INTRODUCTION

{07130} violent death, don't try these at home

Nothing that pertains to human suffering and death is outside the larger domain of human pathology. Knowing what motives underlie most homicides and suicides is as important for a student physician as knowing which special stain helps the lab define a hemangiopericytoma.

Most of this unit is about violence. Like most other mammals, when we human beings are hurting and confused at the same time, we have a natural (though lamentable) tendency to lash out against (blame, physically attack) someone else, regardless of the realities of the situation. We've all seen individuals do this, and perhaps we've even done this ourselves.

Especially, groups of people who are hurting and confused will lash out against neighbors who are slightly (but not too much) different from themselves. This behavior begins with "extremists", who of course can explain to you why they are right, what past injustices they are redressing, how they are "doing God's work", "cleansing the evil", and so forth. Soon the savvy politicians follow, and next, many "normal" people are doing things that most will regret when they come to their senses, if they themselves survive. This happens around the world, and in the "developed world's" slums and prisons.

* Physical anthropologists examining human remains from ancient cultures find rates of violent death (most often from head trauma) vary considerably, from lows of around 5% to far higher. As one would expect, there's far more violence when there is poverty, social stress, and population pressure (Am. J. Phys. Anthro. 130: 60, 2006).

George Orwell wrote, "We sleep safe in our beds because rough men stand ready in the night to visit violence on those who would do us harm." Like it or not, this is the truth.

Force, or the credible threat of force, will always govern human affairs. The best for which we can hope is that this will be the force of good laws. Even the great pacifists of our era (Gandhi, Martin Luther King, others) knew this. To their credit, they were able to bring about change with as little violence as possible, by placing their own lives on the line. I wish this kind of personal courage from "the world's leaders" and "grievance-group spokespersons" was the norm today.

Of course, neither I nor anybody else has any quick fix for a world that is still too violent. You already know the right-wing and left-wing crackpot solutions; these would be funny if only....

The public does not see, or think about, military combat as it really is, and has always been. The Iliad and All Quiet on the Western Front are much closer to the reality than the movies or the newspapers. Even those who survive combat uninjured return with memories of beloved companions having limbs and faces blown off, having guts gush out over their hands, being burned to cinders, screaming for hours, bleeding to death per rectum, etc., etc. Returning to civilian life, combatants find that those for whom they fought do not want to hear about these experiences or their impact. Most of them decide that this is knowledge from which their loved ones must be protected. Remember this when you care for people who have been in combat.

Especially since the rise of guerilla warfare, political violence has been directed primarily against civilians. Soldiering, once the honorable life of a brave man, has become largely a matter of armed thugs killing (or starving) civilians and trying to leave no witnesses to the actual violence. In a war zone, the opposite sides take turns, and the soldiers (government, guerillas, child recruits) are often safer than the non-combatants.

* Your lecturer is a man of peace. He predicts that this historical trend will reverse when, and only when, ordinary people in the poor nations have plenty of private firearms. Whatever your own feelings about firearms, if you actually talk with these people, I think they'll tell you the same thing.

There has never been a war between two genuine democracies. When a democracy and a non-democracy go to war, it has become the norm for the non-democratic side deliberately to place their own non-combatants, especially children, in harm's way so as to generate misguided sympathy.

People with agendas (especially the Left: J. Pub. Health. Pol. 19: 289, 1998) deluge us with claims that the United States is an extraordinarily violent society. This ignores the fact that the violence is concentrated in underclass communities. These communities, for whatever reason, are lawless and ridden with substance abuse, and the "code of the streets" requires posturing ("keeping respect") that ultimately invites re-injury (Am. J. Pub. Health 95: 816, 2005). Monitoring serial admissions of "penetrating trauma recidivists" shows "it only gets worse", and that the manner (shooting, stabbing) usually stays the same until death occurs (J. Trauma 61: 16, 2006). Where there is not a culture of lawlessness, dependency, failure and despair, and where illegal drugs are not being dealt, people in the US are as safe as anywhere in the world (and safer than most places). Among "indigenous peoples" and in the slums of the poor nations, violence and murder are far more prevalent. Despite the "noble savages" claims of the Left, the evidence of archeology is every bit as horrorific (Sci. Am. 289(2): 33, 2003).

* The left-wing fringe still uses terms like "nontraditional violence" and "implied violence" for any criticism whatsoever directed against a leftist individual, leftist agenda, or grievance-group. Despite what can still happen on a left-wing campus, United States law has consistently refused to recognize such things either as "violence" or "hate speech" or "hate crimes".

Some episodes of mass killing (past / present) get a great deal of attention in the US media and schools; others get ignored.

Cambodia

In the late 1800's, the Belgians under megalomaniac King Leopold II looted the Congo, killing around 10 million people and enslaving, torturing and mutilating many more. This prompted massive outrage at the time in the US and Britain but has now been mostly forgotten. The genocide in Armenia (about 6 million dead) in the early 1900's rarely gets mentioned. (In 1939, Hitler, preparing to "kill without pity or mercy all men, women, and children of Polish race or language", said, "Who still talks today about the Armenians?") We almost never hear about the slaughter of millions of civilians, especially in China, by the Japanese military as the empire was expanding. And it's pretty clear that they did experiment with germ warfare, including plague and anthrax, on civilian populations (for example,Lancet 360: 857, 2002; Clin. Microb. Inf. 8: 450, 2002). So as not to "offend" the wrong people, the popular movie "Pearl Harbor" (2001) actually portrayed the Japanese as being at peace before Pearl Harbor. The greatest mass-murderer of all time (about 20 million people executed, not counting over 35 million more who died in his famine) was Mao Zedong, who is now remembered in many circles primarily as the popularizer of cute unisex jackets. We hear surprisingly little about Stalin's policy of slaughtering every Soviet citizen who had ever made a profit by farming, even though he killed millions of his own people. Pol Pot's recent death got a few sentences in the news; he killed at least a million people in Cambodia, engaged in systematic electrical torture (Tuol Sleng, elsewhere), began his attempt to realize his left-wing, anti-Western, back-to-nature fantasy by shooting everybody who wore eyeglasses, and then banned all institutions (schools, hospitals banks, stores, and even the family). Of course a famine followed with about 2 million more deaths. What has been happening in Central Africa for decades got noticed only when the "Rwanda genocide" heated up in the mid-1990's; it is now being ignored once again. The world's largest ongoing war since 1998 has been in the Congo (Zaire) where "the national crude mortality rate is 2.1 deaths per 1000 per MONTH (Lancet 367: 44, 2006); it got an article in Time magazine in 2006. As in other wars in which the purpose is to wreck the economy, most deaths are from easily-treatable illness or hunger. I have seen no real US press coverage of the current civil war in Haiti, where there have been around 4000 political murders of civilians, and widespread rape, alternating among the national police, the rebels, and even the very frustrated "UN peacekeepers" (Lancet 368: 864, 2006.)

As before, my best prescription is Dr. Virchow's: reduce the hurting and confusion through real democracy, honest science, reasonable security of person and property, and access to education and rewarding work. Nothing else can possibly work.

Bosnia

If we make peaceful revolution impossible, we make violent revolution inevitable.

--Jack Kennedy

People who abuse alcohol, do drugs, choose a violent lifestyle, and/or do tobacco consume a grossly disproportionate amount of health care. You'll be very impressed when you go on rotations.

In the next few years, you are going to hear about third-party payers trying to exclude SPORTS injuries from coverage "because you accepted the risk voluntarily." This is already on Capitol Hill. Square this with injuries from alcohol and tobacco and cocaine and heroin and joining gangs, people.

DEATH INVESTIGATION AND THE PRIMARY CARE PHYSICIAN

Especially if you choose rural medicine, you're likely to be called to the scene when a dead body is discovered.

The first problem in any examination of death is find out whose body it was. Remember that identification of remains by distraught relatives is notoriously unreliable. The police will almost always do fingerprinting and/or dental identification. For skeletonized remains, the forensic anthropologist (a Ph.D. specialty allied to pathology) can be extremely helpful.

* Death is a great disguiser. -- Shakespeare.

Next, you may be asked to estimate the time of death. This is not an exact science.

Even estimates of the rate of body cooling (probably best, in the absence of such evidence as bloodstains on the morning paper) are only moderately useful, as both temperatures at death and rates of cooling vary widely.
* Post-mortem rectal temperature time of death nomogram: For. Sci. Int. 54: 51, 1992; the actual ranges vary hugely; post-mortem hypoxanthine For. Sci. Int. 51: 139, 1991; vitreous potassium For. Sci. Int. 46: 277, 1990 & AMFJP 18: 158, 1997; CSF chemistry J. For. Sci. 38: 603, 1993. All about post-mortem chemistry: Am. J. For. Med. Path. 14: 91, 1993.

