Infectious Disease Compendium

Sepsis

Diagnosis

Infection with multi-organ system involvement. It has, for the sake of precision most ignore, the following syndromes:

- Bacteremia: bugs in the blood.

- Sepsis: bacteremia with end organ manifestations: DIC, ARF, ARDS, hypotension that responds to fluids/low dose pressors.

- Septic shock: bacteremia with end organ manifestations: DIC, ARF, ARDS, hypotension that does not respond to fluids or pressors. It is not the same as toxic shock syndrome.

The current indication for troponins is the presence of heart; if elevated in sepsis it portends increased mortality (PubMed).

Epidemiologic Risks

Depends on the infecting organism.

The name of the bug has significance. Different bugs have different reasons for being in the blood, so if a patient has, say, S. aureus in the blood, and you can't give me a list of the reasons, perhaps you should look it up or call an ID doc.

Obesity is beneficial for sepsis; they are less likely to die (PubMed). Since I think we will all die of a disease in our specialty I keep telling my wife I do not need to lose weight. She isn't buying it.

Transplant immunosuppression also protective from death (PubMed) as is HIV and being on steroids at the time of admission (PubMed).

Microbiology

Any organism can cause sepsis, but it is aerobic gram negative organisms that are most likely to kill patients: E. coli etc.

">50% of patients identified and treated for severe sepsis in the emergency department had negative culture results. Of patients identified with a sepsis syndrome at presentation, 18% had a noninfectious diagnosis that mimicked sepsis, and the clinical characteristics of these patients were similar to those of patients with culture-positive sepsis (PubMed)."

Many viruses will reactivate with sepsis: "CMV (24.2%), EBV (53.2%), HSV (14.1%), HHV-6 (10.4%), and TTV (77.5%). 42.7% of septic patients had presence of two or more viruses. (PubMed)." CMV, and other Herpes virus reactivation, is associated with worse outcome (PubMed). Zero data as of 2014 as to whether it is causal or whether treatment would help. The one CMV prophylaxis study shows INCREASED mortality in the treatment arm (PubMed).

Culture negative sepsis has more organ failure and death. (PubMed).

Therapy

Bacteremia

How long to treat? It depends in part the underlying infection, but with the exception of S. aureus, the data suggests that shorter (5-7 days) are no worse than longer courses of antibiotics for bacteremia from a variety of sources. Mostly we treat some multiple of 7 since we have 7 days in the week.

"Twenty-four eligible trials were identified, including one trial focusing exclusively on bacteremia, zero in catheter related bloodstream infection, three in intra-abdominal infection, six in pyelonephritis, 13 in pneumonia and one in skin and soft tissue infection. Thirteen studies reported on 227 patients with bacteremia allocated to ‘shorter’ or ‘longer’ durations of treatment. Outcome data were available for 155 bacteremic patients: neonatal bacteremia (n=66), intra- abdominal infection (40), pyelonephritis (9), and pneumonia (40). Among bacteremic patients receiving shorter (5-7 days) versus longer (7-21 days) antibiotic therapy, no significant difference was detected with respect to rates of clinical cure (45/52 versus 47/49, risk ratio 0.88, 95% confidence interval [CI] 0.77-1.01), microbiologic cure (28/28 versus 30/32, risk ratio 1.05, 95% CI 0.91-1.21), and survival (15/17 versus 26/29, risk ratio 0.97, 95% CI 0.76-1.23) (PubMed)."

There is the above, then there is a retrospective study that suggests for uncomplicated gram negative bacteremia 14 days of antibiotics is better (PubMed).

Sepsis

Zeroth: get those antibiotics into the patient ASAP. Every hour of delay increases mortality (PubMed) (PubMed).

First and foremost find the source and drain it / remove it. If you don't drain it /remove it, the patient has an increased chance of dying (Pubmed). Source control rules.

Second: support per you local intensivist. If there is a professional around call them, don't try it alone.

Third: antibiotics

- the exact nature of which depends on the suspected organisms and the source. Generally speaking, you want at a minimum (my order of preference) third generation cephalosporins OR carbapenem OR piperacillin OR penicillin/beta-lactamase inhibitors. If penicillin allergic aztreonam OR quinolone. and maybe give at least one 5-7 mg/kg dose of aminoglycoside (see rants below) plus/minus vancomycin (if a reasonable suspicion of MRSA).

