Intensive Care Med (2006) 32:1336–1343

Central venous oxygen saturation (ScvO2) in initial resuscitation is included in the Surviving Sepsis Campaign guidelines. ScvO2 monitoring has also been suggested to be comparable to mixed venous oxygen saturation (SvO2) for clinical purposes. The aim of our study was to assess the correlation and agreement of ScvO2 and SvO2 and compare ScvO2?SvO2 difference to lactate, oxygen-derived and hemodynamic parameters in early septic shock in ICU after initial resuscitation.

Design and setting
Prospective clinical study with 16 patients with septic shock at two university hospital ICUs. A dose of norepinephrine over 0.1ug/kg/min was required for inclusion.

Measurements and results
Five paired ScvO2 and SvO2 samples at 6-h intervals, altogether 72 samples, were collected during 24 h. The mean SvO2 was below the mean ScvO2 at all time points. Bias of difference was 4.2% and 95% limits of agreement ranged from 8.1% to 16.5%. The difference correlated significantly to CI and DO2.

Conclusion
The difference between paired ScvO2 and SvO2 varies highly. Therefore, SvO2 may not be estimated on the basis of ScvO2 in treatment of septic shock after resuscitation period in ICU.

Current Opinion in Critical Care 2009;15:392-397

Severe sepsis and septic shock are among the most important causes of morbidity and mortality in patients admitted to the intensive care unit. The purpose of this review is to review current understanding of sepsis-induced cardiac dysfunction and discuss pertinent findings regarding its clinical presentation, underlying mechanisms of disease, and therapy. Recent findings: Cardiac dysfunction in sepsis is characterized by decreased contractility, impaired ventricular response to fluid therapy, and in some patients ventricular dilatation. Current data support a complex underlying physiopathology with a host of potential pathways leading to myocardial depression. Circulating factors such as cytokines (TNF-[alpha], IL-1[beta]), lysozyme c, endothelin-1 have direct inhibitory actions on myocyte contractility. Nitric oxide has a complex role in sepsis-induced cardiac dysfunction. Current data suggest a combination of deleterious and positive effects on the myocardium determined by the specific type of nitric oxide expressed. Recent studies have shown that mitochondrial dysfunction and apoptosis also play a role in the development of sepsis-induced cardiac dysfunction. Current treatment for sepsis-induced cardiac dysfunction is based on appropriate treatment for the infectious focus (antibiotics and source control) and hemodynamic support (fluids, vasopressors, and inotropes). Summary: Cardiac dysfunction is common in patients with severe sepsis and septic shock. Current understanding of the underlying mechanisms responsible is rapidly evolving and future novel therapeutic targets may be soon available. Present therapy for sepsis-induced cardiac dysfunction is based on treatment of underlying sepsis with antibiotics and hemodynamic support.

Critical Care 2010, 14:R15

Biomarkers can be useful for identifying or ruling out sepsis, identifying patients who may benefit from specific therapies or assessing the response to therapy.
Methods
We used an electronic search of the PubMed database using the key words “sepsis” and “biomarker” to identify clinical and experimental studies which evaluated a biomarker in sepsis.

Results
The search retrieved 3370 references covering 178 different biomarkers.
Conclusions
Many biomarkers have been evaluated for use in sepsis. Most of the biomarkers had been tested clinically, primarily as prognostic markers in sepsis; relatively few have been used for diagnosis. None has sufficient specificity or sensitivity to be routinely employed in clinical practice. PCT and CRP have been most widely used, but even these have limited ability to distinguish sepsis from other inflammatory conditions or to predict outcome.

Crit Care Med 2010;38:72-83

Endotoxin is a potent stimulus of proinflammatory response and systemic coagulation in patients with severe sepsis. Endotoxin is a component of Gram-negative bacteria that triggers an innate immune response through Toll-like receptor 4 signaling pathways in myeloid cells. We evaluated safety and tolerability of two dose regimens of eritoran tetrasodium (E5564), a synthetic Toll-like receptor 4 antagonist, and explored whether it decreases 28-day mortality rate in subjects with severe sepsis.

Design
Prospective, randomized, double-blind, placebo-controlled, multicenter, ascending-dose phase II trial.

Setting
Adult intensive care units in the United States and Canada.