* Ed's time-of-death program is now getting thanks from police and prosecutors around the world.

* A man convicted (very likely wrongly) of a godawful rape-murder based on unreliable estimates of how fast you digest dinner: AJFMP 12: 344, 1994. Scientific pathologists hate charlatans as much as scientific clinicians hate health-care quacks.

For bodies found in the great outdoors, maggots are the medical examiner's little friends (more than you want to know about maggots: J. For. Sci. 38: 702, 1993).

* Maggots near a skeletonized corpse died of the secobarbital she consumed (AJFMP 21: 59, 2000). * A forensic etymologist proves that the neglectful parents kept the child so filthy that maggots began consuming the child's anogenital area for a week preceding death: For. Sci. Int. 120: 155, 2001.

We fat (i.e., fatten) all creatures else to fat us, and we fat ourselves for maggots.

-- Hamlet

{07024} maggots

Post-mortem animal bites Ed Lulo's Pathology Gallery

In forensic pathology, histologic study of the tissues plays a very limited role.

* Forensic nursing is an up-and-coming field. Nurses focused on forensics can pick up procedural errors in the hospital, and can excel at describing wounds at the time of presentation (which can be very helpful at trial).

If the law does not require a medical examiner's inquest, or if you are the medical examiner, keeping the following in mind will help you avoid the usual pitfalls.

The cause of death is your best opinion, as a physician, with or without an autopsy. You list this on the death certificate.

CAUSE OF DEATH: Thromboembolus in right main pulmonary artery (circa 1 minute)

SECONDARY TO: Thrombophlebitis of leg vein (circa 5 days)

SECONDARY TO: Adenocarcinoma of the pancreas (circa 6 months)

NOTE: You may call the most important (to the lawyers) item on your list the "proximate" cause of death, i.e., what set the fatal chain of events in motion. "Cancer of the breast" is okay; "coronary artery atherosclerosis" probably isn't (why not?)

NOTE: Please don't write "cardiopulmonary arrest" as the cause of death. We already knew that....

The mechanism of death is your story. "The Trousseau pulmonary embolus strained the right ventricle and a rhythm disturbance developed." Once again, this is your best opinion.

The manner of death is for the lawyers. You might list your opinion on your death certificate, too. There may be future disagreement. In the above instance...

MANNER OF DEATH: Natural

Here are your choices:

Homicide: At the very least, someone else did something wrong that set in motion a process that resulted in the person's death. (The lawyers may decide on "first-degree murder", "second-degree murder", "voluntary manslaughter", "involuntary manslaughter", "justifiable homicide", or "excusable homicide.")

Justifiable homicide. This is the kiss of Tosca!

Suicide: At the very least, the person did something that resulted in his or her death, and this was more or less what the person intended.

For the past 30 years, the reported suicide rates have hovered just below 1 in 10,000 people/year, and the report homicide rates just above this number.

Accident: These deaths resulted from some kind of unplanned, unintended injury. They include most "therapeutic misadventures" (i.e., mishaps at the doctor's or dentist's). Notoriously, if sporotrichosis from a rose-thorn prick were to lead to death, it would be an accidental death. Among the grayest areas are "accidents" in the workplace due to employer negligence; many prosecutors now consider these to be homicides (Am. J. Pub. Health 90: 535, 2000).

Natural: Death due to disease or birth defect. (NOTE: "Unnatural death" means homicide, suicide, or accident.)

Undetermined: You're an honest doctor and you know you can't really tell. This isn't a bad category for normal-looking, 300-year-old skeletons found in the desert, most cases of "sudden infant death syndrome" with no proper death-scene workup, substance abusers or organic-brain-syndrome people found at the bottom of the stairs ("did they fall or were they thrown?"), etc., etc.

NOTE: If I wrongfully bite you, and you go to the hospital and are rightly treated with penicillin, and you die of anaphylaxis as a result of the penicillin injection, your death is probably a homicide.

NOTE: If a guy shoots himself, and spends six months in the hospital recovering, and dies of a pulmonary embolus from being at bed-rest for so long, it's still a suicide.

NOTE: By common practice, if a guy has bad emphysema and blows out his lung trying to inflate his kid's balloon, it's "natural", not "accidental".

NOTE: The good medical examiner always asks "Why today rather than yesterday?" especially when the only finding is 3-vessel coronary disease.

NOTE: "Therapeutic misadventures" are of relatively less interest nowadays in which we expect a certain number of fatalities from powerful therapies. If someone dies of pseudomonas sepsis while undergoing a bone marrow transplant for leukemia, death is "natural", i.e., an not-unanticipated consequence of the illness and its treatment.

NOTE: Physician-assisted suicide will be part (though hopefully still an infrequent part, thanks to more humane terminal care in general) of mainstream medicine when you're in practice. These deaths (along with today's discreet acts of euthanasia) will be registered as natural deaths.

NOTE: If you find me dead in front of the TV, with a half-eaten greaseburger dripping over my fat paunch, stinking of tobacco, with a medicine cabinet full of statins and anti-hypertensives that you can tell from the dates on the bottles that I didn't take, and I have known 3-vessel coronary disease and have been complaining of angina, and you don't know something's amiss or see anything curious on examining my body or the scene, go ahead and sign me out as "natural; cause of death is atherosclerotic coronary artery disease". Yeah, a few tricky homicides probably get missed.

NOTE: Although there is no need to point out the irony, deaths from oat cell carcinoma, heroin-shooter's endocarditis, cocaine heart, and Laennec's cirrhosis are "natural deaths".

{07135} morbid obesity, another contributor to "natural" death

Immediate cause of death is what happened just before, regardless of the manner of death or the proximate cause. For example, a person who is accidentally burned and dies three weeks later of pseudomonas sepsis has sepsis as immediate cause of death, the burn as the proximate cause. * Mode of death is an unpopular word for what was apparent without a physician's full workup ("shock", "coma", "pulmonary edema", "sudden cardiac arrest", "pneumonia").

MORE ABOUT DEAD BODIES

Timing...

30 minutes... I can already see lividity on a light-skinned person. Rigor may be present. The body may or may not feel slightly cool.
3 hours... Lividity is usually obvious.
5 hours... Rigor is usually obvious.
10 hours... The body feels cold.
12-18 hours... Rigor is usually maximum.
24 hours... Rigor is usually starting to lyse; this can be later if it's hot out
2 days... Green discoloration (iron sulfide) on the flanks
2-3 days... Green discoloration on the abdomen
3-4 days... Marbling of the skin begins (red discoloration of surface veins)
5-6 days... Epidermis separates from dermis
2 weeks... Bloated, lots of gas in tissues
3 weeks... Gas causes bursting of the organs, eyes bulge, tissues are soft
4 weeks... Semi-liquid, slime


After a near-plateau of variable duration (heat generated by anaerobic metabolism approximately matches heat loss), the body cools at one degree celsius per hour in the first 12 hours, then 1/2 degree celsius for however long it takes to get to room temperature. Circumstances (clothing, obesity, ambient temperature, mystery factors) alter this rate of cooling tremendously.

Things happen very differently in bodies deposited in the water. There are frequent surprises.

A newborn with near-zero internal body flora, and some other folks, may not putrefy.

* Jack Kevorkian's original claim to fame was his attempts to use the optic fundi to determine time of death in very early cases: J. For. Sci. 6: 261, 1961; Am. J. Path. 32: 1253, 1956.

You are already familiar with rigor mortis (one-time stiffening of the body after death. In addition to the conventional teaching that this is due to depletion of ATP with subsequent binding of actin to myosin, I suspect this is due at least in part to the influx of calcium through injured membranes.

You also know livor mortis (I say LYE-vorr; others say "LEE-vorr"; "lividity", pooling of the blood; this becomes fixed/patterned after a while, and can tell you if the body has been moved.)

What's actually happening (I think) is that erythrocyte and endothelial cell membranes become permeable to hemoglobin; as decomposition proceeds, the erythrocytes turn to ghosts.

* Leave the arcana of decomposition ("adipocere burns like candle wax") and the identification of decomposed bodies to us. Again, remember that a distraught family member's identification of a dead body is notoriously unreliable. Check the "electrolytes" handout for more on determining electrolyte status at the moment of death from analyzing the vitreous humor. Approach to the dismembered body: AJFMP 12(4): 291, 1991.

"Cadaveric spasm" is instantaneous rigor, seen when death occurs with considerable muscular exertion (gripping something, as a branch in someone falling down a mountain) and/or major motor seizure and/or emotion (battlefield, torture).

