Emergency clinicians rarely have to worry about oxygen toxicity, but perhaps they should. Our patients are often hypoxic, on a ventilator, comatose, or otherwise supposedly in need of oxygen to treat their underlying problem. The ritual use of low-flow oxygen for a variety of unproven conditions is omnipresent. Very few patients with chest pain, abdominal pain, or other multisystem issues can escape the oxygen-emitting cannula in the ED.
It has become obvious over the years that high-flow 100% oxygen for a prolonged period of time can cause its own toxicity, with the lung being the main target. That's why the oxygen concentration is weaned as soon as possible on the ventilated patients in the ICU, and many are now even decreasing the use of high-flow oxygen in other patients. I highlighted the potential of oxygen toxicity in traumatic brain injury, following cardiac arrest, and even in the cyanotic newborn in an earlier column. (EMN 2013;35:12; http://bit.ly/1mGWOEM.)
The potential harm from oxygen in myocardial infarction has been raised again recently. This sacred cow will nonplus many clinicians, and most will probably not change their routine practice just yet. Hyperbaric oxygen has been posited as a possible intervention for patients with persistent postconcussion syndrome. Likewise, hyperbaric oxygen does not seem to do anything for this subset of patients.
Air Versus Oxygen in Myocardial Infarction Study (AVOID)
Ongoing; Not Recruiting Participants
ClinicalTrials.gov Identifier: NCT01272713
An amazing and rather thought-provoking concept was presented at the recent American Heart Association Scientific Sessions 2014. Ahead-of-publication reports, including Medscape, detailed the results of the AVOID trial. (Jeffrey S, Nov. 21, 2014; http://bit.ly/1Ac2JJ4 [subscription required].) This study compared supplemental oxygen with no oxygen in ST-elevation myocardial infarction, except in hypoxic patients. It found that routine high-dose oxygen would actually increase myocardial injury in patients with ST segment elevation MI but no hypoxia. The routine administration of prolonged high-flow oxygen to patients with normal oxygen saturation was associated with an increase in recurrent myocardial infarction and major cardiac arrhythmias and even a greater infarct size at six months. These are rather startling observations and almost medical heresy.
Supplemental oxygen has been fundamental management in patients with a suspected acute myocardial infarction for many years, and its routine administration is universal. But little evidence on its benefit has been found by randomized clinical trials. It only seems logical to administer oxygen because chest pain is thought to be from lack of oxygen flow to myocardial tissue. As little as 15-20 minutes of oxygen administration can cause hyperoxia, which actually leads to a reduction in coronary blood flow, increased coronary vascular resistance, increase in oxygen free radicals, and adverse changes in cardiac microcirculation. Decrements in vital capacity of up to 20 percent have been noted after hyperoxic exposure. These changes induced by oxygen may contribute to increased reperfusion injury or actual new myocardial injury during acute coronary syndromes.
Patients in the AVOID trial had oxygen saturation in a normal range, defined as greater than 94% saturation by pulse oximetry. Patients had to have a diagnostic EKG demonstrating ST segment elevation consistent with STEMI to be enrolled. They were not included if their oxygen saturation was below 94%, if they had altered consciousness, or if they received oxygen prior to randomization. Those with a confirmed STEMI received room air or oxygen by mask at 8 liters/min given prehospital and continued until they were stable on the floor. Those in the no-oxygen arm were not given oxygen unless they became hypoxic (oxygen saturation less than 94%).
Cardiac arrest and cardiogenic shock occurred similarly in both groups. One interesting fact was that the use of oxygen showed no indication of symptomatic benefit, such as lessening of chest pain. The primary endpoint, myocardial infarction size based on enzyme elevation, revealed a significant 25 percent increase in CK in those delivered oxygen, a clinical suggestion of increased myocardial injury. No significant change was seen in troponin levels. Cardiac MRI evaluating the infarct size at six months suggested an increased infarct size and more myocardial injury in those given oxygen.
The study also showed an overall trend toward harm from oxygen. Mortality was similar between both groups, but a significant increase in recurring MIs and significant arrhythmias was seen in the oxygen-treated group. The authors emphasize that these patients were not hypoxic, and they said only those who had an oxygen saturation less than 96% should not be given oxygen.