Patients
Three hundred adults within 12 hrs of recognition of severe sepsis, with Acute Physiology and Chronic Health Evaluation (APACHE) II-predicted risk of mortality between 20% and 80%.
Interventions
Intravenous eritoran tetrasodium (total dose of either 45 mg or 105 mg) or placebo administered every 12 hrs for 6 days.

Measurements and main results
Prevalence of adverse events was similar among subjects treated with 45 mg or 105 mg of eritoran tetrasodium or with placebo. For modified intent-to-treat subjects, 28-day all-cause mortality rates were 26.6% (eritoran tetrasodium 105 mg), 32.0% (eritoran tetrasodium 45 mg), and 33.3% in the placebo group. Mortality rate in the eritoran tetrasodium 105-mg group was not significantly different from placebo (p = .335). In prespecified subgroups, subjects at highest risk of mortality by APACHE II score quartile had a trend toward lower mortality rate in the eritoran tetrasodium 105-mg group (33.3% vs. 56.3% placebo group, p = .105). A trend toward a higher mortality rate was observed in subjects in the lowest APACHE II score quartile for the eritoran 105-mg group (12.0% vs. 0.0% placebo group, p = .083).

Conclusions
Eritoran tetrasodium treatment appears well tolerated. The observed trend toward a lower mortality rate at the 105-mg dose, in subjects with severe sepsis and high predicted risk of mortality, should be further investigated.

Crit Care Med 2009;37:2733-2739

To describe the composition of metabolic acidosis in patients with severe sepsis and septic shock at intensive care unit admission and throughout the first 5 days of intensive care unit stay. Design: Prospective, observational study.

Setting
Twelve-bed intensive care unit.

Patients
Sixty patients with either severe sepsis or septic shock.

Interventions
None.

Measurements and main results
Data were collected until 5 days after intensive care unit admission. We studied the contribution of inorganic ion difference, lactate, albumin, phosphate, and strong ion gap to metabolic acidosis. At admission, standard base excess was -6.69 +/- 4.19 mEq/L in survivors vs. -11.63 +/- 4.87 mEq/L in nonsurvivors (p < .05); inorganic ion difference (mainly resulting from hyperchloremia) was responsible for a decrease in standard base excess by 5.64 +/- 4.96 mEq/L in survivors vs. 8.94 +/- 7.06 mEq/L in nonsurvivors (p < .05); strong ion gap was responsible for a decrease in standard base excess by 4.07 +/- 3.57 mEq/L in survivors vs. 4.92 +/- 5.55 mEq/L in nonsurvivors with a nonsignificant probability value; and lactate was responsible for a decrease in standard base excess to 1.34 +/- 2.07 mEq/L in survivors vs. 1.61 +/- 2.25 mEq/L in nonsurvivors with a nonsignificant probability value. Albumin had an important alkalinizing effect in both groups; phosphate had a minimal acid-base effect. Acidosis in survivors was corrected during the study period as a result of a decrease in lactate and strong ion gap levels, whereas nonsurvivors did not correct their metabolic acidosis. In addition to Acute Physiology and Chronic Health Evaluation II score and serum creatinine level, inorganic ion difference acidosis magnitude at intensive care unit admission was independently associated with a worse outcome.

Conclusions
Patients with severe sepsis and septic shock exhibit a complex metabolic acidosis at intensive care unit admission, caused predominantly by hyperchloremic acidosis, which was more pronounced in nonsurvivors. Acidosis resolution in survivors was attributable to a decrease in strong ion gap and lactate levels.

Critical Care 2009, 13:R72

To establish a prognostic model for predicting 14-day mortality in ICU patients with severe sepsis overall and according to place of infection acquisition and to sepsis episode number.

Methods
In this prospective multicentre observational study on a multicentre database (OUTCOMEREA) including data from 12 ICUs, 2268 patients with 2737 episodes of severe sepsis were randomly divided into a training cohort (n = 1458) and a validation cohort (n = 810). Up to four consecutive severe sepsis episodes per patient occurring within the first 28 ICU days were included. We developed a prognostic model for predicting death within 14 days after each episode, based on patient data available at sepsis onset.

