Knowledge Workers

 

I wrote this editorial in 2010 for the Minnesota Psychiatric Society newsletter Ideas of Reference as part of my role as the President at the time. Since then, things continue to go in the wrong direction.  Some knowledge workers get more recognition from the business managers than others but it is based on income generation rather than the cognitive aspects of the job. And of course, psychiatrists are managed as if there is no cognitive aspect as all.  In an interesting development at the time, I was contacted by Canadian physicians after this editorial was published in the newsletter, but no American physicians.

 

Imagine working in an environment that is optimized for physicians. There are no obstacles to providing care for your patients. You receive adequate decision support. Your work is valued and you are part of the team that gets you immediate support if you encounter problems outside of your expertise. In the optimized environment you feel that you are working at a level consistent with your training and current capacity. That environment allows you to focus on your diagnosis and treatment of the patient with minimal time needed for documentation and coding and no time wasted responding to insurance companies and pharmacy benefit managers.

As I think about the problems, we all encounter in our work environment on a daily basis I had the recent thought that this is really a management problem. Most of the management that physicians encounter is strictly focused on their so-called productivity. That in turn is based on an RVU system that really has no research evidence and is clearly a political instrument used to adjust the global budget for physicians. Current state-of-the-art management for physicians generally involves a manager telling them that they need to generate more RVUs every year. Managers will also generally design benefits and salary packages that are competitive in order to reduce physician loss, but this

is always in the larger context of increasing RVU productivity. Internet searches on the subject of physician management gener­ally bring back diverse topics like "problem doctors", "managing physician performance", "disruptive behavior", "anger manage­ment", and "alcoholism", but nothing about a management plan that would be mutually beneficial for physicians, their patients and the businesses they work for.

In my research about employee management, I encountered the work of the late Peter Drucker in the Harvard Business Review. Drucker was widely recognized as a management guru with insights into how to manage personnel and information going into the 21st century. One of his key concepts was that of the "knowledge worker".  He discussed the evolution of managing workers from a time where the manager had typically worked all the jobs he was supervising and work output was more typically measured in quantity rather than quality. By contrast knowledge workers will generally know much more about their work than the manager. Work quality is more characteristic than quantity. Knowledge workers typically are the major asset of the corpora­tion and attracting and retaining them is a corporate goal. Physicians are clearly knowledge workers but they are currently being managed like production workers.

The mistakes made in managing physicians in general and psychiatrists in particular are too numerous to outline in this essay. The current payers and companies managing physicians have erected barriers to their physician knowledge workers rather than optimizing their work environments. The end result has been an environment that actually restricts access to the most highly trained knowledge workers. It does not take an expert in management to realize that this is not an efficient way to run a knowledge-based business. Would you restrict access to engineers and architects who are working on projects that could be best accomplished by those disciplines? Would you replace the engineers and architects by general contractors or laborers? I see this dynamic occurring constantly across clinical settings in Minnesota and it applies to any model that reduces psychiatric care to prescribing a limited formulary of drugs.

I think that there are basically three solutions. The first is a partial but necessary step and that is telling everyone we know that we have been mismanaged and this is a real source of the so-called shortage of psychiatrists. The second approach is addressing the issue of RVU-based pay directly. I will address the commonly used 90862 or medication management code. As far as I can tell, people completing this code generally fill out a limited template of information, ask about medication side effects, and record the patient's description of where they are in the longitudinal course of their symptoms and side effects. I would suggest that adding an AIMS evaluation or screen for metabolic syndrome, an in-depth probe into their current nonpsychiatric medications and how they interact with their current therapy, adding a brief psychotherapeutic inter­vention, case management discussions with other providers or family, and certainly any new acute medical or psychiatric problems addressed are all a la carte items that need to be assigned RVU status and added to the basic code. Although there are more, these are just a few areas where psychiatrists add quality care to the prescription of medicines. The final solution looks ahead to the future and the psychiatrist's role in the medical home approach to integrated care. We cur­rently have to decide where we fit in that model and make sure that we don't end up getting paid on an RVU basis while we are providing hours of consultation to primary care physicians every day.

Overall, these are political problems at the legislative, bureau­cratic and business levels. It should be apparent to anyone in practice that when political pressure succeeds in dumbing down the profession, it necessarily impacts adversely on work environ­ment, compensation, and most importantly the ability to deliver quality care. The continued mismanagement of psychiatrists by businesses and bureaucrats who have nothing more to offer than a one-size-fits-all productivity-based model, is the biggest threat to psychiatry today and a much more enlightened man­agement strategy is urgently needed. The Minnesota Psychiat­ric Society and the APA need a strong voice in that change.

