November 2013 Critical Care Journal Club

Four manuscripts were reviewed. The first two were review articles from the New England Journal of Medicine. Both are good assessments of the current state of the art of fluid resuscitation and shock in the intensive care unit.

Myburgh JA, Mythen MG. Resuscitation fluids. N Engl J Med. 2013;369 (13):1243-51. [CrossRef] [PubMed]

Fluid administration is one of the most common interventions in medicine. The authors review the use of resuscitation fluids and point out that until recently that the evidence basis for the selection, timing, and doses of intravenous fluids was empiric, based more on training and preference than data. The authors summarize the literature nicely in Table 2 of their manuscript with the following being major points of the manuscript:

• No currently available resuscitation fluid can be considered to be ideal.
• Fluids should be administered with the same caution that is used with any intravenous drug.
• Fluid resuscitation is a component of a complex physiological process. Replace the fluid and amount most likely to be lost.
• Fluid requirements change over time in critically ill patients.
• Specific considerations apply to different categories of patients.

1.  
   1. Bleeding patients require control of hemorrhage and transfusion with red cells and blood components as indicated.
   2. Isotonic, balanced salt solutions are a pragmatic initial resuscitation fluid for the majority of acutely ill patients.
   3. Albumin is not indicated in patients with traumatic brain injury.
   4. Hydroxyethyl starch is not indicated in patients with sepsis or those at risk for acute kidney injury.
   5. The safety of other semisynthetic colloids has not been established, so the use of these solutions is not recommended.

Vincent JL, De Backer D. Circulatory shock. N Engl J Med. 2013;369(18):1726-34. [CrossRef] [PubMed]

Circulatory shock is associated with high morbidity and mortality. The authors review the major types of shock and emphasize that appropriate, aggressive treatment is based on a good understanding of the underlying pathophysiological

mechanisms (distributive, cardiogenic, hypovolemic, obstructive). Treatment should include correction of the cause of shock and hemodynamic stabilization, primarily through fluid infusion with colloids for most patients. Failing rapid correction, administration of vasoactive agents such as norepinephrine as a vasopressor, dobutamine as an inotropic agent, and in some instances judicious use of vasodilators to reduce afterload. The patient’s response can be monitored by means of careful clinical evaluation and blood lactate measurements; microvascular evaluation may be feasible in the future.

The last two articles were randomized, controlled trials from JAMA.

Morelli A, Ertmer C, Westphal M, Rehberg S, Kampmeier T, Ligges S, Orecchioni A, D'Egidio A, D'Ippoliti F, Raffone C, Venditti M, Guarracino F, Girardis M, Tritapepe L, Pietropaoli P, Mebazaa A, Singer M. Effect of heart rate control with esmolol on hemodynamic and clinical outcomes in patients with septic shock: a randomized clinical trial. JAMA. 2013;310(16):1683-91. [CrossRef] [PubMed]

Epinephrine and norepinephrine levels are elevated in septic shock. β-Blocker therapy may control heart rate and attenuate the deleterious effects of β-adrenergic receptor stimulation. However, β-Blockers are not traditionally used for this condition and may worsen cardiovascular decompensation related through negative inotropic and hypotensive effects. The authors performed an open-label, randomized phase 2 study of esmolol infusion or placebo in 77 septic shock patients with a heart rate of 95/min or higher requiring high-dose norepinephrine to maintain a mean arterial pressure of 65 mmHg or higher. The primary outcome was a reduction in heart rate below the predefined threshold of 95/min and to maintain heart rate between 80/min and 94/min by esmolol treatment over a 96-hour period. Targeted heart rates were achieved in all patients in the esmolol group. Secondary outcomes of arterial lactatemia, norepinephrine requirements, fluid requirements and twenty-eight day mortality were all improved with esmolol.

The role of β-blockers in several diseases such as heart failure has done a complete flip-flop from contraindicated 30 years ago to a standard of care. This is an extension of this expanded role of β-blockers and although the group found the study interesting, it was pointed out that the study was small and the mortality in the control group was high. We agreed with the authors that the observed improvement in mortality and other secondary clinical outcomes warrants further investigation.

