DR. DAVID SERES: Hello again.
I'm Dr. David Seres, and it is my absolute honor to be your moderator for the second
half of this session.
Session two moving toward beyond the terminology of malnutrition.
I'm Professor of medicine in the Institute of Human Nutrition and Director of Medical
Nutrition and an associate clinical ethicist at Columbia University Medical Center in New
York.
Just as, just to remind you, you'll note that our oral presentations of our illustrious
speakers are brief, their CVs are long, and to maximize time for the presentations, we
have posted their bios on the, in the speaker's section, which you can find the controls for
on the left side of your screen, along with all of the other boxes you might want, including
the Q&A box which we encourage you to use to submit questions at the end.
We have had some really robust discussions.
We have a half an hour to pester our speakers and get them to clarify the issues that they're
presenting.
Yesterday, we started with an introduction to malnutrition, starting with the impact
of those prior to illness from Nancy Rahman from the Partnership for a Healthier America,
and then Gordon Jensen gave us a bit of a review of the history of malnutrition diagnostic
criteria.
We then moved into a presentation of the AHRQ report that really spurred this particular
conference, along with many others.
A presentation of a value project that was done through the auspices of the American
Society of Parenteral Enteral Nutrition in which the financial consequences of malnutrition
in the sick were discussed.
We looked at quality of care interventions, the economics of nutrition in health care.
We talked about how to figure out what the optimal number of dietitians were, and we
talked about issues of of payments and reimbursement in the hospital.
We also talked about how people go about making a diagnosis of malnutrition and systems that
people have put into place, both with technology and people to capture the diagnosis.
And then we had a presentation on how lifestyle interventions are reimbursed.
And I will say that it was really a little disheartening to find that a very brief visit
to give somebody a medication was paid far in a way better than a longer session for
counseling.
Then we moved into this session, the second session.
I will reintroduce this by saying that I think that this particular topic is really the fundamental
question surrounding our approach to malnutrition, and that is what is it that we're talking
about when we actually speak of malnutrition?
Because a lot of us disagree to a degree in what we mean.
I, for one, will not use the expression that to say, to describe somebody as malnourished
if they have malnutrition, where others automatically say that those who have malnutrition are malnourished.
And my philosophy on this is that if somebody is malnourished, then there has to be a new
nourishment that will make them better.
And in fact, a lot of our research has shown that, that there, our interventions are either
ineffective or that we're choosing the wrong populations.
And that's a lot of what was discussed in the first part of this session, session two.
We talked about the efforts to, the most recent efforts to define malnutrition by GLIM and
others.
We talked about the fact that the diagnosis of malnutrition is highly, highly validated
to predict poorer outcomes.
But we also have shown that the diagnosis does not predict who will respond to nutrition
intervention.
And this is why there's a dichotomy of opinion about whether or not people who have malnutrition
are also malnourished.
And this is what I feel is one of the most important research questions that we can seek
out because we had data presented to us that, in fact, that if somebody has a high level
of inflammation, and I will say as an aside that a high level of inflammation will, is
often times we think the cause of a lot of what we use to distinguish people as having
malnutrition.
Regardless, that high amount of inflammation predicted people not responding to any nutrition
intervention in a randomized controlled trial finally.
And that the, all of the, excuse me, current schemes the subjective global assessment types
of pre-assessments of assessment of risk.
Again, all are very predictive of outcomes in general but are not predictive of who will
respond to nutrition interventions.
We then reviewed the micronutrient deficiencies and their impact, the cause, consequences
and treatment.
And then we talked about the nutritionally vulnerable and hidden hunger, which, again,
talks about sort of those who are out of the hospital and looked at some of the research
that's going on, trying to see if interventions in those populations improves health outcomes.
So, excuse me, for this afternoon, or whatever it happens to be for those of you who are
watching this either another time zones or not live, we're going to, we're going to talk
now about what we as a team, the organizing committee, sort of stumbled across the term
that we'd like to coin, which is refractory malnutrition, which is really what I am sort
of describing, and what others are describing when we say inflammation counters the nourishment
effect, excuse me.
Rose Ann DiMaria-Ghalili is going to be speaking about nutrition and aging across the care
continuum.
Excuse me.
Carrie Earthman will be speaking about body composition and nutrition status.
Professor Reid from Belfast will be speaking about a really interesting project that is
ongoing to try and define cachexia in patients with advanced renal disease.
Mary Platek will be speaking about cachexia in cancer patients and specifically about
the new ASCO guidelines.
And then we'll have a discussion at the end.
So with all of that, let's begin our talks.
DR. ROSE ANN DIMARIA-GHALILI: Hello, everyone.
My name is Rose Ann DiMaria-Ghalili.
I am the senior associate dean for research and professor of nursing at Drexel University
College of Nursing and Health Professions.
Today I will be presenting on nutrition and older adults across the care continuum.
These are my objectives.
We are a super aging nation.
By 2035, there will be more older adults than children under the age of 18 years of age.
And not only will there be more adults 65 and older, but older adults will be living
longer.
And by the year 2060, we will see unprecedented growth in those 85 years of age and older.
As individual's age, they are, will experience risk factors from malnutrition.
Some of these risk factors include physiological risk factors, losses of all their changes
in their sense of taste and smell, poor oral health and loss of lean mass.
Older adults who are also experienced are more likely to experience one or more chronic
conditions as they age.
Some chronic conditions can lead to impairments in their activities of daily living and their
instrumental activities of daily living, which can impact their ability to prepare or ingest
food.
As one ages, they may experience Alzheimer's disease or dementia and impairment in cognitive
status such as ADRT can impact swallowing, appetite, behavioral issues, especially during
mealtime, which can impact their food intake.
And this slide here just shows you the percentage of older adults in 2019 that had one or more
physical functioning difficulties with their physical functioning.
Medications from chronic, prescribed medications as a result of one or more chronic conditions
can also impact dietary intake.
Depression is common or increased in older adults, and that can also cause decreased
dietary intake, appetite and weight loss.
Older adults, if they live alone, they may lose their desire to cook because of loneliness.
The appetite of widows decreases after the loss of a spouse or significant other.
And they may, if they live alone, they may have not be, they may lack access to transportation
to buy food, and that can also put them at risk for malnutrition.
We know that many older adults are on a limited income and they may restrict the number of
meals eaten per day or the dietary quality of their meals because they have to struggle
with food vs. medicine vs. utilities.
And the environment in which one lives can also be a risk factor for malnutrition.
In one study that we did with southeast Pennsylvania, we found that those who lived alone lived
below the poverty level, experienced difficulties with housing costs, used public transportation
and housing services and receive food stamps and didn't have the internet were more
likely to be malnourished than those older adults who didn't experience these environmental
conditions.
And so put this all together, if there's a decrease in dietary intake, we will see increased
risk for malnutrition.
And when we put this all together, we know that in older adults that experience poor
nutritional status, who have inadequate intake of their protein energy or micronutrient intake
can lead to, this can lead to functional decline and eventually lead to negative outcomes,
poor recovery, disability and frailty.
So, we say, what is the risk of malnutrition across the care continuum?
We know for older adults, we want older adults to experience the most appropriate care in
the most appropriate setting.
And much of what we know in the literature is what's happening in the hospital setting
in terms of malnutrition risk and incidence and prevalence or in some post-acute care
settings.
But on this continuum, you can see there's lots of touch points in which we could provide
care for older adults and we should be doing nutrition screening and assessment.
Over on the right, because older adults may age and place in different settings aside
from their home, they're, again, we need to rethink this continuum of care and think about
different opportunities for us to provide nutrition screening and assessment for older
adults.
Now, much of what we know about the prevalence of malnutrition in older adults is from the
acute care setting.
This is nationally representative data from the Health Care Costs and Utilization Project
in 2010 and in 2018.
In 2010 of the, there were 1.2 million people who had malnutrition, who were discharged
from the hospital with malnutrition.
The mean age of those who were malnourished was 64.8 years of age, and 58.3 percent of older
adults had a malnutrition diagnosis.
Fast forward to 2018 and there is the same similar trends.
The mean age of those with malnutrition was 64.8 and older adults accounted for 59.5 percent
of all those who had a malnutrition diagnosis during the hospital stay.
But that's the acute care setting.
What happens?
Many older adults live, are free living older adults in the community.
There's very little nationally representative data that describes nutrition prevalence or
malnutrition prevalence in older adults living in the community.
We ran some data from the National Health and Ageing Trends Study, which is a nationally
representative sample.
This data was presented at the Gerontological Society of America meeting and we're in the
process of writing up this paper and what we found was 19% of those 85 years of age
and older were malnourished and 39% of community dwelling older adults, 75 to 84 were malnourished.
And so there is more malnutrition in the older age groups in this setting.
We also know that there is a gap in not only, there is a gap in how prevalent malnutrition
is in older adults across the care continuum, including these transitions of care when people
are transferred from the hospital to their home and what are the best treatment options
in each setting.
So we need more research in this area.
Another gap that we see is how to best differentiate malnutrition from other tissue loss syndromes
in older adults such as cachexia, sarcopenia, and frailty and how to treat malnutrition
when it co-occurs with these tissue loss syndromes.
Another gap we see are what are the best guidelines for clinical nutrition in hydration in older
adults across the care continuum?
Given that more than 50% of hospitalized patients in the U.S. with the diagnosis of malnutrition
are older adults, now is the time for us in the US to develop age appropriate nutrition
and hydration guidelines.
The Europeans have done that. ESPAN has published their guidelines in 2019.
And lastly, how prepared is the health care workforce to recognize and treat malnutrition
in older adults?
In 2008, the then Institute of Medicine published a report on retooling for an aging America,
building the health care workforce to really shed light on this.
But the call to action today is are we prepared to address the unique needs of an aging society?
Are age appropriate nutrition screening and assessment tools routinely used?
And are we prepared to implement interdisciplinary interventions?
So, in summary, nutrition plays an important role in healthy aging.
There are bio psychosocial risk factors that can impact nutritional status in older adults.
Malnutrition can negatively impact health outcomes.
What is needed is an interdisciplinary collaborative approach to recognize and treat malnutrition
in older adults.
And there is a great need for further research on the role of tailored nutritional interventions
to promote healthy aging, to treat malnutrition and other related syndromes and to promote
quality of life across the care continuum.
So with that, thank you, and I look forward to your questions.
DR. CARRIE EARTHMAN: Hello, I'm Carrie Earthman, and I'm pleased to be here to talk to you
about body composition tools and nutrition assessment.
I have nothing to disclose.
In this session, we'll talk about CT, ultrasound and bio impedance variables for clinical nutrition
assessment and consider research needs and future directions.
It is now well recognized that muscle is a central component of nutritional status, and
muscle loss is associated with poor clinical outcomes and poor functional status.
Interventions targeting muscle aim to improve both clinical and functional outcomes.
We need ways of measuring muscle both in our initial assessments and ideally so we can
monitor response to our interventions.
The most common techniques available to clinicians include CT, ultrasound and bio impedance.
In order to interpret the measurements of muscle or its surrogates that we obtain by
a particular method, we need to have appropriate cut points that define low muscularity.
These are typically derived based on healthy population data, whereas the fifth or tenth
percentile for a particular clinical population based on clinical outcomes.
It is imperative to recognize that low muscularity cut points differ by body composition method,
by device and by the algorithm or prediction equation applied.
Clinicians should know that selection of reference cut points should match the assessment method
for best results in interpreting the information obtained.
So first, let's talk about CT.
The most widely studied CT generated variables come from total abdominal muscle at the level
of the lumbar three vertebra.
There have been some studies looking at just the psoas muscles at the same location and
the pectoralis muscle from chest CTs.
We can look at muscle area and extrapolated whole body measures like skeletal muscle index
in terms of quantity measures and muscle density reflected by mean Hounsfield units to indicate
muscle quality.
I'll just highlight a few of the recent studies in ICU patients to exemplify the CT-derived
variables that could be useful for nutrition assessment and monitoring.
CT of the total abdomen at the level of L3 can be used to assess total abdominal
muscle area, which predicts mortality and other clinical outcomes in cancer, liver failure
and critical illness.
And from these studies we have reference cut points now for low muscularity.
Total abdominal muscle area is also superior to SGA for identifying low muscularity in
ICU patients and can be used to track muscle changes over an ICU stay.
CT at the level of L3 can also be used to evaluate the psoas major muscle area, and
this can be used to track muscle quantity changes in pancreatic cancer and lower psoas
muscle density predicts 90-day mortality and other adverse outcomes in trauma patients.
For any of the body composition variables that might serve as nutrition biomarkers,
we typically start by looking at its ability to predict clinical outcomes, and then we
want to know if the variable can identify low muscularity or malnutrition.
An important next step is to see how well the variable can track changes in response
to nutrition interventions.
In terms of CT, the largest amount of data has been generated around the use of total
abdominal muscle to predict clinical outcomes, including mortality.
These primarily come from cancer patients with a limited number of studies and patients
with critical illness and liver failure.
There's growing interest in the use of quality measures.
For example, mean Hounsfield units, which represents the density of the abdominal muscle
to predict outcomes like mortality.
Little or no data are available on the psoas muscle also at the L3 or the pectoralis
muscles in the chest for any of these areas.
Tracking changes can be challenging because CTs are not always repeated for follow ups.
Now let's talk about ultrasound.
Although three or more site protocols are thought to produce the best results, the most
widely studied single site has been the quadriceps muscles due to clinical feasibility.
Muscles can be quantified in terms of area or thickness, and muscle quality can be assessed
by quantifying echogenicity of a defined area through histogram analysis.
This is a similar concept to muscle density done in CT.
So here's a snapshot of where we are with ultrasound derived variables.
Quadriceps muscle thickness can differentiate malnourished from normally nourished hospitalized
individuals and a 3-site muscle protocol using the biceps, forearm and thigh can provide
reliable estimates of muscle changes during ICU stays and during nutrition intervention.
Other studies have shown that the rectus femoris cross-sectional area measures can track muscle
changes over a course of an ICU stay.
And then quadriceps muscle quality as assessed by echogenicity has been shown to decrease
with diminished function and tissue necrosis during an ICU stay.
We have some data on the use of total quadriceps and rectus femoris thickness and quality
to predict poor outcomes in malnourished status.
But in general, we need more work on ultrasound.
The use of it is complicated by lack of consensus on protocol, including sites to measure, and
which, if any, single site is best to use to represent whole body, muscle and nutritional
status.
Commercially available ultrasound instruments don't record the angle or anisotropy of your
measurement, and this is a concern for longitudinal measures of muscle quality because echogenicity
or density measures are altered by the probe not being 90 degrees to the muscle.
Furthermore, landmarking and visualization of the muscle can be quite challenging in
individuals with extreme obesity and in those with substantial edema.
Finally, it's not clear that it will be possible to establish appropriate reference cut points
for muscle thickness or quality measures given device and protocol differences.
Next, let's talk about bio impedance techniques.
There are three primary categories of bio impedance devices, including single frequency
bioelectrical impedance analysis, multi frequency BIA, and bio impedance spectroscopy.
A number of whole body and raw variables have been proposed as nutrition biomarkers.
I've shown the most commonly studied ones.
The bars indicate which type of device can generate the variable.
For example, BIS devices can generate all of the whole body variables.
Similarly, raw variables are listed on the right side of the slide in a similar fashion.
As shown on the previous slide, these are some of the more promising whole body measures
and raw variables.
So here's a snapshot of some of the bio impedance derived variables that have been used for
nutritional assessment in ICU and hospitalized patients.
Appendicular skeletal muscle index and other muscle indices by single frequency BIA equations
such as the Kyle or Janssen equation have been shown to correlate with CT-derived muscle
mass in ICU patients.
Fat free mass by single frequency BIA using the Kyle equation and 50 kilohertz phase angle
have been shown to agree with SGA and hospitalized patients for identifying malnutrition.
Normally hydrated lean tissue by BIS has been shown to correlate with CT abdominal muscle
area and tracks losses over an ICU stay.
Impedance ratio at 200 to over five kilohertz and 50 kilohertz phase angle can differentiate
malnourished from nourished hospitalized patients and are correlated with low muscle quantity
and quality by CT of the abdomen in ICU patients.
BIS-generated variables including higher characteristic frequency resistance at infinity over zero
frequency and 200 to 5 kilohertz impedance ratio and lower membrane capacitance and phase
angle were associated with worse clinical outcomes and muscle function in ICU patients.
50 kilohertz phase angle is the most widely studied raw bio impedance variable, followed
by whole body fat free mass generated by the Kyle equation, which is a single frequency
BIA equation.
To a lesser extent, the 200 to 5 kilohertz impedance ratio generated by multifrequency
or BIS devices has been shown to predict outcomes and identify malnourished individuals in some
clinical populations.
Normally hydrated lean tissue generated by one of the BIS algorithms applied in patients
on dialysis has been shown to predict outcomes and nutritional status in that population.
There is growing interest in BIS-generated variables, but more data are needed on all
of the bioimpedance-derived variables, particularly to understand which ones might
be most useful to monitor response to interventions in various clinical populations.
Reference cut points for interpretation of measures are device and population specific
and data are lacking in most populations.
The GLIM Working group has called for greater detail on what body composition measures should
be used and the specific cut points required for determining low muscle mass.
So where do we go from here?
Clinical nutrition intervention studies can help us validate the GLIM malnutrition diagnostic
criteria, specifically low muscularity or muscle deficits, and further refine the methods
we can use to determine low muscle mass or quality in clinical settings by capturing
muscle changes.
These studies should include reference measures of body composition in addition to field methods.
And although it's not easy, it would be ideal to include repeat measures so we can understand
the precision of a method so we can determine if the change that it is measuring is real.
These intervention studies can help us establish relevant cut points for various body composition
variables to define low muscle mass and/or muscle quality, and to differentiate moderate
from severe malnutrition using muscle measures.
We need to know how should low muscularity cut points best be defined. By reference method
muscle measures or malnutrition reference standards, or by clinical outcomes?
We know that reference cut points are typically specific to device in addition to ethnicity,
sex and age.
We could have whole body or isolated muscle quantity or quality measures or simple variables
such as 50 kilohertz phase angle or BIS derived variables that serve as biomarkers for muscle
health or nutritional status.
In summary, we know how important muscle is to the assessment of nutritional status and
clinical outcomes, but it's not always easy to measure and there are no direct ways of
getting at it.
Several CT, ultrasound, and bio impedance generated variables are potential candidates to serve
as biomarkers of muscle health and thus nutritional status.
A growing number of these have been shown to predict clinical outcomes and to identify
malnutrition and low muscularity.
Fewer of them have been evaluated for their ability to track changes in response to interventions.
Ultimately, precision and reliability need to be evaluated in order to determine how
well a body composition derived biomarker can detect meaningful changes in a given setting.
And we need to know which ones are worth the time for clinicians to measure during nutrition
assessments.
Thank you for your attention.
DR. JOANNE REID: Hello and thank you for joining this presentation on Renal Cachexia.
My name is Joanne Reid.
I work at the School of Nursing and Midwifery and Queen's University in Belfast within the
United Kingdom, where I need a program of research on renal cachexia.
To start with, I would like to thank the organizing committee for the opportunity to present at
this virtual meeting.
Chronic kidney disease has become a global health burden and it's associated with increased
morbidity and mortality.
And particular wasting is highly prevalent in the later stages of illness.
Protein energy wasting syndrome and chronic kidney disease was a term first developed
by the International Society of Renal Nutrition and Metabolism, and it's defined as a state of decreased
body stores of protein and energy fuels which occurs progressively under specific to chronic
kidney disease.
There's multiple terminology in relation to malnutrition that has been identified, linked
to wasting and chronic kidney disease.
These include malnutrition, disease-related malnutrition, protein energy wasting, cachexia,
sarcopenia and muscle wasting.
The etiology and the progression of renal cachexia is complex and it's multifactorial,
and there is a need to have consistent terminology which has been agreed when referring to renal
cachexia.
And that's really important because the treatment approach for this needs to be specific to
reflect the multifactorial etiology of renal cachexia.
The review shown here highlights that the recent understanding of cachexia pathophysiology
during chronic kidney disease progression suggests that protein energy wasting and cachexia
are closely related.
And that protein energy wasting corresponds to the initial state of a continuous process
that leads onto cachexia implicating the same metabolic pathways as in other chronic diseases.
The paper also advocates the application of a uniform term such as kidney disease cachexia
to inform future research and practice.
In 2008, Belevence and colleagues developed a consensus operational definition for cachexia
and chronic illness, and also associated clinical features which are shown here.
Cachexia is known to increase morbidity and mortality, and to date, there is no gold standard
treatment.
While malnutrition is often present in cachexia, the clinical characteristic of cachexia is
that it cannot be treated with nutrition alone.
In terms of research gaps and opportunities in relation to renal cachexia, we have led
national and international studies on this area and the publications from that are shown
here.
Previous work has focused on the clinical phenotype of renal cachexia, and also healthcare
professionals in the management of renal cachexia.
We're going to take a look at those in the next few slides.
Our initial study sought to ascertain the clinical phenotype of renal cachexia.
And we drew from the work of Evans et. al., shown in slide four to inform the inclusion
criteria for this study.
This was a longitudinal study of adult hemodialysis patients who were attending two
nephrology units within the United Kingdom.
There are approximately 310 patients with end stage renal disease receiving hemodialysis
who were cared for within those two nephrology sites.
And we did a prospective sample size and we recruited 106 patients who satisfied
an 80% confidence level limit and we followed these participants for one year.
At baseline, we had 17 patients who were identified as cachectic.
You can see here the clinical characteristics of the patients who were recruited into the
study.
And along the left hand side, we have those clinical characteristics based on the Evans
definition of cachexia previously shared, with note to appetite were significantly lower
in the cachectic population mental upper arm, muscle circumference and handgrip strength
were also lower and CRP was raised within the cachectic group.
We had 70 patients included in the final assessment point at the end of month 12.
