Myths and facts in antibiotic stewardship

The current issue of the American Journal of Medicine (the Green Journal) has an article titled Top Myths of Diagnosis andManagement of Infectious Diseases in Hospital Medicine. This is one of the better articles pertaining to antibiotic stewardship that I have seen. Ten myths are listed. They are not complete myths (exceptions apply to just about all of these principles); rather, they are misconceptions.

Myth one: antibiotics do no harm. High-level data refute this myth. For example, a recent metaanalysis showed that the use of procalcitonin guidance to shorten the duration of antibiotic therapy was associated with lower mortality.

Myth two: antibiotic durations of 7, 14, or 21 days are typically necessary. Although these are common recommendations, evidence is lacking. In many situations (and there are exceptions) shorter duration therapy is as good as longer duration. Examples include 3 to 5 days for community acquired pneumonia; eight days for nosocomial pneumonia; 5 to 7 days for pyelonephritis; four days for intraabdominal infection; five days for acute exacerbations of COPD and 5 to 6 days for cellulitis. There are notable exceptions. Certain deep-seated and difficult to eradicate infections are not candidates for either shorter duration or procalcitonin guidance for discontinuation. These include tuberculosis, meningitis, prosthetic joint infections, staphylococcal bacteremia, endocarditis and invasive fungal infections. The same caution applies to some immunocompromised patients.

Myth three: if one drug is good two (or more!) must be better. This requires nuance.There are some indications for combination therapy. They are exceptions rather than the rule. The main indication for combination therapy is initial empiric treatment for life-threatening infection such as sepsis. The rationale is to cover all likely pathogens. De-escalation is appropriate if and when culture and sensitivity results indicate that a single agent would be appropriate. This principle is also applied in meningitis where in patients 50 years of age or older we include listeria coverage such that in non pen allergic patients ampicillin is added to the combination of ceftriaxone and vancomycin. Also in meningitis the combination of ceftriaxone and vancomycin accommodates the possibility of relative resistance of strep pneumo which might cause treatment failure with cephalosporin monotherapy. In community acquired pneumonia requiring hospitalizations the guidelines call for combination cephalosporin and macrolid therapy. For patients admitted to ICU it is recommended that MRSA coverage be added (this is in the IDSA MRSA guideline, not the pneumonia guidelines).

A frequently asked question is what to do about serious gram negative infections. Traditionally “double coverage“ with two gram-negative agents has been used. For the most part this is not supported by evidence. One exception is in the initial (empiric) antipseudomonal coverage for HAP/VAP., the guidelines for which indicate double coverage initially which should be de-escalated later if microbiologic data allow. In contrast, the CAP guidelines for patients with pseudomonas risk recommend monotherapy---not double coverage--from the start.

Myth four: oral antibiotics are not as good as IV antibiotics for hospitalized patients. This is, in general, a myth but there are exceptions. IV therapy is not inherently better than oral if there’s adequate bioavailability with the oral agent and if susceptibilities allow switch to an oral agent. Cautions apply in bacteremia. Some of these (eg staphylococcal bacteremia ) require intravenous therapy for the entire course. In other bacteremic infections step down to oral agents may be appropriate. Examples include certain streptococcal bacteremias and gram-negative bacteremic urinary tract infections. In such cases a switch to oral therapy can be considered as early as day four.

Myth five: bacteria in the urine signifies a UTI and should be treated. If it is asymptomatic treatment is only warranted in pregnancy and patients about to undergo a urologic procedure.

Myth six: history of penicillin allergy means the patient can never receive a beta lactam antibiotic. Former thinking was that there’s a 10 to 15% cross sensitivity rate between penicillin and cephalosporins. More recent findings indicate that the cross sensitivity rate to penicillin allergy is more like 3% for cephalosporins and 1% for carbapenems. The article provides some general principles for decision making in patients with purported penicillin allergy. For reactions that are mild and non specific a cephalosporin can be given. If the reaction was anaphylactoid either an alternative antibiotic to a cephalosporin or penicillin desensitization is recommended. Severe non anaphylactic reactions such as Stevens-Johnson syndrome, toxic epidermal necrolysis and DRESS syndrome are in a different category. In those cases the use of any beta lactam is contraindicated as is penicillin desensitization.

Myth seven: antibiotics for surgical prophylaxis should be continued for 24 hours or more .

Myth eight: antibiotics must be continued for as long as drains are in place. Although clinical judgment is required here there is no robust evidence to support such a practice.

Myth nine: nitrofurantoin can be used for UTIs only if the creatinine clearance is greater than 60. This is in accordance with product labeling but the data indicate 30 may be more reasonable cut off.

Myth ten: fluoroquinolones are first line agents for many infections. We now have mounting evidence of adverse effects (CNS toxicity,, tendon rupture, dysglycemias, irreversible neuropathy, QT prolongation and aortic dissection) such that fluoroquinolones have been relegated to a lower position in the sequence. They should be used only when safer and equally effective alternatives are not available.

