December 2011 Critical Care Journal Club

Reference as: Raschke RA. December 2011 critical care journal club. Southwest J Pulm Crit Care 2011;3:173-6. (Click here for a PDF version of the journal club)

After a long intermission, critical care journal club is back! There really are some impactful articles to discuss this month, and the fellows did a great job reviewing them.  As always, we appreciate the faculty who participated in the discussion: Drs. Gerkin, Robbins, Bajo, and Khazin.

Amir Qassem et al.  Venous thromboembolism prophylaxis in hospitalized patients: A clinical practice guideline from the American College of Physicians. Ann Intern Med 2011;155:625-632. Reviewed in conference by Josh Jewel and Henry Leudy.  (Click here for PDF version of manuscript)

This article was recommended to us by Dr. Jay Blum.  The three recommendations of the ACP are based on extensive literature review. 

Recommendation 1: “ACP recommends assessment of the risk for thromboembolism and bleeding in medical (including stroke) patients prior to initiation of prophylaxis of venous thromboembolism (Grade: strong recommendation, moderate-quality evidence)”.

A meta-analysis of the evidence-base for venous thromboembolism (VTE) prophylaxis with heparin and LMWH was presented.  The statistical presentation was concise but understandable.  The meta-analysis of studies that looked at heparin prophylaxis in medical (non-stroke) patients is representative.  No statistical mortality benefit was demonstrated, but there was a significant reduction in pulmonary embolism (PE) balanced by a significant  increase in bleeding events - for every 1000 patients, heparin prophylaxis is estimated to prevent four PEs, but cause nine bleeds.  This risk/benefit ratio is likely to be strongly influenced in any individual patient by their specific health characteristics.  However, the authors state, “because no standard accepted formula for risk assessment exists to identify which medical patients are likely to benefit from VTE prophylaxis, the decision is best left to physician judgment”.

This conclusion is extended in a "Policy implication": “ACP does not support the application of performance measures in medical (including stroke) patients that promotes universal VTE prophylaxis regardless of risk”.

Recommendation 2: “ACP recommends pharmacologic prophylaxis with heparin or a related drug for VTE in medical (including stroke) patients unless the assessed risk of bleeding outweighs the likely benefits (Grade: Strong recommendation, moderate-quality evidence).”  

The risk reduction for PE will likely outweigh the increased risk of bleeding in most patients.  The first recommendation should not be interpreted as an argument for prophylactic nihilism. 

Recommendation 3: “ACP recommends against the use mechanical prophylaxis with graduated compression stockings for prevention of venous thromboembolism (Grade: strong recommendation, moderate quality evidence).”

There is little evidence from randomized controlled trials regarding clinical benefit of mechanical prophylaxis, and none of the available trials showed any benefit in mortality, PE or deep venous thrombosis.   This section seemed a little confused in distinguishing graduated compression stockings from intermittent pneumatic compression devices, but this seemed due to an inherent limitation of the available data.  Although not specifically mentioned in the recommendation, the discussion implies that there is no clear data regarding possible clinical benefit of intermittent pneumatic compression in medical patients.  In our hospital, many patients that have relative contraindications for heparin or LMWH are treated with intermittent pneumatic compression devices.  Many patients find them uncomfortable to wear, and taking them on and off may distract the nurses from more productive patient safety efforts.

VTE prevention is a major patient safety issue.  But the benefit/risk ratio for prophylaxis is not as robust as some expected.  Even strict compliance with targeted prophylaxis is not likely to impact hospital mortality, and universal prophylaxis would likely harm some patients. The overall rate of VTE prophylaxis should not be used as a physician performance measure, because prophylaxis should not be given to all patients.  Further studies are needed to better define patient groups in which the benefit clearly outweighs the risk.  In the meantime, most patients should still receive heparin prophylaxis, but physicians should use common sense in withholding prophylaxis from patients at increased risk of bleeding.