Reasons for non-follow up included death, withdrawal.
We had three patients who started home peritoneal dialysis and one who was lost to follow up.
Of note, significant changes were seen in handgrip strength, anorexia, fatigue at 12
months for the 70 patients who remained within the study.
And for the cachectic group, they showed significant mean effect on time for handgrip strength,
fatigue and anorexia.
And looking at the multimethod study exploring health care professionals awareness, understanding
and current treatment practices in relation to renal cachexia, we recruited 93 healthcare
professionals from 30 countries globally.
Results from this study highlighted that renal cachexia remains an underdiagnosed and undertreated
condition.
But health care professionals deemed the most important factors when treating renal cachexia
to be an improvement in quality of life and also relief of family distress in relation
to the syndrome.
Looking at the responses of the healthcare professionals who took part within the study,
the most commonly reported symptoms of cachexia were weight loss and also anorexia.
Primary factor leading to treatment for cachexia being prescribed was recorded as weight loss
above 5%.
The majority of participants reported that if a patient had weight loss above 5% which
was involuntary, that they would consider them to be cachectic.
And when asked what improvements they would like to see in relation to renal cachexia,
68% of respondents highlighted the need for a disease specific definition in relation
to renal cachexia to help identify patients within their clinical practice.
For patients with or who are at risk of cachexia, a comprehensive multimodal treatment strategy
is required to target the multifactorial etiology of cachexia.
And we conducted a critical review of the literature looking at the current evidence
in relation to this.
Within this review, we included papers on cancer, COPD and renal disease, and it's the
renal data that's presented here of the included studies.
Two of the four multimodal interventions for CKD did not define criteria for severe wasting.
And the remaining two studies used the protein energy wasting definition that we discussed
earlier that was developed by Danny Folk and colleagues in 2008.
However, even within that, there were differences.
For example, one of the studies did not mention reduced dietary intake as part of their criteria.
Additionally, if you look at these studies, you can see heterogeneity across the treatment
characteristics and also the endpoints measured.
Despite limitations of the study such as small sample size, for example, these studies do
show greater improved endpoints when combining treatment modalities.
But what they also demonstrate is that we need larger and we need better parred
studies and that we also need increased research collaborations to optimize future trials of
multimodal interventions within this area.
Following on from our critical review sought to develop a multimodal intervention which
had components of anti-inflammatory agents, exercise and also dietary counseling.
Importantly, we also incorporated psychosocial support, which none of the studies included
and the critical review reported on.
However, we do know from current and previous research that there is a need to address the
emotional and also the social context around reduced appetite that's seen in cachexia as
they can impact on distress and anxiety.
So, we developed this multimodal intervention around a theory of change.
This slide represents the Theory of Change map for our proposed intervention, our multimodal
intervention, including anti-inflammatory dietary, counseling and exercise intervention
components, which you can see here highlighted within the intervention stage.
We used input from stakeholders from various backgrounds to help inform the development
of this map, and they included personal and public involvement representatives as well
as nephrology health care professionals, our own previous research in this program of work
that we've shown previously on slide five and also international literature within this
area.
So, where are we currently in relation to research gaps and opportunities in relation
to renal cachexia?
Well, we are currently undertaking a qualitative study based on phenomenology to explore the
lived experience of renal cachexia with both patients and their informal carers.
That data hasn't been previously reported.
We'd also like to undertake a Cochrane review of the evidence in relation to multimodal
interventions for cachexia management.
And what we would like to do is continue to develop the evidence base to inform a multi-site
randomized controlled trial for multimodal intervention and renal cachexia.
I'd like to acknowledge our current international interdisciplinary working group and funders
who have been involved in our program of research in relation to renal cachexia.
Thank you for your company during this presentation and I look forward to seeing you in the panel
discussion.
DR. MARY PLATEK: Hi, and thank you for the opportunity to provide a summary of the ASCO
Cancer Cachexia Guidelines that were published in 2020.
Our purpose was to provide evidence-based guidance on the optimal approach for treating
cachexia in patients with advanced cancer.
Based on several published resources, we defined cachexia as a multifactorial syndrome that
is characterized by a variety of clinical features, such as loss of appetite, weight,
skeletal muscle fatigue, functional decline, increased treatment related toxicity, poor
quality of life, and inferior survival.
Among patients with advanced cancer, cachexia is noted in about 50% of the population, despite
the type of malignancy.
Historically, the screening of, assessment of, and management for cancer cachexia has
been beyond challenging.
The methodology for the guideline is established by the ASCO clinical practice guideline committee involving
systematic literature review, expert panel to critically review the evidence and interpret
the evidence, and then a guideline that must be approved by ASCO.
Our target population for the review were adult patients with advanced cancer and with
a loss of appetite, body weight and/or lean body mass.
The audience for the guideline are clinicians providing care for these patients as well
as the patients themselves and the caregivers.
Three clinical questions were established for this review, using the target population
do nutritional interventions, question one, pharmacologic interventions, question two
and or other interventions such as exercise improve weight, lean body, mass appetite,
physical function, or quality of life in these patients?
We searched only for randomized controlled trials.
This search brought in 1,374 papers.
After initial screening we had 134 papers to thoroughly review, leaving 36 papers to
be included in this guideline, 20 of whom were systematic reviews of randomized controlled
trials.
For clinical question number one, the impact of nutrition interventions, we recommend that
clinicians may refer their patients to a registered dietitian for both assessment and counseling,
sessions should include both the patient and the caregiver, there should be a focus on
practical and safe advice for feeding and advice against those fad diets or things unproven,
such as extreme dieting, education should be provided to these patients for high protein,
high calorie and nutrient dense types of foods.
The strength of the recommendation was moderate, as noted on a slide.
In the evidence, quality it was rated low.
For the entire group of nutrition interventions, the best evidence was for dietary counseling.
Unfortunately, in most trials, the definition for dietary counseling details were very,
very vague.
Additionally, for nutrition interventions, in particular, nutrition support should not
be routinely offered to manage cachexia.
A short term trial of parenteral in nutrition might be offered to a very select group of
patients, such as those who have a reversible bowel obstruction and short bowel syndrome, etc.
Discontinuation of previous types of nutrition support near the end of life and the end of
life is appropriate.
Nutrition support should remain to be on an individual basis.
There is no recommendation for omega-3 fatty acids, vitamins, minerals, other particular
dietary supplements because the evidence was lacking.
Next, we investigated pharmacologic interventions and up to the time of this systematic review,
evidence was insufficient to strongly endorse any pharmacologic agent.
To improve outcomes, clinicians could choose not to offer medications for the treatment
of cancer cachexia.
There are currently no FDA-approved medications for the indication of cancer cachexia.
However, based on the evidence, it was recommended that clinicians could offer a short term trial
of progesterone analogue or corticosteroid to their patients experiencing the loss of
appetite and/or body weight, and the choice of the agent and the duration of the treatment
would depend on the treatment goals that were developed for the patient.
And lastly, the third question looked at other interventions; for example, exercise.
It could have been combined with nutrition or pharmacologic, but we were looking at other
interventions, and outside of the context of a clinical trial, there really is no recommendation
that could be made for other interventions, such as exercise for the management of those
who present with cancer cachexia.
Based on our work and our discussions with the expert group, we wanted to highlight the
importance of communication in our approaches to cancer cachexia.
So, communication involving the patient, the caregiver and the clinician, it's a highly
stressful stage and it's important to have good communication.
Here are some key points that could be helpful, and those are listed here on the slide under
bullet number two, these were previously published as well as referring to a registered dietitian
to provide the patients and the caregivers with more opportunity to discuss their concerns
and challenges.
We also include information in our guideline about cost considerations that, for those
patients that are paying higher out-of-pocket costs, that might be a barrier for them to
comply with the treatment, that cost for various types of medications very, very markedly depending
upon negotiated discounts and rebates.
And that when it's practical and when it's reasonable to use a less expensive alternative,
that might be something to be considered.
And that this should all be discussed as part of shared decision making.
The major limitations noted from investigating this clinical research include the use of
highly varied definitions, heterogeneous endpoints and a lack of integrated biomarkers.
The most recent definitions of cancer cachexia do not capture the clinical impact of this
syndrome.
Future research could focus on a number of endpoints as well as an assessment of changes
in patient reported outcomes.
Additionally, cancer cachexia research should be identifying and validating novel biomarkers.
Currently there are multiple clinical trials evaluating novel pharmacologic agents for
this treatment, for the treatment of cancer cachexia and so those results are pending.
And lastly, another area of future research interest might involve evaluating an earlier
nutritional interventions in patients that have metastatic cancer.
Additional information may be found on the ASCO.org site for clinicians and patient information
is available at cancer.net.
This is a listing of the expert panel that was involved in this work and references follow
on this slide deck.
I thank you all for your attention.
DR. DAVID SERES: Wonderful presentations.
We have a number of questions.
Oh, good, there is Mary.
The first one was going to be for you.
Thank you.
One of the themes that's come out of this conference, and especially in this part of
the session, we were talking about refractory nutrition and certainly the way that the ASCO
guidelines have presented, it would seem, given the similarities between cachexia and
malnutrition, that you are sort of saying that malnutrition in patients with cancer
is a refractory malnutrition.
I'm wondering if there's been any work done on looking at the cancer types, specifically
those that are inflammatory versus those that are not.
We have experience taking care of patients with sarcomas that live for years versus patients
with, you know, an adenocarcinoma of the pancreas living for months.
And one would assume that the patients who have the longer longevity might benefit from
nutrition support.
Any thoughts on that?
(RECORDING PLAYS) One would assume that patients who have a longer longevity. (RECORDING ENDS)
DR. MARY PLATEK: For some reason I have bad audio, does anybody else?
No?
DR. DAVID SERES: And my voice just echoed (INAUDIBLE).
(RECORDING PLAYS) And my voice just echoed (INAUDIBLE). (RECORDING ENDS)
DR. MARY PLATEK: I have an answer, but I've got double things going on here.
So, maybe move on from me and maybe someone can help me with my audio?
I'm really sorry.
DR. DAVID SERES: Mute your speaker or your mic, I mean.
Mute your mic. OK.
So, actually it's sort of a related question and, Dr. Reid, you can talk about this with us.
Do you think we're going to find different kinds of cachexia, that there are different
mechanisms or that there's something different between disease states? You know, should we
try and come up with a universal definition of cachexia or should we stick with going
with disease specific definitions?
What are your thoughts there?
DR. JOANNE REID: Thanks so much, David.
I think that it's great to have a universal definition of cachexia and chronic illness as a jumping
off point.
And that work was really important because it helped them refine checking who was in
the cancer population, a cancer cachexia specific definition.
But my personal view is that it is really important to look at that definition across
different diseases.
So, for example, within a cancer cachexia population you'd expect to CRP over five.
Well, if you think about cachexia in patients who have hemodialysis, who are receiving hemodialysis,
their CRPs are all going to be over five due to the fact that they're receiving hemodialysis.
And if you think about the hemoglobin, so the cancer population, looking at that definition,
if you're looking for a hemoglobin less than 12, again because of active anemia management,
because they're receiving hemodialysis, those populations will have a hemoglobin less than 12.
So, it is really important, I think, that we can discern differences across disease
groupings so that we identify these patients.
It creates greater homogeneity, especially even if we were looking out from the trials
and specifically in relation to treatment modalities, so that we're treating patients
who have cachexia and can have specific treatment modalities depending on their rates of the
characteristics or rates of inflammation, for example.
So, yes, I do think it's really important that we continue to move forward with disease-specific
definitions.
DR. DAVID SERES: Alright. Dr. Platek, you want to try again?
DR. MARY E. PLATEK: Yeah, I think I'm OK, right?
DR. DAVID SERES: Yes.
DR. MARY E. PLATEK: Don't ask me what's going on.
It was like I was on Mars, but I was on Earth.
In any case...
DR. DAVID SERES: Why don't you address that question and then go back to the previous.
DR. MARY E. PLATEK: Yeah, and I'll probably have to quickly.
So, I think, so here's the deal, I mean, I've been looking at this area forever.
I've done a deep dive like a scoping review, nothing published, looking at what are really
the differences between disease-related cachexia or even disease-related malnutrition.
And we haven't moved forward and in the papers that I've reviewed with these reports, it's
a wasting syndrome.
So, I'm not saying and I completely get the differences with renal disease versus liver
disease because we're talking about different organs, in some cases, some organ systems
are working, in other cases they aren't.
So indeed, the intervention has to be specific.
But to identify could we not consider a global definition for cachexia like we are considering
for malnutrition?
And that whole idea of where cachexia assists with malnutrition, where malnutrition
assits with cachexia, that's another discussion.
But to move forward in identification, could we not do that with complete respect that
there could be some nuances between diseases, certainly in the intervention?
But if so, in that respect, I'd have to say that I would like to see a global move towards
identifying cachexia because, you know, the papers we reviewed with the ASCO committee,
there wasn't a lot to glean from those as far as information for moving forward.
DR. DAVID SERES: So, it sounds like you would like a universal sort of pathway to a syndrome that
may have other inputs from other directions.
DR. MARY E. PLATEK: Yeah.
DR. DAVID SERES: And I think that universal pathway will have something to do with systemic inflammation,
if I'd hazard a guess.
Yeah.
So, the question I had asked earlier, which sort of ties into that, which is there any
understanding of cancer type and its impact on whether or not malnutrition develops?
And specifically, I said that in inflammatory cancers there's probably a...
Oh, I got distracted, I lost my train of thought.
Anyway, so there's probably a difference between inflammatory and non-inflammatory cancers
in terms of whether or not they develop cachexia in the first place, but that there's certainly
benefit for long survivors who have non-inflammatory cancers from being nourished.
At least that's what physiology would teach us.
Anyway, go on.
I'm sorry.
DR. MARY E. PLATEK: Yes.
And I completely agree with that.
And I think the best that we can say today, because definitions were that were used in
the papers that we reviewed were either vague or different, that those with more an inflammatory
component, they were the how we identified cachexia in those papers, you know, there
were certain cancers that had higher prevalence of cachexia.
So, there weren't many papers, for example, for breast cancer survivors.
But, you know, I'm going to stop myself there as well because you can look at these differences
in cancer types and you can think of the physiology, but then you have to think of the stage and
the treatment, because the treatment will also change what we see in a patient, what the presentation is.
DR. DAVID SERES: OK, great. Thank you.
Dr. DiMaria-Ghalili, you talked a lot about doing nutrition screening and the importance
of doing so in the elderly, given the prevalence and the fact and sort of the under identification.
I'm wondering if there's been any data to assert that the screening process and the
assessment process then alters outcomes when interventions are applied based on them.
One of the themes of yesterday's talk was that a lot of the assessment tools used in
the hospital in particular, to determine nutrition risk don't predict who's going to respond to
nourishment.
But I also imagine that in these populations a multidisciplinary approach goes beyond nutrition.
Anyway, your comments.
DR. ROSE DIMARIA-GHALILI: Well, I think it's really important to think about nutrition screening
in older adults using age appropriate tools, number one, because there are a lot of risk
factors that could be targeted by not only nutritional interventions, but social interventions.
Like do people, you know, are we giving them the services that they need to age in place
appropriately?
And that has to be part of our intervention criteria when we're getting ready to move
people from the hospital to the home, and also when primary care practitioners are actually
doing their assessment on older adults.
So, it's just not the nutritional component but also the social component as well.
So, I think for us, in order to really target outcomes, we need to make sure that the interventions
are appropriate for the age group, number one.
DR. DAVID SERES: OK.
A lot more to come.
And there is a question that I'll ask you too. I don't know if you're in the Moonshot
discussion, but if you could look at Charlotte's questions, you want know which, many studies
were would you would pick?
And if you could let us know, we'll make sure it represented that in that discussion.
DR. ROSE ANN DIMARIA-GHALILI: Well...well just to dovetail on what everyone else just commented on, I think that
the critical piece, especially for aging, is that these tissue loss syndromes are going to
occur simultaneously.
So, we need to be able to differentiate and figure out how to develop the best
multimodal interventions in this population.
DR. DAVID SERES: Yeah.
And I would hazard a guess that, you know, as we understand the longer term consequences
of hospital illness is now termed frailty, we're going to find out that frailty isn't too
different from cachexia and from malnutrition, as we've defined each of those separately,
and that they all need multimodal intervention.
Dr. Earthman, you had a number of very specific questions, and let me try and summarize them
quickly:
Why didn't you talk about DEXA?
DR. CARRIE EARTHMAN: OK.
Well, I didn't talk about DEXA because for clinicians, you know, most of us are looking
at bedside techniques, you know, in terms of the ease of use and access and that kind
of thing.
So, globally, you know, a lot of clinician researchers and, you know, in their research
studies, but also just in bedside assessment, you know, we're talking about using techniques
like bioimpedance, the most commonly used is by far and away single frequency BIA.
But ultrasound is on the rise and people are also thinking about using CT.
So, yeah, DEXA, if you have access to DEXA, I would consider it, you know, one of our
reference standards.
And if we can get DEXA in our studies, where we're looking at bedside techniques, that'd
be great, right?
So, it's a, you know, I agree DEXA is very good data, but it's not available for many
clinicians, you know?
DR. DAVID SERES: We have like a research center that's devoted, that happens to have one...
DR. CARRIE EARTHMAN: Yeah.
DR. DAVID SERES: The University of Texas at Austin, a colleague of mine just told me they have
one and they're very excited to be using it.
DR. CARRIE EARTHMAN: Yeah.
And like, you know, some places where, you know, they've got active, you know, body composition
assessment as kind of standard in their protocols, then they might get that.
But for many people, it's not really something that is easily achievable.
DR. DAVID SERES: So, there were several questions that boiled down to what are the pros and cons
of each method.
You know, I know that there are issues with BIA and fluid shifts and so forth, and I don't
know that you can really give a full course on this in about 30 seconds, but give it a try.
DR. CARRIE EARTHMAN: Like asking to do a 10 minute talk on three techniques, it was too much, I realize. Yeah.
So, I think the thing is there is no one perfect method, obviously and part of it is what people
have access to.
So, what I always try to just have people understand is that every method has limitations
that you just need to be aware of.
There are bioimpedance techniques just to start with, with that by impedance spectroscopy
devices that are multi-spectral, you know, offer more than single-frequency BIA in terms
of differentiating fluid compartments and kind of accounting for some of the limitations
or challenges that are presented when you use a really simple linear regression derived
equation that you would apply with a single frequency measure, for example.
So, there are nuances and bioimpedance has come a long way bioimpedance spectroscopy
being used quite a lot in dialysis patients.
So, I think that's something to just keep in mind.
Ultrasound is wonderful in many ways.
It's so prevalent, you know, ubiquitous, the devices are around, people can learn how to
do them.
The difficulties with any of these that I'm hoping when we talk about Moonshot studies,
that the ideal is to understand your technician who's taking these measures, the precision
of your measurements, so that you can understand whether you are precise enough to actually
detect changes and to know what that percent change, minimal detectable change is.
And that's a huge challenge.
All of the clinician researchers I talked to around the world doing these types of studies,
it's really challenging to do multiple measures, you know, in a sick population, especially
if you're in ICU or hospital patients.
But that would be an ideal to have if we can understand, you know, what our repeatability
and the precision of our measures are.
I'll leave it at that.
I'm sure I didn't fully answer that question.
DR. DAVID SERES: Well, it's an entire semester course for anybody who's really devoted to measuring
body composition.
I mean, there are all sorts of other techniques, total body potassium, underwater weighing,
you know, there's an entire literature for the person who asked the question.
And it's a fascinating one; the history of it is really quite interesting.
I will also say that coming up in a subsequent session, there are going to be discussions
of using biochemical markers, including D3-creatinine.
There's a wonderful validation of that as a way of looking at muscle mass, it correlates
with MRI and so forth and Bill Evans is going to talk about that.
Thank you, Christopher, for reminding me.
Anyway, so for the audience, please stay tuned and tune in to those.
So, you actually raise a question or a good segway into a question that I'll ask all of
you to think about and answer.
And that is, you know, we've been pretty clear that in our current approach to malnutrition,
we're not very effective at treating it and I would hazard to guess that that's in part
because of the, you know, in the hospital, the patients who have malnutrition and are
refractory or those who are highly inflamed and they're just not getting medically better
and we don't really know what the long term consequences of hospital starvation is.
But setting that aside, do you think that perhaps there's a role to predicting whatever
this syndrome is, malnutrition?
Picking it up really early and seeing if there's early interventions, nutritional interventions
or otherwise that could be applied earlier to prevent it from getting to that point where
it really is refractory?
Any thoughts about that?
Is that in any work that you're aware of?
DR. MARY E. PLATEK: In a couple of comments.
I think we know from, you know, most of the literature is not from randomized controlled
trials, but some from very good observational data we know that if you have a certain cancer
type, for example, GI, head, neck, lung, OK?
That those are associated with poor nutritional status and those people, if not intervened,
will do poorly.
We also know any cancer type that has multi modality treatment, right?
So, you could pick almost anything and let's say you have an induction chemo and you have
a surgery and then you have a radiation treatment, you will do poorly and your nutritional status
will decline.
Also, if you add in older age and certain lifestyle behaviors before, those are usually
associated.
So, based on associations, there are some points where we could predict that.
And since we've decided on certain of our surgeries, for example, oh my goodness.
So, now I'm going to forget what I was just reading last night, bladder cancer, excuse me.
So, if you have invasive bladder cancer, that population just from reading, so off the top
of my head looks older.
I did do cohort observational where it did malnutrition risk, their malnutrition risk
was pretty high based on the NRS 2002 and those people who were targeted at high
nutritional risk did, you know, have more complications surgically just based out of
the small study that I had done.
So, we do have points where we could pick right people and we could intervene earlier.
We are doing some of that with surgical patients, right?
We're getting in there and we're doing supplementation before and we have some protocols for that,
getting them on a treadmill or whatever the case may be before.
