Therapeutic Misadventures
How you might accidently kill a patient with intubation? Want to know what drug Kafka called the only remedy against the misery of being? The compound that might’ve played a role in Rasputin’s influence over the Romanovs? Listen to find out!
This is the Pick Your Poison podcast. I’m your host Dr. JP and I’m here to share my passion for poisons in this interactive show. Will our patients survive this podcast? It’s up to you and the choices you make. Our episode today is called Therapeutic Misadventures.
How you might accidently kill a patient with intubation? Want to know what drug Kafka called the only remedy against the misery of being? The compound that might’ve played a role in Rasputin’s influence over the Romanovs? Listen to find out.
Today's episode starts in the emergency department with a 42-year-old man in respiratory distress. According to the medics, he was smoking methamphetamine and developed shortness of breath. They know him well, reporting a history of schizophrenia and substance abuse.
The patient is sitting bolt upright, breathing very rapidly at 40 breaths per minute. His oxygen saturation is 88% on 100% oxygen, low. He’s so short of breath, he can't speak. His blood pressure is high at 190/87 as is his pulse at 120 beats per minute. He’s agitated but able to follow basic commands.
You have a lot of questions, but he’s in no position to answer. We don't know if he has a history of lung disease like asthma, or chronic bronchitis, i.e. COPD. Probably doesn’t matter because he’s at risk regardless. Meth causes a lot of problems including bronchitis and congestive heart failure, which in turn causes pulmonary edema or fluid in the lungs.
I’d do a quick physical exam focused on findings related to respiratory distress. Obviously, a lung exam, listening for wheezing from bronchospasm caused by bronchitis, or crackles the sound of pulmonary edema. I’d listen to the heart for a murmur. We don't know if he's an injection drug user, we do know those patients are at risk for endocarditis or bacterial infections on the heart valves which can also result in congestive heart failure. Lastly, a quick check of his legs for swelling.
His lungs have crackles, bilaterally. No wheezing, no murmur and no peripheral edema in the legs. His oxygen saturation has dropped to 84% in the few seconds it took for the exam. There’s no more time for diagnosis, we have to skip right to treatment. There are two main options to treat respiratory failure. The first we've discussed many times: intubation and ventilation. The other option is non-invasive ventilation, or BiPAP. Many people these days know what CPAP is, if you do, BiPAP is similar, essentially, but stronger. The machine blows oxygen into the lungs via a tight mask strapped to the face.
Whenever possible, we start with BiPAP, to avoid risks of mechanical ventilation. It’s safe and effective, there's only one caveat. The person must have a normal mental status and be able to tolerate the tight, uncomfortable mask.
This agitated patient isn’t the best candidate, though honestly, I’d still give it a try in the hopes of avoiding intubation. The respiratory therapist puts the mask over the patient's face and tightens the straps. The patient rips it off. She calms him down and tries again. This time he throws it across the room and attempts to get off the stretcher. Unfortunately, bipap isn’t an option here.
You call for RSI, rapid sequence intubation meds. We give a sedative and a paralytic to put the patient to sleep. Once you give the meds, it takes about 60 seconds to work. Just as you pass the tube through his vocal cords, the monitor starts beeping like crazy and the nurse says his heart rate is dropping. Before you can react, he goes into asystole. A flat line moves across the monitor. The nurse starts CPR. You call for epinephrine.
What the hell just happened?
With intubation, as with any procedure, there’s always a risk of complications, in this case, cardiac arrest. Once you give paralytics, the person’s diaphragm doesn’t work and they can’t breathe. If you don’t get the tube into the trachea fast enough, lack of oxygen can cause a cardiac arrest. If you put the tube in the wrong place, ie the esophagus, the same thing happens. Also, sedatives cause low blood pressure, which can cause cardiac arrest. Anyone whose taken care of a sick patient knows the risk of rapid decompensation and cardiac arrest during this procedure is real, not theoretical.
Did we just kill our patient?
