THE CLOSTRIDIAL SYNDROMES
Tetanus DAVID B. TILLMAN, MD*
History "THE MASTER of a large ship mashed the index finger of his right hand with the anchor. Seven days later a somewhat foul discharge appeared; then trouble with his tongue-he complained he could not speak properly. The presence of tetanus was diagnosed, his jaws became pressed together, his teeth were locked, then symptoms appeared in his neck; on the third day opisthotonos appeared with sweating. Six days after the diagnosis was made he died."34 This accurate clinical description of tetanus by Hippocrates dates to 400 BC. Over the next 22 centuries many theories regarding its origin were proposed. It was not until 1884 that Nicolaier showed its infective nature by producing tetanus in animals that he had injected with soil. By 1897 Nocard showed the protective effect of antitoxin, and passive immunization was used on a large scale during World War I. Tetanus toxoid was developed in the 1920's and was used almost universally during World War II. The advances made in controlling tetanus are most dramatically illustrated by examining the incidence during war. Because wounds contaminated by soil are such a common battlefield occurrence, tetanus has always been a prominent feature of war. During the Peninsular War in Spain from 1808 to 1814, British soldiers contracted tetanus at a rate of 12.5 cases per 1,000 wounded. On the western front during World War I (1914 to 1918) where passive immunization was available, the rate dropped to 1.47 cases per 1,000 wounds. During World War lI the United States Army actively immunized all soldiers. The rate was 0.0062 per 1,000 wounded (one case of tetanus in 160,254 wounded).35 The availability of tetanus toxoid has had striking impact and made tetanus a preventable disease. Etiology
Clostridium tetani is a slender, motile, Grampositive anaerobic rod. It exists in both a vegetative and a sporulated form. The sporulated form is characteristically drumstick-shaped in appearance, with the spore at one end of the rod. The vegetative forms are sus-ceptible to heat and to a variety of chemical agents while the spores are highly resistant to boiling, antiseptic agents and *Fellow, Division of Infectious Diseases, Harbor General Hospital, Torrance, California.
even autoclaving at 1200C for 15 to 20 minutes. Both forms are ubiquitous in nature and may be found in the feces of domestic animals and humans, in operating rooms and house dust, and in contaminated heroin.36 Acquisition of the organism, usually the sporulated form, is the first event in the sequence leading to tetanus. Because the organisms do not possess any special ability to invade the body tissues, some traumatic injury often precedes infection.37 The spores must also be converted into the vegetative form. This transformation will occur only under certain circumstances-for example, introduction of a foreign body or the development of suppuration-which reduces local oxidation-reduction potential. Only after the vegetative form begins to proliferate and produce tetanospasmin does disease occur. The incubation period is usually 3 to 21 days, but it can be as short as one day or as long as several months. Tetanospasmin acts on several areas of the nervous system. Its primary effect is on the spinal cord leading to dysfunction of inhibitory polysynaptic reflexes; this action accounts for the spasm seen in tetanus.38 39 The toxin also acts on the sympathetic nervous system,40 resulting in labile hypertension, tachycardia, cardiac arrhythmias, diaphoresis or fever. A third site of action is at the level of the neuromyal junction resulting in interference with neuromuscular transmission by inhibiting the release of acetylcholine.41 The clinical importance of this effect is not known.
