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Treatment of the Patient With Severe Tetanus
Treatment of the Patient With Severe Tetanus NORMAN A. CHRISTENSEN, M.D.
Special attention to the treatment of tetanus is warranted not because the disease is common in the United States9 ,11 or at the Mayo Clinic4 -it is not- but because it continues to occur, Important, and somewhat surprising, has been the observation that the annual number of tetanus patients admitted to the Mayo Clinic and affiliated hospitals has changed little over the years, We continue to see an average of two to four patients a year. Not unlike patients in other reported series generally,2 most of the 119 patients seen here have had the severe form of the disease. It is this severe form that continues to provide a real therapeutic challenge to the medical profession, Fortunately, recent advances in medical technology as well as greater knowledge of tetanus and its complexities have helped place physicians attending these patients in a more positive position,!' 14-16 Though a specific dependable cure is still lacking, immensely improved symptomatic and supportive treatment, the cornerstone of therapy, provides new hope for victims of this disease. Regardless of severity, the course of clinical tetanus does seem to be self-limited, Consequently, if the patient's vital functions can be adequately maintained during the period of detoxication, he can be expected to recover physically, mentally, and emotionally."
PRINCIPLES OF TREATMENT The sudden, sporadic, unexpected nature of tetanus makes it imperative that physicians responsible for the care of the afflicted patient remain knowledgeable regarding its unique features and ready to implement promptly a well-conceived plan of treatment. The formation of a tetanus team at our institution several years ago has been useful in this respect. Before our plan of treatment is described, a summary of the concepts on which this plan is based will be presented for the benefit of physicians not familiar with this disease. The disease tetanus goes through essentially three stages, each deserving therapeutic attention. The initial stage - the wound-bacterial or Surgical Clinics of North America- VoL 49, No.5, October, 1969
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focus-of-infection stage-is characterized by a tetanal wound, anaerobic in nature and containing relatively noninvasive yet potent toxin-producing Clostridium tetani organisms. In this stage the disease obviously is readily treatable with appropriate wound care. But if treatment is inadequate in the first stage, then the second stage develops. This stage - the tetanotoxemic stage - is characterized by liberation and spread of the soluble, readily diffusible neurotoxin into the body fluids and eventually into the general circulation and also along the regional nerve trunks. In this stage, too, the disease is considered readily treatable except possibly when toxin has spread to involve the nerve trunks. Presumably tetanotoxin dissolved in the body fluids and as yet uncombined with nerve tissue is quickly neutralized by an equivalent dose of tetanus antitoxin, if such is present in the body fluids as the result of previous active immunization with tetanus toxoid or of passive immunization with serum tetanus antitoxin (preferably homologous) administered at the time or soon after the tetanal infection was acquired. The initial symptom of clinical tetanus signals the onset of the final, or neurologic, stage of the disease. This critical stage is reached when the disease in the previous two stages, particularly in the tetanotoxemic stage, has been treated inadquately. In the neurologic stage, better known as "clinical tetanus," the toxin has combined with certain neuromotor cells within the central nervous system. These cells have a unique affinity for the tetanotoxin and no amount of antitoxin seems to have any neutralizing effect on toxin combined with them. Furthermore, no agent or method of treatment yet available has exhibited any beneficial effect on the rate of detoxication. Nevertheless, detoxication does occur in a seemingly orderly fashion to completeness if allowed sufficient time. Another concept is that the severity of clinical tetanus is directly related to the amount of toxin fixed within the central nervous system. Important therapeutically in this disease, in which the dose of toxin necessary to produce tetanus is small, is the fact that the difference between the amount that produces mild or moderately severe disease and the amount that produces severe, fulminating tetanus must be minute indeed. Presumably the duration of clinical tetanus (neurologic stage), too, is related to the amount of toxin combined with cells in the central nervous system. When the dose is small and the disease mild or moderately severe, detoxication and recovery occur within about 2 to 6 weeks. If the dose is larger and produces severe symptoms, detoxication and recovery require 6 to 12 weeks or more. Though severity and duration of symptoms vary, the course of clinical tetanus is characteristic. Symptoms reach maximal severity usually within the first week (build-up phase), tend to stabilize and remain essentially the same for another week or so (plateau phase) regardless of the intensity of treatment, and then slowly subside (recovery phase). Early in clinical tetanus it is impossible to predict the course and
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eventual severity of the disease in a given patient. Stated conversely, only in retrospect, after the patient has passed through the build-up phase, is it possible to judge whether he has mild, moderately severe, or severe fulminating disease. Another important concept is that tetanus has to be diagnosed on clinical grounds. Laboratory studies aid in a negative way - they help rule out other disease. As yet, there is no method to determine the presence or amount of toxin fixed within the central nervous system, and no readily available method to determine the titer or even the presence of circulating toxin (or antitoxin) in body fluids. A final concept is that immunity to tetanus is not acquired from having had the disease. Presumably the amount of toxin that produces even severe tetanus is so small that it fails to activate the body's immunologic processes. 7
PLAN OF TREATMENT FOR SEVERE TET ANUS* The plan of treatment to be presented has evolved during the past 20 years and is the one currently used by the Mayo Clinic Tetanus Team. t All patients with a diagnosis of tetanus are admitted directly to the hospital emergency service, where they are seen immediately by the director or assistant director of the team. If he concurs in the diagnosis, the treatment plan is implemented. In addition to the administration of sedatives such as diazepam (Valium) and barbiturates, analgesic drugs such as propoxyphene (Darvon), codeine, and meperidine (Demerol), and other treatment to provide comfort for the patient, the following procedures are used as emergency measures.
Administration of Tetanus Antitoxin As determined by the nature of the suspected focus of infection and by the severity and rate of progression of the disease, 1000 to 5000 units of human tetanus antitoxin (tetanus human hyperimmune globulin) is given intramuscularly. To promote rapid absorption and dissemination of the antitoxin and, more specifically, its neutralization of any yet uncombined toxin in the body fluids, the dose of antitoxin is divided and injected into multiple sites, usually the upper part of the arms and the buttocks. If the suspected focus is in an extremity, at least one of these injections is given into that extremity. All injected sites are then massaged and heat is applied. Since experimental work with animals has demonstrated that several "minimal lethal doses" of tetanotoxin can accumulate within the immediate area of the focus of tetanal infection, surgical manipulation of the focus is delayed an hour or so to permit, *All dosages of medications as well as all procedures given in this article are for adults and must be adjusted for children and infants. Dosages are those customarily prescribed unless noted otherwise. tThis team, of which the author is director, consists of three internists, a general surgeon, an orthopedic surgeon, an anesthesiologist, a neurologist, a physiatrist, a microbiologist, a clinical pathologist, and a physiologist.
