Another mini-review where I agree with the Cochrane Review that essentially concludes: too much cost/risk, not enough proven benefit.
Hyperbaric oxygen therapy is of proven value in rapidly clearing carboxyhemoglobin from the serum – half-life approaches 20 minutes at 3 atmospheres vs. 1 hour on 100% face mask and several hours at lower concentrations of oxygen. In addition, HBO has all sorts of beneficial effects in terms of preventing the damaging intracellular effects of carbon monoxide, including impairment of cytochrome oxidase a3 and of lipid peroxidation. Lipid peroxidation, as you might imagine, in a brain full of lipids, is where you really end up in trouble with permanent neurologic sequelae.
Unfortunately, the first animal models that prove how well HBO works go directly from CO poisoning into multiple atmospheres of therapy. As few HBO centers there are in the U.S., this is absolutely not a clinically relevant model because of the delays to therapy – and that’s why the human literature is less conclusive.
There are essentially three large studies that contribute most of the weight to the 2011 Cochrane Review – one from 1989 that demonstrates no benefit, a second from 2002 in the New England Journal of Medicine that has a broad following, and, finally, a 2011 publication in Intensive Care Medicine. Most toxicologists who are pro-HBO base their opinions on the 2002 Weaver article.
The good news about the Weaver article – it’s a great study. It enrolls a lot of patients, it enrolls all kinds of patients, it dives them to three atmospheres, it does three dives in a 24 hour period, and it has excellent objective testing and subjective evaluation follow-up. This study was well-designed to give us the answers. And, in the end, it finds a significant difference in objective neurologic function in the HBO group and a subjective difference in memory ability in the HBO group. What is odd, however, is that there were many objective tests of cognitive function. Most trended towards favoring the HBO group, but only one of them reached statistical significance – a trail marking test in which a line was drawn between similar numbers. The absolute change in cognitive function between treatment and follow-up wasn’t that much different between the two groups. And, unfortunately, the larger issue for me is the baseline difference between the two groups in amount of time exposed to CO which trended towards much higher in the NBO group – 22 +/- 64 hours in the NBO group and 13 +/- 41 hours in the HBO group.
This difference is much more important because animal studies have demonstrated it’s not the carboxyhemoglobin concentration that matters as much as the dissolved CO that diffuses intracellularly. There’s a fabulous study in dogs demonstrating this difference. In one group, they exposed dogs to CO to get their carboxyhemoglobin concentration to 68% – and they all died. In a second group, they bled dogs until they had lost 68% of their hemoglobin – in theory, the same level of deoxygenation as the CO group – and they all lived. Third, they bled dogs down until they had lost 68% of their hemoglobin, then exposed that hemoglobin to CO in vitro and re-transfused it back into the dogs – in theory, the same 68% carboxyhemoglobin level as group 1 – and those dogs lived. The difference between group 1 and 3 was the amount of dissolved CO in the blood and intracelluarly, and it was demonstrated that their cytochrome oxidase a3 activity was normal in group 3 despite the carboxyhemoglobin levels.
So, that’s where I can’t take the Weaver evidence as strong enough as the sole large study favoring HBO, even though it was well-designed. The 2011 evidence, as mentioned before, is a study by Annane in Intensive Care Medicine. This is the more recent study showing no benefit. However, if you thought the Weaver study had flaws, this one is even worse. They enrolled patients between 1989 and 2000 – but didn’t publish until 2011, which is a massive red flag. Their endpoint is fuzzier, as they simply have a questionnaire and a physical examination as their follow-up without a lot of details. But, for what it’s worth, they found HBO was futile in non-comatose patients and harmful in comatose patients. They also do not dive as low or as long as the patients in the Weaver study.
Each of these studies makes it in the Cochrane Review which finds a cumulative nonsignificant trend towards minimal improvement in the HBO group. The problem is, HBO therapy is expensive, causes hyperoxic seizures, barotrauma, anxiety, oxidative stress and both hyperthermia and hypothermia. Weak evidence for mild improvement in delayed neurologic sequelae at 6 weeks is not a strong enough motivator for me to be enthusiastic about subjecting someone to the risks of HBO therapy. I’d love to see more data.
