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58-591: Although regulatory and civil proceedings found conflicting evidence about Zion's death, today, her death is widely believed to have been caused by serotonin syndrome from the drug interaction between the phenelzine she was taking prior to her hospital visit, and the pethidine administered by a resident physician . The lawsuits and regulatory investigations following her death, and their implications for working conditions and supervision of interns and residents, were highly publicized in both lay media and medical journals. Libby Zion (November 1965 – March 5, 1984)

116-523: A "flu-like ailment" for the past several days. The article stated that after being admitted to New York Hospital , she died of cardiac arrest , the cause of which was not known. Libby Zion had been admitted to the hospital through the emergency room by the resident physician assigned to the ER on the night of March 4. Raymond Sherman, the Zion family physician, agreed with their plan to hydrate and observe her. Zion

174-440: A "murder", and wrote "They gave her a drug that was destined to kill her, then ignored her except to tie her down like a dog." Sidney also questioned the long hours that residents worked at the time. In a New York Times op-ed piece, he wrote: "You don't need kindergarten to know that a resident working a 36-hour shift is in no condition to make any kind of judgment call—forget about life-and-death." The case eventually became

232-629: A benefit from serotonin antagonists. Cyproheptadine is only available as tablets and therefore can only be administered orally or via a nasogastric tube ; it is unlikely to be effective in people administered activated charcoal and has limited use in severe cases. Cyproheptadine can be stopped when the person is no longer experiencing symptoms and the half life of serotonergic medications already passed. Additional pharmacological treatment for severe case includes administering atypical antipsychotic drugs with serotonin antagonist activity such as olanzapine or asenapine . Critically ill people should receive

290-454: A consequence of hyperthermia. The symptoms are often present as a clinical triad of abnormalities: Numerous medications and street drugs can cause SS when taken alone at high doses or in combination with other serotonergic agents. The table below lists some of these. Many cases of serotonin toxicity occur in people who have ingested drug combinations that synergistically increase synaptic serotonin. It may also occur due to an overdose of

348-427: A large amount of muscle breakdown. This breakdown can cause severe damage to the kidneys through a condition called rhabdomyolysis . Treatment for hyperthermia includes reducing muscle overactivity via sedation with a benzodiazepine. More severe cases may require muscular paralysis with vecuronium , intubation , and artificial ventilation. Suxamethonium is not recommended for muscular paralysis as it may increase

406-448: A longer time frame in patients taking drugs which have a long elimination half-life , active metabolites, or a protracted duration of action. Cases have reported persisting chronic symptoms, and antidepressant discontinuation may contribute to ongoing features. Following appropriate medical management, SS is generally associated with a favorable prognosis. Epidemiological studies of SS are difficult as many physicians are unaware of

464-671: A primary care physician at the Albert Einstein College of Medicine in the Bronx . Bell was well known for his critical stance regarding the lack of supervision of physicians-in-training. Formally known as the Ad Hoc Advisory Committee on Emergency Services, and more commonly known as the Bell Commission, the committee evaluated the training and supervision of doctors in the state, and developed

522-493: A protracted high-profile legal battle, with multiple abrupt reversals; case reports about it appeared in major medical journals. In May 1986, Manhattan District Attorney Robert Morgenthau agreed to let a grand jury consider murder charges, an unusual decision for a medical malpractice case. Although the jury declined to indict for murder, in 1987 the intern and resident were charged with 38 counts of gross negligence and/or gross incompetence. The grand jury considered that

580-462: A role as CNS norepinephrine concentrations are increased in SS and levels appear to correlate with the clinical outcome. Other neurotransmitters may also play a role; NMDA receptor antagonists and γ-aminobutyric acid have been suggested as affecting the development of the syndrome. Serotonin toxicity is more pronounced following supra-therapeutic doses and overdoses , and they merge in a continuum with

