June 2012 Critical Care Journal Club

Another rapid-fire Journal club this month: We covered 6 articles very concisely.

Stein PD, Matta F. Thrombolytic therapy in unstable patients with acute pulmonary embolism: saves lives but underused.  Am J Med. 2012;125:465-70.  (presented in conference by Henry Leudy). (click here for abstract)

It's interesting to note that there is no definitive clinical trial that proves the benefit of thrombolytic therapy for life-threatening pulmonary embolism.  On first blush, this study looked promising - with a sample size of >72,000 patients, and a huge protective effect for thrombolytic therapy, reducing mortality from 47 to 15% (p<0.0001).

Unfortunately, this study is based on very low quality data.  The clinical diagnoses of pulmonary embolism and hemodynamic instability and the administration of thrombolytic therapy were all based on ICD-9-CM billing codes - notoriously inaccurate for use in clinical research.  The study design was a retrospective cohort - but there was a high risk of selection bias - patients who did not receive thrombolytic therapy were significantly older and sicker to begin with.  The authors made no attempt to adjust for this as they should have, with statistical techniques such as multiple logistic regression.

Although we share a bias towards using thrombolytics in patients with hemodynamically significant pulmonary embolism, the low quality of this study design does not add much to what we already think we know.  Our group routinely performs bedside echocardiography in ICU patients with pulmonary embolism, and feel that right ventricular dilation/dysfunction support the decision to give lytics - as previously suggested by Goldhaber (N Engl J Med 2002; 347:1131-2).  Anecdotally, we have seen several patients with large right atrial clots visible on echo, who immediately died from pulmonary embolism upon receiving lytic therapy - we worried whether lytics might have catastrophically liberated these clots.  The optimal management of life-threatening pulmonary embolism needs to be better defined through high-quality clinical research.

Van Rompaey B, Elseviers MM, Van Drom W, Fromont V, Jorens PG. The effect of earplugs during the night on the onset of delirium and sleep perception: a randomized controlled trial in intensive care patients. Crit Care. 2012;16:R73.  (presented in conference by Jessica Hurley) (click here for full text of article)

This is an intriguing idea - a cheap and simple preventative measure for one of the major iatrogenic complications of critical illness.  Unfortunately, the design of this study was so seriously flawed that this promising hypothesis remains just that. 

The authors randomized 136 patients to nighttime earplug use or control for the first 5 days of ICU stay.  The primary outcome variable was the incidence of delirium based on a validated clinical scoring system.  This all seems pretty good.  Unfortunately no reduction was found in delirium (19% vs 20%), so the authors analyzed a combined endpoint (delirium + confusion) using a 24-hour duration survival analysis.     

Survival analysis (and associated hazard ratios) should only be used when a delay in the outcome of interest - usually death - is of significant duration to be beneficial.  It is often used in studies of cancer chemotherapy.  Most would agree that a therapy that shows significant survival advantage at 5 years is clinically worthwhile.  The shorter the duration of a study, the less applicable survival analysis becomes.  It's simply ridiculous to use it over a 24-hour period of observation as these authors have done.  This particular paper is the worst example I have ever seen of misuse of this statistic.  The author's contention that "a vast improvement" in the incidence of confusion is demonstrated by the calculated hazard ratio shows a lack of understanding of what the statistic means  - in this case, that the onset of confusion is delayed over a 24-hour period in patients wearing earplugs - a clinically meaningless result. Additionally, the external validity of the study was severely limited by the exclusion of all patients requiring sedation - these are the very patients who are at highest risk for ICU delirium. This paper should have been rejected for publication, but the hypothesis has merit.  Hopefully someone will pick up on it and do a better job.  

NHLBI ARDS clinical trials network.  Initial trophic vs full enteral feeding in patients with acute lung injury.  JAMA 2012;307:795-803.  (Tonya Whiting presented this paper in conference). (click here for full text of article)

There are many theoretical reasons why feeding should be better than starving a critically-ill patient, yet definite proof that early nutritional support is beneficial in critical illness is still lacking.  Some observational studies show benefit - others seem to suggest that permissive underfeeding may actually reduce ventilator LOS and mortality.  It is therefore a bit disappointing that the authors set out to compare two nutritional regimens without any non-intervention control group.  This was probably done on the presumption that short-term permissive starvation is harmful.