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hopefully, the development of protective titers of antitoxin that will ward off any toxin that may flood the circulation. Administration of Antibiotics In addition to surgical care of wounds, antibiotic therapy is given supplementally to help eliminate any tetanal infection. Penicillin'~ is the agent of choice against C. tetani and is useful too against other grampositive organisms, which frequently are present. Since the tetanal infection is symbiotic and frequently includes gram-negative organisms as well, it is important to provide broad coverage. Kanamycin, streptomycin, or a similar agent effective against gram-negative bacteria is given in combination with penicillin. When penicillin is used, as much as 1,000,000 units of the sodium or potassium salt is given intramuscularly every 4 hours, or 10,000,000 units is given by continuous intravenous drip during the first day. Thereafter, 1,000,000 units of procaine penicillin is given intramuscularly daily. Unless contraindicated, and with the usual precautions, 0.5 gm of kanamycin (or streptomycin) is given intramuscularly two or three times a day for the initial 4 to 7 days and then its use is generally discontinued. Currently, antibiotic therapy is continued prophylactically essentially as long as the patient uses a cuffed tracheostomy tube. During this critical period, other antibiotics can be used in combination with penicillin or instead of it, in accordance with the results of tracheobronchial and other cultures and the status of the patient. Troublesome organisms such as staphylococci, Klebsiella, Aerobacter aerogenes, and Pseudomonas organisms emerge frequently after the first week, and their presence requires specific antibiotic treatment if they are thought to be causing significant infection. Care of Foci of Infection and Use of Other Surgical Procedures During the delay of 1 to 2 hours required for absorption of antitoxin, essential laboratory tests are performed and the appropriate members of the team, including the nursing staff of the respiratory intensive-care unit, are notified of the patient's admission. Thereafter the team surgeon removes any foci of infection and performs any other indicated surgical procedures. Since in the patient with severe tetanus these procedures are often major and multiple, he is usually transferred to the general operating room and given general anesthesia. Intravenously administered sodium thiopental (Pentothal) or other customary anesthetic agents that are essentially nonirritating to the respiratory system are used. When indicated, curare is given supplementally to control tetanospasms and provide suitable muscle relaxation. Tracheostomy is performed routinely in the patients with severe tetanus and, like other sterile procedures, it precedes surgical treatment of infected foci. Because of the vital nature and duration of use of the *Tetracycline is currently the drug used in patients sensitive to penicillin.
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tracheal opening, a double-cuffed tracheostomy tube is used by the team surgeon. The double cuffs help provide a closed system so that pressure may be alternated every hour or so to prevent complicating focal erosion, necrosis, hemorrhage, perforation, or fistula formation. Because of inability to swallow, every patient with severe tetanus requires tube feeding during the critical first 3 to 4 weeks of therapy. A small nasogastric plastic catheter passed so that the tip preferably lies within the jejunum functions well in most patients. However, an alternate method, namely gastrostomy, is preferable in some cases and, when indicated, can be used at this time. It is particularly helpful in small children and infants in whom the risk of complicating pressure necrosis in the region of the tracheostomy tube is increased with the use of a nasogastric tube. When indicated, gastrostomy is performed by making a small upper midline incision in the abdominal wall and then passing a double-lumen tube through a I-cm opening made in the midportion of the anterior wall of the stomach. The longer tube is advanced until its tip lies within the proximal part of the jejunum and the shorter tube is positioned so that its tip lies within the antrum of the stomach. After inversion and closure of the small opening in the stomach wall around the double-lumen tube with two rows of interrupted sutures, the omentum is interposed between the gastric wall and the anterior parietal peritoneum. The tube is brought out through a stab incision in the abdominal wall where it is held in position by skin sutures. The primary midline incision is closed in a routine manner. The intrajejunal tube will serve as the primary route for tube feedings, as will be discussed later, and the intragastric tube will aid in monitoring gastrointestinal function and will permit decompression of the stomach whenever indicated. Occasionally postoperative ileus occurs, but it is usually transitory and responds to general measures within a day or two. Finally, all foci of infection are surgically treated. Cleansing and debridement are considered adequate for superficial wounds, but careful excision is preferable for the more deeply infected wounds even though they may appear to be healing. Radical treatment of the tetanal wound seems justified in the patient with severe disease. Such treatment may require amputation of a digit or even an extremity to eliminate an extensive, seriously infected wound. Delayed wound closure is required whenever there still exists a question of infectivity. To further help provide an aerobic environment, the loosely placed dressings can be kept moistened for a few days with an oxidizing agent. The wound can be closed or grafted with skin, if indicated, when infection has been surely eliminated and the patient's condition permits. While the patient is in the operating room the dental surgeon extracts any badly infected teeth. Though infected teeth have been blamed for tetanus, another reason for extraction is to help prevent infection of the respiratory tract. Provision of a dependable intravenous route is essential in the treatment plan for these severely ill patients who will require intravenous curarization for approximately 2 to 3 weeks. While the patient is in the operating room and usually prior to the above surgical procedures, the
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anesthesiologist introduces an indwelling, large-bore catheter into one of the major veins of the arm. The catheter is generally passed proximally until its tip lies within the superior vena cava. A three-way cock attached to the proximal end of the catheter provides a system for intravenous administration of curare and other medications, and initially a primary (later secondary) route for nutrition and hydration. Furthermore, this system permits the emergency sampling of venous blood when indicated and permits monitoring of the central venous pressure. Hypotension and even shock are not unusual in these desperately ill patients. 5 • 6 Before the patient is removed from the operating room an indwelling Foley catheter is placed in the bladder to permit free excretion of urine and to aid in the monitoring of renal function in the curarized patient.
ROLE OF THE RESPIRATORY INTENSIVE-CARE UNIT IN THE TREATMENT OF SEVERE TETANUS From the operating room the patient is transferred to the respiratory intensive-care unit. This unit is staffed with personnel trained and oriented in the care of patients with respiratory problems, who obviously include patients with severe tetanus. The unit is equipped with modern facilities to help meet any eventuality, and within its confines is located a special laboratory equipped to do special tests that help monitor the patient's respiratory and other vital functions. The team anesthesiologist heads ,this unit and supervises the pulmonary ventilation and curarization of the patient.