It is axiomatic that cardiac patients with ischemic chest pain should receive oxygen, morphine, nitrates, and aspirin, but this trial questioned whether oxygen should be given. It also noted that a recent Cochrane review on oxygen therapy was inconclusive and suggested harm, but the prestigious review offered no real conclusion that oxygen delivery was detrimental. The most astounding finding of this study was that the infarct size was significantly less when oxygen was avoided. The relatively high use of oxygen at 8 liters/min was also discussed. It's not known whether the effect of the very high extra oxygen was harmful, or if lower doses would give the same adverse effects during MI. The authors also highlighted an increase in arrhythmias and recurrent infarction in those given oxygen.
Comment: This is a rather provocative study. Who would ever think that high-flow oxygen administered to patients in the throes of an acute myocardial infarction would ultimately worsen outcome, namely increasing myocardial infarction size, increasing arrhythmias, and increasing the rate of recurrent myocardial infarction? The outcome does, however, make sense when one considers the effect of hyperoxygenation. Numerous detrimental effects are seen with high-dose oxygen on myocardial tissue and myocardial blood flow. One issue is the fact that 8 liters of oxygen per minute was administered, clearly above the normal 2-4 liters that is standard practice. Arterial blood gas analysis was not performed, but one would assume that most patients were 100% saturated and had PAO2 of more than 250 mm Hg.
Effects of Hyperbaric Oxygen on Symptoms and Quality of Life among Service Members with Persistent Postconcussion Syndrome: A Randomized Clinical Trial
Miller RS, Weaver LK, et al.
JAMA Intern Med
Nov. 17, 2014; http://1.usa.gov/1xrmhK7
The authors of this article examined whether hyperbaric oxygen (HBO) is beneficial as an adjunctive treatment for postconcussive syndrome. A beneficial effect has been suggested, but it has not been rigorously studied. These authors used a multicenter double-blind, sham-controlled clinical trial of 72 military service members. These individuals had ongoing symptoms for at least four months after mild traumatic brain injury. The hyperbaric treatment consisted of 40 sessions of hyperbaric oxygen at 1.5 atmospheres or 40 sham sessions consisting of room air at 1.2 atmospheres. An assessment occurred before randomization, at the midpoint of therapy, and within one month of completing interventions.
The participants had sustained an average of three lifetime mild traumatic brain injuries, the most recent within three months of enrollment. No significant outcome difference was observed between the two treatment groups. The patients treated with HBO showed no benefit over sham compressions; both groups demonstrated a slightly improved outcome compared with standard postconcussive syndrome treatments. The authors conclude that the observed improvements were not oxygen-mediated but the effects of placebo or nonspecific interventions.
Comment: It's not an emergency medicine issue, but emergency clinicians frequently see patients with persistent postconcussive symptoms. Evaluating minor head injury is an everyday ritual. Even a minor head injury can cause persistent abnormalities, and it has become a huge issue with sports-related head injuries. Apparently even mild repetitive brain injury can cause detriments in cerebral function, and there is no good way to intervene with effective therapies. Probably the most important issue for emergency clinicians is to prohibit contact sports until all symptoms go away, and the most reasonable way to do this is to refer them to appropriate follow-up.
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The Toxicity of Inappropriate High-Flow Supplemental Oxygen
Supplemental oxygen is valuable in many clinical scenarios, but inappropriate high-flow supplemental oxygen can be harmful. High concentrations of inspired oxygen can cause a spectrum of lung injuries, ranging from mild tracheobronchitis to diffuse alveolar damage. The alveolar damage is histologically the same as in the ARDS syndrome. The mechanism of oxygen toxicity is vague, but it probably includes an increase in reactive oxygen species, such as superoxide, the hydroxyl radical, and hydrogen peroxide. Oxygen radicals can result in cellular death, and oxygen free radicals can lead to a deleterious inflammatory response. Lung tissue is at the greatest risk for hyperoxic toxicity. In addition to free radical formation, hyperoxia increases mucus plugging and atelectasis and impairs the bactericidal capacity of immune cells.
The term oxygen toxicity is generally used for the well-described consequences to lung tissue. High-oxygen administration causes absorptive atelectasis and a washout of alveolar nitrogen producing focal atelectasis. Shunting from absorption atelectasis can occur in otherwise healthy volunteers breathing 100% oxygen for a mere 30 minutes. Even normal individuals will become symptomatic following the inhalation of pure oxygen for 24 hours, likely from a combination of tracheobronchitis and atelectasis. Erythema and edema of the large airways also occur.