The authors screened almost 8000 patients with acute lung injury receiving mechanical ventilation but only randomized 1000 - one group received trophic enteral feeding (fixed rate of 20 Kcal/hr), the other group received full enteral feeding (escalating rate to achieve 25-30 Kcal/kg/day).   The intervention was continued for 6 days, then all patients received full enteral feeding.  Initial trophic feeding did not benefit ventilator-free days or reduce 60-day mortality.  Differences in gastrointestinal symptoms were statistically, but not clinically important.     

The study was generally well-designed in terms of internal validity.  However the conclusion that hypocaloric feeding was no better than full enteral feeding is anticlimactic.  The external generalizability of the study is called into question by the large proportion of screened patients who were excluded from participation (87%).  One clinical point we took home from this paper - if you believe early early feeding is beneficial, you needn't fuss too much - trophic feeding through an nasogastric tube is likely to be OK.

Schuetz P, Amin DN, Greenwald JL.  Role of procalcitonin in managing adult patients with respiratory tract infections.  Chest 2012;141:1063-73. (presented in conference by Chris Jivcu).  (click here for full text of article)

We've reviewed procalcitonin several times in the past two years waiting to see whether it will fulfill it's promise.  In this review, we briefly concentrate on sections related to ICU patient care.

Procalcitonin is a serum marker of acute bacterial infection that might be useful in differentiating bacterial from viral respiratory infections.  The test has reasonable operating characteristics in community-acquired pneumonia, with an area-under-the-ROC curve of >80%.  However, it has still not proven to be reliable in the workup of ventilator associated pneumonia.  Studies that have investigated procalcitonin-guided management of sepsis in the ICU, have shown reduction in duration of antibiotics, but mixed effects on ICU length of stay, and no effect on mortality.  The authors attempt a list of recommendations, but these seem premature given the current state of the literature. We will continue to keep an eye on this as more research comes along. 

Schortgen F, Clabault K, Katsahian S, et al.  Fever control using external cooling in septic shock: A randomized controlled trial.  Am J Respir Crit Care Med 2012;185:1088-95. (presented in conference by Emad Wissa). (click here for abstract of article)

Most clinicians treat fever for the patient's comfort, but we've wondered whether doing so might actually be short-circuiting a beneficial host response.  This paper touches on this subject but doesn't provide a clear answer. 

The authors randomized 200 febrile patients with septic shock requiring pressors, mechanical ventilation and sedation to either external cooling for 48 hours to achieve normothermia, or no external cooling.  The primary endpoint was vasopressor dose reduction at 48 hours. 

The conduct of the study seemed reasonable, but the choice of outcome variables, statistics and the conclusions the authors reached are questionable.  There was no statistically significant benefit seen in the primary endpoint, but the authors noted slight improvements in some related secondary outcomes such as an increase in shock reversal during the ICU stay in the cooling group.  They also report a reduction in 14-day mortality from 34 to 19% (p=0.013) with cooling using survival analysis.  It is widely believed that 14-day survival is not a useful clinical outcome because survival over such a short follow-up may simply represent a delay in death rather than a beneficial return to health.  The standard is 28-day survival or longer. 

One take home point is noted in relation to refractory shock - this study suggests that cooling the patient to normothermia in this situation might help support perfusion pressure.  I wonder if this is part of why it sometimes seems that patients in shock do better on continuous renal replacement therapy, which generally cools the patient a degree or two.      

Krikorian A, Limonero JT. An integrated view of suffering in palliative care.  J Palliative Care 2012;28:41-9.  (presented in conference by Roxanne Garciaorr). (no abstract available)

This paper was chosen to help us think about how to respond to the family of a critically-ill patient when they ask: "Is my Dad suffering?"  The authors don't provide an easy answer, but develop several useful concepts related to the question.

Suffering is much more than just pain - and many elements of suffering cannot be ameliorated by analgesics.  Suffering is a form of distress caused by events that threaten the patient's intactness, or even their very existence, over which they feel helpless to save themselves.  It follows that suffering is a very personal experience - the degree to which a patient feels helpless and threatened is the degree to which they will suffer.  Culture, religious beliefs and personality will clearly influence this.  Suffering can be treated by reducing the perception of threat, and by increasing the patient's feeling they can have some control over events.  These are concepts that can be applied at the bedside.  Prayer is one example of an intervention that might address both issues for some patients.

