The Case Files

Welcome to the Case Files!
The Case Files is an anecdotal collection of emergency medicine cases to enable physicians and researchers to find clinically important information on unusual conditions.

Case reports should focus on:

  • Unusual side effects or adverse interactions.
  • Unusual presentations of a disease.
  • Presentations of new and emerging diseases, including new street drugs.
  • Findings that shed new light on a disease or an adverse effect.

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Thursday, April 13, 2017


A 46-year-old man presented to the ED with multiple complaints, including fatigue and dizziness for one day. His primary care physician had diagnosed him with diabetes the previous day, and had prescribed him an oral hypoglycemic as well as insulin. Neither, however, was started at the time of presentation. The patient had a medical history significant for HIV, with his most recent CD4 count above 500, and bilateral sensorineural hearing loss, which had progressively worsened since its initial onset in his 20s. His physical exam was unremarkable except for decreased hearing bilaterally.

A laboratory workup was ordered, including CBC with differential, CMP, blood glucose, β-hydroxybutyrate, and an ECG. Laboratory results were remarkable for a blood glucose level of 593 mg/dl, β-hydroxybutyrate of 7.52 mmol/L, CO2 of 15 mmol/L, and an anion gap of 20, indicating that the patient was suffering from diabetic ketoacidosis. Laboratory results were also significant for a GFR of 33.3 ml/min and creatinine of 2.15 mg/dl, indicating kidney failure. All other results were within normal limits, and his ECG showed no abnormalities.

A thorough family history was taken, and was significant for both diabetes and deafness throughout the patient's maternal side and absent on the paternal side. (Figure.) The patient's brother and mother were deaf and had diabetes, and both were diagnosed before they were 45. His mother's siblings are all affected by at least one pathology. His maternal aunt and uncle were deceased due to stroke and kidney failure, respectively. His maternal grandmother was also affected by diabetes and deafness. His cousins born to maternal uncles were not affected.

The patient was immediately treated with insulin, and was admitted for further investigation and treatment. Due to the patient's strong family history of diabetes, hypoacusis, and pattern of inheritance, a working diagnosis of maternally inherited diabetes and deafness (MIDD) was explored. At the time of admission, the patient was being counseled on genetic testing for confirmation.

An Unrecognized Genetic Disease

MIDD is a distinct subtype of diabetes, caused by a single point mutation in mitochondrial DNA. The mutation most associated with MIDD involves the mtRNALeu(UUR) gene and consists of a 3243A>G transition. (Diabetes 1994;43[6]:746.) It is believed to be part of a spectrum where patients most affected present with MELAS. (Arch Soc Esp Oftalmol 2009;84[7]:360.) As a result of the involvement of mitochondrial DNA, MIDD is inherited by children of all the affected women, while the affected men pose no risk of passing on the mutated genes. (Diabetologia 1996;39[4]:375.)

The syndrome consists of diabetes and sensorineural hearing loss, and may include other organ system manifestations, including ophthalmologic, cardiac, renal, muscular, and neurological pathologies. The organs that are most metabolically active are most commonly involved; they are most affected by deficiencies in mitochondrial-based respiratory oxidation, leading to inefficient cellular energy production. (Diabet Med 2008;25[4]:383.) It is believed that MIDD is responsible for approximately one percent of all diabetic diagnoses. It is, however, often misdiagnosed as Type 1 or 2 diabetes or as Alport syndrome when only deafness and renal symptoms are present. (Diabet Med 2008;25[4]:383.)

The diabetes of MIDD appears to be due to lack of insulin secretion rather than insulin insensitivity. (Ann Intern Med 2001;134[9 Part 1]:721.) The onset of diabetes is usually gradual, with age of onset occurring at 37± 11 years, although up to 20 percent of patients will present acutely and up to eight percent will experience ketoacidosis. (Diabet Med 2008;25[4]:383.)

More than 75 percent of patients will experience sensorineural hypoacusis attributed to the cochlea rather than the cranial nerve. This hearing loss most often presents before the diabetes manifests itself, and is often the only clinical manifestation of the mutation. (Ann Intern Med 2001;134[9_Part_1]:721.)

Associated diseases include end-stage renal failure, myocardiopathies with early heart failure and stroke, muscular abnormalities including biopsies indicating ragged red fibers, characteristic macular retinal dystrophy, and psychiatric disorders such as depression and schizophrenia. (Diabet Med 2008;25[4]:385.)

