Postoperative infections are a major source of morbidity and mortality for patients after cranial neurosurgery. To minimize these complications, irrigating the wound with antibiotic solution has become a pervasive practice within neurosurgery. However, there is debate over the utility of these agents, with bacitracin irrigation being made unavailable in some US markets.1–4 To understand how the use of antibiotic irrigation became entrenched in neurosurgical technique, we trace the origins of antiseptic use from antiquity to modern day. By highlighting the important advances achieved in the care of patients with penetrating cranial wounds during World War I (WWI) and World War II (WWII), we draw a sequential link between battlefield strategies for neurotrauma care to the adoption of antibiotic irrigation, and the modern concept of antibiotic prophylaxis in civilian and military practice (Fig. 1).
Timeline with significant developments in the use of antiseptic irrigation and antibiotic prophylaxis in the management of penetrating cranial injuries.
Before Germ Theory
The integration of topical agents to promote wound healing in the care of human disease and injury predates the modern-day discovery of antibiotics by more than 4000 years.5 The earliest record of topical salves for traumatic injuries, including descriptions of neurotrauma, dates back to the Edwin Smith Papyrus, the oldest known surgical text in human history.6 Originally written in 1600 bc, this text details the diagnosis and management of traumatic brain injuries, brain contusions, and other forms of cranial injuries through a 27-patient case series. The topical use of alcohol, honey, and turpentine (an oil derived from pine tree resin) to aid in wound healing is outlined.6,7 Although the understanding of human physiology and injury was superficial at the time, the papyrus draws clear connections between these healing salves and successful wound management.
Additional archaeological remnants from ancient societies impart more insight into the use of topical salves. In ancient Egypt, green dye made from malachite, a copper carbonate mineral, was incorporated in eye paint as a symbol of fertility, new life, and vegetation.8 However, the use of malachite around the eyes has been subsequently found to combat Chlamydia trachomatis, a common cause of infectious blindness.9 In the Nubian kingdom, modern-day Sudan, the population would store harvested grains in clay pots, leading to the inadvertent cultivation of tetracycline-producing Streptomycetes, the consumption of which was used as a treatment for gum disease and other ailments.5
The year 300 bc marked the start of the era of Hippocrates, the father of modern medicine, whose clinical texts informed medical practice for centuries to come. It is believed that Hippocrates and his disciples had knowledge of the Edwin Smith Papyrus, which may have guided their early medical works, as suggested by the rich discussions on the utility of vinegar, honey, and mineral salves.10 Most notable is Hippocrates’ use of tar ointment, an organic source of carbolic acid, on wounds for the prevention of purulence.11 More than 2000 years later, carbolic acid would resurface in the treatment of infection after the acceptance of germ theory.11
In the Middle Ages, specific accounts of the use of topical agents to prevent purulence for head injuries appear in the writings of Abu Bakr Muhammad Ibn Zakariya al-Razi (ad 865–925), a Persian physician whose work was influenced by Hippocrates. In a chapter dedicated to neurotrauma in his book Liber Almansoris, al-Razi recommended the use of a concoction consisting of aloe, myrrh, dragon’s blood (resin of the Calamus plant species), starch, olibanum, and coral—several of which are compounds that have been found to have antimicrobial properties.12,13
Despite an extensive history of wound dressings to promote healing transcending civilizations and centuries, there remained a lack of understanding surrounding the etiology of infection.14 Modern germ theory had not been developed, and there was a litany of speculation on the cause of purulence and poor healing, most notably stemming from imbalances among the four humors of yellow bile, phlegm, black bile, and blood.14
The end of the Middle Ages and transition to the Renaissance (ad 1450–1750) was marked by rapid population growth. At the same time, the development of and mass access to firearms by civilians and militaries led to a surge of penetrating traumatic injuries, particularly with regard to penetrating neurotrauma. Before the advent of firearms, military surgeons and physicians, although centuries apart, were treating a similar composition of wounds. However, firearm injuries carried high morbidity and mortality rates, with the blast-induced injury requiring interventions beyond the traditional wound management strategies of the time. Cauterization rose in popularity during this period as a quick method for hemostasis and wound management.11,14 A notable dissident to cauterization was the French surgeon Ambroise Paré (1510–1590), who recognized the excruciating pain cauterization inflicted on his patients, with mediocre rates of successful wound healing, and used topical salves much like his predecessors.11,14
In the late 1700s, John Hunter, surgeon general of the British Army and founder of modern "scientific surgery," began to publish extensively on wound management after his experiences with the expedition to Belle Isle in the Seven Years’ War, including in his text titled "A treatise on the blood, inflammation and gun-shot wounds."15 He advocated for the application of wine to topical burns and hog lard to full-thickness burns, techniques that were adopted by many.16 The soaring popularity of medical journals during the 17th century served as an agent through which the wound care practices of Hunter and many others spread across Europe.17
Thus, across centuries and civilizations, the topical application of various compounds to traumatic injuries became the standard of care for wound management. While the mechanisms of action were not fully understood, the link between these agents and the improved outcomes, particularly alcohol and honey, saw their persistent use throughout the Middle Ages and into the early 20th century.