So, I think there are ways to predict and time will tell the difference what needs to
be changed in models that we can actually take a look at.
DR. DAVID SERES: In other words, that would be a good target for research.
Yeah.
And that's really the focus of this conference.
A quick comment and, you know, the terminology that, that we keep throwing around here is
intentionally, as far as I'm concerned, confusing because my hope is that we come to a better
consensus about this in terms of coming up, you know, what is cachexia?
What is malnutrition?
What is malnourishment.
And I'll comment that several of our speakers use the terms interchangeably.
And I'd urge everyone to think about when they describe patients as being malnourished,
do they mean it?
And somebody help me come up with a different term for malnutrition.
As I've said before, when when said Gordon Jensen first presented ASPEN AND guidelines at
ASPEN...hundreds of people in the room, I raised my hand.
hand and said, "Hey, Gordon, can we call it something else?
Can we call it Matilda?
Anything other than malnutrition?
Because people who have malnutrition may or may not be malnourished."
And that didn't go over very well, and I've not been very popular ever since.
Alright.
Dr. Reid, can you just quickly go over what is in the multi-modal intervention that you
are applying and maybe a little reason?
DR. JOANNA REID: Yeah.
So...sorry I've got a minute.
It's based around the ideology of cachexia and there's three core components to it.
So, one is resistance training to try and help sustain or rebuild some of the muscle
mass.
And the third is an anti-inflammatory agent.
So, we're using fatty fish oils in relation to that.
And the third component then is dietary counseling.
And one of the things that we do, particularly with the hemodialysis population, is that
they are multimorbid and quite frequently they're seeing a renal dietician, a cardiac
dietician and several other disease specific definitions.
And there's a lot of confusion around what their diet is.
So, what we want to provide is a global assessment and a tailored nutritional plan, focusing
particularly on protein and protein intake.
And alongside all of that then are these psychological components and psychological support that
we really want to give to this particular patient cohort so that they will not only
take part within the study, but also remain within the study.
And we've seen great benefit of doing that in our earlier study, which is the longitudinal
study looking at cachexia.
DR. DAVID SERES: Excellent.
Alright.
Listen, thank you all very much.
I'm afraid we're out of time.
I'd love to spend the entire day talking with you, but unfortunately, that can't happen.
We're going to take a little break right now until, let's see 1, Oops, sorry, I opened
the wrong thing.
The break is until 1:25 and we'll see you back then.
Thank you all.
DR. GAIL CRESCI: Hello and welcome to Session three on Measuring Malnutrition Methods and
Tools.
My name is Gail Cresci and I'm an associate professor in the Cleveland Clinic, Lerner
College of Medicine of Case Western Reserve University, and full staff in the Department
of Pediatric Gastroenterology and Inflammation and Immunity at the Cleveland Clinic in Cleveland,
Ohio.
I am also the immediate past president of the American Society for Parenteral and Enteral
Nutrition.
I will be your moderator for this session.
We have a phenomenal panel of experts presenting on this topic today. For detailed information
regarding their impressive backgrounds,
please refer to the speaker tab that you can find on the left column and this page.
And it's the third icon down.
Or you can go to the main page for this site and you will also find it under the speakers tab.
This session is broken into two parts.
In part one, we will hear about the strengths and caveats of current biomarkers and tools
used to assess malnutrition.
Dr. David Evans will discuss visceral proteins and Dr. Alison Steiber will present physical
and composite measurements.
The second part we will learn about emerging biomarkers and tools for measuring malnutrition.
Dr. William Evans will present on deuterium creatinine dilution method for muscle composition.
Dr. Tom Ziegler will provide an overview on the use of metabolomics for potential utility
in nutrition and metabolic support.
Dr. Kenneth Christopher will follow with more discussion on metabolomics in the clinical
setting, Dr. Raed Dweik will discuss the use of breath analysis of volatile organic compounds
in clinical diseases, including malnutrition.
Lastly, we will hear from Dr. John Alverdi regarding the gut microbiome and malnutrition
in critical illness.
The presentations will be followed by a live question and answer period with the speakers.
During the session, please share your questions for the presenters in the chat box.
We will try to address as many questions as we can during this session.
So here we go.
DR. DAVID EVANS: It's a privilege to be here speaking with you today about albumin and prealbumin
and their current role in practice.
These are my disclosures.
Certainly, albumin and prealbumin are often misunderstood and misapplied.
And when I'm making rounds at the hospital and the residents will often told me that
they sent some nutrition labs and they mean of course albumin and prealbumin. And, you know
this is an area that really challenges results on a regular basis and our nutrition support
team often gets a call that goes something like this; Mr. Jones' Albumin or prealbumin is
very low.
Can we increase the prescribed, you know, amino acids in the TPN or make some other
intervention to try to improve the nutrition support?
So this was a challenge and ASPEN was very well aware of this challenge and their malnutrition
committee formed a group to develop a position paper.
And the key point of this position paper was that albumin and prealbumin are not components
of currently accepted definitions of malnutrition and that they shouldn't be misapplied.
I think the key perception or misperception out there is that albumin and prealbumin would be proxy measures
of total body protein or total muscle mass.
And, you know, we needed to dispel this and make it clear that even if total lean body
mass is changing, but the serum albumin and prealbumin typically aren't.
And so there are several kind of lines of reasoning that supported this finding and recommendation.
So first, albumin and prealbumin in healthy patients, even when starving, typically do
not decline until the patient's body mass index was dropped down to 12 or the starvations
are gone for six weeks or more.
They do not decline in elderly malnourished patients as well.
Their levels do not really correlate with dietary intake, and that's been shown in both
inpatient and critical care settings and albumin and prealbumin levels don't correlate with
restrictive eating disorders such as anorexia nervosa either.
So really the average patient at home starving themselves or whatever can't shift that level
particularly.
But what we do know is that serum concentrations of albumin and prealbumin do decline in the
presence of inflammation.
And this is pretty well known and pretty well understood.
And it's really regardless of the underlying nutritional status.
So we typically refer to these as negative acute phase reactants.
And what happens is the liver reprioritizes its protein synthesis and as a result of being
stimulated by IL-6 and inflammatory cytokines and the signals that inflammation is present.
What happens is the liver shifts its production away from albumin and prealbumin to C-reactive
protein serum amyloid proteins, fibrinogen mannose, lectin-binding proteins, and complement.
And so as that shift occurs, certainly albumin and prealbumin are going to go down.
There's another process at play. In inflammation,
there's increased capillary permeability and albumin and prealbumin moved to the interstitial
third space and albumin functions as an antioxidant in that extracellular space.
So, it really has kind of an almost evolutionary purpose when it does that.
So really, they must be recognized as inflammatory markers associated with nutrition risk rather
than in the context of a nutrition assessment as being, you know, malnutrition per say.
And so this was really one of the key points of our position paper.
And certainly, this makes sense in the setting of, you know, what now have been around for
about 10 years. The etiology-based malnutrition diagnoses, where really, "Is inflammation present,
yes or no?" lies at the heart of the decision tree determining what that nutrition diagnosis is.
And inflammation may limit the effectiveness of nutrition interventions in the settings.
So, we'll talk a lot about nutrition risk in this talk.
And, you know, I think there may not really be a consensus definition around that.
When I'm talking about nutrition risk, I'm typically talking about a patient who is at
risk for a poor outcome without the delivery of adequate nutrition support.
Certainly, nutritionally at risk has been defined by kind of standardized diagnostic
criteria, including, you know, one or more of the following categories that I won't read
off similar to a malnutrition diagnosis.
But this idea of nutrition risk is powerful and it takes several angles.
One is, is that we know that albumin or prealbumin on their own are powerful screening tools.
Albumin in particular for surgical complications, Going back to the 80s and 90s, this has been well
examined.
The VA preoperative risk assessment study looked at 87,000 patients and concluded that
preoperative albumin levels were the single best predictor of overall operative risk.
They looked at several high-risk operations and really determined that a cut point of
approximately 3.5 anything less than that 3.5 grams per deciliter was associated with
increased postoperative mortality.
And furthermore, there were also increases in postoperative pneumonias and anastomotic
leaks, abscesses, respiratory failure, and then, you know, need increased utilization,
such as the intensive care unit, the length of stay in the hospital or the need and the
use of postoperative parenteral nutrition.
So clearly a screening tool like that was very valuable.
And in fact, albumin has been implemented into in the NSQIP risk calculator, which is
going to be one of our standardized surgical risk tools.
It's very widely accepted and the ASPEN guidelines have really used albumin as one of the four
key criteria, including also, you know, weight loss, low BMI or an SGA of C, as you know,
really one of the four reasons to stop and pause and say, "You know, who is going to need
preoperative enteral or parenteral support in order to have a successful surgical outcome?"
The concept of nutrition risk can be quite quantitative, as in this example from the
critical care setting where NUTRIC scores are used to identify nutrition risk, and those
patients with high NUTRIC scores are much more sensitive to feeding and have a much
higher survival when fed well versus underfed compared to patients with low NUTRIC scores
who have low nutrition risk and do not appear to be as sensitive to feeding,
whether it is underfeeding or full feeding. Not just are outcomes often not as good in
patients that are at high nutrition risk.
But we see that even postoperatively they're less likely to meet their energy targets,
more likely to need nutrition support, more likely to have a delayed return to solid food,
less mobility, and a longer recovery of activities of daily living.
When providing nutrition support, we commonly monitor albumin and prealbumin levels, but
their role really remains undefined.
When I see them normalize, I tend to assume that this represents resolution of inflammation
or reduction of the nutrition risk, a transition from catabolism to anabolism, and probably
in most patients, lower calorie and protein requirements.
We also know that with recovery, the albumin goes up and the C-reactive protein goes down.
We also know that extra feeding does not improve prealbumin levels and in critically ill patients.
Whether calories are just appropriately or underdosed, the prealbumin does not change.
This was the same with albumin in the EDEN ARDS trial where trophic versus full
feeding in ARDS for seven days did not result in achange.
Albumin and prealbumin monitoring though are still in the ASPEN guidance for Home PN
monitoring, and I believe that they can be useful providing some insight into fluid status
inflammatory processes where the patient's medical condition was directly quoted here.
Certainly, in my practice I think that I see the transition from catabolism to anabolism
and the resolution of inflammation by looking at the wound, looking at the patient, looking
at their functional status.
We see the wound,the fistula close the wound granulate, the skin grafts successfully take
as in this patient example.
And in this example we see the necrosis debrided away the wound granulates well, and we see
the inflammation resolving.
So thank you for your time.
DR. ALISON STEIBER: Good afternoon.
I am Dr. Allison Steiber, and today I will be speaking briefly on composite measures
for the diagnosis of malnutrition.
I want to thank the NIH and the Office of Nutrition Research for hosting this workshop
and for highlighting research and practice in the area of hospital malnutrition.
Individual nutrition indicators vary in their capacity to comprehensively assess nutrition
status and have been shown to predict different outcomes, with no single indicator shown to
determine whether a person will respond or not to a specific nutrition intervention.
In hospital patients nutrition status is not only about alteration of an imbalance and
nutrient intake which might be modified by abnormal absorption or utilization, but is
also influenced by disease, trauma, sepsis and fever, which induce the impact of inflammation
and oxidative stress.
This figure shows the confounding influence of inflammation.
If we use an ecological approach to understanding nutrition, then macro and micronutrients,
fluid, and multiple other factors need to be taken into consideration when conducting
a nutrition assessment.
Currently, none of the validated composite measures do this comprehensively.
It has been hypothesized that in the hospital patient, a composite of nutrition indicators
is more likely to predict an outcome than any single variable.
Currently in the field of nutrition there are a number of composite tools used to screen
for risk of malnutrition and to diagnose malnutrition, and examples of some of those are on the screen
today.
For example, we have the Subjective Global Assessment that was first published by Dr.
Detsky et. al. in 1986 and in 1987.
We have the patient-generated subjective global assessment and of course, the Academy ASPEN
indicators for malnutrition.
These tools have undergone varying degrees of validation in different populations.
Some of those populations are the hospitalized patients who are there for surgery, such as
studied by Detsky.
Some are the patients with chronic kidney disease receiving hemodialysis, such as the
study that we did a number of years ago.
And there are studies with patients with different types of cancer.
And this systematic review and meta-analysis is just an example of examining those studies.
Another example of a composite diagnostic tool is the nutrition-focused physical exam.
It is a comprehensive exam with a goal to assess the patient from head to toe for different
areas of subcutaneous fat loss or muscle wasting, in addition to assessing for signs and symptoms
of micronutrient deficiencies.
They also look at fluid accumulation or hydration status, functional status utilizing the Handgrip
Dynamometer.
Unfortunately, this method has yet to be validated.
In 2012, White et. al. published a paper describing a method for diagnosing malnutrition different
than the methods that I previously showed you.
This method focuses on inflammation as an ideology and is context specific.
The tool was developed using a consensus process, and thus we needed to validate it.
So the Academy of Nutrition Dietetics Research Team secured funding from Abbott Nutrition
to conduct a feasibility study that would test methods for validating the malnutrition
diagnostic tool.
The results of this pilot were published in 2016 and inform a larger study funded through
the Academy's Foundation.
The goal of this larger study was to examine both the validity of the AAIM tool and staffing
requirements for hospital dieticians.
You heard some of that staffing data by Dr. Hand earlier in the workshop.
The sample I will be discussing today is the adult AAIM data and later in the early life
section, this workshop you will hear Dr. Beth Jimenez discuss the pediatric data.
You can see in the reddish box that the original adult AAIM sample size goal was 600 with a
1-to-1 ratio for malnutrition risk.
Eventually, we will examine the nutrition-focused physical exam and other diagnostic tools in
comparison to the outcomes.
But for today, I am just showing data from the original AAIM tool.
If you look at the green box for outcomes, you can see that we have multiple levels of
outcomes.
We have the dietician-reported nutrition outcomes, we have medical outcomes and the disease severity
indicators Charlson Comorbidity Index, and the MS-DRG relative weight.
Using some of this data, we developed a 90-day composite score which includes both ER
visits and admission within the 90-day period.
For the larger study we considered inflammation, disease severity, ICU presence of stay, socio-demographics
and body size to be potential confounders.
And we use length of stay readmission and ER visits as previously noted, as our outcomes.
This figure shows recruitment for the project, but additionally, to the full study it focuses
on the AAIM subgroup.
And that's what I'll be showing you some data from today.
To be noted is we have pending data from six different sites for their 90-day outcomes.
Thus, I will show you data from 26 different sites and 213 patients.
I would like to note that we think that this is one of the first studies to look at malnutrition
diagnosis and include data from over 25 different studies.
The patient characteristics are shown here.
I'm not going to walk through all the data due to time, but I really wanted to show the types
of data that we collected.
This particular study collected huge amounts of data both on the facility and on the individual
dietitian and of course, on the patient.
Of note is the median age of the patients of 65 and a relatively equal distribution
by education level.
This is about the patient medical characteristics, including nutrition.
You can see on the first line that we are looking at malnutrition screening tool, which
is how they determined whether the person was at risk or not for that 1-to-1 distribution.
Our median number was a two and for MST a two indicates moderate risk, which is logical
because then when the dieticians use the AAIM tool, you can see the distribution.
44% had no malnutrition, 26 had moderate and 30 had severe malnutrition.
As you can see, we also collected data and a variety of other medical characteristics.
In the next couple of slides, I will show the models that were developed to examine
predictive validity for the two primary outcomes 90-day composite score and length of stay.
This first model was developed using a multilevel model, which included random effects for the
different sites.
These data are still preliminary but exciting.
The current data shows that there is an independent, significantly higher incidence of the 90-day
composite outcome for individuals with severe malnutrition as diagnosed with the AAIM tool.
It also shows that for individuals with a higher Charlson Comorbidity Index, there's
an independent, significant association and for women versus men and finally for Native
American and Alaskan natives and black individuals when compared to white individuals.
For the outcome length of stay a multilevel generalized linear model was developed and
assessed, which includes the random effects of sites.
In this model, we have found independent significantly longer length of stay for individuals with
moderate or severe malnutrition diagnosis for individuals who are living with obesity
versus normal weight and for individuals with a MS-DRG relative weight.
Well, both of these models for the 90 day composite score and the length of stay are
exciting and seem to indicate that the diagnostic tool AAIM has predictive validity for poor
outcomes in the hospital setting.
More data will be added to these models and further analyses done to confirm these findings.
There are many opportunities for further research to better understand how we can feasibly diagnose
malnutrition in both the hospital setting and others.
First, we need to validate tools that are commonly used, and as I indicated, nutrition-focused
physical exam is a commonly used tool which has not been validated.
It is one of the few tools that also assesses micronutrient deficiencies and thus even more
important, that tool has validation.
But even bigger than that, regardless of tool, we need to understand does malnutrition as
diagnosed resolve with different nutrition interventions?
Do all patients who are identified as malnourished respond similarly to any specific intervention?
And what other factors need to be considered when predicting response?
Is this tool valid, reliable, and feasible in outpatient community and low-resource settings?
And finally, what is the implementability of diagnosis with a composite measure, whether
ours another one, in all settings with different levels of nutrition practitioners?
Thank you.
DR. WILLIAM EVANS: Thank you very much for allowing me to speak at this important meeting.
Today, I'll be talking about a new method to directly and accurately measure the amount
of skeletal muscle mass.
It's non-invasive and it's direct.
And the first thing that's important to say is that the assessment of lean body mass is
not muscle mass, although we've used lean body mass as a surrogate for muscle for many
years.
And that has provided, I think, inaccurate information about the nature of changes in
muscle mass and its relationship to outcomes.
We use deuterated or stable isotope labeled creatine as our tracer.
Important to say, first of all, that about 98% of all the creatine in your body is in
skeletal muscle.
And yet muscle has no capacity to synthesize creatine.
It's made in the liver and the kidney.
It's transported against a huge concentration gradient, and then it's turned over by the
conversion of creatine to creatinine which is then rapidly lost in urine.
So in our method, we use a single oral tracer dose of deuterated creatine.
In adults, it's about 30 to 60 milligrams.
It's absorbed, distributed, and then actively transported into muscle.
So it's distributed to all skeletal muscles.
The conversion of creatinine to I'm sorry of creatine to creatinine at the rate of about
1.7% allows us then to simply sample a urine, a single spot urine, measure the enrichment
of creatinine, and then know what the intramyocellular dilution or enrichment of creatine is and
calculate skeletal muscle mass.
The measurement is done by mass spec.
Important to note that creatine and creatine phosphate is co-located with the contractile
component of muscle.
So we think that it's a measurement of functional muscle mass.
It's undiluted by fibrotic tissue or fat.
Our initial validation study, we measured the creatine dilution muscle mass against
whole-body MRI.
You can see we had young men, older men, older women, and postmenopausal women.
And what you can see here is a pretty strong relationship between these two measurements.
Importantly, following right along the line of identity, indicating that they're measuring
something that's very, very similar.
We were fortunate to collaborate with Dr. Peggy Cawthon, we wrote an NIH grant that
was funded so we could introduce the method into the cohort, the MrOS cohort, which is
a cohort of older men who are now over the age of 80.
We're able to obtain 1,322 usable samples in this initial analysis, and I'll show you
some of those results.
The first thing to say is that when we look at the relationship between total body muscle
mass, and total body lean mass by DXA, you can see that it's only a moderate relationship,
and certainly does not fall along the line of identity.
We see no relationship between muscle mass, and DXA appendicular lean mass, which is used
frequently as perhaps, a better surrogate measurement of muscle mass, we see no relationship
at all.
We can also see in this study where we superimpose our measurement on DXA measurement and DXA
appendicular lean mass body composition in all 1,300 men.
The muscle mass values are dark blue, they're ranked from the most to the least over here,
and what you can see is that the dark blue + light blue = lean body mass.
So, there is a tremendous amount of what we call residual lean mass, non-muscle lean mass,
that's part of the measurement of DXA lean mass. The yellow dots here are appendicular
lean mass.
Now, does it make a difference?
Well, in this study, we can see that our measurement of time to complete chair stands strongly
related to how much muscle they'd have, with no relationship with appendicular lean mass,
a strong relationship to time to complete a 400-meter walk, a strong relationship with
a short physical performance battery, and then a strong relationship with force production,
no relationship at all with appendicular lean mass measured by DXA.
We looked at mortality, and you can see with multivariate analysis, there was a pretty
strong relationship between the loss of muscle, the amount of muscle, and risk of mortality,
with no significant relationship with lean mass, or appendicular lean mass.
I'll show you some data that we have looking at changes in muscle mass over time. In this
population we were able to get a sample of 40 older men.
We measured them about a year and a half apart, their age was about 83 at the start of the
study.
We also measured whole body DXA, grip strength, walking speed, and I'll show you some of those
results.
So, the first thing to say, over a year and a half, there was no change in lean mass,
appendicular lean mass, or appendicular lean mass divided by height, or weight, and yet there was
what we think is a substantial loss of muscle mass measured by D3Cr, or muscle mass, as
a percentage of body weight.
Interestingly, there was no change in weight over that period of time, so it appears that
the principal component of body composition that was changing was muscle mass.
What you can see also is that there was a significant loss of grip strength and a slowing
of walking speed.
And if you didn't have a measurement of muscle mass, you only had lean mass, your conclusion
might be that the loss in function was not due to any changes in mass, but only due to
some change in intrinsic, as unexplained, quality of muscle.
Recently, I wrote a commentary in the Journal of Parenteral Enteral Nutrition where I stated
my position that lean body mass should not be used as a surrogate measurement of muscle
mass.
Lean body mass is highly responsive to changes in water content, for example, that I think
can hide significant changes in muscle mass.
And our recent studies in randomized controlled trials examining the effect of severe energy
restriction, we see that DXA and D3Cr showed disparate results, and right now we think
that any changes in body water content, or even fibrotic content, will show up as changes
in muscle mass, or functional muscle mass.