While acknowledging the fact anyone can code during intubation, it shouldn’t be happening in this guy. You double check the tube, it’s in the trachea where it belongs. His oxygen was low to begin with, but didn’t drop any lower during the procedure. His blood pressure and heart rate were high, so even if our intubation meds dropped the pressure, there was plenty of room to spare.
What caused him to code?
No idea. Let’s admit it and keep moving forward. The intern squeezes the bag valve mask attached to the breathing tube. He's overly enthusiastic and squeezing too quickly. The respiratory therapist tells him to slow down keeping the breaths around 12-15 per minute. Stacking breaths means the lungs don't have time to exhale and essentially become over-inflated. On the next pulse check, you breathe a huge sigh of relief when the nurse palpates a pulse.
Respiratory hooks the patient up to the ventilator, setting the respiratory rate to 15 breaths per minutes, a normal value. The radiology tech shoots a portable chest x-ray. Labs are pending.
The patients heart rate slows down again, and he has another asystolic cardiac arrest. We restart CPR and epinephrine. Following standard procedure, the intern takes the patient off the ventilator and reattaches the bag valve mask.
This cannot be a coincidence. What is happening?
Is it the meth he smoked? Certainly, meth can be lethal, but the patient doesn’t have a sympathomimetic toxidrome. Yes, his blood pressure and heart rate are high, no doubt from the drug, but not dangerously so. This isn’t a stroke or an intracranial hemorrhage and he’s not having a lethal arrythmia like v.fib.
The x-ray confirms your physical exam findings. The patient has pulmonary edema, fluid in the lungs. This could be from meth. Heart failure, as I mentioned, is one cause. Noncardiogenic causes include lung injury and inflammation. Regardless of the etiology, fluid in the lungs, instead of air leads to hypoxia. Intubation is a mainstay of treatment. He should’ve improved, not coded. I’m not convinced meth is the immediate cause of this cardiac arrest.
If you’re paying attention, you’ve noticed he’s arresting when we put him on the ventilator. This is actually a huge clue and I’d do a little test here. I'd tell the intern to increase the rate at which he’s squeezing the bag, to take it all the way up to the patient’s respiratory rate before we intubated him. Realistically, 40 breaths per minute might be tough, but at least up to 30. The respiratory therapist objects, given this is clearly outside of standard practice.
It works! The patient gets a pulse back again. This time, when you put him on the ventilator you insist on a rate of at least 30 in addition to a large tidal volume, the medical word for big, deep breaths. You hold your own breath for a few seconds, waiting to see if it works. The ventilator beeps like crazy objecting to the settings. The patient doesn’t have another cardiac arrest. Excellent.
Now we have to figure out the cause. In short, we have a patient with schizophrenia, pulmonary edema with hypoxia, and cardiac arrest.
Question number one. What is the next best step?
An ABG, and arterial blood gas
A BNP, blood natriuretic peptide, a measure of heart failure
a CAT scan of his lungs
a fingerstick blood glucose
Answer: A. A blood gas. All of these tests might be useful, but the blood gas is quick and easy. We take an arterial specimen from the wrist and, unlike our usual tests, it takes just a few minutes to result. Blood gases measure levesl of oxygen and carbon dioxide, useful to ensure the ventilator settings are correct. It also measures the pH of the blood and bicarbonate levels. The incessant beeping from the ventilator is loud enough to wake the dead, but so far, the patient is still alive.
His blood gas shows the following results. A pH of 7.35, PO2 of 200 mmHg, a PCo2 of 28 and bicarbonate 18 mEq/L. Let me sum this up for you if you're not used to blood gases or if you use different units. The pH of the blood is normal. The oxygen level is higher than normal because we have him on oxygen, the carbon dioxide is low and so is the bicarb.
The patient’s pH is normal, so at first glance, you might think he doesn’t have an acid/base disturbance. Acidosis, or acidemia, is when there’s too much acid in the blood and alkalosis, or alkalemia, is too much base. However, his bicarb is low. This is because its buffering excessive acid build up. Why is the pH normal if he has extra acid? Because he has two disturbances, an acidosis AND an alkalosis. They are balancing each other out, for now, leaving the pH in a normal range.
