This slide set and associated background notes are provided by the Surviving Sepsis Campaign (SSC) as a service to all those interested in furthering the cause of the campaign. Educators, using the slide set for lecture purposes, should select the slides that satisfy content needs and the time constraints of their lecture. Table of Content Slides 1 – 9:Introduction and Background Slides 10 – 85:Recommendations and Rationale Slides 86 – 90:Pediatric Considerations Slides 91 – 98:Phase III, Development of the Sepsis Bundles
The Surviving Sepsis Campaign was initiated in 2002 by the European Society of Intensive Care Medicine, the International Sepsis Forum, and the Society of Critical Care Medicine with the intent to reduce mortality rates in severe sepsis by 25% in 5 years. An open invitation exists for unrestricted education grants from industry to help support this campaign. Thus far, education grants have come from Baxter Bioscience, Edwards Lifesciences, and Eli Lilly and Company.
The campaign was divided into three phases to include the Barcelona declaration, creation of evidence-based guidelines, and implementation in education. Phase 1 began with the issuance of the Barcelona declaration at the European Society of Intensive Care Medicine meeting in Barcelona, Spain in 2002. The declaration proclaimed an attempt by the Surviving Sepsis Campaign to reduce mortality in severe sepsis by 25% in 5 years.
Phase 2 of the campaign was targeted toward the creation of evidence-based guidelines in the management of severe sepsis.
An unprecedented 11 international organizations, with interest and expertise in the management of the septic patient, came together as co-sponsors of the evidence-based guidelines.
Forty-seven committee members from the 11 organizations worked over a year to finalize the guidelines. Of note, the decision was made to exclude from committee selection primary investigators who had recently participated in positive trials with implications for septic patients. Although this excluded leaders in the field, it minimized perception of influence on the guidelines.
The guidelines were published in both Critical Care Medicine and in Intensive care Medicine, and are available on-line.
The grading system built upon an adaptation from Sackett et al., which had previously been used by the Society of Critical Care Medicine in the Pulmonary Artery Consensus Conference published in Critical Care Medicine. The rationale for using this particular grading system was that the current guidelines built upon a document published as a supplement in Intensive Care Medicine in 2001 by the International Sepsis Forum which had used this grading system.
The recommendations are listed in a logical order of encounter with the septic patient and the order does not imply listing by importance. Likewise, the grading system allows higher grades where clinical trials have been performed and do not necessarily reflect the committee’s implication of importance, as some of the more important recommendations received a grade E (expert opinion) since no clinical trials have been performed to validate these recommendations.
The initial resuscitation of the patient is of utmost importance and frequently occurs in the emergency department or on hospital wards.
The physiological changes occurring in patients with severe sepsis and septic shock are myriad and include changes that are clearly detrimental such as decreased contractility of the left and right ventricle, increased venous capacitance, increased pulmonary vascular resistance, and capillary leak. Increased ventricular compliance and sinus tachycardia are likely adaptive responses allowing the ventricle to maintain, and even manifest increased cardiac input, following volume resuscitation in despite decreased contractility. The decreased arteriolar resistance may also be adaptive, although when profound, produces detrimental and potentially lethal hypotension.
The recommendations for initial resuscitation are centered around the Rivers trial (above) of early goal-directed therapy, which showed significant improvement in (a) hospital mortality, (b) 28-day mortality, and (c) 60-day mortality.
The recommendation for initial resuscitation in patients with sepsis induced hypoperfusion, defined as hypotension (requiring vasopressors or lactic acidosis) is targeted toward the Rivers’ protocol.
Previous literature supports equivalent tissue perfusion (measured by five different tissue perfusion parameters) between 65 mm Hg and 85 mm Hg of mean arterial blood pressure with norepinephrine in septic shock.
The recommendations for initial resuscitation include those goals targeted in both the standard and early goal-directed therapy (EGDT) groups of the Rivers’ study to include CVP 8–12 mm Hg, mean arterial pressure 65 mm Hg, and a goal of urine output .5 ml/kg/hr, as well as a central venous (superior vena cava) O2 saturation of 70%, the additional target in the EGDT group. In addition, intubation and mechanical ventilation was performed if necessary to maintain an arterial saturation of 93% or greater.
Again, based on the Rivers study, if volume resuscitation fails to achieve a mixed venous O2 sat of 70% or greater, packed red blood cells to a hematocrit of 30% and/or dobutamine to a max of 20 g/kg/min to achieve this goal is recommended.
Appropriate cultures should be obtained from all potential sites of infection. In addition, a minimum of two blood cultures, of which at least one should be percutaneous and one from each vascular access site in place for 48 hours should be obtained.
Although high-level evidence is not currently available, the early administration of intravenous antibiotics is a high priority in patients with severe sepsis, and should begin within the first hour of recognition of severe sepsis.
Covering broad initially in patients with severe sepsis to include one or more drugs active against all likely bacterial or fungal pathogens is recommended. It is important to consider microorganisms susceptibility patterns in the community and hospital, which may vary from region to region.
Equally important as broad initial coverage is the willingness of the physician to reassess antimicrobial regimen at 48–72 hours in an attempt to use microbiologic and clinical data to narrow the antibiotic coverage. In addition, if noninfectious causes are now thought to have likely been the reason for the patient’s deterioration and cultures are negative, antibiotics should be discontinued. This is important to prevent emergence of resistant organisms, which has become a major problem, as well as to reduce toxicity and cost.
Early emphasis on identification of source control problems is a high priority to avoid morbidity and mortality. All patients should be evaluated for a focus of infection, amenable to source control measures, to include abscess drainage or tissue debridement. Following stabilization the clinician should move rapidly to achieve this goal. The potential physiologic upset of the measure chosen for source control should be considered (for example percutaneous drainage may be preferred over operative theatre intervention). All intravascular access devices that may be a source of infection should be removed and, in the absence of identified site, should be assumed to be a potential site.
