Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock, 2012

Objective: To provide an update to the "Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock," last published in 2008. Design: A consensus committee of 68 international experts representing 30 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict of interest policy was developed at the onset of the process and enforced throughout. The entire guidelines process was conducted independent of any industry funding. A stand-alone meeting was held for all subgroup heads, co- and vice-chairs, and selected individuals. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. Methods: The authors were advised to follow the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to guide assessment of quality of evidence from high (A) to very low (D) and to determine the strength of recommendations as strong (1) or weak (2). The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasized. Recommendations were classified into three groups: (1) those directly targeting severe sepsis; (2) those targeting general care of the critically ill patient and considered high priority in severe sepsis; and (3) pediatric considerations. Results: Key recommendations and suggestions, listed by category, include: early quantitative resuscitation of the septic patient during the first 6 h after recognition (1C); blood cultures before antibiotic therapy (1C); imaging studies performed promptly to confirm a potential source of infection (UG); administration of broad-spectrum antimicrobials therapy within 1 h of the recognition of septic shock (1B) and severe sepsis without septic shock (1C) as the goal of therapy; reassessment of antimicrobial therapy daily for de-escalation, when appropriate (1B); infection source control with attention to the balance of risks and benefits of the chosen method within 12 h of diagnosis (1C); initial fluid resuscitation with crystalloid (1B) and consideration of the addition of albumin in patients who continue to require substantial amounts of crystalloid to maintain adequate mean arterial pressure (2C) and the avoidance of hetastarch formulations (1B); initial fluid challenge in patients with sepsis-induced tissue hypoperfusion and suspicion of hypovolemia to achieve a minimum of 30 mL/kg of crystalloids (more rapid administration and greater amounts of fluid may be needed in some patients (1C); fluid challenge technique continued as long as hemodynamic improvement is based on either dynamic or static variables (UG); norepinephrine as the first-choice vasopressor to maintain mean arterial pressure ≥65 mmHg (1B); epinephrine when an additional agent is needed to maintain adequate blood pressure (2B); vasopressin (0.03 U/min) can be added to norepinephrine to either raise mean arterial pressure to target or to decrease norepinephrine dose but should not be used as the initial vasopressor (UG); dopamine is not recommended except in highly selected circumstances (2C); dobutamine infusion administered or added to vasopressor in the presence of (a) myocardial dysfunction as suggested by elevated cardiac filling pressures and low cardiac output, or (b) ongoing signs of hypoperfusion despite achieving adequate intravascular volume and adequate mean arterial pressure (1C); avoiding use of intravenous hydrocortisone in adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability (2C); hemoglobin target of 7­9 g/dL in the absence of tissue hypoperfusion, ischemic coronary artery disease, or acute hemorrhage (1B); low tidal volume (1A) and limitation of inspiratory plateau pressure (1B) for acute respiratory distress syndrome (ARDS); application of at least a minimal amount of positive end-expiratory pressure (PEEP) in ARDS (1B); higher rather than lower level of PEEP for patients with sepsis-induced moderate or severe ARDS (2C); recruitment maneuvers in sepsis patients with severe refractory hypoxemia due to ARDS (2C); prone positioning in sepsis-induced ARDS patients with a PaO 2/FiO 2 ratio of ≤100 mm Hg in facilities that have experience with such practices (2C); head-of-bed elevation in mechanically ventilated patients unless contraindicated (1B); a conservative fluid strategy for patients with established ARDS who do not have evidence of tissue hypoperfusion (1C); protocols for weaning and sedation (1A); minimizing use of either intermittent bolus sedation or continuous infusion sedation targeting specific titration endpoints (1B); avoidance of neuromuscular blockers if possible in the septic patient without ARDS (1C); a short course of neuromuscular blocker (no longer than 48 h) for patients with early ARDS and a PaO 2/FI O 2<150 mm Hg (2C); a protocolized approach to blood glucose management commencing insulin dosing when two consecutive blood glucose levels are >180 mg/dL, targeting an upper blood glucose ≤180 mg/dL (1A); equivalency of continuous veno-venous hemofiltration or intermittent hemodialysis (2B); prophylaxis for deep vein thrombosis (1B); use of stress ulcer prophylaxis to prevent upper gastrointestinal bleeding in patients with bleeding risk factors (1B); oral or enteral (if necessary) feedings, as tolerated, rather than either complete fasting or provision of only intravenous glucose within the first 48 h after a diagnosis of severe sepsis/septic shock (2C); and addressing goals of care, including treatment plans and end-of-life planning (as appropriate) (1B), as early as feasible, but within 72 h of intensive care unit admission (2C). Recommendations specific to pediatric severe sepsis include: therapy with face mask oxygen, high flow nasal cannula oxygen, or nasopharyngeal continuous PEEP in the presence of respiratory distress and hypoxemia (2C), use of physical examination therapeutic endpoints such as capillary refill (2C); for septic shock associated with hypovolemia, the use of crystalloids or albumin to deliver a bolus of 20 mL/kg of crystalloids (or albumin equivalent) over 5­10 min (2C); more common use of inotropes and vasodilators for low cardiac output septic shock associated with elevated systemic vascular resistance (2C); and use of hydrocortisone only in children with suspected or proven "absolute"' adrenal insufficiency (2C). Conclusions: Strong agreement existed among a large cohort of international experts regarding many level 1 recommendations for the best care of patients with severe sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for this important group of critically ill patients.