The authors make one point that gave me pause - they say a patient has to be conscious in order to suffer.  It makes me wonder how this applies to a comatose patient in the ICU.  Although we cannot be sure the patient is suffering in this situation, the imminent destruction of the patient causes suffering for the family and medical caregivers.  This suffering is often unfairly discounted when the costs/benefits of potentially futile intensive care unit interventions are weighed.   

Robert A. Raschke, MD

Associate Editor

Critical Care Journal Club

Reference as: Raschke RA. June 2012 critical care journal club. Southwest J Pulm Crit Care 2012;5:20-3. (click here for a PDF version of the journal club)

May 2012 Critical Care Journal Club

May Journal club focused on Clinical Epidemiology and Research Design using a classic paper that demonstrated the relationship between smoking and lung cancer:  Doll R and Hill AB.  A study of the aetiology of carcinoma of the lung.  Br Med J 1952;2:1271-86. (Click here for a full text version of the article)

A little background is needed to truly appreciate the imagination, innovation and perseverance that went into this research.   At the time the study was performed, just after World War II over 80% of men in Great Britain smoked, and it was almost inconceivable that tobacco might cause cancer.  Doll and Hill themselves smoked, and Doll originally thought that car exhaust, or perhaps fumes rising from the tarred surface of streets were more likely to be implicated in the rising incidence of lung cancer observed after the war. 

The case control study design that Doll and Hill employed is now considered “classic", but at the time it was entirely novel, with no established standard methodology.  Doll and Hill thoughtfully and meticulously designed the study from scratch to eliminate all three threats to internal validity: bias, confounding and chance. 

At its core, the study compared 1357 men with lung cancer admitted to hospitals in London, Bristol, Cambridge, Leeds and Newcastle-upon-Tyne, to 1357 control patients who were matched by age, hospital of admission, area of residence and social status.  Matching was carefully performed to eliminate any potential bias related to exposure to occupational or environmental toxins.  “Almoners” (essentially British hospital social workers) administered a standardized three and a half page "questionary" that detailed the smoking history in terms of quantity, duration and method of smoking.  The questionary was designed to illuminate potential confounding variables, such as whether cigarette holders and petrol lighters were used, because it was just possible that lighter fumes rather than cigarette smoke might be carcinogenic.  Other potential confounders including occupation, residence near a Gasworks, exposure to different types of home heating, and previous respiratory illnesses were all closely examined and shown to be independently unrelated to lung cancer.   

Doll and Hill considered the concept of blinding.  They originally sought to keep the almoners uninformed as to each patient’s diagnosis at the time of the questionary, but when they specifically assessed this blind, they found the almoners often had discerned the diagnosis.  Later, they were able to compare data from the subset of patients originally thought to have had cancer who eventually ruled out, and show that their smoking history was identical to that of patients without cancer - thereby demonstrating that the almoners were not biased in their history-taking. 

Doll himself visited each hospital in order to confirm the diagnosis of lung cancer for each patient – this diagnostic process typically required 2-3 weeks.  Doll noted that non-smoking patients with suspected lung cancer almost always ruled out.  Although the association between smoking and lung cancer became apparent to the researchers early in the study – enough so to convince Doll to quit smoking - they pushed ahead with their work in order to achieve a convincing statistical result.  Of course, computers were not available at the time to perform statistical tests such as the Fisher exact test, but a Chi-squared statistic showed that the relationship between smoking and lung cancer had a p value of < 0.000001 - less than one in a million to have occurred by chance alone.  Despite the apparent methodological and statistical validity of their study, cancer researchers advising the Ministry of Health reportedly remained skeptical and initially advised against publishing the results "for fear of scaring people" unnecessarily. 

