High Frequency Oscillatory Ventilation is Dead

“High-Frequency Oscillation in Early Acute Respiratory Distress Syndrome” – the OSCILLATE Trail Investigators, The New England Journal of Medicine, February 28, 2013


Mechanical ventilation improves patient outcomes by supplementing pulmonary function – to remove carbon dioxide and replace oxygen in the blood. There are multiple different ways to ventilate a patient, and different strategies target different physiologic parameters and different respiratory disease categories. Acute Respiratory Distress Syndrome (ARDS) is a disease pathology characterized by diffuse inflammation in the lungs and reduced ability of the lungs to oxygenate the blood. Some strategies for improving oxygenation include adding positive end-expiratory pressure and reversing the ratio of inhalation to exhalation times (a strategy known as Airway Pressure Release Ventilation (APRV)). A previous landmark study also noted the importance of reducing total lung volumes in ARDS in order to prevent pressure-induced injury (barotrauma) and overall mortality.

High frequency oscillatory ventilation (HFOV) is a strategy aimed at reducing barotrauma by making small changes in airway pressures around a set mean pressure. The mean pressure can be higher due to small peak pressures, allowing for improved oxygenation. The downside of low amplitude pressure changes is reduced air movement, and therefore reduced ventilation, which impairs gas exchange. Therefore, high frequency breaths given at greater than four times the normal rate are used to move more air in and out of the lungs and achieve adequate gas exchange. This study compared HFOV with traditional low-stretch protocol (established in the landmark ARDSnet study) with a primary outcome of in-hospital mortality.


The trial was terminated early, after only 571 patients were enrolled, due to a significant increased mortality in patients being treated with HFOV. Patients on HFOV also required more vasopressors and neuromuscular blockers after therapy despite no differences in baseline requirements prior to randomization. There were no significant differences in fraction of inspired oxygen between HFOV and control, but mean airway pressures were lower in the control group.

Why We Do What We Do

Mechanical ventilation during ARDS is a supportive therapy that is aimed at maintaining oxygenation, removing carbon dioxide and minimizing barotrauma until the lungs recover from the primary insult. HFOV is a strategy that is generally used in infants and preterm infants with respiratory distress or interstitial emphysema. Due to the potential for HFOV to reduce lung injury, and previous evidence that pressure-induced injury is a major factor in mechanically ventilated patient mortality from ARDS, it was believed to be a possible improvement. However, the results of this trial definitively showed the potential for this strategy to cause harm.

The harm associated with HFOV noted here may be the result of a need for increased mean airway pressures. These pressures were determined by blood oxygenation levels and were increased to achieve an adequate level. Conventional ventilation achieved the same oxygenation with lower mean pressures, suggesting that it is a better oxygenation strategy.

It is also important to note that the HFOV strategy used here is only one of many different HFOV strategies. There are multiple other parameters that can be varied, such as inspiratory to expiratory times and amplitude of pressures. However, another independent large study comparing HFOV to conventional ventilation failed to show any difference in 30 day mortality between the two groups [2]. Given the harm shown in this study,clinical practice should avoid HFOV as a primary strategy for ARDS and more importantly, pursue the conventional ventilation strategy with low tidal volumes that has previously been shown to be beneficial.


1. Ferguson ND, Cook DJ, Guyatt GH, Mehta S, Hand L, Austin P, Zhou Q, Matte A,
Walter SD, Lamontagne F, Granton JT, Arabi YM, Arroliga AC, Stewart TE, Slutsky
AS, Meade MO; OSCILLATE Trial Investigators; Canadian Critical Care Trials Group.
High-frequency oscillation in early acute respiratory distress syndrome. N Engl J
Med. 2013 Feb 28;368(9):795-805. doi: 10.1056/NEJMoa1215554. Epub 2013 Jan 22.
PubMed PMID: 23339639.