In a related antibiotic stewardship topic this article from Cinical Infectious Disease looked at the utility of MRSA PCR screening. Negative PCR can allow for discontinuation or avoidance of MRSA therapy such as vancomycin in many situations. Those studied in the article were bloodstream infections, intra-abdominal infections, respiratory infections, wound infections and urinary tract infections. Negative predictive value was 93% or better in all those situations.

Diagnostic time out

What is a diagnostic time out? Succinctly defined, it’s a deliberate exercise in differential diagnosis and systematic clinical reasoning in the care of an individual patient. But wait, I hear someone say… isn’t that what we do already? Well, no. We’re all familiar with the traditional model for clinical reasoning that we’re taught in medical school but those of us in the real world of practice nowadays, if we’re honest, realize that it seldom happens. There’s just not enough time when you’re forced to see too many patients each day. And hospitalist incentives, with their emphasis on speed and quick adoption of specific diagnostic labels, run in opposition. What do we as hospitalists do instead? Well, aside from all the care pathways and metric incentives that tell us what to do, we rely on clinical instincts and rules of thumb. Because they bypass formal analysis, they save time. They serve as cognitive shortcuts. We call these heuristics. This method of thinking (fast, instinctive, intuitive) is sometimes known as system 1 thinking. It has the advantages of being efficient and fast and sometimes, in critical situations, life saving. But it comes at the cost of a certain error rate. In order to better understand the process of system 1 thinking we have given the various heuristics names and categories. I recently listed some of those in this post. 

If system 1 is our usual measure of processing to get around time constraints the alternative is system 2: formal clinical reasoning .  System 2 thinking was the topic of a recent paper in CriticalCare Clinics. Although based on a survey of people working in a NICU the article has general applicability. The authors contrast system 1 and system 2 thinking in this manner:

Dual process theory holds that individuals engaging in medical decision-making use one of 2 distinct cognitive processes: a system 1 process based on heuristics – the use of rapid pattern recognition and rules of thumb – or a system 2 process, based on deliberate analytical modeling and hypothesis generation. While invoking system one processes individuals can think fast and reflexively and can even operate at a subconscious level, using pattern recognition to sort vast amounts of clinical information quickly before an illness script that allows for the rapid elaboration of a differential diagnosis. In contrast system 2 processes require focused attention and are purposefully analytical, relying on deliberate counter-factual reasoning to generate hypotheses regarding the pathophysiologic mechanisms by which a patient’s symptoms are produced.

The authors introduced the concept of the diagnostic time out to describe this shift of thinking because it requires deliberate effort. It’s not going to arise spontaneously in the natural course of the ward routine. (The authors were not the first ones to use this term). The diagnostic time out can be considered the cognitive equivalent of the better known procedural time out.

Why is a diagnostic time out needed? Research on diagnostic error has indicated that while some instances are due to system problems (such as failure to communicate test results) most are cognitive errors. These can be linked to the heuristics of system 1 thinking. The diagnostic time out, or the deliberate exercise of system 2 thinking, is a way to complement these cognitive shortcuts with a more analytical process.

Some opinion leaders in the field of diagnostic error have suggested universal adoption of system 2 thinking. This is problematic due to time constraints. Besides, there are some essential benefits of system 1 thinking, particularly in acute life-threatening situations. The real trick is how best to selectively employ system 2 thinking. In other words what are the situations in which system 2 thinking should be used? The authors suggest handoff situations in complex patients including ER to hospitalist, off service/on service and ICU to ward transfers.

How does it work? The authors propose a template but it’s really just the traditional clinical reasoning process. One of their points really got my attention: during the time out diagnostic labels should be removed and replaced by signs, symptoms, manifestations and clinical concerns. This of course is the opposite of what your coders and hospitalist leaders want you to do.

What are some of the barriers to implementation? In addition to time constraints, fear of ambiguity is an important factor. We are afraid to admit what we don’t know. One thing you will never hear a hospitalist say out loud is “I’ll have to think about that.”

A little more on metacognition

This article from Academic Emergency Medicine, published in 2002, remains applicable today. It makes the point that heuristics in medicine are valuable even though they can lead to error. The article also makes the statement:

The increasing use of clinical decision rules, as well as other aids that reduce uncertainty and cognitive load, e.g., computerized clinical decision support,will improve certain aspects of clinical decision making, but much flesh-and-blood clinical decision making will remain and there will always be a place for intuition and clinical acumen.

It presents an exhaustive list with detailed descriptions of the various cognitive shortcuts.

Indulge me in a little metacognition

I found an interesting post about cognitive shortcuts in medicine. I have a minor objection to the title of the post which is Cognitive Errors. Cognitive shortcuts, known as heuristics, which are examples of fast instinctive thinking (system one), often lead to error. In some cases, however, they can be useful because they are efficient and time saving. There is an up side as well as a down side to system one thinking in medicine.

Let’s go down the list. I’ve skipped some of them.

The first example given is affective error. This refers to an emotional response surpassing objectivity.

