New Guidelines Issued for Asthma Assessment

The American Thoracic Society (ATS) and the European Respiratory Society (ERS) have released official standards regarding asthma evaluation for clinical trials and practice. The joint statement containing the new recommendations and underlying evidence base was approved by the ATS Board of Directors on March 13, 2009, and by the ERS Executive Committee on November 27, 2008, and it is published in the July 1 issue of the American Journal of Respiratory and Critical Care Medicine.

"In the past, there has been no standard way of assessing asthma," Helen K. Reddel, MB, PhD, from the Woolcock Institute of Medical Research in Camperdown, Australia, and cochair of the ATS/ERS Task Force on Asthma Control and Exacerbations, said in a news release. "This has led to a lot of confusion for doctors who are managing asthma, and in research, it was difficult to compare the results of different studies."

Although evaluation and monitoring of asthma control are crucial to determining treatment response both in individual patients and in clinical trials, there have been a variety of definitions and assessments for asthma control, severity, and exacerbations. The ATS/ERS therefore convened a task force of 24 asthma experts from North America, Europe, South Africa, Australia, and New Zealand.

Their objective was to issue guidelines applicable to adults and children 6 years or older regarding standardization of outcomes relating to asthma control, severity, and exacerbations in clinical trials and clinical practice.

The task force performed a narrative review of the literature to assess the measurement properties and strengths and limitations of outcome measures pertinent to asthma control and exacerbations, including diary variables, physiologic measurements, composite scores, biomarkers, quality-of-life questionnaires, and indirect measures.

New Definitions for Asthma

Based on current therapeutic standards and relevance to clinical practice and research trials, the task force developed new definitions for asthma control, severity, and exacerbations. Asthma control was defined as the degree to which treatment can ameliorate or eradicate the features of asthma regarding both current clinical control and future risk. Specifically including future risk in the new definition of asthma control is a departure from earlier definitions, which primarily highlighted current clinical control.

"The addition of future risk is important for three reasons: first, because some medications can improve symptoms while not treating the underlying disease; second, because some patients are at increased risk of asthma attacks despite having few symptoms; and third, because medication side-effects should be taken into account when deciding a patient's need for treatment," Dr. Reddel said.

Frequency of asthma exacerbations, repeated measures of pulmonary function, and treatment-related adverse effects were the most robust predictors of future risk.

"If a study is not long enough to measure these directly, the task force provided recommendations about surrogate markers such as sputum analysis or bronchial challenges which can predict the risk of these outcomes," Dr. Reddel said.

Because the many facets of asthma and asthma control are widely recognized, no single outcome measure is sufficient to evaluate asthma control. Outcome measures should reflect both main objectives of asthma treatment, namely optimizing clinical control while minimizing future risk for adverse outcomes.

However, the task force listed standardized endpoints for use in clinical trials, which were characterized as essential, desirable, and optional. All clinical trials attempting to study the effect of an intervention on asthma control should include and report the minimal or "essential" outcomes.

Robust outcome measures for current clinical control were symptom-free days, use of symptom relievers, pulmonary function, quality of life, and a validated composite score. Additional endpoints that could be considered included a daily diary, preferably electronic, of symptoms and exacerbations and a record of clinician and emergency department visits.

"In clinical practice, it is particularly important to measure lung function for the diagnosis of asthma, and also for assessment of patients whose asthma is troublesome either because they have a lot of symptoms despite treatment, or because they have few symptoms but a lot of severe attacks," Dr. Reddel said.

Evaluation of Asthma Control

The statement offers recommended strategies to evaluate asthma control in clinical trials and in clinical practice, both at baseline and in determining response to therapeutic interventions. These multicomponent evaluations can be used by clinicians, researchers, and others involved in designing, performing, and interpreting the findings of clinical trials, as well as by those in patient care settings. Detailed information is included regarding measurement and interpretation of each endpoint and the range of normal values.

The task force redefined asthma severity as the intensity of treatment required to achieve good asthma control. Severe asthma requires high-intensity treatment, whereas mild asthma can be well controlled with low-intensity treatment. Pathologic and physiologic markers may describe the underlying disease activity and the patient's phenotype, both of which may affect asthma severity.

"In the past, asthma severity was usually defined before a patient started asthma treatment, using measures which were almost identical to those used to assess asthma control," Dr. Reddel said. "This was very confusing, and it meant that asthma severity could not be re-assessed once treatment had started."

The statement now defines asthma exacerbations as events in which symptoms become sufficiently severe to mandate a change in therapy. The definition of severe asthma exacerbations to be used in clinical trials was standardized to refer to events requiring urgent treatment, such as systemic corticosteroids (tablets, suspension, or injection), or an increase from a stable maintenance dose, for at least 3 days. In clinical practice, an exacerbation could also be defined as a hospitalization or emergency department visit because of asthma, requiring systemic corticosteroids.

Advice for Clinicians

The task force recommended that clinicians routinely ask every patient with asthma simple questions regarding short- and long-term symptoms and management. These should cover the number of days with symptoms in the past 1 to 4 weeks; the number of days per week with symptoms; use of medication for symptom relief; symptoms causing nocturnal awakening; and the number of severe attacks in the past year, which may identify patients at risk for future severe exacerbations.

Future Research

The statement included suggestions for future research in the different areas highlighted. An important goal is identifying appropriate biomarkers and evaluating their role in determining appropriate treatment for some patient subgroups.

"More research is needed to understand more clearly how asthma control — and risks for asthma exacerbations — can be best assessed for the different types (ie, phenotypes) of asthma, which have different responses to therapy," said John Heffner, MD, past president of the ATS. "The task force identified that studies will need to characterize the clinical features of study patients during enrolment to 'type' their asthma and then note patterns of treatment responses for each type. With enough information, accurate type-specific measures to assess asthma control will emerge that will guide physicians in adjusting therapy for each phenotype."

Source : http://www.medscape.com/viewarticle/705033?sssdmh=dm1.492501&src=nldne

Acute Lung Injury

Introduction

Acute Lung Injury (ALI) is a distinct form of acute respiratory failure characterized by diffuse pulmonary infiltrates, progressive hypoxemia, reduced lung compliance and normal hydrostatic pressures.
In 1967 Ashbaugh and colleagues published a case series in the Lancet which described a clinical syndrome, which they (later) termed “Adult Respiratory Distress Syndrome” (ARDS). The 12 patients involved complained of acute respiratory distress, cyanosis refractory to oxygen therapy, decreased lung compliance and diffuse pulmonary infiltrates on chest x-ray.

Trauma doctors involved in treating victims of war had long been familiar with this syndrome, which came to be known as “wet lung”, “shock lung” or “Da-nang lung”. This problem had been identified during World War II but with the advent of advanced trauma (M.A.S.H. units during the Vietnam war) the prevalence of this form of respiratory failure was truly recognized.
Over the past 30 or so years, this syndrome has come to be one of the central problems of intensive care: lung injury arising from a variety of different etiologies, each characterized by bilateral diffuse infiltrates on x-ray, hypoxemia, and non-cardiogenic pulmonary edema.

Learning Objectives

• To understand the pathology and pathophysiology of ALI/ARDS
• To devise a ventilation strategy for these patients.To introduce the concept of ventilator induced lung injury
• To address adjunct and rescue therapy for patients with resistant hypoxemia.

The definition of the syndrome was clarified by a 1992 American-European Consensus Conference. The term “Acute Lung Injury” has been used as an umbrella term for hypoxemic respiratory failure, a severe version of which is “Acute Respiratory Distress Syndrome” (ARDS).

The characteristics follow:

• Bilateral pulmonary infiltrates on chest x-ray
• Pulmonary Capillary Wedge Pressure <18mmhg 300 =" ALI">
Although not strictly part of the definition, there is widespread airway collapse (low lung volumes), surfactant deficiency and reduced lung compliance.

Classic Chest X Ray of a patient with ARDS, although the lung injury appears diffuse, when you look at the CT scan of the same patient on the right you can see that the lower lobes are densely consolidated and the upper lobes relatively spared. Nevertheless, this patient was severely hypoxic, and responded well to prone positioning.

What causes it?
ALI is caused by any stimulus of local or systemic inflammation, principally sepsis.
ALI is most often seen as part of a systemic inflammatory process, particularly systemic sepsis, where the lung manifestations parallel those of other tissues – widespread destruction of the capillary endothelium, extravascation of protein rich fluid and interstitial edema.
In addition, the alveolar basement membrane is damaged, and fluid seeps into the airspaces, stiffening the lungs and causing ventilation-perfusion mismatch.
Other causes of ARDS are listed below, as you can see, this is a mixture of virtually every disorder seen in ICU.

