A letter from Alexis Carrel concerning the preantibiotic treatment of war wounds: The Carrel–Dakin solution

Introduction

Early during the First World War, a French-American surgeon, Alexis Carrel (1873–1944), devised an exacting protocol for treating battle field wounds. This involved irrigating such injuries intermittently day and night over a week or more with an antibacterial solution containing an oxidizing agent, sodium hypochlorite (the Carrel–Dakin solution). His method was labor intensive and was slow to be employed properly by military surgeons. Carrel had sought to correct this weakness by enlisting the support of an American army colonel overseeing the U.S. medical contingent. I recently acquired a letter sent by Carrel in early 1917 to Colonel Alfred Eugene Bradley (1864–1922), which alluded to the difficulty in training medical attendants in the most effective use of the new antiseptic solution ¹ (Figure 1). The body of the letter reads as follows. OPEN IN VIEWER

The early rejection of Carrel’s method

An official British memorandum in 1915 concerning war injuries stated that “the treatment of suppurating wounds by means of antiseptics is illusory.” ⁵ One of its four authors was Sir Almroth E. Wright (1861–1947), who had become famous for emphasizing the importance of humoral immunity over cellular immunity and for having developed a typhoid vaccine in the 1890s. He reasoned that microbes carried by projectiles and bits of clothing were forced “deep into the tissues and were beyond reach of [topically applied] antiseptics.” ⁵ He also contended that germicides in wounds favored the development of microbes there. ⁶

Wright believed that local infections should be treated with drainage, which, however, might be impeded by fibrin clots. To prevent them forming, he recommended irrigating war wounds with a hypertonic solution, which, he reasoned, would draw lymph to the wound through osmosis. The lymph would contain humoral substances and leukocytes. The former would prevent clots from forming and blocking drainage, while the latter would release trypsin and promote the sloughing of dead tissue. ⁷

Abroad, Carrel’s ⁸ method also met with “much opposition from certain individuals at the head of the medical profession in France.” In the introductory chapter of The Treatment of Infected Wounds (1917) by Alexis Carrel and Georges Dehelly, the authors upbraided “the surgeons who still deny the universality of infection” and those ignorant of the methods they criticized at réunions chirurgicales. ⁹ One such critic derided the “American” antiseptic method introduced by Carrel ¹⁰ with the comment, “cela d’Amέrique, laissez-moi rire” (“regarding [the method] from America, let me smile” [in derision]).

The four contributors—Introduction

The many skeptics of the aseptic–antiseptic treatment of wounds have been noted above, while the four persons involved in devising and implementing Carrel’s method are introduced here.

Colonel Alfred Eugene Bradley (1864–1922) was a Military Observer with the British forces and the Chief Surgeon of the American Expeditionary Force in France, when in January 1917 he received the above letter from Carrel. Bradley was born in Jamestown, NY, graduated from Jefferson Medical College in 1887, and entered the Army medical corps that year. He served at various army posts in the U.S. west and during the Spanish-American War and the Philippine Insurrection. The letter indicates that he and Carrel had discussed previously the difficulty of treating wounds. The short note may have been a further effort to persuade Bradley to promote Carrel’s method among the American and British army surgeons and staff.

Alexis Carrel (1873–1944) was trained in surgery in Lyon, France and came to the Rockefeller Institute in 1906 via Canada and Chicago to pursue his long-term goal of transplanting organs. In 1912 he received the Nobel Prize in medicine, which honored his developing a suturing technique for anastomosing small blood vessels—a skill essential in any future transplantation work. He also became a pioneer in the technique of cell culture, which in the preantibiotic era required fastidious attention to sterile conditions. His interest in cell growth extended to that in wounds. He speculated that someday chemical treatment of wounds might hasten their healing over many days to within a few hours. ¹¹

During the summer of 1914, Carrel was in France for his annual vacation and was about to return to New York when in August the fighting of First World War began. He joined the French Army and soon set about developing a new treatment for battle wounds, which were not protected from infection by the conventional germicides, such as carbolic acid, silver nitrate, hydrogen peroxide, and other agents. He sought to devise a more effective antiseptic solution and enlisted the help of the following British chemist and French pharmacologist. They worked at the Beaujon Hôpital in Paris and at a field hospital at Compiègne (80 km NE of Paris).

Henry Drysdale Dakin (1880–1952) was born in London, studied in Heidelberg and obtained a DSc degree in chemistry from the Yorkshire College at Leeds. In 1905 he moved to New York City, having been recruited to do research in the private laboratory of a wealthy physician, Dr Christian A. Herter (1845–1910), at his home in New York City. Herter cofounded and edited the Journal of Biological Chemistry and was affiliated with the Bellevue Hospital Medical College and the Rockefeller Institute, where Carrel worked. During the early war period, Dakin joined Carrel in France and provided the chemical expertise which led to the eponymic antiseptic solution, generally referred to as the Carrel–Dakin solution, or simply the Dakin solution.

