Evidence Underpinning the Centers for Medicare & Medicaid Services' Severe Sepsis and Septic Shock Management Bundle (SEP-1): A Systematic Review.

This article has been corrected. To see what has changed, please read the Letter to the Editor and the authors' response. The original version (PDF) is appended to this article as a Supplement. Background: The Severe Sepsis and Septic Shock Early Management Bundle (SEP-1), the sepsis performance measure introduced in 2015 by the Centers for Medicare & Medicaid Services (CMS), requires the reporting of up to 5 hemodynamic interventions, as many as 141 tasks, and 3 hours to document for a single patient. Purpose: To evaluate whether moderate- or high-level evidence shows that use of the 2015 SEP-1 or its hemodynamic interventions improves survival in adults with sepsis. Data Sources: PubMed, Embase, Scopus, Web of Science, and ClinicalTrials.gov from inception to 28 November 2017 with no language restrictions. Study Selection: Randomized and observational studies of death among adults with sepsis who received versus those who did not receive either the entire SEP-1 bundle or 1 or more SEP-1 hemodynamic interventions, including serial lactate measurements; a fluid infusion of 30 mL/kg of body weight; and assessment of volume status and tissue perfusion with a focused examination, bedside cardiovascular ultrasonography, or fluid responsiveness testing. Data Extraction: Two investigators independently extracted study data and assessed each study's risk of bias; 4 authors rated level of evidence by consensus using CMS criteria published in 2013. High- or moderate-level evidence required studies to have no confounders and low risk of bias. Data Synthesis: Of 56 563 references, 20 studies (18 reports) met inclusion criteria. One single-center observational study reported lower in-hospital mortality after implementation of the SEP-1 bundle. Sixteen studies (2 randomized and 14 observational) reported increased survival with serial lactate measurements or 30-mL/kg fluid infusions. None of the 17 studies were free of confounders or at low risk of bias. In 3 randomized trials, fluid responsiveness testing did not alter survival. Limitations: Few trials, poor-quality and confounded studies, and no studies (with survival outcomes) of the focused examination or bedside cardiovascular ultrasonography. Use of the 2015 version of SEP-1 and 2013 version of CMS evidence criteria, both of which were updated in 2017. Conclusion: No high- or moderate-level evidence shows that SEP-1 or its hemodynamic interventions improve survival in adults with sepsis. Primary Funding Source: National Institutes of Health. (PROSPERO: CRD42016052716).

Anthrax immune globulin improves hemodynamics and survival during B. anthracis toxin-induced shock in canines receiving titrated fluid and vasopressor support.

BACKGROUND: Although anthrax immune globulin (AIG) improved survival in antibiotic-treated Bacillus anthracis-challenged animal models, whether it adds to the benefit of conventional hemodynamic support for B. anthracis toxin-associated shock is unknown. METHODS: We therefore tested AIG in sedated, mechanically ventilated canines challenged with 24-h B. anthracis lethal and edema toxin infusions and supported for 96 h with a previously demonstrated protective regimen of titrated normal saline and norepinephrine. RESULTS: Compared to controls, proportional survival (%) was increased with AIG treatment started 4 h before (33 vs. 100%, n = 6 each) or 2 h (17 vs. 86%, n = 6 and 7 respectively) or 5 h (0 vs. 67%, n = 3 each) after the start of toxin (p ≤ 0.05) and overall [3 survivors of 15 controls (20%) vs. 14 of 16 AIG animals (88%); p = 0.006]. Averaged across treatment times, AIG increased blood pressure at 48 h and decreased norepinephrine requirements at 72 h (p ≤ 0.02), increased left ventricular ejection fraction at 48 and 72 h (p ≤ 0.02), and increased urine output and decreased net fluid balance at 72 and 96 h (p ≤ 0.04). AIG also reduced acidosis and renal and hepatic injury markers between 24 and 96 h. CONCLUSIONS: These findings further support AIG's potential benefit for patients with B. anthracis infection and developing toxin-associated shock.

Bacillus anthracis Edema Toxin Increases Fractional Free Water and Sodium Reabsorption in an Isolated Perfused Rat Kidney Model.