{07558} livor mortis
{07195} found in the woods
{07021} found in the pond
{07576} post-mortem roach bites (see also AMFJP 18: 177, 1997)

Decomposed body

Decomposed body

Rigor mortis

THE MEDICAL EXAMINER'S OFFICE

The medical examiner is a physician who autopsies, or has a pathologist autopsy, certain dead bodies. It is a government-appointed position.

In big cities, the medical examiner is likely also to have his subspecialty boards in forensic pathology, i.e., have chosen to devote most of his/her career to this activity.

Plenty of medical examiners are general pathologists. And in rural communities, physicians who are not pathologists can do this work, getting consultation as needed.

By contrast, the coroner is a government official who makes official rulings about the natures of particular deaths.

In some jurisdictions, the coroner is the medical examiner.

Elsewhere, the coroner may simply be a college student whose real job is completing routine paperwork, rubber-stamping the medical examiner's conclusions.

And in others, it may be a funeral director, or way out in the country, whoever owns a truck and is willing to transport dead bodies.

Laws involving coroners can be interesting, and in some jurisdictions, it's also the coroner's job to arrest the sheriff should he/she misbehave.

If you, the licensed physician, are caring for someone and he or she dies of his or her disease, you fill out the death certificate and you needn't even notify the Medical Examiner's office.

Certain deaths must be referred to the medical examiner. These include:

• anyone dying with no physician to complete the death certificate;
• any death from something other than disease; this includes apparent suicides, homicides, trauma, radiation, poisoning, heat exposure, cold exposure, electrocutions, and complications of illegal abortion;
• any death in which homicide, suicide, or accident might be the manner, even if there is intercurrent disease as the actual mechanism of death;
• any death that might provide important information about a public health problem;
• any death of someone thought to be in good health, or without known disease;
• anyone dying in police custody, jail, or prison, a detox center, or a halfway-house;
• anybody dying under age 18;
• any death thought perhaps to be due to occupational disease or injury;
• any death during surgery;
• any death thought to perhaps be due to illegal drugs;
• anyone dying in an "unusual or suspicious manner";
• deaths from "therapeutic misadventure" (i.e., really unfortunate, unexpected iatrogenic disease)
• deaths in the first 24 hours following admission to the hospital.

If there is a bullet in the body, even from long ago and unrelated to the death, the medical examiner (or perhaps a surgeon) should remove it for ballistics examination.

In a typical community, around 15% of deaths will fall under the medical examiner's jurisdiction, and of these, maybe 35-45% will get autopsied.

All homicides and suspected homicides get autopsied.

Where it's an obvious, non-questionable suicide, the medical examiner will at least attempt to obtain the bullet if there is one. I used to do more extensive autopsies when I could, in the hopes of finding some hidden physical disease (i.e., cancer of the pancreas, brain tumor) and if a woman, determine whether she was pregnant. It's only an hour or two extra work for me, and would make a lot of difference for the family.

For deaths in fires, the medical examiner will at least examine the airways.

If a driver dies after losing control of the car or bicycle, or a swimmer is observed to go under, I always did a complete autopsy in search of natural disease.

If a body is discovered in the water, usually there will be a complete autopsy. The pathologist will take blood from both sides of the heart and check electrolytes.

Of course, even without an autopsy, we'll usually take urine (by suprapubic puncture) and blood (femoral vein puncture is best) and check for drugs and alcohol. Where time of death is an issue, vitreous humor will be sampled. Hair samples (roots and all, please) are helpful for the drug history and more. Vaginal swabs and smears will be obtained on all possible homicides.

Terminology: Whether the person is killed with a firearm or some other weapon, the pathologist examining the wounds will be asked, "Could this weapon have caused this injury?" The pathologist will examine class characteristics ("Rope used in strangling will produce a bruise-abrasion like this one") and individualizing characteristics ("This rope's twists and thickness exactly match the impression left on the victim's neck.")

* Good reading: I'm in debt to all these.

Spitz, W.U., and Fisher, R.S., "Medicolegal Investigation of Death", ed. 2, Springfield: Thomas, 1980. Do not read chapter 19.

DiMaio, D.J., and DiMaio, V.J.M., "Forensic Pathology", New York: Elsevier, 1989.

"American Journal of Forensic Medicine and Pathology" (AJFMP). Great for study-breaks; the UHS library's subscription begins in 1993.

ANATOMIC PATHOLOGY OF CHILD ABUSE:

* The great forensic pathologist Ambrose Tardieu wrote an extensive account of physical findings in child abuse in 1860. It was ignored. The story of how we came to recognize the existence of "the battered child syndrome", and the decades of denial that such things could actually happen, is chronicled in Clin. Lab. Med. 3: 321, 1983. ("Isn't it strange how fragile some kids' bones were in life, but not after death?" "When you question the family, be sure not to say anything that might make them feel guilty." "This syndrome of 'osseous discontinuity' can be mistaken for trauma.")

There is much appropriate discussion of "the battered child syndrome" with evidence of repeated past injury. But the majority of infanticides are the result of sudden anger by a frustrated parent ("I thought at least my baby would love and comfort me"), and you will not find old trauma.

In the "shaken baby syndrome" (review NEJM 338: 1822, 1998), an acute subdural hematoma follows avulsion of the subdural bridging veins. Look also for retinal bleeds and cerebral edema. You may or may not see a bruise (if the head has been struck; or the striking of the head caused the bleed.) One would think it'd be unnecessary, but it's not -- the worldwide "Don't Shake the Baby" media campaign of the early 1990's: Br. Med. J. 310: 344, 1995. Retinal hemorrhages are common enough just from getting born or even c-sectioned, but are almost always gone by 4 weeks (Ophthalmology 108: 36, 2001).

Worth knowing:

Of course, two fractures of different ages in a kid is probably child abuse. And any history that obviously doesn't fit is pretty much diagnostic.

Babies simply don't get accidental fractures until they start walking by themselves.

It's now clear that household accidents can and do cause serious / fatal head injury -- very rarely (AJFMP 2001). This article provoked a firestorm of criticism from the ideologically-minded, but no scientific rebuttal so far, and it seems open-and-shut.

Future clinicians: Don't mistake any of these for child abuse:
• Osteogenesis imperfecta (this one's real)
• Mongolian spot. "Bruise" on the small of the back that doesn't change. Kids have been taken away from parents and people prosecuted for this.
• Common and not-so-common rashes. (You'd be surprised what some ignorant folks will mistake for "child abuse.")
• AV malformation in the brain (this one's real)
• Brain atrophy with resulting subdural hematomas (this is probably the origin of stories about "this inborn error of metabolism produces subdural hematomas")
• * Glutaric aciduria (GA-1. Defense lawyer folklore, though nothing I could find in the literature, claims this grim, vanishingly-rare mostly-motor syndrome, which can come on suddenly, is a cause of retinal hemorrhages and subdural hematomas. Type II is the infamous disease in which the entire body smells like stinky feet.)
• * Alagille's and Byler's syndromes (if neglected, vitamin K malabsorption can cause a bleeding tendency)
• Vitamin K resistance syndromes (tricky call)
• Other easy-bruising disorders (not-so-tricky calls, but again you'd be surprised. Remember the fragile vessels of Ehlers-Danlos, the coagulopathies of von Willebrand's and the hemophilias, and the thrombocytopenias and platelet dysfunctions.

Shaken baby
Axonal retraction spheroids
WebPath Photo

Occasionally, psychotherapy helps violent people live better lives, but it's an uphill battle. Review of psychiatry and the treatment of violent patients: Arch. Gen. Psych. 49: 493, 1992.

Chilling reading: The neurology of violence (Arch. Neurol. 49: 595, 1992). It is simplistic to attribute all violence either to biologic or sociologic factors.

Major trauma cases (from Sherwin B. Newland, How We Die):

35%... automobile riders
7%... motorcyclists
7%... pedestrians
10%... gunshot wounds
10%... stabbings
17%... falls
14%... other (bicycles, industrial accidents, botched suicide attempts, etc.)

ALL DRUGS ARE POISONS

... and all poisons are (potentially) drugs. "Big Robbins" provides a sampler of drug side-effects ranging from the annoying to the lethal. Your lecturer remains skeptical about the noted claim by the Institute of Medicine that 44,000 to 98,000 deaths in the USA every year result from medical errors. He believes most of these are due to 20/20 hindsight and use of the retrospectoscope (which isn't fair), and the Institute's willingness to see as cause of death anything that happened during the course of an illness that wasn't textbook-perfect (which is silly). Be this as it may, the claim that the pharmacy / the nurses giving the wrong medication kills 7000 Americans yearly (JAMA 296: 384, 2006) seems easier to believe; it's hard to study. Having a pharmacist in the ICU seems to help prevent "adverse drug events" (no surprise: JAMA 282: 267, 1999). Certain drug effects are predictable, and will occur in most people (given a high enough dose), or in those predisposed to problems (i.e., from disease, other drug therapy, or genes). The following are worth remembering always:

The Wizard of Oz -- Poppy Field

Thalidomide caused the shortening of the limbs ("phocomelia") of unborn children.