Next is aggregate bias. I struggle with this one. The author says that the aggregate bias is the belief that data in the aggregate don’t apply to the patient in front of you. My understanding (maybe I’m wrong) is that aggregate bias, otherwise known as the ecological fallacy, is the opposite. That is, it refers to inappropriate application of population data to an individual. It has more to do with treatment decisions than diagnostic error. Remember, one of the first principles of evidence-based medicine is that clinical reasoning decision making starts with the unique aspects of the individual patient. After looking at a variety of references, it would appear that both definitions have been used. Most medical references define aggregation bias the way the blog author does. Those outside of medicine define it as inappropriate extrapolation.

The ambiguity effect is really a bias against ambiguity. So we tend to stick with things we are more familiar with. That may cause us to ignore other possibilities and take too narrow a view of things. As originally conceived it had to do with probability. That is, people have a tendency to gravitate toward choices in which the probability is known or explicitly stated. Of note, the ambiguity effect was first described by Daniel Ellsberg.

The anchoring heuristic is one of the better known cognitive biases. This refers to the tendency to stick with one’s initial hunch despite new evidence to the contrary. You may be so proud of your initial hunch that you ignore new information. Confirmation bias and diagnostic momentum are related concepts.

Ascertainment bias, as the author points out, is an umbrella category. It encompasses a lot of stereotypes and biases. In essence it’s just—-well, bias. It’s not very useful as a unique category in discussions of cognitive error.

Availability bias is one of the better known cognitive shortcuts. This refers to the influence of prior experience. This causes bias toward the first thing that comes to your mind. For example, if you’ve been burned by having missed a case of aortic dissection you may tend to be over concerned about aortic dissection in every future case of chest pain. The flip side is you may fail to consider things you haven’t seen in a long time.

Base rate neglect is a cognitive shortcut that may be considered harmful and wasteful in ambulatory medicine but may be your friend in the arena of hospital and emergency medicine. It’s a failing to consider the true prevalence of diseases in clinical reasoning. It ignores the old aphorism “common things happen most often.” In the high acuity world of the hospital, where you really need to be risk-averse, base rate neglect may be beneficial. Put another way you and and your patient may be better off if you consider worst case scenario.

Then there’s belief bias. I’m not sure this belongs in a discussion of diagnostic shortcuts as it has more to do with treatment recommendations. I cringe when I hear somebody say they “believe“ in a particular treatment, implying that belief surpasses reasoning from evidence .

Blind spot bias is similar to the Dunning Kruger effect in which we think we're smarter than we really are. Humility is the remedy here. Does this lead to a form of cognitive shortcut? Maybe in that we fail to pause and consider carefully that we might be wrong.

Confirmation bias is akin to anchoring. This is the tendency to be selective in what type of accumulating evidence you consider. That is, you consider mainly evidence that supports your original hunch.

The framing heuristic is another well known shortcut. We are biased toward diagnostic possibilities in accordance with the way the initial presentation is framed. Though it can be useful it restricts our differential diagnosis in a way that excludes a wide range of possibilities. Not every returning travel with fever has a parasite, for example.

The gamblers fallacy, according to the blog author, is “the erroneous belief that chance his self correcting.“ This is a cognitive error that tends in the opposite direction to the availability heuristic.

The order effect is something I was vaguely aware of but had not considered as a cognitive error category. It refers to the tendency to focus on information that is proximate in time and to do so at the expense of the totality of events over time. This typically occurs at the point of hand off in a patient who has had a very long hospital course.

Premature closure is just what it says. It’s a tendency for thinking to stop once a tentative diagnosis has been made. It overlaps with other categories such as anchoring. There is probably a subtle difference between premature closure and anchoring. Anchoring implies an emotional attachment to a diagnosis whereas premature closure implies diagnostic laziness.

Representativeness restraint has also been known as a representativeness heuristic. It is a cognitive shortcut characterized by focusing too much on the prototypical manifestations of a disease. This may cause the clinician to miss atypical presentations.

Search satisfaction is another example of laziness in clinical reasoning. It’s a tendency to stop searching once an answer has been found. The author gives the example of missing a second fracture on an x-ray once the first one is identified.

Sunk cost fallacy is a type of emotional heuristic as well as diagnostic laziness. It is the tendency to ignore new information and not consider alternative diagnoses once the original diagnosis has been arrived at after a great time effort and expense (the sunk cost).

Sutton’s slip might be the dark side of Sutton’s law (going where the money is). Pursuing the obvious might lead to error because of other possibilities being ignored.

Zebra retreat is the avoidance of rare diagnoses to a fault. It’s an opposite of base rate neglect.

Stepford doctors

Ever since variation was declared to be an enemy of medicine there has been a multifaceted unrelenting effort to constrain the autonomy of clinicians.

In an article in the Medical Humanities journal titled “Stepford doctors”: an allegory GM Sayers described this trend creeping towards the ultimate creation of a workforce of Stepford doctors. 

