Greetings to all SilverList members,
This is a belated posting following Catherine's communication .
Creel reported:
< Here are a few things that you must know--
Positing:
* The hypoxemia is severe and the CXR can deteriorate rapidly. Patients
desaturate at the slightest provocation - talking, movement, coughing.
* There is a preponderance of barotrauma, even in nonventilated patients -
pneumothoraces, pneumomediastinum, and surgical emphysema.
* Weaning from mechanical ventilation can be difficult and prolonged. While
oxygenation eventually improves, many patients are easily fatigued.
COMMENT: What is Adult Respiratory Distress Syndrome, commonly called simply:
ARDS? What ARDS is not. What are the phases/stages of ARDS?
Adult (or Acute) Respiratory Distress Syndrome (ARDS) is a medical condition
which prevents the normal breathing process from taking place. ARDS occurs
when there is severe inflammation in both lungs resulting in an inability of
the lungs to function properly. ARDS is a devastating, often fatal,
inflammatory lung condition that usually occurs in conjunction with
catastrophic medical conditions, such as pneumonia, shock, sepsis (or severe
infection throughout the body, sometimes also referred to as systemic
infection, and may include or also be called a blood or blood-borne infection),
and trauma. It is a form of sudden and often severe lung failure. Lung
failure means that the lungs can no longer carry out their normal function of
getting oxygen into the blood and removing carbon dioxide from the body.
As will be seen, ARDS may result in a relatively short period of battle to
recover characterized by what seems to be a remarkably speedy recovery with
little if any damage to the lungs. More often, if death does not occur, there
is a very protracted period of battle with varying levels of lung damage
sometimes but not always leading to the need for extensive physical and
pulmonary rehabilitation.
Thousands upon thousands of individuals suffer from ARDS (and the less severe
precusor medical condition known as Acute Lung Injury - ALI) each year in the
US alone. Worldwide, the cases of ARDS and ALI total in the hundreds of
thousands. Patients, family members and friends, survivors, medical personnel
and facilities, are severely tested emotionally, morally, financially, and
significantly effected by the devastating consequences of ARDS each year.
The pathogenesis of ARDS generally has been characterized into three
phases/stages. It is important to remember each individual is different and
the path through battling ARDS may vary widely. There may usually are many ups
and downs along the way.
1.) Exudative phase/stage. Characterized by accumulation of excessive fluid
in the lungs due to exudation (leaking of fluids) and acute injury
Characterized by accumulation of excessive fluid in the lungs due to exudation
(leaking of fluids) and acute injury (Acute Lung Injury "ALI" often is a
precusor injury medical condition to the more severe development of ARDS,
although ALI is more prevalent and not all ALI cases develop into ARDS).
Arterial oxygention is usually most severe during this phase of actute injury,
including injury to the endothelium (lining membrane) and epithelium (surface
layer of cells). Some individuals quickly recover from this first phase; many
others progress after about a week into the second phase/stage.
2.) Fibroproliferative (or sometimes shortened to proliferative) phase/stage.
Connective tissue and other structural elements in the lungs proliferate in
response to the initial injury, including development of fibroblasts (cells
giving rise to connective tissue). Under a microscope, lung tissue appears
densely cellular. Terms "stiff lung" and "shock lung" have been known to
characterize this phase/stage. Two to four weeks after the onset of lung
injury, abnormally enlarged air spaces and fibrotic tissue (scarring) are
increasingly apparent. There is ongoing danger of barotrauma or volutrauma
causing a pneumothorax - a rupture allowing leakage of air from the damaged
lung into surrounding spaces, driven by the high pressure (barotrauma) or the
volume of air used (volutrauma) in mechanically assisted breathing. There is
also danger of pneumonia and blood-born infection (sepsis) developing, or
difficulty in resolving one or both of these conditions if they were the
precipita
ting conditions leading to the ARDS. Many people die during this phase/stage
because of Multiple Organ Failure (MOF) or infectious complications. The
second phase/stage typically lasts 3-10 weeks. The first two phases/stages
generally are the most critically severe stages from a life or death
consequence standpoint.
3.) Fibrosis (or fibrotic) phase/stage-Repair and recovery (or the healing
stage). The lung reorganizes and recovers during this phase/stage. Resolution
of inflammation, excess cellularity, and fibrosis settles. Oxygenation
improves to the point of liberation from mechanical ventilation becomes
possible. Lung function may continue to improve for as long as 6 to 12 months
after onset of respiratory failure, depending on the precipitating condition
and severity of the initial injury. It is important to remember that there may
be and often are different levels of pulmonary fibrotic changes between
individuals who suffer from ARDS.