This picture demonstrates a 38-year-old man with pharyngitis who presents with high fever, leukocytosis, hypotension, elevated BUN/creatinine, and early evidence of coagulopathy who now has redness and swelling of the anterior neck and chest pain.
An EKG obtained in this patient demonstrates a diffuse ST segment elevation (or PR depression) diagnostic of pericarditis, and in this case indicating the presence of mediastinitis requiring urgent operative drainage of the mediastinum in order to prevent mortality.
Colloid or crystolloid resuscitation is considered equal. Colloids are associated with less peripheral edema and crystolloids with considerable less cost.
Meta analyses reveal no difference between crystalloids and colloids in general populations of critically ill patients.
The initial fluid resuscitation and ongoing resuscitation of patients with severe sepsis and tissue hypoperfusion is built around fluid challenges delivered over 30 minutes using either 500 – 1000 ml of crystolloid or 300 – 500 ml of colloids. These should be repeated based on response until tissue hypoperfusion is relieved or there is evidence of intolerance of fluid resuscitation, i.e. volume overload.
Norepinephrine or dopamine, as combined inotrope/vasopressors (to match the sepsis-induced decrease in contractility and systemic vascular resistance) are considered equal choices as the initial vasopressor of choice. It is important to remember that vasopressors should be utilized not only when fluid resuscitation fails to reverse hypotension, but also during fluid resuscitation to maintain minimally adequate blood pressure while fluid resuscitation is administered in attempts to decrease vasopressor requirement.
Considerable data (such as that shown above) indicates that epinephrine, although a combined inotrope/vasopressor, is not the best initial vasopressor of choice because of concerns with decrease in splanchnic blood flow. The study above comparing dopamine, norepinephrine, and epinephrine in moderate shock, and norepinephrine and epinephrine in severe shock supports epinephrine induced decrease in splanchnic blood flow.
Although low-dose dopamine was routinely used for years in hopes of renal protection in patients with acute tissue hypoperfusion and multi-organ system dysfunction, and in combination with vasopressor level blood pressure support, it is now clear that low-dose dopamine does not improve outcome in these patient groups.
Patients requiring vasopressors should have an arterial catheter in place so that sudden changes in blood pressure can be monitored and vasopressors can be titrated more easily. This may not be practical, however, during initial resuscitation in the emergency department or on hospital wards.
Vasopressin levels are elevated during the initial presentation of septic shock and then decrease to basal levels over the next 48 to 96 hours. Since vasopressin levels are expected to be a normal body response to hypotension, this occurrence has been labeled as relative vasopressin deficiency and has led to the use of vasopressin in patients with septic shock.
When patients with septic and cardiogenic shock are maintained at the same mean arterial blood pressure with vasopressors, it is noted that cardiogenic shock patients maintain elevated vasopressin levels while patients with septic shock over time have lower levels that approach baseline. In addition, prospective, randomized, blinded studies have demonstrated the potential for low-dose vasopressin to decrease or eliminate requirements of traditional pressors. However, as a pure vasopressor/vasopressin would be expected to decrease stroke volume and cardiac output as traditional vasopressors are replaced. This may be problematic, particularly in patients with significant decrease in ejection fraction and low baseline cardiac outputs.
Although vasopressin has been demonstrated in some studies to improve renal function, there are other studies that raise concern about preservation of splanchnic perfusion. Vasopressin should not be considered a replacement for norepinephrine or dopamine as a first-line agent in septic shock. However, it may be considered in refractory shock despite high-dose conventional vasopressors or when high vasopressor requirements continue for 48 hours or longer. If used, it should be administered at very low doses, not to exceed .04 units/min in adults. Higher doses may be associated with coronary or mesenteric ischemia.
This slide demonstrates radionuclide angiography in a patient during septic shock and following recovery. The top left panel shows end-diastole and demonstrates increased diastolic size of the ventricles (increased compliance), which is thought to be an adaptive mechanism. The top right image shows end-systole in this patient demonstrating a very low ejection fraction (little change in chamber size compared to end-diastole). The bottom two frames following recovery demonstrate a decrease in end-diastole volume, smaller ventricle at end systole and therefore significant improvement in ejection fraction.
A significant contractility decrease may occur in some patients with septic shock. When cardiac output is being measured (either invasively or noninvasively) and a low cardiac output is present despite adequate fluid resuscitation, the consideration of adding dobutamine to raise cardiac output to a normal range is appropriate. It is important when this is done to continue to titrate vasopressors to maintain a mean arterial pressure of 65 mm Hg.
Since patients with septic shock typically have a lactic acidosis, and since lactic acidosis is associated with a “oxygen debt”, the the possibility of improving outcome by reversing oxygen debt by producing supranormal oxygen delivery has led to multiple clinical trials in this area. Unfortunately, none of these trials have shown clinical outcome benefit, and one study (Hayes) suggested harm when very high level inotropes were used to drive oxygen delivery to supranormal levels. Therapy should therefore be targeted toward reversing clinical signs of tissue hypoperfusion and not toward an arbitrarily pre-defined level of oxygen delivery.
The largest randomized prospective trial done to study the effect of stress-dose steroids in septic shock is the “French multi-center trial”, which targeted, “apriori,” patients who did not respond to ATCH stimulation as the group that would likely benefit from steroid therapy (slide shows results in that group). This group represented 77% of the population, and in this group significant improvement in survival by Kaplan-Meier curve with logistic regression adjustment for other variables influencing survival was shown.
Single center studies also support significant clinical benefit as to morbidities and/or mortality.
The Annane, Bollaert and Briegel studies used a variety of doses, routes of administration, and stop and tapering rules, but all three studies supported the ability of low-dose (stress-dose), i.e., 200-300 mg of hydrocortisone a day to improve clinical outcome. Although the Annane study has the highest evidence based support since it was a multicenter study with significant p-value on a priori survival cure logistic regression adjusted analysis, this study had a very rigorous entry requirement, requiring that patients be hypotensive despite therapy for at least an hour to be included. The Bollaert and Briegel studies, although smaller, suggest benefit of steroids in septic patients with vasopressor requirement only, a more commonly encountered group in clinical practice.