Bacillus anthracis edema toxin (ET) consists of protective antigen (PA), necessary for host cell toxin uptake, and edema factor (EF), the toxic moiety which increases host cell cyclic AMP (cAMP). Since vasopressin stimulates renal water and sodium reabsorption via increased tubular cell cAMP levels, we hypothesized the ET would also do so. To test this hypothesis, we employed an isolated perfused rat kidney model. Kidneys were isolated and perfused with modified Krebs-Henseleit buffer. Perfusate and urine samples were obtained at baseline and every 10 min over 150 min following the addition of challenges with or without treatments to the perfusate. In kidneys perfused under constant flow or constant pressure, compared to PA challenge (n = 14 or 15 kidneys, respectively), ET (13 or 15 kidneys, respectively) progressively increased urine cAMP levels, water and sodium reabsorption, and urine osmolality and decreased urine output (P ≤ 0.04, except for sodium reabsorption under constant pressure [P = 0.17]). In ET-challenged kidneys, compared to placebo treatment, adefovir, an EF inhibitor, decreased urine cAMP levels, water and sodium reabsorption, and urine osmolality and increased urine output, while raxibacumab, a PA-directed monoclonal antibody (MAb), decreased urine cAMP levels, free water reabsorption, and urine osmolality and increased urine output (P ≤ 0.03 except for urine output with raxibacumab [P = 0.17]). Upon immunohistochemistry, aquaporin 2 was concentrated along the apical membrane of tubular cells with ET but not PA, and urine aquaporin 2 levels were higher with ET (5.52 ± 1.06 ng/ml versus 1.51 ± 0.44 ng/ml [means ± standard errors of the means {SEM}; P = 0.0001). Edema toxin has renal effects that could contribute to extravascular fluid collection characterizing anthrax infection clinically.

Tidal volume and plateau pressure use for acute lung injury from 2000 to present: a systematic literature review.

OBJECTIVE: Since publication of the Respiratory Management of Acute Lung Injury and Acute Respiratory Distress Syndrome (ARMA) trial in 2000, use of tidal volume (VT) less than or equal to 6 mL/kg predicted body weight with corresponding plateau airway pressures (PPlat) less than or equal to 30 cm H2O has been advocated for acute lung injury. However, compliance with these recommendations is unknown. We therefore investigated VT (mL/kg predicted body weight) and PPlat (cm H2O) practices reported in studies of acute lung injury since ARMA using a systematic literature review (i.e., not a meta-analysis). DATA SOURCES: PubMed, Scopus, and EMBASE. STUDY SELECTION: Randomized controlled trials and nonrandomized studies enrolling patients with acute lung injury from May 2000 to June 2013 and reporting VT. DATA EXTRACTION: Whether the study was a randomized controlled trial or a nonrandomized study and performed or not at an Acute Respiratory Distress Syndrome Network center; in randomized controlled trials, the pre- and postrandomization VT (mL/kg predicted body weight) and PPlat (cm H2O) and whether a VT protocol was used postrandomization; in nonrandomized studies, baseline VT and PPlat. DATA SYNTHESIS: Twenty-two randomized controlled trials and 71 nonrandomized studies were included. Since 2000 at acute respiratory distress syndrome Network centers, routine VT was similar comparing randomized controlled trials and nonrandomized studies (p = 0.25) and unchanged over time (p = 0.75) with a mean value of 6.81 (95% CI, 6.45, 7.18). At non-acute respiratory distress syndrome Network centers, routine VT was also similar when comparing randomized controlled trials and nonrandomized studies (p = 0.71), but decreased (p = 0.001); the most recent estimate for it was 6.77 (6.22, 7.32). All VT estimates were significantly greater than 6 (p ≤ 0.02). In randomized controlled trials employing VT protocols, routine VT was reduced in both acute respiratory distress syndrome Network (n = 4) and non-acute respiratory distress syndrome Network (n = 11) trials (p ≤ 0.01 for both), but even postrandomization was greater than 6 (6.47 [6.29, 6.65] and 6.80 [6.42, 7.17], respectively; p ≤ 0.0001 for both). In 59 studies providing data, routine PPlat, averaged across acute respiratory distress syndrome Network or non-acute respiratory distress syndrome Network centers, was significantly less than 30 (p ≤ 0.02). CONCLUSIONS: For clinicians treating acute lung injury since 2000, achieving VT less than or equal to 6 mL/kg predicted body weight may not have been as attainable or important as PPlat less than or equal to 30 cm H2O. If so, there may be equipoise to test if VT less than or equal to 6 mL/kg predicted body weight are necessary to improve acute lung injury outcome.