Respiration and Ventilation A fully automated respirator is attached to the patient's tracheostomy tube and the respirator is set to deliver properly heated, humidified air containing 40% oxygen. Oxygen concentration, volume, cycling pressure, and respiratory rate are adjusted from time to time as indicated to maintain adequate alveolar ventilation. The automated sigh mechanism of the respirator is set to produce four to six deep breaths every 10 to 15 minutes. In addition, a device to produce an artificial cough can be used three to four times a day, when warranted, to keep the airway clean and lung compliance normal. During the critical period of the illness, and until the tracheal stoma has been closed (usually 4 to 5 weeks later), continuous attention and meticulous tracheostomy toilet are required of the nursing staff. At first, secretions are troublesome and require frequent removal. Clean technique is followed in the removal of secretions in the mouth and hypopharynx. Sterile technique must be observed in the removal of secretions from the tracheobronchial system. The aim always is to maintain a patent airway and avoid complicating infection. Other procedures that help maintain adequate respiration include hourly repositioning of the patient and passive respiratory physical
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therapy given two or three times a day. Mechanical beds help in this regard. Before each change of position and alteration of pressure within the balloon cuffs of the tracheostomy tube, secretions that accumulate above and below this tube should be removed. The tracheostomy tube should never be detached from the respirator longer than 20 seconds, to avoid the risk of dangerous hypoxia. Initially, arterial blood gases and pH are determined at least every 2 or 3 days and then as indicated during the period of curarization and controlled respiration. Other studies used to monitor the respiratory system as well as alveolar ventilation include x-ray examination of the chest (with a portable machine) and the taking of tracheobronchial cultures. These cultures are obtained at least every 3 to 4 days during the critical period of the disease. Complicating bronchial obstruction, with resultant pulmonary atelectasis due to plugs of mucus or to aspirated material, and tracheobronchial pneumonia occur frequently in these patients and must be recognized early and treated promptly. At times, bronchoscopy is required to remove the bronchial obstruction. Antibiotic therapy is adjusted when tracheobronchial cultures and the condition of the patient dictate.
Curarization Since no single sedative or combination of sedatives will control the tetanospasms safely and satisfactorily in severe tetanus, curarization is currently preferred for this purpose. Curarization is started on admission of the patient to the intensive-care unit and is continued until he has entered the recovery phase of the illness approximately 3 weeks later. During this period of induced respiratory paralysis, controlled ventilation is required. Currently we give tubocurarine intravenously via the catheter system previously described. A bottle of 500 ml of 5% glucose in water containing 1 mg of curare per milliliter is prepared and administered with the aid of a pediatric setup. This measuring device permits the nurse to give a predetermined dose of the drug whenever generalized tetanospasms recur and interfere with the ventilation and comfort of the patient. At first, tubocurarine must be given about every 30 to 60 minutes. Later, as symptoms subside, the interval gradually becomes longer and finally use of the drug can be discontinued. Once the patient is curarized, his requirement for sedation is usually greatly reduced. Currently, diazepam is used in the customary dosage according to the patient's needs, the aim being to allay apprehension and maintain a restful state from which he can be easily aroused. Striking yet fortunate it is that after recovery the patient has a relative amnesia for the period of curarization. Nevertheless, since he is conscious, attending personnel should always be discreet in conversation and encouraging in their remarks in the presence of the patient.
Nutrition and Hydration Until tube feedings can be instituted, the intravenous system serves as the primary route for administration of fluids, nutrients, and electro-
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lytes. Unless contraindicated, half-strength physiologic saline solution containing 5 to 10% glucose and fortified with vitamins is given to meet the patient's requirements. A urine output of 1200 ml or more per day is desired. Because of the hypermetabolic state associated with tetanus and the frequently increased perspiration, the patient often needs additional calories and extra fluids. If he is elderly, especially if he has cardiorenal disease, adjustments in electrolyte administration may be necessary. Early use of a gastric tube, whether a nasogastric or a gastrostomy tube, provides the method of choice for handling nutrition and hydration during the critical period of treatment. Administration of clear liquids can be started on the same day that the nasogastric tube is positioned, or usually by the second or third day if gastrostomy is performed. Fifty milliliters of liquid are given at hourly intervals. Tube feedings are substituted for clear liquids after the first day. Unless problems develop, the amount can be increased progressively to 100 to 200 ml in adults. Feedings are started at 6 A.M. and continued every 1 to 2 hours until 10 P.M. Preceding each feeding, the nurse or aide checks the tube system with a syringe to ensure that the system is functioning properly. In addition, she makes sure the tracheal cuff system is properly inflated and keeps the head of the patient slightly elevated during and immediately after tube feedings. These feedings are given with the aid of a special pump added to the system. The content of the tube feedings is carefully formulated with the help of the dietitian and is tailored from time to time to meet the patient's specific needs. Interval blood studies of electrolytes, urea, and, when indicated, creatinine help in monitoring this aspect of the problem. A "flow sheet" for pertinent information is started on admission and is kept current throughout the critical period of the illness. This record shows the status of the patient at any given time and helps one to recognize developing complications so that corrective measures may be applied promptly and, hopefully, before the complications have become fully developed. Of concern has been the frequent development of anemia during the period of intensive therapy, usually within the first 3 weeks. Though the cause may be apparent in some patients and iron medication and specific measures are helpful in those with anemia apparently due to blood loss, a number of patients have had unexplained anemia that required infusions of whole blood or packed red blood cells. Fortunately, it usually responds quickly and without further treatment once the patient has entered the recovery phase, has been weaned from the respirator, and is taking a regular diet. Miscellaneous Measures Consistent and meticulous general nursing care is as important as special attention to vital functions. This is particularly true while the patient is curarized and requires controlled respiration. Eyedrops instilled at regular intervals and, when indicated, eyeshields are used to keep the eyes moist and to protect them against corneal ulceration and
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infection. Footboards are used to prevent contractures of the calf muscles of the legs. Proper positioning of the extremities and passive exercises are important in the paralyzed patient. Good oral hygiene is practiced, and special attention is given to the skin, particularly the pressure points.
RECOVERY PHASE AND REHABILITATION THERAPY The patient with severe tetanus can be expected to enter the recovery phase after approximately 12 to 14 days. This phase is evidenced by a decreasing need for curare and sedation and by an increasing alertness and subsidence in symptoms. Since, in our experience, symptoms have not recurred after unequivocal improvement, discontinuance of the use of the respirator is started as soon as it is evident that the patient can be controlled without curarization. Initially the change is from controlled to assisted ventilation, and then from assisted to self-ventilation. To accomplish the latter step, assisted ventilation is replaced by another system that delivers a 40% oxygen mist to the region of the orifice of the tracheostomy tube, and the patient is encouraged to breathe on his own for 3 to 5 minutes two or three times the first day. The duration and frequency of these periods are increased progressively as the patient's condition permits. When completely weaned from the ventilator, the cuffed tracheostomy tube is replaced with a smaller, uncuffed, corked tracheostomy tube which remains until the functions of respiration and digestion are safely reestablished. During this period when the patient is able to swallow, oral feedings consisting of clear liquids are started. This is followed by the use of a full liquid diet, then soft foods, and finally a full diet as tolerated. Once all this has been accomplished, both the tracheostomy tube and the gastrostomy tube can be removed simply and without suturing. When curarization has been discontinued, both the intravenous catheter and the one in the bladder are removed and antibiotic therapy is discontinued unless infection is present. Special care of wounds, such as grafting, can be given at this time, if indicated. J The team's physiatrist institutes and supervises a progressive plan of physical therapy and rehabilitation, at first in the hospital room and then, when the patient's condition permits, in the section of physical medicine. Usually by the fourth week the patient's general condition has improved so that he can be transferred from the intensive-care unit to another room in the hospital, where he receives required nursing care and continues his rehabilitation program. Within the next week or two he can usually be dismissed from the hosptial. During this final period, active immunization with tetanus toxoid is started and arrangements are made for him to complete the basic series of injections in the prescribed manner. B,13 A wallet-sized medical identification card is provided, which serves not only as a record but as a reminder for him to complete this last, yet important step in the plan of treatment.
