J Royal Naval Medical Service 2009, 95.3 145-150

General ‘The Drug of War’ - a historical review of the use of in military conflicts

S J Mercer

Abstract techniques that require a minimum of Anaesthesia for surgery during armed conflict equipment and drugs, and that ensure a rapid was traditionally based on simple and reliable and safe recovery (1). techniques. These often required a minimum was introduced into clinical of equipment and drugs while ensuring rapid practice in 1958 and although it proved a and safe patient recovery. Ketamine, which useful anaesthetic agent, it was associated first became available in Britain in the 1970s, with such severe adverse psychological effects was thought to offer certain favorable in the recovery period that its use was soon characteristics for use as a military anaesthetic abandoned (4). Ketamine, then named C1581, agent. This article discusses the use of was one of the 200 phencyclidine derivatives ketamine in many of the major armed conflicts that were investigated for clinical purposes. It that have occurred since its introduction. It underwent animal testing in 1962 and also catalogues the methods used by subsequent pharmacological studies in early anaesthetists at the time and their opinions of 1964 (5-7). The first human administration was the drug’s success. by Dr Guenter Corssen in August 1966 (8) and Anaesthesia and surgery have taken place the effects and findings were subsequently on the battlefield under difficult and stressful reported in the Journal of Anesthesia & conditions, often with basic equipment and Analgesia later that year (9). This led to resources. Any armed conflict has the ketamine first becoming available in Britain for potential for mass casualties who will require clinical trials in the January of 1970, but early surgery by a limited number of staff (1). In evaluations reported a high incidence of modern military conflicts, patients may require delirium and unpleasant dreams during the more than one anaesthetic for debridement or recovery period (10). Even as early as 1971 it delayed primary suture of their wounds (2). was commented in the literature that the use This is particularly pertinent with the central of ketamine, despite its ease of administration, protection offered by modern combat body ‘must be restricted to physicians skilled in the armor resulting in soldiers surviving with management of airway problems’ (11). peripheral injuries. In order to maintain an In June 1970 a conflict erupted between efficient throughput of injured personnel, the Palestine Liberation Army and the patients must be able to recover quickly from Jordanian Army and although a cease-fire was the effects of the anaesthetic agents and be rapidly negotiated, the situation escalated once able to maintain a clear airway as soon as more on the 17th September 1970. Casualties possible (1). A prolonged recovery period has increased in the Jordanian capital Amman and the potential to delay surgery on further on 19th September King Hussein made an casualties and place additional demands on the appeal to the British, French and American recovery staff (3). Anaesthesia in a military Governments for medical aid. Wounded conflict therefore must be based, at least in casualties were lying in the streets as the initial phases, on reliable and simple hospitals became overwhelmed and the

