Pediatric Systemic Capillary Leak Syndrome- Challenges in Diagnosis and Treatment-

Transcript

• 00:00My name is Rick Pierce,
• 00:01and I'm an associate professor
• 00:03of pediatrics in the section
• 00:04of pediatric critical care medicine
• 00:06at the Yale New Haven
• 00:07Children's
• 00:08Hospital and Yale School of
• 00:10Medicine.
• 00:11I'm talking today about pediatric
• 00:14systemic capillary leak syndrome
• 00:16and the challenges in its
• 00:17diagnosis
• 00:18and treatment.
• 00:19The purpose of this module
• 00:21is to raise awareness
• 00:23about the diagnosis
• 00:24and inpatient and outpatient treatment
• 00:26of systemic capillary leak disease
• 00:28so that it may be
• 00:29better recognized
• 00:30in critically ill children. Systemic
• 00:32capillary leak disease is a
• 00:34rare syndrome
• 00:36characterized by episodes of recurrent
• 00:38shock that are not related
• 00:40to systemic infection.
• 00:42It's been called idiopathic
• 00:44capillary leak syndrome or Clarkson's
• 00:46disease because it was first
• 00:47described by Bayard Clarkson in
• 00:50nineteen fifty eight.
• 00:52He described a woman who
• 00:53would have episodes of shock
• 00:55every five to eight months.
• 00:58She is shown here on
• 00:59the top picture in her
• 01:00well state and shown on
• 01:01the below in a state
• 01:03of leak where she has
• 01:05facial edema and extremity edema.
• 01:08She would have episodes,
• 01:10starting at thirty two years
• 01:11of age in nineteen fifty
• 01:13six. Her episodes would occur
• 01:15every five to eight months
• 01:16and progressively worsened.
• 01:18They were characterized
• 01:19by,
• 01:20malaise,
• 01:21abdominal pain, nausea, and vomiting
• 01:24for about thirty six hours,
• 01:25and then she would have
• 01:26extremity edema
• 01:28and hypotension. And her cases
• 01:30became her episodes of leak
• 01:31became worse and worse
• 01:33until unfortunately,
• 01:35she had an episode in
• 01:36nineteen fifty eight, which caused
• 01:38led to hypovolemic shock and
• 01:39caused a terminal cardiac arrest.
• 01:42Since that time,
• 01:44we've learned a lot about
• 01:45systemic capillary leak disease,
• 01:47and it's recharacterized by recurrent
• 01:49episodes of hypovolemic shock.
• 01:52These episodes are recurrent
• 01:53and they're not explained by
• 01:55infection or other abnormalities.
• 01:58These episodes typically have three
• 02:01phases.
• 02:02The first phase is called
• 02:03the prodrome.
• 02:05This phase is quite nonspecific
• 02:07and can can be composed
• 02:09of fever,
• 02:10general malaise,
• 02:12abdominal pain,
• 02:14myalgias,
• 02:16and patients will typically have
• 02:17lower urine output, be drinking
• 02:19more, and have an increase
• 02:21in body weight.
• 02:23The prodrome phase may last
• 02:24for several days
• 02:26and then comes the leak
• 02:27phase.
• 02:29The leak phase is characterized
• 02:31by hypotension,
• 02:33hypoalbuminemia,
• 02:34and hemoconcentration.
• 02:37These three findings constitute the
• 02:39diagnostic
• 02:40triad of systemic capillary leak
• 02:42disease.
• 02:43Patients in the leak phase
• 02:44may also have generalized edema
• 02:46ranging from mild swelling of
• 02:48the extremities
• 02:50to,
• 02:51severe ascites,
• 02:52pleural effusions,
• 02:54and even compartment syndrome
• 02:56of of the extremities.
• 02:58The leak phase may last
• 02:59for hours to days
• 03:01and then, transitions
• 03:03rather suddenly and unexpectedly
• 03:05to the recovery phase. In
• 03:07the recovery phase, volume that
• 03:09has leaked out of the
• 03:10blood vessels
• 03:11is rapidly recruited back into
• 03:13the blood vessels and may
• 03:14result in sudden unexpected
• 03:17volume overload.
• 03:18This may produce
• 03:20pulmonary edema
• 03:21or cardiac failure from the
• 03:23sudden increase in intravascular
• 03:25volume.
• 03:26The cause of SCLS is
• 03:28unknown, but there are two
• 03:29general
• 03:30noncompeting
• 03:31theories.
• 03:32The first is that there
• 03:33is some systemic
• 03:35insult that results in a
• 03:38exaggerated response of pro inflammatory
• 03:40mediators.
• 03:41In this theory, the blood
• 03:42vessels are responding normally.
• 03:44The other theory is that
• 03:46there may be normal systemic
• 03:48responses to inflammation or insults
• 03:50and that the endothelial
• 03:51cells
• 03:52are hyper reactive to normal
• 03:54stimuli.
• 03:56Both theories have been supported
• 03:58by circumstantial evidence.
