Today, Dr. Nhat Pham took us through the pathophysiology for and evidence behind SGLT2 inhibitor use in our patients with nephropathy. Here is a review:

What are SGLT2 inhibitors and how do they work to control blood glucose in our diabetic patients? 

SGLT2 is a sodium/glucose cotransporter expressed in the proximal tubules of the kidney. Its function is to reabsorb sodium and glucose after they are filtered through the glomerulus. When we inhibit SGLT2 with these medications, it results in significant natriuresis, glucosuria, and associated osmotic diuresis. This lowers blood glucose by losing more serum glucose in the urine, but only modestly, resulting in Hemoglobin A1C reduction of only 0.5-0.8%. Three SGLT2 inhibitors are currently available in the United States: empagliflozin (Jardiance), canagliflozin (Invokana), and dapagliflozin (Farxiga). 

Why are the SGLT2 inhibitors SUCH a hot topic lately?

Recent trials (EMPA-REG, CANVAS, CREDENCE, and DAPA-HF among others) have shown improvement in not only glycemic control, but also cardiovascular and renal outcomes above that which is expected from their effect on A1c. There are many theories on the mechanism by which these meds improve cardiovascular outcomes (improved afterload by changing vascular structure and function, improved cardiac metabolism via ketogenesis, inhibition of myocardial Na/H exchange, decrease in cardiac fibrosis and necrosis, and uric acid metabolism), but it is not clear what is actually driving this decrease in mortality. It is clear that something beyond just their diuretic effect is at play.

We went over the following 2 trials:

The CANVAS/CANVAS-R trials took over 10,000 patients with type 2 diabetes and known CAD or elevated risk of CAD and randomized them to receive high dose Canagliflozin (300mg) or placebo. The results showed a decrease in cardiovascular mortality, decrease in heart failure admissions, decreased nonfatal stroke, decreased nonfatal MIs, decreased progression to ESRD, and slower decline in GFR. Some adverse effects were highlighted in the trial including lower extremity amputation, mycotic genital infections, and volume depletion from osmotic diuresis.

The CREDENCE trial took over 4 thousand patients with DM2 and albuminuria and randomized them to lower dose Canagliflozin (100mg). These patients were already on ACEI/ARBs for at least 4 weeks prior to initiation of the trial. Canagliflozin was found to decrease the progression of GFR decline so significantly that it was stopped early due to clear benefit. This trial did not show an increase in lower extremity amputation risk.

How do they delay decline in GFR in our patients with diabetic nephropathy?

In diabetes, chronically elevated serum glucose levels cause lots of glucose to be filtered through the glomerulus. This upregulates SGLT2 expression in the proximal tubule, causing it to reabsorb more and more glucose and sodium in a process called hyperfiltration. The macula densa then senses a low sodium concentration in the distal tubule, making it think the kidneys are being hypoperfused, and signals the afferent arterial to vasodilate. This causes increased pressure in the glomerulus due to increased blood flow, which over time causes scarring and nephron loss, eventually leading to a decrease in GFR.

SGLT2 inhibitors alter the physiology of diabetic nephropathy through a mechanism called tubuloglomerular feedback (or TG feedback for short). By inhibiting the upregulated reabsorption of glucose and sodium by SGLT2 in the proximal tubule, we increase the amount of sodium that the macula densa senses in the distal tubule. It no longer thinks the kidneys are hypoperfused, but thinks that they are getting too much blood flow and signals the afferent arteriole to vasoconstrict. This decreases the pressure in the glomerulus, preventing some of the scarring and nephron loss that occurs with hyperfiltration.

How do they interact with ACEI/ARBs?

ACEI/ARBs are the mainstay of therapy for diabetic nephropathy and have a robust body of evidence supporting their use to prevent progression to ESRD. They work by decreasing glomerular pressure via dilating the efferent arteriole. All of our patients with diabetic nephropathy should be on ACEI/ARBs if they can tolerate them. The effects of SGLT2 inhibitors are thought to be synergistic, as evidenced by the added renal benefit of SGLT2 inhibitors in patients already on ACEI/ARBs.