145 146 J Royal Naval Medical Service 2009, Vol 95.3

number of injured rose to within the region of laryngeal reflexes was noted, respiratory five thousand. A composite medical team, exchange was reported to be adequate and code-named ‘Ferrie Force’ , was dispatched patients were able to maintain their own from the UK to Cyprus on 21st September airway. In a busy environment this allowed the 1970. This unit consisted of a 50-bedded nursing staff to look after some of the patients, element of the No. 2 Field Hospital, the 50th particularly those undergoing burns treatment, Field Surgical Team, Hygiene, Field Ambulance without a supervising anaesthetist, who was and Signals detachments. The British Field free to deal with more urgent tasks. This was a Hospital arrived in Amman on 30th September very favorable attribute in a military 1970 and subsequently described their work in environment. Postoperatively there were very the Annals of the Royal College of Surgeons few undesirable affects reported although two (12), a summary of which is given below. patients suffered what was described as The use of ketamine ( or Ketalar as it was ‘severe vomiting ’ and an 11 year old child known as at the time ) was said to produce a became confused and experienced ‘ bad ‘form of dissociative anaesthesia ’ and also dreams ’. These complications were controlled provided ‘ a reasonable degree of analgesia ’ as by intravenous diazepam at a dose of 0.3-0.5 it was employed in the treatment of burns mg.kg- 1 as this had been described previously victims. Many of these casualties were young in the literature (13) and patients were generally children who understandably found the allowed to recover undisturbed. We now know procedures frightening and painful. A dose of that ketamine is the only anaesthetic agent 10 mg.kg- 1 of ketamine was administered available which has analgesic, hypnotic and intramuscularly and allowed a treatment time of amnesic effects and that it produces a state of 30-50 minutes before there were signs of ‘dissociative anaesthesia’ which results in discomfort (12). Intramuscular ketamine was electrophysiological dissociation between the also used for changing the burns dressing in limbic and cortical systems (14). children and was described as ‘ placing the Mass casualties in a war zone can lead to child in a trance-like state for about 20 a shortage of resources and surgeons were minutes ’ and this generally allowed the nurses keen to have an anaesthetic agent at their sufficient time to complete their duties. In disposal that they could administer total, 230 general anaesthetics were themselves. This would allow their administered by the field hospital team and anaesthetic colleagues to concentrate on ketamine was given 51 times to 22 different other, more important duties. A review in patients, being used as the sole anaesthetic 1970 by Phillips and colleagues (15) proposed agent on 33 occasions. Anaesthetists used that an ideal agent for the ‘surgeon- ketamine via the intramuscular route in the anaesthetist’ should be able to ‘ leave the majority of cases and a dose of 10 mg.kg- 1 was surgeon free to forget about the patient’s administered with occasional supplementations general condition and airway whilst he of 2-3 mg.kg- 1 intravenously. The absence of concentrates on the surgery ’. A rapid accessible veins in many of the burns patients recovery ‘ free from any special nursing made the intramuscular route invaluable and requirements ’ was also desirable. The Ketamine was well suited to administration in intravenous administration of ketamine this way. From a surgical point of view, ‘proved disappointing’ and was found to be occasional limb movement was noted to occur unreliable in producing anaesthesia. In their in a few patients, as was increased muscle view, ketamine provided such a short tone, although this did not seem to interfere analgesic time that patients ended up with surgery. A premedication of atropine was requiring constant attention instead of given to all patients receiving ketamine and this reducing the clinical input as was expected. appeared to reduce salivation (12). Ketamine was also noted to cause marked Regarding the other properties of ketamine, increases in blood pressure and casualties the advantage of patients retaining their experienced distressing hallucinations. ‘The Drug of War’ 147

Intramuscular ketamine in contrast was more work as part of the field surgical team reliable and patients were free from supporting counterinsurgency operations in hypertensive effects and hallucinatory Oman over a 32 month period in 1972 (16). phenomena, although a disadvantage was a Ketamine was used for the daily dressing prolonged recovery time. In the series of changes of a mine (blast) victim. This time there patients reviewed, ‘ the average time from the was a less favorable report as ketamine seemed last dose of the drug to accessibility (not to result in hallucinations and as a consequence defined) was 122 minutes ’, which was was abandoned and replaced by and deemed impractical in a military setting. They diazepam. The authors however reported that it concluded that ketamine could be had been useful in another patient requiring the recommended as the anaesthetic of choice in same treatment without complications. remote hospitals and to lone medical officer The literature is replete with anecdotal stations but that the indications for its use in case reports of ketamine use by anaesthetists larger and better staffed establishments were working in the various war zones during ‘less obvious’ . subsequent years and some of these are British Army anaesthetists reported their summarized in Table 1.

Table 1 – A summary of the use of Ketamine through Military Conflicts

Reference Conflict/ Study Main conclusions

(17) Yom Kippur War, 1975 Series of 51 patients. Ketamine caused a ‘catatonic schizophrenic-like stupor with loss of response to painful stimuli’ . Favorable effects on the cardiovascular system with an increase in cardiac output

(18) Afghanistan, 1983 Intra muscular Ketamine ‘adequate, safe, and easy to administer’ for patients requiring amputation to damaged limbs caused by the pencil mines ‘even in a race of people who were known to express their emotions so strongly’.

