American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference : Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 1992; 20:864–874

Infection : A host response to the presence of micro-organisms or tissue invasion by microorganisms.

Bacteremia.
The presence of viable bacteria in circulating blood

Systemic Inflammatory Response Syndrome (SIRS)
The systemic inflammatory response to a wide variety of severe clinical insults, manifested by two or more of the following conditions:

l       Temperature > 38°C or < 36°C
l       Heart rate > 90 beats/min
l       Respiratory rate > 20 breaths/min or PaCO2 < 32 mm Hg
l        WBC count > 12,000/mm3 , < 4000/mm3, or > 10% immature (band) forms.

Sepsis
The systemic inflammatory response to infection. In association with infection, manifestations of sepsis are the same as those previously defined for SIRS. It should be determined whether they are a direct systemic response to the presence of an infectious process and represent an acute alteration from baseline in the absence of other known causes for such abnormalities. The clinical manifestations would include two or more of the following conditions as a result of a documented infection :

Severe Sepsis / SIRS.
Sepsis (SIRS) associated with organ dysfunction, hypoperfusion, or hypotension. Hypoperfusion and perfusion abnormalities may include, but are not limited to, lactic acidosis, oliguria, or an acute alteration in mental status.

Refractory (Septic) Shock / SIRS Shock.
A subset of severe sepsis (SIRS) and defined as sepsis (SIRS) induced hypotension despite adequate fluid resuscitation along with the presence of perfusion abnormalities that may include, but are not limited to, lactic acidosis, oliguria, or an acute alteration in mental status. Patients receiving inotropic or vasopressor agents may no longer be hypotensive by the time they manifest hypoperfusion abnormalities or organ dysfunction, yet they would still be considered to have septic (SIRS) shock.

Multiple Organ Dysfunction Syndrome (MODS).
Presence of altered organ functions in an acutely ill patient such that homeostasis cannot be maintained without intervention.

Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock

Dellinger, RP, Carlet, JM; Masur, H, et al; for the Surviving Sepsis Campaign Management Guidelines Committee. (Crit Care Med 2004; 32:858–873)

Grades of Recommendation
A. Supported by at least 2 level I investigations
B. Supported by 1 level I investigation
C. Supported by level II investigations only
D. Supported by at least 1 level III investigation
E. Supported by level IV or V evidence

Grading of evidence
I. Large, randomized trials with clearcut results; low risk of false-positive (alpha) error or false-negative (beta) error
II. Small, randomized trials with uncertain results; moderate-to-high risk of false-positive (alpha) and/or false-negative (beta) error
III. Non-randomized, contemporaneous controls
IV. Non-randomized, historical controls and expert opinion
V. Case series, uncontrolled studies, and expert opinion

A. Initial Resuscitation
1. The resuscitation of a patient in severe sepsis or sepsis-induced tissue hypoperfusion (hypotension or lactic acidosis) should begin as soon as the syndrome is recognized and should not be delayed pending ICU admission. An elevated serum lactate concentration identifies tissue hypoperfusion in patients at risk who are not hypotensive. During the first 6 hrs of resuscitation, the goals of initial resuscitation of sepsis-induced hypoperfusion should include all of the following as one part of a treatment protocol (Grade B) :
1.1. Central venous pressure : 8–12 mm Hg
1.2. Mean arterial pressure : > 65 mm Hg
1.3. Urine output > 0.5 mL/kg/hr.
1.4. Central venous (superior vena cava) or mixed venous oxygen saturation > 70%

2. During the first 6 hrs of resuscitation of severe sepsis or septic shock, if central venous oxygen saturation or mixed venous oxygen saturation of 70% is not achieved with fluid resuscitation to a central venous pressure of 8–12 mm Hg, then transfuse packed red blood cells to achieve a hematocrit of > 30% and/or administer a dobutamine infusion (up to a maximum of 20 micrograms/kg/min) to achieve this goal. (Grade B).

