Case report of asystole after intralipid treatment

A Brave Account.

Cole et al from the Hennepin Regional Poison Center have published a 2-person case series on asystolic cardiac arrest follow administration of intralipid (epub J Medical Toxicology 2014). Both cases involve patients with cardiogenic shock refractory to calcium, vasopressors, and high-dose insulin. Rescue intravenous fat emulsion was given and in both cases the patients had an systolic cardiac arrest in an under 1 minute. Both patients were resuscitated, but ultimately died of multiorgan failure.

The paper is remarkable for several features beyond the very interesting cases. The authors readily acknowledge the limitations of assigning causality. They then retell the cautionary tale of physostigmine. Clinical practice was dramatically altered after a case series of two patients was reported demonstrated a temporal relationship between physostigmine and asystolic cardiac arrest (Pentel, Ann Emerg Med 1980;9(11):588). I appreciated their tempered reporting of a potentially practice changing paper.

It is an interesting read.

Physical Exam Clues in Toxicology – Part 2: Skin

Diagnosis of the poisoned patient can often be accomplished before toxicologic laboratory tests by obtaining a detailed history and directed physical exam. In this second of three articles, we will examine the toxicology clues revealed by the skin. Part 1 dealt with clues found in eyes, hair, nails, and tongue, and Part 3 will be on body fluids including saliva, sweat, urine, breath, vomit, and stool.



  • Arsenic

Arsenic-related Cancers

  • Bowen’s Disease (intraepithelial carcinoma in situ)
  • Basal cell carcinoma
  • Internal malignancies (lung, liver, esophagus, bladder)

Skin Color Changes (usually hyperpigmentation)

  1. Increased melanin production or deposition of abnormal pigment
    • “Raindrops on a Dusty Road” (As)
    • Addison’s Disease (tan, esp scars and flexion creases)
    • Melanosis (metastatic malignant melanoma)
  2. Differential diagnosis of “Gray Man” (slate gray, blue-gray, slate-blue)
    • Ag (Argyria), Hg, Bi, Pb, As, Au (Chrysiasis) intoxication
    • Amiodarone (more marked on sun-exposed skin)
    • Chemotherapy (fluorouracil)
    • Ochronosis (gray to brown external ears, sclerae)
  3. Red Man Syndromes (usually 2º vasodilation)
    • Redness non-pigmentary, usually blanches
    • Rapid infusion of vancomycin, NAC
      • Flushing from histamine release
    • Borate poisoning (“red lobster”)
    • Degreaser’s Flush (TCE + alcohol)
    • Disulfiram reaction
      • alcohol + metronidazole, sometimes cefazolin
      • alcohol + coprine mushrooms (“Tippler’s Bane)
    • Diff’l Dx of erythroderma: Toxic Shock Syndrome
  4. Blue Man Syndromes
    • Cyanosis
    • Methemoglobinemia
      • aniline dyes, nitrites, local anesthetics (benzocaine)
      • unlike jaundice, sclerae remain white!
    • Pseudocyanosis (faux bleu)
      • Skin staining by fabric dye
  5. Toxic jaundice
    • Hepatotoxins
      • Jaundice is late sign, delayed by days after intoxication
      • Acetaminophen, Amanita and Lepiota mushrooms
    • Hemolytic toxins (often oxidizing agents that also cause methemoglobinemia, esp in patients with G6P deficiency)
      • chlorates, dapsone
      • gases: arsine, stibine
      • Loxosceles (brown recluse) envenomation, esp in children
  6. Other cutaneous discoloration syndromes
    • Hemochromatosis (bronze hyperpigmentation)
    • Carotenemia (sclerae remain white)
    • Skin and clothing stains from paint and glue-sniffing
      • gold and silver most common

Pressure lesions (narcotics and sedative-hypnotics)

  1. Redness
    • early bruising or pressure lesion
    • persists > 20 minutes after pressure relieved
    • failure to blanche on pressure distinguishes from flushing
    • 2º pressure-induced epidermal ischemia, but lesions also form on non-dependent skin
  2. Imprints
    • pattern ecchymoses from objects lain upon
  3. Bullous (“Coma Bullae”)
    • Barbiturates
    • Benzodiazepines
    • Carbon monoxide
  4. Any pressure lesion: check for myoglobinuria and rhabdomyolysis

Vesiculobullous Lesions

  1. Mustard gas
  2. Sulfuric and other acids
  3. Antibiotics, ACEI’s
  4. Caterpillars (Puss caterpillar of Texas; tarantulas (urticating hairs)
  5. Pemphigus, bullous pemphigoid
  6. Poison Ivy (also maculopapular)