(22) Fighting on the Thai- Study involving 17 men and 1 woman injured by land Cambodian border, 1984 mines. Ketamine would have a substantial advantage over in patients suffering from shock or respiratory impairment and recommended for use at the scene of an accident or ‘whenever a difficult transfer to hospital is anticipated’.

(23). Study - Intrathecal As a single agent, ketamine did not produce motor block. ketamine to obtain The addition of adrenaline caused a complete motor surgical analgesia, 1984 block, which persisted for the same duration as surgical analgesia. Intrathecal ketamine could provide analgesia of sufficient intensity to allow surgery, without interfering with cardiovascular or respiratory function.

(1). Study: The effect of Ketamine ‘did not fulfill its apparent potential’. Adequate heavy papaveretum anaesthesia could not be guaranteed and there was a premedication and high incidence of side effects. Althesin induction on the incidence of emergence phenomena,1984. 148 J Royal Naval Medical Service 2009, Vol 95.3

Reference Conflict/ Study Main conclusions

(24) Case series: 206 Asian Administering ketamine as an infusion ‘was much more adult patients satisfactory’ than intermittent boluses. Less than 1 anaesthetised with mg.kg- 1 of ketamine was required for induction. The total ketamine under field dose administered was less than that required in a conditions, 1985 repeated bolus method.

(25) Study: Ketamine, 100 ASA I-II patients, aged between 16 and 50 years midazolam and underwent elective abdominal, thoracic or body surface vecuronium, delivered surgery. Concluded that this technique was advantageous intravenously to the when inhalational agents were either not available or patient via a syringe were not suitable and was ‘simple, effective (and) pump, 1988. versatile‘.

(27) Desert Anaesthesia The infusion rate of mixture described in [27] should Symposium, be reduced by one third after one hour and stopped 10 January 1991 minutes before the end of surgery. Extubationwas possible between 2 - 3 minutes and the patients were awake and able to correctly answer questions between 22 - 29 minutes.

(26) Gulf War, 1992. Modification of technique described in [27] to a rapid sequence induction using suxamethonium bromide. Description of two patients undergoing extensive debridement following trauma with anaesthetic times of 111 and 113 minutes. Ketamine produced hypotension in 10% on induction of anaesthesia.

(28) Kitgum Government Ketamine was a useful agent when an induction dose Hospital in North was administered and a maintenance infusion of 10- Uganda in 1999 20mcg.kg.min -1 maintained in combination with a premedication of diazepam, glycopyrrolate and a local anaesthetic block.

In 1982, anaesthetists serving with the to aid dressing change was becoming very British forces administered ketamine during popular, particularly due to the many burns the Falklands campaign. HMS Hermes, one of victims that resulted from modern warfare. the Royal Navy’s aircraft carriers, was tasked to On the 9th of June 1982, 150 patients treat casualties from the warships and were admitted to the hospital ship SS auxiliaries of the battle group and to provide a UGANDA as a result of the bombings of the routine hospital service for the smaller ships. landing ships Sir GALAHAD and Sir TRISTRAM EXOCET missile attacks on HMS SHEFFIELD (19). 10% of these casualties required surgery and HMS GLAMORGAN resulted in 11 sailors within 2 hours of admission and, as most of who required general anaesthesia but only one the anaesthetics given ashore had included patient with 60% burns and shrapnel injuries halothane, this was usually avoided as an presented problems (not stated) for the anaesthetic agent on board. This therefore serving anaesthetists (19). Techniques favored the use of ketamine which was involving droperidol and ketamine to facilitate employed in 50 cases, usually in combination wound debridement and burn dressing with diazepam. Interestingly on this occasion changes were employed. The use of ketamine emergence phenomena was not a problem. ‘The Drug of War’ 149

