and flat tracing.
- Helps to decrease maternal O2 consumption, so can tolerate baby’s flat tracing.
- Current options for treatment of Remdesivir, Chloroquine, Hydrochhloroquine, Azithromycin are all options in pregnancy if being considered by ICU/ID teams.
- Goal to improve V/Q mismatch.
- Feasibility has been documented in pregnant women, case reports of success but data is limited.
- Need to cushion maternal gravid abdomen (pregnancy mattress on order for this).
- Pregnancy is a hypercoagulable state.
- Would follow similar guidelines for anticoagulation as in the nonpregnant population, but hold if delivery is imminent. Consider UFH antepartum in case of need for urgent delivery and balance of bleeding concern with coagulopathy.
Other Conditions in Pregnancy
- COVID-19 labs can mimic HELLP syndrome in pregnancy.
- COVID-19 can elevate BP via ACE2 and be confused with preeclampsia.
- Schnettler, William T., Ahwel, Y, Suhag, A. Severe ARDS in CVID-19-infected pregnancy: obstetric and intensive care considerations. Am J Obstet Gynecol. 2020 Apr 14; Epub ahead of print.
- DiMascio D, Khalil A, Saccone G, et al. Outcome of coronavirus spectrum infections (SARS, MERS, COVID-19) during pregnancy: A systemic review and meta-analysis. Am J Obstet Gynecol. 2020 Mar 25; Epub ahead of print.
- Graves, C, Goffman D, Halscott T, Dombrowski M. COVID-19 and ICU: Respiratory Failure in Pregnancy. Webinar, Society of Maternal Fetal Medicine. 2020 Mar 25.
- Juusela A, Nazir M, Gimovsky M. Two cases of COVID-19 related cardiomyopathy in pregnancy. Am J Obstet Gynecol. 2020 Mar; Epub ahead of print.
- Dennis AT, Hardy L, Leeton L. The prone position in healthy pregnant women and in women with preeclampsia- a pilot study. BMC Pregnancy Chilbirth. 2018 Nov 16; 18 (1): 445.
- Ray B, Trikha A. Prone position ventilation in pregnancy: concerns and evidence. J Obstet Anesth Crit Care. 2018 Jan-June; 8 (1) 7-9.
- Ashokka B, Loh M-H, Tan CH, SU LL, Young BE, Lye DC, Biswas A, E Illanes S, Choolani M, Care of the Pregnant Woman with COVID-19 in Labor and Delivery: Anesthesia, Emergency cesarean delivery, Differential diagnosis in the acutely ill parturient, Care of the newborn, and Protection of the healthcare personnel, Amer J Obstet Gynecol. 2020 Mar 25.
April 30, 2020: SARS-COVID-2 and Acute Kidney Injury (AKI)
Contributors: Ibrahim Elali, MD
Rate of AKI reported in SARS-CoV-2 patients is around 5-8% 1,2,3,4, some with urinary manifestations (proteinuria, albuminuria, hematuria), with or without evidence of AKI. Outcome data is generally lacking, especially in patients with underlying CKD. Past experiences with CoV (SARS CoV, MERS) kidneys involvement are not very well understood.
Pathogenesis of the AKI could be in the setting of either sepsis - cytokine storm syndrome, direct cellular injury due to the virus, or a combination of both.
SARS-CoV2 and AKI
- Hematuria ~ 28%, proteinuria 44% (even massive albuminuria) reported in patients during hospitalization4
- Mortality risk, ICU admission and mechanical ventilation all increased when AKI present4
- Virus most likely binds to ACE-2 receptor, which is highly expressed in the brush border of proximal tubular cells, less in podocytes, and not in glomerular endothelial and mesangial cells
- Post mortem tissue analysis showed evidence of virus in tubular epithelium and podocytes. Parenchymal infection of tubular epithelial cells and podocytes, with marked acute tubular injury and sometimes necrosis. No evidence of vasculitis, interstitial inflammation or hemorrhage5
SARS-CoV, and MERS-CoV and AKI
- Acute kidney injury (AKI) developed in ~ 7 % of SARS-CoV cases and carried a high ~ 92% mortality rate vs ~ 9% if no renal impairement6
- Post mortem renal tissue analysis did not detect SARS-COV ultrastructurally, yet PCR fragments of CoV found in urine in 21-50% of patients. Pathology findings consistent with ATN in all samples with no evidence of glomerular involvement or interstitial infiltrate6
- Angiotensin converting enzyme-2 and dipeptidyl peptidase-4, both expressed on renal tubular cells, were identified as likely binding partners for SARS-CoV and MERS-CoV7
- MERS-CoV associated AKI, limited statistical data available, not very common in general, no post mortem renal tissue data found7
Early screening for possible viral kidney involvement in otherwise relatively stable patient. In addition to routine blood tests, obtain complete automated urinalysis testing with microscopic urine sediment examination, urine protein creatinine ratio, urine microalbumin creatinine ratio, sodium, creatinine, and urea nitrogen in random urine samples. Establish early intervention strategy to avoid complications.
