Medical Doctor Notes

Tuberculosis Drugs Under Development Expected To Have Major Impact On The Disease

2009-08-15T14:29:00.000+07:00

The latest drug regimens, vaccines and diagnostic tools under development to combat tuberculosis could have a potentially large impact on the disease once they become available, according to research findings published in the Aug. 3 early edition online of the Proceedings of the National Academy of Sciences.

Using a mathematical model that examined TB in Southeast Asia, a region with a large proportion of TB cases worldwide, researchers in the Vaccine and Infectious Disease Institute at Fred Hutchinson Cancer Research Center found that the incidence of the disease could be reduced between 13 percent and 71 percent by 2050, depending upon the type of interventions used and whether they are implemented singly or in combination.

The study was led by M. Elizabeth "Betz" Halloran, M.D., D.Sc., a member of the Hutchinson Center's Public Health Sciences Division and professor of biostatistics at the University of Washington, and directed by Laith Abu-Raddad, Ph.D., an assistant member of the Hutchinson Center's Public Health Sciences Division and a visiting assistant professor of public health at Weill Cornell Medical College in Qatar.

Halloran and colleagues examined the expected benefits of implementing the new TB tools developed with support from the Bill & Melinda Gates Foundation. They chose to apply their modeling to the 11-country Southeast Asia region as defined by the World Health Organization (Bangladesh, Bhutan, Democratic People's Republic of Korea, India, Indonesia, Maldives, Myanmar, Nepal, Sri Lanka, Thailand and Timor-Leste) because it already has successful TB-intervention programs.

"Our results demonstrate that each of the novel vaccines, drug regimens and diagnostics currently under development offers substantial reductions in TB incidence and TB-related mortality compared with current approaches," said Abu-Raddad, the study's first author. "Were these technologies used in combination, there would be an additional powerful synergistic effect," he said.

Some of the study's key findings:

Vaccination of newborns with the vaccine under development by the Aeras Global TB Vaccine Foundation could decrease TB incidence by 39 percent to 52 percent by 2050.
The Global Alliance for TB Drug Development is working on new drug regimens that shorten treatment duration and are effective against drug-resistant TB strains which could reduce TB incidence 10 percent to 27 percent.
The Foundation for Innovative New Diagnostics New leads the effort on new diagnostic tools that could reduce TB incidence by 13 percent to 42 percent. Diagnostics and treatment go hand-in-hand because new diagnostic tests have an epidemiological effect by moving people to treatment more rapidly. The three diagnostic methods examined in the study achieve their improvements in TB incidence and mortality fairly rapidly. The four-month, two-month, and 10-day novel active disease treatment regimens produce 10 percent, 23 percent, and 27 percent reductions in TB incidence by 2050 compared to 2015.
In combination, the triple application of vaccination, new drugs and diagnostics the products could prevent 55.3 million cases and lower TB incidence by 71 percent (to 509.2 cases per million) by 2050, far more than any of the individual approaches.

"Combinations of the new technologies currently under development could have an enormous benefit," said Halloran. "However, there is a big difference between what is in the current portfolio and what could be achieved by going beyond it. To achieve further improvements, technologies and delivery strategies not currently under development should be considered."

The findings could alter the practice of tuberculosis control, particularly if mass vaccination catch-up campaigns were added to the current practice of vaccinating newborns, Halloran noted. The study results have already changed the way that Aeras is considering its vaccination strategies and goals to include mass vaccination options.

Halloran and colleagues are world renowned for creating disease models. For this study, they created a model of tuberculosis within a population, similar to previous TB models. Individuals have a defined disease state at all times, such as susceptible, latently infected, or recovered. The rates at which individuals transition from one state to another, and the factors that affect these transitions were determined from an extensive search of the existing TB literature. The team discussed the novel portfolio interventions with FIND, Aeras and TB Alliance to understand the expected efficacies and improvements over current approaches to TB intervention. The ways in which the new technologies are expected to work, and on whom, were plugged into the model. The group took the expected effects of the novel technologies and applied them to the large TB model to understand the results of these technologies on a population scale.

In 2006, Southeast Asia accounted for 35 percent of all new TB cases in the world and 32 percent of the world's TB-related deaths. With no novel interventions, 101.7 million new TB cases and 17.9 million TB-related deaths are expected in the region between 2015 and 2050, according to researchers. Despite these grim numbers, the Southeast Asia region was chosen for the study because it already has generally successful TB intervention programs.

TB is considered to be the leading cause of death worldwide from a curable infection, and it is estimated that one-third of the world's population is latently infected with the disease.

Co-authors on the paper included researchers from the Office of HIV/AIDS, Tuberculosis, Malaria and Neglected Tropical Diseases at the World Health Organization; the University of Washington; and the Vaccine and Infectious Disease Institute at the Hutchinson Center.

Source : http://www.sciencedaily.com/releases/2009/08/090803172951.htm

Emphysema

2009-07-23T21:21:00.002+07:00

It is often caused by exposure to toxic chemicals or long-term exposure to tobacco smoke.

Emphysema is characterized by loss of elasticity of the lung tissue; destruction of structures supporting the alveoli; and destruction of capillaries feeding the alveoli.

The result is that the small airways collapse during expiration, leading to an obstructive form of lung disease (airflow is impeded and air is generally "trapped" in the lungs in obstructive lung diseases).

Symptoms are: shortness of breath on exertion - typically when climbing stairs or inclines (and later at rest), hyperventilation and an expanded chest.

As emphysema progresses, clubbing of the fingers may be observed, a feature of longstanding hypoxia..

For more information about the topic Emphysema, read the full article at Wikipedia.org, or see the following related articles:

Bronchitis — Bronchitis is an obstructive pulmonary disease characterized by inflammation of the bronchi of the lungs. Bronchitis can be acute (short-term), or ... > read more

COPD — Chronic obstructive pulmonary disease (COPD) is an umbrella term for a group of respiratory tract diseases that are characterized by airflow ... > read more

Pulmonary alveolus — An alveolus (plural: alveoli), is an anatomical structure that has the form of a hollow cavity. In the lung, the pulmonary alveoli are spherical ... > read more

Gas exchange — Gas exchange or respiration takes place at a respiratory surface; a boundary between the external environment and the interior of the body. For ... > read more

Source : http ://www.sciencedaily.com/article/e/emphysema.htm

Treatment Of Cystic Fibrosis: Encouraging New Results For Miglustat

2009-07-23T21:11:00.001+07:00

Miglustat is a drug currently under phase 2 clinical trials on patients suffering from cystic fibrosis ⁽¹⁾. Its potential for treating the disease was discovered in 2006 thanks to the work of Frédéric Becq's team at the Institute of Cell Physiology and Biology (CNRS/Université de Poitiers), funded by the associations Vaincre la Mucoviscidose, MucoVie66, La Pierre Le Bigaut and ABCF2.

In new work to be published on 1 August 2009 in the American Journal of Respiratory Cell and Molecular Biology, the researchers show that daily, long-term treatment of human cystic fibrosis cells with low doses of miglustat corrects the main pathological abnormalities. They are therefore extremely hopeful that miglustat will prove effective with patients, and become the first drug able to treat the disease rather than the symptoms.

Cystic fibrosis is a genetic disease, transmitted jointly by both parents, and affects around 6000 people in France. It is caused by the dysfunction of a membrane protein (CFTR), present especially in the epithelial cells in the lungs, which controls exchange of water and mineral salts between the cell and the exterior. On the cell level, the disease manifests itself by the absence of chloride secretion, sodium hyperabsorption, deregulation of calcium homeostasis, and heightened inflammatory response. This results in thickening of the mucus that lines the bronchial tubes and the pancreatic ducts, leading to lung infections and digestive disorders. At the current time, there is no treatment that cures cystic fibrosis. In order to alleviate the symptoms, extremely strict daily treatment is necessary.

In 2006, Frédéric Becq's team at the Institute of Cell Physiology and Biology (CNRS/Université de Poitiers) showed that a drug called miglustat restored the activity of the CFTR protein and could thus temporarily correct the specific phenotype characteristic of cystic fibrosis. Used to treat two rare diseases (Gaucher's disease and Niemann-Pick type C disease), its safety and tolerance had already been assessed, and clinical trials could be rapidly begun in September 2007.

In the new study published in American Journal of Respiratory Cell and Molecular Biology, the researchers show that daily treatment of human respiratory cells that are homozygous for the F508del mutation with low concentrations of miglustat leads to progressive, sustained and reversible correction of the diseased phenotype. The researchers cultured diseased human respiratory cells in the presence of miglustat for two months. The correction observed in the cells takes place after 3-4 days, and then stabilizes. When the treatment is stopped, the cells revert to the diseased phenotype. The low doses used (3 micromolars) mean that they can be administered to patients and that their presence in the bloodstream causes no problems.

This study is the first that shows that a cystic fibrosis cell can acquire a sustained non-diseased phenotype when treated daily with a pharmacological agent. The researchers are therefore very optimistic about the results of the clinical trials under way.

(1) The clinical study is being carried out by the Actelion pharmaceutical laboratory on 15 patients suffering from cystic fibrosis and carrying the delta F508 mutation (F508del), which is the most common and the most serious of the mutations affecting children with cystic fibrosis. The results will be known in the coming weeks.

Journal reference:

C. Norez, F. Antigny, S. Noel, C. Vandebrouck, F. Becq. A CF respiratory epithelial cell chronically treated by miglustat acquires a non-CF like phenotype. American Journal of Respiratory Cell and Molecular Biology, August 2009

Source : http://www.sciencedaily.com/releases/2009/07/090721090134.htm

Pulmonary Embolism

2009-07-19T06:48:00.002+07:00

Introduction

Background

Pulmonary embolism (PE) is a common and potentially lethal condition that can cause death in all age groups. A good clinician should consider the diagnosis if any suspicion of pulmonary embolism exists, because prompt diagnosis and treatment can dramatically reduce the morbidity and mortality of the disease. Unfortunately, the diagnosis is often missed, because pulmonary embolism frequently causes only vague and nonspecific symptoms.

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The most sobering lessons about pulmonary embolism (PE) are those obtained from a careful study of the autopsy literature. Deep vein thrombosis (DVT) and pulmonary embolism are much more common than usually realized. In a long-range population cohort study, an equal number of venous thrombotic events were discovered after death, at autopsy, as were predicted by death certificate.¹

The variability of presentation sets the patient and clinician up for potentially missing the diagnosis. The challenge is that the "classic" presentation with abrupt onset of pleuritic chest pain, shortness of breath, and hypoxia is rarely the case. Studies of patients who die unexpectedly of pulmonary embolism reveal that they complained of nagging symptoms often for weeks before death related to pulmonary embolism. Forty percent of these patients had been seen by a physician in the weeks prior to their death.²

Pathophysiology

The pathophysiology of pulmonary embolism. Although pulmonary embolism can arise from anywhere in the body, most commonly it arises from the calf veins. The venous thrombi predominately originate in venous valve pockets (inset) and at other sites of presumed venous stasis. To reach the lungs, thromboemboli travel through the right side of the heart. RA, right atrium; RV, right ventricle; LA, left atrium; LV, left ventricle.

Pulmonary thromboembolism is not a disease in and of itself. Rather, it is a complication of underlying venous thrombosis. Under normal conditions, microthrombi (tiny aggregates of red cells, platelets, and fibrin) are formed and lysed continually within the venous circulatory system. This dynamic equilibrium ensures local hemostasis in response to injury without permitting uncontrolled propagation of clot. Under pathological conditions, microthrombi may escape the normal fibrinolytic system to grow and propagate. Pulmonary embolism (PE) occurs when these propagating clots break loose and embolize to block pulmonary blood vessels.

Thrombosis in the veins is triggered by venostasis, hypercoagulability, and vessel wall inflammation. These 3 underlying causes are known as the Virchow triad. All known clinical risk factors for DVT and PE have their basis in one or more elements of the triad.

Patients who have undergone gynecologic surgery, those with major trauma, and those with indwelling venous catheters may have DVTs that start in an area related to their pathology. For other patients, venous thrombosis most often involves the lower extremities and nearly always starts in the calf veins, which are involved in virtually all cases of symptomatic spontaneous lower extremity DVT. Although DVT starts in the calf veins, in cases of pulmonary embolism, it will usually propagate proximally to the popliteal vessels, and from that area embolize.

Frequency

United States

Venous thromboembolism is a major health problem. The average annual incidence of venous thromboembolism in the United States is 1 per 1000,^1,3,4with about 250,000 incident cases occurring annually. The challenge in understanding the real disease is that autopsy studies show that an additional equal number of patients are diagnosed with pulmonary embolism at autopsy, as were initially diagnosed by clinicians.^1,5This is led to estimates of between 650,000 to 900,000 fatal and nonfatal VTE events occurring in the US annually. The incidence of venous thromboembolism has not changed significantly over the last 25 years.¹Capturing the true incidence going forward will be challenging because of the decreasing rate of autopsy. In a longitudinal, 25-year prospective study from 1966 to 1990, autopsy rates dropped from 55% to 30% over the study period.¹Current trends would suggest a continued decline in autopsy rate.

International

International journal articles cite similar population incidence of deep vein thrombosis and pulmonary embolism as the United States studies.

Mortality/Morbidity

Mortality for acute pulmonary embolism can be broken down into 2 categories: massive pulmonary embolism and nonmassive pulmonary embolism.

Massive pulmonary embolism is defined as presenting with a systolic arterial pressure less than 90 mm Hg. In two large international studies, this accounted for 4-4.5% of the patients. Nonmassive pulmonary embolism is defined as having a systolic arterial pressure greater than or equal to 90 mm Hg. This is the more common presentation for pulmonary embolism and accounts for 95.5-96% of the patients.^6,7

The mortality for patients presenting with massive pulmonary embolism is between 30% and 60% depending on the study cited.^8,7,3The majority of these deaths occur in the first 1-2 hours of care, so it is important for the initial treating physician to have a systemized aggressive evaluation and treatment plan for patients presenting with pulmonary embolism. The diagnosis of massive pulmonary embolism is not solely a function of the size of the clot, rather it is a function of the size of the clot and the functional capability of the patient's cardiovascular system.

Hemodynamically stabile pulmonary embolism has a much lower mortality rate, especially in recent years, because of treatment with anticoagulant therapy. In nonmassive pulmonary embolism, the death rate is less than 5% in the first 3-6 months of anticoagulant treatment. The rate of recurrent thromboembolism is less than 5% during this time. However, recurrent thromboembolism reaches 30% after 10 years.⁹

Race

Studies looking at the incidence of pulmonary embolism in various races show that African American patients are the highest risk group, with a 50% higher incidence than American whites. Asian/Pacific Islanders/American Indian patients have a markedly lower risk of thromboembolism.^9,10

Sex

Across all age groups, there is a fairly equal distribution of initial pulmonary embolism between males and females.¹However, most studies find that women have a significantly lower rate of recurrent pulmonary embolism.¹¹

Age

Venous thromboembolism and pulmonary embolism are diseases associated with advancing age. Furthermore, pulmonary embolism accounts for a larger proportion of venous thromboembolic disease with increasing age for both sexes. This may well be the result of a cumulative effect of risk factors that patients acquire with aging.^1,11

Clinical

History

Pulmonary embolism (PE) is so common and so lethal that the diagnosis should be sought actively in every patient who presents with any chest symptoms that cannot be proven to have another cause.

Symptoms that should provoke a suspicion of pulmonary embolism must include chest pain, chest wall tenderness, back pain, shoulder pain, upper abdominal pain, syncope, hemoptysis, shortness of breath, painful respiration, new onset of wheezing, any new cardiac arrhythmia, or any other unexplained symptom referable to the thorax.
The classic triad of signs and symptoms of PE (hemoptysis, dyspnea, chest pain) are neither sensitive nor specific. They occur in fewer than 20% of patients in whom the diagnosis of PE is made, and most patients with those symptoms are found to have some etiology other than PE to account for them. Of patients who go on to die from massive PE, only 60% have dyspnea, 17% have chest pain, and 3% have hemoptysis. Nonetheless, the presence of any of these classic signs and symptoms is an indication for a complete diagnostic evaluation.
Many patients with PE are initially completely asymptomatic, and most of those who do have symptoms have an atypical presentation.
Patients with PE often present with primary or isolated complaints of seizure, syncope, abdominal pain, high fever, productive cough, new onset of reactive airway disease ("adult-onset asthma"), or hiccoughs. They may present with new-onset atrial fibrillation, disseminated intravascular coagulation, or any of a host of other signs and symptoms.
Pleuritic or respirophasic chest pain is a particularly worrisome symptom. PE has been diagnosed in 21% of young, active patients who come to the ED complaining only of pleuritic chest pain. These patients usually lack any other classical signs, symptoms, or known risk factors for pulmonary thromboembolism. Such patients often are dismissed inappropriately with an inadequate workup and a nonspecific diagnosis, such as musculoskeletal chest pain or pleurisy.