• 04:00Supporting the circulating pro inflammatory
• 04:03mediator theory are studies that
• 04:05have shown that patients have
• 04:06abnormal paraproteins.
• 04:08These are
• 04:09these are termed
• 04:11the monoclonal
• 04:12gammopathy of undetermined significance that
• 04:15we'll talk about later,
• 04:17or vascular targeted cytokines such
• 04:19as vascular endothelial
• 04:21growth factor or VEGF,
• 04:23interleukin two, angiopoietin two,
• 04:26leukotrienes,
• 04:27or other chemokines
• 04:29or cytokines.
• 04:30These levels may be elevated
• 04:32in patients when they're sick
• 04:33compared to when they're well
• 04:35or elevated in patients with
• 04:37capillary leak disease compared
• 04:39to not. But they're hard
• 04:40to interpret because of all
• 04:42of those multiple comparisons.
• 04:44And no studies have conclusively
• 04:46shown a single systemic
• 04:49cytokine or chemokine is responsible
• 04:52for the leak phase of
• 04:53systemic capillary leak disease.
• 04:56The other theory is that
• 04:57the endothelial cells are hyperreactive,
• 05:00and this theory is supported
• 05:02by increased markers of endothelial
• 05:04cell apoptosis
• 05:06in patients during the leak
• 05:07phase or
• 05:09isolation of endothelial cells from
• 05:11patients with SCLS
• 05:12and investigating their overreactive
• 05:14signaling in the lab in
• 05:16response to,
• 05:18normal circulating cytokines.
• 05:20And this is what, I
• 05:22do in addition to caring
• 05:23for critically ill children is
• 05:25I run a, research lab
• 05:27focused
• 05:28on blood vessel dysfunction in
• 05:30critically ill children.
• 05:32And I am keenly interested
• 05:34in understanding
• 05:35how the junctions in blood
• 05:37vessels break down and allow
• 05:39leak from inside the vascular
• 05:41space to outside of the
• 05:43vascular space.
• 05:44The goals of my laboratory
• 05:46are to understand this, how
• 05:47this happens in critically ill
• 05:48children, and identify ways to
• 05:51ultimately treat it to reduce
• 05:53the burden of critical illness
• 05:55in children.
• 05:56I do research patients with
• 05:58systemic capillary leak disease, and
• 06:00my goal is to understand
• 06:01how vascular leak occurs in
• 06:03those patients so that we
• 06:04may develop new treatments for
• 06:06them, but also a better
• 06:08understand how vascular leak occurs
• 06:10in all critically ill children
• 06:12and develop therapies
• 06:13to reduce that leak and
• 06:15reduce the time children have
• 06:16to stay in the intensive
• 06:18care unit.
• 06:20The first case of pediatric
• 06:21capillary leak disease was reported
• 06:23in nineteen ninety five. This
• 06:25was a nine year old
• 06:26Canadian female,
• 06:28and she started having episodes
• 06:29at age three. And she
• 06:31had episodes every eight to
• 06:33nine months,
• 06:34until,
• 06:36she became almost nine years
• 06:38old when she had an
• 06:39episode that again resulted in
• 06:41hypovolemic
• 06:42shock, cardiac arrest, and her
• 06:45unfortunate death.
• 06:46The youngest patient described with
• 06:48capillary leak disease was a
• 06:50twenty three week premature infant
• 06:53who developed their first episode
• 06:54of leak at twenty eight
• 06:56days of life or a
• 06:57corrected gestational age of twenty
• 06:59seven weeks. So systemic capillary
• 07:02leak disease has been reported
• 07:04in very young babies,
• 07:06very young children,
• 07:08adolescents,
• 07:09and now adults.
• 07:11Since nineteen ninety five, there
• 07:13are about thirty cases
• 07:15of pediatric systemic capillary leak
• 07:17identified,
• 07:18and we've not been able
• 07:19to determine any sex,
• 07:21ethnicity, or inheritance patterns for
• 07:24this disease,
• 07:24although that remains an area
• 07:26of ongoing research. About three
• 07:28hundred adults have been identified
• 07:30with this disease, and children
• 07:32have the same disease phases
• 07:34as adults. That is they
• 07:35have this prodrome
• 07:37of not feeling well, a
• 07:39sudden leak phase followed by
• 07:41a sudden recovery phase. But
• 07:43there are reasons to think
• 07:44that pediatric systemic capillary leak
• 07:47disease may be different from
• 07:49adult systemic capillary leak disease.
• 07:51And those differences are summarized
• 07:53in, this table.
• 07:55First,
• 07:56are the demographic data.
• 07:59Although more than three hundred
• 08:00adults with SCLS have been
• 08:02described, only about thirty children
• 08:03with SCLS have been described.
• 08:06And the average age of
• 08:07diagnosis is about,
• 08:09five point five years or
• 08:10young childhood
• 08:11in children, whereas adults are
• 08:13diagnosed into middle age, about
• 08:15forty two years of age.