There are two major stages :

1. The acute phase characterized by disruption of the alveolar-capillary interface, leakage of protein rich fluid into the interstitium and alveolar space and extensive release of cytokines and migration of neutrophils.
2. A later reparative phase is characterized by fibroproliferation, and organization of lung tissue

If resolution does not occur, disordered collagen deposition occurs leading to extensive lung scarring.The core pathology is disruption of the capillary-endothelial interface: this actually refers to two separate barriers – the endothelium and the basement membrane of the alveolus. In the acute phase of ALI, there is increased permeability of this barrier, and protein rich fluid leaks out of the capillaries.

There are two types of alveolar epithelial cells :

• Type 1 pneumocytes represent 90% of the cell volume, and are easily damaged.
• Type 2 pneumocytes are more resistant to damage, which is important as these cells produce surfactant, transport ions and proliferate and differentiate into Type 1 cells.

The damage to the endothelium and the alveolar epithelium results in the creation of an open interface between the lung and the blood, facilitating the spread of micro-organisms from the lung systemically, stoking up a systemic inflammatory response. Moreover, the injury to epithelial cells handicaps the lung’s ability to pump fluid out of airspaces. Fluid filled airspaces, loss of surfactant, microvascular thrombosis and disorganized repair (which leads to fibrosis) reduces resting lung volumes (decreased compliance), increasing ventilation-perfusion mismatch, right to left shunt and the work of breathing.

In addition, lymphatic drainage of lung units appears to be curtailed – stunned by the acute injury: this contributes to the build up of extravascular fluid.Some patients rapidly recover from acute lung injury, and have no permanent sequelae. Prolonged inflammation and destruction of pneumocytes leads to fibroblastic proliferation, hyaline membrane formation and lung fibrosis. This fibrosing alveolitis may become apparent as early as five days after the initial injury. Subsequent recovery may be characterized by reduced physiologic reserve, and increased susceptibility to further lung injuries.

Extensive microvascular thrombosis may lead to pulmonary hypertension, myocardial dysfunction and systemic hypotension.Finally, it is essential to understand that although ALI is a diffuse process, it is also a heterogeneous process, and not all lung units are affected equally: normal and diseased tissue may exist side-by-side.
The cornerstone of treatment is to keep the PaO2 >60mmHg, without causing injury to the lungs with excessive O2 or volutrauma.
Pressure control ventilation is more versatile than volume control, although breaths should be volume limited, to prevent stretch injury to the alveoli.

In general tidal volumes should not exceed 6ml/kg and plateau pressure should not exceed 30cmH2O. However tidal volumes of 4ml/kg should be delivered irrespective of airway pressure.
The management of patients with respiratory failure goes beyond ventilation strategies, we must have a holistic multisystem approach:
I like to remind residents of the ABCDEFG mnemonic.
A = Airway, establish an patient airway, intubate as necessary.
B = Breathing, commence mechanical ventilation and obtain an adequate minute volume to maintain oxygen delivery.
C = Circulation: blood pressure, pulse, intravascular volume – fluid
resuscitation and vasopressors as necessary
D = Diagnosis, find the underlying problem and control the source.
E = Empiric therapy, for example antimicrobials for sepsis
FG = Feed the Gut, to prevent villus atrophy and bacterial translocation

The principles of mechanical ventilation are simple:
1. Give enough oxygen to keep the PaO2 over 60mmHg preferably, and over 50mmHg at the very least.
2. Avoid volutrauma and barotrauma, by keeping the tidal volumes in the 4-6ml/kg range and the airway plateau pressure below 30 - 35cmH2O (the tidal volume should not be less than 4ml/kg, irrespective of airway pressure).

The PaO2 is a function of the FiO2, the PEEP level, the mean airway pressure and the minute ventilation. The tidal volume, depending on what mode of ventilation is used, is determined by the pressure control level (in pressure controlled modes) or the tidal volume dialed up on the ventilator (in volume controlled modes).There is no clear evidence that any particular mode or strategy improves outcome in ALI, except for controlling tidal volumes and airway pressures.

What follows is a suggested starting strategy:
1. Start with a high FiO2 (use the same FiO2 on the patient following intubation as before).
2. Set the CPAP/PEEP level – if the patient has a P/F ratio of 200-300 start with CPAP/PEEP of 5cmH2O, if the P/F ratio is <200.

It is important to note that ARDS is a disease of altered lung compliance. This is reduced due to the presence of large quantities of extravascular lung water. However, chest wall compliance may also be low - in patients who are edematous, have had massive fluid resuscitation or have abdominal hypertension. In this situation, the chamber in which the lungs are inflating (the chest), bears more resemblance to a brick wall than a rib cage with muscles. Higher inflation pressures are required to inflate the lungs in these circumstances and higher PEEP is required to maintain FRC.

The choice of mode of ventilation is institution specific. The majority of intensive care units in the United States continue to use volume controlled modes of ventilation to treat ARDS. Severe hypoxemia is managed by increasing mean airway pressure by escalating levels of PEEP and rapid respiratory rates. The logic behind increasing mean airway pressure is that much of the ventilation perfusion mismatch contributing to hypoxia occurs at end expiration (click here for more information). Although the majority cases can be managed in this way, more versatile modes are available, under the pressure control umbrella.

Pressure control modes have the advantage of allowing us manipulate the mean airway pressure by prolonging inspiration, and this may improve oxygenation without increasing peak or plateau pressures . In addition, pressure control may improve gas distribution at the end of inspiration, particularly where different lung units have different resistance patterns (ALI is, after all, a heterogeneous process).

The drawback of prolonging inspiration, and, in effect, inverting the I:E ratio (2;3), is that the patient may experience a lot of discomfort, and requires deep sedation. Further, incomplete expiration tends to reduce CO2 elimination, and the patient will develop “permissive hypercapnia” and respiratory acidosis. As we now know that ventilator induced lung injury causes much more trouble than respiratory acidosis, we do not consider the latter to be a major problem. Newer pressure control modes such as BiLevel / Airway Pressure Release ventilation have been developed to address the problem of patient discomfort in inverse ratio ventilation; with some success.

A number of adjunct therapies are available, none have proven effective. Prone positioning and inhaled nitric oxide are the most commonly used.It is uncertain what the lowest safe PaO2 is. Profound hypoxia will lead to death. In this situation it is necessary to oxygenate the patient at all costs – if this means increasing the FiO2, tidal volume or peak pressure, then so be it. Often neuromuscular blocking agents are required to improve patient-ventilator interaction, and increase chest wall compliance. It is my practice to assume mucus plugging and derecruitment until otherwise proven. The therapy involves aggressive suctioning with or without bronchoscopy, followed by recruitment maneuvers. There are many different methods of performing this: e.g. switch off the control breaths, and gradually increase the CPAP level to 10cmH2O above the peak airway pressure, and hold it there for 30 to 40 seconds. Multiple methods of lung recruitment have been described (1-3).
The efficacy and safety of recruitment maneuvers has not been established.Another method of improving oxygenation is to alter the alveolar gas content. This is achieved by washing carbon dioxide out of the anatomical dead space by insufflating oxygen at the level of the carina during expiration. When the next breath is delivered this dead space gas is the first to arrive into the alveoli. This process, tracheal gas insufflation (TGI) can be performed by placing a catheter at the level of the catheter and delivering a flow of gas. The catheter can be inside or outside the endotracheal tube (outside is better as it does not increase airways resistance). The problem with this technique is in the application: the easiest method is continuous gas flow at 2 to 5 liters per minute. Unfortunately, this will significantly increase end inspiratory volumes, even in pressure control ventilation. Care must be taken that the patient does not develop large amounts of auto-PEEP.

In addition, there are a number of unproven adjunct therapies available, which may, at least in the short term, improve oxygenation:

1. Turn the patient prone – this improves ventilation-perfusion matching, although the exact mechanism is unknown (4).

2. Administer inhaled nitric oxide – this is a local vasodilator, which dilates up the capillaries around the well-ventilated alveoli, potentially improving ventilation-perfusion matching(5;6). Due to the high cost of administering this agent, nebulized prostacyclin has been used as an alternative.
3. Add almitrine – which enhances hypoxic pulmonary vasoconstriction, and may reduce right to left shunt (7). This agent is not available in the USA; phenylephrine can be used instead.

4. High frequency oscillation – full tidal volume ventilation, with no cyclic opening and closing of lung units. Experience with this mode has been very good in pediatric and neonatal practice; there is little published data in adults.5. Tracheal gas insufflation - 2 or more litres of oxgen are delivered into the major bronchi in expiration to wash out dead space gas.

6. Partial liquid ventilation (PLV) with perfuocarbons, which carry oxygen. This very attractive proposition of “liquid PEEP” has been underutilized, due to lack of availability. The FRC is filled with the liquid, and the patient ventilated above it. PLV has the added advantage of lavaging the airways and removing cellular debris (7;8). Although of academic interest, this strategy is not currently available.