Clinical Manifestations The first clinical manifestation of tetanus is trismus in over 50 percent of the cases.36 Persistent trismus produces a characteristic expression, the risus sardonicus. The trismus may be replaced by stiffness of the neck or other muscles, difficulty swallowing or rigidity of the abdominal muscles. Intense, persistent spasm of the back musculature can result in opisthotonos. Tetanic "seizures" are characterized by a sudden painful burst of tonic contractions causing opisthotonos, flexion and adduction of the arms, and extension of the lower extremities. In addition to generalized tetanus described above, syndromes of both local and cephalic tetanus may occur. Local tetanus is characterized by persistent rigidity of the muscle groups in close proximity to the site of injury and carries a low mortality. Cephalic tetanus is an unusual form of the disease with a short incubation period followTHE WESTERN JOURNAL OF MEDICINE
107
THE CLOSTRIDIAL SYNDROMES
ing injuries to the head. While generalized tetany may occur, usually this form of the disease is characterized by involvement of the 3rd, 4th, 7th, 9th, 10th and 12th cranial nerves. The diagnosis of tetanus is made clinically; a Gram-stain and anaerobic culture of material obtained from a wound may be negative. The diagnosis of the disease is based primarily on a history of injury followed by the development of one of the syndromes described above. It is important to remember that the organism may grow in any type of wound. This includes bums and surgical wounds. During the past year we have seen a case of tetanus in a woman in whom a gangrenous leg had been amputated. No disease fully resembles tetanus, so the differential diagnosis is brief. Strychnine poisoning may closely mimic tetanus, but the strychnine will be detectable in the urine. Early in its course the combination of fever and neck stiffness may suggest meningitis. A lumbar puncture is normal in tetanus, however, so meningitis can be easily ruled out.
Treatment The therapy of tetanus involves two major principles. The first is neutralization of circulating toxin and elimination of the organism. Human immune globulin (TIG, tetanus immune gobulin) is now universally available. The recommended dose is 3,000 to 10,000 units given once intramuscularly,42 although there is evidence that as little as 500 units may be as effective.43 Retrospective analysis has shown a lower case-fatality ratio in patients treated with antitoxin than in those who did not receive antitoxin.'8 Surgical debridement and penicillin therapy (1,000,000 units given intravenously every six hours) will help eliminate the infecting organism and, therefore, will stop the production of any new toxin. Tetracycline should be used in patients allergic to penicillin. The second major principle of therapy concerns constant support of the patient. Antitoxin does not affect tetanospasmin already bound to nerve tissue. It is necessary to support the patient for the days to weeks it takes for the toxin to be eliminated. The patient should be kept in a quiet environment to minimize spasms and generalized seizures. Rigid attention should be paid to skin and bladder care. Because of the work associated with the muscular contractions, insensible water loss may be high. For this reason, strict monitor108
AUGUST 1978 *
129 * 2
ing of fluids and electrolytes is mandatory. These patients consume thousands of calories because of this muscular work. Some authors suggest nasogastric feedings while others express fear of aspiration. Parenteral nutrition must be considered, as nitrogen loss can be significant.50 Because the muscular spasms may involve the upper airway and because these patients have great difficulty with their secretions, tracheostomy is frequently necessary. While this procedure should not be done routinely, as soon as airway problems become evident, a -tracheostomy is indicated.36 Sedation and control of the spasms are also mainstays of therapy. Diazepam is very effective because it both sedates the patient and reduces spasm.44 Large doses, up to 20 mg every two hours, may be necessary. Other drugs which are used include secobarbital sodium, chlorpromazine and meprobamate. (All act to both sedate the patient and to eliminate spasms.) As with diazepam, the dose or combination of drugs that is required may be one that is toxic for normal people. Although fever may be secondary to sympathetic nervous system involvement or to the heat generated by extremes of muscular activity, infection must be considered with each temperature elevation. In these patients aspiration pneumonia, skin infections or urinary tract infections are likely to develop, especially if the urinary tract is instrumented.
Prevention Even with the widespread availability of antitoxin and the use of intensive care units, the mortality of tetanus remains in excess of 40 percent.36"45 Of the 102 cases of tetanus reported in 1945, a total of 45 (44 percent) resulted in death.'6(PP2') It seems evident, therefore, that preventing the disease is the most efficient way to eliminate these- deaths. This can be accomplished through proper immunization of both children and adults. Primary immunization is of great importance. In children, this means diphtheria-pertussis-tetanus (DPT) given intramuscularly on four occasions, with three doses at fOur to six week intervals and a fourth dose approximately one year later. This series should begin at two to three months of age. In adults, a series of three doses of adult type tetanus and diphtheria toxoids should be given. The second dose should follow the first by about six weeks with the last coming six months to one year later. Boosters
THE CLOSTRIDIAL SYNDROMES
TABLE 4.-Guide to Tetanus Prophylaxis in Wound Management* History of Tetantus Immunization (doses)
Uncertain ....... 0-1 ....... 2 ....... 3 or more .......