Mentzelopoulos SD, Malachias S, Chamos C, Konstantopoulos D, Ntaidou T, Papastylianou A, Kolliantzaki I, Theodoridi M, Ischaki H, Makris D, Zakynthinos E, Zintzaras E, Sourlas S, Aloizos S, Zakynthinos SG. Vasopressin, steroids, and epinephrine and neurologically favorable survival after in-hospital cardiac arrest: a randomized clinical trial. JAMA. 2013;310(3):270-9. [CrossRef] [PubMed]

The authors performed a randomized, double-blind, placebo-controlled, parallel-group trial to determine whether combined vasopressin-epinephrine and corticosteroid supplementation for cardiopulmonary resuscitation (CPR). 268 consecutive patients with cardiac arrest requiring epinephrine according to resuscitation guidelines (from 364 patients assessed for eligibility).were randomized and the primary endpoints of a return of spontaneous circulation (ROSC) for 20 minutes or longer and survival to hospital discharge with a CPC score of 1 or 2. Patients treated with vasopressin-epinephrine had higher probability for return of spontaneous circulation of 20 minutes or longer and survival to hospital discharge with a CPC score of 1 or 2.

Like the previous study we found this interesting. Also like the previous study, the improvement in mortality and other secondary clinical outcomes warrants further investigation. However, it is difficult to determine if the effects, if confirmed, are due to one of the therapies or the combination is necessary.

Richard A. Robbins, MD

Editor

Reference as: Robbins RA. November 2013 critical care journal club. Southwest J Pulm Crit Care. 2013;7(5):308-10. doi: http://dx.doi.org/10.13175/swjpcc166-13 PDF

September 2013 Banner Good Samaritan / Phoenix VA Critical Care Journal Club

Raschke RA, Curry SC, Warkentin TE, Gerkin RD. improving clinical interpretation of the anti-platelet factor 4/heparin enzyme-linked immunosorbent assay for the diagnosis of heparin-induced thrombocytopenia through the use of receiver operating characteristic analysis, stratum-specific likelihood ratios, and Bayes theorem. Chest. 2013;144(4):1269-75. [CrossRef] [PubMed] 

I have to apologize for being a little self-serving in choosing my own publication for review, but I wanted to crow a little, and relate a small personal experience regarding bedside research.  To this end, I’m going to discuss how the research came about rather than offering critical appraisal.  Nick Sparacino did a great job reviewing this article in conference without stepping on the toes of his program director (sorry to put you in that difficult position Nick!). 

Our study reanalyzed previously published data on 1958 patients with suspected heparin-induced thrombocytopenia, and showed that the current cutoff for a positive anti-heparin/PF4 ELISA (HIT ELISA) of 0.4 OD is suboptimal – leading to the confusing situation in which a mildly “positive” test result in the 0.4-1.0 range actually rules HIT out.  Receiver operating curve analysis shows that the optimal cutoff for the discriminant accuracy of the HIT ELISA is 0.8 OD, and that interpretation can be further improved by using an algorithm that utilizes clinical suspicion and a stratified interpretation of the test result.  This algorithm allows confident diagnostic and treatment decisions to be made in about 90% without the need for confirmation by serotonin release assay (SRA).   

