Critical Care 2009, 13:R40

Perioperative hypovolemia arises frequently and contributes to intestinal hypoperfusion and subsequent postoperative complications. Goal-directed fluid therapy (GDT) might reduce these complications. The aim of this study was to compare the effects of goal-directed administration of crystalloids and colloids on distribution of systemic, hepato-splanchnic and microcirculatory (small intestine) blood flow after major abdominal surgery in a clinically relevant pig model.

Methods
Twenty-seven pigs were anesthetized, mechanically ventilated and underwent open laparotomy. They were randomly assigned to one of the three following treatment groups: the restricted Ringer’s lactate group (R-RL, n=9) received 3 ml.kg-1.h-1 RL; the goal-directed RL group (GD-RL, n=9) received 3 ml.kg-1.h-1 RL and intermittent boluses of 250 ml RL and the goal-directed colloid group (GD-C, n=9) received 3 ml.kg-1.h-1 RL and boluses of 250 ml 6% hydroxyethyl starch (130/0.4). The two latter groups received a bolus infusion when mixed venous oxygen saturation (SvO2) was below 60% (lock out time 30 minutes). Regional blood flow was measured in the superior mesenteric artery and the celiac trunk. In the small bowel, microcirculatory blood flow was measured using laser Doppler flowmetry. Intestinal tissue oxygen tension was measured with intramural Clark-type electrodes.

Results
After 4 hours of treatment, arterial blood pressure, cardiac output, mesenteric artery flow and mixed oxygen saturation were significantly higher in groups GD-C and GD-RL than in group R-RL. Microcirculatory flow in the intestinal mucosa increased by 50% in GD-C but remained unchanged in the other two groups. Likewise, tissue oxygen tension in the intestine increased by 30% in GD-C but remained unchanged in GD-RL and decreased by 18% in the R-RL group. Mesenteric venous glucose concentrations were higher and lactate levels lower in group GD-C compared with the two crystalloid groups.

Conclusions
Goal-directed colloid administration markedly increased microcirculatory blood flow in the small intestine and intestinal tissue oxygen tension after abdominal surgery. In contrast, goal-directed crystalloid and restricted crystalloid administrations had no such effects. Additionally, mesenteric venous glucose and lactate concentrations suggest that intestinal cellular substrate levels were higher in the colloid-treated than in the crystalloid-treated animals. These results support the notion that perioperative goal-directed therapy with colloids might be beneficial during major abdominal surgery.

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

Chest 2006;129:507-508

Mixed venous oxygen saturation (SvO₂) in sepsis is commonly referred to as an end point of low impact on clinical decisions in sepsis patients because of the following common refrain: “SvO₂ is always increased in septic ICU patients.” However, there are fundamental principles that render this modality clinically useful when applying it to the supply-dependent phase of sepsis (ie, global tissue hypoxia). The presence of global tissue hypoxia not only has pathologic significance in vitro, but there is a pathologic link among the clinical presence of global tissue hypoxia (ie, low SvO₂ and cardiac index), the generation of inflammatory mediators, and mitochondrial impairment of oxygen utilization that is seen in septic ICU patients. Furthermore, identifying sudden episodes of supply dependency in septic ICU patients (ie, sudden decreases in SvO₂) has diagnostic and prognostic significance. With this background, the rationale for using central venous oxygen (ScvO₂) saturation as a surrogate for SvO₂ to detect and treat global tissue hypoxia in the most proximal phase of sepsis management (supply dependency) was the basis for its use in the Early Goal Directed Therapy in Severe Sepsis and Septic Shock Study (EGDT).

Chest 2003;124:90S

Despite the current definition of septic shock, patients with normal or high blood pressure may still display global tissue hypoxia. The following study evaluates early, goal-directed therapy (EGDT) in patients with severe sepsis in the absence of hypotension.

METHODS
This is a post-hoc anlysis of patients presenting to an urban ED in severe sepsis and septic shock. Patients were included if they had SIRS critieria, lactic acidosis (> 4 mmol/liter), and mean arterial pressure (MAP) > 100 mm Hg. Patients were randomized to conventional care (inclusive of central venous pressure (CVP) monitoring) or EGDT. EGDT consisted of 6 hours of resuscitation to goals of CVP between 8–12, MAP between 65–90, and central venous oximetry (ScvO₂) greater than 70%.