638-734: A series of mistakes contributed to Zion's death, including the improper prescription of drugs and the failure to perform adequate diagnostic tests. Under New York law, the investigative body for these charges was the Hearing Committee of the State Board for Professional Medical Conduct . Between April 1987 and January 1989, the committee conducted 30 hearings at which 33 witnesses testified, including expert witnesses in toxicology , emergency medicine , and chairmen of internal medicine departments at six prominent medical schools, several of whom stated under oath that they had never heard of

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696-510: A series of recommendations that addressed several patient-care issues, including restraint usage, medication systems, and resident work hours. The Bell Commission recommendations that attending physicians should be present at all times and limiting residents to 80 hours a week and 24 hours at a time were adopted by New York in 1989. Implementation of the recommendations caused some hospitals to introduce doctors who worked overnight to spell their colleagues. Periodic follow-up audits have prompted

754-442: A single serotonergic agent. The combination of monoamine oxidase inhibitors (MAOIs) with precursors such as L-tryptophan or 5-hydroxytryptophan pose a particularly acute risk of life-threatening serotonin syndrome. The case of combination of MAOIs with tryptamine agonists (commonly known as ayahuasca ) can present similar dangers as their combination with precursors, but this phenomenon has been described in general terms as

812-414: Is neuroleptic malignant syndrome (NMS). The clinical features of neuroleptic malignant syndrome and SS share some features which can make differentiating them difficult. In both conditions, autonomic dysfunction and altered mental status develop. However, they are actually very different conditions with different underlying dysfunction (serotonin excess vs dopamine blockade). Both the time course and

870-462: Is a predictable consequence of excess serotonin on the central nervous system . Onset of symptoms is typically within a day of the extra serotonin. Diagnosis is based on a person's symptoms and history of medication use. Other conditions that can produce similar symptoms such as neuroleptic malignant syndrome , malignant hyperthermia , anticholinergic toxicity , heat stroke , and meningitis should be ruled out. No laboratory tests can confirm

928-459: Is an important factor in determining the course of treatment. Serotonin is catabolized by monoamine oxidase A in the presence of oxygen , so if care is taken to prevent an unsafe spike in body temperature or metabolic acidosis, oxygenation will assist in dispatching the excess serotonin. The same principle applies to alcohol intoxication. In cases of SS caused by MAOIs, oxygenation will not help to dispatch serotonin. In such instances, hydration

986-422: Is based primarily on stopping the usage of the precipitating drugs, the administration of serotonin antagonists such as cyproheptadine (with a regimen of 12 mg for the initial dose followed by 2 mg every 2 hours until clinical, while some claim that a higher initial dose up to 32 mg has more benefit ), and supportive care including the control of agitation, the control of autonomic instability, and

1044-663: Is complex. SS has been reported in patients of all ages, including the elderly, children, and even newborn infants due to in utero exposure. The serotonergic toxicity of SSRIs increases with dose, but even in overdose, it is insufficient to cause fatalities from SS in healthy adults. Elevations of central nervous system (CNS) serotonin will typically only reach potentially fatal levels when drugs with different mechanisms of action are mixed together. Various drugs, other than SSRIs, also have clinically significant potency as serotonin reuptake inhibitors, (such as tramadol , amphetamine , and MDMA) and are associated with severe cases of

1102-680: Is the main concern until the enzyme is regenerated. Specific treatment for some symptoms may be required. One of the most important treatments is the control of agitation due to the extreme possibility of injury to the person themselves or caregivers, benzodiazepines should be administered at first sign of this. Physical restraints are not recommended for agitation or delirium as they may contribute to mortality by enforcing isometric muscle contractions that are associated with severe lactic acidosis and hyperthermia. If physical restraints are necessary for severe agitation they must be rapidly replaced with pharmacological sedation . The agitation can cause

1160-543: Is typically caused by the use of two or more serotonergic medications or drugs. This may include selective serotonin reuptake inhibitor (SSRI), serotonin norepinephrine reuptake inhibitor (SNRI), monoamine oxidase inhibitor (MAOI), tricyclic antidepressants (TCAs), amphetamines , pethidine (meperidine), tramadol , dextromethorphan , buspirone , L-tryptophan , 5-hydroxytryptophan , St. John's wort , triptans , MDMA , ondansetron , metoclopramide , or cocaine . It occurs in about 15% of SSRI overdoses. It