6. Extracorporeal membrane oxygenation: the patient is put on an extracorporeal circuit and oxygenated by a type of heart-lung bypass machine: there is little evidence of efficacy in adults (9).
Although none of these techniques have been shown to improve outcome, when a patient is severely hypoxemic many physicians feel that their backs are to the wall, and there is little alternative but to go down the road of adjunct therapy.

Current ventilation strategies involve using low tidal volumes with or without high levels of PEEP. The open lung approach attempts to optimize lung mechanics and minimize phasic damage by strategically placing PEEP above Pflex.Two modern approaches to ventilating patients with acute lung injury are the open lung approach and the low tidal volume approach. These are not mutually exclusive. The premise of both is that phasic opening and closing of injured lung units causes further injury to lung tissue and can worsen the lung injury. The low tidal volume approach involves minimizing the amount of phasic stretch of lung units in inspiration, to prevent ventilator induced lung injury. This technique has been proven to be effective: in a landmark NIH coordinated multicenter trial, patients ventilated with tidal volumes of 2-6ml/kg had a 22% reduction in mortality than patients ventilated with tidal volumes of 10-12ml/kg (1).
The open lung approach takes a slightly different tack: it is believed that reinflating collapsed lung units also causes lung injury and cytokine release. By stenting the airways open at end expiration, using PEEP, it may be possible to reduce these shearing injuries. There has been a preliminary trial by Amato and colleagues (2), demonstrating the efficacy of this technique.
This group painstakingly constructed pressure volume curves on each patient to determine “Pflex” (the lower inflection point on the pressure volume curve), and applied PEEP just above this level. The patients invariably receive a higher than conventional PEEP level, with lower tidal volumes.
Critics of this technique have suggested that plotting pressure volume curves is difficult, that Pflex often is impossible to find, and that overdistension of less diseased tissues may occur. As a consequence of this controversy, the NIH is currently performing the “Alveoli” trial, which randomizes patients into two groups, low and high PEEP in patients on low tidal volume strategies (the trial is now complete an the early indications is that there was no difference in outcomes with this approach). It is important to note that while Amato and most other "open lung" practitioners performed recruitment maneuvers (moderate to high pressures are applied to the airway intermittently to re-open collapsed alveoli), this was not a part of the Alveoli study.Above: Quasi Static volume pressure curve of an injured lung: the lungs are said to be most compliant between the lower inflection point of the curve and the upper inflection point, beyond which overdistension takes place.


The advantages of using pressure controlled ventilaton in acute lung injury (ALI):
1) Gas Distribution:
acute lung injury is a heterogeneous disease process. Lung units are affected differently by disease. Some are effectively normal, some have low compliance, some have normal compliance but long time constants. Others are not involved in gas exchange. In volume ventilation, gas is preferentially delivered to more compliant lung units, causing overdistension and poor mixing. In pressure control, there is better distribution of gas to these differing lung units.In the cartoon above, see, on the left side an injured lung segment: this contains normal alveoli (A1), non compliant alveoli (A2 e.g. consolidation) and alveoli with long time constants due, in this case, to proximal obstruction - such as a mucus plug or bronchial constriction. When a volume breath is delivered (with constant flow pattern) the gas passes down the path of least resistance into the most compliant alveoli - so there is relative overdistension of A1, A2 is inflated as expected, and A3 does not have time to inflate before the ventilator cycles off.In the second cartoon, a pressure controlled breath is delivered. In this case there is better distribution of gas - because A1 will not overdistend to the same extent as before, and there is sufficient time for A3 to inflate.
Gas Distribution the main reason for using pressure control ventilation (along with variable flow in the spontaneously breathing patient. The same effect can actually be achieved in volume control - using low peak flow rates, decelerating flow patterns and an inspiratory pause. However this requires a considerable amount of skill to apply than using pressure control. The major drawbacks of pressure control is changing tidal volume in relation to 1. changes in lung compliance, and 2. auto-PEEP.2) Control of mean airway pressure: it is possible to increase the mean airway pressure, by varying the inspiratory time, without increasing the peak or plateau pressure. This facilitates maintaining oxygenation within a pressure limit, without overstretching the alveoli. However, if the prolongation of inspiration causes auto-PEEP, this advantage is lost. The remedy is to reduce the respiratory rate initially, and then to reduce the I:E. This concept, inverse ratio ventilation, is a key part of the open lung approach to ARDS and is the basis of some modern pressure controlled modes - BiLEVEL/APRV.
Ventilator induced lung injury is caused by volutrauma and excessive use of oxygen.Ventilator induced lung injury occurs when the lung is directly damaged by the action of mechanical ventilation. It is not a new concept. Macroscopic injuries associated with the ventilation of patients with ARDS have been described for decades: pneumothorax, pneumomediastinum, pneumoperitoneum, associated with alveolar rupture from overdistension. The term historically applied to this situation was “barotrauma”. This word expressed the tendency towards alveolar overdistension when high inspiratory pressures are applied. However the paradigm has shifted somewhat in recent years away from pressure induced to volume induced lung injury – “volutrauma”. This term recognizes that alveolar overdistension is more likely to occur as a result of excessive volume, than excessive pressure.

There is a considerable body of animal evidence to support this claim. A number of researchers have demonstrated that applying the same airway pressure in a volume limited animal (their chests were bound to prevent expansion), causes considerably less lung damage than when volume is not limited. If the alveoli cannot overdistend, then they are unlikely to become damaged (1). Moreover, if normal lungs are exposed to tidal volumes of 10-15ml/kg, there is parenchymal inflammation, increased vascular permeability, accumulation of fluid in the lung and alveolar space and atelectasis. These findings are very similar to what is seen in ALI. So if high tidal volumes injure the lung, then in patients ventilated in this way with ALI, repair of the lungs will be slowed and resolution may not take place.

We know, empathically, that if you inflate a balloon excessively, it bursts. Alveoli will burst if excessive volumes inflate them. However, there is more to ventilator induced lung injury than just overdistension. It is believed that the phasic opening an closing of lung units causes release of cytokines and reinforcement and amplification of the local and systemic inflammatory response (2). Limiting the extent of volume expansion certainly curtails this, as may the prevention of phasic opening and closing of lung units – keeping the lungs open with PEEP. Undoubtedly, the best way to heal an injury is to rest it, and this is also true of the lungs(3). The less the lungs are forced to expand-collapse, the less likely a lung injury is. The ultimate question therefore is – should we be moving towards full tidal volume ventilation (i.e. the lungs are not permitted to deflate at all). This can be achieved using high frequency oscillation.

The other notable source of lung injury is, of course, oxygen. High FiO2 can cause lung injury by two effective mechanisms – the first is the formation of oxygen free radicals which are cytotoxic, the second is the problem of absorption atelectasis – as the FiO2 increases, the alveoli that are well ventilated rapidly empty of oxygen along the concentration gradient (into the blood), their volume falls and they are vulnerable to collapse. It was the obsession with controlling the FiO2 that led physicians to develop the high tidal volume strategies of the 1970s and 1980s, which we have since discovered cause lung injury in their own right. However, it appears that an FiO2 of greater than 50% should be considered toxic (4).

For patients with acute lung injury, the ventilation strategy is thus low tidal volumes with a relatively fast rate, with or without more generous PEEP has heretofore been given. For the patient who does not have ALI, there is little evidence that any particular ventilation strategy has any advantage. In all cases, keeping the FiO2 below 50% is appropriate where possible.
Steroids may have a role in chronic ARDS in patients, without infection, with high O2 requirements days to weeks into the disease process.Acute lung injury is an inflammatory disease. We know that circulating cytokines decline in survivors over the first week, and persist in non survivors (1). At this time, the disease appears to take on a life of it’s own, and begins to involve lobules previously unaffected, and cause fibroproliferation in already injured lung units. A series of studies utilizing glucocorticoids to prevent progression of inflammation in early ARDS have had very disappointing outcomes. Certainly immunosupression in the presence of infection can be expected to worsen outcomes. Conversely, there appears to be a small body of data supporting the use of steroids in the treatment of chronic persistent ARDS. Meduri and colleagues (2) have looked at the “single hit model” of persistent lung inflammation and postulated that ongoing inflammation due to host defense response was responsible for poor outcomes. Their study of 24 patients (it was originally powered for 100, but was cut short by the supervisory committee) demonstrated statistically significant improvement in outcomes, both in terms of lung injury scores and mortality figures. The results await confirmation by a multicenter trial, being conducted by the NIH-ARDS network.

