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Game Changers

The 20 Most Important Anesthesia Articles Ever Published

Barash, Paul MD; Bieterman, Karen MLIS; Hersey, Denise MA, MLS

doi: 10.1213/ANE.0000000000000513
General Articles: Special Article
Free

From the *Department of Anesthesiology, Yale University, New Haven, Connecticut; Wood Library-Museum of Anesthesiology, Schaumburg, Illinois; and Harvey Cushing/John Hay Whitney Medical Library, Yale University, New Haven, Connecticut.

Accepted for publication September 11, 2014.

Funding: No.

The authors declare no conflicts of interest.

This report was previously presented, in part, at the Poster session 2013 NYPGA, and has not been submitted for publication previously.

Reprints will not be available from the authors.

Address correspondence to Paul Barash, MD, Department of Anesthesiology, Yale University, 333 Cedar St., PO Box 298051, New Haven, CT 06520. Address e-mail to paul.barash@yale.edu.

Of the thousands of published articles related to the specialty of anesthesiology, only an elite few can be considered seminal, landmark or, for the purposes of this article, a “game changer.” A clinical game changer is a publication that results in a revolutionary transformation that has been maintained in clinical practice since the article first appeared. Advancements and discoveries in anesthesiology did lead to transformative changes, not only in this specialty but also to related fields. These contributions have in common the unique ability of the creative mind to perceive connections where others see none. They follow Louis Pasteur’s dictum “In the fields of observation, chance favors only the well-prepared mind.” The modern version of this statement is “connecting the dots.” Deciding which of these writings has had the most profound effect on the practice of anesthesiology and medicine is a challenging task, albeit subjective. Various methods have been used to identify these papers, including number of citations, opinions of journal editors, and use of an “expert” board. Using specified criteria, we chose the top 20 publications that, in our opinion, are the clinical game changers for the specialty of anesthesiology. Three recent publications are recommended to the reader for further in-depth analysis.1–3

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METHODS

Initially, based on the authors’ experience, a large group of articles was selected (approximately 400). Additional bibliographic research and personal communication with physicians expert in a given knowledge area were also undertaken, and additional publications were identified. The academic rank of these 67 individuals include: 47 professors, 10 associate professors, 5 assistant professors, and 5 others; of which 10 were not faculty at U. S. medical centers. Our selection criteria included: (1) articles published in the medical literature regardless of age; (2) articles in English, or a publication where an English translation is available; (3) 4 types of publications were considered: original scientific publications, case reports, review articles, and abstracts; (4) publications were selected based on their lasting impact on clinical practice in anesthesiology. Exclusion criteria included: (1) reports involving animal studies and (2) a copy of the scientific publication was unavailable. Using the resources of the Wood Library-Museum of Anesthesiology, and the Cushing/Whitney Medical Library at Yale University, publications were gathered, read, and evaluated. Based on these factors and the authors’ judgment, this methodology resulted in a final list of the 20 most important publications.

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RESULTS

The results demonstrate the wide contributions of the specialty of anesthesiology to the field of medicine. Although not selected for any “political” agenda, the chosen publications reflect major themes: (1) innovation and creativity, (2) combating prejudicial practices (gender, racial, and religious), (3) public health, (4) bioethics, (5) patient safety, and (6) reduction of medical costs. In many cases, these articles were published in premier, high-impact journals (both U.S. and international) and in both medical and surgical, as well as anesthesia, journals. The selected articles cover a range of publication dates from 1846 through 1987. Finally, although not chosen by anesthesia subspecialty, the major subspecialties are represented. Each article is ranked on the list in order of its importance, with those having the greatest impact listed first, by its original citation and a short paragraph concerning its uniqueness. A summary table is included (Table 1) which lists the Game Changers as well as the leading “contender article” that was not chosen for the primary list.