Brodie D, and Bacchetta M.  Extracorporeal membrane oxygenation in ARDS in adults. New Engl J Med 2011;365:1905-14.  Reviewed in conference by Emad Wissa. (Click here for abstract of mansucript)

It describes the many limitations of the literature, but offers a practical approach, focusing on several aspects of care that might improve our future ECMO performance.       

Evidence-based management of ARDS currently includes three strategies shown in randomized controlled trials to reduce mortality: low-tidal volume ventilation, conservative fluid therapy, and early use of neuromuscular blocking agents (we will review this article next month).  All other methods used to manage refractory hypoxemia, including high-frequency oscillation ventilation, inhaled nitric oxide, prone positioning, steroids, and ECMO are of uncertain clinical benefit.  There is no data that would allow these to be ranked in an algorithm, and therefore the decision to implement them, and what order to use them in, should depend on the clinician’s preference for the individual patient and the availability of resources.

Older clinical trials of ECMO are no longer pertinent due to dramatic technological advances. The recent CESAR trial showed a significant clinical benefit of transferring patients with severe ARDS to a center capable of providing ECMO, but did not directly compare ECMO to standard ventilator management. Guidelines from extracorporeal life support organization (ELSO) state that ECMO is recommended for patients suffering respiratory failure when the PaO2/FiO2 ratio is < 80, and should be considered when PaO2/FiO2 is < 150.  This is a reasonable approach at centers that offer ECMO, but does not represent a standard of care. 

Several technological advances may reduce adverse events associated with ECMO and thereby increase its benefit/risk ratio.  The advent of bicaval dual lumen catheters allows veno-venous ECMO to be implemented via a single vascular access.  More biocompatible materials and improved pump design have reduced the risks of thrombosis, disseminated intravascular coagulation and hemolysis - this translates into more conservative transfusion thresholds and reduced anticoagulation targets, which will likely reduce the risks of transfusion-related lung injury and bleeding.  

Perhaps the most important mechanism by which veno-venous ECMO might benefit a patient with ARDS is that it allows the lung to recover from ventilator-associated lung injury.  The authors recommend using very gentle  lung-protective ventilator settings during ECMO  i.e., pressure support with peak pressure of 20 cm H₂O, a rate of 10, and FiO₂ of 30%  - these settings typically produce tidal volumes below 4 mL/Kg ideal body weight, and theoretically should allow the lung a chance to heal.

Like any other life support modality, the mortality benefit of ECMO will become clear only when ECMO becomes safer than the alternatives.  In the near future, this advantage is likely only to occur in ARDS patients at highest risk for ventilator-associated lung injury, and only at centers which practice ECMO in the safest possible manner.

Hoeper MM, and Granton J.  Intensive care unit management of patients with severe pulmonary hypertension and right heart failure.  Am J Respir Crit Care Med  2011;184:1114-24.  Reviewed in conference by Roxanne Garciaorr. (Click here for abstract of manuscript)

The authors focused on patients with chronic pulmonary hypertension who suffer acute right heart failure.  For practical purposes, this group is largely comprised of patients with type 1 (pulmonary arterial hypertension) and type 4 (chronic thromboembolic pulmonary hypertension).

Right heart failure in patients with chronic pulmonary hypertension is often triggered by events such as medication noncompliance, tachyarrhythmias, infections, anemia, and pregnancy.  As the right ventricular ejection fails due to critical afterload and preload conditions, a vicious cycle begins in which systemic hypotension reduces right ventricular coronary perfusion, and a dilating right ventricle (RV) increasingly impinges on left ventricular (LV) filling.    

In some patients in this situation, the administration of IV fluids can benefit cardiac output by increasing RV preload.  But fluid management is complicated by the interdependence of the ventricles.  A fluid bolus that further dilates the RV might actually further impinge on LV filling, paradoxically reducing cardiac output.  The authors therefore recommend consideration of monitoring such patients with a Swan Ganz catheter.  It should be noted that the pulmonary artery wedge pressure (PAWP) may overestimate LV preload in the presence of a severely dilated RV.  In this case, the PAWP minus the right atrial pressure more closely approximates filling pressure of the LV.

