Surviving Sepsis Guidelines 2013

The most recent iteration of Surviving Sepsis has been published in Critical Care Medicine and Intensive Care Medicine. The can be downloaded here (please click).

Below is a summary of the Guidelines:

A. Initial Resuscitation

1. Protocolized, quantitative resuscitation of patients with sepsis-induced tissue hypoperfusion (defined in this document as hypotension persisting after initial fluid challenge or blood lactate concentration ≥ 4 mmol/L).

Goals during the first 6 hrs of resuscitation:

a) Central venous pressure 8–12 mm Hg

b) Mean arterial pressure (MAP) ≥ 65 mm Hg c) Urine output ≥ 0.5 mL/kg/hr d) Central venous (superior vena cava) or mixed venous oxygen saturation 70% or 65%, respectively (grade 1C).

c). In patients with elevated lactate levels targeting resuscitation to normalize lactate (grade 2C).

B. Screening for Sepsis and Performance Improvement

1. Routine screening of potentially infected seriously ill patients for severe sepsis to allow earlier implementation of therapy (grade 1C).

2. Hospital–based performance improvement efforts in severe sepsis (UG).

 C. Diagnosis

1. Cultures as clinically appropriate before antimicrobial therapy if no significant delay (> 45 mins) in the start of antimicrobial(s) (grade 1C). At least 2 sets of blood cultures (both aerobic and anaerobic bottles) be obtained before antimicrobial therapy with at least 1 drawn percutaneously and 1 drawn through each vascular access device, unless the device was recently (<48 hrs) inserted (grade 1C).

2. Use of the 1,3 beta-D-glucan assay (grade 2B), mannan and anti-mannan antibody assays (2C), if available, and invasive candidiasis is in differential diagnosis of cause of infection.

3. Imaging studies performed promptly to confirm a potential source of infection (UG).

D. Antimicrobial Therapy

1. Administration of effective intravenous antimicrobials within the first hour of recognition of septic shock (grade 1B) and severe sepsis without septic shock (grade 1C) as the goal of therapy.

2a. Initial empiric anti-infective therapy of one or more drugs that have activity against all likely pathogens (bacterial and/or fungal or viral) and that penetrate in adequate concentrations into tissues presumed to be the source of sepsis (grade 1B).

2b. Antimicrobial regimen should be reassessed daily for potential de-escalation (grade 1B).

3. Use of low procalcitonin levels or similar biomarkers (e.g. CRP) to assist the clinician in the discontinuation of empiric antibiotics in patients who initially appeared septic, but have no subsequent evidence of infection (grade 2C).

4a. Combination empirical therapy for neutropenic patients with severe sepsis (grade 2B) and for patients with difficult-to-treat, multidrug-resistant bacterial pathogens such as Acinetobacter and Pseudomonas spp. (grade 2B). For patients with severe infections

associated with respiratory failure and septic shock, combination therapy with an extended spectrum beta-lactam and either an aminoglycoside or a fluoroquinolone is for P. aeruginosa bacteremia (grade 2B). A combination of beta-lactam and macrolide for

patients with septic shock from bacteremic Streptococcus pneumoniae infections (grade 2B).

4b. Empiric combination therapy should not be administered for more than 3–5 days. De-escalation to the most appropriate single therapy should be performed as soon as the susceptibility profile is known (grade 2B).

5. Duration of therapy typically 7–10 days; longer courses may be appropriate in patients who have a slow clinical response, undrainable foci of infection, bacteremia with S. aureus; some fungal and viral infections or immunologic deficiencies, including neutropenia (grade 2C).

6. Antiviral therapy initiated as early as possible in patients with severe sepsis or septic shock of viral origin (grade 2C).

7. Antimicrobial agents should not be used in patients with severe inflammatory states determined to be of noninfectious cause (UG).

E. Source Control

1. A specific anatomical diagnosis of infection requiring consideration for emergent source control be sought and diagnosed or excluded as rapidly as possible, and intervention be undertaken for source control within the first 12 hr after the diagnosis is made, if feasible (grade 1C).

2. When infected peripancreatic necrosis is identified as a potential source of infection, definitive intervention is best delayed until adequate demarcation of viable and nonviable tissues has occurred (grade 2B).

3. When source control in a severely septic patient is required, the effective intervention associated with the least physiologic insult should be used (eg, percutaneous rather than surgical drainage of an abscess) (UG).

4. If intravascular access devices are a possible source of severe sepsis or septic shock, they should be removed promptly after other vascular access has been established (UG).

F. Infection Prevention

1a. Selective oral decontamination and selective digestive decontamination should be introduced and investigated as a method to reduce the incidence of ventilator-associated pneumonia; this infection control measure can then be instituted in health care settings and regions where this methodology is found to be effective (grade 2B).

1b. Oral chlorhexidine gluconate be used as a form of oropharyngeal decontamination to reduce the risk of ventilator-associated pneumonia in ICU patients with severe sepsis (grade 2B).

G. Fluid Therapy of Severe Sepsis

1. Crystalloids as the initial fluid of choice in the resuscitation of severe sepsis and septic shock (grade 1B).

2. Against the use of hydroxyethyl starches for fluid resuscitation of severe sepsis and septic shock (grade 1B).

3. Albumin in the fluid resuscitation of severe sepsis and septic shock when patients require substantial amounts of crystalloids (grade 2C).

4. Initial fluid challenge in patients with sepsis-induced tissue hypoperfusion with suspicion of hypovolemia to achieve a minimum of 30 mL/kg of crystalloids (a portion of this may be albumin equivalent). More rapid administration and greater amounts of fluid may be needed in some patients (grade 1C).

5. Fluid challenge technique be applied wherein fluid administration is continued as long as there is hemodynamic improvement either based on dynamic (eg, change in pulse pressure, stroke volume variation) or static (eg, arterial pressure, heart rate) variables (UG).

H. Vasopressors

1. Vasopressor therapy initially to target a mean arterial pressure (MAP) of 65 mm Hg (grade 1C).

2. Norepinephrine as the first choice vasopressor (grade 1B).

3. Epinephrine (added to and potentially substituted for norepinephrine) when an additional agent is needed to maintain adequate blood pressure (grade 2B).

4. Vasopressin 0.03 units/minute can be added to norepinephrine (NE) with intent of either raising MAP or decreasing NE dosage (UG).

5. Low dose vasopressin is not recommended as the single initial vasopressor for treatment of sepsis-induced hypotension and vasopressin doses higher than 0.03-0.04 units/minute should be reserved for salvage therapy (failure to achieve adequate MAP with other vasopressor agents) (UG).

6. Dopamine as an alternative vasopressor agent to norepinephrine only in highly selected patients (eg, patients with low risk of tachyarrhythmias and absolute or relative bradycardia) (grade 2C).