Wednesday, March 29, 2017


A 62-year-old tall, thin African American man presented to the emergency department after four days of constipation and vomiting. He had decreased mental status, and was unable to provide a complete medical background. His spouse reported that the patient had diffuse abdominal pain for the past four days, and had been experiencing increased thirst and excessive urination for the past four weeks.

She reported that the patient was unresponsive to over-the-counter laxatives and had been unable to produce bowel movements. The patient had no prior abdominal surgery, medication use, or primary care visits. The patient used to be a 20-pack-a-year smoker, but he had quit smoking almost 10 years earlier. The patient also had shortness of breath for the past day but no fever, chills, or chest pain.

Patient's vital signs had a blood pressure of 150/77 mm Hg, heart rate of 58 beats/minute, temperature of 98.1°F, and oxygen saturation of 99%. The patient later admitted to drinking two cans of beer a day and smoking marijuana habitually, but denied any family history of diabetes or hypertension.

The patient appeared lethargic during the physical exam. He also had rapid deep breathing that required increased respiratory efforts. Vesicular breath sounds were heard bilaterally with the use of accessory muscles observed. The abdominal exam revealed a diffusely tender abdomen on palpation. There was no guarding, rebound tenderness, or organomegaly. Bowel sounds were present but hypoactive.

Multiple finger stick glucose tests revealed levels exceeding the instrument's testing parameter of 500 mg/dL; later laboratory testing confirmed the actual glucose value to be 1,750 mg/dL. In the first hour of the patient's ED visit, laboratory studies ordered included comprehensive metabolic panel (CMP), serum troponin I, lactic acid, complete blood count (CBC), ketone panel, serum lipase, arterial blood gas (ABG), and an electrocardiogram (ECG). (Table 1.) The ECG revealed sinus tachycardia with an atrial rate of 104, a long QT interval, and a right bundle branch block.

The patient soon became more lethargic, and was immediately given a 1,000 mL intravenous bolus of normal saline (0.9% sodium chloride) for his dehydration. To alleviate nausea and vomiting and to prevent any complications of acid reflux, the patient was given 4 mg IV-push ondansetron and 20 mg IV-push famotidine. One hour after the initial medications were given, another round of 1,000 mL normal saline and 4 mg ondansetron was given IV-push. A rectal temperature taken two hours after admission to the ED revealed a core body temperature of 97.2°F.

After the first round of labs, 50 mEq sodium bicarbonate IV-push was given to the patient to help reduce his acidotic state. A 2,000 mL IV saline bolus was given to further assist with his dehydration. To decrease his hyperglycemia, the patient was given 8 units of regular insulin and started on an insulin drip at a rate of 6 units/hour. Additionally, 3.375 grams IV-piggyback (PB) of piperacillin/tazobactam and 1 gram IV-PB of vancomycin was given to prevent any bacteremia or infection. Another 30 grams of Kayexalate (sodium polystyrene sulfonate) at a concentration of 15g/60mL were also given to help adjust electrolyte imbalance caused by pseudohyperkalemia.
The patient's condition further deteriorated in the third hour. IV medications were ineffective in preventing the patient's lapse into a diabetic coma due to the severity of the patient's hyperosmolar state at admission. The patient became unresponsive to auditory stimuli and could be aroused only by a sternal rub. A finger stick glucose test was repeated, and the patient's results still exceeded the testing parameters of the instrument. Unable to accurately assess the patient's true glucose value by point-of-care testing, efforts were then focused on stabilizing the patient's vital signs. The patient's condition remained stable but unimproved.

Just as the patient lapsed into a diabetic coma during the fourth hour, his body temperature dropped abruptly. Rectal thermometer revealed a decrease in core body temperature from 96.2°F to 92.0°F within one hour. (Table 2.) Warming blankets were promptly applied; blood culture, urine culture, urinalysis, and urine microscopy were ordered to rule out other organic causes of hypothermia.

Two hours after the blankets were applied, the patient's temperature increased to the normal baseline at 98.5°F, and the patient awoke and muttered under his breath about excessive warmth. The blanket was disconnected and reapplied in intervals to stabilize the patient's body temperature.

A new set of labs was drawn during the 11th hour, and the patient was transferred to the ICU for further management. After three hours of continuous ICU care, the patient was finally stabilized and regained full consciousness.