Atrial fibrillation is poorly tolerated by patients with severe chronic pulmonary hypertension.  Rate control often doesn't adequately restore preload to the dilated RV that has become dependent on coordinated atrial contraction.  Medications typically used to achieve rate control, such as beta-blockers and Ca-channel blockers may worsen hypotension and further impair RV coronary perfusion.  Amiodarone may be tried, but the best course is often to proceed to electrical cardioversion.

Support may include measures such as dobutamine to improve systolic function, vasopressin or levophed to improve perfusion pressure, and transfusion to a hemoglobin of 10 g/dL.  RV afterload may be reduced by intravenous prostacyclin derivatives such as epoprostenol or by inhaled vasodilators such as nitric oxide or iloprost.  Endotracheal intubation should be avoided if at all possible - sedation drugs and alterations in intrathoracic pressure associated with positive pressure ventilation may precipitate cardiopulmonary arrest. 

The outcome of patients with acute right heart failure secondary to chronic pulmonary hypertension is critically dependent on a coordinated approach that is specific to a unique pathophysiology.  This paper should be studied in detail by all the fellows - the article is full of important clinical pearls, of which only a few are reviewed herein.

Robert A. Raschke, M.D.

Associate Editor, Critical Care Journal Club

November 2011 Critical Care Journal Club

Reference as: Robbins RA. November 2011 Critical Care Journal Club. Southwest J Pulm Crit Care 2011;3:172. (Click here for PDF version of journal club)

Raschke RA, Garcia-Orr R. Hemophagocytic lymphohistiocytosis: a potentially underrecognized association with systemic inflammatory response syndrome, severe sepsis, and septic shock in adults. Chest 2011;140:933-8. (Click here for abstract)

I was asked to do Critical Care Journal Club for November and have taken the opportunity to review an article authored by Roaxanne Garciaorr and Robert Raschke, the Critical Care Journal Club editor who normally writes this journal club.

Hemophagocytic lymphohistiocytosis (HLH) was originally described as a genetic disorder of immune regulation in neonates with protracted fever, hepatosplenomegaly, and cytopenia. A secondary form of HLH, triggered by serious infections, was subsequently described in adults. This manuscript reports three adult patients who presented with systemic inflammatory response syndrome and features consistent with severe sepsis and septic shock, who subsequently received a diagnosis of secondary HLH.  The hyperinflammatory pathophysiologic characteristics of HLH and septic shock are closely intertwined. Clinical and laboratory features of HLH and septic shock overlap in some patients, making the syndromes difficult to distinguish. In the authors experience and review, progressive pancytopenia was the feature most likely to suggest secondary HLH in the adult patient with presumed (or definite) septic shock. Use of other HLH-2004 diagnostic criteria is hindered by the poor operating characteristics of these tests in critically ill adults. Bone marrow aspiration is the most useful diagnostic test, but may yield an initial false-negative result. Treatment by aggressive immunosuppressive therapy with dexamethasone, etoposide, cyclosporine, and IV immunoglobulin should not be delayed.

This manuscript describes an entity which is underrecognized and treatable. It emphasizes awareness and is well worth reading those unfamiliar with HLH.

Paulos JA. Bigger plates, more food--or is it the other way around? Scientific American 2011;305:20.

Another article was brought to our attention by Clement Singarajah. This single page article describes when dealing with weakly correlated quantities, spurious trends and associations can be created by artfully defining the size of categories. The author uses an example of plate size and ounces of food consumed at a buffet. He shows that either large or small plates can be shown to lead to increased food consumption depending on how large or small plates are defined. This article will increase the awareness of how these manipulations can be used by the unscrupulous or the naïve to support a preconceived conclusion.

Richard A. Robbins, M.D.