Table 1

Table 1

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1. Bigelow HJ. Insensibility during surgical operations produced by inhalation. Boston Med Surg J 1846;35:309–17

The greatest contribution of American medicine to mankind is the discovery and application of anesthesia. On the occasion of the 200th anniversary of the New England Journal of Medicine, Dr. Atul Gawande wrote, “the crucial spark of transformation – the moment that changed not just the future of surgery but medicine as a whole – was the publication on November 18, 1846, of Henry Jacob Bigelow’s groundbreaking report “Insensibility during Surgical Operations Produced by Inhalation.”4 Interestingly enough, compared to the most widely cited article (14,556) from the New England Journal of Medicine,5,a the Bigelow article may seem inconsequential (179 citations).b Yet the readership voted the Bigelow article as the most important article the New England Journal of Medicine ever published.c Even today, debate continues as to whom credit should be given for the discovery of anesthesia. The United States Congress awarded Georgia physician Dr. Crawford Long the honor, along with a postage stamp bearing his picture. The French scientific academy (Academie des Sciences) awarded both Dr. William Morton and Dr. Charles Jackson the recognition. However, the Medical Society of Paris gave Dr. Horace Wells the honor.6 Interestingly, The Ether Monument in the Boston Public Garden does not recognize any of the protagonists, rather it is to commemorate “… the greatest medical discovery of our time:” the first public demonstration of ether at the Massachusetts General Hospital.7 As an interesting sidebar to the entire saga, Dr. Frank Boland hypothesizes that Dr. Charles Jackson, a geologist as well as the physician who told Morton of ether’s properties, may have actually traveled to Jefferson, Georgia, on a mining survey.8 There, he may have observed Dr. Crawford Long administering ether anesthesia before giving the idea to Morton about its potential use as an anesthetic. Finally, perhaps none of these individuals should be given credit. Rather, William Edward Clarke, an upstate New York medical school student who had experience with ether from “ether frolics,” administered an anesthetic to a Miss Hobbie for a dental extraction in January 1842.1 This was 2 months before Crawford Long, who also attended ether frolics, gave an anesthetic to James Venable (March 1842) and 4½ years before Morton anesthetized Edward Abbott at the Massachusetts General Hospital (October 1846).1 These different dates of administration of ether (combined with Horace Wells’ use of nitrous oxide [December 1844]) are at the core of the debate as to which individual(s) merits priority for administering the first anesthetic. Dr. William Osler, the esteemed Johns Hopkins Professor of Medicine, addressed this problem by quoting Sir Francis Darwin: “…in science the credit goes to the man who convinces the world, not to the man to whom the idea first occurs.”9

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2. Koller C. Ueber die verwendung des cocain zu anasthesirung am auge. Wien Med Wochensehr 1884;43:1276–8

Koller C. Ueber die verwendung des cocain zur anasthesirung am auge. Wien Med Wochensehr 1884; 44:1309–11

Koller C. On the use of cocaine for producing anaesthesia on the eye. Lancet 1884;124:990–2

Koller’s discovery of the anesthetic properties of cocaine is the classic example of connecting the dots. Well known by the Inca Indians for centuries, if not millennia, cocaine was successfully used for neurosurgical procedures (trepanation). Furthermore, the anesthetic properties of cocaine were also well known to contemporaries of Koller, including Sigmund Freud, but no one thought of using the compound as a local anesthetic for surgery. It took Koller, an ophthalmologic trainee, to realize the importance of the compound as an alternative to general anesthesia. Koller had a colleague present his findings at a scientific conference. It is unclear whether this was a result of his inability to secure funds for the meeting or antisemitism.10 This discovery completed the triad of techniques of contemporary anesthesia: inhaled, IV, and local anesthesia. The original report in German is cited, as well as the contemporaneous translation in Lancet by JN Bloom, MD.