1218-637: The New York State Department of Health to crack down on violating hospitals. Similar limits have since been adopted in numerous other states. In July 2003 the Accreditation Council for Graduate Medical Education (ACGME) adopted similar regulations for all accredited medical training institutions in the United States. Serotonin syndrome Serotonin syndrome ( SS ) is a group of symptoms that may occur with

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1276-518: The cheese effect . Many MAOIs irreversibly inhibit monoamine oxidase . It can take at least four weeks for this enzyme to be replaced by the body in the instance of irreversible inhibitors. With respect to tricyclic antidepressants, only clomipramine and imipramine have a risk of causing SS. Many medications may have been incorrectly thought to cause SS. For example, some case reports have implicated atypical antipsychotics in SS, but it appears based on their pharmacology that they are unlikely to cause

1334-461: The medulla oblongata was responsible for the development of the syndrome. Further study has determined that overstimulation of primarily the 5-HT 2A receptors appears to contribute substantially to the condition. The 5-HT 1A receptor may still contribute through a pharmacodynamic interaction in which increased synaptic concentrations of a serotonin agonist saturate all receptor subtypes. Additionally, noradrenergic CNS hyperactivity may play

1392-406: The mucosa of the mouth , the size and reactivity of the pupils, the intensity of bowel sounds, skin color, and the presence or absence of sweating. The patient's history also plays an important role in diagnosis, investigations should include inquiries about the use of prescription and over-the-counter drugs , illicit substances, and dietary supplements , as all these agents have been implicated in

1450-540: The "strange jerking motions" that Zion had been exhibiting when she was admitted. Weinstein and Stone were both responsible for covering dozens of other patients. After evaluating Zion, they left. Luise Weinstein went to cover other patients, and Stone went to sleep in an on-call room in an adjacent building. Zion, however, did not improve, and continued to become more agitated. After being contacted by nurses by phone, Weinstein ordered medical restraints be placed on Zion. She also prescribed haloperidol by phone to control

1508-526: The Board of Regents overruled the Commissioner's recommendation. The hospital also admitted it had provided inadequate care and paid a $ 13,000 fine to the state. In 1991, however, the state's appeals court completely cleared the records of the two doctors of findings that they had provided inadequate care to Zion. In parallel with the state investigation, Sidney Zion also filed a separate civil case against

1566-469: The Board of Regents, which was under no obligation to consider either the Commissioner's or the Hearing Committee's recommendations. The Board of Regents, which at the time had only one physician among its 16 members, voted to "censure and reprimand" the resident physicians for acts of gross negligence. This decision did not affect their right to practice. The verdict against the two residents was considered very surprising in medical circles. In no other case had

1624-537: The above therapies as well as sedation or neuromuscular paralysis. People who have autonomic instability such as low blood pressure require treatment with direct-acting sympathomimetics such as epinephrine , norepinephrine, or phenylephrine . Conversely, hypertension or tachycardia can be treated with short-acting antihypertensive drugs such as nitroprusside or esmolol ; longer acting drugs such as propranolol should be avoided as they may lead to hypotension and shock. The cause of serotonin toxicity or accumulation

1682-425: The agitation. Zion finally managed to fall asleep, but by 6:30, her temperature had soared to 107 °F (42 °C). Weinstein was once again called, and measures were quickly taken to try to reduce her temperature, but Zion had a cardiac arrest and could not be resuscitated. Several years later, physicians concluded the combination of phenelzine and the pethidine given to her by Stone and Weinstein contributed to