INHALED NITRIC OXIDE GAS THERAPY and ARDS
This writing is intended to briefly introduce
ARDS patients, their families, and significant
others, with the properties of nitric oxide
and the clinical implications associated with
the use of this gas. Nitric oxide (NO) should
not be confused with nitrous oxide (N20), the
mild anesthetic often used by dental
professionals that is more commonly known as
"laughing gas." As a matter of fact, nitric
oxide was known as a common environmental
I pollutant and contaminant during the
manufacturing process of nitrous oxide. NO is
normally manufactured from the reaction of
sulfur dioxide with nitric acids. Nitric oxide
is a component of smog that can be measured in
urban area air at 10 to 100 parts per billion
(ppb), is naturally produced in the body in
the upper and lower airway at 100 to 1000 ppb,
and is present in cigarette smoke at 400 to
1000 parts per million (ppm). Clinical
research found that the concentration of
exhaled NO is increased during exercise and in
patient's with asthma.Physiology of ARD
Those of you familiar with this newsletter may
have as much information on ARDS as many
physicians and researchers. Nevertheless, a
limited review of the pulmonary disease ARDS
is necessary to gain an understanding of the
way in which NO affects this pulmonary
ailment.
Patients with ARDS, whether precipitated by
inhalation of vomited stomach contents
(aspiration), injury, pneumonia, inhalation of
toxic substances, or a severe infection
somewhere in the body (sepsis), usually all
have high blood pressure in the vessels
leading to and around the lungs (pulmonary
hypertension.) Also, under normal conditions,
if the tiny air sacs in the lung (alveoli) do
not receive enough air or are collapsed
(atelectasis), the blood vessels supplying
these alveoli will constrict (become smaller
or narrower). In ARDS however, these collapsed
or underventilated alveoli continue to receive
full blood supply from the surrounding blood
vessels (capillaries). Since these collapsed
or underventilated alveoli are not receiving
oxygen, they are not capable of providing
oxygen to the blood stream. The net effect may
be a severe reduction in oxygen levels in the
blood stream.
Basic Science
Certain substances that occur naturally in the
body exert control over blood flow in and
around the lungs. These substances can cause
blood vessels near the lungs to dilate (become
wider or larger, vasodilation). They produce
this vasodilation by causing cells lining the
blood vessels to produce the gaseous product
NO. NO accounts for the physiological effects
of vasodilating drugs such as nitroglycerin; a
drug commonly used to treat high blood
pressure. Recent studies have found that
excess NO production in the body plays a role
in the massive vasodilation and low blood
pressure associated with septic shock
syndrome.
Since NO exists in a gaseous form, it can be
applied to the pulmonary vessels by
administering it as an inhaled gas. What this
means, is that when NO is inhaled, it
selectively dilates blood vessels in only
those lung segments that are actively
participating in gas exchange (oxygen & carbon
dioxide) at the alveolar-capillary level. In
other words, this increases the blood flow to
areas of the lung where oxygen is being
provided and thus improves oxygen levels in
the body. This is known as
ventilation-perfusion (V/Q) matching.
NO was not the first drug discovered that
causes pulmonary vasodilation. There are
several other drugs that are known
vasodilators that have been on the market for
years. These include the aforementioned
nitroglycerin and nitroprusside. The
shortcoming of these types of drugs is that
they increase the pulmonary blood flow to all
lung segments, including those that are not
well ventilated. This further inhibits oxygen
delivery to the blood stream because
capillaries are dilated that are in contact
with alveoli that are not providing or do not
contain oxygen.
After the NO is inhaled and passes through the
lungs and into the patient's blood stream, its
effects are quickly deactivated. This is
because NO quickly reacts with the
iron-containing pigment of the red blood cell
that functions to carry oxygen from the lungs
to the tissues (hemoglobin). Hemoglobin
inactivates NO and thus when it is carried to
the rest of the body, it does not cause
vasodilation to blood vessels beyond the lung
area. This is in stark contrast with some of
the other pulmonary vasodilator drugs that not
only cause vasodilation of blood vessels in
and around the lungs, but also cause
vasodilation throughout the body. This can
potentially lead to a serious decrease in a
patient's blood pressure.
Gas Delivery Systems
As mentioned earlier, the way in which this
drug is administered is simply by providing
the gas for the patient to inhale. There are a
variety of delivery systems that are presently
in use. These either encompass a homemade or
"rigged" system or a commercially available
delivery system. They can provide gas delivery
via a ventilator circuit, a facemask, or a
nasal cannula.