Physical

Massive pulmonary embolism (PE) causes hypotension due to acute cor pulmonale, but the physical examination findings early in submassive PE may be completely normal.
After 24-72 hours, loss of pulmonary surfactant often causes atelectasis and alveolar infiltrates that are indistinguishable from pneumonia on clinical examination and by radiography.
New wheezing may be appreciated. If pleural lung surfaces are affected, a pulmonary rub may be heard.
In patients with recognized PE, the incidence of physical signs has been reported as follows:
- 96% have tachypnea (respiratory rate >16/min)
- 58% develop rales
- 53% have an accentuated second heart sound
- 44% have tachycardia (heart rate >100/min)
- 43% have fever (temperature >37.8°C)
- 36% have diaphoresis
- 34% have an S₃or S₄gallop
- 32% have clinical signs and symptoms suggesting thrombophlebitis
- 24% have lower extremity edema
- 23% have a cardiac murmur
- 19% have cyanosis

Causes

As stated in the Pathophysiology section, the etiology of venous thrombosis and subsequent thromboembolism results from a distortion in Virchow's triad by venostasis, hypercoagulability, or vessel wall inflammation. These risk factors for venous thrombosis and pulmonary embolism can be broken down into hereditary factors and acquired factors.

Hereditary factors (most result in a hypercoagulable state)
- Antithrombin III deficiency
- Protein C deficiency
- Protein S deficiency
- Factor V Leiden (most common genetic risk factor for thrombophilia)
- Plasminogen abnormality
- Plasminogen activator abnormality
- Fibrinogen abnormality
- Resistance to activated protein C
Acquired factors (The most important clinically identifiable risk factors for DVT and PE are a prior history of DVT or PE, recent surgery or pregnancy, prolonged immobilization, or underlying malignancy.)
- Reduced mobility
  - Fractures
  - Immobilization
  - Burns
  - Obesity
- Old age
- Malignancy
  - Chemotherapy
- Acute medical illness
  - AIDS (lupus anticoagulant)
  - Behçet disease
  - Congestive heart failure (CHF)
  - Myocardial infarction
  - Polycythemia
  - Systemic lupus erythematosus
  - Ulcerative colitis
- Trauma/major surgery
  - Spinal cord injury
  - Catheters (indwelling venous infusion catheters)
  - Postoperative
- Pregnancy
  - Postpartum period
  - Oral contraceptives
  - Estrogen replacements (high dose only)
- Drug abuse (intravenous [IV] drugs)
- Drug-induced lupus anticoagulant
- Hemolytic anemias
- Heparin-associated thrombocytopenia
- Homocysteinemia
- Homocystinuria
- Hyperlipidemias
- Phenothiazines
- Thrombocytosis
- Varicose veins
- Venography
- Venous pacemakers
- Venous stasis
- Warfarin (first few days of therapy)

Differential Diagnoses

Workup

Laboratory Studies

The challenge of evaluating laboratory studies and pulmonary embolism (PE) is that no one study can provide the answer. The clinical scoring guidelines seek to quantify the aforementioned risk factors to help guide decision-making with pulmonary embolism.

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Clinical scoring algorithms are less objective and less powerful than some authors would claim. The objective components of the Wells (Canadian Pulmonary Embolism Score) criteria, for example, have been shown to have little effect on the stratification power of the criteria; virtually all of the classification power is associated with a physician's subjective prejudgment of the likelihood of PE. The Geneva criteria, which depend only on objective measures, lead to a stratification with a PE prevalence of 8% in the lowest-risk group (Geneva score of zero)—a prevalence too high to be neglected. When PE is suspected, diagnostic tests must be performed.
Unfortunately, no known blood or serum test can move a patient with a high clinical likelihood of pulmonary thromboembolism into a low likelihood category or vice versa.
The PO₂ on arterial blood gases analysis (ABG) has a zero or even negative predictive value in a typical population of patients in whom PE is suspected clinically. This is contrary to what has been taught in many textbooks, and it seems counterintuitive, but it is demonstrably true. The reason is as follows:
- Other etiologies that masquerade as PE are more likely to lower the PO₂ than is PE. In fact, because other diseases that may masquerade as PE (eg, chronic obstructive pulmonary disease [COPD], pneumonia, CHF) affect oxygen exchange more than PE, the blood oxygen level often has an inverse predictive value for PE.
- In most settings, fewer than half of all patients with symptoms suggestive of PE actually turn out to have PE as their diagnosis. In such a population, if any reasonable level of PaO₂ is chosen as a dividing line, the incidence of PE will be higher in the group with a PaO₂ above the dividing line than in the group whose PaO₂ is below the divider. This is a specific example of a general truth that may be demonstrated mathematically for any test finding with a Gaussian distribution and a population incidence of less than 50%.
- Conversely, in a patient population with a very high incidence of PE and a lower incidence of other respiratory ailments (eg, postoperative orthopedic patients with sudden onset of shortness of breath), a low PO₂ has a strongly positive predictive value for PE.
- The discussion above holds true not only for arterial PO₂ but also for the alveolar-arterial oxygen gradient and for the oxygen saturation level as measured by pulse oximetry. In particular, pulse oximetry is extremely insensitive, is normal in the majority of patients with PE, and should not be used to direct a diagnostic workup.
The white blood cell (WBC) count may be normal or elevated. A WBC count as high as 20,000 is not uncommon in patients with PE.
Clotting study results are normal in most patients with pulmonary thromboembolism.
- Prolongation of the prothrombin time (PT), activated partial thromboplastin time (aPTT), or clotting time have no prognostic value in the diagnosis of PE. DVT and PE can and often do recur in patients who are fully anticoagulated.
- New PE in the hospital occurs in the following despite therapeutic anticoagulation:
  - Patients who have nonfloating DVT without PE at presentation (3%)
  - Patients who present with a floating thrombus but no PE (13%)
  - Patients who already had PE at presentation but had no floating thrombus (11%)
  - Patients presenting with PE who have a floating thrombus visible at venography (39%)

D-dimer is a unique degradation product produced by plasmin-mediated proteolysis of cross-linked fibrin. D-dimer is measured by latex agglutination or by an enzyme-linked immunosorbent assay (ELISA) and a test result is considered positive if the level is greater than 500 ng/mL.

Latex agglutination tests are notoriously unreliable, with a historical sensitivity of only 50-60% for DVT and PE.
The ELISA test is more sensitive than the latex agglutination test, with a sensitivity of 96-98%. The challenge is that the test is nonspecific and results may be positive in patients with infection, cancer, trauma, or other inflammatory states.
A D-dimer screen is best used in conjunction with a clinical assessment of the patient's probability of pulmonary embolism. This can be done systematically using a scoring criteria^12,13,14or in a more gestalt style, basing the probability on the patient's history of predisposing conditions.¹⁵

Imaging Studies

The initial chest radiographic findings of a patient with pulmonary embolism (PE) are virtually always normal, although on rare occasions, they may show the Westermark sign (ie, a dilatation of the pulmonary vessels proximal to an embolism along with collapse of distal vessels, sometimes with a sharp cutoff).
- Over time, an initially normal chest radiograph often begins to show atelectasis, which may progress to cause a small pleural effusion and an elevated hemidiaphragm.
- After 24-72 hours, one third of patients with proven PE develop focal infiltrates that are indistinguishable from an infectious pneumonia.
- A rare late finding of pulmonary infarction is the Hampton hump, a triangular or rounded pleural-based infiltrate with the apex pointed toward the hilum, frequently located adjacent to the diaphragm.
Because chest radiography is unreliable, conduct high-resolution multidetector computed tomographic angiography (MDCTA) in patients suspected of having PE.
- MDCTA has been shown to have sensitivity and specificity comparable to that of contrast pulmonary angiography, and, in recent years, has become accepted both as the preferred primary diagnostic modality and as the criterion standard for making or excluding the diagnosis of pulmonary embolism.
- In many patients, multidetector CT scans with intravenous contrast can resolve third-order pulmonary vessels without the need for invasive pulmonary artery catheters.
- MDCTA is more likely to miss lesions in a patient with pleuritic chest pain due to multiple small emboli that have lodged in distal vessels, but these lesions also may be difficult to detect using conventional angiography.
If MDCTA is unavailable, conduct pulmonary angiography. Long the criterion standard for PE diagnosis, pulmonary angiography is nevertheless more invasive and harder to perform than MDCTA and, for these reasons, is rapidly being replaced. Pulmonary angiography remains a useful diagnostic modality when MDCTA cannot be performed.
- When performed carefully and completely, a positive pulmonary angiogram provides virtually 100% certainty that an obstruction to pulmonary arterial blood flow does exist. A negative pulmonary angiogram provides greater than 90% certainty in the exclusion of PE.
- A positive angiogram is an acceptable endpoint no matter how abbreviated the study. However, a complete negative study requires the visualization of the entire pulmonary tree bilaterally. This is accomplished via selective cannulation of each branch of the pulmonary artery and injection of contrast material into each branch, with multiple views of each area. Even then, emboli in vessels smaller than third order or lobular arteries are not seen.
- Small emboli cannot be seen angiographically, yet embolic obstruction of these smaller pulmonary vessels is very common when postmortem examination follows a negative angiogram. These small emboli can produce pleuritic chest pain and a small sterile effusion even though the patient has a normal V/Q scan and a normal pulmonary angiogram.
- In most patients, however, PE is a disease of multiple recurrences, with both large and small emboli already present by the time the diagnosis is first suspected. Under these circumstances, both the V/Q scan and the angiogram are likely to detect at least some of the emboli.
Until recently, nuclear scintigraphic ventilation-perfusion (V/Q) scanning of the lung had been the single most important diagnostic modality for detecting pulmonary thromboembolism available to the clinician. Other alternatives were less sensitive, less specific, or significantly more invasive. Multidetector CT angiography is now a preferred primary diagnostic modality, but the V/Q scan remains an important part of the evaluation when multidetector CT angiography is not available or not appropriate for the patient.
- V/Q scanning is indicated whenever the diagnosis of PE is suspected and no alternative diagnosis can be proved.
- A repeat V/Q scan is indicated before stopping anticoagulation in a patient with irreversible risk factors for DVT and PE, because recurrent symptoms are common and a reference "posttreatment" V/Q scan can serve as a new baseline for comparison, often sparing the patient the need for a future angiogram.
- The Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) classification scheme allows interpretation of the results of the V/Q scan in a meaningful way, but this standard classification is not used in its entirety at every institution. At some institutions, V/Q scan findings are never reported as normal no matter what the actual pattern of perfusion. This is unfortunate because normal perfusion is the scan pattern with the highest predictive value. Some institutions continue to report nondiagnostic V/Q patterns using obsolete and clinically confusing terminology, such as indeterminate, intermediate, or low probability.
- Diagnostic V/Q patterns classified as high probability or as normal perfusion may be relied upon to guide the clinical management of patients when the prior clinical assessment is concordant with the scan result.
- No matter what language is used, a nondiagnostic V/Q pattern is not an acceptable endpoint in the workup for pulmonary thromboembolism. Pulmonary angiography or another definitive test must be performed when the diagnosis remains uncertain.
Normal V/Q scan
- No perfusion defects are seen.
- At least 2% of patients with PE have this pattern, and 4% of patients with this pattern have PE. This means that approximately 1 of every 25 patients sent home after a normal V/Q scan actually has a PE that has been missed. This is unfortunate, but risk-benefit analysis supports the idea that unless the presentation is highly convincing and no alternate diagnosis is demonstrable, a normal perfusion scan pattern often may be considered negative for PE.
High-probability scan
- This includes scans with any of the following findings:
  - Two or more segmental or larger perfusion defects with normal chest radiographs and normal ventilation
  - Two or more segmental or larger perfusion defects where chest radiographic abnormalities and ventilation defects are substantially smaller than the perfusion defects
  - Two or more subsegmental and one segmental perfusion defect with normal chest radiograph and normal ventilation
  - Four or more subsegmental perfusion defects with normal chest radiograph and normal ventilation
- Forty-one percent of patients with PE have this pattern, and 87% of patients with this pattern have PE.
- In most clinical settings, a high-probability scan pattern may be considered positive for PE.
Nondiagnostic scan (with a pattern type that was formerly graded as low probability)
- This includes scans with any of the following findings:
  - Small perfusion defects, regardless of number, ventilation findings, or chest radiographic findings
  - Perfusion defects substantially smaller than a chest radiographic abnormality in the same area
  - Matching perfusion and ventilation defects in less than 75% of one lung zone or in less than 50% of one lung, with a normal or nearly normal chest radiograph
  - A single segmental perfusion defect with a normal chest radiograph, regardless of ventilation match or mismatch
  - Nonsegmental perfusion defects
- Sixteen percent of patients with PE have this pattern, and 14% of patients with this pattern have PE. This pattern often is called "low probability," but the term is a misnomer: in a typical population, 1 in 7 patients with this pattern turn out to have a PE.
- This scan pattern is an indication for pulmonary angiography or some other definitive test. All patients suspected of PE who have a nondiagnostic scan must have PE definitively ruled out or some definitive alternative diagnosis made.
Nondiagnostic scan (with a pattern type that was formerly graded as "intermediate probability")
- Any V/Q abnormality not otherwise classified: Approximately 40% of patients with PE fall into this category, and 30% of all patients with this pattern have PE.
- This scan pattern is always an indication for pulmonary angiography or another definitive test to rule out PE. Failure to pursue the diagnosis further in these patients leads to disastrous outcomes.
Duplex ultrasonography
- The diagnosis of PE can be proven by demonstrating the presence of a DVT at any site. Sometimes, this may be accomplished noninvasively, by using duplex ultrasonography.
- To look for DVT using ultrasonography, the ultrasound transducer is placed against the skin and then is pressed inward firmly enough to compress the vein being examined. In an area of normal veins, the veins are easily compressed completely closed, while the muscular arteries are extremely resistant to compression.
- Where DVT is present, the veins do not collapse completely when pressure is applied using the ultrasound probe.
- A negative ultrasound scan does not rule out DVT, because many DVTs occur in areas that are inaccessible to ultrasonic examination. Before an ultrasound scan can be considered negative, the entire deep venous system must be interrogated using centimeter-by-centimeter compression testing of every vessel.
- In two thirds of patients with PE, the site of DVT cannot be visualized by ultrasound, so a negative duplex ultrasound scan does not markedly reduce the likelihood of PE.

Other Tests

Electrocardiography
- The most common ECG abnormalities in the setting of pulmonary embolism (PE) are tachycardia and nonspecific ST-T wave abnormalities. The finding of S₁Q₃T₃is nonspecific and insensitive in the absence of clinical suspicion for PE.
- The classic findings of right heart strain and acute cor pulmonale are tall, peaked P waves in lead II (P pulmonale), right axis deviation, right bundle-branch block, an S₁Q₃T₃pattern, or atrial fibrillation. Unfortunately, only 20% of patients with proven PE have any of these classic ECG abnormalities.
- If ECG abnormalities are present, they may be suggestive of PE, but the absence of ECG abnormalities has no significant predictive value.
Echocardiography or cardiac ultrasonography¹⁶
- The subcostal view is preferred at initial screening for mechanical activity and pericardial fluid and for gross assessment of global and regional abnormalities. To obtain a subcostal view, place the transducer the left subcostal margin with the beam aimed at the left shoulder.
- The parasternal view allows visualization of the aortic valve, proximal ascending aorta, and posterior pericardium and allows determination of left ventricular size. It is particularly helpful when the subcostal view is difficult to obtain. To obtain a parasternal view, place the transducer in the left parasternal area between the second and fourth intercostal spaces. The plane of the beam is parallel to a line drawn from the right shoulder to the left hip.
- Several echocardiographic findings have been proposed for noninvasive diagnosis of RV dysfunction at the bedside, including RV enlargement and/or hypokinesis of the free wall, leftward septal shift, and evidence of pulmonary hypertension. If right ventricular dysfunction is seen on cardiac ultrasonography, the diagnosis of acute submassive or massive PE is supported. While the presence of RV dysfunction can be used to support the clinical suspicion of PE, prognostic information can be obtained by assessing the severity of RV dysfunction.
Under investigation
- Prompt diagnosis and stratification in patients with suspected PE and a high risk of adverse events may help to improve outcomes. Serum troponin, although seemingly marginal for purposes of diagnosis of PE, may contribute significantly to the ability to stratify patients by risk for short-term death or adverse outcome events when they reach the ED. In patients with PE and normal blood pressure specifically, elevated serum troponin level has been associated with right ventricular overload.^17,18,19,20
- Elevated levels of brain-type natriuretic peptides (BNP) may also provide prognostic information.¹⁹A recent meta-analysis demonstrated a significant association between elevated N-terminal–pro-BNP (NT-pro-BNP) and right ventricular function in patients with PE (p<0.001),>21 Importantly, increased NT-pro-BNP alone does not justify more invasive treatment.
An potential alternative to D-dimer is ischemia-modified albumin (IMA) level, which data suggest, is 93% sensitive and 75% specific for PE.²² Notably, in a recent study comparing the prognostic value of IMA to D-dimer, IMA in combination with Wells and Geneva probability scores appears to positively impact overall sensitivity and negative predictive value.²² The positive predictive value of IMA, in particular, is better than D-dimer. However, it should not be used alone and, apparently, is still unable to confirm a PE diagnosis with further investigation.²³

Procedures

The primary indication for placement of an inferior vena cava filter in the setting of pulmonary embolism include contraindications to anticoagulation, major bleeding complications during anticoagulation, and recurrent embolization while the patient is receiving adequate therapy.

Treatment

Prehospital Care

The most important thing that can be done in the prehospital setting is to transport the patient to a hospital. As long as no reliable method is available of making a clinical diagnosis of pulmonary embolism (PE) without diagnostic tests, treating PE in a meaningful way in the field will remain difficult.