 

George Dawson, MD, DFAPA

Committees and Stakeholders

 

I wrote this editorial in 2010 for the Minnesota Psychiatric Society newsletter Ideas of Reference as part of my role as the President at the time. It was subtitled: "A new approach is needed and I think that approach needs to be psychiatrists redesigning the system."  Since then, things continue to go in the wrong direction. I still find the term "stakeholders" to be cringeworthy. The only stakeholders as far as I am concerned are physicians, patients, and their families. 

 

Who are the real stakeholders when you are face to face with your patient and you are being coerced into doing something that is not in the patient's best interest? Where does the profession stand on this? For almost two decades now we have been complacent while insurance companies, government bureaucrats and politicians, and pharmaceutical companies have directly intruded on the physician-patient relationship in a way that has seriously impacted the resources available for patient care and the quality of that care.  The operative word is complacency. I still have a habit that I learned from my freshman English composition professor. I compulsively look up word definitions to make sure I am using them correctly. I think you develop a lot of insight into your changing knowledge base when you look up words that you think you know very well and find that they seem to have taken on more important meaning. For me complacency has become such a word. Looking it up in several dictionaries, the definition I like the best is: "self-satisfied and unaware of possible dangers". With few exceptions, that seems to be the position we have been in for the past 20 years.

I can't think of a better word to describe how physicians were duped into believing that an RVU based pay system would somehow result in better reimbursement for cognitive specialists. Or that coders could determine who was submitting correct billing based on documentation, much less committing fraud. Or that utilization review for inpatient stays and prior authorization for medications is a legitimate practice. Or that managed care com­panies and behavioral carveouts reduce health-care inflation. Or that the focus of psychiatric assessment and treatment involves the prescription of a pill in roughly the same time frame that an antibiotic could be prescribed for otitis media. The list of things that we've been complacent about is long and it is growing every day.

For those psychiatrists working in institutions, committees are often a starting point. Much of the time, committees and meet­ings focus on issues that are peripheral to patient care and quality care. They rarely focus on the actual practice environment for the psychiatrist and the patient. In many cases, the fatal flaw is that the people making the major decisions are not in the meetings. The meetings are frequently held to make it seem like physicians actually have input into what is going on. At times the physicians are prepared by someone telling them that the old days in medicine are dead. The implication is that physicians used to be all powerful, now they are not, and in fact they should expect to have the equivalent input of any other employee.

The strategies we have observed for dealing with a broad array of stakeholders at the table have all been inadequate. We have allowed stakeholders with clear conflicts of interest to suggest that we are more conflicted than they are. The only solution is to be clearly differentiated from everyone else. We are squarely focused on assessing and treating patients in an ethical manner and any political initiative that we endorse or participate in should be consistent with that focus.

What does this mean in a practical sense? First off, it means coming into a meeting with a clear position rather than showing up to broker a deal. It means prioritizing patient care over profits from rationing or political gain from rationing. It means pointing out that the physician-patient dyad is in no way equivalent to any other political agenda in the room. It means not signing off on the status quo when we are the only people in the room speaking to the interests of physicians and their patients.

The recent changes to the way that psychiatric care is delivered to the state's low-income population illustrate all of the problems. Patients with GAMC have significant psychiatric comorbidity, and, even prior to the cuts by Governor Pawlenty, were also subjected to more rationing by private and government payers than other patients. The ultimate change, in the form of Coordinated Care Delivery System (CCDS) clinics, takes this rationing to a whole new level. At the same time the state has attempted to reinvent the state hospital system. Both of these changes disproportionately affect patients with severe mental illness. Any rational analysis would show that these patients did not have enough treatment resources before the new rationing initiatives. A new approach is needed and I think that approach needs to be psychiatrists redesigning the system. That needs to happen through the MPS because we have psychiatrists with the knowledge and focus to accomplish this task. Rather than endorse a rationed and blended version designed by people who are not providing the care, psychiatrists need to articulate a clear statement of what public mental health should be like in the state of Minnesota.

 

George Dawson, MD, DFAPA

The Best Neurosurgery Clinic in the World

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I wrote this editorial in 2010 for the Minnesota Psychiatric Society newsletter Ideas of Reference as part of my role as the President at the time. Since then things continue to go in the wrong direction.  We no longer have insurance that covers the Mayo Clinic. My wife continues to do very well.