  1. Barbiturates, borates, methadone, colchicine
  2. Toxic Epidermal Necrolysis (antibiotics), Stevens-Johnson Syndrome
  3. Non-Toxic Dffl Dx of Desquamation: Toxic Shock, Kawasaki’s Disease, Staphylococcal Scalded Skin Syndrome

Petechiae, purpura, hematomas

  1. Non-blanching discolorations of skin
  2. Anticoagulant rat poisons
  3. Heparin (thrombocytopenia)
  4. Ergot (acral cyanosis → thrombosis & necrosis)

Acneiform Rashes (skin cysts, comedones: blackheads and whiteheads)

  1. Halogenated hydrocarbons (dioxin)
    • Case of Viktor Yuschenko, Ukraine
    • Yu-Cheng Oil Disease, Taiwan
    • Factory explosion in Seveso, Italy, 1986
  2. Cushing’s Syndrome
  3. Oral Contraceptives


  1. Common allergic reaction to therapeutic course of antibiotics and other medications rather than overdose
    • Examples: sulfa, diphenylhydantoin
    • May be accompanied by fever, eosinophilia, lymphadenopathy
  2. Allergic contact dermatitis
    • Type IV hypersensitivity reaction, cell-mediated
    • Examples: poison ivy, metals (Ni), thiurams (rubber)
    • May also be vesicular


  • Formication (EtOH), cocaine bugs

Summary: Mechanisms of dermal injury

  1. Oxidizing (concentrated hydrogen peroxide)
  2. Reducing
  3. Corrosive (acids, alkalis)
  4. Protoplasmic (HF)
  5. Dessicant
  6. Vesicant (nitrogen mustard)
  7. Thermal
  8. Cryogenic
  9. Staining
  10. Neoplastic (As)
  11. Immunologic (poison ivy, Ni)
  12. Defatting (gasoline)
  13. Vasodilatory (disulfiram reaction)
  14. 14. mechanical (excoriation)

Prepared by Dr. Dave Roberts, of the Hennepin Regional Poison Center.

Physical Exam Clues in Toxicology – Part 1: Eyes, Hair, Nails, and Tongue

Diagnosis of the poisoned patient can often be accomplished before toxicologic laboratory tests by obtaining a detailed history and directed physical exam. In this first of three articles, we will examine the toxicology clues that can be found in eyes, hair, nails, and tongue. Part 2 will focus on skin findings, and Part 3 on body fluids including saliva, sweat, urine, breath, vomit, and stool.



  1. Narcotics, cholinergics (organophosphates, nerve agents, dementia drugs, myasthenia gravis drugs, physostigmine, pilocarpine)
  2. Clonidine, nicotine
  3. Non-toxic DDx
    1. Traumatic miosis (rare, usually unilateral)
    2. Horner’s Syndrome (unilateral, with ptosis): affected pupil is the smaller one
    3. Pontine hemorrhage or infarct, SAH


  1. Sympathomimetics: cocaine, amphetamines, methylphenidate, albuterol, TAC, LET
  2. Anticholinergics (diphenhydramine, scopolamine, atropine)
    1. Corn picker’s pupil (Jimson weed growing in the cornfield)
    2. Pupils often unreactive to light
  3. Non-toxic DDx
    1. Traumatic mydriasis (common, usually unilateral)
    2. Anoxia
    3. Uncal herniation
    4. Withdrawal


  1. Yellow: jaundice 2° hepatotoxicity or hemolysis (bili > 2 mg%)
    1. leading hepatotoxins: acetaminophen, Amanita mushrooms
    2. oxidizing gases (arsine, stibine) cause severe hemolysis
    3. no scleral “icterus” in carotenemia; sclerae remain white
  2. Blue: osteogenesis imperfecta
    1. no scleral bluing in methemoglobinemia


  1. orange with rifampin; red with hydroxocobalamin



  1. Alopecia areata vs alopecia totalis or universalis
  2. Toxic Etiologies (usually anagen effluvium secondary to anti-mitotic agents: onset in 1-2 weeks)
    1. Anagen effluvium: Radiation, heavy metals, cytotoxic drugs, vitamin A derivatives, colchicine, propranolol, antithyroid drugs, clofibrate, valproic acid, bromocriptine
    2. Telogen effluvium: Anticoagulants, oral contraceptives
  3. Non-toxic (usually telogen effluvium) : onset usually 2-4 months
    1. pregnancy/childbirth, endocrine, hereditary, fungus (tinea capitis), high fever, major surgery, illness, trauma; idiopathic




