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.

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.

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.

Vaso-Occlusive Crisis in Sickle Cell Patients

Hemoglobin S (HbS) is an abnormal form of hemoglobin and is transmitted through genetically from parents to a child. Normal hemoglobin is mostly made up of 4 globin chains; 2 alpha chains and 2 beta chains. The underlying problem is a single mutation in the beta-chain of the hemoglobin where adenine nucleotide is replaced with a thymidine nucleotide resulting in a missense mutation and changing the amino acid glutamate at no. 6 position with valine. This change in amino acids from glutamate to valine results in changes in the 3-dimensional structure of the beta-chain of hemoglobin. These changes include 1) lower affinity for oxygen, 2) ability to join with other hemoglobin molecules and form polymers, 3) increase oxidation of the RBC cell membrane proteins.

Normal hemoglobin gets oxygenated in the lungs and carries oxygen to the tissues. Oxygen is released in the tissues and hemoglobin gets deoxygenated and returns back to the lungs for oxygenation. Normal hemoglobin remains soluble within the RBC throughout this process. On the other hand, deoxygenated HbS starts forming long filamentous through polymerization of hemoglobin molecules. Importantly, the process takes several seconds in fresh red blood cells (RBC) before polymerizations occurs and there is sufficient time for RBCs to return back to the lungs and get oxygenated.

However, some cells continue to get stuck in blood vessels resulting in completion of polymerization and breakdown of RBCs within the vessels (called intravascular hemolysis). This chronic, slow process of premature destruction of RBC in sickle cell patients is the reason for chronic anemia as well as other slowly developing manifestations of sickle cell disease.

In sickle cell vaso-occlusive crisis, large number of blood vessels are blocked resulting in marked pain and morbidity. Typically, the crisis is precipitated by some event, such as dehydration or an infection. The event stimulates the vascular endothelium making them sticky through expression of cell-binding receptors on the surface. These receptors then bind with other receptors on the surface of RBCs, white blood cells, and platelets resulting in blockage of the vessel lumen. The red blood cells with HbS are already primed to binding with other cells through expression of certain proteins as well as exposure of certain lipid products on the surface. Thus, the vaso-occlusive crisis results from the interaction of HbS containing RBC, endothelium, white blood cells, and platelets.

Selepressin: Not so useful in Septic Shock

Septic shock is an advanced stage of body’s response to an infection and manifests as marked decrease in blood pressure with resulting decrease blood flow (and hence nutrients and oxygen) to the tissues. The decreased blood pressure is due to vasodilatation and increased capillary permeability (leaky capillaries).

The treatment of septic shock includes antibiotics to treat the infection, intravenous fluids to replenish fluid that has seeped out into the tissues from leaky capillaries, and vasopressors (such as norepinephrine) to counter vasodilation. Not uncommonly, norepinephrine is not sufficient to raise blood pressure and increase blood flow to the tissues. Vasopressin, another vasopressor, is sometimes used in addition to norepinephrine to support blood pressure. However, vasopressin has other adverse effects. These adverse effects are due to the fact that vasopressin stimulates three types of vasopressin receptors (V1a, V1b, and V2). Stimulation of V1a has vasopressor effect while stimulation of V1b and V2 results in increased coagulation activity, nitric oxide release, corticosteroid secretion, and excessive water retention.

Selepressin is a selective V1a receptor agonist and has only vasopressor effect. One would assume that selective stimulation of V1a receptors with selepressin will result in beneficial outcome. However, in a clinical trial (N=868), selepressin was not found to be effective in reducing ventilator-free days, norepinephrine-free days, mortality, lower ICU days, or lower need for kidney replacement therapy.

Serum creatinine in critically ill patient

An interesting, short and sweet article in JAMA highlighting that serum creatinine increase in critically-ill patients may underestimate the degree of AKI.

They give following reasons for this underestimation:
1. Creatinine production decreases in sepsis, hence there is decreased release of creatinine and slow rise in serum creatinine
2. Critically-ill patients receive large-volume resuscitation and hence dilute serum creatinine. Of note, the volume of distribution of creatinine is about 65% of body weight.

Having said that, there does not appear to be any good alternatives for determining renal function ad GFR estimation in such population.

MIMIC Database

I ran across this publicly available dataset which looks great for someone interested in data-analysis. The dataset appears to be extensive. I have not worked with its analysis yet but this will be something that will be on my ‘things-to-do” list. According to its website “MIMIC is an openly available dataset developed by the MIT Lab for Computational Physiology, comprising deidentified health data associated with ~40,000 critical care patients. It includes demographics, vital signs, laboratory tests, medications, and more.”

Sepsis and qSOFA, SIRS, NEWS

Sepsis is a rather common admitting diagnosis to hospital with high mortality rate. Identifying patients who are at a higher risk of adverse outcomes may help to optimize resource allocation. To this end, initially SIRS definition was recommended. More recently, qSOFA is being promoted as a predictor of adverse events during hospitalization due to sepsis. However, there is a lesser known NEWS score that is also being used at few hospitals.
This study compared the three scores in a retrospective sample and found that NEWS may be similar or superior to qSOFA. Note that qSOFA (3 variables) is the quickest and simplest of the three while NEWS is the most complex (20 variables).