From the paper:

The Stepford Wives, a novel by Ira Levin, provides the theme for this allegory. The men of Stepford belong to the Men’s Association. Their wives are “perfect”, in that they do nothing other than clean, cook, preen, and provide satisfaction without argument for their husbands. They are, furthermore, content with their lot, and believe that their previous interests and freedoms were self indulgent.

Applying the allegory to hospital medicine, Sayers wrote:

In the hospitals, doctors were pooled and moved like pawns to fill clinical slots, by masters who controlled both board and pieces...

The masters were not doctors; they were experts in managing time, costs, and doctors. They had not studied medicine, bioethics, or humanities; they were devoid of empathy. They did not treat patients, perform operations or do clinical research. They did not break bad news or get consent from patients for surgery. Nevertheless, they knew what sort of doctors they wanted—‘‘Stepford doctors’’. These were not ‘‘excellent’’ doctors, but ‘‘good enough’’ doctors, who would devote themselves to the masters’ objective of expediency, and the masters’ duty to balance the budget.

It is not completely clear how the masters changed the thinking and acting of so many doctors, but they did. Some of the doctors accepted the superficial plausibility of the reasoning that informed the masters’ demands. Some of the doctors themselves became masters, and they persuaded other doctors that the way the masters saw medicine was the way medicine should be.

 

The article was published in 2006 and might be considered dated but the premise is even more relevant today. In the words of the author: “This allegory cannot be concluded because it is on going.”

Are internal medicine’s core values effectively applied in today’s hospitalist practice?

Hospital medicine has changed. The change has been brought by business and regulatory pressures rather than the core values of internal medicine. Internal medicine’s core values are timeless.

Phillip Tumulty was famous as one of internal medicine’s great teachers. He was a lead faculty member in the department of internal medicine at Johns Hopkins for over 20 years. He published an article in JAMAInternal Medicine in 1977 in which he laid out some of the core values of internal medicine. Tumulty, an exemplar of internal medicine if their ever was one, had these things to say (paraphrasing from some of the points he made):

An internist is meticulous in the application of expertise in history and physical examination.

An internist develops a “referral practice” which leads to distinction among peers. (In other words, an internist is a specialist).

An internist “must not nod, nor grow bored, but sustain his enthusiasm through constantly searching for the unexpected in the seemingly obvious. Its occasional discovery in a patient’s problem hitherto passed over as routine brings self renewal.“ In other words the internist’s professional satisfaction feeds on being able to spot zebras in the morass of “bread and butter“ problems.

The internist should not be regarded “merely as some useful indispensable medical work horse, ably attending to the daily clinical chores.“

Tumulty summarizes his points this way: “some may say this is all very well but only as an idealistic concept of a kind of clinician and care that is no longer practical. I agree; it is indeed a concept of excellence. However, in the care of the sick, should one plan for less?“

Are the pressures and expectations placed on hospitalists today aligned with these core principles and values of internal medicine as articulated by Tumulty?

Update on management of the acute abdomen in critically ill patients

 

From a recent review in Current Opinion in Critical Care Medicine:

Purpose of review

The aim of this study was to describe important features of clinical examination for the surgical abdomen, relevant investigations, and acute management of common surgical problems in the critically ill.

Recent findings

Lactate remains a relatively nonspecific marker of gut ischemia. Dual energy computed tomography (DECT) scan can improve diagnosis of bowel ischemia. Further evidence supports intravenous contrast during CT scan in critically ill patients with acute kidney injury. Outcomes for acute mesenteric ischemia have failed to improve over time; however, increasing use of endovascular approaches, including catheter-directed thrombolysis, may decrease need for laparotomy in the appropriate patient. Nonocclusive mesenteric ischemia remains a challenging diagnostic and management dilemma. Acalculous cholecystitis is managed with a percutaneous cholecystostomy and is unlikely to require interval cholecystectomy. Surgeon comfort with intervention based on point-of-care ultrasound for biliary disease is variable. Mortality for toxic megacolon is decreasing.

Summary

Physical examination remains an integral part of the evaluation of the surgical abdomen. Interpreting laboratory investigations in context and appropriate imaging improves diagnostic ability; intravenous contrast should not be withheld for critically ill patients with acute kidney injury. Surgical intervention should not be delayed for the patient in extremis. The intensivist and surgeon should remain in close communication to optimize care.

The fight to curb antimicrobial resistance: how are we doing?

 

From a recent NEJM review on this topic:

In November 2019, the CDC released an updated version of its antibiotic-resistance report…

The new report reveals reductions in the incidence of infections caused by carbapenem-resistant acinetobacter species, multidrug-resistant Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococcus, and drug-resistant candida species. In addition, it identifies an increasing incidence of Enterobacterales that produce extended-spectrum beta-lactamase and drug-resistant Neisseria gonorrhoeae infections and the emergence of the multidrug-resistant yeast Candida auris.

Primary aldosteronism: an update

 

Here's an update on this topic recently published in Cardiology in Review.