  1. Striate (As, Tl) vs punctate or irregular leukonychia (minor trauma)
  2. Mees-Aldrich Lines (1919)

Clinical course of arsenic poisoning

  1. Acute – Abdominal pain, N & V, tinnitus, hearing loss, garlic odor, metallic taste
  2. 2-10 days – Sensory neuropathy
  3. 10-30 days – Hair Loss (primarily scalp)
  4. 2-3 weeks – Mees Lines
  5. 3-4 weeks – Motor neuropathy
  6. Most common misdiagnosis: Guillain Barre Syndrome


  • Clubbing – Idiopathic, nontoxic, pulmonary disease
  • Spooning – Pb, macrocytic anemia
  • Banding – As, Tl, cyclophosphamide, melphan
  • Stippling – Non-toxic
  • Staining – Ag, acids, nicotine, hemochromatosis, tetracycline, chemotherapy  (Adriamycin, bleomycin, 5FU)
  • Ridging – cytoxan, melphalan, trauma, fungus
  • Forget about toenails the news is 6-12 months old.



  1. Angioedema
    1. Hereditary vs ACE inhibitor
  2. Bite wound
    1. Toxic seizure
    2. Cocaine, amphetamines, INH, TCA, Wellbutrin, SSRI’s, tramadol
  3. Burns from caustic ingestion
  4. Abnormal color
    1. Usually food dye
    2. Green: vanadium
    3. Orange: pyridium

Prepared by Dr. Dave Roberts, of the Hennepin Regional Poison Center.

Acute subclavian artery thrombosis causing ACS

The patient is 79-year-old women has severe aortic stenosis and 2-vessel coronary artery disease s/p coronary artery bypass graft who lives independently and is very active who presented to the emergency department for acute dyspnea.

Seven years earlier she was diagnosed with coronary artery disease. Cardiac catheterization at the time showed a left dominant system with moderate stenosis of the proximal LCx and severe stenosis of proximal PDA, and severe stenosis of the proximal LAD. She had a saphenous vein skip graft to the LCx and PDA, and a internal thoracic artery (LIMA) graft to the mid-LAD. She has declined surgery for her aortic stenosis and has a valve area of 1.1 cm2. Her coronary artery anatomy is shown in the figure below.

Native coronary arteries and a vein skip graft to proximal LCx then PDA and LIMA to mid-LAD.

Native coronary arteries with a vein skip graft to proximal LCx then PDA and LIMA to mid-LAD.

On the day of presentation, she had been doing several loads of laundry, going up-and-down the stairs to her basement about six times. On her last trip she had developed severe shortness of breath. She did not experiencing any chest pain. She was so dyspneic however, that she called her daughter to have her bring her to hospital to “be looked at”. Her daughter was able to arrive with 5 minutes, but the patient was so short of breath she couldn’t walk. EMS was notified who brought the patient to the emergency department.

Prehospital ECG of subclavian plaque rupture causing diffuse ST-segment depression

Prehospital 12-lead ECG

During transport, a 12-lead ECG was obtained. There is 2mnm of ST-segment elevation in V1, V2, and aVR, with diffuse ST-depression through the remainder of the leads. On arrival in the emergency department she underwent an expedited an expedited evaluation. She was treated with an aspirin. Her vital signs were normal except for tachypnea. A 12-lead ECG was obtained, which was similar to the one obtained prehospital.

Presenting ECG of subclavian plaque rupture causing diffuse ST-segment depression

Presenting 12-lead ECG

She was taken to the cardiac catheterization lab for emergent angiography and possible PCI. Unfortunately there were substantial problems. The vein graft was chronically occluded which had been the blood supply to the LCx and PDA. There was a large subclavian artery acute plaque rupture proximal LIMA cutting off its blood supply. It had been the main blood to the LAD and anterior heart, and by collaterals the lateral and posterior heart. Fortunately, there were well developed right to left collaterals. Multiple attempts to reperfuse the subclavian artery were unsuccessful.

Coronary artery anatomy with subclavian artery plauqe rupture

Coronary anatomy with chronically thrombosed vein graft and proximal LAD, with acute subclavian plaque rupture.

The elevation in V1 and V2 were seen in previous ECGs. These changes were attributed to LV aneurysm for old ischemic damage prior to her original bypass surgery.

Her peak troponin I was 65 ng/mL. Unfortunately, the patient developed profound cardiogenic shock. She had clear advance directives so further aggressive interventions were not pursued. The patient was transitioned to comfort cares.