Editor, Southwest Journal of Pulmonary and Critical Care

September 2011 Critical Care Journal Club

Reference as: Raschke RA. September 2011 critical care journal club. Southwest J Pulm Crit Care 2011;3:75-77. (Click here for a PDF version)

Levy MM, and colleagues.  Association between Critical Care physician management and patient mortality in the intensive care unit.  Annals of Internal Medicine 2008;148:801. (Click here for full text version of manuscript)

I picked this “oldy” because we have reviewed several large non-randomized observation studies over the past several months, and I thought reviewing this study might encourage more discussion regarding critical appraisal of such studies.

Levy’s study was a cohort study that included data on 101, 832 patients from 123 ICUs.  The aim was to quantitate the mortality benefit of care provided by a board certified intensivist.  The Simplified Acute Physiology score (SAPS) II was used to quantitate severity of illness, and calculate standardized mortality ratios.  Logistic regression and propensity scoring were used to adjust for the tendency to refer sicker patients to intensivist care. 

The results reported in this study were confusing, because the data was fractionated into numerous subgroup analyses.  However, it could be best summarized by observing that the standardized mortality ratio for patients who received intensivist-directed care in ICUs predominantly managed by intensivists was 1.09 (95% CI 1.05-1.13).  Patients who did not receive intensivist-directed care, in institutions in which intensivists were involved <5% of the time, had a superior standardized mortality ratio of 0.91 (95% CI 0.88-0.94).  Patient’s receiving intensivist-directed care were sicker, but even after statistical adjustment for severity of illness, the OR for death was 1.40 (p<0.001) if an intensivist provided care.

An unbiased critical appraisal of this paper would have to consider the hypothesis that this result is valid – that intensivist involvement actually increases mortality.  However, I am going to set that possibility aside, and proceed on the assumption that the training we receive as intensivists is of some mortality benefit to our patients.   With this in mind, the question arises: How can an apparently well-designed cohort study, with data on over 100,000 patients, yield what appears likely to be a false result?

Several good explanations were put forth, and a general review of critical appraisal of cohort studies was referenced (Grimes DA et al.  Cohort Studies. Lancet 2002;359:341). The main threats to the validity of cohort studies are bias and confounding.  An example of bias in this study is that sicker patients were systematically referred to intensivist care.  Confounding is a similar concept in which there is no bias per se, but the natural association between variables leads to spurious associations.  It’s a little harder to conceptualize than bias, but suppose it was true that mortality was increased with each additional consultant that took care of a patient, independent from the patient’s severity of illness.  This could for instance be due to lack of coordination of patient care.  In this case, consultation of an intensivist (along with all the other specialists) could be associated with increased mortality even though it had nothing to do with the care provided by the intensivists themselves.  

All the sophisticated statistics used in this study were meant to try to reduce the effects of bias and confounding.  The reason they don’t always work, is that we have to be able to identify and measure all the determinants of mortality in order to optimally adjust for them.  This just isn’t possible.  One look at SAPS II, Apache IV, or any of the other available severity adjustment tools should suggest to a critical thinker that much more must be involved in a patient’s propensity to perish or survive than what is contained therein. 

This essential flaw in observational studies is probably easiest to remember when the result doesn’t make sense to us, as in this case.  But equal caution should be exercised when the result makes sense – especially if we are biased in favor of the result a priori. 

Randomization is the key to handling bias and confounding, since even unrecognized sources will generally be effectively nullified by this approach.  We don’t have an RCT to guide every bedside decision, but I think that decisions to standardize care ought to be based on well-designed randomized controlled trials.  This should help us avoid the situation in which we lock-step clinicians into providing useless or potentially harmful care.  

Next, we looked at two current articles from Chest:  

Marini JJ.  Point: Is Pressure Assist-Control Preferred Over Volume Assist-Control Mode for Lung Protective Ventilation in Patients With ARDS? Yes. Chest August 2011 140:2 286-290 

and MacIntyre N. Counterpoint: Is Pressure Assist-Control Preferred Over Volume Assist-Control Mode for Lung Protective Ventilation in Patients With ARDS? No. Chest August 2011 140:2 290-292.