Clean, minor wounds
Toxoid
TIG
yes yes yes
no no no no
not
All other
wounds TIG Toxoid
yes yes yes
no§
yes yes
not no
TIG = Tetanus Immune Globulin *Modified from reference 42. i Unless wound more than 24 hours old. lUnless more than 10 years since last dose. § Unless more than 5 years since last dose.
should be given to children upon entering school and then every ten years. Except as noted below, more frequent boosters are not indicated and may be associated with increased- incidence and severity of reactions.47 The correct use of tetanus toxoid and immune globulin is important for tetanus prophylaxis in the management of wounds. Persons with clean, minor wounds should receive a primary vaccination series if they have never received one. If a patient has been previously immunized, but more than ten years have passed since last receiving toxoid, then a booster is indicated. Tetanus immune globulin is not needed. The above holds true for dirty wounds, but a cutoff of five years should-be used in deciding whether or not to give a booster to those with previous immunization. Tetanus immune globulin should be administered if any of the following criteria are met: previously unimmunized patients, patients with fewer than two previous doses of tetanus toxoid who have large or contaminated wounds, patients presenting with a wound which is more than 24 hours old who have had fewer than three doses of toxoid. These data are summarized in Table 4. The amount of tetanospasmin that induces tetanus is not sufficient to stimulate an immune response. For this reason, it is important to remember to fully immunize any patient with tetanus. Clearly, the best prophylaxis against tetanus involves routine immunization and boosters every ten years. It should be a part of each physician's routine to make sure that his patients are adequately immunized. This includes the elderly as well. In 1976 the incidence of tetanus was greatest in patients over 50 years old.40(P02) Another group in whom immunization is extremely important is heroin users. As noted above, C tetani has been found in heroin.36 Heroin addicts are routinely
violating their skin and creating minor wounds. Women addicts, in particular, may destroy their veins and begin to inject subcutaneously ("skin pop"). This produces an anaerobic environment which will allow vegetative forms to grow. Additionally, many men enter the military and receive routine immunization as young adults. Women, not having served in the military, may not have received primary immunization or recent boosters. Once it develops, tetanus in heroin addicts is usually severe and has a high mortality rate.48 In summary, tetanus is a severe neuromuscular disease produced by an exotoxin of Clostridium tetani. Therapy involves administration of antitoxin and supportive management of the patient. Prevention through immunization is effective and inexpensive, requiring only primary immunization and then boosters every ten years. Proper immunization and wound management combine to make tetanus an easily preventable disease. While specific therapy for both botulism and tetanus has been developed, the decrease in mortality and morbidity seen in both syndromes over the past 15 years is primarily due to pronounced improvement in nonspecific supportive care of patients with severe neuromuscular diseases. The cornerstone of this supportive care is careful respiratory management of these patients. Because the pulmonary care is so important we have asked Dr. Herbert Webb to discuss this subject in depth for us.
Respiratory Care of Tetanus and Botulism HERBERT H. WEBB, MD*
IT IS APPROPRIATE to discuss respiratory care of patients with these diseases in some detail since the majority of fatalities in clinical tetanus and botulism, as in many neuromuscular diseases, results from pulmonary complications. Moreover, these problems can be anticipated, prevented, and treated in the modern intensive care unit with adequate equipment and, most important, a competent respiratory care team.50-53 The team must consist of an experienced, knowledgeable and readily available physician who guides the team of nurses and respiratory therapists with fore*Director of Pulmonary Medicine, San Pedro and Peninsula Hospital, San Pedro, California, and Associate Clinical Professor of Medicine UCLA.