The idea for this publication came from one of our fellowship M&M conferences, in which we presented a patient with an acute right-sided myocardial infarction caused by HIT.  A discussion ensued regarding the sensitivity and specificity of the HIT ELISA, and we were left confused by the section on HIT diagnosis in UptoDate^®, which stated that a mildly positive ELISA result essentially ruled HIT out.  I pulled the reference (for which Dr. Warkentin was the lead author), and began re-analyzing the tabulated data in the publication with help from Dr. Curry, Dr. Gerkin and Dr. Jack Peirce.  We called the manufacturer of the HIT ELISA and talked to several company representatives to learn that the manufacturer cut off for diagnostic interpretation of the ELISA result was determined using the distribution of results in normal healthy volunteers, not with data on patients suspected of having HIT.  This seemed highly suspect.  We contacted Dr. Warkentin (in my opinion the world’s leading expert on HIT) and he graciously agreed to supply his original data and work with us to reanalyze it.  It was an honor to work with Dr. Warkentin.  I think it’s safe to say that we all learned an astonishing amount about ROC curves, which turn out to be far more interesting than any of us originally imagined.  This interest has led to several didactic sessions on ROC curves in our fellowship conferences, and for the Mayo Pulmonary fellowship.  Our fellow Tonya Whiting is currently working on a validation study for the HIT ELISA algorithm, which is in process to implement throughout Banner Health.  It is fascinating to me that a simple clinical question that arose out of one of our M&M conferences led to such a cascade of benefits.  This is a good example of benefits fellowship training brings to our institutions.

Hung IF, To KK, Lee CK, Lee KL, Yan WW, Chan K, Chan WM, Ngai CW, Law KI, Chow FL, Liu R, Lai KY, Lau CC, Liu SH, Chan KH, Lin CK, Yuen KY. Hyperimmune IV immunoglobulin treatment: a multicenter double-blind randomized controlled trial for patients with severe 2009 influenza A(H1N1) infection. Chest. 2013;144(2):464-73. [CrossRef] [PubMed] 

This study was a small randomized controlled trial with a primary outcome of mortality.  However, the methods of this study are not adequate to support the author’s conclusion that hyperimmune IV immunoglobulin (H-IVIg) benefits mortality of patients with severe H1N1 influenza if given within five days. The primary outcome analysis of 34 patients presented in table 1 shows that five of seventeen patients who received H-IVIg died compared to four of seventeen control patients (obviously no benefit there).  The authors subsequently performed a subgroup analysis of 22 patients who received treatment within five days of symptom onset.  All five of the H-IVIg fatalities are excluded from this analysis, but all four of the control deaths are retained.  This is not explicitly stated by the authors, but can be discerned by comparing survival data in tables 1 (overall analysis) and 2 (subgroup analysis).   There is no mention of any plan to perform this subgroup analysis in the methods section – therefore there is no guarantee that this subgroup wasn’t specifically formulated by data-dredging to elicit a presupposed conclusion.  This is an excellent example of why unplanned subgroup analysis should not be accepted as a basis for scientific conclusions.  The Editors of Chest accepted a letter we wrote in regards to this issue, so if you’re interested, look for the authors reply in a subsequent issue of Chest.   

Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013;369(9):840-51. [CrossRef] [PubMed] 

Our thanks to Hargobind Khurana who helped us summarize this review article.  For the sake of brevity, I will just relate a few comments that came forward in our discussion – most of these relate to treatment.  Table 2 of the article reviews current treatment guidelines from the Surviving Sepsis Campaign.  Initial fluid resuscitation for patients with hypotension and suspected tissue hypoperfusion should rapidly deliver > 30 mL/Kg of crystalloid – and should continue so long as there is hemodynamic improvement.  Of note, the definition of “hemodynamic improvement” is clearly moving beyond simply achieving a central venous pressure > 8 cmH₂0 (a parameter that has been convincingly shown to not be predictive of fluid responsiveness).  The level of evidence for this recommendation is only “C” – it is somewhat incredible that in 2013, we still don’t have better evidence to guide fluid resuscitation of septic shock.  Of 35 recommendations listed in the table 2, only three are based on level "A" evidence: low tidal volume mechanical ventilation, use of ventilator weaning protocols, and use of a glucose management protocol.  Nineteen of thirty-five (54%) are level C or ungraded.  The authors contend that our limited success in establishing high-level evidence for the management of sepsis might be explained by flaws in our current research strategy, which focuses on heterogeneous patient populations, with highly variable pathogens, clinical syndromes, and host immune responses.  As more is learned about this heterogeneity, it might be found that treatment can be focused more specifically to the host-pathogen interaction – this approach may be more likely to succeed in clinical trials and at the bedside. 