2. Young D, Lamb SE, Shah S, MacKenzie I, Tunnicliffe W, Lall R, Rowan K,
Cuthbertson BH; OSCAR Study Group. High-frequency oscillation for acute
respiratory distress syndrome. N Engl J Med. 2013 Feb 28;368(9):806-13. doi:
10.1056/NEJMoa1215716. Epub 2013 Jan 22. PubMed PMID: 23339638.

Management of Type 2 Diabetes in Patients with Cardiac Risk Factors

“Effects of Intensive Glucose Lowering in Type 2 Diabetes” – The Action to Control Cardiovascular Risk in Diabetes Study Group, The New England Journal of Medicine, June 12, 2008


Type 2 Diabetes is a disease well known to cause major secondary complications such as renal failure, blindness, amputations and cardiac disease. Control of diabetes is measured by control of blood sugar levels, and treatments, whether they include oral drugs or injected insulin, are aimed at maintaining blood sugar levels within a normal range of < 125 mg/dL. Improved blood glucose control correlates with fewer complications from diabetes. However, as discussed in previous inpatient studies (NICE-SUGAR), there are complications associated with over-controlling blood sugar levels, such as episodes of hypoglycemia, and the overall mortality was higher when blood sugars were strictly controlled in the Intensive Care Unit (ICU). However, before the ACCORD trial, there were conflicting data regarding the best targets to control type 2 diabetes as an outpatient.

Glycosylated hemoglobin, or hemoglobin A1c (HgbA1c), is a useful surrogate to measure the average blood sugar concentration over the previous 2-3 months. It has become the standard of measurement for diabetes control. However, the exact HgbA1c value to target was previously unknown. An average blood glucose of 125 mg/dL correlates with an HgbA1c of ~ 6%, but as expected with diabetic patients, these averages inherently include abnormal high and consequently abnormal low blood sugar episodes. In order to determine the best target for HgbA1c, the ACCORD trial tested whether patients receiving either an intensive blood sugar management regimen with a goal of 6.0% for all patients or a standard liberal schedule where sugars were maintained between 7.0 – 7.9% differ in terms of non-fatal myocardial infarctions, non-fatal strokes, deaths from cardiovascular causes and all-cause mortality. The study population was old and sick (40-79 years of age with cardiovascular disease or 55-79 years of age with precursor cardiovascular disease or multiple risk factors).


The average HgbA1c of the patients in the study at the start was 8.1%. Patients in the intensive and liberal groups achieved and maintained HgbA1c’s of 6.4% and 7.5%, respectfully, after one year of the study. The trial was terminated 18 months prior to schedule due to increased all-cause mortality in the intensive therapy arm. This was a secondary outcome. There was an emerging decreased incidence of the composite primary outcome (non-fatal myocardial infarction, non-fatal stroke and death from cardiovascular causes) in the intensive therapy arm after three years, but this finding was not statistically significant. There was a significant decrease in non-fatal myocardial infarction but increase in death from cardiovascular causes in the intensive therapy arm.

Why We Do What We Do

Treatment of type 2 diabetes is essential to prevent or delay the numerous complications it is associated with. Cardiovascular causes are leading causes of morbidity and mortality in this population, but cannot be the only determinant for therapy. This study served to examine the risks and benefits of intensive glucose management with respect to cardiovascular disease in generally older and sicker patients. The results showed that intensive glucose management may have a benefit in long term cardiovascular outcomes, especially myocardial infarction, but was associated with increased all-cause and cardiovascular mortality in the first few years following initiation of intensive therapy.

The treatment goals for older patients with multiple risk factors are therefore more liberal in practice today, such as a HgbA1c of 7.5%. How this level is achieved, in terms of which drugs, insulin regimens or diet and exercise routines are used, is dependent on the physician and the patient, but treating to this goal avoids the immediate complications of low blood sugars and excessive pharmacotherapy. However, the additional results from this study also indicate that intensive therapy if tolerated over a longer term will start to show benefits in non-fatal cardiovascular outcomes. Therefore, a physician may choose to adjust targets along the course of a patient’s treatment once a tolerable regimen has been established. In studies of inpatient management of hyperglycemia, younger, healthier patients tolerated intensive therapy better and actually showed improved outcomes when compared with liberal approaches. Similarly, younger, healthier patients with type 2 diabetes may avoid the early complications and experience benefits from intensive glucose management. However, further study is necessary to confirm this.

Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC,
Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse JB, Cushman WC, Genuth S,
Ismail-Beigi F, Grimm RH Jr, Probstfield JL, Simons-Morton DG, Friedewald WT.
Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008 Jun
12;358(24):2545-59. doi: 10.1056/NEJMoa0802743. Epub 2008 Jun 6. PubMed PMID:

PIOPED II: Assessing CTAs in PE diagnosis

Pulmonary embolism (PE) is the blockage of arteries that perfuse the lungs, generally due to clots. Rapid assessment and initiation of anti-coagulation in suspected PE cases is paramount as the risk of recurrent PE in confirmed cases could be as high as 25% within the first 24 hours. Fortunately, diagnosis and management of pulmonary embolism quickly improved at the turn of the 21st century. Between 1995 and 2001, Wells et al developed criteria to assess the likelihood of a pulmonary embolism based on the clinical presentation. At the same time, a new development in computed tomography (CT), termed spiral CT, permitted visualization of pulmonary vasculature. The Prospective Investigation of Pulmonary Embolism Diagnosis II (PIOPED II) study addressed the benefits of CTA.

One issue when attempting to assess the accuracy and usefulness of a new imaging modality is having a strong gold standard with which to compare. Given that the existing gold standard for PE is a pulmonary angiography or digital subtraction pulmonary angiography (DSPA) – a highly invasive, time-consuming study that uses direct arterial catheter access for contrast-enhanced imaging – an alternative method was needed. Using multiple ancillary tests, the authors employed a composite reference diagnosis as a gold standard in addition to DSPA. A diagnosis of PE was given when ventilation-perfusion (V/Q) scanning showed high probability in a patient without a history of PE or when V/Q scans showed moderate probability with positive lower extremity venous ultrasonography. PE was ruled out with low pre-test probability and negative results from V/Q scans or venous ultrasonography. Using these standards, 632 patients were ruled out for PE. 592 received a CT-PA and were followed for 6 months. Of that group, only 2 required anticoagulation, indicating that the composite reference diagnosis was a suitable substitute in situations where DSPA was not necessary.

The results, while impressive on their own, are more indicative when compared to the results from the first PIOPED study, which examined V/Q scans. In the original study, V/Q scans achieved 98% sensitivity but very poor specificity (10%). In contrast, CTA achieved 83% sensitivity and 96% specificity. When venous angiography was included (CTA-CTV), sensitivity improved to 92%. CTA also inherently provided imaging of the whole chest and upper neck, which in certain cases produced alternative diagnoses.

The results of PIOPED II demonstrate that, when used in conjunction with modified Wells criteria, CTA provides high positive and negative predictive values for PE. Effectively, concordant clinical assessment and imaging results can rule-in or rule-out a diagnosis which was not possible with V/Q scans alone. In patients with suspected PE and who do not have contraindications for IV contrast, it offers a shorter clinical algorithm for diagnosis and management by eliminating the uncertainty of moderate probability V/Q scans. Today CTA has become a second gold standard in the diagnosis of PE due to the invasiveness of pulmonary angiograms. Nevertheless, in both algorithms, any inconclusive results must be followed up by DSPA or serial lower extremity ultrasounds. As the authors themselves admit, the benefits of CTA-CTV are largely dependent on the expertise of the radiology staff reading the film. For institutions with this capability, the diagnosis and management of PE is greatly improved with CTA.


Multidetector computed tomography for acute pulmonary embolism. Stein PD, Fowler SE, Goodman LR, et al. N Engl J Med. 2006. Jun 1;354(22):2317-27.