• 08:16Children also much more frequently
• 08:18have a viral prodrome
• 08:20that is
• 08:21fever, abdominal pain, myalgias,
• 08:24as opposed to adult capillary
• 08:26leak disease where about fifty
• 08:28percent of patients have those.
• 08:30And then another striking difference
• 08:31is the monoclonal gammopathy of
• 08:33undetermined
• 08:44SCLS.
• 08:45So this is a very
• 08:46big difference and may tell
• 08:47us that there's some difference
• 08:48in the underlying pathology,
• 08:50but we haven't determined what
• 08:52this means yet.
• 08:53Finally, the time between episodes
• 08:55and diagnoses
• 08:57is more than a year
• 08:58in adult SCLS and we
• 09:00don't know that interval in
• 09:02pediatric SCLS.
• 09:03And we also don't know
• 09:05the five year mortality,
• 09:07which
• 09:08untreated was about seventy five
• 09:10percent in adults, but newer
• 09:12treatments
• 09:13that I'll talk about later
• 09:15have dramatically
• 09:16reduced
• 09:17that. But these are unknown
• 09:19in children with SCLS
• 09:21and many children may have
• 09:23several episodes
• 09:24before capillary leak is diagnosed.
• 09:27And these episodes may be
• 09:29severe,
• 09:30which is one of the
• 09:30major points of this education
• 09:32module
• 09:33is that pediatric systemic capillary
• 09:35leak disease is likely underdiagnosed
• 09:38due to a lack of
• 09:39provider awareness
• 09:41about the disease.
• 09:43And this is very, very
• 09:44important because these episodes can
• 09:45be severe.
• 09:47They can be severe hypovolemic
• 09:49shock. They can have severe
• 09:50problems, but they can also
• 09:52be prevented
• 09:53if we can make the
• 09:54diagnosis
• 09:55early.
• 09:56I'd like to talk about
• 09:57a typical case presentation for
• 10:00pediatric systemic capillary leak disease
• 10:02and include a parent testimonial
• 10:05that is used with their
• 10:06consent.
• 10:07Children typically will present to
• 10:09the emergency room with edema
• 10:11and distributive shock.
• 10:13Key elements of the history
• 10:15include the patient was otherwise
• 10:16healthy. They may have a
• 10:18vague viral prodrome for two
• 10:20to three days that include
• 10:22things like abdominal pain,
• 10:25a little bit of eating
• 10:26less, a little bit of
• 10:27nausea,
• 10:29myalgias,
• 10:30low grade fever, but non
• 10:32nonspecific
• 10:33prodromal symptoms.
• 10:35They may have had a
• 10:36history of unexplained,
• 10:38episodes of facial or extremity
• 10:40edema,
• 10:41and there's an absence of
• 10:43known allergies
• 10:44or other triggering factors such
• 10:46as drugs, infection, environmental exposures,
• 10:49or other chronic diseases
• 10:51that would suggest or or
• 10:53lead to,
• 10:55edema.
• 10:56Some key elements of the
• 10:57physical exam include those that
• 10:59are consistent with distributive shock.
• 11:01These patients will have a
• 11:03high heart rate and a
• 11:04low blood pressure.
• 11:05They may have,
• 11:07signs of volume overload already
• 11:10such as a third heart
• 11:12sound or crackles on their
• 11:13lung exam.
• 11:14Their skin color is typically,
• 11:17modeled consistent with distributive shock,
• 11:20and their temperature and capillary
• 11:21refill time may also be
• 11:23abnormal.
• 11:24These patients usually do not
• 11:26have a rash.
• 11:27Their mental status may be
• 11:29decreased, and if available at
• 11:30your institution,
• 11:31they may have you may
• 11:32be able to do point
• 11:33of care heart or lung
• 11:35ultrasound revealing
• 11:37increased, cardiac function,
• 11:40pericardial effusions,
• 11:42and plural effusions or pulmonary
• 11:44parenchymal edema by lung ultrasound.
• 11:47Reverie,
• 11:49woke up in April of
• 11:50twenty twenty two
• 11:52with very swollen eyes. So
• 11:55it was bilateral
• 11:56swelling in both of her
• 11:58eyes, periorbital edema,
• 12:00which we now know is
• 12:01the official term.
• 12:03And we thought it was
• 12:04allergies.
• 12:06At that time, she was
• 12:07not acting lethargic
• 12:09or ill in any way.
• 12:12We phoned the doctor and
• 12:14were instructed to start a
• 12:16typical course of antihistamines.
• 12:18In that first episode, no
• 12:19fever, nothing like that. We
• 12:21thought, oh, freak incident. And
• 12:22then lo and behold, come
• 12:24July, she's running a fever
• 12:26and her eyes start swelling.
• 12:27And that's where we really
• 12:28were like, this is not
• 12:30allergies. Something else is going
• 12:31on.
• 12:33Second time, they said, okay.
• 12:36Let's put a referral into,
• 12:38eye doctor.