Maurice Daufresne (1881–1944) was a French-trained pharmacologist, who had worked in Carrel’s laboratory at the Rockefeller Institute before and after First World War and during the war collaborated with Carrel and Dakin in France. He devised a well-buffered hypochlorite irrigation solution, which in the literature was sometimes termed the Carrel–Dakin–Daufresne solution. ¹²

The Dakin solution

Dakin and Daufresne examined the germicidal potential of over 200 chemical agents. ¹³ They determined the highest dilution which killed within 2 h various bacteria suspended in an aqueous solution (water) or in the presence of blood serum. The latter condition resembles more closely that in a suppurating wound, where the proteins of serum coat and protect bacteria from antiseptic agents or bind to them. The organisms tested included staphylococci, streptococci, Bacillus pyocyaneus, and Clostridium welchii. A table in the book by Carrel and Dehelly records the dilutions of seven agents which killed staphylococci in blood serum. ¹⁴ Starting with the most potent (based on the highest dilution), they are mercury bichloride (1:25,000) > silver nitrate (1:10,000) > hydrogen peroxide (1:1700) > sodium hypochlorite (1:1500) > iodine (1:1000) > salicylic acid (1:100) > carbolic acid (1:50). Note that carbolic acid at 1:50 had the weakest germicidal action of the seven agents. But the rank order of antibacterial potency of various agents in the test tube was not the only consideration in the choice of a clinically useful germicide.

A limiting factor in the choice of agents was whether they injure living tissue or have other weaknesses. Mercury bichloride, silver nitrate, and iodine irritate the skin at the concentrations tested here and commonly used. Hydrogen peroxide decomposes rapidly in wounds. Sodium hypochlorite (NaClO at 1:1500) is 30 times more effective than carbolic acid (C₆H₅OH at 1:50). Thus, hypochlorite proved to be the optimal germicide among those examined and was determined to be an effective antiseptic in infected wounds at concentrations of 0.45–0.50%. Higher concentrations were irritating to the tissues. Also, the solution should have a neutral pH. This was achieved by Daufresne ¹⁵ when he introduced the carbonate–bicarbonate buffer in the latter variations of hypochlorite solution. It is curious that Carrel and Dehelly did not study a commonly used antiseptic—Edinburgh University Solution of Lime, which is a solution of chlorinated lime (CaOCl₂). ¹⁶

The Carrel method

The Carrel method involved first the removal of foreign material from the wound (metal, cloth fragments, and other debris) and any blood clots and then a thorough debridement of dead tissue. The surface of bony cavities in which projectiles lodged was scraped and resected. Lesions were deliberately kept open initially to allow natural drainage. ¹⁷

The detailed treatment protocol was developed at the bedside by Carrel, while the optimal germicide was determined in the laboratory by Dakin and Daufresne. A wound’s septic course was followed by examining bacterial smears taken from it daily. Few bacteria were found in smears from wounds during the first day or so of injury, although cultures taken from them were positive for growth. ¹⁸ The French-Belgian soil rich in animal feces yielded wounds contaminated with facultative and anaerobic organisms. ¹⁹ Bacteria multiplied and spores germinated in warm wounds so that by the second or third days after injury purulent infections were evident in wounds. These sometimes became crepitant, indicating gas-producing organisms, such as clostridial species. The rapid transfer of the wounded from the field to treatment facilities was important, since early wounds could be sterilized more readily by topical treatment before the microorganisms had proliferated and penetrated into the underlying tissue.

The Dakin solution losses its antibacterial potency in a wound within an hour or so, possibly because of hypochlorite molecules being bound to tissue proteins, as suggested earlier. Thus, the solution needed to be replaced every 2 h over many days until the microscopic bacterial count became negligible. For the antiseptic to reach all surfaces of the open wound, Carrell ²⁰ devised a gravity-driven irrigation system involving small rubber tubes slowly releasing the germicidal agent through tiny holes along the length of the tubing lying in the wound. Only when the daily microscopic bacterial count in a smear taken from the wound was two or less in a high power field was the wound surgically closed by tertiary intention, if it had not already begun to close naturally by secondary intention.

Carrel’s reported clinical results

Carrel and Dehelly reported on 303 injured combatants admitted to the hospital between December 1915 and October 1916. Thirteen soldiers died within 24 h of severe anatomical injuries or gangrenous infections. There were 23 amputations because of severe tissue destruction. The authors listed in detail many case histories and claimed that 90% of the remaining wounds became “sterile” within 5–20 days of treatment and were then surgically closed or closed naturally. ²¹

At a meeting of the Académie médecine in October 1915, a French member reported in Carrel’s place that his method produced complete healing in one-tenth of the usual time and reduced amputations by 50%. ²² The Carrel–Dehelly book abounds in such favorable generalizations and clinical case reports but is short on statistically credible data, e.g. no controls of comparable wounds treated by “usual” methods. ²² In unpublished notes, Dakin wrote that “war conditions made it impossible to secure statistical data of any value.” ²³ Similarly, Almroth Wright ²⁴ recognized the absence of objective data to support his hypertonic method of treating infected wounds and explained that “the evidence required … was not of easy access.” Conspicuously missing were data recording the time between the battle field injury and the beginning of treatment by one of the various methods.