Whilst working in the field, British Army with ketamine and diazepam ‘proved to be of Anaesthetist Major MD Jowitt developed a tremendous value for a number of short cases technique using ketamine as his induction and not involving body cavities’. There were also analgesic agent, to cause ‘sleep and intensive favorable recovery times and the usual analgesia’ at the start of operations (20). He emergence phenomena were not reported. then used increments of ketamine to provide As discussed, ketamine has been additional analgesia, with diazepam being given associated with psychomatic effects leading to towards the end of the procedure. If the concerns that it may increase the risk of post- surgery was expected to last more than traumatic stress disorder (PTSD). Recently, an twenty minutes, casualties were induced with American Military study (29) addressed this by Ketamine and then had their anaesthetic investigating the prevalence of PTSD in maintained with Halothane and American troops with burns injuries returning Trichloroethylene via the Triservice Apparatus from conflict in the Middle East. They (21). Pethidine was also used to provide concluded that the use of ketamine may additional analgesia. Major Jowitt considered actually decrease the prevalence of PTSD in the ketamine / diazepam combination to be the combat-burned patient. Explanations for adequate for those short cases that did not this finding included the better pain involve body cavity surgery. He felt that there management received by those administered were several advantages of a total intravenous ketamine, the neuronal protection provided by technique that included ‘simplicity, a rapid ketamine, and antagonism of the N-methyl-D- onset of dissociative hypnosis, adequate aspartate (NMDA) receptor. analgesia, a relatively safe airway and an Ketamine has also been considered in a acceptable recovery’ . In view of the recent review to be an ideal drug for use in psychological side effects of ketamine that had many pre-hospital situations (30) with been described previously, patients were experience again suggesting that it is ‘safe, interviewed postoperatively concentrating on effective, and may be more appropriate than whether they had had nightmares or drugs currently used by pre-hospital providers’ . unpleasant dreams, but no adverse comments This will be of interest to military anaesthetists were recorded. In this instance, ketamine was who are involved in care of casualties forward considered as good as thiopentone as an of the traditional Role 3 field hospital. Despite induction agent. negative comments, ketamine has been a very Other reports from the Falklands Campaign useful drug since its discovery and licensing in (3) described anaesthesia being induced the early 1970s and is still used by many intravenously with either 2 mg.kg -1 ketamine or military anaesthetists today. Recently, a 'sleep dose' of sodium thiopentone and a controversies surrounding the use of ketamine dose of 300mcg of atropine was usually in head injured patients have been re- administered. Ketamine received favorable addressed and it has also been suggested that reports as even though it did not always as a very rational choice for rapid sequence increase pulse and blood pressure in the induction in haemodynamically compromised severely shocked patient, it rarely caused patients (31). We await the reports of ongoing cardiovascular depression. Slow injections did and future conflicts to see if ketamine not result in respiratory depression and there continues to serve well as the anaesthetists was a rapid onset of hypnosis and ‘intense ‘drug of war’. analgesia’. Interestingly, it was commented that ‘the initial and frequently turbulent period References of anaesthesia between intravenous induction 1. Jago RH, Restall J, Thompson MC. Ketamine and and the volatile agents attaining their minimal military anaesthesia. The effect of heavy alveolar concentrations (MAC) could be papaveretum premedication and Althesin covered with the use of ketamine’. In contrast induction on the incidence of emergence to other authors, the dissociative anaesthesia phenomena . Anaesthesia 1984; 39: 925-927 150 J Royal Naval Medical Service 2009, Vol 95.3