Below is a protocol for steroids in late ARDS, based on the Meduri paper (2):The patient must have no demonstrable infection, broncho-alveolar lavage may be necessary to confirm this. This includes undrained abscesses, disseminated fungal infection and septic shock. Steroids should not be started less than 7 days, or more than 28 days, from admission. The patient should not have a history of gastric ulceration of active gastrointestinal bleeding. Patients with burns requiring skin grafting, pregnant patients, AIDS, and those in whom life support is expected to be withdrawn, are unsuitable. The patient should have evidence of ALI and require an FiO2 >/= 50% The steroid regimen:Loading dose 2mg/kg
Then 2mg/kg/day from day 1 to 14
Then 1mg/kg/day from day 15 to 21
Then 0.5mg/kg/day from day 22 to 28
Then 0.25mg/kg/day on days 29 and 30
Finally 0.125mg/kg on days 31 and 32.Patients should be meticulously screened for evidence of lower respiratory tract infection, by performing protected lavage every 3 to 4 days (while the patient is ventilated), and line sepsis (lines should be changed at regular intervals in immunosuppressed patients like this)

ALI is a diffuse heterogeneous lung injury characterized by hypoxemia, non cardiogenic pulmonary edema, low lung compliance and widespread capillary leakage. ALI is caused by any stimulus of local or systemic inflammation, principally sepsis.

Acute Lung Injury (ALI) & Acute Respiratory Distress Syndrome (ARDS) are defined as:Bilateral pulmonary infiltrates on chest x-ray Pulmonary Capillary Wedge Pressure <18mmhg 300 =" ALI" 200 =" ARDS.">60mmHg, without causing injury to the lungs with excessive O2 or volutrauma. Pressure control ventilation is more versatile than volume control: but a volume limited strategy should be used. A number of adjunct therapies are available, none have proven effective. Of these, inhaled nitric oxide and prone positioning are most frequently used. Current ventilation strategies involve using low tidal volumes with or without high levels of PEEP. The open lung approach attempts to optimize lung mechanics and minimize phasic damage by strategically placing PEEP above Pflex. Ventilator induced lung injury is caused by volutrauma and excessive use of oxygen. Steroids may have a role in chronic ARDS in patients, without infection, with high O2 requirements days to weeks into the disease process.

Source : http://www.ccmtutorials.com/rs/ali/

OXYGEN

Introduction

Aerobic metabolism is the most efficient and effective method of optimizing energy extraction from foodstuffs. Our sun provides the energy for plant metabolism, through photosynthesis, and plants provide oxygen for mammalian metabolism and consume the waste product of this process, carbon dioxide. Although humans utilize oxygen to break down sugars into carbon dioxide and water, anaerobic metabolism also occurs, but is much less efficient. Highly metabolically active tissues such as the brain, kidney, heart and gut require large amounts of chemical energy to maintain normal function: oxygen and glucose are the sources. It is the most frequently prescribed and misunderstood drug in our hospitals.

In this tutorial we will look at the process by which oxygen is extracted from the atmosphere and ultimately delivered to the mitochondria, how disease interferes with this process and how we, as physicians, can redress the balance.

Learning Objectives

• To understand the basic physiology of oxygen

• To understand the physiological basis of hypoxemia

• To explore methods of oxygen therapeutics.

What is the Oxygen Cascade?

• The oxygen cascade describes the process of declining oxygen tension from atmosphere to mitochondria.

The purpose of the cardio-respiratory system is to extract oxygen from the atmosphere and deliver it to the mitochondria of cells. Oxygen, being a gas, exerts a partial pressure, which is determined by the prevailing environmental pressure. At sea level, the atmospheric pressure is 760mmHg, and oxygen makes up 21% (20.094% to be exact) of inspired air: so oxygen exerts a partial pressure of 760 x 0.21 = 159mmHg. This is the starting point of the oxygen cascade, as one moves down through the body to the cell, oxygen is diluted down, extracted or otherwise lost, so that at cellular level the PO₂ may only be 3 or 4mmHg.

The first obstacle that oxygen encounters is water vapor, which humifies inspired air, and dilutes the amount of oxygen, by reducing the partial pressure by the saturated vapor pressure (47mmHg). This will, obviously, affect the PIO2 (the partial pressure of inspired oxygen), which is recalculated as: (760 - 47) x 0.2094 = 149mmHg.

Air consists of oxygen and nitrogen, but as gas moves into the alveoli, a third gas, carbon dioxide, is present. The alveolar carbon dioxide level, the PACO2, is usually the same as the PaCO2, which can be measured by a blood gas analyzer. The alveolar partial pressure of oxygen PAO2 can be calculated from the following equation: PAO2 = PIO2 – PaCO2/R. R is the respiratory quotient, which represents the amount of carbon dioxide excreted for the amount of oxygen utilized, and this in turn depends on the carbon content of food (carbohydrates high, fat low). For now let us assume that the respiratory quotient is 0.8, the PAO2 will then be 149 – (40/0.8) = 100mmHg (approx).

The next step is the movement of oxygen from alveolus to artery, and as you would expect, there is a significant gradient, usually 5 –10 mmHg, explained by small ventilation perfusion abnormalities, the diffusion gradient and physiologic shunt (from the bronchial arteries).

Oxygen is progressively extracted thru the capillary network, such that the partial pressure of oxygen in mixed venous blood, PVO2, is approx 47mmHg.

What is essential to understand about the oxygen cascade is that if there is any interference to the delivery of oxygen at any point in the cascade, significant injury can occur downstream. The most graphic example of this is ascension to altitude. At 19,000 feet (just above base camp at Mount Everest, the barometric pressure is half that at sea level, and thus, even though the FiO2 is 21%, the PIO2 is only 70mmHg, half that at sea level. Conversely, if the barometric pressure is increased, such as in hyperbaric chambers, the PIO2 will actually be higher.

Four factors influence transmission of oxygen from the alveoli to the capillaries 1. Ventilation perfusion mismatch, 2. Right to left shunt, 3. Diffusion defects, 4. Cardiac output.

The amount of oxygen in the bloodstream is determined by the oxygen carrying capacity, the serum hemoglobin level, the percentage of this hemoglobin saturated with oxygen, the cardiac output and the amount of oxygen dissolved (see below).

The PVO2 is determined by whole body oxygen demand, and the capacity of the tissues to extract oxygen. In sepsis there appears to be a fundamental abnormality of tissue oxygen extraction.

How much oxygen is in the blood?

• The amount of oxygen in the blood is calculated using the formula: [1.34 x Hb x (SaO2/100)] + 0.003 x PO2 = 20.8ml

Oxygen is carried in the blood in two forms: dissolved and bound to hemoglobin. Dissolved oxygen obeys Henry’s law – the amount of oxygen dissolved is proportional to the partial pressure. For each mmHg of PO₂ there is 0.003 ml O₂/dl (100ml of blood). If this was the only source of oxygen, then with a normal cardiac output of 5L/min, oxygen delivery would only be 15 ml/min. Tissue O₂ requirements at rest are somewhere in the region of 250ml/min, so this source, at normal atmospheric pressure, is inadequate.

Hemoglobin is the main carrier of oxygen. Each gram of hemoglobin can carry 1.34ml of oxygen. This means that with a hemoglobin concentration of 15g/dl, the O2 content is approximately 20ml/100ml. With a normal cardiac output of 5l/min, the delivery of oxygen to the tissues at rest is approximately 1000 ml/min: a huge physiologic reserve.

Hemoglobin has 4 binding sites for oxygen, and if all of these in each hemoglobin molecule were to be occupied, then the oxygen capacity would be filled or saturated. This is rarely the case: under normal conditions, the hemoglobin is 97% to 98% saturated. The amount of oxygen in the blood is thus related to the oxygen saturation of hemoglobin.

Taking all of these factors into account, we can calculate the oxygen content of blood where the PO2 is 100mmHg, and the hemoglobin concentration is 15g/L:

[1.34 x Hb x (saturation/100)] + 0.003 x PO2 = 20.8ml

As one would expect, this figure changes mostly with the hemoglobin concentration: when the patient is anemic the oxygen content falls, when polycytemic, it rises. In either case the O2 saturation of hemoglobin may be 97 – 100%, but there may be a large discrepancy in content.

How much oxygen is delivered to the tissues per minute?

• The delivery of oxygen to the tissues per minute is calculated from: DO2 = [1.39 x Hb x SaO₂ + (0.003 x PaO₂)] x Q

The following is the single most commonly quoted equation in critical care, and it’s worth remembering:

DO2 = [1.39 x Hb x SaO₂ + (0.003 x PaO₂)] x Q

The Delivery of oxygen (DO₂) to the tissues is determined by:

The amount of oxygen in the blood: the oxygen binding capacity of haemoglobin x the concentration of haemoglobin x the saturation of haemoglobin + the amount of dissolved oxygen all Multiplied by the Cardiac Output (Q).

The cardiac output is determined by preload, afterload and contractility.

The hemoglobin concentration is determined by production, destruction and loss.