The original Conn syndrome was described in 1956 as a case report of a young woman with hypertension and severe hypokalemia who was found to have an adrenal adenoma and was cured after adrenalectomy. Subsequently we've found that primary aldosteronism is much more common than previously thought. It's certainly not a rare cause of secondary hypertension but it is markedly under-diagnosed.

The mechanism of action of aldosterone is described in the paper thusly:

Aldosterone, which is synthesized in the adrenal zona glomerulosa, acts primarily at the renal collecting tubule where it binds to mineralocorticoid receptors leading to an increased number of open epithelial sodium channels (ENaC) in the luminal membrane4 and increased Na-K-ATPase expression.5 Reabsorbed sodium leaves the luminal cell via the Na-K-ATPase pump. Subsequent intraluminal electronegativity triggers potassium secretion through membrane potassium channels. Additionally, aldosterone has been found to act at the second part of the distal convoluted tubule, where both the thiazide-sensitive sodium chloride cotransporter and ENaC are expressed. By regulating the function of these transporters, aldosterone is thought to have effects on sodium and chloride balance and blood pressure (BP) control.6

Hypokalemia is characteristic but only a minority of patients exhibit it at presentation.

Regarding the different etiologies, again, from the paper:

The most common cause of primary hyperaldosteronism is bilateral idiopathic hyperplasia (IHA), accounting for 60% of cases. An aldosterone-producing adenoma (APA) is seen in 30%, primary (unilateral) adrenal hyperplasia in 2%, aldosterone-producing adrenocortical carcinoma in less than 1%, familial hyperaldosteronism (FH) type 1 (glucocorticoid-remediable) in less than 1%, FH type 2 (APA or IHA) in less than 6%, and FH type 3 (germline KCNJ5 mutations) in less than 1%.9 Although germline mutations of KCNJ5 are quite rare, causing FH type 3 PA, somatic mutations of KCNJ5 are relatively common, and in one study was seen in 38% of patients with APA. These mutations are believed to increase expression of CYP11B2, the aldosterone synthase gene.10Glucocorticoid-remediable aldosteronism, which is inherited as an autosomal dominant trait, usually presents in childhood with moderate to severe hypertension. The pathophysiology involves ectopically synthesized aldosterone in the zona fasciculata under adrenocorticotropin control.

Patients with primary hyperaldosteronism have a higher cardiovascular risk then do those with comparable degrees of essential hypertension. This is believed to be due to direct extrarenal damaging effects of of aldosterone such as endothelial damage and myocardial fibrosis.

The two big questions are who should be screened and how to work it up. Guidelines are fairly aggressive in their recommendations for screening. They are covered in the paper. In brief, things that should trigger a workup include severity of hypertension (levels persistently exceeding 150 / 100), resistant hypertension which could be translated to mean failure to control the hypertension on 3 drugs or essentially any patient who is on four drugs even if controlled and hypokalemia whether spontaneous or diuretic associated. Additional candidates would include those with family history, those with early onset, and those with an adrenal incidentaloma. In addition those with sleep apnea are candidates. There is a somewhat poorly understood connection between sleep apnea and hyperaldosteronism.

It has been estimated that if these criteria or fully applied around 50% of hypertensive patients in primary care would be candidates for screening. This is straight out of of the Endocrine Society guidelines. This may seem like over testing and will certainly rule out the disorder in a substantial number of patients but it is promulgated in guidelines and published recommendations due to a substantially under-diagnosed disease burden.

Diagnosis starts with simultaneous measurement of renin and aldosterone. The renin measurement can either be plasma renin activity or renin concentration. Preferably these are done in the morning, seated for 5 to 15 minutes. The patient should be potassium and sodium replete and have diuretics discontinued. Unless the aldosterone to renin ratio is very high or spontaneous hypokalemia is observed further confirmatory testing is likely to be necessary followed by testing for the etiology of hyperaldosteronism. This includes ruling out glucocorticoid responsive hyperaldosteronism. Imaging is generally required followed often by adrenal vein sampling. Once one is past the initial screening test help from an endocrinologist or hypertension specialist might be warranted.

Procalcitonin guided antibiotic treatment is beneficial in a variety of infections

From a recent report in the American Journal of Respiratory and Critical Care Medicine :

Rationale: Although early antimicrobial discontinuation guided by procalcitonin (PCT) has shown decreased antibiotic consumption in lower respiratory tract infections, the outcomes in long-term sepsis sequelae remain unclear.

Objectives: To investigate if PCT guidance may reduce the incidence of long-term infection-associated adverse events in sepsis.

Methods: In this multicenter trial, 266 patients with sepsis (by Sepsis-3 definitions) with lower respiratory tract infections, acute pyelonephritis, or primary bloodstream infection were randomized (1:1) to receive either PCT-guided discontinuation of antimicrobials or standard of care. The discontinuation criterion was greater than or equal to 80% reduction in PCT levels or any PCT less than or equal to 0.5 μg/L at Day 5 or later. The primary outcome was the rate of infection-associated adverse events at Day 180, a composite of the incidence of any new infection by Clostridioides difficile or multidrug-resistant organisms, or any death attributed to baseline C. difficile or multidrug-resistant organism infection. Secondary outcomes included 28-day mortality, length of antibiotic therapy, and cost of hospitalization.