Fluid balance, change in serum creatinine and urine output as markers of acute kidney injury post cardiac surgery: an observational study.

BACKGROUND: Acute kidney injury (AKI) is defined as oliguria or rise in serum creatinine but oliguria alone as a diagnostic criterion may over-diagnose AKI. OBJECTIVES: Given the association between fluid overload and AKI, we aimed to determine if positive fluid balance can complement the known parameters in assessing outcomes of AKI. DESIGN: Prospective observational study. SETTING: Teaching hospital in Vancouver, Canada. PATIENTS: 111 consecutive patients undergoing elective cardiac surgery from January to April 2012. MEASUREMENTS: Outcomes of cardiac surgery intensive care unit (CSICU) and hospital length of stay (LOS) in relation to fluid balance, urine output and serum creatinine. METHODS: All fluid input and output was recorded for 72 hours post-operatively. Positive fluid balance was defined as >6.5 cc/kg. Daily serum creatinine and hourly urine output were recorded and patients were defined as having AKI according to the AKIN criteria. RESULTS: Of the patients who were oliguric, those with fluid overload trended towards longer LOS than those without fluid overload [CSICU LOS: 62 and 39 hours (unadjusted p-value 0.02, adjusted p-value 0.58); hospital LOS: 13 and 9 days (unadjusted p-value: 0.05, adjusted p-value: 0.16)]. Patients with oliguria who were fluid overloaded had similar LOS to patients with overt AKI (change in serum creatinine ≥ 26.5 µmol/L), [CSICU LOS: 62 and 69 hours (adjusted p value: 0.32) and hospital LOS: 13 and 14 days (adjusted p value: 0.19)]. Patients with oliguria regardless of fluid balance had longer CSICU LOS (adjusted p value: 0.001) and patients who were fluid overloaded in the absence of AKI had longer hospital LOS (adjusted p value: 0.02). LIMITATIONS: Single centre, small sample, LOS as outcome. CONCLUSIONS: Oliguria and positive fluid balance is associated with a trend towards longer LOS as compared to oliguria alone. Fluid balance may therefore be a useful marker of AKI, in addition to urine output and serum creatinine.

CONTEXTE: L'insuffisance rénale aiguë (IRA) se définit comme une oligurie ou une élévation de la créatininémie. Par contre, l'oligurie comme unique critère diagnostique peut mener abusivement au diagnostic d'IRA. OBJECTIFS: Étant donné l'association entre l'hyperhydratation et l'IRA, nous cherchons à déterminer si une balance liquidienne positive peut complémenter les paramètres connus dans l'évaluation des résultats de l'IRA. TYPE D'ÉTUDE: Étude d'observation prospective. CONTEXTE: Hôpital universitaire à Vancouver, Canada. PARTICIPANTS: 111 patients consécutifs qui subissent une chirurgie cardiaque non urgente, entre janvier et avril 2012. MESURES: On a mis en parallèle les résultats de l'unité de soins intensifs en chirurgie cardiaque (USICC), de même que la durée de l'hospitalisation (soins actifs), avec la balance liquidienne, la diurèse et la créatininémie. MÉTHODES: On a mesuré les ingesta et excreta durant les 72 heures postopératoires. On a défini une balance liquidienne positive à >6,5 cc/kg. On a enregistré la créatininémie quotidienne et la diurèse aux heures, et on a déterminé que les patients souffraient d'IRA en nous basant sur les critères de l'Acute Kidney Injury Network (AKIN). RÉSULTATS: Parmi les patients oliguriques, ceux qui avaient une surcharge liquidienne tendaient davantage vers une hospitalisation prolongée que ceux qui n'en avaient pas [durée de soins actifs à l'USICC: 62 et 39 heures (valeur de p non ajustée: 0,02, valeur de p ajustée: 0,58); durée de soins actifs à l'hôpital: 13 et 9 jours (valeur de p non ajustée: 0,05, valeur de p ajustée: 0,16)]. Les patients présentant une oligurie qui présentaient aussi une surcharge liquidienne requéraient une durée de soins actifs similaire aux patients souffrant d'IRA (modification de la créatininémie ≥ 26,5 µmol/L), [soins actifs USICC: 62 et 69 heures (valeur de p ajustée: 0,32) soins actifs à l'hôpital: 13 et 14 jours (valeur de p ajustée: 0,19)]. Les patients présentant une oligurie, indépendamment de la balance liquidienne, bénéficiaient d'une durée de soins actifs à l'USICC prolongée (valeur p ajustée: 0,001), tandis que les patients en surcharge liquidienne, mais ne souffrant pas d'IRA bénéficiaient davantage de soins actifs à l'hôpital (valeur de p ajustée: 0,02). LIMITES DE L'ÉTUDE: Un seul centre, un échantillon restreint, les soins actifs considérés comme une issue. CONCLUSION: Les patients avec oligurie et une balance liquidienne positive ont nécessité des soins actifs prolongés à l'USICC, comparativement aux patients ne présentant qu'une oligurie. La balance liquidienne peut donc constituer un marqueur d'IRA, en plus de la diurèse et la créatininémie.