B. Diagnosis

1. Appropriate cultures should always be obtained before antimicrobial therapy is initiated. To optimize identification of causative organisms, at least two blood cultures should be obtained with at least one drawn percutaneously and one drawn through each vascular access device, unless the device was recently (< 48 hrs) inserted. Cultures of other sites such as urine, cerebrospinal fluid, wounds, respiratory secretions, or other body fluids should be obtained before antibiotic therapy is initiated as the clinical situation dictates. (Grade D)

2. Diagnostic studies should be performed promptly to determine the source of the infection and the causative organism. Imaging studies and sampling of likely sources of infection should be performed; however, some patients may be too unstable to warrant certain invasive procedures or transport outside of the ICU. Bedside studies, such as ultrasound, may be useful in these circumstances. (Grade E)

C. Antibiotic Therapy

1. Intravenous antibiotic therapy should be started within the first hour of recognition of severe sepsis, after appropriate cultures have been obtained. (Grade E)

2. Initial empirical anti-infective therapy should include one or more drugs that have activity against the likely pathogens (bacterial or fungal) and that penetrate into the presumed source of sepsis. The choice of drugs should be guided by the susceptibility patterns of microorganisms in the community and in the hospital. (Grade D)

3. The antimicrobial regimen should always be reassessed after 48–72 hrs on the basis of microbiological and clinical data with the aim of using a narrow spectrum antibiotic to prevent the development of resistance, to reduce toxicity, and to reduce costs. Once a causative pathogen is identified, there is no evidence that combination therapy is more effective than monotherapy. The duration of therapy should typically be 7–10 days and guided by clinical response. (Grade E)

4. If the presenting clinical syndrome is determined to be due to a noninfectious cause, antimicrobial therapy should be stopped promptly to minimize the development of resistant pathogens and superinfection with other pathogenic organisms. (Grade E)

D. Source Control

1. Every patient presenting with severe sepsis should be evaluated for the presence of a focus on infection amenable to source control measures, specifically the drainage of an abscess or local focus on infection, the debridement of infected necrotic tissue, the removal of a potentially infected device, or the definitive control of a source of ongoing microbial contamination. (Grade E)

2. The selection of optimal source control methods must weigh benefits and risks of the specific intervention. Source control interventions may cause further complications such as bleeding, fistulas, or inadvertent organ injury; in general, the intervention that accomplishes the source control objective with the least physiologic upset should be employed, for example, consideration of percutaneous rather than surgical drainage of an abscess. (Grade E)

3. When a focus of infection amenable to source control measures such as an intra-abdominal abscess, a gastrointestinal perforation, cholangitis, or intestinal ischemia has been identified as the cause of severe sepsis or septic shock, source control measures should be instituted as soon as possible following initial resuscitation. (Grade E)

4. If intravascular access devices are potentially the source of severe sepsis or septic shock, they should be promptly removed after establishing other vascular access. (Grade E)

E. Fluid Therapy
See initial resuscitation recommendations (A1–2) for timing of resuscitation.

1. Fluid resuscitation may consist of natural or artificial colloids or crystalloids. There is no evidence-based support for one type of fluid over another. (Grade C)

2. Fluid challenge in patients with suspected hypovolemia (suspected inadequate arterial circulation) may be given at a rate of 500–1000 mL of crystalloids or 300–500 mL of colloids over 30 mins and repeated based on response (increase in blood pressure and urine output) and tolerance (evidence of intravascular volume overload). (Grade E)

F. Vasopressors

1. When an appropriate fluid challenge fails to restore adequate blood pressure and organ perfusion, therapy with vasopressor agents should be started. Vasopressor therapy may also be required transiently to sustain life and maintain perfusion in the face of life-threatening hypotension, even when a fluid challenge is in progress and hypovolemia has not yet been corrected. (Grade E)

2. Either norepinephrine or dopamine (through a central catheter as soon as available) is the first-choice vasopressor agent to correct hypotension in septic shock. (Grade D)

3. Low-dose dopamine should not be used for renal protection as part of the treatment of severe sepsis. (Grade B)

4. All patients requiring vasopressors should have an arterial catheter placed as soon as practical if resources are available. (Grade E)

