Tranexamic Acid and GI Bleeding

Tranexamic acid is often used to reduce bleeding, particularly after surgery and may reduce bleeding-related death in patients with trauma. It remains unclear if tranexamic acid reduces deaths in patients who present with acute GI bleeding.

An international, multicenter, randomized, placebo-controlled trial examined this question. Adult patients with acute GI bleeding were randomly assigned to either a loading dose of 1 g tranexamic acid, which was added to 100 mL infusion bag of 0·9% sodium chloride and infused by slow intravenous injection over 10 min, followed by a maintenance dose of 3 g tranexamic acid added to 1 L of any isotonic intravenous solution and infused at 125 mg/h for 24 h, or placebo (sodium chloride 0·9%). The primary outcome was death due to bleeding within 5 days of randomization. 12 009 patients were randomly allocated to receive tranexamic acid (5994, 49·9%) or matching placebo (6015, 50·1%).

Death due to bleeding within 5 days of randomization occurred in 222 (4%) of 5956 patients in the tranexamic acid group and in 226 (4%) of 5981 patients in the placebo group (risk ratio [RR] 0·99, 95% CI 0·82-1·18).

Arterial thromboembolic events (myocardial infarction or stroke) were similar in the tranexamic acid group and placebo group (42 [0·7%] of 5952 vs 46 [0·8%] of 5977; 0·92; 0·60 to 1·39).

Venous thromboembolic events (deep vein thrombosis or pulmonary embolism) were higher in tranexamic acid group than in the placebo group (48 [0·8%] of 5952 vs 26 [0·4%] of 5977; RR 1·85; 95% CI 1·15 to 2·98).

In other words, this large clinical trial showed that tranexamic acid did not reduce death from gastrointestinal bleeding but may result in higher venous thromboembolic events. Thus, IV tranexamic acid is not useful in patients with acute GI bleeding.

Prone-Positioning in Non-intubated patients with COVID-19 & acute hypoxic respiratory failure

In non-intubated patients with COVID-19 and acute hypoxic respiratory failure, prone-positioning may result in better oxygenation. The study was single center and performed on 29 patients.

Countries with BCG Vaccinations and COVID-19 Deaths

An interesting study, examining the association of BCG vaccination and risk of COVID-19 deaths using country level data. Authors make a compelling case that there is an association using data from a large number of countries.

Such studies have potential for ecological fallacy – however, there is underlying biological plausibility and further, as we are collecting data on these cases, knowing about patients who had BCG vaccination versus those who did not may help to solidify the evidence in support of BCG. In other words, the evidence in not solid but need further study.

Indeed, clinical trial examining the role of BCG in stimulating immunity and generating resistance is ongoing Australia where they are planning to enroll approximately 4,000 healthcare workers at hospitals across Australia.

Plasma From Recovered Patients Can Help Critically-sick COVID-19 Patients

Interesting case series of 5 patients who received transfusion with plasms from patients who had recovered from COVID-19 infection and had high titers of immunoglobulins against COVID-19. All 5 patients were on ventilator, critically sick, and febrile. With days of receiving plasma, their condition improved. Three of the five have now been discharged while the other two are doing better.

Myocarditis in Novel Coronavirus (COVID-19) Infected Patients

Due to significant similarities between SARS-CoV and COVID-19 virus (also called SARS-CoV-2), ACE2 has been proposed as a possible mechanism of entry and possible lung injury.

ACE2 is also expressed in heart and some studies have shown the ACE2 may play a role in the size of ischemic injury. Hence, one can propose that there may be myocardial injury in patients infected with novel corona virus (COVID-19).

A recently reported study found that the cardiac troponin levels were elevated in many patients, markedly elevated in patients who died, and that some of the patients died due to myocardial damage related to myocarditis. Further, patients with prior cardiovascular disease did poorly. In other words, while majority of patients have lung disease, a significant number of patients may also develop cardiac inflammation.

ACE2 May be a Receptor for COVID-19 Virus Entry into the Cells

Because SARS-COV virus has significant similarities to the COVID-19 virus (also called SARS-CoV-2), it is worth comparing the two viruses for similarities to learn about COVID-19.

SARS-CoV has surface spikes that bind to Angiotensin Converting Enzyme 2 (ACE2) and gain entry into human cells. Once inside the human cell, virus downregulates the further expression of ACE2 on cell surface. Importantly, ACE2 surface expression is important to keep inflammatory response in check and low levels of ACE2 results in increased inflammatory response.