7. Phenylephrine is not recommended in the treatment of septic shock except in circumstances where (a) norepinephrine is associated with serious arrhythmias,

(b) cardiac output is known to be high and blood pressure persistently low or (c) as salvage therapy when combined inotrope/vasopressor drugs and low dose vasopressin have failed to achieve MAP target (grade 1C).

8. Low-dose dopamine should not be used for renal protection (grade 1A).

9. All patients requiring vasopressors have an arterial catheter placed as soon as practical if resources are available (UG).

I. Inotropic Therapy

1. A trial of dobutamine infusion up to 20 micrograms/kg/min be administered or added to vasopressor (if in use) 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 MAP (grade 1C).

2. Not using a strategy to increase cardiac index to predetermined supranormal levels (grade 1B).

J. Corticosteroids

1. Not using intravenous hydrocortisone to treat adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability (see goals for Initial Resuscitation). In case this is not achievable, we suggest intravenous hydrocortisone alone at a dose of 200 mg per day (grade 2C).

2. Not using the ACTH stimulation test to identify adults with septic shock who should receive hydrocortisone (grade 2B).

3. In treated patients hydrocortisone tapered when vasopressors are no longer required (grade 2D).

4. Corticosteroids not be administered for the treatment of sepsis in the absence of shock (grade 1D).

5. When hydrocortisone is given, use continuous flow (grade 2D).

K. Blood Product Administration

1. Once tissue hypoperfusion has resolved and in the absence of extenuating circumstances, such as myocardial ischemia, severe hypoxemia, acute hemorrhage, or ischemic heart disease, we recommend that red blood cell transfusion occur only when hemoglobin concentration decreases to <7.0 g/dL to target a hemoglobin concentration of 7.0 –9.0 g/dL in adults (grade 1B).

2. Not using erythropoietin as a specific treatment of anemia associated with severe sepsis (grade 1B).

3. Fresh frozen plasma not be used to correct laboratory clotting abnormalities in the absence of bleeding or planned invasive procedures (grade 2D).

4. Not using antithrombin for the treatment of severe sepsis and septic shock (grade 1B).

5. In patients with severe sepsis, administer platelets prophylactically when counts are <10,000/mm3 (10 x 109/L) in the absence of apparent bleeding. We suggest prophylactic platelet transfusion when counts are < 20,000/mm3 (20 x 109/L) if the patient has a significant risk of bleeding. Higher platelet counts (≥50,000/mm3 [50 x 109/L]) are advised for active bleeding, surgery, or invasive procedures (grade 2D).

L. Immunoglobulins

1. Not using intravenous immunoglobulins in adult patients with severe sepsis or septic shock (grade 2B).

M. Selenium

1. Not using intravenous selenium for the treatment of severe sepsis (grade 2C).

N. History of Recommendations Regarding Use of rhAPC

A history of the evolution of SSC recommendations as to rhAPC (no longer available) is provided.

O. Mechanical Ventilation of Sepsis-Induced ARDS

1. Target a tidal volume of 6 mL/kg predicted body weight in patients with sepsis-induced ARDS (grade 1A vs. 12 mL/kg).

2. Plateau pressures be measured in patients with ARDS and initial upper limit goal for plateau pressures in a passively inflated lung be ≤30 cm H2O (grade 1B).

3. Positive end-expiratory pressure (PEEP) be applied to avoid alveolar collapse at end expiration (atelectotrauma) (grade 1B).

4. Strategies based on higher rather than lower levels of PEEP be used for patients with sepsis-induced moderate or severe ARDS (grade 2C).

5. Recruitment maneuvers be used in sepsis patients with severe refractory hypoxemia (grade 2C).

6. Prone positioning be used in sepsis-induced ARDS patients with a Pao2/Fio2 ratio ≤100 mm Hg in facilities that have experience with such practices (grade 2B).

7. That mechanically ventilated sepsis patients be maintained with the head of the bed elevated to 30-45 degrees to limit aspiration risk and to prevent the development of ventilator-associated pneumonia (grade 1B).

8. That noninvasive mask ventilation (NIV) be used in that minority of sepsis-induced ARDS patients in whom the benefits of NIV have been carefully considered and are thought to outweigh the risks (grade 2B).

9. That a weaning protocol be in place and that mechanically ventilated patients with severe sepsis undergo spontaneous breathing trials regularly to evaluate the ability to discontinue mechanical ventilation when they satisfy the following criteria:

a) arousable; b) hemodynamically stable (without vasopressor agents); c) no new potentially serious conditions; d) low ventilatory and end-expiratory pressure requirements; and e) low Fio2 requirements which can be met safely delivered with a face mask or nasal cannula. If the spontaneous breathing trial is successful, consideration should be given for extubation (grade 1A).

10. Against the routine use of the pulmonary artery catheter for patients with sepsis induced ARDS (grade 1A).

11. A conservative rather than liberal fluid strategy for patients with established sepsis-induced ARDS who do not have evidence of tissue hypoperfusion (grade 1C).

12. In the absence of specific indications such as bronchospasm, not using beta 2-agonists for treatment of sepsis-induced ARDS (grade 1B).

P. Sedation, Analgesia, and Neuromuscular Blockade in Sepsis

1. Continuous or intermittent sedation be minimized in mechanically ventilated sepsis patients, targeting specific titration endpoints (grade 1B).

2. Neuromuscular blocking agents (NMBAs) be avoided if possible in the septic patient without ARDS due to the risk of prolonged neuromuscular blockade following discontinuation. If NMBAs must be maintained, either intermittent bolus as

required or continuous infusion with train-of-four monitoring of the depth of blockade should be used (grade 1C). 3. A short course of NMBA of not greater than 48 hours for patients with early sepsis-induced ARDS and a Pao2/Fio2 < 150 mm Hg (grade 2C).

Q. Glucose Control

1. A protocolized approach to blood glucose management in ICU patients with severe sepsis commencing insulin dosing when 2 consecutive blood glucose levels are >180 mg/dL. This protocolized approach should target an upper blood glucose ≤180 mg/dL rather than an upper target blood glucose ≤ 110 mg/dL (grade 1A).

2. Blood glucose values be monitored every 1–2 hrs until glucose values and insulin infusion rates are stable and then every 4 hrs thereafter (grade 1C).

3. Glucose levels obtained with point-of-care testing of capillary blood be interpreted with caution, as such measurements may not accurately estimate arterial blood or plasma glucose values (UG).

R. Renal Replacement Therapy

1. Continuous renal replacement therapies and intermittent hemodialysis are equivalent in patients with severe sepsis and acute renal failure (grade 2B).