Doll and Hill went on to follow this study up with another classic - the British Doctor’s Study, a large prospective cohort study which confirmed their initial findings and also demonstrated the previously unsuspected relationships between smoking and chronic bronchitis and ischemic heart disease.  Despite the profound statistical significance of many of their studies, Hill would later argue against overemphasis on statistical significance in medical research – noting that systematic design errors were much more of a threat to validity than random error – this lesson is fundamental to critical appraisal of the medical literature.  In the course of their research, Doll and Hill developed much of what we now consider standard research design in Clinical Epidemiology.  Ultimately, our standard approach to consideration of causative associations in medicine was derived from these studies and codified as Sir Austin Bradford Hill's Criteria for Causation - which we will examine at a future date.  

Robert A. Raschke, MD

Associate Editor, Critical Care Journal Club

Reference as: Raschke RA. May 2012 critical care journal club. Southwest J Pulm Crit Care 2012;4:178-9. (Click here for a PDF version of the journal club)

April 2012 Critical Care Journal Club

Present:  Most all the fellows, Dr. Robbins, Singarajah, Bajo, Raschke and Gerkin

This month we looked at 7 articles, so the ground rules were to be concise and try to pick out just one or two take-home points from each article.

Hilton AK, Bellomo R.  A critique of fluid bolus resuscitation in severe sepsis.  Critical Care 2012;16:302-7. (Click here for abstract)

A fascinating and provocative editorial that takes a strict evidence-based approach to appraisal of the use of IV fluid boluses for septic shock.  The authors make a number of valid but seemingly heretical statements.  We all give fluid boluses to patients with septic shock in the belief that their cardiac output is compromised and that fluid administration will restore tissue perfusion resulting in improved clinical outcomes.  However the authors point out that none of the assumptions in this approach are proven.  Furthermore, the adverse effects of liberal fluid resuscitation are clearly demonstrated by a large randomized controlled trial in patients with ARDS, and by the only RCT that looked at IV fluid bolus therapy in severe infections – the FEAST trial published in NEJM in 2011 – that showed fluid boluses increased the mortality of severely ill African children.  The authors make the provocative statement that it is possible that the hypotensive state of septic shock might actually be a protective mechanism, and that artificially perturbing it should not be assumed to be beneficial without study.  They suggest ongoing research comparing our standard approach to IVF bolus resuscitation with a more fluid conservative approach that employs earlier use of pressor agents to maintain blood pressure.

This paper is bravely written and should stand as a reminder to us of how little we really know, and how cautious we should be when standardizing care based on incomplete knowledge.  I also hope this editorial might encourage our fellowship to consider performing the clinical trial that Hilton and Bellomo suggest.

Garcia MIM et al.  Non-invasive assessment of fluid responsiveness by changes in partial end-tidal CO2 pressure during a passive leg-raising maneuver.  Ann Intensive Care 2012;26:2-9. (Click here for full text manuscript)

This study showed that an increase of >5% in end-tidal CO2 triggered by a two-minute leg raising maneuver accurately predicted fluid-responsiveness (defined as a 15% increase in cardiac output in response to a 500mL colloid infusion), with a sensitivity of 91% and a specificity of 94%.

Taken in context with the previous editorial, this study provides additional background that might be useful in a clinical trial of fluid resuscitation in septic shock.  It would be relatively easy, and non-invasive to assess fluid responsiveness by this technique, and the weight of evidence points strongly to the assertion that dynamic measures of fluid responsiveness are superior to static measures such as the CVP.  The problem pointed out by Bellomo is this – even if a patient is fluid responsive, we have not proven that an increase in cardiac output of uncertain duration outweighs the potential detriment of fluid overloading the patient. 

Jakob SM et al.  Dexmedetomidine vs. Midazolam or propofol for sedation during prolonged mechanical ventilation.   JAMA 2012;307:1151-60. (Click here for abstract)

This study reported the results of two multicenter randomized controlled trials comparing long-term sedation with dexmedetomidine to midazolam and to propofol respectively in a total of 998 adult ICU patients receiving mechanical ventilation.  All three drugs provided good sedation.  In the comparison between midazolam and dexmedetomidine, median length of mechanical ventilation was about 40 hours longer with midazolam p=0.03, but dexmedetomidine had more associated hemodynamic side effects of hypotension 21 vs. 12%, p=0.007 and bradycardia 14 vs. 5%, p<0.001.  In both comparisons, patients receiving dexmedetomidine were somewhat more interactive while under sedation.  All other comparisons between propofol and dexmedetomidine were equivalent.