Etiology and Presentation

Diabetic ketoacidosis (DKA) and hyperosmolar state (HSS) are major acute complications in patients with diabetes mellitus, and both may occur in patients with type 1 or type 2 diabetes. (Diabetes Care 2004;27 Suppl 1:S94.) Risk factors include infection, alcohol abuse, pancreatitis, myocardial infarction, trauma, drugs, and selective racial backgrounds. African Americans and Hispanics are at the greatest risk of developing acute diabetic complications. (Ann Intern Med 2006;144[5]:350.)

DKA and HSS occur due to the absence or deficiency of the net effective concentration of insulin. Dysfunction of the insulin pathway shifts body metabolism toward lipolysis. Breakdown of lipids increase ketone serum concentration, which, along with elevated serum glucose, results in classic DKA/HSS signs and symptoms such as nausea, vomiting, abdominal pain, polyuria, polydipsia, Kussmaul breathing, and altered mental status. (Robbins and Cotran Pathologic Basis of Disease, 9th Edition. Philadelphia: Elsevier; 2015.) The basic pathophysiology of both conditions can be seen as a consequence of osmotic diuresis due to hyperglycemia. (Diabetes Care 2004;27[Suppl 1]:S94.)

A significant number of patients present with DKA as the initial symptom of diabetes mellitus because they do not seek medical care for the initial polyuria and polydipsia. (Diabetes Spectrum 2002; 15[1]: 28.) Many of these patients are older than the average age of diabetes patients, especially among African Americans. In fact, a community study has determined that more than 40 percent of DKA patients were over age 40, and as many as 20 percent of DKA patients were over age 55. (Arch Intern Med 1997;157[6]:669.)

The mortality rate for DKA is about five percent, while the mortality for HHS is around 15 percent; both conditions are significantly more severe in those over age 65 and in the presence of diabetic coma. (Diabetes Care 2004;27[Suppl 1]:S94.) Most DKA patients have type 1 diabetes, but a subset of patients with type 2 diabetes are afflicted with “ketosis-prone” diabetes, which account for 20-50 percent of all DKA patients. These patients are usually obese, elderly, male, and African American or Hispanic. (Ann Intern Med 2006;144[5]:350.)

The most common electrolyte imbalance in DKA is the phenomenon of pseudohyperkalemia. Two mechanisms falsely elevate serum potassium in diabetic patients. Insulin directly stimulates the sodium-potassium ATPase pump, so insulin deficiency causes a predictable decrease in the driving force of extracellular potassium intracellularly, resulting in potassium accumulating extracellularly. Acidosis stimulates the exchange of intracellular potassium with extracellular protons. An elevated potassium value in laboratory tests is, therefore, considered “normal” in DKA/HSS patients because it is a compensatory physiological mechanism.

If such patients were to present with potassium in the ranges of 3.5-5.5 mEq, they should promptly receive potassium infusion because they actually are suffering from hypokalemia. DKA/HSS patients with low body temperature, however, may also present with low to normal potassium due to hypothermia and the subsequent induction of hypokalemia. (Mil Med 1998;163[10]:719.) This patient's inability to produce a bowel movement, even with the aid of laxatives, was most likely due to his intrinsic hypokalemic state.

Complications and Coma

Hypothermia is a reduction in core temperature below 95°F (35°C), with the most accurate reading taken by rectally. (Med Sci Law 1969;9[4]:231.) Hypothermia can be caused by starvation, malnutrition, immobility, myocardial infarction, pulmonary embolism, and endocrine disorders such as hypopituitarism and hypothyroidism. A British study determined that DKA-induced hypothermia (11.8% of all cases of hypothermia admissions) is more common than hypothyroidism-induced hypothermia (8% of all cases of hypothermia admissions). (Br Med J 1978;2[6149]:1387.)

Hypothermia is the result of severe decompensation during hypoglycemia as well as lactic acidosis. The main mechanism of decreased body temperature in DKA/HSS is due to impaired metabolism of glucose to produce heat. Diabetic Kussmaul breathing impairs adequate oxygen intake, further contributing to the development of hypothermia because oxygen is needed for thermoregulation. Hypothermia results in suboptimal conditions for insulin to function, another detriment to the body's attempt to re-establish homeostasis. (Recent Advances in Medicine. London: Churchill; 1968.) The tendency of diabetic patients to experience hypothermia produces a vicious cycle that exacerbates hyperglycemic states and induces severe diabetic coma in susceptible patients.