Measurements and Main Results: The rate of infection-associated adverse events was 7.2% (95% confidence interval [CI], 3.8–13.1%; 9/125) versus 15.3% (95% CI, 10.1–22.4%; 20/131) (hazard ratio, 0.45; 95% CI, 0.20–0.98; P = 0.045); 28-day mortality 15.2% (95% CI, 10–22.5%; 19/125) versus 28.2% (95% CI, 21.2–36.5%; 37/131) (hazard ratio, 0.51; 95% CI, 0.29–0.89; P = 0.02); and median length of antibiotic therapy 5 (range, 5–7) versus 10 (range, 7–15) days (P less than  0.001) in the PCT and standard-of-care arms, respectively. The cost of hospitalization was also reduced in the PCT arm.

Conclusions: In sepsis, PCT guidance was effective in reducing infection-associated adverse events, 28-day mortality, and cost of hospitalization.

At a Glance Commentary

Scientific Knowledge on the Subject

The procalcitonin (PCT)-guided discontinuation of antibiotic therapy was demonstrated to reduce antibiotic exposure in patients with lower respiratory tract infections and/or sepsis in several randomized trials. However, the effect on the incidence of infections by resistant microorganisms has not been studied.

What This Study Adds to the Field

The PROGRESS (Procalcitonin-guided Antimicrobial Therapy to Reduce Long-Term Sequelae of Infections) trial was designed as a real-world pragmatic trial, enrolling patients with sepsis. The trial demonstrated that PCT-guided antimicrobial treatment in sepsis was effective in reducing infection-associated adverse events like infections by multidrug-resistant organisms and Clostridioides difficile, as well as in-hospital and 28-day mortality. Generated evidence implicates that PCT guidance in sepsis is a safe strategy with long-term benefits that may have a substantial impact on public health, particularly for countries with high baseline antimicrobial consumption.

Here is a related editorial in the same issue.

Since pneumonia patients were included in the study, do these results contradict the recommendations of the community acquired pneumonia guidelines? The idea that procalcitonin levels should not be measured in patients with community-acquired pneumonia is a popular misconception of the guidelines, often promulgated via institutional pathways. All the guideline says is that if clinical judgement leads to a diagnosis of pneumonia antimicrobial treatment should be initiated regardless of the initial procalcitonin result. The guideline does not preclude calcitonin guided therapy.

Is evidence based medicine the same as science based medicine?

 In its original notion, yes.   In its widespread popular distortion, no.  Harriet Hall explains.

 

 

Widespread misunderstanding of hypoxemia, hypoxia and pulse oximetry

 

A recent article in the American Journal of Respiratory and Critical Care Medicine about hypoxemia and covid-19 concludes with this:

In conclusion, COVID-19 has engendered many surprises, but features that baffle physicians are less strange when contemplated through the lens of long-established principles of respiratory physiology.  

Read this paper when you're well rested and well fed and you will find it a great exercise in the physiology of hypoxemia. It's much more about that, and the misconceptions derived from our current obsession with pulse oximetry, than it is about covid.

First let's list what I think are some of the main ideas in the paper.

There was widespread over-reliance and misunderstanding of pulse oximetry.

There is not a simple correlation between dyspnea and hypoxemia.

The threat of hypoxemia is poorly understood by clinicians.

The seeming paradox of asymptomatic hypoxemia is not unique to covid-19 but is explained by well established principles of respiratory physiology.

Dyspnea is mediated by hypercapnia,  afferent signals produced by inflammatory stimuli, mechanical properties of the lungs and, least of all, hypoxemia.  As will be brought out in the physiology below, multiple  conditions seem to have a permissive effect on the dyspnea produced by hypoxemia.

Hypercapnia is a very important cause of dyspnea.   It has a permissive effect on hypoxemia as a cause of dyspnea. Hypercapnia causes a drop in pH in the blood perfusing the CNS respiratory control center.  An acute increase in pCO2 of 10 mm Hg quickly causes profound dyspnea. The situation is different for hypoxemia.  As pO2 falls there appears to be a threshold of 60 mm Hg  below which stimulation of ventilation and dyspnea occur. (The so called hypoxic drive). In terms of mechanism, hypoxemia stimulates the carotid bodies which send messages to the respiratory control center. From there impulses are relayed to the cortex cruising the sensation of dyspnea. The correlation between dyspnea and the ventilatory response to hypoxemia is poor. This response to hypoxemia is blunted if the pCO2 is 39 or below.  These responses are blunted in individuals with diabetes and individuals over 65 which constitute a high portion patients presenting clinically with covid.