We applied the User’s Guide’s to Critical Appraisal and uncovered one concern regarding the conduct of the study – there were 11,911 patients receiving mechanical ventilation, but only 1001 (5%) met inclusion and exclusion criteria of the study.  The external generalizability of the findings is certainly eroded by excluding 95% of potential participants.

We didn’t feel this study added much to what we already know.  Increasing evidence suggests that prolonged use of benzodiazepine sedation in the ICU might contribute to ICU delirium and prolong mechanical ventilation.  The near equivalence of dexmedetomidine and propofol in this study is not much of an argument for the added cost of dexmedetomidine.

Carlisle JB.  The analysis of 169 randomised controlled trials to test data integrity.  Anaesthesia 2012; doi: 10.1111/j.1365-2044.2012.07128 (Click here for abstract)

This fascinating article was brought to our attention by Steve Curry.

The author analyzed 169 randomized controlled trials published by a single author in the field of anesthesia over a 20-year period.  He found many instances in which the distribution of data reported in the studies were statistically as unlikely as 10 ^-33 power of having occurred naturally.  It’s hard to imagine how such results could have been anything but fabricated, although I am not aware whether the original researcher had a chance to reply to the implicit accusation. 

I was trying to get my mind around the magnitude of the number 10³³ and I noted that our entire solar system weighs about 2 X 10³³ grams.

Albert RK.  The role of ventilation-induced surfactant dysfunction and atelectasis in causing acute respiratory distress syndrome.  Am J Respir Crit Care Med 2012;185:702-8. (Click here for abstract)

The author puts forth a theory and supporting evidence regarding the etiology of ARDS.   Essentially he posits that ARDS is an iatrogenic disease, largely caused by our practice of sedating patients and confining them to supine bedrest with inadequate PEEP.  The resulting alveolar collapse causes surfactant dysfunction and atelectasis that underlie ARDS.   I don’t think any of us were completely sold on this theory, but I think we all recognize that less sedation, and adequate PEEP are important aspects of good practice.  Although proning might one day be proven clinically preferable to supine bedrest, many practical concerns make it difficult and costly to consider as part of routine care.  More evidence is required in this respect.

Streiner DL et al.  Mine is bigger than yours: Measures of effect size in research.  Chest  2012:141:595-598.  (Click here for abstract)

A single take-home point:  be careful when authors report results such as a “10% reduction in mortality p=0.05”.  Although statistically significant, the clinical importance of relative risk reduction is not clear until you also consider the absolute risk reduction.   If the mortality in the control group of this hypothetical study is only 1%, then a 10% reduction, down to 0.9% represents only a 0.1% absolute risk reduction – a very small effect size.  Such a result can become statistically significant if the sample size of the study is large.  Calculation of the number needed to treat (NNT = 1/absolute risk reduction) reveals that 1000 patients would have to be treated to prevent one death in this example. 

Grasso S et al.  ECMO criteria for influenze A associated ARDS: role of transpulmonary pressure.  Intensive Care Medicine 2012;38:395-403. (Click here for abstract)

Briefly, this study with only fourteen patients showed that half had significant bellows stiffness that contributed to high airway pressures during mechanical ventilation.  This is potentially clinically important because measurement of esophageal pressures and calculation of transpulmonary pressures demonstrated that higher levels of PEEP could be tolerated in these patients without exceeding the upper physiological limit of transpulmonary pressure.  Increased PEEP guided by this method allowed the patients to achieve acceptable oxygenation status and avoid ECMO. 

We discussed the possibility of performing esophageal pressure measurements in our patients to help guide PEEP management.  One comment in regard to ECMO.  The potential benefit of ECMO in lung failure is not likely related to providing improved oxygenation parameters as these authors suggest.  It is not uncommon to tolerate oxygen saturations in the mid 80s for prolonged periods while on ECMO.  The potential benefit of ECMO lies in the reduction of ventilator associated lung injury that can be avoided when the ventilator need no longer be relied on to provide all oxygenation support. 

Robert A. Raschke, M.D.