Once we determine the type of disturbance, the next step is to determine the source, either metabolic or respiratory. Metabolic acidosis results from diarrhea or renal disease and of course from toxins. Remember the mnemonic CAT MUDPILES. If you’ve forgotten, listen to the White Lightning episode. Metabolic alkaloses are usually from losing acids in vomit or in the urine as a side effect of diuretic medicines.
Your lungs help regulate acid base status. Carbon dioxide when exposed to water in the body becomes an acid. So, if you are breathing fast and exhaling carbon dioxide, you can develop a respiratory alkalosis, due to things like anxiety or pneumonia. If you are breathing too slowly, or not ventilating, CO2 builds up resulting a respiratory acidosis. You see this in asthma, opioid overdoses and diseases like muscular dystrophy causing diaphragmatic dysfunction.
Our patient’s CO2 level is low, resulting in a respiratory alkalosis. In summary, our patient has been breathing too fast, causing a respiratory alkalosis and has acid in his blood causing a metabolic acidosis. Review of the rest of his labs shows it’s an anion gap acidosis, bringing us back to the unmeasured acids of CAT MUDPILES.
The ABG has given us the answer. This is a tough case, it’s taken us a long time, but we haven’t given up. In real life we could easily miss this diagnosis. What toxin causes this classic mixed acid base disturbance and is poisoning our patient?
Carbon Monoxide
Aspirin
Acetaminophen or Tylenol
Fentanyl
Answer: B aspirin. A mixed metabolic acidosis with a respiratory alkalosis is a classic finding in aspirin, or any salicylate, overdose. We confirm with the results with a salicylate level. It’s 150 mg/dL. Yikes. Therapeutic levels range from 10-30. To answer our earlier question, yes we did almost kill our patient by intubating him. More on this in a bit.
Salicylates are one of, if not the, oldest medicines in existence, in use for at least 3,500 years. Question #2. Where does aspirin come from?
Willow tree
Yew Tree
Cinchona
Eucalyptus
Answer: A. Willow bark is the original source of aspirin. Yew trees are poisonous, but also the source of Taxol used to treat breast cancer. Eucalyptus oil can be poisonous, but not the trees. Willow bark use is record as far back as the Sumerians. It’s mentioned in the Ebers Papyrus from Egypt. In ancient Greece, Hippocrates prescribed it for inflammatory pain and childbirth.
Cinchona is the source of quinine to treat malaria, and interestingly, associated with modern use of salicylates in medicine. In 1758, Reverand Edward Stone was looking for a cheaper alternative to cinchona for treatment of agues or fever. This was during the Napoleonic Wars, blockades interfered with importation of Cinchona bark from Peru, making it very expensive. He decided to try willow bark instead, showing it reduced fever in the 50 patients he treated.
Salicylic acid is the active ingredient in the bark, identified in 1828. Seven years later, modern aspirin, or acetylsalicylic acid, was synthesized by Felix Hoffman, who worked for the Bayer company. He was motivated to find an alternative because his father who used salicylic for rheumatism had begun vomiting due to the very strong gastrointestinal side effects. Acetylsalicylic acid was easier on the stomach. Side note: Hoffman’s next success was diacetylmorphine or heroin.
Once Bayer marketed the drug, its popularity exploded worldwide. Hilariously, there was initial concern for cardiac toxicity, which though disproven, prompted a warning on the label saying “Does not affect the heart.” In a letter to his fiancé, Franz Kafka called aspirin the only remedy against the misery of being. It’s mentioned in works by Thomas Mann, Henry Miller and Gabriel Garcia Marquez.
One really fascinating fact is salicylate toxicity probably increased the influence of Rasputin over the Romanovs. Tsar Nicholas II’s son Alexei took aspirin like many during this time. Rasputin, advocating less Western, more mystical cures told him to stop. Alexei had hemophilia, so of course without the drug he improved, strengthening Rasputin’s position within the family.