Results
Independent predictors of death were logistic organ dysfunction (odds ratio (OR), 1.22 per point, P < 10-4), septic shock (OR, 1.40; P = 0.01), rank of severe sepsis episode (1 reference, 2: OR, 1.26; P = 0.10 ≥ 3: OR, 2.64; P < 10-3), multiple sources of infection (OR; 1.45, P = 0.03), simplified acute physiology score II (OR, 1.02 per point; P < 10-4), McCabe score ([greater than or equal to]2) (OR, 1.96; P < 10-4), and number of chronic co-morbidities (1: OR, 1.75; P < 10-3, ≥ 2: OR, 2.24, P < 10-3). Validity of the model was good in whole cohorts (AUC-ROC, 0.76; 95%CI, 0.74 to 0.79; and HL Chi-square: 15.3 (P = 0.06) for all episodes pooled).

Conclusions
In ICU patients, a prognostic model based on a few easily obtained variables is effective in predicting death within 14 days after the first to fourth episode of severe sepsis complicating community-, hospital-, or ICU-acquired infection.

Critical Care 2009, 13:R74

The protective effect of glutamine, as a pharmacological agent against lung injury, has been reported in experimental sepsis; however, its efficacy at improving oxygenation and lung mechanics, attenuating diaphragm and distal organ injury has to be better elucidated. In the present study, we tested the hypothesis that a single early intravenous dose of glutamine was associated not only with the improvement of lung morpho-function, but also the reduction of the inflammatory process and epithelial cell apoptosis in kidney, liver, and intestine villi.

Methods
Seventy-two Wistar rats were randomly assigned into four groups. Sepsis was induced by cecal ligation and puncture surgery (CLP), while a sham operated group was used as control (C). One hour after surgery, C and CLP groups were further randomized into subgroups receiving intravenous saline (1 ml, SAL) or glutamine (0.75 g/kg, Gln). At 48 hours, animals were anesthetized, and the following parameters were measured: arterial oxygenation, pulmonary mechanics, and diaphragm, lung, kidney, liver, and small intestine villi histology. At 18 and 48 hours, Cytokine-Induced Neutrophil Chemoattractant (CINC)-1, interleukin (IL)-6 and 10 were quantified in bronchoalveolar and peritoneal lavage fluids (BALF and PLF, respectively).

Results
CLP induced: a) deterioration of lung mechanics and gas exchange; b) ultrastructural changes of lung parenchyma and diaphragm; and c) lung and distal organ epithelial cell apoptosis. Glutamine improved survival rate, oxygenation and lung mechanics, minimized pulmonary and diaphragmatic changes, attenuating lung and distal organ epithelial cell apoptosis. Glutamine increased IL-10 in peritoneal lavage fluid at 18 hours and bronchoalveolar lavage fluid at 48 hours, but decreased CINC-1 and IL-6 in BALF and PLF only at 18 hours.

Conclusions
In an experimental model of abdominal sepsis, a single intravenous dose of glutamine administered after sepsis induction may modulate the inflammatory process reducing not only the risk of lung injury, but also distal organ impairment. These results suggest that intravenous glutamine may be a potentially beneficial therapy for abdominal sepsis.

Critical Care 2009, 13:R78

Early multimodal treatment of severe sepsis, including the use of drotrecogin alfa (activated) (DrotAA) when indicated, is considered essential for optimum outcome. However, predicting which infected patients will progress to severe sepsis and the need for aggressive intervention continues to be problematic. We therefore wished to explore whether there were any potential early markers that might predict improved survival in response to early use of DrotAA in patients with severe sepsis. In particular, in the dynamic setting of severe sepsis, we postulated that changes in markers reflecting evolving rather than baseline clinical status might guide therapy.

Methods
Data on a cohort of 305 Canadian patients from the open label ENHANCE trial of DrotAA in severe sepsis was retrospectively analyzed to search for potential clinical predictors of outcome in severe sepsis. Patients received a 96-hour infusion of DrotAA and were followed for 28 days. The association between time to treatment and mortality within subgroups defined by dynamic changes in various potential markers was explored.

Results
Mortality at 28 days was 22.6% and the variables of age, time to treatment, and early changes in serum creatinine and platelet count were identified by logistic regression as independent predictors of mortality. Across all age ranges, 28-day mortality was lower when DrotAA was administered within 24 hours of first sepsis-induced organ dysfunction compared to administration after 24 hours for both subgroups of patients defined by changes in platelet count and creatinine within the first day.

Conclusions
These findings suggest that when indicated, treatment with DrotAA should be initiated as soon as possible, regardless of age.