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SUMMARY Tetanus, though rare, continues to occur sporadically and unexpectedly in most areas of the United States. When it is severe, few diseases are more challenging therapeutically. The detailed plan of treatment presented is based on more than 20 years of experience with this disease and provides what is considered the best plan of therapy currently available. The plan is offered as a guide both to the physician in this country who has little experience with this disease but who suddenly finds himself responsible for the care of one of these desperately ill patients and to physicians throughout the world, especially those in countries where tetanus is still common. Admittedly, to be effective, treatment for the severely ill patient with tetanus is expensive and timeconsuming, but this is the price that must be paid when the life of one of these patients is at stake. The plan of treatment presented utilizes the environment of a respiratory intensive-care unit and, when indicated, includes the use of a tracheostomy, curarization, and artificial respiration. Based on our experience and that of others, this plan can be expected to reduce significantly the notoriously high mortality rate now associated with severe tetanus. Though not the final answer to treatment, hopefully further refinements of the plan presented and further advances in technology and knowledge of the disease will help to find that answer eventually. Although Pascale and colleagues12 in 1964 reported optimistically on the use of hyperbaric oxygen in the treatment of nine patients with clinical tetanus, subsequent studies either in marl° or in animals3 • 15 have failed to substantiate these significant beneficial effects either on mortality or on morbidity. In the meantime, a greater effort should be made to attain the even more important goal of world-wide prevention of this disease by universal active immunization with tetanus toxoid.
REFERENCES 1. Adams, E. B., Holloway, R., Thambiran, A. K., and Desai, S. D.: Usefulness of intermittent positive-pressure respiration in the treatment of tetanus. Lancet 2: 1176-1180 (Nov. 26) 1966. 2. Bytchenko, B.: Geographic distribution of tetanus in the world, 1951-60: A review of the problem. Bull WHO 34:71-104, 1966. 3. Christensen, N. A., Ackerman, E., Weed, L. A., Gatewood, L. C., and Drube, C.: Hyperbaric oxygen therapy in mice injected with tetanus toxin. JAMA 200:129-131 (April 10) 1967. 4. Christensen, N. A., and Thurber, D. L.: Clinical experience with tetanus: 91 cases. Proc Staff Meet Mayo Clin 32:146-158 (April 3) 1957. 5. Christensen, N. A., and Thurber, D. L.: Current treatment of clinical tetanus. Mod Treatm 5:729-757 (July) 1968. 6. Clifton, B.: Hypotension associated with tetanus. Lancet 1 :785-788 (April 11) 1964. 7. Cooke, Jean V., and Jones, F. G.: The duration of passive tetanus immunity and its effect on active immunization with tetanus toxoid. JAMA 121 :1201-1209 (April 10) 1943. 8. Guide Lines for the Medical Profession Regarding the Prevention of Tetanus. In Eckmann, L.: Principles on Tetanus. (Proceedings of the International Conference on Tetanus, Bern, July 15-19, 1966.) Bern, Hans Huber, 1967, pp. 576-577.
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9. Heath, C. W., Jr., Zusman, J., and Sherman, Ida L.: Tetanus in the United States, 19501960. Amer J Public Health 54:769-779 (May) 1964. 10. Milledge, J. S.: Hyperbaric oxygen therapy in tetanus. JAMA 203:875-876 (March 4) 1968. 11. National Communicable Disease Center: Morbidity and Mortality: Weekly Report. (Annual Supplement, Summary 1967, No. 53.) United States Department of Health, Education and Welfare, Public Health Service, November, 1968, vol. 16, pp. 20; 53-54. 12. Pascale, L. R., Wallyn, R. J., Goldfein, S., and Gumbiner, S. H.: Treatment of tetanus by hyperbaric oxygenation. JAMA189:408-410 (Aug. 10) 1964. 13. Peebles, T. C., Levine, L., Eldred, Mary C., and Edsall, G.: Tetanus-toxoid emergency boosters: A reappraisal. New Eng J Med 280:575-581 (March 13) 1969. 14. Smythe, P. M.: The treatment of tetanus neonatorum on experimental and clinical level. In Eckmann, L.: Principles on Tetanus. (Proceedings of the International Conference on Tetanus, Bern, July 15-19, 1966.) Bern, Hans Huber, 1967, pp. 495-500. 15. Stirnemann, H.: Treatment of tetanus: A 50-year review. Minn Med 52:15-22 (Jan.) 1969. 16. Wright, R., Sykes, M. K., Jackson, B. G., Mann, N. M., and Adams, E. B.: Intermittent positive-pressure respiration in tetanus neonatorum. Lancet 2:678-680 (Sept. 23) 1961.
Statement afOwnership, Management, and Circulation (Act of October 23, 1962; Section 4369, Title 39, United States Code) 1. Date of filing: September 15, 1969.
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Special attention to the treatment of tetanus is warranted not because the disease is common in the United States9 ,11 or at the Mayo Clinic4 -it is not- but because it continues to occur, Important, and somewhat surprising, has been the observation that the annual number of tetanus patients admitted to the Mayo Clinic and affiliated hospitals has changed little over the years, We continue to see an average of two to four patients a year. Not unlike patients in other reported series generally,2 most of the 119 patients seen here have had the severe form of the disease. It is this severe form that continues to provide a real therapeutic challenge to the medical profession, Fortunately, recent advances in medical technology as well as greater knowledge of tetanus and its complexities have helped place physicians attending these patients in a more positive position,!' 14-16 Though a specific dependable cure is still lacking, immensely improved symptomatic and supportive treatment, the cornerstone of therapy, provides new hope for victims of this disease. Regardless of severity, the course of clinical tetanus does seem to be self-limited, Consequently, if the patient's vital functions can be adequately maintained during the period of detoxication, he can be expected to recover physically, mentally, and emotionally."
