Trends in respiratory medicine: ARDS and pulmonary embolism

Trends in respiratory medicine: ARDS and pulmonary embolism – acute respiratory distress syndrome

G. Douglas Campbell Jr

ABSTRACT The Editorial Board concludes its discussion of key developments in pulmonary medicine. First, the focus is on advances in the management of the acute respiratory distress syndrome (ARDS). Despite disappointing results with a variety of investigational pharmacologic agents, new ventilatory strategies for managing ARDS have been developed, and outcome has improved. The Editorial Board next addresses the prevention, diagnosis, and treatment of pulmonary thromboembolism. Notable advances include more diligent use of prophylaxis in high-risk patients, the introduction of low molecular weight heparin, and advances in noninvasive testing. (J Respir Dis. 1999;20(12):793-799)


The Journal of Respiratory Diseases (JRD): At our roundtable discussion 10 years ago (former Editorial Board member) Dr Kenneth Moser mentioned the need for new therapies that could be introduced in the early stages of the acute respiratory distress syndrome (ARDS). At the time, there was some hope that protease inhibitors, elastase inhibitors, and antioxidants might be effective. What is the current status of those agents and other therapies for ARDS?

Dr Matthay: In the last 10 years, no single pharmacologic therapy or combination of therapies has been shown (in properly controlled, prospective, randomized trials) to improve outcome in ARDS. The most significant breakthrough–perhaps since the introduction of positive-end expiratory pressure (PEEP)–is a recent report from the National Heart, Lung, and Blood Institute (NHLBI) ARDS network.’ These investigators demonstrated that using lower tidal volumes on the mechanical ventilator–6 mL/kg of ideal body weight, as opposed to the more traditional level of 10 to 12 mL/kg–resulted in a 25% decrease in mortality in patients with acute lung injury.

This is by far the largest ARDS study of mechanical ventilation that has been conducted; it included more than 800 patients. I think that the study is persuasive for two reasons–first, because of its size, and second, because the results make physiologic sense; overdistending the lungs may be injurious, amplifying the acute lung injury.

Dr Campbell: There is also evidence that mortality from ARDS has been decreasing.

Dr Matthay: Yes. Aside from the disappointing results concerning the pharmacologic therapies, we are learning to manage ARDS better. In the NHLBI study, the overall mortality for the control group (the group with the higher tidal volume) was 39%, and the mortality in the group that received lower tidal volumes was 31%. Historically, ARDS was associated with a 60% or higher mortality.

Dr Campbell: Many new ventilator modes have been developed. Also, bilevel positive airway pressure (BIPAP) represents an important development in managing respiratory failure.

Dr Matthay: Absolutely In the past 10 years, there has been a wider use of the BIPAP mask to treat patients with impending or de facto respiratory failure, especially those with chronic obstructive pulmonary disease. Noninvasive ventilation has also been effective in some patients with sleep apnea. [Editor’s note: See “The growing recognition of sleep apnea.”]

Dr Lillington: Another advance in the management of ARDS is that we have learned that some patients can be ventilated more easily with a lower tidal volume if you rotate them so they are in the prone, then supine, then prone position. [2]

Also, we now recognize that some patients who appear to have ARDS actually have a condition called acute interstitial pneumonitis, which is corticosteroid-responsive. This is particularly likely to occur in patients who do not seem to have a clear-cut precipitating cause of ARDS, such as trauma and hemolysis. It is extremely difficult to make the distinction except with a lung biopsy, which we hesitate to do in these patients.

Dr Matthay: Meduri’s [3,4] research suggests that corticosteroids may improve outcome in ARDS if they are given on or about days 7 to 9 in patients who are not clearly improving in terms of ventilatory requirements. So the benefit for corticosteroids may be in the fibroproliferative phase of ARDS rather than on the first day. To evaluate this further, the NHLBI-ARDS network is carrying out a large, randomized, controlled trial assessing the potential benefit of administering corticosteroids during this phase of ARDS.