Cancer chemotherapy in general is rough on the bone marrow, causing neutropenia and thrombocytopenia. You'll learn about specific agents in "Pharm". For now: Bleomycin, in high doses predictably cause pulmonary fibrosis. Cyclophosphamide causes a vicious urinary bladder inflammation. Adriamycin causes a cardiomyopathy. Vincristine produces a dysautonomia and painful, disabling peripheral neuropathy.

Reserpine, a great anti-hypertensive drug, causes depression, and even suicide. Methyldopa and propranolol are also depressing.

Phenytoin and cyclosporine produce hyperplasia of the fibrous tissue of the gingiva.

Phenytoin and coumarin are notable teratogens.

The mono-amine oxidase inhibitors can render a person highly susceptible to tyramine in strong cheese and wine, resulting in hypertensive crisis, brain hemorrhage, and so forth.

The side-effects of glucocorticoids range from immunosuppression to osteoporosis to Cushingoid body habitus. What's more, going off glucocorticoids quickly is a good way to die of addisonian crisis (the adrenal cortex atrophies while exogenous corticosteroids are being taken).

Several good anti-malarial drugs are oxidizers and will cause hemolysis, especially in patients with G6PD deficiency.

Aspirin is rough on the gastric mucosa, renders all circulating platelets largely and permanently ineffective (until replaced in 7 days or so, of course), and (in overdose settings) produces a famous sequence of respiratory alkalosis followed by metabolic acidosis.

The benzodiazepines are amnesic agents. (PLEASE don't prescribe these "to help people study.") So is scopolamine (and perhaps atropine).

Caffeine produces a mild physical dependency, and withdrawal is accompanied by headache, drowsiness and lots of REM-rebound (sweet dreams....); see below.

Penicillin at very high doses (i.e., meningitis) causes a non-immunologic hemolysis of red cells.

If bromsulphthalein dye or adriamycin infiltrate out of the vein, you'll need a skin graft.

Amphotericin B regularly causes acute tubular necrosis, which is so bad it tends to calcify. Cyclosporine, for renal and other transplants, is also a renal glomerular and tubular poison.

Man problems often result from drugs (ask): Methyldopa, the classic anti-hypertensive, and opiates (prescribed, street) prevent erections. Clomipramine and the other selective serotonin-reuptake inhibitors make ejaculation much more difficult (dudes, this has its uses....) Thioridazine causes retrograde ejaculation, which can scare the guy. Anabolic steroids are fun but will (at least) accelerate your hair loss (more about gym steroids later). Spanish fly (cantharidin) is supposed to be an aphrodisiac for both you and her, but it's not safe (Forens. Sci. Int. 56: 37, 1992, or ask the Marquis de Sade, who was put away after poisoning some CSW's with it).

Woman problems: Estrogens have a host of side-effects, the most alarming being the increased risk of atypical hyperplasias and (generally low-grade) carcinomas of the endometrium. Deep-vein thrombosis is an unpredictable but serious complication.

The alterations in lipid metabolism and fat distribution of the highly-effective anti-HIV drugs are now famous.

In the past, "clever" murderers used digitalis, succinylcholine, sodium fluoride, or insulin to commit "the perfect crime". Today's savvy medical examiner can detect all this foul play.

Here's this pathologist's personal list of "the most infamous" unpredictable drug side-effects (i.e., nobody knows who will get them, the dose doesn't matter, and it's likely that the chaos of the immune system plays a role). "Are you allergic to any medications?"

Penicillin is a great antibiotic and a great IgE sensitizer. Anaphylaxis following injected penicillin in a noteworthy complication.

Quinidine, a good anti-dysrhythmic, causes sudden cardiac death in maybe 1% of people who start taking it.

Clozapine (the epoch-making anti-schizophrenic drug) and phenylbutazone are noteworthy causes of agranulocytosis. Remember this risk for any drug you prescribe!

Gold (for arthritis) and penicillamine (for Wilson's, scleroderma, etc.) are notable causes of glomerular protein leakage, often with devastating long-term effects.

Nitrofurantoin, cyclophosphamide, bleomycin, busulfan, azathioprine, and amiodarone are lung poisons, producing ARDS or chronic interstitial pneumonitis, often at low doses.

Phocomelia
WebPath Photo


Amiodarone, griseofulvin, and isoniazid (ask the pharmacologists about "fast acetylators") are liver poisons. (Lots of other drugs can do the same.) The histopathology can mimic alcoholism. (Amiodarone is a horrid lysosome poison.)

The non-steroidal anti-inflammatory agents are the most common cause of outpatient renal failure nowadays. The old sulfonamide drugs crystallized in the glomerular filtrate and cut up the tubules, while the classic NSAID-prototype phenacetin caused frank necrosis of the renal papillae.

Halothane is a classic cause of massive hepatic necrosis in unlucky individuals. Overdosing on acetaminophen will do the same thing (big doses overload the safe metabolic pathway via glutathione, and a bizarre, toxic free-radical metabolite then forms by a second pathway).

Hydralazine, procainamide and isoniazid often produce lupus (anti-histone disease, etc.) The first two are the worst.

Methysergide occasionally causes retroperitoneal fibrosis, with obstruction of the ureters.

Certain anti-malarial agents will blind occasional patients by causing a retinopathy.

Abacavir, a very important anti-HIV medication, causes a frightening hypersensitivity syndrome; having a particular HLA allele seems to be required to get this, and antiretroviral therapy is now planned around this.i

Pretty much anything can give you a rash. Types range from IgE, type-I immune injury-mediated urticaria, to type IV mediated phenomena that follow presentation of the drug by Langerhans cells in the epidermis, to the serious vasculitis syndromes, to the dread toxic epidermal necrolysis.

In the future, we'll know more biomarkers (i.e., genetic alleles) that correlate with different drug allergies (there are about ten known as of 2008: NEJM 358: 637, 2008.)

{53779} phenytoin-induced birth defect, trust me
{53781} phenytoin-induced birth defect

If all this alarms you, remember that Dr. Hippocrates had no specific drug prescription for any specific disease. Dr. Still didn't have a whole lot more. Both of them, unlike many of their contemporaries, realized the situation and had the integrity to say as much. Today's physician must weigh the benefits and risks of any prescription.

NOTE: "The Physician's Desk Reference" lists side effects of drugs for the judge and jury, ranging from the probable to the improbable. Pretty much everything can supposedly cause "headache", "dizziness", etc., etc.

THE ILLEGAL DRUGS

Pathology of Illegal Drug Use WebPath Tutorial

I see the Truth, when I'm all stupid-eyed...

-- Nine Inch Nails, The Perfect Drug

There's no room here for a major treatise on recreational drug abuse, but when you start seeing patients, you'll be impressed with the problems they cause.

Uncle Sam (1994) reported that usage peaked in 1975, with 23 million users (i.e., people who'd taken a recreational drug in the previous month). Now that the public is more savvy (maybe), and people can lose their jobs if they flunk random drug tests (definitely), the count is down to maybe 11 million, but this is the hard-core.

Your lecturer has been observing the drug scene for the past quarter-century. In my honest, considered opinion, the recreational use of today's illegal drugs has nothing to recommend it.

* I can't explain to you why people do the illegal drugs or drink heavily. Of course, every culture, from stone-age to high tech, has parties where a bunch of people get goofy on the same drug. The same anthropologists who praise this as a "cherished cultural tradition" among primitives may not carry this over to America's illegal drug culture (Subst. Abuse 37: 853, 2002). How are the situations alike, and how are they different? Especially, decide how much of this behavior is identity-group membership. This might explain why minority groups (racial minorities, "disenfranchised youth") usually prefer different intoxicants and/or patterns of consumption than the majority culture.

Bess and Sportin' Life: "Happy Dust"

Some of the essential pathophysiology remains mysterious. We don't even know why pulmonary edema is usual in opiate overdoses, or why people who do street drugs tend to have a hepatic triaditis and enlarged portal lymph nodes.

No one questions that the use of the addictive drugs induce long-term cellular changes of some sort in the brain; this is reflected in the behavior and is what makes drug abuse such a notoriously relapsing illness.