Could covid have effects on the brain that blunt the dyspnea response? A similar question has been asked regarding the symptom of anosmia. ACE2, the receptor for covid-19, is expressed both in the carotid bodies and the nasal mucosa so mucosal effects rather than brain involvement could account for these manifestations. This is a question yet to be answered.

The authors imply that our usual concerns about low pulse oximeter  readings are misdirected.  Another quote from the article:

Physicians are fearful of hypoxemia, and many view saturations between 80% and 85% as life threatening. We served as volunteers in an experiment probing the effect of hypoxemia on breathing patterns; our pulse oximeter displayed an SpO2 of 80% for over an hour, and we were not able to sense differences between an SpO2 of 80% and an SpO2 of 90% (24). In investigations on control of breathing and oximeter accuracy, subjects experience an SpO2 of 75% (12), or briefly 45% (25), without serious harm. Tourists on drives to the top of Mount Evans near Denver experience oxygen saturations of 65% for prolonged periods; many are comfortable, whereas some sense dyspnea (25).

The finding of a low pulse oximetry reading does not enable a complete physiological assessment. Instead it should lead the clinician to ask: what's going on? Pitfalls in the interpretation of pulse oximetry were cited in the article. Correlation with blood gas readings deteriorates at lower levels of saturation. Accuracy of pulse oximetry is less in critically ill patients than in normal volunteers. The oxyhemoglobin dissociation curve should factor into any interpretation of pulse oximetry readings but this is seldom the topic of bedside discussions. Fever and low pH, common in critically ill patients, cause a shift of the curve to the right. This leads to lower saturation readings at a given pO2. It is an adaptive mechanism by which hemoglobin unloads oxygen more readily. Herein lies another reason why oxygen saturation correlates poorly with dyspnea: the carotid bodies respond to changes in pO2 but  not to oxygen saturation.

Further complicating the discussion is the definition of terms. Though not addressed in the article, there is the common confusion between hypoxemia and hypoxia. Low pO2 or saturation readings indicate hypoxemia. However, to diagnose hypoxia, which is a reduction in oxygen delivery to the tissues, one must apply the oxygen delivery equation. This equation takes into account hemoglobin bound oxygen, oxygen dissolved in plasma, hemoglobin concentration and cardiac output. As to  the definition of hypoxemia the authors point out that it has been an evolving concept. The definition of hypoxemia is not essential, but rather a matter of usage and convention. For example, in the 1990s it was often defined as the raw number without regard to the FiO2. Recently hypoxemia is more often referred to in terms of the oxygen requirement. Both are important: the former for estimating oxygen delivery and the latter for making an assessment of ventilation and gas exchange.

After reading this article I have the following concluding thoughts:

We over rely on pulse oximetry. Blood gases are underutilized.

Misunderstanding of pulse oximetry readings is widespread.

The hypoxemia of covid-19 is not as unique as popularly believed.

Anticoagulation for atrial fibrillation in stages 4 and 5 of CKD

From a recently published study:

Purpose

The aim of this study was to investigate whether oral anticoagulants can provide efficacy and safety profiles better than no anticoagulant in patients with stages 4 or 5 chronic kidney disease and atrial fibrillation.

Methods

From 2001 to 2017, a cohort of patients with stages 4 or 5 chronic kidney disease and atrial fibrillation based on electronic medical records were selected from Chang Gung Memorial Hospital system in Taiwan. Patients were divided into nonvitamin K antagonist oral anticoagulants (NOACs), warfarin, and nonanticoagulated groups. They were followed from the index date to the occurrence of the study outcomes or for 5 years, whichever occurred first. The outcomes were admissions due to ischemic stroke or systemic embolism or major bleedings. Survival analyses were conducted to estimate the incidence rates of outcomes.

Results

A total of 3771 patients with atrial fibrillation and estimated glomerular filtration rate less than 30 mL/min/1.73m 2 were enrolled, of whom 2971 were in the nonanticoagulated group, 280 in the NOAC group, and 520 in the warfarin group. About 25% of all subjects (940 patients) were on dialysis. The mean follow-up was 3.2 years. After adjusting for sex, age, comorbidities, and comedication, the warfarin group had a significantly higher risk of ischemic stroke or systemic embolism (adjusted hazard ratio [aHR] 3.1, 95% confidence interval [CI] 2.1-4.6) than the nonanticoagulated group. The NOAC group had a similar risk of ischemic stroke or systemic embolism (aHR 1.1; 95% CI 0.3-3.4) to that of the nonanticoagulated group. Both the warfarin and the NOAC groups had a significantly higher major bleeding risk than the noncoagulated group (aHR 2.8 [95% CI 2.0-3.8] for warfarin; aHR 3.1 [95% CI 1.9-5.2] for NOAC).

Conclusion

The use of NOACs or warfarin is not more effective than using no anticoagulants at all in reducing the risk of ischemic stroke or systemic embolism. Both NOACs and warfarin are associated with increased risk of major bleeding. Our results do not support the use of anticoagulants in patients with atrial fibrillation and stages 4-5 chronic kidney disease.