The Rise of Germ Theory
The modern understanding of the role of microorganisms (bacteria, fungi, and viruses) in the pathobiology of infectious disease is routed in advancements from the 19th-century agricultural industry. Crop blights such as the Great Irish Potato Famine of 1845–1847 were traced to microscopic fungi by natural scientists, popularizing the idea that living organisms could be responsible for infection.18 It was around this time that Louis Pasteur proposed his unifying germ theory of disease, in which he attributed infections to the activities of microorganisms. Through his experiments in fermentation, Pasteur showed that imperfections of the fermentation process were due to microbial contamination.19 He subsequently demonstrated that this contamination could be prevented through iterative cycles of heating.19 The adaptation of this theory to infectious diseases of living organisms came during his time in Alès, France, while investigating an epidemic afflicting the silkworms of the region. After elucidating that the reason why the silkworms were unable to produce silkworm thread was due to a nutritional deficiency that permitted a pathologic bacterium to proliferate unchecked in their guts, Pasteur proposed germ theory as an explanation for infectious diseases.19
The final bridge to bringing the idea of germ theory to medical practice, and in particular to surgical wounds, came via British surgeon Joseph Lister (1827–1912) in his 1867 article "On a new method of treating compound fracture, abscess, etc." published in The Lancet.20 In introducing his surgical series, Lister directly credited Pasteur for his demonstration that microorganisms lead to infection. Lister then highlighted the town of Carlisle, England, for his inspiration to use carbolic acid, an organic aromatic compound isolated from tar, as an agent to combat infection. In 1864, the town of Carlisle added carbolic acid to its sewage, and Lister commented that its addition eliminated the "odour" from the lands irrigated with the refuse and seemed to rid the cattle that grazed on the land of a common parasite to the region.20 He then reported his success of avoiding infections in cases of compound fractures by soaking surgical instruments, the surgeons’ hands, and the wound dressings in carbolic acid. One of the first translations of carbolic acid use for infection prevention in neurosurgery was outlined by Sir Victor Horsley in 1886.21 Horsley’s protocol included applying lint soaked in carbolic acid to the operative site for a minimum of 12 hours before surgery, combined with the application of carbolic acid–soaked gauze for several days after.
Pasteur, Lister, and their colleagues continued to publish on their experiences and promote ideas surrounding the interplay between infection, septicemia, and surgery. By the 1880s, surgeons across the globe began to accept microbes as the cause of infections and conceptualize the pivotal role that antimicrobial agents could play in combating infection-related death rates and morbidity (Fig. 1).
Lessons From the World Wars
World War I
At the onset of WWI, many prominent surgeon-scientists were called into military service. With trench warfare tactics at play, wound infections presented major limitations to medical care; it is estimated that up to 70% of WWI deaths were due to infected wounds.22 Penetrating cranial injuries presented a particularly challenging aspect of surgical care, as Harvey Cushing commented in 1917, "Our early operations, under a general anesthetic, with flap exposures and imperfect cleansing of the track, did very badly, and the mortality, usually due to infection, ranged between 50 and 60 percent."23
It was in this setting that the early standards for the surgical technique in the treatment of craniocerebral injuries arose from the experience of Sir Victor Horsley and R. Whitaker during their time with British forces in modern-day Iraq, where Horsley unfortunately died prematurely.24 The surgical technique included excision of the scalp wound; piecemeal removal of the skull fracture; enlargement of the dural opening; extraction of bone or metal fragments, usually with the insertion of a finger; and leaving the wound open. Carbolic acid was applied directly to cerebral tissue to irrigate the tract, in addition to local application at the open wound site postoperatively.23–27 This technique invariably led to a condition known as "fungus cerebri," which describes the strangulated, necrotic mass of brain tissue that would herniate through the dural defect left open28 (Fig. 2). In their 1915 series from the base hospital at Boulogne-sur-Mer, France, Percy Sargent and Gordon Holmes remarked, "The development of a fungus cerebri is therefore the most deplorable incident, to the prevention of which our treatment must be directed."28
Representative illustration of fungus cerebri with strangulated and edematous brain tissue protruding through the open dural defect resulting in an infectious nidus. Reproduced from Br Med J, Preliminary notes on the treatment of the cranial injuries of warfare, Sargent P, Holmes G, vol 1, pp 537-541, 1915, with permission from BMJ Publishing Group Ltd.