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3. Cushing H. On routine determinations of arterial tension in operating room and clinic. Boston Med Surg J 1903;148:250–6

As a result of investigation into anesthetic complications by fourth-year medical students Harvey Cushing and Ernest Codman, the anesthesia record was developed.11–13 Even modern electronic medical records and computerized displays of anesthesia machines and monitors rely on their pioneering graphic design. As originally devised, heart rate and respirations were recorded every 5 minutes. However, it was not until Cushing, on a tour of European medical centers, saw the use of the Riva-Rocci method of measuring arterial blood pressure that this variable was incorporated into the intraoperative measurements made on his patients. This was met with opposition from the Harvard faculty, who thought a “finger on the pulse” was more accurate and “natural.”11–13

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4. Saklad M. Grading of patients for surgical procedures. Anesthesiology 1941;2:281–4

The use of the American Society of Anesthesiologists’ Physical Status (ASA PS) classification system is not only used in operating rooms around the world, but it has been adopted and refined by other specialties for their unique patient populations. It was originally designed as a method to collect and tabulate statistical data and allow investigators to compare various patient groups. Interestingly, the original ASA PS did not even use 1 patient to test this theory. However, with little modification it has evolved into the most widely used assessment of perioperative patient risk and compares favorably to other more complex systems of risk appraisal.14,15

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5. MacEwen W. Clinical observations on the introduction of tracheal tubes by the mouth instead of performing tracheotomy or laryngotomy. Brit Med J 1880;2:163–5

Jackson C. The technique of insertion of intratracheal insufflation tubes. Surg Gynecol Obstet 1913;17:507–9

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Guedel AE, Waters RM. A new intratracheal catheter. Anesth Analg 1928;7:238–9

Game changer #5 required 3 interrelated but separate publications to enhance the intrinsic value of advances in airway management. Each step was required to develop techniques of endotracheal intubation: (1) direct oral introduction of an endotracheal tube, (2) use laryngoscopy to place the endotracheal tube per os, and (3) the cuffed endotracheal tube to allow for an “airtight fit.” This is the only selection on the list that is by necessity composed of >1 article. Before MacEwen’s paper, patients’ tracheas were intubated via a tracheostomy or cricothyroidotomy, a procedure associated with its own intrinsic morbidity and mortality. Although laryngoscopes were in use, it was Chevalier Jackson who popularized a laryngoscope that forms the basis of the modern instrument and advanced the technique for endotracheal intubation. Subsequently, Guedel and Waters developed a technique to attach an inflatable cuff to the endotracheal tube. To demonstrate the successful isolation of the trachea, they used an anesthetized dog (Guedel’s family pet, Airway) submerged in a fish tank (the “dunked dog”), whose trachea was intubated with a cuffed endotracheal tube.1 The dog was included in the case series report along with data from 2 patients!

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6. Wood A. On a new method of treating neuralgia by the direct application of opiates to the painful points. Edinb J Med Surg 1855;82:265–81

Three individuals have been given credit for the development of the hypodermic syringe-needle system. Irish physician Dr. Francis Rynd created the hollow needle to treat neuralgias (1845), and French physician Gabriel Pravaz developed the syringe for perineural injections (1853).1 However, historians give Alexander Wood the credit for perfecting this delivery system for clinical use. Using the syringe-needle system, Wood treated a patient with neuralgias. The hypodermic syringe-hollow needle system offered physicians an alternative to inhaled anesthesia. However, it was not until the next century that IV anesthesia evolved and anesthesiologists had a multitude of drugs from which to choose.

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7. Simpson JY. Notes on the employment of the inhalation of sulphuric ether in the practice of midwifery. Monthly J Med Sci 1847;7:721–8

Reminiscent of religious and medical debates that continue today, Simpson’s actions in 19th century Scotland, in anesthetizing a parturient for cephalopelvic disproportion, unleashed a torrent of verbal abuse. The medical community’s arguments (pain is important in following labor; it was not natural to have childbirth anesthesia, etc.) were in some ways easier for Simpson to deflect. It was the religious orthodoxy that was more problematic. The issue focused on Genesis III: 16

Unto the woman He said: “I will greatly multiply thy pain and thy travail; in pain thou shalt bring forth children; and they desire shall be to thy husband, and he shall rule over thee.”