This is a very interesting and unusual case of acute subclavian thrombosis causing acute coronary syndrome. I had not seen this before. The thrombosis usually arises secondary to damage to the intima of the artery in the setting of atherosclerotic disease. This damage can occur as a result of external muscular compression and repetitive stress to the artery, atherosclerotic changes to the vessel, or inflammatory processes.


  1. Ann Thorac Surg 2009 Dec;88(6):2036. Subclavian artery thrombosis associated with acute ST-segment elevation myocardial infarction.
  2. Ann Surg 1963 January;157(1):48. Subclavian Arterial Occlusion.

Difficult intubation caused by subglottic tracheal stenosis

Intubations can be difficult for numerous reasons, but in my mind the most frustrating circumstances is when you have the trachea cannulated and are unable to pass the endotracheal tube. This occurred to me on a recent patient.

The patient was a 69-year-old woman nursing home resident who was admitted to the ICU with right lower lobe pneumonia and early sepsis. On admission she had only mildly respiratory. She was treated aggressively with fluids and antiinfectives, and stabilized quickly. However, during the first day of her ICU stay her respiratory status worsened and she ultimately developed hypoxemic respiratory failure requiring orotracheal intubation.

She was preoxygenated with 100% noninvasive bilevel ventilation. Per protocol she was quickly assessed prior to intubation.

  1. BVM ventilation Risk: Moderate
    • good mask seal
    • no obstruction
    • no tongue edema
    • obesity
    • advanced age
    • many missing teeth
    • moderate airway pressures
  2. Intubation Risk: Moderate
    • gestalt
    • 3 finger widths
    • Mallampati II
    • previous intubation and tracheostomy
    • latero-rotational torticollis

She was given etomidate 20 mg and succinylcholine 200 mg.

On the first attempt, under direct laryngoscopy a gum elastic bougie was visualized passing through the cords. It passed easily and was able to be advanced to the carina. The 7.5 mm ETT was passed over the bougie and through the vocal cords, but stopped about 1-2 cm below the cords and was unable to be advanced any further. The endotracheal tube was rotated through a 180° turn and was still stuck. The attempt was stopped, and she was able to be BVM ventilated easily. A repeat attempt was made with a video laryngoscope and a 7.0 mm endotracheal tube, with identical results of the endotracheal hanging up below the vocal cords. On the third attempt, a 6.5 mm ETT was passed over a bougie and into the trachea using very firm pressure.

This was a difficult intubation. During the intubation, the patient’s supraglottic space appeared normal and cannulation of the vocal cords was easy, but placing the endotracheal tube proved frustrating. We were unclear of the reason. Her SpO2 nadir during the intubation was 85%, and once the cuff was inflated and placed on mechanical ventilation there was no air leak and the patient was easy to ventilate.. She was treated for her pneumonia and sepsis, and on hospital day 4 she was extubated. During the extubation, microdirect laryngoscopy of the trachea revealed a stenosis in the subglottic space. This can be seen in the figure below, and is the white fibrotic material just past the vocal cords.

Subglottic Tracheal stenosis

Subglottic tracheal stenosis seen from just above vocal cords.

Tracheal stenosis affects 4-13 % of adults after prolonged intubation in United States. The causes of adult tracheal stenosis include trauma, chronic inflammatory diseases, benign neoplasm, malignant neoplasm and collagen vascular diseases. The most common cause of tracheal stenosis continues to be trauma, which can be internal (prolonged endotracheal intubation, tracheostomy, flame burn injury) or external (blunt or penetrating neck trauma). Approximately 90 % of all cases of acquired chronic subglottic stenosis result from endotracheal intubation or tracheostomy.

The cuff-pressure of endotracheal tubes plays an important role on the development of tracheal damage in intubated patients. To minimize this injury, use of high volume and low pressure cuff endotracheal tubes are advocated. When the cuff pressure exceeds the mucosal capillary pressure (30 mm of Hg) of the trachea, the mucosa that lies between the cuff of the balloon and the underlying cartilages develops ischemia. Long standing ischemia can lead to ulceration and chondritis of tracheal cartilages, followed by fibrotic healing leading to progressive tracheal stenosis. Usual factors responsible for stenosis are: cuff pressure, size of the tube relative to tracheal lumen, duration of intubation, cardiovascular status during intubation, movement of tube during the period of intubation, sex and age of the patient, material of the cuff and the possible adverse effects of steroids. However, tracheal stenosis can also develop by intubation lasting as short as 24 hours only.

Our patient had an old tracheostomy which had been decannulated about 5 years prior. She had developed tracheal stenosis at this site. Ultimately, she required permanent tracheostomy.