It is quite likely that COVID-19 (SARS-CoV-2) also binds to ACE2 receptors. In fact, there is significant homology in the amino acid and gene sequence of virus spikes. Further, the computer-generated 3-D models show similar structure and maintenance of the binding site.

Thus, one can propose a model similar to SARS-CoV where COVID-19 binds to the ACE2 on surface of pulmonary epithelial cells, downregulates these receptors, worsens local inflammatory responses and leads to the lung disease that we see on lung imaging (particularly on CT scans) that is so prevalent in these patients.

Of note, ACE2 is present on the intestinal epithelial cells luminal surface giving another portal of entry for these patients and presence of diarrhea in some patients with COVID-19. Other places where ACE2 expression is particularly high include heart, kidneys, and testes.

While there are several inhibitors of ACE1 in the market and are one of the most commonly prescribed medications for hypertension, these inhibitors don’t work on ACE2. Further, inhibition of ACE2 might potentially lead to worsening of the disease in these patients.

Other methods that can be tested include vaccinations against the viral spike proteins, inhibition of ACE2 downstream pathways such as TMPRSS2, and delivering excessive amounts of ACE2 (or homologues) to saturate viral surface receptors.

The role of ACE2 as potential anti-inflammatory agent in human body makes developing any vaccine or therapeutic drugs challenging as it is difficult to predict the responses inside our bodies. Because ACE2 pathways are not fully discovered yet, the development of effective treatments with minimal adverse effects likely will be challenging.

Clinical Course of 4 Patients with Coronavirus (COVID-19)

Patients seen from Jan 1, Feb 15, 2020

3 of the 4 patients had cough and fever on presentation; the fourth patients was noted to have CT scan changes which was performed due to history of exposure

Oseltamivir was given to all patients and all patients recovered (difficult to say if it was drug or if it was recovery on their own).

Between 12 and 32 days, all patients became afebrile and had two consecutive negative RT-PCR (diagnostic test for the presence of virus in the body). One patient had some remaining finding on Chest CT by the end of follow up.

Somewhat surprising is that it took  up to 32 days to get rid of virus completely and that a patient may be a carrier up to 32 days. This is in contrast to commonly thought duration of up to 14 days.

Here is the link to the actual study.

COVID-19 (Novel Coronavirus) risk of Pandemic

A recent article estimated the case fatality rate (CFR) 5.3% and 8.4%. While the severity of COVID-19 is not as high as that of other diseases caused by coronaviruses, including severe acute respiratory syndrome (SARS), which had an estimated CFR of 17% in Hong Kong, and Middle East respiratory syndrome, which had an estimated CFR of 20% in South Korea, a 5%–8% risk of death is by no means insignificant. Further, there is strong possibility of presymptomatic transmission with a substantial impact on public health response to the epidemic as well as overall predictability of the epidemic during the containment stage

Peer Observations to Enhancing Bedside Clinical Teaching

In academic medical centers, residents and studies get bedside teaching and direct patients care experience by teaching clinical attendings. To improve their teaching skills, these teaching attendings need feedback on their teaching. Teaching attendings receive feedback through learner evaluations, which has been shown to improve teaching effectiveness, but to provide anonymity to the learner, these evaluations are usually aggregated and given to the attending months later, limiting timely improvements. In addition, learners may lack the framework to give effective feedback on teaching and may base evaluations on a variety of factors, such as a desire to achieve a good grade. It is not uncommon that a learner who received poor feedback during a clinical rotation gives poor evaluations to a teaching attending.

Peer observation with feedback is a solution to the drawbacks of learner evaluation of teaching attendings. Peer observation of teaching behaviors encourages reflection by both the observer and the teaching attending being observed, leading to increased confidence and performance. Peer observation of teaching skills in lecture or small group settings has been evaluated but there is a paucity of studies examining the effect of feedback provided by peers observing the teacher during bedside rounds.

One framework often used is the Stanford Faculty Development Program (SFDP). The SFDP describes seven domains of effective clinical teaching: learning climate, control of teaching session, communication of goals, promotion of understanding and retention, evaluation, feedback, and promotion of self-directed learning. Investigators for this study designed a survey tool using SFDP and used it for peer-observation of teaching skills. Such a study is tedious, time consuming, difficult to do, and requires very engaged faculty who is ready to volunteer significant amount of their personal time for observation.