* The most interesting new work in this area, an examination of gene expression profiles in the nucleus accumbens, tends to discredit the recently-popular idea that the various addictive drugs work through a common pathway ("the addicted brain..."). See Neuropsychopharmacology 31: 2304, 2006.

* The amygdalas (brain areas that have to do with self-control) in the experienced cocaine-user afflicted with craving seem much smaller than those of normal folks (Neuron 44: 729, 2004). Cause (weak-willed in the first place / stupid enough to try cocaine) or effect (damage from cocaine) or both? We are eagerly awaiting an answer.

Likewise, the medicolegal evaluation of the deaths of drug-users is fraught with pitfalls.

The physical findings at autopsy in deaths due to drugs are usually non-specific.

Tolerance, i.e., decreasing drug effect as the dose is held constant, makes it difficult to say whether the amount that the person took could / could not have been lethal.

Illegal drugs and their metabolites are easily measured in blood and tissue after death, but post-mortem drug levels must not be over-interpreted.

Especially, drugs redistribute after death in ways that so far have baffled the best forensic scientists (J. For. Sci. 44: 10, 1999). Obviously as body proteins denature and temperature and pH change, affinities for the molecules change and drugs diffuse. Most forensic pathologists will simply tell you, "This lab result means the person did this drug."

The specificities of your screening tests may be insufficient to detect particular drugs. For example, today's "opiate screen" is likely to miss fentanyl.

And of course, the drugs that were at the scene at the time of overdose are likely to be stolen by the time that the police arrive.

* Centers or wooden frames are put under the arches of a bridge, to remain no longer than till the latter are consolidated, and then are thrown away or cast into the fire. Even so, sinful pleasures are the devil's scaffolding to build a habit upon; and once formed and fixed; the pleasures are sent for firewood, and hell begins in this life. -- Samuel Taylor Coleridge, opium addict

Cocaine

Today, this euphoriant-anesthetic substance needs no introduction. Taken by needle or smoked in heat-resistant form as "crack" (from the cracking sound made by the crystals), it's has long been major evil presence. There's a mild physiologic withdrawal syndrome. More seriously, once the drug is sampled, the psychologic craving is intense.

Even experimenting a little with cocaine, even "to help you study", is extremely dangerous. Apparently cocaine use destroys your capacity to be happy without the drug. The cocaine addict will do anything to get more of the drug.

In the 1980's, the introduction of a cheap, smokable form ("crack", from the sound of the blocks breaking as they burn in the pipe) caused a striking increase in use. According to Sci. Am. 290: 82, Feb. 2004, the use of crack dropped precipitously in the early 1990's. The author's explanation was that community leaders recognized that the danger to their communities' health was too great to accept as "politics as usual", and "extra-judicial street justice" removed the crack dealers.

Cocaine kills people in at least five different ways:

• Massive overdose, with blocking of the sodium channels in the heart ("cocaine is a local anesthetic"), bradyarrhythmias and death. Body packers, "stuffers" who swallow the evidence, accidents, probably suicides
• Stroke (infarct or hemorrhage)
• Excited delirium (see below)
• Myocardial infarction / ischemia (cocaine coronary vasoconstriction) / cardiomyopathy (notably left-ventricular diastolic dysfunction (Am. J. Card. 97: 1085, 2006); sdden death (of course; Am. J. Card. 99: 822, 2007).
• Tachyarrhythmias ("sudden arrhythmic death", the most common). Recently a group at Columbia got a group of habitual crack smokers to smoke their stuff while hooked up to EKG's; the changes (tachycardia, much-prolonged QTc interval, etc.) are similar to those for other sympathomimetic agents (Am. J. Card. 97: 1244, 2006).

Cocaine and the heart: NEJM 345: 351, 2001; Am. J. Card. 100: 1040, 2007. It is adrenergically mediated and potentiated by both ethanol and tobacco. Cocaine depletes dopamine receptors on the coronary arteries, and renders them super-sensitive to alpha-adrenergic stimuli. This is most likely the cause of the vasospasm (Am. J. Card. 86: 1054, 2000) and symptoms and signs of cardiac ischemia.

Less well-known is smoked cocaine's ability to produce damage to the pulmonary microvasculature (Ches 121: 1231, 2002). Even if the patient does not have hemoptysis, this is one cause of a lung's being full of hemosiderin-laden macrophages. Check the blood for cocaine in any young person with unexplained hemoptysis.

Remember that even though the brain rapidly develops tolerance to the euphoriant effects of the drug, the sodium channels of the heart never develop tolerance to the effects of cocaine. This triggers rhythm disturbances and death.

Pathologists look for these findings, which are typical of heavy cocaine users and to a lesser extent other stimulant users: (1) Replacement of single cardiac myocytes by fibrous tissue (probably why we get the diastolic dysfunction of the left ventricle; this is distinctive for "chronic catecholamine cardiomyopathy" of which cocaine heart is the chief example); (2) Medial hypertrophy of the small coronary resistance arteries. (For a review with photos see South Med. J. 98: 794, 2005).

Tachyarrhythmias probably result from the underlying anatomic changes in the heart, since (unlike myocardial infarction), they won't happen during the first experimenting.

Brain hemorrhages happen even if the vessels in the head are "normal": Neurology 46: 1741, 1996; brain vessel constriction can also produce stroke: JAMA 279: 376, 1998.

"Crack lung" produces a spectacular anthracosis.

* You may be told that cocaine produces a vasculitis, especially in the brain (Neurology 40: 1092, 1990). I don't know whether this is true; most cocaine users get no vasculitis from the drug. So far as I've been able to find out, there's no distinctive lesion; it may be just a rare Stevens-Johnson drug-allergy vasculitis.

Future medical examiners:

Cocaine's serum half-life is 1 hour. The post-mortem cocaine levels in people whose deaths are attributed to cocaine overlap nearly with those in which cocaine's presence was judged to be an incidental finding. There seems to be a consensus today that cocaine-related deaths are independent of blood levels and dose taken (South. Med. J. 98: 794, 2005).

Cocaine is metabolized into benzoylecgonine (serum half life 6 hours, urine half-life 12 hours) and ecgonine methyl ester (serum half-life 4 hours); both degrade into ecgonine which is stable indefinitely. If there is also alcohol on board, about 10% of the cocaine will be turned into cocaethylene, a psychoactive compound with a half-life of 3 hours.

Watch for post-mortem studies on brain receptors in cocaine addicts, to demonstrate and understand tolerance.

Crack lung
Lung pathology series
Dr. Warnock's Collection


Cocaine lung washings
Virginia
Good pictures


The famous perforation of the nasal septum is simply an ischemic infarct from vasoconstriction. Cocaine can also kill unborn children by abruption of the placenta or direct toxicity to the fetus (For. Sci. Int. 47: 181, 1990), or make babies small and/or premature. Today's "crack babies" need no description (ask a pediatrician, or see Pediatrics 97: 851, 1996; these babies are significantly smaller Pediatrics 101: 229, 1998; Although the most dire predictions have not held up and non-crack-exposed underclass kids also have special problems (Pediatrics 98: 938, 1996; J. Ped. 132: 291, 1998) the "crak babies" do seem to have been damaged permanently by the drug (Pediatrics 120: e1017, 2007).

* The best news lately is a vaccine, i.e., a cocaine analogue that is immunogenic, producing antibodies that bind cocaine and prevent its having an effect. Hope it works. See Nature 378: 727, 1995; Proc. Nat. Acad. Sci. 98: 1988, 2001.

Excited delirium is a curious phenomenon in which a person (most often on cocaine, though the blood levels need not be high) requires physical restraint, then stops struggling and shows labored / agonal breathing and immediately goes into cardiopulmonary arrest. The syndrome is defined to be each of these in succession: (1) hyperthermia, (2) delirium, (3) respiratory arrest; (4) death. Nobody really knows the mechanism (Am. J. Emerg. Med. 19: 187, 2001).

There's talk of an acquired channelopathy (seems unlikely, since it seems to have to do mostly with brain function; Am. J. Forensic Med. Path. 20: 120, 1999), and some intriguing work on up-regulation of kappa opioid receptors in the amygdala as the marker for excited delirium (Ann. NY. Acad. Sci. 877: 507, 1999).

Of course, excited delirium generates a lot of bogus "police brutality" lawsuits.

Dr. Halsted, the famous surgeon, and his cocaine addiction: NEJM 352: 966, 2005.