1740-458: The civil trial. The jury decided that the hospital was negligent for leaving Weinstein alone in charge of 40 patients that night, but they also concluded that this negligence did not directly contribute to Zion's death. The trial was shown on Court TV . After the grand jury's indictment of the two residents, Axelrod decided to address the systemic problems in residency by establishing a blue-ribbon panel of experts headed by Bertrand M. Bell ,

1798-829: The clinical features of NMS differ significantly from those of serotonin toxicity. Serotonin toxicity has a rapid onset after the administration of a serotonergic drug and responds to serotonin blockade such as drugs like chlorpromazine and cyproheptadine . Dopamine receptor blockade (NMS) has a slow onset, typically evolves over several days after administration of a neuroleptic drug, and responds to dopamine agonists such as bromocriptine . Differential diagnosis may become difficult in patients recently exposed to both serotonergic and neuroleptic drugs. Bradykinesia and extrapyramidal "lead pipe" rigidity are classically present in NMS, whereas SS causes hyperkinesia and clonus; these distinct symptoms can aid in differentiation. Management

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1856-673: The combined use of either SSRIs or SNRIs with triptan medications or sibutramine could potentially lead to severe cases of SS. This has been disputed by other researchers, as none of the cases reported by the FDA met the Hunter criteria for SS. The condition has however occurred in surprising clinical situations, and because of phenotypic variations among individuals, it has been associated with unexpected drugs, including mirtazapine. The relative risk and severity of serotonergic side effects and serotonin toxicity, with individual drugs and combinations,

1914-456: The comorbidity of pain and depression. Cases where opioids alone are the cause of SS are typically seen with tramadol, because of its dual mechanism as a serotonin-norepinephrine reuptake inhibitor . SS caused by tramadol can be particularly problematic if an individual taking the drug is unaware of the risks associated with it and attempts to self-medicate symptoms such as headache, agitation, and tremors with more opioids, further exacerbating

1972-513: The condition. Serotonin is a neurotransmitter involved in multiple complex biological processes including aggression, pain, sleep, appetite, anxiety, depression, migraine, and vomiting. In humans the effects of excess serotonin were first noted in 1960 in patients receiving an MAOI and tryptophan . The syndrome is caused by increased serotonin in the CNS. It was originally suspected that agonism of 5-HT 1A receptors in central grey nuclei and

2030-492: The control of hyperthermia. Additionally, those who ingest large doses of serotonergic agents may benefit from gastrointestinal decontamination with activated charcoal if it can be administered within an hour of overdose. The intensity of therapy depends on the severity of symptoms. If the symptoms are mild, treatment may only consist of discontinuation of the offending medication or medications, offering supportive measures, giving benzodiazepines for myoclonus, and waiting for

2088-626: The development of SS. To fulfill the Hunter Criteria, a patient must have taken a serotonergic agent and meet one of the following conditions: Serotonin toxicity has a characteristic picture which is generally hard to confuse with other medical conditions , but in some situations it may go unrecognized because it may be mistaken for a viral illness , anxiety disorders , neurological disorder , anticholinergic poisoning, sympathomimetic toxicity, or worsening psychiatric condition. The condition most often confused with serotonin syndrome

2146-456: The development of serotonin syndrome, which led to increased agitation. This led Zion to pull on her intravenous catheter , causing Weinstein to order physical restraints, which Zion also fought against. By the time she finally fell asleep, her fever had already reached dangerous levels, and she died soon after of cardiac arrest. Zion's parents became convinced their daughter's death was due to inadequate hospital staffing. Sidney Zion questioned

2204-726: The diagnosis or they may miss the syndrome due to its variable manifestations. In 1998 a survey conducted in England found that 85% of the general practitioners that had prescribed the antidepressant nefazodone were unaware of SS. The incidence may be increasing as a larger number of pro-serotonergic drugs (drugs which increase serotonin levels) are now being used in clinical practice. One postmarketing surveillance study identified an incidence of 0.4 cases per 1000 patient-months for patients who were taking nefazodone. Additionally, around 14–16% of persons who overdose on SSRIs are thought to develop SS. The most widely recognized example of SS