Dellinger RP, Townsend SR. Point: are the best patient outcomes achieved when ICU bundles are rigorously adhered to? Yes. Chest. 2013;144(2):372-4. [CrossRef] [PubMed] 

Marik PE, Raghunathan K, Bloomstone J. Counterpoint: are the best patient outcomes achieved when ICU bundles are rigorously adhered to? No. Chest. 2013;144(2):374-8. [CrossRef] [PubMed] 

Sandra Till did a good job summarizing this set of editorials.  Dellinger and Marik both make good points – and probably most of our participants learned a few arguments for and against their personal stand on this issue.  In very brief summary, Dellinger points out that bundles are not perfect, but are as evidenced-based as the current state of the literature permits.  They promote consistency, help change practice behaviors, and provide compliance outcomes that are measurable.  Marik points out that bundle elements frequently have poor quality evidence to support them, and that the concept of measuring compliance with the entire bundle as a measure of quality of care is flawed, because failure to comply with any single bundle element, even the most poorly supported, is interpreted as a failure to provide good care.  Dr. O’Hea pointed out that chasing bundle compliance can sometimes distract us from what’s most important for the individual patient.    

Regardless which side of this issue you stand on, the use of bundle compliance as a measure of quality of care in the ICU is not likely to go away anytime soon.  I think one of the most important things we can do is to express some local autonomy, and practice common sense in our definition of bundle compliance.  For instance, it is highly unlikely that achieving a particular CVP is a specific measure of good ICU care – it is much more likely that good care entails paying careful attention to the patient’s perfusion state and volume status in order to guide ongoing resuscitation, by whatever valid methods are employed.  We might soon incorporate this concept by allowing use of inferior vena cava ultrasonography, and other appropriate methods, as a surrogate for CVP measurements, when determining bundle compliance.  This will be a step in the right direction.         

Page VJ, Ely EW, Gates S, et al. Effect of intravenous haloperidol on the duration of delirium and coma in critically ill patients (Hope-ICU): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med 2013;1: 515-23. [CrossRef]

This study was a double blind, randomized controlled trial that enrolled 142 general adult ICU patients to receive either haloperidol 2.5mg IV Q8 hourly or placebo, irrespective of delirium or coma state.  Study treatment was continued until discharged from ICU, or awake for 2 days, for a maximum of 14 days.  All patients also received fentanyl or propofol infusions titrated to Richmond agitation sedation scale target of 0 to -1 if needed.  Patients in either group could also receive haloperidol doses as needed for agitation.  The main outcome variable was the incidence of delirium as determined by the confusion assessment method (CAM-ICU).  All but one patient was included in the intention to treat analysis.  There was no difference in delirium free days, coma free days, mortality, or QT prolongation.

The study was well designed.  Treatment groups did not differ in baseline characteristics.  All but one patient was followed into the intension to treat analysis.  Recruitment achieved a sample size with better than 80% power to demonstrate a clinically significant benefit.  Other important outcomes including 21 potential drug side effects were assessed.

The conclusion of this study is not surprising. Haloperidol, and other sedation and anti-agitation medications all have negative effects on cognitive function.  It is much more likely that haloperidol and related medications act by simply reducing agitated behavior, making the patient more docile – rather than by clearing the mind.  Prevention of delirium is most likely best achieved by avoiding or minimizing sedation medications, and other medications that have negative CNS effects, and by providing an environment in which the patient’s orientation is supported.  This might best be accomplished by good nursing-patient interaction, presence of family and friends, maintenance of normal sleep/wake cycles, proper use of analgesia, and other common sense measures. 