Skeletal muscle is a highly plastic tissue, which changes rapidly due to diet, energy,
and protein restriction, or increased protein and energy, and those that are already malnourished.
Inactivity, or immobilization, exercise, hypogonadism, and inflammation, can all affect skeletal
muscle mass.
Importantly, this method is now being incorporated into a number of longitudinal cohort studies.
As I said, we have incorporated this into the Osteoporotic Fractures
in Men, the MrOS Study.
We were recently funded to incorporate this method into the Women's Health Initiative,
the Life and Longevity After Cancer trial, in which we have more than 6,000 participants.
The Tobago Longitudinal Aging Study in which we'll be able to measure changes in Caribbean
Africans, the Study of Muscle Mobility, and Aging, the Framingham Heart
Study just incorporated this method into that study.
We have a new grant looking at components of cellular senescence in muscle, and matching
it to changes in muscle mass.
We have a number of studies in patients with cancer. We think that changes in muscle mass
may be a powerful predictor of disease progression.
We have now, data in women with breast, ovarian, colorectal, and in patients with multiple
myeloma, we have a large study looking at older cancer survivors.
We also have funded studies to look at longitudinal changes in boys with Duchenne dystrophy, and
our funded data from the Bill and Melinda Gates Foundation has allowed us to validate
this method in neonates, infants, and children.
We recently completed a study looking at muscle mass in malnourished four-year-old children
in Bangladesh.
So, it's important to say that this method is non-invasive, it's safe, requires only
a single spot fasting urine, and provides a direct assessment of functional muscle mass.
Thank you very much.
DR. THOMAS R. ZIEGLER: Hello, I'd like to thank the organizers so much for inviting me to
give this talk on nutritional metabolomics and its potential utility in nutrition and
metabolic support today.
I'd like to first talk about research gaps in malnutrition and catabolic states from
which metabolomics may be useful.
First of all, malnutrition is often difficult to identify, especially in hospital and post-hospital
settings.
Further, determining micronutrient and protein-energy status is often uncertain.
And optimal doses of protein, energy, fat, and micronutrients in many clinical conditions
remain unclear.
Further, biomarkers for improving, or worsening, nutritional status are needed.
And a better understanding of nutritional pathophysiology is needed in many disease
states.
Now, metabolomics which is profiling small molecules in biologic systems is useful to
explore nutrition-related pathophysiology.
It allows us to measure the core nutritional metabolome, and the non-nutritive chemicals
in diet, as shown here.
We can also assess the metabolites that are derived from the gut microbiome, which is largely
uncharacterized but may represent 10-20% of the plasma metabolome.
As well as supplements, pharmaceuticals and their derivatives, commercial products, and
environmental chemicals.
Now, this KEGG map shows the breadth of what high-resolution metabolomics can allow us
to explore, including lipid metabolism, carbohydrate metabolism on the top, on the bottom, energy
metabolism, xenobiotic metabolism, etc.
And currently, we can measure over 20,000 metabolites in individual plasma samples spanning
the known human metabolic pathways.
Now, for high-resolution metabolomics, we use various approaches, targeted HRM can focus
on a predefined list of metabolites such as amino acids shown here, untargeted or discovery
high-resolution metabolomics, looks at all detected metabolic features, or metabolites.
And the third thing is, pathway and network analysis, which can map metabolic features,
or metabolites, to biological pathways, and identify interconnections.
In reality, it's common for all three of these approaches to be used in a metabolomics study.
This is the workflow for plasma high-resolution metabolomics in the Dean Jones lab at Emory.
I'm not going to go through the details, this has been well worked out over the past decade,
and it's a now very robust system.
But we basically use high-resolution mass spectrometry instruments, dual chromatography
with HILIC positive, and C18 negative columns, sophisticated data extraction and quality
evaluations, and then Biostatistics and Bioinformatics programs that are built in.
And then finally, we do a program called Mummichog for network and pathway analysis and are able
to confirm our metabolites using reference standardization or Tandem MS.
Now, metabolome-wide association studies, or MWAS is the study of the associations between
a measured variable or phenotype of interest and all detected metabolites.
We can correlate metabolites that we detect, for example in plasma, with specific clinical,
and phenotypic variables.
And this list is highly relevant to nutritional metabolomics.
For example number one, we can correlate metabolomic changes to, for example, subgroups of survivors
compared to nonsurvivors.
Further down, we can look at body composition, exploring links with lean mass, bone, and fat.
We can look at respiratory quotient links with metabolomic analysis, and we can correlate
the human metabolome with functional endpoints such as FEV1, a key marker of lung function,
or handgrip strength, as well as several other aspects as shown here.
Now, I'd like to show the utility of plasma metabolomics in body composition analysis,
and here, a graduate student in our lab, Moriah Bellissimo explored the link with lean mass
index, and we studied working adults from Emory who were clinically stable, not hospitalized
within the past year, no uncontrolled chronic diseases, or acute diseases.
And we looked at 180 participants, we had plasma high-resolution metabolomics done using
the workflow I showed earlier.
We looked at fasting blood draws, which is important because diet, or food intake, can
obviously affect the metabolome.
We did body composition by DEXA and calculated the lean mass index with the equation shown
there, and did reference standardization to quantitate targeted amino acids and linked
metabolites.
In this Mummichog plot, you can see that we identified the dots which are 5,360 total
metabolic features, or metabolites, in this particular experiment.
93 of the features were related to lean mass index using very stringent FDR criteria, or
false discovery rate criteria, with the line shown there, and then several hundred over 500
to be exact, were statistically significant using raw p-values as shown in the lower line.
The dots indicate that the blue metabolites are positively related to the lean mass index,
and the red metabolites were negatively related on a continuous variable analysis.
We took these 500-plus metabolites and incorporated them into the software program, and found
that diverse metabolic pathways were linked to lean mass index in this population.
The horizontal blue bars are the statistical significance shown, and then the metabolic
pathways that were significant are all outlined on the left side, you can see the arrows showing
that a number of amino acid metabolic pathways, including branched chain amino acids, etc.,
were significantly linked to lean mass index.
We also found that butyrate metabolism, purine metabolism, and niacin metabolism were also
linked to lean mass index in this experiment.
We did network analysis in these data which links metabolites that are most strongly associated
with each other, and we found that there was a network that was derived from branched-chain
amino acids, phenylalanine, glutamate, and tryptophan metabolism, highlighted here.
But we also found a number of gut microbiome-derived metabolites, including indoles, phenylpyruvate,
etc., which we found quite interesting because it's something that's not been previously
well-described.
So, moving on to another example of nutritional metabolomics, this is 33 healthy adults who
had indirect calorimetry done at fasting, and we used the same workflow that I showed
earlier, and we have two columns C18 on the left, and HILIC on the right.
And you can see in this bubble plot that, a whole range of metabolic pathways are linked
to the respiratory quotient value, tyrosine metabolism, pyrimidine metabolism, and several
lipid metabolic pathways, including glycerolphospholipid, bile acid synthesis, butyrate metabolism,
all linked to respiratory quotient in healthy adults at fasting.
Another example is linking metabolomics data to relevant nutritional outcomes.
This was a study I did with my colleague Jessica A. Alvarez, and others, in patients with cystic
fibrosis admitted within 48 hours for hospitalization due to a pulmonary exacerbation.
And they were age 29 on average, roughly balanced by sex, and their FEV1, or their lung function,
was about half of what it should be.
And here we did a study using similar methods as I showed you, to link lung function associated
with nutrient-related metabolic pathways using plasma metabolomics.
And, you can see here in the arrows, a number of amino acid pathways were significantly
linked to FEV1 using this methodology.
We also found a number of lipid-related pathways that were linked to FEV1, including on top
glycerolphospholipid, next linoleic metabolism, lower down omega-6 fatty acid metabolism,
etc.
The last example is using high-resolution metabolomics to explore micronutrient status
in a particular patient population.
Here we looked at with my colleague Kürşat Gundogan from Turkey, adults who were admitted
to a single ICU.
We obtained plasma on ICU admission for thiamine pyrophosphate, TPP, the active form of thiamin,
and we did the concomitant high-resolution metabolomics.
We adjusted the HRM data for age, sex, BMI, and APACHE II score, or illness severity, on
ICU admission.
And this is also a Mummichog plot, we've colored it a little bit different way, but we found
there were broad associations of plasma TPP with metabolism in these critically ill adults
that were as a function of thiamine status, we did a TPP MWAS, if you will.
And you can see that glucose metabolism, including pentose phosphate pathway, lipid metabolism
including, you know, linoleic metabolism, further down vitamin metabolism including
niacin metabolism, were all linked to the level of TPP on admission to the ICU.
I think significant utility of metabolomics in nutrition, and obesity research, we can
gain pathophysiologic insight into complex diseases.
We can use metabolomics to link metabolites and their link to metabolic pathways with
clinical outcomes such as survival, non-survival, time on the ventilator, etc., to inform
targeted nutritional interventions.
We can explore metabolic responses to specific nutritional interventions.
We can generate hypotheses for later targeted studies, and we can identify potential biomarkers
for disease onset, progression, and resolution.
We can also use this data, and available open access programs, to explore the host metabolome
in response to various situations with other omics, including the gut microbiome.
And finally, we can use metabolomics, I believe, in the future to optimize nutritional therapies
in individuals or precision medicine, or precision nutrition.
Thank you very much.
DR. KENNETH CHRISTOPHER: Hello, my name is Kenneth Christopher, I'm delighted to have the opportunity
to present to you, on BMI metabolomics, Making the Complex Simple.
In terms of my disclosures, I don't accept honoraria, nor do consulting work for the
pharmaceutical or device industries, and this work was funded by the National Institutes
of Health.
In terms of how to study metabolomics, first, we have sample collection, then the actual
sample is analyzed using mass spectrophotometry where one can separate and identify the different
metabolites that are identifiable.
And then the third step is data analysis, and data analysis can be data visualization
to help you see patterns, it can be things like logistic, or linear regression, to see
patterns over time in terms of adjusting for common features like age and severity of illness,
etc.
This particular project that we're going to talk about comes from a randomized controlled
trial that was published in 2014, that randomized patients to high-dose vitamin D, this, as
in most critical illness trials, was a neutral trial.
The way that this particular study that we're going to talk about was designed, patients were
enrolled who had a vitamin D less than 20 ng/mL.
They received either high-dose vitamin D, or they received placebo, and lucky for me,
blood was collected on days zero, three, and seven, along with all of the clinical trial
covariates, and outcomes.
I had those particular blood samples analyzed for metabolites, we analyzed 983 metabolites
in each sample.
What I wanted to focus on today is looking at the differences in terms of patients who
do or do not have excess adipose tissue by proxy, measured by body mass index.
So, the question that we asked was, does individual metabolite abundance, say the amount of each
metabolite in one's bloodstream at a particular time, in critically ill patients with BMI
greater than, or equal to 30?
Does that differ in those who have a normal body mass index?
So, we have the normal body mass index, and metabolomics, and we have the equal to or
over 30 BMI metabolomics analyzed.
And the idea is to compare those two and see if we can find a consistent pattern with the
large number of samples we have, and the large number of patients.
The hypothesis was that critically ill patients with BMI greater or equal to 30 will have
differential metabolomics, meaning that their metabolome in terms of all of the metabolites
together will differ in terms of the BMI groups.
I thought specifically energy utilization would be different simply because of the large
number of, like the lipolysis of potential cells in terms of adipose tissue, that could respond
to these stress hormones.
And this is, again, in comparison to patients who have a normal BMI.
You see, the exposure was patients who had BMI greater than 30, the comparator was a
normal BMI, and the outcome was the individual metabolite abundance of 983 individual outcomes
in terms of looking at each one of these metabolites.
And so the overall design, we have our different patient groups, all of the patients had a
critical illness, the patients were all randomized to either high-dose vitamin D, or placebo,
plasma was obtained on all patients in the time points of days zero, three, and seven,
and metabolomics was run on all of the plasma samples.
And so metabolite identification, and the relative abundance, could be determined for
each metabolite, each one of the 983 metabolites.
In terms of the baseline characteristics, it's very similar to the actual baseline trial
where in terms of our differences between patients with normal BMI, and BMI greater
than 30, a 28-day mortality was statistically different with the percentage of normal being
28, and the BMI greater than 30, being 16%, otherwise, the cohorts were relatively matched.
Looking at unadjusted analyses at day three, and the question is, what is the metabolic
difference between the two groups?
And we used a technique called Orthogonal Projections to Latent Structures Discriminant
Analysis, and I'll show you that particular analysis result.
These particular score plots, we call them OPLS-DA score plots, well, let us ask the question: Are
the two groups different metabolically?
What it does is it sums up all of the metabolites into one spot, so the spot will be the patient,
I'll show you the graphic in a second.
We also looked at the Variable Importance Plot, and this is figuring out which of the
983 metabolites are the most important for difference in this particular score plot.
So, we will see differences between the two groups, the question is, which individual
metabolites are most important for that difference?
And then looking at what's called an S-plot, which helps us identify which individual metabolites
are potentially of interest. A little bit different way of looking at the data.
So, in terms of this OPLS score plot, what it does essentially is, it takes this multi-dimensional
metabolome if you will.
It shines a light through it and ends up with a two-dimensional type of figure, and it allows
us to try to figure out, number one, are there differences in the groups?
And then look into whether or not those particular metabolites make up for those particular differences.
Which metabolites are responsible for the two groups being separated?
And so this is an example where we have normal-weight patients in green and the obese patients in
the blue.
Each dot is a summation of all the 983 metabolites.
It is the individual's metabolome.
And what I've done is I have subtracted the colors on each one with the next slide so
you can see the differences.
And so if we look at the normal weight patients, those are all in the green, I've subtracted the
blue and then we look at the blue patients or the overweight patients, you can see that
those particular patients are on different sides of this particular circle indicating
that there is separation at day three in terms of obese patients versus normal weight patients
in the way all of their metabolites respond to their illness.
Looking at the VIP scores and this is the variable in terms of the projection, which
metabolites are the most important for separating the two groups in terms of the individuals
themselves, which metabolites are high or low?
And in this particular analysis, we can see that most of the metabolites that are responsible
for the differences between the two groups are things called diacylglycerol and also
long-chain acylcarnitines.
This is the S-plot where we're looking at feature importance, a little bit different
way of looking at the data.
And if we look at the absolute extremes at the top and the bottom of the S, if you will,
we have diacylglycerol and then long-chain acylcarnitines, those pop out and at the other
end we have androgens.
So our first obstacle where human variability is a problem, and we only have 254 patients,
we need a large sample size.
Our repeat sampling actually increases study power.
The number two, the repeat sampling is a problem.
It's not independent.
And so we use a special model called Linear Mixed Model that accounts for this non-independence
between samples using the patient identity as a particular way of accounting for that.
Age and sex and severity of illness probably account for some of our observations.
Sure, we adjust for all of those particular pieces.
And then what about this intervention?
We also adjust for the response to intervention because we have 25 OHD levels, which
would be the proxy for how patients responded to the intervention.
And then this repeated measure issue, we correct for what's called multiplicity using a False
Discovery Rate adjustment.
And what that does it's the rate that metabolites that are called significant are actually not
significant.
So it's a penalization.
And so our P-value that we're looking at is no longer 0.05.
So, the solution again for this multiplicity is Linear Mixed Models.
This is a slide of the metabolites that were increased with obesity.
And what we see is we see a large number of metabolites all from the diacylglycerol family.
And we also can find that same pattern with the long-chain acylcarnitines.
So, that's our adjusted analysis with day zero, three and seven data.
And the highlights now are the diacylglycerol, again, involved in immune cell activation,
regulation and function.
And then the long-chain acylcarnitines where elevated fatty acid supply from high lipolysis
exceeds mitochondrial oxidative capacity.
And so in summary, we have significant metabolomic differences that exist between obese critically
ill patients compared to those with normal BMI.
We have an elevation of diacylglycerol and we have an increase in long-chain acylcarnitines.
Thank you very much for your attention.
I look forward to your questions.
DR. RAED A.DWEIK: Hello, everyone.
I'm Raed Dweik, chairman of the Respiratory Institute at the Cleveland Clinic.
And I'm pleased to be here today to talk to you about breath analysis to identify malnutrition
in clinical settings.
While it is thought that breath analysis is a recent advance in medicine, it actually
is as old as medicine itself when Hippocrates identified in his Treatise on breath aroma
and disease, fetor oris and fetor hepaticus.
Several other advances in our understanding of physiology and medicine we have breath
analysis, including the identification that respiration consumes oxygen and eliminates
carbon dioxide, that diabetics emit acetone and exhale breath and our ability to isolate
alcohol from breath, which is the basis of current law enforcement testing.
But I think arguably the 21st century has experienced an explosion in our understanding
of breath analysis due to major advancements in technology.
So what is in our breath?
While we all recognize that our breath contains oxygen, which we inhale and carbon dioxide
which we exhale, predominantly our breath is nitrogen like the atmosphere.
And once we exhale it, it's fully saturated with water.
But I want to point you to the fact that our breath also contains small amounts of compounds
like alkanes, aldehydes and ketones, etc., that are known collectively as volatile organic
compounds.
While these represent only 1% or less of the breath, they have significant implications
for understanding health and disease, and they are present in very small amounts, sometimes
in parts per million or even parts per billion range.
So, technological advancements is what allowed us to be able to detect these compounds in
exhale breath.
And the table here shows the different methods that currently available to analyze the breath.
But I want to point you to the right side of the slide here, to the fact that all of these
really fall under two general categories, either electronic nose, which is part of a
larger group known as the sensor arrays or mass spectrometry.
And they're completely different approaches to analyzing the breath.
The electronic nose functions in a very similar fashion to the human nose where it recognizes
patterns.
And it once it's trained on a smell, it can recognize it.
So like even if I blindfold you and give you an orange to smell, you know it's an orange,
but I've given you something that you never smelled before, you either would not know
or would guess wrongly.
Mass spectrometry, on the other hand, analyzes all the compounds and the peaks in exhaled breath
but unable to recognize patterns.
So, the way we approach breath analysis is really to combine the best of both these worlds
in that we look at mass spectrometry, which is our main method of analysis, but analyze
the data in a pattern recognition approach like the electronic nose would do.
Utilizing this best of both worlds approach, we are able to identify many disease states,
including lung cancer, different liver diseases, as well as kidney disease and renal failure.
These I refer to as the low hanging fruit since patients with liver disease or kidney
disease are known to have an abnormal smell to their breath.
But we were, so that did not surprise us that we were pleased that we were able to identify
and quantify the breath of these patients.
We were surprised, however, to be able to identify that patients with heart failure,
which usually have a bland breath and also have a distinct breath print.
And you can see in this particular study the patients with heart failure in the blue and
green dots here have a distinct breath print compared to those who are controls in red.
We were surprised by this finding to the point that we repeated it twice, and that's why
there are green dots and blue dots to represent two different cohorts of patients done separately
to make sure that our findings are correct.
Once we were able to identify the breath print of heart failure, we really started looking
into many disease states.
And the way I think of it now, as the breath being the headspace of the blood, anything,
any compound that is in the blood that is potentially volatile at room or body temperature
can be identified in the breath and can help identify different disease states.
One area I focused my research on and my clinical expertise in pulmonary hypertension and in
those patients, like patients with heart failure, they really do not have a particular breath
smell, but we were able to identify their breath print as shown here in this graph compared
to controls.
And again, we repeated this twice to make sure that is accurate.
So in addition to this pattern recognition, we're able to identify certain compounds that
are elevated in pulmonary hypertension patients you see in the red graphs here compared to
controls in the blue.
So, you know, we were pleased to find out that we were able to identify multiple breathprints
for multiple disease states.
We still have many challenges that we have to overcome for breath analysis to become
mainstream in testing.
One of them is the mouth.
Of course, all breath analysis is done through the mouth, and you can see if there are any
particular volatiles coming from the mouth we have to deal with those as well.
The medications we take affect our breath print, the microbiome or the gut bacteria produce
many compounds that can be detected in the blood and the breath.
And importantly, the environment.
We are sampling vessels as we walk around.
We are inhaling whatever our environment has, and once breath is analyzed and exhaled, we
can detect these compounds in the breath as well.
For the sake of today's presentation, diet also is a major contributor to our breath print.
And while here I'm proposing it as a challenge, and the rest of the presentation, I'm going to
talk to how we started looking at the breath prints as a way maybe to identify the nutritional
status of individuals.
This is when we partnered with Dr. John Kirwan and Jacob Mey to look at the breath print
of patients with pulmonary arterial hypertension, a disease that we studied extensively to see
if we can also identify a nutritional status in these patients.
We collaborated with our nutrition department and multiple dietitians in the Cleveland Clinic
to be able to look back in the medical records of those patients we had breath prints on
and to see if we can also identify their nutrition status.
So this is a diagram showing how we identified these patients.
We are going through multiple inclusion and exclusion criteria.
We identified 74 patients to be assigned into PAH with malnutrition, or without malnutrition
and controls, with or without malnutrition.
And the ICD 10 diagnostic codes for malnutrition are listed here for your interest.
The patient characteristics, I'm going to focus on the PAH, patients without the majority
of the patients here.
They're similar in age.
They're predominantly female because pulmonary hypertension predominantly affects females.
And the BMI was quite similar between PAH with or without malnutrition.
And the time from breath data collection to the nutrition assessment was anywhere from
30 days to 47 days, which is within a reasonable timeframe.
What we found is really a couple of things.
One, it was reassuring to find out that still the breast print of patients with pulmonary
hypertension identified in red is quite distinct from those who don't have pulmonary hypertension
or controls in green.
There's only minor overlap with two patients, individuals without pulmonary hypertension
identified with pulmonary hypertension.
But of course the more exciting finding here is what you see here represented in black
dots are these patients with pulmonary hypertension who have malnutrition, which ended up having
a distinct breath print from those with pulmonary hypertension without malnutrition and from
controls.