2. Use continuous therapies to facilitate management of fluid balance in hemodynamically unstable septic patients (grade 2D).

S. Sodium Bicarbonate Therapy

1. Not using sodium bicarbonate therapy for the purpose of improving hemodynamics or reducing vasopressor requirements in patients with hypoperfusion-induced lactic acidemia with pH ≥7.15 (grade 2B).

T. Deep Vein Thrombosis Prophylaxis

1. Patients with severe sepsis receive daily pharmacoprophylaxis against venous thromboembolism (VTE) (grade 1B). This should be accomplished with daily subcutaneous low-molecular weight heparin (LMWH) (grade 1B versus twice daily UFH, grade 2C versus three times daily UFH). If creatinine clearance is <30 mL/min, use dalteparin (grade 1A) or another form of LMWH that has a low degree of renal metabolism (grade 2C) or UFH (grade 1A).

2. Patients with severe sepsis be treated with a combination of pharmacologic therapy and intermittent pneumatic compression devices whenever possible (grade 2C).

3. Septic patients who have a contraindication for heparin use (eg, thrombocytopenia, severe coagulopathy, active bleeding, recent intracerebral hemorrhage) not receive pharmacoprophylaxis (grade 1B), but receive mechanical prophylactic treatment, such

as graduated compression stockings or intermittent compression devices (grade 2C), unless contraindicated. When the risk decreases start pharmacoprophylaxis (grade 2C).

U. Stress Ulcer Prophylaxis

1. Stress ulcer prophylaxis using H2 blocker or proton pump inhibitor be given to patients with severe sepsis/septic shock who have bleeding risk factors (grade 1B).

2. When stress ulcer prophylaxis is used, proton pump inhibitors rather than H2RA (grade 2D)

3. Patients without risk factors do not receive prophylaxis (grade 2B).

V. Nutrition

1. Administer oral or enteral (if necessary) feedings, as tolerated, rather than either complete fasting or provision of only intravenous glucose within the first 48 hours after a diagnosis of severe sepsis/septic shock (grade 2C).

2. Avoid mandatory full caloric feeding in the first week but rather suggest low dose feeding (eg, up to 500 calories per day), advancing only as tolerated (grade 2B).

3. Use intravenous glucose and enteral nutrition rather than total parenteral nutrition (TPN) alone or parenteral nutrition in conjunction with enteral feeding in the first 7 days after a diagnosis of severe sepsis/septic shock (grade 2B).

4. Use nutrition with no specific immunomodulating supplementation rather than nutrition providing specific immunomodulating supplementation in patients with severe sepsis (grade 2C).

W. Setting Goals of Care

1. Discuss goals of care and prognosis with patients and families (grade 1B).

2. Incorporate goals of care into treatment and end-of-life care planning, utilizing palliative care principles where appropriate (grade 1B).

3. Address goals of care as early as feasible, but no later than within 72 hours of ICU admission (grade 2C).

Source: Dellinger RP, Levy MM, Rhodes A, et al: Surviving Sepsis Campaign: International guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013; 41:580-637

High Frequency Oscillation – Shaken by Bad News!

oscillatorSummary: Two Papers Published Online in the NEJM, OSCILLATE and OSCAR, have failed to demonstrate that HFOV benefits patients with ARDS. In the OSCILLATE study there was an 11% increase in 28 day mortality (NNH 9). HFOV should not be used in routine management of patients with ARDS.

For the past two decades many intensivists have used an “open lung” approach to managing hypoxaemia in ARDS. This approach involves using high levels of PEEP, inverse ratio ventilation (IRV), airway pressure release ventilation (APRV) or high frequency oscillation ventilation (HFOV) – to keep severely injured lungs in a state of inflation during most of the respiratory cycle. “Open Lung” can be achieved by using high PEEP and small tidal volumes, or moderate levels of PEEP and long inspiratory times. In either case mean airway pressure increases. The most sophisticated method of using PEEP involves the construction of pressure volume curves and setting the PEEP above the lower inflection point. To date, the high PEEP approach has neither been proven to be better or worse than the incremental PEEP approach based on fiO2. However a 2010 meta-analysis has suggested that high PEEP may be beneficial in ARDS. With long inspiratory times oxygenation occurs principally during inspiration rather than expiration; functionally ventilation occurs on the expiratory limb of the volume-pressure curve.
There is good physiologic reasoning behind the open lung approach. Severe ARDs is characterized by massive atelectasis, increased lung water and pleural effusions; functional residual capacity is obliterated. As most gas exchange occurs in expiration, and end expiratory lung volumes are lost, open lung approaches use the inspiratory reserve volume. Further, it is widely believed that phasic opening and closing of injured lung units and uninjured adjacent units results in ventilator induced lung injury (atelectrauma). Open lung approaches prevent atelectrauma. The majority of ICUs utilize conventional ventilator strategies such as pressure support, pressure control (or bilevel) or volume assist-control in early ARDs. However, in patients with severe and refractory hypoxic respiratory failure, units differ between using high PEEP and so called “advanced” modes to maintain oxygenation. Despite the conceptual attractiveness of IRV, APRV and HFOV there has always been an evidence gap in support of these modes: nobody knows how much the lung stretches. There is no easy way to measure end inspiratory lung volumes and hence to evaluate the risk of volutrauma. Proponents of “advanced” modes will argue that absence of evidence does not mean absence of efficacy: clearly open lung modes of ventilation improve oxygenation – so this must be good. However, we have decades of data suggesting that prone positioning improves oxygenation, but not outcomes.

After a long wait, we have now seen the publication of two studies on HFOV – the multi-national OSCILLATE study, and UK based OSCAR trial. The results are not good.


Background and Methods: This was a multi center trial of 38 hospitals in Canada, the United States, Saudi Arabia, Chile, and India from July 2009 thru August 2012. Patients were eligible for inclusion if they had had an onset of pulmonary symptoms within the previous 2 weeks (i.e. this was an acute illness), had been intubated, had hypoxemia defined as a PaO2/FiO2 (PF) ratio of ≤200, with an FiO2 of ≥0.5), and had bilateral infiltrates on CXR. These criteria must have been met within the previous 72 hours. The authors were careful – patients who met criteria were put on pressure control ventilation, TV 600ml, FiO2 0.6 and PEEP 10cmH2O. If, after 30 minutes, the PF ratio was still below 200, the patients were enrolled in the trial. Patients were randomized to HFOV or conventional ventilation (CV). The patients were remarkably well balanced at baseline – and very sick – with mean Apache II scores in both groups of 29.