THE WESTERN JOURNAL OF MEDICINE
109
Tetanus DAVID B. TILLMAN, MD*
History "THE MASTER of a large ship mashed the index finger of his right hand with the anchor. Seven days later a somewhat foul discharge appeared; then trouble with his tongue-he complained he could not speak properly. The presence of tetanus was diagnosed, his jaws became pressed together, his teeth were locked, then symptoms appeared in his neck; on the third day opisthotonos appeared with sweating. Six days after the diagnosis was made he died."34 This accurate clinical description of tetanus by Hippocrates dates to 400 BC. Over the next 22 centuries many theories regarding its origin were proposed. It was not until 1884 that Nicolaier showed its infective nature by producing tetanus in animals that he had injected with soil. By 1897 Nocard showed the protective effect of antitoxin, and passive immunization was used on a large scale during World War I. Tetanus toxoid was developed in the 1920's and was used almost universally during World War II. The advances made in controlling tetanus are most dramatically illustrated by examining the incidence during war. Because wounds contaminated by soil are such a common battlefield occurrence, tetanus has always been a prominent feature of war. During the Peninsular War in Spain from 1808 to 1814, British soldiers contracted tetanus at a rate of 12.5 cases per 1,000 wounded. On the western front during World War I (1914 to 1918) where passive immunization was available, the rate dropped to 1.47 cases per 1,000 wounds. During World War lI the United States Army actively immunized all soldiers. The rate was 0.0062 per 1,000 wounded (one case of tetanus in 160,254 wounded).35 The availability of tetanus toxoid has had striking impact and made tetanus a preventable disease. Etiology
Clostridium tetani is a slender, motile, Grampositive anaerobic rod. It exists in both a vegetative and a sporulated form. The sporulated form is characteristically drumstick-shaped in appearance, with the spore at one end of the rod. The vegetative forms are sus-ceptible to heat and to a variety of chemical agents while the spores are highly resistant to boiling, antiseptic agents and *Fellow, Division of Infectious Diseases, Harbor General Hospital, Torrance, California.
even autoclaving at 1200C for 15 to 20 minutes. Both forms are ubiquitous in nature and may be found in the feces of domestic animals and humans, in operating rooms and house dust, and in contaminated heroin.36 Acquisition of the organism, usually the sporulated form, is the first event in the sequence leading to tetanus. Because the organisms do not possess any special ability to invade the body tissues, some traumatic injury often precedes infection.37 The spores must also be converted into the vegetative form. This transformation will occur only under certain circumstances-for example, introduction of a foreign body or the development of suppuration-which reduces local oxidation-reduction potential. Only after the vegetative form begins to proliferate and produce tetanospasmin does disease occur. The incubation period is usually 3 to 21 days, but it can be as short as one day or as long as several months. Tetanospasmin acts on several areas of the nervous system. Its primary effect is on the spinal cord leading to dysfunction of inhibitory polysynaptic reflexes; this action accounts for the spasm seen in tetanus.38 39 The toxin also acts on the sympathetic nervous system,40 resulting in labile hypertension, tachycardia, cardiac arrhythmias, diaphoresis or fever. A third site of action is at the level of the neuromyal junction resulting in interference with neuromuscular transmission by inhibiting the release of acetylcholine.41 The clinical importance of this effect is not known.