Furthermore, if you looked at the right graph, we were able to identify certain compounds
like ammonia and octene which are lower in PAH with malnutrition compared with those
without malnutrition.
So if you use this data to construct an ROC curve, we were able to have a curve with an
area under the curve of .85, which is a high degree of sensitivity and specificity.
So I'm really, very excited about the results of this proof of concept study.
Many challenges remain, and of course, the breath matrix remains complex as you see it
on the right side here.
We are able to identify many disease states to the point we are close to kind of use the
traffic light analogy of red, you have the disease or the particular state, you're looking
at the green, the patient doesn't have it and yellow is indeterminate.
But still, the technology we use to do this is the mass spectrometry, which is very complex
and requires extensive analysis.
The promise of breath analysis however is similar to what many people think when they
think breath analysis is the point of care testing for alcohol that is used by law enforcement.
And I can see probably in the near future how with more advancement in technology, like
certain attachments, sensor attachments can be used in combination with devices like iPhones
to identify breath prints of certain health status or disease states.
So, key takeaways from today are that human breath contains thousands of volatile organic
compounds.
Advances in technology allowed us to explore the complex matrix and breath analysis of
volatile organic compounds can identify breath prints of health and disease.
And in the proof of concept study I showed you today, we were able to provide the first
evidence that breath print is altered in malnutrition and breath analysis, thus is a promising approach
to determine nutritional status.
Thank you for the opportunity to talk to you today.
Have a great day.
DR. JOHN ALVERDY: Hello, my name is Dr. John Alverdy.
I first would like to thank the NIH, in particular Dr. Christopher Lynch, Dr. Charlotte Pratt
and Dr. Ashley Vargas for the opportunity to speak to you today and of course, to the
NIH for supporting our work over the years.
Now the definition of malnutrition has many definitions, but I prefer to focus on this
one, not eating enough of the right things.
One question that often comes up is between visceral protein status, muscle grip strength
and sarcopenia.
We have to ask, is this enough information to diagnose malnutrition?
I think not.
I think we need to go beyond this and look at our microbiota because microbes have co-evolved
with us.
They can sense our health status before we can.
Remember they were here first, and it is in their best interest to know the health status
of their host upon whom their survival depends.
So one hypothesis is that interrogating the gut microbiome will generate a more predictive
picture of host health status during critical illness.
And another might be that preserving essential functions of the gut microbiome can change
the occurrence course and outcome of critical illness.
Now, this represents 25 years of work from my laboratory, and I think it's important
to recognize that host-derived bacterial activating cues are released into the host-pathogen interaction
during critical illness.
These host factors signal bacteria and bacteria release products that re-signal against the
host in a bidirectional interkingdom signal exchange.
In addition, bacteria and bacterial communities have a similar system in which there is interspecies
and intraspecies signal exchange, resulting in a matchless web of dense, dynamic interactions
unique to and dependent on the environmental context.
So virulence or harmfulness is neither a sole property of the pathogen nor that of the host,
but rather it is a property of their interaction.
And it's complicated.
Yet nearly all biologic research is centered on host genes.
Why?
Well, because we, animals, think we are the only life on earth that really matters.
However, there are now multiple gene pools to consider when interrogating the occurrence,
course and outcome of human disease.
And guess what?
You are missing most of them because unless you look at the entire environmental metagenome
or what's known as the hologenome, you don't really realize that the soil bacteria give
us the very food that we eat, the air that we breathe.
In fact, the gas that we put in our cars that we then, you know, allow emissions to blow
out into the atmosphere.
And critical illness involves exposure to many things hyperoxia, antibiotics, chemically
defined diets, ECMO, polypharmacy, etc..
And you could imagine that the gut microbiota metabolites that are produced become depleted.
And we became interested in this particular area when we started looking at aryl hydrocarbon
receptor ligands and found that they bind to specific cell types and the immune system
that can regulate what I call a recovery-directed immune response.
And critically ill patients harbor a depleted gut microbiome dominated by virulent healthcare-associated
pathogens.
This paper that we wrote is now nearly 10 years old, really showed this in starking
detail among critically ill patients.
So we've been working for the last several years on the hypothesis that metabolites from
the gut microbiome are systemically distributed and regulate the interaction between infecting
pathogens and the immune system.
We focus on several pathogens and macrophages in this interkingdom signal exchange and
discovered that indoles secreted by the microbiome can drive homeostatic gene expression that
crescendo/decrescendo cytokines that leads to bacterial clearance, smooth bacterial clearance
and recovery, versus a more patho-adaptive position where you have impaired bacterial
clearance, excess cytokine release, organ damage, sepsis and mortality. And critical illness or sepsis or severe infection is not an immune disorder.
-And critical illness or sepsis or severe infection is not an immune disorder.
system is that very interaction.
Now, a lot can be measured these days, as we know.
We can measure so many things have a very robust, dense and visually appealing image
display of large data sets.
In fact, you know, big data science is the next big thing.
But we still cannot resist the most common reasoning error in medicine and biology, which
is confusing association with causation.
For example, serum albumin is diminished in critical illness.
We know this.
It's also a prognostic marker for poor outcome.
Is the solution just to provide albumin and increase the serum albumin and it will improve
outcome.
No, we know that doesn't work.
Yet now we can measure multiple metabolites in many different compartments in the gut,
including the gut and including areas remote from the gut, the peritoneum, cerebrospinal
fluid, blood, etc..
And then we feel that we can design chemically defined diets with missing metabolites.
This is committing the same sort of reasoning error.
And now there are all sorts of agents out on the market.
And in this one, I'm just poking a little fun at.
It's the number one doctor-recommended brand because it supports immunity, it boosts your
immune system.
These are very weak claims that can't be really applied to our patients in many cases because
they're on antibiotics and they're in a damage control situation.
So there's a big push to modulate gut microbiomes, which you can do with a fecal microbiota transplant,
which in my opinion, is messy and dangerous.
There are now been reports of drug-resistant E.coli bacteremia and fatalities with this
approach in critically ill patients because we know they have a hyperpermeable gut.
This idea of a one size fits all capsule has been proposed.
Again, it's not unique to the environmental context, which is highly personalized depending
on the patient's life history.
But this is the easiest way, in my opinion, to do this.
It's safe and evolutionarily stable.
And now we know that the gut microbiome plays a key role in host recovery because there's
loss and gain of microbiota mutualism, depending on how the patient fares over the course of
critical illness.
And these immuno-regulatory metabolites actually drive immune cell phenotype transition.
What you can see is this is a moving target and we need to promote homeostatic gene expression.
This crescendo/decrescendo of cytokines, inflammation is good assuming that it gets dampened and
attenuated at the appropriate time.
And the best way to do that is a plant-based food diet which drives the microbial consortia
to release these immunoregulatory metabolites that diffuse systemically and can shift things
in the right direction.
And so our hypothesis is that proper interrogation and modulation of the gut microbiome can drive
a recovery-directed immune response during critical illness.
So critically ill patients need to consume a plant-based unprocessed food type diet,
and they need point of care diagnostics to define or monitor key efficacious endpoints.
And this is not going to be simple.
You need to think about the public goods that need to be present in the microbiome on top
of those microbiota that need to be present.
And we have to promote both their stability and diversity among the community members
because this is quite complicated.
It's a living ecosystem.
Then we have to keep in mind that these chemically defined sterile liquid products are not this.
Earth's food evolved over millions of years.
Patients need to eat this.
Not this.
And/or this.
But in many cases, patients have no choices because they're no choice, because their bodies
will not accept the foods that we think they need to be properly nourished.
But if we do not properly and repeatedly assess the microbiome over the course of illness,
in this case critical illness, we will not be able to properly modulate its function.
Again, I want to thank the National Institutes of Health and the program developers for the
opportunity to speak to you today. Thank you.
DR. GAIL CRESCI: Wow, thank you, everyone, for your excellent presentations.
What a wealth of information.
Let's begin our question and answer session now and while we're going through the questions
that have already been submitted.
(AUDIO DISTORTS) Please continue to submit your questions as they may arise.
So, for our first question, I'm going to ask actually everybody on the panel because and
feel free whoever wants to answer.
But there was many of the presentations were about data and critical illness.
And critically ill patients, as we know, have a lot of ongoing interventions such as ventilators,
pressure agents, sedatives, other drugs.
How do you control for those potential confounding variables to make sense of the data that's
being generated?
GAIL CRESCI: Dr. Alverdi, do you want to?
DR. JOHN ALVERDI: Oh, sure, yeah. I'll take a stab at it, thank you.
You know, as I mentioned in my last slide, you know, repeat measurements are needed,
you know, it's the area under the curve, if you will.
That's probably going to be important because as you mentioned, you know, these patients
are on, and I mentioned, you know, have multiple interventions, they're are a moving target,
and we all want this one measurement one-time point of care measurement to be predictive of the entire
occurrence course, and outcome, but it can't be, we're asking too much of it.
So, I think what we need to do, and I really enjoyed everybody's presentation, is pick
a product that we think has a scientific premise to it.
And then repeatedly measure over the course of the patient's illness what the output is,
you know, we have now, as we heard, gas chromatography of exhaled gas, we have metabolomics in the
blood, as Tom Ziegler told us, we have multiple proteomics, that we can measure.
There's so much to measure to determine the efficacy of what we're doing, and that might
change the next day, but we can repeat the measurement.
DR. GAIL CRESCI: Yeah, I think that is really key is to, you know, it's a continuum, it's
not just a snapshot of what might be going on at that particular point in time.
Another question for everyone is regarding these emerging tools, and we're getting so
much valuable data about the patient, their metabolism, the metabolites they're producing,
do we envision that these tools will eventually be able to help identify or stratify our patients,
that may be likely to respond to nutrition intervention
and would this intervention then be able to be personalized based on these data?
The metabolomics, the breath analysis, and the microbiome.
DR. TOM ZIEGLER: Gail, can you hear me?
DR. GAIL CRESCI: Yes, I can hear you.
THOMAS ZIEGLER: Hi Gail, hi everybody, great presentations everybody it was very interesting.
This is Tom Ziegler, let me just say, I think we might be like Law and Order in 10 years,
we may have a mass spec machine in every ICU or, you know, on every floor if I could be,
you know, optimistic or, you know, certainly more expensive or...
Well, I think that as these machines that can measure these fancy things become (LAUGHS)
less expensive, and more specific, we might be able to take a drop of blood over time
from our patients, for example, in the ICU and, you know, do amino acid grams, you know,
in five minutes, and be able to tell what the amino acid situation is in that particular
day, or we might be able to measure thiamine metabolites and get a sense of, is the patient
potentially thiamine deficient?
I think that this will help us to guide our therapies in a personalized way going forward.
You know we're probably less than a decade off from that, starting to happen obviously,
we'll need research in these areas, point of care, if you will, mass spectrometry, is
one example.
Thank you.
DR. DAVID EVANS: Hey, it's Dave Evans, can you hear me?
DR. GAIL CRESCI: Yeah, David, we can hear you, Dr. Evans.
DAVID EVANS: Yeah, may I just comment?
I think the one concern is, you know, on the other side of the spectrum is that you know,
U.S. healthcare costs are out of control.
And, you know, we know a lot of very basic, you know, easy-to-do things right now that
we're not doing.
Well, I think that you know, the high-end research, and I'm really excited about awesome
presentations, I really enjoyed seeing everything everybody is doing.
I think there also needs to be a focus on, you know, what can we implement practically,
and affordably, and you know, put it in the hands of every clinician, and not just, you
know, the high-end kind of university research-based ICU?
And so, you know, I would just, you know, well, I'm super excited about all these possible
innovations.
I think, you know, we can need to continue investing in you know, education and, you
know, rolling out the simpler tools, and the knowledge that we already have because we
still fail to appropriately screen, and appropriately optimize, you know, many patients who come
into our hospitals.
DR. GAIL CRESCI: Thank you, Dr. Evans.
Dr. Dweik, did you have a comment you wanted to add?
DR. RAED A. DWEIK: Yeah, I can add to that I think these are all excellent points raised by other
speakers, but I think, with the promise of what we are doing, you see the holy grail
of all of that is the ability to do point of care testing at the bedside, or in the
clinic, or in the office.
And I think hopefully the future developments would be not really necessarily mass specs
of the bedside, but new technologies that can do similar measurements, but they are
not as complicated as mass specs.
And I think that hopefully, will be the true benefit of the kind of work that I heard of,
and the kind of work that we are doing as well.
Thank you.
DR. JOHN ALVERDI: Yeah, I would only add, I'm sorry.
DR. GAIL CRESCI: No, go ahead Dr. Alverdi.
DR. JOHN ALVERDI: Yeah, I'd only add as a general surgeon, you know, watching anesthesiology
evolve over the last 30 years is, you know, we had this crummy little machine, no pulse
oximeter, no entitled CO2, no gas analysis, and it was fine, most patients did fine, but
you know, when you say most patients, there should be no outliers.
And so if you go into a modern operating room today, you know, there's end-tidal CO2 being
measured, pulse oximetry being measured, there's endoscopy to intubate the patient, there's,
you know, three different inhalational agents, each of which can be measured, their blood,
partition coefficients can be measured in blood, and in exhaled gas.
I mean, we're in a new era, we drive fancy cars, we all have, you know, smartphones.
I think that Tom's point, you know, we're in a new era where, yeah, you don't need it.
You could drive a Yugo with a three-speed, but the fact of the matter is your fancy car
with the lane changers and your smartphone and your Bluetooth.
And so I think it's very difficult to imagine, you know, not applying these things in point
of care diagnostics, and being as precise, and to your point, as personalized as we can be.
And, you know, it's a good point, not everybody can afford everything, but it's also a good
point to say, we can do better.
DR. GAIL CRESCI: Yeah, I think that all the points are really well made by all the speakers because
we're dealing with the current situation we have, and what do we currently have available?
And then where's the future?
And that's really what this workshop is about, is to help identify where the gaps are, and
where can future research development come about.
And so, I think we have...it seems like we've identified that, and I'm going to bring up a question that came up
for Dr. Steiber, related to our current tools.
So, you discussed with us the data surrounding the AAIM tool, and there are six suggested
parameters for that, of which I think the nutrition-focused physical exam to some extent
is included in that.
So, are there any parameters?
Do you need all of those six parameters to have the validation or just some of them?
Can you address that topic?
DR. ALISON STEIBER: Sure, thanks, Gail. I mean, I think this is a really interesting conversation
because we're sort of on the cusp of, yes, we can do it technically in a lot of these
cases, and we're on cutting-edge research for a variety of things.
But the reality is I completely agree with the speaker that said, you know, our costs
are out of control.
And when we think about access to care, so many people don't have access to quality care
in general, but certainly not nutrition care.
And so what can we do from a very practical perspective, both within our country, in those
areas with low resources, and those areas with high resources?
The current tool that we have, the AAIM tool does have six parameters.
That was derived through a consensus process, and what we are hoping to do but have not
yet done, is to really look individually, and see which of those six parameters most
strongly contribute to the model, for its predictive value.
And we're not constrained, right?
We have a huge amount of data from this dataset, and so what we would like to be able to do
is look and see.
Are there biochemical parameters that we happen to have?
Are there other measures that we can do, is four parameters equally as strong for prediction
as six?
Can we make it simpler?
Can we make it a better way to predict with less burden on the patient, and on the practitioner?
So, we haven't done those analyses yet, but that's our plan in the future.
DR. GAIL CRESCI: That's great. So another question is related to the current method, but futuristic
as well with the context of inflammation.
So, we know we're taking into account inflammation with the current methods. And how does inflammation...has that been...
it's kind of related to the question I asked earlier, how do these emerging tools take
into account inflammation?
And maybe that, you know, on the continuum for measurement of these outputs, how do you
factor that into the equation?
DR. ALISON STEIBER: Can I just say one thing about that?
So, I noticed that a couple of the speakers did this, and we certainly
did it in our study as well.
But when you control for acuity, there is, you know by some level of a proxy, you're
able to say, you know, a lot of our disease acuity impacts inflammation on board with
the patient, and so by controlling for acuity, I think we're taking that into account to
a large degree.
But I also think in, I think this was mentioned as well and was a great point about anabolic
versus catabolic, and how we think about that from a nutrition perspective, inflammation
obviously driving a huge amount of catabolism.
So, I just wanted to throw that out, about the disease severity.
DR. GAIL CRESCI: Thank you, and I'm thinking, you know, in lines with the microbiome, and
of course, in the context of the critically ill patient, we know they're inflamed, they've
got inflammation going on.
Is there any data to show how that impacts the microbiome?
And then as a consequence of that, their metabolism?
And then the metabolites that may be produced?
DR. JOHN ALVERDI: Yeah, you know, our group has shown that specific pro-inflammatory cytokines
literally activate bacterial virulence circuits, which then feed back onto the host.
And so it's a feedforward, feedback system, it's what I call a bi-directional interchange,
which is why we say, you know, virulence, harmfulness, clinical infections, sepsis,
is neither a property of pathogen or the microbiome alone or the immune system alone, it's a property
of their interaction.
And so when we think about this, we need to think about this interactome, which is what
I think all the speakers are trying to say is at our fingertips.
When you look at some of the principal component analyses, or the ordination plots, that Tom
and others are trying to put together when you measure 1,350 different or 3,000 different
metabolites, you have a huge array of data.
But you've got to harness, and manage, those data so that they tell you something that's
what we call actionable.
Something you can do something about, not just say, "Well, this went up, this went down,
this went sideways," you know, it's like gene arrays, you can't sequence your way to truth.
You've got to understand how to manage the data in a big dataset, with bioinformaticists
who'll tell you, "This finding is actionable."
And I think therein lies the challenge, which is why, you know, people who are doing sequencing,
metabolomics on CSF, blood, urine, exhaled gas, you're getting a ridiculous amount of
data that you know, moment-to-moment you need to deal with.
And you can understand the complexities, so when you ask the question, is there a feedforward
and feedback system?
It's constantly ongoing.
And that's why when somebody says, "We have to contain costs, let's try one-size-fits-all
for everybody," that's a problem, like, you know, with antibiotics, and prophylaxis, in
general surgery.
We give everybody the same antibiotic, that can't be right.
I mean, well, it's right most of the time, except for the 3% that it's not right, who
don't do well.
DR. GAIL CRESCI: Yeah, I agree, I mean, that's where I was trying to lead, is any of this
data we're generating helping us to identify a personalized approach to nutrition to these different
patient populations?
Will it inform us on how to feed our patient, and when to...
understanding who may respond to a certain type of feeding?
So, Dr. Alverdi, you bring up about plant-based diets, and that they should be provided to
our critically ill patient, how do we know if they're going to tolerate these feedings or
not?
What are your thoughts on that?
DR. JOHN ALVERDI: Well, yeah, I mentioned that in my talk, you know, it's a balance between
how sick is the patient, and what will their gut tolerate versus what you should
put into their gut.
And you know, I trained a long time ago when we had a product called Complete B Modify which was
basically, you know, ultra blenderized real food, you know, it was meat, potatoes, and
peas.
And the nurses complained about it because the patients had too many bowel movements,
and their stool smelled.
Now, we put in sterile, chemically defined liquid diets, that we go, "It has
everything you need.
Trust me." And yet, you know, as I listened to all the talks today, I'm thinking, boy,
there's a lot we don't know, that can't be right.
Like I said in one of my slides, we evolved to eat the food that comes out of the ground.
How is it that when we get sick, we think we know what to feed patients?
So, there's a lot to learn yet, and this wonderful session told us what we can measure to learn
it better, not just to try, hey, how about this?
How about that?
No, how about giving this, and measuring what is its response is?
That's what's so exciting about this field, and this session, in my opinion.
DR. GAIL CRESCI: Yes, I think we would all agree to that, it's really exciting, and where the
direction hopefully, is going to help inform us, for our patient care.
So, I have a question again, this is for David Evans, and it's regarding that, for surgical
patients a question came in, have you looked at other relationships between muscle mass
and function, and surgical outcomes?
So, CT measures of muscle mass, the psoas muscle, mass or density, have you looked at that?
And what about functional measures for lactate clearance?
Because there was a paper that shows time stair climb actually are the best predictors.
DR. DAVID EVANS: Yeah, well, thanks for that, and you know, I really just to echo on everybody
else, you know, I still think there's incredible potential for personalized medicine.
I certainly didn't mean my comment to not imply that, it's just that I think that perhaps,
more than in some other areas in medicine we haven't gotten the basics right yet; we
haven't gotten the simple stuff.
And I think your question is actually a really good example of that, because, you know, in
my research, we've spent a lot of time, and thought, on muscle mass measures,
we looked at, you know, CT scans, and first, we were looking at mass, and then we were
looking at psoas density.
And...I mean, actually, just in the last year or so, you know, a lot of that has kind of been
blown out of the water.
We saw a paper published in the Annals of Surgery, I think, in the last year, that's
the one that they were referencing, that showed that timed stair climb is actually a better
predictor of surgical outcomes.
Of course, this is, you know, surgical patients, it's not ICU patients where the injuries already
happened, but pre-operatively, that having a patient go down a flight of stairs, and
up a flight of stairs, and timing how fast they can do that, which kind of gives you
this global assessment of muscle mass, muscle function, coordination.
Clearly, it's not just a nutritional measure, but that outperformed any of our kind of analytical
assessments of muscle and, you know, lactate clearance, you mentioned that too, you know,
we have data kind of trying to get at that question about muscle function, about how
fast a patient can trigger lactate.
And of course, we know that like a well-trained athlete can clear lactate faster than a poorly
trained athlete, for example, and that often sets athletes apart.
Well, the same is true in clinical medicine, but at the end of the day, the time stair
climb has actually outperformed almost every tool.
Now, we haven't gotten to, you know, take it to like Dr. Ziegler or, you know, some
of these other labs to see if that data would be superior.
But certainly, in terms of things that we can do today in our office, we still have
a lot of opportunities that we're not taking advantage of, thank you.