PRINCIPLES OF TREATMENT The sudden, sporadic, unexpected nature of tetanus makes it imperative that physicians responsible for the care of the afflicted patient remain knowledgeable regarding its unique features and ready to implement promptly a well-conceived plan of treatment. The formation of a tetanus team at our institution several years ago has been useful in this respect. Before our plan of treatment is described, a summary of the concepts on which this plan is based will be presented for the benefit of physicians not familiar with this disease. The disease tetanus goes through essentially three stages, each deserving therapeutic attention. The initial stage - the wound-bacterial or Surgical Clinics of North America- VoL 49, No.5, October, 1969
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focus-of-infection stage-is characterized by a tetanal wound, anaerobic in nature and containing relatively noninvasive yet potent toxin-producing Clostridium tetani organisms. In this stage the disease obviously is readily treatable with appropriate wound care. But if treatment is inadequate in the first stage, then the second stage develops. This stage - the tetanotoxemic stage - is characterized by liberation and spread of the soluble, readily diffusible neurotoxin into the body fluids and eventually into the general circulation and also along the regional nerve trunks. In this stage, too, the disease is considered readily treatable except possibly when toxin has spread to involve the nerve trunks. Presumably tetanotoxin dissolved in the body fluids and as yet uncombined with nerve tissue is quickly neutralized by an equivalent dose of tetanus antitoxin, if such is present in the body fluids as the result of previous active immunization with tetanus toxoid or of passive immunization with serum tetanus antitoxin (preferably homologous) administered at the time or soon after the tetanal infection was acquired. The initial symptom of clinical tetanus signals the onset of the final, or neurologic, stage of the disease. This critical stage is reached when the disease in the previous two stages, particularly in the tetanotoxemic stage, has been treated inadquately. In the neurologic stage, better known as "clinical tetanus," the toxin has combined with certain neuromotor cells within the central nervous system. These cells have a unique affinity for the tetanotoxin and no amount of antitoxin seems to have any neutralizing effect on toxin combined with them. Furthermore, no agent or method of treatment yet available has exhibited any beneficial effect on the rate of detoxication. Nevertheless, detoxication does occur in a seemingly orderly fashion to completeness if allowed sufficient time. Another concept is that the severity of clinical tetanus is directly related to the amount of toxin fixed within the central nervous system. Important therapeutically in this disease, in which the dose of toxin necessary to produce tetanus is small, is the fact that the difference between the amount that produces mild or moderately severe disease and the amount that produces severe, fulminating tetanus must be minute indeed. Presumably the duration of clinical tetanus (neurologic stage), too, is related to the amount of toxin combined with cells in the central nervous system. When the dose is small and the disease mild or moderately severe, detoxication and recovery occur within about 2 to 6 weeks. If the dose is larger and produces severe symptoms, detoxication and recovery require 6 to 12 weeks or more. Though severity and duration of symptoms vary, the course of clinical tetanus is characteristic. Symptoms reach maximal severity usually within the first week (build-up phase), tend to stabilize and remain essentially the same for another week or so (plateau phase) regardless of the intensity of treatment, and then slowly subside (recovery phase). Early in clinical tetanus it is impossible to predict the course and
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eventual severity of the disease in a given patient. Stated conversely, only in retrospect, after the patient has passed through the build-up phase, is it possible to judge whether he has mild, moderately severe, or severe fulminating disease. Another important concept is that tetanus has to be diagnosed on clinical grounds. Laboratory studies aid in a negative way - they help rule out other disease. As yet, there is no method to determine the presence or amount of toxin fixed within the central nervous system, and no readily available method to determine the titer or even the presence of circulating toxin (or antitoxin) in body fluids. A final concept is that immunity to tetanus is not acquired from having had the disease. Presumably the amount of toxin that produces even severe tetanus is so small that it fails to activate the body's immunologic processes. 7
PLAN OF TREATMENT FOR SEVERE TET ANUS* The plan of treatment to be presented has evolved during the past 20 years and is the one currently used by the Mayo Clinic Tetanus Team. t All patients with a diagnosis of tetanus are admitted directly to the hospital emergency service, where they are seen immediately by the director or assistant director of the team. If he concurs in the diagnosis, the treatment plan is implemented. In addition to the administration of sedatives such as diazepam (Valium) and barbiturates, analgesic drugs such as propoxyphene (Darvon), codeine, and meperidine (Demerol), and other treatment to provide comfort for the patient, the following procedures are used as emergency measures.
Administration of Tetanus Antitoxin As determined by the nature of the suspected focus of infection and by the severity and rate of progression of the disease, 1000 to 5000 units of human tetanus antitoxin (tetanus human hyperimmune globulin) is given intramuscularly. To promote rapid absorption and dissemination of the antitoxin and, more specifically, its neutralization of any yet uncombined toxin in the body fluids, the dose of antitoxin is divided and injected into multiple sites, usually the upper part of the arms and the buttocks. If the suspected focus is in an extremity, at least one of these injections is given into that extremity. All injected sites are then massaged and heat is applied. Since experimental work with animals has demonstrated that several "minimal lethal doses" of tetanotoxin can accumulate within the immediate area of the focus of tetanal infection, surgical manipulation of the focus is delayed an hour or so to permit, *All dosages of medications as well as all procedures given in this article are for adults and must be adjusted for children and infants. Dosages are those customarily prescribed unless noted otherwise. tThis team, of which the author is director, consists of three internists, a general surgeon, an orthopedic surgeon, an anesthesiologist, a neurologist, a physiatrist, a microbiologist, a clinical pathologist, and a physiologist.
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hopefully, the development of protective titers of antitoxin that will ward off any toxin that may flood the circulation. Administration of Antibiotics In addition to surgical care of wounds, antibiotic therapy is given supplementally to help eliminate any tetanal infection. Penicillin'~ is the agent of choice against C. tetani and is useful too against other grampositive organisms, which frequently are present. Since the tetanal infection is symbiotic and frequently includes gram-negative organisms as well, it is important to provide broad coverage. Kanamycin, streptomycin, or a similar agent effective against gram-negative bacteria is given in combination with penicillin. When penicillin is used, as much as 1,000,000 units of the sodium or potassium salt is given intramuscularly every 4 hours, or 10,000,000 units is given by continuous intravenous drip during the first day. Thereafter, 1,000,000 units of procaine penicillin is given intramuscularly daily. Unless contraindicated, and with the usual precautions, 0.5 gm of kanamycin (or streptomycin) is given intramuscularly two or three times a day for the initial 4 to 7 days and then its use is generally discontinued. Currently, antibiotic therapy is continued prophylactically essentially as long as the patient uses a cuffed tracheostomy tube. During this critical period, other antibiotics can be used in combination with penicillin or instead of it, in accordance with the results of tracheobronchial and other cultures and the status of the patient. Troublesome organisms such as staphylococci, Klebsiella, Aerobacter aerogenes, and Pseudomonas organisms emerge frequently after the first week, and their presence requires specific antibiotic treatment if they are thought to be causing significant infection. Care of Foci of Infection and Use of Other Surgical Procedures During the delay of 1 to 2 hours required for absorption of antitoxin, essential laboratory tests are performed and the appropriate members of the team, including the nursing staff of the respiratory intensive-care unit, are notified of the patient's admission. Thereafter the team surgeon removes any foci of infection and performs any other indicated surgical procedures. Since in the patient with severe tetanus these procedures are often major and multiple, he is usually transferred to the general operating room and given general anesthesia. Intravenously administered sodium thiopental (Pentothal) or other customary anesthetic agents that are essentially nonirritating to the respiratory system are used. When indicated, curare is given supplementally to control tetanospasms and provide suitable muscle relaxation. Tracheostomy is performed routinely in the patients with severe tetanus and, like other sterile procedures, it precedes surgical treatment of infected foci. Because of the vital nature and duration of use of the *Tetracycline is currently the drug used in patients sensitive to penicillin.