Robert A Raschke MD MS

Associate Editor

Reference as: Raschke RA. September 2013 banner good samaritan / phoenix va critical care journal club. Southwest J Pulm Crit Care. 2013;7(4):241-4. doi: http://dx.doi.org/10.13175/swjpcc138-13 PDF

September 2013 Tucson Critical Care Journal Club: Early Tracheostomy

Young D, Harrison DA, Cuthbertson BH, Rowan K for the TracMan Collaborators. Effect of Early vs Late Tracheostomy Placement on Survival in Patients Receiving Mechanical Ventilation: The TracMan Randomized Trial. JAMA. 2013;309(20):2121-29. [CrossRef] [PubMed]  

Tracheostomy is a commonly performed procedure in the critical care unit; however, the most appropriate time to perform the procedure remains uncertain.  Rumbak et. al. (1) demonstrated a 50% reduction in mortality in 2004 when tracheostomy was performed within the first 2 days of intubation compared to day 14 to 16. This study was sponsored by the University of Oxford with funding provided by the UK Intensive Care Society and the Medical Research Council to evaluate potential benefits associated with early tracheostomy in a larger patient population.  Patients from 72 different UK critical care centers were randomized to early tracheostomy (within the first 4 days) or late tracheostomy (after day 10 if still clinically indicated).

Between November 2004 and November 2008, 909 patients were randomized with 2 years of follow-up data available (January 2011).  Inclusion and exclusion criteria were relatively straightforward.  Patients were included if a senior physician believed they were likely to require another 7 days of intubation.  Patients were excluded if they required immediate, life-saving tracheostomy; tracheostomy was contraindicated for anatomical or other reasons; or if respiratory failure was due to chronic neurological disease.  The primary outcome was all cause mortality 30 days post-randomization.  Secondary outcomes included mortality at discharge from the critical care unit, from the hospital, 1 year post randomization, and 2 year post randomization, duration of critical care and hospital stay, days of intravenous sedative administration, and antimicrobial free days in the critical care.  The authors had planned a sample size of 1692 patients to detect a 6.3% absolute reduction in mortality with 80% power but because of declining recruitment, the final study had an 80% power to detect an 8.3% absolute reduction in mortality.

The results demonstrated no statistical difference between the two study groups in the primary outcome and most of the secondary outcomes.  The only significant finding was patients in the early tracheostomy group received less days of intravenous sedation.  Among the late tracheostomy group, 53.7% of the patients never had tracheostomy performed because they had been discharged from the critical care unit or no longer required mechanical ventilation.  The primary outcome of this study agrees with many recently published smaller randomized controlled trials which showed early versus late tracheostomy provided no improvement in mortality (2-5).

In conclusion, this study suggests that a “wait and see” approach to tracheostomy is justified in the majority of patients admitted to the intensive care unit requiring mechanical ventilation.  It is not clear why the earlier Rumbak (1) study yielded such a strong signal for reduced mortality with early tracheostomy.  It is possible that ventilation devices and management strategies have improved since the original study period, thereby, reducing harms associated with prolonged translaryngeal intubation.

Wendy Hsu, MD; Pulmonary Fellow¹

Joe Gerald, MD PhD; Assistant Professor²

¹Pulmonary, Allergy, Critical Care, & Sleep Medicine

²College of Public Health

University of Arizona

Tucson, AZ

References

1. Rumbak MJ, Newton M, Truncale T, Schwartz SW, Adams JW, Hazard PB. A prospective, randomized study comparing early percutaneous dilational tracheotomy to prolonged translaryngeal intubation (delayed tracheotomy) in critically ill medical patients. Crit Care Med. 2004;32(8):1689-94. [CrossRef] [PubMed]  
2. Koch T, Hecker B, Hecker A, Brenck F, et al. Early tracheostomy decreases ventilation time but has no impact on mortality of intensive care patients: a randomized study. Langenbecks Arch Surg. 2012;397(6):1001-8. [CrossRef] [PubMed]  
3. Zheng Y, Sui F, Chen XK, Zhang GC, et al. Early versus late percutaneous dilational tracheostomy in critically ill patients anticipated requiring prolonged mechanical ventilation. Chinese Medical Journal (Engl). 2012;125(11):1925-30.
4. Blot F, Similowski T, Trouillet JL, Chardon P, et al. Early tracheotomy versus prolonged endotracheal intubation in unselected severely ill ICU patients. Intensive Care Med. 2008;34(10):1779-87. [CrossRef] [PubMed] 
5. Terragni PP, Antonelli M, Fumagalli R, et al. Early vs late tracheotomy for prevention of pneumonia in mechanically ventilated adult ICU patients: a randomized controlled trial. JAMA. 2010;303(15):1483-9. [CrossRef] [PubMed] 