5. Vasopressin use may be considered in patients with refractory shock despite adequate fluid resuscitation and highdose conventional vasopressors. Pending the outcome of ongoing trials, it is not recommended as a replacement for norepinephrine or dopamine as a first-line agent. If used in adults, it should be administered at infusion rates of 0.01–0.04 units/min. It may decrease stroke volume. (Grade E)

G. Inotropic Therapy

1. In patients with low cardiac output despite adequate fluid resuscitation, dobutamine may be used to increase cardiac output. If used in the presence of low blood pressure, it should be combined with vasopressor therapy. (Grade E)

2. A strategy of increasing cardiac index to achieve an arbitrarily predefined elevated level is not recommended. (Grade A)

H. Steroids

1. Intravenous corticosteroids (hydrocortisone 200–300 mg/day, for 7 days in three or four divided doses or by continuous infusion) are recommended in patients with septic shock who, despite adequate fluid replacement, require vasopressor therapy to maintain adequate blood pressure. (Grade C)

2. Doses of corticosteroids > 300 mg hydrocortisone daily should not be used in severe sepsis or septic shock for the purpose of treating septic shock. (Grade A)

3. In the absence of shock, corticosteroids should not be administered for the treatment of sepsis. There is, however, no contraindication to continuing maintenance steroid therapy or to using stress dose steroids if the patient’s history of corticosteroid administration or the patient’s endocrine history warrants. (Grade E)

I. Recombinant Human Activated Protein C (rhAPC)

1. rhAPC is recommended in patients at high risk of death (Acute Physiology and Chronic Health Evaluation II > 25, sepsis-induced multiple organ failure, septic shock, or sepsis-induced acute respiratory distress syndrome [ARDS]) and with no absolute contraindication related to bleeding risk or relative contraindication that outweighs the potential benefit of rhAPC. (Grade B)

J. Blood Product Administration
1. Once tissue hypoperfusion has resolved and in the absence of extenuating circumstances, such as significant coronary artery disease, acute hemorrhage, or lactic acidosis (see recommendations for initial resuscitation), red blood cell transfusion should occur only when hemoglobin decreases to < 7.0 g/dL (< 70 g/L) to target a hemoglobin of 7.0–9.0 g/dL. (Grade B)

2. Erythropoietin is not recommended as a specific treatment of anemia associated with severe sepsis but may be used when septic patients have other accepted reasons for administration of erythropoietin such as renal failure induced compromise of red blood cell production. (Grade B)

3. Routine use of fresh frozen plasma to correct laboratory clotting abnormalities in the absence of bleeding or planned invasive procedures is not recommended. (Grade E)

4. Antithrombin administration is not recommended for the treatment of severe sepsis and septic shock. (Grade B)

5. In patients with severe sepsis, platelets should be administered when counts are <5000/mm3 (5 X 109/L) regardless of apparent bleeding. Platelet transfusion may be considered when counts are 5000–30,000/mm3 (5–30 X 109/L) and there is a significant risk of bleeding. Higher platelet counts (>50,000/mm3[50 X 109/L]) are typically required for surgery or invasive procedures. (Grade E)

K. Mechanical Ventilation of Sepsis-Induced Acute Lung Injury (ALI)/ARDS

1. High tidal volumes that are coupled with high plateau pressures should be avoided in ALI/ARDS. Clinicians should use as a starting point a reduction in tidal volumes over 1–2 hrs to a “low” tidal volume (6 mL per kilogram of predicted body weight) as a goal in conjunction with the goal of maintaining end-inspiratory plateau pressures < 30 cm H2O. (See Appendix C for a formula to calculate predicted body weight.) (Grade B)

2. Hypercapnia (allowing PaCO2 to increase above normal, so-called permissive hypercapnia) can be tolerated in patients with ALI/ARDS if required to minimize plateau pressures and tidal volumes. (Grade C)

3. A minimum amount of positive endexpiratory pressure should be set to prevent lung collapse at end-expiration. Setting positive end-expiratory pressure based on severity of oxygenation deficit and guided by the FiO2 required to maintain adequate oxygenation is one acceptable approach. Some experts titrate positive end-expiratory pressure according to bedside measurements of thoracopulmonary compliance (to obtain the highest compliance, reflecting lung recruitment). (Grade E)

