The development of albumin solutions in the Second World War

He was unconscious in the morning when he was given 250 g of albumin. In the afternoon, he was talking but was disoriented. The following morning, he was given the same amount of albumin. Twenty-four hours later, the edema had disappeared and he was taking food by mouth.

Lieutenant Colonel (later Major General) Isidor Ravdin, describing the effects of human albumin solution (HAS) in a severely burned casualty, Pearl Harbor, Oahu, Hawaii, December 1941. ¹

By the spring of 1940 it had become clear that the United States of America would eventually enter the Second World War, and there was a need to mobilise the nation’s scientific resources in anticipation of the conflict. ^{1 , 2} Among the requests made to the National Research Council (which had been established during the First World War to encourage and coordinate ‘the employment of scientific methods in strengthening the national defense’) ² the US army and navy sought advice on the procurement of whole blood, as well as the production of stable blood derivatives, or substitutes, which could be used in the ‘emergency treatment of traumatic shock, burns and haemorrhage resulting from modern military operations.’ ³

Chaired by Walter Cannon, Professor of Physiology at Harvard Medical School, the National Research Council Committee on Transfusions first met in Washington DC on 31 May 1940. Representatives of the American Red Cross were also in attendance. In addition to discussing issues relating to whole blood and plasma, hopes were expressed that a substitute for human plasma could be found. ‘In the interest of clear thinking’, it was agreed that protein biochemists should be engaged in this pursuit, ¹ and Cannon therefore approached Edwin Cohn and colleagues from the Department of Physical Chemistry, Harvard Medical School, to investigate whether a safe and effective plasma fraction could be isolated from bovine blood, which was readily available as a by-product of the meatpacking industry. ^{4 , 5}

During the summer of 1940, novel techniques for the separation of plasma into five major fractions were devised at Harvard. Later known as the Cohn process, this utilised ethanol–water mixtures at low temperature and controlled pH, protein and salt concentration, and could easily be scaled up for industrial production.^4–6 It quickly became apparent that the albumin fraction had many desirable physiological properties for the maintenance of blood volume, and was ‘more stable, less viscous, and less antigenic’ than whole animal plasma. Furthermore, there appeared to be no physicochemical differences between bovine and human albumin, and it was ‘remarkably inert in the circulation, in which it remained detectable for long periods of time.’ ¹

Clinical testing of bovine albumin began in April 1941, and proceeded for almost 2 years. Intravenous injections were initially administered to Harvard Medical School students, as well as inmates at the Norfolk State Prison Colony. Cohn later wrote: ‘over a third of the prisoners volunteered as subjects after hearing careful explanations of the reasons for the experiment and of the possible risks involved’. ⁴ By October 1942 the programme had expanded to include the surgical clinic at the Johns Hopkins Hospital, where Alfred Blalock reported beneficial results following the administration of 25–50 g of bovine albumin to four patients with traumatic shock. ¹ However, the use of bovine albumin was associated with a high incidence of delayed serum sickness. In several instances this was severe enough to require hospitalisation, and in two cases, proved fatal. Twenty-seven-year-old Arthur St Germaine died at Norfolk State Prison Colony in September 1942. ⁷ He was later granted an exceptional posthumous pardon in honour of his contribution to the war effort. ⁵ Unable to find a way to make bovine albumin safe for human use, the programme was terminated in March 1943. ¹

While Cohn regretted that the early promise of bovine albumin had not been borne out, ¹ the cold ethanol process which had been developed as an integral part of the project could be utilised to produce albumin (as well as fibrinogen, thrombin and immune globulins) from human plasma. The first fractionation of human plasma had, in fact, been carried out in the Harvard laboratory in August 1940, using blood purchased from ‘a few professional donors’. ⁴ Six months later, in the interest of making larger amounts of albumin, the American Red Cross began collecting blood from 19 volunteers who attended the outpatient department of Peter Bent Brigham Hospital on a weekly basis.

Clinical trials using human albumin commenced in Boston in April 1941. Initial experiments were performed in healthy volunteers (mostly medical students), and aimed to evaluate the physiological effects of a concentrated (25%) HAS following rapid venesection of 15% of the circulating blood volume. ^{4 , 8} Its administration was shown to increase plasma volume, with each gram of albumin drawing approximately 18 ml of fluid into the circulation by virtue of its colloid osmotic pressure. ⁸ The following month, the first clinical trial of human albumin in traumatic shock was undertaken at Walter Reed General Hospital. A 20-year-old man was admitted with bilateral compound comminuted fractures of the tibia and fibula, and five fractured ribs. On initial assessment he was ‘confused and irrational, with a BP of 76/30 mmHg’. Following injection of 200 ml 25% HAS the blood pressure (BP) rose to 106/70 mmHg, and 2 hours later, it was 130/80 mmHg. ¹

Soon after, a pilot plant for plasma fractionation was constructed at Harvard. ⁴ This permitted the large-scale production and distribution of HAS to clinical research groups across the US, who sought to determine its efficacy in the management of shock, burns, and hypoproteinaemic states.^9–12

Meanwhile, on the morning of Sunday 7 December 1941, the Imperial Japanese Navy Air Service launched a surprise attack on the US naval base at Pearl Harbor, Oahu, Hawaii. More than 2400 Americans were killed, and 1143 were wounded. ¹³ The following day the US Congress declared war on the Empire of Japan, and ‘every bottle of HAS in Boston’ was flown to Pearl Harbor, ⁴ where it was administered to seven severely burned casualties, under the direction of Lieutenant Colonel Isidor Ravdin. He later reported: ‘All were edematous and … losing plasma at the site of their burns. Some of them were so edematous, in fact, that albumin had to be injected into the femoral vein because other veins could not be located’. ¹ All the patients survived, and Ravdin concluded that ‘albumin accomplished osmotically everything that normal plasma could accomplish’. ¹

In early 1942 the US military accepted concentrated human albumin as a ‘blood substitute which could be transported and administered in small volumes with great facility and … safety’. ¹ A compact standard army–navy serum albumin package, comprising three 100 ml ampoules of 25% HAS and equipment for its administration, was devised by Lieutenant Commander Lloyd Newhouser and Captain Douglas Kendrick. ^{14 , 15} Commercial production of human albumin to the standard of purity specified by the military was subsequently undertaken by seven pharmaceutical firms. By the end of hostilities, these companies had processed 2,329,175 individual blood donations to produce more than 570,000 packages of human albumin. ¹ Countless lives were saved.

Cover photo. Pressure bandaged after they suffered burns when their ship was hit by a kamikaze attack, men are fed aboard the USS Solace (AH-5). c. 1945. Courtesy of US National Archives and Record Administration.