Reference as: Hsu W, Gerald J. September 2013 Tucson critical care journal club: early tracheostomy. Southwest J Pulm Crit Care. 2013;7(3):194-5. doi: http://dx.doi.org/10.13175/swjpcc129-13 PDF

August 2013 Critical Care Journal Club: Less is More

Our August journal club reviewed failed efforts to impact the mortality of critical illness over the past 25 years.  We looked at six landmark randomized controlled trials with certain things in common. 

They each addressed treatment of a major aspect of critical illness.  Each was well-supported by previous literature, and biologically plausible.  Each resulted in a statistically-significant mortality benefit, and was published in a well-respected journal.  And each had an immediate, and in many cases, lasting effect on the bedside practice of critical care.

Yet the positive result of each of these six studies was subsequently convincingly refuted.

It is important to note, that these studies make up a good part of what we’ve learned in critical care over the past 25 years.  There have been some influential positive studies as well, but a great deal of effort has been spent implementing evidence-based practice, based on studies that were later shown to be ineffective.

Still, some good can come from reconsideration of these studies.  The purpose of this review is to encourage healthy skepticism based on a historical perspective of our past failures.  The main question we tried to answer for each study is: Why did the authors arrive at the wrong conclusions?

Suresh Uppalapu, Nick Sparacino, Elijah Poulos, Sandra Till, Heemesh Seth, and Josh Jewell reviewed the articles respectively in the order in which they appear in table 1, which summarizes some characteristics of each study.  The six studies represent efforts to develop protocols for goal-directed resuscitation using hemodynamic parameters (1); favorably alter the immunological (2,6) or microcirculatory (4) pathophysiology of sepsis; support the metabolic (glycemic) response to critical illness (5); and alter the immunological pathophysiology of ARDS (3).

Our analysis did not reveal any common methodological flaw to explain why these studies yielded misleading conclusions (summarized in Table 1).

Table 1. Summary of the 6 studies discussed in this journal club  

Items in red font possibly contributed to misleading study conclusions.  * post op mortality; ** mortality in a subgroup with gram negative rod bacteremia; *** ICU mortality. 

Two had small sample sizes and analyzed very small numbers of clinical events (1,3) - thus the p-value might dramatically increase if even a single event had turned out differently.  The same studies only reported short-term mortality (1,3) - it is clear now that ICU mortality should be followed out at least 28 days to avoid the mistake of interpreting a delayed death as a beneficial event.  Two of the studies were supported by pharmaceutical companies with significant potential financial interest in a positive result (2,4).  Two were stopped early at interim analysis (4,5).  Several had problems with external generalizability – having studied surgical patients at a single site (1,5).  But only one (2) was obviously flawed in terms of internal validity (although the flaw was not obvious to the editors of NEJM at the time of publication).  In general, these studies were widely accepted as valid when they were published. 

It is not an exaggeration to suggest that the practice of “evidence-based medicine” based on these studies, likely resulted in significant mortality and morbidity, and much wasted effort over the past 20 years.  Shoemaker’s study – the one our fellows are least likely to remember – did much to promote the general use of Swan Ganz catheters.  The concept of goal-directed therapy using supraphysiological Swan parameters was not convincingly refuted until nearly 20 years later.  Approximately a billion dollars was spent on Drotrecogin alpha over a decade in which it was recommended.  It is unclear how many patients may have suffered hemorrhagic complications of the drug.  The NICE-SUGAR trial provided a point estimate that suggests that one of every 38 patients treated with an intensive insulin protocol died likely related to severe hypoglycemia.  This is probably an overestimation, but extrapolation suggests the potential that great harm may have been done.