The concern for God’s admonition to women is based on the translation of the Hebrew word “Etsev,” which has a number of meanings depending on the context (mental anguish, travail, sorrow, pain, and work).16 Most modern biblical scholars do not use the word “pain” but rather “labor.” It took John Snow’s anesthetizing Queen Victoria, 6 years later for her delivery, for the use of anesthesia for childbirth to gain acceptance.

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8. Anand KJ, Hickey PR. Pain and its effects in the human neonate and fetus. N Engl J Med 1987;317:1321–9

This review article shares important elements with another review article on the game changer list. Similar to Beecher’s bioethical concerns (Game Changer #9), Anand and Hickey set forth the idea, “that humane considerations should apply as forcefully to the care of neonates and young, nonverbal infants as they do to children and adults in similar painful and stressful situations.” This review changed perioperative care of the neonate more than any other scientific contribution.

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9. Beecher HK. Ethics and clinical research. N Engl J Med 1966;274:1354–60

This article is considered the most important clinical bioethical research article published in the modern era. It came at a time when Nazi war crimes were too familiar and ethical issues were being raised as a result of clinical research in this country.17–20 These acts, coupled with a significant governmental clinical research initiative, led Beecher to outline the abuses seen in medical studies and a proposed solution to end them. He states, “Nonetheless, it is evident that in many of the examples presented, the investigators have risked the health or the life of their subjects.” His words are as prescient today as they were more than a half-century ago when he stated that 2 fundamental requirements for clinical research are informed consent and an “intelligent, informed, conscientious, compassionate responsible investigator.” For example, the current debate on the ethics of the multicenter, National Institutes of Health-funded Surfactant, Positive Pressure and Oxygenation, Randomized Trial (SUPPORT) involving premature infants exposed to differing levels of oxygen concentration hinges on the 2 issues Beecher enunciated.21 The Department of Health and Human Services’ Office of Human Research Protections questioned both the quality of informed consent and the adequacy of the investigators’ explanation as to whether parents were fully informed as to the consequences of enrolling their children in the study. In response to these criticisms, both the editor of the New England Journal of Medicine and the Director of the National Institutes of Health questioned this report and were concerned about its negative effect on future clinical research in this population.22,23

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10. Eichhorn JH, Cooper JB, Cullen DJ, Maier WR, Philip JH, Seeman RG. Standards for patient monitoring during anesthesia at Harvard Medical School. JAMA 1986;256:1017–20

Under the leadership of ASA President Ellison “Jeep” Pierce, organized anesthesia had to confront a burgeoning malpractice crisis, and thus began the modern patient safety movement. Although a number of articles from this era can be considered game changers, this article by Eichhorn and colleagues at Harvard Medical School brought together all the key elements of patient safety in the operating room. It was revolutionary to have a detailed standard, not a guideline, for clinical management that was practical, cost-effective, and within the technical/economic reach of practitioners. Even though significant resistance to the concept of patient safety and standards resulted, this paper is an extension of the concept that a single person (Pierce) with a vision can instigate change, affecting millions of people. These standards were eventually adapted in the United States, as well as numerous other countries.

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11. Waters RM, Hathaway HR, Cassels WH. The relation of anesthesiology to medical education. JAMA 1939;112:1667–71

Dr. Ralph Waters made a number of seminal contributions to the specialty. His most important was the establishment of the first American academic anesthesia department at the University of Wisconsin. Not only did he organize the department, he was also responsible for producing more future chairs of major academic anesthesia departments than any other individual. Waters ends this article by emphasizing a core value of academic anesthesia departments: “The patient under the influence of pain-relieving drugs, together with the department of anesthesia, constitutes a natural discussion of many pathways between basic science and clinical teaching.”