Combination therapy in most studies does not alter mortality (PubMed) BUT if the monotherapy turns out to be ineffective, the patient is toast, no organism is 100% susceptible in this century, so I think combination therapy is reasonable pending sensitivities, especially if there is a lot of resistance in your neck of the woods.

In areas were resistance is rare, even 2 days of an aminoglycoside leads to increased renal toxicity without improving outcomes (PubMed).

Two active agents decreases mortality to a greater extent than one active agent (51.7% versus 36.4%) and an aminoglycoside is better than a quinolone (PubMed) if addition of a quinolone does much; some studies show no benefit (PubMed).

Combination therapy may be optimal for management of high-risk, life-threatening infections, particularly those associated with septic shock but may be detrimental to low-risk patients (PubMed)."

If the patient has been on antibiotics in the prior 90 days, the bug will probably be resistant to that antibiotic. Give a different class or watch mortality rise (PubMed). It is amazing how often when patients go south in the hospital after course of antibiotics and the prior antibiotics are restarted. Change the class of antibiotics; the new infection is probably resistant.

The patient should probably receive a macrolide for its immunomodulatory effects whether or not the organism is susceptible to a macrolide; it decreases mortality (PubMed).

After a day or three, when cultures are back, de-escalation of antibiotics is associated with decreased mortality (PubMed).

Fourth: Adjunctive therapy. Lots and lots and lots of fluids and pressors, which ones I leave to the fad of the day. Goal directed therapy may not be the cats pyjamas anymore (PubMed).

Clarithromycin, perhaps due to immunomodulatory effects (PubMed), at a dose of 1 gm a day for three days markedly decreases days on the ventilator and may decrease mortality (PubMed).

Steroids? It comes and goes.

- with severe pneumonia maybe should receive hydrocortisone 200 mg bolus followed by 10mg/hr for days. It decreases mortality. Maybe. The 2008 NEJM study suggests more harm than good. The data issue is not yet resolved definitively (PubMed). The CID meta-analysis suggests it is safe but not effective at decreasing mortality (PubMed). Back and forth back and forth, for thirty years we still can't say what the use of steroids in sepsis should be.

Most important for Candida sepsis: Start an echinocandin and pull the damn catheter (PubMed).

The wonder drug that works wonders? In sepsis "10.9% mortality for acetyl salicylic acid users and 17.2% mortality in the propensity-matched nonusers " (PubMed).

Treating fever in sepsis in the ICU has no benefit (PubMed). And if it does no good then it only can harm. Like all of alternative medicine.

The physiology can be tricky. Increased levels of cell free hemoglobin is associated with death and, if elevated, acetaminophen may be protective (PubMed). But how often do you check cell free Hgb? Not often I bet. Perhaps we should.

Drotrecogin alfa [Xigris®] or activated protein C pulled from the market in 2011 as repeat studies demonstrated it is not better than placebo. 20 grand a course for nothing. A lesson on the importance of remembering that most of medical literature is wrong.

"Polymyxin B hemoperfusion added to conventional therapy significantly improved hemodynamics and organ dysfunction and reduced 28-day mortality in a targeted population with severe sepsis and/or septic shock from intra-abdominal gram-negative infections (PubMed)".

That is just the ID part of treatment. There is the whole surviving sepsis protocol, with many interventions that will improve outcome (PubMed) from the abstract:

"Key recommendations and suggestions, listed by category, include (and this is why we have intensivists):

- early quantitative resuscitation of the septic patient during the first 6 hrs after recognition (1C)

- blood cultures before antibiotic therapy (1C)

- imaging studies performed promptly to confirm a potential source of infection (UG)

- administration of broad-spectrum antimicrobials therapy within 1 hr of recognition of septic shock (1B) and severe sepsis without septic shock (1C) as the goal of therapy

- reassessment of antimicrobial therapy daily for de-escalation, when appropriate (1B)

- infection source control with attention to the balance of risks and benefits of the chosen method within 12 hrs of diagnosis (1C)