 

"We have the best neurosurgery clinic in the world." My wife Linda was in a conversation with a staff person at the Mayo Clinic, and somewhere along the line that statement was made. Just a few weeks earlier she had been diagnosed as having a growth hormone secreting pituitary adenoma and we were in the process of looking for neurosurgeons. I was concerned about that statement and wondered what the motivation was. I have called a lot of clinics and never heard a statement like that. I had talked with a lot of doctors and had never really heard many physicians talk like that.

The pituitary fossa is a dark and dangerous place for even a small tumor. Psychiatrists are generally familiar with the area because of patients with microadenomas that have been discov­ered during evaluations for what is usually hyperprolactinemia secondary to D2 receptor antagonists. In Linda's situation it was a 1.3 cm diameter cystic lesion that involved the cavernous portion of the right carotid artery. The surgery involves a transnasal and transsphenoidal approach to remove the tumor through an endoscope. Cutting into the carotid artery is a potential catastrophe. Damaging the pituitary and needing lifelong hormone supplementation was also a possible outcome. We wanted the best neurosurgeon for the job.

I had just finished reading a NEJM article on robotic surgery that suggested that surgeons need to do 150-200 procedures with this device to be proficient. There was no data available for endoscopic transsphenoidal tumor resections, much less what might be reasonable stratifications like size and type. I figured that the surgeon doing the most was probably the best bet.

At Mayo we were given a timely appointment and met the surgeon. He was confident, detail oriented and personable.

He assured us that his goal was to cure Linda, but that he was not going to trade off safety at any point for a cure. He openly acknowledged the potential problem of the carotid artery being involved with the tumor.

He performed the surgery and the next day came by to explain the results. They were uniformly good but would need confirmatory IGF levels at 3 months. He carefully explained the possible post op complications, how long we had to look for them, and exactly what to do about them. He told me that if any­thing happened during recovery and I was not at the hospital, I would be called immediately. At the time of discharge, he said that he was available through the hospital operator, and that if we called from a cell phone we might have to pull over and wait for him to call back.

While all of this was going on, I learned from other health care providers in the state that the "Mayo Clinic option" was being eliminated from some employee health plans. I had just spoken with a local expert in health economics who said that this suggestion had been made in the past and plan subscribers had rejected it. I thought about the implications for all of the free market and "quality" hyperbole that we hear from politi­cians and business leaders. If we have the best neurosurgical service in the country, why are health plans limiting access to it? If it is the best on a competitive quality basis, why aren't they rewarded rather than being penalized by the market? Most of all, what are the implications for the most heavily rationed health care, namely mental health care?

From a quality perspective, I was hard pressed to think of the best psychiatric service in the state, and not because we lack great psychiatrists. Most of the ·inpatient units I know of are pretty intolerable places. The emphasis is largely to put the patient on medications and discharge them as soon as pos­sible, even when many are highly symptomatic. By comparison with medicine and surgery services, it is difficult to consider this as even a minimal standard of care. Imagine the patient with congestive heart failure being placed on medications and discharged, and making it the family's responsibility to monitor the response and adjust cardiac medications. Imagine me doing post operative neuro checks and monitoring urine volumes, labs, and pain medications on my wife in a Rochester hotel room. In either example, medicine and surgery patients are more likely to follow recommended discharge instructions compared with over half of discharged psychiatric patients not recognizing that they are ill.

What about actual time spent with a psychiatrist? The time that my wife and I spent with her neurosurgeon probably exceeded the time that many hospitalized patients see their psychiatrist. Inpatient settings are usually very poor work environments for psychiatrists because the central fact is that it is no longer an environment where high quality work can be done. Unlike our neurosurgeon, psychiatrists have been mar­ginalized to the role of medication prescribers in both inpatient and outpatient settings. In many inpatient settings psychiatrists no longer control crucial discharge decisions.

When I walked out of the hospital with Linda, we were hope­ful that she had been cured. We knew what we needed to look out for and that there were future options. I noticed that the hospital looked like most of the teaching hospitals I had worked at in the past. There was no valet parking, massage or aroma therapy, harpsichord player, or high-end coffee shop. There were 19 plaques on the wall showing that Mayo Clinic Neurology and Neurosurgery was ranked #1 in the country for each of the past 19 years by US News and World Report. But most of all, we knew that we had just encountered medical and hospital staff with a high degree of expertise and professionalism and that there was an administration supportive of their efforts.

