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.

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

Introduction

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.

Results

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:
11794168.

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.

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.

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

Introduction

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.

Results

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.

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

Transfuse at 7 – The TRICC Trial

“A Multicenter, Randomized, Controlled Clinical Trial of Transfusion Requirements in Critical Care” – Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group; February 11, 1999, The New England Journal of Medicine

Introduction

Ask any physician when he initiates blood transfusions and you will get many different answers. The most appropriate one (and the one medical students should memorize for their wards services) is when it matters – when the patient has lost enough red blood cells (RBC) to cause symptoms. However, there are many situations where symptoms related to RBC loss or destruction are confounded by numerous other medical conditions. Patients who go to the Intensive Care Unit (ICU) are usually the most difficult to assess due to the severity and complexity of the illnesses that they present with. For this reason, this Canadian group attempted to set a standard threshold for when to initiate blood transfusions based on a simple, routine laboratory blood study – the hemoglobin concentration (Hgb). The Hgb is a study of the concentration of oxygen-carrying molecules in RBCs, and normal values for adults run from 13-15 g/dL.

Blood transfusions save lives. In the general sense, if your blood cannot carry oxygen, then there is no point in breathing it in. If your Hgb drops too low, it is just as bad as suffocating. However, blood transfusions are also high-risk and harmful interventions. When you receive blood from another individual, your own immune system recognizes the blood as foreign. This leads to an immune response, whether severe or mild, which may divert resources away from fighting the pathogen that was originally the reason for the illness and further weakening the body. Additionally, there is always the risk of acquiring blood borne illnesses, such as Hepatitis C or HIV, despite the screeningefforts of blood banks. Due to the value and risk, blood transfusions must be used carefully, and the TRICC trial was vital to understanding how to do so.

Results

This trial split patients into two groups. The first, the restricted group, was given blood transfusions only when their Hgb dropped below 7, and their Hgb was maintained in the 7 to 9 range. The second, the liberal group, was transfused any time the Hgb fell below 10, and their Hgb was maintained in the 10 to 12 range. The primary outcome, all cause mortality at 30 days, showed no statistical difference between the two groups. However, when the analysis was repeated for patients who were less than 55 years old, there was significantly less mortality in the restrictive (transfuse at 7) group. The analysis was also repeated for patients who were less sick, as defined by an APACHEII score of <20 (APACHEII is a score calculated from multiple physiologic factors (vital signs, lab values, etc.), on a range from 0-71 that indicates increasing severity of disease and risk of death with an increasing score). In this sub-analysis as well, there was reduced mortality in the restrictive group. For patients older than 55 and with an APACHEII > 20, there was no difference in 30 day mortality between the restrictive and liberal groups.

Why We Do What We Do

The authors of this study presented their results in a very objective and humble manner. Even though there was a clear trend towards reduced mortality in the restrictive group for the entire study (18.7 percent mortality in the restrictive group vs. 23.3 percent mortality in the liberal group), they refused to acknowledge it due to lack of statistical significance (P = 0.11). At the least, this validates that there is no additional harm done if transfusions are restricted to patients with Hgb < 7. Patients in the restricted group received less blood overall in this study, reducing their risk for contracting transfusion-associated infectious diseases and major transfusion-associated complications, such as lung injury (TRALI) or cardiac overload (TACO). For younger patients and those who were not as severely ill, it is clearly apparent that over-transfusion is actually deleterious, and this is statistically significant. So the next time you approach a patient with possible blood requirements, it is not a bad idea to use the Hgb of 7 as a starting point to guide management.

Hébert PC, Wells G, Blajchman MA, Marshall J, Martin C, Pagliarello G,
Tweeddale M, Schweitzer I, Yetisir E. A multicenter, randomized, controlled
clinical trial of transfusion requirements in critical care. Transfusion
Requirements in Critical Care Investigators, Canadian Critical Care Trials Group.
N Engl J Med. 1999 Feb 11;340(6):409-17. Erratum in: N Engl J Med 1999 Apr
1;340(13):1056. PubMed PMID: 9971864.
http://www.ncbi.nlm.nih.gov/pubmed/9971864