Anesth Analg 2009;108:1841–1847

Although detailed analyses of the postmortem findings of various critically ill patient groups have been published, no such study has been performed in patients with sepsis. In this retrospective cohort study, we reviewed macroscopic postmortem examinations of surgical intensive care unit (ICU) patients who died from sepsis or septic shock.

Methodes
Between 1997 and 2006, the ICU database and autopsy register were reviewed for patients who were admitted to the ICU because of sepsis/septic shock, or who developed sepsis/septic shock at a later stage during their ICU stay and subsequently died from of sepsis/septic shock. Clinical data and postmortem findings were documented in all patients.

Results
Postmortem results of 235 patients (84.8%) were available for statistical analysis. The main causes of death as reported in the patient history were refractory multiple organ dysfunction syndrome (51.5%) and uncontrollable cardiovascular failure (35.3%). Pathologies were detected in the lungs (89.8%), kidneys/urinary tract (60%), gastrointestinal tract (54%), cardiovascular system (53.6%), liver (47.7%), spleen (33.2%), central nervous system (18.7%), and pancreas (8.5%). In 180 patients (76.6%), the autopsy revealed a continuous septic focus. The most common continuous foci were pneumonia (41.3%), tracheobronchitis (28.9%), peritonitis (23.4%), uterine/ovarial necrosis (9.8% of female patients), intraabdominal abscesses (9.1%), and pyelonephritis (6%). A continuous septic focus was observed in 63 of the 71 patients (88.7%) who were admitted to the ICU because of sepsis/septic shock and treated for longer than 7 days

Conclusions
Relevant postmortem findings explaining death in surgical ICU patients who died because of sepsis/septic shock were a continuous septic focus in approximately 80% and cardiac pathologies in 50%. The most frequently affected organs were the lungs, abdomen, and urogenital tract. More diagnostic, therapeutic and scientific efforts should be launched to identify and control the infectious focus in patients with sepsis and septic shock.

Anesth Analg 2009;108:1731:1733

Yes, they still die. Yes, we still do our best not to let them die. And no, ultimately, we do not know why they die, do we?

It is no news that, even today, sepsis is associated with high mortality. All of us who regularly practice intensive care medicine have seen our patients with sepsis die. Yet, it seems acceptable to claim that we do not know ultimately why these patients die. Some die despite full continuing therapeutic efforts, although others die after therapy has been withheld or withdrawn. Most patients who die with or because of sepsis, die with established multiple organ dysfunction or failure.1–3 Although the clinical cause of death can be classified as “refractory septic shock,” “multiple organ failure,” or “acute circulatory failure,” the actual causes and mechanisms for treatment failure and death remain mostly unidentified.

Sepsis has perplexed clinicians for centuries. One of the few breakthroughs in understanding sepsis came from the Hungarian obstetrician Ignác Semmelweiss working in Austria. He was puzzled by the high mortality rate in one of the two obstetrics clinics in Vienna 150 yr ago. Although merely 3% of mothers died from childbed fever in the second clinic, mortality was some 18% in the first clinic of obstetrics. In the first clinic, it was customary for clinicians and students alike to perform autopsies (bare-handed) before examining the mothers during labor. After his colleague Dr. Kolletschka, a professor of pathology, died from sepsis (open wound in his finger during autopsy!), Semmelweiss realized, on reading through the autopsy report, that Kolletschka’s autopsy findings were identical with those of mothers dying from childbed fever.

Critical Care 2009, 13:R44

The goals for septic shock resuscitation remain controversial. Despite the normalization of systemic hemodynamic variables, tissue hypoperfusion can still persist. Indeed, lactate or oxygen venous saturation may be difficult to interpret. Our hypothesis was that a gastric intramucosal pH-guided resuscitation protocol might improve the outcome of septic shock compared to a standard approach aimed at normalizing systemic parameters such as cardiac index (CI).

Methods
130 septic shock patients were randomized to two different resuscitation goals: CI greater than or equal to 3.0 L/min/m2 (CI group: 66 patients) or intramucosal pH (pHi) greater than or equal to 7.32 (pHi group: 64 patients). After correcting basic physiologic parameters, additional resuscitation consisting in more fluids and dobutamine was started if specific goals for each group had not been reached. Several clinical data were registered at baseline and during evolution. Hemodynamic data and pHi values were registered every 6 hours during the protocol. Primary end-point was 28 days mortality.