The SaO₂ (the saturation of haemoglobin at arterial level with oxygen - as opposed to the SpO₂ which is measured by pulse oximetery) is determined by:

The oxygen saturation curve: which equates PaO₂ (arterial oxygen tension) against SaO₂.

So if a patient has a hemoglobin of 15g/l, a cardiac output of 5L, a PaO2 of 100 and a SaO₂ of 100%, what is his oxygen delivery?

DO2 = [1.39 x 15 x 100 + (0.003 x PaO₂)] x Q = 1000 ml

How much oxygen is extracted per minute?

• Tissue oxygen extraction is calculated by subtracting mixed venous oxygen content from arterial oxygen content.

The Fick equation is used to calculate the VO₂, the oxygen consumption. This is computed by figuring out how much oxygen has been lost between the arterial side and the venous side of the circulation and multiplying the result by the cardiac output. In the following equation, VO₂ is the oxygen consumption per minute, CaO₂ is the content of oxygen in arterial blood, and CvO₂ is the content of oxygen in venous blood:

VO2 = Q x (CaO₂-CvO₂) mlO₂/min

The CnO₂ is (1.34 x Hb x SnO₂/100) + 0.003 x PnO₂, where n = a or v

The major difference between the two is obviously the hemoglobin saturation, which is roughly 100% on the arterial side and 75% on the venous side.

Substituting inwards, where hemoglobin is 15g/dl: CaO₂ is approx 20ml/100ml, CvO₂ is 15ml/100ml: the difference is 5ml/100ml = 50 ml/l multiplied by a cardiac output of 5L = O2 consumption per minute is 250ml.

So the mixed venous O₂ saturation can be used to calculate the oxygen consumption: if SvO₂ is decreasing, the O₂ consumption is increasing.

What is the oxyhemoglobin dissociation curve and why is it important?

• The Oxyhemoglobin dissociation curve describes the non-linear tendency for oxygen to bind to hemoglobin: below a SaO₂ of 90%, small differences in hemoglobin saturation reflect large changes in PaO₂

The oxyhemoglobin dissociation curve mathematically equates the percentage saturation of hemoglobin to the partial pressure of oxygen in the blood. The strange sigmoid shape of the curve relates to peculiar properties of the hemoglobin molecule itself:

Hemoglobin and oxygen act a little like parents and children. When all are living at home (i.e. hemoglobin is fully saturated) then the parents don’t want any to leave: but once one has flown the nest (i.e. dissociated from hemoglobin) – parents find it progressively easier to let go. What this means that the conformation of the hemoglobin molecule depends on the number of molecules bound: as one molecule of oxygen becomes unbound, the affinity for the others falls [and vice-versa]. This is represented by the oxyhemoglobin dissociation curve.

The lack of linearity of the curve makes interpretation of the oxygen content of blood difficult. At higher saturation levels, above 90%, the curve is flat, but below this level the PaO₂ declines sharply, such that at 75% saturation the PaO₂ is about 47mmHg (mixed venous blood), at 50% saturation the PaO₂ is 26.6mmHg, and at 25% saturation the PaO₂ is a miserable 15mmHg.

The oxyhemoglobin dissociation curve

The position of this curve may shift rightwards (lower saturation for given PaO₂) or leftwards (higher saturation for a given PaO₂). Certain circumstances make the blood more likely to dump oxygen into the tissues, and others make it more likely to cling on to oxygen. Active muscle needs more oxygen, so heat, exercise, acidosis, hypercarbia and increased 2,3-DPG all cause a shift in the curve rightwards – releasing oxygen. Conversely, when activity is minimal – such as in cold weather or during rest, when the tissues are cold, alkalotic, hypocarbic and low 2,3-DPG, then hemoglobin holds onto oxygen. The curve also shifts leftwards in carbon monoxide poisoning.

The oxygen dissociation curve is an essential component in understanding critical care medicine. Everything we do is about optimizing the delivery of blood to the tissues as a means of maintaining homeostasis and promoting healing, and in the end it is the oxygen content of blood that is more important than the partial pressure of oxygen (which we commonly measure). The oxygen content relates specifically to the amount of hemoglobin present and how saturated it is. A reduction in the hemoglobin concentration from 15 to 10g/dl reduces the arterial oxygen content (CaO₂) by as much as a reduction in PaO₂ from 100mmHg to 40mmHg. Moreover a small drop in SaO₂ may represent a large drop in PaO₂, due to the shape of the oxyhemoglobin dissociation curve: when hemoglobin is 50% saturated the PaO₂ is 28mmHg, at 75% the PaO2 is about 40mmHg (mixed venous blood).

Although many pages of critical care textbooks are often devoted to discussions about oxygen delivery, there is no clear indication what the optimal hemoglobin actually is. We know from the TRICC (transfusion requirements in critical care) study (1) that transfusing patients with blood above a hemoglobin of 7.0g is probably harmful. This probably relates to problems associated with the actual process of storing and transfusing products, than the effect of a “normal” hemoglobin itself. The availability of therapeutic erythropoietin has allowed intensivists induce red cell production, and replace blood mass without external transfusion.

In any case, there is a large physiologic reserve between oxygen delivery and oxygen consumption. The cardiac output is probably a bigger player in the delivery of O₂ to the tissues that the O₂ content. This is because the cardiac output can almost instantaneously respond to a fall in PaO₂ saturation of Hb. Moderate hypoxemia leads to an increase in the cardiac output and a reduction in peripheral vascular resistance. On the other hand, compensation for a fall in cardiac output is slow and weak – that is because it takes time to increase Hb production and the oxyhemoglobin dissociation curve is flat – it can’t become anymore saturated. Nevertheless, in the clinical setting, it is often easier to increase the Hb or the FiO₂ than to increase the cardiac output

Reference

(1) Hebert PC. Transfusion requirements in critical care (TRICC): a multicentre, randomized, controlled clinical study. Transfusion Requirements in Critical Care Investigators and the Canadian Critical care Trials Group. Br J Anaesth 1998; 81 Suppl 1:25-33.

What problems are associated with right to left shunting?

• Right to left shunting causes hypoxemia resistant to oxygen therapy.

When blood passes through the lungs without coming in contact with air, a right to left shunt exists. This deoxygenated blood mixes with well oxygenated blood on the far side of the lung, and reduces the percentage saturation of hemoglobin. In all individuals a small physiologic shunt is present, principally arising from blood in the bronchial circulation. This has little effect on blood oxygen content. Larger shunts may cause significant problems, however. The reason for this is the curious shape of the oxyhemoglobin dissociation curve, as you can see from the diagram below:

The effect of shunt on the oxyhemoglobin dissociation curve

The addition of mixed venous blood, slides the patient down the curve to the steep slope, where severe hypoxemia may result. Shunt classically does not respond to oxygen, although the administration of 100% oxygen may increase the dissolved oxygen content and increase the mixed venous oxygen saturation. The higher the SVO₂, the less damaging a shunt is. The PaCO₂ is usually normal, as the patient increases minute ventilation to blow off CO₂ derived from the shunt, due to activation of chemoreceptors.

The shunt equation is used to calculate the magnitude of a shunt:

Qs/Qt = CcO₂ – CaO₂/CcO₂ – CvO₂ where CcO₂ is the capillary oxygen content in the ideal capillary, CaO₂ is the arterial oxygen content, and CvO₂ is the mixed venous oxygen content. The content is calculated by using the equation discussed above: CnO₂ is (1.34 x Hb x SnO2/100) + 0.003 x PnO₂, where n = a or v or c. The PO₂ is derived from the alveolar gas equation.

As one would expect, the greater the magnitude of the shunt, the larger the PAO₂ – PaO₂ difference.

A 17 year old male presents to the emergency room after being stabbed in the chest, on chest x-ray his right lung was fully collapsed, and yet his SpO2 was 94% on room air - why?

What is hypoxic pulmonary vasoconstriction?

• Hypoxic Pulmonary Vasoconstriction is a physiologic protective mechanism which prevents right to left shunting of blood.

• Right to left shunt causes hypoxemia unresponsive to oxygen therapy

One would expect that this patient would have a 50% shunt due to perfusion but no ventilation of the right lung; this does not happen. Hypoxic pulmonary vasoconstriction (HPV) takes place. Many of the tissues in the body are capable of regulating their own blood flow – the heart, the kidney, the brain and the gut all autoregulate blood flow. It appears that HVP is a similar mechanism within the lung, to prevent right to left intrapulmonary shunting, and thus the presence of deoxygenated blood in the peripheral circulation. This process is most florid in utero, when blood is diverted away from the lungs through the ductus arteriosis, due to high pulmonary arterial pressures. We know that pulmonary smooth muscle cells are extremely sensitive to alveolar oxygen tensions, but the mechanism of vasoconstriction is unknown. HPV is probably multifactorial in origin and modulated by a variety of endothelium dependent factors (nitric oxide, endothelin, prostacyclin etc).