4. In facilities with experience, prone positioning should be considered in ARDS patients requiring potentially injurious levels of FiO2 or plateau pressure who are not at high risk for adverse consequences of positional changes. (Grade E)

5. Unless contraindicated, mechanically ventilated patients should be maintained semi recumbent, with the head of the bed raised to 45° to prevent the development of ventilator-associated pneumonia. (Grade C)

6. A weaning protocol should be in place and mechanically ventilated patients should undergo a spontaneous breathing trial to evaluate the ability to discontinue mechanical ventilation when they satisfy the following criteria: a) arousable; b) hemodynamically stable (without vasopressor agents); c) no new potentially serious conditions; d) low ventilatory and end-expiratory pressure requirements; and e) requiring levels of FiO2 that could be safely delivered with a face mask or nasal cannula. If the spontaneous breathing trial is successful, consideration should be given for extubation. Spontaneous breathing trial options include a low level of pressure support with continuous positive airway pressure 5 cm H2O or a T-piece. (Grade A)

L. Sedation, Analgesia, and Neuromuscular Blockade in Sepsis

1. Protocols should be used when sedation of critically ill mechanically ventilated patients is required. The protocol should include the use of a sedation goal, measured by a standardized subjective sedation scale. (Grade B)

2. Either intermittent bolus sedation or continuous infusion sedation to predetermined end points (e.g., sedation scales) with daily interruption/lightening of continuous infusion sedation with awakening and retitration, if necessary, are recommended methods for sedation administration. (Grade B)

3. Neuromuscular blockers should be avoided if at all possible in the septic patient due to the risk of prolonged neuromuscular blockade following discontinuation. If neuromuscular blockers must be used for longer than the first hours of mechanical ventilation, either intermittent bolus as required or continuous infusion with monitoring of depth of block with train of four monitoring should be used. (Grade E)

M. Glucose Control

1. Following initial stabilization of patients with severe sepsis, maintain blood glucose <150 mg/dL (8.3 mmol/L). Studies supporting the role of glycemic control have used continuous infusion of insulin and glucose. With this protocol, glucose should be monitored frequently after initiation of the protocol (every 30 – 60 mins) and on a regular basis (every 4 hrs) once the blood glucose concentration has stabilized. (Grade D)

2. In patients with severe sepsis, a strategy of glycemic control should include a nutrition protocol with the preferential use of the enteral route. (Grade E)

N. Renal Replacement

1. In acute renal failure, and in the absence of hemodynamic instability, continuous venovenous hemofiltration and intermittent hemodialysis are considered equivalent. Continuous hemofiltration offers easier management of fluid balance in hemodynamically unstable septic patients. (Grade B)

O. Bicarbonate Therapy

1. Bicarbonate therapy for the purpose of improving hemodynamics or reducing vasopressor requirements is not recommended for treatment of hypoperfusion induced lactic acidemia with pH >7.15. The effect of bicarbonate administration on hemodynamics and vasopressor requirement at lower pH as well as the effect on clinical outcome at any pH has not been studied. (Grade C)

P. Deep Vein Thrombosis

Prophylaxis
1. Severe sepsis patients should receive deep vein thrombosis (DVT) prophylaxis with either low-dose unfractionated heparin or low-molecular weight heparin. For septic patients who have a contraindication for heparin use (i.e., thrombocytopenia, severe coagulopathy, active bleeding, recent intracerebral hemorrhage), the use of a mechanical prophylactic device (graduated compression stockings or intermittent compression device) is recommended (unless contraindicated by the presence of peripheral vascular disease). In very high-risk patients such as those who have severe sepsis and history of DVT, a combination of pharmacologic and mechanical therapy is recommended. (Grade A)

Q. Stress Ulcer Prophylaxis

1. Stress ulcer prophylaxis should be given to all patients with severe sepsis. H2 receptor inhibitors are more efficacious than sucralfate and are the preferred agents. Proton pump inhibitors have not been assessed in a direct comparison with H2 receptor antagonists and, therefore, their relative efficacy is unknown. They do demonstrate equivalency in ability to increase gastric pH. (Grade A)

R. Consideration for Limitation of Support

1. Advance care planning, including the communication of likely outcomes and realistic goals of treatment, should be discussed with patients and families. Decisions for less aggressive support or withdrawal of support may be in the patient’s best interest. (Grade E)

 

ABSTRACTS

17. A Comparison of Albumin and Saline for Fluid Resuscitation in the Intensive Care Unit. The SAFE Study Investigators. N Engl J Med 2004;350:2247-56.