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tracheal opening, a double-cuffed tracheostomy tube is used by the team surgeon. The double cuffs help provide a closed system so that pressure may be alternated every hour or so to prevent complicating focal erosion, necrosis, hemorrhage, perforation, or fistula formation. Because of inability to swallow, every patient with severe tetanus requires tube feeding during the critical first 3 to 4 weeks of therapy. A small nasogastric plastic catheter passed so that the tip preferably lies within the jejunum functions well in most patients. However, an alternate method, namely gastrostomy, is preferable in some cases and, when indicated, can be used at this time. It is particularly helpful in small children and infants in whom the risk of complicating pressure necrosis in the region of the tracheostomy tube is increased with the use of a nasogastric tube. When indicated, gastrostomy is performed by making a small upper midline incision in the abdominal wall and then passing a double-lumen tube through a I-cm opening made in the midportion of the anterior wall of the stomach. The longer tube is advanced until its tip lies within the proximal part of the jejunum and the shorter tube is positioned so that its tip lies within the antrum of the stomach. After inversion and closure of the small opening in the stomach wall around the double-lumen tube with two rows of interrupted sutures, the omentum is interposed between the gastric wall and the anterior parietal peritoneum. The tube is brought out through a stab incision in the abdominal wall where it is held in position by skin sutures. The primary midline incision is closed in a routine manner. The intrajejunal tube will serve as the primary route for tube feedings, as will be discussed later, and the intragastric tube will aid in monitoring gastrointestinal function and will permit decompression of the stomach whenever indicated. Occasionally postoperative ileus occurs, but it is usually transitory and responds to general measures within a day or two. Finally, all foci of infection are surgically treated. Cleansing and debridement are considered adequate for superficial wounds, but careful excision is preferable for the more deeply infected wounds even though they may appear to be healing. Radical treatment of the tetanal wound seems justified in the patient with severe disease. Such treatment may require amputation of a digit or even an extremity to eliminate an extensive, seriously infected wound. Delayed wound closure is required whenever there still exists a question of infectivity. To further help provide an aerobic environment, the loosely placed dressings can be kept moistened for a few days with an oxidizing agent. The wound can be closed or grafted with skin, if indicated, when infection has been surely eliminated and the patient's condition permits. While the patient is in the operating room the dental surgeon extracts any badly infected teeth. Though infected teeth have been blamed for tetanus, another reason for extraction is to help prevent infection of the respiratory tract. Provision of a dependable intravenous route is essential in the treatment plan for these severely ill patients who will require intravenous curarization for approximately 2 to 3 weeks. While the patient is in the operating room and usually prior to the above surgical procedures, the
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anesthesiologist introduces an indwelling, large-bore catheter into one of the major veins of the arm. The catheter is generally passed proximally until its tip lies within the superior vena cava. A three-way cock attached to the proximal end of the catheter provides a system for intravenous administration of curare and other medications, and initially a primary (later secondary) route for nutrition and hydration. Furthermore, this system permits the emergency sampling of venous blood when indicated and permits monitoring of the central venous pressure. Hypotension and even shock are not unusual in these desperately ill patients. 5 • 6 Before the patient is removed from the operating room an indwelling Foley catheter is placed in the bladder to permit free excretion of urine and to aid in the monitoring of renal function in the curarized patient.
ROLE OF THE RESPIRATORY INTENSIVE-CARE UNIT IN THE TREATMENT OF SEVERE TETANUS From the operating room the patient is transferred to the respiratory intensive-care unit. This unit is staffed with personnel trained and oriented in the care of patients with respiratory problems, who obviously include patients with severe tetanus. The unit is equipped with modern facilities to help meet any eventuality, and within its confines is located a special laboratory equipped to do special tests that help monitor the patient's respiratory and other vital functions. The team anesthesiologist heads ,this unit and supervises the pulmonary ventilation and curarization of the patient.
Respiration and Ventilation A fully automated respirator is attached to the patient's tracheostomy tube and the respirator is set to deliver properly heated, humidified air containing 40% oxygen. Oxygen concentration, volume, cycling pressure, and respiratory rate are adjusted from time to time as indicated to maintain adequate alveolar ventilation. The automated sigh mechanism of the respirator is set to produce four to six deep breaths every 10 to 15 minutes. In addition, a device to produce an artificial cough can be used three to four times a day, when warranted, to keep the airway clean and lung compliance normal. During the critical period of the illness, and until the tracheal stoma has been closed (usually 4 to 5 weeks later), continuous attention and meticulous tracheostomy toilet are required of the nursing staff. At first, secretions are troublesome and require frequent removal. Clean technique is followed in the removal of secretions in the mouth and hypopharynx. Sterile technique must be observed in the removal of secretions from the tracheobronchial system. The aim always is to maintain a patent airway and avoid complicating infection. Other procedures that help maintain adequate respiration include hourly repositioning of the patient and passive respiratory physical
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therapy given two or three times a day. Mechanical beds help in this regard. Before each change of position and alteration of pressure within the balloon cuffs of the tracheostomy tube, secretions that accumulate above and below this tube should be removed. The tracheostomy tube should never be detached from the respirator longer than 20 seconds, to avoid the risk of dangerous hypoxia. Initially, arterial blood gases and pH are determined at least every 2 or 3 days and then as indicated during the period of curarization and controlled respiration. Other studies used to monitor the respiratory system as well as alveolar ventilation include x-ray examination of the chest (with a portable machine) and the taking of tracheobronchial cultures. These cultures are obtained at least every 3 to 4 days during the critical period of the disease. Complicating bronchial obstruction, with resultant pulmonary atelectasis due to plugs of mucus or to aspirated material, and tracheobronchial pneumonia occur frequently in these patients and must be recognized early and treated promptly. At times, bronchoscopy is required to remove the bronchial obstruction. Antibiotic therapy is adjusted when tracheobronchial cultures and the condition of the patient dictate.
Curarization Since no single sedative or combination of sedatives will control the tetanospasms safely and satisfactorily in severe tetanus, curarization is currently preferred for this purpose. Curarization is started on admission of the patient to the intensive-care unit and is continued until he has entered the recovery phase of the illness approximately 3 weeks later. During this period of induced respiratory paralysis, controlled ventilation is required. Currently we give tubocurarine intravenously via the catheter system previously described. A bottle of 500 ml of 5% glucose in water containing 1 mg of curare per milliliter is prepared and administered with the aid of a pediatric setup. This measuring device permits the nurse to give a predetermined dose of the drug whenever generalized tetanospasms recur and interfere with the ventilation and comfort of the patient. At first, tubocurarine must be given about every 30 to 60 minutes. Later, as symptoms subside, the interval gradually becomes longer and finally use of the drug can be discontinued. Once the patient is curarized, his requirement for sedation is usually greatly reduced. Currently, diazepam is used in the customary dosage according to the patient's needs, the aim being to allay apprehension and maintain a restful state from which he can be easily aroused. Striking yet fortunate it is that after recovery the patient has a relative amnesia for the period of curarization. Nevertheless, since he is conscious, attending personnel should always be discreet in conversation and encouraging in their remarks in the presence of the patient.