With the goal to decrease infectious complications and improve patient outcomes, Harvey Cushing modified Horsley’s techniques into what resembles a more modern approach to penetrating cranial injuries. Across two publications, he detailed his experience treating 250 patients with penetrating cranial injuries over a 3-month period at Base Hospital No. 5 in Camiers, France.23,29 Cushing proposed four main modifications to Horsley’s surgical technique: 1) turning a formal craniotomy around the location of skull penetration, as opposed to the piecemeal removal of fragments; 2) the use of a suction method that he developed for removal of in-driven bone and metal fragments (Fig. 3); 3) irrigation with dichloramine-T in eucalyptus oil and topical application postoperatively to the wound and dressings; and 4) primary tension-free closure with buried galeal sutures.29 Dichloramine-T was an important advance in antiseptic irrigation regarding the central nervous system. As Cushing observed, "The use of watery solutions of antiseptics in the brain is disappointing, for they lead to oedema with swelling of the tissue and an increased tendency to herniate…. Dakin’s dichloramine-T in eucalyptus oil came to be utilized as a routine during the latter weeks of our service [and] there was a notable diminution in the number of infections."29
Illustrated schematic of Harvey Cushing’s rubber catheter and suction apparatus used to clear the projectile tract of debris. Reproduced from Cushing H. Br Med J. 1918;1(2982):221-226.29 Public domain.
In addition to his use of dichloramine-T, Cushing also trialed the Carrel-Dakin technique widely used for open extremity wounds.23,30 This technique comprised periodical irrigation of the wound with a diluted solution of sodium hypochlorite until cultures of the wound exudate showed sterility, at which time primary closure would be undertaken.30 Another important contribution of Cushing in relation to infection prevention was the timing of the primary surgical procedure. He advocated for formal surgical washout as soon as feasible, citing several case examples of contaminated wounds becoming infected before reaching the operating table because of delays in field evacuation of more than 12–24 hours.23 Alongside Cushing in his prominence during WWI, and later in establishing the field of neurosurgery, was Geoffrey Jefferson, who served at the British Base Hospital No. 14 in Wimereux, France, writing extensively on his experiences in treating penetrating cranial trauma.24,27 Wisdom from the battlefield experiences of Wilfred Trotter, Gilbert Horrax, William John Adie, and W. W. Wagstaffe additionally contributed to our understanding of the morbidity associated with these injuries23,26,27,31–33 (Table 1).
Representative cohort studies across the decades from the onset of WWI of patients with penetrating cranial injuries in both military and civilian settings that included information on infectious complications and antibiotic prophylaxis
| Authors & Year | Infection Rate (%) | Antibiotics Used |
|---|---|---|
| Pre-IV antibiotics | ||
| Whitaker, 191526 | 58.8 | |
| Cushing, 191723 | 32.3 | |
| Adie & Wagstaffe, 191833 | 27.0 | |
| Jefferson, 191927 | 45.1 | |
| Ascroft, 194344 | 27.2 | |
| Martin & Campbell, 194645* | 19.0 | |
| Mean % | 34.9 | |
| Post-IV antibiotics | ||
| Martin & Campbell, 194645† | 16.0 | IV penicillin |
| Webster et al., 194646 | 16.0 | IV &/or local sulfadiazine or penicillin |
| Small & Turner, 194747 | 8.4 | Topical sulfamethazine & penicillin |
| Cairns et al., 194742 | 14.0 | IV sulfadiazine |
| Hagan, 197148 | 12.6 | IV cephalothin &/or colistin |
| Lillard, 197849 | 6.0 | Not specified |
| Hubschmann et al., 197950 | 4.9 | IV oxacillin & ampicillin for 14 days |
| Clark et al., 198651 | 3.9 | Not specified |
| Nagib et al., 198652 | 1.8 | IV cefazolin |
| Taha et al., 199153 | 5.0 | Not specified |
| Aarabi et al., 199854 | 4.4 | IV penicillin, chloramphenicol, gentamicin |
| Ozkan et al., 200255 | 15.0 | IV third-generation cephalosporins for 14 days |
| Martins et al., 200356 | 5.8 | Not specified; 14-day course |
| Liebenberg et al., 200557 | 8.0 | IV cefazolin followed by penicillin/chloramphenicol/metronidazole |
| Jimenez et al., 201358 | 25.0 | Variable; IV cephalosporins most common |
| Khan et al., 201459 | 11.7 | Not specified |
| Johnson et al., 202160 | 10.7 | Variable; IV cephalosporins most common |
| Mean % | 10.0 |
IV = intravenous.