Associate Editor, Critical Care Journal Club

Reference as: Raschke RA. April 2012 critical care journal club. Southwest J Pulm Crit Care 2012;4:130-3. (Click here for a PDF version of the Journal Club)

February 2012 Critical Care Journal Club

Snyder L.  American College of Physicians Ethics Manual.  Sixth Edition.  Ann Intern Med.  156;1:suppl 73-101. (Click here for a PDF version of the manuscript)

All the fellows, and Drs. Robbins, Bajo, Singarajah and Raschke attended Journal Club.   

This article related concepts of traditional medical ethics to current legal and social values.  The scope was very broad, touching on many bedside patient care issues. 

Our discussion began with some valid criticisms.  The chief among these is something I missed altogether: the author of this article is not a physician, but a lawyer. 

With all due respect to Lois Snyder, this was a mistake.  The very first statement of the article speaks to the fundamental and timeless nature of the patient-physician relationship.  How can someone who has never been a part of this relationship from a physician’s perspective be chosen to express our ethical standard?  The ACP should have looked within our own profession for a qualified author.   

Some reviewers also felt certain areas of the review were condescending, for instance, the section entitled “Sexual contact between physician and patient.  Some rudiments of ethical common-sense on the part of physician audience could probably have been reasonably assumed. 

Others felt there were content errors in the review.  One example was in the section on end of life.  The author states that physicians should not write a do-not-intubate order in the absence of a full DNR, because the patient who dies from respiratory failure will invariably suffer cardiac arrest as a consequence. 

Patients occasionally request do-not-intubate status in our practice, typically after having seen a family member suffer prolonged mechanical ventilation.   We have honored the patient’s wishes, and avoided the theoretical dilemma posed by the author by using common sense.  It is typically apparent when a patient is dying of respiratory failure – of course we wouldn’t perform ACLS in a DNI patient dying from respiratory failure.  But there isn’t any reason why such a patient shouldn’t receive treatment in the event of cardiac arrest, if that is their well-informed wish.

Despite these shortcomings, most of the content of this review was valid, and applicable to patient care. Sections on health care system catastrophes, surrogacy, futile treatments, and the impaired physician were particularly informative.  The explicit statement that physicians have an ethical obligation in regards to medical education is particularly important in a healthcare economy that seems to increasingly devalue trainees and faculty.  

The most important part of the review, from my perspective, had to do with our primary goal as physicians. “The physician’s primary commitment must always be to the patient’s welfare and best interests., . . . regardless of financial arrangements, the health care setting; or patient characteristics . . . “ 

Physicians and healthcare administrators and physicians are increasingly being asked to work together.  The advent of Accountable Care Organizations may hasten this process.   It is therefore increasingly important that we hold our responsibility to our patients foremost as financial goals receive increasing attention.  Maintaining patient welfare might be increasingly challenged by payment systems such as capitation that may disincentivize care.  Other payment systems, such as pay-for-performance, will only be compatible with good patient care if “performance” is defined by important clinical patient outcomes, rather than by compliance or surrogate outcome measures.   

Robert A. Raschke, M.D.

Associate Editor, Critical Care Journal Club

Reference as: Raschke RA. February 2012 critical care journal club. Southwest J Pulm Crit Care 2012;4:51-2. (Click here for a PDF version of the journal club)

January 2012 Critical Care Journal Club

Papazian L, Forel JM, Gacouin A, Penot-Ragon C, Perrin G, Loundou A, Jaber S, Arnal JM, Perez D, Seghboyan JM, Constantin JM, Courant P, Lefrant JY, Guérin C, Prat G, Morange S, Roch A; ACURASYS Study Investigators. Neuromuscular blockers in early acute respiratory distress syndrome. N Engl J Med 2010;363:1107-16. (Click here for full text version of article)

We reviewed this “older” article to teach the fellows adjusted mortality and biological plausibility. In this multicenter, double-blind trial, 340 patients presenting to the intensive care unit (ICU) with an onset of severe ARDS within the previous 48 hours were randomly assigned to receive, for 48 hours, either cisatracurium besylate (178 patients) or placebo (162 patients). The primary outcome was the proportion of patients who died either before hospital discharge or within 90 days after study enrollment, adjusted for predefined covariates and baseline differences between groups with the use of a Cox model. The hazard ratio for death at 90 days in the cisatracurium group, as compared with the placebo group, was 0.68 (95% confidence interval, 0.48 to 0.98; p=0.04), after adjustment for both the baseline PaO2:FIO2 and plateau pressure and the Simplified Acute Physiology II score. The crude 90-day mortality was 31.6% in the cisatracurium group and 40.7% in the placebo group (p=0.08). Mortality at 28 days was 23.7% with cisatracurium and 33.3% with placebo (p=0.05). The rate of ICU-acquired paresis did not differ significantly between the two groups.