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12. Saidman LJ, Eger II EI. Effect of nitrous oxide and of narcotic premedication on the alveolar concentration of halothane required for anesthesia. Anesthesiology 1964;25:302–6

One hundred fifty years in development, the minimum alveolar concentration concept was predicted by John Snow’s work on the 5 degrees of depth of anesthesia.24 In contrast to a common notion that there was a wide range of responses to an anesthetic drug, this study demonstrated that inhaled anesthetic drug requirement remains constant among individuals. Minimum alveolar concentration revolutionized both clinical research and clinical care in anesthesiology. It is also an important factor in improving patient safety by allowing comparison of patient depth of anesthesia.

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13. Griffith HR, Johnson GE. The use of Curare in general anesthesia. Anesthesiology 1942;3:418–20

The effects of d-tubocurare were clinically known to prevent fractures in patients during convulsive shock therapy. However, Griffith and Johnson were the first to use the drug as a supplement to general anesthesia. Although administered in an operating room in 1912 by a German surgeon, Dr. Arthur Lawen, and subsequently in 1928 by an English anesthetist, Dr. Francis de Caux, curare was abandoned by both physicians due to lack of standardization of the compound.25 Griffith and Johnson, without institutional research approval, clinical experience, or administrative oversight, administered the drug with success to increase muscular relaxation.25 Interestingly, the authors state, “In none of our patients has there been any serious depressing effect on respiration…” Furthermore, “It has not been necessary to administer artificial respiration or stimulants in any of our cases.” These statements suggest that an extraordinarily small dose of curare was administered.

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14. Wang JK, Nauss LA, Thomas JE. Pain relief by intrathecally applied morphine in man. Anesthesiology 1979;50:149–51

Based on previous animal studies with powerful results, Wang et al. reported the first clinical use of neuraxial (subarachnoid) opioids in humans.26 Using a double-blind, prospective design, the study involved 8 patients with intractable pain (cancer of the genitourinary tract) being treated with intrathecal morphine versus intrathecal normal saline. Interestingly, 2 of 8 patients had some relief of pain with normal saline, thus documenting the importance of measuring for the placebo effect in analgesia studies. This investigation set the stage for the investigation and use of neuraxial opioids (spinal and epidural) in clinical practice.

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15. Engstrom, CG. Respirator enligt ny princip. Svenska Lakartidningen 1953;50:545–52

Engstrom CG. Treatment of severe cases of respiratory paralysis by the Engstrom universal respirator. Br Med J 1954;2:666–9

This selection is a serendipitous finding by the authors of this review. Surprisingly, the 3 American giants in the field of mechanical ventilation, Forrest Bird, Ray Bennett, and John Emerson, produced no original research on the use of mechanical ventilation in clinical practice in the 1960s. The contributions of Bird and Bennett to this area followed from their earlier work on high-altitude flying during World War II.1,27 Although they devoted time to writing a number of patents, there are no scientific publications in this timeframe from any of these inventors. As a result of the Copenhagen polio epidemic, with its incumbent requirement for a continuous source of mechanical ventilation, Carl-Gunnar Engstrom developed a ventilator (Engstrom Universal Respirator) and published a significant number of articles on his experience. The 1953 reference is the original article, while the 1954 reference, in English, parallels the 1953 report.

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16. Severinghaus JW, Bradley AF. Electrodes for blood PO2 and PCO2 determination. J Appl Physiol 1958;13:515–20

Among the major contributions of John Severinghaus is the conceptualization and development of the first modern blood gas analysis apparatus. Based on the work of Stow (PCO2 electrode) and Clark (PO2 electrode), Severinghaus and colleagues redesigned these electrodes, added the pH electrode, and set the stage for the classic 3-function blood gas machine. To improve stability of the CO2 parameter (read as pH change), Severinghaus suggested adding sodium bicarbonate to the distilled water of the electrode bath. He has since quipped, “The joke here is that I got all the credit for inventing the CO2 electrode, but all I did was add soda.”28

