Tuesday, March 26, 2019

Sepsis: When infection overwhelms

New research has shaken up a time-honored strategy for treating advanced prostate cancer that’s begun to metastasize, or spread. Doctors ordinarily treat these cases with systemic therapies designed to kill off metastatic tumors appearing throughout the body. But they don’t use local therapy to treat the primary tumor in the prostate. That’s because the primary tumor — unlike the metastases that it spawns — is rarely lethal. So doctors have been reluctant to give local therapy, such as radiation to the prostate or surgery to remove the organ, if it’s not going to improve the odds of survival.

Now investigators are turning that assumption on its head. According to their findings, men who received local therapy while being treated for metastatic prostate cancer lived longer than those who didn’t, “and that makes a case for being more aggressive in how we manage patients who present with metastatic disease,” said Dr. Chad Rusthoven, a radiation oncologist and assistant professor at the University of Colorado School of Medicine in Denver, and the study’s first author.
Looking back

Rusthoven and his colleagues scoured eight years of data collected by a national cancer registry between 2004 and 2014. Their retrospective study identified 6,382 men who had metastatic prostate cancer at initial diagnosis. All the men were treated with systemic androgen deprivation therapy (ADT) for metastatic prostate cancer, but 538 of them were also treated with local radiation to the prostate. At just over five years of follow-up, on average the men who got local therapy had a median overall survival of 55 months compared to 37 months among those who did not. In addition, 49% of the men who were treated with both ADT and local radiation lived for five years compared to 33% of the men who got ADT alone.

Should the findings be confirmed in studies that monitor survival forward in time, “then standard therapy for metastatic prostate cancer will shift to a comprehensive strategy that includes control of the primary tumor,” said Dr. Ana Aparicio, a medical oncologist at the University of Texas MD Anderson Cancer Center in Houston, who was not involved in the study.
Why this approach might work

Aparicio said that treating the primary tumor makes sense for several reasons: First, since men now live with metastatic disease for longer than they used to, they’re more likely to develop symptoms— pain, urinary obstruction, and infections — that can be controlled with local treatment. Furthermore, mounting evidence suggests that tumors in the prostate release chemical and biological substances that promote the cancer’s spread.

Still, Rusthoven and Aparicio both emphasized that local treatments should only be given to men participating in a clinical trial. Local therapy can have significant side effects, “and moreover we need a better understanding of who benefits from the treatment most,” Aparicio said. Her team at MD Anderson is currently enrolling patients for a clinical trial that provides standard systemic therapy for metastatic disease to one group of patients, and ADT combined with either local radiation or surgery to remove the prostate to another.

Rusthoven said he would only give local therapy outside of a clinical trial to a “select group of young patients with limited metastatic burden who are interested in maximally aggressive therapy and who clearly understand the risks and benefits of that approach.”

“This study suggests a different and very novel way of thinking about how to manage men who present with metastatic prostate cancer,” said Dr. Marc Garnick, the Gorman Brothers Professor of Medicine at Harvard Medical School and Beth Israel Deaconess Medical Center, and editor in chief of “There are other cancers where treating the primary cancer in the setting of metastatic disease has been associated with improvements — and this study provides an important impetus to consider this option both in the context of clinical studies and individualized patient selection.”
Your doctor says that you need to wear that Darth Vader mask, which caps off a bad month. First, that little bit of shortness of breath you were having when walking fast turned out to be coronary artery disease. That led to the placement of stents in the blood vessels in your heart. In addition to new medications, you were then referred to a cardiac rehabilitation program where instruction was provided on exercising more, losing weight, and changing to a healthier diet. The last straw is that because of a history of snoring, a sleep study was done and showed obstructive sleep apnea, a condition where you stop breathing at night. Your doctor recommended treatment with continuous positive airway pressure (CPAP) to reduce the risk that your coronary heart disease will progress to a heart attack or stroke.

But, is there evidence to support this recommendation?

The best treatment for moderate to severe obstructive sleep apnea is CPAP. It is a device worn while asleep that works like a reverse vacuum cleaner and applies pressure through a mask into the airway to keep it from collapsing during breathing. Obstructive sleep apnea is a risk factor for the development of high blood pressure, coronary artery disease, stroke, and premature death. Treatment with CPAP lowers blood pressure, and there is some evidence that it may prevent the development of heart disease and eliminate the risk of early death. Until recently, however, evidence that CPAP is beneficial in those who already have heart disease was not available. Now, the results of a large international clinical trial indicate that CPAP may not reduce the risk of heart disease progression.

The SAVE trial recruited 2,717 adults with coronary artery disease or history of stroke from seven countries (though not the United States). Half were treated with CPAP and half were not. After an average follow-up of 3.7 years, the number of people who died from heart disease, had a heart attack, had a stroke, or were hospitalized for heart failure was the same — for both the people using CPAP and those who didn’t.

Does this mean that you should not use CPAP if you have heart disease and sleep apnea? Not at all. Despite its lack of benefit in reducing heart disease and stroke in this study, people in the CPAP group had an improvement in daytime sleepiness, depression and anxiety symptoms, and overall quality of life. Furthermore, there was a suggestion that stroke risk was lower in the CPAP group. In addition, it is important to note that most of the subjects were Asian, and that the risk factors for obstructive sleep apnea are different in Asians than in other ethnic groups.

Finally, only 42% of the subjects in the CPAP group used it for more than four hours per night, which is the minimum amount of time considered as acceptable use in the United States. It is possible that any benefit of CPAP in preventing progression of heart disease will require greater usage. Although one could use the results of this study as an excuse to not use CPAP, until there is further information it would be a mistake to do so. The study reaffirms that CPAP reduces sleepiness and improves quality of life. More studies will be necessary to conclude that it does not reduce risk of progression in those who already have heart disease. For the past few years, I’ve been talking to parents about a new approach to introducing their babies to solid foods. Along with talking about baby cereals and purees, I’ve been talking about baby-led weaning.