Certain pharmacological interventions and disease processes interfere with HPV: general anesthesia with volatile agents such as isoflurane, and the use of systemic vasodilators such as sodium nitroprusside and prostacyclin, reverse HPV and may cause ventilation-perfusion mismatch. Acute lung injuries and, in particular, lung contusions, may have a similar effect. The result is ventilation-perfusion mismatch and possible right to left shunting of deoxygenated blood. The treatment is recruitment of collapsed alveoli using continuous positive airway pressure (CPAP), and positioning the patient away from the injury side (good side down, always).

What are the effects of diffusion defects and ventilation-perfusion mismatches on arterial oxygenation?

• Diffusion defects and ventilation perfusion mismatches cause hypoxemia, responsive to exogenous oxygen and positive pressure ventilation.

Oxygen diffuses from the alveoli to the pulmonary capillaries along a partial pressure gradient – there is less oxygen in the blood, the higher the inspired concentration of oxygen, the more rapidly the gases diffuse. For most individuals, an equilibrium position occurs early in inspiration, when the arterial blood becomes fully saturated with oxygen, and the rate of uptake of oxygen depends on capillary blood flow.

The diffusion capacity depends on the thickness of the alveolar wall, the area available for gas exchange and the partial pressure difference between the two sides. If the thickness of the wall increases – such as in pulmonary fibrosis, chronically, or pulmonary edema, acutely, the diffusion capacity is lower. Moreover, with increasing heart rate, the time for equilibration may be shorted, and the patient may become hypoxemic. The treatment is to increase the partial pressure gradient for oxygen by administering exogenous oxygen to the patient. If the patient has pulmonary edema, the surface area may be increased by increasing the transalveolar pressure (and marginalizing fluid), through administration of continuous positive airway pressure (CPAP).

Ventilation perfusion mismatch occurs along a spectrum: on one end alveoli are ventilated but not perfused (pure dead space ventilation), and on the other end alveoli are perfused but not ventilated (pure shunt). The best ventilation perfusion (V/Q) ratios occur in dependent regions of the lung, due to the preferential effect of gravity on both ventilation and perfusion. The non dependent regions are relatively better ventilated than perfused (alveolar dead space). Extensive ventilation perfusion mismatch occurs due to lung injuries, whether due to consolidation (filling alveoli with exudates), perioperative atelectasis, or “acute lung injury” where there is alveolar edema and capillary microthrombosis. Hypoxemia due to ventilation-perfusion mismatch can usually be reversed with application of supplemental oxygen. Where there is extensive atelectasis due to gas absorption (see below) or mucus plugging, the treatment is oxygen, bronchial toilet and perhaps CPAP, to recruit collapsed airways. Stiff lungs (low compliance) may induce an overwhelming workload to breathing, and additional inspiratory support may be required to reduce workload and improve V/Q matching.

What is “absorption atelectasis”?

• Absorption atelectasis refers to the tendency for airways to collapse if proximally obstructed. Alveolar gases are reabsorbed; this process is accelerated by nitrogen washout techniques.

Oxygen shares alveolar space with other gases, principally Nitrogen. Nitrogen is poorly soluble in plasma, and thus remains in high concentration in alveolar gas. If the proximal airways are obstructed, for example by mucus plugs, the gases in the alveoli gradually empty into the blood along the concentration gradient, and are not replenished: the alveoli collapse, a process known as atelectasis. This is limited by the sluggish diffusion of Nitrogen. If nitrogen is replaced by another gas, that is if it is actively “washed out” of the lung by either breathing high concentrations of oxygen, or combining oxygen with more soluble nitrous oxide in anesthesia, the process of absorption atelectasis is accelerated. It is important to realize that alveoli in dependent regions, with low V/Q ratios, are particularly vulnerable to collapse.

What is pathological supply dependence on oxygen?

The mixed venous oxygen saturation is a measurement of oxygen consumption, made using a pulmonary artery catheter (the measurements are made from the pulmonary artery, and are thus accurate). The SvO₂ (mixed venous oxygen saturation) is proportional to SaO₂ – VO₂/Q x Hb (VO₂ is the venous oxygen content).

This diagram describes oxygen delivery (DO2) and consumption (VO2) in normal and pathological states.

We know that we can go from being completely sedentary to taking high impact exercise without developing tissue hypoxia. This is because we have a physiologic reserve. Under normal conditions, during exercise, if oxygen demand is increased, supply is increased also – by increasing minute ventilation and cardiac output. But what happens if, for example, oxygen delivery starts to fall off (e.g. in a patient who has progressively worsening respiratory or cardiovascular function)? What actually happens, in normal people, is that we compensate for this lower O₂ delivery by making use of our physiologic reserve, we redistribute blood preferentially to the tissues that need them and the amount of oxygen extracted (extraction ratio) increases. Eventually reserve runs out and a critical point (point A on the diagram above) is reached: there just isn’t enough O₂ to match supply, and anaerobic glycolysis takes place.

This is known as “physiological dependence of VO₂ on DO₂”, and can be measured by an increase in arterial lactate concentration.

This plateau in VO₂ is maintained by increasing the extraction ratio for oxygen (O₂ER). Blood flow is redistributed to match local demand for oxygen. The meditors for this process are multiple, the most important of which are the autonomic nervous system and nitric oxide. The critical O₂ER is the point where anaerobic glycolysis takes place. The critical DO₂ in health is about 7 to 10ml/kg/min.

In pathological circumstances, such as systemic sepsis, this whole protective system falls apart: in diseases that affect the microcirculation, there is a loss of O₂ extraction capacity. There is a school of thought that believes that DO₂ needs to be maintained at a higher level that in health, as the tissues are less able to efficiently extract O₂ (1;2). There is a higher critical DO₂ (to 12ml/kg/min) and pathological dependence of VO₂ on DO₂. A hypothesis was formed that by increasing the DO₂ (supernormalization) by increasing cardiac output and oxygen carriage in sepsis, then oxygen extraction would improve. Randomized controlled trials have been disappointing. We now believe that the inability to extract oxygen occurs on the demand side, due to microcirculatory abnormalities, rather that overall oxygen delivery.

References

(1) Appel PL, Shoemaker WC. Relationship of oxygen consumption and oxygen delivery in surgical patients with ARDS. Chest 1992; 102(3):906-911.

(2) Shoemaker WC, Appel PL, Kram HB. Role of oxygen debt in the development of organ failure sepsis, and death in high-risk surgical patients. Chest 1992; 102(1):208-215.

How much oxygen do I give?

• The objective of oxygen therapy is to give the patient as much oxygen as is required to return the PaO2 to what is normal for the particular patient.

There is no secret to this – you give as much oxygen as is required to return the PaO₂ to what is normal for the particular patient. You perform a therapeutic maneuver – giving Oxygen, and you measure the result, by performing serial blood gases. There is nothing to be gained by giving too much oxygen, and a huge amount to be lost by not giving enough.

The initial inspired concentration of oxygen depends on the clinical circumstances – if the patient is only mildly hypoxemic, saturating in the late 80s, then small amounts of supplemental oxygen given by nasal cannulae are all that is necessary. However, if the patient is in-extremis, then always start with 100% (or thereabouts) and work downwards.

Shouldn’t I be careful about the amount of oxygen that I give COPD patients?

There is a universal misnomer that if you give too much oxygen to patients with COPD that they stop breathing, and hence medical and nursing students are often taught that COPD patients should not be given more than 28% oxygen because their respiratory drive is oxygen dependent (due to chronic CO₂ retention) and they will lose their stimulus to breath. Physicians will cite rising CO₂ levels in patients treated with oxygen as evidence of this.

There is a fundamental flaw in this theory: throughout this tutorial we have discussed the mechanisms by which oxygen is prevented from entering the blood. It is the blood oxygen content that is important, not the inspired fraction. Patients, depending on the extent of disease, will have differing extents of ventilation-perfusion mismatch and diffusion defects: the patient needs enough inspired oxygen to return the PaO₂ to what is normal for them, and the way to establish this is by starting high and working downwards with serial blood gases.

We know that high CO₂ levels are well tolerated by the body, but hypoxia is not: withholding oxygen therapy for fear of hypercarbia is negligent. It is not clear that such hypercarbia results, in any case, from hypoventilation: a number of studies (1;2) have demonstrated that the increase in PaCO₂ after administration of oxygen is due mainly to an increase in the ratio of dead space to tidal volume (Vd/Vt). This is probably due to reversal of hypoxic pulmonary vasoconstriction. Moreover, the increase in oxygenated hemoglobin leads to an increase in CO₂ release by way of the Haldane effect.

References

(1) Crossley DJ, McGuire GP, Barrow PM, Houston PL. Influence of inspired oxygen concentration on deadspace, respiratory drive, and PaCO2 in intubated patients with chronic obstructive pulmonary disease. Crit Care Med 1997; 25(9):1522-1526.