RESULTS
There was no difference in mean MAP (116.0 mm Hg in the control and 117.6 mm Hg in the treatment group), and there was no difference in APACHE, MODS, and SAPS scores between groups. Forty-eight patients (23 in the control group and 25 in the EGDT group) were analyzed. The mortality was 60.9% in the control group compared to 20% in the EGDT group [p < 0.004]. The mean initial ScvO₂ was 45 % and 44 % in the control and treatment groups respectively. At six hours, ScvO₂ was higher in the EGDT (76% versus 59%), whereas the lactate and MODS score were reduced (p < 0.05). The EGDT group received more total intravenous fluids than the treatment group (p < 0.05) during the first six hours. At sixty days, mortality in the control (70%) and in the treament group (24%) remained significant (p=0.002).

CONCLUSIONS
This study confirms that patients with severe sepsis accompanied by lactic acidosis may display global tissue hypoxia in the absence of hypotension. Early identification and goal-directed therapy of this subgroup leads to a reduction in morbidity and mortality.

Critical Care Medicine 2006;34:2842-2843

The article from Rivers et al. published a few years ago, raised huge international enthusiasm because it was dealing with a simple principle (early goal-directed therapy and good organization) applied to a very complex and multifactorial medical problem considered as a serial killer (severe sepsis and septic shock). It was graded pretty high in the last Surviving Sepsis Campaign guidelines and is an important step of the Surviving Sepsis Campaign. No doubt that it is likely to remain an important component of the second edition of those guidelines, which will be published shortly.

Critical Care 2006;10:R80

The purpose of the present study was to measure the incidence and outcome of septic patients presenting at the emergency department (ED) with criteria for early goal-directed therapy (EGDT).

Method
This hospital-based, retrospective, observational study using prospectively collected electronic databases was based in a teaching hospital in Melbourne, Australia. We conducted outcome-blinded electronic screening of patients with infection admitted via the ED from 1 January 2000 to 30 June 2003. We obtained data on demographics, laboratory and clinical features on admission. We used paper records to confirm electronic identification of candidates for EGDT and to study their treatment. We followed up all patients until hospital discharge or death.

Results
Of 4,784 ED patients with an infectious disease diagnosis, only 50 fulfilled published clinical inclusion criteria for EGDT (EGDT candidates). Of these patients, 37 (74%) survived their hospital admission, two (4%) died in the ED, eight (16%) died in the intensive care unit and three (6%) died in the ward. After review of all ward cardiac arrests and non-NFR (‘not for resuscitation’) ward deaths, we identified a further two potential candidates for EGDT for an overall mortality of 28.8% (15 out of 52 patients). Analysis of treatment showed that twice as many (70%) of the EGDT candidates received vasopressor therapy in the ED, and their initial mean central venous pressure (10.8 mmHg) was almost twice that in patients from the EGDT study conducted by Rivers and coworkers.

Conclusion
In an Australian teaching hospital candidates for EGDT were uncommon and, in the absence of an EGDT protocol, their mortality was lower than that reported with EGDT.

Critical Care Medicine. 2006;34:943-949

Objective
To assess the impact of an algorithm defining resuscitation according to early goal-directed therapy, glycemic control, administration of stress doses of hydrocortisone, and use of recombinant human activated protein C (rhAPC) on measures of organ dysfunction and outcome in septic shock.

Design
Retrospective cohort study.

Setting
Multidisciplinary ten-bed intensive care unit of a university hospital.

Patients
Sixty patients were analyzed: 30 consecutive patients fulfilling criteria for diagnosis of septic shock, treated from September 2002 until December 2003 after implementation of a standard operating procedure (SOP) for severe sepsis and septic shock; and 30 patients with septic shock treated from January until August 2002 in the same unit, who served as controls.

Measurements and Results
Data for blood gas analysis, lactate, glucose, serum creatinine, bilirubin, white blood cells, platelets, and C-reactive protein were obtained from patient files on admission or at time of diagnosis of septic shock and at 7:00 a.m. on days 2 and 4; Sequential Organ Failure Assessment scores were calculated and 28-day survival was assessed. With implementation of the SOP, use of dobutamine (12/30 vs. 2/30), insulin (blood glucose <150 mg/dL, day 4: 26/28 vs. 13/25), hydrocortisone (30/30 vs. 13/30), and rhAPC (7/30 vs. 0/30) significantly increased, whereas volume for resuscitation and use of packed red blood cells were unaffected. Mortality was 53% in the historical control group and 27% after implementation of the SOP (p < .05).

Conclusion
The combined approach of early goal-directed therapy, intensive insulin therapy, hydrocortisone administration, and additional application of rhAPC in selected cases seems to favorably influence outcome. The implementation of a “sepsis bundle” can be facilitated by a standardized protocol while significantly reducing the time until the defined therapeutic measures are realized in daily practice.