Technique: a recruitment maneuver was performed initially (40cmH2O for 40 seconds) then HFOV was commenced at a mean airway pressure of 30 cmH2O, adjusted to keep the PaO2 between 55 to 80 mm Hg (7.3 to 10.5 kPa). The frequency was adjusted to keep the pH above 7.2. Once mean airway pressure (mPaw) dipped below 24 cmH2O conversion to CV was considered; if mPaw went below 20cmH2O – conversion was mandatory. The CV group received a recruitment maneuver, then pressure controlled ventilation with TV 6ml/Kg and PEEP adjusted according to protocol. Initial PEEP was 20cmH2O. Patients could also receive volume assist control or pressure support ventilation. For patients with good compliance and gas exchange (presumably during the weaning phase), the investigators did not set limits for tidal volumes. A weaning protocol governed both limbs.

Results: the primary outcome was in-hospital mortality. The study was stopped early because of increased risk in the study group. At the time of termination, 571 patients had been enrolled, of whom 548 had undergone randomization: 275 to the HFOV group and 273 to the control-ventilation group. A total of 129 patients (47%) in the HFOV group, as compared with 96 patients (35%) in the control group, died in the hospital (relative risk of death with HFOV, 1.33; 95% confidence interval, 1.09 to 1.64; P=0.005) – an absolute risk INCREASE of 12%! This was independent of any other risk factor other than HFOV and was consistent at 28 days. Indeed 28 day mortality was 40% in HFOV group (which is not particularly bad) versus 29% (which is really excellent) in the conventional ventilation group – absolute risk increase 11% – number needed to injure 9. The duration of hospital stay for survivors was, on average, 5 days fewer in the CV group (although statistical significance is not reported) 25 versus 30 days.

Did HFOV have a physiological effect? Yes – patients almost immediately needed more vasopressors, more sedation and more neuromuscular blockade. There were fewer cases of refractory hypoxaemia but this had no statistically significant impact on outcomes.

My Impression

So, what to make of this study? Firstly, let us be clear – this was an excellent study (that we were all awareards of) performed by experts in the field of mechanical ventilation, who have a long track record of publication and interest in HFOV. They were not expecting the published results. This is a significant setback to our understanding of ARDS and interventions to rescue patients from severe hypoxaemia. Among my critical care colleagues, there are those of us who are proponents of ARPV and those of us who use HFOV. The published results ask as many questions about APRV as they do about oscillation. Can the worse outcomes be explained by increased doses of vasopressors and more sedation? No, I don’t believe it to be so: it is inconceivable that increased drug utilization could explain an 11% risk increase at 28 days. It is more likely that HFOV exacerbates ventilator induced lung injury (VILI).


The OSCAR study took place in the UK and included nearly 800 patients that had PF ratio <200 and wereOscar randomized to HFOV or CV. There was no significant between-group difference in the primary outcome, death at 28 days, which occurred in 166 of 398 patients (41.7%) in the HFOV group and 163 of 397 patients (41.1%) in the conventional-ventilation group (P=0.85). In other words – HFOV did not benefit these patients. Patients enrolled in this study had an average Apache II of 21 – lower than Oscillate – but had equally bad gas exchange when recruited. Although there was an increase in the use of muscle relaxants, there was no evidence of increased vasopressor requirements.

Of interest, patients in OSCAR had similar (although worse) 28 day mortality rates to those in the HFOV arm of the OSCILLATE study. It is worth looking at the LOV and EXPRESS trials for comparison. The EXPRESS trial had slightly older patients (60y both groups) with better gas exchange – PF ratio 143 and 144. Twenty eight day mortality was 31.2% and 27.8% (lower in high PEEP approach but not significant). The LOV study had patients in the same age range as both of these studies, but the PF ratios were significantly higher (144 in both groups); Apache II scores were 24 and 25 (patients were sicker than OSCAR). Mortality rates for all cause in hospital were 36.4% and 40.4% (again not significant). The lower end outcome is similar to the conventional group (and indeed had similar vent strategy to that group) in OSCILLATE. This suggests that the better outcomes in the conventional group in OSCILLATE accurately reflect true outcomes, and that the 28 day mortality in the LOV trial over-estimates outcomes at hospital discharge. But, can the difference in gas exchange really explain why the outcomes in OSCAR, in the conventional group at least, were 10% worse than EXPRESS? I don’t know – but comparing OSCILLATE to OSCAR – a 29% 28 day mortality (similar to LOV) is substantially lower than the 41% in the UK trial. These data suggest that the conventional group in that study did worse than expected. And, if this were the case, then HFOV was harmful in the OSCAR study too: the mortality rate for HFOV was essentially the same in both studies. Ok that might be conjecture – but take my point: a 41% mortality rate for ARDS is very high in the setting of a randomized controlled trial. For example, in the original ARMA trial the mortality rate in the control group (high TV) was 39.8% versus 31%; PF ratios 138 and 134. In the ALVEOLI trial the mortality rates were 24.9% (high PEEP) and 27.5%; PF ratios were 165 and 154. I have long argued that many of the patients in the NIH studies probably didn’t have ARDS – but the outcomes in OSCAR are the worst published in a multi center trial since the control group in Aries. Whatever way you look at it – this is all BAD NEWS for HFOV.

HFOV – is it safe?

One striking thing about these studies is how much the conflict with a previous meta-analysis of previously published papers. In that paper eight randomized controlled trials (n=419 patients) were included; the majority of patients had ARDS. Patients on HFOV had better oxygenation and reduced mortality (risk ratio 0.77, 95% confidence interval 0.61 to 0.98, P=0.03; six trials, 365 patients, 160 deaths). These results conflict directly with the outcomes of OSCILLATE and OSCAR: it is scary how meta-analysis of small studies (publication bias) can be misleading.

So, is it time to wrap up your oscillator and consign it to the ventilator graveyard? For ARDS – for routine practice – I think so.

1-forward-2-backFor rescue therapy or as a bridge to ECMO – HFOV may still have a role. Oscillation remains a useful therapy for broncho-pleural fistula and perhaps for severe lung contusion. But in other settings – I believe – use with extreme care. Is it time for a complete re-evaluation of open lung approaches in ARDS? Perhaps so – certainly before we put patients on extreme IRV modes (such as APRV) or HFO we should ask – “have I maxed out my options with conventional ventilation?”
One Step Forward – Two Steps Back.

Transfusion Strategy – Think Restrictive

nejm_transf_1.2013A half generation ago, the TRICC trial (here) suggested that routine blood transfusion in critically ill patients did not confer benefit if the haemoglobin level was above 7g/dl. This resulted in a evidence based paradigm for lower transfusion triggers. The problem was – how do you deal with the bleeding patients?
A recent study in NEJM (here) looked at liberal versus restrictive transfusion practices on patients admitted with gastrointestinal bleeding.