Adenoviral vector transfection into the pulmonary epithelium after cecal ligation and puncture in rats.

BACKGROUND: Adenoviral-targeted gene delivery to respiratory epithelium can augment production of specific proteins. Therefore, it may be valuable in treating the acute respiratory distress syndrome. The authors tested the hypothesis that adenoviral vector uptake after cecal ligation and double puncture in rats, an animal model of the acute respiratory distress syndrome, is higher than that observed in controls that did not undergo operation ("nonoperated") or those that underwent a sham operation ("sham-operated"). METHODS: Adenoviruses expressing green fluorescent protein or Lac-Z were delivered into the lungs of anesthetized rats via tracheal catheter. Animals were killed 24 or 48 h later. Histopathology and green fluorescent protein expression were examined using light of fluorescence microscopy. Cellular localization of Lac-Z was determined with electron microscopy or semithin sectioning. Viral receptor density and localization were determined using imunoblotting and immunohistochemistry. RESULTS: After cecal ligation and double puncture, rats were hypoxic and tachypneic. Alveoli were segmentally consolidated, contained proteinaceous debris and neutrophils, and had thickened septa. Administration of adenoviruses to rats that were sham-operated or underwent cecal ligation and double puncture resulted in high levels of marker protein expression in cells lining alveoli. Use of 3 x 10(11) plaque-forming units instead of 3 x 10(12) plaque-forming units resulted in similar levels of green fluorescent protein expression with negligible viral-mediated lymphocytic infiltration. Semithin section and electron microscopy revealed expression primarily localized to type II alveolar cells. Abundance of alpha(v)beta3 integrins and human coxsackie-adenovirus receptor (receptors that modulate viral attachment and internalization) was increased after cecal ligation and double puncture, predominantly in type II pneumocytes. CONCLUSIONS: Cecal ligation and double puncture induces histologic and functional changes consistent with the acute respiratory distress syndrome, increases surface expression of viral receptors, and enhances adenoviral-mediated gene transfer.

Intrahepatic nuclear factor-kappa B activity and alpha 1-acid glycoprotein transcription do not predict outcome after cecal ligation and puncture in the rat.

OBJECTIVE: Sepsis is the leading cause of death in critically ill surgical patients. Septic hepatic dysfunction, an important determinant of outcome, is poorly understood but includes inappropriate transcriptional down-regulation. This may be modulated by proinflammatory cytokines. We hypothesized that intrahepatic changes in tumor necrosis factor (TNF)/interleukin (IL)-1-linked processes, such as the activation of the p50 homodimeric and the p65/p50 heterodimeric isoforms of the transcription factor nuclear factor (NF)-kappaB or transcription of the acute phase reactant alpha1-acid glycoprotein (AGP), would correlate with recovery from sepsis. DESIGN: Prospective experimental comparison of sham operation and nonlethal and lethal sepsis in male Sprague-Dawley rats. INTERVENTIONS: Nonlethal sepsis was induced by using single-puncture cecal ligation and puncture (CLP). Lethal sepsis was induced via double-puncture CLP. NF-kappaB DNA binding activity was determined by using electrophoretic mobility shift analysis with differentiation of p50/p50 and p50/p65 isoforms by using appropriate antibodies. AGP transcription was assessed with transcription elongation analysis, intrahepatic IL-1beta, and TNF-alpha abundance by using immunohistochemistry, and serum IL-1beta was assessed by using ELISA. MAIN RESULTS: Overall NF-kappaB activity increased equivalently over time after both single- and double-puncture CLP, with a peak occurring 3 hrs after intervention. In single-puncture CLP, there was an increase in the binding of the p50 homodimer form over time. After double-puncture CLP, no such change was observed. AGP transcription was increased equivalently in both models. Intrahepatic IL-1beta was detected 16 and 24 hrs after single-puncture CLP and 6 hrs after double-puncture CLP. After double-puncture CLP, intrahepatic TNF-alpha was detected at 6, 16, and 24 hrs. Serum IL-1beta was undetectable after both single- and double-puncture CLP. CONCLUSIONS: Although AGP transcription was similar in mild and fulminant sepsis, double-puncture CLP increased the binding activity of the p50 homodimer relative to binding of the p50/p65 NF-kappaB heterodimer. These results imply that transcriptional activity not linked to acute phase responses is an important determinant of outcome in sepsis.