2. Restall J, Tully AM, Ward PJ et al. Total 297: 1044-47 intravenous anaesthesia for military surgery. A 19. Bull PT, Merrill SB, Moody RA et al. Anaesthesia technique using ketamine, midazolam and during the Falklands campaign. The experience vecuronium. Anaesthesia 1988; 43: 46-49 of the Royal Navy . Anaesthesia 1983; 38: 770-75 3. Jowitt MD. Anaesthesia ashore in the Falklands . 20. Jowitt MD, Knight RJ. Anaesthesia during the Ann Roy Coll Surg 1984; 66: 197-200 Falklands campaign. The land battles . 4. Pai A, Heining M. Ketamine . Contin Educ Anaesthesia 1983; 38: 776-83 Anaesth, Crit Care Pain 2007; 7: 59-63 21. Houghton I. The Triservice anaesthetic apparatus . 5. Chen G. Evaluation of phencyclidine-type cataleptic Anaesthesia 1981; 36: 1094-1108 activity . Arch Int Pharmacod T 1965; 157: 193-201 22. Bion JF. Infusion analgesia for acute war injuries . 6. Chen G, Ensorc R, Bohner B . The Anaesthesia 1984; 39: 560-64 neuropharmacology of 2-(omicron-chlorophenyl)- 23. Bion JF. Intrathecal ketamine for war surgery. 2-methylaminocyclohexanone hydrochloride. J A preliminary study under field conditions. Pharmacol Exp Ther 1966; 152: 332-9. Anaesthesia, 1984: 39; 1023-28 7. McCarthy DA, Chen G, Kaump DH, et al. General 24. Bion J. Ketamine . Anaesthesia 1985; 40: 306 anesthetic and other pharmacological properties of 25. Restall J, Tully AM, Ward PJ et al. Total 2-(0-chlorophenyl)-2-methylamino cyclohexanone intravenous anaesthesia for military surgery. A HCl (CI-581). J New Drugs 1965; 5: 21-33 technique using Ketamine, Midazolam and 8. Dundee JW. Twenty-five years of ketamine . A Vecuronium . Anaesthesia. 1988:43; 46-49 report of an international meeting. Anaesthesia 26. Ward PJ, Restall J. Ketamine, midazolam and 1990; 45: 159-160 vecuronium infusion . Anaesthesia 1991; 46: 598 9. Corssen G, Domino EF. Dissociative anesthesia: 27. Restall J, Tully AM, Ward PJ et al. A Reply . Further pharmacologic studies and first clinical Anaesthesia 1989: 44; 534 experience with the phencyclidine derivative CI- 28. F.G. Bonanno. Ketamine in war/tropical surgery (a 581. Anesth Analg 1966; 45: 29–40. final tribute to the racemic mixture). Injury 2002; 10. Coppel DL, Bovill JG, Dundee JW. The Taming of 33: 323–27 Ketamine. Anaesthesia 1973; 28: 293-296 29. McGhee LL, Maani CV, Garza TH, et al. The 11. Coppel DL. Ketamine Anaesthesia . BMJ 1971; Correlation Between Ketamine and 3: 46 Posttraumatic Stress Disorder in Burned Service 12. Boyd NA, Barry NA, Davies AK. British Surgical Aid Members. J Trauma. 2008; 64: S195–S199. to Jordan . Ann Roy Coll Surg 1971; 49: 291-309 30. Svenson JE, Abernathy MK. Ketamine for 13. Dundee JW, Bovill J, Knox JWD, et al. Ketamine prehospital use: new look at an old drug. Am J as an induction agent in anaesthetics. Lancet Emerg Med 2007; 25: 977-980 1970; 1: 1370-1 31. Morris C, Perris A, Klein J et al. Anaesthesia in 14. Craven R. Ketamine. Anaesthesia 2007; 62 (S1): haemodynamically compromised emergency 48–53 patients: does ketamine represent the best 15. Phillips LA, Seruvatu SG, Rika PN et al. choice of induction agent? Anaesthesia 2009; Anaesthesia for the surgeon-anaesthetist in 64: 532–539 difficult situations. Anaesthesia 1970; 25: 36-45 16. Melsom MA, Farrar MD, Volkers RC. Battle Acknowledgements Casualties. Annals of the Royal College of The author would like to thank Colonel Peter Surgeons of England 1975; 56: 289-303 Mahoney, RAMC for his advice on the preparation of 17. Davidson JT, S Cotev S. Anaesthesia in the Yom the manuscript, Dr Michael Moneypenny for his help Kippur War. Annals of the Royal College of with proof reading and Group Captain Neil McGuire, Surgeons of England 1975; 56: 304-312 Royal Air Force for assistance with security 18. Blatchley C. Working in Afghanistan . BMJ 1983; clearance.

Surgeon Lieutenant Commander S J Mercer Royal Navy

Specialist Registrar in Anaesthesia and Critical Care, Defence Postgraduate Medical Deanery