The utilization of stress dose (“low-dose”) steroids is recommended for the treatment of patients with severe sepsis who continue to require significant amounts of vasopressors despite adequate fluid replacement. It should be noted that this recommendation includes a range of daily steroid dosing as well as alternative dosing methods to include intermittent dosing or continuous infusion. The rationale behind the construction of this recommendation is that it is a hybrid of regimens from the Ananne study, the Bollard study and the Briegel study.
The apriori analysis group in the 2002 Annane study were patients who were non-responders to ACTH stimulation, i.e., relative adrenal insufficiency (see previous slide). This patient population was defined based on a previous Annane study showing that septic shock patients who were unable to raise their cortisol by 10 or more at either 30 or 60 minutes following 250 g ACTH stimulation, were at high risk for death. There was no evidence of benefit in non-responders (as shown above).
Experts disagree on the best way to characterize relative adrenal insufficiency. In addition to the criteria used by Annane (incremental increase after high-dose ACTH (250 g) stimulation), other investigators have used random cortisol level, peak cortisol after stimulation, lower dose ACTH stimulation test, and combinations of these criteria.
The use of ACTH stim test to define non-responders (post-stimulation cortisol 9 g/dl) as those who will have steroids continued is optional. If this approach is taken, steroid therapy is discontinued in responders.
If the ACTH stimulation test is to be performed dexamethasone can be initiated pending performance of the ACTH stim test, as unlike hydrocortisone or methylprednisolone, it does not have cortisol-like metabolites, which interfere with the cortisol assay.
Another option during steroid therapy is to taper and then discontinue steroids earlier when shock rapidly resolves (as opposed to a set course of 7 days).
Corticosteroid dose may also be tapered at the end of 7-day therapy to avoid possible rebound effect of inflammation and decrease a blood pressure (see next slide).
In this study by Keh and colleagues patients were randomized to low-dose steroids or placebo and then crossed over after three days. The patients going from steroids to placebo exhibited a significant pro-inflammatory rebound associated with increased vasopressor requirements.
A final option for steroid therapy of septic shock includes the addition of fludrocortisone (a pure mineralocorticoid) . Fludrocortisone was utilized in the Annane study, but not in the Bollaert or Briegel studies. Hydrocortisone does have significant mineralocorticoid activity, although fludrocortisone is a pure mineralocorticoid. (See next slide.)
In a study by Witek-Janusek and colleagues, utilizing a rodent preparation of septic shock, a comparison was made among effect of intact adrenal gland, ablation of adrenal cortex function (ADRNX) and ablation of adrenal medullary function (MEDX) on survival. The ablation of the glucocorticoid producing cortex produced a significant increase in mortality, whereas ablation of the medulla (mineralocorticoids production) had no significant effect on survival, and was similar to the intact adrenal (see above). This type of animal evidence supports the importance of glucocorticoids and not mineralocorticoids in ameliorating sequelae of septic shock.
Based on several studies demonstrating lack of efficacy when high-dose corticosteroids (up to a gram of methylprednisolone) are given during the first 24 hours of severe sepsis and septic shock, the use of corticosteroids greater than 300 mg a day is not recommended.
A key modulator of the thrombin triggered coagulation response to sepsis is the activation of protein C. Inactive protein C zymogen is activated by a combination of the endothelial surface receptors (thrombin/thrombomodulin receptor, and the protein C receptor). In patients with severe sepsis, these endothelial receptors are stripped off the surface of the endothelium and can be identified in the circulation leading to decreased capability for activating protein C. Once protein C is activated protein S is a co-factor for amplification of activity. 1.Faust SN, Levin M, Harrison OB, et al. Dysfunction of endothelial protein C activation in severe meningococcal sepsis. N Engl J Med 2001; 345:408-416
Activated protein C when administered in a blinded, randomized fashion to over 1600 patients with severe sepsis and septic shock produced a 6.1% absolute reduction in mortality.
In considering patient selection for rhAPC, the patient should be full support, have an infection induced organ system dysfunction that is associated with a high risk of death, and have no absolute contraindications to drug use (significant risk of fatal hemorrhage such as previous hemorrhagic stroke or recent visceral trauma).
The FDA labeling for rhAPC indicates use for patients with sepsis induced organ dysfunction associated with a high risk of death, such as APACHE II of 25 or greater. This is based on subset analysis of the four APACHE II quartiles in the rhAPC clinical trial showing that most of the benefit occurred in patients with APACHE II of 25 or greater.
The European regulatory authority lists multiple organ failure as the indication for rhAPC therapy in severe sepsis. This is based on subset analysis indicating that patients with multiple organ failure are most likely to benefit.
The SSC recommendation lists four patient findings that would be linked to high risk of death for which rhAPC is recommended. In addition to no absolute contraindications, relative contraindications should also be weighed.
In 1999, Herbert al. published a large study that randomized a general population of ICU patients to receive either restrictive transfusion strategy in which transfusion occurred (1) when the hemoglobin decreased to less than 7g/dl to maintain a 7–9 g/dl versus (2) transfusing when the hemoglobin decreased to less than 10 g/dl to maintain 10–12 g/dl. There was no statistically significant difference in mortality in the two ICU patient groups, with a trend in survival favoring the restrictive transfusion strategy.
Once tissue hypoperfusion has resolved, and in absence of the extenuating circumstances as listed, the transfusion threshold should be as it was in the restrictive group in the Herbert study.
Although erythropoietin may be used for other accepted reasons such as chronic renal failure, it should not be used to treat sepsis related anemia in the absence of these other indications.
Fresh frozen plasma should be reserved for the bleeding patient or for planned invasive procedures. In those circumstances targeting an INR of 1.5 or less would be appropriate.
Antithrombin therapy is not recommended. One clinical trial performed in patients with severe sepsis demonstrated no benefit.