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17. Safar P, Brown TC, Holtey WJ, Wilder RJ. Ventilation and circulation with closed-chest cardiac massage in man. JAMA 1961;176:574–6

Safar et al. observed that successful cardiopulmonary resuscitation requires both ventilatory and circulatory maneuvers. For >500 years, the A (airway), B (breathing), and C (circulation) of resuscitation were known but not integrated into a successful resuscitation protocol. In this classic example of Pasteur’s dictum of connecting the dots, recognizing the importance of the early clinical results of the engineer Kouwenhoven and colleagues, it took a Peter Safar to combine these 3 steps into modern cardiopulmonary resuscitation: A, B, and C.29–31

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18. Lowenstein E, Hallowell P, Levine FH, Daggett WM, Austen WG, Laver MB. Cardiovascular response to large doses of intravenous morphine in man. N Engl J Med 1969;281:1389–93

Based on the experience of caring for >1100 patients undergoing predominantly cardiac surgical procedures for acquired valvular heart disease anesthetized with morphine (0.5–3.0 mg/kg), Lowenstein et al. evaluated 2 groups of subjects: 8 normal volunteers and 7 patients with aortic stenosis. In addition to developing a unique anesthetic technique for patients requiring open-heart surgery, the “high-dose narcotic technique” was also applicable to “cardiac” patients having noncardiac surgery. Perhaps more importantly, this study foreshadowed the use of other high-dose synthetic narcotic regimens, for example, the fentanyl family, in the 1970s.

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19. Michenfelder JD, Gronert GA, Rehder K. Neuroanesthesia. Anesthesiology 1969;30:65–100

Although Rosomoff initially used the term “neuroanesthesia,” Michenfelder et al. popularized the terms “neuroanesthesia” and “neuroanesthetists” in this review article and elegantly developed the scientific foundations of this specialty while integrating these principles with clinical practice.32,33 They note “Neuroanesthesia is unique in only one respect: in the patient undergoing intracranial surgery, the brain becomes the target organ for the anesthesiologist and surgeon.” Michenfelder later concludes, “Various anesthetic agents and techniques may be used in neurosurgery; specific choices can be based on the needs of the patient, the needs of the surgeon, and the experience of the anesthesiologist” (italics added).

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20. Ford JL, Reed WA. The surgicenter. An innovation in the delivery and cost of medical care. Ariz Med 1969;26:801–4

In the 1960s, Dr. Wallace Reed thought the cost of health care had to decrease without forgoing quality. After hearing of an uninsured barber who stated that he would need to do 125 haircuts to pay for his child’s surgery, Reed and his business partner Dr. John Ford developed the concept and built the first freestanding “surgicenter” (1970).34 Although ambulatory surgical centers had been incorporated into hospitals, none was geographically separated from the hospital. These freestanding units made both economic and medical contributions to health care. First, they saved billions of dollars in medical expenditures. It is estimated that from 2008 to 2011, these facilities saved the Medicare Program and its beneficiaries $7.5 billion, and over the next decade, this savings is projected to be $57.6 billion.35,36 Furthermore, by minimizing and making more efficient preoperative laboratory testing, as well as earlier discharge from the postanesthesia care unit, freestanding ambulatory surgery units changed medical practices for inpatient and outpatient surgical patients.

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DISCUSSION

Dr. Arthur Keats, on the occasion of the 22nd Annual Rovenstine Lecture at the 1983 annual meeting of the American Society of Anesthesiologists, stated:

I believe, as did the late Myron Laver, that anesthesiology is at its best when the observations it makes on the sample of patients we care for apply equally to all patients and contributes benefits to medicine at large.37

Certainly the articles chosen here represent anesthesiology’s major contributions to improvement of medical care. One only needs to review the first 2 selections on this list, the discoveries of ether and cocaine, to understand the insight required to make important discoveries. In the former, a number of historians have questioned why the discovery of ether was prolonged by at least 40 years.6,38,39 In an even stronger example, the local anesthetic effects of cocaine were well known for ages by the Inca Indians. Yet in both instances, it took individuals such as Drs. William Morton and Karl Koller, respectively, to realize the important promise and clinical application of these compounds.