DR. GAIL CRESCI: Yeah, because that's a really good point, you know, that's more of a practical
outcome too for the patient that, you know, we talk about frailty index and you know,
just being able to get back to their activities of daily living, and the impact of nutrition
on that, is that a better outcome to perhaps look at?
But we did have a question that came in regarding, you know because we've been talking mostly
about inpatients' critical illness, but there was a question about, what are the best parameters
to assess nutritional status amongst outpatients with disease?
And is this still left to weight loss over the past six months, or looking at BMI?
That's for everyone, everyone might like want to look at that question.
DR. THOMAS ZIEGLER: Can I just make a comment about BMI?
Can you hear me, Gail?
DR. GAIL CRESCI: Yes, I can hear you.
DR. THOMAS ZIEGLER: You know, so the thing about BMI, you know, the data getting, I mean, the
data, it's really becoming quite clear that BMI is a very, you know, crude measurement.
And we need better, for example, there is something called normal-weight obesity where
someone walks into the office with a normal BMI of 23, but they have an excessive body
fat mass.
And normal-weight obesity we've defined in cystic fibrosis, and others have defined it,
is really associated with coronary artery, and other outcomes.
But as you know, we just definitely need better markers of body composition.
We need to measure body composition in everybody as best we can, even if it's DEXA or some
of the methods that Dr. Earthman talked about earlier, and get away from BMI.
If we can, according to cost, I really like what John said about, you know, (LAUGHS) I
mean, we could use a flip phone, although flip phones are back, I guess, or we could
use an iPhone, and yeah, it's more expensive but if you look at all the money being spent
in any typical ICU, or even a hospital floor, if anybody's been in the hospital lately,
and you get the hospital bill, it's ridiculous.
And so, you know, I think we need to take advantage of higher-tech instrumentation,
and stuff, particularly to look at clinical outcomes.
And that could include metabolomics, breath tests, gut microbiome, all that, but I just
think we need to move forward past BMI, and as was said in the first talk, prealbumin,
and albumin measures.
DR. GAIL CRESCI: Yeah, and perhaps I don't know what you think, Dr. Dweik, regarding the volatile
organic compounds in the inpatient versus outpatient setting.
Do you have any thoughts on that?
You've done a lot of work in a lot of different disease states showing a correlation with
that, what are your thoughts on that as far as assessing for nutrition, and nutrition
intervention?
DR. RAED A. DWEIK: Yeah, thank you for asking, so definitely, you know, breath analysis allows,
lends itself to be done in both settings, the inpatient and the outpatient.
You know, I think the future, of course, if you have a point of care test, it'll be even
in other locations, like in the field, or in low-resource areas, similar to the breathalyzer
for alcohol.
So, the complication with the inpatient is similar to the questions that were raised
earlier, the clinical illness, there are so many confounding variables, and that becomes
a lot more complicated.
And I think it's true for breath analysis as it's true for other metabolic testing is
that these patients are on so many confounding interventions that may difficult.
I think that outpatients are kind of simpler in a way, they still have the confounding
variables, but they are easier to control than the inpatient setting.
But definitely, breath testing can be done in both settings, and beyond that as well.
DR. GAIL CRESCI: Thank you for that, well, we have run out of time, we had such a robust
list of questions submitted to us, and I thank everyone for their questions.
Unfortunately, we didn't get to all of them and Dr. William Evans was unable to join us.
So, for any of the speakers, if you have any further insight, or you want insight, you
can write to nutritionresearch@nih.gov with your questions, and we will try to get those
addressed.
Again, I wanna thank our stellar speakers, this was really an exciting event today, I
really enjoyed this interaction that we had, and identification of clinical gaps, and potential
future research opportunities.
So, now we're going to take a quick break before joining Dr. Steiber for Session 4
which will begin at 3:20 ET.
Thank you.
DR. ALISON STEIBER: Welcome to the session four, which is on implementation challenges and
case examples, addressing malnutrition and reducing health disparities.
I'm Dr. Alison Steiber and I'll be your moderator for this session.
So for this session, I'd like to just walk you through the agenda about what to expect.
We'll begin with a talk by Dr. Mirtallo, who will address supply chain shortages.
Then we will move on to Dr. Mechanick, who will discuss dual burden of overweight, obesity
and malnutrition.
We will then hear a talk by Dr. Newberry on malabsorptive and small bowel disorders.
And on to Dr. Patel for ICU nutrition, moving beyond support.
To Dr. Seres, Dementia and enteral feeding needs.
And then to Dr. McMacken Nutrition and Lifestyle Medicine Services.
And finally, we will end with a robust discussion on quality question and answers.
And so we hope that you will take a few minutes and put your questions in the Q&A box.
And that way, we can address as many of them as possible during the Q&A session.
So with that, thank you very much.
DR. JAY MIRTALLO: Hello, my name is Jay Mirtallo.
I am a Clinical Practice Specialist of the American Society for Parenteral and Enteral
Nutrition and Professor Emeritus at The Ohio State University College of Pharmacy.
It's my pleasure to present to you the topic of problems related to shortages.
To get started, I wanted to show you a picture of the supply chain.
This is for drugs available from the FDA.
Just to show you the complexity of what it takes to take a raw product, over on the left-hand
side of the slide, going to the final product that's in a form that can be a nutrition,
nutritional product that can be administered to patients to manage malnutrition.
You can see there's a number of different reasons why there is problems for the supply
chain that I've highlighted in red here that can happen at any one particular point in
time.
The main point to make is our supply chain for nutrients is vulnerable and prone to shortages
over long periods of time.
Provided an example, these are the parental nutrition shortages we were dealing with in
ASPEN during 2010.
If you look at the nutrients, it pretty much includes all of the nutrients that we need
in our body at any point in time.
Now, I noted 2010 most because since that time we have still continued to have shortages
at any one time for any one of these products.
They haven't really gone away and it might be for a different products, but also we've
seen an extension of these shortages to include both enteral nutrition as well, which would
be the specialty infant formulas that have been struggling with regards to making them
available to that population.
We've also seen shortages of just the ability to infuse these products since with our nutrition
you need some kind of device to infuse it.
And so we've seen shortages also occurring with pumps, infusion pumps, we've seen them
with IV filters, we've seen them even with the products that are needed to make these
products in the pharmacy.
So we've really had critical issues with regards to making sure we have an adequate supply.
These are examples of problems that result from shortages because clinicians are exposed
to less desirable or unfamiliar products.
There could be errors with regards to prescribing, such as omission of the product or a provision
of an overdosage for the product.
With bringing new products into the organization that people aren't familiar with, there's
confusion on how to prescribe due to the substitution as other systems issues related to compounding
and distribution of workarounds.
All of these are systems issues that need process improvement efforts, education of
staff, as well as clinicians that need to purchase the products in order to avoid clinical
issues in the patients.
But the real problems with the shortages really comes from the fact that we don't have enough
nutrients available to provide all the patients that it would be prescribed for, that have
the need.
So because of a shortage, we need to develop some sort of rules for constraining this inadequate
supply and those things that we need to do in order to identify which patients that this
is going to apply to.
And so we really are looking at identifying risk in this patient population and in this
case, a risk of deficiency.
If a patient has little or no risk, they may just omit the product from a patient and monitor
closely to make sure a deficiency doesn't occur.
If they have a little risk, they might just reduce the dose again, monitor more closely
to see if the deficiency would occur.
But if those patients are at high risk or already have a deficiency, they'll be required
to have a full dose.
And we hope we have enough of the product to be able to do that for the patients we
really believe are at the highest risk.
Now, any other things that can happen is or we can use diet modification or maybe oral
supplements if possible. The "if possible" is if they're available or if they're tolerated
by the patients.
But the main thing is because of these issues, we have a predisposition to nutrient deficiencies
and an increased need for monitoring for our patient population.
On the next few slides.
I want to provide some examples of clinical issues related to shortages, starting here
with macronutrients.
Looking at Amino Acids, Lipid Injectable emulsions, and L-cysteine.
Looking at contaminated PN causing infection and death, fluid overload, hyperglycemia,
when use of glucose as a calorie source instead of fat.
And then last is an inability to provide adequate doses of calcium and phosphorus for neonates,
which could be a problem that cause permanent problems in that population.
We have electrolytes.
One of the issues here we have here with electrolytes is diarrhea that's caused by an oral electrolyte
supplement.
So all oral doses of drugs, per se, are not tolerated very well by patients that have
gastrointestinal disorders that require enteral or parental nutrition.
Vitamins have always been an issue with parental nutrition, and we have had in the past deaths
that have been attributed to thiamin deficiency because of multi-vitamin shortages in our
patient population and not understanding how we need to be able to constrain the supply so
those high-risk patients receive therapy.
I wanted to note this slide, just note that the clinical issues related to nutrient deficiencies
are not age dependent.
Anybody at any age that has a gastrointestinal disorder and has had poor nutrition up until
the point that they're receiving parental nutrition or enteral nutrition are going to
be at risk for nutrient deficiencies.
And so you can see this for a copper, 62-year-old, versus selenium, 2-year-old, and thiamine,
a 16-year-old.
So hopefully what this information provides you is that we have a vulnerable nutrition
support population.
They have gastrointestinal dysfunction and oral/intestinal failure.
That is, the inability to maintain normal nutritional status on an oral diet or nutritional
needs are altered due to disease.
And that means that normal nutrition if you try to provide it to them to keep their nutritional
status adequate, is poorly tolerated or could exacerbate the underlying gastrointestinal
disorder and require hospitalization or other acute care medical therapy as a result.
I'd like to tie this together by bringing in the patient perspective.
This is a statement that was submitted by a parent writing to their congressman to support
a bill to preserve medications at that time.
This was on behalf of their nine-year-old son who could not receive intravenous calcium
in his approach to nutrition and subsequently developed complications from oral calcium
therapy.
She stated, "Imagine knowing your child needs vitamins, vitamins, and there is none available
to give him knowing this will cause a decline in his health and well-being and you have
to, in essence, watch your child starve because in this great country there are drug shortages."
So this brings me to what I consider to be the knowledge gaps or areas that we can really
start asking questions to research in order to help us do better for our patient population,
because shortages are always going to be there.
The first question I have is how is nutrition or nutrient risk of the patient identified?
Or specifically, how can we more accurately assign a patient to no, reduced, or full dose
of a nutrient when supply must be constrained due to shortages?
And this, I think, ties into one of the issues we have in just nutrition in general.
You know, what are the best and most reliable methods for determining the presence and severity
of malnutrition in a timely manner available across all healthcare settings?
Second is what is the best and most reliable method for determining the micronutrient status
of a patient in a timely manner available across all health care settings?
And the main points I want to make is when we look at these deficiencies we have seen
in this population, that that's actually a great population to study because you have
controlled doses of nutrients that are being provided and it's kind of like you've got
a placebo effect and those individuals that aren't receiving any kind of nutrients and
in addition to the patients that are receiving full nutrition, but we've had a number of
years big issues with regards to being able to get the diagnosis of our patients in a
reliable manner before it causes clinical problems that cause either temporary, permanent
nutritional deficits, or death in a patient population.
I know we're going to have more questions related to this in the future.
I think this ties in probably to some of the other discussions that have come up already
previously related to this.
But with this population, these I think are the major focuses that we should have with
regards to being able to come up with information that we can provide better decisions that
protect our patients and can manage them clinically so they don't have to suffer as a result of
shortages.
These are the references that I've used, and I really look forward to hearing the discussion
on this topic.
DR. JEFFREY MECHANICK: Hello, this is Jeff Mechanick.
I'm pleased to speak to you today on the dual burden of overweight, obesity and malnutrition,
a transculturalized driver-based chronic disease modeling and real-world implementation tactics
approach.
Here are my disclosures.
And let's go through an outline.
We begin with what the question is.
Then we're going to move into theoretical modeling of driver-based chronic diseases,
particularly overweight obesity and malnutrition.
Well, then move into epidemiology - present just a few studies, mechanisms, preventive
care strategies, implementation tactics, and then a conclusion.
What's the question?
Well, is there a connection between obesity and malnutrition that impacts clinical burden?
Now, the implication of this is to reinterpret obesity within a novel, robust theoretical
model, particularly one that includes aspects of cardiometabolic risk, malnutrition, chronic
disease and preventive care.
Let's now look at driver-based chronic disease models.
Now, the purpose of devising these models or these constructs is to expose early and
sustainable opportunities for preventive care in the natural history of chronic disease
in order to reduce clinical and, in fact, economic burdens as well.
Let's look at the structure, there's three dimensions.
The first dimension is stage progression over time, and the map prevention type. Risk
would be primordial prevention, to prevent disease primary prevention, to prevent progression
of disease secondary, and to prevent complications and the impact of complications on suffering
and mortality, that's tertiary prevention.
The second dimension is to look at the key mechanistic drivers.
This is networking, causation, and then from a clinical standpoint, to prioritize these.
The third dimension is the social determinants of health and also the transcultural factors.
Now examples of these models pertain to adiposity, dysglycemia, hypertension, lipids, cardiometabolic
risk, and, of course, malnutrition.
How did this all start?
Well, we wrote a paper for the Journal of the American College of Cardiology back in
2016, and we looked at the networking effects of adipokines, cardiovascular system, and the
impact of lifestyle medicine.
And what we found is really this complexity that really needed to be teased out.
You can see here in the yellow highlighted boxes are small world phenomenon of diet and
obesity within this network.
And that inspired us to then come up with these models, the first on the top left for
abnormal adiposity rather than just dwelling on amount or BMI to also look at abnormal
distribution.
That would be a topic fat, right?
And also abnormal function looking at various levels or indicators of inflammation, then
interpreting them through the lens of context, physical and non-physical world culture, and
you come up with the burden of disease.
Our next paper was looking at dysglycemia and in this paper, we actually were able to
configure this stage progression over time, four stages.
Stage one: risk, Stage two: pre-disease, Stage three: disease, Stage four: complications.
And here we're actually merging together insulin resistance, pre-diabetes, type 2 diabetes
and diabetes vascular complications.
On the right side, you can see we pulled the drivers together, that's second dimension,
and we get cardiometabolic based chronic disease.
Essentially looking at these key drivers of abnormal adiposity, A, B, C, D, dysglycemia
DBCD on various forms of cardiovascular disease or cardiometabolic based chronic disease.
And these models form the context in order to interpret this interaction between malnutrition
and obesity.
If we evolve this model even further, we start to introduce a third dimension.
If you look at the two-by-two matrix of time versus driver on that right side, you can
see for each cell you could transculturalize or find social determinants that modulate
the phenotype, modulate the way in which you can more precisely introduce an intervention
in this model for a cardiometabolic based chronic disease.
Now let's look at how a chronic disease model for adiposity, ABCD on the left, interacts with
the chronic disease model for malnutrition.
You have the same primary drivers, genetics, environment, and behavior, all interacting
to create a particular lifestyle which could be healthy or unhealthy.
And then if you look at the particular drivers, there are interactions among diet, metabolism,
energy balance, and adiposity.
And then ultimately what happens is you have different stages and you can codify where
you are in this particular chronic disease by the stage.
So for instance, stage two ABCD is what we commonly referred to as overweight.
Stage three would be obesity.
For the MBCD or malnutrition model, stage three would be malnutrition-fulfilling criteria.
Now, stage two might still have some abnormal descriptors of nutritional risk, nutritional
status, but not formally meeting the diagnostic criteria that may find in various societies
like ASPEN.
And then together they merge and you can configure a preventive and lifestyle medicine type of
management.
So let's look at the epidemiology.
Let's look at the scientific substantiation for these models.
I just picked four studies here.
In the first, we found that one third of patients with overweight/obesity were actually at risk
for malnutrition at hospital admission using various scoring systems.
And you know, what this tells us is that we, in fact, do need new models for abnormal adiposity
and malnutrition to better represent risk classifiers.
In another study among low-income countries, modest increases in income, reduced underweight
prevalence, but without affecting obesity prevalence.
And here we need to better understand the social determinants of health with high-quality,
population-based studies.
In the third study, the risk of undernutrition, those risks where per capita GDP, levels of
urbanization, supply of fatty foods, various population-based vulnerability shocks, and
diseases.
While the risks for overnutrition were cereal import dependency again per capita GDP, domestic
food production, and dietary energy supply.
We need more policy actions, better policy actions for sustainable and balanced food
and nutrition systems.
Transformation through trade, openness, and reduction of adverse effects of urbanization.
In the last study, we look at the obesity paradox, where obesity would be associated
with increased survival, with, let's just say, for example, heart failure and actually
all types of heart failure.
Malnutrition doubled the mortality risk in patients with obesity and heart failure, showing
the interaction of those two states, obesity and malnutrition compared with patients with
normal nutritional status.
So actually, what do we need?
We need routine recommendations in patients with obesity, not just talking about weight
loss, but actually nutritional status as well.
We look at mechanisms in a computer community-based cohort, patients with obesity, a higher BMI
and poor nutritional status had the highest comorbidity burden in terms of adverse cardiac
remodeling and composite clinical outcomes.
So this had to do with ectopic fat inflammation, pro-BNP, better nutrition protects against
endothelial inflammation and damage, and the net effect was maladaptive cardiac remodeling.
And this affirms this networking interaction of adiposity and malnutrition.
In another study there were metabolic sub phenotypes that reflected different responses
to macronutrients may impact microbiome and other genetic susceptibilities, and clearly,
we need more translational research.
Here are the various preventive strategies to reduce this dual burden of abnormal adiposity
and malnutrition on the left for adiposity, the preventive strategies deal with cardiometabolic
risk, biomechanical complications, ectopic fat, inflammation, stigma, social determinants,
transcultural factors for malnutrition on the right, macronutrient amount and distribution,
micronutrient deficiencies, endocrine disruptors, body composition, sarcopenia, and then, of
course, social determinants and transcultural factors.
Implementation over the short term, you need a mandate, then a champion, a person who's
credentialed and experience.
Assemble a team, get your funding, leverage technology, which is a force multiplier, create
your infrastructure, your physical and non-physical immersive infrastructure, and then you adapt
and optimize based on data.
Let's conclude. Patients with nutritionally unhealthy obesity represent a distinct high-risk
population, and this is supported by theoretical, epidemiologic, mechanistic, and social relationships
and can be better understood and pragmatically managed using our driver-based chronic disease
models.
Next steps should address research gaps, knowledge gaps, and practice gaps.
Thank you.
DR. CAROLYN NEWBERRY: So I wanted to thank the organizers for asking me to speak today about
malabsorptive and small bowel disorders and the increased burden of malnutrition in GI
patients and what to do about it, and what research directions we can take to improve
care in this population.
Here are my current disclosures, none of which are pertinent to this talk.
In terms of a lecture outline today.
We'll be reviewing small bowel anatomy and absorptive properties, the small bowel
pathology as a high risk disease state using inflammatory bowel disease as an example,
risk stratification and care management pathways, and future directions for clinical care and
research.
The small bowel is one of the most important areas of the luminal GI tract for digestion
and nutrient absorption, the total length is achieved by the age of nine.
And it includes about 500 to 700 centimeters or 16 to 20 feet, the height of a giraffe.
The colon, in comparison is only about 150 centimeters long.
The total absorptive capacity of the small intestine is about 8.5 liters, which is 85%
of total ingested fluids and digestive secretions.
Surface area is enhanced by the presence of villi.
Different gastric secretions, bile and pancreatic secretions allow for further breakdown of
macronutrients and micronutrients into their byproducts, which is then primarily absorbed
throughout the length of the small intestine, as depicted here.
Considering the absorptive properties of the small intestine, it's not hard to see why
patients with pathology in this area are at high risk for malnutrition.
The combination of malabsorption, which leads to reduced calorie and nutrient utilization,
inflammatory changes such as found in things like inflammatory bowel disease, which increases
resting energy expenditure and associated digestive symptoms and anorexia, which reduce
oral intake, would all lead to a high risk of malnutrition in this population, putting
them at risk of chronic disease state related malnutrition, as per ASPEN guidelines.
The prevalence of significance of malnutrition in patients with small bowel diseases, including
things like inflammatory bowel disease, is quite high.
And current studies estimate that between 20 and 85% of patients with IBD have some
degree of malnutrition.
And obviously this number varies widely based on patient demographics, underlying disease
state in Crohn's versus ulcerative colitis, with Crohn's having higher rates of malnutrition
due to more extensive disease processes and surgical history.
In terms of clinical outcomes of these patients when they are hospitalized, the results are
also quite staggering.
So this is some information about a large all-payer database maintained by the AHRQ
that provides a nationwide inpatient sampling of thousands of patients.
Patients who are admitted to the hospital who had inflammatory bowel disease were actually
six times more likely to be coded as having protein calorie malnutrition per ICD 10 coding
versus those without inflammatory bowel disease.
Mortality was actually up to five times higher in the population of patients with inflammatory
bowel disease that also had concomitant malnutrition in comparison to those who didn't.
Their length of stay was twice as long, and their hospital charges were more than double.
In light of statistics like these, national guidelines like those put forth by the European
Society for Parenteral and Enteral Nutrition, have spelled out that these patients are at
high risk for malnutrition and that we need to start both risk stratifying and intervening
when appropriate.
Here are two guidelines that are important to highlight in this population.
The first is the patients with IBD are at high risk and therefore should be screened
for malnutrition at the time of diagnosis or on a regular basis thereafter.
And that documented malnutrition in these patients should be treated appropriately,
but it can worsen prognosis, complication rates, mortality and quality of life.
Extensive literature has shown that early identification of malnourished patients in
this population using a two step approach of nutritional screening followed by a subsequent
assessment in those that are high risk can lead to earlier intervention and impact on
clinical outcomes.
However, the optimal approach to screening and the optimal approach intervention are
still under negotiation.
Risk stratification tools really come in two flavors.
The first is the actual screening tool, which you've probably heard about in this conference
already, examples being the NRS-2002, the MUST score, the nutritional risk index, the
Malnutrition Inflammation Risk Tool.