921 patients with severe acute upper gastrointestinal bleeding were included in the study: and 461 of them were randomly assigned to a restrictive strategy (transfusion when the hemoglobin level fell below 7 g per deciliter) and 460 to a liberal strategy (transfusion when the hemoglobin fell below 9 g per deciliter). Randomisation was stratified according to the presence or absence of hepatic cirrhosis.

Substantially more patients in the liberal strategy group received transfusion: 395 (85%)  versus 236  (49%) liberal versus restrictive (P<0.001). The conventional wisdom would hold that greater oxygen carrying capacity in the liberal group would result in better outcomes. The null hypothesis would be that there was no difference. However, the patients in the restrictive group had BETTER OUTCOMES. The hazard ratio for 6 week mortality was 0.55; 95% confidence interval [CI], 0.33 to 0.92; P=0.02) [with HR a number of <1 reflects benefit, >1 reflects injury]. The absolute risk reduction was 4% (5% restrictive, 9% liberal p = 0.02; NNT 25). In addition, patients in the liberal strategy group had a 6% absolute increase (number needed to injure 16; (P=0.01) ) in the risk of further bleeding.
There was an absolute risk reduction of adverse events of 8% in the restrictive group (NNT 12; p = 0.02). Restrictive transfusion also resulted in better survival in patients with peptic (gastric or duodenal) ulcers, and those with mild to moderate cirrhosis.

Why would bleeding patients do better if transfusions are witheld? There are many potential reasons: 1. The concept of damage control resuscitation: teleologically we have evolved to handle hypovolaemia and can survive considerable blood loss. Blood transfusion without source control may cause clots to destabilise and further bleeding to occur. 2. Blood is immunosuppressive: patients who are transfused are at elevated risk of infectious complications. 3. In this particular study patients in the liberal transfusion group had higher portal pressures and were more likely to rebleed (but so too were patients with peptic ulcers). 4. Transfusion may result in volume overload, abdominal compartment syndrome, myocardial ischaemia and transfusion related lung injury.

What are the implications of this study. Approach with caution! This study does not license clinicians to withhold blood from ex-sanguinating patients. Nor does it prove anything about transfusion in the setting of non gastrointestinal blood loss. However, it does provide us with further information about the safety and implications of blood transfusion in a specific setting. Allied with accumulating data detailing the hazards of colloid transfusion, adverse outcomes associated with crystalloid over-resuscitation, and the ongoing controversy regarding albumin – one has to wonder where we are with fluid resuscitation. Remembering that red cell transfusion is a key component of the Rivers’ surviving sepsis protocol, one wonders if this is the first real nail in the coffin for that approach.

Comments are welcome here.

Is it time to re-evaluate core concepts of Neuro-Intensive Care?

Over the past 2 or 3 decades a variety of technologies have been introduced into the clinical care of the brain injured patient – intraventricular ICP monitoring devices,SjVO2, brain tissue oxygen devices, microdialysis, xenon flow scanning, etc. However, compared with general critical care, the evidence base for protocols based on the utilization of these technologies is poor. There are 3 clinical approaches to managing the patient with traumatic brain injury – an ICP based strategy (the intracranial pressure is targeted at below 20mmhg), a CPP based strategy (cerebral perfusion pressure is targeted above 60mmhg = MAP-ICP) and an anti-adrenergic strategy (the “Lund” approach) that strives to reduce cytotoxic cerebral oedema by administering opioids, beta blockers etc. Many NICUs combine an ICP and a CPP strategy such that patients are administered vasopressors and osmotic diuretics simultaneously. To an outsider this is frequently puzzling, as the major cause or raised ICP is both cerebral oedema and increased blood flow. Hence there is a constant argument about hyperaemic versus hypoaemic brain injury – too much versus too little flow. How do you decide? Also, there is concern that ICP does not monitor global intracranial pressure, but merely a compartment pressure in that part of the brain in which the bolt or catheter has been inserted. Although it is claimed that ICP monitoring is a global standard of care for the management of the brain injured patient (TBI plus GCS<8), clearly this presumes that such patients are admitted to a hospital that can insert ICP measurement devices, and can cope with complications. However, as we are all very aware in Ireland, neurosurgery and neuro-trauma tends to be located in superspecialist centres, remote from where many trauma patients are initially admitted, and in our case – bed capacity in those centres is severely limited. Many patients with TBI are cared for in general ICUs in Ireland without ICP measurement devices. Anecdotally, they appear to be doing pretty well: could it be that ICP monitors don’t make a huge difference.

To do a study of ICP monitors in advanced healthcare systems would be problematic – how could you get IRB approval, in the USA, for example? Despite the appearance of equipoise of opinion, “standards are standards”. Of course, bleeding patients with fevers was a standard of 2,000 years. I had despaired whether or not a proper randomised controlled trial of ICP monitoring would be performed. No longer – here it is (click here pdf available here).

Chestnut and colleagues in this weeks NEJM noted: “The identification of a group of intensivists in Latin America who routinely managed severe traumatic brain injury without using available monitors and for whom there was equipoise regarding its efficacy eliminated that ethical constraint and led to the implementation of the randomized, controlled trial described here.” So, in Equador and Bolivia, the Benchmark Evidence from South American Trials: Treatment of Intracranial Pressure (BEST:TRIP) trial, was performed. The primary hypothesis was that “a management protocol based on the use of intracranial-pressure monitoring would result in reduced mortality and improved neuropsychological and functional recovery at 6 months. Our secondary hypothesis was that incorporating intracranial-pressure monitoring into the management of severe traumatic brain injury would have benefits for the health care system, including a reduced risk of complications and a shorter ICU stay.”

To be included in the study, patients had to be older than 13 and have a GCS of 3 8 at the time of enrollement. The study was a multicenter, parallel-group trial, with randomized assignment to intracranial-pressure monitoring (the pressure-monitoring group – ICP with and intraparenchymal bolt) or imaging and clinical examination (the imaging–clinical examination group – GEG ). Essentially, the control group were managed conservatively, scanned several times and examined carefully – protocol . 324 patient were enrolled and the study ran for 3 years.

“There was no significant between-group difference in the primary outcome, a composite measure based on percentile performance across 21 measures of functional and cognitive status (score, 56 in the pressure-monitoring group vs. 53 in the imaging–clinical examination group; P=0.49). There was no difference in 6 month mortality (39% in the ICP group and 41% in the control group (CEG) (P=0.60)). The median length of stay in the ICU was similar in the two groups (12 days in ICP and 9 days in the imaging–CEG; P=0.25). Although aftercare from TBI in these countries is clearly weak, and 6 month outcomes were relatively poor, 14 day outcomes were comparable with those in wealthy countries, and there was no difference between the groups at that stage either.