Nutrition and Hydration Until tube feedings can be instituted, the intravenous system serves as the primary route for administration of fluids, nutrients, and electro-
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lytes. Unless contraindicated, half-strength physiologic saline solution containing 5 to 10% glucose and fortified with vitamins is given to meet the patient's requirements. A urine output of 1200 ml or more per day is desired. Because of the hypermetabolic state associated with tetanus and the frequently increased perspiration, the patient often needs additional calories and extra fluids. If he is elderly, especially if he has cardiorenal disease, adjustments in electrolyte administration may be necessary. Early use of a gastric tube, whether a nasogastric or a gastrostomy tube, provides the method of choice for handling nutrition and hydration during the critical period of treatment. Administration of clear liquids can be started on the same day that the nasogastric tube is positioned, or usually by the second or third day if gastrostomy is performed. Fifty milliliters of liquid are given at hourly intervals. Tube feedings are substituted for clear liquids after the first day. Unless problems develop, the amount can be increased progressively to 100 to 200 ml in adults. Feedings are started at 6 A.M. and continued every 1 to 2 hours until 10 P.M. Preceding each feeding, the nurse or aide checks the tube system with a syringe to ensure that the system is functioning properly. In addition, she makes sure the tracheal cuff system is properly inflated and keeps the head of the patient slightly elevated during and immediately after tube feedings. These feedings are given with the aid of a special pump added to the system. The content of the tube feedings is carefully formulated with the help of the dietitian and is tailored from time to time to meet the patient's specific needs. Interval blood studies of electrolytes, urea, and, when indicated, creatinine help in monitoring this aspect of the problem. A "flow sheet" for pertinent information is started on admission and is kept current throughout the critical period of the illness. This record shows the status of the patient at any given time and helps one to recognize developing complications so that corrective measures may be applied promptly and, hopefully, before the complications have become fully developed. Of concern has been the frequent development of anemia during the period of intensive therapy, usually within the first 3 weeks. Though the cause may be apparent in some patients and iron medication and specific measures are helpful in those with anemia apparently due to blood loss, a number of patients have had unexplained anemia that required infusions of whole blood or packed red blood cells. Fortunately, it usually responds quickly and without further treatment once the patient has entered the recovery phase, has been weaned from the respirator, and is taking a regular diet. Miscellaneous Measures Consistent and meticulous general nursing care is as important as special attention to vital functions. This is particularly true while the patient is curarized and requires controlled respiration. Eyedrops instilled at regular intervals and, when indicated, eyeshields are used to keep the eyes moist and to protect them against corneal ulceration and
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infection. Footboards are used to prevent contractures of the calf muscles of the legs. Proper positioning of the extremities and passive exercises are important in the paralyzed patient. Good oral hygiene is practiced, and special attention is given to the skin, particularly the pressure points.
RECOVERY PHASE AND REHABILITATION THERAPY The patient with severe tetanus can be expected to enter the recovery phase after approximately 12 to 14 days. This phase is evidenced by a decreasing need for curare and sedation and by an increasing alertness and subsidence in symptoms. Since, in our experience, symptoms have not recurred after unequivocal improvement, discontinuance of the use of the respirator is started as soon as it is evident that the patient can be controlled without curarization. Initially the change is from controlled to assisted ventilation, and then from assisted to self-ventilation. To accomplish the latter step, assisted ventilation is replaced by another system that delivers a 40% oxygen mist to the region of the orifice of the tracheostomy tube, and the patient is encouraged to breathe on his own for 3 to 5 minutes two or three times the first day. The duration and frequency of these periods are increased progressively as the patient's condition permits. When completely weaned from the ventilator, the cuffed tracheostomy tube is replaced with a smaller, uncuffed, corked tracheostomy tube which remains until the functions of respiration and digestion are safely reestablished. During this period when the patient is able to swallow, oral feedings consisting of clear liquids are started. This is followed by the use of a full liquid diet, then soft foods, and finally a full diet as tolerated. Once all this has been accomplished, both the tracheostomy tube and the gastrostomy tube can be removed simply and without suturing. When curarization has been discontinued, both the intravenous catheter and the one in the bladder are removed and antibiotic therapy is discontinued unless infection is present. Special care of wounds, such as grafting, can be given at this time, if indicated. J The team's physiatrist institutes and supervises a progressive plan of physical therapy and rehabilitation, at first in the hospital room and then, when the patient's condition permits, in the section of physical medicine. Usually by the fourth week the patient's general condition has improved so that he can be transferred from the intensive-care unit to another room in the hospital, where he receives required nursing care and continues his rehabilitation program. Within the next week or two he can usually be dismissed from the hosptial. During this final period, active immunization with tetanus toxoid is started and arrangements are made for him to complete the basic series of injections in the prescribed manner. B,13 A wallet-sized medical identification card is provided, which serves not only as a record but as a reminder for him to complete this last, yet important step in the plan of treatment.
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SUMMARY Tetanus, though rare, continues to occur sporadically and unexpectedly in most areas of the United States. When it is severe, few diseases are more challenging therapeutically. The detailed plan of treatment presented is based on more than 20 years of experience with this disease and provides what is considered the best plan of therapy currently available. The plan is offered as a guide both to the physician in this country who has little experience with this disease but who suddenly finds himself responsible for the care of one of these desperately ill patients and to physicians throughout the world, especially those in countries where tetanus is still common. Admittedly, to be effective, treatment for the severely ill patient with tetanus is expensive and timeconsuming, but this is the price that must be paid when the life of one of these patients is at stake. The plan of treatment presented utilizes the environment of a respiratory intensive-care unit and, when indicated, includes the use of a tracheostomy, curarization, and artificial respiration. Based on our experience and that of others, this plan can be expected to reduce significantly the notoriously high mortality rate now associated with severe tetanus. Though not the final answer to treatment, hopefully further refinements of the plan presented and further advances in technology and knowledge of the disease will help to find that answer eventually. Although Pascale and colleagues12 in 1964 reported optimistically on the use of hyperbaric oxygen in the treatment of nine patients with clinical tetanus, subsequent studies either in marl° or in animals3 • 15 have failed to substantiate these significant beneficial effects either on mortality or on morbidity. In the meantime, a greater effort should be made to attain the even more important goal of world-wide prevention of this disease by universal active immunization with tetanus toxoid.
