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Septic shock: diagnosis and management

Are hospitalists incorporating the latest research findings into sepsis treatment?

April 2020
septic shock

IT’S ONE OF THE BIGGEST emergencies hospitalists deal with: patients going into shock, usually from sepsis.

But as new research and recommendations about sepsis come out—some very controversial—it’s hard to keep up with how management and treatment of septic shock is evolving. At the same time, new evidence is providing information clinicians can use to treat other forms of shock, including cardiogenic shock.

At last fall’s management of the hospitalized patient conference at the University of California, San Francisco (UCSF), Lekshmi Santhosh, MD, MA, a UCSF intensivist, gave hospitalists an update on how to manage shock and approach its treatment. And through polling her audience, Dr. Santhosh helped provide a snapshot of how—and if—hospitalists nationwide are incorporating the latest research findings into treating sepsis.

No switch to SOFA
Dr. Santhosh pointed out that one recent and much-debated change came in 2016 from the Sepsis-3 task force. That task force recommended that clinicians move away from using SIRS criteria, claiming that the SOFA (Sequential Organ Failure Assessment) score provided superior predictive ability—at least among ICU patients. Sepsis-3 also endorsed the use of qSOFA (for quick SOFA) to identify patients with a suspected infection who were likely to do poorly.

“Early norepi can help you get control of shock more quickly.”

Lekshmi Santhosh, MD, MA

~ Lekshmi Santhosh, MD, MA
University of California, San Francisco

So have those recommendations caught on? Not according to Dr. Santhosh’s audience poll. While 10% of audience members said they do document SOFA/qSOFA scores (along with SIRS findings) for patients with suspected sepsis, more than 70% reported still documenting only SIRS criteria.

“You’re not wrong,” said Dr. Santhosh, referring to those who rely exclusively on SIRS. “There’s a reason why most institutions in the country have not switched yet to SOFA/qSOfA.”

For one, qSOFA—which assesses blood pressure, altered mental status and tachypnea—has been validated only in the outpatient setting. Further, a study in the August 2019 issue of Chest revealed qSOFA’s shortcomings in the hospital. Analyzing data on more than 1 million patients, the authors found that only one in three patients with qSOFA-positive scores on admission had a suspected infection. And only one in six proved to have sepsis.

“That’s a positive predictive value of only 17%,” Dr. Santhosh noted. While SIRS criteria—rightly so—get a bad rap for being nonspecific, “qSOFA is also not good at ruling sepsis in or out.” That’s why, she added, “neither the CMS nor any of the critical care or emergency medical societies has fully endorsed the new sepsis-3 criteria or verbiage. I think it’s totally appropriate to keep thinking in terms of SIRS.”

In the meantime, she views SOFA as a useful research tool.

“I use it like an Apache score to assess how sick patients may be and how much end organ dysfunction they’re experiencing,” she said. While she expects to see the scores used more frequently in research, “they’re not really ready for clinical practice.”

Sepsis bundles
Another big area of controversy: In 2018, the Surviving Sepsis Campaign (a joint initiative among international critical care societies) recommended using a one-hour bundle instead of the three-hour bundle that clinicians often struggled to meet.

“It was almost like a dare,” said Dr. Santhosh. “Can you do this all in one hour?” In fact, that one-hour recommendation sparked such a backlash—with articles saying the effort to implement such a bundle would require a complete overhaul of how EDs manage patients with vague symptoms or hypotension—that the Surviving Sepsis Campaign briefly dropped it. (It has since been reinstated with slight revisions and is still causing an uproar.)

So what are hospitalists actually using? In a poll, the majority of audience members—58%—said they still used the three-hour bundle. But 23% reported having adopted the one-hour bundle, while 13% said they weren’t using any bundle at all. Six percent claimed to not know what a sepsis bundle was.

“Bundles and checklists can certainly help,” Dr. Santhosh concluded, “but three hours may be more realistic than one.”

Sepsis management
• Blood cultures: Everyone knows that you should get blood cultures for patients with suspected sepsis and septic shock before administering antibiotics.

A study in the March 2019 Clinical Microbiology and Infection really drove that point home. Among ICU patients who got blood cultures, only 51% had positive cultures, “which isn’t great,” Dr. Santhosh admitted. But culture positivity plummeted to 28% in those who’d already received antibiotics.

“We really need to push our colleagues to get those cultures before antibiotics,” she noted. Even that 51% “can buy us something. It can help us tailor our antibiotic sensitivity/specificity if, for example, we know we have sepsis from a urinary source.”