This brief history provides a background to support caution in our optimism for future research findings, and humility in the formulation of consensus recommendations and guidelines. In most all cases, our experience should have taught us that less is more.

Robert A. Raschke, MD

Associate Editor

References

1. Shoemaker WC, Appel PL, Kram HB, Waxman K, Lee TS. Prospective trial of supranromal values of survivors as therapeutic goals in high risk surgical patients. Chest. 1988;94:1176-86. [CrossRef] [PubMed] 
2. Ziegler EJ, Fisher CJ Jr, Sprung CL, Straube RC, Sadoff JC, Foulke GE, Wortel CH, Fink MP, Dellinger RP, Teng NN, et al. Treatment of gram-negative bacteremia and septic shock with HA-1A human monoclonal antibody against endotoxin. A randomized, double-blind, placebo-controlled trial. The HA-1A Sepsis Study Group. N Engl J Med. 1991;324(7):429-36. [CrossRef] [PubMed] 
3. Meduri GU, Headley AS, Golden E, Carson SJ, Umberger RA, Kelso T, Tolley EA. Effect of prolonged methylprednisolone therapy in unresolving acute respiratory distress syndrome: a randomized controlled trial. JAMA. 1998;280(2):159-65. [CrossRef] [PubMed] 
4. Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ Jr; Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001;344(10):699-709. [CrossRef] [PubMed] 
5. van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F, Schetz M, Vlasselaers D, Ferdinande P, Lauwers P, Bouillon R. Intensive insulin therapy in critically ill patients. N Engl J Med. 2001;345(19):1359-67. [CrossRef] [PubMed] 
6. Annane D, Sébille V, Charpentier C, Bollaert PE, François B, Korach JM, Capellier G, Cohen Y, Azoulay E, Troché G, Chaumet-Riffaud P, Bellissant E. Effect of treatment with low doses of hydrocortisone and fludrocortisone on mortality in patients with septic shock. JAMA. 2002;288(7):862-71. [CrossRef] [PubMed] 

Reference as: Raschke RA. August 2013 critical care journal club: less is more. Southwest J Pulm Crit Care. 2013;7(3):162-4. doi: http://dx.doi.org/10.13175/swjpcc121-13 PDF

July 2013 Critical Care Journal Club

This month we focused on prone ventilation in our journal club.  Fellows Josh Jewell, Elijah Poulos, Heemesh Seth, Suresh Uppalapu, Nithya Menon, Sandra Till and Nick Sparacino presented articles.  Faculty including Rick Robbins, Al Thomas, Jay Blum, Huw Owen Reece, Roxanne Garcia Orr, Dick Gerkin and Bob Raschke were present, and Dr. Shiva Birdi attended and assisted our discussion (thanks).

This Journal Club was prompted by a randomized controlled trial published recently in the NEJM that showed that mortality of severe ARDS could be dramatically reduced by prone ventilation.  Our current practice has been based on previous findings that proning could improve oxygenation, but not mortality.  Proning is currently considered a rescue therapy by most clinicians, to be used when ARDSnet ventilator settings fail to provide adequate oxygenation.  Therefore, this study had the potential to significantly change practice.  

Prone positioning during mechanical ventilation is thought to improve oxygenation by several gravitational mechanisms.  In the supine position, dorsal transpulmonary pressure is less than ventral transpulmonary pressure.  Transpulmonary pressure is related to alveolar filling.  Proning reduces the difference between dorsal and ventral transpulmonary pressures, ameliorating both dorsal atelectasis and ventral alveolar over-distention that occur in the supine position.  The second of these effects might theoretically reduce the incidence of ventilator-associated lung injury.  Additionally, proning relieves compression of dorsal lung by the weight of the heart, lungs, and abdomen.  The dorsal lung continues to receive the majority of pulmonary blood flow in the prone position; therefore, as dorsal atelectasis is reduced, V/Q matching improves.