- D. Wang et al., JAMA. 2020:323(11):1061-1069.
- A.J. Rodriguez-Morales et al., Travel Medicine and Infectious Disease, 2020, March 13:101623.
- W. Guan, NEJM, Feb. 28, 2020.
- Y. Cheng et al., Kidney International, Mar 202.
- H. Su et al., Kidney International, Apr 2020.
- KH Chu et al., Kidney International, 2005 Feb;67(2):698-705.
- I. Eckerle et al., Virology Journal, 2013, 10:359.
April 30, 2020: Cytokines and Endotoxins Removal via Extracorporeal Therapy in SARS-CoV-2 Positive Patients
Contributors: Ibrahim Elali, MD
On April 10, 2020, the FDA approved an “emergency use” procedure for cytokine removal in the critically ill SARS-CoV-2 patients that was previously not available in the U.S. It is delivered via the Spectra Optia Apheresis system using an adsorption cartridge (CytoSorb). Briefly, the technology involves a non-selective extracorporeal cytokine adsorber. Previously used mainly as an adjunct therapy to treat cytokine storm in critically ill and cardiac surgery patients, but can also be used in other non infectious hyperinflammatory conditions like trauma, burns, etc. Currently, strong data supporting the clinical implementation of such technology are lacking, mainly because of non-selective removal of cytokines whereby some can act as an inflammatory agonist while others act as antagonists1,2. Data in the CoV-2 clinical setting are also limited and mostly coming from China1.
On April 14, 2020, the FDA approved another “experimental” emergency use procedure to remove endotoxin. The procedure has been used in the treatment of septic shock patients outside the U.S. for almost 2 decades. The procedure involves the passage of blood through a “PMX” cartridge using a standard hemodialysis or continuous renal replacement therapy machine. The PMX cartridge contains polymyxin B immobilized on the surface of the fibers and will adsorb and remove the endotoxin circulating in the blood. It can clear almost 90% of circulating endotoxins with 2 treatments. Two previous RCTs showed some mortality benefit4,5, yet with higher endotoxin activity assay (EAA) > 0.9 the benefit seems to disappear6. Recently with CoV-2 outbreak, there are reports that endotoxins have been detected through the EAA test in this patient population. Data on the exact origin of the endotoxin are not available. No outcome data available in the CoV-2 population, with some limited use reported outside the U.S., mainly in Japan and Italy.
In summary, neither of the 2 procedures have a consistent track record, but in severely ill patients refractory to traditional care and high endotoxin level, the 2 procedures that might have a benefit and can be used as “adjunct therapy” is either the polymyxin B hemoperfusion or standard therapeutic plasma exchange, both therapies can effectively remove endotoxins and might ultimately influence the cytokine production and hence the outcome, yet neither procedure is supported by a solid clinical data in this population.
- Friesecke S et al., Med Klin Intensivmed Notfmed, Sep 2017.
- Schadler D et al., PLOS ONE. 2017;12(10).
- Zhang Y et al., Engineering, March 20, 2020.
- Cruz DN et al., JAMA. EUPHAS, 2009;301:2445-52.
- Klein DJ et al., Intensive Care Medicine, 2018.
- Dellinger RP et al., JAMA. EUPHRATES, 2018;320(14):1455-63.
April 13, 2020: Role of Thrombosis in COVID-19 Patients and Use of Anticoagulants
Contributors: Michael Blechner, MD, Blood Bank Medical Director, UConn Health
Coagulopathy has been a significant management issue in ICU COVID patient. Current evidence suggests a possible increase in risk for VTE and DIC, confirmed by autopsy findings of pulmonary microthrombi in Wuhan.
Elevated D-dimer on admission or 3-4-fold increase over time, associated with high mortality (Tang et al.). Limited data suggests ~20% decrease in mortality with prophylactic anticoagulation in most severe patients (Tang et al.).
Patients with significantly elevated D-dimers should be considered for admission even in the absence of other signs and symptoms
Worsening of DIC labs (PLT, PT, aPTT, D-dimer, fibrinogen) indicates progressive severity and suggests need for more aggressive care, experimental therapies might be considered
What Is the Role for Anticoagulation?