Dr Campbell: Incidentally, not everybody who survives ARDS recovers with normal lung function. Recent studies have looked at posttraumatic stress disorder following mechanical ventilation. This is not specific to ARDS, but we need to be cognizant of the possibility that it may occur in these patients. Also, it underscores the importance of considering longer-term effects if we are going to develop new treatment modalities.

Pulmonary thromboembolism JRD: Ten years ago, Dr Moser [5] emphasized that prophylaxis for venous thromboembolism was considerably underused in high-risk patients. Is this still true?

Dr Matthay: My sense is that there is a wider appreciation of the importance of implementing deep venous thrombosis (DVT) prophylaxis in high-risk patients. An important development has been the introduction of low molecular weight heparin, which is FDA-approved for DVT prophylaxis in patients who undergo hip or knee surgery and for the treatment of DVT with or without pulmonary thromboembolism (PTE). Low molecular weight heparin shows great promise. We can expect to see it more widely used in both inpatients and outpatients.

JRD: A number of studies provide evidence of the efficacy and safety of low molecular weight heparins. [6,7] But are these agents too expensive to be used routinely?

Dr Squillace: I have not seen a cost analysis, but considering the safety and efficacy data, I think low molecular weight heparin should be used routinely, at least for DVT. At our center, we use it on an outpatient basis.

Dr Campbell: One of the advantages of low molecular weight heparm is that you do not have to measure partial thromboplastin time (PTT). If the patient has DVT, you can treat him or her as an outpatient. That would result in a cost savings. If you continue to measure PTTs and keep the patient in the hospital for the usual length of time for intravenous heparin, there is no cost savings.

Dr Matthay: In patients with DVT or PTE, if we can give low molecular weight heparin twice a day, keep them out of the hospital, and avoid serial measurements of PTT, the health care system may be well served. Platelet counts can drop in patients receiving low molecular weight heparin, although the incidence of this is not as high as it is with traditional heparin. [8]

There is no question that using traditional heparin is more challenging, because it requires the measurement of PIT at least every 4 to 6 hours in the first 24 to 36 hours of therapy. Deaths from recurrent PTE tend to occur in patients who do not achieve an adequate PIT in the first 24 to 36 hours of therapy.

We are at a crossroads with respect to deciding which patients can be treated with low molecular weight heparin on an outpatient basis. If I understand the managed care environment correctly, the trend is going to be toward more outpatient therapy.

Another development in the use of heparin is the realization that the dosage should be based on a weight nomogram. If the patient weighs 300 lb–and that is not uncommon, since DVT and PTE are more common in obese patients–a larger constant intravenous infusion is needed than for a patient who weighs substantially less. A loading dose of 5,000 to 10,000 units of heparin and a traditionally used constant IV infusion of 1,000 units per hour is not adequate for a patient who weighs 300 lb. Table 1 shows a weight-based regimen for heparin administration.

Almost all hospitals now have nomograms for the dosage of heparin according to the patient’s weight, and these nomograms allow a therapeutic PTT to be achieved in the first 24 hours in about 70% to 80% of patients.

Dr Campbell: A recent study found that giving warfarin for 6 months rather than 3 months significantly reduced the risk of recurrence in patients with a first episode of idiopathic venous thromboembolism. [9] We used to think that at 3 months, the risk of significant bleeding more or less matched the risk of PTE, so we did not treat beyond 3 months. But this study found that treating for 6 months did not increase the risk of major complications but did reduce the risk of PIE and DVT.

JRD: What is the current role for the inferior vena cava (IVC) filter?

Dr Matthay: There is a growing interest in the prophylactic use of the IVC filter in patients who are at extremely high risk for DVT and PTE. This includes patients who have had major trauma and patients who are acutely quadriplegic. The IVC filter may be indicated in these and other high-risk patients in whom pharmacologic and physical means of prophylaxis, such as subcutaneous heparin, low molecular weight heparin, and intermittent compression devices, have not been satisfactory in preventing DVT and PTE. In 1997, Schilz and Wirth [10,11] addressed the data that were beginning to appear about the prophylactic use of IVC filters.