• 12:40So then we did a
• 12:40referral to eye doctor. Eye
• 12:42doctor did not do tests,
• 12:43but they did do a
• 12:44full full exam. It was
• 12:46a pediatric ophthalmologist,
• 12:48not an optometrist.
• 12:50So that was her second
• 12:51week.
• 12:52When that came back clear,
• 12:54the ophthalmologist
• 12:55sent us to the ENT.
• 12:57The ENT did do testing
• 12:59day of. They did that
• 13:01c the head CT,
• 13:03but insurance
• 13:05requires them to do, like,
• 13:07thirty days of antibiotics, which
• 13:09I'm sure you guys have
• 13:10heard with yep. So she
• 13:12they put her on thirty
• 13:13days of antibiotics for a
• 13:15potential what if sinus infection
• 13:17that's, like, stuck somewhere in
• 13:19her system. Third and fourth
• 13:21one, we went to urgent
• 13:22care twice,
• 13:24and they only did urine
• 13:25protein,
• 13:26zero labs, no labs.
• 13:30And
• 13:31like I said, her fourth
• 13:32one,
• 13:33the which was influenza a
• 13:35October twenty twenty two, she
• 13:37was very sick, and we
• 13:39I'm upset that there was
• 13:41no further care administered.
• 13:44She was, like, two weeks
• 13:45of school for sure. And
• 13:47she was febrile for
• 13:49I feel like her body
• 13:51temperature did not get back
• 13:52to, like, ninety eight six
• 13:53for, like, a month. And
• 13:54for that swelling to resolve,
• 13:56it was every bit of
• 13:57two weeks.
• 13:59Yeah. In May of twenty
• 14:01twenty three, it was Cinco
• 14:03de Mayo weekend.
• 14:05And once again, she was
• 14:07very, very ill, fever, lethargic,
• 14:11and it got to the
• 14:11point where she was unable
• 14:13to walk. And
• 14:15that's when the red flags,
• 14:17I was like, this is
• 14:18just not right. She was
• 14:19very slow to respond verbally.
• 14:21As you can see from
• 14:22the patient testimonial,
• 14:24the signs and symptoms may
• 14:26not be conclusive
• 14:27of any diagnosis.
• 14:29And the acute presentation,
• 14:31severity of shock, and availability
• 14:33of life saving personnel and
• 14:35resources
• 14:36may limit the consideration of
• 14:37a thorough differential diagnosis.
• 14:40But not all distributive shock
• 14:43is sepsis, and it's important
• 14:45to have a broader differential
• 14:47when considering patients who have
• 14:49come in one or more
• 14:51time with the somewhat unique
• 14:53finding of
• 14:55hypotension
• 14:56distributive shock
• 14:57with
• 14:58edema. The differential is listed
• 15:00here on the left side
• 15:01of this table.
• 15:02Systemic capillary leak disease is
• 15:04on top, and sepsis, the
• 15:06most common etiology confused with
• 15:08systemic capillary leak disease, is
• 15:10on the next line.
• 15:12Other specific causes of sepsis
• 15:13such as toxic shock syndrome
• 15:15or inborn errors of immunity
• 15:17that lead to,
• 15:18shock states are shown there
• 15:20as well, along with anaphylaxis,
• 15:22nephrotic syndrome, hereditary angioedema,
• 15:26and Addison's disease.
• 15:27These differentials may seem broad,
• 15:29but you'll see how certain
• 15:31parts of different diseases overlap
• 15:33with different parts of the
• 15:35systemic capillary leak disease history,
• 15:38physical exam, clinical course, laboratory
• 15:40findings,
• 15:41and how they may be
• 15:42confused for systemic capillary leak
• 15:44disease.
• 15:46Discussing the history and physical
• 15:47exam,
• 15:48there in systemic capillary leak
• 15:50disease, there may be one
• 15:52or more of these episodes,
• 15:54wet patients coming in with
• 15:56the unique combination of hypotension
• 15:59and edema.
• 16:00In septic shock, toxic shock
• 16:02syndrome, or septic shock from
• 16:04inborn errors of immunity,
• 16:06patients may come in with
• 16:07fever and hypotension and tachycardia
• 16:09very similar to systemic capillary
• 16:11leak disease,
• 16:12but the signs of edema
• 16:15will be absent,
• 16:17and they may have other
• 16:18findings such as rash
• 16:21or a known genetic abnormality.
• 16:23Patients with anaphylaxis may come
• 16:25in with hypotension
• 16:26and,
• 16:28some edema. Typically, that's localized
• 16:30to the face or to
• 16:31the area where there was
• 16:32an exposure to a known
• 16:33allergen.
• 16:34These patients will also have
• 16:36profound respiratory distress such as,
• 16:38manifested by wheezing,
• 16:41or airway edema.
• 16:43They may also have a
• 16:44urticarial rash.
• 16:46Patients with hereditary angioedema may
• 16:49also have localized edema to
• 16:51the face. They typically will
• 16:53come in not with cardiovascular
• 16:54symptoms, but with signs of
• 16:56respiratory distress from upper airway
• 16:58swelling.