N Engl J Med 2001; 345:1368-1377

Background
Goal-directed therapy has been used for severe sepsis and septic shock in the intensive care unit. This approach involves adjustments of cardiac preload, afterload, and contractility to balance oxygen delivery with oxygen demand. The purpose of this study was to evaluate the efficacy of early goal-directed therapy before admission to the intensive care unit.

Methods
We randomly assigned patients who arrived at an urban emergency department with severe sepsis or septic shock to receive either six hours of early goal-directed therapy or standard therapy (as a control) before admission to the intensive care unit. Clinicians who subsequently assumed the care of the patients were blinded to the treatment assignment. In-hospital mortality (the primary efficacy outcome), end points with respect to resuscitation, and Acute Physiology and Chronic Health Evaluation (APACHE II) scores were obtained serially for 72 hours and compared between the study groups.

Results
Of the 263 enrolled patients, 130 were randomly assigned to early goal-directed therapy and 133 to standard therapy; there were no significant differences between the groups with respect to base-line characteristics. In-hospital mortality was 30.5 percent in the group assigned to early goal-directed therapy, as compared with 46.5 percent in the group assigned to standard therapy (P=0.009). During the interval from 7 to 72 hours, the patients assigned to early goal– directed therapy had a significantly higher mean (+/-SD) central venous oxygen saturation (70.4+/-10.7 percent vs. 65.3+/-11.4 percent), a lower lactate concentration (3.0+/-4.4 vs. 3.9+/-4.4 mmol per liter), a lower base deficit (2.0+/-6.6 vs. 5.1+/-6.7 mmol per liter), and a higher pH (7.40+/-0.12 vs. 7.36+/-0.12) than the patients assigned to standard therapy (P<=0.02 for all comparisons). During the same period, mean APACHE II scores were significantly lower, indicating less severe organ dysfunction, in the patients assigned to early goal-directed therapy than in those assigned to standard therapy (13.0+/-6.3 vs. 15.9+/-6.4, P<0.001).

Conclusions
Early goal-directed therapy provides significant benefits with respect to outcome in patients with severe sepsis and septic shock.

Critical Care Medicine 2004; 32:S448-S450

Objective
In 2003, critical care and infectious disease experts representing 11 international organizations developed management guidelines for early goal-directed therapy that would be of practical use for the bedside clinician, under the auspices of the Surviving Sepsis Campaign, an international effort to increase awareness and improve outcome in severe sepsis.

Design
The process included a modified Delphi method, a consensus conference, several subsequent smaller meetings of subgroups and key individuals, teleconferences, and electronic-based discussion among subgroups and among the entire committee.

Methods
The modified Delphi methodology used for grading recommendations built on a 2001 publication sponsored by the International Sepsis Forum. We undertook a systematic review of the literature graded along five levels to create recommendation grades from A to E, with A being the highest grade. Pediatric considerations to contrast adult and pediatric management are in the article by Parker et al. on p. S591.

Conclusion
During the first 6 hrs of resuscitation of sepsis-induced hypoperfusion, specific levels of central venous pressure, mean arterial pressure, urine output, central venous (or mixed venous) oxygen saturation should be targeted. When central venous oxygen saturation remains low, despite achieving central venous pressure and mean arterial pressure targets, packed red blood cells or dobutamine should be considered. Increasing cardiac index to achieve an arbitrarily predefined elevated level is not recommended.

Critical Care 2005, 9:307-308 http://ccforum.com/content/9/4/307
Editorial
When assessing outcome studies, the beneficial portion of any therapeutic strategy may not be clearly identified, especially in a condition as complex as sepsis. In the randomized controlled trial conducted by Rivers and coworkers, early goal-directed therapy (EGDT) was associated with significantly improved outcomes in sepsis. The study group received a package of care that focused on early resuscitation for the first 6 hours as an inpatient. This comprised fluid, including blood, pressors and inotropes. The goals of resuscitation were based on hemodynamic variables and central venous oxygen saturation (ScvO₂). The technology used to measure this was a central venous catheter with integrated oximetry. This device is examined in this issue of Critical Care. In keeping with the style we previously adopted for technology assessment reviews, the article begins with a Q&A from the industry.

Early resuscitation in sepsis is standard practice. If the treatment effect reported by Rivers and coworkers is not due to bias in the study design, then to what part(s) of the resuscitation ‘package’ is the benefit attributable? Opinions vary regarding the contribution an oximetric catheter makes in severe sepsis. Previous studies of therapy directed by mixed venous saturation have found no similar improvement in outcome. It seems more likely to us that the timing of resuscitation is the crucial aspect rather than the technology employed.