There are excellent videos on airway management by Dr. John McGill available at

Therapeutic Hypothermia: The History of General Refrigeration (Podcast 02)

A paper by Niklas Nielsen et al titled “Targeted temperature management at 33°C versus 36°C after cardiac arrest”. Published online by The New England Journal of Medicine on November 17, 2013 has brought a lot of attention to the use of therapeutic hypothermia for post-cardiac arrest cares. It stormed through the social media channels. Within days, EMRAP, Emcrit, Life in the Fast Lane, St. Emlyn’s, Intensive Care Network and most other ED/critical care websites and podcasts had devoted time to covering it. It may very well be practice changing in emergency departments and ICUs through throughout the world. Or maybe not. Before we can figure out what “truth” this research study may have uncovered, we will look at the development of therapeutic hypothermia and what the literature has already told us.

Download Episode: ResusReview-Podcast-02-Therapeutic-Hypothermia-History-and-TTM-Trial.mp3

Chapter 1 The Beginning

Ancient societies had long figured out that hypothermia was useful for acute hemorrhage control. But Hippocrates had figured out a way to use the body’s heat production as a diagnosis tool. He would take his patients, and cake them in mud. The areas that dried first were warmer. “In whatever part of the body excess of heat or cold is felt, the disease is there to be discovered.” And once they figured out the diseased are, the proceeded to inflict their “cures” on the patient.

Typhoid fever which had been the plague of Athens in 400 BC and caused the die out of the Jamestown Colony in the early 1600s, led Robert Boyle around 1650 to attempt to cure Typoid by dunking patients in ice-cold brine. While this is likely the first true application of therapeutic hypothermia, it was unfortunately unsuccessful and failed to alter the 30-40% mortality rate of Typhoid. 100 years later James Currie expanded on Boyle’s work to look at the effects of hot, cold, and warm to treat fevers…both by applying it to the surface and having the patients drink it. These innovations did not seem to bring any more success than the ice-cold brine did however. He did find some usefulness from his other work with opium and alcohol for inanition though.

In the early 1800s, hydropaths had become popular though separate from medicine. Osler referred to them as “hermaphrodite practitioners who look upon water as a cure-all”. BUt he realized the hygienic and therapeutic effects of their use of compresses, douches, and baths. Brand, a hydropath from Settin, ended up teach Osler that systematic rigid protocol of cold baths for Typhoid fever did save lives, and Osler implemented this at John Hopkins with success. He published this protocol in an article “The Cold-Bath Treatment of Typhoid Fever” in 1892, and a drop in mortality was seen throughout by physicians everywhere.

During this time, Russian physicians had independently begun using cold for resuscitation. People who suddenly became unresponsive, were covered with snow hoping for return of spontaneous circulation.

Chapter 2 The 1930s and breaking the thermal barrier

This “thermal barrier” was so deeply ingrained into medical techniques at the time that subnormal temperature were to be combated at all cost. All of the clinical thermometers of the time were calibrated down to only 94 F, as the lowest temperature compatible with survival in human being. Below this level, they were confident that human life could not be sustained. Shock cabinets with electrical heating devices or hot water bottles and warm blankets were considered as necessary emergency equipment in every hospital. But this was about to change.

Therapeutic Hypothermia’s father is Dr. Temple Fay. A Neurosurgeon at Temple University. As a medical student one day he was quizzed by his mentor on why tumors were less common in the extremities. He was unable to come up with a reasoned response. This ultimately led him down the path of experimental cancer work. In 1937, he published work on suspending the growth of cancer cells when they were made hypothermic, but their growth would resume normally when normal temperatures were restored.

In a remarkable bench to bedside transition, the next year in 1938, he treated is first cancer patient with hypothermia in an attempt to prevent cancer cells from further multiplying. Chloral hydrate, sodium bromide (both sedatives) were given by rectum the night before. Paraldehyde, another sedative, was given immediately before hypothermia induction. The patient was cooled to 32 deg C for 24 hours, and he was a meticulous record keeper continuously monitoring pulse pressure, Hgb, pH, CO2, urine, blood analysis.

He described it like this.

The First attempt at general refrigeration was made on November 28, 1938, which was welcomed as a cool crisp day in Philadelphia. Cool enough so that when I move other patients out of a small four-bed ward, shut off the heat, closed the door to the hall, and opened the winders, Nature herself supplied the cold air that aided the cracked ice, 150 pounds of which was begged from the hospital kitchen. For many reasons, chiefly because of the prejudice on the part of the nurses, we had not dared submerge the entire patient in a bed of cracked ice. As it was, the Superintendent of the hospital was more concerned about the wet mattresses from the melting ice than the scientific principle. The nurses’ home, interns quarters and many members of the staff of other services, were alive with dubious comment and conjecture regarding the idea of human refrigeration.