As composed, our list has limitations. First, it is the subjective judgment of the authors based on their perception of the relative contribution of a given publication. The difference in the papers included in our list, compared with the list compiled by Webster and Galley in their recent book Landmark Papers in Anaesthesia illustrates the subjective nature of these selections, since there was congruence in only 3 of the 210 articles between these publications!2 Second, by not being specialty-specific in our choices, we had to select between 2 or more intellectually unrelated papers for placement to the list and ranking on the list. Third, to keep this purely clinical, we have chosen not to include some seminal articles involving animal subjects. Fourth, although we are comfortable starting in 1846 (first public demonstration of ether) and concluding to the latest article published in 1987 (neonatal anesthesia), we realize a number of excellent articles have been published since this date. However, similar to ranking of United States presidents, a certain amount of historical perspective is required to fully appreciate the importance of an article’s contribution. Finally, by limiting our choices to articles available in English (or translation available), we may have not included noteworthy seminal publications in other languages. Whether in medicine or other disciplines, these limitations (subjectivity, citation index, etc) are also present in other “top 10 lists.”40–43

The richness of anesthesia history, noted by its important publications, supports the suggestion of Desai and Desai to add the history of anesthesia to training curriculum and capitalize on traditional sources (scientific articles, etc.) as well as nontraditional sources (movies, videos, etc.) to facilitate the trainees’ understanding of the remarkable story of anesthesia and its importance to mankind’s well-being.44

In summary, the Game Changers list is proof of the statement, “Major achievements of modern surgery could not have occurred without the accompanying vision of pioneers in anesthesiology.”45

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DISCLOSURES

Name: Paul Barash, MD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Paul Barash, MD, approved the final manuscript.

Name: Karen Bieterman, MLIS.

Contribution: This author helped design the study, conduct the study, and analyze the data. Karen Bieterman provided assistance in preparing this article in her personal capacity. The opinions expressed in this article are her own and do not reflect the view of the Wood Library-Museum of Anesthesiology or the American Society of Anesthesiologists.

Attestation: Karen Bieterman approved the final manuscript.

Name: Denise Hersey, MA, MLS.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Denise Hersey approved the final manuscript.

This manuscript was handled by: Steven L. Shafer, MD.

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FOOTNOTES

a Scopus—http://www.scopus.com/results/results.url?sort=plf-f&src=s&st1=%22The+effect+of+intensive+treatment+of+diabetes+on+the+development+and+progression+of+long-term+complications+in+insulin-dependent+diabetes+mellitus%22&sid=7D63E5BA04A8016211F6624ADD81CBD2.N5T5nM1aaTEF8rE6yKCR3A%3a120&sot=b&sdt=b&sl=163&s=TITLE-ABS-KEY%28%22The+effect+of+intensive+treatment+of+diabetes+on+the+development+and+progression+of+long-term+complications+in+insulin-dependent+diabetes+mellitus%22%29&origin=searchbasic&txGid=7D63E5BA04A8016211F6624ADD81CBD2.N5T5nM1aaTEF8rE6yKCR3A%3a12. Accessed August 19, 2014.
Cited Here...

b Google Scholar—http://scholar.google.com/scholar?hl=en&q=%22+Insensibilty+during+surgical+operations+produced+by+inhalation&btnG=&as_sdt=1%2C7&as_sdtp=. Accessed August 19, 2014.
Cited Here...

c Buckley K. The most important article in NEJM history. Available at: http://blogs.nejm.org/now/index.php/the-most-important-article-in-nejm-history/2012/11/01/. Accessed August 19, 2014.
Cited Here...

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REFERENCES

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