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

Introduction

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.

Results

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.

References

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.

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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

Introduction

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).

Results

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:
18539917.

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

Introduction

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.

Results

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.

References

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.

Albumin or Normal Saline? Either way you’re SAFE

“A Comparison of Albumin and Saline for Fluid Resuscitation in the Intensive Care Unit” – The SAFE Study Investigators, The New England Journal of Medicine, May 27, 2004

Introduction

One of the most powerful acute interventions in medicine today is fluid resuscitation. It is possible to instantly increase perfusion to all vital organs, saving unfathomable amounts of nutrient and oxygen-deprived tissue with adequate administration of fluids. The fluids that are administered are simple sterile water-based concoctions that do not carry the adverse effects or complications of blood or other medications. Therefore, initial responses to patients in extremis, those who require immediate and acute care, usually include obtaining vascular access and infusing large amounts of fluids.

Although there are many types of fluids, two major categories provide two physiologic approaches to fluid management. Crystalloid solutions are solutions of water and small molecules – small enough to leak out of capillaries and equilibrate with extracellular body fluid (body fluid that surrounds cells).  Colloid solutions are solutions of water with large molecules – large enough to not travel through intact vascular membranes (they do not leak out of healthy blood vessels). Among other differing effects, colloid solutions tend to hold water inside the vessels better, but they can increase intravascular density, predisposing high-viscosity-low-flow states. Prior to this publication, small disputing studies had shown both benefits and lack of benefits from choosing one fluid type or the other. The SAFE investigators settled this dispute with a large (~7000 patients), double-blinded clinical trial that compared fluid management between 0.9% Normal Saline (NS, a crystalloid) and 4% Albumin (a colloid) in Intensive Care Unit (ICU) patients with the primary outcome being all cause mortality after 28 days.

Results

After initial fluid resuscitation with Albumin or NS, there was no difference in mortality after 28 days in all patients admitted to the ICU. Patients given NS tended to receive more fluid initially resulting in a greater net positive fluid balance than those that received Albumin. However, even when broken down by common presenting illnesses to the ICU – sepsis, trauma or Acute Respiratory Distress Syndrome (ARDS), mortality was unchanged between Albumin and NS in each individual group. In fact, the only significant result this study produced was that NS administration produced lower mortality than Albumin in trauma patients with brain injury, a very small subgroup of all patients in this study.

Why We Do What We Do

We give NS. We give Albumin. The SAFE study showed that the two main fluids categories and the two most popular fluids are relatively safe. When administered to ICU patients – those least able to defend their body against physiologic challenges – neither fluid identified itself as inferior or superior. So was this study worthless because it did not identify a single solution and change or guide medical practice? I contend that strong, robust studies such as the SAFE study that do not find significant differences actually strengthen medical practice as a whole. Knowing these results provides doctors with both options of fluid when treating a patient. More importantly, doctors are able to use logical physiologic evidence, derived from basic scientific principles, to tailor their choice in fluids and management to the presenting patient.

Large studies such as SAFE are designed to adequately test and compare interventions. However, these studies are not intended to dictate prognosis for the patients. The data does not imply that one patient resuscitated with albumin will have the same outcome as if he had been treated with NS. Each patient is different, and giving the clinician the opportunity to apply his knowledge and training along with the guiding clinical evidence is how optimal care is provided.

Finfer S, Bellomo R, Boyce N, French J, Myburgh J, Norton R; SAFE Study
Investigators. A comparison of albumin and saline for fluid resuscitation in the 
intensive care unit. N Engl J Med. 2004 May 27;350(22):2247-56. PubMed PMID:
15163774.
http://www.ncbi.nlm.nih.gov/pubmed/15163774

Stroke, t-PA and the NINDS trial

“Tissue Plasminogen Activator for Acute Ischemic Stroke” – The National Institute for Neurologic Disorders and Stroke rt-PA Stroke Study Group, New England Journal of Medicine, December 14th, 1995

Introduction

Prior to the advent of intravenous thrombolytics, there was no direct treatment for ischemic strokes. The clot occluding the artery was allowed to sit in place and the area of brain deprived of blood flow, nutrients and oxygen was allowed to expand while the associated risk factors were controlled. Eventually the body would dissolve the clot (ironically, with it’s own “homemade” version of tissue plasminogen activator, or t-PA) and start the long road to recovery of brain function.

The difficulty with strokes is not mortality. In fact, people who die from large strokes due to massive clots are often dead before they reach a hospital or care facility. Preventing stroke mortality was only one component of the analysis conducted by these authors. Strokes cause disability. Depending on the region of the brain affected, strokes can cause weakness, inability to speak, inability to control emotions or any other mental function without killing, and often this is the most devastating result. Additionally, once disability has set in, the only treatment available is long term physical therapy, which is usually accompanied with large costs and uncertain outcomes. It is important to also note that there is a proportion of stroke patients who regain function of the affected brain region  without intervention. Often this indicates a smaller or less severe stroke, but even with advanced imaging at the initial assessment, it is difficult to characterize which patients will follow this course.

Results

This study assessed the risks and benefits of administering intravenous t-PA within 90 and within 180 minutes of onset of stroke symptoms. The patients were assessed at 24 hours after stroke and 3 months after stroke. The tools for assessment were a variety of scales that measured disability. For example, the NIH Stroke Scale looks at multiple physical exam findings, such as strength in one extremity, to determine how much brain function the patient has lost. Mortality was also compared after 3 months.

The following results from the study were statistically significant: In comparing groups who received t-PA within 90 minutes and placebo, more t-PA patients than placebo patients showed significant improvement within the first 24 hours. After 3 months, more patients who received t-PA within 180 minutes were disability free than patients who received placebo, and this result was the same when patient groups were broken down by age and type and severity of stroke. There was an increased risk of symptomatic intracranial bleeding in patients given t-PA during the first 36 hours, but there was no difference in mortality between patients receiving t-PA and placebo after 3 months.

Why We Do What We Do

This study clearly showed that t-PA increases the chance of eliminating disability after three months if it is administered in the first 3 hours after symptom onset. The authors of this study chose a very difficult outcome measurement – the total reduction of disability to baseline, regardless of how severe the stroke was initially. By validating t-PA in this setting, they make a very strong case for its general use in ischemic strokes across the board.

Intravenous t-PA was the first direct treatment of stroke and is still, 18 years after the NINDS trial, the only effective therapy that we have. It has trounced intravascular mechanical clot-busting, numerous surgical procedures and many other drugs, therapies and delivery mechanisms. Most importantly, it works. For the patients who emerge with no disability, it is not just a therapy, it is a stroke cure. The NINDS study did not just validate the use and effectiveness of t-PA. For those who understand the metrics and analysis properly, it is a sign of hope that someday we will be able to eliminate, and not just reduce, the debilitating disability that results from stroke.

Tissue plasminogen activator for acute ischemic stroke. The National Institute
of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med. 1995
Dec 14;333(24):1581-7. PubMed PMID: 7477192.
http://www.nejm.org/doi/full/10.1056/NEJM199512143332401