A series of patients were treated, but the nurses detested working on the “refrigeration service” as they called it.

“Frankly, the nurses were scared: they could not get the patient’s temperature with the clinical thermometers. the long-stem laboratory thermometers might break in getting a rectal reading. The ice and ice water were always in the way, even when the patient was turned. The pulse was weak. The breathing was shallow. I can’t get the patient’s blood pressure. Were all reports that kept the staff in a constant state of alarm. The entire project of general refrigeration had snowballed into a vast issue of distortions of truth, and even my friendly colleagues began to look askance and asked how long was this absurd experiment going to be permitted”.

The program was almost shut down, but Fay and the hospital engineering staff developed blankets made from rubber tubes devised to carry a cold solution from a special “beer cooler” machine pumps were commercially available and were found to be useful in this technique. Also developed electric thermocouples for 24-hour charting of rectal temperatures were also designed. This lead to the disappearance of dedicated cold rooms.

“What we learned after breaking the human thermal barrier on the hypothermic side, was that human survival was possible under proper supervision. When total body refrigeration was established above 24 C and that a hypothermic state could be maintained for 10 days (probably longer if required) when temperature levels of 29.4-32.3 C were maintained.

In addition to his work on cancer treatment, he developed local refrigeration techniques to reduce pain, and In 1945, Dr. Fay was the first to publish a case series on using hypothermia for cerebral trauma.

During WWII, Germans captured one of Fay’s manuscripts “Observations on Prolonged Human Refrigeration” that had been sent to Belgium for publication. German pilots who were downed in frigid waters, would succumb to the freezing temperatures, even if they were rescued quickly. This lead to a series of hypothermia recovery experiments conducted on concentration camp victims, in one of the most grotesque and unethical distortions of medicine. When the German atrocities were discovered, it set back the field by 10 years.

The 1950s saw the expansion of of general refrigeration. A period when great strides were made in therapeutic hypothermia. Bigelow, in 1950, developed and quickly perfected the use of general hypothermia for intracardiac surgery, benefiting both the brain and the heart. In 1954 and 1955, Rosomoff lead a group of bench researchers who worked out much of the physiology figuring out that therapeutic hypothermia reduced cerebral oxygen consumption, blood flow, and metabolic rate. Demonstrated a direct effect between body temperature, and intracranial pressure and brain volume.

Suad Niazi and John Lewis, at the University of Minnesota and Ancker Hospital (Now Regions Hospital) in St Paul Minnesota, worked out first an animals and then in a case report that even profound hypothermia of 9 deg C, was achievable and then was able to be rewarmed with complete recovery. This would impact the treatment for for patients with accidental hypothermia.

The first landmark paper from this period however, is by G Raney Williams and frank Spencer, both from Johns Hopkins, published 4 cases of hypothermia, published in 1959 in the Annals of Surgery. “Clinical Use of hypothermia following cardiac arrest”. This is an absolutely fascinating series of 4 case reports of patients who suffered cardiac arrest, received open chest cardiac massage to achieve ROSC, and then were treated with hypothermia.

38 yo male was admitted to the ED during the evening of September 28, 1957 after sustaining a knife wound of the left chest. On admission he was unconscious and pulseless but was breathing. Neck veins were distended. About two minutes after admission that shallow respirations ceased entirely. Endotracheal intubation and left thoracotomy was performed. The pericardium was distended with blood; the heart was in complete arrest. When the pericardium was opened, bleeding from a laceration of the right ventricle was controlled by pressure while cardiac massage was begun. Good contractions began quickly, and the wound in the ventricle was closed with catgut sutures. The patient was deeply unconscious and unresponsive, with dilated pupils slightly responding to light. There was an increase in extensor tone with hyperactive deep tendon reflexes. Cooling was begun immediately, temperature was maintained at 32-33 deg C. A tracheotomy was performed. Twenty four hours after the injury, the patient would respond to spoken voice and motor power was present in all extremities. At 48 hours there was no neurologic deficit.

This is a resuscitation note that could be written in any emergency department today, 56 years later.

Later that same year, Williams and Spencer, now joined by Donald Benson as the lead author published a larger case series of 27 patients. The paper titled “Use of Hypothermia after Cardiac Arrest.”. Of the 27 pts in this case report,2 failed to get ROSC, 6 had no coma and were excluded from the analysis. Of the 19 remaining, 12 received hypothermia and 7 did not. 1/7 survived in not treated group, 6/12 in hypothermia group (14 vs 50%). They treated at 30-32 deg C from 34-84 hours, and was stopped based on the patient’s response.