- initial fluid resuscitation with crystalloid (1B) and consideration of the addition of albumin in patients who continue to require substantial amounts of crystalloid to maintain adequate mean arterial pressure (2C) and the avoidance of hetastarch formulations (1C)

- initial fluid challenge in patients with sepsis-induced tissue hypoperfusion and suspicion of hypovolemia to achieve a minimum of 30 mL/kg of crystalloids (more rapid administration and greater amounts of fluid may be needed in some patients) (1C)

- fluid challenge technique continued as long as hemodynamic improvement, as based on either dynamic or static variables (UG)

- norepinephrine as the first-choice vasopressor to maintain mean arterial pressure ≥ 65 mm Hg (1B)

- epinephrine when an additional agent is needed to maintain adequate blood pressure (2B)

- vasopressin (0.03 U/min) can be added to norepinephrine to either raise mean arterial pressure to target or to decrease norepinephrine dose but should not be used as the initial vasopressor (UG)

- dopamine is not recommended except in highly selected circumstances (2C)

- dobutamine infusion administered or added to vasopressor in the presence of a) myocardial dysfunction as suggested by elevated cardiac filling pressures and low cardiac output, or b) ongoing signs of hypoperfusion despite achieving adequate intravascular volume and adequate mean arterial pressure (1C)

- avoiding use of intravenous hydrocortisone in adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability (2C)

- hemoglobin target of 7-9 g/dL in the absence of tissue hypoperfusion, ischemic coronary artery disease, or acute hemorrhage (1B)

- low tidal volume (1A) and limitation of inspiratory plateau pressure (1B) for acute respiratory distress syndrome (ARDS)

- application of at least a minimal amount of positive end-expiratory pressure (PEEP) in ARDS (1B)

- higher rather than lower level of PEEP for patients with sepsis-induced moderate or severe ARDS (2C) - recruitment maneuvers in sepsis patients with severe refractory hypoxemia due to ARDS (2C)

- prone positioning in sepsis-induced ARDS patients with a PaO2/FIO2 ratio of ≤ 100 mm Hg in facilities that have experience with such practices (2C) - head-of-bed elevation in mechanically ventilated patients unless contraindicated (1B)

- a conservative fluid strategy for patients with established ARDS who do not have evidence of tissue hypoperfusion (1C)

- protocols for weaning and sedation (1A)

- minimizing use of either intermittent bolus sedation or continuous infusion sedation targeting specific titration endpoints (1B) - avoidance of neuromuscular blockers if possible in the septic patient without ARDS (1C)

- a short course of neuromuscular blocker (no longer than 48 hrs) for patients with early ARDS and a Pao2/Fio2 < 150 mm Hg (2C)

- a protocolized approach to blood glucose management commencing insulin dosing when two consecutive blood glucose levels are > 180 mg/dL, targeting an upper blood glucose ≤ 180 mg/dL (1A)

- equivalency of continuous veno-venous hemofiltration or intermittent hemodialysis (2B)

- prophylaxis for deep vein thrombosis (1B) - use of stress ulcer prophylaxis to prevent upper gastrointestinal bleeding in patients with bleeding risk factors (1B)

- oral or enteral (if necessary) feedings, as tolerated, rather than either complete fasting or provision of only intravenous glucose within the first 48 hrs after a diagnosis of severe sepsis/septic shock (2C)

- and addressing goals of care, including treatment plans and end-of-life planning (as appropriate) (1B), as early as feasible, but within 72 hrs of intensive care unit admission (2C). Recommendations specific to pediatric severe sepsis include: therapy with face mask oxygen, high flow nasal cannula oxygen, or nasopharyngeal continuous PEEP in the presence of respiratory distress and hypoxemia (2C), use of physical examination therapeutic endpoints such as capillary refill (2C)

- for septic shock associated with hypovolemia, the use of crystalloids or albumin to deliver a bolus of 20 mL/kg of crystalloids (or albumin equivalent) over 5 to 10 mins (2C)

- more common use of inotropes and vasodilators for low cardiac output septic shock associated with elevated systemic vascular resistance (2C)

- and use of hydrocortisone only in children with suspected or proven "absolute"' adrenal insufficiency (2C)."