(2) Sassoon CS, Hassell KT, Mahutte CK. Hyperoxic-induced hypercapnia in stable chronic obstructive pulmonary disease. Am Rev Respir Dis 1987; 135(4):907-911.

How do I administer Oxygen?

• Oxygen is given thru fixed and variable performance devices.

• Fixed performance devices deliver a flow of oxygen equal to or in excess of peak inspiratory flow

• Variable performance devices use the deadspace of the nasopharynx or face masks as a reservoir of oxygen. They cannot deliver high inspired concentrations of oxygen.

Oxygen can be delivered to the upper airway by a variety of devices, in this section we will address only the non invasive methods. There are two types of devices – variable performance devices and fixed perfomance devices. The differentiation is based on the difference between the delivered concentration of oxygen FDO₂ and the actual inspired concentration FiO₂. Performance is based on matching the flow rate of gas leaving the device with the inspiratory flow rate entering the patient.

Take a deep breath in: you have probably just inspired 1 liter of air in about 1 second. Your inspiratory flow rate is thus approximately 60 liters per minute during this deep breath. Every breath you take varies in depth and volume, but if you were in respiratory failure you may well require flow rates of this magnitude (or more). To be guaranteed a FiO₂ appropriate to your flow demand, a fixed performance flow-generating device must be placed at your airway with a flow rate of 60 or so liters of oxygen-air (mixed as required) to satisfy demand. To be a fixed performance device, the gas flow must exceed the patient’s peak inspiratory flow. Machines with this type of performance are expensive, and are usually only located in intensive care or high dependency units. Moreover, not all patients requiring supplemental oxygen require facemasks, which are unpleasant to wear.

Variable performance devices fit into two categories, nasal cannula and facemasks. The premise behind nasal cannula is to use the dead space of the nasopharynx as a reservoir for oxygen. When the patient inspires, entrained air mixes with the reservoir air and the inspired gas is enriched. Obviously, the FIO₂ depends on the magnitude of flow of oxygen, the patient’s minute ventilation and peak flow. For most patients, each addition 1litre per minute of O₂ flow with nasal cannula represents an increase in the FIO₂ by 4%. So 1 liter is 24%, 2 liters is 28% and so on. At 6 liters (44%), it is not possible to raise the FIO₂ further, due to turbulence, in the tubing and in the airway.

There are a couple of problems with nasal cannula: if they are not positioned at the nares, they are useless. Disorientated patients appear to be remarkably successful at dislodging cannula. Secondly, the effectiveness may be disrupted by the pattern of breathing: there appears to be little difference whether the patient is a mouth or a nose breather, but it is preferable if the patient exhales through his/her mouth rather than nose, so the reservoir is maintained.

The big advantage of nasal cannula is comfort for the patient – they can eat and speak easily while receiving oxygen.

Standard oxygen masks provide a reservoir for oxygen, but the FIO₂ is difficult to calculate unless calibrated Venturi devices are attached. With Venturis, there are slits in the oxygen delivery system which become smaller or larger depending whether a high or low FIO₂ is required. The rate of delivery of oxygen is calibrated for the size of the Venturi and amount of mixing therein. For example, a 60% oxygen Venturi requires 15L/min fresh gas flow. Standard masks struggle to provide an FIO₂ of greater than 60%. A non rebreather reservoir bag can be attached to the facemask, to provide a larger reservoir (the bag fills when the patient is not actively inspiring), the two liter capacity should, in theory at least, allow the patient to inspire 100% oxygen.

What is Hyperbaric Oxygen therapy?

• Hyperbaric oxygen therapy is used to increase the amount of oxygen dissolved in the plasma, by increasing the ambient pressure.

At normal atmospheric pressure, the amount of oxygen dissolved in the blood is so low, that we don’t even bother to quantify it. However, increasing the environmental pressure, using a hyperbaric chamber, increases the solubility of oxygen in the blood. If 100% oxygen is inspired at 3 atmospheres, the inspired PO₂ is over 2000mmHg, and this should increase the volume of oxygen in solution in the blood to approximately 6ml/100ml of blood. The normal A-V oxygen difference is 5ml/100ml. Increases in tissue oxygen tensions, however, vary widely – depending on local perfusion and metabolic conditions. The high pressure increases the solubility of other gases, principally nitrogen, which can come out of solution in rapid diving ascents (the bends) and embolize to tissues; a similar problem can occur with air embolism. Hyperbaric treatment reduces bubble size and improves oxygen delivery to tissues. In addition, anerobic bacteria which infect poorly perfused tissue should be terminally sensitive to increased tissue oxygen concentration, and hyperbaric oxygen (HBO) treatment is thus potentially bactericidal to clostridial and other anerobic species.

Diseases for which hyperbaric oxygen therapy is indicated (1):

• Arterial gas embolism

• Decompression sickness (the bends)

• Severe carbon monoxide poisoning

• Osteoradionecrosis

• Clostridial myonecrosis

References

(1) Moon RE, Camporesi EM. Hyperbaric oxygen therapy: from the nineteenth to the twenty-first century. Respir Care Clin N Am 1999; 5(1):1-5.

What is Carbon Monoxide Poisoning?

• Carbon monoxide causes tissue ischemia by avidly binding to hemoglobin and displacing oxygen. The treatment is 100% oxygen, and possibly HBO therapy.

Carbon monoxide (CO) binds to hemoglobin approximately 200 times more avidly than oxygen. This results in impaired oxygen transport and utilization (the oxyhemogloblin dissociation curve shifts leftwards). Conventional pulse oximetery overestimates the true saturation of hemoglobin with oxygen, and, in addition to reduced oxygen delivery to tissues, CO binds to cellular proteins and causes tissue hypoxemia.

Carbon monoxide poisoning causes cell and tissue ischemia, and can prove fatal. It has been established that breathing 100% oxygen considerably reduces the half time of COHb (carboxyhemoglobin) binding. If oxygen is delivered in a hyperbaric environment, this half time is reduced further (1). In patients with moderate to severe CO poisoning, hyperbaric oxygen may reduce late neurological sequelae as compared to normobaric oxygen (2). Although there is no compelling data to support the use of HBO in this group of patients, if facilities are available HBO should be strongly considered if the COHb is greater than 25%, there is a history of neurological impairment or the patient has evidence of cardiac abnormalities (ischemia, arrhythmias etc) (3).

References

(1) Moon RE, DeLong E. Hyperbaric oxygen for carbon monoxide poisoning. Med J Aust 1999; 170(5):197-199.

(2) Thom SR, Taber RL, Mendiguren II, Clark JM, Hardy KR, Fisher AB. Delayed neuropsychologic sequelae after carbon monoxide poisoning: prevention by treatment with hyperbaric oxygen. Ann Emerg Med 1995; 25(4):474-480.

(3) Piantadosi CA. The role of hyperbaric oxygen in carbon monoxide, cyanide and sulfide intoxication. Probl Respir Care 1991; 4:215-231.

Why is Oxygen considered toxic?

• High inspired oxygen concentrations cause toxicity by causing formation of oxygen free radicals (which damage tissues), and by causing absorption atelectasis and V/Q mismatch.

The issue of oxygen toxicity has been topical for a generation, following the discovery that therapeutic oxygen causes blindness in premature babies (retrolental fibroplasias) with respiratory distress syndrome. In addition, it has been established that high inspired concentrations of oxygen may cause acute lung injury, probably due to oxygen free radical production – superoxide, hydroxyl, hydrogen peroxide and singlet O₂ molecules. These agents damage biomolecules such as membrane lipids, enzymes and nucleic acids. The extent of injury appears to depend on 1. The FiO₂, 2. The duration of exposure, 3. The barometric pressure under which exposure occurred. It appears that the critical FiO2 for toxicity is around 50% (1), above which lung recruitment maneuvers should be condidered (CPAP).

High concentrations of inspired oxygen may cause absorption atelectasis. In addition high FiO₂ may cause increased peripheral vascular resistance in congestive heart failure leading to reduced cardiac output.

How much oxygen is safe is a moot point. It is more important that you do not withhold life saving oxygen therapy than to be concerned about oxygen toxicity. It is, nonetheless, important that FiO₂ is minimized to normalization of blood gas in intensive care patients: i.e. there is little to be gained in having a PaO₂ of greater than 100mmHg. Often elevated oxygen requirements can be compensated for by appropriate patient positioning and increasing mean airway pressures to improve matching of ventilation and perfusion.

References

(1) Register SD, Downs JB, Stock MC, Kirby RR. Is 50% oxygen harmful? Crit Care Med 1987; 15(6):598-601.

How do Pulse Oximeters work?