Cocaine lung
Virginia Pathology Cases

Lacerations and incisions Cocaine "excited delirium" WebPath Photo

Dead body packer WebPath Photo

Downers (barbiturates, others)

Overdoses can be fatal, especially if you've had a drink. (NOTE: Your lecturer doesn't believe that it's common for people to "forgetfully" take the rest of the bottle of sleepers while groggy from taking just one.) For big-time abusers, there's a physical tolerance and withdrawal syndrome (excitement, seizures) which can kill you. Remember skin blisters in people in "barb" coma; nobody knows why they happen.

Gamma-hydroxybutyrate (gamma hydroxyburytic acid), gamma-butyrolactone, and 1,4-butanediol (the latter is an industrial solvent, yuck) are popular yuppie downers. Gamma-hydroxybutyrate mimics GABA, the inhibitory neurotransmitter, and crosses the blood-brain barrier easily. Again, there's a physical dependence and the risk of acute toxic death (NEJM 344: 87, 2001).

* GBH is also a product of decomposition following death, so post-mortem levels are less helpful. We do not test for it routinely (J. For. Sci. 133: 17, 2003); finding it in a dead person's urine is more helpful than in the blood. It also is produced in citrated blood samples simply as they stand. Antemortem blood samples taken in fluoride tubes, and post-mortem urine are more helpful specimens (Am. J. For. Med. Path. 22: 266, 2001).

Even old-fashioned sedatives like chloral hydrate still kill people.

Anna Nicole Smith Chloral hydrate overdose Coexisting morbidities

The benzodiazepines ("Valium", etc.) are amnesic drugs. You won't learn well while you're taking the stuff "for test anxiety" or anything else. Today's "more sophisticated" exam-takers are choosing propranolol, a drug with effects on the heart that are not always salutary. Put that stuff away, too.

Uppers

The amphetamines ("speed"; most-used right now is methamphetamine) are rough on the heart (sudden death is famous; also "meth cardiomyopathy" Am. J. Med. 120: 165, 2007), brain, and kidneys, and may incline their users to do foolish, hurtful things. However, death from these substances are rare, and tend to mimic cocaine's anatomic pathology.

In particular, intracerebral hemorrhage from doing "meth" is very well-known (AJFMP 25: 334, 2004.)

Phencyclidine's pathology is being worked out.

The famously-bad tooth decay and fractured teeth seen in the methamphetamine user is caused by a combination of xerostomia, the noxious smoke ("crystal meth" / "ice), bruxism, and a craving for sugar (Am. J. Health-Syst. Pharm 63: 2078, 2006; Gen. Dent. 54: 125, 2006). It's hard to show in the lab, but your lecturer believes that vasoconstriction from the drug probably infarcts the mouth tissues.

Like "crack babies", "meth babies" born to women who did methamphetamine are much smaller than their counterparts. We await follow-up (Pediatrics 118: 1149, 2006).

3,4-methyleyedioxymethamphetamine ("Ecstasy" / MDMA) is a familiar yuppie drug whose problems are now being studied intensively.

The drug probably damages serotoninergic axons, with some long-term effects on thinking (old work that impressed me Pharm. Tox. 84: 261, 1999; the idea of real brain damage from casual use is supported Arch. Gen. Psych. 64: 728, 2007; and specifically damage to the serotoninergic axons is now a robust finding Am. J. Psych. 161: 1181, 2004).

A curious effect is hyponatremia, as the drug seemes to cause both inappropriate secretion of ADH and also a tendendy to drink a lot of water. This is now a robust finding (Am. J. Med. Sci. 326, 89, 2003; Ann. Emerg. Med. 49: 164, 2007), and can be lethal.

Use of MDMA is common, deaths from MDMA are rare, and they usually resemble other amphetamine-type deaths (Legal Med. 9 185, 2007).

* Ketamine has caused surprisingly few deaths in recreational users, who are likely to be medical types. See Int. J. Leg. Med. 116: 113, 2002.

{07615} tattoo on public-spirited person

Montana Meth Project
Drug-ed ads.
Enjoy.

Opiates (heroin, morphine, meperidine, codeine, others)

Addictive drugs, usually taken by needle (except codeine; intravenous or skin-popping; there are ways of inhaling "the dragon" heroin). Your lecturer is not impressed with the adverse personality or health consequences of opiate use itself (well, it's constipating and bad for the libido). However, the stuff is addictive, expensive, and illegal (which causes some of the problems) and overdose is very lethal. Stories from eyewitnesses describe collapse, gurgling, and a massive gush of foam from the mouth.

Unlike cocaine, heroin is not known to have any direct tissue toxicities. There are maybe 4000 deaths from heroin overdose in the US each year. Those dying of heroin overdose either (1) stopped breathing from medullary depression, or (2) got pulmonary edema (nobody knows why opiates can do this, but it's likely that it's neurally-mediated, because of tolerance and because brain injury itself can produce similar edema). Of course, there are plenty of heroin-related deaths due to lifestyle and/or unsanitary injection practices.

It's commonplace for an "accidental" overdose to have been preceded by a critical life-event, and many of these "unfortunate tragic accidents" are probably suicides (Forens. Sci. Int. 62: 129, 1993).

* Confusingly, there is an illness seen only in people who snort cooked heroin, and that much be due to a poison generated in this way. It looks clinically and anatomically like prion disease, but some patients recover; it's called "heroin spongiform encephalopathy" and is recognizable now on MRI scans: For. Sci. Int. 113: 435, 2000.

Methadone maintenance keeps drug addiction, which is a relapsing problem, under partial control with great savings to society. There are about 100,000 people on methadone maintenance in the US, and only about 500 deaths per year from overdosing. Most deaths result from increasing the initial dose too rapidly.

You'll review the various molecules in "Pharm". Don't try too hard to interpret a post-mortem morphine level, either to decide whether "it's enough to kill the person", or how much of the drug was taken. Tolerance varies tremendously, and attempts to second-guess tolerance by high-tech assays of brain receptors have been non-helpful: For. Sci. Int. 113: 423, 2000. During life, 98% of a dose of opiate is in the tissues; as the body decomposes, much of it will return to the bloodstream. Review J. For. Sci. 46: 1138, 2001. Redistribution is less of a problem than for other drugs: J. For. Sci. 45: 843, 2000.

* Future medical examiners: The S-enantiomer of methadone is inert but is measured by some of the toxicology techniques.

* Don't forget to look for pupa cases from the maggots that fed on the body. Morphine can be analyzed from here: For. Sci. Int. 120: 127, 2001.

"Big Robbins's" statement that a third of heroin addicts had diluted their drug with water from the toilet comes as no surprise to this physician. Heroin may be cut with Baby's talcum powder (stays in the lungs forever), quinine (rough on the heart), or whatever else is handy (who knows?) Heroin addicts seldom use sterile technique, and abscesses and endocarditis (notably on the tricuspid valve, notably staphylococcal) are commonplace, as is the bad retrovirus. "Heroin nephropathy" is usually FSGS (also amyloidosis A, from the abscesses.)

It's worth remembering that tolerance to opiates is lost VERY fast. One common scenario is a fatal overdose after a 2-3 day stay in jail; the addict simply took the customary dose and died as a result. Savvy medical examiners are now estimating these people's tolerance history using hair samples.

Drug abuser "works" WebPath Photo

Heroin-cocaine death Note foam around mouth Supposedly Chris Farley

Ask a forensic pathologist to show you needle marks ("tracks"). These are scars, often pigmented (carbon, hemosiderin), overlying veins and often arranged in a line (savvy dopesters start distal). One reason addicts get tattoos is to make it harder to see their injection sites. "Skin poppers" are often covered with old craters.

* A long-overdue review on the dermatology of injected drug abuse, emphasizing the long-term problems: Arch. Derm. 143: 1305, 2007.
* An outbreak of anthrax among skin-poppers whose heroin was mixed with dirt: Science 288: 1941, 2000; Lancet 356: 1574, 2000.

{08170} heroin tracks

Starch granules in tissue Warning: Gross out Dino Laporte's PathosWeb

Subcutaneous bleed Needle user WebPath Photo

Needle scars WebPath Photo

People who inject "Ritalin", "Talwin" or methadone from powdered tablets are also certain to get interesting stuff in their lungs. Talcum powder and pill-fillers both produce little granulomas, which can eventually cause fatal cor pulmonale.

Crystals in the lungs of drug abusers Lung pathology series Dr. Warnock's Collection

Talc in the lungs Granulomas WebPath Photo

The management of patients with chronic pain is only now receiving the recognition it deserves from the medical profession, and is still restricted by laws that don't make sense (a fact that is finally getting media attention). Heroin may perhaps have some use in the management of chronic pain, but the discussion is totally dominated by ideological concerns. Today, however, most users chose heroin not for a physical analgesic but as a powerful anesthetic against deplorable living conditions. It works (and this would lead me to ask why so many people feel they need it -- perhaps the cause is having to live around other substance-abusers, criminals, and mean people), but the problems only begin with impotence, constipation, and infections.