We felt from the onset that this debate likely was not going to yield a clear answer (and suspected that Drs. Marini and MacIntyre probably could easily have supported either side of the argument).  There are no randomized controlled trials that demonstrate the clinical benefit of any particular mode of ventilation over another.

There were several interesting aspects of the discussion we had over these articles.  The essence of the debate revolved about whether strain (pressure) or stretch (volume) was more injurious to the lung.  Proponents of the strain theory support pressure control – proponents of stretch theory, volume control.  This debate has been going on for decades, and was clearly evident in the classic low-tidal-volume ARDSnet trial. The title of this trial suggested that the authors felt volume was the more important variable, yet plateau pressure was also strictly limited.  I’m still not sure which of these closely related variables is more important, but it’s worthwhile to know that some newer ventilator features minimize the clinical difference.  For instance, the volume-controlled mode of controlled mechanical ventilation (CMV) on our Drager ventilators can provide the patient with variable flow rates and a flat pressure waveform.  These allow volume controlled ventilation to mimic the advantages that Marini attributes to pressure controlled ventilation.  Whichever mode you use, the lessons from ARDSnet should be remembered – limitation of tidal volume and plateau pressure should both be carefully observed.     

Robert A. Raschke MD

Associate Editor, Critical Care Journal Club

August 2011 Critical Care Journal Club

Reference as : Raschke RA. August 2011 Critical Club Journal Club. Southwest J Pulm Crit Care 2011;3:37-39. (Click here for PDF version)

Two manuscripts recently appeared back-to-back in the New England Journal of Medicine. Both dealt with the use of cultures and barrier precautions to prevent new cases of resistant bacterial infection in the ICU, but the manuscripts came to different conclusions regarding the usefulness of these interventions.  Taken together, these articles raise an important question in regards to evidence-based practice: How do we synthesize research into practice when studies yield conflicting results?   

Huskins CW, and colleagues.  Intervention to reduce transmission of resistant bacteria in intensive care.  New Engl J Med 2011;364:1407.  (Click here for the abstract of the manuscript)

The first study was a randomized controlled trial carried out in 18 ICUs over a 6 month period.  Surveillance cultures were obtained to detect nasal carriage of methicillin resistant Staphylococcus aureus (MRSA) and gastrointestinal carriage of vancomycin resistant Enterococcus (VRE) in all the involved ICUs.  The ICUs themselves were the unit of randomization.  In the intervention ICUs, the results of the cultures were reported to the clinicians.  These units also received enhanced training on contact precaution procedures, and an aggregate report on compliance with universal gloving.  In the control ICUs, the reports of surveillance cultures were not disclosed.  Patients in either type of ICU could be placed into contact precautions based on results of clinical microbiology – otherwise, standard precautions were practiced.  The main outcome was the incidence of new events of colonization/infection with MRSA or VRE based solely on culture positivity.  No attempt was made to distinguish colonization from infection.

Eighteen ICUs entered the study, and over 9000 patients were admitted during the study period.  The presence of MRSA or VRE was recognized more commonly in the intervention ICUs because of the reports of surveillance cultures (although I could not quantitate this effect despite re-reading the results several times).  The use of barrier precautions in patients who were colonized or infected was correspondingly higher in the intervention ICUs [92% vs. 38% p<0.001].  However, the incidence of new colonization or infection events failed to improve [40.4 events per 1000 patient days vs. 35.6, p=0.35].  

This study showed that a bundle of interventions including surveillance cultures and expanded use of barrier precautions for MRSA and VRE failed to reduce spread of these organisms. 

Randomization by ICU unit avoids many of the possible sources of bias inherent in the second study we will discuss, but this study still has some flaws.  Studies with bundled interventions are difficult to interpret because there is no way of determining whether each individual bundle component contributed or detracted from the overall result. Approximately 20% of patients in this study were not eligible for analysis of the primary outcome because initial surveillance cultures were not obtained within 2 days of admission.  Still. this study provides the best designed analysis of this research question. 