Isolated case reports exist of patients who have been resuscitated successfully after receiving fibrinolytic agents in the field for cardiac arrest strongly believed (and later proven) to be due to PE.
Presumptive fibrinolysis in the field is aggressive, but it may be a reasonable course of action today when patients being treated as outpatients for known DVT suddenly become short of breath and hypotensive.
Oxygen always should be started in the prehospital phase, and an IV line should be placed if it can be accomplished rapidly without delaying transport. Fluid loading should be avoided unless the patient's hemodynamic condition is deteriorating rapidly, because IV fluids may worsen the patient's condition. Without invasive testing or trial and surveillance, the physician cannot know whether additional preload will help or hurt a heart that is failing already because of high outflow pressures from pulmonary vascular obstruction.

Emergency Department Care

Fibrinolytic therapy has been the standard of care for patients with massive or unstable pulmonary embolism (PE) since the 1970s. Unless overwhelming contraindications are evident, a rapidly acting fibrinolytic agent should be administered immediately to every patient who has suffered hypotension (even if resolved) or is significantly hypoxemic from PE.
- Improvement of hypotension in response to hydration or pressors does not remove the indication for immediate fibrinolysis. The fact that hypotension has occurred at all is a sufficient indication that the patient has exhausted his or her cardiopulmonary reserves and is at high risk for sudden collapse and death.
- Fibrinolysis also is indicated for patients with PE who have any evidence of right heart strain, because evidence indicates that the mortality rate can be cut in half by early fibrinolysis in this patient population.
- Today, fibrinolysis may be considered for any patient with PE who lack specific contraindications to the therapy. Some centers now regard fibrinolysis as the primary treatment of choice for all patients with PE. Interventional radiology has made it possible to perform transcatheter fibrinolysis for patients who have DVT without evidence of PE.
- Heparin reduces the mortality rate of PE because it slows or prevents clot progression and reduces the risk of further embolism.
- Heparin does nothing to dissolve clot that has developed already, but it is still the single most important treatment that can be provided, because the greatest contribution to the mortality rate is the ongoing embolization of new thrombi. Prompt effective anticoagulation has been shown to reduce the overall mortality rate from 30% to less than 10%.
- Early heparin anticoagulation is so essential that heparin should be started as soon as the diagnosis of significant pulmonary thromboembolism is considered.
- Oxygen should be administered to every patient with suspected PE, even when the arterial PO₂ is perfectly normal, because increased alveolar oxygen may help to promote pulmonary vascular dilatation.
IV fluids may help or may hurt the patient who is hypotensive from PE depending on which point on the Starling curve describes the patient's condition.
- A Swan-Ganz catheter is helpful to determine whether a fluid bolus is indicated; as an alternative, a cautious trial of a small fluid bolus may be attempted, with careful surveillance of the systolic and diastolic blood pressures and immediate cessation if the situation worsens after the fluid bolus.
- Improvement or normalization of blood pressure after fluid loading does not mean the patient has become hemodynamically stable.
- Fibrinolysis is indicated for any patient with a PE large enough to cause hypotension, even if the hypotension is transient or correctable. As noted above, early fibrinolysis may reduce the mortality rate by 50% for patients who have right ventricular dysfunction due to PE, even if they are hemodynamically stable.
Compression stockings
- Compression stockings that provide a 30-40 mm Hg compression gradient should be used, because they are a safe and effective adjunctive treatment that can limit or prevent extension of thrombus.
- True gradient compression stockings (30-40 mm Hg or higher) are highly elastic, providing a gradient of compression that is highest at the toes and gradually decreases to the level of the thigh. This reduces capacitive venous volume by approximately 70% and increases the measured velocity of blood flow in the deep veins by a factor of 5 or more. Compression stockings of this type have been proven effective in the prophylaxis of thromboembolism and are also effective in preventing progression of thrombus in patients who already have DVT and PE.
- A 1994 meta-analysis calculated a DVT risk odds ratio of 0.28 for gradient compression stockings (as compared to no prophylaxis) in patients undergoing abdominal surgery, gynecologic surgery, or neurosurgery.
- Other studies have found that gradient compression stockings and low-molecular-weight heparin (LMWH) were the most effective modalities in reducing the incidence of DVT after hip surgery; they were more effective than subcutaneous unfractionated heparin, oral warfarin, dextran, or aspirin.
- The ubiquitous white stockings known as "anti-embolic stockings" or "Ted hose" produce a maximum compression of 18 mm Hg. Ted hose rarely are fitted in such a way as to provide even that inadequate gradient compression. Because they provide such limited compression, they have no efficacy in the treatment of DVT and PE, nor have they been proven effective as prophylaxis against a recurrence.
- True 30-40 mm Hg gradient compression pantyhose are available in sizes for pregnant women. They are recommended by many specialists for all pregnant women because they not only prevent DVT, but they also reduce or prevent the development of varicose veins during pregnancy.

Consultations

Fibrinolytic therapy should not be delayed while consultation is sought. The decision to treat PE by fibrinolysis is properly made by the responsible emergency physician alone, and fibrinolytic therapy is properly administered in the ED.
An interventional radiology consultation may be helpful for catheter-directed fibrinolysis in selected patients. In rare cases, arranging for placement of a venous filter may be appropriate if the patient is not a candidate for thrombolytic therapy.

Medication

Immediate full anticoagulation is mandatory for all patients with suspected deep vein thrombosis (DVT) or pulmonary embolism (PE) because effective anticoagulation with heparin reduces the mortality rate of PE from 30% to less than 10%. Heparin works by activating antithrombin III to slow or prevent the progression of DVT and to reduce the size and frequency of PE. Heparin does not dissolve existing clot.

Anticoagulation is essential, but anticoagulation alone does not guarantee a successful outcome. DVT and PE may recur or extend despite full and effective heparin anticoagulation.

Fibrinolytic therapy should be considered for 3 groups of patients: those who are hemodynamically unstable, those with right heart strain and exhausted cardiopulmonary reserves, and those who are expected to have multiple recurrences of pulmonary thromboembolism over a period of years. Patients with a prior history of PE and those with known deficiencies of protein C, protein S, or antithrombin III should be included in this latter group.

Fibrinolysis should be considered as a potential therapy for every patient with proven PE.

Long-term anticoagulation is essential for patients who survive an initial DVT or PE. The optimum total duration of anticoagulation has been controversial in recent years, but general consensus holds that at least 6 months of anticoagulation is associated with significant reduction in recurrences and a net positive benefit.

Fibrinolytics

Fibrinolysis is always indicated for hemodynamically unstable patients with PE, because no other medical therapy can improve acute cor pulmonale quickly enough to save the patient's life.

Because it is less invasive and has fewer complications, fibrinolytic therapy has replaced surgical embolectomy as the primary mode of treatment for hemodynamically unstable patients with pulmonary thromboembolism. Surgical thromboembolectomy now is reserved for patients in whom fibrinolysis has failed or cannot be tolerated.

Fibrinolytic regimens currently in common use for PE include 2 forms of recombinant tissue plasminogen activator, t-PA (alteplase) and r-PA (reteplase), along with urokinase and streptokinase. Alteplase usually is given as a front-loaded infusion over 90 or 120 minutes. Urokinase and streptokinase usually are given as infusions over 24 hours or more. Reteplase is a new-generation thrombolytic with a longer half-life that is given as a single bolus or as 2 boluses administered 30 minutes apart.

Of the 4, the faster-acting agents reteplase and alteplase are preferred for patients with PE, because the condition of patients with PE can deteriorate extremely rapidly.

Many comparative clinical studies have shown that administration of a 2-hour infusion of alteplase is more effective (and more rapidly effective) than urokinase or streptokinase over a 12-hour period. One prospective randomized study comparing reteplase and alteplase found that total pulmonary resistance (along with pulmonary artery pressure and cardiac index) improved significantly after just 0.5 hours in the reteplase group as compared to 2 hours in the alteplase group. Fibrinolytic agents do not seem to differ significantly with respect to safety or overall efficacy.

Streptokinase is least desirable of all the fibrinolytic agents because antigenic problems and other adverse reactions force the cessation of therapy in a large number of cases.

Empiric thrombolysis may be indicated in selected hemodynamically unstable patients, particularly when the clinical likelihood of PE is overwhelming and the patient's condition is deteriorating. The overall risk of severe complications from thrombolysis is low and the potential benefit in a deteriorating patient with PE is high. Empiric therapy especially is indicated when a patient is compromised so severely that he or she will not survive long enough to obtain a confirmatory study. Empiric thrombolysis should be reserved, however, for cases that truly meet these definitions, as many other clinical entities (including aortic dissection) may masquerade as PE, yet may not benefit from thrombolysis in any way.

If indicated, fibrinolysis may be used in pregnancy at the same dose used for nonpregnant patients. Fear of complications should not prevent the use of fibrinolytics when a pregnant patient has significant right ventricular dysfunction from PE, as the best predictor of fetal outcome in this setting remains maternal outcome.

Reteplase (r-PA, Retavase)

Second-generation recombinant tissue-type plasminogen activator. As fibrinolytic agent, seems to work faster than its forerunner, alteplase, and also may be more effective in patients with larger clot burden. Also has been reported more effective than other agents in lysis of older clots.
Two major differences help explain these improvements. Compared to alteplase, reteplase does not bind fibrin so tightly, allowing drug to diffuse more freely through clot. Another advantage seems to be that reteplase does not compete with plasminogen for fibrin-binding sites, allowing plasminogen at site of clot to be transformed into clot-dissolving plasmin.
FDA has not approved reteplase for use in PE.
Studies of reteplase for PE have used same dose approved by FDA for coronary artery fibrinolysis.

Adult

Two 10-U IV boluses, given 30 min apart
In setting of cardiac arrest or impending arrest due to PE, single IV bolus of 20 U has been used successfully in small number of cases

Pediatric

Not established

Antiplatelet agents or anticoagulants may increase risk of bleeding

Active internal bleeding; history of cerebrovascular accident; recent intracranial or intraspinal surgery or trauma; intracranial neoplasm, arteriovenous malformation, or aneurysm; known bleeding diathesis; severe uncontrolled hypertension

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

In following conditions, risks of fibrinolytic therapy may be increased and should be weighed against anticipated benefits: recent major surgery; recent puncture of noncompressible vessels; cerebrovascular disease; recent GI or GU bleeding; recent trauma; hypertension: systolic BP >180 mm Hg and/or diastolic BP >110 mm Hg; high likelihood of left heart thrombus (eg, mitral stenosis with atrial fibrillation); acute pericarditis; subacute bacterial endocarditis; hemostatic defects including those secondary to severe hepatic or renal disease; significant hepatic dysfunction; pregnancy; diabetic hemorrhagic retinopathy or other hemorrhagic ophthalmic conditions; septic thrombophlebitis or occluded AV cannula at seriously infected site; advanced age (ie, >75 y); patients currently receiving oral anticoagulants (eg, warfarin sodium); any other condition in which bleeding would be particularly difficult to manage because of its location; documented hypersensitivity
Combining fibrinolytic agents and heparin can be confusing; heparin never should be given concurrently with urokinase, streptokinase, or APSAC to treat any condition; instead, heparin is started when thrombin time or aPTT is at or below twice normal control value; heparin should be given concurrently with alteplase or reteplase for treatment of acute MI; neither heparin nor aspirin should be given concurrently when tissue plasminogen activator used for acute ischemic stroke; when tissue-type plasminogen activators used for PE, heparin may be given concurrently or may be held and restarted after end of fibrinolytic therapy or when thrombin time or aPTT is at or below twice normal control value
Coagulation studies should be performed 4 h after initiation of fibrinolytic therapy

Alteplase (rt-PA, Activase)

Drug most often used to treat PE in ED. One advantage of alteplase is that FDA has approved it for this indication. Another advantage is that most ED personnel are familiar with alteplase because it is used so widely for treatment of patients with acute MI.

Adult

100 mg IV infusion over 2 h (FDA-approved regimen for PE)
Accelerated 90-min regimen is used widely, and most authors believe it is both safer and more effective than 2-h infusion; for accelerated regimen, recommended total dose based upon patient weight, not to exceed 100 mg
<67 kg: drug administered as 15-mg IV bolus, followed by 0.75 mg/kg infused over next 30 min (not to exceed 50 mg) and then 0.50 mg/kg over next 60 min (not to exceed 35 mg)
>67 kg: 100 mg given as 15-mg IV bolus followed by 50 mg infused over next 30 min and then 35 mg infused over next 60 min
Heparin therapy should be instituted or reinstituted near end of or immediately following alteplase infusion, when aPTT or thrombin time returns to twice normal or less

Pediatric

Use weight-adjusted accelerated regimen as in adults

Antiplatelet agents or anticoagulants increase risk of bleeding

Documented hypersensitivity; active internal bleeding; history of cerebrovascular accident; recent intracranial or intraspinal surgery or trauma; intracranial neoplasm, arteriovenous malformation, or aneurysm; known bleeding diathesis; severe uncontrolled hypertension

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

In following conditions, risks of fibrinolytic therapy may be increased and should be weighed against anticipated benefits:
Recent major surgery; recent puncture of noncompressible vessels; cerebrovascular disease; recent GI or GU bleeding; recent trauma; hypertension: systolic BP >180 mm Hg and/or diastolic BP >110 mm Hg; high likelihood of left heart thrombus (eg, mitral stenosis with atrial fibrillation); acute pericarditis; subacute bacterial endocarditis; hemostatic defects including those secondary to severe hepatic or renal disease; significant hepatic dysfunction; pregnancy; diabetic hemorrhagic retinopathy or other hemorrhagic ophthalmic conditions; septic thrombophlebitis or occluded AV cannula at seriously infected site; advanced age (ie, >75 y); patients currently receiving oral anticoagulants (eg, warfarin sodium); any other condition in which bleeding would be particularly difficult to manage because of its location; documented hypersensitivity
Combining fibrinolytic agents and heparin can be confusing; heparin never should be given with urokinase, streptokinase, or APSAC to treat any condition; instead, heparin started when thrombin time or aPTT is at or below twice normal control value; heparin should be given concurrently with alteplase or reteplase for treatment of acute MI; neither heparin nor aspirin should be given concurrently when tissue plasminogen activator used for acute ischemic stroke; when tissue-type plasminogen activators used for PE, heparin may be given concurrently or may be held and restarted after end of fibrinolytic therapy or when thrombin time or aPTT is at or below twice normal control value
Coagulation studies should be performed 4 h after initiation of fibrinolytic therapy

Urokinase (Abbokinase)

Direct plasminogen activator produced by human fetal kidney cells grown in culture. Relatively low in antigenicity. At time of this writing, production of urokinase and many other human cell culture products has been put on hold because of concerns about viral infections that can colonize human cell production facilities.
When used for localized fibrinolysis, given as local catheter-directed continuous infusion directly into area of thrombus with no loading dose. When used for PE, loading dose necessary.

Adult

Loading dose: 2000 U/lb infused IV over 10 min
Maintenance dose: 2000 U/lb/h IV for 24 h

Pediatric

Loading dose: 4400 U/kg IV over 10 min
Maintenance dose: 4400 U/kg/h IV for 12-72 h

Antiplatelet agents or anticoagulants increase risk of bleeding

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

In following conditions, risks of fibrinolytic therapy may be increased and should be weighed against anticipated benefits: recent major surgery; recent puncture of noncompressible vessels; cerebrovascular disease; recent GI or GU bleeding; recent trauma; hypertension: systolic BP >180 mm Hg and/or diastolic BP >110 mm Hg; high likelihood of left heart thrombus (eg, mitral stenosis with atrial fibrillation); acute pericarditis; subacute bacterial endocarditis; hemostatic defects including those secondary to severe hepatic or renal disease; significant hepatic dysfunction; pregnancy; diabetic hemorrhagic retinopathy or other hemorrhagic ophthalmic conditions; septic thrombophlebitis or occluded AV cannula at seriously infected site; advanced age (ie, >75 y); patients currently receiving oral anticoagulants (eg, warfarin sodium); any other condition in which bleeding would be particularly difficult to manage because of its location; documented hypersensitivity
Combining fibrinolytic agents and heparin can be confusing; heparin never should be given concurrently with urokinase, streptokinase, or APSAC to treat any condition; instead, heparin started when thrombin time or aPTT at or below twice normal control value; heparin should be given concurrently with alteplase or reteplase for treatment of acute MI; neither heparin nor aspirin should be given concurrently when tissue plasminogen activator used for acute ischemic stroke; when tissue-type plasminogen activators used for PE, heparin may be given concurrently or may be held and restarted after end of fibrinolytic therapy or when thrombin time or aPTT at or below twice normal control value
Coagulation studies should be performed 4 h after initiation of fibrinolytic therapy

Anticoagulants

Heparin augments the activity of antithrombin III and prevents the conversion of fibrinogen to fibrin. Full-dose LMWH or full-dose unfractionated IV heparin should be initiated at the first suspicion of DVT or PE.

With proper dosing, several LMWH products have been found safer and more effective than unfractionated heparin both for prophylaxis and for treatment of DVT and PE. Monitoring the aPTT is neither necessary nor useful when giving LMWH, because the drug is most active in a tissue phase and does not exert most of its effects on coagulation factor IIa.

Many different LMWH products are available around the world. Because of pharmacokinetic differences, dosing is highly product specific. Several LMWH products are approved for use in the United States: enoxaparin (Lovenox), dalteparin (Fragmin), and tinzaparin (Innohep). Enoxaparin and tinzaparin are currently approved by the FDA for treatment of DVT. Dalteparin is FDA approved for prophylaxis and has approval for cancer patients. Each of the other agents has been approved by the FDA at a lower dose for prophylaxis, but all appear to be safe and effective at some therapeutic dose in patients with active DVT or PE.