What are the adverse effects of SGLT2 inhibitors and how seriously should we take them?

The data is still emerging on SGLT2 inhibitors and more studies are necessary to fully understand how we should look at each of these adverse effects, but some are widely accepted. These medications do cause a significant diuretic effect and do require a reduction in baseline diuretic regimen upon initiation to avoid overdiuresis. In addition, there is an initial reduction in GFR (or AKI) that is to be expected from the reduction in glomerular pressure from vasoconstriction of the afferent arteriole. Dr. Pham considers an increase in Cr of 20% or less acceptable. An increase in the incidence of mycotic genital infections is also an accepted consequence of thees medications.

The FDA has a boxed warning about SGLT2 inhibitors’ increase in risk of lower limb amputation, which is a significant concern for our diabetic patients. This effect was not seen in the CREDENCE trial, but more studies are needed to evaluate fully the extent of this risk. For now, Dr. Pham doesn’t prescribe these meds to patients with current diabetic foot ulcers. Some sources recommend caution in patients with known peripheral vascular disease as well.

Other potential risks include bone fractures, hyperkalemia, euglycemic DKA, Fournier’s gangrene, and UTIs.

So who should we be prescribing these medications to?

The American Diabetes Association abridged their recommends considering these medications early in your patients with HFrEF (EF <45%) and CKD with GFR 30-60. They recommend consideration of these medications after starting metformin and lifestyle modifications regardless of baseline A1c or A1c target.

On Wednesday, we went over an interesting case of esophageal rupture with Dr. Vibha Mohindra. She took us through the case step by step, letting us hear her differential and how different pieces of data changed how she viewed the case and prompted her to ask different questions.

Our patient was an elderly gentleman with a history of diabetes, hypertension, and osteoarthritis on chronic NSAIDs who presented with days of progressive, nonspecific chest pain. Shortly after presentation, he had an episode of hematemesis and subsequently experienced rapid respiratory and hemodynamic decompensation, requiring emergency intubation, high doses of multiple vasopressors, and broad spectrum antibiotics. Subsequent imaging revealed a large left pleural effusion, which was found to be a Candida empyema after chest tube placement. Fungal empyemas are most commonly a postoperative complication of cardiothoracic surgery, but also occur in esophageal rupture. Interestingly, this patient’s pleural cytology later showed thick proteinaceous material intermixed with inflammatory cells and vegetable material. Gastrograffin swallow study revealed extravasation of constrast outside of the GI tract into the left pleural space and mediastinum, confirming a distal esophageal perforation. Cardiothoracic surgery was consulted for repair.

Esophageal perforation is an extremely rare, but potentially fatal diagnosis. 15% of esophageal perforations are considered spontaneous (Boerhaave’s syndrome). The following is our illness script for Esophageal rupture:

Epidemiology:

• VERY rare (3 cases per million per year)
• 15% of those are spontaneous (Boerhaave’s)

Signs/symptoms:

• Excruciating retrosternal chest pain
• Odynophagia, dyspnea, and sepsis
• Crepitus on palpation of the chest wall
• Hamman’s sign (mediastinal crackling with each heartbeat esp in left lateral decub position)

Diagnosis: 

• Established by contrast esophogram (gastrograffin is first line given its water solubility, barium causes a mediastinitis)
• Clues:
  • CXR: mediastinal widening, mediastinal air, hydropneumothorax.
  • Pleural fluid with undigested food, elevated salivary amylase level, and pH <6

Treatment:

• Strict NPO
• IV broad spectrum abx
• IV PPI
• Drainage of fluid collections and debridement of necrotic tissue if present.
• Surgical repair.
• After recovery, EGD with esophageal biopsies should be performed to find any underlying pathology (malignancy, eosinophilic esophagitis, etc)

Yesterday we went over a case of pancytopenia in an elderly woman, found to have severely hypocellular bone marrow consistent with a diagnosis of aplastic anemia. Below are the main teaching points from the discussion:

PLATELET TRANSFUSION: 

Prophylactic Platelets Transfusion: To prevent spontaneous bleeding in high risk patients.