The survey tool focused on five teaching domains (learning climate, control of session, promotion of understanding and retention, evaluation, and feedback) relevant to the inpatient teaching environment excluding the other two. Teaching attendings were observed at the beginning of a two-week teaching rotation, given feedback, and then observed at the end of the rotation. Overall, they completed 70 observations over 27 teaching attendings. Mean survey tool scores in teaching behavior domains ranged from 2.1 to 2.7. In unadjusted and adjusted analysis, each teaching observation was followed by higher scores in learning climate (adjusted improvement = 0.09; 95% CI = 0.02-0.15; p = 0.007) and promotion of understanding and retention (adjusted improvement = 0.09; 95% CI = 0.02-0.17; p = 0.01). The standardized observation tool had Cronbach’s alpha of 0.81 showing high internal validity.

The study shows that the peer observation of bedside teaching followed by feedback using a standardized tool is feasible and results in measured improvements in desirable teaching behaviors.

Hydrate or not to Hydrate that is the Question

A large amount of previous evidence have suggested that hydration of patients undergoing an intravenous contrast study reduces the risk of kidney injury. However, recently some data suggests that the contrast induced injury may simply be because patients who are undergoing emergent intravenous contrast study are sicker patients and are likely to develop kidney injury irrespective of getting contrast.

Timal and colleagues conducted a randomized controlled trial enrolling 523 patients with stage 2 chronic kidney disease and found that there was no benefit of giving intravenous fluids to patients who were getting intravenous contrast. The study details are here

Another Drug (Interferon beta-1A) is Found to be Ineffective in Patients with Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) is a life-threatening disease. It is characterized by leaky lungs blood vessels resulting in fluid in the lungs (pulmonary edema) which results in low oxygenation of the blood flowing through lungs. Usually, there is an underlying severe disease, often sepsis, that results in ARDS. Currently, the treatment of patients with ARDS is treatment of the underlying cause and supportive care with a hope that lungs will recover on their own.

The main mechanisms underlying underlying ARDS is an uncontrolled inflammatory response resulting in injury to the walls of the lung blood vessels leading to increased leakage of fluids into the lung alveoli. Interferon beta-1A (IBA) has been shown to reduce leakage from blood vessels and dampen inflammatory response. An early study showed some benefit.

A recently reported randomized controlled trial found no benefit of the drug. Investigators did not find any benefit with regard to ventilator free days or 28-day mortality. In fact, if anything, significant number of patients suffered adverse effects. While the study was not effective in showing a benefit, it raised important question about possibility of other therapies affecting the beneficial effect of this drug. In conclusion, more research is needed for this disease for which we have no therapies available.

VITAMINS Trial Presentation and Discussion

Time Sucked Away from Patients by EHRs

Sticking results from this descriptive study – on an average physicians are spending 16 minutes per encounter working with electronic health record. Now you know why your physicians are spending little time with you and always appear in a hurry. They are still very busy, reviewing the chart, ordering tests, and documenting the encounter. Machine has taken over the space between a doctor and a patient.

Obviously, very few (likely none) physicians enjoy spending time away from their patients. However, the regulatory burdens, some national mandates,some state mandates, some regulatory body mandates, and some institutional mandates require increasing documentation. All this increased documentation requirement has been placed without providing any additional time to a physician. As a result, physicians decreased the only discrete time they had – time with the patient.

Most of these mandates are there to make sure that the quality of care delivered is adequate. However, these mandates have worsened physician burnout and are perhaps not improving overall care except only those processes that are being measured.

The Saga of Vitamin C and Septic Shock

Vitamin C has been proposed as a drug that may help patients with sepsis due to its antioxidant effects. Earlier studies have been inconclusive. Another randomized trial was reported this week. Investigators wanted to examine if the combination of vitamin C, hydrocortisone, and thiamine, compared with hydrocortisone alone, improves the duration of time alive and free of vasopressor administration in patients with septic shock.

This was a multicenter studies conducted in 10 ICU in Australia, New Zealand, and Brazil. The study was open label (treating physicians were aware of the therapy), randomized (patients were allocated to the treatment or control arm randomly) clinical trial.  Investigators recruited 216 patients fulfilling the Sepsis-3 definition of septic shock.

Patients in the vitamin C arm (n = 109) received intravenous vitamin C (1.5 g every 6 hours), hydrocortisone (50 mg every 6 hours), and thiamine (200 mg every 12 hours). Patients in the control arm (n = 107) received only intravenous hydrocortisone (50 mg every 6 hours) alone until shock resolution or up to 10 days.