Treatment and Prognosis

As many as 25 percent of elderly patients above age 65 suffer from diabetes mellitus (Centers for Disease Control and Prevention. National Diabetes Fact Sheet, 2011), and the management protocol for these patients was created in 2012 by the American Diabetes Association (ADA). Late presentation of diabetes mellitus is positively correlated to the likelihood of developing ketosis-prone diabetes or latent autoimmune diabetes of the adult (LABA). (Diabetes Care 2001;24[8]:1460.) Depending on the patient population, LABA could account for a large portion of diabetic patients, and this proportion is magnified in the elderly. To aid in diagnosis, further testing such as detection of glutamic acid decarboxylase autoantibody (GADA), islet cell autoantibody (ICA), insulinoma-associated (IA-2) autoantibody, and zinc transporter autoantibody (ZnT8) as well as low C-peptide levels are required. (Diabetes Care 2012;35[12]:2650.) GAD is absent (patients with Aβ+ phenotype) in many African American patients with LABA, and should not be used to rule out ketosis-prone diabetic presentations in African Americans. (Diabetes Care 2009;32[7]:1335.)

Diabetic ketoacidosis is managed with multiple IV medications and saline aimed at reducing symptoms of dehydration, hyperglycemia, and electrolyte imbalance. The most crucial therapies are normal saline at a rate of 1 to 1.5 L/hour and insulin at 0.14 units per kilogram of body weight per hour (approximately 10 units per hour in a 70kg patient). (Diabetes Care 2009;32[7]:1335.) Uncomplicated DKA may be reversed when patient's pH is greater than 7.3 with a glucose level of 200 mg/dL, and bicarbonate levels greater than 18 mmol/L. These patients may be discharged and managed at home with prescribed insulin. (Emerg Med 2015;47[9]:410.) If DKA does not resolve with treatment, further care should be aimed at reducing comorbid precipitating events and complications such as hypokalemia and hypothermia.

Uncomplicated and complicated DKA carry significant mortality risk, with complicated DKA more likely to occur in the elderly. Both conditions may adversely contribute to long-term complications such as diabetic retinopathy and nephropathy. African American and Hispanic patients with LABA belong to a particularly high-risk patient group because there is no accurate method of expressing how long their condition has existed. Hemoglobin A1c (HgbA1c) is often used as a prognostic tool in determining long-term complications in these patients. HgbA1c's predictive value for risk of long-term diabetic complications tapers off at around 65 years of age, and further glycemic control as monitored by this index does not significantly improve patient's quality of life. (Clin Diabetes 1999;17[1].)

This case demonstrates the severity of DKA in a patient who has never experienced any symptoms of diabetes mellitus before his ED visit. Prompt diagnosis and proper management of the patient yielded favorable results with reversal of DKA, despite the patient's temporary hypothermic event. Treatment of DKA includes IV therapy of fluids and insulin to improve hydration and electrolyte balance, as well as management of potential hypothermia. Diligent monitoring of patient laboratory values and vital signs allows clinicians to take prompt measures that will minimize the damage caused by DKA before restoring the patient to normal functional status.

Diabetes mellitus can occur in any patient, and the onset can occur at any age, though the average age of onset for diabetes mellitus is 45 to 64. (Centers for Disease Control and Prevention, National Diabetes Statistics Report, May 15, 2015.) The patient in this case was 62. A late presentation suggests a diagnosis of ketosis-prone latent autoimmune diabetes of adults (LADA) or type 1.5 diabetes mellitus, but confirmatory testing is required for definitive diagnosis and proper long-term management of such patients.​

Thursday, February 2, 2017


A 56-year-old black man presented to the ED complaining of face and neck swelling. An initial history was difficult to obtain because the patient did not speak English fluently and had slurred speech. Symptoms started approximately a week earlier when the patient was at his nursing home. He denied dysphagia or odynophagia, he had no rashes, pruritus, dyspnea, or peripheral edema, his face was flushed, and he had visibly engorged neck veins. He noticed that his tongue was mildly swollen, so he took Benadryl for a week with no relief. The patient said he believed that the symptoms might have been because a nurse gave him an incorrect medication at the nursing home. He had been a pack-a-day smoker for 30 years, and had a history of schizoaffective disorder, bipolar disorder with psychotic features, and GERD.