• Transfuse if platelets <10
• Avoid prophylactic platelet transfusion in patients with consumptive platelet disorders like DIC or TTP unless they are undergoing invasive procedures requiring platelet transfusion
• Consider transfusing at a higher platelet number if:
  • patient had a previous spontaneous bleed at a certain platelet count above 10
  • coexisting inflammation, infection, and fever (some sources suggest a platelet goal of 20-30 for septic patients)

Platelet Transfusion for Bleeding Patients: To aid in hemostasis

• Transfuse with a platelet goal of >50
• If there is CNS bleeding, transfuse with a platelet goal of >100
• Platelet transfusions should be given to bleeding patients with consumptive platelet disorders such as DIC or TTP

APLASTIC ANEMIA:

Aplastic anemia is a rare disorder with a high mortality if left untreated. In essence, it is the asymptomatic autoimmune destruction of hematopoietic stem cells in the bone marrow, leading to severe pancytopenia and its associated complications. Medications, radiation, toxic chemicals, viral infections, autoimmune disorders,  pregnancy, anorexia nervosa, and paroxysmal nocturnal hemoglobinuria can all trigger this autoimmune process, in theory by altering our stem cells in such a way that our immune system attacks them. Here is the illness script for aplastic anemia:

An important note about antithymocyte globulin is that it is a polyclonal antibody to human T cells manufactured from horse serum (or alternatively, rabbit serum). It must be given with prednisone and premedication with acetaminophen and diphenhydramine to reduce the risk of serum sickness. Skin testing for hypersensitivity to horse serum prior to administration is recommended.

When caring for our aplastic anemia patients, early evaluation for stem cell transplant is important. If they are eligible for transplant and a donor search is initiated, it is important to avoid any unnecessary transfusions to decrease sensitization for host antigens and reduce risk of future transplant rejection.

Yesterday, we discussed transfusion reactions and went through the difference between TRALI and TACO, which can both cause respiratory distress within 6 hours of a blood transfusion, but are very different entities. Here’s a handy table to help you remember the differences:

Fever DDx (MISO!)

• Malignancy/Infection/Systemic Vascular/Other

Hypertheremia DDx (NEED!)

• Neurologic/Endocrine/Environmental/Drugs

In clinical practice, impossible to tell the difference between fever (raising of the body’s set point) and hypertheremia (failure of thermoregulation)

*Sincere thanks to Dr. Julie Lee for correcting a critical error in the table!

Today we discussed a variety of topics, and most excitingly, revealed that our inpatient anti-infective therapy guideline is now published on HHSConnect on the ASP page.

Same disclaimer applies: we have no direct clinical experience dealing with COVID+ patients and information has been taken from a variety of excellent resources as listed in the prior post. We make no claims for originality!

Pathophysiology and Stages of COVID

This is key folks. There seems to be a early viral replication phase, followed by a later dysregulated inflammatory response phase marked by ARDS and a cytokine storm. In the early phase, antiviral therapy may be much more helpful than delayed initiation. Once the late phase has arrived the mainstay of treatment will likely be immune-modulating agents (anti-IL6 agents and steroids..more on this later.

Modes of Transmission of COVID

• Droplet (main)
• Airborne
• Contact

Yes, you read that correctly. There is evidence that aerosolization does occur and therefore in our hospital, we use a N95/face shield for all PUIs and confirmed patients – a move we strongly believe will improve the safety of our healthcare workers (HCWs)

https://www.nejm.org/doi/full/10.1056/NEJMc2004973

• Air – 3 hours
• Copper – 4 hours
• Cardboard 24 hours
• Stainless steel – 2-3 days
• Plastic – 3 days [we should all be cleaning our work surfaces as frequently as possible]