• Pulse oximeters measure the absorption of red and infrared light by pulsatile blood. They are inexpensive, continuous and portable. Accuracy declines below a SpO₂ of 90%.

Oxygenated blood absorbs light at 660nm (red light), whereas deoxygenated blood absorbs light preferentially at 940nm (infra-red). Pulse oximeters consist of two light emitting diodes, at 600nm and 940nm, and two light collecting sensors, which measure the amount of red and infra-red light emerging from tissues traversed by the light rays. The relative absorption of light by oxyhemoglobin (HbO) and deoxyhemoglobin is processed by the device and an oxygen saturation level is reported. The device directs its attention at pulsatile arterial blood and ignores local noise from the tissues. The result is a continuous qualitative measurement of the patients oxyhemoglobin status. Oximeters deliver data about pulse rate, oxygen saturation (SpO₂) and even cardiac output. They are, however, far from perfect monitors.

The use of pulse oximeters is limited by a number of factors: they are set up to measure oxygenated and deoxygenated haemoglobin, but no provision is made for measurement error in the presence of dyshemoglobin moieties – such as carboxyhemoglobin (COHb) and methemoglobinemia. COHb absorbs red light as well as HbO, and saturation levels are grossly over-represented. Arterial gas analysis or use of co-oximetery is essential in this situation. Co-oximeters measure reduced haemoglobin, HbO, COHb and methemoglobin. Abnormal movement, such as occurs with agitated patients, will cause interference with SpO₂ measurement. Low blood flow, hypotension, vasoconstriction and hypothermia will reduce the pulsatility of capillary blood, and the pulse-oximeter will under-read or not read at all. Conversely, increased venous pulsation, such as occurs with tricuspid regurgitation, may be misread by the pulse-oximeter as arterial blood, with a low resultant reading. Finally, it is generally accepted that the percentage saturation is unreliably reported on the steep part of the oxyhemoglobin dissociation curve. While the trend between the SaO₂ (arterial saturation) and SpO₂ appears accurate, the correlation between the two numbers is not. Thus a drop in the SpO₂ below 90% must be considered a significant clinical event.

In spite of these limitations, the pulse oximeter has emerged as the de-facto monitoring device in the operating room, patient transport and intensive care.

Clinical Scenario 1

An 18 year old male is brought to the recovery room following an appendectomy. He has just been extubated. He is awake and breathing normally, but his SpO₂ is 88%. You administer 60% oxygen, and after a few moments his SpO₂ increases to 99%.

What has just happened?

This is a process known as diffusion hypoxia, which is not uncommon after anesthesia with nitrous oxide. This agent is floods back into the alveoli from the blood at termination of anesthesia, along the concentration gradient, and displaces oxygen. As the partial pressure of oxygen in the alveoli has fallen, so too has the tension of oxygen in the blood. The treatment is to increase the FiO₂, which, according to the alveolar gas equation, will increase the PAO₂. Patients who hypoventilate, such as those given opioids, have increased alveolar levels of CO₂ and may require supplemental oxygen.

Scenario 2

A 59 year old female undergoes abdominal surgery. She is extubated and returned from the recovery room to the floor. She becomes moderately short of breath three hours later. The nurse applies a pulse-oximeter. Her SpO₂ is 89%. She treats the patient with 40% oxygen and calls you. When you arrive, the patient’s SpO₂ is 94%.

What is the cause of this patient’s hypoxemia and what is your plan of management?

This patient has atelectasis, presumably in the dependent regions of her lungs, as a result of anesthesia and surgery. This is manifesting itself as ventilation-perfusion abnormalities. The treatment is supplemental oxygen, chest physical therapy, and mobilization.

Scenario 3

You are called to the emergency room (ER). A 62 year old male with a history of chronic bronchitis has been admitted with a lower respiratory tract infection. The ER resident is requesting admission to intensive care for mechanical ventilation. On examination, the patient is tachypneic and cyanosed. His blood gas is pH 7.34, PCO₂ 54, PO₂ 45, HCO₃ 30, BE-2.

You request a piece of information, perform a therapeutic maneuver and 30 minutes later the patient’s blood gas is: pH 7.32 pCO₂ 60 PO₂ 55 HCO₃ 31 BE 0. The nurse wishes to reduce the FiO₂.

What information did you look for? What therapeutic maneuver did you perform, and what do you plan to do about the last blood gas?

What you were interested in was the patient’s baseline blood gas (from a previous admission): it was pH 7.38 PCO₂ 55 PO₂ 55 HCO₃ 32. The patient is hypoxemic at baseline, and retains CO₂.

You increased the FiO₂ to 40%, and have returned the PaO₂ to baseline for this patient.

The nurses concern about the blood gas is inappropriate: this relates to the widely held misconception that inspired oxygen tension should be minimized in COPD patients to prevent loss of respiratory drive. This is incorrect, even if there is some truth in the basic science (questionable), chemoreceptors respond to arterial oxygen tension, not what is given at the mouth. In this case, the patients PaO₂ is normal for him, and he is receiving the appropriate amount of oxygen. The raised CO₂ relates to ventilation-perfusion mismatch, resulting from the underlying acute injury, and release of hypoxic pulmonary vasoconstriction. The administration of oxygen may have increased the amount of dead space ventilation. In addition, raised PACO₂ displaces O₂ at alveolar level, requiring a higher FiO₂.

Scenario 4

A 78 year old male is admitted with a six month history of shortness of breath, ankle edema, orthopnea, a productive cough, hoarseness and 30-40lb weight loss. He has a palpable mass in his abdomen, which turns out to be colonic cancer. As part of his preoperative work up, a blood gas is performed: pH 7.42 PaCO₂ 36 PaO₂ 41 SaO2 78%. He is put on 100% oxygen, has a chest x-ray performed, which is normal, and a spiral CT of his thorax, which also appears normal. His blood gas on 100% oxygen is: pH 7.46, PaCO₂ 36, PaO₂ 42, SaO₂ 78%.

What do you think is wrong with this patient?

Hypoxemia refractory to oxygen therapy is a right to left shunt until otherwise proven. This patient underwent echocardiography which showed a markedly enlarged right ventricle with reduced right ventricular function; there was reduced global left ventricular function. On cardiac catheterization this patient had a patent foramen ovale, a right to left shunt (with Eisenmenger physiology), and equalization of pulmonary and systemic blood pressures. Of his 8 liter cardiac output, 6 litres were shunting right to left. He was unsuitable for surgery.

Key Points

1. The oxygen cascade describes the process of declining oxygen tension from atmosphere to mitochondria.
   

2. The amount of oxygen in the blood is calculated using the formula: [1.34 x Hb x (SaO2/100)] + 0.003 x PO2 = 20.8ml
   

3. The delivery of oxygen to the tissues per minute is calculated from: DO2 = [1.39 x Hb x SaO2 + (0.003 x PaO2)] x Q
   

4. Tissue oxygen extraction is calculated by subtracting mixed venous oxygen content from arterial oxygen content.
   

5. The Oxyhemoglobin dissociation curve describes the non-linear tendency for oxygen to bind to hemoglobin: below a SaO2 of 90%, small differences in hemoglobin saturation reflect large changes in PaO2 Right to left shunting causes hypoxemia resistant to oxygen therapy.
   

6. Hypoxic Pulmonary Vasoconstriction is a physiologic protective mechanism which prevents right to left shunting of blood.
   

7. Right to left shunt causes hypoxemia unresponsive to oxygen therapy Diffusion defects and ventilation perfusion mismatches cause hypoxemia, responsive to exogenous oxygen and positive pressure ventilation. Absorption atelectasis refers to the tendency for airways to collapse if proximally obstructed, gases are reabsorbed, this process is accelerated by nitrogen washout techniques.
   

8. The objective of oxygen therapy is to give the patient as much oxygen as is required to return the PaO2 to what is normal for the particular patient.
   

9. Oxygen is given thru fixed and variable performance devices.
   

10. Fixed performance devices deliver a flow of oxygen equal to or in excess of peak inspiratory flow
    

11. Variable performance devices use the deadspace of the nasopharynx or face masks as a reservoir of oxygen. They cannot deliver high inspired concentrations of oxygen.
    

12. Hyperbaric oxygen therapy is used to increase the amount of oxygen dissolved in the plasma, by increasing the ambient pressure Carbon monoxide causes tissue ischemia by avidly binding to hemoglobin and displacing oxygen. The treatment is 100% oxygen, and possibly HBO therapy.
    

13. High inspired oxygen concentrations cause toxicity by causing formation of oxygen free radicals (which damage tissues), and by causing absorption atelectasis and V/Q mismatch.
    

14. Pulse oximeters measure the absorption of red and infrared light by pulsatile blood. They are inexpensive, continuous and portable. Accuracy declines below a SpO2 of 90%.

Source : http://www.ccmtutorials.com/rs/oxygen/