Surprisingly, the CEG group received more hypertonic saline, barbiturates and hyperventilation than the ICP group: I can’t quite figure out why – perhaps normal range ICP reassured that clinicians looking after those patients. The interventions in question were part of the protocol.

So, where does this leave us: is the ICP bolt the Swan Ganz catheter of the 2010s? Or does this study show that monitors do not improve outcomes, algorithms that use them appropriately do?

My own opinion – I believe this study at least casts doubt on arbitrary guidelines that continue to accumulate as a means of controlling clinicians clinical practice. It reinforces the importance of clinical examination alongside clinical monitoring, and emphasises the importance of having good doctors at the bedside looking at their patients (as opposed to the telemedicine concept of decision making based on measured data rather than clinical signs). It also emphasises the importance of not over sedating patients, and hence obliterating clinical signs, and slowing recovery. Is it the beginning of the end for ICP monitoring – unlikely, but at least it might row back a little on the “paint by numbers” approach to critical care that has become prevalent over the past decade or so.

EUSOS follow up – is it the beds?

Over the next few months I am sure that the real reasons for the comparatively poor outcomes of Irish patients in the EUSOS study will emerge. In the meantime, we can only guess the reasons. Aside from blaming surgeons for poor patient selection (which is suspiciously convenient), case volume may be a problem, the time of day (exhaustion), the amount of emergency surgery (including case volume) or the issue may lie in our own backyard – in the availability of beds for high risk postoperative patients. Emergency surgery patients, in particular, do poorly.

A US study of 25,710 nonemergency colorectal resections performed at 142 hospitals reported a 1.9% (492 patients) mortality rate. For emergency colorectal resection the mortality rate was 15.3% (780 of 5,083 patients). Fifty percent of emergency surgery patients had at least 1 complication versus 24% of elective surgery patients. This is horrifying.

The first report of the UK emergency laparotomy network (here), published in the BJA, presents similar mortality data. As a guide, mortality rates for major elective general surgery have been reported as follows: colorectal resection – 2.7%,  oesophagectomy – 3.1%, gastrectomy – 4.2% and liver metastasis resection – 1%. In this study (data from 1853 patients were collected from 35 NHS hospitals) the unadjusted 30 day mortality was 14.9% for all patients and 24.4% in patients aged 80 or over.

We are aware that emergency surgery patients come in at all hours of the night and are frequently operated on by junior doctors. The time of day was an issue (table below) – 30 day mortality was 50% higher if surgery took place between midnight and 8am. Obviously confounders may be present – surgeons may only take the sickest patients to theatre at night, and this may represent selection bias.

Time of day* n Consultant anaesthetist present (%) Consultant surgeon present (%) 30 day mortality (%)
08:00–17:59 1044 75.2 80.8 14.2
18:00–23:59 442 54.8 67.7 17.8
00:00–07:59 152 40.8 61.8 20.3

Bad outcomes occurred for patients admitted under a medical service who actually had a surgical problem, increasing age, increasing ASA physical status.

What about beds? “Of the patients who were felt to need intensive care immediately after surgery, 99% were transferred to a level 3 bed. Similarly, 89% of those who were judged to require a high-dependency bed received this level of care, with a further 4% receiving level 2 care in an ICU bed. Mortality in patients returning to the ward (level 1) was 6.7%, HDU 10.1%, and ICU 30.7%. 2.2% of patients were cared for after operation in an extended recovery area (presumably because there was no HDU bed available), and this group had a mortality of 13.5%. For the group of patients aged 60 or greater, and of ASA III or more (∼50% of all patients), 22% returned to the general ward after operation and had a mortality of 17.8%.” One must presume that this 22% represented at least part of the 11% that didn’t get the needed HDU beds. Hence, one could crudely argue that the patients that needed HDU beds but didn’t get them had an absolute mortality risk increase of 7.7% (the authors do not give us sufficient data to make direct comparisons, but more than 50% of patients were >60y and ASA III or greater). The overall mortality for patients sent to a regular ward was 6.7%, which appears to be very high when compared with data from general elective surgery (above). However, a recent study of all 160,920 patients who underwent bowel resection for colorectal cancer between 1998 and 2006 in the English NHS reported a mortality rate of 6.7%

These data at least suggest that lack of availability of a HDU/ICU bed significantly increases the risk of poor postoperative outcomes for emergency surgical patients.

The utilization of critical care services has been known to be suboptimal for many years. A previous study, published in Anaesthesia (here) looked at 26000 patients undergoing surgery in an NHS trust: “only 852 (35.3%) high-risk patients were admitted to a critical care unit at any stage after surgery. Of 294 high-risk patients who died, only 144 (49.0%) were admitted to a critical care unit at any time and only 75 (25.6%) of these deaths occurred within a critical care area. Mortality rates were high amongst patients discharged and readmitted to critical care (37.7%) and amongst those admitted to critical care following initial postoperative care on a standard ward (29.9%).” So, inadequate numbers of ICU/HDU beds are associated with poor outcomes, and early discharge (presumably for bed pressure) and readmission is associated with 1/3 of patients dying.

Ireland has a similar number of critical care beds per 100,000 population (6.5/100,000) to the UK (6.6/100,000). In a recent pan European study conducted by Andy Rhodes (here), Ireland ranked 26th out of 31 (UK was 25th) in critical care bed numbers per 100,000. The European average was 11.5. Overall, Ireland ranked 28th/31 for number of acute care beds and  23rd out of 31 for ICU beds as a % of acute care beds. So, we have very few beds for sick patients, and of these very few of them are critical care beds. Ireland spends 7.2% of GDP on healthcare (15th/31) and has the 6th highest GDP in proportion to ICU beds. In other words – we spend very little money comparatively on critical care compared with Europe. This might reflect the fact that we have the 2nd youngest population in Europe (10.4% are 65 or older).

In summary – is lack of critical care beds a likely factor for Irelands poor showing in EUSOS: almost certainly. Do these studies fully explain the difference – no! Unfortunately, the OR death was still 2.6 times the UK with a similar number of ICU/HDU beds. It could be argued that the bed numbers are inflated in Ireland, due to poor distribution between hospitals – community hospitals have underused ICU beds, referral centers have inadequate capacity. But that is another discussion….

24 hour Intensivist Presence – desirable? Maybe. Efficient, Economic and Effective – Unlikely

Few issues have been more controversial in the past 20 years than the implementation of the intensivist model. Fundamentally this involves delegation of primary responsibility for critically ill patients to a narrow group of clinicians, whose primary training may be in an entirely different specialty. Hence, surgical patients may be managed by internists, and medical patients may be managed by anesthetists. I like to think of intensivists as coordinators of patient care, experts at resuscitation, who pay meticulous attention to detail and careful users of resources. As a result, each organ system does not have it’s own consultant, and medicines, interventions and tests are reduced, saving the institution a lot of money and resources.