The focus of our discussion – Guerin’s randomized controlled trial (RCT) - should be considered in the context of previous RCTs.  Table 1 presents an overview of this context.   Note that the earlier studies lacked detail in their methods sections, and some reported significant cross-over between treatment and control groups, reducing their methodological quality.  Over the course of the last 12 years, researchers have increasingly focused their attention on more severe forms of ARDS, as can be seen by the falling p_aO₂/FiO₂ of eligible patients over time.  Earlier studies did not employ ARDSnet ventilator settings, and may no longer be as clinically applicable.  Researchers have increasingly sought to start proning earlier, and maintain it for longer periods throughout each day of mechanical ventilation.  In Guerin’s study, patients spent 73% of their ventilator time proned.  Mortality outcomes are difficult to compare, because studies varied in reporting ICU-mortality, 10-day mortality, 28-day mortality and 60-day mortality – with a general trend towards longer-term follow-up in more recent studies.  Overall, the results of Guerin’s study stand out in this comparison.  The dramatic reduction in mortality by over half is unheralded by the earlier studies.  The p-value of 0.001 shows that the results even surprised the statisticians who calculated the sample size of the study.  Only Taccone’s study reported significant incidence of what seem to us to be relatively common complications of prone ventilation.  Many of the clinicians present at our journal club have personally witnessed cardiopulmonary instability, and the inadvertent discontinuation of IV catheters or the endotracheal tube (ETT) during the proning maneuver.   

Table 1: Randomized controlled trials of prone ventilation that reported mortality outcomes. (Editor's Note: You may need to go to view on your browser and enlarge the display to adequately view the table.)

Guerin’s study appears to meet many criteria for a well-conducted RCT (6) – specifically, their follow-up was adequate, the groups were treated equally except for the intervention, intention-to-treat analysis was employed, and clinically-significant and statistically-precise effect size was demonstrated.  The patients in the study seemed similar to ones that we typically care for (i.e., the results seem generalizable).  A few potential problems with internal validity were noted.  The randomization did not appear to have been concealed, and control group had statistically worse SOFA scores and higher vasopressor requirements, indicating that they were sicker at baseline.   

Their results indicate a “number-needed-to-treat” of six – that is, a life was saved for every six patients who underwent prone ventilation.  The magnitude of this effect size is greater than for any other well-studied intervention in critical care.  It is our consensus that this result is too good to be true, and will require confirmation by further studies before proning ought to be routinely recommended for patients with severe ARDS (p_aO₂/FiO₂<150).  Our opinion is consistent with the larger context of randomized controlled trials in the field of critical care – we are often ultimately disappointed by treatments that appear to have significant mortality benefit in a single randomized controlled trial (e.g. use of Swan-Ganz catheters to guide goal-directed resuscitation, corticosteroids for ARDS, Ha-1a for septic shock, corticosteroids for septic shock, drotrecogin-alfa for septic shock, tight glucose control in critical illness, etc.).  Finally, we noted that the low complication rate in Guerin’s study likely understates the potential difficulties of proning in most institutions.     

The point is well-taken that our current compliance with ARDSnet low tidal volume mechanical ventilation is suboptimal.  We can likely best benefit our patients at the current time by focusing system-level quality improvement efforts on this foundational aspect of ventilator care, until more is known about the potential benefits of proning.  In the meantime, we retain prone ventilation as a rescue therapy, but will be more likely to consider it favorably in comparison to other rescue therapies such as inhaled nitric oxide, which have less evidence to suggest clinical benefit.

Robert A. Raschke, MD, MS

Associate Editor

References

1. Gattinoni L, Tognoni G, Pesenti A, Taccone P, Mascheroni D, Labarta V, Malacrida R, Di Giulio P, Fumagalli R, Pelosi P, Brazzi L, Latini R; Prone-Supine Study Group. Effect of prone positioning on the survival of patients with acute respiratory failure. N Engl J Med. 2001;345(8):568-73. [CrossRef] [PubMed] 
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Reference as: Raschke RA. July 2013 critical care journal club. Southwest J Pulm Crit Care. 2013:7(1):55-8. doi: http://dx.doi.org/10.13175/swjpcc101-13 PDF