Background : It remains uncertain whether the choice of resuscitation fluid for patients in intensive care units (ICUs) affects survival. We conducted a multicenter, randomized, double-blind trial to compare the effect of fluid resuscitation with albumin or saline on mortality in a heterogeneous population of patients in the ICU. Methods : We randomly assigned patients who had been admitted to the ICU to receive either 4 percent albumin or normal saline for intravascular-fluid resuscitation during the next 28 days. The primary outcome measure was death from any cause during the 28-day period after randomization. Results : Of the 6997 patients who underwent randomization, 3497 were assigned to receive albumin and 3500 to receive saline; the two groups had similar baseline characteristics. There were 726 deaths in the albumin group, as compared with 729 deaths in the saline group (relative risk of death, 0.99; 95 percent confidence interval, 0.91 to 1.09; P=0.87). The proportion of patients with new single-organ and multiple-organ failure was similar in the two groups (P=0.85). There were no significant differences between the groups in the mean (±SD) numbers of days spent in the ICU (6.5±6.6 in the albumin group and 6.2±6.2 in the saline group, P=0.44), days spent in the hospital (15.3±9.6 and 15.6±9.6, respectively; P=0.30), days of mechanical ventilation (4.5±6.1 and 4.3±5.7, respectively; P=0.74), or days of renal-replacement therapy (0.5±2.3 and 0.4±2.0, respectively; P=0.41). Conclusions : In patients in the ICU, use of either 4% albumin or normal saline for fluid resuscitation results in similar outcomes at 28 days.

18. Corticosteroids for severe sepsis and septic shock: a systematic review and meta-analysis. Annane, D, et al. BMJ. 2004;329:480

Objective : To assess the effects of corticosteroids on mortality in patients with severe sepsis and septic shock. Data sources : Randomised and quasi-randomised trials of corticosteroids versus placebo (or supportive treatment alone) retrieved from the Cochrane infectious diseases group’s trials register, the Cochrane central register of controlled trials, Medline, Embase, and LILACS. Review method : Two pairs of reviewers agreed on eligibility of trials. One reviewer entered data on to the computer and four reviewers checked them.We obtained some missing data from authors of trials and assessed methodological quality of trials. Results : 16/23 trials (n = 2063) were selected. Corticosteroids did not change 28 day mortality (15 trials, n = 2022; relative risk 0.92, 95% confidence interval 0.75 to 1.14) or hospital mortality (13 trials, n = 1418; 0.89, 0.71 to 1.11). There was significant heterogeneity. Subgroup analysis on long courses (= 5 days) with low dose (= 300 mg hydrocortisone or equivalent) corticosteroids showed no more heterogeneity. The relative risk for mortality was 0.80 at 28 days (five trials, n = 465; 0.67 to 0.95) and 0.83 at hospital discharge (five trials, n = 465, 0.71 to 0.97). Use of corticosteroids reduced mortality in intensive care units (four trials, n = 425, 0.83, 0.70 to 0.97), increased shock reversal at 7 days (four trials, n = 425; 1.60, 1.27 to 2.03) and 28 days (four trials, n = 425, 1.26, 1.04 to 1.52) without inducing side effects. Conclusions : For all trials, regardless of duration of treatment and dose, use of corticosteroids did not significantly affect mortality. With long courses of low dose corticosteroids, however, mortality at 28 days and hospital mortality was reduced.

19. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. Annane D, et al. JAMA 2002;288: 862-71

Context : Septic shock may be associated with relative adrenal insufficiency. Thus, a replacement therapy of low doses of corticosteroids has been proposed to treat septic shock. Objective : To assess whether low doses of corticosteroids improve 28-day survival in patients with septic shock and relative adrenal insufficiency. Design and Setting : Placebo-controlled, randomized, double-blind, parallel-group trial performed in 19 intensive care units in France from October 9, 1995, to February 23, 1999. Patients : Three hundred adult patients who fulfilled usual criteria for septic shock were enrolled after undergoing a short corticotropin test. Intervention : Patients were randomly assigned to receive either hydrocortisone (50-mg intravenous bolus every 6 hours) and fludrocortisone (50-µg tablet once daily) (n = 151) or matching placebos (n = 149) for 7 days. Main Outcome Measure : Twenty-eight-day survival distribution in patients with relative adrenal insufficiency (nonresponders to the corticotropin test). Results : One patient from the corticosteroid group was excluded from analyses because of consent withdrawal. There were 229 nonresponders to the corticotropin test (placebo, 115; corticosteroids, 114) and 70 responders to the corticotropin test (placebo, 34; corticosteroids, 36). In nonresponders, there were 73 deaths (63%) in the placebo group and 60 deaths (53%) in the corticosteroid group (hazard ratio, 0.67; 95% confidence interval, 0.47-0.95; P = .02). Vasopressor therapy was withdrawn within 28 days in 46 patients (40%) in the placebo group and in 65 patients (57%) in the corticosteroid group (hazard ratio, 1.91; 95% confidence interval, 1.29-2.84; P = .001). There was no significant difference between groups in responders. Adverse events rates were similar in the 2 groups. Conclusion : In our trial, a 7-day treatment with low doses of hydrocortisone and fludrocortisone significantly reduced the risk of death in patients with septic shock and relative adrenal insufficiency without increasing adverse events.

20. Early goal-directed therapy in the treatment of severe sepsis and septic shock. Rivers E, al. for the early goal directed therapy collaborative group. N Engl J Med 2001;345:1368-7

Background : Goal-directed therapy has been used for severe sepsis and septic shock in the intensive care unit. This approach involves adjustments of cardiac preload, afterload, and contractility to balance oxygen delivery with oxygen demand. The purpose of this study was to evaluate the efficacy of early goal-directed therapy before admission to the intensive care unit. Methods : We randomly assigned patients who arrived at an urban emergency department with severe sepsis or septic shock to receive either six hours of early goal-directed therapy or standard therapy (as a control) before admission to the intensive care unit. Clinicians who subsequently assumed the care of the patients were blinded to the treatment assignment. In-hospital mortality (the primary efficacy outcome), end points with respect to resuscitation, and Acute Physiology and Chronic Health Evaluation (APACHE II) scores were obtained serially for 72 hours and compared between the study groups. Results : Of the 263 enrolled patients, 130 were randomly assigned to early goal-directed therapy and 133 to standard therapy; there were no significant differences between the groups with respect to base-line characteristics. In-hospital mortality was 30.5 percent in the group assigned to early goal-directed therapy, as compared with 46.5 percent in the group assigned to standard therapy (P=0.009). During the interval from 7 to 72 hours, the patients assigned to early goal directed therapy had a significantly higher mean (±SD) central venous oxygen saturation (70.4±10.7 percent vs. 65.3±11.4 percent), a lower lactate concentration (3.0±4.4 vs. 3.9±4.4 mmol per liter), a lower base deficit (2.0±6.6 vs. 5.1±6.7 mmol per liter), and a higher pH (7.40±0.12 vs. 7.36±0.12) than the patients assigned to standard therapy (P«0.02 for all comparisons). During the same period, mean APACHE II scores were significantly lower, indicating less severe organ dysfunction, in the patients assigned to early goal-directed therapy than in those assigned to standard therapy (13.0±6.3 vs. 15.9±6.4, P<0.001). Conclusions : Early goal-directed therapy provides significant benefits with respect to outcome in patients with severe sepsis and septic shock.