There are some reasons why surveillance cultures and barrier precautions might not be effective.  Implementation of barrier precautions were often delayed pending results of surveillance cultures.  Universal gloving (used in 43% of the intervention patients) may not be as effective as full contact precautions, and compliance with full contact precautions was imperfect.  It may be that in order for these measures to work, they need to be carried out more rapidly and with better fidelity, and perhaps combined with other interventions to reduce bacterial colonization and contamination.    

Jain R, and colleagues.  Veterans Affairs initiative to prevent methiclllin-resistant Staphylococcus aureus infections.  New Engl J Med 2011;364:1419. (Click here for the abstract of the manuscript)

This retrospective observational study followed the impact of a bundle of MRSA disease control interventions launched in VA hospitals nationwide.  The bundle included nasal surveillance for MRSA, contact precautions for patients with MRSA, improved hand hygiene, and a positive “change in the institutional culture” in relation to improved infectious disease control.  These were implemented from March through October of 2007, and then results were followed through June 2010. 

The rate of MRSA surveillance cultures exceeded 90% once the bundle was implemented.   Compared to historical controls, the rate of healthcare-associated MRSA infections decreased from 1.64 to 0.62 infections per 1000 patient days (p <0.001) in the ICUs and from 0.47 to 0.26 infections per 1000 patient days in non ICU settings (p<0.001).  The incidence of healthcare-associated MRSA infections over time is nicely graphically displayed – it’s clear from the persistent reduction over more than 2 years after the intervention, that Hawthorne effect does not explain these results.  Internal validity also seems supported by subgroup analyses which show reductions in all types of MRSA infections. The VA system investigators should be congratulated for carrying out research of this magnitude. 

However, the design of this study is essentially observational.  It’s extremely large sample size does not compensate for the potential bias introduced by the use of historical controls.  Many other factors, besides those in the intervention bundle, might have reduced infection and colonization rates over the years the study was performed.  Possibilities include improved barrier precautions during central line placement, improved processes to prevent ventilator associated pneumonia, even changes in the epidemiology of the involved organisms.  The method by which the diagnosis of MRSA infections was determined was not adequately explained, and may have introduced detection bias.  The diagnosis seems to have been made by the same clinicians and nurses who were being held responsible for preventing spread of the organisms.  This situation might lead to biased reporting of MRSA infections. There were several months during the study in which not a single MRSA central line infection was reported at any VA in the nation.  This is a flaw that was avoided in the previous study by including any new case of MRSA in the outcome variable, without attempting to distinguish infections from colonization.  Although not reported in the manuscript, the standardized mortality rate of the VA ICUs did not decrease during the intervention period (Robbins RA, personal communication) despite hospital acquired infections with MRSA being a major cause of hospital mortality (1).    

The situation in which randomized and non-randomized studies have examined the same research questions has recurred in the medical literature.  Correlation is good in many cases, but nonrandomized trials are statistically more likely to demonstrate greater treatment effect (2).  Many well-recognized international consensus groups have agreed that randomized controlled trial(s) are required for high level evidence based practice.  It is my opinion that historically-controlled studies should be used only to generate hypotheses.  They do not have the inherent internal validity to allow firm conclusions, and they should certainly not form the basis of healthcare policy.  

On a personal note, I try to do my best to practice very careful infection control hygiene.  But I find it very difficult to be 100% compliant with strict contact precautions under all circumstances in the ICU, and this is part of human nature that will likely continue to degrade the effectiveness of infection control, even in highly motivated groups of clinicians.

Robert A. Raschke MD

Associate Editor, Critical Care Journal Club

References

1. Wenzel RP. Health Care–Associated Infections: Major Issues in the Early Years of the 21st Century. Clin Infect Dis 2007;45:S85-S88.
2. Ioannidis JPA, et al.  Comparison of Evidence of Treatment Effects in Randomized and Nonrandomized Studies. JAMA.   2001;286:821-30.