Compensatory hepatic regeneration after mild, but not fulminant, intraperitoneal sepsis in rats.

Sepsis is the leading cause of death in surgical intensive care units. Although both mild sepsis secondary to cecal ligation and single puncture (CLP) and fulminant, double puncture CLP (2CLP) may provoke hepatocyte death, we hypothesize that regeneration compensates for cell death after CLP but not 2CLP. In male Sprague-Dawley rats, hepatic necrosis, as determined by serum alpha-glutathione S-transferase (alpha-GST) levels, was significantly but equally elevated over time after both CLP and 2CLP. Apoptosis, evaluated using both terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and morphological examination, was minimal after both CLP and 2CLP. Regeneration, assayed by staining tissue for incorporation of exogenously administered bromodeoxyuridine, was present after CLP but not after 2CLP. To further substantiate impaired regeneration, steady-state levels of mRNAs encoding JunB, LRF-1, and cyclin D1 were determined. After 2CLP, the absence of JunB, LRF-1, and cyclin D1 mRNAs confirmed failed activation of the mitogen-activated protein kinase-linked proliferative pathway and progression through the cell cycle. Therefore, failed hepatocyte regeneration may be a manifestation of hepatic dysfunction in fulminant sepsis.

Intraabdominal sepsis down-regulates transcription of sodium taurocholate cotransporter and multidrug resistance-associated protein in rats.

Hepatic dysfunction in sepsis is characterized by hyperbilirubinemia and intrahepatic cholestasis. We hypothesize that sepsis causes decreased hepatic transcription of the bile acid transporter sodium taurocholate cotransporter (Ntcp) and the organic anion transporter multidrug resistance-associated protein (Mrp2) and that interleukin (IL)-6 is important in the down-regulation of Ntcp and Mrp2 expression. Male Sprague-Dawley rats underwent induction of mild, nonlethal sepsis by cecal ligation and single puncture (CLP) or fulminant sepsis by cecal ligation and double puncture (2CLP). Hepatic transcription of Ntcp and Mrp2 rapidly decreased after CLP or 2CLP. Seventy-two hours later, transcription was 60% of baseline in CLP and 14% of baseline in 2CLP. Serum bilirubin was elevated from 24 h onward and cholestasis was observed on fixed liver specimens at 24, 48, and 72 h after 2CLP but not after CLP. Steady-state Ntcp and Mrp2 mRNA was decreased in IL-6-treated cultured hepatocytes and in normal rats given 1 mg/kg intravenous IL-6. We conclude that 1) Ntcp and Mrp2 transcription is down-regulated transiently after CLP and persistently after 2CLP; 2) 2CLP results in hyperbilirubinemia and cholestasis, in part due to persistently decreased transcription of Ntcp and Mrp2; and 3) altered Ntcp and Mrp2 transcription is mediated in part by IL-6.

Emergent airway management. Indications and methods in the face of confounding conditions.

Optimal airway management requires an experienced caregiver, attention to detail, and knowledge of the patient's physiology. A variety of pharmacologic agents have proved useful in obtaining a secure airway and minimizing risk to the patient. Depending on the skills of the caregiver, oral intubation has become the preferred means of airway control in most patients. Advances in technique, equipment, and pharmacology have greatly improved the art of airway management; however, there is no substitute for an experienced clinician.

The role of fiberoptic bronchoscopy in airway management of the critically ill patient.

Fiberoptic bronchoscopes (FOB) play a pivotal role in airway management in the operating room and critical care environments. This article examines the role of FOBs in modern airway management based on a review of recent literature and personal experience.

Airway management in the obstetric patient.

In summary, the need to manipulate the airway in the pregnant patient requires careful consideration and substantial planning. Anatomic and physiologic changes of pregnancy, coexisting conditions, and the potential for aspiration all carry a risk of morbidity and, indeed, mortality. Preparation, including early and repeated airway evaluations throughout pregnancy and labor, is encouraged. Knowledge of an emergency airway algorithm and a well thought-out plan for difficult intubations are imperative. Equipment must be available and in good condition. Finally, proper education and review for individuals involved in the delivery of care on the labor floor are mandatory. Although it is not always possible to control the manner in which these patients present, it is usually possible to control the environment into which they present.