21. Intensive insulin therapy in critically ill patients. Van den Berghe G et al. N Engl J Med 2001;345:1359-67.

Background : Hyperglycemia and insulin resistance are common in critically ill patients, even if they have not previously had diabetes. Whether the normalization of blood glucose levels with insulin therapy improves the prognosis for such patients is not known. Methods : We performed a prospective, randomized, controlled study involving adults admitted to our surgical intensive care unit who were receiving mechanical ventilation. On admission, patients were randomly assigned to receive intensive insulin therapy (maintenance of blood glucose at a level between 80 and 110 mg per deciliter) or conventional treatment (infusion of insulin only if the blood glucose level exceeded 215 mg per deciliter and maintenance of glucose at a level between 180 and 200 mg per deciliter). Results : At 12 months, with a total of 1548 patients enrolled, intensive insulin therapy reduced mortality during intensive care from 8.0 percent with conventional treatment to 4.6 percent (P<0.04, with adjustment for sequential analyses). The benefit of intensive insulin therapy was attributable to its effect on mortality among patients who remained in the intensive care unit for more than five days (20.2 percent with conventional treatment, as compared with 10.6 percent with intensive insulin therapy; P=0.005). The greatest reduction in mortality involved deaths due to multiple-organ failure with a proven septic focus. Intensive insulin therapy also reduced overall in-hospital mortality by 34 percent, bloodstream infections by 46 percent, acute renal failure requiring dialysis or hemofiltration by 41 percent, the median number of red-cell transfusions by 50 percent, and critical-illness polyneuropathy by 44 percent, and patients receiving intensive therapy were less likely to require prolonged mechanical ventilation and intensive care.

Conclusions : Intensive insulin therapy to maintain blood glucose at or below 110 mg/dL reduces morbidity and mortality among critically ill patients in the surgical intensive care unit.

22. Intensive Insulin Therapy in the Medical ICU. Van den Berghe, Wilmer A et al. N Engl J Med 2006, 354;449-461

BACKGROUND: Intensive insulin therapy reduces morbidity and nortality in patients in surgical intensive care units (ICUs), but its role in patients in medical ICUs is unknown. METHODS: In a prospective, randomized, controlled study of adult patients admitted to our medical ICU, we studied patients who were considered to need intensive care for at least three days. On admission, patients were randomly assigned to strict normalization of blood glucose levels (80 to 110 mg per deciliter [4.4 to 6.1 mmol per liter]) with the use of insulin infusion or to conventional therapy (insulin administered when the blood glucose level exceeded 215 mg per deciliter [12 mmol per liter], with the infusion tapered when the level fell below 180 mg per deciliter [10 mmol per liter]). There was a history of diabetes in 16.9 percent of the patients. RESULTS: In the intention-to-treat analysis of 1200 patients, intensive insulin therapy reduced blood glucose levels but did not significantly reduce in-hospital mortality (40.0 percent in the conventional-treatment group vs. 37.3 percent in the intensive-treatment group, P=0.33). However, morbidity was significantly reduced by the prevention of newly acquired kidney injury, accelerated weaning from mechanical ventilation, and accelerated discharge from the ICU and the hospital. Although length of stay in the ICU could not be predicted on admission, among 433 patients who stayed in the ICU for less than three days, mortality was greater among those receiving intensive insulin therapy. In contrast, among 767 patients who stayed in the ICU for three or more days, in-hospital mortality in the 386 who received intensive insulin therapy was reduced from 52.5 to 43.0 percent (P=0.009) and morbidity was also reduced.

CONCLUSIONS: Intensive insulin therapy significantly reduced morbidity but not mortality among all patients in the medical ICU. Although the risk of subsequent death and disease was reduced in patients treated for three or more days, these patients could not be identified before therapy. Further studies are needed to confirm these preliminary data.