The results of a prospective, randomized study of the prophylactic use of IVC filters were published in 1998. [12] The patients in this study had proximal DVT and were considered to be at high risk for PTE. All received either unfractionated heparin or low molecular weight heparin; half had an IVC filter placed. The patients who had an IVC filter in place had a lower incidence of PTE in the early phase of care. However, after 2 years, they had a higher incidence of DVT. The results suggest that if we use an IVC filter in an early phase– perhaps after acute major trauma or in an acutely quadriplegic patient–we might need to consider giving long-term warfarin once the initial risk of bleeding from heparin has passed.

Dr Squillace: Another development in the last 10 years has been the increased use of venous ultrasonography for diagnosis of DVT.

The difficulty occurs with patients who have indeterminate or intermediate probability scans, the so-called nondiagnostic scans. This is where lower extremity ultrasonography can be helpful. If the results of ultrasonography are positive for DVT, the patient is anticoagulated. If the results are negative, some would recommend pulmonary angiography. However, others would use the contrast-enhanced chest CT scan because of the growing interest in using a less invasive test. Basically, contrast-enhanced CT is a method for finding defects in pulmonary blood vessels without having to insert a catheter through the right heart.

Dr Matthay: The Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) study, published in 1990, has been of great interest throughout the world. [13] This study established that the ventilation-perfusion lung scan can be extremely helpful in many patients in whom PTE is suspected. When the results indicate a high probability of PTE and there is a high clinical probability PTE is confirmed by pulmonary angiography–the so-called gold standard for diagnosis– in 96% of cases. In contrast, when there is a low clinical suspicion and the lung scan indicates low probability PTE is detected by pulmonary angiography in only about 4% of patients (Table 2). [13]

This field is evolving rapidly in an interesting fashion (Table 3). The PIOPED-II study, which will begin soon, will assess the potential role of contrast-enhanced chest CT in the diagnosis of PTE. Many centers are extremely enthusiastic and believe that their radiologists can detect significant PTE as long as there are defects in reasonably large pulmonary blood vessels. Emboli located only in the tiny blood vessels can be missed.

The diagnosis of PTE is in transition. Currently, many physicians use an algorithm that starts with the lung scan when PTE is suspected; if the lung scan is considered nondiagnostic, lower extremity ultrasonography is ordered. If ultrasonography is negative for DVT, pulmonary angiography or a contrast-enhanced CT scan is done.

Dr Campbell: What role is there for the D-dimer test in the work-up? There is some evidence that elevated D-dimer levels are associated with PTE. [14]

Dr Matthay: Hospitals vary in terms of how they measure D-dimers. If the test is not done by a certain technique, the results are not reliable. I would not encourage physicians to rely on D-dimer.

Roundtable participants

* G. Douglas Campbell, Jr, MD, Professor of Medicine, Division of Pulmonary/Critical Care Medicine, Louisiana State University, Shreveport.

* Thomas M. File, Jr, MD, Professor of Internal Medicine, Northeastern Ohio Universities College of Medicine, Rootstown; Chief, Infectious Disease Service, Summa Health System, Akron.

* Glen A. Lillington, MD, Clinical Professor of Medicine, Stanford University, Stanford; Professor of Medicine Emeritus, Division of Pulmonary Medicine/Critical Care, University of California, Davis.

* Richard A. Matthay, MD, Professor of Medicine; Associate Director, Pulmonary and Critical Care Section, Yale University, New Haven, Conn.

* Susan P. Squillace, MD, Associate Professor of Family Medicine; Assistant Professor of Internal Medicine, University of Virginia, Charlottesville.

Editorial Board member William W Busse, MD (Professor of Medicine and Chief, Section of Allergy and Clinical Immunology, University of Wisconsin, Madison), was unable to attend.


(1.) Matthay MA. Conference summary: acute lung injury. Chest. 1999;116:119S 126S.

(2.) Martinez M, Diaz E, Joseph D, et al. Improvement in oxygenation by prone position and nitric oxide in patients with acute respiratory distress syndrome. Intensive Care Med. 1999;25:304-312.

(3.) Meduri GU, Belenchia JM, Estes RJ, et al. Fibroproliferative phase of ARDS. Clinical findings and effects of corticosteroids. Chest. 1991;100:943.