Fractionated LMWH administered subcutaneously is now the preferred choice for initial anticoagulation therapy. Unfractionated IV heparin can be nearly as effective but is more difficult to titrate for therapeutic effect. Warfarin maintenance therapy may be initiated after 1-3 days of effective heparinization.

The weight-adjusted heparin dosing regimens that are appropriate for prophylaxis and treatment of coronary artery thrombosis are too low to be used unmodified in the treatment of active DVT and PE. Coronary artery thrombosis does not result from hypercoagulability but rather from platelet adhesion to ruptured plaque. In contrast, patients with DVT and PE are in the midst of a hypercoagulable crisis, and aggressive countermeasures are essential to reduce mortality and morbidity rates.

Enoxaparin (Lovenox)

First LMWH released in US. Approved by FDA for both treatment and prophylaxis of DVT and PE.
LMWH has been used widely in pregnancy, although clinical trials not yet available to demonstrate that it is as safe as unfractionated heparin.
Except in overdoses, checking PT or aPTT has no utility, as aPTT does not correlate with anticoagulant effect of fractionated LMWH.

Adult

Treatment of DVT and PE: 1 mg/kg SC q12h or 1.5 mg/kg SC qd for 5 d; overlap w/warfarin until INR 2-3
DVT prophylaxis: 30 mg SC q12h
DVT prophylaxis in abdominal surgery: 40 mg SC qd, with first dose given 2 h prior to surgery

Pediatric

For treatment of acute DVT or PE: 1 mg/kg SC q12h

Platelet inhibitors or oral anticoagulants such as aspirin, NSAIDs, dipyridamole, salicylates, sulfinpyrazone, and ticlopidine can potentiate risk of bleeding

Documented hypersensitivity; major bleeding; thrombocytopenia

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Reversible elevation of hepatic transaminases occasionally seen; heparin-associated thrombocytopenia has been seen with fractionated LMWH; for significant bleeding complications, 1 mg of protamine sulfate reverses effect of approximately 1 mg of enoxaparin

Dalteparin (Fragmin)

LMWH with many similarities to enoxaparin but with different dosing schedule. Approved for DVT prophylaxis in patients undergoing abdominal surgery.
Except in overdoses, checking PT or aPTT has no utility, as aPTT does not correlate with anticoagulant effect of fractionated LMWH.

Adult

200 IU/kg SC q24h for at least 5 d; initiate warfarin sodium therapy simultaneously and continue for 90 d

Pediatric

Not established

Platelet inhibitors or oral anticoagulants such as aspirin, NSAIDs, dipyridamole, salicylates, sulfinpyrazone, and ticlopidine can potentiate risk of bleeding

Documented hypersensitivity; major bleeding; thrombocytopenia

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Reversible elevation of hepatic transaminases occasionally seen; heparin-associated thrombocytopenia has been seen with fractionated LMWH
If necessary, 1 mg protamine can neutralize 100 U of dalteparin

Tinzaparin (Innohep)

Approved for treatment of DVT in hospitalized patients. Enhances inhibition of factor Xa and thrombin by increasing antithrombin III activity. In addition, preferentially increases inhibition of factor Xa

Adult

175 IU/kg SC q24h for at least 5 d; initiate warfarin sodium therapy simultaneously and continue for 90 d

Pediatric

Not established; adult dose suggested

Platelet inhibitors or oral anticoagulants such as aspirin, NSAIDs, dipyridamole, salicylates, sulfinpyrazone, and ticlopidine can potentiate risk of bleeding

Documented hypersensitivity; major bleeding; thrombocytopenia

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Reversible elevation of hepatic transaminases occasionally seen; heparin-associated thrombocytopenia has been seen with LMWH

Unfractionated heparin

When unfractionated heparin used, aPTT should not be checked until 6 h after initial heparin bolus, as an extremely high or low value during this time should not provoke any action.

Adult

Initial bolus: 120-140 U/kg IV or approximately 10,000 U/70-kg person
Initial infusion: 20 U/kg/h IV
After bolus, check aPTT q6h until stable, and heparin dosing should be adjusted as follows:
If aPTT is low ( <1.5 times control value), administer second bolus of 5000 U and increase drip by 10%
If aPTT is high (>2.5 times control value), decrease drip 10%
If aPTT is extremely high (>100 s), hold heparin drip for 1 h and decrease drip 10%

Pediatric

Pediatric loading dose: 100 U/kg/h IV
Maintenance infusion: 15-25 U/kg/h IV; increase dose by 2-4 U/kg/h IV q6-8h prn using aPTT results

Digoxin, nicotine, tetracycline, and antihistamines may decrease effects; NSAIDs, aspirin, dextran, dipyridamole, and hydroxychloroquine may increase toxicity and risks of bleeding

Documented hypersensitivity; subacute bacterial endocarditis; active noncompressible bleeding; any history of heparin-induced thrombocytopenia

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Most important risk associated with unfractionated heparin is that it will be ineffective because of insufficient doses
All forms of heparin may cause hemorrhagic complications and all can trigger immune thrombotic thrombocytopenia 1-2 wk after beginning of treatment; heparin-associated thrombocytopenia is very serious, causes widespread thrombosis that is refractory to treatment, and can be fatal if not recognized quickly and managed appropriately
If significant bleeding complications develop, 15 mg of protamine sulfate (infused over 3 min) usually reverse anticoagulant effect
Some preparations contain benzyl alcohol as preservative; benzyl alcohol, used in large amounts, has been associated with fetal toxicity (gasping syndrome); use of preservative-free heparin recommended in neonates
Use with caution in patients with shock or severe hypotension

Warfarin (Coumadin)

Interferes with hepatic synthesis of vitamin K-dependent coagulation factors. Never give to patient with thrombosis until after patient has been anticoagulated fully with heparin, because first few days of warfarin therapy produce hypercoagulable state. Failing to anticoagulate with heparin before starting warfarin will cause clot extension and recurrent thromboembolism in about 40% of patients, compared with 8% of those who receive full-dose heparin before starting warfarin. Heparin should be continued for first 5-7 d of oral warfarin therapy, regardless of PT, to allow time for depletion of procoagulant vitamin K–dependent proteins.
Anticoagulant effect of warfarin adjusted by varying dose to keep INR within target range. An INR target range of 2.5 to 3.5 makes sense for DVT and PE because rate of recurrence increases dramatically when INR drops below 2.5 and decreases when INR is kept above 3.0. The risk of serious bleeding (including hemorrhagic stroke) is approximately constant when INR is between 2.5 and 4.5 but rises dramatically when INR is 5.0 or higher. In UK, higher INR target of 3.0 - 4.0 is recommended more often. Best evidence suggests that 6 mo of anticoagulation reduces rate of recurrence to half of that observed when only 6 wk of anticoagulation given.
Long-term anticoagulation indicated for patients with irreversible underlying risk factor with recurrent DVT or recurrent PE.
Procoagulant vitamin K–dependent proteins responsible for transient hypercoagulable state when warfarin first started and when stopped. This phenomenon occasionally causes warfarin-induced necrosis of large areas of skin or of distal appendages. Heparin always used to protect against this hypercoagulability when warfarin started, but when warfarin stopped, problem resurfaces, causing abrupt temporary rise in rate of recurrent venous thromboembolism.
At least 186 different foods and drugs have been reported to interact with warfarin. Clinically significant interactions have been verified for a total of 26 common drugs and foods, including 6 antibiotics and 5 cardiac drugs. Every effort should be made to keep patient adequately anticoagulated at all times because procoagulant factors recover first when warfarin therapy is inadequate.
Patients who have difficulty maintaining adequate anticoagulation while taking warfarin may be asked to limit their intake of foods that contain vitamin K. Foods that have moderate to high amounts of vitamin K include brussel sprouts, kale, green tea, asparagus, avocado, broccoli, cabbage, cauliflower, collard greens, liver, soybean oil, soybeans, certain beans, mustard greens, peas (black-eyed peas, split peas, chick peas), turnip greens, parsley, green onions, spinach, and lettuce.

Adult

Initial dose: 5-15 mg/d PO qd
After initial anticoagulation obtained, adjust dose according to desired INR

Pediatric

Administer weight-based dose of 0.05-0.34 mg/kg/d PO and adjust dose according to desired INR
Infants may require doses at high end of this range

Follow-up

Further Inpatient Care

Any degree of hemodynamic compromise or hypoxemia in a patient with pulmonary embolism (PE) is an indication that the patient should be assigned to a monitored unit rather than to a regular floor bed. These patients have exhausted their cardiopulmonary reserves and, because PE is a condition of many frequent recurrences, many of these patients may worsen suddenly at some point during their hospitalization.

Further Outpatient Care

Outpatient treatment after diagnosis of pulmonary embolism consists of anticoagulation for 3 months. This is typically done by 5 days of either happening or low molecular weight heparin started in the hospital, followed by warfarin treatment for an INR of 2. In a study comparing the advantages of 3 to 6 months treatment with anticoagulation, no additional benefit was found; however, there were more bleeding-related complications.²⁴

Deterrence/Prevention

Preventing idiopathic outpatient pulmonary embolism is difficult if not impossible. That said, the majority of pulmonary embolism occurs in hospitalized patients, and their incidence of pulmonary embolism can be reduced by providing the patient with appropriate prophylaxis. This can be done with heparin, low molecular weight heparin, warfarin, or mechanical prophylaxis.²⁵

Patient Education

For excellent patient education resources, visit eMedicine's Lung and Airway Center and Circulatory Problems Center. Also, see eMedicine's patient education articles Pulmonary Embolism and Blood Clot in the Legs.

Miscellaneous

Medicolegal Pitfalls

Because pulmonary embolism (PE) is both extremely common and fairly difficult to diagnose, many patients are seen in the ED and later die from undiagnosed PE. In fact, respiratory complaints are the most common complaints in patients who are seen alive in the ED and later die unexpectedly.
A small number of often repeated mistakes in diagnosis and treatment are responsible for a large proportion of the bad outcomes with serious legal repercussions. The most common and most serious of these errors are as follows:
- Dismissing complaints of unexplained shortness of breath as anxiety or hyperventilation without an adequate workup
- Dismissing complaints of unexplained chest pain as musculoskeletal pain without an adequate workup
- Failure to properly diagnose and treat symptomatic deep vein thrombosis (DVT)
- Failure to recognize that DVT below the knee is just as serious as more proximal DVT
- Failure to order a CTPA or V/Q scan when a patient has symptoms consistent with PE
- Failure to start full-dose heparin at the first real suspicion of PE, before the V/Q scan
- Failure to give fibrinolytic therapy immediately when a patient with PE becomes hemodynamically unstable

Special Concerns

Pregnancy
- Deep vein thrombosis (DVT) and pulmonary embolism (PE) are common during all trimesters of pregnancy and for 6-12 weeks after delivery.
- The diagnostic approach should be exactly the same in a pregnant patient as in a nonpregnant one. A nuclear perfusion lung scan is safe in pregnancy. A chest CT is safe in pregnancy. Heparin is safe in pregnancy. Fibrinolysis is safe in pregnancy. Failure to treat the mother properly is the most common cause of fetal demise.
Geriatric
- PE becomes increasingly common with age, yet the diagnosis of PE is missed more often in the geriatric population, largely because respiratory symptoms often are dismissed as chronic in geriatric patients.
- Even when the diagnosis is made, appropriate therapy more often is withheld inappropriately in this population than in any other group.

http ://emedicine.medscape.com/article/759765

Advance Toward Early Diagnosis Of Chronic Obstructive Pulmonary Disease

2009-07-11T10:20:00.002+07:00

Researchers in Finland are reporting identification of the first potential "biomarker" that could be used in development of a sputum test for early detection of chronic obstructive pulmonary disease (COPD). That condition, which causes severe difficulty in breathing — most often in cigarette smokers — affects 12 million people in the United States.

Vuokko L. Kinnula and colleagues point out that no disease marker for COPD currently exists, despite extensive efforts by scientists to find one. Past research pointed to a prime candidate — surfactant protein A (SP-A), which has a major role in fighting infections and inflammation in the lung.

The scientists compared levels of a variety of proteins obtained from the lung tissues of healthy individuals, patients with COPD, and those with pulmonary fibrosis. They found that the lungs of COPD patients contained elevated levels of SP-A. The scientists also found elevated levels of SP-A in the sputum samples of COPD patients. "This suggests that SP-A might represent a helpful biomarker in the early detection of COPD and other related disorders," the article notes.

Source : http://www.sciencedaily.com/releases/2008/12/081208085002.htm

Severe COPD May Lead To Cognitive Impairment

2009-07-11T10:15:00.001+07:00

Severe chronic obstructive pulmonary disease (COPD) is associated with lower cognitive function in older adults, according to research from Mount Sinai School of Medicine. Researchers compared cognitive performance in over 4,150 adults with and without COPD and found that individuals with severe COPD had significantly lower cognitive function than those without, even after controlling for confounding factors such as comorbidities.

"Our findings should raise awareness that adults with severe COPD are at greater risk for developing cognitive impairment, which may make managing their COPD more challenging, and will likely further worsen their general health and quality of life," wrote lead author of the study, William W. Hung, M.D., M.P.H., assistant professor at Mount Sinai School of Medicine.

Patients with COPD may experience periods of hypoxia—low oxygen levels—that might lead to brain abnormalities that could reduce cognitive capacity. Alternatively, hypoxia may cause or exacerbate diseases that are characterized by cognitive impairment, such as Alzheimer's disease. Although past studies have observed a higher rate of cognitive impairment among adults with COPD, the relationship has not been formally tested longitudinally in large populations until now.

"We wanted to determine whether the observed relationship between COPD and cognitive impairment was, in fact, something we could document over time, and if so, we wanted to determine whether the degree to which it occurred was significant," said Dr. Hung.

To do so, Dr. Hung and colleagues obtained data from the Health and Retirement Study, a national prospective biennial survey of Americans 50 and older. They included data from survey takers who had undergone cognitive testing in 1996 and again in 1998, 2000 or 2002.

Of the 4,150 individuals ultimately included, 492 had COPD, and of those, about one-third (153) had severe disease. Using a 35-point cognition scale, the researchers found that scores among all patients with COPD declined on average by one point over the six-year period between 1996 and 2002.

After further classifying those with COPD as having severe or nonsevere disease, the researchers found that severity and cognitive decline were linked. Even after controlling for sociodemographic characteristics and other confounding factors, the mean cognition scores for those with severe COPD were significantly lower (0.9 points; p=0.01) than those without COPD.

"These objective measures of cognition used in survey research do correlate with functional impairment," said Dr. Hung. In particular, executive functions that require greater cognitive ability, such as handling money and medications, are more poorly performed at greater levels of cognitive impairment. Extrapolating from past research using the same cognitive test, Dr. Hung and colleagues suggest that their findings would likely be associated with a 22 percent increase in the mean number of difficulties the severe COPD population would experience with daily tasks.

"While this number may not appear to be of major concern on the individual level, on a population level, it is roughly equivalent to nearly a quarter of severe COPD patients experiencing difficulty with a basic life skill," said Dr. Hung. "In this regard, these findings have serious implications. Often patients with cognitive difficulties, if undetected and untreated, have lower adherence to their treatment and follow-up regimens, and as a consequence may deteriorate more rapidly and have worse health outcomes."

In conclusion, Dr. Hung suggested that physicians and other clinical staff managing the care of these patients should be aware of their increased risk for cognitive decline and the greater needs and challenges associated with caring for cognitively impaired older adults.