• 16:59Patients with nephrotic syndrome,
• 17:01may come in with edema,
• 17:02but typically these patients are
• 17:04hypertensive and their course has
• 17:06been more gradual onset.
• 17:08And patients with Addison's disease
• 17:10may also have a gradual
• 17:11onset and come in with
• 17:12hypotension, but there may be
• 17:14some skin pigmentation findings.
• 17:16So what are the initial
• 17:18workup, for a patient with
• 17:19systemic capillary leak disease? Well,
• 17:21the initial focus has to
• 17:23be on the distributive shock.
• 17:25And so you would do
• 17:26all of the things at
• 17:27your institution
• 17:29associated with your septic shock
• 17:31bundle
• 17:32or, that you would do
• 17:33for distributive shock. These may
• 17:35include blood cultures, urinalysis,
• 17:37urine cultures, CBC, complete metabolic
• 17:39panel. Depending on the severity
• 17:42of the presentation,
• 17:44you you may get a
• 17:45blood gas to look at
• 17:46gas exchange or perfusion with
• 17:47lactate.
• 17:48If you have suspicion of
• 17:50decreased cardiac output, you may
• 17:52consider cardiac enzymes or natriuretic
• 17:54peptides,
• 17:55a tox screen, and coagulation
• 17:57panel.
• 17:58When these, come back, a
• 18:00secondary evaluation may include chest
• 18:02radiography
• 18:03or CT scan to look
• 18:05for a nidus of infection,
• 18:06other viral testing,
• 18:08or more,
• 18:10in in-depth testing such as
• 18:12cortisol, thyroid, or cytokine panels
• 18:14as they're available at your
• 18:15institution.
• 18:16We took her to the
• 18:17ED and, of course, she
• 18:19presented with a very high
• 18:21heart rate. So they immediately
• 18:23started fluids,
• 18:25which, of course, is a
• 18:26detrimental error
• 18:28and a reason that a
• 18:29lot of these kiddos
• 18:31end up in ICU type
• 18:33situations.
• 18:34Her lower extremity swelled.
• 18:37You started to see just
• 18:38overall puffiness and Yes. To
• 18:40the point where you couldn't
• 18:41pull her shorts up over
• 18:42her legs. Yes. And, you
• 18:43know, you pick her up.
• 18:44And and at that point,
• 18:45she weighed,
• 18:47I think, forty pounds or
• 18:49so, and she gained five
• 18:50pounds overnight. I know with
• 18:52other kids who ended up
• 18:53in the ICU, they were
• 18:55treating for what they thought
• 18:56was sepsis or septic shock,
• 18:59hence the fluid overload.
• 19:02Once we got her labs
• 19:03back with low albumin and
• 19:05low sodium,
• 19:06we insisted on being transferred
• 19:08to Big Duke.
• 19:09The laboratory findings of SCLS
• 19:12are quite unique as well.
• 19:14Again, the diagnostic triad of
• 19:16this is hypotension,
• 19:18which can be as severe
• 19:20as hypotensive shock and cardiac
• 19:22arrest,
• 19:23hemoconcentration,
• 19:24where patients
• 19:26hematocrit may double or even
• 19:28triple from their baseline levels,
• 19:30and hypoalbuminemia,
• 19:32where unreadably low albumin is
• 19:34common,
• 19:35but at least below,
• 19:37one and a half or
• 19:38two milligrams per deciliter.
• 19:41These patients will also have
• 19:42high lactate, but normal inflammatory
• 19:44markers, which will differentiate them
• 19:46from sepsis, toxic shock syndrome,
• 19:49and many inborn errors of
• 19:50immunity.
• 19:52Other tests that may clue
• 19:54into a diet alternate
• 19:55other tests that may clue
• 19:56into an alternate diagnosis
• 19:59include elevated tryptase for anaphylaxis,
• 20:02abnormal complement levels for hereditary
• 20:05angioedema,
• 20:06and abnormal lipid profiles
• 20:09for nephrotic syndrome,
• 20:11and low cortisol
• 20:13or
• 20:14ACTH
• 20:15for Addison's disease.
• 20:18The initial treatment
• 20:19for pediatric SCLS disease has
• 20:22to be focused on the
• 20:23severity of shock. This includes
• 20:25stabilizing the airway and breathing
• 20:27with supplemental oxygen
• 20:29or mechanical support as needed.
• 20:32Next, you must stabilize the
• 20:33cardiovascular
• 20:34dysfunction,
• 20:35and this is done with
• 20:36a conservative
• 20:38fluid resuscitation
• 20:39strategy. Patients with systemic capillary
• 20:41leak disease are
• 20:43at high risk to become
• 20:45fluid overloaded very quickly.
• 20:47This means you must monitor
• 20:48the fluid responsiveness and fluid
• 20:50overload frequently and risk of
• 20:52fluid overload frequently. Also consider
• 20:54early use of vasopresso therapies
• 20:56as opposed to additional
• 20:58fluid boluses.