(4.) Meduri GU, Headley AS, Golden E, et al. Effect of prolonged methyiprednisolone in unresolving acute respiratory distress syndrome: a randomized controlled trial. JAMA. 1998:280:159-165.

(5.) Moser KM. Pulmonary thromboembolism: your challenge is prevention. J Respir Dis. 1989:10(10):83-93.

(6.) The Columbus Investigators. Low-molecular-weight heparin in the treatment of patients with venous thromboembolism. N Engl J Med. 1997;337:657-662.

(7.) Simonneau G, Sors H, Charbonnier B, et al. A comparison of low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism. N Engl J Med. 1997;337:663-669.

(8.) Warkentin TE, Levine MN, Hirsh J, et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med. 1995;332:1330-1335.

(9.) Kearon C, Gent M, Hirsh J, et al. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med. 1999;340:901-907.

(10.) Schilz R, Wirth JA. Does your patient need an inferior vena cava filter? J Respir Dis. 1996;17:1022-1030.

(11.) Schilz R, Wirth JA. IVC filters: update on evolving indications. J Respir Dis. 1997;18:30-44.

(12.) Decousus H, Leizorovicz A, Parent F, et al. A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. N Engl J Med. 1998;338:409-415.

(13.) PIOPED Investigators. Value of ventilation perfusion scan in acute pulmonary embolism. Results of the prospective investigation of pulmonary embolism diagnosis (PIOPED). JAMA 1990;263:2753-2759.

(14.) Ginsberg JS, Wells PS, Kearon C, et al. Sensitivity and specificity of rapid whole-blood assay for D-dimer in the diagnosis of pulmonary embolism. Ann In fern Med. 1998;129:1006-1011.

(15.) Teran-Santos J, Jimenez-Gomez A, Cordero-Guevara J, et al. The association between sleep apnea and the risk of traffic accidents. N Engl J Med. 1999;340:847-851.

(16.) Woodson RT. Surgical approaches to obstructive sleep apnea. Curr Opin Pulm Med. 1998;4:344-350.

(17.) Knaack L, Podazus T. Electric stimulation of the upper airway muscle. Curr Opin Pulm Med. 1998;4:370-375.

(18.) Hyers TM. venous thromboembolism. Am J Respir Crit Care Med. 1999;159:1-14.

(19.) George RB, Light RW, Matthay MA, Matthay RA, eds. Chest Medicine–Essentials of Pulmonary and Critical Care Medicine. 3rd ed. Baltimore: Williams & Wilkins: 1995.

Body weight-based dosing if intravenous heparin

Initial dosing: Loading: 80 U/kg

Maintenance infusion [*]: 18 U/kg/h (APTT in 6 h)

Subsequent dose adjustments:

Dose change Additional Next

APTT (s) (U/kg/h) action APTT (h)

Less than 35 +4 Rebolus 6

(less than 1.2 X mean normal) with 80 U/kg

35 – 45 +2 Rebouls 6

(1.2 – 1.5 X mean normal) with 40 U/kg

46 – 70 [+] 0 0 6 [++]

(1.5 – 2.3 X mean normal)

71 – 90 -2 0 6

(2.3 – 3.0 X mean normal)

More than 90 -3 Stop 6

(more than 3 X mean normal) infusion 1 h

APTT, activated partial thromboplastin time.

(*.)Heparin, 25,000 U in 250 [mLD.sub.5]W. Infuse at rate dictated by body

weight through an infusion apparatus calibrated for low flow rates.

(+.)The therapeutic range in seconds should correspond to a plasma heparin

level of 0.2-0.4 U/mL by portamine sulfate titration. When APTT is checked

at 6 h or longer, steady-state kinetics can be assumed.

(++.)During the first 24, h repeat APTT every 6 h. Thereafter, obtain APTT

once every morning unless it is outside the therapeutic range.