Source : http://www.sciencedaily.com/releases/2009/07/090707121413.htm?tr=y&auid=5063625

Streptococcus pneumoniae: Epidemiology, Risk Factors, and Strategies for Prevention

2009-07-04T22:53:00.002+07:00

Abstract and Introduction

Abstract

Streptococcus pneumoniae is the most common cause of community-acquired pneumonia, meningitis, and bacteremia in children and adults. Invasive pneumococcal disease (IPD) primarily affects young children, older adults (> 65 years of age), and individuals with comorbidities or impaired immune systems. Case fatality rates range from 10 to 30% in adults with IPD but are much lower (<>

Introduction

Streptococcus pneumoniae is the most common cause of community-acquired pneumonia (CAP) in adults, accounting for 30 to 70% of cases requiring hospitalization.^[1-4] A meta-analysis of 122 reports of CAP between 1966 and 1995 implicated S. pneumoniae in 66% of nearly 7000 cases with an established etiology.^[2] In addition, S. pneumoniae is the leading cause of bacteremia,^[5-7] meningitis,^[8] upper respiratory tract infections, and otitis media^[9] worldwide. Bacteremia is present in ∼20% of pneumococcal pneumonias in adults, with case-fatality rates of 10 to 30%.^[2,6,10-16] Mortality rates are much lower in children (<>[11,17,18] Invasive pneumococcal disease (IPD), defined as isolation of S. pneumoniae from a normally sterile site [e.g., blood; cerebrospinal fluid (CSF); surgical aspirate; pleural, pericardial, peritoneal, bone, or joint fluid],^[19] most frequently affects young children (particularly age 6 to 24 months), older adults (age ≥ 65 years), and immunocompromised individuals (children or adults).^[1,20] The World Health Organization (WHO) estimates that 1.6 million people, including up to 1 million children <>[21] with developing countries bearing the greatest burden.^[22] In North America and Europe, the annual incidence of pneumococcal bacteremia is 15 to 40/100,000 individuals.^[1,7,11,17] In the United States in 2003, 35,000 cases of IPD in adults ≥ age 18 led to 5600 deaths; 44% of cases and 60% of deaths were in adults ≥ 65 years of age (www.cdc.gov/abcs). The incidence is age dependent ( Table 1 ). In the United States, the annual incidence of IPD in children <> 65 years of age.^[11,17,23] Regional differences in the incidence of IPD have been noted.^[1,7,17,24] In Europe, the annual incidence of IPD in children <>[24-27] In the early to mid-1990s the reported incidence of pneumococcal bacteremia increased in several countries, including the United States,^[11,28] Belgium,^[25] Sweden,^[29,30] Norway,^[31] and Denmark.^[32] Following the introduction of pediatric heptavalent pneumococcal conjugate vaccine (PCV7) in the United States in February 2000, the incidence of IPD declined substantially in both children and nonvaccinated adults (by herd immunity).^{[7,15,23,33-36]} Unfortunately, the incidence of IPD due to non-PCV7 serotypes is increasing globally.^[37,38] Further, fluctuations in incidence of IPD within countries may occur due to clonal spread or other factors (in the absence of vaccine effect).^[27,30]

Clinical manifestations of pneumococcal infections are varied and include asymptomatic colonization,^[20,39] upper respiratory tract infections, otitis media,^[9,40] sinusitis,^[41] conjunctivitis,^[42,43] bacteremia (with or without a definite site of infection),^[5,6] pneumonia,^[1,6,10,11] empyema,^[44-47] meningitis,^[8,48] endocarditis,^[41,49-51] septic arthritis,^[52] cellulitis,^[53] and so forth. In young children, bacteremia without identifiable source accounts for 50 to 70% of episodes of IPD, pneumonia (15 to 25%), meningitis (4%), otitis media or miscellaneous sites (10%).^[54,55] In adults, pneumonia accounts for 50 to 80% of episodes of IPD. Other sites of infections include bacteremia without identifiable focus (15 to 20%), meningitis (4 to 8%), miscellaneous sites (2 to 5%).^[17,54-57]

Ecology of Streptococcus Pneumoniae Infections

The nasopharynx is the major ecological reservoir of S. pneumoniae; spread from the nasopharynx to lower respiratory tract or other sites may cause invasive disease.^[58] Children are the major carriers.^[39,59-62] Thirty to 50% of young children (<>S. pneumoniae in the nasopharynx,^[39,61,63] compared with carriage rates of only 4 to 12% in adults^[39,62,64] and 8.2% in adolescents.^[65] Higher rates of carriage (13 to 34%) were noted in adults in select populations.^[66-68] Young age (<>[39,59,60,63] Risk factors for NP carriage in adolescents or adults include acute upper respiratory tract infection,^[39,65] exposure to passive cigarette smoke,^[64,65] and asthma.^[65] Transmission from children to siblings, household contacts, or adults is the major cause of IPD.^[40,69,70] Interestingly, in Utah, children with IPD due to nonvaccine serotypes tended to be from larger households.^[71] Most children have at least one pneumococcal infection (typically of the middle ear) within the first 5 years of life.^[72-75] In subsequent years, pneumococcal infections are less common, due to acquisition of humoral immunity.^[72] Pneumococcal infections are more common in immunocompromised individuals (children or adults),^[76,77] older adults (age ≥ 65 years),^[78,79] or in the presence of comorbidities.^[55,79]

Pathogenesis of Streptococcus Pneumoniae Infections

NP carriage of S. pneumoniae is required for transmission of bacteria and for invasive disease.^[80] Pneumococci bind to mucosal epithelial cells of the nasopharynx.^[72] In normal healthy children, NP carriage of pneumococci is transient and is not associated with disease.^[21] However, disease is caused by contiguous spread to the sinuses or middle ear, aspiration into the lung, or invasion of the bloodstream.^[72] Progression to pneumonia requires additional factors (e.g., antecedent viral infections, lung injury, impaired host defenses, etc.). Clearance of pneumococci is facilitated by both humoral and cellular immune responses involving monocyte/macrophages, polymorphonuclear leukocytes (PMNs), anticapsular antibodies, and lymphocytes.^[72] Further, nonimmune factors (e.g., anatomical barriers, cilia, mucins, colectins, surfactant, etc.) are also critical to clear bacteria.^[81] Prognosis of pneumococcal infections depends upon both host- and organism-dependent factors.^[72]

The polysaccharide capsule serves as a major pathogenic factor for invasive disease by preventing phagocytosis.^[72] Humoral antibodies directed against the polysaccharide capsule usually develop within the first 2 years of life; colonization with specific serotypes may elicit serotype-specific humoral antibodies.^[72,82] Protection is serotype specific but some cross-serotype protection is found in some cases.^[80] However, these anticapsular antibodies (whether acquired naturally or by vaccination) provide incomplete protection against IPD.^[80,83,84] Antibodies to serotype 19F reduced colonization rates in some^[80] but not all studies.^[82] Additional serotype-independent factors are important in preventing or resolving pneumococcal disease and carriage.^[80] Components of the pneumococcal cell walls recruit PMNs to the lung, enhance permeability of alveolar epithelial cells, and stimulate cytokine release.^[72] The host's primary cellular immune response against S. pneumoniae is mediated by alveolar macrophages (AMs); neutrophils represent a second line of defense.^[85] The immune response against S. pneumoniae is complex, involving proinflammatory cytokines released by AMs [e.g., tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β)],^[81,86] macrophage inflammatory protein-2 (MIP-2),^[81] upregulation of myriad cytokines and chemokines (e.g., IL-6, IL-8, and IL-18)^[81,87]], and adhesion molecules on endothelial cells.^[81] Toll-like receptors (TLRs), expressed on both immune and nonimmune cells, are important to recognize S. pneumoniae and promote bactericidal response by mononuclear cells.^[88] Further, granulocyte-colony stimulating factor (G-CSF) recruits and stimulates PMNs, facilitating phagocytosis and oxidative burst.^[81] T lymphocyte cells also play a role in eradicating pathogens from the alveolar spaces.^[81] Dendritic cells present the antigen to T cells, expanding CD4+ T cell responses, specifically T-helper 1 (Th1) and Th2 phenotypes.^[81] Th1 immunity, characterized by production of IL-2, IL-12, IL-18, granulocyte monocyte-colony stimulating factor (GM-CSF), and interferon-γ (INF-γ), is critical to the eradication of pneumococci.^[81] Interestingly, deficiency of IL-12 in humans has been associated with recurrent pneumococcal pneumonia.^[89] Th2 cells release cytokines that stimulate B cell antibody production, thereby facilitating humoral responses.^[81] Other cells/products critical to eradicating pneumococci include antibody- and complement-mediated opsonization; IL-1 receptor-associated kinase-4- and nuclear factor kappaB^[90]; and memory T cells (generated in the spleen).^[91] In summary, eradication of pneumococci is achieved by myriad interactions involving anatomical boundaries, diverse cells (immune and nonimmune), cytokines, chemokines, and humoral antibodies, and other factors that work in concert. Deficiency of specific immune components (e.g., asplenia, hypogammaglobulinemia, B cell dysfunction, etc.) can lead to recurrent or fatal pneumococcal infections. Further, prognosis of pneumococcal infections depends upon both host- and organism-dependent factors.^{[13,57,92,93]} Antiinflammatory cytokines (e.g., IL-4 and IL-10) have a role in harnessing (blunting) immune responses to infection and can be beneficial or detrimental depending upon the extent of infectious burden and host inflammatory response. Unregulated release of pneumococcal cell wall components during lysis can stimulate brisk inflammatory cytokine responses that may enhance pathological damage and heighten mortality.^[81] Optimal response to pneumococcal infections requires a carefully orchestrated and regulated response sufficient to kill the organism without causing excessive injury to the host.

Molecular Epidemiology: Importance of Serotypes

Virtually all strains of S. pneumoniae have a polysaccharide capsule, which is the basis for serotyping.^[80,94] Currently, 91 distinct capsular types have been identified.^[80] More than 99% of IPDs are caused by S. pneumoniae-containing capsules.^[42] Nonencapsulated strains are rare but were implicated in outbreaks of conjunctivitis in military trainees^[43] and college students.^[42] Globally, ∼20 serotypes account for > 80% of IPD in all age groups; 13 serotypes have been implicated in > 75% of IPD in children.^[21] The dominant serotypes associated with IPD worldwide include 14, 4, 1, 6A, 6B, 3, 8, 7F, 23F, 18C, 19F, and 9V.^[1,92,95] In young children, the number of serotypes is more limited, with types 6, 14, 18, 19, and 23F predominating.^[1] The reasons for the dominance of these serotypes in children, with their immature immune systems, is that these serotypes are less immunogenic than other types.^[1,78,96] In most series, more than 80% of IPDs were due to serotypes encompassed in the 23-valent PPV (pneumococcal polysaccharide vaccine), and 40 to 70% were due to serotypes included in the PCV7 (i.e., 4, 6B, 9V, 14, 18C, 19F, 23F).^{[1,15,54,80,92,96]} A major shift in the distribution of serotypes has been noted over time. In the beginning of the twentieth century, serotypes 1, 2, 3, and 5 accounted for up to 75% of bacteremic cases in the United States and Europe.^[1,97] Today, types 2 and 5 are rarely isolated in Western countries, and type 1 is uncommon.^[1] Instead, other serotypes have increased in prevalence. Interestingly, types 1 and 5 are common today in developing countries.^[1] Substantial differences in the distribution of serotypes have been noted in different geographical regions; further, the distribution may change over time.^[1,29] Serotype 3 has decreased in frequency over the past few decades, whereas type 14 has become more prevalent.^{[1,29,31,32,96,98]} In Sweden, the incidence of type 14 isolates increased threefold from 1987 to 1992; type 1 increased 10-fold from 1992 to 1997.^[30] The increase in type 14 reflected a hypervirulent clone that has also been found in the United States and Canada.^[30] Clonal expansion of other serotypes (e.g., type 1,^[99] serotypes 15 and 33^[38] and type 19A^[74,100-103]) has been noted in the United States. Changes in serotype distribution can be modified by antibiotic usage and vaccination patterns. In recent years (following the introduction of PCV7), nonvaccine serotypes are increasing in frequency.^[37,103,104] In a review of pneumococcal pneumonia in children in Utah, nonvaccine serotypes represented 49% of isolates from 1997 to 2000 and 88% of isolates from 2001 to 2006.^[37] Different serotypes exhibit differences in attack rate and colonization,^{[92,95,105-107]} case-fatality rates, and clinical expression of disease.^{[15,56,57,92,105]} In a study of pneumococcal pneumonia in children, serotype 3 was 15 times more likely to cause necrotizing pneumonia compared with other serotypes.^[37] Further, serotype 3 was associated with an increased risk of empyema and need for surgical procedures compared with other serotypes.^[37] Other investigators cited higher case fatality rates with IPD caused by serotype 3,^{[13,57,92,93]} although this was not a consistent finding.^[15,108] Sandgren et al evaluated 273 invasive (257 from adults) and 246 NP isolates (all from children) of S. pneumoniae in Stockholm in 1997.^[95] The isolates formed two major classes: one class comprised serotypes 1, 4, 7, and 9V and was highly clonally related; a second class caused invasive disease but also was common in carriage (including type 6A, 6B, 14, and 19F isolates) and was genetically more diverse.^[95] Serotypes 9V accounted for 7% of invasive isolates but only 2% of carrier isolates. By contrast, serotypes 6A and 19F accounted for 34% of isolates among carriers but only 3% of invasive isolates. Specific clones within the same serotype exhibited different abilities to cause invasive disease. Further, isolates belonging to the same clone that exhibited capsular switch displayed the same disease potential. In a subsequent study by these investigators, serotypes with the highest invasive potential (e.g., types 1 and 7F) were associated with low fatality rates, whereas serotypes 3, 6A, 6B, 11A, 19F, and 23F were associated with low invasive potential but caused more severe disease and increased mortality.^[56] Isolates with high invasive potential behave as primary pathogens, whereas strains with low invasive potential behave as opportunists (e.g., among patients with underlying disease).^[56] An international study from five countries from 1993 to 1995 found that serotype 14 was most common, but type 3 dominated in the fatal cases and in the United States and Spain, countries with the highest mortality rates.^[92] A study of 494 adults with IPD noted correlations between age and serotypes causing IPD.^[56] Serotype 1 was associated with IPD only among patients <> 65 years old (78%).^[56] In one study, serotype 12 was associated with lower mortality,^[57] whereas a prospective international study found no association with serotype and mortality when other risk factors were taken into account.^[15] Nonetheless, an association between serotype and enhanced virulence and severity of disease is plausible. In a murine model, cytokine proinflammatory responses were more robust in clones with less invasive potential,^[109] suggesting that differences in innate immune responses to specific clones (strains) may explain differences in the clinical expression/severity of disease. Serotype prevalence varies among geographic regions and may change over time in response to selective pressure or clonal spread.^{[30,95,110-113]} Further, capsular switching may occur, thus providing a survival advantage to the organism (by eluding capsular-specific opsonizing antibodies), and may facilitate survival of specific clones.^[56,95] In addition to capsular types, other properties of the organism (e.g., virulence factors, etc.)^[30,114] may influence disease severity and invasive potential. However, host factors are likely more important than serotype regarding severity of disease and mortality rates.^[15]

Risk Factors for Invasive Pneumococcal Disease

The incidence of IPD is much higher at extremes of age (<>[17,57,73-75,115,116] (Table 2), in patients with comorbidities or defects in immune defenses^{[1,17,57,71,76,115]} (Table 3 and Table 4), and in the winter months.^[1,117] In both children and adults, chronic illness is the strongest risk factor for IPD^[71,76] (Table 3). Invasive pneumococcal infections usually reflect transmission from NP carriage in children. Outbreaks of IPD may occur in crowded, closed settings such as schools,^[42] day care centers,^{[115,118,119]} households with multiple children,^{[40,75,115,120,121]} long-term care facilities (LTCFs),^[68,122-124] closed communities,^[125] military camps,^[43,126] shelters,^[127] jails,^[128] and hospitals.^{[119,129,130]} Interestingly, South African women infected with human immunodeficiency virus (HIV)were more likely to develop IPD with pediatric serotypes compared with HIV-infected men, likely because of women's closer proximity to small children.^[131] Widespread pneumococcal vaccination may reduce risk of IPD in closed populations^[68,132] and the community at large.^[23,55]

Infants <>[71,115,133,134] However, the risk of IPD is increased among preterm and low birth weight infants <>[115] In one study, day care attendance was associated with increased risk of IPD in infants between 6 and 23 months old, but not in older children (age 2 to 5 years).^[115] These trends reflect natural acquisition of immunity (usually by 2 to 3 years of age), that is durable. A history of tympanostomy tube was associated with an increased risk.^[71] In adults, advanced age predisposes to IPD, owing to the presence of comorbidities or immune senescence.^[17,76,124]

Ethnic and Socioeconomic Factors

Regional and racial differences in the incidence of IPD have been noted globally.^{[24,74,76,135]} Pneumococcal infections are more common in indigenous peoples of Alaska^[136-138] and the Canadian arctic,^[138] Inuits in Greenland,^[139] American Indians (White Mountain Apache and Navaho),^[82,140-142] blacks in the United States,^{[17,74,76,135]} Australian aborigines,^[143] Maoris of New Zealand,^[144] and Bedouins of Israel.^[145] Socioeconomic factors likely are responsible for the higher incidence in these groups, but genetics may play a contributory role. Genetic factors (e.g., polymorphisms) may play a role in susceptibility to IPD,^[146-149] but one large study from Denmark found no higher risk of IPD among relatives apart from risk associated with sharing the same household.^[75]

Risk Factors in Immunocompetent Individuals

Exposure to cigarette smoke and multiple children in the household are risk factors for IPD in healthy children.^[121] In otherwise immunocompetent adults, the incidence of IPD is increased with the following comorbidities: alcohol abuse,^{[76,142,150-152]} congestive heart failure,^{[76,135,142,153]} chronic lung disease,^[76,151,153] cigarette smoking,^{[151,153,154]} asthma,^[155] recent influenza infection,^[156] diabetes mellitus,^[76,135,157] institutionalization,^[124,153] neurological disorders,^[153] male gender,^[154] and black race^[17,76] (Table 2). Among immunocompetent adults 18 to 64 years of age, current cigarette smoking was the strongest risk factor for IPD.^[154] Further, a dose-response relation was found between number of cigarettes smoked and risk of IPD.^[154] Multiple comorbidities or age ≥ 65 years amplify the risk.^{[17,57,76,158]}

Immunosupressed Individuals

Patients with primary or acquired immune deficiencies have a heightened risk for IPD.^[76,90,135] The risk is highest among patients with B cell defects (due to intrinsic B cell anomaly or impaired T cell helper activity) or deficiencies of early components of the classical pathway of complement.^[90] Disorders associated with increased risk of IPD include asplenia,^[159-161] hemoglobinopathies (particularly sickle cell disease),^{[151,162-164]} hematological^[76,135,165] or solid^{[76,135,166,167]} malignancies,^[168-170] organ transplant recipients,^{[168,171-173]} HIV infection,^[151,174] and primary or acquired immunodeficiency states or receipt of immunosuppressive drugs (including corticosteroids).^[90,168-170] Each of these disorders is discussed separately in the sections that follow. Recurrent episodes of IPD are uncommon in immunocompetent hosts but may be observed in patients with severe immunodeficiency states (e.g., HIV infection or asplenia).^{[17, 54, 175-177]}.