Patients treated before the routine use of intravenous penicillin, beginning in the spring of 1944.
Patients treated after the routine use of IV penicillin began.
While the availability of these topical antiseptics during WWI reduced infectious morbidity and mortality, more was desired. Kellogg Speed complained that, despite the variety of options, none was a "cure-all."34 Additionally, not all practitioners were convinced. The British field surgeon F. F. Burghard argued against antiseptic use, citing the idea that antiseptics inhibited the protective phagocytic activity of leukocytes.35 Moreover, while giving the Hunterian Lecture to the Royal College of Surgeons in 1919, Alexander Fleming warned of an overreliance on antiseptic solutions, stating, "All the great successes of primary wound treatment have been due to efficient surgery, and it seems a pity that the surgeon should wish to share his glory with a chemical antiseptic of more than doubtful utility."36
Clearly, many still believed that pristine and timely surgical technique was key to preventing infectious complications. Nevertheless, the concepts of antisepsis and irrigation and the beginnings of the concept of prophylaxis were all in place to serve as the foundation for work to come.
World War II
A decade after voicing concerns about the antiseptics of the time, Fleming discovered the antibacterial properties of the Penicillium mold.37 In studying its antibiotic mechanisms, he outlined a list of susceptible bacteria, including Staphylococcus and Streptococcus species, which were major causes of infection in head injuries.23,26,27,37 Contrary to previous antimicrobial agents, penicillin showed no signs of toxicity when injected intravenously or irrigated topically.37 Nonetheless, despite the efficacy of penicillin, it was an unstable compound, losing its antibacterial characteristics within 2 weeks even when stored between 10°C and 20°C, rendering it impractical for widespread distribution and storage until its stability could be improved.37
Until such a time, antibiotics that could be mass-produced in stable crystalline, powder, or tablet form, such as chloramphenicol and the sulfonamides, became integrated into medical practice. Early adopters of these novel agents for cranial neurotrauma included Dr. William Cone, an American who cofounded the Montreal Neurological Institute and served in the Royal Canadian Army at No. 1 Neurological Hospital in Hampshire, England.38 In addition to advocating that all combat-ready men wear their hair cropped, as to expedite preoperative preparation in the event that they needed a cranial operation, Dr. Cone conducted experiments on the safety of direct topical application of chloramphenicol crystals to cerebral tissue.38,39 With a growing canon establishing the efficacy and safety of antibiotics, political and military leaders, including the US surgeon general, helped ensure the widespread distribution of these agents.40 The utility of systemic antibiotics for penetrating cranial injuries during WWII was recognized by Hugh Cairns, an Australian-born British neurosurgeon who had trained under Harvey Cushing. Cairns advocated for the prophylactic administration of sulfonamides, orally or intravenously, from the moment of wounding, in addition to the irrigated and topical application of sulfonamide powder at the time of operative intervention.41,42 His ideas were subsequently widely adopted by the Allied side during WWII, with a decreased rate of observed infectious complications after penetrating neurotrauma43–60 (Table 1).
By 1940, Sir Howard Florey and Ernst Chain, two prominent Oxford scientists, had devised a method by which a stable form of penicillin could be purified and widely distributed.61 Because of its efficacy and spectrum of coverage for common infectious agents, penicillin quickly became as widely used as sulfonamides, with multiple modes of delivery, including oral, intravenous, within irrigation, and topically via the Carrel-Dakin technique postoperatively.62–64 With these observed benefits in mind, surgeons began using these two antibiotic classes in combination. In his 1947 article, Cairns described his protocol for prophylactic antibiotic use in penetrating cranial neurotrauma: "All patients received sulphonamindes, usually sulphadiazine, by mouth or intravenously in adequate doses from the moment of wounding, and the majority also received systemic penicillin … 1-2 g. of penicillin-sulphamethazine powder were insufflated and this provided adequate penicillin in the wound juices for 12-18 hours."42
With the availability of systemic antibiotic therapy, some of the fundamental aspects of the surgical technique from WWI for penetrating cranial injuries began to be questioned. The push for urgent surgical debridement and forward neurosurgical units was throttled by increased air evacuation capability and systemic antibiotics. Cairns and Calvert reported a 14% infection rate for operations performed at Radcliffe Infirmary in Oxford, England, on soldiers with head injuries evacuated by air from Normandy more than 48 hours after injury, with similar results replicated by other groups.42,62,65 These outcomes firmly established the role of prophylactic systemic antibiotic therapy for wartime penetrating cranial injuries. Toward the end of the war, some writers argued that operative debridement and systemic antibiotic prophylaxis alone were sufficient and went so far as to call the local application of antibiotics "scant."66 Thus, after thousands of years of gradual improvements in wound management through topical antiseptics, the immense potential of systemic antibiotics exposed the marginal benefit of these local applications (Table 1).