Results
Both groups were comparable at baseline. The most frequent sources of infection were abdominal sepsis and pneumonia. Twenty-eight day mortality (30.3 vs. 28.1%), peak Therapeutic Intervention Scoring System scores (32.6 +/- 6.5 vs. 33.2 +/- 4.7) and ICU length of stay (12.6 +/- 8.2 vs. 16 +/- 12.4 days) were comparable. A higher proportion of patients exhibited values below the specific target at baseline in the pHi group compared to the CI group (50% vs. 10.9%; P < 0.001). Of 32 patients with a pHi < 7.32 at baseline, only 7 (22%) normalized this parameter after resuscitation. Areas under the receiver operator characteristic curves to predict mortality at baseline, and at 24 and 48 hours were 0.55, 0.61, and 0.47, and 0.70, 0.90, and 0.75, for CI and pHi, respectively.

Conclusions
Our study failed to demonstrate any survival benefit of using pHi compared to CI as resuscitation goal in septic shock patients. Nevertheless, a normalization of pHi within 24 hours of resuscitation is a strong signal of therapeutic success and in contrast, a persistent low pHi despite treatment is associated with a very bad prognosis in septic shock patients.

AACN Advanced Critical Care 2008;19:281-287

Septic shock continues to be one of the leading causes of death in the intensive care unit today. The confluence of many factors contributes to the deterioration of patients’ condition in septic shock. Increased levels of nitric oxide, in part, mediate the cardiovascular effects of septic shock. Nitric oxide is major mediator of vasodilation and hypotension as well as myocardial depression. It also contributes to decreased production and release of endogenous vasopressin. Vasopressin effects are actualized by stimulation …

Crit Care Med 2009;37:417-423

Alkaline phosphatase (AP) attenuates inflammatory responses by lipopolysaccharide detoxification and may prevent organ damage during sepsis. To investigate the effect of AP in patients with severe sepsis or septic shock on acute kidney injury.

Design and setting
A multicenter double-blind, randomized, placebo-controlled phase IIa study (2:1 ratio).

Patients
Thirty-six intensive care unit patients (20 men/16 women, mean age 58 ± 3 years) with a proven or suspected Gram-negative bacterial infection, ≥2 systemic inflammatory response syndrome criteria (<24 hours), and <12 hours end-organ dysfunction onset were included.

Intervention
An initial bolus intravenous injection (67.5 U/kg body weight) over 10 minutes of AP or placebo, followed by continuous infusion (132.5 U/kg) over the following 23 hours and 50 minutes.

Measurements and main results
Median plasma creatinine levels declined significantly from 91 (73-138) to 70 (60-92) μmol/L only after AP treatment. Pathophysiology of nitric oxide (NO) production and subsequent renal damage were assessed in a subgroup of 15 patients. A 42-fold induction (vs. healthy subjects) in renal inducible NO synthase expression was reduced by 80% ± 5% after AP treatment. In AP-treated patients, the increase in cumulative urinary NO metabolite excretion was attenuated, whereas the opposite occurred after placebo. Reduced excretion of NO metabolites correlated with the proximal tubule injury marker glutathione S-transferase A1-1 in urine, which decreased by 70 (50-80)% in AP-treated patients compared with an increase by 200 (45-525)% in placebo-treated patients.

Conclusions
In severe sepsis and septic shock, infusion of AP inhibits the upregulation of renal inducible NO synthase, leading to subsequent reduced NO metabolite production, and attenuated tubular enzymuria. This mechanism may account for the observed improvement in renal function.

Crit Care Med 2009;37:811-818

Vasopressin and corticosteroids are often added to support cardiovascular dysfunction in patients who have septic shock that is nonresponsive to fluid resuscitation and norepinephrine infusion. However, it is unknown whether vasopressin treatment interacts with corticosteroid treatment.

Design
Post hoc substudy of a multicenter randomized blinded controlled trial of vasopressin vs. norepinephrine in septic shock.

Setting
Twenty-seven Intensive Care Units in Canada, Australia, and the United States.

Patients
Seven hundred and seventy-nine patients who had septic shock and were ongoing hypotension requiring at least 5 μg/min of norepinephrine infusion for 6 hours.