• Fluids: A quick poll of audience members indicated that about 54% of the audience now use Lactated Ringer’s for resuscitation, while 41% use normal saline. According to Dr. Santhosh, those results show the impact of two big studies published in 2018, the SALT-ED and the SMART trials.

“Earlier this decade, the colloids vs. crystalloids issue was settled,” she said. “But that still left the question of which crystalloid to use.” In the SALT-ED trial, for instance, patients receiving either balanced crystalloids (primarily Lactated Ringer’s) or isotonic crystalloids (normal saline) had about the same length of stay and number of hospital-free days.

“But the normal saline group had much higher risk of kidney injury: 5.6% vs. 4.7%,” she noted. “When you’re pounding the patient with normal saline for septic shock, it’s a great volume expander—but at the cost of worse AKI down the road.” Another consideration: “Maybe that hyperchloremic metabolic acidosis could actually make your pressors not work as well.”

• Pressors: For fluids, the Surviving Sepsis campaign recommends 30 ccs per kg. “So when do you make the jump and escalate to vasopressors?” Dr. Santhosh asked. Polling the audience, a big majority—84%—said they opt for what she called “standard practice”: giving patients two to three liters of fluids, then pressing.

But results of the randomized CENSER trial published in the May 1, 2019, American Journal of Respiratory and Critical Care Medicine make a strong case for giving pressors sooner.

In that trial, one group received norepinephrine (the first-line pressor to use in shock) significantly earlier than the other: within 93 minutes vs. 192. The early group had significantly better shock control at six hours, meeting a target MAP and tissue perfusion goal or achieving target MAP with urine output and lactate clearance of greater than 10%.

“This is much earlier than we’re used to, and the authors concluded that the early norepi can help you get control of shock more quickly,” she said. “This is adding to the evolving body of evidence that we tend to over-fluidize people, and we’re seeing bad effects on their kidneys with worse AKI over the long term.”

At the same time, Dr. Santhosh admitted that escalating to pressors sooner may mean placing a central line and transferring a patient to the ICU earlier as well.

“All of these are limited resources, right?” she noted. “But a growing body of literature shows that peripheral pressors can be very well-tolerated.” A September 2015 study in the Journal of Hospital Medicine, for instance, found that by using a protocolized system with good ultrasound-guided large-bore IV, “you could run norepinephrine peripherally for up to 24 hours”—something that Dr. Santhosh said “we’re seeing more and more.”

“Peripheral pressors are being used short-term,” she added, “if you think patients can come off them quickly.”

As for which pressors to add onto the first-line norepinephrine, Dr. Santhosh said that vasopressin was second line, “particularly at the dose of .02 or .04. We used to give super-high doses but saw limb, digit or gut ischemia. We don’t see those now with these low doses.” She tells people to consider starting vasopressin “when you’re getting into double-digit norepinephrine doses of 10 or 12 mcg/min. That can spare the norepinephrine and lower those requirements.

Epinephrine is the best third-line drug, she added. “And fourth-line are things like angiotensin 2, steroids, vitamin C, even methylene blue.” While dopamine was once used a lot, studies in the early 2000s showed that norepinephrine had a mortality benefit compared to dopamine and dobutamine. “Most of that mortality was from arrhythmias.”

Other shock
When it comes to other types of shock, cardiogenic shock “is the big one that confuses everyone,” Dr. Santhosh said, particularly mixed septic and cardiogenic shock.

“Even in cardiogenic shock, norepinephrine is the best first-line pressor.” But when should you add an inotrope? An article in August 2019 in Chest on reconsidering vasoconstrictors in cardiogenic shock produced what she called “a crazy, complicated format” that she proceeded to break down.

“They basically said that to manage cardiogenic shock, you have to remember three physiologic philosophies or concepts.” First, optimize patients’ metabolic rate and avoid energy demand. “Think about paralytics.”

You also want to optimize pump function. “That’s when you think about things like dobutamine or milrinone.” One of UCSF’s anesthesiology attendings taught her to break pump function down into its three compartments: right heart, left heart and pulmonary vasculature.

“Different drugs actually work differently on those separate components,” she explained. Keeping those three compartments in mind can help you titrate pressors or know which pressor to use to address right heart dysfunction or pulmonary hypertension. For patients with pulmonary hypertension, for instance, “you might think about adding things like vasopressin instead of escalating norepinephrine.”

And third, optimize tissue perfusion. “A pure alpha-vasoconstrictor like phenylephrine is not a great go-to because you’re actually worsening tissue perfusion.”

Keeping all three concepts in mind, according to the authors of the Chest article, means finding the right compromise between having the best possible tissue perfusion at the lowest myocardial energy cost. “Your mixed shock patients need multiple layers of optimization.”