Back to our patient. We need to start treating him for ASA toxicity. We are already using the ventilator for hyperventilation; this helps keep salicylate out of his brain. I would give multidose activated charcoal to bind to and inactivate salicylates. Why? Aspirin clumps together, forming what’s called a pharmcobezoar. A bezoar is indigestible material found in the stomach, and interestingly bezoars from animals were believed to be an antidote for poisoning in the Middle Ages, but that’s a topic for another day. A pharmacobezoar behaves like a delayed release preparation, so among other mechanisms, administering charcoal every 2-4 hours can bind the toxin as it’s slowly released.
The mainstay of treatment for salicylate poisoning is alkalinization. This serves two purposes, first increasing the pH of the blood pulls salicylate out of the brain and tissues into the blood. Second, an alkaline urine traps salicylate in the urine, allowing increased elimination from the body. How do we alkalinize? By giving bicarbonate. I’d give him a bolus dose of 1-2 mEq/kg, then tell the nurse to spike a bag of D5 water with 3 amps of bicarb (or 150 mEq) and run it as a drip at 150 ml/hr. The exact rate varies, and in our patient, we need to be careful because he already has too much fluid in his lungs. You want to titrate the rate to an alkaline serum pH, keeping it well above 7.45 but below 7.5. The urine pH should be greater than 8.
What about extracorporeal removal? Dialysis removes salicylate from the blood, so it’s a great option, but it’s an invasive procedure. The indications, ie where the benefits of dialysis outweigh the risks, are in patients with an altered mental status, a high salicylate level of 100 mg/dL (7.2 mmol/L) or higher. Severe acidosis with a pH <7.2. Hypoxia requiring oxygen. Or failure of standard treatment.
Our patient meets just about all of the criteria with an altered mental status, hypoxia and a dangerously high level. You call nephrology for dialysis. If you had any doubts about intubating him earlier, I can tell you we’d be doing it now regardless of his respiratory status, for dialysis catheter placement. He was too agitated to tolerate this procedure.
I'm sure you know about aspirin and its effects on thinning the blood, the reason we use it in heart attacks and strokes. Subacute or chronic exposure leads to well-known side effects of bleeding and gastric ulcers. In overdose, salicylates have a lot of effects. Let’s discuss some of them, focusing on what happened with our patient and how we accidentally almost killed him.
First, salicylates stimulate the respiratory center in the brain, causing an increased respiratory rate and increased depth of breaths. This blows off CO2, causing a respiratory alkalosis. Second, salicylate toxicity causes metabolic changes including uncoupling oxidative phosphorylation, resulting in energy failure at the cellular level. For more detail on this, listen to the Explosive Heat episode. Salicylic acid is itself an unmeasured anion, contributing to the anion gap acidosis, along with results of energy failure including an elevated lactate and ketones. This combination acid/base disturbance gives us the classic clinical picture associated with toxicity. Of note this finding is less common in children and in chronic toxicity.
CNS toxicity due to salicylates in the brain leads to altered mental status, cerebral edema or swelling of the brain, and ultimately seizures, coma, and death. Thus, the goals of treatment focus on keeping salicylates out of the brain. Our patient had pulmonary edema and ARDS, fluid in the lungs. This is not uncommon, though the mechanism is poorly understood, it’s likely a result of vascular changes with resulting fluid accumulation.
How do these effects cause cardiac arrest during intubation? Well, cells are optimized to work at normal pH levels. When the body becomes severely acidotic, they stop working properly. The classic example is diabetic ketoacidosis. When the blood sugar sky rockets, acids build up. Before insulin existed as a drug, DKA led to certain death in Type 1 diabetics. In the case of severe acidosis, if you stop the patient from breathing, you stop the body from attempting to compensate by blowing off CO2. Cardiac cells also require normal pH to function. Acidosis allows more salicylate to get in the brain. The results is immediate, and I do mean immediate, decompensation.
The risk of intubation worsening the clinical status is real. Unfortunately, I’ve seen this occur many cases. The first type of case is intubation before you know it’s an aspirin overdose, as with our patient.