2262-430: The diagnosis. Initial treatment consists of discontinuing medications which may be contributing. In those who are agitated, benzodiazepines may be used. If this is not sufficient, a serotonin antagonist such as cyproheptadine may be used. In those with a high body temperature, active cooling measures may be needed. The number of cases of SS that occur each year is unclear. With appropriate medical intervention

2320-439: The doctors and the hospital. The civil trial came to a close in 1995 when a Manhattan jury found that the two residents and Libby Zion's primary care doctor contributed to her death by prescribing the wrong drug, and ordered them to pay a total of $ 375,000 to Zion's family for her pain and suffering. The jury also found that Raymond Sherman, the primary care physician , had lied on the witness stand in denying he knew that Libby Zion

2378-517: The drug or drug interaction causing excessive levels of serotonin rather than an effect of elevated serotonin itself. Tremor is a common side effect of MDMA 's action on dopamine , whereas hyperreflexia is symptomatic of exposure to serotonin agonists . Moderate intoxication includes additional abnormalities such as hyperactive bowel sounds, high blood pressure and hyperthermia ; a temperature as high as 40 °C (104 °F). The overactive reflexes and clonus in moderate cases may be greater in

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2436-399: The gold standard of diagnosis by a medical toxicologist. As of 2007, Sternbach's criteria were still the most commonly used. The most important symptoms for diagnosing SS are tremor, extreme aggressiveness, akathisia , or clonus (spontaneous, inducible and ocular). Physical examination of the patient should include assessment of deep tendon reflexes and muscle rigidity, the dryness of

2494-411: The interaction between pethidine and phenelzine prior to this case. At the end of these proceedings, the committee unanimously decided that none of the 38 charges against the two residents were supported by evidence. Its findings were accepted by the full board, and by the state's Health Commissioner, David Axelrod . Under New York law, however, the final decision in this matter rested with another body,

2552-452: The lower limbs than in the upper limbs . Mental changes include hypervigilance or insomnia and agitation . Severe symptoms include severe increases in heart rate and blood pressure. Temperature may rise to above 41.1 °C (106.0 °F) in life-threatening cases. Other abnormalities include metabolic acidosis , rhabdomyolysis , seizures , kidney failure , and disseminated intravascular coagulation ; these effects usually arising as

2610-443: The risk of cardiac dysrhythmia from hyperkalemia associated with rhabdomyolysis. Antipyretic agents are not recommended as the increase in body temperature is due to muscular activity, not a hypothalamic temperature set point abnormality. Upon the discontinuation of serotonergic drugs, most cases of SS resolve within 24 hours, although in some cases delirium may persist for a number of days. Symptoms typically persist for

2668-620: The risk of death is low, likely less than 1%. The high-profile case of Libby Zion , who is generally accepted to have died from SS, resulted in changes to graduate medical school education in New York State . Symptom onset is usually relatively rapid, and SS encompasses a wide range of clinical findings. Mild symptoms may consist of increased heart rate , shivering, sweating , dilated pupils , myoclonus (intermittent jerking or twitching), as well as hyperreflexia (overresponsive reflexes). Many of these symptoms may be side effects of

2726-401: The staff's competence for two reasons. The first was the administration of pethidine, which can cause fatal interactions with phenelzine, the antidepressant that Zion was taking. Few clinicians knew of this interaction at the time, though it is now widely known because of this case. The second issue was the use of restraints and emergency psychiatric medication. Sidney referred to Libby's death as

2784-508: The symptoms to resolve. Moderate cases should have all thermal and cardiorespiratory abnormalities corrected and can benefit from serotonin antagonists. The serotonin antagonist cyproheptadine is the recommended initial therapy, although there have been no controlled trials demonstrating its efficacy for SS. Despite the absence of controlled trials, there are a number of case reports detailing apparent improvement after people have been administered cyproheptadine. Animal experiments also suggest