We need to get that back in psychiatry.

 

George Dawson, MD, DFAPA

 

Supplementary 1:

Since writing this I read Neurosurgeon Henry Marsh’s book Do No Harm. In it he describes how modern technology has reduced the risk of neurosurgery but not eliminated it and how even operations that seem to have gone well can have catastrophic results.

 

Xylazine – Another Dangerous Street Drug

Xylazine is the latest veterinary tranquilizer to be sold as a street drug. It has no approved human uses.  It is used as both a light and general anesthetic for horses depending on the extent of the surgery. Xylazine is a presynaptic alpha-2 adrenoceptor agonist inhibiting the release of norepinephrine from synaptic vesicles. This leads to decreased postsynaptic activation of adrenoceptors, inhibited sympathetic activity, leading to analgesia, sedation and anxiolysis.  This mechanism of action is also seen with clonidine and dexmedetomidine.  Xylazine has low potency and affinity for Alpha-2 receptor adrenergic receptors. It has been demonstrated by the use of a knock out genetic mouse model that the clinical effects are mediated through the alpha-2A receptor subtype (5).

Alpha-2 receptor adrenergic receptor (AR) profiles are complicated by the fact that there are 4 subtypes with central, peripheral and behavioral effects but very little seems to be written about the D subtype so I have not included it here.  The general associated mechanisms include a decrease in adenyl cyclase activity, suppressed voltage gated calcium currents, increased potassium currents and increased mitogen-activated protein kinase (MAP kinase) activity. At steady state the α-2A and α-2B receptor types are at the cell surface and the α-2C type is at the cell surface and intracellular.  Some drugs like clonidine and guanfacine promote α-2A internalization. The author (3) of the review suggests that this may account for the unique duration of signaling. α-2AR trafficking and signaling also undergoes complex regulation by a number of factors including protein kinases, G protein coupled receptors (GPCRs), and scaffolding proteins.  A table of receptor affinities for various drugs are listed below. These affinities are primarily from reference 2 and generally represent results for human cloned receptors of the averages of several experiments. Please note the very low affinities for xylazine. I have tried to corroborate these numbers from outside sources and have not been successful. If you have better affinities for xylazine please email me or post them here in the comments section.  

From a pharmacodynamic standpoint there are several relevant Alpha-2 AR polymorphisms that have been tentatively linked disease states like ADHD and hypertension. They have also been studied in heart rate, heart rate variability, blood pressure control, obesity and insulin resistance (4). As expected, these polymorphisms also effect drug response.  

Although Xylazine is approved only for veterinary uses, reports of human use and accidental or inadvertent overdoses began to appear in the 1980s.  A review of initial reports looking at the compound as an adulterant that was done in 2014 (7) and concluded that half of the human overdoses resulted in death.  

Central effects of alpha 2 agonists, results in decreased sympathetic output and resulting imbalances in the peripheral autonomic nervous system.  Decreased sympathetic output leads to the expected effects of bradycardia, hypotension, sedation and decreased level of consciousness. Unopposed vagal parasympathetic effects can lead to increasing heart block and arrhythmias.  

In addition to the central effects of α-2 agonists there are also peripheral effects.  A common α-1 and α-2 agonist used peripherally is oxymetazoline that is used as a topical nasal decongestant. It exhibits very high affinity for both receptors and the following K_is  α-2A (7.24 nM), α-2B (483.5 nM), α-2C (144.07 nM), α-1 (402.75 nM).  Peripheral α-2 adrenergic effects can lead to increased systemic vascular resistance due to effects at the level of arterioles. This is important from a toxicological perspective because it can cause hypertension and is probably the mechanism leading to soft tissue necrosis at injection sites.

The epidemiology of xylazine use is discussed in a few studies at this point (7,12,13). The original paper suggested it may have started in Puerto Rico and spread Philadelphia with the highest prevalence of overdoses in eastern states.  It is well described at this point both in terms of overdoses and as an adulterant when it is added to heroin, fentanyl, cocaine, methamphetamine, alcohol or combinations like heroin + cocaine. There are expected synergies with opioids including a depressed level of consciousness, and decreased respiratory drive. Synergies with stimulants would include increased likelihood of cardiac arrhythmias, hypertension, and tissue necrosis.