• 21:00Conservative fluid resuscitation is not
• 21:02unfamiliar
• 21:03to pediatric emergency medicine and
• 21:05critical care providers.
• 21:06Think about how we would
• 21:08resuscitate a patient
• 21:09in hypovolemic
• 21:11shock as part of diabetic
• 21:12ketoacidosis
• 21:14To avoid or minimize the
• 21:16risk of subsequent cerebral edema,
• 21:18we would employ a similar
• 21:20strategy
• 21:21of smaller intravascular boluses with
• 21:23more frequent reassessment
• 21:25and early vasopressor
• 21:27use.
• 21:28Patients with systemic capillary leak
• 21:30disease,
• 21:31can be can have their
• 21:32cardiac output monitored the same
• 21:33way you would for other
• 21:35etiologies of shock, and that
• 21:37includes lactate, mixed venous oxygen
• 21:39saturation,
• 21:40urine output mental status, or
• 21:42if available at your institution
• 21:43echocardiography.
• 21:46Patients with s with SCLS
• 21:48are at higher risk for
• 21:49complications of resuscitation, however,
• 21:52and this can include compartment
• 21:54syndrome.
• 21:55Aggressive fluid resuscitation
• 21:57will lead to excessive extravascular
• 21:59leak of that fluid
• 22:01into the extremities
• 22:02and may quite quickly result
• 22:04in loss of systemic pulses,
• 22:07profound extremity pain,
• 22:09and,
• 22:10resulting all from compartment syndrome,
• 22:13which needs to be addressed
• 22:14immediately
• 22:15by your orthopedic or plastic
• 22:17surgery
• 22:18services.
• 22:19Patients are also at high
• 22:20risk for other
• 22:22vascular leak complications including abdominal
• 22:25compartment syndrome,
• 22:27pericardial
• 22:28effusions,
• 22:29or pleural effusions,
• 22:31which may all result in
• 22:33worse end organ dysfunction.
• 22:35These patients are also at
• 22:36high risk for coagulation abnormalities
• 22:38and deep venous thrombosis
• 22:40due to stasis of blood,
• 22:42and may require early treatment
• 22:44with anticoagulation,
• 22:46but that should be done
• 22:47in conjunction with your hospital
• 22:49policies.
• 22:50The sharp drop in intravascular
• 22:52volume may also result in
• 22:54more profound acute kidney injury,
• 22:56than typically seen in distributive
• 22:58shock. All of these complications,
• 23:00need to be monitored frequently
• 23:02in the patient in the
• 23:03leak phase.
• 23:06Unfortunately, there are no specific
• 23:07therapies for the leak phase.
• 23:10There have been many tried,
• 23:11but none are effective. Those
• 23:13that have been tried include
• 23:14IVIG, plasma exchange,
• 23:17aminophylline or tributyline, methylene blue,
• 23:19targeted immunotherapies,
• 23:21or even extracorporeal
• 23:23membranous oxygenation or ECMO.
• 23:25These therapies have not shown
• 23:27to be effective at reducing
• 23:28the intensity or duration of
• 23:30the leak phase and should
• 23:31only be leveraged for your
• 23:33patients in collaboration with local
• 23:35experts.
• 23:36The leak phase may last
• 23:37as little as several hours
• 23:39or up to seven days.
• 23:41They instantly stopped fluids.
• 23:44So they did not know
• 23:45what was going on. Their
• 23:46initial,
• 23:49assumption as almost all of
• 23:51the kids that I know
• 23:52with SCLS was nephrotic syndrome.
• 23:54We that was the first
• 23:55people we had in. We
• 23:56actually were admitted on a
• 23:58Sunday in the middle of
• 23:58the night. Monday morning rounds,
• 24:00the entire children's
• 24:02nephrology team is in with
• 24:03us
• 24:04taking all of that. I
• 24:06will say during some of
• 24:07those previous leaks, her urine
• 24:09was tested for protein. So
• 24:11that was always top of
• 24:12mind awareness was checking kidney
• 24:14functions, but it was always
• 24:16perfect.
• 24:17So we did do imaging,
• 24:19of her kidneys. Everything was
• 24:21perfect. No protein in urine.
• 24:23And at this time, she
• 24:24started dumping that IV fluid,
• 24:26and she gained ten percent
• 24:28of her body weight
• 24:29within about twelve hours.
• 24:31The recovery phase of
• 24:33systemic capillary leak disease may
• 24:35start suddenly.
• 24:36And this is associated with
• 24:38rapid recruitment
• 24:39of all of the volume
• 24:41that had leaked out of
• 24:42the patient's blood vessels back
• 24:44into the intravascular
• 24:45space.
• 24:46This may be associated with
• 24:48flash pulmonary edema
• 24:50due to increased hydrostatic pressures
• 24:53and heart failure due to
• 24:55sudden
• 24:55circulatory
• 24:57overload.
• 24:58This needs to be monitored
• 24:59carefully in these patients and
• 25:01treat treated with aggressive
• 25:03diuresis.