Pearls

The combination of a beta -lactam PLUS an aminoglycoside is arguably the best initial choice for survival. Not a beta-lactam and a quinolone. I kept this in strikethrough as there is now a study to show all cause 28 day mortality is decreased with the combination of a beta-lactam and a quinolone. Ouch. I hate having to change my mind. One dose of gentamicin cannot hurt anyone kidneys (Pubmed) and if they are in ARF, the kidneys are protected. And what is better? A dead patient with live kidneys or a live patient with dead kidneys? I suppose if you are waiting for a renal transplant, the former.

(PubMed).

How long to treat? 5-7 days? It is enough for bacteremic cellulits, pneumonia and cystitis (PubMed). For uncomplicated gram negative, perhaps 14 days (PubMed). Does NOT have to be IV as long as there is good source control.

Bacteremia, like most infections, is long term bad for you. People admitted with bacteremia have an increased risk of death in the next year often from cardiovascular disease (PubMed).   But then all infections lead to an increase in vascular events.

Rants

Get the blood cultures before antibiotics just for once, would you puh-lease?

And vitamin C? Here is my take from Science-Based Medicine from April, 2017

Doctor: Not so sick, my lord,
As she is troubled with severe sepsis,
That keep her from her rest.
Macbeth: Cure her of that…
Doctor: Therein the patient
Must minister to himself.
Macbeth: Throw ascorbic acid to the dogs; I’ll none of it.

Writing about pseudo-medicine is relatively easy. Most pseudo-medicines are simple and self-contained. Being fundamentally fictional, outside of real complications, you do not have to fret overmuch about physiology and anatomy and plausibility and all the other aspects of medicine that make being a doctor a lot like Barbie in a math class. It’s tough.

After the flood, I’m left high and dry

I have been inundated (two is an inundation for me) with emails about “Hydrocortisone, Vitamin C and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study.” What, they ask, as an ID doctor and skeptic, do you make of it?

I have 34 years plus of taking care of severe sepsis and septic shock and I have seen interventions come and go in the attempt to decrease the mortality from sepsis. Using steroids has waxed and waned, combination antibiotics have had their day in the sun, anti-endotoxin antibodies looked promising, and over a billion dollars was spent on Xigris before studies showed it didn’t work, so never mind.

A career of disappointed hopes has rendered me skeptical. Headlines like:

They fail to impress. Been there, done that. Vitamin C has had such a bad reputation for so long as King of the overhype, having actually efficacy would be like an apology from the current POTUS. Never gonna happen. But let us have a Joan Jett moment and see where the literature leads us.

Before we get to the study, back to basics. Is there any reason to suspect vitamin C would have any effect on sepsis? Maybe.

Some fundamentals

Vitamin C has beneficial effects on the mediators of sepsis in mouse models, although mice are not men:

Highlighting just how poorly the mice reflected the human disease, the correlations of the gene changes in the mouse models with their human disease counterparts came close to those expected by random chance alone.

Vitamin C levels are often very low in septic patients, so repletion and/or super-therapeutic doses may have beneficial effects on variety of septic pathophysiologic processes, especially the low blood pressure that accompanies sepsis.

Patients with severe sepsis present with hypovitaminosis C, and pre-clinical and clinical studies have indicated that administration of high-dose ascorbate decreases the levels of pro-inflammatory biomarkers, attenuates organ dysfunction and improves haemodynamic parameters. It is conceivable that administration of ascorbate to septic patients with hypovitaminosis C could improve endogenous vasopressor synthesis and thus ameliorate the requirement for exogenously administered vasopressors.

I never find these kinds of extrapolations compelling. Sepsis/septic shock is a jaw-droppingly complex reaction to a variety of processes, most often infection, and most of these hoped for effects would appear to be no more than pissing on a forest fire.

But there are a pair of prior studies. One is a prior small, placebo controlled trial that showed benefit from intravenous vitamin C, with septic patients requiring less vasopressors and a decrease in mortality. Another preliminary safety trial also showed benefit. And vitamin C has been used with some benefit in other severely ill patients, including burn unit and surgical patients. The studies had different designs and end points, but pointed the same direction: less organ failure, less mortality, and faster resolution. And with no side effects. A wonder drug working wonders?