Inflammatory responses and mediators.

The host response to injury is usually appropriate in degree and is self-limited. In more severe injury, the host response may persist inappropriately, leading to SIRS and MODS and possibly multiple organ failure. The initial response to injury is mediated primarily by norepinephrine, and is directed toward preservation of circulation to the heart and brain at the expense of other vascular beds. If fluid resuscitation is adequate and necrotic tissue is débrided, a hypermetabolic state ensues, mediated by epinephrine and directed toward supporting repair of injured tissue by leukocytes. Inflammatory cells are recruited to the site of injury and elaborate cytokines, which promote repair locally, but in severe injury may be systemically released and trigger remote inflammation. Cytokine biology presently is poorly understood, and simple anticytokine strategies have failed to improve survival of critically ill patients. Current therapy of SIRS and MODS is directed toward symptoms. Presently, it is unclear how an abnormal stress response arises. Cytokine spillover into the systemic circulation may occur. Selective transcriptional failure may be the cellular basis of organ dysfunction. Inappropriate production of peroxynitrite or its precursor, NO, is implicated in mediating cellular injury in SIRS and MODS.

Cecal ligation and double puncture impairs heat shock protein 70 (HSP-70) expression in the lungs of rats.

Induction of the heat shock response may improve outcome from pathophysiological disturbances. This improvement is associated with and believed to result from expression of heat shock protein (HSP)-70. Therefore, we examined the temporal expression of HSP-70 in an animal model of acute respiratory distress syndrome (ARDS) secondary to fecal peritonitis. Specifically, we hypothesize that sepsis in rats impairs pulmonary HSP-70 expression. ARDS was induced in adolescent rats via cecal ligation and double puncture (2CLP). Sham-operated animals served as controls. Lung tissue was collected 0, 3, 6, 16, 24, and 48 h after 2CLP and sham operation. Northern blot hybridization analysis was performed to detect steady-state HSP-70 messenger ribonucleic (mRNA) levels. HSP-70 protein levels were determined via immunoblotting and immunohistochemistry. Mortality after 2CLP was 50% at 24 h and 75% at 48 h. Northern blot hybridization analysis revealed no significant change in steady-state HSP-70 mRNA levels in lung at any time after 2CLP. HSP-70 steady-state mRNA levels increased after sham operation and was higher than values in 2CLP at 6, 16, and 24 h. HSP-70 protein levels did not change over time in either group. Thus, the expression of HSP-70 does not change after 2CLP. Although lack of an increase in protein levels may be adaptive after sham operation, it is not appropriate after 2CLP. Therefore, failed HSP-70 expression represents a form of pulmonary epithelial dysfunction that may contribute to lung injury in sepsis.

Computer assisted physiologic monitoring and stability assessment in vascular surgical patients undergoing general anesthesia--preliminary data.

BACKGROUND: Physiologic monitors present an influx of numerical data that can be overwhelming to the clinician. We combined several parameters in an effort to reduce the amount of information that must be continuously monitored including oxyhemoglobin saturation by pulse oximetry, end-tidal CO2 concentration, arterial blood pressure, and heart rate into an integrated measure--the health stability magnitude (HSM). The HSM is computed for a predetermined basal period, the reference HSM (RHSM), and recalculated continuously for comparison with the baseline value. In this study we present the HSM concept and examine changes in the HSM during abdominal aortic aneurysm surgery. MATERIALS AND METHODS: After IRB approval, nine patients were studied. The anesthesiologist recorded all significant intra-operative events. Within a defined time interval, data were recorded and used to calculate a combined parameter, the HSM. The baseline or reference value of this index (RHSM) was calculated after the induction of anesthesia. Individual HSM values were repeatedly calculated for ten second periods after the RHSM value was established. A > 30% deviation of the HSM from the RHSM was considered significant. Deviations in the HSM were compared with events recorded by the anesthesiologist on a paper record and with the record from an electronic record-keeping system. The deviation observed between two consecutive HSMs, called dHSM, was plotted against HSM to construct a contour diagram of data from all patients to which individual cases could be compared. RESULTS: The plot showed that dHSM vs. HSM values were tightly clustered. The inner contour on the distribution plot contained 90% of values. Individual patient's time course, projected on this diagram, revealed deviations form "normal" physiology. Fifty-nine events led to > 30% deviations in the HSM; 27 were anticipated events and 32 were unanticipated. CONCLUSION: The correlation between HSM and dHSM depicts changes in multiple monitored parameters that can be viewed using a single graphical representation. Projection of individual cases on the contour diagram may help the clinician to distinguish relative intraoperative stability from important events. Data reduction in this manner may guide clinical decision-making in response to unanticipated or unrecognized events.