Interventions
Patients were randomized to blinded vasopressin (0.01-0.03 units/min) or norepinephrine (5-15 μg/min) infusion added to open-label vasopressors. Corticosteroids were given according to clinical judgment at any time in the 28-day postrandomization period.

Measurements
The primary end point was 28-day mortality. We tested for interaction between vasopressin treatment and corticosteroid treatment using logistic regression. Secondary end points were organ dysfunction, use of open-label vasopressors and vasopressin levels.

Main results
There was a statistically significant interaction between vasopressin infusion and corticosteroid treatment (p = 0.008). In patients who had septic shock and were also treated with corticosteroids, vasopressin, compared to norepinephrine, was associated with significantly decreased mortality (35.9% vs. 44.7%, respectively, p = 0.03). In contrast, in patients who did not receive corticosteroids, vasopressin was associated with increased mortality compared with norepinephrine (33.7% vs. 21.3%, respectively, p = 0.06). In patients who received vasopressin infusion, use of corticosteroids significantly increased plasma vasopressin levels by 33% at 6 hours (p = 0.006) to 67% at 24 hours (p = 0.025) compared with patients who did not receive corticosteroids.

Conclusions
There is a statistically significant interaction between vasopressin and corticosteroids. The combination of low-dose vasopressin and corticosteroids was associated with decreased mortality and organ dysfunction compared with norepinephrine and corticosteroids.

Crit Care Med 2009;37:803-810

The impact of continuous venovenous hemofiltration on sepsis-induced multiple organ failure severity is controversial. We sought to assess the effect of early application of hemofiltration on the degree of organ dysfunction and plasma cytokine levels in patients with severe sepsis or septic shock.

Design
Prospective, randomized, open, multicenter study setting, 12 French intensive care units.

Patients
A total of 80 patients were enrolled within 24 hours of development of the first organ failure related to a new septic insult.

Interventions
Patients were randomized to group 1 (HF), who received hemofiltration (25 mL/kg/hr) for a 96-hour period, or group 2 (C) who were managed conventionally.

Measurements and main results
The primary end point was the number, severity, and duration of organ failures during 14 days, as evaluated by the Sepsis-Related Organ Failure Assessment score, on an intention-to-treat analysis. Strict guidelines were provided to perform continuous hemofiltration under the same conditions and bearing the same objectives in all centers. Because of inclusion stagnation, the trial was discontinued after an interim analysis by which time 76 patients had been randomized. The number and severity of organ failures were significantly higher in the HF group (p < 0.05). No modifications in plasma cytokine levels could be detected.

Conclusion
These data suggest that early application of standard continuous venovenous hemofiltration is deleterious in severe sepsis and septic shock. This study does not rule out an effect of high-volume hemofiltration (>35 mL/kg/hr) on the course of sepsis.

Critical Care Med 2008;37:7-18

Fluid refractory septic shock can develop into a hypodynamic cardiovascular state in both children and adults. Despite management of these patients with empirical inotropic therapy (with or without a vasodilator), mortality remains high.

Objectives
The effect of cardiovascular support using intra-aortic balloon counterpulsation was investigated in a hypodynamic, mechanically ventilated canine sepsis model in which cardiovascular and pulmonary support were titrated based on treatment protocols.

Methods
Each week, three animals (n = 33, 10-12 kg) were administered intrabronchial Staphylococcus aureus challenge and then randomized to receive intra-aortic balloon counterpulsation for 68 hrs or no intra-aortic balloon counterpulsation (control). Bacterial doses were increased over the study (4-8 x 109 cfu/kg) to assess the effects of intra-aortic balloon counterpulsation during sepsis with increasing risk of death.

Main results
Compared with lower bacterial doses (4-7 x 109 colony-forming units/kg), control animals challenged with the highest dose (8 x 109 colony-forming units/kg) had a greater risk of death (mortality rate 86% vs. 17%), with worse lung injury ([A - a]o2), and renal dysfunction (creatinine). These sicker animals required higher norepinephrine infusion rates to maintain blood pressure (and higher Fio2) and positive end-expiratory pressure levels to maintain oxygenation (p <= 0.04 for all). In animals receiving the highest bacterial dose, intra-aortic balloon counterpulsation improved survival time (23.4 +/- 10 hrs longer; p = 0.003) and lowered norepinephrine requirements (0.43 +/- 0.17 [mu]g/kg/min; p = 0.002) and systemic vascular resistance index (1.44 +/- 0.57 dynes/s/cm5/kg; p = 0.0001) compared with controls. Despite these beneficial effects, intra-aortic balloon counterpulsation was associated with an increase in blood urea nitrogen (p = 0.002) and creatinine (p = 0.12). In animals receiving lower doses of bacteria, intra-aortic balloon counterpulsation had no significant effects on survival or renal function.