The CDC recently published a study of xylazine in Cook County, IL (Chicago area) in MMWR (12).  The study ran from January 2017 to October 2021.  Xylazine associated deaths were defined as positive post-mortem toxicology in any substance related death where the intent was unintentional, undetermined or pending. The authors identified 236 xylazine associated deaths that increased over the study period and are graphed below. The graph on the right is the percentage of fentanyl associated deaths involving xylazine by month. That graph peaks at 11.4% in October. Overall, fentanyl or its metabolites was present in 99.2% of xylazine associated deaths. The authors point out that naloxone does not reverse the effects of xylazine but it should be administered for any suspected opioid use in a polypharmacy toxidrome. They also state that better surveillance for this compound is probably indicated.  

 

The toxidromes from these drug combinations can be complex so that on a clinical basis it will be hard to tell if the patient you are seeing has used xylazine. I was fortunate enough to attend a Hennepin County Medical Center Addiction Medicine Journal Club on 4/5/2022. In that presentation the pharmacology, clinical effects and toxicology of xylazine were discussed. The cases presented all had xylazine combined with other substances and severe necrosis of the lower extremities in two cases and hand and wrist in the other. In one case the patient no longer had venous access and was injecting into the area of necrosis.  All of these patients required skin grafting wanted to leave the hospital after the acute phase of intoxication had passed. In these cases, the transition to detoxification and maintenance medications is complicated because of the possible synergy between opioids and α-2 adrenergic agonists and the question of rebound or withdrawal from preadmission use of xylazine. The question of Takotsubo cardiomyopathy was discussed because some patients the literature were described as using xylazine. Rebound or withdrawal from xylazine and the associated rapid increase in catecholamines was discussed as a potential mechanism. A toxicologist attending the meeting also pointed out that with overdoses the α-2 adrenergic agonists can cause hypertension by peripheral effects and this has caused some acute cardiac problems. That toxicologist was also familiar with local testing for xylazine and it was not currently being done. He pointed out that a half life of 5 hours was determined in humans as contrasted with a few minutes in several animal species.   He suggested that in the case of a patient unresponsive to high dose naloxone, without hypercapnia via arterial blood gases, and normal brain imaging it would be reasonable to request xylazine toxicology.

In an interesting development, the FDA recently approved a dexmedetomidine sublingual film for the treatment of acute agitation in schizophrenia and bipolar disorder (14).  Dexmedetomidine has been available for intravenous use for 20 years with the indication “sedation of non-intubated patients prior to and/or during surgical and other procedures” (15).  It also has a place in critical care medicine – addressing all three aspects of the ICU triad of pain, agitation, and delirium (16). The film comes in 120 mcg and 180 mcg doses with a schedule in the package insert with dosing for adults and geriatric patients with and without varying degrees of hepatic impairment.  The clinical trials in the package insert describe the medication as effective for this indication. As a psychiatrist who spent most of his career in acute care there are fairly frequent situations where medications that are typically used to treat agitation (antipsychotics and benzodiazepines) do not work – even at high doses. It will be interesting to see if acute care psychiatrists find dexmedetomidine preparation useful. When I ran into that situation it was typically cases of severe mania with agitation or delirious mania with catatonia and the only available option was conscious sedation by anesthesiology. The other unknown at this point is how effective this medication will be over time.  The package insert specifies a maximum of two or three doses.  Clinicians will be on their own after that. It reminds me of how another α-2 adrenergic agonist – clonidine is currently used for anxiety, agitation, and insomnia. Many patients experience it as transiently effective until a more sustained preparation (typically a transdermal patch) is used.  

The appearance and gradual increase in xylazine as a street drug is not good news.  It is clearly used as an adulterant in both opioids and stimulants.  Its use can result in severe complications and death. The surveillance for this compound is not good at this time and clinicians have to have a high index of suspicion to request toxicology for it. People with substance use disorders need to be educated about this compound and its use as an adulterant and that deciding to use it with an opioid or other CNS depressants (including alcohol) is very dangerous and needs to be avoided. Using it with stimulants can also have significant negative effects.  At this point it is also an unknown danger because like fentanyl - it can be sold as anything.

 

George Dawson, MD, DFAPA

 

References:

 

1:  Törneke K, Bergström U, Neil A. Interactions of xylazine and detomidine with alpha2-adrenoceptors in brain tissue from cattle, swine and rats. J Vet Pharmacol Ther. 2003 Jun;26(3):205-11. doi: 10.1046/j.1365-2885.2003.00466.x. PMID: 12755905.