2842-460: The syndrome. Although the most significant health risk associated with opioid overdoses is respiratory depression , it is still possible for an individual to develop SS from certain opioids without the loss of consciousness . However, most cases of opioid-related SS involve the concurrent use of a serotergenic drug such as antidepressants . Nonetheless, it is not uncommon for individuals taking opioids to also be taking antidepressants due to

2900-463: The syndrome. It has also been suggested that mirtazapine has no significant serotonergic effects and is therefore not a dual action drug. Bupropion has also been suggested to cause SS, although as there is no evidence that it has any significant serotonergic activity, it is thought unlikely to produce the syndrome. In 2006 the US Food and Drug Administration (FDA) issued an alert suggesting that

2958-610: The terms serotonin toxicity or serotonin toxidrome, to more accurately reflect that it is a form of poisoning . There is no specific test for SS. Diagnosis is by symptom observation and investigation of the person's history. Several criteria have been proposed. The first evaluated criteria were introduced in 1991 by Harvey Sternbach. Researchers later developed the Hunter Toxicity Criteria Decision Rules, which have better sensitivity and specificity , 84% and 97%, respectively, when compared with

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3016-482: The toxic effects of overdose. A postulated "spectrum concept" of serotonin toxicity emphasises the role that progressively increasing serotonin levels play in mediating the clinical picture as side effects merge into toxicity. The dose-response relationship is the effect of progressive elevation of serotonin, either by raising the dose of one drug, or combining it with another serotonergic drug which may produce large elevations in serotonin levels. Some experts prefer

3074-578: The use of certain serotonergic medications or drugs . The symptoms can range from mild to severe, and are potentially fatal. Symptoms in mild cases include high blood pressure and a fast heart rate ; usually without a fever . Symptoms in moderate cases include high body temperature , agitation, increased reflexes , tremor , sweating , dilated pupils , and diarrhea . In severe cases, body temperature can increase to greater than 41.1 °C (106.0 °F). Complications may include seizures and extensive muscle breakdown . Serotonin syndrome

3132-548: Was a freshman at Bennington College in Bennington, Vermont . She took a prescribed MAOI antidepressant, phenelzine , daily. A hospital autopsy revealed traces of cocaine , but other later tests showed no traces. She was the daughter of Sidney Zion , a lawyer who had been a writer for The New York Times . Her obituary in The New York Times , written the day after her death, stated that she had been ill with

3190-450: Was assigned to two residents, Luise Weinstein and Gregg Stone, who both evaluated her. Weinstein, a first-year resident physician (also referred to as intern or PGY -1), and Stone, a PGY-2 resident, were unable to determine the cause of Zion's illness, though Stone tentatively suggested that her condition might be a simple overreaction to a normal illness. After consulting with Dr. Sherman, the two prescribed pethidine (meperidine) to control

3248-491: Was caused by a combination of pethidine and phenelzine . A medical intern prescribed the pethidine. The case influenced graduate medical education and residency work hours. Limits were set on working hours for medical postgraduates , commonly referred to as interns or residents, in hospital training programs, and they also now require closer senior physician supervision. Creutzfeldt–Jakob disease District Attorney Too Many Requests If you report this error to

3306-740: Was the death of Libby Zion in 1984. Zion was a freshman at Bennington College at her death on March 5, 1984, at age 18. She died within 8 hours of her emergency admission to the New York Hospital Cornell Medical Center . She had an ongoing history of depression, and came to the Manhattan hospital on the evening of March 4, 1984, with a fever, agitation and "strange jerking motions" of her body. She also seemed disoriented at times. The emergency room physicians were unable to diagnose her condition definitively but admitted her for hydration and observation. Her death

3364-453: Was to be given pethidine. Although the jury found the three doctors negligent, none of them was found guilty of "wanton" negligence, i.e. demonstrating utter disregard for the patient, as opposed to a simple mistake. Payouts for wanton negligence would not have been covered by the doctors' malpractice insurance. The emergency room physician, Maurice Leonard, as well as the hospital (as legal persona) were found not responsible for Zion's death in

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