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A perplexing case
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A young man with a history of seizures and alcoholism presented with a generalized seizure. His seizure responded to lorazepam, but he was intubated for airway protection and was transferred to the Genius General ICU. He was also loaded with levtiracetam to prevent further seizures.
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Overnight he developed agitation. Despite increasing his propofol to 80 mcg/kg/min and adding fentanyl, his agitation worsened (e.g. sitting bolt upright in bed). There was concern that he was likely suffering from alcohol withdrawal, which may also have contributed to his seizure. Consequently, he was loaded with 10 mg/kg of intravenous phenobarbital, with the goal of treating his alcohol withdrawal and also reducing the likelihood of recurrent seizures. Given concern about the risk of propofol infusion syndrome, propofol was weaned off after the phenobarbital was delivered.
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Subsequently he entered a stupor. Fentanyl was stopped as well, but he remained very difficult to arouse. What had happened? Generally, 10 mg/kg phenobarbital should not cause that degree of sedation.
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After a few hours, he woke up and was successfully extubated. It ultimately turned out that his seizure was due to noncompliance with his antiepileptic, probably not alcohol withdrawal. The remainder of his recovery was uneventful, without any recurrent seizures or any symptoms of withdrawal.
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In retrospect, he may have been having a paradoxical reaction to propofol. Perhaps he was agitated because of the propofol, not despite it. His transition from agitation to stupor may have been due to the combined effects of discontinuing propofol and adding phenobarbital (in the context of some residual lorazepam and post-ictal confusion). Over time, his post-ictal state improved and the lorazepam was metabolized, allowing him to wake up.
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Introduction
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Benzodiazepines and propofol are widely used in critical care. Both have similar mechanisms of action, based on activating inhibitory GABA receptors. Rarely, these drugs may cause paradoxical agitation. In the setting of an elective procedure, this diagnosis may be obvious. Conversely, in the context of a complex critically ill patient, recognizing this diagnosis may be nearly impossible. Regardless, this is an important diagnosis to recognize because it requires specific management.
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Clinical features of paradoxical reactions
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Central features of paradoxical reactions (PRs) are emotional lability, agitation, excessive movement, and confusion. This may be associated with increased autonomic activity including tachycardia, hypertension, and tachypnea. Unfortunately, there is no uniform definition of a PR, with the above description based on case studies describing PRs following benzodiazepines. There is less literature describing PRs induced by propofol, but clinical features appear to be similar (Jeong 2011).
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Epidemiology of paradoxical reactions
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Procedural sedation
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The rate of PRs following benzodiazepine is probably on the order of 1-2% (Tae 2014). Rates appear to be higher with propofol. For example, one RCT found a rate of 36% with propofol vs. 5% with midazolam (p<0.05; Ibrahim 2001). Risk factors include alcoholism, extremes of age, and psychiatric comorbidity.
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Jeong 2011 performed a prospective observational study of 190 patients undergoing propofol sedation combined with spinal anesthesia for knee surgery. Patients with a history of hazardous drinking were much more likely to experience PRs. This difference was more notable at higher doses of propofol:
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Abbreviations: HD = Hazardous drinking, NHD = Non-hazardous drinking. Study 1 involved titration of propofol to target a bispectral index of 70-80. Study 2 involved fixed infusions of propofol at two rates. A severe PR was defined as requiring physical restraint. For further details see open-access manuscript here. |
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Does this happen in critically ill patients?
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Based on the frequency of benzodiazepine and propofol use among critically ill patients, PRs would be expected to occur with some regularity. However, there is no mention of this in the medical literature. Why not?
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This may be due to the difficulty of diagnosing a PR in the ICU. PRs are largely a diagnosis of exclusion, which may be very difficult in a complicated patient. Agitation is common among ICU patients, so distinguishing a PR from garden-variety agitation may be like finding a needle in a haystack.
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PRs may be more common in the ICU than appreciated. For example, occasionally intubated patients are encountered who remain agitated even despite high doses of propofol or benzodiazepine. We may raise an eyebrow and perhaps comment on the patient's history of alcoholism, but otherwise little attention is paid to this. Perhaps these patients are having untreated PRs.
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Neurobiology of paradoxical reactions
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This remains unclear. Some idiosyncratic reactions may be based on genetic variability. Notably, one report documented a pair of identical twins who both had dramatic reactions to midazolam (Short 1987). The increased rate of PR in alcoholism might relate to changes in GABA receptors and GABAergic pathways induced by alcoholism (e.g. differences in receptor subunit composition; Bhandage 2014).
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Management of paradoxical reactions
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Step 1: Stop the offending agent
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The most important aspect is recognizing the PR and discontinuing the causative medication. Some early investigators felt that that PR might reflect “undersedation” which would respond to dose escalation, but this has proven to be counterproductive in an RCT and case reports involving benzodiazepines (Golparvar 2004, Fiset 1992). Jeong 2011 found the highest rate of severe PRs when the propofol was titratedto a target sedation level, suggesting that responding to agitation with higher propofol doses simply aggravated the PR. With propofol it may be possible to overpower a PR with coma-inducing doses, but this is an undesirable sedation strategy.