By 1959, induced hypothermia was also widely used by neurosurgeons for head and spinal cord injuries as well as during cardiac surgery.

Chapter 3 Lost decades

Despite the apparent success of therapeutic hypothermia, as it moved into more widespread practice the severe complications difficulties with the treatment became apparent, overwhelming its benefits. Cardiac irritability and ventricular fibrillation when patient’s temperatures were below 30°C, which was a problem because the accuracy and precision meeting a target temperature with the available equipment was nearly impossible. There was a much higher rate of infections, most significantly a decreased clearance rate of staphylococcal bacteremia. There were additional problems with vasospasm, increased plasma viscosity, hyperglycemia, cardiac dysfunction, and coagulopathies.

So, even though there were clear protective effects of therapeutic hypothermia during brain ischemia and head injury, it became apparent that the complications of this therapy made its use risky, and very difficult to manage without intensive care. The technique was essentially abandoned.

Chapter 4 Resurgence

So hypothermia was put on a shelf. Not forgotten, labelled a once promising therapy that failed to be benficial. There were periodic papers published after 1960, but much of it focused on techniques in cardiac surgery, or basic animal model work.

The few human papers on therapeutic hypothermia published during this time, only reinforced the downsides of hypothermia. In 1986, Bohn published a case series of 24 children resuscitated after drowning who remained in persistent coma. They were treated with therapeutic hypothermia to treat elevated intracranial pressures. Those treated with hypothermia had a much higher rate of neutropenia and septicemia, than the control group.

Cardiac arrest care, however, advanced during this period. Zoll published his work on externally applied counter shocks for ventricular fibrillation. 1960 and 61 saw Kouwenhoven and Safar introduce closed chest massage. The 70s and 80s saw the development of the cardiac arrest care systems. Mobile defibrillator units were developed in 1979. “The White Paper” in 1966 by the National Academy of Sciences spurred the development of EMS systems across the country. Cummins, Ornato, Thies, and Pepe published their “Chain of survival” concept in 1991, along with the american heart association. With CPR and defibrillators now available out of the hospital and in the field, and trained personnel there to tend to the patients, the possibility of widespread early resuscitation from cardiac arrest became a reality.

Disappointment set in again though. Despite the improvements in cardiac arrest care, patients continued to do poorly. Only a tiny fracture were surviving, and of those that did, they were suffering profound neurologic recovery. Becker in Annals of Emergency Medicine, summed up frustration with their paper titled “Outcome of CPR in a large metropolitan area-where are the survivors?”

The same year 1991, Frtiz Sterz published a large animal study in dogs that showed that mild hypothermia initiated immediately after return of spontaneous circulation, improved neurologic outcomes. The target of 34-36 deg C was unique in its temperature target, and several degrees warmer than the 32-33 deg C of much of the earlier literature. more than that, the maintained the target temperature only for 1 hour post-resuscitation, and then let the temperature climb passively.

With abilities to resuscitate cardiac arrest patients, it was felt better post-arrest cares would improve outcomes. So researchers turned to therapeutic hypothermia. In 1996 alone, Sterz published a major review article, Peter Safer, who had developed closed cardiac massage published a major animal study using hypothermia, Stephen Bernard published a major review in the Anesthesia critical care literature, and a Symposium was held at the Society of Critical Care Medicine conference on hypothermia.

Chapter 5 Hypothermia becomes the Golden Child

The next year, 1997, was the first of two landmark papers by Stephan Bernard and colleagues from Monash Medical Center in Australia. Published in Annals of Emergency Medicine, “Clinical trial of Induced Hypothermia in Comatose Survivors of Out-of-Hospital Cardiac Arrest”. This was a pilot study and the followed 22 patients prospectively with 22 retrospective matched controls. They treated the comatose resuscitated patients at 33 deg C for 12 hours. Mortality was 10 vs 17, and CPC 1 or 2, was 11 vs 3. In 1998, Yanagawa and Zeiner in 2000, published similar small pilot studies which also showed the promise of improved outcomes.

Peter Safar summarized the history and state of therapeutic hypothermia in 2000 commentary in Academic Emergency Medicine. Brilliantly title “On the future of reanimatology”, it ended by calling for a randomized control trial.

Two groups working independently answered this call. In 2002, their results of their work were published in the same issue the New England Journal of Medicine.