A CBC with differential, PT, PTT, BMP, and UA were all within normal limits. A chest x-ray confirmed a large mediastinal mass, and a soft tissue neck CT scan with contrast found a large mass in the upper mediastinum with extensive adenopathy in the base of the right side of his neck on the right, a right lobe thyroid mass, and occlusion of the superior vena cava and left subclavian vein. The report suggested that the findings were consistent with aggressive lymphoma or lung cancer.


The patient was admitted to the hospital with a scheduled emergent biopsy of the neck mass/lymph nodes. He was diagnosed with superior vena cava (SVC) syndrome and small cell lung carcinoma (SCLC) by tissue biopsy and pathology.

The SVC drains venous blood from the head, neck, upper extremities, and thorax. Obstruction of the SVC is usually because of neoplasms that invade the tissue wall or put pressure on the SVC. (J Clin Oncol 1984;2[8]:961.) SCLC accounts for 25 percent of SVC syndrome because of malignancy. (HemOnc Today Feb. 10, 2012; Clinical features of SVC syndrome include facial edema, difficulty swallowing, engorged neck veins, cough, and dyspnea. (Int J Radiat Oncol Biol Phys 1987;13[4]:531.) Obstruction of the SVC can divert blood flow to the azygous veins, internal mammary veins, superior and inferior epigastric veins, and femoral and vertebral veins, but the venous pressure remains elevated. Complications of this condition include cerebral edema, coma, and death. (Joint Bone Spine 2002;69[4]:416.)

The patient presented with only neck swelling and difficulty speaking. The speech impediment was most likely from the combination of SVC syndrome and right-sided thyroid mass occluding the right recurrent laryngeal nerve. The prognosis of SVC syndrome is poor because of the underlying neoplasm. The patient was promptly started on a dose of approximately 2900 cGy in 13 fractions to the mediastinum and neck nodes and scheduled to receive chemotherapy. After three weeks, he was medically stabilized, and had tolerated chemotherapy and radiation. The SVC syndrome did not compromise his breathing. The patient was advised that he could be discharged with a PORT-A-CATH for future chemotherapy, but the prognosis of his condition remained poor.

Lung cancer is the leading cause of cancer-related death in the United States. (CA Cancer J Clin 2008;58[2]:71.) Its incidence is decreasing, but 13 percent of all new cancers are still from lung cancer. ("Lung Cancer Statistics," American Cancer Society, March 4, 2015; Even with current screening techniques, approximately half of patients have a metastatic presentation and a 45 percent five-year survival rate. Approximately 90 percent of lung cancer patients are active smokers or had recently stopped.

Signs and symptoms of this cancer include shortness of breath, cough, bone pain, weight loss, fatigue, and neurologic dysfunction. (Medscape, March 26, 2014; None of these was present in the patient. Most SCLCs are metastasized by the time of diagnosis, and are not curative by surgery. A combination of chemotherapy and radiation therapy is required. SCLCs are centrally located masses found in the lung parenchyma. (J Clin Oncol 2006;24[28]:4526.) These pale gray tumors are fusiform-shaped and quite fragile. They can also express neuroendocrine markers and secrete polypeptide hormones that can cause paraneoplastic syndromes, such as syndrome of inappropriate antidiuretic hormone. (Chest 2003;123[1 Suppl]:97S.)

The time frame of disease development was unclear, but this patient's presentation was unique because he had nonthreatening symptoms. Lung cancer and SVC syndrome symptoms are usually aggressive, and can compromise the quality of life for patients. Our patient is now being treated to try to prevent the expected disease outcomes.

Mr. Hassan-Ali is a third-year medical student at the Windsor University School of Medicine in Cayon, Saint Kitts. Dr. Raziuddin is an internist specializing in emergency medicine at Louis A. Weiss Memorial and Thorek Memorial hospitals in Chicago.

Tuesday, January 17, 2017



A 43-year-old woman presented to our emergency department with complaints of anxiety, intermittent “cramping” in her left hand, and jerking movements of her body that had been going on for five days. She had depression following the death of her son 14 months earlier, for which she was started on Effexor 37.5 mg once daily two weeks earlier.

One week before this visit, the patient had back pain and headache, for which she was evaluated at a local emergency department. She had lumbar x-rays showing mild degenerative changes in her spine and a normal head CT scan. The emergency physician who saw her prescribed tramadol 50 mg for every eight hours as needed for pain and cyclobenzaprine 10 mg for every eight hours as needed for spasm.