A modern perspective

During more recent wars, the antibacterial treatment of wounds has depended mainly on antibiotics administered orally or parenterally. Here the bacteriocidal action is distributed throughout the body’s tissues and presumably reaches the surface of open wounds. However, local germicidal levels there may not be adequate to suppress a well-established infection, hence the potential value of applying the antiseptic agent directly to the surface of an open wound. Topical antiseptics developed in modern times include sulfa powder (sulfonamide), bacitracin, neosporan, polymyxin, chlorhexidine, benzalkonium chloride, iodine-containing agents (povidone iodine), and others.^25,26 An article in 2014 reaffirms that hypochlorous acid solution (HOCl) is “an ideal wound care agent with powerful microbiocidal, antibiofilm, and wound healing potency.” ²⁷

A debate about the value of various irrigation treatments of wounds appeared in the literature of the 1970s. Hamer et al. ²⁸ cited reports of decreased wound infections following simple saline irrigation, but other studies concluded that low pressure irrigation was ineffective. During the war in Vietnam (1954–1975), early pulsatile lavage was reported to be more effective decontaminating combat wounds than gravity flow or bulb syringe methods of irrigation. ²⁹ In this combat situation, the wounded were received into rear hospitals (echelon II facilities) on average within 4½ h after injury, when reportedly a single irrigation treatment was performed before primary closure. This was in contrast to Carrel’s practice of leaving the wounds open to facilitate drainage and to allow irrigations every 2 h until relative sterility of the wound was achieved.

The four contributors—Their later histories

Col. Bradley had recurrent, unstated illnesses after the war. He died in 1922 and was buried with military honors at Arlington National Cemetery. ³⁰

Alexis Carrel led a productive life during the interwar period back at the Rockefeller Institute and attracted public attention in three areas: (1) his growing cells in culture from a chicken heart presumably for over 20 years, (2) his collaboration with Charles Lindbergh in developing a device for perfusing small organs outside the body, and (3) his best-selling book, Man the Unknown (1935) and others writings. ³¹ In February 1941, with the outbreak of Second World War, Carrel returned to France, joined the Vichy government in Paris, and directed a foundation he established, which investigated the health and welfare of the French people during the German occupation. In August 1943, he had a heart attack at his Paris home. A year later, on 25 August 1944, Gen. Charles de Gaulle and French troops entered Paris and assumed control of the government. Carrel was removed from his position at the Foundation and came under scrutiny as a suspected Nazi collaborator. He died of heart failure on 5 November 1944. ³²

Immediately after the war, the eugenics and euthanasia which he advocated in Man the Unknown for mentally diseased and criminals were found politically and ethically offensive. Because of these rejected ideas and his association with the Vichy government, Carrel’s name was removed from streets in Montreal and more than 21 French cities. The “Alexis Carrel Medical Faculty” in Lyon was renamed in honor of René Laënnec. ³³

Henry Dakin resumed privately funded research after the war and published over a hundred papers on enzymes and amino acid metabolism. His studies were recognized by Fellowship in the Royal Society, honorary degrees from Yale and Heidelberg, and in 1941 the Davy Medal. He later became associated with Merck & Co. He died in 1952. Nowhere in Dakin's long obituary notice was Carrel mentioned. ³⁴

Maurice Daufresne resumed work in Carrel’s laboratory at the Rockefeller Institute after the war and published papers on chloramine-T paste for the sterilization of wounds. ³⁵ He left the Institute in 1925. His later history is unknown except for the fact that he died in Le Havre probably in September 1944, two months before Carrel’s death. The Anglo-American invasion of Normandy, which had begun in June 1944, was accompanied by intense bombing of many cities and towns in occupied France, notably those in the north. The Allied aerial strikes on Le Havre continued during the week of 5–11 September and sought to destroy the German garrison still holding out in the city. More than 5000 civilians were killed and 82% of the houses were destroyed. ³⁶ Maurice Daufresne was among the dead. ³⁷

Conclusions

Since Second World War, the chemical treatment of wound infections has relied mainly on modern antibiotics. During the First World War, Almroth Wright warned that the therapy of wounds with antiseptic solutions might promote the local growth of microorganisms, but he never elaborated. A more precise modern threat is that of a wound becoming infected with bacterial strains resistant to all available antibiotics. ³⁸ The emergence of multiresistant microbial strains is a continuing risk for open wounds and surgery in general. ³⁹ This must be addressed by the development of more versatile antibiotics whose actions may be based on new insights into the biology of the human host and its pathogens. Otherwise, the only antimicrobial therapy available might be the Carrel–Dakin solution or some locally applied antiseptic chemical, i.e. a topical treatment first employed over a century ago.