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.

Ranson’s Criteria: For the History Books

Acute pancreatitis – a common indication for hospitalization in the US – is a feared complication of alcohol use, gallstones, abdominal trauma, steroids, mumps, high fat and calcium level, ERCPs and even scorpion stings. Up to 25% of patients with acute pancreatitis will develop severe acute pancreatitis. It’s a tricky clinical situation to manage due to the difficulty in estimating the severity of the disease; yet distinguishing between the two is critical as mortality rates are 1-2% for mild pancreatitis and up to 17% for severe cases. Prior to this study, physicians relied purely on clinical judgment to triage patients to the floor or the ICU, a method known to underestimate the severity of the disease. Ranson et al provided 11 criteria – 5 assessed at admission and the other 6 at 48 hours – to help predict the most severe cases, with the goal of aggressively treating these patients in the ICU or the OR.

The study suffered from many shortcomings, which complicated data analysis. The data itself was likely skewed due to selection and observer bias, the number of patients enrolled, and the variety of treatment methods employed. For example, 21 patients underwent abdominal exploration within 7 days of admission. Another 10 patients were randomized to early operative or non-operative management. Of those, all but one spent at least 8 days in the ICU. An additional category was non-randomized early management where 17 patients were managed by early operation within 48 hours of diagnosis. Operations varied widely, but the existing standard “recommended early laparotomy with cholecystostomy, gastrostomy, [jejunostomy] and pancreatic drainage in patients with severe acute pancreatitis”. With all these variables, it becomes impossible to assess outcomes based on the various treatment modalities employed – the power in each group and for the whole study is greatly reduced. Nonetheless some of the conclusions regarding blood loss and fluid depletion were accurate. Importantly, the authors noted that a worsening BUN in the face of aggressive fluid replacement was a more sensitive index for survival than the BUN at admission.

At the time, the 11 criteria now known as Ranson’s Criteria were the best available for predicting severity. However, more recent studies have demonstrated that Ranson’s criteria as an aggregate are a relatively poor predictor of disease severity. Today we have at our disposal a number of scoring systems that have been shown to be better prognosticators than Ranson’s Criteria. One, the APACHE II scoring, was developed for critically ill ICU patients. Modern guidelines from the American Gastroenterology Association recommend using the APACHE II scoring system because of its good negative predictive value for severe acute pancreatitis. Still, it continues to be difficult to accurately predict outcomes and severity, although early aggressive management and the use of other diagnostic modalities not available to the authors at the time have improved survival.

The complexity of the interactions of numerous risk factors that ultimately lead to an attack of acute pancreatitis almost precludes having a simple scoring system. It seems that Ranson’s criteria are best used during hospital rounds where medical students and residents can rapidly regurgitate them. It is our hope that they recognize this study for its historic value and instead employ APACHE II to guide early management.

Ranson JH, Rifkind KM, Roses DF, Fink SD, Eng K, Spencer FC. Prognostic signs and the role of operative management in acute pancreatitis. Surg Gynecol Obstet. 1974; 139:69.

(Unfortunately there isn’t even an abstract of the original article available online. For those at UTSW, I can e-mail you a photocopy of the article since it isn’t available online through the library)