The second, actually more common, is the following scenario. The patient is awake but very agitated. They have a high salicylate level and are altered, so they need dialysis. It requires a very large central line catheter to be placed into a major blood vein in the chest or neck, like the internal jugular. The procedure is relatively safe, if the patient lays down and holds still. If not, it’s extremely easy for the needle to go into the wrong place, like the carotid artery or the lung, puncturing and collapsing it. An agitated, confused patient simply can’t cooperate.
The answer for this potentially life-saving procedure in a critically ill patient is sedation and intubation. If they don’t get dialysis, they might die. If we intubate them to facilitate dialysis, they might die. It’s truly a rock and a hard place. We try to optimize the physiology in advance, I can tell you from experience, it’s always a gamble.
Pretreating with bicarb helps reduce the level of acidemia during the time the patient isn’t breathing. The most experienced provider intubates, this isn’t the intern’s chance, to minimize the time it takes and to ensure the tube is in the right place on the first pass. Despite these precautions, patients often deteriorate into cardiac arrest.
I feel terrible we missed the initial diagnosis and almost killed our patient, as I would in real life. That said, a little perspective is helpful. A review of US poison center data, found 7 cases of intubated patients with salicylate poisoning with enough data to analyze. Of these, two died immediately after intubation, and a third suffered serious neurological injury. Making the odds about 50/50.
Our patient has acute salicylate toxicity, hard enough to diagnose without the history, as you can see. Chronic salicylate poisoning is even more difficult. It occurs typically in older adults taking high doses over days to weeks. While the presentation is similar to acute toxicity, the symptoms can be more insidious and may mimic other diseases.
Question #3. Which of the following diseases has chronic salicylism been mistaken for?
Dementia
Encephalitis
Alcohol intoxication
Alcohol withdrawal
Answer: If you answered this question, you answered correctly. It’s been mistaken for all of those problems, in addition to delirium, sepsis, and respiratory failure just to name a few. Adding to the difficulty, salicylate levels correlate poorly with toxicity. Delay in diagnosis increases mortality rates to as high as 25% in some studies.
Our patient is transferred to the ICU where he gets dialysis and the team monitors alkalinization, adjusting to optimize his blood and urine pH. They check serial salicylate levels which begin to drop with treatment.
In the 1950s-1970s salicylates were leading cause of pediatric poisoning deaths in the US. The popularity of aspirin continued until the association with Reye’s syndrome in children was discovered. Aspirin isn’t the only form of salicylate available. Bismuth subsalicylate (Pepto-Bismol) causes salicylate poisoning. A 12 oz or 350 mL bottle can have as much as 3,000 mg of salicylate. For reference, a baby aspirin is 81 mg and a full dose 325 mg.
The dangers of topical salicylate preparations are often underestimated. Oil of wintergreen, methyl salicylate, is a one pill can kill drug. One pill can kill is a list of toxins that can be lethal in children with exposure to single dose. Oil of wintergreen is a liquid, but exposure to 1 ml, or 1/5 of a teaspoon, is dangerous, and depending on the concentration can have 1400mg of salicylate.
Topical creams carry a similar risk. Sports muscle creams, Bengay for example, cause salicylate toxicity. A 17-year-old girl in Long Island died after topical application of a lot of cream. Another teenager developed toxicity after using a tube of cream for masturbation. An interesting study of healthy volunteers showed exercise and heat resulted in absorption of three times as much salicylate than a typical exposure.
Our patient wakes, up and is extubated after his salicylate level drops below 50. The fluid in his lungs resolve. Eventually, we get to the bottom of what happened. The patient developed ankle pain, after twisting it. Due to schizophrenia and meth use, his thinking was not clear. He ingested handfuls of aspirin over the course of a day to treat the pain, without understanding the risks. He returns to his baseline mental status and has no sequela from the therapeutic misadventures. This is a fictional case, as are all our cases, to protect the innocent. But it is based on real poisonings.
Today’s Pop Culture Consult and the last question. What actor’s death was attributed to an aspirin hypersensitivity reaction?
Richard Pryor
John Wayne
Lucille Ball
Bruce Lee
To note – likely misattributed.
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