* For the not-pretty picture of both TB and morphine addiction in the pre-illegal era, read or see Eugene O'Neill's autobiographical "Long Day's Journey into Night".

{07062} talc in heroin-abuser's lung

Absinthe
"The green muse" was a liqueur distilled from wormwood and sometimes other herbs, was popular in the late 1800's. It affected its users more radically than did other alcoholic beverages, producing a different kind of acute intoxication, then addiction, brain damage, and psychosis. Review Br. Med. J. 319: 1590, 1999.

Baudelaire, Toulouse-Lautrec, Van Gogh, and Rimbaud were devotees of the drug, which raises the question (for me anyway) whether their devotion to the drug was the cause of, or the result of, their particular outlooks on life. The movie "Moulin Rouge" (2001) celebrates the hallucinations generated by absinthe. A Jayhawk argues that VanGogh's psychosis was at least exacerbated by his absinthe: JAMA 260: 3042, 1988; more by this author on absinthe: Sci. Am. 260(6): 112, June 1989.

The special ingredient that produced the weird intoxication is supposedly thujone. If you believed everything you read about this, you'd be reading uncritically. Despite its molecular resemblance to the active ingredient of marijuana, it doesn't work on the cannabinoid receptors. More credible is work showing that it acts on the GABA type A receptors (Proc. Nat. Acad. Sci. 97: 3826 & 4417, 2000). This suggests excitotoxicity as the cause of the permanent brain damage.

* The sad story of a man who drank wormwood obtained via the internet: NEJM 337: 827, 1997.

After the first glass you see things as you wish they were. After the second, you see them as they are not. Finally, you see things as they really are, and that is the most horrible sight in the world. -- Oscar Wilde

Cannabis (marijuana, pot, grass, hashish, etc.; "I did not inhale" -- Bill; "Life is way too short to be self-absorbed" -- Ed)

The Case Against Marijuana For the fraternity By Ed

What did the two stoners say to each other when they finally ran out of marijuana? "Hey, this music sounds terrible!"

The familiar weed, which archeologists tell us goes back at least to the 6th millennium BC, binds to particular receptors in the brain, as do most other drugs. The active agent is delta-9-tetrahydrocannabinol. Ask a neuropharmacologist about the "cannabinoid receptors", and the endogenous cannabinoids, notably * N-arachidonoylethanolamine (charmingly named "anandamide", ananda being Sanskrit for "bliss.")

* Your lecturer predicts that the brain receptors responsible for the nausea of chemotherapy will turn out to be the CB1 receptors, which use anandamine. CB1 blockers exist and produce severe nausea. Nobody is looking at clinical uses for these blockers, which tells me that nobody really believes that marijuana smoking is a major menace to individuals or to society.

* Formerly the hemp plant was cultivated widely in the US for rope and canvas (same word as "cannabis"). People seeking rational explanations for our curious marijuana laws have suspected the political influence of the cotton industry ("King Cotton"; canvas clothes are less comfortable but more durable) and of course the big liquor companies. Or (and this seems right to me) this is just another example of "the law of alien poisons", i.e., that every dominant culture abhors the mind-altering substances preferred by its minority groups, and cannabis was primarily used by Hispanics (Substance Use and Misuse 37: 853, 2002: from Nova Southeastern COM). Something on this history of the international ban on marijuana, with a reminder that it was largely driven by a disinformation campaign by a single US politician: Lancet 313: 344, 2004.

There is a mild withdrawal syndrome seen only in heavy users (i.e., four or more joints per day) that lasts less than a month, with the ex-stoner losing weight, sleeping fitfully, and being crabbier ("increased aggression" shows only on lab tests that seem to measure irritability): Am. J. Psych. 161: 1967, 2007.

Right or wrong, the government crusade against marijuana has long been a part of "politics as usual". Marijuana smoking was a "political" act during the 1960's, when the government's several "credibility gaps" were obvious and many people were given absurdly long prison terms simply for possessing a joint or two. It seemed to make its known users unmotivated, and your lecturer suspects this means it causes subtle brain damage that may or may not be reversible. If the latter is really true, it has resisted scientific demonstration.

* Ironically, at the same time that marijuana was the drug of choice for the 1960's, mostly anti-Vietnam-war "counterculture", it was also the drug preferred by front-line troops during the war, who preferred it to alcohol since they wanted to be able to fight effectively in case of surprise attack.

* Government and government-promoted (D.A.R.E.) material for young people about the supposed risks of marijuana includes obvious, preposterous untruths. For example:

It is known that marijuana undermines the immune system so it is likely that in another 20 years, if use continues to escalate, the death toll from side effects of long-term marijuana use will equal those of longer-term tobacco use.

Sandra S. Bennett, D.A.R.E. website
Retrieved July 21, 2007

* Of course, this undermines the credibility of warnings about dangers of heroin, cocaine, methamphetamine, and the other genuinely-life-threatening drugs. In the US, politics-as-usual includes the maintenance of an illegal drug culture among the poor and the stupid, with marijuana as the gateway drug. Draw your own conclusion.

Your lecturer makes yearly medline searches that always reveal exactly nothing plausible about serious health consequences of marijuana smoking. Nor can this writer imagine how the neurologic "amotivational" syndrome (if it is real) could be clearly distinguished from the apathy and ennui of spoiled modern-day U.S. kids. This includes the effort in JAMA 287: 1123, 2002, in which Aussies who smoke weed daily for decades have progressive impairment of memory and attention (thanks for trying). Even the Canadians, not known for liberalism, found that the known stupidity (i.e., lowered IQ) of stoners is measurable only in those smoking five or more joints weekly, and that looking at past users, "we conclude that marijuana does not have a long-term negative impact on global intelligence" (CMAJ 166: 887, 2002). In 1999, Bethesda funded a huge study on medical marijuana; it is reviewed in Arch. Gen. Psych. 57: 547, 2000 -- after a lot of hearings and calls for more research, the one solid recommendation was a metered inhaler rather than just letting the patient smoke the weed as a joint. The 2002 claim that cannabis smoking causes 30,000 deaths in Great Britain seems built on faulty assumptions -- you decide: Br. Med. J. 327: 165, 2003. How frankly nonsensical the world marijuana laws are: Lancet 363: 344, 2004 (again, not a bastion of liberalism).

You should not smoke cannabis and then drive a car. This was "prove-able" only after blood assays for marijuana smoking became available. See Lancet, Spril 24, 1976, page 884.

* A single article in 1994 suggested that pot-smoking schizophrenics get more and worse relapses (Arch. Gen. Psych. 51: 273, 1994; but maybe they were just crazier to begin with.)

* In 1997, a team in Italy noticed that cannabis and heroin both activated mesolimbic dopamine transmission by a common receptor mechanism. The subsequent claim that this suggested marijuana was addictive met with guffaws; it seems to me that it simply reflects the fact that both drugs make people happy while they're high (Science 276: 1967, 1997; this would not be worth mentioning except that it got published, somehow, in this distinguished journal.)

Of course, marijuana use results in very few domestic-violence calls. Contrast alcohol. It's also very widely reported to be easily the best way to overcome the dreadful subjective side effects of cancer chemotherapy. This is intensely politicized (your chemotherapy patients will try it themselves, and probably not tell you). Even Canada, not known for radical social politics, legalized medical marijuana in 2001.

Your lecturer hasn't seen anyone physically sick or dead from marijuana, and believes that claims of grave health threats, birth defects, and so forth are simply disinformation. Nor has your lecturer heard of dreadful harm from countries where marijuana is available legally at convenience stores. Even the new edition of "Big Robbins" trimmed its warnings against marijuana down to concern about smoke damaging the lungs and being stoned making your thinking fuzzy. JAMA 287: 1172, 2002 confirms what everybody knows -- even 17 hours after getting zonked on marijuana, your head's not quite clear. The JAMA editors, not known for being left-wing, also pointed out that most current work does NOT really support the idea that marijuana causes long-term brain damage, and that it's also impossible to tell in any case whether people who smoke a lot of dope are stupider to begin with. (You think?) Science takes a back seat to politics, and truth be told, almost nobody's doing meaningful scientific work with marijuana use itself today. This is a shame, since (for good or ill) the drug is a well-established part of U.S. culture, and (because it is illegal) might be purchased from the same kind of folks as the much more dangerous drugs (i.e., kids learn how to buy from drug dealers). Plus, the brain systems on which it works are evidently quite inportant (Nat. Med. 9: 1227, 2003).