23. Efficacy and Safety of Recombinant Human Activated Protein C for Severe Sepsis Bernard GR, et al for the Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) Study Group. N Engl J Med 2001, 344:699-709

Background : Drotrecogin alfa (activated), or recombinant human activated protein C, has antithrombotic, antiinflammatory, and profibrinolytic properties. In a previous study, drotrecogin alfa activated produced dose-dependent reductions in the levels of markers of coagulation and inflammation in patients with severe sepsis. In this phase 3 trial, we assessed whether treatment with drotrecogin alfa activated reduced the rate of death from any cause among patients with severe sepsis. Methods: We conducted a randomized, double-blind, placebo-controlled, multicenter trial. Patients with systemic inflammation and organ failure due to acute infection were enrolled and assigned to receive an intravenous infusion of either placebo or drotrecogin alfa activated (24 µg per kilogram of body weight per hour) for a total duration of 96 hours. The prospectively defined primary end point was death from any cause and was assessed 28 days after the start of the infusion. Patients were monitored for adverse events; changes in vital signs, laboratory variables, and the results of microbiologic cultures; and the development of neutralizing antibodies against activated protein C. Results : A total of 1690 randomized patients were treated (840 in the placebo group and 850 in the drotrecogin alfa activated group). The mortality rate was 30.8 percent in the placebo group and 24.7 percent in the drotrecogin alfa activated group. On the basis of the prospectively defined primary analysis, treatment with drotrecogin alfa activated was associated with a reduction in the relative risk of death of 19.4 percent (95 percent confidence interval, 6.6 to 30.5) and an absolute reduction in the risk of death of 6.1 percent (P=0.005). The incidence of serious bleeding was higher in the drotrecogin alfa activated group than in the placebo group (3.5 percent vs. 2.0 percent, P=0.06). Conclusions: Treatment with drotrecogin alfa (activated) significantly reduces mortality in patients with severe sepsis and may be associated with an increased risk of bleeding.

24. 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. N Engl J Med 2000;342:1301-8.

Background : Traditional approaches to mechanical ventilation use tidal volumes of 10 to 15 ml/kg body weight and may cause stretch-induced lung injury in patients with acute lung injury and the acute respiratory distress syndrome. We therefore conducted a trial to determine whether ventilation with lower tidal volumes would improve the clinical outcomes in these patients. Methods : Patients with acute lung injury and the acute respiratory distress syndrome were enrolled in a multicenter, randomized trial. The trial compared traditional ventilation treatment, which involved an initial tidal volume of 12 ml/kg of predicted body weight and an airway pressure measured after a 0.5-second pause at the end of inspiration (plateau pressure) of 50 cm of water or less, with ventilation with a lower tidal volume, which involved an initial tidal volume of 6 ml/kg of predicted body weight and a plateau pressure of 30 cm of water or less. The first primary outcome was death before a patient was discharged home and was breathing without assistance. The second primary outcome was the number of days without ventilator use from day 1 to day 28. Results : The trial was stopped after the enrollment of 861 patients because mortality was lower in the group treated with lower tidal volumes than in the group treated with traditional tidal volumes (31.0 percent vs. 39.8 percent, P=0.007), and the number of days without ventilator use during the first 28 days after randomization was greater in this group (mean [±SD], 12±11 vs. 10±11; P=0.007). The mean tidal volumes on days 1 to 3 were 6.2±0.8 and 11.8±0.8 ml/kg of predicted body weight (P<0.001), respectively, and the mean plateau pressures were 25±6 and 33±8 cm of water (P<0.001), respectively.

Conclusions : In patients with acute lung injury and the acute respiratory distress syndrome, mechanical ventilation with a lower tidal volume than is traditionally used results in decreased mortality and increases the number of days without ventilator use.

The Surviving Sepsis Guidelines represent simple, effective and universally applicable guidelines for the management of severe sepsis and septic shock. Most recommended interventions are not expensive. Early recognition of severe sepsis, early fluid resuscitation, effective source control and early and appropriate antibiotic therapy are vital to outcome. Fluid resuscitation may be guided by the CVP and central venous oxygen saturation, thus obviating the need for routine pulmonary artery catheterization. Saline is as effective and a cheaper alternative to albumin for fluid resuscitation. Other interventions include the use of vasopressors and intoropes without aiming for arbitrary supranormal hemodynamic targets, corticosteroids in vasopressor-dependent septic shock and tight control of blood sugar. Mechanical ventilation with low tidal volumes (4-6ml/kg and plateau pressure <30cmH2O) in patients with acute lung injury, and careful attention to other systems are an integral part of the comprehensive management of the septic patient in the ICU.