July 2011 Critical Care Journal Club

Reference as : Raschke RA, Robbins RA. July 2011 Critical Club Journal Club. Southwest J Pulm Crit Care 2011;3:11-14. (Click here for PDF version)

Maitland K et al.  Mortality after fluid bolus in African children with severe infection.  N Engl J Med 2011;364:2483-95.  (Click here for PDF version)

I think this paper is potentially one of the most important we’ve reviewed in the past year.  Please carefully review it yourself – the following is just a brief summary, with some editorial comment. 

The authors set out to prove a fundamental hypothesis – that a fluid bolus is beneficial for children with severe febrile illness with impaired perfusion.  Shockingly, (no pun intended), they found the reverse.  Fluid bolus therapy significantly increased mortality – with one excess death for every 30 children who received fluid bolus therapy.  How can this be?

The study took place in 6 (non-ICU) centers in sub-Saharan Africa.  Children up to age 12 were eligible upon presentation with a febrile illness and evidence of impaired perfusion (evidenced by severe tachycardia, weak radial pulse volume, cool extremities, or poor capillary refill), plus evidence of organ dysfunction (impaired consciousness or respiratory distress).  The main study group was randomized to receive either 20mL/kg 5% albumin bolus, 20mL/kg saline bolus, or no bolus.  Patients in the bolus therapy groups received additional boluses if perfusion did not improve.  All patients received otherwise equivalent care including antibiotics and maintenance IV fluids at 2.5-4 mL/kg/hr. 

The study was stopped when an interim analysis showed that mortality in the patients receiving bolus therapy was significantly increased.  At that time, 3141 patients had been randomized to the main study stratum.  The 48-hour mortality was 10.6%, 10.5% and 7.3% in the albumin bolus, saline bolus and control groups (p=0.003 for the comparison of any bolus vs control).  The 4-week mortalities were 12.2%, 12% and 8.7% (p=0.004 for bolus vs control).  Although study design did not allow precise classification of sepsis in these patients, it appears that most would have at least satisfied criteria for severe sepsis.  Thirty-nine percent had serum lactate levels >5 mmol/L.    

We used a standardized approach to critical appraisal.  The study was found to have unusually high internal validity.  It was well-powered, randomized and blinded.  Patients were well-matched upon randomization, and were treated equally and with high adherence to study protocol.  Follow-up exceeded 97%, and the statistical analysis was based on intention-to-treat.  The effect size was large and precise, with a relative risk for death by 4 weeks of 1.45 (95%CI of 1.13 – 1.86).  Additionally, the authors demonstrated that excess mortality with fluid resuscitation was consistent across all subgroups, including those based on age, hypotension, lactic acidosis, coma, and microbial pathogens (particularly malaria).  This finding is remarkable not only in that it speaks to the validity of the association that these authors uncovered, but also because it shows that fluids were deleterious even in patients in whom we might think they would be most beneficial, e.g., those with hypotension, organ dysfunction and lactic acidosis. 

We can only speculate why this might be.  The authors propose that the vasoconstrictor response in shock may confer protection by reducing perfusion to nonvital tissues, and that rapid reversal by fluid bolus may induce a reperfusion injury.  Rapid fluid shifts caused by bolus therapy might exacerbate capillary leak in the lungs or brain (although the study did not show an increase in pulmonary or cerebral edema in children that received bolus therapy).  Recently, it’s been recognized that intravenous resuscitation fluids might have direct deleterious immunomodulatory effects.  If any of these explanations are valid in African children, there is no reason to believe that they could not also possibly contribute to the pathophysiology of resuscitated septic shock in adults.  

The direct external generalizability of this study is poor in relation to the practice of adult critical care in the developed world.  Yet few articles in regard to therapy or pathophysiology of sepsis, in any group of patients, approach the internal validity achieved by these authors.  This study challenges such an entrenched and fundamental aspect of what we think we know about resuscitation, that it would not likely have even been considered ethical to perform in the US.  Therefore, we should take advantage and consider the implications these findings might have on the practice of adult critical care.   