Sickle Cell Disease

The incidence of IPD in children with sickle cell disease (SCD), particularly those with homozygous disease (SS), is 30- to 600-fold higher than in individuals of comparable age and race without SCD^{[151,162-164,178,179]} (Table 4). Pneumococcal septicemia and meningitis are important causes of death in SCD patients, with case/fatality rates of 15 to 35%.^{[164,180-186]} The risk of IPD is highest in children <>[162,164,181] Disease severity is usually worse in patients with homozygous (SS) and heterozygous (SC) disease. In one series, hypotension was more common with SS, whereas acute chest syndrome and otitis media were more common findings in patients with SC.^[164] The incidence of IPD and mortality due to bacterial infections in SCD has declined over the past 2 decades,^{[164,182,184,187]} likely reflecting the impact of penicillin prophylaxis, earlier recognition and treatment of infections,^{[181,182,186,188]} vaccines,^{[162,181,189,190]} and improved medical care.^[162]

However, even with prophylactic measures (e.g., antimicrobial prophylaxis and vaccination with the 23-valent polysaccharide pneumococcal vaccine (23PPV) at age ≥ 2 years), the incidence of IPD was 10-fold higher among SCD patients compared with controls.^[164] Further, many children with SCD do not receive antibiotic prophylaxis.^[163,188] Since 2001, the use of PCV7 has markedly reduced the incidence of IPD in children with SCD.^[162,179] From 1995 to 2000, the rate of IPD (per 1000 patient years) in children ages 0 to 10 years with SCD in Atlanta was 1.7; by 2001-02, the rate had declined to 0.5.^[179] In Tennessee, the rate of IPD decreased by 93.4% in SCD children ≤ 5 years old.^[162] Antibody responses are enhanced by using both PCV7 and 23PPV vaccines in children or young adults with SCD.^[191] Optimal duration of antibiotic prophylaxis is uncertain.^[163] Because the rate of IPD declines substantially in older children (> 5 years),^{[164,181,192]} it is reasonable to discontinue antibiotic prophylaxis after age 5 provided (1) patients have not had prior severe IPD, (2) vaccination has been administered, and (3) splenic function is adequate.^[193,194] Further, penicillin prophylaxis may not be necessary in countries or regions associated with a low rate of pneumococcal infections (e.g., Africa).^[195]

Splenectomy or Asplenia

Splenectomized patients or those with functional asplenia are at increased risk for life-threatening infections due to encapsulated bacteria (including pneumococcus).^{[160,169,170,196,197]} The risk of IPD after surgical splenectomy among nonvaccinated children ranges from 1 to 9%.^{[160,196,198]} Most IPD occur within 1 to 2 years of splenectomy,^[160] but the risk may persist for > 15 years in some cases.^[197] The incidence of IPD is even higher (up to 8.5%) among children with congenital asplenia.^{[160,161,199]} Further, the case-fatality rate of IPD is higher among asplenic children.^[160] Administering vaccines and prophylactic antibiotics reduces the risk.^[160,198] All asplenic children <>[160] However, response to vaccination may be blunted in asplenic patients.^[169] Antibiotic prophylaxis is warranted, but appropriate duration or therapy is controversial.

Risk in Solid and Hematologic Malignancies

The incidence of IPD is increased in patients with solid or hematologic malignancies^{[76,135,165-170,200]} ( Table 4 ). Kumashi et al reported 135 consecutive episodes of S. pneumoniae bacteremia in 122 cancer patients.^[166] Fifty-two percent of patients had hematological malignancies; 48% had solid cancers. Only 24 episodes (18%) occurred during neutropenia. Pneumonia was present in 67%; infected catheters accounted for 18% of episodes. Most (88%) episodes of bacteremia were community acquired. Overall, 19 patients (16%) died within 2 weeks of diagnosis. In a study of 56 cancer patients with pneumococcal bacteremia, the incidence was highest (> 1000 cases per 100,000) in the following groups: Hodgkin disease postsplenectomy, multiple myeloma, and chronic lymphocytic leukemia.^[167] In a recent study, German investigators cited a 10-fold increased incidence of IPD in children with acute lymphoblastic leukemia compared with the general pediatric population.^[200] This increased incidence of IPD reflects chemotherapy-induced immune aberrations, including: loss of B or T cell activity, neutropenia, chemotherapy-induced hyposplenism, impaired antibody responses to vaccines, and disruption of respiratory mucosa ciliary function.^[76,166]

Organ Transplant Recipients

The risk of IPD is much higher in recipients of hematopoietic stem cell (HSC)^{[168,172,173]} or solid organ^[171,201] transplants^{[168,172,173]} compared with healthy controls (Table 4). Infection risk depends upon intensity of immunosuppression and environmental factors and usually occurs > 3 months posttransplantation.^[171,172] The incidence is highest in allogeneic HSC recipients with chronic graft versus host disease (GVHD).^{[172,173,202-204]} Compared with the general population, the relative risk (RR) of IPD was 30.2 among HSC recipients^[172] and 12.8 among solid organ transplant (SOT) recipients residing in the same geographic region.^[205] Serotypes implicated among transplant recipients are similar to those reported in immunocompetent patients.^{[171,172,205]} Vaccination is important for all transplant recipients (SOT and HSC).^[206,207] Efficacy of vaccination may be blunted, however, by depletion of T and B cells among HSC recipients or the effects of immunosuppression on B cells in SOT recipients.^{[171,172,207,208]} The conjugate vaccine (PCV7) has enhanced immunogenicity compared with 23PPV and elicits a T cell and memory response.^[171,207] In a randomized trial, 3 doses of PCV7 administered at 3, 6, and 12 months after HSC conferred protection in most patients (72 to 100% for different serotypes) by 12 months after transplantation.^[209] Although the optimal vaccination schedule, type of vaccine, and efficacy among transplant recipients have not been validated in clinical trials,^[207] sequential doses of 23PPV at 12 and 24 months post-HSC transplant or combinations of both 23PPV and PCV7 are reasonable.^[172,207] For small children and patients (all ages) with chronic GVHD, administering 3 doses of PCV7 starting at 6 to 12 months after HSC is reasonable.^[207] Given the high risk of IPD among allogeneic HSC recipients and chronic GVHD, long-term antimicrobial prophylaxis may be warranted in this group.^[203,206] The choice of antibiotic depends on local antibiotic resistance patterns.^[207]

Human Immunodeficiency Virus Infected

In the era prior to highly active antiretroviral therapy (HAART), the rate of IPD among adults with HIV infection or acquired immunodeficiency syndrome (AIDS) in the United States or Europe was > 40 times higher than age-matched populations^{[19,151,174,210-214]} (Table 4). The incidence of IPD was highest among injection drug users with HIV.^[210,211] In HIV-infected children, the incidence rates of IPD are exceptionally high (ranging from 183 to 18,500 episodes per 100,000 child years.^[215-219] Recurrent episodes of IPD are more common among HIV-infected patients.^[54,210,214] A study of Gambian women with HIV/AIDS noted increased rates of NP colonization, often with pediatric serotypes.^[220] Surveillance data from the ABC Study in the United States noted that HIV-infected persons accounted for 15 to 20% of cases of IPD from 1998 to 1999.^[221]

Since the introduction of HAART, marked declines in the incidence of IPD^{[210-212,222-224]} have been noted in HIV-infected adults in developed countries (Table 4). Fewer data are available in children, but epidemiological studies cited severalfold reductions in the incidence of bacteremias^[225] or pneumonias^[225,226] in children between the pre-HAART and HAART eras.^[227] Unfortunately, in areas of the world with a large burden of HIV infection, the incidence of IPD may be increasing.^[228] Some studies reported lower mortality rates for IPD, including meningitis, among HIV-infected patients.^[210,229] This lower mortality rate may in part reflect a blunted inflammatory response to S. pneumoniae ^[230] and younger age of HIV-infected patients.^[210]

In the ABC surveillance study from 1998 to 1999, the distribution of serotypes causing IPD differed among adults with HIV/AIDS compared with adults with no underlying disease.^[221] The serotype distribution among HIV/AIDS patients was similar to those with hematogenous cancers.^[221] Similarly, a series of IPD in South Africa noted differences in serotypes and antimicrobial resistance patterns among HIV-infected and non-HIV-infected persons.^{[217,228,231]}

The use of trimethoprim/sulfamethoxazole (TMP/SMX) prophylaxis may select for more resistant pathogens,^[210,232] but prior use of TMP/SMX prophylaxis was not associated with TMP/SMX susceptibility in a large cohort (n = 416) of HIV-infected patients with pneumococcal bacteremia.^[221] However, in South African children with IPD, resistance to penicillin, TMP/SMX, and multidrug resistance were more common in HIV-infected children.^[217]

Pneumococcal vaccination is recommended for HIV-infected adults and adolescents with CD4+ lymphocyte counts > 200 cells/µL,^[233] but data supporting efficacy are limited.^[210,223] Immune deficits associated with HIV infection may dampen the antibody response to 23PPV.^{[230,234-236]} The use of 23PPV did not reduce the incidence of IPD, all-cause pneumonia, or mortality in a cohort of HIV-infected adults in Uganda.^[237] Retrospective studies in the United States suggested that 23PPV protects against IPD among certain groups of HIV-infected patients, specifically those with CD4 counts ≥ 200 cells/µL^[238] or ≥ 500 cells/µL^[212] at the time of vaccination or those receiving HAART.^[212,223] These studies were not controlled for comorbidities. A recent prospective study in the United States (the Veterans Aging Cohort 5-Site Study) found that vaccination with 23PPV reduced the risk of pneumonia in HIV-infected adults; current smoking, low hemoglobin level, and low CD4 cell count significantly increased the risk.^[239] Among non-HIV infected patients, vaccination with 23PPV did not confer protection (possibly because of lack of statistical power).^[239] Benefits associated with HAART may reflect its effects on improving B cell function^[240] and qualitative and quantitative responses to pneumococcal antigens.^[241] One randomized trial in HIV-infected adults found that vaccination with two injections of either PCV7 or 23PPV 2 months apart elicited higher antibody responses compared with placebo/23PPV.^[242] Vaccination with 23PPV after previous vaccination with PCV7 enhanced antibody response in HIV-infected adults.^[243] In HIV-infected children, PCV7 has been shown to be safe.^{[215,244,245]} PCV7 is immunogenic in HIV-infected children, but less so than in HIV-uninfected children.^{[215,244-246]} In children with HIV-infection, a positive correlation between antibody concentration elicited by PCV7 and duration of HAART was found.^[245] However, the functional activity of pneumococcal antibodies elicited by PCV7 was lower in HIV-infected compared with noninfected children.^[247] Clinical efficacy of PCV7 in HIV-infected patients remains uncertain. However, a South African trial noted significant reductions in IPD and pneumonia in HIV-infected children with a nine-valent vaccine.^[248] This effect was attenuated at 5 years compared with non-HIV-infected children.^[249] The impact of PCV7 in communities with high rates of HIV infections is not known. In the United States, the rate of IPD in HIV-infected adults (aged 18 to 64 years) declined by 19% from 1998-99 to 2003; vaccine-type IPD fell by 62% in this group.^[73] The optimal vaccination policy for HIV-infected persons has not been elucidated. However, universal vaccination of HIV-infected patients is reasonable to reduce colonization and infection.^[215]

Risk Factors for Mortality in Pneumococcal Pneumonia

Mortality for bacteremic pneumococcal pneumonia ranges from 10 to 30% in adults and <>[2,6,10,11,17,250] Case fatality rates for meningitis range from 16 to 37% in adults^[8,34] and 1 to 2.6% in children.^[34,251] Extrapulmonary manifestations will not be further addressed here. Mortality rates are much higher in the elderly and patients with comorbidities. Although disparate results have been noted, factors associated with higher mortality in bacteremic pneumococcal pneumonia include age (> 65 years),^{[2,5,11-13,15,252,253]} multilobar involvement,^{[2,12,14,252,254]} renal failure,^[11,12,17] leukopenia,^{[14,252,255-257]} alcohol abuse,^[6,257] immunosuppression,^[5] chronic cardiac disease,^[11,17] malignancy,^[17] chronic pulmonary disease,^[2,254] residence in a nursing home,^[2] serious underlying disease,^[5,14,15] need for intensive care unit (ICU)^[6] or mechanical ventilation,^[2,253] shock,^[14,257] high acute physiology scores,^[2] severity of disease,^[15] and treatment with parenteral nutrition.^[253] Discordant therapy was associated with higher mortality in some^[254,258] but not all^[5,259,260] studies. The impact of antimicrobial resistance and discordant antibiotic therapy is discussed in depth in the next article. HIV-infected patients have lower mortality in some studies,^[14] likely due to younger age. However, when patients were stratified by clinical status, patients with AIDS had far higher mortality than HIV-infected persons without AIDS.^{[17,174,211,215]} Interestingly, in a prospective, international study of IPD in adults, rigors and chest pain were associated with a lower mortality.^[15]

Clinical features of pneumococcal pneumonia are reviewed in detail elsewhere.^[1,6,10] We will limit our remarks to changes in the clinical presentation of pneumococcal pneumonia within the past few years (concomitant with the use of PCV7). Recent studies cited a marked increase in pneumococcal empyemas^{[44,47,261-263]} and necrotizing pneumonias^{[37,45,262,264]} in children, which reflects replacement by non-PCV7 serotypes (particularly serotypes 1, 3, and 19A).^{[37,261,265,266]}

Laboratory Diagnosis

Nonbacteremic pneumococcal pneumonia may be difficult to diagnose. Gram stains and microbiological cultures are the mainstays of diagnostic tests but are positive in fewer than 50% of cases of pneumococcal pneumonia.^[10] S. pneumoniae appear as lancet-shaped gram-positive diplococci. For bacteremic pneumococcal pneumonia in adults, sputum Gram stain and cultures had sensitivities of 80% and 93%, respectively, provided an adequate specimen was produced prior to therapy.^[10] In actual clinical practice, sensitivity is lower (<>[10,267,268] Rapid detection of pneumococcal antigens in urine,^[269,270] CSF,^[271] or pleural fluid^[272] may be helpful in selected patients (especially patients with meningitis or those who have received prior antibiotics).^[267] Latex agglutination tests are widely used to diagnose pneumococcal meningitis,^[271] but the value of these tests for urine or blood is controversial.^[267] An immunochromatographic test (NOW Streptococcus pneumoniae Antigen Test, Binax, Inc., Scarborough, ME), detects the C-polysaccharide wall antigen of S. pneumoniae.^[272,273] This urinary antigen test enables a rapid diagnosis (within 15 minutes) of pneumococcal pneumonia, but was less sensitive than sputum Gram stains in some studies.^[270,273] False positives, rare in adults,^[273] may be noted in children with NP carriage of S. pneumoniae.^[274,275] The combination of urinary antigen detection and sputum Gram stain increases the sensitivity^[270] but is expensive and time consuming in clinical practice. Binax NOW may be most useful for rapid diagnosis of pneumococcal meningitis, empyema, or pneumonia in high-risk patients in whom adequate sputum is unavailable.^{[270,272,273]} In children, Binax NOW lacks specificity and cannot distinguish colonization from infection.^[276] None of these techniques replaces culture, the only technique that allows antimicrobial susceptibility testing.