An absolute threshold is recommended for transfusion of platelets in all patients with severe sepsis, a second range when there is significant bleeding risk, and a third threshold in the presence of bleeding or when invasive procedures are planned.
This chest radiograph shows a patient with ARDS characterized by diffuse bilateral infiltrates.
Sepsis is the most frequent cause of acute lung injury and acute respiratory distress syndrome (ARDS). Acute lung injury is the most common system dysfunction in sepsis and is associated with significant morbidity and mortality. Patients with severe lung injury, i.e., sepsis induced ARDS almost always require mechanical ventilation, and many patients with acute lung injury are also mechanically ventilated.
The ARDSnet trial compared 6 ml/kg ideal body weight vs. 12 ml/kg ideal body weight (low tidal volume/high tidal volume comparison). The low tidal volume group demonstrated a significant decrease in mortality.
Measurement of inspiratory plateau pressure allows estimation of the end inspiratory alveolar pressure as a marker of lung inflation. A .5 second end inspiratory typically allows this measurement.
The recommendation for mechanical ventilation of sepsis induced ALI/ARDS is to reduce tidal volume (TV) over 1 to 2 hours to 6ml/kg predicted body weight (PBW—formula available on the ARDSnet and SSC websites) starting at 8ml/kg. In addition, inspiratory plateau pressure should be measured and maintained &lt; 30 cm H2O. This may require further reduction of TV to as low as 4.0 ml/kg/PBW.
In addition to avoiding lung overinflation during mechanical ventilation of ARDS by limiting tidal volume, it is also important to institute a minimum amount of PEEP that will prevent end-expiratory lung collapse. Because of the increased lung water and associated decreased compliance, end-expiratory lung collapse occurs at low levels of PEEP. Repeated closing and opening of lung with tidal excursion is thought to produce sheer force injury. There are two potential ways of setting minimal PEEP. One is to utilize the ARDSnet table (web site address) another more sophisticated method, not usually practical in the typical hospital environment, is measuring thoracopulmonary compliance and setting PEEP in an area of optimal compliance.
Despite significant improvement in oxygen in 70% of patients proned in one large study there was no difference in clinical outcome through a 180 days. However, in patients with the severest of hypoxemia there was a suggestion of benefit.
Pending additional clinical trials prone positioning remains unproven as a modality that will alter outcome in ARDS. However, based on the significant improvement in physiology with proning as well as improvement in oxygenation, the committee recommends that it be considered in ARDS patients who have potentially injurious levels of F1O2 or plateau pressure despite optimization of traditional mechanical ventilation. Patients at high risk from proning such as (a) hemodynamic instability, (b) placement of multiple anterior invasive devices/tubes/lines, or (c) morbid obesity are likely not good candidates for prone positioning. In that circumstance and in the presence of life-threatening hypoxemia, inhaled nitric oxide therapy could be considered as salvage therapy.
In order to decrease the incidence of ventilator acquired pneumonia, the semirecumbent position should be utilized, unless contraindicated, in all mechanically ventilated septic patients. Although 30°–45° is often mentioned as the target elevation, 45° has the best supportive evidence.
In mechanically ventilated septic patients, a weaning protocol should be in place to evaluate on a daily basis the likelihood of weaning and extubation. Protocol criteria should exist for preforming a spontaneous breathing trial at least daily.
Options for spontaneous trial include low-level pressure support with CPAP of 5 or T-piece (humidified gas delivered to endotracheal tube off mechanical ventilator support).
Certain criteria should be assessed and met prior to spontaneous breathing trial performance. If a spontaneous breathing trial is successful (typically frequency/tidal volume ratio &lt; 105) after 30-60 minutes, serious consideration should be given for extubation.
Most patients mechanically ventilated with severe sepsis require some degree of sedation and analgesia. However, overuse of these drugs leads to prolonged need for mechanical ventilation. It is therefore important to titrate sedation and analgesia to the minimal effective dose. This is likely best done using bolus administration so that the drug is only given when bedside evaluation indicates a lack of sedation or analgesia. When continuous infusion is needed there should be daily awakening and retitration to minimally effective doses to avoid oversedation and tissue accumulation of sedating agents.
Neuromuscular blockade (NMB) is being used less and less in mechanically ventilated patients with severe sepsis. NMB beyond the initial stabilization period is associated with a significant incidence of prolonged neuromuscular blockade following discontinuation of NMB. Neuromuscular blockade should be avoided if possible. When utilized longer then 2–3 hours, NMB administration should be either (a) PRN bolus with drug administration only when a clearly identified patient need arises or (b) by continuous infusion with a twitch monitor. The twitch monitor is kept at a minimum of 2 or more twitches following a train of four delivery of electric signals. Neuromuscular blockade is primarily used to control patient respiratory rate (equal to or less than set ventilator rate). When patient rate control can be achieved with four out of four twitches that is optimal.
Results of the van den Berghe trial demonstrated an impressive improvement in survival with intensive glycemic control. Patients admitted to SICU mechanically ventilated All patients received 200–300 g glucose/day on admission and continuous infusion intravenous insulin as needed to achieve target glucose level. – Conventional: titrate glucose to 180–200 mg/dL –Intensive: titrate glucose to 80–110 mg/dL TPN or parenteral fluid within 24 hours of admission with 60% to 80% glucose calories
The SSC recommendation uses a less stringent glucose threshold then that used by van den Berghe et al., recommending glucose be maintained &lt; 150 mg/dl. Many hospitals may have difficulty securing the intense bedside resources needed to maintain levels between 80 and 110. Finney et al. also demonstrated improved outcome in critically ill patients when glucose was maintained at 110-145 mg/dl (JAMA 2003; 290:2041-2047) It is important that patients who are receiving continuous infusion insulin also be receiving glucose in some form, either TPN, enteral or peripheral glucose infusion. Enteral nutrition is the preferred method of glucose delivery. The initial monitoring will need to be more intense requiring 30–60 minute monitoring. After glucose stabilization is achieved monitoring may be extended to 4 hours.