Hyperglycemia management in the ICU

“Intensive versus conventional glucose control in critically ill patients.” – the NICE-SUGAR investigators, The New England Journal of Medicine, March 26th, 2009

“Intensive insulin therapy in critically ill patients.” – Greet van de Berghe et al., The New England Journal of Medicine, November 8, 2001

“Intensive insulin therapy in the medical ICU.” – Greet van de Berghe et al., The New England Journal of Medicine, February 2, 2006


Control of blood glucose in the Intensive Care Unit (ICU) and the hospital has implications in many disease processes, including cardiovascular, renal, and infectious problems. Elevated or abnormally low blood glucose values can compound with the primary problem and complicate a patient’s hospital stay. Over the course of the 2000s, three large studies attempted to establish and validate a strategy to control blood sugar in the ICU.

The first two trials (van de Berge 2001 and van de Berghe 2006) were conducted at a single center with patient numbers in the 1400-1500 range. The 2001 study followed patients in the Surgical ICU, and the 2006 study in the Medical ICU. These investigators proposed an intensive glucose control regimen where an insulin infusion was initiated at levels higher than 110 mg/dL (the upper limit of normal blood sugars) and titrated to blood levels in the 80-110 mg/dL normoglycemic range. This was compared with a conventionally treated group where insulin drips were started once blood sugar exceeded 215 mg/dL, and titrated to a range of 180-215 mg/dL.

The NICE-SUGAR study was a multi-centered study that included medical and surgical ICUs, with a total patient population of 6104. The intensive therapy was repeated similar to the studies above. The conventional arm of patients received an insulin drip once blood glucose levels exceeded 180 mg/dL. Insulin drip was discontinued when glucose levels fell below 144 mg/dL. The target glucose level was < 180 mg/dL. Importantly, inclusion criteria for this trial selected patients that expected to remain in the ICU > 3 days.


Van de Berghe 2001 found that the intensive therapy resulted in reduced in-hospital mortality and ICU mortality, especially in patients staying longer that 5 days. The intensive therapy group also had fewer morbidity rates including lower rates of sepsis. Hypoglycemia did occur more frequently in the intensive therapy group.

Van de Berghe 2006 also found ICU and in-hospital death was lower in the intensive treatment arm in patients who stayed in the ICU for longer than 3 days. There was no significance in mortality between the two arms in terms of in-hospital or ICU mortality for all ICU patients. Hypoglycemia occurred more frequently in the intensive therapy arm. There was an improvement in morbidities – requirements of mechanical ventilation, ICU stay and hospital stay in the intensive arm, but no significant fewer episodes of sepsis.

The NICE-SUGAR study found an increased all-cause mortality at 90 days after admission to the ICU in the intensive treatment arm when compared to conventional treatment. The majority of the deaths in both arms of the study were in-hospital or in the ICU. There was no significant difference in morbidities, including sepsis, except for an increased number of hypoglycemic episodes in the intensive glucose management group.

Why We Do What We Do

After the 2001 van de Berghe paper, intensive glucose management became the standard of practice in the ICU. However, after the striking results of the NICE-SUGAR study, the recommended practice is now a liberal approach to glucose management with a goal of blood sugars < 180 mg/dL and treatment only above this level. Large sample size and diversity in multiple trial centers provide this study with validity in a broad range of ICU and hospital applications.

Statistical significance of the data is also important – the 2006 medical ICU van de Berghe study failed to find a difference between in-hospital and ICU mortality between the two arms of the study for all patients, so the contemporary standard of practice (intensive management) was considered to be safe and valid. However, NICE-SUGAR’s results were statistically significant in showing that intensive therapy actually led to increased mortality. Clinical practice changed quickly as a result of this significant data.

After the results of the NICE-SUGAR study, there was extensive discussion into why intensive glucose control increased mortality, in stark contrast to the previous two landmark studies by van de Berghe. The authors of NICE-SUGAR did not expand on a cause for the increased mortality, but referred to lower blood sugars, increased insulin administration and increased episodes of hypoglycemia as being possible explanations. When under stress, as critical patients are, the body naturally produces a hyperglycemic state with increased corticosteroid responses, and dampening this response with artificial insulin administration may work against the complex defense mechanisms of the stressed-state body. The results of NICE-SUGAR interestingly correlate with another landmark trial on outpatient diabetes, the ACCORD trial, which also found that intensive glucose management increased mortality. However, more research was requested by both the ACCORD and NICE-SUGAR studies to explain their results.