• 25:04Also, during hospital stays,
• 25:06patients should have consults for
• 25:08dedicated pediatric subspecialties.
• 25:11These include rheumatology
• 25:13and or
• 25:14allergy and immunology,
• 25:16as well as those consults
• 25:18dictated by end organ dysfunction,
• 25:21such as infectious disease, nephrology,
• 25:23cardiology,
• 25:25or or neurology or other,
• 25:27services.
• 25:28In conjunction with these services,
• 25:30tertiary evaluation
• 25:32for systemic capillary leak disease
• 25:34include
• 25:35immunoelectrophoresis
• 25:37to look for the monoclonal
• 25:39gammopathy of undetermined significance both
• 25:41in the blood and the
• 25:42urine,
• 25:43urine analyses,
• 25:45to, rule out nephrotic syndrome,
• 25:48targeted,
• 25:49tests to rule out anaphylaxis
• 25:51such as negative tryptase or
• 25:53rule out hereditary angioedema
• 25:55such as c one esterase
• 25:56inhibitor levels. If there's cardiac
• 25:58dysfunction,
• 26:00you may consider advanced imaging
• 26:02of of heart function.
• 26:03And if available at your
• 26:05institution,
• 26:06rapid whole genome or other
• 26:07targeted genetic testing. She never
• 26:10went to PICU.
• 26:11She all she stayed on
• 26:12the main floor. Her albumin
• 26:14was always low. They never
• 26:16gave her replacement albumin. They
• 26:18waited to see if she
• 26:19could pee all of that
• 26:20extra fluid out, which she
• 26:22did.
• 26:23But Monday was nephrology.
• 26:25Tuesday, we met with endocrinology
• 26:27and explored Addison's disease,
• 26:30again, having some symptoms but
• 26:32missing others.
• 26:34That cleared up. We also
• 26:36saw allergy immunology for angioedema.
• 26:40He quickly was like, this
• 26:41is not angioedema,
• 26:43but they still ruled it
• 26:44out.
• 26:45And then the last
• 26:47specialty that explored was gastro.
• 26:49I have celiac, so we
• 26:51thought maybe something's going on.
• 26:53Maybe the protein is leaking
• 26:55through the GI system. So
• 26:56she had stool samples sent
• 26:58off, all of that, and
• 26:59that came back clear. And
• 27:01it was not until the
• 27:02rheumatology
• 27:03team came in,
• 27:05and it was actually the
• 27:06fellow
• 27:07who,
• 27:09took the assessment and presented
• 27:11it to her attending. And
• 27:12it was the attending, doctor
• 27:13Rebecca Sedoun,
• 27:15who came in maybe five
• 27:17minutes later. Yeah. And she
• 27:18was like, your daughter is
• 27:19a unicorn.
• 27:21I have never seen this.
• 27:22I will probably never see
• 27:24this again.
• 27:25And she told us the
• 27:27diagnosis.
• 27:29This table summarizes the inpatient
• 27:31treatment differences between the differential
• 27:33diagnosis.
• 27:35Again, I would note the
• 27:36conservative fluid resuscitation and early
• 27:39vasopressor therapy
• 27:40for patients with systemic capillary
• 27:42leak disease to help minimize
• 27:44the complications
• 27:46of the recovery phase.
• 27:48Although there are no
• 27:50effective therapies to decrease
• 27:52the duration or intensity of
• 27:53the leak phase, there are
• 27:55effective therapies to
• 27:57reduce the risk of having
• 27:58another leak phase. In addition
• 28:00to all of the pediatric
• 28:02subspecialty follow-up based on organ
• 28:04injury, children should be followed
• 28:06by rheumatology
• 28:07or allergy immunology
• 28:09depending on who's most comfortable
• 28:11prescribing
• 28:11intravenous immunoglobulin
• 28:13or IVIG,
• 28:15to these patients.
• 28:16IVIG is the first line
• 28:18treatment
• 28:19for preventing
• 28:20leak episodes in patients with
• 28:22SCLS.
• 28:23It significantly,
• 28:25reduces relapse rates and increases
• 28:27ten year survival
• 28:29up to one hundred percent,
• 28:31in adults.
• 28:33Typically, IVIG doses are starting
• 28:35on the higher end,
• 28:36of one to two kilograms
• 28:38per month and then titrated
• 28:40in close collaboration with rheumatology
• 28:43or allergy immunology experts
• 28:45to the, tolerated,
• 28:47dose.
• 28:48If patients are unable to
• 28:49tolerate IVIG, and that may
• 28:51be due to headaches or
• 28:53migraines associated with infusion,
• 28:55other infusion reactions, or the
• 28:57cost or the time required,
• 29:00to administer this drug at
• 29:01infusion centers, they may benefit
• 29:03from subcutaneous
• 29:04immunoglobulin
• 29:05or SCIG
• 29:07at a dose of eighty
• 29:08milligrams per kilogram up to
• 29:09three times a week.