Airway Management Prior to Intubation

• Goal SpO2 92-96% when on supplemental O2
• In our institution, O2 may be escalated to NRB at 6LPM, after which ICU should be consulted for ‘refractory’ hypoxia when the SpO2 <92%
• Our hospital discourages HFNC/NIPPV due to aerosolization risk and encourages early intubation, a position consistent with many other organizations, including MGH
• We discussed the data from SARS however that there is no definitive evidence that HFNC places HCWs at increased risk, and in fact, the act of intubation is linked with increased risk of HCWs.
• The six risk factors that placed HCW at highest risk for contracting SARS were:
  • minimum distance between beds of 1 m
  • availability of washing or changing facilities for staff
  • whether resuscitation was ever performed in the ward
  • whether staff members worked while experiencing symptoms
  • whether any host patients required oxygen therapy [of any kind]
  • whether any host patients required bi-level positive airway pressure ventilation
• SCCM position – “For adults with COVID-19 and acute hypoxemic respiratory failure despite conventional oxygen therapy, we suggest using HFNC over conventional oxygen therapy”
• ANZICS position –“High flow nasal oxygen (HFNO) therapy (in ICU): HFNO is a recommended therapy for hypoxia associated with COVID-19 disease, as long as staff are wearing optimal airborne PPE. The risk of airborne transmission to staff is low with well fitted newer HFNO systems when optimal PPE and other infection control precautions are being used. Negative pressure rooms are preferable for patients receiving HFNO therapy.”
• In summary, while early intubation is the official policy of our institution, I would not be surprised if during a surge, HFNC may be used to prevent intubation and protect a scarce resource for those who need it the most
• Once your O2 <92% on 6L O2 – for now, call your consultant for likely early intubation

Sources:

a. ‘Why Did Outbreaks of Severe Acute Respiratory Syndrome Occur in Some hospital Wards But Not in Others – Yu et al in Clinical Infectious Diseases 2007

b. Risk Factors for SARS Transmission from Patients Requiring Intubation: A Multicentre Investigation in Toronto, Canada – PLOS1 2010

Pharmacological Therapies

• Hydroxychloroquine + Azithromycin – Marseille Study – Gautret et al
  • Tiny study of 20 patients in France found that on Day 6, Tx group individuals showed a much lower than average PCR positive compared to untreated controls
  • This effect was magnified by the addition of Azithromycin
  • Reasonable dosing is currently HCQ 400 BID x 1 day, followed by 200mg q12rs x 5 – 10 days. Azithromycin is 500mg x 1d followed by 250mg daily
  • There is a long list of contraindications, including QT prolongation to be aware of and G6PD deficiency for HCQ
  • https://www.mediterranee-infection.com/wp-content/uploads/2020/03/Hydroxychloroquine_final_DOI_IJAA.pdf
  • Who Should Get It?
    • Our ASP guideline states those with moderate-severe COVID SHOULD receive it while PUIs who are deteriorating quickly should also receive it
• Remdesivir
  • antiviral drug developed as a treatment for Ebola and Warburg virus
  • Gilead suspended compassionate use and restricted it to clinical trial use only so we will withhold discussing this for now
• Lopinavir+Ritonavir
  • NEJM study of 199 patients with laboratory confirmed SARS-CoV-2 infection underwent randomization and no difference in clinical improvement and mortality for the 28 days that patients were tracked
  • https://www.nejm.org/doi/pdf/10.1056/NEJMoa2001282?articleTools=true
• Anti-IL6 Therapy – Tocilizumab
  • During a potential cytokine storm, this medication may be crucial, but studies are underway
• Steroids – Consider Giving During Dysregulated Immune/ARDS Phase
  • Controversial, as early use thought to increase viral shedding – but my personal opinion is consistent with one of our ICU doctors,  that there is evidence for its use in critically ill patients [i.e in the later phase once ARDS develops
  • Other guidelines state to withhold unless other indication for steroid develops but this is not consistent with strong evidence from the following study that showed a significant survival benefit to acutely ill patients who did receive methylprednisolone
  • https://jamanetwork.com/journals/jamainternalmedicine/fullarticle/2763184
• ACEi/ARBs – Continue!
  • There is concern that ACEi/ARB use association with increase in expression of ACE2, which is the binding site of the virus BUT it is unknown what exactly that finding means and the European Society of Cardiology issues an extremely strongly worded statement that in the absence of any evidence that it actually leads to acquisition/transmission of the virus, that patients should continue their RAAS inhibition
  • In fact, some have even postulated an anti-inflammatory benefit
  • Bottom lines – insufficient evidence and no one knows
• NSAIDs – No conclusive evidence
  • A variety of mechanisms have been postulated, WHO states insufficient evidence to recommend discontinuation
• Fluids – AVOID excessive administration