The patient subsequently developed uncontrollable anxiety and clenching of her left hand. The patient called her psychiatrist to inquire if it might be related to her taking Effexor, but her psychiatrist said the patient's symptoms were unlikely to be side effects of the drug.

The patient then followed up with her primary care physician, who observed an episode of uncontrollable clenching of the patient's left hand and was concerned about hypocalcemia or a central neurologic issue such as focal motor seizure. Her primary care provider then ordered laboratory tests, including calcium levels, ionized calcium levels, PTH, vitamin D levels, TSH, C-reactive protein, complete blood counts, electrolytes including magnesium and phosphorus levels, and liver function tests, all of which returned normal results. The primary provider scheduled an outpatient MRI of the brain and wrote prescription refills for tramadol and cyclobenzaprine.

The patient subsequently developed jerking movements involving her entire body, which seemed worse on the left side. The patient had not yet had her MRI brain scan, which was scheduled for later that afternoon, but presented to our emergency department with uncontrollable flinging and jerking movements of her body along with worsening anxiety.

Her physical exam was remarkable for frequent myoclonic jerking, tremor, hyperreflexia, and some incoordination with finger-to-nose and heel-to-shin testing. The patient was able to ambulate, but she intermittently had truncal ataxia while sitting. Otherwise, neurologic examination found her motor, sensory, and cranial nerve functions to be normal. Routine labs were normal, and the myoclonus was considerably improved with lorazepam 1 mg via IV.

We suspected that the patient had serotonin syndrome and recommended discontinuation of her meds, except for Ativan, to control the myoclonus. MRI of the brain was normal. Symptoms rapidly improved after discontinuing the medications, and the patient completely recovered within a few days.

Serotonin Syndrome

Signs and symptoms of serotonin syndrome include agitation or restlessness, diarrhea, rapid heart rate, elevated blood pressure, increased body temperature, loss of coordination, hyperreflexia, ataxia, myoclonus, agitation, nausea and vomiting, and hallucinations. (Ochsner J 2013;13[4]:533; Pain Med 2014;15[8]:1429.) Diagnosis of serotonin syndrome is typically made by identifying the clinical signs and symptoms when the patient is exposed to drugs known to elevate serotonin. The simple-to-follow Hunter Serotonin Toxicity Criteria offer simple if-then-else rules to diagnose the condition. (Am Fam Physician 2010;81[9]:1139; QJM 2003;96[9]:635.)

Offending drugs increase serotonin levels by inhibiting serotonin reuptake, inhibiting degradation of serotonin, or increasing serotonin release. (Am J Case Rep 2014;15:562.) A few drugs are also direct or indirect serotonin receptor agonists. (See table.)

The Rise of Tramadol

Tramadol is a blockbuster drug, and it became the 20th most prescribed drug in the United States by 2015. (IMS Health, Dec 2015; A total of 424 tons of tramadol was consumed worldwide in 2012 alone. (WHO, 2014;

The Drug Enforcement Agency re-categorized hydrocodone from a schedule III to a schedule II drug on Oct. 6, 2014, requiring it to be prescribed using triplicate prescription pads. This move was a response to the growing problem of prescription opioid abuse and diversion. Consequently, the burden of having to write triplicates may prompt physicians to seek alternatives such as tramadol. Tramadol had previously been placed into the schedule IV category on July 7, 2014.

Beware Cyclobenzaprine

Antidepressant medications are the most prescribed class of drugs in the United States, and one in 10 Americans is on antidepressants, according to the CDC. SSRIs are widely used as antidepressants, but frequent prescribing of tramadol and a lack of knowledge about the major drug interaction between tramadol and SSRIs can result in a growing number of patients experiencing the negative effects of these interactions.

Emergency physicians often prescribe a muscle relaxant in cases of muscle strain, spasm, or blunt trauma. Cyclobenzaprine should also be given with caution (if at all) to patients on other drugs that increase serotonin levels. The FDA instituted a safety labeling change to cyclobenzaprine in April 2013: “The development of a potentially life-threatening serotonin syndrome has been reported with Flexeril when used in combination with other drugs, such as selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), tramadol, bupropion, meperidine, verapamil, or MAO inhibitors.” (

Physicians should be aware that cyclobenzaprine potentially poses some risk in combination therapies.