- Pharmacologic prophylaxis for all patients unless CI
- Not therapeutic anticoagulation unless VTE (Recommendations for therapeutic anticoagulation from China may be skewed by settings where prophylactic anticoagulation was not used)
- Mechanism for thrombosis likely multifactorial – SAR, stasis, endothelial damage
- Anti-inflammatory properties of heparin
- Bidirectional relationship between immune response and thrombin generation
- Blocking thrombin generation with heparin may blunt the inflammatory response
- Heparin binds and sequesters acute phase proteins including inflammatory cytokines and histones that can cause endothelial damage
- Antiviral role of heparin studied in animal models showed possible interactions with spike protein. It is possible that spike protein is cleaved by FXa and FIIa and thus anticoagulation might inhibit infectivity
- All COVID-19 positive in-patients should receive pharmacological thromboprophylaxis unless otherwise contraindicated
- For CrCl > 30: LMWH or fondaparinux
- For CrCl < 30 or AKI: UFH 5,000 units SC BID or TID
- Immobilized patients can also benefit from intermittent pneumatic compression
- Use mechanical thromboprophylaxis only if platelets < 30,000
- Abnormal coagulation test results are not a contraindication in the absence of bleeding
- Should be held for platelet count < 25,000 or fibrinogen < 50 mg/dL
- Therapeutic anticoagulation has no known benefit and is not recommended unless documented VTE
- Consider switching to therapeutic levels of LMWH or UFH for patients taking oral anticoagulants due to drug interactions (covid19-druginteractions.org) and easier reversal of anticoagulation
- Patients with significantly elevated D-dimers should be considered for admission even in the absence of other signs and symptoms
- Worsening of DIC labs (PLT, PT, aPTT, D-dimer, fibrinogen) indicates progressive severity and suggests need for more aggressive care … experimental therapies might be considered
Management of Bleeding
- FFP: 12-15 ml/kg (typically I unit for every 20 kg or 4 units in an adult) for PT or PTT > 1.5 times upper limit of normal or INR > 1.8
- Consider 4F-PCC (KCentra) for patients with significant volume issues
- Platelets: 1 dose for platelet count < 50,000
- Cryoprecipitate: 2 doses (10 pooled units) for fibrinogen < 150 mg/dL
- Abnormal coagulation test results do not require correction in non-bleeding patients
Management of Coagulopathy in DIC
- Typically, not associated with bleeding, but active bleeding should be managed as above
- Non-bleeding patients
- Cryoprecipitate: 2 doses (10 pooled units) for fibrinogen < 150 mg/dL
- Platelets: 1 dose for platelet count < 30,000
- ISTH (International Society on Thrombosis and Haemostasis) COVID-19 Resource Page
- ASH (American Society of Hematology) COVID-19 Resources Page
- Thachil, J et al, ISTH interim guidance on recognition and management of coagulopathy in COVID‐19, peer reviewed and accepted for publication in J Thromb Haemost.
- Tang, N et al, Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy, J Thromb Haemost. 2020.
- Wang, J et al, Tissue Plasminogen Activator (tPA) Treatment for COVID-19 Associated Acute Respiratory Distress Syndrome (ARDS): A Case Series, J Thromb Haemost. 2020 Apr 8.
- Liu, X, et al, Therapeutic effects of dipyridamole on COVID-19 patients with coagulation dysfunction, not yet peer reviewed, accessed from medRxiv.
April 13, 2020: Cancer Care During the COVID-19 Pandemic
Contributor: Bradford Whitcomb, MD
Cancer care has been disrupted worldwide due to the COVID-19 pandemic. Areas most impacted in the United States have adjusted treatment approaches to those with new malignancies and with recurrences to reduce transmission to these more susceptible patients. There is limited information regarding specific treatment recommendations at this time, but early information from cancer patients affected by COVID in China revealed an increased risk of infection and severity. A more recent pooled meta-analysis reiterated the risk in these patients (ref).NCCN, ASCO, and other societies (such as the Society of Gynecologic Oncology) have made broad recommendations for care of our malignancy population which we have mostly adopted to our practice at UConn Health. Specific treatment, or delay of treatment, is very individualized, of course, and would defer to the patient and provider to formulate the ultimate plan. This is also dependent on the COVID infection curves in the specific region in which the patient is being treated. More importantly, we must plan ahead for after the first wave. We will be very busy with surgeries and new diagnoses in the summer, but also need to be prepared for a seasonal resurgence of the virus.
Yu J, Ouyang W, Chua MLK, Xie C. SARS-CoV-2 Transmission in Patients With Cancer at a Tertiary Care Hospital in Wuhan, China. JAMA Oncol. Published online March 25, 2020. doi:10.1001/jamaoncol.2020.0980
Zheng, L. et al. Clinical characteristics of COVID-19-infected cancer patients: A retrospective case study in three hospitals within Wuhan, China. Ann. Oncol. (2020).
Liang, W., Guan, W., Chen, R., Wang, W., Li, J., Xu, K., . . . He, J. (2020). Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China. Lancet Oncol, 21(3), 335-337. doi:10.1016/S1470-2045(20)30096-6
Sidaway, P. COVID-19 and cancer: what we know so far. Nat Rev Clin Oncol (2020).