Whether or not intensivists improve patient outcomes, versus primary medical or surgical teams rounding on patients, remains controversial. I have written about this in detail elsewhere (here subscription needed).  To summarize: daily rounds by an intensive care specialist improve outcomes in high risk surgical patients; intensive care teams (multidisciplinary) improve outcomes, as does the presence of a ICU medical director who sets standards. An article in Annals of Internal Medicine (conducted by well known intensivists) found that, in a study of >100,000 patients, critically ill patients managed by intensivists had worse outcomes (here). Patients managed by critical care physicians were sicker, had more procedures, and had higher hospital mortality rates than those managed by other physicians. I have always found this article confusing – for example in the non-intensivist model there were hospitals that had critical care fellows but no intensivist! The assumption that leads to the headline (“intensivists kill patients”), is that SAPS II is a good predictor of mortality and that adjustments based on SAPS II can separate out patients. If SAPS is not so good, then adjustments for severity of illness are meaningless. Also, there were significantly more patients transferred from other hospitals and more patients ventilated on admission in the CCM (intensivist) model. This suggests lead time bias: patients with similar severity of illness scores on admission to ICU that have been pre-resuscitated or transferred have worse outcomes.

The Irish government clearly believe in the intensivist model, as they seem to think that having us present in the ICU 24/7 will improve outcomes and save lots of money. In today’s Irish Times:

For the first time, consultants in areas such as emergency medicine, intensive care, neonatology and obstetrics will be rostered on a 24-hour basis, working eight-hour shifts. Dr Reilly has said the proposals could save up €200 million.” (article here). I don’t know how the geniuses in the Department of Health have come up with this number, but it is complete fiction. In addition, for a Hospital to provide 24 hour consultant in house cover for ICU, I calculate that this would require approx €1 million a year in direct salary costs (5 FTEs to cover around the clock plus 2 or 3 more to cover their daytime assignments – remember the EWTD applies to consultants as well). This may appear insignificant compared with the staggering savings that they are anticipating – but there is no systematic proof that over investigation (where available and it is not) at night, and over treatment (with what?) at night and bad decision making, by registrars, is costing the health system a fortune. In fact – there is not a single study published anywhere ever that shows that having a consultant intensivist present for patient resuscitation improves outcomes. Outcome improvement has been demonstrated in scenarios where patients have received timely fluids and antibiotics, and subsequent care with ventilator strategy, sedation and mobilization. Has anyone ever studied the 24 hour intensivist model? Yes they have….

A study in the Lancet in 2000 suggested that 24 hour availability of intensivists (the current model in ALL Irish level 3 ICUS) significantly improved outcomes (here). A group from Saudi Arabia claimed the 24/7 staffing led to similar mortality out of hours as within weekday hours (here) proving – well nothing. A nice pro-con debate on this topic can be read in Critical Care (here). A passionate plea for 24/7 coverage can be read in the “blue journal” (here). A core discussion point is that patients that are admitted out of hours (9-5 Monday to Friday) appear more likely to die. This assumes that worse outcomes are due to lack of consultant staffing in the ICU rather than confounders like: patient was getting sick, but no GP available, no elective surgery admitted out of hours, fewer investigations (radiology) available out of hours, patients on wards not being seen by primary care team out of hours etc. In other words, it may be the health system rather than the absence of continuous critical care consultant staffing that is at fault. A study from Paris suggested that out of hours admission patients did better! (here). A US study suggested no difference (here). Indeed, even in July changeover season, mortality is not greater (here). Moreover, papers that claim cost savings tend to massage their data (here).

In the NEJM in May 2012, a group from Pittsburgh looked at night time physician (intensivist) staffing in ICU versus outcomes in North America (article here). What the study showed, in a nutshell, was if the hospital had an intensivist and a critical care team during the day, having a consultant present, on site, at night made no difference to outcomes (our current model in Ireland). However, in hospitals where there was no critical care team during the day (low intensity staffing), having an intenisivist at night improved outcomes [I am still trying to figure out what kind of ICU would pay a consultant at night but not during the day – perhaps they were covered by Tele-ICU]. Also, having any doctor dedicated to the ICU at night (a resident) improved outcomes – very much our model in Ireland.

So, before we are forced to embrace 24/7 cover perhaps it is worth questioning why and for what benefit. I am not suggesting that there should not be 24/7 anesthesia, EM  or obstetrics (where you would anticipate fewer lawsuits, I presume) coverage, I am just relaying the best current evidence, which is that expending 5 FTEs worth of staff to cover 24/7 in adult ICU is not supported by best available evidence.

At last – Chloride is nephrotoxic

For years I have been trotting around the world telling everyone that NaCl 0.9% is evil, because each litre delivers 50mmol of HCL and chloride is nephrotoxic. This belief has come from a series of studies in volunteers (reduced GFR, reduced splanchnic perfusion, reduced cortical blood flow) and observations (increased contrast nephropathy with NaCl versus NaHCO3. I suggested that the CHEST trial failed to prove that HES was dangerous because the control fluid was saline. But where was the real proof of nephrotoxicity.
Here it is in JAMA (click here).

A group in Melbourne, Australia, performed a sequential patient cohort study during 2 time periods: in phase 1 any IV fluid could be used; in phase 2 (the following year), chloride rich fluids were unavailable, so balanced salt solutions only could be prescribed.

Chloride administration fell considerably: from 694 to 496 mmol/patient from the control period to the intervention period. Patients in the chloride rich period had significantly worse renal outcomes: the mean serum creatinine level increase while in the ICU was 22.6 μmol/L (95% CI, 17.5-27.7 μmol/L) vs 14.8 μmol/L (95% CI, 9.8-19.9 μmol/L) (P = .03), the incidence of injury and failure class of RIFLE-defined AKI was 14% (95% CI, 11%-16%; n = 105) vs 8.4% (95% CI, 6.4%-10%; n = 65) (P <.001), and the use of RRT was 10% (95% CI, 8.1%-12%; n = 78) vs 6.3% (95% CI, 4.6%-8.1%; n = 49) (P = .005). In other words – patients given balanced chloride fluids had a 3.7% reduction in the risk of needing dialysis (NNT <30). As you would expect, there was no difference in mortality figures.

The accompanying editorial can be read here.

No I won’t do it and here is the proof!

As a junior doctor how many times were you called to replace an iv catheter on a veinless patient because with was 3 days old (and “hospital policy” and all that). There was no point asking to see the evidence on which this “policy” was based. Whatever! – here is the counter evidence, and it is in the Lancet (here).