Toxic Combinations

Our patient on Effexor was prescribed a potentially toxic cocktail of tramadol and cyclobenzaprine by an emergency physician. This combination can result in a major reaction, potentially increasing serotonin levels and lowering the seizure threshold. (Psychiatry [Edgmont] 2009;6[4]:17.) Pairing any two of the three drugs prescribed to our patient — Effexor, tramadol, and cyclobenzaprine — will have major interactions.

Studies show only 15 to 20 percent of physicians are aware of the potentially serious interaction between tramadol and SSRIs. (Clinical Therapeutics 2015;37[8]:e43.) Symptoms of serotonin syndrome can range from mild to severe. It is likely that many patients with mild symptoms are simply overlooked by their physicians. Many patients who receive concomitant tramadol and SSRIs will likely have no symptoms, but it is difficult to anticipate which patients will have problems. A physician who prescribes tramadol monotherapy cannot predict whether a second physician may add other medications that can cause severe drug interactions. The use of electronic medical record systems that include drug interaction checking is encouraged.

The patient in this case either did not disclose these new medications or the psychiatrist failed to recognize the combination as dangerous. The patient then saw her own primary care provider who issued a new prescription for the same medications, apparently also not recognizing the risk of the combination. It is unfortunately common for physicians to fail to recognize the risk of serotonin syndrome from commonly prescribed drugs. (Eur J Hosp Pharm 23 March 2016 [ePub Ahead of Print].) Physicians who prescribe tramadol as part of their practice should take note of the myriad problems associated with tramadol in polypharmacy, and hospital pharmacies may play an important role in signaling the interactions and advising prescribers.

Partial List of Drugs Known to Increase Serotonin Levels

* Amphetamines and derivatives

* Ecstasy

* Dextroamphetamine

* Methamphetamine

* Sibutramine

* Analgesics

* Cyclobenzaprine

* Fentanyl

* Meperidine

* Tramadol

* Antidepressants/mood stabilizers

* Buspirone

* Lithium

* Monoamine oxidase inhibitors (selegiline, phenelzine, tranylcypromine)

* Selective serotonin reuptake inhibitors (SSRIs) (fluoxetine, sertraline, paroxetine, citalopram, escitalopram, dapoxetine, seproxetine, zimelidine, mesembrine)

* Serotonin-norepinephrine reuptake inhibitors (venlafaxine, duloxetine, desvenlafaxine, milnacipran)

* Serotonin 2A receptor blockers (trazodone)

* Tricyclic antidepressants (amitriptyline, imipramine, nortriptyline)

* Antiemetics (metoclopramide, ondansetron)

* Antimigraine drugs

* Carbamazepine

* Ergot Alkaloids

* Triptans

* Valproic acid

* Miscellaneous

* Cocaine

* Dextromethorphan

* Linezolid

* L-tryptophan

Dr. Barrows is a physician with Code 3 Emergency Physicians in Dallas. He trained at Baylor College of Medicine and the University of Texas, Southwestern, in Houston and Dallas, respectively.

Tuesday, December 27, 2016


A 32-year-old man was found unresponsive at home by his mother who immediately called the paramedics. The patient was in asystole upon their arrival, and CPR/ACLS protocol was started along with intubation. The patient was transported to the hospital, where ACLS protocol was continued and eventually resulted in the return of a stable pulse. The patient had a significant history of alcohol abuse resulting in liver disease, but had no prior episodes of such events. He also was a smoker of tobacco and marijuana. The patient's mother reported that he had had dark, tarry, melanotic stools and palpitations beginning a few days prior to his unresponsive episode.

The EMT on site administered 6 amps of epinephrine, 2 mg of naloxone, 1 amp of bicarbonate, and D50 via intraosseous line. Resuscitation continued in the ED with another 4 amps of epinephrine administered, resulting in a pulse being re-established. Two peripheral intravenous lines and a subclavian line were then placed to maintain the patient hemodynamically.

The patient was transfused a unit of O negative blood along with a bicarbonate bolus. This allowed for blood to be drawn for tests, and a CBC, CMP, troponin, lactic acid, arterial blood gas, urine analysis, and toxicology screens were ordered. A unique clinical finding in this patient was that the fluid aspirated into the catheter lumen appeared serosanguinous (like pink water) when the central access line was placed, raising the question of whether the catheter was appropriately placed in the subclavian vein.