“Hyperbaric Oxygen for Acute Carbon Monoxide Poisoning.”
www.ncbi.nlm.nih.gov/pubmed/12362006
“Hyperbaric Therapy for Acute Domestic Carbon Monoxide Poisoning: Two Randomized Controlled Trials.”
www.ncbi.nlm.nih.gov/pubmed/21125215
“Hyperbaric Oxygen for Carbon Monoxide Poisoning (Review).”
www.ncbi.nlm.nih.gov/pubmed/21491385
We’re Covered in Filth
This is not the first study showing physician white coats and nursing uniforms are colonized with bacteria, nor that may of those bacteria are pathogenic and multi-drug resistant. In the past, this has been used as a call for the abolishment of physician white coats, ties, and all long-sleeved apparel.
This study, however, shows that short-sleeved nursing uniforms were just as likely to be coated with bacteria – 49% to 54%. Interestingly, even “changing uniform daily” still resulted in colonization with pathogenic bacteria. The authors speculate the main issues are that all textiles easily transmit bacteria, and that hand hygiene might be more critical than uniforms in prevent transmission from patients to physician clothing.
This study also, like the many before it, doesn’t demonstrate anything but colonization – not documented patient-to-patient transmission via healthcare worker clothing or any specific outcome measures. However, I am a believer that white coats are fomites and medical relics that should go the way of bloodletting and golden elixirs. The studies in support of white coats cite patient satisfaction and ease of identification of roles – which, while important, could be mitigated by new interventions for identification of healthcare providers. Even though we yet have no evidence of harms from this colonization with pathogenic bacteria, it’s essentially a zero-cost intervention to stop wearing white coats and ties – so even if the number needed to treat to prevent a transmissible infection is immense, it’s a free way to protect our patients as best we can.
“Nursing and Physician Attire as Possible Source of Nosocomial Infections.”
www.ncbi.nlm.nih.gov/pubmed/21864762
CMS ED Quality Measures Are Coming
When the government is the largest healthcare payor, you pay attention when they start measuring “quality” – because it’s usually not long after that payments are tied to “quality”.
This is an Annals study looking at the pilot reporting program from CMS, which includes seven metrics that hospitals are going to have report in the next two years. These metrics are:
– Throughput time for admitted patients.
– Throughput time for discharged patients.
– Admit order to bed placement for admitted patients.
– Time to pain management for long bone fractures (discharged and admitted)
– Time to chest x-ray after order placed (discharged and admitted)
I love the pain management metric. The literature that supports how poorly ED physicians manage pain is extensive. Not a day goes by where have a resident trying to give a 2 milligram dose of morphine to treat acute pain. The other metrics – well, so, faster is more and more is better, so therefore more, faster is “quality”, right? Well, there are some studies that show improved outcomes when patients reach the floor more rapidly, so, perhaps that’s what they’re getting at. I don’t know if we’ll ever really know how improving these measures affects quality, because there are so many other confounding variables affecting these issues.
What is good about these metrics is that it should make a lot of EDs re-examine their processes and see how they can maximize the resources they have. But, after the low-hanging fruit, you run up against issues of physical and financial resources – many of which are hospital-wide issues. It will be interesting to see how our workplace changes in response to this. Unsurprisingly, academic centers and busy EDs had the worst throughput statistics; not sure about magical solutions there.
“A Field-Test of Time-Based Emergency Department Quality Measures.”
www.ncbi.nlm.nih.gov/pubmed/21868129
How Do We Miss Aortic Dissection?
This is a retrospective look at 109 cases eventually diagnosed with aortic dissection – with a focus on the differentiating clinical features present in the 17 cases where the diagnosis was initially missed in the Emergency Department.