REFERENCES 1. Adams, E. B., Holloway, R., Thambiran, A. K., and Desai, S. D.: Usefulness of intermittent positive-pressure respiration in the treatment of tetanus. Lancet 2: 1176-1180 (Nov. 26) 1966. 2. Bytchenko, B.: Geographic distribution of tetanus in the world, 1951-60: A review of the problem. Bull WHO 34:71-104, 1966. 3. Christensen, N. A., Ackerman, E., Weed, L. A., Gatewood, L. C., and Drube, C.: Hyperbaric oxygen therapy in mice injected with tetanus toxin. JAMA 200:129-131 (April 10) 1967. 4. Christensen, N. A., and Thurber, D. L.: Clinical experience with tetanus: 91 cases. Proc Staff Meet Mayo Clin 32:146-158 (April 3) 1957. 5. Christensen, N. A., and Thurber, D. L.: Current treatment of clinical tetanus. Mod Treatm 5:729-757 (July) 1968. 6. Clifton, B.: Hypotension associated with tetanus. Lancet 1 :785-788 (April 11) 1964. 7. Cooke, Jean V., and Jones, F. G.: The duration of passive tetanus immunity and its effect on active immunization with tetanus toxoid. JAMA 121 :1201-1209 (April 10) 1943. 8. Guide Lines for the Medical Profession Regarding the Prevention of Tetanus. In Eckmann, L.: Principles on Tetanus. (Proceedings of the International Conference on Tetanus, Bern, July 15-19, 1966.) Bern, Hans Huber, 1967, pp. 576-577.
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9. Heath, C. W., Jr., Zusman, J., and Sherman, Ida L.: Tetanus in the United States, 19501960. Amer J Public Health 54:769-779 (May) 1964. 10. Milledge, J. S.: Hyperbaric oxygen therapy in tetanus. JAMA 203:875-876 (March 4) 1968. 11. National Communicable Disease Center: Morbidity and Mortality: Weekly Report. (Annual Supplement, Summary 1967, No. 53.) United States Department of Health, Education and Welfare, Public Health Service, November, 1968, vol. 16, pp. 20; 53-54. 12. Pascale, L. R., Wallyn, R. J., Goldfein, S., and Gumbiner, S. H.: Treatment of tetanus by hyperbaric oxygenation. JAMA189:408-410 (Aug. 10) 1964. 13. Peebles, T. C., Levine, L., Eldred, Mary C., and Edsall, G.: Tetanus-toxoid emergency boosters: A reappraisal. New Eng J Med 280:575-581 (March 13) 1969. 14. Smythe, P. M.: The treatment of tetanus neonatorum on experimental and clinical level. In Eckmann, L.: Principles on Tetanus. (Proceedings of the International Conference on Tetanus, Bern, July 15-19, 1966.) Bern, Hans Huber, 1967, pp. 495-500. 15. Stirnemann, H.: Treatment of tetanus: A 50-year review. Minn Med 52:15-22 (Jan.) 1969. 16. Wright, R., Sykes, M. K., Jackson, B. G., Mann, N. M., and Adams, E. B.: Intermittent positive-pressure respiration in tetanus neonatorum. Lancet 2:678-680 (Sept. 23) 1961.
Statement afOwnership, Management, and Circulation (Act of October 23, 1962; Section 4369, Title 39, United States Code) 1. Date of filing: September 15, 1969.
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Title of Publication: The Surgical Clinics of North America. Frequency of issue: Six times annually. Location of known office of publication: 580 Hampton Road, Cherry Hill Township, New Jersey 08034. Location of the headquarters or general business offices of the publisher: West Washington Square, Philadelphia, Pa. 19105. Names and addresses of publisher, editor, and managing editor: Publisher, W. B. Saunders Company, a division of CBS, Inc., West Washington Square, Philadelphia, Pa. 19105; Editor, Albert E. Meier, clo W. B. Saunders Company, West Washington Square, Philadelphia, Pa. 19105; Managing Editor, none. Owners: Atwell & Company, 45 Wall St., New York, N.Y. 10005; Anderson & Company, 135 S. Broad St., Phila., Pa. 19109; Bark & Company, P.O. 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Box 2051, Harrisburg, Penna. 17108; Crocker Citizens National Bank, 1 Montgomery St., San Francisco, Calif. 94120; Cummings & Company, 20 Pine St., New York, N.Y. 10015; First National City Bank, 399 Park Ave., New York, N.Y. 10022; Heil & Company, 45 Wall St., New York, N.Y. 10005; Hemfar & Company, 16 Wall St., New York, N.Y. 10015; Kane & Company, 1 Chase Manhattan Plaza, New York, N.Y. 10015; Kennedy & Company, 20 Pine St., New York, N.Y. 10015; King & Company, 399 Park Ave., New York, N.Y. 10022; Morgan Guaranty Trust Company, 23 Wall St., New York, N.Y. 10015; Pace & Company, Mellon Square, Pittsburgh, Pa. 15230; Pension Fund of Pacific Telephone & Telegraph Co., Bankers Trust Company, Trustee, 16 Wall St., New York, N.Y. 10015; Prudential Insurance Co. of America, P.O. Box 1404, Church St. Station, New York, N.Y. 10008; Reing & Company, 23 Wall St., New York, N.Y. 10015; The Shell Pension Trust, clo Brown Bros. Harriman, Inc., 59 Wall St., New York, N.Y. 10015; Shaw & Company, 23 Wall St., New York, N.Y. 10015; Security Pacific National Bank, 411 S. Main St., Los Angeles, Calif. 90013. Paragraphs 7 and 8 include, in cases in which the stockholder or security holder appears upon the books of the company as a trustee or in any other fiduciary relation, the name of the person or corporation for whom such trustee is acting. Also the statements in the two paragraphs show the affiant's full knowledge and belief as to the circumstances and conditions under which stockholders and security holders who do not appear upon the books of the company as trustees hold stock and securities in a capacity other than that of a bona fide owner. Names and addresses of individuals who are stockholders of a corporation which itself is a stockholder or holder of bonds, mortgages, or other securities of the publishing corporation have been included in paragraphs 7 and 8 when the interests of such individuals are equivalent to 1 per cent or more of "the total amount of stock or securities of the publishing corporation. Av. No. Copies Each Single Issue Issue During Nearest to Preceding 12 Mos. Filing Date 30,000 30,000 A. Total number of copies printed (net press run) B. Paid circulation 1. Sales through dealers and carriers, street vendors, and 18,100 18,300 counter sales 9,700 9,900 2. Mail subscriptions 28,200 C. Total paid circulation 27,800 D. Free distribution (including samples) by mail, carrier, or other 300 means 300 E. Total distribution (sum of C and D) 28,100 28,500 1,900 1,500 F. Office use, left-over. unaccounted. spoiled after printing 30,000 30,000 G. Total (sum of E and F - should equal net press run shown in A) I certify that the statements made by me above are correct and complete. T. VandenBeemt, Vice President and Treasurer