These things include things like BMI, recent weight loss trends, especially in terms of
percentage of total body weight loss, current disease severity, and basic laboratory data.
And then the nutritional assessment tools that are often used as a second step if the
nutritional screening comes back positive.
These include things like comprehensive dietitian and gastroenterologist assessment, the SGA,
skeletal muscle assessment, and free fat mass assessment, which includes things like taking
a complete inflammatory bowel disease history, again, BMI, more comprehensive nutritional
labs and micronutrient screenings, and then body impedance analysis or cross-sectional
imaging, like CAT scan to define body composition.
Determining whether screening tools are accurately identifying patients that are malnourished
requires comparing them with formal assessment tools.
This study did just that in IBD populations.
It determined that the NRS-2002, which is usually used in the inpatient setting, had
reasonable correlation with assessment tools, as did the newer malnutrition inflammatory
risk tool, which is developed for use in Crohn's patients but hasn't been extensively validated.
The MUST score which has been validated in a large percentage of populations had some
correlation in some studies and weak correlation in others.
A newer tool called the SaskIBD-NR tool has also been analyzed, which takes into account
more digestive complaints that may be pertinent to the IBD patient.
Considering the lack of definitive evidence for which screening tool corresponds to the
best outcomes, there's still more work to be done in this field.
I did want to highlight another potential area of study which looks at nutrition education
in gastroenterology fellowships.
I pulled some studies that actually analyzed this question and found that GI fellows actually
get very little nutrition education, like other physician specialties, and perform poorly
in knowledge-based assessment as well as in terms of how comfortable they are providing
nutritional assessment support tools and understanding how to utilize nutrition in disease states.
I do ask if gastroenterologist are not trained in proper nutrition principles in the first
place, will they even know to use these malnutrition screening tools in practice?
And I think this is a further area that we need to analyze.
In terms of intervention tactics.
We also don't really know the best way to intervene on these patients.
There's been an increase in addressing multidisciplinary care modeling, in particular for complex disease
states like IBD.
And a number of papers have been published in the gastroenterology literature highlighting
the need for incorporating people like dietitians into clinical care teams.
With this, a number of large academic centers have done just that, including teams that
have been developed at Cedars-Sinai as well as my home institution.
National societies have also developed more guidance for providers, both with traditional
tool assessments as well as interventional tactics.
However, literature is lacking to determine how these perform in clinical practice and
how they affect patient outcomes.
And so in closing, we know that patients with small bowel pathology like found in the IBD
population are at high risk for malnutrition due the small bowel's important role in digestion
and absorption.
We also know that studies have confirmed high rates of malnutrition in this population,
which correlates with poorer clinical outcomes.
There are a number of things we don't know however.
The optimal means for risk stratify patients to provide targeted intervention, especially
in the outpatient setting in this subset population of small bowel diseases like IBD is still
unclear.
National physician nutritional educational efforts need to be augmented across the board,
especially in specialties who care for higher risk patients.
We don't actually know if these efforts will improve clinical outcomes.
Additionally, multidisciplinary teams and patient-centered medical homes may play a
role in populations like IBD as well as other complex disease states, but we need to study this.
DR. JAY PATEL: Hello, my name is Jay Patel, and I am joining you from the Medical College
of Wisconsin.
Thank you to the NIH, the Office of Nutrition and the Organizing Committee for the opportunity
to speak with you today.
I will be discussing intensive care unit nutrition and how we can move beyond just support.
I have no disclosures related to the contents of this talk.
Let's start by examining common critical care trajectories.
Our ICU patients typically follow one of three patterns.
First, there are some patients that no matter what we do, they succumb to fulminant death
within 24 to 48 hours.
Fortunately, these patients represent the minority.
The second patient in green is probably the most common phenotype, where they spend a
few days to a week on various forms of life support but recover and leave our ICU and
even go home.
The third patients in blue is the individual who has an undulating course marred by repeated
ICU admissions, nosocomial infections, severe malnourishment, and often culminating in
an indolent death.
In their most recent guideline, the European Society of Parenteral and Enteral Nutrition
outlined the phases of critical illness during that first week.
You'll notice that there are two phases: an acute phase and a late phase.
And the acute phase is partitioned into an early acute phase and a late acute phase.
Now notice that there's days, one to two, and days three to seven listed here, but in
reality, we just don't know when patients transition from one phase to another.
And some research gaps in this context include, can biomarkers distinguish between the phases
of critical illness?
And we'll see why that might be important a little bit later.
And can biomarkers inform anabolism?
Again, we'll see why that might be important a little bit later as well.
Now, if we isolate the early acute phase, that is when there's dysregulated inflammatory
and immune responses.
And the clinical phenotype is one where the patient is newly intubated, febrile, undergoing
circulatory resuscitation, started on vasopressors.
What is the role of nutrition during this early acute phase?
Well, if we shift our focus to micronutrients for just a moment, the concept of metabolic
resuscitation seems to suggest that supraphysiologic doses of micronutrients, examples include
vitamin C, vitamin D, selenium, could serve to extinguish that rapidly burning inflammatory
fire.
Now, even though there are numerous negative trials in this space, the paradigm may be
weakened by the fact that we don't have proper dosing studies and additional needs work may
need to be done, particularly test the various types, combinations, and doses of micronutrients.
So in that context, research gaps here could include, which critically ill patients would
benefit most from supraphysiologic doses of micronutrients?
And in critically ill patients, what are the optimal and safe doses and delivery methods
for various micronutrients?
And what is the efficacy of combination micronutrients with perhaps pleiotropic effects?
Let's go back to our trajectories and let's home in on the second and third, which represent
patients that spend more than a few days in the ICU.
And because of dysregulated inflammatory immune responses.
The question is what happens during this early acute phase that nutrition has the capacity
to modify?
First, let's point out that hyper-catabolism and ensuing caloric debt are common during
this phase and persist throughout the intensive care unit stay and beyond.
So when we think of the provision of micronutrients, what is often asked is when, how much, and
through which route should I deliver nutrition?
I think many of us would agree that earlier nutrition is favored over delayed.
But in answering the dose question, numerous trials that have compared the dose of nutrition
during the first week of critical illness have been negative, and there were negative
for outcomes, including mortality.
So if not mortality, what could dose impact?
Well, here's the third thing that happens.
And there may be varying degrees of gut dysfunction.
And the role of nutrition, especially macronutrients, may be to mitigate the silently brewing threats
of gut dysfunction, again, during that early acute phase of critical illness.
Now, this is an oversimplification, but it turns out that these mechanisms listed here,
along with the emergence of a pathobiome can generate gut-derived inflammation.
And it's that gut-derived inflammation, as you all know, that serves as the motor that
drives multiple organ failure.
And research gaps related to nutrition and therefore gut dysfunction include, what is
the variance in gut dysfunction based on the type and severity of critical illness?
Can bedside biomarkers identify gut epithelial functions?
What is the impact of various doses of enteral nutrition on gut dysfunction?
And what is the efficacy of various doses of enteral nutrition in subsets of critically
ill patients with varying amounts of gut dysfunction?
Because again, if we can identify when patients are going to tolerate nutrition based on a favorable
gut function, then perhaps it's time to push more nutrition.
But we just don't know right now.
And then there are a subgroup of critically ill patients who are more unstable, and that
includes individuals who are in circulatory shock, on ECMO, and even those who are prone.
And they may be more unstable because they might have a more heightened inflammatory
state and more susceptible therefore to gut dysfunction and acquired malnutrition.
And so in these patients, we have a conundrum.
On one hand, if we do not introduce luminal nutrients, we risk gut dysfunction, which
can then serve to perpetuate the multiple organ dysfunction syndrome.
And, of course, some of the downstream effects include escalating energy debt and acquired
malnutrition.
But on the other hand, if we feed these so-called unstable patients, we risk GI intolerance,
which as you can see, it can manifest in many ways, including vomiting.
And the gravest consequence includes bowel necrosis, often reported in patients who are
on ECMO and in circulatory shock.
And so for the unstable patients, those perhaps prone to greater gut dysfunctions and acquired
malnutrition, here are some research related gaps.
What's the efficacy of EN in those circulatory shock?
What's the efficacy of various doses of EN in patients undergoing various forms of ECMO?
And then what is the efficacy of various doses of EN in patients undergoing prone positioning?
Finally, here's a fourth consequence, and that is proteolysis, which often begins in
the early acute phase of critical illness and leads to loss of muscle mass.
So here's a study of 60-some ICU patients that underwent ultrasound of the rectus femoris
muscle for cross-sectional area assessment and biopsies on ICUs days, one, three, seven
and ten.
And what you can see here from this graph is that the rectus femoris cross-sectional
area decreased by 17% an ICU day.
And so why is focusing on muscle importance?
Well, for starters, this figure shows that short-term mortality from critical illness
has decreased from greater than 40% in the 1980s and 90s to under 30% by 2011.
And so if our patients are dying, what happens to them when they leave our ICU?
It turns out that survivorship post ICU is plagued by physical complications that impacts
quality of life.
And that quality of life impairments can persist for up to five years, which really has a significant
disability on things such as active activities of daily living.
So to preserve muscle or stimulate synthesis, it makes intuitive sense to deliver protein.
So here's a recent meta analysis of 15 randomized controlled trials comparing high versus low
protein in critically ill patients.
And it found no benefit of high or low dose protein on mortality.
But one important finding highlighted here in green is a higher protein was associated
with an improvement in the loss of muscle mass.
And future protein trials should assess outcomes that are going to be important to survivors.
Parenthetically, this meta-analysis did not include the recent effort trial, which, as
you know, was a negative trial, and we hope to have it published soon.
But the story with protein is more complicated, that high versus low dose.
So for starters, here's what happens to muscle protein synthesis with a protein load.
The arrows show protein intake, and the green areas under the curve represent periods of
increased muscle protein synthesis.
The red represents muscle protein breakdown.
As you can see, there's a net even nitrogen valance.
But here's what happens with aging and muscle disuse.
Muscle protein synthesis is attenuated, and you can extrapolate that this could even happen
in our critically ill patients who have impaired anabolic responses.
And as you can glean from the white areas under the curve, there's more protein breakdown,
culminating in a negative nitrogen valance.
But when protein loading is coupled with resistance exercise, there's a much greater increase
in muscle protein synthesis.
And the story certainly doesn't end there.
We still don't know the optimal type of amino acid, method of infusion, or its effect in
subgroups of critically ill patients.
And so questions related to protein provision and critical illness include, can admission
bedside ultrasound measurements of muscle groups risk stratify our critically ill patients?
Can serum biomarkers inform muscle protein synthesis?
And then what is the feasibility, acceptability, and efficacy of protein loading and resistance
exercise on parameters of physical functioning in survivors of critical illness?
And then what is the optimal safe dose of protein in subgroups of critically ill patients,
including those with cirrhosis, kidney injury, and obesity?
Thank you for your attention.
DR. DAVID SERES: Thank you for attending.
I'm Dr. David Seres at Columbia.
And we'll be talking about dementia and artificial feeding.
This is a rather controversial subject, and the data on it is really rather poor.
Just to reiterate what I've said in the past, I don't have any commercial conflicts but
I am opinionated, and hopefully, I'll be able to stick to the evidence.
Also to reiterate my concerns about basic practice on observational research I remind
you that I go to the pilot every time I get on a plane to ask that the seatbelt not be
turned on because there's a 100% concordance between them turning on the seatbelt sign
and the plane ride getting rough.
Obviously, this is not causal, but it is an example of how this kind of thinking could
lead us astray.
Speaking of observational research, this is one of the better studies in which patients
were all offered gastrostomy, this is from the VA, approximately 45 patients.
And there was a cohort of patients who did not get a gastrostomy based on surrogate refusal
or an advance directive.
And their longevity was tracked, and there was no difference in the life expectancy between
the two cohorts whether they received the gastrostomy or not.
There have been some studies that have shown some improvements in some characteristics
in these patients, but only in patients with mild dementia.
This is also retrospective, and the patients that benefited had mild dementia.
The ones with severe dementia did not.
The benefits were improvement in independent living, in oral intake.
Both of these were improved in this study.
Pneumonia was not.
In fact, the most common cause of death for patients who have gastrostomies is pneumonia.
So the idea that putting a gastrostomy on a patient and not letting them eat because
of swallowing dysfunction is probably erroneous.
Through the past 30 years or so, there has been a growing trend for nursing homes to
refuse to take nasal feeding tubes and require gastrostomies.
Back in 2015, we surveyed every nursing home in New York City, and then an adequately powered
sample of the rest of the United States.
We had a tenacious young student who called every nursing home five and six times, so
we had an 85% response rate.
Eighty percent of the nursing homes in New York City refused to take nasal feeding tubes.
Nationally, the refusal rate was only 35%.
I would wager that this has gotten far worse.
It's all based on anecdote when I was working in.
SPEAKER: Early in my career, I was working in three different hospitals.
And on the same day, two of the same patients in each of those hospitals, a feeding tube
was placed.
It went down to the trachea through the lung parenchyma into the pleural.
A patient was fed into the pleural and died.
And I say again, it happened to the same patient in each of the three hospitals on the same
day.
So it must not have happened at all.
I've never been able to find the index patient.
That said, I'm sure that this has happened, but this spread like wildfire.
And within about a year we started hearing about nursing homes starting to refuse nasal
tubes because of this story.
Currently, if you were to ask the nursing homes why they were refusing them, the answers
are really quite interesting.
The tubes will fall out, the patient will aspirate and die, we'll lose our license.
This was actually a quote of somebody in tears telling me, 'Please, don't do this.'
In my efforts to try and get nursing homes to take them once again, there are complete
misquotes of both state and CMS policy, and having been to the state and CMS,
I can tell you, that they absolutely do not have a preference for nasal tubes or
gastrostomies nor do they pay differently.
Long-term comparative effectiveness studies are small.
And in the aggregate and the Cochrane Review, there are about 750 patients really showing no substantive
differences.
There are similar complication rates, but the complication severity strongly favors
the nasal tubes.
And the conclusions of the paper say that there might be a benefit to using gastrostomies
because of a decrease in what they call the treatment failure, which was mostly clogging,
which is really quite preventable.
There was no difference in survival.
There were no difference in readmission.
But the thing that worries me the most is the severity of the complications.
In a cohort of patients that we followed in the hospital over a period of three months.
Every patient was...who had been receiving tube feeding.
And on average, that's about 60 patients in our hospital.
Every one of them was visited twice a week where adverse event...adverse events were
sampled, collected, and recorded.
And we did this at the bedside because we have also shown that the incidence of complications
in the chart is far, far less than what actually happens.
So this was based on patient, family, and nurse interviews, and examinations.
And you can see here that the complication rates were far higher with the gastrostomies
than they were with the nasal tubes.
Our final conclusion was that the adverse event rate was something on the order of at
least twice of...in the patients who had gastrostomies that the nursing homes are forcing us to put
in these.
We think that it's really quite unethical and have been trying over the years to change
this behavior.
We have certainly had success in presenting the data to nursing homes and training them
once again to use these nursing homes...using these nasal tubes.
The practice of placing a gastrostomy at the same
time as a tracheostomy has become standard practice in a lot of places.
In anticipation of the fact that if you're sick enough to need a tracheostomy, of course,
you're going to need to be discharged to a nursing home with a gastrostomy.
To test this, we put in a policy of delaying gastrostomy until discharge planning was underway.
Usually, that gives us three or four days and our endoscopists were willing to make
sure that these patients were prioritized so that length of stay was not delayed...increased.
As a result of this delay process, we decreased the frequency of gastrostomy from 60% of tracheostomy
patients down to 26%, meaning that more than half of the gastrostomies we were replacing
were unnecessary or futile, meaning that the patient was either discharged eating or had
expired during their hospitalization.
So the research questions boil down to needing randomized controlled trials.
Does artificial feeding prolong life?
And what is the differential effect with different levels of dementia?
What kind of nourishment is required to have an impact?
Other alternatives to tube feeding?
Certainly, there's a large literature on hand feeding of patients with dementia and swallowing
problems.
What are the predictors of response?
As with all this kind of research, there are confounders we have to look at.
As I've mentioned, the severity of types of malnutrition.
The causes for feeding difficulty, whether it's dysphagia or anorexia.
The cause for the malnutrition, whether it's starvation or catabolism.
I would wager that patients with catabolism will not respond to nutrition intervention,
whereas those who are purely starved might.
We have to look at the route, whether it's nasal versus a gastrostomy or even parenteral
nutrition.
And there are a lot of ick factors here.
We feel very strongly about whether or not it's moral to prolong the life of somebody
in a state of severe dementia and so forth.
And so there's a lot of emotion around these issues.
The Moonshot study that I'd love to see would be with the patients with advanced dementia
and feeding problems randomized to tube feeding or hand feeding and looking at these outcomes.
Thank you for your attention and I look forward to discussing this with you in the discussion
section coming up.
DR. MICHELLE MCMACKEN: Hi, I'm Dr. Michelle McMacken and I'll be speaking today on nutrition
and lifestyle medicine efforts at New York City Health and Hospitals, the nation's largest
public health care system.
So we serve all New Yorkers regardless of their ability to pay or their immigration
status.
The majority of our patients have Medicaid or are uninsured.
We have very high racial and ethnic diversity, and a significant proportion of our visits
are conducted in languages other than English.
So it's not uncommon in a typical week of clinical practice to conduct visits in all
of these languages and sometimes more.
So I've been a primary care internal medicine physician for 18 years, and my practice over
this time has really revolved around all of these conditions, which, as we know, are related
to lifestyle behaviors, particularly nutrition.
In fact, we know that a suboptimal diet is actually the number one risk factor for dying
of a chronic disease in the United States.
And yet, nutrition is vastly under-emphasized in primary care and general clinical practice.
So enter lifestyle medicine.
This is an evidence-based approach for preventing and treating lifestyle-related conditions
through the adoption of healthy behaviors.
So those behaviors, you can think of them across six different pillars.
There's healthful eating or the nutrition pillar.
There's physical activity, stress management, forming positive relationships or connections,
improving sleep and avoiding risky substances such as tobacco.
And I want to draw a distinction between lifestyle medicine and other fields, such as functional,
integrative, or alternative medicine.
Lifestyle medicine is an approach that uses well-established behavior changes to improve
health.
In fact, major guidelines emphasize the critical role of lifestyle modification in preventing
and treating chronic disease.
So this is really quite mainstream.
So after many years of promoting lifestyle change as a primary care physician in practice,
in 2019, I had the opportunity to launch the plant-based lifestyle medicine program at
New York City Health and Hospitals/Bellevue.
And our mission with this program is to provide intensive support using an interdisciplinary
team for evidence-based lifestyle modification, including a more plant-based diet.
We really aim to reach communities that are facing inequities, including a disproportionate
burden of cardiometabolic disease in the community, as well as structural barriers to even adopting
a healthy lifestyle in the first place, such as food insecurity or housing issues.
And I'm very proud that we are the first program of its kind in a public health care system
in the United States.
Now, I mentioned earlier helping our patients move towards a more plant-based diet.
So I want to explain why we chose a plant-based diet and what that means.
So a plant-based diet, as we define it, is really a diet that's rich in fruits and vegetables,
proteins that come from plants such as legumes, plant fats like nuts, seeds, avocados, and
an emphasis on whole grains instead of their refined counterparts.
It does not need to be an exclusive...exclusively plant-based diet.
Just simply that we're increasing the focus on these very helpful foods on the plate to
the extent possible.
And these plant predominant eating patterns, really, there's a very compelling wealth of
evidence around chronic disease prevention and treatment from coronary heart disease
to blood pressure, cholesterol, or LDL reduction.
Prevention of diabetes, improving blood sugar control in type 2 diabetes, reducing the
incidence and progression of chronic kidney disease, promoting healthy weight management,
and reducing overall cancer risk.
And again, as I mentioned, for lifestyle medicine, plant-predominant diets are aligned with numerous
nutrition guidelines, whether it's for general health, cardiovascular health, cancer prevention,
or diabetes prevention and treatment.
So our program at Bellevue takes adults living with one or more of these cardiometabolic
conditions.
Our referrals are based on referrals internally from providers through our e-consult system,
or we can get referrals from our telephone contact center.
So we encourage any individual in New York City who's interested in working on their
lifestyle and meets our criteria to call our number and refer themselves.
And we get many, many referrals that way.
Our interdisciplinary team uses physicians, a dietitian, a health coach, an exercise trainer,
and a program coordinator.
We have two phases to our program.
The active phase is six months long and the support phase is really indefinite after that.
So in the active phase, each patient will have 2 to 3 individual visits with every clinical
team member.
And the backbone of this phase is our weekly video group sessions, which involve lifestyle
education and guided exercise.
We also offer resources to our patients, such as cookbooks, resistance bands, and our own
starter guide to a plant-based diet.
And in support phase, we continue to have monthly video support groups to help patients
continue to have that peer support that's so beneficial for lifestyle change.
This is just a list of the different topics that we cover in our Lifestyle Starter series
group classes.
You can see that there's numerous topics related to nutrition.
It's very practical, helps meet patients where they're at.
Focuses also on fitness, mindful eating, stress management, and sleep health.
Our approach from all of our providers is really to focus on a very patient-centered
goal setting and action planning approach.
So we tailor this very carefully to our patients' cultural background, their family situation,
their socioeconomic situation.
We work very hard to help address our patients' social needs, and we really help to welcome
any movement towards healthier habits.
So we tell our patients that they can move at the pace that they're ready for.
And we will really celebrate them as they move along the spectrum towards change.
In terms of our outcomes, we've had a very, very robust interest in our program with more
than 1500 referrals.
We've taken care of more than 500 patients since we started.
We've seen clinically significant and statistically significant improvements in diet quality,
physical activity, sleep health, glycemic control, and body weight.
And we've had very high patient satisfaction, which has been so rewarding to see.