The trial was well done but several issues were raised. The first was regarding p values. In this study p=0.08 for the unadjusted mortality but was p=0.04 when the adjusted mortality was calculated. Although it was thought to be reasonable to adjust the mortality based on predefined criteria, it was pointed out that there is nothing magic about a p value of 0.05 and these results are marginally significant. There was also a lack of biological plausibility, i.e., it is unclear why neuromuscular blockers should improve survival in ARDS. Although several explanations were offered, none were particularly convincing. Several minor issues were also raised which were summarized in the letters to the editor (NEJM 2010;363:2562-4) including whether the patients could be truly randomized. We discussed whether we should adopt neuromuscular blockers routinely in ARDS but most thought the evidence was sufficiently weak that watchful waiting pending a confirmatory trial was the best course.

Kakkar AK, Cimminiello C, Goldhaber SZ, Parakh R, Wang C, Bergmann JF; LIFENOX Investigators. Low-molecular-weight heparin and mortality in acutely ill medical patients. N Engl J Med 2011;365:2463-72. (Click here for abstract)

Although thromboprophylaxis reduces the incidence of venous thromboembolism in acutely ill medical patients, a reduction in mortiality has not been shown. The authors conducted a double-blind, placebo-controlled, randomized trial to assess the effect of subcutaneous enoxaparin (40 mg daily) compared to placebo — both administered for 10±4 days in patients who were wearing elastic stockings with graduated compression — on the rate of death from any cause among hospitalized, acutely ill medical patients at participating sites in China, India, Korea, Malaysia, Mexico, the Philippines, and Tunisia. The primary efficacy outcome was the rate of death from any cause at 30 days after randomization. The primary safety outcome was the rate of major bleeding during and up to 48 hours after the treatment period. A total of 8307 patients were randomly assigned to receive enoxaparin or placebo. The rate of death from any cause at day 30 was 4.9% in the enoxaparin group as compared with 4.8% in the placebo group (p= 0.83). There was also no difference in the rate of major bleeding, sudden Residents' suggestions for reducing errors in teaching hospitals. Enoxaparin was not associated with a reduction in the rate of death from any cause among hospitalized, acutely ill medical patients.

This article was chosen because it complements and supports the ACP thromboembolism prophylaxis guidelines which were reviewed in the December 2011 Critical Care Journal Club. These guidelines recommend assessment of the risk for thromboembolism and bleeding in medical (including stroke) patients prior to initiation of prophylaxis of venous thromboembolism.

Volpp KG, Grande D. Residents' suggestions for reducing errors in teaching hospitals. N Engl J Med 2003;348:851-5. (No abstract or free full text available)

The Institute of Medicine’s 2000 report “To Err Is Human” precipitated a firestorm of publicity on the issue of medical errors which continues to this day. We reviewed this older article which described errors or situations identified by residents in a teaching hospital potentially leading to poor patient outcomes.

Table 1. Errors or situations predisposing to errors in teaching hospitals (Adapted from Volpp and Grande. N Engl J Med 2003;348:851-5).

1. Frequent interruptions with paging
2. Errors in orders and medical records
3. Errors in sign-out procedures
4. Excessive hours of work
5. Reluctance in reporting of errors
6. Poor training in procedures
7. Resident inability to act as a leader of a medical team

Although it is not clear from the article how the authors obtained the list of errors from the residents, most agreed that each of these can be a problem. However, it was unclear whether there was progress made in any of these areas other than reduction in work hours which may have led to increased errors in other areas.

Richard A. Robbins, MD

Editor, SWJPCC

Reference as: Robbins RA. January 2012 critical care journal club. Southwest J Pulm Crit Care 2012;4:22-3. (Click here for a PDF version of the journal club)