In the absence of hemodynamic instability intermittent hemodialysis and continuous venovenous hemofiltration (CVVH) offer equal clinical outcome effects. Because intermittent hemodialysis is difficult to maintain in the presence of hemodynamic instability, CVVH is preferred in that circumstance.
Literature supports that in patients with type 1 lactic acidosis (cellular hypoxia) and pH of 7.15, there is no hemodynamic benefit associated with pH correction. Presence of lactate acidosis indicates cellular hypoxia and anaerobic metabolism. Correcting the pH does not alter the hypoxic cellular state.
Cooper and colleagues compared equimolar amounts of sodium bicarbonate and normal saline in patients with vasopressor requiring lactic acidosis (pH range down to 7.15 with mean 7.23) and demonstrated that although pH was significantly increased with bicarbonate versus normal saline there was no difference in cardiac output. There was also no difference between the two groups as to weaning of vasopressors.
Numerous clinical trials containing significant numbers of sepsis patients have demonstrated ability of DVT prophylaxis to decrease incidence of deep vein thrombosis and pulmonary embolism. Either unfractionated heparin or low molecular heparin is recommended. In patients with contraindication for heparin, mechanical compression devices of the lower extremities are recommended unless there is contraindications to compression device, i.e. severe peripheral vascular disease or leg injury. High risk patients should have combination pharmacologic and mechanical therapy considered.
Patients with severe sepsis frequently have literature identified risk factors for stress ulcer bleeding including mechanical ventilation, coagulopathy and hypotension.
Stress ulcer prophylaxis is recommended and H2 receptive blockers are the therapy of choice. Proton pump inhibitors have been demonstrated to show equivalence in raising stomach pH although no clinical studies have been performed.
Many patients with severe sepsis and septic shock have terminal illnesses with short expected life spans. In these patients the highly unlikely benefit of therapy and the potential discomfort associated with aggressive therapy warrants serious consideration for limitation of support with implementation of comfort care, emotional support to the patient and family, and pain control.
Although there is limited data available from prospective clinical trials in pediatric septic patients, there are considerable differences in the pathophysiology of pediatric sepsis that warrants comment.
Fluid resuscitation of pediatric patients is weight based and aggressive, with initial resuscitation of 20ml/kg and often up to 40–60ml/kg required during the initial resuscitation. Blood pressure itself is not a reliable endpoint for resuscitation. Physical exam, urine output, and pulse response are the primary response monitors.
The hemodynamic profile of pediatric sepsis is quite variable. Dopamine with its combined inotrope and vasopressor characteristics is recommended for pediatric hypotension because of the tendency for a lower cardiac output in this patient population. Epinephrine or norepinephrine are then added for dopamine refractory shock. When cardiac output is measured, dobutamine is recommended for low cardiac output states. Inhaled nitric oxide may be useful in neonates who are septic with post-partum pulmonary hypertension.
Physical exam findings indicating successful resuscitation include a capillary refill &lt; 2sec, warm extremities, and normal mental status. Other objective targets include urine output &gt; 1ml/kg/hr and normalization of lactate, and as in the adult, central venous O2 sat 70%.
As in adults, steroids are recommended for children with catecholamine resistance and suspected or proven adrenal insufficiency. Activated protein C has not been studied in pediatric severe sepsis. Unlike adults GM-CSF has been shown to be of benefit in neonates in circumstances of neutropenia and sepsis. ECMO, not recommended in adults, may be useful in children with refractory shock or respiratory failure.
The third and most important phase of the Surviving Sepsis Campaign is implementation and education, since only behavior change will effect clinical outcome improvement. The creation of guidelines, although an important component of the process, does not in itself change behavior.
The SSC sepsis change bundle description and process is covered in depth on the SSC/IHI web site accessible through either of the two web sites above. There is a direct link available from home page of the SSC web site. From the home page of the IHI web site select Topics Critical Care Sepsis.
1. Surviving Sepsis Campaign
Guidelines for Management of
Severe Sepsis/Septic Shock
2. Surviving Sepsis
A global program to:
Reduce mortality rates in severe sepsis
3. Phase 1 Barcelona declaration
Phase 2 Evidence based guidelines
Phase 3 Implementation and education
4. Phase 1 Barcelona declaration
Phase 2 Evidence based guidelines
Phase 3 Implementation and education
5. Sponsoring Organizations
 American Association of Critical Care Nurses
 American College of Chest Physicians
 American College of Emergency Physicians
 American Thoracic Society
 Australian and New Zealand Intensive Care Society
 European Society of Clinical Microbiology and Infectious
 European Society of Intensive Care Medicine
 European Respiratory Society
 International Sepsis Forum
 Society of Critical Care Medicine
 Surgical Infection Society
6. Guidelines Committee*
*Primary investigators from recently performed positive trials with implications for
septic patients excluded from committee selection.
7. Surviving Sepsis Campaign (SSC)
Guidelines for Management of Severe
Sepsis and Septic Shock
Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T,
Cohen J, Gea-Banacloche J, Keh D, Marshall JC, Parker
MM, Ramsay G, Zimmerman JL, Vincent JL, Levy MM and
SSC Management Guidelines Committee
Crit Care Med 2004;32:858-873
Intensive Care Med 2004;30:536-555
available online at
8. Sackett DL. Chest 1989; 95:2S–4S
Sprung CL, Bernard GR, Dellinger RP. Intensive Care Medicine 2001; 27(Suppl):S1-S2
Recommendations grouped by category
and not by hierarchy
Grading of recommendation implies
literature support and not priority of
10. Initial Resuscitation
11. Figure B, page 948, reproduced with permission from Dellinger RP. Cardiovascular
management of septic shock. Crit Care Med 2003;31:946-955.
12. The Importance of Early Goal-Directed
Therapy for Sepsis Induced Hypoperfusion
Adapted from Table 3, page 1374, with permission from Rivers E, Nguyen B, Havstad S, et al.
Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med
60 Standard therapy
NNT to prevent 1 event (death) = 6-8
13. Initial Resuscitation
 In the presence of sepsis-induced
 Lactic acidosis
output (mL) 49 +18 56 + 21 43 +13 .60/.71
Capillary blood flow
(mL/min/100 g) 6.0 + 1.6 5.8 + 11 5.3 + 0.9 .59/.55
Velocity (au) 0.42 + 0.06 0.44 +016 0.42 + 0.06 .74/.97
Pico2 (mm Hg) 41 + 2 47 + 2 46 + 2 .11/.12
Pa-Pico2 (mm Hg) 13 + 3 17 + 3 16 + 3 .27/.40
75 mm Hg65 mm Hg 85 mm Hg F/LT
Adapted from Table 4, page 2731, with permission from LeDoux, Astiz ME, Carpati CM,
Rackow ED. Effects of perfusion pressure on tissue perfusion in septic shock. Crit Care
Med 2000; 28:2729-2732
15. Initial Resuscitation
Goals during first 6 hours:
 Central venous pressure: 8–12 mm Hg
 Mean arterial pressure ≥ 65 mm Hg
 Urine output ≥ 0.5 mL kg-1
 Central venous (superior vena cava) or
mixed venous oxygen [SvO2] saturation ≥
16. Initial Resuscitation
Goals during first 6 hours:
 Central venous or mixed venous O2 sat <
70% after CVP of 8–12 mm Hg
• Packed RBCs to Hct 30%
• Dobutamine to max 20 µg/kg/min
 Appropriate cultures
 Minimum 2 blood cultures
• 1 percutaneous
• 1 from each vascular access ≥ 48
18. Antibiotic Therapy
 Begin intravenous antibiotics within
first hour of recognition of severe
19. Antibiotic Therapy
 One or more drugs active against likely
bacterial or fungal pathogens.
 Consider microorganism susceptibility
patterns in the community and hospital.
20. Antibiotic Therapy
Reassess antimicrobial regimen
at 48-72 hrs
• Microbiologic and clinical data
• Narrow-spectrum antibiotics
• Non-infectious cause identified
• Prevent resistance, reduce toxicity,
21. Source Control
 Evaluate patient for a focused infection
amendable to source control measures
including abscess drainage or tissue
• Move rapidly
• Consider physiologic upset of measure
• Intravascular access devices
22. Photograph used with permission from Janice L. Zimmerman, MD
23. EKG tracing reproduced with permission from Janice L. Zimmerman, MD
24. Fluid Therapy
 Fluid resuscitation may consist of natural or
artificial colloids or crystalloids.
25. Figure 2, page 206, reproduced with permission from Choi PT, Yip G, Quinonez L, Cook DJ.
Crystalloids vs. colloids in fluid resuscitation: A systematic review. Crit Care Med 1999; 27:200–210
26. Fluid Therapy
 Fluid challenge over 30 min
• 500–1000 ml crystalloid
• 300–500 ml colloid
 Repeat based on response
 Either norepinephrine or dopamine
administered through a central
catheter is the initial vasopressor of
• Failure of fluid resuscitation
• During fluid resuscitation
28. Effects of Dopamine, Norepinephrine,
and Epinephrine on the Splanchnic
Circulation in Septic Shock
Figure 2, page 1665, reproduced with permission from De Backer D, Creteur J, Silva E, Vincent
JL. Effects of dopamine, norepinephrine, and epinephrine on the splanchnic circulation in
septic shock: Which is best? Crit Care Med 2003; 31:1659-1667
 Do not use low-dose dopamine for
Bellomo R, et al. Lancet 2000; 356:2139-2143
 In patients requiring vasopressors,
place an arterial catheter as soon as
31. Circulating Vasopressin Levels in Septic Shock
Figure 2, page 1755 reproduced with permission from Sharshar T, Blanchard A, Paillard
M, et al. Circulating vasopressin levels in septic shock. Crit Care Med 2003; 31:1752-1758
32. Vasopressin and Septic Shock
• Versus cardiogenic shock
• Decreases or eliminates
requirements of traditional
• As a pure vasopressor expected
to decrease cardiac output
Not a replacement for norepinephrine or
dopamine as a first-line agent
Consider in refractory shock despite high-
dose conventional vasopressors
If used, administer at 0.01-0.04 units/minute
34. During Septic Shock
10 Days Post Shock
Images used with permission from Joseph E. Parrillo, MD
35. Inotropic Therapy
 Consider dobutamine in patients with
measured low cardiac output despite
 Continue to titrate vasopressor to mean
arterial pressure of 65 mm Hg or greater.
36. Inotropic Therapy
 Do not increase cardiac index to achieve
an arbitrarily predefined elevated level of
Yu, et al. CCM 1993; 21:830-838
Hayes, et al. NEJM 1994; 330-1717-1722
Gattinoni, et al. NEJM 1995; 333:1025-1032
37. Figure 2A, page 867, reproduced with permission from Annane D, Sébille V, Charpentier C, et
al. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in
patients with septic shock. JAMA 2002; 288:862-871
38. P = .045
Figure 2 and Figure 3, page 648, reproduced with permission from
Bollaert PE, Charpentier C, Levy B, et al. Reversal of late septic
shock with supraphysiologic doses of hydrocortisone. Crit Care
Med 1998; 26:645-650
Figure 2 and Figure 3, page 727, reproduced with permission from
Briegel J, Forst H, Haller M, et al. Stress doses of hydrocortisone
reverse hyperdynamic septic shock: A prospective, randomized,
double-blind, single-center study. Crit Care Med 1999; 27:723-732
P = .007
39. Annane, Bollaert and Briegel
 Different doses, routes of administration
and stopping/tapering rules
 Required hypotension despite
Bollaert and Briegel
 Required vasopressor support only
 Treat patients who still require
vasopressors despite fluid
replacement with hydrocortisone
200-300 mg/day, for 7 days in three
or four divided doses or by
41. Figure 2B, page 867, reproduced with permission from Annane D, Sébille V, Charpentier C, et al.
Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients
with septic shock. JAMA 2002; 288:862-871
42. Identification of
Relative Adrenal Insufficiency
Recommendations vary based on
different measurements and different
 Peak cortisol after stimulation
 Random cortisol
 Incremental increase after stimulation
 Lower dose ACTH stimulation test
 Combinations of these criteria
 Adrenocorticotropic hormone
(ACTH) stimulation test (250-µg)
Continue treatments only in
nonresponders (rise in
cortisol ≤9 µg/dl)
44. Dexamethasone and
 Decrease steroid dose if septic
 Taper corticosteroid dose at
end of therapy.