Pneumoccocal Vaccines

Currently, two pneumococcal vaccines are available. The 23-valent PPV (23 PPV), composed of purified free polysaccharides derived from the surface capsule of the bacterium, was introduced in 1983.^[277] These polysaccharide antigens elicit a T cell independent immune response and are therefore poor inducers of immunologic memory.^[1,245] Recommendations for using 23PPV in the United States are listed in Table 5.^[278] Indications for and extent of usage of 23PPV vary considerably among countries.^[277] 23PPV was efficacious and cost-effective in reducing the incidence of IPD in adults^[1,279,280] and may prevent outbreaks of pneumococcal pneumonia in institutional settings (e.g., nursing homes).^[68,132] The vaccine confers 60 to 80% protection against IPD in young healthy adults^[1] and elderly adults^[1,280-283] but is less effective in immunocompromised patients.^{[237,280,284]} Further, 23PPV is less effective in preventing nonbacteremic pneumonia^[282,285] or noninvasive infections (e.g., otitis media, conjunctivitis).^[286,287] Studies in elderly adults found that high serum antibody titers persist for 1 to 2 years^[288,289] but wane substantially over 5 years,^[290] as does the clinical effectiveness of the vaccine.^[280] In the United States, vaccination with 23PPV is recommended for all adults ≥ age 65 years and for high-risk individuals 2 to 64 years of age^[277] (Table 5). In Europe, indications for vaccination are variable among countries. In one survey, 17 of 21 countries recommended 23PPV for all adults ≥ 65 years of age.^[291] Recommendations for the use of PCV7 in Europe vary among countries.^[291] Revaccination for at risk adults after 5 years is safe and immunogenic,^[292,293] but vaccine responses are attenuated.^[294] Self-limited local reactions at the injection site following revaccination are more common (particularly in immunocompetent patients) but are not a contraindication to revaccination.^[21,295] Unfortunately, many patients who are candidates for 23PPV remain unvaccinated.^[296]

The 23PPV is poorly immunogenic in children ≤ age 2 years old, but PCV7 (introduced in the United States in February 2000) elicits good antibody responses in infants and young children.^[21,297] Conjugation of the capsular polysaccharide to a protein carrier elicits T cell responses that establish immunologic priming and a memory response.^[21,298] The serotypes incorporated into PCV7 include 4, 6B, 9V, 14, 18C, 19F, and 23F.^[299] In 2000 these seven serotypes accounted for > 80% of IPD in children in North America^[55,300] and were also prevalent in elderly adults.^[301] Currently, PCV7 is the only commercially available pneumococcal conjugate vaccine, but 10- and 13-valent conjugate vaccines may be available soon.^[21] As of January 2007, PCV7 was licensed in more than 70 countries.^[21] In 2000, recommendations for PCV7 use were published by the American Academy of Pediatrics Committee on Infectious Disease^[194] and Centers for Disease Control and Prevention^[297] (Table 6).^[302] In Europe, recommendations for the use of PCV7 in Europe vary among countries.^[291] In 1997, the WHO advised that PCV7 vaccination in children should be a priority, particularly in countries where mortality was high among children <>[21] Additionally, PCV7 should be prioritized in countries with a high prevalence of HIV, sickle cell disease, or other high-risk populations.^[21] Although precise schedules of vaccination differ, most countries administer 3 doses in infants within the first 6 months of life.^[299,303] In the United States, a booster dose of PCV7 is given at 12 to 15 months, and 23PPV is given at 2 years of age to broaden serotype coverage.^[297] Among developing countries, 3 doses of PCV7 to infants were immunogenic but data regarding clinical outcomes are limited.^[21] A 9-valent PCV that contains serotypes 1 and 5 in addition to the serotypes in PCV-7 was efficacious in Gambian children^[304] and HIV-infected children from South Africa,^[248] but it is not commercially available.^[300,305] The duration of protection against IPD due to PCV7 serotypes is at least 2 to 3 years, but probably is considerably longer.^[21] Although data are limited, PCV7 may have a role in elderly or immunocompromised adults. A recent randomized trial in vaccine naive adults ≥ 70 years of age assessed the impact of initial vaccination with either 23PPV or PCV7, followed by a booster vaccine (PCV7 or 23PPV) administered at 1 year. The seven serotypes encompassed by PCV7 were assessed. Initial vaccination with PCV7, followed by 23PPV at 1 year, elicited antibody responses that were comparable or higher than 23PPV alone. Importantly, initial vaccination with 23PPV followed by PCV7 induced lower antibody responses than PCV7/PCV7 or PCV7/23PPV. Thus 23PPV was ineffective as a priming dose and may induce hyporesponsiveness to subsequent booster doses (likely by depleting polysaccharide-specific memory B cells). Others have shown that revaccination with 23PPV after 5 years elicits lower antibody levels compared with the priming dose.^[294]

Following the use of PCV7 in children, marked declines in IPD were observed among all age groups (even in nonvaccinated adults) in North America,^{[21,23,35,36,55,57,138,299,305-307]} including high-risk^[189] and immunosuppressed^[57,162,308] individuals.^{[21,191,299,305,307]} In the United States, rates of vaccine-type IPD declined by 62% among people ≥ 5 years old between 1998-99 and 2003.^[307] In Canada, the rate of IPD in adults over 65 declined by 63% between 1998-2001 and 2004.^[309] Importantly, PCV7 reduced both colonization and infection with S. pneumoniae.^{[21,57,308,310,311]} By contrast, the incidence of IPD increased in Spain following the introduction of PCV7 and was associated with emergence of nonvaccine serotypes.^[112] In Alaskan native adults, colonization with vaccine-serotypes declined from 28 to 4.5% after introduction of PCV7 in children.^[312] Further, after 2001, the incidence of pneumococcal meningitis declined in the United States in both children and adults.^[251] The use of PCV7 in the United States led to reduction in racial disparity in IPD.^[74] However, in recent years, case-fatality rates have increased, reflecting a higher proportion of cases with comorbidities or non-PCV7 serotypes.^[57] In the United States and globally nonvaccine serotypes account for an increasing proportion of IPD, acute otitis media, and NP colonization.^{[36,38,55,73,101,102,112,137,307,313,314]} Ominously, in a study of Alaskan native infants, IPD due to nonvaccine serotypes increased by 140% since 2004 compared with the prevaccine period.^[137] During the same period (after 2004), IPD due to PCV7 serotypes declined by 96%.^[137] Further, the proportion of IPD cases with empyema increased from 2 to 13%.^[137] Several other studies cited an increased incidence of empyema in children in recent years due to nonvaccine serotypes.^{[37,44,47,261-263]} A prospective study of IPD from eight children's hospitals in the United States noted emergence of replacement serotypes 15 and 33; two dominant clones were observed.^[38] Currently, 19A has been the most common replacement serotype in the United States,^[74,101-103] whereas serotypes 1 and 5 have been most common in Spain.^[112] In some areas, this expansion has been clonal.^[112,137]

Vaccination strategies in both children and adults will continue to evolve. Serotypes affecting adults and children differ, mandating different strategies for specific populations. Changes in the distribution of serotypes following PCV7 will be a challenge for future vaccination strategies. Conjugate vaccines containing up to 13 serotypes are in development to improve coverage in adults and children on a global basis.^[21,315] It should also be emphasized that vaccinating elderly adults against influenza has reduced the risk of all-cause pneumonia,^[316,317] and may protect against IPD.^[318]

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Source : http://www.medscape.com/viewarticle/702635

Legionnaires Disease

2009-07-02T13:47:00.002+07:00

Introduction

Background

Legionella pneumophila is an important cause of both nosocomial and community-acquired pneumonia (CAP) and must be considered a possible causative pathogen in any patient who presents with pneumonia.

The Legionella bacterium was first identified in the summer of 1976 during the 58th annual convention of the American Legion, which was held at the Bellevue-Stratford Hotel in Philadelphia. Infection was presumed to be spread by contamination of the water in the hotel's air conditioning system. The presentation ranged from mild flulike symptoms to multisystem organ failure. Of the 182 people infected, 29 died. A bacterium that would later be named L pneumophila was isolated from different organ tissues of guinea pigs inoculated with lung tissue samples from 4 individuals who died. Although this pathogen was not identified until 1976, retrospective analysis suggests that L pneumophila may have been responsible for previous pneumonia epidemics in Philadelphia; Washington, DC; and Minnesota. L pneumophila was identified in a clinical specimen dating to 1943.

Legionellosis is the term that collectively describes infections caused by members of the Legionellaceae family. Legionnaires disease (LD) is the pneumonia caused by L pneumophila. LD also refers to a more benign, self-limited, acute febrile illness known as Pontiac fever, which has been linked serologically to L pneumophila, although it presents without pneumonia.

Pathophysiology

The Legionella bacterium is a small, aerobic, waterborne, gram-negative, unencapsulated bacillus that is nonmotile, catalase-positive, and weakly oxidase-positive. Legionella is a fastidious organism and does not grow anaerobically or on standard media. Buffered charcoal yeast extract (CYE) agar is the primary medium used for isolation of the bacterium.

The Legionellaceae family consists of more than 42 species constituting 64 serogroups. L pneumophila is the most common species, causing up to 90% of the cases of legionellosis, followed by Legionella micdadei (otherwise known as the Pittsburgh pneumonia agent), Legionella bozemanii, Legionella dumoffii, and Legionella longbeachae. Fifteen serogroups of L pneumophila have been identified, with serogroups 1, 4, and 6 being the primary causes of human disease. Serogroup 1 is thought to be responsible for 80% of the reported cases of legionellosis caused by L pneumophila.

Legionella species are obligate or facultative intracellular parasites. Water is the major environmental reservoir for Legionella. The bacterium can infect and replicate within protozoa such as Acanthamoeba and Hartmannella species, which are free-living amoebae found in both natural and manufactured water systems. The Legionella species within the amebic cells can avoid the endosomal-lysosomal pathway and can replicate within the phagosome. Legionella can survive and grow in the amebic cells, thereby enabling the organism to persist in nature.

Legionella species infect human macrophages and monocytes, and intracellular replication of the bacterium is observed within these cells in the alveoli. The intracellular infections of protozoa and macrophages have many similarities.

Transmission is thought to occur via inhalation of aerosolized mist from water sources (eg, whirlpools, showers, cooling towers¹) contaminated with either the bacterium or amebic cells infected with the bacterium. Direct inhalation is the most likely method of transmission, with aerosol-generating systems playing a crucial role.²Person-to-person transmission has not been documented. The highest incidence occurs during the warmer months, when air-conditioning systems are used more frequently. Nosocomial acquisition likely occurs via aspiration³, respiratory therapy equipment², or contaminated water. In addition, transmission has been linked to the use of humidifiers, nebulizers, and items that were rinsed with contaminated tap water.

The following features increase the likelihood of colonization and amplification of legionellae in man-made water environments: (1) temperature of 25-42°C, (2) stagnation, (3) scale and sediment, and (4) presence of certain free-living aquatic amoebae capable of supporting intracellular growth of legionellae. Legionellae can resist low levels of chlorine used in water distribution systems.

Activated T cells produce lymphokines that stimulate increased antimicrobial activity of macrophages. This cell-mediated activation is key to halting the intracellular growth of legionellae. The significant role of cellular immunity explains why legionellae are observed more frequently in immunocompromised patients. Humoral immunity is thought to play a secondary role in the host response to legionellae infection.

Frequency

United States

LD has a reported incidence of 8000-18,000 cases per year. In certain geographic areas, community-acquired LD is more common.

LD is reportable in all 50 states. Only 5-10% of cases are estimated to be reported. While most cases of LD are sporadic, 10-20% are linked to outbreaks. LD is among the top 3-4 microbial causes of CAP, constituting approximately 1-9% of patients with CAP who require hospitalization. LD is an even more common cause of severe pneumonia in patients who require admission to an intensive care unit (ICU). LD ranks second, after pneumococcal pneumonia, as the etiology of pneumonia severe enough to require ICU admission.

Some LD cases are acquired in the hospital; they usually occur as outbreaks. Legionellae in the hospital setting is usually due to its presence in water sources and on surfaces (eg, pipes, rubber, plastics). The organism is also found in water sediment, which may explain its ability to persist despite flushing of hospital water systems.

International

LD is thought to occur worldwide and to be the cause of 2-15% of all CAP cases that require hospitalization.

Mortality/Morbidity

The mortality rate may approach 100% in patients with underlying disease. In untreated patients, the mortality rate may be as high as 80%.

Sex

Men have a greater risk of acquiring L pneumophila infection.

Age

Elderly persons have a greater risk of acquiring infection with Legionella species.

Clinical

History

L pneumophila causes 2 distinct disease entities. Legionnaires disease (LD) is characterized by pneumonia. Pontiac fever is a milder illness than LD and is not characterized by pneumonia; Pontiac fever manifests as fever and myalgias that resolve without treatment.

Legionnaires disease
- The incubation period ranges from 2-10 days.
- Patients who develop legionellae infection and who have been hospitalized continuously for 10 or more days before the onset of illness are classified as having definite nosocomial LD. Patients with laboratory-confirmed infection that develops 2-9 days after hospitalization are classified as having possible nosocomial LD.
- Nosocomial LD occurs in clusters.
- Individuals with LD can present with a broad spectrum of symptoms.
Symptoms of legionnaires disease
- Fever greater than 40^ºC (>102 º F)
- Chills
- Cough - Dry or productive; hemoptysis rare
- Pleuritic or nonpleuritic chest pain
- Neurologic symptoms
  - Headache
  - Lethargy
  - Encephalopathy
  - Mental status changes - The most common neurologic symptom
- GI symptoms
  - Diarrhea - Watery, not bloody
  - Nausea, vomiting, and abdominal pain
- Myalgias

Physical

Manifestations of LD may include the following:
- Mental status changes
- Fever greater than 40°C (range, 38.8-40.5°C)
- Hypotension
- Relative bradycardia in all (excluding patients with pacemakers or arrhythmias or those receiving beta-blockers, diltiazem, or verapamil)
- Tachypnea
- Localized rales
- Depressed mental status or agitation
Extrapulmonary manifestations
- In addition to relative bradycardia, cardiac manifestations are common findings and include myocarditis, pericarditis, and prosthetic valve endocarditis.
- Pancreatitis
- Peritonitis
- Acute renal failure

Modified Winthrop-University Hospital Infection Disease Division's Point System for Diagnosing Legionnaires Disease in Adults

Table

Clinical Features	Qualifying Conditions	Point Score
Temperature >103°F*	With relative bradycardia	+5
Headache	Acute onset	+2
Mental confusion/lethargy*	Not drug induced	+4
Ear pain	Acute onset	-3
Nonexudative pharyngitis	Acute onset	-3
Hoarseness	Acute, not chronic	-3
Sputum (purulent)	Excluding chronic bronchitis	-3
Hemoptysis*	Mild/moderate	-3
Chest pain (pleuritic)	Rapidly progressive asymmetrical infiltrates* (excluding severe influenza/severe acute respiratory syndrome)	-3
Loose stools/watery diarrhea*	Not drug induced	+3
Abdominal pain*	With or without diarrhea	+5
Renal failure*	Acute, not chronic	+3
Shock/hypotension*	Not 2° to acute cardiac	-5
	/pulmonary causes	+5
Splenomegaly	Excluding non-CAP causes	-5
Lack of response to beta lactams	After 72 h (excluding viral pneumonias)	+5
Laboratory Features
Chest radiograph	Rapidly progressive asymmetrical infiltrates* (excluding severe influenza/SARS)	+3
↓ PO2 with ↑ A-a gradient (>35)*	(Excluding severe influenza/SARS)	-5
↓ Na+	Acute onset	+1
↓ PO₄ =*	Acute onset	+5
↑ SGOT/SGPT (early mild/transient)*	Acute onset	+4
↑ Total bilirubin	Otherwise unexplained	+1
↑ LDH (>400 U/L)*	Excluding HIV/PCP	-5
↑ CPK/aldolase	Otherwise unexplained	+4
↑ CRP (>30 mg/L)	Acute onset	+5
↑ Cold agglutinins (≥1:64)	Acute onset	-5
↑ Creatinine	Acute onset	+2
Microscopic hematuria*	Excluding trauma, BPH, Foley catheter, bladder/renal neoplasms	+2
	*Likelihood of Legionella* infection**
Total points	>15 Legionella infection very likely
	5-15 Legionella infection likely
	<5>Legionella infection unlikely

Clinical Features	Qualifying Conditions	Point Score
Temperature >103°F*	With relative bradycardia	+5
Headache	Acute onset	+2
Mental confusion/lethargy*	Not drug induced	+4
Ear pain	Acute onset	-3
Nonexudative pharyngitis	Acute onset	-3
Hoarseness	Acute, not chronic	-3
Sputum (purulent)	Excluding chronic bronchitis	-3
Hemoptysis*	Mild/moderate	-3
Chest pain (pleuritic)	Rapidly progressive asymmetrical infiltrates* (excluding severe influenza/severe acute respiratory syndrome)	-3
Loose stools/watery diarrhea*	Not drug induced	+3
Abdominal pain*	With or without diarrhea	+5
Renal failure*	Acute, not chronic	+3
Shock/hypotension*	Not 2° to acute cardiac	-5
	/pulmonary causes	+5
Splenomegaly	Excluding non-CAP causes	-5
Lack of response to beta lactams	After 72 h (excluding viral pneumonias)	+5
Laboratory Features
Chest radiograph	Rapidly progressive asymmetrical infiltrates* (excluding severe influenza/SARS)	+3
↓ PO2 with ↑ A-a gradient (>35)*	(Excluding severe influenza/SARS)	-5
↓ Na+	Acute onset	+1
↓ PO₄ =*	Acute onset	+5
↑ SGOT/SGPT (early mild/transient)*	Acute onset	+4
↑ Total bilirubin	Otherwise unexplained	+1
↑ LDH (>400 U/L)*	Excluding HIV/PCP	-5
↑ CPK/aldolase	Otherwise unexplained	+4
↑ CRP (>30 mg/L)	Acute onset	+5
↑ Cold agglutinins (≥1:64)	Acute onset	-5
↑ Creatinine	Acute onset	+2
Microscopic hematuria*	Excluding trauma, BPH, Foley catheter, bladder/renal neoplasms	+2
	*Likelihood of Legionella* infection**
Total points	>15 Legionella infection very likely
	5-15 Legionella infection likely
	<5>Legionella infection unlikely

*Otherwise unexplained (acute and associated with pneumonia)

Adapted from Cunha BA. Antibiotic Essentials. 5^th ed. Royal Oak, Mich: Physicians Press; 2006.

A clinical point score may be helpful in increasing probability of LD and prompting specific/definitive LD testing.

Causes

The risk of infection increases with the type and intensity of the exposure, as well as the health status of the exposed individual. Numerous factors increase the risk of acquiring legionellae infections.

Risk factors for infection
- Advanced age
- Smoking
- Chronic heart or lung disease
- Immunocompromised state or immunosuppressive medication use (especially corticosteroids)
- Recent exposure to water or soil
Pediatric cases of Legionella pneumonia are less common. Most of these cases occur in children who are immunosuppressed or in immunocompetent children who have undergone surgery or who are on a ventilator.