Just sharing a testimonial from one of our patients who said, "Since starting the program
four months ago, I've lost 18 pounds, lowered my blood pressure, lowered my triglycerides,
and reduced my blood sugar.
The program is nothing short of life-saving.
I hope it can continue to be offered to more New Yorkers."
And that's exactly what we're going to do.
So earlier this year, we announced together with the mayor's office and City Hall, that
we are going to be expanding our Bellevue program to six new sites covering all five
boroughs of New York City.
With the expansion to our new sites, they'll be based on the Bellevue program model, but
with some key upgrades.
First, we are going to collaborate with behavioral health by hiring psychologists to work with
patients in our program, particularly those who are experiencing disordered eating, emotional
eating, a history of trauma, anxiety, or depression.
We'll have community health workers that are dedicated to our program to help meet our
patients' social needs.
We'll have nurse practitioners to co-lead our shared medical appointments to turn them
into billable group visits.
And finally, we're very excited that we have the ability to offer produce prescriptions
to all of our patients during the active phase of the program.
So where do we go from here?
I think there's a couple of big research questions that I would love to see answered.
The first is how do we implement effective nutrition-focused programs in traditional
health care settings like my own?
How do you design programs?
Do you focus just on nutrition?
Do you also broaden to looking at lifestyle?
Which are the appropriate health professionals to join the team?
How do you leverage telehealth in these programs?
How do you scale these programs?
Especially when we suspect that our individualized approach is actually very, very useful for
patients.
How do you convince healthcare systems to invest upfront in a program like this?
How do you navigate very challenging situations regarding payor coverage?
There's so much variability in coverage of some of these services, for example, dietician
visits or shared medical appointments.
How do you address the needs of diverse patient populations?
And finally, of course, how do you develop programs that can address patients' social
needs while you're also counseling on lifestyle?
Because we know that goes hand in hand.
Another question that I have is how do we define "effective" when it comes to these
nutrition-focused programs?
Are we looking just at dietary behavior changes?
And if so, how do we measure that effectively in clinical practice, or are we looking also
at clinical outcomes?
And obviously some clinical outcomes you see quickly and others take a long time to see.
So how do you account for that?
And of course, how do you really think about the cost-benefit or the return on investment,
if you will, for programs like this, especially when we're really talking about is long-term
prevention in addition to treating established chronic disease?
So I'll stop there and I hope to hear your thoughts during the Q&A section.
Thank you.
DR. ALISON STEIBER: Presentations.
I think that what you saw today was a breadth of everything from thinking about very basic
lifestyle medicine, as we just heard at the end to very clinical shortages of TPN and
parenteral nutrition.
And so what I'd like to do today is start a little bit with some question and answer.
And I have a number of great questions in our Q&A box, but I really encourage the audience
to submit burning questions that you all may have for this great panel.
So I think if we just kind of start out sort of basically, I think we heard some very interesting
presentations that talked about dual burden, that talked about both macronutrient and micronutrient
deficiencies that related to individuals in a variety of settings and with a variety of
disease states.
But perhaps we start out with obesity.
So I would love to think a little bit more.
And I...I think that Dr. Mechanick, this is probably for you.
What are just some key practical or clinical recommendations for patients with obesity
from a malnutrition standpoint?
And maybe you can talk a little bit about, you know, practitioners.
And I will say as a dietician, we would often assess the wasting of lean body mass muscle,
muscle loss, and micronutrients.
And perhaps our other clinical colleagues would say, well, that person is overweight,
they have to be well-nourished.
And so if you could talk to us a little bit about why that may or may not be true.
DR. JEFFREY MECHANICK: Great.
Thanks.
Thanks, Alison.
So, unfortunately, there are still silos even within the nutrition subspecialty.
And we have training programs in obesity and training programs in nutrition.
And I think the purpose of the talk was that this dual burden means that when you routinely
encounter anybody, any patient with obesity or any place on that adiposity-based chronic
disease spectrum, that a formal nutritional assessment ought to be done.
So I presented some of the data showing statistical associations, but also mechanisms of poor
nutrition, malnutrition, undernutrition with the obese state.
Even in the ICU, there's always been that dilemma, right?
How do you properly feed somebody with obesity?
So the first thing is a formal assessment.
The second prong would be your endpoints that when you're managing a patient with obesity
or abnormal adiposity, even if it's just ectopic fat, you need to pay attention to body composition
and also some of the nutritional markers.
And David, bringing up the point about inflammation.
Now we know that obesity is, in fact, an inflammatory condition.
So those nutritional markers play more of a role, right?
Reflecting some of the adipokines and the detrimental effects of obesity on an organ
function.
And then the third prong would be when you put together a comprehensive preventive care
approach.
And now we start getting into the whole lifestyle medicine narrative.
You're talking about nonpharmacologic therapies for obesity, which include healthy eating
and nutrition and averting malnutrition, but also pharmacotherapies and the detriment that
pharmacotherapies can have.
And lastly, the lessons we've learned in bariatric surgery, in our bariatric surgery guidelines
that a lot of these patients who are rolling into bariatric procedures already have micronutrient
deficiencies, right?
68% to 85% for vitamin D and B12 and even protein because it dysgeusia.
So there are a lot of commonalities among the threats of malnutrition and abnormal adiposity.
DR. ALISON STEIBER: Excellent.
Thank you.
That is exactly right.
And you really gave us a great entry into thinking about if I'm a practitioner or a
researcher and I want to systematically understand micronutrient deficiencies, perhaps caused
by something like a shortage within our country nutrition or just as you just pointed out,
because we have individuals who may have consumed too much energy but are deficient in micronutrients.
How do we assess that?
You know, if you do it in the hospital, it's going to be 'A' very expensive biomarker perspective.
It may or may not represent the actual body stores, and it takes a very long time to get
those values back.
And so I'd like to start out with Dr. Martel, if you want to address this a bit from your
perspective, and then others maybe could give their perspective as well.
I think a number of the speakers addressed this question.
DR. JAY MIRTALLO: Well, if you're talking about biomarkers and getting these tests available.
You know, one of the biggest issues we have is just like what you said, if we want to
assess micronutrient status, if we don't have a dietitian that can do the physical diagnosis
around any of the clinical tests, take a long time.
And usually in the hospital, the patient's gone by the time you get the values back and
the challenge is then to get the follow-up for the patients when they're not your patients,
they were somebody else's that you consulted on.
And so, the information comes back at a time where you don't have access to the patient
any longer and is kind of a moot point.
And that's why I made the emphasis in regards to, you know, we have these diagnostic tools,
but one is we need to have the experts that are available to be able to assess those data
points.
But we also have to make sure that they're accessible in all healthcare environments.
And one of the things we found in Ohio when we advised the governor with regards to nutrition
care for elderly patients is one of the biggest issues we had was the fact that all the hard
work in nutrition that's done in the hospital doesn't get transferred to any of the care
providers that's providing care for the patients on the outside because the nutrition assessment
isn't included as a part of the discharge summary, because the person doing a discharge
summary doesn't think that that's important and it doesn't make it on that tool.
And so, we developed a nutrition screening tool to be used in any healthcare environment
for people to identify nutrition risk in the patient population.
That's one of the primary focuses of what we did with that process.
So, having that information available in regards to being in any environment, being cheap as
well as accessible and reliable, never ever to replace a dietician, I think that's one
of the other bigger issues with regards to what I was talking about
with shortages. It's an access issue and there's access issues to other things in health care
that are really needed for us to have a good system of nutrition support.
And that is access to people.
That's a dietician in environments to make sure that any patient that gets screened positive
gets a nutrition assessment done by a qualified individual.
And it's also the products available as well, mostly oral nutrition supplements as well
as medical foods.
We have a real hard time with policymakers convincing them that those products aren't
just meal replacements, but they're medical nutrition therapy that's needed.
DR. DAVD SERES: Can I just...
you know, the flip side of it is that we don't know what to make of nutrient levels, micro
or otherwise, in people who are ill because so many of them are protein bound.
And, you know, there's this entire literature on, I've mentioned this before, on vitamin
D and critical illness as if the low vitamin D levels were causing the critical illness.
And it's actually the other way around.
So, you know, we need to learn how to, and this was discussed in a prior session, how
to better assess these nutrients and understand the meaning of the assessment, and we're far
away from that.
And it's part of what I would hope would be our Moonshot.
DR. ALISON STEIBER: Right, and so Dr. Seres, you bring up some great points there.
When we think about transitions of care, we think about going out into the outpatient
clinic or a long-term care facility like you mentioned in your presentation, and often,
nutrition care does not travel with the patient, particularly from an electronic data perspective.
And so, Dr. Newberry, you mentioned one of the biggest challenges was identifying patients
at risk for malnutrition in this outpatient setting.
And I would wonder if you could talk about that a little bit, particularly maybe talk
about the new screener that was validated that you put out, and how we can connect those
dots between inpatient and outpatient.
DR. CAROLYN NEWBERRY: Right.
I mean, I think this is a huge challenge and I think it's one of the reasons why conferences
like this are so important.
You know, we don't do a great job of stratifying patients in the hospital.
And I think we do an even worse job in the outpatient setting.
I think there's a couple of reasons for this.
I mean, the first is that I think a lot of providers, we as physicians just aren't trained
to ask the questions that we need to ask.
And so, you know, we're not even talking to patients about oral intake and doing sort
of like malnutrition, like screening tools in the first place.
Even for the small percentage of people that maybe think about these things, there's not
a lot of validated tools that can be used in an outpatient setting, and you don't have
the data right there for you like you do in an inpatient.
And so, I mean, I think until we start addressing 'A', sort of the educational efforts that
need to be increased for the providers for taking care of patients that are high risk
for malnutrition and 'B', coming up with better screening tools and also intervention tools
for patients in an outpatient setting.
It is a hard population to take care of and it's a lot of research that we need to do
to better care for these patients.
DR. ALISON STEIBER: Yes.
Thank you.
That's perfect.
And so, you know, kind of switching now over to Dr. Sears.
When you were talking about the long-term care facility, it feels like not only are
there challenges maybe from a workforce capacity angle, but also with policies and thinking
about how we have structural policies in place and staffing in place to care nutritionally
for very high-risk patients in the long term care facilities anymore.
DR. DAVID SERES: Yeah, there are.
It's almost more like a cultural problem than a policy problem.
It's the policies of the nursing homes themselves, not of the state or the Federal Government
that's driving this.
And it's based, basically, on urban legend and complete misunderstanding not only of
the data that's available, which basically says there's no difference and the complications.
People just have these complete biases about, you know, nasal tubes.
They're going to cause all these problems.
And what about gastrostomies?
I mean, you know, how many?
We have, you know, to talk to our gastroenterologists.
We have a hospital that's sort of a catchment for a lot of the nursing homes in the area,
and they just spend all day putting in tubes that have fallen out or become embedded.
And, you know...
So I think there's been a lack of attention on this.
I think that, actually, we tried to get policymakers to drive it in the other way, but they wouldn't
touch it.
So I think that we need to go out and do some education and training in these places to
try to get them to understand that they're stripping patients of autonomy, basically.
I mean, they're forcing patients to have gastrostomy and withholding necessary medical care, meaning
subacute rehab often enough, and coercing the patients into having these surgical tubes
placed.
And this needs to be changed.
DR. ALISON STEIBER: Alright.
Very good.
I think that as long as we're sort of in this space of outpatient and that's a great time
to bring up Dr. Machen.
You talked a lot about the lifestyle, medicine, and how you do it, both kind of inpatient
and outpatient.
And similar to the last speaker in the previous session where you really brought up the need
for plant-based interventions.
You also have brought that forward.
And I think as we're thinking about malnutrition and nutrition support, the idea of bringing
in plant-based options seems a little out of sync.
Do you want to talk a little bit more about that?
DR. MICHELLE MCMACKEN: Sure.
So, I mean, I think that what we're talking about with our programs is really the reduction
in cardiometabolic risk.
And when we look at our patient population and we think about how we can sort of make
dietary shifts towards evidence-based eating patterns that promote reduction in cardiometabolic
risk, we're really talking about, you know, as I mentioned, increasing whole fruits and
vegetables, shifting towards more plant sources of protein and plant sources of fat and increasing
whole grains instead of refined grains in the diet.
And so there's really wide consensus around those nutritional principles.
To your point, I think it is really important and something that we do in our program for
any individual who is working on intensive dietary shifts, we also want to be very cautious
that they are meeting their macro and micronutrient needs.
So one of the wonderful things about our program is we do have...
This is a very dietician-centered program and we currently have a wonderful dietician,
and we're going to be hiring more, who will actually be doing medical nutrition therapy
with our patients and ensuring that, for example, how do you meet your calcium needs on a plant-based
diet?
Are you meeting your protein targets if you're losing weight and you're increasing your resistance
training and your physical activity?
What about other Omega-3s?
And what about other nutrients that we want to make sure that we're being cautious about?
So, and of course, B12.
Right?
The ultimate, with a fully plant-based diet.
So we're very aggressive about that.
But I think that, not to sort of lose the forest for the trees.
I mean, our patients do very, very well when they eat more whole foods and they're making
these shifts.
And as I said, we sort of welcome them to move as far along the spectrum as they're
willing to go.
This is not about telling everyone they have to be 100% plant based.
This is about making healthy choices that are sustainable, that are culturally relevant,
and that are, most importantly, probably delicious, right?
Tastes good and they are something that patients are going to be willing to keep doing.
DR. ALISON STEIBER: Absolutely.
OK.
Well, I'm going to shift just a little bit back into the hospital setting and go right
into the ICU.
And Dr. Patel, you talked about a variety of things relating to the ICU, but I think
it's something that is challenging for a lot of research, and thinking about our Moonshot
study is thinking about the right outcomes.
And so, how do we think about outcomes?
How do we think about those people who respond to nutrition information?
How do we figure out who does not respond?
Is that part of our malnutrition diagnosis process?
And then maybe think a little bit about short versus long-term outcomes.
I wonder if you could just touch on those things for us.
DR. JAY PATEL: Thank you, Alison, for that question.
There is certainly a lot to unpack there.
But what I will say is that I think there has been a tremendous paradigm shift in the
way we think about nutrition in the ICU.
And so over the past decade, for example, there have been a lot of trials that have
been conducted with the use of supraphysiologic doses of micronutrients to mitigate some of
the acute effects of critical illness.
And so the paradigm has shifted such that nutrition is beyond just sort of a passive
form of support, but now it's used as a form of therapy or particularly related to micronutrients.
When we relate to macronutrients, we can almost think the same way as well where we can suggest
that, you know, giving small amounts of macronutrients, at least in animal models, seems to suggest
that there's preservation of things like the epithelial barrier function.
So if I go in reverse order, what I'm really getting at here is that I think future trials
and studies really have to start to form, you know, a biologically plausible threat.
And that biologically plausible threat has to start with, you know, asking questions
like what is it that we want this nutrition to actually accomplish?
And if it's that we're trying to preserve the epithelial barrier function and prevent
all the detrimental effects of an impaired barrier function, then we have to demonstrate
that that's actually what's going to happen.
It's also going to be really important that we sort of partner with our basic scientists
in trying to figure that out.
Once we establish sort of the biological link that macronutrients provide in certain subsets
of critically ill patients, for example in patients with sepsis, then the goal is to
say, you know what, by preserving the epithelial barrier function, we're going to have less
complications such as, you know, infectious risks.
Patients might be able to get off the ventilator faster.
And in looking at more patient-centered outcomes, since patients are surviving critical illness
more they are today compared to, say, you know, even a few years ago, the patient-centered
outcomes are going to be important, then ultimately are going to be looking at things like, you
know, is the nutrition that I receive in the ICU truly helping me, 'A', get off the ventilator
faster, 'B', helping me ambulate a little bit better, 'C', that improve my quality of
life, 'D', along those same lines, help me with my muscle function and what that's sort
of need it for.
Now, what do we have so far?
In terms of all the data that's been produced from contemporary randomized controlled trials,
we have trials that have looked at the effect of nutrition in just the first 4 to 7 days
of ICU stay.
And then we want the nutrition that's provided in that first week of ICU to have an impact
on mortality 30, 60, 90 days, six months out.
And you know, if you were a layperson, you might look at and say, "Well, how is that
supposed to happen?
How can you give me a little bit of nutrition and have an impact?"
Because the nutrition journey for patients doesn't end at ICU discharge.
It continues well beyond survivorship.
And so, I think that we need to study so we can, again, demonstrate that biological link.
I think we need to focus on subsets of critically ill patients that may derive the most benefit
from our micro and macronutrients.
And then I think that for some macronutrients we have to perhaps stop thinking of nutrition
as, you know, a drug where the effect is immediate and maybe we should reserve that for some
of the micronutrient studies where we might see an immediate effect as well.
DR. ALISON STEIBER: So, so many interesting points, as you say, lots to unpack.
But when we think about, for example, the WHO's definition on malnutrition, it is both
a macro and micronutrient issue.
Clearly, we don't have tools that are validated or biomarkers that encompass all there is
to look at when we think about assessing for nutrition.
So I think that's a really important piece.
And because of that, I'm going to David, Dr. Sears here.
We don't really know in the best way possible how to comprehensively say someone has malnutrition
or not.
We're sort of the individuals with the elephant.
We're blind trying to figure it out, and thus we have a difficult time, I think.
And David, you would say how do we know who's going to respond to our intervention and
not only just purely who's going to respond to this intervention, but which interventions
are going to be best for which types of patients?
And so I don't know if you want to touch a bit on that.
DR. DAVID SERES: Yeah, no, this is the message
throughout is that, and I've said this before, I'd really rather we not use the term malnutrition.
And how different is the term malnutrition from cachexia and the other terms that we
use when we're describing this combination of inflammation and its consequences and starvation
and its consequences?
And what are the consequences of starvation in the context of inflammation?
And all of these are...
This is what's being built up in this whole conference is this question of, you know,
how do we know who is going to respond?
And fortunately, there is at least some data on who is not.
So anyway, thank you for asking the question.
It really is, I think, the most important one of the entire conference.
DR. ALISON STEIBER: I guess finally, in our last couple of minutes here, I want to throw that question
to the group.
You know, in our previous session, we talked a lot about cutting-edge ways of identifying
potential malnutrition or micronutrient deficiencies through the microbiome and through different
tracers and isotope mechanisms.
But really for this session, we've actually talked about very practical issues.
And Dr. McMacken, I think you said it best.
How are we going to implement these in an equitable way, which we don't create more
disparity by having such expensive, difficult-to-use methods of diagnosis that we miss the population
that needs it the most?
And so I would just throw out to you all as a group, how do we implement malnutrition?
How do we build awareness and implement our ability to screen and diagnose, and intervene
for malnutrition?
I won't do that, "I'll call you" thing unless everybody is very silent and then I will.
DR. JAY MIRTALLO: Well, I have a thought on this.
This is Jay.
And I think one of the basic things that's been threaded through the whole discussion
is that we're talking to each other at a very high level with regards to nutrition care,
nutrition practices, and nutrition skill.
And what we see in the healthcare environment is a big disparity in what we know
and what we can do versus what the other clinicians and what our compatriots can do.
I'm a pharmacist.
I'm not sure very many other pharmacists other than the 600 board-certified pharmacists in
nutrition can do what I do in relationship to that.
I think a large portion of what we see is a lot of nutritional cripples coming to us
as experts because the main core of health care practitioners don't have a good understanding
of where nutrition fits in the overall care and health of a patient population.
And so they don't know what to do with it.
They're not educated well in it.
There's not a consistent thread with regards to all their training.
And so I think one of the basic core components is that we need to educate our healthcare
practitioners on just being able to recognize that nutrition is important to outcomes, it's
important to the quality and health of a healthy living person.
And it's very important to the health and recovery of a patient that survived an ICU
stay.
And unless we can get those groups on board, a lot of what we talk about, is really
not going to impact what we really want to impact.
And that's good nutrition across all healthcare environments and all healthcare settings.
And so everyone from, we just did the nutrition screening in a pharmacy and identified nutrition
risk.
And our main problem is we didn't have access to a dietician to do a nutrition consultation,
but we do see the patients every 30 to 60 days so we can establish goals for them and
follow up with them in regards to what they're doing, with regards to our objectives for maintaining their hypertension.
Similar to your, Dr. Mechanick, your "Food is Medicine" kind of principle, but we're just starting
in that. We're just pharmacists and so we need to have an interdisciplinary group that
can work with us to do that.
And so we see these pockets of excellence in nutrition, but there's not enough of them
to handle the nutrition problems that are out there.
I often wondered when I was practicing in the hospital, you know, we see these patients
come into our cancer hospital and they say, well, we want to do another course of chemotherapy.
But they had ignored that person's nutrition for the past three months.
So, they've handed to me a nutritional cripple and expect us to create a miracle so that
they could do another course of treatmentw
And it's like, Why?
When we've got such great products and things available, does this happen when we've got
bright people that we're working with that have just missed the boat with regards to
nutrition and thought about it too late.
So...and I’ll get off my soapbox and [inaudible] let anybody else talk about it,
but I think that's one of the core problems we have, is making sure that our everyone
in healthcare can identify and assess for nutrition risk and be able to know what to
do with it once they find it.
DR. DAVID SERES: Just do a little self-promoting here.
The organizers of this meeting also agree with you, Jay, that educating practitioners
is critical.
And there are some sessions coming up on this.
And ACGME is actually calling a summit that it'll be next spring to try and discuss this
issue.
So it's fortunately making...
It's percolating up at least.
DR. ALISON STEIBER: Right.
Well, I think we are at time.
This has been a terrific discussion.
And you all were magnificent in your presentations and we really appreciate your time for this
workshop.
So, I think that concludes this session.
And I want to thank everyone and thank all the audience for participating and for sticking
with us on a long afternoon.
And we hope that you will come back tomorrow because, as David just said, we have a great session
on thinking about training a workforce in diversity and enhancing diversity in the nutrition
space. So, thanks to everyone. Have a great evening.