Conclusions
In a canine model of severe septic shock with a low cardiac index, intra-aortic balloon counterpulsation prolongs survival time and lowers vasopressor requirements.

Intensive Care Med 2008:34;2218-2225

To test the hypothesis that, in resuscitated septic shock patients, central venous-to-arterial carbon dioxide difference [P(cv-a)CO₂] may serve as a global index of tissue perfusion when the central venous oxygen saturation (ScvO₂) goal value has already been reached.

Design
Prospective observational study.

Setting
A 22-bed intensive care unit (ICU).

Patients
After early resuscitation in the emergency unit, 50 consecutive septic shock patients with ScvO₂ > 70% were included immediately after their admission into the ICU (T0). Patients were separated in Low P(cv-a)CO₂ group (Low gap; n = 26) and High P(cv-a)CO₂ group (High gap; n = 24) according to a threshold of 6 mmHg at T0.

Measurements
Measurements were performed every 6 h over 12 h (T0, T6, T12).

Results
At T0, there was a significant difference between Low gap patients and High gap patients for cardiac index (CI) (4.3 ± 1.6 vs. 2.7 ± 0.8 l/min/m≤, P < 0.0001) but not for ScvO₂ values (78 ± 5 vs. 75 ± 5%, P = 0.07). From T0 to T12, the clearance of lactate was significantly larger for the Low gap group than for the High gap group (P < 0.05) as well as the decrease of SOFA score at T24 (P < 0.01). At T0, T6 and T12, CI and P(cv-a)CO₂ values were inversely correlated (P < 0.0001).

Conclusion
In ICU-resuscitated patients, targeting only ScvO₂ may not be sufficient to guide therapy. When the 70% ScvO₂ goal-value is reached, the presence of a P(cv-a)CO₂ larger than 6 mmHg might be a useful tool to identify patients who still remain inadequately resuscitated.

Intensive Care Med 2008:34;1065-1075

The ACCM/PALS guidelines address early correction of paediatric septic shock using conventional measures. In the evolution of these recommendations, indirect measures of the balance between systemic oxygen delivery and demands using central venous or superior vena cava oxygen saturation (ScvO₂>=70%) in a goal-directed approach have been added. However, while these additional goal-directed endpoints are based on evidence-based adult studies, the extrapolation to the paediatric patient remains unvalidated.

Objective
The purpose of this study was to compare treatment according to ACCM/PALS guidelines, performed with and without ScvO₂ goal-directed therapy, on the morbidity and mortality rate of children with severe sepsis and septic shock.

Design, participants and interventions
Children and adolescents with severe sepsis or fluid-refractory septic shock were randomly assigned to ACCM/PALS with or without ScvO₂ goal-directed resuscitation.

Measurements
Twenty-eight-day mortality was the primary endpoint.
Results  Of the 102 enrolled patients, 51 received ACCM/PALS with ScvO₂ goal-directed therapy and 51 received ACCM/PALS without ScvO₂ goal-directed therapy. ScvO₂ goal-directed therapy resulted in less mortality (28-day mortality 11.8% vs. 39.2%, p=0.002), and fewer new organ dysfunctions (p=0.03). ScvO₂ goal-directed therapy resulted in more crystalloid (28 (20–40) vs. 5 (0–20)ml/kg, p<0.0001), blood transfusion (45.1% vs. 15.7%, p=0.002) and inotropic (29.4% vs. 7.8%, p=0.01) support in the first 6h.

Conclusions
This study supports the current ACCM/PALS guidelines. Goal-directed therapy using the endpoint of a ScvO₂>=70% has a significant and additive impact on the outcome of children and adolescents with septic shock.

See the Editorial by M J Peters and J Brierley: Back to basics in septic shock

Crit Care Med 2008;36:2973-2979

Sepsis and septic shock represent a systemic inflammatory state with substantial pro-coagulant elements. Unfractionated heparin is a known anticoagulant, which also possesses anti-inflammatory properties. Unfractionated heparin has been shown to increase survival in experimental models of septic shock.