Differential Diagnoses

Workup

Laboratory Studies

While pneumonias caused by numerous pathogens share similar laboratory findings, hyponatremia (sodium <130>
Additional laboratory findings in LD and in pneumonias due to other causes include the following:
- Elevated liver enzyme levels
- Increased creatine phosphokinase levels
- Increased creatine phosphokinase (CPK) levels
- Increased C-reactive protein levels (>30 mg/L)
- Hypophosphatemia (specific to LD excluding other causes of hypophosphatemia)⁴
- Microscopic hematuria
- Proteinuria (40%)
Gram stain
- Typically, many leukocytes and a paucity of organisms are observed.
- If visible, the organisms are small, faintly staining, gram-negative bacilli.
Culture of respiratory secretions
- The definitive method for diagnosing Legionella is isolation of the organism in the respiratory secretions (ie, sputum, lung fluid, pleural fluid). However, Legionella species do not grow on standard microbiologic media.
- Legionella requires buffered CYE agar and cysteine for growth. Optimal growth occurs at 35-37°C.
- Legionella is a slow-growing organism and can take 3-5 days to produce visible colonies. The organisms typically have a ground-glass appearance.
- Routine sputum cultures have a sensitivity and specificity of 80% and 100%, respectively.
- Transtracheal aspiration of secretions or bronchoscopy specimen increases the sensitivity.
- Bronchoalveolar lavage (BAL) fluid provides a higher yield than bronchial wash specimens.
Blood cultures: Legionella can be isolated from blood, but it shows a much lower sensitivity.
Direct fluorescent antibody staining of sputum
- Direct fluorescent antibody staining (DFA) is a rapid test that yields results in 2-4 hours but has a lower sensitivity. The specificity of DFA is 96-99% using monoclonal antibody instead of polyclonal antibody.
- A positive result depends on finding large numbers of organisms in the specimen; therefore, the sensitivity is increased when samples from the lower respiratory tract are used.
- DFA results rapidly become negative (in 4-6 d).
Serology
- The most widely used tests include the immunofluorescent antibody (IFA) and enzyme-linked immunosorbent assay (ELISA). A single increased antibody titer confirms LD if the IFA titer is greater than or equal to 1:256.
- While LD serologic tests are the most readily available, they require a 4-fold increase in antibody titer to 1:128 or greater, which takes 4-8 weeks. Paired measurements from both the acute and convalescent periods should be obtained, since an antibody response may not be apparent for up to 3 months. Of note, antibody levels do not increase in approximately one third of patients with LD.
Urinary antigen test
- The Legionella lipopolysaccharide antigen is detected with ELISA, radioimmunoassay (RIA), and the latex agglutination test. The Legionella lipopolysaccharide antigen becomes detectable in 80% of patients on days 1-3 of clinical illness.
- The urinary antigen assay can be used to detect only L pneumophila (serogroup 1).⁵
- The advantages of this test include rapidity and simplicity. In addition, the relative ease of obtaining a urine sample compared with obtaining sputum specimens and the persistence of antigen secretion in patients who are on antibiotic therapy increase the usefulness of the urine antigen detection method.⁵
- The urinary antigen result can remain positive for months after the acute episode has resolved.⁵
Amplification with polymerase chain reaction
- Polymerase chain reaction (PCR) of urine, serum, and bronchiolar lavage fluid is very specific for the detection of legionellae, but the sensitivity is not greater than that of culture.
- The primary benefit of this procedure, like IFA titers, is that it can be used to detect infections caused by legionellae other than L pneumophila serogroup 1.⁶

Imaging Studies

No typical LD radiographic presentation exists.⁷
Rapidly progressive asymmetrical infiltrates are characteristic of LD.
Approximately one quarter of patients had infiltrates that were described as interstitial. Almost half of the patients had patchy alveolar infiltrates.
In general, the abnormalities are typically unilateral and are found in the lower lobes.
Pleural effusions are found in one third of patients.
Cavity and abscess formation are rare and can occur in immunocompromised hosts.
Improvement revealed on the chest radiograph can lag behind the clinical improvement by 5-7 days. The abnormalities on chest radiograph can take up to 3-4 months to resolve completely.

Procedures

Bronchoscopy: While the sensitivity of specimens retrieved via bronchoscopy is comparable to that of sputum, BAL fluid gives a higher yield than bronchial wash specimens.
Thoracentesis: If a pleural effusion is present, fluid can be evaluated using DFA or LD culture.

Histologic Findings

Typically, legionellae histopathological lesions are found in interstitial lining and alveoli with polymorphonuclear cells and macrophages.

Treatment

Medical Care

A delay in treatment significantly increases the risk of mortality. Therefore, include empiric anti-Legionella therapy in the regimen for severe CAP and in specific cases of nosocomial pneumonia.
Although Legionella pneumonia can present as a mild illness, most patients require hospitalization with parenteral antibiotics.
Historically, erythromycin was used for L pneumophila infection, but doxycycline, azithromycin, macrolides, and quinolones are more active against legionnaires disease (LD) than erythromycin.⁸
Fluoroquinolones, telithromycin, and azithromycin have greater in vitro activity and better intracellular penetration than erythromycin.⁸In addition, animal studies of L pneumophila infection have shown these agents to have superior activity.
The fluoroquinolones doxycycline, telithromycin, and azithromycin are superior because of their activity and pharmacokinetic properties (eg, better bioavailability, better penetration into macrophages, longer half-life).
For severe disease, a fluoroquinolone is recommended. Severe disease is defined by respiratory failure, bilateral pneumonia, rapidly worsening pulmonary infiltrates, or the presence of at least 2 of the following 3 characteristics:
- Blood urea nitrogen greater than or equal to 30 mg/dL
- Diastolic blood pressure lower than 60 mm Hg
- Respiratory rate greater than 30/min
With doxycycline or fluoroquinolones, rifampin does not need to be added in severely ill patients.
Most healthy hosts exhibit clinical response to treatment within 3-5 days.

Consultations

Infectious disease specialist

Medication

Treat intravenously until clinically improved; then, consider changing to an oral with a 10- to 14-day course after patients begin to show signs of clinical improvement. A 21-day course is recommended in patients who are immunocompromised, who have severe underlying disease, or who develop severe Legionella pneumonia.

For immunosuppressed patients, fluoroquinolone therapy is recommended for several reasons. The fatality rate of Legionella pneumonia is high in this patient population.

Antibiotics

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

Levofloxacin (Levaquin)

Fluoroquinolone for pseudomonal infections and infections due to multidrug-resistant gram-negative organisms.

Dosing

Adult

500 mg PO/IV qd, adjust dose in renal disease

Pediatric

<18>18 years: Administer as in adults

Interactions

Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h before or after taking fluoroquinolones; cimetidine may interfere with metabolism of fluoroquinolones; levofloxacin reduces therapeutic effects of phenytoin; probenecid may increase levofloxacin serum concentrations; may increase toxicity of theophylline, caffeine, cyclosporine, and digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT)

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

In prolonged therapy, periodically evaluate organ system functions (eg, renal, hepatic, hematopoietic); adjust dose in renal function impairment; superinfections may occur with prolonged or repeated antibiotic therapy; photosensitivity may occur with prolonged exposure to sunlight or tanning equipment

Azithromycin (Zithromax)

Macrolide antibiotic used to treat mild-to-moderate microbial infections.

Adult

Day 1: 500 mg PO
Days 2-7: 250-500 mg PO qd; may treat for 10 d
500 mg IV qd for 7-10 d

Pediatric

<6>6 months: 10 mg/kg PO on day 1, not to exceed 500 mg; 5-10 mg/kg/d PO qd on days 2-7, not to exceed 500 mg/d; may treat for 10 d

May increase toxicity of theophylline, warfarin, and digoxin; effects are reduced with coadministration of aluminum and/or magnesium antacids; nephrotoxicity and neurotoxicity may occur when coadministered with cyclosporine

Documented hypersensitivity; hepatic impairment; do not administer with pimozide

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Site reactions can occur with IV route; bacterial or fungal overgrowth may result with prolonged antibiotic use; may increase hepatic enzymes and cholestatic jaundice; caution in patients with impaired hepatic function, prolonged QT intervals, or pneumonia; caution in patients who are hospitalized, geriatric, or debilitated

Clarithromycin (Biaxin)

Macrolide antibiotic. Inhibits bacterial growth, possibly by blocking dissociation of peptidyl t-RNA from ribosomes, causing RNA-dependent protein synthesis to arrest.

Dosing

Adult

250 mg PO bid; may increase to 500 mg PO tid or 500 mg PO q12h

Pediatric

15 mg/kg/d PO divided bid; not to exceed 1 g qd

Interactions

Toxicity increases with coadministration of fluconazole and pimozide; clarithromycin effects decrease and GI adverse effects may increase with coadministration of rifabutin or rifampin; may increase toxicity of anticoagulants, cyclosporine, tacrolimus, digoxin, omeprazole, carbamazepine, ergot alkaloids, triazolam, HMG CoA-reductase inhibitors; plasma levels of certain benzodiazepines may increase, prolonging CNS depression; arrhythmia and increase in QTc intervals occur with disopyramide; coadministration with omeprazole may increase plasma levels of both agents

Contraindications

Documented hypersensitivity; coadministration of pimozide

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Coadministration with ranitidine or bismuth citrate is not recommended with CrCl <25>

Ciprofloxacin (Cipro)

Fluoroquinolone with activity against pseudomonads, streptococci, MRSA, S epidermidis, and most gram-negative organisms but no activity against anaerobes. Inhibits bacterial DNA synthesis, and, consequently, growth.

Dosing

Adult

250-750 mg PO q12h; 200-400 mg IV q12h

Pediatric

15-30 mg/kg/d PO divided q12h; not to exceed 1.5 g/d

Interactions

Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h before or after taking fluoroquinolones; cimetidine may interfere with metabolism of fluoroquinolones; ciprofloxacin reduces therapeutic effects of phenytoin; probenecid may increase ciprofloxacin serum concentrations; may increase toxicity of theophylline, caffeine, cyclosporine, and digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT)

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Sparfloxacin (Zagam)

No longer available in the United States. Inhibits bacterial DNA synthesis and, consequently, growth.

Dosing

Adult

200 mg PO qd

Pediatric

<18>18 years: Administer as in adults

Interactions

Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h before or after taking fluoroquinolones; cimetidine may interfere with metabolism of fluoroquinolones; reduces therapeutic effects of phenytoin; probenecid may increase serum concentrations; may increase toxicity of theophylline, caffeine, cyclosporine, and digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT)

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Telithromycin (Ketek)

First antibiotic in a new class called ketolides. Combats resistant bacteria by inhibiting the protein synthesis necessary for bacterial reproduction, binding 10 times tighter than macrolides at 2 different sites on bacterial ribosomes. Blocks protein synthesis by binding to 50S ribosomal subunit (23S rRNA at domain II and V). Binding at domain II retains activity against gram-positive cocci (eg, S pneumoniae) in the presence of resistance mediated by methylases (e rm genes) that alter the domain V binding site. May also inhibit the assembly of nascent ribosomal units.Resistance and cross-resistance have not been observed. Active against Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, Haemophilus influenzae, and Moraxella catarrhalis, as well as atypical bacteria (eg, Chlamydia pneumoniae, Mycoplasma pneumoniae, Legionella pneumoniae). Indicated to treat mild-to-moderate CAP, including infections caused by multidrug-resistant S pneumoniae.

Dosing

Adult

800 mg PO qd for 7-10 d

Pediatric

Not established

Interactions

CYP 3A4 inhibitor and substrate; coadministration with other CYP 3A4 inhibitors (eg, itraconazole, ketoconazole) decreases elimination and increases C_max and AUC; CYP 3A4 inducers (eg, rifampin) decreases telithromycin C_max and AUC by 79% and 86%, respectively; increases C_max and AUC of other CYP 3A4 substrates (eg, cisapride, pimozide, simvastatin, lovastatin, atorvastatin, midazolam, triazolam); HMG-CoA reductase inhibitors (eg, simvastatin, atorvastatin, lovastatin) should be temporarily discontinued owing to increased myopathy risk when coadministered; increases digoxin and theophylline serum levels; decreases sotalol C_max and AUC secondary to decreased absorption; caution with other drugs that increase QTc interval (eg, quinidine, procainamide, dofetilide)

Contraindications

Documented hypersensitivity; coadministration with cisapride or pimozide; myasthenia gravis; history of hepatitis and/or jaundice with use of macrolides

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in severe renal impairment (limited data exist); consider the diagnosis of pseudomembranous colitis if diarrhea occurs following antibiotic treatment; may prolong QTc interval (caution in heart conduction abnormalities); common adverse effects include diarrhea and nausea; may rarely cause visual disturbances; acute hepatic failure and severe liver injury (in some cases fatal) have been reported (if clinical hepatitis or liver enzyme elevations combined with other systemic symptoms occur, permanently discontinue)

Doxycycline (Vibramycin)

Inhibits protein synthesis and, thus, bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria.

Dosing

Adult

100 mg PO/IV q12h

Pediatric

<8>8 years: Not established

Interactions

Bioavailability decreases with antacids containing aluminum, calcium, magnesium, iron, or bismuth subsalicylate; tetracyclines can increase hypoprothrombinemic effects of anticoagulants; tetracyclines can decrease effects of oral contraceptives, causing breakthrough bleeding and increased risk of pregnancy

Contraindications

Documented hypersensitivity; severe hepatic dysfunction

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Photosensitivity may occur with prolonged exposure to sunlight or tanning equipment; reduce dose in renal impairment; consider measuring drug serum level in prolonged therapy; tetracycline use during tooth development (last half of pregnancy through 8 y) can cause permanent discoloration of teeth; Fanconi-like syndrome may occur with outdated tetracyclines

Moxifloxacin (Avelox)

Inhibits bacterial DNA synthesis and growth. Activity is similar to that of ciprofloxacin and levofloxacin.

Dosing

Adult

400 mg PO qd for 10 d

Pediatric

<18>18 years: Administer as in adults

Interactions

Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 4 h before or 8 h after taking fluoroquinolones; cimetidine may interfere with metabolism of fluoroquinolones; reduces therapeutic effects of phenytoin; probenecid may increase serum concentrations; may increase toxicity of theophylline, caffeine, cyclosporine, and digoxin (monitor digoxin levels); may increase effects of anticoagulants (monitor PT)

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Shown to prolong QT interval; avoid in uncorrected hypokalemia and patients receiving class IA (eg, quinidine, procainamide) or class III (eg, amiodarone, sotalol) antiarrhythmic agents; superinfections may occur with prolonged or repeated antibiotic therapy; photosensitivity may occur with prolonged exposure to sunlight or tanning equipment

Follow-up

Further Inpatient Care

Patients with mild-to-moderate pneumonia are admitted to the hospital for parenteral antibiotics and supportive measures. Patients deemed to have a severe pneumonia may require ICU admission for closer monitoring. Quickly initiate empiric antibiotic treatment and obtain a diagnostic workup.

Further Outpatient Care

In milder cases, patients can be treated in the outpatient setting with oral antibiotics.
For patients who are hospitalized and treated with intravenous antibiotics, start oral antibiotics while in the hospital and observe for continued response. Continue oral antibiotics on an outpatient basis for 14-21 days, depending on the severity of the presenting illness. Patients should receive close follow-up care to ensure complete resolution of their respiratory symptoms.

Inpatient & Outpatient Medications

Patients should complete the full course of their antibiotics, whether the treatment is initiated in the outpatient setting or in the hospital.

Deterrence/Prevention

Prevention and control of nosocomial legionellosis
- Legionellae should be sought in hospitalized patients with an increased risk for infection and subsequent death.
- If one definite case or 2 possible cases of nosocomial legionnaires disease (LD) occur among inpatients, initiate an investigation for a hospital source.
- Routinely maintain cooling towers and use only sterile water for filling and rinsing of nebulization devices.
- Improve the design and maintenance of cooling towers and plumbing systems.
Disinfection
- Superheating water to 70-80°C, with flushing of distal sites
- Installation of copper-silver ionization units, which produce metallic ions that disrupt the bacterial cell wall, thus resulting in lysis and cell death: This method provides sustained protection and is very effective at eradicating legionellae.
- Use of ultraviolet light, which kills legionellae by damaging cellular DNA: This system is effective when disinfecting localized areas; however, because it provides no sustained protection, adjunctive treatments must be used.
- Hyperchlorination of water is no longer recommended because legionellae are fairly chlorine resistant, and chlorine decomposes at higher water temperatures found in hot water systems being treated.

Complications

Decreased pulmonary function
Abscess formation (in the lungs or at extrapulmonary sites)
Pulmonary fibrosis or scarring
Fulminant respiratory failure
Death

Prognosis

Progressive respiratory failure is the most common cause of death in patients with Legionella pneumonia. The mortality rate depends on the comorbid conditions of the patient, as well as the choice and timeliness of antibiotics administration. The site of acquisition (eg, nosocomial, community-acquired) may also affect the outcome.

Patient Education

For excellent patient education resources, visit eMedicine's Procedures Center. Also, see eMedicine's patient education article Bronchoscopy.

Miscellaneous

Medicolegal Pitfalls

Failure to recognize L pneumophila as an important cause of CAP could lead to suboptimal treatment with inappropriate antibacterial agents and could result in unnecessary patient morbidity and mortality.

Source : http//emedicine.medscape.com/article/220163

New Guidelines Issued for Asthma Assessment

2009-06-30T15:13:00.000+07:00

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

2009-06-27T19:13:00.003+07:00

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 :
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.
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

2009-06-27T17:50:00.002+07:00

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 PaO₂saturation 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

The oxygen cascade describes the process of declining oxygen tension from atmosphere to mitochondria.
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
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
Tissue oxygen extraction is calculated by subtracting mixed venous oxygen content from arterial oxygen content.
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.
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 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.
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.
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.
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.
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.
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/

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