Civilian Adoption of Military Practices and the Development of Standard of Care
The experiences of neurosurgeons returning from the war were instrumental in integrating the use of sulfonamides and penicillin in the control and prevention of infectious complications after civilian neurotrauma.66 These improved outcomes were disseminated in publications, meetings, lectures, and courses, leading to a significant government and industry interest, prompting an era of antibiotics.22,67 The next 20 years witnessed a rapid boom in the number of antibiotics available and increased capability for production. Physicians now had an extensive range of antibiotics at their disposal, including aminoglycosides, cephalosporins, and other beta-lactams.68 In neurotrauma specifically, chloromycetin, chloramphenicol, or streptomycin with penicillin for basal skull fractures, and cloxacillin for compound depressed skull fractures quickly gained traction.69–71 However, this dramatic increase in the variety of available antibiotics was matched with an increase in the diversity of opinions and recommendations on the use of prophylaxis, many of which were founded on personal preference or anecdotal experiences.71,72 It became clear that unified guidelines informed by systematically collected evidence were needed.
The development of these recommendations began in the 1960s, with continual revision over the subsequent decades.73 A manual titled Neurological Surgery of Trauma, published under the direction of the then surgeon general in 1965, Lieutenant General Heaton, was an early iteration of such standards.73 The manual recommended the "immediate preoperative prophylactic" administration of antibiotics, namely penicillin and streptomycin, for patients with penetrative craniocerebral injury; however, also noted was the growing list of available antibiotics, complicating the recommendations of specific drugs. Thus, the ever-changing landscape of antibiotics preserved the importance of clinical judgment by surgeons in infection management. In a 1991 survey of more than 1000 American neurosurgeons in civilian practice on management practices for penetrating cranial injuries, 87% of the respondents reported using prophylactic antibiotics.1 Cephalosporins were most used; however, the duration of their use perioperatively varied significantly.1
In 2005, recommendations supported by the Brain Trauma Foundation were published, endorsing the use of broad-spectrum antibiotics prophylactically for victims of penetrative brain injury, citing the "Guidelines for the management of penetrating brain injury" published in 2001 in the Journal of Trauma.2,3 The most recent version of these guidelines, released in conjunction with the Congress of Neurological Surgeons, again recommends antibiotic prophylaxis for "open, (compound) depressed fractures," without specific comment on penetrating injuries.74 Additionally, the "Guidelines for the prevention of infections associated with combat-related injuries," released in 2011 and endorsed by the Infectious Diseases Society of America and the Surgical Infection Society, provides specific antibiotic recommendations for various injuries. For maxillofacial, neck, and central nervous system traumatic injuries, the use of intravenous cefazolin is recommended.4 It is important to note that within these guidelines there is a distinct lack of mention of antibiotic irrigation in the operative care of these patients, with some commentators arguing for a less aggressive surgical debridement and more aggressive antibiotic prophylaxis.75 Clearly, almost 100 years from the realization of the potential of systemic antibiotics to improve patient outcomes, the optimal and judicious use of these agents in various clinical situations remains debated.
Conclusions
Through this review, one can trace the roots of modern-day antibiotic prophylaxis practices in neurotrauma as they were adapted from their various, yet interlinked, origins. Over the centuries, practices have advanced from the rudimentary use of natural substances to the discovery and mass production of complex chemicals to prevent infection. Yet, despite this rich bank of knowledge and even richer history regarding the topic, recent years have witnessed medical professionals start to question the lack of evidence underlying recommendations on antibiotic prophylaxis.
From this comprehensive historic review of the use of antimicrobials, integration of germ theory, and wartime practices of infection prevention, we find that clinical practices may be informed by the experiences of prominent figures in medicine as opposed to solely systematic research. Perhaps a call for evidence underlying clinical guidelines will further adapt how we use antiseptic and antibiotic agents. Yet, there is much room for further research without completely abandoning practices that have withstood the test of time.
Disclosures
The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.
Author Contributions
Conception and design: Ngwenya. Acquisition of data: Alfawares, Folz, Johnson. Analysis and interpretation of data: all authors. Drafting the article: Alfawares, Folz, Johnson. Critically revising the article: Ngwenya, Johnson, Prestigiacomo. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Ngwenya. Study supervision: Ngwenya, Prestigiacomo.
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