Median time alive and vasopressor free up to day 7 was 122.1 hours (interquartile range [IQR], 76.3-145.4 hours) in the intervention group and 124.6 hours (IQR, 82.1-147.0 hours) in the control group; the median of all paired differences was –0.6 hours (95% CI, –8.3 to 7.2 hours; P = .83). Ninety-day mortality was 30/105 (28.6%) in the intervention group and 25/102 (24.5%) in the control group (hazard ratio, 1.18; 95% CI, 0.69-2.00). No serious adverse events were reported.

The findings strengthen the clinical data, which is in contrast to the basic science data, that vitamin C may have clinical benefit in septic patients. At the minimum, the study findings suggest that treatment with intravenous vitamin C, hydrocortisone, and thiamine does not lead to a more rapid resolution of septic shock compared with intravenous hydrocortisone alone. For some, this might be end of vitamin C story, others may still want to examine vitamin C potential little more.

Vitamin D, Calcium Supplementation, and Bone Fracture Risk

Osteoporosis can be considered an aging process. In a lifetime, osteoporotic fracture affects about 1 in 2 women and 1 in 5 men aged 50 years or older with hip fracture being the most serious type of osteoporotic fracture. Vitamin D is essential for optimal musculoskeletal health because it promotes calcium absorption, mineralization of bone, and maintenance of muscle function. Vitamin D supplementation in several observational studies have been shown to decrease the risk of fracture. Similarly, calcium supplementation has also been shown to be preventive. However, results from the randomized clinical trials, the gold standard for determining if a given therapy is effective or not are lacking.

Yao and colleagues published a systematic review and meta-analysis and pooled data from large observation studies and randomized clinical trials to answer some key questions. In particular, they wanted to assess the risks of fracture associated with supplementation with vitamin D alone or in combination with calcium in RCTs. To identify relevant studies, they searched several medical literature databases: PubMed, EMBASE, Cochrane Library, and other randomized controlled trial databases. The search was from the start of database until December 31, 2018. They selected observational studies involving at least 200 fracture cases and randomized clinical trials enrolling at least 500 participants and reporting at least 10 incident fractures were included.

They identified 11 observational studies with a total number of 39 141 participants who had total of 6278 fractures, out of which 2367 were hip fractures. When they pooled the study results, they found that each increase of 10.0 ng/mL (ie, 25 nmol/L) in vitamin D was associated with an adjusted rate ratio for any fracture of 0.93 (95% CI, 0.89-0.96) and an adjusted rate ratio for hip fracture of 0.80 (95% CI, 0.75-0.86).

They also identified 11 RCTs of vitamin D supplementation alone enrolling 34 243 participants, 2843 fractures of which 740 were hip fractures. These trials did not find any decrease in risk of any fracture with Vitamin D supplementation alone (rate ratio, 1.06; 95% CI, 0.98-1.14). Similarly, there was no decrease in risk of hip fracture (rate ratio, 1.14; 95% CI, 0.98-1.32).

In contrast, a meta-analysis of 6 RCTs (49 282 participants, 5449 fractures, 730 hip fractures) of combined supplementation with daily vitamin D (daily doses of 400-800 IU) and daily calcium (daily doses of 1000-1200 mg) found a 6% reduced risk of any fracture (rate ratio, 0.94; 95% CI, 0.89-0.99) and a 16% reduced risk of hip fracture (rate ratio, 0.84; 95% CI, 0.72-0.97).

The final word: If you take vitamin D and/or calcium to reduce the risk of osteoporosis and osteoporotic fractures, you should take both calcium and vitamin D supplements together. Taking just one medication is unlikely to decrease fracture risk.

Physician Burnout and Self-perception of Medical Errors

Another study was just published examining the relationship between surgeon burnout and self-perceived medical errors. As expected, they found a strong correlation between the two. It is pretty well-known that when a physician is burned out, his/her own perception of quality of work goes down.In other words, finding a relationship between burnout and self-perception of medical errors is an issue of physician’s perception and not that actually medical errors occurred. To be confident, we need to objectively measure medical errors.

High Utilizers and Social Support

There is a common theme within the readmission reduction community that a large number of readmissions are due to limited social network around patients and only if we can provide patients with resources in community, we will be able to decrease these readmissions. Some observations studies have noticed a decrease in readmissions when patients are provided access to social/community resources, however, such studies are limited by risk of bias due to the ‘regression to the mean’ phenomenon.

Regression to mean phenomenon stipulates that if we examine participants once only performing a certain activity (or for an outcome), some of them will perform better while others will perform poorly simply due to some random factors. If we observe these participants longitudinally, we will find that those who performed well will perform poorly while those who performed poorly will perform better than their initial performance. Both groups will try to reach towards their mean (or true value).