The blood results correlated with the observed findings in reporting a hemoglobin level of 1.2 g/dL with a hematocrit value of 6.3% and a normal MCV. The patient was found to be acidotic with a pH value of < 6.8, lactic acid of 20.5 mmol/L, troponin elevated at 0.166 ng/mL, and ammonia at 473.3 ug/dL. The patient's WBC count was elevated at 16,260, but the rest of his laboratory workup was relatively normal except for mildly elevated LFTs. The patient's stool sample was melanotic and tested heme-positive.

Despite continued maintenance efforts, the patient eventually expired later in the ICU before further workup could be done to explain the cause of his sepsis and dramatically low hemoglobin value. This raises the question of how low a hemoglobin value can be while sustaining life in a normal individual.

Anemia in Alcoholics

Hemoglobin levels of less than 13.5 g/dL in men and less than 12.0 g/dL in women defines anemia. Anemia in chronic alcoholics is often multifactorial and involves poor nutrition, chronic inflammation, blood loss, liver dysfunction, and ineffective erythropoiesis. (Medicine [Baltimore] 1986;65[5]:322.) Alcohol also has direct toxic effects on the bone marrow red blood cell production as well as red blood cell functionality and lifespan. The table summarizes contributory factors to anemia in alcoholics.

Compensatory Mechanisms


Factors causing anemia in chronic alcoholics.

Physiologic mechanisms will compensate for the decrease in red blood cell mass primarily by alterations in hemoglobin oxygen affinity, blood flow redistribution, and cardiac output adjustments. These mechanisms work in unison to attempt adequate oxygenation, butthe body cannot decrease its tissues' oxygen requirement.

Increases in oxidative metabolism occur as a consequence of the energy required for the compensatory activities. The severity of the clinical presentation relates less to the hemoglobin level and more to the length of time in which the condition develops. Anemias that develop over years will allow the compensatory mechanisms to maintain the patient in an asymptomatic state despite a greater RBC mass loss than an acute hemorrhage. (


Normochromic normocytic RBC on peripheral smear.

* Hemoglobin oxygen affinity: Anemic blood undergoes an increased extraction of oxygen from tissues, increasing the deoxyhemoglobin in the RBC. The hemoglobin-oxygen curve is shifted to the right due to an increased production of 2,3-diphosphoglycerate. The overall decrease in hemoglobin oxygen affinity improves oxygen delivery to target tissues.

* Blood flow redistribution: Chronic anemic states cause selective vasoconstriction of vessels supplying the kidneys and non-vital areas of the body such as cutaneous sites leading to the clinical finding of pallor. Chronic anemic patients will also paradoxically increase total blood volume due to a plasma volume expansion despite the decrease in RBC mass.

* Increased cardiac output: Severe anemics (Hgb < 7 g/dL) will compensate for tissue hypoxia by increasing cardiac output. The change in output is counteracted by a lower blood viscosity and decreased peripheral vascular resistance so it does not cause a rise in blood pressure. (Semin Hematol 1980;17[3]:164.)

These mechanisms allow the body to adapt, but at what point are these adaptations no longer adequate to maintain vital organ oxygenation? How low can the hemoglobin fall before life can no longer be sustained? Several case reports have attempted to answer this question. De Araujo Azi, et al., presented a case of a 27-year-old Jehovah's Witness patient who survived a hemoglobin level as low as 1.4mg/dL following surgery for scoliosis without receiving blood transfusions. (Transfusion 2014;54[4]:1153.) Further case reports have suggested that patients have survived with hemoglobin levels below 2.0mg/dL even in the setting of aging comorbidities.

Imaizumi, et al., reported a case of a 61-year-old man with bladder cancer and previous gastrectomy for cancer who survived a preoperative hemoglobin level of 1.8mg/dL. (J Anesth 1999;13[2]:125.) The most dramatic of all cases recorded low hemoglobin values with patient survival occurring intraoperatively during a liver transplant for a patient with hepatocellular carcinoma and decompensated liver failure. This patient was recorded as having a hemoglobin level of 0.6 g/dL with associated ventricular tachycardia, sustained ST depressions, and elevated serum lactate levels. (A A Case Rep 2015;4[10]:132.)

It is clear that the human body has a formidable capacity to heal itself and maintain life in the direst of circumstances. Prolonged episodes of chronic anemia lead to significant changes in body homeostasis, allowing it to operate at critically low values of hemoglobin. Notwithstanding patient comorbidities, the human body may appear relatively asymptomatic while demonstrating dangerously low hemoglobin values. We have seen the body's compensatory mechanisms given these circumstances and confirmed sustainability of life even in unique situations such as severe chronic anemia.