Another aspect of the study by Rivers and colleagues that has attracted discussion is the difference in the use of blood transfusion between the groups. The use of blood to improve oxygen delivery is controversial; a liberal transfusion strategy is not beneficial in general intensive care patients and the ability of stored red cells to improve oxygen delivery acutely is known to be impaired. Finally, although blinding in a trial of resuscitation is very difficult to achieve, unfortunately the capacity for this methodological shortcoming to introduce bias remains undiminished.

In light of these considerations, we present a review, paired with the Q&A, which forms part of a process of critical review that any new health technology should be subjected to by the critical care community. In our view, we must remain critical; ScvO₂ monitoring cannot be assumed to be central to the success of EGDT. Other goals are presented in the review that are feasible and less invasive. It will take time for ScvO₂ monitoring to find its rightful place.

Critical Care 2005, 9:R764-R770 http://ccforum.com/content/9/6/R764

Introduction
Compliance with the ventilator care bundle affects the rate of ventilator-associated pneumonia. It was not known, however, whether compliance with sepsis care bundles has an impact on outcome. The aims of the present study were to determine the rate of compliance with 6-hour and 24-hour sepsis bundles and to determine the impact of the compliance on hospital mortality in patients with severe sepsis or septic shock.

Methods
We conducted a prospective observational study on 101 consecutive adult patients with severe sepsis or septic shock on medical or surgical wards, or in accident and emergency areas at two acute National Health Service Trust Teaching hospitals in England. The main outcome measures were: the rate of compliance with 6-hour and 24-hour sepsis care bundles adapted from the Surviving Sepsis Campaign guidelines on patients’ clinical care; and the difference in hospital mortality between the compliant and the non-compliant groups.

Results
The median age of the patients was 69 years (interquartile range 51 to 78), and 53% were male. The sources of infection were sought and confirmed in 87 of 101 patients. The chest was the most common source (50%), followed by the abdomen (22%). The rate of compliance with the 6-hour sepsis bundle was 52%. Compared with the compliant group, the non-compliant group had a more than twofold increase in hospital mortality (49% versus 23%, relative risk (RR) 2.12 (95% confidence interval (CI) 1.20 to 3.76), P = 0.01) despite similar age and severity of sepsis. Compliance with the 24-hour sepsis bundle was achieved in only 30% of eligible candidates (21/69). Hospital mortality was increased in the non-compliant group from 29% to 50%, with a 76% increase in risk for death, although the difference did not reach statistical significance (RR 1.76 (95% CI 0.84 to 3.64), P = 0.16).

Conclusion
Non-compliance with the 6-hour sepsis bundle was associated with a more than twofold increase in hospital mortality. Non-compliance with the 24-hour sepsis bundle resulted in a 76% increase in risk for hospital death. All medical staff should practise these relatively simple, easy and cheap bundles within a strict timeframe to improve survival rates in patients with severe sepsis and septic shock.

Critical Care 2005, 9:R687-R693 http://ccforum.com/content/9/6/R687

Introduction
Goal-directed therapy (GDT) has been shown to improve outcome when commenced before surgery. This requires pre-operative admission to the intensive care unit (ICU). In cardiac surgery, GDT has proved effective when commenced after surgery. The aim of this study was to evaluate the effect of post-operative GDT on the incidence of complications and duration of hospital stay in patients undergoing general surgery.

Methods
This was a randomised controlled trial with concealed allocation. High-risk general surgical patients were allocated to post-operative GDT to attain an oxygen delivery index of 600 ml min-1 m-2 or to conventional management. Cardiac output was measured by lithium indicator dilution and pulse power analysis. Patients were followed up for 60 days.

Results
Sixty-two patients were randomised to GDT and 60 patients to control treatment. The GDT group received more intravenous colloid (1,907 SD ± 878 ml versus 1,204 SD ± 898 ml; p < 0.0001) and dopexamine (55 patients (89%) versus 1 patient (2%); p < 0.0001). Fewer GDT patients developed complications (27 patients (44%) versus 41 patients (68%); p = 0.003, relative risk 0.63; 95% confidence intervals 0.46 to 0.87). The number of complications per patient was also reduced (0.7 SD ± 0.9 per patient versus 1.5 SD ± 1.5 per patient; p = 0.002). The median duration of hospital stay in the GDT group was significantly reduced (11 days (IQR 7 to 15) versus 14 days (IQR 11 to 27); p = 0.001). There was no significant difference in mortality (seven patients (11.3%) versus nine patients (15%); p = 0.59).

Conclusion
Post-operative GDT is associated with reductions in post-operative complications and duration of hospital stay. The beneficial effects of GDT may be achieved while avoiding the difficulties of pre-operative ICU admission.