Effect of an emergency department sepsis protocol on the care of septic patients admitted to the intensive care unit.

OBJECTIVE: We sought to determine whether the implementation of a sepsis protocol in a Canadian emergency department (ED) improves care for the subset of patients admitted to the intensive care unit (ICU). METHODS: After implementing a sepsis protocol in our ED we used an ICU database and chart review to compare various time-dependent end points and outcomes between a historical control year and the first year after implementation. We re-viewed the charts of all patients admitted to the ICU within 24 hours of ED admission with a primary or other diagnosis of sepsis, severe sepsis or septic shock, who met criteria for early goal-directed therapy within the first 6 hours of their ED stay. RESULTS: We compared 29 patients from the control year with 30 patients from the year after implementation of our sepsis protocol. We found that patients treated during the postintervention year had improvements in time to antibiotics (4.2 v. 1.0 h, difference = -3.2 h, 95% CI -4.8 to -2.0), time to central line placement (above the diaphragm) (11.6 v. 3.2 h, difference = -8.4 h, 95% CI -12.1 to -4.7), time to arterial line placement (7.5 v. 2.3 h, difference = -5.2 h, 95% CI -7.4 to -3.0), and achievement of central venous pressure and central venous oxygen saturation goals (11.1 v. 5.1 h, difference = -6.0 h, 95% CI -11.03 to -1.71, and 13.1 v. 5.5 h, difference = -7.6 h, 95% CI -11.97 to -3.16, respectively). There were no statistically significant differences in ICU length of stay, hospital length of stay or mortality (31.0% v. 20.0%, difference = -11.0%, 95% -33.1% to 11.1%). CONCLUSION: Implementation of an ED sepsis protocol im-proves care for patients with severe sepsis and septic shock.

Treatment of polyomavirus infection in kidney transplant recipients: a systematic review.

BACKGROUND.: Polyomavirus-associated nephropathy (PVAN) is an important cause of kidney graft loss but there is no consensus on its management. This study aimed to systematically document all published treatments for PVAN to determine the most effective therapy. METHODS.: A computerized search in MEDLINE, EMBASE, and Cochrane databases (1950-2008) was performed. References from review articles and published abstracts from the American Transplant Congress (2005-2008) were also included. Study selection criteria included (a) population: adult (>18 years) kidney-only, primary or repeat renal transplant recipients; (b) setting: polyoma viruria, viremia or biopsy-proven PVAN or both; and (c) treatment: immunosuppression reduction alone or with adjuvant agents. The primary outcome was graft failure rate, and secondary outcomes included acute rejection rate, elimination of viruria and viremia, graft function, patient survival, and adverse events. RESULTS.: Of 555 identified citations, 40 studies examining the effect of immunosuppression reduction alone or in combination with cidofovir, leflunomide, intravenous immunoglobulin, or ciprofloxacin were included for appraisal. Pooled results found a death-censored graft loss rate of 8/100 patient-years for immunosuppression reduction alone and 8 and 13/100 patient-years for the addition of cidofovir or leflunomide, respectively. CONCLUSIONS.: There does not seem to be a graft survival benefit of adding cidofovir or leflunomide to immunosuppression reduction for the management of PVAN. However, the evidence base is poor and highlights the urgent need for adequately powered randomized trials to define the optimal treatment of this important condition.