1. NICE-SUGAR Study Investigators, Finfer S, Chittock DR, Su SY, Blair D, Foster
D, Dhingra V, Bellomo R, Cook D, Dodek P, Henderson WR, Hébert PC, Heritier S,
Heyland DK, McArthur C, McDonald E, Mitchell I, Myburgh JA, Norton R, Potter J,
Robinson BG, Ronco JJ. Intensive versus conventional glucose control in
critically ill patients. N Engl J Med. 2009 Mar 26;360(13):1283-97. doi:
10.1056/NEJMoa0810625. Epub 2009 Mar 24. PubMed PMID: 19318384.

2. van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M,
Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R. Intensive insulin therapy in
critically ill patients. N Engl J Med. 2001 Nov 8;345(19):1359-67. PubMed PMID:

3. Van den Berghe G, Wilmer A, Hermans G, Meersseman W, Wouters PJ, Milants I,
Van Wijngaerden E, Bobbaers H, Bouillon R. Intensive insulin therapy in the
medical ICU. N Engl J Med. 2006 Feb 2;354(5):449-61. PubMed PMID: 16452557.

Statins: Game Changers in CVD

In a recent post we had discussed the use of aspirin in the setting of an acute MI. Our second look at landmark trials examining the treatment of coronary vascular disease (CVD) focuses on primary prevention of CVD. Elevated cholesterol levels have long been implicated in the progression of CVD, and numerous medications have been developed to reduce plasma cholesterol levels as a means to reduce the incidence of myocardial infarctions and other cardiovascular events. In fact, the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) revealed that the CVD risk reduction was proportional to the reduction in LDL cholesterol. Through the 1980s, fibrates and bile acid resins (cholestyramine) were in use, and studies from multiple institutions had demonstrated their ability to moderately reduce cholesterol levels. Used alone, neither cholestyramine nor the fibrates could achieve greater than a 10-15% reduction in LDL. The most promising development was the approval of HMG-CoA reductase inhibitors, otherwise known as statins. Several smaller studies suggested an improvement in plasma cholesterol levels and cardiovascular outcomes with statin therapy. The Scandinavian Simvastatin Survival Study (4S) assessed the effect of simvastatin on total mortality and cardiovascular outcomes and confidently addressed the question.

Between 1988 and 1994, 4444 patients between the ages of 35 and 70 were randomly assigned to receive various doses of simvastatin or placebo. Dosing was titrated to a specific serum cholesterol value; patients who were above this value received up to 40mg per day, and those below this value were titrated down. The study group was followed for an average of 5.4 years. The primary endpoint for 4S was total mortality – an important distinction since a few research trials with fibrates, including one from the WHO, had shown an increase in non-cardiovascular deaths. Randomization was successful in evenly dividing patients already on multiple medications for hypertension, angina and diabetes. A similar study conducted at the same time in Scotland, the WOSCOP study, was looking at the effect of pravastatin on primary prevention. While 4S was not as straightforward as WOSCOPS, it was far more generalizable in a number of ways. For one, it included women. Other aspects of the study that stand out are the broader age range, existing CVD or diabetes and a percentage of smokers closer to that of the US.

The data from 4S were impressive. Patients on simvastatin on average saw a 35% decrease in LDL cholesterol. More importantly, this decrease correlated with a relative risk of death of 0.70 when compared to placebo (182 vs 256 deaths). This reduction in deaths was attributable to a 42% decrease in cardiovascular mortality. Likewise, simvastatin also lead to a pronounced decrease in non-fatal cardiovascular events (RR 0.66). Adverse effects were few – 1 episode of rhabdomyolysis in the simvastatin group. Complaints of myalgias and elevations in LFTs were similar between placebo and simvastatin.