That’s all for now, much of what was said will likely change. Thank you all for your incredible dedication to each other and to our patients. You all are heroes and I am so proud of you.

Today, Dr. Hakim is presenting a case of COVID-19 infection. We wanted to take this opportunity to give a general overview of COVID-19 and the available data. Just a quick disclaimer: we have extremely limited clinical experience in the treatment of COVID-19 and the following information is collected from various resources and articles. We anticipate that the details of COVID-19 will continue changing rapidly and the information here may become out of date very quickly.

ILLNESS SCRIPT:

Epidemiology: Median age is 47, slight male predominance (41.9% are female)

Symptoms and Signs of COVID-19: There are 7-9 large studies documenting signs and symptoms of COVID-19 infection with most data coming from China. The largest study, recently published in NEJM: Clinical Characteristics of Coronavirus Disease 2019 in China- W. Guan, Z. Ni, Yu Hu, et al. 

The most common symptoms of COVID-19 are fever and cough. These symptoms may not be present on admission. 

Systemic symptoms: Fever, fatigue, myalgias, anorexia, dizziness, headache

Respiratory symptoms: Dry cough, dyspnea, expectoration, pharyngalgia

GI symptoms: Diarrhea, nausea, vomiting, and abdominal pain

***There is no reliable way to distinguish influenza, other viral respiratory infections, and COVID-19 by symptoms alone. 

Incubation Period: median of 4 days, range up to 14 days

Lab Findings: White blood cell counts can vary!! Leukocytosis and leukopenia are reported.

• Lymphopenia (absolute lymphocyte count <0.8) is the most common finding, but is extremely nonspecific as it occurs in many viral infections
• Elevated LDH (>245), ferritin (>300), AST/ALT, troponin, and D-dimer (>1000) have all been reported
• Procalcitonin is not elevated in most patients with COVID19 according to the Guan et al study cited above

Imaging: 

• CXR may show infiltrates, but it really depends on the degree of respiratory symptoms
• Chest CT most commonly shows bilateral peripheral ground-glass opacities (GGOs), and “crazy paving” in some instances
  • “Crazy paving”= GGOs with superimposed septal thickening
• Imaging is NOT specific, but can add to your clinical picture and rule out non-pneumonia etiologies of respiratory distress

Diagnosis here at SCVMC:

• ALL persons under investigation (PUIs) for COVID should be on airborne and contact precautions
• Order Flu/RSV reflex to SARS-CoV2
• Always notify Dr. Stephanie Chan and Dr. Jen Eng when COVID testing is sent via SecureChat message
• If your patient is high risk or will need aerosolizing procedures (nebulized medications, sputum induction, open suctioning of airways, BIPAP/CPAP, HFNC, intubation, bronchoscopy), they should be admitted to a negative pressure room

Sensitivity and Specificity of Testing:

• Sicker patients are thought to have higher viral loads and are more likely to have positive test results
• Sensitivity is thought to be around 75% for swab PCR testing and there is evidence that CT scan may show disease sooner than PCR positivity. BAL has higher sensitivity than swab testing.
• Repeat testing can be performed if necessary

Coinfection:

• In China, the coinfection rate with COVID-19 and other viruses was thought to be low (1-5%), but data from Stanford University, show that >20% of patients had a coinfection with another virus

Key Resources for further COVID-19 Information:

UpToDate COVID19 article

EMCrit- Internet Book of Critical Care

MedCram.com COVID videos