2:  PDSP Ki Database referenced as The Multiplicity of Serotonin Receptors: Uselessly diverse molecules or an embarrassment of riches? BL Roth, WK Kroeze, S Patel and E Lopez: The Neuroscientist, 6:252-262, 2000

3:  Wang Q.  α2-Adrenergic Receptors. In: Primer on the Autonomic Nervous System, Third Edition.  Robertson D, Biaggioni I, Burnstock G, Low PA, Paton JFR. 2012. Elsevier, Amsterdam. 55-58.

4:  Matušková L, Javorka M. Adrenergic receptors gene polymorphisms and autonomic nervous control of heart and vascular tone. Physiol Res. 2021 Dec 30;70(Suppl4):S495-S510. doi: 10.33549/physiolres.934799. PMID: 35199539.

5:  Kitano T, Kobayashi T, Yamaguchi S, Otsuguro K. The α_2A -adrenoceptor subtype plays a key role in the analgesic and sedative effects of xylazine. J Vet Pharmacol Ther. 2019 Mar;42(2):243-247. doi: 10.1111/jvp.12724. Epub 2018 Nov 11. PMID: 30417462.

6:  Weerink MAS, Struys MMRF, Hannivoort LN, Barends CRM, Absalom AR, Colin P. Clinical Pharmacokinetics and Pharmacodynamics of Dexmedetomidine. Clin Pharmacokinet. 2017 Aug;56(8):893-913. doi: 10.1007/s40262-017-0507-7. PMID: 28105598; PMCID: PMC5511603.

7:  Ruiz-Colón K, Chavez-Arias C, Díaz-Alcalá JE, Martínez MA. Xylazine intoxication in humans and its importance as an emerging adulterant in abused drugs: A comprehensive review of the literature. Forensic Sci Int. 2014 Jul;240:1-8. doi: 10.1016/j.forsciint.2014.03.015. Epub 2014 Mar 26. PMID: 24769343.

8:  Sinclair MD. A review of the physiological effects of alpha 2-agonists related to the clinical use of medetomidine in small animal practice. Can Vet J. 2003 Nov;44(11):885-97. PMID: 14664351; PMCID: PMC385445.

9:  Giovannitti JA Jr, Thoms SM, Crawford JJ. Alpha-2 adrenergic receptor agonists: a review of current clinical applications. Anesth Prog. 2015 Spring;62(1):31-9. doi: 10.2344/0003-3006-62.1.31. PMID: 25849473; PMCID: PMC4389556.

10:  Kanagy NL. Alpha(2)-adrenergic receptor signalling in hypertension. Clin Sci (Lond). 2005 Nov;109(5):431-7. doi: 10.1042/CS20050101. PMID: 16232127.

Activation of alpha(2A)-ARs in cardiovascular control centres of the brain lowers blood pressure and decreases plasma noradrenaline (norepinephrine), activation of peripheral alpha(2B)-ARs causes sodium retention and vasoconstriction, whereas activation of peripheral alpha(2C)-ARs causes cold-induced vasoconstriction

11:  Talke P, Lobo E, Brown R. Systemically administered alpha2-agonist-induced peripheral vasoconstriction in humans. Anesthesiology. 2003 Jul;99(1):65-70. doi: 10.1097/00000542-200307000-00014. PMID: 12826844.

12:  Chhabra N, Mir M, Hua MJ, et al. Notes From the Field: Xylazine-Related Deaths — Cook County, Illinois, 2017–2021. MMWR Morb Mortal Wkly Rep 2022;71:503–504. DOI: http://dx.doi.org/10.15585/mmwr.mm7113a3

13:  Friedman J, Montero F, Bourgois P, Wahbi R, Dye D, Goodman-Meza D, Shover C. Xylazine spreads across the US: A growing component of the increasingly synthetic and polysubstance overdose crisis. Drug Alcohol Depend. 2022 Apr 1;233:109380. doi: 10.1016/j.drugalcdep.2022.109380. Epub 2022 Feb 26. PMID: 35247724.

14:  FDA Package Insert. IGALMITM (dexmedetomidine) sublingual film, for sublingual or buccal use.  April 5, 2022.  https://www.igalmihcp.com/igalmi-pi.pdf

15:  FDA Package Insert.  Dexmedetomidine hydrochloride injection. 1999. https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/206628s000lbl.pdf

16:  Reade MC, Finfer S. Sedation and delirium in the intensive care unit. N Engl J Med. 2014 Jan 30;370(5):444-54. doi: 10.1056/NEJMra1208705. PMID: 24476433.