The study in question was a multicentre, randomised, non-blinded equivalence trial recruited adults (≥18 years) with an intravenous catheter of expected use longer than 4 days from three hospitals in Queensland, Australia in 2008-09 (why so long to publish?). There were 3283 patients randomised (5907 catheters- 1593 clinically indicated; 1690 routine replacement).

The mean time the iv cannulae lasted when they were in situ on day 3 was 99 h (SD 54) when replaced as clinically indicated and 70 h (13) when routinely replaced. In other words – not routinely changing the catheter resulted in it being in place for 1.25 extra days. Phlebitis occurred in 114 of 1593 (7%) patients in the clinically indicated group and in 114 of 1690 (7%) patients in the routine replacement group: ABSOLUTELY NO DIFFERENCE, NONE, STOP ASKING ME LEAVE ME ALONE!

So, if the iv site looks ok – it is ok. Don’t go prodding the patient.

Just when you thought it was unsafe….HES again!

A couple of weeks ago I announced the imminent death of colloid. Now it’s back with another “Safe” trial (known as CHEST) from our colleagues in Australia and New Zealand (here). The study enrolled a colossal number of patients (7000) to either isotonic saline (IS) or Voluven (R). This is a 130/0.4 tetrastarch in isotonic saline. I now understand the kerfuffle over the 6s trial (of tetraspan) that mislabeled 130.42 in balanced salt as 130/0.4 (read here). The paper should be subtitled: “ours – the starch that doesn’t kill!” Perhaps…
The authors randomly assigned 7000 patients who had been admitted to an intensive care unit (ICU) in a 1:1 ratio to receive either 6% HES with a molecular weight of 130 kD and a molar substitution ratio of 0.4 (130/0.4, Voluven) in 0.9% sodium chloride or 0.9% sodium chloride (saline) for all fluid resuscitation until ICU discharge, death, or 90 days after randomization. The patients were permitted 50ml/kg HES per day and then were given saline. Similar to the SAFE (albumin) trial, clinicians were permitted to resuscitate patients according to their own goals and preferences.
The primary outcome was death within 90 days. Secondary outcomes included acute kidney injury and failure and treatment with renal-replacement therapy.
There was no mortality difference. A total of 597 of 3315 patients (18.0%) in the HES group and 566 of 3336 (17.0%) in the saline group died (relative risk in the HES group, 1.06; 95% confidence interval [CI], 0.96 to 1.18; P=0.26). There was no significant difference in mortality in six predefined subgroups. Renal-replacement therapy was used in 235 of 3352 patients (7.0%) in the HES group and 196 of 3375 (5.8%) in the saline group (relative risk, 1.21; 95% CI, 1.00 to 1.45; P=0.04).
HES was associated with less renal injury than saline, by RIFLE criteria, but post hoc creatinine and urinary output were worse for HES In the HES and saline groups, renal injury occurred in 34.6% and 38.0% of patients, respectively (P=0.005), and renal failure occurred in 10.4% and 9.2% of patients, respectively (P=0.12). There was a 1.2% absolute increase in the risk of needing renal replacement therapy (p<;0.5) in the HE’S group.
HES was associated with significantly more adverse events (5.3% vs. 2.8%, P<;0.001). These included itching, skin rash and “other” (not explained).

A few comments: the mortality rate for a critical care study was astonishingly low, suggesting that the addition of surgical patients (42%) and some entry restrictions may have biased the study [Of the 7000 patients 2,876 were admitted from the operating room]. Almost 10% of patients came from another hospital. Only 1 in 4 came from the emergency department. So there is likely lead-time bias (incidentally, this distribution is near identical to the 6S study. It is highly unlikely that the majority of patients received, exclusively, one of these investigation fluids prior to ICU admission. Patients were in the ICU for 10 or 11 hours prior to randomization: the “golden window”. The patients should have been resuscitated by this stage. This is suggested by the almost ludicrously small amount of fluid that patients received day 0 (see below).

As expected HES patients received less fluid early on, but this did not translate into better outcomes. What is surprising is how little fluid the patients received in the first 24 hours (1500ml to <;2000ml net fluid balance). Patients received between 1000ml (HES) and 1500ml (IS) in addition to study fluids. In fact they seem to have gotten a lot more non study fluid than study fluid. This is presumably due to the 50ml/kg limit (400ml for an 80kg patient). As the on study fluid of choice was IS, this was really a crystalloid plus colloid versus crystalloid study. Indeed patients almost exclusively received IS
It is remarkable how little fluid the patients accumulated over the first 3 days (by the end of day 3 the IS group appear to have a net negative balance). What ever way you look at it, patients received significantly less fluid than in the 6S study (nearly 6L day 1). I return to my previous observations: nearly 50% surgical patients, with resolving stress responses, patients probably already resuscitated before randomized to the study.

It would have useful to know the electrolyte and acid base status. These patients all received a lot of chloride: what proportion of the had hyperchloremic acidosis?

It is very hard to make anything of the renal function tests in this study. On first sight the 36% rate of renal dysfunction at baseline was similar to 6S. But Scandanavian patients were significantly sicker. They had a mortality rate of 43-50%, consistent with other sepsis trials (such as VISEP). RRT use in the 6S study was 16% in the Ringer’s acetate group versus 5.8% in the IS group in this study. So I would be inclined to ignore RIFLE numbers and consider “real” kidney injury to be represented by the need for RRT.

So, how to evaluate this study? Does this study demonstrate the safety of HES in critical illness? No, it just shows that HES doesn’t increase mortality versus isotonic saline. They may be equally bad. Does this paper conflict with the 6S study? Only 30% of patients in the study were septic, the mortality was substantially lower in this study and it is likely that HES worsens outcomes in patients that require more of it (i.e. sicker patients). The onus of proof is on the intervention: HES demonstrates no mortality advantage over crystalloid, it may worsen outcome, it may be associated with more organ (particularly kidney) dysfunction. I am less likely to use these products in ICU. However, there is still a small argument for colloid administration in the peri operative period based on a series of oesophageal Doppler studies (from the UK). It is highly unlikely that 500ml HE’S will harm a patient. However, I don’t quite see the point: HES is expensive compared with crystalloid and only appears to have a marginally better volume expanding effect: why take the risk without clear benefit.
I presume some clever scientist will take this, the 6S and other crystalloid-colloid studies and inform us about all of the residual questions in a nice meta-analysis. In the near future, it would be helpful if the CHEST investigators would give us data on chloride levels and acid-base status. Perhaps their next study should be to compare isotonic saline to balanced salt solutions.
Finally, congrats again to the ANZICS trial group for showing the rest of us what can be done.