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Failure to diagnose that the patient is experiencing a PR may lead to progressive up-titration of sedative dose, leading to a vicious cycle:
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Step #2: Counteract residual drug: Flumazenil
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Propofol will be rapidly metabolized, so residual drug is only an issue for benzodiazepines. Flumazenil appears to be an excellent treatment if not contraindicated (e.g. by chronic benzodiazepine use). About a dozen case reports describe flumazenil as being uniformly effective in rapidly terminating a PR due to a benzodiazepine. Furthermore, flumazenil appears to terminate the PR while preserving amnesia and sedation, generally allowing completion of the procedure.
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Step #3: Add a non-GABA sedating medication
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If the patient still requires sedation following the above steps, a sedative that doesn’t interact with GABA receptors may be added. There are several reports of patients who had a PR with one benzodiazepine, yet were able to tolerate a different benzodiazepine (Mancuso 2004). However, for acute management it may be safest to avoid this class of drugs entirely.
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Non-GABA options include opioids, antipsychotics, dexmedetomidine, and ketamine. There is little evidence to determine the best option:
- Ketamine: One RCT of 24 children <6 YO with PRs due to midazolam found ketamine 0.5 mg/kg to be effective (Golparvar 2004). However, since all patients in this study were subsequently intubated for surgical procedures, it is possible that general anesthesia may have masked any emergence reactions from ketamine.
- Haloperidolwas successful in one case report (Mancuso 2004).
- Opioids: One prospective series of 4,140 patients undergoing gastrointestinal endoscopy showed that higher doses of opioid and lower doses of benzodiazepine correlated with a lower risk of PR, implying that opioids would not worsen a PR (Tae 2014).
- Occasionally benzodiazepines induce a paradoxical reaction marked by agitated delirium with emotional lability and restlessness. This may be more common with propofol.
- Risk factors for paradoxical reactions include psychiatric comorbidity, extremes of age, and alcoholism.
- Treatment consists of discontinuing the offending agent and reversing it if possible (with flumazenil for PRs due to benzodiazepine). If needed, non-GABA sedatives may be used (e.g. ketamine, haloperidol, opioids).
- Failing to recognize and treat a PR might lead to a vicious cycle of ongoing agitation:
Related blogs: The paradoxical excitation response by ScanCrit
Stay tuned, this is the first of a series of two posts about GABA receptors run amok in critically ill patients.
Conflicts of Interest: None.
Image credits:
http://www.freeimages.com/photo/closeups-eyes-rage-emotion-1478626
https://en.wikipedia.org/wiki/Iceberg#/media/File:Iceberg.jpg
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I’ve has two alcoholic patients with presumed withdrawal, given high dose benzos, after 2 days, they are psychotic, with normal vital signs. I stop their benzos and they’re fine in 24 hours. I’m afraid to try flumezenil due to risking a seizure in these patients. Should I be?
I’d try. I’d just do it in the ICU and would have IV Dilantin or depakote at the ready in case it did precipitate seizures. Psychiatrist. ThedaCare, Wisconsin.
Personally I’d be afraid to give flumazenil in this situation without consulting a toxicologist. The paper about flumazenil was mostly included as a proof-of-concept paper, not necessarily a recommendation for practice. It might be safe, you might be right… but I’m just not sure.
I just finished reading your article, and the same thing happened to my son. It first happened with clonazepam, at first I thought he was a poor Metabolizer on the cyp2d6 gene, but clonazepam is metabolized by the cyp3a4 gene, and his is normal. Then he was put on xanax and it took 45 min to calm down and lasted 1/2hr and back to anxiety and no sleep. I gave him benedryl today to see if that would help but only had the same reaction. His Dr. Discontinued Risperdone because of the interaction with his genes. We tried Latuda but… Read more »
For years after having any anesthesia I would find myself feeling liked a caged tiger. I was restless and agitated. I began looking at possible side effects of all the meds used and found it was the versed that gave me that feeling. Later in life I was taking clonazipam and every day I became more and more “mean”. after a week of yelling at people, saying hateful things,I looked at all the meds I was taking and the only NEW one was the clonazipam. Spoke to my doctor and she took me off the med and within a few… Read more »
I have bouts of uncontrollable agitation. I have been diagnosed with RLS( restless leg syntdromeI take Ropinorol for this. I also take Citalopram 40 mg for depression. Often I can not sit still in a movie theater. Or in the evening watching television. When I have mentioned this to my health care provider, they don’t have an answer.. Would you have any suggestions for me?
Sometimes Anthistamines help with that And then of course with me it’s just low-dose opioids
Akathisia. Common with SSRI’S.