Objective
To evaluate the impact of intravenous therapeutic dose unfractionated heparin in a cohort of patients diagnosed with septic shock.

Design
Retrospective, propensity matched, multicenter, cohort study.

Setting
Regional intensive care units in Winnipeg, Canada between 1989 and 2005.

Patients
Two thousand three hundred fifty-six patients diagnosed with septic shock, of which 722 received intravenous therapeutic dose heparin.

Measurements and Main Results
The primary outcome of study was 28-day mortality, and mortality stratified by severity of illness (Acute Physiologic and Chronic Health Evaluation II quartile). Safety was assessed by comparing rates of gastrointestinal hemorrhage, intracranial hemorrhage, and the need for transfusion. By using a Cox proportional hazards model, systemic heparin therapy was associated with decreased 28-day mortality (307 of 695 [44.2%] vs. 279 of 695 [40.1%]; hazard ratio 0.85 [confidence interval (CI) 95% 0.73-1.00]; p = 0.05). In the highest quartile of severity of illness (Acute Physiologic and Chronic Health Evaluation II score 29-53), heparin administration was associated with a clinically and statistically significant reduction in 28-day mortality [127 of 184 (69.0%) vs. 94 of 168 (56.0%); hazard ratio 0.70 (CI 95% 0.54-0.92); p = 0.01]. The use of intravenous unfractionated heparin was associated with successful liberation from mechanical ventilation [odds ratio of 1.42 (CI 95% 1.13-1.80); p = 0.003], and successful discontinuation of vasopressor/inotropic support [odds ratio of 1.34 (CI 95% 1.06-1.71); p = 0.01]. No significant differences in the rates of major hemorrhage or need for transfusion were identified.

Conclusion
Early administration of intravenous therapeutic dose unfractionated heparin may be associated with decreased mortality when administered to patients diagnosed with septic shock, especially in patients with higher severity of illness. Prospective randomized trials are needed to further define the role of this agent in sepsis and septic shock.

Crit Care Med 2008; 36:2542-2546

High B-type natriuretic peptide (BNP) levels are reported in the context of septic shock. We hypothesized that high BNP levels might be related to an alteration in BNP clearance pathway, namely neutral endopeptidase (NEP) 24.11. NEP 24.11 activity was measured in septic shock and in cardiogenic shock patients. We further evaluated whether baseline plasma BNP can predict fluid responsiveness and whether BNP can still be released in plasma despite high initial BNP levels, in response to overloading.

Material and Methods
Prospective observational study. Patients in severe sepsis (S) or in septic shock (SS) needing a fluid challenge were included. Stroke volume (SV) and BNP were measured before (SV1, BNP1) and 45 mins after (SV2, BNP2) a standardized fluid challenge. DeltaBNP was defined as the difference between BNP2 and BNP1. NEP 24.11 activity was determined by fluorometry in 12 SS and 4 S patients before fluid challenge and in 5 cardiogenic shock patients.

Results
Twenty-three patients (61 +/- 18 years old, Simplified Acute Physiology Score II: 54 +/- 21; 19 SS, 4 S; BNP1: 1371 +/- 1434 pg/mL) were studied. BNP1 concentrations were significantly higher in SS than in S (1643 +/- 1437 vs. 80 +/- 35 pg/mL; p = 0.002). There was no correlation between baseline BNP and fluid responsiveness. Nine of the 11 patients with BNP1 >1000 pg/mL were fluid responders. DeltaBNP was greater in fluid nonresponders than in fluid responders (22 +/- 27% vs. 6 +/- 11%, p = 0.028). Plasma BNP was higher in SS than in cardiogenic shock patients (1367 +/- 1438 vs. 750 +/- 346 respectively; p = 0.027). NEP 24.11 activity was lower in SS than in S patients (0.10 +/- 0.06 nmole/mL/min vs. 0.50 +/- 0.22 nmole/mL/min, p <0.0001) cardiogenic shock patients (0.10 +/- 0.06 nmole/mL/min vs. 0.58 +/- 0.19 nmole/mL/min; p = 0.002).

Conclusion
High levels of BNP might be related to an alteration in BNP clearance. During sepsis, high BNP levels are not predictive of fluid nonresponsiveness. Nevertheless, in fluid nonresponders, acute ventricular stretching can result in further BNP release.