* Why do you THINK they call it "dope"? -- Ed

The inhalants ("glue sniffing", etc.)

Some people have fun inhaling solvents (acetone, ethyl acetate), gasoline, isobutane (cigaret lighter fluid Int. J. Leg. Med. 120: 168, 2006); isobutyl-, amyl- and butyl-nitrites ("pig pokers", etc.), nitrous oxide ("Whippets", from aerosolized whipped cream cans; a yuppie favorite), toluene (airplane glue), and fluorocarbon (J. For. Sci. 38: 477, 1993) propellants.

Solvents probably act (like general anesthetics) by solubilizing the lipid in nervous tissue and acting on the same proteins as anesthetics do. Use of some of these drugs can be bad for the heart (sensitizes to rhythm disturbances), kidney, and brain. Intoxicated people can die of aspiration or asphyxia.

Nitrous oxide users are prone to develop a peripheral neuropathy and megaloblastic anemia.

* My favorite article from 2007 was the account of the autopsy of a sniffer of toluene from paint. Granules of aerosolized paint in the lungs were magnificently demonstrated on electron microscopy (For. Sci. Int. 171: 118, 2007).

Drug testing (review Clin. Lab. Med. 18: 781, 1998)   

There's no time or reason to dwell on the arcane, political-legal subject of testing for drugs of abuse.

Worth knowing: Heroin is metabolized to morphine, and cocaine to benzoylecgonine and ecgonine methyl ester. You measure these.

RULE: If there's to be a legal impact of your findings, you must confirm all positives using a test based on a different chemical principle.

* It is possible to test meconium to see whether Mom has used drugs during pregnancy. Early work (J. Ped. 122: 152, 1993) suggested this might become routine, but understandably it's primariy a research tool, though it has finally come into widespread use (Pediatrics 118: 1149, 2006; Arch. Dis. Child F&N 91: F291, 2006; Clin. Chim. Acta 366: 101, 2006; For. Sci. Int. 153: 59, 2005).

* All about the "war on drugs": NEJM 330: 357, 1994; JAMA 273: 1143, 1995, update Lancet 357: 971, 2001; "a quagmire for our times J. Pub. Health Policy 23: 286, 2002. It is one of the mainstays of "politics as usual". Talking about this subject is now considered appropriate for the classroom. The war on drugs directly consumes about $17 billion of our tax dollars per year. There are around 3.5-4 million hard-core addicts (cocaine, crack, heroin), mostly underclass, who are doing most of the crime (robbery, shoplifting, low-level dealing, also child neglect and abuse.) Nobody likes people being addicted to drugs like cocaine and heroin. But despite the rhetoric, it is obvious that vested interests are in control of drug policy. Addiction treatment on demand remains unavailable for most people (Am. J. Psych. 151: 631, 1994; Forens. Sci. Int. 62: 129, 1993; Am. J. Pub. Health 89: 657, 1999). The unavailability of treatment is, of course, the result of politics. (Nancy Reagan's "Just Say No!" campaign, the Republican-Right response to conservative suburbanites who wanted the government to focus on preventing their children from smoking marijuana, ended the Nixon-Carter policy of quietly providing detoxification. Conversely, communities that profit massively from the drug trade strongly oppose detoxification -- their left-wing rhetoric is "curious".) Thankfully, cheap detoxification is becoming more available, but for decades, an addict would have to wait months; this satisfies me that neither the "liberal" nor the "conservative" politicians really wanted criminals/addicts off the streets. (You'll hear the current strategy of interdiction compared to the game "whack-a-mole". Notice that neither "liberal" nor "conservative" politicians ever talk about military action against the cocaine and heroin lords. Is this because they both benefit from the status quo? Or is it because they realize that this wouldn't work?) Drug addiction is notorious for relapsing, and no one expects that methadone maintenance patients will really remain free of street drugs, only that the maintenance will diminish their illegal activities (JAMA 281: 1000, 1999). Drug-related crime has turned our inner cities into war zones (there were around 1500 drive-by shootings in 1995 in Los Angeles alone), young children are brought into criminal lifestyles by drug dealers since they will be punished less severely when caught, and drug-related crime is the #1 or #2 concern of Americans in the surveys lately (after the health-care mess of course). Pediatrics 93: 1050 & 1065, 1994 showcases the disastrous effects on black males ages 9-15; this is one you oughta read, though I don't know whether the "multilevel strategies" the left-wing authors propose will solve the problem while the "war on drugs" continues and there's easy money to be made by those who are not "future-oriented". Drug availability is undiminished (because it is illegal, a high school kid has a much easier time getting marijuana than alcohol), and the number of deaths from drug overdose (not to mention the associated crime and that retroviral disease that is still increasing among IV drug abusers) continues to increase. At least we are putting away more drug dealers, who now occupy a third of our penitentiary spaces (additional $$ beyond the $17 billion/year). Parents: If you don't take a personal, friendly interest in your kids and their happiness, then the local drug dealer probably will. and if you have given your kids nothing credible to feel part-of, then the local drug culture probably will. The case for continued prohibition of the recreational drugs is persuasive for many people (who generally assume that decriminalization / legalization would increase drug use, which you might reasonably doubt). But their arguments could be applied equally well to alcohol and tobacco (Nature 374: 391, 1995) -- but you knew that.

Interdicters, moralists, "educators", certain (not all) "drug counsellors" (tough-talk, warm peer support, and monitoring costs mega-bucks for rich professionals or medicaid-recipients caught doing drugs; I'm told "alcohol rehab" now costs $30,000 even though AA's / NA's, still the best, is still free), and (of course) drug dealers all have vested interests in keeping this "war" (and addiction itself) going rather than making timely physician-directed treatment available. If Newt and Bill ("a new advertising campaign against drugs for 1998") really wanted to end the problem, it would be possible for any strung-out addict to present himself/herself for humane treatment (for example, an ultrarapid opioid detoxification using naloxone and artificial sleep: JAMA 279: 229, 1998). Is this available? Ads for it are just starting to appear. The strung-out addict is going to rob somebody instead. It is easy to recognize politically-motivated, futile escalation (remember Vietnam?), war-profiteering, or how the current policy of ensuring that drugs generate crime (and crime-profits) serves politics-at-its-worst for both right-wingers and left-wingers. Bill Clinton actually talked about "harm reduction" (JAMA 273: 1143, 1995) rather than a "war" we can win, and the British (not known for being soft-hearted) already consider "damage control" and not "fighting drugs" is the only rational option (Br. Med. J. 315: 329, 1997). Stay tuned (Sci. Am. 269(1): 24, 1993; CIBA Found. Symp. 166: 224, 1992.) Jocelyn Elders, M.D., was pilloried for suggesting decriminalization; a few years later, Newt Gingrich said the same thing and no right-wingers got upset.

Your lecturer, while no expert on social policy, believes that addiction is bad. Yet I would prefer accessible treatment of addiction (how much does humane detoxification and ongoing monitoring, without other frills, have to cost, anyway?), some ongoing public education (it doesn't have to cost much, and by now everybody knows, anyway...), and other reasonable incentives (as with ethanol -- remember Prohibition? alcohol abuse probably went down after it was repealed; and this doctor will give you a urine specimen anytime you like, thank you) instead of the continued emphasis on attempting to enforce laws as a means of containing what is a very serious problem. Other physicians are now coming around to your lecturer's position as well (Acad. Med. 70: 355, 1995). Maybe the "Smokers' Rights" proponents might make the logical step to drug decriminalization. Amsterdam, where drugs are legal and treatment is readily available, hasn't exactly become a horrible place to be.... Even the British Medical Journal (312: 1655, 1996), not exactly a hotbed of radicals, is now calling the "war on drugs" a defeat, and calling for decriminalization and even legalization.

As always, you're welcome to disagree.

Nothing is more destructive of respect for the government and the law of the land than passing laws which cannot be enforced.

-- Albert Einstein

OTHER NOTABLE POISONS

Thallium poisoning requires a very high index of suspicion whether or not it has been fatal, unless the distinctive sign has appeared -- hair loss, * perhaps preceded by blackening of the hair roots.

* Criminal poisoning by thallium and arsenic in an auto manufacturing plant: Ann. Emerg. Med. 39: 307, 2002. A near-miss homicide, described by the victim, who was crippled: South. Med. J. 96: 632, 2003. A famous double-death suspected to be arsenic poisoning is proven to be such: BMR 333: 1299, 2007. A case fully worked-up for pathology: Arch. Derm. 143: 93, 2007.

Thallium poisoning Source unknown

Thallium poisoning Cyril Wecht

Mercury

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