The basic design and goal of each system is to
provide a system for safe gas delivery and
precision gas analysis or monitoring. If
delivering the gas through a ventilator,
either a continuos or intermittent flow of NO
is fed into the inspiratory limb of the
ventilator tubing. The rate of NO gas flow is
controlled to maintain the desired levels of
NO. Prior to the patient connection of the
ventilator tubing, a sensor or sample line is
connected to an analyzer that displays NO, NO2
(discussed in further detail later) and
possibly oxygen levels. Usually the displayed
NO and NO2 readings are measured in parts per
million.
Safety Concerns
As with any drug, there are legitimate safety
and toxicity concerns regarding the use of
inhaled NO. Inhaling very high levels of NO
(5,000 to 20,000 ppm) can be lethal causing a
severe and acute accumulation of fluid in the
lungs (pulmonary edema) and methomoglobinemia
(described below). However, there is little
evidence of such toxicity when the
concentration is kept in the normal
concentration range (1 to 80 ppm). Animals
have breathed the gas in concentrations of 10
to 40 ppm, for six days to six months, without
evidence of toxicity.
Virtually all patients receiving NO will also
be receiving oxygen (O2). ARDS patients
usually require high levels of O2. The
by-product of NO and O2 yields nitrogen
dioxide (NO2). NO2 is a highly toxic chemical.
Although OSHA has set the safety limit for NO2
at 5 ppm, some investigators have found that
prolonged exposure to even 2 ppm of NO2 can be
injurious to the lungs. The amount of NO2
produced is dependent upon the levels of NO
and O2 and the amount of time they are
combined together prior to inhalation.
Therefore, the lowest dose of NO and lowest
concentration of O2 that achieve the desired
effect are used. NO is usually fed into the
ventilator tubing as close to the patient as
possible, limiting the mixing time between O2
and NO.
All delivery systems monitor NO2 levels
continuously. Newer delivery systems have been
designed to limit NO2 production or inhibit
its delivery to the patient, but situations
may occur where the NO dose, the O2
concentration, or both, may have to be
reduced.
One of the potential adverse side effects for
patients receiving inhaled NO is the formation
of methemoglobin. Methemoglobin is hemoglobin
that cannot release the oxygen its carrying,
nor can it combine with more oxygen.
Therefore, it impairs the blood's ability to
deliver oxygen to the tissues. This is a rare
complication because the body contains certain
chemicals and enzymes that convert
methemoglobin back to hemoglobin.
Nevertheless, blood levels should be closely
monitored.
Patient Outcomes
Virtually since the discovery of NO for
medical use in the mid-to-late '80s, it has
been trialed on patients with acute
respiratory distress syndrome (ARDS). Numerous
formal studies have been completed that
examined the effect NO had on ARDS patients.
Virtually every study found that inhaled NO:
1) induced a redistribution of blood flow in
the lungs to areas that were well ventilated,
2) reduced the blood pressure in the arteries
surrounding the lungs, and 3) improved oxygen
levels in the blood. How NO is capable of
producing this effect was described earlier.
This research has also found that not every
patient responds to inhaled NO in the same
manner. Some patients have an almost immediate
positive and recognizable response. While
others have a limited response. Some studies
have found that only about one-third of
patients with ARDS due to sepsis had a
positive response to inhaled NO. Among other
factors, patients who had high blood pressure
in the arteries near the lungs and who
demonstrated a positive response to PEEP
(positive end-expiratory pressure from the
ventilator), appeared to be most likely to
have a positive response to inhaled NO. For
some patients, the positive response to
inhaled NO appears to last for only hours to
days while others respond positively for
weeks. The reason for this phenomenon is still
being investigated.
As mentioned earlier, ARDS patients are
usually receiving high concentrations of
oxygen. High-level oxygen administration for
an extended period of time (usually > 72
hours) is well known for its pulmonary
toxicity. Since NO has been proven to improve
oxygen levels in the body, numerous clinical
studies have found that adding NO to a
patient's inhaled gas allowed a reduction in
the oxygen concentration being delivered to
the patient, and thus a concomitant reduction
in possible toxicity to the lungs.
So how has NO affected mortality and length of
intensive care unit or hospital stays? Since
NO is a relatively new medical adjunct, there
have been only a limited number of studies
that have tracked and reported patient
outcomes. Most research has focused on the
physiological effects and patient response to
inhaled NO.