47. Immunologic and Hemodynamic Effects
of “Low-Dose” Hydrocortisone in Septic Shock
Figure 3, page 515, reproduced with permission from Keh D, Boehnke T, Weber-
Cartens S, et al. Immunologic and hemodynamic effects of “low dose” hydrocortisone
in septic shock. Am J Respir Crit Care Med 2003;167:512-520
 Add fludrocortisone (50 µg orally
once a day) to this regimen.
49. ADRENALS AND SURVIVAL
INTACT SHAM ADRNX MEDX
Adapted from Figure 7, page 437, with permission from Witek-Janusek L, Yelich MR.
Role of the adrenal cortex and medulla in the young rats’ glucoregulatory response
to endotoxin. Shock 1995; 3:434-439
 Do not use corticosteroids >300
mg/day of hydrocortisone to treat
Bone, et al. NEJM 1987; 317-658
VA Systemic Sepsis Cooperative Study Group. NEJM 1987; 317:659-665
Protein C Activity
Blood Flow ⇒
Human Activated Protein C
Endogenous Regulator of Coagulation
Results: 28-Day All-Cause Mortality
Primary analysis results
2-sided p-value 0.005
Adjusted relative risk reduction 19.4%
Increase in odds of survival 38.1%
Adapted from Table 4, page 704, with permission from Bernard GR, Vincent JL, Laterre PF, et al.
Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med
53. Patient Selection for rhAPC
 Full support patient
 Infection induced organ/system
 High risk of death
 No absolute contraindications
54. Mortality and APACHE II Quartile
APACHE II Quartile
*Numbers above bars indicate total deaths
1st (3-19) 2nd (20-24) 3rd (25-29) 4th (30-53)
Adapted from Figure 2, page S90, with permission from Bernard GR. Drotrecogin alfa (activated)
(recombinant human activated protein C) for the treatment of severe sepsis. Crit Care Med 2003;
55. Mortality and Numbers of Organs Failing
1 2 3 4 5
Number of Organs Failing at Entry
Adapted from Figure 4, page S91, with permission from Bernard GR. Drotrecogin alfa (activated)
(recombinant human activated protein C) for the treatment of severe sepsis. Crit Care Med 2003;
56. Recombinant Human Activated
Protein C (rhAPC)
 High risk of death
 APACHE II ≥ 25
 Sepsis-induced multiple organ failure
 Septic shock
 Sepsis induced ARDS
 No absolute contraindications
 Weigh relative contraindications
57. Transfusion Strategy
in the Critically Ill
Figure 2A, page 414, reproduced with permission from Hebert PC, Wells G, Blajchman MA, et al. A multicenter,
randomized, controlled clinical trial of transfusion requirements in critical care. N Engl J Med 1999; 340:409-417
58. Blood Product Administration
Red Blood Cells
Tissue hypoperfusion resolved
No extenuating circumstances
 Coronary artery disease
 Acute hemorrhage
 Lactic acidosis
Transfuse < 7.0 g/dl to maintain 7.0-9.0 g/dL
59. Blood Product Administration
 Do not use erythropoietin to treat sepsis-
related anemia. Erythropoietin may be
used for other accepted reasons.
61. Blood Product Administration
• Do not use antithrombin therapy.
Warren et al. JAMA 2001; 1869-1878
62. Blood Product Administration
 Platelet administration
 Transfuse for < 5000/mm3 -
 Transfuse for 5000/mm3
significant bleeding risk
 Transfuse < 50,000/mm3
procedures or bleeding
63. Mechanical Ventilation of
ARDSnet Mechanical Ventilation Protocol
Adapted from Figure 1, page 1306, with permission from The Acute Respiratory Distress
Syndrome Network. N Engl J Med 2000;342:1301-1378
65. Peak Airway
PEEP (5 cm
66. Mechanical Ventilation of
Reduce tidal volume over 1–2 hrs
to 6 ml/kg predicted body weight
Maintain inspiratory plateau
pressure < 30 cm H20
67. Mechanical Ventilation of
 Minimum PEEP
 Prevent end expiratory lung
 Setting PEEP
 FIO2 requirement
 Thoracopulmonary compliance
68. The Role of Prone Positioning in ARDS
 70% of prone
 70% of response
within 1 hour
 10-day mortality rate in
quartile with lowest
PaO2:FIO2 ratio (≤88)
 Prone —
 Supine – 47.2%
Gattinoni L, et al. N Engl J Med 2001;345:568-73; Slutsky AS. N Engl J Med 2001;345:610-2.
survival at 6 months
30 60 90 120 150 1800
69. The Role of Prone Positioning in ARDS
Consider prone positioning in ARDS when:
 Potentially injurious levels of F1O2 or
plateau pressure exist
 Not at high risk from positional changes
70. Mechanical Ventilation
of Severe Sepsis
 Semirecumbent position unless
contraindicated with head of the bed
raised to 45o
Drakulovic et al. Lancet 1999; 354:1851-1858
71. Mechanical Ventilation
of Septic Patients
 Use weaning protocol and a
spontaneous breathing trial (SBT),
at least daily
Ely, et al. NEJM 1996; 335:1864-1869
Esteban, et al. AJRCCM 1997; 156:459-465
Esteban, et al. AJRCCM 1999; 159:512-518
72. Mechanical Ventilation
of Septic Patients
• Low level of pressure support
with continuous positive airway
pressure 5 cm H2O
73. Prior to SBT
b) Hemodynamically stable (without
c) No new potentially serious conditions
d) Low ventilatory and end-expiratory
e) Requiring levels of FIO2 that could be
safely delivered with a face mask or nasal
Consider extubation if SBT is unsuccessful
74. Sedation and Analgesia in Sepsis
 Sedation protocol for mechanically
ventilated patients with standardized
subjective sedation scale target.