From Hyers TM. Am J Respir Crit Care Med. 1999 [18]

Predicting the likelihood

of pulmonary thromboembolism

Probability of pulmonary thromboembolism (%)

V/Q lung scan High clinical

interpretation probability

High probability 96

Intermediate probability 66

Low probability 40

Near-normal/normal 0

V/Q lung scan Intermediate Low clinical

interpretation clinical probability probability

High probability 88 56

Intermediate probability 28 16

Low probability 16 4

Near-normal/normal 6 2

V/Q, ventilation-perfusion.

From George RB et al. Chest Medicine–Essentials of Pulmonay and Critical

Care Medicine. 1995. [19]

Major developments and future trends: ARDS, PTE, and sleep apnea

Major developments in the past 10 years:

Improved ventilation techniques, including the use of lower tidal volumes in mechanically ventilated patients who have ARDS

Improved use of prophylaxis for venous thromboembolism

Use of low molecular weight heparin inpatients with DVT

Prophylactic use of inferior vena cava filters in patients at very high risk for PTE

Advances in noninvasive diagnostic tests, including ultrasonography and contrastenhanced CT

Increased recognition of sleep apnea

Advances in use of noninvasive ventilation and surgical approaches for sleep apnea

What to expect in the next 5 to 10 years:

Improved survival rates in patients with ARDS

More efficient diagnosis of PTE

More widespread use of low molecular weight heparin for venous thromboembolism

ARDS, acute respiratory distress syndrome; PTE, pulmonary thrombowmbolism, DVT, deep venous thrombosis.

The growing recognition of sleep apnea

Dr Campbell: A recent article showed that 25% of the people coming to an emergency department after an accident were found to have sleep apnea. [15]

Dr Lillington: One of the first patients I saw with significant obstructive sleep apnea was about 35 years old and had a heroic Wagnerian build. He said that sleep apnea was interfering with his livelihood. He said, “I have to drive, but I keep going in the ditch.” I asked, “Why do you have to drive?” and he said, “I’m an ambulance driver.” These forms of sleep-disordered breathing–obstructive or central sleep apnea, and now the partially obstructed form–are real conditions.

Dr Matthay: In the past 10 years, there is no question that sleep-disordered breathing has become a much more widely recognized problem. We are realizing that some patients who have systemic hypertension or are overweight have sleep-disordered breathing. Sleep apnea–multiple apneic episodes during the night–is clearly associated with the onset of systemic hypertension. A vivid example is an acquaintance of mine who, at age 50, had a stroke. Systemic hypertension was thought to be the cause, but it was established that severe sleep apnea was the most likely cause of his hypertension. Now he is being treated for sleep apnea, and his hypertension is under much better control.

We are realizing that the complications of sleep-disordered breathing can be severe. Patients can have decreased mental functioning during the day because of poor sleep, and this results in a higher incidence of car accidents.

Dr File: With the growth of sleep centers and increased interest in this topic, I’ve noticed that several of the neurology colleagues I have worked with are now focusing on sleep disorders. Is sleep-disordered breathing primarily a neurologic or a pulmonary disorder?

Dr Lillington: Actually, much of the original work on sleep disorders was done by a psychiatrist at Stanford, Dr William Dement.

Dr Matthay: In addition to psychiatrists, neurologists, and pulmonologists, some ear, nose, and throat specialists specialize in sleep disorders. I don’t think any one group has a particular claim to these disorders. Ideally, these specialists work together.

Dr Campbell: Continuous positive airway pressure has been effective in some patients with sleep apnea. Bilevel positive airway pressure is also an important development.

Dr Lillington: Noninvasive ventilation is a significant improvement over tracheostomy However, many patients dislike these treatments, and compliance maybe a problem.

Standard approaches to the management of obstructive sleep apnea include weight reduction, if the patient is obese, and a variety of surgical approaches to improve upper airway patency. These include uvulopalatopharyngoplasty and laser-assisted uvulopalatoplasty; the latter is still somewhat controversial.

Surgery for the lower pharynx includes a variety of maxillofacial procedures and even tongue operations, such as midline glossectomy and lingualpasty. [16] Oral appliances are helpful in some cases. New surgical approaches include radiofrequency volumetric reduction of tissue and electrical stimulation of the tongue. [17]

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