• 29:11Other older therapies,
• 29:13for SCLS include terbutaline or
• 29:16theophylline.
• 29:17In,
• 29:19other therapies for SCLS include
• 29:21terbutaline
• 29:22or theophylline.
• 29:23These have been used together
• 29:24or separately,
• 29:26and are really much, much
• 29:27less effective than IVIG.
• 29:30Failed therapies,
• 29:31are listed here but includes
• 29:32steroids, diuretics,
• 29:34leukotriene
• 29:35modifying agents, and other drugs
• 29:37or herbal supplements are not
• 29:39recommended and they do not
• 29:41prevent
• 29:42episodes of leak.
• 29:44So here is our completed
• 29:46table,
• 29:46which highlights the differences between
• 29:48systemic capillary leak disease
• 29:51and, other diagnostic
• 29:53considerations
• 29:54in the short term, long
• 29:55term, and response to treatment?
• 29:58At almost every single pediatric
• 30:00case, it's like reading her
• 30:02MyChart notes.
• 30:04Child presents to the ED
• 30:06with court with, cold like
• 30:08symptoms,
• 30:09high heart rate, low blood
• 30:11pressure, low albumin. And so
• 30:12to me, that was so
• 30:13frustrating as a parent that
• 30:15how could it be these
• 30:17three or four
• 30:18identical
• 30:19simple clinical presentations
• 30:22and no one has heard
• 30:23of this.
• 30:25And that's where my passion
• 30:26comes from with raising awareness.
• 30:29So those first three episodes,
• 30:31I think I was doing
• 30:34I reacted how any mom
• 30:35would. I was still very
• 30:36concerned, and I was still
• 30:37calling the nurse line. I
• 30:39feel like I did everything
• 30:40right.
• 30:41If I were to whisper
• 30:42in my ear back with
• 30:44the influenza a, that really
• 30:46bad
• 30:47third fourth week,
• 30:49I would have insisted on
• 30:50blood work. And but it's
• 30:52really hard to convince pediatric
• 30:54providers
• 30:55to do labs. And it's
• 30:56also hard because I don't
• 30:58you don't wanna do labs
• 30:59on your kids. It's a
• 31:00nightmare. Right? It's terrible. They're
• 31:01screaming and crying. So it's
• 31:02not like you necessarily wanna
• 31:04ask for blood work. And
• 31:05when your pediatrician who you
• 31:07trust and knows your child
• 31:09isn't saying you need it,
• 31:11you know, but we both
• 31:12knew something was going on.
• 31:14The frustration was there probably
• 31:16since the second week. I
• 31:17was like,
• 31:18this is not just unknown
• 31:20eyes falling, this random eyes
• 31:21falling. Like, there has to
• 31:22be a reason.
• 31:24Education is huge.
• 31:26And and bring it to
• 31:27your doctors because a lot
• 31:28of them, you have to
• 31:30become, like, your own expert
• 31:32on it. They're not gonna
• 31:34have read as many papers
• 31:35as you on it most
• 31:36likely.
• 31:37They're you know, they may
• 31:39not know who to contact,
• 31:41but it's a very small
• 31:43circle
• 31:44with this
• 31:45disease. And we feel very,
• 31:47very blessed for doctor Drury's
• 31:49research,
• 31:50which I know is more
• 31:51adult based and even more
• 31:52blessed that, doctor Pierce, you're
• 31:54kinda taking the torch and
• 31:56and moving the needle, if
• 31:57you will, here in the
• 31:58United States for SCLS.
• 32:01So, yeah, I think just
• 32:02advocate and educate and read
• 32:05and talk to one another
• 32:07as parents.
• 32:09So I hope that I
• 32:09have convinced you to consider
• 32:11systemic capillary leak disease,
• 32:14in children that have one
• 32:15or more unexplained episodes of
• 32:18hypovolemic shock.
• 32:20This is especially important for
• 32:21those that have,
• 32:23episodes of
• 32:24culture negative septic shock,
• 32:27to be considering systemic capillary
• 32:29leak disease.
• 32:30And that's because many children
• 32:31will have more than one
• 32:32episode of leak before this
• 32:33is diagnosed,
• 32:35and that's preventable.
• 32:36I hopefully, I've convinced you
• 32:37that there's effective
• 32:39outpatient treatment that can reduce
• 32:41the episodes of leak or
• 32:43prevent the episodes of leak
• 32:44with IVIG or SCIG.
• 32:48An increased awareness,
• 32:49of pediatric emergency medicine and
• 32:52critical care providers
• 32:53may decrease the number of
• 32:55episodes of leak before there's
• 32:57a diagnosis.
• 32:58I continue to run a
• 33:00lab focused on blood vessel
• 33:01dysfunction in critically ill children
• 33:02and am actively invested and
• 33:04involved
• 33:05in children diagnosed with capillary
• 33:07leak syndrome.
• 33:08I'd be happy to hear
• 33:09from providers or patients at
• 33:11the email address listed there.