• Intermittent bolus
• Continuous infusion with daily
Kollef, et al. Chest 1998; 114:541-548
Brook, et al. CCM 1999; 27:2609-2615
Kress, et al. NEJM 2000; 342:1471-1477
75. Neuromuscular Blockers
Avoid if possible
Used longer than 2-3 hrs
 PRN bolus
 Continuous infusion with twitch monitor
76. The Role of Intensive
Insulin Therapy in the Critically Ill
At 12 months, intensive insulin
therapy reduced mortality by
Adapted from Figure 1B, page 1363, with permission from van den Berghe G, Wouters P,
Weekers F, et al. Intensive insulin therapy in critically ill patients. N Engl J Med 2001;345:1359-67
Days after admission
50 100 150 200 250
77. Glucose Control
 After initial stabilization
 Glucose < 150 mg/dL
 Continuous infusion insulin and glucose
or feeding (enteral preferred)
• Initially q30–60 mins
• After stabilization q4h
78. Renal Replacement
Absence of hemodynamic instability
 Intermittent hemodialysis and
continuous venovenous filtration equal
 CVVH preferred
79.  Bicarbonate therapy not recommended to
improve hemodynamics in patients with
lactate induced pH >7.15
Cooper, et al. Ann Intern Med 1990; 112:492-498
Mathieu, et al. CCM 1991; 19:1352-1356
80. Changing pH Has Limited Value
Treatment Before After
NaHCO3 (2 mEq/kg)
pH 7.22 7.36
PAOP 15 17
Cardiac output 6.7 7.5
pH 7.24 7.23
PAOP 14 17
Cardiac output 6.6 7.3
Cooper DJ, et al. Ann Intern Med 1990; 112:492-498
81. Deep Vein Thrombosis Prophylaxis
Heparin (UH or LMWH)
Contraindication for heparin
 Mechanical device (unless contraindicated)
High risk patients
 Combination pharmacologic and mechanical
82. Primary Stress Ulcer Risk Factors
Frequently Present in Severe Sepsis
83. Choice of Agents for
Stress Ulcer Prophylaxis
H2 receptor blockers
Role of proton pump inhibitors
Cook DJ, et al. Am J Med 1991; 91:519-527
84. Consideration for
Limitation of Support
 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.
85. Phase 1 Barcelona declaration
Phase 2 Evidence based guidelines Paediatric issues
Phase 3 Implementation and education
86. Fluid Resuscitation
Aggressive fluid resuscitation with boluses
of 20 ml/kg over 5-10 min
Blood pressure by itself is not a reliable
endpoint for resuscitation
Initial resuscitation usually requires 40-60
ml/kg, but more may be required
87. Hemodynamic Support
 Hemodynamic profile may be variable
 Dopamine for hypotension
 Epinephrine or norepinephrine for dopamine-
 Dobutamine for low cardiac output state
 Inhaled NO useful in neonates with post-partum
pulmonary hypertension and sepsis
89. Other Therapies
 Steroids: recommended for children with
catecholamine resistance and suspected or
proven adrenal insufficiency.
 Activated protein C not studied adequately in
 GM-CSF shown to be of benefit in neonates
with sepsis and neutropenia.
 Extracorporeal membrane oxygenation
(ECMO) may be considered in children with
refractory shock or respiratory failure.
90. Phase 1 Barcelona declaration
Phase 2 Evidence based guideline
Phase 3 Implementation and education
91. Sepsis Resuscitation Bundle
Serum lactate measured
Blood cultures obtained prior to
From the time of presentation, broad-
spectrum antibiotics administered
within 3 hours for ED admissions and
1 hour for non-ED ICU admissions
92. Sepsis Resuscitation Bundle
In the event of hypotension and/or
lactate >4 mmol/L (36 mg/dl):
 Deliver an initial minimum of 20 ml/kg of
crystalloid (or colloid equivalent*)
 Apply vasopressors for hypotension not
responding to initial fluid resuscitation to
maintain mean arterial pressure (MAP) ≥65
*See the individual chart measurement tool for an equivalency chart.
93. Sepsis Management Bundle
Low-dose steroids* administered for
septic shock in accordance with a
standardized ICU policy
Drotrecogin alfa (activated)
administered in accordance with a
standardized ICU policy
*See the individual chart measurement tool for an equivalency chart.
94. Sepsis Management Bundle
 Glucose control maintained ≥ lower limit
of normal, but < 150 mg/dl (8.3 mmol/L)
 Inspiratory plateau pressures maintained
< 30 cm H2O for mechanically ventilated
95. Sepsis Resuscitation Bundle
In the event of persistent hypotension
despite fluid resuscitation (septic
shock) and/or lactate > 4 mmol/L (36
 Achieve central venous pressure (CVP) of
8 mm Hg
 Achieve central venous oxygen saturation
(ScvO2) of ≥ 70%**
**Achieving a mixed venous oxygen saturation (SvO2) of 65% is an acceptable
96. A clinician, armed with the sepsis bundles, attacks the three heads of severe
sepsis: hypotension, hypoperfusion and organ dysfunction. Crit Care Med 2004;
97. Actual title of painting is “Hercules Kills
Cerberus,” by Renato Pettinato, 2001.
Painting hangs in Zuccaro Place in Agira,
Sicily, Italy. Used with permission of artist
and the Rubolotto family.