From an accompanying editorial:

The present study makes a significant contribution to the controversial field of oral anticoagulation in chronic kidney disease patients and advises against an unselected anticoagulant treatment of elderly chronic kidney disease stages 4-5 patients with atrial fibrillation to prevent thromboembolic events. Physicians are again left with an individualized approach to these patients weighing carefully in the inherent benefits and risks of oral anticoagulation.

Elevated BP in hospitalized patients: what to do?

From a recently published review:

Elevated blood pressure is common in patients who are hospitalized. There are no guidelines and few recommendations to help inpatient providers manage patients with elevated blood pressure. There are no normal reported values for blood pressure in the inpatient and recording circumstances often widely vary. Many factors may influence blood pressure such as pain, anxiety, malaise, nicotine withdrawal, or withholding home medications. This review of available literature suggests potential harm and little to no potential benefit in treating asymptomatic patients with elevated blood pressure. This review also found no evidence that asymptomatic elevated blood pressure progresses to lead to end-organ damage. However, there are clear instances of hypertensive emergency where treatment is indicated. Conscientious adjustment of an anti-hypertensive regimen should be undertaken during episode of elevated blood pressure associated with end-organ damage.

Cardiac complications of psoriasis

Look at the epicardial fat. From a recent paper in the green journal:

Psoriasis is a systemic inflammatory disorder that can target adipose tissue; the resulting adipocyte dysfunction is manifest clinically as the metabolic syndrome, which is present in ≈20%-40% of patients. Epicardial adipose tissue inflammation is likely responsible for a distinctive pattern of cardiovascular disorders consisting of 1) accelerated coronary atherosclerosis leading to myocardial infarction, 2) atrial myopathy leading to atrial fibrillation and thromboembolic stroke, and 3) ventricular myopathy leading to heart failure with a preserved ejection fraction. If cardiovascular inflammation drives these risks, then treatments that focus on blood pressure, lipids, and glucose will not ameliorate the burden of cardiovascular disease in patients with psoriasis, especially in those who are young and have severe inflammation. Instead, interventions that alleviate systemic and adipose tissue inflammation may not only minimize the risks of atrial fibrillation and heart failure but may also have favorable effects on the severity of psoriasis. Viewed from this perspective, the known link between psoriasis and cardiovascular disease is not related to the influence of the individual diagnostic components of the metabolic syndrome.

Updated atrial fib guidelines: the essentials

 

From Joseph S.Alpert.

A case of relapsing polychondritis

From a case report and mini review in the American Journal of Medicine:

McAdam and the Damiani/Levine diagnostic criteria. 12 RPC is diagnosed if 3 of 6 clinical findings are present: 1) auricular chondritis; 2) nonerosive inflammatory arthritis; 3) nasal chondritis; 4) ocular inflammation, including conjunctivitis, keratitis, scleritis, episcleritis, or uveitis; 5) laryngotracheal chondritis; and 6) cochlear or vestibular damage presenting as sensorineural hearing loss, tinnitus, or vertigo. A diagnosis of RPC also can be made if a patient meets one of 6 criteria AND has compatible cartilage biopsy histology or meets 2 of 6 criteria AND improves clinically after receiving corticosteroids or dapsone. 2

RPC is a rare inflammatory disease with a peak age of onset between ages 40 and 50 years and an estimated incidence of 3.5 cases per million people per year. 3 Cases have been diagnosed across all racial groups. Men and women are equally affected. 3 RPC is defined by abrupt-onset inflammation of the cartilaginous ear, nose, joints, laryngotracheobronchial tree, or heart valves. The disease usually follows an indolent, relapsing-remitting course but may also present fulminantly and threaten vision and organ function. 4 …

Up to one-third of cases of RPC present prior to, during, or after another disease. 6 The most commonly associated syndrome is systemic vasculitis, followed by rheumatoid arthritis and systemic lupus erythematosus.

Thyroid acropachy: an unusual complication of Graves disease

From a recent published case report and mini-review:

The pathogenesis of acropachy is unknown, except for the anatomic location, in that it is probably similar to that of pretibial myxedema. It appears that TRAb molecules bind to the TSH receptors of fibroblasts present in the periosteum region and trigger an inflammatory response, producing cell proliferation and glycosaminoglycan deposition (7,8). The musculoskeletal manifestation is almost never seen without the remaining components of the triad of orbitopathy, dermopathy, and acropachy (9,10). Some studies suggest smoking is a predisposing factor for acropachy in GD patients (9).

In most cases, acropachy is asymptomatic, but the main clinical manifestations are digital clubbing, skin tightness with or without digital clubbing and usually with small-joint pain (in severe cases), soft tissue edema, and reactional periosteum, and skin alterations in fingers and nails may also be present (7). The disorder mostly affects the metacarpus phalangeal and proximal interphalangeal regions in the upper and lower limbs, especially the ankles and metatarsal phalangeal joints (11).