There are no spoons involved in baby-led weaning. In this approach, babies literally feed themselves solids they can pick up and put in their mouths themselves. There are some interesting benefits to this approach. First, it puts babies in charge of how much they eat, and studies have shown that this may decrease the risk of obesity by teaching them to listen to their own hunger cues. It also puts babies in charge of when they are ready to start solids, delaying it until they are ready (as opposed to when their parents are ready). And what I also like about it is that it encourages family meals: instead of quickly feeding Baby before sitting down to eat, parents can include Baby in the eating experience.

When I talk to parents about this approach, they often worry about the risk of choking. Although I spend time talking about safe ways to let babies feed themselves, this is a very understandable worry. Researchers in New Zealand were also worried and did a study that was recently published in the journal Pediatrics.

In the study, 206 healthy infants were randomized to either starting solids through baby-led weaning or to a control group. The parents in the baby-led weaning group were also given written information about choking hazards and feeding their baby safely. The researchers called the families regularly to ask about choking episodes.

What the researchers found was that 35% of the babies choked at least once between 6 and 8 months — but there was no difference between the groups. Babies feeding themselves didn’t choke any more than babies in the control group.  The babies in the study group gagged more than the control group at 6 months, but less than the control group at 8 months, which makes sense: at 6 months they were handling larger pieces of food than the control group, but by 8 months they had it figured out.

Just over half of the babies were given foods that were choking hazards, such as teething cookies, hard crackers or raw vegetables — but again, there was no difference between the two groups.

If you are thinking about doing baby-led weaning, talk to your doctor about the best foods (soft enough to mash in the mouth, or large and fibrous enough — like strips of meat — that chunks won’t break off) and the best ways (such as seated upright, always supervised) to feed your baby. You can also do a combination of baby-led weaning and spoon-feeding. When I was a doctor in training I was involved in a very sad case, the unexpected death of a patient, a woman in her fifties who had diabetes.* She had been seen in the clinic and diagnosed with pneumonia only two days before her passing. The diagnosis was correct, as well as the prescribed antibiotics. But she had been sent home, and her condition deteriorated quickly. By the time her family brought her into the emergency room, she was in septic shock.
What is sepsis?

What does it mean to be in septic shock? Sepsis is when the body’s response to a serious infection gets out of control. As the illness progresses, the cells of the immune system release a cascade of chemicals that eventually cause massive inflammation and can lead to organ malfunction, shock (“septic shock”), and death. The death rate from sepsis can range from 25%50%.

Generally, infections of the lungs (like pneumonia), urinary tract, abdomen, and skin are more likely to cause sepsis, and certain bacteria are the most common culprits.
Who is most likely to develop sepsis?

Some people are more likely to develop sepsis: those older than 65, infants younger than one year, and anyone with a weakened immune system are all particularly susceptible. The immune system can be weakened by certain medications, such as steroids, chemotherapy, or drugs to prevent transplant organ rejection; many chronic diseases such as diabetes, heart failure, and kidney failure hinder the immune system as well. This makes it easier for germs to multiply, and infections can quickly become overwhelming,

In the case of our patient above, she had a lung infection with a strain of bacteria called pneumococcus, which commonly causes pneumonia. She also had a weakened immune system due to diabetes, and she had declined the pneumonia vaccine. These factors made her very vulnerable to sepsis, and she should have been admitted to the hospital from the clinic for more aggressive treatment and closer monitoring, rather than sent home.

Since this case almost two decades ago, I have seen multiple patients who developed sepsis. Each case is very different, but they are all pretty much seared into my memory. (And, for the record, no one under my immediate care has died.) Sepsis is an emergency. People with infections or even early sepsis often first seek the help of their primary care doctors, so I am very interested in preventing it when possible, and recognizing it quickly when it does happen.
Early recognition and treatment of sepsis are critical

The Centers for Disease Control and Prevention recently published an analysis of several hundred cases of septic shock, from 2012 to 2015. The CDC partnered with the New York State Department of Health and Emerging Infections Program to examine the records of 246 adults and 79 children diagnosed with sepsis to see what factors contributed, and how it could have been prevented.

One huge factor is whether people had been properly vaccinated, and specifically whether they had gotten a pneumonia vaccine. The CDC authors state: “pneumonia is the most common infection causing sepsis, and vaccination is an important and highly effective prevention strategy.” Appropriate vaccination can prevent the worst infections from starting in the first place.

Another key finding in the CDC study was that approximately 72% of these patients had had contact with the healthcare system in the days prior to their illness. Many of these patients had chronic health problems, and so would be in medical offices or hospitals more often than healthy people. But, the report suggests that contact with the medical system itself could pose a risk for infections (and therefore sepsis), for example from hospital-acquired infections of intravenous lines and urinary catheters. Another important finding was that there may have been opportunities for providers to intervene earlier in the infections. With sepsis, early recognition and treatment is essential; once septic shock sets in, the risk of dying from sepsis increases greatly. Prevention efforts such as appropriate vaccination and minimizing hospital-acquired infection are important, and early and urgent recognition of sepsis is critical.

The CDC authors recommend that family members of susceptible patients should know the common symptoms of sepsis. These can include fevers, shaking chills, flushed skin, racing heartbeat, and confusion, among other things. As the illness progresses, the blood pressure drops dangerously low, and organs can stop functioning correctly. This can take hours or days, depending on the individual. If sepsis is at all suspected, the patient should be brought to medical attention as quickly as possible. Remember, sepsis is a medical emergency and rapid treatment can make all the difference in whether or not a person recovers.

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