I Can name more people than not who become intolerably grumpy and angry and agitated on any type of benzo especially oh the one is escaping me they give for neuropathic pain it’s not a pure benzo but another Hanna agonist benzo substitute. It makes folks just intolerably unhappy but they keep feeding it to us when in many cases Opioids would work so much better but instead they deny them to us and drive the vulnerable to the streets and report their deaths as overdoses when they’re from heroin and fentanyl and these folks would be fine if their… Read more »
Hi guys, recently had an isolated opiate withdrawl. Quite restless but GCS 15, a small dose of versed was given to facilitate safe transport as she was quite hyperactive. Shortly after, patient demonstrated an acute psychosis (decreased GCS but akathsia like display) almost dissociated like presentation. Any ideas here? BZD’s were discontinued. Small dose of an opaite or clonidine appropriate here or move to a atypical antipsychotic?
Doubt its isolated opioid wd. Pupils dilated? Send out dectromethirphan, cathinone and nbome panels so you get an answer next week. Maybe the medics also gave ketamine and didnt tell you? Meanwhile treating with an alpha ag will be fine. Clonidine or dex (starting 0.1 mcg/kg/hr titrate to a rass of -1. I’d avoid angipsychotics. Can try depakon 250-500mg iv q6 for extra sedation.
Truly all due respect but really try to avoid the sedation. Have found low-dose clonidine suppositories quite helpful but in your world if you have an opportunity please experienced these meds yourself and then you might be a little bit more reluctant to use some of them especially the anti-psychotics etc. New Age anesthesia is causing horrible trauma to patients as compared to the traditional methods of I Marin with an opioid or Valium. I personally don’t like for sad and don’t respond to it and had many surgeries with the old approaches but now they want you to walk… Read more »
Absolutely agree with the low-dose opioid and/or benzo. I’ve been using benzo suppositories and found them really nice because they don’t affect my mind as much and go more directly to the source of the agitation which is always alleviated by the opioid. Many people are just wired differently. They have an endogenous deficiency of opioids but the classic corporate world who wants to feed us FDA drugs don’t want us having access to what we need
paradoxical rage reaction very important to see in patients like iceberg sign overdosage is a big hazard counteracted by antagonist medication immediately for respiratory depression and failure and to select oxidative and nonoxidative benzodiazepines also important alcohlism comorbidity psychosis extremes of ages very important to see and carefully scan the words of patients
Hello I become extremely combative on versed. I’m 55 now and have reacted to “light sedation” since I was in my 20s. At 29 I had a deviated septum repaired. Upon waking I fought hospital staff and knocked several carts over before being re-sedated. I was retrained once I re awoke. During a colonoscopy at 45 I tried to get off the table and ended up hitting hospital staff. My most recent at 54 i had oral surgery to remove 3 teeth. I hit the oral surgeon and an assistant. I ended up with 2 bones fractured my hand. Prior… Read more »
Oh my gosh I really feel for you. I had many surgeries prior to 1998 and all went smoothly on the old slow approach gentle premed opioid premed and thiopental but ever since they started using ketamine again and now propyl fall I have woken up strangling nurses in the recovery room and believing I was in a cow pasture totally disoriented I’m sure due to ketamine that they were told not to give me. This is corporate healthcare folks that’s taking over medicine and the drugs we need versus the drugs they want to give us and it’s Damn… Read more »
This is such an interesting piece it has given much food for thought, as a care-coordinator I am excited to go to work tomorrow…. although I am lucky enough to feel like that most days. Thank you
Also is it possible for a person who has allergy to morphine to have an allergy to buprenorhine also?
One day back in 2010 I took one Unisom soft gel, a benzodiazepine to help me sleep. Though I had used it occasionally for 5 years and had worked very well, on this day it had a dramatic paradoxical effect on me. After I started to feel sleepy, before I got to stage one of sleep(unconscious) process, my whole body suddenly jerked (I later learned this is called sleep onset myoclonus). The sleepy feeling disappeared my brain very stimulated and I could not sleep! I immediately stopped taking it (Unisom) but I have had the sleep onset myoclonus jerk ever… Read more »
Consider the MDR genes!!’ Common in folks with epilepsy and certain brain tumors, mesial temporal sclerosis and cortical dysplasia. OPIOIDS safer and more predictable ! Bring back thiopental
Extremes of age. 21 month old is given Versed (pending cardiac procedure) and has moderate to severe PR symptoms. Screaming for help and shaking. I wonder if it would be safe to try it at a later date in this type of patient.
I have paradoxical effect to nearly all medications . I cannot drink any pain pills it causes the pain to get more
I may have to go under general anesthesia for impacted wisdom tooth surgery. I have recently tapered off diazepam and am 9 weeks post taper. What would be the safest general anesthetic as my gaba a receptors are still down regulated. What alternatives are there that do not potentiate the gaba a receptors