Confounding clinical attributes that were associated with a missed diagnosis were walk-in vs. ambulance arrival and presence of anterior chest pain. Chest x-rays lacking a wide mediastinum were nonsignificantly associated with missed aortic dissection, and with only 55% of their diagnosis cohort having a wide mediastinum vs. 25% of their misdiagnosis cohort. Interestingly, over 75% of each group received a d-Dimer and they were all positive in the misdiagnosis group as well as all but one in the diagnosis group. It would seem that they order so many d-Dimers that they’ve become fatigued to its clinical usefulness due to its poor specificity.
The good news is the patients who were initially misdiagnosed had similar mortality (18% vs. 15%) – despite 7 of the 17 being treated with antithrombotic agents. Most of the missed diagnoses were classified as undifferentiated possible ischemic chest pain, but two were diagnosed with renal colic.
As always, the main problem with missed-diagnosis literature is there’s no guarantee the authors didn’t miss another set of cases themselves.
“Factors leading to failure to diagnose acute aortic dissection in the emergency room.”
www.ncbi.nlm.nih.gov/pubmed/21889877
Ondansetron, Just Like Droperidol
Droperidol used to be one of the most widely used anti-nausea medications, particularly in the peri-operative period. Now, none of my residents are familiar with it because it’s rarely used since the FDA gave it a black box warning for its QT-prolonging effects. We have largely and copiously replaced it with ondansetron, the supposedly safe alternative.
Now, the FDA is asking GlaxoSmithKline to go back and look at the safety profile for ondansetron…due to QT-prolonging effects: http://reut.rs/pDq6Yw They are already changing the labels to reflect cardiovascular risk in the meantime.
It should be interesting to see the results. It is fairly clear that ondansetron prolongs the QT interval probably nearly, but not quite, as much as droperidol. The droperidol black box was based on cardiovascular events including only a mere 10 patients receiving doses in the therapeutic range of 0.625mg to 1.25mg, and those events had multiple confounding factors or drug co-administrations. It would not surprise me if ample, if equally flimsy, evidence exists implicating ondansetron as well.
“Food and drug administration black box warning on the perioperative use of droperidol: a review of the cases.”
“Droperidol and ondansetron-induced QT interval prolongation: a clinical drug interaction study.”
“The effects of droperidol and ondansetron on dispersion of myocardial repolarization in children.”
Putting Acetylcysteine To Rest
Essentially, another study to nail the coffin shut for using n-acetylcysteine to prevent contrast-induced acute kidney injury.
Over 1000 patients each in the acetylcysteine and placebo groups, this study showed exactly equal 12.7% chance of acute kidney injury resulting from contrast exposure during cardiac catheterization. In addition, the 30-day mortality was nearly identical at 2.2% for acetylcysteine and 2.3% for placebo, and only 3 patients in each group required dialysis within 30 days.
Perplexingly enough, the only advantage acetylcysteine had was a lower incidence in adverse effects versus placebo, 2.2% vs. 1.3%. They do not mention what formulation their placebo formulation was, but apparently it caused more nausea & vomiting.
The authors also do a mini meta-analysis to evaluate why previous studies showed a benefit, and they additionally find that studies that had appropriately blinded allocation showed identical outcomes while patients with inadequate blinding demonstrated an acetylcysteine advantage.
“Acetylcysteine for Prevention of Renal Outcomes in Patients Undergoing Coronary and Peripheral Vascular Angiography.”
Rivaroxaban Can Be Reversed, But Not Dabigatran
We all hate coumadin – difficult to control levels and causes life-threatening bleeding, but at least we can measure its activity and reverse it in a straightforward manner. However, coumadin’s days are at an end with the approval of the new oral anticoagulants – and the two most extensively evaluated are dabigatran (direct thrombin inhibitor) and rivaroxaban (factor Xa inhibitor).
This is a randomized, placebo-controlled trial of the reversal of dabigatran and rivaroxaban using prothrombin complexe concentrates – which, most importantly, have been theorized to be the only used agent for dabigatran. Their results – in groups of 12 healthy volunteers – is that PCCs have no effect on any of the laboratory clotting parameters for dabigatran, but fully reverse rivaroxaban.