Prior to this study, the benefits of lipid-lowering therapy lacked a consensus. The 4S trial conclusively determined that statin therapy was a safe and more effective treatment choice in lowering serum LDL cholesterol than other lipid-lowering agents. Moreover, it provided the largest reduction in cardiovascular mortalities, and the benefit was witnessed in all age groups. Today many newer variations of statins exist but simvastatin continues to be the first line therapy for many of our patients.


The Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994. 344:1383-1389.

Surviving Sepsis

“Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock” – Emanuel Rivers et al., The New England Journal of Medicine, November 8, 2001


Sepsis and septic shock are common conditions associated with high mortality, and the incidence and mortality continue to rise [1,2]. Sepsis is defined as a systemic inflammatory response with deteriorating hemodynamic parameters, most often due to disseminated infection, and septic shock occurs when the blood, oxygen and nutrient supply is so compromised that it causes multi-organ failure. Sepsis is an acute problem, characterized by rapid onset and deterioration, and treatment is time sensitive. Antibiotics are the mainstay of therapy, as they will eliminate the offending microbes, but supportive care to maintain organ function is crucial in reducing mortality.

The investigators of this study proposed an early (within the first 72 hrs) goal-directed treatment schedule for this supportive care. They outlined parameters to measure organ perfusion with goals for therapy – central venous pressures (goal 8-12 mmHg), central venous oxygen content (goal > 70%) and arterial pressures (goal 65-90 mmHg). To meet these goals, they administered fluids, blood, vasopressors, vasodilators and inotropes. This therapy regimen was compared with standard therapy at clinicians’ discretion. The outcomes measured were organ dysfunction by APACHEII scores, MODS scores,arterial pH and serum lactate levels and 28 and 60-day all cause mortality.


During the first 72 hours, central venous oxygen saturation goals were achieved in ~60% of standard therapy patients and ~95% of goal directed therapy patients. Hemodynamic parameters (arterial pressures, central venous pressures) were at goal in 86% of standard therapy patients and 99% of goal directed therapy patients. Patients in the goal directed arm had higher blood pressures and higher central venous oxygen saturations during the entire 72 hours. Goal directed therapy patients received more fluids, more blood and more inotropes within the first 6 hours of therapy, but required less fluids, less blood and less vasopressors after that (hours 7-72).

APACHE II and MODS scores of organ dysfunction were lower in patients in the goal directed group during hours 7-72. Base deficit was lower, serum lactate was lower and arterial pH was higher during the same time period. Twenty-eight day and 60-day mortality figures were lower in the goal directed group, which was mainly the result of in-hospital mortality.

Why We Do What We Do

Treatment and management of sepsis is highly dependent on early therapy. As illustrated in this trial, aggressive fluid, blood and inotropic resuscitation in the first 6 hours can have profound impact on further treatment requirements and organ dysfunction in the following 3 days, as well as in-hospital mortality. Early recognition is also key to initiating therapy during the period where it is most helpful. Increased volume and blood administration outside the first 6 hours did not result in improved organ function or mortality. Directing therapy towards specific hemodynamic goals standardizes practice and gives clinicians strong guidelines to treat towards. Therefore, the benefits of placing invasive central venous and arterial lines outweigh the complications of these procedures.

Organ perfusion in septic shock is a simple physiologic system that must be aggressively managed early on to improve patient outcomes. Even though cardiac output and vascular permeability might be severely limited, administration of fluid and blood to carry oxygen and nutrients can support the body during the critical period of the disease. As clinicians, we must all learn to recognize sepsis early and target therapy to hemodynamic goals to provide the best outcome for our patients in such a dangerous and common disease.


1. Dombrovskiy VY, Martin AA, Sunderram J, Paz HL. Rapid increase in
hospitalization and mortality rates for severe sepsis in the United States: a
trend analysis from 1993 to 2003. Crit Care Med. 2007 May;35(5):1244-50. PubMed
PMID: 17414736.

2. Melamed A, Sorvillo FJ. The burden of sepsis-associated mortality in the
United States from 1999 to 2005: an analysis of multiple-cause-of-death data.
Crit Care. 2009;13(1):R28. doi: 10.1186/cc7733. Epub 2009 Feb 27. PubMed PMID:
19250547; PubMed Central PMCID: PMC2688146.

3. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E,
Tomlanovich M; Early Goal-Directed Therapy Collaborative Group. Early
goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl
J Med. 2001 Nov 8;345(19):1368-77. PubMed PMID: 11794169.

ARDSnet – the mechanical ventilation trial

“Ventilation with Lower Tidal Volumes as Compared with Traditional Tidal Volumes for Acute Lung Injury and the Acute Respiratory Distress Syndrome” – the Acute Respiratory Distress Syndrome Network, May 4, 2000, The New England Journal of Medicine


Since its inception in the late 1920s with the Iron Lung, mechanical ventilation has been an invaluable therapeutic intervention available to physicians treating almost every kind of severe illness. Mechanical ventilation, usually achieved by placing an endotracheal tube directly into the trachea of the patient, establishes a direct sealed connection with the lungs down to the terminal alveoli, where gas exchange occurs. The lung is little more than air tracts with alveolar gas exchange units, so mechanical ventilation essentially gives the operator total physiologic control over the respiratory system. No other organ system in the body can be modulated this way, and the vital importance of the lungs in terms of providing oxygen and removing carbon dioxide make mechanical ventilation remarkable.

In Acute Lung Injury (ALI) and Acute Respiratory Distress Syndrome (ARDS), lung collapse and excess inflammatory fluid in the lungs reduces the amount of lung that is aerated. As a result, traditional tidal volumes were kept large to retribute. The investigators of this trial were interested in studying whether these high tidal volumes caused further lung injury by stretching out the lungs, and whether lower tidal volumes with associated decreased ventilation would be provide a mortality benefit without an associated detriment due to reduced carbon dioxide removal and ventilation.


The tidal volumes in the low tidal volume group were maintained around 6.2 mL/kg body weight, while the traditional group received 11.8 mL/kg. The associated peak airway pressures were 25 and 33 cmH20, respectively. One hundred eighty day mortality was improved in the low tidal volume group (31% vs 39%), and probability of discharge home without breathing assistance was increased. The number of ventilator-free days was higher in the low tidal volume group, as was the number of days without organ failure. Plasma IL-6 levels were found to be lower and drop faster in the low tidal volume group. The trial was stopped after interim analysis due to the finding that use of low tidal volumes was efficacious in terms of mortality and a stringent significance threshold had been reached.

Why We Do What We Do

ARDS and ALI carried about a 40-50% mortality rate at the time that these investigators initiated their study. Their hypothesis that high tidal volumes cause barotrauma was supported by the increased levels of IL-6, a marker of inflammation, in the high tidal volume group. However, as previous theory had predicted, lower tidal volumes also led to higher blood CO2 levels and lower pH in this trial. Low tidal volumes were also correlated with increased respiratory rate, increased fraction of oxygen percentage in inspired air (FiO2) and increased positive end-expiratory pressure (PEEP – a back pressure used at the end of a breath to keep airways from collapsing) during this study, most likely to maintain oxygenation given a lower ventilation volume. The most important result, however, is that mortality was decreased in patients receiving lower tidal volumes.

In most medical interventions, there is always a cost-benefit trade off. In this case, the cost was higher CO2 levels and acidemia in patients with ARDS or ALI with the benefit of reducing further inflammation due to increased pressures on the lung parenchyma. The trade off was beneficial in this case. Some may argue that the provisions of PEEP and increased FiO2 skewed the results by providing the low tidal volume group with added benefit. These adjustments are, however, commonly used (in both arms of the study) and carry a trade off as well, all of which was factored into the primary mortality outcome.

The ARDSnet trial, as this is known, is not only remarkable because of the drastic improvements in mortality in dismal diseases such as ARDS and ALI or the implications it has in ventilator management today, but also in how it used basic physiologic principles of volume-pressure relationships to hypothesize a result and then show evidence to support the hypothesis. This trial is a true example of translational medicine – using basic science principles to directly impact and improve patient care. The elegance of thought and execution are an example for every clinician-researcher to strive for.