Clinical Manifestations The first clinical manifestation of tetanus is trismus in over 50 percent of the cases.36 Persistent trismus produces a characteristic expression, the risus sardonicus. The trismus may be replaced by stiffness of the neck or other muscles, difficulty swallowing or rigidity of the abdominal muscles. Intense, persistent spasm of the back musculature can result in opisthotonos. Tetanic "seizures" are characterized by a sudden painful burst of tonic contractions causing opisthotonos, flexion and adduction of the arms, and extension of the lower extremities. In addition to generalized tetanus described above, syndromes of both local and cephalic tetanus may occur. Local tetanus is characterized by persistent rigidity of the muscle groups in close proximity to the site of injury and carries a low mortality. Cephalic tetanus is an unusual form of the disease with a short incubation period followTHE WESTERN JOURNAL OF MEDICINE
107
THE CLOSTRIDIAL SYNDROMES
ing injuries to the head. While generalized tetany may occur, usually this form of the disease is characterized by involvement of the 3rd, 4th, 7th, 9th, 10th and 12th cranial nerves. The diagnosis of tetanus is made clinically; a Gram-stain and anaerobic culture of material obtained from a wound may be negative. The diagnosis of the disease is based primarily on a history of injury followed by the development of one of the syndromes described above. It is important to remember that the organism may grow in any type of wound. This includes bums and surgical wounds. During the past year we have seen a case of tetanus in a woman in whom a gangrenous leg had been amputated. No disease fully resembles tetanus, so the differential diagnosis is brief. Strychnine poisoning may closely mimic tetanus, but the strychnine will be detectable in the urine. Early in its course the combination of fever and neck stiffness may suggest meningitis. A lumbar puncture is normal in tetanus, however, so meningitis can be easily ruled out.
Treatment The therapy of tetanus involves two major principles. The first is neutralization of circulating toxin and elimination of the organism. Human immune globulin (TIG, tetanus immune gobulin) is now universally available. The recommended dose is 3,000 to 10,000 units given once intramuscularly,42 although there is evidence that as little as 500 units may be as effective.43 Retrospective analysis has shown a lower case-fatality ratio in patients treated with antitoxin than in those who did not receive antitoxin.'8 Surgical debridement and penicillin therapy (1,000,000 units given intravenously every six hours) will help eliminate the infecting organism and, therefore, will stop the production of any new toxin. Tetracycline should be used in patients allergic to penicillin. The second major principle of therapy concerns constant support of the patient. Antitoxin does not affect tetanospasmin already bound to nerve tissue. It is necessary to support the patient for the days to weeks it takes for the toxin to be eliminated. The patient should be kept in a quiet environment to minimize spasms and generalized seizures. Rigid attention should be paid to skin and bladder care. Because of the work associated with the muscular contractions, insensible water loss may be high. For this reason, strict monitor108
AUGUST 1978 *
129 * 2
ing of fluids and electrolytes is mandatory. These patients consume thousands of calories because of this muscular work. Some authors suggest nasogastric feedings while others express fear of aspiration. Parenteral nutrition must be considered, as nitrogen loss can be significant.50 Because the muscular spasms may involve the upper airway and because these patients have great difficulty with their secretions, tracheostomy is frequently necessary. While this procedure should not be done routinely, as soon as airway problems become evident, a -tracheostomy is indicated.36 Sedation and control of the spasms are also mainstays of therapy. Diazepam is very effective because it both sedates the patient and reduces spasm.44 Large doses, up to 20 mg every two hours, may be necessary. Other drugs which are used include secobarbital sodium, chlorpromazine and meprobamate. (All act to both sedate the patient and to eliminate spasms.) As with diazepam, the dose or combination of drugs that is required may be one that is toxic for normal people. Although fever may be secondary to sympathetic nervous system involvement or to the heat generated by extremes of muscular activity, infection must be considered with each temperature elevation. In these patients aspiration pneumonia, skin infections or urinary tract infections are likely to develop, especially if the urinary tract is instrumented.
Prevention Even with the widespread availability of antitoxin and the use of intensive care units, the mortality of tetanus remains in excess of 40 percent.36"45 Of the 102 cases of tetanus reported in 1945, a total of 45 (44 percent) resulted in death.'6(PP2') It seems evident, therefore, that preventing the disease is the most efficient way to eliminate these- deaths. This can be accomplished through proper immunization of both children and adults. Primary immunization is of great importance. In children, this means diphtheria-pertussis-tetanus (DPT) given intramuscularly on four occasions, with three doses at fOur to six week intervals and a fourth dose approximately one year later. This series should begin at two to three months of age. In adults, a series of three doses of adult type tetanus and diphtheria toxoids should be given. The second dose should follow the first by about six weeks with the last coming six months to one year later. Boosters
THE CLOSTRIDIAL SYNDROMES
TABLE 4.-Guide to Tetanus Prophylaxis in Wound Management* History of Tetantus Immunization (doses)
Uncertain ....... 0-1 ....... 2 ....... 3 or more .......