In the largest study to date, 177 patients
diagnosed with ARDS, from various test sites
throughout the country, were randomized to
receive NO or a control gas (placebo). Results
of this study were: 1) an initial increase in
oxygenation allowed a reduction in O2
concentration, 2) there were no differences
among the groups receiving NO and the placebo
with respect to mortality rate, the number of
days alive and off mechanical ventilation, or
the number of days alive after meeting a
criteria for removal of mechanical
ventilation, 3) however, the percentage of
patient's alive and off mechanical ventilation
by day 28 that were receiving 5 ppm of inhaled
NO, was higher (62% vs. 44%) than the placebo
group. Even though most other studies were
conducted using much smaller patient
populations, almost all had the similar
findings of improved gas exchange, but no
effect on mortality.
The difficulty in analyzing the success or
failure of patient outcomes (mortality and
length of stay) for patients with ARDS is that
the reversal of lung failure may be obscured
by the development of other organ system
malfunctions that often may occur with ARDS.
Studies continue to address the use of NO to
improve the overall prognosis for ARDS
patients. Actual studies that are underway
include methods of predicting which patients
will respond positively to inhaled NO, the
optimal dose concentrations, patient
positioning during NO delivery, and
examination of potential long term toxicity.
Research has been proposed that would make
comparisons of NO delivery devices on patient
outcomes, and standardization of ventilator
management during NO administration.
By Dean Miller, BSRC, RRT
Education Coordinator
Respiratory Care Services
St. Luke's Medical Center
Milwaukee, WI
The author would like to acknowledge the kind
support of Dr. David Rein and Dr. Stuart Levy,
St. Luke's Medical Center, and Dr. Robert
Lunn, Sioux Valley Hospital, Sioux Falls, SD.
***********************
Resources:
http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/N/NO.html
Positing:
* We cannot use a nebulizer. This is probably the single most important
factor in the spread of droplets on the medical ward at the Prince of Wales
Hospital in early March. The patient who received the nebulizer has been
identified as the index case for this hospital. Many patients, healthcare
workers, and relatives who entered that ward contracted SARS.
Comment:
http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/N/NO.html
Positing:
* Because of the vast improvement of patients when high dose steroids are
introduced it has become apparent that the majority of damage being caused
to the lungs is not from the pathogen but from an over-response by the
immune system.>
Comment:
Apoptosis, or programmed cell death, is a normal component of the development
and health of multicellular organisms. Cells die in response to a variety of
stimuli and during apoptosis they do so in a controlled, regulated fashion.
This makes apoptosis distinct from another form of cell death called necrosis
in which uncontrolled cell death leads to lysis of cells, inflammatory
responses and, potentially, to serious health problems. Apoptosis, by contrast,
is a process in which cells play an active role in their own death (which is
why apoptosis is often referred to as cell suicide).
Upon receiving specific signals instructing the cells to undergo apoptosis a
number of distinctive biochemical and morphological changes occur in the cell.
A family of proteins known as caspases are typically activated in the early
stages of apoptosis. These proteins breakdown or cleave key cellular substrates
that are required for normal cellular function including structural proteins in
the cytoskeleton and nuclear proteins such as DNA repair enzymes. The caspases
can also activate other degradative enzymes such as DNases, which begin to
cleave the DNA in the nucleus. The result of these biochemical changes is
appearance of morphological changes in the cell.
Resources:
http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/N/NO.html
With regards
Lew
***************
CS>Nebulizing CS for SARS Redux
* From: C Creel (view other messages by this author)
* Date: Mon, 19 May 2003 21:03:36
------------------------------------------------------------------------
Dear List Members,
A few weeks ago we had an extended discusssion on nebulizing CS for SARS
patients. I appreciated all the thoughts and POVs I received from you.
Since then, I've had the opportunity to present CS to a group of physicians
on Hong Kong. It was received with mixed feelings, but the dialogue between
us remains alive today. Here is one of the comments I've received from the
Hong Kong group. Please note the fourth item down on nebulizer treatments
for SARS.
Good day, Catherine,
Here are a few things that you must know--
* The hypoxemia is severe and the CXR can deteriorate rapidly. Patients
desaturate at the slightest provocation - talking, movement, coughing.
* There is a preponderance of barotrauma, even in nonventilated patients -
pneumothoraces, pneumomediastinum, and surgical emphysema.
* Weaning from mechanical ventilation can be difficult and prolonged. While
oxygenation eventually improves, many patients are easily fatigued.
* We cannot use a nebulizer. This is probably the single most important
factor in the spread of droplets on the medical ward at the Prince of Wales
Hospital in early March. The patient who received the nebulizer has been
identified as the index case for this hospital. Many patients, healthcare
workers, and relatives who entered that ward contracted SARS.
* Because of the vast improvement of patients when high dose steroids are
introduced it has become apparent that the majority of damage being caused
to the lungs is not from the pathogen but from an over-response by the
immune system.
I look forward to continued discussions.
[Name deleted]
Regards,
Catherine
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