Hepatic gene expression and cytokine responses to sterile inflammation: comparison with cecal ligation and puncture sepsis in the rat.

Inflammatory stimulation of hepatic acute phase protein expression is, in part, modulated by tumor necrosis factor-alpha (TNFalpha), interleukin-1beta (IL-beta), and IL-6. These cytokines also may mediate some aspects of the persistent inflammation and metabolic dysregulation of sepsis. Cecal ligation and puncture (CLP) sepsis in male Sprague-Dawley rats inappropriately decreases hepatocellular transcription of phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphatase (G6Pase), carnitine palmitoyltransferase II (CPTII), acetyl CoA acyltransferase (ACA), and ornithine transcarbamylase (OTC). We hypothesize that 1) transcriptional reprogramming does not occur after simple inflammation induced by subcutaneous turpentine injection, 2) the pattern of acute phase gene expression after CLP differs from that following turpentine injection, and 3) the different responses reflect differences in the intrahepatic activity of TNFalpha/IL-1beta or IL-6. Gene expression, transcription factor activity, and cytokine abundance were determined after either a subcutaneous injection of turpentine or CLP. After turpentine injection, PEPCK, G6Pase, CPTII, ACA, and OTC expression were unchanged, different from previously reported data following CLP. Both turpentine injection and CLP increased expression of TNFalpha/IL-1beta-regulated alpha1-acid glycoprotein, and IL-6-regulated alpha2-macroglobulin and decreased expression of transthyretin (a negative acute phase protein). However, the magnitude and temporal pattern of expression differed. Turpentine injection increased the activity of the TNFalpha/IL-1beta-linked transcription factor NF-kappaB and the intrahepatic abundance of TNFalpha in a manner similar to that observed after CLP but only slightly altered the activity of the IL-6-linked transcription factor Stat-3 and intrahepatic IL-6 abundance. This differed significantly from observations after CLP. We conclude that CLP-induced alterations in hepatic gene expression may reflect differences in IL-6 activity.

Effects of an organized critical care service on outcomes and resource utilization: a cohort study.

OBJECTIVE: To determine whether the presence of an on-site, organized, supervised critical service improves care and decreases resource utilization. DESIGN: The study compared two patient cohorts admitted to a surgical intensive care unit during the same period of time. The study cohort was cared for by an on-site critical care team supervised by an intensivist. The control cohort was cared for by a team with patient care responsibilities in multiple sites supervised by a general surgeon. The main outcome measures were duration of stay, resource utilization, and complication rate. SETTING: Study patients were general surgical patients in an academic medical center. RESULTS: Despite having higher Acute Physiology and Chronic Health Evaluation II scores, patients cared for by the critical care service spent less time in the surgical intensive care unit, used fewer resources, had fewer complications and had lower total hospital charges. The difference between the two cohorts was most evident in patients with the worst APACHE II score. CONCLUSIONS: Critical care interventions are expensive and have a narrow safety margin. It is essential to develop structured and validated approaches to study the delivery of this resource. In this study, the critical care service model performed favorably both in terms of quality and cost.

Intrahepatic STAT-3 activation and acute phase gene expression predict outcome after CLP sepsis in the rat.

Interleukin-6 (IL-6) regulates hepatic acute phase responses by activating the transcription factor signal transducer and activator of transcription (STAT)-3. IL-6 also may modulate septic pathophysiology. We hypothesize that 1) STAT-3 activation and transcription of alpha2-macroglobulin (A2M) correlate with recovery from sepsis and 2) STAT-3 activation and A2M transcription reflect intrahepatic and not serum IL-6. Nonlethal sepsis was induced in rats by single puncture cecal ligation and puncture (CLP) and lethal sepsis via double-puncture CLP. STAT-3 activation and A2M transcription were detected at 3-72 h and intrahepatic IL-6 at 24-72 h following single-puncture CLP. All were detected only at 3-16 h following double-puncture CLP and at lower levels than following single-puncture CLP. Loss of serum and intrahepatic IL-6 activity after double-puncture CLP correlated with mortality. Neither intrahepatic nor serum IL-6 levels correlated with intrahepatic IL-6 activity. STAT-3 activation following single-puncture CLP inversely correlated with altered transcription of gluconeogenic, ketogenic, and ureagenic genes. IL-6 may have both beneficial and detrimental effects in sepsis. Fulminant sepsis may decrease the ability of hepatocytes to respond to IL-6.