Stephen Bernard and his colleagues, had expanded on their earlier paper. Titled “Treatment of Comatose Survivors of Out-of-Hospital Cardiac Arrest with Induced Hypothermia”, they prospectively randomized 77 patients with resuscitated VF with persistent coma. They excluded pregnancy and persistent cardiogenic shock despite epinephrine. All received lidocaine. The MAPs were maintained between 90-100 mmHg, pO2 > 100, pCO2 of 40. Patients were cooled to 33 deg C for 12 hours before being allowed to passively rewarm. Mortality was similar in both groups, but patients with CPC 1 or 2 was 21 vs 9 if they had been treated with hypothermia.

The second study was conducted in Austria. “Mild Therapeutic Hypothermia to Improve the Neurologic Outcome after Cardiac Arrest”. Enrolled 237 patients with resuscitated ventricular fibrillation arrest who were treated with therapeutic hypothermia to 32-34 deg C fr 24 hours compared to patients with normothermia. Median time to starting cooling was 105 minutes post-arrest, but the patients did not reach target temperature until nearly 8 hr after arrest. the was a 14% absolute risk reduction in mortality and 16% improvement in CPC 1 and 2 scores for patients treated with hypothermia. Overall a remarkable benefit.

Based on the strength of the previous smaller studies by Bernard, Yanagawam and Nagaeo, and these two larger papers, hypothermia was endorsed as a recommended treatment first by the American Heart Association in 2002, and then in 2003 by Advance Life Support Task Force of the International Liaison Committee on Resuscitation.

Therapeutic hypothermia was considered a settled question, and its use in post-resuscitation cares spread widely and quickly as a standard of care. It was incorporated into all manner of guidelines. But settled questions in medicine are rarely so.

As the practice became more widespread, areas of controversy developed. Treatment was expanded to resuscitated rhythms other the ventricular fibrillation and ventricular tachycardia, under the assumption that brain ischemia from any source would benefit from hypothermia. The optimal temperature target was also uncertain. Guidelines had adopted 32-24 deg C, which had been the traditional target as we have talked about.

Work at the Peter Safar Center for Resuscitation in Pittsburgh lead to a paper published by Eric Louge and Clifton Callaway in 2007 in Academic Emergency Medicine. “Comparison of the Effects of Hypothermia at 33 or 35 after Cardiac Arrest in Rats” They were able to demonstrate the minimal hypothermia at 35 deg C was just as good as cooling to 33 deg C in terms of mortality and neurologic outcomes, and both performed better than normothermia.

Zeiner published data that a fever in the post-cardiac arrest period had adverse neurologic outcomes. So researchers postulated that the neurologic benefit has little to do with hypothermia, and is the result of prevention of hyperthermia. We are back to improving the mortality of Typhoid patients by preventing their fever by making them cold.

This was the setting in which the Targeted Temperature Management paper by Nielsen et al paper was introduced. They enrolled 950 pts in 36 centers in Europe and australia, who suffered a resuscitated out-of-hospital cardiac arrest who remained unconscious. Any initial rhythm was allowed which is in-line with current practice. They were randomized to temperatures of 33 or 36 deg C for 28 hours, and the rewarmed. Normothermia was then maintained until 72-hours post-arrest. There was a non-significant 2% mortality difference at the end of the treatment protocol and 180 days later. Patients with CPC score 3-5, was 54 vs 52% and also was not statistically significant.

But was this a definitive non-inferiority study on the temperature target question. That was the resounding initial comments from many, though a strong cautionary post by Dr. Simon Carley at St Emlyn’s blog keeps the study results in perspective. I really encourage you to read it. He points out that the study is powered to find an 11% absolute risk reduction between 36 and 33 deg C, which would be a NNT of 9. That is asking a lot.

So here we are. What would Osler do? How would Drs Temple Fay or Peter Safar treat there next resuscitated cardiac arrest patient. There is no doubt that the critical care involved in maintaining a patient at 33 as compared to 36 is much larger. The risks and complications are higher. Is there benefit. Do more patients benefit? Are more better off neurologically? Hypothermia does seem to convey benefit as compared to normothermia, and certainly to patients who develop a fever. Actively maintaining the temperature at goal for the duration of the treatment seems reasonable. As for the temperature. 36 degrees C has support for the new standard. With increasing NNT, there may be benefit to going lower but with diminishing returns in return for more adverse events. Duration of treatment remains murky in my mind, but 24 hours is my current practice.

As every paper states in their conclusion…more research is needed. I think I got the new issue of Resuscitation in the mail today. I wonder what we will find.

Until next time, stay cold…or cool. This is Charles Bruen, with Resus Review.