The extra pulmonary toxicity of oxygen includes retinopathy of prematurity and the previously described alterations in cardiovascular physiology. Importantly, increased oxygen tension leads to local coronary vasoconstriction, and microscopic myocardial necrosis has been observed in animals. No well-defined threshold of inhaled oxygen or duration of supplemental oxygen yet clearly defines when oxygen toxicity can occur. Efforts to provide just enough inhaled oxygen required to make oxygen saturation between 60 and 70 mm Hg with an oxygen saturation of 90-94% have been suggested. Additional measures, such as the institution of PEEP, bronchial pulmonary hygiene, prone positioning, and diuresis, have also been suggested. The UpToDate medical reference says these additions should be considered when the FiO2 exceeds 60% for more than six hours. Many ventilated patients who remain in the ED may be candidates for downward titration of the level of inhaled oxygen to prevent oxygen toxicity.
The 2010 oxygen administration guidelines from the American Heart Association list potential adverse effects of oxygen administration during adult and neonatal resuscitation. They recommend 100% oxygen during initial resuscitation from cardiac arrest but then titrating oxygen to the lowest level required to achieve an arterial saturation of 94%. This is thought to reduce oxygen toxicity while not being harmful to post-resuscitative care. An arterial oxygen saturation of 100% may correspond to a PaO2 anywhere between 80 and 500 mm Hg, so it is always appropriate to wean the FiO2 when the saturation is 100% and aim to keep the saturation maintained at greater than 94%. This was a class 1 recommendation by the AHA in 2010.
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Ectopic Pregnancy Without Abdominal Pain Possible
Dr. Roberts: Yes, it is possible to have an ectopic pregnancy without any abdominal pain, a topic that was mentioned briefly in your August column. (“Identifying Life-Threatening Syncope in Children,” EMN 2014;36:14;http://bit.ly/1qNUkt0.) Fifteen years ago, we saw a young woman late in the evening for syncope without any pain, bleeding, or other complaint. She knew she was pregnant, estimated to be eight weeks or so, but ultrasound (US) was not readily available at that time.
She looked good otherwise, and we put her in the observation unit on fluids because she had persistent, unexplained tachycardia. In the morning, her blood pressure dropped, a repeat Hb was down significantly, and an US was positive for ectopic and free fluid. Still no pain. Laparoscopy confirmed an ectopic that had perforated the posterior fornix. She did well postoperatively. — Robert E. Suter, DO, Dallas
Dr. Roberts responds: Just another example of how difficult it is to be an ED doc who has to make decisions in a short time frame and without much data. Many would have sent her home because fainting is quite common during pregnancy. Good pickup, Dr. Suter; you may have saved her life. Tachycardia was a tipoff, but it is well known that ruptured ectopics often have bradycardia, possibly vagal in origin.
My Personal Experience with Chikungunya
Dr. Roberts: I am very familiar with chikungunya, having worked in St. Thomas over the summer right in the middle of their epidemic. (“InFocus: Forgotten but Not Gone: Chikungunya,” EMN 2014;36:8; http://bit.ly/1FHVOae.)
As you can imagine, their resources are minimal, and there is no way to get timely results. Dengue is also rampant there, and it can be difficult to distinguish between the two. NSAIDs are actually contraindicated until the chikungunya is confirmed because of the possibility of thrombocytopenia with dengue. Our management consisted primarily of CBCs and loads of Tylenol. The pain can truly be debilitating, but fluids and Tylenol work wonders. Patients do quite well once the fear of the disease is overcome.
The locals seemed to be more afflicted than tourists likely because of mosquitoes avoiding the trade winds off the beach (primary location of the resorts) and the resorts utilizing screens and frequent spraying. Chikungunya spread like wild fire through the Caribbean because there is zero immunity, and it is now being reported in the idyllic South Pacific. Short of leukopenia or significant thrombocytopenia, neither infectious disease specialists nor hospitalists generally get involved because of the sheer volume of the patients afflicted.
Thanks for bringing this to the forefront of our specialty. — Jason Nelson, MD, Louisville, KY
Dr. Roberts responds: Great comments, Dr. Nelson; thanks for the feedback. I am sure most physicians in endemic areas are, like you, quite familiar with the diseases, but it is currently quite a diagnostic challenge in the United States that would usually be dismissed as a simple unknown viremia. Unexpected thrombocytopenia, more common with dengue, is another reason to be generous with lab testing in the ED. Doubt you will see much chikungunya and dengue in Louisville ... yet. Maybe you will see it in a recent vacationer if that history is elicited.