Similarly, when we examine high-utilizer patients of health care services during a given period, those patients are likely at their worst and will do better anyway during the follow-up. This has nothing to do with the intervention but rather due to the regression to mean phenomenon. The way to address this problem is either to have several longitudinal measurements of the whole cohort where we can identify regression to the mean or to conduct a randomized clinical trial.

Finkelstein et al., conducted such a trial. They randomly assigned 800 hospitalized patients with medically and socially complex conditions with at least one additional hospitalization in the preceding 6 months, to either usual care (control group) or to the intervention group where social workers and community health workers coordinated and helped patients to access community resources.

To their, and frankly everyone else’s, surprise, they found to benefit of all the efforts of social workers and community health workers in reducing readmissions. The 180-day readmission rate was 62.3% in the intervention group and 61.7% in the control group. The adjusted between-group difference was not significant (0.82 percentage points; 95% confidence interval, −5.97 to 7.61).

More importantly, study highlighted the phenomenon of regression to the mean showing that the patients with high readmission rates resulting in enrollment generally had a decline in their readmission rate irrespective of whether they received intervention or not.

The study has few caveats but still raises very important questions – what should hospitals, healthcare systems, physicians, and other healthcare team members do to reduce readmissions and healthcare resource utilization in a very vulnerable population.

Are Young Women Getting Unnecessary Medical Care?

The annual pelvic examination in otherwise healthy women is considered part of the well-woman visit. Similarly, Pap-smear is performed for cervical cancer screening among sexually active women. Screening for cervical cancer is not recommended for women younger than 21 years, a consensus reached by the US Preventive Services Task Force, the American College of Obstetricians and Gynecologists, and American Cancer Society. The general recommendation is against performing pelvic examinations in asymptomatic, nonpregnant women younger than 21 years. However, young women are still undergoing such exams during their physical examinations.

How big is the problem of these unnecessary exams? Qin et al has recently published their findings using the National Survey of Family Growth. They estimated that between 2011 and 2017, an estimated 2.6 million women aged 15 to 20 years in the United States (22.9%) received a pelvic examination in the past year, and 54.4% of these examinations were potentially unnecessary. Further, an estimated 2.2 million young women (19.2%) received a Pap-smear test in the past year, and 71.9% of these tests were potentially unnecessary.

The Best Time to Take Your Blood Pressure Pills

Majority of blood pressure medicines are one daily and people take their blood pressure medicines often in the morning. There have been some data based on our understanding of the diurnal variations or circadian rhythms that taking medications at bedtime may work better. For example, peak activity of the renin–angiotensin–aldosterone system (RAAS) occurs during sleep. Further, data from some uncontrolled studies have suggested that taking blood pressure medications at evening (or bedtime) may be beneficial. However, a randomized controlled clinical trial (the gold standard for scientific evidence) has been lacking. That is until now!

A recent study published in the European Heart Journal, by Hermida et al, addressed this very same question. Investigators enrolled 19 084 hypertensive patients (10 614 men and 8470 women) and assigned patients to take the entire dose of their blood pressure pills at bedtime or in the morning. Of all the patients, 1752 experienced either a death due to heart attack, heart attack without death, had stent placed in their heart blood vessels, developed new heart failure, or a stroke. Patients who were taking their medications had 45% lower risk of all outcomes combined, 56% lower risk of heart attach death, 34% lower risk of heart attack, 40% lower risk of stents in their heart blood vessels, 42% lower risk of heart failure, and 49% lower risk of stroke.

Note, these are large differences – these patients were taking their blood pressure pills but just taking pills at a different time made a huge difference. The difference is larger than many other pills that are often prescribed by physicians. If you, or your loved one, takes blood pressure pills, consider talking to your doctor if you should take your pills at bed-time.

Tele-Health and Liver Transplant

Liver transplantation is the only treatment that increases survival times of patients with decompensated cirrhosis. Patients who live further away from a transplant center are disadvantaged. Health care delivery via telehealth is an effective way to remotely manage patients with decompensated cirrhosis. Authors investigated the effects of telehealth on the liver transplant evaluation process.

Using regression models, authors evaluated the differential effects of telehealth vs. usual care on placement on the liver transplant waitlist. We also investigated the effects of telehealth on time from referral to initial evaluation by a transplant hepatologist, liver transplantation, and mortality.

Authors found that the use of telehealth was associated with a substantial reduction in time from referral to initial evaluation by a hepatologist and placement on the liver transplant waitlist-especially for patients with low MELD scores, with no changes in time to transplantation or pre-transplant mortality.