Although this study will not have an immediate effect on sepsis resuscitation guidelines for adults, it will should raise questions in the minds of bedside clinicians, and cause investigators to take a step back.  The current recommended practice of giving repeated fluid boluses to septic patients in order to achieve a goal central venous pressure is particularly vulnerable in this regard.  In many institutions, this practice is now relentlessly driven by protocols that do not require any subsequent bedside evaluation by the physician.          

In a wider context, this paper represents another stepping stone in the history of the evidence-based practice of Critical Care Medicine over the past 40 years – particularly in regards to the therapy of sepsis and associated multisystem organ failure.  It is my observation that this history can be characterized by several generalizations: 1) initially promising therapies are ultimately proven to be disappointing; 2) less aggressive support measures are generally found to be superior to more aggressive strategies.  [More on this topic in an upcoming editorial]

Robert A. Raschke MD, Critical Care Journal Club Editor

Wilson KC and Schunemann HJ. An appraisal of the evidence underlying performance measures for community-acquired pneumonia. Am J Respir Crit Care Med 201;183:1454–62. (Click here for PDF version of abstract)

Numerous organizations use performance measures to monitor the quality of care. An appraisal of the evidence underlying such performance measures has never been reported. The authors’ objective was to estimate the effects of interventions recommended by performance measures and to determine the quality of evidence from which those estimates derive, using the Joint Commission and the Centers for Medicare and Medicaid Services’ performance measures for community-acquired pneumonia (CAP) as examples.

The authors performed systematic reviews of the literature to identify evidence related to the performance measures for CAP which are listed below:

1. Pneumococcal vaccination
2. Smoking cessation counseling
3. Influenza vaccination
4. Blood cultures
5. Antibiotics within 6 hours
6. Guideline-compliant antibiotics

Metaanalyses were then performed to estimate the absolute and relative effects of the interventions recommended by the performance measures. The Grading Recommendations, Assessment, Development, and Evaluation system was used to determine the quality of evidence. Among these performance measures, only influenza vaccination was supported by high-quality evidence. One-step smoking cessation counseling was contradicted by moderate- quality evidence (smoking quit rate: RR, 1.05; 95% CI, 0.90–1.22).

The results suggest that the estimated effect usually favors the intervention that is recommended by the performance measure, but the evidence is frequently not high quality. This implies that there is uncertainty about the balance of desirable and undesirable effects of the intervention. Wilson and Schunemann believe that “…when such uncertainty exists, there should be other compelling factors that favor the intervention if it is going to be recommended by a performance measure”. We could not agree more.

The authors of the article did not have the opportunity of reading a recent article by Attridge et al. (reviewed in the May, 2011 Pulmonary Journal Club) which demonstrated an increased mortality when the ATS/IDSA antibiotic guidelines were followed (1,2). We could quibble about the beneficial effect of the other guidelines, but regardless, it would appear that their benefit is weak, and in the case of smoking cessation, potentially harmful.

The importance of this manuscript not only lies in the quality of the investigation but in the prestige of the authors. Wilson is the Deputy Editor — Pulmonary, Critical Care, and Sleep Medicine of UpToDate and Schunemann is the Chair of Medicine at McMaster University. He is also one of two chairs of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group and editor-in-chief of Health and Quality of Life Outcomes and co-convenor of the Applicability and Recommendations Methods Group of the Cochrane Collaboration. Criticism of a widely used guideline by such eminently qualified investigators should have some influence on the policy makers who implement these guidelines prior to doing the necessary investigation to ensure the guidelines’ evidence basis.

Richard A Robbins MD, Editor Southwest Journal of Pulmonary and Critical Care

References

1. Attridge RT, Frei CR, Restrepo MI, Lawson KA, Ryan L, Pugh MJV, Anzueto A, Mortensen EM. Guideline-Concordant Therapy and Outcomes in Healthcare-Associated Pneumonia. E Resp J. Published online before print March 24, 2011, doi: 10.1183/​09031936.00141110
2. Mathew M., May 2011 pulmonary journal club. Southwest J Pulm Crit Care 2011;2:65-66.