A good start, but…

So an encouraging, albeit it small and preliminary, literature. Which brings us to the current paper. It is everything you don’t want a clinical trial to be. It is not blinded, placebo controlled, or randomized, and has small numbers of patients. It is the kind of paper that, when seen through the lens of “Why Most Published Research Findings Are False” leads to a sigh and an eye roll.

After a Hail Mary of giving vitamin C to three septic patients who unexpectedly survived, they started routinely giving vitamin C (plus thiamin and low dose steroids) to all their septic patients.

The paper is a comparison of 47 patients before the intervention with vitamin C and 47 patients after the intervention. In other words 94 anecdotes, an extended riff on the theme of what I call the three most dangerous words in medicine: in my experience.

The patients were similar in both groups, but only a small number had positive blood cultures. But, in line with prior studies, treatment decreased the need for vasopressors and mortality:

The hospital mortality was 8.5% (4 of 47 patients) in the treatment group compared to 40.4% (19 of 47 patients) in the control group (p < 0.001).

The treatment group also improved their SOFA score (a measure of disease severity) more rapidly:

The 72-hour delta SOFA score was 4.8 ± 2.4 in the treatment group compared to 0.9 ± 2.7 in the control group

Impressive results from an unimpressive methodology. Such an impressive effect by vitamin C on such a complex pathophysiology seems just too good to be true. Which means it probably is.

What does the future hold?

What is going to happen now? If history repeats itself, first IV vitamin C will be in short supply followed by a marked increase in acquisition cost. Never saw a pharmaceutical company yet that that didn’t take the opportunity to price gouge. There will be a clinical trial with a good methodology that will show no overall benefit but there will be benefit in post hoc subgroup analysis. And another trial of the subgroup will be done and, a decade from now, after I am retired or dead, vitamin C will be found to be ineffective for sepsis. I sure hope I am wrong.

The pseudo-medical world is already getting their paranoid conspiracy boxers in a twist over suppression of a ‘natural’ way to treat sepsis while demonstrating a lack of understanding of the scientific process.

This story also provides a good case study into how medicine should work: doctors use their knowledge and experience—as well as the work of their colleagues—to test new treatments for intractable diseases, and then determine what works. The government has time and time again proven itself incapable of determining whether the drugs it approves are effective, and the FDA is, of course, susceptible to the self-interested manipulation of scientific research carried out by Big Pharma. The question of efficacy should be left to doctors and patients.

As if massive doses of intravenous vitamin C is natural. I would not be surprised if a naturopath gave patients IV orange juice, you know, to potentiate the effects with a natural source of vitamin C.

I like big buts and I cannot lie

But but but but but. One big but.

What to do now as a clinician? When a patient hits the ICU septic, how to apply this scant, preliminary, unsatisfactory information? Death. That is one hard, impressive, endpoint. Death is not the usual subjective, biased, soft result that is the effect of pseudo-medical interventions. An 8.5% mortality rate for sepsis is damn good. It may be the ICU equivalent of flipping a coin and getting heads 10 times in a row. Or it may be the real deal. It appears they keep coming up heads.

We have now treated over 150 patients with severe sepsis and septic shock. We have had only one patient die from sepsis, this being a complex surgical case who died in the immediate post-operative period. While a few of the treated patients have died, none died from progressive organ failure related to sepsis. All these patients were weaned off pressors/mechanical ventilation and died from their underlying disease

Vitamin C for decreasing mortality from sepsis, no matter how preliminary the data, is so far consistent, and is so tempting, despite my pessimism that it will be yet another overhyped flash in the pan. But we have to fight our wars with the equipment at hand. The future? Hamlet or Macbeth?

Let me see. (Takes the vial) Alas, poor ascorbate! I knew it, Horatio, a vitamin of infinite therapeutic effects, of most excellent fancy. It hath treated a thousand pestilences, and now, how abhorred in my imagination it is!

Or:

I dreamt last night of the three weird trials:
To you they have show’d some truth.

But given the risks, the benefits, and the data until there is a definitive trial I have to side with Vizzini:

Never go in against vitamin C when death is on the line!