Surviving sepsis
As for post-sepsis care, Dr. Santhosh said she appreciated a graphic in the February 2018 issue of Nature Reviews Nephrology study that provided a timeline of what sepsis patients die from.

About 10% have what those authors called “early mortality,” in the first many hours of their illness due to systemic inflammation.

But there is also delayed mortality of weeks to months characterized by immunosuppression. Then, months to years after patients “recover,” long-term mortality may range as high as 50% to 70%, due to long-lasting immune disturbances.

“This is now being actively researched,” said Dr. Santhosh. “Why are people who survive sepsis more prone to infections and have more cardiovascular disease later on?” A study in May 2019 from JAMA Network Open looked at sepsis survivors post-discharge and matched them to controls.

“They found that 15% are dying by the end of year one,” she noted. “Every year after that for five years, an additional 6% to 8% die. Sepsis is fundamentally altering something—your body’s inflammation, cardiovascular risk factors or immune state. We’re going to find out more about that in the coming years.”

Phyllis Maguire is Executive Editor of Today’s Hospitalist.

Sepsis mimics

To suss out mimics of septic shock, Lekshmi Santhosh, MD, MA, a UCSF intensivist, wants hospitalists to take a broad, head-to-toe approach with any patient who has fever. Could that patient have fungal sinusitis or a hospital-acquired upper respiratory infection? Could there be an infection like C. diff or a UTI, or a noninfectious cause like DVT or PE?

Dr. Santhosh told an audience at last fall’s UCSF’s management of the hospitalized patient conference that she breaks sepsis mimics into common ones and rare ones. On the common list: hypovolemic and hemorrhagic shock, PE, cardiogenic shock, and obstructive/tamponade.

For hemorrhagic shock, “pay attention to where you can hide a unit of blood or two,” she said. “Retroperitoneal bleeds are really tricky, and I’ve seen patients with an RP bleed that looked like they have sepsis.” Thigh hematomas “are another place where you can hide blood,” and always consider possible GI bleeds.

Then there are the rare mimics—”the ones that come up maybe once a year”—including unrecognized anaphylactic shock, adrenal crisis or myxedema coma.

“That person with a TSH greater than 100 looks just like sepsis,” she pointed out. “But remember, those people are usually bradycardic rather than tachycardic.”

Other rare mimics: HLH (hemophagocytic lymphohistiocytosis) and toxidromes. “Poison controls are reporting increased incidences of unintentional beta-blocker-calcium channel blocker overdoses. Sometimes, you have patients tip into renal failure without really being aware of it.”

Vitamin C: a reality check

The idea of using vitamin C to treat sepsis has generated a great deal of interest since a June 2017 study in Chest reported astonishing results from a single-center retrospective study: Sepsis patients given a cocktail of vitamin C, steroids and thiamine had an in-hospital mortality rate of 8.5% vs. 40% among controls.

But as a reality check on those results, the CITRIS-ALI trial in JAMA in October 2019 looked specifically at ARDS due to sepsis. Interestingly, said Lekshmi Santhosh, MD, MA, a UCSF intensivist who spoke to hospitalists about shock at last fall’s UCSF hospitalized patient conference, “the primary endpoint was actually looking at biomarkers—CRP and thrombomodulin—as well as changes in SOFA score, not mortality.”

The authors concluded that there were no significant differences between the vitamin C group and controls. And in January 2020, the authors of the randomized VITAMINS trial concluded that vitamin C combination therapy vs. intravenous hydrocortisone alone didn’t resolve sepsis more quickly, boost mortality or save patients from needing pressors.

Meanwhile, “we’re not using vitamin C much except in our Hail Mary, kitchen-sink approach if someone is maxed out on three pressors and you’re throwing on steroids for septic shock.” While some viewed the VITAMINS trials as the final nail in the coffin for vitamin C therapy, others have argued that perhaps the trial intervention was not deployed early enough in the course of the disease. When there isn’t much else you can do, “you often don’t see much benefit or harm.”

Dr. Santhosh also pointed out that giapreza (angiotension II) is another drug that’s been introduced. It works on the renin angiotensin aldosterone system.

“It’s been very expensive,” she noted, “and it has a lot of contraindications.” The big one is coagulation issues. “We found a big increase in signals for DVT, PE and thrombosis,” she explained. “But again, it’s for refractory septic shock, so it’s end-of-the-line therapy. We don’t use it regularly, but on a case-by-case basis.”

Published in the April 2020 issue of Today’s Hospitalist
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