Clean, minor wounds
Toxoid
TIG
yes yes yes
no no no no
not
All other
wounds TIG Toxoid
yes yes yes
no§
yes yes
not no
TIG = Tetanus Immune Globulin *Modified from reference 42. i Unless wound more than 24 hours old. lUnless more than 10 years since last dose. § Unless more than 5 years since last dose.
should be given to children upon entering school and then every ten years. Except as noted below, more frequent boosters are not indicated and may be associated with increased- incidence and severity of reactions.47 The correct use of tetanus toxoid and immune globulin is important for tetanus prophylaxis in the management of wounds. Persons with clean, minor wounds should receive a primary vaccination series if they have never received one. If a patient has been previously immunized, but more than ten years have passed since last receiving toxoid, then a booster is indicated. Tetanus immune globulin is not needed. The above holds true for dirty wounds, but a cutoff of five years should-be used in deciding whether or not to give a booster to those with previous immunization. Tetanus immune globulin should be administered if any of the following criteria are met: previously unimmunized patients, patients with fewer than two previous doses of tetanus toxoid who have large or contaminated wounds, patients presenting with a wound which is more than 24 hours old who have had fewer than three doses of toxoid. These data are summarized in Table 4. The amount of tetanospasmin that induces tetanus is not sufficient to stimulate an immune response. For this reason, it is important to remember to fully immunize any patient with tetanus. Clearly, the best prophylaxis against tetanus involves routine immunization and boosters every ten years. It should be a part of each physician's routine to make sure that his patients are adequately immunized. This includes the elderly as well. In 1976 the incidence of tetanus was greatest in patients over 50 years old.40(P02) Another group in whom immunization is extremely important is heroin users. As noted above, C tetani has been found in heroin.36 Heroin addicts are routinely
violating their skin and creating minor wounds. Women addicts, in particular, may destroy their veins and begin to inject subcutaneously ("skin pop"). This produces an anaerobic environment which will allow vegetative forms to grow. Additionally, many men enter the military and receive routine immunization as young adults. Women, not having served in the military, may not have received primary immunization or recent boosters. Once it develops, tetanus in heroin addicts is usually severe and has a high mortality rate.48 In summary, tetanus is a severe neuromuscular disease produced by an exotoxin of Clostridium tetani. Therapy involves administration of antitoxin and supportive management of the patient. Prevention through immunization is effective and inexpensive, requiring only primary immunization and then boosters every ten years. Proper immunization and wound management combine to make tetanus an easily preventable disease. While specific therapy for both botulism and tetanus has been developed, the decrease in mortality and morbidity seen in both syndromes over the past 15 years is primarily due to pronounced improvement in nonspecific supportive care of patients with severe neuromuscular diseases. The cornerstone of this supportive care is careful respiratory management of these patients. Because the pulmonary care is so important we have asked Dr. Herbert Webb to discuss this subject in depth for us.
Respiratory Care of Tetanus and Botulism HERBERT H. WEBB, MD*
IT IS APPROPRIATE to discuss respiratory care of patients with these diseases in some detail since the majority of fatalities in clinical tetanus and botulism, as in many neuromuscular diseases, results from pulmonary complications. Moreover, these problems can be anticipated, prevented, and treated in the modern intensive care unit with adequate equipment and, most important, a competent respiratory care team.50-53 The team must consist of an experienced, knowledgeable and readily available physician who guides the team of nurses and respiratory therapists with fore*Director of Pulmonary Medicine, San Pedro and Peninsula Hospital, San Pedro, California, and Associate Clinical Professor of Medicine UCLA.
THE WESTERN JOURNAL OF MEDICINE
109