So, while there are no studies as of yet describing the acute reversal of either of these agents in a clinical situation, this is definitely concerning that we still have no theoretical way to treat life-threatening bleeding with dabigatran.
“Reversal of Rivaroxaban and Dabigatran by Prothrombin Complex Concentrate.”
Predicting Poor-Performing Residents
This is an entertaining look into the residency training experience in the United States, which is renowned for its brutality in certain specialities. As far as sleep-deprivation goes, it ranks right up there with some of the lowest quality of life professional jobs.
This is, basically, the quality-of-life information from the Internal Medicine in-service training examination, as reported in JAMA. The authors have linked it to in-training examination results for the, probably predictable, association of poor work/life balance and poor in-training scores.
Interesting tidbits I noticed:
– 15.3% of residents stated that life was as good as it could be.
– PGY-1 and PGY-2 residents had nearly equal poor quality-of-life and work/life balance – which improves significantly PGY-3.
– Over 40% of residents have >$100,000 in debts – and that was associated with poorer quality-of-life scores.
– Improvements in quality-of-life for PGY-3 was mirrored by a corresponding increase in depersonalization.
Not a healthy experience, by a longshot. Pity those whose residencies are longer than the bare minimum of 3 years.
“Quality of Life, Burnout, Educational Debt, and Medical Knowledge Among Internal Medicine Residents.”
More Platelets In Massive Transfusion
Where are we going to get all these blood products? The rapidly growing body of literature backing early transfusion of FFP and platelets in massive transfusion protocols continues to tilt towards the 1:1:1 ratio.
This is a retrospective review of whether platelet transfusion impacts survival in trauma. They identify three categories of ratios of platelets to RBCs (>1:20, 1:2, and 1:1) and measure a variety of different outcomes. Briefly, more platelets helped with survival to 24 hours, but more platelets also increased multi-organ failure. In the end, the initial survival differences were great enough that they outweighed the additional multi-organ failure for a significant survival benefit (52% vs. 57% vs. 70%).
They exclude 25 patients who died within an hour in an effort to mitigate survival bias. However, looking at the breakdown of survival times, it looks as though almost all the mortality benefit to increased platelet ratios was realized in the first 6 hours – and then the mortality numbers worsen in tandem after that. The authors state they were unable to truly quantify retrospectively whether the patients survived because they received more platelets vs. whether patients surviving longer were able to receive more platelets, and note that prospective trials will need to be performed.
I would also note that a significant portion of their high ratio patients also received Factor VII, for whatever that’s worth.
So, we continue to await high quality prospective trials that specifically address the impact of survival bias.
“Increased Platelet:RBC Ratios Are Associated With Improved Survival After Massive Transfusion.”
http://journals.lww.com/jtrauma/Abstract/2011/08003/Increased_Platelet_RBC_Ratios_Are_Associated_With.2.aspx
Impedance Threshold Devices Are Useless
So, supposedly, impedance threshold devices installed inline for ventilation during CPR potentially improve hemodynamics via negative intrathoracic pressure. This is a prospective, randomized, multi-center, placebo-controlled sham study that really meets a very high standard for internal validity. Over 4000 patients in the ITD group, the sham ITD group, and the not-enrolled comparison cohort.
Short summary:
– Minimal differences between groups.
– 27.8% sham vs. 27.1% active device ROSC in the ED.
– 8.2% sham vs. 8.2% active device discharge from the hospital.
– No apparent harms from the ITD device, but no benefits either.
The most important point from this article is that we have gotten sloppy in our rush to implement supposedly new and beneficial therapies in medicine. Hypothermia, TPA for stroke, Factor VIIa, direct thrombin inhibitors, etc. and we should add impedance threshold devices to the list. The AHA has had ITD as a class IIa recommendation to improve hemodynamics since 2005 – six years of useless therapy and costs based solely on a theoretical model without proof of improved outcomes. Hammering this point home never gets old.
“A Trial of an Impedance Threshold Device in Out-of-Hospital Cardiac Arrest.”
www.ncbi.nlm.nih.gov/pubmed/21879897